Oxazole and thiazole compounds as beta-catenin modulators and uses thereof
A series of oxazole and thiazole compounds are shown herein to be small molecule inhibitors of the Wnt pathway that specifically target the activity of the stabilized pool of β-catenin. Oxazole and thiazole compounds are disclosed that have a formula represented by the following: The compounds may be prepared as pharmaceutical compositions, and may be used for the prevention and treatment of a variety of conditions in mammals including humans, including by way of non-limiting example, cancer, and others.
1. A method for treating or ameliorating in a mammal a disease or condition that is causally related to the aberrant activity of the Wnt signaling pathway in vivo, wherein the disease or condition is a cancer, which method comprises administering to the mammal an effective disease-treating or condition-treating amount of a compound according to formula I:
wherein A is A 1 ;
A 1 is
x is 1;
L 1 is S, SO or SO 2 ;
m1 is 1, 2 or 3; n is 1, 2, 3, 4 or 5;
each R 1 , R 2a , R 2b , R 2c , and R 2d is independently selected from hydrogen, halo, and substituted or unsubstituted C 1 -C 6 alkyl;
R 3 is hydroxy, alkoxy, substituted or unsubstituted amino or cycloheteroalkyl;
each R 4 is independently selected from H, alkyl, substituted alkyl, acyl, substituted acyl, substituted or unsubstituted acylamino, substituted or unsubstituted alkylamino, substituted or unsubstituted alkythio, substituted or unsubstituted alkoxy, alkoxycarbonyl, substituted alkoxycarbonyl, substituted or unsubstituted alkylarylamino, arylalkyloxy, substituted arylalkyloxy, amino, aryl, substituted aryl, arylalkyl, substituted or unsubstituted sulfonyl, substituted or unsubstituted sulfinyl, substituted or unsubstituted sulfanyl, substituted or unsubstituted aminosulfonyl, substituted or unsubstituted arylsulfonyl, azido, carboxy, substituted or unsubstituted carbamoyl, cyano, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloheteroalkyl, substituted or unsubstituted dialkylamino, halo, heteroaryloxy, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroalkyl, hydroxy, nitro, and thiol;
or a pharmaceutically acceptable salt, solvate or prodrug thereof;
and stereoisomers, isotopic variants and tautomers thereof.
2. The method according to claim 1 , wherein the compound is according to formula IIa:
and wherein L 1 , m1, n, R 1 , R 2a , R 2b , R 2c , R 2d , R 3 and R 4 are as in claim 1 .
3. The method according to claim 2 , wherein the compound is according to formula IVa:
wherein n, and R 4 are as stated, and each R 3a and R 3b is independently selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl; or R 3a and R 3b join together to form a cycloheteroalkyl heteroaryl ring.
4. The method according to claim 2 , wherein the compound is according to formula VIIa, VIIb, VIIc or VIId:
wherein R 3b is selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl; or R 3b is joined together with R 3a to form a cycloheteroalkyl heteroaryl ring.
5. The method according to claim 1 , wherein the compound is according to formula VIIIa, VIIIb, VIIIc, or VIIId:
wherein Cy is
and wherein R 3c is H or alkyl.
6. The method according to claim 1 , wherein the compound is according to formula IXa, IXb, IXc or IXd:
7. The method according to claim 1 , wherein the compound is according to formula Xa, Xb, Xc or Xd:
8. The method according to claim 1 , wherein the compound is according to formula XIa, XIb, XIc or XId:
9. The method according to claim 1 , wherein the compound is according to formula XIIa, XIIb, XIIc or XIId:
10. The method according to claim 1 , wherein the compound is according to formula XIIIa, XIIIb, XIIIc or XIIId:
11. The method according to claim 1 , wherein the compound is selected from Tables 1-6.
12. The method of claim 1 , wherein the cancer is prostate cancer, head and neck cancer, lung cancer, gastric cancer, mesothelioma, Barrett's esophagus, synovial sarcoma, cervical cancer, endometrial ovarian cancer, Wilm's tumor, bladder cancer or leukemia.
13. The method of claim 12 , wherein the lung cancer is non-small cell lung cancer.
14. The method according to claim 2 , wherein L 1 is S.
15. The method according to claim 2 , wherein the subscript ml is 1 or 2.
16. The method according to claim 2 , wherein each of R 2a , R 2b , R 2c and R 2d is H.
17. The method according to claim 2 , wherein R 1 is halo or Me.
18. The method according to claim 2 , wherein n is 1 or 2; and R 4 is independently alkyl, alkoxy, haloalkyl, or halo.
19. The method according to claim 3 , wherein one of R 3a and R 3b is substituted or unsubstituted alkyl, substituted or unsubstituted benzyl, substituted or unsubstituted phenethyl, substituted or unsubstituted cycloalkyl; and the other is H; or R 3a and R 3b join together to form a heterocycloalkyl or heteroaryl ring.