SHIP1 modulators and methods related thereto
Compounds of formula (II): wherein A, 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 (III):
wherein:
is an optionally substituted fused oxazolyl, pyrazolyl or thiazolyl;
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 4a and R 4b are each independently hydrogen, alkyl, alkenyl or alkynyl;
or R 4a is hydrogen, alkyl, alkenyl or alkynyl and R 4b is a direct bond to the carbon to which R 7 is attached;
or R 4a and R 4b together form alkylidene;
R 5 is alkyl or R 5 is a direct bond to the carbon at C14;
R 7 is hydrogen, —R 8 —OR 9 , —R 8 —N(R 9 ) 2 , or a direct bond to C15, provided that when R 7 is a direct bond to C15, R 4b is not a direct bond to the carbon to which R 7 is attached;
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;
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:
is an optionally substituted fused oxazolyl, pyrazolyl or thiazolyl;
R 2 is —R 8 —OR 9 ;
R 4a and R 4b are each independently hydrogen, alkyl, alkenyl or alkynyl;
or R 4a is hydrogen, alkyl, alkenyl or alkynyl and R 4b is a direct bond to the carbon to which R 7 is attached;
or R 4a and R 4b together form alkylidene;
R 5 is alkyl or R 5 is a direct bond to the carbon at C14;
R 7 is hydrogen, —R 8 —OR 9 , —R 8 —N(R 9 ) 2 , or a direct bond to C15, provided that when R 7 is a direct bond to C15, R 4b is not a direct bond to the carbon to which R 7 is attached;
R 13 is —R 8 —OR 9 ;
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:
is an optionally substituted fused oxazolyl, pyrazolyl or thiazolyl;
R 2 is —R 8 —OR 9 ;
R 4a and R 4b are each independently hydrogen, alkyl, alkenyl or alkynyl;
or R 4a and R 4b together form alkylidene;
R 5 is alkyl or R 5 is a direct bond to the carbon at C14;
R 7 is hydrogen;
R 13 is —R 8 —OR 9 ;
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.
4. The compound of claim 3 wherein:
is an optionally substituted fused oxazolyl, pyrazolyl or thiazolyl;
R 2 is —R 8 —OR 9 ;
R 4a and R 4b are each independently hydrogen or alkyl;
or R 4a and R 4b together form alkylidene;
R 5 is alkyl or R 5 is a direct bond to the carbon at C14;
R 7 is hydrogen;
R 13 is —R 8 —OR 9 ;
each R 8 is independently a direct bond or a straight or branched alkylene chain; and
each R 9 is hydrogen or alkyl.
5. The compound of claim 1 selected from:
((3aS,4R,5S,7aS)-5-((5R,6S)-6-(hydroxymethyl)-5-methyl-4,5,6,7-tetrahydro-1H-indazol-5-yl)-7a-methyl-1-methyleneoctahydro-1H-inden-4-yl)methanol;
((3aS,4R,5S,7aS)-5-((5R,6S)-6-(hydroxymethyl)-5-methyl-4,5,6,7-tetrahydrobenzo[c]isoxazol-5-yl)-7a-methyl-1-methyleneoctahydro-1H-inden-4-yl)methanol;
((5R,6S)-5-((4R,5S)-4-(hydroxymethyl)-1,1-dimethyl-2,3,4,5,6,7-hexahydro-1H-inden-5-yl)-5-methyl-4,5,6,7-tetrahydrobenzo[d]isoxazol-6-yl)methanol; and
((3aS,4R,5S,7aS)-5-((5S,6R)-5-(hydroxymethyl)-2,6-dimethyl-4,5,6,7-tetrahydrobenzo[d]thiazol-6-yl)-7a-methyl-1-methyleneoctahydro-1H-inden-4-yl)methanol.
6. 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.
7. 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 6 to a mammal in need thereof.
8. 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 6 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.