Dihydropyrimidin-2-one compounds and medical use thereof

Abstract

wherein each symbol is defined as in the specification.

1 - 37 . (canceled) 
     
     
         38 : A method of preparing a compound of Formula [Q-109]: 
       
         
           
           
               
               
           
         
         the method comprising reacting a compound of Formula [Q-107]: 
       
       
         
           
           
               
               
           
         
         with a compound of Formula [Q-108]:
   H 2 N—R 5q    [Q108]
 
 
         in a solvent and optionally in the presence of a base, wherein 
         R 1  is
 (1) C 4-8  alkyl, 
 (2) C 3-8  alkyl substituted with one hydroxy, 
 (3) C 4-8  alkyl substituted with one halogen, 
 (4) C 4-8  alkenyl, 
 (5) C 4-8  alkynyl, 
 (6) C 3-7  alkyl substituted with one trifluoromethyl, 
 (7) C 1-5  alkyl substituted with one substituent selected from Group X a1 , 
 (8) C 3-6  alkoxy, 
 (9) C 2-7  alkoxy substituted with one trifluoromethyl, 
 (10) C 1-3  alkoxy substituted with one substituent selected from Group X a2 , 
 (1H) C 4-6  cycloalkyl, 
 (12) C 3-6  cycloalkyl substituted with the same or different one to two C 1-5  alkyl, 
 (13) C 5-6  cycloalkenyl optionally substituted with the same or different one to two C 1-4  alkyl, 
 (14) spiro C 6-11  cycloalkyl, 
 (15) C 1-3  alkoxycarbonyl, 
 (16) C 3-6  alkylsulfanyl, 
 (17) C 3-6  alkylsulfinyl, 
 (18) C 3-6  alkylsulfonyl, 
 (19) C 3-6  cycloalkylsulfanyl, 
 (20) C 3-6  cycloalkylsulfinyl, 
 (2H) C 3-6  cycloalkylsulfonyl, 
 (22) cyclobutylidenemethyl, 
 (23) cyclopentylidenemethyl, 
 (24) cyclohexylidenemethyl optionally substituted with the same or different one to two C 1-3  alkyl, 
 (25) tetrahydropyran-4-ylidenemethyl, 
 (26) C 3-6  cycloalkyl substituted with one to the same two halogen, or 
 (27) C 5-6  cycloalkenyl substituted with one to the same two halogen; 
 Group X a1  is 
 (a) C 3-6  cycloalkyl optionally substituted with the same or different one to three C 1-5  alkyl, 
 (b) C 3-6  cycloalkyl substituted with the same or different one to two halogen, 
 (c) phenyl, 
 (d) C 2-4  alkoxy, 
 (e) trimethylsilyl, 
 (f) carboxy, or 
 (g) tetrahydropyran-4-yl; 
 Group X a2  is 
 (a) C 3-6  cycloalkyl, 
 (b) phenyl, or 
 (c) C 1-4  alkoxy; 
 R 2  is 
 (1) halogen, 
 (2) C 1-6  alkyl, 
 (3) C 1-3  alkoxy optionally substituted with phenyl, or 
 (4) trifluoromethyl; 
 n is an integer of 0, 1 or 2, provided that when n is 2, each R 2  may be different from each other; or 
 R 1  and R 2  may combine together with the benzene ring to which they attach to form indanyl where the indanyl may be substituted with the same or different one to two C 1-6  alkyl; 
 R 3q1  is —Y b —CH 2 OP 2 , C 1-6  alkyl optionally substituted with hydroxy protected with one P 2 , C 3-6  cycloalkyl optionally substituted with the same or different one to three substituents from Group X b , 4-tetrahydropyranyl, or I-methanesulfonyl-3-azetidinyl; 
 
         Y b  is C 1-6  alkylene or C 3-6  cycloalkylene; 
         p 2  is a protective group selected from the group consisting of trimethylsilyl (TMS) and tertbutyldimethylsilyl; 
         Group X b  is halogen or C 1-6  alkyl; 
         R 4  is
 (1) hydrogen or 
 (2) methyl; 
 R 5q  is —Y c —COO—R q50 , hydrogen, C 1-4  alkyl optionally substituted with one C 1-3  alkoxy, or C 3-6  cycloalkyl optionally substituted with hydroxy-C 1-4  alkyl protected with one p 2 ; 
 R q50  is C 1-4  alkyl; 
 Y c  is C 1-6  alkylene optionally substituted with hydroxy protected with one P 2 , CH 2 —CH 2 —O—CH 2 , or (CH 2 ) m —Y c1 —(CH 2 ) w ; 
 m is an integer of 0, 1, or 2; 
 w is an integer of 0, 1, or 2; and 
 Y c1  is C 3-6  cycloalkylene optionally substituted with one C 1-3  alkyl, phenylene, crosslinked C 5-8  cycloalkylene, or 
 
       
       
         
           
           
               
               
           
         
         
            and 
           R 6  is 
           (1) hydrogen or 
           (2) methyl. 
         
       
     
     
         39 : The method of  claim 38 , wherein
 the base is triethylamine; and   the solvent is benzene, toluene, dichloromethane, chloroform, diethyl ether, tetrahydrofuran, 1,2-dimethoxyethane, ethyl acetate, N,N-dimethylformamide, dimethylsulfoxide, acetonitrile, acetone, or any mixture of the foregoing; and   the reacting is carried out at a temperature of from 0° C. to 80° C.   
     
     
         40 : The method of  claim 38 , wherein the compound of Formula [Q-107] is obtained by reacting a compound of Formula [Q-106]: 
       
         
           
           
               
               
           
         
         with an azidation agent followed by a Curtius rearrangement in the presence of a base and a solvent. 
       
     
     
         41 : The method of  claim 40 , wherein
 the azidation agent is diphenylphosphoryl azide (DPPA);   the base is triethylamine or diisopropylethylamine;   the solvent is benzene, toluene, or xylene; and   the reacting is carried out at a temperature of from 0° C. to 140° C.   
     
     
         42 : The method of  claim 40 , wherein the compound of Formula [Q-106] is obtained by an Ireland Claisen rearrangement reaction of Formula [Q-105]: 
       
         
           
           
               
               
           
         
         by in a solvent, in the presence of a base and a chlorosilane compound, and 
         optionally in the presence of an additive. 
       
     
     
         43 : The method of  claim 42 , wherein
 the base is lithium diisopropylamide (LDA), lithium hexamethyldisilazide (LFMDS), or lithium 2,2,6,6-tetramethylpiperidide (LiTMP);   the chlorosilane compound is trimethylsilyl chloride or tert-butyldimethylsilyl chloride;   the additive is hexamethylphosphoric triamide (HMPA) or N,N′-dimethylpropyleneurea (DMPU);   the solvent is diethyl ether, 1,2-dimethoxyethane, or tetrahydrofuran; and   the Ireland Claisen rearrangement reaction is carried out at a temperature of from −78° C. to 80° C.   
     
     
         44 : The method of  claim 42 , wherein the compound of Formula [Q-105] is obtained by reacting a compound of formula [Q-103]: 
       
         
           
           
               
               
           
         
         with a compound of Formula [Q-104]: 
       
       
         
           
           
               
               
           
         
         in the presence of a condensation agent, a solvent, and optionally an additive. 
       
     
     
         45 : The method of  claim 44 , wherein
 the condensation agent is 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride, N,N′-dicyclohexylcarbodiimide (DCC), diphenylphosphoryl azide (DPPA), or carbonyldiimidazole;   the additive is 1-hydroxy-1H-benzotriazole monohydrate (HOBt.H 2 O) or 4-dimethylaminopyridine (DMAP); and   the solvent is toluene, dichloromethane, chloroform, tetrahydrofuran, dixoane, N,N-dimethylformamide, dimethylsulfoxide, acetonitrile, acetone, or any mixture of the foregoing; and   the reacting is carried out at a temperature of from 0° C. to 100° C.   
     
     
         46 : A compound of Formula [Q-109]: 
       
         
           
           
               
               
           
         
         wherein
 R 1  is 
 (1) C 4-8  alkyl, 
 (2) C 3-8  alkyl substituted with one hydroxy, 
 (3) C 4-8  alkyl substituted with one halogen, 
 (4) C 4-8  alkenyl, 
 (5) C 4-8  alkynyl, 
 (6) C 3-7  alkyl substituted with one trifluoromethyl, 
 (7) C 1-5  alkyl substituted with one substituent selected from Group X a1 ; 
 (8) C 3-6  alkoxy, 
 (9) C 2-7  alkoxy substituted with one trifluoromethyl, 
 (10) C 1-3  alkoxy substituted with one substituent selected from Group X a2 , 
 (1H) C 4-6  cycloalkyl, 
 (12) C 3-6  cycloalkyl substituted with the same or different one to two C 1-5  alkyl, 
 (13) C 5-6  cycloalkenyl optionally substituted with the same or different one to two C 1-4  alkyl, 
 (14) spiro C 6-11  cycloalkyl, 
 (15) C 1-3  alkoxycarbonyl, 
 (16) C 3-6  alkylsulfanyl, 
 (17) C 3-6  alkylsulfinyl, 
 (18) C 3-6  alkylsulfonyl, 
 (19) C 3-6  cycloalkylsulfanyl, 
 (20) C 3-6  cycloalkylsulfinyl, 
 (2H) C 3-6  cycloalkylsulfonyl, 
 (22) cyclobutylidenemethyl, 
 (23) cyclopentylidenemethyl, 
 (24) cyclohexylidenemethyl optionally substituted with the same or different one to two C 1-3  alkyl, 
 (25) tetrahydropyran-4-ylidenemethyl, 
 (26) C 3-6  cycloalkyl substituted with one to the same two halogen, or 
 (27) C 5-6  cycloalkenyl substituted with one to the same two halogen; 
 Group X a1  is 
 (a) C 3-6  cycloalkyl optionally substituted with the same or different one to three C 1-5  alkyl, 
 (b) C 3-6  cycloalkyl substituted with the same or different one to two halogen, 
 (c) phenyl, 
 (d) C 2-4  alkoxy, 
 (e) trimethylsilyl, 
 (f) carboxy, or 
 (g) tetrahydropyran-4-yl; 
 Group X a2  is 
 (a) C 3-6  cycloalkyl, 
 (b) phenyl, or 
 (c) C 1-4  alkoxy; 
 R 2  is 
 (1) halogen, 
 (2) C 1-6  alkyl, 
 (3) C 1-3  alkoxy optionally substituted with phenyl, or 
 (4) trifluoromethyl; 
 n is an integer of 0, 1 or 2, provided that when n is 2, each R 2  may be different with each other; or 
 R 1  and R 2  may combine together with the benzene ring to which they attach to form indanyl where the indanyl may be substituted with the same or different one to two C 1-6  alkyl; 
 
         R 3q1  is —Y b —CH 2 OP 2 , C 1-6  alkyl optionally substituted with hydroxy protected with one P 2 , C 3-6  cycloalkyl optionally substituted with the same or different one to three substituents from Group X b , 4-tetrahydropyranyl, or I-methanesulfonyl-3-azetidinyl;
 Y b  is C 1-6  alkylene or C 3-6  cycloalkylene; 
 P 2  is a protective group selected from the group consisting of trimethylsilyl (TMS) and tertbutyldimethylsilyl; 
 Group X b  is halogen or C 1-6  alkyl; 
 R 4  is 
 (1) hydrogen or 
 (2) methyl; 
 R 5q  is —Y c —COO—R q50 , hydrogen, C 1-4  alkyl optionally substituted with one C 1-3  alkoxy or C 3-6  cycloalkyl optionally substituted with hydroxy-C 1-4  alkyl protected with one P 2 ; 
 R q50  is C 1-4  alkyl; 
 Y c  is C 1-6  alkylene optionally substituted with hydroxy protected with one P 2 , CH 2 —CH 2 —O—CH 2  or (CH 2 ) m —Y c1 —(CH 2 ) w ; 
 m is an integer of 0, 1, or 2; 
 w is an integer of 0, 1, or 2; and 
 Y c1  is C 3-6  cycloalkylene optionally substituted with one C 1-3  alkyl, phenylene, crosslinked C 5 s cycloalkylene, or 
 
       
       
         
           
           
               
               
           
         
         
            and 
           R 6  is 
           (1) hydrogen or 
           (2) methyl. 
         
       
     
     
         47 : A compound of Formula [Q-107]: 
       
         
           
           
               
               
           
         
         wherein
 R 1  is 
 (1) C 4-8  alkyl, 
 (2) C 3-8  alkyl substituted with one hydroxy, 
 (3) C 4-8  alkyl substituted with one halogen, 
 (4) C 4-8  alkenyl, 
 (5) C 4-8  alkynyl, 
 (6) C 3-7  alkyl substituted with one trifluoromethyl, 
 (7) C 1-5  alkyl substituted with one substituent selected from Group X a1    
 (8) C 3-6  alkoxy, 
 (9) C 2-7  alkoxy substituted with one trifluoromethyl, 
 (10) C 1-3  alkoxy substituted with one substituent selected from Group X a2 , 
 (1H) C 4-6  cycloalkyl, 
 (12) C 3-6  cycloalkyl substituted with the same or different one to two C 1-5  alkyl, 
 (13) C 5-6  cycloalkenyl optionally substituted with the same or different one to two C 1-4  alkyl, 
 (14) spiro C 6-11  cycloalkyl, 
 (15) C 1-3  alkoxycarbonyl, 
 (16) C 3-6  alkylsulfanyl, 
 (17) C 3-6  alkylsulfinyl, 
 (18) C 3-6  alkylsulfonyl, 
 (19) C 3-6  cycloalkylsulfanyl, 
 (20) C 3-6  cycloalkylsulfinyl, 
 (2H) C 3-6  cycloalkylsulfonyl, 
 (22) cyclobutylidenemethyl, 
 (23) cyclopentylidenemethyl, 
 (24) cyclohexylidenemethyl optionally substituted with the same or different one to two C 1-3  alkyl, 
 (25) tetrahydropyran-4-ylidenemethyl, 
 (26) C 3-6  cycloalkyl substituted with one to the same two halogen, or 
 (27) C 5-6  cycloalkenyl substituted with one to the same two halogen; 
 Group X a1  is 
 (a) C 3-6  cycloalkyl optionally substituted with the same or different one to three C 1-5  alkyl, 
 (b) C 3-6  cycloalkyl substituted with the same or different one to two halogen, 
 (c) phenyl, 
 (d) C 2-4  alkoxy, 
 (e) trimethylsilyl, 
 (f) carboxy, or 
 (g) tetrahydropyran-4-yl; 
 Group X a2  is 
 (a) C 3-6  cycloalkyl, 
 (b) phenyl, or 
 (c) C 1-4  alkoxy; 
 R 2  is 
 (1) halogen, 
 (2) C 1-6  alkyl, 
 (3) C 1-3  alkoxy optionally substituted with phenyl, or 
 (4) trifluoromethyl; 
 n is an integer of 0, 1 or 2, provided that when n is 2, each R 2  may be different with each other; or 
 R 1  and R 2  may combine together with the benzene ring to which they attach to form indanyl where the indanyl may be substituted with the same or different one to two C 1-6  alkyl; 
 R 3q1  is —Y b —CH 2 OP 2 , C 1-6  alkyl optionally substituted with hydroxy protected with one P 2 , C 3-6  cycloalkyl optionally substituted with the same or different one to three substituents from Group X b , 4-tetrahydropyranyl, or I-methanesulfonyl-3-azetidinyl; 
 Y b  is C 1-6  alkylene or C 3-6  cycloalkylene; 
 P 2  is a protective group selected from the group consisting of trimethylsilyl (TMS) and tertbutyldimethylsilyl; 
 Group X b  is halogen or C 1-6  alkyl; 
 R 4  is 
 (1) hydrogen or 
 (2) methyl; and 
 R 6  is 
 (1) hydrogen or 
 (2) methyl.