BICYCLIC SULFONE COMPOUNDS FOR INHIBITION OF RORgamma ACTIVITY AND THE TREATMENT OF DISEASE

摘要

The invention provides bicyclic sulfone compounds, pharmaceutical compositions, methods of inhibiting RORy activity, reducing the amount of iL-17 in a subject, and treating immune disorders and inflammatory disorders using such bicyclic sulfone compounds. Another aspect of the invention provides a method of treating a subject suffering from a medical disorder. The method comprises administering to the subject a therapeutically effective amount of one or more bicyclic sulfone compounds described herein. In certain other embodiments, the disorder is rheumatoid arthritis.

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, or —C(R6)2—N(R8)—[C(R6)(R7)]—[C(R6)2]m-ψ; wherein ψ is a bond to the ring carbon atom bearing the sulfonyl in Formula I; Y1 and Y2 are each independently C(R3) or N; R1 represents independently for each occurrence hydrogen 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 represents independently for each occurrence hydrogen, halogen, 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; and m and p each represent independently for each occurrence 0, 1, or 2.