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Title:
SHIP1 MODULATORS AND METHODS RELATED THERETO
Document Type and Number:
WIPO Patent Application WO/2014/110036
Kind Code:
A4
Abstract:
Compounds of formula (I): [Formula should be inserted here]; where [Formula should be inserted here], 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.

Inventors:
MACKENZIE, Lyoyd, F. (242 24th Street West, North Vancouver, British Columbia V7M 2C4, 2C4, CA)
MACRURY, Thomas, B. (1636 Edwards Drive, Point Roberts, Washington, 98281, US)
HARWIG, Curtis (515 East 15th Avenue #403, Vancouver, British Columbia V5T 4S4, 4S4, CA)
BOGUCKI, David (14th Avenue, Surrey, British Columbia V3S 4S6, 4S6, CA)
RAYMOND, Jeffery, R. (#19 - 2658 Morningstar Crescent, Vancouver, British Columbia V5S 4P4, 4P4, CA)
PETTIGREW, Jeremy, D. (7328 Arcola Street #1407, Burnaby, British Columbia V5E 0A7, 0A7, CA)
KHLEBNIKOV, Vladimir (3803 - 111A Street, Edmonton, Alberta Y6J 1G2, 1G2, CA)
SHAN, Rudong (331 Magrath Blvd, N.W.Edmonton, Alberta T6R 0M7, 0M7, CA)
Application Number:
US2014/010501
Publication Date:
October 02, 2014
Filing Date:
January 07, 2014
Export Citation:
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Assignee:
AQUINOX PHARMACEUTICALS INC. (450 - 887 Great Northern Way, Vancouver, British Columbia V5T 4T5, 4T5, CA)
International Classes:
C07D213/82; A61K31/05; A61K31/09; C07C39/08; C07C43/205; C07C49/83; C07C61/39; C07C233/76; C07D213/38; C07D213/89; C07D233/64; C07D401/12
Attorney, Agent or Firm:
ROTH, Carol, J. et al. (Seed Intellectual Property Law Group PLLC, Suite 5400701 Fifth Avenu, Seattle Washington, 98104-7064, US)
Download PDF:
Claims:
AMENDED CLAIMS

received by the International Bureau on 08 August 2014 (08.08.2014)

A compound of formula (I):

is selected from:

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

R is -R9a-C(R10)2-R9 -, -R9a-C(0)-R9 -, -R9a-S(0),-R9 - (where t is 0, 1 or 2),

-R9a-0-R9\ -R9a-C(0)N(R11a)-R9 -, -R9a-N(R 1a)C(0)-R9 - or -R9a-N(R a)-R9 -;

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 R4 are each independently selected from hydrogen, alkyl, -R9-OR11 or

-C(0)OR11 ,

or R4a is selected from hydrogen, alkyl, -R9-OR11, or -C(0)OR11 and R4 is a direct bond to the carbon at numeral 1 or a direct bond to the carbon at numeral 3; R5 is independently selected from hydrogen, oxo, cyano, nitro, halo, alkyl, haloalkyi, 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(0)R11, -R9-C(0)OR11, -R9-N(R )R12, -R9-C(0)N(R )R12, -R9-N(R )C(0)R12,

-R9-N(R )-R 4-N(R )R12, -R9-N(R )C(0)-R9-N(R )R12,

-R9-N(R )C(0)N(R )-OR12, -R9-N(R )C(=NR )N(R )R12, -R9-N(R )S(0)pR11

(where p is 1 or 2), -R9-N(R )C(S)N(R )R12 or

-R9-N(R )C(0)-R9-N(R )S(0)pR12 (where p is 1 or 2);

each R6 and R8 is independently selected from hydrogen, alkyl, halo or haloalkyi; R7 is hydrogen, alkyl, halo or haloalkyi;

each R9, R9a and R9 is independently a direct bond or a straight or branched alkylene chain;

each R 0 is independently hydrogen, alkyl, -OR11 , -C(0)OR11 , -C(0)N(R )R12,

-N(R )R 2 or -N(R )C(0)R11;

each R , R a and R 2 is independently hydrogen, alkyl, alkenyl, haloalkyi, 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 4 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:

(1 S,2S,4aS,8aR)-decahydro-1-[2-(3-methoxyphenyl)ethyl]-5,5,8a-trimethyl-

2-naphthalenecarboxylic acid;

(1 S,2S,4aS,8aR)-decahydro-1-[2-(3-methoxyphenyl)ethyl]-5,5,8a-trimethyl-2- naphthalenemethanol;

a-(3,5-dimethoxyphenyl)decahydro-2-hydroxy-2,5,5,8a-tetramethyl-

1-naphthalenemethanol;

(4aS,8aS)-3,4,4a,5,6,7,8,8a-octahydro-a-(3-methoxy-5- methylphenyl)-2,5,5,8a- tetramethyl-1-naphthalenemethanol;

(1 S,2R,4aS,8aS)-decahydro-2-hydroxy-a-(3-methoxy-5- methylphenyl)-2,5,5,8a- tetramethyl-1-naphthalenemethanol;

(1 R,2R,4aS,8aS)-decahydro-1-[(3-methoxy-5-methylphenyl)methyl]-2,5,5,8a- tetramethyl-2-naphthalenol;

(1 S,2R,4aS,8aS)-1-(3-methoxy-5-methylphenoxymethyl)-2,5,5,8a-tetramethyl- decahydronaphthalen-2-ol;

(1 S,2R,4aS,8aS)-1-(3,5-dimethoxyphenoxymethyl)-2,5,5,8a-tetramethyl- decahydronaphthalen-2-ol;

(1 S,2R,4aS,8aS)-1-[3,5-bis(propan-2-yloxy)phenoxymethyl]-2,5,5,8a-tetramethyl- decahydronaphthalen-2-ol;

(1 R,2R,8aS)-1-((3,5-dimethoxyphenylsulfonyl)methyl)-2,5,5,8a- tetramethyldecahydronaphthalen-2-ol;

(1 R,2R,4aS,8aS)-1-{[(3-methoxy-5-methylphenyl)sulfanyl]methyl}-2,5,5,8a-tetramethyl- decahydronaphthalen-2-ol;

(1 R,2R,4aS,8aS)-1-{[(3-methoxyphenyl)sulfanyl]methyl}-2,5,5,8a-tetramethyl- decahydronaphthalen-2-ol; and

(1 R.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 (la):

wherein n, R1 , R2, R3, R4a, R4 , R5, R6, R7 and R8 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 is -R9a-C(0)-R9 -, i.e., a compound of formula (Ia1):

wherein R and R are as defined above in Claim 1 , or a stereoisomer thereof or a pharmaceutically acceptable salt thereof.

4. The compound of Claim 2 wherein R is -R9a-C(R 0)2-R9 -, i.e., the compound of formula (Ia2):

wherein R9a, R9 and R 0 are as defined above in Claim 1 , or a stereoisomer thereof or a pharmaceutically acceptable salt thereof.

5. The compound of Claim 2, wherein R is -R9-S(0)t-R9-, i.e., a compound of formula (Ia3):

wherein t, R and R are as defined above in Claim 1 , or a stereoisomer thereof or a pharmaceutically acceptable salt thereof.

6. The compound of Claim 2, wherein R is -R9a-0-R9 -, i.e., a compound of formula (Ia4):

wherein R and R are as defined above in Claim 1 , or a stereoisomer thereof or a pharmaceutically acceptable salt thereof.

7. The compound of Claim 2, wherein R is -R9a-C(0)N(R a)-R9 -, i.e., a compound of formula (Ia5):

wherein R9a, R9 and R a are as defined above in Claim 1 , or a stereoisomer thereof or a pharmaceutically acceptable salt thereof.

8. The compound of Claim 2 where R is -R9a-N(R a)C(0)-R9 -, i.e., a compound of formula (Ia6):

wherein R9a, R9 and R11a are as defined above in Claim 1 , or a stereoisomer thereof or a pharmaceutically acceptable salt thereof.

9. The compound of Claim 2 wherein R is -R9a-N(R a)-R9 -, i.e., a compound of formula (Ia7):

wherein R9a, R9 and R11a are as defined above in Claim , or a stereoisomer thereof or a pharmaceutically acceptable salt thereof.

The compound of Claim 1 having the formula (lc):

wherein n, R1 , R4a, R4 , R5, R6, R7 and R8 are as defined above in Claim 1 , or a

stereoisomer thereof or a pharmaceutically acceptable salt thereof.

11. The compound of Claim 10 wherein R is -R9a-N(R a)C(0)-R9 -, i.e., a compound of formula (Id):

wherein R9a, R9 and R a are as defined above in Claim 1 , or a stereoisomer thereof or a pharmaceutically acceptable salt thereof.

12. The compound of Claim 1 having the formula (Id):

wherein n, R1 , R4a, R4 , R5, R6, R7 and R8 are as defined above in Claim 1 , or a

stereoisomer thereof or a pharmaceutically acceptable salt thereof.

13. The compound of Claim 12 wherein R is -R9a-C(R 0)2-R9 -, i-e., a compound of formula (Id 1 ):

wherein R9a, R9 and R 0 are as defined above in Claim 1 , or a stereoisomer thereof or a pharmaceutically acceptable salt thereof. The compound of Claim 1 having the formula

wherein n, R1 , R4a, R4 , R5, R6, R7 and R8 are as defined above in Claim 1 , or a

stereoisomer thereof or a pharmaceutically acceptable salt thereof.

15. The compound of Claim 14 wherein R is -R9a-C(R 0)2-R9 -, a compound of formula (Ie1):

wherein R9a, R9 and R 0 are as defined above in Claim 1 , or a stereoisomer thereof or a pharmaceutically acceptable salt thereof.

16. The compound of Claim 1 having the formula (If):

wherein n, R1 , R4a, R4 , R5, R6, R7 and R8 are as defined above in Claim 1 , or a

stereoisomer thereof or a pharmaceutically acceptable salt thereof.

17. The compound of Claim 16 wherein R is -R9a-C(R0)2-R9-, a compound of formula (If1):

wherein R9a, R9 and R0 are as defined above in Claim 1, or a stereoisomer thereof or a pharmaceutically acceptable salt thereof.

18. The compound of Claim 1 wherein:

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

R is -R9a-C(R0)2-R9-, -R9a-C(0)-R9-, -R9a-S(0)t-R9- (where t is 0, 1 or 2),

-R9a-0-R9-, or-R9a-C(0)N(R a)-R9- or -R9a-N(R a)C(0)-R9-;

R4a and R4 are each independently selected from hydrogen, alkyl, -R9-OR11 or

-C(0)OR11,

or R4a is selected from hydrogen, alkyl, -R9-OR11, or -C(0)OR11 and R4 is a direct bond to the carbon at numeral 1 or a direct bond to the carbon at numeral 3;

R5 is independently selected from hydrogen, oxo, cyano, nitro, halo, alkyl, haloalkyi, optionally substituted cycloalkyi, optionally substituted cycloakylalkyi, optionally substituted aryl, optionally substituted aralkyl, optionally substituted

heterocyclyl, optionally substituted heterocyclylalkyi, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, -R9-OR11, -R9-C(0)R11, -R9-C(0)OR11, -R9-N(R )R12, -R9-C(0)N(R )R12, -R9-N(R )C(0)R12,

-R9-N(R )-R4-N(R )R12, -R9-N(R )C(0)-R9-N(R )R12,

-R9-N(R )C(0)N(R )-OR12, -R9-N(R )C(=NR )N(R )R12, -R9-N(R )S(0)pR11 (where p is 1 or 2), -R9-N(R )C(S)N(R )R12 or

291 -R9-N(R )C(0)-R9-N(R )S(0)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 R9 is independently a direct bond or a straight or branched alkylene chain;

each R 0 is independently hydrogen, alkyl, -OR11 , -C(0)OR11 , -C(0)N(R )R12,

-N(R )R 2 or -N(R )C(0)R11;

each R , R a and R 2 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 4 is a straight or branched alkylene chain;

or a stereoisomer thereof or a pharmaceutically acceptable salt thereof.

19. A compound selected from the group consisting of:

(2R,4R,4aS,8aS)-4-[(3,5-dimethoxyphenyl)carbonyl]-4a,8,8-trimethyl-3-methylidene- decahydronaphthalen-2-ol;

(4aS,5S,8aS)-5-[(3-methoxy-5-methylphenyl)methyl]-1 , 1 ,4a-trimethyl-6-methylidene- decahydronaphthalene;

N-((2R,3S,4S,4aS)-4-((furan-2-carboxamido)methyl)-3,4a,8,8- tetramethyldecahydronaphthalen-2-yl)nicotinamide;

N-((2R,3S,4S,4aS)-4-((furan-2-carboxamido)methyl)-3,4a,8,8- tetramethyldecahydronaphthalen-2-yl)-4-methylpiperazine-1-carboxamide; and N-((2R,3S,4S,4aR)-4-(2-(furan-2-carboxamido)ethyl)-3,4a,8,8- tetramethyldecahydronaphthalen-2-yl)-4-methylpiperazine-1-carboxamide; or a pharmaceutically acceptable salt thereof.

20. A composition comprising a compound of Claim 1 or Claim 19, or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, and a

pharmaceutically acceptable excipient.

21. A method for modulating SHIP1 comprising administering an effective amount of a compound of Claim 1 or Claim 19, or a pharmaceutically acceptable salt thereof or a stereoisomer thereof, or a composition of Claim 20 to a mammal in need

292 thereof.

22. A method for treating a disease, disorder or condition comprising administering an effective amount of a compound of Claim 1 or Claim 19, or a pharmaceutically acceptable salt or stereoisomer thereof, or a composition of Claim 20 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.

293