SHIP1 MODULATORS AND METHODS RELATED THERETO

摘要

Compounds of formula (I): where R1, R2, R3, R4a, R4b, R5, R6 and R7 are defined herein, or stereoisomers or pharmaceutically acceptable salts thereof, are described herein. Such 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:
C1, C4, C11 and C12 are each independently substituted with two hydrogens; C9 is substituted with one hydrogen; C14 is substituted with one hydrogen when R5 is not a direct bond to C14; C15 is substituted with two hydrogens when R7 is not a direct bond to C15, and one hydrogen when R7 is a direct bond to C15; R1 is —R8—OR9 or —R8—N(R9)2; R2 is —R8—OR9, —R8—CN, —R8—C(O)OR9, —R8—C(O)N(R9)2, —R8—N(R9)2, —R8—N(R9)C(O)R9, optionally substituted heterocyclylalkyl or optionally substituted heteroarylalkyl; R4a is hydrogen or alkyl, R4b is a direct bond to the carbon to which R7 is attached, and R3 is —CH2NH2 or —CH2N(H)C(O)(CH2)3CH3; or R4a and R4b are each independently selected from hydrogen and alkyl and R3 is —CH2OH, —CH2NH2, —CH2N(H)CH3, —CH2N(CH3)2, —CH2N(H)CH2-cyclopropyl, —CH2N(H)CH2-pyrrolyl, —CH2N(H)C(O)CH3, —CH2N(H)C(O)-phenyl, —CH2N(H)S(O)2CH3 or —CH2N(H)C(═NH)NH2; or R4a and R4b together form methylene and R3 is —OH, —CH2—OH, —CH2—CH2—OH, —CH2—O-(3,5-dimethoxy)benzyl, —CH2—O-benzyl, —CH2—O—CH2-pyridinyl, —C(O)OH, —CH2—CN, —CH2—C(O)NH2, —CH2—NH2, —CH2—CH2—NH2, —CH2—N(H)—CN, —CH2—N(H)—OCH3, —CH2—N(H)C(O)-(2-methyl)phenyl, —CH2—N(H)C(O)-(3-methyl)phenyl, —CH2—N(H)C(O)-(4-fluoro)phenyl, —CH2—N(H)C(O)-(4-methoxy)phenyl, —CH2—N(H)C(O)-(4-methyl)phenyl, —CH2—N(H)C(O)-(4-trifluoromethyl)phenyl, —CH2—N(H)C(O)-2-pyridinyl, —CH2—N(H)C(O)-2-pyrrolyl, —CH2—N(H)C(O)-3-pyridinyl, —CH2—N(H)C(O)-4-pyridinyl, —CH2—N(H)C(O)-benzodioxolyl, —CH2—N(H)C(O)-butyl, —CH2—N(H)C(O)CF3, —CH2—N(H)C(O)-cyclohexyl, —CH2—N(H)C(O)-cyclopropyl, —CH2—N(H)C(O)-ethyl, —CH2—N(H)C(O)-furanyl, —CH2—N(H)C(O)-isopropyl, —CH2—N(H)C(O)-naphthyl, —CH2—N(H)C(O)-phenyl, —CH2—N(H)C(O)-propyl, —CH2—N(H)C(O)-pyrazinyl, —CH2—N(H)C(O)-t-butyl, —CH2—CH2—N(H)C(O)benzodioxolyl, —CH2—N(H)CH2-(2,2-difluorobenzodioxolyl), —CH2—CH2—N(4-methoxybenzyl)2, —CH2—CH2—N(H)-(4-methoxy)benzyl, —CH2—N(H)-(2-fluoro-4-methoxy)benzyl, —CH2—N(H)-(2-fluoro-4-methyl)benzyl, —CH2—N(H)-(2-methoxy-4-fluoro)benzyl, —CH2—N(H)-(2-methyl)benzyl, —CH2—N(H)-(2-methyl-4-fluoro)benzyl, —CH2—N(H)-(3,5-dimethoxy)benzyl, —CH2—N(H)-(3-methyl)benzyl, —CH2—N(H)-(4-fluoro)benzyl, —CH2—N(H)-(4-methoxy)benzyl, —CH2—N(H)-(4-methyl)benzyl, —CH2—N(H)-(4-nitro)benzyl, —CH2—N(H)-(4-trifluoromethyl)benzyl, —CH2—N(H)-(4-benzoyl)benzyl, —CH2—N(H)CH2-benzimidazolyl, —CH2—CH2—N(H)CH2-benzodioxolyl, —CH2—N(H)CH2CH2-(4-methoxy)phenyl, —CH2—N(H)CH2-pyridinyl, —CH2—N(H)C(O)N(H)-benzyl, —CH2—N(H)C(O)N(H)-ethyl, —CH2—N(H)C(O)N(H)-phenyl, —CH2—N(H)C(S)N(H)CH3, —CH2-benzimidazolyl, —CH2-indolinyl, —CH2-indolyl, —CH2-purinyl, —CH2-pyrazolyl, or —CH2-triazolyl; R5 is alkyl or R5 is a direct bond to C14; R6 is hydrogen; R7 is hydrogen, —R8—OR9 or a direct bond to C15, provided that when R7 is a direct bond to C15, R4b is not a direct bond to the carbon to which R7 is attached; each R8 is independently a direct bond or a straight or branched alkylene chain; and each R9 is independently hydrogen, alkyl, 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; or a stereoisomer, enantiomer or tautomer thereof or mixtures thereof; or a pharmaceutically acceptable salt or solvate thereof.