WO2010091104A1 - Glucosylceramide synthase inhibitors - Google Patents

Glucosylceramide synthase inhibitors Download PDF

Info

Publication number
WO2010091104A1
WO2010091104A1 PCT/US2010/023080 US2010023080W WO2010091104A1 WO 2010091104 A1 WO2010091104 A1 WO 2010091104A1 US 2010023080 W US2010023080 W US 2010023080W WO 2010091104 A1 WO2010091104 A1 WO 2010091104A1
Authority
WO
WIPO (PCT)
Prior art keywords
alkyl
oxy
compound
methyl
formula
Prior art date
Application number
PCT/US2010/023080
Other languages
French (fr)
Other versions
WO2010091104A8 (en
Inventor
Wai Ki Vicky Chan
Hongwang Du
Patrick Kearney
Elena S. Koltun
Jason August Nachtigall
Kevin Noson
Michael Pack
Original Assignee
Exelixis, Inc.
Richards, Steven, James
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Exelixis, Inc., Richards, Steven, James filed Critical Exelixis, Inc.
Priority to ARP100100326A priority Critical patent/AR075367A1/en
Priority to TW099103670A priority patent/TW201040156A/en
Publication of WO2010091104A1 publication Critical patent/WO2010091104A1/en
Publication of WO2010091104A8 publication Critical patent/WO2010091104A8/en

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/62—Oxygen or sulfur atoms
    • C07D213/63—One oxygen atom
    • C07D213/64—One oxygen atom attached in position 2 or 6
    • C07D213/643—2-Phenoxypyridines; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic 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
    • C07D471/02—Heterocyclic 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 system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • the invention relates to inhibitors of glucosylceramide synthase (GCS) useful for the treatment of cancer and metabolic diseases.
  • GCS glucosylceramide synthase
  • Glucosylceramide synthase is a pivotal enzyme which catalyzes the initial glycosylation step in the biosynthesis of glucosylceramide -based glycosphingolipids (GSLs) namely via the pivotal transfer of glucose from UDP-glucose (UDP-GIc) to ceramide to form glucosylceramide.
  • GCS is a transmembrane, type III integral protein localized in the cis/medial Golgi.
  • Glycosphingolipids are believed to be integral for the dynamics of many cell membrane events, including cellular interactions, signaling, and trafficking.
  • GSL structures have been shown (see, Yamashita et al., Proc. Natl. Acad. Sci. USA 1999, 96(16), 9142-9147) to be essential for embryonic development and for the differentiation of some tissues. Ceramide plays a central role in sphingolipid metabolism and downregulation of GCS activity has been shown to have marked effects on the sphingolipid pattern with diminished expression of glycosphingolipids. Sphingo lipids (SLs) have a biomodulatory role in physiological as well as pathological cardiovascular conditions.
  • sphingolipids and their regulating enzymes appear to play a role in adaptive responses to chronic hypoxia in the neonatal rat heart (see, El Alwani et al., Prostaglandins & Other Lipid Mediators 2005, 78(1-4), 249-261).
  • GCS inhibitors have been proposed for the treatment of a variety of diseases (see, for example, WO2005068426). Such treatments include treatment of glycolipid storage diseases (e.g., Tay Sachs, Sandhoffs, GMl gangliosidosis and Fabry diseases), diseases associated with glycolipid accumulation (e.g., Gaucher disease; Miglustat (Zavesca), a GCS inhibitor, has been approved for therapy in type 1 Gaucher disease patients, see, Treiber et al., Xenobiotica 2007, 37(3), 298-314), diseases that cause renal hypertrophy or hyperplasia such as diabetic nephropathy; diseases that cause hyperglycemia or hyperinsulemia; cancers in which glycolipid synthesis is abnormal, infectious diseases caused by organisms which use cell surface glycolipids as receptors, infectious diseases in which synthesis of glucosylceramide is essential or important, diseases in which excessive glycolipid synthesis occurs (e.g., atherosclerosis, polycystic kidney disease, and renal hypertrophy
  • GCS inhibitors can be useful for treatment of proliferative disorders by inducing apoptosis in diseased cells.
  • the present invention comprises glucosylceramide synthase (GCS) modulators of structural formula (I),
  • the invention comprises pharmaceutical compositions which comprise a GCS modulator compound of the invention, optionally as a pharmaceutically acceptable salt, and a pharmaceutically acceptable carrier, diluent, or excipient.
  • the invention comprises method for the treatment of a cancer or a metabolic disease in a subject in need of such treatment comprising administering to the subject an effective amount of a GCS inhibitor of the invention or a pharmaceutical composition comprising an effective amount of a GCS inhibitor of the invention.
  • the invention comprises GCS modulators.
  • the invention comprises GCS modulators of structural formula (I),
  • R A is independently R ⁇ , Ci-C 6 alkyl, Ci-C 4 haloalkyl, aryl, aryl(Ci-C 4 )alkyl, or -Ci-C 6 alkyl-R ⁇ , wherein the aryl of the aryl(Ci-C 4 )alkyl group is optionally substituted with one, two, or three R A2 groups, wherein each R A2 is independently halogen, cyano, nitro, -OR A1 , -SR
  • E is -(CH 2 )-, -C(H)(CH 3 )-, or -C(O)-;
  • L is -[C(R L ) 2 ] p -L 1 -[C(R L ) 2 ] q -, wherein p is 1, 2, or 3;
  • q is an integer selected from 0 to (3-p);
  • L 1 is a bond, -O- or -NH-; and each R L is independently hydrogen, methyl, or halomethyl;
  • R 1 is -N(R 10 XR 11 ) or a moiety of formula,
  • R 10 is hydrogen or C 1 -C 4 alkyl
  • R 11 is -R 13 , -C 3 -C 6 cycloalkyl-N(R 12 ) 2 , -C 3 -C 6 cycloalkyl-R 13 , -Ci-C 6 alkyl-N(R 12 ) 2 , or -Ci-C 6 alkyl-R 13 , wherein each R 12 is independently hydrogen or C 1 -C 4 alkyl; and R 13 is (a) a 4 - 10 membered monocyclic, 4 - 10 membered fused-bicyclic, 5 - 10 membered bridged-bicyclic, or 5 - 10 membered spiro-bicyclic heterocyclyl ring, where the heterocyclyl ring comprises one, two, or three annular nitrogen atoms, and optionally comprises one annular oxygen or sulfur atom, or (b) a 5 or 6 membered monocyclic heteroaryl or a 8 - 10 membered fused-bicyclic heteroaryl
  • each R B3 is independently hydrogen, Ci-C 4 alkyl, Ci-C 4 haloalkyl, aryl, or aryl(Ci-C 4 )alkyl; or two R B3 taken together with the nitrogen atom to which they are both attached form a saturated or unsaturated monocyclic heterocyclyl or heteroaryl, wherein the heterocyclyl and heteroaryl are each optionally substituted with one, two, or three groups which are each independently (Ci-C 3 )alkyl, halogen, or Ci-C 4 haloalkyl; and each R 21 is independently halogen or -R 20 ;
  • R 20 and R 21 when present, are not aryl(Ci-C 4 )alkyl; and provided that when L 1 is a bond, E is -C(O)-, R 1 is -N(R 10 XR 11 ), R 11 is R 13 , and R 13 is
  • R 13A when present, is not aryl(Ci-C 4 )alkyl.
  • the present invention further comprises GCS modulators of structural formula (IV),
  • R 1 , E, A, L, X 1 , Q, R 4 , R 5 , m and n as defined herein in embodiment (1).
  • the compounds of the invention, or their pharmaceutically acceptable salts may have asymmetric carbon atoms or quaternized nitrogen atoms in their structure, and may exist as single stereoisomers, racemates, and mixtures of stereoisomers.
  • the compounds of the invention, or their pharmaceutically acceptable salts, as single stereoisomers, racemates, and mixtures of stereoisomers are all intended to be within the scope of this invention.
  • the invention also comprises each of the following embodiments:
  • Embodiment (2) In another embodiment, the compound of Formula (I) is that where Q is -O-; and all other groups are as defined in embodiment (1). In subembodiment
  • the compound of Formula (I) is that where Q is -O-, and m is 1, 2, or 3; and all other groups are as defined in embodiment (1).
  • Embodiment (3) In another embodiment, the compound of Formula (I) is that where E is -C(O)-; and all other groups are as defined in embodiment (1) or (2).
  • Embodiment (4) In another embodiment, the compound of Formula (I) is that where E is -(CH 2 )- or -C(H)(CHs)-; and all other groups are as defined in embodiment (1) or embodiment (2). In subembodiment (4-a), the compound of Formula (I) is that where E is -CH 2 -; and all other groups are as defined in one of embodiment (1) or (2).
  • Embodiment (5) In another embodiment, the compound of Formula (I) is that where A is C 3 -Cs cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally substituted by one, two, or three R A groups; and all other groups are as defined in any one of embodiments (1) - (4).
  • the compound of Formula (I) is that where A is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, naphthyl, imidazolyl, oxazolyl, or pyridyl, wherein the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, naphthyl, imidazolyl, oxazolyl, and pyridyl are optionally substituted by one, two, or three R A groups; and all other groups are as defined in any one of embodiments (1) - (4).
  • the compound of Formula (I) is that where A is C 3 -Cs cycloalkyl or aryl, wherein the cycloalkyl and aryl are optionally substituted by one, two, or three R A groups; and all other groups are as defined in any one of embodiments (1) - (4).
  • the compound of Formula (I) is that where A is phenyl, cyclopropyl, or cyclohexyl, wherein the phenyl, cyclopropyl, and cyclohexyl are optionally substituted by one, two, or three R A groups; and all other groups are as defined in any one of embodiments (1) - (4).
  • the compound of Formula (I) is that where A is C 3 -Cs cycloalkyl or heteroaryl, wherein the cycloalkyl and heteroaryl are optionally substituted by one, two, or three R A groups; and all other groups are as defined in any one of embodiments (1) - (4).
  • the compound of Formula (I) is that where A is C 3 -Cs cycloalkyl; optionally substituted by one, two, or three R A groups; and all other groups are as defined in any one of embodiments (1) - (4).
  • the compound of Formula (I) is that where A is aryl; optionally substituted by one, two, or three R A groups; and all other groups are as defined in any one of embodiments (1) - (4).
  • the compound of Formula (I) is that where A is heteroaryl optionally substituted by one, two, or three R A groups; and all other groups are as defined in any one of embodiments (1) - (4).
  • the compound of Formula (I) is that where A is aryl or heteroaryl, wherein the aryl and heteroaryl are optionally substituted by one, two, or three R A groups; and all other groups are as defined in any one of embodiments (1) - (4).
  • Embodiment (6) In another embodiment, the compound of Formula (I) is that where R 20 is -R B2 , hydrogen, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 3 -C 8 cycloalkyl, aryl(d-C 4 )alkyl, or -Ci-C 4 alkyl-R B2 , wherein each R B2 is independently cyano, nitro, -OR B3 , -SR B3 , -N(R B3 ) 2 , -C(O)R B3 , -S(O)R B3 , -S(O) 2 R 63 , -S(O)N(R B3 ) 2 , -S(O) 2 N(R B3 ) 2 , -C(O)OR B3 , -C(O)N(R B3 ) 2 , -N(R B3 )C(O)R B3
  • the compound of Formula (I) is that where R 20 is hydrogen, -OR B3 , -N(R B3 ) 2 , Ci-C 4 alkyl, Ci-C 4 haloalkyl, C 3 -C 8 cycloalkyl, aryl(Ci-C 4 )alkyl, or -Ci-C 4 alkyl-R B2 ; wherein R B2 is -OR B3 or -N(R B3 ) 2; and when R 21 is present, each R 21 is independently halogen or -R 20 ; and all other groups are as defined in any one of embodiments (1) - (5).
  • the compound of Formula (I) is that where R 20 is hydrogen, Ci-C 4 alkyl, -OR B3 , or -N(R B3 ) 2 , wherein each R B3 is independently hydrogen, Ci-C 4 alkyl, Ci-C 4 haloalkyl, aryl, or aryl(Ci-C 4 )alkyl; and when R 21 is present, each R 21 is independently halogen or -R 20 ; and all other groups are as defined in any one of embodiments
  • the compound of Formula (I) is that where R 1 is: (i) -N(R 10 )R ⁇ , wherein R 10 is hydrogen or -Ci-C 4 alkyl; and R 11 is -R 13 , -C 3 -C 6 cycloalkyl-N(R 12 ) 2 , -C 3 -C 6 cycloalkyl-R 13 , -Ci-C 6 alkyl-N(R 12 ) 2 , or -Ci-C 6 alkyl-R 13 , wherein each R 12 is independently hydrogen or Ci-C 4 alkyl; and R 13 is (a) a 4 - 10 membered monocyclic, 4 - 10 membered fused-bicyclic, 5 - 10 membered bridged-bicyclic, or 5 - 10 membered spiro-bicyclic heterocyclyl ring, where the heterocyclyl ring comprises one, two
  • the compound of Formula (I) is that where R 1 is -N(R 10 XR 11 ), wherein R 10 is hydrogen or -Ci-C 4 alkyl; and R 11 is -R 13 , -C 3 -C 6 cycloalkyl-N(R 12 ) 2 , -C 3 -C 6 cycloalkyl-R 13 , -C 1 -C 6 alkyl-N(R 12 ) 2 , or -C 1 -C 6 alkyl-R 13 , wherein each R 12 is independently hydrogen or Ci-C 4 alkyl; and R 13 is a 4 - 10 membered monocyclic, a 5 - 10 membered bridged-bicyclic, or a 5-10 membered spiro-bicyclic heterocyclyl ring, where
  • Embodiment (8) In another embodiment, the compound of Formula (I) is that where R 1 is (i) -N(R 10 XR 11 ), wherein R 10 is hydrogen or methyl; or R 1 is (ii) a moiety of formula (a),
  • ring B is a 5-10 membered bridged-bicyclic or 5 - 10 membered spiro-bicyclic heterocyclyl ring, where the heterocyclyl ring optionally comprises one annular oxygen or sulfur atom, and optionally one, two, or three additional annular nitrogen atoms; or the moiety of formula (a) is:
  • Embodiment (9) In another embodiment, the compound of Formula (I) is that where R 1 is -N(R 10 XR 1 J ) or a moiety of formula (a), wherein
  • ring B in the moiety of formula (a) is a 5-10 membered bridged-bicyclic heterocyclyl ring, where the heterocyclyl ring optionally comprises one annular oxygen or sulfur atom, and optionally one, two, or three additional annular nitrogen atoms;
  • R 20 is hydrogen, -OR B3 , -N(R B3 ) 2 , Ci-C 4 alkyl, Ci-C 4 haloalkyl, C 3 -C 8 cycloalkyl, aryl(Ci-C 4 )alkyl, or -Ci-C 4 alkyl-R B2 ;
  • R B2 is -OR B3 or -N(R B3 ) 2 ;
  • R 21 when present, is Ci-C 4 alkyl or Ci-C 4 haloalkyl;
  • R 21 when present, is Ci-C 4 alkyl or Ci-C 4 haloalkyl; and all other groups are as defined in any one of embodiments (1) - (8).
  • Embodiment (10) In another embodiment, the compound of Formula (I) is that where R 1 is -N(R 10 XR 11 ) or a moiety of formula (a),
  • ring B is a 5-10 membered bridged-bicyclic heterocyclyl ring; and R 10 , R 11 , w, R 20 , R 21 , and all other groups are as defined in any one of embodiments (1) - (9).
  • R 1 is -N(R 10 XR 11 ) or a moiety of formula (a), wherein ring B is 8-azabicyclo[3.2.1]octyl, 3,8-diazabicyclo[3.2.1]octyl, 2,5-diazabicyclo[2.2.1]heptyl, or l-azabicyclo[2.2.2]oct-3-yl; and R 10 , R 11 , w, R 20 , R 21 , and all other groups are as defined in any one of embodiments (1) - (9).
  • Embodiment (11) In another embodiment, the compound of Formula (I) is that where R 1 is -N(R 10 XR 11 ) or a moiety of formula (a),
  • ring B is piperazin-1-yl or 1,4-diazepan-l-yl; and R 10 , R 11 , R 20 , R 21 , w, and all other groups are as defined in any one of embodiments (1) - (9).
  • the compound of formula (I) is that where R 1 is -N(R 10 XR 11 ) or a moiety of formula (a), wherein
  • R 1 is -N(R 10 XR 11 ) or 4-methylpiperazin-l-yl, 3-methylpiperazin-l-yl, 4-methyl-l,4- diazepan-1-yl, piperazin-1-yl, 4-(l-methylethyl)-piperazin-l-yl, 4-(2-fluoroethyl)piperazin-l- yl, or 4-ethylpiperazin-l-yl; and R 10 , R 11 , and all other groups are as defined in any one of embodiments (1) - (5), (7) and (8).
  • Embodiment (12) In another embodiment, the compound of Formula (I) is that where R 1 is -N(R 10 XR 11 ) or a moiety of formula (a),
  • R 1 is -N(R 10 )(R ⁇ ) or a moiety of formula (a), wherein ring B is azetidin-1-yl, pyrrolidin-1-yl, or piperidin-1-yl and R 10 , R 11 , R 20 , R 21 , w, and all other groups are as defined in any one of embodiments (1) - (9).
  • R 1 is -N(R 10 XR 11 ) or 3-(dimethylamino)azetidin-l-yl, 3-(dimethylamino)pyrrolidin-l-yl, 3- aminoazetidin-1-yl, 3-aminopyrrolidin-l-yl, 4-amino-4-methylpiperidin-l-yl, 3- aminopiperidin-1-yl, 4-aminopiperidin-l-yl, 3-(methylamino)pyrrolidin-l-yl, 4- (methylamino)piperidin-l-yl, (l-methylethyl)amino-piperidinyl, or 4-hydroxypiperidin-l-yl, and R 10 , R 11 , and all other groups are as defined in any one of embodiments (1) - (5), (7) and (8).
  • Embodiment (13) In another embodiment, the compound of Formula (I) is that where L is -[C(R L )2] p -L 1 -[C(R L )2] q -, wherein/? is 1, 2, or 3; q is an integer selected from 0 to (3-p); L 1 is a bond, -O- or -NH-; and each R L is independently hydrogen, methyl, or halomethyl; and all other groups are as defined in any one of embodiments (1) - (12).
  • the compound of Formula (I) is that where L is -[C(R L ) 2 ] p -L 1 -[C(R L ) 2 ] q -, wherein/? is 1, 2, or 3; q is an integer selected from 0 to (3-p); L 1 is a bond or -O-; and each R L is independently hydrogen, methyl, or halomethyl; and all other groups are as defined in any one of embodiments (1) - (12).
  • the compound of Formula (I) is that where L is -[C(R L ) 2 ] p -L 1 -[C(R L ) 2 ] q -,wherein p is 1 or 2; q is an integer selected from 0 to (3-p); L 1 is a bond or -O-; and each R L is independently hydrogen or methyl; and all other groups are as defined in any one of embodiments (I) - (12).
  • the compound of Formula (I) is that where L is - [C(R L )2]p-L 1 -[C(R L )2] q -, wherein/?
  • Embodiment (14) In another embodiment, the compound of Formula (I) is that
  • R 1 is a moiety of formula (a), (a); and ring B, R 20 , R 21 , w, and all other groups are as defined in any one of embodiments (1) - (13).
  • Embodiment (15) in another embodiment, the compound of Formula (I) is that where R 1 is -N(R 10 XR 1 J ) or a moiety of formula (a), wherein R 11 is R 13 , wherein R 13 is a 4 - 10 membered monocyclic heterocyclyl ring, where the heterocyclyl ring comprises one, two, or three annular nitrogen atoms, and optionally comprises one annular oxygen or sulfur atom, wherein said heterocyclyl ring is optionally substituted with one, two, or three R 13A groups; and all other groups are as defined in any one of embodiments (1) - (13).
  • the compound of Formula (I) is that where R 1 is -N(R ⁇ )R 11 or a moiety of formula (a), wherein R 11 is R 13 , wherein R 13 is azetidinyl, pyrrolidinyl, or piperidinyl, wherein said azetidinyl, pyrrolidinyl, and piperidinyl are optionally substituted with one, two, or three R 13A groups; and all other groups are as defined in any one of embodiments (1) - (13).
  • Embodiment (16) in another embodiment, is that where R 1 is -N(R 10 )(R ⁇ ) or a moiety of formula (a), wherein R 11 is R 13 , wherein R 13 is a 5 - 10 membered bridged-bicyclic heterocyclyl ring, where the heterocyclyl ring comprises one, two, or three annular nitrogen atoms, and optionally comprises one annular oxygen or sulfur atom, wherein said heterocyclyl ring is optionally substituted with one, two, or three R 13A groups; and all other groups are as defined in any one of embodiments (1) - (13).
  • the compound of Formula (I) is that where R 1 is -N (R ⁇ )R 11 or a moiety of formula (a), wherein R 11 is R 13 , wherein R 13 is 8-azabicyclo[3.2.1]oct-3-yl, 8-azabicyclo[3.2.1]oct-8-yl, l-azabicyclo[2.2.2]oct-3-yl, l-azabicyclo[2.2.2]oct-4-yl, 3,8-diazabicyclo[3.2.1]oct-3-yl, or 2,5-diazabicyclo[2.2.1]hept-2-yl, wherein
  • 8-azabicyclo[3.2.1]oct-3-yl, 8-azabicyclo[3.2.1]oct-8-yl, l-azabicyclo[2.2.2]oct-3-yl, l-azabicyclo[2.2.2]oct-4-yl, 3,8-diazabicyclo[3.2.1]oct-3-yl, and 2,5-diazabicyclo[2.2.1]hept- 2-yl are optionally substituted with one, two, or three R 13A groups; and all other groups are as defined in any one of embodiments (1) - (13).
  • each R 13A group is independently halogen, cyano, nitro, C1-C4 alkyl, Ci-C 4 haloalkyl, aryl(Ci-C 4 )alkyl, -OR B1 , -SR B1 , -N(R B1 ) 2 , -C(O)R B1 , -S(O)R B1 , -S(O) 2 R B1 , -S(O)N(R B1 ) 2 , -S(O) 2 N(R B1 ) 2 , -C(O)OR B1 , -C(O)N(R B1 ) 2 , -N(R B1 )C(O)R B1 , -N(R B1 )C(O)OR B1 , -N(R B1 )C(O)N
  • each R 13A group is independently halogen, Ci-C 4 alkyl, Ci-C 4 haloalkyl, aiyl(C 1 -C 4 )alkyl, -OR B1 , -SR B1 , or -N(R B1 ) 2 , wherein each R B1 is independently hydrogen, Ci-C 4 alkyl, Ci-C 4 haloalkyl, aryl, or aryl(Ci-C 4 )alkyl; and all other groups are as defined in any one of embodiments (1) - (12), (14), and (15).
  • Embodiment (18) in another embodiment, the compound of Formula (I) is that where R 1 is -N(R 10 XR 1 J ) or a moiety of formula (a), wherein R 11 is-Ci-C 6 alkyl-N(R 12 ) 2 or -C3-C6 cycloalkyl-N(R 12 ) 2 ; and all other groups are as defined in any one of embodiments (1) - (13).
  • the compound of Formula (I) is that where R 1 is -N(R 10 XR 11 ) or a moiety of formula (a), wherein R 11 is 2-aminoethyl, 2-(methylamino)ethyl, 2-(dimethylamino)ethyl, 2-(dimethylamino)-l-methylethyl, 2-(ethylamino)ethyl, 2- (diethylamino)ethyl, 2-(diethylamino)- 1 -methylethyl, 3 -aminopropyl,
  • Embodiment (19) In another embodiment, the compound of Formula (I) is that where R 1 -N(R 10 )(R ⁇ ); and all other groups are as defined in any one of embodiments (1) - (8), (13), and (15) - (18).
  • Embodiment (21) in another embodiment, the compound of Formula (I) is that where R 21 is halogen or -R 20 , wherein R 20 is -R B2 , hydrogen, Ci-C 4 alkyl, Ci-C 4 haloalkyl, C 3 -Cg cycloalkyl, aryl(Ci-C 4 )alkyl, or -Ci-C 4 alkyl-R B2 ; wherein each R B2 is independently cyano, nitro, -OR B3 , -SR B3 , -N(R B3 ) 2 , -C(O)R B3 , -S(O)R B3 , -S(O) 2 R 63 , -S(O)N(R B3 ) 2 , -S(O) 2 N(R B3 ) 2 , -C(O)OR B3 , -C(O)N(R B3 ) 2 , -N(R B3
  • the compound of Formula (I) is that where R 21 is Ci-C 4 alkyl, Ci-C 4 haloalkyl, or -N(R B3 ) 2 ; and all other groups are as defined in any one of embodiments (1) - (5), (7), (8), (10) - (18) and (20).
  • the compound of Formula (I) is that where w is zero or 1, and R 21 is Ci-C 4 alkyl, Ci-C 4 haloalkyl, or -N(R B3 ) 2 ; and all other groups are as defined in any one of embodiments (1) - (5), (7), (8), (10) - (18) and (20).
  • the compound of Formula (I) is that where w is zero or 1, and R 21 is Ci-C 4 alkyl or -N(R B3 ) 2 ; and all other groups are as defined in any one of embodiments (1) - (5), (7), (8), (10) - (18) and (20).
  • the compound of Formula (I) is that where w is zero or 1, and R 21 is Ci-C 4 alkyl; and all other groups are as defined in any one of embodiments (1) - (18) and (20).
  • the compound of Formula (I) is that where w is zero or 1, and R 21 is -N(R B3 ) 2 ; and all other groups are as defined in any one of embodiments (1) - (5), (7), (8), (10) - (18) and (20).
  • Embodiment (22) In another embodiment, the compound of Formula (I) is that where L is -CH 2 -, -CH 2 CH 2 -, -CH 2 CH 2 CH 2 -, -CH(CH 3 )-, -CH 2 -O-, -CH 2 CH 2 -O-, or -CH 2 -O-CH 2 -; and all other groups are as defined in any one of embodiments (1) - (12) and (14) - (21).
  • the compound of Formula (I) is that where L is -CH 2 CH 2 -, -CH 2 CH 2 CH 2 -, -CH 2 -O-, -CH 2 CH 2 -O-, or -CH 2 -O-CH 2 -; and all other groups are as defined in any one of embodiments (1) - (12) and (14) - (21).
  • the compound of Formula (I) is that where L is Ci-Csalkylene; and all other groups are as defined in any one of embodiments (1) - (12) and (14) - (21).
  • Embodiment (23) In another embodiment, the compound of Formula (I) is that where L is -CH 2 -O-CH 2 -; and all other groups are as defined in any one of embodiments (I) - (12) and (14) - (21).
  • each R A is independently R A2 , Ci-C 6 alkyl, C 1 -C 4 haloalkyl, aryl, aryl(Ci-C4)alkyl, or -Ci-C 6 alkyl-R A2 , wherein the aryl of the aryl(Ci-C4)alkyl group is optionally substituted with one, two, or three R A2 groups, wherein each R A2 is independently halogen, cyano, nitro, -OR A1 , -SR A1 , -N(R A1 ) 2 , -C(O)R A1 , -S(O)R A1 , -S(O) 2 R A1 , -S(O)N(R A1 ) 2 , -S(O) 2 N(R A1 ) 2 , -C(O)OR A1
  • the compound of Formula (I) is that where when R A is present, each R A is independently halogen, cyano, Ci-C 4 alkyl, Ci-C 4 haloalkyl, aryl, aryl(C 1 -C 4 )alkyl, -OR A1 , -N(R A1 ) 2 , or -C(O)R A1 , wherein each R A1 is independently hydrogen or Ci-C 4 alkyl; or two R A attached to adjacent carbon atoms, taken together, form -O-(G) y _O-, wherein each G is independently -CH 2 -, -C(H)(F)-, or -CF 2 -, and y is 1, 2, or 3; and all other groups are as defined in any one of embodiments (1) - (23).
  • the compound of Formula (I) is that where when R A is present, each R A is independently halogen, cyano, Ci-C 4 alkyl, Ci-C 4 haloalkyl, phenyl, benzyl, -OR A1 , -N(R A1 ) 2 , or -C(O)R A1 , wherein each R A1 is independently hydrogen, Ci-C 4 alkyl, or Ci-C 4 haloalkyl; or two R A attached to adjacent carbon atoms, taken together, form -O-(G) y _O-; wherein each G is independently -CH 2 -, -C(H)(F)-, or -CF 2 -, and y is 1, 2, or 3; and all other groups are as defined in any one of embodiments (1) - (23).
  • Embodiment (25) In another embodiment, the compound of Formula (I) is that where each R 4 , when present, is independently halo, Ci-C 4 alkyl, Ci-C 4 haloalkyl, Ci-C 4 alkoxy, Ci-C 4 haloalkoxy, or benzyl; and all other groups are as defined in any one of embodiments (1) - (24). In subembodiment (25-a), the compound of Formula (I) is that where each R 4 , when present, is independently chloro, fluro, bromo, methyl, trihalomethyl, methoxy, or benzyl; and all other groups are as defined in any one of embodiments (1) - (24). [0037] Embodiment (26): In another embodiment, the compound of Formula (I) which is a compound of formula (Ia):
  • Embodiment (27) In another embodiment, the compound of Formula (I) which is a compound of formula (Ib):
  • Embodiment (28) In another embodiment, the compound of Formula (I) is that which is a compound of Table 1.
  • Embodiment (29) In another embodiment, the compound of Formula (I) is that where A is phenyl optionally substituted by one, two, or three R A groups; and all other groups are as defined in any one of embodiments (1) - (4) and (6) - (27). In subembodiment (29-a), the compound of Formula (I) is that where A is phenyl substituted by one, two, or three R A groups; and all other groups are as defined in any one of embodiments (1) - (4) and (6) - (27).
  • the compound of Formula (I) is that where A is phenyl; and all other groups are as defined in any one of embodiments (1) - (4) and (6) - (27).
  • the compound of Formula (I) is that where A is phenyl substituted by two R A groups attached to adjacent carbon atoms, and the two R A groups taken together, form -O-(G) y _O-; wherein each G is independently -CH 2 -, -C(H)(F)-, or -CF 2 -, and y is 1, 2, or 3; and all other groups are as defined in any one of embodiments (1) - (4), (6) - (23), and (25) - (27); for example, A is 2,3-dihydro-l,4-benzodioxin-6-yl or 2,2-difluoro-l,3-benzodioxol-5- yi.
  • Embodiment (31) In another embodiment, the compound of Formula (I) is a compound of formula (III):
  • ring B in the definition of R 1 is (i) a heterocyclyl ring optionally comprising one annular oxygen or sulfur atom, and optionally one, two, or three additional annular nitrogen atoms; or (ii) a 5 or 6 membered monocyclic heteroaryl or a 8 - 10 membered fused-bicyclic heteroaryl.
  • Ring B refers to the annular atoms which together with the nitrogen atom to which they are attached form a heterocyclyl or heteroaryl ring.
  • ring B is, for example, piperazinyl
  • the moiety of formula (a) is a piperazinyl ring substituted with R 20 and (R 21 ) w , wherein R 20 , R 21 , and w are as defined herein.
  • ring B is a 4 - 10 membered monocyclic heterocyclyl ring optionally comprising one annular oxygen or sulfur atom, and optionally one, two, or three additional annular nitrogen atoms
  • the moiety of formula (a) is, for example, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, or thiomorpholinyl and the like, wherein the 4 - 10 membered monocyclic heterocyclyl ring is substituted with R 20 and (R 21 ) w , wherein R 20 , R 21 , and w are as defined herein.
  • Embodiment (32) In another embodiment, the compound of Formula (I) is that where when R 1 is a moiety of formula (a), ring B is azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, diazepanyl, 8-azabicyclo[3.2.1]octyl, 3,8-diazabicyclo[3.2.1]octyl, 2,5-diazabicyclo[2.2.
  • R 20 , R 21 , w, and all other groups are as defined in any one of embodiments (1) - (9), (13) - (18), (20) - (27), and (29) - (31).
  • ring B is a 7 - 10 membered fused-bicyclic heterocyclyl ring, optionally comprising one, two, or three additional nitrogen atoms within the heterocyclyl ring; and R 20 , R 21 , w, and all other groups are as defined in any one of embodiments (1) - (9), (13) - (18), (20) - (27), and (29) - (31).
  • ring B is a 7 - 10 membered bridged-bicyclic heterocyclyl ring, optionally comprising one or two additional nitrogen atoms within the heterocyclyl ring; and R 20 , R 21 , w, and all other groups are as defined in any one of embodiments (1) - (10), (13) - (18), (20) - (27), and (29)
  • ring B is a 7 - 10 membered spiro-bicyclic heterocyclyl ring, optionally comprising one additional nitrogen atom within the heterocyclyl ring; and R 20 , R 21 , w, and all other groups are as defined in any one of embodiments (1) - (9), (13) - (18), (20) - (27), and (29) - (31).
  • ring B is a 5 or 6 membered heteroaryl; and R 20 , R 21 , w, and all other groups are as defined in any one of embodiments (1)
  • ring B is an 8 - 10 membered fused-bicyclic heteroaryl; and R 20 , R 21 , w, and all other groups are as defined in any one of embodiments (1) - (9), (13) - (18), (20) - (27), and (29) - (31).
  • ring B is azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, or diazepanyl; and R 20 , R 21 , w, and all other groups are as defined in any one of embodiments (1) - (9), (13) - (18), (20) - (27), and (29) - (31).
  • Embodiment (33) In another embodiment, the compound of Formula (I) is that where n is 0, 1, 2, or 3; and all other groups are as defined in any one of embodiments (I) - (27) and (29) - (32). In subembodiment (33-a), the compound of Formula (I) is that where n is 0 or 1; and all other groups are as defined in any one of embodiments (1) - (27) and (29) - (32). In subembodiment (33-b), the compound of Formula (I) is that where n is 0; and all other groups are as defined in any one of embodiments (1) - (27) and (29) - (32).
  • Embodiment (34) In another embodiment, the compound of Formula (I) is that where m is 0, 1, 2, or 3; Q is -O-; and all other groups are as defined in any one of embodiments (1), (3) - (27), and (29) - (33). In subembodiment (34-a), the compound of Formula (I) is that where m is 1, 2, or 3; and all other groups are as defined in any one of embodiments (1), (3) - (27), and (29) - (33).
  • Embodiment (35) In another embodiment, the compound of Formula (I) is that where when present, R 5 is independently halogen or C 1 -C 4 alkyl, wherein the alkyl group is optionally substituted with one, two, or three R 51 groups wherein each R 51 is independently hydroxy or halogen; and all other groups are as defined in any one of embodiments (1) - (27) and (29) - (34).
  • the compound of Formula (I) is that where when present, R 5 is independently halogen or Ci-C 4 alkyl; and all other groups are as defined in any one of embodiments (1) - (27) and (29) - (34).
  • the invention also comprises as another embodiment, a pharmaceutical composition which comprises a GCS modulator compound, optionally as a pharmaceutically acceptable salt thereof, according to any one of the embodiments herein, together with a pharmaceutically acceptable diluent, excipient, and/or carrier.
  • a pharmaceutical composition which comprises a GCS modulator compound, optionally as a pharmaceutically acceptable salt thereof, according to any one of the embodiments herein, together with a pharmaceutically acceptable diluent, excipient, and/or carrier.
  • Such compositions are substantially free of non-pharmaceutically acceptable components, i.e., contain amounts of non-pharmaceutically acceptable components lower than permitted by US regulatory requirements at the time of filing this application.
  • the composition further optionally comprises an additional pharmaceutically acceptable carrier, diluent, or excipient.
  • the invention also comprises as another embodiment a method for treating a disease or disorder mediated by GCS or a disease or disorder in which GCS is implicated in a subject in need of such treatment comprising administering to the subject an effective amount of a compound according to any of the preceding embodiments or a composition of the invention ⁇ supra).
  • Diseases and disorders mediated by GCS or implicated by GCS include, but are not limited to cancers, metabolic disorders, and lysosomal storage diseases.
  • cancers which may be modulated by a compound or composition of the invention include, but are not limited to, cancers in which glycolipid synthesis is abnormal, for example, breast cancer, renal adenocarcinoma, brain cancer, neuroblastoma, lung cancer, intestinal cancer, pancreas and prostrate cancer.
  • the invention also comprises as another embodiment a method for inducing decreased GCS catalytic activity in a cell, in vitro, comprising contacting the cell with an effective amount of a compound according to any of the preceding embodiments.
  • the invention also comprises as another embodiment, use of a GCS modulator of any of the preceding embodiments of the invention for the preparation of a medicament for treating a disease or disorder mediated by GCS or a disease or disorder in which GCS is implicated in a subject in need of such treatment.
  • Administration of the compounds of this disclosure, or their pharmaceutically acceptable salts, in pure form or in an appropriate pharmaceutical composition can be carried out via any of the accepted modes of administration or agents for serving similar utilities.
  • administration can be, for example, orally, nasally, parenterally (intravenous, intramuscular, or subcutaneous), topically, transdermally, intravaginally, intravesically, intracistemally, or rectally, in the form of solid, semi-solid, lyophilized powder, or liquid dosage forms, such as for example, tablets, suppositories, pills, soft elastic and hard gelatin capsules, powders, solutions, suspensions, or aerosols, or the like, preferably in unit dosage forms suitable for simple administration of precise dosages.
  • compositions will include a conventional pharmaceutical carrier, excipient, and/or diluent and a compound of this disclosure as the/an active agent, and, in addition, can include carriers and adjuvants, etc.
  • Adjuvants include preserving, wetting, suspending, sweetening, flavoring, perfuming, emulsifying, and dispensing agents. Prevention of the action of microorganisms can be ensured by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, and the like. It can also be desirable to include isotonic agents, for example sugars, sodium chloride, and the like. Prolonged absorption of the injectable pharmaceutical form can be brought about by the use of agents delaying absorption, for example, aluminum monostearate and gelatin.
  • a pharmaceutical composition of the compounds in this disclosure can also contain minor amounts of auxiliary substances such as wetting or emulsifying agents, pH buffering agents, antioxidants, and the like, such as, for example, citric acid, sorbitan monolaurate, triethanolamine oleate, butylalted hydroxytoluene, etc.
  • auxiliary substances such as wetting or emulsifying agents, pH buffering agents, antioxidants, and the like, such as, for example, citric acid, sorbitan monolaurate, triethanolamine oleate, butylalted hydroxytoluene, etc.
  • formulations depend 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 suitable for parenteral injection can comprise physiologically acceptable sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions.
  • suitable aqueous and nonaqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols (propyleneglycol, polyethyleneglycol, glycerol, and the like), suitable mixtures thereof, vegetable oils (such as olive oil) and injectable organic esters such as ethyl oleate.
  • Proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersions and by the use of surfactants.
  • One preferable route of administration is oral, using a convenient daily dosage regimen that can be adjusted according to the degree of severity of the disease-state to be treated.
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules.
  • the active compound is admixed with at least one inert customary excipient (or carrier) such as sodium citrate or dicalcium phosphate or
  • fillers or extenders as for example, starches, lactose, sucrose, glucose, mannitol, and silicic acid
  • binders as for example, cellulose derivatives, starch, alignates, gelatin, polyvinylpyrrolidone, sucrose, and gum acacia
  • humectants as for example, glycerol
  • disintegrating agents as for example, agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, croscarmellose sodium, complex silicates, and sodium carbonate
  • solution retarders as for example paraffin
  • absorption accelerators as for example,
  • Solid dosage forms can be prepared with coatings and shells, such as enteric coatings and others well known in the art. They can contain pacifying agents, and can also be of such composition that they release the active compound or compounds in a certain part of the intestinal tract in a delayed manner. Examples of embedded compositions that can be used are polymeric substances and waxes. The active compounds can also be in microencapsulated form, if appropriate, with one or more of the above-mentioned excipients. [0062] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs.
  • Such dosage forms are prepared, for example, by dissolving, dispersing, etc., a compound(s) of this disclosure, or a pharmaceutically acceptable salt thereof, and optional pharmaceutical adjuvants in a carrier, such as, for example, water, saline, aqueous dextrose, glycerol, ethanol and the like; solubilizing agents and emulsifiers, as for example, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propyleneglycol, 1,3-butyleneglycol, dimethylformamide; oils, in particular, cottonseed oil, groundnut oil, corn germ oil, olive oil, castor oil and sesame oil, glycerol, tetrahydrofurfuryl alcohol, polyethyleneglycols and fatty acid esters of sorbitan; or mixtures of these substances, and the like, to thereby form a solution
  • Suspensions in addition to the active compounds, can contain suspending agents, as for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, or mixtures of these substances, and the like.
  • suspending agents as for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, or mixtures of these substances, and the like.
  • compositions for rectal administrations are, for example, suppositories that can be prepared by mixing the compounds of this disclosure with, for example, suitable non-irritating excipients or carriers such as cocoa butter, polyethyleneglycol or a suppository wax, which are solid at ordinary temperatures but liquid at body temperature and therefore, melt while in a suitable body cavity and release the active component therein.
  • suitable non-irritating excipients or carriers such as cocoa butter, polyethyleneglycol or a suppository wax, which are solid at ordinary temperatures but liquid at body temperature and therefore, melt while in a suitable body cavity and release the active component therein.
  • Dosage forms for topical administration of a compound of this disclosure include ointments, powders, sprays, and inhalants.
  • the active component is admixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants as can be required.
  • compositions can contain about 1% to about 99% by weight of a compound(s) of this disclosure, or a pharmaceutically acceptable salt thereof, and 99% to 1% by weight of a suitable pharmaceutical excipient.
  • the composition will be between about 5% and about 75% by weight of a compound(s) of this disclosure, or a pharmaceutically acceptable salt thereof, with the rest being suitable pharmaceutical excipients.
  • composition to be administered will, in any event, contain a therapeutically effective amount of a compound of this disclosure, or a pharmaceutically acceptable salt thereof, for treatment of a disease-state in accordance with the teachings of this disclosure.
  • the compounds of this disclosure are administered in a therapeutically effective amount which will vary depending upon a variety of factors including the activity of the specific compound employed, the metabolic stability and length of action of the compound, the age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, the severity of the particular disease-states, and the host undergoing therapy.
  • the compounds of this disclosure can be administered to a patient at dosage levels in the range of about 0.1 to about 1,000 mg per day. For a normal human adult having a body weight of about 70 kilograms, a dosage in the range of about 0.01 to about 100 mg per kilogram of body weight per day is an example. The specific dosage used, however, can vary.
  • compositions will include a conventional pharmaceutical carrier or excipient and a compound of this disclosure as the/an active agent, and, in addition, can include other medicinal agents and pharmaceutical agents.
  • Compositions of the compounds in this disclosure can be used in combination with anticancer and/or other agents that are generally administered to a patient being treated for cancer, e.g. surgery, radiation and/or chemotherapeutic agent(s).
  • Chemotherapeutic agents that can be useful for administration in combination with compounds of Formula I in treating cancer include alkylating agents, platinum containing agents.
  • a substituent "R” can reside on any atom of the ring system, assuming replacement of a depicted, implied, or expressly defined hydrogen from one of the ring atoms, so long as a stable structure is formed. [0074] If a group "R” is depicted as floating on a heterocyclic ring system, as for example
  • the "R” group can reside on either the 5-membered or the 6-membered ring of the fused ring system.
  • L is a divalent moiety linking A to the parent structure.
  • particular members defining L may be written, for example, in the form -X-Y- or -Y-X-.
  • Such members are intended to replace the term being defined, in this case L, as written, such that the leading (left) bond is attached to the parent moiety and the ending (right) bond is attached to A.
  • L is of the form -X-Y-
  • the X is bonded to the parent moiety and Y is bonded to A.
  • administering and variants thereof (e.g., “administering” a compound) in reference to a compound of the invention means introducing the compound of the invention into the system of the animal in need of treatment.
  • a compound of the invention or prodrug thereof is provided in combination with one or more other active agents (e.g., surgery, radiation, chemotherapy, and the like)
  • “administration” and its variants are each understood to include concurrent and sequential introduction of the compound or prodrug thereof and other agents.
  • Alkoxy means the group -OR 0 wherein R 0 is alkyl, as defined herein.
  • Representative examples include methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy,
  • Alkyl means a linear or branched hydrocarbon group having from 1 to 10 carbon atoms unless otherwise defined. Representative examples for alkyl groups include methyl, ethyl, propyl, butyl, pentyl, hexyl, 4-methylhexyl, 4-methylheptyl, 4,7-dimethyloctyl, and the like. (Ci_4)alkyl means a group selected from methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl and tert-butyi.
  • Alkylamino means an alkyl group, as defined herein, appended to a parent moiety through an -NH- group (i.e., substituents of the form -N(H)R 0 , where R 0 is an alkyl group).
  • alkylamino groups include, but are not limited to, methylamino, ethylamino, isopropylamino, hexylamino, and the like.
  • Aryl means a monovalent, monocyclic, or polycyclic radical having 6 to 14 ring carbon atoms.
  • the monocyclic aryl radical is aromatic and whereas the polycyclic aryl radical may be partially saturated, at least one of the rings comprising a polycyclic radical is aromatic.
  • the valency may be located on any atom of any ring of the aryl group, valency rules permitting.
  • Representative examples include phenyl, naphthyl, indanyl, benzodioxolyl, benzodioxanyl, benzopyranyl, 2,3-dihydro-lH-indolyl (including, for example, 2,3-dihydro-lH-indol-2-yl, 2,3-dihydro-lH-indol-5-yl, and the like), isoindolinyl, tetrahydroisoquinolinyl (including, for example, tetrahydroisoquinolin-4-yl, tetrahydroisoquinolin-6-yl, and the like), phthalimidyl, and the like.
  • Aryl(Ci-C 4 )alkyl means an aryl moiety attached to a parent structure via a one- to-four carbon alkylene group. Examples include benzyl, phenethyl, and the like.
  • “Bridged-bicyclic heterocyclyl ring” refers to a heterocyclyl ring system in which a valence bond, an atom, or a chain of atoms connects two or more non-adjacent positions of a heterocyclyl ring system. Such a system may contain isolated or conjugated unsaturation, but not aromatic or heteroaromatic rings in its core structure (but may have aromatic
  • Examples of 5 - 10 membered bridged- bicyclic heterocylyl rings include 8-azabicyclo[3.2.1]oct-3-yl, 8-azabicyclo[3.2.1]oct-8-yl, 1- azabicyclo[2.2.2]oct-3-yl, l-azabicyclo[2.2.2]oct-4-yl, 3,8-diazabicyclo[3.2.1]oct-3-yl, and 2,5-diazabicyclo[2.2.1]hept-2-yl, and the like.
  • Cycloalkyl means a monocyclic or polycyclic hydrocarbon radical having 3 to 13 carbon ring atoms.
  • the cycloalkyl radical may be saturated or partially unsaturated, but cannot contain an aromatic ring.
  • the cycloalkyl radical includes fused bicyclic, bridged bicyclic and spiro ring systems. Examples of such radicals include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[2.2.1]heptanyl, bicyclo[2.2.1]heptenyl, and bicyclo[2.2.2]octanyl.
  • fused-bicyclic refers to a bicyclic ring system where two rings have more than one shared atom in their ring structures, where each bond is part of a ring, where each ring is ortho-fused to the other ring; and where no bond is common to more than two rings.
  • a spiro ring system is not a fused-bicyclic by this definition, but fused bicyclic ring systems of the invention may themselves have spiro rings attached thereto via a single ring atom of the fused-polycyclic.
  • two adjacent groups on an aromatic system may be fused together to form a ring structure.
  • the fused ring structure may contain heteroatoms.
  • Halo and halogen mean a fluoro, chloro, bromo or iodo group.
  • Haloalkyl means an alkyl radical, as defined herein, substituted with one or more halo atoms.
  • halo-substituted (Ci_4)alkyl includes trifluoromethyl, 2,2-dichloroethyl, 2,2,2-trifluoroethyl, perchloroethyl, 2-bromopropyl, and the like.
  • Haloalkyl includes, for example, halomethyl which means a methyl group substituted by one, two, or three halogen atoms, where each halogen is independently selected.
  • Halomethyl includes, for example, trifluoromethyl, difluoromethyl, fluoromethyl, chloromethyl, chlorofluoromethyl, and the like.
  • Heteroaryl means a monovalent monocyclic or polycyclic radical having 5 to 14 ring atoms of which one or more of the ring atoms, for example one, two, three, or four ring atoms, are heteroatoms independently selected from oxygen, sulfur, and nitrogen, and the remaining ring atoms are carbon atoms.
  • the monocyclic heteroaryl radical is aromatic and whereas the polycyclic heteroaryl radical may be partially saturated, at least one of the rings comprising a polycyclic radical is aromatic, where the aromatic ring contains at least one heteroatom.
  • the polycyclic heteoaryl radical includes fused, bridged and spiro ring systems.
  • the valency may be located on any atom of any ring of the heteroaryl group, valency rules permitting.
  • heteroaryl includes, but is not limited to, 1,2,4-triazolyl, 1,3,5-triazolyl, pyridinyl, pyrrolyl, imidazolyl, thienyl, furanyl, indolyl, isoindolyl, benzimidazolyl, benzo furanyl, cinnolinyl, indolizinyl, naphthyridin-3-yl, phthalazin-3-yl, phthalazin-4-yl, pteridinyl, purinyl, quinazolinyl, quinoxalinyl, tetrazoyl, pyrazolyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, isooxazolyl, oxadiazolyl, benzoxazolyl, quinolinyl, isoquinolinyl, pyrrolo[3,2-c]pyr
  • Heterocyclyl means a monovalent, monocyclic or polycyclic hydrocarbon radical having 3 to 13 ring atoms of which one or more of the ring atoms, for example 1, 2, 3 or 4 ring atoms, are heteroatoms independently selected from oxygen, sulfur, and nitrogen, and the remaining ring atoms are carbon.
  • the heterocyclyl group may be saturated or partially unsaturated, but cannot contain an aromatic ring.
  • the heterocyclyl radical includes fused-bicyclic, bridged-bicyclic, and spiro ring systems. Unless otherwise stated, the heterocyclyl may be attached at any annular or bridge carbon or heteroatom which results in the creation of a stable structure.
  • heterocyclyl includes, but is not limited to, azetidinyl, pyrrolidinyl, 2,5-dihydro-lH-pyrrolyl, piperidinyl, morpholinyl, piperazinyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, perhydroazepinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, dihydropyridinyl, tetrahydropyridinyl, oxazolinyl, oxazolidinyl, isoxazolidinyl, thiazolinyl, thiazolidinyl, quinuclidinyl, isothiazolidinyl, octahydroindolyl, octahydroisoindolyl, decahydroisoquinolyl, tetrahydrofuryl,
  • substitution may or may not occur and includes instances where said substitution occurs and instances in which it does not.
  • substituents only sterically practical and/or synthetically feasible compounds are meant to be included.
  • Spiro ring refers to a ring originating from a particular annular carbon of another ring. For example, as depicted below:
  • a ring atom of a saturated bridged ring system (rings C and C), but not a bridgehead atom, can be a shared atom between the saturated bridged ring system and a spiro ring (ring D) attached thereto.
  • a representative example of a spiro ring system is 2,3-dioxa-8-azaspiro[4.5]decan-8-yl.
  • Stepoisomer means any of two or more isomers containing the same atoms bonded to each other in an identical manner but differing from each other in the spatial arrangement of the atoms or groups of atoms.
  • Stepreoisomer includes, for example, an enantiomer, a geometric isomer, a diastereomer, a rotamer, cis-isomer, trans-isomer, and conformational isomer.
  • the names and illustration used in this application to describe compounds of the invention, unless indicated otherwise, are meant to encompass all possible stereoisomers and any mixture, racemic or otherwise, thereof.
  • the present invention also includes N-oxidc derivatives of the compounds of the invention.
  • JV-oxide derivatives mean derivatives of compounds of the invention in which nitrogens are in an oxidized state (i.e., N ⁇ O), e.g., pyridine iV-oxide, and which possess the desired pharmacological activity.
  • Patient and “subject” for the purposes of the present invention includes humans and other animals, particularly mammals, and other organisms. Thus the methods are applicable to both human therapy and veterinary applications. In another embodiment the patient is a mammal, and in another embodiment the patient is human.
  • a "pharmaceutically acceptable salt” of a compound means a salt that is pharmaceutically acceptable and that possesses the desired pharmacological activity of the parent compound. It is understood that the pharmaceutically acceptable salts are non-toxic. Additional information on suitable pharmaceutically acceptable salts can be found in Remington 's Pharmaceutical Sciences, 17 th ed., Mack Publishing Company, Easton, PA, 1985, which is incorporated herein by reference or S. M. Berge, et al., "Pharmaceutical Salts," J. Pharm. ScL, 1977;66:1-19 both of which are incorporated herein by reference. It is also understood that the compound can have one or more pharmaceutically acceptable salts associated with it.
  • Examples of pharmaceutically acceptable acid addition salts include those formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; as well as organic acids such as acetic acid, trifluoroacetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, 3-(4-hydroxybenzoyl)benzoic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1 ,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 2-
  • Examples of a pharmaceutically acceptable base addition salts include those formed when an acidic proton present in the parent compound is replaced by a metal ion, such as sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts and the like.
  • a metal ion such as sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts and the like.
  • Preferable salts are the ammonium, potassium, sodium, calcium and magnesium salts.
  • Salts derived from pharmaceutically acceptable organic non-toxic bases include, but are not limited to, salts of primary, secondary and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins.
  • organic bases examples include isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine, N-ethylpiperidine, tromethamine, JV-methylglucamine, polyamine resins, and the like.
  • Exemplary organic bases are isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline, and caffeine.
  • Effective amount is an amount of a compound of the invention, that when administered to a patient, effectively treats the disease.
  • the amount of a compound of the invention which constitutes an “effective amount” will vary depending upon a sundry of factors including the activity, metabolic stability, rate of excretion and duration of action of the compound, the age, weight, general health, sex, diet and species of the patient, the mode and time of administration of the compound, the concurrent administration of adjuvants or additional therapies and the severity of the disease for which the therapeutic effect is sought.
  • the effective amount for a given circumstance can be determined without undue experimentation.
  • Treating" or "treatment” of a disease, disorder, or syndrome includes (i) preventing the disease, disorder, or syndrome from occurring in a human, i.e., causing the clinical symptoms of the disease, disorder, or syndrome not to develop in an animal that may be exposed to or predisposed to the disease, disorder, or syndrome but does not yet experience or display symptoms of the disease, disorder, or syndrome; (ii) inhibiting the disease, disorder, or syndrome, i.e., arresting its development; and (iii) relieving the disease, disorder, or syndrome, i.e., causing regression of the disease, disorder, or syndrome.
  • 3-benzyloxy-2-aminopropanyl amide (3) is coupled with a suitably functionalized carboxylic acid, wherein X 1 , Q, R 4 , R 5 , m and n are as defined herein, such as, for example, 2-phenyloxy benzoic or 2-phenyloxy-nicotinic acid.
  • the coupling reaction is typically carried out in the presence of l-[3-(Dimethylamino)propyl]-3-ethylcarbodiimide methiodide (EDC, Novabiochem) and 1-Hydroxybenzotriazole (HOBt, Novabiochem) to give 3-benzyloxy(2-phenyloxyarylamido)propanyl amide (4).
  • the Boc protected amino acid (5) is coupled with a suitably functionalized amine, wherein -N(R X )(R Y ) is R 1 , wherein one of R x and R Y is R 10 and the other of R x and R Y is R 11 , or R x and R Y and the nitrogen atom to which they are attached form a moiety of formula (a),
  • the coupling reaction is typically carried out in the presence EDC and HOBt to give a 3-hydroxy propanyl amide (6).
  • the resulting alcohol (6) may then be alkylated by treatment with sodium hydride and a suitably functionalized electrophile (where A, R L , and q are as defined herein, and LG 1 is a leaving group, such as halo), such as, for example, benzyl bromide, followed by the de-protection reaction performed under acidic conditions to provide a suitably functionalized amine (8).
  • a suitably functionalized electrophile where A, R L , and q are as defined herein, and LG 1 is a leaving group, such as halo
  • amine (8) is coupled with a suitably functionalized carboxylic acid, wherein X 1 , Q, R 4 , R 5 , m and n are as defined herein, such as, for example, 2-phenyloxy benzoic or 2-phenyloxy-nicotinic acid.
  • the coupling reaction is typically carried out in the presence of EDC and HOBt to afford (9), a compound of formula (I), where E is -C(O)-, L is -[C(R L ) 2 ] q -O-(CH 2 ) p -, A, X 1 , R 4 , R 5 , m and n are as defined herein, and -N(R X )(R Y ) is R 1 , wherein one of R x and R Y is R 10 and the other of R and R is R , or R and R and the nitrogen atom to which they are attached form a moiety of formula (a).
  • the invention further comprises a method of preparing a compound of formula (I), the method comprising: (i) coupling a compound of formula (14),
  • A, L, and E are as defined herein, * indicates optional (R) or (S) chirality of the adjacent carbon atom, and -N(R X )(R Y ) is R 1 , wherein one of R x and R Y is R 10 and the other of R x and R Y is R 11 , or R x and R Y and the nitrogen atom to which they are attached form a moiety of formula (a),
  • A, L, X 1 , Q, R 4 , R 5 , m and n are as defined herein, and * indicates optional (R) or (S) chirality of the adjacent carbon atom; with a compound of formula (17) wherein -N(R X )(R Y ) is R 1 , wherein one of R x and R Y is R 10 and the other of R x and R Y is R 11 , or R x and R Y and the nitrogen atom to which they are attached form a moiety of formula (a),
  • R 20 , R 21 , and w are as defined herein; to provide a compound of formula (II); or a single stereoisomer or mixture of stereoisomers thereof; and optionally separating individual isomers; and optionally modifying any of the R 20 and R 21 groups to provide a compound of formula (I); and optionally forming a pharmaceutically acceptable salt thereof.
  • Example 1
  • Step 1 (R)-tert-butyl 3-(benzyloxy)-l-(4-methylpiperazin-l-yl)-l-oxopropan- 2-yl(methyl)carbamate: To a solution of (R)-3-(benzyloxy)-2-(tert-butoxycarbonylamino)- propanoic acid ( 2.95 g, 10 mmol) in dichloromethane (250 niL) were added N- methylpiperazine (1.11 g, 10 mmol) , 1-hydroxybenzotriazole (1.53 g, 10 mmol), diisopropylethylamine (3.4 mL, 20 mmol), and l-[3-(dimethylamino)propyl]-3- ethylcarbodiimide methiodide (2.11 g, 11 mmol).
  • the reaction was stirred at room temperature for 8 hours.
  • the organic solution was extracted with water (2 X 250 mL) and 2N aqueous sodium hydroxide solution (2 X 250 mL) and then dried with magnesium sulfate.
  • the dichloromethane was removed via rotary evaporation and the residual oil treated with a solution of hexane/ethyl acetate (4:1) to yield the desired product as a white crystalline solid that was collected by filtration (1.68 g, 4.45 mmol).
  • Step 2 (R)-2-amino-3-(benzyloxy)-l-(4-methylpiperazin-l-yl)propan-l-one: To a solution of (R)-tert-butyl 3-(benzyloxy)-l-(4-methylpiperazin-l-yl)-l-oxopropan-2- yl(methyl)-carbamate (1.68 g, 4.45 mmol) in methanol (20 mL) was added 4N solution of hydrochloric acid in dioxane (4.4 mL, 17.6 mmol). The solution was heated at 55 0 C for three hours then cooled to room temperature. LCMS analysis indicated complete Boc- deprotection of the starting material.
  • Step 3 2-[(4-chlorophenyl)oxy]-N-[(lR)-2-(4-methylpiperazin-l-yl)-2-oxo-l- ⁇ [(phenylmethyl)oxy] methyl ⁇ ethyl] pyridine-3-carboxamide: The (R)-2-amino-3 - (benzyloxy)-l-(4-methylpiperazin-l-yl)propan-l-one from step 2 (4.44 mmol assumed) was dissolved into dry acetonitrile (50 mL).
  • Step 1 (R)-tert-butyl 3-hydroxy-l-(4-methylpiperazin-l-yl)-l-oxopropan-2- ylcarbamate: To a solution of (R)-2-(tert-butoxycarbonylamino)-3-hydroxypropanoic acid (3.0 g, 14.62 mmol) in dichloromethane (50 niL) was added N-methylmorpholine (16 mL, 146.2 mmol), 1-methylpiperazine (1.78 mL, 16.08 mmol), l-[3-(Dimethylamino)propyl]-3- ethylcarbodiimide methiodide (EDC) (3.0 g, 16 mmol), and 1-Hydroxybenzotriazole (HOBt) (2.1 g, 16 mmol).
  • Step 2 (R)-2-amino-3-(3-methylbenzyloxy)-l-(4-methylpiperazin-l- yl)propan-l-one: To a solution of (R)-tert-butyl 3 -hydroxy- l-(4-methy lpiperazin-1 -yl)-l- oxopropan-2-ylcarbamate (200 mg, 0.7 mmol) in tetrahydrofuran (4 mL) at 0 0 C was added sodium hydride (18 mg, 0.77 mmol).
  • reaction mixture was stirred at 0 0 C for 5 minutes followed by the addition of 3-methylbenzyl bromide (103 ⁇ L, 0.77 mmol) in tetrahydrofuran (1 mL). The reaction was stirred at 0 0 C for 2 h. The reaction was quenched with 5 drops of water and concentrated in vacuo. The concentrated reaction mixture was dissolved in methanol (5 mL) followed by the addition of 4N HCl in dioxane (3 mL). The reaction was heated to 65 0 C for 1 h.
  • Step 3 2-[(4-chlorophenyl)oxy]-N-[(lR)-l-( ⁇ [(3-methylphenyl)methyl]oxy ⁇ - methyl)-2-(4-methylpiperazin-l-yl)-2-oxoethyl]pyridine-3-carboxamide: To a solution of (R)-2-amino-3-(3-methylbenzyloxy)-l-(4-methylpiperazin-l-yl)propan-l-one (0.7 mmol) in dichloromethane (4 rnL) was added N-methylmorpholine (0.77 rnL, 7 mmol), 2-(4- chlorophenoxy)nicotinic acid (203 mg, 0.77mmol), l-[3-(Dimethylamino)propyl]-3- ethylcarbodiimide methiodide (EDC) (148 mg, 0.77 mmol), and 1-Hydroxybenzotriazole (
  • Step 1 6-(bromomethyl)-2,3-dihydrobenzo[b][l,4]dioxine: To a solution of (2,3-dihydrobenzo[b][l,4]dioxin-6-yl)methanol (1.0 g, 6.0 mmol) in dichloromethane (25 mL) was added carbontetrabromide (3.0 g, 9 mmol), and triphenylphosphine (2.35 g, 9.0 mmol).
  • Step 2 2- ⁇ [2-chloro-4-(trifiuoromethyl)phenyl]oxy ⁇ -N-[(lR)-l- ⁇ [(2,3-dihydro- 1 ,4-benzodioxin-6-ylmethyl)oxy]methyl ⁇ -2-(4-methylpiperazin- 1 -yl)-2-oxoethyl]pyridine-3- carboxamide was synthesized in a manner similar to Example 2 wherein 6-(bromomethyl)- 2,3-dihydrobenzo[b][l,4]dioxine was substituted for 3-methylbenzyl bromide, and 2-(2- chloro-4-fluorophenoxy)nicotinic acid was substituted for 2-(4-chlorophenoxy)nicotinic acid.
  • the aqueous layer was collected, acidified with IM HCl to pH 3, and extracted with ethyl acetate (3 X 100 mL) with addition of saturated aqueous lithium chloride (100 mL). The organic layer was dried over magnesium sulfate. The ethyl acetate was concentrated in vacuo to give 630 mg (55%) of 2-(2-chloro-6-methylphenoxy)nicotinic acid which was used without further purification.
  • Step 1 Ethyl S-bromo-l-chloronicotinate: To a solution of 5-bromo-2- chloronicotinic acid (1.00 g, 4.23 mmol) in ethanol (8.5 mL) was added concentrated H 2 SO 4 (1.40 mL, 25.38 mmol) drop wise over a minute. The reaction was heated to reflux for 2 hours. All solvent was removed in vacuo and the residue was taken up in ethyl acetate (20 mL) and washed once with 1 M NaOH (20 mL) and then dried over anhydrous magnesium sulfate. The magnesium sulfate was filtered off and the ethyl acetate was removed in vacuo. The remaining oil was used in the next step without further purification. MS (EI) for C 8 H 7 BrClNO 2 found 263.90 (MH + ).
  • Step 2 Ethyl 5-bromo-2-(4-chlorophenoxy)nicotinate: A solution of ethyl 5- bromo-2-chloronicotinate (939.00 mg, 3.55 mmol), 4-chlorophenol (547.68, 4.26 mmol), and cesium carbonate (1735.04 mg, 5.33 mmol) in dimethylacetamide (35 mL) was heated to 130 0 C for 16 hours.
  • Step 3 5-bromo-2-(4-chlorophenoxy)nicotinic acid: Ethyl 5-bromo-2-(4- chlorophenoxy)nicotinate (1120.00 mg, 3.14 mmol) was dissolved in tetrahydrofuran (15 mL) and 12.5 mL (12.5 mmol) of a 1 M LiOH solution was added and this was heated to 70 0 C for 6 hours. After cooling to room temperature, the reaction was washed with diethyl ether (20 mL) and the water layer was acidified to pH 2 and extracted with ethyl acetate (2 X 20 mL).
  • 2-(2-benzyl-4-chlorophenoxy)nicotinic acid was (prepared in the manner of Example 4) wherein 2-chloronicotinic acid was substituted for 5- bromo-2-chloronicotinic acid and 2-benzylphenol was substituted for 4-chlorophenol.
  • 1 H NMR 400 MHz DMSO-J 6 ): ⁇ 8.87 (d, IH), 8.21 (m, IH), 8.09 (m, IH), 7.32 (s, 2H), 7.21 (m, 7H), 7.07 (m, 5H), 5.21 (q, IH), 4.45 (q, 2H), 3.83 (s, 2H), 3.66 (m, 2H), 3.46 (m, 4H),
  • Step 1 (R)-l-tert-butyl 2-methyl aziridine-l,2-dicarboxylate: To a solution of (R)-methyl aziridine-2-carboxylate [prepared according to Tetrahedron: Asymmetry (2002), 13(11), 1129-1134] (1000.00 mg, 9.89 mmol) in acetonitrile (20 mL) was added Boc anhydride (2374.63mg, 10.88 mmol). The reaction was stirred at room temperature for two hours after which all solvent was removed on the rotary evaporator. The remaining oil was utilized without further purification for the next step.
  • 1 H NMR 400 MHz, DMSO-J 6 ): ⁇ 3.70 (s, 3H), 3.14 (q, IH), 2.46 (m, IH), 2.39 (m, IH), 1.38 (s, 9H).
  • Step 2 (R)-methyl 2-(tert-butoxycarbonylamino)-3-((l-methylcyclopropyl)- methoxy)propanoate: (R)-l-tert-butyl 2-methyl aziridine-l,2-dicarboxylate (1200.00 mg, 5.96 mmol) was dissolved in anhydrous chloroform (20 mL) followed by (1- methylcyclopropyl)methanol (1540.94 mg, 17.89 mmol) and 0.04 mL (0.28 mmol) of a 7 M boron trifluoride diethyl etherate solution. The reaction was stirred at room temperature for 24 hours and quenched with a few drops of methanol.
  • Step 3 (R)-2-(tert-butoxycarbonylamino)-3-((l-methylcyclopropyl)methoxy)- propanoic acid: (R)-methyl 2-(tert-butoxycarbonylamino)-3-((l- methylcyclopropyl)methoxy)-propanoate (1150.00 mg, 4.00 mmol) was dissolved in tetrahydrofuran (20 mL) and 6 mL (6.00 mmol) of a 1 M LiOH solution was added and this was heated to 70 0 C for 4 hours.
  • Step 1 (2R)-methyl 2-amino-3-(l-phenylethoxy)propanoate: (2R)-methyl 2- (tert-butoxycarbonylamino)-3-(l-phenylethoxy)propanoate was prepared as described in Example 4 (steps 1 and 2) wherein alpha methyl benzyl alcohol was substituted for (1- methylcyclopropyl)methanol.
  • This Boc-ester (880 mg, 2.72 mmol) was suspended in ether (2.7 mL) and treated with 4M solution of HCl in dioxane (13.6 mL, 54.4 mmol) and stirred at room temperature for 2h. The solvents were removed in vacuo and the residue was used directly in the next step.
  • Step 2 (2R)-methyl 2-(2-(4-chlorophenoxy)benzamido)-3-(l-phenylethoxy)- propanoate: (2R)-methyl 2-amino-3-(l-phenylethoxy)propanoate (706 mg, 2.72 mmol) was suspended in dichloroethane (9.1 mL). To the suspension was added 2-(4- chlorophenoxy)nicotinic acid (1019 mg, 4.08 mmol), prepared as described in Example 4, HATU (1550 mg, 4.08 mmol) and diisopropylethyl amine (0.71 mL, 4.08 mmol). The reaction mixture was stirred overnight at room temperature.
  • Step 3 (2R)-2-(2-(4-chlorophenoxy)benzamido)-3-(l-phenylethoxy)propanoic acid: (R)-methyl 2-(2-(4-chlorophenoxy)nicotinamido)-3-(l-phenylethoxy)propanoate (800 mg, 1.76 mmol) was dissolved in THF (8.8 mL). To that solution was added IM LiOH (7.0 mL). After stirring at room temperature for Ih, the organic solvent was removed in vacuo. The aqueous solvent was washed with diethyl ether, diluted with ethyl acetate and washed with IM HCl. The organic layer was separated and dried with MgSO 4 . The crude semi-solid was used without further purification.
  • Step 4 2-[(4-chlorophenyl)oxy]-N-[(lR)-2-(4-methylpiperazin-l-yl)-2-oxo-l- ⁇ [(l-phenylethyl)oxy]methyl ⁇ ethyl]pyridine-3-carboxamide: 2-[(4-chlorophenyl)oxy]-N- [(I R)-2-(4-methylpiperazin- 1 -yl)-2-oxo- 1 - ⁇ [( 1 -phenylethyl)oxy]methyl ⁇ -ethyl]pyridine-3 - carboxamide.
  • Step 1 (R)-tert-butyl 3-hydroxy-l-(4-methylpiperazin-l-yl)-l-oxopropan-2- ylcarbamate: To a solution of (R)-2-(tert-butoxycarbonylamino)-3-hydroxypropanoic acid (3.0 g, 14.62 mmol) in dichloromethane (50 mL) was added N-methylmorpholine (16 mL, 146.2 mmol), 1-methylpiperazine (1.78 mL, 16.08 mmol), l-[3-(Dimethylamino)propyl]-3- ethylcarbodiimide methiodide (EDC) (3.0 g, 16 mmol), and 1-Hydroxybenzotriazole (HOBt) (2.1 g, 16 mmol).
  • Step 2 (R)-2-(tert-butoxycarbonylamino)-3-(4-methylpiperazin-l-yl)-3- oxopropyl methanesulfonate: To a solution of (R)-tert-butyl 3 -hydroxy- 1 -(4- methylpiperazin-l-yl)-l-oxopropan-2-ylcarbamate (200 mg, 0.7 mmol) in dichloromethane (5 rnL) and triethylamine (0.3 rnL) at 0 0 C was added methanesulfonyl chloride (0.06 rnL, 0.77 mmol) and N'N'-Dimethyaminopyridine (10 mg, 0.08 mmol).
  • Step 3 (R)-2-amino-3-(benzylamino)-l-(4-methylpiperazin-l-yl)propan-l- one: To a solution of (R)-2-(tert-butoxycarbonylamino)-3-(4-methylpiperazin-l-yl)-3- oxopropyl methanesulfonate (100 mg, 0.27 mmol) in acetonitrile (5 mL) was added benzyl amino (0.5 mL, 4.2 mmol). The reaction mixture was heated to 65 0 C for 16 h, and concentrated in vacuo.
  • Step 4 2-[(4-chlorophenyl)oxy]-N-[(lR)-2-(4-methylpiperazin-l-yl)-2-oxo-l- ⁇ [(phenylmethyl)amino]methyl ⁇ ethyl]pyridine-3-carboxamide: To a solution of (R)-2- amino-3-(benzylamino)-l-(4-methylpiperazin-l-yl)propan-l-one (150 mg, 0.43 mmol) in dichloromethane (10 mL) was added N-methylmorpholine (0.23 mL, 2.15 mmol), 2-(4- chlorophenoxy)nicotinic acid (203 mg, 0.77mmol), l-[3-(Dimethylamino)propyl]-3- ethylcarbodiimide methiodide (EDC) (148 mg, 0.77 mmol), and 1-Hydroxybenzotriazole (HOBt) (
  • Step 1 (R)-ethyl 2-amino-3-(benzyloxy)propanoate: To a solution of (R)-3- (benzyloxy)-2-(tert-butoxycarbonylamino)propanoic acid (10 g, 33.8 mmol, Acros) in dichloromethane (120 niL) were added 1-hydroxybenzotriazole (6.8 g, 50.8 mmol), N- methylmorpholine (7.4 mL, 67.8 mmol), l-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (9.7 g, 50.8 mmol), and Ethyl alcohol (40 mL, 676 mmol).
  • Step 2 (R)-ethyl 3-(benzyloxy)-2-(2-(2-chloro-4-(trifluoromethyl)phenoxy)- nicotinamido)propanoate: To a solution of (R)-ethyl 2-amino-3-(benzyloxy)propanoate (750 mg, 3.36 mmol) in dichloromethane (20 mL) were added 1-hydroxybenzotriazole (500 mg, 3.70 mmol), N-methylmorpholine (3.0 mL, 26.88 mmol), l-[3-(dimethylamino)propyl]- 3-ethylcarbodiimide hydrochloride (700 mg, 3.70 mmol), and 2-(2-chloro-4- (trifluoromethyl)phenoxy)nicotinic acid (1.0 g, 3.36 mmol).
  • Step 4 N-[(lR)-2-[(3R)-3-aminopyrrolidin-l-yl]-2-oxo-l-
  • Step 5 2- ⁇ [2-chloro-4-(trifluoromethyl)phenyl]oxy ⁇ -N-[(lR)-2-oxo-2- ⁇ (3R)-3- [(phenylmethyl)amino]pyrrolidin-l-yl ⁇ -l- ⁇ [(phenylmethyl)oxy]methyl ⁇ ethyl]pyridine-3- carboxamide: To a solution of N-((R)-l-((R)-3-aminopyrrolidin-l-yl)-3-(benzyloxy)-l- oxopropan-2-yl)-2-(2-chloro-4-(trifluoromethyl)phenoxy)nicotinamide (50 mg, 0.08 mmol) in dichloromethane (3 rnL) were added benzaldehyde (0.08 rnL, 0.08 mmol) and glacial acetic acid (1 drop).
  • Glucosylceramide synthase (GCS) activity was measured as the amount of UDP-glucose consumed during the synthase-catalyzed reaction by using the enzyme UDP-glucose dehydrogenase to create NADH from UDP-glucose and then quantitatively converting low fluorescence resazurin to high fluorescence resorufm with diaphorase and the NADH that is formed by the dehydrogenase.
  • the synthase-catalyzed reaction transferred glucose from UDP-glucose to C6-ceramide to give UDP and glucosylceramide as products; the assay measured the disappearance of the UDP-glucose substrate.

Abstract

The present invention comprises glucosylceramide synthase (GCS) inhibitors of structural formula (I), and pharmaceutically acceptable salts thereof, wherein R1, E, A, L, X1, Q, R4, R5, m and n, are as defined herein, as well as N-oxides of them and pharmaceutically acceptable salts thereof. The invention further comprises composition comprising the compounds, N-oxides, and/or pharmaceutically acceptable salts thereof. The invention also comprises use of the compounds and compositions for treating diseases in which GCS is a mediator or is implicated. The invention also comprises use of the compounds in and for the manufacture of medicaments, particularly for treating diseases in which GCS is a mediator or is implicated.

Description

GLUCOSYLCERAMIDE SYNTHASE INHIBITORS
BACKGROUND OF THE INVENTION Field of the Invention
[0001] The invention relates to inhibitors of glucosylceramide synthase (GCS) useful for the treatment of cancer and metabolic diseases.
Summary of the Related Art
[0002] Glucosylceramide synthase (GCS) is a pivotal enzyme which catalyzes the initial glycosylation step in the biosynthesis of glucosylceramide -based glycosphingolipids (GSLs) namely via the pivotal transfer of glucose from UDP-glucose (UDP-GIc) to ceramide to form glucosylceramide. GCS is a transmembrane, type III integral protein localized in the cis/medial Golgi. Glycosphingolipids (GSLs) are believed to be integral for the dynamics of many cell membrane events, including cellular interactions, signaling, and trafficking. Synthesis of GSL structures has been shown (see, Yamashita et al., Proc. Natl. Acad. Sci. USA 1999, 96(16), 9142-9147) to be essential for embryonic development and for the differentiation of some tissues. Ceramide plays a central role in sphingolipid metabolism and downregulation of GCS activity has been shown to have marked effects on the sphingolipid pattern with diminished expression of glycosphingolipids. Sphingo lipids (SLs) have a biomodulatory role in physiological as well as pathological cardiovascular conditions. In particular, sphingolipids and their regulating enzymes appear to play a role in adaptive responses to chronic hypoxia in the neonatal rat heart (see, El Alwani et al., Prostaglandins & Other Lipid Mediators 2005, 78(1-4), 249-261).
[0003] GCS inhibitors have been proposed for the treatment of a variety of diseases (see, for example, WO2005068426). Such treatments include treatment of glycolipid storage diseases (e.g., Tay Sachs, Sandhoffs, GMl gangliosidosis and Fabry diseases), diseases associated with glycolipid accumulation (e.g., Gaucher disease; Miglustat (Zavesca), a GCS inhibitor, has been approved for therapy in type 1 Gaucher disease patients, see, Treiber et al., Xenobiotica 2007, 37(3), 298-314), diseases that cause renal hypertrophy or hyperplasia such as diabetic nephropathy; diseases that cause hyperglycemia or hyperinsulemia; cancers in which glycolipid synthesis is abnormal, infectious diseases caused by organisms which use cell surface glycolipids as receptors, infectious diseases in which synthesis of glucosylceramide is essential or important, diseases in which excessive glycolipid synthesis occurs (e.g., atherosclerosis, polycystic kidney disease, and renal hypertrophy), neuronal disorders, neuronal injury, inflammatory diseases or disorders associated with macrophage recruitment and activation (e.g., rheumatoid arthritis, Crohn's disease, asthma and sepsis), and diabetes mellitus and obesity (see, WO 2006053043).
[0004] In particular, it has been shown that overexpression of GCS is implicated in multi-drug resistance and disrupts ceramide-induced apoptosis. For example, Turzanski et ah, (Experimental Hematology 2005, 33(1), 62-72) have shown that ceramide induces apoptosis in acute myeloid leukemia (AML) cells and that P-glycoprotein (p-gp) confers resistance to ceramide-induced apoptosis, with modulation of the ceramide-glucosylceramide pathway making a marked contribution to this resistance in TF-I cells. Thus, GCS inhibitors can be useful for treatment of proliferative disorders by inducing apoptosis in diseased cells.
SUMMARY OF THE INVENTION
[0005] In light of the preceding diseases that can be affected by GCS inhibitors, there is a need in the art for new inhibitors. Towards this end, novel compounds have been identified that are useful in inhibiting GCS's catalytic activity and are useful for the treatment of cancer and metabolic disease.
[0006] The present invention comprises glucosylceramide synthase (GCS) modulators of structural formula (I),
Figure imgf000003_0001
(I) and optionally pharmaceutically acceptable salts thereof, wherein R1, E, L, A, X1, Q, R4, R5, m and n are as defined hereinbelow.
[0007] In another aspect, the invention comprises pharmaceutical compositions which comprise a GCS modulator compound of the invention, optionally as a pharmaceutically acceptable salt, and a pharmaceutically acceptable carrier, diluent, or excipient.
[0008] In another aspect, the invention comprises method for the treatment of a cancer or a metabolic disease in a subject in need of such treatment comprising administering to the subject an effective amount of a GCS inhibitor of the invention or a pharmaceutical composition comprising an effective amount of a GCS inhibitor of the invention. DETAILED DESCRIPTION OF THE INVENTION
[0009] In a first aspect, the invention comprises GCS modulators. As embodiment (1), the invention comprises GCS modulators of structural formula (I),
Figure imgf000004_0001
(I) or a single stereoisomer or mixture of stereoisomers thereof, N-oxides thereof, and additionally optionally as a pharmaceutically acceptable salt thereof, wherein A is isopropyl, t-butyl, C3-Cg cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally substituted by one, two, or three RA groups, wherein each RA is independently R^, Ci-C6 alkyl, Ci-C4 haloalkyl, aryl, aryl(Ci-C4)alkyl, or -Ci-C6 alkyl-R^, wherein the aryl of the aryl(Ci-C4)alkyl group is optionally substituted with one, two, or three RA2 groups, wherein each RA2 is independently halogen, cyano, nitro, -ORA1, -SRA1, -N(RA1)2, -C(O)RA1, -S(O)RA1, -S(O)2RA1, -S(O)N(RA1)2, -S(O)2N(RA1)2, -C(O)ORA1, -C(O)N(RA1)2, -N(RA1)C(O)RA1, -N(RA1)C(O)ORA1, -N(RA1)C(O)N(RA1)2, -N(RA1)S(O)2RA1, -N(RA1)C(=NRA1)N(RA1)2, -P(O)(ORA1)2, or -OP(O)(ORA1)2, wherein each RA1 is independently hydrogen, Ci-C4 alkyl, or Ci-C4 haloalkyl, or two RA attached to adjacent carbon atoms, taken together, form -O-(G)y_O-, wherein each G is independently -CH2-, -C(H)(F)-, or -CF2-, and y is 1, 2, or 3;
E is -(CH2)-, -C(H)(CH3)-, or -C(O)-; L is -[C(RL)2]p-L1-[C(RL)2]q-, wherein p is 1, 2, or 3; q is an integer selected from 0 to (3-p); L1 is a bond, -O- or -NH-; and each RL is independently hydrogen, methyl, or halomethyl; R1 is -N(R10XR11) or a moiety of formula,
Figure imgf000005_0001
wherein
R10 is hydrogen or C1-C4 alkyl;
R11 is -R13, -C3-C6 cycloalkyl-N(R12)2, -C3-C6 cycloalkyl-R13 , -Ci-C6 alkyl-N(R12)2, or -Ci-C6 alkyl-R13, wherein each R12 is independently hydrogen or C1-C4 alkyl; and R13 is (a) a 4 - 10 membered monocyclic, 4 - 10 membered fused-bicyclic, 5 - 10 membered bridged-bicyclic, or 5 - 10 membered spiro-bicyclic heterocyclyl ring, where the heterocyclyl ring comprises one, two, or three annular nitrogen atoms, and optionally comprises one annular oxygen or sulfur atom, or (b) a 5 or 6 membered monocyclic heteroaryl or a 8 - 10 membered fused-bicyclic heteroaryl, where the heteroaryl ring comprises one, two, or three annular nitrogen atoms, and optionally comprises one annular oxygen or sulfur atom, wherein the heterocyclyl and heteroaryl are each optionally substituted with one, two, or three R13A groups, wherein each R13A group is independently halogen, cyano, nitro, C1-C4 alkyl, Ci-C4 haloalkyl, aryl(Ci-C4)alkyl, -ORB1, -SRB1, -N(RB1)2, -C(O)RB1, -S(O)RB1, -S(O)2RB1, -S(O)N(RB1)2, -S(O)2N(RB1)2, -C(O)ORB1, -C(O)N(RB1)2, -N(RB1)C(O)RB1, -N(RB1)C(O)ORB1, -N(RB1)C(O)N(RB1)2, or -N(RB1)S(O)2RB1, wherein each RB1 is independently hydrogen, Ci-C4 alkyl, Ci-C4 haloalkyl, aryl, or aryl(Ci-C4)alkyl; w is 0, 1, 2, or 3; ring B in the definition of R1 is (a) a 4 - 10 membered monocyclic, 4 - 10 membered fused-bicyclic, 5 - 10 membered bridged-bicyclic, or 5 - 10 membered spiro-bicyclic heterocyclyl ring, where the heterocyclyl ring optionally comprises one annular oxygen or sulfur atom, and optionally one, two, or three additional annular nitrogen atoms, or (b) a 5 or 6 membered monocyclic heteroaryl or a 8 - 10 membered fused-bicyclic heteroaryl, where the heteroaryl ring optionally comprises one annular oxygen or sulfur atom, and optionally one, two, or three additional annular nitrogen atoms; R20 is -RB2, hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, C3-C8 cycloalkyl, aryl(Ci-C4)alkyl, or -Ci-C4 alkyl-RB2, wherein each RB2 is independently cyano, nitro, -ORB3, -SRB3, -N(RB3)2, -C(O)RB3,
-S(O)RB3, -S(O)2R63, -S(O)N(RB3)2, -S(O)2N(RB3)2, -C(O)ORB3,
-C(O)N(RB3)2, -N(RB3)C(O)RB3, -N(RB3)C(O)ORB3, -N(RB3)C(O)N(RB3)2, or -N(RB3)S(O)2RB3, wherein each RB3 is independently hydrogen, Ci-C4 alkyl, Ci-C4 haloalkyl, aryl, or aryl(Ci-C4)alkyl; or two RB3 taken together with the nitrogen atom to which they are both attached form a saturated or unsaturated monocyclic heterocyclyl or heteroaryl, wherein the heterocyclyl and heteroaryl are each optionally substituted with one, two, or three groups which are each independently (Ci-C3)alkyl, halogen, or Ci-C4 haloalkyl; and each R21 is independently halogen or -R20; XMs -C(H)= Or -N=; Q is -O- or -N(H)-; each R4 is independently halogen, Ci-C4 alkyl, benzyl, Ci-C4 haloalkyl, amino, Ci-C4 alkylamino, di(Ci-C4 alkyl)amino, or -(O)RB4, wherein each RB4 is independently hydrogen, Ci-C4 alkyl, or Ci-C4 haloalkyl; or two adjacent R4 groups, together with the carbon atoms to which they are attached, form a phenyl ring; m is 0, 1, 2, or 3; n is 0, 1, 2, or 3; and
R5 is independently halogen or Ci-C4 alkyl, wherein the alkyl group is optionally substituted with one, two, or three R51 groups wherein each R51 is independently hydroxy or halogen; provided that when X1 is -N=, E is -C(O)-, L1 is a bond or -NH-, A is isopropyl or t-butyl, R1 is a moiety of formula (a), and Ring B is pyrrolidinyl, then R20 is not -C(O)ORB3 or -C(O)N(RB3)2; and R21, when present, is not -C(O)ORB3 or -C(O)N(RB3)2; provided that when L1 is a bond, E is -CH2- or -CH(CH3)-, and Q is -NH-, then A is not isopropyl or tert-butyl; provided that when L1 is a bond, A is isopropyl or t-butyl, E is -CH2- or -CH(CHs)-, and R1 is a moiety of formula (a), then Ring B is not pyrazolyl, indazolyl, indolyl, or benzimidazolyl; provided that when E is -CH2- or -CH(CH3)-, R1 is a moiety of formula (a), and Ring B is a
4-10 membered monocyclic heterocyclyl ring, then R20 and R21, when present, are not aryl(Ci-C4)alkyl; and provided that when L1 is a bond, E is -C(O)-, R1 is -N(R10XR11), R11 is R13, and R13 is
8-azabicyclo[3.2.1]octanyl, then R13A, when present, is not aryl(Ci-C4)alkyl. [00010] The present invention further comprises GCS modulators of structural formula (IV),
Figure imgf000007_0001
(IV) or a single stereoisomer or mixture of stereoisomers thereof, N-oxides thereof, and additionally optionally as a pharmaceutically acceptable salt thereof, wherein R is
Figure imgf000007_0002
and R1, E, A, L, X1, Q, R4, R5, m and n as defined herein in embodiment (1).
[00011] The compounds of the invention, or their pharmaceutically acceptable salts, may have asymmetric carbon atoms or quaternized nitrogen atoms in their structure, and may exist as single stereoisomers, racemates, and mixtures of stereoisomers. The compounds of the invention, or their pharmaceutically acceptable salts, as single stereoisomers, racemates, and mixtures of stereoisomers are all intended to be within the scope of this invention.
[0012] So, for example, the invention also comprises each of the following embodiments:
[0013] Embodiment (2): In another embodiment, the compound of Formula (I) is that where Q is -O-; and all other groups are as defined in embodiment (1). In subembodiment
(2-a), the compound of Formula (I) is that where Q is -O-, and m is 1, 2, or 3; and all other groups are as defined in embodiment (1).
[0014] Embodiment (3): In another embodiment, the compound of Formula (I) is that where E is -C(O)-; and all other groups are as defined in embodiment (1) or (2). [0015] Embodiment (4): In another embodiment, the compound of Formula (I) is that where E is -(CH2)- or -C(H)(CHs)-; and all other groups are as defined in embodiment (1) or embodiment (2). In subembodiment (4-a), the compound of Formula (I) is that where E is -CH2-; and all other groups are as defined in one of embodiment (1) or (2). [0016] Embodiment (5): In another embodiment, the compound of Formula (I) is that where A is C3-Cs cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally substituted by one, two, or three RA groups; and all other groups are as defined in any one of embodiments (1) - (4). In subembodiment (5 -a), the compound of Formula (I) is that where A is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, naphthyl, imidazolyl, oxazolyl, or pyridyl, wherein the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, naphthyl, imidazolyl, oxazolyl, and pyridyl are optionally substituted by one, two, or three RA groups; and all other groups are as defined in any one of embodiments (1) - (4). In subembodiment (5-b), the compound of Formula (I) is that where A is C3-Cs cycloalkyl or aryl, wherein the cycloalkyl and aryl are optionally substituted by one, two, or three RA groups; and all other groups are as defined in any one of embodiments (1) - (4). In subembodiment (5-c), the compound of Formula (I) is that where A is phenyl, cyclopropyl, or cyclohexyl, wherein the phenyl, cyclopropyl, and cyclohexyl are optionally substituted by one, two, or three RA groups; and all other groups are as defined in any one of embodiments (1) - (4). In subembodiment (5-d), the compound of Formula (I) is that where A is C3-Cs cycloalkyl or heteroaryl, wherein the cycloalkyl and heteroaryl are optionally substituted by one, two, or three RA groups; and all other groups are as defined in any one of embodiments (1) - (4). In subembodiment (5-e), the compound of Formula (I) is that where A is C3-Cs cycloalkyl; optionally substituted by one, two, or three RA groups; and all other groups are as defined in any one of embodiments (1) - (4). In subembodiment (5-f), the compound of Formula (I) is that where A is aryl; optionally substituted by one, two, or three RA groups; and all other groups are as defined in any one of embodiments (1) - (4). In subembodiment (5-g), the compound of Formula (I) is that where A is heteroaryl optionally substituted by one, two, or three RA groups; and all other groups are as defined in any one of embodiments (1) - (4). In subembodiment (5-h), the compound of Formula (I) is that where A is aryl or heteroaryl, wherein the aryl and heteroaryl are optionally substituted by one, two, or three RA groups; and all other groups are as defined in any one of embodiments (1) - (4). [0017] Embodiment (6): In another embodiment, the compound of Formula (I) is that where R20 is -RB2, hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, C3-C8 cycloalkyl, aryl(d-C4)alkyl, or -Ci-C4 alkyl-RB2, wherein each RB2 is independently cyano, nitro, -ORB3, -SRB3, -N(RB3)2, -C(O)RB3, -S(O)RB3, -S(O)2R63, -S(O)N(RB3)2, -S(O)2N(RB3)2, -C(O)ORB3, -C(O)N(RB3)2, -N(RB3)C(O)RB3, -N(RB3)C(O)ORB3, -N(RB3)C(O)N(RB3)2, or -N(RB3)S(O)2RB3, wherein each RB3 is independently hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, aryl, or aryl(Ci-C4)alkyl; or two RB3 taken together with the nitrogen atom to which they are both attached form a saturated or unsaturated monocyclic heterocyclyl or heteroaryl, wherein the heterocyclyl and heteroaryl are each optionally substituted with one, two, or three groups which are each independently (Ci-C3)alkyl, halogen, or Ci -C4 haloalkyl; and when R21 is present, each R21 is independently halogen or -R20; and all other groups are as defined in any one of embodiments (1) - (5). In subembodiment (6-a), the compound of Formula (I) is that where R20 is hydrogen, -ORB3, -N(RB3)2, Ci-C4 alkyl, Ci-C4 haloalkyl, C3-C8 cycloalkyl, aryl(Ci-C4)alkyl, or -Ci-C4 alkyl-RB2; wherein RB2 is -ORB3 or -N(RB3)2; and when R21 is present, each R21 is independently halogen or -R20; and all other groups are as defined in any one of embodiments (1) - (5). In subembodiment (6-b), the compound of Formula (I) is that where R20 is hydrogen, Ci-C4 alkyl, -ORB3, or -N(RB3)2, wherein each RB3 is independently hydrogen, Ci-C4 alkyl, Ci-C4 haloalkyl, aryl, or aryl(Ci-C4)alkyl; and when R21 is present, each R21 is independently halogen or -R20; and all other groups are as defined in any one of embodiments
(I) - (5).
[0018] Embodiment (7): In another embodiment, the compound of Formula (I) is that where R1 is: (i) -N(R10)Rπ, wherein R10 is hydrogen or -Ci-C4 alkyl; and R11 is -R13, -C3-C6 cycloalkyl-N(R12)2, -C3-C6 cycloalkyl-R13 , -Ci-C6 alkyl-N(R12)2, or -Ci-C6 alkyl-R13, wherein each R12 is independently hydrogen or Ci-C4 alkyl; and R13 is (a) a 4 - 10 membered monocyclic, 4 - 10 membered fused-bicyclic, 5 - 10 membered bridged-bicyclic, or 5 - 10 membered spiro-bicyclic heterocyclyl ring, where the heterocyclyl ring comprises one, two, or three annular nitrogen atoms, and optionally comprises one annular oxygen or sulfur atom, or (b) a 5 or 6 membered monocyclic heteroaryl or a 8 - 10 membered fused-bicyclic heteroaryl, where the heteroaryl ring comprises one, two, or three annular nitrogen atoms, and optionally comprises one annular oxygen or sulfur atom, wherein the heterocyclyl and heteroaryl are each optionally substituted with one, two, or three R13A groups; or R1 is (ii) a moiety of formula (a),
Figure imgf000009_0001
(a); wherein w is 0, 1, or 2; and all other groups are as defined in any one of embodiments (I) - (6). In subembodiment (7-a), the compound of Formula (I) is that where R1 is -N(R10XR11), wherein R10 is hydrogen or -Ci-C4 alkyl; and R11 is -R13, -C3-C6 cycloalkyl-N(R12)2, -C3-C6 cycloalkyl-R13, -C1-C6 alkyl-N(R12)2, or -C1-C6 alkyl-R13, wherein each R12 is independently hydrogen or Ci-C4 alkyl; and R13 is a 4 - 10 membered monocyclic, a 5 - 10 membered bridged-bicyclic, or a 5-10 membered spiro-bicyclic heterocyclyl ring, where the heterocyclyl ring comprises one, two, or three annular nitrogen atoms, and optionally comprises one annular oxygen or sulfur atom, wherein the heterocyclyl is optionally substituted with one, two, or three R13A groups, wherein each R13A group is independently halogen, Ci-C4 alkyl, Ci-C4 haloalkyl, aryl(Ci-C4)alkyl, -ORB1, or-N(RB1)2, wherein each RB1 is independently hydrogen, Ci-C4 alkyl, Ci-C4 haloalkyl, aryl, or aryl(Ci-C4)alkyl; or R1 is (ii) a moiety of formula (a),
Figure imgf000010_0001
(a), wherein w is 0, 1, or 2; and all other groups are as defined in any one of embodiments (1) - (6).
[0019] Embodiment (8): In another embodiment, the compound of Formula (I) is that where R1 is (i) -N(R10XR11), wherein R10 is hydrogen or methyl; or R1 is (ii) a moiety of formula (a),
Figure imgf000010_0002
wherein ring B is a 5-10 membered bridged-bicyclic or 5 - 10 membered spiro-bicyclic heterocyclyl ring, where the heterocyclyl ring optionally comprises one annular oxygen or sulfur atom, and optionally one, two, or three additional annular nitrogen atoms; or the moiety of formula (a) is:
Figure imgf000010_0003
wherein t is 1, 2, or 3; and r is 0, 1, 2, or 3; and R11, R20, R21, w, and all other groups are as defined in any one of embodiments (1) - (7). [0020] Embodiment (9): In another embodiment, the compound of Formula (I) is that where R1 is -N(R10XR1 J) or a moiety of formula (a),
Figure imgf000011_0001
wherein
(a) ring B in the moiety of formula (a) is a 5-10 membered bridged-bicyclic heterocyclyl ring, where the heterocyclyl ring optionally comprises one annular oxygen or sulfur atom, and optionally one, two, or three additional annular nitrogen atoms; R20 is hydrogen, -ORB3, -N(RB3)2, Ci-C4 alkyl, Ci-C4 haloalkyl, C3-C8 cycloalkyl, aryl(Ci-C4)alkyl, or -Ci-C4 alkyl-RB2; RB2 is -ORB3 or -N(RB3)2; and R21, when present, is Ci-C4 alkyl or Ci-C4 haloalkyl;
(b) the moiety of formula (a) is
Figure imgf000011_0002
t is 1, 2, or 3, R20 is hydrogen,
Ci-C4 alkyl, Ci-C4 haloalkyl, C3-C8 cycloalkyl, aiyl(C1-C4)alkyl, or -Ci-C4 alkyl-RB2, wherein RB2 is -ORB3 or -N(RB3)2, and R21, when present, is Ci-C4 alkyl or Ci-C4 haloalkyl; or
(c) the moiety of formula (a) is
Figure imgf000011_0003
, wherein r is 0, 1, 2, or 3, R20 is -
N(RB3)2 or -Ci-C4 alkyl-N(RB3)2; and R21, when present, is Ci-C4 alkyl or Ci-C4 haloalkyl; and all other groups are as defined in any one of embodiments (1) - (8).
[0021] Embodiment (10): In another embodiment, the compound of Formula (I) is that where R1 is -N(R10XR11) or a moiety of formula (a),
Figure imgf000011_0004
wherein ring B is a 5-10 membered bridged-bicyclic heterocyclyl ring; and R10, R11, w, R20, R21, and all other groups are as defined in any one of embodiments (1) - (9). In subembodiment (10-a), R1 is -N(R10XR11) or a moiety of formula (a), wherein ring B is 8-azabicyclo[3.2.1]octyl, 3,8-diazabicyclo[3.2.1]octyl, 2,5-diazabicyclo[2.2.1]heptyl, or l-azabicyclo[2.2.2]oct-3-yl; and R10, R11, w, R20, R21, and all other groups are as defined in any one of embodiments (1) - (9). [0022] Embodiment (11): In another embodiment, the compound of Formula (I) is that where R1 is -N(R10XR11) or a moiety of formula (a),
Figure imgf000012_0001
wherein ring B is piperazin-1-yl or 1,4-diazepan-l-yl; and R10, R11, R20, R21, w, and all other groups are as defined in any one of embodiments (1) - (9). In subembodiment (11-a), the compound of formula (I) is that where R1 is -N(R10XR11) or a moiety of formula (a), wherein
said moiety of formula (a) is
Figure imgf000012_0002
t is 1, 2, or 3; and R10, R11, R20, R21, w, and all other groups are as defined in any one of embodiments (1) - (9). In subembodiment (11-b), R1 is -N(R10XR11) or 4-methylpiperazin-l-yl, 3-methylpiperazin-l-yl, 4-methyl-l,4- diazepan-1-yl, piperazin-1-yl, 4-(l-methylethyl)-piperazin-l-yl, 4-(2-fluoroethyl)piperazin-l- yl, or 4-ethylpiperazin-l-yl; and R10, R11, and all other groups are as defined in any one of embodiments (1) - (5), (7) and (8).
[0023] Embodiment (12): In another embodiment, the compound of Formula (I) is that where R1 is -N(R10XR11) or a moiety of formula (a),
Figure imgf000012_0003
, wherein r is 0, 1, 2, or 3; and R10, R11, R20, R21, w, and all other groups are as defined in any one of embodiments (1) - (9). In subembodiment (12-a), R1 is -N(R10)(Rπ) or a moiety of formula (a), wherein ring B is azetidin-1-yl, pyrrolidin-1-yl, or piperidin-1-yl and R10, R11, R20, R21, w, and all other groups are as defined in any one of embodiments (1) - (9). In subembodiment (12-b), R1 is -N(R10XR11) or 3-(dimethylamino)azetidin-l-yl, 3-(dimethylamino)pyrrolidin-l-yl, 3- aminoazetidin-1-yl, 3-aminopyrrolidin-l-yl, 4-amino-4-methylpiperidin-l-yl, 3- aminopiperidin-1-yl, 4-aminopiperidin-l-yl, 3-(methylamino)pyrrolidin-l-yl, 4- (methylamino)piperidin-l-yl, (l-methylethyl)amino-piperidinyl, or 4-hydroxypiperidin-l-yl, and R10, R11, and all other groups are as defined in any one of embodiments (1) - (5), (7) and (8).
[0024] Embodiment (13): In another embodiment, the compound of Formula (I) is that where L is -[C(RL)2]p-L1-[C(RL)2]q-, wherein/? is 1, 2, or 3; q is an integer selected from 0 to (3-p); L1 is a bond, -O- or -NH-; and each RL is independently hydrogen, methyl, or halomethyl; and all other groups are as defined in any one of embodiments (1) - (12). In subembodiment (13-a), the compound of Formula (I) is that where L is -[C(RL)2]p-L1-[C(RL)2]q-, wherein/? is 1, 2, or 3; q is an integer selected from 0 to (3-p); L1 is a bond or -O-; and each RL is independently hydrogen, methyl, or halomethyl; and all other groups are as defined in any one of embodiments (1) - (12). In subembodiment (13-b), the compound of Formula (I) is that where L is -[C(RL)2]p-L1-[C(RL)2]q-,wherein p is 1 or 2; q is an integer selected from 0 to (3-p); L1 is a bond or -O-; and each RL is independently hydrogen or methyl; and all other groups are as defined in any one of embodiments (I) - (12). In subembodiment (13-c), the compound of Formula (I) is that where L is - [C(RL)2]p-L1-[C(RL)2]q-, wherein/? is 1, 2, or 3; q is an integer selected from 0 to (3-p); L1 is -NH-; and each RL is independently hydrogen, methyl, or halomethyl; and all other groups are as defined in any one of embodiments (1) - (12). [0025] Embodiment (14): In another embodiment, the compound of Formula (I) is that
where R1 is a moiety of formula (a),
Figure imgf000013_0001
(a); and ring B, R20, R21, w, and all other groups are as defined in any one of embodiments (1) - (13).
[0026] Embodiment (15): In another embodiment, the compound of Formula (I) is that where R1 is -N(R10XR1 J) or a moiety of formula (a), wherein R11 is R13, wherein R13 is a 4 - 10 membered monocyclic heterocyclyl ring, where the heterocyclyl ring comprises one, two, or three annular nitrogen atoms, and optionally comprises one annular oxygen or sulfur atom, wherein said heterocyclyl ring is optionally substituted with one, two, or three R13A groups; and all other groups are as defined in any one of embodiments (1) - (13). In sub-embodiment (15-a), the compound of Formula (I) is that where R1 is -N(R^)R11 or a moiety of formula (a), wherein R11 is R13, wherein R13 is azetidinyl, pyrrolidinyl, or piperidinyl, wherein said azetidinyl, pyrrolidinyl, and piperidinyl are optionally substituted with one, two, or three R13A groups; and all other groups are as defined in any one of embodiments (1) - (13). [0027] Embodiment (16): In another embodiment, the compound of Formula (I) is that where R1 is -N(R10)(Rπ) or a moiety of formula (a), wherein R11 is R13, wherein R13 is a 5 - 10 membered bridged-bicyclic heterocyclyl ring, where the heterocyclyl ring comprises one, two, or three annular nitrogen atoms, and optionally comprises one annular oxygen or sulfur atom, wherein said heterocyclyl ring is optionally substituted with one, two, or three R13A groups; and all other groups are as defined in any one of embodiments (1) - (13). In subembodiment (16-a) , the compound of Formula (I) is that where R1 is -N (R^)R11 or a moiety of formula (a), wherein R11 is R13, wherein R13 is 8-azabicyclo[3.2.1]oct-3-yl, 8-azabicyclo[3.2.1]oct-8-yl, l-azabicyclo[2.2.2]oct-3-yl, l-azabicyclo[2.2.2]oct-4-yl, 3,8-diazabicyclo[3.2.1]oct-3-yl, or 2,5-diazabicyclo[2.2.1]hept-2-yl, wherein
8-azabicyclo[3.2.1]oct-3-yl, 8-azabicyclo[3.2.1]oct-8-yl, l-azabicyclo[2.2.2]oct-3-yl, l-azabicyclo[2.2.2]oct-4-yl, 3,8-diazabicyclo[3.2.1]oct-3-yl, and 2,5-diazabicyclo[2.2.1]hept- 2-yl are optionally substituted with one, two, or three R13A groups; and all other groups are as defined in any one of embodiments (1) - (13).
[0028] Embodiment (17): In another embodiment, the compound of Formula (I) is that where when R13A is present, each R13A group is independently halogen, cyano, nitro, C1-C4 alkyl, Ci-C4 haloalkyl, aryl(Ci-C4)alkyl, -ORB1, -SRB1, -N(RB1)2, -C(O)RB1, -S(O)RB1, -S(O)2RB1, -S(O)N(RB1)2, -S(O)2N(RB1)2, -C(O)ORB1, -C(O)N(RB1)2, -N(RB1)C(O)RB1, -N(RB1)C(O)ORB1, -N(RB1)C(O)N(RB1)2, or -N(RB1)S(O)2RB1, wherein each RB1 is independently hydrogen, Ci-C4 alkyl, Ci-C4 haloalkyl, aryl, or aryl(Ci-C4)alkyl; and all other groups are as defined in any one of embodiments (1) - (13), (15), and (16). In subembodiment (16-a) the compound of Formula (I) is that where when R13A is present, each R13A group is independently halogen, Ci-C4 alkyl, Ci-C4 haloalkyl, aiyl(C1-C4)alkyl, -ORB1, -SRB1, or -N(RB1)2, wherein each RB1 is independently hydrogen, Ci-C4 alkyl, Ci-C4 haloalkyl, aryl, or aryl(Ci-C4)alkyl; and all other groups are as defined in any one of embodiments (1) - (12), (14), and (15).
[0029] Embodiment (18): In another embodiment, the compound of Formula (I) is that where R1 is -N(R10XR1 J) or a moiety of formula (a), wherein R11 is-Ci-C6 alkyl-N(R12)2 or -C3-C6 cycloalkyl-N(R12)2; and all other groups are as defined in any one of embodiments (1) - (13). In subembodiment (18-a), the compound of Formula (I) is that where R1 is -N(R10XR11) or a moiety of formula (a), wherein R11 is 2-aminoethyl, 2-(methylamino)ethyl, 2-(dimethylamino)ethyl, 2-(dimethylamino)-l-methylethyl, 2-(ethylamino)ethyl, 2- (diethylamino)ethyl, 2-(diethylamino)- 1 -methylethyl, 3 -aminopropyl,
3 -(methylamino)propyl, 3 -(dimethylamino)propyl, 3 -(ethylamino)propyl,
3-(diethylamino)propyl, 2-amino-2-methylpropyl, 3-(dimethylamino)-2,2-dimethylpropyl, 3-(diethylamino)-2,2-dimethylpropyl, 2-aminocyclohexyl, 3-aminocyclohexyl, or 4-aminocyclohexyl; and all other groups are as defined in any one of embodiments (1) - (13). [0030] Embodiment (19): In another embodiment, the compound of Formula (I) is that where R1 -N(R10)(Rπ); and all other groups are as defined in any one of embodiments (1) - (8), (13), and (15) - (18).
[0031] Embodiment (20): In another embodiment, the compound of Formula (I) is that where X1 is =N-; and all other groups are as defined in any one of embodiments (1) - (19). In another embodiment, the compound of Formula (I) is that where X1 is -C(H)=; and all other groups are as defined in any one of embodiments (1) - (19).
[0032] Embodiment (21): In another embodiment, the compound of Formula (I) is that where R21 is halogen or -R20, wherein R20 is -RB2, hydrogen, Ci-C4 alkyl, Ci-C4 haloalkyl, C3-Cg cycloalkyl, aryl(Ci-C4)alkyl, or -Ci-C4 alkyl-RB2; wherein each RB2 is independently cyano, nitro, -ORB3, -SRB3, -N(RB3)2, -C(O)RB3, -S(O)RB3, -S(O)2R63, -S(O)N(RB3)2, -S(O)2N(RB3)2, -C(O)ORB3, -C(O)N(RB3)2, -N(RB3)C(O)RB3, -N(RB3)C(O)ORB3, -N(RB3)C(O)N(RB3)2, or -N(RB3)S(O)2RB3; wherein each RB3 is independently hydrogen, Ci-C4 alkyl, Ci-C4 haloalkyl, aryl, or aryl(Ci-C4)alkyl; or two RB3 taken together with the nitrogen atom to which they are both attached form a saturated or unsaturated monocyclic heterocyclyl or heteroaryl, wherein the heterocyclyl and heteroaryl are each optionally substituted with one, two, or three groups which are each independently (Ci-C3)alkyl, halogen, or Ci-C4 haloalkyl; and all other groups are as defined in any one of embodiments (1) - (5), (7), (8), (10) - (18) and (20). In subembodiment (21-a) , the compound of Formula (I) is that where R21 is Ci-C4 alkyl, Ci-C4 haloalkyl, or -N(RB3)2; and all other groups are as defined in any one of embodiments (1) - (5), (7), (8), (10) - (18) and (20). In subembodiment (21-b), the compound of Formula (I) is that where w is zero or 1, and R21 is Ci-C4 alkyl, Ci-C4 haloalkyl, or -N(RB3)2; and all other groups are as defined in any one of embodiments (1) - (5), (7), (8), (10) - (18) and (20). In subembodiment (21-c), the compound of Formula (I) is that where w is zero or 1, and R21 is Ci-C4 alkyl or -N(RB3)2; and all other groups are as defined in any one of embodiments (1) - (5), (7), (8), (10) - (18) and (20). In subembodiment (21-d), the compound of Formula (I) is that where w is zero or 1, and R21 is Ci-C4 alkyl; and all other groups are as defined in any one of embodiments (1) - (18) and (20). In subembodiment (21-e), the compound of Formula (I) is that where w is zero or 1, and R21 is -N(RB3)2; and all other groups are as defined in any one of embodiments (1) - (5), (7), (8), (10) - (18) and (20).
[0033] Embodiment (22): In another embodiment, the compound of Formula (I) is that where L is -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH(CH3)-, -CH2-O-, -CH2CH2-O-, or -CH2-O-CH2-; and all other groups are as defined in any one of embodiments (1) - (12) and (14) - (21). In subembodiment (22-a), the compound of Formula (I) is that where L is -CH2CH2-, -CH2CH2CH2-, -CH2-O-, -CH2CH2-O-, or -CH2-O-CH2-; and all other groups are as defined in any one of embodiments (1) - (12) and (14) - (21). In another embodiment, the compound of Formula (I) is that where L is Ci-Csalkylene; and all other groups are as defined in any one of embodiments (1) - (12) and (14) - (21).
[0034] Embodiment (23): In another embodiment, the compound of Formula (I) is that where L is -CH2-O-CH2-; and all other groups are as defined in any one of embodiments (I) - (12) and (14) - (21).
[0035] Embodiment (24): In another embodiment, the compound of formula (I) is that where when RA is present, each RA is independently RA2, Ci-C6 alkyl, C1-C4 haloalkyl, aryl, aryl(Ci-C4)alkyl, or -Ci-C6 alkyl-RA2, wherein the aryl of the aryl(Ci-C4)alkyl group is optionally substituted with one, two, or three RA2 groups, wherein each RA2 is independently halogen, cyano, nitro, -ORA1, -SRA1, -N(RA1)2, -C(O)RA1, -S(O)RA1, -S(O)2RA1, -S(O)N(RA1)2, -S(O)2N(RA1)2, -C(O)ORA1, -C(O)N(RA1)2, -N(RA1)C(O)RA1, -N(RA1)C(O)ORA1, -N(RA1)C(O)N(RA1)2, -N(RA1)S(O)2RA1, -N(RA1)C(=NRA1)N(RA1)2, -P(O)(ORA1)2, or -OP(O)(ORA1)2, wherein each RA1 is independently hydrogen, C1-C4 alkyl, or C1-C4 haloalkyl, or two RA attached to adjacent carbon atoms, taken together, form -O-(G)y_O-, wherein each G is independently -CH2-, -C(H)(F)-, or -CF2-, and y is 1, 2, or 3; and all other groups are as defined in any one of embodiments (1) - (23). In subembodiment (24-a), the compound of Formula (I) is that where when RA is present, each RA is independently halogen, cyano, Ci-C4 alkyl, Ci-C4 haloalkyl, aryl, aryl(C1-C4)alkyl, -ORA1, -N(RA1)2, or -C(O)RA1, wherein each RA1 is independently hydrogen or Ci-C4 alkyl; or two RA attached to adjacent carbon atoms, taken together, form -O-(G)y_O-, wherein each G is independently -CH2-, -C(H)(F)-, or -CF2-, and y is 1, 2, or 3; and all other groups are as defined in any one of embodiments (1) - (23). In subembodiment (24-b), the compound of Formula (I) is that where when RA is present, each RA is independently halogen, cyano, Ci-C4 alkyl, Ci-C4 haloalkyl, phenyl, benzyl, -ORA1, -N(RA1)2, or -C(O)RA1, wherein each RA1 is independently hydrogen, Ci-C4 alkyl, or Ci-C4 haloalkyl; or two RA attached to adjacent carbon atoms, taken together, form -O-(G)y_O-; wherein each G is independently -CH2-, -C(H)(F)-, or -CF2-, and y is 1, 2, or 3; and all other groups are as defined in any one of embodiments (1) - (23).
[0036] Embodiment (25): In another embodiment, the compound of Formula (I) is that where each R4, when present, is independently halo, Ci-C4 alkyl, Ci-C4 haloalkyl, Ci-C4 alkoxy, Ci-C4 haloalkoxy, or benzyl; and all other groups are as defined in any one of embodiments (1) - (24). In subembodiment (25-a), the compound of Formula (I) is that where each R4, when present, is independently chloro, fluro, bromo, methyl, trihalomethyl, methoxy, or benzyl; and all other groups are as defined in any one of embodiments (1) - (24). [0037] Embodiment (26): In another embodiment, the compound of Formula (I) which is a compound of formula (Ia):
Figure imgf000017_0001
and all other groups are as defined in any one of embodiments (1) - (25). [0038] Embodiment (27): In another embodiment, the compound of Formula (I) which is a compound of formula (Ib):
Figure imgf000017_0002
and all other groups are as defined in any one of embodiments (1) - (25). [0039] Embodiment (28): In another embodiment, the compound of Formula (I) is that which is a compound of Table 1.
[0040] Embodiment (29): In another embodiment, the compound of Formula (I) is that where A is phenyl optionally substituted by one, two, or three RA groups; and all other groups are as defined in any one of embodiments (1) - (4) and (6) - (27). In subembodiment (29-a), the compound of Formula (I) is that where A is phenyl substituted by one, two, or three RA groups; and all other groups are as defined in any one of embodiments (1) - (4) and (6) - (27). In subembodiment (29-b), the compound of Formula (I) is that where A is phenyl; and all other groups are as defined in any one of embodiments (1) - (4) and (6) - (27). In subembodiment (29-c), the compound of Formula (I) is that where A is phenyl substituted by two RA groups attached to adjacent carbon atoms, and the two RA groups taken together, form -O-(G)y_O-; wherein each G is independently -CH2-, -C(H)(F)-, or -CF2-, and y is 1, 2, or 3; and all other groups are as defined in any one of embodiments (1) - (4), (6) - (23), and (25) - (27); for example, A is 2,3-dihydro-l,4-benzodioxin-6-yl or 2,2-difluoro-l,3-benzodioxol-5- yi. [0041] Embodiment (30): In another embodiment, the compound of Formula (I) is a compound of formula (II):
Figure imgf000018_0001
(H); and all other groups are as defined in any one of embodiments (1) - (3), (5) - (27), and (29).
[0042] Embodiment (31): In another embodiment, the compound of Formula (I) is a compound of formula (III):
Figure imgf000018_0002
and all other groups are as defined in any one of embodiments (1) - (27), and (29). [0043] When R1 is a moiety of formula (a),
Figure imgf000018_0003
(a)
"ring B in the definition of R1" is (i) a heterocyclyl ring optionally comprising one annular oxygen or sulfur atom, and optionally one, two, or three additional annular nitrogen atoms; or (ii) a 5 or 6 membered monocyclic heteroaryl or a 8 - 10 membered fused-bicyclic heteroaryl. "Ring B" refers to the annular atoms which together with the nitrogen atom to which they are attached form a heterocyclyl or heteroaryl ring. Thus, when ring B is, for example, piperazinyl, the moiety of formula (a) is a piperazinyl ring substituted with R20 and (R21)w, wherein R20, R21, and w are as defined herein. Similarly, when ring B is a 4 - 10 membered monocyclic heterocyclyl ring optionally comprising one annular oxygen or sulfur atom, and optionally one, two, or three additional annular nitrogen atoms, the moiety of formula (a) is, for example, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, or thiomorpholinyl and the like, wherein the 4 - 10 membered monocyclic heterocyclyl ring is substituted with R20 and (R21)w, wherein R20, R21, and w are as defined herein. [0044] Embodiment (32): In another embodiment, the compound of Formula (I) is that where when R1 is a moiety of formula (a), ring B is azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, diazepanyl, 8-azabicyclo[3.2.1]octyl, 3,8-diazabicyclo[3.2.1]octyl, 2,5-diazabicyclo[2.2. l]heptyl, l-azabicyclo[2.2.2]oct-3-yl, 2,6-diazaspiro[3,3]heptyl, 2,8-diazaspiro[4.5]decyl, 2,7-diazaspiro[4.4]nonyl, or l,7-diazaspiro[4.4]nonyl; and R20, R21, w, and all other groups are as defined in any one of embodiments (1) - (9), (13) - (18), (20) - (27), and (29) - (31). In subembodiment (32-a), ring B is a 7 - 10 membered fused-bicyclic heterocyclyl ring, optionally comprising one, two, or three additional nitrogen atoms within the heterocyclyl ring; and R20, R21, w, and all other groups are as defined in any one of embodiments (1) - (9), (13) - (18), (20) - (27), and (29) - (31). In subembodiment (32-b), ring B is a 7 - 10 membered bridged-bicyclic heterocyclyl ring, optionally comprising one or two additional nitrogen atoms within the heterocyclyl ring; and R20, R21, w, and all other groups are as defined in any one of embodiments (1) - (10), (13) - (18), (20) - (27), and (29)
- (31). In subembodiment (32-c), ring B is a 7 - 10 membered spiro-bicyclic heterocyclyl ring, optionally comprising one additional nitrogen atom within the heterocyclyl ring; and R20, R21, w, and all other groups are as defined in any one of embodiments (1) - (9), (13) - (18), (20) - (27), and (29) - (31). In subembodiment (32-d), ring B is a 5 or 6 membered heteroaryl; and R20, R21, w, and all other groups are as defined in any one of embodiments (1)
- (9), (13) - (18), (20) - (27), and (29) - (31). In subembodiment (32-e), ring B is an 8 - 10 membered fused-bicyclic heteroaryl; and R20, R21, w, and all other groups are as defined in any one of embodiments (1) - (9), (13) - (18), (20) - (27), and (29) - (31). In subembodiment (32-f), ring B is azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, or diazepanyl; and R20, R21, w, and all other groups are as defined in any one of embodiments (1) - (9), (13) - (18), (20) - (27), and (29) - (31).
[0045] Embodiment (33): In another embodiment, the compound of Formula (I) is that where n is 0, 1, 2, or 3; and all other groups are as defined in any one of embodiments (I) - (27) and (29) - (32). In subembodiment (33-a), the compound of Formula (I) is that where n is 0 or 1; and all other groups are as defined in any one of embodiments (1) - (27) and (29) - (32). In subembodiment (33-b), the compound of Formula (I) is that where n is 0; and all other groups are as defined in any one of embodiments (1) - (27) and (29) - (32). [0046] Embodiment (34): In another embodiment, the compound of Formula (I) is that where m is 0, 1, 2, or 3; Q is -O-; and all other groups are as defined in any one of embodiments (1), (3) - (27), and (29) - (33). In subembodiment (34-a), the compound of Formula (I) is that where m is 1, 2, or 3; and all other groups are as defined in any one of embodiments (1), (3) - (27), and (29) - (33).
[0047] Embodiment (35): In another embodiment, the compound of Formula (I) is that where when present, R5 is independently halogen or C1-C4 alkyl, wherein the alkyl group is optionally substituted with one, two, or three R51 groups wherein each R51 is independently hydroxy or halogen; and all other groups are as defined in any one of embodiments (1) - (27) and (29) - (34). In subembodiment (35-a), the compound of Formula (I) is that where when present, R5 is independently halogen or Ci-C4 alkyl; and all other groups are as defined in any one of embodiments (1) - (27) and (29) - (34).
[0048] The invention also comprises as another embodiment, a pharmaceutical composition which comprises a GCS modulator compound, optionally as a pharmaceutically acceptable salt thereof, according to any one of the embodiments herein, together with a pharmaceutically acceptable diluent, excipient, and/or carrier. Such compositions are substantially free of non-pharmaceutically acceptable components, i.e., contain amounts of non-pharmaceutically acceptable components lower than permitted by US regulatory requirements at the time of filing this application. In some embodiments of this aspect, if the compound is dissolved or suspended in water, the composition further optionally comprises an additional pharmaceutically acceptable carrier, diluent, or excipient. [0049] The invention also comprises as another embodiment a method for treating a disease or disorder mediated by GCS or a disease or disorder in which GCS is implicated in a subject in need of such treatment comprising administering to the subject an effective amount of a compound according to any of the preceding embodiments or a composition of the invention {supra).
[0050] Diseases and disorders mediated by GCS or implicated by GCS include, but are not limited to cancers, metabolic disorders, and lysosomal storage diseases. Examples of cancers which may be modulated by a compound or composition of the invention include, but are not limited to, cancers in which glycolipid synthesis is abnormal, for example, breast cancer, renal adenocarcinoma, brain cancer, neuroblastoma, lung cancer, intestinal cancer, pancreas and prostrate cancer. Examples of metabolic disorders include, but are not limited to, Tay Sachs, Sandhoffs, GMl gangliosidosis, atherosclerosis, polycystic kidney disease, renal hypertrophy, rheumatoid arthritis, Crohn's disease, asthma, sepsis, diabetes mellitus, and obesity; and lysosomal storage diseases, such as Fabry diseases and Gaucher disease. [0051] The invention also comprises as another embodiment a method for inducing decreased GCS catalytic activity in a cell, in vitro, comprising contacting the cell with an effective amount of a compound according to any of the preceding embodiments. [0052] The invention also comprises as another embodiment, use of a GCS modulator of any of the preceding embodiments of the invention for the preparation of a medicament for treating a disease or disorder mediated by GCS or a disease or disorder in which GCS is implicated in a subject in need of such treatment.
Pharmaceutical Formulations and Dosage Forms
[0053] Administration of the compounds of this disclosure, or their pharmaceutically acceptable salts, in pure form or in an appropriate pharmaceutical composition, can be carried out via any of the accepted modes of administration or agents for serving similar utilities. Thus, administration can be, for example, orally, nasally, parenterally (intravenous, intramuscular, or subcutaneous), topically, transdermally, intravaginally, intravesically, intracistemally, or rectally, in the form of solid, semi-solid, lyophilized powder, or liquid dosage forms, such as for example, tablets, suppositories, pills, soft elastic and hard gelatin capsules, powders, solutions, suspensions, or aerosols, or the like, preferably in unit dosage forms suitable for simple administration of precise dosages.
[0054] The compositions will include a conventional pharmaceutical carrier, excipient, and/or diluent and a compound of this disclosure as the/an active agent, and, in addition, can include carriers and adjuvants, etc.
[0055] Adjuvants include preserving, wetting, suspending, sweetening, flavoring, perfuming, emulsifying, and dispensing agents. Prevention of the action of microorganisms can be ensured by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, and the like. It can also be desirable to include isotonic agents, for example sugars, sodium chloride, and the like. Prolonged absorption of the injectable pharmaceutical form can be brought about by the use of agents delaying absorption, for example, aluminum monostearate and gelatin.
[0056] If desired, a pharmaceutical composition of the compounds in this disclosure can also contain minor amounts of auxiliary substances such as wetting or emulsifying agents, pH buffering agents, antioxidants, and the like, such as, for example, citric acid, sorbitan monolaurate, triethanolamine oleate, butylalted hydroxytoluene, etc.
[0057] 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.
[0058] Compositions suitable for parenteral injection can comprise physiologically acceptable sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Examples of suitable aqueous and nonaqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols (propyleneglycol, polyethyleneglycol, glycerol, and the like), suitable mixtures thereof, vegetable oils (such as olive oil) and injectable organic esters such as ethyl oleate. Proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersions and by the use of surfactants.
[0059] One preferable route of administration is oral, using a convenient daily dosage regimen that can be adjusted according to the degree of severity of the disease-state to be treated.
[0060] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is admixed with at least one inert customary excipient (or carrier) such as sodium citrate or dicalcium phosphate or (a) fillers or extenders, as for example, starches, lactose, sucrose, glucose, mannitol, and silicic acid, (b) binders, as for example, cellulose derivatives, starch, alignates, gelatin, polyvinylpyrrolidone, sucrose, and gum acacia, (c) humectants, as for example, glycerol, (d) disintegrating agents, as for example, agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, croscarmellose sodium, complex silicates, and sodium carbonate, (e) solution retarders, as for example paraffin, (f) absorption accelerators, as for example, quaternary ammonium compounds, (g) wetting agents, as for example, cetyl alcohol, and glycerol monostearate, magnesium stearate and the like (h) adsorbents, as for example, kaolin and bentonite, and (i) lubricants, as for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, or mixtures thereof. In the case of capsules, tablets, and pills, the dosage forms can also comprise buffering agents.
[0061] Solid dosage forms, as described above, can be prepared with coatings and shells, such as enteric coatings and others well known in the art. They can contain pacifying agents, and can also be of such composition that they release the active compound or compounds in a certain part of the intestinal tract in a delayed manner. Examples of embedded compositions that can be used are polymeric substances and waxes. The active compounds can also be in microencapsulated form, if appropriate, with one or more of the above-mentioned excipients. [0062] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs. Such dosage forms are prepared, for example, by dissolving, dispersing, etc., a compound(s) of this disclosure, or a pharmaceutically acceptable salt thereof, and optional pharmaceutical adjuvants in a carrier, such as, for example, water, saline, aqueous dextrose, glycerol, ethanol and the like; solubilizing agents and emulsifiers, as for example, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propyleneglycol, 1,3-butyleneglycol, dimethylformamide; oils, in particular, cottonseed oil, groundnut oil, corn germ oil, olive oil, castor oil and sesame oil, glycerol, tetrahydrofurfuryl alcohol, polyethyleneglycols and fatty acid esters of sorbitan; or mixtures of these substances, and the like, to thereby form a solution or suspension.
[0063] Suspensions, in addition to the active compounds, can contain suspending agents, as for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, or mixtures of these substances, and the like.
[0064] Compositions for rectal administrations are, for example, suppositories that can be prepared by mixing the compounds of this disclosure with, for example, suitable non-irritating excipients or carriers such as cocoa butter, polyethyleneglycol or a suppository wax, which are solid at ordinary temperatures but liquid at body temperature and therefore, melt while in a suitable body cavity and release the active component therein. [0065] Dosage forms for topical administration of a compound of this disclosure include ointments, powders, sprays, and inhalants. The active component is admixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants as can be required. Ophthalmic formulations, eye ointments, powders, and solutions are also contemplated for the compounds in this disclosure. [0066] Compressed gases can be used to disperse a compound of this disclosure in aerosol form. Inert gases suitable for this purpose are nitrogen, carbon dioxide, etc. [0067] Generally, depending on the intended mode of administration, the pharmaceutically acceptable compositions will contain about 1% to about 99% by weight of a compound(s) of this disclosure, or a pharmaceutically acceptable salt thereof, and 99% to 1% by weight of a suitable pharmaceutical excipient. In one example, the composition will be between about 5% and about 75% by weight of a compound(s) of this disclosure, or a pharmaceutically acceptable salt thereof, with the rest being suitable pharmaceutical excipients.
[0068] Actual methods of preparing such dosage forms are known, or will be apparent, to those skilled in this art; for example, see Remington's Pharmaceutical Sciences, 18th Ed., (Mack Publishing Company, Easton, Pa., 1990). The composition to be administered will, in any event, contain a therapeutically effective amount of a compound of this disclosure, or a pharmaceutically acceptable salt thereof, for treatment of a disease-state in accordance with the teachings of this disclosure.
[0069] The compounds of this disclosure, or their pharmaceutically acceptable salts, are administered in a therapeutically effective amount which will vary depending upon a variety of factors including the activity of the specific compound employed, the metabolic stability and length of action of the compound, the age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, the severity of the particular disease-states, and the host undergoing therapy. The compounds of this disclosure can be administered to a patient at dosage levels in the range of about 0.1 to about 1,000 mg per day. For a normal human adult having a body weight of about 70 kilograms, a dosage in the range of about 0.01 to about 100 mg per kilogram of body weight per day is an example. The specific dosage used, however, can vary. For example, the dosage can depend on a number of factors including the requirements of the patient, the severity of the condition being treated, and the pharmacological activity of the compound being used. The determination of optimum dosages for a particular patient is well known to one of ordinary skill in the art. [0070] The compositions will include a conventional pharmaceutical carrier or excipient and a compound of this disclosure as the/an active agent, and, in addition, can include other medicinal agents and pharmaceutical agents. Compositions of the compounds in this disclosure can be used in combination with anticancer and/or other agents that are generally administered to a patient being treated for cancer, e.g. surgery, radiation and/or chemotherapeutic agent(s). Chemotherapeutic agents that can be useful for administration in combination with compounds of Formula I in treating cancer include alkylating agents, platinum containing agents.
[0071] If formulated as a fixed dose, such combination products employ the compounds of this disclosure within the dosage range described above and the other pharmaceutically active agent(s) within its approved dosage range. Compounds of this disclosure can alternatively be used sequentially with known pharmaceutically acceptable agent(s) when a combination formulation is inappropriate.
Definitions
[0072] Terms used herein may be preceded and/or followed by a single dash, "-", or a double dash, "=", to indicate the bond order of the bond between the named substituent and its parent moiety; a single dash indicates a single bond and a double dash indicates a double bond. In the absence of a single or double dash it is understood that a single bond is formed between the substituent and its parent moiety; further, substituents are intended to be read "left to right" unless a dash indicates otherwise. For example, Ci-Cβalkoxycarbonyloxy and -OC(O)OC i-Cβalkyl indicate the same functionality. [0073] If a group "R" is depicted as "floating" on a ring system, as for example in the
formula:
Figure imgf000025_0001
unless otherwise defined, a substituent "R" can reside on any atom of the ring system, assuming replacement of a depicted, implied, or expressly defined hydrogen from one of the ring atoms, so long as a stable structure is formed. [0074] If a group "R" is depicted as floating on a heterocyclic ring system, as for example
in the formulae:
Figure imgf000025_0003
, or
Figure imgf000025_0002
, or then, unless otherwise defined, a substituent "R" can reside on any atom of the fused ring system, assuming replacement of a depicted hydrogen (for example the -NH- in the formula above), implied hydrogen (for example as in the formula above, where the hydrogens are not shown but understood to be present), or expressly defined hydrogen (for example where in the formula above, "X" equals =CH-) from one of the ring atoms, so long as a stable structure is formed. In the example depicted, the "R" group can reside on either the 5-membered or the 6-membered ring of the fused ring system. In the formula depicted above, when y is 2 for example, then the two "R's" can reside on any two atoms of the ring system, again assuming each replaces a depicted, implied, or expressly defined hydrogen on the ring [0075] When a group "R" is depicted as existing on a ring system containing saturated
carbons, as for example in the formula:
Figure imgf000026_0001
where, in this example, "y" can be more than one, assuming each replaces a currently depicted, implied, or expressly defined hydrogen on the ring; then, unless otherwise defined, where the resulting structure is stable, two "R's" can reside on the same carbon. A simple example is when R is a methyl group; there can exist a geminal dimethyl on a carbon of the depicted ring (an "annular" carbon).
[0076] Certain variables used herein are indicated as divalent linking moieties, for example, L is a divalent moiety linking A to the parent structure. For such divalent variables, particular members defining L may be written, for example, in the form -X-Y- or -Y-X-.
Such members are intended to replace the term being defined, in this case L, as written, such that the leading (left) bond is attached to the parent moiety and the ending (right) bond is attached to A. For example, if L is of the form -X-Y-, the X is bonded to the parent moiety and Y is bonded to A.
[0077] "Administration" and variants thereof (e.g., "administering" a compound) in reference to a compound of the invention means introducing the compound of the invention into the system of the animal in need of treatment. When a compound of the invention or prodrug thereof is provided in combination with one or more other active agents (e.g., surgery, radiation, chemotherapy, and the like), "administration" and its variants are each understood to include concurrent and sequential introduction of the compound or prodrug thereof and other agents.
[0078] "Alkoxy" means the group -OR0 wherein R0 is alkyl, as defined herein.
Representative examples include methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy,
4-methylhexyloxy, 4-methylheptyloxy, 4,7-dimethyloctyloxy, and the like.
[0079] "Alkyl" means a linear or branched hydrocarbon group having from 1 to 10 carbon atoms unless otherwise defined. Representative examples for alkyl groups include methyl, ethyl, propyl, butyl, pentyl, hexyl, 4-methylhexyl, 4-methylheptyl, 4,7-dimethyloctyl, and the like. (Ci_4)alkyl means a group selected from methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl and tert-butyi.
[0080] "Alkylamino" means an alkyl group, as defined herein, appended to a parent moiety through an -NH- group (i.e., substituents of the form -N(H)R0, where R0 is an alkyl group). Examples of alkylamino groups include, but are not limited to, methylamino, ethylamino, isopropylamino, hexylamino, and the like.
[0081] "Aryl" means a monovalent, monocyclic, or polycyclic radical having 6 to 14 ring carbon atoms. The monocyclic aryl radical is aromatic and whereas the polycyclic aryl radical may be partially saturated, at least one of the rings comprising a polycyclic radical is aromatic. The polycyclic aryl radical includes fused, bridged, and spiro ring systems. Any 1 or 2 ring carbon atoms of any nonaromatic rings comprising a polycyclic aryl radical may be replaced by a -C(O)-, -C(S)-, or -C(=NH)- group. Unless stated otherwise, the valency may be located on any atom of any ring of the aryl group, valency rules permitting. Representative examples include phenyl, naphthyl, indanyl, benzodioxolyl, benzodioxanyl, benzopyranyl, 2,3-dihydro-lH-indolyl (including, for example, 2,3-dihydro-lH-indol-2-yl, 2,3-dihydro-lH-indol-5-yl, and the like), isoindolinyl, tetrahydroisoquinolinyl (including, for example, tetrahydroisoquinolin-4-yl, tetrahydroisoquinolin-6-yl, and the like), phthalimidyl, and the like.
[0082] "Aryl(Ci-C4)alkyl" means an aryl moiety attached to a parent structure via a one- to-four carbon alkylene group. Examples include benzyl, phenethyl, and the like. [0083] "Bridged-bicyclic heterocyclyl ring" refers to a heterocyclyl ring system in which a valence bond, an atom, or a chain of atoms connects two or more non-adjacent positions of a heterocyclyl ring system. Such a system may contain isolated or conjugated unsaturation, but not aromatic or heteroaromatic rings in its core structure (but may have aromatic
substitution thereon), such as
Figure imgf000027_0001
wherein x is an integer of 1 to 3; and y is an integer of 1 to 3. Examples of 5 - 10 membered bridged- bicyclic heterocylyl rings include 8-azabicyclo[3.2.1]oct-3-yl, 8-azabicyclo[3.2.1]oct-8-yl, 1- azabicyclo[2.2.2]oct-3-yl, l-azabicyclo[2.2.2]oct-4-yl, 3,8-diazabicyclo[3.2.1]oct-3-yl, and 2,5-diazabicyclo[2.2.1]hept-2-yl, and the like.
[0084] "Cycloalkyl" means a monocyclic or polycyclic hydrocarbon radical having 3 to 13 carbon ring atoms. The cycloalkyl radical may be saturated or partially unsaturated, but cannot contain an aromatic ring. The cycloalkyl radical includes fused bicyclic, bridged bicyclic and spiro ring systems. Examples of such radicals include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[2.2.1]heptanyl, bicyclo[2.2.1]heptenyl, and bicyclo[2.2.2]octanyl. [0085] "Fused-bicyclic" refers to a bicyclic ring system where two rings have more than one shared atom in their ring structures, where each bond is part of a ring, where each ring is ortho-fused to the other ring; and where no bond is common to more than two rings. A spiro ring system is not a fused-bicyclic by this definition, but fused bicyclic ring systems of the invention may themselves have spiro rings attached thereto via a single ring atom of the fused-polycyclic. In some examples, as appreciated by one of ordinary skill in the art, two adjacent groups on an aromatic system may be fused together to form a ring structure. The fused ring structure may contain heteroatoms.
[0086] "Halo" and "halogen" mean a fluoro, chloro, bromo or iodo group. [0087] "Haloalkyl" means an alkyl radical, as defined herein, substituted with one or more halo atoms. For example, halo-substituted (Ci_4)alkyl includes trifluoromethyl, 2,2-dichloroethyl, 2,2,2-trifluoroethyl, perchloroethyl, 2-bromopropyl, and the like. Haloalkyl includes, for example, halomethyl which means a methyl group substituted by one, two, or three halogen atoms, where each halogen is independently selected. Halomethyl includes, for example, trifluoromethyl, difluoromethyl, fluoromethyl, chloromethyl, chlorofluoromethyl, and the like.
[0088] "Heteroaryl" means a monovalent monocyclic or polycyclic radical having 5 to 14 ring atoms of which one or more of the ring atoms, for example one, two, three, or four ring atoms, are heteroatoms independently selected from oxygen, sulfur, and nitrogen, and the remaining ring atoms are carbon atoms. The monocyclic heteroaryl radical is aromatic and whereas the polycyclic heteroaryl radical may be partially saturated, at least one of the rings comprising a polycyclic radical is aromatic, where the aromatic ring contains at least one heteroatom. The polycyclic heteoaryl radical includes fused, bridged and spiro ring systems. Unless stated otherwise, any 1 or 2 ring carbon atoms of any nonaromatic rings comprising a polycyclic heteroaryl radical may be replaced by a -C(O)-, -C(S)-, or -C(=NH)- group. Unless stated otherwise, the valency may be located on any atom of any ring of the heteroaryl group, valency rules permitting. More specifically, the term heteroaryl includes, but is not limited to, 1,2,4-triazolyl, 1,3,5-triazolyl, pyridinyl, pyrrolyl, imidazolyl, thienyl, furanyl, indolyl, isoindolyl, benzimidazolyl, benzo furanyl, cinnolinyl, indolizinyl, naphthyridin-3-yl, phthalazin-3-yl, phthalazin-4-yl, pteridinyl, purinyl, quinazolinyl, quinoxalinyl, tetrazoyl, pyrazolyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, isooxazolyl, oxadiazolyl, benzoxazolyl, quinolinyl, isoquinolinyl, pyrrolo[3,2-c]pyridinyl (including, for example, pyrrolo[3,2-c]pyridin-2-yl, pyrrolo[3,2-c]pyridin-7-yl, and the like), thiazolyl, isothiazolyl, thiadiazolyl, benzothiazolyl, benzothienyl, and the TV-oxide derivatives thereof. [0089] "Heterocyclyl" means a monovalent, monocyclic or polycyclic hydrocarbon radical having 3 to 13 ring atoms of which one or more of the ring atoms, for example 1, 2, 3 or 4 ring atoms, are heteroatoms independently selected from oxygen, sulfur, and nitrogen, and the remaining ring atoms are carbon. The heterocyclyl group may be saturated or partially unsaturated, but cannot contain an aromatic ring. The heterocyclyl radical includes fused-bicyclic, bridged-bicyclic, and spiro ring systems. Unless otherwise stated, the heterocyclyl may be attached at any annular or bridge carbon or heteroatom which results in the creation of a stable structure. More specifically the term heterocyclyl includes, but is not limited to, azetidinyl, pyrrolidinyl, 2,5-dihydro-lH-pyrrolyl, piperidinyl, morpholinyl, piperazinyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, perhydroazepinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, dihydropyridinyl, tetrahydropyridinyl, oxazolinyl, oxazolidinyl, isoxazolidinyl, thiazolinyl, thiazolidinyl, quinuclidinyl, isothiazolidinyl, octahydroindolyl, octahydroisoindolyl, decahydroisoquinolyl, tetrahydrofuryl, l,4-dioxa-8-azaspiro[4.5]decan-8-yl, 2,3,3a,7a-tetrahydro-lH-isoindolyl, and tetrahydropyranyl, and the TV-oxide derivatives thereof.
[0090] The term "optionally substituted" means the substitution may or may not occur and includes instances where said substitution occurs and instances in which it does not. One of ordinary skill in the art would understand that with respect to any molecule described as containing one or more substituents, only sterically practical and/or synthetically feasible compounds are meant to be included.
[0091] "Spiro ring" refers to a ring originating from a particular annular carbon of another ring. For example, as depicted below:
Figure imgf000029_0001
a ring atom of a saturated bridged ring system (rings C and C), but not a bridgehead atom, can be a shared atom between the saturated bridged ring system and a spiro ring (ring D) attached thereto. A representative example of a spiro ring system is 2,3-dioxa-8-azaspiro[4.5]decan-8-yl.
[0092] "Stereoisomer" means any of two or more isomers containing the same atoms bonded to each other in an identical manner but differing from each other in the spatial arrangement of the atoms or groups of atoms. "Stereoisomer" includes, for example, an enantiomer, a geometric isomer, a diastereomer, a rotamer, cis-isomer, trans-isomer, and conformational isomer. The names and illustration used in this application to describe compounds of the invention, unless indicated otherwise, are meant to encompass all possible stereoisomers and any mixture, racemic or otherwise, thereof.
[0093] The present invention also includes N-oxidc derivatives of the compounds of the invention. JV-oxide derivatives mean derivatives of compounds of the invention in which nitrogens are in an oxidized state (i.e., N→O), e.g., pyridine iV-oxide, and which possess the desired pharmacological activity.
[0094] "Patient" and "subject" for the purposes of the present invention includes humans and other animals, particularly mammals, and other organisms. Thus the methods are applicable to both human therapy and veterinary applications. In another embodiment the patient is a mammal, and in another embodiment the patient is human.
[0095] A "pharmaceutically acceptable salt" of a compound means a salt that is pharmaceutically acceptable and that possesses the desired pharmacological activity of the parent compound. It is understood that the pharmaceutically acceptable salts are non-toxic. Additional information on suitable pharmaceutically acceptable salts can be found in Remington 's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, PA, 1985, which is incorporated herein by reference or S. M. Berge, et al., "Pharmaceutical Salts," J. Pharm. ScL, 1977;66:1-19 both of which are incorporated herein by reference. It is also understood that the compound can have one or more pharmaceutically acceptable salts associated with it.
[0096] Examples of pharmaceutically acceptable acid addition salts include those formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; as well as organic acids such as acetic acid, trifluoroacetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, 3-(4-hydroxybenzoyl)benzoic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1 ,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, glucoheptonic acid, 4,4'-methylenebis-(3-hydroxy-2-ene-l-carboxylic acid), 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, p-toluenesulfonic acid, salicylic acid and the like. [0097] Examples of a pharmaceutically acceptable base addition salts include those formed when an acidic proton present in the parent compound is replaced by a metal ion, such as sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts and the like. Preferable salts are the ammonium, potassium, sodium, calcium and magnesium salts. Salts derived from pharmaceutically acceptable organic non-toxic bases include, but are not limited to, salts of primary, secondary and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins. Examples of organic bases include isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine, N-ethylpiperidine, tromethamine, JV-methylglucamine, polyamine resins, and the like. Exemplary organic bases are isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline, and caffeine.
[0098] "Effective amount" is an amount of a compound of the invention, that when administered to a patient, effectively treats the disease. The amount of a compound of the invention which constitutes an "effective amount" will vary depending upon a sundry of factors including the activity, metabolic stability, rate of excretion and duration of action of the compound, the age, weight, general health, sex, diet and species of the patient, the mode and time of administration of the compound, the concurrent administration of adjuvants or additional therapies and the severity of the disease for which the therapeutic effect is sought. The effective amount for a given circumstance can be determined without undue experimentation.
[0099] "Treating" or "treatment" of a disease, disorder, or syndrome, as used herein, includes (i) preventing the disease, disorder, or syndrome from occurring in a human, i.e., causing the clinical symptoms of the disease, disorder, or syndrome not to develop in an animal that may be exposed to or predisposed to the disease, disorder, or syndrome but does not yet experience or display symptoms of the disease, disorder, or syndrome; (ii) inhibiting the disease, disorder, or syndrome, i.e., arresting its development; and (iii) relieving the disease, disorder, or syndrome, i.e., causing regression of the disease, disorder, or syndrome. As is known in the art, adjustments for systemic versus localized delivery, the age, weight, general health, sex, diet and species of the patient, the mode and time of administration of the compound, the concurrent administration of adjuvants or additional therapeutically active ingredients and the severity of the disease for which the therapeutic effect is sought may be necessary, and will be ascertainable with routine experimentation.
Synthesis
[00100] The following abbreviations and acronyms are used herein,
BnNH2 Benzylamine
BOC t-butoxycarbonyl
BOC-anhydride di(t-butyl) dicarbonate
BzI benzyl
CHAPS 3-[(3-cholamidopropyl)dimethylammonio]-l-propanesulfonate
DCE 1,2-dichloroethane
DCM dichloromethane
DIEA diisopropyl(ethyl)amine
DMA N,N-dimethylacetamide
DMF N,N-dimethylformamide
DMSO dimethylsulfoxide
DOPC dioleoyl phosphatidylcholine
EDC 1 - [3 -(dimethylamino)propyl] -3 -ethylcarbodiimide methiodide
Et3N triethylamine
Et2O diethyl ether
EtOH ethanol
EtOAc Ethyl acetate
HATU Λ/,Λ/,Λf',Λf '-tetramethyl-0-(7-azabenzotriazol- 1 -yl)uronium hexafluorophosphate
HEPES 4-(2-hydroxyethyl)-l-piperazineethanesulfonic acid
HOBt 1-hydroxybenzotriazole
MeBnBr 3-methylbenzyl bromide
MeOH methanol
MsCl Methylsulfonyl chloride
NADH Nicotinamide adenine dinucleotide
NMM N-methylmorpholine
THF tetrahydrofuran
UDP-glucose Uridine diphosphate glucose
[00101] Compounds of the invention that are of the 3-benzyloxy propanyl amide-2-phenyloxy aryl amide class may be synthesized by the synthetic route outlined in Scheme 1. The commercially available hydroxysuccinimide ester of Boc-O-benzyl-D-Serine (Boc-D-Ser(Bzl)-OSu; Bachem, Torrance, CA) (1) is coupled with a suitably functionalized amine, wherein -N(RX)(RY) is R1, wherein one of Rx and RY is R10 and the other of Rx and Rγ is R11, or Rx and RY and the nitrogen atom to which they are attached form a moiety of formula (a),
Figure imgf000033_0001
(a) followed by the deprotection reaction carried out under acidic conditions to give the corresponding amine (3).
Scheme 1
Figure imgf000033_0002
[00102] Subsequently, 3-benzyloxy-2-aminopropanyl amide (3) is coupled with a suitably functionalized carboxylic acid, wherein X1, Q, R4, R5, m and n are as defined herein, such as, for example, 2-phenyloxy benzoic or 2-phenyloxy-nicotinic acid. The coupling reaction is typically carried out in the presence of l-[3-(Dimethylamino)propyl]-3-ethylcarbodiimide methiodide (EDC, Novabiochem) and 1-Hydroxybenzotriazole (HOBt, Novabiochem) to give 3-benzyloxy(2-phenyloxyarylamido)propanyl amide (4).
[00103] Alternatively, the synthesis can be carried out starting from a commercially available Boc-D-Serine (5) (Aldrich) or other Boc-protected amino acid, where/? is 1, 2, or 3, as shown in Scheme 2. Scheme 2
N HRXRY
Figure imgf000034_0002
Figure imgf000034_0001
(5) (6)
Figure imgf000034_0003
(7)
(8)
Figure imgf000034_0004
[00104] The Boc protected amino acid (5) is coupled with a suitably functionalized amine, wherein -N(RX)(RY) is R1, wherein one of Rx and RY is R10 and the other of Rx and RY is R11, or Rx and RY and the nitrogen atom to which they are attached form a moiety of formula (a),
Figure imgf000034_0005
The coupling reaction is typically carried out in the presence EDC and HOBt to give a 3-hydroxy propanyl amide (6). The resulting alcohol (6) may then be alkylated by treatment with sodium hydride and a suitably functionalized electrophile
Figure imgf000034_0006
(where A, RL, and q are as defined herein, and LG1 is a leaving group, such as halo), such as, for example, benzyl bromide, followed by the de-protection reaction performed under acidic conditions to provide a suitably functionalized amine (8). Subsequently, amine (8) is coupled with a suitably functionalized carboxylic acid, wherein X1, Q, R4, R5, m and n are as defined herein, such as, for example, 2-phenyloxy benzoic or 2-phenyloxy-nicotinic acid. The coupling reaction is typically carried out in the presence of EDC and HOBt to afford (9), a compound of formula (I), where E is -C(O)-, L is -[C(RL)2]q-O-(CH2)p-, A, X1, R4, R5, m and n are as defined herein, and -N(RX)(RY) is R1, wherein one of Rx and RY is R10 and the other of R and R is R , or R and R and the nitrogen atom to which they are attached form a moiety of formula (a).
[00105] Similarly, compounds of formula (I) where E is -C(O)-, A is phenyl, L is -CH2- NH-CH2-, and all other groups are as defined herein, can be synthesized using the synthetic scheme described in Example 8.
[00106] Compounds of formula (I) where L1 is a bond, such that L is alkylene, can be synthesized in a manner similar to Example 1, for example, where (R)-5-phenyl-2-(tert- butoxycarbonylamino)pentanoic acid was substituted for (R)-3-(benzyloxy)-2-(tert- butoxycarbonylamino)propanoic acid.
[00107] Compounds of the invention that are of the 3-benzyloxy-2-(2-phenyloxy-aryl- amide)propanyl amine class may be synthesized by the synthetic route outlined in Scheme 3. The commercially available Boc-O-benzyl-serinol (10) is converted to an amine derivative (12) via the preparation of a methyl sulfone derivative (11) and a subsequent treatment with a suitably functionalized amine, followed by a deprotection reaction that is carried out under acidic conditions to give the corresponding amine (12). Scheme 3.
Figure imgf000035_0001
(10) (11 ) (12) (13)
The resulting amino hydrochloride derivative is coupled with a suitably functionalized
2-phenyloxy benzoic or 2-phenyloxy-nicotinic acid. The coupling reaction is typically carried out in the presence of EDC and HOBt to afford 3-benzyloxy propanyl amino-2-phenyloxy aryl amide (13), a compound of formula (I) where E is -CH2-, A-L is benzyloxymethyl, X1, R4, R5, m and n are as defined herein, and -N(RX)(RY) is R1, wherein one of Rx and RY is R10 and the other of Rx and RY is R11, or Rx and RY and the nitrogen atom to which they are attached form a moiety of formula (a).
[00108] The invention further comprises a method of preparing a compound of formula (I), the method comprising: (i) coupling a compound of formula (14),
Figure imgf000036_0001
wherein A, L, and E are as defined herein, * indicates optional (R) or (S) chirality of the adjacent carbon atom, and -N(RX)(RY) is R1, wherein one of Rx and RY is R10 and the other of Rx and RY is R11, or Rx and RY and the nitrogen atom to which they are attached form a moiety of formula (a),
Figure imgf000036_0002
(a) wherein R20, R21, and w are as defined herein; with a compound of formula (15), wherein X1, Q, R4, R5, m and n are as defined herein, to provide a compound of formula (I); or (ii) when E is -C(O)-, coupling a compound of formula (16),
Figure imgf000036_0003
wherein A, L, X1, Q, R4, R5, m and n are as defined herein, and * indicates optional (R) or (S) chirality of the adjacent carbon atom; with a compound of formula (17) wherein -N(RX)(RY) is R1, wherein one of Rx and RY is R10 and the other of Rx and RY is R11, or Rx and RY and the nitrogen atom to which they are attached form a moiety of formula (a),
Figure imgf000036_0004
wherein R20, R21, and w are as defined herein; to provide a compound of formula (II); or a single stereoisomer or mixture of stereoisomers thereof; and optionally separating individual isomers; and optionally modifying any of the R20 and R21 groups to provide a compound of formula (I); and optionally forming a pharmaceutically acceptable salt thereof. Example 1
2-[(4-chlorophenyl)oxy]-N-[(lR)-2-(4-methylpiperazin-l-yl)-2-oxo-l-{[(phenylmethyl)oxy]m ethyl} ethyl] pyridine-3-carboxamide
Figure imgf000037_0001
[00109] Step 1: (R)-tert-butyl 3-(benzyloxy)-l-(4-methylpiperazin-l-yl)-l-oxopropan- 2-yl(methyl)carbamate: To a solution of (R)-3-(benzyloxy)-2-(tert-butoxycarbonylamino)- propanoic acid ( 2.95 g, 10 mmol) in dichloromethane (250 niL) were added N- methylpiperazine (1.11 g, 10 mmol) , 1-hydroxybenzotriazole (1.53 g, 10 mmol), diisopropylethylamine (3.4 mL, 20 mmol), and l-[3-(dimethylamino)propyl]-3- ethylcarbodiimide methiodide (2.11 g, 11 mmol). The reaction was stirred at room temperature for 8 hours. The organic solution was extracted with water (2 X 250 mL) and 2N aqueous sodium hydroxide solution (2 X 250 mL) and then dried with magnesium sulfate. The dichloromethane was removed via rotary evaporation and the residual oil treated with a solution of hexane/ethyl acetate (4:1) to yield the desired product as a white crystalline solid that was collected by filtration (1.68 g, 4.45 mmol). 1U NMR (400 MHz, CDCl3): δ 7.33 (t, IH), 7.30 (dd, 2H), 7.28 (d, 2H), 5.53 (d, IH), 4.84 (dd, IH), 4.50 (dd, 2H), 3.74 (br d, IH), 3.64 (m, IH), 3.55 (m, 4H), 2.40 (m, IH), 2.30 (m, IH), 2.22 (s, 3H), 2.15 (m, IH), 1.42 (s, 9H). MS (EI) for C20H3IN3O4 found 378.3 (MH+).
[00110] Step 2: (R)-2-amino-3-(benzyloxy)-l-(4-methylpiperazin-l-yl)propan-l-one: To a solution of (R)-tert-butyl 3-(benzyloxy)-l-(4-methylpiperazin-l-yl)-l-oxopropan-2- yl(methyl)-carbamate (1.68 g, 4.45 mmol) in methanol (20 mL) was added 4N solution of hydrochloric acid in dioxane (4.4 mL, 17.6 mmol). The solution was heated at 55 0C for three hours then cooled to room temperature. LCMS analysis indicated complete Boc- deprotection of the starting material. The solvent was removed by rotary evaporation. The residual oil was stirred with THF for several minutes after which time the solvent was again removed by rotary evaporation. The material was used directly in the next step without further purification as the presumed dihydrochloride salt.
[00111] Step 3: 2-[(4-chlorophenyl)oxy]-N-[(lR)-2-(4-methylpiperazin-l-yl)-2-oxo-l- { [(phenylmethyl)oxy] methyl} ethyl] pyridine-3-carboxamide: The (R)-2-amino-3 - (benzyloxy)-l-(4-methylpiperazin-l-yl)propan-l-one from step 2 (4.44 mmol assumed) was dissolved into dry acetonitrile (50 mL). To the organic solution was added diisopropylethylamine (3.8 mL, 22 mmol), 2-(4-chlorophenoxy)nicotinic acid (1.11 g, 4.44 mmol) and HATU (2.09 g 4.44 mol). The solution was stirred for six hours after which time the solvent was removed by rotary evaporation. The residue was dissolved in methylene chloride and extracted twice with a 2N solution of aqueous sodium hydroxide and twice with water. The organic solution was then dried with magnesium sulfate, filtered and concentrated. The product was then purified by preparatory HPLC (reverse-phase, acetonitrile/aqueous 10 mM ammonium acetate buffer, pH =4) to give 243 mg of the title compound as the monoacetate salt. 1H NMR (400 MHz, DMSO-J6): δ 8.90 (d, IH), 8.23 (AB, IH), 8.22(AB, IH), 7.50 (m, 3H), 7.25 (m, 5 H), 5.22 (dd, 1 H), 4.48 (dd, 2H), 3.68 (m, 2H), 3.50 (br s, 4H), 2.36 (br s, 4H), 2.21 (s, 3H). MS (EI) for C27H29ClN4O4 found 509.2 (MH+).
[00112] The following compounds were made in a manner analogous to Example 1: [00113] N-[(lR)-2-(4-methylpiperazin-l-yl)-2-oxo-l-
{ [(phenylmethyl)oxy] methyl} ethyl] -2- { [3-(trifluor omethyl)phenyl] oxy}pyridine-3- carboxamide: N-[( 1 R)-2-(4-methylpiperazin- 1 -yl)-2-oxo- 1 -
{[(phenylmethyl)oxy]methyl}ethyl]-2-{[3-(trifluoromethyl)-phenyl]oxy}pyridine-3- carboxamide was synthesized in a manner similar to Example 1 wherein 2-(3- trifluoromethylphenoxy)nicotinic acid was substituted for 2-(4-chlorophenoxy)nicotinic acid. 1H NMR (400 MHz, DMSO-J6): δ 8.91 (m, IH), 8.23 (m, 2H), 7.66 (m, 3H), 7.29 (m, 7H), 5.23 (m, IH), 4.50 (m, 2H), 3.73 (m, 2H), 3.50 (m, 4H), 2.25 (m, 4H), 2.12 (s, 3H). MS (EI) for C28H29F3N4O4 found 543.55 (MH+).
[00114] 2-[(4-chloro-2-methylphenyl)oxy]-N-[(lR)-2-(4-methylpiperazin-l-yl)-2-oxo- l-{[(phenylmethyl)oxy]methyl}ethyl]pyridine-3-carboxamide: 2-[(4-chloro-2- methylphenyl)oxy]-N- [( 1 R)-2-(4-methylpiperazin- 1 -yl)-2-oxo- 1 - { [(phenylmethyl)oxy] - methyl} ethyl]pyridine-3-carboxamide was synthesized in a manner similar to Example 1 wherein 2-(4-chloro-2-methylphenoxy)nicotinic acid was substituted for 2-(4- chlorophenoxy)nicotinic acid. 1H NMR (400 MHz, DMSO-J6): δ 8.91 (d, IH), 8.29 (dd, IH), 8.21 (d, IH), 7.43 (s, IH), 7.33 (dd, IH), 7.25 (m, 6H), 7.18 (d, IH), 5.23 (m, IH), 4.48 (m, 2H), 3.70 (m, 2H), 3.47 (m, 4H), 2.22 (m, 4H), 2.12 (s, 3H), 2.08 (s, 3H). MS (EI) for C28H3IClN4O4 found 524.04 (MH+).
[00115] 2-[(4-chlorophenyl)oxy]-N-[(lR)-2-(4-methyl-l,4-diazepan-l-yl)-2-oxo-l- {[(phenylmethyl)oxy]methyl}ethyl]pyridine-3-carboxamide: 2-[(4-chlorophenyl)oxy]-N- [(I R)-2-(4-methyl- 1 ,4-diazepan- 1 -yl)-2-oxo- 1 - { [(phenylmethy l)oxy] -methyl} ethyljpyridine- 3-carboxamide was synthesized in a manner similar to Example 1 wherein N-methyl homo piperazine was substituted for N-methyl piperazine. 1H NMR (400 MHz, DMSO-J6): δ 8.83 (d, IH), 8.22 (m, 3H), 7.49 (d, 2H), 7.25 (m, 7H), 5.20 (m, IH), 4.48 (s, 2H), 3.74-3.39 (m, 6H), 2.56 (m, 2H), 2.43 (m, 2H), 2.21 (s, 3H), 1.82 (m, IH), 1.72 (m, IH). MS (EI) for C28H3IClN4O4 found 524.0 (MH+).
[00116] 2-[(4-methylphenyl)oxy]-N-[(lR)-2-(4-methylpiperazin-l-yl)-2-oxo-l- {[(phenylmethyl)oxy]methyl}ethyl]benzamide: 2-[(4-methylphenyl)oxy]-N-[(lR)-2-(4- methylpiperazin- 1 -yl)-2-oxo- 1 - { [(phenylmethyl)oxy]methyl} ethyljbenzamide was synthesized in a manner similar to Example 1 wherein 2-(p-tolyloxy)benzoic acid bromide was substituted for 2-(4-methylphenoxy)nicotinic acid. 1H NMR (400 MHz, DMSO-J6): δ 7.95 (d, IH), 7.43 (m, 2H), 7.30-7.10 (m, 7H), 6.95 (m, 2H), 6.85 (d, IH), 5.28 (t, IH), 4.45 (dd, 2H), 3.75-3.48 (m, 6H), 2.45-2.24 (m, 7H), 2.20 (s, 3H). MS (EI) for C29H33N3O4 found 488.6 (MH+).
[00117] 2- [(4-chlor ophenyl)oxy] -N- [(I S)-2-(4-methylpiper azin- l-yl)-2-oxo- 1- {[(phenylmethyl)oxy]methyl}ethyl]pyridine-3-carboxamide: The title compound was synthesized in a manner similar to Example 1 wherein (R)-tert-butyl 3-(benzyloxy)-l-(4- methylpiperazin-l-yl)-l-oxopropan-2-yl(methyl)carbamate was substituted for (S)-tert-butyl 3-(benzyloxy)-l-(4-methylpiperazin-l-yl)-l-oxopropan-2-yl(methyl)carbamate. MS (EI) for C27H29ClN4O4 found 509 (MH+).
[00118] 2-[(2-chloro-4-methylphenyl)oxy]-N-[(lR)-2-(4-methylpiperazin-l-yl)-2-oxo- l-{[(phenylmethyl)oxy]methyl}ethyl]pyridine-3-carboxamide: 2-[(2-chloro-4- methylphenyl)oxy]-N- [( 1 R)-2-(4-methylpiperazin- 1 -yl)-2-oxo- 1 -
{[(phenylmethyl)oxy]methyl}-ethyl]pyridine-3-carboxamide was synthesized in a manner similar to Example 1 wherein 2-(2-chloro-4-methylphenoxy)nicotinic acid was substituted for 2-(4-chlorophenoxy)nicotinic acid. 1H NMR (400 MHz, DMSO-J6): δ 8.80 (d, IH), 8.26 (dd, IH), 8.18 (dd, IH), 7.40 (s, IH), 7.24 (m, 8H), 5.21 (t, IH), 4.47 (dd, 2H), 3.67 (m, 2H), 3.44 (m, 4H), 2.33 (s, 3H), 2.20 (m, 4H), 2.09 (s, 3H). MS (EI) for C28H3iClN4O4 found 524 (MH+). [00119] 2-[(4-methylphenyl)oxy]-N-[(lS)-2-(4-methylpiperazin-l-yl)-2-oxo-l- {[(phenylmethyl)oxy]methyl}ethyl]pyridine-3-carboxamide: 2-[(4-methylphenyl)oxy]-N- [(I S)-2-(4-methylpiperazin- 1 -yl)-2-oxo- 1 - {[(phenylmethyl)oxy] -methyl} ethyl]pyridine-3- carboxamide was synthesized in a manner similar to Example 1 wherein 2-(p- tolyloxy)nicotinic acid was substituted for 2-(4-chlorophenoxy)nicotinic acid. 1H NMR (400 MHz, DMSO-J6): δ 8.92 (d, IH), 8.25 (dd, IH), 8.21 (dd, IH), 7.25 (m, 8H), 7.05 (d, 2H), 5.22 (t, IH), 4.49 (dd, 2H), 3.71 (m, 2H), 3.48 (m, 4H), 2.33 (s, 3H), 2.23 (m, 4H), 2.13 (s, 3H). MS (EI) for C28H32N4O4 found 490 (MH+). [00120] N-[(lS)-2-(4-methylpiperazin-l-yl)-2-oxo-l-
{ [(phenylmethyl)oxy] methyl} ethyl] -2- { [3-(trifluor omethyl)phenyl] oxy}pyridine-3- carboxamide: N- [( 1 S)-2-(4-methylpiperazin- 1 -yl)-2-oxo- 1 -
{[(phenylmethyl)oxy]methyl}ethyl]-2-{[3-(trifluoromethyl)-phenyl]oxy}pyridine-3- carboxamide was synthesized in a manner similar to Example 1 wherein 2-(3- (trifluoromethyl)phenoxy)nicotinic acid was substituted for 2-(4-chlorophenoxy)nicotinic acid. 1H NMR (400 MHz, DMSO-J6): δ 8.91 (d, IH), 8.24 (dd, IH), 8.20 (dd, IH), 7.67 (m, 3H), 7.55 (d, IH), 7.28 (m, 5H), 5.22 (t, IH), 4.49 (dd, 2H), 3.70 (m, 2H), 3.50 (m, 4H), 2.25 (m, 4H), 2.10 (s, 3H). MS (EI) for C28H29F3N4O4 found 544 (MH+). [00121] 2- [(4-chlorophenyl)oxy] -N- {(1 R)- 1- [(4-methylpiperazin- l-yl)carbonyl] -3- [(phenylmethyl)oxy] propyl}pyridine-3-carboxamide : 2- [(4-chlorophenyl)oxy] -N- {( 1 R)- 1 - [(4-methylpiperazin- 1 -yl)carbonyl] -3 - [(phenylmethyl)oxy]-propyl} pyridine-3 -carboxamide was synthesized in a manner similar to Example 1 wherein (R)-3-(benzyloxy)-2-(tert- butoxycarbonylamino)propanoic acid was substituted for (R)-2-(tert-butoxycarbonylamino)- 3-phenethoxypropanoic acid. 1H NMR (400 MHz, DMSO-J6): δ 8.82(d, IH), 8.22 (dd, IH), 8.12 (dd, IH), 7.47 (d, 2H), 7.24 (m, 8H), 5.12 (t, IH), 4.38 (dd, 2H), 3.60 (m, 2H), 3.47 (m, 4H), 2.30 (m, 4H), 2.18 (s, 3H), 2.01 (m, IH), 1.87(m, IH). MS (EI) for C28H3iClN4O4 found 524 (MH+).
[00122] 2- [(4-chlorophenyl)oxy] -N- [(lR)-2- [(l-methylpiperidin-4-yl)amino] -2-oxo-l- {[(phenylmethyl)oxy]methyl}ethyl]pyridine-3-carboxamide: 2-[(4-chlorophenyl)oxy]-N- [(lR)-2-[(l-methylpiperidin-4-yl)amino]-2-oxo-l-{[(phenylmethyl)oxy]- methyl}ethyl]pyridine-3-carboxamide was synthesized in a manner similar to Example 1 wherein l-methylpiperidin-4-amine was substituted for 4-methylpiperazine. 1H NMR (400 MHz, DMSO-J6): δ 8.70 (d, IH), 8.25 (m, 2H), 8.16 (m, IH), 8.11 (m, IH), 7.48 (m, 2H), 7.26 (m, 7H), 4.70 (m, IH), 4.47 (m, 2H), 3.75 (m, 2H), 3.66 (m, IH), 2.85 (m, 2H), 2.30 (s, 3H), 2.26 (m, 2H), 1.72 (m, 2H), 1.45 (m, 2H). MS (EI) for C28H3IClN4O4 found 523.19 (MH+).
[00123] 2-[(4-chlorophenyl)oxy]-N-[(lR)-2-{4-[3-(dimethylamino)propyl]piperazin-l- yl}-2-oxo-l-{[(phenylmethyl)oxy]methyl}ethyl]pyridine-3-carboxamide: 2-[(4- chlorophenyl)oxy]-N-[( 1 R)-2- {4-[3-(dimethylamino)propyl]piperazin- 1 -yl} -2-oxo- 1 - {[(phenylmethyl)oxy]methyl}ethyl]pyridine-3-carboxamide was synthesized in a manner similar to Example 1 wherein 4-(3-dimethylaminopropyl)piperazine was substituted for 4- methylpiperazine. 1H NMR (400 MHz, DMSO-J6): δ 8.89 (m, IH), 8.25 (m, 2H), 7.48 (m, 2H), 7.26 (m, 8H), 5.21 (m, IH), 4.49 (m, 2H), 3.69 (m, 2H), 3.42 (m, 4H), 2.19 (m, 8H), 2.17 (s, 6H), 1.52 (m, 2H). MS (EI) for C3IH38ClN5O4 found 580.19 (MH+). [00124] 2-[(4-chlorophenyl)oxy]-N-{(lR)-l-[(4-methylpiperazin-l-yl)carbonyl]-4- phenylbutyl}pyridine-3-carboxamide: 2-[(4-chlorophenyl)oxy]-N-{(lR)-l-[(4- methylpiperazin-l-yl)carbonyl]-4-phenylbutyl}pyridine-3-carboxamide was synthesized in a manner similar to Example 1 wherein (R)-5-phenyl-2-(tert-butoxycarbonylamino)pentanoic acid was substituted for (R)-3-(benzyloxy)-2-(tert-butoxycarbonylamino)propanoic acid. 1H NMR (400 MHz, DMSO-J6): δ 8.79 (d, IH), 8.22 (d, IH), 8.13 (d, IH), 7.48 (m, 2H), 7.26 (m, 7H), 7.07 (d, 2H), 4.99 (q, IH), 3.48 (m, 4H), 2.61 (m, 2H), 2.22 (m, 4H), 2.14 (s, 3H), 1.58 (m, 4H). MS (EI) for C28H3iClN4O3 found 507.15 (MH+).
[00125] 2- [(2,4-dichlor ophenyl)oxy] -N- [(I R)-2-(3-methylhexahydropyrrolo [ 1 ,2-a] - pyrazin-2(lH)-yl)-2-oxo-l-{[(phenylmethyl)oxy]methyl}ethyl]pyridine-3-carboxamide: 2-[(2,4-dichlorophenyl)oxy]-N-[(lR)-2-(3-methylhexahydropyrrolo[l,2-a]pyrazin-2(lH)-yl)- 2-oxo-l-{[(phenylmethyl)oxy]methyl}ethyl]pyridine-3-carboxamide was synthesized in a manner similar to Example 1 wherein 3-methyloctahydropyrrolo[l,2-a]pyrazine was substituted for N-methylpiperazine. 1H NMR (400 MHz, DMSO-J6): δ 8.76 (m, IH), 8.21 (m, 2H), 7.80 (m, IH), 7.49 (m, 2H), 7.28 (m, 6H), 5.18 (m, IH), 4.50 (m, 3H), 3.70 (m, 2H), 2.89 (m, 2H), 2.78 (dd, IH), 1.67 (m, 7H), 1.3 (dd, IH), 1.11 (d, IH), 1.05 (d, 2H). MS (EI) for C30H32Cl2N4O4 found 584.6 (MH+).
[00126] 2-[(4-chlorophenyl)oxy]-N-[(lR)-2-(4-cyclopropylpiperazin-l-yl)-2-oxo-l- {[(phenylmethyl)oxy]methyl}ethyl]pyridine-3-carboxamide: 2-[(4-chlorophenyl)oxy]-N- [(I R)-2-(4-cyclopropylpiperazin- 1 -yl)-2-oxo- 1 - { [(phenylmethyl)oxy]methyl} ethyljpyridine- 3-carboxamide was synthesized in a manner similar to Example 1 wherein 1- cyclopropylpiperazine was substituted for N-methylpiperazine. 1-Cyclopropylpiperazine was prepared according to the method of Tetrahedron Letters (1995), 36(41), 7399-7402. 1H NMR (400 MHz, DMSO-J6): δ 8.89 (d, IH), 8.22 (m, 2H), 7.49 (m, 2H), 7.25 (m, 8H), 5.20 (q, IH), 4.47 (m, 2H), 3.69 (m, 2H), 3.43 (m, 4H), 2.47 (m, 4H), 1.52 (m, IH), 0.39 (m, 2H), 0.30 (m, 2H). MS (EI) for C29H3IClN4O4 found 535.22 (MH+).
[00127] 2-[(4-chlorophenyl)oxy]-N-[(lS)-2-(4-methyl-l,4-diazepan-l-yl)-2-oxo-l- {[(phenylmethyl)oxy]methyl}ethyl]pyridine-3-carboxamide: 2-[(4-chlorophenyl)oxy]-N- [(I S)-2-(4-methyl- 1 ,4-diazepan- 1 -yl)-2-oxo- 1 - { [(phenylmethyl)oxy]methyl} ethyljpyridine- 3-carboxamide was synthesized in a manner similar to Example 1 wherein N- methylhomopiperazine was substituted for N-methylpiperazine. 1H NMR (400 MHz, DMSO-J6): δ 8.55 (dd, IH), 8.21 (m, 2H), 7.48 (m, 2H), 7.26 (m, 7H), 5.20 (m, IH), 4.49 (m, 2H), 3.71 (m, 3H), 3.50 (m, 3H), 2.56 (m, 2H), 2.40 (m, 2H), 1.91 (s, 3H), 1.78 (m, 2H). MS (EI) for C28H3IClN4O4 found 584.55 (MH+).
[00128] 2-{[2-chloro-4-(trifluoromethyl)phenyl]oxy}-N-[(lR)-2-[3-(dimethylamino)- azetidin-l-yl]-2-oxo-l-{[(phenylmethyl)oxy]methyl}ethyl]pyridine-3-carboxamide: 2- { [2-chloro-4-(trifluoromethyl)phenyl]oxy } -N- [( 1 R)-2- [3 -(dimethylamino)azetidin- 1 -yl]-2- oxo-l-{[(phenylmethyl)oxy]methyl}ethyl]pyridine-3-carboxamide was synthesized in a manner similar to Example 1 wherein N,N-dimethylazetidin-3 -amine (Small Molecules Inc) was substituted for N-methylpiperazine, and 2-(2-chloro-4-
(trifluoromethyl)phenoxy)nicotinic acid (Example 3) was substituted for 2-(4-chloro- phenoxy)nicotinic acid. 1H NMR (400 MHz, CDCl3): δ 8.57 (dt, IH), 8.50 (t, IH), 8.16 (dd, IH), 8.73 (s, IH), 7.59 (dd, IH), 7.37 (d, IH), 7.25 (m, 3H), 7.18 (dd, 2H), 4.95 (m, IH), 4.14-4.34 (dt, IH), 4.11 (m, IH), 4.06 (m, IH), 3.86 (m, 2H), 3.71 (m, IH), 3.14-3.09 (m, IH), 1.78 (s, 6H). MS (EI) for C28H28ClF3N4O4 found 578.0 (MH+). [00129] 2-[(2,4-dichlorophenyl)oxy]-N-[(lR)-2-(5,6-dihydro[l,2,4]triazolo[4,3- a]pyrazin-7(8H)-yl)-2-oxo-l-{[(phenylmethyl)oxy]methyl}ethyl]pyridine-3- carboxamide: 2-[(2,4-dichlorophenyl)oxy]-N-[(lR)-2-(5,6-dihydro[l,2,4]triazolo[4,3- a]pyrazin-7(8H)-yl)-2-oxo-l-{[(phenylmethyl)oxy]methyl}ethyl]pyridine-3-carboxamide was synthesized in a manner similar to Example 1 wherein 5,6,7,8-tetrahydro- [l,2,4]triazolo[4,3-a]pyrazine was substituted for N-methyl piperazine and 2-(2,4- dichlorophenoxy)nicotinic acid was substituted for 2-(4-chlorophenoxy)nicotinic acid. 2- (2,4-dichlorophenoxy)nicotinic acid was synthesized in a manner similar to Example 3 wherein 2,4-dichlorophenol was substituted for 2-chloro-6-methylphenol. 1H NMR (400 MHz, DMSO-J6): δ 8.78 (s, IH), 8.59 (d, IH), 8.39 (s, IH), 8.27 (m, IH), 8.15 (m, 2H), 7.71 (m, IH), 7.45 (m, 2H), 7.39 (m, IH), 7.23 (m, IH), 7.13 (m, 2H), 5.28 (t, IH), 4.43 (s, 2H), 4.38 (s, 2H), 3.93 (m, 2H), 3.74 (m, 2H), 3.68 (m, 2H). MS (EI) for C27H24Cl2N6O4, found 568.46 (MH+). [00130] 2-[(2,4-dichlorophenyl)oxy]-N-[(lR)-2-[3- (hydroxymethyl)hexahydropyrrolo[l,2-a]pyrazin-2(lH)-yl]-2-oxo-l- {[(phenylmethyl)oxy]methyl}ethyl]pyridine-3-carboxamide: 2-[(2,4-dichlorophenyl)oxy]- N-[(lR)-2-[3-(hydroxymethyl)hexahydropyrrolo[l,2-a]pyrazin-2(lH)-yl]-2-oxo-l- {[(phenylmethyl)oxy]methyl}ethyl]pyridine-3-carboxamide was synthesized in a manner similar to Example 1 wherein (octahydropyrrolo[l,2-a]pyrazin-3-yl)methanol was substituted for N-methyl piperazine and 2-(2,4-dichlorophenoxy)nicotinic acid was substituted for 2-(4-chlorophenoxy)nicotinic acid. 2-(2,4-dichlorophenoxy)nicotinic acid was synthesized in a manner similar to Example 3 wherein 2,4-dichlorophenol was substituted for 2-chloro-6-methylphenol. 1H NMR (400 MHz, DMSO-J6): δ 8.72 (s, IH), 8.24 (d, IH), 8.16 (d, IH), 7.73 (m, IH), 7.47-7.39 (m, 2H), 7.26-7.12 (m, 6H), 4.79 (t, IH), 4.44 (s, 2H), 4.03 (m, IH), 3.93 (m, IH), 3.73-3.57 (m, 6H), 2.90 (m, IH), 2.82 (m, IH), 2.58 (m, IH), 2.16 (m, 2H), 1.61-1.46 (m, 4H). MS (EI) for C30H32Cl2N4O5, found 600.50 (MH+). [00131] 2-[(2,4-dichlorophenyl)oxy]-N-[(lR)-2-(l,3-dihydro-2H-pyrrolo[3,4- c]pyridin-2-yl)-2-oxo-l-{[(phenylmethyl)oxy]methyl}ethyl]pyridine-3-carboxamide: 2- [(2,4-dichlorophenyl)oxy]-N-[(lR)-2-(l,3-dihydro-2H-pyrrolo[3,4-c]pyridin-2-yl)-2-oxo-l- {[(phenylmethyl)oxy]methyl}ethyl]pyridine-3-carboxamide was synthesized in a manner similar to Example 1 wherein 2,3-dihydro-lH-pyrrolo[3,4-c]pyridine was substituted for N- methyl piperazine and 2-(2,4-dichlorophenoxy)nicotinic acid was substituted for 2-(4- chlorophenoxy)nicotinic acid. 2-(2,4-dichlorophenoxy)nicotinic acid was synthesized in a manner similar to Example 3 wherein 2,4-dichlorophenol was substituted for 2-chloro-6- methylphenol. 1H NMR (400 MHz, DMSO-J6): δ 8.77 (d, IH), 8.51 (d, IH), 8.42 (t, IH), 8.19-8.14 (m, 2H), 7.70 (d, IH), 7.46-7.30 (m, 3H), 7.25-7.22 (m, IH), 7.14 (m, 5H), 5.10- 4.94 (m, 3H), 4.72-4.58 (m, 2H), 4.46 (s, 2H), 3.75 (d, 2H). MS (EI) for C29H24Cl2N4O4, found 564.45 (MH+).
[00132] 2-[(4-chlorophenyl)oxy]-N-[(lR)-2-(4-methylpiperidin-l-yl)-2-oxo-l- {[(phenylmethyl)oxy]methyl}ethyl]pyridine-3-carboxamide: 2-[(4-chlorophenyl)oxy]-N- [(I R)-2-(4-methylpiperidin- 1 -yl)-2-oxo- 1 - { [(phenylmethyl)oxy]methyl} ethyl]pyridine-3 - carboxamide was synthesized in a manner similar to Example 1 wherein 4-methylpiperidine was substituted for N-methyl piperazine. 1H NMR (400 MHz, DMSO-J6): δ 8.87 (m, IH), 8.22 (m, 2H), 7.49 (d, 2H), 7.25 (m, 8H), 5.20 (m, IH), 4.48 (q, 2H), 4.33 (bd, IH), 3.97 (m, IH), 3.68 (m, 2H), 2.98 (q, IH), 2.54 (m, IH), 1.54 (m, 4H), 0.84 (m, 4H). MS (EI) for C28H30ClN3O4 found 508.07 (MH+). [00133] 2-[(2,4-dichlorophenyl)oxy]-N-[(lR)-2-oxo-l-{[(phenylmethyl)oxy]methyl}-2- (l,5,6,7-tetrahydro-4H-imidazo[4,5-b]pyridin-4-yl)ethyl]pyridine-3-carboxamide: 2-
[(2,4-dichlorophenyl)oxy]-N-[(lR)-2-oxo-l-{[(phenylmethyl)oxy]methyl}-2-(l,5,6,7- tetrahydro-4H-imidazo[4,5-b]pyridin-4-yl)ethyl]pyridine-3-carboxamide was synthesized in a manner similar to Example 1 wherein 4,5,6,7-tetrahydro-lH-imidazo[4,5-b]pyridine was substituted for N-methyl piperazine and 2-(2,4-dichlorophenoxy)nicotinic acid was substituted for 2-(4-chlorophenoxy)nicotinic acid. 2-(2,4-dichlorophenoxy)nicotinic acid was synthesized in a manner similar to Example 3 wherein 2,4-dichlorophenol was substituted for 2-chloro-6-methylphenol. 1H NMR (400 MHz, DMSO-<4):δ 8.21-8.27 (m, 2H), 7.78 (d, IH), 7.46-7.54 (m, 3H), 7.28-7.31 (m, IH), 7.19 (m, 4H), 7.15-7.19 (m, IH), 5.35 (m, IH), 4.53 (d, 2H), 3.72-3.86 (m, 4H), 3.35-3.48 (m, 2H), 2.61-2.67 (m, 2H). MS (EI) for C28H25Cl2N5O4 found 567.5 (MH+).
[00134] 2-[(4-chlorophenyl) oxy]-N-[(lR)-2-[4-(2-fluoroethyl)piperazin-l-yl]-2-oxo-l- {[(phenylmethyl)oxy] methyl} ethyl] pyridine-3-carboxamide: 2-[(4-chlorophenyl) oxy]-N- [(lR)-2-[4-(2-fluoroethyl)piperazin- 1 -yl]-2-oxo- 1 -
{[(phenylmethyl)oxy]methyl}ethyl]pyridine-3-carboxamide was synthesized in a manner similar to Example 1 wherein l-(2-fluoroethyl)piperazine was substituted for N-methyl piperazine. 1H NMR (400 MHz, DMSO-<4):δ 8.87 (d, IH), 8.21 (m, 2H), 7.46 (m, 2H), 7.17- 7.28 (m, 8H), 5.19 (m, 2H), 4.51-4.56 (m, 2H), 4.41-4.46 (m, 2H), 3.66-3.71 (m, 2H), 3.19- 3.53 (m, 2H), 3.42-3.41 (m, 2H), 2.47-2.51 (m, 2H), 2.33-2.45 (m, 4H). MS (EI) for C28H30ClFN4 O4 found 542.3 (MH+).
[00135] 2-[(4-chlorophenyl)oxy]-N-[(lR)-2-(4-ethylpiperazin-l-yl)-2-oxo-l- { [(phenylmethyl)oxy] methyl} ethyl] pyridine-3-carboxamide : 2- [(4-chlorophenyl)oxy]-N- [(I R)-2-(4-ethylpiperazin- 1 -yl)-2-oxo- 1 - { [(phenylmethyl)oxy]methyl} ethyl]pyridine-3 - carboxamide was synthesized in a manner similar to Example 1 wherein N-ethyl piperazine was substituted for N-methyl piperazine. 1H NMR (400 MHz, DMSO-J6):δ 8.57 (d, IH), 8.18-8.21 (m, 2H), 7.45-7.48 (m, 2H), 7.21-7.27 (m, 8H), 5.18 (m, IH), 4.42-4.51 (m, 2H), 3.63-3.71 (m, 2H), 3.44-3.51 (m, 4H), 2.19-2.25 (m, 6H), 0.93 (t, 3H). MS (EI) for C28H3IClN4O4 found 523.9 (MH+).
[00136] 2-[(4-chlorophenyl)oxy]-N-[(lR)-2-[4-(2-hydroxyethyl)piperazin-l-yl]-2-oxo- 1- { [(phenylmethyl)oxy] methyl} ethyl] pyridine-3-carboxamide : 2- [(4-chlorophenyl)oxy] - N-[( 1 R)-2-[4-(2-hydroxyethyl)piperazin- 1 -yl]-2-oxo- 1 -
[(phenylmethyl)oxy]methyl}ethyl]pyridine-3 -carboxamide was synthesized in a manner similar to Example 1 wherein 2-(piperazin-l-yl)ethanol was substituted for N-methyl piperazine. 1H NMR (400 MHz, DMSO-J6): δ 8.86 (d, IH), 8.19-8.22 (m, 2H), 7.45-7.48 (m,
2H), 7.20-7.27 (m, 8H), 5.18 (m, IH), 4.46 (m, 2H), 3.63-3.70 (m, 2H), 3.34-3.49 (m, 6H),
2.27-2.32 (m, 6H). MS (EI) for C28H3IClN4O5 found 540.2 (MH+).
[00137] N-[(lR)-2-(l-azabicyclo[2.2.2]oct-3-ylamino)-2-oxo-l-
{ [(phenylmethyl)oxy] methyl}ethyl] -2-{ [2-chloro-4-(trifluoromethyl)phenyl] oxy}- pyridine-3-carboxamide
1H NMR (400 MHz, d6-CDCl3): δ 8.60 (m, 2H), 8.38 (s, IH), 8.18 (m, IH), 7.74 (s, IH),
7.60 (d, IH), 7.39 (m, IH), 7.22 (m, 6H), 4.83 (m, IH), 4.55 (m, 2H), 4.19 (m, IH), 4.10 (m, IH), 3.70 (m, IH), 3.41 (m, IH), 2.98 (m, 4H), 2.79 (m, IH), 2.14 (m, IH), 1.72 (m, 3H), 1.54 (m, IH). MS (EI) for C30H30ClF3N4O4, found 604.03 (MH+).
[00138] N-[(lR)-2-[(3S)-l-azabicyclo[2.2.2]oct-3-ylamino]-2-oxo-l-
{ [(phenylmethyl)oxy] methyl} ethyl] -2- { [2-chloro-4-
(trifluoromethyl)phenyl]oxy}pyridine-3-carboxamide
1H NMR (400 MHz, d6-DMSO): δ 8.64 (d, IH), 8.24 (m, 4H), 8.06 (s, IH), 7.82 (d, IH),
7.66 (d, IH), 7.32 (m, IH), 7.19 (m, 5H), 4.78 (m, IH), 4.46 (m, 2H), 3.72 (m, 4H), 3.07 (m,
IH), 2.68 (m, 4H), 1.67 (m, 2H), 1.50 (m, 2H), 1.23 (m, IH). MS (EI) for C30H30ClF3N4O4, found 604.03 (MH+).
[00139] N-[(lR)-2-[(3R)-l-azabicyclo[2.2.2]oct-3-ylamino]-2-oxo-l-
{ [(phenylmethyl)oxy] methyl} ethyl] -2- { [2-chloro-4-
(trifluoromethyl)phenyl]oxy}pyridine-3-carboxamide
1H NMR (400 MHz, d6-DMSO): δ 8.58 (d, IH), 8.18 (m, 4H), 8.00 (s, IH), 7.77 (d, IH),
7.61 (d, IH), 7.27 (m, IH), 7.15 (m, 5H), 4.73 (m, IH), 4.42 (m, 2H), 3.38 (m, 4H), 3.04 (m, IH), 2.62 (m, 3H), 2.37 (m, IH), 1.65 (m, 2H), 1.46 (m, 2H), 1.21 (m, IH). MS (EI) for C30H30ClF3N4O4, found 604.03 (MH+).
[00140] N-[(lR)-2-[(3S)-l-azabicyclo[2.2.2]oct-3-ylamino]-l-({[(3- methylphenyl)methyl] oxy} methyl)-2-oxoethyl] -2- { [2-chloro-4-
(trifluoromethyl)phenyl]oxy}-pyridine-3-carboxamide
1H NMR (400 MHz, d6-DMSO): δ 8.63 (d, IH), 8.28 (m, IH), 8.21 (m, IH), 8.15 (m, IH),
8.05 (s, IH), 7.81 (d, IH), 7.65 (d, IH), 7.32 (m, IH), 7.07 (m, IH), 6.99 (m, 3H), 4.79 (m,
IH), 4.42 (m, 2H), 3.70 (m, 4H), 3.04 (m, IH), 2.62 (m, 4H), 2.18 (s, 3H), 1.64 (m, 2H), 1.50
(m, 2H), 1.19 (m, IH). MS (EI) for C31H32ClF3N4O4, found 618.06 (MH+). Example 2
2-[(4-chlorophenyl)oxy]-N-[(lR)-l-({[(3-methylphenyl)methyl]oxy}methyl)-2-(4- methylpiperazin-l-yl)-2-oxoethyl]pyridine-3-carboxamide
Figure imgf000046_0001
[00141] Step 1: (R)-tert-butyl 3-hydroxy-l-(4-methylpiperazin-l-yl)-l-oxopropan-2- ylcarbamate: To a solution of (R)-2-(tert-butoxycarbonylamino)-3-hydroxypropanoic acid (3.0 g, 14.62 mmol) in dichloromethane (50 niL) was added N-methylmorpholine (16 mL, 146.2 mmol), 1-methylpiperazine (1.78 mL, 16.08 mmol), l-[3-(Dimethylamino)propyl]-3- ethylcarbodiimide methiodide (EDC) (3.0 g, 16 mmol), and 1-Hydroxybenzotriazole (HOBt) (2.1 g, 16 mmol). The reaction mixture was stirred at room temperature for 16 h, concentrated under rotary evaporation, then partitioned between dichloromethane and saturated sodium bicarbonate. The combined organic layers were dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to give 3.5 g (83%) of (R)-tert-butyl 3- hydroxy-l-(4-methylpiperazin-l-yl)-l-oxopropan-2-ylcarbamate and used in the next step without further purification.
[00142] Step 2: (R)-2-amino-3-(3-methylbenzyloxy)-l-(4-methylpiperazin-l- yl)propan-l-one: To a solution of (R)-tert-butyl 3 -hydroxy- l-(4-methy lpiperazin-1 -yl)-l- oxopropan-2-ylcarbamate (200 mg, 0.7 mmol) in tetrahydrofuran (4 mL) at 0 0C was added sodium hydride (18 mg, 0.77 mmol). The reaction mixture was stirred at 0 0C for 5 minutes followed by the addition of 3-methylbenzyl bromide (103 μL, 0.77 mmol) in tetrahydrofuran (1 mL). The reaction was stirred at 0 0C for 2 h. The reaction was quenched with 5 drops of water and concentrated in vacuo. The concentrated reaction mixture was dissolved in methanol (5 mL) followed by the addition of 4N HCl in dioxane (3 mL). The reaction was heated to 65 0C for 1 h. Upon cooling, the mixture was concentrated in vacuo to give (R)-2- amino-3-(3-methylbenzyloxy)-l-(4-methylpiperazin-l-yl)propan-l-one and used in the next step without further purification.
[00143] Step 3: 2-[(4-chlorophenyl)oxy]-N-[(lR)-l-({[(3-methylphenyl)methyl]oxy}- methyl)-2-(4-methylpiperazin-l-yl)-2-oxoethyl]pyridine-3-carboxamide: To a solution of (R)-2-amino-3-(3-methylbenzyloxy)-l-(4-methylpiperazin-l-yl)propan-l-one (0.7 mmol) in dichloromethane (4 rnL) was added N-methylmorpholine (0.77 rnL, 7 mmol), 2-(4- chlorophenoxy)nicotinic acid (203 mg, 0.77mmol), l-[3-(Dimethylamino)propyl]-3- ethylcarbodiimide methiodide (EDC) (148 mg, 0.77 mmol), and 1-Hydroxybenzotriazole (HOBt) (104 mg, 0.77 mmol). The reaction mixture was stirred at room temperature for 16 h, concentrated in vacuo and dissolved in methanol. The product was purified by preparatory HPLC (reverse-phase, acetonitrile/water with 0.1% formic acid) to give 43 mg (12%) of the title compound: 1H NMR (400 MHz, DMSO-J6): δ 8.88 (d, IH), 8.23 (m, 2H), 7.49 (d, 2H), 7.26 (m, 3H), 7.16 (m, IH), 7.05 (m, 3H), 5.20 (m, IH), 4.45 (m, 2H), 3.68 (m, 2H), 3.48 (m, 4H), 2.28 (m, 4H), 2.26 (s, 3H), 2.16 (s, 3H). MS (EI) for C28H3IClN4O4 found 524.0 (MH+). [00144] The following compounds were made in a manner analogous to Example 2: [00145] 2-[(4-chlorophenyl)oxy]-N-[(lR)-l-({[(4-fluorophenyl)methyl]oxy}methyl)-2- (4-methylpiperazin-l-yl)-2-oxoethyl]pyridine-3-carboxamide: 2-[(4-chlorophenyl)oxy]- N- [( 1 R)- 1 -( { [(4-fluorophenyl)methyl]oxy } methyl)-2-(4-methylpiperazin- 1 -yl)-2- oxoethyl]pyridine-3-carboxamide was synthesized in a manner similar to Example 2 wherein 4-fluorobenzyl bromide was substituted for 3-methylbenzyl bromide. 1H NMR (400 MHz, DMSO-J6): δ 8.88 (d, IH), 8.21 (m, 2H), 7.49 (d, 2H), 7.27 (m, 5H), 7.09 (t, 2H), 5.20 (m, IH), 4.47 (dd, 2H), 3.67 (m, 2H), 3.49 (m, 4H), 2.20 (m, 4H), 2.11 (s, 3H). MS (EI) for C27H28ClFN4O4, found 528.0 (MH+). [00146] 2-[(2,4-dichlorophenyl)oxy]-N-[(lR)-l-({[(4- fluorophenyl)methyl]oxy}methyl)-2-(4-methylpiperazin-l-yl)-2-oxoethyl]pyridine-3- carboxamide: 2-[(2,4-dichlorophenyl)oxy]-N-[( 1 R)- 1 -( { [(4- fluorophenyl)methyl]oxy}methyl)-2-(4-methylpiperazin-l-yl)-2-oxoethyl]pyridine-3- carboxamide was synthesized in a manner similar to Example 2 wherein 4-fluorobenzyl bromide was substituted for 3-methylbenzyl bromide, and 2-(2,4-dichlorophenoxy)nicotinic acid was substituted for 2-(4-chlorophenoxy)nicotinic acid. 1H NMR (400 MHz, CDCI3): δ 8.63 (d, IH), 8.56 (d, IH), 8.21 (s, IH), 8.18 (d, IH), 7.50 (s, IH), 7.34 (d, IH), 7.24 (m, 3H), 6.99 (t, 2H), 5.41 (m, IH), 4.47 (s, 2H), 3.67 (m, 2H), 3.89 (m, 2H), 3.70 (m, 2H), 2.69 (m, 2H), 2.50 (m, 2H), 2.33 (s, 3H). MS (EI) for C27H27Cl2FN4O4 found 561.0 (MH+). [00147] 2- [(2-chloro-4-fluorophenyl)oxy] -N- [(lR)-l-({ [(4-methylphenyl)methyl] oxy}- methyl)-2-(4-methylpiperazin-l-yl)-2-oxoethyl]pyridine-3-carboxamide: 2-[(2-chloro-4- fluorophenyl)oxy] -N-[(lR)-l-({ [(4-methylphenyl)methyl]oxy } methyl)-2-(4-methylpiperazin- l-yl)-2-oxoethyl]pyridine-3-carboxamide was synthesized in a manner similar to Example 2 wherein 4-methylbenzyl bromide was substituted for 3-methylbenzyl bromide and 2-(2- chloro-4-fluorophenoxy)nicotinic acid was substituted for 2-(4-chlorophenoxy)nicotinic acid. 1H NMR (400 MHz, DMSO-J6): δ 8.77 (d, IH), 8.21 (m, 2H), 7.61 (m, IH), 7.46 (m, IH), 7.28 (m, 2H), 7.07 (q, 4H), 5.19 (m, IH), 4.41 (q, 2H), 3.65 (m, 2H), 3.44 (m, 4H), 2.23 (s, 3H), 2.19 (m, 4H), 2.09 (s, 3H). MS (EI) for C28H30ClFN4O4 found 540.89 (MH+). [00148] 2-[(4-fluoro-2-methylphenyl)oxy]-N-[(lR)-l-({[(4-methylphenyl)methyl]- oxy}methyl)-2-(4-methylpiperazin-l-yl)-2-oxoethyl]pyridine-3-carboxamide: 2-[(4- fluoro-2-methylphenyl)oxy] -N- [( 1 R)- 1 -( { [(4-methylphenyl)methyl]oxy } methyl)-2-(4- methylpiperazin-l-yl)-2-oxoethyl]pyridine-3-carboxamide was synthesized in a manner similar to Example 2 wherein 4-methylbenzyl bromide was substituted for 3-methylbenzyl bromide and 2-(4-fluoro-2-methylphenoxy)nicotinic acid was substituted for 2-(4- chlorophenoxy)nicotinic acid. 1H NMR (400 MHz, DMSO-J6): δ 8.88 (d, IH), 827 (m, IH), 8.18 (m, IH), 7.12 (m, 10H), 5.20 (m, IH), 4.40 (q, 2H), 3.65 (m, 2H), 3.48 (br s, 4H), 2.23 (s, 3H), 2.18 (br s, 4H), 2.09 (s, 3H), 2.05 (s, 3H). MS (EI) for C29H33FN4O4 found 520.8 (MH+).
[00149] 2-[(4-chloro-2-methylphenyl)oxy]-N-[(lR)-l-({[(4-fluorophenyl)methyl]- oxy}methyl)-2-(4-methylpiperazin-l-yl)-2-oxoethyl]pyridine-3-carboxamide: 2-[(4- chloro-2-methylphenyl)oxy]-N-[( 1 R)- 1 -( { [(4-fluorophenyl)methyl]oxy }methyl)-2-(4- methylpiperazin-l-yl)-2-oxoethyl]pyridine-3-carboxamide was synthesized in a manner similar to Example 2 wherein 4-flurobenzyl bromide was substituted for 3-methylbenzyl bromide and 2-(4-chloro-2-methylphenoxy)nicotinic acid was substituted for 2-(4- chlorophenoxy)nicotinic acid. 1H NMR (400 MHz, DMSO-J6): δ 8.90 (d, IH), 8.27 (m, IH), 8.20 (m, IH), 7.27 (m, 7H), 5.22 (m, IH), 4.46 (q, 2H), 3.70 (m, 2H), 3.49 (m, 4H), 2.19 (m, 4H), 2.11 (s, 3H), 2.07 (s, 3H). MS (EI) for Chemical Formula: C28H30ClFN4O4 found 541.1 (MH+).
[00150] 2-[(2-chloro-4-fluorophenyl)oxy]-N-[(lR)-l-({[(4-fluorophenyl)methyl]- oxy}methyl)-2-(4-methylpiperazin-l-yl)-2-oxoethyl]pyridine-3-carboxamide: 2-[(2- chloro-4-fluorophenyl)oxy]-N-[(lR)-l-({[(4-fluorophenyl)methyl]oxy}methyl)-2-(4- methylpiperazin-l-yl)-2-oxoethyl]pyridine-3-carboxamide was synthesized in a manner similar to Example 2 wherein 4-flurobenzyl bromide was substituted for 3-methylbenzyl bromide and 2-(2-chloro-4-flurophenoxy)nicotinic acid was substituted for 2-(4- chlorophenoxy)nicotinic acid. 1H NMR (400 MHz, DMSO-J6): δ 8.79 (d, IH), 8.23 (m, IH), 8.18 (m, IH), 7.60 (m, IH), 7.46 (m, IH), 7.29 (m, 4H), 7.06 (m, 2H), 5.20 (m, IH), 4.45 (q, 2H), 3.68 (m, 2H), 3.46 (m, 4H), 2.18 (m, 4H), 2.08 (s, 3H). MS (EI) for C27H27ClF2N4O4 found 544.92 (MH+).
[00151] 2- [(4-fluoro-2-methylphenyl)oxy] -N- [(I R)- 1-({ [(4-fluorophenyl)methyl] - oxy}methyl)-2-(4-methylpiperazin-l-yl)-2-oxoethyl]pyridine-3-carboxamide: 2-[(4- fluoro-2-methylphenyl)oxy] -N- [( 1 R)- 1 -( { [(4-fluorophenyl)methyl] -oxy } methyl)-2-(4- methylpiperazin-l-yl)-2-oxoethyl]pyridine-3-carboxamide was synthesized in a manner similar to Example 2 wherein 4-flurobenzyl bromide was substituted for 3-methylbenzyl bromide and 2-(4-fluoro-2-methylphenoxy)nicotinic acid was substituted for 2-(4- chlorophenoxy)nicotinic acid. 1H NMR (400 MHz, DMSO-J6): δ 8.89 (d, IH), 8.26 (m, IH), 8.18 (m, IH), 7.17 (m, 9H), 5.21 (m, IH), 4.44 (q, 2H), 3.68 (m, 2H), 3.44 (m, 4H), 2.18 (m, 4H), 2.08 (s, 3H), 2.04 (s, 3H). MS (EI) for C28H30F2N4O4 found 524.76 (MH+). [00152] N-[(lR)-l-({[(2-chlorophenyl)methyl]oxy}methyl)-2-(4-methylpiperazin-l-yl)- 2-oxoethyl] -2-[(4-chlorophenyl)oxy] pyridine-3-carboxamide: N-[( 1 R)- 1 -( { [(2- chlorophenyl)methyl]oxy}methyl)-2-(4-methylpiperazin-l-yl)-2-oxoethyl]-2-[(4- chlorophenyl)oxy]pyridine-3-carboxamide was synthesized in a manner similar to Example 2 wherein 2-chlorobenzyl bromide was substituted for 3-methylbenzyl bromide. 1H NMR (400 MHz, DMSO-J6): δ 8.91 (d, IH), 8.22 (m, 2H), 7.48 (d, 2H), 7.41 (d, 2H), 7.27 (m, 5H), 5.22 (t, IH), 4.56 (dd, 2H), 3.77 (m, 2H), 3.48 (m, 4H), 2.23 (m, 4H), 2.11 (s, 3H). MS (EI) for C27H28Cl2N4O4 found 544 (MH+).
[00153] 2-[(4-chlorophenyl)oxy]-N-[(lR)-2-(4-methylpiperazin-l-yl)-l-{[(naphthalen- 2-ylmethyl)oxy]methyl}-2-oxoethyl] pyridine-3-carboxamide: 2-[(4-chlorophenyl)oxy]-N- [(I R)-2-(4-methylpiperazin- 1 -yl)- 1 - { [(naphthalen-2-ylmethyl)oxy]methyl} -2- oxoethyl]pyridine-3-carboxamide was synthesized in a manner similar to Example 2 wherein 2-(bromomethyl)naphthalene was substituted for 3-methylbenzyl bromide. 1H NMR (400 MHz, DMSO-J6): δ 8.88 (d, IH), 8.20 (m, 2H), 7.86 m, IH), 7.73 (m, 3H), 7.45 (m, 4H), 7.37 (m, IH), 7.23 (m, 3H), 5.21 (t, IH), 4.64 (dd, 2H), 3.71 (m, 2H), 3.46 (m, 4H), 2.17 (m, 4H), 2.03 (s, 3H). MS (EI) for C3iH3iClN4O4 found 560 (MH+). [00154] 2-[(4-chlorophenyl)oxy]-N-[(lR)-l-[({[3-
(methyloxy)phenyl] methyl} oxy)methyl] -2-(4-methylpiper azin- l-yl)-2-oxoethyl] pyridine- 3-carboxamide : 2- [(4-chlorophenyl)oxy] -N- [( 1 R)- 1 - [( { [3 - (methyloxy)phenyl]methyl}oxy)methyl]-2-(4-methylpiperazin-l-yl)-2-oxoethyl]pyridine-3- carboxamide was synthesized in a manner similar to Example 2 wherein 3-methoxybenzyl bromide was substituted for 3-methylbenzyl bromide. 1H NMR (400 MHz, DMSO-J6): δ 8.89 (d, IH), 8.22 (m, 2H), 7.49 (d, 2H), 7.24 (m, 4H), 6.82 (m, 3H), 5.21 (t, IH), 4.47 (dd, 2H), 3.70 (s, 3H), 3.66 (m, 2H), 3.54 (m, 4H), 2.25 (m, 4H), 2.13 (s, 3H). MS (EI) for C28H3IClN4O5 found 540 (MH+).
[00155] 2-[(4-chlorophenyl)oxy]-N-[(lR)-l-({[(4-methylphenyl)methyl]oxy}methyl)-2- (4-methylpiperazin-l-yl)-2-oxoethyl]pyridine-3-carboxamide: 2-[(4-chlorophenyl)oxy]- N- [( 1 R)- 1 -( { [(4-methylphenyl)methyl]oxy } methyl)-2-(4-methylpiperazin- 1 -yl)-2- oxoethyl]pyridine-3 -carboxamide was synthesized in a manner similar to Example 2 wherein 4-methylbenzyl bromide was substituted for 3-methylbenzyl bromide. 1H NMR (400 MHz, DMSO-J6): δ 8.86 (d, IH), 8.22 (m, 2H), 8.18 (s, IH), 7.49 (d, 2H), 7.26 (m, 3H), 7.13 (d, 2H), 7.06 (d, 2H), 5.19 (t, IH), 4.43 (dd, 2H), 3.68 (m, 2H), 3.48 (m, 4H), 2.26 (s, 3H), 2.20 (m, 4H), 2.11 (s, 3H). MS (EI) for C28H3IClN4O4 found 524 (MH+).
[00156] N-[(lR)-l-({[(3-chlorophenyl)methyl]oxy}methyl)-2-(4-methylpiperazin-l-yl)- 2-oxoethyl] -2- [(4-chlorophenyl)oxy] pyridine-3-carboxamide: N-[( 1 R)- 1 -( { [(3 - chlorophenyl)methyl]oxy}methyl)-2-(4-methylpiperazin-l-yl)-2-oxoethyl]-2-[(4- chlorophenyl)oxy]pyridine-3 -carboxamide was synthesized in a manner similar to Example 2 wherein 3-chlorobenzyl bromide was substituted for 3-methylbenzyl bromide. 1H NMR (400 MHz, DMSO-J6): δ 8.91 (d, IH), 8.22 (m, 2H), 7.49 (d, 2H), 7.32 (m, 3H), 7.25 (m, 4H), 5.22 (t, IH), 4.50 (dd, 2H), 3.71 (m, 2H), 3.48 (m, 4H), 2.20 (m, 4H), 2.11 (s, 3H). MS (EI) for C27H28Cl2N4O4 found 544 (MH+). [00157] 2-[(4-chlorophenyl)oxy]-N-[(lR)-l-({[(2,6- dichlorophenyl)methyl]oxy}methyl)-2-(4-methylpiperazin-l-yl)-2-oxoethyl]pyridine-3- carboxamide: 2-[(4-chlorophenyl)oxy]-N-[(lR)-l-({[(2,6- dichlorophenyl)methyl]oxy}methyl)-2-(4-methylpiperazin-l-yl)-2-oxoethyl]pyridine-3- carboxamide was synthesized in a manner similar to Example 2 wherein 2,6-dichlorobenzyl bromide was substituted for 3-methylbenzyl bromide. 1H NMR (400 MHz, DMSO-J6): δ 8.85 (d, IH), 8.23 (m, 2H), 7.48 (m, 4H), 7.37 (m, IH), 7.26 (m, 3H), 5.18 (t, IH), 4.68 (dd, 2H), 3.76 (m, 2H), 3.48 (m, 4H), 2.22 (m, 4H), 2.06 (s, 3H). MS (EI) for C27H27Cl3N4O4 found 579 (MH+).
[00158] N-[(lR)-l-({[(4-chlorophenyl)methyl]oxy}methyl)-2-(4-methylpiperazin-l-yl)- 2-oxoethyl] -2-[(4-chlorophenyl)oxy] pyridine-3-carboxamide: N-[( 1 R)- 1 -( { [(4- chlorophenyl)methyl]oxy}methyl)-2-(4-methylpiperazin-l-yl)-2-oxoethyl]-2-[(4- chlorophenyl)oxy]pyridine-3 -carboxamide was synthesized in a manner similar to Example 2 wherein 4-chlorobenzyl bromide was substituted for 3-methylbenzyl bromide. 1H NMR (400 MHz, DMSO-J6): δ 8.88 (d, IH), 8.21 (m, 2H), 7.49 (d, 2H), 7.28 (m, 7H), 5.20 (t, IH), 4.48 (dd, 2H), 3.69 (m, 2H), 3.48 (m, 4H), 2.20 (m, 4H), 2.11 (s, 3H). MS (EI) for C27H28Cl2N4O4 found 544 (MH+). [00159] 2-[(4-chlorophenyl)oxy]-N-[(lR)-l-({[(2,4- dimethylphenyl)methyl]oxy}methyl)-2-(4-methylpiperazin-l-yl)-2-oxoethyl]pyridine-3- carboxamide : 2-[(4-chlorophenyl)oxy] -N- [( 1 R)- 1 -( { [(2,4- dimethylphenyl)methyl]oxy}methyl)-2-(4-methylpiperazin-l-yl)-2-oxoethyl]pyridine-3- carboxamide was synthesized in a manner similar to Example 2 wherein 2,4-dimethylbenzyl bromide was substituted for 3-methylbenzyl bromide. 1H NMR (400 MHz, DMSO-J6): δ 8.83 (d, IH), 8.20 (m, 2H), 7.46 (d, 2H), 7.22 (m, 3H), 7.06 (d, IH), 6.91 (m, IH), 6.85 (d, IH), 5.16 (t, IH), 4.40 (m, 2H), 3.64 (m, 2H), 3.46 (m, 4H), 2.25 (m, 4H), 2.20 (s, 3H), 2.10 (m, 6H). MS(EI) for C29H33ClN4O4 found 538 (MH+).
[00160] 2-[(4-chlorophenyl)oxy]-N-[(lR)-2-(4-methylpiperazin-l-yl)-2-oxo-l- {[(pyridin-3-ylmethyl)oxy]methyl}ethyl]pyridine-3-carboxamide: 2-[(4- chlorophenyl)oxy]-N- [( 1 R)-2-(4-methy lpiperazin- 1 -yl)-2-oxo- 1 - { [(pyridin-3 - ylmethyl)oxy]methyl}ethyl]pyridine-3-carboxamide was synthesized in a manner similar to Example 2 wherein 3-(bromomethyl)pyridine was substituted for 3-methylbenzyl bromide. 1H NMR (400 MHz, DMSO-J6): δ 8.83 (d, IH), 8.40 (m, 2H), 8.14 (m, 2H), 7.58 (d, 2H), 7.41 (d, 2H), 7.19 (m, 4H), 5.15 (t, IH), 4.47 (dd, 2H), 3.64 (m, 2H), 3.45 (m, 4H), 2.14 (m, 4H), 2.03 (s, 3H). MS (EI) for C26H28ClN5O4, found 511 (MH+).
[00161] 2-[(4-chlorophenyl)oxy]-N-[(lR)-l-[({[4-(l-methylethyl)phenyl]methyl}oxy)- methyl]-2-(4-methylpiperazin-l-yl)-2-oxoethyl]pyridine-3-carboxamide: 2-[(4- chlorophenyl)oxy]-N-[( 1 R)- 1 -[( { [4-( 1 -methylethyl)phenyl]methyl} oxy)methyl]-2-(4- methylpiperazin-l-yl)-2-oxoethyl]pyridine-3 -carboxamide was synthesized in a manner similar to Example 2 wherein 4-isopropylbenzyl bromide was substituted for 3-methylbenzyl bromide. 1H NMR (400 MHz, DMSO-J6): δ 8.85 (d, IH), 8.21 (m, 2H), 7.47 (d, 2H), 7.24 (m, 3H), 7.13 (d, 2H), 7.08 (d, 2H), 5.18 (t, IH), 4.41 (m, 2H), 3.66 (m, 2H), 3.46 (m, 4H), 2.81 (m, IH), 2.31 (m, 4H), 2.16 (s, 3H), 1.15 (s, 3H), 1.13 (s, 3H). MS (EI) for C30H35ClN4O4 found 552 (MH+).
[00162] 2-[(4-chlorophenyl)oxy]-N-[(lR)-l-({[(2-methylphenyl)methyl]oxy}methyl)-2- (4-methylpiperazin-l-yl)-2-oxoethyl]pyridine-3-carboxamide: 2-[(4-chlorophenyl)oxy]- N- [( 1 R)- 1 -( { [(2-methylphenyl)methyl]oxy } methyl)-2-(4-methylpiperazin- 1 -yl)-2- oxoethyl]pyridine-3 -carboxamide was synthesized in a manner similar to Example 2 wherein 2-methylbenzyl bromide was substituted for 3-methylbenzyl bromide. 1H NMR (400 MHz, DMSO-J6): δ 8.88 (d, IH), 8.23 (m, 2H), 7.48 (d, 2H), 7.25 (m, 4H), 7.12 (m, 3H), 5.20 (t, IH), 4.47 (m, 2H), 3.70 (m, 2H), 3.46 (m, 4H), 2.23 (m, 4H), 2.20 (s, 3H), 2.10 (m, 3H). MS (EI) for C28H3IClN4O4 found 524 (MH+).
[00163] N-[(lR)-l-({[(2-chloropyridin-4-yl)methyl]oxy}methyl)-2-(4-methylpiperazin- l-yl)-2-oxoethyl]-2-{[2-chloro-4-(trifluoromethyl)phenyl]oxy}pyridine-3-carboxamide: N- [( 1 R)- 1 -( { [(2-chloropyridin-4-yl)methyl]oxy } methyl)-2-(4-methylpiperazin- 1 -yl)-2- oxoethyl]-2-{[2-chloro-4-(trifluoromethyl)phenyl]oxy}pyridine-3-carboxamide was synthesized in a manner similar to Example 2 wherein 4-(bromomethyl)-2-chloropyridine was substituted for 3-methylbenzyl bromide, and 2-(2-chloro-4- (trifluoromethyl)phenoxy)nicotinic acid (Example 3) was substituted for 2-(4-chloro- phenoxy)nicotinic acid. 1H NMR (400 MHz, CDCl3): δ 8.62 (d, IH), 8.50 (dd, IH), 8.20 (d, IH), 8.10 (dd, IH), 7.68 (m, IH), 7.56 (m, IH), 7.31 (d, IH), 7.18 (m, IH), 7.13 (dd, IH), 7.05 (d, IH), 5.36 (m, IH), 4.47 (s, 2H), 3.77 (m, 2H), 3.61 (m, 4H), 2.36 (m, 4H), 2.23 (s, 3H). MS (EI) for C27H26Cl2F3N5O4, found 613.0 (MH+).
[00164] 2-{[2-chloro-4-(trifluoromethyl)phenyl]oxy}-N-[(lR)-l-{[(2,3-dihydro-l,4- benzodioxin-6-ylmethyl)oxy]methyl}-2-(4-methylpiperazin-l-yl)-2-oxoethyl]pyridine-3- carboxamide: Step 1 : 6-(bromomethyl)-2,3-dihydrobenzo[b][l,4]dioxine: To a solution of (2,3-dihydrobenzo[b][l,4]dioxin-6-yl)methanol (1.0 g, 6.0 mmol) in dichloromethane (25 mL) was added carbontetrabromide (3.0 g, 9 mmol), and triphenylphosphine (2.35 g, 9.0 mmol). The reaction mixture was stirred at room temperature for 24 h and concentrated under reduced pressure. Purification by column chromatography (Silica gel, EtOAc/Hexanes) resulted in 1.1 g (80% Yield) of 6-(bromomethyl)-2,3- dihydrobenzo[b][l,4]dioxine. MS (EI) for C9H9BrO2 found 229 (MH+). [00165] Step 2: 2-{[2-chloro-4-(trifiuoromethyl)phenyl]oxy}-N-[(lR)-l-{[(2,3-dihydro- 1 ,4-benzodioxin-6-ylmethyl)oxy]methyl} -2-(4-methylpiperazin- 1 -yl)-2-oxoethyl]pyridine-3- carboxamide was synthesized in a manner similar to Example 2 wherein 6-(bromomethyl)- 2,3-dihydrobenzo[b][l,4]dioxine was substituted for 3-methylbenzyl bromide, and 2-(2- chloro-4-fluorophenoxy)nicotinic acid was substituted for 2-(4-chlorophenoxy)nicotinic acid. 1H NMR (400 MHz, CDCl3): δ 8.64 (d, IH), 8.57 (dd, IH), 8.18 (m, IH), 7.73 (d, IH), 7.63 (m, IH), 7.45 (d, IH), 7.19 (dd, IH), 6.78(m, 2H), 6.73 (m, IH), 5.39 (q, IH), 4.38 (s, 2H), 4.22 (s, 4H), 3.87 (m, 3H), 3.65 (m, 3H), 2.64 (m, 2H), 2.41 (m, 2H), 2.31 (s, 3H). MS (EI) for C30H30ClF3N4O6 found 635.00 (MH+). [00166] 2-{[2-chloro-4-(trifluoromethyl)phenyl]oxy}-N-[(lR)-l-({[(2-methyl-l,3- oxazol-5-yl)methyl]oxy}methyl)-2-(4-methylpiperazin-l-yl)-2-oxoethyl]pyridine-3- carboxamide : 2- { [2-chloro-4-(trifluoromethyl)phenyl]oxy } -N- [( 1 R)- 1 -( { [(2-methyl- 1,3- oxazol-5 -yl)methyl] -oxy } methyl)-2-(4-methylpiperazin- 1 -yl)-2-oxoethyl]pyridine-3 - carboxamide was synthesized in a manner similar to Example 2 wherein 5-(bromomethyl)-2- methyloxazole was substituted for 3-methylbenzyl bromide, and 2-(2-chloro-4- fluorophenoxy)nicotinic acid was substituted for 2-(4-chlorophenoxy)nicotinic acid. 1H NMR (400 MHz, CDCl3): δ 8.64 (d, IH), 8.56 (m, IH), 8.18 (m, IH), 7.77 (m, IH), 7.63 (m, IH), 7.45 (m, IH), 7.20 (m, IH), 6.05 (m, IH), 5.40 (m, IH), 4.56 (m, 2H), 3.89 (m, 2H), 3.79 (m, 4H), 2.48 (m, 4H), 2.39 (s, 3H), 2.26 (s, 3H). MS (EI) for C26H27ClF3N5O5 found 582.00 (MH+).
[00167] 2-{[2-chloro-4-(trifluoromethyl)phenyl]oxy}-N-{(lR)-l-{[(2,3-dihydro-l,4- benzodioxin-6-ylmethyl)oxy]methyl}-2-[3-(dimethylamino)azetidin-l-yl]-2- oxoethyl}pyridine-3-carboxamide: 2-{[2-chloro-4-(trifluoromethyl)phenyl]oxy}-N-{(lR)- l-{[(2,3-dihydro-l,4-benzodioxin-6-ylmethyl)oxy]methyl}-2-[3-(dimethylamino)azetidin-l- yl]-2-oxoethyl}pyridine-3-carboxamide was synthesized in a manner similar to Example 2 wherein 6-(bromomethyl)-2,3-dihydrobenzo[b][l,4]dioxine was substituted for 3- methylbenzyl bromide, and 2-(2-chloro-4-fluorophenoxy)nicotinic acid was substituted for 2- (4-chlorophenoxy)nicotinic acid, and N,N-dimethylazetidin-3-amine (Small Molecules Inc) was substituted for N-methylpiperazine. 1H NMR (400 MHz, CDCl3): δ 8.57 (dd, IH), 8.48 (m, IH), 8.16 (dd, IH), 7.75 (d, IH), 7.59 (m, IH), 7.43 (d, IH), 7.20 (dd, IH), 6.78(m, 2H), 6.70 (m, IH), 4.92 (q, IH), 4.35 (s, 2H), 4.35 (m, IH), 4.21 (s, 4H), 4.11 (m, 2H), 3.38 (m, 2H), 3.64 (m, IH), 3.06 (m, IH), 2.17 (s, 6H). MS (EI) for C30H30ClF3N4O6 found 635.0 (MH+).
[00168] 2-{[2-chloro-4-(trifluoromethyl)phenyl]oxy}-N-[(lR)-2-[(3R)-3- (dimethylamino)-pyrrolidin-l-yl]-l-({[(3-methylphenyl)methyl]oxy}methyl)-2- oxoethyl]pyridine-3-carboxamide: 2-{[2-chloro-4-(trifluoromethyl)phenyl]oxy}-N-[(lR)-2- [(3R)-3 -(dimethylamino)pyrrolidin- 1 -yl] - 1 -( { [(3 -methylphenyl)methyl]oxy } methyl)-2- oxoethyl]pyridine-3 -carboxamide was synthesized in a manner similar to Example 2 wherein (R)-N ,N-dimethylpyrrolidin-3 -amine was substituted for 1-methylpiperazine, and 2-(2- chloro-4-(trifluoromethyl)phenoxy)nicotinic acid was substituted for 2-(4- chlorophenoxy)nicotinic acid. 1H NMR (400 MHz, DMSO-J6): δ 8.77 (d, IH), 8.23 (dd, IH), 8.20 (dd, IH), 8.05 (s, IH), 7.81 (dd, IH), 7.64 (dd, IH), 7.31 (m, IH), 7.09 (m, IH), 7.01 (m, 3H), 4.99 (t, IH), 4.44 (dd, 2H), 3.86 (m, IH), 3.71 (m, 2H), 3.48 (m, IH), 3.54 (m, IH), 3.00 (m, IH), 2.55 (m, IH), 2.20 (s, 3H), 2.09 (s, 6H), 1.99 (m, IH), 1.61 (m, IH). MS (EI) for C30H32ClF3N4O4 found 606.05 (MH+).
[00169] 2-[(2,4-dichlorophenyl)oxy]-N-[(lR)-2-(4-methylpiperazin-l-yl)-2-oxo-l- {[(pyridin-4-ylmethyl)oxy]methyl}ethyl]pyridine-3-carboxamide: 2-[(2,4- dichlorophenyl)oxy] -N-[( 1 R)-2-(4-methylpiperazin- 1 -yl)-2-oxo- 1 - { [(pyridin-4- ylmethyl)oxy]methyl}ethyl]pyridine-3-carboxamide was synthesized in a manner similar to Example 2 wherein 4-(bromomethyl)pyridine was substituted for 3-methylbenzyl bromide, and 2-(2,4-dichlorophenoxy)nicotinic acid was substituted for 2-(4-chlorophenoxy)nicotinic acid. 1H NMR (400 MHz, DMSO-J6): δ 8.83 (d, IH), 8.41 (d, IH), 8.21 (m, 2H), 8.14 (s, IH), 7.75 (d, IH), 7.50 (dd, IH), 7.44 (d, IH), 7.28 (m, IH), 7.22 (d, 2H), 5.24 (t, IH), 4.55 (d, 2H), 3.74 (m, 2H), 3.52 (m, 4H), 2.26 (m, 4H), 2.13 (s, 3H). MS (EI) for C26H27Cl2N5O4 found 545.43 (MH+).
[00170] 2-[(2,4-dichlorophenyl)oxy]-N-[(lR)-l-({[(2,6-dichloropyridin-4- yl)methyl]oxy}methyl)-2-(4-methylpiperazin-l-yl)-2-oxoethyl]pyridine-3-carboxamide: 2-[(2,4-dichlorophenyl)oxy]-N-[(lR)-l-({[(2,6-dichloropyridin-4-yl)methyl]oxy}methyl)-2- (4-methylpiperazin-l-yl)-2-oxoethyl]pyridine-3-carboxamide synthesized in a manner similar to Example 2 wherein 4-(bromomethyl)-2,6-dichloropyridine was substituted for 3- methylbenzyl bromide, and 2-(2,4-dichlorophenoxy)nicotinic acid was substituted for 2-(4- chlorophenoxy)nicotinic acid. 1H NMR (400 MHz, DMSO-J6): δ 8.87 (d, IH), 8.19 (m, 2H), 8.14 (s, IH), 7.71 (d, IH), 7.48 (dd, IH), 7.41 (d, IH), 7.36 (s, IH), 7.27 (m, IH), 5.24 (t, IH), 4.58 (m, 2H), 3.74 (m, 2H), 3.52 (m, 4H), 2.27 (m, 4H), 2.14 (s, 3H). MS (EI) for C26H25Cl4N5O4 found 614.32 (MH+).
[00171] 2-{[2-chloro-4-(trifluoromethyl)phenyl]oxy}-N-[(lR)-2-(4-methylpiperazin-l- yl)-2-oxo-l-{[(pyridin-4-ylmethyl)oxy]methyl}ethyl]pyridine-3-carboxamide: 2-{[2- chloro-4-(trifluoromethyl)phenyl]oxy } -N-[( 1 R)-2-(4-methylpiperazin- 1 -yl)-2-oxo- 1 - {[(pyridin-4-ylmethyl)oxy]methyl}ethyl]pyridine-3-carboxamide was synthesized in a manner similar to Example 2 wherein 4-(bromomethyl)pyridine was substituted for 3- methylbenzyl bromide, and 2-(2-chloro-4-(trifluoromethyl)phenoxy)nicotinic acid was substituted for 2-(4-chlorophenoxy)nicotinic acid. 1U NMR (400 MHz, DMSO-J6): δ 8.86 (d, IH), 8.41 (d, 2H), 8.21 (m, 2H), 8.03 (s, IH), 7.81 (d, IH), 7.64 (d, IH), 7.30 (d, IH), 7.20 (m, 2H), 5.24 (t, IH), 4.55 (d, 2H), 3.74 (m, 2H), 3.55 (m, 4H), 2.22 (m, 4H), 2.09 (s, 3H). MS (EI) for C27H27Cl2F3N5O4 found 578.98 (MH+).
[00172] N-[(lR)-l-({[(2-bromopyridin-4-yl)methyl]oxy}methyl)-2-(4-methylpiperazin- l-yl)-2-oxoethyl]-2-{[2-chloro-4-(trifluoromethyl)phenyl]oxy}pyridine-3-carboxamide: N- [( 1 R)- 1 -( { [(2-bromopyridin-4-yl)methyl]oxy } methyl)-2-(4-methylpiperazin- 1 -yl)-2- oxoethyl]-2-{[2-chloro-4-(trifluoromethyl)phenyl]oxy}pyridine-3-carboxamide was synthesized in a manner similar to Example 2 wherein 2-bromo-4-(bromomethyl)pyridine was substituted for 3-methylbenzyl bromide, and 2-(2-chloro-4- (trifluoromethyl)phenoxy)nicotinic acid was substituted for 2-(4-chlorophenoxy)nicotinic acid. 1H NMR (400 MHz, DMSO-J6): δ 8.88 (d, IH), 8.21 (m, 3H), 8.01 (s, IH), 7.80 (d, IH), 7.64 (d, IH), 7.46 (s, IH), 7.28 (m, 2H), 5.25 (t, IH), 4.55 (d, 2H), 3.74 (m, 2H), 3.49 (m, 4H), 2.19 (m, 4H), 2.09 (s, 3H). MS (EI) for C27H26BrClF3N5O4 found 657.88 (MH+). [00173] l-lIl-chloro^-CtrifluoromethyOphenylJoxyJ-N-KlRJ-l-lICl^-dihydro-l^- benzodioxin-6-ylmethyl)oxy]methyl}-2-[3-(methylamino)azetidin-l-yl]-2- oxoethyl}pyridine-3-carboxamide: 2-{[2-chloro-4-(trifluoromethyl)phenyl]oxy}-N-{(lR)- l-{[(2,3-dihydro-l,4-benzodioxin-6-ylmethyl)oxy]methyl}-2-[3-(methylamino)azetidin-l- yl]-2-oxoethyl}pyridine-3-carboxamide was synthesized in a manner similar to Example 2 wherein 6-(bromomethyl)-2,3-dihydrobenzo[b][l,4]dioxine was substituted for 3- methylbenzyl bromide, 2-(2-chloro-4-fluorophenoxy)nicotinic acid was substituted for 2-(4- chlorophenoxy)nicotinic acid, and tert-butyl azetidin-3-yl(methyl)carbamate (Beta Pharma) was substituted for N-methylpiperazine. IH NMR (400 MHz, DMSO-J6): δ 8.65 (dd, IH), 8.26 (m, 2H), 8.19 (dd, IH), 8.05 (d, IH), 7.83 (dd, IH), 7.65 (d, IH), 7.32 (dd, IH), 6.71(m, IH), 6.64 (m, 2H), 4.73 (q, IH), 4.38-4.25 (dt, IH), 4.33 (s, 2H), 4.16 (s, 4H), 3.95 (m, 3H), 3.85 (m, IH), 3.64 (m, IH), 3.51 (m, IH), 2.14 (d, 3H). MS (EI) for C29H28ClF3N4O6 found 622.0 (MH+).
[00174] N-[(lR)-2-(3-aminoazetidin-l-yl)-l-{[(2,3-dihydro-l,4-benzodioxin-6- ylmethyl)oxy]methyl}-2-oxoethyl]-2-{[2-chloro-4-(trifluoromethyl)phenyl]oxy}pyridine- 3-carboxamide: N-[( 1 R)-2-(3-aminoazetidin- 1 -yl)- 1 - { [(2,3-dihydro- 1 ,4-benzodioxin-6- ylmethyl)oxy]methyl} -2-oxoethyl]-2- { [2-chloro-4-(trifluoromethyl)phenyl]oxy}pyridine-3- carboxamide was synthesized in a manner similar to Example 2 wherein 6-(bromomethyl)- 2,3-dihydrobenzo[b][l,4]dioxine was substituted for 3-methylbenzyl bromide, and 2-(2- chloro-4-fluorophenoxy)nicotinic acid was substituted for 2-(4-chlorophenoxy)nicotinic acid, and tert-butyl azetidin-3-ylcarbamate (Anthem) was substituted for N-methylpiperazine. IH NMR (400 MHz, CDC13): δ 8.90 (s, 2H), 8.57 (dd, IH), 8.47 (m, 2H), 8.09 (dd, IH), 7.69 (s, IH), 7.53 (m, IH), 7.39 (m, IH), 7.10 (m, IH), 6.62 (m, IH), 6.54 (m, IH), 4.89 (q, IH), 4.67 (s, 2H), 4.44 (m, IH), 4.31 (s, 4H), 4.20-4.09 (m, 4H), 3.84 (m, IH), 3.68 (m, IH). MS (EI) for C28H26ClF3N4O6 found 607.0 (MH+). Example 3
2-(2-chloro-6-methylphenoxy)nicotinic acid H
Figure imgf000056_0001
[00175] To a solution of ethyl-2-chloronicotinate (800 mg, 4.3 mmol) in dimethylacetamide (8 niL) were added 2-chloro-6-methylphenol (737 mg, 5.17 mmol) and cesium carbonate (2.1 g, 6.47 mmol). The reaction mixture was heated to 130 0C for 6 hours and then 4 mL of water was added and heated the mixture to 110 0C for an additional 4 hours. The crude reaction mixture was concentrated in vacuo and diluted with 100 mL of water. The resulting aqueous solution was extracted with 100 mL of ethyl acetate. The aqueous layer was collected, acidified with IM HCl to pH 3, and extracted with ethyl acetate (3 X 100 mL) with addition of saturated aqueous lithium chloride (100 mL). The organic layer was dried over magnesium sulfate. The ethyl acetate was concentrated in vacuo to give 630 mg (55%) of 2-(2-chloro-6-methylphenoxy)nicotinic acid which was used without further purification.
[00176] The following compounds were made in a manner which employed the methods of Example 1 and Example 3:
[00177] l-IIl-chloro^-CtrifluoromethylJphenylloxyJ-N-IClRJ-l-C^methylpiperazin-l- yl)-2-oxo-l-{[(phenylmethyl)oxy]methyl}ethyl]pyridine-3-carboxamide: 2-{[2-chloro-4- (trifluoromethyl)phenyl]oxy } -N- [( 1 R)-2-(4-methylpiperazin- 1 -yl)-2-oxo- 1 - {[(phenylmethyl)oxy]methyl}ethyl]pyridine-3-carboxamide was synthesized in a manner similar to Example 1 wherein 2-(2-chloro-4-(trifluoromethyl)phenoxy)nicotinic acid was substituted for 2-(4-chlorophenoxy)nicotinic acid. 2-(2-chloro-4-
(trifluoromethyl)phenoxy)nicotinic acid was synthesized in a manner similar to Example 3 wherein 2-chloro-4-trifluoromethylphenol was substituted for 2-chloro-6-methylphenol. 1H NMR (400 MHz, DMSO-J6): δ 8.81 (d, IH), 8.22 (m, 2H), 8.05 (m, IH), 7.82 (m, IH), 7.63 (m, IH), 7.30 (m, IH), 7.22 (m, 5H), 5.20 (t, IH), 4.47 (m, 2H), 3.69 (m, 2H), 3.53 (m, 4H), 2.21 (m, 4H), 2.08 (s, 3H). MS (EI) for C28 H28ClF3N4O4 found 578 (MH+). [00178] 2-[(4-bromo-2-chlorophenyl)oxy]-N-[(lR)-2-(4-methylpiperazin-l-yl)-2-oxo- l-{[(phenylmethyl)oxy]methyl}ethyl]pyridine-3-carboxamide: 2-[(4-bromo-2- chlorophenyl)oxy]-N- [( 1 R)-2-(4-methylpiperazin- 1 -yl)-2-oxo- 1 - {[(phenylmethyl)oxy]methyl}ethyl]pyridine-3-carboxamide was synthesized in a manner similar to Example 1 wherein 2-(4-bromo-2-chlorophenoxy)nicotinic acid was substituted for 2-(4-chlorophenoxy)nicotinic acid. 2-(4-bromo-2-chlorophenoxy)nicotinic acid was synthesized in a manner similar to Example 3 wherein 4-bromo-2-chlorophenol was substituted for 2-chloro-6-methylphenol. 1U NMR (400 MHz, DMSO-J6): δ 8.79 (d, IH),
8.23 (dd, IH), 8.19 (dd, IH), 7.88 (s, IH), 7.63 (dd, IH), 7.39 (d, IH), 7.28 (m, IH), 7.23 (m, 5H), 5.20 (t, IH), 4.47 (dd, 2H), 3.68 (m, 2H), 3.46 (m, 4H), 2.20 (m, 4H), 2.09 (s, 3H). MS (EI) for C27H28BrClN4O4 found 589 (MH+).
[00179] 2-[(4-chloro-2-methoxyphenyl)oxy]-N-[(lR)-2-(4-methylpiperazin-l-yl)-2- oxo-l-{[(phenylmethyl)oxy]methyl}ethyl]pyridine-3-carboxamide: 2-[(4-chloro-2- methoxyphenyl)oxy]-N- [( 1 R)-2-(4-methylpiperazin- 1 -yl)-2-oxo- 1 -
{[(phenylmethyl)oxy]methyl}ethyl]pyridine-3-carboxamide was synthesized in a manner similar to Example 1 wherein 2-(4-chloro-2-methoxyphenoxy)nicotinic acid was substituted for 2-(4-chlorophenoxy)nicotinic acid. 2-(4-chloro-2-methoxyphenoxy)nicotinic acid was synthesized in a manner similar to Example 3 wherein 4-chloro-2-methoxyphenol was substituted for 2-chloro-6-methylphenol. 1H NMR (400 MHz, DMSO-J6): δ 8.75 (d, IH),
8.24 (dd, IH), 8.16 (dd, IH), 7.23 (m, 8H), 7.06 (dd, IH), 5.21 (t, IH), 4.47 (dd, 2H), 3.67 (m, 5H), 3.47 (m, 4H), 2.20 (m, 4H), 2.09 (s, 3H). MS (EI) for C28H3IClN4O5 found 540 (MH+).
[00180] 2-{[2-bromo-4-(trifluoromethyl)phenyl]oxy}-N-[(lR)-2-(4-methylpiperazin-l- yl)-2-oxo-l-{[(phenylmethyl)oxy]methyl}ethyl]pyridine-3-carboxamide: 2-{[2-bromo-4- (trifluoromethyl)phenyl]oxy } -N- [( 1 R)-2-(4-methylpiperazin- 1 -yl)-2-oxo- 1 - {[(phenylmethyl)oxy]methyl}ethyl]pyridine-3-carboxamide was synthesized in a manner similar to Example 1 wherein 2-(2-bromo-4-(trifluoromethyl)phenoxy)nicotinic acid was substituted for 2-(4-chlorophenoxy)nicotinic acid. 2-(2-bromo-4-
(trifluoromethyl)phenoxy)nicotinic acid was synthesized in a manner similar to Example 3 wherein 2-bromo-4-trifluoromethylphenol was substituted for 2-chloro-6-methylphenol. 1H NMR (400 MHz, DMSO-J6): δ 8.80 (d, IH), 8.23 (dd, IH), 8.19 (dd, IH), 7.88 (s, IH), 7.63 (dd, IH), 7.39 (d, IH), 7.28 (m, IH), 7.23 (m, 5H), 5.20 (t, IH), 4.47 (dd, 2H), 3.68 (m, 2H), 3.46 (m, 4H), 2.20 (m, 4H), 2.09 (s, 3H). MS (EI) for C28H28BrF3N4O4 found 622 (MH+). [00181] 2- [(2,4-dichloro-6-methylphenyl)oxy ] -N- [(lR)-2-(4-methylpiper azin- l-yl)-2- oxo-l-{[(phenylmethyl)oxy]methyl}ethyl]pyridine-3-carboxamide: 2-[(2,4-dichloro-6- methylphenyl)oxy]-N- [( 1 R)-2-(4-methylpiperazin- 1 -yl)-2-oxo- 1 -
{[(phenylmethyl)oxy]methyl}ethyl]pyridine-3-carboxamide was synthesized in a manner similar to Example 1 wherein 2-(2,4-dichloro-6-methylphenoxy)nicotinic acid was substituted for 2-(4-chlorophenoxy)nicotinic acid. 2-(2,4-dichloro-6- methylphenoxy)nicotinic acid was synthesized in a manner similar to Example 3 wherein 2,4-dichloro-6-methylphenol was substituted for 2-chloro-6-methylphenol. 1H NMR (400 MHz, DMSO-J6): δ 8.83 (d, IH), 8.31 (d, IH), 8.18 (dd, IH), 7.60 (s, IH), 7.45 (dd, IH), 7.29 (m, IH), 7.22 (m, 5H), 5.22 (t, IH), 4.48 (dd, 2H), 3.70 (m, 2H), 3.48 (m, 4H), 2.20 (m, 4H), 2.10 (s, 6H). MS (EI) for C28H30Cl2 N4O4 found 558 (MH+). [00182] N-[(lR)-2-(4-methylpiperazin-l-yl)-2-oxo-l-
{ [(phenylmethyl)oxy] methyl} ethyl] -2- { [4-(trifluor omethyl)phenyl] oxy}pyridine-3- carboxamide: N-[( 1 R)-2-(4-methylpiperazin- 1 -yl)-2-oxo- 1 -
{[(phenylmethyl)oxy]methyl}ethyl]-2-{[4-(trifluoromethyl)phenyl]oxy}pyridine-3- carboxamide was synthesized in a manner similar to Example 1 wherein 2-(4- (trifluoromethyl)phenoxy)nicotinic acid was substituted for 2-(4-chlorophenoxy)nicotinic acid. 2-(4-(trifluoromethyl)phenoxy)nicotinic acid was synthesized in a manner similar to Example 3 wherein 4-(trifluoromethyl)phenol was substituted for 2-chloro-6-methylphenol. 1H NMR (400 MHz, DMSO-J6): δ 8.80 (d, IH), 8.23 (dd, IH), 8.19 (dd, IH), 7.80 (d, 2H), 7.40 (d, 2H), 7.29 (m, IH), 7.24 (m, 4H), 5.18 (t, IH), 4.47 (dd, 2H), 3.66 (m, 2H), 3.44 (m, 4H), 2.20 (m, 4H), 2.08 (s, 3H). MS (EI) for C28H29F3N4O4 found 544 (MH+). [00183] 2-[(2,4-difluorophenyl)oxy]-N-[(lR)-2-(4-methylpiperazin-l-yl)-2-oxo-l- {[(phenylmethyl)oxy]methyl}ethyl]pyridine-3-carboxamide: 2-[(2,4-difluorophenyl)oxy]- N- [( 1 R)-2-(4-methylpiperazin- 1 -yl)-2-oxo- 1 - { [(phenylmethyl)oxy]methyl} ethyl]pyridine-3 - carboxamide was synthesized in a manner similar to Example 1 wherein 2-(2,4- difluorophenoxy)nicotinic acid was substituted for 2-(4-chlorophenoxy)nicotinic acid. 2- (2,4-difluorophenoxy)nicotinic acid was synthesized in a manner similar to Example 3 wherein 2,4-difluorophenol was substituted for 2-chloro-6-methylphenol. 1H NMR (400 MHz, DMSO-J6): δ 8.84 (d, IH), 8.21 (m, 2H), 7.45 (m, 2H), 7.27 (m, 2H), 7.24 (m, 4H), 7.16 (m, IH), 5.20 (t, IH), 4.47 (dd, 2H), 3.68 (m, 2H), 3.48 (m, 4H), 2.21 (m, 4H), 2.09 (s, 3H). MS (EI) for C27H28F2N4O4 found 512 (MH+).
[00184] 2-[(2,6-dichlorophenyl)oxy]-N-[(lR)-2-(4-methylpiperazin-l-yl)-2-oxo-l- {[(phenylmethyl)oxy]methyl}ethyl]pyridine-3-carboxamide: 2-[(2,6-dichlorophenyl)oxy]- N- [( 1 R)-2-(4-methylpiperazin- 1 -yl)-2-oxo- 1 - { [(phenylmethyl)oxy]methyl} ethyl]pyridine-3 - carboxamide was synthesized in a manner similar to Example 1 wherein 2-(2,6- dichlorophenoxy)nicotinic acid was substituted for 2-(4-chlorophenoxy)nicotinic acid. 2- (2,6-dichlorophenoxy)nicotinic acid was synthesized in a manner similar to Example 3 wherein 2,6-dichlorophenol was substituted for 2-chloro-6-methylphenol. 1H NMR (400 MHz, DMSO-J6): δ 8.74 (d, IH), 8.33 (dd, IH), 8.20 (dd, IH), 7.62 (d, 2H), 7.38 (d, IH), 7.32 (m, IH), 7.22 (m, 5H), 5.23 (t, IH), 4.48 (dd, 2H), 3.70 (m, 2H), 3.43 (m, 4H), 2.2 l(m, 4H), 2.10 (s, 3H). MS (EI) for C27H28Cl2N4O4 found 544 (MH+).
[00185] 2-[(2-chloro-6-methylphenyl)oxy]-N-[(lR)-2-(4-methylpiperazin-l-yl)-2-oxo- l-{[(phenylmethyl)oxy]methyl}ethyl]pyridine-3-carboxamide: 2-[(2-chloro-6- methylphenyl)oxy]-N- [( 1 R)-2-(4-methylpiperazin- 1 -yl)-2-oxo- 1 -
{[(phenylmethyl)oxy]methyl}ethyl]pyridine-3-carboxamide was synthesized in a manner similar to Example 1 wherein 2-(2-chloro-6-methylphenoxy)nicotinic acid was substituted for 2-(4-chlorophenoxy)nicotinic acid. 2-(2-chloro-6-methylphenoxy)nicotinic acid was synthesized in a manner similar to Example 3 wherein 2-chloro-6-methylphenol was substituted for 2-chloro-6-methylphenol. 1U NMR (400 MHz, DMSO-J6): δ 8.86 (m, IH), 8.34 (d, IH), 8.19 (m, IH), 7.41 (d, IH), 7.25 (m, 8H), 5.24 (t, IH), 4.48 (dd, 2H), 3.70 (m, 2H), 3.49 (m, 4H), 2.21 (m, 4H), 2.10 (s, 3H). MS (EI) for C28H3IClN4O4 found 524 (MH+). [00186] 2-[(2,4-dichlorophenyl)oxy]-N-[(lR)-2-(4-methylpiperazin-l-yl)-2-oxo-l- {[(phenylmethyl)oxy]methyl}ethyl]pyridine-3-carboxamide: 2-[(2,4-dichlorophenyl)oxy]- N- [( 1 R)-2-(4-methylpiperazin- 1 -yl)-2-oxo- 1 - { [(phenylmethyl)oxy]methyl} ethyl]pyridine-3 - carboxamide was synthesized in a manner similar to Example 1 wherein 2-(2,4- dichlorophenoxy)nicotinic acid was substituted for 2-(4-chlorophenoxy)nicotinic acid. 2- (2,4-dichlorophenoxy)nicotinic acid was synthesized in a manner similar to Example 3 wherein 2,4-dichlorophenol was substituted for 2-chloro-6-methylphenol. 1H NMR (400 MHz, DMSO-J6): δ 8.79 (d, IH), 8.23 (dd, IH), 8.19 (dd, IH), 7.77 (s, IH), 7.51 (dd, IH), 7.45(d, IH), 7.25 (m, 6H), 5.20 (t, IH), 4.47 (dd, 2H), 3.68 (m, 2H), 3.48 (m, 4H), 2.20 (m, 4H), 2.08 (s, 3H). MS (EI) for C27H28Cl2N4O4 found 544 (MH+).
[00187] 2-{[2-chloro-5-(trifluoromethyl)phenyl]oxy}-N-[(lR)-2-(4-methylpiperazin-l- yl)-2-oxo-l-{[(phenylmethyl)oxy]methyl}ethyl]pyridine-3-carboxamide: 2-{[2-chloro-5- (trifluoromethyl)phenyl]oxy } -N- [( 1 R)-2-(4-methylpiperazin- 1 -yl)-2-oxo- 1 - {[(phenylmethyl)oxy]methyl}ethyl]pyridine-3-carboxamide was synthesized in a manner similar to Example 1 wherein 2-(2-chloro-5-trifluoromethylphenoxy)nicotinic acid was substituted for 2-(4-chlorophenoxy)nicotinic acid. 2-(2-Chloro-5- triflioromethylphenoxy)nicotinic acid was synthesized in a manner similar to Example 3 wherein 2-chloro-5-trifluoromethyl phenol was substituted for 2-methyl-6-chlorophenol. 1H NMR (400 MHz, CDCl3): δ 8.68 (d, IH), 8.58 (d, IH), 8.17 (d, IH), 7.61 (m, 2H), 7.58 (m, IH), 7.26 (m, 5H), 7.20 (m, IH), 5.40 (q, IH), 4.51 (m, 2H), 3.82 (m, 2H), 3.69 (m, 2H), 3.57 (m, 2H), 2.41 (m, 4H), 2.22 (s, 3H). MS (EI) for C28H28ClF3N4O4 found 577.19 (MH+). [00188] N-[(lR)-2-(4-methylpiperazin-l-yl)-2-oxo-l-
{[(phenylmethyl)oxy]methyl}ethyl]-2-(phenyloxy)pyridine-3-carboxamide: N-[(lR)-2-(4- methylpiperazin- 1 -yl)-2-oxo- 1 - { [(phenylmethyl)oxy]methyl} ethyl] -2-(phenyloxy)pyridine-3 - carboxamide was synthesized in a manner similar to Example 1 wherein 2-phenoxynicotinic acid was substituted for 2-(4-chlorophenoxy)nicotinic acid. 2-Phenoxynicotinic acid was synthesized in a manner similar to Example 3 wherein phenol was substituted for 2-methyl- 6-chlorophenol. 1H NMR (400 MHz, DMSO-J6): δ 8.92 (d, IH), 8.26 (m, 2H), 8.15 (d, IH), 7.45 (m, 2H), 7.24 (m, 8H), 5.23 (q, IH), 4.53 (m, 2H), 3.69 (m, 2H), 3.48 (m, 4H), 2.23 (m, 4H), 2.12 (s, 3H). MS (EI) for C27H30N4O4 found 475.70 (MH+). [00189] 2-[(3,4-dimethylphenyl)oxy]-N-[(lR)-2-(4-methylpiperazin-l-yl)-2-oxo-l- {[(phenylmethyl)oxy]methyl}ethyl]pyridine-3-carboxamide: 2-[(3,4- dimethylphenyl)oxy] -N-[( 1 R)-2-(4-methylpiperazin- 1 -yl)-2-oxo- 1 -
{[(phenylmethyl)oxy]methyl}ethyl]pyridine-3-carboxamide was synthesized in a manner similar to Example 1 wherein 2-(3,4-dimethylphenoxy)nicotinic acid was substituted for 2- (4-chlorophenoxy)nicotinic acid. 2-(3,4-Dimethylphenoxy)nicotinic acid was synthesized in a manner similar to Example 3 wherein 3,4-dimethylphenol was substituted for 2-methyl-6- chlorophenol. 1H NMR (400 MHz, DMSO-J6): δ 8.88 (d, IH), 8.24 (m, 2H), 7.26 (m, 6H), 6.89 (s, IH), 6.79 (s, 2H), 5.22 (q, IH), 4.50 (m, 2H), 3.69 (m, 2H), 3.46 (m, 4H), 2.78 (s, 6H), 2.29 (m, 4H), 2.12 (s, 3H). MS (EI) for C29H34N4O4 found 503.10 (MH+). [00190] 2-[(2,6-difluorophenyl)oxy]-N-[(lR)-2-(4-methylpiperazin-l-yl)-2-oxo-l- {[(phenylmethyl)oxy]methyl}ethyl]pyridine-3-carboxamide: 2-[(2,6-difluorophenyl)oxy]- N- [( 1 R)-2-(4-methylpiperazin- 1 -yl)-2-oxo- 1 - { [(phenylmethyl)oxy]methyl} ethyl]pyridine-3 - carboxamide was synthesized in a manner similar to Example 1 wherein 2-(2,6- difluorophenoxy)nicotinic acid was substituted for 2-(4-chlorophenoxy)nicotinic acid. 2- (2,6-Difluorophenoxy)nicotinic acid was synthesized in a manner similar to Example 3 wherein 2,6-difluorophenol was substituted for 2-methyl-6-chlorophenol. 1H NMR (400 MHz, DMSO-J6): δ 8.53 (d, IH), 8.26 (m, 2H), 7.31 (m, 9H), 5.23 (q, IH), 4.51 (m, 2H), 3.72 (m, 2H), 3.46 (m, 4H), 2.23 (s, 4H), 2.11 (s, 3H). MS (EI) for C27H28F2N4O4 found 511.10 (MH+).
[00191] N-[(lR)-2-(4-methylpiperazin-l-yl)-2-oxo-l-
{ [(phenylmethyl)oxy] methyl} ethyl] -2-(naphthalen- l-yloxy)pyridine-3-carboxamide : N- [(I R)-2-(4-methylpiperazin- 1 -yl)-2-oxo- 1 - { [(phenylmethyl)oxy]methyl} ethyl]-2- (naphthalen-l-yloxy)pyridine-3 -carboxamide was synthesized in a manner similar to Example 1 wherein -(l-naphthalenyloxy)nicotinic acid was substituted for 2-(4- chlorophenoxy)nicotinic acid. 2-(l-Naphthalenyloxy)nicotinic acid was synthesized in a manner similar to Example 3 wherein 1-napthalenol was substituted for 2-methyl-6- chlorophenol. 1H NMR (400 MHz, DMSO-J6): δ 9.12 (d, IH), 8.29 (d, IH), 8.11 (dd, IH), 8.03 (d, IH), 7.87 (dd, 2H), 7.56 (m, 2H), 7.48 (t, IH), 7.37 (d, IH), 7.25 (m, 1H),7.2O (m, 5H), 5.27 (q, IH), 4.48 (q, 2H), 3.72 (m, 2H), 3.43 (m, 4H), 2.16 (m, 4H), 2.04 (s, 3H). MS (EI) for C3IH32N4O4 found 525.10 (MH+).
[00192] 2-[(4-fluorophenyl)oxy]-N-[(lR)-2-(4-methylpiperazin-l-yl)-2-oxo-l- {[(phenylmethyl)oxy]methyl}ethyl]pyridine-3-carboxamide: [(4-fluorophenyl)oxy]-N- [(I R)-2-(4-methylpiperazin- 1 -yl)-2-oxo- 1 - { [(phenylmethyl)oxy]methy 1} ethyl]pyridine-3 - carboxamide was synthesized in a manner similar to Example 1 wherein 2-(4- fluorophenoxy)nicotinic acid was substituted for 2-(4-chlorophenoxy)nicotinic acid. 2-(4- Fluorophenoxy)nicotinic acid was synthesized in a manner similar to Example 3 wherein A- fluorophenol was substituted for 2-methyl-6-chlorophenol. 1H NMR (400 MHz, DMSO-J6): δ 8.90 (d, IH), 8.21 (d, 2H), 7.26 (m, 10H), 5.22 (q, IH), 4.50 (m, 2H), 3.69 (m, 2H), 3.47 (m, 4H), 2.22 (s, 4H), 2.11 (s, 3H). MS (EI) for C27H29FN4O4 found 493.15 (MH+). [00193] 2-[(4-methylphenyl)oxy]-N-[(lR)-2-(4-methylpiperazin-l-yl)-2-oxo-l- {[(phenylmethyl)oxy]methyl}ethyl]pyridine-3-carboxamide: [(4-methylphenyl)oxy]-N- [(I R)-2-(4-methylpiperazin- 1 -yl)-2-oxo- 1 - { [(phenylmethyl)oxy]methy 1} ethyl]pyridine-3 - carboxamide was synthesized in a manner similar to Example 1 wherein 2-(4- methylphenoxy)nicotinic acid was substituted for 2-(4-chlorophenoxy)nicotinic acid. 2-(4- Methylphenoxy)nicotinic acid was synthesized in a manner similar to Example 3 wherein A- methylphenol was substituted for 2-methyl-6-chlorophenol. 1H NMR (400 MHz, DMSO- d6): δ 8.91 (d, IH), 8.26 (d, 2H), 8.15 (s, IH), 7.26 (m, 7H), 7.03 (d, 2H), 5.22 (q, IH), 4.50 (m, 2H), 3.69 (m, 2H), 3.47 (m, 4H), 2.33 (s, 3H), 2.23 (m, 4H), 2.12 (s, 3H). MS (EI) for C28H32N4O4, found 489.15 (MH+).
[00194] 2-[(4-bromophenyl)oxy]-N-[(lR)-2-(4-methylpiperazin-l-yl)-2-oxo-l- {[(phenylmethyl)oxy]methyl}ethyl]pyridine-3-carboxamide: [(4-bromophenyl)oxy]-N- [(I R)-2-(4-methylpiperazin- 1 -yl)-2-oxo- 1 - { [(phenylmethyl)oxy]methy 1} ethyl]pyridine-3 - carboxamide was synthesized in a manner similar to Example 1 wherein 2-(4- bromophenoxy)nicotinic acid was substituted for 2-(4-chlorophenoxy)nicotinic acid. 2-(4- Bromophenoxy)nicotinic acid was synthesized in a manner similar to Example 3 wherein A- bromophenol was substituted for 2-methyl-6-chlorophenol. 1H NMR (400 MHz, DMSO-J6): δ 8.88 (d, IH), 8.24 (d, 2H), 8.15 (s, IH), 7.62 (d, 2H), 7.26 (m, 5H), 7.03 (d, 2H), 5.22 (q, IH), 4.50 (m, 2H), 3.69 (m, 2H), 3.47 (m, 4H), 2.23 (m, 4H), 2.12 (s, 3H). MS (EI) for C27H29N4O4 found 554.15 (MH+).
[00195] 2-{[2-chloro-4-(methyloxy)phenyl]oxy}-N-[(lR)-2-(4-methylpiperazin-l-yl)-2- oxo-l-{[(phenylmethyl)oxy]methyl}ethyl]pyridine-3-carboxamide: {[2-chloro-4-
(methyloxy)phenyl]oxy } -N-[( 1 R)-2-(4-methylpiperazin- 1 -yl)-2-oxo- 1 - {[(phenylmethyl)oxy]methyl}ethyl]pyridine-3-carboxamide was synthesized in a manner similar to Example 1 wherein 2-(2-chloro-4-methoxyphenoxy)nicotinic acid was substituted for 2-(4-chlorophenoxy)nicotinic acid. 2-(2-Chloro-4-methoxy phenoxy)nicotinic acid was synthesized in a manner similar to Example 3 wherein 2-chloro-4-methoxyphenol was substituted for 2-methyl-6-chlorophenol. 1H NMR (400 MHz, DMSO-J6): δ 8.83 (d, IH), 8.29 (d, IH), 8.20 (d, IH), 7.34 (d, IH), 7.25 (m, 6H), 7.18 (d, IH), 7.03 (dd, IH), 5.22 (q, IH), 4.50 (m, 2H), 3.81 (s, 3H), 3.69 (m, 2H), 3.47 (m, 4H), 2.21 (m, 4H), 2.11 (s, 3H). MS (EI) for C28H3IClN4O5 found 540.15 (MH+).
[00196] 2-[(2-bromo-4-chlorophenyl)oxy]-N-[(lR)-2-(4-methylpiperazin-l-yl)-2-oxo- l-{[(phenylmethyl)oxy]methyl}ethyl]pyridine-3-carboxamide: 2-[(2-bromo-4- chlorophenyl)oxy]-N- [( 1 R)-2-(4-methylpiperazin- 1 -yl)-2-oxo- 1 -
{[(phenylmethyl)oxy]methyl}ethyl]pyridine-3-carboxamide was synthesized in a manner similar to Example 1 wherein 2-(2-bromo-4-chlorophenoxy)nicotinic acid was substituted for 2-(4-chlorophenoxy)nicotinic acid. 2-(2-Bromo-4-chlorophenoxy)nicotinic acid was synthesized in a manner similar to Example 3 wherein 2-bromo-4-chlorophenol was substituted for 2-methyl-6-chlorophenol. 1H NMR (400 MHz, DMSO-J6): δ 8.79 (d, IH), 8.27 (d, IH), 8.25 (d, IH), 7.90 (d, IH), 7.57 (dd, IH), 7.45 (d, IH), 7.29 (dd, IH), 7.28 (m, 5H), 5.22 (q, IH), 4.50 (dd, 2H), 3.69 (m, 2H), 3.47 (m, 4H), 2.21 (m, 4H), 2.11 (s, 3H). MS (EI) for C27H28BrClN4O4 found 588.15 (MH+). [00197] N-[(lR)-2-(4-methylpiperazin-l-yl)-2-oxo-l- { [(phenylmethyl)oxy] methyl} ethyl] -2- [(2,4,6-trichlorophenyl)oxy] pyridine-3- carboxamide: N-[( 1 R)-2-(4-methylpiperazin- 1 -yl)-2-oxo- 1 -
{[(phenylmethyl)oxy]methyl}ethyl]-2-[(2,4,6-trichlorophenyl)oxy]pyridine-3-carboxamide was synthesized in a manner similar to Example 1 wherein 2-(2,4,6- trichlorophenoxy)nicotinic acid was substituted for 2-(4-chlorophenoxy)nicotinic acid. 2- (2,4,6-Trichlorophenoxy)nicotinic acid was synthesized in a manner similar Example 3 wherein 2,4,6-trichlorophenol was substituted for 2-methyl-6-chlorophenol. 1H NMR (400 MHz, CDCl3): δ 8.53 (d, 2H), 8.07 (d, IH), 7.33 (d, IH), 7.19 (m, 6H), 7.09 (dd, IH), 5.33 (q, IH), 4.44 (s, 2H), 3.78 (m, 2H), 3.64 (m, 4H), 2.35 (m, 4H), 2.16 (s, 3H). MS (EI) for C27H27Cl3N4O4 found 577.15 (MH+).
[00198] 2-{[3-(dimethylamino)phenyl]oxy}-N-[(lR)-2-(4-methylpiperazin-l-yl)-2-oxo- l-{[(phenylmethyl)oxy]methyl}ethyl]pyridine-3-carboxamide: 2-{[3-
(dimethylamino)phenyl]oxy } -N- [( 1 R)-2-(4-methylpiperazin- 1 -yl)-2-oxo- 1 - {[(phenylmethyl)oxy]methyl}ethyl]pyridine-3-carboxamide was synthesized in a manner similar to Example 1 wherein 2-(3-dimethylaminophenoxy)nicotinic acid was substituted for 2-(4-chlorophenoxy)nicotinic acid. 2-(3-Dimethylaminophenoxy)nicotinic acid was synthesized in a manner similar to Example 3 wherein 3-dimethylaminophenol was substituted for 2-methyl-6-chlorophenol. 1U NMR (400 MHz, DMSO-J6): δ 8.89 (d, IH), 8.24 (m, 2H), 7.26 (m, 7H), 6.61 (dd, IH), 6.52 (m, IH), 6.44 (dd, IH), 5.22 (m, IH), 4.49 (m, 2H), 3.69 (m, 2H), 3.47 (m, 4H), 2.88 (s, 6H), 2.21 (m, 4H), 2.11 (s, 3H). MS (EI) for C29H35N5O4 found 518.2 (MH+).
[00199] The following compounds were made in a manner which employed the methods of Example 2 and Example 3:
[00200] 2- [(4-chloro-2-methylphenyl)oxy] -N- [(lR)-l-({[(3- methylphenyl)methyl]oxy}methyl)-2-(4-methylpiperazin-l-yl)-2-oxoethyl]pyridine-3- carboxamide: 2- [(4-chloro-2-methylphenyl)oxy] -N- [( 1 R)- 1 -( { [(3 - methylphenyl)methyl]oxy}methyl)-2-(4-methylpiperazin-l-yl)-2-oxoethyl]pyridine-3- carboxamide was synthesized in a manner similar to Example 2 wherein 2-(2-methyl-4- chlorophenoxy)nicotinic acid was substituted for 2-(4-chlorophenoxy)nicotinic acid. 2-(2- Methyl-4-chlorophenoxy)nicotinic acid was synthesized in a manner similar to Example 3 wherein 2-methyl-4-chlorophenol was substituted for 2-methyl-6-chlorophenol. 1H NMR (400 MHz, DMSO-J6): δ 8.88 (d, IH), 8.27 (dd, IH), 8.18 (m, IH), 7.40 (d, IH), 7.29 (m, IH), 7.24 (dd, IH), 7.12 (m, 2H), 7.01 (m, 3H), 5.19 (m, IH), 4.43 (s, 2H), 3.67 (m, 2H), 3.43 (m, 4H), 2.18 (m, 4H), 2.20 (s, 3H), 2.09 (s, 3H), 2.05 (s, 3H). MS (EI) for C29H33ClFN4O4 found 537.0 (MH+).
[00201 ] 2- [(4-chlor ophenyl)oxy] -N- [(1R)- 1- [(4-methylpiper azin- l-yl)carbonyl] -3- (phenyloxy)propyl] pyridine-3-carboxamide: 2- [(4-chlorophenyl)oxy] -N-[( 1 R)- 1 - [(4- methylpiperazin-l-yl)carbonyl]-3-(phenyloxy)propyl]pyridine-3-carboxamide was synthesized in a manner similar to Example 2 wherein (R)-2-(tert-butoxycarbonylamino)-4- hydroxybutanoic acid was substituted for (R)-2-(tert-butoxycarbonylamino)-3- hydroxypropanoic acid, and wherein phenol was substituted for 3-methylbenzyl bromide in a manner similar to Example 3. 1U NMR (400 MHz, DMSO-J6): δ 8.91 (d, IH), 8.19 (dd, IH), 8.07 (dd, IH), 7.44 (d, 2H), 7.24 (m, 5H), 6.88 (t, IH), 6.79 (d, 2H), 5.15 (t, IH), 4.01 (m, 2H), 3.49 (m, 4H), 2.29 (m, 4H), 2.17 (m, IH), 2.13 (s, 3H), 2.04 (m, IH). MS (EI) for C27H29ClN4O4 found 510 (MH+).
[00202] 2-{[2-chloro-4-(trifluoromethyl)phenyl]oxy}-N-[(lR)-l-({[(4- fluorophenyl)methyl]oxy}methyl)-2-(4-methylpiperazin-l-yl)-2-oxoethyl]pyridine-3- carboxamide: 2- { [2-chloro-4-(trifluoromethyl)phenyl]oxy } -N- [( 1 R)- 1 -( { [(4- fluorophenyl)methyl]oxy}methyl)-2-(4-methylpiperazin-l-yl)-2-oxoethyl]pyridine-3- carboxamide was synthesized in a manner similar to Example 2 wherein 2-(2-chloro-4- triflioromethylphenoxy)nicotinic acid was substituted for 2-(4-chlorophenoxy)nicotinic acid, and 4-fluorobenzyl bromide was substituted for 3-methylbenzyl bromide. 2-(2-Chloro-4- trifluoromethylphenoxy)nicotinic acid was synthesized in a manner similar to Example 3 wherein 2-chloro-4-trifluoromethyl phenol was substituted for 2-methyl-6-chlorophenol. 1H NMR (400 MHz, CDCl3): δ 8.60 (d, IH), 8.50 (d, IH), 8.10 (m, IH), 7.68 (s, IH), 7.53 (d, IH), 7.35 (d, IH), 7.14 (m, 3H), 7.91 (m, 2H), 5.29 (q, IH), 4.40 (m, 2H), 3.74 (m, 2H), 3.63 (m, 2H), 3.59 (m, 2H), 2.30 (m, 4H), 2.17 (s, 3H). MS (EI) for C28H27ClF4N4O4 found 594.0 (MH+).
[00203] 2-[(2,4-dichlorophenyl)oxy]-N-[(lR)-l-[(4-methylpiperazin-l-yl)carbonyl]-3- (phenyloxy)propyl]pyridine-3-carboxamide: 2-[(2,4-dichlorophenyl)oxy]-N-[(lR)-l-[(4- methylpiperazin-l-yl)carbonyl]-3-(phenyloxy)propyl]pyridine-3-carboxamide was synthesized in a manner similar to Example 2 wherein (R)-2-(tert-butoxycarbonylamino)-4- hydroxybutanoic acid was substituted for (R)-2-(tert-butoxycarbonylamino)-3- hydroxypropanoic acid, phenol was substituted for 3-methylbenzyl bromide, and 2-(2,4- dichlorophenoxy)nicotinic acid was substituted for 2-(4-chlorophenoxy)nicotinic acid. 2- (2,4-dichlorophenoxy)nicotinic acid was synthesized in a manner similar to Example 3 wherein 2,4-dichlorophenol was substituted for 2-chloro-6-methylphenol. 1H NMR (400 MHz, DMSO-J6): δ 8.86 (d, IH), 8.16 (dd, IH), 8.12 (dd, IH), 7.74 (d, IH), 7.49 (dd, IH), 7.43 (d, IH), 7.25 (dd, IH), 7.19 (t, 2H), 6.86 (t, IH), 6.79 (d, 2H), 5.17 (t, IH), 4.02 (m, 2H), 3.52 (m, 4H), 2.26 (m, 4H), 2.16 (m, IH), 2.11 (s, 3H), 2.05 (m, IH). MS (EI) for C27H28Cl2N4O4 found 544 (MH+). Example 4
5-bromo-2- (4-chlorophenoxy)nicotinic acid
Figure imgf000065_0001
Figure imgf000065_0002
[00204] Step 1: Ethyl S-bromo-l-chloronicotinate: To a solution of 5-bromo-2- chloronicotinic acid (1.00 g, 4.23 mmol) in ethanol (8.5 mL) was added concentrated H2SO4 (1.40 mL, 25.38 mmol) drop wise over a minute. The reaction was heated to reflux for 2 hours. All solvent was removed in vacuo and the residue was taken up in ethyl acetate (20 mL) and washed once with 1 M NaOH (20 mL) and then dried over anhydrous magnesium sulfate. The magnesium sulfate was filtered off and the ethyl acetate was removed in vacuo. The remaining oil was used in the next step without further purification. MS (EI) for C8H7BrClNO2 found 263.90 (MH+).
[00205] Step 2: Ethyl 5-bromo-2-(4-chlorophenoxy)nicotinate: A solution of ethyl 5- bromo-2-chloronicotinate (939.00 mg, 3.55 mmol), 4-chlorophenol (547.68, 4.26 mmol), and cesium carbonate (1735.04 mg, 5.33 mmol) in dimethylacetamide (35 mL) was heated to 130 0C for 16 hours. After cooling to room temperature, the solvent was removed in vacuo and the remaining residue was taken up in ethyl acetate (100 mL) and washed with 1 M NaOH (2 X 100 mL) followed by water (100 mL) and dried over anhydrous magnesium sulfate. The magnesium sulfate was filtered off and the ethyl acetate was removed in vacuo. The remaining oil was sufficiently pure for use in the subsequent step. MS (EI) for Ci4HIiBrClNO3 found 355.97 (MH+).
[00206] Step 3: 5-bromo-2-(4-chlorophenoxy)nicotinic acid: Ethyl 5-bromo-2-(4- chlorophenoxy)nicotinate (1120.00 mg, 3.14 mmol) was dissolved in tetrahydrofuran (15 mL) and 12.5 mL (12.5 mmol) of a 1 M LiOH solution was added and this was heated to 70 0C for 6 hours. After cooling to room temperature, the reaction was washed with diethyl ether (20 mL) and the water layer was acidified to pH 2 and extracted with ethyl acetate (2 X 20 mL). The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated on the rotary evaporator. A white solid remained that was sufficiently pure to be used without further purification. MS (EI) for Ci2H7BrClNO3 found 327.81 (MH+). [00207] The following compounds were made in a manner which employed the methods of Example 1 and Example 4:
[00208] 2-[(2,4-dichlorophenyl)oxy]-5-fluoro-N-[(lR)-2-(4-methylpiperazin-l-yl)-2- oxo-l-{[(phenylmethyl)oxy]methyl}ethyl]pyridine-3-carboxamide: 2-[(2,4- dichlorophenyl)oxy]-5-fluoro-N-[(lR)-2-(4-methylpiperazin- 1 -yl)-2-oxo- 1 - {[(phenylmethyl)oxy]methyl}ethyl]pyridine-3-carboxamide was synthesized in a manner similar to Example 1 wherein 2-(2,4-dichlorophenoxy)-5-fluoronicotinic acid (prepared as in Example 4) was substituted for 2-(4-chlorophenoxy)nicotinic acid. 1H NMR (400 MHz, DMSO-J6): δ 8.88 (d, IH), 8.25 (d, IH), 8.09 (dd, IH), 7.77 (d, IH), 7.47 (m, 2H), 7.23 (m, 5H), 5.19 (q, IH), 4.46 (q, 2H), 3.68 (m, IH), 2.19 (br s, 4H), 2.08 (s, 3H). MS (EI) for C27H27Cl2FN4O4 found 561.17 (MH+).
[00209] 2-[(4-fluoro-2-methylphenyl)oxy]-N-[(lR)-2-(4-methylpiperazin-l-yl)-2-oxo- l-{[(phenylmethyl)oxy]methyl}ethyl]pyridine-3-carboxamide: 2-[(4-fluoro-2- methylphenyl)oxy]-N- [( 1 R)-2-(4-methylpiperazin- 1 -yl)-2-oxo- 1 -
{[(phenylmethyl)oxy]methyl}ethyl]pyridine-3-carboxamide was synthesized in a manner similar to Example 1 wherein 2-(4-fluoro-2-methylphenoxy)nicotinic acid (prepared as in Example 4) was substituted for 2-(4-chlorophenoxy)nicotinic acid. 1H NMR (400 MHz, DMSO-J6): δ 8.90 (d, IH), 8.27 (m, IH), 8.18 (m, IH), 7.18 (m, 9H), 5.22 (m, IH), 4.46 (q, 2H), 3.68 (m, 2H), 3.44 (m, 4H), 2.19 (m, 4H), 2.09 (s, 3H), 2.05 (s, 3H). MS (EI) for C28H3IFN4O4 found 506.69 (MH+).
[00210] 2-[(2-chloro-4-fluorophenyl)oxy]-N-[(lR)-2-(4-methylpiperazin-l-yl)-2-oxo-l- { [(phenylmethyl)oxy] methyl} ethyl] pyridine-3-carboxamide: 2- [(2-chloro-4- fluorophenyl)oxy] -N-[( 1 R)-2-(4-methylpiperazin- 1 -yl)-2-oxo- 1 -
{[(phenylmethyl)oxy]methyl}ethyl]pyridine-3-carboxamide was synthesized in a manner similar to Example 1 wherein 2-(2-chloro-4-fluorophenoxy)nicotinic acid (prepared as in Example 4) was substituted for 2-(4-chlorophenoxy)nicotinic acid. 1H NMR (400 MHz, DMSO-J6): δ 8.79 (d, IH), 8.24 (m, IH), 8.18 (m, IH), 7.60 (m, IH), 7.47 (m, IH), 7.27 (m, 8H), 5.21 (m, IH), 4.47 (q, 2H), 3.68 (m, 2H), 3.46 (m, 4H), 2.19 (m, 4H), 2.09 (s, 3H). MS (EI) for C27H28ClFN4O4 found 527.16 (MH+).
[00211] 2-[(4-chlorophenyl)oxy]-6-methyl-N-[(lR)-2-(4-methylpiperazin-l-yl)-2-oxo- l-{[(phenylmethyl)oxy]methyl}ethyl]pyridine-3-carboxamide: 2-[(4-chlorophenyl)oxy]-6- methyl-N-[( 1 R)-2-(4-methylpiperazin- 1 -yl)-2-oxo- 1 - {[(phenylmethyl)oxy]methyl}ethyl]pyridine-3-carboxamide was synthesized in a manner similar to Example 1 wherein 2-(4-chlorophenoxy)-6-methylnicotinic acid (prepared as in Example 4) was substituted for 2-(4-chlorophenoxy)nicotinic acid. 1H NMR (400 MHz, DMSO-J6): δ 8.77 (d, IH), 8.14 (m, IH), 7.46 (m, 2H), 7.22 (m, 7H), 7.12 (d, IH), 5.17 (m, IH), 4.45 (q, 2H), 3.65 (m, 2H), 2.29 (s, 3H), 2.18 (m, 4H), 2.09 (s, 3H). MS (EI) for C28H3IClN4O4 found 523.25 (MH+).
[00212] 2-[(4-chlorophenyl)oxy]-5-fluoro-N-[(lR)-2-(4-methylpiperazin-l-yl)-2-oxo-l- {[(phenylmethyl)oxy]methyl}ethyl]pyridine-3-carboxamide: 2-[(4-chlorophenyl)oxy]-5- fluoro-N- [( 1 R)-2-(4-methylpiperazin- 1 -yl)-2-oxo- 1 -
{[(phenylmethyl)oxy]methyl}ethyl]pyridine-3-carboxamide was synthesized in a manner similar to Example 1 wherein 2-(4-chlorophenoxy)-5-fluoronicotinic acid (prepared as in Example 4) was substituted for 2-(4-chlorophenoxy)nicotinic acid. 1H NMR (400 MHz, DMSO-J6): δ 8.94 (d, IH), 8.25 (d, IH), 8.06 (m, IH), 7.47 (m, 2H), 7.24 (m, 7H), 5.17 (m, IH), 4.46 (q, 2H), 3.65 (m, 2H), 3.43 (m, 4H), 2.19 (m, 4H), 2.09 (s, 3H). MS (EI) for C27H28ClFN4O4 found 526.25 (MH+).
[00213] 2-[(2,4-dichlorophenyl)oxy]-N-[(lR)-2-[methyl(l-methylpiperidin-4- yl)amino]-2-oxo-l-{[(phenylmethyl)oxy]methyl}ethyl]pyridine-3-carboxamide: 2-[(2,4- dichlorophenyl)oxy]-N-[(lR)-2-[methyl(l-methylpiperidin-4-yl)amino]-2-oxo-l- {[(phenylmethyl)oxy]methyl}ethyl]pyridine-3-carboxamide was synthesized in a manner similar to Example 1 wherein N,l-dimethylpiperidin-4-amine was substituted for N- methylpiperazine and 2-(2,4-dichlorophenoxy)nicotinic acid (prepared as in Example 4) was substituted for 2-(4-chlorophenoxy)nicotinic acid. 1H NMR (400 MHz, DMSO-J6): δ 8.78 (dd, IH), 8.22 (m, 2H), 7.77 (m, IH), 7.49 (m, 2H), 7.22 (m, 6H), 5.20 (m, IH), 4.48 (m, 2H), 3.96 (m, IH), 3.70 (m, 2H), 2.90 (s, 2H), 2.67 (m, 4H), 2.10 (m, 3H), 1.63 (m, 6H). MS (EI) for C29H32Cl2N4O4 found 571.12 (MH+).
[00214] 2-{[2-chloro-4-(trifluoromethyl)phenyl]oxy}-N-[(lR)-2-[methyl(l- methylpiperidin-4-yl)amino]-2-oxo-l-{[(phenylmethyl)oxy]methyl}ethyl]pyridine-3- carboxamide: 2- { [2-chloro-4-(trifluoromethyl)phenyl]oxy } -N-[( 1 R)-2-[methyl( 1 - methylpiperidin-4-yl)amino] -2-oxo- 1 - { [(phenylmethyl)oxy]methyl} ethyl]pyridine-3 - carboxamide was synthesized in a manner similar to Example 1 wherein N,l- dimethylpiperidin-4-amine was substituted for N-methylpiperazine and 2-(2-chloro-4- (trifluoromethyl)phenoxy)nicotinic acid (prepared as in Example 4) was substituted for 2-(4- chlorophenoxy)nicotinic acid. 1H NMR (400 MHz, DMSO-J6): δ 8.80 (dd, IH), 8.21 (m, 2H), 8.05 (m, IH), 7.81 (m, IH), 7.64 (m, IH), 7.30 (m, IH), 7.22 (m, 6H), 5.20 (m, IH), 4.47 (m, 2H), 4.15 (m, IH), 3.70 (m, 3H), 2.90 (s, 2H), 2.68 (m, 4H), 2.10 (s, 3H), 1.60 (m, 4H). MS (EI) for C30H32ClF3N4O4 found 605.01 (MH+).
[00215] 2- [(2,4-dichlor ophenyl)oxy] -N- [(I R)-2- [(l-methylpiperidin-4-yl)amino] -2- oxo-l-{[(phenylmethyl)oxy]methyl}ethyl]pyridine-3-carboxamide: 2-[(2,4- dichlorophenyl)oxy]-N-[(lR)-2-[(l-methylpiperidin-4-yl)amino]-2-oxo-l- {[(phenylmethyl)oxy]methyl}ethyl]pyridine-3-carboxamide was synthesized in a manner similar to Example 1 wherein l-methylpiperidin-4-amine was substituted for N- methylpiperazine and 2-(2,4-dichlorophenoxy)nicotinic acid (prepared as in Example 4) was substituted for 2-(4-chlorophenoxy)nicotinic acid. 1H NMR (400 MHz, DMSO-J6): δ 8.59 (d, IH), 8.28 (m, IH), 8.20 (m, IH), 8.09 (m, IH), 7.77 (d, IH), 7.48 (m, 2H), 7.29 (m, IH),
7.19 (m, 5H), 4.70 (m, IH), 4.45 (m, 2H), 3.70 (m, 2H), 3.56 (br s, IH), 2.80 (br s, IH), 2.26 (m, 4H), 1.70 (m, 2H), 1.42 (m, 2H). MS (EI) for C28H30C12N4O4 found 556.76 (MH+). [00216] 5-bromo-2-[(4-chlorophenyl)oxy]-N-[(lR)-2-(4-methylpiperazin-l-yl)-2-oxo- 1- { [(phenylmethyl)oxy] methyl} ethyl] pyridine-3-carboxamide: 5 -bromo-2- [(4- chlorophenyl)oxy]-N- [( 1 R)-2-(4-methylpiperazin- 1 -yl)-2-oxo- 1 -
{[(phenylmethyl)oxy]methyl}ethyl]pyridine-3-carboxamide was synthesized in a manner similar to Example 1 wherein 5-bromo-2-(4-chlorophenoxy)nicotinic acid was substituted for 2-(4-chlorophenoxy)nicotinic acid (prepared in the manner of Example 4). 1H NMR (400 MHz, DMSO-J6): δ 8.94 (d, IH), 8.38 (d, IH), 8.26 (d, IH), 7.50 (d, 2H), 7.25 (m, 7H), 5.18 (m, IH), 4.48 (q, 2H), 3.68 (m, 2H), 3.46 (m, 4H), 2.21 (br s, 4H), 2.10 (s, 3H). MS (EI) for C27H28BrClN4O4 found 587.00 (MH+).
[00217] 2-{[4-chloro-2-(phenylmethyl)phenyl]oxy}-N-[(lR)-2-(4-methylpiperazin-l- yl)-2-oxo-l-{[(phenylmethyl)oxy]methyl}ethyl]pyridine-3-carboxamide: 2-{[4-chloro-2- (phenylmethyl)pheny l]oxy } -N- [( 1 R)-2-(4-methylpiperazin- 1 -yl)-2-oxo- 1 - {[(phenylmethyl)oxy]methyl}ethyl]pyridine-3-carboxamide was synthesized in a manner similar to Example 1 wherein 2-(2-benzyl-4-chlorophenoxy)nicotinic acid was substituted for 2-(4-chlorophenoxy)nicotinic acid. 2-(2-benzyl-4-chlorophenoxy)nicotinic acid was (prepared in the manner of Example 4) wherein 2-chloronicotinic acid was substituted for 5- bromo-2-chloronicotinic acid and 2-benzylphenol was substituted for 4-chlorophenol. 1H NMR (400 MHz DMSO-J6): δ 8.87 (d, IH), 8.21 (m, IH), 8.09 (m, IH), 7.32 (s, 2H), 7.21 (m, 7H), 7.07 (m, 5H), 5.21 (q, IH), 4.45 (q, 2H), 3.83 (s, 2H), 3.66 (m, 2H), 3.46 (m, 4H),
2.20 (m, 4H), 2.09 (s, 3H). MS (EI) for C34H35ClN4O4 found 599.22 (MH+). Example 5
(R)-2-(tert-butoxycarbonylamino)-3-((l-methylcyclopropyl)methoxy)propanoic acid (i -methylcyclopropyOmethanol, Boc -anhydride e)'"' boron trifluoride diethyl etherate
Figure imgf000069_0001
CH3CN anhydrous CHCI3
Figure imgf000069_0002
Figure imgf000069_0003
[00218] Step 1: (R)-l-tert-butyl 2-methyl aziridine-l,2-dicarboxylate: To a solution of (R)-methyl aziridine-2-carboxylate [prepared according to Tetrahedron: Asymmetry (2002), 13(11), 1129-1134] (1000.00 mg, 9.89 mmol) in acetonitrile (20 mL) was added Boc anhydride (2374.63mg, 10.88 mmol). The reaction was stirred at room temperature for two hours after which all solvent was removed on the rotary evaporator. The remaining oil was utilized without further purification for the next step. 1H NMR (400 MHz, DMSO-J6): δ 3.70 (s, 3H), 3.14 (q, IH), 2.46 (m, IH), 2.39 (m, IH), 1.38 (s, 9H).
[00219] Step 2: (R)-methyl 2-(tert-butoxycarbonylamino)-3-((l-methylcyclopropyl)- methoxy)propanoate: (R)-l-tert-butyl 2-methyl aziridine-l,2-dicarboxylate (1200.00 mg, 5.96 mmol) was dissolved in anhydrous chloroform (20 mL) followed by (1- methylcyclopropyl)methanol (1540.94 mg, 17.89 mmol) and 0.04 mL (0.28 mmol) of a 7 M boron trifluoride diethyl etherate solution. The reaction was stirred at room temperature for 24 hours and quenched with a few drops of methanol. The product was purified by normal phase chromatography (5% ethyl acetate in hexanes) to afford a clear oil. 1H NMR (400 MHz, DMSO-J6): δ 7.13 (d, IH), 4.23 (m, IH), 3.63 (s, 3H), 3.59 (m, 2H), 3.17 (m, 2H), 1.38 (s, 9H), 1.01 (s, 3H), 0.33 (m, 2H), 0.24 (m, 2H).
[00220] Step 3: (R)-2-(tert-butoxycarbonylamino)-3-((l-methylcyclopropyl)methoxy)- propanoic acid: (R)-methyl 2-(tert-butoxycarbonylamino)-3-((l- methylcyclopropyl)methoxy)-propanoate (1150.00 mg, 4.00 mmol) was dissolved in tetrahydrofuran (20 mL) and 6 mL (6.00 mmol) of a 1 M LiOH solution was added and this was heated to 70 0C for 4 hours. After cooling to room temperature, the reaction was washed with diethyl ether (20 mL) and the water layer was acidified to pH 2 and extracted with ethyl acetate (2 X 20 mL). The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated on the rotary evaporator. The clear oil was sufficiently pure and used without further purification. MS (EI) for Ci3H23NO5 found 274.10 (MH+). [00221] The following compounds were made in a manner involving the methods of Example 5 and Example 4:
[00222] 2-{[2-chloro-4-(trifluoromethyl)phenyl]oxy}-N-[(lR)-l-{[(2,2- dimethylpropyl)oxy]methyl}-2-(4-methylpiperazin-l-yl)-2-oxoethyl]pyridine-3- carboxamide: 2-{[2-chloro-4-(trifluoromethyl)phenyl]oxy}-N-[(lR)-l-{[(2,2- dimethylpropyl)oxy]methyl} -2-(4-methylpiperazin- 1 -yl)-2-oxoethyl]pyridine-3-carboxamide was synthesized in a manner similar to Example 1 wherein (R)-tert-butyl l-(4- methylpiperazin-l-yl)-3-(neopentyloxy)-l-oxopropan-2-ylcarbamate was substituted for (R)- 3-(benzyloxy)-2-(tert-butoxycarbonylamino)propanoic acid and 2-(2-chloro-4- (trifluoromethyl)phenoxy)nicotinic acid was substituted for 2-(4-chlorophenoxy)nicotinic acid. (R)-tert-butyl 1 -(4-methylpiperazin- 1 -yl)-3 -(neopentyloxy)- 1 -oxopropan-2-ylcarbamate was synthesized according to Example 5 and 2-(2-chloro-4- (trifluoromethyl)phenoxy)nicotinic acid was synthesized according to Example 4 by substituting 2-chloro, 4-trifluromethylphenol for 4-chlorophenol and 2-chloronicotinic acid ethyl ester for 5-bromo-2-chloronicotinic acid ethyl ester. 1H NMR (400 MHz, DMSO-J6): δ 8.75 (d, IH), 8.21 (m, 2H), 8.06 (m, IH), 7.82 (m, IH), 7.64 (m, IH), 7.30 (m, IH), 5.18 (q, IH), 3.52 (m, 6H), 3.36 (m, 4H), 3.03 (m, 2H), 2.27 (br s, 4H), 2.11 (s, 3H), 0.74 (s, 9H). MS (EI) for C26H32ClF3N4O4 found 557.17 (MH+). [00223] 2-[(4-chloro-2-methylphenyl)oxy]-N-[(lR)-l-
{[(cyclohexylmethyl)oxy]methyl}-2-(4-methylpiperazin-l-yl)-2-oxoethyl]pyridine-3- carboxamide: 2-[(4-chloro-2-methylphenyl)oxy]-N-[(lR)-l-
{[(cyclohexylmethyl)oxy]methyl}-2-(4-methylpiperazin-l-yl)-2-oxoethyl]pyridine-3- carboxamide was synthesized in a manner similar to Example 1 wherein (R)-2-(tert- butoxycarbonylamino)-3-(cyclohexylmethoxy)propanoic acid was substituted for (R)-3- (benzyloxy)-2-(tert-butoxycarbonylamino)propanoic acid and 2-(4-chloro-2- methylphenoxy)nicotinic acid was substituted for 2-(4-chlorophenoxy)nicotinic acid. (R)-2- (tert-butoxycarbonylamino)-3-(cyclohexylmethoxy)propanoic acid was synthesized according to Example 5 by substituting cyclohexylmethanol for (1- methylcyclopropyl)methanol and 2-(4-chloro-2-methylphenoxy)nicotinic acid was synthesized according to Example 4 by substituting 4-chloro-2-methylphenol for 4- chlorophenol and 2-chloronicotinic acid for 5-bromo-2-chloronicotinic acid. 1H NMR (400 MHz, DMSO-J6): δ 8.84 (d, IH), 8.30 (dd, IH), 8.20 (dd, IH), 7.44 (br d, IH), 7.33 (dd, IH), 7.27 (m, IH), 7.18 (d, IH), 5.17 (m, IH), 3.26 (d, 2H), 3.57 (br s, 2H), 3.46 (br s, 2H), 3.17 (d, 2H), 2.31 (m, 2H), 2.23 (m, 2H), 2.15 (s, 3H), 2.10 (s, 3H), 1.56 (br d, 5H), 1.38 (m, IH), 1.06 (m, 3H), 0.77 (m, 2H). MS (EI) for C28H37ClN4O4 found 528.86 (MH+). [00224] N-[(lR)-l-{[(cyclohexylmethyl)oxy]methyl}-2-(4-methylpiperazin-l-yl)-2- oxoethyl] -2- [(2,4-dichlorophenyl)oxy] pyridine-3-carboxamide: N- [( 1 R)- 1 -
{[(cyclohexylmethyl)oxy]methyl}-2-(4-methylpiperazin-l-yl)-2-oxoethyl]-2-[(2,4- dichlorophenyl)oxy]pyridine-3-carboxamide was synthesized in a manner similar to Example 1, wherein (R)-2-(tert-butoxycarbonylamino)-3-(cyclohexylmethoxy)propanoic acid was substituted for (R)-3-(benzyloxy)-2-(tert-butoxycarbonylamino)propanoic acid and 2-(2,4-dichlorophenoxy)nicotinic acid was substituted for 2-(4-chlorophenoxy)nicotinic acid. (R)-2-(tert-butoxycarbonylamino)-3-(cyclohexylmethoxy)propanoic acid was synthesized according to Example 5 by substituting cyclohexylmethanol for (1- methylcyclopropyl)methanol and 2-(2,4-dichlorophenoxy)nicotinic acid was synthesized according to Example 4 by substituting 2,4-dichlorophenol for 4-chlorophenol and 2- chloronicotinic acid for 5-bromo-2-chloronicotinic acid. 1H NMR (400 MHz, DMSO-dβ): δ 8.71 (d, IH), 8.27 (dd, IH), 8.21 (dd, IH), 7.81 (d, IH), 7.54 (dd, IH), 7.48 (d, IH), 7.30 (m, IH), 5.16 (m, IH), 3.62 (d, 2H), 3.57 (m, 2H), 3.46 (m, 2H), 3.18 (m, 2H), 2.31 (m, 2H), 2.23 (m, 2H), 2.15 (s, 3H), 1.56 (br d, 5H), 1.39 (m, IH), 1.07 (m, 3H), 0.78 (m, 2H). MS (EI) for C27H34Cl2N4O4 found 549.08 (MH+).
[00225] 2-[(2-chloro-4-fluorophenyl)oxy]-N-[(lR)-l-{[(cyclohexylmethyl)oxy]methyl}- 2-(4-methylpiperazin-l-yl)-2-oxoethyl]pyridine-3-carboxamide: 2-[(2-chloro-4- fluorophenyl)oxy] -N- [( 1 R)- 1 - { [(cyclohexylmethyl)oxy]methyl} -2-(4-methylpiperazin- 1 -yl)- 2-oxoethyl]pyridine-3-carboxamide was synthesized in a manner similar to Example 1 wherein (R)-2-(tert-butoxycarbonylamino)-3-(cyclohexylmethoxy)propanoic acid was substituted for (R)-3-(benzyloxy)-2-(tert-butoxycarbonylamino)propanoic acid and 2-(2- chloro-4-fluorophenoxy)nicotinic acid was substituted for 2-(4-chlorophenoxy)nicotinic acid. (R)-2-(tert-butoxycarbonylamino)-3-(cyclohexylmethoxy)propanoic acid was synthesized according to Example 5 by substituting cyclohexylmethanol for (1- methylcyclopropyl)methanol and 2-(2-chloro-4-fluorophenoxy)nicotinic acid was synthesized according to Example 4 by substituting 2-chloro-4-fluorophenol for 4- chlorophenol and 2-chloronicotinic acid for 5-bromo-2-chloronicotinic acid. 1H NMR (400 MHz, DMSO-J6): δ 8.73 (d, IH), 8.28 (dd, IH), 8.21 (dd, IH), 7.64 (dd, IH), 7.50 (m, IH), 7.35 (td, IH), 7.29 (m, IH), 5.17 (m, IH), 3.62 (d, 2H), 3.57 (m, 2H), 3.46 (m, 2H), 3.18 (m, 2H), 2.32 (m, 2H), 2.23 (m, 2H), 2.15 (s, 3H), 1.56 (br d, 5H), 1.40 (m, IH), 1.07 (m, 3H), 0.78 (m, 2H). MS (EI) for C27H34ClFN4O4 found 532.89 (MH+). [00226] 2-{[2-chloro-4-(trifluoromethyl)phenyl]oxy}-N-[(lR)-l-({[(l- methylcyclopropyl)methyl]oxy}methyl)-2-(4-methylpiperazin-l-yl)-2-oxoethyl]pyridine- 3-carboxamide : 2- { [2-chloro-4-(trifluoromethyl)phenyl]oxy } -N-[( 1 R)- 1 -( { [( 1 - methylcyclopropyl)methyl]oxy}methyl)-2-(4-methylpiperazin-l-yl)-2-oxoethyl]pyridine-3- carboxamide was synthesized in a manner similar to Example 1 wherein (R)-2-(tert- butoxycarbonylamino)-3-((l-methylcyclopropyl)methoxy)propanoic acid was substituted for (R)-3-(benzyloxy)-2-(tert-butoxycarbonylamino)propanoic acid and 2-(2-chloro-4- (trifluoromethyl)phenoxy)nicotinic acid was substituted for 2-(4-chlorophenoxy)nicotinic acid. (R)-2-(tert-butoxycarbonylamino)-3 -(( 1 -methylcyclopropyl)methoxy)propanoic acid was synthesized according to Example 5 and 2-(2-chloro-4- (trifluoromethyl)phenoxy)nicotinic acid was synthesized according to Example 4 by substituting 2-chloronicotinic acid for 5-bromo-2-chloronicotinic acid and 2-chloro-4- (trifluoromethyl)phenol for 4-chlorophenol. 1H NMR (400 MHz DMSO-J6): δ 8.60 (d, IH), 8.07 (m, 2H), 7.91 (d, IH), 7.68 (dd, IH), 7.50 (d, IH), 7.16 (m, IH), 5.00 (q, IH), 3.48 (d, 2H), 3.40 (m, 2H), 2.29 (m, 2H), 3.02 (s, 2H), 2.15 (br s, 2H), 2.06 (br s, 2H), 1.96 (s, 3H), 0.79 (s, 3H), 0.12 (m, 2H), 0.01 (m, 2H). MS (EI) for C26H30ClF3N4O4 found 555.19 (MH+). [00227] 2-[(2,4-dichlorophenyl)oxy]-N-[(lR)-l-({[(l-methylcyclopropyl)methyl]oxy}- methyl)-2-(4-methylpiperazin-l-yl)-2-oxoethyl]pyridine-3-carboxamide: 2-[(2,4- dichlorophenyl)oxy] -N- [(I R)-l-({ [(I -methylcyclopropyl)methyl]oxy} methyl)-2-(4- methylpiperazin-l-yl)-2-oxoethyl]pyridine-3 -carboxamide was synthesized in a manner similar to Example 1 wherein (R)-2-(tert-butoxycarbonylamino)-3-((l-methylcyclopropyl)- methoxy)propanoic acid was substituted for (R)-3-(benzyloxy)-2-(tert- butoxycarbonylamino)propanoic acid and 2-(2,4-dichlorophenoxy)nicotinic acid was substituted for 2-(4-chlorophenoxy)nicotinic acid. (R)-2-(tert-butoxycarbonylamino)-3-((l- methylcyclopropyl)methoxy)propanoic acid was synthesized according to Example 5 and 2- (2,4-dichlorophenoxy)nicotinic acid was synthesized according to Example 4 by substituting 2,4-dichlorophenol for 4-chlorophenol and 2-chloronicotinic acid for 5-bromo-2- chloronicotinic acid. 1H NMR (400 MHz, DMSO-J6): δ 8.74 (d, IH), 8.26 (m, IH), 8.21 (m, IH), 7.80 (d, IH), 7.54 (m, IH), 7.48 (d, IH), 7.30 (m, IH), 5.18 (q, IH), 3.62 (d, 2H), 3.58 (m, 2H), 3.47 (m, 2H), 3.19 (s, 2H), 2.33 (br s, 2H), 2.23 (br s, 2H), 2.14 (s, 3H), 0.97 (s, 3H), 0.29 (m, 2H), 0.19 (m, 2H). MS (EI) for C25H30Cl2N4O4, found 521.17 (MH+). [00228] 2-{[2-chloro-4-(trifluoromethyl)phenyl]oxy}-N-{(lR)-l-({[(l- methylcyclopropyl)-methyl]oxy}methyl)-2-[(l-methylpiperidin-4-yl)amino]-2- oxoethyl}pyridine-3-carboxamide: 2-{[2-chloro-4-(trifluoromethyl)phenyl]oxy}-N-{(lR)- 1 -( { [( 1 -methylcyclopropyl)methyl]oxy } methyl)-2- [( 1 -methylpiperidin-4-yl)amino] -2- oxoethyl}-pyridine-3-carboxamide was synthesized in a manner similar to Example 1 wherein (R)-2-(tert-butoxycarbonylamino)-3 -(( 1 -methylcyclopropyl)methoxy)propanoic acid was substituted for (R)-3-(benzyloxy)-2-(tert-butoxycarbonylamino)propanoic acid, 2-(2- chloro-4-(trifluoromethyl)-phenoxy)nicotinic acid was substituted for 2-(4- chlorophenoxy)nicotinic acid and l-methylpiperidin-4-amine was substituted for N- methylpiperazine. (R)-2-(tert-butoxycarbonylamino)-3-((l- methylcyclopropyl)methoxy)propanoic acid was synthesized according to Example 5 and 2- (2-chloro-4-(trifluoromethyl)phenoxy)nicotinic acid was synthesized according to Example 4 by substituting 2-chloronicotinic acid for 5-bromo-2-chloronicotinic acid and 2-chloro-4- (trifluoromethyl)phenol for 4-chlorophenol. 1H NMR (400 MHz, DMSO-J6): δ 8.56 (d, IH), 8.31 (dd, IH), 8.23 (m, IH), 8.09 (d, IH), 7.99 (d, IH), 7.86 (dd, IH), 7.69 (d, IH), 7.34 (m, IH), 6.16 (q, IH), 3.66 (m, 2H), 3.50 (m, IH), 3.16 (m, 2H), 2.66 (m, 2H), 2.11 (s, 3H), 1.92 (m, 2H), 1.86 (s, 3H), 1.65 (m, 2H), 1.36 (m, 2H), 0.91 (s, 2H), 0.25 (m, IH), 0.14 (m, IH). MS (EI) for C27H32ClF3N4O4 found 569.17 (MH+).
[00229] The following compounds were made in a manner which employed the methods of Example 5:
[00230] 2-[(4-chlorophenyl)oxy]-N-[(lR)-l-({[(l- methylcyclopropyl)methyl]oxy}methyl)-2-(4-methylpiperazin-l-yl)-2-oxoethyl]pyridine- 3-carboxamide : 2- [(4-chlorophenyl)oxy] -N- [( 1 R)- 1 -( { [( 1 - methylcyclopropyl)methyl]oxy}methyl)-2-(4-methylpiperazin-l-yl)-2-oxoethyl]pyridine-3- carboxamide was synthesized in a manner similar to Example 1 wherein (R)-2-(tert- butoxycarbonylamino)-3-((l-methylcyclopropyl)-methoxy)propanoic acid was substituted for (R)-3 -(benzyloxy)-2-(tert-butoxycarbonylamino)propanoic acid. (R)-2-(tert- butoxycarbonylamino)-3-((l-methyl-cyclopropyl)methoxy)propanoic acid was synthesized according to Example 5. 1H NMR (400 MHz, DMSO-J6): δ 8.82 (d, IH), 8.22 (m, 2H), 7.50 (m, 2H), 7.27 (m, 3H), 5.16 (q, IH), 3.64 (d, 2H), 3.57 (br s, 2H), 3.47 (br s, 2H), 3.19 (s, 2H), 2.33 (br s, 2H), 2.23 (br s, 2H), 2.15 (s, 3H), 0.98 (s, 3H), 0.30 (m, 2H), 0.20 (m, 2H). MS (EI) for C25H3IClN4O4 found 486.97 (MH+).
[00231 ] N- [(1R)-I- [(bicyclo [2.2.1] hept-2-yloxy)methyl] -2-(4-methylpiper azin- l-yl)-2- oxoethyl] -2- [(4-chlorophenyl)oxy] pyridine-3-carboxamide : N- [( 1 R)- 1 - [(bicyclo[2.2.1]hept-2-yloxy)methyl]-2-(4-methylpiperazin-l-yl)-2-oxoethyl]-2-[(4- chlorophenyl)oxy]pyridine-3-carboxamide was synthesized in a manner similar to Example 1 wherein (2R)-3-(bicyclo[2.2.1 ]heptan-2-yloxy)-2-(tert-butoxycarbonylamino)propanoic acid was substituted for (R)-3-(benzyloxy)-2-(tert-butoxycarbonylamino)propanoic acid. (2R)-3-(bicyclo[2.2.1 ]heptan-2-yloxy)-2-(tert-butoxycarbonylamino)propanoic acid was synthesized according to Example 5 by substituting bicyclo[2.2.1]heptan-2-ol for (1- methylcyclopropyl)methanol. 1H NMR (400 MHz, DMSO-J6): δ 8.77 (d, IH), 8.23 (m, 2H), 7.51 (m, 2H), 7.27 (m, 3H), 5.10 (m, IH), 3.55 (m, 4H), 3.46 (br s, 2H), 3.33 (t, IH), 2.31 (br s, 2H), 2.22 (m, 2H), 2.15 (br s, 3H), 2.08 (m, IH), 1.91 (s, 3H), 1.41 (m, 2H), 1.29 (m, IH), 1.20 (m, IH), 0.93 (m, 2H). MS (EI) for C27H33ClN4O4 found 513.80 (MH+). [00232] 2-[(4-chlorophenyl)oxy]-N-[(lR)-l-[(cyclohexyloxy)methyl]-2-(4-methyl- piperazin-l-yl)-2-oxoethyl]pyridine-3-carboxamide: 2-[(4-chlorophenyl)oxy]-N-[(lR)-l- [(cyclohexyloxy)methyl]-2-(4-methylpiperazin-l-yl)-2-oxoethyl]pyridine-3-carboxamide was synthesized in a manner similar to Example 1 wherein (R)-2-(tert-butoxycarbonylamino)-3- (cyclohexyloxy)propanoic acid was substituted for (R)-3-(benzyloxy)-2-(tert- butoxycarbonylamino)propanoic acid. (R)-2-(tert-butoxycarbonylamino)-3 -
(cyclohexyloxy)propanoic acid was synthesized according to Example 5 by substituting cyclohexanol for (l-methylcyclopropyl)methanol. 1H NMR (400 MHz, DMSO-J6): δ 8.78 (d, IH), 8.23 (d, 2H), 7.51 (m, 2H), 7.27 (m, 3H), 5.11 (m, IH), 3.63 (d, 2H), 3.56 (br s, 2H), 3.47 (br s, 2H), 3.24 (m, IH), 2.32 (br s, 2H), 2.23 (br s, 2H), 2.15 (s, 3H), 1.70 (m, 2H), 1.56 (m, 2H), 1.40 (m, IH), 1.15 (m, 5H). MS (EI) for C26H33ClN4O4 found 501.08 (MH+). [00233] 2-[(4-chlorophenyl)oxy]-N-[(lR)-l-{[(cyclohexylmethyl)oxy]methyl}-2-(4- methylpiperazin-l-yl)-2-oxoethyl]pyridine-3-carboxamide: 2-[(4-chlorophenyl)oxy]-N- [(I R)- 1 - { [(cyclohexylmethyl)oxy]methyl} -2-(4-methylpiperazin- 1 -yl)-2-oxoethyl]pyridine- 3-carboxamide was synthesized in a manner similar to Example 1 wherein (R)-2-(tert- butoxycarbonylamino)-3-(cyclohexylmethoxy)propanoic acid was substituted for (R)-3- (benzyloxy)-2-(tert-butoxycarbonylamino)propanoic acid. (R)-2-(tert-butoxycarbonylamino)- 3-(cyclohexylmethoxy)propanoic acid was synthesized according to Example 5 by substituting cyclohexylmethanol for (l-methylcyclopropyl)methanol. 1H NMR (400 MHz, DMSO-J6): δ 8.80 (d, IH), 8.22 (m, 2H), 7.50 (m, 2H), 7.26 (m, 3H), 5.14 (q, IH), 3.60 (d, 2H), 3.56 (br s, 2H), 3.46 (br s, 2H), 3.17 (m, 2H), 2.31 (br s, 2H), 2.23 (br s, 2H), 2.15 (s, 3H), 1.57 (d, 5H), 1.39 (m, IH), 1.08 (m, 3H), 0.80 (m, 2H). MS (EI) for C27H35ClN4O4 found 515.06 (MH+). Example 6
2-[(4-chlorophenyl)oxy]-N-[(lR)-2-(4-methylpiperazin-l-yl)-2-oxo-l-{[(l- phenylethyl)oxy]methyl}ethyl]pyridine-3-carboxamide
Figure imgf000075_0001
Figure imgf000075_0002
Figure imgf000075_0003
[00234] Step 1: (2R)-methyl 2-amino-3-(l-phenylethoxy)propanoate: (2R)-methyl 2- (tert-butoxycarbonylamino)-3-(l-phenylethoxy)propanoate was prepared as described in Example 4 (steps 1 and 2) wherein alpha methyl benzyl alcohol was substituted for (1- methylcyclopropyl)methanol. This Boc-ester (880 mg, 2.72 mmol) was suspended in ether (2.7 mL) and treated with 4M solution of HCl in dioxane (13.6 mL, 54.4 mmol) and stirred at room temperature for 2h. The solvents were removed in vacuo and the residue was used directly in the next step.
[00235] Step 2: (2R)-methyl 2-(2-(4-chlorophenoxy)benzamido)-3-(l-phenylethoxy)- propanoate: (2R)-methyl 2-amino-3-(l-phenylethoxy)propanoate (706 mg, 2.72 mmol) was suspended in dichloroethane (9.1 mL). To the suspension was added 2-(4- chlorophenoxy)nicotinic acid (1019 mg, 4.08 mmol), prepared as described in Example 4, HATU (1550 mg, 4.08 mmol) and diisopropylethyl amine (0.71 mL, 4.08 mmol). The reaction mixture was stirred overnight at room temperature. The solvent was then removed in vacuo and the residue was suspended in ethyl acetate. The suspension was washed sequentially with IM HCl, sat. aq. NaHCO3 and brine. The organic layer was separated and dried with MgSO4. After removal of the solvent in vacuo, the crude product was purified by column chromatography.
[00236] Step 3: (2R)-2-(2-(4-chlorophenoxy)benzamido)-3-(l-phenylethoxy)propanoic acid: (R)-methyl 2-(2-(4-chlorophenoxy)nicotinamido)-3-(l-phenylethoxy)propanoate (800 mg, 1.76 mmol) was dissolved in THF (8.8 mL). To that solution was added IM LiOH (7.0 mL). After stirring at room temperature for Ih, the organic solvent was removed in vacuo. The aqueous solvent was washed with diethyl ether, diluted with ethyl acetate and washed with IM HCl. The organic layer was separated and dried with MgSO4. The crude semi-solid was used without further purification.
[00237] Step 4: 2-[(4-chlorophenyl)oxy]-N-[(lR)-2-(4-methylpiperazin-l-yl)-2-oxo-l- {[(l-phenylethyl)oxy]methyl}ethyl]pyridine-3-carboxamide: 2-[(4-chlorophenyl)oxy]-N- [(I R)-2-(4-methylpiperazin- 1 -yl)-2-oxo- 1 - { [( 1 -phenylethyl)oxy]methyl} -ethyl]pyridine-3 - carboxamide. (2R)-2-(2-(4-chlorophenoxy)benzamido)-3-(l-phenylethoxy)-propanoic acid (569 mg, 1.29 mmol) was dissolved in dichloroethane (4.3 mL). To that solution was added HATU (736, 1.93 mmol) and N-methyl piperazine (0.43 mL, 3.87 mmol). The resulting mixture was stirred overnight at room temperature. The solvent was removed in vacuo and the residue was purified by reverse phase chromatography and gave the title compound. 1H NMR (400 MHz, DMSO-J6): δ 8.79 (m, IH), 8.19 (m, 2H), 7.48 (m, 2H), 7.23 (m, 8H), 5.11 (q, IH), 4.43 (m, IH), 3.36 (m, 4H), 3.48 (m, 6H), 2.20 (m, 4H), 2.10 (d, 3H), 1.22 (m, 3H). MS (EI) for C28H3IClN4O4 found 523.19 (MH+).
Example 7
2-[(4-chlorophenyl)oxy]-N-[(lR)-2-(4-methylpiperazin-l-yl)-2-oxo-l- {[(phenylmethyl)oxy] methyl} ethyl] benzamide
Figure imgf000076_0001
[00238] Preparation of 2-(4-chlorophenoxy)benzoic acid: To a round-bottom flask was added 4-chlorophenol (2.56 g, 20 mmol), 2-iodobenzoic acid (2.48 g, 10 mol), CuI (190 mg), cesium carbonate (6.50 g, 20 mmol) and DMF ( 20 mL). The flask was purged with nitrogen and the reaction mixture heated to 110 0C overnight. The reaction was cooled and partitioned between water and ethyl acetate then filtered. The organic layer was dried and concentrated. Purification by column chromatography gave 2-(4-chlorophenoxy)benzoic acid as a white solid.
[00239] 2-[(4-chlorophenyl)oxy]-N-[(lR)-2-(4-methylpiperazin-l-yl)-2-oxo-l-
{ [(phenylmethyl)oxy] methyl}ethyl] benzamide: 2-[(4-chlorophenyl)oxy]-N-[( 1 R)-2-(4- methylpiperazin- 1 -yl)-2-oxo- 1 - { [(phenylmethyl)oxy]methyl} ethyljbenzamide was then synthesized in a manner similar to Example 1 wherein 2-(p-tolyloxy)benzoic acid bromide was substituted with 2-(4-chlorophenoxy) benzoic acid. 1H NMR (400 MHz, DMSO-J6): δ
7.95 (d, IH), 7.50 (m, IH), 7.35-7.20 (m, 7H), 7.05-6.95 (m, 3H), 5.22 (t, IH), 4.45 (dd, 2H),
3.75-3.60 (m, 6H), 2.65-2.42 (m, 4H), 2.35 (s, 3H). MS (EI) for C28H30ClN3O4 found 508.0
(MH+).
Example 8
2-[(4-chlorophenyl)oxy]-N-[(lR)-2-(4-methylpiperazin-l-yl)-2-oxo-l- {[(phenylmethyl)amino]methyl}ethyl]pyridine-3-carboxamide
Figure imgf000077_0001
[00240] Step 1: (R)-tert-butyl 3-hydroxy-l-(4-methylpiperazin-l-yl)-l-oxopropan-2- ylcarbamate: To a solution of (R)-2-(tert-butoxycarbonylamino)-3-hydroxypropanoic acid (3.0 g, 14.62 mmol) in dichloromethane (50 mL) was added N-methylmorpholine (16 mL, 146.2 mmol), 1-methylpiperazine (1.78 mL, 16.08 mmol), l-[3-(Dimethylamino)propyl]-3- ethylcarbodiimide methiodide (EDC) (3.0 g, 16 mmol), and 1-Hydroxybenzotriazole (HOBt) (2.1 g, 16 mmol). The reaction mixture was stirred at room temperature for 16 hours, concentrated in vacuo then partitioned between dichloromethane and saturated sodium bicarbonate. The combined organic layers were dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to give 3.5 g (83%) of (R)-tert-butyl 3 -hydroxy- 1 -(4- methylpiperazin-l-yl)-l-oxopropan-2-ylcarbamate and used in the next step without further purification. [00241] Step 2: (R)-2-(tert-butoxycarbonylamino)-3-(4-methylpiperazin-l-yl)-3- oxopropyl methanesulfonate: To a solution of (R)-tert-butyl 3 -hydroxy- 1 -(4- methylpiperazin-l-yl)-l-oxopropan-2-ylcarbamate (200 mg, 0.7 mmol) in dichloromethane (5 rnL) and triethylamine (0.3 rnL) at 0 0C was added methanesulfonyl chloride (0.06 rnL, 0.77 mmol) and N'N'-Dimethyaminopyridine (10 mg, 0.08 mmol). The reaction mixture was stirred at 0 0C for 15 min and was quenched with 5 drops of water at 0 0C. The organic layer was washed with 2 mL of water, 2 mL of saturated sodium bicarbonate, and then dried over magnesium sulfate. Concentration under reduced pressure resulted in 200 mg of (R)-2-(tert- butoxycarbonylamino)-3-(4-methylpiperazin-l-yl)-3-oxopropyl methanesulfonate which was taken to the next step without further purification.
[00242] Step 3: (R)-2-amino-3-(benzylamino)-l-(4-methylpiperazin-l-yl)propan-l- one: To a solution of (R)-2-(tert-butoxycarbonylamino)-3-(4-methylpiperazin-l-yl)-3- oxopropyl methanesulfonate (100 mg, 0.27 mmol) in acetonitrile (5 mL) was added benzyl amino (0.5 mL, 4.2 mmol). The reaction mixture was heated to 65 0C for 16 h, and concentrated in vacuo. The concentrated reaction mixture was dissolved in methanol (5 mL) followed by the addition of 4 N HCl in dioxane (3 mL). The reaction was heated to 65 0C for 1 h. Upon cooling the mixture was concentrated in vacuo to result in 150 mg of (R)-2-amino- 3-(benzylamino)-l-(4-methylpiperazin-l-yl)propan-l-one which was used in the next step without further purification.
[00243] Step 4: 2-[(4-chlorophenyl)oxy]-N-[(lR)-2-(4-methylpiperazin-l-yl)-2-oxo-l- {[(phenylmethyl)amino]methyl}ethyl]pyridine-3-carboxamide: To a solution of (R)-2- amino-3-(benzylamino)-l-(4-methylpiperazin-l-yl)propan-l-one (150 mg, 0.43 mmol) in dichloromethane (10 mL) was added N-methylmorpholine (0.23 mL, 2.15 mmol), 2-(4- chlorophenoxy)nicotinic acid (203 mg, 0.77mmol), l-[3-(Dimethylamino)propyl]-3- ethylcarbodiimide methiodide (EDC) (148 mg, 0.77 mmol), and 1-Hydroxybenzotriazole (HOBt) (104 mg, 0.77 mmol). The reaction mixture was stirred at room temperature for 16 h, concentrated in vacuo and dissolved in methanol. The product was purified by preparatory HPLC (reverse-phase, acetonitrile/water with 0.1% formic acid) to give 17 mg of the title compound. 1H NMR (400 MHz, DMSO-J6): δ 8.85 (d, IH), 8.21 (m, 2H), 7.50 (d, 2H), 7.26 (m, 8H), 5.07 (q, IH), 3.69 (m, 7H), 2.85 (m, IH), 2.72 (m, IH), 2.21 (m, 4H), 2.12 (s, 3H). MS (EI) for C27H30ClN5O3 found 508.19 (MH+). Example 9
2-{[2-chloro-4-(trifluoromethyl)phenyl]oxy}-N-[(lR)-2-oxo-2-{(3R)-3- [(phenylmethyl)amino]pyrrolidin-l-yl}-l-{[(phenylmethyl)oxy]methyl}ethyl]pyridine-3- carboxamide
Figure imgf000079_0001
[00244] Step 1: (R)-ethyl 2-amino-3-(benzyloxy)propanoate: To a solution of (R)-3- (benzyloxy)-2-(tert-butoxycarbonylamino)propanoic acid (10 g, 33.8 mmol, Acros) in dichloromethane (120 niL) were added 1-hydroxybenzotriazole (6.8 g, 50.8 mmol), N- methylmorpholine (7.4 mL, 67.8 mmol), l-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (9.7 g, 50.8 mmol), and Ethyl alcohol (40 mL, 676 mmol). The reaction was stirred at room temperature for 18 hours. The resulting solution was extracted with water (50 mL), saturated sodium bicarbonate solution (50 mL), and IN HCl solution (50 mL). The layers were separated and the organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. The resulting oil was dissolved in methanol (30 mL) followed by the addition of 4 N HCl in dioxane (30 mL, Aldrich). The reaction was stirred at room temperature for 18 hours. The resulting solution was concentrated in vacuo to give 6.0 g (79%) of the title compound which was used in the next step without further purification. MS (EI) for Ci2Hi7NO3, found 224.27 (MH+).
[00245] Step 2: (R)-ethyl 3-(benzyloxy)-2-(2-(2-chloro-4-(trifluoromethyl)phenoxy)- nicotinamido)propanoate: To a solution of (R)-ethyl 2-amino-3-(benzyloxy)propanoate (750 mg, 3.36 mmol) in dichloromethane (20 mL) were added 1-hydroxybenzotriazole (500 mg, 3.70 mmol), N-methylmorpholine (3.0 mL, 26.88 mmol), l-[3-(dimethylamino)propyl]- 3-ethylcarbodiimide hydrochloride (700 mg, 3.70 mmol), and 2-(2-chloro-4- (trifluoromethyl)phenoxy)nicotinic acid (1.0 g, 3.36 mmol). The reaction was stirred at room temperature for 18 hours. The resulting solution was extracted with water (15 mL), saturated sodium bicarbonate solution (15 mL), and IN HCl solution (15 mL). The layers were separated and the organic layer was dried over magnesium sulfate. The resulting solution was concentrated in vacuo to give 1.7 g (95%) of the title compound which was used in the next step without further purification. MS (EI) for C25H22ClF3N2O5, found 523.9 (MH+). [00246] Step 3: (R)-3-(benzyloxy)-2-(2-(2-chloro-4-(trifluoromethyl)phenoxy)- nicotinamido)propanoic acid: To a solution of (R)-ethyl 3-(benzyloxy)-2-(2-(2-chloro-4- (trifluoromethyl)phenoxy)nicotinamido)propanoate (1.7 g, 3.25 mmol) in 20 mL of MeOH was added 10 mL of 2 N NaOH solution and the reaction mixture stirred at room temperature for 18 hours. The resulting solution was concentrated down under reduced pressure, acidified with 1 N HCl to pH=3, and extracted with 100 mL of EtOAc. The organic layer was dried over magnesium sulfate. Filtration and concentration under reduced pressure resulted in 1.2 g (74%) of the title compound which was used in the next step without further purification. MS (EI) for C23Hi8ClF3N2O5, found 495.85 (MH+).
[00247] Step 4: N-[(lR)-2-[(3R)-3-aminopyrrolidin-l-yl]-2-oxo-l-
{ [(phenylmethyl)oxy] -methyl} ethyl] -2- { [2-chloro-4-
(trifluoromethyl)phenyl]oxy}pyridine-3-carboxamide: To a solution of (R)-3-(benzyloxy)- 2-(2-(2-chloro-4-(trifluoromethyl)phenoxy)-nicotinamido)propanoic acid (1 g, 2.03 mmol) in dichloromethane (15 mL) were added 1-hydroxybenzotriazole (300 mg, 2.23 mmol), N- methylmorpholine (2.2 mL, 20.29 mmol), 1- [3 -(dimethylamino)propyl] -3-ethylcarbodiimide hydrochloride (428 mg, 2.23 mmol), and (R)-tert-butyl prrolidin-3-ylcarbamate (378 mg, 2.03 mmol, Oakwood Products, West Columbia, SC). The reaction was stirred at room temperature for 18 hours. The resulting solution was washed with water (25 mL), and saturated sodium bicarbonate solution (25 mL). The layers were separated and the organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. The resulting oil was dissolved in methanol (10 mL) followed by the addition of 4 N HCl in dioxane (10 mL, Aldrich, Milwaukee, WI). The reaction was stirred at room temperature for 18 hours. The resulting solution was concentrated in vacuo. The product was then purified by preparatory HPLC (reverse-phase, acetonitrile/aqueous 10 mM formic acid buffer) to give 400 mg of the title compound. 1H NMR (400 MHz, DMSO-J6): δ 8.76 (m, IH), 8.23 (m, 2H), 8.05(s, IH), 7.82 (d, IH), 7.64 (m, IH), 7.31 (m, IH), 7.20 (s, 5H), 4.99 (m, IH), 4.47 (m, 2H), 3.87 (m, IH), 3.71 (m, 2H), 3.48 (m, 2H), 3.20 (m, IH), 3.00 (m, IH), 2.62 (m, IH), 2.00 (m, IH). MS (EI) for C27H26ClF3N4O4, found 563.9 (MH+).
[00248] Step 5: 2-{[2-chloro-4-(trifluoromethyl)phenyl]oxy}-N-[(lR)-2-oxo-2-{(3R)-3- [(phenylmethyl)amino]pyrrolidin-l-yl}-l-{[(phenylmethyl)oxy]methyl}ethyl]pyridine-3- carboxamide: To a solution of N-((R)-l-((R)-3-aminopyrrolidin-l-yl)-3-(benzyloxy)-l- oxopropan-2-yl)-2-(2-chloro-4-(trifluoromethyl)phenoxy)nicotinamide (50 mg, 0.08 mmol) in dichloromethane (3 rnL) were added benzaldehyde (0.08 rnL, 0.08 mmol) and glacial acetic acid (1 drop). The reaction mixture was stirred at room temperature for Ih, and then sodium cyanoborohydride (IM THF solution (Aldrich), 0.167 mL, 0.17 mmol) was added. The reaction mixture was stirred at room temperature for additional 18 hours. Formation of product was confirmed by LC/MS and the product was purified by preparatory HPLC (reverse-phase, acetonitrile/water with 0.1% formic acid) to yield 12 mg (23%) of the title compound. 1H NMR (400 MHz, DMSO-J6): δ 8.75 (m, IH), 8.25 (m, IH), 8.20 (m, IH), 8.04 (s, IH), 7.81 (m, IH), 7.64 (m, IH), 7.30 (m, 5H), 7.19 (m, 6H), 4.98 (m, IH), 4.47 (m, 2H), 3.69 (m, 6H), 3.13 (m, IH), 1.89 (m, IH), 1.69 (m, IH). MS (EI) for C34H32ClF3N4O4, found 654.1 (MH+).
[00249] The following compounds were synthesized in a manner similar to Example 9. [00250] 2-[(4-chlorophenyl)oxy]-N-[(lR)-2-[(3R)-3-(dimethylamino)pyrrolidin-l-yl]- 2-oxo-l-{[(phenylmethyl)oxy]methyl}ethyl]pyridine-3-carboxamide: 2-[(4- chlorophenyl)oxy]-N-[(lR)-2-[(3R)-3-(dimethylamino)pyrrolidin-l-yl]-2-oxo-l- {[(phenylmethyl)oxy]methyl}ethyl]pyridine-3-carboxamide was synthesized in a manner similar to Example 9 wherein (R)-N ,N-dimethylpyrrolidin-3 -amine was substituted for (R)- tert-butyl pyrrolidin-3-ylcarbamate, and 2-(4-chlorophenoxy)nicotinic acid was substituted for 2-(2-chloro-4-(trifluoromethyl)phenoxy)nicotinic acid. 1H NMR (400 MHz, DMSO-J6): δ 8.81 (d, IH), 8.21 (m, 2H), 7.46 (m, 2H), 7.23 (m, 8H), 4.98 (t, IH), 4.47 (dd, 2H), 3.87 (m, IH), 3.70 (m, 2H), 3.56 (m, IH), 3.18 (m, IH), 3.04 (m, IH), 2.66 (m, IH), 2.12 (d, 6H), 2.00 (m, IH), 1.64 (m, IH). MS (EI) for C28H3iClN4O4 found 524.02 (MH+). [00251] 2-{[2-chloro-4-(trifluoromethyl)phenyl]oxy}-N-[(lR)-2-[(3R)-3- (dimethylamino)pyrrolidin-l-yl]-2-oxo-l-{[(phenylmethyl)oxy]methyl}ethyl]pyridine-3- carboxamide: 2-{[2-chloro-4-(trifluoromethyl)phenyl]oxy}-N-[(lR)-2-[(3R)-3-
(dimethylamino)pyrrolidin- 1 -yl]-2-oxo- 1 - { [(phenylmethyl)oxy]methyl} ethyl]pyridine-3- carboxamide was synthesized in a manner similar to Example 9 wherein (R)-N5N- dimethylpyrrolidin-3-amine was substituted for (R)-tert-butyl pyrrolidin-3-ylcarbamate. 1H NMR (400 MHz, DMSO-J6): δ 8.77 (d, IH), 8.23 (dd, IH), 8.20 (dd, IH), 8.05 (s, IH), 7.81 (dd, IH), 7.64 (dd, IH), 7.30 (m, IH), 7.21 (m, 5H), 5.00 (t, IH), 4.47 (dd, 2H), 3.87 (m, IH), 3.73 (m, 2H), 3.48 (m, IH), 3.20 (m, IH), 3.00 (m, IH), 2.62 (m, IH), 2.12 (d, 6H), 2.00 (m, IH), 1.62 (m, IH). MS (EI) for C29H30ClF3N4O4 found 592.02 (MH+). [00252] 2-{[2-chloro-4-(trifluoromethyl)phenyl]oxy}-N-[(lR)-2-[3- (methylamino)pyrrolidin- 1-yl] -2-oxo- 1- { [(phenylmethyl)oxy] methyl} ethyl] pyridine-3- carboxamide: 2-{[2-chloro-4-(trifluoromethyl)phenyl]oxy}-N-[(lR)-2-[3-
(methylamino)pyrrolidin- 1 -yl] -2-oxo- 1 - { [(phenylmethyl)oxy Jmethyl} ethyl]pyridine-3 - carboxamide was synthesized in a manner similar to Example 9 wherein tert-butyl methyl(pyrrolidin-3-yl)carbamate was substituted for (R)-tert-butyl pyrrolidin-3-ylcarbamate. 1H NMR (400 MHz, DMSO-J6): δ 8.74 (m, IH), 8.23 (m, 2H), 8.05 (s, IH), 7.82 (dd, IH), 7.64 (dd, IH), 7.31 (m, IH), 7.21 (m, 5H), 4.99 (t, IH), 4.47 (dd, 2H), 3.60 (m, 5H), 3.09 (m, 2H), 2.21(s, 3H), 1.87 (m, IH), 1.63 (m, IH). MS (EI) for C28H28ClF3N4O4 found 578.00 (MH+).
[00253] 2-{[2-chloro-4-(trifluoromethyl)phenyl]oxy}-N-[(lR)-2-{3-[methyl- (phenylmethyl)amino]pyrrolidin-l-yl}-2-oxo-l-
{ [(phenylmethyl)oxy] methyl} ethyl] pyridine-3-carboxamide: 2- { [2-chloro-4-
(trifluoromethyl)phenyl]oxy}-N-[(lR)-2-{3-[methyl(phenylmethyl)amino]pyrrolidin-l-yl}-2- oxo-l-{[(phenylmethyl)oxy]methyl}ethyl]pyridine-3-carboxamide was synthesized in a manner similar to Example 9 wherein tert-butyl methyl(pyrrolidin-3-yl)carbamate was substituted for (R)-tert-butyl pyrrolidin-3-ylcarbamate. 1H NMR (400 MHz, DMSO-J6): δ 8.77 (m, IH), 8.22 (m, 2H), 8.05 (m, IH), 7.79 (m, IH), 7.63 (m, IH), 7.26 (m, HH), 5.00 (t, IH), 4.48 (dd, 2H), 3.73 (m, 2H), 3.60 (m, IH), 3.43 (m, 2H), 3.16 (m, IH), 2.92 (m, IH), 2.07 (m, IH), 1.99 (m, 3H), 1.76 (m, IH). MS (EI) for C35H34ClF3N4O4 found 668.12 (MH+).
[00254] 2-{[2-chloro-4-(trifluoromethyl)phenyl]oxy}-N-[(lR)-2-oxo-2-{(3R)-3-[(2- phenylethyl)amino]pyrrolidin-l-yl}-l-{[(phenylmethyl)oxy]methyl}ethyl]pyridine-3- carboxamide: 2-{[2-chloro-4-(trifluoromethyl)phenyl]oxy}-N-[(lR)-2-oxo-2-{(3R)-3-[(2- phenylethyl)amino]pyrrolidin- 1 -yl} - 1 - { [(phenylmethyl)oxy]methyl} ethyl]pyridine-3- carboxamide was synthesized in a manner similar to Example 9 wherein 2- phenylacetaldehyde was substituted for benzaldehyde. 1H NMR (400 MHz, DMSO-J6): δ 8.77 (m, IH), 8.23 (m, 2H), 8.05 (m, IH), 7.81 (m, IH), 7.64 (m, IH), 7.30 (m, IH), 7.24 (m, 2H), 7.19 (m, 8H), 4.99 (m, IH), 4.47 (dd, 2H), 3.83 (m, IH), 3.71 (m, 2H), 3.64 (m, IH), 3.43 (m, 2H), 3.16 (m, IH), 2.73 (m, 2H), 2.67 (m, 2H), 1.93 (m, IH), 1.70 (m, IH). MS (EI) for C35H34ClF3N4O4 found 668.12 (MH+). [00255] 2-{[2-chloro-4-(trifluoromethyl)phenyl]oxy}-N-[(lR)-2-{(3R)-3-[(2- methylpropyl)amino]pyrrolidin-l-yl}-2-oxo-l-
{ [(phenylmethyl)oxy] methyl} ethyl] pyridine-3-carboxamide: 2- { [2-chloro-4-
(trifluoromethyl)phenyl]oxy} -N-[(lR)-2- {(3R)-3-[(2-methylpropyl)amino]pyrrolidin- 1 -yl} - 2-oxo-l-{[(phenylmethyl)oxy]methyl} ethyl] -pyridine-3-carboxamide was synthesized in a manner similar to Example 9 wherein isobutyraldehyde was substituted for benzaldehyde. 1H NMR (400 MHz, DMSO-J6): δ 8.77 (m, IH), 8.23 (m, 2H), 8.05 (m, IH), 7.81 (m, IH), 7.64 (m, IH), 7.30 (m, IH), 7.21 (m, 5H), 4.99 (m, IH), 4.48 (dd, 2H), 3.80 (m, IH), 3.71 (m, 2H), 3.64 (m, IH), 3.43 (m, 2H), 3.16 (m, IH), 2.28 (m, 2H), 1.91 (m, IH), 1.61 (m, 2H), 0.81 (s, 6H). MS (EI) for C3IH34ClF3N4O4 found 619.08 (MH+). [00256] 2-{[2-chloro-4-(trifluoromethyl)phenyl]oxy}-N-[(lR)-2-[(3R)-3- (methylamino)pyrrolidin- 1-yl] -2-oxo- 1- { [(phenylmethyl)oxy] methyl} ethyl] pyridine-3- carboxamide: 2-{[2-chloro-4-(trifluoromethyl)phenyl]oxy}-N-[(lR)-2-[3-(methylamino)- pyrrolidin- 1 -yl] -2-oxo- 1 - { [(phenylmethyl)oxy]methyl} ethyl]pyridine-3 -carboxamide was synthesized in a manner similar to Example 9 wherein (R)-N-methylpyrrolidin-3 -amine was substituted for (R)-tert-butyl pyrrolidin-3-ylcarbamate. IH NMR (400 MHz, DMSO-J6): δ
8.75 (t, IH), 8.23 (m, 2H), 8.05 (s, IH), 7.82 (dd, IH), 7.64 (dd, IH), 7.31 (m, IH), 7.21 (m, 5H), 4.99 (t, IH), 4.49 (dd, 2H), 3.71 (m, 2H), 3.53 (m, 3H), 3.15 (m, 2H), 2.23 (s, 3H), 1.90 (m, IH), 1.67 (m, IH). MS (EI) for C28H28ClF3N4O4 found 578.00 (MH+).
[00257] 2-{[2-chloro-4-(trifluoromethyl)phenyl]oxy}-N-[(lR)-2-[(3S)-3- (methylamino)pyrrolidin- 1-yl] -2-oxo- 1- { [(phenylmethyl)oxy] methyl} ethyl] pyridine-3- carboxamide: 2-{[2-chloro-4-(trifluoromethyl)phenyl]oxy}-N-[(lR)-2-[3-(methylamino)- pyrrolidin- 1 -yl] -2-oxo- 1 - { [(phenylmethyl)oxy]methyl} ethyl]pyridine-3 -carboxamide was synthesized in a manner similar to Example 9 wherein (S)-N-methylpyrrolidin-3 -amine was substituted for (R)-tert-butyl pyrrolidin-3-ylcarbamate. 1H NMR (400 MHz, DMSO-J6): δ
8.76 (t, IH), 8.23 (m, 2H), 8.05 (s, IH), 7.82 (dd, IH), 7.64 (dd, IH), 7.31 (m, IH), 7.21 (m, 5H), 4.99 (t, IH), 4.47 (dd, 2H), 3.72 (m, 2H), 3.63 (m, 3H), 3.11 (m, 2H), 2.24 (s, 3H), 1.91 (m, IH), 1.69 (m, IH). MS (EI) for C28H28ClF3N4O4 found 578.00 (MH+).
Example 10
2-{[2-chloro-4-(trifluoromethyl)phenyl]oxy}-N-[(lS)-2-[(3S)-3-(dimethylaniino)pyrrolidin-l- yl]-l-{[(phenylmethyl)oxy]methyl}ethyl] pyridine-3-carboxamide
Figure imgf000084_0001
Step 1. tert-butyl (S)-3-(Benzyloxy)-l-mesyloxypropan-2-ylcarbamate
[00258] To a solution of Boc-O-benzyl-serinol (800 mg, 2.84 mmol) in dichloromethane
(20 niL) and triethylamine (0.44 niL, 3.13 mmol) at 00C was added methanesulfonyl chloride
(0.22 mL, 2.84 mmol) and N'N'-Dimethylaminopyridine (10 mg, 0.08 mmol). The reaction mixture was stirred at 0 0C for Ih and was quenched with 5 drops of water at 0 0C. The organic layer was washed with 2 mL of water, 2 mL of saturated sodium bicarbonate, and then dried over magnesium sulfate. Concentration under reduced pressure resulted in the title compound that was taken to the next step without further purification.
Step 2. (S)-l-((S)-2-Amino-3-(benzyloxy)propyl)-N,N-dimethylpyrrolidin-3-amine hydrochloride
[00259] To a solution of tert-butyl (S)-3-(benzyloxy)-l-mesyloxypropan-2-ylcarbamate
(1.42 mmol) in acetonitrile (10 mL) was added (S)-N,N-dimethylpyrrolidin-3-amine (0.5 mL). The reaction mixture was heated to 60 0C for 16 h, and concentrated in vacuo. The concentrated reaction mixture was dissolved in methanol (5 mL) followed by the addition of
4 N HCl in dioxane (3 mL). The reaction was heated to 65 0C for 1 h. Upon cooling the mixture was concentrated in vacuo to result in the title compound that was submitted to the next step without further purification.
Step 3. 2-{ [2-Chloro-4-(trifluoromethyl)phenyl] oxy}-N- [(I S)-2- [(3S)-3-
(dimethylamino)pyrrolidin-l-yl]-l-{[(phenylmethyl)oxy]methyl}ethyl]pyridine-3- carboxamide
[00260] To a solution of ((S)-l-((S)-2-Amino-3-(benzyloxy)propyl)-N,N- dimethylpyrrolidin-3 -amine hydrochloride (440 mg, 1.42 mmol) in dichloromethane (10 mL) was added N-methylmorpholine (0.5 mL, 4.3 mmol), 2-(2-chloro-4-
(trifluoromethyl)phenoxy)pyridine-3-carboxylic acid (450 mg, 1.42 mmol), l-[3-
(Dimethylamino)propyl]-3-ethylcarbodiimide methiodide (EDC) (300 mg, 1.54 mmol), and
1-Hydroxybenzotriazole (HOBt) (208 mg, 1.54 mmol). The reaction mixture was stirred at room temperature for 16 h, concentrated in vacuo and dissolved in methanol. The product was purified by preparatory HPLC (reverse-phase, acetonitrile/water with 0.1% formic acid) to give 110 mg of the title compound. 1H NMR (400 MHz, d6-DMSO): δ 8.33 (d, IH), 8.18
(m, 3H), 8.03 (s, IH), 7.79 (m, IH), 7.63 (d, IH), 7.30 (m, IH), 7.22 (m, 4H), 4.46 (s, 2H),
4.24 (m, IH), 3.58 (m, 2H), 2.74 (m, IH), 2.57 (m, 4H), 2.45 (m, 2H), 2.12 (s, 6H), 1.73 (m,
IH), 1.56 (m, IH). MS (EI) for C28H32ClF3N4O3, found 578.04 (MH+).
[00261] The following compounds were made in a manner which employed the methods of Example 10 and suitably functionalized reagents.
[00262] 2-{ [2-chloro-4-(trifluoromethyl)phenyl] oxy}-N-[(l S)-2- [(phenylmethyl)oxy] - l-(pyrrolidin-l-ylmethyl)ethyl]pyridine-3-carboxamide
1H NMR (400 MHz, d6- CDCl3): δ 8.52 (m, IH), 8.48 (m, IH), 8.30 (s, IH), 8.15 (m, IH),
7.70 (s, IH), 7.57 (d, IH), 7.40 (d, IH), 7.18 (m, 6H), 4.51 (m, 3H), 3.76 (m, 2H), 3.04 (m,
2H), 2.88 (m, 4H), 1.82 (m, 4H). MS (EI) for C27H27ClF3N3O3, found 534.97 (MH+).
[00263] 2-{[2-chloro-4-(trifluoromethyl)phenyl]oxy}-N-[(lS)-2-(4-methylpiperazin-l- yl)-l- { [(phenylmethyl)oxy] methyl} ethyl] pyridine-3-carboxamide
1H NMR (400 MHz, d6- CDCl3): δ 8.58 (d, IH), 8.42 (s, IH), 8.16 (m, 2H), 7.73 (s, IH),
7.60 (d, IH), 7.35 (d, IH), 7.20 (m, 6H), 4.48 (s, 2H), 4.39 (m, IH), 3.72 (m, 2H), 2.68 (m,
10H), 2.38 (s, 3H). MS (EI) for C28H30ClF3N4O3, found 564.01 (MH+).
[00264] 2-[(2,4-dichlorophenyl)oxy]-N-[(lS)-2-morpholin-4-yl-l-
{ [(phenylmethyl)oxy] methyl} ethyl] pyridine-3-carboxamide
1H NMR (400 MHz, d6-DMSO): δ 8.29 (d, IH), 8.17 (m, 2H), 7.76 (m, IH), 7.47 (m, 2H),
7.27 (m, IH), 7.22 (m, 5H), 4.46 (s, 2H), 4.28 (m, IH), 3.58 (m, 2H), 3.30 (m, 4H), 2.38 (m,
6H). MS (EI) for C26H27Cl2N3O4, found 517.42 (MH+).
[00265] 2-[(2,4-dichlorophenyl)oxy]-N-[(lS)-2-[3-(dimethylamino)pyrrolidin-l-yl]-l-
{ [(phenylmethyl)oxy] methyl} ethyl] pyridine-3-carboxamide
1H NMR (400 MHz, d6-DMSO): δ 8.31 (m, IH), 8.19 (m, 2H), 7.76 (m, IH), 7.47 (m, 2H),
7.27 (m, IH), 7.22 (m, 5H), 4.46 (s, 2H), 4.20 (m, IH), 3.59 (m, 2H), 2.59 (m, 4H), 2.45 (m,
2H), 2.29 (m, IH), 1.98 (s, 6H), 1.66 (m, IH), 1.47 (m, IH). MS (EI) for C28H32Cl2N4O3, found 544.49 (MH+).
[00266] 2-[(2,4-dichlorophenyl)oxy]-N-[(lS)-2-(4-methylpiperazin-l-yl)-l-
{ [(phenylmethyl)oxy] methyl} ethyl] pyridine-3-carboxamide
1H NMR (400 MHz, d6-DMSO): δ 8.28 (d, IH), 8.21 (m, IH), 8.17 (m, 2H), 7.76 (m, IH),
7.50 (m, IH), 7.45 (m, IH), 7.27 (m, IH), 7.22 (m, 4H), 4.46 (m, 2H), 4.23 (m, IH), 3.58 (m,
2H), 2.47-2.09 (m, 10H), 2.07 (s, 3H). MS (EI) for C26H30Cl2N4O3, found 530.46 (MH+). [00267] 2-[(2,4-dichlorophenyl)oxy]-N-[(lS)-2-[(3R)-3-(dimethylamino)pyrrolidin-l- yl] -1- { [(phenylmethyl)oxy] methyl} ethyl] pyridine-3-carboxamide
1H NMR (400 MHz, d6-CDCl3): δ 8.33 (d, IH), 8.18 (m, 3H), 7.74 (d, IH), 7.46 (m, 2H),
7.27 (m, IH), 7.22 (m, 4H), 4.46 (s, 2H), 4.26 (m, IH), 3.57 (m, 2H), 2.93 (m, IH), 2.66 (m,
2H), 2.54 (m, 4H), 2.20 (s, 6H), 1.79 (m, IH), 1.61 (m, IH). MS (EI) for C28H32Cl2N4O3, found 544.49 (MH+).
[00268] ) 2- [(2,4-dichlorophenyl)oxy] -N- [(I S)-2- [(3 S)-3-(dimethylamino)pyr rolidin-
1-yl] - 1- { [(phenylmethyl)oxy] methyl} ethyl] pyridine-3-carboxamide
1H NMR (400 MHz, d6-DMSO): δ 8.31 (d, IH), 8.18 (m, 3H), 7.75 (d, IH), 7.46 (m, 2H),
7.27 (m, IH), 7.22 (m, 4H), 4.45 (s, 2H), 4.23 (m, IH), 3.57 (m, 2H), 2.71 (m, IH), 2.56 (m,
4H), 2.43 (m, 2H), 2.10 (s, 6H), 1.73 (m, IH), 1.55 (m, IH). MS (EI) for C28H32Cl2N4O3, found 544.49 (MH+).
Example 11
GCS Fluorescent Dehydrogenase-Diaphorase-Coupled-Enzyme Assay
[00269] Glucosylceramide synthase (GCS) activity was measured as the amount of UDP-glucose consumed during the synthase-catalyzed reaction by using the enzyme UDP-glucose dehydrogenase to create NADH from UDP-glucose and then quantitatively converting low fluorescence resazurin to high fluorescence resorufm with diaphorase and the NADH that is formed by the dehydrogenase. The synthase-catalyzed reaction transferred glucose from UDP-glucose to C6-ceramide to give UDP and glucosylceramide as products; the assay measured the disappearance of the UDP-glucose substrate. Reactions were conducted in 384-well black, medium binding microtiter plates (Greiner). Synthase reaction mixtures (25 mM HEPES, pH = 7.4, 50 mM KCl and 5 mM MgCl2) were prepared by first adding 0.0005 mL of compound in 100% DMSO to the plate. A volume V = 0.010 mL of 30 mol% C6-ceramide (Avanti Polar Lipids, Inc) and 70 mol % dioleoyl phosphatidylcholine (DOPC, Avanti Polar Lipids) with total concentration = 0.3 mM in 25 mM HEPES, pH = 7.4, was added to the wells.
[00270] C6-ceramide and DOPC were prepared as 20 mg/mL stock solutions in 95% ethanol and stored at -20 0C. The appropriate volumes were transferred to a 40 mL glass vial with screw-cap septum and taken to "dryness" with a stream of argon gas. The lipids were resuspended in 1 mL of dH20, frozen and lyophilized overnight. The lipids were hydrated by first adding enough 25 mM HEPES, pH = 7.4, to give 4x the required concentration for addition to the plate, vortexed to suspend the lyophilized lipids and waited for 1 h or more. The solution was then frozen, placed in a bath sonicator and thawed with sonication. This was repeated three additional times to give four freeze-thaw sonication cycles. The resulting solution was diluted four-fold with 25 mM HEPES, pH = 7.4, to give the solution of lipids that was added to the plate.
[00271] Full-activity controls (100% activity) contained DMSO only. No-activity control reactions (0% control) contained 0.010 rnL of 100 mol % DOPC (0.3 mM) and DMSO only. The reactions were initiated by the addition of V = 0.020 mL of 0.020 mM UDP-glucose, 1.5 mg/mL CHAPS, 0.17 mg/mL GCS in 25 mM HEPES, pH = 7.4, 75 mM KCl and 7.5 mM MgCl2 to all wells of the plate. The plate was kept at 26 0C for 3 h. The UDP-glucose that remained was measured by the addition of 0.015 mL of 0.30 mM NAD+, 0.30 mM resazurin, 0.11 mg/mL UDP-glucose dehydrogenase and 0.030 mg/mL diaphorase in 25 mM HEPES, pH = 7.4, 50 mM KCl and 5 mM MgCl2. The plate was kept at 26 0C for 30 minutes or longer, and the increase in fluorescence with excitation = 530 nm and emission = 560 nm was measured with an Envision 1 plate reader (Perkin Elmer). Consumption of UDP-glucose was limited to 40-60% of the total UDP-glucose in the assay. IC50 values were calculated by nonlinear regression analysis using the four-parameter equation [Y = max - (max - min) / (1 + (X/IC5o)N)] where Y was the observed fluorescence, X was the concentration of inhibitor, max was the fluorescence in the absence of C6-ceramide (0% control), min was the fluorescence in the absence of inhibitor (100% control), IC50 was the concentration of inhibitor that gave 50 increase in fluorescence and N the empirical "Hill" slope. N should approximate unity. Curve fitting was performed using commercial software (idbs ActivityBase XE).
Example 12
GCS Assay Results
[00272] The IC50 data presented in Tables 1 and 2 were generated via the testing methodology of Example 11 and are coded as follows: A < 200 nm, B = 200-1000 nm, C > 1000 nm. Compounds of the invention are considered active if their IC50 values were < 4000 nM. In this assay, a compound with a smaller IC50 value, for example an IC50 of 10 nM, is considered more potent than a compound with a larger IC50 value, for example, an IC50 value of 100O nM.
Figure imgf000088_0001
Figure imgf000089_0001
Figure imgf000090_0001
Figure imgf000091_0001
Figure imgf000092_0001
Figure imgf000093_0001
Figure imgf000094_0001
Figure imgf000095_0001
Figure imgf000096_0001
Figure imgf000097_0001
Figure imgf000098_0001
Figure imgf000099_0001
Figure imgf000100_0001
Figure imgf000101_0001
Figure imgf000102_0001

Claims

We claim:
1. A compound of the formula,
Figure imgf000103_0001
(I) or a single stereoisomer or mixture of stereoisomers thereof, N-oxides thereof, and additionally optionally as a pharmaceutically acceptable salt thereof, wherein A is isopropyl, t-butyl, C3-Cs cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally substituted by one, two, or three RA groups, wherein each RA is independently R^, Ci-C6 alkyl, Ci-C4 haloalkyl, aryl, aryl(Ci-C4)alkyl, or -Ci-C6 alkyl-R^, wherein the aryl of the aryl(Ci-C4)alkyl group is optionally substituted with one, two, or three RA2 groups, wherein each RA2 is independently halogen, cyano, nitro, -ORA1, -SRA1, -N(RA1)2, -C(O)RA1, -S(O)RA1, -S(O)2RA1, -S(O)N(RA1)2, -S(O)2N(RA1)2, -C(O)ORA1, -C(O)N(RA1)2, -N(RA1)C(O)RA1, -N(RA1)C(O)ORA1, -N(RA1)C(O)N(RA1)2, -N(RA1)S(O)2RA1, -N(RA1)C(=NRA1)N(RA1)2, -P(O)(ORA1)2, or -OP(O)(ORA1)2, wherein each RA1 is independently hydrogen, Ci-C4 alkyl, or Ci-C4 haloalkyl, or two RA attached to adjacent carbon atoms, taken together, form -O-(G)y_O-, wherein each G is independently -CH2-, -C(H)(F)-, or -CF2-, and y is 1, 2, or 3;
E is -(CH2)-, -C(H)(CH3)-, or -C(O)-; L is -[C(RL)2]p-L1-[C(RL)2]q-, wherein p is 1, 2, or 3; q is an integer selected from 0 to (3-p); L1 is a bond, -O- or -NH-; and each RL is independently hydrogen, methyl, or halomethyl; R1 is -N(R10XR11) or a moiety of formula (a),
Figure imgf000104_0001
wherein
R10 is hydrogen or C1-C4 alkyl;
R11 is -R13, -C3-C6 cycloalkyl-N(R12)2, -C3-C6 cycloalkyl-R13 , -Ci-C6 alkyl-N(R12)2, or -Ci-C6 alkyl-R13, wherein each R12 is independently hydrogen or C1-C4 alkyl; and R13 is (a) a 4 - 10 membered monocyclic, 4 - 10 membered fused-bicyclic, 5 - 10 membered bridged-bicyclic, or 5 - 10 membered spiro-bicyclic heterocyclyl ring, where the heterocyclyl ring comprises one, two, or three annular nitrogen atoms, and optionally comprises one annular oxygen or sulfur atom, or (b) a 5 or 6 membered monocyclic heteroaryl or a 8 - 10 membered fused-bicyclic heteroaryl, where the heteroaryl ring comprises one, two, or three annular nitrogen atoms, and optionally comprises one annular oxygen or sulfur atom, wherein the heterocyclyl and heteroaryl are each optionally substituted with one, two, or three R13A groups, wherein each R13A group is independently halogen, cyano, nitro, C1-C4 alkyl, Ci-C4 haloalkyl, aryl(Ci-C4)alkyl, -ORB1, -SRB1, -N(RB1)2, -C(O)RB1, -S(O)RB1, -S(O)2RB1, -S(O)N(RB1)2, -S(O)2N(RB1)2, -C(O)ORB1, -C(O)N(RB1)2, -N(RB1)C(O)RB1, -N(RB1)C(O)ORB1, -N(RB1)C(O)N(RB1)2, or -N(RB1)S(O)2RB1, wherein each RB1 is independently hydrogen, Ci-C4 alkyl, Ci-C4 haloalkyl, aryl, or aryl(Ci-C4)alkyl; w is 0, 1, 2, or 3; ring B in the definition of R1 is (a) a 4 - 10 membered monocyclic, 4 - 10 membered fused-bicyclic, 5 - 10 membered bridged-bicyclic, or 5 - 10 membered spiro-bicyclic heterocyclyl ring, where the heterocyclyl ring optionally comprises one annular oxygen or sulfur atom, and optionally one, two, or three additional annular nitrogen atoms, or (b) a 5 or 6 membered monocyclic heteroaryl or a 8 - 10 membered fused-bicyclic heteroaryl, where the heteroaryl ring optionally comprises one annular oxygen or sulfur atom, and optionally one, two, or three additional annular nitrogen atoms; R20 is -RB2, hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, C3-C8 cycloalkyl, aryl(Ci-C4)alkyl, or -Ci-C4 alkyl-RB2, wherein each RB2 is independently cyano, nitro, -ORB3, -SRB3, -N(RB3)2, -C(O)RB3,
-S(O)RB3, -S(O)2R63, -S(O)N(RB3)2, -S(O)2N(RB3)2, -C(O)ORB3,
-C(O)N(RB3)2, -N(RB3)C(O)RB3, -N(RB3)C(O)ORB3, -N(RB3)C(O)N(RB3)2, or -N(RB3)S(O)2RB3, wherein each RB3 is independently hydrogen, Ci-C4 alkyl, Ci-C4 haloalkyl, aryl, or aryl(Ci-C4)alkyl; or two RB3 taken together with the nitrogen atom to which they are both attached form a saturated or unsaturated monocyclic heterocyclyl or heteroaryl, wherein the heterocyclyl and heteroaryl are each optionally substituted with one, two, or three groups which are each independently (Ci-C3)alkyl, halogen, or Ci-C4 haloalkyl; and each R21 is independently halogen or -R20; XMs -C(H)= Or -N=; Q is -O- or -N(H)-; each R4 is is independently halogen, Ci-C4 alkyl, benzyl, Ci-C4 haloalkyl, amino, Ci-C4 alkylamino, di(Ci-C4 alkyl)amino, or -(O)RB4, wherein each RB4 is independently hydrogen, Ci-C4 alkyl, or Ci-C4 haloalkyl; or two adjacent R4 groups, together with the carbon atoms to which they are attached, form a phenyl ring;m is 0, 1, 2, or 3; n is 0, 1, 2, or 3; and
R5 is independently halogen or Ci-C4 alkyl, wherein the alkyl group is optionally substituted with one, two, or three R51 groups wherein each R51 is independently hydroxy or halogen; provided that when X1 is -N=, E is -C(O)-, L1 is a bond or -NH-, A is isopropyl or t-butyl, R1 is a moiety of formula (a), and Ring B is pyrrolidinyl, then R20 is not -C(O)ORB3 or -C(O)N(RB3)2; and R21, when present, is not -C(O)ORB3 or -C(O)N(RB3)2; provided that when L1 is a bond, E is -CH2- or -CH(CH3)-,and Q is -NH-, then A is not isopropyl or tert-butyl; provided that when L1 is a bond, A is isopropyl or t-butyl, E is -CH2- or -CH(CH3)-, and R1 is a moiety of formula (a), then Ring B is not pyrazolyl, indazolyl, indolyl, or benzimidazolyl; provided that when E is -CH2- or -CH(CH3)-, R1 is a moiety of formula (a), and Ring
B is a 4-10 membered monocyclic heterocyclyl ring, then R20 and R21, when present, are not aryl(Ci-C4)alkyl; and provided that when L1 is a bond, E is -C(O)-, R1 is -N(R10XR11), R11 is R13, and R13 is
8-azabicyclo[3.2.1]octanyl, then R13A, when present, is not aryl(Ci-C4)alkyl.
2. The compound of claim 1 or claim 2, wherein Q is -O-, and m is 1, 2, or 3; or a single stereoisomer or mixture of isomers thereof, and additionally optionally as a pharmaceutically acceptable salt thereof.
3. The compound of claim 1 or claim 2, wherein E is -C(O)- ; or a single stereoisomer or mixture of isomers thereof, and additionally optionally as a pharmaceutically acceptable salt thereof.
4. The compound of claim 1 or claim 2, wherein E is -(CH2)- or -C(H)(CH3)-; or a single stereoisomer or mixture of isomers thereof, and additionally optionally as a pharmaceutically acceptable salt thereof.
5. The compound of any one of claims 1 -4, wherein A is C3-Cs cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally substituted by one, two, or three RA groups; or a single stereoisomer or mixture of isomers thereof, and additionally optionally as a pharmaceutically acceptable salt thereof.
6. The compound of any one of claims 1 - 5, wherein R20 is hydrogen, -ORB3, -N(RB3)2, Ci-C4 alkyl, Ci-C4 haloalkyl, C3-C8 cycloalkyl, aryl(Ci-C4)alkyl, or -Ci-C4 alkyl-RB2; wherein RB2 is -ORB3 or -N(RB3)2; and when R21 is present, each R21 is independently halogen or -R20; or a single stereoisomer or mixture of isomers thereof, and additionally optionally as a pharmaceutically acceptable salt thereof.
7. The compound of any one of claims 1 -6, wherein R1 is
(i) -N(R1^R1 \ wherein
R10 is hydrogen or -Ci-C4 alkyl; and R11 is -R13, -C3-C6 cycloalkyl-N(R12)2, -C3-C6 cycloalkyl-R13, -Ci-C6 alkyl-N(R12)2, or -Ci-C6 alkyl-R13, wherein each R12 is independently hydrogen or C1-C4 alkyl; and R13 is a 4 - 10 membered monocyclic, a 5 - 10 membered bridged-bicyclic, or a 5-10 membered spiro-bicyclic heterocyclyl ring, where the heterocyclyl ring comprises one, two, or three annular nitrogen atoms, and optionally comprises one annular oxygen or sulfur atom, wherein the heterocyclyl is optionally substituted with one, two, or three R13A groups, wherein each R13A group is independently halogen, Ci-C4 alkyl, Ci-C4 haloalkyl, aryl(Ci-C4)alkyl, -ORB1, or-N(RB1)2, wherein each RB1 is independently hydrogen, Ci-C4 alkyl, Ci-C4 haloalkyl, aryl, or aryl(Ci-C4)alkyl; or R1 is (ii) a moiety of formula (a),
Figure imgf000107_0001
(a), wherein w is 0, 1, or 2; or a single stereoisomer or mixture of isomers thereof, and additionally optionally as a pharmaceutically acceptable salt thereof.
8. The compound of any one of claims 1 - 7, wherein R1 is
(i) -N(R1^R1 \ wherein R10 is hydrogen or methyl; or R1 is (ii) a moiety of formula (a),
Figure imgf000107_0002
wherein ring B is a 5-10 membered bridged-bicyclic or 5 - 10 membered spiro-bicyclic heterocyclyl ring, where the heterocyclyl ring optionally comprises one annular oxygen or sulfur atom, and optionally one, two, or three additional annular nitrogen atoms; or the moiety of formula (a) is:
Figure imgf000107_0003
wherein t is 1, 2, or 3; and r is 0, 1, 2, or 3; or a single stereoisomer or mixture of isomers thereof, and additionally optionally as a pharmaceutically acceptable salt thereof.
9. The compound of any one of claims 1 - 8, wherein R1 is -N(R^)R11 or a moiety of formula (a),
Figure imgf000108_0001
wherein
(a) ring B in the moiety of formula (a) is a 5-10 membered bridged-bicyclic heterocyclyl ring, where the heterocyclyl ring optionally comprises one annular oxygen or sulfur atom, and optionally one, two, or three additional annular nitrogen atoms; R20 is hydrogen, -ORB3, -N(RB3)2, Ci-C4 alkyl, Ci-C4 haloalkyl, C3-C8 cycloalkyl, aryl(Ci-C4)alkyl, or -Ci-C4 alkyl-RB2; RB2 is -ORB3 or -N(RB3)2; and R21, when present, is Ci-C4 alkyl or Ci-C4 haloalkyl;
(b) the moiety of formula (a) is
Figure imgf000108_0002
wherein t is 1, 2, or 3, R20 is hydrogen, Ci-C4 alkyl, Ci-C4 haloalkyl, C3-C8 cycloalkyl, aryl(Ci-C4)alkyl, or -Ci-C4 alkyl-RB2, wherein RB2 is -ORB3 or -N(RB3)2, and R21, when present is C1-C4 alkyl or C1-C4 haloalkyl; or
(c) the moiety of formula (a) is
Figure imgf000108_0003
, wherein r is 0, 1, 2, or 3, R20 is -
N(RB3)2 or -Ci-C4 alkyl-N(RB3)2; and R21, when present, is Ci-C4 alkyl or Ci-C4 haloalkyl; or a single stereoisomer or mixture of stereoisomers thereof, and additionally optionally as a pharmaceutically acceptable salt thereof.
10. The compound of any one of claims 1 - 9, wherein R1 is -N(R^)R11 or a moiety of formula (a),
Figure imgf000109_0001
wherein ring B is a 5-10 membered bridged-bicyclic heterocyclyl ring; or a single stereoisomer or mixture of stereoisomers thereof, and additionally optionally as a pharmaceutically acceptable salt thereof.
11. The compound of any one of claims 1 - 9, wherein R1 is -N(R^)R11 or a moiety of formula (a),
Figure imgf000109_0002
wherein said moiety of formula (a) is
Figure imgf000109_0003
wherein t is 1 , 2, or 3; or a single stereoisomer or mixture of stereoisomers thereof, and additionally optionally as a pharmaceutically acceptable salt thereof.
12. The compound of any one of claims 1 - 9, wherein R1 is -N(R10)Rπ or a moiety of formula (a),
wherein said moiety of formu
Figure imgf000109_0004
la (a) is , wherein r is 0, 1, 2, or 3; or a single stereoisomer or mixture of stereoisomers thereof, and additionally optionally as a pharmaceutically acceptable salt thereof.
13. The compound of any one of claims 1 - 12, wherein L is -[C(RL)2]p-L1-[C(RL)2]q-,wherein p is 1 or 2; q is an integer selected from 0 to (3-p); L1 is a bond or -O-; and each RL is independently hydrogen or methyl; or a single stereoisomer or mixture of stereoisomers thereof, and additionally optionally as a pharmaceutically acceptable salt thereof.
14. The compound of any one of claims 1 -13, wherein R1 is a moiety of formula (a),
Figure imgf000110_0001
or a single stereoisomer or mixture of stereoisomers thereof, and additionally as a pharmaceutically acceptable salt thereof.
15. The compound of any one of claims 1 - 13, wherein R1 is -N(R10XR11) or a moiety of formula (a), wherein R11 is R13, wherein R13 is a 4 - 10 membered monocyclic heterocyclyl ring, where the heterocyclyl ring comprises one, two, or three annular nitrogen atoms, and optionally comprises one annular oxygen or sulfur atom, wherein said heterocyclyl ring is optionally substituted with one, two, or three R13A groups; or a single stereoisomer or mixture of stereoisomers thereof, and additionally optionally as a pharmaceutically acceptable salt thereof.
16. The compound of any one of claims 1 - 13, wherein when R1 is -N(R10)(Rπ) or a moiety of formula (a), wherein R11 is R13, wherein R13 is a 5 - 10 membered bridged-bicyclic heterocyclyl ring, where the heterocyclyl ring comprises one, two, or three annular nitrogen atoms, and optionally comprises one annular oxygen or sulfur atom, wherein said heterocyclyl ring is optionally substituted with one, two, or three R13A groups; or a single stereoisomer or mixture of stereoisomers thereof, and additionally optionally as a pharmaceutically acceptable salt thereof.
17. The compound of any one of claims 1 - 13, 15, and 16, wherein when R13A is present, each R13A group is independently halogen, C1-C4 alkyl, Ci-C4 haloalkyl, aryl(Ci-C4)alkyl, -ORB1, -SRB1, or -N(RB1)2, wherein each RB1 is independently hydrogen, Ci-C4 alkyl, Ci-C4 haloalkyl, aryl, or aryl(Ci-C4)alkyl; or a single stereoisomer or mixture of stereoisomers thereof, and additionally optionally as a pharmaceutically acceptable salt thereof.
18. The compound of any one of claims 1 - 13, wherein R1 is -N(R10XR11) or a moiety of formula (a), wherein R11 is-Ci-C6 alkyl-N(R12)2 or -C3-C6 cycloalkyl-N(R12)2; or a single stereoisomer or mixture of stereoisomers thereof, and additionally optionally as a pharmaceutically acceptable salt thereof.
19. The compound of any one of claims 1 - 8, 13, and 15 - 18, wherein R1 is - N(R10XR11); or a single stereoisomer or mixture of stereoisomers thereof, and additionally optionally as a pharmaceutically acceptable salt thereof.
20. The compound of any one of claims 1 - 19, wherein X1 is =N-; or a single stereoisomer or mixture of stereoisomers thereof, and additionally optionally as a pharmaceutically acceptable salt thereof.
21. The compound of any one of claims 1 - 8, 10 - 18, and 20, wherein w is zero or 1, and R21 is C1-C4 alkyl, Ci-C4 haloalkyl, or -N(RB3)2; or a single stereoisomer or mixture of stereoisomers thereof, and additionally optionally as a pharmaceutically acceptable salt thereof.
22. The compound of any one of claims 1 - 21, wherein L is -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH(CH3)-, -CH2-O-, -CH2CH2-O-, or -CH2-O-CH2-; or a single stereoisomer or mixture of stereoisomers thereof, and additionally optionally as a pharmaceutically acceptable salt thereof.
23. The compound of any one of claims 1 - 22, wherein L is -CH2-O-CH2-; or a single stereoisomer or mixture of stereoisomers thereof, and additionally optionally as a pharmaceutically acceptable salt thereof.
24. The compound of any one of claims 1 - 23, wherein when present, each RA is independently halogen, cyano, Ci-C4 alkyl, Ci-C4 haloalkyl, aryl, aryl(Ci-C4)alkyl, -ORA1, -N(RA1)2, or-C(O)RA1, wherein each RA1 is independently hydrogen or Ci-C4 alkyl; or two RA attached to adjacent carbon atoms, taken together, form -O-(G)y_O-, wherein each G is independently -CH2-, -C(H)(F)-, or -CF2-, and y is 1, 2, or 3; or a single stereoisomer or mixture of isomers thereof, and additionally optionally as a pharmaceutically acceptable salt thereof.
25. The compound of any one of claims 1 - 24, wherein when present, each R4 is independently halo, C1-C4 alkyl, Ci-C4 haloalkyl, Ci-C4 alkoxy, Ci-C4 haloalkoxy, or benzyl; or a single stereoisomer or mixture of stereoisomers thereof, and additionally optionally as a pharmaceutically acceptable salt thereof.
26. The compound of any one of claims 1 - 25, which is a compound of formula (Ia):
Figure imgf000112_0001
or a single stereoisomer or mixture of stereoisomers thereof, and additionally optionally as a pharmaceutically acceptable salt thereof.
27. The compound of any one of claims 1 - 25, which is a compound of formula (Ib):
Figure imgf000112_0002
or a single stereoisomer or mixture of stereoisomers thereof, and additionally optionally as a pharmaceutically acceptable salt thereof.
28. A compound listed in Table 1, or a single stereoisomer or mixture of stereoisomers thereof, and additionally optionally as a pharmaceutically acceptable salt thereof.
29. A pharmaceutical composition which comprises a compound, optionally as a pharmaceutically acceptable salt thereof, according to any one of claims 1 - 28, and a pharmaceutically acceptable excipient, diluent, or carrier.
30. A method for treating a disease or disorder mediated by glucosylceramide synthase (GCS) or a disease or disorder in which GCS is implicated in a subject in need of such treatment comprising administering to the subject an effective amount of a compound according to any one of claims 1 - 28 or a composition according to claim 29.
I l l
31. The method of claim 30, wherein the disease or disorder is cancer.
32. The method of claim 30, wherein the disease or disorder is a metabolic disorder.
33. A method for inducing decreased glucosylceramide synthase catalytic activity in a cell, in vitro, comprising contacting the cell with an effective amount of a compound according to any one of claims 1 - 28.
34. A method of preparing a compound of claim 1 , the method comprising:
(i) coupling a compound of formula (14),
Figure imgf000113_0001
wherein * indicates optional (R) or (S) chirality of the adjacent carbon atom, and -N(RX)(RY) is R1, wherein one of Rx and RY is R10 and the other of Rx and RY is R11, or Rx and RY and the nitrogen atom to which they are attached form a moiety of formula (a),
Figure imgf000113_0002
with a compound of formula (15), to provide a compound of formula (I) or a single stereoisomer or mixture of stereoisomers thereof; and optionally separating individual isomers; and optionally modifying any of the R20 and R21 groups to provide a compound of formula (I); and optionally forming a pharmaceutically acceptable salt thereofor; or (ii) when E is -C(O)-, coupling a compound of formula (16),
Figure imgf000113_0003
wherein * indicates optional (R) or (S) chirality of the adjacent carbon atom; with a compound of formula (17) wherein -N(RX)(RY) is R1, wherein one of Rx and RY is R10 and the other of Rx and RY is R11, or Rx and RY and the nitrogen atom to which they are attached form a moiety of formula (a),
Figure imgf000114_0001
(a) to provide a compound of formula (II) or a single stereoisomer or mixture of stereoisomers thereof; and optionally separating individual isomers; and optionally modifying any of the R20 and R21 groups to provide a compound of formula (I); and optionally forming a pharmaceutically acceptable salt thereof.
PCT/US2010/023080 2009-02-06 2010-02-03 Glucosylceramide synthase inhibitors WO2010091104A1 (en)

Priority Applications (2)

Application Number Priority Date Filing Date Title
ARP100100326A AR075367A1 (en) 2009-02-06 2010-02-05 GLUCOSILCERAMIDE SINTASA INHIBITORS
TW099103670A TW201040156A (en) 2009-02-06 2010-02-06 Glucosylceramide synthase inhibitors

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US15043409P 2009-02-06 2009-02-06
US61/150,434 2009-02-06

Publications (2)

Publication Number Publication Date
WO2010091104A1 true WO2010091104A1 (en) 2010-08-12
WO2010091104A8 WO2010091104A8 (en) 2011-04-07

Family

ID=42148396

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2010/023080 WO2010091104A1 (en) 2009-02-06 2010-02-03 Glucosylceramide synthase inhibitors

Country Status (3)

Country Link
AR (1) AR075367A1 (en)
TW (1) TW201040156A (en)
WO (1) WO2010091104A1 (en)

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014043068A1 (en) * 2012-09-11 2014-03-20 Genzyme Corporation Glucosylceramide synthase inhibitors
WO2012129084A3 (en) * 2011-03-18 2014-04-24 Genzyme Corporation Glucosylceramide synthase inhibitors
CN105189490A (en) * 2013-03-15 2015-12-23 建新公司 Salt forms of (S)-quinuclidin-3-yl (2-(2-(4-fluorophenyl)thiazol-4-yl)propan-2-yl)carbamate
EP3318277A1 (en) 2016-11-04 2018-05-09 Institut du Cerveau et de la Moelle Epiniere-ICM Inhibitors of glucosylceramide synthase for the treatment of motor neuron diseases
WO2021221953A1 (en) 2020-04-28 2021-11-04 The Regents Of The University Of Michigan Pyridine inhibitors of glucosylceramide synthase and therapeutic methods using the same
EP4041734A4 (en) * 2019-11-15 2023-08-30 Yuhan Corporation Novel derivatives having 1,2,3,4-tetrahydronaphthalene moiety or pharmaceutically acceptable salt thereof and pharmaceutical compositions comprising the same
EP4041733A4 (en) * 2019-11-15 2023-08-30 Yuhan Corporation Novel derivatives having 2,3-dihydro-1h-indene or 2,3-dihydrobenzofuran moiety or pharmaceutically acceptable salt thereof and pharmaceutical compositions comprising the same
WO2023177563A3 (en) * 2022-03-14 2023-10-26 Merck Sharp & Dohme Llc Fused pyrazole amide analogs as glucosylceramide synthase inhibitors
WO2023172475A3 (en) * 2022-03-11 2023-10-26 Merck Sharp & Dohme Llc Non-aromatic cyclic-pyrimidine analogs as glucosylceramide synthase inhibitors
US11857512B2 (en) 2020-07-24 2024-01-02 Genzyme Corporation Pharmaceutical compositions comprising venglustat

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4107288A (en) 1974-09-18 1978-08-15 Pharmaceutical Society Of Victoria Injectable compositions, nanoparticles useful therein, and process of manufacturing same
US5145684A (en) 1991-01-25 1992-09-08 Sterling Drug Inc. Surface modified drug nanoparticles
WO2005068426A1 (en) 2004-01-14 2005-07-28 Actelion Pharmaceuticals Ltd Piperidine derivatives as gcs inhibitors
WO2006053043A2 (en) 2004-11-10 2006-05-18 Genzyme Corporation Methods of treating diabetes mellitus
WO2006133802A1 (en) * 2005-06-14 2006-12-21 Laboratorios Almirall, S.A. N-amide derivatives of 8-azabicyclo[3.2.1]oct-3-yl as ccr1 antagonists
WO2008150486A2 (en) * 2007-05-31 2008-12-11 Genzyme Corporation 2-acylaminopropoanol-type glucosylceramide synthase inhibitors

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4107288A (en) 1974-09-18 1978-08-15 Pharmaceutical Society Of Victoria Injectable compositions, nanoparticles useful therein, and process of manufacturing same
US5145684A (en) 1991-01-25 1992-09-08 Sterling Drug Inc. Surface modified drug nanoparticles
WO2005068426A1 (en) 2004-01-14 2005-07-28 Actelion Pharmaceuticals Ltd Piperidine derivatives as gcs inhibitors
WO2006053043A2 (en) 2004-11-10 2006-05-18 Genzyme Corporation Methods of treating diabetes mellitus
WO2006133802A1 (en) * 2005-06-14 2006-12-21 Laboratorios Almirall, S.A. N-amide derivatives of 8-azabicyclo[3.2.1]oct-3-yl as ccr1 antagonists
WO2008150486A2 (en) * 2007-05-31 2008-12-11 Genzyme Corporation 2-acylaminopropoanol-type glucosylceramide synthase inhibitors

Non-Patent Citations (8)

* Cited by examiner, † Cited by third party
Title
"Remington's Pharmaceutical Sciences", 1985, MACK PUBLISHING COMPANY
EL ALWANI ET AL., PROSTAGLANDINS & OTHER LIPID MEDIATORS, vol. 78, no. 1-4, 2005, pages 249 - 263
S. M. BERGE ET AL.: "Pharmaceutical Salts", J. PHARM. SCI., vol. 66, 1977, pages 1 - 19, XP002675560, DOI: doi:10.1002/jps.2600660104
TETRAHEDRON LETTERS, vol. 36, no. 41, 1995, pages 7399 - 7402
TETRAHEDRON: ASYMMETRY, vol. 13, no. 11, 2002, pages 1129 - 1134
TREIBER ET AL., XENOBIOTICA, vol. 37, no. 3, 2007, pages 298 - 314
TURZANSKI ET AL., EXPERIMENTAL HEMATOLOGY, vol. 33, no. 1, 2005, pages 62 - 72
YAMASHITA ET AL., PROC. NATL. ACAD. SCI. USA, vol. 96, no. 16, 1999, pages 9142 - 9147

Cited By (25)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103917094B (en) * 2011-03-18 2016-11-09 建新公司 Glucosylceramide synthase inhibitor
WO2012129084A3 (en) * 2011-03-18 2014-04-24 Genzyme Corporation Glucosylceramide synthase inhibitors
CN103917094A (en) * 2011-03-18 2014-07-09 建新公司 Glucosylceramide synthase inhibitors
KR20140092239A (en) * 2011-03-18 2014-07-23 젠자임 코포레이션 Glucosylceramide synthase inhibitors
US9126993B2 (en) 2011-03-18 2015-09-08 Genzyme Corporation Glucosylceramide synthase inhibitors
KR101987736B1 (en) 2011-03-18 2019-06-11 젠자임 코포레이션 Glucosylceramide synthase inhibitors
US9139580B2 (en) 2011-03-18 2015-09-22 Genzyme Corporation Glucosylceramide synthase inhibitors
RU2645675C2 (en) * 2011-03-18 2018-02-27 Джензим Корпорейшн Glucosylceramide-synthase inhibitors
CN114533729A (en) * 2012-09-11 2022-05-27 建新公司 Glucosylceramide synthase inhibitors
EP4098654A1 (en) * 2012-09-11 2022-12-07 Genzyme Corporation Glucosylceramide synthase inhibitors
JP2015527406A (en) * 2012-09-11 2015-09-17 ジェンザイム・コーポレーション Glucosylceramide synthase inhibitor
US11008316B2 (en) 2012-09-11 2021-05-18 Genzyme Corporation Glucosylceramide synthase inhibitors
EA038536B1 (en) * 2012-09-11 2021-09-10 Джензим Корпорейшн Glucosylceramide synthase inhibitors
WO2014043068A1 (en) * 2012-09-11 2014-03-20 Genzyme Corporation Glucosylceramide synthase inhibitors
CN105189490A (en) * 2013-03-15 2015-12-23 建新公司 Salt forms of (S)-quinuclidin-3-yl (2-(2-(4-fluorophenyl)thiazol-4-yl)propan-2-yl)carbamate
US9518049B2 (en) 2013-03-15 2016-12-13 Genzyme Corporation Salt forms of (S)-quinuclidin-3-yl (2-(2-(4-fluorophenyl)thiazol-4-yl)propan-2-yl)carbamate
EP3318277A1 (en) 2016-11-04 2018-05-09 Institut du Cerveau et de la Moelle Epiniere-ICM Inhibitors of glucosylceramide synthase for the treatment of motor neuron diseases
WO2018083223A1 (en) 2016-11-04 2018-05-11 Icm (Institut Du Cerveau Et De La Moelle Épinière) Inhibitors of gangliosides metabolism for the treatment of motor neuron diseases
US11065238B2 (en) 2016-11-04 2021-07-20 Icm (Institut Du Cerveau Et De La Moelle Épinière) Inhibitors of gangliosides metabolism for the treatment of motor neuron diseases
EP4041733A4 (en) * 2019-11-15 2023-08-30 Yuhan Corporation Novel derivatives having 2,3-dihydro-1h-indene or 2,3-dihydrobenzofuran moiety or pharmaceutically acceptable salt thereof and pharmaceutical compositions comprising the same
EP4041734A4 (en) * 2019-11-15 2023-08-30 Yuhan Corporation Novel derivatives having 1,2,3,4-tetrahydronaphthalene moiety or pharmaceutically acceptable salt thereof and pharmaceutical compositions comprising the same
WO2021221953A1 (en) 2020-04-28 2021-11-04 The Regents Of The University Of Michigan Pyridine inhibitors of glucosylceramide synthase and therapeutic methods using the same
US11857512B2 (en) 2020-07-24 2024-01-02 Genzyme Corporation Pharmaceutical compositions comprising venglustat
WO2023172475A3 (en) * 2022-03-11 2023-10-26 Merck Sharp & Dohme Llc Non-aromatic cyclic-pyrimidine analogs as glucosylceramide synthase inhibitors
WO2023177563A3 (en) * 2022-03-14 2023-10-26 Merck Sharp & Dohme Llc Fused pyrazole amide analogs as glucosylceramide synthase inhibitors

Also Published As

Publication number Publication date
WO2010091104A8 (en) 2011-04-07
TW201040156A (en) 2010-11-16
AR075367A1 (en) 2011-03-30

Similar Documents

Publication Publication Date Title
WO2010091104A1 (en) Glucosylceramide synthase inhibitors
KR101544624B1 (en) Pyrimidinyl pyridazinone derivatives
US9914702B2 (en) Amine derivatives as potassium channel blockers
EP3265456B1 (en) Fluorinated lysyl oxidase-like 2 inhibitors and uses thereof
US10100016B2 (en) Condensed ring derivative, and preparation method, intermediate, pharmaceutical composition and use thereof
EP2344470B1 (en) 3-azabicyclo[3.1.0]hexyl derivatives as modulators of metabotropic glutamate receptors
US9434695B2 (en) Nitrogenous heterocyclic derivatives and their application in drugs
US9181186B2 (en) Aromatic ring compound
WO2010091164A1 (en) Inhibitors of glucosylceramide synthase
US8883819B2 (en) Bicyclic heterocycle derivatives for the treatment of pulmonary arterial hypertension
DK2367815T3 (en) pyridazinone
US9776962B2 (en) Aromatic compounds with GPR40 agonistic activity
EA015835B1 (en) 4-oxa(thia)methylpiperidine derivatives, use thereof as antidiabetic compounds
CA2787248C (en) Piperazine compound having a pgds inhibitory effect
WO2011071565A1 (en) Tgr5 agonists
EP2616443A1 (en) Phtalazine derivatives as jak1 inhibitors
KR20110123657A (en) Picolinamide and pyrimidine-4-carboxamide compounds, process for preparing and pharmaceutical composition comprising the same
EP3585772B1 (en) 1, 4, 6-trisubstituted-2-alkyl-1h-benzo[d]imidazole derivatives as dihydroorotate oxygenase inhibitors
US20170369492A1 (en) 1,3-substituted 2-amino-indole derivatives and analogues useful in the treatment or prevention of diabetes mellitus, obesity, and inflammatory bowel disease
KR102365535B1 (en) 2,6-diamino pyridine compound
TW202204331A (en) Cd38 inhibitors
US20220348564A1 (en) Phenyl-[1,3]dioxolo[4,5-c]pyridinyl-phenyl-, phenyl-[1,3]dioxolo[4,5-c]pyridinyl-heteroaryl-, or phenyl-(1,3)dioxo[4,5-c]pyridinyl-piperidinyl-methyl-oxetanylmethyl-1h-benzo[d]imidazole-carboxylic acid derivatives and methods of using same
US20110294858A1 (en) Substituted 6-methylnicotinamides as mglur5 positive allosteric modulators
US20230312522A1 (en) Cyp46a1 inhibitors and methods of use thereof
US20110183980A1 (en) O-benzyl nicotinamide analogs as mglur5 positive allosteric modulators

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 10703401

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 10703401

Country of ref document: EP

Kind code of ref document: A1