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; 
         Z1 and Z2 are independently CR2 or N; 
         Z3 is CH or N; 
         and wherein one or two of Z1, Z2 and Z3 is 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 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. 
       
     
     
         3 . The compound of  claim 2 , wherein R3 is —C(O)R4. 
     
     
         4 . The compound of  claim 2 , wherein R3 is —C(O)—C6-C10-aryl, —C(O)—C4-C6-heterocyclyl, or —C(O)—C5-C6-heteroaryl. 
     
     
         5 . The compound of  claim 1 , wherein the compound is a compound of Formula Ij, 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof. 
       
     
     
         6 . The compound of  claim 5 , wherein R3 is —C(O)R4. 
     
     
         7 . The compound of  claim 5 , 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 the compound of formula I is N-(4-(2-acetamidopyrimidin-4-yloxy)-2,5-difluorophenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide. 
     
     
         9 . A method of treating mammalian disease wherein the disease etiology or progression is at least partially mediated by a kinase activity, wherein the kinase is a wildtype form, a mutant oncogenic form, an aberrant fusion protein form or a polymorph, the method comprising administering to a mammal in need thereof an effective amount of a compound of  claims 1 . 
     
     
         10 . The method of  claim 9 , wherein the disease etiology or progression is at least partially mediated by the kinase activity of c-MET, mutant oncogenic forms, aberrant fusion proteins, or polymorphs thereof. 
     
     
         11 . A pharmaceutical composition, comprising a compound of  claim 1  and a pharmaceutically acceptable carrier. 
     
     
         12 . The composition of  claim 11 , further comprising an additive selected from adjuvants, excipients, diluents, or stabilizers. 
     
     
         13 . A method of treating cancer, gastrointestinal stromal tumors, hyperproliferative diseases, metabolic diseases, neurodegenerative diseases, or diseases characterized by angiogenesis, such as solid tumors, melanomas, glioblastomas, ovarian cancer, pancreatic cancer, prostate cancer, lung cancers, breast cancers, renal cancers, hepatic cancers, cervical carcinomas, metastasis of primary tumor sites, myeloproliferative diseases, chronic myelogenous leukemia, leukemias, papillary thyroid carcinoma, non-small cell lung cancer, mesothelioma, hypereosinophilic syndrome, colonic cancers, ocular diseases characterized by hyperproliferation leading to blindness including retinopathies, diabetic retinopathy, age-related macular degeneration, hypereosinophilic syndrome, rheumatoid arthritis, asthma, chronic obstructive pulmonary, mastocytosis, or mast cell leukemia, the method comprising administering to a patient in need thereof an effective amount of a compound of  claim 1 . 
     
     
         14 . The method of  claim 13 , wherein the compound is administered orally, parenterally, by inhalation, or subcutaneously. 
     
     
         15 . A pharmaceutical composition, comprising the compound of  claim 2  and a pharmaceutically acceptable carrier. 
     
     
         16 . The composition of  claim 15 , further comprising an additive selected from adjuvants, excipients, diluents, or stabilizers. 
     
     
         17 . A pharmaceutical composition, comprising the compound of  claim 5  and a pharmaceutically acceptable carrier. 
     
     
         18 . The composition of  claim 17 , further comprising an additive selected from adjuvants, excipients, diluents, or stabilizers. 
     
     
         19 . A pharmaceutical composition comprising the compound N-(4-(2-acetamidopyrimidin-4-yloxy)-2,5-difluorophenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide, or a pharmaceutically acceptable salt, thereof and a pharmaceutically acceptable carrier. 
     
     
         20 . The composition of  claim 19 , further comprising an additive selected from adjuvants, excipients, diluents, or stabilizers.