Tyrosine kinase inhibitors

Abstract

and pharmaceutically acceptable salts, prodrugs and N-oxides thereof (and solvates and hydrates thereof), wherein R1, X, Y1, Y2, Y3 and Z are as described herein. In certain embodiments, a compound disclosed herein inhibits a cellular TAM receptor, and can be used to treat disease mediated by or involving the TAM receptor family.

We claim: 
     
         1 . A method of inhibiting a cellular TAM receptor, the method comprising contacting a cell comprising a TAM receptor with a compound according to structural formula (I): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt, prodrug, or N-oxide thereof, or a solvate or hydrate thereof, 
         wherein
 X is selected from 
 
       
       
         
           
           
               
               
           
         
       
       wherein n is 0, 1, 2, 3 or 4;
   each —R X1  is independently halogen, cyano, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, —C 1 -C 6 alkoxy, —C 1 -C 6 haloalkoxy, oxo, —OR, —SR, —NR 2 , —C(O)R, —C(O)OR, —C(O)NR 2 , —S(O) 2 NR 2 , —S(O) 2 R, —OC(O)R, —N(R)C(O)R, —OC(O)OR, —OC(O)NR 2 , —N(R)C(O)OR, —N(R)C(O)NR 2 , —N(R)S(O) 2 R, —OP(O)(OR) 2 , —CH 2 —OP(O)(OR), Cak(C 0 -C 6 alkyl), Ar(C 0 -C 6 alkyl) or Hca(C 0 -C 6 alkyl), wherein Cak, Ar and Hca are optionally substituted with one or two —R X2  groups,
 wherein each —R X2  is independently halogen, cyano, nitro, oxo, —OR, —SR, —NR 2 , —C(O)OR, —C(O)NR 2 , —C(O)R, —S(O)R, —S(O) 2 R, —S(O)OR, —S(O) 2 OR, —S(O)NR 2 , —S(O) 2 NR 2 , —OC(O)R, —OC(O)OR, —OC(O)NR 2 , —N(R)C(O)R, —N(R)C(O)OR, —N(R)C(O)NR 2 , —N(R)S(O)R, —N(R)S(O) 2 R, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl or Ar; 
   Y 1  is CH or CF;   Y 2  is N or CH;   Y 3  is N or CH;   Z is C 1 -C 6 alkyl, Ar(C 0 -C 6 alkyl) or Hca(C 0 -C 6 alkyl), each optionally substituted by 1, 2 or 3 —R Z1  groups;
 wherein each —R Z1  is independently halogen, cyano, C 1 -C 6 alkyl, Cak, C 1 -C 6 haloalkyl, —C 1 -C 6 alkoxy, oxo, —OR, —SR, —NR 2 , —C(O)R, —C(O)OR, —C(O)NR 2 , —S(O) 2 NR 2 , —S(O) 2 R, —OC(O)R, —N(R)C(O)R, —OC(O)OR, —OC(O)NR 2 , —N(R)C(O)OR, —N(R)C(O)NR 2 , —N(R)S(O) 2 R, —OP(O)(OR) 2  or —CH 2 —OP(O)(OR); 
   each R is independently hydrogen or C 1 -C 6 alkyl; and   R 1  is hydrogen or C 1 -C 6 alkyl;   wherein
 Hca is a 3-15 membered ring or ring system comprising at least one ring and 1, 2, 3, or 4 O, S, or N atoms, provided no O or S is adjacent to another O or S; 
 Het is a 5-15 membered aromatic ring or ring system comprising at least one ring and 1, 2, 3, or 4 O, S, or N atoms, provided no O or S is adjacent to another O or S; 
 Cak is a 3-8 membered non-aromatic carbocyclic ring or ring system, which may be saturated or partially unsaturated; and 
 Ar is a 6-16 membered aromatic ring or ring system having at least one carbocyclic aromatic ring optionally fused one or more aromatic or non-aromatic rings. 
   
 
     
     
         2 . The method of  claim 1 , wherein
 n is 1, 2, 3 or 4, wherein
 each —R X1  is independently halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, oxo, —OR, Ar(C 0 -C 6 alkyl) or Hca(C 0 -C 6 alkyl), wherein Ar and Hca are optionally substituted with one or two —R X2  groups, or when —R X1  is Hca(C 0 -C 6 alkyl), two —R X2  groups taken together, when attached to the same carbon atom, form an Hca, 
 or two —R X1  groups taken together, when attached to adjacent atoms, form a Ar or Hca, wherein the Hca comprises a 3-8 membered ring optionally substituted with one or two —R X2  groups, 
 wherein each —R X2  is independently halogen, —OR, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl or Ar; and 
   Z is unsubstituted C 1 -C 6 alkyl, Ar(C 0 -C 6 alkyl) or Hca(C 0 -C 6 alkyl).   
     
     
         3 . The method of  claim 1 , wherein X is 
       
         
           
           
               
               
           
         
       
       wherein n is 0, 1, 2, 3 or 4. 
     
     
         4 . The method of  claim 1 , wherein X is 
       
         
           
           
               
               
           
         
       
     
     
         5 . The method of  claim 1 , wherein X is 
       
         
           
           
               
               
           
         
       
     
     
         6 . The method of  claim 1 , wherein X is 
       
         
           
           
               
               
           
         
       
     
     
         7 . The method of  claim 1 , wherein X is 
       
         
           
           
               
               
           
         
       
     
     
         8 . The method of  claim 1 , wherein the compound has the structure of formula (IIa): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt, prodrug or N-oxide thereof, or solvate or hydrate thereof, 
         X 1  is —N═, —C(H)═; 
         X 2  is ═C(H)—, ═N—, —N(H)—; and 
         R Xa  and R Xb  are each hydrogen, or R Xa  and R Xb  combine with the atoms to which they are attached to form an Ar or Hca. 
       
     
     
         9 . The method of  claim 1 , wherein the compound has the structure of formula (IIc): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt, prodrug or N-oxide thereof, or solvate or hydrate thereof, 
         X 1  is —N═, —C(H)═; and 
         R Xa  and R Xb  are each hydrogen, or R Xa  and R Xb  combine with the atoms to which they are attached to form an Ar or Hca. 
       
     
     
         10 . The method of  claim 1 , wherein the compound has the structure of formula (Ina): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt, prodrug or N-oxide thereof, or solvate or hydrate thereof, 
         X 3  is —N═ or —S—; 
         X 4  is ═N—, ═C(H)—; and 
         X 5  is —S—, ═C(H)—. 
       
     
     
         11 . The method of  claim 10 , wherein the compound has the structure of formula (Me): 
       
         
           
           
               
               
           
         
       
     
     
         12 . The method of  claim 1 , wherein
 each —R X1  is independently halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, oxo, —OR, Ar(C 0 -C 6 alkyl) or Hca(C 0 -C 6 alkyl), wherein Ar and Hca are optionally substituted with one or two —R X2  groups.   
     
     
         13 . The method of  claim 1 , wherein —R X1  is Hca(C 0 -C 6 alkyl). 
     
     
         14 . The method of  claim 1 , wherein each —R X2  is independently halogen, —OR, C 1 -C 6 alkyl or C 1 -C 6 haloalkyl. 
     
     
         15 . The method of  claim 1 , wherein each —R X2  is independently halogen or —OR. 
     
     
         16 . The method of  claim 1 , wherein R 1  is C 1 -C 6 alkyl. 
     
     
         17 . A method of inhibiting a cellular TAM receptor, the method comprising contacting a cell comprising a TAM receptor with a compound
 N-(5-((6-Methoxy-7-(3-morpholinopropoxy)quinolin-4-yl)oxy)pyridin-2-yl)-4-(4-methylpiperazin-1-yl)picolinamide;   N-(5-(((6-Methoxy-7-(3-morpholinopropoxy)quinolin-4-yl)oxy)pyridin-2-yl)-8-phenyl-3,4-dihydro-2H-1,4-ethano-1,5-naphthyridine-6-carboxamide;   N-(5-((6-Methoxy-7-(3-morpholinopropoxy)quinolin-4-yl)oxy)pyridin-2-yl)-4-phenylpicolinamide;   N-(5-((6-Methoxy-7-(3-morpholinopropoxy)quinolin-4-yl)oxy)pyridin-2-yl)-4-phenylpyrimidine-2-carboxamide;   N-(5-((6-Methoxy-7-(3-morpholinopropoxy)quinolin-4-yl)oxy)pyridin-2-yl)-4-phenylquinazoline-2-carboxamide;   N-(5-(((6-methoxy-7-(3-morpholinopropoxy)quinolin-4-yl)oxy)pyridin-2-yl)-4-phenyl-7,8-dihydro-6H-5,8-ethanopyrido[3,2-d]pyrimidine-2-carboxamide, hydrochloric acid;   N-(5-(((6-Methoxy-7-(3-morpholinopropoxy)quinolin-4-yl)oxy)pyridin-2-yl)-8-phenyl-3,4-dihydro-2H-1,4-ethano-1,5-naphthyridine-6-carboxamide, hydrochloric acid;   4-(4-Hydroxypiperidin-1-yl)-N-(5-(((6-methoxy-7-(3-morpholinopropoxy)quinolin-4-yl)oxy)pyridin-2-yl)picolinamide, trifluoroacetic acid;   N-(5-((6-Methoxy-7-(3-morpholinopropoxy)quinolin-4-yl)oxy)pyridin-2-yl)-4-oxo-3,4-dihydroquinazoline-2-carboxamide, trifluoroacetic acid;   N-(5-((6-Methoxy-7-(3-morpholinopropoxy)quinolin-4-yl)oxy)pyridin-2-yl)-6-phenylpicolinamide;   4-(4-Hydroxypiperidin-1-yl)-N-(5-(((6-methoxy-7-(3-morpholinopropoxy)quinolin-4-yl)oxy)pyridin-2-yl)picolinamide;   N-(5-((6-Methoxy-7-(3-morpholinopropoxy)quinolin-4-yl)oxy)pyridin-2-yl)-4-oxo-3,4-dihydroquinazoline-2-carboxamide;   N-(5-(((6-methoxy-7-(3-morpholinopropoxy)quinolin-4-yl)oxy)pyridin-2-yl)-4-(piperidin-1-yl)picolinamide;   N-(5-((6-methoxy-7-(3-morpholinopropoxy)quinolin-4-yl)oxy)pyridin-2-yl)-4-morpholinopicolinamide;   4-(4-ethoxypiperidin-1-yl)-N-(5-(((6-methoxy-7-(3-morpholinopropoxy)quinolin-4-yl)oxy)pyridin-2-yl)picolinamide;   N-(5-((6-methoxy-7-(3-morpholinopropoxy)quinolin-4-yl)oxy)pyridin-2-yl)-4-(pyrrolidin-1-yl)picolinamide;   N-(5-((6-methoxy-7-(3-morpholinopropoxy)quinolin-4-yl)oxy)pyridin-2-yl)-4-(4-phenylpiperidin-1-yl)picolinamide;   N-(5-((6-methoxy-7-(3-morpholinopropoxy)quinolin-4-yl)oxy)pyridin-2-yl)-4-(7-oxa-2-azaspiro[3.5]nonan-2-yl)picolinamide;   N-(5-((6-methoxy-7-(3-morpholinopropoxy)quinolin-4-yl)oxy)pyridin-2-yl)-4-(2-oxa-6-azaspiro[3.3]heptan-6-yl)picolinamide;   4-(3,3-difluoroazetidin-1-yl)-N-(5-((6-methoxy-7-(3-morpholinopropoxy)quinolin-4-yl)oxy)pyridin-2-yl)picolinamide;   4-(4,4-difluoropiperidin-1-yl)-N-(5-((6-methoxy-7-(3-morpholinopropoxy)quinolin-4-yl)oxy)pyridin-2-yl)picolinamide;   4-(4,4-dimethylpiperidin-1-yl)-N-(5-((6-methoxy-7-(3-morpholinopropoxy)quinolin-4-yl)oxy)pyridin-2-yl)picolinamide;   N-(5-((6-methoxy-7-(3-morpholinopropoxy)quinolin-4-yl)oxy)pyridin-2-yl)-6-(piperidin-1-yl)picolinamide;   6-(4-hydroxypiperidin-1-yl)-N-(5-((6-methoxy-7-(3-morpholinopropoxy)quinolin-4-yl)oxy)pyridin-2-yl)picolinamide;   N-(5-((6-methoxy-7-(3-morpholinopropoxy)quinolin-4-yl)oxy)pyridin-2-yl)-6-morpholinopicolinamide;   N-(5-((6-methoxy-7-(3-morpholinopropoxy)quinolin-4-yl)oxy)pyridin-2-yl)-6-(pyrrolidin-1-yl)picolinamide;   6-(4,4-dimethylpiperidin-1-yl)-N-(5-((6-methoxy-7-(3-morpholinopropoxy)quinolin-4-yl)oxy)pyridin-2-yl)picolinamide;   6-(4,4-difluoropiperidin-1-yl)-N-(5-((6-methoxy-7-(3-morpholinopropoxy)quinolin-4-yl)oxy)pyridin-2-yl)picolinamide;   6-(4-ethoxypiperidin-1-yl)-N-(5-(((6-methoxy-7-(3-morpholinopropoxy)quinolin-4-yl)oxy)pyridin-2-yl)picolinamide;   6-(3,3-difluoroazetidin-1-yl)-N-(5-((6-methoxy-7-(3-morpholinopropoxy)quinolin-4-yl)oxy)pyridin-2-yl)picolinamide;   4-Fluoro-N-(5-((6-methoxy-7-(3-morpholinopropoxy)quinolin-4-yl)oxy)pyridin-2-yl)picolinamide;   N-(5-((6-Methoxy-7-(3-morpholinopropoxy)quinolin-4-yl)oxy)pyridin-2-yl)-4-methylpicolinamide;   4-Methoxy-N-(5-((6-methoxy-7-(3-morpholinopropoxy)quinolin-4-yl)oxy)pyridin-2-yl)picolinamide;   N-(5-((6-Methoxy-7-(3-morpholinopropoxy)quinolin-4-yl)oxy)pyridin-2-yl)-4-(trifluoromethyl)picolinamide;   N-(5-((6-methoxy-7-(3-morpholinopropoxy)quinolin-4-yl)oxy)pyridin-2-yl)-4-phenyl-7,8-dihydro-6H-5,8-ethanopyrido[3,2-d]pyrimidine-2-carboxamide;   N-(3-fluoro-4-((6-methoxy-7-(3-morpholinopropoxy)quinolin-4-yl)oxy)phenyl)-4-phenyl-7,8-dihydro-6H-5,8-ethanopyrido[3,2-d]pyrimidine-2-carboxamide;   N-(5-((7-(benzyloxy)-6-methoxyquinolin-4-yl)oxy)pyridin-2-yl)-4-phenyl-7,8-dihydro-6H-5,8-ethanopyrido[3,2-d]pyrimidine-2-carboxamide;   N-(5-((6,7-dimethoxyquinolin-4-yl)oxy)pyridin-2-yl)-4-phenyl-7,8-dihydro-6H-5,8-ethanopyrido[3,2-d]pyrimidine-2-carboxamide;   N-(5-((6-methoxy-7-(3-(piperidin-1-yl)propoxy)quinolin-4-yl)oxy)pyridin-2-yl)-4-phenyl-7,8-dihydro-6H-5,8-ethanopyrido[3,2-d]pyrimidine-2-carboxamide;   2-bromo-N-(5-((6-methoxy-7-(3-morpholinopropoxy)quinolin-4-yl)oxy)pyridin-2-yl)thiazole-4-carboxamide;   2-(4-hydroxypiperidin-1-yl)-N-(5-((6-methoxy-7-(3-morpholinopropoxy)quinolin-4-yl)oxy)pyridin-2-yl)thiazole-4-carboxamide;   N-(5-(((6-methoxy-7-(3-morpholinopropoxy)quinolin-4-yl)oxy)pyridin-2-yl)-2-phenylthiazole-4-carboxamide;   2-(4-fluorophenyl)-N-(5-((6-methoxy-7-(3-morpholinopropoxy)quinolin-4-yl)oxy)pyridin-2-yl)thiazole-4-carboxamide;   5-bromo-N-(5-((6-methoxy-7-(3-morpholinopropoxy)quinolin-4-yl)oxy)pyridin-2-yl)thiazole-2-carboxamide;   2-(4-hydroxypiperidin-1-yl)-N-(5-((6-methoxy-7-(3-morpholinopropoxy)quinolin-4-yl)oxy)pyridin-2-yl)thiazole-4-carboxamide, hydrochloric acid;   N-(5-((6-methoxy-7-(3-morpholinopropoxy)quinolin-4-yl)oxy)pyridin-2-yl)-2-(piperidin-1-yl)thiazole-4-carboxamide;   N-(5-((6-methoxy-7-(3-morpholinopropoxy)quinolin-4-yl)oxy)pyridin-2-yl)-5-(piperidin-1-yl)thiazole-2-carboxamide;   N-(5-((6-methoxy-7-(3-morpholinopropoxy)quinolin-4-yl)oxy)pyridin-2-yl)-5-phenylthiazole-2-carboxamide;   N-(5-((6,7-dimethoxyquinazolin-4-yl)oxy)pyridin-2-yl)-4-phenyl-7,8-dihydro-6H-5,8-ethanopyrido[3,2-d]pyrimidine-2-carboxamide;   or a pharmaceutically acceptable salt, prodrug or N-oxide thereof, or solvate or hydrate thereof.   
     
     
         18 . The method of  claim 1 , wherein contacting the cell comprising a TAM receptor comprises administering the compound to a subject. 
     
     
         19 . The method of  claim 18 , wherein the TAM receptor is a Tyro receptor, an Axl receptor, or a Mer receptor. 
     
     
         20 . The method of  claim 18 , wherein the subject has a disease or condition mediated by or involving the TAM receptor family 
     
     
         21 . The method of  claim 20 , wherein the disease or condition comprises a hematological neoplasm. 
     
     
         22 . The method of  claim 21 , wherein the hematological neoplasms is acute myeloid leukemia (AML). 
     
     
         23 . A method for treating a disease or condition mediated by or involving the TAM receptor family in a subject in need thereof, comprising administering an effective TAM receptor inhibiting amount of a compound of  claim 1  in combination with the administration of a therapeutically effective amount of one or more chemotherapeutic agents.