Novel Imidazole Amines as Modulators of Kinase Activity

Abstract

The invention provides novel imidazole amine compounds according to Formula (I) and Formula (II) their manufacture and use for the treatment of hyperproliferative diseases, such as cancer.

1 - 13 . (canceled) 
     
     
         14 . A method for treating cancer, comprising administering to a subject a compound of Formula (I): 
       
         
           
           
               
               
           
         
         and pharmaceutically acceptable salts, solvates, solvates of salts, or prodrugs thereof, wherein: 
         R 1  is Hal, LA, OH, O(LA), NH 2  and/or NH(LA), N(LA) 2 , NO 2 , CN, OCN, SCN, COOH, COO(LA), CONH 2 , CONH(LA), CON(LA) 2 , NHCO(LA), NHCONH(LA), NHCONH 2 , NHSO 2 (LA), CHO, CO(LA), SO 2 NH 2 , SO 2 (LA), or a mono- or bicyclic, aliphatic or aromatic homo- or heterocycle having 0, 1, 2, 3 or 4 N, S and/or O atoms and 4, 5 or 6, 7, 8, 9, or 10 skeleton atoms which may be unsubstituted or, independently of one another, mono-, di- or trisubstituted by Hal, LA, OH, O(LA), NH 2  and/or NH(LA), N(LA) 2 , NO 2 , CN, OCN, SCN, COOH, COO(LA), CONH 2 , CONH(LA), CON(LA) 2 , NHCO(LA), NHCONH(LA), NHCONH 2 , NHSO 2 (LA), CHO, CO(LA), SO 2 NH 2 , SO 2 (LA) and/or SO 2 Hal or an unbranched or branched linear or cyclic alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 C atoms, in which one or two CH 2  groups may be replaced by an O atom and/or by an —NH—, NH(LA), —CO—, —NHCO— or —CH═CH— group, and/or in which a CH group may be replaced by —N—; 
         R 2  is H, NH 2 , NH(LA), N(LA) 2  or NHCO(LA); 
         R 3  is N or CH; 
         R 4  is H, an unbranched or branched linear or mono- or bicyclic alkyl group having 1, 2, 3, 4, 5, 6, 7, 8 or 9 C atoms, in which one or two CH 2  groups may be replaced by an —O—, —NH—, group, and/or in which one or two CH groups may be replaced by —N—,
 and/or in which 1, 2 or 3 H atoms may be replaced by Hal or OH, 
 
         R 5  is a monocyclic aromatic or aliphatic homo- or heterocycle having 0, 1 or 2 N, S and/or O atoms and 5 or 6 skeleton atoms which may be unsubstituted or, independently of one another, mono-, di- or trisubstituted by Hal, LA, OH, O(LA), NH 2  and/or NH(LA), N(LA) 2 , NO 2 , CN, OCN, SCN, COOH, COO(LA), CONH 2 , CONH(LA), CON(LA) 2 , NHCO(LA), NHCONH(LA), NHCONH 2 , NHSO 2 (LA), CHO, CO(LA), SO 2 NH 2 , SO 2 (LA); 
         Hal is F, Cl, Br or I, and 
         LA is an unbranched or branched, saturated or partially unsaturated, linear hydrocarbon chain having 1, 2, 3 or 4 C atoms, wherein 1, 2 or 3 H atoms may be replaced by Hal. 
       
     
     
         15 . The method of  claim 14 , wherein said cancer is selected from the group consisting of brain, lung, colon, epidermoid, squamous cell, bladder, gastric, pancreatic, breast, head, neck, renal, kidney, liver, ovarian, prostate, colorectal, uterine, rectal, oesophageal, testicular, gynecological, thyroid cancer, melanoma, hematologic malignancies such as acute myelogenous leukemia, multiple myeloma, chronic myelogneous leukemia, myeloid cell leukemia, glioma and Kaposi's sarcoma. 
     
     
         16 . The method of  claim 14 , wherein the compound is of Formula (II): 
       
         
           
           
               
               
           
         
         and pharmaceutically acceptable salts, solvates, solvates of salts, or prodrugs thereof. 
       
     
     
         17 . The method of  claim 14 , wherein
 R 1  is Hal, LA, O(LA), CN, CONH 2 , or a monocyclic aliphatic or aromatic homo- or heterocycle having 0, 1 or 2 N or O atoms and 5 or 6 skeleton atoms.   
     
     
         18 . The method of  claim 14 , wherein
 R 1  is Hal, LA, O(LA), CN, CONH 2 , or a monocyclic aliphatic or aromatic homo- or heterocycle having 0, 1 or 2 N or O atoms and 5 or 6 skeleton atoms,   R 2  is NH 2 , and   R 3  is N.   
     
     
         19 . The method of  claim 14 , wherein
 R 2  is NH 2 ,   R 3  is N, and   R 4  is unbranched or branched, linear or monocyclic alkyl having 1, 2, 3, 4, 5, 6, 7, 8 or 9 C atoms, in which one or two CH 2  groups may be replaced by an —O—, —NH—, group, and/or in which one or two CH groups may be replaced by —N—.   
     
     
         20 . The method of  claim 14 , wherein
 R 2  is NH 2 ,   R 3  is N, and   R 5  is cyclohexyl, phenyl or pyridyl, which is unsubstituted or mono- or disubstituted by Hal or LA.   
     
     
         21 . The method of  claim 14 , wherein
 R 1  is Hal, LA, O(LA), CN, CONH 2 , or a monocyclic aliphatic or aromatic homo- or heterocycle having 0, 1 or 2 N or O atoms and 5 or 6 skeleton atoms,   R 2  is NH 2 ,   R 3  is N, and   R 5  is cyclohexyl, phenyl or pyridyl, which is unsubstituted or mono- or disubstituted by Hal or LA.   
     
     
         22 . The method of  claim 14 , wherein
 R 1  is Hal, LA, O(LA), CN, CONH 2 , or a monocyclic aliphatic or aromatic homo- or heterocycle having 0, 1 or 2 N or O atoms and 5 or 6 skeleton atoms,   R 2  is NH 2 ,   R 3  is N, and   R 4  is unbranched or branched, linear or monocyclic alkyl having 1, 2, 3, 4, 5, 6, 7, 8 or 9 C atoms, in which one or two CH 2  groups may be replaced by an by —O— or —NH—, and/or in which one or two CH groups may be replaced by —N—.   
     
     
         23 . The method of  claim 14 , wherein
 R 2  is NH 2 ,   R 3  is N,   R 4  is unbranched or branched, linear or monocyclic alkyl having 1, 2, 3, 4, 5, 6, 7, 8 or 9 C atoms, in which one or two CH 2  groups may be replaced by by —O— or —NH—, and/or in which one or two CH groups may be replaced by —N—, and   R 5  is cyclohexyl, phenyl or pyridyl, which is unsubstituted or mono- or disubstituted by Hal or LA.   
     
     
         24 . The method of  claim 14 , wherein
 R 1  is Hal, LA, O(LA), CN, CONH 2 , or a monocyclic aliphatic or aromatic homo- or heterocycle having 0, 1 or 2 N or O atoms and 5 or 6 skeleton atoms,   R 2  is NH 2 ,   R 3  is N,   R 4  is unbranched or branched, linear or monocyclic alkyl having 1, 2, 3, 4, 5, 6, 7, 8 or 9 C atoms, in which one or two CH 2  groups may be replaced by —O— or —NH—, and/or in which one or two CH groups may be replaced by —N—, and   R 5  is cyclohexyl, phenyl or pyridyl, which is unsubstituted or mono- or disubstituted by Hal or LA.   
     
     
         25 . The method of  claim 14 , wherein
 R 1  is Cl, CN, CONH 2 , isopropyl, isopropyloxy, ethyl, ethenyl, ethyloxy,   R 2  is NH 2 , and   R 3  is N.   
     
     
         26 . The method of  claim 14 , wherein
 R 2  is NH 2 ,   R 3  is N, and   R 4  is branched monocyclic alkyl having 5, 6 or 7 C atoms, of which 3 or 4 C atoms are ring atoms, and in which one CH 2  group may be replaced by —O— or —NH—, and/or in which one CH group may be replaced by —N—,
 or unbranched or branched linear alkyl having 5, 6 or 7 C atoms, in which one CH 2  group may be replaced by —O— or —NH—, and/or in which one CH group may be replaced by —N—. 
   
     
     
         27 . The method of  claim 14 , wherein
 R 2  is NH 2 ,   R 3  is N, and   R 5  is phenyl or pyridyl, which is para-substituted by Hal and/or meta-substituted by Hal or LA.   
     
     
         28 . The method of  claim 14 , wherein the compound is selected from:
 4-Amino-6-{4-[1-(2-azetidin-1-yl-ethyl)-4-(4-fluoro-3-trifluoromethyl-phenyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidine-5-carboxylic acid amide;   6-(4-(1-(2-(azetidin-1-yl)ethyl)-4-(2-(trifluoromethyl)pyridin-4-yl)-1H-imidazol-2-yl)piperidin-1-yl)-5-chloropyrimidin-4-amine;   6-(4-(1-(2-(azetidin-1-yl)ethyl)-4-(4-fluoro-3-(trifluoromethyl)phenyl)-1H-imidazol-2-yl)piperidin-1-yl)-5-isopropoxypyrimidin-4-amine;   4-Amino-6-{4-[1-(2-azetidin-1-yl-ethyl)-4-(3-chloro-4-fluoro-phenyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidine-5-carboxylic acid amide;   6-(4-(1-(2-aminoethyl)-4-(4-fluoro-3-(trifluoromethyl)phenyl)-1H-imidazol-2-yl)piperidin-1-yl)-5-ethylpyrimidin-4-amine;   4-Amino-6-(4-{4-(4-fluoro-3-trifluoromethyl-phenyl)-1-[2-(2-methoxy-ethylamino)-ethyl]-1H-imidazol-2-yl}-piperidin-1-yl)-pyrimidine-5-carbonitrile;   4-amino-6-(4-(1-(2-(azetidin-1-yl)ethyl)-4-(4-fluoro-3-methylphenyl)-1H-imidazol-2-yl)piperidin-1-yl)pyrimidine-5-carboxamide;   4-Amino-6-{4-[1-(2-azetidin-1-yl-ethyl)-4-cyclohexyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidine-5-carbonitrile;   4-Amino-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-(2-isopropylamino-ethyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidine-5-carboxylic acid amide;   4-Amino-6-{4-[1-[2-(cyclopropylmethyl-amino)-ethyl]-4-(4-fluoro-3-methyl-phenyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidine-5-carboxylic acid amide;   4-amino-6-(4-(4-(4-fluoro-3-(trifluoromethyl)phenyl)-1-(pyrrolidin-3-yl)-1H-imidazol-2-yl)piperidin-1-yl)pyrimidine-5-carboxamide;   5-ethyl-6-(4-(4-(4-fluoro-3-(trifluoromethyl)phenyl)-1-(piperidin-4-yl)-1H-imidazol-2-yl)piperidin-1-yl)pyrimidin-4-amine;   4-Amino-6-{4-[1-(2-cyclopentylamino-ethyl)-4-(4-fluoro-3-methyl-phenyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidine-5-carboxylic acid amide;   4-Amino-6-{4-[4-(4-fluoro-3-methyl-phenyl)-1-(2-methylamino-ethyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidine-5-carboxylic acid amide;   5-Ethoxy-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-(2-isopropylamino-ethyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamine;   5-chloro-6-(4-(1-(2-(cyclopropylamino)ethyl)-4-(2-(trifluoromethyl)pyridin-4-yl)-1H-imidazol-2-yl)piperidin-1-yl)pyrimidin-4-amine;   6-(4-(1-(2-(ethylamino)ethyl)-4-(4-fluoro-3-(trifluoromethyl)phenyl)-1H-imidazol-2-yl)piperidin-1-yl)-5-isopropoxypyrimidin-4-amine;   6-(4-(1-(2-(dimethylamino)ethyl)-4-(4-fluoro-3-methylphenyl)-1H-imidazol-2-yl)piperidin-1-yl)-5-(1H-pyrazol-4-yl)pyrimidin-4-amine;   6-(4-(1-(2-(azetidin-1-yl)ethyl)-4-(2-isopropylpyridin-4-yl)-1H-imidazol-2-yl)piperidin-1-yl)-5-vinylpyrimidin-4-amine; and   6-(4-(1-(azetidin-3-ylmethyl)-4-(4-fluoro-3-methylphenyl)-1H-imidazol-2-yl)cyclohexyl)-5-isopropylpyrimidin-4-amine.