WO2014100021A1 - Agonistes de tgr5 : composés d'imidazole et de triazole contenant un azote quaternaire - Google Patents

Agonistes de tgr5 : composés d'imidazole et de triazole contenant un azote quaternaire 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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English (en)
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Brenton T. Flatt
Raju Mohan
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Exelixis, Inc.
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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

La présente invention concerne des agonistes de TGR5 (également GBPAR1) de formule structurale I (Q), dans laquelle R1, R2, et R5 ont la signification indiquée dans la description, leurs sels pharmaceutiquement acceptables, des compositions les contenant, et l'utilisation des composés et des compositions pour traiter des maladies dans lesquelles TGR5 est un médiateur ou est impliqué. L'invention porte aussi sur l'utilisation des composés dans et pour la fabrication de médicaments, en particulier pour traiter des maladies dans lesquelles TGR5 est un médiateur ou est impliqué.
PCT/US2013/075834 2012-12-17 2013-12-17 Agonistes de tgr5 : composés d'imidazole et de triazole contenant un azote quaternaire WO2014100021A1 (fr)

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