SHIP1 modulators and methods related thereto

1. A compound of formula (I):

wherein:

is selected from:

n is 1, 2, 3, 4, 5, or 6;

R 1 is —R 9a —C(R 10 ) 2 —R 9b —, —R 9a —C(O)—R 9b —, —R 9a —S(O) t —R 9b — (where t is 0, 1 or 2), —R 9a —O—R 9b —, —R 9a —C(O)N(R 11a )—R 9b —, —R 9a —N(R 11a )C(O)—R 9b — or —R 9a —N(R 11a )—R 9b —; provided that when A is

R 1 is not —R 9a —C(R 10 ) 2 —R 9b —;

R 2 and R 3 are each independently selected from hydrogen, alkyl or —R 9 —OR 11 , provided that at least one of R 2 and R 3 is —R 9 —OR 11 when R 6 is hydrogen;

R 4a and R 4b are each independently selected from hydrogen, alkyl, —R 9 —OR 11 or —C(O)OR 11 ,

R 5 is independently selected from hydrogen, oxo, cyano, nitro, halo, alkyl, haloalkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, —R 9 —OR 11 , —R 9 —C(O)R 11 , —R 9 —C(O)OR 11 , —R 9 —N(R 11 )R 12 , —R 9 —C(O)N(R 11 )R 12 , —R 9 —N(R 11 )C(O)R 12 , —R 9 —N(R 11 )—R 14 —N(R 11 )R 12 , —R 9 —N(R 11 )C(O)—R 9 —N(R 11 )R 12 , —R 9 —N(R 11 )C(O)N(R 11 )—OR 12 , —R 9 —N(R 11 )C(═NR 11 )N(R 11 )R 12 , —R 9 —N(R 11 )S(O) p R 11 (where p is 1 or 2), —R 9 —N(R 11 )C(S)N(R 11 )R 12 or —R 9 —N(R 11 )C(O)—R 9 —N(R 11 )S(O) p R 12 (where p is 1 or 2);

each R 6 and R 8 is independently selected from hydrogen, alkyl, halo or haloalkyl;

R 7 is hydrogen, alkyl, halo or haloalkyl;

each R 9 , R 9a and R 9b is independently a direct bond or a straight or branched alkylene chain;

each R 10 is independently hydrogen, alkyl, —OR 11 , —C(O)OR 11 , —C(O)N(R 11 )R 12 , —N(R 11 )R 12 or —N(R 11 )C(O)R 11 ;

each R 11 , R 11a and R 12 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; and

R 14 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,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.

2. The compound of claim 1 having the formula (Ia):

wherein n, R 1 , R 2 , R 3 , R 4a , R 4b , R 5 , R 6 , R 7 and R 8 are as defined above in claim 1 , or a stereoisomer thereof or a pharmaceutically acceptable salt thereof.

3. The compound of claim 2 where R 1 is —R 9a —C(O)—R 9b — wherein the compound is a compound of formula (Ia1):

wherein n, R 2 , R 3 , R 4a , R 4b , R 5 , R 6 , R 7 and R 8 are as defined above in claim 2 ; and

R 9a and R 9b are each independently a direct bond or a straight or branched alkylene chain;

or a stereoisomer thereof or a pharmaceutically acceptable salt thereof.

4. The compound of claim 2 wherein R 1 is —R 9 —S(O) t —R 9 — wherein the compound is a compound of formula (Ia3):

wherein n, R 2 , R 3 , R 4a , R 4b , R 5 , R 6 , R 7 and R 8 are ad defined above in claim 2 ;

t is 0, 1, or 2; and

R 9a and R 9b are each independently a direct bond or a straight or branched alkylene chain;

or a stereoisomer thereof or a pharmaceutically acceptable salt thereof.

5. The compound of claim 2 , wherein R 1 is —R 9a —O—R 9b — wherein the compound is a compound of formula (Ia4):

wherein n, R 2 , R 3 , R 4a , R 4b , R 5 , R 6 , R 7 and R 8 are as defined above in claim 2 ; and

R 9a and R 9b are each independently a direct bond or a straight or branched alkylene chain;

or a stereoisomer thereof or a pharmaceutically acceptable salt thereof.

6. The compound of claim 2 , wherein R 1 is —R 9a —C(O)N(R 11a )—R 9b — wherein the compound is a compound of formula (Ia5):

wherein n, R 2 , R 3 , R 4a , R 4b , R 5 , R 6 , R 7 and R 8 are as defined above in claim 2 ;

R 9a and R 9b are each independently a direct bond or a straight or branched alkylene chain; and

R 11a is 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;

or a stereoisomer thereof or a pharmaceutically acceptable salt thereof.

7. The compound of claim 2 where R 1 is —R 9a —N(R 11a )C(O)—R 9b — wherein the compound is a compound of formula (Ia6):

wherein n, R 2 , R 3 , R 4a , R 4b , R 5 , R 6 , R 7 and R 8 are as defined above in claim 2 ;

R 9a and R 9b are each independently a direct bond or a straight or branched alkylene chain; and

R 11a is 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;

or a stereoisomer thereof or a pharmaceutically acceptable salt thereof.

8. The compound of claim 2 wherein R 1 is —R 9a —N(R 11a )—R 9b — wherein the compound is a compound of formula (Ia7):

wherein n, R 2 , R 3 , R 4a , R 4b , R 5 , R 6 , R 7 and R 8 are as defined above in claim 2 ;

R 9a and R 9b are each independently a direct bond or a straight or branched alkylene chain; and

R 11a is 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;

or a stereoisomer thereof or a pharmaceutically acceptable salt thereof.

9. The compound of claim 1 having the formula (Ic):

wherein n, R 1 , R 4a , R 4b , R 5 , R 6 , R 7 and R 8 are as defined above in claim 1 , or a stereoisomer thereof or a pharmaceutically acceptable salt thereof.

10. The compound of claim 9 wherein R 1 is —R 9a —N(R 11a )C(O)—R 9b — wherein the compound is a compound of formula (Ic1):

wherein n, R 4a , R 4b , R 5 , R 6 , R 7 and R 8 are as defined above in claim 9 ;

R 9a and R 9b are each independently a direct bond or a straight or branched alkylene chain; and

R 11a is 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;

or a stereoisomer thereof or a pharmaceutically acceptable salt thereof.

11. The compound of claim 1 having the formula (Id):

wherein n, R 1 , R 4a , R 4b , R 5 , R 6 , R 7 and R 8 are as defined above in claim 1 , or a stereoisomer thereof or a pharmaceutically acceptable salt thereof.

12. The compound of claim 11 wherein R 1 is —R 9a —C(R 10 ) 2 —R 9b — wherein the compound is a compound of formula (Id1):

wherein n, R 4a , R 4b , R 5 , R 6 , R 7 and R 8 are as defined above in claim 11 ;

R 9a and R 9b are each independently a direct bond or a straight or branched alkylene chain; and

each R 10 is independently hydrogen, alkyl, —OR 11 , —C(O)OR 11 , —C(O)N(R 11 )R 12 , —N(R 11 )R 12 or —N(R 11 )C(O)R 11 ; and

each R 11 and R 12 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;

or a stereoisomer thereof or a pharmaceutically acceptable salt thereof.

13. The compound of claim 1 having the formula (Ie):

wherein n, R 1 , R 4a , R 4b , R 5 , R 6 , R 7 and R 8 are as defined above in claim 1 , or a stereoisomer thereof or a pharmaceutically acceptable salt thereof.

14. The compound of claim 13 wherein R 1 is —R 9a —C(R 10 ) 2 —R 9b — wherein the compound is a compound of formula (Ie1):

wherein n, R 4a , R 4b , R 5 , R 6 , R 7 and R 8 are as defined above in claim 13 ;

R 9a and R 9b are each independently a direct bond or a straight or branched alkylene chain; and

each R 10 is independently hydrogen, alkyl, —OR 11 , —C(O)OR 11 , —C(O)N(R 11 )R 12 , —N(R 11 )R 12 or —N(R 11 )C(O)R 11 ; and

each R 11 and R 12 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;

or a stereoisomer thereof or a pharmaceutically acceptable salt thereof.

15. The compound of claim 1 having the formula (If):

wherein n, R 1 , R 4a , R 4b , R 5 , R 6 , R 7 and R 8 are as defined above in claim 1 , or a stereoisomer thereof or a pharmaceutically acceptable salt thereof.

16. The compound of claim 15 wherein R 1 is —R 9a —C(R 10 ) 2 —R 9b — wherein the compound is a compound of formula (If1):

wherein n, R 4a , R 4b , R 5 , R 6 , R 7 and R 8 are as defined above in claim 15 ;

R 9a and R 9b are each independently a direct bond or a straight or branched alkylene chain; and

each R 10 is independently hydrogen, alkyl, —OR 11 , —C(O)OR 11 , —C(O)N(R 11 )R 12 , —N(R 11 )R 12 or —N(R 11 )C(O)R 11 ; and

each R 11 and R 12 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;

or a stereoisomer thereof or a pharmaceutically acceptable salt thereof.

17. The compound of claim 1 wherein:

is selected from:

n is 1, 2, 3, 4, 5, or 6;

R 1 is —R 9a —C(R 10 ) 2 —R 9b —, —R 9a —C(O)—R 9b —, —R 9a —S(O) t —R 9b — (where t is 0, 1 or 2), —R 9a —O—R 9b —, or —R 9a —C(O)N(R 11a )—R 9b — or —R 9a —N(R 11a )C(O)—R 9b —;

R 4a and R 4b are each independently selected from hydrogen, alkyl, —R 9 —OR 11 or —C(O)OR 11 ,

R 5 is independently selected from hydrogen, oxo, cyano, nitro, halo, alkyl, haloalkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, —R 9 —OR 11 , —R 9 —C(O)R 11 , —R 9 —C(O)OR 11 , —R 9 —N(R 11 )R 12 , —R 9 —C(O)N(R 11 )R 12 , —R 9 —N(R 11 )C(O)R 12 , —R 9 —N(R 11 )—R 14 —N(R 11 )R 12 , —R 9 —N(R 11 )C(O)—R 9 —N(R 11 )R 12 , —R 9 —N(R 11 )C(O)N(R 11 )—OR 12 , —R 9 —N(R 11 )C(═NR 11 )N(R 11 )R 12 , —R 9 —N(R 11 )S(O) p R 11 (where p is 1 or 2), —R 9 —N(R 11 )C(S)N(R 11 )R 12 or —R 9 —N(R 11 )C(O)—R 9 —N(R 11 )S(O) p R 12 (where p is 1 or 2);

each R 6 and R 8 is independently selected from hydrogen, alkyl, halo or haloalkyl;

R 7 is hydrogen, alkyl, halo or haloalkyl;

each R 9 , R 9a and R 9b is independently a direct bond or a straight or branched alkylene chain;

each R 10 is independently hydrogen, alkyl, —OR 11 , —C(O)OR 11 , —C(O)N(R 11 )R 12 , —N(R 11 )R 12 or —N(R 11 )C(O)R 11 ;

each R 11 , R 11a and R 12 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; and

R 14 is a straight or branched alkylene chain;

or a stereoisomer thereof or a pharmaceutically acceptable salt thereof.

18. A composition comprising a compound of claim 1 , or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

19. A method for treating acute myelogenous leukemia, chronic myelogenous leukemia, acute lymphocytic leukemia, chronic lymphocytic leukemia or basophilic leukemia in a mammal comprising administering an effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt or stereoisomer thereof, to the mammal in need thereof.