Pyrazole Amide Derivative

摘要

The present invention relates to a novel compound having a function of inhibiting RORγ activity. The present invention also relates to pharmaceutical composition comprising the compound, a use of the compound in treating or preventing autoimmune diseases, inflammatory diseases, metabolic diseases, or cancer diseases.

主权项

1. A compound represented by formula (I) or a pharmaceutically acceptable salt thereof:wherein:
R1 is selected from F, Cl, Br, a C1 to C6 alkyl group substituted by 0, 1, 2 or 3 Ra groups and a C3 to C8 cycloalkyl group substituted by 0, 1, 2 or 3 Ra groups; Y is selected from a C4 to C6 cycloalkyl group, a C6 to C9 bicycloalkyl group and a C6 to C9 spiroalkyl group, all of which are substituted by a R2 group, 0 or 1 R6 group and 0, 1, 2 or 3 R7 groups; R2 is selected from —OH, —CO2H, —SO3H, —CONH2, —SO2NH2, a (C1 to C6 alkoxy)carbonyl group substituted by 0, 1, 2 or 3 Rc groups, a (C1 to C6 alkyl)aminocarbonyl group substituted by 0, 1, 2 or 3 Rc groups, a C1 to C6 alkylsulfonyl group substituted by 0, 1, 2 or 3 Rc groups, a C1 to C6 alkylaminosulfonyl group substituted by 0, 1, 2 or 3 Rc groups, a (hydroxycarbonyl)(C1 to C3 alkyl) group substituted by 0, 1, 2 or 3 Rc groups, a (C1 to C6 alkoxy)carbonyl(C1 to C3 alkyl) group substituted by 0, 1, 2 or 3 Rc groups, a (C1 to C6 alkyl)sulfonyl(C1 to C3 alkyl) group substituted by 0, 1, 2 or 3 Rc groups and a (C2 to C6 alkenyl)(C1 to C3 alkyl) group substituted by 0, 1, 2 or 3 Rc groups; R6 and R7 are independently selected from H, F, —OH, —NH2, —CN, a C1 to C6 alkyl group substituted by 0, 1, 2 or 3 Rb groups and a C1 to C6 alkoxy group substituted by 0, 1, 2 or 3 Rb groups; R3 is selected from H, F, Cl, —CH3 and —CF3; R4 is selected from a C1 to C6 alkyl group substituted by 0, 1, 2, 3, 4 or 5 Re groups, a (C2 to C6 alkenyl)(C1 to C3 alkyl) group substituted by 0, 1, 2, 3, 4 or 5 Re groups, a (C2 to C6 alkynyl)(C1 to C3 alkyl) group substituted by 0, 1, 2, 3, 4 or 5 Re groups, a (C1 to C6 alkoxy)(C2 to C4 alkyl) group substituted by 0, 1, 2, 3, 4 or 5 Rc groups, a (C6 to C10 aryl)(C1 to C3 alkyl) group substituted by 0, 1, 2, 3, 4 or 5 Rf groups, a (5- to 10-membered heteroaryl)(C1 to C3 alkyl) group substituted by 0, 1, 2, 3, 4 or 5 Rf groups, a C3 to C8 cycloalkyl group substituted by 0, 1, 2, 3, 4 or 5 Rg groups, a C3 to C8 cycloalkenyl group substituted by 0, 1, 2, 3, 4 or 5 Rg groups, a (C3 to C8 cycloalkyl)(C1 to C3 alkyl) group substituted by 0, 1, 2, 3, 4 or 5 Rg groups, a (C3 to C8 cycloalkenyl)(C1 to C3 alkyl) group substituted by 0, 1, 2, 3, 4 or 5 Rg groups, a 3- to 8-membered heterocycloalkyl group substituted by 0, 1, 2, 3, 4 or 5 Rg groups and a (3- to 8-membered heterocycloalkyl)(C1 to C3 alkyl) group substituted by 0, 1, 2, 3, 4 or 5 Rg groups, a C6 to C9 spiroalkyl group substituted by 0, 1, 2, 3, 4 or 5 Rg groups, a (C6 to C9 spiroalkyl)(C1 to C3 alkyl) group substituted by 0, 1, 2, 3, 4 or 5 Rg groups, a C6 to C9 spiroheteroalkyl group substituted by 0, 1, 2, 3, 4 or 5 Rg groups, a C5 to C9 bicycloalkyl group substituted by 0, 1, 2, 3, 4 or 5 Rg groups, a (C5 to C9 bicycloalkyl)(C1 to C3 alkyl) group substituted by 0, 1, 2, 3, 4 or 5 Rg groups, a C6 to C9 heterobicycloalkyl group substituted by 0, 1, 2, 3, 4 or 5 Rg groups, and a (C6 to C9 heterobicycloalkyl)(C1 to C3 alkyl) group substituted by 0, 1, 2, 3, 4 or 5 Rg groups; R5 is selected from a C6 to C10 aryl group substituted by 0, 1, 2, 3, 4 or 5 Ri groups, a 5- to 10-membered heteroaryl group substituted by 0, 1, 2, 3, or 4 Ri groups, a C3 to C8 cycloalkyl group substituted by 0, 1, 2, 3, 4 or 5 Rj groups, a C3 to C8 cycloalkenyl group substituted by 0, 1, 2, 3, 4 or 5 Rj groups and a 3- to 8-membered heterocycloalkyl group substituted by 0, 1, 2, 3, 4 or 5 Rj groups; R8 and R9 are independently selected from H, F, —OH, —NH2, a C1 to C3 alkyl group substituted by 0, 1, 2 or 3 Rh groups, and a C1 to C6 alkoxy group substituted by 0, 1, 2 or 3 Rh groups; or R8 and R9 together form an oxo group or a thioxo group; R12 is H; or R4 and R12 together are —CRmRm—CR13R14—CRmRm- or —CR13R14—CRmRm—CRmRm— to form a pyrrolidine ring; R13 is selected from H, a C1 to C6 alkyl group substituted by 0, 1, 2, 3, 4 or 5 Re groups, a C6 to C10 aryl group substituted by 0, 1, 2, 3, 4 or 5 Rf groups, a C6 to C10 aryloxy group substituted by 0, 1, 2, 3, 4 or 5 Rf groups, a (C2 to C6 alkenyl)(C1 to C3 alkyl) group substituted by 0, 1, 2, 3, 4 or 5 Re groups, a (C2 to C6 alkynyl)(C1 to C3 alkyl) group substituted by 0, 1, 2, 3, 4 or 5 Rc groups, a (C1 to C6 alkoxy)(C2 to C4 alkyl) group substituted by 0, 1, 2, 3, 4 or 5 Re groups, a (C6 to C10 aryl)(C1 to C3 alkyl) group substituted by 0, 1, 2, 3, 4 or 5 Rf groups, a (5- to 10-membered heteroaryl)(C1 to C3 alkyl) group substituted by 0, 1, 2, 3, 4 or 5 Rf groups, a C3 to C8 cycloalkyl group substituted by 0, 1, 2, 3, 4 or 5 Rg groups, a C3 to C8 cycloalkenyl group substituted by 0, 1, 2, 3, 4 or 5 Rg groups, a (C3 to C8 cycloalkyl)(C1 to C3 alkyl) group substituted by 0, 1, 2, 3, 4 or 5 Rg groups, a (C3 to C8 cycloalkenyl)(C1 to C3 alkyl) group substituted by 0, 1, 2, 3, 4 or 5 Rg groups, a 3- to 8-membered heterocycloalkyl group substituted by 0, 1, 2, 3, 4 or 5 Rg groups and a (3- to 8-membered heterocycloalkyl)(C1 to C3 alkyl) group substituted by 0, 1, 2, 3, 4 or 5 Rg groups, a C6 to C9 spiroalkyl group substituted by 0, 1, 2, 3, 4 or 5 Rg groups, a (C6 to C9 spiroalkyl)(C1 to C3 alkyl) group substituted by 0, 1, 2, 3, 4 or 5 Rg groups, a C6 to C9 spiroheteroalkyl group substituted by 0, 1, 2, 3, 4 or 5 Rg groups, a C6 to C9 bicycloalkyl group substituted by 0, 1, 2, 3, 4 or 5 Rg groups, a (C8 to C9 bicycloalkyl)(C1 to C3 alkyl) group substituted by 0, 1, 2, 3, 4 or 5 Rg groups, a C6 to C9 heterobicycloalkyl group substituted by 0, 1, 2, 3, 4 or 5 Rg groups, and a (C6 to C9 heterobicycloalkyl)(C1 to C3 alkyl) group substituted by 0, 1, 2, 3, 4 or 5 Rg groups; R14 is independently selected from H and a C1 to C6 alkyl group substituted by 0, 1, 2, 3, 4 or 5 Re groups; or R13 and R14 together form a C3 to C8 cycloalkane ring substituted by 0, 1, 2, 3, 4 or 5 Rg groups, C3 to C8 cycloalkene ring substituted by 0, 1, 2, 3, 4 or 5 Rg groups, or a 3- to 8-membered heterocycloalkane ring substituted by 0, 1, 2, 3, 4 or 5 Rg groups; Rm is independently selected from H, F, Cl, —CH3 and —CF3; Rg and Rj are, independently selected from F, Cl, a C1 to C6 alkyl group, —OH, —CN, —NH2, —NO2, —CO2H, a C1 to C6 alkoxy group, a mono(C1 to C6 alkyl)amino group, a di(C1 to C6 alkyl)amino group, —CF3, a C1 to C6 alkylene group substituted by 0, 1, 2 or 3 R1 groups, a C2 to C6 alkenylene group substituted by 0, 1, 2 or 3 R1 groups and an oxo group; Rf and Ri are independently selected from F, Cl, Br, —OH, —CN, —NO2, —CO2H, a C1 to C6 alkyl group substituted by 0, 1, 2 or 3 Rk groups, a C2 to C6 alkenyl group substituted by 0, 1, 2 or 3 Rk groups, a C2 to C6 alkynyl group substituted by 0, 1, 2 or 3 Rk groups, a C3 to C8 cycloalkyl group substituted by 0, 1, 2 or 3 Rk groups, a C1 to C6 alkoxy group substituted by 0, 1, 2 or 3 Rk groups, a C3 to C8 cycloalkyloxy group substituted by 0, 1, 2 or 3 Rk groups, —SH, a C1 to C6 alkylthio group substituted by 0, 1, 2 or 3 Rk groups, a C3 to C8 cycloalkylthio group substituted by 0, 1, 2 or 3 Rk groups, a (C1 to C6 alkyl)carbonyl group substituted by 0, 1, 2 or 3 Rk groups, a (C1 to C6 alkoxy)carbonyl group substituted by 0, 1, 2 or 3 Rk groups, a (C1 to C6 alkyl)aminocarbonyl group substituted by 0, 1, 2 or 3 Rk groups, a 3- to 8-membered heterocycloalkyl group substituted by 0, 1, 2 or 3 Rk groups, a C1 to C6 alkylsulfonyl group substituted by 0, 1, 2 or 3 Rk groups, —NH2, a mono(C1 to C6 alkyl)amino group substituted by 0, 1, 2 or 3 Rk groups and a di(C1 to C6 alkyl)amino group substituted by 0, 1, 2 or 3 Rk groups; and Ra, Rb, Rc, Re, Rh, Rk and Rl are independently selected from F, a C1 to C4 alkyl group, —OH, —CN, —NO2, —NH2, —CO2H, a C1 to C6 alkoxy group, a mono(C1 to C6 alkyl)amino group, a di(C1 to C6 alkyl)amino group, —CF3 and an oxo group.