SHIP1 modulators and methods related thereto
Compounds of formula (II): wherein R 1 , R 2 , R 5 and R 13 are described herein, or a stereoisomer, enantiomer or tautomer thereof or mixtures thereof, or a pharmaceutically acceptable salt or solvate thereof, are described herein, as well as other compounds. These compounds have activity as SHIP1 modulators, and thus may be useful in treating a variety of diseases, disorders or conditions that would benefit from SHIP1 modulation. Compositions comprising a compound of the invention are also disclosed, as are methods of SHIP1 modulation by administration of such compounds to an animal in need thereof.
1. A compound of formula (IV):
wherein:
R 1 is —R 8 —OR 9 , —R 8 —N(R 9 ) 2 , —R 8 —O—R 10 —OR 9 , —R 8 —O—R 10 —N(R 9 ) 2 , —R 8 —N(R 9 )—R 10 —OR 9 , —R 8 —N(R 9 )—R 10 —N(R 9 ) 2 , —R 8 —C(O)OR 9 , —R 8 —C(O)N(R 9 ) 2 or —N(R 9 )C(O)OR 9 ;
R 2 is —R 8 —OR 9 , —R 8 —N(R 9 ) 2 , —R 8 —O—R 10 —OR 9 , —R 8 —O—R 10 —N(R 9 ) 2 , —R 8 —N(R 9 )—R 10 —OR 9 , —R 8 —N(R 9 )—R 10 —N(R 9 ) 2 , —R 8 —OC(O)R 9 , —R 8 —C(O)OR 9 , —R 8 —C(O)N(R 9 ) 2 , —N(R 9 )C(O)OR 9 , —R 8 —N(R 9 )S(O) t R 9 (where t is 1 or 2), —R 8 —N(R 9 )C(═NR 9 )N(R 9 ) 2 , alkyl, alkenyl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted heterocyclylalkyl, optionally substituted heteroarylalkyl or optionally substituted heteroarylalkenyl;
R 5 is alkyl or R 5 is a direct bond to the carbon at C14;
R 6 is hydrogen, —R 8 —OR 9 or —R 8 —N(R 9 ) 2 ;
R 13 is —R 8 —OR 9 , —R 8 —N(R 9 ) 2 , —R 8 —O—R 10 —OR 9 , —R 8 —O—R 10 —N(R 9 ) 2 , —R 8 —N(R 9 )—R 10 —OR 9 , —R 8 —N(R 9 )—R 10 —N(R 9 ) 2 , —R 8 —OC(O)R 9 , —R 8 —C(O)OR 9 , —R 8 —C(O)N(R 9 ) 2 , —N(R 9 )C(O)OR 9 , —R 8 —N(R 9 )S(O) t R 9 (where t is 1 or 2), —R 8 —N(R 9 )C(═NR 9 )N(R 9 ) 2 , alkyl, alkenyl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted heterocyclylalkyl, optionally substituted heteroarylalkyl or optionally substituted heteroarylalkenyl;
R 14 is alkyl, alkenyl, alkynyl, optionally substituted aryl or optionally substituted heteroaryl;
R 15 is alkyl, —R 8 —OR 9 or a direct bond to the carbon to which R 16 is attached, provided that R 15 is not alkyl when R 14 is alkyl, alkenyl or alkynyl;
R 16 is hydrogen, —R 8 —OR 9 , —R 8 —N(R 9 ) 2 , or a direct bond to C15, provided that when R 16 is a direct bond to C15, R 15 is not a direct bond to the carbon to which R 16 is attached; and
each R 8 is independently a direct bond, a straight or branched alkylene chain, a straight or branched alkenylene chain or a straight or branched alkynylene chain;
each R 9 is hydrogen, alkyl, optionally substituted aryl and optionally substituted aralkyl; and
each R 10 is independently a straight or branched alkylene chain, a straight or branched alkenylene chain or a straight or branched alkynylene chain;
or a stereoisomer, enantiomer or tautomer thereof or mixtures thereof, or a pharmaceutically acceptable salt or solvate thereof.
2. The compound of claim 1 wherein:
R 1 is —R 8 —OR 9 ;
R 2 is —R 8 —OR 9 ;
R 5 is alkyl or R 5 is a direct bond to the carbon at C14;
R 6 is hydrogen, —R 8 —OR 9 or —R 8 —N(R 9 ) 2 ;
R 13 is —R 8 —OR 9 or —R 8 —N(R 9 ) 2 ;
R 14 is alkyl, alkenyl, alkynyl, optionally substituted aryl or optionally substituted heteroaryl;
R 15 is alkyl, —R 8 —OR 9 or a direct bond to the carbon to which R 16 is attached, provided that R 15 is not alkyl when R 14 is alkyl, alkenyl or alkynyl;
R 16 is hydrogen or —R 8 —OR 9 , —R 8 —N(R 9 ) 2 ; and
each R 8 is independently a direct bond or a straight or branched alkylene chain; and
each R 9 is hydrogen, alkyl, optionally substituted aryl and optionally substituted aralkyl.
3. The compound of claim 2 wherein:
R 1 is —R 8 —OR 9 ;
R 2 is —R 8 —OR 9 ;
R 5 is alkyl;
R 6 is hydrogen;
R 13 is —R 8 —OR 9 or —R 8 —N(R 9 ) 2 ;
R 14 is alkyl or alkynyl;
R 15 is —R 8 —OR 9 ;
R 16 is hydrogen; and
each R 8 is independently a direct bond or a straight or branched alkylene chain; and
each R 9 is hydrogen or alkyl.
4. The compound of claim 3 selected from:
(1S,3aS,4R,5S,7aS)-4-(aminomethyl)-5-((1R,2S,4S)-4-hydroxy-2-(hydroxymethyl)-1-methylcyclohexyl)-1,7a-dimethyloctahydro-1H-inden-1-ol;
(1S,3aS,4R,5S,7aS)-5-((1R,2S,4S)-4-hydroxy-2-(hydroxymethyl)-1-methylcyclohexyl)-4-(hydroxymethyl)-1,7a-dimethyloctahydro-1H-inden-1-ol; and
(1R,3aS,4R,5S,7aS)-1-ethynyl-5-((1R,2S,4S)-4-hydroxy-2-(hydroxymethyl)-1-methylcyclohexyl)-4-(hydroxymethyl)-7a-methyloctahydro-1H-inden-1-ol.
5. The compound of claim 2 wherein:
R 1 is —R 8 —OR 9 ;
R 2 is —R 8 —OR 9 ;
R 5 is alkyl or R 5 is a direct bond to the carbon at C14;
R 6 is hydrogen;
R 13 is —R 8 —OR 9 or —R 8 —N(R 9 ) 2 ;
R 14 is optionally substituted aryl;
R 15 is alkyl, —R 8 —OR 9 or a direct bond to the carbon to which R 16 is attached;
R 16 is hydrogen or —R 8 —OR 9 ; and
each R 8 is independently a direct bond or a straight or branched alkylene chain; and
each R 9 is hydrogen or alkyl.
6. The compound of claim 5 selected from:
(1S,3S,4R)-4-((3aS,6S,7R,7aS)-7-(aminomethyl)-3a-methyl-3-phenyl-3a,4,5,6,7,7a-hexahydro-1H-inden-6-yl)-3-(hydroxymethyl)-4-methylcyclohexano;
(1S,3aS,4R,5S,7aS)-4-(aminomethyl)-5-((1R,2S,4S)-4-hydroxy-2-(hydroxymethyl)-1-methylcyclohexyl)-7a-methyl-1-phenyloctahydro-1H-inden-1-ol;
(1 S,2R,4R,5S)-4-(aminomethyl)-5-((1R,2S,4S)-4-hydroxy-2-(hydroxymethyl)-1-methylcyclohexyl)-1-methyl-1-phenyl-2,3,4,5,6,7-hexahydro-1H-inden-2-ol;
(1S,3S,4R)-3-(hydroxymethyl)-4-((3aS,6S,7R,7aS)-7-(hydroxymethyl)-3a-methyl-3-phenyl-3a,4,5,6,7,7a-hexahydro-1H-inden-6-yl)-4-methylcyclohexanol;
(1S,3aS,4R,5S,7aS)-5-((1R,2S,4S)-4-hydroxy-2-(hydroxymethyl)-1-methylcyclohexyl)-4-(hydroxymethyl)-7a-methyl-1-phenyloctahydro-1H-inden-1-ol; and
(1 S,2R,4R,5S)-5-((1R,2S,4S)-4-hydroxy-2-(hydroxymethyl)-1-methylcyclohexyl)-4-(hydroxymethyl)-1-methyl-1-phenyl-2,3,4,5,6,7-hexahydro-1H-inden-2-ol.
7. The compound of claim 2 wherein:
R 1 is —R 8 —OR 9 ;
R 2 is —R 8 —OR 9 ;
R 5 is alkyl or R 5 is a direct bond to the carbon at C14;
R 6 is hydrogen;
R 13 is —R 8 —OR 9 or —R 8 —N(R 9 ) 2 ;
R 14 is optionally substituted heteroaryl;
R 15 is alkyl, —R 8 —OR 9 or a direct bond to the carbon to which R 16 is attached;
R 16 is hydrogen or —R 8 —OR 9 , —R 8 —N(R 9 ) 2 ; and
each R 8 is independently a direct bond or a straight or branched alkylene chain; and
each R 9 is hydrogen or alkyl.
8. The compound of claim 7 selected from:
(1S,3aS,4R,5S,7aS)-4-(aminomethyl)-1-(furan-2-yl)-5-((1R,2S,4S)-4-hydroxy-2-(hydroxymethyl)-1-methylcyclohexyl)-7a-methyloctahydro-1H-inden-1-ol;
(1S,3S,4R)-4-((3aS,6S,7R,7aS)-7-(aminomethyl)-3-(furan-2-yl)-3a-methyl-3a,4,5,6,7,7a-hexahydro-1H-inden-6-yl)-3-(hydroxymethyl)-4-methylcyclohexanol;
(1S,3aS,4R,5S,7aS)-4-(aminomethyl)-5-((1R,2S,4S)-4-hydroxy-2-(hydroxymethyl)-1-methylcyclohexyl)-7a-methyl-1-(thiophen-2-yl)octahydro-1H-inden-1-ol;
(1S,3S,4R)-4-((3aS,6S,7R,7aS)-7-(aminomethyl)-3a-methyl-3-(thiophen-2-yl)-3a,4,5,6,7,7a-hexahydro-1H-inden-6-yl)-3-(hydroxymethyl)-4-methylcyclohexanol;
(1S,3aS,4R,5S,7aS)-4-(aminomethyl)-5-((1R,2S,4S)-4-hydroxy-2-(hydroxymethyl)-1-methylcyclohexyl)-7a-methyl-1-(pyridin-2-yl)octahydro-1H-inden-1-ol;
(1S,3aS,4R,5S,7aS)-4-(aminomethyl)-5-((1R,2S,4S)-4-hydroxy-2-(hydroxymethyl)-1-methylcyclohexyl)-7a-methyl-1-(thiazol-2-yl)octahydro-1H-inden-1-ol;
(1S,3S,4R)-4-((3aS,6S,7R,7aS)-3-(furan-2-yl)-7-(hydroxymethyl)-3a-methyl-3a,4,5,6,7,7a-hexahydro-1H-inden-6-yl)-3-(hydroxymethyl)-4-methylcyclohexanol;
(1S,3aS,4R,5S,7aS)-1-(furan-2-yl)-5-((1R,2S,4S)-4-hydroxy-2-(hydroxymethyl)-1-methylcyclohexyl)-4-(hydroxymethyl)-7a-methyloctahydro-1H-inden-1-ol;
(1S,3aS,4R,5S,7aS)-5-((1R,2S,4S)-4-hydroxy-2-(hydroxymethyl)-1-methylcyclohexyl)-4-(hydroxymethyl)-7a-methyl-1-(thiophen-2-yl)octahydro-1H-inden-1-ol;
(1S,3S,4R)-3-(hydroxymethyl)-4-((3aS,6S,7R,7aS)-7-(hydroxymethyl)-3a-methyl-3-(thiophen-2-yl)-3a,4,5,6,7,7a-hexahydro-1H-inden-6-yl)-4-methylcyclohexanol;
(1S,3aS,4R,5S,7aS)-5-((1R,2S,4S)-4-hydroxy-2-(hydroxymethyl)-1-methylcyclohexyl)-4-(hydroxymethyl)-7a-methyl-1-(pyridin-2-yl)octahydro-1H-inden-1-ol; and
(1S,3aS,4R,5S,7aS)-5-((1R,2S,4S)-4-hydroxy-2-(hydroxymethyl)-1-methylcyclohexyl)-4-(hydroxymethyl)-7a-methyl-1-(thiazol-2-yl)octahydro-1H-inden-1-ol.
9. A composition comprising a compound of claim 1 , or a stereoisomer, enantiomer or tautomer thereof or mixtures thereof, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient.
10. A method for modulating SHIP1 comprising administering an effective amount of a compound of claim 1 , or a stereoisomer, enantiomer or tautomer thereof or mixtures thereof, or a pharmaceutically acceptable salt or solvate thereof, or a composition of claim 9 to a mammal in need thereof.
11. A method for treating a disease, disorder or condition comprising administering an effective amount of a compound of claim 1 , or a stereoisomer, enantiomer or tautomer thereof or mixtures thereof, or a pharmaceutically acceptable salt or solvate thereof, or a composition of claim 9 to a mammal in need thereof, where the disease, disorder or condition is an autoimmune disease, disorder or condition, an inflammatory disease, disorder or condition, or a neoplastic or cell proliferative disease, disorder or condition.