(Indazol-4-YL) Hexahydropyrrolopyrrolones and Methods of Use

摘要

Compounds of formula (I);;and pharmaceutically acceptable salts, esters, amides, or radiolabelled forms thereof, wherein GAr, L1, Z1 and Z2 are as defined in the specification, are useful in treating conditions or disorders prevented by or ameliorated by voltage-gated sodium channels, e.g., Nav 1.7 and/or Nav 1.8. Methods for making the compounds are disclosed. Also disclosed are pharmaceutical compositions of compounds of formula (I), and methods for using such compounds and compositions.

主权项

1. A compound of formula (I): or a pharmaceutically acceptable salt or isotopically labelled form thereof, wherein: one of Z1 and Z2 is NR1 and the other of Z1 and Z2 is CH2; R1 is selected from the group consisting of —CH2G1, —CH2G2, —C(O)-G1, —C(O)-G2, —C(O)—R2, —C(O)N(Ra)—R2, —C(O)N(Ra)(Rb), —SO2-G1, —SO2-G2, —SO2—R2, —SO2N(Ra)—R2, and —SO2N(Ra)(Rb); R2 is selected from the group consisting of C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, —(CR4aR5a)m—NO2, —(CR4aR5a)m—OR1a, —(CR4aR5a)m—OC(O)R1a, —(CR4aR5a)m—OC(O)N(Rb)(R3a), —(CR4aR5a)m—SR1a, —(CR4aR5a)m—S(O)2R2a, —(CR4aR5a)m—S(O)2N(Rb)(R3a), —(CR4aR5a)m—C(O)R1a, —(CR4aR5a)m—C(O)OR1a, —(CR4aR5a)m—C(O)N(Rb)(R3a), —(CR4aR5a)m—N(Rb)(R3a), —(CR4aR5a)m—N(Ra)C(O)R1a, —(CR4aR5a)m—N(Ra)S(O)2R2a, —(CR4aR5a)m—N(Ra)C(O)O(R1a), —(CR4aR5a)m—N(Ra)C(O)N(Rb)(R3a), —(CR4aR5a)m-G1, —(CR4aR5a)m-G2, cyano-C1-C6-alkyl, and halo-C1-C6-alkyl; Ra and Rb, at each occurrence, are each independently hydrogen, C1-C6-alkyl, or halo-C1-C6-alkyl; Rc at each occurrence, is independently hydrogen, C1-C6-alkyl, aryl, aryl-C1-C6-alkyl, cycloalkyl, cycloalkyl-C1-C6-alkyl, or halo-C1-C6-alkyl; wherein said aryl, the aryl of aryl-C1-C6-alkyl, the cycloalkyl, and the cycloalkyl of cycloalkyl-C1-C6-alkyl are independently unsubstituted or substituted with 1, 2 3, 4, or 5 substituents independently selected from the group consisting of C1-C6-alkyl, halo-C1-C6-alkyl, and halogen; Rd at each occurrence, is independently C1-C6-alkyl or halo-C1-C6-alkyl; R1a and R3a, at each occurrence, are each independently hydrogen, C1-C6-alkyl, halo-C1-C6-alkyl, -G1, or —(CR4aR5a)n-G1; R2a, at each occurrence, is independently C1-C6-alkyl, halo-C1-C6-alkyl, -G1, or —(CR4aR5a)n-G1; R4a and R5a, at each occurrence, are each independently hydrogen, halogen, C1-C6-alkyl, or halo-C1-C6-alkyl; GAr is phenyl or a 6-membered heteroaryl; wherein GAr is unsubstituted or substituted with 1, 2, 3, 4, or 5 substituents selected from the group consisting of C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, cyano, halo-C1-C6-alkyl, and halogen; G1 is aryl or heteroaryl; wherein G1 is unsubstituted or substituted with 1, 2, 3, 4, or 5 substituents selected from the group consisting of C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, cyano, halo-C1-C6-alkyl, halogen, nitro, —N(Rc)2, —N(Rc)C(O)Rc, —C(O)Rc, —C(O)ORc, —C(O)N(Rc)2, —SO2Ra, —SO2N(Rc)2, and —CH2G3; G2 is cycloalkyl, cycloalkenyl, or heterocycle; wherein G2 is unsubstituted or substituted with 1, 2, 3, 4, or 5 substituents selected from the group consisting of C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, cyano, halo-C1-C6-alkyl, halogen, nitro, oxo, —N(Rc)2, —N(Rc)C(O)Rc, —C(O)Rc, —C(O)OR, —C(O)N(Rc)2, —SO2Ra, and —SO2N(Rc)2; G3 is aryl, heteroaryl, heterocycle, cycloalkyl, or cycloalkenyl, wherein each G3 is independently unsubstituted or substituted with 1, 2, 3, 4 or 5 substituents selected from the group consisting of C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, halogen, cyano, oxo, —NO2, —OR1a, —OC(O)R1a, —OC(O)N(Rb)(R3a), —SR1a, —S(O)2R2a, —S(O)2N(Rb)(R3a), —C(O)R1a, —C(O)OR1a, —C(O)N(Rb)(R3a), —N(Rb)(R3a), —N(Ra)C(O)R1a, —N(Ra)S(O)2R2a, —N(Ra)C(O)O(R1a), —N(Ra)C(O)N(Rb)(R3a), —(CR4aR5a)m—NO2, —(CR4aR5a)m—OR1a, —(CR4aR5a)m—OC(O)R1a, —(CR4aR5a)m—OC(O)N(Rb)(R3a), —(CR4aR5a)m—SR1a, —(CR4aR5a)m—S(O)2R2a, —(CR4aR5a)m—S(O)2N(Rb)(R3a), —(CR4aR5a)m—C(O)R1a, —(CR4aR5a)m—C(O)OR11, —(CR4aR5a)m—C(O)N(Rb)(R3a), —(CR4aR5a)m—N(Rb)(R3a), —(CR4aR5a)m—N(Ra)C(O)R1a, —(CR4aR5a)m—N(Ra)S(O)2R2a, —(CR4aR5a)m—N(Ra)C(O)O(R1a), —(CR4aR5a)m—N(Ra)C(O)N(Rb)(R3a), cyano-C1-C6-alkyl, and halo-C1-C6-alkyl; L1 is a bond or —CH2—; and m and n, at each occurrence, are each independently 1, 2, 3, 4, or 5.