WO2014100021A1 - Tgr5 agonists: imidazole and triazole compounds containing a quaternary nitrogen - Google Patents

Tgr5 agonists: imidazole and triazole compounds containing a quaternary nitrogen Download PDF

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Publication number
WO2014100021A1
WO2014100021A1 PCT/US2013/075834 US2013075834W WO2014100021A1 WO 2014100021 A1 WO2014100021 A1 WO 2014100021A1 US 2013075834 W US2013075834 W US 2013075834W WO 2014100021 A1 WO2014100021 A1 WO 2014100021A1
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alkyl
optionally substituted
group
halo
groups
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PCT/US2013/075834
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French (fr)
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Brenton T. Flatt
Raju Mohan
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Exelixis, Inc.
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Publication of WO2014100021A1 publication Critical patent/WO2014100021A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • A61P3/04—Anorexiants; Antiobesity agents
    • 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
    • A61P3/06—Antihyperlipidemics
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing aromatic rings

Definitions

  • the invention relates to agonists of the G protein-coupled receptor TGR.5, compositions comprising them, methods of making the compounds and compositions and using them for the treatment of diseases TGR5 mediates or is implicated in.
  • Bile acids play essential roles in the absorption of dietary lipids and in the regulation of bile acid biosynthesis. While bile acids have long been known to be essential in dietary lipid absorption and cholesterol cataboiism, in recent years an important role for bile acids as signaling molecules has emerged. Eboard acids activate mitogen-activated protein kinase pathways, are ligands for the G-protein-conpled receptor (GPCR) TGR5. and activate nuclear hormone receptors such as famesoid X receptor a (FXR-a). Through activation of these diverse signaling pathways, biie acids can regulate their own enterohepatie circulation, but also triglyceride, cholesterol, energy, and glucose homeostasis.
  • GPCR G-protein-conpled receptor
  • biie acid (BA) controlled signaling pathways are promising novel drag targets to treat common metabolic diseases, such as obesity, type li diabetes, hyperlipidemia, and atherosclerosis. Houten et at., The EMBO Journal (2006) 25, 1419 -1425).
  • Watanabe et ai Nature 2006, 439(7075) 484-489 showed that the administra t ion of bile acids to mice increases energy expenditure in brown adipose tiss ue, preventing obesity and resistance to insulin.
  • This novel metabolic effect of bile acids is critically dependent on induction of the cyclie-AMP-dependent thyroid hormone activating enzyme type 2 iodothyronine deiodinase (D2) because it is lost in D2-/- mice.
  • D2 iodothyronine deiodinase
  • Glucagon-like peptide- 1 (GL M) is produced by L -cells in the distal digestive tract and affects multiple metabolic parameters, including enhanced insulin secretion, glucagon suppression, and lowering of blood glucose.
  • TG 5 expression in L-cells is linked to increased GLP-1 secretion.
  • Katsuma, et ah, Biochem. Biophys. Res. Commun. 2005, 329(1), 386-390) showed that bile acids promote glucagon-like peptide- 1 (GLP- 1) secretion through TGR5 in a murine enteroendocrine cell line STC-1.
  • RNA interference experiments showed that reduced expression of TGR5 resulted in reduced secretion of GLP- 1.
  • transient transfection of STC-1 cells with an expression plasmid containing TGR5 significantly enhanced GLP-1 secretion.
  • WO/2008/097976 Heterocyclic Modulators of TGR5 for Treatment of Disease
  • WO/2008/091540 Substituted Bile Acids as TGR5 Modulators and Methods of Use
  • WO/2008/067219 Quinazolinone Modulators of TGR5
  • the present invention comprises TGR5 agonists of structural formula I(Q),
  • the invention further comprises compositions comprising the compounds and/or pharmaceutically acceptable salts thereof.
  • the invention also comprises use of the compounds and compositions for treating diseases in which TGR5 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 TGR5 is a mediator or is implicated.
  • pharmaceutically acceptable counter ion for each of the quaternary ammonium ion moieties present in the compounds of the invention can he any pharmaceutically acceptable counter ion known to one skilled in the art.
  • pharmaceutically acceptable counter ions that can be used include chlonde, bromide, sulfate, tosyiate, phosphate, tartrate, maleate, acetate, formate, fumarate, mesylate, nitrate, oxalate, ascorbate, citrate, ammonium, arginine, dieihylamme, ethylenediamine, magnesium, sodium, calcium, and potassium, it is also understood that the source of the counter ions can be from either intermolecular sources, or, when possible, intramolecular sources.
  • the present in vention comprises TGR5 agonists of structural formula I(Q):
  • R 1 is Q A or P. c ;
  • R c is selected from phenyl, -(Cs-CeVcycloalkyl, -C3 ⁇ 4-phenyk heieroaryl, and -(Ci-C4)alkyl optionally substituted with -OR 013 , -N(R C !J ) 2 or -S( Cl3 ), wherein the cyclic group of R c can be optionally substituted with 1, 2, 3, 4 or 5 R Cs0 groups, wherein the 1, 2, 3, 4, or 5 R C!0 groups are independently selected from R U0A and R Ci ' jB , provided that R c cannot be substituted with more than two R C1" ° groups, wherein
  • each R CI0A is independently selected from halo, cyano, and optionally substituted with one, two, or three groups selected from -OH and halo;
  • each R C10B is independently selected from -C(0)NH 2 , (5-6 membered)heterocycloalkyl» -0-(C C 4 )alkyl-R cn , -C(0)OR CI2 , -OC(0)OR C12 , and -0-(C]-C 4 )alkyi optionally substituted with -OH or -C(0)OH;
  • each R CB is independently selected from hydrogen, -(Q -Chalky!, and -(Ci-C4)haioalkyl,
  • R c when R c exists, is substituted with one or two Q A groups, wherein R c is substituted with Q" by replacing a hydrogen that is covalently bonded to carbon or nitrogen;
  • R 2 is -L D -R D1 ;
  • L D is ⁇ [C(R)2j 1 ,- Y-[C(R.)2j q S
  • p 0 or 1 :
  • q is 0 or 1 ;
  • each R is independently selected from H, ⁇ (Ci -C 3 )a!ky], halo, -OH, and - ⁇ 3 ⁇ 40 ⁇ ;
  • R Di is selected from phenyl -(C 6 -C ! o)ar l, -N(H)-pheny1, -(Cs-Cycycloalkyl, heterocycloalkyl, or heteroaryl, wherein R Dl can be optionally substituted with one, two, three, or four R D1 °. wherein the one, two, three, or four R D1 ° groups are independently selected from A groups and B groups, provided that R D! cannot be substituted with more than two B groups;
  • each A group when they occur, is independently selected from halo, -CF3, -ON, -NO2, -OH; -0-(Ci-C4)alky ⁇ optionally substituted at the aikyl group with one, two, or three substituents independently selected from -OH and halo; and -((.VC jalkyl optionally substituted with one, two, or three substituents independently selected from -OH and halo; each B group, when they occur, is independently selected from -(Ct-C 4 )alkylN(R D ")2, -C(0)-NH 2 , -C(0)-N(H)-OH, -C(0)-N(H)-R D1 IC , ⁇ C(0)-(C C 4 )alkyl, -C(0)QH, -C(0)0-(C r C 4 )alkyi, -S(OMCi-C 4 )alkyl-N(R D1 !
  • R DH and R D11B when they both exist and are each attached to nitrogen, can join together with the nitrogen to which they are attached to form a (5-6 membered) heterocycloalkyl optionally substituted with a group selected from -OH,
  • R 5 is ⁇ O ⁇ phenyl -[C(R s ) 2 ] -naphthalenyl, or -[C(R a ) 2 ]-(5-iO membered) heteroaryl, wherein the heteroaryl is selected from benzo[d][.l,3]dioxolyl, benzo[d]isoxazolyl, quinoxalinyl, quinolinyl, and 2,3,4a,8a-tetrahydrobenzo[b][l ,4jdioxinyl, wherein the cyclic group of R 5 is optionally substituted with one, two, three, four, or five R A '° groups, wherein the one, two, three, four, or five A1 ° groups are independently selected from A10A groups and R A,0B groups, provided that R 3 cannot be substituted with more than two R AluB groups; each R A,0A , when they occur, is independently selected from halo, alk
  • each R A,0B when they occur, is selected from -0-(C r C 4 )aikyl-R A ", -S(0) 2 -NH 2 , -8(0) 2 CH 3 , -N(H>S(0) 2 CH 3 , ⁇ S(0) 2 N(H) ⁇ C3 ⁇ 4, -C(0)OH, -(Ci-C 4 )alkyl-OH,
  • R Ai ! is selected from -C(0)QH, (5-6 membered)heterocycloaikyl, halogen, cyano, nitro, -(C C 4 )alkyl, -N(R A,2 ) 2 , -OR Ai2 , -SR A12 , -N(OR Ai2 )R A!2 , -C(0)R Ai2 , -C(0)OR A12 , -C(0)N(R A!2 ) 2 , -N(R A,2 )S(0)R A12 , -N(R Al2 )S(0) 2 R A12 , -S(0)N(R A12 ) 2 , -S(0) 2 N(R A:2 ) 2 , -S(0) 2 R' 2 , -OC(0)R A ' 2 , -OC(0)OR A12 , -OC(0)N(R A 3 ⁇ 4,
  • each R A12 is independently hydrogen, -(Ci-Q)alkyl, or -(Ci-Ci)haloalkyl;
  • each R s is independently hydrogen, halogen, or methyi, or both 6 taken together with the carbon to which they are both attached form either a (C3 ⁇ C 6 )eyeloaIkyi or a (3-6 membered)heterocycloalkyl;
  • Q A is Q L or Q R ;
  • Q L is -N[(CrC 3 )alkyl]j "r wherein an alkyl group of -N[(Ci-C3)alk l]3 T is optionally substituted with ⁇ (Co-C6)alkyl-S(0) 2 OH;
  • Q x is selected from:
  • R QA is -(Ci-Csjalkyl
  • R QB is -(Ci-C 3 )alkyl optionally substituted with -C(0)OH;
  • R QC is H, -OH. -(Co-C 4 )alkyl-COOH, or -(C r C 5 )alkyl.
  • X is C(iO ⁇ :
  • each R is independently selected from H, -(C; -C 3 )aikyL -OH, and -CH 2 OH;
  • Y is -S-, -S(0>2-, -C(il C(H)-, -C(0)-, -(C, -C 4 )aikyl-S-, -(C, -C 4 )alkyl-N(R Y )-, -C(H)(halo)-, -(C 5 ⁇ C 4 )alkyl-S(0) 2 -, -S(0) r N(R Y )-, -(C C 4 )a!kyl-0-, or -C(0)-N(R Y )-, wherein is H, -(Ci-C 4 )alky], or hydroxyl ⁇ C]-C 4 )alky!;
  • R 0, is selected from phenyl, -(C 6 -Cio)aryl, -N(H)-phenyl, -(C.v Ctjcycioaikyl, heterocycloalkyl, or heteroaryl, wherein R DI can be optionally substituted with one, two, three, or four R DS0 , wherein the one, two, three, or four R D5 ° groups are independently selected from A groups and B groups, provided that R Dl cannot be substituted with more than two B groups;
  • each A group when they occur, is independently selected from halo, -CF 3 , -CN, -NO ? ., -OH; -0-(CrC4)alkyl optionaliy substituted at the alkyl group with one, two, o three substituents independently selected from -OH and halo; and -(Ci-Ct)alkyl optionaliy substitined with one, two, or three substituents independently selected from -OH and halo; each B group, when they occur, is independently selected from -(Ci-C4)aikylN(R D ")2, -C(0)-NH 2 , -C(0)-N(H)-OH, ⁇ C(0)-N(H)-R DHC , - ⁇ 3 ⁇ 40)-(Ci-C4)a]kyI, -C(0)OH, -C(0)0-(Ci-C 4 )alkyl, -S(0>2-(C I -C 4 )alk>'l-N
  • heterocycloalkenyl optionally substituted with oxo or R Dl 1 ; heteroaryl optionally substituted with R Di l ; -0-(Ci-C 4 )alkyl optionally substituted at the alkyl group with one or two R Di iB ; ⁇ S(0) 2 -(4-6 membered)heterocycloalkyl optionally substituted with R DJ iC ; -N(H)-C(0)-(C ! -C 4 )alkyl optionally substituted at the alkyl group with one or two R Dl !i!
  • each R li ⁇ i is independently selected from H, -(C3-C(,)cycioaikyl,
  • R DnB is selected from H, -OH, -CF 3 , ⁇ N(R Dn )2, -C(0)OH, -0-(C r C 4 1 ⁇ 2]kyl,
  • X is -C(R 4 )-:
  • Y is a bond, -S-, -S(0) 2 -, -CH(CH 3 )-S(0) 2 -, -CH(CH 3 )-S-, -CH(C3 ⁇ 4)-S(0) 2 -, -CH(OH)-, -CH(CH 3 )-0-, -C(O)-, -(CH 2 )-S-, -CH.
  • R Y is H, ⁇ (C C 3 )alkyl or hydroxyi(C t -C 3 )alkyl:
  • each R is independently selected from H, -CH 3 , - OH. F, and -CH 2 OH;
  • R D! is selected from phenyl, -N(H)-phenyl, -(CVCejcyeloaikyl, -(5-6
  • R D5 is optionally substituted with one.
  • two, or three R D!0 wherein the one, two, or three R D!0 groups are independently selected from A groups and B groups, provided that R D5 cannot be substituted with more than one B groups;
  • each A group when they occur, is independently selected from halo, -CF 3 , -CN, -NO 2 , -OH, -G-(C r C 4 )alkyl optionally substituted with one, two, or three substituents independently selected from -OH and halo, and -(CrCjjalkyl optionaliy substituted with one, two, or three substituents independently selected from -Oil and halo;
  • each R is independently selected from H, -(Cj-C2)alkyl, fluoro, -OH, and -CH2OH;
  • R D! is selected from phenyl, -N(H)-phenyI, cyclohexyl, cyelopentyL piperidinyl, piperazinyl, pyrrolidinyl, morpholinyl, 1 ,2,3,6-tettahydropyridinyl, heteroarylheterocycloalkyl, pyridinyl, oxazolyl, pyrazinyi, qumolinyi, 1,2,4-oxadiazoiyt, 1 ,2,3,4-tetxahydroquinolinyl, and pyrazolyl, wherein R Dl can be optionally substituted one, two, or three R Di0 , wherein the one, two, or three R Di0 groups are independently selected from A groups and B groups, provided that R D1 cannot be substituted with more than
  • each A group when they occur, is independently selected from halo, -CF 3 , -CN, -NO?, -OH; -0-(Ci-C 4 )alkyl optionally substituted with one, two, or three substituents independentl selected from -OH and halo; and -(Ci-C 4 )alkyl optionally- substituted with one, two, or three substituents independently selected from -OH and halo;
  • the B group is selected from -0-(C C 4 )alkyl-C(OpH, -0-(d-C 4 )a!kyl, -0-(C i -C 4 )aikyi-C(0)-(C , -C 3 )alkyl, -0-(Q -C 4 )alkylN(R D E l ) 2 ,
  • a heterocycioalkyl selected from morpiioiinyi, pyirolidinyl, piperazinyl, and piperidinyi, wherein the heterocycioalkyl can be optionally substituted with one, two, or three R Dn ; cyelopropanyl; cyclopentyl; imidazolyl; pyridinyl; thiazolyl; l(H)-tetrazolyl; and phenyl optionally substituted with one, two, or three halo,
  • R l i and R l lB when they both exist and are each attached to nitrogen, can join to form a (5-6 membered) heterocycoalkyl optionally substituted with R H ;
  • X is C(iiV
  • each R is independently selected from H, -(C
  • R J! is selected from phenyl, -N(H)-phenyl, cyclohexyl, cyclopentyl, piperidinyl, piperazinyl, pyrroiidinyl, morpholinyl, 1 ,2,3,6-tetrahydropyridinyL heteroarylheterocycloalkyl, pyridinyl, oxazolyl, pyrazinyl, qumolinyl, 1,2,4-oxadiazolyi, i,2,3,4-tetraliydroquinoiinyl. and pyrazolyl, wherein R D1 is substituted with one, two, or three R D! ' J , wherein the one, two, or three R Di0 groups are zero, one, or two A groups and zero or one B group;
  • each A group when they occur, is independently selected from halo, -CFj, -CN, -NO 2 , -OH: -0-(C I -Chalky! optionally substituted with one, two, or three substituents independently selected from -OH and halo; and -(Ci-C 4 )alkyl optionally substituted with one, two, or thi'ee substituents independently selected from -OH and halo;
  • the B group when it occurs, is selected from -0-(C; -Chalky 1 optionally substituted at the alley!
  • R D! SB is selected from H, -OH, -CF 3 , -NH 2 , -C(0)OH, -0-(Ci-Ct)alkyl,
  • R J! t and R D, ,B when they both exist and are each attached to nitrogen, can join to form a (5-6 membercd) heterocycoaikyl optionally substituted with R' 1 ;
  • X is C(k' ;
  • R Y is H, -(d-G ⁇ alkyl or hydroxyl(Ci -C ⁇ alkyl;
  • each R is independently selected from H, -(Ci-C2)alkyi, fiuoro, -OH, and -CH?OH;
  • R D1 is selected from phenyl, -N(H)-phenyl, eyclohexyl, cyclopentyl, piperidinyl, piperazinyl, pyrrolidinyl, morpholinyl, 1 ,2,3,6-tetrahydropyridinyl, hetexoarylheterocycloaikyl, pyridinyl, oxazolyl, pyrazinyi, quinolinyl, 1 ,2.,4-oxadiazoiyl, 1 ,2,3,4-tetrahydroquinolinyl, and pyrazolyl, wherein R Di is substituted with one, two, or three R l °, wherein the one, two, or three R D '° groups are zero, one, or two A groups and one B group;
  • each A group when they occur, is independently selected from halo, -CF 3 , --CN, -NO?, -OH; -0-(Ci -Chalky! optionally substituted with one, two, or three substituents independently selected from -OH and halo; and optionally substituted with one, two, or three substituents independently selected from -OH and halo;
  • the B group is selected from -0-(Ci-Ci)alkyl-C(0)OH, -0-(CrC 4 )alkyi, -0-(C 1 -C 4 )alkyl-C(0)-(C,-C :i )alkyI, -C(0)OH, -NH 2 , -(C C )alkyl-C(0)OH, 2,3-dihydro-lH-tetrazolyl, -0-(C !
  • iB -0-(Ci ⁇ C4)alkyl » (5-6 membered)heterocycloalkyl optionally substituted with oxo or methyl,; -C(0)-heterocycloalkyl optionally substituted with -S(0) 2 OH; -C(0)-N(H) ⁇ (Ci-C 4 )alky?
  • heterocycloalkyl selected from 1 H-tetrazofyL piperizinyl, 2,3-dihydro-l ,3,4-oxadiazolyL and 4,5-dihydro-l,2,4 ⁇ oxadiazQlyl, wherein the heterocycloalkyl can be optionally substituted with oxo or
  • R Di i and R D1 !B when they both exist and are each attached to nitrogen, can join to form a (5-6 embered) heterocycoalkyl optionally substituted with R ! l ;
  • L D is selected from -(Ci-C 3 )alkyl-0-, -(Co-C 3 )alkyI-NR Y -(Co-C3)alkyI-, -(Co-C 3 )aikyi-S-(CQ-C 3 )alkyl-, -(Co-C 3 )alkyl-S(0)2-(Co-C3)alkyl-; -C(0)N(R Y )-(Co-C 3 )alkyK -S(O) 2 -N(R Y )-(C 0 -C 3 )alkyk -C(O)-(C 0 -C 3 )alkyl-, -OC-(C 0 -C 3 )alkyl-, -(Co-C 3 )alkyl-, and -(Ci-C 4 )alkyi- optionally substituted
  • L D is selected from -(CH?.)i-3-0-, -(CH 2 ) ! _3 ⁇ NR / ⁇ , -(C 0 -C 3 )alkyl-S-(C C 3 )alkyl-; -(C3 ⁇ 4),, 3 -S-, -S-(CH 2 ),. 3 , -S(0) 2 -(CH 2 ),. 3 -, -S(0) 2 -, -C(0)N(HHCH 2 )i,3-, -S(0) 2 -N(H)-(CH 2 )i-3-.
  • L D is selected from -(CH 2 )-0-, -(CH 2 ) ⁇ NR Y -, -(CH 2 )-S-, -8-(CH 2 , ⁇ S(0) 2 ⁇ , -S(0) r (C3 ⁇ 4K -C.(0)N(R Y )-(Co-C 3 )alkyls -S(0) 2 -N(H)-(CH 2 ⁇ i. 3 -, CtO) (U i y J,. : ⁇ , -OC-(C2-C 3 )alkyl-, and -(Ci-C4)aikyl- optionally substituted with halo or -OH.
  • L D is selected from -(CH 2 )-0-, -(CH 2 )--NR Y ⁇ , -(CH 2 )-S- , -S-(CH 2 )-, -S(0) 2 -, -S(0) 2 ⁇ (CH 2 >, -C(0)N(R y )-(Co-C 3 )alky -S(0) 2 -N(H)-(CH 2 ) !-3 -, -C(0)-(CH 2 )i- 2 -,
  • L D is selected from -(CH 2 )-0-, -(CH 2 )-NH-, -(CH 2 )-S-, -S-(CH 2 )-,
  • R c is phenyl, -CH 2 -phenyL -(Cs-Cs)-cydoalkyL or pyridinyl, wherein R c can be optionally substituted with one.
  • R C1 ° wherein the one, two, or three R C1 ° groups are independently selected from R C10A and R 0B , provided that R c cannot be substituted with more than one R U0B group;
  • each R Ci0A when they occur, is independently selected from halo; -(CrCj)alk l optionally substituted with one, two, or three groups selected from halo and -OH; rnethoxy;
  • R C10B is selected from -C(0)N3 ⁇ 4, (5-6 memberedjheterocycloalkyl; -0-(Ci-C )a3kyl optionally substituted with -OH, -C(0)OH, or - [-(C;-C,!alkyl3 2 ; and -(C C 4 )alkyl substituted with - [-(Cj-C4)alkyl] 2 ; and
  • R ⁇ is substituted with one or two Q A groups, wherein R is substituted with Q A by replacing a hydrogen th t is covalentiy bonded to carbon or nitrogen.
  • R° is phenyl, -CH 2 -phenyl, -(Cs-CeJ-cycIoalkyl, or pyridinyl, wherein the cyclic group of R c can be optionally substituted with one, two, or three R U d groups and, wherein the one, two, or three R o groups are independently selected from R C !0 " and R. ' " l0B , provided that R c cannot be substituted with more than one C!CB group; each R clwA , when they occur, is independently selected from methoxy, -CF$, halo, and -(Ci -Chalky! optionally substituted with one, two, or three groups selected from halo and -OH;
  • R C!0B is selected from (5-6 membered)heterocycloalkyl; -(Ci-C 4 )aikyi substituted with -N[-(Ci-C 4 )alk l] 2 ,; -C(0)NH 2 ;and -0-(CrC 4 )alkyl optionally substituted with
  • R c is substituted with one Q A group, wherein R c is substituted with Q A by replacing a hydrogen, that is covalently bonded to carbon or nitrogen.
  • R c is phenyl, -CH 2 -phenyl or pyridinyl, wherein the cyclic group of R c can be optionally substituted with one, two, or three R cs0 , wherein the one, two, or three R C I' "' groups are independently selected from R C!0A and R 0B , provided that R c cannot be substituted with more than one R C10B group;
  • each R C!0A when they occur, is independently selected from --(Ci-Ci kyl optionally substituted with one, two, or three groups selected from -OH, methoxy, -CF3 and halo;
  • R C10B is selected from -C(O)NH 2 , (5-6 :membered)heterocycioalkyl; substituted with -N[-(Ci-C 4 )alkyl] 2 ,; and ⁇ 0-(Ci-C )a!kyl optionally substituted with -OH, -C(0)OH, or -N[-(C-.-C 4 )aiky1]2; and
  • R ' " is substituted with one or two Q A groups, wherein R L is substituted with Q A by replacing a hydrogen that is covalently bonded to carbon or nitrogen.
  • R c is phenyl or pyridinyl, wherein the cyclic group of R c can be optionally substituted with one, two, or three R c, °, wherein the one, two, or three R C
  • each R C 10A when they occur, is independently selected from methoxy and halo;
  • R C,0B is selected from -C(0)NH 2> (5-6 membered)heterocycloalkyl; -(CrC jalkyl substituted with -N[-(Ci -C 4 )alkyl] 2 ; and --0-(Ci -C )aIkyl optionally substituted with -OH, -C(0 ⁇ OH, or ⁇ N[-(C r C4)alky3 ⁇ 4; and
  • R c is substituted with one Q A group, wherein R c is substituted with Q A by- replacing a hydrogen mat is covalently bonded to carbon or nitrogen.
  • R c is phenyl or pyridiny!, wherein the cyclic group of R c can be optionally substituted with one or two groups selected from methoxy, methyl and halo; and wherein R c is substituted with one Q A group, wherein R c is substituted with Q A by replacing a hydrogen that is covalently bonded to carbon or nitrogen.
  • R ' " ' is phenyl or pyridinyl, wherein the cyclic group of R k ' can be optionally substituted one or two groups selected from methoxy, methyl, fluoro and chloro; and wherein R c is substituted with one Q A group; wherein R 1"' is substituted with Q A by replacing a hydrogen that is covalently bonded to carbon or nitrogen.
  • R ' " "' is phenyl substituted with one or two groups selected from methoxy, fluoro or chloro; wherein R c is substituted with one Q A group; wherein R c is substituted with Q A by replacing a hydrogen that is covalently bonded to carbon or nitrogen.
  • the compound of formulae I(Q) is one of formula II, III, IV, V, VI or
  • R cs0 is substituted with one Q A group; wherein R C!0 is substituted with Q A by replacing a hydrogen that is covalently bonded to carbon or nitrogen.
  • each R A!0 is selected from fhioro, chloro arid methoxy
  • R 2 is -L D -R D1 , wherein:
  • L D is selected from -(C3 ⁇ 4)-0-, -iCH 2 )-NH-, -(CH 2 )-S-, -S-(CH 2 )-, -S(0) 2 -,
  • R D1 is one of:
  • each A is chloro or fluoro, and B is selected from:
  • L D is selected from -(CH 2 )-0, -(CH?)-NH - ⁇ , -(C3 ⁇ 4)-S-, -S-(CH 2 )-, -S(0) 2 -, -S(0) 2 -(CH 2 )-, -C(0)N(H)-(CH 2 )i.
  • L. D is selected from -S-(C(-C3)alkyi-, -(C3 ⁇ 4) 2 - and -(Ci-C 3 )alkyl-0-.
  • R 3 is -[0((3 ⁇ 4) 2 ] -phenyl, -[C(C3 ⁇ 4) 2 ]-naphthalenyl, ⁇ -[ €( € ⁇ 3 ) 2 ]-(5-10 membered) heteroaryl, wherein the heteroaryl is selected from (beiizo[d][l ,3]dioxolyl, benzo[d]isoxazolyI, quinoxalinyl, qxiinolinyl and 2,3,4a,8a-tetrahydrobenzo
  • each R AlwA when they occur, is independently selected from halo, -(Ci-C3)alkoxyl, and hydroxy!;
  • R AI0B is -(C) -Chalky! optionally substituted with one, two, or three groups selected from -OH and halo; ⁇ 0-(Cj-C 4 )alkyl-C(0)OH; ( (CrC4)alkyl-N[(C r C 3 )aIkyl] 2 ; -NH 2 ; -S(0> 2 -NH 2 ; -SO 2 CH 3 ; -N(H) ⁇ S0 2 CH 3 ; -S0 2 N(H)-CH 3 ; -CN; -C(0)OH; -(C t -C 4 )alkyl-OH; -OCF 3 ; or -C(0) 3 ⁇ 4.
  • R J is -[C(CH 3 ) 2 ]-phenyl
  • the phenyl group of R 5 is optionally substituted with one, two, or three R 0 groups, wherein the one, two, or three R A '° groups are independently selected from R Ai0A and R Al0B , provided that R 5 cannot be substituted with more than one R Al0B group;
  • each R Ai0A when they occur, is independently selected from halo, methoxy, and hydroxy!;
  • R A!0B is -0-(CrC4)alkyl-C(0)OH, 0-(CrC4)alkyi-N[(CrC 3 )a3kyl]2, -NH 2 ,
  • R 5 is -[C(CH 3 ) 2 ⁇ -phenyl, wherein the phenyl group is optionally substituted with one or two groups selected from halo, methoxy, and hydroxy!.
  • R J is -[C CHs ⁇ J- henyl, wherein the phenyl group is optionally substituted with one or two groups selected from halo and methoxy. $5]
  • R 3 is:
  • R C is substituted with one, two, three, four, or five R CI " A groups, wherein one substituent of R is Q A .
  • R C is substituted with zero, one, two, three, or four R" " groups and 1 R ' " ' group, wherein one substituent of R ' is Q A
  • R c is substituted with zero, one. two, or three R CL0A groups and one or two R'- ,UB groups, wherein one substituent of R c is Q ⁇
  • R D1 is substituted with zero, one, two, three, or four A groups and one B group.
  • R D1 1B is -(Cj-G alkyl optionally substituted with one, two, or three groups independently selected from halo, -OH, -S(0)20H, C(0)OH, -NH 2 , -N[(C,-C 3 )alkyl] ⁇ + , 1 > 4-diazabicyclo[2.2.2]octanyl, and -N(H)C(-NH)N3 ⁇ 4.
  • R DNB is -(C1 ⁇ 4-Cj)alkyl-(5-8 memberediheterocycioalkyl optionally substituted at the heterocycloalkyi group with 1 to 3 R Dn
  • R Di !d is -(Co-C3)alkyl-(C3-C6)cycloalkyl optionally substituted with R D U .
  • D1 1B is aryi optionally substituted with one, two, or three halo.
  • the invention also comprises as another embodiment, a composition comprising a TGR5 agonist compound according to any one of the preceding embodiments together with a pharmaceutically acceptable diluent, excipient, and/or carrier.
  • a composition comprising a TGR5 agonist compound according to any one of the preceding embodiments together with a pharmaceutically acceptable diluent, excipient, and/or carrier.
  • Such compositions are substantially free of non-pharrnaceutically acceptable components, i. e., contain amounts of non-phar aceuticaliy 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 or preventing a metabolic disease in a subject in need of such treatment comprising administering to the. subject an effective amount of a TGR5 agonist compound according to any one of the preceding embodiments.
  • Metabolic diseases that may be treated or prevented include, without limitation, metabolic syndrome, insulin resistance, and Type 1 and Type 2 diabetes.
  • the invention also comprises as another embodiment a method for treating obesity or type II diabetes in a subject in need of such treatment comprising administering to the subject an effective amount of a TGR5 agonist compound or pharmaceutical composition according to any one of the preceding embodiments.
  • the invention also comprises as another embodiment a method for treating hyperlipidemia in a subject in need of such treatment comprising administering to the subject an effective amount of a TGR5 agonist compound or pharmaceutical composition according to any one of the preceding embodiments.
  • the invention also comprises as another embodiment a method for treating athersclerosis in a subject in need of such treatment comprising administering to the subject an effective amount of a TGR5 agonist compound or pharmaceutical composition according to any one of the preceding embodiments.
  • the invention also comprises as another embodiment a method for lowering blood glucose in a subject in need of such treatment comprising administering to the subject an effective amount of a TGR5 agonist compound or pharmaceutical composition according to any one of the preceding embodiments.
  • the invention also comprises as another embodiment a method for enhancing insulin secretion in a subject in need of such treatment comprising administering to the subject an effective amount of a TGR5 agonist compound or pharmaceutical composition ⁇ according to any one of the preceding embodiments.
  • the invention also comprises as another embodiment a method for treating a disease associated with perturbed bile acid metabolism in a subject in need of such treatment comprising administering to the subject an effective amount of a TGR5 agonist compound or pharmaceutical composition according to any one of the preceding embodiments.
  • diseases include, but are not limited to, gall bladder stones, cholecystitis, cholangitis, choledocholithiasis, jaundice, and obstetric cholestasis and the itch associated with it.
  • the invention also comprises as another embodiment a method for treating obesity or type II diabetes in a subject in need of such treatment comprising co -administering to the subject, simultaneously or sequentially, an effective amount of a TGR5 agonist compound according to any one of the preceding embodiments and a second anti-diabetic drug or pharmaceutical composition comprising an effective amount of a TGR5 agonist compound according to any one of the preceding embodiments and a second anti-diabetic drug.
  • anti-diabetic drugs include:
  • Sulfonylureas e.g., tolbutamide (3-butyl- 1 -(4-methylphenyl)sulfonylurea), acetohexamide (4-acetyl-. ⁇ -(cyc3ohexylcarbamoyl)benzenesulfonainide), tolazamide (3-azepan- 1-yi-l -(4-metb.ylphenyl)sulfonyl-urea), chlorpropamide (N ⁇ (4-chiorophenyl)sulfoi!y3methanamide), glipizide ( ⁇ '-[2-[4-
  • Megiitinides e.g., repaglinide (5(+)2-ethoxy-4(2((3-methyl-i-(2-(l- piperidmyl)phenyl)-butyl)amino)-2--ox.oethy])behzoic acid), nateglinide (3-phenyl- 2-(4-propan-2-ylcyclohexyl)carbonylamino-propanoic acid), and mitiglmide ((25)- 2-benzyl-4-[(3ai?,7aS)-octahydro-2H-isoindol- 2-yl]-4-oxobutanoic acid))
  • Biguanides e.g., metformin (Av A /-dimethylimidodicarbonimidic diamide), phenformin (2-(N-phenethy!carbamimidoyl)guanidine), and buformin (2-buty)-] - (diammomethylidene)guanidine)
  • Alpha-glucosidase inhibitors e.g., miglitoi ((2R,3R,4R,5S) ⁇ 1 -(2-hydroxyethyl)-2 ⁇ (hydroxymethyl)piperidine-3,4,5-triol), acarbose ((2R,3R,4R,5S,6R)-5- ⁇ [(2A ⁇ 3i?,4ii,5 ⁇ 0 3 ⁇ 4-5- ⁇
  • GLP Glucagon-iike peptide
  • agonists e.g., exenatide and liraglutide
  • Amyiin analogues e.g., pramlintide acetate (Symlin)
  • Dipeptidyl peptidase-4 (DPP-4) inhibitors e.g., vildagliptin, (2.S)-l- ⁇ 2-[(3- hydroxy-l-adamantyl)ainino]acetyl ⁇ pyrrolidine-2-carbonitrile and sitagliptin ((37 -3-amino-l -[9-(irifluoromethyl)-l J 4 7 7,8 etra7abicyclo[4.3 ]nona-6,8-dien- 4-yl]-4-(2,4,5-trifluorophenyl)butan- l-one)), and
  • Tbiazolidinedioiies e.g., rosiglitazone, 5-((4-(2-(methyl-2-pyridinylamino) ethoxy)phenyl)methyl)- 2,4-thiazolidinedione, pioglitazorte (5-((4-(2-(5-ethyl-2- pyndmyi)etiioxy)pheiiyl)methy])",(+'-)- 2,4-thiazoiidinedione,) and troglitazone (5- (4-((6-hy(koxy-2,5,7 "teiramethyichroman-2-yl-methoxy)beBzyl)-2,4- tbiazolidinedione)).
  • the invention also comprises as another embodiment, a method for inducing increased GLP- 1 secretion in cell, in vitro, comprising contacting the cell with an inducing effective amount of a TGR5 agonist compound according to any one of the preceding embodiments.
  • the invention also comprises as another embodiment the use of an effective amount of a TGR5 agonist compound according to any one of the preceding embodiments for the preparation of a medicament for treating a metabolic disease in a subject in need of such treatment,
  • the invention also comprises as another embodiment, the use of an effective amount of a TGR.5 agonist compound according to any one of the preceding embodiments for the preparation of a medicament for treating obesity or type II diabetes in a subject in need of siich treatment.
  • the invention also comprises as another embodiment, the use of an effective amount of a TGR5 agonist compound according to any one of the preceding embodiments for the preparation of a medicament for treating hyperlipidemia in a subject in need of such treatment.
  • the invention also comprises as another embodiment, the use of an effective amount of a TGR5 agonist compo und according to any one of the preceding embodiments for the preparation of a medicament for treating athersclerosis in a subject in need of such treatment.
  • the invention also comprises as another embodiment, the use of an effective amount of a TGR5 agonist compound according to any one of the preceding embodiments for the preparation of a medicament for lowering blood glucose in a subject in need of such treatment.
  • the invention also comprises as another embodiment, the use of an effective amount of a TGR5 agonist compound according to any one of the preceding embodiments for the preparation of a medicament for enhancing insulin secretion in a subject in need of such treatment.
  • the invention also comprises as another embodiment, the use of an effective amount of a TGR5 agonist compound according to any one of the preceding embodiments for the preparation of a medicament for treating a disease associated with perturbed bile acid metabolism in a subject in need of such treatment.
  • the invention also comprises as another embodiment, the use of an effective amount of a TGR5 agonist compound according to any one of the preceding embodiments and a second anti-diabetic drug for the preparation of a medicament for treating obesity or type II diabetes 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, transdermal! ⁇ ', intravaginally, mtravesically, 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.
  • 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.
  • 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, friethanolarnine oleate, buty!alted 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, friethanolarnine oleate, buty!alted hydroxytoluene, etc.
  • 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 (propylenegiycol, 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, 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, aiignates, 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 par
  • 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 past 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. ⁇ 0071] 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; solubi!izing agents and emulsifiers, as for example, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propyieneglycoi, 1,3- butyleneglycol, dimethylformamide; oils, in particular, cottonseed oil, groundnut oil, com germ oil, olive oil, castor oil and sesame oil, glycerol, tetrahydrofurfuryl alcohol, polyet yleaneglycols and fatty acid esters of sorbitan; or mixtures of these substances, and the like
  • Suspensions in addition to the active compounds, can contain suspending agents, as for example, ethoxylated isosteatyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum rnetahydroxide, bentonite, agar-agar and tragacanth, or mixtures of these substances, and the like.
  • suspending agents as for example, ethoxylated isosteatyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum rnetahydroxide, 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, polyethyienegiycol 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, polyethyienegiycol 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 propellanis as can be required.
  • Ophthalmic formulations, eye ointments, powders, and solutions are also contemplated for the compounds in this disclosure.
  • Compressed gases can be used to disperse a compound of this disclosure in aerosol form.
  • Inert gases suitable for this memepose are nitrogen, carbon dioxide, etc.
  • the pharmaceutically acceptable compositions will contain about 1% to about 99% by weight of a corripound(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, drag 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.
  • the dosage can depend or. a number of factors inc!udmg 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.
  • 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), Cheniotherapeutic agents that can be useful for administration in combination with compounds of Formula I in treating cancer include alkylating agents, platinum containing agents.
  • the compounds described herein, as well as their pharmaceutically acceptable salts or other derivatives thereof, can exist in isotopically-labeled form, in which one or more atoms of the compounds are replaced by an atom having the same atomic number but an atomic mass different from the atomic mass usually found in nature.
  • isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulfur, fluorine and chloride, such as 2 H (deuterium), 3H (tritium), !3 C, ,4 C, ! 5 N, !8 0, , "O, 51 P, :52 P, 35 S, !8 F and 36 CL respectively.
  • Isotopicalty labeled compounds of the present invention as well as pharmaceutically acceptable salts, esters, prodrugs, solvates, hydrates or other derivatives thereof, generally can be prepared by carrying out the procedures disclosed in the Schemes and/or in the Examples and Preparations below, by substituting a readily available isotopically labeled reagent for a non- isotopically labeled reagent.
  • any atom not specifically designated as a particular isotope is meant to represent any stable isotope of that atom at its natural abundance.
  • a position is designated as "H” or "hydrogen”
  • the position is to be understood to have hydrogen at its natural abundance isoiopic composition, with the understanding that some variation of natural isotopic abundance occurs in a synthesized compound depending upon the origin of chemical materials used in the synthesis.
  • D or “deuterium”
  • the abundance of deuterium at that position is substantially greater than the natural abundance of deuterium, which is 0.015%, and typically has at least 50% deuterium incorporation at that position.
  • the methods disclosed herein also include methods of treating diseases by administering deuterated compounds of the invention or other isotopically-iabeled. compounds of the invention alone or as pharmaceutical compositions. In some of these situations, substitution of hydrogen atoms with heavier isotopes such as deuterium can afford certain therapeutic advantages resulting from greater metabolic stability (for example, increased in vivo half-life or reduced dosage requirements).
  • isotopicaily-labeled compounds for example those into which radioactive isotopes such as 3 H and 14 C are incorporated, are useful in drug and or substrate tissue distribution assays such as positron emission tomgrapfay (PET), Tritiated, ii) and carbon-14 ( ! C) isotopes are useful for these embodiments because of their detectability.
  • PET positron emission tomgrapfay
  • ii positron emission tomgrapfay
  • carbon-14 ! C
  • L° is a divalent moiety linking R Dl to the parent structure.
  • particular members defining L D may be written, for example, in the form -X-Y- or -Y-X-.
  • certain groups, such as aikyl groups, are part of a linker these groups are also divalent moieties.
  • administering in reference to a compound of the invention means introducing the compound or a prodrug of the compound into the system of the animal in need of treatment.
  • a compound of the invention or prodrag 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 wherein R is aikyl, as defined herein. Representative examples include methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, 4-methylhexyloxy, 4-methylheptyloxy, 4,7-dimethyloctyloxy, and the like.
  • Alkoxycarbonyl means an alkoxy group, as defined herein, appended to a parent moiety via a carbonyl group (i.e., a group of the form, -C(O)OR 0 , wherein R° is aikyl, as defined herein).
  • alkoxycarbonyl groups include, but are not limited to, methoxycarbonyl, ethoxyearbonyl, isopropoxycarbonyl, t-butoxycarbonyl, and n- hexylcarbonyl.
  • Alkyl means a linear or branched hydrocarbon group having from 1 to 10 carbon atoms unless otherwise defined.
  • Representative examples for aikyl groups include methyl, ethyl, propyl, butyl, pentyi, hexyl, 4-methylhexyl, 4-methylheptyl, 4,7-dimethyloctyl, and the like.
  • Alkylamino means an aikyl group, as defined herein, appended to a parent moiety through an -NH- group (i.e., substituents of the form -N(H)R°, where R° is an aikyl group).
  • alkylamino groups include, but are not limited to, methylamino, ethylamino, isopropyiamino, hexylamino, and the like.
  • Alkylammocarbonyl means an alkyiarnino group, as defined herein, appended to a parent moiety via a carbonyl group (i.e., a group of the form, ⁇ C(0)N(H)R°, wherein R° is alkyi, as defined herein).
  • alkylaminocarbonyl groups include, but are not limited to, methylarninocarbonyl, ethylaminocarbonyl, isopropylaminocarbonyl, t- butylaminocarbonyl, and n-hexylaminocarbonyl.
  • Amino means a -N3 ⁇ 4 group.
  • Aryl means a monovalent, monocyclic, or poiycychc radical having 6 to 14 ring carbon atoms.
  • the monocyclic aryl radical is aromatic and whereas the poiycychc 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, and the like.
  • Carbonyl means a --C(Q)- group.
  • Cycioalkyl means a monocyclic or polycyclic hydrocarbon radical having 3 to 13 carbon ring atoms.
  • the cycioalkyl radical may be saturated or partially unsaturated, but cannot contain an aromatic ring.
  • the cycioalkyl radical includes fused, bridged and spiro ring systems. Examples of such radicals include cyclopropyl, cyclobutyl, cyctopentyl and cyclohexyL
  • Dialkylamino means two alkyl groups, each independently as defined herein, appended to a parent moiety through a nitrogen atom (i.e., substituents of the form -N ⁇ R°) ? ., where each R° is an alkyl group).
  • dialkylamino groups include, but are not limited to N,N-dimethylamrno, N,N-diethylamino, N-isopropyl- -methylamino, N-ethyl-N- hexylarnino, arid the like.
  • Dia(Ci-C alkyd)aminocarbonyl means a dialkylamino group, as defined herein, appended to a parent moiety via a carbonyl group (i.e., a group of the form, -C(0)N(.R°)2, wherein each R" is alkyl, as defined herein).
  • dialkylamino groups include, but. are not limited to ⁇ , ⁇ -dimethylaminocarbonyl, ⁇ , ⁇ -diethyiaminocarbonyl, N-isopropyi-N- methylaminocarbonyl, N-ethyi-N-hexylaminocarbonyl, and the like.
  • fused-eyclopropyl means any alkyl group that has a carbon substituted in such a way to form the following structure: 3 ⁇ 4 [01003 "Fused ring system” and "fused ring” refer to a poiycyclic ring system that contains bridged or fused rings; that is, where two rings have more than one shared atom in their ring structures.
  • fused -poly cyclics and fused ring systems are not necessarily all aromatic ring systems.
  • fused-polycyclics share a vicinal set of atoms, for example naphthalene or 1 ,2,3,4-tetxahydro-naphthalene.
  • a spiro ring system is not a fused-polycyclic by this definition, but fused poiycyclic 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 and may be optionally substituted with one or more groups. It should additionally be noted that saturated carbons of such fused groups (i.e., saturated ring structures) can contain two substitution groups.
  • Halo and halogen mean a fiuoro, chloro, bromo or iodo group.
  • Haloalkyl means an atkyi radical, as defined herein, substituted with one or more halo atoms.
  • halo-substituted includes trifluoromethyl, 2,2-dichioroethyl, 2,2,2-rrifluoroethyl, perchloroethyl, 2-bromopropyl, and the like.
  • Fieteroaryl means a monovalent monocyclic or poiycyclic 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 -0-, -S(0) n - (n is 0. 1, or 2), -N-, -N(R*K and the remaining ring atoms are carbon atoms, where R* is hydrogen, alky], hydroxy, alkoxy, -C(O)R 0 or -S(Q)-R°, where R° is alkyl.
  • the monocyclic heteroaryl radical is aromatic and whereas the poiycyclic heteroaryl radical may be partially saturated, at least one of the rings comprising a poiycyclic radical is aromatic.
  • heteroaryl includes, but is not limited to, 1 ,2,4-triazolyl, 1,3,5-triazoly , phthalimidyl, pyridinyl, pyrroiyl, imidazolyl, thienyl, furanyl, indolyl, 2,3-dihydro- lH-indolyl (including, for example, 2,3-dihydro- lH-indol-2-yl, 2,3-dihydro- lH-indoI-5-yl, and the like), isoindolyl, indolinyl, isoindolinyl, benzimidazolyl, benzodioxol-4-yl, benzofuranyl, cirmoiinyl, indolizinyl, naphthyridin-3-yl, phthalazin-3-yl, phthal
  • 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 -0-, -S(0) n - (n is 0, 1, or 2), ⁇ -N- and -NCR 3 )- (where R y is hydrogen, alkyl, hydroxy, alkoxy, -C(Q)R° or -S(O) 2 ° : where R° is alkyl, as defined herein), and the remaining ring atoms are carbon.
  • the heterocycioalkyl radical may be saturated or partially unsaturated, but cannot contain an aromatic ring.
  • the valency of the group may be located on any atom of any ring within the radical, valency rules permitting. In particular, when the point of valency is located on a nitrogen atom, R y is absent.
  • heterocycioalkyl includes, but is not limited to, azeiidinyl, pyrrolidinyl, 2 -oxopyrrolidinyl, 2 > S-dihydro-lHpyrrolyl, piperidinyL 4-piperidonyl, morpholitryl, piperazinyl, 2-oxopiperazinyl, tetrabydropyranyl, 2-oxopiperidinyl, tiiiomorpholinyi, ihiamorpholiny!, perhydroazepinyl, pyrazolidinyl, iniidazolinyl, imidazolidinyl, dihydropyridinyl, tetrahydropyridinyl, oxazolinyi, oxazolidinyl, isoxazolidmyl, thiazolinyl, thiazolidinyl, quinuclidinyl, isothiazoiid
  • Heterocyclyl alkyl means a heterocyclyl group appended to a parent moiety via an alkyl group, as defined herein.
  • heterocyclylalkyl groups include, but are not limited to, 2-(moipholin -4-yl)ethyi, 2- (morpholin-2-yl)ethyl, morpholin-3-ylmethyl, 2-(morphoJin-3-yl)ethyl, piperazin-1 -ylmethyl, 2-(piperazin-l -yl)ethyl, piperidin-1 -ylmethyl, 2-(piperidin-l -ylieihyi, piperidin-2 -ylmethyl, 2--(pipendm-2-yl)ethyl, piperidin-4-yhnethyl, 2 ⁇ (piperidk-4-yl)ethyl, pyrrolidin- 1 -ylmethyl , 2-Cpyrrolidin- 1 -yl)ethyL
  • Hydroxyalkyl means an alkyl group, as defined herein, substituted with at least one, for example one, two, or three, hydroxy group(s), provided mat if two hydroxy groups are present they are not both on the same carbon atom.
  • Representative examples include, but are not limited to, hydroxymethyt, 2-hydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl, 1 -(hydroxymethyl)-2 ⁇ methylbutyl, 2-hydroxy butyl, 3-hydroxybutyl, 4-hy droxybutyl,
  • variable E° can be optionally substituted with R o , this means that this substitution, when it occurs, takes place by replacing a hydrogen that is covalently bound to R c with R ' " 10 .
  • Other non-limiting examples of variables that are described in certain instances in the specification as being optionally substituted or substituted with various substituents include, but are not limited to, R D1 , A groups, B groups, and R " ⁇
  • Polyethylene glycol are polymers of ethylene oxide.
  • Polyethylene glycol refers to the polymer with molecular weight less than 50,000.
  • a polymer is made by joining molecules of ethylene oxide and water together in a repeating pattern.
  • Polyethylene glycol has the following structure: -(CH 2 -CH 2 -0)n-.
  • saturated bridged ring system refers to a bicyclic or polycyclic ring system that is not aromatic. 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). For example, hexahydro-nsro[3,2-i>]furan, 2,3,3a > 4,7 > 7a-hexahydrc-lH-indene, 7-aza-bic clo[2.2.1 ]heptane and l,2,3,4,4a,5,8,8a-octahydro-naphthalene are all included in the class "saturated bridged ring system.”
  • 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-azaspj:ro[4.5]decan ⁇ 8-yi.
  • “Isomers” means compounds having identical molecular formulae but differing in the nature or sequence of bonding of their atoms or in the arrangement of their atoms in space, isomers that differ in the arrangement of their atoms in space are termed “stereoisomers.”
  • stereoisomers that are not mirror images of one another are termed “diastereomers” and stereoisomers that are nonsuperimposable mirror images are termed “enantiomers” or sometimes "optical isomers.”
  • a carbon atom bonded to four nonidentical substituents is termed a "cbirai center.”
  • a compound with one chiral center has two enantiomeric forms of opposite chirality is termed a "racemic mixture.”
  • a compound that has more than one chiral center has 2 r ' "!
  • n is the number of chiral centers.
  • Compounds with more than one chiral center may exist as ether an individual diastereomer or as a mixture of diastereomers, termed a "diastereomeric mixture.”
  • a stereoisomer may be characterized by the absolute configuration of that chiral center. Absolute configuration refers to the arrangement in space of the substituents attached to the chiral center. Enantiorners are characterized by the absolute configuration of their chiral centers and described by the R- and S-sequencing rules of Cahn, Ingoid and Prelog.
  • N-oxide derivatives mean derivatives of compounds of the invention in which nitrogens are in an oxidized state (i.e., N-->0), e.g., pyridine N-ox de, and which possess the desired pharmacological activity.
  • Methodabolite refers to the break-down or end product of a compound or its salt produced by metabolism or biotransformation in the animal or human body; for example, biotransformation to a more polar molecule such as by oxidation, reduction, or hydrolysis, or to a conjugate (see Goodman and Gilman, "The Pharmacological Basis of Therapeutics” 8.sup.th Ed., Pergamon Press, gilman et al. (eds), 1990 for a discussion of biotransformation).
  • the metabolite of a compound of the invention or its salt may be the biologicaliy active fonn of the compound in the body.
  • a prodrug may be used such that the biologically active form, a metabolite, is released in vivo.
  • a biologicaliy active metabolite is discovered serendipitously, that is, no prodrug design per se was undertaken.
  • An assay for activity of a metabolite of a compound of the present invention is known to one of skill in the art in light of the present disclosure.
  • 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* ed., Mack Publishing Company, Easton, PA, 1985, or S. M. Berge, et al, "Pharmaceutical Salts," J. Pharm. Sci., 1977;66: 1-19. 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, glycoiic acid, pyruvic acid, lactic acid, oxalic acid, maleic acid, maionic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, 3-(4-hydroxybenzoyl)benzoic acid, mandeiic acid, methanesulfonic acid, ethanesulfonic acid, 1 ,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesuifonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid
  • 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.
  • organic bases examples include isopropylaniine, trimethyiamine, diethylamine, triethylamine, tripropylamine, ethanolamine, 2-dimemylaminoethanol, 2-diethylamiooethanol, dicyclohexylarnine, lysine, arginine, histidine, caffeine, procaine, hydrabaraine, choline, betaine, ethylenediamine, glucosamine, memylglucamine, theobromine, purines, piperazine, piperidine, N-ethylpiperidine, tromethamine, N-methylglucamine, polyamine resins, and the like.
  • Exemplary organic bases are isopropyiamine, diethylamine, ethanolamine, trimethyiamine, dicyclohexylarnine, choline, and caffeine.
  • Prodrug refers to compounds that are transformed (typically rapidly) in vivo to yield the parent compound of the above formulae, for example, by hydrolysis in blood.
  • Aommon examples include, but are not limited to, ester and amide forms of a compound having an active form bearing a carboxylic acid moiety.
  • Examples of pharmaceutically acceptable esters of the compounds of this invention include, but are not limited to, alkyl esters (for exampie with between about one and about six carbons) the alkyl group is a straight or branched chain. Acceptable esters also include cycloalkyl esters and arylalkyl esters such as, but not limited to benzyl.
  • Examples of pharmaceutically acceptable amides of the compounds of this invention include, but are not limited to, primary amides and secondary and tertiary alkyl amides (for example with between about one and about six carbons).
  • Amides and esters of the compounds of the present invention may be prepared according to conventional methods. A thorough discussion of prodrugs is provided in T. Higucht and V. Stella, '"Pro-drugs as Novel Delivery Systems," Vol 14 of the A.C.S. Symposium Series, and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Perganson Press, 1987, both of which are incorporated herein by reference for all purposes.
  • “Therapeutically 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 a “therapeutically 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 seventy of the disease for which the therapeutic effect is sought.
  • the therapeutically 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 (hi) relieving the disease, disorder, or syndrome, i.e., causing regression of the disease, disorder, or syndrome.
  • the compounds disclosed herein and their pharmaceutically acceptable salts can exist as single stereoisomers, racemates, and as mixtures of enantiomers and diastereomers.
  • the compounds disclosed herein can also exist as geometric isomers. All such single stereoisomers, racemates and mixtures thereof, and geometric isomers are intended to be within the scope of the compounds disclosed herein.
  • optically active (R)- and (S)- isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques.
  • Enantioroers can be resol ved by methods known to one of ordinary skill in the art, for example by: formation of diastereoisomeric salts or complexes which can be separated, for example, by crystallization; via formation of diastereoisomeric derivatives which can be separated, for example, by crystallization, selective reaction of one enantiomer with an enantiomer-specific reagent, for example enzymatic oxidation or reduction, followed by separation of the modified and unmodified enantiomers; or gas-liquid or liquid chromatography in a chiral environment, for example on a chiral support, such as silica with a bound chiral ligand or in the presence of a chirai solvent.
  • enantiomer can be synthesized by asymmetric synthesis using optically active reagents, substrates, catalysts or solvents or by converting on enantiomer to the other by asymmetric transformation.
  • enantiomers enriched in a particular enantiomer, the major component enantiomer can be further enriched (with concomitant loss in yield) by recrystallization.
  • the compounds of this disclosure can exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanoi, and the like.
  • the solvated forms are considered equivalent to the unsolvated forms for the purposes of the compounds of this disclosure.
  • Step (a): An aldehyde of formula (Hi) may be prepared by reaction of nitrile (II) with diisobutylalaminum hydride in a suitable solvent, such as THF.
  • Step (h): Formation of carbinol (IV) may be achieved by treatment of aldehyde (III) with methylmagnesium bromide in a suitable solvent, such as diethyl ether or THF.
  • a suitable solvent such as diethyl ether or THF.
  • Step (d): Bronioketone (VI) may be prepared by bromination of ketone (V) under typical conditions, such as with tetrabutylammonium tribromide in 1 :2 mixture of MeOH- DCM.
  • a suitable solvent such as DMF
  • Step (f): Isothiocyanate R ⁇ NCS may react with amino-ketone hydrochloride (VII) in a suitable solvent, such as DCM or toluene, and in the presence of a base, such as triethy!amine, at elevated temperature to yield the corresponding thiourea, which may condense upon treatment with HOAc at elevated temperature to give a compound of formula (VIII).
  • a suitable solvent such as DCM or toluene
  • a base such as triethy!amine
  • a suitable oxidant such as mCPBA. (2.5- 3.0 eq)
  • a suitable solvent such as DCM
  • Step (i): Thione (I A ) may be converted to the corresponding sulfonyl chloride (IX) under standard conditions, such as adding NaOCl (3 eq) to thione (1 A ) in a 1 : 1 mixture of DCM and I N HC1 at reduced temperature, preferably below 0 °C.
  • Step (j): Compounds of formula (!' " ) may be prepared by reaction of amine HN(R Y )R D! with sulfonyl chloride (IX) in a suitable solvent, such as DCM, and in the presence of a base, such as triethylamme.
  • a suitable solvent e.g., THF
  • a suitable electrophile e.g., isocyanate or carbamoyl chloride
  • a suitable nucleophile HYR° ! such as a phenol or thiophenol wherein Y represents O or S, respectively, and R 1"'1 is ary!, under Mitsunobu conditions— known to one skilled in the art.
  • carbinoi (XII) may be converted to the corresponding chloride, for example, by treatment with thionyl chloride (2 eq) in chloroform, followed by reaction with a suitable nucleophile HYR D l in MeCN (or acetone) and in the presence of a base (e.g., K2CO 3 ) to yield compounds of formula (I G ).
  • a suitable halogen source such as, for example, N-bromosojccinimide in DCM.
  • N-chlorosuccinimide and SelectfluorTM in a suitable solvent such as DCM or MeCN
  • a suitable oxidant such as mCPBA (1-1.1 equiv) in DCM
  • thiol (XVI) may undergo de- sulfurization to afford triazole (XVII).
  • Step (w): Hydroxymethylation of triazole (XVII) may proceed under standard conditions, such as with paraformaldehyde in toluene heated at reflux, to afford the corresponding hydroxymethyltnazole. which may undergo oxidation upon treatment with a suitable oxidant, such as ⁇ (1 ⁇ 4, in THF to yield the corresponding aldehyde (XVIIi).
  • a suitable oxidant such as ⁇ (1 ⁇ 4, in THF to yield the corresponding aldehyde (XVIIi).
  • Amine (I A ) may undergo diazotization under typical conditions, such as with aqueous sodium nitrite, and then may be converted to the corresponding sulfonyl chloride (XXIX) upon reaction with a mixture of copper (II) chloride, sulfur dioxide. HC1 and HO Ac.
  • Step (af) Imidazole (X) may be converted to the corresponding organolithium, as described previously, and then treated with tosyi azide in a suitable solvent (e.g., THF), preferably at -78 °C for 30 minutes, to yield azide (XXV).
  • a suitable solvent e.g., THF
  • Step (ag)i Azide (XXV) may undergo catalytic hydrogenatiorj under standard conditions, such as with a suitable palladium catalyst, preferably Lindlar catalyst, under hydrogen at ambient pressure, to give amine (XXVI).
  • a suitable palladium catalyst preferably Lindlar catalyst
  • a suitable solvent e.g., DCM
  • a base e.g., pyridine
  • Step (r) Under conditions previously described in step (r), imidazole (XXVII) may be brominated to give bromoimidazole (XXVill).
  • a suitable solvent e.g., acetone
  • a base e.g., potassium carbonate
  • a suitable isocyanate and Lewis acid e.g., aluminum trichloride
  • R D) is a benzoate ester, ;rt a suitable solvent (e.g., acetone) and with a base (e.g., potassium carbonate) may afford compounds of formula (l v ),
  • acid (I v ) may be treated with a suitably protected amino ester (e.g.. Alanine methyl ester) and HATU in DCM to afford compounds of formula (I v ).
  • a suitably protected amino ester e.g.. Alanine methyl ester
  • HATU HATU
  • acid (I v ) may be treated with a suitably protected amino ester, such as one derived from Ornithine (wherein n - 2). and HATU in DCM to afford compounds of formula (I z ).
  • a suitably protected amino ester such as one derived from Ornithine (wherein n - 2).
  • acid (I ⁇ ) may react with diphenylphosphoryl azide, a suitable alcohol (e.g., tert-butanol), an organic base (e.g., EtjN) and toluene at elevated temperature, preferably 80 to 100 °C, to yield compounds of formula ( ⁇ ' ).
  • a suitable alcohol e.g., tert-butanol
  • an organic base e.g., EtjN
  • toluene at elevated temperature, preferably 80 to 100 °C, to yield compounds of formula ( ⁇ ' ).
  • a base such as Et 3 N
  • Step (1) Reaction of imidazole (X) with butyllithium in a suitable solvent (eg,, THF) at reduced temperature, preferably at -78 °C for 30-40 minutes, may yield the corresponding organolithium, which may react with a suitable electrophile (e.g., isocyanatc or carbamoyl chloride) at the same temperature to afford a compound of formula (I D ).
  • a suitable solvent e.g, THF
  • a suitable electrophile e.g., isocyanatc or carbamoyl chloride
  • phenol (XXXIII) may react with carbinol (XII) to afford compounds of formula (I A ⁇ i ).
  • Phenol (XXXIII) may react under standard conditions, for example, with dime hylihiocarbamoyl chloride (1 eq) and DABCO (1.25 eq) in NMP at 50 °C, to yield the respective O-aryl-thiocarbamate (XXXIV).
  • thiophenol (XXXVI) may react with carbinol (XII) to afford compounds of formula (! AR ).
  • acid (I 1 ) may react with an amine to afford compounds of formula (i AT ), wherein Y is O or 8.
  • acid ( ⁇ ) may be converted to compounds of formula (I AL ), wherein Y is O or S.
  • amine (I AU ) may be converted to compounds of formula (1 AV ), wherein Y is O or S.
  • step (an) compounds of formula (I AW ), therein R C!0 is C(0)OR, may be hydrolyzed to yield the corresponding acid ( ⁇ ⁇ )
  • acid (I ) may be coupled with a diamine, such as an ammoalkyltrialkyiammonium bromide, to afford compounds of formula (I AY ).
  • a suitable electrophiie for example, bromoaJ.kyl-trialkyiammolium bromide
  • HEK 293 ceils stably expressing human TGR5 (h-TGR.5) or mouse TG 5 (m- TGR5) can be generated from HEK 293 CRE-Luciferase cells.
  • HEK 293 hTGR5/CRE-Luc cells are plated in DMEM in a 384 well assay plate at a density of 25k cells/45 ⁇ _ per well and grown for 18-20 hours.
  • Compounds axe serially diluted in DMEM containing 5% DM.SO and 5 jiL of compound or media alone are transferred to each well and plates were incubated for about 6 hours. Following incubation, 30 pL of iysis/luciferase buffer are added to each well. The luciferase activity is then measured on the EnVisionTM plate reader and the dose response data was analyzed using Activity Base.

Abstract

TGR5 (a.k.a.GPBARl) agonists of structural formula l(Q), wherein X, R1, R2, and R5 are defined in the specification, phannaceutically acceptable salts thereof, compositions thereof, and use of the compounds and compositions for treating diseases in which TGR5 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 TGR5 is a mediator or is implicated.

Description

TGR5 AGONISTS: IMIDAZOLE AND TRIAZOLE COMPOUNDS
CONTAINING A QUATERNARY NITROGEN
BACKGROUND OF THE INVENTION
Field of the Is entiois
[0001] The invention relates to agonists of the G protein-coupled receptor TGR.5, compositions comprising them, methods of making the compounds and compositions and using them for the treatment of diseases TGR5 mediates or is implicated in.
Summary of the Related Art
(0ΘΘ2] Bile acids play essential roles in the absorption of dietary lipids and in the regulation of bile acid biosynthesis. While bile acids have long been known to be essential in dietary lipid absorption and cholesterol cataboiism, in recent years an important role for bile acids as signaling molecules has emerged. Eiile acids activate mitogen-activated protein kinase pathways, are ligands for the G-protein-conpled receptor (GPCR) TGR5. and activate nuclear hormone receptors such as famesoid X receptor a (FXR-a). Through activation of these diverse signaling pathways, biie acids can regulate their own enterohepatie circulation, but also triglyceride, cholesterol, energy, and glucose homeostasis. Thus, biie acid (BA) controlled signaling pathways are promising novel drag targets to treat common metabolic diseases, such as obesity, type li diabetes, hyperlipidemia, and atherosclerosis. Houten et at., The EMBO Journal (2006) 25, 1419 -1425).
0003] Watanabe et ai, Nature 2006, 439(7075) 484-489 showed that the administration of bile acids to mice increases energy expenditure in brown adipose tiss ue, preventing obesity and resistance to insulin. This novel metabolic effect of bile acids is critically dependent on induction of the cyclie-AMP-dependent thyroid hormone activating enzyme type 2 iodothyronine deiodinase (D2) because it is lost in D2-/- mice. Treatment of brown adipocytes and human skeletal myocytes with bile acids increases D2 activity and oxygen consumption. These effects are independent of FXR-a, and instead are mediated by increased cAMP production that stems from the binding of bile acids with TGRS. in both rodents and humans, the most thermogenically important tissues are specifically targeted by this mechanism because they coexpress D2 and TGR5. The BA-TGR5-cAMP-D2 signaling pathway is therefore a crucial mechanism for fine-tuning energy homeostasis that can be targeted to improve metabolic control.
[0004] Glucagon-like peptide- 1 (GL M) is produced by L -cells in the distal digestive tract and affects multiple metabolic parameters, including enhanced insulin secretion, glucagon suppression, and lowering of blood glucose. TG 5 expression in L-cells is linked to increased GLP-1 secretion. Katsuma, et ah, Biochem. Biophys. Res. Commun. 2005, 329(1), 386-390) showed that bile acids promote glucagon-like peptide- 1 (GLP- 1) secretion through TGR5 in a murine enteroendocrine cell line STC-1. RNA interference experiments showed that reduced expression of TGR5 resulted in reduced secretion of GLP- 1. Furthermore, transient transfection of STC-1 cells with an expression plasmid containing TGR5 significantly enhanced GLP-1 secretion.
[0005] TGR5 and modulators of it have been the subject of several patent applications:
WO/2008/097976 - Heterocyclic Modulators of TGR5 for Treatment of Disease WO/2008/091540 - Substituted Bile Acids as TGR5 Modulators and Methods of Use WO/2008/067219 - Quinazolinone Modulators of TGR5
WO/2008/067222 - Heterocyclic Modulators of TGR5
WO/2004/067008 - Receptor Agonists
WO/2004/043468 - Screening Method
US 2006/0199795 - Receptor Agonists
US 2008/0031968 - Methods for increasing Cellular Energy Expenditure
SUMMARY OF THE INVENTION
[0006] The present invention comprises TGR5 agonists of structural formula I(Q),
X-N „
I(Q)
wherein X, R1, R2, and R5 are defined hereinbelow, and pharmaceutically acceptable salts thereof. The invention further comprises compositions comprising the compounds and/or pharmaceutically acceptable salts thereof. The invention also comprises use of the compounds and compositions for treating diseases in which TGR5 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 TGR5 is a mediator or is implicated.
DETAILED DESCRIPTION OF THE INVENTION
10007] All of the compounds of Formulae I(Q), II, ill, IV, V, VI and XII disclosed herein have quaternary ammonium ion moieties, and it is understood to one skilled in the art that these compounds are all in in the presence of a pharmaceutically acceptable counter ion.
9 These compounds with quaternary ammonium ion moieties have more non-sytstemic effects than with the same compounds without quaternary ammonium ion moieties. The
pharmaceutically acceptable counter ion for each of the quaternary ammonium ion moieties present in the compounds of the invention can he any pharmaceutically acceptable counter ion known to one skilled in the art. Non-limiting examples of the pharmaceutically acceptable counter ions that can be used include chlonde, bromide, sulfate, tosyiate, phosphate, tartrate, maleate, acetate, formate, fumarate, mesylate, nitrate, oxalate, ascorbate, citrate, ammonium, arginine, dieihylamme, ethylenediamine, magnesium, sodium, calcium, and potassium, it is also understood that the source of the counter ions can be from either intermolecular sources, or, when possible, intramolecular sources.
[0008] 'The present in vention comprises TGR5 agonists of structural formula I(Q):
Figure imgf000004_0001
I(Q)
or pharmaceutically acceptable salt thereof, wherein:
X is =N- or =C(R4)-, wherin R4 is H, -(Ci-C3)aikyi or halo;
R1 is QA or P.c;
Rc is selected from phenyl, -(Cs-CeVcycloalkyl, -C¾-phenyk heieroaryl, and -(Ci-C4)alkyl optionally substituted with -OR013, -N(RC !J)2 or -S( Cl3), wherein the cyclic group of Rc can be optionally substituted with 1, 2, 3, 4 or 5 RCs0 groups, wherein the 1, 2, 3, 4, or 5 RC!0 groups are independently selected from RU0A and RCi'jB, provided that Rc cannot be substituted with more than two RC1"° groups, wherein
each RCI0A is independently selected from halo, cyano, and
Figure imgf000004_0002
optionally substituted with one, two, or three groups selected from -OH and halo;
each RC10B is independently selected from -C(0)NH2, (5-6 membered)heterocycloalkyl» -0-(C C4)alkyl-Rcn, -C(0)ORCI2, -OC(0)ORC12, and -0-(C]-C4)alkyi optionally substituted with -OH or -C(0)OH;
Rcn is cyano, nitro, ~N(RCi2)2, -ORC12, -SRCi2, -C(0)RCi2, -C(0)ORC52, -C(0)N(RC 12)2, -S(0)N(RC i2)2, -S(0)2N(RC12)2, -S(0)2RC12, ~OC(0)Rcn, -OC(0)ORC!2, -0C(0)N(RC12)2, -N(Rc,2)C(0)RC!2, -N(RC! )C(0)ORC12, -N(RC I2)C(0)N(RC, )2, or -N(RC12)C(=NRC12)N(RC12)2;
each R. C!2 jendently selected from hydrogen, - (C j- Chalky 1,
(C j - C )haJ oalky 1 ; each RCB is independently selected from hydrogen, -(Q -Chalky!, and -(Ci-C4)haioalkyl,
wherein Rc, when Rc exists, is substituted with one or two QA groups, wherein Rc is substituted with Q" by replacing a hydrogen that is covalently bonded to carbon or nitrogen;
R2 is -LD-RD1;
LD is■[C(R)2j1,- Y-[C(R.)2jqS
p is 0 or 1 :
q is 0 or 1 ;
each R is independently selected from H, ~(Ci -C3)a!ky], halo, -OH, and -Ο¾0Η;
Y is a bond, -S-, -S(0)2--, -CH(OH)-, -0-, -C(H)=C(H)-, -C(0)-(CrC4)alkyl- , -(C,-(¾alkyl-S-(Ci-C4)alkyl-, -(CrC4)alkyl-N(RY)-(CrC4)alkyl-, -C(H)(halo)-,
-(CI-C4)alkyI-S(0)2-> - S(0)2-N(RY)-, -(Ci-Ct)alkyi-O-, or -C(0)-N(RY)~, wherein RY is H, -{CVC4)alkyi, hydroxyl(C C )alkyl or -C-C-(CrC3)alkyl-;
RDi is selected from phenyl -(C6-C!o)ar l, -N(H)-pheny1, -(Cs-Cycycloalkyl, heterocycloalkyl, or heteroaryl, wherein RDl can be optionally substituted with one, two, three, or four RD1°. wherein the one, two, three, or four RD1° groups are independently selected from A groups and B groups, provided that RD! cannot be substituted with more than two B groups;
each A group, when they occur, is independently selected from halo, -CF3, -ON, -NO2, -OH; -0-(Ci-C4)alky{ optionally substituted at the aikyl group with one, two, or three substituents independently selected from -OH and halo; and -((.VC jalkyl optionally substituted with one, two, or three substituents independently selected from -OH and halo; each B group, when they occur, is independently selected from -(Ct-C4)alkylN(RD")2, -C(0)-NH2, -C(0)-N(H)-OH, -C(0)-N(H)-RD1 IC, ~C(0)-(C C4)alkyl, -C(0)QH, -C(0)0-(CrC4)alkyi, -S(OMCi-C4)alkyl-N(RD1 !)2, -S(0)2-N(RD1 ')R° !C, -S(0)2-N(H)C(0)-(Ci-C4)aikyi, -S(0 - (H)C{0)0-(Ci-C4)aikyi, -S(0)2-N(H)C(0)-N(RD' !) RD! !B„ -S{0)2-{C;-C.,)alkyl; -C(0>heterocycloaikyl optionally substituted with RDHB,; -C(0)- (H)-(C|-Cf,)aikyl optionally substituted at the aikyl group with one or two R°' lB; heterocycloalkyl optionally substituted with oxo or R01 '; heteroeycloalkenyl optionally substituted with oxo or RB1'; heteroaryl optionally substituted with RDi i; -0-(Ci-C4)alkyI optionally substituted at. the aikyl group with one or two Rm iB;-S(0')2-(4-6 membered)heterocycloalkyl optionally substituted with RD1 l ; -N{H)-C(0)-(CrC4)alkyl optionally substituted at the aikyl group with one or two RDI iB: - (H)-C(0)-N(H)-(Ci-C3)alkyl optionally substituted at the aikyl group with RDi lB; -(Ci-Q alkyl optionally substituted with one or two RDnB; -C(=NH)-NH2, and
Figure imgf000006_0001
optionally substituted with R lB;
each RJ1 ! is independently selected from H, -(Cj-C6)eycioalkyi, -(Ci-C4)haloalkyL -OH, -S(0)2OH, C(0)OH, -NH2, -N(H)C(= H)NH2; -(CrC4)alkyi optionally substituted with halo, -OH or -C(0)OH; -(Cj -Chalk 1-phenyl optionally substituted at the phenyl group with one, two, or three subsiituents selected from methoxy, hydroxy!, and haio;
RD11B is selected from H, -OH, -CF3, -N(RDi l)2, -C(0)OH, -0-<CrC4)alkyI, ~S(0)2OH, -C(= H)- H2, -N(H)C(=NH)N¾, -C(H)=NN(H)C(=NH)NH2s -0-(CrC4)alkyl-C(0)OH, -N(H)C(=NH)-N(H)C(=NH)NH2j (5-6 membered)heteroaryi, -C(0)-(Ci-C3)alkyl -(Cr-C4)alkyl optionally substituted with one. two, or three groups independently selected from halo and -OH; -(CVC^alkyl optionally substituted with one, two, or three groups independently selected from halo, -OH, -S(0)2OH, -C(0)OH, -NH2, and -N(H)C(=NH)NI¾; -(C0-C3)alky3-(5-8 membered)heterocycloalkyl optionally substituted with one, two, or three RD! 1 -(Co-C3)alkyl-(C3-C6)cycloalk.yl optionally substituted with RD1 \; and -(C6-C-,o)aryl optionally substituted with one, two, or three halo;
or RDH and RD11B, when they both exist and are each attached to nitrogen, can join together with the nitrogen to which they are attached to form a (5-6 membered) heterocycloalkyl optionally substituted with a group selected from -OH,
Figure imgf000006_0002
-S(0)2OH, C(0)OH, -NH2, -N(H)C(=NH)NH2j -(C3-C6)cycloalkyl; -(Ci-C4)alkyl optionally substituted with halo, -OH or -C(0)OH; and -(C'. -Cj)alkyl -phenyl optionally substituted at the phenyl group with one, two, or three substipaents selected from methoxy, hydroxy], and halo;
RDi lc is selected from H, -OH, -CF3, -0~(C;-C4)a!kyi, -(Cr-C4)alkyl-N(H)C(=NH)-NH2, -(C0-C3)alkyl-(5-6 menibered)heteroaryl; -(Cs-C4)aikyi optionally substituted with one, two, or three groups independently selected from haio, -OH, -S(0)2OH, C(0)OH, -NH , and N(H)C(-NH)NH2, -(C0-C3)alkyl-<5-0 membered)heterocycloalkyl optiona!iy substituted with a -(5-6 membered)heteroaryI; -(Co-C,)alkyl-(5-6 membered)heterocycloalkyl substituted one, two, or three groups selected from selected from -OH and -(Ci -C3)aikyL; and -(C8-C:;)alkyl-ary3 optionally substituted at the aryl group with one, two, or three halo;
R5 is \O \ phenyl -[C(Rs)2] -naphthalenyl, or -[C(Ra)2]-(5-iO membered) heteroaryl, wherein the heteroaryl is selected from benzo[d][.l,3]dioxolyl, benzo[d]isoxazolyl, quinoxalinyl, quinolinyl, and 2,3,4a,8a-tetrahydrobenzo[b][l ,4jdioxinyl, wherein the cyclic group of R5 is optionally substituted with one, two, three, four, or five RA'° groups, wherein the one, two, three, four, or five A1° groups are independently selected from A10A groups and RA,0B groups, provided that R3 cannot be substituted with more than two RAluB groups; each RA,0A, when they occur, is independently selected from halo, alkoxyl, hydroxy], -CN, -OCF3, -(Ci-C4)alkyl, and -N¾,
each RA,0B, when they occur, is selected from -0-(CrC4)aikyl-RA ", -S(0)2-NH2, -8(0)2CH3, -N(H>S(0)2CH3, ~S(0)2N(H)~C¾, -C(0)OH, -(Ci-C4)alkyl-OH,
-C(0)NH2, and -(CV 4)alkyi substituted with one, two, or three groups selected from -OH and halo;
RAi ! is selected from -C(0)QH, (5-6 membered)heterocycloaikyl, halogen, cyano, nitro, -(C C4)alkyl, -N(RA,2)2, -ORAi2, -SRA12, -N(ORAi2)RA!2, -C(0)RAi2, -C(0)ORA12, -C(0)N(RA!2)2, -N(RA,2)S(0)RA12, -N(RAl2)S(0)2RA12, -S(0)N(RA12)2, -S(0)2N(RA:2)2, -S(0)2R' 2, -OC(0)RA'2, -OC(0)ORA12, -OC(0)N(RA¾,
-N(RAi2)C(0)RA1VN(RA12)S(0)2RAi2, -N(RA!2)C(0)ORA I2, -N(RA!2)C(0)N(RA,2)2, -N(RA!2)C(=NRA12)N(RAI2)2, and heteroaryl, wherein each RA12 is independently hydrogen, -(Ci-Q)alkyl, or -(Ci-Ci)haloalkyl;
each Rs is independently hydrogen, halogen, or methyi, or both 6 taken together with the carbon to which they are both attached form either a (C3~C6)eyeloaIkyi or a (3-6 membered)heterocycloalkyl;
QA is QL or QR;
QL is -N[(CrC3)alkyl]j"r wherein an alkyl group of -N[(Ci-C3)alk l]3T is optionally substituted with ~(Co-C6)alkyl-S(0)2OH;
Qx is selected from:
Figure imgf000007_0001
RQA is -(Ci-Csjalkyl;
RQB is -(Ci-C3)alkyl optionally substituted with -C(0)OH; and
RQC is H, -OH. -(Co-C4)alkyl-COOH, or -(CrC5)alkyl.
10009] in another embodiment of the compound of formula i(Q), including all embodiments of the compound of formual f(Q) described above, or a pharmaceutically acceptable salt of any of these embodiments:
X is C(iO~:
each R is independently selected from H, -(C; -C3)aikyL -OH, and -CH2OH;
Y is -S-, -S(0>2-, -C(il C(H)-, -C(0)-, -(C, -C4)aikyl-S-, -(C, -C4)alkyl-N(RY)-, -C(H)(halo)-, -(C5^C4)alkyl-S(0)2-, -S(0)rN(RY)-, -(C C4)a!kyl-0-, or -C(0)-N(RY)-, wherein is H, -(Ci-C4)alky], or hydroxyl{C]-C4)alky!;
R0, is selected from phenyl, -(C6-Cio)aryl, -N(H)-phenyl, -(C.v Ctjcycioaikyl, heterocycloalkyl, or heteroaryl, wherein RDI can be optionally substituted with one, two, three, or four RDS0, wherein the one, two, three, or four RD5° groups are independently selected from A groups and B groups, provided that RDl cannot be substituted with more than two B groups;
each A group, when they occur, is independently selected from halo, -CF3, -CN, -NO?., -OH; -0-(CrC4)alkyl optionaliy substituted at the alkyl group with one, two, o three substituents independently selected from -OH and halo; and -(Ci-Ct)alkyl optionaliy substitined with one, two, or three substituents independently selected from -OH and halo; each B group, when they occur, is independently selected from -(Ci-C4)aikylN(RD")2, -C(0)-NH2, -C(0)-N(H)-OH, ~C(0)-N(H)-RDHC, -<¾0)-(Ci-C4)a]kyI, -C(0)OH, -C(0)0-(Ci-C4)alkyl, -S(0>2-(CI -C4)alk>'l-N(RI>i ,)2, -S(Q)2-N(RDn)RDnc, -S(0)2-N(H)C(0)-(CrC4)alkyl, -S(0)2-N(H)C(0)0-(C,-C4)alkyl, -S(0)2-N(H)C(0)-N(RD: |) RDi !B, -S(0)2-(C C4)a3kyi; -C(0)-heterocycloalkyl optionally substituted with RD] 1B; -C(0)-N(H)-(Ci-C6)alkyl optionally substituted at the alkyl group with one or two RDUB; heterocycloalkyl optionaliy substituted with oxo or RD! :; heterocycloalkenyl optionally substituted with oxo or RDl 1; heteroaryl optionally substituted with RDi l; -0-(Ci-C4)alkyl optionally substituted at the alkyl group with one or two RDi iB; ~S(0)2-(4-6 membered)heterocycloalkyl optionally substituted with RDJ iC; -N(H)-C(0)-(C!-C4)alkyl optionally substituted at the alkyl group with one or two RDl !i!, -N(H)-C(0)-N(H)-(CrC3)a3kyi optionally substituted at the alkyl group with RDnB; -(Ci-C6)alkyl optionally substituted with one or two RDl ,B; -C(^ H)-NH2; and -C≡C-(Ci-C3)alkyl optionally substituted with RDnE; each Rli < i is independently selected from H, -(C3-C(,)cycioaikyl,
Figure imgf000009_0001
-OH, -S(0)2OH, C(0)OH, -NIL, -N(H)C(-NH)NH2; -(C-C^alk l optionally substituted with halo, -OH or -C(0)OH; -(CrC3)a3.kyi -phenyl optionally substituted at the phenyl group with one, two, or three substituents selected from methoxy. hydroxyl and halo;
RDnB is selected from H, -OH, -CF3, ~N(RDn)2, -C(0)OH, -0-(CrC4½]kyl,
-8(0)2011, -C(=NH)-NH2, -N(H)C(=NH)NH2, -C(H)== (H)C(=NH)NH2,
Figure imgf000009_0002
(5-6 membered)heteroaiyl, -C(0)-(C C3)alkyl;
Figure imgf000009_0003
optionally substitiUed with one, two, or three groups independently selected from halo and -OH;
Figure imgf000009_0004
optionally substituted with one, two, or three groups independently selected from halo, -OH, ~S(0)20H, -C(0)OH, -N¾, and -N(H)C(=NH)N¾; -(Co-C3)alkyl-(5-8 membered)heterocycloalkyl optionally substituted with one, two, or three Di !; -(Co-C})alkyl-(CrQ)cycloalkyl optionally substituted with RDU, and -(C6-C;o)aryl optionally substituted with one, two, or three halo;
or RDn and R0nB, when they both exist and are each attached to nitrogen, can join together with the nitrogen to which they are attached to form a (5-6 membered) heterocycloalkyi optionally substituted with a group selected from -OH, -(Ci-COhaloalkyl, -S(0)2OH, C(0)OH, -NH2, -N(H)C(=NH)NH2, -(C C6)cycloalkyl; -(Ci-C4)alkyl optionally substituted with halo, -OH or -C(0)OH; and -(C rC})alkyi-phenyl optionally substituted at the phenyl group with one, two, or three substituents selected from methoxy, hydroxyl and halo; and
RDnc is selected from H, -OH, -C.F3, -0-(Ci-C4)alkyl, -(C,-C4)alkyl- (H)C(=NH)-NH2, -(Co-C3)alkyl~(5-6 membered)beteroaryl; -(C;-C4)alkyl optionally substituted with one, two, or three groups independently selected from halo, -OH, -S(0)20H, C(0)0H, -NH2, and N(H)C(-NH)NH2; Co-C3)alkyl-(5-6 membeied)heterocycloaikyl optionally substituted with a -(5-6 membered)heteroaryl; -(Co-C3)alkyl-(5-6 membered)heterocycloalkyl substituted one, two, or three groups selected from selected from -OH and -(Ci-C})aikyl; and -(Co-C3)alkyl-aryl optionally substituted at the aryl group with one, two, or tliree halo.
[0010] In another embodiment of the compound of formula I(Q), including all embodiments of the compound of formual I(Q) described above, or a pharmaceutically acceptable salt of any of these embodiments:
X is -C(R4)-:
Y is a bond, -S-, -S(0)2-, -CH(CH3)-S(0)2-, -CH(CH3)-S-, -CH(C¾)-S(0)2-, -CH(OH)-, -CH(CH3)-0-, -C(O)-, -(CH2)-S-, -CH.2-i (RY)-, -CH(halo)-, -CH2-S(0)2-, -S(0)2-N(RY)-, ~(CH2>0~, or -C(0)-N(RY)-, wherein RY is H, ~(C C3)alkyl or hydroxyi(C t -C3)alkyl:
each R is independently selected from H, -CH3, - OH. F, and -CH2OH;
RD! is selected from phenyl, -N(H)-phenyl, -(CVCejcyeloaikyl, -(5-6
membered)heterocycioalkyl, -(5-6 membered)heteroaryi-(5-6 membered)heterocycloalkyl, and -(5-6 membered)heteroaryi, wherein RD5 is optionally substituted with one. two, or three RD!0, wherein the one, two, or three RD!0 groups are independently selected from A groups and B groups, provided that RD5 cannot be substituted with more than one B groups;
each A group, when they occur, is independently selected from halo, -CF3, -CN, -NO2, -OH, -G-(CrC4)alkyl optionally substituted with one, two, or three substituents independently selected from -OH and halo, and -(CrCjjalkyl optionaliy substituted with one, two, or three substituents independently selected from -Oil and halo;
the B group is selected from -0-(Q ~C4)alkyl~C(0)OH, -G~(CrC4)alkyL -0-(CrC4)alkyl-C(0)-(C,-C3)aikyi, -0-(Cr-C4)alkylN(RD! ')2, -(C C4)alk l-C(0)OH, -(5-6 menibered)heiexoaiyL -C(=NH)-NH2, -S(0)2-N(H)C(0)-(C1-C4)aikyL
-S(0)2- (H)C(0)0-(Ci-C4)alkyl, -S(0)2-N(H)C(0)- (H)-(C!-C4)alkyi, -S(0)2- (H)C(0)-N(H)-(5-6 membered)heterocycloalkyl, -S(0)2-(C,- )alkyl,
-0-(Ci-C )alkyl-]S!(H)-C(=NH)-NH25 -0-(CrC4)alkyl-(5-6 membered)heteroaryl, -(C,-C )aikylN(Rm i)2, -C(0)-N¾, -C(0)-N(H)-OH, -C(0)-N(H)-RDnc, -C(0)-(Ci-Cj)alkyl, -C(0)OH, -C(0)0-(C C4)aikyI, -S(0)2-NH2; -0-(Ct-C4)alkyl-(5-6 membered heteroeycioalkyl optionaliy substituted with oxo or methyl; -C(0)-(5-6 membered)heterocycloalkyl optionally substituted with -S(Q) QH, -C(0)OH, -NH2, or -C(0)-N(H)-(Ci-C4)alkyl optionally substituted at tire aikyi group with one or two groups selected from -S(0)2OH, -C(0)OH, -N¾, and -N(H)C(=NH)NH2; -(5-6 membered)heterocycloalkyl optionally substituted with oxo or RD1 I
~S(0)2-N(H)-(C;-C4)a!kyl optionally substituted at the alky! group with one or two groups selected from -8(0)2OFi, C(0)OH, -NH2, and -N(H)C(=NH)NH2 ; -S(0>2-N(C!-C3)alkyl-(Ci-C )alkyl optionally substituted at the (Ci-C4)alkyl group with one or two groups selected from -8(Q)20H, C(0)OH, -NH,2, and -N(H)C(=NH)NH¾; ~S(0)2-(4-6 membered)heterocycloalkyl optionally substituted with -S(0)2OH, C(0)OH, -NH2, or -N(H)C(-NH)N¾; -N(H)-C(0)-(C1-G!)aikyi optionally substituted at the alky! group with one or two groups selected from -S(0)2OH, C(OjOH, -NH2 and -N(H)C(=NH)NH2; -N(H)-C(0)-N(H)-(Ci-C3)alkyl optionally substituted at the alky! group with -S(0)2OH, C(0)OH, -NH2> or -N(H)C(=NH)N¾; -(Ci-C6)alkyl optionally substituted with one or two groups selected from -S(0)2OH, C(0)OH, -NH¾ and -N(H)C(=NH)NH2 : and
Figure imgf000011_0001
optionally substituted with one or two groups selected from -S(Q)2OH, C(0)OH, -NH2, and -N(H)C(=NH)NH2;
each RDi ! is independently selected from H, -(C3-C6)cycloaiky!, -OH, -S(0)2OH, C(0)OH, ~NH2, -N(H)C(=NH)NH2j -(CrC )haIoalk l; -(CrC3)alkyI-phenyl optionally substituted at the phenyl group with one, two, or three substituents selected from methoxy, hydroxyl and halo,; and -(Ci-C )alkyl optionally substituted with halo, -OH or -C(0)OH;
RD1 !B is selected from H, -OH, -CF3, -N(RDn)2, -C(0)OH, »0-(C C4)aikyi, -S(0)2OH, -C(=NH)-NH2j -N(H)C(=NH)NH2, -C(H)=NN(H)C(=NH)NH2, (5-6 membered)heteroaryl, -N(H)C(=NH)-N(H)C(=NH)NH2, -0-(Cj-C4)alkyl-C(0)OH, -(Co-C3)alkyl-(5-8 membered)heterocycloalkyl, ~C(0)~(C<-C3)a3kyl; -(C C4)alkyl optionally substituted with one, two, or three groups independently selected from halo and -OH; -•(Cr-C4)alkyl optionally substituted with one or two groups independently selected from, halo, ■OH, -S(0)2OH, C(0)OH, -NH2) and -N(H)C(=NH)NH2; -(C0-C3)a3kyl-(C3-C6)cycloalky optionally substituted with R^" 1 ; and phenyl optionally substituted with one, two, or three halo; and
RDUC is selected from H, -OH, -CF3, -0-(C C4)alkyl; -(C3-C4)alkyl optionally substituted with one or two groups independently selected from halo, -OH, -8(0)2QH, C(0)OH, -NH2, and -N(H)C(-NH)NH2, -(C0-C3)alkyl-(5-6 meinbered)heierocycloa.lkyl, -C(0)-(5-6 membered)heterocycloalkyl optionally substituted with a (5-6 membered)heteroaryl; -(Co-Cj)alkyl-(5-6 membered)heterocycloalkyl substituted with one, two, or three groups selected from -OH and -(Ci-C3)alkyl; -(C]-C4)alkyl-i i(H)C(=NH)-N¾; -(Co-C3)alkyl-(5-'6 mernbered}heteroaryl,; and -(Co-Cj)alkyl-phenyl optionally substituted at the phenyl group with one, two, or three halo.
fOOll] In another embodiment of the compound of formula i(Q), including ail embodiments of the compound of formual I(Q) described above, or a pharmaceutically acceptable salt of any of these embodiments:
p is 0;
Y is a bond, -S-, -S(0)2-, -CH(CH3)-S(0)2-, -CH(CH3)-S-, -CH{CH3)-S(0)2-, -CH(OH)-, -CH(C¾)-0-, -C(H)=C(H)-, -C(O)-, -(CH2)-S-, -CH2-N(RY)-, -CH(halo)-, -CH2-S(0)2-, -S(0)2-N(RY)-, -(CH2)-0-, or -C(0)-N(RY)-, wherein RY is H, -(C,-C4)alkyl or hydroxy 1(C 1 -C4)alkyl;
each R is independently selected from H, -(Cj-C2)alkyl, fluoro, -OH, and -CH2OH; RD! is selected from phenyl, -N(H)-phenyI, cyclohexyl, cyelopentyL piperidinyl, piperazinyl, pyrrolidinyl, morpholinyl, 1 ,2,3,6-tettahydropyridinyl, heteroarylheterocycloalkyl, pyridinyl, oxazolyl, pyrazinyi, qumolinyi, 1,2,4-oxadiazoiyt, 1 ,2,3,4-tetxahydroquinolinyl, and pyrazolyl, wherein RDl can be optionally substituted one, two, or three RDi0, wherein the one, two, or three RDi0 groups are independently selected from A groups and B groups, provided that RD1 cannot be substituted with more than one B group;
each A group, when they occur, is independently selected from halo, -CF3, -CN, -NO?, -OH; -0-(Ci-C4)alkyl optionally substituted with one, two, or three substituents independentl selected from -OH and halo; and -(Ci-C4)alkyl optionally- substituted with one, two, or three substituents independently selected from -OH and halo; the B group is selected from -0-(C C4)alkyl-C(OpH, -0-(d-C4)a!kyl, -0-(C i -C4)aikyi-C(0)-(C , -C3)alkyl, -0-(Q -C4)alkylN(RD E l)2,
-0-(CrC4)alkyl-N(H)-C(= H)-NH2, -0-(Ci-C4)alkyl-(5~6 raembered)heteroaryl, -(C,-C4)alkylN(RDU)2( -C(0)-NH2, -C(0)-N(H)-OH, -C(0)-N(H)-RD1 iC, -QOMQ-C^alkyl, -(Ci-C4)alkyl-C(0)OH, -C(0)OH, -C(0)0-{C, -C^alkyl, -S(0)2-(CrC4)alkyi~NiRDS -S(0)2-NH2, -S(0)2-N(H)C(0)-(Ci-C4)alk l, -8(Q)2-N(H)C(Op~(C C4)alkyi,
-S(0)2-N(H)C(0)-N(H)-(Ci-C4)alkyl, -S(0)2-N(H)C(0)-N(H)-morpholinyl, -S(0): N(H)C(0)-N{H)-pyrroiidinyl, -S(0)2-N(H)C(0)-N(H)-piperidinyl, -S(0)2-<¾, -C(=NH)-NH2, 2,3-dihydro-lH-tetrazolyl; -0-(Ci~C4)alkyl optionally substituted at the alky! group with one or two RD! 1B; -0-(C{-C )alkyl-(5-6 membered)heterocycloalkyl optionally substituted with oxo or methyl; -C(0)-heterocycioalkyl optionally substituted with -S(0)2OH, C(0)OH or -NH2 provided that substitution of the -C(0)-heterocye!oalkyl can only occur by replacing a hydrogen that is covalently bound to either a carbon or a nitrogen of the ~C(0)-heterocycloaikyl; -C(0)-N{H)-(C]-C4)alkyl optionally substituted at the aikyi group with one or two groups selected from -8(G)20H, C(0)OH, -NH2 and -N(H)C(=NH)NH2; heterocvcloalkvl selected from IH-tetrazolyl, piperizinyl, 2,3-dihydro-l ,3,4-oxadiazolyl, and 4,5-dihydro-l ,2,4-oxadiazolyl, optionally substituted with oxo or --(Ci-C4)alkyi; -S(0)2-N(H)-{Ci -C4)alkyl optionally substituted at the aikyi group with one or two groups selected from -S(0)2QH, C(0)OH, -NH2, and -N(H)C{=NH)NH;2; -S(0)2-N(Ci-C3)alkyl-(Ci-C )alky1 optionally substituted at the (C)-C4)alkyl group with one or two groups selected from -S(0)2OH, C(0)OH, -N¾, and -N(H)C(=NH)N¾,; -S(0)2-(4-6 membered iheterocyeloalkyl optionally substituted with -S(0)2OH, C(0)OH, -N¾, or -N(H)C(=NH)NH2; -N(H)-C(0)-(Ci-C4)alkyl optionally substituted at the alkyl group with one or two groups selected from ~8(0)2OH, CYOiOH . ~N¾, and -N(H)C(=NH) H,; -N(¾-C(Q)-N(H)-(CrC3)alkyl optionally substituted at the alkyl group with a group selected from -S(0)2OH, C(0)OH, -NH2 and -N(H)C(=NH)NH2 ; (C,-C6)alkyl optionally substituted with one group selected from -S(Q)2OH, C(0)OH, -N¾ and -N(H)C(»NH)NH2 : and -C≡C-(Ci-C3)alkyl optionally substituted at the alkyl group with one group selected from -S(0)2OH, C(0)OH, -NH2, and -N(H)C(-NH)NH2;
each Dn is independently selected from H, --(Cv-Cskycloaikyt; ~(Ci-C4)alkyl optionally substituted with halo, -OH or < (( >)( > I !. -OH, -S(0)2OH, C(0)OH, -N¾, -N(H)C(=NH)NH2, -(Ci-Cj Jalkyi-phenyl optionally substituted at the phenyl group with one, two, or three substitueirts selected from methoxy, hydroxyl and haio, and -(C< -C4)haloalkyl;
RD1 !B is selected from H, -OH, -CF3, -NH2, -C(0)OH, --0-(CrC4)alkyl, -S(0)2OH, •C(= H)-NH2, -N(H)C(-NH)NH2, -C(H)H (H)C(=NH)NH2,
-N(H}C{-Ni-i)-N(ii)C(-NII)NH?, -C(0)-(Ci-C¼)alkyl,; -(C C4)alkyl optionally substituted with one, two, or three groups independently selected from ha!o and -OH; -(€¾)■ _4-C(0)OH, -(Cj-C4)alky! optionally substituted with one or two groups independently selected from halo, -OH, -S(0)2OH, C(0)OH, -NH2, and - (H)C(=NH)N¾: -0-(C,-C4)alkyl-C(0)OH, a heterocycioalkyl selected from morpiioiinyi, pyirolidinyl, piperazinyl, and piperidinyi, wherein the heterocycioalkyl can be optionally substituted with one, two, or three RDn; cyelopropanyl; cyclopentyl; imidazolyl; pyridinyl; thiazolyl; l(H)-tetrazolyl; and phenyl optionally substituted with one, two, or three halo,
or R l i and R l lB, when they both exist and are each attached to nitrogen, can join to form a (5-6 membered) heterocycoalkyl optionally substituted with RH; and
RDUC is selected from H, -OH, -CF3, -0-(C!-C4)alkyl; -(C(-C4)alkyl optionally substituted with one or two groups independently selected from halo, -OH, -S(0)2OH, C(0)OH, -NH2 and -N(H)C(=NH)NH2; a heterocycioalkyl selected from morpholinyl, pyrrolidmyl, piperidinyi and piperazinyl, wherein the heterocycioalkyl is optionally substituted with a (5-6 membered)heteroaryl; -Co-C3alky!-(5-6 rnemberedjheterocyc!oaikyl, wherein the (5-6 membered)keteroeyck>a!kyl group of -Co-C3alkyl-(5-6 membered)hetefocycloalkyl is selected from morphoiinyl, pyirolidinyl, piperidinyi. and piperazinyl and wherein the -Co-C3alkyl-(5-6 member edjheterocycloaikyl group is substituted with one, two, or three substituents selected from -OH and -(C Qt)aikyl; -(Ci-C4)alkyi-N(H)C(==-NH)-NH2; -Co-Cjalkyl-imidazolyl; -Co-C3alkyl-pyridinyl,; and -Co-Csalkyl-phenyl optionally substituted at the phenyl group with one, two, or three halo. [0012] In another embodiment of She compound of formula I(Q), including all embodiments of the compound of formual I(Q) described above, or a pharmaceutically acceptable salt of any of these embodiments:
X is C(iiV,
p is 0;
Y is a bond, -S-, -8(0)2-, --CH(C¾)-S(0)2-s -CH(CH;;)-S-, -CH(CH3)-S(0)2-,-CH(OH)- -CH(CH3)-0-, -C(H)=C(H)-, -C(0)-, -(CH2)-S-, -C¾-N(RY)-S -CH(halo)-, -CH2-S(0)2-, -S(0)2-N(RY)-, -(CH2)-0-, or -C(0)-N(RY)-, wherein RY is H, -(Cj-C4)alkyl or hyciroxyl(Ci--C4)alkyl;,
each R is independently selected from H, -(C| -C2)alk l, fluoro, -OH, and -CH2OH;
RJ! is selected from phenyl, -N(H)-phenyl, cyclohexyl, cyclopentyl, piperidinyl, piperazinyl, pyrroiidinyl, morpholinyl, 1 ,2,3,6-tetrahydropyridinyL heteroarylheterocycloalkyl, pyridinyl, oxazolyl, pyrazinyl, qumolinyl, 1,2,4-oxadiazolyi, i,2,3,4-tetraliydroquinoiinyl. and pyrazolyl, wherein RD1 is substituted with one, two, or three RD!'J, wherein the one, two, or three RDi0 groups are zero, one, or two A groups and zero or one B group;
each A group, when they occur, is independently selected from halo, -CFj, -CN, -NO2, -OH: -0-(C I -Chalky! optionally substituted with one, two, or three substituents independently selected from -OH and halo; and -(Ci-C4)alkyl optionally substituted with one, two, or thi'ee substituents independently selected from -OH and halo; the B group, when it occurs, is selected from -0-(C; -Chalky 1 optionally substituted at the alley! group with one or two RDi lB,; -0-(C,-C4)alkyl-C(0)OH; -0-(C C4)alkyl; -0-(Ci -C4)alkyl- C(0> (C , - C3)alkyl; -0-(d - C4)alkyiN(RD 1 ;
-0-(CrC4)alkyl-N(H)-C(=NH)-NH2; -0-(C C4)alkyl-(5-6 membered)heteroaryl; -0~(Ci-C4)alkyl-(5-6 membered)heterocycloalkyl optionally substituted with oxo or methyl; -(Ci-C4)alkylN(RDi ')¾; -C(0)-NH2; -C(0)-N(H)-OH; -C(0)-N(H)-RD*! IC;
-C(0)-(CrC )alkyl; -C(0)OH; -C(0)0-(C C4)alkyl; -C(0)-heterocycloa!kyl optionally substituted with -S(0)2OH, -C(0)OH, or -NH2; -C(0)-N(H)-(C;-C4)alkyi optionally substituted at the alkyl group with one or two groups selected from -S(0)2OH, C(0)OH, -NH2, and -N(H)C(=NH)NH2; -(Ci-C4)alkyl-C(0)OH,; 2,3-dihydro- 1 H-tetrazolyl; hetsrocvcloaikyl selected from lH-tetrazolyi, piperizmyl, 2,3-dihydro- 1,3,4-oxadiazotyl, and 4,5-dihydro-l,2,4-oxadiazoiy , wherein the heterocycloalkyl is optionally substituted with oxo or -(Ci-C4)alkyi; -S(0)r(Ci-C )aikyl-N(RD11)2; -S(0)2-N¾; -S(0)2-N(H)-(C|-C )alkyl optionally substituted at the alkyl group with one or two groups selected from -S(0)2OH, C(0)OH, -N3¾ and -N(H)C(-NH)N¾ -S(0)2-N(Ci-C3)alky!-(C, -C4)a!k>'1 optionally substituted at the (Q-C^alkyl group with one or two groups selected from -S(0)2OH, C(0)OH, -NH2, and -N(H)C(=NH)NH2„ -S(0)2-(4-6 membered)heterocycloalk l optionally substituted with -S(0)2OH, C(0)OH, -NH2 or -N(H)C(=NH)NH2;
-S(0)2- {H)C(0)-(CrC4)alkyi; -S(0}2-N(H)C(0)0-(Cr-C4)a3kyl; -S(0)2-N(H)C(0)- (H)-(Ci-C4)alkyl; ■S(0)2-N(H)C(0)-N(H)-morpholinyl;
-S(0)2- (H)C(0)-N(H)-pyrrolidinyl; -S(0>2-N(H)C(0)-N(H)-piperidinyl; -S(0)2-CH3; -N(H)-C(0)-(Ci -CUjalky! optionally substituted at the alky! group with one or two groups selected from -8(0)2OH, C(0)OH, ~NH2, and -N(H)C(=NH)NH2; -N(H)-C(0)-N(H)-(C[-C3)alkyl optionally substituted at the alkyl group with a group selected from -S(0)2OH, C(0)OH, -NH2, and -N(H)C(-NH)NH2 ; -(C]-C6)alkyl optionally substituted with one group selected from -S(0)2OH, C(0)OH, -NH2 and -N(H)C(=NH)NH2 ; -C(=NH)-NH2; and -C≡ -(C]-C3)alkyl optionally substituted at the alkyl group with one group selected from -S(0)2OH, C(0)QH, -NH2, and -N(H)C(=NH)NH2;
each Rm l is independently selected from H, ~(C:$-C6)cycloalkyi, -OH, -SCO^OH, C(0)OH, -N¾, -N{H)C(=NH)N¾; -(C,-C )aikyl optionally substituted with halo, -OH or -C(0)OH; -{CrC3)alkyl-phenyi optionally substituted at the phenyl group with one, two. or three substituents selected from methoxy, hydroxyl and halo,; and "(Ci--C4)ha.Ioaik.yl;
RD! SB is selected from H, -OH, -CF3, -NH2, -C(0)OH, -0-(Ci-Ct)alkyl,
-S(0)2OH, -C(-NH)-N¾, -N(H)C(=NH)NH2, -C(H)=NN(H)C(=NH)NH2, -0-(Ci-C )alkyl-C(0)OH, -N(H)C(=NH)-N(H)C(=NH)NH2, -C(0)-(Ci-C3)alkyl, -(CH2)i-4-C(0)OH, cyclopropanyl, cycSopentyl, imidazolyl, pyridinyl, thiazoly!, l(H)-ietrazo!yi,
-(C C4)alky! optionally substituted with one, two, or three groups independently selected from halo and -OH; -(Ci-C^alkyl optionally substituted with one or two groups independently selected from halo, -OH, -S(0)2OH, C(0)OH, -N¾, and -N(H)C(=NH)N¾; a heterocycloalkyl selected from morpholinyl, pyrrolidinyl, piperazinyl, and piperidinyl, wherein the heterocycloalkyl is optionally substituted with one, two, or three R1"" 1; and phenyl optionally substituted with one, two, or three halo,
or RJ! t and RD, ,B, when they both exist and are each attached to nitrogen, can join to form a (5-6 membercd) heterocycoaikyl optionally substituted with R'1; and
RDnc is selected from H, -OH, -CF3, -0-{Ci-C4)aikyl; -(Ci-C4)alkyl optionally substituted with one or two groups independently selected from halo, -OH, -S(0)2OH, C(0)OH, -NH2> and -N(H)C(= H)N¾ -(Cj-C4)aikyi-N(H)C(=== H)- H2; -Co-Cjalkyi-imidazoIyi; -Co-Cjalkyl-pyridinyl; a heterocycloalkyl selected from morpholinyl, pyrroSidiayl, piperidinyl, and piperazinyl, wherein the heterocycloalkyl is optionally substituted with a (5-6 membered)heteroaryi; -Co-C3alkyl-(5-6 merabered)heterocycloalkyL wherein the (5-6 membered)heterocycioaIkyl group of -Cc.~C¾alkyi-(5-0 mernbered)heterocycloalkyl is selected from morpholinyl, pyrrolidinyl, piperidinyl, and piperazinyl, and wherein the -(5-6 membered)heterocycloaIkyl group is substituted with a one, two, or three groups selected from -OH and -(C-, -C?,)alkyl; and -Co-Cjalkyl-pheny] optionally substituted at the phenyl group with one, two, or three halo.
|0013] In another embodiment of the compound of formula I(Q), including all embodiments of the compound of form al I(Q) described above, or a pharmaceutically acceptable salt of any of these embodiments:
X is C(k' ;
p is 0;
Y is a bond, -S-, -S(0)2-, -CHfC¾)»8(0)2-, -CH(CH3)-S-, -CH(CH3)-S(0)2-,-CH(OH)-, -CH(CH3)-0-, -C(H)==C(HV, -C(0)-, -(CH2)-S-, -CH?-N(RY)-, -CHihalo)-, -CH2-S(0} , -S(0)2-N(RY)-, -(CH2)-0-, or -C(0)-N(Ry)-, wherein RY is H, -(d-G^alkyl or hydroxyl(Ci -C^alkyl;
each R is independently selected from H, -(Ci-C2)alkyi, fiuoro, -OH, and -CH?OH;
RD1 is selected from phenyl, -N(H)-phenyl, eyclohexyl, cyclopentyl, piperidinyl, piperazinyl, pyrrolidinyl, morpholinyl, 1 ,2,3,6-tetrahydropyridinyl, hetexoarylheterocycloaikyl, pyridinyl, oxazolyl, pyrazinyi, quinolinyl, 1 ,2.,4-oxadiazoiyl, 1 ,2,3,4-tetrahydroquinolinyl, and pyrazolyl, wherein RDi is substituted with one, two, or three R l°, wherein the one, two, or three RD'° groups are zero, one, or two A groups and one B group;
each A group, when they occur, is independently selected from halo, -CF3, --CN, -NO?, -OH; -0-(Ci -Chalky! optionally substituted with one, two, or three substituents independently selected from -OH and halo; and
Figure imgf000016_0001
optionally substituted with one, two, or three substituents independently selected from -OH and halo;
the B group is selected from -0-(Ci-Ci)alkyl-C(0)OH, -0-(CrC4)alkyi, -0-(C1-C4)alkyl-C(0)-(C,-C:i)alkyI, -C(0)OH, -NH2, -(C C )alkyl-C(0)OH, 2,3-dihydro-lH-tetrazolyl, -0-(C!-C4)alkylN(RI,n)2, -0-(C; -Q)alkyi-N(H}-C(=NH)-NH2, ■0-(Cr-C4)alkyl-(5-6 membered)heteroaryl, -(CrC4)alkylN(RDi ')2, -C(0)-NH2, -C(0)-N(H)-OH, -C(0)-N(H)-Rrmc, -C(0)-(C,-C4)alkyl, -C(0)OH, -C(0)0-(CrC4)alkyi, -S(OMCi-C4)alkyl-N(RD1 -S(0)2-N¾, -S(0)2-N(H)C(0)-(C,-Q)alkyl, j)2-mi) ((}}0■{<■. -C Viikyi . -S(0)2-N(H)C(0)-N(H)-.(CrC4)alkyl, -S(0)2»N(H)C(0)-N(H)-morpbolinyl5 -S(0>2-N(H)C(0)-N(H)-pyrrolidinyl, -S(0)2-N(H)C(0)-N(H)-pipendinyi, -S(Q)2-C¾, -C(-NH)-NH2; -0-(CrC4)alkyl optionally substituted at the alkyl group with one or two RD! iB; -0-(Ci~C4)alkyl»(5-6 membered)heterocycloalkyl optionally substituted with oxo or methyl,; -C(0)-heterocycloalkyl optionally substituted with -S(0)2OH; -C(0)-N(H)~(Ci-C4)alky? optionally substituted at the alkyl group with one or two groups selected from -S(0)2OH, C(0)OH, -NH2 arid -N(H)C(=NH)NH2; heterocycloalkyl selected from 1 H-tetrazofyL piperizinyl, 2,3-dihydro-l ,3,4-oxadiazolyL and 4,5-dihydro-l,2,4~oxadiazQlyl, wherein the heterocycloalkyl can be optionally substituted with oxo or
Figure imgf000017_0001
-S(0)2-N(H)-(Ci-Ci)aIkyl optionally substituted at the alkyl group with one or two groups selected from -S(0)2OH, C(0)OH, ~N3¾, and -N(H)C(=NH)NH2; ■•S(0)2~ (Ci-C3)alkyl-(CrC4)alkyi optionally substimted at the (Ci-C4)alkyi group with one or two groups selected from -S(0)2OH, -C(0)OH, -NH2, and -N(H)C(=NH)NH¾; -S(0)2-(4-6 membered)heterocycloalkyl optionally substituted with -8(0)201-1, C(0)OH, -NH2, or -N(H)C(=NH)NH2; -N(H)-C(0)-(Ci-C4)alkyl optionally substituted at the alkyl group with one or two groups selected from -S(0)2OH, C(0)OH, -NH2, and -N(H)C(=NH)NH2; -N(H)-C(0)-N(H)-(C!-C3)alky3 optionally substituted at the alkyl group with a group selected from -S(0)2OH, C(0)OH, -NH2 and -N(H)C(=NH)NH2; -(CrCg)alky! optionally substituted with one group selected from -S(0)2OH, C(0)OH, -N¾ and -N(H)C(=NH)NH2 : and ■•C=C-(Cr-C: alkyl optionally substituted at the alkyl group with one group selected from -S(0)20H, C(0)OH, -NHj and - (H)C(-NH)NH2;
each RDl i is independently selected from H, -(C3-C6)cycloalky3, -OH, -(CrC4)haloalkyl -S(0)2OH, C(0)OH, -NH2, -N(H)C(=NH)NH2; -(Cr-C4)alkyl optionally substituted with halo, -OH or -C(G)QH; and -(Cs-C3)alkyl-phenyl optionally substituted at the phenyl group with one, two, or three substituents selected from methoxy, hydroxy! and halo;
RDHB is selected from H, -OH, -CF3, -NH& -C(0)OH, -0~(C C4)alkyl, -S(0)2OH, -C(=NH)-NH2, -N(H)C(=NH)NH2, -C(H)=NN(H)C(= ffl)NH2,
-N(H)C(=NH)-N(H)C(=NH)N¾, -C(0)-(Ct-Cj)alkyL -0-(Ci-C4)alkyl-C(0)OH, -(CH2)!-4-C(0)OH, cyclopropanyi, cyclopentyl, imidazoiyl, pyridinyl, thiazolyl, 1 (H)-tetrazolyl; -(C]-C4)alkyl optionally substituted with one, two, or three groups independently selected from halo and -OH; -(Ci-C4)alkyl optionally substimted with one or two groups independently selected from halo, -OH, -S(0)2QH, C(0)OH, -NH2, and -N(H)C(=NH)N¾; a heterocycloalkyl selected from morpholinyl, pyrrolidinyl, piperazinyl, and piperidinyl, wherein the heterocycloalkyl is optionally substituted with one, two, or three RDn; and phenyl optionally substituted with one, two, or three halo;
or RDi i and RD1 !B, when they both exist and are each attached to nitrogen, can join to form a (5-6 embered) heterocycoalkyl optionally substituted with R! l; and
RD! iC is selected from H, -OH, -CF3, -0-(CrC4)alkyl, ••(C i -C4)alkyl-N(H)C(=NH)-NH2, -C0-C3aiky l-imidazolyl, -Co-C3alkyl-pyridinyl; ■(Ci- alkyl optionally substituted with one or two groups independently selected from halo, -OH, -S(0)2OH, C(0)OH, -NH2, and -N(H)C(=NH)NH2; a heterocycloalkyl selected from morpholinyL pyrrolidinyl, piperidinyl and piperazinyl, wherein the heterocycloalkyl is optionally substituted with a (5-6 membered)heteroaryl; -Co~C3alkyl-(5-6 membered)heterocycloalkyl, wherein the (5-6 membered)heterocycloalkyi group of ••Co-Cjalkyl-(5-6 membered)heterocycloalkyl is selected from morpholinyl, pyrrolidinyl, piperidinyl, and piperazinyl, and wherein the -Cc.-C:,aikyl-(5-6 membered)heterocycloalkyl group is substituted with a group selected from one, two, or three groups selected from -OH and -(Ci-C3)a!kyl; and -Co-Cjalkyl-phenyl optionally subststoted at the phenyl group with one, two, or three halo.
[§0141 In another embodiment of the compound of formula I(Q), or a pharmaceutically acceptable salt thereof, LD is selected from -(Ci-C3)alkyl-0-, -(Co-C3)alkyI-NRY-(Co-C3)alkyI-, -(Co-C3)aikyi-S-(CQ-C3)alkyl-, -(Co-C3)alkyl-S(0)2-(Co-C3)alkyl-; -C(0)N(RY)-(Co-C3)alkyK -S(O)2-N(RY)-(C0-C3)alkyk -C(O)-(C0-C3)alkyl-, -OC-(C0-C3)alkyl-, -(Co-C3)alkyl-, and -(Ci-C4)alkyi- optionally substituted with halo or -OH.
(0015] In another embodiment of the compound of formula 1(Q), or a pharmaceutically acceptable salt thereof, LD is selected from -(CH?.)i-3-0-, -(CH2)!_3~NR/~, -(C0-C3)alkyl-S-(C C3)alkyl-; -(C¾),,3-S-, -S-(CH2),.3, -S(0)2-(CH2),.3-, -S(0)2-, -C(0)N(HHCH2)i,3-, -S(0)2-N(H)-(CH2)i-3-. -C(0)-(CH2)i-2-, -C-C-(C0-C3)alkyl-, a bond, and -(Ci-Gj)alkyi- optionally substituted with halo or -OH.
[00161 In another embodiment of the compound of formula I(Q), or a pharmaceutically acceptable salt thereof, LD is selected from -(CH2)-0-, -(CH2)~NRY-, -(CH2)-S-, -8-(CH2 , ~S(0)2~, -S(0)r(C¾K -C.(0)N(RY)-(Co-C3)alkyls -S(0)2-N(H)-(CH2}i.3-, CtO) (U iyJ,.:< , -OC-(C2-C3)alkyl-, and -(Ci-C4)aikyl- optionally substituted with halo or -OH.
[0017] In another embodiment of the compound of formula I(Q), or a pharmaceutically acceptable salt thereof, LD is selected from -(CH2)-0-, -(CH2)--NRY~, -(CH2)-S- , -S-(CH2)-, -S(0)2-, -S(0)2~(CH2>, -C(0)N(Ry)-(Co-C3)alky -S(0)2-N(H)-(CH2)!-3-, -C(0)-(CH2)i-2-,
-OC- (C2-C3)alkyl-, and -(C|-C4)alkyl- optionally substituted with halo or -OH.
[0018] in another embodiment of the compound of formula 1(Q), or a pharmaceutically acceptable salt thereof, LD is selected from -(CH2)-0-, -(CH2)-NH-, -(CH2)-S-, -S-(CH2)-,
-S(0)2-s -8(0)2-(€ί¾)-, -C(0)N(H)-(CH2)i.3-, -S(0)2-N(H)-(CH?.)j.3-3 -C(0)-(C¾)i_2-,
-C^C-(C6-C3)aikyl- and --(Cr-C^alky!-- optionally substituted with halo or -OH.
[Θ019] In arioiher embodiment of the compound of formula I(Q), or a pharmaceutically acceptable salt thereof, wherein the B rou of RD; is selected from:
Figure imgf000019_0001
In another embodiment of the compound of formula I(Q), including ail embodiments of the compound of formual I(Q) described above, or a pharmaceutically acceptable sal t of any of these embodiments, Rc is phenyl, -CH2-phenyL -(Cs-Cs)-cydoalkyL or pyridinyl, wherein Rc can be optionally substituted with one. two, or three RC1°, wherein the one, two, or three RC1° groups are independently selected from RC10A and R 0B, provided that Rc cannot be substituted with more than one RU0B group;
each RCi0A, when they occur, is independently selected from halo; -(CrCj)alk l optionally substituted with one, two, or three groups selected from halo and -OH; rnethoxy;
-CF3; and halo;
RC10B is selected from -C(0)N¾, (5-6 memberedjheterocycloalkyl; -0-(Ci-C )a3kyl optionally substituted with -OH, -C(0)OH, or - [-(C;-C,!)alkyl32; and -(C C4)alkyl substituted with - [-(Cj-C4)alkyl]2; and
wherein R~ is substituted with one or two QA groups, wherein R is substituted with QA by replacing a hydrogen th t is covalentiy bonded to carbon or nitrogen.
[0021] In another embodiment of the compound of formula I(Q), including all embodiments of the compound of formual 1(Q) described above, or a pharmaceutically acceptable salt of any of these embodiments:
R° is phenyl, -CH2-phenyl, -(Cs-CeJ-cycIoalkyl, or pyridinyl, wherein the cyclic group of Rc can be optionally substituted with one, two, or three RU d groups and, wherein the one, two, or three R o groups are independently selected from RC !0" and R.'" l0B, provided that Rc cannot be substituted with more than one C!CB group; each RclwA, when they occur, is independently selected from methoxy, -CF$, halo, and -(Ci -Chalky! optionally substituted with one, two, or three groups selected from halo and -OH;
RC!0B is selected from (5-6 membered)heterocycloalkyl; -(Ci-C4)aikyi substituted with -N[-(Ci-C4)alk l]2,; -C(0)NH2;and -0-(CrC4)alkyl optionally substituted with
-OH, -C(0)OH, or -N[-(C C )alkyl]2; and
wherein Rc is substituted with one QA group, wherein Rc is substituted with QA by replacing a hydrogen, that is covalently bonded to carbon or nitrogen.
[0022] Irs another embodiment of the compound of formula I(Q), including all embodiments of the compound of formual I(Q) described above, or a pharmaceutically acceptable salt of any of these embodiments, Rc is phenyl, -CH2-phenyl or pyridinyl, wherein the cyclic group of Rc can be optionally substituted with one, two, or three Rcs0, wherein the one, two, or three RC I'"' groups are independently selected from RC!0A and R 0B, provided that Rc cannot be substituted with more than one RC10B group;
each RC!0A, when they occur, is independently selected from --(Ci-Ci kyl optionally substituted with one, two, or three groups selected from -OH, methoxy, -CF3 and halo;
RC10B is selected from -C(O)NH2, (5-6 :membered)heterocycioalkyl;
Figure imgf000020_0001
substituted with -N[-(Ci-C4)alkyl]2,; and ~0-(Ci-C )a!kyl optionally substituted with -OH, -C(0)OH, or -N[-(C-.-C4)aiky1]2; and
wherein R'": is substituted with one or two QA groups, wherein RL is substituted with QA by replacing a hydrogen that is covalently bonded to carbon or nitrogen.
[00231 In another embodiment of the compound of formula I(Q), including all embodiments of the compound of formual I(Q) described above, or a pharmaceutically acceptable salt of any of these embodiments:
Rc is phenyl or pyridinyl, wherein the cyclic group of Rc can be optionally substituted with one, two, or three Rc,°, wherein the one, two, or three RC|° groups are independently selected from RCI0A and RCi0B, provided that Rc cannot be substituted with more than one R group;
each RC 10A, when they occur, is independently selected from methoxy and halo;
RC,0B is selected from -C(0)NH2> (5-6 membered)heterocycloalkyl; -(CrC jalkyl substituted with -N[-(Ci -C4)alkyl]2; and --0-(Ci -C )aIkyl optionally substituted with -OH, -C(0}OH, or ~N[-(CrC4)alky¾; and
wherein Rc is substituted with one QA group, wherein Rc is substituted with QA by- replacing a hydrogen mat is covalently bonded to carbon or nitrogen. In another embodiment of the compound of formula I(Q), including all embodiments of the compound of formual i(Q) described above, or a pharmaceutically acceptable salt of any of these embodiments, Rc is phenyl or pyridiny!, wherein the cyclic group of Rc can be optionally substituted with one or two groups selected from methoxy, methyl and halo; and wherein Rc is substituted with one QA group, wherein Rc is substituted with QA by replacing a hydrogen that is covalently bonded to carbon or nitrogen.
[0025] In another embodiment of the compound of formula i(Q), or a pharmaceutically acceptable salt thereof, R'"' is phenyl or pyridinyl, wherein the cyclic group of Rk' can be optionally substituted one or two groups selected from methoxy, methyl, fluoro and chloro; and wherein Rc is substituted with one QA group; wherein R1"' is substituted with QA by replacing a hydrogen that is covalently bonded to carbon or nitrogen.
[0026] In another embodiment, of the compound of formula I(Q), or a pharmaceutically acceptable salt thereof, R'""' is phenyl substituted with one or two groups selected from methoxy, fluoro or chloro; wherein Rc is substituted with one QA group; wherein Rc is substituted with QA by replacing a hydrogen that is covalently bonded to carbon or nitrogen.
[0027] In other embodiments of the compound of formula I(Q), or a pharmaceutically acceptable salt thereof, the compound of formulae I(Q) is one of formula II, III, IV, V, VI or
Figure imgf000021_0001
wherein one. Rcs0 is substituted with one QA group; wherein RC!0 is substituted with QA by replacing a hydrogen that is covalently bonded to carbon or nitrogen. [0028] In other embodiments of the compound of formulae formula II, HL IV, V, VI or VII.
each RA!0 is selected from fhioro, chloro arid methoxy;
R2 is -LD-RD1, wherein:
LD is selected from -(C¾)-0-, -iCH2)-NH-, -(CH2)-S-, -S-(CH2)-, -S(0)2-,
-S(0)2-(CH2)-, -C(0)N(H)-(CH2)i-3-, -S(0)2-N(H)-(CH2)i.3-, -C(0)-(CH2),.r, -OC-(C;rC3)alkyl, and -(Ci-C3 dkyl- optionally substituted with halo or -OH; and
RD1 is one of:
Figure imgf000022_0001
wherein each A is chloro or fluoro, and B is selected from:
Figure imgf000022_0002
19] In another embodiment of the compound of formula I(Q), including all embodiments of the compound of formual I(Q) described above, or a pharmaceutically acceptable salt of any of these embodiments, LD is selected from -(CH2)-0, -(CH?)-NH -·, -(C¾)-S-, -S-(CH2)-, -S(0)2-, -S(0)2-(CH2)-, -C(0)N(H)-(CH2)i.3-, -S(0)2-N(H)-(CH2)i-3-, -C(0)-(CH?)i-2-, -OC-(C2-C3)alkyl-, and -(Ci-C4)alkyl- optionally substituted with halo or - OH.
[0030] In another embodiment of the compound of formula I(Q), including all embodiments of the compound of formual I(Q) described above, or a pharmaceutically acceptable salt of any of these embodiments, L.D is selected from -S-(C(-C3)alkyi-, -(C¾)2- and -(Ci-C3)alkyl-0-.
[0031] In another embodiment of the compound of formula 1(Q), including all embodiments of the compound of formual KQ) descri bed above, or a pharmaceutically
2.1 acceptable salt of any of these embodiments, R3 is -[0((¾)2] -phenyl, -[C(C¾)2]-naphthalenyl, ΟΓ -[€(€Η3)2]-(5-10 membered) heteroaryl, wherein the heteroaryl is selected from (beiizo[d][l ,3]dioxolyl, benzo[d]isoxazolyI, quinoxalinyl, qxiinolinyl and 2,3,4a,8a-tetrahydrobenzo|¾][l ,4]dioxinyl, wherein the cyclic group of R5 is optionally substituted with one, two, or three RA'° groups, wherein the one, two, or three RA I 0 groups are independently selected from RAl0A and RA10B, provided that R5 cannot be substituted with more than one RA!0B group;
each RAlwA, when they occur, is independently selected from halo, -(Ci-C3)alkoxyl, and hydroxy!; and
RAI0B is -(C) -Chalky! optionally substituted with one, two, or three groups selected from -OH and halo; ~0-(Cj-C4)alkyl-C(0)OH; ( (CrC4)alkyl-N[(CrC3)aIkyl]2; -NH2; -S(0>2-NH2; -SO2CH3; -N(H)~S02CH3; -S02N(H)-CH3; -CN; -C(0)OH; -(Ct-C4)alkyl-OH; -OCF3; or -C(0) ¾.
0832] In another embodiment of the compound of formula I(Q), including all embodiments of the. compound of formual I(Q) described above, or a pharmaceutically acceptable salt of any of these embodiments, RJ is -[C(CH3)2]-phenyl, and the phenyl group of R5 is optionally substituted with one, two, or three R 0 groups, wherein the one, two, or three RA'° groups are independently selected from RAi0A and RAl0B, provided that R5 cannot be substituted with more than one RAl0B group;
each RAi0A, when they occur, is independently selected from halo, methoxy, and hydroxy!; and
RA!0B is -0-(CrC4)alkyl-C(0)OH, 0-(CrC4)alkyi-N[(CrC3)a3kyl]2, -NH2,
-S(0)2-N¾, -SO2CH3, -N(H)-S02CH3, -S02N(H)-CH3, -CN, -C(0}OH, -(C, -C4)alkyl~OH, -OCF3, ~C(0)NH2, or -(C!-C4)alkyl optionally substituted with one, two, or three groups selected from -OH and halo.
[0033] in another embodiment of the compound of formula I(Q), including all embodiments of the compound of formual I(Q) described above, or a pharmaceutically acceptable salt of any of these embodiments, R5 is -[C(CH3)2}-phenyl, wherein the phenyl group is optionally substituted with one or two groups selected from halo, methoxy, and hydroxy!.
|O0341 In another embodiment of the compound of formula I(Q), including all embodiments of the compound of formual I(Q) described above, or a pharmaceutically acceptable salt of any of these embodiments, RJ is -[C CHs^J- henyl, wherein the phenyl group is optionally substituted with one or two groups selected from halo and methoxy. $5] In another embodiment of the compound of formula I(Q), including all embodiments of the compound of formual I(Q) described above, or a pharmaceutically acceptable salt of any of these embodiments, R3 is:
Figure imgf000024_0001
[0036] In another embodiment of the compound of Formula i(Q), RC is substituted with one, two, three, four, or five RCI"A groups, wherein one substituent of R is QA.
[0037] In another embodiment of the compound of Formula I(Q), RC is substituted with zero, one, two, three, or four R" " groups and 1 R ' "' group, wherein one substituent of R ' is QA
[8038] In another embodiment of the compound of formula i(Q), Rc is substituted with zero, one. two, or three RCL0A groups and one or two R'-,UB groups, wherein one substituent of Rc is Q\
[0039] In another embodiment of She compound of Formula I(Q), RD1 is substituted with zero, one, two, three, or four A groups and one B group.
[8040] In other embodiments of the compounds of formula i(Q), or in any of the above embodiments of the compounds of formula I(Q) described herein as it may apply, or a pharmaceutically acceptable salt of any of these compounds, RD1 1B is -(Cj-G alkyl optionally substituted with one, two, or three groups independently selected from halo, -OH, -S(0)20H, C(0)OH, -NH2, -N[(C,-C3)alkyl]}+, 1 >4-diazabicyclo[2.2.2]octanyl, and -N(H)C(-NH)N¾.
[0041 j in other embodiments of the compounds of formula I(Q), or in any of the above embodiments of the compounds of formula I(Q) described herein as it may apply, or a pharmaceutically acceptable salt of any of these compounds, RDNB is -(C¼-Cj)alkyl-(5-8 memberediheterocycioalkyl optionally substituted at the heterocycloalkyi group with 1 to 3 RDn
[0942] In other embodiments of the compounds of formula I(Q), or in any of the above embodiments of the compounds of formula I(Q) described herein as it may apply, or a pharmaceutically acceptable salt of any of these compounds, RDi !d is -(Co-C3)alkyl-(C3-C6)cycloalkyl optionally substituted with RD U.
[0043] In other embodiments of the compounds of formula I(Q), or in any of the above embodiments of the compounds of formula I(Q) described herein as it may apply, or a pharmaceutically acceptable salt of any of these compounds. D1 1B is aryi optionally substituted with one, two, or three halo.
[0044} The invention also comprises as another embodiment, a composition comprising a TGR5 agonist compound according to any one of the preceding embodiments together with a pharmaceutically acceptable diluent, excipient, and/or carrier. Such compositions are substantially free of non-pharrnaceutically acceptable components, i. e., contain amounts of non-phar aceuticaliy 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.
[0045J The invention also comprises as another embodiment a method for treating or preventing a metabolic disease in a subject in need of such treatment comprising administering to the. subject an effective amount of a TGR5 agonist compound according to any one of the preceding embodiments. Metabolic diseases that may be treated or prevented include, without limitation, metabolic syndrome, insulin resistance, and Type 1 and Type 2 diabetes.
[0046] The invention also comprises as another embodiment a method for treating obesity or type II diabetes in a subject in need of such treatment comprising administering to the subject an effective amount of a TGR5 agonist compound or pharmaceutical composition according to any one of the preceding embodiments.
[0047] The invention also comprises as another embodiment a method for treating hyperlipidemia in a subject in need of such treatment comprising administering to the subject an effective amount of a TGR5 agonist compound or pharmaceutical composition according to any one of the preceding embodiments.
|0048] The invention also comprises as another embodiment a method for treating athersclerosis in a subject in need of such treatment comprising administering to the subject an effective amount of a TGR5 agonist compound or pharmaceutical composition according to any one of the preceding embodiments.
[0049] The invention also comprises as another embodiment a method for lowering blood glucose in a subject in need of such treatment comprising administering to the subject an effective amount of a TGR5 agonist compound or pharmaceutical composition according to any one of the preceding embodiments.
{Θ050] The invention also comprises as another embodiment a method for enhancing insulin secretion in a subject in need of such treatment comprising administering to the subject an effective amount of a TGR5 agonist compound or pharmaceutical composition ■ according to any one of the preceding embodiments.
{0051] The invention also comprises as another embodiment a method for treating a disease associated with perturbed bile acid metabolism in a subject in need of such treatment comprising administering to the subject an effective amount of a TGR5 agonist compound or pharmaceutical composition according to any one of the preceding embodiments. Such diseases include, but are not limited to, gall bladder stones, cholecystitis, cholangitis, choledocholithiasis, jaundice, and obstetric cholestasis and the itch associated with it.
[0952] The invention also comprises as another embodiment a method for treating obesity or type II diabetes in a subject in need of such treatment comprising co -administering to the subject, simultaneously or sequentially, an effective amount of a TGR5 agonist compound according to any one of the preceding embodiments and a second anti-diabetic drug or pharmaceutical composition comprising an effective amount of a TGR5 agonist compound according to any one of the preceding embodiments and a second anti-diabetic drug. Non-limiting examples of anti-diabetic drugs include:
» Sulfonylureas (e.g., tolbutamide (3-butyl- 1 -(4-methylphenyl)sulfonylurea), acetohexamide (4-acetyl-.¥-(cyc3ohexylcarbamoyl)benzenesulfonainide), tolazamide (3-azepan- 1-yi-l -(4-metb.ylphenyl)sulfonyl-urea), chlorpropamide (N~ (4-chiorophenyl)sulfoi!y3methanamide), glipizide (Λ'-[2-[4-
(cy lohexy1caibamoyisulfamoyl)phenyS]ethyl]-5-inethyi-pyrazme-2- carboxamide), glyburide (5-cbloro-.V-[2-[4-(cyclohexylcarbamoylsidfamoyl)phenyilethyi]~2- xnet oxy-benzamide), glimepiride (3-ethyi-N^-bis(3-ethyl-4-methyl-2-oxo-5H- pyrrol-2-yi)-4-methyl-2-oxo-5H-pyrrole-l -carboxamide), gliclazide (3-(7- azabicyclo[3.3.0]oct-7-yl)~ 1 -(4-methylphenyl)suifonyl-urea), and gliquidone (3- cyclohexyl- 1 -[4--[2-(7-methoxy-4,4-dimethyi- 1 ,3 - dioxo-isoquiiiolin-2--y3)etl^yljphenyi]sulfonyl-urea))
* Megiitinides (e.g., repaglinide (5(+)2-ethoxy-4(2((3-methyl-i-(2-(l- piperidmyl)phenyl)-butyl)amino)-2--ox.oethy])behzoic acid), nateglinide (3-phenyl- 2-(4-propan-2-ylcyclohexyl)carbonylamino-propanoic acid), and mitiglmide ((25)- 2-benzyl-4-[(3ai?,7aS)-octahydro-2H-isoindol- 2-yl]-4-oxobutanoic acid))
• Biguanides (e.g., metformin (AvA/-dimethylimidodicarbonimidic diamide), phenformin (2-(N-phenethy!carbamimidoyl)guanidine), and buformin (2-buty)-] - (diammomethylidene)guanidine)) » Alpha-glucosidase inhibitors (e.g., miglitoi ((2R,3R,4R,5S)~ 1 -(2-hydroxyethyl)-2 · (hydroxymethyl)piperidine-3,4,5-triol), acarbose ((2R,3R,4R,5S,6R)-5- {[(2A\3i?,4ii,5^0 ¾-5- ^
{ [( 1 S,4jR ,5S,6S)-4,5 ,6-trihydroxy-3 -(hydroxymethyl)cyclohex-2-en- 1 - yi] amino} tetrahydro-2H-pyran-2 -yl]ox } -3 ,4-dihydroxy-6- (rrydroxymethyl)tetrahydr0-2H-pyran-2-yl]oxy}-6-{hydroxymethyl)teto pyran-2 ,3.4-iriol), and voglibose ((I5,25' A 4S,55j-5-(ls3-dihydiOxypropan-2 - ykmino)-l-{¾ydroxymethyI)cyclohexane-l ,2,3,4-tetrol))
* Glucagon-iike peptide (GLP) analogs and agonists (e.g., exenatide and liraglutide) » Amyiin analogues (e.g., pramlintide acetate (Symlin))
» Dipeptidyl peptidase-4 (DPP-4) inhibitors (e.g., vildagliptin, (2.S)-l-{2-[(3- hydroxy-l-adamantyl)ainino]acetyl}pyrrolidine-2-carbonitrile and sitagliptin ((37 -3-amino-l -[9-(irifluoromethyl)-l J477,8 etra7abicyclo[4.3 ]nona-6,8-dien- 4-yl]-4-(2,4,5-trifluorophenyl)butan- l-one)), and
* Tbiazolidinedioiies (e.g., rosiglitazone, 5-((4-(2-(methyl-2-pyridinylamino) ethoxy)phenyl)methyl)- 2,4-thiazolidinedione, pioglitazorte (5-((4-(2-(5-ethyl-2- pyndmyi)etiioxy)pheiiyl)methy])",(+'-)- 2,4-thiazoiidinedione,) and troglitazone (5- (4-((6-hy(koxy-2,5,7 "teiramethyichroman-2-yl-methoxy)beBzyl)-2,4- tbiazolidinedione)).
[0053] The invention also comprises as another embodiment, a method for inducing increased GLP- 1 secretion in cell, in vitro, comprising contacting the cell with an inducing effective amount of a TGR5 agonist compound according to any one of the preceding embodiments.
| 54f The invention also comprises as another embodiment the use of an effective amount of a TGR5 agonist compound according to any one of the preceding embodiments for the preparation of a medicament for treating a metabolic disease in a subject in need of such treatment,
[0055] The invention also comprises as another embodiment, the use of an effective amount of a TGR.5 agonist compound according to any one of the preceding embodiments for the preparation of a medicament for treating obesity or type II diabetes in a subject in need of siich treatment.
[0056] The invention also comprises as another embodiment, the use of an effective amount of a TGR5 agonist compound according to any one of the preceding embodiments for the preparation of a medicament for treating hyperlipidemia in a subject in need of such treatment.
[0O57J The invention also comprises as another embodiment, the use of an effective amount of a TGR5 agonist compo und according to any one of the preceding embodiments for the preparation of a medicament for treating athersclerosis in a subject in need of such treatment.
{0058} The invention also comprises as another embodiment, the use of an effective amount of a TGR5 agonist compound according to any one of the preceding embodiments for the preparation of a medicament for lowering blood glucose in a subject in need of such treatment.
[0059] The invention also comprises as another embodiment, the use of an effective amount of a TGR5 agonist compound according to any one of the preceding embodiments for the preparation of a medicament for enhancing insulin secretion in a subject in need of such treatment.
10060] The invention also comprises as another embodiment, the use of an effective amount of a TGR5 agonist compound according to any one of the preceding embodiments for the preparation of a medicament for treating a disease associated with perturbed bile acid metabolism in a subject in need of such treatment.
10061] The invention also comprises as another embodiment, the use of an effective amount of a TGR5 agonist compound according to any one of the preceding embodiments and a second anti-diabetic drug for the preparation of a medicament for treating obesity or type II diabetes in a subject in need of such treatment
Pharmaceutical Formulations and Dosage Forms
[0062] 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, transdermal!}', intravaginally, mtravesically, 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. [0063] 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.
(0064] 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.
[0065] 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, friethanolarnine oleate, buty!alted hydroxytoluene, etc.
|0066| 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 nni 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.
(0067] 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 (propylenegiycol, 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.
[0068] 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.
(0069J 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, aiignates, 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 tnonostearate, 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.
[0070] 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 past 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. {0071] 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; solubi!izing agents and emulsifiers, as for example, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propyieneglycoi, 1,3- butyleneglycol, dimethylformamide; oils, in particular, cottonseed oil, groundnut oil, com germ oil, olive oil, castor oil and sesame oil, glycerol, tetrahydrofurfuryl alcohol, polyet yleaneglycols and fatty acid esters of sorbitan; or mixtures of these substances, and the like, to thereby form a solution or suspension.
{0072} Suspensions, in addition to the active compounds, can contain suspending agents, as for example, ethoxylated isosteatyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum rnetahydroxide, bentonite, agar-agar and tragacanth, or mixtures of these substances, and the like.
[0073] 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, polyethyienegiycol 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.
0074] 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 propellanis as can be required. Ophthalmic formulations, eye ointments, powders, and solutions are also contemplated for the compounds in this disclosure.
[0075] Compressed gases can be used to disperse a compound of this disclosure in aerosol form. Inert gases suitable for this puipose are nitrogen, carbon dioxide, etc.
[0076] Generally, depending on the intended mode of administration, the pharmaceutically acceptable compositions will contain about 1% to about 99% by weight of a corripound(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.
[00771 Actual methods of preparing such dosage forms are know n, 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.
007S] 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, drag 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 or. a number of factors inc!udmg 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.
[0079] 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), Cheniotherapeutic agents that can be useful for administration in combination with compounds of Formula I in treating cancer include alkylating agents, platinum containing agents.
|0Θ80] 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 ageiit(s) when a combination formulation is inappropriate.
[0081] The compounds described herein, as well as their pharmaceutically acceptable salts or other derivatives thereof, can exist in isotopically-labeled form, in which one or more atoms of the compounds are replaced by an atom having the same atomic number but an atomic mass different from the atomic mass usually found in nature. Examples of isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulfur, fluorine and chloride, such as 2H (deuterium), 3H (tritium), !3C, ,4C, ! 5N, !80, , "O, 51P, :52P, 35S, !8F and 36CL respectively. Isotopicalty labeled compounds of the present invention, as well as pharmaceutically acceptable salts, esters, prodrugs, solvates, hydrates or other derivatives thereof, generally can be prepared by carrying out the procedures disclosed in the Schemes and/or in the Examples and Preparations below, by substituting a readily available isotopically labeled reagent for a non- isotopically labeled reagent.
[0082] In the compounds of the invention, unless otherwise stated, any atom not specifically designated as a particular isotope is meant to represent any stable isotope of that atom at its natural abundance. When a position is designated as "H" or "hydrogen", the position is to be understood to have hydrogen at its natural abundance isoiopic composition, with the understanding that some variation of natural isotopic abundance occurs in a synthesized compound depending upon the origin of chemical materials used in the synthesis. When a particular position is designated as "D" or "deuterium", it is to be understood that the abundance of deuterium at that position is substantially greater than the natural abundance of deuterium, which is 0.015%, and typically has at least 50% deuterium incorporation at that position.
[0083] The methods disclosed herein also include methods of treating diseases by administering deuterated compounds of the invention or other isotopically-iabeled. compounds of the invention alone or as pharmaceutical compositions. In some of these situations, substitution of hydrogen atoms with heavier isotopes such as deuterium can afford certain therapeutic advantages resulting from greater metabolic stability (for example, increased in vivo half-life or reduced dosage requirements).
[0084] Moreover, certain isotopicaily-labeled compounds, for example those into which radioactive isotopes such as 3H and 14C are incorporated, are useful in drug and or substrate tissue distribution assays such as positron emission tomgrapfay (PET), Tritiated, ii) and carbon-14 (! C) isotopes are useful for these embodiments because of their detectability.
.Definitions
10085] 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-Cealkoxycarbonyloxy and -OC(0)OC C6aikyl indicate the same functionality. Also, for instance, when variable X of formual I(Q) is defined as =N- or =C(R4)-, the bonds are only to indicate attachment points and the bonds are not meant to add additional bonds to the parent structure. So, for instance, when variable X of formula T(Q) is defined as =N-, this would mean the same thing as X being defined as N.
|(M)86| Certain variables used herein are indicated as divalent linking moieties, for example, L° is a divalent moiety linking RDl to the parent structure. For such divalent variables, particular members defining LD may be written, for example, in the form -X-Y- or -Y-X-. When certain groups, such as aikyl groups, are part of a linker, these groups are also divalent moieties.
[0087} "Administration" and variants thereof (e.g., "administering" a compound) in reference to a compound of the invention means introducing the compound or a prodrug of the compound into the system of the animal in need of treatment. When a compound of the invention or prodrag 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.
[0088] "Alkoxy" means the group -OR wherein R is aikyl, as defined herein. Representative examples include methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, 4-methylhexyloxy, 4-methylheptyloxy, 4,7-dimethyloctyloxy, and the like.
[0089J "Alkoxycarbonyl" means an alkoxy group, as defined herein, appended to a parent moiety via a carbonyl group (i.e., a group of the form, -C(O)OR0, wherein R° is aikyl, as defined herein). Examples of alkoxycarbonyl groups include, but are not limited to, methoxycarbonyl, ethoxyearbonyl, isopropoxycarbonyl, t-butoxycarbonyl, and n- hexylcarbonyl.
100 0J "Aikyl" means a linear or branched hydrocarbon group having from 1 to 10 carbon atoms unless otherwise defined. Representative examples for aikyl groups include methyl, ethyl, propyl, butyl, pentyi, hexyl, 4-methylhexyl, 4-methylheptyl, 4,7-dimethyloctyl, and the like. -(C C^alkyl, which means exactly the same as (Chalk 1, includes groups selected from methyl, ethyl, propyl, isopropyl, butyl, sec -butyl,
Figure imgf000034_0001
- isobut l, and t ert -butyl.
[00 1J "Alkylamino" means an aikyl group, as defined herein, appended to a parent moiety through an -NH- group (i.e., substituents of the form -N(H)R°, where R° is an aikyl group). Examples of alkylamino groups include, but are not limited to, methylamino, ethylamino, isopropyiamino, hexylamino, and the like. [0092] "Alkylammocarbonyl" means an alkyiarnino group, as defined herein, appended to a parent moiety via a carbonyl group (i.e., a group of the form, ~C(0)N(H)R°, wherein R° is alkyi, as defined herein). Examples of alkylaminocarbonyl groups include, but are not limited to, methylarninocarbonyl, ethylaminocarbonyl, isopropylaminocarbonyl, t- butylaminocarbonyl, and n-hexylaminocarbonyl.
0093] "Amino" means a -N¾ group.
|0094] "Aryl" means a monovalent, monocyclic, or poiycychc radical having 6 to 14 ring carbon atoms. The monocyclic aryl radical is aromatic and whereas the poiycychc 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 one or two 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, and the like.
10095] "Carbonyl" means a --C(Q)- group.
[0096] "Cycioalkyl" means a monocyclic or polycyclic hydrocarbon radical having 3 to 13 carbon ring atoms. The cycioalkyl radical may be saturated or partially unsaturated, but cannot contain an aromatic ring. The cycioalkyl radical includes fused, bridged and spiro ring systems. Examples of such radicals include cyclopropyl, cyclobutyl, cyctopentyl and cyclohexyL
[0097] "Dialkylamino" means two alkyl groups, each independently as defined herein, appended to a parent moiety through a nitrogen atom (i.e., substituents of the form -N{R°)?., where each R° is an alkyl group). Examples of dialkylamino groups include, but are not limited to N,N-dimethylamrno, N,N-diethylamino, N-isopropyl- -methylamino, N-ethyl-N- hexylarnino, arid the like.
]0098] "Di(Ci-C alkyd)aminocarbonyl" means a dialkylamino group, as defined herein, appended to a parent moiety via a carbonyl group (i.e., a group of the form, -C(0)N(.R°)2, wherein each R" is alkyl, as defined herein). Examples of dialkylamino groups include, but. are not limited to Ν,Ν-dimethylaminocarbonyl, Ν,Ν-diethyiaminocarbonyl, N-isopropyi-N- methylaminocarbonyl, N-ethyi-N-hexylaminocarbonyl, and the like.
[0099] "Gem-eyclopropyl" means any alkyl group that has a carbon substituted in such a way to form the following structure: ¾ [01003 "Fused ring system" and "fused ring" refer to a poiycyclic ring system that contains bridged or fused rings; that is, where two rings have more than one shared atom in their ring structures. In this application, fused -poly cyclics and fused ring systems are not necessarily all aromatic ring systems. Typically, but not necessarily, fused-polycyclics share a vicinal set of atoms, for example naphthalene or 1 ,2,3,4-tetxahydro-naphthalene. A spiro ring system is not a fused-polycyclic by this definition, but fused poiycyclic ring systems of the invention may themselves have spiro rings attached thereto via a single ring atom of the fused-polycyclic. Irs 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 and may be optionally substituted with one or more groups. It should additionally be noted that saturated carbons of such fused groups (i.e., saturated ring structures) can contain two substitution groups.
[0101] "Halo" and "halogen" mean a fiuoro, chloro, bromo or iodo group.
[0102] "Haloalkyl" means an atkyi radical, as defined herein, substituted with one or more halo atoms. For example, halo-substituted (Chalky! includes trifluoromethyl, 2,2-dichioroethyl, 2,2,2-rrifluoroethyl, perchloroethyl, 2-bromopropyl, and the like.
[0103] "Fieteroaryl" means a monovalent monocyclic or poiycyclic 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 -0-, -S(0)n- (n is 0. 1, or 2), -N-, -N(R*K and the remaining ring atoms are carbon atoms, where R* is hydrogen, alky], hydroxy, alkoxy, -C(O)R0 or -S(Q)-R°, where R° is alkyl. The monocyclic heteroaryl radical is aromatic and whereas the poiycyclic heteroaryl radical may be partially saturated, at least one of the rings comprising a poiycyclic radical is aromatic. The poiycyclic heteoaryl radical includes fused, bridged and spiro ring systems. Any one or two ring carbon atoms of any nonaromatic rings comprising a poiycyclic 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. In particular, when the point of valency is located on the nitrogen, then R is absent. More specifically, the term heteroaryl includes, but is not limited to, 1 ,2,4-triazolyl, 1,3,5-triazoly , phthalimidyl, pyridinyl, pyrroiyl, imidazolyl, thienyl, furanyl, indolyl, 2,3-dihydro- lH-indolyl (including, for example, 2,3-dihydro- lH-indol-2-yl, 2,3-dihydro- lH-indoI-5-yl, and the like), isoindolyl, indolinyl, isoindolinyl, benzimidazolyl, benzodioxol-4-yl, benzofuranyl, cirmoiinyl, indolizinyl, naphthyridin-3-yl, phthalazin-3-yl, phthalazin-4-yl, pteridinyl, purinyl, quinazolinyl, quinoxalmyl, tetrazoyl, pyrazoiyi, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, isooxazoly!, oxadiazolyl, benzoxazolyl, q inolinyl, isoquinolinyl, tetrahy troisoqumoiinyl (including, for example, tetrahydroisoquinolin-4-yl, tetrabydroisoquinolm-6-yi, and the like), 2,3,3a,7a-tetrahydro-lH-isoindolyl, pyixolo[3,2-c]pyridinyl (including, for example, pyrrolo[3,2-c]pyridin-2-yl, pyrrolo[3,2-c]pyridin~7-yl, and the like), benzopyranyl, thiazolyl, isothiazolyi, thiadiazolyl, benzothiazolyl, bsnzothienyl, and fee N-oxide derivatives thereof.
[0104] "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 -0-, -S(0)n- (n is 0, 1, or 2), ■-N- and -NCR3)- (where Ry is hydrogen, alkyl, hydroxy, alkoxy, -C(Q)R° or -S(O)2 °: where R° is alkyl, as defined herein), and the remaining ring atoms are carbon. The heterocycioalkyl radical may be saturated or partially unsaturated, but cannot contain an aromatic ring. The heteocycloalkyl radical includes fused, bridged and spiio ring systems. Any one or two ring carbon atoms independently may be replaced by a ~C(Q)~, -C(S)-, or -C(=NH)- group. Unless otherwise stated, the valency of the group may be located on any atom of any ring within the radical, valency rules permitting. In particular, when the point of valency is located on a nitrogen atom, Ry is absent. More specifically the term heterocycioalkyl includes, but is not limited to, azeiidinyl, pyrrolidinyl, 2 -oxopyrrolidinyl, 2>S-dihydro-lHpyrrolyl, piperidinyL 4-piperidonyl, morpholitryl, piperazinyl, 2-oxopiperazinyl, tetrabydropyranyl, 2-oxopiperidinyl, tiiiomorpholinyi, ihiamorpholiny!, perhydroazepinyl, pyrazolidinyl, iniidazolinyl, imidazolidinyl, dihydropyridinyl, tetrahydropyridinyl, oxazolinyi, oxazolidinyl, isoxazolidmyl, thiazolinyl, thiazolidinyl, quinuclidinyl, isothiazoiidmyl, octahydroindolyi, octahydroisoindolyl, decahydroisoqutetolyl, letrahydrofuryl,
1 ,4-dioxa-8-azaspiro[4.53decan-8-yl and tetrahydropyranyl, and the Λ-oxide derivatives thereof.
[0105] "Heterocyclyl alkyl" means a heterocyclyl group appended to a parent moiety via an alkyl group, as defined herein. Examples of heterocyclylalkyl groups include, but are not limited to,
Figure imgf000037_0001
2-(moipholin -4-yl)ethyi, 2- (morpholin-2-yl)ethyl, morpholin-3-ylmethyl, 2-(morphoJin-3-yl)ethyl, piperazin-1 -ylmethyl, 2-(piperazin-l -yl)ethyl, piperidin-1 -ylmethyl, 2-(piperidin-l -ylieihyi, piperidin-2 -ylmethyl, 2--(pipendm-2-yl)ethyl, piperidin-4-yhnethyl, 2~(piperidk-4-yl)ethyl, pyrrolidin- 1 -ylmethyl , 2-Cpyrrolidin- 1 -yl)ethyL pyrrolidin-2 -ylmethyl, 2-(pyrrolidin-2-yl)ethyl.
(0106] "Hydroxyalkyl" means an alkyl group, as defined herein, substituted with at least one, for example one, two, or three, hydroxy group(s), provided mat if two hydroxy groups are present they are not both on the same carbon atom. Representative examples include, but are not limited to, hydroxymethyt, 2-hydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl, 1 -(hydroxymethyl)-2~methylbutyl, 2-hydroxy butyl, 3-hydroxybutyl, 4-hy droxybutyl,
2.3- dihydroxypropyl, 1 -(hy droxymethyl)--2-hydroxyethyl, 2,3-dihydroxybutyl,
3.4- dihydroxybutyl, 2-(hydroxymethyl)-3-hydroxypropyl, 2-hydroxyethyfene, 2,3-dihydroxypropyl, 1 -(hydroxymethyl)-2-hydroxyethyl, and the like.
0i07] 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 ordmaiy skill in the art would imderstand 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. Unless otherwise specified in this specification, when a variable is said to optionally substituted or substituted with a substituent(s), this is to be understood that this substitution occurs by replacing a hydrogen thai is covalently bound to the variable with one these substituent(s). This meaning shall apply to all variables that are stated to be substituted or optionally substituted in the specification. For instance, when it. is stated that variable E° can be optionally substituted with R o, this means that this substitution, when it occurs, takes place by replacing a hydrogen that is covalently bound to Rc with R'"10. Other non-limiting examples of variables that are described in certain instances in the specification as being optionally substituted or substituted with various substituents include, but are not limited to, RD1, A groups, B groups, and R"\
0108] Polyethylene glycol (PEG) are polymers of ethylene oxide. Polyethylene glycol refers to the polymer with molecular weight less than 50,000. A polymer is made by joining molecules of ethylene oxide and water together in a repeating pattern. Polyethylene glycol has the following structure: -(CH2-CH2-0)n-.
J0109] "Saturated bridged ring system" refers to a bicyclic or polycyclic ring system that is not aromatic. 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). For example, hexahydro-nsro[3,2-i>]furan, 2,3,3a>4,7>7a-hexahydrc-lH-indene, 7-aza-bic clo[2.2.1 ]heptane and l,2,3,4,4a,5,8,8a-octahydro-naphthalene are all included in the class "saturated bridged ring system."
[Θ118] "Spiro ring" refers to a ring originating from a particular annular carbon of another ring. For example, as depicted below:
Figure imgf000039_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-azaspj:ro[4.5]decan~8-yi.
[0111J "Isomers" means compounds having identical molecular formulae but differing in the nature or sequence of bonding of their atoms or in the arrangement of their atoms in space, isomers that differ in the arrangement of their atoms in space are termed "stereoisomers." Stereoisomers that are not mirror images of one another are termed "diastereomers" and stereoisomers that are nonsuperimposable mirror images are termed "enantiomers" or sometimes "optical isomers." A carbon atom bonded to four nonidentical substituents is termed a "cbirai center." A compound with one chiral center has two enantiomeric forms of opposite chirality is termed a "racemic mixture." A compound that has more than one chiral center has 2r'"! enantiomeric pairs, where n is the number of chiral centers. Compounds with more than one chiral center may exist as ether an individual diastereomer or as a mixture of diastereomers, termed a "diastereomeric mixture." When one chiral center is present a stereoisomer may be characterized by the absolute configuration of that chiral center. Absolute configuration refers to the arrangement in space of the substituents attached to the chiral center. Enantiorners are characterized by the absolute configuration of their chiral centers and described by the R- and S-sequencing rules of Cahn, Ingoid and Prelog. Conventions for stereochemical nomenclature, methods for the determination of stereochemistry and the separation of stereoisomers are well known in the art (e.g. , see "Advanced Organic Chemistry," 3rd edition, March, Jerry, John Wiley & Sons, New York, 1 985). The names and illustration used in this application to describe compounds of the invention, unless indicated otherwise, are meant to be encompassed all possible stereoisomers and any mixture, racemic or otherwise, thereof.
(01121 The present invention also includes N-oxide derivatives of the compounds of the invention. N-oxide derivatives mean derivatives of compounds of the invention in which nitrogens are in an oxidized state (i.e., N-->0), e.g., pyridine N-ox de, and which possess the desired pharmacological activity. [0113] "Metabolite" refers to the break-down or end product of a compound or its salt produced by metabolism or biotransformation in the animal or human body; for example, biotransformation to a more polar molecule such as by oxidation, reduction, or hydrolysis, or to a conjugate (see Goodman and Gilman, "The Pharmacological Basis of Therapeutics" 8.sup.th Ed., Pergamon Press, gilman et al. (eds), 1990 for a discussion of biotransformation). As used herein, the metabolite of a compound of the invention or its salt may be the biologicaliy active fonn of the compound in the body. In one example, a prodrug may be used such that the biologically active form, a metabolite, is released in vivo. In another example, a biologicaliy active metabolite is discovered serendipitously, that is, no prodrug design per se was undertaken. An assay for activity of a metabolite of a compound of the present invention is known to one of skill in the art in light of the present disclosure.
[0114] "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.
[01 IS] 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* ed., Mack Publishing Company, Easton, PA, 1985, or S. M. Berge, et al, "Pharmaceutical Salts," J. Pharm. Sci., 1977;66: 1-19. It is also understood that the compound can have one or more pharmaceutically acceptable salts associated with it.
[0116] 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, glycoiic acid, pyruvic acid, lactic acid, oxalic acid, maleic acid, maionic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, 3-(4-hydroxybenzoyl)benzoic acid, mandeiic acid, methanesulfonic acid, ethanesulfonic acid, 1 ,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesuifonic 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 -pheny {propionic acid, trimethyiacetic acid, tertiary butylacetic acid, lauryi sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, p-toluenesulfonic acid, salicylic acid and ie like.
[0117] 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 isopropylaniine, trimethyiamine, diethylamine, triethylamine, tripropylamine, ethanolamine, 2-dimemylaminoethanol, 2-diethylamiooethanol, dicyclohexylarnine, lysine, arginine, histidine, caffeine, procaine, hydrabaraine, choline, betaine, ethylenediamine, glucosamine, memylglucamine, theobromine, purines, piperazine, piperidine, N-ethylpiperidine, tromethamine, N-methylglucamine, polyamine resins, and the like. Exemplary organic bases are isopropyiamine, diethylamine, ethanolamine, trimethyiamine, dicyclohexylarnine, choline, and caffeine.
[0118] "Prodrug" refers to compounds that are transformed (typically rapidly) in vivo to yield the parent compound of the above formulae, for example, by hydrolysis in blood. Aommon examples include, but are not limited to, ester and amide forms of a compound having an active form bearing a carboxylic acid moiety. Examples of pharmaceutically acceptable esters of the compounds of this invention include, but are not limited to, alkyl esters (for exampie with between about one and about six carbons) the alkyl group is a straight or branched chain. Acceptable esters also include cycloalkyl esters and arylalkyl esters such as, but not limited to benzyl. Examples of pharmaceutically acceptable amides of the compounds of this invention include, but are not limited to, primary amides and secondary and tertiary alkyl amides (for example with between about one and about six carbons). Amides and esters of the compounds of the present invention may be prepared according to conventional methods. A thorough discussion of prodrugs is provided in T. Higucht and V. Stella, '"Pro-drugs as Novel Delivery Systems," Vol 14 of the A.C.S. Symposium Series, and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Perganson Press, 1987, both of which are incorporated herein by reference for all purposes. [0119] "Therapeutically 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 a "therapeutically 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 seventy of the disease for which the therapeutic effect is sought. The therapeutically effective amount for a given circumstance can be determined without undue experimentation.
[0120] "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 (hi) 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. (0121] The compounds disclosed herein and their pharmaceutically acceptable salts can exist as single stereoisomers, racemates, and as mixtures of enantiomers and diastereomers. The compounds disclosed herein can also exist as geometric isomers. All such single stereoisomers, racemates and mixtures thereof, and geometric isomers are intended to be within the scope of the compounds disclosed herein.
[0122] It is assumed Chat when considering generic descriptions of compounds of the disclosed herein for the purpose of constructing a compound, such construction results in the creation of a stable structure. That is, one of ordinary skill in the art would recognize that theoretically some constructs which would not normally be considered as stable compounds (that is, sterically practical and/or synthetically feasible, supra).
[0123] Methods for the preparation and/or separation and isolation of single stereoisomers from racemic mixtures or non-racemic mixtures of stereoisomers are well known in the art. For example, optically active (R)- and (S)- isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. Enantioroers (R- and S-isomers) can be resol ved by methods known to one of ordinary skill in the art, for example by: formation of diastereoisomeric salts or complexes which can be separated, for example, by crystallization; via formation of diastereoisomeric derivatives which can be separated, for example, by crystallization, selective reaction of one enantiomer with an enantiomer-specific reagent, for example enzymatic oxidation or reduction, followed by separation of the modified and unmodified enantiomers; or gas-liquid or liquid chromatography in a chiral environment, for example on a chiral support, such as silica with a bound chiral ligand or in the presence of a chirai solvent. It will be appreciated thai where a desired enantiomer is converted into another chemical entity by one of the separation procedures described above, a further step can be required to liberate the desired enantiomeric form. Alternatively, specific enantiomer can be synthesized by asymmetric synthesis using optically active reagents, substrates, catalysts or solvents or by converting on enantiomer to the other by asymmetric transformation. For a mixture of enantiomers, enriched in a particular enantiomer, the major component enantiomer can be further enriched (with concomitant loss in yield) by recrystallization.
|0O4| In addition, the compounds of this disclosure can exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanoi, and the like. In general, the solvated forms are considered equivalent to the unsolvated forms for the purposes of the compounds of this disclosure.
[0125] In addition, it is intended that the present disclosure cover compounds made either using standard organic synthetic techniques, including combinatorial chemistry or by biological methods, such as bacterial digestion, metabolism, enzymatic conversion, and the like.
|01261 The examples and scheme below depict the general synthetic procedure for the compounds disclosed herein. Synthesis of the compounds of Formulae I(Q) disclosed herein, and embodiments thereof, are not limited by these examples and schemes. One skilled in the art will know that other procedures can be used to synthesize the compounds of Formulae I(Q) disclosed herein, and that the procedures described in the examples and schemes is only one such procedure. In the descriptions below, one of ordinary skill in the art would recognize that specific reaction conditions, added reagents, solvents, and reaction temperatures can be modified for the synthesis of specific compounds that fall within the scope of this disclosure. All intermediate compounds described below, for which there is no descriptor! of how to synthesize such intermediates within these examples he!ow, are commercially available compounds unless otherwise specified.
[0127J 1» all of the synthetic schemes described below (Schemes 1-27), the portion of the molecule that corresponds to Rc of the compound of formula I(Q) is QA or is substituted with one or two QA groups, wherein c is substituted with QA by replacing a hydrogen that is covaientty bonded to carbon or nitrogen. One skilled in the art would understand how to add QA to Rc by Schemes 28-31 and by methods known to the skilled artisan.
[0128] In the following general methods, X, LD, Q'\ R1, R2, R4, R8, RA,°, RDt, RDi0, RD1 Κοηύ, and ¾ are as previously defined for a compound of formula I(Q), and embodiments thereof, unless otherwise stated. The following abbreviations and acronyms are used herein.
Ei:3N triethylamine
or HO Ac
azobisisobutyronitrile g!iicagoH-iike peptide-1 cAMP cyclic adenosine Hex
CD-FBS charcoal-dextran-treated fetal HATU 0-(7-Azabenzotriazol-l-
/me serum Ν,Ν,Ν', '- tetramethyluroniun}
irophc
carboxymethyl cellulose HMTA hexarneihylenetetramiiie cone. concentrated IBMX isobiiiylmethylxasiihiiie dichloromethane KOtBu potassium tert-b toxide
DIBAH diisobutylatamiisiiffl hydride mCPBA m-chloroperoxybenzoic ί dusopropylethylai ne MeCN acetonitrile
DMEM Dislbecco's modified essential MeMgBr methylmagnesium bromide
N^-dimethylformamide
-bromosuccimmide
OAc acetate dipeptidyl peptidase IV pyridmium chlorochromate ethylenediaminetetraacetic acid polyethylene glycol Et20 protecting groap
H ethanol STC-1 stanmocatcin i
FAF-BSA Fatty acid-free bovine serum TFA trifluoroacetlc
FBS fetal bovine serum
[0129} When LD represents -SCFL- and X represents =C(H}-, then compounds of formula (iA) ma be prepared as depicted in Scheme 1 .
Figure imgf000045_0001
Figure imgf000045_0002
(Vli!) (l )
Scheme 1
[0130] Compounds of formula (II) are commercially available or may be prepared from known compounds using standard methodologies as exemplified in the preparations below.
[0131] Step (a): An aldehyde of formula (Hi) may be prepared by reaction of nitrile (II) with diisobutylalaminum hydride in a suitable solvent, such as THF.
[0132] Step (h): Formation of carbinol (IV) may be achieved by treatment of aldehyde (III) with methylmagnesium bromide in a suitable solvent, such as diethyl ether or THF.
[0133] Step (c): Conversion of carbinol (IV) to ketone (V) may occur under standard conditions, such as the Swern oxidation— known to one trained in the art of chemistry.
[0134] Step (d): Bronioketone (VI) may be prepared by bromination of ketone (V) under typical conditions, such as with tetrabutylammonium tribromide in 1 :2 mixture of MeOH- DCM.
[0135] Step (e): Reaction of bronioketone (VI) with sodium azide in a suitable solvent, such as DMF, followed by reduction of the resulting azido-ketone under standard conditions, such as with zinc dust and hydrochloric acid in THF, may afford amino-ketone hydrochloride (Vil).
[0136] Step (f): Isothiocyanate R}NCS may react with amino-ketone hydrochloride (VII) in a suitable solvent, such as DCM or toluene, and in the presence of a base, such as triethy!amine, at elevated temperature to yield the corresponding thiourea, which may condense upon treatment with HOAc at elevated temperature to give a compound of formula (VIII).
(0137] Step (g): Aikylaiion of imidazol-2-thione (VIII) with an electrophile
Figure imgf000046_0001
in a suitable solvent, such as acetone or MeCN, and in the presence of a base, such as potassium carbonate, may afford a compound of formula (1A).
[Θ138] Compounds of formula (iB) may be prepared as shown in Scheme 2.
Figure imgf000046_0002
Scheme 2
[0139] Step (h): Reaction of thioether (iA) with a suitable oxidant, such as mCPBA. (2.5- 3.0 eq), in a suitable solvent such as DCM may yield a compound of formula (ϊΒ).
[0140] Compounds of formula (Ic) may be synthesized as shown in Scheme 3.
Figure imgf000046_0003
Scheme 3
[0141] Step (i): Thione (IA) may be converted to the corresponding sulfonyl chloride (IX) under standard conditions, such as adding NaOCl (3 eq) to thione (1A) in a 1 : 1 mixture of DCM and I N HC1 at reduced temperature, preferably below 0 °C.
(0142] Step (j): Compounds of formula (!'") may be prepared by reaction of amine HN(RY)RD! with sulfonyl chloride (IX) in a suitable solvent, such as DCM, and in the presence of a base, such as triethylamme.
[0143] Compounds of formula (ID) may be synthesized as depicted in Scheme 4.
Figure imgf000047_0001
(P)
Scheme 4
[0144] Step (k): Thione (VMI) may undergo desulfurization under standard conditions, such as with H2O2 in a mixture of HOAc-DCM, to afford imidazole (X).
| 14S] Step (i): Reaction of imidazole (X) with butyllithium in a suitable solvent (e.g., THF) at reduced temperature, preferably at -78 °C for 30-40 minutes, may yield the corresponding organolithiuni, which may react with a suitable electrophile (e.g., isocyanate or carbamoyl chloride) at the same temperature to afford a compound of formula (1°).
[01461 Compounds of formulae (IE) and (IF) may be prepared as shown in Scheme 5.
Figure imgf000047_0002
Figure imgf000047_0003
(lE)
Scheme 5
[0147] Step (rn): Imidazole (X) may be converted to the corresponding organolithium, as described previously, and then treated with DMF, preferably at -78 °C for 30-49 minutes, to yield aldehyde (Xi).
(0148] Step (n): Compounds of formula (IE) may be prepared by reaction of aldehyde (XI) with a phosphorus ylide under Wtttig or Homer-Emmons conditions—both known to one skilled in the art of chemistry.
(0149] Step (o): Compounds of formula (IF) may be prepared by catalytic hydrogenolysis of alkene (1E) under standard conditions, such as in MeOH under 50-60 psi of hydrogen and over Pt(¾ (10-20 mole ). [0150J Compounds of formula (I1*), wherein Y is chosen from NR O or S, may be prepared as depicted in Scheme 6.
Figure imgf000048_0001
.) Step (p): Reduction of aldehyde (Xt) using standard conditions, such as NaBH in EtOH at ambient temperature, may afford the corresponding carbinoi (XII).
|0152] Step (q): Compounds of formula (IG) may be prepared from carbinoi (XII) and a suitable nucleophile HYR°!, such as a phenol or thiophenol wherein Y represents O or S, respectively, and R1"'1 is ary!, under Mitsunobu conditions— known to one skilled in the art. Alternatively carbinoi (XII) may be converted to the corresponding chloride, for example, by treatment with thionyl chloride (2 eq) in chloroform, followed by reaction with a suitable nucleophile HYRD l in MeCN (or acetone) and in the presence of a base (e.g., K2CO3) to yield compounds of formula (IG).
[0153] Compounds of formula (iH), wherein ¾ is chosen from Br, Ci or F, may be prepared as shown in Scheme 7.
Figure imgf000048_0002
(iA)
[0154] Step (r): Compounds of the formula (IH) may be prepared from imidazole (iA) by treatment with a suitable halogen source such as, for example, N-bromosojccinimide in DCM. N-chlorosuccinimide and Selectfluor™ in a suitable solvent, such as DCM or MeCN, may be used to generate the corresponding chloro- and fluoro-substituted compounds (IH), respectively.
[0155] When LD represents -SCH2- and X is N, then compounds of formula (?) may be synthesized as depicted in Scheme 8.
Figure imgf000049_0001
Scheme 8
[9156] Compounds of formula (XIII) are commercially available or may be prepared from known compounds using standard methodologies.
|0157] Step (s): Ester (XIII), wherein R represents alkyl (e.g., methyl), may react with hydrazine in a suitable solvent, such as MeOH. at elevated temperature and in a sealed vessel to yield hydrazide (XIV). Alternatively acid (XIII), wherein R is H, may be converted to its hydrazide (XIV) under standard conditions -known to one skilled in the art.
[0158] Step (t): Hydrazide (XIV) may react with isothiocyanate R'NCS in a suitable solvent, such as EtOH, at elevated temperature, preferably at reflux, to generate thiourea
(XV) .
[0159] Step (u): Reaction of thiourea (XV) under basic conditions, such as in 5-10% aqueous NaOH at elevated temperature, preferably at reflux, may condense to yield thiol
(XVI) .
[0160] Next compounds of formula (i'?) may be prepared from thiol (XVI) under conditions previously described in step (g).
(0I61J Compounds of formula (1K) may be prepared as depicted in Scheme 9.
Figure imgf000049_0002
Scheme 9
[0162] Step (v): Reaction of thioether (IJ) with a suitable oxidant, such as mCPBA (1-1.1 equiv) in DCM, may yield compounds of rormula (I ).
[0163] Compounds of formula (IL), wherein R8 is H, may be prepared as depicted in Scheme 10.
Figure imgf000050_0001
Vil) (XVII!)
Figure imgf000050_0002
Scheme 10
Under conditions previously described in step (k), thiol (XVI) may undergo de- sulfurization to afford triazole (XVII).
[8165] Step (w): Hydroxymethylation of triazole (XVII) may proceed under standard conditions, such as with paraformaldehyde in toluene heated at reflux, to afford the corresponding hydroxymethyltnazole. which may undergo oxidation upon treatment with a suitable oxidant, such as Μη(¼, in THF to yield the corresponding aldehyde (XVIIi).
[8166] Step (x): Reaction of aldehyde (XVIII) with amine HN(RY)RD1 under typical reductive animation conditions, such as with NaB(OAc)3H in a suitable solvent, may give compounds of formula (i ').
Figure imgf000050_0003
Scheme 1 1
1 167J Step (aw): Amine (IA ) may undergo diazotization under typical conditions, such as with aqueous sodium nitrite, and then may be converted to the corresponding sulfonyl chloride (XXIX) upon reaction with a mixture of copper (II) chloride, sulfur dioxide. HC1 and HO Ac.
[0168] Step (ax): Sulfonyl chloride (XXIX) may react with an amine HN(R l l)RD155 in the presence of a base, such as K2CO3, to afford compounds of formula (IAG). in addition, ammonia may react with sulfonyl chloride (XXIX) to yield a sulfonamide (IAG), wherein both R01 1 are H. 101691 Co n in Scheme 12.
Figure imgf000051_0001
(X) (XXV)
Figure imgf000051_0002
Scheme 12
[§170] Step (af); Imidazole (X) may be converted to the corresponding organolithium, as described previously, and then treated with tosyi azide in a suitable solvent (e.g., THF), preferably at -78 °C for 30 minutes, to yield azide (XXV).
| 171] Step (ag)i Azide (XXV) may undergo catalytic hydrogenatiorj under standard conditions, such as with a suitable palladium catalyst, preferably Lindlar catalyst, under hydrogen at ambient pressure, to give amine (XXVI).
[0172] Step (ah): Reaction of amine (XXV ) with an acid chloride in a suitable solvent (e.g., DCM) and with a base (e.g., pyridine) may afford compounds of formula (Ip).
[0173] Compounds of formula (IQ), for example, wherein R4 is chosen from aryi or heteroar l, may be prepared as shown in Scheme 13.
Figure imgf000051_0003
Scheme 13
[0174] Step (r): Under conditions previously described in step (r), imidazole (XXVII) may be brominated to give bromoimidazole (XXVill).
[0175J Step (ai): Compounds of the formula (I*3) may be prepared from bromoimidazole (XXVHI) using standard cross-coupling conditions, such as with suitable boronic acids under Suzuki conditions known to one skilled in the art of chemistry.
[1)176] Compounds of formula (IR) may be prepared as depicted in Scheme 14,
SO
Figure imgf000052_0001
Scheme 14
[0177] Step (aj): Reaction of aldehyde (Xi) and a suitable amine lfN'(RY)RD1 under standard reductive amination conditions, such as with toluene sulfonic acid followed by sodium borohydride in EtOH at ambient temperature, may afford compounds of formula (IR).
[0178] Compounds of formula (Is) may be prepared as depicted in Scheme 15.
Figure imgf000052_0002
Scheme 15
[0179] Step (ak): Aikyiation of imidazol-2-thione (VH1) with an electrophi!e RD1CH2Br, wherein RJ1 is a benzenesulfonatnide, in a suitable solvent (e.g., acetone) and with a base (e.g., potassium carbonate) may afford compounds of formula (Is).
[0180] Compounds of formula (IT) may be. prepared as depicted in Scheme 16.
Figure imgf000052_0003
Scheme 16
Step (al): Reaction of sulfonamide (I^) with a suitable isocyanate and Lewis acid (e.g., aluminum trichloride) in a solvent such as toluene, preferably at 80 °C for over 12 hours, may yield compounds of formula (IT).
[0182] Compounds of formula (I1' - 1) may be prepared as depicted in Scheme 17
Figure imgf000053_0001
[6183] Step (am): Alkylatio of imidazol-2-thione (VIII) with an electrophile R Ci¾Br. wherein RD) is a benzoate ester, ;rt a suitable solvent (e.g., acetone) and with a base (e.g., potassium carbonate) may afford compounds of formula (lv),
\{)ΙΗ4] Step (an): Hydrolysis of ester (Iu) may proceed under standard conditions, e.g., NaOH in aqueous methanol, to afford compounds of formula (Iv).
[8185] Step (ao): Conversion of acid (iv) to compounds of formula (Iw) may occur under standard peptide coupling conditions, e.g., upon addition of an amine HN(Rt,u)RDl lD and coupling agent HATU in a suitable solvent, such as DCM or DMF,
[0186] Compounds of formula (Ix - IY) may be prepared as depicted in Scheme 18.
Figure imgf000053_0002
Scheme 18
[0187| Under conditions previously described in step (ao), acid (Iv) may be treated with a suitably protected amino ester (e.g.. Alanine methyl ester) and HATU in DCM to afford compounds of formula (Iv).
[0188] Step (ap): Hydrolysis of ester (Ix) may proceed under standard conditions, e.g..
y
LiOH in a THF -water mixture, to afford compounds ot lormula (I ).
[0189] Compounds of formula (.Γ,-' - ΙΑΛ) may be synthesized as shown in Scheme 19,
Figure imgf000054_0001
Scheme 19
[0190J Under conditions previously described in step (ao), acid (Iv) may be treated with a suitably protected amino ester, such as one derived from Ornithine (wherein n - 2). and HATU in DCM to afford compounds of formula (Iz).
[0191] Step (aq): Hydrolysis of ester (ix) and deprotection of the amine moiety may proceed under standard conditions, e.g., HCl in dioxane (wherein R = tert-butyl and PG = BOC), to afford compounds of formula (IAA).
Figure imgf000054_0002
Scheme 20
|0193{ Step (ar): Under typical Curtius rearrangement conditions, acid (I¥) may react with diphenylphosphoryl azide, a suitable alcohol (e.g., tert-butanol), an organic base (e.g., EtjN) and toluene at elevated temperature, preferably 80 to 100 °C, to yield compounds of formula (ϊ' ).
[0194J Compounds of formula (Γ - Γ ) may be synthesized as shown in Scheme 21.
Figure imgf000054_0003
Scheme 21 [8195] Step (as): Deprotection of carbamate (Γ ), may occur under standard conditions, such as with 1 : 1 TFA-DCM, to give compounds of formula (IAC).
|0196] Step (at): Amine (1 ') may react with acid chlorides in the presence of a base, such as EtjN, to afford compounds of formula (i AD).
[0197] Compounds of formula IAE AF) may be synthesized as shown in Scheme 22.
Figure imgf000055_0001
Scheme 22
[§198] Step (au): Amine (IAC) may react with sulfonyl chlorides in the presence of a base, such as EtjN, to afford compounds of formula (IA£).
[0199] Step (au): Amine (IAC) may react with isocyanates or isothiocyanates in the presence of a base, such as Et3N, to afford compounds of formula (Γ ), wherein Y is O or S, respectively.
[0200] Compounds of formula (IAG) may be synthesized as shown in Scheme 23.
Figure imgf000055_0002
Scheme 23
[0281] Step (k): Thione (VIII) may undergo desulfurizaiion under standard conditions, such as with H2O2 in a mixture of HOAc-DCM, to afford imidazole (X).
[Θ202] Step (1): Reaction of imidazole (X) with butyllithium in a suitable solvent (eg,, THF) at reduced temperature, preferably at -78 °C for 30-40 minutes, may yield the corresponding organolithium, which may react with a suitable electrophile (e.g., isocyanatc or carbamoyl chloride) at the same temperature to afford a compound of formula (ID).
Compounds of formula (IA< ) may be prepared as depicted in Scheme 24.
Figure imgf000056_0001
Scheme 24
Under conditions previously described in step (q), phenol (XXXIII) may react with carbinol (XII) to afford compounds of formula (IA<i).
85} .
Figure imgf000056_0002
)
(be) "C02R (q) 3A10 -C 02R
RD 11 R
(XXXVI) 0AR)
Scheme 25
[0206] Step (be): Phenol (XXXIII) may react under standard conditions, for example, with dime hylihiocarbamoyl chloride (1 eq) and DABCO (1.25 eq) in NMP at 50 °C, to yield the respective O-aryl-thiocarbamate (XXXIV).
[0207J Step (bd): Upon heating, such as at 240 °C for 20 min in a microwave apparatus, tbiocarbamate (XXXIV) may undergo a Newmann-Kwart rearrangement to give S-aryl- thiocarbamate (XXXV).
(0208] Step (be): Hydrolysis of tbiocarbamate (XXXV), for example, with sodium hydroxide in methanol, may afford the corresponding thiophenol (XXXVI).
(0209} Under conditions previously described in step (q), thiophenol (XXXVI) may react with carbinol (XII) to afford compounds of formula (!AR).
(0210] Compounds of formula (IAS - IAT) may be prepared as depicted in Scheme 26.
Figure imgf000057_0001
021I j Under conditions previously described in step (an), ester (I or Γ ) may be hydroivzed to yield compounds of formula (IAS), wherein Y is O or S, respectively.
{0212] Under conditions previousiy described in step (ao), acid (I 1 ) may react with an amine to afford compounds of formula (iAT), wherein Y is O or 8.
[0213] Compounds of formula (IAU - IAV) may be prepared as depicted in Scheme 27.
Figure imgf000057_0002
Scheme 27
|i 214] Under conditions previously described in steps (ar) to (as), acid ( Β) may be converted to compounds of formula (IAL), wherein Y is O or S.
[0215] Under conditions previousiy described in steps (aw) to (ax), amine (IAU) may be converted to compounds of formula (1AV), wherein Y is O or S.
|0216] Compounds of formula (IA - 1A¾) may be prepared as shown in Scheme 28.
Figure imgf000057_0003
Scheme 28
[0217] Under conditions previousiy described in step (an), compounds of formula (IAW), therein RC!0 is C(0)OR, may be hydrolyzed to yield the corresponding acid (ΓνΛ) [0218] Under conditions previously described in step (ao), acid (I ) may be coupled with a diamine, such as an ammoalkyltrialkyiammonium bromide, to afford compounds of formula (IAY).
{0219J Compounds of formula (IBA— I8B), wherein R1 is piperdinyl, may be prepared as shown in Sche
Figure imgf000058_0001
Scheme 29
[(5220] Step (ay): Deprotection of amine (I ") under standard conditions, known to one skilled in the art of chemistry, may give amine (IBA). that may undergo subsequent aikylation with suitable electrophiie XRQC to give compounds of formula (iBB) .
[0221] Compounds of formula (IBD - IBE), wherein R1 is phenyl and RC!0 is methoxy, may be prepared as shown in Scheme 30.
Figure imgf000058_0002
Scheme 30
[0222] Step (ba): Demethylation of ether (IBC) under standard conditions, such as with BBrj in DCM, may afford the corresponding phenol (ΪΒΒ).
[0223] Step (bb): Compounds of formula (iB3>) may then be alkylated under standard conditions with a suitable electrophiie, for example, bromoaJ.kyl-trialkyiammolium bromide, to yield compounds of formula (IBE).
[Θ224] Compounds of formula (1BG), wherein R1 is pyridyl, may be prepared as shown in Scheme 31.
Figure imgf000058_0003
Scheme 31 f0225J Step (be): Compounds of formula (I ) could be alkylated with a suitable electrophile XRQD under conditions know to one skilled in the art to give compounds of formula (iBG).
TGR5/CRE-Luciferiase Assay
[0226] HEK 293 ceils stably expressing human TGR5 (h-TGR.5) or mouse TG 5 (m- TGR5) can be generated from HEK 293 CRE-Luciferase cells. The day before the assay, HEK 293 hTGR5/CRE-Luc cells are plated in DMEM in a 384 well assay plate at a density of 25k cells/45 μΙ_ per well and grown for 18-20 hours. Compounds axe serially diluted in DMEM containing 5% DM.SO and 5 jiL of compound or media alone are transferred to each well and plates were incubated for about 6 hours. Following incubation, 30 pL of iysis/luciferase buffer are added to each well. The luciferase activity is then measured on the EnVision™ plate reader and the dose response data was analyzed using Activity Base.
[§227] From the foregoing it will be appreciated that, although specific embodiments of this disclosure have been described hereiii for purposes of illustration, various modifications may be made without deviating from the spirit and scope of the invention. Accordingly, the invention is not limited except as by the appended claims.

Claims

What is claimed is:
1. A compound of Formula 1(Q) :
Figure imgf000060_0001
or pharmaceutically acceptable salt thereof, wherein:
X is =N- or -C(R4)-, wherein R4 is H, -(Ci-Cjjalkyl or halo;
R! is QA or Rc;
° is selected from phenyl, -(C5-Ce)-cycloalkyl, -CH2-p enyl, heteroaryl, and -(Ci-C4)alkyl optionally substituted with -OR013, -N(RCi3)2 or -S(RC,3)5 wherein the cyclic group of R can be optionally substituted with 1. 2, 3, 4 or 5 RC1° groups, wherein the I , 2, 3, 4, or 5 R ,w groups are independently selected from RCi0A and RU0B, provided that R5" cannot be substituted with more that) two RC! B groups, wherein
each RCi0A is independently selected from halo, cyano, and -(Ci --Chalky 1 optionally substituted with one, two, or three groups selected from -OH and halo;
each RC!uB is independently selected from -C(0)NH2, (5-6 membered)heterocycloalkyl, -0-(CrC4)alkyi-Rcn, -C(0)ORC12, -OC(0)ORC!2, and -0-(Ci-C4)alkyi optionally substituted with -OH or -C(0)OH;
RCi l is cyano, nitro, -N(RCI2)2, -ORc'2, -SRC'2, -C(0)RC12, -C(0)ORC12, -C(0)N(RCi2)2, -S(0)N(RCi2)2, ~S(0)2N(RC!2)?, -S(0)2RC12, -OC(0)RCi2, -OC(0)ORC12, -0C(0)N(RC12)2, -N(Rc )C(0)RC!2, -N(RC!2)C(0)ORCi2, -N(RC12)C(0)N(RCS2)2, or -N(RC32)C(- RCi2)N{Rc, 2)2;
each RCi7" is independently selected from hydrogen, -(Ci -Gi)aikyl, and
"(Ci-C4)haloalkyl;
each '3 is independently selected from hydrogen. -(C[-C4)alkyl, and
-(Cj -C4)haloalkyi,
wherein Rc, is substituted with one or two QA groups, wherein Rc is substituted with QA by replacing a hydrogen that is covalently bonded to carbon or nitrogen;
R2 is -LD-RD 1 ;
LD is -[C(R)2]p-Y-[C(R)2]q-;
p is 0 or 1 :
q is 0 or 1 ; each R is independently selected from H, -(Ci-C3)atkyi, halo, -OH, and -CH?OH;
Y is a bond, -S-, ~S(0)2-, -CH(OH)-, -0-, -C(H)==C(H)-, -C(0)-(C C4)alkyk -(C t -C4)alkyl~S~(CrC4)alkyl-, -(C j -C4)alkyl-N(RY)-(C , -C4)alkyl-, -C(H)(halo)-,
-(C|-C4)alkyl-S(0)2-, -S{0)2-N(RY)-, -(CrC4)alkyl-0-, or -C(OVN(RY)--, wherein RY is H, ~(CrCi)a3kyl, hydroxyl(CrC4)alkyl or -OC-(CrC3)alkyJs
RDi is selected from phenyl -(Cg-G^aryl, -N(H)-phenyl, -(Cs-C6)cycloalkyl, heterocycloalkyl, or heteroaryl, wherein RD" can be optionally substituted with one, two, three, or four R010, wherein the one, two, three, or four R01° groups are independently selected from A groups and B groups, provided that RD1 cannot be substituted with more than two B groups;
each A group, when they occur, is independently selected from halo, -CF3, -CN, -NO2, -OH; -0-(Ci-C4)alkyl optionally substituted at the alky! group with one, two, or three substituents independently selected from -OH and halo; and -(C!-C4)alkyl optionally substituted with one, two, or three substituents independently selected from -OH and halo; each B group, when they occur, is independently selected from ■(Ci-C alkylNCR1511),, -C(Q)-N¾ -C(0)-N(H)-OH, -C(0)-N(H)-RDHC, -C(0)-(Ci-G,)alkyl, ~C(0)OH, -C(0)0-(Cj-C4)alkyl, -S(0)2-(C,•C4)alky3-N(R ! '% -S(0)2-N(RD1 ')R0¾ sc, -S(0)2- (H)C(0)-(CrC4)aikyS, -S(0)2-N{H)C(0)0-(CrC4)alkyl, -S(0)2-N(H)C(0)-N(RD! J) R0nB, -S(0)2-(C|-C4)alkyl; -C(0)-heterocyc3oalkyl optionally substituted with RDnB,; -C(0)-N(H)-(Ct-C6)alkyl optionally substituted at the alkyl group with one or two RDl lB; heterocycloalkyl optionally substituted with oxo or RDi i; heterocycloalkenyl optionally substituted with oxo or RU1 !; heteroaryl optionally substituted with RDH; -0-(Ci-C4)alkyl optionally substituted at the alkyl group with one or two RDl iB; -S(0)2-(4-6 membered)heterocycloalkyl optionaily substituted with R ! iC; -N(H)-C(0)~(CrC4)alkyi optionally substituted at the alkyl group with one or two RD! !B; -N(H)-C(0)-N(H)-(Ci-C3)alkyl optionally substituted at the alkyl group with RDnB; -(C;-C6)a3kyl optionaily substituted with one or two RDl lB, -C(:::NH)-NH2; and -C≡ -(Ci-C3)alkyl optionally substituted with RD1 !B;
each RDi i is independently selected from H, -(C3-Cs)cycloalkyl, -(Ci-C4)haloalkyl, -OH, ~S(0)2OH, C(0)OH, -NH2, -N(H)C(=NH)NH2; ~(Ci-C4)alkyl optionally substituted with halo, -OH or -C(0)OH; -(Cj-Cj)alkyl-phenyl optionally substituted at the phenyl group with one, two, or three substituents selected from methoxv, hydroxvl, and halo;
RD1 1B is selected from H, -OH, -CFj, -N(RD! 1)2> -C(0)OH, -0-(CrC4)alkyl, -S(0)2OH, -C(=NH)-NH2, - (H)C(-NH)NH2, -C(H)-NN(H)C(-NH)NH2, -0-(C,-C4)alkyl-C(0)OH, -N(H)C(=NH)-N(H)C(=NH)NH2, (5-6 membered)heteroaryl, -C(0)-(Ci-C3)alkyl; -(Ci-Q)alkyl optionally substituted with one, two, or three groups independently selected from halo and ~OH; -(Ci-C4)alk.yl optionally substituted with one, two, or three groups independently selected from halo, -OH, -S(0)2OH, -C(0)OH, -NH2, and -N(H)C(:::NH)NH2; -(Co-C3>alkyl-(5-8 membered)heterocyc3oalkyl optionally substituted with one, two, or three RL'U, -(Co-Ci'jalkyl-CC.^Cgjcycloalkyl optionally substituted with RD' \; and -(Ce-Cio)aryl optionally substituted with one, two, or three halo:
or RD! < and Rb B, when they both exist and are each attached to nitrogen, can join together with the nitrogen to which they are attached to form a (5-6 membered) heterocycloalkyl optionally substituted with a group selected from -OH, -(Ci-C4)haloalkyl, -S(0)? H, C(0)OH, -N¾, -N(H)C(=NH)NH2, -(C3-C*)cycloalkyl; -{CrC4)alkyi optionally substituted with halo. -OH, or -C(0)OH; and -(Ci-C3)alkyl-phenyl optionally substituted at the phenyl group with one, two, or three substituents selected from methoxy, hydroxy], and haio;
RDnc is selected from H, -OH, -CF3, -0-(C,-Q)a]kyl, -(C C4)alkyl-N(H)C(-NH)-NH2, -(C0-C3)alkyl-(5-6 membered)heteroaryl; -(C;-C4)alkyl optionally substituted with one, two, or three groups independently selected from halo, -OH, -S(0)2OH, C(0)OH, -NH2, and N(H)C(-NH)NH2: -(C0-C3)alkyl-(5-6 membered)heterocycloalk.yl optionally substituted with a -(5-6 membered)hetexOaryl; -(Co-C3)aIkyl-(5-6 membered)heterocycloalkyl substituted one, two. or three groups selected from selected from. -OH and -(Ci-CjjalkyL; and -(Co-C3)alkyl -aryl optionally substituted at the aryl group with one, two, or three halo;
R5 is -[C(R8)2j-phenyi, -[C(R8)2]-naphthalenyl, or -[C(R8)2]-(5-10 membered) heteroaryl, wherein the heteroaryl is selected from benzo[d][13]dioxolyL benzo[d]isoxazo3yl, quinoxalinyl, qisinolinyl, and 2,3,4a,8a-tetrahydrobenzo[b][l ,4]dioxmyl, wherein the cyclic group of Rs is optionally substituted with one, two, three, four, or five RA|° groups, wherein the one, two, three, four, or five RA'° groups are independently selected from RA ,wA groups and RA 10B groups, provided that Rs cannot be substituted with more than two RAl0B groups; each RAl0A, when they occur, is independently selected from halo, alkoxyl, hydroxyl, -C , -OCF3, -(C,-C4)alkyl, and -NH¾
each RA10B, when they occur, is selected from -0-(C3-C4)a]kyl-RAI !, -8(0)2-NH2, -S(0)2C¾, -N(H)-S(0)2C¾, -S(0)2N(H)-CH3, -C(0)OH, -(Ci-Q)alkyl-OH, ~C(0)NH¾ and -(Ci-Ci alkyl substituted with one, two, or three groups selected from -OH and halo: RA " is selected from -C(0)OH, (5-6 membered)heterocyeloalkyl, halogen, cyano, nitro, -(CrC4)alkyI, -N(RA12)2j -ORA'2, -SRA!2, -N(ORA I2)RA!2, -C(0)RA12, -C(0)ORA12, -C(0)N(RA12)2, -N(RAi2)S(0)RAl2, -N(RA12)S(0)2RAi2, -S(0)N(RA12)2, -S(0)2N(RA)2)2, -S(0)2RA12, »OC(0)RA!2, ~OC(0)ORAi2, -OC(0)N(RA,2)2, -N(RAl2)C(0)RAi2, -N(RA!2)S(0)2RA!2, -N(RA12)C(0)ORA12, -N(RA l2)C(0)N(RA,2)2>
-N(RA,2)C(=NR's'i2) (RA! 2)2, and heteroaryl, wherein each RA U is independently hydrogen, -(Ci -G alkyi, or -(Ci -C^haioaikyl;
each Rs is independently hydrogen, halogen, or methyl, or both R8 taken together with the carbon to which they are both attached form either a (C3-C«)cycloalkyI or a (3-6 memberedjheteroeycloaiky!;
QA is QL or QR;
QL is -N[(C;-C¾)alk.yl];! ÷ wherein an alky! group of -N[(Cj-C3)aikyij3+ is optionally substituted with -(C0-C6)alkyl-S(O)2OH:
Q is selected from:
Figure imgf000063_0001
RQA is ~(CrC6}alkyl;
RQB is ~(Ct-C6)alkyl optionally substituted with -C(0)OH; and
RQC is H, -OH, -(C0-C4)alkyl-COOH, or -(CrC6)alkyl.
2. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein:
X is =C(R4)-;
each R is independently selected from H, --(C> -C:i)alky3, -OH, and -CH?OH; Y is -S-, -SCO),-, -C(H)=C(H)-, -C(0)-, -(C,-C )alkyl-S~, -(Ci-C4)alkyl-N(RY)-, -C(H)(halo)-, -iCi-C4)alkyl-S(0)2-, -8(0)2-N(RYV, -(C,-C4)alkyl-0-, or -C(0}-N(RY)-, wherein RY s H, -(CrC4)aikyi, or hydroxyI(C.-C4)alkyl;
RDi is selected from phenyl, -(C6-Cio)aryl, -N(H)-phenyi, -(Cs-Cftjcycloalkyl, heterocycloalkyl, or heteroaryl, wherein RD1 can be optionally substituted with one, two, three, or four RDl°, wherein the one, two, three, or four RDl° groups axe independently selected from A groups and B groups, provided that RD1 cannot be substituted with more than two B groups;
each A group, when they occur, is independently selected from halo, -CF3, -CN, -N<¼, -OH; -0-(C|-C4)alkyl optionally substituted at the alky! group with one, two, or three substituents independently selected from -OH and halo; and -(Ci-C4)alkyl optionally substituted with one, two, or three substituents independently selected from -OH and halo; each B group, when they occur, is independently selected from -(Ci-C4)alkylN(RDn)2, -C(0)-NH2, -C(0)-N(H)-OH, -C(0)-N(H)-RD, , c, -C(0)-(C ,-Q)alkyl. -C(0)OH, -C(0)0-(C C4)aIk>i -S(0)2-(CrC4)alkyl-N(RDn)2, -S(0)2-N(RDn)RDnc, -S(0)2- (H)C(0)-(C C4)alkyL -S(0)2-N(H)C(0)0-(C, -C4)alkyl, -S(0)2-N(H)C(0)-N(RDi ') RDS 1B, -S(0)2-(CrC4)alkyl; -C(0 heterocycloalkyl optionally substituted with R: ') i :\; -C(0)-N(H)-(Ci-C6)alkyl optionally substituted at the alkyl group wish one or two RDl iB; heterocycloalkyl optionally substituted with ox or RD: i„ heterocycJoa!kenyl optionally substituted with oxo or RD"; heteroaryl optionally substituted with R°" ; -0-(Ci-C )alkyl optionally substituted at the alkyl group with one or two RDHB; -S(0)2-(4-6 membered)heterocycloafkyI optionally substituted with RDl lc; - (H)-C(0)-(C-.-C.4)alkyl optionally substituted at. the alkyl group with one or two RD' :B; -N(H)-C(0)-N(H)-(Ci-C3)alkyl optionally substituted at the alkyl group with RD! IB; -(CrC^alkyl optionally substituted with one or two RL" 1B; -C(=NH)-NH2; and -C≡C-(Ci-C3)alkyl optionally substituted with RDl iB;
each RD l i is independently selected from H, -(C3-C6)cycioa!kyI, -(Ci-C4)haloa!kyl; ■OH, -S(0)2OH, C(0)OH, -NH2, -N(H)C(=NH)NH2; -(CrC4)alkyl optionally substituted with halo, -OH or -C(0)OH; -(C]-C3)alkyl-phenyl optionally substituted at the phenyl group with one, two, or three substituents selected from methoxy, hydroxyl and halo:
RDi iB is selected from H, -OH, -CF3, -N(RD1 % -C(0)OH, -0-(C)-C4)alkyl,
-S(0)2OH, -C(=NH)-NH2> ·Ν(Η)€(=ΝΗ)ΝΗ2, -C(H)- TM(H)C(- H)Ni-I2, -0-(Ci-C )alkyl-C(0)OH, -N(H)C(=NH)-N(H)C(=NH)NH2, (5-6 membered)heteroaryl, -C(0)-(C ] -C3)alkyl; -(Ci-C )alkyl optionally substituted with one, two, or three groups independently selected frorri halo and -OH; -(CrC^alkyi optionally svibsiitirted with one, two, or ihree groups independently selected from halo, -OH, -S(0)2OH, -C(0)OH, -NH2, and -N(H)C(=NH)NH2; --(C0--C3)alkyl-(5-8 membered)heterocycloaikyl optionally substituted with one, two, or three RD, !; -(C0-C3)alkyl-(C3-C5)cycloalkyl optionally substituted with RD ' ', and -(Cg-Cio)aryl optionally substituted with one, two, or three halo:
or RDi ! and RDnB, when they both exist and are each attached to nitrogen, can join together with the nitrogen to which they aire attached to form a (5-6 membered) heterocycloalkyi optionally substituted with a group selected from -OH, -(C; -C^haloaikyi, -S(0)2OH, C(0)OH, ~ ¾, -N(H)C(=NH)NH2, -(C3~C6)eycloaIkyi; -(C,-C4)alkyl optionally substituted with halo, -OH or -C(0)OH; and -(CrC3)alkyl-phenyl optionally substituted at the phenyl group with one, two, or three substituents selected from roethoxy, hydroxy! and halo; and
RD! !C is selected from H, -OH, -CF3, -0-(CrC4)alkyl, -(C,-C4)alkyl-N(H)C(--NH)- H2, -(C0-C3)alkyl-(5-6 membered)heteroaryl; -(CrC4)alkyi optionally substituted with one, two, or three groups independently selected from halo, -OH, -S(0)2OH, C(0)OH, -NH2, and N(H)C(=NH)NH2; -(Co-Cj)alkyl-(5-6 memhered)heterocyeloaikyl optionally substituted with a -(5-6 membered)heteroaryl; -(Co-C3)alkyI-(5-6 membered)heterocycloalkyI substituted one, two, or three groups selected from selected from -OH and -(CrC;j)alkyl; and -(Co-Chalky I-ary! optionally substituted at the aryl group with one, two, or three halo.
3. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein:
X is =C(R4)-;
Y is a bond, -S-, -S(0)2-, -CH(C¾)-S(0)?.-, -CH(C¾)-S-, -CH(CH3)-S(0)2-, -CH(OH)-, -CH(CH3)-0-, -C(0)-, -(CH2)-S-, -CH2-" (RY)-, -CH(halo)-, -CH2-S(0)2-, -S(0)2-N(RY)-, -(CH2)-0-, or -C(0)-N(RY)-, wherein RY is H, -(Ci-C3)alkyl or hydroxyl(Ci-C3)aikyl;
each R is independently selected from H, -CH3, -OH, F, and -CH2OH;
RD1 is selected from phenyl, -N(H)-phenyl, -(C3-Q)cycloaikyh -(5-6
membered)heterocycloalkyl, -(5-6 membered)heteroaryl-(5 -6 membered)heterocycloalkyl, and -(5-6 raembered)heteroaryl, wherein RD| is optionally substituted with one, two, or three R"1 ,0, wherein the one, two, or three RDlu groups are independently selected from A groups and B groups, provided that RDl cannot be substituted with more than one B groups; each A group, when they occur, is independently selected from halo, -CF3, -CN, -N02, -OH, -0-(Ci-C4)alkyl optionally substituted with one, two, or three substituents independently selected from -OH and halo, and -(Cj- G:)alkyl optionally substituted with one, two, or three substituents independently selected from -OH and halo;
the B group is selected from -0-(C1-C4)alkyl-C(0)OH> -0-(C C4)alkyl, -0-(C 1 -C )alkyl- C(0)-(C s■ -C j)alkyl, ~0-(C , -C4)alky !N(RD! 5 )2, -(€■ -Chalky 1- C(0)OH, -(5-6 membered)heteroaryl, -C(=NH)-NH2, -S(0)2~N(H)C(0>(CrC4)alkyl,
-S(0)2-N(H)C(0)0-(C j -C jalkyl, -S(0)2-N(H)C(0)-N (H)-(C , -C4)alkyi,
■ S(0)2-N(H)C(0)-N(H)-(5-6 membered)heterocydoalkyl, -S(0)2-(Ci -C3)aikyL
-0-(C;-C,4)alkyI-N(H)-C(-NH)-NH2, -0-(CrC4)alkyl-(5-6 membered)heteroaryl, -(C] -C4)alkylN(RDU)2> -C(0)-NH2, -C(0)-N(H)-OH, -C(0)-N(H)-RDUC, -C(0)-(Ci-C3)afkyl, -C(0)OH, -C(0)0- C C )alkyi, -S(0)2-NH2; -0-(CrC4)aikyl-(5-6 memberedjheterocycloaikyl optionaily substituted with oxo or methyl; -C(0)-(5-6 memberedjheteroeycloalkyl optionally substituted with -S(Q)2OH, -C(0)OH, -NHj, or -C(0)-N(H)-(Ci-C4)alkyl optionally substituted at the alkyi group with one or two groups selected from -8(0)201-?, -C(0)OH, -NH2, and ~N(H)C(-NH)NH2; -(5-6 membered)heterocycloalkyl optionally substituted with oxo or RWI'; -S(0)2-N(H)-(CrC4)alkyl optionally substituted at the alkyl group with one or two groups selected from -S(0)2OH, C(0)OH, -NH2, and ~N(H)C(=NH)NH¾; -S(0)2-N(CrC3)a3kyl-(Ci-C )alJ yl optionally substituted at the (Ci-C4)alkyl group with one or two groups selected from -S(0)2OH, C(0)OH,
-NH , and -N(H)C(=NH)NH2j; -S(0)2-(4-6 memberedjheterocycloaikyl optionally substituted with -3(0)201-1, C(0)OH, -NH2, or -N(H)C(= H)NH2; -N(H)-C(0)-(Ci-C4)alkyl optionally substituted at the alkyl group with one or two groups selected from -S(0)2OH, C(0)OH, ~NK2 and
-N(H)C(=NH)NH2; -N(H)-C(0)-N(H)-(Ci-C3)a!kyl optionally substituted at the alkyl group with -S(0)2OH, C(0)OH, -NH2> or ~N(H)C(-NH)NH2 ; -(C C6)a!ky! optionaily substituted with one or two groups selected from -S(0)2OH, C(0)QH, -NH2, and
Figure imgf000066_0001
optionally substituted with one or two groups selected from -S(0)2OH, C(0)OH, -NH2, and -N(H)C(=NH)NH2;
each RD! ! is independently selected from H, -(C3-C6)cycloalkyl, -OH, -S(0)2OH, C(0)OH, -NH2, -N(H)C(-NH)NH2, -(C,-C4)baloalkyl; -(C[-C3)alkyl-phenyi optionally substituted at the phenyl group with one, two, or three substituents selected from methoxy, hydroxyl and halo,; and -(CrC4)alkyl optionally substituted with halo, -OH or -C(0)OH; RD, 1B is selected from H, -OH, -CF3, -N(RDU)2, -C(0)OH, -0-(C, -C4)alkyl, -S(0)2OH, -C(=NH>NH2, -N(H)C(=NH)NH2, -C(H ==NN(H)C(=NH)NH2, (5-6 membered)heteroaryl, -N(ii)C(=NH)-N(H)C(== H)NH2, -0-(C Q)alkyl-C(0)OH, -(C0-C3)alkyt-(5-8 membered)heterocycloalkyl, -C(Q)-(C 3 -C3)alkyi; -( -C4)alkyl optionally substituted with one, two, or three groups independently selected from halo and -OH; -(Ci-G alkyl optionally substituted with one or two groups independently selected from halo, -OH, -S(0)2OH, C(0)OH, -NH2, and -N(H)C(=NH)NH2; -(Co-C3)alkyl-(C3-C6)cycloalkyl optionally substituted with RD"; and phenyl optionally substituted with one, two, or three halo; and
RDnc is selected from H, -OH, -CF3, -0-(Ci-C4)alkyl; -(C,-C4)alkyl optionally substituted with one or two groups independently selected from halo, -OH, -S(0)zOH, C(0)OH, -NH2, and -N(H)C(=NH)N¾; -(Q>-C3)alkyl-(5-6 membered)heterocycloalkyl, -C(0)-(5-6 membered)heterocycioalkyl optionally substituted with a (5-6 membered)heteroaryl; -(Co-C3)alkyl-(5-6 membered)heterocycloalkyl substituted with one, two, or three groups selected from -OH and -(C C3)alkyl; -(CrC4)alkyl-N(H)C(=NH)-NH2; -(Co-C3)alkyl-(5-6 membered)heteroaryl;>; and -(Cc.~C3)aSkyl-phenyl optionally substituted at the phenyl group with one, two, or three halo.
4. The compound according to any one of the above claims, or a pharmaceutically acceptable salt thereof, wherein:
is O;
Y is a bond, -S-, -S(0)2-, -CH(CH3)-S(0)2-, -CH(CH3)-S-, -CH(C¾)-S(0)2~, -CH(OH)-, -CH(C¾)-0-, -C(H)=C(H)-, -C(0)-, -(CH2)-S-, -C¾- (RY)-, -CH(halo)-, -CH2-S(0)2-, -S(0)2-N(RY)-, -(CHz)-O-, or -C(0)-N(RY)-, wherein RY is H, -(C,-C4)alkyl or hy droxylfC ; ~C )alky I ;
each R is independently selected from H, -(Cs-C2)alkyl, fiuoro, -OH, and -CH2OH;
R | is selected from phenyl, -N(H)-phenyl, cyclohexyl, cyclopentyl, piperidinyl, piperazinyl, pyrrolidinyl, morpholinyl, 1 >2,3>6-tetrahydropyridinyl, heteroarylheterocycloalkyl, pyridinyl, oxazolyl, pyrazinyl, quinolinyl, 1 ,2,4-oxadiazolyl, 1,2,3 4-tetrahydroquinolinyl, and pyrazolyl, wherein Ru' can be optionally substituted one, two, or three R0l°, wherein the one, two, or three Rmo groups are independently selected from A groups and B groups, provided thai RD! cannot be substituted with more than one B group; each A group, when they occur, is independently selected from halo, -CP's, -CN, -NO2, -OH; -0-(Ci-C4)alkyl optionally substituted with one, two, or three substituents independently selected from -OH and halo; and
Figure imgf000068_0001
optionally substituted with one, two, or three substituents independently selected from -OH and halo;
the B group is selected from -0-(C1-C4)alkyl-C(0)OH, -0-(Ci-C4)aIkyl, -0-(Cr-C )alkyl-C(0)-(Ci-C3)alkyl; -0-(CrC4)alk lN(Rt>! ')2,
-0-(CrC4)alkyl-N(H)-C(=NH)-NH2, -0-(CrC4)alkyl-(5-6 merobered)heteroary1, -(CrC4)alkylN(RD' !)2, -C(0)-N¾, -C(0)-N(H)-OH, -C(0)-N(H)-Ro l lc, -C(0)-(Ci-C4)alkyl, -(C 1 -C4)alkyl-C(0)OH, -C(0)OH, -C(0)0-(C , -C4)alkyl, -S(0)2-(C , -C4)alkyi-N(RD 11 )2, ~S(0)2-NH2, -S(0)r-N(H)C(0)-(CrC )alkyl, -S(0)2-N(H)C(O)0-(C,-C4)alkyl,
-S(0)2-N(H)C(0)-N(H)-(C1-C4)alkyi, -S(0)2-N(H)C(0)-N(H)-morphohnyl, -S(0)2-N(H)C(0)-N(H)-pyirolidinyl, -S(O)2-N(H)C(0)-N(H)-pipeiidinyl, -S(0)2-C¾, -C(= H)- H2, 2,3-dihydro-lH-tetrazolyl; -0-(Ci -C4)alkyI optionally substituted at the alkyl group with one or two RDi lB; -0-(C}-C4)alkyl-(5-6 membered)heterocycloaikyi optionally substituted with oxo or methyl; -C(0)-heterocycIoalkyl optionally substittited with -S(0)2OH, C(0)OH or -NH2, provided that substitution of the -C(0)-heterocycloalkyI can only occur by replacing a hydrogen that is covaSently bound to either a carbon or a nitrogen of the -C(0)-heterocycloalkyl; -C(0)-N(H)-(Ci-C4)alkyl optionally substituted at the alkyl group with one or two groups selected from -S(0)2OH, C(0)OH, -MH2 and -N(H)C(=NH)N¾;, heterocycloalkyi selected from lH-letrazolyl, piperizinyl, 2,3-dihydro- 1 ,3 ,4-oxadiazolyl, and 4,5-dihydro- 1 ,2,4-oxadiazolyl, optionally substituted with oxo or -(Ci-C4)alkyi; -S(0);rN(H)-(Cj-C4)aikyl optionally substituted at the alkyl group with one or two groups selected from -S(0)2QH, C(0)OH, -NH2, and -N(H)C(=NH)NH2; -S(0)rN(Ci-C3)alkyl-(CrC4)a1kyl optionally substituted at the (Ci-C4)alkyl group with one or two groups selected from -S(0)2OH, C(0)OH, -NH2, and -N(H)C(=NH)NH2,; -S(0)2-(4-6 membered)heterocycloalkyl optionally substituted with -S(0)20H, C(0)OH, -NH2, or -N(H)C(=NH)NH¾; -N(H')-C(0)-(C]-C4)alkyl optionally substituted at the alkyl group with one or two groups selected from -S(0)2OH, C(0)OH, -NH , and -N(H)C(-NH)NH2; -N(H)-C(0)-N(H)-(Ci-C3)aIkyl optionally substituted at the alkyl group with a group selected from -S(0)2OH, C(0)OH, -NH2 and -N(H)C(=NH)NH2 ; (C1-C6)alkyl optionally substituted with one group selected from -S(0)2OH, C(0)OH, -NH2 and -N(H)C(-NH)NH2 ; and -C≡C-(C{-C3)alkyl optionally substituted at the alkyl group with one group selected from -S(0)2OH, C(0)OH, -NH?, and -N(H)C(=NH)NH2; each RDl i is independently selected from H, -(Qt-Celcycloalkyl, -(Ci-C4)alkyl optionally substituted with halo, -OH or -C(0)OH, -OH, -S(0)2OH, C(0)QH, -NH2, or -N(H)C(- H)NH2, -(CrC3)a].ky! -phenyl optionally substituted at the phenyl group with one, two, or three substituents selected from methoxy, hydroxy! and halo, and -(Ci -Q haloalkyl
RD, iB is selected from H, -OH, -CF3, -NH2, -C(0)OH, -O^C C^alkyl, -S(0)2OH, -C(=NH)-NH2, -N (H)C(=NH)NH2, -C(H)- N(H)C(-NH)NH2,
-N(H)C(=NH)-N(H)C(=NH)NH2, -C(0)-(Cj-C3)alkyl,; -{C]-C4)aikyl optionally substituted with one, two. or three groups independently selected from halo and -OH;
Figure imgf000069_0001
-(Ci-C4)aikyl optionally substituted with one or two groups independently selected from halo, -OH, -S(0)2OH, C(0)OH, -NH2, and - (H)C(=== H)NH2; -0-(C,-C4)aikyl-C(0)OH, a heterocycloalkyl selected from morpholinyl, pyrroiiditiyl, piperazinyl, and piperidinyi, wherein, the heterocycloalkyl can be optionally substituted with one, two, or three RDl i; cyclopropanyl; cyclopentyl; iinidazolyl; pyridinyl; thiazolyl; 1 (H)-telrazolyl; and phenyl optionally substituted with one, two, or three halo;
or R n and RL' , 1B, when they both exist and are each attached to nitrogen, can join to form a (5-6 membered) heterocycoalkyl optionally substituted with Rn; andRDUC is selected from H, -OH, ~CF3, -0-(Ci-C4)alkyl; -(Ci-C )alk l optionally substituted with one or two groups independently selected from halo, -OH, -S(0)2OH, C(0)OH, -NH2 and -N(H)C(=NH)NH2; a heterocycloalkyl selected from morpholinyl, pyrrolidinyl, piperidinyi and piperazinyl, wherein the heterocycloalkyl is optionally substituted with a (5-6 membered)heteroaryl; -Co-C3alkyK5~6 membered)heterocycloaIkyL wherein the (5-6 membered)heterocycloalkyl group of -Co-Cjalkyl-(5-6 membered)heterocycloaikyi is selected from morpholinyl, pyrrolidinyl, piperidinyi. and piperazinyl and wherein the -Co-Cjalkyl-(5-6 memberedjheterocycloalkyl group is substituted with one, two, or three substituents selected from -OH and -<C,--C3)alkyl;
Figure imgf000069_0002
-Co-Cjalkyl-imidazofyl; -Co-Cjalkyl-pyridinyl,; and -Co-Cjaikyl-phenyl optionally substituted at the phenyl group with one, two, or three halo.
5. The compound according to any of the above claims, or a pharmaceutically acceptable salt thereof, wherein:
X is Γίίϊ) :
p is O;
Y is a bond, -S-, -S(0) , -CH(CH3)-S{0)2-, -CH(CH3)-S-S -Cri(Cfi3)-S(0)r, -CH(OH)-, -CH(CHj)-0-, -C(H)=C(H)-, -C(O)-, -<CH2)-S-, -CH2-N(RY)-, -CH(haio)-, -CH2-S(0>}-, -S(0)2-N(RY)-, -(CH2)-0-, or -C(0)-N(RY)-, wherein RY is H, -(Ci-C )alk l or hydroxy i(C ; -Cjja!kyl;
each R is independently selected from H, -(CrC2)alkyl, fluoro, -OH, arid -CH2OH;
RD1 is selected from phenyl, -N(H)-phenyl, cyclohexyl, cyclopentyl, piperidinyl, piperazinyl, pyrrolidmyi, morpho!inyl, 1,2,3,6-tetrahydropyridinyl, heteroaryiheteroeycioalkyl, pyridinyl, oxazolyl, pyrazinyl, quinolinyl, 1,2,4-oxadiazolyl, 1 ,2 ,4-tetrahydroquinoliayl, and pyrazoiyl, wherein RDi is substituted with one, two, or three RD: 0, wherein the one, two, or three Rl '° groups are zero, one, or two A groups and zero or one B group;
each A group, when they occur, is independently selected from halo, -CF3, -CN, -NO2, -OH; -0-(Ci-C4)alkyi optionally substituted with one, two, or three substituents independently selected from -OH and halo; and --(Ci -Chalky! optionally substituted with one, two, or three substituents independently selected from -OH and halo;
the B group, when it occurs, is selected from -0-(CrQ)alkyl optionally substituted at the alky! group with one or two Rm sB,; -0-(C C4)alkyl-C(0)OH; -0-(CrQ)alkyj; -0-(C,-C4)alkyl-C(0)-(Ct-C5)alkyl; -0-(C )alkylN(RD, 1>2; -0-(Cr-C4)a!kyl,-N(H)-C(=NH)-NH?,; -0-(C,-C4)alkyl-(5-6 membered)heteroaryl; -0-(Cf-C4)alkyl-(5-6 membered)heterocycloalkyl optionally substituted with oxo or methyl; -(CrC4)alkyiN(RDl i)2,; -C(0)-NH2; -C(0)-N(H)-OH; -C(0)-N(II)-RDi lc;
-C(0)-(C|-C4)alkyl; -C(0)OH; -C(0)0-{C C,,)alkyi; -C(0)-heterocycloalkyl optionally substituted witli -S(0)2OH, C(Q)OH, or -NH2; -C(0)-N(H)-(Ci-C4)alkyl optionally substituted at the alkyl group with one or two groups selected from -S(0)2OH, C(0)OH, -NI-I2, and -N(H)C(=NH)NH2; -(C C4)alkyl-C(0)OH,; 2,3-dihydro- 1 H-tetrazolyl; heterocycloalkyl selected from 1 H-tetrazolyl, piperizinyl, 2,3-dihydro-l,3,4-oxadiazolyl, and 4,5-dihydro- 1,2,4-oxadiazolyl, wherein the heterocycloalkyl is optionally substituted with oxo or -(Ci- VUlkyi;
-S(0)2-(Ci-C4)alkyl-N(RD l i)2; -S(0)2-NH2; -S(0)2-N(H)-(CrC4)alkyl optionally substituted at the alkyl group with one or two groups selected from -8(0)2QH, C(0)OH, - i-I2 and
-N(H)C(-NH)N¾; -S(0)?- (C1-C3}aikyl-(CrC4)alky] optionally substituted at the (Ci~G?)alkyl group with one or two groups selected from -S(0)2OH, C(0)OH, -NH2, and
-N(H)C(=NH)NH2>; -8{0)2-(4~6 membered)heterocycloalkyl optionally substituted with -S(0)2OH, C(0)OH, -NH, or -N(H)C(-NH)NH2; -S(0)2-N(H)C(0)-(C C )alk>rI;
-S(0):,- (H)C(0)0-(C, -C4)alkyl; -S{0)2-N(H)C(0)- (H)-(C ; -C4)alkyl; -S(0)2-N(H)C(0)-N(H)-morpholinyl; -S(0)2-N(H)C(0)-N(H)-pyrrolidinyI;
-S(0)2-N(H)C(0)-N(H)-pipcridinyl; -S(0)2-CH3; -N(H)-C(0)-(CrC4)alkyl optionally substituted at the alkyl group with one or two groups selected from -S(0)20H, C(0)OH, -NH2> and ~N(H)C(=NH)NH2; -N(H)-C(0)-N(H)-(CrC3)alkyl optionally substituted at the alkyl group with a group selected from -S(0)2OH, C(0)OH, -NH2, and -N(H)C(=NH)NH2; -(Ct-C6)alkyl optionally substituted itli one group selected from -S{0)2OH, C(0)OH, -NH2 and -N(H)C(=NH)NH2 ; -C(-NH)-NH2; and -OC-(Ci-C3)aIkyt optionally substituted at the alkyl group with one group selected from -S(0)2OH, C(0)OH, -NH2, and -N(H)C(=NH)NH2; each RDa is kdependently selected from H, -(C -C'ejcycloalkyl, -OH, -S O^OH, C(0)OH, -NH2, -N(H)C(=NH)NH2; -(C C alkyl optionally substituted with halo, -OH or -C(0)0; -(Ci-Cs)alkyl-phenyl optionally substituted at the phenyl group with one, two, or three substituents selected from methoxy, hydroxyl and halo,; and -(CrC^haloalkyl;
RD, !B is selected from H, -OH, -CF3, -NH2, -C(0)OH, -0-(C C4)alkyL
-S(0)2OH, -C(=NH)-NH2, -N(H)C(=NH)NH2, -C(H)-NN(H)C(-NH)NH2> -0 -(CrC4)a]kyl-C(0)OH, - {H)C(=NH)-N(H)C(-NH)NH2) -C(0)-(CrC3)alkyl, ■■(CH2) i .4-C(0)OH, cyclopropanyl, cyclopentyl, imidazolyl, pyridinyl, thiazolyi, 1 (H)-tetrazolyl; ~(Cj -Chalky! optionally substituted with one, two, or three groups independently selected from halo and -OH; ~(Cj-C4)alkyl optionally substituted with one or two groups independently selected from halo, -OH, -S(0)2OH, C(0)OH, -NH2, and -N(H)C(-NH)NH2; a heterocycloalkyl selected from morpholinyl, pyrrolidinyl, piperazinyi, and piperidinyl, wherein the heterocycloalkyl is optionally substituted with one, two, or three RD! l; and phenyl optionally substituted with one, two, or three haio;
or RDn and RDi lB, when they both exist and are each attached to nitrogen, can join to form a (5-6 membered) heterocycoalkyl optionally substituted with R! i; and
RD1 !C is selected from H, -OH, -CF3, -0-(C,-C )alky{; -(CrC,<)alkyl optionally substituted with one or two groups independently selected from halo, -Oil, -S(0)2OH, C(0)OH, -NH¾ and -N(H)C(=NH)NH2; -(Ci-C )alkyl-N(H)C(===NH)-NH2; -Co-Cialkyl-imidazolyl; -Co-Csalky!-pyridinyl; a heterocycloalkyl selected from morpholiny!, pyrrolidinyl, piperidinyl and piperazinyi, wherein the heterocycloalkyl is optionally substituted with a (5-6 membered)heteroaryl; -Co-C3alkyl-(5-6 membered)heterocycloalkyl, wherein the (5-6 membered)heterocycloaikyi group of -Co-C3alky!-(5-6 membered heterocycloalkyl is selected from morpholmyl, pyrrolidinyl, piperidinyl, and piperazinyl, and wherein the -(5-6 membered)heterocycIoalkyl group is substituted with a one, two, or three groups selected from -OH and -(Ci-C3)alkyl; and ~Co-C3alkyl-phenyl optionally substituted at the phenyl group with one, two, or three halo.
6. The compound according to any one of the above claims, or a pharmaceutically acceptable salt thereof, wherein:
X is ==C(R4)- ;
p is 0;
Y is a bond, -S-, -S(0)2-, -CH(C¾)-8(0)2-, -CH(CH3)-S-, -CH(C¾)-S(0}2-, •CH(OH)-, -CH(CH3)-0-, -C(H)=C(I-I)-, -C(O)-, -(CH2)-S~, ~CH2-N(RY)-, -CH(haio)-, -CH2-S(0)2-, -S(0)2-N(RY)-, -(CI-I2)-0-, or -C(0)-N(RY , wherein RY is H. -(C C4)alkyl or hydroxyl(C] -C4)alkyl;
each R is independently selected from H, -(Ci-C2)alkyl, fluoro, -OH, and -CH2OH, Rbl is selected from phenyl, -N(H)-phenyl, cyclohexyl, cyclopentyl, piperidinyl, piperazinyl, pyrrolidinyl, morpholinyl, I ,2,3,6-tetrahydropyridinyl, heteroarylheterocycloalkyl, pyridinyl, oxazolyl, pyrazinyl, quinolmyl, 1 ,2,4-oxadiazolyl, 1 ,2,3,4-tetrahydroquinolrnyl, and pyrazolyl, wherein RDl is substituted with one, two, or three RDi0, wherein the one, two, or three RDl° groups are zero, one, or two A groups and one B group;
each A group, when they occur, is independently selected from halo, -CF3, -CN, - O2, -OH; -0-(Ci -Chalky! optionally substituted with one, two, or three substituents independently selected from -OH and halo; and -(Ci -Chalky! optionally substituted with one, two, or three substituents independently selected from -OH and halo;
the B group is selected from -0-(C C4)aIkyi-C(0)OH,
Figure imgf000072_0001
-0-(CrC4)alkyl-C(0)-(C !-C3)aIkyI, -C(0)OH, -N¾, -(C,-C4)alkyl-C(0)OH, 2,3-dihydi'o- lH-teirazolyl, -0-(Ci-C )alkylN(RDt l)2, -0-(CrQ)alkyl-N(H)-C(-NH)-NH2, -0-(C C )alkyl-(5-6 membered)heteroaryl, -(d -C4)alkylN(RDn)2, -C(0)-NH2, -C(0)-N(H)-OH, -C(0)-N(H)-RD11C, -C(0)-(C, -C4)alkyl, -C(0)OH, -C(0)0-(CrC,)alkyl, -S(0)2-(Ci-C4)alkyl-N(RD5 , -S(0)2-NH2> -S(0)2-N(H)C(Q)-(C,-C4)aikyJ,
-8(Ο)2-Ν(Η)€(Ο)Ο-(0 ; -α ¾ν1, -S(0)2-N(H)C(0)-N(H)-(CI -C4)alkyl, - S(0)2-N(H)C(0)-N(H)-morpholinyl, -S(0)2-N(H)C(0)-N(H)-pyrrolidinyl, -S(0)2-N(H)C{0)-N(H)-p3peridinyl, -S(0)2-CH3, -C(=NH)-NH2; O (C, C, >uiky! optionally substituted at the alkyl group with one or two RDI !B; -0-(Ci-C4)alkyl-(5-6 membered).heterocycloalkyl optionally substituted with oxo or methyl; ~C(0)-heterocycloaikyi optionally substituted with -S(0)2OH: -C(0)-N(H)-(C> -C4)alkyl optionally substituted at the alky! group with one or two groups selected from -SCO^OH, C(0)OH, -NH2 and -N(H)C(=MH)NH2; heterocycioalkyl selected from I H-tetrazolyL piperizmyl, 2,3-di y<iro-l ,3,4-oxadiazolyl, and 4,5-dihydro-l ,2,4-oxadiazolyl, wherein the heterocyc!oaikyi can be optionally substituted with oxo or -(C ) - Chalky!; -S(0)2- (H)-(Ci-C4)alkyl optionally substituted at the alkyl group with one or two groups selected from -S(0)2GH, C(0)OH, -NH2, and -N(H)C(=NH)NH2; -S(0)2-N(C C3)alk l-(C3-C )alkyl optionally substituted at the (Ci -C^alkyl group with one or two groups selected from -S(0)2OH, -C(0)OH, -NIL, and -N(H)C(-NH)NH2>; -S(0)2-(4-6 membered)heterocycloalkyl optionally substituted with -S(0)2OH, C(0)OH, -N¾, or -N(H)C(=NH)NH2; ~N(H)-C(0)-(C C4)alkyl optionally substituted at the alkyl group with one or two groups selected from -S(0)2OH; C(0)OH, -NH& and -N(H)C(=NH)N¾; -N(H)-C(0)-N(H)-(Ci-C3)alkyl optionally substituted at the alkyl group with a group selected from -S(0)2OH, C(0)OH, -NH2 and ~N(H)C(- H)'NH2; -(C]-Q)alkyl optionally substituted with one group selected from -S(0)7OH, C(0)OH, -NH2 and -N(H)C(=NH)NH2 and
Figure imgf000073_0001
optionally substituted at the alkyl group with one group selected from -S(0)2OH, C(0)OH, -N¾ and
-N(H)C(-NH)NH2;
each RD, ! is independently selected from H, -(C'3-C6)cycloaikyi, OH. -(CrC4)haloalkyl -S(0)2OH, C(0)OH, -NH2, -N(H)C(=NH)NH2; -(Ci-C4)alkyl optionally substituted with halo, -OH or -C(0)OH; and -^Ci-C^alkyi-phenyl optionally substituted at the phenyl group with one, two, or three substituents selected from methoxy, hydroxy! and halo;
RDi SB is selected from H, -OH, -CF3, -NH2, -C(0)OH, -0-(CrC4)alkyl, ~S(0)2OH, -C(=NH)-NH¾ -N(H)C(=NH)NH2, -C(H)=NN(H)C(-NH)NH2,
-N(H)C(-NH)-N(H)C(-NH)NH2, -C(0)-(C|-C3)alfcyl, -0-(Ci-C4)alkyi-C(0)OH, -(CH2)i-4-C(0)OH, cyclopropanyl, cyclopentyi, imidazolyl, pyridinyl, thiazolyl, i (H)-tetrazolyl; -(CrC4)alkyl optionally substituted with one, two, or three groups independently selected from halo and -OH; -(Ci-C4)alkyl optionally substituted with one or two groups independently selected from halo, -OH, -S(0)2OH, C(0)OH, -NH2> and ~N(H)C(~NH)NH2; a heterocycioalkyl selected from moipho!inyl, pyrrolidinyl, piperazinyi, and piperidinyi. wherein the heterocycioalkyl is optionally substituted with one, two, or three RDi !„ and phenyl optionally substituted with one, two, 01 three halo, or R°' 1 and RDt tB, when they both exist and are each attached to nitrogen, can join to form a (5-6 rnembered) heterocycoalkyl opiionally substituted with Rn; and
Dnc is selected from H, -OH, -CF3, -0-(C C4)alkyi, -(C i -C4)alky 1· -N(H)C(-NH)-N¾5 -Co-Cjalkyi-imidazoiyl, -C0-C3alky l-pyridinyl,
-(C'. -C4)a3kyl optionally substituted with one or two groups independently selected from halo, -OH, -S(0)2OH, C(0)OH, -NH2, and -N(H)C(=NH)N¾; a heterocycloalkyl selected from morpholinyl, pyrrolidinyl, piperidinyi, and piperazinyl, wherein the heterocycloalkyl is optionally substituted with a (5-6 membe:red)heteroaryl; -CcrC3alkyl-(5-6 mernbered)heterocycloalkyI, wherein the (5-6 m mberedjheteroeycfoalkyl group of -Co-C3alkyl~(5-6 membered)heterocycIoalkyl is selected from morphoiinyl, pyrrolidinyl, piperidinyi arid piperazinyl, and wherein the -Co-C3alkyl-(5-6 membered)heterocycloalkyl group is substituted with a group selected from one, two, or three groups selected from -OH and -(Ci-C3)alkyl; and -Co-Cjalkyl-phenyl optionally substituted at the phenyl group with one, two, or three halo.
7. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein LD is selected from -(CrC3)alkyl-0-, -(C0-C3)alkyl-NRY-(Co-C3)alkyl-, -(Co-C3)alkyl-S-(CcrC3)alkyl-, -(C0-C3)alkyl-S(0)2-(Co-C3)alkyl-; -C(0)N(RY)-(Co-C3)a]kyl-, -S(0)2-N(RY)-(Co-C3)alky{-, -C(O)-(C0-C3)alkyl-, -C=C-(Co-C3)alky{-, -(C0-C3)alkyi-, and -(Cj-C4)alkyl- optionally substituted with halo or -OH.
8. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein LD is selected from -(CH2)i.j-0-, -(CH2)i-3-NRY-, -(Co-C3)alkyl-S-(Co-C3)alkyl-; -(CH2)i.3-S-, -S-(CH2) i-3, -S(0)2-(CH2),.3-, -S(0)2-, -C(0)N(HMCH2),.3-, S(0)2-N(H)-(CH2);.3-, -C(0)-(C¾),. , -C-C-(Co-C3)alkyK a bond, and -(Ci-C4)alkyl- optionally substituted with halo or -OH.
9. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein L is selected from -(CH2)-0-, -(CH2)-"NRY~, -(CH2 S-, -S-(CH2)-, -S(0)2 », -S(0)2-(CH2)-, -C(0)N(R.Y)-(Co-C3)alkyl-; -S(0)2-N(H)-(CH2),-3-, -CiOMCH^-, -C^C-(C2~C3)alk l- ·, and -(Ci -C )alkyl- optionally substituted with halo or -OH.
10. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein LD is selected from -(CH2)-0-, -(C¾)-NRY-, -(CH2)-S-, -S-(CH2)-, -S(0)2-, --S(0)2-(CH,)-, -C(0)N{R (Co-C3)alkyl-, -S(0>2-N(HMCH2)i.}-, -C(0)-(CH2)i-2-» -C=C-(CYC3)alkyl-, and -(C;-C4)alkyl- optionally substituted with halo or -OH.
11. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein LD is selected from -(CH2)-Q-, -(CH2)-NH-, -(CH2)-S-> -S-{C¾)-, -S(Oj2-, -S(0)2-(CH2V, -C(0)N(H (CH2)i.3-, -S(0)2-N(H)-(CH2)i-3-, -C(0)-(CH2)i-2-, -C≡C-(C2-C3)alkyl- and -((.VC^alkyl- optionally substituted with halo or -OH.
12. The compound according to claim 3 , or a pharmaceutically acceptable salt thereof, wherein the B group of Κϋι is selected from:
O 0
C— N— "R0110 f-O- iCH-^- 0118 - (CH2)M-RD1 5S
Figure imgf000075_0001
13. The compound according to any one of claims 1 ■■ 12, or a pharmaceutically acceptable salt thereof, wherein Rc is phenyl, -CH2--pheoyl, -(Cs-C^-cycloaikyl, or pyridinyl, wherein R1' can be optionally substituted with one, two, or three RUu, wherein the one. two, or three R'"'!° groups are independently selected from RU0A and R 0B, provided that RL cannot be substituted with more than one R. 0B group;
each RC!0A, when they occur, is independently selected from halo; -(Ci- Cyalkyl optionally substituted with one, two, or three groups selected from halo and -OH; methoxy; -CFj; ;md halo;
Rc l0B is selected from -C(0)N¾, (5-6 rnembered)heterocycloalJkyl; -0-(C i-C4)alkyl optionally substituted with -OH, -C(0)OH, or -N[-(Ci-C4)alkyl]2; and -(C]-C4)alkyl. substituted with -N[-(C]-C4)alkyl]2; and
wherein Rc is substituted with one or two QA groups, wherein Rc is substituted with QA by replacing a hydrogen that is covalently bonded to carbon or nitrogen.
14. The compound according to any one of the above claims, or a pharmaceutically acceptable salt thereof, wherein:
RL is phenyl, -CH2-phenyl, -{Cs-Ce^eycloalkyl, or pyridinyl, wherein tire cyclic group
C C * 0
of R can be optionally substituted with one, two, or three R ' ' groups and, wherein tire one, two, or three Rc'° groups are independently selected from RC,0A and RC,0B, provided that Rc cannot be substituted with more than one RC10B group;
each R l0A, when they occur, is independently selected from methoxy, -CF3, halo, and ~(C |-C3)alkyi optionally substituted with one, two, or three groups selected from halo and -OH;
RCi0B is selected from {5-6 membered)heterocycloalkyl; -(Ci -C4)alky ί substituted with -N[-(Ci-C4)alkyl]2,; -C(0)NH2; and -0-(C C,;)alkyl optionally substituted with -OH, ~C(0)OH, or -N[- CrC,)aikyl]2; and
wherein Rc is substituted with one QA group, wherein Rc is substituted with QA by replacing a hydrogen that is covalently bonded to carbon or nitrogen.
15. The compound according to any one of the above claims, or a pharmaceutically acceptable salt thereof, wherein Rc is phenyl, -C¾-phenyl or pyridinyl, wherein the cyclic group of R^ car. be optionally substituted with one, two, or three Ruo, wherein the one, two, or three RCi0 groups are independently selected from R'"'l0A and RU0H, provided that Rc cannot be substituted with more than one RCl0B group;
each RC10A, when they occur, is independently selected from -(Ci-C3)alk l optionally substituted with one, two, or three groups selected from -OH, methoxy, -CF3 and halo;
Raofs is selected from -C(0)NH2, (5-6 membered)heterocycloalkyl;••(Cr-C4)alkyl substituted with -N[--(CrC4)alkyij2,; and ~0~{C; -Chalky! optionally substituted with -OH, -C(0)OH, or -N[-(Ci-C4)alkyl]2; and
wherein Rc is substituted with one or two QA groups, wherein R"'" is substituted with QA by replacing a hydrogen that is covalently bonded to carbon or nitrogen.
16. The compound according to any one of the above claims, or a pharmaceutically acceptable salt thereof, wherein R'" is phenyl or pyridinyl, wherein the cyclic group of Rc can be optionally substituted with one, two, or three. Rciu, wherein the one, two, or three RCi0 groups are independently selected from RCl0A and RC!0B, provided that Rc cannot be substituted with more than one R OlJ group;
each RCi°A, when they occur, is independently selected from methoxy and halo;
Rc,uB is selected from -C(0)NH2, (5-6 membered)beterocycloalkyl; -(Ci-C4)alkyl substituted with -N[-(CrC4)alkyi]?; and -0-(Ci-C4)a3kyl optionally substituted with -OH, -C(0)OH, or -N[-(Ci-C4)a}kyl]2; and wherein c is substituted with one QA group, wherein Rc is substituted with Q" by replacing a hydrogen that is covalently bonded to carbon or nitrogen.
17. The compound according to any one of the above claims, or a pharmaceutically acceptable salt thereof, wherein Rc is phenyl or pyridinyl, wherein the cyclic group of Rc can he optionally substituted with one or two groups selected from metiioxy, methyl and halo; and wherein R1" is substituted with one QA group, wherein Rc is substituted with QA by replacing a hydrogen that is covalently bonded to carbon or nitrogen,
18. The compound according to any one of claims one or two, or a pharmaceutically acceptable salt thereof, wherein Rc is phenyl or pyridinyl, wherein the cyclic group of Rc can be optionally substituted one or two groups selected from metiioxy, methyl, fluoro and chloro; and wherein Rc is substituted with one QA group; wherein R is substituted with QA by replacing a hydrogen that is covalently bonded to carbon or nitrogen.
19. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein R is phenyl substituted with one or two groups selected from methoxy, fluoro or chloro; wherein Rc is substituted with one QA group: wherein Rc is substituted with QA by replacing a hydrogen that is covalently bonded to carbon or nitrogen.
20. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, having formula II, III, IV, V, VI or VII:
Figure imgf000078_0001
wherein one R 0 is substituted with one QA group; wherein Ruo is substituted with QA by replacing a hydrogen that is covalently bonded to carbon or nitrogen.
21. The compound according to claim 20, or a pharmaceutically acceptable salt thereof, wherein
each RA!0 is selected from fluoro, chloro and methoxy;
R2 is -LD-RD! , wherein:
LD is selected from -(CH2)-0-, -(CH2)-NH-, -(CH2)-S-, -S-(CH2)-, -S(0)2-, -S(0)2-(CH2)-, -C(0)N(H)-(CH2)i-}-, -S(0)2-N(H)-(CH2)_i-3-, -C(0)-(CH2)|.2-, ~C≡ -(C2-C3) lkyl, and -(Ci-Cs alkyl- optionally substituted with halo or -OH; and
RD1 is one of:
Figure imgf000078_0002
wherein each A is chloro or fluoro, and B is selected from: 9 H 5
--N--R' •O— (CH,),.,""~R r 9r ■(CH,v,-RD
Figure imgf000079_0001
22. The compound according to any one of the above claims, or a pharmaceutically acceptable salt thereof, wherein: LD is selected from -(CH?)-G--, -(CH2)-NH-, -(Cl¾)-S-, -S-(CH2)-, -S(0)2-, -S(0)2-(CH2)-, -C(0)N(H)-(CH2)i-3-, -S(0)2-N(H)-(CH2)i-3-, •-C(0)-(CH2)i-2-, -(Ci-C.4)alkyl- optionally substituted with halo or -OH, and -C≡C-(C2-C3)alkyl-.
23. The compound according to according to any one of the above claims, or a pharmaceutically acceptable salt thereof, wherem LD is selected from -S-(C}-C3)alkyl-, -(CH2)2- and -(Ci-C3)alkyl-0-.
24. The compound according to any one of the above claims, or a pharmaceutically acceptable salt, thereof, wherein R is -[C(CHj)z]-phenyl, -[C(CI-L)2]-na.phthalerryl., or -[C(CIl3)2] -(5- 10 membered) heteroaryl, wherein the heteroaryl is selected from (beirzo[d][l,3]dioxolyl, be.nzo[d]isoxazolyL quinoxalinyl, quinoiinyl and 2,3,4a,8a-tetrahydrobenzo[b][I ,4]dioxiny3, wherein the cyclic group of Rs is optionally substituted with one, two, or three A1° groups, wherem the one, two, or three RA,0groups are independently selected from RAluA and RAl0B, provided that R5 cannot be substituted with more than one RA10B group; and
each RA! A, when they occur, is independently selected from halo, -(C!-Cj)alkoxyl, and hydroxy!;
RAl0B is -(Ci-C4)alkyl optionally substituted with one, two, or three groups selected from -OH and halo; -0-(0}-04) 11ί>4-0(Ο)0Η; 0-(CrC4)alkyl-N[(CrC3)alkyl32; -N¾ ■•S(Q)2--NH2; -S(¾CH3; -N(11)~802CH3; -SQ2N(H)-CH ; -ON; -C(0)OH; ~(Ci~C )a!kyl-OH;
Figure imgf000079_0002
25. The compound according to any one of the above claims, or a pharmaceutically acceptable salt thereof, wherein R3 is -[C(CH3)2]-phenyi, and the phenyl group of R5 is optionally substituted with one, two, or three RA,° groups, wherem the one, two, or three RAly groups are independently selected from R, l0A and RAU; , provided that R' cannot be substitiited with more than one RA10ts group;
each RAi0A, when they occur, is independently selected from halo, methoxy, and hydroxy!; and
RA i0B is -0-(CrC4)alkyl-C(0}OH, 0-(Cr C4)alkyl--N[(Cr C3)alkyl]2j -NH¾ -S(0)2-NH2j -SO2CH3, -N(H)-SO:jCH3, -S02N(H)~C¾, -CN, -C(0)OH, -(Ci -C4)alkyl-OH, -OCF3, -C(0) ¾, or -(Ci -Q)alkyl optionally substituted with one, two, or three groups selected from -OH and halo.
26. The compound according to any one of the above claims, or a pharmaceutically acceptable salt thereof, wherein R* is -[C(C¾)2]-phenyl, wherein the phenyl group is optionally substitiited with one or two groups selected from halo, Kiethoxy, and hydroxy!.
27. The compound according to any one of the above claims, or a pharmaceutically acceptable salt thereof, wherein R5 is -[C(CHj)2]-phenyL wherein the phenyl group is optionally substituted with one or two groups selected from halo and methoxy.
28. The compound according to any one of the above claims, or a pharmaceutically
Figure imgf000080_0001
29. A composition comprising a compound according to any one of claims 1 - 28 and a pharmaceutically acceptable diluent, excipient, or carrier.
30. A method for treating obesity or type 11 diabetes in a subject in need of such treatment comprising administering to the subject an effective amount of a compound of any one of claims 1 - 28 or a composition of claim 29.
31. A method for treating obesity or type II diabetes in a subject in need of such treatment comprising co-administering to the subject, simultaneously or sequentially, an effective amount of a compound according to any one of claims 1 - 28 and a second anti-diabetic drug.
32. The method according to claim 31 wherein the anti-diabetic drug is a sulfonylurea, meglitinide, biguanide, alpha-glueosidase inhibitor, glucagon-like peptide (GLP) analog or agonist, amylin analogues, dipeptidyl peptidase-4 (DPP-4) inhibitor, or thiazolidinedione.
33. The method according to claim 31 wherein the anti-diabetic drug is
(2S)- 1 - {2-[(3 -hydroxy- 1 -adarnantyl)amino]acety 1} ynO3idme-2-carbonitn3e; or
5-((4~(2-(methyl-2-pyridinylamino) ethoxy)phenyl)methyl)- 2,4 -thiazolidinedione.
34. A method for inducing increased GLP-1 secretion in cell, in vitro, comprising contacting the cell with an inducing effective amount of a conipound of any one of claims 1 - 28 or a composition of claim 29.
35. A method for treating hyperlipidemia in a subject in need of such treatment comprising administering to the subject an effective amount of a compound of any one of claims 1— 28 or a composition of claim 29.
36. A method for treating atherscierosis in a subject in need of such treatment comprising adixiiiiisiering to the subject an effective amount of a compound of any one of claims 1 - 28 or a composition of claim 29.
37. A method for lowering blood glucose in a subject in need of such treatment comprising administering to the subject an effective amount of a compound of any one of claims 1— 28 or a composition of claim 29.
38. A method for enhancing insulin secretion in a subject in need of such treatment comprising administering to the subject an effective amount of a compound of any one of claims 1 - 28 or a composition of claim 29.
39. A method for treating a disease associated with perturbed bile acid metabolism in a subject in need of such treatment comprising administering to the subject an effective amount of a compound of any one of claims 1 - 28 or a composition of claim 29.
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