SHIP1 MODULATORS AND METHODS RELATED THERETO

摘要

Compounds of formula (I): where, n, R1, R4a, R4b, R5, R7 and R8 are defined herein, or pharmaceutically acceptable salts thereof, are described herein. The disclosed compounds have activity as SHIP1 modulators, and thus may be used to treat any of a variety of diseases, disorders or conditions that would benefit from SHIP1 modulation. Compositions comprising a compound of formula (I) in combination with a pharmaceutically acceptable carrier or diluent are also disclosed, as are methods of SHIP1 modulation by administration of such compounds to an animal in need thereof.;

主权项

1. A compound of formula (I): wherein:is selected from: n is 1, 2, 3, 4, 5, or 6; R1 is —R9a—C(R10)2—R9b—, —R9a—C(O)—R9b—, —R9a—S(O)t—R9b— (where t is 0, 1 or 2), —R9a—O—R9b—, —R9a—C(O)N(R11a)—R9b—, —R9a—N(R11a)C(O)—R9b— or —R9a—N(R11a)—R9b; R2 and R3 are each independently selected from hydrogen, alkyl or —R9—OR11, provided that at least one of R2 and R3 is —R9—OR11 when R6 is hydrogen; R4a and R4b are each independently selected from hydrogen, alkyl, —R9—OR11 or —C(O)OR11, or R4a is selected from hydrogen, alkyl, —R9—OR11, or —C(O)OR11 and R4b is a direct bond to the carbon at numeral 1 or a direct bond to the carbon at numeral 3; or R4a and R4b together form ═C(R13)2; R5 is independently selected from hydrogen, oxo, cyano, nitro, halo, alkyl, haloalkyl, optionally substituted cycloalkyl, optionally substituted cycloakylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, —R9—OR11, —R9—C(O)R11, —R9—C(O)OR11, —R9—N(R11)R12, —R9—C(O)N(R11)R12, —R9—N(R11)C(O)R12, —R9—N(R11)—R14—N(R11)R12, —R9—N(R11)C(O)—R9—N(R11)R12, —R9—N(R11)C(O)N(R11)—OR12, —R9—N(R11)C(═NR11)N(R11)R12, —R9—N(R11)S(O)pR11 (where p is 1 or 2), —R9—N(R11)C(S)N(R11)R12 or —R9—N(R11)C(O)—R9—N(R11)S(O)pR12 (where p is 1 or 2); each R6 and R8 is independently selected from hydrogen, alkyl, halo or haloalkyl; R7 is hydrogen, alkyl, halo or haloalkyl; each R9, R9a and R9b is independently a direct bond or a straight or branched alkylene chain; each R10 is independently hydrogen, alkyl, —OR11, —C(O)OR11, —C(O)N(R11)R12, —N(R11)R12 or —N(R11)C(O)R11; each R11, R11a and R12 is independently hydrogen, alkyl, alkenyl, haloalkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl or optionally substituted heteroarylalkyl; each R13 is hydrogen, alkyl or haloalkyl; and R14 is a straight or branched alkylene chain; or a stereoisomer thereof or a pharmaceutically acceptable salt thereof; provided that compounds of formula (I) do not include the following compounds: (1S,2S,4aS,8aR)-decahydro-1-[2-(3-methoxyphenyl)ethyl]-5,5,8a-trimethyl-2-naphthalenecarboxylic acid; (1S,2S,4aS,8aR)-decahydro-1-[2-(3-methoxyphenyl)ethyl]-5,5,8a-trimethyl-2-naphthalenemethanol; α-(3,5-dimethoxyphenyl)decahydro-2-hydroxy-2,5,5,8a-tetramethyl-1-naphthalenemethanol; (4aS,8aS)-3,4,4a,5,6,7,8,8a-octahydro-α-(3-methoxy-5-methylphenyl)-2,5,5,8a-tetramethyl-1-naphthalenemethanol; (1S,2R,4aS,8aS)-decahydro-2-hydroxy-α-(3-methoxy-5-methylphenyl)-2,5,5,8a-tetramethyl-1-naphthalenemethanol; (1R,2R,4aS,8aS)-decahydro-1-[(3-methoxy-5-methylphenyl)methyl]-2,5,5,8a-tetramethyl-2-naphthalenol; (4aS,5S,8aS)-decahydro-5-[2-(3-methoxyphenyl)ethyl]-1,1,4a-trimethyl-6-methylene-naphthalene; 2-[(1S,4aS,8aS)-decahydro-5,5,8a-trimethyl-2-methylene-1-naphthalenyl]-1-(3-methoxyphenyl)-ethanone; (1S,2R,4aS,8aS)-1-(3-methoxy-5-methylphenoxymethyl)-2,5,5,8a-tetramethyl-decahydronaphthalen-2-ol; (1S,2R,4aS,8aS)-1-(3,5-dimethoxyphenoxymethyl)-2,5,5,8a-tetramethyl-decahydronaphthalen-2-ol; (1S,2R,4aS,8aS)-1-[3,5-bis(propan-2-yloxy)phenoxymethyl]-2,5,5,8a-tetramethyl-decahydronaphthalen-2-ol; (1R,2R,8aS)-1-((3,5-dimethoxyphenylsulfonyl)methyl)-2,5,5,8a-tetramethyldecahydronaphthalen-2-ol; (1R,2R,4aS,8aS)-1-{[(3-methoxy-5-methylphenyl)sulfanyl]methyl}-2,5,5,8a-tetramethyl-decahydronaphthalen-2-ol; (1R,2R,4aS,8aS)-1-{[(3-methoxyphenyl)sulfanyl]methyl}-2,5,5,8a-tetramethyl-decahydronaphthalen-2-ol; and (1R,2R,4aS,8aS)-1-{[(3,5-dimethoxyphenyl)sulfanyl]methyl}-2,5,5,8a-tetramethyl-decahydronaphthalen-2-ol.