IP Library › Granted Patent US 8,288,382

Granted Patent B2

US 8,288,382 · App. 12/978,260 · Granted Oct 16, 2012

Diaminothiazoles useful as Axl inhibitors

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Quick Facts

Patent No.: US 8,288,382
App. No.: 12/978,260
Granted: Oct 16, 2012
Kind: B2

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Abstract

Diaminothiazoles and pharmaceutical compositions containing them are disclosed as being useful in inhibiting the activity of the receptor protein tyrosine kinase Axl. Methods of using the diaminothiazoles in treating diseases or conditions associated with Axl activity are also disclosed.

Claims (164)

1. A method of inhibiting a disease or condition associated with Axl activity in a mammal, wherein the method comprises administering to the mammal a therapeutically effective amount of a compound of formula (I)

wherein:

R 1 , R 4 and R 5 are each independently hydrogen, alkyl, aryl, aralkyl, —C(O)R 10 , or —C(O)N(R 6 )R 7 ;

R 2 is aryl or heteroaryl, the aryl or heteroaryl being optionally substituted with one or more substituents selected from the group consisting of cyano, nitro, halo, haloalkyl, alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, —R 10 —OR 9 , —R 10 —O—R 11 —OR 9 , —R 10 —O—R 11 —O—R 11 —OR 9 , —R 10 —O—R 11 —CN, —R 10 —O—R 11 —C(O)OR 9 , —R 10 —O—R 11 —C(O)N(R 6 )R 7 , —R 10 —O—R 11 —S(O) p R 9 (where p is 0, 1 or 2), —R 10 —O—R 11 —N(R 6 )R 7 , —R 10 —O—R 11 —C(NR 12 )N(R 12 )H, —R 10 —OC(O)—R 9 , —R 10 —N(R 6 )R 7 , —R 10 —C(O)R 9 , —R 10 —C(O)OR 9 , —R 10 —C(O)N(R 6 )R 7 , —R 10 —N(R 6 )C(O)OR 14 , —R 10 —N(R 6 )C(O)R 9 , —R 10 —N(R 6 )S(O) t R 9 (where t is 1 or 2), —R 10 —S(O) t OR 9 (where t is 1 or 2), —R 10 —N(R 6 )C(O)R 9 , —R 10 —N(R 6 )S(O) t R 9 (where t is 1 or 2), —R 10 —S(O) t OR 9 (where t is 1 or 2), —R 10 —S(O) p R 9 (where p is 0, 1 or 2), and —R 10 —S(O) t N(R 6 )R 7 (where t is 1 or 2);

R 3 is heteroaryl having at least six ring atoms, the heteroaryl being optionally substituted with one or more substituents selected from the group consisting of cyano, nitro, halo, haloalkyl, alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, —R 10 —OR 9 , —R 10 —O—R 11 —OR 9 , —R 10 —O—R 11 —O—R 11 —OR 9 , —R 10 —O—R 11 —CN, —R 10 —O—R 11 —C(O)OR 9 , —R 10 —O—R 11 —C(O)N(R 6 )R 7 , —R 10 —O—R 11 —S(O) p R 9 (where p is 0, 1 or 2), —R 10 —O—R 11 —N(R 6 )R 7 , —R 10 —O—R 11 —C(NR 12 )N(R 12 )H, —R 10 —OC(O)—R 9 , —R 10 —N(R 6 )R 7 , —R 10 —N(R 6 )C(O)R 9 , —R 10 —N(R 6 )S(O) t R 9 (where t is 1 or 2), —R 10 —S(O) t OR 9 (where t is 1 or 2), —R 10 —S(O) p R 9 (where p is 0, 1 or 2), and —R 10 —S(O) t N(R 6 )R 7 (where t is 1 or 2);

each R 6 and R 7 are each independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, hydroxyalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted cycloalkylalkenyl, optionally substituted cycloalkylalkynyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heterocyclylalkenyl, optionally substituted heterocyclylalkynyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heteroarylalkenyl, optionally substituted heteroarylalkynyl, —R 11 —OR 9 , —R 11 —CN, —R 11 —NO 2 , —R 11 —N(R 9 ) 2 , —R 11 —C(O)OR 9 and —R 11 —C(O)N(R 9 ) 2 ;

each R 9 is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted cycloalkylalkenyl, optionally substituted cycloalkylalkynyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heterocyclylalkenyl, optionally substituted heterocyclylalkynyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heteroarylalkenyl and optionally substituted heteroarylalkynyl;

each R 10 is independently selected from the group consisting of a direct bond, an optionally substituted straight or branched alkylene chain, an optionally substituted straight or branched alkenylene chain and an optionally substituted straight or branched alkynylene chain;

each R 11 is independently selected from the group consisting of an optionally substituted straight or branched alkylene chain, an optionally substituted straight or branched alkenylene chain and an optionally substituted straight or branched alkynylene chain; and

each R 12 is hydrogen, alkyl, cyano, nitro or —OR 9 ;

with the proviso that the compound is not N 2 -(1,4-benzodioxan-6yl)-5-(pyridin-2-yl)thiazole-2,4-diamine, and when R 2 is phenyl, 4-chlorophenyl or methoxy-substituted phenyl, R 3 is not quinolin-2yl, pyridinyl or substituted pyridinyl,

as an isolated stereoisomer or mixture thereof, as a tautomer or mixture thereof, or as a pharmaceutically acceptable salt, or N-oxide thereof, wherein the disease or condition associated with Axl activity is selected from the group consisting of: endometriosis, rheumatoid arthritis, psoriasis, visual impairment due to macular degeneration, diabetic retinopathy, retinopathy of prematurity, osteoporosis, osteoarthritis, cataracts, vascular diseases selected from the group consisting of restenosis, atherosclerosis thrombosis, hypertension, and vascular injury, kidney diseases selected from the group consisting of glomerulonephritis, diabetic nephropathy and renal transplant rejection, solid tumor formation selected from the group consisting of breast carcinoma, renal carcinoma, endometrial carcinoma, ovarian carcinoma, thyroid carcinoma, non-small cell lung carcinoma, melanoma, prostate carcinoma, gastric cancer and uveal melanoma, and liquid tumor formation selected from the group consisting of myeloid leukemia and lymphoma.

2. The method of claim 1 wherein the disease or condition is alleviated by a decrease in Axl activity.

3. The method of claim 2 wherein the disease or condition is selected from the group consisting of rheumatoid arthritis, vascular disease selected from the group consisting of restenosis, atherosclerosis, thrombosis, hypertension, and vascular injury, psoriasis, visual impairment due to macular degeneration, diabetic retinopathy, retinopathy of prematurity, kidney disease selected from the group consisting of glomerulonephritis, diabetic nephropathy and renal transplant rejection, osteoporosis, osteoarthritis, and cataracts.

4. The method of claim 2 , wherein a manifestation of the disease or condition is solid tumor formation selected from the group consisting of breast carcinoma, renal carcinoma, endometrial carcinoma, ovarian carcinoma, thyroid carcinoma, non-small cell lung carcinoma, melanoma, prostate carcinoma, gastric cancer and uveal melanoma.

5. The method of claim 2 , wherein a manifestation of the disease or condition is liquid tumor formation selected from the group consisting of myeloid leukemia and lymphoma.

6. The method of claim 2 wherein the disease or condition is endometriosis.

7. The method of claim 1 , wherein in formula (I):

R 1 , R 4 and R 5 are each hydrogen,

R 2 is aryl or heteroaryl, the aryl or heteroaryl being optionally substituted with one or more substituents selected from the group consisting of cyano, nitro, halo, haloalkyl, alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, —R 10 —OR 9 , —R 10 —O—R 11 —OR 9 , —R 10 —O—R 11 —O—R 11 —OR 9 , —R 10 —O—R 11 —CN, —R 10 —O—R 11 —C(O)OR 9 , —R 10 —O—R 11 —C(O)N(R 6 )R 7 , —R 10 —O—R 11 —S(O) p R 9 (where p is 0, 1 or 2), —R 10 —O—R 11 —N(R 6 )R 7 , —R 10 —O—R 11 —C(NR 12 )N(R 12 )H, —R 10 —OC(O)—R 9 , —R 10 —N(R 6 )R 7 , —R 10 —C(O)R 9 , —R 10 —N(R 6 )S(O) t R 9 (where t is 1 or 2), —R 10 —S(O) t OR 9 (where t is 1 or 2), —R 10 —S(O) p R 9 (where p is 0, 1 or 2), and —R 10 —S(O) t N(R 6 )R 7 (where t is 1 or 2);

R 3 is heteroaryl having at least six ring atoms, the heteroaryl being optionally substituted with one or more substituents selected from the group consisting of cyano, nitro, halo, haloalkyl, alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, —R 10 —OR 9 , —R 10 —O—R 11 —OR 9 , —R 10 —O—R 11 —O—R 11 —OR 9 , —R 10 —O—R 11 —CN, —R 10 —O—R 11 —C(O)OR 9 , —R 10 —O—R 11 —C(O)N(R 6 )R 7 , —R 10 —O—R 11 —S(O) p R 9 (where p is 0, 1 or 2), —R 10 —O—R 11 —N(R 6 )R 7 , R 10 —O—R 11 —C(NR 12 )N(R 12 )H, —R 10 —OC(O)—R 9 , —R 10 —N(R 6 )R 7 , —R 10 —C(O)R 9 , —R 10 —C(O)OR 9 , —R 10 —C(O)N(R 6 )R 7 , —R 10 —N(R 6 )C(O)OR 14 , —R 10 —N(R 6 )C(O)R 9 , —R 10 —N(R 6 )S(O) t R 9 (where t is 1 or 2), —R 10 —S(O) t OR 9 (where t is 1 or 2), —R 10 —S(O) p R 9 (where p is 0, 1 or 2), and —R 10 —S(O) t N(R 6 )R 7 (where t is 1 or 2);

each R 12 is hydrogen, alkyl, cyano, nitro or —OR 9 .

8. The method of claim 7 , wherein in formula (I):

R 1 , R 4 and R 5 are each hydrogen,

R 2 is aryl optionally substituted with one or more substituents selected from the group consisting of cyano, nitro, halo, haloalkyl, alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, —R 10 —OR 9 , —R 10 —O—R 11 —OR 9 , —R 10 —O—R 11 —O—R 11 —OR 9 , —R 10 —O—R 11 —CN, —R 10 —O—R 11 —C(O)OR 9 , —R 10 —O—R 11 —C(O)N(R 6 )R 7 , —R 10 —O—R 11 —S(O) p R 9 (where p is 0, 1 or 2), —R 10 —O—R 11 —N(R 6 )R 7 , —R 10 —O—R 11 —C(NR 12 )N(R 12 )H, —R 10 —OC(O)—R 9 , —R 10 —N(R 6 )R 7 , —R 10 —C(O)R 9 , —R 10 —C(O)OR 9 , —R 10 —C(O)N(R 6 )R 7 , —R 10 —N(R 6 )C(O)OR 14 , —R 10 —N(R 6 )C(O)R 9 , —R 10 —N(R 6 )S(O) t R 9 (where t is 1 or 2), —R 10 —S(O) t OR 9 (where t is 1 or 2), —R 10 —S(O) p R 9 (where p is 0, 1 or 2), and —R 10 —S(O) t N(R 6 )R 7 (where t is 1 or 2);

R 3 is heteroaryl having at least six ring atoms, the heteroaryl being optionally substituted with one or more substituents selected from the group consisting of cyano, nitro, halo, haloalkyl, alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, —R 10 —OR 9 , —R 10 —O—R 11 —OR 9 , —R 10 —O—R 11 —O—R 11 —OR 9 , —R 10 —O—R 11 —CN, —R 10 —O—R 11 —C(O)OR 9 , —R 10 —O—R 11 —C(O)N(R 6 )R 7 , —R 10 —O—R 11 —S(O) p R 9 (where p is 0, 1 or 2), —R 10 —O—R 11 —N(R 6 )R 7 , —R 10 —O—R 11 —C(NR 12 )N(R 12 )H, R 10 —OC(O)—R 9 , —R 10 —N(R 6 )R 7 , —R 10 —C(O)R 9 , —R 10 —C(O)OR 9 , —R 10 —C(O)N(R 6 )R 7 , —R 10 —N(R 6 )C(O)OR 14 , —R 10 —N(R 6 )C(O)R 9 , —R 10 —N(R 6 )S(O) t R 9 (where t is 1 or 2), —R 10 —S(O) t OR 9 (where t is 1 or 2), —R 10 —S(O) p R 9 (where p is 0, 1 or 2), and —R 10 —S(O) t N(R 6 )R 7 (where t is 1 or 2); and

each R 12 is hydrogen, alkyl, cyano, nitro or —OR 9 .

9. The method of claim 8 , wherein in formula (I):

R 1 , R 4 and R 5 are each hydrogen,

R 2 is phenyl optionally substituted with one or more substituents selected from the group consisting of cyano, nitro, halo, haloalkyl, alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, —R 10 —OR 9 , —R 10 —O—R 11 —OR 9 , —R 10 —O—R 11 —OR 9 , —R 10 —O—R 11 —CN, —R 10 —O—R 11 —C(O)OR 9 , —R 10 —O—R 11 C(O)NR 6 )R 7 , —R 10 —O—R 11 S(O) p R 9 (where p is 0, 1 or 2), —R 10 —O—R 11 —N(R 6 )R 7 , —R 10 —O—R 11 —C(NR 12 )N(R 12 )H, —R 10 —OC(O)—R 9 , —R 10 —N(R 6 )R 7 , —R 10 —C(O)R 9 , —R 10 —C(O)OR 9 , —R 10 —C(O)N(R 6 )R 7 , —R 10 —N(R 6 )C(O)OR 14 , —R 10 —N(R 6 )C(O)R 9 , —R 10 —N(R 6 )S(O) t R 9 (where t is 1 or 2), —R 10 —S(O) t OR 9 (where t is 1 or 2), —R 10 —S(O) p R 9 (where p is 0, 1 or 2), and —R 10 —S(O) t N(R 6 )R 7 (where t is 1 or 2);

R 3 is heteroaryl selected from the group consisting of pyridinyl, pyrazolo[3,4-d]pyrimidinyl, pyrido[3,2-d]pyrimidinyl, pyrido[3,4-d]pyrimidinyl, thieno[2,3-d]pyrimidinyl, thieno[3,2-d]pyrimidinyl, quinazolinyl, quinoxalinyl, quinolinyl, isoquinolinyl and benzo[d]thiazolyl, the heteroaryl being optionally substituted with one or more substituents selected from the group consisting of alkyl and —R 10 —OR 9 ;

each R 12 is hydrogen, alkyl, cyano, nitro or —OR 9 .

10. The method of claim 9 , wherein in formula (I):

R 1 , R 4 and R 5 are each hydrogen,

R 2 is phenyl substituted with one or more —OR 9 ; and

each R 9 is independently selected from the group consisting of alkyl and optionally substituted heterocyclylalkyl.

11. The method of claim 10 , wherein the compound of formula (I) is selected from the group consisting of:

5-(quinoxalin-2-yl)-N 2 -(3,4,5-trimethoxyphenyl)thiazole-2,4-diamine;

N 2 -(4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)-5-(quinoxalin-2-yl)thiazole-2,4-diamine;

N 2 -(4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)-5-(quinazolin-4-yl)thiazole-2,4-diamine;

5-(quinazolin-4-yl)-N 2 -(3,4,5-trimethoxyphenyl)thiazole-2,4-diamine;

5-(isoquinolin-1-yl)-N 2 -(4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)thiazole-2,4-diamine;

5-(benzo[d]thiazol-2-yl)-N 2 -(4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)thiazole-2,4-diamine;

5-(6,7-dimethoxyquinazolin-4-yl)-N 2 -(4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)thiazole-2,4-diamine; and

N 2 -(3-chloro-4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)-5-(6,7-dimethoxyquinazolin-4-yl)thiazole-2,4-diamine.

12. The method of claim 9 , wherein in formula (I):

R 1 , R 4 and R 5 are each hydrogen;

R 2 is phenyl substituted with one or more optionally substituted heterocyclyl; and

each R 9 is independently alkyl.

13. The method of claim 12 , wherein in formula (I):

R 2 is phenyl substituted with one or more N-heterocyclyl, the N-heterocyclyl being optionally substituted with one or more substituents selected from the group consisting of alkyl, cycloalkyl and —C(O)R 9 ; and

each R 9 is independently alkyl.

14. The method of claim 13 , wherein the compound of formula (I) is selected from the group consisting of:

5-(isoquinolin-1-yl)-N 2 -(4-morpholinophenyl)thiazole-2,4-diamine;

5-(6,7-dimethoxyquinazolin-4-yl)-N 2 -(4-morpholinophenyl)thiazole-2,4-diamine;

5-(6,7-dimethoxyquinazolin-4-yl)-N 2 -(4-(4-methylpiperazin-1-yl)phenyl)thiazole-2,4-diamine;

N 2 -(4-(4-(bicyclo[2.2.1]heptan-2-yl)piperazin-1-yl)phenyl)-5-(thieno[3,2-d]pyrimidin-4-yl)thiazole-2,4-diamine; and

N 2 -(4-(4-(bicyclo[2.2.1]heptan-2-yl)piperazin-1-yl)phenyl)-5-(6,7-dimethoxyquinazolin-4-yl)thiazole-2,4-diamine.

15. The method of claim 9 , wherein in formula (I):

R 1 , R 4 and R 5 are each hydrogen;

R 2 is phenyl substituted with one or more substituents selected from the group consisting of optionally substituted heterocyclylalkyl, halo, —OR 9 and —C(O)R 9 ; and

16. The method of claim 1 , wherein in formula (I):

R 1 , R 4 and R 5 are each hydrogen,

R 2 is heteroaryl optionally substituted with one or more substituents selected from the group consisting of cyano, nitro, halo, haloalkyl, alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, —R 10 —OR 9 , —R 10 —O—R 11 —OR 9 , —R 10 —O—R 11 —O—R 11 —OR 9 , —R 10 —O—R 11 —CN, —R 10 —O—R 11 —C(O)OR 9 , —R 10 —O—R 11 —C(O)N(R 6 )R 7 , —R 10 —O—R 11 —S(O) p R 9 (where p is 0, 1 or 2), —R 10 —O—R 11 —N(R 6 )R 7 , —R 10 —O—R 11 —C(NR 12 )N(R 12 )H, R 10 —OC(O)—R 9 , —R 10 —N(R 6 )R 7 , —R 10 —C(O)R 9 , R 10 —C(O)OR 9 , —R 10 —C(O)N(R 6 )R 7 , —R 10 —N(R 6 )C(O)OR 14 , —R 10 —N(R 6 )C(O)R 9 , —R 10 —N(R 6 )S(O) t R 9 (where t is 1 or 2), —R 10 —S(O) t OR 9 (where t is 1 or 2), —R 10 —S(O) p R 9 (where p is 0, 1 or 2), and —R 10 —S(O) t N(R 6 )R 7 (where t is 1 or 2);

R 3 is heteroaryl having at least six ring atoms, the heteroaryl being optionally substituted with one or more substituents selected from the group consisting of cyano, nitro, halo, haloalkyl, alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, —R 10 —OR 9 , —R 10 —O—R 11 —OR 9 , —R 10 —O—R 11 —O—R 11 —OR 9 , —R 10 —O—R 11 —CN, —R 10 —O—R 11 —C(O)OR 9 , —R 10 —O—R 11 —C(O)N(R 6 )R 7 , —R 10 —O—R 11 —S(O) p R 9 (where p is 0, 1 or 2), —R 10 —O—R 11 —N(R 6 )R 7 , —R 10 —O—R 11 —C(NR 12 )N(R 12 )H, —R 10 —OC(O)—R 9 , —R 10 —N(R 6 )R 7 , —R 10 —C(O)R 9 , —R 10 —C(O)R 9 , —R 10 —C(O)OR 9 , —R 10 —C(O)N(R 6 )R 7 , —R 10 —N(R 6 )C(O)OR 14 , —R 10 —N(R 6 )C(O)R 9 , —R 10 —N(R 6 )S(O) t R 9 (where t is 1 or 2), —R 10 —S(O) t OR 9 (where t is 1 or 2), —R 10 —S(O) p R 9 (where p is 0, 1 or 2), and —R 10 —S(O) t N(R 6 )R 7 (where t is 1 or 2);

each R 12 is hydrogen, alkyl, cyano, nitro or —OR 9 ; as an isolated stereoisomer or mixture thereof, as a tautomer or mixture thereof, or as a pharmaceutically acceptable salt, or N-oxide thereof.

17. The method of claim 1 , wherein in formula (I):

R 1 , R 4 and R 5 are each independently hydrogen, alkyl, aryl, aralkyl, —C(O)R 10 , or —C(O)N(R 6 )R 7 ;

R 2 is aryl or heteroaryl, the aryl or heteroaryl being optionally substituted with one or more substituents selected from the group consisting of cyano, nitro, halo, haloalkyl, alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, —R 10 —OR 9 , —R 10 —O—R 11 —OR 9 , —R 10 —O—R 11 —O—R 11 —OR 9 , —R 10 —O—R 11 —CN, —R 10 —O—R 11 —C(O)OR 9 , —R 10 —O—R 11 —C(O)N(R 6 )R 7 , —R 10 —O—R 11 —S(O) p R 9 (where p is 0, 1 or 2), —R 10 —O—R 11 —N(R 6 )R 7 , —R 10 —O—R 11 —C(NR 12 )N(R 12 )H, —R 10 —OC(O)—R 9 , —R 10 —N(R 6 )R 7 , —R 10 —C(O)R 9 , —R 10 —C(O)OR 9 , —R 10 —C(O)N(R 6 )R 7 , —R 10 —N(R 6 )C(O)OR 14 , —R 10 —N(R 6 )C(O)R 9 , —R 10 —N(R 6 )S(O) t R 9 (where t is 1 or 2), —R 10 —S(O) t OR 9 (where t is 1 or 2), —R 10 —S(O) p R 9 (where p is 0, 1 or 2), and —R 10 —S(O) t N(R 6 )R 7 (where t is 1 or 2);

R 3 is polycyclic heteroaryl optionally substituted with one or more substituents selected from the group consisting of cyano, nitro, halo, haloalkyl, alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, —R 10 —OR 9 , —R 10 —O—R 11 —OR 9 , —R 10 —O—R 11 —O—R 11 —OR 9 , —R 10 —O—R 11 —CN, —R 10 —O—R 11 —C(O)OR 9 , —R 10 —O—R 11 —C(O)N(R 6 )R 7 , R 10 —O—R 11 —S(O) p R 9 (where p is 0, 1 or 2), —R 10 —O—R 11 —N(R 6 )R 7 , —R 10 —O—R 11 —C(NR 12 )N(R 12 )H, R 10 —OC(O)— 9 , —R 10 —N(R 6 )R 7 , —R 10 —C(O)R 9 , —R 10 —C(O)OR 9 , —R 10 —C(O)N(R 6 )R 7 , —R 10 —N(R 6 )C(O)OR 14 , —R 10 —N(R 6 )C(O)R 9 , —R 10 —N(R 6 )S(O) t R 9 (where t is 1 or 2), —R 10 —S(O) t OR 9 (where t is 1 or 2), —R 10 —S(O) p R 9 (where p is 0, 1 or 2), and —R 10 —S(O)N(R 6 )R 7 (where t is 1 or 2);

each R 6 and R 7 are each independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, hydroxyalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted cycloalkylalkenyl, optionally substituted cycloalkylalkynyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heterocyclylalkenyl, optionally substituted heterocyclylalkynyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heteroarylalkenyl, optionally substituted heteroarylalkynyl, —R 11 —OR 9 , —R 11 —CN, —R 11 NO 2 , —R 11 —N(R 9 ) 2 , —R 11 —C(O)OR 9 and —R 11 —C(O)N(R 9 ) 2 ;

each R 12 is hydrogen, alkyl, cyano, nitro or —OR 9 ; as an isolated stereoisomer or mixture thereof, as a tautomer or mixture thereof, or as a pharmaceutically acceptable salt, or N-oxide thereof.

18. The method of claim 17 , wherein the compound of formula (I) is represented by formula (Ia):

wherein:

X is N or CH;

w is 0, 1, 2, 3, 4, 5, 6, 7 or 8;

R 1 , R 3a , R 4 and R 5 are each independently hydrogen, alkyl, aryl, aralkyl, —C(O)R 10 , or —C(O)N(R 6 )R 7 ;

R 2 is aryl or heteroaryl optionally substituted with one or more substituents selected from the group consisting of cyano, nitro, halo, haloalkyl, alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, —R 10 —OR 9 , —R 10 —O—R 11 —OR 9 , —R 10 —O—R 11 —O—R 11 —OR 9 , —R 10 —O—R 11 —CN, —R 10 —O—R 11 —C(O)OR 9 , —R 10 —O—R 11 —C(O)N(R 6 )R 7 , —R 10 —O—R 11 —S(O) p R 9 (where p is 0, 1 or 2), —R 10 —O—R 11 —N(R 6 )R 7 , —R 10 —O—R 11 —C(NR 12 )N(R 12 )H, —R 10 —OC(O)—R 9 , —R 10 —N(R 6 )R 7 , —R 10 —C(O)R 9 , —R 10 —C(O)OR 9 , —R 10 —C(O)N(R 6 )R 7 , —R 10 —N(R 6 )C(O)OR 14 , —R 10 —N(R 6 )C(O)R 9 , —R 10 —N(R 6 )S(O) t R 9 (where t is 1 or 2), —R 10 —S(O) t OR 9 (where t is 1 or 2), —R 10 —S(O) p R 9 (where p is 0, 1 or 2), and —R 10 —S(O) t N(R 6 )R 7 (where t is 1 or 2);

A is cycloalkyl, heterocyclyl, heteroaryl or aryl;

each R 3b is independently selected from the group consisting of cyano, nitro, halo, haloalkyl, alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, —R 10 —OR 9 , —R 10 —O—R 11 —OR 9 , —R 10 —O—R 11 —O—R 11 —OR 9 , —R 10 —O—R 11 —CN, —R 10 —O—R 11 C(O)OR 9 , —R 10 —O—R 11 —C(O)N(R 6 )R 7 , —R 10 —O—R 11 —S(O) p R 9 (where p is 0, 1 or 2), —R 10 —O—R 11 —N(R 6 )R 7 , —R 10 —O—R 11 —C(NR 12 )N(R 12 )H, —R 10 —OC(O)—R 9 , —R 10 —N(R 6 )R 7 , —R 10 —C(O)R 9 , —R 10 —C(O)OR 9 , —R 10 —C(O)N(R 6 )R 7 , —R 10 —N(R 6 )C(O)OR 14 , —R 10 —N(R 6 )C(O)R 9 , —R 10 —N(R 6 )S(O) t R 9 (where t is 1 or 2), —R 10 —S(O) t OR 9 (where t is 1 or 2), —R 10 —S(O) p R 9 (where p is 0, 1 or 2), and —R 10 —S(O) t N(R 6 )R 7 (where t is 1 or 2);

each R 12 is hydrogen, alkyl, cyano, nitro or —OR 9 ; as an isolated stereoisomer or mixture thereof, as a tautomer or mixture thereof, or as a pharmaceutically acceptable salt, or N-oxide thereof.

19. The method of claim 18 , wherein in formula (Ia):

w is 0, 1, 2, 3 or 4;

R 1 , R 3a , R 4 and R 5 are each hydrogen;

R 2 is phenyl optionally substituted with one or more substituents selected from the group consisting of cyano, nitro, halo, haloalkyl, alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, —R 10 —OR 9 , —R 10 —O—R 11 —OR 9 , —R 10 —O—R 11 —O—R 11 —OR 9 , —R 10 —O—R 11 —CN, —R 10 —O—R 11 —C(O)OR 9 , —R 10 —O—R 11 —C(O)N(R 6 )R 7 , —R 10 —O—R 11 —S(O) p R 9 (where p is 0, 1 or 2), —R 10 —O—R 11 —N(R 6 )R 7 , —R 10 —O—R 11 —C(NR 12 )N(R 12 )H, —R 10 —OC(O)—R 9 , —R 10 —N(R 6 )R 7 , —R 10 —C(O)R 9 , —R 10 —C(O)OR 9 , —R 10 —C(O)N(R 6 )R 7 , —R 10 —N(R 6 )C(O)OR 14 , —R 10 —N(R 6 )C(O)R 9 , —R 10 —N(R 6 )S(O) t R 9 (where t is 1 or 2), —R 10 —S(O) t OR 9 (where t is 1 or 2), —R 10 —S(O) p R 9 (where p is 0, 1 or 2), and —R 10 —S(O) t N(R 6 )R 7 (where t is 1 or 2);

A is aryl; and

each R 3b is independently selected from the group consisting of cyano, nitro, halo, haloalkyl, alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, —R 10 —OR 9 , —R 10 —O—R 11 —OR 9 , —R 10 —O—R 11 —O—R 11 —OR 9 , —R 10 —O—R 11 —CN, —R 10 —O—R 11 —C(O)OR 9 , —R 10 —O—R 11 —C(O)N(R 6 )R 7 , —R 10 —O—R 11 —S(O) p R 9 (where p is 0, 1 or 2), —R 10 —O—R 11 —N(R 6 )R 7 , —R 10 —O—R 11 —C(NR 12 )N(R 12 )H, —R 10 —OC(O)—R 9 , —R 10 —N(R 6 )R 7 , —R 10 —C(O)R 9 , —R 10 —C(O)OR 9 , —R 10 —C(O)N(R 6 )R 7 , —R 10 —N(R 6 )C(O)OR 14 , —R 10 —N(R 6 )C(O)R 9 , —R 10 —N(R 6 )S(O) t R 9 (where t is 1 or 2), —R 10 —S(O) t OR 9 (where t is 1 or 2), —R 10 —S(O) p R 9 (where p is 0, 1 or 2), and —R 10 —S(O) t N(R 6 )R 7 (where t is 1 or 2).

20. The method of claim 19 , wherein in formula (Ia):

X is N;

w is 0, 1 or 2;

R 1 , R 3a , R 4 and R 5 are each hydrogen;

R 2 is phenyl substituted with one or more substituents selected from the group consisting of —OR 9 and N-heterocyclyl optionally substituted with one or more substituents selected from the group consisting of alkyl, cycloalkyl and —C(O)R 9 ;

A is phenyl;

each R 3b is independently —OR 9 ; and

each R 9 is independently alkyl or heterocyclylalkyl.

21. The method of claim 20 , wherein the compound of formula (Ia) is selected from the group consisting of:

5-(6,7-dimethoxyquinazolin-4-yl)-N 2 -(4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)thiazole-2,4-diamine;

N 2 -(4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)-5-(quinazolin-4-yl)thiazole-2,4-diamine;

5-(quinazolin-4-yl)-N 2 -(3,4,5-trimethoxyphenyl)thiazole-2,4-diamine;

5-(6,7-dimethoxyquinazolin-4-yl)-N 2 -(4-morpholinophenyl)thiazole-2,4-diamine;

5-(6,7-dimethoxyquinazolin-4-yl)-N 2 -(4-(4-methylpiperazin-1-yl)phenyl)thiazole-2,4-diamine;

N 2 -(4-(4-(bicyclo[2.2.1]heptan-2-yl)piperazin-1-yl)phenyl)-5-(6,7-dimethoxyquinazolin-4-yl)thiazole-2,4-diamine; and

N 2 -(3-chloro-4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)-5-(6,7-dimethoxyquinazolin-4-yl)thiazole-2,4-diamine.

22. The method of claim 19 , wherein in formula (Ia):

X is CH;

w is 0;

R 1 , R 3a , R 3b , R 4 and R 5 are each hydrogen;

A is phenyl;

each R 9 is independently alkyl or heterocyclylalkyl.

23. The method of claim 22 , wherein the compound of formula (Ia) is selected from the group consisting of:

5-(isoquinolin-1-yl)-N 2 -(4-morpholinophenyl)thiazole-2,4-diamine; and

5-(isoquinolin-1-yl)-N 2 -(4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)thiazole-2,4-diamine.

24. The method of claim 18 , wherein in formula (Ia):

w is 0, 1, 2, 3 or 4;

R 1 , R 3a , R 4 and R 5 are each hydrogen;

R 2 is phenyl optionally substituted with one or more substituents selected from the group consisting of cyano, nitro, halo, haloalkyl, alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, —R 10 —OR 9 , —R 10 —O—R 11 —OR 9 , —R 10 —O—R 11 —CN, R 10 —O—R 11 —C(O)OR 9 , —R 10 —O—R 11 —C(O)N(R 6 )R 7 , —R 10 —O—R 11 —S(O) p R 9 (where p is 0, 1 or 2), —R 10 —O—R 11 —N(R 6 )R 7 , —R 10 —O—R 11 —C(NR 12 )N(R 12 )H, —R 10 —OC(O)—R 9 , —R 10 —N(R 6 )R 7 , —R 10 —C(O)R 9 , —R 10 —C(O)OR 9 , —R 10 —C(O)N(R 6 )R 7 , —R 10 —N(R 6 )C(O)OR 14 , —R 10 —N(R 6 )C(O)R 9 , —R 10 —N(R 6 )S(O) t R 9 (where t is 1 or 2), —R 10 —S(O) t OR 9 (where t is 1 or 2), —R 10 —S(O) p R 9 (where p is 0, 1 or 2), and —R 10 —S(O) t N(R 6 )R 7 (where t is 1 or 2);

A is heteroaryl; and

each R 3b is independently selected from the group consisting of cyano, nitro, halo, haloalkyl, alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, —R 10 —OR 9 , —R 10 —O—R 11 —OR 9 , —R 10 —O—R 11 —O—R 11 —OR 9 , —R 10 —O—R 11 —C(O)OR 9 , —R 10 —O—R 11 —C(O)N(R 6 )R 7 , —R 10 —O—R 11 —S(O) p R 9 (where p is 0, 1 or 2), —R 10 —O—R 11 —N(R 6 )R 7 , —R 10 —O—R 11 —C(NR 12 )N(R 12 )H, —R 10 —OC(O)—R 9 , —R 10 —N(R 6 )R 7 , —R 10 —C(O)R 9 , —R 10 —C(O)OR 9 , —R 10 —C(O)N(R 6 )R 7 , —R 10 —N(R 6 )C(O)OR 14 , —R 10 —N(R 6 )C(O)R 9 , —R 10 —N(R 6 )S(O) t R 9 (where t is 1 or 2), —R 10 —S(O) t OR 9 (where t is 1 or 2), —R 10 —S(O) p R 9 (where p is 0, 1 or 2), and —R 10 —S(O) t N(R 6 )R 7 (where t is 1 or 2).

25. The method of claim 24 , wherein in formula (Ia):

w is 0;

R 1 , R 3a , R 3b , R 4 and R 5 are each hydrogen;

R 2 is phenyl substituted with one or more N-heterocyclyl optionally substituted with one or more substituents selected from the group consisting of alkyl, cycloalkyl and —C(O)R 9 ;

A is thienyl; and

each R 9 is independently alkyl.

26. The method of claim 25 , wherein the compound is N 2 -(4-(4-(bicyclo[2.2.1]heptan-2-yl)piperazin-1-yl)phenyl)-5-(thieno[3,2-d]pyrimidin-4-yl)thiazole-2,4-diamine.

27. A method of inhibiting a disease or condition associated with Axl activity in a mammal, wherein the method comprises administering to the mammal a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a therapeutically effective amount of a compound of formula (I):

wherein:

R 1 , R 4 and R 5 are each independently hydrogen, alkyl, aryl, aralkyl, —C(O)R 10 , or —C(O)N(R 6 )R 7 ;

R 2 is aryl or heteroaryl, the aryl or heteroaryl being optionally substituted with one or more substituents selected from the group consisting of cyano, nitro, halo, haloalkyl, alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, —R 10 —OR 9 , —R 10 —O—R 11 —OR 9 , R 10 —O—R 11 —O—R 11 —OR 9 , —R 10 —O—R 11 —CN, —R 10 —O—R 11 —C(O)OR 9 , —R 10 —O—R 11 —C(O)N(R 6 )R 7 , —R 10 —O—R 11 —S(O) p R 9 (where p is 0, 1 or 2), —R 10 —O—R 11 —N(R 6 )R 7 , —R 10 —O—R 11 —C(NR 12 )N(R 12 )H, —R 10 —OC(O)—R 9 , —R 10 —N(R 6 )R 7 , —R 10 —C(O)R 9 , —R 10 —C(O)OR 9 , —R 10 —C(O)N(R 6 )R 7 , —R 10 —N(R 6 )C(O)OR 14 , —R 10 —N(R 6 )C(O)R 9 , —R 10 —N(R 6 )S(O) t R 9 (where t is 1 or 2), —R 10 —S(O) t OR 9 (where t is 1 or 2), —R 10 —S(O) p R 9 (where p is 0, 1 or 2), and —R 10 —S(O) t N(R 6 )R 7 (where t is 1 or 2);

R 3 is heteroaryl having at least six ring atoms, the heteroaryl being optionally substituted with one or more substituents selected from the group consisting of cyano, nitro, halo, haloalkyl, alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, —R 10 —OR 9 , —R 10 —O—R 11 —OR 9 , —R 10 —O—R 11 —OR 9 , —R 10 —O—R 11 —CN, —R 10 —O—R 11 —C(O)OR 9 , —R 10 —O—R 11 —C(O)N(R 6 )R 7 , —R 10 —O—R 11 —S(O) p R 9 (where p is 0, 1 or 2), —R 10 —O—R 11 —N(R 6 )R 7 , —R 10 —O—R 11 —C(NR 12 )N(R 12 )H, R 10 —OC(O)—R 9 , —R 10 —N(R 6 )R 7 , —R 10 —C(O)R 9 , R 10 —C(O)OR 9 , —R 10 —C(O)N(R 6 )R 7 , R 10 —N(R 6 )C(O)OR 14 , —R 10 —N(R 6 )C(O)R 9 , —R 10 —N(R 6 )S(O) t R 9 (where t is 1 or 2), —R 10 —S(O) t OR 9 (where t is 1 or 2), —R 10 —S(O) p R 9 (where p is 0, 1 or 2), and —R 10 —S(O) t N(R 6 )R 7 (where t is 1 or 2);

each R 6 and R 7 are each independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, hydroxyalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted cycloalkylalkenyl, optionally substituted cycloalkylalkynyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heterocyclylalkenyl, optionally substituted heterocyclylalkynyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heteroarylalkenyl, optionally substituted heteroarylalkynyl, —R 11 —OR 9 , R 11 —CN, —R 11 —NO 2 , —R 11 —N(R 9 ) 2 , —R 11 —C(O)OR 9 and —R 11 —C(O)N(R 9 ) 2 ;

each R 12 is hydrogen, alkyl, cyano, nitro or —OR 9 ;

as an isolated stereoisomer or mixture thereof, as a tautomer or mixture thereof, or as a pharmaceutically acceptable salt, or N-oxide thereof, wherein the disease or condition associated with Axl activity is selected from the group consisting of endometriosis, rheumatoid arthritis, psoriasis, visual impairment due to macular degeneration, diabetic retinopathy, retinopathy of prematurity, osteoporosis, osteoarthritis, cataracts, vascular diseases selected from the group consisting of restenosis, atherosclerosis, thrombosis, hypertension, and vascular injury, kidney diseases selected from the group consisting of glomerulonephritis, diabetic nephropathy and renal transplant rejection, solid tumor formation selected from the group consisting of breast carcinoma, renal carcinoma, endometrial carcinoma, ovarian carcinoma, thyroid carcinoma, non-small cell lung carcinoma, melanoma, prostate carcinoma, gastric cancer and uveal melanoma, and liquid tumor formation selected from the group consisting of myeloid leukemia and lymphoma.

Assignments (1)

SECURITY INTEREST Recorded Aug 25, 2022

From: RIGEL PHARMACEUTICALS, INC.

To: MIDCAP FINANCIAL TRUST

Reel/Frame 061327/0712 →