A method of treating a disease or disorder associated with activation of TGR5 comprising, administering to a patient in need thereof an effective amount of a compound of Formula (I′), wherein the disease or disorder associated with the activation of TGR5 is selected the group consisting of diabetes, Type II diabetes, gestational diabetes, impaired fasting glucose, impaired glucose tolerance, insulin resistance, hyperglycemia, obesity, metabolic syndrome, fatty liver, non-alcoholic fatty liver disease (NAFLD), liver fibrosis, non-alcoholic steatohepatitis (NASH), primary sclerosing cholangitis (PSC), liver cirrhosis, and primary biliary cirrhosis (PBC):
- or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof,
- wherein:
- Q is C═(O), —CH2—, —NR5— or —O—;
- when Q is C═(O) then Q1 is —NR5—, when Q is —NR5— or —O— then Q1 is —CH2—, or when Q is —CH2— then Q1 is −O(CH2)0-1— or —NR5—;
- X1 is CR6 or N;
- X2 is CR7 or N;
- X3 is CR8 or N;
- X4 is CR9 or N;
- Y is CRb or N;
- Ra and Rb are each independently H, (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) haloalkyl, (C1-C6) haloalkoxy, or halogen;
- R1 is H, (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) haloalkyl, (C1-C6) haloalkoxy, halogen, —S(O)p(C1-C6) alkyl, (C3-C8) cycloalkyl, heterocycloalkyl, —O—(C3-C8) cycloalkyl, or —O-heterocycloalkyl, wherein the alkyl, alkoxy, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more substituents selected from the group consisting of halogen, (C1-C4) alkoxy, —OH, —NH2, —NH(C1-C4) alkyl, and —N((C1-C4) alkyl)2;
- or
- R1 and Ra together with the carbon atoms to which they are attached form a heterocycloalkyl;
- or
- R1 and R3, when on adjacent atoms, together with the carbon atoms to which they are attached form a heterocycloalkyl optionally substituted with one or more substituents selected from the group consisting of (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) haloalkyl, (C1-C6) haloalkoxy, and halogen;
- R2 is (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) haloalkyl, or (C1-C6) haloalkoxy;
- R2′ is H, (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) haloalkyl, or (C1-C6) haloalkoxy;
- or
- R2 and R2′ together with the carbon atom to which they are attached form a (C3-C8) cycloalkyl or heterocycloalkyl;
- each R3 is independently, at each occurrence, (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) haloalkyl, (C1-C6) haloalkoxy, halogen, —S(O)p(C1-C6) alkyl, (C3-C8) cycloalkyl, heterocycloalkyl, —O—(C3-C8) cycloalkyl, or —O-heterocycloalkyl, wherein the alkyl, alkoxy, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more substituents selected from the group consisting of halogen, (C1-C4) alkoxy, —OH, —NH2, —NH(C1-C4) alkyl, and —N((C1-C4) alkyl)2;
- or
- R1 and R3 together with the carbon atoms to which they are attached form a heterocycloalkyl optionally substituted with one or more substituents selected from the group consisting of (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) haloalkyl, (C1-C6) haloalkoxy, and halogen;
- R4 is H, (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) haloalkyl, (C1-C6) haloalkoxy, (C1-C6) hydroxyalkyl, (C1-C6) aminoalkyl, halogen, (C3-C8) cycloalkyl, heterocycloalkyl, —OH, —NH2, CN, —S(O)m(C1-C6) alkyl, —NH(C1-C4) alkyl, or —N((C1-C4) alkyl)2;
- each R5 is independently H, (C1-C6) alkyl, —C(O)NR10R11, —C(O)(C1-C6) alkyl, or —C(O)O(C1-C6) alkyl;
- each R6 and R9 is independently H, (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) haloalkyl, (C1-C6) haloalkoxy, (C1-C6) hydroxyalkyl, (C1-C6) aminoalkyl, halogen, (C3-C8) cycloalkyl, heterocycloalkyl, —OH, —NH2, CN, —S(O)o(C1-C6) alkyl, —NH(C1-C4) alkyl, or —N((C1-C4) alkyl)2;
- each R7 and R8 is independently H, (C1-C8) alkenyl, (C1-C8) alkynyl, (C1-C6) alkoxy, (C1-C6) haloalkyl, (C1-C6) haloalkoxy, (C1-C6) hydroxyalkyl, (C1-C6) aminoalkyl, halogen, (C3-C8) cycloalkyl, (C3-C8) cycloalkenyl, heterocycloalkyl, —OH, —NH2, —S(O)qNH2, —S(O)qOH, CN, or (C1-C18) alkyl, wherein 0 to 7 methylene of the (C1-C18) alkyl is optionally replaced by a moiety selected from the group consisting of —O—, —NR13—, —S(O)q—, —C(O)—, —C(CH2)—, or —C(NH)—, provided that when any two methylene in the alkyl is replaced, then two —O—, two —S(O)q—, or two —NR13— and —O— and —NR13— are not contiguous, wherein the alkyl is optionally substituted with one or more R12, and wherein the cycloalkyl and cycloalkenyl are optionally substituted with one or more R13;
- R10 and R11 are each independently H or (C1-C6) alkyl optionally substituted with one or more substituent independently selected from the group consisting of —NH2 and OH;
- R12 is D, —OH, halogen, —NH2, —NH(C1-C6) alkyl, —N((C1-C6) alkyl)2, —C(O)OH, —OC(O)(C1-C6) alkyl, (C3-C8) cycloalkyl, heterocycloalkyl, (C6-C10) aryl, heteroaryl, or R17, wherein the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally substituted with one or more substituents selected from the group consisting of —OH, —NH2, —NH(C1-C6) alkyl, —N((C1-C6) alkyl)2, halogen, and R14;
- R13 is H, —OH, (C3-C8) cycloalkyl, heterocycloalkyl, (C6-C10) aryl, heteroaryl, or (C1-C12) alkyl, wherein 0 to 7 methylene of the (C1-C12) alkyl is optionally replaced by a moiety selected from the group consisting of —O—, —NR13—, —S(O)r—, —C(O)—, or —C(NH)—, provided that a when any two methylene in the alkyl is replaced, then O and N are not contiguous and wherein the alkyl is optionally substituted with one or more R15, and wherein the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally substituted with one or more substituents selected from the group consisting of —OH, —C(O)OH, —NH2, —NH(C1-C6) alkyl, and —N((C1-C6) alkyl)2;
- R14 is (C3-C8) cycloalkyl, heterocycloalkyl, —O—(C3-C8) cycloalkyl, —O-heterocycloalkyl, (C1-C12) alkyl or (C2-C12) alkenyl, wherein 0 to 7 methylene of the (C1-C12) alkyl and the (C2-C12) alkenyl are optionally replaced by a moiety selected from the group consisting of —O—, —NR13—, —S(O)r—, —C(O)—, or —C(NH)—, provided that a when any two methylene in the alkyl or alkenyl is replaced, then O and N are not contiguous and wherein the alkyl and alkenyl are optionally substituted with one or more R15, and the cycloalkyl and heterocycloalkyl are optionally substituted with one or more R16;
- or
- when R12 is cycloalkyl or heterocycloalkyl, two R14 together with the atom to which they are attached form C═(O);
- or when R12 is cycloalkyl or heterocycloalkyl, two R14 together with the atoms to which they are attached form a (C3-C8) cycloalkyl or heterocycloalkyl optionally substituted with one or more R13;
- or when R12 is cycloalkyl or heterocycloalkyl, two R14 together with the atom to which they are attached form a (C3-C8) spirocycloalkyl or a spiroheterocycloalkyl optionally substituted with one or more R13;
- or when R12 is cycloalkyl or heterocycloalkyl, two R14 together with the atom to which they are attached form a (C6-C10) aryl or heteroaryl optionally substituted with one or more R13;
- R15 is —OH, —NH2, —NH(C1-C6) alkyl, —N((C1-C6) alkyl)2, (C3-C8) cycloalkyl, heterocycloalkyl, (C6-C10) aryl or heteroaryl, wherein the (C3-C8) cycloalkyl and heterocycloalkyl are optionally substituted with one or more substituents selected from the group consisting of (C1-C6) hydroxyalkyl, (C1-C6) aminoalkyl, —C(O)OH, —OH, —NH2, —NH(C1-C6) alkyl, —N((C1-C6) alkyl)2, and oxo;
- R16 is —OH, —C(O)OH, —NH2, —NH(C1-C6) alkyl, —N((C1-C6) alkyl)2, (C1-C6) alkoxy, (C1-C6) hydroxyalkyl, (C3-C8) cycloalkyl, heterocycloalkyl, —O—(C3-C8) cycloalkyl, —O-heterocycloalkyl, (C6-C10) aryl or heteroaryl, wherein the (C3-C8) cycloalkyl and heterocycloalkyl are optionally substituted with one or more substituents selected from the group consisting of (C1-C6) hydroxyalkyl, (C1-C6) aminoalkyl, —C(O)OH, —OH, —NH2, —NH(C1-C6) alkyl, —N((C1-C6) alkyl)2, and oxo;
- R17 is (C1-C18) alkyl or (C2-C18) alkenyl, wherein 0 to 8 methylene of the (C1-C18) alkyl and the (C2-C18) alkenyl are optionally replaced by a moiety selected from the group consisting of —O—, —NR13—, —S(O)r—, —C(O)—, or —C(NH)—, provided that a when any two methylene in the alkyl or alkenyl is replaced, then O and N are not contiguous and wherein the alkyl and alkenyl are optionally substituted with one or more R18;
- R18 is R19, (C6-C10) aryl, or heteroaryl optionally substituted with one or more R21;
- R19 is (C1-C18) alkyl wherein 0 to 8 methylene of the (C1-C18) alkyl is optionally replaced by a moiety selected from the group consisting of —O—, —NR13—, —S(O)r—, —C(O)—, or —C(NH)—, provided that a when any two methylene in the alkyl or alkenyl is replaced, then O and N are not contiguous and wherein the alkyl is optionally substituted with one or more R20;
- R20 is (C6-C10) aryl or heteroaryl optionally substituted with one or more R21;
- R21 is H, (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) haloalkyl, (C1-C6) haloalkoxy, or halogen;
- or
- two R21 together when on adjacent atoms form a cycloalkyl or heterocycloalkyl optionally substituted with one or more R22;
- R22 is —C(O)NH2, —C(O)NH(C1-C6) alkyl, —C(O)N((C1-C6) alkyl)2, —C(O) (C3-C7) cycloalkyl, or —C(O)heterocycloalkyl, wherein the cycloalkyl and heterocycloalkyl are optionally substituted with one or more substituents independently selected from the group consisting of —OH and CN;
- each m, o, p, q, and r is independently, at each occurrence, 0, 1, or 2;
- and
- n is 0, 1, or 2.