Substituted pyridazine carboximide compounds

Abstract

The new pyridazine derivatives have unexpected drug properties as inhibitors of protein kinases especially against ALK and are useful in treating disorders related to abnormal protein kinase activities such as cancer, neurological and psychiatric diseases.

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 , R 2 , R 3 , R 4 , R 5  each are independently H, alkyl or Z 1 ; 
 R 6  is alkyl, OR 7 , NR 7 R 8 , 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, and Z 1 ; 
 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 mono- or bi-cyclic 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 ) m OH, (CH 2 ) m OR 15 , (CH 2 ) m C(O)NR 15 R 16 , NR 15 S(O) 2 R 17 , where each m is independently 0-6; 
 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; 
 with the proviso that R 6  is not methylpiperazinyl, pyrrolidinyl, methanamino, or piperazinyl. 
 
     
     
         2 . A compound 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 1 , R 2 , R 3 , R 4 , R 5  each are independently H, alkyl or Z 1 ; 
 R 6  is alkyl, OR 7 , NR 7 R 8 , 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, and Z 1 ; 
 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 mono- or bi-cyclic 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 ) m OH, (CH 2 ) m OR 15 , (CH 2 ) m C(O)NR 15 R 16 , NR 15 S(O) 2 R 17 , where each m is independently 0-6; 
 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. 
 
     
     
         3 . (canceled) 
     
     
         4 . A compound of formula III 
       
         
           
           
               
               
           
         
       
       or a salt thereof; or a prodrug, or a salt of a prodrug thereof; or a hydrate, solvate, or polymorph thereof; wherein
 n is 2; 
 R 5 , R 9 , R 10 , R 11  each are independently H, alkyl or Z 1 ; 
 each Z 1  is independently 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 ) m OH, (CH 2 ) m OR 15 , (CH 2 ) m C(O)NR 15 R 16 , NR 15 S(O) 2 R 17 , where each m is independently 0-6; 
 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. 
 
     
     
         5 . The compound of formula I in  claim 1  wherein R 7  and R 8  together with nitrogen form a bi-cyclic heterocyclyl or heteroaryl optionally substituted by 1-3 groups of Z 1 . 
     
     
         6 . (canceled) 
     
     
         7 . The compound of  claim 4 , wherein R 11  is hydrogen. 
     
     
         8 . A compound selected from the following:
 {5-[(1R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy]-6-aminopyridazin-3-yl}-N-{4-[(4-methylpiperazinyl)carbonyl]phenyl}carboxamide; and   {5-[(1S)-1-(2,6-dichloro-3-fluorophenyl)ethoxy]-6-aminopyridazin-3-yl}-N-{4-[(4-methylpiperazinyl)carbonyl]phenyl}carboxamide.   
     
     
         9 . 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}-N-[4-(morpholin-4-ylcarbonyl)phenyl]carboxamide; 
 {6-amino-5-[(2,6-dichloro-3-fluorophenyl)ethoxy]pyridazin-3-yl}-N-(4-{[4-(2-hydroxyethyl)piperazinyl]carbonyl}phenyl)carboxamide; 
 {6-amino-5-[(2,6-dichloro-3-fluorophenyl)ethoxy]pyridazin-3-yl}-N-{4-[(4-pyrrolidinylpiperidyl)carbonyl]phenyl}carboxamide; 
 {6-Amino-5-[(2,6-dichloro-3-fluorophenyl)ethoxy]pyridazin-3-yl}-N-{4-[(4-ethylpiperazinyl)carbonyl]phenyl}carboxamide; 
 {6-Amino-5-[(2,6-dichloro-3-fluorophenyl)ethoxy]pyridazin-3-yl}-N-{4-[(4-cyclopropylpiperazinyl)carbonyl]phenyl}carboxamide; 
 N-(4-{[(2R)-2-(pyrrolidinylmethyl)pyrrolidinyl]carbonyl}phenyl) {6-amino-5-[(2,6-dichloro-3-fluorophenyl)ethoxy]pyridazin-3-yl}carboxamide; and 
 N-{4-[((3S,5R)-3,5-dimethylpiperazinyl)carbonyl]phenyl}{6-amino-5-[(2,6-dichloro-3-fluorophenyl)ethoxy]pyridazin-3-yl}carboxamide. 
 
     
     
         10 . The compound of  claim 2 , wherein the compound is selected from the following:
 {5-[(1R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy]-6-aminopyridazin-3-yl}-N-{3-fluoro-4-[(4-methylpiperazinyl)carbonyl]phenyl}carboxamide;   {5-[(1R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy]-6-aminopyridazin-3-yl}-N-(4-{[4-(4-methylpiperazinyl)piperidyl]carbonyl}phenyl)carboxamide;   {5-[(1R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy]-6-aminopyridazin-3-yl}-N-[4-(4-pyridylcarbonyl)phenyl]carboxamide;   {5-[(1R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy]-6-aminopyridazin-3-yl}-N-{4-[(3,6-diazabicyclo[4.3.0]non-3-yl)carbonyl]phenyl}carboxamide;   {5-[(1R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy]-6-aminopyridazin-3-yl}-N-{4-[(3-oxopiperazinyl)carbonyl]phenyl}carboxamide;   {5-[(1R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy]-6-aminopyridazin-3-yl}-N-{4-[(4-methyl(1,4-diazaperhydroepinyl))carbonyl]phenyl}carboxamide;   {5-[(1R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy]-6-aminopyridazin-3-yl}-N-[4-(1,4-diazaperhydroepinylcarbonyl)phenyl]carboxamide;   {5-[(1R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy]-6-aminopyridazin-3-yl}-N-{4-[(3,3-dimethylpiperazinyl)carbonyl]phenyl}carboxamide;   {5-[(1R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy]-6-aminopyridazin-3-yl}-N-{4-[((3S,5R)-3,5-dimethylpiperazinyl)carbonyl]phenyl}carboxamide;   {5-[(1R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy]-6-aminopyridazin-3-yl}-N-{4-[(4-hydroxypiperidyl)carbonyl]phenyl}carboxamide; and   {5-[(1R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy]-6-aminopyridazin-3-yl}-N-(4-{N-[2-(diethylamino)ethyl]carbamoyl}phenyl)carboxamide.   
     
     
         11 . A method of treating a disease in a subject comprising administering to the subject a compound of  claim 1 . 
     
     
         12 . (canceled) 
     
     
         13 . The method of  claim 11 , wherein the disease is mediated by the c-met, ron, Axl, or ALK or its fusion proteins such as EML4-ALK and NPM-ALK kinases, or the alterations of one or more of the c-met, ron, Axl, and ALK kinases. 
     
     
         14 . The method of  claim 11 , wherein the disease is cancer or a proliferation disease. 
     
     
         15 . 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. 
     
     
         16 . The method of  claim 11 , wherein the disease is non-small cell lung cancer (NSCLC) resistant to the treatment by PF-2341066. 
     
     
         17 . The method of  claim 11 , wherein the disease is non-small cell lung cancer (NSCLC) with brain metastasis. 
     
     
         18 . The method of  claim 11 , wherein the disease is a neurological disease, psychiatric disease, schizophrenia, depression, substance abuse, cocaine addiction, tobacco addiction, alcohol addiction, obesity, diabetes, or cardiovascular diseases. 
     
     
         19 . A composition comprising a compound of  claim 1  and a pharmaceutically acceptable carrier.