Triazole and imidazole derivatives for use as TGR5 agonists in the treatment of diabetes and obesity

A compound of Formula VIII:

• or pharmaceutically acceptable salt thereof, wherein:
• X is ═C(R4)—;
• R1 is RC;
• or X can be ═C(RC)— only when R1 is phenyl optionally substituted with one, two, or three RC10 groups;
• RC is selected from phenyl, —(C5-C6)-cycloalkyl, —CH2-phenyl, heteroaryl, optionally substituted with —ORC13, —N(RC13)2 or —S(RC13), wherein the cyclic group of RC can be optionally substituted with 1, 2, 3, 4 or 5 RC10 groups, wherein the 1, 2, 3, 4, or 5 RC10 groups are independently selected from RC10A and RC10B, provided that RC cannot be substituted with more than 2 RC10B groups, and provided that substitution of RC with RC10 can only occur by replacing a hydrogen that is covalently bound to either a carbon or a nitrogen of RC, wherein
• each RC10A is independently selected from halo, cyano and —(C1-C4)alkyl optionally substituted with 1-3 groups selected from —OH and halo;
• each RC10B is independently selected from —C(O)NH2, (5-6 membered)heterocycloalkyl, —O—(C1-C4)alkyl-RC11, —C(O)ORC12, —OC(O)ORC12 and —O—(C1-C4)alkyl optionally substituted with —OH or —C(O)OH;
• RC11 is cyano, nitro, —N(RC12)2, —ORC12, —SRC12, —C(O)RC12, —C(O)ORC12, —C(O)N(RC12)2, —S(O)N(RC12)2, —S(O)2N(RC12)2, —S(O)2RC12, —OC(O)RC12, —OC(O)ORC12, —OC(O)N(RC12)2, —N(RC12)C(O)RC12, —N(RC12)C(O)ORC12, —N(RC12)C(O)N(RC12)2, or —N(RC12)C(═NRC12)N(RC12)2;
• each RC12 is independently selected from hydrogen, —(C1-C4)alkyl, and —(C1-C4)haloalkyl;
• each RC13 is independently selected from hydrogen, —(C1-C4)alkyl, and —(C1-C4)haloalkyl;
• R2 is -LD-RD1;
• 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, —(C1-C3)alkyl, halo, —OH, and —CH2OH;
• Y is a bond, —S—, —S(O)2—, —CH(OH)—, —O—, —C(H)═C(H)—, —C(O)—(C1-C4)alkyl-, —(C1-C4)alkyl-S—(C1-C4)alkyl-, —(C1-C4)alkyl-N(RY)—(C1-C4)alkyl-, —C(H)(halo)-, —(C1-C4)alkyl-S(O)2—, —S(O)2—N(RY)—, —(C1-C4)alkyl-O—, or —C(O)—N(RY)—, wherein RY is H, —(C1-C4)alkyl, hydroxyl(C1-C4)alkyl or —C≡C—(C1-C3)alkyl-;
• RD1 is selected from —(C6-C10)aryl, —N(H)-phenyl, cycloalkyl, heterocycloalkyl, and heteroaryl, wherein RD1 can be optionally substituted with 1, 2, 3, 4 or 5 RD10, provided that substitution of RD1 with RD10 can only occur by replacing a hydrogen that is covalently bound to either a carbon or a nitrogen of RD1, wherein the 1-5 RD10 groups are independently selected from A groups and B groups, provided that RD1 cannot be substituted with more than 2 B groups;
• each A group, when they occur, is independently selected from halo, —CF3, —CN, —NO2, —OH, —NH2, —O—(C1-C4)alkyl optionally substituted at the alkyl group with 1-3 substituents independently selected from —OH and halo, and —(C1-C4)alkyl optionally substituted with 1-3 substituents independently selected from —OH and halo;
• each B group, when they occur, is independently selected from —(C1-C4)alkylN(RD11)2, —C(O)—NH2, —C(O)—N(H)—OH, —C(O)—N(H)—RD11C, —C(O)—(C1-C4)alkyl optionally substituted with RD11B, —C(O)OH, —S(O)2—(C1-C4)alkyl-N(RD11)2, —S(O)2—N(RD11)RD11C, —S(O)2—N(H)C(O)—N(RD11)RD11B, —C(═NH)—NH2, —C(O)O—(C1-C4)alkyl optionally substituted with RD11B, —O—(C1-C4)alkyl optionally substituted at the alkyl group with 1 or 2 RD11B, —C(O)-heterocycloalkyl, wherein the —C(O)-heterocycloalkyl can be optionally substituted with RD11B, provided that substitution of —C(O)-heterocycloalkyl with RD11B can only occur by replacing a hydrogen that is covalently bound to either a carbon or a nitrogen of —C(O)-heterocycloalkyl, —C(O)—N(H)—(C1-C6)alkyl optionally substituted at the alkyl group with 1 or 2 RD11B, heterocycloalkyl optionally substituted with oxo or RD11, provided that substitution of the heterocycloalkyl with RD11 can only occur by replacing a hydrogen that is covalently bound to either a carbon or a nitrogen of the heterocycloalkyl, heterocycloalkenyl optionally substituted with oxo or RD11, provided that substitution of the heterocycloalkenyl with RD11 can only occur by replacing a hydrogen that is covalently bound to either a carbon or a nitrogen of the heterocycloalkenyl, heteroaryl optionally substituted with RD11, provided that substitution of the heteroaryl with RD11 can only occur by replacing a hydrogen that is covalently bound to either a carbon or a nitrogen of the heteroaryl, —S(O)2-(4-6 membered)heterocycloalkyl optionally substituted with RD11C provided that substitution of the —S(O)2-(4-6 membered)heterocycloalkyl with RD11C can only occur by replacing a hydrogen that is covalently bound to either a carbon or a nitrogen of the —S(O)2-(4-6 membered)heterocycloalkyl, —S(O)2—N(H)C(O)—(C1-C4)alkyl optionally substituted with RD11B, —S(O)2—N(H)C(O)O—(C1-C4)alkyl optionally substituted with RD11B, —S(O)2—(C1-C4)alkyl optionally substituted with RD11B, —N(H)—C(O)—(C1-C4)alkyl optionally substituted at the alkyl group with 1 or 2 RD11B, —N(H)—C(O)—N(H)—(C1-C3)alkyl optionally substituted at the alkyl group with RD11B, —(C1-C6)alkyl optionally substituted with 1 or 2 RD11B, and —C≡C—(C1-C3)alkyl optionally substituted with RD11B;
• each RD11 is independently selected from H, —(C3-C6)cycloalkyl, —OH, —(C1-C4)haloalkyl, —(C1-C4)alkyl optionally substituted with halo, —OH, —C(O)OH, —S(O)2OH, C(O)OH, —NH2, or —N(H)C(═NH)NH2, and —(C1-C3)alkyl-phenyl optionally substituted at the phenyl group with 1-3 substituents selected from methoxy, hydroxyl and halo;
• RD11B is selected from H, —OH, —CF3, a PEG polymer, —N(RD11)2, —C(O)OH, —O—(C1-C4)alkyl, —S(O)2OH, —C(═NH)—NH2, —N(H)C(═NH)NH2, —C(H)═NC(═NH)NH2, —C(H)═NN(H)C(═NH)NH2, —N(H)C(═NH)—N(H)C(═NH)NH2, —C(O)—(C1-C3)alkyl, —O—(C1-C4)alkyl-C(O)OH, (5-6 membered)heteroaryl, —(C1-C4)alkyl optionally substituted with 1-3 groups independently selected from halo, —OH, —S(O)2OH, C(O)OH, —NH2, and —N(H)C(═NH)NH2, —(C0-C3)alkyl-(5-8 membered)heterocycloalkyl, optionally substituted with 1, 2 or 3 RD11, provided that substitution of —(C0-C3)alkyl-(5-8 membered)heterocycloalkyl with RD11 can only occur by replacing a hydrogen that is covalently bound to either a carbon or a nitrogen of —(C0-C3)alkyl-(5-8 membered)heterocycloalkyl, —(C0-C3)alkyl-(C3-C6)cycloalkyl optionally substituted with RD11, and aryl optionally substituted with 1-5 halo;
• or RD11 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 —(C3-C6)cycloalkyl, —(C1-C4)haloalkyl, —OH, —S(O)2OH, C(O)OH, —NH2, —N(H)C(═NH)NH2, —(C1-C4)alkyl optionally substituted with halo, —OH or —C(O)OH, and —(C1-C3)alkyl-phenyl optionally substituted at the phenyl group with 1-3 substituents selected from methoxy, hydroxyl and halo, provided that substitution of the (5-6 membered) heterocycloalkyl can only occur by replacing a hydrogen that is covalently bound to either a carbon or a nitrogen of the (5-6 membered) heterocycloalkyl;
• RD11C is selected from H, —OH, —CF3, —O—(C1-C4)alkyl, —(C1-C4)alkyl-N(H)C(═NH)—NH2, —(C0-C3)alkyl-(5-6 membered)heteroaryl, —(C1-C4)alkyl optionally substituted with 1-3 groups independently selected from halo, —OH, —S(O)2OH, C(O)OH, —NH2, and —N(H)C(═NH)NH2, —(C0-C3)alkyl-(5-6 membered)heterocycloalkyl optionally substituted with one (5-6 membered)heteroaryl, provided that substitution of the —(C0-C3)alkyl-(5-6 membered)heterocycloalkyl with (5-6 membered)heteroaryl can only occur by replacing a hydrogen that is covalently bound to either a carbon or a nitrogen of the —(C0-C3)alkyl-(5-6 membered)heterocycloalkyl, —(C0-C3)alkyl-(5-6 membered)heterocycloalkyl substituted with 1, 2 or 3 groups selected from —OH and —(C1-C3)alkyl, provided that substitution of the —(C0-C3)alkyl-(5-6 membered)heterocycloalkyl can only occur by replacing a hydrogen that is covalently bound to either a carbon or a nitrogen of the —(C0-C3)alkyl-(5-6 membered)heterocycloalkyl, and —(C0-C3)alkyl-aryl optionally substituted at the aryl group with 1-3 halo;
• R4 is H, —(C1-C3)alkyl or halo;
• R5 is —[C(R8)2]-phenyl, —[C(R8)2]-naphthalenyl, or —[C(R8)2]-(5-10 membered) heteroaryl, wherein the heteroaryl is selected from (benzo[d][1,3]dioxolyl, benzo[d]isoxazole, quinoxalinyl, quinolinyl and 2,3,4a,8a-tetrahydrobenzo[b][1,4]dioxinyl, wherein the cyclic group of R5 is optionally substituted with 1, 2, 3, 4 or 5 RA10, provided that substitution of R5 with RA10 can only occur by replacing a hydrogen that is covalently bound to either a carbon or a nitrogen of R5, wherein the 1-5 RA10 groups are independently selected from RA10A groups and RA10B groups, provided that R5 cannot be substituted with more than 2 RA10B groups;
• each RA10A, when they occur, is independently selected from halo, alkoxyl, hydroxyl, —CN, —OCF3, —(C1-C4)alkyl and —NH2,
• each RA10B, when they occur, is selected from —O—(C1-C4)alkyl-RA11, —S(O)2—NH2, —S(O)2CH3, —N(H)—S(O)2CH3, —S(O)2N(H)—CH3, —C(O)OH, —(C1-C4)alkyl-OH, —C(O)NH2, and —(C1-C4)alkyl substituted with 1-3 groups selected from —OH and halo;
• RA11 is selected from —C(O)OH, (5-6 membered)heterocycloalkyl, halogen, cyano, nitro, —(C1-C4)alkyl, —N(RA12)2, —ORA12, —SRA12, —N(ORA12)RA12, —C(O)RA12, —C(O)ORA12, —C(O)N(RA12)2, —N(RA12)S(O)RA12, —N(RA12)S(O)2RA12, —S(O)N(RA12)2, —S(O)2N(RA12)2, —S(O)2RA12, —OC(O)RA12, —OC(O)ORA12, —OC(O)N(RA12)2, —N(RA12)C(O)RA12, —N(RA12)S(O)2RA12, —N(RA12)C(O)ORA12, —N(RA12)C(O)N(RA12)2, —N(RA12)C(═NRA12)N(RA12)2, and heteroaryl, wherein each RA12 is independently hydrogen, —(C1-C4)alkyl, or —(C1-C4)haloalkyl;
• and
• each R8 is independently hydrogen, halogen, or methyl, or both R8 taken together with the carbon to which they are both attached form either a (C3-C6)cycloalkyl or a (3-6 membered)heterocycloalkyl.