Substituted pyridazine carboxamide compounds as kinase inhibitor compounds

Abstract

Pyridazine derivatives have unexpected drug properties as inhibitors of protein kinases and are useful in treating disorders related to abnormal protein kinase activities such as cancer.

1 . A compound of formula I: 
       
         
           
           
               
               
           
         
       
       or a salt thereof; or a prodrug, or a salt of a prodrug thereof; or a hydrate, solvate, or polymorph thereof; wherein:
 R 1  is arylalkyl or heteroarylalkyl, each optionally substituted with 1-4 independent Z 1 ; 
 R 3  is hydrogen, hydroxyl, alkoxy, or alkylamino; 
 R 6  is optionally substituted aryl or heteroaryl, saturated or unsaturated heterocyclyl, wherein R 6  is optionally substituted by 1-3 groups, independently selected from alkyl, cycloalkyl, heterocyclyl, alkoxy, hydroxyalkyl, —C(O)NR 7 R 8 , and Z 1 ; each of which may be further optionally substituted; 
 R 7  and R 8  are each independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heterocyclyl, heteroaryl, or R 7  and R 8  together with nitrogen form a heterocyclyl or heteroaryl; 
 each Z 1  is halogen, CN, NO 2 , OR 15 , SR 15 , S(O) 2 OR 15 , NR 15 R 16 , C 1 -C 2  perfluoroalkyl, C 1 -C 2  perfluoroalkoxy, 1,2-methylenedioxy, C(O)OR 15 , C(O)NR 15 R 16 , OC(O)NR 15 R 16 , NR 15 C(O)NR 15 R 16 , C(NR 16 )NR 15 R 16 , NR 15 C(NR 16 )NR 15 R 16 , S(O) 2 NR 15 R 16 , R 17 , C(O)R 17 , NR 15 C(O)R 17 , S(O)R 17 , S(O) 2 R 17 , R 16 , oxo, C(O)R 16 , C(O)(CH 2 )nOH, (CH 2 )nOR 15 , (CH 2 )nC(O)NR 15 R 16 , NR 15 S(O) 2 R 17 , where n is independently 0-6 inclusive; 
 each R 15  is independently hydrogen, C 1 -C 4  alkyl or C 3 -C 6  cycloalkyl; 
 each R 16  is independently hydrogen, alkenyl, alkynyl, C 3 -C 6  cycloalkyl, aryl, heterocyclyl, heteroaryl, C 1 -C 4  alkyl or C 1 -C 4  alkyl substituted with C 3 -C 6  cycloalkyl, aryl, heterocyclyl or heteroaryl; and 
 each R 17  is independently C 3 -C 6  cycloalkyl, aryl, heterocyclyl, heteroaryl, C 1 -C 4  alkyl or C 1 -C 4  alkyl substituted with C 3 -C 6  cycloalkyl, aryl, heterocyclyl or heteroaryl. 
 
     
     
         2 . The compound of  claim 1 , wherein R 6  is optionally substituted aryl or heteroaryl, wherein R 6  is substituted by alkyl, alkoxyl, or —C(O)NR 7 R 8 . 
     
     
         3 . The compound of  claim 2 , wherein R 6  is substituted aryl, wherein R 6  is substituted by —C(O)NR 7 R 8 . 
     
     
         4 . The compound of  claim 2 , wherein R 6  is substituted heteroaryl, wherein R 6  is substituted by alkoxy or —C(O)NR 7 R 8 . 
     
     
         5 . The compound of  claim 1 , wherein R 6  is optionally substituted saturated or unsaturated heterocyclyl. 
     
     
         6 . The compound of  claim 1 , wherein R 1  is arylalkyl optionally substituted with 1-4 independent Z 1 . 
     
     
         7 . The compound of  claim 2 , wherein each Z 1  is independently halogen. 
     
     
         8 . The compound of  claim 1 , wherein R 3  is H. 
     
     
         9 . The compound of  claim 1 , of formula II: 
       
         
           
           
               
               
           
         
       
       or a salt thereof; or a prodrug, or a salt of a prodrug thereof; or a hydrate, solvate, or polymorph thereof; wherein:
 R 6  is optionally substituted aryl or heteroaryl, saturated or unsaturated heterocyclyl, wherein R 6  is optionally substituted by alkyl, cycloalkyl, heterocyclyl, alkoxy, hydroxyalkyl, or —C(O)NR 7 R 8 ; and 
 R 7  and R 8  are each independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heterocyclyl, heteroaryl, or R 7  and R 8  together with nitrogen form a heterocyclyl or heteroaryl. 
 
     
     
         10 . The compound of  claim 1 , wherein the compound is selected from the following:
 {6-amino-5-[(2,6-dichloro-3-fluorophenyl)ethoxy]pyridazin-3-yl}-6-morpholin-4-yl-pyridin-3-yl-carboxamide (1);   {6-amino-5-[(2,6-dichloro-3-fluorophenyl)ethoxy]pyridazin-3-yl}-N-pyrazol-4-ylcarboxamide (2);   {6-amino-5-[(2,6-dichloro-3-fluorophenyl)ethoxy]pyridazin-3-yl}-N-(1-methylpyrazol-4-yl)carboxamide (3);   {6-amino-5-[(2,6-dichloro-3-fluorophenyl)ethoxy]pyridazin-3-yl}-N-isoxazol-4-ylcarboxamide (4);   {6-amino-5-[(2,6-dichloro-3-fluorophenyl)ethoxy]pyridazin-3-yl}-N-[4-(pyrrolidinylcarbonyl)phenyl]carboxamide (5);   {6-amino-5-[(2,6-dichloro-3-fluorophenyl)ethoxy]pyridazin-3-yl}-N-[4-(N-methylcarbamoyl)phenyl]carboxamide (6);   {6-amino-5-[(2,6-dichloro-3-fluorophenyl)ethoxy]pyridazin-3-yl}-N-(6-methoxy(3-pyridyl))carboxamide (7);   {6-amino-5-[(2,6-dichloro-3-fluorophenyl)ethoxy]pyridazin-3-yl}-N-[6-(N-methylcarbamoyl)(3-pyridyl)]carboxamide (8);   {6-amino-5-[(2,6-dichloro-3-fluorophenyl)ethoxy]pyridazin-3-yl}-N-[1-(2-hydroxyethyl)pyrazol-4-yl]carboxamide (9);   N-(1-(2H-3,4,5,6-tetrahydropyran-4-yl)pyrazol-4-yl){6-amino-5-[(2,6-dichloro-3-fluorophenyl)ethoxy]pyridazin-3-yl}carboxamide (10);   6-amino-5-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)-pyridazin-3-yl-N-(pyridin-4-yl)-carboxamide (11);   6-amino-5-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)-pyridazin-3-yl-N-(pyridin-3-yl)-carboxamide (12);   6-amino-5-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)-pyridazin-3-yl-N-(pyrimidin-5-yl)-carboxamide (13);   6-Amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridazine-3-carboxylic acid (tetrahydro-pyran-4-yl)-amide (14);   {6-amino-5-[(2,6-dichloro-3-fluorophenyl) ethoxy]pyridazin-3-yl}-N-(4-methoxyphenyl)carboxamide (15);   {6-amino-5-[(2,6-dichloro-3-fluorophenyl) ethoxy]pyridazin-3-yl}-N-(4-morpholin-4-ylphenyl)carboxamide (16);   {6-amino-5-[(2,6-dichloro-3-fluorophenyl) ethoxy]pyridazin-3-yl}-N-benzamide (17);   {6-amino-5-[(2,6-dichloro-3-fluorophenyl) ethoxy]pyridazin-3-yl}-N-[4-(2-morpholin-4-ylethoxy)phenyl]carboxamide (18);   6-amino-5-[(2,6-dichloro-3-fluorophenyl) ethoxy]pyridazin-3-yl}-N-(1-methyl-6-oxo-1,6-dihydro-pyridin-3-yl))carboxamide (19);   {6-amino-5-[(2,6-dichloro-3-fluorophenyl) ethoxy]pyridazin-3-yl}-N-(1-methyl-6-oxo(3-piperidyl))carboxamide (20);   6-amino-5-[(2,6-dichloro-3-fluorophenyl) ethoxy]pyridazin-3-yl}-N-(6-oxo-1,6-dihydropyridin-3-yl))carboxamide (21);   6-amino-5-[(2,6-dichloro-3-fluorophenyl) ethoxy]pyridazin-3-yl}-N-(6,7-dihydro-4H-pyrano[4,3-d]1,3-thiazol-2-yl)carboxamide (22);   {6-amino-5-[(2,6-dichloro-3-fluorophenyl) ethoxy]pyridazin-3-yl}-N-(4,5,6,7-tetrahydro-1,3-thiazolo[5,4-c]pyridin-2-yl)carboxamide (23);   {6-amino-5-[(2,6-dichloro-3-fluorophenyl) ethoxy]pyridazin-3-yl}-N-(1-(4-piperidyl)pyrazol-4-yl)carboxamide (24);   {6-amino-5-[(2,6-dichloro-3-fluorophenyl) ethoxy]pyridazin-3-yl}-N-{4-[(4-methylpiperazinyl)carbonyl]phenyl}carboxamide (25); and   {6-amino-5-[(2,6-dichloro-3-fluorophenyl)ethoxy]pyridazin-3-yl}-N-[4-(piperazinylcarbonyl)phenyl]carboxamide (26);   {6-amino-5-[(2,6-dichloro-3-fluorophenyl)ethoxy]pyridazin-3-yl}-N-[1-(2-methoxyethyl)-6-oxo-1,6-dihydro-pyridin-3-yl)]carboxamide (27);   {6-amino-5-[(2,6-dichloro-3-fluorophenyl)ethoxy]pyridazin-3-yl}-N-(1-ethyl-6-oxo-1,6-dihydro-pyridin-3-yl))carboxamide (28); and   {6-amino-5-[(2,6-dichloro-3-fluorophenyl)ethoxy]pyridazin-3-yl}-N-(2-methoxy(4-pyridyl))carboxamide (29).   
     
     
         11 . A method of treating a disease in a subject comprising administering to the subject a compound of  claim 1 . 
     
     
         12 . A method of treating a disease in a subject comprising administering to the subject a composition comprising a compound of  claim 1 . 
     
     
         13 . The method of  claim 11 , wherein the disease is mediated by the c-met, ron, or ALK or fusion proteins. 
     
     
         14 . The method of  claim 13 , wherein the fusion proteins are selected from EML4-ALK and NPM-ALK kinases. 
     
     
         15 . The method of  claim 11 , wherein the disease is cancer or a proliferation disease. 
     
     
         16 . The method of  claim 11 , wherein the disease is lung, colon, breast, prostate, liver, pancreas, brain, kidney, ovaries, stomach, skin, and bone cancers, gastric, breast, pancreatic cancer, glioma, lymphoma, neuroblastoma, and hepatocellular carcinoma, papillary renal carcinoma, or head and neck squamous cell carcinoma. 
     
     
         17 . The method of  claim 11 , wherein the disease is skin cancer. 
     
     
         18 . The method of  claim 12 , wherein the disease is skin cancer.