Heterocyclic compound as protein kinase inhibitor

Abstract

Provided are novel heterocyclic compounds useful as anti-cancer drugs by suppressing protein kinase activities of growth factor receptors such as c-Met, pharmaceutical compositions containing the same, and methods for using the compound.

1 . A compound represented by Chemical Formula 1, or a pharmaceutically acceptable salt or a stereoisomer thereof: 
       
         
           
           
               
               
           
         
         wherein 
         R 1  is alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, arylalkyl, substituted arylalkyl, aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, heteroaryl, substituted heteroaryl, heterocyclyl, substituted heterocyclyl, heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl or substituted heterocycloalkyl; 
         R 2  is C 1 -C 6  alkyl or substituted C 1 -C 6  alkyl; 
         R 3  is alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, arylalkyl, substituted arylalkyl, aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, heteroaryl, substituted heteroaryl, heterocyclyl, substituted heterocyclyl, heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl or substituted heterocycloalkyl; 
         X is hydrogen or halogen; 
         Y is CH or N; 
         Z is CH or N; and 
         Q is selected from structures below: 
       
       
         
           
           
               
               
           
         
         wherein the structures above, 
         R 4  is hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, arylalkyl, substituted arylalkyl, halogen, aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkylcarbonyl, substituted alkylcarbonyl, hydroxyalkyl, substituted hydroxyalkyl, saturated or unsaturated heterocyclyl, substituted saturated or unsaturated heterocyclyl, saturated or unsaturated heterocyclyl-alkyl, or substituted saturated or unsaturated heterocyclyl-alkyl; and 
         R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19  and R 20  are independently is hydrogen, C 1 -C 6  alkyl, C 1 -C 6  alkoxy, —NH(C 1 -C 6  alkyl) or —NRR′ where R and R′ are independently C 1 -C 6  alkyl, 
         or a pharmaceutically acceptable salt or a stereoisomer thereof. 
       
     
     
         2 . The compound according to  claim 1 , wherein R 1  is C 1 -C 6  alkyl, substituted C 1 -C 6  alkyl, O 2 —C 6  alkenyl, C 2 -C 6  alkynyl, C 3 -C 7  cycloalkyl, substituted C 3 -C 7  cycloalkyl, C 3 -C 7  heterocycloalkyl, C 6 -C 10  aryl, substituted C 6 -C 10  aryl, C 5 -C 11  monocyclic or bicyclic heteroaryl, or substituted C 5 -C 11  monocyclic or bicyclic heteroaryl, or a pharmaceutically acceptable salt or a stereoisomer thereof. 
     
     
         3 . The compound according to  claim 2 , wherein R 1  is phenyl, substituted phenyl, naphthyl, substituted naphthyl, pyridyl, azepanyl, pyrazolyl, thiazolyl, indolyl, indazolyl, indenyl, cyclopropyl, isopropyl, phenylethyl, aminoalkyl, benzyl, amidoalkyl, morpholinyl or furanylmethyl, or a pharmaceutically acceptable salt or a stereoisomer thereof. 
     
     
         4 . The compound according to  claim 3 , wherein R 1  is phenyl, substituted phenyl, naphthyl or substituted naphthyl, or a pharmaceutically acceptable salt or a stereoisomer thereof. 
     
     
         5 . The compound according to  claim 1 , wherein R 3  is C 1 -C 6  alkyl, substituted C 1 -C 6  alkyl, C 6 -C 10  aryl or substituted C 6 -C 10  aryl, or a pharmaceutically acceptable salt or a stereoisomer thereof. 
     
     
         6 . The compound according to  claim 1 , wherein X is halogen selected from the group consisting of F, Cl, Br and I, or a pharmaceutically acceptable salt or a stereoisomer thereof. 
     
     
         7 . The compound according to  claim 1 , wherein Q is 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt or a stereoisomer thereof. 
     
     
         8 . The compound according to  claim 7 , wherein R 4  is hydrogen, halogen selected from the group consisting of F, Cl, Br and I, C 1 -C 6  alkyl, substituted C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, C 3 -C 7  cycloalkyl, substituted C 3 -C 7  cycloalkyl, C 6 -C 10  aryl, substituted C 6 -C 10  aryl, C 1 -C 6  alkylcarbonyl, substituted C 1 -C 6  alkylcarbonyl, C 1 -C 6  hydroxyalkyl, substituted C 1 -C 6  hydroxyalkyl, 3- to 10-membered saturated or unsaturated heterocyclyl having one or more heteroatom(s) selected from the group consisting of N, S and O, or substituted 3- to 10-membered saturated or unsaturated heterocyclyl, or a pharmaceutically acceptable salt or a stereoisomer thereof. 
     
     
         9 . The compound according to  claim 8 , wherein R 4  is hydrogen, halogen, phenyl, substituted phenyl, naphthyl, substituted naphthyl, pyridyl, substituted pyridyl, pyrazinyl, pyrimidinyl, azepanyl, pyrazolyl, thiazolyl, thiophenyl, isoxazolyl, substituted isoxazolyl, ethyl, acetyl, 1-hydroxyethyl, hydroxypropyl, cyclopropyl, isopropyl, aminoalkyl, benzyl, amidoalkyl, morpholinyl, furanylmethyl or piperidinyl, or a pharmaceutically acceptable salt or a stereoisomer thereof. 
     
     
         10 . The compound according to  claim 9 , wherein R 4  is hydrogen, halogen, phenyl, substituted phenyl, naphthyl, substituted naphthyl, pyridyl, substituted pyridyl, pyrazinyl, pyrimidinyl, thiazolyl, thiophenyl, isoxazolyl, ethyl, acetyl, 1-hydroxyethyl, hydroxypropyl, substituted isoxazolyl or piperidinyl, or a pharmaceutically acceptable salt or a stereoisomer thereof. 
     
     
         11 . The compound according to  claim 10 , wherein R 4  is halogen, phenyl, or phenyl substituted with halogen or alkoxy, or a pharmaceutically acceptable salt or a stereoisomer thereof. 
     
     
         12 . The compound according to  claim 7 , wherein Q is 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt or a stereoisomer thereof. 
     
     
         13 . The compound according to  claim 12 , wherein R 4  is hydrogen, halogen, phenyl, substituted phenyl, naphthyl, substituted naphthyl, pyridyl, substituted pyridyl, pyrazinyl, pyrimidinyl, thiazolyl, thiophenyl, isoxazolyl, substituted isoxazolyl, ethyl, acetyl, 1-hydroxyethyl, hydroxypropyl, 5- or 6-membered saturated or unsaturated heterocyclyl having one or more heteroatom(s) selected from a group consisting of N, S and O, or substituted 5- or 6-membered saturated or unsaturated heterocyclyl, or a pharmaceutically acceptable salt or a stereoisomer thereof. 
     
     
         14 . The compound according to  claim 1 , which is selected from the group consisting of:
 N-(4-(5-bromopyrrolo[1,2-b]pyridazin-4-yloxy)-3-fluorophenyl)-1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide;   N-(3-fluoro-4-(5-phenylpyrrolo[1,2-b]pyridazin-4-yloxo)phenyl)-1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide;   N-(3-fluoro-4-(5-(4-fluorophenyl)pyrrolo[1,2-b]pyridazin-4-yloxy)phenyl)-1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide;   N-(3-fluoro-4-(5-(4-methoxyphenyl)pyrrolo[1,2-b]pyridazin-4-yloxy)phenyl)-1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide;   N-(3-fluoro-4-(5-(3-fluorophenyl)pyrrolo[1,2-b]pyridazin-4-yloxo)phenyl)-1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide;   N-(3-fluoro-4-(5-(3-methoxyphenyl)pyrrolo[1,2-b]pyridazin-4-yloxy)phenyl)-1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide;   N-(4-(5-bromopyrrolo[1,2-b]pyridazin-4-yloxy)-3-fluorophenyl)-2-(4-fluorophenyl)-1,5-dimethyl-3-oxo-2,3-dihydro-1H-pyrazole-4-carboxamide;   N-(3-fluoro-4-(5-phenylpyrrolo[1,2-b]pyridazin-4-yloxy)phenyl)-2-(4-fluorophenyl)-1,5-dimethyl-3-oxo-2,3-dihydro-1H-pyrazole-4-carboxamide;   1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxylic acid   [3-fluoro-4-(pyrrolo[1,2-b]pyridazin-4-yloxy)-phenyl]-amide;   N-(3-fluoro-4-(pyrrolo[1,2-f][1,2,4]triazin-4-yloxy)phenyl)-2-(4-fluorophenyl)-1,5-dimethyl-3-oxo-2,3-dihydro-1H-pyrazole-4-carboxamide;   N-(3-fluoro-4-(pyrrolo[1,2-f][1,2,4]triazin-4-yloxy)phenyl)-1,5-dimethyl-3-oxy-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide   N-(3-fluoro-4-(6-phenylpyrrolo[1,2-f][1,2,4]triazin-4-yloxy)phenyl)-2-(4-fluorophenyl)-1,5-dimethyl-3-oxo-2,3-dihydro-1H-pyrazole-4-carboxamide;   N-(4-(6-chloropyrrolo[1,2-f][1,2,4]triazin-4-yloxy)-3-fluoro phenyl)-2-(4-fluorophenyl)-1,5-dimethyl-3-oxo-2,3-dihydro-1H-pyrazole-4-carboxamide;   N-(4-(6-chloropyrrolo[1,2-f][1,2,4]triazin-4-yloxy)-3-fluoro phenyl)-1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide;   N-(3-fluoro-4-(6-phenylpyrrolo[1,2-f][1,2,4]triazin-4-yloxy)phenyl)-1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide;   N-(3-fluoro-4-(5-phenylpyrrolo[1,2-b]pyridazin-4-yloxy)phenyl)-1,2-dimethyl-3-oxo-5-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide;   N-(3-fluoro-4-(5-(pyridin-2-yl)pyrrolo[1,2-b]pyridazin-4-yloxy)phenyl)-2-(4-fluorophenyl)-1,5-dimethyl-3-oxo-2,3-dihydro-1-pyrazole-4-carboxamide;   N-(3-fluoro-4-(5-(thiophen-2-yl)pyrrolo[1,2-b]pyridazin-4-yloxy)phenyl)-2-(4-fluorophenyl)-1,5-dimethyl-3-oxo-2,3-dihydro-1H-pyrazole-4-carboxamide;   N-(3-fluoro-4-(5-(pyrimidin-5-yl)pyrrolo[1,2-b]pyridazin-4-yloxy)phenyl)-2-(4-fluorophenyl)-1,5-dimethyl-3-oxo-2,3-dihydro-1H-pyrazole-4-carboxamide;   N-(3-fluoro-4-(5-(thiazol-2-yl)pyrrolo[1,2-b]pyridazin-4-yloxy)phenyl)-2-(4-fluorophenyl-1,5-dimethyl-3-oxo-2,3-dihydro-1H-pyrazole-4-carboxamide;   N-(3-fluoro-4-(5-(pyrazin-2-yl)pyrrolo[1,2-b]pyridazin-4-yloxy)phenyl)-2-(4-fluorophenyl)-1,5-dimethyl-3-oxy-2,3-dihydro-1H-pyrazole-4-carboxamide;   N-(3-fluoro-4-(5-(piperidin-4-yl)pyrrolo[1,2-b]pyridazin-4-yloxy)phenyl)-2-(4-fluorophenyl)-1,5-dimethyl-3-oxy-2,3-dihydro-1H-pyrazole-4-carboxamide;   N-(3-fluoro-4-(5-(pyridin-3-yl)pyrrolo[1,2-b]pyridazin-4-yloxy)phenyl)-2-(4-fluorophenyl)-1,5-dimethyl-3-oxy-2,3-dihydro-1H-pyrazole-4-carboxamide;   N-(3-fluoro-4-(5-(pyridin-4-yl)pyrrolo[1,2-b]pyridazin-4-yloxy)phenyl)-2-(4-fluorophenyl)-1,5-dimethyl-3-oxy-2,3-dihydro-1H-pyrazole-4-carboxamide;   N-(3-fluoro-4-(5-(thiophen-3-yl)pyrrolo[1,2-b]pyridazin-4-yloxy)phenyl)-2-(4-fluorophenyl)-1,5-dimethyl-3-oxy-2,3-dihydro-1H-pyrazole-4-carboxamide;   N-(3-fluoro-4-(5-(3,5-dimethylisoxazol-4-yl)pyrrolo[1,2-b]pyridazin-4-yloxy)phenyl)-2-(4-fluorophenyl)-1,5-dimethyl-3-oxy-2,3-dihydro-1H-pyrazole-4-carboxamide;   N-(3-fluoro-4-(5-(6-methylpyridin-3-yl)pyrrolo[1,2-b]pyridazin-4-yloxy)phenyl)-2-(4-fluorophenyl)-1,5-dimethyl-3-oxy-2,3-dihydro-1H-pyrazole-4-carboxamide;   N-(3-fluoro-4-(5-(2-methylpyridin-4-yl)pyrrolo[1,2-b]pyridazin-4-yloxy)phenyl)-2-(4-fluorophenyl)-1,5-dimethyl-3-oxy-2,3-dihydro-1H-pyrazole-4-carboxamide;   N-(3-fluoro-4-(5-(1-hydroxyethyl)pyrrolo[1,2-b]pyridazin-4-yloxy)phenyl)-2-(4-fluorophenyl)-1,5-dimethyl-3-oxo-2,3-dihydro-1H-pyrazole-4-carboxamide;   N-(4-(5-acetylpyrrolo[1,2-b]pyridazin-4-yloxy)-3-fluorophenyl)-2-(4-fluorophenyl)-1,5-dimethyl-3-oxo-2,3-dihydro-1H-pyrazole-4-carboxamide;   N-(4-(5-acetylpyrrolo[1,2-b]pyridazin-4-yloxy)-3-fluorophenyl)-1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide;   N-(3-fluoro-4-(5-(1-hydroxyethyl)pyrrolo[1,2-b]pyridazin-4-yloxy)phenyl)-1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide;   N-(3-fluoro-4-(5-thiazol-2-yl)pyrrolo[1,2-b]pyridazin-4-yloxy)phenyl)-1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide;   N-(3-fluoro-4-(5-(pyridin-3-yl)pyrrolo[1,2-b]pyridazin-4-yloxy)phenyl)-1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide;   N-(4-(5-ethylpyrrolo[1,2-b]pyridazin-4-yloxy)-3-fluorophenyl)-2-(4-fluorophenyl)-1,5-dimethyl-3-oxo-2,3-dihydro-1H-pyrazole-4-carboxamide;   N-(3-fluoro-4-(pyrrolo[1,2-b]pyridazin-4-yloxy)phenyl)-2-(4-fluorophenyl)-1,5-dimethyl-3-oxo-2,3-dihydro-1H-pyrazole-4-carboxamide;   N-(3-fluoro-4-(5-(pyridin-4-yl)pyrrolo[1,2-b]pyridazin-4-yloxy)phenyl)-1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide;   N-(4-(5-chloropyrrolo[1,2-b]pyridazin-4-yloxy)-3-fluorophenyl)-2-(4-fluorophenyl)-1,5-dimethyl-3-oxo-2,3-dihydro-1H-pyrazole-4-carboxamide;   N-(4-(5-chloropyrrolo[1,2-b]pyridazin-4-yloxy)-3-fluorophenyl)-1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide;   N-(3-fluoro-4-(5-(1-hydroxypropyl)pyrrolo[1,2-b]pyridazin-4-yloxy)phenyl)-1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide; or   a pharmaceutically acceptable salt or a stereoisomer thereof.   
     
     
         15 . A pharmaceutical composition comprising a therapeutically effective amount of one or more compound(s) according to  claim 1  in admixture with one or more pharmaceutically acceptable carrier(s). 
     
     
         16 . The pharmaceutical composition according to  claim 15 , which is for treating cancer, asthma, allergy, atopic skin disease, psoriasis or rheumatoid arthritis. 
     
     
         17 . A method for treating HGF-mediated disorders in a subject in need thereof, comprising administering a therapeutically effective amount of the compound according to  claim 1  to the subject.