Bicyclic nitrogen containing heteroaryl TGR5 receptor modulators

摘要

Novel compounds of Formula I:or an enantiomer, diastereomer, tautomer, prodrug or salt thereof, wherein m, Q, T, U, V, ring A, X, Y, R3, R4, R4a, R5a, R5b, R5c, R5d, R5e, R6a, R6b, and R6c are defined herein, are provided which are TGR5 G protein-coupled receptor modulators. TGR5 G protein-coupled receptor modulators are useful in treating, preventing, or slowing the progression of diseases requiring TGR5 G protein-coupled receptor modulator therapy. Thus, the disclosure also concerns compositions comprising these novel compounds and methods of treating diseases or conditions related to the activity of the TGR5 G protein-coupled receptor by using any of these novel compounds or a composition comprising any of such novel compounds.;

主权项

1. A compound of formula Ienantiomer, diastereomer, tautomer, prodrug or salt thereof wherein:
m is 1; Q is CR2aR2; T is (C1-C5)-alkyl, (C2-C6)-alkenyl, (C5-10)-aryl or (C5-10)-heteroaryl, all of which may be optionally substituted with one or more substituents selected from hydrogen, 2H, halogen, C1-C6 alkyl, C1-C6 alkoxy, CN, (C3-C12)-cycloalkyl or halo(C1-C6)-alkyl and wherein a carbon atom of the alkyl chain may be replaced with a heteroatom selected from N, O, and S; U is a bond, S, NR7a, O or a (C3-C6)-cycloalkyl; V is a bond, —CH2—, O or a (C3-C6)-cycloalkyl; Ring A is a 5- to 6-membered aryl or heteroaryl, wherein the aryl and heteroaryl may be optionally substituted with one or more substituents selected from hydrogen, halogen, oxo, C1-C6 alkyl, C1-C6 alkoxy, CN, (C3-C12)-cycloalkyl and halo(C1-C6)-alkyl and the heteroaryl contains 1-4 heteroatoms selected from N, O, and S; X is a bond, (C1-C6)-alkyloxy, (C3-C6)-cycloalkyl, (C3-C6)-cycloalkyl-(C1-C6)-alkyl, (C5-10)-aryl, (C5-10)-aryloxy, (C5-10)-aryl-(C1-C6)-alkyl, (C5-10)-aryl-oxy-(C1-C6)-alkyl, (C5-10)-aryl-(C1-C6)-alkyloxy or heteroaryl-(C1-C6)-alkyl, wherein the heteroaryl contains 4- to 10-members and 1-4 heteroatoms selected from N, O, and S and any alkyl, aryl and heteroaryl may be optionally substituted with one or more substituents selected from hydrogen, halogen, C1-C6 alkyl, C1-C6 alkoxy, CN, —COOH, —NR28R29, —OH, (C3-C12)-cycloalkyl, (C3-C12)-cycloalkyloxy and halo(C1-C6)-alkyl; Y is —(CR22R22a)n—W; W is hydrogen, —OH, cyano, heteroaryl, which may be optionally substituted with one or more R20's, heterocycle, which may be optionally substituted with one or more R20's, —N(R18)R19,wherein the amino, hydroxy or acidic moiety may attach at any position of R18;
R2 is hydrogen, —OH, oxo, (C1-C6)-alkyl, (C3-C12)-cycloalkyl or halo(C1-C6)-alkyl; R2a is hydrogen, —OH, oxo, (C1-C6)-alkyl, (C3-C12)-cycloalkyl or halo(C1-C6)-alkyl; or R2 and R2a can optionally be linked to form a linking group containing 1-2 carbon atoms; R3 is hydrogen, (C1-C6)-alkyl, (C3-C12)-cycloalkyl or halo(C1-C6)-alkyl; or R2 and R3 can optionally be linked to form a linking group containing 1-5 carbon atoms to form a (C3-C7)-cycloalkyl ring, a halo(C3-C7)-cycloalkyl ring or an aryl ring; R4, at each occurrence, is independently hydrogen, —OH, halogen, halo(C1-C6)-alkyl or (C1-C8)alkyl; R4a, at each occurrence, is independently is hydrogen, —OH, halogen, halo(C1-C6)-alkyl or (C1-C8)alkyl; or R3 and R4 can optionally be linked with the carbons to which they are attached to form a linking group containing 1-5 carbon atoms to form a (C3-C7)-cycloalkyl ring, a halo(C3-C7)-cycloalkyl ring or an aryl ring; or R4 and R4a can optionally be linked to form a linking group containing 1-4 carbon atoms; R5a is hydrogen, halogen, C1-C6 alkyl, C1-C6 alkoxy, CN, (C3-C6)-cycloalkyl or halo(C1-C6)-alkyl; R5b is hydrogen, halogen, C1-C6 alkyl, C1-C6 alkoxy, CN, (C3-C6)-cycloalkyl or halo(C1-C6)-alkyl; R5c is hydrogen, halogen, C1-C6 alkyl, C1-C6 alkoxy, CN, (C3-C6)-cycloalkyl or halo(C1-C6)-alkyl; R5d is hydrogen, halogen, C1-C6 alkyl, C1-C6 alkoxy, CN, (C3-C6)-cycloalkyl or halo(C1-C6)-alkyl; R5e is hydrogen, halogen, C1-C6 alkyl, C1-C6 alkoxy, CN, (C3-C6)-cycloalkyl or halo(C1-C6)-alkyl; or two of R5a, R5b, R5c, R5d or R5e may be taken together with the atoms to which both are attached form a 3- to 8-membered ring, which may optionally contain 1-4 heteroatoms selected from N, O, and S; R6a is hydrogen, halogen or C1-C6 alkyl; R6b is hydrogen, halogen or C1-C6 alkyl; R6c is hydrogen, halogen or C1-C6 alkyl; R7a is hydrogen, C1-C6 alkyl or —CO2(C1-C6)-alkyl; n is 0-6; R16 is H or —CN; R18, at each occurrence, is independently (C1-C8)alkyl, (C3-C12)-cycloalkyl, a fused (C3-C18)-cycloalkyl, (C1-C8)alkyl-(C3-C12)-cycloalkyl-(C1-C8)alkyl, (C1-C8)alkyl-(C3-C12)-cycloalkyl, (C5-10)-aryl, (C5-C10)-aryl(C1-C8)alkyl, a heteroaryl, a heteroaryl(C1-C8)alkyl, a heterocyclo(C1-C8)alkyl or a heterocyclo, all of which may be optionally substituted with one or more R20's and wherein the heteroaryl and heterocyclo contain 4- to 10-members and contain 1-4 heteroatoms selected from N, O, and S; R19, at each occurrence, is independently hydrogen, (C1-C6)-alkyl, (C3-C12)-cycloalkyl, (C6-10)aryl, a 4- to 10-membered heteroaryl, which contains 1-4 heteroatoms selected from N, O, and S; or a 4- to 10-membered heterocyclo, which contains 1-4 heteroatoms selected from N, O, and S, wherein the alkyl, cycloalkyl, aryl, heteroaryl and heterocyclo may be optionally substituted with one or more R20's; or R18 and R19 are taken together with the nitrogen to which both are attached to form a 3- to 8-membered ring, which may optionally contain 1-4 heteroatoms selected from N, O, and S and be optionally substituted with one or more R20's; R20, at each occurrence, is selected from halo, —OH, (C1-C6)-alkyl, (C2-C6)-alkenyl, (C2-C6)-alkynyl, —(C3-C12)-cycloalkyl, (C1-C6)-alkyloxy, cyano, oxo, nitro, —COOH, —SO3H, —CO(C1-C6)-alkyl, —CO(C6-C12)-aryl, —CO2(C1-C6)-alkyl, —CONR28R29, —NR28R29, —NR28C(═O)NR28R29, —NR28C(═NR29)NR28R29, —SR28, —S(═O)(═NR28)R29, —S(—OH)R29, —S(═O)R29, —S(═O)2R29, —NR29CO2(C1-C6)-alkyl, —NR28SO2R19, —O(C═O)—(C1-C6)-alkyl, —O(C═O)NR28R29; —(C1-C6)-alkylCOOH, —(C1-C6)-alkylOH, —(C1-C6)-alkyl(NH2)COOH, —(C1-C6)-alkylCONR28R29, —(C1-C6)-alkyl-CO2(C1-C6)-alkyl, —O—P(═O)(OH)(OR29), —O—CR28R29—P(═O)(OH)(OR29), —P(═O)(OH)(OR29), (C6-10)aryl, (C6-10)aryl(C1-C6)-alkyl, (C6-10)aryloxy, a 4- to 10-membered heteroaryl, which contains 1-4 heteroatoms selected from N, O, and S; or a 4- to 10-membered heterocyclo, which contains 1-4 heteroatoms selected from N, O, and S; wherein any alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclo may be optionally substituted with one or more substituents selected from the group consisting of: halo, —OH, (C1-C6)-alkyl, (C2-C6)-alkenyl, (C2-C6)-alkynyl, (C1-C6)-alkyloxy, cyano, nitro, —COOH, —CO(C1-C6)-alkyl, —CO2(C1-C6)-alkyl, —CONR28R29, —NR28R29, —N(R28)R29R29, —O(C═O)—(C1-C6)-alkyl, —O(C═O)NR28R29; —(C1-C6)-alkylCOOH, —(C1-C6)-alkylOH, —(C1-C6)-alkyl(NH2)COOH, —(C1-C6)-alkylCONR28R29, —(C1-C6)-alkyl-CO2(C1-C6)-alkyl, —O—P(═O)(OH)(OR29), —O—CR28R29—P(═O)(OH)(OR29), —P(═O)(OH)(OR29), —S(═O)2OH, (C6-10)aryl, a 4- to 10-membered heteroaryl, which contains 1-4 heteroatoms selected from N, O, and S, a 4- to 10-membered heterocyclo, which contains 1-4 heteroatoms selected from N, O, and S; halo(C1-C6)alkyl, and halo(C1-C6)alkyloxy; R22, at each occurrence, is independently hydrogen, —OH, (C1-C6)-alkyl, (C3-C12)-cycloalkyl, (C6-10)aryl, a 4- to 10-membered heteroaryl, which contains 1-4 heteroatoms selected from N, O, and S; or a 4- to 10-membered heterocyclo, which contains 1-4 heteroatoms selected from N, O, and S, wherein the alkyl, cycloalkyl, aryl, heteroaryl and heterocyclo may be optionally substituted with one or more substituents selected from hydrogen, —OH, halogen, C1-C6 alkyl, C1-C6 alkoxy, CN, (C3-C12)-cycloalkyl and halo(C1-C6)-alkyl; R22a, at each occurrence, is independently hydrogen, —OH, (C1-C6)-alkyl, (C3-C12)-cycloalkyl, (C6-10)aryl, a 4- to 10-membered heteroaryl, which contains 1-4 heteroatoms selected from N, O, and S; or a 4- to 10-membered heterocyclo, which contains 1-4 heteroatoms selected from N, O, and S, wherein the alkyl, cycloalkyl, aryl, heteroaryl and heterocyclo may be optionally substituted with one or more substituents selected from hydrogen, —OH, halogen, C1-C6 alkyl, C1-C6 alkoxy, CN, (C3-C12)-cycloalkyl and halo(C1-C6)-alkyl; R28 and R29, at each occurrence, are independently hydrogen, (C3-C12)-cycloalkyl, or (C1-C8)alkyl, wherein the cycloalkyl and alkyl may be optionally substituted with one or more substituents selected from the group consisting of: halo, —OH, (C1-C6)-alkyl, (C2-C6)-alkenyl, (C2-C6)-alkynyl, (C1-C6)-alkyloxy, cyano, nitro, —COOH, —CO(C1-C6)-alkyl, —CO2(C1-C6)-alkyl, —CONR38R39, —NR38R39, —O(C═O)—(C1-C6)-alkyl, —O(C═O)NR38R39; —(C1-C6)-alkylCOOH, —(C1-C6)-alkylOH, —(C1-C6)-alkyl(NH2)COOH, —(C1-C6)-alkylCONR38R39, —(C1-C6)-alkyl-CO2(C1-C6)-alkyl, —O—P(═O)(OH)(OR39), —O—CR38R39—P(═O)(OH)(OR39), —P(═O)(OH)(OR39), —S(═O)2OH, (C6-10)aryl, a 4- to 10-membered heteroaryl, which contains 1-4 heteroatoms selected from N, O, and S, a 4- to 10-membered heterocyclo, which contains 1-4 heteroatoms selected from N, O, and S; halo(C1-C6)alkyl, and halo(C1-C6)alkyloxy; or R28 and R29 are taken together with the nitrogen to which both are attached to form a 3- to 8-membered ring, which may optionally contain 1-4 heteroatoms selected from N, O, and S; R38 and R39, at each occurrence, are independently hydrogen or (C1-C8)alkyl; or R38 and R39 are taken together with the nitrogen to which both are attached to form a 3- to 8-membered ring, which may optionally contain 1-4 heteroatoms selected from N, O, and S.