Cyclopropyl dicarboxamides and analogs exhibiting anti-cancer and anti-proliferative activities

Abstract

The disclosed compounds are useful in the treatment of mammalian cancers and especially human cancers. Compounds, pharmaceutical compositions, and methods of Formula I are disclosed: or a pharmaceutically acceptable salt, hydrate, solvate, enantiomer, stereoisomer, or tautomer thereof.

1 . A compound of Formula I, 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, 
         wherein 
         X is halogen; 
         Z and Z2 are CR2; 
         Z3 is CH or N; 
         each R1 is independently and individually halogen, H, C1-C6 alkyl, branched C3-C7 alkyl, C3-C7 cycloalkyl, or —CN; 
         each R2 is individually and independently H, halogen, C1-C6 alkyl, or cyano; 
         R3 is —C(O)R4, —C(O)—C6-C10-aryl, —C(O)—C4-C6-heterocyclyl, or —C(O)—C5-C6-heteroaryl, wherein
 aryl is phenyl, naphthyl, tetrahydronaphthyl, indenyl or indanyl; and 
 with the proviso that when R3 is —C(O)—C4-C6-heterocyclyl, the heterocyclyl does not have a N bonding hand to —C(O); 
 
         R4 is C3-C8 cycloalkyl, C1-C7 alkyl, —(CH 2 ) p —CN, —(CH 2 ) p —OR6, —(CH 2 ) p —NR6(R7), —(CH 2 ) p —SO 2 —C1-C6-alkyl, —(CH 2 ) p —C6-C10-aryl, —(CH 2 ) p —C5-C6-heteroaryl, or —(CH 2 ) p —C4-C6-heterocyclyl, wherein
 each alkyl or alkylene is optionally substituted with one or two C1-C6 alkyl; and 
 aryl is phenyl, naphthyl, tetrahydronaphthyl, indenyl or indanyl; 
 
         each R6 and R7 is individually and independently H, C1-C6 alkyl, or C3-C8 branched alkyl; each cycloalkyl, aryl, heteroaryl and heterocyclyl is independently substituted with —(R25) m ; 
         each R25 is individually and independently C1-C6 alkyl, branched C3-C8 alkyl, halogen, —(CH 2 ) m —CN, —(CH 2 ) m —OR6, —(CH 2 ) m —NR6(R7), —(CH 2 ) m —SO 2 —C1-C6-alkyl, —(CH 2 ) m —C(O)NR6(R7), —(CH 2 ) m —C(O)—C4-C6-heterocyclyl, or —(CH 2 ) m —C4-C6-heterocyclyl, wherein each alkyl or alkylene is optionally substituted with one or two C1-C6 alkyl; 
         each m is individually and independently 0, 1, 2, or 3; and 
         p is 1, 2, or 3. 
       
     
     
         2 . The compound of  claim 1 , wherein Z3 is CH. 
     
     
         3 . The compound of  claim 2 , wherein the compound is a compound of Formula Ic, 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, and 
         wherein n is 0, 1, or 2. 
       
     
     
         4 . The compound of  claim 3 , wherein R3 is —C(O)R4. 
     
     
         5 . The compound of  claim 4 , wherein R4 is C3-C8 cycloalkyl, C1-C7 alkyl, —(CH 2 ) p —CN, —(CH 2 ) p —OR6, —(CH 2 ) p —NR6(R7), —(CH 2 ) p —SO 2 —C1-C6-alkyl, or —(CH 2 ) p —C4-C6-heterocyclyl, and wherein each alkyl or alkylene is optionally substituted with one or two C1-C6 alkyl. 
     
     
         6 . The compound of  claim 4 , wherein R4 is C3-C8 cycloalkyl or C1-C7 alkyl, and wherein each alkyl or alkylene is optionally substituted with one or two C1-C6 alkyl. 
     
     
         7 . The compound of  claim 3 , wherein R3 is —C(O)—C6-C10-aryl, —C(O)—C4-C6-heterocyclyl, or —C(O)—C5-C6-heteroaryl. 
     
     
         8 . The compound of  claim 1 , wherein Z3 is N. 
     
     
         9 . The compound of  claim 8 , wherein the compound is a compound of Formula If, 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, and 
         wherein 
         n is 0, 1, or 2. 
       
     
     
         10 . The compound of  claim 9 , wherein R3 is —C(O)R4. 
     
     
         11 . The compound of  claim 9 , wherein R3 is —C(O)—C6-C10-aryl, —C(O)—C4-C6-heterocyclyl, or —C(O)—C5-C6-heteroaryl. 
     
     
         12 - 19 . (canceled) 
     
     
         20 . A compound of  claim 1  selected from the group consisting of N-(4-(2-acetamidopyridin-4-yloxy)-2,5-difluorophenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide, N-(4-(2-acetamidopyridin-4-yloxy)-5-chloro-2-fluorophenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide, N-(4-(2-acetamidopyridin-4-yloxy)-2,5-difluorophenyl)-N′-phenylcyclopropane-1,1-dicarboxamide, N-(4-(2-(2-(dimethylamino)acetamido)pyridin-4-yloxy)-2,5-difluorophenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide, N-(4-(2-acetamidopyrimidin-4-yloxy)-2,5-difluorophenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide, N-(4-(2-(cyclopropanecarboxamido)pyridin-4-yloxy)-2,5-difluorophenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide, N-(2,5-difluoro-4-(2-propionamidopyridin-4-yloxy)phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide, N-(2,5-difluoro-4-((2-(2-methoxyacetamido)pyridin-4-yl)oxy)phenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide, N-(2,5-difluoro-4-(2-isobutyramidopyridin-4-yloxy)phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide, N-(4-(2-(2-cyanoacetamido)pyridin-4-yloxy)-2,5-difluorophenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide, N-(4-(2-(azetidine-3-carboxamido)pyridin-4-yloxy)-2,5-difluorophenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide, N-(4-(2-(cyclobutanecarboxamido)pyridin-4-yloxy)-2,5-difluorophenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide, (R)-N-(2,5-difluoro-4-((2-(2-methoxypropanamido)pyridin-4-yl)oxy)phenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide, (R)-N-(2,5-difluoro-4-((2-(2-hydroxypropanamido)pyridin-4-yl)oxy)phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide, N-(2,5-difluoro-4-((2-pivalamidopyridin-4-yl)oxy)phenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide, (S)-N-(2,5-difluoro-4-((2-(2-methoxypropanamido)pyridin-4-yl)oxy)phenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide, (S)-1-((4-(2,5-difluoro-4-(1-((4-fluorophenyl)carbamoyl)cyclopropanecarboxamido)phenoxy)pyridin-2-yl)amino)-1-oxopropan-2-yl acetate, N-(2,5-difluoro-4-((2-(2-fluoro-2-methylpropanamido)pyridin-4-yl)oxy)phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide and pharmaceutically acceptable salts and tautomers thereof. 
     
     
         21 . A compound of  claim 1  selected from N-(4-(2-(cyclopropanecarboxamido)pyridin-4-yloxy)-2,5-difluorophenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide, N-(2,5-difluoro-4-(2-propionamidopyridin-4-yloxy)phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide, N-(2,5-difluoro-4-(2-isobutyramidopyridin-4-yloxy)phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide, N-(4-(2-acetamidopyridin-4-yloxy)-2,5-difluorophenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide. 
     
     
         22 . A method of treating mammalian disease wherein the disease etiology or progression is at least partially mediated by a kinase activity of c-MET, mutant oncogenic forms, aberrant fusion proteins or polymorphs thereof, the method comprising administering to a mammal in need thereof an effective amount of a compound of  claim 1 . 
     
     
         23 . (canceled) 
     
     
         24 . A pharmaceutical composition, comprising a compound of  claim 1  and a pharmaceutically acceptable carrier. 
     
     
         25 . The composition of  claim 24 , further comprising an additive selected from adjuvants, excipients, diluents, or stabilizers. 
     
     
         26 . A method of treating cancer, the method comprising administering to a patient in need thereof an effective amount of a compound of  claim 1 . 
     
     
         27 . The method of  claim 26 , wherein the compound is administered orally, parenterally, by inhalation, or subcutaneously. 
     
     
         28 . The method of  claim 26  wherein the cancer is solid tumors, gastric tumors, esophageal cancer, melanomas, glioblastomas, head and neck cancer, ovarian cancer, pancreatic cancer, prostate cancer, lung cancers, breast cancers, renal cancers, hepatic cancers, cervical carcinomas, metastasis of primary tumor sites, thyroid carcinoma, non-small cell lung cancer, mesothelioma, or colonic cancers. 
     
     
         29 . The compound N-(4-(2-(cyclopropanecarboxamido)pyridin-4-yloxy)-2,5-difluorophenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide, or a pharmaceutically acceptable salt thereof. 
     
     
         30 . A pharmaceutical composition, comprising the compound of  claim 29  and a pharmaceutically acceptable carrier. 
     
     
         31 . The composition of  claim 30 , further comprising an additive selected from adjuvants, excipients, diluents, or stabilizers. 
     
     
         32 . The compound N-(2,5-difluoro-4-(2-propionamidopyridin-4-yloxy)phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide, or a pharmaceutically acceptable salt thereof. 
     
     
         33 . A pharmaceutical composition, comprising the compound of  claim 32  and a pharmaceutically acceptable carrier. 
     
     
         34 . The composition of  claim 33 , further comprising an additive selected from adjuvants, excipients, diluents, or stabilizers. 
     
     
         35 . The compound N-(4-(2-acetamidopyridin-4-yloxy)-2,5-difluorophenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide, or a pharmaceutically acceptable salt, thereof. 
     
     
         36 . A pharmaceutical composition, comprising the compound of  claim 35  and a pharmaceutically acceptable carrier. 
     
     
         37 . The composition of  claim 36 , further comprising an additive selected from adjuvants, excipients, diluents, or stabilizers.