Glucokinase activators

摘要

Provided are compounds of Formula I wherein R1, R2, Y, Z and G are as defined herein, that are useful in the treatment and/or prevention of diseases mediated by deficient levels of glucokinase activity, such as diabetes mellitus. Also provided are methods of treating or preventing diseases and disorders characterized by underactivity of glucokinase or which can be treated by activating glucokinase.;

主权项

1. A compound selected from the Formulaand pharmaceutically acceptable salts thereof, wherein:
G is N or CR11; Z is N or CR3; Y is N or CR4, wherein at least one of G or Z is not N; R1 is R2 is a monocyclic or bicyclic aryl or heteroaryl, wherein said monocyclic and bicyclic aryl and heteroaryl are optionally substituted with one or more groups independently selected from alkyl, alkenyl, alkynyl, heteroalkyl, saturated and partially unsaturated Vn-cycloalkyl, saturated and partially unsaturated Vn-heterocycloalkyl, Vn-aryl, Vn-heteroaryl, F, Cl, Br, I, CF3, cyano, Vn—OR6, Vn—C(═O)R6, Vn—C(═O)OR6, Vn—OC(═O)R6, Vn—O(CH2)nC(═O)OR6, Vn—O(CH2)C(═O)NR6R7, Vn—C(═O)NR6R7, Vn—NR6R7, Vn—NR6C(═O)R7, Vn—SR6, Vn—S(O)R6, and Vn—S(O)2R6, wherein said alkyl, alkenyl, alkynyl, heteroalkyl, Vn-cycloalkyl, Vn-heterocycloalkyl, Vn-aryl, and Vn-heteroaryl are optionally substituted with one or more groups independently selected from oxo, alkyl, alkenyl, alkynyl, heteroalkyl, saturated and partially unsaturated Vn-cycloalkyl, saturated and partially unsaturated Vn-heterocycloalkyl, Vn-aryl, Vn-heteroaryl, F, Cl, Br, I, CF3, cyano, Vn—OR8, Vn—C(═O)R8, Vn—C(═O)OR8, Vn—OC(═O)R8, Vn—C(═O)NR8R9, Vn—NR8R9, Vn—NR8C(═O)R9, Vn—SR8, Vn—S(O)R8, and Vn—S(O)2R8; R3 is H, alkyl, alkenyl, alkynyl, heteroalkyl, saturated or partially unsaturated Vn-cycloalkyl, saturated or partially unsaturated Vn-heterocycloalkyl, Vn-aryl, Vn-heteroaryl, F, Cl, Br, I, CN, Vn—OR6, Vn—C(═O)R6, Vn—C(═O)OR6, Vn—OC(═O)R6, Vn—C(═O)NR6R7, Vn—NR6R7, Vn—NR6C(═O)R7, Vn—SR6, Vn—S(O)R6, Vn—S(O)2R6, or Vn—S(O)2NR6R7, wherein said alkyl, alkenyl, alkynyl, heteroalkyl, Vn-cycloalkyl, Vn-heterocycloalkyl, Vn-aryl, and Vn-heteroaryl are optionally substituted with one or more groups independently selected from oxo, alkyl, alkenyl, alkynyl, heteroalkyl, saturated and partially unsaturated Vn-cycloalkyl, saturated and partially unsaturated Vn-heterocycloalkyl, Vn-aryl, Vn-heteroaryl, F, Cl, Br, I, CF3, cyano, Vn—OR8, Vn—C(═O)R8, Vn—C(═O)OR8, Vn—OC(═O)R8, Vn—C(═O)NR8R9, Vn—NR8R9, Vn—NR8C(═O)R9, Vn—SR8, Vn—S(O)R8, Vn—S(O)2R8, and Vn—S(O)2NR8R9; R4 is H, methyl, ethyl, F, Cl, Br, I, CF3, CHF2, or CH2F; R6 and R7 are independently H, alkyl, alkenyl, alkynyl, saturated or partially unsaturated Vn-cycloalkyl, saturated or partially unsaturated Vn-heterocycloalkyl, Vn-aryl, Vn-heteroaryl, Vn—OR8, Vn—NR8R9, Vn—C(═O)NR8R9, or Vn—C(═O)R8, wherein said alkyl, alkenyl, alkynyl, Vn-cycloalkyl, Vn-heterocycloalkyl, Vn-aryl, and Vn-heteroaryl are optionally substituted with one or more groups independently selected from oxo, alkyl, alkenyl, alkynyl, heteroalkyl, saturated and partially unsaturated Vn-cycloalkyl, saturated and partially unsaturated Vn-heterocycloalkyl, Vn-aryl, Vn-heteroaryl, F, Cl, Br, I, CF3, cyano, Vn—OR8, Vn—C(═O)R8, Vn—C(═O)OR8, Vn—OC(═O)R8, Vn—C(═O)NR8R9, Vn—NR8R9, Vn—NR8C(═O)R9, Vn—SR8, Vn—S(O)R8, Vn—S(O)2R8, and Vn—S(O)2NR8R9; or R6 and R7 together with the atoms to which they are attached form a saturated or partially unsaturated heterocyclic ring, wherein said heterocyclic ring optionally comprises one or more additional ring heteroatoms independently selected from N, O or S, wherein said heterocyclic ring is optionally substituted with one or more groups independently selected from oxo, F, Cl, Br, I, Vn—OR8, Vn—C(═O)OR8, Vn—C(═O)NR8R9, Vn—NR8R9, Vn—NR8C(═O)R9, Vii—NR8C(═O)NR9R10, alkyl, alkenyl, and alkynyl; R8, R9 and R10 are independently H, alkyl, alkenyl, alkynyl, saturated or partially unsaturated Vn-cycloalkyl, saturated or partially unsaturated Vn-heterocycloalkyl, Vn-aryl or Vn-heteroaryl, wherein said alkyl, alkenyl, alkynyl, Vn-cycloalkyl, Vn-heterocycloalkyl, Vn-aryl and Vn-heteroaryl are optionally substituted with one or more groups independently selected from oxo, alkyl, alkenyl, alkynyl, saturated and partially unsaturated Vn-cycloalkyl, saturated and partially unsaturated Vn-heterocycloalkyl, Vn-aryl, Vn-heteroaryl, F, Cl, Br, I, Vn—ORa, Vn—NRaRb, Vn—C(═O)ORa, Vn—C(═O)NRaRb, and Vn—NRaC(═O)Rb, or R8 and R9 together with the atoms to which they are attached form a saturated or partially unsaturated heterocyclic ring, wherein said heterocyclic ring optionally comprises one or more additional ring heteroatoms independently selected from N, O or S, wherein said heterocyclic ring is optionally substituted with one or more groups independently selected from oxo, alkyl, alkenyl, alkynyl, F, Cl, Br, I, Vn—ORa, and CN; or R9 and R10 together with the atoms to which they are attached form a saturated or partially unsaturated heterocyclic ring, wherein said heterocyclic ring optionally comprises one or more additional ring heteroatoms independently selected from N, O or S, wherein said heterocyclic ring is optionally substituted with one or more groups independently selected from oxo, alkyl, alkenyl, alkynyl, F, Cl, Br, I, Vn—ORa, and CN; R11 is H, methyl, ethyl, F, Cl, Br, I, CF3, CHF2, CH2F, OH, O—(C1-C4 alkyl), or NH2; R12 is hydrogen; R13 is selected from H, Cl, methyl, ethyl, isopropyl, butyl, isobutyl, cyclopropyl, cyclohexyl, —CH2CH2OH, —CO2H, —(CH2)2CO2H, —CH2CO2CH3, —(CH2)2CO2CH3, —CH2C(O)NH2, —(CH2)2NHC(O)CH3, CH2CH2NHSO2—N(CH3)2, 4-piperidyl, —(CH2-isoincloline-1,3-dion-2-yl, Ra and Rb are independently H, alkyl, alkenyl, alkynyl, saturated or partially unsaturated Vn-cycloalkyl, saturated or partially unsaturated Vn-heterocycloalkyl, Vn-aryl, or Vn-heteroaryl, wherein said alkyl, alkenyl, alkynyl, saturated or partially unsaturated Vn-cycloalkyl, saturated or partially unsaturated Vn-heterocycloalkyl, Vn-aryl, or Vn-heteroaryl are optionally substituted by OH; V is alkylene having from 1 to 4 carbons, or alkenylene or alkynylene each having from 2 to 4 carbons, wherein said alkylene, alkenylene, or alkynylene are optionally substituted with one or more groups independently selected from alkyl, alkenyl, alkynyl, heteroalkyl, saturated and partially unsaturated Vn-cycloalkyl, saturated and partially unsaturated Vn-heterocycloalkyl, Vn-aryl, Vn-heteroaryl, F, Cl, Br, I, CF3, cyano, Vn—OR8, Vn—C(═O)OR8, Vn—OC(═O)R8, Vn—C(═O)NR8R9, Vn—NR8R9, and Vn—NR8C(═O)R9; and n is 0, 1, 2, 3 or 4.