WO2014022752A1 - Macrocycles as pim inhibitors - Google Patents

Macrocycles as pim inhibitors Download PDF

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Publication number
WO2014022752A1
WO2014022752A1 PCT/US2013/053380 US2013053380W WO2014022752A1 WO 2014022752 A1 WO2014022752 A1 WO 2014022752A1 US 2013053380 W US2013053380 W US 2013053380W WO 2014022752 A1 WO2014022752 A1 WO 2014022752A1
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alkyl
compound
pharmaceutically acceptable
acceptable salt
mmol
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PCT/US2013/053380
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French (fr)
Inventor
Victor J. Cee
James Brown
Frank Chavez Jr.
Jian J. Chen
Bradley J. Herberich
Essa Hu Harrington
Brian Alan Lanman
Matthew Lee
Liping H. Pettus
Anthony B. Reed
Andrew Tasker
Hui-Ling Wang
Bin Wu
Ryan Wurz
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Amgen Inc.
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Publication of WO2014022752A1 publication Critical patent/WO2014022752A1/en

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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D471/00Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/22Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed systems contains four or more hetero rings
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00Antineoplastic agents
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D498/00Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/22Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains four or more hetero rings

Definitions

  • the present invention relates to certain macrocycles that are Pirn inhibitors, pharmaceutical compositions containing such compounds, and processes for preparing such compounds.
  • Provided herein also are methods of treating disorders or diseases treatable by inhibition of Pims, such as cancer, and the like.
  • Pirn serine/threonine kinases The role of Pirn serine/threonine kinases in the pathogenesis and therapy of hematological malignancies and solid cancers is of interest to the medical community. Pirn proteins are constitutively active and are over-expressed in a subset of human cancers, many of hematological origin. Pirn kinases also regulate aspects of transformation and drug resistance in hematological malignancies such as DLBCL, MM, and AML where they are overexpressed or mutated. Aberrant expression of Pim-1 or Pim-2 promotes tumor development in mouse models of lymphoma and prostate cancer. Elevated Pim-1 levels correlate with poor prognosis in DLBCL and mantle cell lymphoma. Pims play a role in some solid tumors (e.g.
  • Pirn kinases are constitutively active and their activity supports in vitro and in vivo tumour cell growth and survival through modification of an increasing number of common as well as isoform-specific substrates including several cell cycle regulators and apoptosis mediators.
  • Pim-1 mediates homing and migration of normal and malignant hematopoietic cells by regulating chemokine receptor surface expression.
  • Knockdown experiments by RNA interference or dominant-negative acting mutants suggested that Pirn kinases are important for maintenance of a transformed phenotype and therefore potential therapeutic targets.
  • the present invention comprises a new class of macrocyclic compounds useful in the treatment of diseases, such as Pim-mediated diseases, for example cancer.
  • the invention also comprises pharmaceutical compositions comprising the compounds, methods for the treatment of Pim-mediated diseases and other maladies, such as treatment of hematological malignancies and of solid tumors, for example prostate cancer, and head and neck cancer, using the compounds and compositions of the invention, and intermediates and processes useful for the preparation of the compounds of the invention.
  • One aspect of the current invention relates to compounds having the general structure of formula 1 :
  • ring a is a ring that together with the 2 carbon atoms to which it attaches, forms a phenyl ring or a 5-6 membered heterocyclic ring;
  • X is N or CH
  • Z is O, S, NR b , CO, CHR b or C(R b ) 2 ;
  • Q is a linker saturated or unsaturated chain
  • q is NH or CH
  • r is CH 2 or N
  • s is N or C
  • w is CH or N
  • ring b is unsaturated, or partially saturated
  • ring c is saturated, or partially saturated
  • R 1 is H, or halo
  • R b is H, alkyl, haloalkyl, hydroxyalkyl, alkylsulfonylalkyl, BOC-aminoalkyl, aminoalkyl, cyanoalkyl, alkoxyalkyl, alkylsulfonylalkylaminoalkyl, alkylsulfonylaminoalkyl, alkylcarbonylaminoalkyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted aryl, unsubstituted or substituted arylalkyl or unsubstituted or substituted heterocyclyl; and
  • R e is H, -PO(OCH 3 ) 2 , alkylcarbonyl or hydroxyalkyl;
  • ring a is
  • R 1 is H, or halo; and a pharmaceutically acceptable salt thereof.
  • the compounds of Formula I comprise
  • X is N or CH
  • Z is O, S, NR b , CO, CHR b or C(R b ) 2 ;
  • R 1 is H, or halo
  • R b is H, alkyl, haloalkyl, hydroxyalkyl, alkylsulfonylalkyl, BOC-aminoalkyl, aminoalkyl, cyanoalkyl, alkoxyalkyl, alkylsulfonylalkylaminoalkyl, alkylsulfonylaminoalkyl, alkylcarbonylaminoalkyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted aryl, unsubstituted or substituted arylalkyl or unsubstituted or substituted heterocyclyl;
  • R 6 is H
  • R 7 is H or C1-3 alkyl; and a pharmaceutically acceptable salt thereof.
  • the compounds of Formula I comprise
  • X is N or CH
  • Q is optionally substituted C 4 -C 5 alkenylenyl, or optionally substituted phenyl-Ci_ 2 alkylenyl, optionally substituted C 4 -C 5 alkylenyl, optionally substituted C 4 -C 5 alkenylenyl, optionally substituted C4-C5 alkynylenyl, optionally substituted phenyl- Ci_2 alkylenyl or -(CH2) n -0-(CH 2 ) m -, optionally substituted C 4 -C 5 alkenylenyl, or optionally substituted Q_2 alkylenyl-aminocarbonyl- C1.2 alkylenyl, or optionally substituted C3-C4 alkenylenyl; when Q attaches to Z; or wherein Q is optionally substituted 5-7 membered heterocyclyl-alkyl, or optionally substituted 5-7 membered heterocyclyl-alkenyl; when Q incorporate
  • R 1 is H, or halo
  • R b is H, alkyl, haloalkyl, hydroxyalkyl, alkylsulfonylalkyl, BOC-aminoalkyl, aminoalkyl, cyanoalkyl, alkoxyalkyl, alkylsulfonylalkylaminoalkyl, alkylsulfonylaminoalkyl, alkylcarbonylaminoalkyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted aryl, unsubstituted or substituted arylalkyl or unsubstituted or substituted heterocyclyl;
  • R 6 is H
  • R 7 is H
  • Z is O, S, NR b , or CHR b ; and R b is H, Ci_ 2 alkyl, Ci_ 2 hydroxyalkyl, C 1 . 2 alkylsulfonyl-Cu alkyl, BOC -amino- C 1 . 2 alkyl, amino-Ci. 2 alkyl, C 1 . 2 alkylsulfonyl-Cij alky lamino-C 1 . 2 alkyl, C 1 . 2 alkylsulfonylamino-Ci. 2 alkyl or d_ 2 alkylcarbonylamino-Ci_ 2 alkyl; and a pharmaceutically acceptable salt thereof.
  • R 1 is H or fluoro; and a pharmaceutically acceptable salt thereof.
  • ring a is ; and R 2 is H or fluoro; and a pharmaceutically acceptable salt thereof.
  • R e is H, methylcarbonyl or hydroxymethyl; and a pharmaceutically acceptable salt thereof.
  • R 2 is H; and a pharmaceutically acceptable salt thereof.
  • Another aspect of the current invention relates to compounds having the general structure of Formula 2
  • Z is O or NH
  • Q is optionally substituted C 4 -C 5 alkenylenyl, or optionally substituted phenyl-
  • Z is O; and a pharmaceutically acceptable salt thereof.
  • Z is NH; and a pharmaceutically acceptable salt thereof.
  • Q is but-2-enylenyl, 4-methylbut-2-enylenyl, 3- methylbut-2-enylenyl, 2-methylbut-2-enylenyl or phenylmethylenyl; and a
  • a family of specific compounds of particular interest within Formula 1 consists of compounds and a pharmaceutically-acceptable salt thereof as follows:
  • Another aspect of the current invention relates to compounds having the general structure of Formula 3
  • R 1 is H or fluoro
  • Z is O, S or NR b ;
  • R b is H, Ci_ 2 alkyl, Ci_ 2 hydroxyalkyl, Ci_ 2 alkylsulfonyl-Cu alkyl, BOC-amino- Ci-2 alkyl, amino-Ci_ 2 alkyl, Ci_ 2 alkylsulfonyl-Cu alkylamino-Ci_ 2 alkyl, Ci_ 2 alkylsulfonylamino-Ci- 2 alkyl or Ci_ 2 alkylcarbonylamino-Ci. 2 alkyl;
  • Q is optionally substituted C 4 -C 5 alkylenyl, optionally substituted C 4 -C 5
  • alkenylenyl optionally substituted C 4 -C 5 alkynylenyl, optionally substituted phenyl- Ci_ 2 alkylenyl or -(CH 2 ) n -0-(CH 2 ) m - ;
  • R 1 is H; and a pharmaceutically acceptable salt thereof.
  • R 2 is H or methyl; and a pharmaceutically acceptable salt thereof.
  • Z is O or S; and a pharmaceutically acceptable salt thereof.
  • Z is HN, methylamino, hydroxyethylamino, BOC- aminoethylamino, aminoethylamino, methylsulfonylethylaminoethylamino,
  • Q is butylenyl, 4-methylbutylenyl, 4- hydroxymethylbutylenyl, 2,3-dihydroxy-4-methylbutylenyl, but-2-enylenyl, 4- hydroxymethylbut-2-enylenyl, 4-hydroxyethylbut-2-enylenyl, 4-methylbut-2-enylenyl, 4,4-dimethylbut-2-enylenyl, 4-trifluoromethylbut-2-enylenyl, 4-(methylsulfonylethyl)but- 2-enylenyl, 3-methylbut-2-enylenyl, 2-methylbut-2-enylenyl, but-2-ynylenyl, 4- methylbut-2-ynylenyl, pentylenyl, pent-2-enylenyl, -(CH 2 )2-0-(CH 2 )2- or
  • a family of specific compounds of particular interest within Formula 1 consists of compounds and a pharmaceutically-acceptable salt thereof as follows:
  • Another aspect of the current invention relates to compounds having the general structure of Formula 4
  • R 1 is H
  • R 2 is Ci_ 2 alkyl
  • Z is CH 2 or NH
  • Q is optionally substituted C 4 -C 5 alkenylenyl, or optionally substituted Ci_ 2 alkylenyl-aminocarbonyl- Ci_2 alkylenyl,
  • R 2 is methyl; and a pharmaceutically acceptable salt thereof.
  • Z is NH; and a pharmaceutically acceptable salt thereof.
  • Q is 3-methylbut-2-enylenyl
  • ethylenylaminocarbonylmethylenyl (2-methylethylenyl)aminocarbonylmethylenyl, or methylenylaminocarbonylmethylenyl; and a pharmaceutically acceptable salt thereof.
  • a family of specific compounds of particular interest within Formula 1 consists of compounds and a pharmaceutically-acceptable salt thereof as follows:
  • Another aspect of the current invention relates to compounds having the general structure of Formula 5
  • ring d forms a 4-7 membered nitrogen containing heterocyclyl
  • R 1 is H
  • R 2 is H or Ci_2 alkyl
  • R 2 is methyl; and a pharmaceutically acceptable salt thereof.
  • ring d is morpholinyl or 2-oxo-oxazolidinyl; and a pharmaceutically acceptable salt thereof.
  • ring d is and a
  • Q is 2-propenylenyl, or 3-propenylenyl; and a pharmaceutically acceptable salt thereof.
  • a family of specific compounds of particular interest within Formula 1 consists of compounds and a pharmaceutically-acceptable salt thereof as follows: (9S, 1 1 Z, 13 S)-20-methyl- 15-oxa-3 ,7, 18,21 ,27- pentaazahexacyclo[l 7.6.2.1-2, 5 ⁇ .0 ⁇ 4,9 ⁇ .0-13,18 ⁇ .0-22,26 ⁇ ]octacosa-
  • Another aspect of the current invention relates to compounds having the general structure of Formula 1 '
  • ring a is a ring that together with the 2 carbon atoms to which it attaches, forms a phenyl ring or a 5-6 membered heterocyclic ring;
  • X is N or CH
  • Q is a linker saturated or unsaturated chain
  • q is N, NH, CH or CH 2 ;
  • r is CH, NH, CH 2 or N;
  • s is N or CH
  • w is CH, CH 2 , N or NH
  • ring b is unsaturated, or partially saturated
  • ring c is saturated, or partially saturated
  • R 1 is H, or halo;
  • R b is H, alkyl, haloalkyl, hydroxyalkyl, alkylsulfonylalkyl, BOC-aminoalkyl, aminoalkyl, cyanoalkyl, alkoxyalkyl, alkylsulfonylalkylaminoalkyl, alkylsulfonylaminoalkyl, alkylcarbonylaminoalkyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted aryl, unsubstituted or substituted arylalkyl or unsubstituted or substituted heterocyclyl; and
  • R e is H, -PO(Oalkyl) 2 , alkylcarbonyl, alkylcarbonyloxyalkoxycarbonyl, alkoxycarbonyl, aminoalkylcarbonyloxyalkoxycarbonyl or hydroxyalkyl;
  • ring a is
  • R 1 is H, or halo; and a pharmaceutically acceptable salt thereof.
  • Another aspect of the current invention relates to compounds having the general structure of Formulas l 'a-l 'f
  • R b is H, Ci_ 6 alkyl, Ci_ 6 haloalkyl, Ci_ 6 hydroxyalkyl, Ci_6 alkylsulfonyl-Ci.6 alkyl, BOC-amino-Ci_6 alkyl, amino-Ci_6 alkyl, cyano-Ci_6-alkyl, Ci.
  • Another aspect of the current invention relates to compounds having the general structure of Formulas l 'b and l 'e
  • Q is optionally substituted C 4 -C 6 alkenylenyl, optionally substituted C 4 -C 5 alkylenyl, optionally substituted C 4 -C 5 alkynylenyl, optionally substituted cycloalkyl-C2-C4 alkenylenyl, optionally substituted phenyl-Ci_ 2 alkylenyl, -(CH 2 ) n -0-(CH 2 ) m -, or optionally substituted Ci_ 2 alkylenyl-aminocarbonyl-Ci_ 2 alkylenyl, when Q attaches to Z; or wherein Q is optionally substituted 5-7 membered heterocyclyl-alkyl, or optionally substituted 5-7 membered heterocyclyl-alkenyl, when Q incorporates Z into the heterocyclic ring;
  • R b is H, Ci_ 4 alkyl, Ci_ 6 -haloalkyl, Ci.4-hydroxyalkyl, Ci. 4 -alkylsulfonyl-Ci.
  • Z is O, S, NR b , or CHR b ;
  • R b is H, Ci_ 2 alkyl, Q_ 2 hydroxyalkyl, Ci_ 2 alkylsulfonyl-Cu-alkyl, BOC-amino-Ci_ 2 alkyl, amino-Ci_ 2 alkyl, Ci_ 2 alkylsulfonyl-Cij alkylamino-Ci_ 2 alkyl, cyano-Cu alkyl, Ci_ 2 alkylsulfonylamino-Ci_ 2 alkyl or Ci_ 2 alkylcarbonylamino-Ci_ 2 alkyl; and a pharmaceutically acceptable salt thereof.
  • R 1 is H or fluoro; and a pharmaceutically acceptable salt thereof.
  • ring a is ; and R is H or fluoro; and a pharmaceutically acceptable salt thereof.
  • R e is H, methylcarbonyl, -PO(0-methyl) 2 , -PO(0-tert- butyl) 2 , methylcarbonyloxy -methoxycarbonyl, tert-butylcarbonyloxy-methoxycarbonyl, isopropylcarbonyloxy-methoxycarbonyl, 1 ,5 -diaminopentyl-carbonyloxy- methoxycarbonyl, butoxycarbonyl or hydroxymethyl; and a pharmaceutically acceptable salt thereof.
  • R 2 is H; and a pharmaceutically acceptable salt thereof.
  • Z is O; and a pharmaceutically acceptable salt thereof.
  • Z is NH; and a pharmaceutically acceptable salt thereof.
  • the current invention relates to compounds of Formula 3'
  • R 1 is H or fluoro
  • Z is O, S or
  • R b is H, Ci -2 alkyl, Ci -2 hydroxyalkyl, Ci -2 alkylsulfonyl-Cu-alkyl, BOC- amino- Ci_2-alkyl, amino-Ci_2-alkyl, Ci.2-alkylsulfonyl-Ci.3-alkylamino-Ci.2-alkyl, Q.
  • R e is H, -PO(0-Ci_2-alkyl) 2 , Ci_ alkylcarbonyl, Ci_ -alkylcarbonyloxy-Ci_ 2 - alkoxycarbonyl, Ci.4-alkoxycarbonyl, amino-Ci_6-alkylcarbonyloxy- C1.2- alkoxycarbonyl or Ci_ hydroxyalkyl;
  • Q is optionally substituted C 4 -C 5 alkylenyl, optionally substituted C -C 6 alkenylenyl, optionally substituted C -C 5 alkynylenyl, optionally substituted phenyl-Ci_ 2 alkylenyl, optionally substituted cycloalkyl-C 2 -C alkenylenyl, or -(
  • R 1 is H; and a pharmaceutically acceptable salt thereof.
  • R 2 is H or methyl; and a pharmaceutically acceptable salt thereof.
  • Z is O or S; and a pharmaceutically acceptable salt thereof.
  • Z is HN, methylamino, hydroxyethylamino, BOC- aminoethylamino, aminoethylamino, cyanopropylamino,
  • Q is butylenyl, 2-methylbutylenyl, 3-methylbutylenyl, 4- methylbutylenyl, 4-hydroxymethylbutylenyl, 2,3-dihydroxy-4-methylbutylenyl, but-2- enylenyl, 4-hydroxymethylbut-2-enylenyl, 4-hydroxyethylbut-2-enylenyl, 4-methoxybut- 2-enylenyl, 2-methylbut-2-enylenyl, 3-methylbut-2-enylenyl, 4-methylbut-2-enylenyl, 4,4-dimethylbut-2-enylenyl, 4-trifluoromethylbut-2-enylenyl, 4-(methylsulfonylethyl)but- 2-enylenyl, 3-methylbut-2-enylenyl, 2-methylbut-2-enylenyl, but-2-ynylenyl, 4- methylbut-2-yn
  • R e is H; and a pharmaceutically acceptable salt thereof.
  • Another family of specific compounds of particular interest within Formula 1 and 1 ' consists of compounds and a pharmaceutically-acceptable salt thereof as follows: (9S, 11Z, 13R)-13,16-dimethyl-3,7,14,17,23-pentaazapentacyclo[13.6.2.1-2,5 ⁇ .0-
  • Another aspect of the invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formulas (1 and 1 ') and a pharmaceutically-acceptable diluent or carrier.
  • Another aspect of the invention relates to the use of a compound according to any of the above embodiments as a medicament.
  • Another aspect of the invention relates to the use of a compound according to any of the above embodiments in the manufacture of a medicament for the treatment of cancer.
  • the compounds of this invention may have in general several asymmetric centers and are typically depicted in the form of racemic mixtures. This invention is intended to encompass racemic mixtures, partially racemic mixtures and separate enantiomers and diasteromers.
  • the present invention includes all pharmaceutically acceptable isotopically- labelled compounds of the present invention wherein one or more atoms are replaced by atoms having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number which predominates in nature.
  • isotopes suitable for inclusion in the compounds of the invention include, but are not limited to, isotopes of hydrogen, such as 2 H and 3 H, carbon, such as
  • chlorine such as 38 CI
  • fluorine such as 18 F
  • iodine such as 123 I and 125 I
  • nitrogen such as 13 N and 15 N
  • oxygen such as 15 O, 17 O and 18 O
  • phosphorus such as 32 P
  • sulphur such as 35 S.
  • isotopically-labelled compounds of the present invention for example, those incorporating a radioactive isotope, are useful in drug and/or substrate tissue distribution studies.
  • the radioactive isotopes tritium, i.e. 3 H, and carbon-14, i.e. 14 C, are particularly useful for this purpose in view of their ease of incorporation and ready means of detection.
  • substitution with heavier isotopes such as deuterium, i.e. 2 H, may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements, and hence may be preferred in some circumstances.
  • Isotopically-labeled compounds of the present invention can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the accompanying Examples and Preparations using an appropriate isotopically-labeled reagent in place of the non-labeled reagent previously employed.
  • solvates in accordance with the invention include those wherein the solvent of crystallization may be isotopically substituted, e.g. D 2 0, de- acetone, de-DMSO.
  • H denotes a single hydrogen atom. This radical may be attached, for example, to an oxygen atom to form a hydroxyl radical.
  • haloalkyl and “alkylamino” it embraces linear or branched radicals having one to about twelve carbon atoms. More preferred alkyl radicals are “lower alkyl” radicals having one to about six carbon atoms. Examples of such radicals include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, teri-butyl, pentyl, isoamyl, hexyl and the like. Even more preferred are lower alkyl radicals having one or two carbon atoms.
  • alkylenyl embraces bridging divalent alkyl radicals such as methylenyl and ethylenyl.
  • alkenyl embraces linear or branched radicals having at least one carbon-carbon double bond of two to about twelve carbon atoms. More preferred alkenyl radicals are “lower alkenyl” radicals having two to about six carbon atoms. Most preferred lower alkenyl radicals are radicals having two to about four carbon atoms. Examples of alkenyl radicals include ethenyl, propenyl, allyl, propenyl, butenyl and 4- methylbutenyl.
  • alkenyl and “lower alkenyl” embrace radicals having "cis” and “trans” orientations, or alternatively, "E” and "Z” orientations.
  • alkenylenyl embraces bridging divalent alkenyl radicals.
  • alkynyl embraces linear or branched radicals having two to about twelve carbon atoms. More preferred alkynyl radicals are "lower alkynyl” radicals having two to about six carbon atoms. Examples of such radicals include ethynyl and the like. Even more preferred are lower alkynyl radicals having two to three carbon atoms.
  • alkynylenyl embraces bridging divalent alkynyl radicals.
  • halo means halogens such as fluorine, chlorine, bromine or iodine atoms.
  • haloalkyl embraces radicals wherein any one or more of the alkyl carbon atoms is substituted with halo as defined above. Specifically embraced are monohaloalkyl, dihaloalkyl and poly haloalkyl radicals including perhaloalkyl.
  • a monohaloalkyl radical for one example, may have either an iodo, bromo, chloro or fluoro atom within the radical.
  • Dihalo and polyhaloalkyl radicals may have two or more of the same halo atoms or a combination of different halo radicals.
  • “Lower haloalkyl” embraces radicals having 1-6 carbon atoms.
  • haloalkyl radicals having one to three carbon atoms.
  • haloalkyl radicals include fluorom ethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl and dichloropropyl.
  • Perfluoroalkyl means alkyl radicals having all hydrogen atoms replaced with fluoro atoms. Examples include trifluoromethyl and pentafluoroethyl.
  • hydroxyalkyl embraces linear or branched alkyl radicals having one to about ten carbon atoms any one of which may be substituted with one or more hydroxyl radicals. More preferred hydroxyalkyl radicals are "lower hydroxyalkyl” radicals having one to six carbon atoms and one or more hydroxyl radicals. Examples of such radicals include hydroxymethyl, hydroxy ethyl, hydroxypropyl, hydroxybutyl and hydroxyhexyl. Even more preferred are lower hydroxyalkyl radicals having one to three carbon atoms.
  • cyanoalkyl embraces linear or branched alkyl radicals having one to about ten carbon atoms any one of which may be substituted with one or more cyano radicals. More preferred cyanoalkyl radicals are "lower cyanoalkyl” radicals having one to six carbon atoms and one or more cyano radicals. Examples of such radicals include cyanomethyl, cyanopropyl, and cyanohexyl.
  • alkoxy embrace linear or branched oxy-containing radicals each having alkyl portions of one to about ten carbon atoms. More preferred alkoxy radicals are "lower alkoxy" radicals having one to six carbon atoms. Examples of such radicals include methoxy, ethoxy, propoxy, butoxy and teri-butoxy. Even more preferred are lower alkoxy radicals having one to three carbon atoms. Alkoxy radicals may be further substituted with one or more halo atoms, such as fluoro, chloro or bromo, to provide "haloalkoxy" radicals. Even more preferred are lower haloalkoxy radicals having one to three carbon atoms. Examples of such radicals include fluoromethoxy, chloromethoxy, trifluoromethoxy, trifluoroethoxy, fluoroethoxy and fluoropropoxy.
  • alkoxyalkyl embraces linear or branched alkyl radicals having one to about ten carbon atoms any one of which may be substituted with one or more alkoxyl radicals. More preferred alkoxyalkyl radicals are "lower alkoxyalkyl” radicals having one to six carbon atoms and one or more alkoxyl radicals. Examples of such radicals include methoxymethyl, ethoxyethyl, propoxypropyl and methoxyethyl. Even more preferred are lower alkoxyalkyl radicals having one to three carbon atoms.
  • aryl alone or in combination, means a carbocyclic aromatic system containing one or two rings wherein such rings may be attached together in a fused manner.
  • aryl embraces aromatic radicals such as phenyl, naphthyl, indenyl, tetrahydronaphthyl, and indanyl. More preferred aryl is phenyl.
  • Said "aryl” group may have 1 to 3 substituents such as lower alkyl, hydroxyl, halo, haloalkyl, nitro, cyano, alkoxy and lower alkylamino. Phenyl substituted with -0-CH 2 -0- forms the aryl benzodioxolyl substituent.
  • heterocyclyl embraces saturated, partially saturated and unsaturated heteroatom-containing ring radicals, where the heteroatoms may be selected from nitrogen, sulfur and oxygen. It does not include rings containing - ⁇ - ⁇ -,- ⁇ -S- or -S-S- portions. Said "heterocyclyl” group may have 1 to 3 substituents such as hydroxyl, Boc, halo, haloalkyl, cyano, lower alkyl, lower aralkyl, oxo, lower alkoxy, amino and lower alkylamino.
  • saturated heterocyclic radicals include saturated 3 to 6-membered heteromonocyclic groups containing 1 to 4 nitrogen atoms [e.g. pyrrolidinyl, imidazolidinyl, piperidinyl, pyrrolinyl, piperazinyl]; saturated 3 to 6-membered heteromonocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms [e.g. morpholinyl]; saturated 3 to 6-membered heteromonocyclic group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms [e.g., thiazolidinyl].
  • partially saturated heterocyclyl radicals include dihydrothienyl, dihydropyranyl, dihydrofuryl and dihydrothiazolyl.
  • unsaturated heterocyclic radicals also termed "heteroaryl” radicals
  • unsaturated heterocyclic radicals include unsaturated 5 to 6 membered heteromonocyclyl group containing 1 to 4 nitrogen atoms, for example, pyrrolyl, imidazolyl, pyrazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, triazolyl [e.g., 4H-l,2,4-triazolyl, lH-l,2,3-triazolyl, 2H- 1,2, 3 -triazolyl]; unsaturated 5- to 6-membered heteromonocyclic group containing an oxygen atom, for example, pyranyl, 2-furyl, 3-furyl, etc.; unsaturated 5 to 6-membered heteromonocyclic group containing a sulfur atom, for example, 2-thienyl, 3-thienyl,
  • heterocyclic radicals are fused/condensed with aryl radicals: unsaturated condensed heterocyclic group containing 1 to 5 nitrogen atoms, for example, indolyl, isoindolyl, indolizinyl, benzimidazolyl, quinolyl, isoquinolyl, indazolyl, benzotriazolyl, tetrazolopyridazinyl [e.g., tetrazolo [l,5-b]pyridazinyl];
  • unsaturated condensed heterocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms e.g. benzoxazolyl, benzoxadiazolyl
  • unsaturated condensed heterocyclic group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms e.g., benzothiazolyl, benzothiadiazolyl
  • saturated, partially unsaturated and unsaturated condensed heterocyclic group containing 1 to 2 oxygen or sulfur atoms e.g. benzofuryl, benzothienyl, 2,3-dihydro-benzo[l,4]dioxinyl and dihydrobenzofuryl.
  • Preferred heterocyclic radicals include five to ten membered fused or unfused radicals. More preferred examples of heteroaryl radicals include quinolyl, isoquinolyl, imidazolyl, pyridyl, thienyl, thiazolyl, oxazolyl, furyl, and pyrazinyl.
  • heteroaryl radicals are 5- or 6-membered heteroaryl, containing one or two heteroatoms selected from sulfur, nitrogen and oxygen, selected from thienyl, furyl, pyrrolyl, indazolyl, pyrazolyl, oxazolyl, triazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, pyridyl, piperidinyl and pyrazinyl.
  • non-nitrogen containing heteroaryl include pyranyl, 2- furyl, 3-furyl, 2-thienyl, 3-thienyl, benzofuryl, benzothienyl, and the like.
  • Particular examples of partially saturated and saturated heterocyclyl include pyrrolidinyl, imidazolidinyl, piperidinyl, pyrrolinyl, pyrazolidinyl, piperazinyl, morpholinyl, tetrahydropyranyl, thiazolidinyl, dihydrothienyl, 2,3-dihydro- benzo[l,4]dioxanyl, indolinyl, isoindolinyl, dihydrobenzothienyl, dihydrobenzofuryl, isochromanyl, chromanyl, 1,2-dihydroquinolyl, 1,2,3,4-tetrahydro-isoquinolyl, 1,2,3,4- tetrahydro-quinolyl, 2,3,4,4a,9,9a-hexahydro-lH-3-aza-fluorenyl, 5,6,7-trihydro-l,2,4- triazolo[3,4-a]isoquinolyl
  • Heterocycle means a ring comprising at least one carbon atom and at least one other atom selected from N, O and S. Examples of heterocycles that may be found in the claims include, but are not limited to, the following:
  • carboxy or “carboxyl”, whether used alone or with other terms, such as “carboxyalkyl”, denotes -C0 2 H.
  • alkylcarbonyl denotes a carbonyl radical substituted with an alkyl group.
  • alkoxycarbonyl denotes an ester group, containing an alkoxy substituted carbonyl.
  • aralkyl or arylalkyl embraces aryl-substituted alkyl radicals.
  • Preferable aralkyl radicals are "lower aralkyl” radicals having aryl radicals attached to alkyl radicals having one to six carbon atoms.
  • Even more preferred are “phenylalkylenyl” attached to alkyl portions having one to three carbon atoms. Examples of such radicals include benzyl, diphenylmethyl and phenylethyl.
  • the aryl in said aralkyl may be additionally substituted with halo, alkyl, alkoxy, halkoalkyl and haloalkoxy.
  • the term "optionally substituted phenylalkylenyl" when used in a linker may be divalent on either the alkyl portion or the phenyl ring and the alkyl portion.
  • arylalkenyl embraces aryl-substituted alkenyl radicals.
  • Preferable aralkyl radicals are “lower arylalkenyl” radicals having aryl radicals attached to alkenyl radicals having two to six carbon atoms. Even more preferred are “phenylalkenyl” where a phenyl ring is attached to alkenyl portions having two to three carbon atoms.
  • the aryl in said arylalkenyl may be additionally substituted with halo, alkyl, alkoxy, halkoalkyl and haloalkoxy.
  • cycloalkylalkyl embraces cycloalkyl-substituted alkyl radicals.
  • Preferable cycloalkylalkyl radicals are "C3.6 cycloalkyl-Ci_6 alkyl” radicals having C3.6 cycloalkyl radicals attached to alkyl radicals having one to six carbon atoms.
  • the cycloalkyl in said cycloalkylalkyl may be additionally substituted with halo, alkyl, and the like.
  • cycloalkylalkenyl embraces cycloalkyl-substituted alkenyl radicals.
  • Preferable cycloalkylalkenyl radicals are "C3.6 cycloalkyl-C2-6 alkenyl” radicals having C3. 6 cycloalkyl radicals attached to alkenyl radicals having two to six carbon atoms.
  • the cycloalkyl in said cycloalkylalkenyl may be additionally substituted with halo, alkyl, and the like.
  • heterocyclylalkyl embraces heterocyclyl-substituted alkyl radicals.
  • Preferable heterocyclylalkyl radicals are "3-7 membered heterocyclyl-Ci.6 alkyl” radicals having 3-7 membered heterocyclyl radicals attached to alkyl radicals having one to six carbon atoms.
  • Other heterocyclylalkyl radicals are "5-7 membered heterocyclyl-Cu alkyl” radicals having 5-6 membered heterocyclyl radicals attached to alkyl radicals having one to six carbon atoms.
  • the heterocyclyl in said 3-7 membered heterocyclylalkyl may be additionally substituted with halo, alkyl, and the like.
  • aryloxy embraces optionally substituted aryl radicals, as defined above, attached to an oxygen atom. Suitable aryloxy radicals may be phenyloxy and the like.
  • alkylamino embraces “N-alkylamino” and " ⁇ , ⁇ -dialkylamino” where amino groups are substituted with one alkyl radical and with two independent alkyl radicals, respectively. More preferred alkylamino radicals are “lower alkylamino” radicals having one or two alkyl radicals of one to six carbon atoms, attached to a nitrogen atom. Even more preferred are lower alkylamino radicals having one to three carbon atoms. Suitable alkylamino radicals may be mono or dialkylamino such as N-methylamino, N- ethylamino, N,N-dimethylamino, ⁇ , ⁇ -diethylamino and the like.
  • alkenylamino embraces "N-alkenylamino" where amino groups are substituted with one alkenyl radical. More preferred alkenylamino radicals are “lower alkenylamino” radicals having an alkenyl radical of two to six carbon atoms, attached to a nitrogen atom. Even more preferred are lower alkenylamino radicals having two to three carbon atoms.
  • arylamino denotes amino groups which have been substituted with one or two aryl radicals, such as N-phenylamino.
  • the arylamino radicals may be further substituted on the aryl ring portion of the radical.
  • cycloalkylamino denotes amino groups which have been substituted with one or two cycloalkyl radicals, such as N-cyclohexylamino.
  • the cycloalkylamino radicals may be further substituted on the cycloalkyl ring portion of the radical.
  • heteroarylamino denotes amino groups which have been substituted with one or two heteroaryl radicals, such as N-thienylamino.
  • heteroarylamino radicals may be further substituted on the heteroaryl ring portion of the radical.
  • heterocyclylamino denotes amino groups which have been substituted with one or two heterocyclyl radicals, such as N-piperidinylamino.
  • heterocyclylamino radicals may be further substituted on the heterocyclyl ring portion of the radical.
  • aralkylamino denotes amino groups which have been substituted with one or two aralkyl radicals. More preferred are phenyl-Ci-C3-alkylamino radicals, such as N-benzylamino. The aralkylamino radicals may be further substituted on the aryl ring portion.
  • cycloalkylalkylamino denotes amino groups which have been substituted with one or two cycloalkylalkyl radicals. More preferred are C1-3 cycloalkyl- Ci-C3-alkylamino radicals. The cycloalkylalkylamino radicals may be further substituted on the cycloalkyl portion.
  • heterocyclylalkylamino denotes amino groups which have been substituted with one or two heterocyclylalkyl radicals. More preferred are 3-7 membered heterocyclyl-Ci-C6-alkylamino radicals. Other preferred are 5-6 membered heterocyclyl- Ci-C3-alkylamino radicals.
  • the heterocyclylalkylamino radicals may be further substituted on the cycloalkyl portion.
  • aminoalkyl embraces linear or branched alkyl radicals having one to about ten carbon atoms any one of which may be substituted with one or more amino radicals. More preferred aminoalkyl radicals are "lower aminoalkyl” radicals having one to six carbon atoms and one or more amino radicals. Examples of such radicals include aminomethyl, aminoethyl, aminopropyl, aminobutyl and aminohexyl. Even more preferred are lower aminoalkyl radicals having one to three carbon atoms.
  • alkylaminoalkyl embraces alkyl radicals substituted with alkylamino radicals. More preferred alkylaminoalkyl radicals are "lower alkylaminoalkyl” radicals having alkyl radicals of one to six carbon atoms. Even more preferred are lower alkylaminoalkyl radicals having alkyl radicals of one to three carbon atoms. Suitable alkylaminoalkyl radicals may be mono or dialkyl substituted, such as N- methylaminomethyl, N,N-dimethyl-aminoethyl, ⁇ , ⁇ -diethylaminomethyl and the like.
  • carboxyalkyl embraces linear or branched alkyl radicals having one to about ten carbon atoms any one of which may be substituted with one or more carboxy radicals. More preferred carboxyalkyl radicals are "lower carboxyalkyl” radicals having one to six carbon atoms and one carboxy radical. Examples of such radicals include carboxymethyl, carboxypropyl, and the like. Even more preferred are lower carboxyalkyl radicals having one to three CH 2 groups.
  • carboxyalkylamino embraces amino groups substituted with a carboxyalkyl radical. More preferred carboxyalkylamino radicals are "lower
  • carboxyalkylamino radicals having one to six carbon atoms.
  • Other preferred carboxyalkylamino groups have alkyl portions with one to three carbon atoms.
  • cycloalkyl includes saturated carbocyclic groups.
  • Preferred cycloalkyl groups include C 3 -C 6 rings. More preferred compounds include, cyclopentyl, cyclopropyl, and cyclohexyl.
  • sulfonyl whether used alone or linked to other terms such as alkylsulfonyl, denotes respectively divalent radicals -S0 2 -.
  • alkylsulfonyl includes sulfonyl radicals substituted with an alkyl radical. More preferred alkylsulfonyl radicals are "lower alkylsulfonyl” radicals having one to six carbon atoms. Even more preferred are lower alkylsulfonyl radicals having one to three carbon atoms. Examples of such lower alkylsulfonyl radicals include methylsulfonyl and ethylsulfonyl.
  • alkylsulfonylamino embraces amino groups substituted with an alkylsulfonyl radical. More preferred alkylsulfonylamino radicals are "lower
  • alkylsulfonylamino radicals having one to six carbon atoms.
  • Other preferred alkylsulfonylamino groups have alkyl portions of one to three carbon atoms.
  • alkylsulfonylalkylamino embraces alkylamino groups substituted with an alkylsulfonyl radical. More preferred alkylsulfonylalkylamino radicals are "lower alkylsulfonylalkylamino" radicals having alkyl groups of one to six carbon atoms. Other preferred alkylsulfonylalkylamino groups have alkyl portions of one to three carbon atoms.
  • alkoxyalkylamino embraces amino groups substituted with an alkoxyalkyl radical, as previously described. More preferred alkoxyalkylamino radicals are "lower alkoxyalkylamino" radicals having aklyl radicals of one to six carbon atoms. Other preferred alkoxyalkylamino groups have alkyl portions of one to three carbon atoms.
  • hydroxyalkylamino embraces amino groups substituted with an hydroxyalkyl radical, as previously described. More preferred hydroxyalkylamino radicals are "lower hydroxyalkylamino" radicals having aklyl radicals of one to six carbon atoms. Other preferred hydroxyalkylamino groups have alkyl portions of one to three carbon atoms.
  • haloalkylamino embraces amino groups substituted with a haloalkyl radical, as previously described. More preferred haloalkylamino radicals are "lower haloalkylamino" radicals having aklyl radicals of one to six carbon atoms. Other preferred haloalkylamino groups have alkyl portions of one to three carbon atoms.
  • aminoalkylamino embraces alkylamino groups substituted with an amino (-NH 2 ) group. More preferred aminoalkylamino radicals are "lower
  • aminoalkylamino radicals having alkyl groups of one to six carbon atoms.
  • Other preferred aminoalkylamino groups have alkyl portions of one to three carbon atoms.
  • aminocarbonylalkylammo embraces amino groups substituted with an aminocarbonyl radical, as previously described. More preferred
  • aminocarbonylalkylammo radicals are "lower aminocarbonylalkylammo" radicals having aklyl radicals of one to six carbon atoms.
  • Other preferred aminocarbonylalkylammo groups have alkyl portions of one to three carbon atoms.
  • alkoxycarbonylalkylamino embraces amino groups substituted with an alkoxycarbonyl radical, as previously described. More preferred
  • alkoxycarbonylalkylamino radicals are "lower alkoxycarbonylalkylamino" radicals having aklyl radicals of one to six carbon atoms. Other preferred
  • alkoxycarbonylalkylamino groups have alkyl portions of one to three carbon atoms.
  • “Pharmaceutically-acceptable salt” means a salt prepared by conventional means, and are well known by those skilled in the art.
  • the “pharmacologically acceptable salts” include basic salts of inorganic and organic acids, including but not limited to hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, malic acid, acetic acid, oxalic acid, tartaric acid, citric acid, lactic acid, fumaric acid, succinic acid, maleic acid, salicylic acid, benzoic acid, phenylacetic acid, mandelic acid and the like.
  • suitable pharmaceutically acceptable cation pairs for the carboxy group are well known to those skilled in the art and include alkaline, alkaline earth, ammonium, quaternary ammonium cations and the like.
  • pharmaceutically acceptable salts see infra and Berge et al., J. Pharm. Sci. 66:1 (1977).
  • “Saturated, partially-saturated or unsaturated” includes substituents saturated with hydrogens, substituents completely unsaturated with hydrogens and substituents partially saturated with hydrogens.
  • leaving group generally refers to groups readily displaceable by a nucleophile, such as an amine, a thiol or an alcohol nucleophile. Such leaving groups are well known in the art. Examples of such leaving groups include, but are not limited to,
  • N-hydroxysuccinimide N-hydroxybenzotriazole, halides, triflates, tosylates and the like. Preferred leaving groups are indicated herein where appropriate.
  • Protecting group generally refers to groups well known in the art which are used to prevent selected reactive groups, such as carboxy, amino, hydroxy, mercapto and the like, from undergoing undesired reactions, such as nucleophilic, electrophilic, oxidation, reduction and the like. Preferred protecting groups are indicated herein where appropriate. Examples of amino protecting groups include, but are not limited to, aralkyl, substituted aralkyl, cycloalkenylalkyl and substituted cycloalkenyl alkyl, allyl, substituted allyl, acyl, alkoxycarbonyl, aralkoxycarbonyl, silyl and the like.
  • aralkyl examples include, but are not limited to, benzyl, ortho-methylbenzyl, trityl and benzhydryl, which can be optionally substituted with halogen, alkyl, alkoxy, hydroxy, nitro, acylamino, acyl and the like, and salts, such as phosphonium and ammonium salts.
  • aryl groups include phenyl, naphthyl, indanyl, anthracenyl, 9-(9-phenylfluorenyl), phenanthrenyl, durenyl and the like.
  • Examples of cycloalkenylalkyl or substituted cycloalkylenylalkyl radicals preferably have 6-10 carbon atoms, include, but are not limited to, cyclohexenyl methyl and the like.
  • Suitable acyl, alkoxycarbonyl and aralkoxycarbonyl groups include benzyloxycarbonyl, t-butoxycarbonyl, iso- butoxycarbonyl, benzoyl, substituted benzoyl, butyryl, acetyl, trifluoroacetyl, trichloro acetyl, phthaloyl and the like.
  • a mixture of protecting groups can be used to protect the same amino group, such as a primary amino group can be protected by both an aralkyl group and an aralkoxycarbonyl group.
  • Amino protecting groups can also form a heterocyclic ring with the nitrogen to which they are attached, for example,
  • heterocyclic groups can further include adjoining aryl and cycloalkyl rings.
  • heterocyclic groups can be mono-, di- or tri-substituted, such as nitrophthalimidyl.
  • Amino groups may also be protected against undesired reactions, such as oxidation, through the formation of an addition salt, such as hydrochloride, toluenesulfonic acid, trifluoroacetic acid and the like.
  • an addition salt such as hydrochloride, toluenesulfonic acid, trifluoroacetic acid and the like.
  • Many of the amino protecting groups are also suitable for protecting carboxy, hydroxy and mercapto groups.
  • Alkyl groups are also suitable groups for protecting hydroxy and mercapto groups, such as tert-butyl.
  • Silyl protecting groups are silicon atoms optionally substituted by one or more alkyl, aryl and aralkyl groups. Suitable silyl protecting groups include, but are not limited to, trimethylsilyl, triethylsilyl, triisopropylsilyl, tert-butyldimethylsilyl,
  • Silylation of an amino groups provide mono- or di-silylamino groups. Silylation of aminoalcohol compounds can lead to a ⁇ , ⁇ , ⁇ -trisilyl derivative. Removal of the silyl function from a silyl ether function is readily accomplished by treatment with, for example, a metal hydroxide or ammonium fluoride reagent, either as a discrete reaction step or in situ during a reaction with the alcohol group.
  • Suitable silylating agents are, for example, trimethylsilyl chloride, tert-butyl-dimethylsilyl chloride, phenyldimethylsilyl chloride, diphenylmethyl silyl chloride or their combination products with imidazole or DMF.
  • Methods for silylation of amines and removal of silyl protecting groups are well known to those skilled in the art.
  • Methods of preparation of these amine derivatives from corresponding amino acids, amino acid amides or amino acid esters are also well known to those skilled in the art of organic chemistry including amino acid/amino acid ester or aminoalcohol chemistry.
  • Protecting groups are removed under conditions which will not affect the remaining portion of the molecule. These methods are well known in the art and include acid hydrolysis, hydrogenolysis and the like.
  • a preferred method involves removal of a protecting group, such as removal of a benzyloxycarbonyl group by hydrogenolysis utilizing palladium on carbon in a suitable solvent system such as an alcohol, acetic acid, and the like or mixtures thereof.
  • a t-butoxycarbonyl protecting group can be removed utilizing an inorganic or organic acid, such as HC1 or trifluoroacetic acid, in a suitable solvent system, such as dioxane or methylene chloride. The resulting amino salt can readily be neutralized to yield the free amine.
  • Carboxy protecting group such as methyl, ethyl, benzyl, tert-butyl, 4-methoxyphenylmethyl and the like, can be removed under hydrolysis and hydrogenolysis conditions well known to those skilled in the art.
  • compounds of the invention may contain groups that may exist in tautomeric forms, such as cyclic and acyclic amidine and guanidine groups, heteroatom substituted heteroaryl groups, and the like, for example as illustrated in the following examples:
  • Prodrugs of the compounds of this invention are also contemplated by this invention.
  • a prodrug is an active or inactive compound that is modified chemically through in vivo physiological action, such as hydrolysis, metabolism and the like, into a compound of this invention following administration of the prodrug to a patient.
  • the suitability and techniques involved in making and using prodrugs are well known by those skilled in the art.
  • For a general discussion of prodrugs involving esters see Svensson and Tunek Drug Metabolism Reviews 165 (1988) and Bundgaard Design of Prodrugs, Elsevier (1985).
  • Examples of a masked carboxylate anion include a variety of esters, such as alkyl (for example, methyl, ethyl), cycloalkyl (for example, cyclohexyl), aralkyl (for example, benzyl, p-methoxybenzyl), and alkylcarbonyloxyalkyl (for example, pivaloyloxymethyl).
  • esters such as alkyl (for example, methyl, ethyl), cycloalkyl (for example, cyclohexyl), aralkyl (for example, benzyl, p-methoxybenzyl), and alkylcarbonyloxyalkyl (for example, pivaloyloxymethyl).
  • Amines have been masked as arylcarbonyloxymethyl substituted derivatives which are cleaved by esterases in vivo releasing the free drug and formaldehyde (Bungaard J. Med. Chem. 2503 (1989
  • drugs containing an acidic NH group such as imidazole, imide, indole and the like, have been masked with N- acyloxymethyl groups (Bundgaard Design of Prodrugs, Elsevier (1985)). Hydroxy groups have been masked as esters and ethers.
  • EP 039,051 (Sloan and Little, 4/11/81) discloses Mannich-base hydroxamic acid prodrugs, their preparation and use.
  • An aspect of the present invention is a method for inhibiting Pim kinase activity in a cell, comprising contacting the cell with an effective amount of a compound of Formulas 1-5, and 3'.
  • Another aspect of the present invention provides a method for treating a condition by modulation of Pim kinase activity comprising administering to a patient in need of such treatment an effective amount of a compound of Formulas 1-5, 1 ' and 3'.
  • Another embodiment of the present invention provides a method for treating a cancer disorder in a patient, comprising administering to the patient a composition comprising an amount of a compound of Formulas 1-5, and 3' effective to inhibit Pim kinase activity in the patient.
  • Another embodiment of the present invention provides a method for treating a cancer disorder in a patient, wherein the cancer is protate, head and neck or lymphoma, comprising administering to the patient a composition comprising an amount of a compound of Formulas 1-5, and 3' effective to inhibit Pim kinase activity in the patient.
  • Another aspect of the present invention provides the use of any one of the compounds of Formulas 1-5, 1 ' and 3' in the manufacture of a medicament for the treatment of cancer.
  • the compounds of this invention can be administered in a therapeutically effective amount by any of the accepted modes of administration for agents that serve similar utilities.
  • the actual amount of a compound of this invention, i.e., the active ingredient depends upon numerous factors, such as the severity of the disease to be treated, the age and relative health of the subject, the potency of the compound used, the route and form of administration, and other factors.
  • Therapeutically effective amounts of compounds of formula (1) may range from approximately 0.1-1000 mg per day.
  • compounds of this invention can be administered as pharmaceutical compositions by any one of the following routes: oral, systemic (e.g., transdermal, intranasal or by suppository), or parenteral (e.g., intramuscular, intravenous or subcutaneous) administration.
  • routes e.g., oral, systemic (e.g., transdermal, intranasal or by suppository), or parenteral (e.g., intramuscular, intravenous or subcutaneous) administration.
  • the preferred manner of administration is oral using a convenient daily dosage regimen, which can be adjusted according to the degree of affliction.
  • Compositions can take the form of tablets, pills, capsules, semisolids, powders, sustained release formulations, solutions, suspensions, elixirs, aerosols, or any other appropriate compositions.
  • formulation depends on various factors, such as the mode of drug administration (e.g., for oral administration, formulations in the form of tablets, pills or capsules are preferred) and the bioavailability of the drug substance.
  • pharmaceutical formulations have been developed especially for drugs that show poor bioavailability based upon the principle that bioavailability can be increased by increasing the surface area, i.e., decreasing particle size.
  • U.S. Pat. No. 4,107,288 describes a pharmaceutical formulation having particles in the size range from 10 to 1 ,000 nm in which the active material is supported on a crosslinked matrix of macromolecules.
  • 5,145,684 describes the production of a pharmaceutical formulation in which the drug substance is pulverized to nanoparticles (average particle size of 400 nm) in the presence of a surface modifier and then dispersed in a liquid medium to give a pharmaceutical formulation that exhibits remarkably high bioavailability.
  • compositions are comprised of, in general, a compounds of the present invention in combination with at least one pharmaceutically acceptable excipient.
  • Acceptable excipients are non-toxic, aid administration, and do not adversely affect the therapeutic benefit of the compounds of the present invention.
  • excipient may be any solid, liquid, semi-solid or, in the case of an aerosol composition, gaseous excipient that is generally available to one of skill in the art.
  • Solid pharmaceutical excipients include starch, cellulose, talc, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, magnesium stearate, sodium stearate, glycerol monostearate, sodium chloride, dried skim milk and the like.
  • Liquid and semisolid excipients may be selected from glycerol, propylene glycol, water, ethanol and various oils, including those of petroleum, animal, vegetable or synthetic origin, e.g., peanut oil, soybean oil, mineral oil, sesame oil, etc.
  • Preferred liquid carriers, particularly for injectable solutions include water, saline, aqueous dextrose, and glycols.
  • Compressed gases may be used to disperse a compound of this invention in aerosol form.
  • Inert gases suitable for this purpose are nitrogen, carbon dioxide, etc.
  • Other suitable pharmaceutical excipients and their formulations are described in Remington's Pharmaceutical Sciences, Gennaro, A. R. (Mack Publishing Company, 18th ed., 1995).
  • the level of the compound in a formulation can vary within the full range employed by those skilled in the art.
  • the formulation contains, on a weight percent (wt %) basis, from about 0.01-99.99 wt % of a compounds of the present invention based on the total formulation, with the balance being one or more suitable pharmaceutical excipients.
  • the compound is present at a level of about 1-80 wt %.
  • the compounds of the invention can be administered as the sole active pharmaceutical agent, they can also be used in combination with one or more compounds of the invention or other agents.
  • the therapeutic agents can be formulated as separate compositions that are administered at the same time or sequentially at different times, or the therapeutic agents can be given as a single composition.
  • co-therapy in defining use of a compound of the present invention and another pharmaceutical agent, is intended to embrace administration of each agent in a sequential manner in a regimen that will provide beneficial effects of the drug combination, and is intended as well to embrace coadministration of these agents in a substantially simultaneous manner, such as in a single capsule having a fixed ratio of these active agents or in multiple, separate capsules for each agent.
  • the administration of compounds of the present invention may be in conjunction with additional therapies known to those skilled in the art in the prevention or treatment of neoplasia, such as with radiation therapy or with cytostatic or cytotoxic agents.
  • Compounds of Formula I may also be administered sequentially with known anticancer or cytotoxic agents when a combination formulation is inappropriate.
  • the invention is not limited in the sequence of administration; compounds of the invention may be administered either prior to, simultaneous with or after administration of the known anticancer or cytotoxic agent.
  • standard treatment of primary tumors consists of surgical excision followed by either radiation or IV administered chemotherapy.
  • the typical chemotherapy regime consists of either DNA alkylating agents, DNA intercalating agents or microtubule poisons.
  • the chemotherapy doses used are just below the maximal tolerated dose and therefore dose limiting toxicities typically include, nausea, vomiting, diarrhea, hair loss, neutropenia and the like.
  • antineoplastic agents available in commercial use, in clinical evaluation and in pre-clinical development, which would be selected for treatment of neoplasia by combination drug chemotherapy.
  • Such antineoplastic agents fall into several major categories, namely, antibiotic-type agents, alkylating agents, antimetabolite agents, hormonal agents, immunological agents, interferon-type agents and a category of miscellaneous agents.
  • a first family of antineoplastic agents which may be used in combination with compounds of the present invention consists of antimetabolite-type/thymidilate synthase inhibitor antineoplastic agents.
  • Suitable antimetabolite antineoplastic agents may be selected from but not limited to the group consisting of 5-FU-fibrinogen, acanthifolic acid, aminothiadiazole, brequinar sodium, carmofur, Ciba-Geigy CGP-30694, cyclopentyl cytosine, cytarabine phosphate stearate, cytarabine conjugates, Lilly DATHF, Merrel Dow DDFC, dezaguanine, dideoxycytidine, dideoxyguanosine, didox, Yoshitomi DMDC, doxifluridine, Wellcome EHNA, Merck & Co.
  • EX-015 benzrabine, floxuridine, fludarabine phosphate, 5-fluorouracil, N-(2'-furanidyl)-5-fluorouracil, Daiichi Seiyaku FO-152, isopropyl pyrrolizine, Lilly LY-188011, Lilly LY-264618, methobenzaprim, methotrexate, Wellcome MZPES, norspermidine, NCI NSC-127716, NCI NSC-264880, NCI NSC-39661, NCI NSC-612567, Warner-Lambert PALA, pentostatin, piritrexim, plicamycin, Asahi Chemical PL-AC, Takeda TAC-788, thioguanine, tiazofurin, Erbamont TIF, trimetrexate, tyrosine kinase inhibitors, Taiho UFT and uricytin.
  • a second family of antineoplastic agents which may be used in combination with compounds of the present invention consists of alkylating-type antineoplastic agents.
  • Suitable alkylating-type antineoplastic agents may be selected from but not limited to the group consisting of Shionogi 254-S, aldo-phosphamide analogues, altretamine, anaxirone, Boehringer Mannheim BBR-2207, bestrabucil, budotitane, Wakunaga CA-102, carboplatin, carmustine, Chinoin-139, Chinoin-153, chlorambucil, cisplatin,
  • prednimustine Proter PTT-119, ranimustine, semustine, SmithKline SK&F-101772, Yakult Honsha SN-22, spiromus-tine, Tanabe Seiyaku TA-077, tauromustine, temozolomide, teroxirone, tetraplatin and trimelamol.
  • a third family of antineoplastic agents which may be used in combination with compounds of the present invention consists of antibiotic-type antineoplastic agents.
  • Suitable antibiotic-type antineoplastic agents may be selected from but not limited to the group consisting of Taiho 4181 -A, aclarubicin, actinomycin D, actinoplanone, Erbamont ADR-456, aeroplysinin derivative, Ajinomoto AN-201-II, Ajinomoto AN-3, Nippon Soda anisomycins, anthracycline, azino-mycin-A, bisucaberin, Bristol-Myers BL-6859, Bristol- Myers BMY-25067, Bristol-Myers BMY-25551, Bristol-Myers BMY-26605, Bristol- Myers BMY-27557, Bristol-Myers BMY-28438, bleomycin sulfate, bryostatin-1, Taiho C-1027, calichemycin, chrom
  • a fourth family of antineoplastic agents which may be used in combination with compounds of the present invention consists of a miscellaneous family of antineoplastic agents, including tubulin interacting agents, topoisomerase II inhibitors, topoisomerase I inhibitors and hormonal agents, selected from but not limited to the group consisting of a-carotene, a-difluoromethyl-arginine, acitretin, Biotec AD-5, Kyorin AHC-52, alstonine, amonafide, amphethinile, amsacrine, Angiostat, ankinomycin, anti-neoplaston A10, antineoplaston A2, antineoplaston A3, antineoplaston A5, antineoplaston AS2-1, Henkel APD, aphidicolin glycinate, asparaginase, Avarol, baccharin, batracylin, benfluron, benzotript, Ipsen-Beaufour BIM-23015, bisant
  • the present compounds may also be used in co-therapies with other antineoplastic agents, such as acemannan, aclarubicin, aldesleukin, alemtuzumab, alitretinoin, altretamine, amifostine, aminolevulinic acid, amrubicin, amsacrine, anagrelide, anastrozole, ANCER, ancestim, ARGLABIN, arsenic trioxide, BAM 002 (Novelos), bexarotene, bicalutamide, broxuridine, capecitabine, celmoleukin, cetrorelix, cladribine, clotrimazole, cytarabine ocfosfate, DA 3030 (Dong- A), daclizumab, denileukin diftitox, deslorelin, dexrazoxane, dilazep, docetaxel, docosanol, dox
  • gimeracil/oteracil/tegafur combination glycopine, goserelin, heptaplatin, human chorionic gonadotropin, human fetal alpha fetoprotein, ibandronic acid, idarubicin, (imiquimod, interferon alfa, interferon alfa, natural, interferon alfa-2, interferon alfa-2a, interferon alfa-2b, interferon alfa-Nl, interferon alfa-n3, interferon alfacon-1, interferon alpha, natural, interferon beta, interferon beta- la, interferon beta- lb, interferon gamma, natural interferon gamma- la, interferon gamma- lb, interleukin-1 beta, iobenguane, irinotecan, irsogladine, lanreotide, LC 9018 (Yakult), leflunom
  • the present compounds may also be used in co-therapies with other agents, such as other kinase inhibitors including CDK inhibitors, mTor inhibitors, Pi3k inhibitors, and Aurora kinase inhibitors.
  • Substituted 6,7-dihydro-lH-pyrrolo[3,2-c]pyridin-4(5H)-ones 4 can be prepared according to the method set out in Scheme 1.
  • a strong alkyl metal such as an organolithium reagents (e.g. butyllithium) is added to a solution of a dihalo-bicyclic ring 1 at a temperature below 0 °C, preferably below -50 °C , even more preferably at about - 72 °C.
  • Treatment with an acetamide at a temperature below 0 °C , preferably below -50 °C , even more preferably at about -70 °C yields the acetyl derivative 2.
  • bromination of the acetyl derivative 2, such as with a base, e.g Et 3 N, teri-butyldimethylsilyl trifluoromethanesulfonate, and bromination such as with NBS provides the desired bromoacetyl compound 2a.
  • a base e.g Et 3 N
  • bromination such as with NBS
  • NBS bromination of the acetyl compound 2a
  • an ammonia salt such as NH 4 OAc
  • piperidine-2,4-dione at a temperature above RT, preferably at about 50 °C affords the 6,7-dihydro-lH-pyrrolo[3,2-c]pyridin-4(5H)-one 3.
  • Substitution of the remaining halo group provides further compounds 4.
  • treatment with arylamines such as aniline in the presence of a strong non-nucleophilic base, e.g. LHMDS, provides the desired amine derivatives.
  • a strong non-nucleophilic base e.g. LHMDS
  • treatment of compound 1 with a palladium catalyst, such as Pd(PPh 3 ) 4 and a tin reagent, such as tributyl(l-ethoxyvinyl)tin at a temperature higher than RT, preferably above about 50 °C, more preferably at about 100 °C provides the corresponding the acetyl derivative 2 [with the ester substitution].
  • Grubbs catalyst 2nd generation is added to 4 and heated such as to reflux to form the macrocycle 5.
  • ether substituted compounds 4 where Z is oxygen can be prepared according to the method set out in Scheme 2.
  • Alcohols [Z a OH] are treated with stong base, such as NaH, then added to the chloro substituted compounds 3 furnished substituted 6,7-dihydro-l//-pyrrolo[3,2-c]pyridin-4(5//)-ones 4.
  • Amino substituted compounds 4, where R 1 is alkylamino, arylamino and the like, are prepared by the method described in Scheme 3. Fluoro-substituted compounds 6 and an optionally substituted amine [Z a NH 2 ] are heated at a temperature higher than RT, preferably above about 50 °C, more preferably at about 80 °C to furnish the desired amines 4.
  • Halo-phenylalkyl substituted quinazolines 11 are prepared by methods described above. Halo-phenylalkyl substituted quinazolines 11 are cyclized using a catalyst such as Brettphos, preferably above about 50 °C, more preferably at about 1 10 °C, to furnish the desired macrocycles 12.
  • a catalyst such as Brettphos, preferably above about 50 °C, more preferably at about 1 10 °C, to furnish the desired macrocycles 12.
  • cyclic amides can be prepared such as the 3,4-dihydropyrrolo[l,2- a]pyrazin-l (2H)-ones 15 as described in Scheme 6.
  • Methyl 4-bromo-lH-pyrrole-2- carboxylate 13 is reacted with base, such as NaH, and 1 ,2 dibromoethane at a temperature higher than RT, preferably above about 50 °C, more preferably at about at 70 °C to afford the bromoethyl derivative 14.
  • Cyclization such as with treatment with (2,4- dimethoxyphenyl)methanamine, at a temperature higher than RT, preferably above about 100 °C, more preferably at about at 150 °C yields the protected bromo-3,4- dihydropyrrolo[l ,2-a]pyrazin-l (2H)-one 15.
  • cyclic amides of the present invention can be prepared such as the 3,4- dihydropyrrolo[l,2-a]pyrazin-l(2H)-ones 23 as described in Scheme 8.
  • Substituted amines are coupled to the 8-bromo-2-chloroquinoline through treatment with base, such as LiHMDS, at a temperature of about RT, to afford the desired 8-bromoquinolin-2 -amine 19.
  • the bromo compound 20 is converted to the boronic acid 21 via treatment with a palladium catalyst, such as Pd(dppf) 2 Cl2, bis(pinacolato)diboron, and a base such as KOAc, at a temperature higher than RT, preferably above about 75 °C, more preferably at about at 115 °C.
  • a palladium catalyst such as Pd(dppf) 2 Cl2, bis(pinacolato)diboron
  • a base such as KOAc
  • a palladium catalyst such as P
  • Macrocycles with amide containing linkers can be prepared as described in Scheme 9. Deprotection of protected amines and esters, such as with base or with acid, provides the desired amino acid. Amide formation such as with treatment with PyBop yields the desired amides 26.
  • Macrocycle prodrug intermediates 27 can be prepared according to the method set out in Scheme 10. Treatment of the 6,7-dihydro-lH-pyrrolo[3,2-c]pyridin-4(5H)-one 3 with a acyl halide, phosphate ester, and the like provides the substituted amides 27. Subsequent steps as described in Scheme 1 fprovides the complete macrocycle prodrug.
  • the starting compounds defined in Schemes 1-10 may also be present with functional groups in protected form if necessary and/or in the form of salts, provided a salt-forming group is present and the reaction in salt form is possible.
  • one compound of formulas 1-5, and 3' can be converted into another compound of formulas 1-5, and 3' or a N-oxide thereof; a compound of formulas 1-5, and 3' can be converted into a salt; a salt of a compound of formulas 1-5, 1 ' and 3' can be converted into the free compound or another salt; and/or a mixture of isomeric compounds of formulas 1-5, and 3' can be separated into the individual isomers.
  • N-Oxides can be obtained in a known manner by reacting a compound of formulas 1-5, 1 ' and 3' with H 2 0 2 or a peracid, e.g. 3-chloroperoxy-benzoic acid, in an inert solvent, e.g. dichloromethane, at a temperature between about -10-35°C, such as about 0°C - RT.
  • a peracid e.g. 3-chloroperoxy-benzoic acid
  • an inert solvent e.g. dichloromethane
  • one or more other functional groups for example carboxy, hydroxy, amino, or mercapto, are or need to be protected in a compound of formulas 1-5, and 3' or in the synthesis of a compound of formulas 1-5, 1 ' and 3', because they should not take part in the reaction, these are such groups as are usually used in the synthesis of peptide compounds, and also of cephalosporins and penicillins, as well as nucleic acid derivatives and sugars.
  • the protecting groups may already be present in precursors and should protect the functional groups concerned against unwanted secondary reactions, such as acylations, etherifications, esterifications, oxidations, solvolysis, and similar reactions. It is a characteristic of protecting groups that they lend themselves readily, i.e. without undesired secondary reactions, to removal, typically by solvolysis, reduction, photolysis or also by enzyme activity, for example under conditions analogous to physiological conditions, and that they are not present in the end-products.
  • the specialist knows, or can easily establish, which protecting groups are suitable with the reactions mentioned above and hereinafter.
  • functional groups of the starting compounds which should not take part in the reaction may be present in unprotected form or may be protected for example by one or more of the protecting groups mentioned above under "protecting groups".
  • the protecting groups are then wholly or partly removed according to one of the methods described there.
  • Salts of a compound of formulas 1-5, and 3' with a salt-forming group may be prepared in a manner known per se. Acid addition salts of compounds of formulas 1-5, 1 ' and 3' may thus be obtained by treatment with an acid or with a suitable anion exchange reagent.
  • a salt with two acid molecules may also be converted into a salt with one acid molecule per compound (for example a monohalogenide); this may be done by heating to a melt, or for example by heating as a solid under a high vacuum at elevated temperature, for example from about 130°C to about 170°C, one molecule of the acid being expelled per molecule of a compound of formulas 1-5, 1 ' and 3 ' .
  • Salts can usually be converted to free compounds, e.g. by treating with suitable basic agents, for example with alkali metal carbonates, alkali metal hydrogen carbonates, or alkali metal hydroxides, typically potassium carbonate or sodium hydroxide.
  • suitable basic agents for example with alkali metal carbonates, alkali metal hydrogen carbonates, or alkali metal hydroxides, typically potassium carbonate or sodium hydroxide.
  • All process steps described here can be carried out under known reaction conditions, preferably under those specifically mentioned, in the absence of or usually in the presence of solvents or diluents, preferably such as are inert to the reagents used and able to dissolve these, in the absence or presence of catalysts, condensing agents or neutralizing agents, for example ion exchangers, typically cation exchangers, for example in the H+ form, depending on the type of reaction and/or reactants at reduced, normal, or elevated temperature, for example in the range from about -100°C to about 190°C, preferably from about -80°C to about 150°C, for example at about -80 to about 60°C, at RT, at about -20 to about 40°C or at the boiling point of the solvent used, under atmospheric pressure or in a closed vessel, where appropriate under pressure, and/or in an inert atmosphere, for example under argon or nitrogen.
  • Salts may be present in all starting compounds and transients, if these contain salt-forming
  • the solvents from which those can be selected which are suitable for the reaction in question include for example water, esters, typically lower alkyl-lower alkanoates, e.g., ethyl acetate, ethers, typically aliphatic ethers, e.g., diethylether, or cyclic ethers, e.g., THF, liquid aromatic hydrocarbons, typically benzene or toluene, alcohols, typically MeOH, EtOH or 1 -propanol, 2-propanol, nitriles, typically ACN, halogenated hydrocarbons, typically DCM, acid amides, typically DMF, bases, typically heterocyclic nitrogen bases, e.g.
  • carboxylic acids typically lower alkanecarboxylic acids, e.g., AcOH
  • carboxylic acid anhydrides typically lower alkane acid anhydrides, e.g., acetic anhydride
  • cyclic linear, or branched hydrocarbons, typically cyclohexane, hexane, or isopentane, or mixtures of these solvents, e.g., aqueous solutions, unless otherwise stated in the description of the process.
  • solvent mixtures may also be used in processing, for example in chromatography.
  • the invention relates also to those forms of the process in which one starts from a compound obtainable at any stage as a transient and carries out the missing steps, or breaks off the process at any stage, or forms a starting material under the reaction conditions, or uses said starting material in the form of a reactive derivative or salt, or produces a compound obtainable by means of the process according to the invention and processes the said compound in situ.
  • the compounds of formulas 1-5, and 3', including their salts, are also obtainable in the form of hydrates, or their crystals can include for example the solvent used for crystallization (present as solvates).
  • New starting materials and/or intermediates, as well as processes for the preparation thereof, are likewise the subject of this invention.
  • such starting materials are used and reaction conditions so selected as to enable the preferred compounds to be obtained.
  • optical isomers can be obtained by resolution of the racemic mixtures according to conventional processes, e.g., by formation of diastereoisomeric salts, by treatment with an optically active acid or base.
  • appropriate acids are tartaric, diacetyltartaric, dibenzoyltartaric, ditoluoyltartaric, and camphorsulfonic acid and then separation of the mixture of diastereoisomers by crystallization followed by liberation of the optically active bases from these salts.
  • a different process for separation of optical isomers involves the use of a chiral chromatography column optimally chosen to maximize the separation of the enantiomers.
  • Still another available method involves synthesis of covalent diastereoisomeric molecules by reacting compounds of the invention with an optically pure acid in an activated form or an optically pure isocyanate.
  • the synthesized diastereoisomers can be separated by conventional means such as chromatography, distillation, crystallization or sublimation, and then hydrolyzed to deliver the enantiomerically pure compound.
  • the optically active compounds of the invention can likewise be obtained by using optically active starting materials. These isomers may be in the form of a free acid, a free base, an ester or a salt.
  • the compounds of this invention may contain one or more asymmetric centers and thus occur as racemates and racemic mixtures, scalemic mixtures, single enantiomers, individual diastereomers and diastereomeric mixtures. All such isomeric forms of these compounds are expressly included in the present invention.
  • the compounds may also occur in cis- or trans- or E- or Z- double bond isomeric forms. All such isomeric forms of such compounds are expressly included in the present invention. All crystal forms of the compounds described herein are expressly included in the present invention.
  • Substituents on ring moieties may be attached to specific atoms, whereby they are intended to be fixed to that atom, or they may be drawn unattached to a specific atom, whereby they are intended to be attached at any available atom that is not already substituted by an atom other than H (hydrogen).
  • the compounds of this invention may contain heterocyclic ring systems attached to another ring system.
  • Such heterocyclic ring systems may be attached through a carbon atom or a heteroatom in the ring system.
  • a compound of any of the formulas delineated herein may be synthesized according to any of the processes delineated herein.
  • the steps may be performed in an alternate order and may be preceded, or followed, by additional protection/deprotection steps as necesssary.
  • the processes may further comprise use of appropriate reaction conditions, including inert solvents, additional reagents, such as bases (e.g., LDA, DIPEA, pyridine, K 2 C0 3 , and the like), catalysts, and salt forms of the above.
  • bases e.g., LDA, DIPEA, pyridine, K 2 C0 3 , and the like
  • Purification methods include, for example, crystallization, chromatography (liquid and gas phase, simulated moving bed (“SMB”)), extraction, distillation, trituration, reverse phase HPLC and the like.
  • Reactions conditions such as temperature, duration, pressure, and atmosphere (inert gas, ambient) are known in the art and may be adjusted as appropriate for the reaction.
  • the compounds of this invention may be modified by appending appropriate functionalities to enhance selective biological properties. Such modifications are known in the art and include those which increase biological penetration into a given biological compartment (e.g., blood, lymphatic system, central nervous system), increase oral availability, increase solubility to allow administration by injection, alter metabolism and alter rate of excretion.
  • a biological compartment e.g., blood, lymphatic system, central nervous system
  • HPLC analyses were run on an Agilent Model 1100 system with an Agilent Technologies Zorbax SB-C 8 (5 ⁇ ) reverse phase column (4.6 x 150 mm) run at 30 °C with a flow rate of about 1.50 mL/min (Agilent Technologies, Santa Clara, CA).
  • the mobile phase used solvent A (H 2 O/0.1 % TFA) and solvent B (ACN/0.1% TFA) with a 11 min gradient from 5% to 100% ACN. The gradient was followed by a 2 min. return to 5% ACN and about a 2.5 min. re-equilibration (flush).
  • compounds of the present invention were purified via reverse phase HPLC using a Gilson (Gilson, Middleton, WI) or Shimadzu (Columbia, MD) workstation utilizing one of the following two protocols: (A) Using a 50 x 100 mm column (Waters, Exterra, Qs, 5 ⁇ ) (Waters, Milford, MA) at 50 mL/min. The mobile phase used was a mixture of solvent A (H 2 O/10 mM ammonium carbonate at pH about 10, adjusted with cone. NH 4 OH) and solvent B (85:15 ACN/water, 10 mM ammonium carbonate at pH of about 10 adjusted with cone. NH 4 OH).
  • Step 1 tert-butyl 5-allyl-2,4-dioxopiperidine-l-carboxylate
  • Step 1 (S)-7-allyl-6,7-dihydro-lH-pyrrolo[3,2-c]pyridin-4(5H)-one
  • Step 1 3-fluoro-2-methyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)quinoxaline
  • KOAc Sigma Aldrich, 29.3 g, 299 mmol
  • PdCl 2 (PPh 3 ) 2 DCM adduct Strem Chemicals, Newburyport, MA, 3.05 g, 3.73 mmol
  • bis(pinacolato)diboron Sigma Aldrich, 37.9 g, 149 mmol
  • 5-bromo-3-fluoro-2- methylquinoxaline (18.0 g, 74.7 mmol)
  • Step 2 (S)-7-allyl-2-(3-fluoro-2-methylquinoxalin-5-yl)-6,7-dihydro-lH-pyrrolo[3,2- c]pyridin-4(5H)-one
  • Argon was bubbled into a mixture of l,l-bis[(di-t-butyl-p- methylaminophenyl]palladium(ii) chloride (Sigma Aldrich, 1.227 g, 1.733 mmol), potassium phosphate, dibasic (EMD Chemicals, Gibbstown, NJ, 21.12 g, 121 mmol), (S)-7-allyl-2-bromo-6,7-dihydro-lH-pyrrolo[3,2-c]pyridin-4(5H)-one (Intermediate B, 8.84 g, 34.7 mmol), 3-fluoro-2-methyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)quinoxaline (19.97 g, 69.3 mmol) (impure, from previous step) in 200 mL DMF and 100 mL water for 2 min.
  • the orange slurry was placed in a 70 °C oil bath under argon. After 2 h the reaction was checked by LCMS and judged complete. The reaction was poured onto ice, and the resulting solid was collected by filtration (glass frit), rinsing 3 x 100 mL water. The slightly wet filter cake was transferred to a 500 mL rbf with
  • Step 1 2-(but-3-en-2-yl)isoindoline-l,3-dione
  • Step 2 (R)-2-(but-3-en-2-yl)isoindoline-l,3-dione and (S)-2-(but-3-en-2-yl)isoindoline- 1,3-dione
  • Step 1 8-bromo-3-methyl-N-(2-methylallyl)quinoxalin-2-amine
  • Step 2 3-methyl-N-(2-methylallyl)-8-(4,4,5,5-tetramethyl-l ,3,2-dioxaborolan-2- yl)quinoxalin-2-amine
  • Step 1 (is)-ethyl 4-(4-bromo-lH-pyrrole-2-carboxamido)but-2-enoate
  • Step 2 ethyl 2-(7-bromo-l-oxo-l,2,3,4-tetrahydropyrrolo[l,2-a]pyrazin-4-yl)acetate (is)-Ethyl 4-(4-bromo-lH-pyrrole-2-carboxamido)but-2-enoate (2.35 g, 7.80 mmol) was treated with ACN (30 mL) under argon and treated with DBU (0.27 mL, 1.795 mmol) and stirred at RT for 1 h 45 min.
  • Step 5 8-bromo-7-fluoro-3-methylquinoxalin-2(lH)-one
  • PrOH 9 1 (6 x 100 mL), dried over MgSO t, filtered and concentrated affording additional 8-bromo-7-fluoro-3-methylquinoxalin-2(lH)-one (12.51 g, 49 mmol, 58 % yield) as a dark brown amorphous solid (ca. 80%o purity). The material was used in the subsequent step without further purification.
  • the reaction mixture was stirred and heated in a Initiator microwave reactor (Personal Chemistry, Biotage AB, Inc., Upssala, Sweden) at 100 °C for 50 min. EtOAc was added and the mixture was filtered through Celite and the filtrate was concentrated.
  • Step 1 tert-butyl 5 -(but-2-yn- 1 -yl)-2,4-dioxopiperidine- 1 -carboxylate
  • Step 4 2-bromo-7-(but-2-yn-l-yl)-6,7-dihydro-lH-pyrrolo[3,2-c]pyridin-4(5H)-one
  • a solution of 7-(but-2-yn-l -yl)-6,7-dihydro-lH-pyrrolo[3,2-c]pyridin-4(5H)-one (1.32 g, 7.01 mmol) in DMF (25 mL) was cooled to -60 °C and l ,3-dibromo-5,5- dimethylhydantoin (Sigma- Aldrich, 1.0 g, 3.51 mmol) was added in one portion.
  • a 1-L, three-necked round-bottomed flask equipped with a mechanical stirrer, a nitrogen gas inlet, and a temperature probe was charged 5-bromo-3-chloro-2- methylquinoxaline (21.5 g, 83 mmol), DMSO (215 mL) and KF (4.85 mL, 209 mmol), and the resulting mixture was heated at 90 °C for 2.5 h. The mixture was cooled to RT and ice/water (430 mL) was added.
  • TBSOTf (2.92 mL, 12.73 mmol) was added (dropwise, over 3 min) to a mixture l-(3-fluoro-2-methylquinoxalin-5-yl)ethanone (2.00 g, 9.79 mmol) and TEA (2.05 mL, 14.7 mmol) in DCM (100 mL) at 0 °C, and the resulting solution was stirred at 0 °C for 30 min. The mixture was diluted with DCM (50 mL), washed with saturated aq.
  • Step 1 2-(2-(allyloxy)quinolin-8-yl)-7-(2-methylallyl)-6,7-dihydro-lH-pyrrolo[3,2- c]pyridin-4(5H)-one
  • This material was treated with 2-bromo-l-(2-chloroquinolin-8-yl)ethanone (0.534 g, 1.876 mmol), NH 4 OAC (Fisher Scientific, 0.723 g, 9.38 mmol), and 10 mL EtOH, sealed, and heated to 50 °C for 4 h.
  • the material was treated with DCM and purified by silica gel chromatography (80 g column) using 0 - 100% 90/10 DCM/MeOH in DCM. The product- containing fractions were concentrated to afford 0.199 g impure material.
  • Step 2 (l lE)-l l-methyl-14-oxa-3,7,23- triazapentacyclo[13.6.2.1 ⁇ 2,5 ⁇ .0 ⁇ 4,9 ⁇ .0 ⁇ 18,22 ⁇ ]tetracosa-l(21),2(24),4,l 1,15, 17,19,22- octaen-6-one
  • the resulting material was dissolved in DMSO and purified by RPHPLC, Phenomenex Gemini 150x30 mm Ci 8 column, 10-100 % ACN/H 2 0 with 0.1 % TFA; product- containing fractions were treated with saturated aqueous NaHCC>3 and DCM.
  • Example 1 A portion of the material prepared in Example 1 was separated by SFC chromatography (ADH (4.6 x 150 mm), 5 ⁇ , 45% MeOH containing 0.2% DEA, 4 ml/min,100 Bar) to give separated enantiomers (9R,11E)-1 l-methyl-14-oxa-3,7,23- triazapentacyclo[13.6.2.1 ⁇ 2,5 ⁇ .0 ⁇ 4,9 ⁇ .0 ⁇ 18,22 ⁇ ]tetracosa-l(21),2(24),4,l 1,15, 17,19,22- octaen-6-one and (9S,11E)-1 l-methyl-14-oxa-3,7,23- triazapentacyclo[13.6.2.1 ⁇ 2,5 ⁇ .0 ⁇ 4,9 ⁇ .0 ⁇ 18,22 ⁇ ]tetracosa-l(21),2(24),4,l 1,15, 17,19,22- octaen-6-one.
  • Example 2 was the first eluting product
  • Example 3 was the second eluting product.
  • Example 4 16-oxa-3,7,25- triazahexacyclo[15.6.2.1 ⁇ 2,5 ⁇ .l ⁇ ll,15 ⁇ .0 ⁇ 4,9 ⁇ .0 ⁇ 20,24 ⁇ ]heptacosa- l(23),2(27),4,ll(26),12,14,17,19,21,24-decaen-6-one
  • Step 1 2-(2-chloroquinolin-8-yl)-7-(3-methoxybenzyl)-6,7-dihydro-lH-pyrrolo[3,2- c]pyridin-4(5H)-one
  • the reaction was treated with water and DCM, and 5% KHSO 4 was added to acidify the aqueous layer.
  • the aqueous layer was extracted 3 x DCM.
  • the combined extracts were dried over Na 2 S0 4 , filtered, and concentrated in vacuo.
  • the material was treated with DCM and purified by silica gel chromatography (40 g column) using 0 - 50% EtOAc/hexane.
  • the product- containing fractions were concentrated to afford 1.34 g of a foam.
  • This material was treated with 40 mL 4.0 M HCl in dioxane (Aldrich) and fitted with a drying tube.
  • Step 2 16-oxa-3,7,25- triazahexacyclo[15.6.2.1 ⁇ 2,5 ⁇ . l ⁇ l l,15 ⁇ .0 ⁇ 4,9 ⁇ .0 ⁇ 20,24 ⁇ ]heptacosa- 1 (23),2(27),4, 11 (26),12,14, 17, 19,21 ,24-decaen-6-one
  • the reaction was cooled and partitioned between saturated aqueous NH 4 C1 and DCM.
  • the aqueous layer was extracted with DCM 3 times, and the combined organics were dried over anhydrous Na 2 S0 4 , filtered, and concentrated in vacuo.
  • the material was treated with DCM and purified by silica gel chromatography (25 g column) using 0 - 100% 90/10 DCM/MeOH in DCM; the product-containing fractions were concentrated to afford impure 7-allyl-2- (2-((2-methylallyl)oxy)quinolin-8-yl)-6,7-dihydro-lH-pyrrolo[3,2-c]pyridin-4(5H)-one (0.133 g).
  • Step 1 7-allyl-2-(2-((2-methylallyl)amino)quinolin-8-yl)-6,7-dihydro-lH-pyrrolo[3,2- c]pyridin-4(5H)-one
  • Argon was bubbled through a slurry of sodium tert-butoxide (0.939 g, 9.77 mmol), 2- methylallylamine (Matrix Scientific, Columbia, SC, 0.347 ml, 4.88 mmol), BrettPhos (0.026 g, 0.049 mmol), 7-allyl-2-(2-chloroquinolin-8-yl)-6,7-dihydro-lH-pyrrolo[3,2- c]pyridin-4(5H)-one (Intermediate F, 0.330 g, 0.977 mmol), BrettPhos precatalyst (0.039 g, 0.049 mmol) in 3 mL dioxane for 30 sec.
  • the reaction was sealed and heated to 80 °C. After 2 h, the reaction was cooled and judged complete by LCMS. The reaction was partitioned between saturated aqueous NH 4 C1 and DCM. The aqueous layer was extracted with DCM 3 times, and the combined organics were dried over anhydrous
  • Step 2 (1 lE)-12-methyl-3,7,14,23- tetraazapentacyclo[13.6.2.1 ⁇ 2,5 ⁇ .0 ⁇ 4,9 ⁇ .0 ⁇ 18,22 ⁇ ]tetracosa- 1 (21 ),2(24),4, 11 , 15, 17, 19,22-octaen-6-one
  • the material was purified by silica gel chromatography (25 g column) using 30 - 70 % 90/10/1 DCM/MeOH/conc. NH 4 OH in DCM. The product-containing fractions were concentrated to give 79 mg yellow solid. This material was dissolved in DMSO and purified by RPHPLC, Phenomenex Gemini 150x30 mm Ci 8 column, 10-70 % ACN/H 2 0 with 0.1% TFA; product-containing fraction was treated with saturated aqueous NaHCC and DCM.
  • Examples 7 and 8 (9R,llE)-12-methyl-3,7,14,23- tetraazapentacyclo[13.6.2.1 ⁇ 2,5 ⁇ .0 ⁇ 4,9 ⁇ .0 ⁇ 18,22 ⁇ ]tetracosa- l(21),2(24),4,ll,15,17,19,22-octaen-6-one and (9S,HE)-12-methyl-3,7,14,23- tetraazapentacyclo[13.6.2.1 ⁇ 2,5 ⁇ .0 ⁇ 4,9 ⁇ .0 ⁇ 18,22 ⁇ ]tetracosa- l(21),2(24),4,ll,15,17,19,22-octaen-6-one
  • Example 7 was the first eluting product.
  • Example 8 was the first eluting product.
  • Step 1 8-bromo-3-methyl-N-(2-methylallyl)quinoxalin-2-amine
  • Step 2 8-( 1 -ethoxyvinyl)-3-methyl-N-(2-methylallyl)quinoxalin-2-amine
  • Argon was bubbled through a mixture of tributyl(l -ethoxyvinyl)tin (Aldrich; 1.025 ml, 3.03 mmol), Cul (Riedel-de-Haen; 0.077 g, 0.405 mmol), cesium fluoride (Aldrich; 0.922 g, 6.07 mmol), Pd 2 (dba) 3 (Strem, 0.185 g, 0.202 mmol), X-Phos (Strem, 0.096 g, 0.202 mmol), 8-bromo-3-methyl-N-(2-methylallyl)quinoxalin-2-amine (0.591 g, 2.023 mmol) in 10 mL dioxane for 2 min.
  • Step 3 7-allyl-2-(2-methyl-3-((2-methylallyl)amino)quinoxalin-5-yl)-6,7-dihydro-lH- pyrrolo [3,2 -c]pyridin-4(5 H)-one
  • the material was treated with NH 4 OAc (0.329 g, 4.26 mmol) and 5- allylpiperidine-2,4-dione (Intermediate A; 0.196 g, 1.279 mmol) and 10 mL EtOH, sealed, and placed in a 50 °C oil bath for 5 h. The reaction was cooled and placed in a freezer over the weekend. The reaction was carefully quenched with saturated aqueous NaHCC . The reaction was partitioned between saturated aqueous NaHCC and DCM.
  • Step 4 (1 lE)-12,16-dimethyl-3,7,14,17,23- pentaazapentacyclo[l 3.6.2.1 ⁇ 2,5 ⁇ .0 ⁇ 4,9 ⁇ .0 ⁇ 18,22 ⁇ ]tetracosa- 1 (21 ),2(24),4, 11 , 15, 17, 19,22-octaen-6-one
  • Examples 10-13 (9R,llZ)-14-oxa-3,7,23- triazapentacyclo[13.6.2.1 ⁇ 2,5 ⁇ .0 ⁇ 4,9 ⁇ .0 ⁇ 18,22 ⁇ ]tetracosa- l(21),2(24),4,ll,15,17,19,22-octaen-6-one, (9S,llZ)-14-oxa-3,7,23- triazapentacyclo[13.6.2.1 ⁇ 2,5 ⁇ .0 ⁇ 4,9 ⁇ .0 ⁇ 18,22 ⁇ ]tetracosa- l(21),2(24),4,ll,15,17,19,22-octaen-6-one, (9R,llE)-14-oxa-3,7,23- triazapentacyclo[13.6.2.1 ⁇ 2,5 ⁇ .0 ⁇ 4,9 ⁇ .0 ⁇ 18,22 ⁇ ]tetracosa- l(21),2(24),4,ll,15,17,19,22-octaen-6-one, (9S
  • the reaction was cooled and partitioned between saturated aqueous NH 4 C1 and EtOAc.
  • the organic layer was washed 1 x water, 1 x brine, and the organics were dried over anhydrous Na 2 S0 4 , filtered, and concentrated in vacuo.
  • the material was treated with DCM and purified by silica gel chromatography (25 g column) using 0 - 80% 90/10 DCM/MeOH in DCM.
  • the product contiaining fractions were concentrated in vacuo to give 0.100 g of impure material.
  • This material was treated with Grubbs 2nd generation catalyst (0.024 g, 0.028 mmol) and 15 mL anhydrous DCM, and argon was bubbled through the reaction for 2 min.
  • Example 14 (9S,HE)-12,16-dimethyl-3,7,14,17,23- pentaazapentacyclo[13.6.2.1 ⁇ 2,5 ⁇ .0 ⁇ 4,9 ⁇ .0 ⁇ 18,22 ⁇ ]tetracosa- l(21),2(24),4,ll,15,17,19,22-octaen-6-one
  • Example 15 (9R,llE)-12,16-dimethyl-3,7,14,17,23- pentaazapentacyclo[13.6.2.1 ⁇ 2,5 ⁇ .0 ⁇ 4,9 ⁇ .0 ⁇ 18,22 ⁇ ]tetracosa- l(21),2(24),4,ll,15,17,19,22-octaen-6-one
  • Example 16 (9S,llZ)-12,16-dimethyl-3,7,14,17,23-pentaaza- pentacyclo[13.6.2.1 ⁇ 2,5 ⁇ .0 ⁇ 4,9 ⁇ .0 ⁇ 18,22 ⁇ ]tetracosa-l(21),2(24),4,ll,15,17,19,22- octaen-6-one
  • Step 1 (S)-7-allyl-2-(2-methyl-3-((2-methylallyl)amino)quinoxalin-5-yl)-6,7-dihydro- 1 H-pyrrolo [3 ,2-c]pyridin-4(5H)-one
  • a glass microwave reaction vessel was charged with (2-methyl-3-((2- methylallyl)amino)quinoxalin-5-yl)boronic acid (Intermediate I, 40 mg, 0.156 mmol) and (S)-7-allyl-2-bromo-6,7-dihydro-lH-pyrrolo[3,2-c]pyridin-4(5H)-one (Intermediate D, 39.7 mg, 0.156 mmol) in 1 ,4-dioxane (1.0 mL)/water (0.25 mL) followed by Pd 2 dba 3 (7.12 mg, 7.78 ⁇ , Strem), 2-(dicyclohexylphosphino)-2',4',6',-tri-isopropyll, -biphenyl (7.42 mg, 0.016 mmol, Sigma- Aldrich) and K 3 P0 4 (66.1 mg, 0.31 1 mmol, Sigma- Aldrich).
  • the reaction mixture was stirred and heated in an oil bath at 100 °C for 40 min, then cooled to RT.
  • the mixture was diluted with DCM (80 mL) and washed with water (15 mL), brine (10 mL).
  • the organic layers was dried (MgS0 4 ), filtered and concentrated.
  • Step 2 (9S,1 lE)-12,16-dimethyl-3,7,14,17,23- pentaazapentacyclo[l 3.6.2.1 ⁇ 2,5 ⁇ .0 ⁇ 4,9 ⁇ .0 ⁇ 18,22 ⁇ ]tetracosa-
  • Example 14 (9S,1 lE)-12,16-dimethyl-3,7,14,17,23-pentaaza- pentacyclo[13.6.2.1 ⁇ 2,5 ⁇ .0 ⁇ 4,9 ⁇ .0 ⁇ 18,22 ⁇ ]tetracosa-l(21),2(24),4,l 1 ,15,17,19,22- octaen-6-one: 'H NMR (400 MHz, DMSO-d 6 ) ⁇ ppm 13.40 (1 H, br.
  • Example 17 (HE)-12-methyl-3,7,14,17,23-pentaaza- pentacyclo[13.6.2.1 ⁇ 2,5 ⁇ .0 ⁇ 4,9 ⁇ .0 ⁇ 18,22 ⁇ ]tetracosa-l(21),2(24),4,ll,15,17,19,22- octaen-6-one
  • Step 1 8-chloro-N-(2-methylallyl)quinoxalin-2-amine
  • the reaction was transferred to a 500 mL rbf with DCM, and adsorbed onto 20 g silica gel in vacuo.
  • the material was purified by silica gel chromatography (160 g column) using 0 - 50% EtOAc/hexane to give 8-(l -ethoxyvinyl)- N-(2-methylallyl)quinoxalin-2 -amine (2.85 g, 10.6 mmol, quantitative yield): !
  • Step 3 2-bromo-l -(3-((2-methylallyl)amino)quinoxalin-5-yl)ethanone
  • Step 5 (1 lE)-12-methyl-3,7,14,17,23-pentaaza- pentacyclo[13.6.2.1 ⁇ 2,5 ⁇ .0 ⁇ 4,9 ⁇ .0 ⁇ 18,22 ⁇ ]tetracosa-l(21),2(24),4,l 1 ,15,17,19,22- octaen-6-one
  • Examples 18 and 19 (9R, llE)-12-methyl-3,7,14,17,23- pentaazapentacyclo[13.6.2.1 ⁇ 2,5 ⁇ .0 ⁇ 4,9 ⁇ .0 ⁇ 18,22 ⁇ ]tetracosa- l(21),2(24),4,ll,15,17,19,22-octaen-6-one and (9S, llE)-12-methyl-3,7,14,17,23- pentaazapentacyclo[13.6.2.1 ⁇ 2,5 ⁇ .0 ⁇ 4,9 ⁇ .0 ⁇ 18,22 ⁇ ]tetracosa- l(21),2(24),4,ll,15,17,19,22-octaen-6-one
  • Example 17 The individual enantiomers of Example 17 were obtained by chiral SFC (Column: Chiralpak AS-H (250 x 21 mm, 5 ⁇ ) Mobile Phase: 75 :25 (A:B); A: Liquid C0 2 B: MeOH (40 mM NH 3 ) ; Flow Rate: 75 mL/min; Oven Temp: 40 °C; Inlet Pressure: 100 bar) to give Example 18 (first eluting product) and Example 19 (second eluting product).
  • Example 20 (9S,llZ)-16-methyl-3,7,14,17,23- pentaazapentacyclo[13.6.2.1 ⁇ 2,5 ⁇ .0 ⁇ 4,9 ⁇ .0 ⁇ 18,22 ⁇ ]tetracosa- l(21),2(24),4,ll,15,17,19,22-octaen-6-one
  • Example 21 (9S,llE)-16-methyl-3,7,14,17,23- pentaazapentacyclo[13.6.2.1 ⁇ 2,5 ⁇ .0 ⁇ 4,9 ⁇ .0 ⁇ 18,22 ⁇ ]tetracosa- l(21),2(24),4,ll,15,17,19,22-octaen-6-one
  • Example 22 (9R,llZ)-16-methyl-3,7,14,17,23- pentaazapentacyclo[13.6.2.1 ⁇ 2,5 ⁇ .0 ⁇ 4,9 ⁇ .0 ⁇ 18,22 ⁇ ]tetracosa- l(21),2(24),4,ll,15,17,19,22-octaen-6-one
  • Example 23 (9R,llE)-16-methyl-3,7,14,17,23- pentaazapentacyclo[13.6.2.1 ⁇ 2,5 ⁇ .0 ⁇ 4,9 ⁇ .0 ⁇ 18,22 ⁇ ]tetracosa- l(21),2(24),4,ll,15,17,19,22-octaen-6-one
  • Step 1 7-allyl-2-(3-(allylamino)-2-methylquinoxalin-5-yl)-6,7-dihydro-lH-pyrrolo[3,2- c]pyridin-4(5H)-one
  • Step 2 (9S,1 lZ)-16-methyl-3,7,14,17,23- pentaazapentacyclo[l 3.6.2.1 ⁇ 2,5 ⁇ .0 ⁇ 4,9 ⁇ .0 ⁇ 18,22 ⁇ ]tetracosa- 1 (21 ),2(24),4, 1 1 , 15 , 17, 19,22-octaen-6-one,
  • reaction was concentrated onto 3 g silica gel from MeOH/DCM and dried in vacuo, and was purified by silica gel chromatography (40 g column) using 0 - 100% 90/10 DCM/MeOH in DCM to give 0.234 g of a mixture of products as a light green solid.
  • Example 20 (9S,11Z)-16- methyl-3,7,14,17,23-pentaazapentacyclo[l 3.6.2.1 ⁇ 2,5 ⁇ .0 ⁇ 4,9 ⁇ .0 ⁇ 18,22 ⁇ ]tetracosa- 1(21),2(24),4,1 l,15,17,19,22-octaen-6-one (first eluting peak, 26 mg containing an impurity, material was sonicated in 0.5 mL MeOH and filtered, rinsing 1 x 0.5 mL MeOH, to give 17 mg, 0.051 mmol, 7% yield),
  • Example 21 (9S,1
  • Example 22 (9R,l lZ)-16-methyl-3,7,14,17,23- pentaazapentacyclo[l 3.6.2.1 ⁇ 2,5 ⁇ .0 ⁇ 4,9 ⁇ .0 ⁇ 18,22 ⁇ ]tetracosa-
  • Example 23 (9R,1 lE)-16-methyl-3,7,14,17,23-pentaaza- pentacyclo[13.6.2.1 ⁇ 2,5 ⁇ .0 ⁇ 4,9 ⁇ .0 ⁇ 18,22 ⁇ ]tetracosa-l(21),2(24),4,l 1,15,17,19,22- octaen-6-one (second eluting peak, 44 mg, 0.13 mmol, 16%o yield).
  • Example 24 (9S,llE)-12,16-dimethyl-14-oxa-3,7,17,23- tetraazapentacyclo[13.6.2.1 ⁇ 2,5 ⁇ .0 ⁇ 4,9 ⁇ .0 ⁇ 18,22 ⁇ ]tetracosa- l(21),2(24),4,ll,15,17,19,22-octaen-6-one
  • Example 25 (9R,llE)-12,16-dimethyl-14-oxa-3,7,17,23- tetraazapentacyclo[13.6.2.1 ⁇ 2,5 ⁇ .0 ⁇ 4,9 ⁇ .0 ⁇ 18,22 ⁇ ]tetracosa- l(21),2(24),4,ll,15,17,19,22-octaen-6-one
  • Step 1 7-allyl-2-(2-methyl-3-((2-methylallyl)oxy)quinoxalin-5-yl)-6,7-dihydro-lH- pyrrolo [3,2 -c]pyridin-4(5 H)-one
  • Step 2 (9S,1 lE)-12,16-dimethyl-14-oxa-3,7,17,23- tetraazapentacyclo[13.6.2.1 ⁇ 2,5 ⁇ .0 ⁇ 4,9 ⁇ .0 ⁇ 18,22 ⁇ ]tetracosa-
  • reaction was sealed and heated to 45 °C. After 4 h, the reaction was concentrated in vacuo, taken up in 3.5 mL DMSO and filtered through a 0.45 ⁇ filter, and purified by RPHPLC, Phenomenex Gemini 150x30 mm Cis column, 15- 80 % ACN/H 2 O with 0.1 % TFA; product-containing fractions were combined and concentrated in vacuo to give 0.028 g material.
  • Example 28 (9R,llZ)-17-methyl-3,7,15,18,24- pentaazapentacyclo[14.6.2.1 ⁇ 2,5 ⁇ .0 ⁇ 4,9 ⁇ .0 ⁇ 19,23 ⁇ ]pentacosa- l(22),2(25),4,ll,16,18,20,23-octaen-6-one
  • Example 29 (9S,llZ)-17-methyl-3,7,15,18,24- pentaazapentacyclo[14.6.2.1 ⁇ 2,5 ⁇ .0 ⁇ 4,9 ⁇ .0 ⁇ 19,23 ⁇ ]pentacosa- l(22),2(25),4,ll,16,18,20,23-octaen-6-one
  • Step 1 7-allyl-2-(3-(but-3-en-l-ylamino)-2-methylquinoxalin-5-yl)-6,7-dihydro-lH ⁇ pyrrolo [3,2 -c]pyridin-4(5 H)-one
  • Step 2 (9R,1 lE)-17-methyl-3,7,15, 18,24- pentaazapentacyclo[l 4.6.2. l ⁇ 2,5 ⁇ .0 ⁇ 4,9 ⁇ .0 ⁇ 19,23 ⁇ ]pentacosa- l(22),2(25),4,l l,16,18,20,23-octaen-6-one, (9S,1 lE)-17-methyl-3,7,15,18,24- pentaazapentacyclo[l 4.6.2.1 ⁇ 2,5 ⁇ .0 ⁇ 4,9 ⁇ .0 ⁇ 19,23 ⁇ ]pentacosa-
  • the material was purified by silica gel chromatography (25 g column) using 0 - 100% 90/10 DCM/MeOH in DCM, to give 0.099 g yellow-green solid.
  • This material was further purified by chiral SFC (AS-H (2 x 15 cm) 40% (1 : 1 : 1 mixture of MeOH:EtOH:IPA with 0.1 % NH 4 OH)/60% C0 2 , 100 bar, 65 mL/min) to give three materials, peak 1 , 2, and 3.
  • Peak 2 was further purified by chiral SFC (AD-H (2 x 15 cm), 35% MeOH(NH 4 OH)/C0 2 , 100 bar, 60 mL/min) to give first eluting (peak 2a) and second eluting (peak 2b) materials:
  • Example 28 (9R,1 lZ)-17-methyl-3,7,15,18,24- pentaazapentacyclo[l 4.6.2.1 ⁇ 2,5 ⁇ .0 ⁇ 4,9 ⁇ .0 ⁇ 19,23 ⁇ ]pentacosa- l(22),2(25),4,l l,16,18,20,23-octaen-6-one (Peak 2a, 0.0025 g, 0.0069 mmol, 2.1 % yield): !
  • Example 30 (9R,llE,13R)-13,16-dimethyl-3,7,14,17,23- pentaazapentacyclo[13.6.2.1 ⁇ 2,5 ⁇ .0 ⁇ 4,9 ⁇ .0 ⁇ 18,22 ⁇ ]tetracosa- l(22),2(24),4,ll,15,17,18,20,22-nonaen-6-one
  • Example 31 (9S,llE,13R)-13,16-dimethyl-3,7,14,17,23- pentaazapentacyclo[13.6.2.1 ⁇ 2,5 ⁇ .0 ⁇ 4,9 ⁇ .0 ⁇ 18,22 ⁇ ]tetracosa- l(22),2(24),4,ll,15,17,18,20,22-nonaen-6-one
  • Example 32 (9S,llZ,13R)-13,16-dimethyl-3,7,14,17,23- pentaazapentacyclo[13.6.2.1 ⁇ 2,5 ⁇ .0 ⁇ 4,9 ⁇ .0 ⁇ 18,22 ⁇ ]tetracosa- l(22),2(24),4,ll,15,17,18,20,22-nonaen-6-one
  • Step 1 7-allyl-2-(3-((R)-but-3-en-2-ylamino)-2-methylquinoxalin-5-yl)-6,7-dihydro-lH- pyrrolo [3,2 -c]pyridin-4(5 H)-one
  • Step 2 (9R,1 lE,13R)-13,16-dimethyl-3,7,14,17,23- pentaazapentacyclo[l 3.6.2.1 ⁇ 2,5 ⁇ .0 ⁇ 4,9 ⁇ .0 ⁇ 18,22 ⁇ ]tetracosa-
  • the material was purified by silica gel chromatography (40 g column) using 0 - 100%o 90/10 DCM/MeOH in DCM. Combined fractions to give 0.188 g of a green-yellow solid. This material was further purified by chiral SFC (ODH (21x250mm, 5 ⁇ ), 45% MeOH with 20 mM NH 3 , 65 ml/min total flow) to give first eluting peak (peak 1, mixture of two components) and pure second eluting peak (peak 2).
  • Peak 1 was further purified by SFC (Pyridine column (21x250mm, 5 ⁇ ), 27% MeOH with 20 mM NH 3 , 70 ml/min) to give first eluting peak (peak la) and second eluting peak (peak lb).
  • Example 30 (9R,1 lE,13R)-13,16-dimethyl-3,7,14,17,23- pentaazapentacyclo[l 3.6.2. l ⁇ 2,5 ⁇ .0 ⁇ 4,9 ⁇ .0 ⁇ 18,22 ⁇ ]tetracosa- l(22),2(24),4,l l,15,17,18,20,22-nonaen-6-one (Peak 2, 0.083 g, 0.231 mmol, 39.8 % yield): ! H NMR (400 MHz, DMSO-d 6 ) ⁇ ppm 13.57 (1 H, br.
  • Example 31 (9S,l lE,13R)-13,16-dimethyl-3,7,14,17,23- pentaazapentacyclo[l 3.6.2. l ⁇ 2,5 ⁇ .0 ⁇ 4,9 ⁇ .0 ⁇ 18,22 ⁇ ]tetracosa- l(22),2(24),4,l l,15,17,18,20,22-nonaen-6-one (Peak la, 0.063 g, 0.175 mmol, 30.2 % yield): ! H NMR (400 MHz, DMSO-d 6 ) ⁇ ppm 13.46 (1 H, br.
  • Example 32 (9S,l lZ,13R)-13,16-dimethyl-3,7,14,17,23- pentaazapentacyclo[l 3.6.2. l ⁇ 2,5 ⁇ .0 ⁇ 4,9 ⁇ .0 ⁇ 18,22 ⁇ ]tetracosa- l(22),2(24),4,l l,15,17,18,20,22-nonaen-6-one (Peak lb, 0.0057 g, 0.016 mmol, 2.73 % yield): !
  • Example 32 alternative preparation: (9S,llZ,13R)-13,16-dimethyl-3,7,14,17,23- pentaazapentacyclo[13.6.2.1 ⁇ 2,5 ⁇ .0 ⁇ 4,9 ⁇ .0 ⁇ 18,22 ⁇ ]tetracosa- l(22),2(24),4,ll,15,17,18,20,22-nonaen-6-one
  • Step 1 (9S,13R)-13,16-dimethyl-3,7,14,17,23- pentaazapentacyclo[l 3.6.2. l ⁇ 2,5 ⁇ .0 ⁇ 4,9 ⁇ .0 ⁇ 18,22 ⁇ ]tetracosa- 1 (22),2(24),4, 15, 17, 18,20,22-octaen-l 1 -yn-6-one
  • Step 2 (9S,1 lZ,13R)-13,16-dimethyl-3,7,14,17,23- pentaazapentacyclo[l 3.6.2.1 ⁇ 2,5 ⁇ .0 ⁇ 4,9 ⁇ .0 ⁇ 18,22 ⁇ ]tetracosa- 1 (22),2(24),4, 11 , 15, 17, 18,20,22-nonaen-6-one
  • Step 1 Acetaldehyde ( Sigma- Aldrich, 285 ml, 5074 mmol) and MgS0 4 ( Sigma- Aldrich, 660 g, 5480 mmol) were added to a solution of (R)-2-methylpropane-2-sulfinamide (AK Scientific, Inc., Union City, CA, 246 g, 2.03 mol) in DCM (1.2 L). The slurry was stirred at RT for 16 h. The reaction mixture was filtered and concentrated to give product contaminated with starting material.
  • Step 2 LiHMDS in THF (1.0 M, Sigma-Aldrich, 235 ml, 235 mmol) was added over 30 min via addition funnel to a solution of 3-chloroprop-l-yne (Sigma-Aldrich, 16.84 ml, 235 mmol) in pentane (400 ml) in a three neck 5 L rbf fixed with a mechanical stirrer and temperature probe at -72 °C. The yellow solution was stirred at -72 °C for 15 min; (R,E)- N-ethylidene-2-methylpropane-2-sulfinamide (34.6 g, 235 mmol) in THF (20 mL) was then added to the reaction mixture. The brown solution was stirred at -78 °C for 15 min and was warmed to 17 °C over 3 h when mostly MS (ESI, pos. ion) m/z: 222.1 (M+l) was observed.
  • Step 3 Tert-butyl 2,4-dioxopiperidine-l-carboxylate (Ark Pharma, Libertyville, IL, 37.6 g, 176 mmol) in THF (400 ml) was added to the reaction mixture; this was cooled to -20 °C (an acetone bath was adjusted to the desired temperature by addition of dry ice), and LiHMDS in THF (1.0 M in THF; Sigma-Aldrich, 564 ml, 564 mmol) was added via addition funnel over 10 min (the internal temperature was kept below -20 °C). The brown solution was stirred at -20 °C for 1 h. The reaction mixture was quenched with water (500 mL) and acidified with 1 N aq.

Abstract

The invention relates to compounds of formula (1), and salts thereof. In some embodiments, the invention relates to inhibitors or modulators of Pim-1 and/or Pim-2, and/or Pim-3 protein kinase activity or enzyme function. In still further embodiments, the invention relates to pharmaceutical compositions comprising compounds disclosed herein, and their use in the prevention and treatment of Pim kinase related conditions and diseases, preferably cancer.

Description

MACROCYCLES AS PIM INHIBITORS
FIELD OF THE INVENTION
The present invention relates to certain macrocycles that are Pirn inhibitors, pharmaceutical compositions containing such compounds, and processes for preparing such compounds. Provided herein also are methods of treating disorders or diseases treatable by inhibition of Pims, such as cancer, and the like.
BACKGROUND
The role of Pirn serine/threonine kinases in the pathogenesis and therapy of hematological malignancies and solid cancers is of interest to the medical community. Pirn proteins are constitutively active and are over-expressed in a subset of human cancers, many of hematological origin. Pirn kinases also regulate aspects of transformation and drug resistance in hematological malignancies such as DLBCL, MM, and AML where they are overexpressed or mutated. Aberrant expression of Pim-1 or Pim-2 promotes tumor development in mouse models of lymphoma and prostate cancer. Elevated Pim-1 levels correlate with poor prognosis in DLBCL and mantle cell lymphoma. Pims play a role in some solid tumors (e.g. prostate cancer, and head and neck cancer). Whereas elevated levels of Pim-1 and Pim-2 were mostly found in hematological malignancies and prostate cancer, increased Pirn- 3 expression was observed in different solid tumors. Pirn kinases are constitutively active and their activity supports in vitro and in vivo tumour cell growth and survival through modification of an increasing number of common as well as isoform-specific substrates including several cell cycle regulators and apoptosis mediators. Pim-1 mediates homing and migration of normal and malignant hematopoietic cells by regulating chemokine receptor surface expression. Knockdown experiments by RNA interference or dominant-negative acting mutants suggested that Pirn kinases are important for maintenance of a transformed phenotype and therefore potential therapeutic targets.
There exists a need for compounds that inhibit the growth of tumors, treat cancer, modulate cell cycle arrest, and/or inhibit molecules such as Pim-1, Pim-2, or Pim-3 and pharmaceutical formulations and medicaments that contain such compounds. SUMMARY OF THE INVENTION
The present invention comprises a new class of macrocyclic compounds useful in the treatment of diseases, such as Pim-mediated diseases, for example cancer.
Accordingly, the invention also comprises pharmaceutical compositions comprising the compounds, methods for the treatment of Pim-mediated diseases and other maladies, such as treatment of hematological malignancies and of solid tumors, for example prostate cancer, and head and neck cancer, using the compounds and compositions of the invention, and intermediates and processes useful for the preparation of the compounds of the invention.
The compounds of the invention are represented by the following general structure:
Figure imgf000003_0001
and a pharmaceutically acceptable salt thereof; wherein Q, X, Z, a, b, c, q, w, s, r, Re, R1; and R2 are defined below.
The foregoing merely summarizes certain aspects of the invention and is not intended, nor should it be construed, as limiting the invention in any way. All patents, patent applications and other publications recited herein are hereby incorporated by reference in their entirety.
DETAILED DESCRIPTION OF THE INVENTION
One aspect of the current invention relates to compounds having the general structure of formula 1 :
Figure imgf000004_0001
wherein
ring a is a ring that together with the 2 carbon atoms to which it attaches, forms a phenyl ring or a 5-6 membered heterocyclic ring;
X is N or CH;
Z is O, S, NRb, CO, CHRb or C(Rb)2;
Q is a linker saturated or unsaturated chain;
q is NH or CH;
r is CH2 or N;
s is N or C;
w is CH or N;
ring b is unsaturated, or partially saturated;
ring c is saturated, or partially saturated;
R1 is H, or halo;
R2 is H, haloalkyl, hydroxyalkyl, alkyl, alkoxy, HC(=0)-, carboxy, alkoxycarbonyl, cycloalkyl, or substituted or unsubstituted heterocyclyl;
Rb is H, alkyl, haloalkyl, hydroxyalkyl, alkylsulfonylalkyl, BOC-aminoalkyl, aminoalkyl, cyanoalkyl, alkoxyalkyl, alkylsulfonylalkylaminoalkyl, alkylsulfonylaminoalkyl, alkylcarbonylaminoalkyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted aryl, unsubstituted or substituted arylalkyl or unsubstituted or substituted heterocyclyl; and
Re is H, -PO(OCH3)2, alkylcarbonyl or hydroxyalkyl;
and a pharmaceutically acceptable salt thereof.
In another embodiment, ring a is
Figure imgf000005_0001
wherein R1 is H, or halo; and a pharmaceutically acceptable salt thereof.
In another embodiment, the compounds of Formula I comprise
Figure imgf000005_0002
wherein
X is N or CH;
Z is O, S, NRb, CO, CHRb or C(Rb)2;
Q is a 3 linker that attaches with Z; ring a is
Figure imgf000005_0003
R1 is H, or halo;
R2 is H, haloalkyl, hydroxyalkyl, alkyl, alkoxy, HC(=0)-, carboxy, alkoxycarbonyl, cycloalkyl, or substituted or unsubstituted heterocyclyl; Rb is H, alkyl, haloalkyl, hydroxyalkyl, alkylsulfonylalkyl, BOC-aminoalkyl, aminoalkyl, cyanoalkyl, alkoxyalkyl, alkylsulfonylalkylaminoalkyl, alkylsulfonylaminoalkyl, alkylcarbonylaminoalkyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted aryl, unsubstituted or substituted arylalkyl or unsubstituted or substituted heterocyclyl;
wherein R6 is H; and
wherein R7 is H or C1-3 alkyl; and a pharmaceutically acceptable salt thereof.
In another embodiment, the compounds of Formula I comprise
wherein
X is N or CH;
Z is O, S, NRb, C=0, CHRb or C(Rb)2;
Q is optionally substituted C4-C5 alkenylenyl, or optionally substituted phenyl-Ci_2 alkylenyl, optionally substituted C4-C5 alkylenyl, optionally substituted C4-C5 alkenylenyl, optionally substituted C4-C5 alkynylenyl, optionally substituted phenyl- Ci_2 alkylenyl or -(CH2)n-0-(CH2)m-, optionally substituted C4-C5 alkenylenyl, or optionally substituted Q_2 alkylenyl-aminocarbonyl- C1.2 alkylenyl, or optionally substituted C3-C4 alkenylenyl; when Q attaches to Z; or wherein Q is optionally substituted 5-7 membered heterocyclyl-alkyl, or optionally substituted 5-7 membered heterocyclyl-alkenyl; when Q incorporates Z into the heterocyclic ring;
ring
Figure imgf000006_0002
R1 is H, or halo;
R2 is H, haloalkyl, hydroxyalkyl, alkyl, alkoxy, HC(=0)-, carboxy, alkoxycarbonyl, cycloalkyl, or substituted or unsubstituted heterocyclyl;
Rb is H, alkyl, haloalkyl, hydroxyalkyl, alkylsulfonylalkyl, BOC-aminoalkyl, aminoalkyl, cyanoalkyl, alkoxyalkyl, alkylsulfonylalkylaminoalkyl, alkylsulfonylaminoalkyl, alkylcarbonylaminoalkyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted aryl, unsubstituted or substituted arylalkyl or unsubstituted or substituted heterocyclyl;
wherein R6 is H; and
wherein R7 is H;
and a pharmaceutically acceptable salt thereof.
In another embodiment, Z is O, S, NRb, or CHRb; and Rb is H, Ci_2 alkyl, Ci_2 hydroxyalkyl, C1.2 alkylsulfonyl-Cu alkyl, BOC -amino- C1.2 alkyl, amino-Ci.2 alkyl, C1.2 alkylsulfonyl-Cij alky lamino-C 1.2 alkyl, C1.2 alkylsulfonylamino-Ci.2 alkyl or d_2 alkylcarbonylamino-Ci_2 alkyl; and a pharmaceutically acceptable salt thereof.
In another embodiment, R1 is H or fluoro; and a pharmaceutically acceptable salt thereof.
In another embodiment, ring a is
Figure imgf000007_0001
; and R2 is H or fluoro; and a pharmaceutically acceptable salt thereof.
In another embodiment, Re is H, methylcarbonyl or hydroxymethyl; and a pharmaceutically acceptable salt thereof.
In another embodiment, Q and Z together form
Figure imgf000007_0002
Figure imgf000008_0001
Figure imgf000009_0001
Figure imgf000010_0001
Figure imgf000011_0001
and a pharmaceutically acceptable salt thereof.
In another embodiment, R2 is H, Ci_2 alkyl, HC(=0)- or Ci_2 hydroxyalkyl; and a pharmaceutically acceptable salt thereof.
In another embodiment, R2 is H, methyl, HC(=0)- or hydroxy methyl; and a pharmaceutically acceptable salt thereof.
In another embodiment, R2 is H; and a pharmaceutically acceptable salt thereof.
Another aspect of the current invention relates to compounds having the general structure of Formula 2
Figure imgf000012_0001
wherein Z is O or NH; and
wherein Q is optionally substituted C4-C5 alkenylenyl, or optionally substituted phenyl-
Ci-2 alkylenyl;
and a pharmaceutically acceptable salt thereof.
In another embodiment, Z is O; and a pharmaceutically acceptable salt thereof.
In another embodiment, Z is NH; and a pharmaceutically acceptable salt thereof.
In another embodiment, Q is but-2-enylenyl, 4-methylbut-2-enylenyl, 3- methylbut-2-enylenyl, 2-methylbut-2-enylenyl or phenylmethylenyl; and a
pharmaceutically acceptable salt thereof.
A family of specific compounds of particular interest within Formula 1 consists of compounds and a pharmaceutically-acceptable salt thereof as follows:
(1 1E)-1 l-methyl-14-oxa-3,7,23- triazapentacyclo[13.6.2.1~2,5~.0~4,9~.0~18,22~]tetracosa-
1 (21 ),2(24),4, 1 1 , 15 , 17, 19,22-octaen-6-one;
(9R, 11 E)- 11 -methyl- 14-oxa-3 ,7,23 - triazapentacyclo[13.6.2.1~2,5~.0~4,9~.0~18,22~]tetracosa-
1 (21 ),2(24),4, 1 1 , 15 , 17, 19,22-octaen-6-one;
(9S, 11 E)- 1 1 -methyl- 14-oxa-3 ,7,23- triazapentacyclo[13.6.2.1~2,5~.0~4,9~.0~18,22~]tetracosa-
1 (21 ),2(24),4, 1 1 , 15 , 17, 19,22-octaen-6-one;
16-oxa-3,7,25-triazahexacyclo[15.6.2.1~2,5~. l~l l,15~.0~4,9~.0~20,24~]heptacosa-
1 (23),2(27),4, 1 1 (26), 12, 14, 17,19,21 ,24-decaen-6-one;
(1 lE)-12-methyl-14-oxa-3,7,23- triazapentacyclo[13.6.2.1~2,5~.0~4,9~.0~18,22~]tetracosa-
1 (21 ),2(24),4, 1 1 , 15 , 17, 19,22-octaen-6-one;
(l lE)-12-methyl-3,7,14,23-tetraazapentacyclo[13.6.2.1~2,5~.0~4,9~.0~18,22~]tetracosa-
1 (21 ),2(24),4, 1 1 , 15 , 17, 19,22-octaen-6-one; (9R, 11 E)- 12-methyl-3 ,7, 14,23 - tetraazapentacyclo[13.6.2.1~2,5~.0~4,9~.0~18,22~]tetracosa-
1 (21 ),2(24),4, 1 1 , 15 , 17, 19,22-octaen-6-one ;
(9S,l lE)-12-methyl-3,7,14,23- tetraazapentacyclo[l 3.6.2. l~2,5~.0~4,9~.0~18,22~]tetracosa-
1 (21 ),2(24),4, 1 1 , 15 , 17, 19,22-octaen-6-one;
(9R,l lZ)-14-oxa-3,7,23-triazapentacyclo[13.6.2.1~2,5~.0~4,9~.0~18,22~]tetracosa-
1 (21 ),2(24),4, 1 1 , 15 , 17, 19,22-octaen-6-one;
(9S,l lZ)-14-oxa-3,7,23-triazapentacyclo[13.6.2.1~2,5~.0~4,9~.0~18,22~]tetracosa- 1 (21 ),2(24),4, 1 1 , 15 , 17, 19,22-octaen-6-one;
(9R,l lE)-14-oxa-3,7,23-triazapentacyclo[13.6.2.1~2,5~.0~4,9~.0~18,22~]tetracosa-
1 (21 ),2(24),4, 1 1 , 15 , 17, 19,22-octaen-6-one; and
(9S,l lE)-14-oxa-3,7,23-triazapentacyclo[13.6.2.1~2,5~.0~4,9~.0~18,22~]tetracosa-
1 (21 ),2(24),4, 1 1 , 15 , 17, 19,22-octaen-6-one.
Another aspect of the current invention relates to compounds having the general structure of Formula 3
Figure imgf000013_0001
wherein R1 is H or fluoro;
wherein R2 is H, HC(=0)- , Ci-2 alkyl or Ci_2 hydroxyalkyl;
wherein Z is O, S or NRb;
wherein Rb is H, Ci_2 alkyl, Ci_2 hydroxyalkyl, Ci_2 alkylsulfonyl-Cu alkyl, BOC-amino- Ci-2 alkyl, amino-Ci_2 alkyl, Ci_2 alkylsulfonyl-Cu alkylamino-Ci_2 alkyl, Ci_2 alkylsulfonylamino-Ci-2 alkyl or Ci_2 alkylcarbonylamino-Ci.2 alkyl;
wherein Q is optionally substituted C4-C5 alkylenyl, optionally substituted C4-C5
alkenylenyl, optionally substituted C4-C5 alkynylenyl, optionally substituted phenyl- Ci_2 alkylenyl or -(CH2)n-0-(CH2)m- ; and
wherein n is 1-2; wherein m is 1-2; provided n+m = 3 or 4;
and a pharmaceutically acceptable salt thereof.
In another embodiment, R1 is H; and a pharmaceutically acceptable salt thereof. In another embodiment, R2 is H, HC(=0)- , methyl or hydroxymethyl; and a pharmaceutically acceptable salt thereof.
In another embodiment, R2 is H or methyl; and a pharmaceutically acceptable salt thereof.
In another embodiment, Z is O or S; and a pharmaceutically acceptable salt thereof.
In another embodiment, Z is HN, methylamino, hydroxyethylamino, BOC- aminoethylamino, aminoethylamino, methylsulfonylethylaminoethylamino,
methylsulfonylaminoethylamino, methylcarbonylaminoethylamino or
methylsulfonylpropylamino; and a pharmaceutically acceptable salt thereof.
In another embodiment, Q is butylenyl, 4-methylbutylenyl, 4- hydroxymethylbutylenyl, 2,3-dihydroxy-4-methylbutylenyl, but-2-enylenyl, 4- hydroxymethylbut-2-enylenyl, 4-hydroxyethylbut-2-enylenyl, 4-methylbut-2-enylenyl, 4,4-dimethylbut-2-enylenyl, 4-trifluoromethylbut-2-enylenyl, 4-(methylsulfonylethyl)but- 2-enylenyl, 3-methylbut-2-enylenyl, 2-methylbut-2-enylenyl, but-2-ynylenyl, 4- methylbut-2-ynylenyl, pentylenyl, pent-2-enylenyl, -(CH2)2-0-(CH2)2- or
phenylmethylenyl; and a pharmaceutically acceptable salt thereof.
A family of specific compounds of particular interest within Formula 1 consists of compounds and a pharmaceutically-acceptable salt thereof as follows:
(l lE)-12,16-dimethyl-3,7,14,17,23- pentaazapentacyclo[l 3.6.2. l~2,5~.0~4,9~.0~18,22~]tetracosa- 1 (21 ),2(24),4, 11 , 15 , 17, 19,22-octaen-6-one;
(9S,1 IE)- 12, 16-dimethyl-3,7, 14,17,23- pentaazapentacyclo[l 3.6.2. l~2,5~.0~4,9~.0~18,22~]tetracosa- 1 (21 ),2(24),4, 11 , 15 , 17, 19,22-octaen-6-one;
(9R, 11 E)- 12, 16-dimethyl-3 ,7, 14,17,23- pentaazapentacyclo[l 3.6.2. l~2,5~.0~4,9~.0~18,22~]tetracosa- 1 (21 ),2(24),4, 11 , 15 , 17, 19,22-octaen-6-one;
9S, 11 Z)- 12, 16-dimethyl-3 ,7, 14,17,23- pentaazapentacyclo[l 3.6.2. l~2,5~.0~4,9~.0~18,22~]tetracosa-
1 (21 ),2(24),4, 11 , 15 , 17, 19,22-octaen-6-one;
(1 lE)-12-methyl-3,7,14,17,23- pentaazapentacyclo[l 3.6.2.1~2,5~.0~4,9~.0~18,22~]tetracosa- 1 (21 ),2(24),4, 11 , 15 , 17, 19,22-octaen-6-one; (9R, 11E)-12-methyl-3,7, 14,17,23- pentaazapentacyclo[l 3.6.2.1~2,5~.0~4,9~.0~18,22~]tetracosa-
1 (21 ),2(24),4, 11 , 15 , 17, 19,22-octaen-6-one;
(9S, 1 lE)-12-methyl-3,7,14,17,23- pentaazapentacyclo[l 3.6.2. l~2,5~.0~4,9~.0~18,22~]tetracosa-
1 (21 ),2(24),4, 11 , 15 , 17, 19,22-octaen-6-one;
(9S,11Z)-16-methyl-3 ,7, 14,17,23- pentaazapentacyclo[l 3.6.2. l~2,5~.0~4,9~.0~18,22~]tetracosa-
1 (21 ),2(24),4, 11 , 15 , 17, 19,22-octaen-6-one
(9S, 11 E)- 16-methyl-3 ,7, 14,17,23- pentaazapentacyclo[l 3.6.2. l~2,5~.0~4,9~.0~18,22~]tetracosa-
1 (21 ),2(24),4, 11 , 15 , 17, 19,22-octaen-6-one
(9R, 11 Z)- 16-methyl-3 ,7,14,17,23- pentaazapentacyclo[l 3.6.2. l~2,5~.0~4,9~.0~18,22~]tetracosa- 1 (21 ),2(24),4, 11 , 15 , 17, 19,22-octaen-6-one
(9R, 11 E)- 16-methyl-3 ,7,14,17,23- pentaazapentacyclo[l 3.6.2. l~2,5~.0~4,9~.0~18,22~]tetracosa-
1 (21 ),2(24),4, 11 , 15 , 17, 19,22-octaen-6-one;
(9S, 11 E)- 12, 16-dimethyl- 14-oxa-3,7, 17,23- tetraazapentacyclo[l 3.6.2. l~2,5~.0~4,9~.0~18,22~]tetracosa-
1 (21 ),2(24),4, 11 , 15 , 17, 19,22-octaen-6-one
(9R, 11 E)- 12, 16-dimethyl- 14-oxa-3 ,7,17,23- tetraazapentacyclo[l 3.6.2. l~2,5~.0~4,9~.0~18,22~]tetracosa-
1 (21 ),2(24),4, 11 , 15 , 17, 19,22-octaen-6-one
(9R, 11 E)- 17-methyl-3 ,7,15,18,24- pentaazapentacyclo[l 4.6.2.1~2,5~.0~4,9~.0~19,23~]pentacosa-
1 (22),2(25),4, 11,16,18,20,23-octaen-6-one
(9S, 11 E)- 17-methyl-3 ,7, 15 , 18,24- pentaazapentacyclo[l 4.6.2.1~2,5~.0~4,9~.0~19,23~]pentacosa- 1 (22),2(25),4, 11,16,18,20,23-octaen-6-one
(9R, 11 Z)- 17-methyl-3 ,7,15,18,24- pentaazapentacyclo[l 4.6.2.1~2,5~.0~4,9~.0~19,23~]pentacosa-
1 (22),2(25),4, 11,16,18,20,23-octaen-6-one (9S,11Z)-17-methyl-3 ,7, 15,18,24- pentaazapentacyclo[l 4.6.2. l~2,5~.0~4,9~.0~19,23~]pentacosa-
1 (22),2(25),4, 11,16,18,20,23 -octaen-6-one;
(9R, 11 E, 13R)- 13, 16-dimethyl-3,7, 14,17,23- pentaazapentacyclo[l 3.6.2. l~2,5~.0~4,9~.0~18,22~]tetracosa-
1 (22),2(24),4, 11 , 15 , 17, 18,20,22-nonaen-6-one
(9S,l lE,13R)-13,16-dimethyl-3,7,14,17,23- pentaazapentacyclo[l 3.6.2.1~2,5~.0~4,9~.0~18,22~]tetracosa- 1 (22),2(24),4, 11 , 15, 17, 18,20,22-nonaen-6-one;
(9S,l lZ,13R)-13,16-dimethyl-3,7,14,17,23- pentaazapentacyclo[l 3.6.2. l~2,5~.0~4,9~.0~18,22~]tetracosa-
1 (22),2(24),4, 11 , 15, 17, 18,20,22-nonaen-6-one;
(9S,l lE,13S)-13,16-dimethyl-3,7,14,17,23- pentaazapentacyclo[l 3.6.2. l~2,5~.0~4,9~.0~18,22~]tetracosa- 1 (22),2(24),4, 11 , 15, 17, 18,20,22-nonaen-6-one;
(9S, 11 E)- 13, 13, 16-trimethyl-3,7, 14, 17,23- pentaazapentacyclo[l 3.6.2. l~2,5~.0~4,9~.0~18,22~]tetracosa-
1 (22),2(24),4, 11 , 15, 17, 18,20,22-nonaen-6-one;
(9R, 11 E, 13 S)- 13, 16-dimethyl-3,7, 14,17,23- pentaazapentacyclo[l 3.6.2. l~2,5~.0~4,9~.0~18,22~]tetracosa-
1 (22),2(24),4, 11 , 15, 17, 18,20,22-nonaen-6-one;
(9R, 11 Z, 13 S)- 13, 16-dimethyl-3,7, 14,17,23- pentaazapentacyclo[l 3.6.2. l~2,5~.0~4,9~.0~18,22~]tetracosa-
1 (22),2(24),4, 11 , 15, 17, 18,20,22-nonaen-6-one;
(9S)-16-methyl-3,7,14,17,23- pentaazapentacyclo[l 3.6.2.1~2,5~.0~4,9~.0~18,22~]tetracosa-
1 (22),2(24),4, 15,17,18,20,22-octaen-6-one;
(9R)-16-methyl-3,7, 14,17,23- pentaazapentacyclo[l 3.6.2.1~2,5~.0~4,9~.0~18,22~]tetracosa- 1 (22),2(24),4, 15,17,18,20,22-octaen-6-one;
(9S,13R)- 13,16-dimethyl-3,7, 14, 17,23- pentaazapentacyclo[l 3.6.2.1~2,5~.0~4,9~.0~18,22~]tetracosa-
1 (22),2(24),4, 15,17,18,20,22-octaen-6-one; (9S,13S)-13,16-dimethyl-3,7,14,17,23- pentaazapentacyclo[l 3.6.2.1~2,5~.0~4,9~.0~18,22~]tetracosa-
1 (22),2(24),4, 15,17,18,20,22-octaen-6-one;
(9R, 11 E)- 12, 16-dimethyl- 14-thia-3,7, 17,23- tetraazapentacyclo[l 3.6.2. l~2,5~.0~4,9~.0~18,22~]tetracosa-
1 (22),2(24),4, 11 , 15, 17, 18,20,22-nonaen-6-one;
(11E)-11, 16-dimethyl-3,7, 14, 17,23 - pentaazapentacyclo[l 3.6.2.1~2,5~.0~4,9~.0~18,22~]tetracosa-
1 (22),2(24),4, 11 , 15, 17, 18,20,22-nonaen-6-one;
(9S, 11 E)- 12, 16-dimethyl- 14-thia-3,7, 17,23 - tetraazapentacyclo[l 3.6.2. l~2,5~.0~4,9~.0~18,22~]tetracosa-
1 (22),2(24),4, 11 , 15, 17, 18,20,22-nonaen-6-one;
(9S, 13R)-l l,12-dihydroxy-13,16-dimethyl-3,7,14,17,23- pentaazapentacyclo[l 3.6.2.1~2,5~.0~4,9~.0~18,22~]tetracosa- 1 (22),2(24),4, 15,17,18,20,22-octaen-6-one;
17-methyl-3,7, 15,18,24- pentaazahexacyclo[l 4.6.2.2-1 l,14~.l~2,5~.0~4,9~.0~19,23~]heptacosa-
1 (23),2(27),4, 11 , 13, 16, 18, 19,21 ,23,25-undecaen-6-one;
(9R, 11 E)- 14, 16-dimethyl-3 ,7, 14,17,23- pentaazapentacyclo[l 3.6.2.1~2,5~.0~4,9~.0~18,22~]tetracosa-
1 (22),2(24),4, 11 , 15, 17, 18,20,22-nonaen-6-one;
(9R, 11 Z)- 14, 16-dimethyl-3 ,7, 14,17,23- pentaazapentacyclo[l 3.6.2.1~2,5~.0~4,9~.0~18,22~]tetracosa-
1 (22),2(24),4, 11 , 15, 17, 18,20,22-nonaen-6-one;
(9S,l lE,13R)-13-methyl-6-oxo-3,7,14,17,23- pentaazapentacyclo[l 3.6.2.1~2,5~.0~4,9~.0~18,22~]tetracosa-
1 (22),2(24),4, 11 , 15 , 17, 18,20,22-nonaene- 16-carbaldehyde;
(9S, 11 E)- 12-methyl-6-oxo-3 ,7, 14,17,23- pentaazapentacyclo[l 3.6.2.1~2,5~.0~4,9~.0~18,22~]tetracosa- 1 (22),2(24),4, 11,15,17,18,20,22-nonaene- 16-carbaldehyde;
(9R,13R)-13,16-dimethyl-3,7,14,17,23- pentaazapentacy clo [13.6.2.1-2,5-.0~4,9~.0—18 ,22~]tetracosa-
1 (22),2(24),4, 15, 17, 18,20,22-octaen- 11 -yn-6-one; (9R, 11 Z, 13R)- 13, 16-dimethyl-3,7, 14,17,23- pentaazapentacyclo[l 3.6.2. l~2,5~.0~4,9~.0~18,22~]tetracosa- 1 (22),2(24),4, 11 , 15, 17, 18,20,22-nonaen-6-one;
(9S, 11 E, 13R)-13-(hydroxymethyl)- 16-methyl-3,7, 14, 17,23- pentaazapentacyclo[l 3.6.2.1~2,5~.0~4,9~.0~18,22~]tetracosa-
1 (22),2(24),4, 11 , 15, 17, 18,20,22-nonaen-6-one;
(9S,1 IE)- 14, 16-dimethyl-3,7, 14,17,23- pentaazapentacyclo[l 3.6.2. l~2,5~.0~4,9~.0~18,22~]tetracosa- 1 (22),2(24),4, 11 , 15, 17, 18,20,22-nonaen-6-one;
(9S,1 lZ)-14,16-dimethyl-3,7,14,17,23- pentaazapentacyclo[l 3.6.2. l~2,5~.0~4,9~.0~18,22~]tetracosa- 1 (22),2(24),4, 11 , 15, 17, 18,20,22-nonaen-6-one;
(9S)- 17-methyl-4,7, 12,15,18,24- hexaazapentacyclo[l 4.6.2. l~2,5~.0~4,9~.0~19,23~]pentacosa- 1 (22),2,5(25), 16, 18,20,23 -heptaene-6, 11 -dione;
(9R)- 17-methyl-4,7, 12,15,18,24- hexaazapentacyclo[l 4.6.2. l~2,5~.0~4,9~.0~19,23~]pentacosa- l(22),2,5(25),16,18,20,23-heptaene-6,l l-dione;
(9S, 13R)-13-(hydroxymethyl)- 16-methyl-3,7,l 4, 17,23- pentaazapentacyclo[l 3.6.2. l~2,5~.0~4,9~.0~18,22~]tetracosa-
1 (22),2(24),4, 15,17,18,20,22-octaen-6-one;
(9S, 11 E, 13 S)- 13 -(hydroxymethyl)- 16-methyl-3,7, 14,17,23- pentaazapentacyclo[l 3.6.2. l~2,5~.0~4,9~.0~18,22~]tetracosa- 1 (22),2(24),4, 11 , 15, 17, 18,20,22-nonaen-6-one;
(9S, 11 Z, 13 S)- 13 -(hydroxymethyl)- 16-methyl-3,7, 14,17,23- pentaazapentacyclo[l 3.6.2.1~2,5~.0~4,9~.0~18,22~]tetracosa- 1 (22),2(24),4, 11 , 15, 17, 18,20,22-nonaen-6-one;
(9S, 11 E)- 12, 14, 16-trimethyl-3,7, 14,17,23- pentaazapentacyclo[l 3.6.2.1~2,5~.0~4,9~.0~18,22~]tetracosa- 1 (22),2(24),4, 11 , 15, 17, 18,20,22-nonaen-6-one;
(9S, 11 E, 13 S)- 13-(2 -hydroxy ethyl)- 16-methyl-3,7, 14,17,23- pentaazapentacyclo[l 3.6.2.1~2,5~.0~4,9~.0~18,22~]tetracosa- 1 (22),2(24),4, 11 , 15, 17, 18,20,22-nonaen-6-one; , 11 E, 13R)- 13-(2-hydroxy ethyl)- 16-methyl-3 ,7, 14,17,23- pentaazapentacyclo[l 3.6.2. l~2,5~.0~4,9~.0~18,22~]tetracosa- 1 (22),2(24),4, 11 , 15, 17, 18,20,22-nonaen-6-one;
, 11 E)-21 -fluoro- 12, 16-dimethyl-3,7,l 4, 17,23- pentaazapentacyclo[l 3.6.2. l~2,5~.0~4,9~.0~18,22~]n tetracosa-
1 (22),2(24),4, 11 , 15, 17, 18,20,22-nonaen-6-one;
- methyl-3,7,14,17,23-pentaazapentacyclo[l 3.6.2. l~2,5~.0~4,9~.0~18,22~]tetracosa-
1 (22),2(24),4, 15(23), 16, 18,20-heptaen- 11 -yn-6-one;
- methyl-12-oxa-3,7, 15,18,24- pentaazapentacyclo[l 4.6.2. l~2,5~.0~4,9~.0~19,23~]pentacosa- l(22),2(25),4,16,18,20,23-heptaen-6-one;
, 11 E)- 16-methyl- 14-(3-(methylsulfonyl)propyl)-3 ,7, 14,17,23- pentaazapentacyclo[l 3.6.2.1~2,5~.0~4,9~.0~18,22~]tetracosa- 1 (22),2(24),4, 11 , 15(23), 16, 18,20-octaen-6-one;
, 11 Z)- 16-methyl- 14-(3-(methylsulfonyl)propyl)-3 ,7, 14,17,23- pentaazapentacyclo[l 3.6.2.1~2,5~.0~4,9~.0~18,22~]tetracosa- 1 (22),2(24),4, 11 , 15(23), 16, 18,20-octaen-6-one;
, 11 E)-14-(2-hydroxyethyl)-16-methyl-3,7, 14,17,23- pentaazapentacyclo[l 3.6.2.1~2,5~.0~4,9~.0~18,22~]tetracosa- 1(22),2(24),4,1 l,15(23),16,18,20-octaen-6-one;
, 11 Z)- 14-(2-hydroxyethyl)-l 6-methyl-3,7, 14,17,23- pentaazapentacyclo[l 3.6.2.1~2,5~.0~4,9~.0~18,22~]tetracosa- 1 (22),2(24),4, 11 , 15(23), 16, 18,20-octaen-6-one;
,l lE,13S)-13,16-dimethyl-14-oxa-3,7,17,23- tetraazapentacyclo[13.6.2.1~2,5~.0~4,9~.0~18,22~]tetracosa- 1 (22),2(24),4, 11 , 15 (23), 16, 18,20-octaen-6-one;
, 11 E, 13R)-13, 16-dimethyl- 14-oxa-3,7, 17,23- tetraazapentacyclo[13.6.2.1~2,5~.0~4,9~.0~18,22~]tetracosa- 1 (22),2(24),4, 11 , 15 (23), 16, 18,20-octaen-6-one;
, 11 Z)- 13, 16-dimethyl- 14-oxa-3,7, 17,23- tetraazapentacyclo[l 3.6.2. l~2,5~.0~4,9~.0~18,22~]tetracosa- 1 (22),2(24),4, 11 , 15(23), 16, 18,20-octaen-6-one; (9R 17-methyl- 12-oxa-3,7, 15,18,24- pentaazapentacyclo[l 4.6.2. l~2,5~.0~4,9~.0~19,23~]pentacosa- l(22),2(25),4,16,18,20,23-heptaen-6-one;
(95)- 17-methyl- 12-oxa-3 ,7, 15,18,24- pentaazapentacyclo[l 4.6.2. l~2,5~.0~4,9~.0~19,23~]pentacosa- l(22),2(25),4,16,18,20,23-heptaen-6-one;
(9R,13R)-13,16-dimethyl-3,7,14,17,23- pentaazapentacyclo[l 3.6.2. l~2,5~.0~4,9~.0~18,22~]tetracosa- 1 (22),2(24),4, 15,17,18,20,22-octaen-6-one;
(9S, 11 E, 13 S)-21 -fluoro- 13,16-dimethyl-3,7, 14, 17,23- pentaazapentacyclo[l 3.6.2.1~2,5~.0~4,9~.0~18,22~]tetracosa- 1 (21 ),2(24),4, 11 , 15 , 17, 19,22-octaen-6-one;
(9S)- 17-methyl-3,7, 15 , 18,24- pentaazapentacyclo[l 4.6.2. l~2,5~.0~4,9~.0~19,23~]pentacosa- 1 (23),2(25),4, 16(24), 17, 19,21 -heptaen-6-one;
(9S,1 IE, 13 S)-l 6-methyl- 13-(2-(methylsulfonyl)ethyl)-3,7, 14, 17,23- pentaazapentacyclo[l 3.6.2.1~2,5~.0~4,9~.0~18,22~]tetracosa- 1 (22),2(24),4, 11 , 15, 17, 18,20,22-nonaen-6-one;
(9S,l lE,13R)-16-methyl-13-(2-(methylsulfonyl)ethyl)-3,7,14,17,23- pentaazapentacyclo[l 3.6.2.1~2,5~.0~4,9~.0~18,22~]tetracosa-
1 (22),2(24),4, 11 , 15, 17, 18,20,22-nonaen-6-one;
(l lE,13R)-16-methyl-13-(trifluoromethyl)-3,7,14,17,23- pentaazapentacyclo[l 3.6.2.1~2,5~.0~4,9~.0~18,22~]tetracosa- 1 (21 ),2(24),4, 11 , 15 , 17, 19,22-octaen-6-one;
(9S, 13 S)-21 -fluoro- 13,16-dimethy 1-3,7, 14,17,23- pentaazapentacyclo[l 3.6.2.1~2,5~.0~4,9~.0~18,22~]tetracosa- 1 (21 ),2(24),4, 15,17,19,22-heptaen-6-one;
tert-butyl (2-((9S,l lZ)-16-methyl-6-oxo-3,7,14,17,23- pentaazapentacyclo[l 3.6.2.1~2,5~.0~4,9~.0~18,22~]tetracosa- 1(21),2(24),4,1 l,15,17,19,22-octaen-14-yl)ethyl)carbamate; tert-butyl (2-((9S,l lE)-16-methyl-6-oxo-3,7,14,17,23- pentaazapentacyclo[l 3.6.2.1~2,5~.0~4,9~.0~18,22~]tetracosa- 1 (21 ),2(24),4, 11 , 15 , 17, 19,22-octaen- 14-yl)ethyl)carbamate; (9S, 11 Z)- 14-(2-aminoethyl)- 16-methyl-3,7, 14, 17,23- pentaazapentacyclo[l 3.6.2.1~2,5~.0~4,9~.0~18,22~]tetracosa-
1 (21 ),2(24),4, 11 , 15 , 17, 19,22-octaen-6-one;
(9S)-14-(2-hydroxyethyl)-l 6-methyl-3,7, 14, 17,23- pentaazapentacyclo[l 3.6.2.1~2,5~.0~4,9~.0~18,22~]tetracosa-
1 (22),2(24),4, 15,17,18,20,22-octaen-6-one;
(9S, 11 Z)- 16-methyl-l 4-(2-((2-(methylsulfonyl)ethyl)amino)ethyl)-3,7, 14, 17,23- pentaazapentacyclo[l 3.6.2. l~2,5~.0~4,9~.0~18,22~]tetracosa-
1 (21 ),2(24),4, 11 , 15 , 17, 19,22-octaen-6-one;
(9S,1 lE)-14-(2-aminoethyl)-16-methyl-3,7,14,17,23- pentaazapentacyclo[l 3.6.2. l~2,5~.0~4,9~.0~18,22~]tetracosa-
1 (21 ),2(24),4, 11 , 15 , 17, 19,22-octaen-6-one;
N-(2-((9S, 11 Z)- 16-methyl-6-oxo-3 ,7, 14,17,23- pentaazapentacyclo[l 3.6.2. l~2,5~.0~4,9~.0~18,22~]tetracosa- 1 (21 ),2(24),4, 11,15,17,19,22-octaen- 14-yl)ethyl)acetamide;
N-(2-((9S, 11 Z)- 16-methyl-6-oxo-3 ,7, 14,17,23- pentaazapentacyclo[l 3.6.2.1~2,5~.0~4,9~.0~18,22~]tetracosa-
1 (21 ),2(24),4, 11 , 15 , 17, 19,22-octaen- 14-yl)ethyl)methanesulfonamide; (9S, 11 E, 13 S)- 13 -(hydroxymethyl)- 16-methyl- 14-oxa-3 ,7, 17,23 - tetraazapentacyclo[13.6.2.1~2,5~.0~4,9~.0~18,22~]tetracosa-
1 (22),2(24),4, 11 , 15 , 17, 18,20,22-nonaen-6-one ;
(9S, 11 Z)- 13-(hydroxymethyl)- 16-methyl-l 4-oxa-3,7, 17,23- tetraazapentacyclo[l 3.6.2. l~2,5~.0~4,9~.0~18,22~]tetracosa-
1 (22),2(24),4, 11 , 15, 17, 18,20,22-nonaen-6-one;
(9S,1 lE,13R)-13-(hydroxymethyl)-16-methyl-14-oxa-3,7,17,23- tetraazapentacyclo[l 3.6.2. l~2,5~.0~4,9~.0~18,22~]tetracosa-
1 (22),2(24),4, 11 , 15, 17, 18,20,22-nonaen-6-one;
(9S, 11 E)- 16-(hydroxymethyl)- 12-methyl-3,7, 14, 17,23- pentaazapentacyclo[l 3.6.2.1~2,5~.0~4,9~.0~18,22~]tetracosa- 1 (22),2(24),4, 11 , 15, 17, 18,20,22-nonaen-6-one;
(9S, 11 E)- 16-methyl-l 4-(2-((2-(methylsulfonyl)ethyl)amino)ethyl)-3,7, 14, 17,23- pentaazapentacyclo[l 3.6.2.1~2,5~.0~4,9~.0~18,22~]tetracosa-
1 (21 ),2(24),4, 11 , 15 , 17, 19,22-octaen-6-one; and N-(2-((9S, 1 1 E)- 16-methyl-6-oxo-3 ,7, 14,17,23- pentaazapentacyclo[l 3.6.2.1~2,5~.0~4,9~.0~18,22~]tetracosa- 1 (21 ),2(24),4, 11 ,15,17,19,22-octaen- 14-yl)ethyl)acetamide.
Another aspect of the current invention relates to compounds having the general structure of Formula 4
Figure imgf000022_0001
wherein R1 is H;
wherein R2 is Ci_2 alkyl;
wherein Z is CH2 or NH; and
wherein Q is optionally substituted C4-C5 alkenylenyl, or optionally substituted Ci_2 alkylenyl-aminocarbonyl- Ci_2 alkylenyl,
and a pharmaceutically acceptable salt thereof.
In another embodiment, R2 is methyl; and a pharmaceutically acceptable salt thereof.
In another embodiment, Z is NH; and a pharmaceutically acceptable salt thereof. In another embodiment, Q is 3-methylbut-2-enylenyl,
ethylenylaminocarbonylmethylenyl, (2-methylethylenyl)aminocarbonylmethylenyl, or methylenylaminocarbonylmethylenyl; and a pharmaceutically acceptable salt thereof.
A family of specific compounds of particular interest within Formula 1 consists of compounds and a pharmaceutically-acceptable salt thereof as follows:
(9S, 14R)- 14,17-dimethyl-4,7, 12,15,18,24- hexaazapentacyclo[l 4.6.2.1~2,5~.0~4,9~.0~19,23~] pentacosa- l(22),2,5(25),16,18,20,23-heptaene-6,l l -dione;
(9R, 14R)- 14, 17-dimethyl-4,7, 12,15,18,24- hexaazapentacyclo[l 4.6.2.1~2,5~.0~4,9~.0~19,23~] pentacosa- l(22),2,5(25),16,18,20,23-heptaene-6,l l -dione;
17-methyl-4,7, 12, 15,18,24- hexaazapentacyclo[l 4.6.2. l~2,5~.0~4,9~.0~19,23~]pentacosa- l(22),2,5(25),16,18,20,23-heptaene-6,l l -dione 6,1 1 -dione; 16-methyl-4,7,12,17,23-pentaazapentacyclo[l 3.6.2. l~2,5~.0~4,9~.0~18,22~]tetracosa-
1 (21 ),2,5(24), 15,17,19,22-heptaene-6, 1 1 -dione; and
(1 1E)-12,16-dimethyl-4,7, 14,17,23- pentaazapentacyclo[l 3.6.2.1~2,5~.0~4,9~.0~18,22~]tetracosa- 1 (21 ),2,5(24), 1 1 , 15 , 17, 19,22-octaen-6-one.
Another aspect of the current invention relates to compounds having the general structure of Formula 5
Figure imgf000023_0001
wherein ring d forms a 4-7 membered nitrogen containing heterocyclyl;
wherein R1 is H;
wherein R2 is H or Ci_2 alkyl; and
wherein Q is optionally substituted C3-C4 alkenylenyl;
and a pharmaceutically acceptable salt thereof.
In another embodiment, R2 is methyl; and a pharmaceutically acceptable salt thereof.
In another embodiment, ring d is morpholinyl or 2-oxo-oxazolidinyl; and a pharmaceutically acceptable salt thereof.
In another embodiment, ring d is
Figure imgf000023_0002
and a
pharmaceutically acceptable salt thereof.
In another embodiment, Q is 2-propenylenyl, or 3-propenylenyl; and a pharmaceutically acceptable salt thereof.
A family of specific compounds of particular interest within Formula 1 consists of compounds and a pharmaceutically-acceptable salt thereof as follows: (9S, 1 1 Z, 13 S)-20-methyl- 15-oxa-3 ,7, 18,21 ,27- pentaazahexacyclo[l 7.6.2.1-2, 5~.0~4,9~.0-13,18~.0-22,26~]octacosa-
1 (26),2(28),4, 11 ,19(27),20,22,24-octaen-6-one;
(9S, 1 1 E, 13 S)-20-methyl- 15-oxa-3 ,7, 18,21 ,27- pentaazahexacyclo[l 7.6.2.1-2, 5~.0~4,9~.0-13,18-.0-22,26~]octacosa-
1 (26),2(28),4, 11 ,19(27),20,22,24-octaen-6-one; and
(9S, 1 1 Z, 13 S)- 19-methyl- 15-oxa-3 ,7, 17,20,26- pentaazahexacyclo[16.6.2.1~2,5~.0~4,9~.0~13,17~.0~21,25~]heptacosa- 1(25),2(27),4, 11,18(26), 19,2 l,23-octaene-6,16-dione.
Another aspect of the current invention relates to compounds having the general structure of Formula 1 '
Figure imgf000024_0001
wherein
ring a is a ring that together with the 2 carbon atoms to which it attaches, forms a phenyl ring or a 5-6 membered heterocyclic ring;
X is N or CH;
Z is O, S, NRb, C=0 or C(Rb )2;
Q is a linker saturated or unsaturated chain;
q is N, NH, CH or CH2;
r is CH, NH, CH2 or N;
s is N or CH;
w is CH, CH2 , N or NH;
ring b is unsaturated, or partially saturated;
ring c is saturated, or partially saturated;
R1 is H, or halo; R is H, haloalkyl, hydroxyalkyl, alkyl, alkoxy, HC(=0)-, carboxy, alkoxycarbonyl, cycloalkyl, or substituted or unsubstituted heterocyclyl;
Rb is H, alkyl, haloalkyl, hydroxyalkyl, alkylsulfonylalkyl, BOC-aminoalkyl, aminoalkyl, cyanoalkyl, alkoxyalkyl, alkylsulfonylalkylaminoalkyl, alkylsulfonylaminoalkyl, alkylcarbonylaminoalkyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted aryl, unsubstituted or substituted arylalkyl or unsubstituted or substituted heterocyclyl; and
Re is H, -PO(Oalkyl)2, alkylcarbonyl, alkylcarbonyloxyalkoxycarbonyl, alkoxycarbonyl, aminoalkylcarbonyloxyalkoxycarbonyl or hydroxyalkyl;
and a pharmaceutically acceptable salt thereof.
In another embodiment, ring a is
Figure imgf000025_0001
R1 is H, or halo; and a pharmaceutically acceptable salt thereof.
Another aspect of the current invention relates to compounds having the general structure of Formulas l 'a-l 'f
Figure imgf000025_0002
Figure imgf000026_0001
wherein X is N or CH; Z is O, S, NRb, C=0, or C(Rb )2; Q is a 3-8 membered linker that attaches with Z;
Figure imgf000026_0002
; R1 is H, or halo; R2 is H, Ci_6 haloalkyl, Ci_6 hydroxyalkyl, Ci_6 alkyl, C e alkoxy, HC(=0)-, carboxy, Ci_6 alkoxycarbonyl, C3.6 cycloalkyl, or substituted or unsubstituted heterocyclyl; Rb is H, Ci_6 alkyl, Ci_6 haloalkyl, Ci_6 hydroxyalkyl, Ci_6 alkylsulfonyl-Ci.6 alkyl, BOC-amino-Ci_6 alkyl, amino-Ci_6 alkyl, cyano-Ci_6-alkyl, Ci.6-alkoxy-Ci_6-alkyl, Ci_6-alkylsulfonyl-Ci_6-alkylamino-Ci_6- alkyl, Ci_6 alkylsulfonylamino-Ci_6 alkyl, Ci_6 alkylcarbonylamino-Ci_6-alkyl, unsubstituted or substituted C3_6-cycloalkyl, unsubstituted or substituted aryl, unsubstituted or substituted aryl-Ci_6-alkyl or unsubstituted or substituted heterocyclyl; R6 is H; and R7 is H or Cu alkyl; and a pharmaceutically acceptable salt thereof.
Another aspect of the current invention relates to compounds having the general structure of Formulas l 'b and l 'e
Figure imgf000026_0003
wherein X is N or CH; Z is O, S, NRb, C=0, or C(Rb )2; Q is optionally substituted C4-C6 alkenylenyl, optionally substituted C4-C5 alkylenyl, optionally substituted C4-C5 alkynylenyl, optionally substituted cycloalkyl-C2-C4 alkenylenyl, optionally substituted phenyl-Ci_2 alkylenyl, -(CH2)n-0-(CH2)m-, or optionally substituted Ci_2 alkylenyl-aminocarbonyl-Ci_2 alkylenyl, when Q attaches to Z; or wherein Q is optionally substituted 5-7 membered heterocyclyl-alkyl, or optionally substituted 5-7 membered heterocyclyl-alkenyl, when Q incorporates Z into the heterocyclic ring; ring
Figure imgf000027_0001
R1 is H, or halo; R2 is H, haloalkyl, hydroxyalkyl, alkyl, alkoxy,
HC(=0)-, carboxy, alkoxycarbonyl, cycloalkyl, or substituted or unsubstituted heterocyclyl; Rb is H, Ci_4 alkyl, Ci_6-haloalkyl, Ci.4-hydroxyalkyl, Ci.4-alkylsulfonyl-Ci. 4-alkyl, BOC-amino-Ci_4-alkyl, Ci.4-aminoalkyl,
Figure imgf000027_0002
Ci -alkoxy-Ci_4-alkyl, Ci_4-alkylsulfonyl-Ci.4-alkylamino-Ci_4-alkyl, Ci_4-alkylsulfonylamino-Ci_4-alkyl, C1.4- alkylcarbonylamino-Ci -alkyl, unsubstituted or substituted C3.6-cycloalkyl, unsubstituted or substituted phenyl, unsubstituted or substituted phenyl-Ci_2-alkyl or unsubstituted or substituted 4-6 memebered heterocyclyl; R6 is H; and R7 is H; and a pharmaceutically acceptable salt thereof.
In another embodiment, Z is O, S, NRb, or CHRb; Rb is H, Ci_2 alkyl, Q_2 hydroxyalkyl, Ci_2 alkylsulfonyl-Cu-alkyl, BOC-amino-Ci_2 alkyl, amino-Ci_2 alkyl, Ci_2 alkylsulfonyl-Cij alkylamino-Ci_2 alkyl, cyano-Cu alkyl, Ci_2 alkylsulfonylamino-Ci_2 alkyl or Ci_2 alkylcarbonylamino-Ci_2 alkyl; and a pharmaceutically acceptable salt thereof.
In another embodiment, R1 is H or fluoro; and a pharmaceutically acceptable salt thereof.
In another embodiment, ring a is
Figure imgf000027_0003
; and R is H or fluoro; and a pharmaceutically acceptable salt thereof.
In another embodiment, Re is H, methylcarbonyl, -PO(0-methyl)2, -PO(0-tert- butyl)2, methylcarbonyloxy -methoxycarbonyl, tert-butylcarbonyloxy-methoxycarbonyl, isopropylcarbonyloxy-methoxycarbonyl, 1 ,5 -diaminopentyl-carbonyloxy- methoxycarbonyl, butoxycarbonyl or hydroxymethyl; and a pharmaceutically acceptable salt thereof.
In another embodiment, together form
Figure imgf000027_0004
1
Figure imgf000028_0001
Figure imgf000029_0001
-28-
1
Figure imgf000030_0001
Figure imgf000031_0001
Figure imgf000032_0001
and a pharmaceutically acceptable salt thereof.
In another embodiment, R2 is H, Ci_2 alkyl, HC(=0)- or C1.2 hydroxyalkyl; and a pharmaceutically acceptable salt thereof.
In another embodiment, R2 is H, methyl, HC(=0)- or hydroxy methyl; and a pharmaceutically acceptable salt thereof.
In another embodiment, R2 is H; and a pharmaceutically acceptable salt thereof.
In another embodiment, Z is O; and a pharmaceutically acceptable salt thereof.
In another embodiment, Z is NH; and a pharmaceutically acceptable salt thereof.
The current invention relates to compounds of Formula 3'
Figure imgf000032_0002
wherein R1 is H or fluoro; R2 is H, HC(=0)- , Ci_2 alkyl or Ci_2 hydroxyalkyl; Z is O, S or
NR ; Rb is H, Ci-2 alkyl, Ci-2 hydroxyalkyl, Ci-2 alkylsulfonyl-Cu-alkyl, BOC- amino- Ci_2-alkyl, amino-Ci_2-alkyl, Ci.2-alkylsulfonyl-Ci.3-alkylamino-Ci.2-alkyl, Q. 2 alkylsulfonylamino-Ci_2-alkyl, cyano-Ci_4-alkyl or C1.2 alkylcarbonylamino-Ci.2- alkyl; Re is H, -PO(0-Ci_2-alkyl)2, Ci_ alkylcarbonyl, Ci_ -alkylcarbonyloxy-Ci_2- alkoxycarbonyl, Ci.4-alkoxycarbonyl, amino-Ci_6-alkylcarbonyloxy- C1.2- alkoxycarbonyl or Ci_ hydroxyalkyl; Q is optionally substituted C4-C5 alkylenyl, optionally substituted C -C6 alkenylenyl, optionally substituted C -C5 alkynylenyl, optionally substituted phenyl-Ci_2 alkylenyl, optionally substituted cycloalkyl-C2-C alkenylenyl, or -(CH2)n-0-(CH2)m- ; n is 1-2; and m is 1-2; provided n+m = 3 or 4; and a pharmaceutically acceptable salt thereof.
In another embodiment, R1 is H; and a pharmaceutically acceptable salt thereof. In another embodiment, R2 is H, HC(=0)- , methyl or hydroxymethyl; and a pharmaceutically acceptable salt thereof.
In another embodiment, R2 is H or methyl; and a pharmaceutically acceptable salt thereof.
In another embodiment, Z is O or S; and a pharmaceutically acceptable salt thereof.
In another embodiment, Z is HN, methylamino, hydroxyethylamino, BOC- aminoethylamino, aminoethylamino, cyanopropylamino,
methylsulfonylethylaminoethylamino, methylsulfonylaminoethylamino,
methylcarbonylaminoethylammo or methylsulfonylpropylammo; and a pharmaceutically acceptable salt thereof.
In another embodiment, Q is butylenyl, 2-methylbutylenyl, 3-methylbutylenyl, 4- methylbutylenyl, 4-hydroxymethylbutylenyl, 2,3-dihydroxy-4-methylbutylenyl, but-2- enylenyl, 4-hydroxymethylbut-2-enylenyl, 4-hydroxyethylbut-2-enylenyl, 4-methoxybut- 2-enylenyl, 2-methylbut-2-enylenyl, 3-methylbut-2-enylenyl, 4-methylbut-2-enylenyl, 4,4-dimethylbut-2-enylenyl, 4-trifluoromethylbut-2-enylenyl, 4-(methylsulfonylethyl)but- 2-enylenyl, 3-methylbut-2-enylenyl, 2-methylbut-2-enylenyl, but-2-ynylenyl, 4- methylbut-2-ynylenyl, pentylenyl, pent-2-enylenyl, 2-methylpent-2-enylenyl, -(CH2)2-0- (CH2)2- , 3-(eth-2-enylenyl)cyclobutyl or phenylmethylenyl; and a pharmaceutically acceptable salt thereof.
In another embodiment, Re is H; and a pharmaceutically acceptable salt thereof.
Another family of specific compounds of particular interest within Formula 1 and 1 ' consists of compounds and a pharmaceutically-acceptable salt thereof as follows: (9S, 11Z, 13R)-13,16-dimethyl-3,7,14,17,23-pentaazapentacyclo[13.6.2.1-2,5~.0-
4,9~.0~18,22~]tetracosa-l(22),2(24),4,l l,15,17,18,20,22-nonaen-6-one;
(9S, HE)-12,16-dimethyl-3,7,14,17,23-pentaazapentacyclo[13.6.2.1-2,5~.0- 4,9~.0~18,22~]tetracosa- 1 (21 ),2(24),4,11 , 15, 17, 19,22-octaen-6-one;
(9S, 1 lZ)-12,16-dimethyl-3,7,14,17,23-pentaazapentacyclo[13.6.2.1-2,5~.0- 4,9~.0~18,22~]tetracosa-l(22),2(24),4,l l,15,17,18,20,22-nonaen-6-one;
(9S, 13S)-13,16-dimethyl-3,7,14,17,23-pentaazapentacyclo[13.6.2.1-2,5~.0- 4,9~.0~18,22~]tetracosa-l(22),2(24),4,15,17,18,20,22-octaen-6-one; and
(9S, HZ)-12,14,16-trimethyl-3,7,14,17,23-pentaazapentacyclo[13.6.2.1-2,5~.0- 4,9~.0~18,22~]tetracosa-l(22),2(24),4,l l,15,17,18,20,22-nonaen-6-one.
Another aspect of the invention relates to a pharmaceutical composition comprising a compound of formulas (1 and 1 ') and a pharmaceutically-acceptable diluent or carrier.
Another aspect of the invention relates to the use of a compound according to any of the above embodiments as a medicament.
Another aspect of the invention relates to the use of a compound according to any of the above embodiments in the manufacture of a medicament for the treatment of cancer.
The compounds of this invention may have in general several asymmetric centers and are typically depicted in the form of racemic mixtures. This invention is intended to encompass racemic mixtures, partially racemic mixtures and separate enantiomers and diasteromers.
The present invention includes all pharmaceutically acceptable isotopically- labelled compounds of the present invention wherein one or more atoms are replaced by atoms having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number which predominates in nature.
Examples of isotopes suitable for inclusion in the compounds of the invention include, but are not limited to, isotopes of hydrogen, such as 2H and 3H, carbon, such as
11 C, 13 C and 14 C, chlorine, such as 38 CI, fluorine, such as 18 F, iodine, such as 123 I and 125 I, nitrogen, such as 13 N and 15 N, oxygen, such as 15 O, 17 O and 18 O, phosphorus, such as 32 P, and sulphur, such as 35S.
Certain isotopically-labelled compounds of the present invention, for example, those incorporating a radioactive isotope, are useful in drug and/or substrate tissue distribution studies. The radioactive isotopes tritium, i.e. 3H, and carbon-14, i.e. 14C, are particularly useful for this purpose in view of their ease of incorporation and ready means of detection.
Substitution with heavier isotopes such as deuterium, i.e. 2H, may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements, and hence may be preferred in some circumstances.
Substitution with positron emitting isotopes, such as 11 C, 18 F, 15 O and 13 N, can be useful in Positron Emission Topography (PET) studies for examining substrate receptor occupancy.
Isotopically-labeled compounds of the present invention can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the accompanying Examples and Preparations using an appropriate isotopically-labeled reagent in place of the non-labeled reagent previously employed.
Pharmaceutically acceptable solvates in accordance with the invention include those wherein the solvent of crystallization may be isotopically substituted, e.g. D20, de- acetone, de-DMSO.
Specific embodiments of the present invention include the compounds exemplified in the Examples below and their pharmaceutically acceptable salts, complexes, solvates, polymorphs, stereoisomers, metabolites, prodrugs, and other derivatives thereof, Unless otherwise specified, the following definitions apply to terms found in the specification and claims:
The term "H" denotes a single hydrogen atom. This radical may be attached, for example, to an oxygen atom to form a hydroxyl radical.
Where the term "alkyl" is used, either alone or within other terms such as
"haloalkyl" and "alkylamino", it embraces linear or branched radicals having one to about twelve carbon atoms. More preferred alkyl radicals are "lower alkyl" radicals having one to about six carbon atoms. Examples of such radicals include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, teri-butyl, pentyl, isoamyl, hexyl and the like. Even more preferred are lower alkyl radicals having one or two carbon atoms. The term "alkylenyl" embraces bridging divalent alkyl radicals such as methylenyl and ethylenyl.
The term "alkenyl" embraces linear or branched radicals having at least one carbon-carbon double bond of two to about twelve carbon atoms. More preferred alkenyl radicals are "lower alkenyl" radicals having two to about six carbon atoms. Most preferred lower alkenyl radicals are radicals having two to about four carbon atoms. Examples of alkenyl radicals include ethenyl, propenyl, allyl, propenyl, butenyl and 4- methylbutenyl. The terms "alkenyl" and "lower alkenyl", embrace radicals having "cis" and "trans" orientations, or alternatively, "E" and "Z" orientations. The term
"alkenylenyl" embraces bridging divalent alkenyl radicals.
The term "alkynyl" embraces linear or branched radicals having two to about twelve carbon atoms. More preferred alkynyl radicals are "lower alkynyl" radicals having two to about six carbon atoms. Examples of such radicals include ethynyl and the like. Even more preferred are lower alkynyl radicals having two to three carbon atoms. The term "alkynylenyl" embraces bridging divalent alkynyl radicals.
The term "halo" means halogens such as fluorine, chlorine, bromine or iodine atoms.
The term "haloalkyl" embraces radicals wherein any one or more of the alkyl carbon atoms is substituted with halo as defined above. Specifically embraced are monohaloalkyl, dihaloalkyl and poly haloalkyl radicals including perhaloalkyl. A monohaloalkyl radical, for one example, may have either an iodo, bromo, chloro or fluoro atom within the radical. Dihalo and polyhaloalkyl radicals may have two or more of the same halo atoms or a combination of different halo radicals. "Lower haloalkyl" embraces radicals having 1-6 carbon atoms. Even more preferred are lower haloalkyl radicals having one to three carbon atoms. Examples of haloalkyl radicals include fluorom ethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl and dichloropropyl. "Perfluoroalkyl" means alkyl radicals having all hydrogen atoms replaced with fluoro atoms. Examples include trifluoromethyl and pentafluoroethyl.
The term "hydroxyalkyl" embraces linear or branched alkyl radicals having one to about ten carbon atoms any one of which may be substituted with one or more hydroxyl radicals. More preferred hydroxyalkyl radicals are "lower hydroxyalkyl" radicals having one to six carbon atoms and one or more hydroxyl radicals. Examples of such radicals include hydroxymethyl, hydroxy ethyl, hydroxypropyl, hydroxybutyl and hydroxyhexyl. Even more preferred are lower hydroxyalkyl radicals having one to three carbon atoms.
The term "cyanoalkyl" embraces linear or branched alkyl radicals having one to about ten carbon atoms any one of which may be substituted with one or more cyano radicals. More preferred cyanoalkyl radicals are "lower cyanoalkyl" radicals having one to six carbon atoms and one or more cyano radicals. Examples of such radicals include cyanomethyl, cyanopropyl, and cyanohexyl.
The term "alkoxy" embrace linear or branched oxy-containing radicals each having alkyl portions of one to about ten carbon atoms. More preferred alkoxy radicals are "lower alkoxy" radicals having one to six carbon atoms. Examples of such radicals include methoxy, ethoxy, propoxy, butoxy and teri-butoxy. Even more preferred are lower alkoxy radicals having one to three carbon atoms. Alkoxy radicals may be further substituted with one or more halo atoms, such as fluoro, chloro or bromo, to provide "haloalkoxy" radicals. Even more preferred are lower haloalkoxy radicals having one to three carbon atoms. Examples of such radicals include fluoromethoxy, chloromethoxy, trifluoromethoxy, trifluoroethoxy, fluoroethoxy and fluoropropoxy.
The term "alkoxyalkyl" embraces linear or branched alkyl radicals having one to about ten carbon atoms any one of which may be substituted with one or more alkoxyl radicals. More preferred alkoxyalkyl radicals are "lower alkoxyalkyl" radicals having one to six carbon atoms and one or more alkoxyl radicals. Examples of such radicals include methoxymethyl, ethoxyethyl, propoxypropyl and methoxyethyl. Even more preferred are lower alkoxyalkyl radicals having one to three carbon atoms.
The term "aryl", alone or in combination, means a carbocyclic aromatic system containing one or two rings wherein such rings may be attached together in a fused manner. The term "aryl" embraces aromatic radicals such as phenyl, naphthyl, indenyl, tetrahydronaphthyl, and indanyl. More preferred aryl is phenyl. Said "aryl" group may have 1 to 3 substituents such as lower alkyl, hydroxyl, halo, haloalkyl, nitro, cyano, alkoxy and lower alkylamino. Phenyl substituted with -0-CH2-0- forms the aryl benzodioxolyl substituent.
The term "heterocyclyl" embraces saturated, partially saturated and unsaturated heteroatom-containing ring radicals, where the heteroatoms may be selected from nitrogen, sulfur and oxygen. It does not include rings containing -Ο-Ο-,-Ο-S- or -S-S- portions. Said "heterocyclyl" group may have 1 to 3 substituents such as hydroxyl, Boc, halo, haloalkyl, cyano, lower alkyl, lower aralkyl, oxo, lower alkoxy, amino and lower alkylamino.
Examples of saturated heterocyclic radicals include saturated 3 to 6-membered heteromonocyclic groups containing 1 to 4 nitrogen atoms [e.g. pyrrolidinyl, imidazolidinyl, piperidinyl, pyrrolinyl, piperazinyl]; saturated 3 to 6-membered heteromonocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms [e.g. morpholinyl]; saturated 3 to 6-membered heteromonocyclic group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms [e.g., thiazolidinyl]. Examples of partially saturated heterocyclyl radicals include dihydrothienyl, dihydropyranyl, dihydrofuryl and dihydrothiazolyl.
Examples of unsaturated heterocyclic radicals, also termed "heteroaryl" radicals, include unsaturated 5 to 6 membered heteromonocyclyl group containing 1 to 4 nitrogen atoms, for example, pyrrolyl, imidazolyl, pyrazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, triazolyl [e.g., 4H-l,2,4-triazolyl, lH-l,2,3-triazolyl, 2H- 1,2, 3 -triazolyl]; unsaturated 5- to 6-membered heteromonocyclic group containing an oxygen atom, for example, pyranyl, 2-furyl, 3-furyl, etc.; unsaturated 5 to 6-membered heteromonocyclic group containing a sulfur atom, for example, 2-thienyl, 3-thienyl, etc.; unsaturated 5- to 6-membered heteromonocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, for example, oxazolyl, isoxazolyl, oxadiazolyl [e.g., 1,2,4- oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl]; unsaturated 5 to 6-membered heteromonocyclic group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms, for example, thiazolyl, thiadiazolyl [e.g., 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5- thiadiazolyl].
The term also embraces radicals where heterocyclic radicals are fused/condensed with aryl radicals: unsaturated condensed heterocyclic group containing 1 to 5 nitrogen atoms, for example, indolyl, isoindolyl, indolizinyl, benzimidazolyl, quinolyl, isoquinolyl, indazolyl, benzotriazolyl, tetrazolopyridazinyl [e.g., tetrazolo [l,5-b]pyridazinyl];
unsaturated condensed heterocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms [e.g. benzoxazolyl, benzoxadiazolyl]; unsaturated condensed heterocyclic group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms [e.g., benzothiazolyl, benzothiadiazolyl]; and saturated, partially unsaturated and unsaturated condensed heterocyclic group containing 1 to 2 oxygen or sulfur atoms [e.g. benzofuryl, benzothienyl, 2,3-dihydro-benzo[l,4]dioxinyl and dihydrobenzofuryl]. Preferred heterocyclic radicals include five to ten membered fused or unfused radicals. More preferred examples of heteroaryl radicals include quinolyl, isoquinolyl, imidazolyl, pyridyl, thienyl, thiazolyl, oxazolyl, furyl, and pyrazinyl. Other preferred heteroaryl radicals are 5- or 6-membered heteroaryl, containing one or two heteroatoms selected from sulfur, nitrogen and oxygen, selected from thienyl, furyl, pyrrolyl, indazolyl, pyrazolyl, oxazolyl, triazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, pyridyl, piperidinyl and pyrazinyl.
Particular examples of non-nitrogen containing heteroaryl include pyranyl, 2- furyl, 3-furyl, 2-thienyl, 3-thienyl, benzofuryl, benzothienyl, and the like.
Particular examples of partially saturated and saturated heterocyclyl include pyrrolidinyl, imidazolidinyl, piperidinyl, pyrrolinyl, pyrazolidinyl, piperazinyl, morpholinyl, tetrahydropyranyl, thiazolidinyl, dihydrothienyl, 2,3-dihydro- benzo[l,4]dioxanyl, indolinyl, isoindolinyl, dihydrobenzothienyl, dihydrobenzofuryl, isochromanyl, chromanyl, 1,2-dihydroquinolyl, 1,2,3,4-tetrahydro-isoquinolyl, 1,2,3,4- tetrahydro-quinolyl, 2,3,4,4a,9,9a-hexahydro-lH-3-aza-fluorenyl, 5,6,7-trihydro-l,2,4- triazolo[3,4-a]isoquinolyl, 3,4-dihydro-2H-benzo[l,4]oxazinyl, benzo[l,4]dioxanyl, 2,3- dihydro-lH- '-benzo[d]isothiazol-6-yl, dihydropyranyl, dihydrofuryl and
dihydrothiazolyl, and the like.
"Heterocycle" means a ring comprising at least one carbon atom and at least one other atom selected from N, O and S. Examples of heterocycles that may be found in the claims include, but are not limited to, the following:
Figure imgf000039_0001
Figure imgf000040_0001
The terms "carboxy" or "carboxyl", whether used alone or with other terms, such as "carboxyalkyl", denotes -C02H.
The term "carbonyl", whether used alone or with other terms, such as
"aminocarbonyl", denotes -(C=0)-.
The term "alkylcarbonyl" denotes a carbonyl radical substituted with an alkyl group.
The term "alkoxycarbonyl" denotes an ester group, containing an alkoxy substituted carbonyl.
The term "aminocarbonyl" denotes an amide group of the formula -C(=0)NH2. The terms "aralkyl" or "arylalkyl" embraces aryl-substituted alkyl radicals. Preferable aralkyl radicals are "lower aralkyl" radicals having aryl radicals attached to alkyl radicals having one to six carbon atoms. Even more preferred are "phenylalkylenyl" attached to alkyl portions having one to three carbon atoms. Examples of such radicals include benzyl, diphenylmethyl and phenylethyl. The aryl in said aralkyl may be additionally substituted with halo, alkyl, alkoxy, halkoalkyl and haloalkoxy. The term "optionally substituted phenylalkylenyl" when used in a linker may be divalent on either the alkyl portion or the phenyl ring and the alkyl portion.
The terms "arylalkenyl" embraces aryl-substituted alkenyl radicals. Preferable aralkyl radicals are "lower arylalkenyl" radicals having aryl radicals attached to alkenyl radicals having two to six carbon atoms. Even more preferred are "phenylalkenyl" where a phenyl ring is attached to alkenyl portions having two to three carbon atoms. The aryl in said arylalkenyl may be additionally substituted with halo, alkyl, alkoxy, halkoalkyl and haloalkoxy.
The terms "cycloalkylalkyl" embraces cycloalkyl-substituted alkyl radicals. Preferable cycloalkylalkyl radicals are "C3.6 cycloalkyl-Ci_6 alkyl" radicals having C3.6 cycloalkyl radicals attached to alkyl radicals having one to six carbon atoms. The cycloalkyl in said cycloalkylalkyl may be additionally substituted with halo, alkyl, and the like.
The terms "cycloalkylalkenyl" embraces cycloalkyl-substituted alkenyl radicals. Preferable cycloalkylalkenyl radicals are "C3.6 cycloalkyl-C2-6 alkenyl" radicals having C3. 6 cycloalkyl radicals attached to alkenyl radicals having two to six carbon atoms. The cycloalkyl in said cycloalkylalkenyl may be additionally substituted with halo, alkyl, and the like.
The terms "heterocyclylalkyl" embraces heterocyclyl-substituted alkyl radicals. Preferable heterocyclylalkyl radicals are "3-7 membered heterocyclyl-Ci.6 alkyl" radicals having 3-7 membered heterocyclyl radicals attached to alkyl radicals having one to six carbon atoms. Other heterocyclylalkyl radicals are "5-7 membered heterocyclyl-Cu alkyl" radicals having 5-6 membered heterocyclyl radicals attached to alkyl radicals having one to six carbon atoms. The heterocyclyl in said 3-7 membered heterocyclylalkyl may be additionally substituted with halo, alkyl, and the like.
The term "aryloxy" embraces optionally substituted aryl radicals, as defined above, attached to an oxygen atom. Suitable aryloxy radicals may be phenyloxy and the like.
The term "alkylamino" embraces "N-alkylamino" and "Ν,Ν-dialkylamino" where amino groups are substituted with one alkyl radical and with two independent alkyl radicals, respectively. More preferred alkylamino radicals are "lower alkylamino" radicals having one or two alkyl radicals of one to six carbon atoms, attached to a nitrogen atom. Even more preferred are lower alkylamino radicals having one to three carbon atoms. Suitable alkylamino radicals may be mono or dialkylamino such as N-methylamino, N- ethylamino, N,N-dimethylamino, Ν,Ν-diethylamino and the like.
The term "alkenylamino" embraces "N-alkenylamino" where amino groups are substituted with one alkenyl radical. More preferred alkenylamino radicals are "lower alkenylamino" radicals having an alkenyl radical of two to six carbon atoms, attached to a nitrogen atom. Even more preferred are lower alkenylamino radicals having two to three carbon atoms.
The term "arylamino" denotes amino groups which have been substituted with one or two aryl radicals, such as N-phenylamino. The arylamino radicals may be further substituted on the aryl ring portion of the radical. The term "cycloalkylamino" denotes amino groups which have been substituted with one or two cycloalkyl radicals, such as N-cyclohexylamino. The cycloalkylamino radicals may be further substituted on the cycloalkyl ring portion of the radical.
The term "heteroarylamino" denotes amino groups which have been substituted with one or two heteroaryl radicals, such as N-thienylamino. The "heteroarylamino" radicals may be further substituted on the heteroaryl ring portion of the radical.
The term "heterocyclylamino" denotes amino groups which have been substituted with one or two heterocyclyl radicals, such as N-piperidinylamino. The
"heterocyclylamino" radicals may be further substituted on the heterocyclyl ring portion of the radical.
The term "aralkylamino" denotes amino groups which have been substituted with one or two aralkyl radicals. More preferred are phenyl-Ci-C3-alkylamino radicals, such as N-benzylamino. The aralkylamino radicals may be further substituted on the aryl ring portion.
The term "cycloalkylalkylamino" denotes amino groups which have been substituted with one or two cycloalkylalkyl radicals. More preferred are C1-3 cycloalkyl- Ci-C3-alkylamino radicals. The cycloalkylalkylamino radicals may be further substituted on the cycloalkyl portion.
The term "heterocyclylalkylamino" denotes amino groups which have been substituted with one or two heterocyclylalkyl radicals. More preferred are 3-7 membered heterocyclyl-Ci-C6-alkylamino radicals. Other preferred are 5-6 membered heterocyclyl- Ci-C3-alkylamino radicals. The heterocyclylalkylamino radicals may be further substituted on the cycloalkyl portion.
The term "aminoalkyl" embraces linear or branched alkyl radicals having one to about ten carbon atoms any one of which may be substituted with one or more amino radicals. More preferred aminoalkyl radicals are "lower aminoalkyl" radicals having one to six carbon atoms and one or more amino radicals. Examples of such radicals include aminomethyl, aminoethyl, aminopropyl, aminobutyl and aminohexyl. Even more preferred are lower aminoalkyl radicals having one to three carbon atoms.
The term "alkylaminoalkyl" embraces alkyl radicals substituted with alkylamino radicals. More preferred alkylaminoalkyl radicals are "lower alkylaminoalkyl" radicals having alkyl radicals of one to six carbon atoms. Even more preferred are lower alkylaminoalkyl radicals having alkyl radicals of one to three carbon atoms. Suitable alkylaminoalkyl radicals may be mono or dialkyl substituted, such as N- methylaminomethyl, N,N-dimethyl-aminoethyl, Ν,Ν-diethylaminomethyl and the like.
The term "carboxyalkyl" embraces linear or branched alkyl radicals having one to about ten carbon atoms any one of which may be substituted with one or more carboxy radicals. More preferred carboxyalkyl radicals are "lower carboxyalkyl" radicals having one to six carbon atoms and one carboxy radical. Examples of such radicals include carboxymethyl, carboxypropyl, and the like. Even more preferred are lower carboxyalkyl radicals having one to three CH2 groups.
The term "carboxyalkylamino" embraces amino groups substituted with a carboxyalkyl radical. More preferred carboxyalkylamino radicals are "lower
carboxyalkylamino" radicals having one to six carbon atoms. Other preferred carboxyalkylamino groups have alkyl portions with one to three carbon atoms.
The term "cycloalkyl" includes saturated carbocyclic groups. Preferred cycloalkyl groups include C3-C6 rings. More preferred compounds include, cyclopentyl, cyclopropyl, and cyclohexyl.
The term "sulfonyl", whether used alone or linked to other terms such as alkylsulfonyl, denotes respectively divalent radicals -S02-.
The term "alkylsulfonyl" includes sulfonyl radicals substituted with an alkyl radical. More preferred alkylsulfonyl radicals are "lower alkylsulfonyl" radicals having one to six carbon atoms. Even more preferred are lower alkylsulfonyl radicals having one to three carbon atoms. Examples of such lower alkylsulfonyl radicals include methylsulfonyl and ethylsulfonyl.
The term "alkylsulfonylamino" embraces amino groups substituted with an alkylsulfonyl radical. More preferred alkylsulfonylamino radicals are "lower
alkylsulfonylamino" radicals having one to six carbon atoms. Other preferred alkylsulfonylamino groups have alkyl portions of one to three carbon atoms.
The term "alkylsulfonylalkylamino" embraces alkylamino groups substituted with an alkylsulfonyl radical. More preferred alkylsulfonylalkylamino radicals are "lower alkylsulfonylalkylamino" radicals having alkyl groups of one to six carbon atoms. Other preferred alkylsulfonylalkylamino groups have alkyl portions of one to three carbon atoms.
The term "alkoxyalkylamino" embraces amino groups substituted with an alkoxyalkyl radical, as previously described. More preferred alkoxyalkylamino radicals are "lower alkoxyalkylamino" radicals having aklyl radicals of one to six carbon atoms. Other preferred alkoxyalkylamino groups have alkyl portions of one to three carbon atoms.
The term "hydroxyalkylamino" embraces amino groups substituted with an hydroxyalkyl radical, as previously described. More preferred hydroxyalkylamino radicals are "lower hydroxyalkylamino" radicals having aklyl radicals of one to six carbon atoms. Other preferred hydroxyalkylamino groups have alkyl portions of one to three carbon atoms.
The term "haloalkylamino" embraces amino groups substituted with a haloalkyl radical, as previously described. More preferred haloalkylamino radicals are "lower haloalkylamino" radicals having aklyl radicals of one to six carbon atoms. Other preferred haloalkylamino groups have alkyl portions of one to three carbon atoms.
The term "aminoalkylamino" embraces alkylamino groups substituted with an amino (-NH2) group. More preferred aminoalkylamino radicals are "lower
aminoalkylamino" radicals having alkyl groups of one to six carbon atoms. Other preferred aminoalkylamino groups have alkyl portions of one to three carbon atoms.
The term "aminocarbonylalkylammo" embraces amino groups substituted with an aminocarbonyl radical, as previously described. More preferred
aminocarbonylalkylammo radicals are "lower aminocarbonylalkylammo" radicals having aklyl radicals of one to six carbon atoms. Other preferred aminocarbonylalkylammo groups have alkyl portions of one to three carbon atoms.
The term "alkoxycarbonylalkylamino" embraces amino groups substituted with an alkoxycarbonyl radical, as previously described. More preferred
alkoxycarbonylalkylamino radicals are "lower alkoxycarbonylalkylamino" radicals having aklyl radicals of one to six carbon atoms. Other preferred
alkoxycarbonylalkylamino groups have alkyl portions of one to three carbon atoms.
"Benzo group", alone or in combination, means the divalent radical C4H4=, one representation of which is -CH=CH-CH=CH-, that when vicinally attached to another ring forms a benzene-like ring— for example tetrahydronaphthylene, indole and the like.
The term "oxo" represents the groups =0 (as in carbonyl).
"Pharmaceutically-acceptable salt" means a salt prepared by conventional means, and are well known by those skilled in the art. The "pharmacologically acceptable salts" include basic salts of inorganic and organic acids, including but not limited to hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, malic acid, acetic acid, oxalic acid, tartaric acid, citric acid, lactic acid, fumaric acid, succinic acid, maleic acid, salicylic acid, benzoic acid, phenylacetic acid, mandelic acid and the like. When compounds of the invention include an acidic function such as a carboxy group, then suitable pharmaceutically acceptable cation pairs for the carboxy group are well known to those skilled in the art and include alkaline, alkaline earth, ammonium, quaternary ammonium cations and the like. For additional examples of "pharmacologically acceptable salts," see infra and Berge et al., J. Pharm. Sci. 66:1 (1977).
"Saturated, partially-saturated or unsaturated" includes substituents saturated with hydrogens, substituents completely unsaturated with hydrogens and substituents partially saturated with hydrogens.
"Leaving group" generally refers to groups readily displaceable by a nucleophile, such as an amine, a thiol or an alcohol nucleophile. Such leaving groups are well known in the art. Examples of such leaving groups include, but are not limited to,
N-hydroxysuccinimide, N-hydroxybenzotriazole, halides, triflates, tosylates and the like. Preferred leaving groups are indicated herein where appropriate.
"Protecting group" generally refers to groups well known in the art which are used to prevent selected reactive groups, such as carboxy, amino, hydroxy, mercapto and the like, from undergoing undesired reactions, such as nucleophilic, electrophilic, oxidation, reduction and the like. Preferred protecting groups are indicated herein where appropriate. Examples of amino protecting groups include, but are not limited to, aralkyl, substituted aralkyl, cycloalkenylalkyl and substituted cycloalkenyl alkyl, allyl, substituted allyl, acyl, alkoxycarbonyl, aralkoxycarbonyl, silyl and the like. Examples of aralkyl include, but are not limited to, benzyl, ortho-methylbenzyl, trityl and benzhydryl, which can be optionally substituted with halogen, alkyl, alkoxy, hydroxy, nitro, acylamino, acyl and the like, and salts, such as phosphonium and ammonium salts. Examples of aryl groups include phenyl, naphthyl, indanyl, anthracenyl, 9-(9-phenylfluorenyl), phenanthrenyl, durenyl and the like. Examples of cycloalkenylalkyl or substituted cycloalkylenylalkyl radicals, preferably have 6-10 carbon atoms, include, but are not limited to, cyclohexenyl methyl and the like. Suitable acyl, alkoxycarbonyl and aralkoxycarbonyl groups include benzyloxycarbonyl, t-butoxycarbonyl, iso- butoxycarbonyl, benzoyl, substituted benzoyl, butyryl, acetyl, trifluoroacetyl, trichloro acetyl, phthaloyl and the like. A mixture of protecting groups can be used to protect the same amino group, such as a primary amino group can be protected by both an aralkyl group and an aralkoxycarbonyl group. Amino protecting groups can also form a heterocyclic ring with the nitrogen to which they are attached, for example,
l,2-bis(methylene)benzene, phthalimidyl, succinimidyl, maleimidyl and the like and where these heterocyclic groups can further include adjoining aryl and cycloalkyl rings. In addition, the heterocyclic groups can be mono-, di- or tri-substituted, such as nitrophthalimidyl. Amino groups may also be protected against undesired reactions, such as oxidation, through the formation of an addition salt, such as hydrochloride, toluenesulfonic acid, trifluoroacetic acid and the like. Many of the amino protecting groups are also suitable for protecting carboxy, hydroxy and mercapto groups. For example, aralkyl groups. Alkyl groups are also suitable groups for protecting hydroxy and mercapto groups, such as tert-butyl.
Silyl protecting groups are silicon atoms optionally substituted by one or more alkyl, aryl and aralkyl groups. Suitable silyl protecting groups include, but are not limited to, trimethylsilyl, triethylsilyl, triisopropylsilyl, tert-butyldimethylsilyl,
dimethylphenylsilyl, l,2-bis(dimethylsilyl)benzene, 1 ,2-bis(dimethylsilyl)ethane and diphenylmethylsilyl. Silylation of an amino groups provide mono- or di-silylamino groups. Silylation of aminoalcohol compounds can lead to a Ν,Ν,Ο-trisilyl derivative. Removal of the silyl function from a silyl ether function is readily accomplished by treatment with, for example, a metal hydroxide or ammonium fluoride reagent, either as a discrete reaction step or in situ during a reaction with the alcohol group. Suitable silylating agents are, for example, trimethylsilyl chloride, tert-butyl-dimethylsilyl chloride, phenyldimethylsilyl chloride, diphenylmethyl silyl chloride or their combination products with imidazole or DMF. Methods for silylation of amines and removal of silyl protecting groups are well known to those skilled in the art. Methods of preparation of these amine derivatives from corresponding amino acids, amino acid amides or amino acid esters are also well known to those skilled in the art of organic chemistry including amino acid/amino acid ester or aminoalcohol chemistry.
Protecting groups are removed under conditions which will not affect the remaining portion of the molecule. These methods are well known in the art and include acid hydrolysis, hydrogenolysis and the like. A preferred method involves removal of a protecting group, such as removal of a benzyloxycarbonyl group by hydrogenolysis utilizing palladium on carbon in a suitable solvent system such as an alcohol, acetic acid, and the like or mixtures thereof. A t-butoxycarbonyl protecting group can be removed utilizing an inorganic or organic acid, such as HC1 or trifluoroacetic acid, in a suitable solvent system, such as dioxane or methylene chloride. The resulting amino salt can readily be neutralized to yield the free amine. Carboxy protecting group, such as methyl, ethyl, benzyl, tert-butyl, 4-methoxyphenylmethyl and the like, can be removed under hydrolysis and hydrogenolysis conditions well known to those skilled in the art.
It should be noted that compounds of the invention may contain groups that may exist in tautomeric forms, such as cyclic and acyclic amidine and guanidine groups, heteroatom substituted heteroaryl groups, and the like, for example as illustrated in the following examples:
Figure imgf000047_0001
and though one form is named, described, displayed and/or claimed herein, all the tautomeric forms are intended to be inherently included in such name, description, display and/or claim.
Prodrugs of the compounds of this invention are also contemplated by this invention. A prodrug is an active or inactive compound that is modified chemically through in vivo physiological action, such as hydrolysis, metabolism and the like, into a compound of this invention following administration of the prodrug to a patient. The suitability and techniques involved in making and using prodrugs are well known by those skilled in the art. For a general discussion of prodrugs involving esters see Svensson and Tunek Drug Metabolism Reviews 165 (1988) and Bundgaard Design of Prodrugs, Elsevier (1985). Examples of a masked carboxylate anion include a variety of esters, such as alkyl (for example, methyl, ethyl), cycloalkyl (for example, cyclohexyl), aralkyl (for example, benzyl, p-methoxybenzyl), and alkylcarbonyloxyalkyl (for example, pivaloyloxymethyl). Amines have been masked as arylcarbonyloxymethyl substituted derivatives which are cleaved by esterases in vivo releasing the free drug and formaldehyde (Bungaard J. Med. Chem. 2503 (1989)). Also, drugs containing an acidic NH group, such as imidazole, imide, indole and the like, have been masked with N- acyloxymethyl groups (Bundgaard Design of Prodrugs, Elsevier (1985)). Hydroxy groups have been masked as esters and ethers. EP 039,051 (Sloan and Little, 4/11/81) discloses Mannich-base hydroxamic acid prodrugs, their preparation and use.
The specification and claims contain listing of species using the language "selected from . . . and . . ." and "is . . . or . . ." (sometimes referred to as Markush groups). When this language is used in this application, unless otherwise stated it is meant to include the group as a whole, or any single members thereof, or any subgroups thereof. The use of this language is merely for shorthand purposes and is not meant in any way to limit the removal of individual elements or subgroups as needed.
Utility and Methods of Use
An aspect of the present invention is a method for inhibiting Pim kinase activity in a cell, comprising contacting the cell with an effective amount of a compound of Formulas 1-5, and 3'.
Another aspect of the present invention provides a method for treating a condition by modulation of Pim kinase activity comprising administering to a patient in need of such treatment an effective amount of a compound of Formulas 1-5, 1 ' and 3'.
Another embodiment of the present invention provides a method for treating a cancer disorder in a patient, comprising administering to the patient a composition comprising an amount of a compound of Formulas 1-5, and 3' effective to inhibit Pim kinase activity in the patient.
Another embodiment of the present invention provides a method for treating a cancer disorder in a patient, wherein the cancer is protate, head and neck or lymphoma, comprising administering to the patient a composition comprising an amount of a compound of Formulas 1-5, and 3' effective to inhibit Pim kinase activity in the patient.
Another aspect of the present invention provides the use of any one of the compounds of Formulas 1-5, 1 ' and 3' in the manufacture of a medicament for the treatment of cancer.
Administration and Pharmaceutical Compositions
In general, the compounds of this invention can be administered in a therapeutically effective amount by any of the accepted modes of administration for agents that serve similar utilities. The actual amount of a compound of this invention, i.e., the active ingredient, depends upon numerous factors, such as the severity of the disease to be treated, the age and relative health of the subject, the potency of the compound used, the route and form of administration, and other factors.
Therapeutically effective amounts of compounds of formula (1) may range from approximately 0.1-1000 mg per day.
In general, compounds of this invention can be administered as pharmaceutical compositions by any one of the following routes: oral, systemic (e.g., transdermal, intranasal or by suppository), or parenteral (e.g., intramuscular, intravenous or subcutaneous) administration. The preferred manner of administration is oral using a convenient daily dosage regimen, which can be adjusted according to the degree of affliction. Compositions can take the form of tablets, pills, capsules, semisolids, powders, sustained release formulations, solutions, suspensions, elixirs, aerosols, or any other appropriate compositions.
The choice of formulation depends on various factors, such as the mode of drug administration (e.g., for oral administration, formulations in the form of tablets, pills or capsules are preferred) and the bioavailability of the drug substance. Recently, pharmaceutical formulations have been developed especially for drugs that show poor bioavailability based upon the principle that bioavailability can be increased by increasing the surface area, i.e., decreasing particle size. For example, U.S. Pat. No. 4,107,288 describes a pharmaceutical formulation having particles in the size range from 10 to 1 ,000 nm in which the active material is supported on a crosslinked matrix of macromolecules. U.S. Pat. No. 5,145,684 describes the production of a pharmaceutical formulation in which the drug substance is pulverized to nanoparticles (average particle size of 400 nm) in the presence of a surface modifier and then dispersed in a liquid medium to give a pharmaceutical formulation that exhibits remarkably high bioavailability.
The compositions are comprised of, in general, a compounds of the present invention in combination with at least one pharmaceutically acceptable excipient.
Acceptable excipients are non-toxic, aid administration, and do not adversely affect the therapeutic benefit of the compounds of the present invention. Such excipient may be any solid, liquid, semi-solid or, in the case of an aerosol composition, gaseous excipient that is generally available to one of skill in the art.
Solid pharmaceutical excipients include starch, cellulose, talc, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, magnesium stearate, sodium stearate, glycerol monostearate, sodium chloride, dried skim milk and the like. Liquid and semisolid excipients may be selected from glycerol, propylene glycol, water, ethanol and various oils, including those of petroleum, animal, vegetable or synthetic origin, e.g., peanut oil, soybean oil, mineral oil, sesame oil, etc. Preferred liquid carriers, particularly for injectable solutions, include water, saline, aqueous dextrose, and glycols.
Compressed gases may be used to disperse a compound of this invention in aerosol form. Inert gases suitable for this purpose are nitrogen, carbon dioxide, etc. Other suitable pharmaceutical excipients and their formulations are described in Remington's Pharmaceutical Sciences, Gennaro, A. R. (Mack Publishing Company, 18th ed., 1995).
The level of the compound in a formulation can vary within the full range employed by those skilled in the art. Typically, the formulation contains, on a weight percent (wt %) basis, from about 0.01-99.99 wt % of a compounds of the present invention based on the total formulation, with the balance being one or more suitable pharmaceutical excipients. Preferably, the compound is present at a level of about 1-80 wt %.
COMBINATIONS
While the compounds of the invention can be administered as the sole active pharmaceutical agent, they can also be used in combination with one or more compounds of the invention or other agents. When administered as a combination, the therapeutic agents can be formulated as separate compositions that are administered at the same time or sequentially at different times, or the therapeutic agents can be given as a single composition.
The phrase "co-therapy" (or "combination-therapy"), in defining use of a compound of the present invention and another pharmaceutical agent, is intended to embrace administration of each agent in a sequential manner in a regimen that will provide beneficial effects of the drug combination, and is intended as well to embrace coadministration of these agents in a substantially simultaneous manner, such as in a single capsule having a fixed ratio of these active agents or in multiple, separate capsules for each agent.
Specifically, the administration of compounds of the present invention may be in conjunction with additional therapies known to those skilled in the art in the prevention or treatment of neoplasia, such as with radiation therapy or with cytostatic or cytotoxic agents.
If formulated as a fixed dose, such combination products employ the compounds of this invention within the accepted dosage ranges. Compounds of Formula I may also be administered sequentially with known anticancer or cytotoxic agents when a combination formulation is inappropriate. The invention is not limited in the sequence of administration; compounds of the invention may be administered either prior to, simultaneous with or after administration of the known anticancer or cytotoxic agent. Currently, standard treatment of primary tumors consists of surgical excision followed by either radiation or IV administered chemotherapy. The typical chemotherapy regime consists of either DNA alkylating agents, DNA intercalating agents or microtubule poisons. The chemotherapy doses used are just below the maximal tolerated dose and therefore dose limiting toxicities typically include, nausea, vomiting, diarrhea, hair loss, neutropenia and the like.
There are large numbers of antineoplastic agents available in commercial use, in clinical evaluation and in pre-clinical development, which would be selected for treatment of neoplasia by combination drug chemotherapy. Such antineoplastic agents fall into several major categories, namely, antibiotic-type agents, alkylating agents, antimetabolite agents, hormonal agents, immunological agents, interferon-type agents and a category of miscellaneous agents.
A first family of antineoplastic agents which may be used in combination with compounds of the present invention consists of antimetabolite-type/thymidilate synthase inhibitor antineoplastic agents. Suitable antimetabolite antineoplastic agents may be selected from but not limited to the group consisting of 5-FU-fibrinogen, acanthifolic acid, aminothiadiazole, brequinar sodium, carmofur, Ciba-Geigy CGP-30694, cyclopentyl cytosine, cytarabine phosphate stearate, cytarabine conjugates, Lilly DATHF, Merrel Dow DDFC, dezaguanine, dideoxycytidine, dideoxyguanosine, didox, Yoshitomi DMDC, doxifluridine, Wellcome EHNA, Merck & Co. EX-015, fazarabine, floxuridine, fludarabine phosphate, 5-fluorouracil, N-(2'-furanidyl)-5-fluorouracil, Daiichi Seiyaku FO-152, isopropyl pyrrolizine, Lilly LY-188011, Lilly LY-264618, methobenzaprim, methotrexate, Wellcome MZPES, norspermidine, NCI NSC-127716, NCI NSC-264880, NCI NSC-39661, NCI NSC-612567, Warner-Lambert PALA, pentostatin, piritrexim, plicamycin, Asahi Chemical PL-AC, Takeda TAC-788, thioguanine, tiazofurin, Erbamont TIF, trimetrexate, tyrosine kinase inhibitors, Taiho UFT and uricytin.
A second family of antineoplastic agents which may be used in combination with compounds of the present invention consists of alkylating-type antineoplastic agents. Suitable alkylating-type antineoplastic agents may be selected from but not limited to the group consisting of Shionogi 254-S, aldo-phosphamide analogues, altretamine, anaxirone, Boehringer Mannheim BBR-2207, bestrabucil, budotitane, Wakunaga CA-102, carboplatin, carmustine, Chinoin-139, Chinoin-153, chlorambucil, cisplatin,
cyclophosphamide, American Cyanamid CL-286558, Sanofi CY-233, cyplatate, Degussa D- 19-384, Sumimoto DACHP(Myr)2, diphenylspiromustine, diplatinum cytostatic, Erba distamycin derivatives, Chugai DWA-2114R, ITI E09, elmustine, Erbamont FCE-24517, estramustine phosphate sodium, fotemustine, Unimed G-6-M, Chinoin GYKI- 17230, hepsul-fam, ifosfamide, iproplatin, lomustine, mafosfamide, mitolactol, Nippon Kayaku NK-121, NCI NSC-264395, NCI NSC-342215, oxaliplatin, Upjohn PCNU,
prednimustine, Proter PTT-119, ranimustine, semustine, SmithKline SK&F-101772, Yakult Honsha SN-22, spiromus-tine, Tanabe Seiyaku TA-077, tauromustine, temozolomide, teroxirone, tetraplatin and trimelamol.
A third family of antineoplastic agents which may be used in combination with compounds of the present invention consists of antibiotic-type antineoplastic agents. Suitable antibiotic-type antineoplastic agents may be selected from but not limited to the group consisting of Taiho 4181 -A, aclarubicin, actinomycin D, actinoplanone, Erbamont ADR-456, aeroplysinin derivative, Ajinomoto AN-201-II, Ajinomoto AN-3, Nippon Soda anisomycins, anthracycline, azino-mycin-A, bisucaberin, Bristol-Myers BL-6859, Bristol- Myers BMY-25067, Bristol-Myers BMY-25551, Bristol-Myers BMY-26605, Bristol- Myers BMY-27557, Bristol-Myers BMY-28438, bleomycin sulfate, bryostatin-1, Taiho C-1027, calichemycin, chromoximycin, dactinomycin, daunorubicin, Kyowa Hakko DC- 102, Kyowa Hakko DC-79, Kyowa Hakko DC-88A, Kyowa Hakko DC89-A1, Kyowa Hakko DC92-B, ditrisarubicin B, Shionogi DOB-41, doxorubicin, doxorubicin- fibrinogen, elsamicin-A, epirubicin, erbstatin, esorubicin, esperamicin-Al, esperamicin- Alb, Erbamont FCE-21954, Fujisawa FK-973, fostriecin, Fujisawa FR-900482, glidobactin, gregatin-A, grincamycin, herbimycin, idarubicin, illudins, kazusamycin, kesarirhodins, Kyowa Hakko KM-5539, Kirin Brewery KRN-8602, Kyowa Hakko KT- 5432, Kyowa Hakko KT-5594, Kyowa Hakko KT-6149, American Cyanamid LL- D49194, Meiji Seika ME 2303, menogaril, mitomycin, mitoxantrone, SmithKline M- TAG, neoenactin, Nippon Kayaku NK-313, Nippon Kayaku NKT-01 , SRI International NSC-357704, oxalysine, oxaunomycin, peplomycin, pilatin, pirarubicin, porothramycin, pyrindanycin A, Tobishi RA-I, rapamycin, rhizoxin, rodorubicin, sibanomicin, siwenmycin, Sumitomo SM-5887, Snow Brand SN-706, Snow Brand SN-07, sorangicin- A, sparsomycin, SS Pharmaceutical SS-21020, SS Pharmaceutical SS-7313B, SS Pharmaceutical SS-9816B, steffimycin B, Taiho 4181-2, talisomycin, Takeda TAN-868A, terpentecin, thrazine, tricrozarin A, Upjohn U-73975, Kyowa Hakko UCN-10028A, Fujisawa WF-3405, Yoshitomi Y-25024 and zorubicin.
A fourth family of antineoplastic agents which may be used in combination with compounds of the present invention consists of a miscellaneous family of antineoplastic agents, including tubulin interacting agents, topoisomerase II inhibitors, topoisomerase I inhibitors and hormonal agents, selected from but not limited to the group consisting of a-carotene, a-difluoromethyl-arginine, acitretin, Biotec AD-5, Kyorin AHC-52, alstonine, amonafide, amphethinile, amsacrine, Angiostat, ankinomycin, anti-neoplaston A10, antineoplaston A2, antineoplaston A3, antineoplaston A5, antineoplaston AS2-1, Henkel APD, aphidicolin glycinate, asparaginase, Avarol, baccharin, batracylin, benfluron, benzotript, Ipsen-Beaufour BIM-23015, bisantrene, Bristol-Myers BMY- 40481, Vestar boron- 10, bromofosfamide, Wellcome BW-502, Wellcome BW-773, caracemide, carmethizole hydrochloride, Ajinomoto CDAF, chlorsulfaquinoxalone, Chemes CHX-2053, Chemex CHX-100, Warner-Lambert CI-921, Warner-Lambert CI- 937, Warner-Lambert CI-941, Warner-Lambert CI-958, clanfenur, claviridenone, ICN compound 1259, ICN compound 4711, Contracan, Yakult Honsha CPT-11, crisnatol, curaderm, cytochalasin B, cytarabine, cytocytin, Merz D-609, DABIS maleate, dacarbazine, datelliptinium, didemnin-B, dihaematoporphyrin ether, dihydrolenperone, dinaline, distamycin, Toyo Pharmar DM-341, Toyo Pharmar DM-75, Daiichi Seiyaku DN-9693, docetaxel elliprabin, elliptinium acetate, Tsumura EPMTC, the epothilones, ergotamine, etoposide, etretinate, fenretinide, Fujisawa FR-57704, gallium nitrate, genkwadaphnin, Chugai GLA-43, Glaxo GR-63178, grifolan NMF-5N,
hexadecylphosphocholine, Green Cross HO-221, homoharringtonine, hydroxyurea, BTG ICRF-187, ilmofosine, isoglutamine, isotretinoin, Otsuka JI-36, Ramot K-477, Otsuak K- 76COONa, Kureha Chemical K-AM, MECT Corp KI-8110, American Cyanamid L-623, leukoregulin, lonidamine, Lundbeck LU-23-112, Lilly LY-186641, NCI (US) MAP, marycin, Merrel Dow MDL-27048, Medco MEDR-340, merbarone, merocyanlne derivatives, methylanilinoacridine, Molecular Genetics MGI-136, minactivin, mitonafide, mitoquidone mopidamol, motretinide, Zenyaku Kogyo MST-16, N-(retinoyl)amino acids, Nisshin Flour Milling N-021 , N-acylated-dehydroalanines, nafazatrom, Taisho NCU-190, nocodazole derivative, Normosang, NCI NSC-145813, NCI NSC-361456, NCI NSC- 604782, NCI NSC-95580, ocreotide, Ono ONO-112, oquizanocine, Akzo Org-10172, paclitaxel, pancratistatin, pazelliptine, Warner-Lambert PD-111707, Warner-Lambert PD- 115934, Warner-Lambert PD-131141, Pierre Fabre PE-1001, ICRT peptide D, piroxantrone, polyhaematoporphyrin, polypreic acid, Efamol po hyrin, probimane, procarbazine, proglumide, Invitron protease nexin I, Tobishi RA-700, razoxane, Sapporo Breweries RBS, restrictin-P, retelliptine, retinoic acid, Rhone-Poulenc RP-49532, Rhone- Poulenc RP-56976, SmithKline SK&F-104864, Sumitomo SM-108, Kuraray SMANCS, SeaPharm SP- 10094, spatol, spirocyclopropane derivatives, spirogermanium, Unimed, SS Pharmaceutical SS-554, strypoldinone, Stypoldione, Suntory SUN 0237, Suntory SUN 2071, superoxide dismutase, Toyama T-506, Toyama T-680, taxol, Teijin TEI-0303, teniposide, thaliblastine, Eastman Kodak TJB-29, tocotrienol, topotecan, Topostin, Teijin TT-82, Kyowa Hakko UCN-01, Kyowa Hakko UCN-1028, ukrain, Eastman Kodak USB- 006, vinblastine sulfate, vincristine, vindesine, vinestramide, vinorelbine, vintriptol, vinzolidine, withanolides and Yamanouchi YM-534.
Alternatively, the present compounds may also be used in co-therapies with other antineoplastic agents, such as acemannan, aclarubicin, aldesleukin, alemtuzumab, alitretinoin, altretamine, amifostine, aminolevulinic acid, amrubicin, amsacrine, anagrelide, anastrozole, ANCER, ancestim, ARGLABIN, arsenic trioxide, BAM 002 (Novelos), bexarotene, bicalutamide, broxuridine, capecitabine, celmoleukin, cetrorelix, cladribine, clotrimazole, cytarabine ocfosfate, DA 3030 (Dong- A), daclizumab, denileukin diftitox, deslorelin, dexrazoxane, dilazep, docetaxel, docosanol, doxercalciferol, doxifluridine, doxorubicin, bromocriptine, carmustine, cytarabine, fluorouracil, HIT diclofenac, interferon alfa, daunorubicin, doxorubicin, tretinoin, edelfosine, edrecolomab, eflornithine, emitefur, epirubicin, epoetin beta, etoposide phosphate, exemestane, exisulind, fadrozole, filgrastim, finasteride, fludarabine phosphate, formestane, fotemustine, gallium nitrate, gemcitabine, gemtuzumab zogamicin,
gimeracil/oteracil/tegafur combination, glycopine, goserelin, heptaplatin, human chorionic gonadotropin, human fetal alpha fetoprotein, ibandronic acid, idarubicin, (imiquimod, interferon alfa, interferon alfa, natural, interferon alfa-2, interferon alfa-2a, interferon alfa-2b, interferon alfa-Nl, interferon alfa-n3, interferon alfacon-1, interferon alpha, natural, interferon beta, interferon beta- la, interferon beta- lb, interferon gamma, natural interferon gamma- la, interferon gamma- lb, interleukin-1 beta, iobenguane, irinotecan, irsogladine, lanreotide, LC 9018 (Yakult), leflunomide, lenograstim, lentinan sulfate, letrozole, leukocyte alpha interferon, leuprorelin, levamisole + fluorouracil, liarozole, lobaplatin, lonidamine, lovastatin, masoprocol, melarsoprol, metoclopramide, mifepristone, miltefosine, mirimostim, mismatched double stranded RNA, mitoguazone, mitolactol, mitoxantrone, molgramostim, nafarelin, naloxone + pentazocine, nartograstim, nedaplatin, nilutamide, noscapine, novel erythropoiesis stimulating protein, NSC 631570 octreotide, oprelvekin, osaterone, oxaliplatin, paclitaxel, pamidronic acid, pegaspargase, peginterferon alfa-2b, pentosan polysulfate sodium, pentostatin, picibanil, pirarubicin, rabbit antithymocyte polyclonal antibody, polyethylene glycol interferon alfa-2a, porfimer sodium, raloxifene, raltitrexed, rasburicase, rhenium Re 186 etidronate, RII retinamide, rituximab, romurtide, samarium (153 Sm) lexidronam, sargramostim, sizofiran, sobuzoxane, sonermin, strontium-89 chloride, suramin, tasonermin, tazarotene, tegafur, temoporfm, temozolomide, teniposide, tetrachlorodecaoxide, thalidomide, thymalfasin, thyrotropin alfa, topotecan, toremifene, tositumomab-iodine 131, trastuzumab, treosulfan, tretinoin, trilostane, trimetrexate, triptorelin, tumor necrosis factor alpha, natural, ubenimex, bladder cancer vaccine, Maruyama vaccine, melanoma lysate vaccine, valrubicin, verteporfin, vinorelbine, VIRULIZIN, zinostatin stimalamer, or zoledronic acid; abarelix; AE 941 (Aeterna), ambamustine, antisense oligonucleotide, bcl-2 (Genta), APC 8015 (Dendreon), cetuximab, decitabine, dexaminoglutethimide, diaziquone, EL 532 (Elan), EM 800 (Endorecherche), eniluracil, etanidazole, fenretinide, filgrastim SDOl (Amgen), fulvestrant, galocitabine, gastrin 17 immunogen, HLA-B7 gene therapy (Vical), granulocyte macrophage colony stimulating factor, histamine dihydrochloride, ibritumomab tiuxetan, ilomastat, IM 862 (Cytran), interleukin-2, iproxifene, LDI 200 (Milkhaus), leridistim, lintuzumab, CA 125 MAb (Biomira), cancer MAb (Japan Pharmaceutical Development), HER-2 and Fc MAb (Medarex), idiotypic 105AD7 MAb (CRC Technology), idiotypic CEA MAb (Trilex), LYM-1 -iodine 131 MAb (Techniclone), polymorphic epithelial mucin-yttrium 90 MAb (Antisoma), marimastat, menogaril, mitumomab, motexafin gadolinium, MX 6 (Galderma), nelarabine, nolatrexed, P 30 protein, pegvisomant, pemetrexed, porfiromycin, prinomastat, RL 0903 (Shire), rubitecan, satraplatin, sodium phenylacetate, sparfosic acid, SRL 172 (SR Pharma), SU 5416 (SUGEN), TA 077 (Tanabe), tetrathiomolybdate, thaliblastine, thrombopoietin, tin ethyl etiopurpurin, tirapazamine, cancer vaccine (Biomira), melanoma vaccine (New York University), melanoma vaccine (Sloan Kettering Institute), melanoma oncolysate vaccine (New York Medical College), viral melanoma cell lysates vaccine (Royal Newcastle Hospital), or valspodar.
Alternatively, the present compounds may also be used in co-therapies with other agents, such as other kinase inhibitors including CDK inhibitors, mTor inhibitors, Pi3k inhibitors, and Aurora kinase inhibitors. Synthetic Methods
The following abbreviations may be used herein:
AcOH or HOAc acetic acid
ACN acetonitrile
aq aqueous
Ar argon
ATP adenosine 5'-triphosphate
A-Phos or Amphos di-t-butyl-(4-dimethylaminophenyl)phosphine BBr3 boron tribromide
(BPin)2 bis(pinacolato)diboron
BrettPhos dicyclohexyl(2',4',6'-triisopropoxy-3,6-dimethoxy-[ 1 , 1 '- biphenyl]-2-yl)phosphine
BrettPhos precatalyst Chloro[2-(dicyclohexylphosphino)-3,6-dimethoxy-2',4',
6'-triisopropyl- 1 , 1 '-biphenyl] [2-(2- aminoethyl)phenyl]palladium(II)
nBuLi n-butyllithium
CHC13 chloroform
CDCI3 deuterated chloroform
C02 carbon dioxide
Calcd or Calc'd calculated
Cone. concentrated
Cul copper (I) iodide
DBU 1 ,8-diazabicyclo[5.4.0] undec-7-ene
DCM dichloromethane
DEA diethylamine
DIPEA, DIEA diisopropylethyl amine
DMF N,N-dimethylformamide
DMSO dimethyl sulfoxide
DTT dithiothreitol
EDTA ethylenediamine tetraacetic acid
ESI electrospray ionization
Et20 diethyl ether
Et3N or TEA triethylamine EtOAc ethyl acetate
EtOH ethyl alcohol
FBS fetal bovine serum
g grams
Grubbs II Catalyst (l,3-Bis(2,4,6-trimethylphenyl)-2- imidazolidinylidene)dichloro(phenylmethylene) (tricyclohexyl phosphine)ruthenium h hour
¾ hydrogen
HC1 hydrochloric acid
HC02H formic acid
H20 water
H202 hydrogen peroxide
HN03 nitric acid
H2S04 sulfuric acid
Hex hexanes
HPLC high pressure liquid chromatography
IPA or iPrOH isopropyl alcohol
KHSO4 potassium bisulfate
KHMDS or KHMDS potassium bis(trimethylsilyl)amide
KOAc potassium hydro xyacetate
K2CO3 potassium carbonate
K3PO4 potassium phosphate
L liter
LCMS, LC-MS or LC/MS liquid chromatography mass spectroscopy
LDA lithium diisopropylamide
LHMDS or LiHMDS lithium bis(trimethylsilyl)amide
m/z mass divided by charge
MeOH methyl alcohol
MePPh3Br methyl triphenylphosphine bromide
mg milligrams
min minutes
mL milliliters
MgSQ4 magnesium sulfate MS mass spectra
N2 nitrogen
NH3 ammonia
NH4OH ammonium hydroxide
NH4OAc ammonium acetate
NH4CI ammonium chloride
NMO n-methylmorpholine oxide
NaH sodium hydride
NaOH sodium hydroxide
NaHCC>3 sodium bicarbonate
Na2C03 sodium carbonate
Na2S04 sodium sulfate
NBS N-bromosuccinimide
NMP l-methyl-2-pyrrolidinone
NMR nuclear magnetic resonance
POCI3 phosphorous oxychloride
Pd/C palladium on carbon
Pd(PPh3)4 tetrakis(triphenylphosphine)-palladium (0)
PdCl2(PPh3)2 dichloro bis(triphenylphosphine)-palladium (II) Pd2dba3 tris(dibenzylideneacetone)dipalladium (0)
Pd(dppf)Cl2 [(1,1 -bis(diphenylphosphino)ferrocene]
dichloropalladium(II)
PdCl2 palladium chloride
P protecting group
Pos. ion positive ion
Pt/C platinum on carbon
rt or RT room temperature
Sat. saturated
SFC supercritical fluid chromatography
TFA trifluoroacetic acid
THF tetrahydrofuran
Ts or tosyl para-toluene sulfonyl
wt weight
Xphos 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl The compounds of the invention can be prepared according to the following procedures of Schemes 1-10, wherein the substituents are as defined for formulas 1-5, 1 ' and 3' above, except where noted.
Scheme 1
Figure imgf000059_0001
1) piperidine 2,4-dione
base
2) Base, 3-bromo- 2-methylpropene '
Figure imgf000059_0002
Substituted 6,7-dihydro-lH-pyrrolo[3,2-c]pyridin-4(5H)-ones 4 can be prepared according to the method set out in Scheme 1. A strong alkyl metal, such as an organolithium reagents (e.g. butyllithium) is added to a solution of a dihalo-bicyclic ring 1 at a temperature below 0 °C, preferably below -50 °C , even more preferably at about - 72 °C. Treatment with an acetamide at a temperature below 0 °C , preferably below -50 °C , even more preferably at about -70 °C yields the acetyl derivative 2. Bromination of the acetyl derivative 2, such as with a base, e.g Et3N, teri-butyldimethylsilyl trifluoromethanesulfonate, and bromination such as with NBS, provides the desired bromoacetyl compound 2a. Treatment of the bromoacetyl compound 2a with an ammonia salt, such as NH4OAc, and piperidine-2,4-dione at a temperature above RT, preferably at about 50 °C affords the 6,7-dihydro-lH-pyrrolo[3,2-c]pyridin-4(5H)-one 3. Substitution of the remaining halo group provides further compounds 4. For example, treatment with arylamines such as aniline, in the presence of a strong non-nucleophilic base, e.g. LHMDS, provides the desired amine derivatives. Alternatively, where the chloro substituent is methyl ester substituent, treatment of compound 1 with a palladium catalyst, such as Pd(PPh3)4 and a tin reagent, such as tributyl(l-ethoxyvinyl)tin, at a temperature higher than RT, preferably above about 50 °C, more preferably at about 100 °C provides the corresponding the acetyl derivative 2 [with the ester substitution]. Grubbs catalyst 2nd generation is added to 4 and heated such as to reflux to form the macrocycle 5.
Scheme 2
Figure imgf000060_0001
Similarly, ether substituted compounds 4, where Z is oxygen, can be prepared according to the method set out in Scheme 2. Alcohols [ZaOH] are treated with stong base, such as NaH, then added to the chloro substituted compounds 3 furnished substituted 6,7-dihydro-l//-pyrrolo[3,2-c]pyridin-4(5//)-ones 4.
Scheme 3
Figure imgf000060_0002
Amino substituted compounds 4, where R1 is alkylamino, arylamino and the like, are prepared by the method described in Scheme 3. Fluoro-substituted compounds 6 and an optionally substituted amine [ZaNH2] are heated at a temperature higher than RT, preferably above about 50 °C, more preferably at about 80 °C to furnish the desired amines 4.
Scheme 4
Figure imgf000061_0001
Compounds 8, where where Rd is phenylalkyl and the like, are prepared by the method described in Scheme 4. Halo-substituted compounds 7 having an optionally substituted MeZ-phenyl portion are treated with boron tribromide. The resulting material is treated with a base, such as NaH, preferably above about 50 °C, more preferably at about 80 °C to furnish the desired macrocycles 8.
Scheme 5
Figure imgf000061_0002
Similarly, compounds 12, where where Rd is phenylalkyl and the like, are prepared by the method described in Scheme 5. Halo-phenylalkyl substituted quinazolines 11 are prepared by methods described above. Halo-phenylalkyl substituted quinazolines 11 are cyclized using a catalyst such as Brettphos, preferably above about 50 °C, more preferably at about 1 10 °C, to furnish the desired macrocycles 12. Scheme 6
Figure imgf000062_0001
Other cyclic amides can be prepared such as the 3,4-dihydropyrrolo[l,2- a]pyrazin-l (2H)-ones 15 as described in Scheme 6. Methyl 4-bromo-lH-pyrrole-2- carboxylate 13 is reacted with base, such as NaH, and 1 ,2 dibromoethane at a temperature higher than RT, preferably above about 50 °C, more preferably at about at 70 °C to afford the bromoethyl derivative 14. Cyclization, such as with treatment with (2,4- dimethoxyphenyl)methanamine, at a temperature higher than RT, preferably above about 100 °C, more preferably at about at 150 °C yields the protected bromo-3,4- dihydropyrrolo[l ,2-a]pyrazin-l (2H)-one 15.
Scheme 7
Figure imgf000062_0002
18
8-(4,4,5,5-Tetramethyl-l,3,2-dioxaborolan-2-yl)quinoxalines 17 can be prepared similar to that shown in Scheme 7. Treatment of the bromo compound 16 with bis(pinacolato)diboron, a palladium catalyst such as PdCl2(dppf)2, and a base, such as potassium acetate, at a temperature higher than RT, preferably above about 75 °C, more preferably at about at 105 °C, affords the desired boron derivative 17.
Scheme 8
Figure imgf000063_0001
Other cyclic amides of the present invention can be prepared such as the 3,4- dihydropyrrolo[l,2-a]pyrazin-l(2H)-ones 23 as described in Scheme 8. Substituted amines are coupled to the 8-bromo-2-chloroquinoline through treatment with base, such as LiHMDS, at a temperature of about RT, to afford the desired 8-bromoquinolin-2 -amine 19. The bromo compound 20 is converted to the boronic acid 21 via treatment with a palladium catalyst, such as Pd(dppf)2Cl2, bis(pinacolato)diboron, and a base such as KOAc, at a temperature higher than RT, preferably above about 75 °C, more preferably at about at 115 °C. Coupling of the boronic acid 21 with the protected 7-bromo-3,4- dihydropyrrolo[l,2-a]pyrazin-l(2H)-one 16 such as in the presence of a palladium catalyst, such as Pd2(dba)3 or bis(di-?er?-butyl(4-dimethylaminophenyl)phosphine)- dichloro-palladium(II), and dicyclohexyl(2',4',6'-triisopropyl-[l,l'-biphenyl]-2- yl)phosphine and a base such as K3PO4, at a temperature higher than RT, preferably above about 75 °C, more preferably at about at 130 °C, gave the protected 7-(quinolin-8- yl)-3,4-dihydropyrrolo[l,2-a]pyrazin-l(2H)-one 22. Deprotection, such as with acid, at a temperature higher than RT, preferably at about 50 °C, affords the desired 7-(quinolin-8- yl)-3 ,4-dihydropyrrolo [1,2 -a]pyrazin- 1 (2H)-one 23.
Scheme 9
Figure imgf000064_0001
Macrocycles with amide containing linkers can be prepared as described in Scheme 9. Deprotection of protected amines and esters, such as with base or with acid, provides the desired amino acid. Amide formation such as with treatment with PyBop yields the desired amides 26.
Scheme 10
Figure imgf000064_0002
Macrocycle prodrug intermediates 27 can be prepared according to the method set out in Scheme 10. Treatment of the 6,7-dihydro-lH-pyrrolo[3,2-c]pyridin-4(5H)-one 3 with a acyl halide, phosphate ester, and the like provides the substituted amides 27. Subsequent steps as described in Scheme 1 fprovides the complete macrocycle prodrug. The starting compounds defined in Schemes 1-10 may also be present with functional groups in protected form if necessary and/or in the form of salts, provided a salt-forming group is present and the reaction in salt form is possible. If so desired, one compound of formulas 1-5, and 3' can be converted into another compound of formulas 1-5, and 3' or a N-oxide thereof; a compound of formulas 1-5, and 3' can be converted into a salt; a salt of a compound of formulas 1-5, 1 ' and 3' can be converted into the free compound or another salt; and/or a mixture of isomeric compounds of formulas 1-5, and 3' can be separated into the individual isomers.
N-Oxides can be obtained in a known manner by reacting a compound of formulas 1-5, 1 ' and 3' with H202 or a peracid, e.g. 3-chloroperoxy-benzoic acid, in an inert solvent, e.g. dichloromethane, at a temperature between about -10-35°C, such as about 0°C - RT.
If one or more other functional groups, for example carboxy, hydroxy, amino, or mercapto, are or need to be protected in a compound of formulas 1-5, and 3' or in the synthesis of a compound of formulas 1-5, 1 ' and 3', because they should not take part in the reaction, these are such groups as are usually used in the synthesis of peptide compounds, and also of cephalosporins and penicillins, as well as nucleic acid derivatives and sugars.
The protecting groups may already be present in precursors and should protect the functional groups concerned against unwanted secondary reactions, such as acylations, etherifications, esterifications, oxidations, solvolysis, and similar reactions. It is a characteristic of protecting groups that they lend themselves readily, i.e. without undesired secondary reactions, to removal, typically by solvolysis, reduction, photolysis or also by enzyme activity, for example under conditions analogous to physiological conditions, and that they are not present in the end-products. The specialist knows, or can easily establish, which protecting groups are suitable with the reactions mentioned above and hereinafter.
The protection of such functional groups by such protecting groups, the protecting groups themselves, and their removal reactions are described for example in standard reference works, such as J. F. W. McOmie, "Protective Groups in Organic Chemistry", Plenum Press, London and New York 1973, in T. W. Greene, "Protective Groups in Organic Synthesis", Wiley, New York 1981, in "The Peptides"; Volume 3 (editors: E. Gross and J. Meienhofer), Academic Press, London and New York 1981, in "Methoden der organischen Chemie" (Methods of organic chemistry), Houben Weyl, 4th edition, Volume 15/1, Georg Thieme Verlag, Stuttgart 1974, in H.-D. Jakubke and H. Jescheit, "Aminosauren, Peptide, Proteine" (Amino acids, peptides, proteins), Verlag Chemie, Weinheim, Deerfield Beach, and Basel 1982, and in Jochen Lehmann, "Chemie der Kohlenhydrate: Monosaccharide und Derivate" (Chemistry of carbohydrates:
monosaccharides and derivatives), Georg Thieme Verlag, Stuttgart 1974.
In the additional process steps, carried out as desired, functional groups of the starting compounds which should not take part in the reaction may be present in unprotected form or may be protected for example by one or more of the protecting groups mentioned above under "protecting groups". The protecting groups are then wholly or partly removed according to one of the methods described there.
Salts of a compound of formulas 1-5, and 3' with a salt-forming group may be prepared in a manner known per se. Acid addition salts of compounds of formulas 1-5, 1 ' and 3' may thus be obtained by treatment with an acid or with a suitable anion exchange reagent. A salt with two acid molecules (for example a dihalogenide of a compound of formulas 1-5, 1 ' and 3') may also be converted into a salt with one acid molecule per compound (for example a monohalogenide); this may be done by heating to a melt, or for example by heating as a solid under a high vacuum at elevated temperature, for example from about 130°C to about 170°C, one molecule of the acid being expelled per molecule of a compound of formulas 1-5, 1 ' and 3 ' .
Salts can usually be converted to free compounds, e.g. by treating with suitable basic agents, for example with alkali metal carbonates, alkali metal hydrogen carbonates, or alkali metal hydroxides, typically potassium carbonate or sodium hydroxide.
All process steps described here can be carried out under known reaction conditions, preferably under those specifically mentioned, in the absence of or usually in the presence of solvents or diluents, preferably such as are inert to the reagents used and able to dissolve these, in the absence or presence of catalysts, condensing agents or neutralizing agents, for example ion exchangers, typically cation exchangers, for example in the H+ form, depending on the type of reaction and/or reactants at reduced, normal, or elevated temperature, for example in the range from about -100°C to about 190°C, preferably from about -80°C to about 150°C, for example at about -80 to about 60°C, at RT, at about -20 to about 40°C or at the boiling point of the solvent used, under atmospheric pressure or in a closed vessel, where appropriate under pressure, and/or in an inert atmosphere, for example under argon or nitrogen. Salts may be present in all starting compounds and transients, if these contain salt-forming groups. Salts may also be present during the reaction of such compounds, provided the reaction is not thereby disturbed.
In certain cases, typically in hydrogenation processes, it is possible to achieve stereoselective reactions, allowing for example easier recovery of individual isomers.
The solvents from which those can be selected which are suitable for the reaction in question include for example water, esters, typically lower alkyl-lower alkanoates, e.g., ethyl acetate, ethers, typically aliphatic ethers, e.g., diethylether, or cyclic ethers, e.g., THF, liquid aromatic hydrocarbons, typically benzene or toluene, alcohols, typically MeOH, EtOH or 1 -propanol, 2-propanol, nitriles, typically ACN, halogenated hydrocarbons, typically DCM, acid amides, typically DMF, bases, typically heterocyclic nitrogen bases, e.g. pyridine, carboxylic acids, typically lower alkanecarboxylic acids, e.g., AcOH, carboxylic acid anhydrides, typically lower alkane acid anhydrides, e.g., acetic anhydride, cyclic, linear, or branched hydrocarbons, typically cyclohexane, hexane, or isopentane, or mixtures of these solvents, e.g., aqueous solutions, unless otherwise stated in the description of the process. Such solvent mixtures may also be used in processing, for example in chromatography.
The invention relates also to those forms of the process in which one starts from a compound obtainable at any stage as a transient and carries out the missing steps, or breaks off the process at any stage, or forms a starting material under the reaction conditions, or uses said starting material in the form of a reactive derivative or salt, or produces a compound obtainable by means of the process according to the invention and processes the said compound in situ. In the preferred embodiment, one starts from those starting materials which lead to the compounds described above as preferred.
The compounds of formulas 1-5, and 3', including their salts, are also obtainable in the form of hydrates, or their crystals can include for example the solvent used for crystallization (present as solvates).
New starting materials and/or intermediates, as well as processes for the preparation thereof, are likewise the subject of this invention. In the preferred embodiment, such starting materials are used and reaction conditions so selected as to enable the preferred compounds to be obtained.
Starting materials of the invention, are known, are commercially available, or can be synthesized in analogy to or according to methods that are known in the art. In the preparation of starting materials, existing functional groups which do not participate in the reaction should, if necessary, be protected. Preferred protecting groups, their introduction and their removal are described above or in the examples.
All remaining starting materials are known, capable of being prepared according to known processes, or commercially obtainable; in particular, they can be prepared using processes as described in the examples.
Compounds of the present invention can possess, in general, one or more asymmetric carbon atoms and are thus capable of existing in the form of optical isomers as well as in the form of racemic or non-racemic mixtures thereof. The optical isomers can be obtained by resolution of the racemic mixtures according to conventional processes, e.g., by formation of diastereoisomeric salts, by treatment with an optically active acid or base. Examples of appropriate acids are tartaric, diacetyltartaric, dibenzoyltartaric, ditoluoyltartaric, and camphorsulfonic acid and then separation of the mixture of diastereoisomers by crystallization followed by liberation of the optically active bases from these salts. A different process for separation of optical isomers involves the use of a chiral chromatography column optimally chosen to maximize the separation of the enantiomers. Still another available method involves synthesis of covalent diastereoisomeric molecules by reacting compounds of the invention with an optically pure acid in an activated form or an optically pure isocyanate. The synthesized diastereoisomers can be separated by conventional means such as chromatography, distillation, crystallization or sublimation, and then hydrolyzed to deliver the enantiomerically pure compound. The optically active compounds of the invention can likewise be obtained by using optically active starting materials. These isomers may be in the form of a free acid, a free base, an ester or a salt.
The compounds of this invention may contain one or more asymmetric centers and thus occur as racemates and racemic mixtures, scalemic mixtures, single enantiomers, individual diastereomers and diastereomeric mixtures. All such isomeric forms of these compounds are expressly included in the present invention.
The compounds may also occur in cis- or trans- or E- or Z- double bond isomeric forms. All such isomeric forms of such compounds are expressly included in the present invention. All crystal forms of the compounds described herein are expressly included in the present invention.
Substituents on ring moieties (e.g., phenyl, thienyl, etc.) may be attached to specific atoms, whereby they are intended to be fixed to that atom, or they may be drawn unattached to a specific atom, whereby they are intended to be attached at any available atom that is not already substituted by an atom other than H (hydrogen).
The compounds of this invention may contain heterocyclic ring systems attached to another ring system. Such heterocyclic ring systems may be attached through a carbon atom or a heteroatom in the ring system.
Alternatively, a compound of any of the formulas delineated herein may be synthesized according to any of the processes delineated herein. In the processes delineated herein, the steps may be performed in an alternate order and may be preceded, or followed, by additional protection/deprotection steps as necesssary. The processes may further comprise use of appropriate reaction conditions, including inert solvents, additional reagents, such as bases (e.g., LDA, DIPEA, pyridine, K2C03, and the like), catalysts, and salt forms of the above. The intermediates may be isolated or carried on in situ, with or without purification. Purification methods are known in the art and include, for example, crystallization, chromatography (liquid and gas phase, simulated moving bed ("SMB")), extraction, distillation, trituration, reverse phase HPLC and the like. Reactions conditions such as temperature, duration, pressure, and atmosphere (inert gas, ambient) are known in the art and may be adjusted as appropriate for the reaction.
As can be appreciated by the skilled artisan, the above synthetic schemes are not intended to comprise a comprehensive list of all means by which the compounds described and claimed in this application may be synthesized. Further methods will be evident to those of ordinary skill in the art. Additionally, the various synthetic steps described above may be performed in an alternate sequence or order to give the desired compounds. Synthetic chemistry transformations and protecting group methodologies (protection and deprotection) useful in synthesizing the inhibitor compounds described herein are known in the art and include, for example, those such as described in R.
Larock, Comprehensive Organic Transformations, VCH Publishers (1989); T.W. Greene and P.G.M. Wuts, Protective Groups in Organic Synthesis, 3rd. Ed., John Wiley and Sons (1999); L. Fieser and M. Fieser, Fieser and Fieser's Reagents for Organic Synthesis, John Wiley and Sons (1994); A. Katritzky and A. Pozharski, Handbook of Heterocyclic Chemistry, 2nd Ed. (2001); M. Bodanszky, A. Bodanszky: The practice of Peptide
Synthesis Springer- Verlag, Berlin Heidelberg 1984; J. Seyden-Penne: Reductions by the Alumino- and Borohydrides in Organic Synthesis, 2nd Ed., Wiley -VCH, 1997; and L. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons (1995). The compounds of this invention may be modified by appending appropriate functionalities to enhance selective biological properties. Such modifications are known in the art and include those which increase biological penetration into a given biological compartment (e.g., blood, lymphatic system, central nervous system), increase oral availability, increase solubility to allow administration by injection, alter metabolism and alter rate of excretion.
The following examples contain detailed descriptions of the methods of preparation of compounds of Formulas 1-5 and and 3'. These detailed descriptions fall within the scope, and serve to exemplify, the above described General Synthetic Procedures which form part of the invention. These detailed descriptions are presented for illustrative purposes only and are not intended as a restriction on the scope of the invention.
EXPERIMENTAL
Unless otherwise noted, all materials were obtained from commercial suppliers and used without further purification. All parts are by weight and temperatures are in degrees centigrade unless otherwise indicated. All microwave assisted reactions were conducted with a Initiator™ Microwave Synthesizer from Biotage™. All compounds showed NMR spectra consistent with their assigned structures. Melting points were determined on a Buchi apparatus and are uncorrected. MS data was determined by electrospray ionization technique. All examples were purified to >90% purity as determined by high-performance liquid chromatography. Unless otherwise stated, reactions were run at RT.
Analytical Methods:
Unless otherwise indicated, HPLC analyses were run on an Agilent Model 1100 system with an Agilent Technologies Zorbax SB-C8 (5 μ) reverse phase column (4.6 x 150 mm) run at 30 °C with a flow rate of about 1.50 mL/min (Agilent Technologies, Santa Clara, CA). The mobile phase used solvent A (H2O/0.1 % TFA) and solvent B (ACN/0.1% TFA) with a 11 min gradient from 5% to 100% ACN. The gradient was followed by a 2 min. return to 5% ACN and about a 2.5 min. re-equilibration (flush).
LC-MS Methods: Unless otherwise indicated, samples were run on an Agilent model- 1100 LC- MSD system with an Agilent Technologies XDB-C8 (3.5μ) reverse phase column (4.6 x 75 mm) at 30 °C. The flow rate was constant and ranged from about 0.75 mL/min to about 1.0 mL/min.The mobile phase used a mixture of solvent A (H2O/0.1% HCO2H or TFA) and solvent B (ACN/0.1 % HC02H or TFA) with a 5 to for a gradient from 10% to 90% solvent B. The gradient was followed by a 0.5 min period 9 min time period to return to 10% solvent B and a 2.5 min 10% solvent B re-equilibration (flush) of the column Preparative HPLC Methods:
Where indicated, compounds of the present invention were purified via reverse phase HPLC using a Gilson (Gilson, Middleton, WI) or Shimadzu (Columbia, MD) workstation utilizing one of the following two protocols: (A) Using a 50 x 100 mm column (Waters, Exterra, Qs, 5μ) (Waters, Milford, MA) at 50 mL/min. The mobile phase used was a mixture of solvent A (H2O/10 mM ammonium carbonate at pH about 10, adjusted with cone. NH4OH) and solvent B (85:15 ACN/water, 10 mM ammonium carbonate at pH of about 10 adjusted with cone. NH4OH). Each purification run utilized a >10 min gradient from 40% to 100% solvent B followed by a 5 min flow of 100% solvent B. The gradient was followed by a 2 min return to 40% solvent B; or (B) Using a Waters 20 x 50 mm column at 20 mL/min or Phenomenex Gemni 5μ Ci§ 100 x 30mm
(Phenomenex, Torrance, CA). The mobile phase used was a mixture of solvent A (H2O/0.1% TFA) and solvent B (ACN/0.1% TFA) with a >10 min gradient from 5% to 100% solvent B. The gradient is followed by a 2 min return to 5% ACN. Mass Spectra (MS)
Unless otherwise indicated, all mass spectral data for starting materials, intermediates and/or exemplary compounds are reported as mass/charge (m/z), having an (M+H+) or (M-FT) molecular ion, depending on the ionization mode (positive or negative). The molecular ion reported was obtained by electrospray detection method. Compounds having an isotopic atom, such as bromine and the like, are reported according to the detected isotopic pattern, as appreciated by those skilled in the art.
Intermediates Intermediate A: 5-allylpiperidine-2,4-dione
Figure imgf000072_0001
Step 1 : tert-butyl 5-allyl-2,4-dioxopiperidine-l-carboxylate
To a solution of tert-butyl 2,4-dioxopiperidine-l-carboxylate (Ark Pharma, Libertyville, IL, 8.50 g, 39.9 mmol) and allyl chloride (Acros Organics, 12.99 ml, 159 mmol) in 400 mL THF at -20 °C (acetone bath with dry ice added periodically) was added LiHMDS, 1.0 M solution in THF (Sigma Aldrich, St. Louis, MO, 100 ml, 100 mmol) dropwise via addition funnel, with the internal temperature of the reaction kept at -18 to -20 °C. A thick precipitate was observed, which disappeared on complete addition. The clear, yellow- orange reaction was stirred for 1 h and was quenched by addition of water and 400 mL Et20. The aqueous layer was acidified with 5 N HCl, and the organic layer was washed 1 x brine, and the combined organics were dried over anhydrous MgS04, filtered, and concentrated in vacuo. The material was treated with DCM and purified by silica gel chromatography (330 g) eluting with 0-100% EtOAc/hexanes. The product containing fractions were combined and concentrated to afford tert-butyl 5-allyl-2,4-dioxopiperidine- 1-carboxylate (7.00 g, 27.6 mmol, 69.3 % yield): !H NMR (400 MHz, DMSO-d6) δ ppm 11.23 (1 H, br. s.), 5.65 - 5.90 (1 H, m), 5.01 - 5.17 (2 H, m), 4.93 (1 H, s), 3.75 (1 H, dd,
J=13.1 , 4.3 Hz), 3.58 (1 H, dd, J=13.2, 4.4 Hz), 2.30 - 2.49 (2 H, m), 2.04 - 2.18 (1 H, m), 1.42 (9 H, s).
Step 2: 5-allylpiperidine-2,4-dione
In a 1 -L round-bottomed flask tert-butyl 5-allyl-2,4-dioxopiperidine-l -carboxylate (35.60 g, 141 mmol) was treated with 4 M HCl in 1 ,4-dioxane (Sigma Aldrich, 176 ml, 703 mmol). The mixture was stirred under inert atmosphere overnight. The progress of the reaction was monitored by TLC (eluent: 100% EtOAc) and LC/MS, which showed reaction completion. The mixture was concentrated in-vacuo. The residue was diluted with DCM (500 ml). Then solid NaHC03 (125 g) was added slowly into the mixture.
The overall mixture was stirred vigourously for 1.5 h, then filtered through a fine-fritted funnel. To the filtrate, was dried over Na2S04, filtered and concentrated in-vacuo. The crude was triturated with EtOAc (200 ml) and hexanes (800 ml). The mixture was filtered and the filtrate was concentrated in-vacuo. This gave 5-allylpiperidine-2,4-dione (16.98 g, 111 mmol, 79 % yield) as a tan oil, which was used without further purification: m/z (ESI, +ve) 154.0 (M+H)+.
Intermediate B: (S)-7-allyl-2-bromo-6,7-dihydro-lH-pyrrolo[3,2-c]pyridin-4(5H)- one
Figure imgf000073_0001
Step 1 : (S)-7-allyl-6,7-dihydro-lH-pyrrolo[3,2-c]pyridin-4(5H)-one
To a solution of aminoacetaldehyde dimethyl acetal (58 g, 553.3 mmol, Sigma-Aldrich) in THF (150 mL) was added tert-butyl 5-allyl-2,4-dioxopiperidine-l-carboxylate (Intermediate A, Step 1; 70 g, 276.6 mmol,). The reaction was heated at 100 °C for 45 min. The solvent was removed in vacuo and the residue was washed with Et20. The crude material was dissolved in DCM (200 mL) and cooled to 0 °C. TFA (200 mL) was added and the mixture was slowly warmed to RT and stirred for 8 h. The solvent was then removed in vacuo and the residue was diluted with DCM and treated with solid NaHC03 (200 g). The suspension was filtered and the filtrate was concentrated. The residue was purified with silica gel chromatography (eluted with 2% MeOH in DCM) to give 7-allyl- 6,7-dihydro-li7-pyrrolo[3,2-c]pyridin-4(5//)-one (8.8 g, 18.1 %) as an off white solid. !H- NMR (400MHz, DMSO-cW): δ 11.20 (s, 1H), 6.80 (s, 1H), 6.70 (t, J= 2.8 Hz, 1H), 6.22 (t, J= 2.4 Hz, 1H), 5.78 - 5.86 (m, 1H), 5.07 - 5.12 (m, 2H), 3.31 - 3.42 (m, 1H), 3.09 - 3.14 (m, 1H), 2.95 - 2.99 (m, 1H), 2.20 - 2.28 (m, 1H). MS (ESI, pos. ion) m/z: 171.1
(M+l). The racemic mixture was resolved by SFC (20% MeOH, Chiralpak ICH (250x20 mm), 70ml/min, 262 -nm, 81/158 Bar) to give separated enantiomers (S)-7-allyl-6,7- dihydro-lH-pyrrolo[3,2-c]pyridin-4(5H)-one (first eluting peak), and (R)-7-allyl-6,7- dihydro-lH-pyrrolo[3,2-c]pyridin-4(5H)-one (second eluting peak). Step 2: (S)-7-allyl-2-bromo-6,7-dihydro-lH-pyrrolo[3,2-c]pyridin-4(5H)-one
To a 250-mL round-bottomed flask was added (S)-7-allyl-6,7-dihydro-lH-pyrrolo[3,2- c]pyridin-4(5H)-one (2.50 g, 14.19 mmol) in DMF (50 mL). The solution was cooled to - 60 °C and l ,3-dibromo-5,5-dimethylhydantoin (2.028 g, 7.09 mmol, Sigma-Aldrich) was added. The reaction was stirred at -60 °C for 20 min. The mixture was poured into ice/water (300 mL) and a solid formed. The suspension was filtered and the solid was washed with EtOAc (80 mL). The solid was dried to give 3.0 g of the product. The filtrate was extracted with EtOAc (150 mL x3) and the combined organic layers were washed with water (80 mL x3), brine (50 mL), dried (MgS04), filtered and concentrated. The residue was purified with silica gel chromatography (eluted with 1-3% MeOH in DCM) to give the product 390 mg. Overall (S)-7-allyl-2-bromo-6,7-dihydro-lH-pyrrolo[3,2- c]pyridin-4(5H)-one (3.39 g, 13.29 mmol, 94 % yield) was obtained: !H NMR (400 MHz, DMSO-de) δ ppm 1 1.83 (1 H, br. s.), 6.96 (1 H, br. s.), 6.23 (1 H, d, J=2.0 Hz), 5.73 - 5.87 (1 H, m), 5.04 - 5.15 (2 H, m), 3.40 (1 H, ddd, J=12.3, 5.5, 2.3 Hz), 3.12 (1 H, ddd, J=12.4, 6.6, 2.9 Hz), 2.89 - 2.99 (1 H, m), 2.46 - 2.49 (1 H, m), 2.18 - 2.30 (1 H, m). MS (ESI, pos. ion) m/z: 255.0/257.0 (M+l).
Intermediate C: 7-allyl-2-(3-fluoro-2-methylquinoxalin-5-yl)-6,7-dihydro-lH- pyrrolo[3,2-c]pyridin-4(5H)-one
Figure imgf000074_0001
NH4OAC (Fisher Scientific, Fair Lawn, NJ, 7.76 g, 101 mmol), 5-allylpiperidine-2,4- dione (Intermediate A, 3.86 g, 25.2 mmol), 2-bromo-l-(3-fluoro-2-methylquinoxalin-5- yl)ethanone (4.75 g, 16.78 mmol) were combined in 160 mL EtOH, sealed, and heated at
50 °C for 5 h. The reaction was concentrated to 1/2 volume, then partitioned between saturated aqueous NaHC03 (caution, gas evolution) and DCM. The aqueous layer was extracted with DCM 3x, and the combined organics were dried over anhydrous Na2S04, filtered, and concentrated in vacuo. The material was treated with a minimal volume of MeOH, sonicated, and filtered, rinsing 2x MeOH, to give 1.6 g (28% yield) 7-allyl-2-(3- fluoro-2-methylquinoxalin-5 -yl)-6,7-dihydro- 1 H-pyrrolo [3 ,2-c]pyridin-4(5H)-one as an orange solid: !H NMR (400 MHz, DMSO-d6) δ ppm 1 1.59 (1 H, s), 8.08 (1 H, dt, .7=7.4, 0.7 Hz), 7.86 - 7.96 (1 H, m), 7.72 - 7.84 (1 H, m), 7.19 (1 H, d, J=2.3 Hz), 7.00 (1 H, t, J=2.6 Hz), 5.83 - 6.04 (1 H, m), 5.02 - 5.28 (2 H, m), 3.40 - 3.55 (1 H, m), 3.03 - 3.26 (3 H, m), 2.69 (3 H, s), 2.53 - 2.61 (1 H, m), 2.28 - 2.41 (1 H, m). m/z (ESI, +ve) 337.1 (M+H)+.
Intermediate D: 2(S)-7-allyl-2-(3-fluoro-2-methylquinoxalin-5-yl)-6,7-dihydro-lH- pyrrolo[3,2-c]pyridin-4(5H)-one
Intermediate E: 2(R)-7-allyl-2-(3-fluoro-2-methylquinoxalin-5-yl)-6,7-dihydro-lH- pyrrolo[3,2-c]pyridin-4(5H)-one
Figure imgf000075_0001
Intermediate C was resolved by SFC (Chiralpak ASH, 5 μ, 250x30, 30% IPA containing 0.2% DEA, 120mL/min, 268 nm, 96/213 Bar) to give separated enantiomers 2(S)-7-allyl- 2-(3-fluoro-2-methylquinoxalin-5-yl)-6,7-dihydro-lH-pyrrolo[3,2-c]pyridin-4(5H)-one (first eluting peak, intermediate D), and 2(R)-7-allyl-2-(3-fluoro-2-methylquinoxalin-5- yl)-6,7-dihydro-lH-pyrrolo[3,2-c]pyridin-4(5H)-one (second eluting peak, intermediate E).
Intermediate D alternative preparation: 2(S)-7-allyl-2-(3-fluoro-2- methylquinoxalin-5-yl)-6,7-dihydro-lH-pyrrolo[3,2-c]pyridin-4(5H)-one
Figure imgf000075_0002
Step 1 : 3-fluoro-2-methyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)quinoxaline A 500 mL rbf was charged with a stir bar, KOAc (Sigma Aldrich, 29.3 g, 299 mmol), PdCl2(PPh3)2 DCM adduct (Strem Chemicals, Newburyport, MA, 3.05 g, 3.73 mmol), bis(pinacolato)diboron (Sigma Aldrich, 37.9 g, 149 mmol), 5-bromo-3-fluoro-2- methylquinoxaline (18.0 g, 74.7 mmol), and 100 mL anhydrous THF. Argon was bubbled into the mixture for 1 min, and the reaction was fitted with a water-cooled reflux condensor and was heated to reflux under argon. After 4 h the reaction was judged complete, was cooled, diluted with 100 mL EtOAc, filtered through Celite, rinsing 3 x 100 mL EtOAc, and concentrated in vacuo. The material was treated with DCM and adsorbed onto 100 g silica gel and purified by silica gel chromatography (split into two batches) (240 g column) using 0 - 70% EtOAc/hexane. The product-containing fractions were concentrated to afford 27.9 g of an orange semi-sold, which was used without further purification. A portion of this material was used in the next step.
Step 2: (S)-7-allyl-2-(3-fluoro-2-methylquinoxalin-5-yl)-6,7-dihydro-lH-pyrrolo[3,2- c]pyridin-4(5H)-one
Argon was bubbled into a mixture of l,l-bis[(di-t-butyl-p- methylaminophenyl]palladium(ii) chloride (Sigma Aldrich, 1.227 g, 1.733 mmol), potassium phosphate, dibasic (EMD Chemicals, Gibbstown, NJ, 21.12 g, 121 mmol), (S)-7-allyl-2-bromo-6,7-dihydro-lH-pyrrolo[3,2-c]pyridin-4(5H)-one (Intermediate B, 8.84 g, 34.7 mmol), 3-fluoro-2-methyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)quinoxaline (19.97 g, 69.3 mmol) (impure, from previous step) in 200 mL DMF and 100 mL water for 2 min. The orange slurry was placed in a 70 °C oil bath under argon. After 2 h the reaction was checked by LCMS and judged complete. The reaction was poured onto ice, and the resulting solid was collected by filtration (glass frit), rinsing 3 x 100 mL water. The slightly wet filter cake was transferred to a 500 mL rbf with
MeOH/DCM and concentrated in vacuo to give 11.6 g material. The material was treated with 20% MeOH in DCM and adsorbed onto 55 g silica gel and purified by silica gel chromatography (220 g) using 0 - 100% 90/10 DCM/MeOH in DCM. The product- containing fractions were concentrated to afford (S)-7-allyl-2-(3-fluoro-2- methylquinoxalin-5-yl)-6,7-dihydro-lH-pyrrolo[3,2-c]pyridin-4(5H)-one (7.40 g, 22.00 mmol, 63.5 % yield) as a orange solid: !H NMR (400 MHz, DMSO-d6) δ ppm 11.59 (1 H, s), 8.08 (1 H, dt, J=1A, 0.7 Hz), 7.86 - 7.96 (1 H, m), 7.72 - 7.84 (1 H, m), 7.19 (1 H, d, J=2.3 Hz), 7.00 (1 H, t, J=2.6 Hz), 5.83 - 6.04 (1 H, m), 5.02 - 5.28 (2 H, m), 3.40 - 3.55 (1 H, m), 3.03 - 3.26 (3 H, m), 2.69 (3 H, s), 2.53 - 2.61 (1 H, m), 2.28 - 2.41 (1 H, m/z (ESI, +ve) 337.1 (M+H)+.
Intermediate F: 7-allyl-2-(2-chloroquinolin-8-yl)-6,7-dihydro-lH-pyrrolo[3,2- c] pyridin-4(5H)-one
Figure imgf000077_0001
2-Bromo-l-(2-chloroquinolin-8-yl)ethanone (0.900 g, 3.16 mmol), 5-allylpiperidine-2,4- dione (Intermediate A, 0.581 g, 3.80 mmol), NH4OAC (Fisher Scientific, 0.975 g, 12.65 mmol) were combined in 15 mL EtOH, sealed, and heated in a 50 °C bath for 4 h. The reaction was partitioned between saturated aqueous NaHCC and DCM. The aqueous layer was extracted with DCM 3x, and the combined organics were dried over anhydrous Na2S04, filtered, and concentrated in vacuo. The material was treated with DCM and purified by silica gel chromatography (80 g column) using 0 - 60% 90/10 DCM/MeOH in DCM. The product- containing fractions were concentrated to give 7-allyl-2-(2- chloroquinolin-8-yl)-6,7-dihydro-lH-pyrrolo[3,2-c]pyridin-4(5H)-one (0.365 g, 1.081 mmol, 34.2 % yield) as a sticky orange- brown oil: !H NMR (400 MHz, DMSO-d6) δ ppm 11.70 (1 H, d, J=0.6 Hz), 8.50 (1 H, d, J=8.6 Hz), 8.13 (1 H, dt, J=1A, 0.8 Hz), 7.90 (1 H, dt, .7=8.0, 0.8 Hz), 7.58 - 7.73 (2 H, m), 7.20 (1 H, d, J=0.4 Hz), 7.00 (1 H, br. s.), 5.87 - 6.05 (1 H, m), 5.12 - 5.24 (2 H, m), 3.43 - 3.58 (1 H, m), 3.04 - 3.27 (2 H, m), 2.53 - 2.62 (1 H, m), 2.30 - 2.43 (1 H, m). m/z (ESI, +ve) 338.1 (M+H)+.
Intermediate G and H: (S)-but-3-en-2-amine hydrochloride and (R)-but-3-en-2- amine hydrochloride
Figure imgf000077_0002
Step 1 : 2-(but-3-en-2-yl)isoindoline-l,3-dione
A mixture of phthalimide potassium (39.3 g, 212 mmol), K2C03 (5.9 g, 42.5 mmol), and DMF (354 ml) was set stirring at RT before adding 3-chloro-l-butene (25.00 ml, 276 mmol). The suspension was fitted with a reflux condenser and heated to 140 °C for 7 h before cooling to RT and pouring in 1.5 L water at 0 °C with rapid stirring. The resulting white precipitate was collected by filtration and was rinsed with cold water. After drying under air for 1 h, the material was transferred to a bottle and dried under vacuum at 50 °C overnight to give 2-(but-3-en-2-yl)isoindoline-l,3-dione (41.05 g, 204 mmol, 96% yield): !H NMR (400 MHz, DMSO-d6) δ ppm 7.75 - 7.94 (4 H, m), 6.11 (1 H, ddd, J=17.3, 10.4, 5.8 Hz), 5.05 - 5.25 (2 H, m), 4.72 - 4.89 (1 H, m), 1.50 (3 H, d, J=7.0 Hz), m/z (ESI, +ve) 202.1 (M+H)+.
Step 2: (R)-2-(but-3-en-2-yl)isoindoline-l,3-dione and (S)-2-(but-3-en-2-yl)isoindoline- 1,3-dione
2-(But-3-en-2-yl)isoindoline-l,3-dione (351 g, 1.7 mol) was resolved by chiral SFC (Column: Chiralpak AD-H, 50 X 250 mm, 5 μιη, Mobile Phase A: C02, Mobile Phase B: MeOH, Isocratic: 10% B with CO2 recycler on, Flow Rate: 225 g/min) to give first eluting peak (R)-2-(but-3-en-2-yl)isoindoline-l,3-dione (135 g, 672 mmol) and second eluting peak (S)-2-(but-3-en-2-yl)isoindoline-l,3-dione (140 g, 698 mmol).
Preparation of intermediate G (S)-but-3-en-2-amine hydrochloride:
(S)-2-(But-3-en-2-yl)isoindoline- 1,3-dione (97.70 g, 486 mmol) was treated with ethanolamine (Sigma Aldrich, 122 ml, 2039 mmol) and EtOH (211 ml) in a 1L round- bottom flask. The flask was sealed with cap/parafilm and placed into a pre-heated (30
°C) bath, then stirred the mixture overnight. The flask was fitted with a water-cooled short path and heated in an oil bath (95 °C). A single fraction was collected boiling at 78 °C. The fraction was added slowly via pipette to a rapidly stirring solution of HC1, 1.0 M solution in Et20 (Sigma Aldrich, 864 ml, 864 mmol) at 0 °C (a white precipitate formed). After 30 min, the reaction mixture was concentrated in vacuo. Hexanes were added into the mixture, then concentrated in vacuo. The residue was placed under high-vac for 2 h. The semi-solid was diluted with Et20 (100 ml) and placed into a sonicator for 3 min. The precipitate was collected by filtration and the flask was rinsed with Et20 and collected precipitate. The solid was dried in reduced-pressure oven (50 °C) 2 h. This gave (S)-but- 3-en-2 -amine hydrochloride (28.89 g, 269 mmol, 55.3 % yield) as white solid: !H NMR (400 MHz, CD3OD) δ ppm 5.92 (t, J=6.65 Hz, 1 H) 5.32 - 5.58 (m, 2 H) 3.87 (s, 1 H) 1.39 (d, J=6.65 Hz, 3 H). Preparation of intermediate H (R)-but-3-en-2-amine hydrochloride:
(R)-2-(But-3-en-2-yl)isoindoline-l,3-dione (14.5 g, 72.1 mmol) in a 250 mL rbf was treated with 30 mL EtOH and ethanolamine ( Sigma- Aldrich, 18.16 ml, 303 mmol). The slurry was sealed and placed in a 30 °C bath for 12 h. The clear, light yellow reaction was fitted with a short path distillation apparatus and heated. A single fraction boiling at about 77 °C, 20.5 g, was collected. The material was added slowly via pipette to a stirring solution of HC1, 1.0 M solution in Et20 (Sigma Aldrich; 100 ml, 100 mmol) at 0 °C. A thick white precipitate was evident. After 1 h, the mixture was concentrated in vacuo to give a waxy material. This was treated with 30 mL anhydrous toluene and concentrated in vacuo to give a white solid. Dried overnight on hood pump to give (R)-but-3-en-2 -amine hydrochloride (6.07 g, 56.4 mmol, 78 % yield). !H NMR (400 MHz, CD3OD) δ ppm 5.92 (t, J=6.65 Hz, 1 H) 5.32 - 5.58 (m, 2 H) 3.87 (s, 1 H) 1.39 (d, J=6.65 Hz, 3 H).
Intermediate I: 3-methyl-N-(2-methylallyl)-8-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)quinoxalin-2-amine
Figure imgf000079_0001
Step 1 : 8-bromo-3-methyl-N-(2-methylallyl)quinoxalin-2-amine
A sealed bottle was charged with 2-methylallylamine (6.74 g, 95 mmol, Matrix Scientific, Columbia, SC), 5-bromo-3-chloro-2-methylquinoxaline (6.10 g, 23.69 mmol) in DMSO (40 mL). The reaction was heated at 100 °C for 1 h, then cooled to RT. The mixture was poured into ice/water (200 mL) and stirred for 10 min. The suspension was filtered and the solid was dried. The solid was further treated with 10% Et20 in hexanes (50 mL) and the suspension was filtered and the solid was dried to give the product 4.2 g. The filtrate was concentrated and the residue was purified with silica gel chromatography (eluted with 15-25% EtOAc in Hexanes) to give another 2.6 g of the product. Overall 8-bromo- 3-methyl-N-(2-methylallyl)quinoxalin-2 -amine (6.8 g, 23.27 mmol, 98 % yield) was obtained: !H NMR (400 MHz, CDCl3) δ ppm 7.83 (1 H, d, J=7.6 Hz), 7.80 (1 H, t, J=8.2 Hz), 7.23 (1 H, t, J=7.9 Hz), 5.14 (1 H, br. s.), 5.03 (1 H, s), 4.94 (1 H, s), 4.30 (2 H, d, J=5.7 Hz), 2.62 (3 H, s), 1.88 (3 H, s). MS (ESI, pos. ion) m/z: 292.0/294.0 (M+l).
Step 2: 3-methyl-N-(2-methylallyl)-8-(4,4,5,5-tetramethyl-l ,3,2-dioxaborolan-2- yl)quinoxalin-2-amine
A mixture of 8-bromo-3-methyl-N-(2-methylallyl)quinoxalin-2 -amine (10.128 g, 34.7 mmol), bis(pinacolato)diboron (17.61 g, 69.3 mmol, Sigma-Aldrich), PdCl2(PPh3)2
(1.415 g, 1.733 mmol, Sigma-Aldrich) and KOAc (13.61 g, 139 mmol, Alfa Aesar) in THF (69.3 ml) was heated at 100 °C in a sealed vessel for 14 h, then cooled to RT. The mixture was diluted with EtOAc (200 mL) and filtered through a pad of Celite. The filtrate was dried, filtered and concentrated. The crude product was purified with silica gel chromatography (eluted with 0-40% EtOAc in Hexanes) to give 3-methyl-N-(2- methylallyl)-8-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)quinoxalin-2 -amine (10.31 g, 30.4 mmol, 88 % yield) as a brown oil: !H NMR (400 MHz, DMSO-i/6) δ ppm 7.75 (dd, J=8.0, 1.4 Hz, 1 H), 7.65 (dd, J=6.9, 1.3 Hz, 1 H), 7.24 - 7.30 (m, 1 H), 7.16 - 7.23 (m, 1 H), 4.87 - 4.93 (m, 1 H), 4.77 (s, 1 H), 4.16 (d, J=5.9 Hz, 2 H), 2.52 (s, 3 H), 1.78 (s, 3 H), 1.33 (s, 12 H). MS (ESI, pos. ion) m/z: 258 (M+l) (the mass of boronic acid was observed).
Intermediate J: ethyl 2-(7-bromo-l-oxo-l,2,3,4-tetrahydropyrrolo[l,2-a]pyrazin-4- yl)acetate
Figure imgf000080_0001
Step 1 : (is)-ethyl 4-(4-bromo-lH-pyrrole-2-carboxamido)but-2-enoate
The title compound was prepared according to WO2010/031816. !H NMR (400 MHz,
CDCl3) δ ppm 9.48 (1 H, br. s.), 6.89 - 7.01 (2 H, m), 6.58 (1 H, dd, J=2.7, 1.4 Hz), 5.89 - 6.02 (2 H, m), 4.16 - 4.24 (2 H, m), 1.23 - 1.32 (3 H, m). m/z (ESI, +ve ion) 301.0/302.9 (M+H)+.
Step 2: ethyl 2-(7-bromo-l-oxo-l,2,3,4-tetrahydropyrrolo[l,2-a]pyrazin-4-yl)acetate (is)-Ethyl 4-(4-bromo-lH-pyrrole-2-carboxamido)but-2-enoate (2.35 g, 7.80 mmol) was treated with ACN (30 mL) under argon and treated with DBU (0.27 mL, 1.795 mmol) and stirred at RT for 1 h 45 min. The mixture was concentrated on the rotovap and the crude residue purified on the ISCO Combiflash Rf (40 g Thomson SingleStep column, using a gradient of 30-50% EtOAc in hexanes) affording ethyl 2-(7-bromo-l-oxo-l, 2,3,4- tetrahydropyrrolo[l,2-a]pyrazin-4-yl)acetate (1.24 g, 4.12 mmol, 52.8 % yield) as a colorless viscous oil which crystallized to a white solid overnight under vacuum. !H NMR (400 MHz, CDCh) δ ppm 6.93 (1 H, d, J=1.6 Hz), 6.84 (1 H, d, J=1.8 Hz), 5.87 (1 H, br. s.), 4.65 (1 H, tt, J=6.8, 3.4 Hz), 4.11 - 4.24 (2 H, m), 3.92 (1 H, dd, J=12.8, 4.0 Hz), 3.46 - 3.54 (1 H, m), 2.74 - 2.90 (2 H, m), 1.26 (3 H, t, J=7.1 Hz), m/z (ESI, +ve ion) 301.0/303.0 (M+H)+.
Intermediate K: 5-bromo-3-chloro-6-fluoro-2-methylquinoxaline
Figure imgf000081_0001
Step 1 : 2-bromo-l,3-difluoro-4-nitrobenzene
l-Bromo-2,6-difluorobenzene (Oakwood Products Inc., West Columbia, SC, 15.4 mL, 104 mmol) was treated with H2SO4, 95-98% (77 mL, 1445 mmol) and cooled in an ice bath. It was then treated with HNO3 69-70% (68 mL, 1050 mmol) slowly dropwise via a dropping funnel and stirred for and additional 30 min. The mixture was poured onto ice (500 mL) and stirred vigourously for 3 min. The resulting suspension was extracted with DCM (4 x 100 mL), washed with brine (500 mL) and dried over Na2S04, filtered and concentrated affording crude 2-bromo-l,3-difluoro-4-nitrobenzene (32.55 g, 137 mmol) as a bright yellow crystalline solid. !H NMR (400 MHz, CDCh) δ ppm 8.13 (1 H, ddd, J=9A, 8.1, 5.5 Hz), 7.13 (1 H, ddd, J=9.3, 7.1, 2.0 Hz). 19F NMR (376 MHz, CDCl3) δ ppm -92.06 (1 F, s), -104.31 (1 F, s). m/z (ESI, +ve ion) 259.1/261.1 (M+Na)+. Step 2: 2-bromo-3-fluoro-6-nitroaniline
Prepared according to WO 2010/046388. 2-Bromo-l ,3-difluoro-4-nitrobenzene (27.15 g, 114 mmol) was treated with ammonium carbonate (Sigma Aldrich, 10.96 g, 1 14 mmol) and DMF (200 mL) followed by Et3N (47.7 mL, 342 mmol) and stirred at RT for 48 h. The mixture was treated with water and extracted with DCM (300 mL). The DCM layer was washed with water (3 x 200 mL) and brine (3 x 200 mL), dried over MgS04, filtered and concentrated affording crude 2-bromo-3-fluoro-6-nitroaniline (25.99 g, 11 1 mmol, 97 % yield) as a bright yellow amorphous solid: !H NMR (400 MHz, CDCl3) δ ppm 8.22 (1 H, dd, J=9.6, 5.9 Hz), 6.81 (2 H, br. s.), 6.56 (2 H, dd, J=9.6, 7.2 Hz). 19F NMR (376 MHz, CDCl3) δ ppm -90.92 (1 F, s). m/z (ESI, +ve ion) 234.9/236.9 (M+H)+.
Step 3 : 3-bromo-4-fluorobenzene-l,2-diamine
A 500 mL round-bottomed flask containing 5% Pt/C (6.00 g, 1.54 mmol) and 2-bromo-3- fluoro-6-nitroaniline (20.85 g, 89 mmol) were treated with EtOH (250 mL) and stirred under an atmosphere of H2 (balloon) for 22 h. LC-MS indicated ca. 35% conversion to the desired material (M+l=204.9/206.9). Another balloon of H2 was added and it was stirred for another 16 h resulting in >90% conversion to the desired product (M+l=204.9/207.1) by LC-MS. The suspension was filtered through a plug of Celite washing with EtOH and concentrated affording crude 3-bromo-4-fluorobenzene-l , 2 -diamine (18 g, 88 mmol, 99 % yield) as a black/purple viscous oil: !H NMR (400 MHz, CDCl3) δ ppm 6.60 (1 H, dd, J=8.5, 5.2 Hz), 6.42 - 6.50 (1 H, m). 19F NMR (376 MHz, CDCl3) δ ppm -1 16.48 (1 F, s). m/z (ESI, +ve ion) 204.9/206.9 (M+H)+.
Step 4: 8-bromo-7-fluoro-3-methyl-3,4-dihydroquinoxalin-2(lH)-one
A 500 mL round-bottomed flask charged with 3-bromo-4-fluorobenzene-l,2-diamine (18 g, 88 mmol), DMF (100 mL), ethyl 2-bromopropionate (Sigma Aldrich, 1 1.54 mL, 89 mmol) and NaHC03, powder (7.60 g, 90 mmol) was heated to 90 °C with a reflux condenser for 30 min, then at 120 °C for 15 h. The reaction was cooled to RT, treated with brine and extracted with EtOAc (2 x 200 mL), washed with brine (3 x) and dried over Na2S04, filtered and concentrated affording crude 8-bromo-7-fluoro-3-methyl-3,4- dihydroquinoxalin-2(lH)-one (21.75 g, 84 mmol, 96 % yield) as an orange-brown viscous oil. The material was used in the subsequent step without further purification: !H NMR (400 MHz, DMSO-d6) δ ppm 9.67 (s, 1 H) 6.78 - 6.89 (m, 1 H) 6.48 - 6.78 (m, 1 H) 6.07 - 6.35 (m, 1 H) 1.25 (d, J=6.46 Hz, 3 H). 19F NMR (377 MHz, DMSO-d6) δ ppm -120.49 (1 F, s). m/z (ESI, +ve ion) 259.0/261.0 (M+H)+.
Step 5 : 8-bromo-7-fluoro-3-methylquinoxalin-2(lH)-one
A mixture of water (14 mL) and 30% H202 (30.0 mL, 294 mmol) was added slowly dropwise to a solution of 8-bromo-7-fluoro-3 -methyl-3 ,4-dihydroquinoxalin-2( 1 H)-one
(21.7 g, 84 mmol) in IN NaOH (168 mL, 168 mmol) and MeOH (140 mL). The flask was fitted with a reflux condenser and heated at 85 °C for 3 h. LC-MS indicated ca. 87% conversion to the desired product (M+l=257.0/259.0). The reaction mixture was cooled to RT and acidified with 2N HC1 to ca. pH 6 and was diluted with CHC13/IPA(4: 1) (100 mL), added to a separatory funnel. The resulting suspension was filtered through a sintered glass frit, washing with water and dried affording 8-bromo-7-fluoro-3- methylquinoxalin-2(lH)-one (5.83 g, 22 mmol, 22 % yield) as a light brown solid, m/z (ESI, +ve ion) 257.0/259.0 (M+H)+. !H NMR (400 MHz, DMSO-d6) δ ppm 1 1.83 (1 H, br. s.), 7.67 - 7.88 (1 H, m), 7.34 (1 H, t, J=8.4 Hz), 2.43 (3 H, s). 19F NMR (377 MHz, DMSO-d6) δ ppm -104.13 (1 F, s). The aqueous solution was extracted with CHCl3:z-
PrOH 9: 1 (6 x 100 mL), dried over MgSO t, filtered and concentrated affording additional 8-bromo-7-fluoro-3-methylquinoxalin-2(lH)-one (12.51 g, 49 mmol, 58 % yield) as a dark brown amorphous solid (ca. 80%o purity). The material was used in the subsequent step without further purification.
Step 6: 5-bromo-3-chloro-6-fluoro-2-methylquinoxaline
In a 500-mL round-bottomed flask, 8-bromo-7-fluoro-3-methylquinoxalin-2(lH)-one (3.57 g, 13.89 mmol) and POCl3 (20.0 mL, 215 mmol) were heated at 90 °C for 1.5 h with a reflux condenser. The reaction was cooled to RT and most of the excess POCI3 was removed under reduced pressure (rotary evaporator). The mixture was treated with EtOAc
(100 mL), cooled in an ice bath, treated with ice chips and IN NaOH slowly. After phase separation, the organic layer was washed with brine (50 mL), dried over MgS04, filtered and concentrated to afford the crude product as a brown solid. The crude residue was purified by chromatography on the ISCO Combiflash Rf (80 g Redisep column, using a gradient of 0-100% DCM in hexanes (eluted with ca. 35-60% DCM)) affording 5-bromo- 3-chloro-6-fluoro-2-methylquinoxaline (1.88 g, 6.82 mmol, 49.1 % yield) as a light orange crystalline solid, m/z (ESI, +ve ion) 275.0/277.0 (M+H)+. !H NMR (400 MHz, CZX¾) 5 ppm 8.01 (1 H, dd, J=9.3, 5.4 Hz), 7.58 (1 H, dd, J=9.1 , 8.1 Hz), 2.86 (3 H, s). 19F NMR (376 MHz, CDCl3) δ ppm -99.07 (1 F, s).
Intermediate L: (S)-7-allyl-2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-6,7- dihydro-lH-pyrrolo[3,2-c]pyridin-4(5H)-one
Figure imgf000084_0001
A glass microwave reaction vessel was charged with (S)-7-allyl-2-bromo-6,7-dihydro- lH-pyrrolo[3,2-c]pyridin-4(5H)-one (Intermediate D, 228 mg, 0.894 mmol), bis(pinacolato)diboron (Sigma Aldrich, 454 mg, 1.787 mmol), PdCl2(dppf) DCM adduct (Sigma Aldrich, 36 mg, 0.045 mmol) and KOAc (Sigma Aldrich, 351 mg, 3.57 mmol) in THF (4.00 mL). The reaction mixture was stirred and heated in a Initiator microwave reactor (Personal Chemistry, Biotage AB, Inc., Upssala, Sweden) at 100 °C for 50 min. EtOAc was added and the mixture was filtered through Celite and the filtrate was concentrated. The crude material was purified by silica gel chromatography (12 g), eluting with 100% EtOAc, to give (S)-7-allyl-2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan- 2-yl)-6,7-dihydro-lH-pyrrolo[3,2-c]pyridin-4(5H)-one (130 mg, 0.430 mmol, 48 % yield) as an off-white solid, m/z (ESI, +ve) 303.2 (M+H)+.
Intermediate M: 7-(but-2-yn-l-yl)-2-(3-fluoro-2-methylquinoxalin-5-yl)-6,7-dihydro- lH-pyrrolo[3,2-c]pyridin-4(5H)-one
Figure imgf000085_0001
Step 1 : tert-butyl 5 -(but-2-yn- 1 -yl)-2,4-dioxopiperidine- 1 -carboxylate
To a solution of tert-butyl 2,4-dioxopiperidine-l -carboxylate (Ark Pharma, Libertyville, IL, 1.0 g, 4.69 mmol) and 1 -bromo-2-butyne (2.49 g, 18.76 mmol) in 80 mL THF at -25 to -20 °C (a few pieces of dry ice tossed in an acetone bath till desired temperature was reached) was added dropwise LiHMDS ( 11.72 mL of 1.0 M solution in THF, 11.72 mmol) such that the internal temperature did not exceed -20 °C. The yellow clear reaction mixtue was stirred for 1 h (final temp -20 °C); then quenched by addition of 25 mL of ice cold 0.5 N HCl, and extracted with 2X75 mL of EtOAc. The combined organic solution was washed with brine (2X10 mL), dried over Na2S04 and concentrated. The brown residue was purified by silica gel chromatography (15-60% EtOAc/hexanes) to give tert-butyl 5-(but-2-yn-l-yl)-2,4-dioxopiperidine-l -carboxylate (809 mg, 65% yield) as a viscous brown oil: !H NMR (400 MHz, DMSO-d6) δ ppm 11.29 (1 H, br. s), 4.95 (1 H, s), 3.88 (1 H, m), 3.73 (1 H, m), 2.57 (1 H, m), 2.46 (1 H, m), 2.30 (1 H, m), 1.75 (3 H, s), 1.45 (9 H, s). m/z (ESI, +ve) 288.0 (M+Na)+.
Step 2: 5-(but-2-yn-l-yl)piperidine-2,4-dione
A solution of tert-butyl 5-(but-2-yn-l-yl)-2,4-dioxopiperidine-l -carboxylate (4.25 g, 16.02 mmol) in 25 mL of DCM at 0 °C was treated with TFA (5.95 mL, 80 mmol) and the resulting mixture was stirred at RT for 30 min. The mixture was concentrated under reduced pressure to give a brown viscous oil, which was treated with 5 mL of toluene and evaporated again under reduced pressure. The remaining brown oil was treated with 100 mL of DCM and an excess of solid NaHCC and stirred rapidly for 10 min. The reaction mixture was filtered, rinsed with 2X25 mL of DCM, and concentrated under reduced pressure to give a tan solid, 5-(but-2-yn-l-yl)piperidine-2,4-dione (2.1 g, 79% yield), which was used without further purification: m/z (ESI, +ve) 166.1 (M+H)+. Step 3 : 7-(but-2-yn-l-yl)-6,7-dihydro-lH-pyrrolo[3,2-c]pyridin-4(5H)-one
A solution of aminoacetaldehyde dimethyl acetal ( Sigma -Aldrich, 5.54 mL, 50.9 mmol) and 5-(but-2-yn-l -yl)piperidine-2,4-dione (2.1 g, 12.71 mmol) in THF (30 mL) was heated in an oil bath at 75 °C for 15 min. The solvents were then removed and the residue was treated with Et20 (5 mL) and hexanes (15 mL) and stirred in an ice bath for 15 min resulting in precipitation of white free-flowing solid. The solid was filtered, rinsed with a mixed solvents of Et20 (3 mL)/hexanes (5 mL), collected and dried to give 5-(but-2-yn-l -yl)-4-((2,2-dimethoxyethyl)amino)-5,6- dihydropyridin-2(lH)-one as a pale yellow amorphous solid, m/z (ESI, +ve) 253.0 (M+H)+. To the yellow amorphous solid in DCM (40 mL) at RT was added TFA (4.72 mL, 63.6 mmol); and the resulting brown solution was stirred at RT for 2 h; then heated in an oil bath at 45 °C for 2 h. The solvents were removed on the rotovap and the crude residue was diluted with DCM (150 mL) and treated with solid NaHC03 (25 g). The suspension was vigorously stirred for 10 min, filtered, and rinsed with 2x25 mL of DCM. The filtrate was concentrated. The brown viscous oil was chromatographed on a silica gel column (1-7% MeOH in DCM)) affording 7-(but-2-yn-l -yl)-6,7-dihydro-lH-pyrrolo[3,2-c]pyridin-4(5H)-one (1.32 g, 55
% yield) as a brown amorphous solid: !H NMR (400 MHz, DMSO-d6) δ ppm 11.16 ( 1 H, br. s), 6.90 (1 H, br. s), 6.71 (1 H, t, J=2.4 Hz), 6.21 (1 H, t, J=2.4 Hz), 3.49 (1 H, m), 3.29 (1 H, m), 3.01 (1 H, m), 2.56 (1 H, m), 2.37 (1 H, m), 1.78 (3 H, t, J=2.4 Hz), m/z (ESI, +ve) 190.1 (M+H)+.
Step 4: 2-bromo-7-(but-2-yn-l-yl)-6,7-dihydro-lH-pyrrolo[3,2-c]pyridin-4(5H)-one A solution of 7-(but-2-yn-l -yl)-6,7-dihydro-lH-pyrrolo[3,2-c]pyridin-4(5H)-one (1.32 g, 7.01 mmol) in DMF (25 mL) was cooled to -60 °C and l ,3-dibromo-5,5- dimethylhydantoin (Sigma- Aldrich, 1.0 g, 3.51 mmol) was added in one portion. The resulting green solution was stirred at -55 °C for 30 min. The mixture was poured into ice/water (35 mL) and a solid was formed. The suspension was filtered and the solid was washed with water (2x2.5 mL) followed by EtOAc (2x5 mL). The solid was collected and dried to give 1.59 g of the title compound, in >95%> pure of m/z (ESI, +ve) 267..0/269.0 (M+H)+. The filtrate was extracted with EtOAc (3x50 mL). The aqueous layer was discarded. The combined organic layers were dried (MgS04), filtered and concentrated. The residue was purified on a silica gel column (1-10% MeOH in DCM) to give 400 mg of the title compound, which contained some DMF. The combined material of 2-bromo- 7-(but-2-yn-l -yl)-6,7-dihydro-lH-pyrrolo[3,2-c]pyridin-4(5H)-one (1.99 g), was used in the subsequent Suzuki coupling reaction without further purification: !H NMR (400 MHz, DMSO-de) δ ppm 11.86 (1 H, br. s), 7.01 (1 H, br. s), 6.23 (1 H, d, J=2.2 Hz), 3.47 (1 H, m), 3.28 (1 H, m), 2.98 (1 H, m), 2.55 (1 H, m), 2.39 (1 H, m), 1.76 (3 H, t, J=2.2 Hz). m/z (ESI, +ve) 267.0/269.0 (M+H)+. Step 5 : 7-(but-2-yn-l-yl)-2-(3-fluoro-2-methylquinoxalin-5-yl)-6,7-dihydro-lH- pyrrolo [3 ,2 -c]pyridin-4(5 H)-one
In a 500 mL round bottomed flask, 2-bromo-7-(but-2-yn-l -yl)-6,7-dihydro-lH- pyrrolo[3,2-c]pyridin-4(5H)-one (1.87 g, 7.01 mmol), potassium phosphate dibasic (3.66 g, 21.03 mmol), l ,l-bis[(di-t-butyl-p-methylaminophenyl]palladium(ii) chloride (Sigma- Aldrich, 0.24 g, 0.35 mmol) and 3-fluoro-2-methyl-5-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)quinoxaline (Intermediate D Step 1 , 2.96 g, 10.27 mmol) were treated with DMF (26.3 mL) and water (8.76 mL), and argon was bubbled through the solution for 10 min then it was heated to 70 °C in an oil bath for 18 h. The reaction mixture was cooled to RT and treated with water (10 mL) and extracted with EtOAc (3 x 50 mL). The organic solution was washed with brine (10 mL) and concentrated. The brown residue was purified on a silica gel column (1-10% MeOH in DCM) affording 7-(but-2-yn-l-yl)- 2-(3-fluoro-2-methylquinoxalin-5-yl)-6,7-dihydro-lH-pyrrolo[3,2-c]pyridin-4(5H)-one (1.50 g, 61 % yield) as a bright yellow amorphous solid. !H NMR (400 MHz, CDCl3) δ ppm 1 1.64 (1 H, br. s), 8.10 (1 H, d, J=7.4 Hz), 7.90 (1 H, d, J=7.6 Hz), 7.73 (1 H, t, J=8.0 Hz), 7.23 (1 H, d, J=2.3 Hz), 5.33 (1 H, br.), 3.72 (1 H, ddd, J=12.1, 5.3, 2.5 Hz), 3.46 (1 H, ddd, J=12.1 , 7.0, 2.6 Hz), 3.34 (1 H, m), 2.9 (3 H, s), 2.58 (1 H, m), 1.93 (1 H, s), 1.87 (3 H, m). 19F NMR (376 MHz, CDCl3) δ ppm -72.40. m/z (ESI, +ve) 349.1 (M+H)+. Intermediate N: (»S)-7-(but-2-yn-l-yl)-2-(2-methyl-3-(( ?)-pent-3-yn-2- ylamino)quinoxalin-5-yl)-6,7-dihydro-lH-pyrrolo[3,2-c]pyridin-4(5H)-one
Intermediate O: (/?)-7-(but-2-yn-l-yl)-2-(2-methyl-3-((/?)-pent-3-yn-2- ylamino)quinoxalin-5-yl)-6,7-dihydro-lH-pyrrolo[3,2-c]pyridin-4(5H)-one
Figure imgf000088_0001
A mixture of 7-(but-2-yn-l -yl)-2-(3-fluoro-2-methylquinoxalin-5-yl)-6,7-dihydro-lH- pyrrolo[3,2-c]pyridin-4(5H)-one (Intermediate M, 200 mg, 0.57 mmol) and (R)-pent-3- yn-2-amine hydrochloride (prepared according to WO 2005051914, 85% ee, 137 mg, 1.14 mmol), and DIPEA (0.2 mL, 1.14 mmol) in 2 mL DMSO in a sealed glass tube was heated at 80 °C in an oil bath for 3.5 h. The reaction was partitioned between sat.
NaHCC (10 mL) and EtOAc (100 mL). The organic layer was separated, washed with water (5 mL) and brine (5 mL), dried over Na2S04, filtered, and concentrated. The residue was purified on a silica gel column (50-100 EtOAc in DCM followed by 1-5% MeOH in DCM) to give material which by LCMS had two peaks with m/z (ESI, +ve) 412.3 (M+H)+, indicating a mixture of diastereomers in about 85% to 15% ratio. In an analytical SFC (Chiralpak IC (15 x 4.6), 5 μ, 50% C02 and 50% MeOH containing 0.2% DEA, flow rate 4.0 mL/min, 100 Bar, oven temperature 40 °C), the material showed 4 peaks, with retention time (peak area %) Peak 1 at 3.70 min (42%), Peak 2 at 3.95 min (7.5%), Peak 3 at 4.59 min (7.5%) and Peak 4 at 4.96 min (42%). The material was separated by preparative SFC chromatography (Chiralpak IC (250 x 21), 5 μ, 55 C02 and 45% MeOH containing 20 mM NH3, flow rate 60 mL/min, 120 Bar, oven temperature 40 °C) to give 3 fractions: the 1st fraction contained Peak 1 and Peak 2, which was further purified (see below); the 2nd fraction contained Peak 3 (6.6 mg of yellow crystalline solid, structure charactization was not carried out); the 3rd fraction contained Peak 4: ( ?)-7-(but-2-yn-l -yl)-2-(2-methyl-3-(( ?)-pent-3-yn-2-ylamino)quinoxalin-5-yl)- 6,7-dihydro-lH-pyrrolo[3,2-c]pyridin-4(5H)-one (Intermediate O, 41 mg) was obatined as a yellow crystalline solid: !H NMR (400 MHz, DMSO-d6) δ ppm 12.00 (1 H, br. s), 7.93 (1 H, dd, J=7.5, 1.3 Hz), 7.63 (1 H, dd, J=8.0, 1.2 Hz), 7.45 (1 H, d, J=7.4 Hz), 7.38 (1 H, t, J=7.8 Hz), 7.01 (1 H, s), 7.40 (1 H, m), 4.97 (1 H, td, J=7.1 , 2.2 Hz), 3.57 (1 H, m), 3.44 (1 H, dt, J=12.7, 3.9 Hz), 3.16 (1 H, m), 2.58 (3 H, s), 2.54 (2 H, m), 1.81 (3 H, s), 180 (3 H, s), 1.61 (3 H, d, J=6.8 Hz), m/z (ESI, +ve) 349.1 (M+H)+. The 1st fraction containing Peakl and Peak 2 was further separated by preparative SFC chromatography (Chiralpak OD-H (250 x 21), 5 μ, 75% C02 and 25% MeOH containing 20 mM NH3, flow rate 70 mL/min, 158 Bar, oven temperature 40 °C) to give 2 fractions: 1st fraction contained Peak 1 : (.S)-7-(but-2-yn-l-yl)-2-(2-metliyl-3-(( ?)-pent-3-yn-2- ylamino)quinoxalin-5-yl)-6,7-dihydro-lH-pyrrolo[3,2-c]pyridin-4(5H)-one (Intermediate N, 38 mg) was obatined as a yellow crystalline solid: !H NMR (400 MHz, DMSO-d6) δ ppm 12.33 (1 H, br. s), 7.97 (1 H, d, J=7.6 Hz), 7.62 (1 H, d, J=8.0 Hz), 7.40 (1 H, m), 7.35 (1 H, m), 7.04 (2 H, m), 4.89 (1 H, m), 3.59 (1 H, dd, J=11.7, 4.7 Hz), 3.40 (1 H, m), 3.13 (1 H, m), 2.66 (2 H, m), 2.58 (3 H, s), 1.83 (3 H, s), 1.76 (3 H, s), 1.62 (3 H, d, J=6.8 Hz), m/z (ESI, +ve) 349.1 (M+H)+. Intermediate O 2-bromo-l-(2-chloroquinolin-8-yl)ethanone
To a solution of 8-bromo-2-chloroquinoline (Biofine International, Vancouver, BC; 10.0 g, 41.2 mmol) in 200 mL THF in a dry ice/acetone bath was added nBuLi solution (2.5 M in hexanes; 18.14 ml, 45.4 mmol) slowly (dropwise) via addition funnel such that the internal temperature did not exceed -72 °C. After 15 min, N- ethoxy-N- methylacetamide (Aldrich; 5.05 ml, 49.5 mmol) was added via syringe such that the internal temperature did not exceed -72 °C. The dry ice/acetone bath was removed and the reaction was quenched with 200 mL saturated aq. NH4C1 and diluted with 300 mL Et20. The organic layer was washed 1 x brine, dried over anhydrous MgS04, filtered, and concentrated in vacuo. The material was treated with DCM and purified by silica gel chromatography (240 g column) using 0-20 % EtOAc/hexanes until less polar impurities elute, then 20-40% EtOAc/hexanes to elute desired material. Fractions were combined and concentrated to give l-(2-chloroquinolin-8-yl)ethanone (3.63 g, 17.65 mmol, 43% yield) as a peach-colored solid: !H NMR (400 MHz, CDCl3) δ ppm 8.16 (1 H, d, J=8.6 Hz), 8.06 (1 H, dd, J=7.2, 1.6 Hz), 7.96 (1 H, dd, J=8.0, 1.6 Hz), 7.59 - 7.66 (1 H, m), 7.46 (1 H, d, J=8.6 Hz), 2.98 (3 H, s). m/z (ESI, +ve) 206.0 (M+H)+. To a solution of 1 - (2-chloroquinolin-8-yl)ethanone (3.25 g, 15.80 mmol) in 3 mL DCM at 0 °C was added Et3N (2.86 ml, 20.55 mmol) followed by TBSOTf (3.99 ml, 17.38 mmol), dropwise. The reaction was stirred for 1 h, and then was partitioned between saturated aq. NaHCC and DCM. The aq. layer was extracted with DCM 3 times, and the combined organics were dried over anhydrous Na2S04, filtered, and concentrated in vacuo to give 5.71 g of an orange oil. This oil was taken up in 70 mL THF, treated with water (4.56 ml, 253 mmol) and NBS (2.95 g, 16.59 mmol), and stirred at 25 °C for 15 min. The reaction was then partitioned between water and Et20. The organic layer was sequentially washed with saturated aq. NaHCC^, water, and saturated aq. NaCl, and the organics layer was dried over anhydrous MgS04, filtered, and concentrated in vacuo to give 6 g of 2-bromo-l-(2- chloroquinolin-8-yl)ethanone as a yellow solid. Intermediate Q 5-bromo-3-chloro-2-methylquinoxaline
A slurry of 8-bromo-3-methylquinoxalin-2(l//)-one (6.33 g, 26.5 mmol) in POCI3 (20 mL, 219 mmol) was heated at reflux for 1.5 h in a round-bottomed flask fitted with a water-cooled reflux condenser and drying tube. Excess POCI3 was removed in vacuo (16 Torr, 36 °C), and the residue was taken up in DCM (50 mL), transferred to an Erlenmeyer flask, cooled to 0 °C, and saturated aq. NaHC03 (ca. 80 mL) was added
(cautiously, with rapid stirring). The resulting biphasic mixture was stirred rapidly for 5 min. Upon cessation of gas evolution, the mixture was extracted with DCM (3 x 200 mL), and the combined extracts were dried over Na2S04, filtered, and concentrated onto silica gel. Chromatographic purification of the residue (silica gel, 0-30%
EtOAc/hexanes) furnished 5-bromo-3-chloro-2-methylquinoxaline (5.12 g, 19.85 mmol, 75% yield) as a light-yellow solid: !H NMR (400 MHz, CDCl3) δ ppm 8.02 (1 H, d, J=7.6 Hz), 8.00 (1 H, dd, J=8.4, 1.2 Hz), 7.60 (1 H, t, J=7.9 Hz), 2.87 (3 H, s). m/z (ESI, +ve) 256.9 (M+H)+. Intermediate R 5-bromo-3-fluoro-2-methylquinoxaline
A 1-L, three-necked round-bottomed flask equipped with a mechanical stirrer, a nitrogen gas inlet, and a temperature probe was charged 5-bromo-3-chloro-2- methylquinoxaline (21.5 g, 83 mmol), DMSO (215 mL) and KF (4.85 mL, 209 mmol), and the resulting mixture was heated at 90 °C for 2.5 h. The mixture was cooled to RT and ice/water (430 mL) was added. The precipitated solid was collected by vacuum filtration and then washed with water (l OOmL) and dried in vacuo to afford 5-bromo-3- fluoro-2-methylquinoxaline (21 g) as a brown solid, which was used without further purification in the subsequent step: !H NMR (400 MHz, CDC13) δ ppm 8.03 (1 H, d, J=2.2 Hz), 8.01 (1 H, d, J=1.2 Hz), 7.59 (1 H, t, J=7.9 Hz), 2.79 (3 H, d, J=1.4 Hz). 19F NMR (377 MHz, CDCl3) δ ppm -70.61 (1 F, br. s.). m/z (ESI, +ve) 240.9 (M+H)+. Intermediate S l-(3-fluoro-2-methylquinoxalin-5-yl)ethanone
A 1 -L, three-necked round-bottomed flask equipped with a mechanical stirrer, reflux condenser, nitrogen gas inlet, and a temperature probe was charged with 5-bromo- 3-fluoro-2-methylquinoxaline (30 g, 124 mmol), Pd(PPh3)4 (4.31 g, 3.73 mmol), toluene (300 mL), and tributyl(l-ethoxyvinyl)tin (Synthonix, Wake Forest, NC; 46.2 mL, 137 mmol), and the resulting mixture was heated under N2 atmosphere at 90 °C for 18 hours. The mixture was cooled to RT, HC1 (6.0 N, aq.; 12.45 mL, 74.7 mmol) was added, and the resulting mixture was stirred at RT for 10 min. The mixture was extracted with EtOAc (500 mL). The organic layer was separated and sequentially washed with brine (2 x 200 mL) and saturated aq. NaHCC (100 mL) and then concentrated in vacuo.
Chromatographic purification of the residue (silica gel, 0-100% DCM/heptane followed by repurification with silica gel, 0-75%o EtOAc/heptane) furnished l-(3-fluoro-2- methylquinoxalin-5-yl)ethanone (16.0 g, 78.4 mmol, 63% yield) as an orange solid: !H NMR (400 MHz, CDCh) δ ppm 8.20 (1 H, dd, J=8.3, 1.3 Hz), 8.10 (1 H, dd, J=7.3, 1.1 Hz), 7.77 (1 H, t, J=7.8 Hz), 2.92 (3 H, s), 2.79 (3 H, d, J=1.6 Hz). 19F NMR (377 MHz, CDCh) δ ppm -69.81 (1 F, s). m/z (ESI, +ve) 205.1 (M+H)+.
Intermediate T 2-bromo-l-(3-fluoro-2-methylquinoxalin-5-yl)ethanone
TBSOTf (2.92 mL, 12.73 mmol) was added (dropwise, over 3 min) to a mixture l-(3-fluoro-2-methylquinoxalin-5-yl)ethanone (2.00 g, 9.79 mmol) and TEA (2.05 mL, 14.7 mmol) in DCM (100 mL) at 0 °C, and the resulting solution was stirred at 0 °C for 30 min. The mixture was diluted with DCM (50 mL), washed with saturated aq. NaHCC (2 x 100 mL), dried over Na2S04, filtered, and concentrated in vacuo to provide 5-(l - ((?eri-butyldimethylsilyl)oxy)vinyl)-3-fluoro-2-methylquinoxaline (3.451 g) as an orange- brown oil. This oil was taken up in THF (100 mL) and cooled to 0 °C, water (2.82 mL,
157 mmol) and NBS (1.743 g, 9.79 mmol) were sequentially added, and the resulting solution was stirred at 0 °C for 2 min. The mixture was diluted with Et20 (100 mL) and sequentially washed with water (80 mL), saturated aq. NaHCC (80 mL), water (80 mL), and brine (80 mL). The resulting solution was dried over Na2S04, filtered, and concentrated onto silica gel. Chromatographic purification (silica gel, 0-20%
EtOAc/hexanes) provided 2-bromo-l-(3-fluoro-2-methylquinoxalin-5-yl)ethanone (2.77 g, 9.78 mmol, 100 % yield) as a yellow solid: !H NMR (400 MHz, CDCl3) δ ppm 8.27 (1 H, d, J=5.3 Hz), 8.25 (1 H, d, J=4.3 Hz), 7.82 (1 H, t, J=7.8 Hz), 5.02 (2 H, s), 2.80 (3 H, d, J=I A Hz). 19F NMR (376 MHz, CDC ) δ ppm -69.34 (1 F, s). m/z (ESI, +ve) 283.0 (M+H)+.
Intermediate U l-(3-chloro-2-methylquinoxalin-5-yl)ethanone l -(3-Fluoro-2-methylquinoxalin-5-yl)ethanone (2.00 g, 9.79 mmol) was treated with HC1 (4.0 M solution in 1,4-dioxane; 24.49 ml, 98 mmol), and the homogeneous reaction was fitted with a drying tube. After 6 h the reaction was concentrated in vacuo, and the solidwas taken up in DCM. Solid NaHC03 was added cautiously with rapid stirring; and saturated aq. NaHC03 was sequentially added cautiously with rapid stirring. The mixture was partitioned between saturated NaHCC and DCM. The aq. layer was extracted with DCM (2x), and the combined organics were dried over anhydrous Na2S04, filtered, and concentrated in vacuo to give l -(3-chloro-2-methylquinoxalin-5-yl)ethanone (99% yield) as an orange-brown solid. MS (ESI, pos. ion) m/z: 221.0 (M+l). Example 1: (llE)-ll-methyl-14-oxa-3,7,23- triazapentacyclo[13.6.2.1~2,5~.0~4,9~.0~18,22~]tetracosa- l(21),2(24),4,ll,15,17,19,22-octaen-6-one
Figure imgf000092_0001
Step 1 : 2-(2-(allyloxy)quinolin-8-yl)-7-(2-methylallyl)-6,7-dihydro-lH-pyrrolo[3,2- c]pyridin-4(5H)-one
To a solution of 3-bromo-2-methylpropene (Aldrich, 1.891 ml, 18.76 mmol) and tert- butyl 2,4-dioxopiperidine-l -carboxylate (Ark Pharm inc, Libertyville IL, 1.00 g, 4.69 mmol) in 50 mL THF at - 17 °C (ice/salt bath) was added LiHMDS, 1.0 M solution in THF (1 1.72 ml, 1 1.72 mmol) via syringe such that the temperature did not exceed -16 °C. After 1 h, the reaction was treated with water and DCM, and the aqueous layer was acidified with 1 N aq. KHSO4. The aqueous layer was extracted 3 x DCM, and the combined organics were dried over anhydrous Na2S04, filtered, and concentrated in vacuo to give 1.8 g of a yellow oil. This was treated with HC1, 4.0 M solution in 1,4- dioxane (Aldrich; 11.72 ml, 46.9 mmol) and was fitted with a drying tube. After 30 min the reaction was judged complete by LCMS and was placed in the freezer overnight. In the morning the reaction was concentrated in vacuo to a thick oil. This material was treated with 2-bromo-l-(2-chloroquinolin-8-yl)ethanone (0.534 g, 1.876 mmol), NH4OAC (Fisher Scientific, 0.723 g, 9.38 mmol), and 10 mL EtOH, sealed, and heated to 50 °C for 4 h. The material was treated with DCM and purified by silica gel chromatography (80 g column) using 0 - 100% 90/10 DCM/MeOH in DCM. The product- containing fractions were concentrated to afford 0.199 g impure material. In a separate flask, a slurry of NaH 60% in mineral oil (Aldrich; 0.113 g, 2.81 mmol) in 2 mL DMF was prepared and to this slurry was added allyl alcohol (Alfa Aesar; 0.191 ml, 2.81 mmol) dropwise. After 10 min, the 0.199 g material was added to the reaction. The orange reaction was sealed and heated to 70 °C for 1 h. The reaction was cooled and partitioned between saturated aqueous NH4C1 and EtOAc. The organic layer was washed with water once, brine once, and the organics were dried over anhydrous Na2S04, filtered, and concentrated in vacuo. The material was treated with DCM and purified by silica gel chromatography (40 g column) using 0- 00% 90/10 DCM/MeOH in DCM The product- containing fractions were concentrated to afford 0.146 g of a 9: 1 mixture of isomers; data for major isomer 2-(2-(allyloxy)quinolin-8-yl)-7-(2-methylallyl)-6,7-dihydro-lH- pyrrolo[3,2-c]pyridin-4(5H)-one: !H NMR (400 MHz, DMSO-d6) δ ppm 11.79 (1 H, br. s), 8.31 (1 H, d, J=8.8 Hz), 8.03 (1 H, dt, .7=7.5, 0.6 Hz), 7.76 (1 H, dt, J=8.0, 0.7 Hz), 7.47 (1 H, t, J=7.7 Hz), 7.13 (1 H, d, J=8.8 Hz), 7.00 - 7.07 (1 H, m), 6.94 (1 H, br. s.), 6.12 - 6.28 (1 H, m), 5.47 (1 H, dd, J=\1.2, 1.6 Hz), 5.32 (1 H, dt, J=10.6, 0.8 Hz), 5.08 - 5.18 (1 H, m), 4.99 - 5.07 (1 H, m), 4.87 (1 H, s), 4.77 (1 H, s), 3.38 - 3.49 (1 H, m), 3.10 - 3.25 (2 H, m), 2.44 - 2.48 (1 H, m), 2.20 - 2.37 (1 H, m), 1.77 (3 H, s) m/z (ESI, +ve) 374.0 (M+H)+.
Step 2: (l lE)-l l-methyl-14-oxa-3,7,23- triazapentacyclo[13.6.2.1~2,5~.0~4,9~.0~18,22~]tetracosa-l(21),2(24),4,l 1,15, 17,19,22- octaen-6-one
To a solution of 2-(2-(allyloxy)quinolin-8-yl)-7-(2-methylallyl)-6,7-dihydro-lH- pyrrolo[3,2-c]pyridin-4(5H)-one (0.116 g, 0.311 mmol) in 15 mL DCM was added Grubbs catalyst 2nd generation (Aldrich; 0.026 g, 0.031 mmol). The light pink reaction was flushed with argon for 2 min, then fitted with a water-cooled reflux condensor, and was heated to reflux. After 1 h, the reaction is nearly complete. After 30 min additional, the reaction was concentrated in vacuo. The resulting material was dissolved in DMSO and purified by RPHPLC, Phenomenex Gemini 150x30 mm Ci8 column, 10-100 % ACN/H20 with 0.1 % TFA; product- containing fractions were treated with saturated aqueous NaHCC>3 and DCM. The aqueous layer was extracted 3 x DCM and combined organics dried over Na2S04, filtered, and concentrated in vacuo to give (11E)-11-methyl- 14-oxa-3,7,23-triazapentacyclo[13.6.2.1~2,5~.0~4,9~.0~18,22~]tetracosa- 1(21),2(24),4,1 l,15,17,19,22-octaen-6-one (0.045 g, 42% yield) as a light yellow solid: !H NMR (400 MHz, DMSO-d6) δ ppm 13.39 (1 H, br. s.), 8.32 (1 H, d, J=9.0 Hz), 8.17 (1 H, dt, J=1A, 0.7 Hz), 7.71 (1 H, dt, J=7.9, 0.7 Hz), 7.44 (1 H, t, J=7.7 Hz), 7.14 (1 H, d, J=9.0 Hz), 7.10 (1 H, d, J=4.7 Hz), 6.95 (1 H, d, J=1.8 Hz), 5.99 (1 H, d, J=7.0 Hz), 4.97 - 5.17 (2 H, m), 3.30 - 3.50 (3 H, m), 3.08 - 3.16 (1 H, m), 2.35 (1 H, t, J=12.0 Hz), 1.81 (3 H, s). m/z (ESI, +ve) 346.3 (M+H)+.
Examples 2-3: (9R,llE)-ll-methyl-14-oxa-3,7,23- triazapentacyclo[13.6.2.1~2,5~.0~4,9~.0~18,22~]tetracosa- l(21),2(24),4,ll,15,17,19,22-octaen-6-one and (9S,HE)-ll-methyl-14-oxa-3,7,23- triazapentacyclo[13.6.2.1~2,5~.0~4,9~.0~18,22~]tetracosa- l(21),2(24),4,ll,15,17,19,22-octaen-6-one
Figure imgf000094_0001
A portion of the material prepared in Example 1 was separated by SFC chromatography (ADH (4.6 x 150 mm), 5 μ, 45% MeOH containing 0.2% DEA, 4 ml/min,100 Bar) to give separated enantiomers (9R,11E)-1 l-methyl-14-oxa-3,7,23- triazapentacyclo[13.6.2.1~2,5~.0~4,9~.0~18,22~]tetracosa-l(21),2(24),4,l 1,15, 17,19,22- octaen-6-one and (9S,11E)-1 l-methyl-14-oxa-3,7,23- triazapentacyclo[13.6.2.1~2,5~.0~4,9~.0~18,22~]tetracosa-l(21),2(24),4,l 1,15, 17,19,22- octaen-6-one. Example 2 was the first eluting product, Example 3 was the second eluting product. Example 4: 16-oxa-3,7,25- triazahexacyclo[15.6.2.1~2,5~.l~ll,15~.0~4,9~.0~20,24~]heptacosa- l(23),2(27),4,ll(26),12,14,17,19,21,24-decaen-6-one
Figure imgf000095_0001
Step 1 : 2-(2-chloroquinolin-8-yl)-7-(3-methoxybenzyl)-6,7-dihydro-lH-pyrrolo[3,2- c]pyridin-4(5H)-one
To a solution of l-(bromomethyl)-3-methoxybenzene (2.63 ml, 18.76 mmol) and tert- butyl 2,4-dioxopiperidine-l-carboxylate (Ark Pharm, LibertyviUe, IL; 1.00 g, 4.69 mmol) in 50 mL THF at -17 °C (ice/salt) was added LiHMDS 1.0 M in THF (11.72 ml, 11.72 mmol) dropwise via syringe such that the internal temperature did not exceed -14 °C. A precipitate formed during the first 1/2 addition, then disappeared upon further LiHMDS addition. The resulting clear yellow solution was stirred 30 min. The reaction was treated with water and DCM, and 5% KHSO4 was added to acidify the aqueous layer. The aqueous layer was extracted 3 x DCM. The combined extracts were dried over Na2S04, filtered, and concentrated in vacuo. The material was treated with DCM and purified by silica gel chromatography (40 g column) using 0 - 50% EtOAc/hexane. The product- containing fractions were concentrated to afford 1.34 g of a foam. This material was treated with 40 mL 4.0 M HCl in dioxane (Aldrich) and fitted with a drying tube. After 2 h, the reaction was checked by LCMS and judged complete, and was concentrated in vacuo to a thick oil which was placed on hood pump overnight. This material was treated with 2-bromo-l-(2-chloroquinolin-8-yl)ethanone (0.534 g, 1.876 mmol), NH4OAC (Fisher Scientific, 1.446 g, 18.76 mmol), and 20 mL EtOH, sealed, and heated to 50 °C.
After 3 h, the reaction was judged complete by LCMS. The reaction was carefully quenched with saturated aqueous NaHC03 and partitioned between saturated aqueous NaHCC and DCM. The aqueous layer was extracted with DCM 3 times, and the combined organics were dried over anhydrous Na2S04, filtered, and concentrated in vacuo. The material was treated with DCM and purified by silica gel chromatography (80 g column) using 0 - 100% 90/10 DCM/MeOH in DCM. The product-containing fractions were concentrated to afford impure 2-(2-chloroquinolin-8-yl)-7-(3-methoxybenzyl)-6,7- dihydro-lH-pyrrolo[3,2-c]pyridin-4(5H)-one (0.42 g, 1.005 mmol, 21.43 % yield) as an orange solid: !H NMR (400 MHz, DMSO-d6) δ ppm 1 1.72 (1 H, s), 8.50 (1 H, d, J=8.6 Hz), 8.08 - 8.19 (1 H, m), 7.85 - 7.95 (1 H, m), 7.61 - 7.76 (2 H, m), 7.20 - 7.31 (2 H, m), 6.97 (1 H, br. s.), 6.72 - 6.90 (3 H, m), 3.74 (3 H, s), 3.04 - 3.31(4 H, m), 2.74 (1 H, dd, J=12.8, 10.3 Hz), m/z (ESI, +ve) 418.1 (M+H)+.
Step 2: 16-oxa-3,7,25- triazahexacyclo[15.6.2.1~2,5~. l~l l,15~.0~4,9~.0~20,24~]heptacosa- 1 (23),2(27),4, 11 (26),12,14, 17, 19,21 ,24-decaen-6-one
To a solution of 2-(2-chloroquinolin-8-yl)-7-(3-methoxybenzyl)-6,7-dihydro-lH- pyrrolo[3,2-c]pyridin-4(5H)-one (0.40 g, 0.957 mmol) in 5 mL DCM under N2 was added BBr3, 1.0 M in DCM (Sigma- Aldrich; 1.053 ml, 1.053 mmol) dropwise via syringe. A thick orange precipitate resulted. 5 mL DCM was added to promote stirring. The orange slurry was stirred for 1 h. An additional 0.5 mL BBr3 (1.0 M in DCM) was added and stirring continued. After 1 h, the reaction was judged complete, was cooled to 0 °C and quenched carefully with dropwise addition of 4 mL MeOH to give a homogeneous solution. 4 g silica gel was added and the mixture concentrated in vacuo, and the residue purified by silica gel chromatography (40 g column) using 0 - 100% 90/10 DCM/MeOH in DCM. The product-containing fractions were concentrated to afford impure material (0.210 g) as an orange solid. The solid was treated with 25 mL DMF and NaH 60% in mineral oil (Aldrich; 0.153 g, 3.83 mmol) under N2. The reaction was heated to 80 °C for 4 h. The reaction was cooled in an ice/water bath and TFA (0.295 ml, 3.83 mmol) was added. This material was concentrated in vacuo, was dissolved in 3.5 mL DMSO and purified by RPHPLC, Phenomenex Gemini 150x30 mm Ci8 column, 15-100 % ACN/H20 with 0.1% TFA; the product-containing fraction was treated with saturated aqueous NaHC03 and DCM. The aqueous layer was extracted 3 x DCM and combined organics dried over Na2S04, filtered, and concentrated in vacuo to give 16-oxa-3,7,25- triazahexacyclo[15.6.2.1~2,5~. l~l l,15~.0~4,9~.0~20,24~]heptacosa- l(23),2(27),4,l l(26),12,14,17,19,21,24-decaen-6-one (0.018 g, 0.049 mmol, 5% yield) as a yellow solid: !H NMR (400 MHz, DMSO-d6) δ ppm 12.90 (1 H, br. s.), 8.48 (1 H, d, J=8.8 Hz), 8.15 (1 H, dt, J=7.5, 0.7 Hz), 7.92 (1 H, t, J=2.1 Hz), 7.70 - 7.81 (1 H, m), 7.33 - 7.63 (4 H, m), 7.09 - 7.25 (2 H, m), 6.88 - 7.01 (1 H, m), 3.47 - 3.60 (1 H, m), 3.18 - 3.31 (3 H, m), 2.77 - 2.87 (1 H, m). m/z (ESI, +ve) 368.1 (M+H)+.
Example 5: (llE)-12-methyl-14-oxa-3,7,23- triazapentacyclo[13.6.2.1~2,5~.0~4,9~.0~18,22~]tetracosa- l(21),2(24),4,ll,15,17,19,22-octaen-6-one
Figure imgf000097_0001
To a slurry of NaH 60% in mineral oil (Aldrich; 0.1 12 g, 2.81 mmol) in 1 mL DMF was added 2-methyl-2-propen-l -ol (Aldrich; 0.237 ml, 2.81 mmol) dropwise via syringe. After 10 min, 7-allyl-2-(2-chloroquinolin-8-yl)-6,7-dihydro-lH-pyrrolo[3,2-c]pyridin- 4(5H)-one (Intermediate F; 0.190 g, 0.562 mmol) was added as a solution in 1 mL DMF (0.5 mL rinse). The reaction was sealed and heated to 80 °C for one h. The reaction was cooled and partitioned between saturated aqueous NH4C1 and DCM. The aqueous layer was extracted with DCM 3 times, and the combined organics were dried over anhydrous Na2S04, filtered, and concentrated in vacuo. The material was treated with DCM and purified by silica gel chromatography (25 g column) using 0 - 100% 90/10 DCM/MeOH in DCM; the product-containing fractions were concentrated to afford impure 7-allyl-2- (2-((2-methylallyl)oxy)quinolin-8-yl)-6,7-dihydro-lH-pyrrolo[3,2-c]pyridin-4(5H)-one (0.133 g). This material was treated with Grubbs 2nd generation catalyst (Aldrich; 0.030 g, 0.036 mmol) and 18 mL anhydrous DCM, and argon was bubbled through the orange solution for 2 min. The reaction was fitted with a water-cooled reflux condensor and heated to reflux in an oil bath. The reaction was heated overnight. The reaction was concentrated, the resulting material was dissolved in DMSO and purified by RPHPLC, Phenomenex Gemini 150x30 mm C18 column, 15-100 % ACN/H20 with 0.1 % TFA; product- containing fractions were concentrated in vacuo. The material was treated with Et20, sonicated, and filtered, rinsing with Et20 to give the (1 IE)- 12 -methyl- 14-oxa- 3,7,23-triazapentacyclo[13.6.2.1~2,5~.0~4,9~.0~18,22~]tetracosa- l(21),2(24),4,l l,15,17,19,22-octaen-6-one (0.012 g, 0.035 mmol, 9.76 % yield) as an off- white solid: !H NMR (400 MHz, DMSO-d6) δ ppm 13.28 (1 H, br. s.), 8.32 (1 H, d, J=8.8 Hz), 8.18 (1 H, dd, J=7.5, 1.5 Hz), 7.71 (1 H, dt, .7=7.9, 0.8 Hz), 7.44 (1 H, t, J=7.7 Hz), 7.15 (1 H, d, J=8.8 Hz), 7.02 - 7.10 (1 H, m), 6.98 (1 H, dd, J=2.0, 0.4 Hz), 5.93 (1 H, d, .7=10.6 Hz), 4.88 - 5.09 (2 H, m), 3.1 1 - 3.47 (4 H, m), 2.36 - 2.46 (1 H, m), 1.74 (3 H, s). m/z (ESI, +ve) 346.1 (M+H)+.
Example 6: (HE)-12-methyl-3,7,14,23- tetraazapentacyclo[13.6.2.1~2,5~.0~4,9~.0~18,22~]tetr
l(21),2(24),4,ll,15,17,19,22-octaen-6-one
Figure imgf000098_0001
Step 1 : 7-allyl-2-(2-((2-methylallyl)amino)quinolin-8-yl)-6,7-dihydro-lH-pyrrolo[3,2- c]pyridin-4(5H)-one
Argon was bubbled through a slurry of sodium tert-butoxide (0.939 g, 9.77 mmol), 2- methylallylamine (Matrix Scientific, Columbia, SC, 0.347 ml, 4.88 mmol), BrettPhos (0.026 g, 0.049 mmol), 7-allyl-2-(2-chloroquinolin-8-yl)-6,7-dihydro-lH-pyrrolo[3,2- c]pyridin-4(5H)-one (Intermediate F, 0.330 g, 0.977 mmol), BrettPhos precatalyst (0.039 g, 0.049 mmol) in 3 mL dioxane for 30 sec. The reaction was sealed and heated to 80 °C. After 2 h, the reaction was cooled and judged complete by LCMS. The reaction was partitioned between saturated aqueous NH4C1 and DCM. The aqueous layer was extracted with DCM 3 times, and the combined organics were dried over anhydrous
Na2S04, filtered, and concentrated in vacuo. The material was treated with DCM and purified by silica gel chromatography (40 g column) using 0 - 50% 90/10/1
DCM/MeOH/conc. NH4OH in DCM The product- containing fractions were concentrated to afford 7-allyl-2-(2-((2-methylallyl)amino)quinolin-8-yl)-6,7-dihydro-lH-pyrrolo[3,2- c]pyridin-4(5H)-one (0.126 g, 0.338 mmol, 34.6 % yield) as a yellow foam: !H NMR
(400 MHz, DMSO-de) δ ppm 12.51 (1 H, br. s.), 7.88 - 7.98 (2 H, m), 7.54 (1 H, t, J=5.6 Hz), 7.49 (1 H, dt, .7=7.9, 0.8 Hz), 7.18 (1 H, t, J=7.6 Hz), 6.96 - 7.00 (1 H, m), 6.88 - 6.95 (2 H, m), 5.79 - 5.92 (1 H, m), 5.06 - 5.17 (2 H, m), 4.99 (1 H, s), 4.88 (1 H, s), 4.02 - 4.09 (2 H, m), 3.43 - 3.55 (1 H, m), 3.16 - 3.26 (1 H, m), 3.00 - 3.10 (1 H, m), 2.53 - 2.60 (1 H, m), 2.26 - 2.41 (1 H, m), 1.84 (3 H, s). m/z (ESI, +ve) 373.1 (M+H)+. Step 2: (1 lE)-12-methyl-3,7,14,23- tetraazapentacyclo[13.6.2.1~2,5~.0~4,9~.0~18,22~]tetracosa- 1 (21 ),2(24),4, 11 , 15, 17, 19,22-octaen-6-one
7-Allyl-2-(2-((2-methylallyl)amino)quinolin-8-yl)-6,7-dihydro-lH-pyrrolo[3,2-c]pyridi^ 4(5H)-one (0.126 g, 0.338 mmol) and Grubbs II Catalyst (Aldrich; 0.029 g, 0.034 mmol) were dissolved in 17 mL anhydrous DCM; the flask was fitted with a water cooled reflux condenser and the reaction was heated to reflux under N2 for 3 h. The reaction was cooled, judged complete by LCMS, and adsorbed onto 1.5 g silica gel from MeOH/DCM and dried. The material was purified by silica gel chromatography (25 g column) using 30 - 70 % 90/10/1 DCM/MeOH/conc. NH4OH in DCM. The product-containing fractions were concentrated to give 79 mg yellow solid. This material was dissolved in DMSO and purified by RPHPLC, Phenomenex Gemini 150x30 mm Ci8 column, 10-70 % ACN/H20 with 0.1% TFA; product-containing fraction was treated with saturated aqueous NaHCC and DCM. The aqueous layer was extracted 3 x DCM and combined organics dried over Na2S04, filtered, and concentrated in vacuo to give (1 lE)-12-methyl-3,7,14,23- tetraazapentacyclo[13.6.2.1~2,5~.0~4,9~.0~18,22~]tetracosa- l(21),2(24),4,l l,15,17,19,22-octaen-6-one (0.039 g, 34% yield) as a light yellow solid: !H NMR (400 MHz, DMSO-d6) δ ppm 13.65 (1 H, br. s.), 7.99 (1 H, dt, .7=7.5, 0.7 Hz), 7.89 (1 H, d, J=9.0 Hz), 7.64 (1 H, t, J=4.8 Hz), 7.40 - 7.49 (1 H, m), 7.17 (1 H, t, J=7.6 Hz), 6.99 (1 H, d, J=4.5 Hz), 6.88 (2 H, d, J=6.7 Hz), 5.64 - 5.93 (1 H, m), 3.97 (2 H, d, J=4.5 Hz), 3.33 - 3.40 (1 H, m), 3.18 - 3.30 (2 H, m), 2.34 - 2.46 (2 H, m), 1.63 (3 H, s). m/z (ESI, +ve) 345.2 (M+H)+.
Examples 7 and 8: (9R,llE)-12-methyl-3,7,14,23- tetraazapentacyclo[13.6.2.1~2,5~.0~4,9~.0~18,22~]tetracosa- l(21),2(24),4,ll,15,17,19,22-octaen-6-one and (9S,HE)-12-methyl-3,7,14,23- tetraazapentacyclo[13.6.2.1~2,5~.0~4,9~.0~18,22~]tetracosa- l(21),2(24),4,ll,15,17,19,22-octaen-6-one
Figure imgf000099_0001
A portion of the material prepared in Example 6 was separated by SFC chromatography (ASH (250 x 20), 5 μ, 40% MeOH containing 20 mM NH3, 70 ml/min, 128/200 Bar) to give separated enantiomers (9R,1 lE)-12-methyl-3,7,14,23- tetraazapentacyclo[13.6.2.1~2,5~.0~4,9~.0~18,22~]tetracosa- 1 (21 ),2(24),4, 11,15,17,19,22-octaen-6-one and (9S, 1 1 E)- 12-methyl-3 ,7, 14,23 - tetraazapentacyclo[13.6.2.1~2,5~.0~4,9~.0~18,22~]tetracosa- l(21),2(24),4,l l,15,17,19,22-octaen-6-one. Example 7 was the first eluting product. Example 8 was the second eluting product.
Example 9: (HE)-12,16-dimethyl-3,7,14,17,23- pentaazapentacyclo[13.6.2.1~2,5~.0~4,9~.0~18,22~]tetr
l(21),2(24),4,ll,15,17,19,22-octaen-6-one
Figure imgf000100_0001
Step 1 : 8-bromo-3-methyl-N-(2-methylallyl)quinoxalin-2-amine
A solution of 5-bromo-3-chloro-2-methylquinoxaline (0.633 g, 2.458 mmol) in 2- methylprop-2-en-l -amine (Matrix Scientific, Columbia, SC; 3.50 g, 49.2 mmol) was stirred at RT overnight. The reaction was judged complete by LCMS and the orange solution was partitioned between water and EtOAc. The organic layer was washed with water 3 times, brine once, and the organics were dried over anhydrous Na2S04, filtered, and concentrated in vacuo to give 8-bromo-3-methyl-N-(2-methylallyl)quinoxalin-2- amine (0.591 g, 2.023 mmol, 82 % yield) as a red oil: !H NMR (400 MHz, CDCl3) δ ppm 7.75 - 7.87 (2 H, m), 7.22 (1 H, t, J=7.9 Hz), 5.00 - 5.05 (1 H, m), 4.92 - 4.97 (1 H, m), 4.30 (2 H, d, J=5.7 Hz), 2.59 (3 H, br. s.), 1.89 (3 H, s). m/z (ESI, +ve) 292.0 (M+H)+. Step 2 : 8-( 1 -ethoxyvinyl)-3-methyl-N-(2-methylallyl)quinoxalin-2-amine
Argon was bubbled through a mixture of tributyl(l -ethoxyvinyl)tin (Aldrich; 1.025 ml, 3.03 mmol), Cul (Riedel-de-Haen; 0.077 g, 0.405 mmol), cesium fluoride (Aldrich; 0.922 g, 6.07 mmol), Pd2(dba)3 (Strem, 0.185 g, 0.202 mmol), X-Phos (Strem, 0.096 g, 0.202 mmol), 8-bromo-3-methyl-N-(2-methylallyl)quinoxalin-2-amine (0.591 g, 2.023 mmol) in 10 mL dioxane for 2 min. The dark reaction was sealed and placed in an 80 °C oil bath. After 5 h, the reaction was judged complete by LCMS. The reaction was transferred to a flask with DCM and adsorbed onto 5 g silica gel and dried in vacuo. The material was purified by silica gel chromatography (40 g column) using 0 - 50% EtOAc/hexane. The major product-containing fractions were concentrated to afford 8-(l -ethoxyvinyl)-3- methyl-N-(2-methylallyl)quinoxalin-2-amine (0.304 g, 1.073 mmol, 53.0 % yield): !H NMR (400 MHz, DMSO-d6) δ ppm 7.65 - 7.71 (2 H, m), 7.36 - 7.42 (1 H, m), 7.27 (1 H, t, J=7.7 Hz), 5.28 (1 H, s), 4.84 (1 H, br. s), 4.72 - 4.78 (1 H, m), 4.54 - 4.60 (1 H, m), 3.99 - 4.08 (2 H, m), 3.89 (2 H, q, J=7.0 Hz), 2.53 (3 H, s), 1.76 (3 H, s), 1.33 (3 H, t, J=6.9 Hz).
Step 3 : 7-allyl-2-(2-methyl-3-((2-methylallyl)amino)quinoxalin-5-yl)-6,7-dihydro-lH- pyrrolo [3,2 -c]pyridin-4(5 H)-one
To a solution of 8-(l-ethoxyvinyl)-3-methyl-N-(2-methylallyl)quinoxalin-2-amine (0.302 g, 1.066 mmol) in 10 mL THF and water (0.307 ml, 17.05 mmol) was added NBS (0.190 g, 1.066 mmol). The orange reaction was stirred for 30 min, at which point it was partitioned between saturated aqueous NaHCC and EtOAc. The organic layer was washed with saturated aqueous NaHC03 once, brine once, and the organics were dried over anhydrous Na2S04, filtered, and concentrated in vacuo to give 0.396 g of an orange solid. The material was treated with NH4OAc (0.329 g, 4.26 mmol) and 5- allylpiperidine-2,4-dione (Intermediate A; 0.196 g, 1.279 mmol) and 10 mL EtOH, sealed, and placed in a 50 °C oil bath for 5 h. The reaction was cooled and placed in a freezer over the weekend. The reaction was carefully quenched with saturated aqueous NaHCC . The reaction was partitioned between saturated aqueous NaHCC and DCM.
The aqueous layer was extracted with DCM 3 times, and the combined organics were dried over anhydrous Na2S04, filtered, and concentrated in vacuo. The material was treated with DCM and purified by silica gel chromatography (40 g column) using 0 - 100% 90/10 DCM/MeOH in DCM. The product- containing fractions were concentrated to afford 7-allyl-2-(2-methyl-3-((2-methylallyl)amino)quinoxalin-5-yl)-6,7-dihydro-lH- pyrrolo[3,2-c]pyridin-4(5H)-one (0.060 g, 0.155 mmol, 14.53 % yield) as a orange solid: !H NMR (400 MHz, DMSO-d6) δ ppm 11.76 (1 H, br. s.), 7.88 (1 H, dt, .7=7.5, 0.7 Hz), 7.53 - 7.62 (1 H, m), 7.50 (1 H, t, J=6.0 Hz), 7.28 - 7.37 (1 H, m), 7.06 - 7.14 (1 H, m), 6.90 (1 H, br. s.), 5.78 - 5.97 (1 H, m), 5.06 - 5.17 (2 H, m), 4.79 - 4.93 (2 H, m), 4.01 - 4.18 (2 H, m), 3.45 - 3.55 (1 H, m), 3.18 - 3.25 (1 H, m), 3.17 (1 H, d, J=5.1 Hz), 2.98 - 3.07 (1 H, m), 2.57 (3 H, s), 2.27 - 2.39 (1 H, m), 1.85 (3 H, s). m/z (ESI, +ve) 388.1 (M+H)+. Step 4: (1 lE)-12,16-dimethyl-3,7,14,17,23- pentaazapentacyclo[l 3.6.2.1~2,5~.0~4,9~.0~18,22~]tetracosa- 1 (21 ),2(24),4, 11 , 15, 17, 19,22-octaen-6-one
Argon was flushed through a suspension of 7-allyl-2-(2-methyl-3-((2- methylallyl)amino)quinoxalin-5-yl)-6,7-dihydro-lH-pyrrolo[3,2-c]pyridin-4(5H)-one (0.060 g, 0.155 mmol) and Grubbs catalyst 2nd generation (Aldrich; 6.57 mg, 7.74 μιηοΐ) and 10 mL DCM for 1 min. The reaction was fitted with a water-cooled reflux condenser and placed in an oil bath and heated to reflux. After 4 h, additional Grubbs catalyst 2nd generation (Aldrich; 6.57 mg, 7.74 μιηοΐ) was added and heating continued. After 2 h, the reaction was concentrated in vacuo, then treated with DMSO. A bright yellow ppt did not dissolve, even with 3 mL DMSO and sonication or heating. The slurry was filtered through a 0.45 uM nylon membrane and the yellow solid was collected and dried in vacuo overnight to give 12 mg yellow solid. The filtrate was purified by preperative HPLC, 10- 80 % ACN/H20 with 0.1% TFA; product-containing fractions were treated with saturated aqueous NaHCC and DCM. The aqueous layer was extracted 3 x DCM and combined organics dried over Na2S04, filtered, and concentrated in vacuo, and the material was combined with the solid isolated by filtration to give a total of (1 lE)-12,16-dimethyl- 3,7,14, 17,23-pentaazapentacyclo[l 3.6.2.1~2,5~.0~4,9~.0~18,22~]tetracosa- l(21),2(24),4,l l,15,17,19,22-octaen-6-one (0.030 g, 0.083 mmol, 54% yield): 'll NMR (400 MHz, DMSO-de) δ ppm 13.38 (1 H, br. s.), 7.97 (1 H, d, J=7.6 Hz), 7.56 - 7.62 (1 H, m), 7.51 - 7.55 (1 H, m), 7.31 (1 H, t, J=7.8 Hz), 7.01 (1 H, d, J=4.7 Hz), 6.87 - 6.92 (1
H, m), 5.82 (1 H, d, J=9.0 Hz), 4.06 - 4.22 (1 H, m), 3.92 - 4.05 (1 H, m), 3.34 - 3.43 (1 H, m), 3.10 - 3.29 (2 H, m), 2.57 (3 H, s), 2.26 - 2.46 (2 H, m), 1.61 (3 H, s). m/z (ESI, +ve) 360.2 (M+H)+. Examples 10-13: (9R,llZ)-14-oxa-3,7,23- triazapentacyclo[13.6.2.1~2,5~.0~4,9~.0~18,22~]tetracosa- l(21),2(24),4,ll,15,17,19,22-octaen-6-one, (9S,llZ)-14-oxa-3,7,23- triazapentacyclo[13.6.2.1~2,5~.0~4,9~.0~18,22~]tetracosa- l(21),2(24),4,ll,15,17,19,22-octaen-6-one, (9R,llE)-14-oxa-3,7,23- triazapentacyclo[13.6.2.1~2,5~.0~4,9~.0~18,22~]tetracosa- l(21),2(24),4,ll,15,17,19,22-octaen-6-one, (9S,llE)-14-oxa-3,7,23- triazapentacyclo[13.6.2.1~2,5~.0~4,9~.0~18,22~]tetracosa- l(21),2(24),4,ll,15,17,19,22-octaen-6-one
Figure imgf000103_0001
To a slurry of NaH 60% in mineral oil (Aldrich; 0.112 g, 2.81 mmol) in 1 mL DMF was added allyl alcohol (Alfa Aesar; 0.191 ml, 2.81 mmol) dropwise via syringe. After 10 min, 7-allyl-2-(2-chloroquinolin-8-yl)-6,7-dihydro-lH-pyrrolo[3,2-c]pyridin-4(5H)-one (Intermediate F, 0.190 g, 0.562 mmol) was added as a solution in 1 mL DMF (0.5 mL rinse). The reaction was sealed and heated to 80 °C for one h. The reaction was cooled and partitioned between saturated aqueous NH4C1 and EtOAc. The organic layer was washed 1 x water, 1 x brine, and the organics were dried over anhydrous Na2S04, filtered, and concentrated in vacuo. The material was treated with DCM and purified by silica gel chromatography (25 g column) using 0 - 80% 90/10 DCM/MeOH in DCM. The product contiaining fractions were concentrated in vacuo to give 0.100 g of impure material. This material was treated with Grubbs 2nd generation catalyst (0.024 g, 0.028 mmol) and 15 mL anhydrous DCM, and argon was bubbled through the reaction for 2 min. The reaction was sealed and heated to 50 °C in an oil bath overnight. The reaction was concentrated, and this material was dissolved in DMSO and purified by shimadzu RPHPLC, Phenomenex Gemini 150x30 mm C18 column, 10-100 % ACN/H20 with 0.1% TFA; product-containing fractions were concentrated in vacuo to give (0.030 g, 0.09 mmol, 33% yield) as a mixture of isomers. A portion of this material was further resolved into four components by preparative SFC chromatography (OJ-H (5 um, 21 x 250 mm, 60 ml/min), 40% IPA/40 mM NH3. T = 40 °C, P = 193 bar) to give:
First (Example 10) and third (Example 12) eluting peaks, separate enantiomers of (11Z)- 14-oxa-3,7,23-triazapentacyclo[13.6.2.1~2,5~.0~4,9~.0~18,22~]tetracosa- l(21),2(24),4,l l,15,17,19,22-octaen-6-one: 1H NMR (400 MHz, 1 : 1 CDCl3:MeOH-d4) δ ppm 13.77 (1 H, br. s.), 8.36 (1 H, d, J=8.8 Hz), 8.12 - 8.28 (1 H, m), 7.83 - 7.90 (1 H, m), 7.65 (1 H, t, J=7.7 Hz), 7.25 (1 H, d, J=8.8 Hz), 7.07 - 7.18 (1 H, m), 5.99 - 6.17 (2 H, m), 5.71 - 5.81 (1 H, m), 4.96 - 5.05 (1 H, m), 3.73 - 3.82 (1 H, m), 3.59 - 3.67 (2 H, m), 2.87 - 3.03 (1 H, m), 2.53 - 2.66 (1 H, m). m/z (ESI, +ve) 332.1 (M+H)+.
Second (Example 11) and fourth (Example 13) eluting peaks, separate enantiomers of (1 lE)-14-oxa-3,7,23-triazapentacyclo[13.6.2.1~2,5~.0~4,9~.0~18,22~]tetracosa- l(21),2(24),4,l l,15,17,19,22-octaen-6-one: !H NMR (400 MHz, 1 :1 CDCl3:MeOH-d4) δ ppm 13.86 (1 H, br. s.), 8.26 - 8.38 (2 H, m), 7.75 - 7.87 (1 H, m), 7.57 - 7.68 (1 H, m), 7.15 - 7.31 (2 H, m), 6.33 - 6.51 (1 H, m), 6.17 - 6.32 (1 H, m), 5.27 - 5.40 (1 H, m), 5.08 - 5.23 (1 H, m), 3.62 - 3.81 (3 H, m), 2.91 (1 H, d, J=14.1 Hz), 2.45 - 2.72 (1 H, m). m/z (ESI, +ve) 332.1 (M+H)+.
Example 14: (9S,HE)-12,16-dimethyl-3,7,14,17,23- pentaazapentacyclo[13.6.2.1~2,5~.0~4,9~.0~18,22~]tetracosa- l(21),2(24),4,ll,15,17,19,22-octaen-6-one
Example 15: (9R,llE)-12,16-dimethyl-3,7,14,17,23- pentaazapentacyclo[13.6.2.1~2,5~.0~4,9~.0~18,22~]tetracosa- l(21),2(24),4,ll,15,17,19,22-octaen-6-one
Figure imgf000104_0001
Example 9 was separated by chiral SFC (AS-H (150x4.6 mm, 5 μ) Mobile Phase: A: Liquid C02, B: MeOH with 0.2% DEA; isocratic, 40% B, Temperature = 40 °C) to gi first eluting peak, Example 14, (9S,1 lE)-12,16-dimethyl-3,7,14,17,23-pentaaza- pentacyclo[13.6.2.1~2,5~.0~4,9~.0~18,22~]tetracosa-l(21),2(24),4,l 1 ,15,17,19,22- octaen-6-one and second eluting peak, Example 15 (9R,1 lE)-12,16-dimethyl- 3,7,14, 17,23-pentaaza-pentacyclo[l 3.6.2. l~2,5~.0~4,9~.0~18,22~]tetracosa- l(21),2(24),4,l l,15,17,19,22-octaen-6-one: !H NMR (400 MHz, DMSO-d6) δ ppm 13.38 (1 H, br. s.), 7.97 (1 H, d, J=7.6 Hz), 7.56 - 7.62 (1 H, m), 7.51 - 7.55 (1 H, m), 7.31 (1 H, t, J=7.8 Hz), 7.01 (1 H, d, J=4.7 Hz), 6.87 - 6.92 (1 H, m), 5.82 (1 H, d, J=9.0 Hz), 4.06 - 4.22 (1 H, m), 3.92 - 4.05 (1 H, m), 3.34 - 3.43 (1 H, m), 3.10 - 3.29 (2 H, m), 2.57 (3 H, s), 2.26 - 2.46 (2 H, m), 1.61 (3 H, s). m/z (ESI, +ve) 360.2 (M+H)+.
Example 14, alternative procedure: (9S,llE)-12,16-dimethyl-3,7,14,17,23-pentaaza- pentacyclo[13.6.2.1~2,5~.0~4,9~.0~18,22~]tetracosa-l(21),2(24),4,ll,15,17,19,22- octaen-6-one
Example 16: (9S,llZ)-12,16-dimethyl-3,7,14,17,23-pentaaza- pentacyclo[13.6.2.1~2,5~.0~4,9~.0~18,22~]tetracosa-l(21),2(24),4,ll,15,17,19,22- octaen-6-one
Figure imgf000105_0001
Step 1 : (S)-7-allyl-2-(2-methyl-3-((2-methylallyl)amino)quinoxalin-5-yl)-6,7-dihydro- 1 H-pyrrolo [3 ,2-c]pyridin-4(5H)-one
A glass microwave reaction vessel was charged with (2-methyl-3-((2- methylallyl)amino)quinoxalin-5-yl)boronic acid (Intermediate I, 40 mg, 0.156 mmol) and (S)-7-allyl-2-bromo-6,7-dihydro-lH-pyrrolo[3,2-c]pyridin-4(5H)-one (Intermediate D, 39.7 mg, 0.156 mmol) in 1 ,4-dioxane (1.0 mL)/water (0.25 mL) followed by Pd2dba3(7.12 mg, 7.78 μιηοΐ, Strem), 2-(dicyclohexylphosphino)-2',4',6',-tri-isopropyll, -biphenyl (7.42 mg, 0.016 mmol, Sigma- Aldrich) and K3P04 (66.1 mg, 0.31 1 mmol, Sigma- Aldrich). The reaction mixture was stirred and heated in an oil bath at 100 °C for 40 min, then cooled to RT. The mixture was diluted with DCM (80 mL) and washed with water (15 mL), brine (10 mL). The organic layers was dried (MgS04), filtered and concentrated. The residue was purified with silica gel chromatography (eluted with 1 -4% MeOH in DCM) to give (S)-7-allyl-2-(2-methyl-3-((2-methylallyl)amino)quinoxalin-5-yl)-6,7- dihydro-lH-pyrrolo[3,2-c]pyridin-4(5H)-one (32 mg, 0.083 mmol, 53.1 % yield) as a yellow solid. !H NMR (400 MHz, DMSO-d6) δ ppm 1 1.76 (1 H, br. s.), 7.88 (1 H, d,
J=7.6 Hz), 7.57 (1 H, dd, J=8.0, 1.2 Hz), 7.49 (1 H, t, J=5.7 Hz), 7.32 (1 H, t, J=7.7 Hz), 7.10 (1 H, d, J=2.2 Hz), 6.89 (1 H, br. s.), 5.78 - 5.92 (1 H, m), 5.08 - 5.16 (2 H, m), 4.89 (1 H, s), 4.82 (1 H, s), 4.09 (2 H, t, J=4.8 Hz), 3.49 (1 H, dd, J=12.6, 3.6 Hz), 3.21 (1 H, dt, J=12.6, 4.1 Hz), 3.02 (1 H, dd, J=9.5, 4.8 Hz), 2.57 (3 H, s), 2.31 - 2.38 (1 H, m), 1.85 (3 H, s). MS (ESI, pos. ion) m/z: 388.3 (M+H)+.
Step 2: (9S,1 lE)-12,16-dimethyl-3,7,14,17,23- pentaazapentacyclo[l 3.6.2.1~2,5~.0~4,9~.0~18,22~]tetracosa-
1 (21 ),2(24),4, 11 , 15, 17, 19,22-octaen-6-one and (9S, 1 1 Z)- 12, 16-dimethyl-3,7, 14,17,23- pentaazapentacyclo[l 3.6.2.1~2,5~.0~4,9~.0~18,22~]tetracosa- 1 (21 ),2(24),4, 11 , 15, 17, 19,22-octaen-6-one
To a 150-mL round-bottomed flask was added (S)-7-allyl-2-(2-methyl-3-((2- methylallyl)amino)quinoxalin-5-yl)-6,7-dihydro-lH-pyrrolo[3,2-c]pyridin-4(5H)-one (3.50 g, 9.03 mmol) in DCM (400 mL) followed by tricyclohexylphosphine[l ,3-bis(2,4,6- trimethylphenyl)-4,5-dihydroimidazol-2-ylidene] [benzylidine]ruthenium (0.767 g, 0.903 mmol, Sigma- Aldrich). The mixture was bubbled with Ar for 5 min, then equiped with a reflux condenser and heated in an oil bath at 50 °C for 90 min, then cooled to RT. The solvent was removed and the residue was purified with silica gel chromatography (eluted with 1 -7% MeOH in DCM) to give the product (2.99 g, 92% yield). The product was further purified with preparative supercritical fluid chromatography (SFC) (Chiralcel
ODH (250x30), 5 μ, 40% MeOH, 286-nm, 1 19/193 bar) to give (9S,1 1E)-12,16- dimethyl-3,7,14,17,23-pentaazapentacyclo[l 3.6.2. l~2,5~.0~4,9~.0~18,22~]tetracosa- 1 (21 ),2(24),4, 11 , 15, 17, 19,22-octaen-6-one (the major peak) and (9S, 11 Z)- 12, 16- dimethyl-3,7,14,17,23-pentaazapentacyclo[l 3.6.2. l~2,5~.0~4,9~.0~18,22~]tetracosa- 1(21),2(24),4,1 l,15,17,19,22-octaen-6-one (the minor peak). Analytical data:
Example 14, (9S,1 lE)-12,16-dimethyl-3,7,14,17,23-pentaaza- pentacyclo[13.6.2.1~2,5~.0~4,9~.0~18,22~]tetracosa-l(21),2(24),4,l 1 ,15,17,19,22- octaen-6-one: 'H NMR (400 MHz, DMSO-d6) δ ppm 13.40 (1 H, br. s.), 7.96 - 8.02 (1 H, m), 7.52 - 7.63 (2 H, m), 7.33 (1 H, t, J=7.7 Hz), 7.02 (1 H, d, J=4.5 Hz), 6.91 (1 H, d, J=2.0 Hz), 5.84 (1 H, d, J=8.4 Hz), 4.13 (1 H, br. s.), 3.98 - 4.06 (1 H, m), 3.40 (1 H, dt, J=10.4, 5.0 Hz), 3.26 - 3.30 (1 H, m), 3.17 - 3.25 (1 H, m), 2.59 (3 H, s), 2.37 - 2.48 (2 H, m), 1.63 (3 H, s). MS (ESI, pos. ion) m/z: 360.2 (M+H)+.
Example 16, (9S,1 lZ)-12,16-dimethyl-3,7,14,17,23-pentaaza- pentacyclo[13.6.2.1~2,5~.0~4,9~.0~18,22~]tetracosa-l(21),2(24),4,l 1 ,15,17,19,22- octaen-6-one: !H NMR (400 MHz, DMSO-d6) δ ppm 7.94 (1 H, br. s.), 7.83 - 7.90 (1 H, m), 7.58 (1 H, d, J=6.5 Hz), 7.29 - 7.38 (1 H, m), 6.96 (1 H, br. s.), 6.75 (1 H, br. s.), 5.63 (1 H, d, J=11.3 Hz), 4.53 (1 H, d, J=15.8 Hz), 3.64 - 3.77 (1 H, m), 3.36 (1 H, br. s.), 3.17 (2 H, br. s.), 2.70 - 2.82 (1 H, m), 2.58 (3 H, br. s.), 2.15 - 2.24 (1 H, m), 1.71 (3 H, br. s.). MS (ESI, pos. ion) m/z: 360.1 (M+H)+.
Example 17: (HE)-12-methyl-3,7,14,17,23-pentaaza- pentacyclo[13.6.2.1~2,5~.0~4,9~.0~18,22~]tetracosa-l(21),2(24),4,ll,15,17,19,22- octaen-6-one
Figure imgf000107_0001
Step 1 : 8-chloro-N-(2-methylallyl)quinoxalin-2-amine
2,8-Dichloroquinoxaline (Pharmabridge Inc., Doylestown, PA; 2.00 g, 10.05 mmol) and 2-methylallylamine (Matrix, Columbia, SC; 4.29 ml, 60.3 mmol) were combined in a tube, sealed, and heated to 80 °C in an oil bath. After 4 h, the reaction was cooled and the reaction was partitioned between saturated aqueous NaHC03 and DCM. The aqueous layer was extracted with DCM 3 times, and the combined organics were dried over anhydrous Na2S04, filtered, and concentrated in vacuo to give 8-chloro-N-(2- methylallyl)quinoxalin-2 -amine (2.40 g, 10.27 mmol, quantitative yield) as an orange semi-solid: !H NMR (400 MHz, CDCl3) δ ppm 8.28 (1 H, s), 7.77 - 7.85 (1 H, m), 7.69 (1 H, d, J=7.7 Hz), 7.29 - 7.34 (1 H, m), 5.04 (1 H, s), 4.96 (1 H, s), 4.20 (2 H, d, J=5.9 Hz), 1.87 (3 H, s). m/z (ESI, +ve) 234.1 (M+H)+.
Step 2: 8-(l-ethoxyvinyl)-N-(2-methylallyl)quinoxalin-2-amine
Argon was bubbled through a mixture of tributyl(l -ethoxyvinyl)tin (Aldrich; 5.20 ml,
15.40 mmol), Cul (Riedel-de-Haen; 0.391 g, 2.054 mmol), cesium fluoride (Aldrich; 4.68 g, 30.8 mmol), Pd2(dba)3 (Strem; 2.351 g, 2.57 mmol), X-Phos (Strem; 1.224 g, 2.57 mmol), 8-chloro-N-(2-methylallyl)quinoxalin-2-amine (2.40 g, 10.27 mmol) in 20 mL dioxane in a sealable pressure vessel for 2 min. The reaction was sealed and heated to 120 °C in an oil bath overnight. The reaction was transferred to a 500 mL rbf with DCM, and adsorbed onto 20 g silica gel in vacuo. The material was purified by silica gel chromatography (160 g column) using 0 - 50% EtOAc/hexane to give 8-(l -ethoxyvinyl)- N-(2-methylallyl)quinoxalin-2 -amine (2.85 g, 10.6 mmol, quantitative yield): !H NMR (400 MHz, DMSO-de) δ ppm 8.36 (1 H, s), 7.90 (1 H, t, J=5.9 Hz), 7.73 (1 H, d, J=7.8 Hz), 7.30 (1 H, t, J=7.8 Hz), 5.22 (1 H, s), 4.91 (1 H, s), 4.81 (1 H, s), 4.58 (1 H, s), 3.98 (2 H, m), 3.90 (2 H, q, J=6.9 Hz), 1.77 (2 H, s), 1.33 (3 H, t, J=6.9 Hz).
Step 3 : 2-bromo-l -(3-((2-methylallyl)amino)quinoxalin-5-yl)ethanone
8-(l -Ethoxyvinyl)-N-(2-methylallyl)quinoxalin-2-amine (2.82 g, 10.47 mmol) was dissolved in 50 mL THF and water (3.02 ml, 168 mmol) was added followed by 1- bromopyrrolidine-2,5-dione (Fluka; 1.770 g, 9.95 mmol). After 30 min, the reaction was partitioned between saturated aqueous NaHCC and Et20. The organic layer was washed with saturated aqueous NaHC03 once, water once, brine once, and the organics were dried over anhydrous Na2S04, filtered, and concentrated in vacuo. The material was treated with DCM and purified by silica gel chromatography (80 g column) using 0 - 30%o EtOAc/hexane to give 2-bromo-l -(3-((2-methylallyl)amino)quinoxalin-5-yl)ethanone (0.96 g, 3.00 mmol, 28.6 % yield): !H NMR (400 MHz, CDCl3) δ ppm 8.32 (1 H, br. s.),
8.04 - 8.19 (2 H, m), 7.41 - 7.51 (1 H, m), 5.07 (1 H, br. s.), 4.96 (1 H, br. s.), 4.12 (2 H, d, J=5.7 Hz), 1.88 (3 H, s). m/z (ESI, +ve) 320.0 (M+H)+. Step 4: 7-allyl-2-(3-((2-methylallyl)amino)quinoxalin-5-yl)-6,7-dihydro-lH-pyrrolo[3 c]pyridin-4(5H)-one
A slurry of NH4OAC (Fisher Scientific, 0.924 g, 1 1.99 mmol), 5-allylpiperidine-2,4- dione (Intermediate A, 0.574 g, 3.75 mmol), 2-bromo-l -(3-((2- methylallyl)amino)quinoxalin-5-yl)ethanone (0.96 g, 3.00 mmol) in 30 mL EtOH was sealed and stirred rapidly. The reaction was placed in a 60 °C oil bath, then the oil bath was turned off and the reaction cooled slowly overnight. In the morning, the reaction was heated to 60 °C. After 2 h, the reaction was judged complete by LCMS. The reaction was partitioned between saturated aqueous NaHC03 and DCM. The aqueous layer was extracted with DCM 3 times, and the combined organics were dried over anhydrous Na2S04, filtered, and concentrated in vacuo. The material was purified by silica gel chromatography (40 g column) using 0 - 60% 90/10 DCM/MeOH in DCM to give 7- allyl-2-(3-((2-methylallyl)amino)quinoxalin-5-yl)-6,7-dihydro-lH-pyrrolo[3,2-c]pyridin- 4(5H)-one (0.140 g, 0.375 mmol, 12.50 % yield) as an orange solid: !H NMR (400 MHz, DMSO-de) δ ppm 1 1.89 (1 H, br. s.), 8.45 (1 H, s), 8.05 - 8.12 (1 H, m), 7.95 (1 H, dt,
J=7.5, 0.7 Hz), 7.63 (1 H, dt, J=8.1 , 0.6 Hz), 7.34 (1 H, t, J=7.8 Hz), 7.06 - 7.12 (1 H, m), 6.92 (1 H, br. s.), 5.79 - 5.98 (1 H, m), 5.05 - 5.17 (2 H, m), 4.98 (1 H, s), 4.88 (1 H, s), 4.06 (2 H, dd, J=6.1, 0.4 Hz), 3.44 - 3.52 (1 H, m), 3.15 - 3.25 (1 H, m), 3.00 - 3.10 (1 H, m), 2.53 - 2.60 (1 H, m), 2.27 - 2.40 (1 H, m), 1.84 (3 H, s). m/z (ESI, +ve) 374.1 (M+H)+.
Step 5 : (1 lE)-12-methyl-3,7,14,17,23-pentaaza- pentacyclo[13.6.2.1~2,5~.0~4,9~.0~18,22~]tetracosa-l(21),2(24),4,l 1 ,15,17,19,22- octaen-6-one
Argon was bubbled into a slurry of 7-allyl-2-(3-((2-methylallyl)amino)quinoxalin-5-yl)-
6,7-dihydro-lH-pyrrolo[3,2-c]pyridin-4(5H)-one (0.140 g, 0.375 mmol) and Grubbs catalyst 2nd generation (Aldrich; 0.032 g, 0.037 mmol) in 19 mL DCM for 2 min. The reaction was fitted with a water-cooled reflux condenser and heated to reflux. The reaction became a brown homogeneous solution. After 6 h, additional Grubbs catalyst 2nd generation (Aldrich; 0.032 g, 0.037 mmol) and 5 mL DCM was added and reflux continued overnight. In the morning, 3 g silica gel was added and the reaction concentated in vacuo. The material was purified by silica gel chromatography (40 g column) using 0 - 70% 90/10 DCM/MeOH in DCM. The product-containing fractions were concentrated to afford (1 lE)-12-methyl-3,7,14,17,23- pentaazapentacyclo[l 3.6.2.1~2,5~.0~4,9~.0~18,22~]tetracosa- l(21),2(24),4,l l,15,17,19,22-octaen-6-one (0.054 g, 0.16 mmol, 42% yield) as a yellow solid: !H NMR (400 MHz, DMSO-d6) δ ppm 13.50 (1 H, br. s.), 8.43 (1 H, s), 8.19 - 8.26 (1 H, m), 8.03 (1 H, dt, .7=7.6, 0.7 Hz), 7.59 (1 H, dt, .7=8.0, 0.7 Hz), 7.33 (1 H, t, J=7.8 Hz), 7.01 (1 H, d, J=4.7 Hz), 6.89 - 6.93 (1 H, m), 5.78 - 5.87 (1 H, m), 3.94 - 4.14 (2 H, m), 3.35 - 3.43 (1 H, m), 3.13 - 3.29 (2 H, m), 2.32 - 2.46 (2 H, m), 1.61 (3 H, s). m/z (ESI, +ve) 346.3 (M+H)+.
Examples 18 and 19: (9R, llE)-12-methyl-3,7,14,17,23- pentaazapentacyclo[13.6.2.1~2,5~.0~4,9~.0~18,22~]tetracosa- l(21),2(24),4,ll,15,17,19,22-octaen-6-one and (9S, llE)-12-methyl-3,7,14,17,23- pentaazapentacyclo[13.6.2.1~2,5~.0~4,9~.0~18,22~]tetracosa- l(21),2(24),4,ll,15,17,19,22-octaen-6-one
Figure imgf000110_0001
The individual enantiomers of Example 17 were obtained by chiral SFC (Column: Chiralpak AS-H (250 x 21 mm, 5 μ) Mobile Phase: 75 :25 (A:B); A: Liquid C02 B: MeOH (40 mM NH3); Flow Rate: 75 mL/min; Oven Temp: 40 °C; Inlet Pressure: 100 bar) to give Example 18 (first eluting product) and Example 19 (second eluting product).
Example 20: (9S,llZ)-16-methyl-3,7,14,17,23- pentaazapentacyclo[13.6.2.1~2,5~.0~4,9~.0~18,22~]tetracosa- l(21),2(24),4,ll,15,17,19,22-octaen-6-one
Example 21 : (9S,llE)-16-methyl-3,7,14,17,23- pentaazapentacyclo[13.6.2.1~2,5~.0~4,9~.0~18,22~]tetracosa- l(21),2(24),4,ll,15,17,19,22-octaen-6-one
Example 22: (9R,llZ)-16-methyl-3,7,14,17,23- pentaazapentacyclo[13.6.2.1~2,5~.0~4,9~.0~18,22~]tetracosa- l(21),2(24),4,ll,15,17,19,22-octaen-6-one Example 23: (9R,llE)-16-methyl-3,7,14,17,23- pentaazapentacyclo[13.6.2.1~2,5~.0~4,9~.0~18,22~]tetracosa- l(21),2(24),4,ll,15,17,19,22-octaen-6-one
Figure imgf000111_0001
Step 1 : 7-allyl-2-(3-(allylamino)-2-methylquinoxalin-5-yl)-6,7-dihydro-lH-pyrrolo[3,2- c]pyridin-4(5H)-one
A slurry of 7-allyl-2-(3-i uoro-2-methylquinoxalin-5-yl)-6,7-dihydro-lH-pyrrolo[3,2- c]pyridin-4(5H)-one (Intermediate C, 0.322 g, 0.957 mmol) in allylamine (Aldrich; 5.02 ml, 67.0 mmol) was sealed and heated to 60 °C for 2 h. The reaction was cooled to RT, judged complete and diluted with ~ 5 mL saturated aqueous NaHC03 and 5 mL water. The thick suspension was filtered, rinsing with water and MeOH, and was dried in vacuo to give 7-allyl-2-(3-(allylamino)-2-methylquinoxalin-5-yl)-6,7-dihydro-lH-pyrrolo[3,2- c]pyridin-4(5H)-one (0.289 g, 0.774 mmol, 81 % yield) as a bright yellow solid: !H NMR (400 MHz, DMSO-de) δ ppm 12.05 (1 H, br. s.), 7.91 (1 H, dt, .7=7.5, 0.8 Hz), 7.54 - 7.61 (2 H, m), 7.33 (1 H, t, J=7.7 Hz), 7.03 (1 H, dd, J=1.8, 0.4 Hz), 6.91 - 6.96 (1 H, m), 6.04 - 6.16 (1 H, m), 5.79 - 5.95 (1 H, m), 5.25 - 5.34 (1 H, m), 5.08 - 5.20 (3 H, m), 4.18 (2 H, t, J=5.3 Hz), 3.50 (1 H, ddt, J=12.4, 5.7, 0.7, 0.7 Hz), 3.18 - 3.24 (1 H, m), 3.01 - 3.08 (1 H, m), 2.57 (3 H, s), 2.44 - 2.51 (1 H, m), 2.28 - 2.40 (1 H, m). m/z (ESI, +ve) 374.1 (M+H)+.
Step 2: (9S,1 lZ)-16-methyl-3,7,14,17,23- pentaazapentacyclo[l 3.6.2.1~2,5~.0~4,9~.0~18,22~]tetracosa- 1 (21 ),2(24),4, 1 1 , 15 , 17, 19,22-octaen-6-one,
(9S, 11 E)- 16-methyl-3 ,7, 14,17,23- pentaazapentacyclo[l 3.6.2.1~2,5~.0~4,9~.0~18,22~]tetracosa- 1 (21 ),2(24),4, 1 1 , 15 , 17, 19,22-octaen-6-one, (9R, 11 Z)- 16-methyl-3 ,7,14,17,23- pentaazapentacyclo[l 3.6.2.1~2,5~.0~4,9~.0~18,22~]tetracosa- 1 (21 ),2(24),4, 11 , 15 , 17, 19,22-octaen-6-one,
(9R, 11 E)- 16-methyl-3 ,7,14,17,23- pentaazapentacyclo[l 3.6.2. l~2,5~.0~4,9~.0~18,22~]tetracosa-
1 (21 ),2(24),4, 11 , 15 , 17, 19,22-octaen-6-one
Argon was bubbled through a slurry of 7-allyl-2-(3-(allylamino)-2-methylquinoxalin-5- yl)-6,7-dihydro-lH-pyrrolo[3,2-c]pyridin-4(5H)-one (0.289 g, 0.774 mmol) and Grubbs II Catalyst (Aldrich; 0.131 g, 0.155 mmol) for 2 min. The reaction was sealed and placed in a 50 °C oil bath overnight (~ 12 h). The green heterogeneous reaction was judged complete by LCMS. The reaction was concentrated onto 3 g silica gel from MeOH/DCM and dried in vacuo, and was purified by silica gel chromatography (40 g column) using 0 - 100% 90/10 DCM/MeOH in DCM to give 0.234 g of a mixture of products as a light green solid. The material was purified by SFC: Column: Cellulose-1 (21mm x 25 cm, 5 μ, phenomenex, Lux- 1 , PO-AX (OD-H clone column), 60% C02 and MeOH 40% with 40 mM NH3, flow rate 70 ml/min, P=193 bar, 40 °C, to give Example 20 (9S,11Z)-16- methyl-3,7,14,17,23-pentaazapentacyclo[l 3.6.2.1~2,5~.0~4,9~.0~18,22~]tetracosa- 1(21),2(24),4,1 l,15,17,19,22-octaen-6-one (first eluting peak, 26 mg containing an impurity, material was sonicated in 0.5 mL MeOH and filtered, rinsing 1 x 0.5 mL MeOH, to give 17 mg, 0.051 mmol, 7% yield), Example 21 (9S,1 lE)-16-methyl- 3,7,14, 17,23-pentaazapentacyclo[l 3.6.2. l~2,5~.0~4,9~.0~18,22~]tetracosa- l(21),2(24),4,l l,15,17,19,22-octaen-6-one (second eluting peak, 51 mg, 0.15 mmol, 19%o yield), and a mixture of (9R,11Z)- and (9R, 1 l-E)-16-methyl-3,7,14,17,23-pentaaza- pentacyclo[13.6.2.1~2,5~.0~4,9~.0~18,22~]tetracosa-l(21),2(24),4,l 1,15,17,19,22- octaen-6-one (third eluting peak). The third-eluting peak was further purified by SFC:
Column: OJ-H (21mmx 250 mm, 5 μ), 70 mL, 30% EtOH 40 mM NH3, P=179 bar 70% C02. 40 °C, to give Example 22 (9R,l lZ)-16-methyl-3,7,14,17,23- pentaazapentacyclo[l 3.6.2.1~2,5~.0~4,9~.0~18,22~]tetracosa-
1 (21 ),2(24),4, 11 , 15, 17, 19,22-octaen-6-one (first eluting peak, 28 mg, 0.081 mmol, 10% yield) and Example 23 (9R,1 lE)-16-methyl-3,7,14,17,23-pentaaza- pentacyclo[13.6.2.1~2,5~.0~4,9~.0~18,22~]tetracosa-l(21),2(24),4,l 1,15,17,19,22- octaen-6-one (second eluting peak, 44 mg, 0.13 mmol, 16%o yield).
Analytical data for Example 20 (9S,1 lZ)-16-methyl-3,7,14,17,23-pentaaza- pentacyclo[13.6.2.1~2,5~.0~4,9~.0~18,22~]tetracosa-l(21),2(24),4,l 1,15,17,19,22-
- I l l - octaen-6-one: !H NMR (400 MHz, DMSO-d6) δ ppm 13.79 (1 H, s), 7.95 - 8.03 (1 H, m), 7.88 (1 H, dt, J=1A, 0.8 Hz), 7.58 (1 H, dt, .7=7.9, 0.8 Hz), 7.34 (1 H, t, .7=7.8 Hz), 6.99 (1 H, d, .7=4.5 Hz), 6.78 (1 H, dd, .7=1.8, 0.4 Hz), 5.72 - 5.89 (1 H, m), 5.51 - 5.66 (1 H, m), 4.40 (1 H, ddd, .7=15.8, 10.4, 4.9 Hz), 3.74 - 3.92 (1 H, m), 3.37 (1 H, t, .7=5.2 Hz), 3.18 - 3.25 (2 H, m), 2.69 - 2.81 (1 H, m), 2.56 (3 H, s), 2.26 (1 H, d, J=13.9 Hz), m/z (ESI, +ve) 346.1 (M+H)+.
Analytical data for Example 21 (9S,1 lE)-16-methyl-3,7,14,17,23-pentaaza- pentacyclo[13.6.2.1~2,5~.0~4,9~.0~18,22~]tetracosa-l(21),2(24),4,l 1 ,15,17,19,22- octaen-6-one: !H NMR (400 MHz, DMSO-d6) δ ppm 13.54 (1 H, br. s.), 7.98 (1 H, dt, .7=7.5, 0.7 Hz), 7.53 (2 H, dd, .7=8.0, 1.4 Hz), 7.31 (1 H, t, .7=7.8 Hz), 7.02 (1 H, d, J=4.5 Hz), 6.89 (1 H, dd, .7=2.0, 0.4 Hz), 6.00 - 6.14 (1 H, m), 5.83 - 5.94 (1 H, m), 4.14 - 4.28 (1 H, m), 3.98 - 4.09 (1 H, m), 3.34 - 3.38 (1 H, m), 3.22 - 3.30 (1 H, m), 3.07 - 3.16 (1 H, m), 2.52 - 2.62 (4 H, m), 2.15 - 2.28 (1 H, m). m/z (ESI, +ve) 346.1 (M+H)+.
Analytical data for Example 22 (9R,1 lZ)-16-methyl-3,7,14,17,23-pentaaza- pentacyclo[13.6.2.1~2,5~.0~4,9~.0~18,22~]tetracosa-l(21),2(24),4,l 1 ,15,17,19,22- octaen-6-one: !H NMR (400 MHz, DMSO-d6) δ ppm 13.79 (1 H, s), 7.95 - 8.03 (1 H, m), 7.88 (1 H, dt, .7=7.4, 0.8 Hz), 7.58 (1 H, dt, .7=7.9, 0.8 Hz), 7.34 (1 H, t, .7=7.8 Hz), 6.99 (1 H, d, .7=4.5 Hz), 6.78 (1 H, dd, .7=1.8, 0.4 Hz), 5.72 - 5.89 (1 H, m), 5.51 - 5.66 (1 H, m), 4.40 (1 H, ddd, .7=15.8, 10.4, 4.9 Hz), 3.74 - 3.92 (1 H, m), 3.37 (1 H, t, .7=5.2 Hz), 3.18 - 3.25 (2 H, m), 2.69 - 2.81 (1 H, m), 2.56 (3 H, s), 2.26 (1 H, d, .7=13.9 Hz), m/z (ESI,
+ve) 346.1 (M+H)+.
Analytical data for Example 23 (9R,1 lE)-16-methyl-3,7,14,17,23-pentaaza- pentacyclo[13.6.2.1~2,5~.0~4,9~.0~18,22~]tetracosa-l(21),2(24),4,l 1 ,15,17,19,22- octaen-6-one: !H NMR (400 MHz, DMSO-d6) δ ppm 13.54 (1 H, br. s.), 7.98 (1 H, dt, .7=7.5, 0.7 Hz), 7.53 (2 H, dd, .7=8.0, 1.4 Hz), 7.31 (1 H, t, .7=7.8 Hz), 7.02 (1 H, d, .7=4.5 Hz), 6.89 (1 H, dd, .7=2.0, 0.4 Hz), 6.00 - 6.14 (1 H, m), 5.83 - 5.94 (1 H, m), 4.14 - 4.28 (1 H, m), 3.98 - 4.09 (1 H, m), 3.34 - 3.38 (1 H, m), 3.22 - 3.30 (1 H, m), 3.07 - 3.16 (1 H, m), 2.52 - 2.62 (4 H, m), 2.15 - 2.28 (1 H, m). m/z (ESI, +ve) 346.1 (M+H)+. Example 24: (9S,llE)-12,16-dimethyl-14-oxa-3,7,17,23- tetraazapentacyclo[13.6.2.1~2,5~.0~4,9~.0~18,22~]tetracosa- l(21),2(24),4,ll,15,17,19,22-octaen-6-one Example 25: (9R,llE)-12,16-dimethyl-14-oxa-3,7,17,23- tetraazapentacyclo[13.6.2.1~2,5~.0~4,9~.0~18,22~]tetracosa- l(21),2(24),4,ll,15,17,19,22-octaen-6-one
Figure imgf000114_0001
Step 1 : 7-allyl-2-(2-methyl-3-((2-methylallyl)oxy)quinoxalin-5-yl)-6,7-dihydro-lH- pyrrolo [3,2 -c]pyridin-4(5 H)-one
To a slurry of NaH, 60% dispersion in mineral oil (Aldrich; 0.059 g, 1.486 mmol) in 1 mL DMF at 0 °C was added 2-methyl-2-propen-l-ol (TCI America; 0.125 ml, 1.486 mmol) slowly dropwise (bubbling). After 5 min the reaction was warmed to RT. After 10 min, 7-allyl-2-(3-fluoro-2-methylquinoxalin-5-yl)-6,7-dihydro-lH-pyrrolo[3,2- c]pyridin-4(5H)-one (Intermediate C, 0.050 g, 0.149 mmol) was added as a solid. The reaction became red. After 30 min, the reaction was treated with saturated aqueous NH4C1 and EtOAc. The organic layer was washed lx water, lx brine, dried over anhydrous Na2S04, filtered, and concentrated in vacuo. The yellow solid was suspended in 5 mL Et20, sonicated, and filtered, rinsing 3 x 1 mL Et20, and the solid collected and dried in vacuo to give 7-allyl-2-(2-methyl-3-((2-methylallyl)oxy)quinoxalin-5-yl)-6,7- dihydro-lH-pyrrolo[3,2-c]pyridin-4(5H)-one (0.052 g, 0.134 mmol, 90 % yield) as a bright yellow solid: !H NMR (400 MHz, DMSO-d6) δ ppm 1 1.56 (1 H, br. s.), 7.98 (1 H, d, J=6.8 Hz), 7.79 (1 H, d, J=7.4 Hz), 7.58 - 7.65 (1 H, m), 7.10 (1 H, d, J=2.2 Hz), 6.95 (1 H, br. s.), 5.81 - 5.95 (1 H, m), 4.90 - 5.18 (7 H, m), 3.47 (1 H, ddd, J= 12.2, 5.3, 1.7 Hz), 3.20 (1 H, ddd, J=12.3, 6.1, 2.9 Hz), 3.06 - 3.15 (1 H, m), 2.60 - 2.69 (4 H, m), 2.35 (1 H, dt, J=14.0, 8.7 Hz), 1.88 (3 H, s). m/z (ESI, +ve) 389.1 (M+H)+.
Step 2: (9S,1 lE)-12,16-dimethyl-14-oxa-3,7,17,23- tetraazapentacyclo[13.6.2.1~2,5~.0~4,9~.0~18,22~]tetracosa-
1 (21 ),2(24),4, 11,15,17,19,22-octaen-6-one and (9R, 1 1 E)- 12, 16-dimethyl- 14-oxa-
3,7,17,23-tetraazapentacyclo[l 3.6.2. l~2,5~.0~4,9~.0~18,22~]tetracosa- 1 (21 ),2(24),4, 11 , 15 , 17, 19,22-octaen-6-one Argon was bubbled into a mixture of 7-allyl-2-(2-methyl-3-((2- methylallyl)oxy)quinoxalin-5-yl)-6,7-dihydro-lH-pyrrolo[3,2-c]pyridin-4(5H)-one (0.052 g, 0.134 mmol) and Grubbs catalyst 2nd generation (Aldrich; 0.023 g, 0.027 mmol) in 6.7 mL anhydrous DCM for 1 min. The reaction was sealed and heated to 45 °C. After 4 h, the reaction was concentrated in vacuo, taken up in 3.5 mL DMSO and filtered through a 0.45 μ filter, and purified by RPHPLC, Phenomenex Gemini 150x30 mm Cis column, 15- 80 % ACN/H2O with 0.1 % TFA; product-containing fractions were combined and concentrated in vacuo to give 0.028 g material. This was further purified by chiral SFC (Chiralpak AS-H (250 x 21 mm, 5 μ); Mobile Phase: 78:22 (A:B) A: Liquid C02; B: MeOH (20 mM NH3); Flow Rate: 75 mL/min; Oven Temp: 40 °C; Inlet Pressure: 100 bar) to give: first eluting peak Example 24 (9S,11 E)- 12,16-dimethyl-14-oxa-3 ,7, 17,23 - tetraazapentacyclo[13.6.2.1~2,5~.0~4,9~.0~18,22~]tetracosa- l(21),2(24),4,l l,15,17,19,22-octaen-6-one (0.008 g, 0.022 mmol, 17% yield) and second eluting peak Example 25 (9R,11 E)- 12,16-dimethyl-14-oxa-3, 7, 17,23 - tetraazapentacyclo[13.6.2.1~2,5~.0~4,9~.0~18,22~]tetracosa- l(21),2(24),4,l l,15,17,19,22-octaen-6-one (0.008 g, 0.022 mmol, 17% yield). Analytical data: !H NMR (400 MHz, DMSO-d6) δ ppm 13.05 (1 H, br. s.), 8.12 (1 H, d, J=6.8 Hz), 7.72 (1 H, d, J=7.8 Hz), 7.51 - 7.62 (1 H, m), 7.06 (1 H, d, J=3.9 Hz), 6.99 (1 H, d, J=2.0 Hz), 5.96 (1 H, d, J=8.0 Hz), 5.16 (1 H, d, J=13.3 Hz), 5.00 (1 H, d, J=13.5 Hz), 3.36 - 3.46 (2 H, m), 3.18 - 3.27 (1 H, m), 2.63 (3 H, s), 2.43 - 2.48 (2 H, m), 1.69 (3 H, s). m/z (ESI, +ve) 361.1 (M+H)+.
Example 26: (9R,llE)-17-methyl-3,7,15,18,24- pentaazapentacyclo[14.6.2.1~2,5~.0~4,9~.0~19,23~]pentacosa- l(22),2(25),4,ll,16,18,20,23-octaen-6-one
Example 27: (9S,llE)-17-methyl-3,7,15,18,24- pentaazapentacyclo[14.6.2.1~2,5~.0~4,9~.0~19,23~]pentacosa- l(22),2(25),4,ll,16,18,20,23-octaen-6-one
Example 28: (9R,llZ)-17-methyl-3,7,15,18,24- pentaazapentacyclo[14.6.2.1~2,5~.0~4,9~.0~19,23~]pentacosa- l(22),2(25),4,ll,16,18,20,23-octaen-6-one
Example 29: (9S,llZ)-17-methyl-3,7,15,18,24- pentaazapentacyclo[14.6.2.1~2,5~.0~4,9~.0~19,23~]pentacosa- l(22),2(25),4,ll,16,18,20,23-octaen-6-one
Figure imgf000116_0001
Step 1 : 7-allyl-2-(3-(but-3-en-l-ylamino)-2-methylquinoxalin-5-yl)-6,7-dihydro-lH^ pyrrolo [3,2 -c]pyridin-4(5 H)-one
A thick orange mixture of 7-allyl-2-(3-fluoro-2-methylquinoxalin-5-yl)-6,7-dihydro-lH- pyrrolo[3,2-c]pyridin-4(5H)-one (Intermediate C; 0.113 g, 0.336 mmol) in 3-buten-l - amine (Alfa-Aesar; 2.172 ml, 23.52 mmol) was sealed and heated to 70 °C. After 2 h, the reaction was judged complete by LCMS. The reaction was diluted with DCM/MeOH, adsorbed onto 1.5 g silica gel, dried, and purified by silica gel chromatography (25 g column) using 0 - 50% 90/10 DCM/MeOH in DCM. The product- containing fractions were concentrated to afford 7-allyl-2-(3-(but-3-en-l-ylamino)-2-methylquinoxalin-5-yl)- 6,7-dihydro-lH-pyrrolo[3,2-c]pyridin-4(5H)-one (0.140 g, 0.361 mmol, quantitative yield) as a yellow solid: !H NMR (400 MHz, DMSO-d6) δ ppm 12.01 (1 H, br. s.), 7.90 (1 H, d, J=7.6 Hz), 7.57 (1 H, d, J=7.8 Hz), 7.22 - 7.40 (2 H, m), 7.09 (1 H, d, J=2.0 Hz), 6.93 (1 H, br. s.), 5.79 - 6.10 (2 H, m), 4.99 - 5.26 (4 H, m), 3.43 - 3.69 (3 H, m), 3.18 - 3.25 (1 H, m), 2.98 - 3.1 1 (1 H, m), 2.50 - 2.62 (6 H, m), 2.21 - 2.40 (1 H, m). m/z (ESI, +ve) 388.1 (M+H)+.
Step 2: (9R,1 lE)-17-methyl-3,7,15, 18,24- pentaazapentacyclo[l 4.6.2. l~2,5~.0~4,9~.0~19,23~]pentacosa- l(22),2(25),4,l l,16,18,20,23-octaen-6-one, (9S,1 lE)-17-methyl-3,7,15,18,24- pentaazapentacyclo[l 4.6.2.1~2,5~.0~4,9~.0~19,23~]pentacosa-
1 (22),2(25),4, 11 , 16, 18,20,23-octaen-6-one, (9R, 1 1Z)-17-methyl-3,7, 15,18,24- pentaazapentacyclo[l 4.6.2. l~2,5~.0~4,9~.0~19,23~]pentacosa- l(22),2(25),4,l l,16,18,20,23-octaen-6-one, (9S,1 lZ)-17-methyl-3,7,l 5,18,24- pentaazapentacyclo[l 4.6.2.1~2,5~.0~4,9~.0~19,23~]pentacosa- 1 (22),2(25),4, 11 , 16, 18,20,23-octaen-6-one
Argon was flushed through a slurry of 7-allyl-2-(3-(but-3-en-l-ylamino)-2- methylquinoxalin-5-yl)-6,7-dihydro-lH-pyrrolo[3,2-c]pyridin-4(5H)-one (0.130 g, 0.336 mmol) and Grubbs catalyst 2nd generation (Aldrich; 0.057 g, 0.067 mmol) in 17 mL anhydrous DCM for 1 min. The reaction was sealed and heated to 45 °C. After 2 h, the reaction was treated with MeOH to give a solution and was adsorbed onto 1.3 g silica gel and dried in vacuo. The material was purified by silica gel chromatography (25 g column) using 0 - 100% 90/10 DCM/MeOH in DCM, to give 0.099 g yellow-green solid. This material was further purified by chiral SFC (AS-H (2 x 15 cm) 40% (1 : 1 : 1 mixture of MeOH:EtOH:IPA with 0.1 % NH4OH)/60% C02, 100 bar, 65 mL/min) to give three materials, peak 1 , 2, and 3. Peak 2 was further purified by chiral SFC (AD-H (2 x 15 cm), 35% MeOH(NH4OH)/C02, 100 bar, 60 mL/min) to give first eluting (peak 2a) and second eluting (peak 2b) materials:
Example 26, (9R,1 lE)-17-methyl-3,7,15,18,24- pentaazapentacyclo[l 4.6.2. l~2,5~.0~4,9~.0~19,23~]pentacosa-
1(22),2(25),4,1 l,16,18,20,23-octaen-6-one (Peak 1 , 0.033 g, 0.092 mmol, 27.4 % yield): !H NMR (400 MHz, DMSO-d6) δ ppm 12.13 (1 H, br. s.), 7.94 (1 H, d, J=7.6 Hz), 7.41 -
7.59 (2 H, m), 7.27 (1 H, t, .7=7.8 Hz), 7.04 (1 H, d, .7=3.1 Hz), 6.91 (1 H, d, .7=1.8 Hz), 6.05 (1 H, dt, .7=14.9, 7.3 Hz), 5.85 (1 H, ddd, .7=15.3, 10.3, 4.8 Hz), 3.64 - 3.77 (1 H, m), 3.49 - 3.60 (1 H, m), 3.33 - 3.41 (1 H, m), 3.14 - 3.25 (1 H, m), 3.01 - 3.13 (1 H, m), 2.52 (3 H, s), 2.13 - 2.47 (4 H, m). m/z (ESI, +ve) 360.2 (M+H)+.
Example 27, (9S,1 lE)-17-methyl-3,7,15,18,24- pentaazapentacyclo[l 4.6.2. l~2,5~.0~4,9~.0~19,23~]pentacosa-
1(22),2(25),4,1 l,16,18,20,23-octaen-6-one (Peak 3, 0.031 g, 0.086 mmol, 25.7 % yield): !H NMR (400 MHz, DMSO-d6) δ ppm 12.13 (1 H, br. s.), 7.94 (1 H, d, .7=7.6 Hz), 7.41 - 7.59 (2 H, m), 7.27 (1 H, t, .7=7.8 Hz), 7.04 (1 H, d, .7=3.1 Hz), 6.91 (1 H, d, .7=1.8 Hz), 6.05 (1 H, dt, .7=14.9, 7.3 Hz), 5.85 (1 H, ddd, .7=15.3, 10.3, 4.8 Hz), 3.64 - 3.77 (1 H, m),
3.49 - 3.60 (1 H, m), 3.33 - 3.41 (1 H, m), 3.14 - 3.25 (1 H, m), 3.01 - 3.13 (1 H, m), 2.52 (3 H, s), 2.13 - 2.47 (4 H, m). m/z (ESI, +ve) 360.2 (M+H)+.
Example 28, (9R,1 lZ)-17-methyl-3,7,15,18,24- pentaazapentacyclo[l 4.6.2.1~2,5~.0~4,9~.0~19,23~]pentacosa- l(22),2(25),4,l l,16,18,20,23-octaen-6-one (Peak 2a, 0.0025 g, 0.0069 mmol, 2.1 % yield): !H NMR (400 MHz, 4:1 CDCl3:MeOH-d4) δ ppm 7.89 (1 H, d, J=6.5 Hz), 7.61 - 7.69 (1 H, m), 7.37 (1 H, t, J=7.8 Hz), 7.02 (1 H, d, J=2.0 Hz), 6.45 (1 H, t, J=6.2 Hz), 5.64 - 5.83 (2 H, m), 3.87 - 4.02 (1 H, m), 3.39 - 3.61 (4 H, m), 2.70 - 2.91 (2 H, m), 2.59 (3 H, s), 2.26 - 2.42 (2 H, m). m/z (ESI, +ve) 360.2 (M+H)+.
Example 29, (9S,1 lZ)-17-methyl-3,7,15,18,24- pentaazapentacyclo[l 4.6.2. l~2,5~.0~4,9~.0~19,23~]pentacosa- l(22),2(25),4,l l,16,18,20,23-octaen-6-one (Peak 2b, 0.0031 g, 0.0087 mmol, 2.6 % yield): !H NMR (400 MHz, 4:1 CDCh:MeOH-d4) δ ppm 7.89 (1 H, d, J=6.5 Hz), 7.61 - 7.69 (1 H, m), 7.37 (1 H, t, J=7.8 Hz), 7.02 (1 H, d, J=2.0 Hz), 6.45 (1 H, t, J=6.2 Hz),
5.64 - 5.83 (2 H, m), 3.87 - 4.02 (1 H, m), 3.39 - 3.61 (4 H, m), 2.70 - 2.91 (2 H, m), 2.59 (3 H, s), 2.26 - 2.42 (2 H, m). m/z (ESI, +ve) 360.2 (M+H)+.
Example 30: (9R,llE,13R)-13,16-dimethyl-3,7,14,17,23- pentaazapentacyclo[13.6.2.1~2,5~.0~4,9~.0~18,22~]tetracosa- l(22),2(24),4,ll,15,17,18,20,22-nonaen-6-one
Example 31: (9S,llE,13R)-13,16-dimethyl-3,7,14,17,23- pentaazapentacyclo[13.6.2.1~2,5~.0~4,9~.0~18,22~]tetracosa- l(22),2(24),4,ll,15,17,18,20,22-nonaen-6-one
Example 32: (9S,llZ,13R)-13,16-dimethyl-3,7,14,17,23- pentaazapentacyclo[13.6.2.1~2,5~.0~4,9~.0~18,22~]tetracosa- l(22),2(24),4,ll,15,17,18,20,22-nonaen-6-one
Figure imgf000118_0001
Step 1 : 7-allyl-2-(3-((R)-but-3-en-2-ylamino)-2-methylquinoxalin-5-yl)-6,7-dihydro-lH- pyrrolo [3,2 -c]pyridin-4(5 H)-one
A mixture of (R)-but-3-en-2-amine hydrochloride (Intermediate H; 0.288 g, 2.68 mmol), 7-allyl-2-(3-fluoro-2-methylquinoxalin-5-yl)-6,7-dihydro-lH-pyrrolo[3,2-c]pyridin- 4(5H)-one (Intermediate C; 0.300 g, 0.892 mmol) in 4 mL THF was treated with DIPEA (Aldrich, 0.931 ml, 5.35 mmol) and the reaction was sealed and heated to 60 °C. 1.5 mL DMSO was added to give a cloudy mixture. After 2 h, the temperature was increased to 80 °C. After 6 h the reaction was partitioned between water and DCM. The aqueous layer was extracted with DCM 3 times, and the combined organics were dried over anhydrous Na2S04, filtered, and concentrated in vacuo. The solid was adsorbed onto 2 g silica gel from DCM/MeOH and dried in vacuo. The material was purified by silica gel chromatography (40 g column) using 0 - 70% 90/10 DCM/MEOH in DCM. The product- containing fractions were concentrated to afford 7-allyl-2-(3-((R)-but-3-en-2-ylamino)-2- methylquinoxalin-5-yl)-6,7-dihydro-lH-pyrrolo[3,2-c]pyridin-4(5H)-one (0.230 g, 0.594 mmol, 66.6 % yield) as a yellow solid: m/z (ESI, +ve) 388.1 (M+H)+.
Step 2: (9R,1 lE,13R)-13,16-dimethyl-3,7,14,17,23- pentaazapentacyclo[l 3.6.2.1~2,5~.0~4,9~.0~18,22~]tetracosa-
1 (22),2(24),4, 11,15,17,18,20,22-nonaen-6-one, (9S, 11 E, 13R)-13, 16-dimethyl- 3,7,14, 17,23-pentaazapentacyclo[l 3.6.2. l~2,5~.0~4,9~.0~18,22~]tetracosa-
1 (22),2(24),4, 11,15,17,18,20,22-nonaen-6-one, (9S, 11 Z, 13R)-13, 16-dimethyl- 3,7,14, 17,23-pentaazapentacyclo[l 3.6.2. l~2,5~.0~4,9~.0~18,22~]tetracosa- 1 (22),2(24),4, 11 , 15, 17, 18,20,22-nonaen-6-one
Ar was bubbled through a solution of Grubbs catalyst 2nd generation (Aldrich; 0.099 g, 0.116 mmol) and 7-allyl-2-(3-((R)-but-3-en-2-ylamino)-2-methylquinoxalin-5-yl)-6,7- dihydro-lH-pyrrolo[3,2-c]pyridin-4(5H)-one (0.225 g, 0.581 mmol) in 30 mL anhydrous DCM for 1 min, the reaction was sealed, and placed in a 50 °C oil bath. After 2 h, the rection was judged complete and was adsorbed onto 3 g silica gel and dried in vacuo. The material was purified by silica gel chromatography (40 g column) using 0 - 100%o 90/10 DCM/MeOH in DCM. Combined fractions to give 0.188 g of a green-yellow solid. This material was further purified by chiral SFC (ODH (21x250mm, 5 μ), 45% MeOH with 20 mM NH3, 65 ml/min total flow) to give first eluting peak (peak 1, mixture of two components) and pure second eluting peak (peak 2). Peak 1 was further purified by SFC (Pyridine column (21x250mm, 5 μ), 27% MeOH with 20 mM NH3, 70 ml/min) to give first eluting peak (peak la) and second eluting peak (peak lb).
Example 30: (9R,1 lE,13R)-13,16-dimethyl-3,7,14,17,23- pentaazapentacyclo[l 3.6.2. l~2,5~.0~4,9~.0~18,22~]tetracosa- l(22),2(24),4,l l,15,17,18,20,22-nonaen-6-one (Peak 2, 0.083 g, 0.231 mmol, 39.8 % yield): !H NMR (400 MHz, DMSO-d6) δ ppm 13.57 (1 H, br. s.), 7.86 - 8.09 (1 H, m), 7.54 (1 H, dd, J=7.8, 1.0 Hz), 7.33 (1 H, t, J=7.8 Hz), 7.02 (1 H, d, J=4.3 Hz), 6.89 (1 H, d, J=2.0 Hz), 6.50 (1 H, s), 5.85 - 6.09 (2 H, m), 4.26 (1 H, t, J=6.7 Hz), 3.01 - 3.36 (3 H, m), 2.57 (4 H, d, J=13.5 Hz), 2.04 - 2.25 (1 H, m), 1.50 (3 H, d, J=7.0 Hz), m/z (ESI, +ve) 360.2 (M+H)+.
Example 31 : (9S,l lE,13R)-13,16-dimethyl-3,7,14,17,23- pentaazapentacyclo[l 3.6.2. l~2,5~.0~4,9~.0~18,22~]tetracosa- l(22),2(24),4,l l,15,17,18,20,22-nonaen-6-one (Peak la, 0.063 g, 0.175 mmol, 30.2 % yield): !H NMR (400 MHz, DMSO-d6) δ ppm 13.46 (1 H, br. s.), 7.96 (1 H, d, J=6.7 Hz), 7.59 (1 H, d, J=6.3 Hz), 7.48 - 7.54 (1 H, m), 7.30 (1 H, t, J=7.8 Hz), 7.01 (1 H, d, J=4.1 Hz), 6.86 (1 H, d, J=2.0 Hz), 6.25 (1 H, d, J=16.0 Hz), 5.77 - 5.95 (1 H, m), 4.28 (1 H, br. s.), 3.28 - 3.42 (2 H, m), 3.04 - 3.18 (1 H, m), 2.52 - 2.70 (4 H, m), 2.14 - 2.37 (1 H, m), 1.48 (3 H, d, J=6.5 Hz), m/z (ESI, +ve) 360.1 (M+H)+.
Example 32: (9S,l lZ,13R)-13,16-dimethyl-3,7,14,17,23- pentaazapentacyclo[l 3.6.2. l~2,5~.0~4,9~.0~18,22~]tetracosa- l(22),2(24),4,l l,15,17,18,20,22-nonaen-6-one (Peak lb, 0.0057 g, 0.016 mmol, 2.73 % yield): !H NMR (400 MHz, DMSO-d6) δ ppm 13.80 (1 H, br.), 7.88 (1 H, m), 7.52 (1 H, m), 7.36 (2 H, m), 7.01 (1 H, d, J=4.5 Hz), 6.80 (1 H, d, J=2.0 Hz), 5.78 (1 H, m), 5.65 (1 H, m), 4.75 (1 H, m), 3.39 (1 H, m), 3.18 (2 H, m), 2.70 (1 H, m), 2.63 (3 H, s), 2.33 (1 H, m), 1.44 (3 H, d, J=7.0 Hz), m/z (ESI, +ve) 360.2 (M+H)+.
Example 32, alternative preparation: (9S,llZ,13R)-13,16-dimethyl-3,7,14,17,23- pentaazapentacyclo[13.6.2.1~2,5~.0~4,9~.0~18,22~]tetracosa- l(22),2(24),4,ll,15,17,18,20,22-nonaen-6-one
Figure imgf000120_0001
Step 1 : (9S,13R)-13,16-dimethyl-3,7,14,17,23- pentaazapentacyclo[l 3.6.2. l~2,5~.0~4,9~.0~18,22~]tetracosa- 1 (22),2(24),4, 15, 17, 18,20,22-octaen-l 1 -yn-6-one
In a glove box, to a solution of (S)-7-(but-2-yn-l-yl)-2-(2-methyl-3-((R)-pent-3-yn-2- ylamino)quinoxalin-5-yl)-6,7-dihydro-lH-pyrrolo[3,2-c]pyridin-4(5H)-one (Intermediate N, 38 mg, 0.092 mmol) in toluene (2.3 mL) in a glass tube was added tri-tert-butoxy(2,2- dimethylpropylidyne)tungsten (Strem Chemicals Inc.; 17 mg, 0.03 mmol). The glass tube was sealed and trasferred out of the glove box. It was heated in an oil bath at 80 °C for 3.5 h. The reaction mixture was concentrated under reduced pressure and the residue was purified on a silica gel column (50-100% EtOAc in DCM followed by 5% MeOH in DCM) to give 18 mg of yellow crystalline solid that was about 85% pure (by LCMS) of m/z (ESI, +ve) 358.1 (M+H)+. The solid was dissolved in 2 mL of DMSO and purified on a reversed phase HPLC [20-95% of 0.1% TFA in CH3CN in 0.1% TFA in water]. The desired fractions were collected, concentrated, and the residue was partitioned between 15 mL of EtOAc and 5 mL of 0.5 N NaOH. The organic layer was separated, washed with 2 mL of brine, dried over Na2S04 and concentrated to give (9S,13R)-13,16-dimethyl- 3,7,14, 17,23-pentaazapentacyclo[l 3.6.2. l~2,5~.0~4,9~.0~18,22~]tetracosa- l(22),2(24),4,15,17,18,20,22-octaen-l l-yn-6-one (8 mg, 24% yield) as a yellow crystalline solid: !H NMR (400 MHz, MeOH-d4) δ ppm 8.01 (1 H, d, J=7.6 Hz), 7.62 (1
H, d, J=8.0 Hz), 7.42 (1 H, t, J=7.9 Hz), 7.01 (1 H, d, J=2.0 Hz), 4.56 (1 H, qd, J=6.8, 3.0 Hz), 3.53 (2 H, m), 3.23 (1 H, m), 2.72 (1 H, m), 2.58 (3 H, s), 2.47 (1 H, m), 1.65 (3 H, d, J=6.8 Hz), m/z (ESI, +ve) 358.1 (M+H)+. Step 2: (9S,1 lZ,13R)-13,16-dimethyl-3,7,14,17,23- pentaazapentacyclo[l 3.6.2.1~2,5~.0~4,9~.0~18,22~]tetracosa- 1 (22),2(24),4, 11 , 15, 17, 18,20,22-nonaen-6-one
A solution of (9S,13R)-13,16-dimethyl-3,7,14,17,23- pentaazapentacyclo[l 3.6.2.1~2,5~.0~4,9~.0~18,22~]tetracosa- l(22),2(24),4,15,17,18,20,22-octaen-l l-yn-6-one (8 mg, 0.022 mmol) in 2 mL of MeOH was treated with quinoline (10 mg, 0.08 mmol) and palladium (Sigma -Aldrich Chemicals, 8 mg of 5% wt on calcium carbonate, poisoned with lead). The mixture was
hydrogenated with a H2 balloon for 4 h. It was diluted with MeOH, filtered through a pad of Celite and the the filtrate was concentrated. Purification on a silica gel column (1-10% MeOH in DCM) gave (9S, l lZ,13R)-13,16-dimethyl-3,7,14,17,23- pentaazapentacyclo[l 3.6.2. l~2,5~.0~4,9~.0~18,22~]tetracosa- l(22),2(24),4,l l,15,17,18,20,22-nonaen-6-one (5.0 mg, 62% yield) as a yellow crystalline solid: !H NMR (400 MHz, DMSO-d6) δ ppm 13.80 (1 H, br.), 7.88 (1 H, m), 7.52 (1 H, m), 7.36 (2 H, m), 7.01 (1 H, d, J=4.5 Hz), 6.80 (1 H, d, J=2.0 Hz), 5.78 (1 H, m), 5.65 (1 H, m), 4.75 (1 H, m), 3.39 (1 H, m), 3.18 (2 H, m), 2.70 (1 H, m), 2.63 (3 H, s), 2.33 (1 H, m), 1.44 (3 H, d, J=7.0 Hz), m/z (ESI, +ve) 360.2 (M+H)+.
Example 32 Alternative Preparation: (9S,llZ,13R)-13,16-dimethyl-3,7,14,17,23- pentaazapentacyclo[13.6.2.1~2,5~.0~4,9~.0~18,22~]tetracosa- -nonaen-6-one
Figure imgf000122_0001
67%
Step 1 : Acetaldehyde ( Sigma- Aldrich, 285 ml, 5074 mmol) and MgS04 ( Sigma- Aldrich, 660 g, 5480 mmol) were added to a solution of (R)-2-methylpropane-2-sulfinamide (AK Scientific, Inc., Union City, CA, 246 g, 2.03 mol) in DCM (1.2 L). The slurry was stirred at RT for 16 h. The reaction mixture was filtered and concentrated to give product contaminated with starting material. A slurry with MgS04 (660 g, 5480 mmol) in a solution of the resulting oil and acetaldehyde (285 ml, 5074 mmol) in DCM (1200 ml) was stirred at RT for 16 h. The reaction mixture was filtered and concentrated to give (R,E)-N-ethylidene-2-methylpropane-2-sulfmamide (248.14 g, 1685 mmol, 83 % yield) as an amber oil. !H NMR (400 MHz, CDC13) δ ppm 1.18 (s, 9 H) 2.22 (d, J=5.09 Hz, 3 H) 8.07 (q, J=5.09 Hz, 1 H). MS (ESI, pos. ion) m/z: 148.2 (M+l).
Step 2: LiHMDS in THF (1.0 M, Sigma-Aldrich, 235 ml, 235 mmol) was added over 30 min via addition funnel to a solution of 3-chloroprop-l-yne (Sigma-Aldrich, 16.84 ml, 235 mmol) in pentane (400 ml) in a three neck 5 L rbf fixed with a mechanical stirrer and temperature probe at -72 °C. The yellow solution was stirred at -72 °C for 15 min; (R,E)- N-ethylidene-2-methylpropane-2-sulfinamide (34.6 g, 235 mmol) in THF (20 mL) was then added to the reaction mixture. The brown solution was stirred at -78 °C for 15 min and was warmed to 17 °C over 3 h when mostly MS (ESI, pos. ion) m/z: 222.1 (M+l) was observed.
Step 3: Tert-butyl 2,4-dioxopiperidine-l-carboxylate (Ark Pharma, Libertyville, IL, 37.6 g, 176 mmol) in THF (400 ml) was added to the reaction mixture; this was cooled to -20 °C (an acetone bath was adjusted to the desired temperature by addition of dry ice), and LiHMDS in THF (1.0 M in THF; Sigma-Aldrich, 564 ml, 564 mmol) was added via addition funnel over 10 min (the internal temperature was kept below -20 °C). The brown solution was stirred at -20 °C for 1 h. The reaction mixture was quenched with water (500 mL) and acidified with 1 N aq. KHSO4 (1.5 L). The organic layer was separated in a separatory funnel and was washed with water (2 x 400 mL); the aqueous layer was extracted with ether (2 x 250 mL); the combined organics were dried over Na2S04 and concentrated to give a red oil. The crude product was directly injected onto a column and was purified via automated flash chromatography (1.5 kg RediSep Rf Gold, silica gel initially eluted with hexanes) with 100% DCM to 30% acetone/DCM to give tert-butyl 5- ((R)-4-((R)- 1 , 1 -dimethylethylsulfmamido)pent-2-yn- 1 -yl)-2,4-dioxopiperidine- 1 - carboxylate (54.09 g, 32.3% yield over two steps) as a yellow foam. !H NMR (400 MHz,
CDCI3) δ ppm 1.19 (s, 9 H) 1.37 - 1.42 (m, 3 H) 1.56 (s, 9 H) 2.49 - 2.65 (m, 2 H) 2.66 - 2.74 (m, 1 H) 3.19 - 3.30 (m, 1 H) 3.37 - 3.49 (m, 1 H) 3.88 - 4.02 (m, 1 H) 4.02 - 4.09 (m, 2 H) 4.43 (dd, J=14.08, 4.89 Hz, 1 H). MS (ESI, pos. ion) m/z: 399.0 (M+l). Step 4: Hydrogen chloride in dioxane (Sigma- Aldrich, 109 ml, 437 mmol) was added to a solution of tert-butyl 5-((R)-4-((R)-l,l-dimethylethylsulfinamido)pent-2-yn-l-yl)-2,4- dioxopiperi dine- 1-carboxy late (57.99 g, 146 mmol) in dioxane (500 ml)/water (31.5 ml, 1746 mmol) at RT for 75 min. The reaction mixture was concentrated to give a red oil. MS (ESI, pos. ion) m/z: 195.1 (M+l).
Step 5: An exotherm was observed after making a solution of the red oil from step 4, acetic acid, ammonia salt (Sigma- Aldrich, 22.43 g, 291 mmol), and ammonia in methanol (Sigma- Aldrich, 728 ml, 1455 mmol) (max. 31 °C); 2-chloroacetaldehyde in water (Sigma- Aldrich, 18.48 ml, 146 mmol) was then added when another exotherm was observed via internal temperature probe (max. 29 °C). The red solution was placed on the rotory evaporator at ambient pressure with the bath at 50 °C for 1 h. The reaction mixture was concentrated to give a red oil. MS (ESI, pos. ion) m/z: 218.1 (M+l).
Step 6: A solution of the resulting red oil, di-tert-butyl dicarbonate (Sigma-Aldrich, 95 g, 437 mmol), and N-ethyl-N-isopropylpropan-2-amine (Sigma-Aldrich, 127 ml, 728 mmol) in DCM (500 ml)/MeOH (250 ml) was stirred at rt for 30 min when MS (ESI, pos. ion) m/z: 318.0 (M+l) was observed. The reaction mixture was washed with saturated aqueous NaHCC (2 x 400 mL) in a separatory funnel; the aqueous layer was extracted with DCM (2 x 200 mL), then the combined organics were dried over Na2S04, and concentrated to give a red oil. The crude product was dissolved in DCM, was directly injected onto a column, and was purified via automated flash chromatography (1.5 kg RediSep Rf Gold, silica gel initially eluted with hexanes) with 100% DCM to 4% methanol in DCM to give tert-butyl ((2R)-5-(4-oxo-4,5,6,7-tetrahydro-lH-pyrrolo[3,2- c]pyridin-7-yl)pent-3-yn-2-yl)carbamate (17.29 g, 54.5 mmol, 37.4 % yield over three steps) as a pale yellow foam. The diastereomers were separated by chiral SFC (Column: Chiralpak AD (20 μιη, 21 mm x 250 mm), F = 120 ml/min, 35% MeOH 20 mM
NH3/carbon dioxide. Sample dissolved in MeOH (50 mg/mL), P = 131 bar, 3.5 ml injection, 262 nm) to give tert-butyl ((R)-5-((S)-4-oxo-4,5,6,7-tetrahydro-lH-pyrrolo[3,2- c]pyridin-7-yl)pent-3-yn-2-yl)carbamate (26.38 g, 83 mmol, 46.5 % yield) as a pale yellow foam. !H NMR (400 MHz, CDCl3-i ) δ ppm 1.37 (d, J=7.04 Hz, 3 H) 1.47 (s, 9 H) 2.34 - 2.45 (m, 1 H) 2.49 - 2.60 (m, 1 H) 3.11 (dq, J=10.69, 5.11 Hz, 1 H) 3.22 - 3.31 (m, 1 H) 3.71 (ddd, J=12.18, 5.43, 1.56 Hz, 1 H) 4.25 - 4.35 (m, 1 H) 4.77 (d, J=6.06 Hz, 1 H) 5.26 (br. s., 1 H) 6.59 (t, J=2.54 Hz, 1 H) 6.78 (t, J=2.54 Hz, 1 H) 10.20 (br. s., 1 H). MS (ESI, pos. ion) m/z: 318.0 (M+l).
Step 7: NanoSelect LF 200 (BASF, Iselin, NJ, 1 g) was stirred in a yellow solution of tert- butyl ((R)-5-((S)-4-oxo-4,5,6,7-tetrahydro-lH-pyrrolo[3,2-c]pyridin-7-yl)pent-3-yn-2- yl)carbamate (10 g, 31 mmol) in 2 M NH3 in MeOH (200 ml) at rt under H2 (15 psig) for 1.5 h. The mixture was filtered to remove the palladium catalyst; activated carbon (16.8 g) was stirred in the yellow solution at rt for 16 h. After filtration and concentration, tert- butyl ((R,Z)-5-((S)-4-oxo-4,5,6,7-tetrahydro-lH-pyrrolo[3,2-c]pyridin-7-yl)pent-3-en-2- yl)carbamate was isolated as a light yellow foam. MS (ESI, pos. ion) m/z: 320.1 (M+l).
Step 8: l,3-dibromo-5,5-dimethylimidazolidine-2,4-dione (Sigma-Aldrich, 3.24 g, 1 1.35 mmol) was added to a solution of tert-butyl ((R,Z)-5-((S)-4-oxo-4,5,6,7-tetrahydro-lH- pyrrolo[3,2-c]pyridin-7-yl)pent-3-en-2-yl)carbamate (7.63 g, 23.89 mmol) in DMF (200 ml) in a 500 mL rbf at -60 °C (dry ice/acetone bath temperature monitored). The yellow solution was stirred at -60 °C for 30 min. The combined reaction mixtures were diluted with DCM (500 mL), added to a separatory funnel, and washed with saturated aqueous NaHCC>3 (2 x 100 mL) and water (5 x 200 mL); the organic layer was separated, dried over Na2S04, and concentrated to give a greenish oil. The crude product in DCM was purified via automated flash chromatography (silica gel) with 100% hexanes to 100%
EtOAc in hexanes to give tert-butyl ((R,Z)-5-((S)-2-bromo-4-oxo-4,5,6,7-tetrahydro-lH- pyrrolo[3,2-c]pyridin-7-yl)pent-3-en-2-yl)carbamate (7.48 g, 18.78 mmol, 52.2 % yield over two steps) as an off-white solid. !H NMR (400 MHz, CDC13) δ ppm 1.19 (d, J=6.65 Hz, 3 H) 1.48 (s, 9 H) 2.16 - 2.26 (m, 1 H) 2.67 - 2.78 (m, 1 H) 2.86 - 2.98 (m, 1 H) 3.37 (dd, J=12.13, 7.24 Hz, 1 H) 3.57 (dd, J=12.13, 5.48 Hz, 1 H) 4.46 - 4.58 (m, 1 H) 4.67 (d, J=6.46 Hz, 1 H) 5.37 (t, J=9.98 Hz, 1 H) 5.55 (td, J=l 1.10, 4.40 Hz, 1 H) 5.62 (br. s., 1 H) 6.49 (d, J=2.35 Hz, 1 H) 10.26 (br. s., 1 H). MS (ESI, pos. ion) m/z: 398.1/400.1 (M+l). Step 9: A solution of tert-butyl ((R,Z)-5-((S)-2-bromo-4-oxo-4,5,6,7-tetrahydro-lH- pyrrolo[3,2-c]pyridin-7-yl)pent-3-en-2-yl)carbamate (12.31 g, 30.9 mmol), 3-fluoro-2- methyl-5-(4,4,5,5-tetramethyl-l ,3,2-dioxaborolan-2-yl)quinoxaline (Intermediate D, Step 1, 17.81 g, 61.8 mmol), and potassium hydrogenphosphate (Sigma-Aldrich, 18.84 g, 108 mmol) in DMF (281 ml)/water (28.1 ml) at 70 °C was sparged with nitrogen for 3 min; PdCl2(Amphos)2 ( Sigma- Aldrich, 1.094 g, 1.545 mmol) was then added, and the solution soon turned red. This was stirred at 70 °C for 30 min. The reaction mixture was diluted with EtOAc (500 mL), added to a separatory funnel, and washed with water (5 x 200 mL); the combined aqueous layers were back extracted with DCM (2 x 200 mL); the combined organic layers were separated, dried over Na2S04, and concentrated; a small amount of product was observed in the aqueous layer. The crude product in DCM was loaded onto the column and was purified via automated flash chromatography (1.5 kg RediSep Rf Gold, silica gel initially eluted with hexanes) with 100% DCM to 5% MeOH in DCM to give tert-butyl ((R,Z)-5-((S)-2-(3-fluoro-2-methylquinoxalin-5-yl)-4-oxo- 4,5,6,7-tetrahydro-lH-pyrrolo[3,2-c]pyridin-7-yl)pent-3-en-2-yl)carbamate (12.07 g, 25.2 mmol, 75 % yield) as a yellow foam. !H NMR (400 MHz, CDC13) δ ppm 1.20 - 1.23 (m, 3 H) 1.24 (s, 9 H) 2.46 - 2.58 (m, 1 H) 2.74 (d, J=7.04 Hz, 1 H) 2.79 (s, 3 H) 3.19 - 3.29 (m, 1 H) 3.40 - 3.47 (m, 1 H) 3.67 (ddd, J=12.08, 5.53, 2.74 Hz, 1 H) 4.46 - 4.63 (m, 2 H) 5.38 (br. s., 1 H) 5.54 - 5.63 (m, 1 H) 5.63 - 5.70 (m, 1 H) 7.22 (d, J=2.15 Hz, 1 H) 7.68 - 7.76 (m, 1 H) 7.85 - 7.91 (m, 1 H) 8.07 (d, J=7.43 Hz, 1 H) 11.41 (br. s., 1 H). 19F NMR (377 MHz, CDC13) δ ppm -72.31 (s, 1 F). MS (ESI, pos. ion) m/z: 480.0 (M+l).
Step 10: A solution of tert-butyl ((R,Z)-5-((S)-2-(3-fluoro-2-methylquinoxalin-5-yl)-4- oxo-4,5,6,7-tetrahydro-lH-pyrrolo[3,2-c]pyridin-7-yl)pent-3-en-2-yl)carbamate (12.07 g, 25.2 mmol) and 2,2,2-trifluoroacetic acid (Sigma- Aldrich, 78 ml, 1007 mmol) in DCM (503 ml) was stirred at rt for 30 min. The dark red solution was concentrated. MS (ESI, pos. ion) m/z: 380.1 (M+l).
Step 11 : A solution of the resulting red oil from Step 10 and N-ethyl-N-isopropylpropan- 2-amine (Sigma- Aldrich, 88 ml, 503 mmol) in DMSO (755 ml) was stirred at 100 °C for
1 h. The reaction mixture was diluted with water (2000 mL), added to a separatory funnel, and extracted with DCM/IPA (3:2) (8 x 200 mL); the combined organic layers were washed with water (4 x 200 mL), separated, dried over Na2S04, and concentrated. The crude product in DCM/MeOH was loaded onto the column and was purified via automated flash chromatography (1.5 kg RediSep Rf Gold, silica gel) with 100%o hexanes to 100% EtOAc in hexanes (removes phosphine ligand) then 100% DCM to 5% MeOH in DCM to give the Z-macrocycle as a yellow slurry (contaminated with DMSO via NMR) with a slightly acrid smell. The yellow slurry was suspended in methanol (100 mL, removes impurities), sonicated for 5 min, filtered, sonicated in absolute ethanol (50 mL, removes residual methanol), and dried in vacuo to give (9S,1 lZ,13R)-13,16-dimethyl- 3,7,14, 17,23-pentaazapenta-cyclo[13.6.2. l~2,5~.0~4,9~.0~18,22~]tetracosa- 1 (22),2(24),4, 11 , 15, 17, 18,20,22-nonaen-6-one (6.09 g, 16.94 mmol, 67.3 % yield over two steps) as a yellow solid. !H NMR (400 MHz, DMSO-i¾) δ ppm 1.42 (d, J=7.04 Hz, 3 H) 2.29 (d, J=13.69 Hz, 1 H) 2.60 (s, 3 H) 2.64 - 2.76 (m, 1 H) 3.14 - 3.25 (m, 2 H)
3.37 (t, J=4.99 Hz, 1 H) 4.71 (ttd, J=13.30, 13.30, 7.04, 7.04, 6.26 Hz, 1 H) 5.60 - 5.68 (m, 1 H) 5.70 - 5.78 (m, 1 H) 6.78 (d, J=1.96 Hz, 1 H) 6.98 (d, J=4.50 Hz, 1 H) 7.30 -
7.38 (m, 2 H) 7.58 (dd, J=8.12, 1.08 Hz, 1 H) 7.88 (dd, J=7.43, 1.17 Hz, 1 H) 13.77 (br. s., 1 H). MS (ESI, pos. ion) m/z: 360.0 (M+l).
Example 33: (9S,llE,13S)-13,16-dimethyl-3,7,14,17,23- pentaazapentacyclo[13.6.2.1~2,5~.0~4,9~.0~18,22~]tetracosa- l(22),2(24),4,ll,15,17,18,20,22-nonaen-6-one
Figure imgf000127_0001
Step 1 : (.S)-7-allyl-2-(3-((S)-but-3-en-2-ylamino)-2-methylquinoxalin-5-yl)-6,7-dihydro- 1 H-pyrrolo [3 ,2-c]pyridin-4(5H)-one
A solution of (.S)-7-allyl-2-(3-fluoro-2-methylquinoxalin-5-yl)-6,7-dihydro-lH- pyrrolo[3,2-c]pyridin-4(5H)-one (Intermediate D; 4.57 g, 13.60 mmol), (5)-but-3-en-2- amine hydrochloride (Intermediate G, 3.07 g, 28.6 mmol), and DIPEA (10.0 ml, 57.5 mmol) in DMSO (28.5 ml) was stirred under argon at 60 °C for 7.5 h. The reaction mixture was then partitioned between EtOAc (300 mL) and sat. aqueous NaHCC>3 (200 mL). The organic layer was separated, and the aqueous layer was extracted with EtOAc (300 mL). The combined organic extracts were sequentially washed with water (2 χ 300 mL) and brine (200 mL), dried over Na2S04, filtered, and concentrated in vacuo to provide (.S)-7-allyl-2-(3-((S)-but-3-en-2-ylamino)-2-methylquinoxalin-5-yl)-6,7-dihydro- lH-pyrrolo[3,2-c]pyridin-4(5H)-one (5.46 g, 14.09 mmol, quantitative yield) as a yellow- orange solid: !H NMR (400 MHz, DMSO-d6) δ ppm 1 1.92 (1 H, br. s.), 7.90 (1 H, dd, J=7.4, 0.8 Hz), 7.56 - 7.61 (1 H, m), 7.33 (1 H, t, J=7.8 Hz), 7.11 (1 H, d, J=7.4 Hz), 7.04 (1 H, d, J=2.0 Hz), 6.94 (1 H, br. s.), 6.10 (1 H, ddd, J=17.3, 10.4, 4.8 Hz), 5.88 (1 H, ddt, J=16.8, 9.8, 7.2, 7.2 Hz), 5.23 (1 H, d, J=17.2 Hz), 5.14 (1 H, s), 5.07 - 5.12 (2 H, m), 4.74 - 4.87 (1 H, m), 3.45 - 3.55 (1 H, m), 3.22 (1 H, dt, .7=12.6, 3.9 Hz), 3.07 (1 H, dq, J=9.6, 4.8 Hz), 2.59 (3 H, s), 2.28 - 2.39 (1 H, m), 1.45 (3 H, d, J=6.8 Hz), 0.95 (1 H, d, J=6.5 Hz), m/z (ESI, +ve) 388.3 (M+H)+.
Step 2: (95,1 l£,13S)-13,16-dimethyl-3,7,14,17,23- pentaazapentacyclo[l 3.6.2. l~2,5~.0~4,9~.0~18,22~]tetracosa- 1 (22),2(24),4, 11,15,17,18,20,22-nonaen-6-one
Grubbs Catalyst - 2nd generation (Aldrich; 2.00 g, 2.356 mmol) was added to a solution of (S)-7-allyl-2-(3-((S)-but-3-en-2-ylamino)-2-methylquinoxalin-5-yl)-6,7-dihydro-lH- pyrrolo[3,2-c]pyridin-4(5H)-one (5.27 g, 13.60 mmol) in DCM (550 mL). The resulting solution was stirred under argon at 40 °C for 5 h. Additional Grubbs Catalyst - 2nd generation (330 mg, 0.389 mmol) was added, and the resulting solution was stirred under argon at 40 °C for 1 h. MeOH (10 mL) and silica gel (30 g) were added, and the resulting mixture was concentrated in vacuo. Chromatographic purification (dry-load, ISCO, 330g, Redi-Sep Gold, 0-10% MeOH/DCM, 30 min, 254 nm) furnished a yellow-green solid (4.42 g). MeOH (30 mL) was added to this solid, and the resulting suspension was sonicated for 30 sec, then vacuum filtered, rinsing the collected material with with MeOH (1 x 10 mL). The collected material was then dried in vacuo to provide (95,117s,135)- 13,16-dimethyl-3,7,14,17,23- pentaazapentacyclo[l 3.6.2. l~2,5~.0~4,9~.0~18,22~]tetracosa- l(22),2(24),4,l l,15,17,18,20,22-nonaen-6-one (3.2 g, 8.90 mmol, 65% yield) as a yellow- green solid: !H NMR (400 MHz, DMSO-d6) δ ppm 13.51 - 13.63 (1 H, m), 7.99 (1 H, d, J=7.4 Hz), 7.54 (1 H, d, J=7.8 Hz), 7.33 (1 H, t, J=7.7 Hz), 7.02 (1 H, d, J=4.3 Hz), 6.89 (1 H, d, J=2.0 Hz), 6.50 (1 H, s), 5.96 - 6.05 (1 H, m), 5.87 - 5.96 (1 H, m), 4.21 - 4.32 (1 H, m), 3.32 - 3.37 (1 H, m), 3.20 - 3.30 (1 H, m), 3.06 - 3.16 (1 H, m), 2.61 (3 H, s), 2.57 (1 H, d, J=14.9 Hz), 2.12 - 2.24 (1 H, m), 1.51 (3 H, d, J=6.8 Hz), m/z (ESI, +ve) 360.2 (M+H)+.
Example 34: (9S,llE)-13,13,16-trimethyl-3,7,14,17,23- pentaazapentacyclo[13.6.2.1~2,5~.0~4,9~.0~18,22~]tetracosa- l(22),2(24),4,ll,15,17,18,20,22-nonaen-6-one
Figure imgf000129_0001
Step 1 : tert-butyl (2-methylbut-3-en-2-yl)carbamate
To a slurry of methyl triphenylphosphonium bromide (Fluka Chemie, Gmbh; 3.53 g, 9.88 mmol) in 50 mL THF under N2 at -78 °C was added KHMDS 0.5 M in toluene (Aldrich; 19.76 ml, 9.88 mmol) dropwise via syringe over ~ 2 min. The reaction became yellow. An ice/water bath was added and the reaction stirred for 30 min. The reaction was re- cooled to -78 °C and tert-butyl 2-formylpropan-2-yl carbamate (BetaPharma Inc., Branford, CT; 1.85 g, 9.88 mmol) was added as a solution in 10 mL THF via syringe. The cooling bath was warmed to RT and the reaction stirred over the weekend. The reaction was partitioned between water and EtOAc. The organic layer was washed with water once, brine once, and the organics were dried over anhydrous Na2S04, filtered, and concentrated in vacuo. The material was treated with DCM and 10 g silica gel, dried in vacuo, and purified by silica gel chromatography (80 g column) using 0 - 20%
EtOAc/hexane. The product-containing fractions were concentrated to afford tert-butyl (2-methylbut-3-en-2-yl)carbamate (0.750 g, 4.05 mmol, 41.0 % yield) as a clear/colorless oil: ¾ NM (400 MHz, CDCl3) δ ppm 5.97 (1 H, dd, J=17.4, 10.6 Hz), 4.98 - 5.17 (2 H, m), 4.57 (1 H, br. s.), 1.38 (6 H, s). Step 2: 2-methylbut-3-en-2-amine hydrochloride
tert-Butyl (2-methylbut-3-en-2-yl)carbamate (0.750 g, 4.05 mmol) was treated with HCI, 4.0 M solution in 1,4-dioxane (Aldrich; 10.12 ml, 40.5 mmol) and the reaction was fitted with a drying tube and stirred at RT for 1 h. The reaction was judged complete by TLC (20% EtOAc/hexanes, visualize with KMnO t). The reaction was treated with 10 mL anhydrous toluene and concentrated in vacuo, then treated with 5 mL anhydrous toluene and concentrated again and dried on hood pump to give 2-methylbut-3-en-2 -amine hydrochloride (0.447 g, 3.68 mmol, 91 % yield) as a white solid: !H NMR (400 MHz, CDCh) δ ppm 8.62 (4 H, br. s.), 6.01 (1 H, dd, J=17.4, 11.0 Hz), 5.43 (1 H, d, J=17.6 Hz), 5.28 (1 H, d, J=10.8 Hz), 1.62 (6 H, br. s.).
Step 3 : (S)-7-allyl-2-(2-methyl-3-((2-methylbut-3-en-2-yl)amino)quinoxalin-5-yl)-6,7- dihydro-lH-pyrrolo[3,2-c]pyridin-4(5H)-one
(S)-7-Allyl-2-(3-fluoro-2-methylquinoxalin-5-yl)-6,7-dihydro-lH-pyrrolo[3,2-c]pyridin- 4(5H)-one (Intermediate D; 0.130 g, 0.386 mmol) and 2-methylbut-3-en-2-amine hydrochloride (0.235 g, 1.932 mmol) were combined in a sealable vessel and 3 mL DMSO and DIPEA (Aldrich; 0.504 ml, 2.90 mmol) were added. The reaction was sealed and heated 12 h at 60 °C, and was then heated approximately 3 h at 100 °C. The reaction was partitioned between saturated aqueous NaHCC and EtOAc. The organic layer was washed with water once, brine once, and the organics were dried over anhydrous Na2S04, filtered, and concentrated in vacuo. The material was treated with DCM and purified by silica gel chromatography (40 g column) using 0 - 70% 90/10 DCM/MeOH in DCM. The product- containing fractions were concentrated to give 0.118 g orange solid. This material was dissolved in DMSO and purified by RPHPLC, Phenomenex Gemini 150x30 mm Cis column, 15-100 % ACN/H2O with 0.1 % TFA; product-containing fractions were treated with saturated aqueous NaHC03 and DCM. The aqueous layer was extracted 3 x DCM and combined organics dried over Na2S04, filtered, and concentrated in vacuo to give (S)- 7-allyl-2-(2-methyl-3-((2-methylbut-3-en-2-yl)amino)quinoxalin-5-yl)-6,7-dihydro-lH- pyrrolo[3,2-c]pyridin-4(5H)-one (0.072 g, 0.179 mmol, 46.4 %> yield) as a yellow glass: !H NMR (400 MHz, DMSO-d6) δ ppm 11.76 (1 H, br. s.), 7.91 (1 H, dd, J=7.6, 1.2 Hz), 7.57 (1 H, dd, J=8.0, 1.2 Hz), 7.34 (1 H, t, J=7.8 Hz), 6.99 (1 H, d, J=2.0 Hz), 6.92 (1 H, d, J=3.7 Hz), 6.37 (1 H, s), 6.20 (1 H, dd, J=17.5, 10.7 Hz), 5.83 - 6.00 (1 H, m), 5.05 - 5.31 (4 H, m), 3.54 (1 H, dd, J=12.4, 5.0 Hz), 3.19 - 3.29 (1 H, m), 2.93 - 3.06 (1 H, m), 2.63 (3 H, s), 2.27 - 2.43 (2 H, m), 1.60 (3 H, s), 1.59 (3 H, s) m/z (ESI, +ve) 402.2 (M+H)+.
Step 4: (9S,1 lE)-13,13,16-trimethyl-3,7,14,17,23- pentaazapentacyclo[l 3.6.2.1~2,5~.0~4,9~.0~18,22~]tetracosa- 1 (22),2(24),4, 11 , 15, 17, 18,20,22-nonaen-6-one Argon was bubbled through a solution of Grubbs catalyst 2nd generation (Aldrich; 0.030 g, 0.036 mmol) and (S)-7-allyl-2-(2-methyl-3-((2-methylbut-3-en-2-yl)amino)quinoxalin- 5-yl)-6,7-dihydro-lH-pyrrolo[3,2-c]pyridin-4(5H)-one (0.072 g, 0.179 mmol) in 9 mL DCM for 2 min. The reaction was sealed and heated to 45 °C for 6 h. Grubbs catalyst 2nd generation (Aldrich; 0.030 g, 0.036 mmol) was added; the reaction was sealed, and heating continued for 1 h. The reaction was placed in the freezer over the weekend, then concentrated in vacuo and treated with DMSO, filtered (0.45 μ filter) to give 3 mL dark brown liquid. This material was purified by RPHPLC, Phenomenex Gemini 150x30 mm Ci8 column, 10-100 % ACN/H20 with 0.1% TFA. The combined product containing fractions were treated with saturated aqueous NaHCC and DCM. The aqueous layer was extracted 3 x DCM and combined organics dried over Na2S04, filtered, and concentrated in vacuo to give (9S,1 lE)-13,13,16-trimethyl-3,7,14,17,23- pentaazapentacyclo[l 3.6.2. l~2,5~.0~4,9~.0~18,22~]tetracosa- l(22),2(24),4,l l,15,17,18,20,22-nonaen-6-one (0.009 g, 0.024 mmol, 13.44 % yield) as a yellow green solid: !H NMR (400 MHz, DMSO-d6) δ ppm 13.50 (1 H, br. s.), 7.98 (1 H, dd, J=7.5, 1.1 Hz), 7.53 (1 H, dd, J=8.0, 1.2 Hz), 7.33 (1 H, t, J=7.8 Hz), 7.01 (1 H, d, J=4.3 Hz), 6.87 (1 H, d, J=2.2 Hz), 6.32 (1 H, s), 6.23 (1 H, d, J=15.8 Hz), 5.78 - 5.95 (1 H, m), 3.00 - 3.35 (2 H, m), 2.54 - 2.73 (4 H, m), 2.12 - 2.41 (2 H, m), 1.56 (3 H, s), 1.51 (3 H, s). m/z (ESI, +ve) 374.1 (M+H)+.
Example 35: (9R,llE,13S)-13,16-dimethyl-3,7,14,17,23- pentaazapentacyclo[13.6.2.1~2,5~.0~4,9~.0~18,22~]tetracosa- l(22),2(24),4,ll,15,17,18,20,22-nonaen-6-one
Example 36: (9R,llZ,13S)-13,16-dimethyl-3,7,14,17,23- pentaazapentacyclo[13.6.2.1~2,5~.0~4,9~.0~18,22~]tetracosa- l(22),2(24),4,ll,15,17,18,20,22-nonaen-6-one
Figure imgf000132_0001
(R)-7-Allyl-2-(3-fluoro-2-methylquinoxalin-5-yl)-6,7-dihydro-lH-pyrrolo[3,2-c 4(5H)-one (Intermediate E; 0.100 g, 0.297 mmol) was treated with (S)-but-3-en-2-amine hydrochloride (Intermediate G; 0.160 g, 1.486 mmol) and DIPEA (Aldrich; 0.388 ml, 2.230 mmol) in 3 mL DMSO. The orange reaction was sealed and heated to 60 °C overnight. The light yellow reaction was analyzed by LCMS and judged complete. The reaction was partitioned between saturated aqueous NaHCC and EtOAc. The organic layer was washed with water once, brine once, and the organics were dried over anhydrous Na2S04, filtered, and concentrated in vacuo, to give 0.113 g yellow solid. This material was treated with Grubbs catalyst 2nd generation (Aldrich; 0.050 g, 0.059 mmol), and 15 mL DCM. Argon was bubbled through the solution for 1 min, the reaction was sealed, and heated to 45 °C. After 1 h, the reaction was judged complete by LCMS and 1 g silica gel was added and the reaction concentrated in vacuo. The material was purified by silica gel chromatography (40 g column) using 0 - 70% 90/10 DCM/MeOH in DCM. The product-containing fractions were concentrated to afford 0.091 g material that was further purified by chiral SFC (ADH (21x250 mm, 5 μ), 35% EtOH + 20 mM NH3 in supercritical C02, Flow = 65 mL/min) to give
Second eluting peak - Example 35 : (9R, 11 E, 13 S)- 13 , 16-dimethyl-3,7, 14, 17,23- pentaazapentacyclo[l 3.6.2. l~2,5~.0~4,9~.0~18,22~]tetracosa- l(22),2(24),4,l l,15,17,18,20,22-nonaen-6-one (0.071 g, 0.198 mmol, 66.4 % yield): !H NMR (400 MHz, DMSO-d6) δ ppm 13.46 (1 H, br. s.), 7.96 (1 H, d, J=6.7 Hz), 7.59 (1 H, d, J=6.3 Hz), 7.48 - 7.54 (1 H, m), 7.30 (1 H, t, J=7.8 Hz), 7.01 (1 H, d, J=4.1 Hz), 6.86 (1 H, d, J=2.0 Hz), 6.25 (1 H, d, J=16.0 Hz), 5.77 - 5.95 (1 H, m), 4.28 (1 H, br. s.), 3.28 - 3.42 (2 H, m), 3.04 - 3.18 (1 H, m), 2.52 - 2.70 (4 H, m), 2.14 - 2.37 (1 H, m), 1.48 (3 H, d, J=6.5 Hz), m/z (ESI, +ve) 360.1 (M+H)+.
First eluting peak - Example 36: (9R, 11 Z, 13 S)- 13, 16-dimethyl-3,7, 14, 17,23- pentaazapentacyclo[l 3.6.2. l~2,5~.0~4,9~.0~18,22~]tetracosa-
1(22),2(24),4,11,15,17,18,20,22-nonaen-6-one (0.013 g, 0.036 mmol, 12.17 % yield): !H NMR (400 MHz, DMSO-d6) δ ppm 13.80 (1 H, br. s), 7.88 (1 H, m), 7.52 (1 H, m), 7.36 (2 H, m), 7.01 (1 H, d, J=4.5 Hz), 6.80 (1 H, d, J=2.0 Hz), 5.78 (1 H, m), 5.65 (1 H, m), 4.75 (1 H, m), 3.39 (1 H, m), 3.18 (2 H, m), 2.70 (1 H, m), 2.63 (3 H, s), 2.33 (1 H, m), 1.44 (3 H, d, J=7.0 Hz), m/z (ESI, +ve) 360.1 (M+H)+.
Example 37: (9S)-16-methyl-3,7,14,17,23- pentaazapentacyclo[13.6.2.1~2,5~.0~4,9~.0~18,22~]tetracosa- l(22),2(24),4,15,17,18,20,22-octaen-6-one
Figure imgf000133_0001
(9S, 11 E)- 16-Methyl-3 ,7,14,17,23- pentaazapentacyclo[l 3.6.2. l~2,5~.0~4,9~.0~18,22~]tetracosa- l(21),2(24),4,l l,15,17,19,22-octaen-6-one (Example 21 ; 0.021 g, 0.061 mmol) and palladium hydroxide 10 wt. % (dry basis) on activated carbon, wet (Strem; 0.065 g) were combined in a sealable vial and flushed with N2. 2 mL MeOH was added and the atmosphere replaced with H2 from a balloon. The reaction was stirred rapidly at RT. After 1 h, the reaction was flushed with N2, filtered through a 0.45 μ syringe filter, rinsing 1 x MeOH, and concentrated down to a 2 mL volume. NaOH 1.0 N aqueous (VWR; 0.304 ml, 0.304 mmol) was added, the reaction was placed in a 60 °C bath, and H202 30% aqueous (Aldrich; 0.062 ml, 0.608 mmol) was added dropwise via syringe. After 30 min, a yellow precipitate had formed. The reaction was cooled and filtered, rinsing 2 x 1 mL MeOH, and the solid dried in vacuo to give (9S)-16-methyl-3,7,14,17,23- pentaazapentacyclo[l 3.6.2. l~2,5~.0~4,9~.0~18,22~]tetracosa- l(22),2(24),4,15,17,18,20,22-octaen-6-one (0.005 g, 0.014 mmol, 23.67 % yield) a yellow solid: !H NMR (400 MHz, DMSO-d6) δ ppm 7.95 (1 H, d, J=7.4 Hz), 7.83 (1 H, t, J=4.7 Hz), 7.56 (1 H, d, J=8.0 Hz), 7.33 (1 H, t, J=7.8 Hz), 6.99 (1 H, d, J=4.1 Hz), 6.90 (1 H, s), 3.47 - 3.73 (1 H, m), 2.91 - 3.41 (4 H, m), 2.52 (3H, s), 2.02 - 2.18 (1 H, m), 1.55 - 1.99 (5 H, m). m/z (ESI, +ve) 348.0 (M+H)+.
Example 38: (9R)-16-methyl-3,7,14,17,23- pentaazapentacyclo[13.6.2.1~2,5~.0~4,9~.0~18,22~]tetr
l(22),2(24),4,15,17,18,20,22-octaen-6-one
Figure imgf000134_0001
(9R, 11 E)- 16-Methyl-3 ,7,14,17,23- pentaazapentacyclo[l 3.6.2. l~2,5~.0~4,9~.0~18,22~]tetracosa- l(21),2(24),4,l l,15,17,19,22-octaen-6-one (Example 23; 0.038 g, 0.110 mmol) and palladium hydroxide 10 wt. % (dry basis) on activated carbon, wet (Strem; 0.1 17 g) were combined in a sealable vial and flushed with N2. 3 mL MeOH was added and the atmosphere replaced with ¾ from a balloon. The reaction was stirred rapidly over the weekend. The reaction was filtered through a 0.45 μ syringe filter rinsing with DCM, and the filtrate was concentrated. The solid was taken up in MeOH, sonicated, and filtered, rinsing 2 x MeOH to give 12 mg yellow solid. The MeOH sonication procedure was repeated, and the solid was collected by filtration and rinsed with MeOH, and dried in vacuo to (9R)-16-methyl-3,7,14,17,23-pentaaza- pentacyclo[13.6.2.1~2,5~.0~4,9~.0~18,22~]tetracosa-l(22),2(24),4,15, 17,18,20,22- octaen-6-one (0.009 g, 0.026 mmol, 23.55 % yield) as a yellow solid: : !H NMR (400 MHz, DMSO-de) δ ppm 7.95 (1 H, d, J=7.4 Hz), 7.83 (1 H, t, J=4.7 Hz), 7.56 (1 H, d, J=8.0 Hz), 7.33 (1 H, t, J=7.8 Hz), 6.99 (1 H, d, J=4.1 Hz), 6.90 (1 H, s), 3.47 - 3.73 (1 H, m), 2.91 - 3.41 (4 H, m), 2.52 (3H, s), 2.02 - 2.18 (1 H, m), 1.55 - 1.99 (5 H, m). m/z (ESI, +ve) 348.0 (M+H)+.
Example 39: (9S,13R)-13,16-dimethyl-3,7,14,17,23- pentaazapentacyclo[13.6.2.1~2,5~.0~4,9~.0~18,22~]tetracosa- l(22),2(24),4,15,17,18,20,22-octaen-6-one
Figure imgf000135_0001
(9S, 11 E, 13R 13, 16-Dimethyl-3,7, 14, 17,23 -pentaaza- pentacyclo[13.6.2.1~2,5~.0~4,9~.0~18,22~]tetracosa-l(22),2(24),4,l 1 ,15,17,18,20,22- nonaen-6-one (Example 31 ; 0.019 g, 0.053 mmol) and palladium hydroxide 10 wt. % (dry basis) on activated carbon, wet (Strem; 0.056 g) were combined in a vial and flushed with N2. 2 mL MeOH was added, and the atmosphere replaced with H2 from a balloon. After 3 h, the reaction was flushed with N2, and filtered through a 0.45 μ syringe filter, rinsing with MeOH, then concentrated down to a 2 mL volume. NaOH 1 N volumetric solution (VWR; 0.264 ml, 0.264 mmol) was added and the reaction was heated to 60 °C. H202
30% in water (Aldrich; 0.027 ml, 0.264 mmol) was added dropwise via syringe. After 30 min, additional H202 30% in water (Aldrich; 0.027 ml, 0.264 mmol) was added. After 30 min additional H202 30% in water (Aldrich; 0.027 ml, 0.264 mmol) was added and the reaction stirred 10 min. The reaction was concentrated, and the residue taken up in 1.5 mL DMSO and several drops TFA were added to neutralize the NaOH. The solution was filtered through a 0.45 μ filter and was purified by RPHPLC, Phenomenex Gemini 150x30 mm Ci8 column, 10-70 % ACN/H20 with 0.1 % TFA; product-containing fraction was treated with saturated aqueous NaHC03 and DCM. The aqueous layer was extracted 3 x DCM and combined organics dried over Na2SO t, filtered, and concentrated in vacuo to give (9S,13R)-13,16-dimethyl-3,7,14,17,23- pentaazapentacyclo[l 3.6.2. l~2,5~.0~4,9~.0~18,22~]tetracosa- l(22),2(24),4,15,17,18,20,22-octaen-6-one (0.004 g, 0.011 mmol, 20.94 % yield) as a yellow solid: !H NMR (400 MHz, DMSO-d6) δ ppm 7.87 (1 H, dd, J=7.4, 1.0 Hz), 7.57 (1 H, dd, J=8.1 , 1.1 Hz), 7.33 (1 H, t, J=7.8 Hz), 7.08 (1 H, d, J=5.3 Hz), 6.94 (1 H, d, J=4.1 Hz), 6.81 (1 H, d, J=1.8 Hz), 3.92 (1 H, br. s.), 3.23 - 3.29 (1 H, m), 3.08 - 3.19 (1 H, m), 2.91 - 3.05 (1 H, m), 2.56 (3 H, s), 2.36 - 2.47 (1 H, m), 1.55 - 1.97 (4 H, m), 1.41 -1.37 (4 H, m) m/z (ESI, +ve) 362.1 (M+H)+.
Example 40: (9S,13S)-13,16-dimethyl-3,7,14,17,23- pentaazapentacyclo[13.6.2.1~2,5~.0~4,9~.0~18,22~]tetracosa- l(22),2(24),4,15,17,18,20,22-octaen-6-one
Figure imgf000136_0001
A suspension of (9S, 1 IE, 13 S)-l 3, 16-dimethyl-3,7, 14, 17,23- pentaazapentacyclo[l 3.6.2. l~2,5~.0~4,9~.0~18,22~]tetracosa- l(22),2(24),4,l l, 15,17,18,20,22-nonaen-6-one (Example 33; 950 mg, 2.64 mmol) and palladium, 10 wt% (dry basis), on activated carbon (wet, degussa type elOl ne/w) (Aldrich; 2813 mg, 1.322 mmol) in THF (55 mL) was stirred under a H2 atmosphere (1 atm) at 55 °C for 17 h. The reaction flask was then flushed with argon, palladium, 10 wt% (dry basis), on activated carbon (wet, degussa type elOl ne/w) (1.97 g, 0.924 mmol) was added, and the resulting mixture was stirred under argon at 55 °C for 15 min.
Additional Pd/C, 10 wt% (dry basis, wet, degussa type el 01 ne/w) (563 mg, 0.264 mmol) was added, and the resulting mixture was stirred under argon at 55 °C for 15 min. The reaction mixture was subsequently filtered through Celite, and the Celite pad was washed with (1 : 1) MeOH/DCM (100 mL). The combined filtrates were concentrated onto silica gel and chromatographically purified (silica gel, 0-10% MeOH/DCM) to provide (9S,13S)-13,16-dimethyl-3,7,14,17,23- pentaazapentacyclo[l 3.6.2. l~2,5~.0~4,9~.0~18,22~]tetracosa- l(22),2(24),4,15,17,18,20,22-octaen-6-one (430.0 mg, 1.190 mmol, 45% yield) as a yellow solid: !H NMR (400 MHz, DMSO-d6) δ ppm 13.47 (1 H, br. s.), 8.01 (1 H, d,
J=7.4 Hz), 7.57 (1 H, d, J=8.0 Hz), 7.34 (1 H, t, J=7.8 Hz), 7.08 (1 H, d, J=4.5 Hz), 7.03 (1 H, d, J=4.1 Hz), 6.96 (1 H, d, J=1.4 Hz), 3.55 - 3.66 (1 H, m), 3.19 - 3.27 (1 H, m), 3.1 1 - 3.19 (1 H, m), 2.96 - 3.06 (1 H, m), 2.57 (3 H, s), 2.34 - 2.44 (1 H, m), 2.19 - 2.32 (1 H, m), 1.94 - 2.05 (1 H, m), 1.58 - 1.73 (1 H, m), 1.42 - 1.52 (1 H, m), 1.39 (3 H, d, J=6.5 Hz), 1.21 - 1.31 (1 H, m). m/z (ESI, +ve) 362.1 (M+H)+.
Example 41: (9R,llE)-12,16-dimethyl-14-thia-3,7,17,23- tetraazapentacyclo[13.6.2.1~2,5~.0~4,9~.0~18,22~]tetracosa- l(22),2(24),4,ll,15,17,18,20,22-nonaen-6-one
Figure imgf000137_0001
Step 1 : (R)-7-allyl-2-(2-methyl-3-((2-methylallyl)thio)quinoxalin-5-yl)-6,7-dihydro-lH pyrrolo [3,2 -c]pyridin-4(5 H)-one
A slurry of NaH as 60% dispersion in mineral oil (Sigma Aldrich , 137 mg, 3.43 mmol) in DMF (3.4 mL) was set stirring under N2 before adding 2-methylprop-2-ene-l -thiol (Oakwood Products, West Columbia, SC, 302 mg, 3.43 mmol). After 15 min, a solution of (R)-4-allyl-6-(3-fluoro-2-methylquinoxalin-5-yl)-2,3,4,5-tetrahydro-lH- cyclopenta[c]pyridin-l -one (Intermediate E, 1 15 mg, 0.343 mmol) in 3 mL DMF was added, and the reaction was stirred for 3 h. The mixture was diluted with water and extracted with DCM, drying over Na2S04, filtering, and concentrating under reduced pressure. The material was triturated with Et20 to give a bright yellow solid. The material was sonicated with DCM and filtered using gravity to give a yellow solution that, when concentrated, gave (R)-7-allyl-2-(2-methyl-3-((2-methylallyl)thio)quinoxalin-5-yl)- 6,7-dihydro-lH-pyrrolo[3,2-c]pyridin-4(5H)-one (98 mg, 71 %) as a yellow solid: !Η NMR (CDCl3) δ: 7.91 - 7.99 (m, 1H), 7.81 - 7.87 (m, 1H), 7.65 - 7.75 (m, 1H), 6.93 - 7.04 (m, 2H), 5.80 - 5.97 (m, 1H), 5.06 - 5.16 (m, 2H), 4.97 - 5.02 (m, 1H), 4.84 - 4.91 (m, 1H), 4.04 - 4.24 (m, 2H), 3.44 - 3.52 (m, 1H), 3.17 - 3.25 (m, 1H), 3.02 - 3.12 (m, 1H), 2.67 - 2.71 (m, 1H), 2.65 (s, 3H), 2.26 - 2.37 (m, 2H), 1.83 (s, 3H). m/z (ESI, +ve) 405.2 (M+H)+.
Step 2: (9R,1 1 E)- 12,16-dimethyl-14-thia-3, 7, 17,23 - tetraazapentacyclo[13.6.2.1~2,5~.0~4,9~.0~18,22~]tetracosa- 1 (22),2(24),4, 11 , 15, 17, 18,20,22-nonaen-6-one
A solution of Grubbs catalyst 2nd generation (Sigma Aldrich, 50.4 mg, 0.059 mmol), (R)- 7-allyl-2-(2-methyl-3-((2-methylallyl)thio)quinoxalin-5-yl)-6,7-dihydro-lH-pyrrolo[3,2- c]pyridin-4(5H)-one (120 mg, 0.297 mmol), and DCM (5.9 mL) was set stirring at 65°C for 1.5 h. The reaction was concentrated under reduced pressure before being solubilized in DMSO and purified by reverse-phase preparative HPLC. The product fractions were concentrated in a Genevac EZ-2 evaporator at 55 °C over night. The dried fractions were solubilized in 10: 1 MeOFLDCM (5 mL) and percolated through a Silicycle Si-carbonate cartridge (pre-washed withn MeOH). The resulting yellow solution was transferred to a round bottom flask and concentrated under reduced pressure to a yellow residue that was dried further under high vacuum to afford (9R,1 1 E)- 12,16-dimethyl-14-thia-3, 7, 17,23 - tetraazapentacyclo[13.6.2.1~2,5~.0~4,9~.0~18,22~]tetracosa- l(22),2(24),4,l l,15,17,18,20,22-nonaen-6-one (0.015 g, 13% yield) as a yellow solid: !H NMR (CDCl3) δ: 12.37 (br. s, 1H), 8.02 - 8.10 (m, 1H), 7.74 - 7.79 (m, 1H), 7.56 - 7.65 (m, 1H), 7.18 - 7.26 (m, 1H), 7.10 - 7.17 (m, 1H), 5.78 - 5.87 (m, 1H), 4.16 - 4.28 (m, 1H), 3.74 - 3.85 (m, 1H), 3.52 - 3.64 (m, 1H), 3.37 - 3.48 (m, 2H), 2.76 (s, 3H), 2.40 - 2.66 (m, 2H), 1.92 (s, 3H). m/z (ESI, +ve) 377.1 (M+H)+.
Example 42: (HE)-ll,16-dimethyl-3,7,14,17,23- pentaazapentacyclo[13.6.2.1~2,5~.0~4,9~.0~18,22~]tetracosa- l(22),2(24),4,ll,15,17,18,20,22-nonaen-6-one
Figure imgf000138_0001
Step 1 : tert-butyl 5-(2-methylallyl)-2,4-dioxopiperidine-l-carboxylate
To a solution of 3-bromo-2-methylpropene (Aldrich; 3.78 ml, 37.5 mmol) and 1 -boc- piperidine-2,4-dione (Ark Pharma, LibertyviUe, IL; 2.00 g, 9.38 mmol) in 80 mL THF at - 17 °C (ice/salt) was added LiHMDS, 1.0 M solution in THF (Aldrich; 23.45 ml, 23.45 mmol) slowly via syringe over 10 min. The reaction became thick with a precipitate that dissolved upon complete addition of LiHMDS. After 45 min, water and DCM were added, and the aqueous layer was acidified with 5 N HC1. The aqueous layer was extracted with DCM 2 times, and the combined organics were dried over anhydrous Na2S04, filtered, and concentrated in vacuo. The material was treated with DCM and purified by silica gel chromatography (80 g column) using 0 - 60% EtOAc/hexane. The product- containing fractions were concentrated to afford tert-butyl 5-(2-methylallyl)-2,4- dioxopiperidine-l -carboxylate (2.0 g, 7.48 mmol, 80 % yield) as a light yellow oil: !H NMR (400 MHz, DMSO-d6) δ ppm 11.23 (1 H, br. s.), 4.92 (1 H, s), 4.85 (1 H, br. s.), 4.68 (1 H, s), 3.73 (1 H, dd, J=13.1, 3.1 Hz), 3.50 (1 H, dd, J=12.9, 3.9 Hz), 2.53 - 2.59 (1 H, m), 2.25 - 2.34 (1 H, m), 2.01 - 2.11 (1 H, m), 1.71 (3 H, s), 1.42 (9 H, s).
Step 2: 2-(3-fluoro-2-methylquinoxalin-5-yl)-7-(2-methylallyl)-6,7-dihydro-lH- pyrrolo [3,2 -c]pyridin-4(5 H)-one
tert-Butyl 5-(2-methylallyl)-2,4-dioxopiperidine-l-carboxylate (1.95 g, 7.29 mmol) in 36 mL DCM at 0 °C was treated with TFA (Aldrich; 2.71 ml, 36.5 mmol). The ice bath was removed and the reaction stirred for 30 min. The reaction was concentrated in vacuo to give an oil. The material was treated with 10 mL DCM and an excess of solid NaHCC and stirred rapidly for 10 min. The reaction was filtered, rinsing with DCM, and concentrated in vacuo to give 1.4 g of an oil. This material was treated with 2-bromo-l - (3-fluoro-2-methylquinoxalin-5-yl)ethanone (1.45 g, 5.12 mmol), and NH4OAc (Fisher, 2.369 g, 30.7 mmol), and 50 mL EtOH, the reaction was sealed, and placed in a 50 °C bath. The reaction became orange and homogeneous. After 4 h, the reaction was heterogeneous. The reaction was concentrated to 1/4 volume and partitioned between saturated aqueous NaHC03 and DCM. The aqueous layer was extracted with DCM 3 times, and the combined organics were dried over anhydrous Na2S04, filtered, and concentrated in vacuo. The residue was adsorbed onto 10 g silica gel from DCM and dried, and purified by silica gel chromatography (80 g column) using 0 - 70% 90/10 DCM/MeOH in DCM. Product- containing fractions were concentrated to give 0.88 g of a red semisolid. This material was treated with 5 mL Et20, sonicated 20 min, then filtered, rinsing 2 x 1 mL Et20, the solid was collected and dried in vacuo to give 2-(3-fluoro-2- methylquinoxalin-5-yl)-7-(2-methylallyl)-6,7-dihydro-lH-pyrrolo[3,2-c]pyridin-4(5H)- one (0.474 g, 1.353 mmol, 26.4 % yield) as an orange solid: !H NMR (400 MHz, DMSO- ί/6) δ ρριη 11.61 (1 H, br. s.), 8.09 (1 H, d, J=7.4 Hz), 7.87 - 7.99 (1 H, m), 7.72 - 7.87 (1 H, m), 7.20 (1 H, d, J=2.2 Hz), 7.02 (1 H, br. s.), 4.93 (1 H, s), 4.84 (1 H, s), 3.38 - 3.52
(1 H, m), 3.12 - 3.28 (2 H, m), 2.71 (3 H, s), 2.45 (1 H, dd, J=13.8, 5.0 Hz), 2.28 (1 H, dd, J=13.8, 9.3 Hz), 1.82 (3 H, s)). m/z (ESI, +ve) 351.0 (M+H)+. Step 3: 2-(3-(allylamino)-2-methylquinoxalin-5-yl)-7-(2-methylallyl)-6,7-dihydro-lH pyrrolo [3,2 -c]pyridin-4(5 H)-one
2-(3-Fluoro-2-methylquinoxalin-5-yl)-7-(2-methylallyl)-6,7-dihydro-lH-pyrrolo[3,2- c]pyridin-4(5H)-one (0.214 g, 0.611 mmol) was treated with allylamine (Aldrich; 4.12 ml, 55.0 mmol) and a stir bar and sealed and stirred rapidly for 4 h. The reaction was partitioned between saturated aqueous aqueous NaHC03 and DCM. The aqueous layer was extracted with DCM 2x, and the combined organics were dried over anhydrous Na2S04, filtered, and concentrated in vacuo. The solid was suspended in MeOH and filtered, rinsing 1 x MeOH, and the solid dried in vacuo to give 2-(3-(allylamino)-2- methylquinoxalin-5-yl)-7-(2-methylallyl)-6,7-dihydro-lH-pyrrolo[3,2-c]pyridin-4(5H)- one (0.170 g, 0.439 mmol, 71.8 % yield) as a yellow solid: !H NMR (400 MHz, DMSO- ί/6) δ ρριη 12.03 (1 H, s), 7.91 (1 H, d, J=7.6 Hz), 7.51 - 7.63 (2 H, m), 7.33 (1 H, t, J=7.8 Hz), 7.03 (1 H, d, J=2.0 Hz), 6.92 (1 H, br. s.), 6.01 - 6.21 (1 H, m), 5.29 (1 H, dd, J=17.2, 1.4 Hz), 5.17 (1 H, d, J=10.4 Hz), 4.88 (1 H, s), 4.78 (1 H, s), 4.18 (2 H, br. s.), 3.38 - 3.51 (1 H, m), 3.07 - 3.23 (2 H, m), 2.57 (3 H, s), 2.20 - 2.43 (2 H, m), 1.78 (3 H, s). m/z (ESI, +ve) 388.1 (M+H)+.
Step 4: (11E)-1 l,16-dimethyl-3,7,14,17,23- pentaazapentacyclo[13.6.2.1~2,5~.0~4,9~.0~18,22~]tetracosa- 1 (22),2(24),4, 11 , 15, 17, 18,20,22-nonaen-6-one
Argon was bubbled through a slurry of Grubbs catalyst 2nd generation (Aldrich; 0.055 g, 0.065 mmol) and 2-(3-(allylamino)-2-methylquinoxalin-5-yl)-7-(2-methylallyl)-6,7- dihydro-lH-pyrrolo[3,2-c]pyridin-4(5H)-one (0.125 g, 0.323 mmol) in 16 mL DCM for 2 min. The reaction was sealed with a cap and parafilm and placed in a 45 °C bath and heated overnight. The reaction was charged with fresh catalyst (Grubbs catalyst 2nd generation (Aldrich; 0.055 g, 0.065 mmol)) and fitted with a water-cooled reflux condeser and heated to reflux. After 8 h, the reaction was cooled, treated with 2 mL MeOH and adsorbed onto 2 g silica gel and dried. The material was purified by silica gel chromatography (40 g column) using 0 - 60% 90/10 DCM/MeOH in DCM. The product- containing fractions were concentrated to afford 0.009 g of impure material. Additonal material was obtained from the following reaction: Argon was bubbled through a slurry of Grubbs catalyst 2nd generation (0.074 g, 0.088 mmol) and 2-(3-(allylamino)-2- methylquinoxalin-5-yl)-7-(2-methylallyl)-6,7-dihydro-lH-pyrrolo[3,2-c]pyridin-4(5H)- one (Aldrich; 0.170 g, 0.439 mmol) in 22 mL DCE for 60 sec. The reation was sealed and heated to 80 °C. After 2 h, additional Grubbs catalyst 2nd generation (Aldrich; 0.150 g, 0.176 mmol) was added, and heating was continued for 1 h. The bath was turned off and cooled slowly to RT. The reaction was stirred overnight. The reaction was adsorbed onto
1.5 g silica gel and dried in vacuo. Purified by silica gel chromatography (40 g redisep gold column) using 0 - 100% 90/10 DCM/MeOH in DCM. The product-containing fractions were concentrated to afford 59 mg impure product-containing material. This was combined with the 0.009 g impure material isolated in the prior reaction, and the combined materials were dissolved in DMSO and purified by RPHPLC, Phenomenex Gemini 150x30 mm Ci8 column, 15-85 % ACN/H20 with 0.1 % TFA; product- containing fractions were treated with saturated aqueous NaHCC and DCM. The aqueous layer was extracted 3 x DCM and combined organics dried over Na2S04, filtered, and concentrated in vacuo to give (HE)-l l ,16-dimethyl-3,7,14,17,23- pentaazapentacyclo[l 3.6.2. l~2,5~.0~4,9~.0~18,22~]tetracosa- l(22),2(24),4,l l,15,17,18,20,22-nonaen-6-one (0.010 g, 0.028 mmol, 3% yield) as a yellow solid: !H NMR (400 MHz, DMSO-d6) δ ppm 13.47 (1 H, br. s.), 7.97 (1 H, d, J=7.4 Hz), 7.63 (1 H, d, J=5.3 Hz), 7.53 (1 H, d, J=7.8 Hz), 7.31 (1 H, d, J=15.5 Hz),
7.06 (1 H, d, J=4.1 Hz), 6.88 (1 H, s), 5.70 (1 H, d, J=6.7 Hz), 3.95 - 4.21 (2 H, m), 3.26 - 3.47 (2 H, m), 3.01 - 3.15 (1 H, m), 2.55 (3 H, s), 2.53-2.46 (1 H, m), 2.23 - 2.32 (1 H, m), 1.82 (3 H, s). m/z (ESI, +ve) 360.2 (M+H)+.
Example 43: (9S,llE)-12,16-dimethyl-14-thia-3,7,17,23- tetraazapentacyclo[13.6.2.1~2,5~.0~4,9~.0~18,22~]tetracosa- l(22),2(24),4,ll,15,17,18,20,22-nonaen-6-one
Figure imgf000141_0001
Step 1 : (S)-7-allyl-2-(2-methyl-3-((2-methylallyl)thio)quinoxalin-5-yl)-6,7-dihydro-lH- pyrrolo [3,2 -c]pyridin-4(5 H)-one
A slurry of NaH as a 60% dispersion in mineral oil (Sigma Aldrich, 1 19 mg, 2.97 mmol) was set stirring in DMF (2.9 mL) at RT under N2. Methallyl mercaptan was added (Oakwood Scientific, 262 μΐ,, 2.97 mmol), and the mixture was set stirring for 30 min. Solid (S)-7-allyl-2-(3-fluoro-2-methylquinoxalin-5-yl)-6,7-dihydro-lH-pyrrolo[3,2- c]pyridin-4(5H)-one (Intermediate D, 100 mg, 0.297 mmol) was added, and the resulting reaction mixture was stirred at RT for 1 h. The reaction mixture was quenched with water and extracted with DCM. The combined organics were dried over Na2S04, filtered, and concentrated under reduced pressure. The residue was triturated with Et20 and sonicated for 5 mintues to give a solid that was isolated by filtration and used in the next step without further purification, m/z (ESI, +ve) 405.2 (M+H)+.
Step 2: (9S,1 lE)-12,16-dimethyl-14-thia-3,7,17,23- tetraazapentacyclo[13.6.2.1~2,5~.0~4,9~.0~18,22~]tetracosa- 1 (22),2(24),4, 11 , 15, 17, 18,20,22-nonaen-6-one
A solution of (S)-7-allyl-2-(2-methyl-3-((2-methylallyl)thio)quinoxalin-5-yl)-6,7- dihydro-lH-pyrrolo[3,2-c]pyridin-4(5H)-one (40 mg, 0.099 mmol), Grubbs 2nd generation catalyst (Sigma Aldrich; 16.79 mg, 0.020 mmol), and DCM (2 mL) was set stirring at 65 °C for 1.5 h. The reaction was concentrated under reduced pressure, diltued with DMSO, and purified by reverse-phase preparative HPLC (Phenomenex Gemini column, 10 μ, Ci8, 100 A, 150 x 30 mm, 0.1 % TFA in ACN/water, gradient 5% to 95%). The product fractions were concentrated in a Genevac EZ-2 evaporator at 55°C. The dried fractions were solubilized in 10: 1 MeOH:DCM (5 mL) and filtered through a Silicycle Si- carbonate cartridge (pre-washed withn MeOH). The filtrate was concentrated under reduced pressure to give (9S,l lE)-12,16-dimethyl-14-thia-3,7,17,23- tetraazapentacyclo[13.6.2.1~2,5~.0~4,9~.0~18,22~]tetracosa- l(22),2(24),4,l l,15,17,18,20,22-nonaen-6-one (23 mg, 22%, 2 steps): ¾ NMR (DMSO- de) δ: 12.08 - 12.22 (m, 1H), 8.19 - 8.27 (m, 1H), 7.70 - 7.78 (m, 1H), 7.57 - 7.69 (m, 1H), 7.05 - 7.18 (m, 2H), 5.86 - 5.98 (m, 1H), 4.23 - 4.36 (m, 1H), 3.94 - 4.10 (m, 1H), 3.33 - 3.45 (m, 2H), 3.17 - 3.28 (m, 2H), 2.69 (s, 3H), 2.36 - 2.47 (m, 1H), 1.83 (s, 3H): m/z (ESI, +ve) 377.1 (M+H)+.
Example 44: (HE)-12,16-dimethyl-4,7,14,17,23- pentaazapentacyclo[13.6 .l~2,5~.0~4,9~.0~18,22~]tetracosa- l(21),2,5(24),ll,15,17,19,22-octaen-6-one
Figure imgf000143_0001
Figure imgf000143_0002
Step 1 : 7-bromo-4-(2-hydroxyethyl)-3,4-dihydropyrrolo[l,2-a]pyrazin-l(2H)-one Ethyl 2-(7-bromo-l-oxo-l,2,3,4-tetrahydropyrrolo[l,2-a]pyrazin-4-yl)acetate
(Intermediate J; 1.23 g, 4.08 mmol) was treated with THF (30 mL), cooled to 0 °C and treated with lithium aluminum hydride, l.OM solution in THF (4.08 mL, 4.08 mmol) and stirred at 0 °C for 30 min. The reaction mixture was quenched by slow dropwise addition of an aqueous solution of sodium potassium tartrate and stirred at RT for 30 min. The reaction mixture was extracted with EtOAc (3 x 25 mL), washed with brine and dried over MgS04, filtered and concentrated affording crude 7-bromo-4-(2-hydroxyethyl)-3,4- dihydropyrrolo[l,2-a]pyrazin-l(2H)-one (987 mg, 3.81 mmol, 93 % yield) as a white crystalline solid: !H NMR (400 MHz, MeOH-d4) δ ppm 7.10 (1 H, s), 6.83 (1 H, s), 4.47 (1 H, tt, .7=7.1, 3.7 Hz), 3.85 (1 H, dd, J=13.2, 4.2 Hz), 3.68 (1 H, dt, J=l 1.2, 5.6 Hz), 3.46 - 3.56 (2 H, m), 1.91 - 2.07 (2 H, m). m/z (ESI, +ve ion) 259.0/261.0 (M+H)+.
Step 2 : 2-(7-bromo- 1 -oxo- 1 ,2,3,4-tetrahydropyrrolo [ 1 ,2-a]pyrazin-4-yl)acetaldehyde 7-Bromo-4-(2-hydroxyethyl)-3,4-dihydropyrrolo[l,2-a]pyrazin-l(2H)-one (908 mg, 3.50 mmol) and Dess-Martin periodinane (1.86 g, 4.38 mmol) were treated with DCM (20 mL) and found to be insoluble so it was treated with THF (10 mL) and stirred at RT overnight (16 h). LC-MS showed little advancement of the reaction. Additional Dess-Martin periodinane (1.00 g, 2.35 mmol) was added and the solution heated to reflux at 70 °C for 2.5 h. The reaction mixture was cooled to RT, treated with water and EtOAc (100 mL) and washed with sodium thiosulfate (2 x 25 mL) and NaHCC (2 x 25 mL) and brine. The aqueous layer was back extracted with DCM (3 x 50 mL) and the combined organic extracts were dried over MgS04, filtered and concentrated affording crude 2-(7-bromo-l - oxo-l,2,3,4-tetrahydropyrrolo[l ,2-a]pyrazin-4-yl)acetaldehyde (788 mg, 3.07 mmol, 87 % yield) as a yellow foam which was used in the subsequent step without further purification: !H NMR (400 MHz, DMSO-d6) δ ppm 9.68 (1 H, s), 7.78 (1 H, br. s.), 7.16 (1 H, d, J=1.6 Hz), 6.67 (1 H, d, J=1.6 Hz), 4.74 (1 H, t, J=4.7 Hz), 3.65 (1 H, ddd, J=13.1 , 4.1 , 2.0 Hz), 3.26 - 3.31 (1 H, m), 3.01 (2 H, d, J=6.5 Hz), m/z (ESI, +ve ion) 257.0/259.0 (M+H)+.
Step 3 : 4-allyl-7-bromo-3,4-dihydropyrrolo[l,2-a]pyrazin-l (2H)-one
Methyl triphenylphosphonium bromide (1.54 g, 4.31 mmol) in THF (20 mL) was cooled to 0 °C and treated with LiHMDS, 1.0M solution in THF (4.31 mL, 4.31 mmol) slowly dropwise resulting in a bright yellow solution. The solution was stirred for 30 min then 2-(7-bromo-l -oxo-1 , 2,3,4-tetrahydropyrrolo[l,2-a]pyrazin-4-yl)acetaldehyde (554 mg, 2.155 mmol) in THF (5 mL) was added and the solution stirred at 0 °C for 1 h. The reaction mixture was quenched with water and extracted with EtOAc (2 x 50 mL), washed with brine and dried over MgS04, filtered and concentrated. Purification on the ISCO Combiflash Rf (40 g Thomson SingleStep column, using a gradient of 0-100% EtOAc in hexanes) afforded 4-allyl-7-bromo-3,4-dihydropyrrolo[l ,2-a]pyrazin-l(2H)-one (97.2 mg, 0.381 mmol, 17.7 % yield) as a light yellow film: !H NMR (400 MHz, CDCl3) δ ppm 7.13 (1 H, br. s.), 6.91 (1 H, d, J=1.6 Hz), 6.83 (1 H, d, J=1.8 Hz), 5.74 (1 H, ddt, J=17.1 , 10.0, 7.1, 7.1 Hz), 5.10 - 5.23 (2 H, m), 4.09 - 4.20 (1 H, m), 3.76 (1 H, ddd,
J=12.9, 4.2, 2.0 Hz), 3.42 - 3.52 (1 H, m), 2.59 - 2.69 (1 H, m), 2.48 - 2.59 (1 H, m). m/z (ESI, +ve ion) 255.0/257.0 (M+H)+.
Step 4: 4-allyl-7-(2-methyl-3-((2-methylallyl)amino)quinoxalin-5-yl)-3,4- dihydropyrrolo [ 1 ,2-a]pyrazin- 1 (2H)-one
A 5-mL glass microwave tube was charged with 4-allyl-7-bromo-3,4-dihydropyrrolo[l,2- a]pyrazin-l (2H)-one (97 mg, 0.380 mmol), dicyclohexyl(2',4',6'-triisopropyl-[l, - biphenyl]-2-yl)phosphine (Strem Chemicals, 10.9 mg, 0.023 mmol), Pd2(dba)3 (Strem Chemicals, 10.5 mg, 0.011 mmol), potassium phosphate (Riedel de Haen, Buchs, Switzerland, 242 mg, 1.14 mmol) and 3-methyl-N-(2-methylallyl)-8-(4,4,5,5-tetramethyl- l,3,2-dioxaborolan-2-yl)quinoxalin-2-amine (Intermediate I, 155 mg, 0.456 mmol). The solids were purged with argon and treated with 1 ,4-dioxane (2.5 mL) and water (0.83 mL) and heated in a microwave reactor at 130 °C for 20 min. The reaction mixture was treated with water, extracted with EtOAc, washed with brine and concentrated. Purification on the ISCO Combiflash Rf (25 g Thomson SingleStep column, using a gradient of 20-100% EtOAc in hexanes) afforded 4-allyl-7-(2-methyl-3-((2- methylallyl)amino)quinoxalin-5-yl)-3,4-dihydropyrrolo[l ,2-a]pyrazin-l(2H)-one (57.9 mg, 0.149 mmol, 79 % yield) as a light yellow amorphous solid: !H NMR (400 MHz, MeOH-d4) δ ppm 8.07 (1 H, d, J=1.4 Hz), 7.81 (1 H, d, J=7.4 Hz), 7.63 (1 H, d, J=8.0 Hz), 7.47 - 7.51 (1 H, m), 7.32 - 7.39 (1 H, m), 5.83 - 5.96 (1 H, m), 5.21 (1 H, d, J=7.8 Hz), 5.17 (1 H, s), 4.96 (1 H, s), 4.90 (2 H, br. s.), 4.34 - 4.42 (1 H, m), 4.15 - 4.28 (2 H, m), 3.83 (1 H, dd, J=13.1, 4.3 Hz), 3.55 (1 H, dd, J=13.0, 3.8 Hz), 2.63 - 2.76 (2 H, m), 2.61 (3 H, s). m/z (ESI, +ve ion) 388.1 (M+H)+.
Step 5: (1 1E)-12,16-dimethyl-4,7, 14,17,23- pentaazapentacyclo[l 3.6.2.1~2,5~.0~4,9~.0~18,22~]tetracosa- 1 (21 ),2,5 (24), 1 1 , 15, 17, 19,22-octaen-6-one
4-Allyl-7-(2-methyl-3 -((2-methylallyl)amino)quinoxalin-5 -yl)-3 ,4-dihydropyrrolo [ 1 ,2- a]pyrazin-l (2H)-one (53 mg, 0.137 mmol) and Grubb's second generation RCM catalyst (Aldrich, 23.2 mg, 0.027 mmol) were purged with Ar and treated with DCM (6.8 mL) and heated to 45 °C for 2.5 h. The reaction mixture was concentrated and purified on the Gilson (Silicycle Silichrome XT Ci8 column; 30 x 150 mm, 5 μηι; 20-95%
0.1 %TFA/CH3CN in 0.1 %TFA/water) affording (1 lE)-12,16-dimethyl-4,7,14,17,23- pentaazapentacyclo[l 3.6.2.1~2,5~.0~4,9~.0~18,22~]tetracosa-
1(21),2,5(24),1 l,15,17,19,22-octaen-6-one as its mono-2,2,2-trifluoroacetate salt (4.4 mg, 9.3 μηιοΐ, 6.8 %> yield) as an orange amorphous solid after drying in a Genevac Series II evaporator overnight. !H NMR (400 MHz, DMSO-d6) δ ppm 7.47 - 7.64 (4 H, m), 7.27 - 7.35 (1 H, m), 7.08 - 7.22 (1 H, m), 6.75 (1 H, s), 5.41 (1 H, br. s.), 4.40 (1 H, br. s.), 3.70 (1 H, d, J=1 1.0 Hz), 3.49 (1 H, dd, J=l l . l , 6.9 Hz), 2.68 (1 H, br. s.), 2.52 (3 H, br. s.), 2.40 - 2.49 (1 H, m), 1.37 (3 H, br. s.). m/z (ESI, +ve ion) 360.2 (M+H)+.
Example 45: (9S, 13R)-ll,12-dihydroxy-13,16-dimethyl-3,7,14,17,23- pentaazapentacyclo[13.6.2.1~2,5~.0~4,9~.0~18,22~]tetracosa- l(22),2(24),4,15,17,18,20,22-octaen-6-one
Figure imgf000145_0001
A cloudy mixture of (9S,l lE,13R)-13,16-dimethyl-3,7,14,17,23- pentaazapentacyclo[l 3.6.2. l~2,5~.0~4,9~.0~18,22~]tetracosa- l(22),2(24),4,l l,15,17,18,20,22-nonaen-6-one (Example 31 ; 0.050 g, 0.139 mmol) and NMO (Aldrich; 0.049 g, 0.417 mmol) and methanesulfonamide (TCI America; 0.013 g, 0.139 mmol) in 2 mL acetone, 0.5 mL THF, and 0.4 mL water was treated with osmium tetroxide 4 wt% in water (Aldrich; 0.088 ml, 0.014 mmol). The reaction was sealed and stirred rapidly at RT. After 12 h, observe 15% conversion. Additional osmium tetroxide 4 wt% in water (Aldrich, 0.088 ml, 0.014 mmol) was added and the reaction stirred over the weekend. The reaction was concentrated to ~l/4 original volume; this material was dissolved in DMSO, filtered, and purified by RPHPLC, Phenomenex Gemini 150x30 mm Ci8 column, 5 -50 % ACN/H20 with 0.1% TFA; product-containing fractions were treated with saturated aqueous NaHCC and DCM. The aqueous layer was extracted 3 x DCM and combined organics dried over Na2S04, filtered, and concentrated in vacuo to give a single Cn,Ci2 isomer (9S, 13R)-1 l,12-dihydroxy-13,16-dimethyl-3,7,14,17,23- pentaazapentacyclo[l 3.6.2. l~2,5~.0~4,9~.0~18,22~]tetracosa- l(22),2(24),4,15,17,18,20,22-octaen-6-one (0.006 g, 0.015 mmol, 10.96 % yield) as an orange solid: !H NMR (400 MHz, DMSO-d6) δ ppm 7.84 (1 H, d, J=7.4 Hz), 7.54 (1 H, d, J=7.8 Hz), 7.31 (1 H, t, J=7.8 Hz), 6.80 - 6.95 (2 H, m), 6.75 (1 H, s), 5.08 (1 H, d, J=5.1 Hz), 4.96 (1 H, br. s.), 4.44 (1 H, br. s.), 3.97 - 4.09 (1 H, m), 3.09 - 3.41 (3 H, m), 2.57 (3 H, s), 2.03 - 2.16 (1 H, m), 1.54 (1 H, dd, J=14.3, 5.5 Hz), 1.38 (3 H, d, J=6.8 Hz), m/z (ESI, +ve) 394.1 (M+H)+.
Example 46: 17-methyl-3,7,15,18,24- pentaazahexacyclo[14.6.2.2~ll,14~.l~2,5~.0~4,9~.0~19,23~]heptacosa- l(23),2(27),4,ll,13,16,18,19,21,23,25-undecaen-6-one
Figure imgf000147_0001
Step 1 : tert-butyl 5-(4-chlorobenzyl)-2,4-dioxopiperidine-l-carboxylate
4-Chlorobenzyl chloride (Fluka Chemie GmbH; 6.04 g, 37.5 mmol) and 1 -boc-piperidine- 2,4-dione (Ark Pharma, Libertyville, IL; 2.00 g, 9.38 mmol) were combined in 75 mL THF under N2 and were cooled in an ice/salt bath. LiHMDS, 1.0 M solution in THF (Aldrich, 23.45 ml, 23.45 mmol) was added slowly dropwise via syringe. After addition of about 5-10 mL, a thick solid formed, which disappeared as additional LiHMDS was added. The reaction was stirred for 15 min. The reaction was stirred for an additional 15 min, then quenched with water, DCM was added, and the aqueous phase was acidified with 5 N HC1. The aqueous layer was extracted 3 x DCM. The combined organic layers were dried over Na2S04, filtered, and concentrated in vacuo. The material was treated with DCM and purified by silica gel chromatography (160 g column) using 0 - 100% EtOAc/DCM. The product-containing fractions were concentrated to afford tert-butyl 5- (4-chlorobenzyl)-2,4-dioxopiperidine-l-carboxylate (2.30 g, 6.81 mmol, 72.6 % yield) as a white foam: !H NMR (400 MHz, DMSO-d6) δ ppm 1 1.31 (1 H, br. s.), 7.37 (2 H, d, J=8.4 Hz), 7.21 (2 H, d, J=8.2 Hz), 4.95 (1 H, s), 3.52 - 3.64 (1 H, m), 3.40 - 3.51 (1 H, m), 2.98 (1 H, d, J=10.4 Hz), 2.53 - 2.72 (2 H, m), 1.42 (9 H, br. s.). Step 2: 7-(4-chlorobenzyl)-2-(3-fluoro-2-methylquinoxalin-5-yl)-6,7-dihydro-lH- pyrrolo [3,2 -c]pyridin-4(5 H)-one
TFA (2.53 ml, 34.0 mmol) was added to a stirring solution of tert-butyl 5-(4- chlorobenzyl)-2,4-dioxopiperidine-l -carboxylate (2.30 g, 6.81 mmol) in 20 mL DCM. Gas evolution observed. After 30 min, the reaction was concentrated in vacuo and the resulting off-white solid was treated with NH4OAc (Fisher Scientific, 2.178 g, 28.3 mmol), 2-bromo-l -(3-fluoro-2-methylquinoxalin-5-yl)ethanone (1.00 g, 3.53 mmol), and 35 mL EtOH under N2. The reaction was sealed and heated to 50 °C for 6 h. The reaction was partitioned between saturated aqueous NaHC03 and DCM. The aqueous layer was extracted with DCM 3 times, and the combined organics were dried over anhydrous Na2S04, filtered, and concentrated in vacuo. The material was treated with DCM and adsorbed onto 10 g silica gel, dried, and purified by silica gel chromatography (80 g column) using 0 - 100% 90/10 DCM/MeOH in DCM. The product-containing fractions were concentrated to afford 7-(4-chlorobenzyl)-2-(3-fluoro-2-methylquinoxalin-5-yl)-6,7- dihydro-lH-pyrrolo[3,2-c]pyridin-4(5H)-one (0.630 g, 1.497 mmol, 42.4 % yield) as a orange foam: !H NMR (400 MHz, DMSO-d6) δ ppm 11.59 (1 H, br. s.), 8.07 (1 H, d, J=7.4 Hz), 7.88 - 7.97 (1 H, m), 7.77 - 7.87 (1 H, m), 7.37 - 7.43 (2 H, m), 7.30 (2 H, d, J=8.2 Hz), 7.21 (1 H, d, J=2.0 Hz), 6.97 (1 H, br. s.), 3.31 - 3.39 (1 H, m), 3.24 - 3.29 (1 H, m), 3.05 - 3.15 (2 H, m), 2.79 (1 H, dd, J=13.4, 10.1 Hz), 2.72 (3 H, s). m/z (ESI, +ve) 421.1 (M+H)+. Step 3 : 2-(3-amino-2-methylquinoxalin-5-yl)-7-(4-chlorobenzyl)-6,7-dihydro-lH- pyrrolo [3,2 -c]pyridin-4(5 H)-one
A slurry of 7-(4-chlorobenzyl)-2-(3-fluoro-2-methylquinoxalin-5-yl)-6,7-dihydro-lH- pyrrolo[3,2-c]pyridin-4(5H)-one (0.270 g, 0.642 mmol) in NH3, 2 M solution in 2- propanol (Aldrich, 6.42 ml, 12.83 mmol) was sealed and heated to 70 °C overnight. The reaction was adsorbed onto 2 g silica gel from DCM and dried in vacuo. Purified by silica gel chromatography (40 g) using 0 - 100% 90/10 DCM/MeOH in DCM. The product- containing fractions were concentrated to afford 2-(3-amino-2-methylquinoxalin- 5-yl)-7-(4-chlorobenzyl)-6,7-dihydro-lH-pyrrolo[3,2-c]pyridin-4(5H)-one (0.103 g, 0.246 mmol, 38.4 % yield) as a yellow solid: !H NMR (400 MHz, DMSO-d6) δ ppm 12.34 (1 H, s), 7.91 (1 H, d, J=7.6 Hz), 7.56 (1 H, d, J=7.4 Hz), 7.21 - 7.45 (5 H, m), 7.09 (2 H, br. s.), 7.00 (1 H, d, J=1.8 Hz), 6.90 (1 H, br. s.), 3.31 - 3.39 (2 H, m), 3.17 (1 H, dd, J=13.4, 4.4 Hz), 3.09 (1 H, dd, J=8.3, 3.6 Hz), 2.77 (1 H, dd, J=13.2, 10.3 Hz), 2.53 (3 H, s). m/z (ESI, +ve) 418.1 (M+H)+. Step 4: 17-methyl-3,7,15,18,24- pentaazahexacyclo[ 14.6.2.2-1 l,14~.l~2,5~.0~4,9~.0~19,23~]heptacosa- l(23),2(27),4,l l,13,16,18,19,21,23,25-undecaen-6-one
Argon was bubbled through a slurry of potassium carbonate (0.11 1 g, 0.804 mmol) (finely ground in a mortar and pestle), Brettphos precatalyst (Strem; 0.048 g, 0.060 mmol), Brettphos (Strem; 0.032 g, 0.060 mmol), and 2-(3-amino-2-methylquinoxalin-5- yl)-7-(4-chlorobenzyl)-6,7-dihydro-lH-pyrrolo[3,2-c]pyridin-4(5H)-one (0.084 g, 0.201 mmol) in 12 mL t-butanol for 1 min. The reaction was sealed and heated to 1 10 °C overnight. The reaction was partitioned between water and DCM and the aqueous layer was extracted 4 x DCM. The combined organics were dried over anhydrous Na2S04, filtered, and concentrated in vacuo. This material was dissolved in DMSO, filtered, and purified by RPHPLC, Phenomenex Gemini 150x30 mm Ci8 column, 10-80 % ACN/H20 with 0.1 % TFA; product- containing fractions were concentrated in vacuo to give 0.015 g of a red film. The material was further purified by SFC (Column: Chiralcel OD-H (Sepax) (250 x 21 mm, 5 μ); Mobile Phase: 60:40 (A:B); A: Liquid C02, B: EtOH
(0.2% DEA); Flow Rate: 70 mL/min; Oven Temp: 40 °C; Inlet Pressure: 100 bar). The product containing fractions were combined to give 17-methyl-3,7,15,18,24-pentaaza- hexacyclo[14.6.2.2~l l,14~.l~2,5~.0~4,9~.0~19,23~]heptacosa- l(23),2(27),4,l l,13,16,18,19,21,23,25-undecaen-6-one (0.0024 g, 0.006 mmol, 3.1% yield) as a yellow solid: !H NMR (400 MHz, DMSO-d6) δ ppm 9.34 (1 H, s), 8.95 (1 H, s), 7.84 (1 H, d, J=7.2 Hz), 7.72 (1 H, d, J=8.4 Hz), 7.57 (1 H, d, J=8.0 Hz), 7.24 - 7.40 (3 H, m), 7.10 (1 H, br. s.), 7.04 (1 H, d, J=6.3 Hz), 6.79 (1 H, s), 3.53 - 3.64 (1 H, m), 3.34 - 3.47 (3 H, m), 2.59 - 2.72 (4 H, m). m/z (ESI, +ve) 382.1 (M+H)+. Example 47: (9R,llE)-14,16-dimethyl-3,7,14,17,23- pentaazapentacyclo[13.6.2.1~2,5~.0~4,9~.0~18,22~]tetracosa- l(22),2(24),4,ll,15,17,18,20,22-nonaen-6-one
Example 48: (9R,llZ)-14,16-dimethyl-3,7,14,17,23- pentaazapentacyclo[13.6.2.1~2,5~.0~4,9~.0~18,22~]tetracosa- l(22),2(24),4,ll,15,17,18,20,22-nonaen-6-one
Figure imgf000149_0001
Step 1 : (R)-7-allyl-2-(3-(allyl(methyl)amino)-2-methylquinoxalin-5-yl)-6,7-dihydro-lH- pyrrolo [3,2 -c]pyridin-4(5 H)-one
A solution of N-methylallylamine (Sigma Aldrich, 21 μΐ,, 0.297 mmol), (R)-7-allyl-2-(3- fluoro-2-methylquinoxalin-5 -yl)-6,7-dihydro- 1 H-pyrrolo [3 ,2-c]pyridin-4(5H)-one (Intermediate E, 100 mg, 0.297 mmol), and DMSO (3.0 mL) was sealed and heated to 100 °C for 1.5 h. The reaction was cooled to RT and diluted with water and saturated aqueous NaCl. The crude mixture was extracted with DCM (3x15 mL). The combined organics were dried over Na2S04, filtered, and concentrated under reduced pressure to a bright yellow solid that was used without purification: m/z (ESI, +ve) 388.3 (M+H)+.
Step 2: (9R,1 lE)-14,16-dimethyl-3,7,14,17,23- pentaazapentacyclo[l 3.6.2. l~2,5~.0~4,9~.0~18,22~]tetracosa-
1 (22),2(24),4, 11 , 15, 17, 18,20,22-nonaen-6-one, (9R, 11 Z)- 14, 16-dimethyl-3 ,7, 14,17,23- pentaazapentacyclo[l 3.6.2. l~2,5~.0~4,9~.0~18,22~]tetracosa- 1 (22),2(24),4, 11 , 15, 17, 18,20,22-nonaen-6-one
A solution of (R)-7-allyl-2-(3-(allyl(methyl)amino)-2-methylquinoxalin-5-yl)-6,7- dihydro-lH-pyrrolo[3,2-c]pyridin-4(5H)-one (85 mg, 0.219 mmol) in DCM (Sigma Aldrich, 4.4 mL) was set stirring before adding Grubbs catalyst 2nd generation (Sigma Aldrich, 186 mg, 0.219 mmol) and heating to 65 °C for 2 h. The reaction was cooled and concentated onto silica gel and purified by silica gel chromatography (eluent: 0 to 6% MeOH/DCM), giving a single peak. The material was further purified by preparative SFC (solubilized in 1 : 1 MeOH at 4 mg/mL, 292 nm, Phenomenex, Lux-1, repack- S/N=1204 ODH Column, 5 urn at 21x150 mm length, 60% C02 with IPA/40 mM NH3, P = 186 bar at 1 mL/min) to give (9R,l lE)-14,16-dimethyl-3,7,14,17,23- pentaazapentacyclo[l 3.6.2. l~2,5~.0~4,9~.0~18,22~]tetracosa- l(22),2(24),4,l l,15,17,18,20,22-nonaen-6-one as the first eluting peak (2 mg, 3%>, 2 steps) and (9R,l lZ)-14,16-dimethyl-3,7,14,17,23- pentaazapentacyclo[l 3.6.2. l~2,5~.0~4,9~.0~18,22~]tetracosa- l(22),2(24),4,l l,15,17,18,20,22-nonaen-6-one (5 mg, 8%>, 2 steps) as the second eluting peak.
Analytical data for (9R,1 lE)-14,16-dimethyl-3,7,14,17,23- pentaazapentacyclo[l 3.6.2.1~2,5~.0~4,9~.0~18,22~]tetracosa-
1(22),2(24),4,1 l,15,17,18,20,22-nonaen-6-one: !H NMR (400 MHz, DMSO-i/6) δ ppm 13.24 - 13.45 (1 H, m) 7.98 - 8.08 (1 H, m) 7.71 - 7.82 (1 H, m) 7.50 - 7.61 (1 H, m) 7.11 - 7.19 (1 H, m) 6.39 - 6.41 (1 H, m) 5.86 - 6.12 (1 H, m) 4.37 - 4.51 (1 H, m) 4.05 - 4.17 (1 H, m) 3.56 - 3.63 (2 H, m) 3.41 - 3.55 (2 H, m) 3.25 (3 H, s) 2.89 (3 H, s) 2.68 - 2.76 (1 H, s) 2.31 - 2.45 (1 H, m). m/z (ESI, +ve) 360.2 (M+H)+.
Analytical data for (9R,1 lZ)-14,16-dimethyl-3,7,14,17,23- pentaazapentacyclo[l 3.6.2. l~2,5~.0~4,9~.0~18,22~]tetracosa-
1(22),2(24),4,1 l,15,17,18,20,22-nonaen-6-one: ¾ NM (400 MHz, DMSO-i¾) δ ppm 13.15 - 13.28 (1 H, m) 7.88 - 7.94 (1 H, m) 7.70 - 7.84 (1 H, m) 7.48 - 7.56 (1 H, m) 6.99
- 7.03 (1 H, m) 5.84 - 5.96 (2H, m) 4.86 - 4.95 (1H, m) 3.71 - 3.82 (1H, m) 3.50 - 3.65 (3H, m) 3.35 - 3.49 (4 H, m) 2.86 - 2.93 (3H, m) 2.69 - 2.84 (1 H, m) 2.24 - 2.36 (1 H, m): m/z (ESI, +ve) 360.2 (M+H)+.
Example 49: 16-methyl-4,7,12,17,23- pentaazapentacyclo[13.6.2.1~2,5~.0~4,9~.0~18,22~]tetr
-heptaene-6,ll-dione
Figure imgf000151_0001
Step 1 : tert-butyl (2-(8-bromo-3-methylquinoxalin-2-yl)ethyl)carbamate
A mixture of PdCi2(PPh3)2 (Aldrich, 15.9 mg, 0.019 mmol), cesium carbonate (Aldrich, 380 mg, 1.165 mmol), potassium tert-butyl N- [2 -(trifluoroboranuidyl)ethyl] carbamate (Frontier Scientific, Newark, DE, 102 mg, 0.408 mmol) and 5-bromo-3-chloro-2- methylquinoxaline (100 mg, 0.388 mmol) in toluene (1.2 mL), dioxane (0.6 mL) and water (0.4 mL) was heated in an oil bath at 85 °C for 18 h (reference, see: Molander, G. A. et al. Org. Lett. 2007, 9, 203-206). The resulting mixture of products was purified on a ISCO Companion (12 g Redisep column, using a gradient 10-35% EtOAc in hexanes) affording tert-butyl (2-(8-bromo-3-methylquinoxalin-2-yl)ethyl)carbamate (25 mg, 0.068 mmol, 17.58 % yield) as a brown solid, m/z (ESI, +ve ion) 366.0/368.0 (M+H)+.
Step 2: ethyl 2-(7-(3-(2-((tert-butoxycarbonyl)amino)ethyl)-2-methylquinoxalin-5-yl)-l- oxo- 1 ,2,3,4-tetrahydropyrrolo [ 1 ,2-a]pyrazin-4-yl)acetate
A mixture of tert-butyl (2-(8-bromo-3-methylquinoxalin-2-yl)ethyl)carbamate (88 mg, 0.240 mmol), bis(pinacolato)diboron (Aldrich, 122 mg, 0.481 mmol), KOAc (Aldrich, 94 mg, 0.961 mmol) and PdCl2(PPh3)2 (Aldrich, 9.8 mg, 0.012 mmol) in DMF (1.5 mL) was heated at 105 °C for 2 h. The reaction mixture was diluted with 50 mL of EtOAc, washed with water (2 x 15 mL). The organic layer was dried over MgS04 and concentrated to give the crude product as a gooey black solid. The crude material was treated with ethyl 2-(7-bromo-l-oxo-l,2,3,4-tetrahydropyrrolo[l,2-a]pyrazin-4-yl)acetate (Intermediate J, 87 mg, 0.290 mmol), dicyclohexyl(2',4',6'-triisopropyl-[l,l'-biphenyl]-2-yl)phosphine (Strem Chemicals, 6.9 mg, 0.014 mmol), Pd2(dba)3 (Strem Chemicals, 6.6 mg, 7.25 μηιοΐ), potassium phosphate (Riedel de Haen, Buchs, Switzerland, 154 mg, 0.725 mmol) in a 20-mL glass microwave tube, purged with argon and treated with dioxane (2.50 mL) and water (0.83 mL) and heated in a microwave reactor at 130 °C for 25 min. The reaction mixture was treated with water, extracted with EtOAc, washed with brine and concentrated. Purification of the crude residue on the ISCO Combiflash Rf (25 g Thomson SingleStep column, using a gradient of 20-100% EtOAc in hexanes) afforded ethyl 2-(7-(3-(2-((tert-butoxycarbonyl)amino)ethyl)-2-methylquinoxalin-5-yl)-l-oxo- l,2,3,4-tetrahydropyrrolo[l,2-a]pyrazin-4-yl)acetate (40 mg, 0.079 mmol, 32.6 % yield) as a white amorphous solid: !H NMR (400 MHz, CDCh) δ ppm 7.97 (1 H, br. s.), 7.86 (2
H, d, J=7.8 Hz), 7.65 - 7.71 (1 H, m), 7.48 - 7.53 (1 H, m), 5.51 (1 H, br. s.), 5.23 (1 H, s), 4.84 (1 H, br. s.), 4.10 - 4.25 (2 H, m), 3.98 - 4.05 (1 H, m), 3.81 (2 H, br. s.), 3.60 (1 H, d, J=12.9 Hz), 3.23 (2 H, t, J=6.3 Hz), 2.97 (2 H, d, J=6.8 Hz), 2.76 (3 H, s), 1.35 (9 H, s), 1.21 - 1.28 (3 H, m). m/z (ESI, +ve ion) 508.1 (M+H)+.
Step 3 : 2-(7-(3 -(2-aminoethyl)-2-methylquinoxalin-5 -yl)-l -oxo- 1 ,2,3 ,4- tetrahydropyrrole [ 1 ,2-a]pyrazin-4-yl)acetic acid hydrochloride
Ethyl 2-(7-(3-(2-((tert-butoxycarbonyl)amino)ethyl)-2-methylquinoxalin-5-yl)-l-oxo-
I, 2,3,4-tetrahydropyrrolo[l,2-a]pyrazin-4-yl)acetate (26.7 mg, 0.053 mmol) was treated with THF (0.5 mL) and EtOH (0.5 mL) then with IN NaOH (0.4 mL, 0.40 mmol) and stirred at RT for 45 min. The reaction mixture was concentrated in vacuo (rotary evaporater) and then treated with 4M HC1 in dioxane (0.25 mL, 1.00 mmol) and stirred at RT for 30 min at which point LC-MS indicated clean conversion to the desired amino acid as its hydrochloride salt. The reaction mixture was dried under high vacuum overnight and the resulting red solid and was used directly in the macrolactamization step without further purification assuming quantitative yield, m/z (ESI, +ve ion) 380.1 (M+H)+.
Step 4: 16-methyl-4,7, 12, 17,23 - pentaazapentacyclo[13.6.2.1~2,5~.0~4,9~.0~18,22~]tetracosa-l (21),2,5(24),15, 17,19,22- heptaene-6, 1 1 -dione
2-(7-(3 -(2-Aminoethyl)-2-methylquinoxalin-5 -yl)- 1 -oxo- 1 ,2,3 ,4-tetrahydropyrrolo [ 1 ,2- a]pyrazin-4-yl)acetic acid hydrochloride (20 mg, 0.048 mmol) was treated with THF (4.0 mL), DMF (1.0 mL) and the resulting suspension was stirred at RT. It was then treated with several drops of DIPEA and the suspension turned light yellow. (Benzotriazol-1 - yloxy)tripyrrolidinophosphonium hexafluorophosphate (59 mg, 0.113 mmol) was added in one portion and stirred at RT for 5 h. The reaction mixture was treated with water and extracted with DCM (4 x 15 mL). The crude residue was dissolved in DMSO and purified on the Gilson (Silicycle Silichrome XT Ci8 column; 30 x 150 mm, 5 μιη; 5-95%
0.1 %TFA/ACN in 0.1 %TF A/water) affording 16-methyl-4,7, 12, 17,23- pentaazapentacyclo[l 3.6.2. l~2,5~.0~4,9~.0~18,22~]tetracosa-l (21),2,5(24),15, 17,19,22- heptaene-6, 11 -dione 2,2,2-trifluoroacetate (8.9 mg, 9.36 μιηοΐ, 19.46 % yield) as an orange amorphous solid after drying in a Genevac Series II evaporator overnight: !H NMR (400 MHz, DMSO-d6) δ ppm 8.52 (1 H, br. s.), 8.19 (1 H, s), 7.87 (1 H, d, J=6.8 Hz), 7.79 (1 H, d, J=7.6 Hz), 7.72 (1 H, t, J=7.7 Hz), 7.62 (1 H, br. s.), 7.00 (1 H, s), 4.63 (1 H, d, J=4.3 Hz), 3.92 - 4.02 (2 H, m), 3.46 - 3.57 (5 H, m), 3.30 (2 H, d, J=5.5 Hz),
2.93 (1 H, dd, J=14.5, 4.1 Hz), 2.70 (3 H, s), 2.61 (1 H, dd, J=14.3, 5.5 Hz), m/z (ESI, +ve ion) 362.0 (M+H)+. Example 50: (9S,llE,13R)-13-methyl-6-oxo-3,7,14,17,23- pentaazapentacyclo[13.6.2.1~2,5~.0~4,9~.0~18,22~]tetracosa- l(22),2(24),4,ll,15,17,18,20,22-nonaene-16-carbaldehyde
Figure imgf000154_0001
A slurry of (9S, 11 E, 13R)- 13, 16-dimethyl-3 ,7, 14,17,23- pentaazapentacyclo[l 3.6.2. l~2,5~.0~4,9~.0~18,22~]tetracosa- l(22),2(24),4,l l,15,17,18,20,22-nonaen-6-one (Example 31 ; 0.017 g, 0.047 mmol) and selenium dioxide (Aldrich; 7.87 mg, 0.071 mmol) in 0.7 mL of 4% water in dioxane was sealed and heated to 60 °C. The reaction was stirred overnight. The reaction was treated with DCM/MeOH; insoluble red precipitate was observed. 0.500 g silica gel was added and the reaction concentrated in vacuo. The material was purified by silica gel chromatography (12 g column) using 0 - 100% 90/10 DCM/MeOH in DCM The product- containing fractions were concentrated to afford (9S,1 lE,13R)-13-methyl-6-oxo- 3,7,14, 17,23-pentaazapentacyclo[l 3.6.2. l~2,5~.0~4,9~.0~18,22~]tetracosa- l(22),2(24),4,l l,15,17,18,20,22-nonaene-16-carbaldehyde (0.0045 g, 0.012 mmol, 25.5 % yield) as a red solid: !H NMR (400 MHz, CDCl3) δ ppm 13.30 (1 H, br. s.), 10.15 (1 H, s), 8.57 (1 H, br. s.), 8.10 (1 H, d, J=7.0 Hz), 7.79 (1 H, dd, J=8.2, 1.0 Hz), 7.48 (1 H, t, J=7.8 Hz), 7.08 (1 H, d, J=2.0 Hz), 6.32 (1 H, d, J=16.0 Hz), 5.75 - 5.96 (1 H, m), 5.52 (1 H, br. s.), 4.25 - 4.46 (1 H, m), 3.23 - 3.65 (3 H, m), 2.66 (1 H, d, J=13.3 Hz), 2.26 - 2.48 (1 H, m), 1.61 (4 H, d, J=6.5 Hz), m/z (ESI, +ve) 374.1 (M+H)+.
Example 51 : (9S,llE)-12-methyl-6-oxo-3,7,14,17,23- pentaazapentacyclo[13.6.2.1~2,5~.0~4,9~.0~18,22~]tetracosa- l(22),2(24),4,ll,15,17,18,20,22-nonaene-16-carbaldehyde
Figure imgf000154_0002
A mixture of selenium dioxide (Aldrich; 0.023 g, 0.209 mmol) and (9S,1 1E)-12,16- dimethyl-3,7,14,17,23-pentaazapentacyclo[l 3.6.2. l~2,5~.0~4,9~.0~18,22~]tetracosa- l(21),2(24),4,l l,15,17,19,22-octaen-6-one (Example 14; 0.050 g, 0.139 mmol) in 1.4 mL dioxane and 0.056 mL water was stirred rapidly at RT. The reaction was sealed and heated to 60 °C After 2 h, the reaction was treated with DCM and MeOH, silica gel was added (0.5 g) and the slurry was concentrated in vacuo. The material was purified by silica gel chromatography (12 g gold column) using 0-100% 90/10 DCM/MeOH in DCM. The product-containing fractions were concentrated to afford (9S,1 lE)-12-methyl-6-oxo- 3,7,14, 17,23-pentaazapentacyclo[l 3.6.2. l~2,5~.0~4,9~.0~18,22~]tetracosa- l(22),2(24),4,l l,15,17,18,20,22-nonaene-16-carbaldehyde (0.0038 g, 10.18 μιηοΐ, 7.32 % yield) as a red solid: !H NMR (400 MHz, CDCl3) δ ppm 13.20 (1 H, br. s.), 10.17 (1 H, s), 8.40 (1 H, d, J=5.3 Hz), 8.13 (1 H, d, J=7.4 Hz), 7.81 (1 H, d, J=8.2 Hz), 7.45 - 7.56 (1 H, m), 7.12 (1 H, d, J=2.0 Hz), 5.81 (1 H, d, J=10.8 Hz), 5.52 (1 H, br. s.), 4.05 - 4.30 (2 H, m), 3.35 - 3.62 (3 H, m), 2.35 - 2.64 (2 H, m), 1.67 - 1.74 (3 H, m). m/z (ESI, +ve) 374.1 (M+H)+. Example 53 17-methyl-4,7,12,15,18,24- hexaazapentacyclo[14.6.2.1~2,5~.0~4,9~.0~19,23~]pentacosa- l(22),2,5(25),16,18,20,23-heptaene-6,ll-dione
Figure imgf000155_0001
Step 1 : tert-butyl (2-((8-bromo-3-methylquinoxalin-2-yl)amino)ethyl)carbamate
A solution of 5-bromo-3-fluoro-2-methylquinoxaline (0.956 g, 3.97 mmol), N-Boc- ethylenediamine (Aldrich , 0.81 mL, 5.16 mmol) and DIPEA (1.38 mL, 7.93 mmol) in DMSO (8.0 mL) was heated at 80 °C for 5 h. The mixture was diluted with EtOAc (100 mL) and washed with water (10 mL) and brine (2 x 25 mL). The organic layer was dried over MgS04, filtered and concentrated. The residue was purified on the ISCO Combiflash Rf (40 g Thomson SingleStep column, using a gradient of 20-100% EtOAc in hexanes) affording tert-butyl (2-((8-bromo-3-methylquinoxalin-2-yl)amino)ethyl)carbamate (1.30 g, 3.40 mmol, 86 % yield) as a white crystalline solid: !H NMR (400 MHz, CDCh) δ ppm 7.81 (1 H, d, J=7.6 Hz), 7.77 (1 H, dd, J=8.2, 1.2 Hz), 7.21 (1 H, t, J=7.9 Hz), 6.1 1 (1 H, br. s.), 5.26 (1 H, br. s.), 3.72 - 3.80 (2 H, m), 3.51 - 3.59 (2 H, m), 2.58 (3 H, s), 1.42 (9 H, s). m/z (ESI, +ve ion) 381.0/383.1 (M+H)+.
Step 2: tert-butyl (2-((3-methyl-8-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)quinoxalin-2-yl)amino)ethyl)carbamate
A mixture of tert-butyl (2-((8-bromo-3-methylquinoxalin-2-yl)amino)ethyl)carbamate (397 mg, 1.041 mmol), bis(pinacolato)diboron (Aldrich , 529 mg, 2.083 mmol), Pd(dppf)Cl2 (Aldrich , 42.5 mg, 0.052 mmol) and KOAc (Aldrich , 409 mg, 4.17 mmol) in THF (4.00 mL) was heated at 100 °C in a sealed vessel for 4 h. The mixture was diluted with EtOAc (50 mL) and treated with water. It was then washed with brine (2 x 25 mL), dried over MgS04, filtered and concentrated. The crude was purified on an ISCO Combiflash Rf (40 g Thomson SingleStep column, using a gradient of 0-100% EtOAc in DCM, then 0-20% MeOH in DCM) to give tert-butyl (2-((3-methyl-8-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)quinoxalin-2-yl)amino)ethyl)carbamate (342 mg, 0.798 mmol, 77 %> yield) as a tan amorphous solid upon concentration of the product containing fractions: !H NMR (400 MHz, CDCl3) δ ppm 8.12 (1 H, d, J=6.1 Hz), 7.84 - 7.95 (1 H, m), 7.65 (2 H, br. s.), 7.42 (1 H, br. s.), 6.76 (1 H, br. s.), 5.05 (1 H, br. s.), 3.83 (1 H, br. s.), 3.58 (5 H, br. s.), 3.49 (2 H, br. s.), 2.59 (3 H, br. s.), 1.47 (12 H, br. s.), 1.26 (3 H, d, J=7.2 Hz), m/z (ESI, +ve ion) 347.1 (M+H)+ (the pinacol ester is labile under the conditions used to run the LC-MS and the observed mass corresponded to the corresponding boronic acid).
Step 3 : ethyl 2-(7-(3-((2-((tert-butoxycarbonyl)amino)ethyl)amino)-2-methylquinoxalin- 5-yl)-l -oxo-l ,2,3,4-tetrahydropyrrolo[l,2-a]pyrazin-4-yl)acetate
A 20-mL glass microwave tube was charged with ethyl 2-(7-bromo-l -oxo-l,2,3,4- tetrahydropyrrolo[l,2-a]pyrazin-4-yl)acetate (Intermediate J, 217 mg, 0.721 mmol), dicyclohexyl(2',4',6'-triisopropyl-[l,l '-biphenyl]-2-yl)phosphine (Strem Chemicals, 20.6 mg, 0.043 mmol), Pd2(dba)3 (Strem Chemicals, 19.8 mg, 0.022 mmol), K3P04 (Riedel de Haen, Buchs, Switzerland, 459 mg, 2.162 mmol) and tert-butyl (2-((3-methyl-8-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)quinoxalin-2-yl)amino)ethyl) carbamate (340 mg, 0.793 mmol) and purged with argon. The solids were then treated with dioxane (5.0 mL) and water (1.65 mL) and heated in a microwave reactor at 130 °C for 30 min. The reaction mixture was treated with water, extracted with EtOAc, washed with brine and concentrated. Purification on the ISCO Combiflash Rf (40 g Thomson SingleStep column, using a gradient of 20-100% EtOAc in hexanes, then 0-15% MeOH in DCM) afforded ethyl 2-(7-(3 -((2-((tert-butoxycarbonyl)amino)ethyl)amino)-2-methylquinoxalin- 5-yl)-l-oxo-l ,2,3,4-tetrahydropyrrolo[l,2-a]pyrazin-4-yl)acetate (165 mg, 0.316 mmol, 43.8 % yield) as a light yellow film: !H NMR (400 MHz, CDCl3) δ ppm 7.90 (1 H, br. s.), 7.66 - 7.80 (3 H, m), 7.32 - 7.40 (1 H, m), 5.89 (1 H, br. s.), 5.67 (1 H, br. s.), 5.49 (1 H, br. s.), 4.80 (1 H, br. s.), 4.08 - 4.21 (3 H, m), 4.02 (1 H, d, J=12.7 Hz), 3.74 (2 H, br. s.), 3.46 - 3.63 (3 H, m), 2.88 - 2.97 (2 H, m), 2.57 (3 H, br. s.), 2.04 (2 H, br. s.), 1.45 (9 H, br. s.). m/z (ESI, +ve ion) 523.2 (M+H)+. Step 4: 2-((8-(4-(carboxymethyl)-l -oxo-l,2,3,4-tetrahydropyrrolo[l,2-a]pyrazin-7-yl)-3- methylquinoxalin-2 -yl)amino)ethanaminium chloride
Ethyl 2-(7-(3-((2-((tert-butoxycarbonyl)amino)ethyl)amino)-2-methylquinoxalin-5-yl)-l- oxo-l ,2,3,4-tetrahydropyrrolo[l ,2-a]pyrazin-4-yl)acetate (165 mg, 0.316 mmol) was treated with THF (5.0 mL) and EtOH (5.0 mL) then treated with IN NaOH (0.95 mL, 0.95 mmol) and stirred at RT for 30 min. The reaction mixture was concentrated in vacuo (rotary evaporator) and then treated with 4M HC1 in dioxane (1.56 mL, 6.31 mmol) and THF (3 mL) and stirred at RT for 30 min. The volatiles were removed in vacuo (rotary evaporator) yielding crude 2-((8-(4-(carboxymethyl)-l-oxo-l ,2,3,4-tetrahydropyrrolo[l,2- a]pyrazin-7-yl)-3-methylquinoxalin-2-yl)amino)ethanaminium chloride as a bright orange amorphous solid which was then dried under vacuum for 2 h. The material was used in the subsequent step without further purification, m/z (ESI, +ve ion) 395.1 (M+H)+.
Step 5 : 17-methyl-4,7, 12,15, 18,24-hexaazapenta- cyclo[14.6.2.1~2,5~.0~4,9~.0~19,23~]pentacosa-l(22),2,5(25), 16,18,20,23-heptaene- 6,1 1-dione
2-((8-(4-(Carboxymethyl)- 1 -oxo- 1 ,2,3 ,4-tetrahydropyrrolo [ 1 ,2-a]pyrazin-7-yl)-3 - methylquinoxalin-2-yl)amino)ethanaminium chloride (136 mg, 0.316 mmol) was treated with THF (10 mL) and DMF (3.75 mL) and the resulting suspension was stirred at RT. It was then treated with DIPEA (0.55 mL, 3.16 mmol) and the suspension turned light pink/purple and (benzotriazol-l-yloxy)tripyrrolidinophosphonium hexafluorophosphate (411 mg, 0.789 mmol) was added in one portion and the resulting solution stirred at RT for 1 h. The reaction mixture was treated with water and extracted with EtOAc (50 mL), DCM (4 x 15 mL) and 10% IPA in CHC13 (3 x 40 mL). A portion of the crude residue was dissolved in DMSO and purified on the Gilson (Silichrome XT Ci8 column; 30 x 150 mm, 5 μ; 5-95% 0.1 %TFA/CH3CN in 0.1%TF A/water) affording 17-methyl- 4,7,12, 15,18,24-hexaazapentacyclo[14.6.2.1~2,5~.0~4,9~.0~19,23~]pentacosa- l(22),2,5(25),16,18,20,23-heptaene-6,l l -dione as a 2,2,2-trifluoroacetate salt (14.9 mg, 0.030 mmol, 9.6 % yield) as an orange amorphous solid after drying in a Genevac Series II evaporator overnight: !H NMR (400 MHz, DMSO-d6) δ ppm 8.87 (1 H, br. s.), 8.75 (1 H, br. s.), 7.79 (1 H, d, J=7.0 Hz), 7.73 (1 H, br. s.), 7.51 (1 H, d, J=7.6 Hz), 7.20 - 7.32 (2 H, m), 7.17 (1 H, br. s.), 4.67 (1 H, br. s.), 3.95 (1 H, br. s.), 3.68 (2 H, br. s.), 3.03 (1 H, br. s.), 2.64 - 2.76 (1 H, m), 2.60 (1 H, d, J=11.7 Hz), m/z (ESI, +ve ion) 377.1 (M+H)+.
Example 54: (9R,13R)-13,16-dimethyl-3,7,14,17,23- pentaazapentacyclo[13.6.2.1~2,5~.0~4,9~.0~18,22~]tetr
l(22),2(24),4,15,17,18,20,22-octaen-ll-yn-6-one
Figure imgf000158_0001
The title compound (31 mg, 89%o yield) was prepared and isolated as a yellow crystalline solid from (R)-7-(but-2-yn- 1 -yl)-2-(2-methyl-3-((R)-pent-3-yn-2-ylamino)quinoxalin-5- yl)-6,7-dihydro-lH-pyrrolo[3,2-c]pyridin-4(5H)-one (Intermediate O, 40 mg, 0.09 mmol) following an analogous procedure to Example 32, Alternative Preparation, Step 1 : !H NMR (400 MHz, MeOH-d4) δ ppm 8.00 (1 H, d, J=7.6 Hz), 7.63 (1 H, d, J=8.2 Hz), 7.43 (1 H, m), 7.01 (1 H, s), 4.65 (1 H, m), 3.54 (2 H, m), 3.23 (1 H, m), 2.66 (1 H, m), 2.64 (3 H, s), 2.46 (1 H, m), 1.71 (3 H, d, J=6.8 Hz), m/z (ESI, +ve) 358.3 (M+H)+.
Example 55. (9R,llZ,13R)-13,16-dimethyl-3,7,14,17,23- pentaazapentacyclo[13.6.2.1~2,5~.0~4,9~.0~18,22~]tetracosa- l(22),2(24),4,ll,15,17,18,20,22-nonaen-6-one
Figure imgf000159_0001
The title compound (6.5 mg, 21% yield) was prepared and isolated as a yellow crystalline solid from (9R,13R)-13,16-dimethyl-3,7,14, 17,23- pentaazapentacyclo[l 3.6.2.1~2,5~.0~4,9~.0~18,22~]tetracosa- l(22),2(24),4,15,17,18,20,22-octaen-l l -yn-6-one (Example 54, 30 mg, 0.08 mmol) following an analogous procedure to Example 32, Alternative Preparation, Step 2: !H NMR (400 MHz, DMSO-d6) δ ppm 13.81 (1 H, br. s), 7.85 (1 H, d, J=6.7 Hz), 7.56 (1 H, d, J=7.4 Hz), 7.34 (1 H, t, J=7.8 Hz), 7.18 (1 H, d, J=4.1 Hz), 6.97 (1 H, d, J=4.3 Hz), 6.70 (1 H, d, J=1.8 Hz), 5.50 (1 H, m), 5.41 (1 H, m), 4.89 (1 H, m), 3.42 (2 H, m), 3.25 (1 H, m), 3.17 (1 H, d, J=4.9 Hz), 2.59 (3 H, s), 2.27 (1 H, d, J=15.1 Hz), 1.43 (3 H, d, J=6.8 Hz), m/z (ESI, +ve) 360.2 (M+H)+.
Example 56: (9S,llE,13R)-13-(hydroxymethyl)-16-methyl-3,7,14,17,23- pentaazapentacyclo[13.6.2.1~2,5~.0~4,9~.0~18,22~]tetracosa- l(22),2(24),4,ll,15,17,18,20,22-nonaen-6-one
Figure imgf000159_0002
Step 1 : (R)-tert-butyl 2,2-dimethyl-4-vinyloxazolidine-3-carboxylate
To a slurry of MePPh3Br (Fluka Chemie GmbH; 3.74 g, 10.47 mmol) in 50 mL THF at - 78 °C was added nBuLi solution, 2.5 M in hexanes (Aldrich; 3.84 ml, 9.60 mmol) dropwise via syringe. After 10 min, the reaction was warmed to RT, then recooled to 0 °C. (S)-(-)-3-(tert-butoxycarbonyl)-(s)-4-formyl-2,2-dimethyl-l,3-oxazolidine (TCI America; 2.00 g, 8.72 mmol) (dissolved in 8 mL THF) was added dropwise via syringe. The reaction was stirred for several hours. The reaction was partitioned between saturated aqueous NH4C1 and Et20. The organic layer was washed with brine once and the organics were dried over anhydrous Na2S04, filtered, and concentrated in vacuo. The material was treated with DCM and adsorbed onto 15 g silica gel, dried, and purified by silica gel chromatography (120 g) using 0 - 30% EtOAc/hexane to give (R)-tert-butyl 2,2-dimethyl-4-vinyloxazolidine-3-carboxylate (1.21 g, 5.32 mmol, 61.0 % yield) as a clear/colorless oil: !H NMR (400 MHz, CDCl3) δ ppm 5.69 - 5.96 (1 H, m), 5.06 - 5.27 (2 H, m), 4.20 - 4.47 (1 H, m), 4.05 (1 H, dd, J=8.8, 6.3 Hz), 3.76 (1 H, dd, J=8.8, 2.2 Hz), 1.37 - 1.71 (15 H, m).
Step 2: (R)-2-aminobut-3-en-l -ol hydrochloride
(R)-tert-Butyl 2,2-dimethyl-4-vinyloxazolidine-3-carboxylate (1.2 g, 5.28 mmol) was treated with HCl, 5 N (Ricca Chemical Company; 4.81 ml, 158 mmol). The reaction was stirred rapidly, and HCl, 4.0 M solution in 1,4-dioxane (Aldrich; 5.04 ml, 145 mmol) was added and bubbling was observed. The reaction was stirred for 1 h, at which point the stir bar was removed and the reaction concentrated in vacuo. The resulting oil was treated with anhydrous toluene and concentrated in vacuo. This was repeated, and the oil was placed on the hood pump, resulting in (R)-2-aminobut-3-en-l-ol hydrochloride (0.696 g, 5.63 mmol, quantitative yield) as a waxy solid: !H NMR (400 MHz, MeOH-d4) δ ppm 5.89 (1 H, ddd, J=17.5, 10.5, 7.0 Hz), 5.42 - 5.53 (2 H, m), 3.74 - 3.84 (2 H, m), 3.52 - 3.64 (1 H, m).
Step 3 : (S)-7-allyl-2-(3-(((R)-l -hydroxybut-3-en-2-yl)amino)-2-methylquinoxalin-5-yl)- 6,7-dihydro-lH-pyrrolo[3,2-c]pyridin-4(5H)-one
A mixture of (S)-7-allyl-2-(3-fluoro-2-methylquinoxalin-5-yl)-6,7-dihydro-lH- pyrrolo[3,2-c]pyridin-4(5H)-one (Intermediate D; 0.150 g, 0.446 mmol), (R)-2-aminobut- 3-en-l -ol hydrochloride (0.165 g, 1.338 mmol), and DIPEA (Aldrich; 0.465 ml, 2.68 mmol) in 2 mL DMSO was sealed and placed in a 70 °C oil bath. After 2 h, the reaction was nearly complete, and was stirred at 45 °C overnight. The reaction was partitioned between saturated aqueous NaHCC and EtOAc. The aqueous layer was extracted 1 x EtOAc, and the combined organic layers were washed with water once, brine once, and the organics were dried over anhydrous Na2S04, filtered, and concentrated in vacuo. The resulting semisolid (0.220 g) was treated with DCM and purified by silica gel chromatography (25 g) using 0 - 100% 90/10 DCM/MeOH in DCM. The product- containing fractions were concentrated to afford (S)-7-allyl-2-(3-(((R)-l-hydroxybut-3- en-2 -yl)amino)-2 -methylquinoxalin-5 -yl)-6,7-dihydro- 1 H-pyrrolo [3 ,2 -c]pyridin-4(5 H)- one (0.157 g, 0.389 mmol, 87 % yield) as a yellow solid: !H NMR (400 MHz, DMSO-d6) δ ppm 12.00 (1 H, br. s), 7.87 - 7.94 (1 H, m), 7.53 - 7.61 (1 H, m), 7.33 (1 H, t, J=7.8 Hz), 7.00 - 7.06 (1 H, m), 6.87 - 7.00 (2 H, m), 6.02 - 6.14 (1 H, m), 5.82 - 5.97 (1 H, m), 5.75 (1 H, s), 5.26 - 5.36 (1 H, m), 5.03 - 5.22 (4 H, m), 4.71 - 4.85 (1 H, m), 3.66 - 3.77 (2 H, m), 3.46 - 3.56 (1 H, m), 3.18 - 3.27 (1 H, m), 3.03 - 3.13 (1 H, m), 2.60 (3 H, s), 2.43 - 2.48 (1 H, m), 2.29 - 2.41 (1 H, m). m/z (ESI, +ve) 404.1 (M+H)+.
Step 4: (9S,1 lE,13R)-13-(hydroxymethyl)-16-methyl-3,7,14,17,23- pentaazapentacyclo[l 3.6.2. l~2,5~.0~4,9~.0~18,22~]tetracosa- 1 (22),2(24),4,1 1 , 15, 17, 18,20,22-nonaen-6-one
Argon was bubbled through a solution of Grubbs catalyst 2nd generation (Aldrich; 0.064 g, 0.075 mmol) and (S)-7-allyl-2-(3-(((R)-l-hydroxybut-3-en-2-yl)amino)-2- methylquinoxalin-5-yl)-6,7-dihydro-lH-pyrrolo[3,2-c]pyridin-4(5H)-one (0.152 g, 0.377 mmol) in 19 mL anhydrous DCM for 60 sec. The homogeneous reaction was sealed and heated to 45 °C. After 2 h, the reaction was treated with MeOH and 1.5 g silica gel and dried in vacuo, purified by silica gel chromatography (24 g) using 0 - 100% 90/10 DCM/MeOH. The product-containing fractions were concentrated to afford 0.085 g of a yellow-green solid. This material was suspended in MeOH, sonicated 1 min, filtered, rinsing 1 x MeOH. The bright yellow solid was collected and dried in vacuo to give (9S, 11 E, 13R)- 13 -(hydroxymethyl)- 16-methyl-3 ,7, 14, 17,23 -pentaazapenta- cyclo[13.6.2.1~2,5~.0~4,9~.0~18,22~]tetracosa-l (22),2(24),4,l l ,15,17,18,20,22-nonaen- 6-one (0.061 g, 0.162 mmol, 43.1 % yield) as a bright yellow solid: !H NMR (400 MHz,
DMSO-de) δ ppm 13.55 (1 H, br. s.), 8.01 (1 H, d, J=7.4 Hz), 7.57 (1 H, d, J=7.8 Hz), 7.35 (1 H, t, J=7.8 Hz), 7.02 (1 H, d, J=4.1 Hz), 6.91 (1 H, d, J=2.0 Hz), 6.35 (1 H, s), 5.98 - 6.17 (1 H, m), 5.79 (1 H, dd, J=15.7, 7.5 Hz), 5.43 (1 H, t, J=5.9 Hz), 4.14 - 4.26 (1 H, m), 3.57 - 3.76 (2 H, m), 3.32 - 3.38 (1 H, m), 3.22 - 3.30 (1 H, m), 3.06 - 3.18 (1 H, m), 2.60 (3 H, s), 2.56 (1 H, br. s.), 2.14 - 2.26 (1 H, m). m/z (ESI, +ve) 376.1 (M+H)+.
Example 57: (9S,llE)-14,16-dimethyl-3,7,14,17,23- pentaazapentacyclo[13.6.2.1~2,5~.0~4,9~.0~18,22~]tetracosa- l(22),2(24),4,ll,15,17,18,20,22-nonaen-6-one
Example 58: (9S,llZ)-14,16-dimethyl-3,7,14,17,23- pentaazapentacyclo[13.6.2.1~2,5~.0~4,9~.0~18,22~]tetracosa- l(22),2(24),4,ll,15,17,18,20,22-nonaen-6-one
Figure imgf000162_0001
Step 1 : (S)-7-allyl-2-(3-(allyl(methyl)amino)-2-methylquinoxalm^
pyrrolo [3,2 -c]pyridin-4(5 H)-one
A solution of N-methylprop-2-en-l -amine (Sigma Aldrich, 85 mg, 1.192 mmol), (S)-7- allyl-2-(3-fluoro-2-methylquinoxalin-5-yl)-6,7-dihydro-lH-pyrrolo[3,2-c]pyridin-4(5H)- one (Intermediate D, 133.7 mg, 0.397 mmol), and DMSO (4.0 mL) was stirred at 100 °C in a sealed tube for 3 h. The material was cooled to RT, diluted with water, and extracted with EtOAc (3x20 mL). The organics were washed with saturated aqueous NH4C1 (30 mL), dried over Na2S04, filtered, and concentrated under reduced pressure to a yellow solid that was used without purification: m/z (ESI, +ve) 388.3 (M+H)+.
Step 2: (9S,1 lE)-14,16-dimethyl-3,7,14,17,23-pentaazapenta- cyclo[13.6.2.1~2,5~.0~4,9~.0~18,22~]tetracosa-l(22),2(24),4,l l,15,17,18,20,22-nonaen- 6-one and (9S, 11 Z)- 14, 16-dimethyl-3 ,7,14,17,23- pentaazapentacyclo[l 3.6.2. l~2,5~.0~4,9~.0~18,22~]tetracosa- 1 (22),2(24),4, 11 , 15, 17, 18,20,22-nonaen-6-one
A solution of Grubbs 2nd generation catalyst (Sigma Aldrich, 114 mg, 0.134 mmol) and (S)-7-allyl-2-(3-(allyl(methyl)amino)-2-methylquinoxalin-5-yl)-6,7-dihydro-lH- pyrrolo[3,2-c]pyridin-4(5H)-one (260 mg, 0.671 mmol) was stirred in DCM (6.7 mL) at
50 °C for 2 h. The mixture was cooled to RT, adsorbed onto silica, and concentrated under reduced pressure. The material was purified on by silica gel chromatography (eluent: 0 to 9% MeOH/DCM). The product fractions were combined and concentrated. The resulting residue was purified a second time by SFC (solubilized in 1 : 1 MeOH at 4 mg/mL, 292 nm, Phenomenex, Lux- 1, repack-S/N= 1204 ODH Column, 5 μ at 21x150 mm length, 60% C02 with IPA/40 mM NH3, P = 186 bar at 1 mL/min, giving (9S,11E)- 14,16-dimethyl-3 ,7, 14,17,23-pentaazapenta- cyclo[13.6.2.1~2,5~.0~4,9~.0~18,22~]tetracosa-l(22),2(24),4,l l,15,17,18,20,22-nonaen- 6-one (33.6 mg, 28%, 2 steps) as the first eluting peak and (9S,1 lZ)-14,16-dimethyl- 3,7,14, 17,23-pentaazapentacyclo[l 3.6.2. l~2,5~.0~4,9~.0~18,22~]tetracosa- l(22),2(24),4,l l,15,17,18,20,22-nonaen-6-one (30.7 mg, 23%) as the second eluting peak.
Analytical data for (9S,l lE)-14,16-dimethyl-3,7,14,17,23-pentaazapenta- cyclo[13.6.2.1~2,5~.0~4,9~.0~18,22~]tetracosa-l (22),2(24),4,l l ,15,17,18,20,22-nonaen- 6-one: !H NMR (DMSO-dg) δ ppm 13.15 - 13.23 (lH, m) 7.98 - 8.13 (lH, m) 7.58 - 7.69 (1H, m) 7.41 - 7.52 (1H, m) 7.06 - 7.13 (1H, m) 6.91 - 7.01 (1H, m) 6.14 - 6.26 (1H, m) 5.93 - 6.06 (1H, m) 4.21 - 4.33 (1H, m) 3.96 - 4.10 (1H, m) 3.34 - 3.40 (1H, m) 3.24 - 3.29 (1H, m) 3.21 (3H, s) 3.08 - 3.18 (1H, m) 2.69 (3H, s), 2.59 - 2.67 (1H, m) 2.20 - 2.36 (1H, m): m/z (ESI, +ve) 360.2 (M+H)+.
Analytical data for (9S,l lZ)-14,16-dimethyl-3,7,14,17,23-pentaazapenta- cyclo[13.6.2.1~2,5~.0~4,9~.0~18,22~]tetracosa-l (22),2(24),4,l l ,15,17,18,20,22-nonaen- 6-one: ¾ NM (DMSO-de) δ ppm 13.21 - 13.31 (1H, m) 7.87 - 7.98 (1H, m) 7.59 - 7.66 (1H, m) 7.36 - 7.47 (1H, m) 6.96 - 7.08 (1H, m) 6.76 - 6.88 (1H, m), 5.75 - 5.92 (2H, m), 4.71 - 4.84 (1H, m), 3.70 - 3.83 (1H, m), 3.41 (3H, s), 3.35 - 3.39 (1H, m), 3.19 - 3.25 (2H, m), 2.79 (3H, s), 2.61 - 2.73 (1H, m), 2.22 - 2.35 (1H, m): m/z (ESI, +ve) 360.2 (M+H)+.
Examples 59-60: (9S)-17-methyl-4,7,12,15,18,24- hexaazapentacyclo[14.6.2.1~2,5~.0~4,9~.0~19,23~]pentacosa- l(22),2,5(25),16,18,20,23-heptaene-6,ll-dione and (9R)-17-methyl-4,7,12,15,18,24- hexaazapentacyclo[14.6.2.1~2,5~.0~4,9~.0~19,23~]pentacosa- l(22),2,5(25),16,18,20,23-heptaene-6,ll-dione
Figure imgf000163_0001
Separated enantiomers were obtained by dissolving 41 mg of racemic Example 53 in 20 mL 1 : 1 MeOH:DCM and subjecting to chiral separation using a preparatory SFC (Conditions: 25%o MeOH containing 20 mM NH3 as a cosolvent in supercritical C02 on a Chiralcel OJ-H column (20 x 250 mm i.d., 5 μηι) with a flow rate of 70 mL/min using injections of 1.2 mL of racemic material). The separated material was then subject to analytical SFC (Conditions: 25% MeOH containing 0.1% DEA as a modifier in supercritical CO2 on a Chiralcel OJ-H column (4.6 mm x 15 cm i.d., 5 μ) with a flow rate of 4.0 mL/min. Example 59 eluted as the second peak under the analytical SFC conditions: !H NMR (400 MHz, DMSO-d6) δ ppm 8.83 (1 H, br. s.), 8.74 (1 H, br. s.), 7.78 (1 H, br. s.), 7.70 (1 H, br. s.), 7.51 (1 H, d, J=6.3 Hz), 7.19 - 7.34 (2 H, m), 7.17 (1 H, br. s.), 4.68 (1 H, br. s.), 3.95 (1 H, br. s.), 3.67 (1 H, br. s.), 3.55 (1 H, d, J=10.2 Hz), 3.43 (2 H, d, J=9.0 Hz), 3.03 (1 H, br. s.), 2.65 - 2.75 (1 H, m), 2.56 - 2.65 (1 H, m). m/z (ESI, +ve ion) 377.1 (M+H)+. Example 60 eluted as the first peak under the analytical SFC conditions described above: !H NMR (400 MHz, DMSO-d6) δ ppm 8.84 (1 H, br. s.), 8.75 (1 H, br. s.), 7.79 (1 H, d, J=7.0 Hz), 7.66 - 7.75 (1 H, m), 7.52 (1 H, d, J=7.6 Hz), 7.27 - 7.33 (1 H, m), 7.20 - 7.27 (1 H, m), 7.17 (1 H, s), 4.62 - 4.74 (1 H, m), 3.88 - 4.02 (1 H, m), 3.63 - 3.77 (1 H, m), 3.55 (1 H, dt, .7=12.7, 4.0 Hz), 3.38 - 3.51 (2 H, m), 2.96 - 3.10 (1 H, m), 2.65 - 2.75 (1 H, m), 2.60 (1 H, dd, J=14.5, 10.2 Hz), m/z (ESI, +ve ion) 377.1 (M+H)+. Examples 61-62: (9S,14R)-14,17-dimethyl-4,7,12,15,18,24- hexaazapentacyclo[14.6.2.1~2,5~.0~4,9~.0~19,23~] pentacosa- l(22),2,5(25),16,18,20,23-heptaene-6,ll-dione and (9R,14R)-14,17-dimethyl- 4,7,12,15,18,24-hexaazapentacyclo[14.6.2.1~2,5~.0~4,9~.0~19,23~] pentacosa- l(22),2,5(25),16,18,20,23-heptaene-6,ll-dione
Figure imgf000164_0001
Step 1 : ( ?)-tert-butyl (2-((8-bromo-3-methylquinoxalin-2-yl)amino)propyl)carbamate A solution of 5-bromo-3-chloro-2-methylquinoxaline (1.00 g, 3.88 mmol), ( ?)-l -N-Boc- propane-1 , 2 -diamine HCI (Acesys Pharmatech, North Brunswick, NJ, Cat#: A1032R, 1.24 g, 5.89 mmol) and DIPEA (2.02 mL, 1 1.65 mmol) in DMSO (8.0 mL) was heated at 80 °C for 16 h. The mixture was diluted with EtOAc (100 mL) and washed with water (2 x 30 rriL) and brine (25 mL). The organic layer was dried over MgSO t, filtered and concentrated. The crude residue was purified on an ISCO Combiflash Rf (80 g Thomson SingleStep column, using a gradient of 30-60% EtOAc in hexanes) to give (R)-tert-butyl (2-((8-bromo-3-methylquinoxalin-2-yl)amino)propyl)carbamate (1.23 g, 3.11 mmol, 80 % yield) as an orange viscous oil. !H NMR (400 MHz, CDCl3) δ ppm 7.78 - 7.83 (1 H, m), 7.76 (1 H, d, J=8.0 Hz), 7.19 (1 H, t, J=7.9 Hz), 6.08 (1 H, d, J=4.7 Hz), 5.20 (1 H, br. s.), 4.33 - 4.47 (1 H, m), 3.41 - 3.52 (1 H, m), 3.29 - 3.41 (1 H, m), 2.56 (3 H, s), 1.40 (9 H, s), 1.38 (3 H, d). m/z (ESI, +ve ion) 395.1/397.0 (M+H)+. Step 2: (R)-tert-butyl (2-((3-methyl-8-(4,4,5,5-tetramethyl-l ,3,2-dioxaborolan-2- yl)quinoxalin-2-yl)amino)propyl)carbamate
A mixture of ( ?)-tert-butyl (2-((8-bromo-3-methylquinoxalin-2- yl)amino)propyl)carbamate (1.20 g, 3.04 mmol), bis(pinacolato)diboron (Aldrich, 1.54 g, 6.07 mmol), Pd(dppf)Cl2 (Aldrich, 0.124 g, 0.152 mmol) and KOAc (Aldrich, 1.19 g, 12.14 mmol) in THF (12 mL) was heated at 100 °C in a sealed vessel for 2 h then stirred at RT overnight (16 h). The mixture was diluted with EtOAc (50 mL) and treated with water. It was then washed with brine (2 x 25 mL), dried over MgS04, filtered and concentrated. The crude was purified with an ISCO Combiflash Rf (40 g Thomson SingleStep column, using a gradient of 0-10% MeOH in DCM) to give (R)-tert-butyl (2- ((3-methyl-8-(4,4,5,5-tetramethyl-l ,3,2-dioxaborolan-2-yl)quinoxalin-2- yl)amino)propyl)carbamate (1.28 g, 2.90 mmol, 96 % yield) as a light brown foam, m/z (ESI, +ve ion) 317.1 (M+H)+ (the pinacol ester is labile under the conditions used to run the LC-MS and the observed mass corresponded to the corresponding boronic acid). Step 3 : ethyl 2-(7-(3-(((R)-l-((tert-butoxycarbonyl)amino)propan-2-yl)amino)-2- methylquinoxalin-5-yl)- 1 -oxo-1 ,2,3,4-tetrahydropyrrolo[ 1 ,2-a]pyrazin-4-yl)acetate A 20-mL glass microwave tube was charged with ethyl 2-(7-bromo-l -oxo-l,2,3,4- tetrahydropyrrolo[l,2-a]pyrazin-4-yl)acetate (Intermediate J, 350 mg, 1.162 mmol), dicyclohexyl(2',4',6'-triisopropyl-[l, -biphenyl]-2-yl)phosphine (Strem Chemicals, 33.2 mg, 0.070 mmol), Pd2(dba)3 (Strem Chemicals, 31.9 mg, 0.035 mmol), potassium phosphate tribasic (Riedel de Haen, Buchs, Switzerland, 740 mg, 3.49 mmol) and (R)- tert-butyl (2-((3-methyl-8-(4,4,5,5-tetramethyl-l ,3,2-dioxaborolan-2-yl)quinoxalin-2- yl)amino)propyl)carbamate (643 mg, 1.453 mmol) were purged with argon and treated with dioxane (5.0 mL) and water (1.65 mL) and heated in a heating block at 130 °C for 30 min. The reaction mixture was diluted with water and extracted with EtOAc (2 x 50 mL), washed with brine and dried over MgSO t, filtered and concentrated. Purification of the crude residue on the ISCO Combiflash Rf (40 g Thomson SingleStep column, using a gradient of 30-100% EtOAc in hexanes, then with 0-20% MeOH in DCM) afforded ethyl 2-(7-(3-(((R)-l-((tert-butoxycarbonyl)amino)propan-2-yl)amino)-2-methylquinoxalin-5- yl)-l -oxo-1 , 2,3,4-tetrahydropyrrolo[l ,2-a]pyrazin-4-yl)acetate (434.9 mg, 0.810 mmol, 69.7 % yield) as a tan foam: m/z (ESI, +ve ion) 537.2 (M+H)+ as two closely eluting peaks. Step 4: (2 ?)-2-((8-(4-(carboxymethyl)-l -oxo-l,2,3,4-tetrahydropyrrolo[l ,2-a]pyrazin-7- yl)-3-methylquinoxalin-2-yl)amino)propan-l -aminium chloride
Ethyl 2-(7-(3-((( ?)- 1 -((tert-butoxycarbonyl)amino)propan-2-yl)amino)-2- methylquinoxalin-5 -yl)-l -oxo- 1 ,2,3 ,4-tetrahydropyrrolo[ 1 ,2-a]pyrazin-4-yl)acetate (430 mg, 0.801 mmol) was treated with THF (7.5 mL) and EtOH (7.5 mL) then with IN NaOH (2.4 mL, 2.40 mmol) and stirred at RT for 30 min. LC-MS indicated clean conversion to the desired carboxylic acids m/z (ESI, +ve ion) 509.1 (M+H)+. The reaction mixture was concentrated in vacuo (rotary evaporater) and then treated with 4M HC1 in dioxane (4.0 mL, 16.03 mmol) and THF (3 mL) and stirred at RT for 30 min at which point LC-MS indicated clean conversion to the desired amino acid m/z (ESI, +ve ion) 409.1 (M+H)+. The volatiles were removed on the rotary evaporator and the bright orange amorphous solid was further dried in the vacuum oven for 2 h at 40 °C. The mixture of diastereomers were used in the subsequent step without further purification.
Step 5: (9S,14R)-14,17-dimethyl-4,7,12,15,18,24-hexaazapenta- cyclo[14.6.2.1~2,5~.0~4,9~.0~19,23~] pentacosa-l(22),2,5(25),16,18,20,23-heptaene- 6,1 1-dione and (9R,14R)-14,17-dimethyl-4,7,12,15,18,24-hexaazapenta- cyclo[14.6.2.1~2,5~.0~4,9~.0~19,23~] pentacosa-l(22),2,5(25),16,18,20,23-heptaene- 6,1 1-dione
(2 ?)-2-((8-(4-(Carboxymethyl)-l -oxo-1 , 2,3 ,4-tetrahydropyrrolo[l ,2-a]pyrazin-7-yl)-3- methylquinoxalin-2-yl)amino)propan-l -aminium chloride (357 mg, 0.802 mmol) was treated with THF (20.0 mL) and DMF (6.3 mL) and the resulting suspension was stirred at RT. It was then treated with DIPEA (1.4 mL, 8.02 mmol) and the suspension turned light pink/purple and (benzotriazol-l-yloxy)tripyrrolidinophosphonium
hexafluorophosphate (1.04 g, 2.01 mmol) was added in two portions (separated by 30 min) and the resulting solution stirred at RT for an additional 45 min. The reaction mixture was treated with water and extracted with DCM (4 x 25 mL) and 10% IPA in CHC13 (4 x 50 mL). The crude residue was dissolved in DMSO and purified on the Gilson (Silichrome XT Ci8 column; 30 x 150 mm, 5 μιη; 5-95% 0.1 %TFA/CH3CN in 0.1 %oTF A/water). The mixture of diastereomers were separated using preparatory SFC (Conditions: 30% MeOH as a cosolvent in supercritical CO2 on a Chiralcel OJ-H column (20 x 250 mm i.d., 5 μιη) with a flow rate of 70 mL/min using injections of 4.9 mg/mL material). Example 61 eluted as the first peak under these conditions and was isolated as a yellow amorphous solid as its 2,2,2-trifluoroacetate salt upon drying under vacuum: !H NMR (400 MHz, DMSO-d6) δ ppm 8.85 - 8.89 (1 H, m), 8.81 (1 H, t, J=5.4 Hz), 7.81 (1 H, d, J=6.7 Hz), 7.70 (1 H, br. s.), 7.51 (1 H, d, J=7.0 Hz), 7.28 (1 H, t, J=7.7 Hz), 7.14 - 7.20 (1 H, m), 6.76 (1 H, d, J=7.6 Hz), 4.71 - 4.82 (1 H, m), 4.36 (1 H, br. s.), 3.60 (1 H, dt, .7=12.5, 3.6 Hz), 3.13 - 3.27 (1 H, m), 2.64 - 2.74 (1 H, m), 1.39 (3 H, d, J=7.0 Hz). m/z (ESI, +ve ion) 391.2 (M+H)+. Example 62 eluted as the second peak under these conditions and was isolated as a yellow amorphous solid as its 2,2,2-trifluoroacetate salt upon drying under vacuum: !H NMR (400 MHz, DMSO-d6) δ ppm 8.24 (1 H, br. s.), 7.58 - 7.67 (2 H, m), 7.56 (1 H, d, J=7.2 Hz), 7.32 (1 H, t, J=7.7 Hz), 7.21 (1 H, s), 6.91 (1 H, d, J=1.4 Hz), 6.86 (1 H, d, J=6.7 Hz), 4.57 (1 H, dd, J=8.9, 3.6 Hz), 3.80 - 3.93 (1 H, m), 3.61 - 3.74 (2 H, m), 2.95 - 3.06 (1 H, m), 2.83 (1 H, dd, .7=13.7, 9.2 Hz), 2.68 (1 H, dd, J=13.5, 2.9 Hz), 2.53 (3 H, s), 1.31 (3 H, d, J=7.0 Hz), m/z (ESI, +ve ion) 391.2 (M+H)+.
Example 63: (9S,13R)-13-(hydroxymethyl)-16-methyl-3,7,14,17,23- pentaazapentacyclo[13.6.2.1~2,5~.0~4,9~.0~18,22~]tetracosa- l(22),2(24),4,15,17,18,20,22-octaen-6-one
Figure imgf000167_0001
Palladium hydroxide 10 wt. % (dry basis) on activated carbon, wet (Strem, 0.669 g) and (9S, 11 E, 13R 13 -(hydroxymethyl)- 16-methyl-3 ,7, 14, 17,23 -pentaaza- pentacyclo[13.6.2.1~2,5~.0~4,9~.0~18,22~]tetracosa-l(22),2(24),4,l 1 ,15,17,18,20,22- nonaen-6-one (Example 56; 0.118 g, 0.314 mmol) were combined and flushed with N2. 3 mL MeOH was added, and the atmosphere was replaced with H2 from a balloon. After 5 h, the reaction was diluted with MeOH and filtered through a pad of Celite, rinsing with 50 mL MeOH and 50 mL 1 : 1 DCM/MeOH. The yellow solution was concentrated in vacuo to give 0.079 g orange solid. This material was treated with 2 mL MeOH and a stir bar, and stirred rapidly open to air overnight. After about 24 h total the reaction was concentrated and treated with 20% MeOH in DCM and adsorbed onto 0.75 g silica gel and purified by silica gel chromatography (12 g column) using 50 - 100% 90/10 DCM/MeOH in DCM. The product-containing fractions were concentrated to afford 22 mg of a yellow solid. The material was sonicated in 1 mL MeOH, filtered, rinsing with 0.5 mL MeOH. The solid was collected and dried in vacuo to give (9S,13R)-13- (hydroxymethyl)- 16-methyl-3 ,7,14,17,23-pentaazapenta- cyclo[13.6.2.1~2,5~.0~4,9~.0~18,22~]tetracosa-l (22),2(24),4,15,17,18,20,22-octaen-6- one (0.0135 g, 0.036 mmol, 11.38 % yield) as a yellow solid: !H NMR (400 MHz, DMSO-de) δ ppm 13.47 (1 H, br. s.), 8.02 (1 H, d, J=7.6 Hz), 7.58 (1 H, d, J=8.0 Hz), 7.35 (1 H, t, J=7.8 Hz), 7.03 (1 H, d, J=4.1 Hz), 6.96 (1 H, d, J=1.4 Hz), 6.81 (1 H, d, J=4.1 Hz), 4.96 (1 H, t, J=6.1 Hz), 3.62 - 3.81 (2 H, m), 3.55 (1 H, br. s.), 3.09 - 3.27 (2 H, m), 2.93 - 3.07 (1 H, m), 2.58 (3 H, s), 2.09 - 2.30 (2 H, m), 1.92 - 2.06 (1 H, m), 1.78 - 1.92 (1 H, m), 1.44 - 1.59 (1 H, m), 1.15 - 1.32 (1 H, m). m/z (ESI, +ve) 378.2 (M+H)+.
Example 64: (9S,llE,13S)-13-(hydroxymethyl)-16-methyl-3,7,14,17,23- pentaazapentacyclo[13.6.2.1~2,5~.0~4,9~.0~18,22~]tetracosa- l(22),2(24),4,ll,15,17,18,20,22-nonaen-6-one
Example 65: (9S,llZ,13S)-13-(hydroxymethyl)-16-methyl-3,7,14,17,23- pentaazapentacyclo[13.6.2.1~2,5~.0~4,9~.0~18,22~]tetracosa- l(22),2(24),4,ll,15,17,18,20,22-nonaen-6-one
Figure imgf000169_0001
Step 1 : (S)-tert-butyl 2,2-dimethyl-4-vinyloxazolidine-3-carboxylate
A suspension of MePPh3Br (Fluka, 8.57 g, 23.99 mmol) in THF (218 ml) was stirred and cooled to -78 °C. A solution of 2.5 M n-BuLi in hexanes (Sigma Aldrich, 10.47 ml, 26.2 mmol) was added dropwise over 5 min, and the reaction was slowly warmed to RT. (R)- (+)-3-Boc-2,2-dimethyloxazolidine-4-carboxaldehyde (Sigma Aldrich; 5 g, 21.81 mmol) was added dropwise via syringe, and the resulting suspension was stirred at RT for 18 h. The reaction was carefully quenched with sat. aq. NH4C1 and extracted with Et20. The combined organics were dried over Na2S04, filtered, and concentrated in vacuo. DCM was added, and the crude reaction was adsorbed onto silica and chromatographically purified (eluent: 0 to 30% EtOAc/hexanes), giving the product, (S)-tert-butyl 2,2- dimethyl-4-vinyloxazolidine-3-carboxylate, as a colorless oil (3.8 g, 77%): !H NMR (MeOH-d4) δ: 5.75 - 5.89 (m, 1H), 5.10 - 5.25 (m, 2H), 4.32 (br. s., 1H), 4.03 - 4.12 (m, 1H), 3.73 (d, J = 8.4 Hz, 1H), 1.57 (s, 3H), 1.49 (s, 3H), 1.44 (s, 9H).
Step 2: (S)-2-aminobut-3-en-l-ol hydrochloride
A solution of (S)-tert-butyl 2,2-dimethyl-4-vinyloxazolidine-3-carboxylate (3.8 g, 16.72 mmol) in 5.0 N aqueous HCl (Sigma Aldrich, 100 ml, 502 mmol) and a 4.0 M solution of HCl in 1,4-dioxane (Sigma Aldrich, 104 ml, 418 mmol) was stirred at RT. Upon addition of the dioxane solution, gas evolution was notable. The reaction was stirred for 2 h at which point the colorless solution was concentrated in vacuo to give a tan oil that was azeotroped with MeOH and toluene. A tan, waxy solid that resulted was dried further under high vacuum, giving (S)-2-aminobut-3-en-l -ol as a hydrochloride salt (1.84 g, 89%): !H NMR (400 MHz, MeOD) δ ppm 5.81 - 5.95 (1 H, m) 5.39 - 5.54 (2 H, m) 3.73 - 3.86 (2 H, m) 3.51 - 3.65 (1 H, m).
Step 3: (S)-7-allyl-2-(3-(((S)-l-hydroxybut-3-en-2-yl)amino)-2-methylqu^
6,7-dihydro-lH-pyrrolo[3,2-c]pyridin-4(5H)-one
A mixture of DIPEA (EMD Biosciences, 778 μΐ, 4.47 mmol), (S)-2-aminobut-3-en-l-ol hydrochloride (276 mg, 2.236 mmol), and (S)-7-allyl-2-(3-(((S)-l-hydroxybut-3-en-2- yl)amino)-2-methylquinoxalin-5-yl)-6,7-dihydro-lH-pyrrolo[3,2-c]pyridin-4(5H)-one (Intermediate D, 250.6 mg, 0.621 mmol) was stirred in DMSO (4.9 mL) at 80°C for 2.5 h. The reaction mixture was cooled to RT with stirring over 1.5 h. It was quenched with saturated aqueous NaHCC and extracted with EtOAc. The combined organics were washed with brine and dried over Na2S04, filtered, and concentrated in vacuo. The resulting residue was taken up in DCM and chromatographically purified (eluent: 0 to 10% MeOH/DCM), giving (S)-7-allyl-2-(3-(((S)-l-hydroxybut-3-en-2-yl)amino)-2- methylquinoxalin-5-yl)-6,7-dihydro-lH-pyrrolo[3,2-c]pyridin-4(5H)-one (251 mg, 83%o): !H NMR (400 MHz, DMSO-i¾) δ ppm 12.03 (1 H, br. s.) 7.90 - 8.01 (1 H, m) 7.58 - 7.64 (1 H, m) 7.33 (1 H, br. s.) 7.04 (1 H, br. s.) 6.94 (2 H, br. s.) 6.00 - 6.15 (1 H, m) 5.90 - 5.97(1 H, m) 5.34 (1 H, m) 5.20 - 5.24 (1 H, m) 5.08 - 5.18 (2 H, m) 4.96 - 5.07 (1 H, m) 4.74 (1 H, br. s.) 3.80 - 3.85 (1 H, m) 3.52 - 3.61 (1 H, m) 3.35 - 3.40 (1 H, m) 2.97 - 3.13 (1 H, m) 2.61 (3 H, s) 2.27 - 2.43 (1 H, m). m/z (ESI, +ve) 404.1 (M+H)+.
Step 4: (9S,1 lE,13S)-13-(hydroxymethyl)-16-methyl-3,7,14,17,23- pentaazapentacyclo[l 3.6.2.1~2,5~.0~4,9~.0~18,22~]tetracosa-
1 (22),2(24),4, 11 , 15, 17, 18,20,22-nonaen-6-one and (9S, 11 Z, 13 S)- 13 -(hydroxy methyl)- 16- methyl-3,7,14,17,23-pentaazapentacyclo[l 3.6.2. l~2,5~.0~4,9~.0~18,22~]tetracosa- 1 (22),2(24),4, 11 , 15, 17, 18,20,22-nonaen-6-one
A suspension of Grubbs 2nd Generation Catalyst (Sigma Aldrich, 105 mg, 0.124 mmol), (S)-7-allyl-2-(3-(((S)-l-hydroxybut-3-en-2-yl)amino)-2-methylquinoxalin-5-yl)-6,7- dihydro-lH-pyrrolo[3,2-c]pyridin-4(5H)-one (250 mg, 0.620 mmol), and DCM (31 mL) was bubbled through with argon gas for two min. The mixture was sealed and stirred at
45 °C for 1.5 h. The reaction was removed from heat and adsorbed onto silica gel. The adsorbed crude mixture was chromatographically purified on silica gel (eluent: 5 to 10%> MeOH/DCM). The product fractions were dried in vacuo, and the isomeric mixture was further purified by SFC (282 nm, Chiralpak ADH Column, 5 μ, 250 x 30mm, 42% MeOH containing 20 mM NH3, 120 mL/min), affording (9S,1 1E,13S)-13- (hydroxymethyl)- 16-methyl-3 ,7,14,17,23-pentaazapenta- cyclo[13.6.2.1~2,5~.0~4,9~.0~18,22~]tetracosa-l (22),2(24),4,l l ,15,17,18,20,22-nonaen- 6-one(56.7 mg, 48%) as the first eluting peak and (9S,1 lZ,13S)-13-(hydroxymethyl)-16- methyl-3,7,14,17,23-pentaazapentacyclo[l 3.6.2.1~2,5~.0~4,9~.0~18,22~]tetracosa- l(22),2(24),4,l l,15,17,18,20,22-nonaen-6-one (16.2 mg, 14%) as the second eluting peak.
Analytical data for (9S,1 lE,13S)-13-(hydroxymethyl)-16-methyl-3,7,14,17,23- pentaazapentacyclo[l 3.6.2. l~2,5~.0~4,9~.0~18,22~]tetracosa- l(22),2(24),4,l l,15,17,18,20,22-nonaen-6-one: ¾ NM (DMSO-d6) δ: 13.42 (br. s, 1H), 7.89 - 8.00 (m, 1H), 7.50 - 7.56 (m, 1H), 7.42 - 7.49 (m, 1H), 7.24 - 7.37 (m, 1H), 6.96 - 7.04 (m, 1H), 6.81 - 6.90 (m, 1H), 6.10 - 6.24 (m, 1H), 5.85 - 5.99 (m, 1H), 4.84 - 4.92 (m, 1H), 4.04 - 4.25 (m, 2H), 3.73 - 4.04 (m, 2H), 3.04 - 3.28 (m, 3H), 2.55 (s, 3H), 2.15 - 2.26 (m, 1H): m/z (ESI, +ve) 376.3 (M+H)+.
Analytical data for (9S, 1 1 Z, 13 S)- 13 -(hydroxymethyl)- 16-methyl-3 ,7, 14,17,23- pentaazapentacyclo[l 3.6.2. l~2,5~.0~4,9~.0~18,22~]tetracosa- l(22),2(24),4,l l,15,17,18,20,22-nonaen-6-one: ¾ NMR (DMSO-d6) δ: 13.68 - 13.80 (1H, m) 7.85 - 7.93 (1H, m) 7.54 - 7.63 (1H, m) 7.31 - 7.40 (1H, m) 7.16 - 7.23 (1H, m) 6.99 (1H, s) 6.79 (1H, s) 5.83 - 5.94 (1H, m) 5.47 - 5.57 (1H, m) 4.92 - 5.01 (1H, m) 4.58 - 4.68 (1H, m) 3.68 - 3.80 (1H, m) 3.54 - 3.64 (1H, m) 3.36 - 3.42 (1H, m) 3.17 - 3.28 (2H, m) 2.65 - 2.78 (1H, m) 2.61 (3H, s) 2.22 - 2.37 (1H, m): m/z (ESI, +ve) 376.3 (M+H)+.
Example 66: (9S,llE)-12,14,16-trimethyl-3,7,14,17,23- pentaazapentacyclo[13.6.2.1~2,5~.0~4,9~.0~18,22~]tetracosa- l(22),2(24),4,ll,15,17,18,20,22-nonaen-6-one
Figure imgf000171_0001
Step 1 : A solution of N,2-dimethylprop-2-en-l -amine (Frontier Scientific, 440 mg, 5.17 mmol), (S)-7-allyl-2-(3-fluoro-2-methylquinoxalin-5-yl)-6,7-dihydro-lH-pyrrolo[3,2- c]pyridin-4(5H)-one (Intermediate D, 579 mg, 1.723 mmol), and DMSO (17.2 ml) was sealed under N2 and stirred at 85 °C for 3 h. The reaction was cooled to RT. The reaction was diluted with water and extracted with DCM (3x). The combined organics were washed with brine, dried over Na2S04, and filtered. The filtrate was concentrated in vacuo to a residue with spectral data consistent with the target diolefin product (680 mg, 98%): !H NMR (DMSO-dg) δ: 11.77 (br. s, 1H), 7.88 - 7.95 (1H, m) 7.60 - 7.67 (1H, m) 7.40 - 7.49 (1H, m) 7.05 - 7.11 (1H, m) 6.89 - 6.98 (1H, m) 5.76 - 5.88 (1H, m) 4.93 - 5.12 (4H, m) 3.95 - 4.01 (2H, m) 3.40 - 3.49 (1H, m) 3.12 - 3.21 (2H, m) 3.01 - 3.06 (4H, m), 2.61 - 2.67 (3H, m) 2.25 - 2.37 (1H, m) 1.69 (3H, s): m/z (ESI, +ve) 402.2 (M+H)+.
Step 2: (9S,1 lE)-12,14,16-trimethyl-3,7,14,17,23- pentaazapentacyclo[l 3.6.2.1~2,5~.0~4,9~.0~18,22~]tetracosa- 1 (22),2(24),4, 11 , 15, 17, 18,20,22-nonaen-6-one
A solution of Grubbs 2nd Generation Catalyst (Sigma Aldrich, 288 mg, 0.339 mmol), (S)- 7-allyl-2-(2-methyl-3-(methyl(2-methylallyl)amino)quinoxalin-5-yl)-6,7-dihydro-lH- pyrrolo[3,2-c]pyridin-4(5H)-one (680 mg, 1.694 mmol), and DCM (33.6 ml) was bubbled with argon for 3 min, and the reaction mixture was sealed and heated to 55 °C for 2 h. An additional 10 mol% catalyst was added, and the reaction was resealed and heated to 55 °C for 18 h. It was cooled to RT, and silica was added. The silica mixture was concentrated in vacuo, and the reaction was chromatography purified on silica gel (eluent: 0 to 5%
MeOH/DCM). The product fractions were combined and concentrated under reduced pressure. Addition of MeOH and sonication afforded the product as a solid that was collected by filtration. The filtrate was concentrated in vacuo and purified by reverse- phase preparative HPLC using a Phenomenex Gemini column, 10 μ, Ci8, 100 A, 150 x 30 mm, 0.1% TFA in ACN/water, gradient 10% to 95% over 10 min (8 x 500 μΐ, injections, compound elution at ~8 min). The fractions were concentrated in vacuo on a Genevac EZ-2 Evaporator at 55 °C. The fractions were solubilized in MeOH, and the free base was generated by allowing the compound to filter through a Silicycle Si-carbonate cartridge (pre-washed with 10 mL MeOH). The yellow filtrate was concentrated under reduced pressure to a yellow residue. The residue was taken up in DCM, combined with the solid collected by filtration, and concentrated under reduced pressure to a give (9S, 11 E)- 12, 14, 16-trimethyl-3,7, 14,17,23- pentaazapentacyclo[l 3.6.2. l~2,5~.0~4,9~.0~18,22~]tetracosa- l(22),2(24),4,l l,15,17,18,20,22-nonaen-6-one as a solid (105 mg, 17%). !H NMR (400 MHz, DMSO-i/e) δ ppm 12.98 - 13.03 (1 H, m) 8.00 - 8.05 (1 H, m) 7.55 - 7.61 (1 H, m) 7.35 - 7.41 (1 H, m) 7.03 - 7.08 (1 H, m) 6.91 - 6.95 (1 H, m) 5.73 - 5.79 (1 H, m) 4.25 - 4.33 (1 H, m) 4.08 - 4.18 (1 H, m) 3.41 (3 H, s) 3.14 - 3.26 (3 H, m) 2.73 (3 H, s) 2.31 - 2.43 (2 H, m) 1.68 (3 H, s): m/z (ESI, +ve) 374.1 (M+H)+.
Example 67: (9S,llE,13S)-13-(2-hydroxyethyl)-16-methyl-3,7,14,17,23- pentaazapentacyclo[13.6.2.1~2,5~.0~4,9~.0~18,22~]tetracosa- l(22),2(24),4,ll,15,17,18,20,22-nonaen-6-one
Example 68: (9S,llE,13R)-13-(2-hydroxyethyl)-16-methyl-3,7,14,17,23- pentaazapentacyclo[13.6.2.1~2,5~.0~4,9~.0~18,22~]tetracosa- l(22),2(24),4,ll,15,17,18,20,22-nonaen-6-one
Figure imgf000173_0001
Step 1 : (7S)-7-allyl-2-(3-((5-hydroxypent-l-en-3-yl)amino)-2-methylquinoxalin-5-yl)- 6,7-dihydro-lH-pyrrolo[3,2-c]pyridin-4(5H)-one
A suspension of DIPEA (EMD Biosciences, 1089 μΐ, 6.26 mmol), 3-aminopent-4-en-l -ol hydrochloride (Squarix Biotechnology, 431 mg, 3.13 mmol), and (S)-7-allyl-2-(3-fluoro- 2-methylquinoxalin-5-yl)-6,7-dihydro-lH-indol-4(5H)-one (Intermediate D, 420 mg, 1.252 mmol) in DMSO (8349 μΐ) was sealed and heated to 85 °C for 2 h. The reaction mixture was cooled, diluted with water and saturated aqueous NH4C1 and extracted with DCM (3x). The combined organics were dried over Na2S04, silica gel was added, and the mixture was concentrated in vacuo. The crude reaction was chromatographically purified on silica gel (eluent: 0.5 to 10% MeOH/DCM). The product fractions were combined and concentrated under reduced presssure to give (7S)-7-allyl-2-(3-((5-hydroxypent-l-en-3- yl)amino)-2-methylquinoxalin-5-yl)-6,7-dihydro-lH-pyrrolo[3,2-c]pyridin-4(5H)-one: !Η ΝΜΚ (400 MHz, DMSO-i/6) δ ppm 1 1.89 - 12.13 (1 H, m) 7.71 - 7.97 (1 H, m) 7.43 - 7.65 (1 H, m) 7.19 - 7.32 (1 H, m) 7.05 - 7.16 (1 H, m) 6.86 - 7.04 (3 H, m) 5.63 - 6.12 (2 H, m) 5.07 - 5.30 (4 H, m) 4.69 - 4.96 (2 H, m) 3.45 - 3.68 (3 H, m) 3.03 - 3.30 (4 H, m) 2.28 - 2.42 (1 H, m) 1.84 - 2.06 (2 H, m): m/z (ESI, +ve) 418.2 (M+H)+. Step 2: (9S,1 lE,13S)-13-(2-hydroxyethyl)-16-methyl-3,7,14,17,23- pentaazapentacyclo[l 3.6.2.1~2,5~.0~4,9~.0~18,22~]tetracosa-
1 (22),2(24),4, 11,15,17,18,20,22-nonaen-6-one and (9S, 11 E, 13R)- 13 -(2 -hydroxy ethyl)- 16-methyl-3,7,14,17,23-pentaazapentacyclo[l 3.6.2. l~2,5~.0~4,9~.0~18,22~]tetracosa- 1 (22),2(24),4, 11 , 15, 17, 18,20,22-nonaen-6-one
A solution of Grubbs 2nd Generation Catalyst (Sigma Aldrich, 252 mg, 0.297 mmol), (7S)-7-allyl-2-(3-((5-hydroxypent-l-en-3-yl)amino)-2-methylquinoxalin-5-yl)-6,7- dihydro-lH-pyrrolo[3,2-c]pyridin-4(5H)-one (620 mg, 1.485 mmol), and DCM (74.300 mL) was bubbled through with argon gas for 60 s. The reaction was sealed and stirred at 50 °C for 2 h. The reaction was cooled, silica gel was added, and the mixture was concentrated in vacuo. The crude reaction was purified on silica gel (eluent: 5 to 10% MeOH/DCM) to give a mixture of isomers. The isomers were further purified by SFC (AD-H Column, 5 μιη in width at 21x150 mm, P = 200 bar, T = 40 °C with 40% EtOH at 1 mL/min, solubilized in 1 : 1 DCM/MeOH), affording (9S,l lE,13S)-13-(2-hydroxyethyl)- 16-methyl-3,7,14,17,23-pentaazapentacyclo[l 3.6.2.1~2,5~.0~4,9~.0~18,22~]tetracosa- l(22),2(24),4,l l,15,17,18,20,22-nonaen-6-one (54 mg, 19%) as the first eluting peak and (9S, 11 E, 13R)-13-(2-hydroxyethyl)-l 6-methyl-3,7, 14, 17,23-pentaazapenta- cyclo[13.6.2.1~2,5~.0~4,9~.0~18,22~]tetracosa-l(22),2(24),4,l l,15,17,18,20,22-nonaen- 6-one (86 mg, 30%>) as the second eluting peak.
Analytical data for (9S,l lE,13S)-13-(2-hydroxyethyl)-16-methyl-3,7,14,17,23- pentaazapentacyclo[l 3.6.2. l~2,5~.0~4,9~.0~18,22~]tetracosa- l(22),2(24),4,l l,15,17,18,20,22-nonaen-6-one: ¾ NMR (DMSO-d6) δ: 13.63 - 13.67 (m, 1H), 7.98 - 8.03 (m, 1H), 7.54 - 7.59 (m, 1H), 7.32 - 7.38 (m, 2H), 7.03 - 7.07 (m, 1H), 6.90 - 6.93 (m, 1H), 5.86 - 6.07 (m, 2H), 5.28 - 5.32 (m, 1H), 4.30 - 4.39 (m, 1H), 3.70 - 3.86 (m, 2H), 3.24 - 3.31 (m, 1H), 3.08 - 3.21 (m, 1H), 2.57 - 2.70 (m, 2H), 2.57 (s, 3H), 2.19 - 2.27 (m, 1H), 2.04 - 2.16 (m, 1H), 1.75 - 1.84 (m, 1H): m/z (ESI, +ve) 390.2 (M+H)+.
Analytical data for 9S,1 lE,13R)-13-(2-hydroxyethyl)-16-methyl-3,7,14,17,23- pentaazapentacyclo[l 3.6.2. l~2,5~.0~4,9~.0~18,22~]tetracosa- l(22),2(24),4,l l,15,17,18,20,22-nonaen-6-one: !H NMR (400 MHz, DMSO-i/6) δ ppm 13.37 - 13.44 (1 H, m) 7.93 - 7.97 (1 H, m) 7.46 - 7.53 (2 H, m) 7.27 - 7.33 (1 H, m) 7.00 - 7.04 (1 H, m) 6.83 - 6.87 (1 H, m) 6.18 - 6.26 (1 H, m) 5.85 - 5.96 (1 H, m) 4.21 - 4.30 (1 H, m) 3.41 - 3.51 (2 H, m) 3.23 - 3.38 (2 H, m) 3.08 - 3.15 (1 H, m) 2.57 - 2.62 (1 H, m) 2.53 - 2.56 (3 H, m) 2.18 - 2.34 (2 H, m) 1.97 - 2.15 (1 H, m) 1.22 - 1.28 (1 H, m): m/z (ESI, +ve) 390.2 (M+H)+.
Example 69: (9S,llE)-21-fluoro-12,16-dimethyl-3,7,14,17,23- pentaazapentacyclo[13.6.2.1~2,5~.0~4,9~.0~18,22~]n tetracosa- l(22),2(24),4,ll,15,17,18,20,22-nonaen-6-one.
Figure imgf000175_0001
Step 1 : 8-bromo-7-fluoro-3-methyl-N-(2-methylallyl)quinoxalin-2 -amine
5-Bromo-3-chloro-6-fluoro-2-methylquinoxaline (Intermediate K, 674 mg, 2.45 mmol) and 2-methylallylamine (Matrix Scientific, Columbia, SC, 0.87 mL, 12.23 mmol) in DMSO (10 mL) was stirred at 100 °C for 4 h. The reaction mixture was treated with DCM (50 mL), and washed with saturated aqueous NaHCC (2 x 25 mL) and then with brine (1 x 25 mL). The organic layer was dried over MgS04, filtered and concentrated. The crude product was adsorbed onto silica gel and was purified using an ISCO
Combiflash Rf (40 g Thomson SingleStep column, using a gradient of 0-60% EtOAc in hexanes) affording 8-bromo-7-fluoro-3-methyl-N-(2-methylallyl)quinoxalin-2-amine (670 mg, 2.16 mmol, 88 % yield) as an orange crystalline solid. !H NMR (400 MHz, CDCl3) δ ppm 7.75 (1 H, br. s.), 7.17 (1 H, t, J=8.5 Hz), 5.06 (1 H, br. s.), 5.02 (1 H, br. s.), 4.94 (1 H, br. s.), 4.30 (2 H, br. s.), 2.58 (3 H, br. s.), 1.88 (3 H, br. s.), 1.54 (2 H, br. s.). 19F NMR (377 MHz, CDCl3) δ ppm -103.10 (1 F, s). m/z (ESI, +ve ion) 310.0/312.0 (M+H)+.
Step 2 : (.S)-7-allyl-2-(6-fluoro-2-methyl-3-((2-methylallyl)amino)quinoxalin-5-yl)-6,7- dihydro-lH-pyrrolo[3,2-c]pyridin-4(5H)-one
A glass microwave tube was charged with (5)-7-allyl-2-(4,4,5,5-tetramethyl-l ,3,2- dioxaborolan-2-yl)-6,7-dihydro-lH-pyrrolo[3,2-c]pyridin-4(5H)-one (Intermediate L, 1 17 mg, 0.387 mmol), K3P04 (Aldrich , 246 mg, 1.161 mmol), Pd2(dba)3 (Strem Chemicals, 17.71 mg, 0.019 mmol), XPhos (Strem Chemicals, 18.44 mg, 0.039 mmol) and 8-bromo- 7-fluoro-3-methyl-N-(2-methylallyl)quinoxalin-2-amine (120 mg, 0.387 mmol) in 1 ,4- dioxane (3.0 mL) and water (1.1 mL). The reaction was stirred and heated in a heating block at 1 10 °C for 1 h. The mixture was treated with water and extracted with EtOAc (2 x 25 mL), washed with brine and concentrated. The residue was purified on the Gilson (Silicycle Silichrome XT Ci8 column; 30 x 150 mm, 5 μ, 20-95% 0.1%TFA/CH3CN in 0.1 %TFA/water) affording (5)-7-allyl-2-(6-fluoro-2-methyl-3-((2- methylallyl)amino)quinoxalin-5-yl)-6,7-dihydro-lH-pyrrolo[3,2-c]pyridin-4(5H)-one 2,2,2-trifluoroacetate (36.3 mg, 0.070 mmol, 18.06 % yield) as a yellow-orange amorphous solid after drying in the genevac overnight: !H NMR (400 MHz, MeOD) δ ppm 7.62 (1 H, br. s.), 7.23 (1 H, t, J=10.2 Hz), 7.17 (1 H, br. s.), 5.81 - 5.96 (1 H, m), 5.10 - 5.20 (2 H, m), 4.98 (2 H, d, J=16.6 Hz), 4.10 - 4.24 (2 H, m), 3.69 (1 H, d, J=12.3 Hz), 3.46 (1 H, d, J=13.1 Hz), 3.09 (1 H, br. s.), 2.60 (3 H, br. s.), 2.54 (1 H, d, J=13.9 Hz), 2.36 - 2.48 (1 H, m), 1.91 (3 H, br. s.). m/z (ESI, +ve ion) 406.1 (M+H)+. The material was treated with DCM and washed with a saturated solution of NaHCC to provide the free-base for submission to the subsequent step.
Step 3 : (.S)-7-allyl-2-(6-fluoro-2-methyl-3-((2-methylallyl)amino)quinoxalin-5-yl)-6,7- dihydro-lH-pyrrolo[3,2-c]pyridin-4(5H)-one (30.9 mg, 0.076 mmol) and Grubbs Second Generation RCM catalyst (Aldrich, 12.9 mg, 0.015 mmol) were combined under argon and treated with DCM (5.0 mL). The reaction vessel was fitted with a water-cooled reflux condenser, and the reaction was heated to reflux for 1 h. The reaction mixture was concentrated and the crude residue taken up in DM SO (4 mL) and purified on the Gilson (Silicycle Silichrome XT Ci8 column; 30 x 150 mm, 5 μ, 20-95% 0.1%TFA/CH3CN in 0.1 %>TFA/water) affording the title compound (29.5 mg, 0.049 mmol, 63.9 % yield) as its bis(TFA) salt as a rust-colored amorphous solid after drying in the genevac overnight: !H
NMR (400 MHz, MeOD) δ ppm 13.48 (1 H, br. s.), 7.52 (1 H, dd, J=9.0, 5.7 Hz), 7.15 - 7.24 (2 H, m), 5.80 (1 H, d, J=9.8 Hz), 4.15 - 4.23 (1 H, m), 4.04 - 4.13 (1 H, m), 3.55 (1 H, d, J=5.9 Hz), 2.59 (3 H, s), 2.41 - 2.55 (2 H, m), 2.33 - 2.40 (1 H, m), 1.69 (3 H, s). 19F NMR (376 MHz, MeOD) δ ppm -77.64 (6 F, s), -108.4 (1 F, s). m/z (ESI, +ve ion) 378.0 (M+H)+. Example 70: (9S,llZ,13S)-20-methyl-15-oxa-3,7,18,21,27- pentaazahexacyclo[17.6.2.1~2,5~.0~4,9~.0~13,18~.0~22,26~]octacosa- l(26),2(28),4,ll,19(27),20,22,24-octaen-6-one
Example 71: (9S,llE,13S)-20-methyl-15-oxa-3,7,18,21,27- pentaazahexacyclo[17.6.2.1~2,5~.0~4,9~.0~13,18~.0~22,26~]octacosa- l(26),2(28),4,ll,19(27),20,22,24-octaen-6-one
Figure imgf000177_0001
TFA (Aldrich, 0.883 ml, 11.89 mmol) was added to a stirring solution of (S)-tert-butyl 3- vinylmorpholine-4-carboxylate (Synthesized from (R)-4-tert-butyl 3-methyl morpholine- 3,4-dicarboxylate (Acesys Pharmatech, North Brunswick, NJ) according to
WO05080386; 0.469 g, 2.200 mmol) in 2 mL DCM at RT. After 1 h, the reaction was concentrated. The material was combined with (S)-7-allyl-2-(3-fluoro-2- methylquinoxalin-5-yl)-6,7-dihydro-lH-pyrrolo[3,2-c]pyridin-4(5H)-one (Intermediate D; 0.200 g, 0.595 mmol) and DIPEA (Aldrich; 0.827 ml, 4.76 mmol) in 2 mL DMSO, was sealed, and heated to 70 °C for 36 h. The reaction was partitioned between saturated aqueous NaHCC and EtOAc. The organic layer was washed with brine once, and the organics were dried over anhydrous Na2S04, filtered, and concentrated in vacuo. The material was treated with DCM and purified by silica gel chromatography (24 g) using 0 - 100 % 90/10 DCM/MeOH. The product containing fractions were concentrated in vacuo to give 0.236 g of an orange foam. This material was combined with Grubbs catalyst, 2nd generation (Aldrich; 0.233 g, 0.275 mmol) and 27 mL DCM, and argon was bubbled through the solution for 1 min. The reaction was sealed and heated to 50 °C for 1 h. 1 mL MeOH was added followed by 2 g silica gel and the mixture was concentrated in vacuo. The material was purified by silica gel chromatography (24 g) using 0 - 100% 90/10 DCM/MeOH in DCM. The product-containing fractions were concentrated to give 0.091 g. This was further purified by chiral SFC (Column: Chiralcel OD-H (Sepax) (250 x 21 mm, 5 μ); Mobile Phase: 50:50 (A:B); A: Liquid C02, B: MeOH (20 mM NH3); Flow Rate: 55 mL/min; Oven Temp: 40 °C; Inlet Pressure: 206 bar) to give:
(9S,1 1Z, 13 S)-20-methyl- 15-oxa-3,7, 18,21 ,27-pentaazahexa- cyclo[17.6.2.1~2,5~.0~4,9~.0~13,18~.0~22,26~]octacosa- l(26),2(28),4,l l,19(27),20,22,24-octaen-6-one (Example 70, first eluting peak; 0.01 1 g, 0.027 mmol, 4.5 % yield) as a yellow solid: !H NMR (400 MHz, DMSO-d6) δ ppm 13.02 (1 H, br. s.), 7.97 (1 H, dd, J=7.4, 1.2 Hz), 7.69 (1 H, dd, J=8.1 , 1.1 Hz), 7.49 - 7.61 (1 H, m), 7.03 (1 H, d, J=4.3 Hz), 6.82 (1 H, d, J=2.0 Hz), 5.97 - 6.09 (1 H, m), 5.85 - 5.97 (1 H, m), 4.57 - 4.70 (1 H, m), 3.76 - 3.97 (3 H, m), 3.56 - 3.69 (2 H, m), 3.42 - 3.51 (1 H, m), 3.35 - 3.42 (1 H, m), 3.15 - 3.28 (2 H, m), 2.72 (3 H, s), 2.62 - 2.71 (1 H, m), 2.34 - 2.43 (1 H, m). m/z (ESI, +ve) 402.2 (M+H)+.
(9S,1 IE, 13 S)-20-methyl- 15-oxa-3,7, 18,21 ,27-pentaazahexa- cyclo[17.6.2.1~2,5~.0~4,9~.0~13,18~.0~22,26~]octacosa- 1(26),2(28),4,1 l,19(27),20,22,24-octaen-6-one (Example 71, second eluting peak; 0.070 g, 0.174 mmol, 29.2 % yield) as a yellow solid: !H NMR (400 MHz, DMSO-d6) δ ppm 11.37 (1 H, br. s.), 7.83 (1 H, d, J=7.2 Hz), 7.72 (1 H, d, J=7.2 Hz), 7.50 - 7.59 (1 H, m), 6.99 (1 H, d, J=3.9 Hz), 6.60 (1 H, s), 6.40 (1 H, dd, J=15.6, 6.3 Hz), 5.68 (1 H, t, J=11.2 Hz), 3.97 (1 H, br. s.), 3.73 - 3.88 (3 H, m), 3.66 (1 H, dd, J=l l . l , 5.2 Hz), 3.49 - 3.61 (1 H, m), 3.34 - 3.42 (3 H, m), 3.22 - 3.30 (1 H, m), 2.79 - 2.93 (1 H, m), 2.67 (3 H, s), 2.28 - 2.39 (1 H, m). m/z (ESI, +ve) 402.2 (M+H)+.
Example 72: 16-methyl-3,7,14,17,23- pentaazapentacyclo[13.6.2.1~2,5~.0~4,9~.0~18,22~]tetracosa- l(22),2(24),4,15(23),16,18,20-heptaen-ll-yn-6-one
Figure imgf000178_0001
Step 1 : tert-butyl (4-chlorobut-2-yn-l -yl)carbamate To a stirring solution of l -amino-4-chloro-2-butyne hydrochloride (Aldrich; 5.00 g, 35.7 mmol) in 125 mL 5 : 1 H20/MeOH was added di-tert-butyl dicarbonate (Aldrich; 8.57 g, 39.3 mmol) and NaOH 10.0 N (Ricca Chemical; 4.29 ml, 42.9 mmol). After 3 h, the reaction was extracted 3 x DCM, and the combined organics were dried over Na2S04, filtered, and concentrated in vacuo. The material was treated with DCM and purified by silica gel chromatography (160 g column) using 0 - 100% DCM/hexane. The product- containing fractions were concentrated to afford tert-butyl (4-chlorobut-2-yn-l- yl)carbamate (3.7 g, 18.17 mmol, 50.9 % yield) as a clear/colorless oil: 'H NMR (400 MHz, CDCh) δ ppm 4.69 (1 H, br. s.), 4.14 (2 H, t, J=2.1 Hz), 3.99 (2 H, br. s.), 1.48 (9 H, br. s.).
Step 2: tert-butyl 5-(4-((tert-butoxycarbonyl)amino)but-2-yn-l-yl)-2,4-dioxopiperidine-l - carboxylate
A solution of tert-butyl (4-chlorobut-2-yn-l-yl)carbamate (0.764 g, 3.75 mmol) and tert- butyl 2,4-dioxopiperidine-l-carboxylate (0.200 g, 0.938 mmol) in 9 mL THF under N2 was cooled in an ice/salt bath (-18 °C). LiHMDS solution 1.0 M in THF (3.28 ml, 3.28 mmol) was added slowly dropwise. A thick precipitate formed, which disappeared upon complete addition of LiHMDS. After 1 h, additional 2 mL LiHMDS 1.0 M in THF was added. After 30 min additional 2 mL LiHMDS 1.0 M in THF was added. After 30 min, the reaction was treated with water and EtOAc, and 5 N HC1 was added to acidify the aqueous layer. The layers were separated, and organic layer was washed lx brine, dried over Na2S04, filtered, and concentrated in vacuo. The material was treated with DCM and purified by silica gel chromatography (24 g) using 0 - 100% EtOAc/hexane. The product- containing fractions were concentrated to afford tert-butyl 5-(4-((tert- butoxycarbonyl)amino)but-2-yn-l -yl)-2,4-dioxopiperidine-l -carboxylate (0.245 g, 0.644 mmol, 68.7 % yield) as a glass: !H NMR (400 MHz, DMSO-d6) δ ppm 11.33 (1 H, br. s.), 7.14 (1 H, br. s.), 4.94 (1 H, s), 3.79 (2 H, d, J=4.7 Hz), 3.69 (2 H, br. s.), 2.50 - 2.70 (2 H, m), 2.19 - 2.43 (1 H, m), 1.44 (9 H, s), 1.37 (9 H, s). Step 3: 16-methyl-3,7,14,17,23- pentaazapentacyclo[l 3.6.2.1~2,5~.0~4,9~.0~18,22~]tetracosa- 1 (22),2(24),4, 15 (23), 16, 18,20-heptaen- 1 1 -yn-6-one
TFA (Aldrich; 0.957 ml, 12.88 mmol) was added to a solution of tert-butyl 5-(4-((tert- butoxycarbonyl)amino)but-2-yn-l -yl)-2,4-dioxopiperidine-l -carboxylate (0.245 g, 0.644 mmol) in 6 mL DCM. The reaction was fitted with a drying tube and stirred rapidly at RT for 1.5 h. The reaction was concentrated in vacuo to give an orange oil. This material was treated with NH4OAc (Fisher, 0.298 g, 3.86 mmol), 2-bromo-l-(3-fluoro-2- methylquinoxalin-5-yl)ethanone (0.182 g, 0.644 mmol), and 6 mL EtOH. The homogeneous reaction was sealed and heated at 50 °C for 4 h. A precipitate had formed. The reaction was cooled and treated with 3 : 1 chloroform/IPA and MeOH, and stirred rapidly for 30 min. The layers were separated and the aqueous layer was extracted 3 x DCM/IPA. The combined organic layers were dried over anhydrous Na2S04, filtered, and concentrated in vacuo. The material was treated with 10% MeOH in DCM and adsorbed onto 1 g silica gel and purified by silica gel chromatography (24 g) using 0 -
100% 90/10 DCM/MeOH in DCM. The product- containing fractions were concentrated to afford 0.020 g material. This was sonicated in MeOH, filtered, rinsing with MeOH, and the solid was collected and dried in vacuo to give 16-methyl-3,7, 14,17,23- pentaazapentacyclo[l 3.6.2. l~2,5~.0~4,9~.0~18,22~]tetracosa- l(22),2(24),4,15(23),16,18,20-heptaen-l l -yn-6-one (0.013 g, 0.038 mmol, 5.88 % yield): !H NMR (400 MHz, DMSO-d6) δ ppm 7.97 - 8.06 (1 H, m), 7.53 - 7.63 (2 H, m), 7.38 (1 H, t, J=7.8 Hz), 7.03 (1 H, d, J=3.9 Hz), 6.94 (1 H, d, J=2.2 Hz), 4.23 - 4.32 (1 H, m), 4.10 - 4.18 (1 H, m), 3.33 - 3.46 (2 H, m), 3.00 - 3.13 (1 H, m), 2.59 - 2.72 (1 H, m), 2.54 (3 H, s), 2.31 - 2.46 (1 H, m). m/z (ESI, +ve) 344.1 (M+H)+.
Example 73: 17-methyl-12-oxa-3,7,15,18,24- pentaazapentacyclo[14.6.2.1~2,5~.0~4,9~.0~19,23~]pent
l(22),2(25),4,16,18,20,23-heptaen-6-one
Figure imgf000180_0001
Step 1 : tert-butyl 5-(2-(2-bromoethoxy)ethyl)-2,4-dioxopiperidine-l -carboxylate To a solution of tert-butyl 2,4-dioxopiperidine-l-carboxylate (Ark Pharma, Libertyville, IL, 1.32 g, 6.19 mmol) and bis(2-bromoethyl) ether (Sigma-Aldrich , 5.74 g, 24.76 mmol) in 30 mL of THF at -25 to -20 °C was added LiHMDS (15.48 mL of 1.0 M in THF, 15.48 mmol) slowly such that the internal temperature did not exceed -20 °C. The clear yellow reaction mixture was stirred for 1 h (final temperature at -20 °C) and was quenched by the addition of 20 mL of ice cold 0.5 N HCl, and extracted with 2X75 mL of EtOAc. The combined organic solution was washed with brine, dried over Na2S04 and concentrated. The residue of was purified on a silica gel column (20-65% EtOAc in hexanes) to give tert-butyl 5-(2-(2-bromoethoxy)ethyl)-2,4-dioxopiperidine-l -carboxylate (750 mg, 33 % yield) as an amorphous solid: !H NMR (400 MHz, DMSO-d6) δ ppm 11.16 (1 H, br. s), 4.85 (1 H, s), 3.97-3.63 (4 H, m), 3.52-3.42 (5 H, m), 1.55 (1 H, m), 1.53 (1 H, m), 1.36 (9 H, s). m/z (ESI, +ve) 386/388 (M+Na)+.
Step 2: 5-(2-(2-azidoethoxy)ethyl)piperidine-2,4-dione
A mixture of tert-butyl 5-(2-(2-bromoethoxy)ethyl)-2,4-dioxopiperidine-l-carboxylate
(750 mg, 2.05 mmol) and sodium azide (268 mg, 4.12 mmol) in 4 mL of DMF was stirred at RT for 18 h. Additional 134 mg of sodium azide was added to the reaction mixture and stirring was continued for 18 h. The reaction mixture was filtered through a pad of Celite and rinsed with 2X15 mL of EtOAc. The filtrate was washed with 10 mL of water. The water layer was extracted with 2X25 mL of EtOAc. The combined organic extracts were concentrated and the residue was purified on a silica gel column (30-50% EtOAc in hexanes) to give tert-butyl 5-(2-(2-azidoethoxy)ethyl)-2,4-dioxopiperidine-l-carboxylate (430 mg) as a viscous clear oil: m/z (ESI, +ve) 349.1 (M+Na)+. A solution of tert-butyl 5- (2-(2-azidoethoxy)ethyl)-2,4-dioxopiperidine-l -carboxylate (430 mg, 1.31 mmol) in 5 mL of DCM at RT was treated with 0.5 mL of TFA and stirred for 1 h. It was concentrated under reduced pressure and the residue was dissolved in 50 mL of DCM and vigorously stirred with 15 g of NaHC03 for 15 min. It was filtered and rinsed with 2X10 mL of DCM. The filtrate was concentrated to give 5-(2-(2-azidoethoxy)ethyl)piperidine- 2,4-dione (300 mg, 64% yield) as a brown oil, which was used in next step without further purification: m/z (ESI, +ve) 227.0 (M+H)+.
Step 3 : 7-(2-(2-azidoethoxy)ethyl)-2-(3-fluoro-2-methylquinoxalin-5-yl)-6,7-dihydro-lH- pyrrolo [3 ,2 -c]pyridin-4(5 H)-one A mixture of 2-bromo-l -(3-fluoro-2-methylquinoxalin-5-yl)ethanone (313 mg, 1.10 mmol), 5-(2-(2-azidoethoxy)ethyl)piperidine-2,4-dione (300 mg, 1.32 mmol), and NH4OAc (51 1 mg, 6.63 mmol) in 10 mL EtOH in a sealed glass tube was heated in an oil bath at 50 °C for 4 h. The reaction was concentrated to 1/4 of its volume; then partitioned between saturated NaHCC>3 (15 mL) and CH2CI2 (15 mL). The aqueous layer was extracted with 3X10 mL of CH2CI2, and the combined organics were dried over anhydrous Na2S04, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (50% EtOAc in DCM followed by 2-10% MeOH in DCM) to give 7- (2-(2-azidoethoxy)ethyl)-2-(3-fluoro-2-methylquinoxalin-5-yl)-6,7-dihydro-lH- pyrrolo[3,2-c]pyridin-4(5H)-one (134 mg, 29%> yield) as a brown amorphous solid: !H
NMR (400 MHz, DMSO-d6) δ ppm 11.56 (1 H, br. s), 8.10 (1 H, d, J=7.4 Hz), 7.92 (1 H, d, J=8.2 Hz), 7.82 (1 H, t, J=7.8 Hz), 7.19 (1 H, d, J=2.2 Hz), 7.02 (1 H, br.), 3.51 - 3.70 (5 H, m), 3.44 (2 H, m), 3.26 (1 H, m), 3.14 (1 H, m), 2.72 (3 H, s), 2.09 (1 H, m), 1.80 (1 H, m). m/z (ESI, +ve) 410.1 (M+H)+.
Step 4: 17-methyl-12-oxa-3,7,15, 18,24- pentaazapentacyclo[l 4.6.2. l~2,5~.0~4,9~.0~19,23~]pentacosa- l(22),2(25),4,16,18,20,23-heptaen-6-one
A mixture of 7-(2-(2-azidoethoxy)ethyl)-2-(3-fluoro-2-methylquinoxalin-5-yl)-6,7- dihydro-lH-pyrrolo[3,2-c]pyridin-4(5H)-one (100 mg, 0.244 mmol) and palladium on activated carbon (10% wt, 26.0 mg, 0.024 mmol) in 7.5 mL of THF and 0.5 mL of EtOH was hydrogenated with a balloon filled with H2 for 18 h. Additional palladium on activated carbon (10% wt, 26.0 mg, 0.024 mmol) was added to the reaction mixture and hydrogenation with a balloon filled with H2 was continued for 18 h. It was filtered through a pad of Celite and rinsed with 10 mL of EtOAc followed by 10 mL of EtOH.
The filtrate was concentrated and the residue was purified on a silica gel column (1 -5% DCM in MeOH) to give 17-methyl-12-oxa-3,7,15,18,24- pentaazapentacyclo[l 4.6.2. l~2,5~.0~4,9~.0~19,23~]pentacosa- l(22),2(25),4,16,18,20,23-heptaen-6-one (34 mg, 38 %> yield) as a yellow crystalline solid: !H NMR (400 MHz, DMSO-d6) δ ppm 12.72 (1 H, br.), 7.96 (1 H, dd, J=7.6, 1.2
Hz), 7.60 (1 H, m), 7.57 (1 H, m), 7.34 (1 H, t, J=7.8 Hz), 6.95 (1 H, m), 3.78 (2 H, m), 3.65 (3 H, m), 3.38 - 3.56 (3 H, m), 3.05 - 3.28 (2 H, m), 2.57 (3 H, s), 1.71 (2 H, m). m/z (ESI, +ve) 364.1 (M+H)+. Example 74: (9S,llE)-16-methyl-14-(3-(methylsulfonyl)propyl)-3,7,14,17,23- pentaazapentacyclo[13.6.2.1~2,5~.0~4,9~.0~18,22~]tetracosa- l(22),2(24),4,ll,15(23),16,18,20-octaen-6-one
Example 75: (9S,llZ)-16-methyl-14-(3-(methylsulfonyl)propyl)-3,7,14,17,23- pentaazapentacyclo[13.6.2.1~2,5~.0~4,9~.0~18,22~]tetracosa- l(22),2(24),4,ll,15(23),16,18,20-octaen-6-one
Figure imgf000183_0001
Step 1 : N-(3-(methylsulfonyl)propyl)prop-2-en-l-amine
A solution of l-bromo-3-(methylsulfonyl)propane (0.355 g, 1.765 mmol)/l -chloro-3- (methylsulfonyl)propane (WO09021965, 0.277 g, 1.765 mmol) in allylamine (2.65 ml, 35.3 mmol) was stirred at RT for 16 h. The crude product was directly injected onto the column and was purified via automated flash chromatography (silica gel) with 100% DCM to 5% 2 M NH3 in MeOH/DCM to give A^-(3-(methylsulfonyl)propyl)prop-2-en-l- amine (0.219 g, 1.235 mmol, 70.0 % yield) as a pale yellow oil: !H NMR (400 MHz, CDCl3) δ ppm 1.56 (br. s., 1 H) 1.88 (tt, =14.28, 7.43 Hz, 2 H) 2.64 (t, J=6.75 Hz, 2 H) 2.81 (s, 3 H) 3.03 (t, J=7.63 Hz, 2 H) 3.12 (d, J=5.87 Hz, 2 H) 4.98 (d, J=10.17 Hz, 1 H) 5.06 (d, J=17.21 Hz, 1 H) 5.75 (ddt, J=16.87, 10.61, 5.82, 5.82 Hz, 1 H). MS (ESI, pos. ion) m/z: 178.2 (M+H)+.
Step 2: (S)-7-allyl-2-(3-(allyl(3-(methylsulfonyl)propyl)amino)-2-methylquinoxalin-5- yl)-6,7-dihydro-lH-pyrrolo[3,2-c]pyridin-4(5H)-one
A solution of (S)-7-allyl-2-(3-fluoro-2-methylquinoxalin-5-yl)-6,7-dihydro-lH- pyrrolo[3,2-c]pyridin-4(5H)-one (Intermediate D, 163 mg, 0.485 mmol) and N-(3- (methylsulfonyl)propyl)prop-2-en-l -amine (172 mg, 0.969 mmol) in DMSO (4846 μΐ) was stirred at 70 °C for 16 h. The reaction mixture was diluted with DCM (100 ml), added to a separatory funnel, and washed with saturated aqueous NaHC03 (2 x 100 ml) before the organic layer was separated, dried over Na2S04, and concentrated. The crude product was adsorbed onto silica and was purified via automated flash chromatography (silica gel) with 100% hexanes/EtOAc (2: 1) to 30% EtOH/[hexanes/EtOAc (2: 1)] to give (S)-7-allyl-2-(3-(allyl(3-(methylsulfonyl)propyl)amino)-2-methylquinoxalin-5-yl)-6,7- dihydro-lH-pyrrolo[3,2-c]pyridin-4(5H)-one (180 mg, 0.365 mmol, 75 % yield) as a yellow solid: !H NMR (400 MHz, CDCl3) δ ppm 2.21 (quin, J=7.38 Hz, 2 H) 2.42 - 2.52 (m, 1 H) 2.54 - 2.60 (m, 1 H) 2.76 (s, 3 H) 2.86 (s, 3 H) 3.04 - 3.10 (m, 2 H) 3.10 - 3.16
(m, 1 H) 3.42 (ddd, J=12.18, 5.72, 3.23 Hz, 1 H) 3.56 - 3.66 (m, 1 H) 3.66 - 3.76 (m, 2 H) 4.04 (d, J=6.06 Hz, 2 H) 5.13 - 5.22 (m, 2 H) 5.32 - 5.42 (m, 3 H) 5.81 - 6.01 (m, 2 H) 7.19 (d, J=2.15 Hz, 1 H) 7.56 (t, J=7.82 Hz, 1 H) 7.77 (dd, J=8.22, 1.17 Hz, 1 H) 7.96 (dd, J=7.63, 1.17 Hz, 1 H) 1 1.58 (br. s., 1 H). MS (ESI, pos. ion) m/z: 494.4 (M+H)+.
Step 3 : A solution of (S)-7-allyl-2-(3-(allyl(3-(methylsulfonyl)propyl)amino)-2- methylquinoxalin-5-yl)-6,7-dihydro-lH-pyrrolo[3,2-c]pyridin-4(5H)-one (0.180 g, 0.365 mmol) and Grubbs catalyst 2nd generation (0.062 g, 0.073 mmol) in DCM (18.23 ml) was sparged with N2 before it was heated to 50 °C for 2 h. The crude product was adsorbed onto silica and was purified via automated flash chromatography (silica gel) with 100% DCM to 6% 2 M NH3 in MeOH/DCM to give a mixture of products (131 mg, 0.281 mmol, 77 % yield) as a ~2: 1 mixture of isomers via NMR as a yellow solid. MS (ESI, pos. ion) m/z: 466.2 (M+H)+. The material was further purified by SFC:
Column: AS-H (5 μιη, 21 mm x 250 mm, S/N = 5172), F = 50 ml/min, 50% MeOH 20 mM NH3/CO2. All sample dissolved in 12 ml MeOH/DCM 1/1 P = 206 bar, 1.1 ml injection, 290 nm, to give (9S,l lE)-16-methyl-14-(3-(methylsulfonyl)propyl)- 3,7,14, 17,23-pentaazapentacyclo[l 3.6.2.1~2,5~.0~4,9~.0~18,22~]tetracosa- l(22),2(24),4,l l,15(23),16,18,20-octaen-6-one (first eluting peak, 46 mg, 0.10 mmol, 35%) and (9S,1 lZ)-16-methyl-14-(3-(methylsulfonyl)propyl)-3,7,14,17,23- pentaazapentacyclo[l 3.6.2. l~2,5~.0~4,9~.0~18,22~]tetracosa- l(22),2(24),4,l l,15(23),16,18,20-octaen-6-one (second eluting peak, 58 mg, 0.13 mmol, 44%).
Analytical data for (9S,l lE)-16-methyl-14-(3-(methylsulfonyl)propyl)-3,7,14,17,23- pentaazapentacyclo[l 3.6.2.1~2,5~.0~4,9~.0~18,22~]tetracosa- l(22),2(24),4,l l,15(23),16,18,20-octaen-6-one: ¾ NM (400 MHz, CDCh) δ ppm 2.31 - 2.47 (m, 3 H) 2.65 (d, J=13.89 Hz, 1 H) 2.74 (s, 3 H) 2.98 (s, 3 H) 3.12 (t, J=7.92 Hz, 2 H) 3.36 - 3.52 (m, 4 H) 3.54 - 3.64 (m, 1 H) 4.15 - 4.32 (m, 2 H) 5.31 (d, J=3.52 Hz, 1 H) 5.96 (dd, J=14.67, 1 1.74 Hz, 1 H) 6.22 (dd, J=15.65, 6.65 Hz, 1 H) 7.11 (d, J=1.96 Hz, 1 H) 7.53 (t, J=7.82 Hz, 1 H) 7.71 (d, J=7.43 Hz, 1 H) 8.00 (d, J=7.43 Hz, 1 H) 13.13 (br. s., 1 H). MS (ESI, pos. ion) m/z: 466.2 (M+H)+.
Analytical data for (9S,l lZ)-16-methyl-14-(3-(methylsulfonyl)propyl)-3,7,14,17,23- pentaazapentacyclo[l 3.6.2. l~2,5~.0~4,9~.0~18,22~]tetracosa- l(22),2(24),4,l l,15(23),16,18,20-octaen-6-one: !H NMR (400 MHz, CDCh) δ ppm 2.17 - 2.29 (m, 1 H) 2.32 (d, J=14.87 Hz, 1 H) 2.40 (dt, J=14.82, 7.36 Hz, 1 H) 2.68 - 2.80 (m, 1 H) 2.81 (s, 3 H) 2.95 (s, 3 H) 3.06 (t, J=7.34 Hz, 2 H) 3.30 - 3.42 (m, 1 H) 3.42 - 3.52 (m, 2 H) 3.65 - 3.78 (m, 3 H) 4.84 (dd, J=16.53, 8.90 Hz, 1 H) 5.26 (d, J=3.13 Hz, 1 H) 5.74 (dd, J=10.76, 9.00 Hz, 1 H) 5.83 (dd, J=12.52, 11.54 Hz, 1 H) 6.99 (d, J=2.35 Hz, 1 H) 7.51 (t, J=8.02 Hz, 1 H) 7.72 (dd, J=8.12, 1.08 Hz, 1 H) 7.88 (dd, J=7.24, 1.17 Hz, 1 H) 12.77 (br. s., 1 H). MS (ESI, pos. ion) m/z: 466.2 (M+H)+.
Example 76: (9S,HE)-14-(2-hydroxyethyl)-16-methyl-3,7,14,17,23- pentaazapentacyclo[13.6.2.1~2,5~.0~4,9~.0~18,22~]tetracosa- l(22),2(24),4,ll,15(23),16,18,20-octaen-6-one
Example 77: (9S,HZ)-14-(2-hydroxyethyl)-16-methyl-3,7,14,17,23- pentaazapentacyclo[13.6.2.1~2,5~.0~4,9~.0~18,22~]tetracosa- l(22),2(24),4,ll,15(23),16,18,20-octaen-6-one
Figure imgf000185_0001
Step 1 : (S)-7-allyl-2-(3-(allyl(2-hydroxyethyl)amino)-2-methylquinoxalin-5-yl)-6,7- dihydro-lH-pyrrolo[3,2-c]pyridin-4(5H)-one
A solution of (S)-7-allyl-2-(3-fluoro-2-methylquinoxalin-5-yl)-6,7-dihydro-lH- pyrrolo[3,2-c]pyridin-4(5H)-one (Intermediate D, 230 mg, 0.684 mmol) and 2- (allylamino)ethanol (Ryan Scientific, Mt. Pleasant, SC, 207 mg, 2.051 mmol) in DMSO (6838 μΐ) was stirred at 70 °C for 24 h. The reaction mixture was diluted with DCM (150 ml), added to a separatory funnel, and washed with saturated aqueous NaHC03 (3 x 100 ml) before the organic layer was separated, dried over Na2S04, and concentrated. The crude product was adsorbed onto silica and was purified via automated flash
chromatography (silica gel) with 100% DCM to 6% 2 M NH3 in MeOH/DCM to give (S)- 7-allyl-2-(3-(allyl(2-hydroxyethyl)amino)-2-methylquinoxalin-5-yl)-6,7-dihydro-lH- pyrrolo[3,2-c]pyridin-4(5H)-one (264 mg, 0.632 mmol, 92 % yield) as a yellow foam: !H NMR (400 MHz, CDCh) δ ppm 2.36 - 2.47 (m, 1 H) 2.51 - 2.59 (m, 1 H) 2.67 (t, .7=5.18 Hz, 1 H) 2.75 (s, 3 H) 3.02 - 3.10 (m, 1 H) 3.30 - 3.37 (m, 1 H) 3.60 - 3.69 (m, 1 H) 3.69 - 3.75 (m, 1 H) 3.75 - 3.83 (m, 1 H) 3.93 (q, J=5.67 Hz, 2 H) 4.12 (d, J=5.48 Hz, 2 H) 5.10 (s, 1 H) 5.14 (d, J=6.46 Hz, 1 H) 5.31 - 5.42 (m, 3 H) 5.76 - 5.89 (m, 1 H) 5.92 - 6.04 (m, 1 H) 7.10 (d, J=2.15 Hz, 1 H) 7.46 (t, J=7.82 Hz, 1 H) 7.70 (dd, J=8.02, 0.98 Hz, 1 H) 7.88 (dd, J=7.53, 1.08 Hz, 1 H) 11.86 (br. s., 1 H). MS (ESI, pos. ion) m/z: 418.4 (M+H)+. Step 2: (9S,1 lE)-14-(2-hydroxyethyl)-16-methyl-3,7,14,17,23- pentaazapentacyclo[l 3.6.2.1~2,5~.0~4,9~.0~18,22~]tetracosa- 1 (22),2(24),4, 11 , 15 (23), 16, 18,20-octaen-6-one and (9S, 11 Z)- 14-(2-hydroxy ethyl)- 16- methyl-3,7,14,17,23-pentaazapentacyclo[l 3.6.2. l~2,5~.0~4,9~.0~18,22~]tetracosa- 1 (22),2(24),4, 11 , 15(23), 16, 18,20-octaen-6-one
A solution of (S)-7-allyl-2-(3-(allyl(2-hydroxyethyl)amino)-2-methylquinoxalin-5-yl)- 6,7-dihydro-lH-pyrrolo[3,2-c]pyridin-4(5H)-one (0.264 g, 0.632 mmol) (sonicated to dissolve in DCM) and Grubbs catalyst 2nd generation (0.107 g, 0.126 mmol) in DCM (31.6 ml) was stirred at 40 °C in a sealed flask for 2 h. The crude product was adsorbed onto silica and was purified via automated flash chromatography (silica gel) with 100% DCM to 6% 2 M NH3 in MeOH/DCM to give a mixture of E and Z isomers (188 mg,
0.483 mmol, 76 % yield) as a yellow solid. The material was purified by SFC:
Column: AS-H (5 μιη, 21 mm x 250 mm, S/N = 5172), F = 60 ml/min, 45% MeOH 20 mM NH3/CO2. All sample dissolved in 50 ml MeOH/DCM 1/4, P = 220 bar, 1.1 ml injection, 288 nm, to give (9S,l lE)-14-(2-hydroxyethyl)-16-methyl-3,7,14,17,23- pentaazapentacyclo[l 3.6.2. l~2,5~.0~4,9~.0~18,22~]tetracosa- l(22),2(24),4,l l,15(23),16,18,20-octaen-6-one (first eluting peak, 52 mg, 0.13 mmol, 28%) and (9S,l lZ)-14-(2-hydroxyethyl)-16-methyl-3,7,14,17,23- pentaazapentacyclo[l 3.6.2.1~2,5~.0~4,9~.0~18,22~]tetracosa- l(22),2(24),4,l l,15(23),16,18,20-octaen-6-one (second eluting peak, 92 mg, 0.24 mmol, 49%).
Analytical data for (9S,1 lE)-14-(2-hydroxyethyl)-16-methyl-3,7,14,17,23- pentaazapentacyclo[l 3.6.2. l~2,5~.0~4,9~.0~18,22~]tetracosa- l(22),2(24),4,l l,15(23),16,18,20-octaen-6-one: !H NMR (400 MHz, DMSO-i/6) δ ppm 2.19 - 2.37 (m, 1 H) 2.62 (d, J=12.52 Hz, 1 H) 2.70 (s, 3 H) 3.12 - 3.20 (m, 1 H) 3.22 - 3.31 (m, 1 H) 3.35 - 3.40 (m, 1 H) 3.51 - 3.60 (m, 1 H) 3.62 - 3.71 (m, 1 H) 3.73 - 3.80 (m, 2 H) 4.28 (br. s., 2 H) 4.84 (t, J=5.18 Hz, 1 H) 5.91 - 6.03 (m, 1 H) 6.28 (d, J=15.45 Hz, 1 H) 6.97 (d, J=2.15 Hz, 1 H) 7.10 (d, J=4.50 Hz, 1 H) 7.48 (t, J=7.82 Hz, 1 H) 7.63 (dd, J=8.02, 1.37 Hz, 1 H) 8.09 (dd, J=7.53, 1.27 Hz, 1 H) 13.18 (br. s., 1 H). MS (ESI, pos. ion) m/z: 390.2 (M+H)+.
Analytical data for (9S,1 lZ)-14-(2-hydroxyethyl)-16-methyl-3,7,14,17,23- pentaazapentacyclo[l 3.6.2. l~2,5~.0~4,9~.0~18,22~]tetracosa- l(22),2(24),4,l l,15(23),16,18,20-octaen-6-one: !H NMR (400 MHz, DMSO-i/6) δ ppm 2.31 (dd, J=12.91, 2.93 Hz, 1 H) 2.63 - 2.74 (m, 1 H) 2.80 (s, 3 H) 3.18 (d, J=5.28 Hz, 3 H) 3.39 (t, J=5.09 Hz, 1 H) 3.63 - 3.75 (m, 3 H) 3.81 - 3.87 (m, 1 H) 3.90 (d, J=16.24 Hz, 1 H) 4.77 (dd, J=16.43, 7.43 Hz, 1 H) 5.74 - 5.88 (m, 2 H) 6.84 (d, J=2.15 Hz, 1 H) 7.05 (d, J=4.50 Hz, 1 H) 7.44 (t, J=7.82 Hz, 1 H) 7.63 (dd, J=8.22, 1.17 Hz, 1 H) 7.94 (dd, J=7.43, 1.17 Hz, 1 H) 13.08 (br. s., 1 H). MS (ESI, pos. ion) m/z: 390.2 (M+H)+.
Example 78-80: (9S,llE,13S)-13,16-dimethyl-14-oxa-3,7,17,23- tetraazapentacyclo[13.6.2.1~2,5~.0~4,9~.0~18,22~]tetracosa- l(22),2(24),4,ll,15(23),16,18,20-octaen-6-one, (9S,llE,13R)-13,16-dimethyl-14-oxa- 3,7,17,23-tetraazapentacyclo[13.6.2.1~2,5~.0~4,9~.0~18,22~]tetracosa- l(22),2(24),4,ll,15(23),16,18,20-octaen-6-one, (9S,llZ)-13,16-dimethyl-14-oxa- 3,7,17,23-tetraazapentacyclo[13.6.2.1~2,5~.0~4,9~.0~18,22~]tetracosa- l(22),2(24),4,ll,15(23),16,18,20-octaen-6-one
Figure imgf000188_0001
Step 1 : NaH (60% in mineral oil, 27.7 mg, 0.693 mmol) was added to a solution of but-3- en-2-ol (ASDI 500014001, 50 mg, 0.693 mmol) in DMF (2311 μΐ) at 0 °C; this was stirred for 10 min at 0 °C before solid (S)-7-allyl-2-(3-fluoro-2-methylquinoxalin-5-yl)- 6,7-dihydro-lH-pyrrolo[3,2-c]pyridin-4(5H)-one (Intermediate D, 78 mg, 0.231 mmol) was added. The reaction mixture was warmed to RT and stirred for 2 h; more (S)-7-allyl- 2-(3-fluoro-2-methylquinoxalin-5-yl)-6,7-dihydro-lH-pyrrolo[3,2-c]pyridin-4(5H)-one (62 mg) was added and stirred at RT (2 h); more (S)-7-allyl-2-(3-fluoro-2- methylquinoxalin-5-yl)-6,7-dihydro-lH-pyrrolo[3,2-c]pyridin-4(5H)-one (62 mg) was added and stirred at RT for 16 h. The reaction mixture was diluted with DCM (100 ml), added to a separatory funnel, and washed with saturated aqueous NaHC03 (2 x 100 ml) before the organic layer was separated, dried over Na2S04, and concentrated. The crude product was adsorbed onto silica and was purified via automated flash chromatography (silica gel) with 100% DCM to 4% 2 M NH3 in MeOH/DCM to give (7S)-7-allyl-2-(3- (but-3 -en-2-yloxy)-2-methylquinoxalin-5 -yl)-6,7-dihydro- 1 H-pyrrolo [3 ,2-c]pyridin- 4(5H)-one (111 mg, 0.286 mmol, 48 % yield) as a yellow oil. !H NMR (400 MHz, CDC13) δ ppm 1.64 (t, J=6.06 Hz, 3 H) 2.43 - 2.64 (m, 2 H) 2.69 (s, 3 H) 3.00 - 3.10 (m, 1 H) 3.43 (dq, J=12.30, 4.25 Hz, 1 H) 3.76 (dd, J=12.23, 5.18 Hz, 1 H) 5.14 (d, J=5.87 Hz, 1 H) 5.17 (t, J=6.65 Hz, 1 H) 5.30 (d, J=10.76 Hz, 1 H) 5.37 (dd, J=17.41, 4.30 Hz, 1 H) 5.63 - 5.71 (m, 1 H) 5.75 (br. s., 1 H) 5.79 - 5.93 (m, 1 H) 6.16 (ddt, J=17.31, 10.76, 4.55, 4.55 Hz, 1 H) 7.14 - 7.18 (m, 1 H) 7.55 (t, J=7.92 Hz, 1 H) 7.79 (d, J=8.22 Hz, 1 H) 7.98 (d, J=7.63 Hz, 1 H) 11.61 (d, J=43.04 Hz, 1 H). MS (ESI, pos. ion) m/z: 389.3 (M+H)+. Step 2: A solution of (7S)-7-allyl-2-(3-(but-3-en-2-yloxy)-2-methylquinoxalin-5-yl)-6,7- dihydro-lH-pyrrolo[3,2-c]pyridin-4(5H)-one (0.111 g, 0.286 mmol) and Grubbs catalyst 2nd generation (0.049 g, 0.057 mmol) in DCM (28.6 ml) was stirred at 40 °C for 1 h. The crude product was adsorbed onto silica and was purified via automated flash chromatography (silica gel) with 100% DCM to 4% 2 M NH3 in MeOH/DCM to give a yellow solid as a mixture of isomers. The mixture was dissolved in 1 : 1 MeOH/DCM (~20 mg/ml) and injected (5 x 1.0 ml) onto the Shimadzu preparatory LC (Phenomenex Gemini Ci8 column (150 * 30 mm, 10 μιη), 35 mL/min, 5-100% CH3CN/H20 + 0.1% TFA) before the pure fractions were combined, basicified with NaHCC (saturated, aqueous), extracted with DCM, separated, dried over Na2S04, and concentrated via rotary evaporation to give a single Cu diastereomer of (9S,1 lE)-13,16-dimethyl-14-oxa- 3,7,17,23-tetraazapentacyclo[l 3.6.2. l~2,5~.0~4,9~.0~18,22~]tetracosa- 1(22),2(24),4,1 l,15(23),16,18,20-octaen-6-one (Example 78, 16 mg, 0.044 mmol, 18% yield) and a mixture of isomers (24 mg). SFC purification of the mixture:
Column: AS-H (5 μπι, 21 mm x 250 mm, S/N = 5172), F = 60 ml/min, 35% MeOH 20 mM NH3/CO2. All sample dissolved in 4 ml MeOH/DCM 1/1, P = 213 bar, 1.1 ml injection, 288 nm, gave a single C13 diastereomer of (9S,1 lE)-13,16-dimethyl-14-oxa- 3,7,17,23-tetraazapentacyclo[l 3.6.2. l~2,5~.0~4,9~.0~18,22~]tetracosa- l(22),2(24),4,l l,15(23),16,18,20-octaen-6-one (Example 79, 15 mg, 0.042 mmol, 17%) and a single Q3 diastereomer of (9S,1 lZ)-13,16-dimethyl-14-oxa-3,7,17,23- tetraazapentacyclo[l 3.6.2. l~2,5~.0~4,9~.0~18,22~]tetracosa- l(22),2(24),4,l l,15(23),16,18,20-octaen-6-one (Example 80, 2 mg, 0.005 mmol, 2%). Analytical data for first isolated C13 diastereomer of (9S,1 lE)-13,16-dimethyl-14-oxa- 3,7,17,23-tetraazapentacyclo[l 3.6.2.1~2,5~.0~4,9~.0~18,22~]tetracosa- l(22),2(24),4,l l,15(23),16,18,20-octaen-6-one, Example 78: ¾ NMR (400 MHz, DMSO-i/e) δ ppm 1.63 (d, J=6.65 Hz, 3 H) 2.27 - 2.39 (m, 1 H) 2.62 (s, 3 H) 2.71 (d, J=13.50 Hz, 1 H) 3.19 - 3.25 (m, 1 H) 3.31 - 3.40 (m, 3 H) 5.40 (br. s., 1 H) 5.86 - 5.97 (m, 1 H) 6.44 (d, J=16.04 Hz, 1 H) 6.92 (s, 1 H) 7.59 (t, J=8.02 Hz, 1 H) 7.74 (dd,
J=8.22, 1.17 Hz, 1 H) 8.08 (d, J=6.65 Hz, 1 H) 12.74 (br. s., 1 H). MS (ESI, pos. ion) m/z: 361.1 (M+H)+.
Analytical data for second isolated C13 diastereomer (9S,1 lE)-13,16-dimethyl-14-oxa- 3,7,17,23-tetraazapentacyclo[l 3.6.2. l~2,5~.0~4,9~.0~18,22~]tetracosa- l(22),2(24),4,l l,15(23),16,18,20-octaen-6-one, Example 79: ¾ NMR (400 MHz,
DMSO-i/e) δ ppm 1.60 (d, J=6.46 Hz, 3 H) 2.19 - 2.29 (m, 1 H) 2.61 (s, 3 H) 2.62 - 2.70 (m, 1 H) 3.10 - 3.19 (m, 1 H) 3.26 - 3.33 (m, 1 H) 3.36 - 3.42 (m, 1 H) 5.24 (quin, J=6.60 Hz, 1 H) 6.03 - 6.19 (m, 2 H) 7.00 (d, J=2.15 Hz, 1 H) 7.10 (d, J=4.30 Hz, 1 H) 7.58 (t, J=7.82 Hz, 1 H) 7.72 (dd, J=8.02, 1.17 Hz, 1 H) 8.14 (dd, J=7.63, 1.17 Hz, 1 H) 13.29 (br. s., 1 H). MS (ESI, pos. ion) m/z: 361.4 (M+H)+.
Analytical data for the single isolated Cu diastereomer of (9S,1 lZ)-13,16-dimethyl-14- oxa-3,7,17,23-tetraazapentacyclo[13.6.2.1~2,5~.0~4,9~.0~18,22~]tetracosa- l(22),2(24),4,l l,15(23),16,18,20-octaen-6-one, Example 80: ¾ NMR (400 MHz, CDCl3) δ ppm 1.58 - 1.60 (m, 3 H) 2.37 (d, J=15.06 Hz, 1 H) 2.62 - 2.73 (m, 1 H) 2.70 (s, 3 H) 3.35 - 3.48 (m, 2 H) 3.48 - 3.55 (m, 1 H) 5.30 (br. s., 1 H) 5.72 (quin, J=6.75 Hz, 1 H) 5.77 - 5.90 (m, 2 H) 6.97 (s, 1 H) 7.57 (t, J=8.02 Hz, 1 H) 7.79 (d, J=8.22 Hz, 1 H) 7.89 (d, J=7.43 Hz, 1 H) 13.14 (br. s., 1 H). MS (ESI, pos. ion) m/z: 361.2 (M+H)+.
Examples 81 and 82: (9tf)-17-methyl-12-oxa-3,7,15,18,24- pentaazapentacyclo[14.6.2.1~2,5~.0~4,9~.0~19,23~]pentacosa- l(22),2(25),4,16,18,20,23-heptaen-6-one and (9»S)-17-methyl-12-oxa-3,7,15,18,24- pentaazapentacyclo[14.6.2.1~2,5~.0~4,9~.0~19,23~]pentacosa- l(22),2(25),4,16,18,20,23-heptaen-6-one
Figure imgf000190_0001
A portion of Example 73 was separated by preparative SFC chromatography (Chiralpak AS-H (250 x 21), 5 μ, 60% C02 and 40% MeOH containing 0.2% DEA, flow rate 70 mL/min, 100 Bar, oven temperature 40 °C) to give separated enantiomers with ee values greater than 99%, each. The 1st eluent was assigned as Example 82 and 2nd eluent was assigned as Example 81. Retention time was 2.04 min for 1st eluent and 2.99 min for 2nd eluent, using analytical SFC (Chiralpak AS-H (150 x 4.6), 5 μ, 60% C02 and 40% MeOH containing 0.2% DEA, flow rate 4.0 mL/min, 100 Bar, oven temperature 40 °C). Example 83: (9R,13R)-13,16-dimethyl-3,7,14,17,23- pentaazapentacyclo[13.6.2.1~2,5~.0~4,9~.0~18,22~]tetracosa- l(22),2(24),4,15,17,18,20,22-octaen-6-one
Figure imgf000191_0001
A suspension of (9R, 1 1 E, 13R 13 , 16-dimethyl-3 ,7,14,17,23- pentaazapentacyclo[l 3.6.2. l~2,5~.0~4,9~.0~18,22~]tetracosa- l(22),2(24),4,l l,15,17,18,20,22-nonaen-6-one (Example 30; 33.0 mg, 0.092 mmol) and palladium on carbon (10% w/w) (Aldrich; 98 mg, 0.092 mmol) in THF (1.5 mL) was stirred under a H2 atmosphere (45 psi) at 25 °C for 20 h. The reaction flask was flushed with argon, additional Pd/C (10% w/w) (49 mg, 0.046 mmol) was added, and the resulting suspension was stirred under a H2 atmosphere (45 psi) at 25 °C for 1 d. The reaction flask was flushed with argon, and the resulting suspension was filtered through Celite, sequentially washing with MeOH (10 mL) and 1 : 1 MeOH/DCM (10 mL). The combined filtrates were concentrated in vacuo to provide a yellow solid. This solid was taken up in MeOH (2.0 mL), NaOH (1.0N, aqueous) (0.184 mL, 0.184 mmol) and H202 (30%o w/w in water) (0.014 mL, 0.138 mmol) were sequentially added, and the resulting mixture was stirred at 25 °C for 10 min. The reaction mixture was then partitioned between 5% MeOH/DCM (40 mL) and 10: 1 water/brine (30 mL). The organic layer was separated, and the aqueous layer was extracted with 5% MeOH/DCM (2 x 30 mL). All organic layers were then combined, dried over Na2S04, filtered, and concentrated in vacuo. Chromatographic purification of the residue (silica gel, 20-100% EtOAc/hexanes, then 0-100% MeOH/DCM) furnished (9R,13R)-13,16-dimethyl-3,7,14,17,23- pentaazapentacyclo[l 3.6.2. l~2,5~.0~4,9~.0~18,22~]tetracosa- l(22),2(24),4,15,17,18,20,22-octaen-6-one (12.1 mg, 0.033 mmol, 36% yield) as a yellow solid: !H NMR (400 MHz, DMSO-d6) δ ppm 13.39 - 13.53 (1 H, m), 8.00 (1 H, dd, J=7.6, 1.2 Hz), 7.56 (1 H, dd, J=8.0, 1.2 Hz), 7.34 (1 H, t, J=7.8 Hz), 7.06 (1 H, d, J=4.9 Hz), 7.01 (1 H, d, J=4.3 Hz), 6.95 (1 H, d, J=2.0 Hz), 3.54 - 3.67 (1 H, m), 3.19 - 3.26 (1 H, m), 3.14 (1 H, br. s.), 3.01 (1 H, t, J=12.0 Hz), 2.57 (3 H, s), 2.39 (1 H, t, J=12.0 Hz), 2.18 - 2.29 (1 H, m), 1.93 - 2.06 (1 H, m), 1.60 - 1.70 (1 H, m), 1.41 - 1.52 (1 H, m), 1.39 (3 H, d, J=6.7 Hz), 1.20 - 1.27 (1 H, m). m/z (ESI, +ve) 362.1 (M+H)+. Example 84: (9S,llE,13S)-21-fluoro-13,16-dimethyl-3,7,14,17,23- pentaazapentacyclo[13.6.2.1~2,5~.0~4,9~.0~18,22~]tetracosa- l(21),2(24),4,ll,15,17,19,22-octaen-6-one
Figure imgf000192_0001
Step 1 : (S)-8-bromo-N-(but-3-en-2-yl)-7-fluoro-3-methylquinoxalin-2 -amine
A mixture of 5-bromo-3-chloro-6-fluoro-2-methylquinoxaline (Intermediate K; 1.00 g,
3.63 mmol), (S)-but-3-en-2 -amine hydrochloride (Intermediate G; 781 mg, 7.26 mmol) and DIPEA (Sigma Aldrich, 2.53 mL, 14.52 mmol) in DMSO (5.2 mL) was stirred at 90 °C for 13 h. The reaction was partitioned between saturated NaHCC (aq.) and Et20. The organic layer was washed with water and brine and dried over anhydrous Na2S04, filtered, and concentrated in vacuo. The crude material was purified by silica gel chromatography (80 g) eluting with a gradient of 0-40% EtOAc/hexane to afford (S)-8- bromo-N-(but-3-en-2-yl)-7-fluoro-3-methylquinoxalin-2 -amine (790 mg, 2.55 mmol, 70 % yield) as an orange solid: !H NMR (400 MHz, CDCk) δ ppm 7.74 (dd, J=9.00, 5.67 Hz, 1 H), 7.17 (t, .7=8.61 Hz, 1 H), 5.99 (ddd, J=17.21, 10.27, 5.77 Hz, 1 H), 5.40 (dt, J=17.21, 1.47 Hz, 1 H), 5.18 (dt, =10.37, 1.37 Hz, 1 H), 5.00 - 5.1 1 (m, 1 H), 4.86 (d, J=8.22 Hz, 1 H), 2.55 (s, 3 H), 1.47 (d, J=6.65 Hz, 3 H). m/z (ESI, +ve) 310.1, 312.1 (M+H)+.
Step 2: (S)-7-allyl-2-(3-((S)-but-3-en-2-ylamino)-6-fluoro-2-methylquinoxalin-5-yl)-6,7- dihydro-lH-pyrrolo[3,2-c]pyridin-4(5H)-one
A glass microwave reaction vessel was charged with (S)-8-bromo-N-(but-3-en-2-yl)-7- fluoro-3-methylquinoxalin-2 -amine (152 mg, 0.491 mmol), (S)-7-allyl-2-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)-6,7-dihydro-lH-pyrrolo[3,2-c]pyridin-4(5H)-one (Intermediate L, 267 mg, 0.663 mmol), Pd2(dba)3 chloroform adduct (Strem Chemicals Inc., 25 mg, 0.025 mmol), XPhos (Strem Chemicals Inc., 23 mg, 0.049 mmol) and K3PO4 (Riedel de Haen AG, 0.122 mL, 1.473 mmol) in dioxane (2.0 mL) and water (0.5 mL). The reaction mixture was stirred and heated in an Initiator microwave reactor (Personal Chemistry, Biotage AB, Inc., Upssala, Sweden) at 100 °C for 30 min. Water was added and the mixture was extracted with EtOAc (3X). The combined organic layers were dried over anhydrous Na2S04, filtered and concentrated. The crude material was purified by preparatory HPLC, 5 - 100 % ACN/H20 with 0.1 % TFA over 15 min; product-containing fraction was treated with saturated NaHCC (aq.) and CH2C12. The aqueous layer was extracted 3 x CH2C12 and the combined organic layers were dried over Na2S04, filtered, and concentrated to afford (S)-7-allyl-2-(3-((S)-but-3-en-2-ylamino)-6-fluoro-2- methylquinoxalin-5-yl)-6,7-dihydro-lH-pyrrolo[3,2-c]pyridin-4(5H)-one (80 mg, 40%): !H NMR (400 MHz, CDCl3) δ ppm 12.49 (br. s., 1 H), 7.63 (dd, 7=9.00, 5.48 Hz, 1 H), 7.35 - 7.39 (m, 1 H), 7.23 (dd, 7=1 1.54, 9.00 Hz, 1 H), 6.1 1 (ddd, 7=17.21, 10.56, 3.91 Hz, 1 H), 5.83 (ddt, 7=16.46, 10.73, 7.14, 7.14 Hz, 1 H), 5.55 (br. s., 1 H), 5.24 - 5.36 (m, 2 H), 5.16 (dd, 7=6.94, 1.66 Hz, 1 H), 5.12 (s, 1 H), 4.99 (d, 7=6.85 Hz, 1 H), 4.69 - 4.80 (m, 1 H), 3.77 (dd, 7=12.13, 5.48 Hz, 1 H), 3.44 (dt, =12.23, 4.06 Hz, 1 H), 2.95 - 3.04 (m, 1 H), 2.61 (s, 3 H), 2.46 - 2.52 (m, 2 H), 2.01 (s, 3 H), 1.56 (d, 7=6.85 Hz, 3 H). m/z (ESI, +ve) 406.1 (M+H)+.
Step 3 : (9S,1 lE,13S)-21-fluoro-13,16-dimethyl-3,7,14,17,23- pentaazapentacyclo[l 3.6.2.1~2,5~.0~4,9~.0~18,22~]tetracosa- 1 (21 ),2(24),4, 11,15,17,19,22-octaen-6-one
Argon was bubbled for 2 min through a solution of (S)-7-allyl-2-(3-((S)-but-3-en-2- ylamino)-6-fluoro-2-methylquinoxalin-5-yl)-6,7-dihydro-lH-pyrrolo[3,2-c]pyridin- 4(5H)-one (0.054 g, 0.133 mmol) and Grubbs catalyst, 2nd generation (Sigma Aldrich, 5.65 mg, 6.66 μηιοΐ) in CH2C12 (7 mL). The reaction was sealed and heated to 45 °C for 1 h. The crude material was absorbed onto a plug of silica gel and purified by silica gel chromatography (4 g), eluting with a gradient of 0-7%o MeOH in CH2C12, to provide (9S, 1 1 E, 13 S)-21 -fluoro- 13,16-dimethyl-3,7, 14,17,23- pentaazapentacyclo[l 3.6.2. l~2,5~.0~4,9~.0~18,22~]tetracosa- l(21),2(24),4,l l,15,17,19,22-octaen-6-one (0.040 g, 0.106 mmol, 80 % yield) as a yellow solid: !H NMR (400 MHz, DMSO-d6) δ ppm 13.53 - 13.65 (1 H, m), 7.58 (1 H, dd, 7=9.0,
5.9 Hz), 7.32 (1 H, dd, 7=12.1 , 9.0 Hz), 7.1 1 (1 H, d, 7=4.3 Hz), 6.89 (1 H, dd, 7=5.4, 1.9 Hz), 6.61 (1 H, d, 7=1.2 Hz), 5.84 - 6.05 (2 H, m), 4.25 (1 H, t, 7=6.4 Hz), 3.34 - 3.40 (1 H, m), 3.20 - 3.31 (1 H, m), 3.06 - 3.17 (2 H, m), 2.60 (6 H, s), 2.54 - 2.59 (1 H, m), 2.13 - 2.26 (2 H, m), 1.51 (3 H, d, 7=6.8 Hz), m/z (ESI, +ve) 378.1 (M+H)+. Example 85: (9S,llE,13R)-19-methyl-15-oxa-3,7,17,20,26- pentaazahexacyclo[16.6.2.1~2,5~.0~4,9~.0~13,17~.0~21,25~]heptacosa- l(25),2(27),4,ll,18(26),19,21,23-octaene-6,16-dione
Example 86: (9S,llZ,13R)-19-methyl-15-oxa-3,7,17,20,26- pentaazahexacyclo[16.6.2.1~2,5~.0~4,9~.0~13,17~.0~21,25~]heptacosa- l(25),2(27),4,ll,18(26),19,21,23-octaene-6,16-dione
Example 87: (9S,llZ,13S)-19-methyl-15-oxa-3,7,17,20,26- pentaazahexacyclo[16.6.2.1~2,5~.0~4,9~.0~13,17~.0~21,25~]heptacosa- l(25),2(27),4,ll,18(26),19,21,23-octaene-6,16-dione
Figure imgf000194_0001
To a solution of 4-vinyloxazolidin-2-one (Prepared from tert-butyl 2,2-dimethyl-4- vinyloxazolidine-3-carboxylate, Annova Chem Inc., San Diego, CA, according to J. Org. Chem. Vol. 74, 2009, 8852-8855, 0.235 g, 2.081 mmol) in 1 mL DMF at 0 °C was added NaH 60% in mineral oil (Aldrich; 0.083 g, 2.081 mmol) in 2 equal portions separated by 5 min. Gas evolution observed. The ice bath was removed and the reaction stirred rapidly at RT 10 min. The foamy mixture was treated with (S)-7-allyl-2-(3-fluoro-2- methylquinoxalin-5-yl)-6,7-dihydro-lH-pyrrolo[3,2-c]pyridin-4(5H)-one (Intermediate D; 0.100 g, 0.297 mmol), 1 mL DMF, and the reaction was sealed and heated to 90 °C After 2 h, the reaction was cooled and partitioned between saturated aqueous NH4C1 and EtOAc. The layers were separated, and the aqueous layer was extracted 1 x EtOAc, and the combined organic layers were washed with water once, brine once, and the organics were dried over anhydrous Na2S04, filtered, and concentrated in vacuo. The material was treated with DCM and purified by silica gel chromatography (24 g) using 0 - 100% 90/10 DCM/MeOH in DCM The product-containing fractions were concentrated to afford 0.080 g of a mixture of isomers. This was treated with Grubbs catalyst 2nd generation (Aldrich; 0.032 g, 0.037 mmol) and 9 mL DCM and argon was bubbled into the solution for 30 sec. The reaction was sealed and placed in a 45 °C bath for 2 h. Additional Grubbs catalyst 2nd generation (Aldrich; 0.032 g, 0.037 mmol) was added, the reaction was sealed, and heated to 45 °C for 1 h. The reaction was cooled, MeOH was added and the reaction was adsorbed onto 1 g silica gel, dried, and purified by silica gel chromatography (12 g) using 0 - 100% 90/10 DCM/MeOH in DCM. The product-containing fractions were concentrated to afford a mixture of isomeric products and impurities (0.035 g) as a yellow-brown solid. The material was further purified by chiral SFC (Column: Chiralcel OJ-H (Sepax) (250 x 21 mm, 5 μ); Mobile Phase: 70:30 (A:B); A: Liquid C02, B: MeOH (20 mM NH3); Flow Rate: 65 mL/min; Inlet Pressure: 158 bar) to give:
(9S,l lE,13R)-19-methyl-15-oxa-3,7,17,20,26- pentaazahexacyclo[16.6.2.1~2,5~.0~4,9~.0~13,17~.0~21,25~]heptacosa-
1(25),2(27),4, 11,18(26), 19,2 l,23-octaene-6,16-dione (First eluting, Example 85, 0.0046 g, 0.01 1 mmol, 6.15 % yield): !H NMR (400 MHz, DMSO-d6) δ ppm 12.59 (1 H, br. s.), 8.21 (1 H, dd, J=7.2, 1.4 Hz), 7.66 - 7.88 (2 H, m), 7.01 - 7.19 (2 H, m), 6.44 (1 H, dd, J=14.6, 10.3 Hz), 6.12 - 6.29 (1 H, m), 5.16 - 5.31 (1 H, m), 4.86 (1 H, t, J=7.8 Hz), 4.31 (1 H, d, J=8.4 Hz), 3.36 - 3.44 (1 H, m), 3.23 - 3.29 (1 H, m), 3.12 - 3.21 (1 H, m), 2.59 - 2.71 (4 H, m), 2.30 - 2.46 (1 H, m). m/z (ESI, +ve) 402.2 (M+H)+.
(9S,l lZ,13R)-19-methyl-15-oxa-3,7,17,20,26- pentaazahexacyclo[16.6.2.1~2,5~.0~4,9~.0~13,17~.0~21,25~]heptacosa- l(25),2(27),4,l l,18(26),19,21,23-octaene-6,16-dione (Second eluting, Example 86, 0.0034 g, 8.47 μιηοΐ, 4.55 % yield): !H NMR (400 MHz, DMSO-d6) δ ppm 12.32 (1 H, br. s.), 8.06 (1 H, dd, J=7.3, 1.1 Hz), 7.78 - 7.87 (1 H, m), 7.68 - 7.77 (1 H, m), 7.04 (1 H, d, J=4.3 Hz), 6.77 (1 H, d, J=2.0 Hz), 6.14 - 6.30 (1 H, m), 5.71 - 5.84 (1 H, m), 5.55 - 5.68 (1 H, m), 4.74 (1 H, t, J=7.8 Hz), 4.19 (1 H, t, J=8.9 Hz), 3.29 - 3.54 (4 H, m), 2.70 (3 H, s), 2.28 (1 H, d, J=14.5 Hz) . m/z (ESI, +ve) 402.2 (M+H)+.
(9S, 1 1 Z, 13 S)- 19-methyl- 15-oxa-3 ,7, 17,20,26- pentaazahexacyclo[16.6.2.1~2,5~.0~4,9~.0~13,17~.0~21,25~]heptacosa- l(25),2(27),4,l l,18(26),19,21,23-octaene-6,16-dione (Third eluting, Example 87, 0.0057 g, 0.014 mmol, 7.62 % yield): !H NMR (400 MHz, DMSO-d6) δ ppm 12.03 (1 H, br. s.), 8.08 (1 H, d, J=6.7 Hz), 7.80 - 7.90 (1 H, m), 7.68 - 7.80 (1 H, m), 7.09 (1 H, d, J=4.3 Hz), 6.92 (1 H, d, J=2.2 Hz), 6.03 - 6.17 (1 H, m), 5.80 - 5.99 (2 H, m), 4.68 (1 H, t,
J=7.7 Hz), 4.15 - 4.30 (1 H, m), 3.43 (1 H, dt, J=10.4, 5.0 Hz), 3.08 - 3.28 (2 H, m), 2.79 - 2.94 (1 H, m), 2.74 (3 H, s), 2.37 (1 H, d, J=13.9 Hz), m/z (ESI, +ve) 402.2 (M+H)+. Example 88: (9S)-17-methyl-3,7,15,18,24- pentaazapentacyclo[14.6.2.1~2,5~.0~4,9~.0~19,23~]pentacosa- l(23),2(25),4,16(24),17,19,21-heptaen-6-one
Figure imgf000196_0001
Step 1 : (S)-7-allyl-2-(3-(but-3-en-l -ylamino)
pyrrolo [3,2 -c]pyridin-4(5 H)-one
3-Buten-l-amine (Alfa Aesar, 0.275 ml, 2.97 mmol) and (S)-7-allyl-2-(3-fluoro-2- methylquinoxalin-5-yl)-6,7-dihydro-lH-pyrrolo[3,2-c]pyridin-4(5H)-one (Intermediate D; 0.100 g, 0.297 mmol) were combined in 1.5 mL DMSO, sealed, and heated to 70 °C overnight. The reaction was treated with ~ 6 mL saturated aqueous NaHCC , and the precipitate was collected by filtration, rinsing 1 x water. Solid was collected and dried in vacuo to give (S)-7-allyl-2-(3-(but-3-en-l -ylamino)-2-methylquinoxalin-5-yl)-6,7- dihydro-lH-pyrrolo[3,2-c]pyridin-4(5H)-one (0.109 g, 0.281 mmol, 95 % yield): !H
NMR (400 MHz, DMSO-d6) δ ppm 12.01 (1 H, br. s.), 7.90 (1 H, d, J=7.6 Hz), 7.57 (1 H, d, J=7.8 Hz), 7.22 - 7.40 (2 H, m), 7.09 (1 H, d, J=2.0 Hz), 6.93 (1 H, br. s.), 5.79 - 6.10 (2 H, m), 4.99 - 5.26 (4 H, m), 3.43 - 3.69 (3 H, m), 3.18 - 3.25 (1 H, m), 2.98 - 3.1 1 (1 H, m), 2.50 - 2.62 (6 H, m), 2.21 - 2.40 (1 H, m). m/z (ESI, +ve) 388.1 (M+H)+.
Step 2: Argon was bubbled through a slurry of Grubbs catalyst 2nd generation (Aldrich; 0.048 g, 0.056 mmol) and (S)-7-allyl-2-(3-(but-3-en-l -ylamino)-2-methylquinoxalin-5- yl)-6,7-dihydro-lH-pyrrolo[3,2-c]pyridin-4(5H)-one (0.109 g, 0.281 mmol) in 14 mL DCM for 30 sec. The reaction was sealed, heated to 45 °C and stirred rapidly. Upon completion, the reaction was treated with MeOH, and silica gel, and dried in vacuo. The residue was purified by silica gel chromatography using 0 - 100% 90/10 DCM/MeOH in DCM. The product-containing fractions were concentrated to afford 0.080 g material. This material and palladium on carbon 10%, wetted (50 wt % water) (0.118 g) were combined under N2 and 4 mL THF was added. The atmosphere was replaced with H2 from a balloon and the reaction was stirred rapidly overnight. The reaction was flushed with N2 and filtered through Celite, rinsing with 100 mL of 1 : 1 DCM/MeOH. The filtrate was concentrated in vacuo to give 0.074 g yellow solid. This material was treated with 4 mL MeOH to give a suspension, and H20230% in water (Aldrich; 0.025 ml, 0.245 mmol) was added followed by iron (ii) chloride (Alfa Aesar, Ward Hill, MA, 0.846 mg, 6.68 μιηοΐ). The reaction was stirred rapidly for 2 h. Additional H202 30% in water (Aldrich; 0.025 ml, 0.245 mmol) was added. After 30 min, the reaction was treated with DCM to give a solution and was adsorbed onto 1 g silica gel, dried, and purified by silica gel chromatography (24 g) using 0 - 100% 90/10 DCM/MeOH in DCM. The product- containing fractions were concentrated to afford (9S)-17-methyl-3, 7,15, 18,24- pentaazapentacyclo[l 4.6.2. l~2,5~.0~4,9~.0~19,23~]pentacosa- l(23),2(25),4,16(24),17,19,21-heptaen-6-one (0.031 g, 0.086 mmol, 38.5 % yield) as a yellow solid: !H NMR (400 MHz, DMSO-d6) δ ppm 12.02 (1 H, br. s.), 7.91 (1 H, d, J=6.7 Hz), 7.51 - 7.69 (2 H, m), 7.30 (1 H, t, J=7.7 Hz), 7.03 (1 H, d, J=4.1 Hz), 6.85 (1 H, d, J=1.8 Hz), 3.56 (1 H, m), 3.01 - 3.35 (4 H, m), 1.56 - 1.96 (6 H, m), 1.47 (2 H, br. s.). m/z (ESI, +ve) 362.2 (M+H)+.
Examples 89-90: (9S,llE,13S)-16-methyl-13-(2-(methylsulfonyl)ethyl)-3,7,14,17,23- pentaazapentacyclo[13.6.2.1~2,5~.0~4,9~.0~18,22~]tetracosa- l(22),2(24),4,ll,15,17,18,20,22-nonaen-6-one and (9S,llE,13R)-16-methyl-13-(2- (methylsulfonyl)ethyl)-3,7,14,17,23- pentaazapentacyclo[13.6.2.1~2,5~.0~4,9~.0~18,22~]tetracosa- l(22),2(24),4,ll,15,17,18,20,22-nonaen-6-one
Figure imgf000197_0001
Step 1 : 5-(methylthio)pent-l-en-3-amine hydrochloride
A slurry of anhydrous MgS04 (Sigma Aldrich, 52.1 g, 433 mmol) and (R)-(+)-2-methyl- 2-propanesulfinamide (AK Scientific, Union City, CA, 0.5 g, 87 mmol) was stirred in DCM (61.9 ml). 3-(methylthio) propionaldehyde (Sigma Aldrich, 17.52 ml, 173 mmol) was added, and the reaction was stirred under N2. After stirring for 26 h, the reaction mixture was filtered with DCM rinsing and concentrated under reduced pressure to a liquid. A portion of the liquid (2.5 g) was treated with DCM (121 ml), and this solution was cooled to -30 °C and a 1.0 M solution of vinylmagnesium bromide in THF (Sigma Aldrich, 15.67 ml, 15.67 mmol) was added dropwise over 10 min, taking care to maintain an internal temperature less than -15 °C. Upon complete addition, the mixture was stirred for 1.5 h at -30 °C. The reaction was warmed to RT and saturated aqueous NH4C1 was added. The mixture was extracted with DCM. The organics were washed with brine, dried over Na2S04, filtered, and concentrated in vacuo. The resulting residue was was stirred with MeOH (10 mL) and 4 M HC1 in 1 ,4-dioxane (Sigma Aldrich, 27 mL, 120 mmol). The mixture was stirred for 2 h and was subsequently concentrated in vauco to afford a residue. It was sonicated with toluene after initial concentration under reduced pressure and concentrated in vacuo from toluene a second time, to give 5- (methylthio)pent-l-en-3-amine hydrochloride (1.2 g) as a viscous residue: !H NMR (DMSO-d6) δ: 8.40 - 8.57 (2H, m) 5.75 - 5.88 (1H, m) 5.35 - 5.45 (2H, m) 3.77 - 3.86 (1H, m) 3.64 - 3.74 (1H, m) 3.15 - 3.23 (2H, m) 3.02 (3H, s) 2.12 - 2.25 (1H, m).
Step 2: tert-butyl (5-(methylthio)pent-l -en-3-yl)carbamate
A solution of 5-(methylthio)pent-l -en-3-amine hydrochloride (2.3 g, 13.71 mmol) in dioxane (18.29 ml) was stirred, and saturated aqueous NaHC03 (EMD Biosciences, 2.304 ml, 27.4 mmol) and di-tert-butyl dicarbonate (Sigma Aldrich, 5.87 ml, 27.4 mmol) were subsequently added. The monophasic solution was stirred at RT overnight. An additional 2 mL saturated aqueous NaHC03 and 0.5 equivalents of DMAP were added, and the reaction was stirred for 30 min. The reaction was diluted with water, extracted with DCM, and the organic layer was washed with saturated aqueous NaHCC . The combined organics were dried over Na2S04, filtered, and concentrated under reduced pressure to give tert-butyl (5-(methylthio)pent-l-en-3-yl)carbamate (865 mg, 31 %) as an oil: ¾ NMR (CDCh) δ: 5.69 - 5.84 (1H, m) 5.08 - 5.23 (2H, m) 4.12 - 4.29 (1H, m) 2.47 - 2.58 (2H, m) 2.12 (3H, s) 1.74 - 1.90 (2H, m) 1.45 (9H, s). Step 3: 5-(methylsulfonyl)pent-l-en-3-amine hydrochloride
A solution of tert-butyl (5-(methylthio)pent-l -en-3-yl)carbamate (1.62 g, 7.00 mmol) in DMF (35.0 ml) was stirred, and 77% 3-chloroperoxybenzoic acid (Sigma Aldrich, 3.38 g, 14.70 mmol) was added as a solution in 5 mL DMF. The mixture was stirred overnight at RT. The reaction was quenched with saturated aqueous Na2S203 and extracted with EtOAc. The combined organics were washed with IN NaOH and dried over Na2S04, filtered, and concentrated under reduced pressure to an oil. The oil was diluted with water and extracted with EtOAc. The combined organics were washed with IN aqueous HC1, dried over Na2S04, filtered, and concentrated under reduced pressure to yield a residue that was carried forward without purification. The residue was stirred in 4 M HCl/dioxane (15 mL) for 1 h. The resulting solution was concentrated under reduced pressure and sonicated twice with toluene. It was concentrated in vacuo then dried under high vacuum to give 5-(methylsulfonyl)pent-l-en-3-amine hydrochloride (534 mg, 19%, 2 steps): !H NMR (DMSO-d6) δ: 8.40 - 8.57 (2H, m) 5.75 - 5.88 (1H, m) 5.35 - 5.45 (1H, m) 3.77 - 3.86 (1H, m) 3.64 - 3.74 (1H, m) 3.15 - 3.23 (2H, m) 3.02 (3H, s) 2.12 - 2.25 (1H, m) 1.94 - 2.06 (lH, m).
Step 4: (7S)-7-allyl-2-(2-methyl-3-((5-(methylsulfonyl)pent-l -en-3-yl)amino)quinoxalin- 5-yl)-6,7-dihydro-lH-pyrrolo[3,2-c]pyridin-4(5H)-one
A solution of (S)-7-allyl-2-(3-fluoro-2-methylquinoxalin-5-yl)-6,7-dihydro-lH- pyrrolo[3,2-c]pyridin-4(5H)-one (Intermediate D, 300 mg, 0.892 mmol), 5- (methylsulfonyl)pent-l-en-3-amine hydrochloride (534 mg, 2.68 mmol),
diisopropylethylamine (EMD Biosciences, 931 μΐ, 5.35 mmol), and DMSO (8919 μΐ) was sealed and stirred at 80°C for 3 h. An additional 200 mg of 5-(methylsulfonyl)pent-l -en-
3 -amine hydrochloride was added as a solution in DMSO, and the reaction was stirred for an additional 2 h at 80°C. The reaction was cooled to RT, diluted with water, and extracted with DCM. The combined organics were dried over Na2S04, filtered, and concentrated in vacuo. The mixture was adsorbed onto silica and purified by column chromatography (eluent: 0 to 8% MeOH/DCM over 20 min). The combined product fractions were concentrated under reduced pressure to give (7S)-7-allyl-2-(2-methyl-3- ((5-(methylsulfonyl)pent-l -en-3-yl)amino)quinoxalin-5-yl)-6,7-dihydro-lH-pyrrolo[3,2- c]pyridin-4(5H)-one (184 mg, 43%): !H NMR (CDCh) δ: 1 1.59 - 1 1.89 (1H, m) 7.90 - 7.94 (1H, m) 7.72 - 7.78 (1H, m) 7.40 - 7.46 (1H, m) 7.09 - 7.14 (1H, m) 5.81 - 6.05 (3H, m) 5.63 - 5.74 (1H, m) 5.33 - 5.41 (2H, m) 5.13 - 5.20 (2H, m) 4.86 - 5.00 (1H, m) 3.72 - 3.81 (1H, m) 3.42 - 3.51 (1H, m) 3.23 - 3.39 (2H) 3.05 - 3.14 (1H, m) 3.01 (2H, s) 2.97 - 3.00 (2H, m) 2.70 (3H, s), 2.44 - 2.58 (3H, m): m/z (ESI, +ve) 480.2 (M+H)+. Step 5: (9S,1 lE,13S)-16-methyl-13-(2-(methylsulfonyl)ethyl)-3,7,14,17,23- pentaazapentacyclo[l 3.6.2. l~2,5~.0~4,9~.0~18,22~]tetracosa- 1 (22),2(24),4, 11,15,17,18,20,22-nonaen-6-one and (9S, 1 1 E, 13R)- 16-methyl- 13-(2- (methylsulfonyl)ethyl)-3 ,7,14,17,23- pentaazapentacyclo[l 3.6.2.1~2,5~.0~4,9~.0~18,22~]tetracosa- 1 (22),2(24),4, 11 , 15, 17, 18,20,22-nonaen-6-one
A solution of (7S)-7-allyl-2-(2-methyl-3-((5-(methylsulfonyl)pent-l -en-3- yl)amino)quinoxalin-5-yl)-6,7-dihydro-lH-pyrrolo[3,2-c]pyridin-4(5H)-one (184 mg, 0.384 mmol), Grubbs' 2nd generation catalyst (Sigma Aldrich, 65.1 mg, 0.077 mmol), and DCM (7673 μΐ) was purged with argon. It was subsequently sealed and heated to 50°C for 3 h. The reaction mixture was cooled to RT, and the mixture was concentrated in vacuo. The mixture of isomers was subsequently purified by SFC SFC (AD-H Column, 5 μηι in width at 21x150 mm, P = 200 bar, T = 40 °C with 40% EtOH at 1 mL/min, solubilized in 1 : 1 DCM/MeOH), affording both d3 diastereomers of (9S,1 1E)-16- methyl-13-(2-(methylsulfonyl)ethyl)-3,7,14,17,23- pentaazapentacyclo[l 3.6.2. l~2,5~.0~4,9~.0~18,22~]tetracosa-
1 (22),2(24),4, 11 , 15, 17, 18,20,22-nonaen-6-one:
First eluting diastereomer, Example 89 (49.5 mg, 56%): ¾ NM (400 MHz, DMSO-i/6) δ ppm 13.38 - 13.44 (1 H, m) 7.94 - 8.00 (1 H, m) 7.56 - 7.61 (1 H, m) 7.51 - 7.56 (1 H, m) 7.26 - 7.36 (1 H, m) 7.00 - 7.06 (1 H, m) 6.88 (1 H, s) 6.18 - 6.28 (1 H, m) 5.94 - 6.09 (1 H, m) 4.19 - 4.28 (1 H, m) 3.13 - 3.24 (3 H, m) 2.95 (3 H, s) 2.59 - 2.69 (1 H, m) 2.57 (3 H, s) 2.36 - 2.43 (2 H, m) 2.21 - 2.36 (2 H, m) 1.45 (1 H, s): m/z (ESI, +ve) 452.1 (M+H)+. Second eluting diastereomer, Example 90 (32 mg, 37%): !H NMR (400 MHz, DMSO-i/6) δ ppm 13.37 - 13.42 (1 H, m) 7.94 - 8.00 (1 H, m) 7.55 - 7.59 (1 H, m) 7.50 - 7.54 (1 H, m) 7.22 - 7.30 (1 H, m) 6.99 - 7.06 (1 H, m) 6.86 (1 H, s) 6.12 - 6.19 (1 H, m) 5.90 - 6.08 (1 H, m) 4.19 - 4.26 (1 H, m) 3.14 - 3.23 (3 H, m) 2.91 (3 H, s) 2.57 - 2.66 (1
H, m) 2.53 (3 H, s) 2.37 - 2.41 (2 H, m) 2.20 - 2.35 (2 H, m) 1.43 (1 H, s): m/z (ESI, +ve) 452.1 (M+H)+. Example 91: (llE,13R)-16-methyl-13-(trifluoromethyl)-3,7,14,17,23- pentaazapentacyclo[13.6.2.1~2,5~.0~4,9~.0~18,22~]tetracosa- l(21),2(24),4,ll,15,17,19,22-octaen-6-one
Figure imgf000201_0001
Step 1 : ( ?)-l-(2-methyl-3-((l,l
Figure imgf000201_0002
A mixture of l-(3-chloro-2-methylquinoxalin-5-yl)ethanone (0.394 g, 1.786 mmol), (R)- l,l ,l-trifluorobut-3-en-2-amine hydrochloride (WO201 1053821, 0.346 g, 2.143 mmol), bis(tri-tert-butylphosphine)palladium (Strem Chemicals, 0.091 g, 0.179 mmol), and K3PO4 (1.327 g, 6.25 mmol) in iBuOH (17.86 ml) was sparged with N2 before it was heated in a sealed flask at 120 °C for 3 h. The crude product was adsorbed onto silica and was purified via automated flash chromatography (silica gel) with 100% hexanes to 40% EtOAc in hexanes to give ( ?)-l -(2-methyl-3-((l ,l ,l-trifluorobut-3-en-2- yl)amino)quinoxalin-5-yl)ethanone (50 mg, 0.162 mmol, 9.05 % yield) as a red oil. !H
NMR (400 MHz, CD CI 3) δ ppm 2.67 (s, 3 H) 2.87 (s, 3 H) 5.10 (d, J=9.00 Hz, 1 H) 5.47 - 5.59 (m, 2 H) 5.68 - 5.80 (m, 1 H) 6.04 (ddd, J=16.87, 10.81 , 5.58 Hz, 1 H) 7.48 (t, J=7.82 Hz, 1 H) 7.93 (dd, J=7.34, 1.47 Hz, 1 H) 8.00 (dd, J=8.22, 1.37 Hz, 1 H). 19F NMR (377 MHz, CD CI 3) δ ppm -75.24 (s, 3 F). MS (ESI, pos. ion) m/z: 310.1 (M+H)+.
Step 2 : ( ?)-2-bromo-l -(2-methyl-3-((l , 1 , 1 -trifluorobut-3-en-2-yl)amino)quinoxalin-5- yl)ethanone
A solution of ( ?)-l -(2-methyl-3-((l,l ,l-trifluorobut-3-en-2-yl)amino)quinoxalin-5- yl)ethanone (50 mg, 0.162 mmol), tert-butyldimethylsilyl trifluoromethanesulfonate (Aldrich, 64.1 mg, 0.242 mmol), and TEA (49.1 mg, 0.485 mmol) in DCM (1617 μΐ) was stirred at 0 °C for 1 h. The reaction mixture was diluted with DCM (100 ml), added to a separatory funnel, and washed with saturated aqueous NaHC03 (2 x 75 ml) before the organic layer was separated, dried over Na2S04, and concentrated to give an oil: MS (ESI, pos. ion) m/z: 424.2 (M+l). A solution of this material, l -bromopyrrolidine-2,5-dione (Aldrich, 28.8 mg, 0.162 mmol), and water (46 μΐ) in THF (1617 μΐ) was stirred at RT for 1 h. The reaction mixture was diluted with DCM (100 ml), added to a separatory funnel, and washed with saturated aqueous NaHCC (2 x 75 ml) before the organic layer was separated, dried over Na2S04, and concentrated. The crude product was adsorbed onto silica and was purified via automated flash chromatography (silica gel) with 100% hexanes to 30% EtOAc in hexanes to give ( ?)-2-bromo- l-(2-methyl-3-(( 1,1, 1 - trifluorobut-3-en-2-yl)amino)quinoxalin-5-yl)ethanone (33 mg, 0.085 mmol, 52.6 % yield) as an off-white solid. !H NMR (400 MHz, CDC ) δ ppm 2.69 (s, 3 H) 4.81 - 4.87 (m, 1 H) 4.94 - 5.00 (m, 1 H) 5.12 (d, J=9.00 Hz, 1 H) 5.52 - 5.61 (m, 2 H) 5.65 - 5.76 (m, 1 H) 6.05 (ddd, J=16.82, 10.76, 5.48 Hz, 1 H) 7.52 (t, J=7.73 Hz, 1 H) 8.06 (s, 1 H) 8.08 (s, 1 H). 19F NMR (377 MHz, CDCl3) δ ppm -75.11 (s, 3 F). MS (ESI, pos. ion) m/z: 388.0/390.0 (M+H)+.
Step 3: 7-allyl-2-(2-methyl-3-((( ?)-l,l ,l -trifluorobut-3-en-2-yl)amino)quinoxalin-5-yl)- 6,7-dihydro-lH-pyrrolo[3,2-c]pyridin-4(5H)-one
A solution of 5-allylpiperidine-2,4-dione (Intermediate A, 19.53 mg, 0.128 mmol), (R)-2- bromo- 1 -(2-methyl-3 -((1,1,1 -trifluorobut-3 -en-2-yl)amino)quinoxalin-5 -yl)ethanone (33 mg, 0.085 mmol), and NH4OAc (Aldrich, 32.8 mg, 0.425 mmol) in MeOH (850 μΐ) was heated to 50 °C for 16 h. The reaction mixture was diluted with DCM (100 ml), added to a separatory funnel, and washed with saturated aqueous NaHC03 (75 ml) before the organic layer was separated, dried over Na2S04, and concentrated. The crude product was adsorbed onto silica and was purified via automated flash chromatography (silica gel) with 100% DCM to 5% 2 M NH3 in MeOH/DCM to give 7-allyl-2-(2-methyl-3-(((^)- 1,1 ,1 -trifluorobut-3-en-2-yl)amino)quinoxalin-5-yl)-6,7-dihydro- lH-pyrrolo[3,2- c]pyridin-4(5H)-one (5 mg, 0.011 mmol, 13%) as a yellow oil: !H NMR (400 MHz, CDCh) δ ppm 2.43 - 2.56 (m, 2 H) 2.70 (s, 3 H) 2.98 - 3.07 (m, 1 H) 3.40 - 3.48 (m, 1 H)
3.73 - 3.80 (m, 1 H) 5.07 (d, J=7.43 Hz, 1 H) 5.10 - 5.21 (m, 2 H) 5.39 - 5.49 (m, 2 H) 5.57 - 5.65 (m, 2 H) 5.77 - 5.90 (m, 1 H) 6.12 (ddt, J=16.77, 11.00, 5.38, 5.38 Hz, 1 H) 7.13 (dd, J=6.46, 2.15 Hz, 1 H) 7.48 (t, J=7.92 Hz, 1 H) 7.75 (d, J=8.22 Hz, 1 H) 7.93 - 7.99 (m, 1 H) 1 1.46 (d, J=53.21 Hz, 1 H). iyF NMR (376 MHz, CDCh) δ ppm -74.60 (s, 3 F) -74.34 (s, 3 F). MS (ESI, pos. ion) m/z: 442.2 (M+H)+.
Step 4: (1 lE,13^)-16-methyl-13-(trifluoromethyl)-3,7,14,17,23- pentaazapentacyclo[l 3.6.2. l~2,5~.0~4,9~.0~18,22~]tetracosa- 1 (21 ),2(24),4, 11 , 15 , 17, 19,22-octaen-6-one
A solution of 7-allyl-2-(2-methyl-3-((( ?)-l ,1 ,1 -trifluorobut-3-en-2-yl)amino)quinoxalin- 5-yl)-6,7-dihydro-lH-pyrrolo[3,2-c]pyridin-4(5H)-one (5 mg, 0.011 mmol) and Grubbs catalyst 2nd generation (1.923 mg, 2.265 μιηοΐ) in DCM (227 μΐ) was stirred at 50 °C in a sealed tube for 2 h. The reaction mixture was concentrated and dissolved in DCE (1.5 ml) before adding more Grubbs catalyst 2nd generation (1.923 mg, 2.265 μιηοΐ); the reaction mixture was sparged with N2 then heated in a sealed tube at 80 °C for 16 h when some product was observed. The crude product was dissolved in MeOH and injected (3 x 1.000 ml) onto the Shimadzu preparatory LC (Phenomenex Gemini Cis column (150 x 30 mm, 10 μιη), 35 mL/min, 5-100% CH3CN/H20 + 0.1 % TFA) before the pure fractions were combined, basicified with NaHC03 (saturated, aqueous), extracted with DCM, separated, dried over Na2S04, and concentrated via rotary evaporation to give impure product. A preparatory TLC plate was loaded with the impure mixture and run 1 time in 30% EtOH/[hexanes/EtOAc (2: 1)]; after scraping the plate, extraction with DCM/MeOH, filtration, and concentration via rotary evaporation, (1 lE,13 ?)-16-methyl-13-
(trifluoromethyl)-3,7, 14,17,23- pentaazapentacyclo[l 3.6.2. l~2,5~.0~4,9~.0~18,22~]tetracosa- l(21),2(24),4,l l,15,17,19,22-octaen-6-one (1 mg, 2.4 μιηοΐ, 28%o) was obtained as a yellow solid: !H NMR (400 MHz, CDCl3) δ ppm 2.36 - 2.47 (m, 1 H) 2.67 (s, 3 H) 2.72 - 2.82 (m, 1 H) 3.43 - 3.52 (m, 3 H) 4.65 - 4.75 (m, 1 H) 5.26 - 5.41 (m, 2 H) 6.06 - 6.16 (m, 1 H) 6.19 - 6.31 (m, 1 H) 7.04 (d, J=1.96 Hz, 1 H) 7.45 - 7.51 (m, 1 H) 7.70 (dd, J=8.22, 1.17 Hz, 1 H) 7.94 (d, J=7.43 Hz, 1 H). 19F NMR (376 MHz, CDCl3) δ ppm - 76.71 (s, 3 F). MS (ESI, pos. ion) m/z: 414.2 (M+H)+. Example 92: (9S,13S)-21-fluoro-13,16-dimethyl-3,7,14,17,23- pentaazapentacyclo[13.6.2.1~2,5~.0~4,9~.0~18,22~]tetracosa- l(21),2(24),4,15,17,19,22-heptaen-6-one
Figure imgf000204_0001
A heterogenous solution of (9S,1 lE,13S)-21-fluoro-13,16-dimethyl-3,7,14,17,23- pentaazapentacyclo[l 3.6.2.1~2,5~.0~4,9~.0~18,22~]tetracosa- l(21),2(24),4,l l,15,17,19,22-octaen-6-one (Example 84, 88 mg, 0.233 mmol) in THF (12 mL) was degassed by bubbling N2 through the solution for 10 min. 10% Pd/C (Sigma Aldrich, 248 mg, 0.233 mmol) was added to the reaction mixture. A gas bag with a 3- way stopcock filled with H2 was attached to the flask. The flask was evacuated under vaccuum and then back-filled with H2 (3X). The mixture was stirred for 21 h at RT. The solution was degassed by bubbling N2 through the solution for 10 min and then filtered through Celite and concentrated. The crude product was resubjected to the reaction conditions. The crude product was dissolved in THF (12 mL) and the solution was degassed by bubbling N2 through the solution for 10 min. 10% Pd/C (Sigma Aldrich, 50 mg, 0.047 mmol, 0.2 eq) was added. A gas bag with a 3-way stopcock filled with H2 was attached to the flask. The flask was evacuated under vaccuum and then back-filled with H2 (3X). The mixture was stirred for 21 h at RT. The solution was degassed by bubbling N2 through the solution for 10 min and then filtered through Celite and concentrated. The yellow solid was dissolved in 4 mL of MeOH and H202 (Sigma Aldrich, 30 wt. % solution in water, 0.026 mL, 0.256 mmol) and FeCl2 (Alfa Aesar, Ward Hill, MA, 1.5 mg, 0.012 mmol) were added at RT. The mixture was stirred at RT for 1 h and then brine and
CH2C12 were added. The layers were separated and the aqueous layer was extracted with 10% MeOH in CH2C12 (2X). The combined organic layers were dried over anhydrous Na2S04, filtered and concentrated to give 120 mg of crude product. The crude material was absorbed onto a plug of silica gel and purified by silica gel chromatography (12 g), eluting with a gradient of 0-5% MeOH in CH2C12, to provide (9S,13S)-21-fluoro-13,16- dimethyl-3,7,14,17,23-pentaazapentacyclo[l 3.6.2.1~2,5~.0~4,9~.0~18,22~]tetracosa- l(21),2(24),4,15,17,19,22-heptaen-6-one (32 mg, 0.084 mmol, 36 % yield) as a yellow solid. !H NMR (400 MHz, DMSO-d6) δ ppm 13.59 (br. s., 1 H), 7.61 (dd, J=8.90, 5.58 Hz, 1 H), 7.33 (dd, J=11.64, 9.10 Hz, 1 H), 7.25 (d, J=4.89 Hz, 1 H), 7.13 (d, J=4.1 1 Hz, 1 H), 6.96 (d, J=4.11 Hz, 1 H), 3.12 - 3.30 (m, 2 H), 2.99 - 3.09 (m, 1 H), 2.57 (s, 3 H),
2.32 - 2.42 (m, 1 H), 2.18 - 2.31 (m, 1 H), 1.94 - 2.07 (m, 1 H), 1.60 - 1.74 (m, 1 H), 1.42 - 1.50 (m, 1 H), 1.40 (d, J=6.65 Hz, 3 H), 1.36 - 1.50 (m, 1 H), 1.23 - 1.35 (m, 1 H). 19F- NMR (376 MHz, DMSO-i/6) δ ppm -108.92. m/z (ESI, +ve) 380.1 (M+H)+.
Example 93: tert-butyl (2-((9S,HZ)-16-methyl-6-oxo-3,7,14,17,23- pentaazapentacyclo[13.6.2.1~2,5~.0~4,9~.0~18,22~]tetracosa- l(21),2(24),4,ll,15,17,19,22-octaen-14-yl)ethyl)carbamate
Example 94: tert-butyl (2-((9S,HE)-16-methyl-6-oxo-3,7,14,17,23- pentaazapentacyclo[13.6.2.1~2,5~.0~4,9~.0~18,22~]tetracosa- l(21),2(24),4,ll,15,17,19,22-octaen-14-yl)ethyl)carbamate
Figure imgf000205_0001
Step 1 : tert-butyl (2-(allylamino)ethyl)carbamate
3-Bromoprop-l -ene (Aldrich, 1.685 ml, 19.47 mmol) was added to a mixture of tert-butyl (2-aminoethyl)carbamate (Fluka, 3.08 ml, 19.47 mmol) and KOAc (2.293 g, 23.37 mmol) in THF (97 ml) at 65 °C; the reaction mixture was stirred at 65 °C for 2 h. The reaction mixture was diluted with DCM (200 ml), added to a separatory funnel, and washed with water (2 x 100 ml). The aqueous layer was extracted with CHC¾/IPA(3 :2) (4 x 100 ml) before the combined organic layers were dried over Na2S04, and concentrated. The crude product was adsorbed onto silica and was purified via automated flash chromatography (silica gel) with 100% EtOAc to 30% MeOH in EtOAc to give tert-butyl (2- (allylamino)ethyl)carbamate (650 mg, 3.25 mmol, 16.67 % yield) as a colorless oil: !H NMR (400 MHz, CDCl3) δ ppm 1.31 (br. s., 1 H) 1.45 (s, 9 H) 2.74 (t, J=5.87 Hz, 2 H) 3.18 - 3.29 (m, 4 H) 4.96 (br. s., 1 H) 5.10 (dd, J=10.17, 1.37 Hz, 1 H) 5.18 (dq, J=17.12, 1.60 Hz, 1 H) 5.88 (ddt, =16.95, 10.54, 6.02, 6.02 Hz, 1 H). MS (ESI, pos. ion) m/z: 201.2 (M+H)+.
Step 2: (S)-tert-butyl (2-(allyl(8-(7-allyl-4-oxo-4,5,6,7-tetrahydro-lH-pyrrolo[3,2- c]pyridin-2-yl)-3-methylquinoxalin-2-yl)amino)ethyl)carbamate
A solution of (S)-7-allyl-2-(3-fluoro-2-methylquinoxalin-5-yl)-6,7-dihydro-lH- pyrrolo[3,2-c]pyridin-4(5H)-one (Intermediate D, 672 mg, 1.997 mmol), tert-butyl (2- (allylamino)ethyl)carbamate (600 mg, 3.00 mmol), and N-ethyl-N-isopropylpropan-2- amine (1044 μΐ, 5.99 mmol) in DMSO (3994 μΐ) was stirred at 80 °C for 16 h. The reaction mixture was diluted with DCM (150 ml), added to a separatory funnel, and washed with saturated aqueous NaHC03 (3 x 100 ml) before the organic layer was separated, dried over Na2S04, and concentrated. The crude product was adsorbed onto silica and was purified via automated flash chromatography (silica gel) with 100% DCM to 3% 2 M NH3 in MeOH/DCM to give (S)-tert-butyl (2-(allyl(8-(7-allyl-4-oxo-4,5,6,7- tetrahydro-lH-pyrrolo[3,2-c]pyridin-2-yl)-3-methylquinoxalin-2- yl)amino)ethyl)carbamate (930 mg, 1.800 mmol, 90 % yield) as a yellow amorphous solid: !H NMR (400 MHz, CDCl3) δ ppm 1.28 (s, 9 H) 2.42 - 2.53 (m, 1 H) 2.60 - 2.68 (m, 1 H) 2.77 (s, 3 H) 3.07 - 3.15 (m, 1 H) 3.32 - 3.45 (m, 3 H) 3.56 - 3.76 (m, 3 H) 4.13 (d, J=5.09 Hz, 2 H) 4.59 (t, J=5.97 Hz, 1 H) 5.09 - 5.20 (m, 2 H) 5.28 - 5.45 (m, 3 H) 5.79 - 5.91 (m, 1 H) 5.91 - 6.04 (m, 1 H) 7.15 (d, J=1.56 Hz, 1 H) 7.52 (t, J=7.92 Hz, 1
H) 7.74 (dd, J=8.22, 1.17 Hz, 1 H) 7.96 (d, J=7.43 Hz, 1 H) 1 1.86 (br. s., 1 H). MS (ESI, pos. ion) m/z: 517.4 (M+H)+.
Step 3 : tert-butyl (2-((9S,l lZ)-16-methyl-6-oxo-3,7,14,17,23- pentaazapentacyclo[l 3.6.2. l~2,5~.0~4,9~.0~18,22~]tetracosa-
1(21),2(24),4,1 l,15,17,19,22-octaen-14-yl)ethyl)carbamate and tert-butyl (2-((9S,l 1E)- 16-methyl-6-oxo-3 ,7, 14, 17,23- pentaazapentacyclo[l 3.6.2.1~2,5~.0~4,9~.0~18,22~]tetracosa- 1 (21 ),2(24),4, 11 , 15, 17, 19,22-octaen-l 4-yl)ethyl)carbamate
A solution of (S)-tert-butyl (2-(allyl(8-(7-allyl-4-oxo-4,5,6,7-tetrahydro-lH-pyrrolo[3,2- c]pyridin-2-yl)-3-methylquinoxalin-2-yl)amino)ethyl)carbamate (0.930 g, 1.800 mmol) and Grubbs catalyst 2nd generation (0.306 g, 0.360 mmol) in DCM (36.0 ml) was sparged with N2 before it was heated to reflux under N2 for 1.5 h. The crude product was adsorbed onto silica and was purified via automated flash chromatography (silica gel) with 100% DCM to 5% 2 M NH3 in MeOH/DCM to give a mixture of E/Z macrocycle isomers as a rust colored solid. SFC purification of the mixture:
Column: AS-H (10 μιη, 21 mm x 250 mm), F = 70 ml/min, 55% MeOH/C02. Entire sample dissolved in 420 ml MeOH/DCM 6/1, P = 100 bar, 7 ml injection, 290 nm, gave tert-butyl (2-((9S,l lZ)-16-methyl-6-oxo-3,7,14,17,23- pentaazapentacyclo[l 3.6.2. l~2,5~.0~4,9~.0~18,22~]tetracosa- l(21),2(24),4,l l,15,17,19,22-octaen-14-yl)ethyl)carbamate (0.40 g, 0.819 mmol, 45.5 % yield) as a brown solid and tert-butyl (2-((9S,l lE)-16-methyl-6-oxo-3,7,14,17,23- pentaazapentacyclo[l 3.6.2. l~2,5~.0~4,9~.0~18,22~]tetracosa- l(21),2(24),4,l l,15,17,19,22-octaen-14-yl)ethyl)carbamate (0.28 g, 0.573 mmol, 31.8 % yield) as a brown solid.
Analytical data for tert-butyl (2-((9S,l lZ)-16-methyl-6-oxo-3,7,14,17,23- pentaazapentacyclo[l 3.6.2. l~2,5~.0~4,9~.0~18,22~]tetracosa-
1(21),2(24),4,1 l,15,17,19,22-octaen-14-yl)ethyl)carbamate: !H NMR (400 MHz, CDCl3) δ ppm 1.37 (s, 9 H) 2.25 - 2.38 (m, 1 H) 2.60 (d, J=13.69 Hz, 1 H) 2.76 (s, 3 H) 3.28 - 3.39 (m, 3 H) 3.43 - 3.56 (m, 3 H) 3.62 (d, J=6.06 Hz, 1 H) 4.13 - 4.23 (m, 1 H) 4.25 - 4.34 (m, 1 H) 5.02 (br. s., 1 H) 5.42 (d, J=2.15 Hz, 1 H) 5.92 (dd, J=13.89, 11.93 Hz, 1 H) 6.20 (dd, J=15.94, 7.34 Hz, 1 H) 7.07 (d, J=1.96 Hz, 1 H) 7.49 (t, J=7.82 Hz, 1 H) 7.69 (d, J=7.82 Hz, 1 H) 7.96 (d, J=7.43 Hz, 1 H) 13.12 (br. s., 1 H). MS (ESI, pos. ion) mix: 489.4 (M+H)+.
Analytical data for tert-butyl (2-((9S,l lE)-16-methyl-6-oxo-3,7,14,17,23- pentaazapentacyclo[l 3.6.2. l~2,5~.0~4,9~.0~18,22~]tetracosa-
1(21),2(24),4,1 l,15,17,19,22-octaen-14-yl)ethyl)carbamate: !H NMR (400 MHz, CDCl3) δ ppm 1.34 (s, 9 H) 2.31 (d, J=14.08 Hz, 1 H) 2.68 - 2.80 (m, 1 H) 2.81 (s, 3 H) 3.28 - 3.39 (m, 2 H) 3.40 - 3.47 (m, 2 H) 3.54 - 3.61 (m, 2 H) 3.73 (d, J=16.04 Hz, 1 H) 3.82 (dt, J=14.23, 7.07 Hz, 1 H) 4.53 (t, J=5.67 Hz, 1 H) 4.83 (dd, J=16.33, 8.12 Hz, 1 H) 5.33 (br. s., 1 H) 5.69 - 5.86 (m, 2 H) 6.99 (d, J=1.96 Hz, 1 H) 7.49 (t, J=7.82 Hz, 1 H) 7.71 (dd, J=8.22, 0.98 Hz, 1 H) 7.86 (d, J=6.65 Hz, 1 H) 12.82 (br. s., 1 H). MS (ESI, pos. ion) mix: 489.2 (M+H)+.
Example 95: (9S,llZ)-14-(2-aminoethyl)-16-methyl-3,7,14,17,23- pentaazapentacyclo[13.6.2.1~2,5~.0~4,9~.0~18,22~]tetracosa- l(21),2(24),4,ll,15,17,19,22-octaen-6-one
Figure imgf000208_0001
A brown solution of tert-butyl (2-((9S,l lZ)-16-methyl-6-oxo-3,7,14,17,23- pentaazapentacyclo[l 3.6.2. l~2,5~.0~4,9~.0~18,22~]tetracosa- 1(21),2(24),4,1 l,15,17,19,22-octaen-14-yl)ethyl)carbamate (Example 93, 0.40 g, 0.819 mmol) and TFA (6.31 ml, 82 mmol) in DCM (8.19 ml) was stirred at RT for 15 min. The reaction mixture was concentrated to give (9S,1 lZ)-14-(2-aminoethyl)-16-methyl- 3,7,14, 17,23-pentaazapentacyclo[l 3.6.2. l~2,5~.0~4,9~.0~18,22~]tetracosa- l(21),2(24),4,l l,15,17,19,22-octaen-6-one (0.368 g, 0.732 mmol, 89 % yield) as a yellow solid. Pure (9S,1 lZ)-14-(2-aminoethyl)-16-methyl-3,7,14,17,23- pentaazapentacyclo[l 3.6.2. l~2,5~.0~4,9~.0~18,22~]tetracosa-
1(21),2(24),4,1 l,15,17,19,22-octaen-6-one (27 mg) was obtained after suspension of the solid in DCM/MeOH, filtration, and drying the solid in vacuo. !H NMR (400 MHz, DMSO-i/6) δ ppm 2.32 (d, J=13.30 Hz, 1 H) 2.69 (d, J=l 1.93 Hz, 1 H) 2.79 (s, 3 H) 3.20 - 3.27 (m, 2 H) 3.33 - 3.42 (m, 3 H) 3.68 - 3.79 (m, 1 H) 3.79 - 3.89 (m, 2 H) 4.75 (dd, J=16.63, 8.61 Hz, 1 H) 5.76 (dd, J=10.95, 7.63 Hz, 1 H) 5.87 (t, J=11.35 Hz, 1 H) 6.85 (d, J=1.76 Hz, 1 H) 7.05 (d, J=4.30 Hz, 1 H) 7.50 (t, J=7.82 Hz, 1 H) 7.67 (d, J=7.83 Hz, 1 H) 7.87 (br. s., 2 H) 7.97 (d, J=7.43 Hz, 1 H) 12.95 (br. s., 1 H). 19F NMR (376 MHz, DMSO-i/6) δ ppm -73.48 (s, 3 F). MS (ESI, pos. ion) m/z: 389.1 (M+H)+.
Example 96: (9S)-14-(2-hydroxyethyl)-16-methyl-3,7,14,17,23- pentaazapentacyclo[13.6.2.1~2,5~.0~4,9~.0~18,22~]tetracosa- l(22),2(24),4,15,17,18,20,22-octaen-6-one
Figure imgf000208_0002
A suspension of (9S,l lE)-14-(2-hydroxyethyl)-16-methyl-3,7,14,17,23- pentaazapentacyclo[13.6.2.1~2,5~.0~4,9~.0~18,22~]tetracosa- l(22),2(24),4,l l,15(23),16,18,20-octaen-6-one (Example 76; 35 mg, 0.090 mmol) and Pd/C (10 wt% (dry basis), wet, degussa type elOl ne/w) (Aldrich; 106 mg, 0.045 mmol) in THF (3.0 mL) was stirred under a H2 atmosphere (1 atm) at 55 °C for 2 h. The reaction mixture was then filtered through Celite, and the Celite pad was washed with (1 :1) MeOH/DCM (10 mL). The combined filtrates were concentrated in vacuo to provide a yellow oil. This oil was taken up in MeOH (0.9 mL), iron(II) chloride (Alfa Aesar, Ward Hill, MA; 0.338 mg, 2.67 μιηοΐ) and 30% aqueous H202 (9.99 μΐ, 0.098 mmol) were sequentially added, and the resulting solution was stirred at 23 °C for 1 h. The reaction mixture was then diluted with DCM (100 ml) and washed with saturated aqueous NaHC03 solution (2 χ 75 ml). The organic layer was separated, dried over Na2S04, filtered, and concentrated onto silica gel. Chromatographic purification (silica gel, 0-4% (2 M NH3 in MeOH)/DCM) followed by rpHPLC purification of product-containing fractions (Phenomenex Gemini Cis column (150 x 30 mm, 10 mm), 35 mL/min, 5-100% CH3CN/H20 + 0.1% TFA) afforded the TFA salt of the product, which was partitioned between DCM and saturated aqueous NaHC03 solution. The organic layer was separated, dried over Na2S04, filtered, and concentrated in vacuo to provide (9S)-14-(2- hydroxyethyl)- 16-methyl-3,7, 14, 17,23- pentaazapentacyclo[l 3.6.2. l~2,5~.0~4,9~.0~18,22~]tetracosa- l(22),2(24),4,15,17,18,20,22-octaen-6-one (2.04 mg, 5.21 μιηοΐ, 6% yield) as a yellow- green solid: !H NMR (400 MHz, DMSO-d6) δ ppm 7.99 (1 H, d, J=7.6 Hz), 7.61 (1 H, d, J=8.2 Hz), 7.42 (1 H, t, J=7.7 Hz), 7.02 (1 H, d, J=3.7 Hz), 6.92 (1 H, s), 4.88 (1 H, t, J=4.9 Hz), 3.87 (1 H, br. s.), 3.68 - 3.77 (4 H, m), 3.37 - 3.47 (2 H, m), 3.11 - 3.18 (1 H, m), 3.05 (1 H, br. s.), 2.77 (3 H, s), 2.08 - 2.20 (1 H, m), 1.95 - 2.08 (1 H, m), 1.87 (1 H, br. s.), 1.71 (3 H, br. s.). m/z (ESI, +ve) 392.1 (M+H)+.
Example 97: (9S,llZ)-16-methyl-14-(2-((2-(methylsulfonyl)ethyl)amino)ethyl)-
3,7,14,17,23-pentaazapentacyclo[13.6.2.1~2,5~.0~4,9~.0~18,22~]tetracosa- l(21),2(24),4,ll,15,17,19,22-octaen-6-one
Figure imgf000210_0001
A mixture of (9S,1 lZ)-14-(2-aminoethyl)-16-methyl-3,7,14,17,23- pentaazapentacyclo[l 3.6.2.1~2,5~.0~4,9~.0~18,22~]tetracosa- l(21),2(24),4,l l,15,17,19,22-octaen-6-one (Example 95, 76 mg, 0.151 mmol), TEA (31.6 μΐ, 0.227 mmol), and (methylsulfonyl)ethene (Aldrich, 132 μΐ, 1.512 mmol) in THF (504 μ1)/ΙΡΑ (1008 μΐ) was heated in the microwave at 120 °C for 10 min (x3). The crude product was adsorbed onto silica and was purified via automated flash chromatography (silica gel) with 100% DCM to 7% 2 M NH3 in MeOH/DCM to give (9S,1 lZ)-16-methyl- 14-(2-((2-(methylsulfonyl)ethyl)amino)ethyl)-3,7,14,17,23- pentaazapentacyclo[l 3.6.2. l~2,5~.0~4,9~.0~18,22~]tetracosa- l(21),2(24),4,l l,15,17,19,22-octaen-6-one (49 mg, 0.099 mmol, 65.5 % yield) as a yellow solid: !H NMR (400 MHz, CDCl3) δ ppm 2.31 (d, J=14.08 Hz, 1 H) 2.69 - 2.80 (m, 1 H) 2.82 (s, 3 H) 2.87 (s, 3 H) 2.91 - 3.01 (m, 2 H) 3.03 - 3.08 (m, 2 H) 3.10 - 3.15 (m, 2 H) 3.29 - 3.39 (m, 1 H) 3.43 - 3.52 (m, 2 H) 3.56 - 3.65 (m, 1 H) 3.68 (t, J=6.94 Hz, 1 H) 3.71 - 3.80 (m, 1 H) 4.84 (dd, J=16.33, 7.92 Hz, 1 H) 5.35 (d, J=3.52 Hz, 1 H) 5.70 - 5.86 (m, 2 H) 6.98 (d, J=2.15 Hz, 1 H) 7.48 (dd, J=8.12, 7.53 Hz, 1 H) 7.70 (dd, J=8.22, 1.17 Hz, 1 H) 7.86 (dd, J=7.43, 1.17 Hz, 1 H) 12.84 (br. s., 1 H). MS (ESI, pos. ion) m/z: 495.2 (M+H)+.
Example 98: (9S,llE)-14-(2-aminoethyl)-16-methyl-3,7,14,17,23- pentaazapentacyclo[13.6.2.1~2,5~.0~4,9~.0~18,22~]tetracosa- l(21),2(24),4,ll,15,17,19,22-octaen-6-one
Figure imgf000210_0002
A solution of tert-butyl (2-((9S,l lE)-16-methyl-6-oxo-3,7,14,17,23- pentaazapentacyclo[l 3.6.2. l~2,5~.0~4,9~.0~18,22~]tetracosa- l(21),2(24),4,l l,15,17,19,22-octaen-14-yl)ethyl)carbamate (Example 94, 0.28 g, 0.573 mmol) and TFA (2.208 ml, 28.7 mmol) in DCM (5.73 ml) was stirred at RT for 30 min. The reaction mixture was concentrated to give (9S,1 lE)-14-(2-aminoethyl)-16-methyl- 3,7,14, 17,23-pentaazapentacyclo[l 3.6.2. l~2,5~.0~4,9~.0~18,22~]tetracosa- l(21),2(24),4,l l,15,17,19,22-octaen-6-one (0.28 g, 0.557 mmol, 97 % yield) as a brown solid: !H NMR (400 MHz, DMSO-i¾) δ ppm 2.24 - 2.35 (m, 1 H) 2.59 - 2.67 (m, 1 H) 2.71 (s, 3 H) 2.97 - 2.98 (m, 1 H) 3.10 - 3.20 (m, 2 H) 3.21 - 3.33 (m, 2 H) 3.61 (t, J=7.73 Hz, 2 H) 4.20 (br. s., 2 H) 5.95 - 6.07 (m, 1 H) 6.22 (d, J=15.26 Hz, 1 H) 6.98 (d, J=2.15 Hz, 1 H) 7.10 (br. s., 1 H) 7.48 - 7.56 (m, 1 H) 7.66 (d, J=8.22 Hz, 1 H) 7.87 (br. s., 2 H) 8.1 1 (d, J=7.63 Hz, 1 H) 13.07 (br. s., 1 H). MS (ESI, pos. ion) m/z: 389.1 (M+H)+.
Example 99: N-(2-((9S,HZ)-16-methyl-6-oxo-3,7,14,17,23- pentaazapentacyclo[13.6.2.1~2,5~.0~4,9~.0~18,22~]tetracosa- l(21),2(24),4,ll,15,17,19,22-octaen-14-yl)ethyl)acetamide
Figure imgf000211_0001
A solution of (9S,l lZ)-14-(2-aminoethyl)-16-methyl-3,7,14,17,23- pentaazapentacyclo[l 3.6.2. l~2,5~.0~4,9~.0~18,22~]tetracosa- l(21),2(24),4,l l,15,17,19,22-octaen-6-one (Example 95, 46 mg, 0.092 mmol), acetic anhydride (Fluka Chemie GmbH, 43.2 μΐ, 0.458 mmol), and TEA (89 μΐ, 0.641 mmol) in DCM (915 μΐ) was stirred at RT for 2 h. The crude product was adsorbed onto silica and was purified via automated flash chromatography (silica gel) with 100% DCM to 7% 2 M
NH3 in MeOH/DCM to give N-(2-((9S, 11 Z)- 16-methyl-6-oxo-3 ,7, 14, 17,23 - pentaazapentacyclo[l 3.6.2. l~2,5~.0~4,9~.0~18,22~]tetracosa-
1(21),2(24),4,1 l ,15,17,19,22-octaen-14-yl)ethyl)acetamide as a red oil contaminated with Et3N. The impure product was dissolved in DMSO (~20 mg/ml) and injected (2 x 1.000 ml) onto the Shimadzu preparatory LC (Phenomenex Gemini Cis column (150 x 30 mm, 10 μιη), 35 mL/min, 5-100% CH3CN/H20 + 0.1% TFA) before the pure fractions were combined, basicified with NaHC03 (saturated, aqueous), extracted with DCM, separated, dried over Na2S04, and concentrated via rotary evaporation to give N-(2-((9S,l 1Z)-16- methyl-6-oxo-3 ,7,14,17,23- pentaazapentacyclo[l 3.6.2. l~2,5~.0~4,9~.0~18,22~]tetracosa- l(21),2(24),4,l l,15,17,19,22-octaen-14-yl)ethyl)acetamide (18 mg, 0.042 mmol, 45.7 % yield) as a yellow solid: !H NMR (400 MHz, DMSO-i/6) δ ppm 1.60 (s, 3 H) 2.29 - 2.37 (m, 1 H) 2.78 (s, 3 H) 3.23 (d, J=8.02 Hz, 2 H) 3.40 (t, J=4.99 Hz, 1 H) 3.54 - 3.62 (m, 1 H) 3.80 - 3.90 (m, 3 H) 4.76 (dd, J=16.73, 7.73 Hz, 1 H) 5.70 - 5.77 (m, 1 H) 5.79 - 5.88 (m, 1 H) 6.85 (d, J=2.15 Hz, 1 H) 7.06 (d, J=4.50 Hz, 1 H) 7.46 (t, J=7.82 Hz, 1 H) 7.65 (dd, J=8.02, 1.17 Hz, 1 H) 7.90 - 7.98 (m, 2 H) 13.06 (s, 1 H). MS (ESI, pos. ion) m/z: 431.1 (M+H)+.
Example 100: N-(2-((9S,llZ)-16-methyl-6-oxo-3,7,14,17,23- pentaazapentacyclo[13.6.2.1~2,5~.0~4,9~.0~18,22~]tetracosa- l(21),2(24),4,ll,15,17,19,22-octaen-14-yl)ethyl)methanesulfonamide
Figure imgf000212_0001
A solution of (9S,l lZ)-14-(2-aminoethyl)-16-methyl-3,7,14,17,23- pentaazapentacyclo[l 3.6.2. l~2,5~.0~4,9~.0~18,22~]tetracosa- l(21),2(24),4,l l,15,17,19,22-octaen-6-one (Example 95, 60 mg, 0.119 mmol), methanesulfonyl chloride (Acros, 46.2 μΐ, 0.597 mmol), and TEA (116 μΐ, 0.836 mmol) in DCM (1194 μΐ) was stirred at RT for 24 h. The reaction mixture was concentrated, charged with pyridine (5 ml) and more methanesulfonyl chloride (46.2 μΐ, 0.597 mmol) and the reaction was stirred at RT for 1 h then at 50 °C for 16 h. The reaction mixture was concentrated, diluted with DCM (100 ml), added to a separatory funnel, and washed with 1 N aqueous citric acid (2 x 75 ml) before the material was dissolved in MeOH (~20 mg/ml) and injected (3 x 1.000 ml) onto the Shimadzu preparatory LC (Phenomenex Gemini Ci8 column (150 * 30 mm, 10 μπι), 35 mL/min, 5-100% CH3CN/H20 + 0.1% TFA) before organic layer was separated, dried over Na2S04, and concentrated. The crude product the pure fractions were combined, basicified with NaHC03 (saturated, aqueous), extracted with DCM, separated, dried over Na2S04, and concentrated via rotary evaporation to give N-(2-((9S,l lZ)-16-methyl-6-oxo-3,7, 14,17,23-pentaaza- pentacyclo[13.6.2.1~2,5~.0~4,9~.0~18,22~]tetracosa-l(21),2(24),4,l 1 , 15,17,19,22- octaen-14-yl)ethyl)methanesulfonamide (6 mg, 0.013 mmol, 10.77 % yield) as a yellow solid: !H NMR (400 MHz, CDCl3) δ ppm 2.22 (d, J=13.11 Hz, 1 H) 2.56 - 2.67 (m, 1 H) 2.85 (s, 3 H) 2.95 (s, 3 H) 3.16 - 3.28 (m, 2 H) 3.32 - 3.39 (m, 1 H) 3.45 (quin, J=6.16 Hz, 2 H) 3.71 - 3.84 (m, 2 H) 3.88 - 3.98 (m, 1 H) 4.86 (dd, J=16.24, 6.85 Hz, 1 H) 5.42 (d, J=4.30 Hz, 1 H) 5.74 (d, J=8.80 Hz, 2 H) 6.78 (d, J=2.15 Hz, 1 H) 7.46 (t, J=7.82 Hz, 1 H) 7.71 (dd, J=8.22, 1.17 Hz, 1 H) 7.75 (dd, J=7.43, 1.17 Hz, 1 H) 12.76 (br. s., 1 H). MS (ESI, pos. ion) m/z: 467.1 (M+H)+.
Example 101: (9S,llE,13S)-13-(hydroxymethyl)-16-methyl-14-oxa-3,7,17,23- tetraazapentacyclo[13.6.2.1~2,5~.0~4,9~.0~18,22~]tetracosa- l(22),2(24),4,ll,15,17,18,20,22-nonaen-6-one
Example 102: (9S,llZ)-13-(hydroxymethyl)-16-methyl-14-oxa-3,7,17,23- tetraazapentacyclo[13.6.2.1~2,5~.0~4,9~.0~18,22~]tetracosa- l(22),2(24),4,ll,15,17,18,20,22-nonaen-6-one
Example 103: (9S,llE,13R)-13-(hydroxymethyl)-16-methyl-14-oxa-3,7,17,23- tetraazapentacyclo[13.6.2.1~2,5~.0~4,9~.0~18,22~]tetracosa- l(22),2(24),4,ll,15,17,18,20,22-nonaen-6-one
Figure imgf000213_0001
Step 1 : l-((tert-butyldimethylsilyl)oxy)but-3-en-2-ol A solution of (tert-butyldimethylsilyloxy)acetaldehyde (Sigma Aldrich, 2.186 ml, 1 1.47 mmol) in THF (57.4 ml) at 0 °C was stirred under N2. A 1.0 M solution of
vinylmagnesium bromide in THF (Sigma Aldrich, 20.08 ml, 20.08 mmol) was added dropwise and the reaction was stirred for 45 min. A saturated aqueous solution of NH4C1 was added to quench the reaction. It was extracted with EtOAc, dried over Na2S04, filtered, and concentrated under reduced pressure. The crude reaction mixture was diluted with DCM, adsorbed onto silica, and purified by silica gel chromatography (eluent: 5 to 100% EtOAc/hexanes). The product fractions were combined and concentrated in vacuo to give l-((tert-butyldimethylsilyl)oxy)but-3-en-2-ol (1.97 g, 84%) as an oil: !H NMR (DMSO-d6) δ: 5.79 - 5.90 (1H, m) 5.17 - 5.31 (lH, m) 5.03 - 5.13 (1H, m) 3.89 - 4.05 (1H, m) 3.32 - 3.62 (2H, m), 0.86 (9H, s), 0.03 (6H, s).
Step 2: (9S,1 lE,13S)-13-(hydroxymethyl)-16-methyl-14-oxa-3,7,17,23- tetraazapentacyclo[13.6.2.1~2,5~.0~4,9~.0~18,22~]tetracosa- 1 (22),2(24),4, 11 , 15, 17, 18,20,22-nonaen-6-one, (9S, 1 1 Z)- 13 -(hydroxymethyl)- 16-methyl- 14-oxa-3,7,17,23-tetraazapentacyclo[13.6.2.1~2,5~.0~4,9~.0~18,22~]tetracosa- l(22),2(24),4,l l,15,17,18,20,22-nonaen-6-one, (9S,l lE,13R)-13-(hydroxymethyl)-16- methyl-14-oxa-3,7,17,23-tetraazapentacyclo[13.6.2.1~2,5~.0~4,9~.0~18,22~]tetracosa- 1 (22),2(24),4, 11 , 15, 17, 18,20,22-nonaen-6-one
A slurry of NaH as a 60% dispersion in mineral oil (Strem Chemicals, 35.7 mg, 0.892 mmol) in DMF (2477 μΐ) was stirred, and l -((tert-butyldimethylsilyl)oxy)but-3-en-2-ol (180 mg, 0.892 mmol) was added in one aliquot. The mixture was stirred until gas evolution ceased, and (S)-7-allyl-2-(3-fluoro-2-methylquinoxalin-5-yl)-6,7-dihydro-lH- pyrrolo[3,2-c]pyridin-4(5H)-one (Intermediate D, 100 mg, 0.297 mmol) was added as a solid. The solution was stirred for 1 h. The reaction was diluted with water and extracted with DCM. The combined organics were dried over Na2S04, filtered, and concentrated under reduced pressure to give a solid. This material was treated with THF (1.9 mL) under N2 and was stirred at RT. A 1.0M solution of tetra-N-butylammonium fluoride in THF (386 xL, 0.386 mmol) was added in one portion, and the resulting suspension was stirred for 1 h. The mixture was diluted with water and extracted with DCM. The combined organics were washed with brine, dried over Na2S04, filtered, and concentrated under reduced pressure. The mixture was suspended in DCM, adsorbed onto silica, and purified by silica gel chromatography (eluent: 0 to 10%> MeOH/DCM) to give the product with impurities. This material was treated with Grubbs 2nd generation catalyst (Sigma Aldrich, 84 mg, 0.099 mmol) and DCM (9.9 mL), and the suspension was sealed at stirred at 50 °C for 3 h. The material was cooled, adsorbed onto silica, and purified by silica gel chromatography (eluent: 0 to 10% MeOH/DCM). The product fractions were combined and concentrated under reduced pressure. The material was further purified by SFC (AD-H Column, 5 μ, 21x150 mm, P = 200 bar, T = 40 °C with 40% EtOH at 1 mL/min, solubilized in 1 :1 DCM/MeOH), to give:
First eluting peak, a single Cu diastereomer of (9S,1 lE)-13-(hydroxymethyl)-16-methyl- 14-oxa-3,7,17,23-tetraazapentacyclo[13.6.2.1~2,5~.0~4,9~.0~18,22~]tetracosa- l(22),2(24),4,l l,15,17,18,20,22-nonaen-6-one (Example 101, 3.2 mg, 5%, 3 steps): !H NMR (400 MHz, CDCh) δ ppm 11.99 - 12.13 (1 H, m) 7.96 - 8.09 (1 H, m) 7.75 - 7.84 (1 H, m) 7.50 - 7.62 (1 H, m) 7.13 - 7.23 (1 H, m) 6.24 - 6.28(2 H, m) 6.10 - 6.13(1 H, dd, m) 5.31 (1 H, s) 4.91 - 4.98 (1 H, m) 4.61 - 4.68 (1 H, m) 4.51 - 4.57 (1 H, m) 3.30 - 3.45 (4 H, m) 2.74 (3 H, s) 2.43 - 2.48 (1 H, m): m/z (ESI, +ve) 377.1 (M+H)+.
Second eluting peak, a single Cn diastereomer of (9S,1 lZ)-13-(hydroxymethyl)-16- methyl-14-oxa-3,7,17,23-tetraazapentacyclo[13.6.2.1~2,5~.0~4,9~.0~18,22~]tetracosa- l(22),2(24),4,l l,15,17,18,20,22-nonaen-6-one (Example 102, 2.2 mg, 4%, 3 steps): !H NMR (400 MHz, CDCh) δ ppm 11.93 - 12.11 (1 H, m) 7.98 - 8.08 (1 H, m) 7.73 - 7.86 (1 H, m) 7.50 - 7.63 (1 H, m) 7.10 - 7.20 (1 H, m) 6.17 - 6.31 (1 H, m) 5.99 - 6.15 (1 H, m) 4.86 - 4.98 (1 H, m) 4.60 - 4.71 (1 H, m) 4.51 - 4.57 (2 H, m) 3.22 - 3.38 (3 H, m) 2.73 (4 H, s) 2.35 - 2.53 (2 H, m): m/z (ESI, +ve) 377.1 (M+H)+.
Third eluting peak, a single Cn diastereomer of (9S,1 lE)-13-(hydroxymethyl)-16-methyl- 14-oxa-3,7,17,23-tetraazapentacyclo[13.6.2.1~2,5~.0~4,9~.0~18,22~]tetracosa- l(22),2(24),4,l l,15,17,18,20,22-nonaen-6-one (Example 103, 2.3 mg, 4%, 3 steps): !H NMR (400 MHz, CDCh) δ ppm 11.98 - 12.10 (1 H, m) 7.96 - 8.10 (1 H, m) 7.75 - 7.82 (1 H, m) 7.51 - 7.64 (1 H, m) 7.13 - 7.20 (1 H, m) 6.21 - 6.29 (1 H, m) 6.09 - 6.13 (1 H, m) 5.31 (1 H, s) 4.94 - 5.03 (1 H, m) 4.60 - 4.63 (1 H, m) 4.49 - 4.54 (1 H, m) 3.30 - 3.40 (4 H, m) 2.65 (3 H, s) 2.32 - 2.38 (2 H, m): m/z (ESI, +ve) 377.1 (M+H)+.
Example 104: (9S,llE)-16-(hydroxymethyl)-12-methyl-3,7,14,17,23- pentaazapentacyclo[13.6.2.1~2,5~.0~4,9~.0~18,22~]tetracosa- l(22),2(24),4,ll,15,17,18,20,22-nonaen-6-one
Figure imgf000216_0001
A solution of (9S,l lE)-12-methyl-6-oxo-3,7,14,17,23- pentaazapentacyclo[l 3.6.2.1~2,5~.0~4,9~.0~18,22~]tetracosa- l(22),2(24),4,l l,15,17,18,20,22-nonaene-16-carbaldehyde (Example 51 ; 40.3 mg, 0.108 mmol) and sodium triacetoxyhydroborate (Aldrich; 34.3 mg, 0.162 mmol) in a mixture of THF (3.0 mL) and MeOH (0.300 mL) was stirred at 25 °C for 10 min. Additional sodium triacetoxyhydroborate (34.3 mg, 0.162 mmol) was added, and the resulting mixture was stirred at 25 °C for 10 min. Saturated aqueous NaHCC>3 solution (10 mL) was then added, and the resulting mixture was partitioned between 5% MeOH/DCM (50 mL) and half-saturated aqueous NaHCC>3 solution (30 mL). The organic layer was separated, and the aqueous layer was extracted with 5% MeOH/DCM (30 mL). The combined organic extracts were sequentially washed with brine (30 mL), dried over Na2S04, filtered, and concentrated in vacuo to provide (9S,1 lE)-16-(hydroxymethyl)-12-methyl-3,7,14,17,23- pentaazapentacyclo[l 3.6.2. l~2,5~.0~4,9~.0~18,22~]tetracosa- l(22),2(24),4,l l,15,17,18,20,22-nonaen-6-one (31.9 mg, 0.085 mmol, 79 % yield) as a yellow-orange solid: !H NMR (400 MHz, DMSO-d6) δ ppm 13.35 (1 H, br. s.), 8.02 (1 H, dd, J=7.6, 1.2 Hz), 7.59 (1 H, dd, J=7.8, 1.2 Hz), 7.56 (1 H, br. s.), 7.34 (1 H, t, J=7.8 Hz), 7.01 (1 H, d, J=4.5 Hz), 6.92 (1 H, d, J=2.0 Hz), 5.82 (1 H, d, J=7.6 Hz), 5.72 (1 H, t, J=5.7 Hz), 4.74 (2 H, dd, J=5.7, 3.1 Hz), 4.21 (1 H, br. s.), 4.00 (1 H, dd, J=15.2, 1.9 Hz), 3.34 - 3.42 (1 H, m), 3.24 - 3.29 (1 H, m), 3.21 (1 H, d, J=10.8 Hz), 2.41 (2 H, d, J=8.0 Hz), 1.62 (3 H, s). m/z (ESI, +ve) 376.1 (M+H)+.
Example 105: (9S,llE)-16-methyl-14-(2-((2-(methylsulfonyl)ethyl)amino)ethyl)- 3,7,14,17,23-pentaazapentacyclo[13.6.2.1~2,5~.0~4,9~.0~18,22~]tetracosa- l(21),2(24),4,ll,15,17,19,22-octaen-6-one
Figure imgf000217_0001
A solution of (9S,l lE)-14-(2-aminoethyl)-16-methyl-3,7,14,17,23- pentaazapentacyclo[l 3.6.2.1~2,5~.0~4,9~.0~18,22~]tetracosa- l(21),2(24),4,l l,15,17,19,22-octaen-6-one (Example 98, 57 mg, 0.113 mmol),
(methylsulfonyl)ethene (Aldrich, 99 μΐ, 1.134 mmol), and triethylamine (23.72 μΐ, 0.170 mmol) in THF (378 μΐ) was heated in the microwave for 30 min at 120 °C. The crude product was adsorbed onto silica and was purified via automated flash chromatography (silica gel) with 100% DCM to 7% 2 M NH3 in MeOH/DCM to give (9S,1 lE)-16-methyl- 14-(2-((2-(methylsulfonyl)ethyl)amino)ethyl)-3,7,14,17,23-pentaazapenta- cyclo[13.6.2.1~2,5~.0~4,9~.0~18,22~]tetracosa-l (21),2(24),4,l l,15,17,19,22-octaen-6- one (25 mg, 0.051 mmol, 44.6 % yield) as a yellow solid: !H NMR (400 MHz, CDCl3) δ ppm 2.31 - 2.43 (m, 1 H) 2.63 (d, .7=13.1 1 Hz, 1 H) 2.74 (s, 3 H) 2.88 (s, 3 H) 2.97 - 3.10 (m, 2 H) 3.10 - 3.16 (m, 2 H) 3.16 - 3.22 (m, 2 H) 3.33 - 3.41 (m, 2 H) 3.41 - 3.52 (m, 2 H) 3.53 - 3.63 (m, 1 H) 4.14 - 4.32 (m, 2 H) 5.43 (d, .7=4.1 1 Hz, 1 H) 5.87 - 5.98 (m, 1 H) 6.18 - 6.28 (m, 1 H) 7.10 (d, .7=2.15 Hz, 1 H) 7.50 (t, .7=8.22 Hz, 1 H) 7.69 (dd, .7=8.12, 1.27 Hz, 1 H) 7.98 (dd, .7=7.63, 1.37 Hz, 1 H) 13.14 (br. s., 1 H). MS (ESI, pos. ion) m/z: 495.2 (M+H)+. Example 106: N-(2-((9S,llE)-16-methyl-6-oxo-3,7,14,17,23- pentaazapentacyclo[13.6.2.1~2,5~.0~4,9~.0~18,22~]tetracosa- l(21),2(24),4,ll,15,17,19,22-octaen-14-yl)ethyl)acetamide
Figure imgf000217_0002
A mixture of (9S,1 lE)-14-(2-aminoethyl)-16-methyl-3,7,14,17,23- pentaazapentacyclo[l 3.6.2. l~2,5~.0~4,9~.0~18,22~]tetracosa- l(21),2(24),4,l l,15,17,19,22-octaen-6-one (Example 98, 66 mg, 0.131 mmol), acetic anhydride (Fluka Chemie GmbH, 62.0 μΐ, 0.657 mmol), and TEA (341 μΐ, 0.919 mmol) in DCM (1313 μΐ) was stirred at RT for 30 min. The reaction mixture was diluted with DCM (100 ml), added to a separatory funnel, and washed with saturated aqueous NaHC03 (2 x 50 ml) before the organic layer was separated, dried over Na2S04, and concentrated. The crude product was adsorbed onto silica and was purified via automated flash chromatography (silica gel) with 100% DCM to 4% 2 M NH3 in MeOH/DCM to give N-(2-((9S,l lE)-16-methyl-6-oxo-3,7,14,17,23-pentaazapenta- cyclo[13.6.2.1~2,5~.0~4,9~.0~18,22~]tetracosa-l(21),2(24),4,l l,15,17,19,22-octaen-14- yl)ethyl)acetamide (21 mg, 0.049 mmol, 37.1 % yield) as a yellow solid: !H NMR (400 MHz, CDCh) δ ppm 1.96 (s, 3 H) 2.09 - 2.20 (m, 1 H) 2.52 (d, J=12.91 Hz, 1 H) 2.73 (s, 3 H) 3.10 - 3.28 (m, 2 H) 3.34 - 3.40 (m, 1 H) 3.44 - 3.52 (m, 2 H) 3.53 - 3.68 (m, 2 H) 4.13 - 4.20 (m, 2 H) 5.71 - 5.82 (m, 2 H) 6.08 (dd, J=15.75, 2.84 Hz, 1 H) 6.47 (t, J=6.26 Hz, 1 H) 7.01 (d, J=1.96 Hz, 1 H) 7.47 (t, J=7.82 Hz, 1 H) 7.66 (dd, J=8.22, 0.98 Hz, 1 H) 7.94 (dd, J=7.53, 1.08 Hz, 1 H) 13.00 (br. s., 1 H). MS (ESI, pos. ion) m/z: 431.1 (M+H)+. Example 107: N-(2-((9S,llE)-16-methyl-6-oxo-3,7,14,17,23- pentaazapentacyclo[13.6.2.1~2,5~.0~4,9~.0~18,22~]tetracosa-
Figure imgf000218_0001
(9S,11Z)-14-(2-Aminoethyl)- 16-methyl-3,7, 14, 17,23-pentaaza- pentacyclo[13.6.2.1~2,5~.0~4,9~.0~18,22~]tetracosa-l(21),2(24),4,l 1,15,17,19,22- octaen-6-one (95, 20 mg, 0.051 mmol), methanesulfonyl chloride (Sigma- Aldrich, 15.94 μΐ, 0.206 mmol), and Et3N (Sigma- Aldrich, 28.7 μΐ, 0.206 mmol) were combined in a manner similar to that described in Example 106 to give N-(2-((9S,l lE)-16-methyl-6- oxo-3,7,14,17,23-pentaazapentacyclo[l 3.6.2.1~2,5~.0~4,9~.0~18,22~]-tetracosa- l(21),2(24),4,l l,15,17,19,22-octaen-14-yl)ethyl)methanesulfonamide (3 mg, 6.43 μmol, 12% yield) as a yellow solid. !H NMR (400 MHz, CDC13) δ ppm 2.25 (td, J=12.32, 11.35 Hz, 1 H) 2.49 (d, J=12.32 Hz, 1 H) 2.76 (s, 3 H) 2.92 (s, 3 H) 3.06 - 3.20 (m, 3 H) 3.37 - 3.55 (m, 2 H) 3.65 - 3.77 (m, 1 H) 3.78 - 3.87 (m, 1 H) 4.11 (d, J=15.65 Hz, 1 H) 4.40 (dd, J=16.82, 7.82 Hz, 1 H) 5.43 (br. s., 1 H) 5.86 - 5.98 (m, 1 H) 6.20 (dd, J=15.85, 7.43 Hz, 1 H) 6.76 (br. s., 1 H) 6.98 (s, 1 H) 7.47 (t, J=7.82 Hz, 1 H) 7.71 (d, J=8.22 Hz, 1 H) 7.91 (d, J=7.43 Hz, 1 H) 13.10 (br. s., 1 H). MS (ESI, pos. ion) m/z: 467.1 (M+l).
Example 108: (9S)-17-methyl-3,7,15,18,24- pentaazahexacyclo[14.6.2.1~2,5~.l~12,14~.0~4,9~.0~19,23~]hexacosa- l(23),2(26),4,ll,16,18,19,21,23-nonaen-6-one
Figure imgf000219_0001
Step 1 : (S)-7-allyl-2-(3-(but-3-en-l-ylamino)-2-methylquinoxalin-5-yl)-6,7-dihydro-lH- pyrrolo [3,2 -c]pyridin-4(5 H)-one
(S)-7-Allyl-2-(3-fluoro-2-methylquinoxalin-5-yl)-6,7-dihydro-lH-pyrrolo[3,2-c]pyridin- 4(5H)-one (Intermediate D; 0.100 g, 0.297 mmol), 3-methylenecyclobutanamine hydrochloride (Sigma Aldrich, 0.049 g, 0.595 mmol), and DIEA (EMD Biosciences, 207\L, 1.189 mmol) were combined in a manner similar to that described in Example 30 to give (S)-7-allyl-2-(2-methyl-3-((3-methylenecyclobutyl)amino)quinoxalin-5-yl)-6,7- dihydro-lH-pyrrolo[3,2-c]pyridin-4(5H)-one (0.130 g, 0.325 mmol, 90%) as an orange residue: !H NMR (400 MHz, DMSO-i/6) δ ppm 12.07 (1 H, s) 7.91 (1 H, dd, J=7.63, 1.37 Hz) 7.58 (1 H, dd, J=8.02, 1.17 Hz) 7.49 (1 H, d, J=5.87 Hz) 7.34 (1 H, t, J=7.73 Hz)
7.04 (1 H, d, J=2.15 Hz) 6.96 (1 H, br. s.) 5.75 - 5.94 (1 H, m) 5.03 - 5.15 (2 H, m) 4.89 (2 H, d, J=9.39 Hz) 4.50 - 4.64 (1 H, m) 3.44 - 3.53 (1 H, m) 3.13 - 3.27 (5 H, m) 2.86 - 2.97 (3 H, m) 2.64 - 2.72 (2 H, m) 2.28 - 2.40 (1 H, m). m/z (ESI, +ve) 400.2 (M+H)+. Step 2: (9S)-17-methyl-3,7,15,18,24- pentaazahexacyclo[14.6.2.1-2, 5~.1-12,14~.0~4,9~.0~19,23~]hexacosa- 1 (23),2(26),4, 11 , 16, 18, 19,21 ,23-nonaen-6-one.
((S)-7-Allyl-2-(2-methyl-3-((3-methylenecyclobutyl)amino)quinoxalin-5-yl)-6,7-di lH-pyrrolo[3,2-c]pyridin-4(5H)-one (Step 1, 0.130 g, 0.325 mmol) and Grubbs' Catalyst 2nd Generation (Sigma Aldrich, 0.055 mg, 0.065 mmol) were combined in a manner similar to that described in Example 30 to give (9S)-17-methyl-3,7,15, 18,24- pentaazahexacyclo[14.6.2.1-2, 5~.1-12,14-.0-4, 9~.0-19,23~]hexacosa- l(23),2(26),4,l l,16,18,19,21,23-nonaen-6-one (0.017 g, 0.046 mmol, 17%) as a yellow- brown solid: !H NMR (400 MHz, DMSO-i/6) δ ppm 11.51 (1 H, s) 7.97 (1 H, d, J=6.26 Hz) 7.57 (1 H, d, J=6.65 Hz) 7.46 (1 H, d, J=7.63 Hz) 7.31 (1 H, t, J=7.73 Hz) 7.13 (1 H, d, J=4.89 Hz) 6.85 (1 H, d, J=2.35 Hz) 5.65 (1 H, br. s.) 4.35 (1 H, br. s.) 4.10 (1 H, br. s.) 3.27 (2 H, br. s.) 3.18 (2 H, d, J=6.65 Hz) 3.05 (3 H, br. s.) 2.28 - 2.39 (2 H, m) 2.16 - 2.28 (2 H, m). m/z (ESI, +ve) 372.2 (M+H)+.
Examples 109-110: (9R,llE)-ll,17-dimethyl-3,7,15,18,24- pentaazapentacyclo [14621~2,5~0~4,9~0~19,23~] pentacosa- l(22),2(25),4,ll,16,18,20,23-octaen-6-one and (9S,HE)-ll,17-dimethyl-3,7,15,18,24- pentaazapentacyclo [14621~2,5~0~4,9~0~19,23~] pentacosa- l(22),2(25),4,ll,16,18,20,23-octaen-6-one
Figure imgf000220_0001
(9R, 11 E)- 11 , 17-dimethyl-3 ,7, 15,18,24- pentaazapentacyclo[l 4621-2,5-0-4,9-0-19,23~]pentacosa- 1 (22),2(25),4, 11 , 16, 18,20,23-octaen-6-one and (9S, 11E)-11 , 17-dimethyl-3,7, 15,18,24- pentaazapentacyclo[l 4621-2,5-0-4, 9-0-19,23~]pentacosa- 1(22),2(25),4,11,16,18,20,23-octaen-6-one were synthesized in a manner similar to Example 1 using but-3-en-l -amine. Individual enantiomers were obtained by chiral SFC (Column: Chiralpak AS-H Sepax (150 x 21 mm, 5 micron); Mobile Phase: 60:40 (A:B) A: Liquid C02; B: MeOH (20 mM NH3); Flow Rate: 75 mL/min; Oven Temp: 40 °C; Outlet Pressure: 100 bar): !H NMR (400 MHz, DMSO-i¾) δ ppm 12.12 (1 H, br. s.) 7.93 (1 H, d, J=6.8 Hz) 7.44 - 7.63 (2 H, m) 7.26 (1 H, t, J=7.8 Hz) 7.04 (1 H, br. s.) 6.92 (1 H, d, J=2.0 Hz) 5.83 (1 H, t, J=7.4 Hz) 3.46 - 3.72 (2 H, m) 3.27 - 3.44 (2 H, m) 3.01 - 3.14 (1 H, m) 2.56 - 2.72 (1 H, m) 2.59 (3H, s), 2.16 - 2.29 (2 H, m) 2.06 (1 H, dt, J=7.0, 3.5 Hz) 1.60 (3 H, s). m/z (ESI, +ve) 374.1 (M+H)+.
Example 111-114: (9S, llZ)-12,14,16-trimethyl-3,7,14,17,23
pentaazapentacyclo[13621~2,5~0~4,9~0~18,22~]tetracosa- l(22),2(24),4,ll,15(23),16,18,20-octaen-6-one; (9S, llZ)-ll,14,16-trimethyl- 3,7,14,17,23-pentaazapentacyclo[13621~2,5~0~4,9~0~18,22~]tetracosa- l(22),2(24),4,ll,15(23),16,18,20-octaen-6-one; (9R, llZ)-12,14,16-trimethyl- 3,7,14,17,23-pentaazapentacyclo[13621~2,5~0~4,9~0~18,22~]tetracosa- l(22),2(24),4,ll,15(23),16,18,20-octaen-6-one; (9R, HZ)-ll,14,16-trimethyl- 3,7,14,17,23-pentaazapentacyclo[13621~2,5~0~4,9~0~18,22~]tetracosa- l(22),2(24),4,ll,15(23),16,18,20-octaen-6-one
Figure imgf000221_0001
Step 1 : mixture of tert-butyl 4-methyl-3,6-dihydro-2H-l,2-oxazine-2-carboxylate and tert-butyl 5-methyl-3,6-dihydro-2H- 1 ,2-oxazine-2-carboxylate
To a 500-mL three neck round-bottomed flask was added n-boc-hydroxylamine (Sigma Aldrich, 5.0 g, 37.6 mmol) in DCM (75 mL) followed by copper (i) chloride (Sigma Aldrich, 186 mg, 1.878 mmol), ethanolamine (Sigma Aldrich, 0.338 mL, 5.63 mmol) and isoprene (Sigma Aldrich, 3.76 mL, 37.6 mmol). The green mixture was stirred at RT for 10 min, then H202 30% in H20 (Sigma Aldrich, 26.9 mL, 263 mmol) was added dropwise through syringe pump in 30 min. The reaction was stirred at RT for 2 h, then quenched with H20 (50 mL). The mixture was extracted with DCM (80 mL X3) and the combined organic layers were dried (MgS04), filtered and concentrated. The residue was purified with silica gel chromatography (eluted with 2-5% EtOAc in DCM) to give a mixture of tert-butyl 4-methyl-3,6-dihydro-2H-l,2-oxazine-2-carboxylate and tert-butyl 5-methyl- 3,6-dihydro-2H-l,2-oxazine-2-carboxylate (2.35 g, 5.90 mmol, 31.4 % yield) as a colorless oil. MS (ESI, pos. ion) m/z: 222.1 (M+Na).
Step 2: (Z)-tert-butyl (4-hydroxy-2-methylbut-2-en-l-yl)carbamate and (Z)-tert-butyl (4- hydroxy-3 -methylbut-2 -en- 1 -yl)carbamate
To a 500-mL round-bottomed flask was added a mxiture of tert-butyl 4-methyl-3,6- dihydro-2H-l,2-oxazine-2-carboxylate and tert-butyl 5-methyl-3,6-dihydro-2H-l,2- oxazine-2-carboxylate (3.00 g, 7.53 mmol) and molybdenum carbonyl (Strem, 3.18 g,
12.05 mmol) in ACN (105 mL)/H20 (15 mL). The mixture was stirred at RT for 10 min, then sodium borohydrate (Riedel de Hsen AG, 0.142 g, 3.76 mmol) was added. The reaction was heated at 85 °C for 15 h, then cooled to RT. Et20 (100 mL) was added and the mixture was filtered through a plug of Celite and washed with Et20 (30 mL x3). The filtrate was concentrated and the residue was purified with silica gel chromatography
(eluted with 5-25% EtOAc in hexanes) to give (Z) -tert-butyl (4-hydroxy-2-methylbut-2- en-l-yl)carbamate and (Z) -tert-butyl (4-hydroxy-3 -methylbut-2 -en- 1 -yl)carbamate (2.60 g, 6.46 mmol, 86 % yield) as a light yellow oil. MS (ESI, pos. ion) m/z: 224.1 (M+Na). Step 3: (Z)-tert-butyl (4-((tert-butyldimethylsilyl)oxy)-2-methylbut-2-en-l-yl)carbamate and (Z) -tert-butyl (4-((tert-butyldimethylsilyl)oxy)-3-methylbut-2-en-l -yl)carbamate To a 100-mL round-bottomed flask was added a mixture of (Z)-tert-butyl (4-hydroxy-2- methylbut-2-en-l-yl)carbamate and (Z) -tert-butyl (4-hydroxy-3-methylbut-2-en-l- yl)carbamate (1.00 g, 2.484 mmol) and tert-butyldimethylchlorosilane (Acros, 0.936 g, 6.21 mmol) in DCM (10 mL) followed by Et3N (0.864 mL, 6.21 mmol) and 4- (dimethylamino)pyridine (Sigma Aldrich, 0.061 g, 0.497 mmol). The reaction was stirred at RT for 2 h, then quenched with water. The mixture was extracted with DCM (50 mL x2). The combined organic layers were dried (MgS04), filtered and concentrated. The residue was purified with silica gel chromatography (eluted with 0-5% EtOAc in
Hexanes) to give (Z)-tert-butyl (4-((tert-butyldimethylsilyl)oxy)-2-methylbut-2-en-l- yl)carbamate and (Z)-tert-butyl (4-((tert-butyldimethylsilyl)oxy)-3-methylbut-2-en-l- yl)carbamate (1.42 g, 2.250 mmol, 91 % yield) as a colorless oil. MS (ESI, pos. ion) m/z: 338 (M+Na).
Step 4: (Z)-tert-butyl (4-((tert-butyldimethylsilyl)oxy)-2-methylbut-2-en-l- yl)(methyl)carbamate and (Z)-tert-butyl (4-((tert-butyldimethylsilyl)oxy)-3-methylbut-2- en- 1 -yl)(methyl)carbamate
To a 100-mL round-bottomed flask was added a mixture of (Z)-tert-butyl (4-((tert- butyldimethylsilyl)oxy)-2-methylbut-2-en-l -yl)carbamate and (Z)-tert-butyl (4-((tert- butyldimethylsilyl)oxy)-3-methylbut-2-en-l-yl)carbamate (1.30 g, 2.060 mmol) in THF (15 mL) and the solution was cooled to 0 °C. NaH, 60% dispersion in mineral oil (Sigma Aldrich, 0.173 g, 4.33 mmol) was added followed by iodomethane (0.320 mL, 5.15 mmol). The reaction was stirred at 0 °C for 1 h, then warmed to RT for 2 h. The reaction was quenched with water and the mixture was extracted with DCM (50 mL X3). The combined organic layers were dried (MgS04), filtered and concentrated to give the crude mixture, which was used in the next reaction without further purification. MS (ESI, pos. ion) m/z: 352.1 (M+Na). Step 5 : (Z)-tert-butyl (4-hydroxy-2-methylbut-2-en-l-yl)(methyl)carbamate and (Z)-tert- butyl (4-hydroxy-3-methylbut-2-en- 1 -yl)(methyl)carbamate
To a 100-mL round-bottomed flask was added a mixture of (Z)-tert-butyl (4-((tert- butyldimethylsilyl)oxy)-2-methylbut-2-en-l-yl)(methyl)carbamate and (Z)-tert-butyl (4- ((tert-butyldimethylsilyl)oxy)-3-methylbut-2-en-l-yl)(methyl)carbamate (1.50 g, 2.276 mmol) in THF (10 mL) followed by tetrabutylammonium fluoride, 1.0 M in THF (Sigma
Aldrich, 5.69 mL, 5.69 mmol). The reaction was stirred at RT for 30 min, then quenched with water. The mixture was extracted with DCM (50 mL X3) and the combined organic layers were dried (MgSO t), filtered and concentrated to give the crude mix, which was used in the next reaction without further purification. MS (ESI, pos. ion) m/z: 238.1 (M+Na).
Step 6 : (Z)-tert-butyl (4-chloro-2-methylbut-2-en-l-yl)(methyl)carbamate and (Z)-tert- butyl (4-chloro-3-methylbut-2-en-l-yl)(methyl)carbamate
To a 150-mL round-bottomed flask was added a mxiture of (Z)-tert-butyl (4-hydroxy-2- methylbut-2-en-l-yl)(methyl)carbamate and (Z)-tert-butyl (4-hydroxy-3-methylbut-2-en- l-yl)(methyl)carbamate (0.98 g, 2.276 mmol) in DCM (50 mL) and the solution was cooled to 0 °C. Triphenylphosphine (Sigma Aldrich, 2.388 g, 9.10 mmol) was added followed by slow addition of chlorosuccinimide (Alfa Aesar, 1.033 g, 7.74 mmol). The mixture was stirred at 0 °C for 30 min, then the solvent was removed. The residue was purified with silica gel chromatography (eluted with 2-5% EtOAc in Hexanes) to give (Z)-tert-butyl (4-chloro-2-methylbut-2-en-l-yl)(methyl)carbamate and (Z)-tert-butyl (4- chloro-3-methylbut-2-en-l-yl)(methyl)carbamate (925 mg, 1.979 mmol, 87 % yield) as a colorless oil. MS (ESI, pos. ion) m/z: 256.1 (M+Na).
Step 7: (Z)-tert-butyl 5-(4-((tert-butoxycarbonyl)(methyl)amino)-2-methylbut-2-en-l-yl)- 2,4-dioxopiperidine-l -carboxylate and (Z)-tert-butyl 5-(4-((tert- butoxycarbonyl)(methyl)amino)-3-methylbut-2-en-l-yl)-2,4-dioxopiperidine-l- carboxylate
To a 100-mL round-bottomed flask was added a mixture of (Z)-tert-butyl (4-chloro-2- methylbut-2-en-l-yl)(methyl)carbamate and (Z)-tert-butyl (4-chloro-3-methylbut-2-en-l- yl)(methyl)carbamate (438 mg, 0.938 mmol) and tert-butyl 2,4-dioxopiperidine-l- carboxylate (400 mg, 1.876 mmol) in THF (10 mL). The solution was cooled to -30 °C and LiHMDS, 1.0m solution in THF (Sigmal Aldrich, 4.69 mL, 4.69 mmol) was added dropwise. The reaction was stirred at -20-30 °C for 1 h, then diluted with DCM and 5% KHSO4. The mixture was separated and the aqueous layer was extracted with DCM. The combined organic layers were dried (MgS04), filtered and concentrated. The residue was purified with silica gel chromatography (eluted with 20-40% EtOAc in Hexanes) to give (Z)-tert-butyl 5 -(4-((tert-butoxycarbonyl)(methyl)amino)-2-methylbut-2-en- 1 -yl)-2,4- dioxopiperidine-1 -carboxylate and (Z)-tert-butyl 5-(4-((tert- butoxycarbonyl)(methyl)amino)-3-methylbut-2-en-l-yl)-2,4-dioxopiperidine-l- carboxylate (1 :1) (560 mg, 0.682 mmol, 72.7 % yield) as a solid. MS (ESI, pos. ion) m/z: 433.1 (M+Na). Step 8: (Z)-tert-butyl 7-(4-((tert-butoxycarbonyl)(methyl)amino
2-(3-fluoro-2-methylquinoxalin-5-yl)-4-
5(4H)-carboxylate and (Z)-tert-butyl 7-(4-((tert-butoxycarbonyl)(methyl)amino)-3- methylbut-2-en-l-yl)-2-(3-i uoro-2-methylquinoxalin-5-yl)-4-oxo-6,7-dihydro-lH- pyrrolo [3 ,2 -c]pyridine-5 (4H)-carboxylate
A glass microwave reaction vessel was charged with a mixture of (Z)-tert-butyl 5-(4- ((tert-butoxycarbonyl)(methyl)amino)-2-methylbut-2-en-l-yl)-2,4-dioxopiperidine-l- carboxylate and (Z)-tert-butyl 5-(4-((tert-butoxycarbonyl)(methyl)amino)-3-methylbut-2- en-l-yl)-2,4-dioxopiperidine-l-carboxylate (750 mg, 0.914 mmol) and 2-bromo-l-(3- fluoro-2-methylquinoxalin-5-yl)ethanone (517 mg, 1.827 mmol) in EtOH (10 mL) followed by NH4OAc (563 mg, 7.31 mmol). The reaction was stirred at RT for 15 h. The mixture was diluted with water and the suspension was filtered. The resulting solid was purified with silica gel chromatography (eluted with 20-40% EtOAc in hexanes) to give (Z)-tert-butyl 7-(4-((tert-butoxycarbonyl)(methyl)amino)-2-methylbut-2-en-l-yl)-2-(3- fluoro-2-methylquinoxalin-5-yl)-4-oxo-6,7-dihydro-lH-pyrrolo[3,2-c]pyridine-5(4H)- carboxylate and (Z)-tert-butyl 7-(4-((tert-butoxycarbonyl)(methyl)amino)-3-methylbut-2- en-l-yl)-2-(3-fluoro-2-methylquinoxalin-5-yl)-4-oxo-6,7-dihydro-lH-pyrrolo[3,2- c]pyridine-5(4H)-carboxylate (227 mg, 0.191 mmol, 20.93 % yield) as a yellow solid. MS (ESI, pos. ion) m/z: 616.1 (M+Na).
Step 9: (Z)-2-(3-fluoro-2-methylquinoxalin-5-yl)-7-(2-methyl-4-(methylamino)but-2-en- l-yl)-6,7-dihydro-lH-pyrrolo[3,2-c]pyridin-4(5H)-one and (Z)-2-(3-fluoro-2- methylquinoxalin-5-yl)-7-(2-methyl-4-(methylamino)but-2-en-l-yl)-6,7-dihydro-lH- pyrrolo [3,2 -c]pyridin-4(5 H)-one
To a 25-mL round-bottomed flask was added a mixture of (Z)-tert-butyl 7-(4-((tert- butoxycarbonyl)(methyl)amino)-2-methylbut-2-en- 1 -yl)-2-(3 -fluoro-2-methylquinoxalin- 5-yl)-4-oxo-6,7-dihydro-lH-pyrrolo[3,2-c]pyridine-5(4H)-carboxylate and (Z)-tert-butyl 7-(4-((tert-butoxycarbonyl)(methyl)amino)-3-methylbut-2-en-l-yl)-2-(3-fluoro-2- methylquinoxalin-5-yl)-4-oxo-6,7-dihydro-lH-pyrrolo[3,2-c]pyridine-5(4H)-carboxylate (225 mg, 0.189 mmol) and TFA (Sigmal Aldrich, 0.146 mL, 1.895 mmol) in DCM (2 mL). The reaction was stirred at RT for 30 min, then the solvent was removed to give the crude mixture, which was used in the next reaction without further purification. MS (ESI, pos. ion) m/z: 394.1 (M+H). Step 10: (1 lZ)-12,14,16-trimethyl-3,7,14,17,23
pentaazapentacyclo [ 13621 ~2,5~0~4,9~0~ 18,22~]tetracosa- l(22),2(24),4,l l,15(23),16,18,20-octaen-6-one, (HZ)-l l ,14,16-trimethyl-3,7,14,17,23- pentaazapentacyclo [ 13621 ~2,5~0~4,9~0~ 18,22~]tetracosa- l(22),2(24),4,l l,15(23),16,18,20-octaen-6-one, (HZ)-12,14,16-trimethyl-3,7,14,17,23- pentaazapentacyclo [ 13621 ~2,5~0~4,9~0~ 18,22~]tetracosa- 1 (22),2(24),4, 11 , 15 (23), 16, 18,20-octaen-6-one: and ( 1 1 Z)- 1 1 , 14, 16-trimethyl- 3,7,14, 17,23-pentaazapentacyclo[13621~2,5~0~4,9~0~18,22~]tetracosa- 1 (22),2(24),4, 11 , 15(23), 16, 18,20-octaen-6-one
A glass microwave reaction vessel was charged with a mixture of (Z)-2-(3-fluoro-2- methylquinoxalin-5-yl)-7-(2-methyl-4-(methylamino)but-2-en-l-yl)-6,7-dihydro-lH- pyrrolo[3,2-c]pyridin-4(5H)-one and (Z)-2-(3-fluoro-2-methylquinoxalin-5-yl)-7-(2- methyl-4-(methylamino)but-2-en-l -yl)-6,7-dihydro-lH-pyrrolo[3,2-c]pyridin-4(5H)-one (179 mg, 0.455 mmol) in DMSO (4 mL) followed by Et3N (0.633 mL, 4.55 mmol) . The reaction mixture was stirred and heated in an oil bath at 100 °C for 90 min. The mixture was cooled to RT and water ( 50 mL) was added. The suspension was filtered and the resulting solid was purified first with preparative SFC chromatography (OJ-H (5 um, 21 x 150 mm, 75 ml/min), 20% Methanol (20 mM NH3). T = 40 °C, P = 100 bar) then the first peak was further purified with preparative SFC chromatography (Column: Chiralpak
AS-H Sepax (150 x 21 mm, 5 micron), 30% MeOH (20 mM NH3), T = 40 °C, P = 100 bar) to give the following compounds in sequence:
Example 1 11 : single enantiomer of (11Z)- 12,14,16-trimethyl-3, 7, 14, 17,23
pentaazapentacyclo [ 13621 ~2,5~0~4,9~0~ 18,22~]tetracosa- l(22),2(24),4,l l,15(23),16,18,20-octaen-6-one: MS (ESI, pos. ion) m/z: 374.1 (M+H); !H NMR (400 MHz, DMSO-d6) δ ppm 13.09 (1 H, br. s.), 7.90 (1 H, dd, J=7.4, 1.4 Hz), 7.61 (1 H, dd, J=8.1, 1.3 Hz), 7.40 (1 H, t, J=7.8 Hz), 6.98 (1 H, d, J=4.3 Hz), 6.78 (1 H, d, J=2.2 Hz), 5.56 - 5.65 (1 H, m), 4.91 (1 H, d, J=16.8 Hz), 3.66 - 3.76 (1 H, m), 3.43 (3 H, s), 3.34 - 3.38 (1 H, m), 3.14 - 3.19 (2 H, m), 2.82 (3 H, s), 2.15 - 2.25 (1 H, m), 1.70 (3 H, s)
Example 1 12: single enantiomer of (l lZ)-l l ,14,16-trimethyl-3,7,14,17,23- pentaazapentacyclo [ 13621 ~2,5~0~4,9~0~ 18,22~]tetracosa- l(22),2(24),4,l l,15(23),16,18,20-octaen-6-one: MS (ESI, pos. ion) m/z: 374.1 (M+H); !H NMR (400 MHz, DMSO-d6) δ ppm 13.12 (1 H, br. s.), 7.87 (1 H, dd, J=7.4, 1.4 Hz), 7.61 (1 H, dd, J=8.1, 1.3 Hz), 7.40 (1 H, t, J=7.8 Hz), 7.03 (1 H, d, J=4.5 Hz), 6.76 (1 H, d, J=2.2 Hz), 5.57 (1 H, d, J=7.8 Hz), 4.78 (1 H, dd, J=16.1 , 8.9 Hz), 3.67 - 3.76 (1 H, m), 3.42 - 3.50 (1 H, m), 3.40 (3 H, s), 3.33 - 3.38 (1 H, m), 3.22 (1 H, d, J=l 1.7 Hz), 2.74 - 2.83 (4 H, m), 2.12 - 2.21 (1 H, m), 1.87 (3 H, s)
Example 1 13: single enantiomer of (11Z)- 12,14,16-trimethyl-3, 7, 14, 17,23- pentaazapentacyclo [ 13621 ~2,5~0~4,9~0~ 18,22~]tetracosa- l(22),2(24),4,l l,15(23),16,18,20-octaen-6-one: MS (ESI, pos. ion) m/z: 374.1 (M+H); !H NMR (400 MHz, DMSO-d6) δ ppm 13.09 (1 H, br. s.), 7.90 (1 H, dd, J=7.4, 1.2 Hz), 7.61 (1 H, dd, J=8.1, 1.1 Hz), 7.40 (1 H, t, J=7.7 Hz), 6.98 (1 H, d, J=4.3 Hz), 6.78 (1 H, d, J=2.2 Hz), 5.53 - 5.67 (1 H, m), 4.91 (1 H, d, J=16.6 Hz), 3.65 - 3.77 (1 H, m), 3.43 (3 H, s), 3.34 - 3.38 (1 H, m), 3.13 - 3.20 (2 H, m), 2.82 (3 H, s), 2.16 - 2.24 (1 H, m), 1.70 (3 H, s)
Example 1 14: single enantiomer of (HZ)-l 1,14,16-trimethyl-3, 7, 14, 17,23- pentaazapentacyclo[l 3621~2,5~0~4,9~0~18,22~]tetracosa- l(22),2(24),4,l l,15(23),16,18,20-octaen-6-one: MS (ESI, pos. ion) m/z: 374.1 (M+H); !H NMR (400 MHz, DMSO-d6) δ ppm 13.12 (1 H, br. s.), 7.84 - 7.89 (1 H, m), 7.61 (1 H, d, J=7.8 Hz), 7.36 - 7.43 (1 H, m), 7.03 (1 H, d, J=3.9 Hz), 6.76 (1 H, d, J=1.8 Hz), 5.52 - 5.61 (1 H, m), 4.79 (1 H, dd, J=16.3, 8.9 Hz), 3.67 - 3.78 (1 H, m), 3.42 - 3.50 (1 H, m), 3.40 (3 H, s), 3.35 (1 H, d, J=6.3 Hz), 3.16 - 3.25 (1 H, m), 2.74 - 2.83 (4 H, m), 2.13 - 2.20 (1 H, m), 1.87 (3 H, s)
Example 115 (9S,12S)-12,16-dimethyl-3,7,14,17,23- pentaazapentacyclo[13621~2,5~0~4,9~0~18,22~]tetracosa-l(21),2(24),4,15,17,19,22- heptaen-6-one
Example 116 (9S,HR)-H,16-dimethyl-3,7,14,17,23- pentaazapentacyclo[13621~2,5~0~4,9~0~18,22~]tetracosa-l(21),2(24),4,15,17,19,22- heptaen-6-one
Example 117 (9R,12S)-12,16-dimethyl-3,7,14,17,23- pentaazapentacyclo[13621~2,5~0~4,9~0~18,22~]tetracosa-l(21),2(24),4,15,17,19,22- heptaen-6-one
Example 118 (9R,llR)-ll,16-dimethyl-3,7,14,17,23- pentaazapentacyclo[13621~2,5~0~4,9~0~18,22~]tetracosa-l(21),2(24),4,15,17,19,22- heptaen-6-one
Figure imgf000228_0001
Step 1 : (S)-l,4-dibromo-2-methylbutane
To a slurry of triphenylphosphine (Aldrich, 50.6 g, 193 mmol) in 280 mL ACN at 3 °C under N2 in a 3 neck flask fitted with internal temperature monitor and mechanical stirrer was added bromine (Aldrich, 9.94 ml, 193 mmol) slowly dropwise via addition funnel, such that the internal temperature did not exceed 12 °C. The resulting yellow suspension was stirred for 15 min, at which point (S)-2-methylbutane-l,4-diol (TCI America; 10.0 g, 96 mmol) was added as a solution in 20 mL ACN, dropwise via addition funnel at a rate such that the temperature did not exceed 5 °C. The reaction became clear upon complete addition. The ice bath was removed and the clear, colorless reaction was stirred overnight. In the morning, a white crystalline material was evident. The reaction was filtered through a glass frit, rinsing 1 x 100 mL ACN. The filtrate was concentrated in vacuo, and the resulting residue was treated with 300 mL pentane and stirred rapidly about an hour. The reaction was filtered, rinsing 1 x 100 mL pentane, and the filtrate was concentrated in vacuo. At about 1/2 volume, a precipitate formed. This was removed by filtration, rinsing 3 x 30 mL pentane, and the filtrate was concentrated in vacuo to give (S)-l,4- dibromo-2-methylbutane (18.5 g, 80 mmol, 84 % yield) as a clear/colorless oil: !H NMR (400 MHz, CDC13) δ ppm 3.37 - 3.54 (8 H, m) 1.98 - 2.18 (4 H, m) 1.81 (2 H, dq, J=13.9, 6.9 Hz) 1.07 (3 H, s) 1.05 (3 H, s).
Step 2: tert-butyl 5-((S)-4-bromo-3-methylbutyl)-2,4-dioxopiperidine-l-carboxylate and tert-butyl 5-((R)-4-bromo-2-methylbutyl)-2,4-dioxopiperidine-l-carboxylate
A 1 L 3 neck rbf was charged with tert-butyl 2,4-dioxopiperidine-l-carboxylate (Ark Pharma; Libertyville, IL; 4.00 g, 18.76 mmol) and (S)-l,4-dibromo-2-methylbutane (21.57 g, 94 mmol) and 150 mL THF, and fitted with a temperature probe, mechanical stirrer, and addition funnel. The reaction was cooled to -20 °C (periodic addition of dry ice chunks to acetone) and LiHMDS, 1.0 M solution in THF (Aldrich, 46.9 ml, 46.9 mmol) was added dropwise via addition funnel such that the temperature of the reaction did not exceed -19 °C. The reaction became thick with a precipitate during addition, which dissolved upon complete addition. The temperature of the reaction was maintained between -1 1 and -20 °C for 1 h. The reaction was quenched with water, HC1 5.0 N solution (18.76 ml, 94 mmol), and Et20 was added. The organic layer was washed with saturated aq NaCl and the organics were dried over anhydrous MgS04, filtered, and concentrated in vacuo. The material was treated with DCM and purified by silica gel chromatography (330 g ISCO redisep gold column) using 0 - 100% EtOAc/hexane to give a mixture of tert-butyl 5-((S)-4-bromo-3-methylbutyl)-2,4-dioxopiperidine-l- carboxylate and tert-butyl 5-((R)-4-bromo-2-methylbutyl)-2,4-dioxopiperidine-l - carboxylate (3.40 g, 9.39 mmol, 50.0 % yield), as an oil with solid: m/z (ESI, +ve) 384.0/386.0 (M+Na)+.
Step 3 : tert-butyl 5-((S)-4-azido-3-methylbutyl)-2,4-dioxopiperidine-l -carboxylate and tert-butyl 5-((R)-4-azido-2-methylbutyl)-2,4-dioxopiperidine- 1 -carboxylate
The mixture of isomers from step 2 (3.40 g, 9.39 mmol) and sodium azide (Fluka; 3.30 ml, 94 mmol) were combined in 19 mL DMF, the reaction was flushed with nitrogen and sealed, and stirred for 48 h at RT. The reaction was judged complete and the reaction was treated with ice, partitioned between H20 and Et20. The aq layer was extracted 1 x Et20, and the organic layers were washed with water once, saturated aqueous NaCl once, and the organics were dried over anhydrous Na2S04, filtered, and concentrated in vacuo to give a mixture of tert-butyl 5-((S)-4-azido-3-methylbutyl)-2,4-dioxopiperidine-l - carboxylate and tert-butyl 5-((R)-4-azido-2-methylbutyl)-2,4-dioxopiperidine-l - carboxylate (2.64 g, 8.14 mmol, 87 % yield), m/z (ESI, +ve) 347.1 (M+Na)+. Step 4: 7-((S)-4-azido-3-methylbutyl)-2-(3-fluoro-2-methylquinoxalin-5-yl)-6,7-dihydro- lH-pyrrolo[3,2-c]pyridin-4(5H)-one and 7-((R)-4-azido-2-methylbutyl)-2-(3-fluoro-2- methylquinoxalin-5-yl)-6,7-dihydro-lH-pyrrolo[3,2-c]pyridin-4(5H)-one
A solution of the mixture from Step 3 (2.64 g, 8.14 mmol) in 30 mL DCM was fitted with a Drierite-filled drying tube and the reaction was cooled to 0 °C. TFA (Aldrich, 6.05 ml, 81 mmol) was added dropwise via syringe, and the ice bath was removed. The reaction was stirred at RT for 1 h and concentrated in vacuo to give 3.62 g of a yellow oil. The material was treated with NH4OAc (5.02 g, 65.1 mmol), 2-bromo-l-(3-fluoro-2- methylquinoxalin-5-yl)ethanone (Intermediate U; 3.00 g, 10.58 mmol), and 75 mL EtOH, sealed, and heated in a 50 °C bath for 6 h. The reaction was quenched by addition of saturated aqueous NaHC03 with rapid stirring (bubbling) and DCM. The aqueous layer was extracted with DCM 3x, and the combined organics were dried over anhydrous Na2S04, filtered, and concentrated in vacuo. The material was treated with 10% MeOH in DCM and adsorbed onto 15 g silica gel and purified by silica gel chromatography (80 g ISCO gold column) using 0 - 100% 90/10 DCM/MeOH in DCM. The product-containing fractions were concentrated to afford a mixture of 7-((S)-4-azido-3-methylbutyl)-2-(3- fluoro-2-methylquinoxalin-5-yl)-6,7-dihydro-lH-pyrrolo[3,2-c]pyridin-4(5H)-one and 7- ((R)-4-azido-2-methylbutyl)-2-(3 -fluoro-2-methylquinoxalin-5 -yl)-6,7-dihydro- 1 H- pyrrolo[3,2-c]pyridin-4(5H)-one (0.880 g, 2.160 mmol, 26.5 % yield) as a orange solid. m/z (ESI, +ve) 408.2 (M+H)+.
Step 5: (9S,12S)-12,16-dimethyl-3,7,14,17,23-pentaaza- pentacyclo[13621~2,5~0~4,9~0~18,22~]tetracosa-l(21),2(24),4,15,17,19,22-heptaen-6- one, (9S, 11 R)- 11 , 16-dimethyl-3,7, 14, 17,23 -pentaaza- pentacyclo[13621~2,5~0~4,9~0~18,22~]tetracosa-l(21),2(24),4,15,17,19,22-heptaen-6- one, (9R, 12 S)- 12, 16 -dimethyl- 3, 7, 14, 17,23-pentaaza- pentacyclo[13621~2,5~0~4,9~0~18,22~]tetracosa-l(21),2(24),4,15,17,19,22-heptaen-6- one and 9R,l lR)-l l,16-dimethyl-3,7,14,17,23- pentaazapentacyclo [ 13621 ~2,5~0~4,9~0~ 18,22~]tetracosa- 1 (21 ),2(24),4, 15, 17, 19,22- heptaen-6-one
To a solution of the mixture from Step 4 (0.880 g, 2.160 mmol) in 18 mL THF under argon was added water (0.389 ml, 21.60 mmol) followed by trimethylphosphine, 1.0 M solution in THF (Aldrich, 3.24 ml, 3.24 mmol). The clear, orange solution was stirred for 2 h. The reaction was concentrated in vacuo and concentrated from anhydrous toluene 3 x, and dried in vacuo for 20 min. The residue was treated with anhydrous DM SO (50 mL) and DIEA (1.878 ml, 10.80 mmol) and placed in a 70 °C oil bath. After 1 h, the reaction was poured into 500 mL ice/water, and a precipitate formed. This was collected by filtration through a 0.45 micron membrane under vacuum. The semisolid was transferred to a flask with DCM/MeOH and adsorbed onto 4.5 g silica gel and dried. The material was purified by silica gel chromatography (40 g ISCO gold column) using 0 -
100% 90/10 DCM/MeOH in DCM. The product- containing fractions were concentrated to afford 0.107 g containing a mixture of isomers. This was further purified by chiral SFC: 1st SFC Purification: AS-H (5 micron, 21x 250 mm, S/N=5172), F=60ml/min, 70% carbon dioxide and 30% MeOH with 20mM ammonia; 282nm, bpr=100 bar, column p=172. Three peaks were collected named by order of elution: peaks 1, 2 and 3. 2nd SFC Purification of peak 3: AD-H (5um, 21x250 mm, S/N=5271), F=60/min, 75% carbon dioxide and 25% MeOH with 20mM ammonia. 282nm, bpr=100 bar to give peak 3-1 and 3-2 (named by order of elution).
Example 1 15 (9S,12S)-12,16-dimethyl-3,7,14,17,23-pentaaza- pentacyclo[13621~2,5~0~4,9~0~18,22~]tetracosa-l (21),2(24),4,15,17,19,22-heptaen-6- one: 'H NMR (400 MHz, DMSO-i/6) δ ppm 7.86 - 7.98 (2 H, m) 7.57 (1 H, dd, J=8.1, 1.1 Hz) 7.33 (1 H, t, J=7.8 Hz) 6.96 (1 H, d, J=4.1 Hz) 6.87 (1 H, d, J=1.8 Hz) 3.88 (1 H, d, J=14.7 Hz) 3.25 - 3.30 (1 H, m) 3.09 - 3.20 (1 H, m) 2.98 (1 H, dt, J=13.6, 7.1 Hz) 2.70 - 2.84 (1 H, m) 2.56 (3 H, s) 2.40 (1 H, br. s.) 1.88 - 2.05 (1 H, m) 1.50 - 1.71 (3 H, m) 1.01 (3 H, d, J=6.3 Hz), m/z (ESI, +ve) 362.1 (M+H)+.
Example 1 16 (9S,1 1R)-1 l,16-dimethyl-3,7,14,17,23- pentaazapentacyclo[13621~2,5~0~4,9~0~18,22~]tetracosa-l(21),2(24),4,15,17,19,22- heptaen-6-one: !H NMR (400 MHz, DMSO-i/6) δ ppm 7.89 (1 H, dd, J=7.4, 1.2 Hz) 7.84 (1 H, t, J=5.0 Hz) 7.57 (1 H, dd, J=8.1 , 1.1 Hz) 7.33 (1 H, t, J=7.8 Hz) 7.00 (1 H, br. s.) 6.83 (1 H, d, J=1.8 Hz) 3.62 (1 H, t, J=13.2 Hz) 3.08 - 3.31 (4 H, m) 2.52 (3 H, s) 1.86 - 2.23 (3 H, m) 1.59 (1 H, dd, J=15.1, 5.3 Hz) 1.38 - 1.53 (1 H, m) 1.05 (3 H, d, J=6.8 Hz). m/z (ESI, +ve) 362.1 (M+H)+.
Example 1 17 (9R,12S)-12,16-dimethyl-3,7,14,17,23- pentaazapentacyclo[13621~2,5~0~4,9~0~18,22~]tetracosa-l(21),2(24),4,15,17,19,22- heptaen-6-one: !H NMR (400 MHz, DMSO-i/6) δ ppm 13.48 (1 H, br. s.) 7.99 (1 H, d, J=7.4 Hz) 7.88 (1 H, br. s.) 7.56 (1 H, d, J=7.8 Hz) 7.33 (1 H, t, J=7.7 Hz) 7.03 (1 H, d, J=3.9 Hz) 6.95 (1 H, s) 3.49 (1 H, d, J=12.7 Hz) 2.94 - 3.28 (4 H, m) 2.54 (3 H, s) 2.29 - 2.44 (1 H, m) 1.99 (1 H, br. s.) 1.74 (2 H, br. s.) 1.19 - 1.37 (1 H, m) 1.06 (3 H, d, J=5.9 Hz), m/z (ESI, +ve) 362.1 (M+H)+.
Example 1 18 (9R,1 1R)-1 l,16-dimethyl-3,7,14,17,23- pentaazapentacyclo[13621~2,5~0~4,9~0~18,22~]tetracosa-l(21),2(24),4,15,17,19,22- heptaen-6-one: !H NMR (400 MHz, DMSO-i/6) δ ppm 7.98 (1 H, dd, J=7.6, 1.0 Hz) 7.78 (1 H, t, J=5.0 Hz) 7.56 (1 H, dd, J=8.0, 1.0 Hz) 7.33 (1 H, t, J=7.8 Hz) 7.02 (1 H, d, J=4.3 Hz) 6.93 (1 H, d, J=1.6 Hz) 3.54 - 3.69 (1 H, m) 2.95 - 3.28 (3 H, m) 2.52 (3 H, s) 2.20 (1
H, br. s.) 1.93 (1 H, br. s.) 1.80 (1 H, br. s.) 1.55 - 1.70 (1 H, m) 1.43 (1 H, d, J=13.9 Hz)
I .1 1 (3 H, d, J=6.7 Hz), m/z (ESI, +ve) 362.1 (M+H)+. Example 119: (9S,llE,13R)-13-(methoxymethyl)-16-methyl-3,7,14,17,23- pentaazapentacyclo[13.6.2.1~2,5~.0~4,9~.0~18,22~]tetracosa- l(22),2(24),4,ll,15,17,18,20,22-nonaen-6-one
Figure imgf000232_0001
Step 1 : (R)-tert-butyl (l-methoxy-3-oxopropan-2-yl)carbamate
A solution of (R)-tert-butyl (l-hydroxy-3-methoxypropan-2-yl)carbamate (CNH
Technologies, 2.49 g, 12.13 mmol) in DCM (121 ml) was stirred, and Dess-Martin periodinane (Sigma Aldrich 5.66 g, 13.34 mmol) was added, giving a milky white suspension. Stirring under N2 for 30 min gave a transparent solution with a purple hue. The reaction was stirred more rapidly, and 15 mL saturated aqueous Na2C03 and 15 mL saturated aqueous sodium thiosulfate were added. The milky mixture was stirred for 1 h. The resulting biphasic solution was extracted with DCM (3x), dried over Na2S04, filtered, and concentrated under reduced pressure to give (R)-tert-butyl (l-methoxy-3-oxopropan- 2-yl)carbamate as a milky white residue (2.19 g, 10.78 mmol, 89%): !H NMR (400 MHz, CDC13) δ ppm 9.65 (1 H, s) 5.40 (1 H, br. s.) 4.22 - 4.39 (1 H, m) 3.93 (1 H, dd, J=9.59, 2.93 Hz) 3.63 (1 H, dd, J=9.59, 4.11 Hz) 3.35 (3 H, s) 1.47 (9 H, s). m/z (ESI, +ve) 400.2 (M+H)+.
Step 2: (R)-l-methoxybut-3-en-2-amine hydrochloride
A suspension of methyltriphenylphosphonium bromide (Sigma Aldrich, 2.53 g, 7.09 mmol) in anhydrous THF (30 mL) was stirred under N2 and cooled to -78°C. n- butyllithium solution, 2.5m in hexanes (Sigma Aldrich, 2.83 mL, 7.09 mmol) was added dropwise over 10 min, and the mixture was warmed to RT. It was cooled to 0°C, and (R)- tert-butyl (l-methoxy-3-oxopropan-2-yl)carbamate (Step 1, 1.2 g, 5.90 mmol) in 10 mL anhydrous THF was added dropwise over 5 min. The mixture was stirred at 0°C as the ice bath expired. The reaction was diluted with saturated aqueous NH4C1. Et20 was added, and the reaction mixture was washed 3x. The organic partition was dried over Na2S04, filtered, and concentrated in vacuo to given a viscous brown-yellow residue. The mixture was diluted with DCM and adsorbed onto silica. It was purified on 24 g S1O2 (eluent: 0 to 50% EtOAc/hexanes then 50 to 80% EtOAc/hexanes). The material was concentrated in vacuo. HC1 in 1,4-dioxane, 4 N (Sigma Aldrich, 7.38 mL, 29.5 mmol) was added to the mixture and stirred for 2 h. The mixture was diluted with MeOH and concentrated in vacuo to a brown residue that was used without additional purification. !H NMR (400 MHz, DMSO-i/6) δ ppm 6.11 (2 H, br. s.) 5.67 - 5.81 (1 H, m) 5.01 - 5.18 (2 H, m) 3.33 - 3.42 (1 H, m) 3.24 - 3.28 (2 H, m) 3.22 - 3.24 (3 H, m).
Step 3: (9S,1 lE,13R)-13-(methoxymethyl)-16-methyl-3,7,14,17,23- pentaazapentacyclo[l 3.6.2.1~2,5~.0~4,9~.0~18,22~]tetracosa- 1 (22),2(24),4, 11 , 15, 17, 18,20,22-nonaen-6-one.
A solution of DIEA (EMD Biosciences, 326 μΐ,, 1.873 mmol), (R)-l-methoxybut-3-en-2- amine hydrochloride (Step 2, 0.129 g, 0.936 mmol), (S)-7-allyl-2-(3-fluoro-2- methylquinoxalin-5-yl)-6,7-dihydro-lH-pyrrolo[3,2-c]pyridin-4(5H)-one (Intermediate D, 0.105 mg, 0.312 mmol), and DMSO (3.1 mL) was sealed and stirred at 80 °C for 60 h. The mixture was cooled, diluted with water, and extracted with DCM. The combined organics were dried over Na2S04, filtered, and adsorbed onto silica in vacuo. The reaction mixture was purified on 12 g S1O2 (eluent: 0 to 4% MeOH/DCM over 30 minutes, RediSep Gold). The product fractions were combined and concentrated in vacuo to an orange residue that contained the product with impurities (0.039 g isolated material). The isolated material was combined with Grubbs' catalyst, 2nd generation (Sigma Aldrich,
0.016 g, 0.019 mmol) and DCM (1.9 mL) and bubbled with argon for 30 s, sealed, and heated to 50 °C for 30 min. The reaction was cooled to RT, transferred to a round bottom flask, and concentrated in vacuo. The residue was taken up in 2 mL DMSO and purified by reverse-phase preparative HPLC using a Phenomenex Gemini column, 10 μ, Ci8, 100 A, 150 x 30 mm, 0.1% TFA in ACN/H20, gradient 5% to 90% over 10 min. The product fractions were dried in a Genevac EZ-2 evaporator at 55 °C. The resulting TFA salts were diluted with MeOH and applied to a pre-washed (MeOH) Silicycle Si-carbonate cartridge. The compound eluted in MeOH as a yellow solution. It was concentrated under reduced pressure to give (9S,1 lE,13R)-13-(methoxymethyl)-16-methyl- 3,7,14, 17,23-pentaazapentacyclo[l 3.6.2.1~2,5~.0~4,9~.0~18,22~]tetracosa- l(22),2(24),4,l l,15,17,18,20,22-nonaen-6-one as a yellow solid (0.013 g, 0.034 mmol, 36%, 2 steps) : !H NMR (400 MHz, DMSO-i/6) δ ppm 13.56 (1 H, br. s.) 8.03 (1 H, d, J=8.02 Hz) 7.59 (1 H, d, J=8.02 Hz) 7.33 - 7.44 (1 H, m) 7.05 (1 H, br. s.) 6.93 (1 H, s) 6.32 (1 H, s) 5.74 - 6.00 (1 H, m) 4.42 (1 H, br. s.) 3.71 (1 H, t, J=9.59 Hz) 3.59 (1 H, dd, .7=10.07, 5.18 Hz) 3.07 - 3.20 (1 H, m) 2.69 (1 H, s) 2.26 - 2.40 (3 H, m) 1.67 - 1.96 (3 H, m) 1.51 (1 H, s) 1.40 (1 H, s) 1.32 (1 H, s) 1.16 (1 H, d, J=13.1 1 Hz), m/z (ESI, +ve) 390.2 (M+H)+. Example 120: 4-((9S,llE)-16-methyl-6-oxo-3,7,14,17,23- pentaazapentacyclo[13.6.2.1~2,5~.0~4,9~.0~18,22~]tetracosa- l(21),2(24),4,ll,15,17,19,22-octaen-14-yl)butanenitrile
Example 121: 4-((9S,llZ)-16-methyl-6-oxo-3,7,14,17,23- pentaazapentacyclo[13.6.2.1~2,5~.0~4,9~.0~18,22~]tetracosa- l(21),2(24),4,ll,15,17,19,22-octaen-14-yl)butanenitrile
Figure imgf000234_0001
Step 1 : 4-(allylamino)butanenitrile
A solution of 4-chlorobutyronitrile (Sigma-Aldrich, 2.0 mL, 20.86 mmol) in prop-2-en-l - amine (Sigma-Aldrich, 31.3 mL, 417 mmol) was stirred at RT for 16 h. The reaction mixture was concentrated to remove excess allylamine. The crude product was directly injected onto a column and was purified via automated flash chromatography (silica gel) with 100% DCM to 4% 2 M NH3 in MeOH/DCM to give 4-(allylamino)butanenitrile (427 mg, 3.44 mmol, 16.48 % yield) as a colorless oil. !H NMR (400 MHz, CDC13) δ ppm 1.18 (br. s., 1 H) 1.82 (quin, J=6.94 Hz, 2 H) 2.46 (t, .7=7.14 Hz, 2 H) 2.75 (t, J=6.75 Hz, 2 H) 3.25 (dt, J=6.02, 1.30 Hz, 2 H) 5.11 (dd, J=10.27, 1.47 Hz, 1 H) 5.18 (dq, J=17.21, 1.56 Hz, 1 H) 5.83 - 5.93 (m, 1 H). MS (ESI, pos. ion) m/z: 125.2 (M+l).
Steps 2-3: Synthesized over two steps from (S)-7-allyl-2-(3-fluoro-2-methylquinoxalin-5- yl)-6,7-dihydro-lH-pyrrolo[3,2-c]pyridin-4(5H)-one (Intermediate D, 150 mg, 0.446 mmol), 4-(allylamino)butanenitrile (111 mg, 0.892 mmol), and N-ethyl-N- isopropylpropan-2-amine (Sigma- Aldrich, 155 μΐ, 0.892 mmol) according to Example 75 to give, after chiral SFC, 4-((9S,l lE)-16-methyl-6-oxo-3,7,14,17,23- pentaazapentacyclo[l 3.6.2. l~2,5~.0~4,9~.0~18,22~]tetracosa- l(21),2(24),4,l l,15,17,19,22-octaen-14-yl)butanenitrile (12 mg, 0.029 mmol, 29.3 % yield, first eluting isomer) and 4-((9S,l lZ)-16-methyl-6-oxo-3,7,14,17,23- pentaazapentacyclo[l 3.6.2. l~2,5~.0~4,9~.0~18,22~]tetracosa- l(21),2(24),4,l l,15,17,19,22-octaen-14-yl)butanenitrile (14 mg, 0.034 mmol, 34% yield, second eluting isomer).
Analytical data for 4-((9S,l lE)-16-methyl-6-oxo-3,7,14,17,23-pentaaza- pentacyclo[13.6.2.1~2,5~.0~4,9~.0~18,22~]tetracosa-l(21),2(24),4,l 1, 15,17,19,22- octaen-14-yl)butanenitrile: !H NMR (400 MHz, CDC13) δ ppm 2.15 - 2.24 (m, 2 H) 2.31 - 2.42 (m, 1 H) 2.48 (td, J=6.94, 4.50 Hz, 2 H) 2.65 (d, J=13.30 Hz, 1 H) 2.75 (s, 3 H) 3.32 - 3.50 (m, 4 H) 3.51 - 3.61 (m, 1 H) 4.12 - 4.21 (m, 1 H) 4.24 - 4.33 (m, 1 H) 5.32 (d,
J=3.13 Hz, 1 H) 5.91 - 6.02 (m, 1 H) 6.22 (ddt, J=15.63, 7.46, 1.96, 1.96 Hz, 1 H) 7.11 (d, J=2.35 Hz, 1 H) 7.53 (t, J=8.02 Hz, 1 H) 7.71 (dd, J=8.12, 1.27 Hz, 1 H) 8.00 (dd, J=7.53, 1.27 Hz, 1 H) 13.12 (br. s., 1 H). MS (ESI, pos. ion) m/z: 413.3 (M+l).
Analytical data for 4-((9S,l lZ)-16-methyl-6-oxo-3,7,14,17,23-pentaaza- pentacyclo[13.6.2.1~2,5~.0~4,9~.0~18,22~]tetracosa-l(21),2(24),4,l 1, 15,17,19,22- octaen-14-yl)butanenitrile: !H NMR (400 MHz, CDCl3) ppm 1.98 - 2.11 (m, 1 H) 2.11 - 2.23 (m, 1 H) 2.28 - 2.37 (m, 1 H) 2.42 (td, J=6.80, 2.45 Hz, 2 H) 2.68 - 2.78 (m, 1 H) 2.82 (s, 3 H) 3.37 (t, J=9.39 Hz, 1 H) 3.42 - 3.53 (m, 2 H) 3.65 (t, J=7.92 Hz, 2 H) 3.71 (d, J=17.80 Hz, 1 H) 4.86 (dd, J=16.43, 8.41 Hz, 1 H) 5.28 (d, J=2.93 Hz, 1 H) 5.70 - 5.79 (m, 1 H) 5.79 - 5.89 (m, 1 H) 6.99 (d, J=2.15 Hz, 1 H) 7.51 (t, J=7.43 Hz, 1 H) 7.73
(dd, J=8.22, 1.17 Hz, 1 H) 7.88 (dd, J=7.43, 1.17 Hz, 1 H) 12.76 (s, 1 H). MS (ESI, pos. ion) m/z: 413.3 (M+l). Example 122 (9S,12R)-12,16-dimethyl-3,7,14,17,23- pentaazapentacyclo[13621~2,5~0~4,9~0~18,22~]tetracosa-l(21),2(24),4,15,17,19,22- heptaen-6-one
Example 123 (9R,12R)-12,16-dimethyl-3,7,14,17,23- pentaazapentacyclo[13621~2,5~0~4,9~0~18,22~]tetracosa-l(21),2(24),4,15,17,19,22- heptaen-6-one
Figure imgf000236_0001
The Compounds were prepared according to a procedure similar to that described Examples 115-1 18 starting from (R)-2-methylbutane-l ,4-diol (TCI America).
Analytical data:
Example 122 (9S,12R)-12,16-dimethyl-3,7,14,17,23-pentaaza- pentacyclo[13621~2,5~0~4,9~0~18,22~]tetracosa-l (21),2(24),4,15,17,19,22-heptaen-6- one: ¾ NM (400 MHz, DMSO-i/6) δ ppm 13.48 (1 H, br. s.) 7.99 (1 H, d, J=7.4 Hz)
7.88 (1 H, br. s.) 7.56 (1 H, d, J=8.0 Hz) 7.26 - 7.38 (1 H, m) 7.03 (1 H, d, J=3.9 Hz) 6.95 (1 H, s) 3.49 (1 H, d, J=l 1.9 Hz) 2.89 - 3.27 (4 H, m) 2.54 (3 H, s) 2.37 (1 H, br. s.) 1.99 (1 H, br. s.) 1.74 (2 H, br. s.) 1.18 - 1.37 (1 H, m) 1.06 (2 H, d, J=5.9 Hz), m/z (ESI, +ve) 362.1 (M+H)+.
Example 123 (9R,12R)-12,16-dimethyl-3,7,14,17,23-pentaaza- pentacyclo[13621~2,5~0~4,9~0~18,22~]tetracosa-l (21),2(24),4,15,17,19,22-heptaen-6- one: !H NMR (400 MHz, DMSO-i/6) δ ppm 7.91 (2 H, d, J=6.5 Hz) 7.56 (1 H, dd, J=8.0, 0.8 Hz) 7.33 (1 H, t, J=7.8 Hz) 6.96 (1 H, d, J=4.3 Hz) 6.86 (1 H, d, J=1.4 Hz) 3.87 (1 H, d, J=14.3 Hz) 3.24 - 3.30 (1 H, m) 3.07 - 3.20 (1 H, m) 2.98 (1 H, dt, J=13.6, 6.7 Hz) 2.70 - 2.83 (1 H, m) 2.56 (3 H, s) 2.39 (1 H, br. s.) 1.85 - 2.04 (1 H, m) 1.49 - 1.71 (3 H, m) 1.01 (3 H, d, J=6.3 Hz), m/z (ESI, +ve) 362.1 (M+H)+.
Example 124: (Acetyloxy)methyl (9S, HE, 13S)-13,16-dimethyl-6-oxo-3,7,14,17,23- pentaazapentacyclo[13.6.2.1~2,5~.0~4,9~.0~18,22~]tetracosa- l(22),2(24),4,ll,15,17,18,20,22-nonaene-7-carboxylate
Figure imgf000237_0001
Step 1 : (S)-7-allyl-2-(3-((S)-but-3-en-2-ylamino)-2-methy
1 H-pyrrolo [3 ,2-c]pyridin-4(5H)-one
(S)-7-Allyl-2-(3-((S)-but-3-en-2-ylamino)-2-methylquinoxa
pyrrolo[3,2-c]pyridin-4(5H)-one (Example 33, Step 1 ; 0.964 g, 2.488 mmol) and DIEA (Aldrich; 0.433 ml, 2.488 mmol) were dissolved in DCM(250 mL) under N2 and cooled in an ice bath. Chloromethyl chloroformate (Aldrich; 1.0 ml, 1 1.24 mmol) was added dropwise and the reaction stirred for 45 min then the solution was removed from the cold bath and stirred at RT After an additional 105 min the solution had turned dark red. The mixture was washed with water (200 mL) and the organic layer was dried with MgS04 before evaporating to dryness under reduced pressure. The crude was triturated with DCM and the solids were discarded. The filtrate was purified using silica
chromatography (0-10% MeOH in DCM gradient) to give the desired (S)-7-allyl-2-(3- ((S)-but-3-en-2-ylamino)-2-methylquinoxalin-5-yl)-6,7-dihydro-lH-pyrrolo[3,2- c]pyridin-4(5H)-one (0.964 g, 2.488 mmol) as a yellow - brown solid : !H NMR (400 MHz, CDCl3) d ppm 12.28 (1 H, br. s.), 7.88 - 7.94 (1 H, m), 7.70 (1 H, dd, J=8.0, 1.2 Hz), 7.39 (1 H, t, J=7.8 Hz), 7.12 (1 H, d, J=2.2 Hz), 6.11 (1 H, ddd, J=\ 1.2, 10.6, 3.9 Hz), 5.88 - 5.94 (2 H, m), 5.77 - 5.88 (1 H, m), 5.23 - 5.35 (2 H, m), 5.13 - 5.21 (2 H, m), 5.00 (1 H, d, J=6.7 Hz), 4.65 - 4.75 (1 H, m), 4.32 (1 H, dd, J= 13.1 , 4.3 Hz), 4.09 (1 H, dd, J=13.0, 4.2 Hz), 3.71 - 3.77 (1 H, m), 3.04 (1 H, dq, J=8.9, 4.5 Hz), 2.62 (3 H, s), 2.37 - 2.56 (2 H, m), 1.82 - 1.89 (1 H, m), 1.55 (3 H, d, J=6.8 Hz), m/z (ESI, +ve) 479.9 (M+H)+.
Step 2: chloromethyl (9S, HE, 13S)-13,16-dimethyl-6-oxo-3,7,14,17,23- pentaazapentacyclo[l 3.6.2.1~2,5~.0~4,9~.0~18,22~]tetracosa- 1 (22),2(24),4, 11 , 15, 17, 18,20,22-nonaene-7-carboxylate
(S)-Chloromethyl 7-allyl-2-(3-((S)-but-3-en-2-ylamino)-2-methylquinoxalin-5-yl)-4-oxo- 6,7-dihydro-lH-pyrrolo[3,2-c]pyridine-5(4H)-carboxylate (0.750 g, 1.563 mmol) was dissolved in CHC13 (100 ml) under N2. Grubbs catalyst 2nd generation (Aldrich; 0.120 g, 0.141 mmol) was added and the reaction heated to reflux. After 10 min, the mixture was cooled and concentrated to ~ 20 mL under reduced pressure. Purification using silica chromatography (0-10% MeOH in DCM gradient) gave the macrocycle (0.619 g, 1.370 mmol, 88 % yield) as a yellow-orange solid, m/z (ESI, +ve) 452.0 (M+H)+. Step 3: (acetyloxy)methyl (9S, HE, 13S)-13,16-dimethyl-6-oxo-3,7,14,17,23- pentaazapentacyclo[l 3.6.2.1~2,5~.0~4,9~.0~18,22~]tetracosa- 1 (22),2(24),4, 11 , 15, 17, 18,20,22-nonaene-7-carboxylate
The chloromethyl (9S, HE, 13S)-13,16-dimethyl-6-oxo-3,7,14,17,23- pentaazapentacyclo[13.6.2.1~2,5~.0~4,9~.0~18,22~]tetracosa- l(22),2(24),4,l l,15,17,18,20,22-nonaene-7-carboxylate from Step 2 (0.053 g, 0.117 mmol) and tetrabutylammonium acetate (Aldrich; 0.070 g, 0.232 mmol) were suspended in dry ACN (5 mL) under N2 and heated in a 75 0 C oil bath. After stirring for 40 minutes the mixture was cooled and evaporated to dryness under reduced pressure. Purification using silica chromatography (DCM to EtOAc gradient) gave the desired macrocycle contaminated with some tetrabutylammonium salts. The material was dissolved in DCM
(10 mL) and washed with water (2 x 10 mL). The organic was dried with MgS04 and evaporated to dryness under reduced pressure to give (acetyloxy)methyl (9S, 1 IE, 13S)- 13,16-dimethyl-6-oxo-3,7,l 4, 17,23-pentaazapenta- cyclo[13.6.2.1~2,5~.0~4,9~.0~18,22~]tetracosa-l(22),2(24),4,l l, 15, 17,18,20,22- nonaene-7-carboxylate (0.0468 g, 0.098 mmol, 84 % yield) : !H NMR (400 MHz, CDC ) d ppm 13.52 (1 H, br. s.), 7.86 - 7.93 (1 H, m), 7.64 (1 H, d, J=8.0 Hz), 7.37 (1 H, t, J=7.8 Hz), 7.04 (1 H, d, J=2.2 Hz), 5.93 (2 H, q, J=5.7 Hz), 5.78 - 5.84 (2 H, m), 4.72 (1 H, s), 4.51 (1 H, dd, J=12.3, 4.7 Hz), 4.20 (1 H, quin, J=6.2 Hz), 3.40 (1 H, t, J=12.5 Hz), 3.22 - 3.32 (1 H, m), 2.50 - 2.63 (4 H, m), 2.06 - 2.19 (4 H, m), 1.51 (3 H, d, J=6.8 Hz), m/z (ESI, +ve) 476.0 (M+H)+.
BIOLOGICAL ACTIVITY
Pim-1 and Pim-2
Cloning and Expression:
Full-length human cDNAs encoding Pim-1 (MGC ID 3913552) or Pim-2 (IMAGE ID 5092935) were purchased from Invitrogen, Carlsbad, CA. These cDNAs were used as templates in PCR reactions to produce full-length DNA clones of the PIMs. Oligonucleotide PCR primers for Pim-1 were 5'-tggctgatcaatgctcttgtccaaaatc-3' and 5'- attagaattctatttgctgggccccggc-3'. Oligonucleotide PCR primers for Pim-2 were 5'- tgcaggatccatgttgaccaagcctctac-3 ' and 5 ' -acgtgaattctatccctgtgacatggcc-3 ' . PCR products were digested with Bell and EcoRI for Pirn-/ and BamHI and EcoRI for Pim-2 and ligated into a modified baculovirus transfer vector (pFastBacl) cleaved with BamHI and EcoRI. For bacterial expression, the same cleaved PCR products encoding Pim-1 or Pim- 2 were ligated into a modified E. coli expression vector pET28(a) cleaved with BamHI and EcoRI. Amino-terminal hexahistidine tags followed by a thrombin cleavage site were previously added to the vectors using standard methods of molecular biology.
Recombinant baculoviruses expressing Pim-1 or Pim-2 were made using standard methods (Fastbac manual, Invitrogen, Carlsbad, CA). Infection of Sf9 cells was done at an m.o.i. of greater than 5 for 24-48 h. Cells were harvested by centrifugation and frozen at -80 C. For E. coli expression, cells carrying pET28-His6-Th-Pim-l or pET28-His6-Th- Pim-2 were picked from a single colony and grown o/n in LB media. The o/n culture was used to inoculate a 2 liter flask with 500 mL media. This was grown o/n and used to inoculate 15-20 liters of Terrific Broth in a New Brunswick Scientific fermentor. The E. coli were grown at 37°C to and OD600 > 1.6. The temperature was dropped to 18°C and o/n expression was induced with 0.5 mM IPTG. Cells were harvested by centrifugation and frozen at -80 °C.
PURIFICATION
The frozen cell pellets were thawed by stirring in chilled lysis buffer (0.05 M HEPES, pH 8.0, 0.25 M NaCl, 0.01 M 2-mercaptoethanol, 10 %(w/v) glycerol, 0.5 %(v/v) protease inhibitor cocktail (Sigma P-8340) at a ratio of lL/200g cells until homogeneous. The thawed suspension was applied to a microfluidizer at 10,000 PSI to disrupt the cells and the whole lysates were clarified by centrifugation at 50,000 x g for 90 min, 4 °C. Imidazole was added to the clarified lysate to a final concentration of 2.5 mM and the lysate was mixed with 10 mL of Talon resin (Clontech) and the slurry rocked gently overnight at 4 °C. The slurry was centrifuged at 1,000 x g for 5 min, the supernatant decanted, and the resin suspended in 40 mL of lysis wash buffer (lysis buffer at 0.75 M NaCl). This step was repeated 3X and the resin was transferred to a 2.5 cm glass column. Ten column volumes of wash buffer (0.05 M HEPES, pH 8.0, 0.1 M NaCl, 0.01 M 2-mercaptoethanol, 10 %(w/v) glycerol) were applied to the resin followed by 10 column volumes of elution buffer (0.05 M HEPES, pH 8.0, 0.25 M NaCl, 0.01 M 2- mercaptoethanol, 10 %(w/v) glycerol, 0.1 M imidazole). Fractions were analyzed by SDS-PAGE and those containing the protein of interest were pooled and concentrated. The concentrated protein was applied to an Amersham Superdex 75 (XK 26/60) column equilibrated in 0.025 M Tris-HCl, pH 7.5, 0.1 M NaCl, 0.01 M 2-mercaptoethanol, 10 %(w/v) glycerol. The protein eluted at a retention time indicative of it being monomelic and fractions were analyzed by SDS-PAGE. Fractions containing the monomelic protein of interest were pooled, concentrated to ~2mg/mL, and stored at -80 °C.
Pirn Enzyme Assays
The assay for the determination of Pirn activity is based on the formation of phosphorylated biotinylated-BAD peptide at the Serine 112 residue (SI 12) and employs HTRF® (homogeneous time resolved fluorescence) technology to detect the product in a 96-well plate format. The phosphorylation of biotinylated-BAD (SI 12) peptide by full length recombinant Pim-1 , Pim-2, or Pim-3 protein was detected with
streptavidin:Allophycocyanin (APC) conjugate and a europium (Eu) labeled antibody directed against phosphorylated-BAD (SI 12). Excitation of Eu by a high energy laser light (337 nm) leads to a transfer of energy to the APC molecule, and results in an emission at 665 nm. The fluorescence is directly proportional to the amount of phosphorylated BAD peptide present in the reaction. Compounds were prepared in DMSO by conducting 3 -fold serial dilutions to give a 10-point dosing curve having a high dose of 1 uM. A reference compound was included on each assay plate in order to validate that plate; on one plate of every assay run, two additional reference compounds were included. The final buffer conditions were as follows: 60mM Hepes, pH 7.0 , 0.05% BSA, 2 mM DTT. Incubations were carried out at RT (22°C) for 2 h for Pim-1, 1 hour and 30 min for Pim-3, and 45 min for Pim-2. The reaction was stopped by the addition of 3 mM EDTA, and fluorescence was measured by an HTRF® Rubystar microplate reader. For each plate, percent of control (POC) values were calculated for each well. Values for the IC50 IP were estimated using a standard 4-parameter logistic model. The results are provided in Tables 1-2.
Pirn -Mn Enzyme Assays
The assay for the determination of Pirn activity is based on the formation of phosphorylated biotinylated-BAD peptide at the Serine 112 residue (SI 12) and employs HTRF® (homogeneous time resolved fluorescence) technology to detect the product in a 384-well plate format. The phosphorylation of biotinylated-BAD (SI 12) peptide by full length recombinant Pim-1, Pim-2, or Pim-3 protein was detected with
streptavidin:Allophycocyanin (APC) conjugate and a europium (Eu) labeled antibody directed against phosphorylated-BAD (SI 12). Excitation of Eu by a high energy laser light (337 nm) leads to a transfer of energy to the APC molecule, and results in an emission at 665 nm. The fluorescence is directly proportional to the amount of phosphorylated BAD peptide present in the reaction. Compounds were prepared in DMSO by conducting 3-fold serial dilutions to give a 22-point dosing curve having a high dose of 1 μΜ. A reference compound was included on each assay plate [Costar 3658] in order to validate that plate; on one plate of every assay run, two additional reference compounds were included. The Reaction Buffer consisted of 45mM Hepes, pH 7.0 , 15 mM NaCl , and 1 mM MgCl. The quench/detection buffer consisted of 50 mM Tris, 100 mM NaCl, 0.05% BSA, 0.1% Tween and 3 mM EDTA. Biotinylated BAD peptide (Biopeptide), 10 mM ATP (Sigma), Labeled p-BAD (SI 12) mAb (Cell Signalling and Perkin Elmer) [with 0.05% BSA and 2 mM DTT added] streptavidin:Allophycocyanin [Perkin Elmer]. Final concentrations - either Pim-1 enzyme [5 pM],or Pim-2 enzyme [0.5 pM], DMSO [1%], BLC BAD (S112) [0.5 μΜ], ΑΤΡ [1.5 μΜ],
streptavidin:Allophycocyanin [0.002 mg/mL] and biotinylated-BAD (SI 12) mAb [100 pM]. Initial incubations were carried out at RT (22°C) for 30 min for both Pim-1 and for Pim-2. Pirn enzyme is added to compound in buffer, and plates are incubated of 30 min.
Biotinylated BAD and ATP are added and plates are incubated for 1 h. A mixture of labeled p-BAD (SI 12) mAb and quench/detection buffer are added and incubated for 2h. Fluorescence was measured by an HTRF® Envision microplate reader. For each plate, percent of control (POC) values were calculated for each well. Values for the IC50 IP were estimated using a standard 3 or 4-parameter logistic model. The results are provided in Tables 1-2.
Pirn Cell Assay
KMS-12-BM
The cellular phosphorylation assay for activity of Pirn inhibitors in the KMS-12-BM myeloma cells measures cellular levels of phospho-BAD and total BAD. It was conducted as follows: The suspension cells were plated out onto 96-well, V-bottom plates at an initial density of 80,000 cells/well in 100 uL of complete growth medium (RPMI Medium 1640- Invitrogen #11875, 10% Heat inactivated FBS- Hyclone #SH 30070.03HI, lx L-glutamine- Invitrogen # 25030). The cells were then incubated overnight at 37°C, 5% C02.
Compounds were initially diluted in DMSO by conducting 3-fold serial dilutions to give a 10-point dosing curve having a high dose of 31.6 uM. In addition to the 10-point dosing curve of the test compound, DMSO alone was run as the high control and 7.9 uM 2510883 as the low control. This dilution in DMSO was then diluted again into cell growth medium. Aliquots (11.1 uL) of the compound diluted in growth medium were then transferred to the appropriate wells of the 96-well plates containing cells to yield a final DMSO concentration of 0.3%. The cell plates were then incubated with compound for 2 hours at 37°C, 5% CO2. After a two h incubation, the compound-containing medium was removed. The cell plates were placed on ice and given 50 uL of ice-cold complete lysis buffer (MSD kit components, Protease Inhibitor Cocktail Tablets- Roche # 04 693 116 001). The cell plates containing lysis buffer were then immediately stored at - 70 °C. These prepared lysates were then assayed for phospho and total BAD according to the manufacturer's protocols (Meso Scale Diagnostics, Cat#K15103C-3 & # K15103D- 3). The plates were read on the MSD Sector Imager 6000, and results were calculated according to the assay protocols (( %Phosphoprotein = (( 2 x Phospho signal) / ( Phospho signal + Total signal)) x 100)). The results are provided in Tables 1-2.
KMS12 #2
The flow cytometry assay for determination of the Pirn activity in the engineered KMS- 12-BM cell lines (DSMZ cat# ACC 551) measures levels of phospho-BAD normalized against total BAD protein levels. It was conducted as follows: Protocol:
Compounds are initially diluted in DMSO by conducting 2-fold serial dilutions to give a 22-point dosing curve having a high dose of 30 μΜ. Exponentially growing KMS- 12-BM cells (50 \L, between 0.5 and 1.5xlOA6/ml, DSMZ) in Assay Media (RPMI/20% heat inactivated FBS/1X NaPyruvate/lX NEAA/1X PSG (pen/strep glutamine)) are added to a 384-well plate containing 200 nL of compound. The cell plates are then incubated with compound for 110 min at 37°C, 5% CO2.. BD Phosflow Lyse/Fix (BD Biosciences) is diluted to 2x with Assay Media. 50 of the diluted BD Phosflow
Lyse/Fix is added to each well. The cell plates are incubated for 15 min at RT. The plates are spun for 15 sec at 2K RPM then aspirated. Staining Media (IxPBS with 0.5% FBS) is added (80 μί). The plates again are spun for 15 sec at 2K RPM then aspirated. BD Perm/Wash Buffer (lx, 50 μί, BD Biosciences) is added. The cell plates are then incubated for >30 min at RT in the dark. The plates are spun for 15 sec at 2K RPM then aspirated. Staining Media (IxPBS with 0.5%o FBS) is added (80 μί). The plates are spun for 15 sec at 2K RPM then aspirated and additional Staining Media (IxPBS with 0.5% FBS) is added (80 μί). The plates are spun for 15 sec at 2K RPM then aspirated. Rabbit anti-human pBAD Serl l2 Ab (Cell Signaling) is diluted in Staining Media (1 :120). The diluted p BAD Ab (10 |jL) is added to each well. The cell plates are incubated for >lhr at
RT. The plates are spun for 15 sec at 2K RPM then aspirated. Staining Media (IxPBS with 0.5% FBS) is added (80 μΐ). Goat Anti Rabbit Alexa-647 (Invitrogen) is diluted in Staining Media (1 :4000). The diluted Goat Anti Rabbit Alexa-647 (70 μί) is added to each well. The cell plates are then incubated for >30 min at RT in the dark. The plates are spun for 15 sec at 2K RPM then aspirated. Staining Media (IxPBS with 0.5% FBS) is added (80 μί). The plates are spun for 15 sec at 2K RPM then aspirated and additional Staining Media (IxPBS with 0.5%o FBS) is added (80 μί). The plates are spun for 15 sec at 2K RPM then aspirated. Staining Media (IxPBS with 0.5% FBS) is added (30 (jL). The plates are read on a BD LSRII, and results were calculated according to the assay protocols (( %oPhosphoprotein = (( 2 x Phospho signal) / ( Phospho signal + Total signal)) x 100)). The results are provided in Tables 1-2. Table 1 IC5o Activity of compounds of the Invention
EX Pim-1 Pim-2 Pim-1 -Mn Pim-2 KMS-12 KMS-12#2
-Mn -Mn -BM flow
IC50 IC50 IC50 IC50 IC50 IC50
ΙΡ (μΜ) IP ( ΥΙ) IP ( ΥΙ) IP ( ΥΙ) IP ( ΥΙ) IP ( ΥΙ
1 0.00114 0.00685 5.93
2 0.00989 0.0152 0.00705 0.0158 NA
3 0.000733 0.00806 0.000542 0.00577 2.94
4 0.0173 0.0618 0.0118 0.0526 > 31.6
5 0.000761 0.00395 1.14
6 0.000263 0.00146 0.347
7 0.000187 0.00151 0.000063 0.000412 0.367
8 0.00151 0.00479 0.000793 0.00359 2.1
9 0.000289 0.0004 9.35E-05 0.0000875 0.0282
10 0.000596 0.00864 0.000537 0.00692 2.49
1 1 0.00141 0.0101 0.00138 0.00743 2
12 0.0112 0.027 0.00643 0.02 NA
13 0.0046 0.0179 0.00295 0.0132 NA
14 0.000209 0.000286 4.98E-05 0.0000634 0.0163 0.0185
15 0.00095 0.000819 0.000373 0.00034 0.0308 0.125
16 0.000107 0.0000581 0.00339
17 0.000553 0.000634 0.000106 0.000133 0.0402 0.0569
18 0.000166 0.000426 6.47E-05 0.0000743 0.0169 0.0108
19 0.00114 0.000899 0.00055 0.00035 0.105 0.212
20 0.0000661 0.000126 5.78E-05 0.0000692 0.0129
21 0.00161 0.000834 0.00125 0.000476 0.0642 0.176
22 0.00762 0.00318 0.00162 0.000808 0.162 0.374
23 0.00444 0.00333 0.00123 0.0013 0.137 0.883
24 0.000479 0.000952 0.136 0.119
25 0.00219 0.00292 0.706 0.531
26 0.00213 0.000454 0.328 0.219
27 0.000576 0.000776 0.144 0.181
28 0.00096 0.000756 0.17 0.194
29 0.0000489 0.000127 0.0281 0.0276
30 0.000822 0.00106 0.394 0.409
31 0.000342 0.0000504 0.0362 0.0418
32 0.000215 0.000431 0.0294 0.0322
33 0.000412 0.000133 0.046 0.0506
34 0.000608 0.000116 0.0959 0.0794
35 0.000181 0.000214 0.0928 0.0749
36 0.00208 0.00164 0.509 0.348
37 0.00007 0.000054 0.0352 0.0197
38 0.000358 0.000216 0.0896 0.0999
39 0.0000852 0.000199 0.0518 0.0371
40 0.00113 0.000296 0.0417 0.0406
41 0.00324 0.00528 0.973
42 0.00026 0.000213 0.0721
43 0.000746 0.000762 0.384
44 0.00606 0.00324 0.361
45 0.00285 0.0143 6.68 46 0.00318 0.00336 0.279 0.23
47 0.00563 0.00497 1.42
48 0.00668 0.00353 1.98 1.82
49 0.526 0.517 18.3
50 0.0041 1 0.00139 0.751 1.82
51 0.000904 0.00115 0.345 0.328
52 0.000261 0.0000653 0.199
53 0.0847 0.0246 > 31 .6 >40
54 0.0105 0.0162 4.65 5.59
55 0.00245 0.00224 0.179 0.0918
56 0.000341 0.0000975 0.0431
57 0.000437 0.000977 0.159
58 0.000101 0.000149 0.0463
59 0.0361 0.0099 8.45
60 0.479 0.528 >40
61 0.0249 0.447 4.9
62 0.462 0.91 >40
63 0.000702 0.000123 0.197
64 0.00288 0.00229 0.21
65 0.000094 0.000177 0.0196
66 0.000792 0.000784 0.0887
67 0.00075 0.000666 0.104
68 0.00634 0.00279 0.622
69 0.000224 0.000295 0.0179
70 0.000264 0.000351 0.176
71 0.0146 0.0346 3.7
72 0.00287 0.00191 0.195
73 0.00613 0.00492 1.14
74 0.000777 0.00203 0.303
75 0.000663 0.00167 0.165
76 0.00159 0.00189 0.0883
77 0.000381 0.000599 0.0275
78 0.00831 0.0014 0.394
79 0.00374 0.00214 0.879
80 0.00165 0.0022 0.199
81 0.00792 0.00426 0.267
82 0.00343 0.00119 0.315
83 0.00281 0.00344 1.58
84 0.000986 0.000444 0.0402
85 0.00308 0.00719 3.33
86 0.00548 0.00757 0.928
87 0.000298 0.000691 0.187
88 0.000327 0.000188 0.1 19
89 0.02 0.0301 >40
90 0.00251 0.00262 1.16
91 0.00129 0.00214 0.983
92 0.000136 0.000318 0.0395
93 0.00102 0.00335 0.742
94 0.00358 0.00734 1.52 95 0.00013 0.0009 0.237
96 0.000328 0.000435 0.172
97 0.000609 0.00188 0.454
98 0.000468 0.00205 2.35
99 0.00197 0.00336 0.919
100 0.0003 0.0015 0.163
101 0.0683 0.0151 3.33
102 0.00614 0.00375 1.04
103 0.0158 0.00289 1.11
104 0.000196 0.000149 0.0464
105 0.00136 0.00204 1.06
106 0.0025 0.00415 1.41
Table 2
Ex # Pim-1 -Mn Pim-2 -Mn KMS12#2
flow
IC50 IC50 IC50
IP (μΜ) IP (μΜ) IP (μΜ)
107 0.00162 0. .00302 0.675
108 0.00357 0. .00224 0.407
109 0.00265 0. .00258 0.329
1 10 0.0017 0. .00203 0.203
1 1 1 0.000143 0. .000277 0.0336
1 12 0.000133 0. .00123 0.176
1 13 0.00189 0. .00413 1 .05
1 14 0.0061 0. .0174 2.6
1 15 0.000327 0. .000288 0.0374
1 16 0.00001 14 0. .0000197 0.319
1 17 0.00775 0. .00978 0.317
1 18 0.000335 0. .000293 0.148
1 19 0.00021 0. .000926 0.734
120 0.000412 0. .00198 0.55
121 0.000221 0. .000753 0.142
122 0.000518 0. .000415 0.0251
123 0.000218 0. .000331 0.107
124 0.0165 0. .00623 0.0269 The compounds of the present invention may be administered orally, parentally, by inhalation spray, rectally, or topically in dosage unit formulations containing conventional pharmaceutically acceptable carriers, adjuvants, and vehicles.
Treatment of diseases and disorders herein is intended to also include the prophylactic administration of a compound of the invention, a pharmaceutical salt thereof, or a pharmaceutical composition of either to a subject (i.e., an animal, preferably a mammal, most preferably a human) believed to be in need of preventative treatment.
The dosage regimen for usng these compounds diseases, cancer, and/or hyperglycemia with the compounds of this invention and/or compositions of this invention is based on a variety of factors, including the type of disease, the age, weight, sex, medical condition of the patient, the severity of the condition, the route of administration, and the particular compound employed. Thus, the dosage regimen may vary widely, but can be determined routinely using standard methods. Dosage levels of the order from about 0.01 mg to 30 mg per kilogram of body weight per day, preferably from about 0.1 mg to 10 mg/kg, more preferably from about 0.25 mg to 1 mg/kg are useful for all methods of use disclosed herein.
The pharmaceutically active compounds of this invention can be processed in accordance with conventional methods of pharmacy to produce medicinal agents for administration to patients, including humans and other mammals.
For oral administration, the pharmaceutical composition may be in the form of, for example, a capsule, a tablet, a suspension, or liquid. The pharmaceutical composition is preferably made in the form of a dosage unit containing a given amount of the active ingredient. For example, these may contain an amount of active ingredient from about 1 to 2000 mg, preferably from about 1 to 500 mg, more preferably from about 5 to 150 mg. A suitable daily dose for a human or other mammal may vary widely depending on the condition of the patient and other factors, but, once again, can be determined using routine methods.
The active ingredient may also be administered by injection as a composition with suitable carriers including saline, dextrose, or water. The daily parenteral dosage regimen will be from about 0.1 to about 30 mg/kg of total body weight, preferably from about 0.1 to about 10 mg/kg, and more preferably from about 0.25 mg to 1 mg/kg.
Injectable preparations, such as sterile injectable aq. or oleaginous suspensions, may be formulated according to the known are using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed, including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables.
Suppositories for rectal administration of the drug can be prepared by mixing the drug with a suitable non-irritating excipient such as cocoa butter and polyethylene glycols that are solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum and release the drug.
A suitable topical dose of active ingredient of a compound of the invention is 0.1 mg to 150 mg administered one to four, preferably one or two times daily. For topical administration, the active ingredient may comprise from 0.001 % to 10% w/w, e.g., from 1% to 2% by weight of the formulation, although it may comprise as much as 10% w/w, but preferably not more than 5% w/w, and more preferably from 0.1 % to 1 % of the formulation.
Formulations suitable for topical administration include liquid or semi-liquid preparations suitable for penetration through the skin (e.g., liniments, lotions, ointments, creams, or pastes) and drops suitable for administration to the eye, ear, or nose.
For administration, the compounds of this invention are ordinarily combined with one or more adjuvants appropriate for the indicated route of administration. The compounds may be admixed with lactose, sucrose, starch powder, cellulose esters of alkanoic acids, stearic acid, talc, magnesium stearate, magnesium oxide, sodium and calcium salts of phosphoric and sulfuric acids, acacia, gelatin, sodium alginate, polyvinyl- pyrrolidine, and/or polyvinyl alcohol, and tableted or encapsulated for conventional administration. Alternatively, the compounds of this invention may be dissolved in saline, water, polyethylene glycol, propylene glycol, ethanol, corn oil, peanut oil, cottonseed oil, sesame oil, tragacanth gum, and/or various buffers. Other adjuvants and modes of administration are well known in the pharmaceutical art. The carrier or diluent may include time delay material, such as glyceryl monostearate or glyceryl distearate alone or with a wax, or other materials well known in the art.
The pharmaceutical compositions may be made up in a solid form (including granules, powders or suppositories) or in a liquid form (e.g., solutions, suspensions, or emulsions). The pharmaceutical compositions may be subjected to conventional pharmaceutical operations such as sterilization and/or may contain conventional adjuvants, such as preservatives, stabilizers, wetting agents, emulsifiers, buffers etc.
Solid dosage forms for oral administration may include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound may be admixed with at least one inert diluent such as sucrose, lactose, or starch. Such dosage forms may also comprise, as in normal practice, additional substances other than inert diluents, e.g., lubricating agents such as magnesium stearate. In the case of capsules, tablets, and pills, the dosage forms may also comprise buffering agents. Tablets and pills can additionally be prepared with enteric coatings.
Liquid dosage forms for oral administration may include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs containing inert diluents commonly used in the art, such as water. Such compositions may also comprise adjuvants, such as wetting, sweetening, flavoring, and perfuming agents.
Compounds of the present invention can possess one or more asymmetric carbon atoms and are thus capable of existing in the form of optical isomers as well as in the form of racemic or non-racemic mixtures thereof. The optical isomers can be obtained by resolution of the racemic mixtures according to conventional processes, e.g., by formation of diastereoisomeric salts, by treatment with an optically active acid or base. Examples of appropriate acids are tartaric, diacetyltartaric, dibenzoyltartaric, ditoluoyltartaric, and camphorsulfonic acid and then separation of the mixture of diastereoisomers by crystallization followed by liberation of the optically active bases from these salts. A different process for separation of optical isomers involves the use of a chiral chromatography column optimally chosen to maximize the separation of the enantiomers. Still another available method involves synthesis of covalent diastereoisomeric molecules by reacting compounds of the invention with an optically pure acid in an activated form or an optically pure isocyanate. The synthesized diastereoisomers can be separated by conventional means such as chromatography, distillation, crystallization or sublimation, and then hydrolyzed to deliver the enantiomerically pure compound. The optically active compounds of the invention can likewise be obtained by using active starting materials. These isomers may be in the form of a free acid, a free base, an ester or a salt.
Likewise, the compounds of this invention may exist as isomers, that is compounds of the same molecular formula but in which the atoms, relative to one another, are arranged differently. In particular, the alkylene substituents of the compounds of this invention, are normally and preferably arranged and inserted into the molecules as indicated in the definitions for each of these groups, being read from left to right. However, in certain cases, one skilled in the art will appreciate that it is possible to prepare compounds of this invention in which these substituents are reversed in orientation relative to the other atoms in the molecule. That is, the substituent to be inserted may be the same as that noted above except that it is inserted into the molecule in the reverse orientation. One skilled in the art will appreciate that these isomeric forms of the compounds of this invention are to be construed as encompassed within the scope of the present invention.
The compounds of the present invention can be used in the form of salts derived from inorganic or organic acids. The salts include, but are not limited to, the following: acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate, camphorsulfonate, digluconate, cyclopentanepropionate, dodecylsulfate, ethanesulfonate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, fumarate, hydrochloride, hydrobromide, hydroiodide, 2- hydroxy ethanesulfonate, lactate, maleate, methansulfonate, nicotinate, 2- naphthalenesulfonate, oxalate, palmoate, pectinate, persulfate, 2-phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, tosylate, mesylate, and undecanoate. Also, the basic nitrogen-containing groups can be quaternized with such agents as lower alkyl halides, such as methyl, ethyl, propyl, and butyl chloride, bromides and iodides; dialkyl sulfates like dimethyl, diethyl, dibutyl, and diamyl sulfates, long chain halides such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides, aralkyl halides like benzyl and phenethyl bromides, and others. Water or oil-soluble or dispersible products are thereby obtained.
Examples of acids that may be employed to from pharmaceutically acceptable acid addition salts include such inorganic acids as HC1 acid, sulfuric acid and phosphoric acid and such organic acids as oxalic acid, maleic acid, succinic acid and citric acid.
Other examples include salts with alkali metals or alkaline earth metals, such as sodium, potassium, calcium or magnesium or with organic bases.
Also encompassed in the scope of the present invention are pharmaceutically acceptable esters of a carboxylic acid or hydroxyl containing group, including a metabolically labile ester or a prodrug form of a compound of this invention. A metabolically labile ester is one which may produce, for example, an increase in blood levels and prolong the efficacy of the corresponding non-esterified form of the compound. A prodrug form is one which is not in an active form of the molecule as administered but which becomes therapeutically active after some in vivo activity or biotransformation, such as metabolism, for example, enzymatic or hydrolytic cleavage. For a general discussion of prodrugs involving esters see Svensson and Tunek Drug Metabolism Reviews 165 (1988) and Bundgaard Design of Prodrugs, Elsevier (1985). Examples of a masked carboxylate anion include a variety of esters, such as alkyl (for example, methyl, ethyl), cycloalkyl (for example, cyclohexyl), aralkyl (for example, benzyl, p- methoxybenzyl), and alkylcarbonyloxyalkyl (for example, pivaloyloxymethyl). Amines have been masked as arylcarbonyloxymethyl substituted derivatives which are cleaved by esterases in vivo releasing the free drug and formaldehyde (Bungaard J. Med. Chem. 2503 (1989)). Also, drugs containing an acidic NH group, such as imidazole, imide, indole and the like, have been masked with N-acyloxymethyl groups (Bundgaard Design of Prodrugs, Elsevier (1985)). Hydroxy groups have been masked as esters and ethers. EP 039,051 (Sloan and Little, 4/11/81) discloses Mannich-base hydroxamic acid prodrugs, their preparation and use. Esters of a compound of this invention may include, for example, the methyl, ethyl, propyl, and butyl esters, as well as other suitable esters formed between an acidic moiety and a hydroxyl containing moiety. Metabolically labile esters, may include, for example, methoxymethyl, ethoxymethyl, iso-propoxymethyl, a- methoxyethyl, groups such as a-((Ci-C4)alkyloxy)ethyl, for example, methoxyethyl, ethoxyethyl, propoxyethyl, iso-propoxyethyl, etc.; 2-oxo-l,3-dioxolen-4-ylmethyl groups, such as 5-methyl-2-oxo-l,3,dioxolen-4-ylmethyl, etc.; C1-C3 alkylthiomethyl groups, for example, methylthiomethyl, ethylthiomethyl, isopropylthiomethyl, etc.; acyloxymethyl groups, for example, pivaloyloxymethyl, a-acetoxymethyl, etc.; ethoxycarbonyl-1- methyl; or α-acyloxy-a-substituted methyl groups, for example a-acetoxyethyl.
Further, the compounds of the invention may exist as crystalline solids which can be crystallized from common solvents such as ethanol, Ν,Ν-dimethyl-formamide, water, or the like. Thus, crystalline forms of the compounds of the invention may exist as polymorphs, solvates and/or hydrates of the parent compounds or their pharmaceutically acceptable salts. All of such forms likewise are to be construed as falling within the scope of the invention.
While the compounds of the invention can be administered as the sole active pharmaceutical agent, they can also be used in combination with one or more compounds of the invention or other agents. When administered as a combination, the therapeutic agents can be formulated as separate compositions that are given at the same time or different times, or the therapeutic agents can be given as a single composition.
The foregoing is merely illustrative of the invention and is not intended to limit the invention to the disclosed compounds. Variations and changes which are obvious to one skilled in the art are intended to be within the scope and nature of the invention which are defined in the appended claims. From the foregoing description, one skilled in the art can easily ascertain the essential characteristics of this invention, and without departing from the spirit and scope thereof, can make various changes and modifications of the invention to adapt it to various usages and conditions.

Claims

What is claimed:
1. A compound of Formula 1 '
Figure imgf000253_0001
wherein
ring a is a ring that together with the 2 carbon atoms to which it attaches, forms a phenyl ring or a 5-6 membered heterocyclic ring;
X is N or CH;
Z is O, S, NRb, C=0 or C(Rb)2;
Q is a linker saturated or unsaturated chain;
q is N, NH, CH or CH2;
r is CH, NH, CH2 or N;
s is N or CH;
w is CH, CH2 , N or NH;
ring b is unsaturated, or partially saturated;
ring c is saturated, or partially saturated;
R1 is H, or halo;
R2 is H, haloalkyl, hydroxyalkyl, alkyl, alkoxy, HC(=0)-, carboxy, alkoxycarbonyl, cycloalkyl, or substituted or unsubstituted heterocyclyl;
Rb is H, alkyl, haloalkyl, hydroxyalkyl, alkylsulfonylalkyl, BOC-aminoalkyl, aminoalkyl, cyanoalkyl, alkoxyalkyl, alkylsulfonylalkylaminoalkyl, alkylsulfonylaminoalkyl, alkylcarbonylaminoalkyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted aryl, unsubstituted or substituted arylalkyl or unsubstituted or substituted heterocyclyl; and
Re is H, -PO(Oalkyl)2, alkylcarbonyl, alkylcarbonyloxyalkoxycarbonyl, alkoxycarbonyl, aminoalkylcarbonyloxyalkoxycarbonyl or hydroxyalkyl; and a pharmaceutically acceptable salt thereof.
2. Compound of Claim 1 wherein ring a is
Figure imgf000254_0001
wherein R1 is H, or halo; and a pharmaceutically acceptable salt thereof.
3. Compound of Claim 1 comprising
Figure imgf000254_0002
X is N or CH;
ZZ iiss OO,, SS,, NNRRbb,, C=0, or C(Rb )2;
wherein Q is a 3-8 membered linker that attaches with Z; R1 is H, or halo;
R2 is H, Ci-6 haloalkyl, Cue hydroxyalkyl, C e alkyl, Ci_6 alkoxy, HC(=0)-, carboxy, C e alkoxycarbonyl, C3.6 cycloalkyl, or substituted or unsubstituted heterocyclyl;
Rb is H, Ci-6 alkyl, Ci_6 haloalkyl, Ci_6 hydroxyalkyl, Ci_6 alkylsulfonyl-Ci_6 alkyl, BOC- amino-Ci_6 alkyl, amino-Ci_6 alkyl, cyano-Ci_6-alkyl, Ci_6-alkoxy-Ci_6-alkyl, Ci_6- alkylsulfonyl-Ci.6-alkylamino-Ci_6-alkyl, Cu6 alkylsulfonylamino-Ci_6 alkyl, Cu6 alkylcarbonylamino-Ci_6-alkyl, unsubstituted or substituted C3.6-cycloalkyl, unsubstituted or substituted aryl, unsubstituted or substituted aryl-Ci_6- or unsubstituted or substituted heterocyclyl;
wherein R6 is H; and
wherein R7 is H or Cu alkyl; and a pharmaceutically acceptable salt thereof.
4. Compound of Claim 1 comprising
Figure imgf000255_0001
wherein
X is N or CH;
Z is O, S, NRb, C=0, or C(Rb )2;
Q is optionally substituted C4-C6 alkenylenyl, optionally substituted C4-C5 alkylenyl, optionally substituted C4-C5 alkynylenyl, optionally substituted cycloalkyl-C2-C4 alkenylenyl, optionally substituted phenyl-Ci_2 alkylenyl, -(CH2)n-0-(CH2)m-, or optionally substituted Q_2 alkylenyl-aminocarbonyl-Ci_2 alkylenyl, when Q attaches to Z; or wherein Q is optionally substituted 5-7 membered heterocyclyl-alkyl, or optionally substituted 5-7 membered heterocyclyl-alkenyl, when Q incorporates Z into the heterocyclic ring; R1 is H, or halo;
R2 is H, haloalkyl, hydroxyalkyl, alkyl, alkoxy, HC(=0)-, carboxy, alkoxycarbonyl, cycloalkyl, or substituted or unsubstituted heterocyclyl;
Rb is H, Ci_4 alkyl, Ci_6-haloalkyl, Ci_4-hydroxyalkyl, Ci.4-alkylsulfonyl-Ci.4-alkyl, BOC- amino-Ci_4-alkyl, Ci.4-aminoalkyl, Ci.4-cyanoalkyl, Ci_4-alkoxy-Ci -alkyl, C1.4- alkylsulfonyl-C 1 _4-alkylamino-C 1.4-alkyl, C 1.4-alkylsulfonylamino-C 1 -alkyl, C 1.4- alkylcarbonylamino-Ci_4-alkyl, unsubstituted or substituted C3.6-cycloalkyl, unsubstituted or substituted phenyl, unsubstituted or substituted phenyl-Ci_2-alkyl or unsubstituted or substituted 4-6 memebered heterocyclyl;
wherein R6 is H; and
wherein R7 is H;
and a pharmaceutically acceptable salt thereof.
5. Compound of Claim 1 wherein Z is O, S, NRb, or CHRb; wherein Rb is H, Ci-2 alkyl, C1.2 hydroxyalkyl, C1.2 alkylsulfonyl-Cu-alkyl, B OC -amino -C 1.2 alkyl, amino-Ci.2 alkyl, C1.2 alkylsulfonyl-Cu alkylamino-Ci.2 alkyl, cyano-Cu alkyl, C1.2
alkylsulfonylamino-Ci_2 alkyl or C1.2 alkylcarbonylamino-Ci.2 alkyl; and a
pharmaceutically acceptable salt thereof.
6. Compound of Claim 1 wherein R1 is H or fluoro; and a pharmaceutically acceptable salt thereof.
7. Compound of Claim 1 wherein ring a is
Figure imgf000256_0001
; wherein R is H or fluoro; and a pharmaceutically acceptable salt thereof.
8. Compound of Claim 1 wherein Re is H, methylcarbonyl, -PO(0-methyl)2, - PO(0-tert-butyl)2, methylcarbonyloxy -methoxycarbonyl, tert-butylcarbonyloxy- methoxycarbonyl, isopropylcarbonyloxy -methoxycarbonyl, 1 ,5 -diaminopentyl- carbonyloxy-methoxycarbonyl, butoxycarbonyl or hydroxymethyl; and a
pharmaceutically acceptable salt thereof. 9. Compound of Claim 1 wherein Q and Z together form
A-1700-WO-PCT
Figure imgf000258_0001
A-1700-WO-PCT
Figure imgf000259_0001
A-1700-WO-PCT
Figure imgf000260_0001
and a pharmaceutically acceptable salt thereof.
10. Compound of Claim 1 wherein R2 is H, Ci_2 alkyl, HC(=0)- or Ci_2 hydroxyalkyl; and a pharmaceutically acceptable salt thereof.
11. Compound of Claim 1 wherein R2 is H, methyl, HC(=0)- or hydroxymethyl; and a pharmaceutically acceptable salt thereof. 12. Compound of Claim 1 wherein R2 is H; and a pharmaceutically acceptable salt thereof.
13. A compound of Formula 2
Figure imgf000262_0001
wherein Z is O or NH; and
wherein Q is optionally substituted C4-C5 alkenylenyl, or optionally substituted phenyl-
Ci_2 alkylenyl;
and a pharmaceutically acceptable salt thereof.
14. Compound of Claim 13 wherein Z is O; and a pharmaceutically acceptable salt thereof.
15. Compound of Claim 13 wherein Z is NH; and a pharmaceutically acceptable salt thereof.
16. Compound of Claim 13 wherein Q is but-2 -enylenyl, 4-methylbut-2- enylenyl, 3-methylbut-2-enylenyl, 2-methylbut-2-enylenyl or phenylmethylenyl; and a pharmaceutically acceptable salt thereof.
17. Compound of Claim 1 selected from
(9S, 1 1Z, 13R)-13,16-dimethyl-3,7,14,17,23-pentaazapentacyclo[13.6.2.1-2,5~.0- 4,9~.0~18,22~]tetracosa-l (22),2(24),4,l l ,15,17,18,20,22-nonaen-6-one;
(9S, l lE)-12,16-dimethyl-3,7,14,17,23-pentaazapentacyclo[13.6.2.1 -2,5~.0- 4,9~.0~18,22~]tetracosa- 1 (21 ),2(24),4,1 1 , 15, 17, 19,22-octaen-6-one;
(9S, l lZ)-12,16-dimethyl-3,7,14,17,23-pentaazapentacyclo[13.6.2.1 -2,5~.0- 4,9~.0~18,22~]tetracosa-l (22),2(24),4,l l ,15,17,18,20,22-nonaen-6-one; (9S, 13S)-13,16-dimethyl-3,7,14,17,23-pentaazapentacyclo[13.6.2.1-2,5~.0- 4,9~.0~18,22~]tetracosa-l(22),2(24),4,15,17,18,20,22-octaen-6-one; and
(9S, HZ)-12,14,16-trimethyl-3,7,14,17,23-pentaazapentacyclo[13.6.2.1-2,5~.0- 4,9~.0~18,22~]tetracosa-l(22),2(24),4,l l,15,17,18,20,22-nonaen-6-one.
18. A compound of Formula 3 '
Figure imgf000263_0001
wherein R1 is H or fluoro;
wherein R2 is H, HC(=0)- , Ci_2 alkyl or Q_2 hydroxyalkyl;
wherein Z is O, S or NRb;
wherein Rb is H, Ci_2 alkyl, Ci_2 hydroxyalkyl, Ci_2 alkylsulfonyl-Cu-alkyl, BOC-amino- Ci_2-alkyl, amino-Ci_2-alkyl, Ci.2-alkylsulfonyl-Ci_3-alkylamino-Ci.2-alkyl, Ci_2 alkylsulfonylamino-Ci_2-alkyl, cyano-Ci_4-alkyl or Ci_2 alkylcarbonylamino-Ci_2- alkyl;
Re is H, -PO(0-Ci_2-alkyl)2, Ci_4 alkylcarbonyl, Ci_4-alkylcarbonyloxy-Ci_2- alkoxycarbonyl, Ci.4-alkoxycarbonyl, amino-Ci_6-alkylcarbonyloxy- Ci_2- alkoxycarbonyl or C1.4 hydroxyalkyl;
wherein Q is optionally substituted C4-C5 alkylenyl, optionally substituted C4-C6
alkenylenyl, optionally substituted C4-C5 alkynylenyl, optionally substituted phenyl- Ci-2 alkylenyl, optionally substituted cycloalkyl-C2-C4 alkenylenyl, or -(CH2)n-0- (CH2)m- ;
wherein n is 1-2; and
wherein m is 1-2; provided n+m = 3 or 4;
and a pharmaceutically acceptable salt thereof.
19. Compound of Claim 18 wherein R1 is H; and a pharmaceutically acceptable salt thereof. 20. Compound of Claim 18 wherein R2 is H, HC(=0)- , methyl or
hydroxymethyl; and a pharmaceutically acceptable salt thereof.
21. Compound of Claim 18 wherein R2 is H or methyl; and a pharmaceutically acceptable salt thereof.
22. Compound of Claim 18 wherein Z is O or S; and a pharmaceutically acceptable salt thereof.
23. Compound of Claim 18 wherein Z is HN, methylamino, hydroxyethylamino, BOC-aminoethylamino, aminoethylamino, cyanopropylamino,
methylsulfonylethylaminoethylamino, methylsulfonylaminoethylamino,
methylcarbonylaminoethylamino or methylsulfonylpropylammo; and a pharmaceutically acceptable salt thereof.
24. Compound of Claim 18 wherein Q is butylenyl, 2-methylbutylenyl, 3- methylbutylenyl, 4-methylbutylenyl, 4-hydroxymethylbutylenyl, 2,3-dihydroxy-4- methylbutylenyl, but-2-enylenyl, 4-hydroxymethylbut-2 -enylenyl, 4-hydroxyethylbut-2- enylenyl, 4-methoxybut-2-enylenyl, 2 -methylbut-2 -enylenyl, 3-methylbut-2-enylenyl, 4- methylbut-2 -enylenyl, 4,4-dimethylbut-2-enylenyl, 4-trifluoromethylbut-2-enylenyl, 4- (methylsulfonylethyl)but-2-enylenyl, 3 -methylbut-2 -enylenyl, 2-methylbut-2-enylenyl, but-2-ynylenyl, 4-methylbut-2-ynylenyl, pentylenyl, pent-2-enylenyl, 2-methylpent-2- enylenyl, -(CH2)2-0-(CH2)2- , 3-(eth-2-enylenyl)cyclobutyl or phenylmethylenyl; and a pharmaceutically acceptable salt thereof.
25. Compound of Claim 18 wherein Re is H; and a pharmaceutically acceptable salt thereof.
26. A compound of Formula 4 wherein R1 is H;
wherein R2 is Ci_2 alkyl;
wherein Z is CH2 or NH; and
wherein Q is optionally substituted C4-C5 alkenylenyl, or optionally substituted Ci_2 alkylenyl-aminocarbonyl- C1.2 alkylenyl,
and a pharmaceutically acceptable salt thereof.
27. Compound of Claim 26 wherein R2 is methyl; and a pharmaceutically acceptable salt thereof.
28. Compound of Claim 26 wherein Z is NH; and a pharmaceutically acceptable salt thereof.
29. Compound of Claim 26 wherein Q is 3-methylbut-2-enylenyl,
ethy lenylammocarbonylmethylenyl, (2 -methylethylenyl)aminocarbonylmethylenyl, or methylenylaminocarbonylmethylenyl; and a pharmaceutically acceptable salt thereof.
30. A compound of Formula 5
Figure imgf000265_0001
wherein ring d forms a 4-7 membered nitrogen containing heterocyclyl;
wherein R1 is H;
wherein R2 is H or C1.2 alkyl; and wherein Q is optionally substituted C3-C4 alkenylenyl;
and a pharmaceutically acceptable salt thereof.
31. Compound of Claim 30 wherein R2 is methyl; and a pharmaceutically acceptable salt thereof.
32. Compound of Claim 30 wherein ring d is morpholinyl or 2-oxo-oxazolidinyl; and a pharmaceutically acceptable salt thereof.
I
33. Compound of Claim 30 wherein ring d is Q O or V ^ ; and a pharmaceutically acceptable salt thereof.
34. Compound of Claim 30 wherein Q is 2-propenylenyl, or 3-propenylenyl; and a pharmaceutically acceptable salt thereof.
A compound of Formula 1
Figure imgf000266_0001
wherein
ring a is a ring that together with the 2 carbon atoms to which it attaches, forms a phenyl ring or a 5-6 membered heterocyclic ring;
X is N or CH;
Z is O, S, NRb, C=0, CHRb or C(Rb)2;
Q is a linker saturated or unsaturated chain;
q is NH or CH; r is CH2 or N;
s is N or C;
w is CH or N;
ring b is unsaturated, or partially saturated;
ring c is saturated, or partially saturated;
R1 is H, or halo;
R2 is H, haloalkyl, hydroxyalkyl, alkyl, alkoxy, HC(=0)-, carboxy, alkoxycarbonyl, cycloalkyl, or substituted or unsubstituted heterocyclyl;
Rb is H, alkyl, haloalkyl, hydroxyalkyl, alkylsulfonylalkyl, BOC-aminoalkyl, aminoalkyl, cyanoalkyl, alkoxyalkyl, alkylsulfonylalkylaminoalkyl, alkylsulfonylaminoalkyl, alkylcarbonylaminoalkyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted aryl, unsubstituted or substituted arylalkyl or unsubstituted or substituted heterocyclyl; and
Re is H, -PO(OCH3)2, alkylcarbonyl or hydroxyalkyl;
and a pharmaceutically acceptable salt thereof.
36. A method for treating a condition by modulation of PIM kinase activity comprising administering to a patient in need of such treatment an effective amount of a compound of any one of Claims 1- 35.
37. A composition comprising a therapeutically effective amount of compound of any one of Claims 1 through 35 or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier.
38. A method for inhibiting Pirn kinase activity in a patient, comprising administering to the patient a composition comprising a pharmacologically effective amount of a compound of any one of Claims 1 through 35.
39. A method for treating a cancer disorder in a patient, comprising administering to the patient a composition comprising an amount of a compound of any one of Claims 1 through 38.
40. A compound of any one of Claims 1 through 35 for use as a therapeutic agent. 41. A compound of any one of Claims 1 through 35 for use in manufacture of a medicament for the treatment of cancer.
42. The method of Claim 39 wherein the cancer disorder is head and neck cancer or prostate cancer.
43. The method of Claim 39 wherein the cancer disorder is a hematological malignancy.
44. The method of Claim 39 wherein the cancer disorder is multiple myeloma or Non Hodgkins Lymphoma, or AML.
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