IP Library › Granted Patent US 7,879,856

Granted Patent B2

US 7,879,856 · App. 11/963,157 · Granted Feb 1, 2011

Diaminothiazoles useful as Axl inhibitors

Assignee: Rigel Pharmaceuticals, Inc.

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Quick Facts

Patent No.: US 7,879,856
App. No.: 11/963,157
Granted: Feb 1, 2011
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 (162)

1. 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 —R 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);

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 )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 —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 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, or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1 wherein:

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 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);

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

3. The compound of claim 2 wherein:

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 —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 .

4. The compound of claim 3 wherein:

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 —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 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 .

5. The compound of claim 4 , wherein:

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.

6. The compound of claim 5 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.

7. The compound of claim 4 wherein:

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.

8. The compound of claim 7 wherein:

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.

9. The compound of claim 8 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.

10. The compound of claim 4 wherein:

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

11. The compound of claim 1 , wherein:

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 —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 —(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 R 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 , —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 isolated stereoisomers or mixtures thereof, as tautomers or mixtures thereof, or as pharmaceutically acceptable salts, or N-oxides thereof.

12. The compound of claim 1 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 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 —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 isolated stereoisomers or mixtures thereof, as tautomers or mixtures thereof, or as pharmaceutically acceptable salts, or N-oxides thereof.

13. The compound of claim 12 , 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 11 —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 isolated stereoisomers or mixtures thereof, as tautomers or mixtures thereof, or as pharmaceutically acceptable salts, or N-oxides thereof.

14. The compound of claim 13 wherein:

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).

15. The compound of claim 14 wherein:

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.

16. The compound of claim 15 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.

17. The compound of claim 14 wherein

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.

18. The compound of claim 17 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.

19. The compound of claim 13 wherein:

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 —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—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 compound of claim 19 wherein:

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.

21. The compound of claim 20 , 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.

22. 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 11 —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);

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

with the proviso that the compound is not N 2 -(1,4-benzodioxan-6-yl)-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, or a pharmaceutically acceptable salt thereof.

Assignments (3)

SECURITY INTEREST Recorded May 8, 2026

From: RIGEL PHARMACEUTICALS, INC.

To: MIDCAP FUNDING IV TRUST

Reel/Frame 075576/0880 →

SECURITY INTEREST Recorded Aug 25, 2022

From: RIGEL PHARMACEUTICALS, INC.

To: MIDCAP FINANCIAL TRUST

Reel/Frame 061327/0712 →

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Mar 11, 2009

From: GOFF, DANE; ZHANG, JING; SINGH, RAJINDER; HOLLAND, SACHA

To: RIGEL PHARMACEUTICALS, INC.

Reel/Frame 022378/0971 →

Continuity (2)

Provisional Application 60876963 · Dec 22, 2006

Related Publication 20080227789A1 · Sep 18, 2008