Tetrahydro[1,8]naphthyridine Sulfonamide and Related Compounds for Use as Agonists of RORy and the Treatment of Disease

摘要

The invention provides tetrahydro[1,8]naphthyridine and related compounds, methods of promoting RORy activity and/or increasing the amount of iL-17 in a subject, and therapeutic uses of the tetrahydro[1,8]naphthyridine and related compounds. In particular, the invention provides sulfonamide-tetrahydro[1,8]naphthyridine and related compounds, methods of using such compounds to promote RORy activity and/or increase the amount of iL-17 in a subject, and treat medical conditions in which activation of immune response would be beneficial such as in cancer and infections.

主权项

1. A compound represented by Formula I: or a pharmaceutically acceptable salt or solvate thereof; wherein: A is aryl, aralkyl, heteroaryl, cycloalkyl, or heterocycloalkyl; each of which is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, hydroxyl, C1-6alkyl, C1-6haloalkyl, C1-6hydroxyalkyl, C1-6alkoxy, C1-6haloalkoxy, —N(R4)(R5), —CO2R6, —C(O)R6, —CN, —C1-4alkylene-C1-4alkoxy, —C1-4alkylene-N(R4)(R5), —C1-4alkylene-CO2R6, —O—C1-6alkylene-N(R4)(R5), —N(R4)C(O)—C1-6alkylene-N(R4)(R5), —S(O)pC1-6alkyl, —SO2N(R4)(R5), —N(R4)SO2(C1-6alkyl), —C(O)N(R4)(R5), and —N(R4)C(O)N(R4)(R5); X is —O—[C(R6)(R7)]-[C(R6)2]m-ψ, —O—C(R6)2—C(R6)(R7)—C(R6)2-ψ, —O—C(R6)2—C(R6)(R7)-ψ, —C(R6)2—[C(R6)(R7)]-[C(R6)2]m-ψ, —C(O)—[C(R6)(R7)]-[C(R6)2]m-ψ, —C(R6)2—N(R8)—[C(R6)(R7)]-[C(R6)2]m-ψ, —C(R6)═N-ψ, —C(R6)2C(R6)═N-ψ, —N═C(R6)-ψ, or —N═C(R6)C(R6)2-ψ; wherein ψ is a bond to the sulfonamide ring nitrogen atom in Formula I; Y is —N(R2)(R3) or —O-aralkyl, wherein said aralkyl is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, hydroxyl, C1-6alkoxy, C1-6haloalkoxy, C1-6alkyl, C1-6haloalkyl, —N(R4)(R5), —CN, —CO2—C1-6alkyl, —C(O)—C1-6alkyl, —C(O)N(R4)(R5), —S(O)pC1-6alkyl, —SO2N(R4)(R5), and —N(R4)SO2(C1-6alkyl); R1 represents independently for each occurrence hydrogen, halogen, or C1-6alkyl; R2 is —C(O)-aryl, —C(O)-aralkyl, —C(O)—[C(R6)2]m-cycloalkyl, —C(O)—[C(R6)2]m-heterocyclyl, —C(O)—C1-8alkyl, —C(O)—C1-6alkylene-C1-6alkoxyl, —C(O)—C1-6alkylene-cycloalkyl, or —C(O)—C1-6alkylene-heterocycloalkyl; each of which is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, hydroxyl, C1-6alkoxy, C1-6haloalkoxy, C1-6alkyl, C1-6haloalkyl, —N(R4)(R5), —CN, —CO2—C1-6alkyl, —C(O)—C1-6alkyl, —C(O)N(R4)(R5), —S(O)pC1-6alkyl, —SO2N(R4)(R5), and —N(R4)SO2(C1-6alkyl); R3 is hydrogen or C1-6alkyl; R4 and R5 each represent independently for each occurrence hydrogen or C1-6alkyl; or R4 and R5 taken together with the nitrogen atom to which they are attached form a 3-7 membered heterocyclic ring; R6 represents independently for each occurrence hydrogen or C1-6alkyl; R7 is hydrogen, hydroxyl, C1-6hydroxyalkyl, C1-6alkyl, C1-6haloalkyl, —CO2R6, C1-6alkylene-CO2R6, C1-4hydroxyalkylene-CO2R6, —N(R4)(R5), C1-6alkylene-N(R4)(R5), C1-6hydroxyalkylene-N(R4)(R5), —N(R4)C(O)R9, C1-6alkylene-N(R4)C(O)R9, C1-6alkylene-C(O)N(R4)(R5), —N(R4)CO2—C1-6alkyl, or C1-6alkylene-N(R4)(C(O)N(R4)(R5); or R7 is heterocycloalkyl or C1-4alkylene-heterocycloalkyl, wherein the heterocycloalkyl is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of oxo, halogen, hydroxyl, C1-6alkyl, C1-6haloalkyl, C1-6hydroxyalkyl, C1-6alkoxy, and C1-6haloalkoxy; R8 is hydrogen, C1-6alkyl, or —C(O)—C1-6alkyl; R9 is hydrogen, C1-6alkyl, C1-6hydroxyalkyl, C1-6alkylene-N(R4)(R5), or C1-6alkylene-N(R4)C(O)—C1-6alkyl; n is 1 or 2; and m and p each represent independently for each occurrence 0, 1, or 2.