Quinazoline derivatives substituted by aniline, preparation method and use thereof

Abstract

The invention relates to quinazoline derivatives substituted by aniline which are represented by the below formula (I), pharmaceutical acceptable salts and stereoisomer thereof, wherein these groups of R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , L and n have the meanings given in the specification. The invention also relates to preparation methods, pharmaceutical compositions, pharmaceutical preparation and the use for preparation of medicine of treating excessive hyperplasia and chronic obstructive pulmonary disease and uses for treating excessive hyperplasia and chronic obstructive pulmonary disease thereof.

1 . A compound represented by a general formula (I), a pharmaceutically acceptable salt thereof or a stereoisomer thereof: 
       
         
           
           
               
               
           
         
         wherein 
         R 1  is selected from the group consisting of the following groups that are unsubstituted or substituted by 1-2 Q 1  substituents: a 6-10-membered fused ring-C 0-6 alkyl group, a 7-10-membered spiro ring-C 0-6 alkyl group or a 7-10-membered bridged ring-C 0-6 alkyl group, wherein 1-3 carbon atoms of said fused ring, spiro ring or bridged ring can be replaced with 1-3 hetero atoms and/or groups that can be identical or different and are selected from the group consisting of O, S(O) m , N(H) m , NCH 3  and C(O), provided that after the replacement, O and C(O) in the ring are not adjacent to each other, 
         Q 1  is selected from the group consisting of halogen, hydroxyl, amino, carboxyl, cyano, a C 1-16 alkyl group, a C 1-6 alkoxyl group, a C 1-6 alkylamino group, a di(C 1-6 alkyl)amino group, a C 1-6 alkylcarbonyloxy group, a C 1-6 alkylacylamino group, a C 1-6 alkylsulfonyl group, a C 1-6 alkylsulfinyl group, a C 1-6 alkylsulfonylamino group and a C 3-8 cycloalkyl group; 
         R 2  is selected from the group consisting of hydrogen, a C 1-6 alkyl group or a C 1-6 alkoxyl group that is unsubstituted or substituted by 1-2 Q 2  substituents, a formyl group that is substituted by a Q 2  substituent or N(H) m , 
         Q 2  is selected from the group consisting of halogen, hydroxyl, amino, carboxyl, cyano, a C 1-16 alkyl group, a C 1-6 alkoxyl group, a C 1-6 alkylamino group, a di(C 1-6 alkyl)amino group, a C 1-6 alkylcarbonyloxy group, a C 1-6 alkylacylamino group, a C 1-6 alkylsulfonyl group, a C 1-6 alkylsulfinyl group, a C 1-6 alkylsulfonylamino group, a C 3-8 cycloalkyl group, an unsaturated C 5-7  cyclic hydrocarbyl and a saturated or unsaturated 3-8-membered heterocyclyl, wherein the C 3-8 cycloalkyl, the unsaturated C 5-7  cyclic hydrocarbyl and the saturated or unsaturated 3-8-membered heterocyclyl can further substituted by 1-2 Q 3  substituents, 
         Q 3  is selected from the group consisting of halogen, hydroxyl, amino, carboxyl, cyano, a C 1-16 alkyl group, a C 1-6 alkoxyl group, a C 1-6 alkylamino group, a di(C 1-6 alkyl)amino group, a C 1-6 alkylcarbonyloxy group, a C 1-6 alkylacylamino group, a C 1-6 alkylsulfonyl group, a C 1-6 alkylsulfinyl group, a C 1-6 alkylsulfonylamino group and a halogen-substituted C 1-6 alkoxy group; 
         R 3  is selected from the group consisting of hydrogen, halogen, hydroxyl, cyano, nitro, a C 1-6 alkyl group, a C 1-6 alkoxyl group, a C 1-6 alkyl group or a C 1-6 alkoxyl group that is substituted by halogen, a C 1-6 alkylcarbonyloxy group, a C 1-6 alkylacylamino group, a C 1-6 alkylsulfonyl group, a C 1-6 alkylsulfinyl group or a C 1-6 alkylsulfonylamino group; 
         R 4 , R 5  and R 6  are each independently selected from the group consisting of hydrogen, halogen, a C 1-6 alkyl group, a C 1-6 alkoxyl group, a C 1-6 alkyl group or a C 1-6 alkoxyl group that is substituted by halogen, a C 1-6 alkylamino group or a di(C 1-6 alkyl)amino group; 
         L is selected from the group consisting of a covalent bond, O, S(O) m , N(H) m , NCH 3  or C(O); 
         n is 1, 2 or 3; and 
         m is 0, 1 or 2. 
       
     
     
         2 . A compound according to  claim 1 , a pharmaceutically acceptable salt thereof or a stereoisomer thereof, wherein
 R 1  is selected from the group consisting of the following groups that are unsubstituted or substituted by 1-2 Q 1  substituents: a 6-10-membered saturated fused ring-C 0-4 alkyl group, a 7-10-membered saturated spiro ring-C 0-4 alkyl group or a 7-10-membered saturated bridged ring-C 0-4 alkyl group, wherein 1-3 carbon atoms of the fused ring, the spiro ring or the bridged ring can be replaced with 1-3 hetero atoms and/or groups that can be identical or different and are selected from the group consisting of O, S(O) m , N(H) m , NCH 3  and C(O), provided that after the replacement, O and C(O) in the ring are not adjacent to each other,   Q 1  is selected from the group consisting of halogen, hydroxyl, amino, carboxyl, cyano, a C 1-4 alkyl group, a C 1-4 alkoxyl group, a C 1-4 alkylamino group, a di(C 1-4 alkyl)amino group, a C 1-4 alkylcarbonyloxy group, a C 1-4 alkylacylamino group, a C 1-4 alkylsulfonyl group, a C 1-4 alkylsulfinyl group, C 1-4 alkylsulfonylamino and C 3-6 cycloalkyl;   R 2  is selected from the group consisting of hydrogen, a C 1-4 alkyl group or a C 1-4 alkoxyl group that is unsubstituted or substituted by 1-2 Q 2  substituents, a formyl group that is substituted by a Q 2  substituent or N(H) m ,   Q 2  is selected from the group consisting of halogen, hydroxyl, amino, cyano, a C 1-4 alkyl group, a C 1-4 alkoxyl group, a C 1-4 alkylamino group, a di(C 1-4 alkyl)amino group, a C 1-4 alkylcarbonyloxy group, a C 1-4 alkylacylamino group, a C 1-4 alkylsulfonyl group, a C 1-4 alkylsulfinyl group, a C 1-4 alkylsulfonylamino group, a C 3-6 cycloalkyl group, an unsaturated C 5-7  cyclic hydrocarbyl and a saturated or unsaturated 5-8-membered heterocyclyl group, wherein the C 3-6 cycloalkyl, the unsaturated C 5-7  cyclic hydrocarbyl and the saturated or unsaturated 5-8-membered heterocyclyl can be further substituted by 1-2 Q 3  substituents,   Q 3  is selected from the group consisting of halogen, hydroxyl, amino, cyano, a C 1-4 alkyl group, a C 1-4 alkoxyl group, a C 1-4 alkylamino group, a di(C 1-4 alkyl)amino group, a C 1-4 alkylcarbonyloxy group, a C 1-4 alkylacylamino group, a C 1-4 alkylsulfonyl group, a C 1-4 alkylsulfinyl group, a C 1-4 alkylsulfonylamino group and a halogen-substituted C 1-4 alkoxy group;   R 3  is selected from the group consisting of halogen, cyano, nitro, a C 1-4 alkyl group, a C 1-4 alkoxyl group, a C 1-4 alkyl group or a C 1-4 alkoxyl group that is substituted by halogen, a C 1-4 alkylcarbonyloxy group, a C 1-4 alkylacylamino group, a C 1-4 alkylsulfonyl group, a C 1-4 alkylsulfinyl group or a C 1-4 alkylsulfonylamino group;   R 4 , R 5  and R 6  are each independently selected from the group consisting of hydrogen, halogen, a C 1-4 alkyl group, a C 1-4 alkoxyl group, a C 1-4 alkyl group or a C 1-4 alkoxyl group that is substituted by halogen, a C 1-4 alkylamino group or a di(C 1-4 alkyl)amino group;   L is selected from the group consisting of a covalent bond, O, S(O) m  or N(H) m ;   n is 1, 2 or 3; and   m is 0, 1 or 2.   
     
     
         3 . A compound according to  claim 1 , a pharmaceutically acceptable salt thereof or a stereoisomer thereof, wherein
 R 1  is selected from the group consisting of the following groups that are unsubstituted or substituted by 1-2 Q 1  substituents;   
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       wherein 1-3 carbon atoms on the ring can be replaced with 1-3 hetero atoms and/or groups that can be identical or different and are selected from the group consisting of O, S(O) m , N(H) m , NCH 3  and C(O), provided that after the replacement, O and C(O) in the ring are not adjacent to each other, p is 0, 1 or 2, Q 1  is selected from the group consisting of halogen, hydroxyl, amino, carboxyl, a C 1-4 alkyl group, a C 1-4 alkoxyl group, a C 1-4 alkylamino group, a di(C 1-4 alkyl)amino group and a C 3-6 cycloalkyl group;
 R 2  is selected from the group consisting of hydrogen, a C 1-4 alkyl group that is unsubstituted or substituted by 1-2 Q 2  substituents, a formyl group that is substituted by a Q 2  substituent or N(H) m , 
 Q 2  is selected from the group consisting of halogen, hydroxyl, amino, a C 1-4 alkyl group, a C 1-4 alkoxyl group, a C 1-4 alkylamino group, a di(C 1-4 alkyl)amino group, a C 1-4 alkylcarbonyloxy group, a C 1-4 alkylacylamino group, a C 1-4 alkylsulfonyl group, a C 1-4 alkylsulfonylamino group, a C 3-5 cycloalkyl group and a saturated or unsaturated 5-8-membered heterocyclyl group, wherein the C 3-5 cycloalkyl, the saturated or unsaturated 5-8-membered heterocyclyl can be further substituted by 1-2 Q 3  substituents, Q 3  is selected from the group consisting of halogen, hydroxyl, amino, a C 1-4 alkyl group, a C 1-4 alkoxyl group, a C 1-4 alkylamino group, a di(C 1-4 alkyl)amino group, a C 1-4 alkylcarbonyloxy group, a C 1-4 alkylacylamino group, a C 1-4 alkylsulfonyl group, a C 1-4 alkylsulfonylamino group and a halogen-substituted C 1-4 alkoxy group; 
 R 3  is selected from the group consisting of fluoro, chloro, bromo, a C 1-4 alkyl group or a C 1-4 alkoxy group; 
 R 4 , R 5  and R 6  are each independently selected from the group consisting of hydrogen, fluoro or chloro; 
 L is selected from the group consisting of a covalent bond, O, S(O) m  or N(H) m ; 
 n is 1, 2 or 3; and 
 m is 0, 1 or 2. 
 
     
     
         4 . A compound according to  claim 1 , a pharmaceutically acceptable salt thereof or a stereoisomer thereof, wherein
 R 1  is selected from the group consisting of the following groups that are unsubstituted or substituted by 1-2 Q 1  substituents:   
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         p is 0, 1 or 2, 
         Q 1  is selected from the group consisting of halogen, amino, a C 1-4 alkyl group, a C 1-4 alkylamino group and a di(C 1-4 alkyl)amino group; 
         R 2  is selected from the group consisting of hydrogen, methyl that is unsubstituted or substituted by 1-2 Q 2  substituents or ethyl that is unsubstituted or substituted by 1-2 Q 2  substituents, a formyl group that is substituted by a Q 2  substituent or N(H) m , 
         Q 2  is selected from the group consisting of: 
         (1) halogen, hydroxyl, amino, a C 1-4 alkoxyl group, a C 1-4 alkylamino group, a di(C 1-4 alkyl)amino group, acetoxyl, acetamido, methylsulfonyl and methylsulfonylamino, 
         (2) cyclopropyl, cyclopentyl, piperidinyl, piperazinyl, morpholinyl, pyrrolidinyl, furyl, thienyl, pyrrolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, pyridyl, pyrazinyl and pyrimidinyl, these Q 2  groups can be further substituted by 1-2 Q 3  substituents, 
         Q 3  is selected from the group consisting of halogen, hydroxyl, amino, a C 1-4 alkyl group, a C 1-4 alkoxyl group, a C 1-4 alkylamino group, a di(C 1-4 alkyl)amino group, a halogen-substituted C 1-4 alkoxyl, acetoxyl, acetamido, methylsulfonyl and methylsulfonylamino; 
         R 3  is selected from the group consisting of fluoro or chloro; 
         R 4 , R 5  and R 6  are hydrogen; 
         L is selected from the group consisting of a covalent bond or O; 
         n is 2; and 
         m is 0, 1 or 2. 
       
     
     
         5 . A compound according to  claim 1 , a pharmaceutically acceptable salt thereof or a stereoisomer thereof, wherein
 R 1  is selected from the group consisting of:   
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         R 2  is selected from the group consisting of hydrogen, methyl that is unsubstituted or substituted by 1-2 Q 2  substituents or ethyl that is unsubstituted or substituted by 1-2 Q 2  substituents, 
         Q 2  is selected from the group consisting of: 
         (1) methoxy and a di(C 1-4 alkyl)amino group, 
         (2) piperidinyl, piperazinyl, morpholinyl, pyrrolidinyl, furyl, cyclopropyl, cyclopentyl, pyrrolyl, pyridyl, pyrimidinyl and thiazolyl, these Q 2  groups can be further substituted by 1-2 Q 3  substituents, 
         Q 3  is selected from the group consisting of halogen, hydroxy, amino, a C 1-4 alkyl group, a C 1-4 alkoxyl group, a C 1-4 alkylamino group, a di(C 1-4 alkyl)amino group and a halogen-substituted C 1-4 alkoxy group; 
         R 3  is selected from the group consisting of fluoro or chloro; 
         R 4 , R 5  and R 6  are hydrogen; 
         L is selected from the group consisting of a covalent bond or O; and 
         n is 2. 
       
     
     
         6 . A compound according to  claim 1 , a pharmaceutically acceptable salt thereof or a stereoisomer thereof, wherein
 R 1  is selected from the group consisting of:   
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         R 2  is selected from the group consisting of hydrogen, methyl that is unsubstituted or substituted by 1-2 Q 2  substituents or ethyl that is unsubstituted or substituted by 1-2 Q 2  substituents, 
         Q 2  is selected from the group consisting of methoxy, dimethylamino, diethylamino, piperidinyl, piperazinyl and morpholinyl; 
         R 3  is selected from the group consisting of fluoro or chloro; 
         R 4 , R 5  and R 6  are hydrogen; 
         L is selected from the group consisting of a covalent bond or O; and 
         n is 2. 
       
     
     
         7 . A compound according to  claim 1 , a pharmaceutically acceptable salt thereof or a stereoisomer thereof, wherein the compound is selected from the group consisting of:
 (E)-N-[7-(8-oxabicyclo[3.2.1]octan-3-yloxy)-4-(3-chloro-4-fluorophenylamino)quinazolin-6-yl]-4-(piperidin-1-yl)-2-butenamide,   (E)-N-[7-(7-oxabicyclo[2.2.1]heptan-2-yloxy)-4-(3-chloro-4-fluorophenylamino)quinazolin-6-yl]-4-(piperidin-1-yl)-2-butenamide,   (E)-N-[4-(3-chloro-4-fluorophenylamino)-7-(2-methyl-2,7-diazaspiro[4.5]decan-7-yl)quinazolin-6-yl]-4-(piperidin-1-yl)-2-butenamide,   N-[4-(3-chloro-4-fluorophenylamino)-7-(8-methyl-8-azabicyclo[3.2.1]octan-3-yloxy)quinazolin-6-yl]-acrylamide,   N-[4-(3-chloro-4-fluorophenylamino)-7-(8-methyl-1-oxa-8-azaspiro[4.5]decan-3-yloxy)quinazolin-6-yl]-acrylamide,   N-[4-(3-chloro-4-fluorophenylamino)-7-((8-methyl-1-oxa-8-azaspiro[4,5]decan-3-yl)methoxy)quinazolin-6-yl]-acrylamide,   N-[4-(3-chloro-4-fluorophenylamino)-7-(8-methyl-1-oxa-8-azaspiro[4,5]decan-2-ylmethoxy)quinazolin-6-yl]-acrylamide,   N-[4-(3-chloro-4-fluorophenylamino)-7-(2-((1R,5S,6S)-3-methyl-3-azabicyclo[3.1.0]hexan-6-ylethoxy)quinazolin-6-yl]-acrylamide,   N-[4-(3-chloro-4-fluorophenylamino)-7-((2-methyloctahydrocyclopenta[c]pyrrol-4-yl)methoxy)quinazolin-6-yl]-acrylamide,   N-[4-(3-chloro-4-fluorophenylamino)-7-((7-methyl-7-azabicyclo[2.2.1]heptan-2-yl)methoxy)quinazolin-6-yl]-acrylamide,   N-[4-(3-chloro-4-fluorophenylamino)-7-(2-(3-methyl-3-azabicyclo[3.2.1]octan-8-yl)ethoxy)quinazolin-6-yl]-acrylamide,   N-[4-(3-chloro-4-fluorophenylamino)-7-((5-methyl-5-azaspiro[2.4]heptan-1-yl)methoxy) quinazolin-6-yl]-acrylamide,   N-[4-(3-chloro-4-fluorophenylamino)-7-((6-methyl-6-azaspiro[2.5]octan-1-yl)methoxy)quinazolin-6-yl]-acrylamide,   N-[4-(3-chloro-4-fluorophenylamino)-7-(2-(6-methyl-6-azaspiro[2.5]octan-1-yl)ethoxy)quinazolin-6-yl]-acrylamide,   (E)-N-[4-(3-chloro-4-fluorophenylamino)-7-(2-((1R,5S,6S)-3-methyl-3-azabicyclo[3.1.0]hexan-6-yl)ethoxy)quinazolin-6-yl]-2-butenamide,   (E)-N-[4-(3-chloro-4-fluorophenylamino)-7-((7-methyl-7-azaspiro[3.5]nonan-2-yl)methoxy)quinazolin-6-yl]-2-butenamide,   (E)-N-[4-(3-chloro-4-fluorophenylamino)-7-((7-methyl-7-azaspiro[3.5]nonan-2-yl)methoxy)quinazolin-6-yl]-2-pentenamide,   N-[4-(3-chloro-4-fluorophenylamino)-7-((7-methyl-7-azaspiro[3.5]nonan-2-yl)methoxy)quinazolin-6-yl]-acrylamide,   N-[4-(3-chloro-4-fluorophenylamino)-7-(2-(7-methyl-7-azaspiro[3.5]nonan-2-yl)ethoxy)quinazolin-6-yl]-acrylamide,   (E)-N-(4-(3-chloro-4-fluorophenylamino)-7-((7-methyl-7-azaspiro[3.5]nonan-2-yl)methoxy)quinazolin-6-yl)-4-dimethylamino-2-butenamide,   (E)-N-[4-(3-chloro-4-fluorophenylamino)-7-((2-(3-methyl-3-aza-bicyclo[3.1.0]-6-hexyl)-ethoxy)quinazolin-6-yl)-4-dimethylamino]-crotonamide,   (E)-N-[4-(3-chloro-4-fluorophenylamino)-7-(((spiro[3.5]octan-2-yl)methoxy)quinazolin-6-yl)-4-dimethylamino]-crotonamide, and   (E)-N-(7-(bicyclo[3.1.0]hexan-6-ylmethoxy)-4-(3-chloro-4-fluorophenylamino)quinazolin-6-yl)-4-(dimethylamino)but-2-enamide.   
     
     
         8 . A process for preparing a compound of general formula (I) according to  claim 1 , comprising the steps of:
 Reaction Procedure:   
       
         
           
           
               
               
           
         
         wherein, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , L and n are as defined in  claim 1 ; the starting material 2=R 1 -LH; the starting material 3=R 2 CH═CH—C(O)Cl or R 2 CH═CH—COOH, 
         (1) Dissolving the starting material 2 in a non-protonic polar solvent, and reacting with the starting material 1 in the presence of a base to produce the Intermediate 1; 
         (2) Reacting the Intermediate 1 with a reducing agent optionally in the presence of an acid to produce the Intermediate 2; and 
         (3) Dissolving the Intermediate 2 in an organic solvent, and reacting with the starting material 3 in the presence of an organic base to produce the compound of formula (I). 
       
     
     
         9 . A pharmaceutical composition, which contains a compound according to any one of  claims 1 - 7 , a pharmaceutically acceptable salt thereof or a stereoisomer thereof. 
     
     
         10 . A pharmaceutical composition according to  claim 9 , which further contains a second therapeutical agent selected from the group consisting of an antineoplastic agent and an immunosuppressive agent, said second therapeutical agent is selected from the group consisting of an antimetabolite, including capecitabine and gemcitabine; a growth factor inhibitor, including pazopanib and imatinib; an antibody, including herceptin and bevacizumab; a mitotic inhibitor, including paclitaxel, vinorelbine, docetaxel, and doxorubicin; an antineoplastic hormone, including letrozole, tamoxifen, and fulvestrant; an alkylating agent, including cyclophosphamide and carmustine; a metal platinum, including carboplatin, cisplatin, and oxaliplatin; a topoisomerase inhibitor, including topotecan; and an immunosuppressant, including everolimus. 
     
     
         11 . A pharmaceutical formulation containing a compound according to any one of  claims 1 - 7 , a pharmaceutically acceptable salt thereof or a stereoisomer thereof and one or more pharmaceutically acceptable carriers, which formulation is in a form of any pharmaceutically acceptable dosage form. 
     
     
         12 . A use of a compound according to any one of  claims 1 - 7 , a pharmaceutically acceptable salt thereof or a stereoisomer thereof for the preparation of a medicament for treating a hyperplasia disease and a chronic obstructive pulmonary disease. 
     
     
         13 . A method of treating a hyperplasia disease and a chronic obstructive pulmonary disease, which comprises a step of administering a compound according to any one of  claims 1 - 7 , a pharmaceutically acceptable salt thereof or a stereoisomer thereof to a mammal in need thereof. 
     
     
         14 . A use according to  claim 12  or a method according to  claim 13 , wherein said hyperplasia disease includes a cancerous disease and a non-cancerous disease, the cancerous disease is selected from the group consisting of cerebroma, lung cancer, nonsmall-cell lung cancer, squamous cell, bladder carcinoma, gastric cancer, ovarian cancer, peritoneal cancer, pancreatic cancer, mammary cancer, head and neck cancer, cervical cancer, endometrial cancer, colorectal cancer, liver cancer, renal carcinoma, adenocarcinoma of esophagus, esophageal squamous cell cancer, solid tumor, non-Hodgkin lymphoma, central nervous system tumor (glioma, gliobastona multiforme, glioma sarcomatosum), prostate carcinoma or thyroid carcinoma; and the non-cancerous disease, for example, is benign hyperplasia of skin or prostate.