Fused heteroaryl derivatives

Abstract

The present invention provides a pharmaceutical composition which is useful as a phosphatidylinositol 3 kinase (PI3K) inhibitor and an antitumor agent, and it provides a novel bicyclic or tricyclic fused heteroaryl derivative or a salt thereof which possesses an excellent PI3K inhibiting activity and cancer cell growth inhibiting activity.

1 . A pharmaceutical composition for a phosphatidylinositol 3 kinase inhibitor comprising a fused heteroaryl derivative represented by general formula (I) or a salt thereof and a pharmaceutically acceptable carrier:  
       
         
           
           
               
               
           
         
         B represents a benzene ring, or a 5- or 6-membered monocyclic heteroaryl containing 1 to 2 hetero atoms selected from O, S and N;  
         R1 represents -a lower alkyl, -a lower alkenyl, -a lower alkynyl, -a cycloalkyl, -an aryl which may have one or more substituents, -a heteroaryl which may have one or more substituents, -a halogen, —NO2, —CN, -a halogenated lower alkyl, —ORb, —SRb, —SO2-Rb, —SO—Rb, —COORb, —CO—Rb, —CONRaRb, —SO2NRaRb, —NRaRb, —NRa—CORb, —NRa—SO2Rb, —O—CO—NRaRb or —NRaCO—COORb, —CO-a nitrogen-containing saturated heterocyclic group, —CONRa-a lower alkylene-ORb, —CONRa-a lower alkylene-NRb, —O-a lower alkylene-ORb, —O-a lower alkylene-O-a lower alkylene-ORb, —O-a lower alkylene-NRaRb, —O-a lower alkylene-O-a lower alkylene-NRaRb, —O-a lower alkylene-NRc-a lower alkylene-NRaRb, —NRc-a lower alkylene-NRaRb, —N(a lower alkylene-NRaRb)2, —CONRa—ORb, —NRa—CO—NRbRc, or —OCORb;  
         each of R2 and R3, which may be the same or different, represents —H, -a lower alkyl, -a lower alkylene-ORa or -a lower alkylene-NRaRc, or R2 and R3 are combined together with the N atom adjacent thereto to form a nitrogen-containing saturated heterocyclic group as —NR2R3 which may have one or more substituents;  
         each of Ra and Rc, which may be the same or different, represents —H or -a lower alkyl;  
         Rb represents —H, -a lower alkyl, a cycloalkyl, an aryl which may have one or more substituents or a heteroaryl which may have one or more substituents;  
         n represents 0, 1, 2 or 3;  
         each of W and X, which may be same or different, represents N or CH;  
         Y represents O, S or NH; and,  
         R4 represents —H, -a lower alkyl, -a lower alkenyl, -a lower alkynyl, -(an aryl which may have one or more substituents), -a lower alkylene-(an aryl which may have one or more substituents), -a lower alkenylene-(an aryl which may have one or more substituents), -a lower alkynylene-(an aryl which may have one or more substituents), -(a cycloalkyl which may have one or more substituents), -(a cycloalkenyl which may have one or more substituents), -a lower alkylene-(a cycloalkyl which may have one or more substituents), -a lower alkenylene-(a cycloalkyl which may have one or more substituents), -a lower alkylene-(a nitrogen-containing saturated heterocyclic group which may have one or more substituents), -a lower alkenylene-(a nitrogen-containing saturated heterocyclic group which may have one or more substituents), -(a heteroaryl which may have one or more substituents), -a lower alkylene-(a heteroaryl which may have one or more substituents), or -a lower alkenylene-(a heteroaryl which may have one or more substituents).  
       
     
     
         2 . The pharmaceutical composition according to  claim 1 , wherein W represents N.  
     
     
         3 . The pharmaceutical composition according to  claim 1 , wherein R2 and R3 forms —NR3 which is a nitrogen-containing saturated heterocyclic group which may have 1˜2 substituents selected from the group comprising of —OH, ═O and -a lower alkyl.  
     
     
         4 . The pharmaceutical composition according to  claim 3 , wherein R2 and R3 forms —NR2R3 which is -morpholino.  
     
     
         5 . The pharmaceutical composition according to  claim 1 , wherein R4 represents -(an aryl which may have one or more substituents) or -(a heteroaryl which may have one or more substituents).  
     
     
         6 . The pharmaceutical composition according to  claim 5 , wherein R4 represents an aryl which has one or more substituents selected from the group comprising of -a lower alkylene-OR, —CONRR′, —NR—CO—Cyc1, —NR—SO2-Cyc1, —OR, —NRR′, —O-a lower alkylene-NRR′and —O-a lower alkylene-(a nitrogen-containing saturated heterocyclic group which may have 1˜5 substituents selected from Group A); wherein Cyc1 is -an aryl which may have 1˜5 substituents selected from Group A, -a heteroaryl which may have 1˜5 substituents selected from Group A, or -a nitrogen-containing saturated heterocyclic group which may have 1˜5 substituents selected from Group A; wherein Group A comprises of -a lower alkyl, -a lower alkenyl, -a lower alkynyl, -a halogen, -a halogenated lower alkyl, -a lower alkylene-OR, —NO2, —CN, ═O, —OR, —O-a halogenated lower alkyl, —O-a lower alkylene-NRR′, —O-a lower alkylene-OR, —O-a lower alkylene-an aryl, —SR, —SO2-a lower alkyl, —SO-a lower alkyl, —COOR, —COO-a lower alkylene-an aryl, —COR, —CO-an aryl, -an aryl, —CONRR′, —SO2NRR′, —NRR′, —NR″-a lower alkylene-NRR′, —NR′-a lower alkylene-OR, —NR-a lower alkylene-an aryl, —NRCO-a lower alkyl, —NRSO2-a lower alkyl, -a cycloalkyl and -a cycloalkenyl; and wherein R, R′ and R″, which may be the same or different, represent H or a lower alkyl.  
     
     
         7 . The pharmaceutical composition according to  claim 1 , wherein B represents a benzene ring; R1 represents -a lower alkyl, -a lower alkenyl, -a lower alkynyl, -a cycloalkyl, -an aryl which may have one or more substituents, -a heteroaryl which may have one or more substituents, -a halogen, —NO2, —CN, -a halogenated lower alkyl, —ORb, —SRb, —SO2-Rb, —SO—Rb, —COORb, —CO—Rb, —CONRaRb, —SO2NRaRb, —NRaRb, —NRa—CORb, —NRa—SO2Rb, —O—CO—NRaRb or —NRaCO—COORb.  
     
     
         8 . The pharmaceutical composition according to one of claims  1 ˜ 7 , wherein the pharmaceutical composition is an antitumor agent.  
     
     
         9 . Use of the fused heteroaryl derivative represented by formula (I) of  claim 1  or a salt thereof for the manufacture of medicament for use in the treatment of a disorder in which phosphatidylinositol 3-kinase plays a role.  
     
     
         10 . Use of the fused heteroaryl derivative represented by formula (I) of  claim 1  or a salt thereof for the manufacture of medicament for use in the treatment of cancer.  
     
     
         11 . A method to treat disorders which are associated with phosphatidylinositol 3 kinase, wherein the method comprises of administering to a patient an effective amount of the fused heteroaryl derivative represented by formula (I) of  claim 1  or a salt thereof.  
     
     
         12 . The treatment method according to  claim 11 , wherein the disorders which are associated with phosphatidylinositol 3 kinase are cancers.  
     
     
         13 . A fused heteroaryl derivative represented by general formula (Ia) or a salt thereof:  
       
         
           
           
               
               
           
         
         wherein:  
         R1 represents -a lower alkyl, -a lower alkenyl, -a lower alkynyl, -a cycloalkyl, -an aryl which may have one or more substituents, -a heteroaryl which may have one or more substituents, -a halogen, —NO2, —CN, -a halogenated lower alkyl, —ORb, —SRb, —SO2-Rb, —SO—Rb, —COORb, —CO—Rb, —CONRaRb, —SO2NRaRb, —NRaRb, —NRa—CORb, —NRa—SO2Rb, —O—CO—NRaRb or —NRaCO—COORb, —CO-a nitrogen-containing saturated heterocyclic group, —CONRa-a lower alkylene-ORb, —CONRa-a lower alkylene-NRbRc, —O-a lower alkylene-ORb, —O-a lower alkylene-O-a lower alkylene-ORb, —O-a lower alkylene-NRaRb, —O-a lower alkylene-O-a lower alkylene-NRaRb, —O-a lower alkylene-NRc-a lower alkylene-NRaRb, —NRc-a lower alkylene-NRaRb, —N(a lower alkylene-NRaRb)2, —CONRa—ORb, —NRa—CO—NRbRc, or —OCORb;  
         each of R2 and R3, which may be the same or different, represents —H or -a lower alkyl, or R2 and R3 are combined together with the N atom adjacent thereto to form a nitrogen-containing saturated heterocyclic group as —NR2R3 which may have one or more substituents;  
         Ra and Rc, which may be the same or different, represent —H or -a lower alkyl;  
         Rb represents —H, -a lower alkyl, a cycloalkyl, an aryl which may have one or more substituents or a heteroaryl which may have one or more substituents;  
         n represents 0, 1, 2 or 3;  
         X represents N or CH;  
         Y represents O, S or NH;  
         and,  
         R4a represents -(an aryl which may have one or more substituents), -a lower alkylene-(an aryl which may have one or more substituents), -a lower alkenylene-(an aryl which may have one or more substituents), -a lower alkynylene-(an aryl which may have one or more substituents), -(a cycloalkyl which may have one or more substituents), -(a cycloalkenyl which may have one or more substituents), -a lower alkylene-(a cycloalkyl which may have one or more substituents), -a lower alkenylene-(a cycloalkyl which may have one or more substituents), -a lower alkylene-(a nitrogen-containing saturated heterocyclic group which may have one or more substituents), -a lower alkenylene-(a nitrogen-containing saturated heterocyclic group which may have one or more substituents), -(a heteroaryl which may have one or more substituents), -a lower alkylene-(a heteroaryl which may have one or more substituents), or -a lower alkenylene-(a heteroaryl which may have one or more substituents);  
         with the proviso that the following compounds are excluded:  
         (1) compounds in which X represents N, Y represents S, n is 3 and R1 represents a combination of —CN, —OEt and phenyl, and R4a represents 2-nitrophenyl;  
         (2) compounds in which X represents CH, and R4a represents -(a heteroaryl which may have one or more substituents);  
         (3) compounds in which X represents CH, Y represents O, n is 0 and R4a represents an unsubstituted phenyl; and  
         (4) compounds in which X represents N, Y represents S, n is 2, R1 represents an unsubstituted phenyl and R4a represents 4-methoxyphenyl or an unsubstituted phenyl.  
       
     
     
         14 . The fused heteroaryl derivative or a salt thereof according to  claim 13 , wherein X represents N, Y represents O and n is 0.  
     
     
         15 . The fused heteroaryl derivative or a salt thereof according to  claim 13 , wherein the fused heteroaryl derivative or a salt thereof is selected from the group comprising of 6-amino-3′-(4-morpholinopyrido[3′,2′:4,5]furo[3,2-d]pyrimidin-2-yl)nicotinanilide,4-(4-morpholinopyrido[3′,2′:4,5]furo[3,2-d]pyrimidin-2-yl)aniline,3-(4-morpholinopyrido[3′,2′:4,5]furo[3,2-d]pyrimidin-2-yl)phenol,4-morpholino-2-[3-(2-piperazin-1-ylethoxy)phenyl]pyrido[3′,2′:4,5]furo[3,2-d]pyrimidine,3′-(4-morpholinopyrido[3′,2′:4,5]furo(3,2-d]pyrimidin-2-yl)acrylanilide, and salts thereof.  
     
     
         16 . A fused heteroaryl derivative represented by general formula (Ib) or a salt thereof:  
       
         
           
           
               
               
           
         
         wherein:  
         B represents a benzene ring, or a 5- or 6-membered monocyclic heteroaryl containing 1 to 2 hetero atoms selected from O, S and N;  
         R1 represents -a lower alkyl, -a lower alkenyl, -a lower alkynyl, -a cycloalkyl, -an aryl which may have one or more substituents, -a heteroaryl which may have one or more substituents, -a halogen, —NO2, —CN, -a halogenated lower alkyl, —ORb, —SRb, —SO2-Rb, —SO—Rb, —COORb, —CO—Rb, —CONRaRb, —SO2NRaRb, —NRaRb, —NRa—CORb, —NRa—SO2Rb, —O—CO—NRaRb, —NRaCO—COORb, —NRaCOORb; —NRaCO-a lower alkylene-an aryl, —NRa-SO2-a lower alkylene-an aryl, —NRa-a lower alkylene-an aryl, -a lower alkylene-ORb, -a lower alkylene-NRaRb, —CO-a nitrogen-containing saturated heterocyclic group, —-CONRa-a lower alkylene-ORb, —CONRa-a lower alkylene-NRcRb, —CONRa-a lower alkylene-a nitrogen-containing saturated heterocyclic group, —O-a lower alkylene-ORb, —O-a lower alkylene-NRaRb, —O-a lower alkylene-a nitrogen-containing saturated heterocyclic group, —O-a lower alkylene-O-a lower alkylene-ORb, —O-a lower alkylene-O-a lower alkylene-NRaRb, —O-a lower alkylene-NRc-a lower alkylene-NRaRb, —NRc-a lower alkylene-NRaRb, —N(a lower alkylene-NRaRb)2, —CONRa—ORb, —NRa—CO—NRbRc, or —OCORb;  
         R2 and R3 are combined together with the N atom adjacent thereto to form —NR2R3 which is a nitrogen-containing saturated heterocyclic group which may have one or more substituents;  
         Ra and Rc, which may be the same or different, represent —H or -a lower alkyl;  
         Rb represents —H, -a lower alkyl, -a cycloalkyl, -(an aryl which may have one or more substituents) or -(a heteroaryl which may have one or more substituents);  
         n represents 0, 1, 2 or 3, whereas n represents 1, 2 or 3 when B represents a benzene ring;  
         W represents N or CH; and,  
         R4b represents -(an aryl which may have one or more substituents), -a lower alkylene-(an aryl which may have one or more substituents), -a lower alkenylene-(an aryl which may have one or more substituents), -a lower alkynylene-(an aryl which may have one or more substituents), -(a cycloalkyl which may have one or more substituents), -(a cycloalkenyl which may have one or more substituents), -a lower alkylene-(a cycloalkyl which may have one or more substituents), -a lower alkenylene-(a cycloalkyl which may have one or more substituents), -a lower alkylene-(a nitrogen-containing saturated heterocyclic group which may have one or more substituents), -a lower alkenylene-(a nitrogen-containing saturated heterocyclic group which may have one or more substituents), -(a heteroaryl which may have one or more substituents), -a lower alkylene-(a heteroaryl which may have one or more substituents), or -a lower alkenylene-(a heteroaryl which may have one or more substituents);  
         with the proviso that the following compounds are excluded:  
         (1) 4-(4-morpholinyl)-2-phenylpyrido[2,3-d]pyrimidine,  
         (2) 4-(4-morpholinyl)-2-phenylpyrido[2,3-d]pyrimidin-7(1H)-one,  
         (3) 4-(4-morpholinyl)-2-pheny-6-quinazolinol and 6-methoxy-4-(4-morpholinyl)-2-phenyquinazoline,  
         (4) 2,4-diamino-6-phenyl-8-piperidinopyrimido[5,4-d]pyrimidine,  
         (5) compounds in which B represents a benzene ring, W represents N, n is 2 or 3, existing R1's all represent —OMe, and R4b is an unsubstituted phenyl or a phenyl which is substituted by 1 to 3 substituents selected from -halogen, —NO2, -a lower alkyl, —O-a lower alkyl, -a hanogenated lower alkyl and —CONRaRc,  
         (6) compounds in which B represents a benzene ring, W represents N, n is 1, R1 represents -halogen or -a lower alkyl and R4b represents -(imidazolyl whch may have one or more substituents),  
         (7) compounds in which B represents a thiophene ring, and W represents CH,  
         (8) compounds in which B represents an imidazole ring, and W represents N,  
         (9) compounds in which B represents a pyridine ring, and R4b represents an unsubstituted phenyl, an unsubstituted pyridyl, or -a lower alkylene-(a nitrogen-containing saturated heterocyclic group which may have one or more substituents),  
         (10) compounds in which B represents a pyrazine ring, and R4b represents an unsubstituted phenyl, or a benzyl,  
         (11) compounds in which B represents a benzene ring, and R4b represents a styryl or 2-(5-nitro-2-furyl)vinyl, and  
         (12) compounds in which B represents a benzene ring, W represents CH, and R2 and R3 are combined together with the N atom adjacent thereto to form -(piperidinyl which may have one or more substituents) or -(piperazinyl which may have one or more substituents).  
       
     
     
         17 . The fused heteroaryl derivative or a salt thereof according to  claim 16 , wherein W represents N, R4b represents -(an aryl which may have one or more substituents), and R2 and R3 form —NR2R3 which is -morpholino.  
     
     
         18 . The fused heteroaryl derivative or a salt thereof according to  claim 16 , wherein B represents a benzene ring, n is 1 or 2, and R1 represents —NO2, —CN, -a halogenated lower alkyl, —ORb, —SRb, —NRaRb, —NRa—CORb or —NRa—SO2Rb.  
     
     
         19 . The fused heteroaryl derivative or a salt thereof according to  claim 16 , wherein B represents a pyridine, pyrazine or thiophene ring, n is 0, and R4b represents a phenyl which has at least one substituent which is selected from —OH, —CH2OH and —CONH2.  
     
     
         20 . The fused heteroaryl derivative or a salt thereof according to  claim 16 , wherein the fused heteroaryl derivative or a salt thereof is selected from the group comprising of N-[2-(3-benzenesulfonylaminophenyl)-4-morphoniloquinazolin-6-yl]acetamide, 3-(4-morpholinopyrido [4,3-d]pyrimidin-2-yl)phenol, 3-(4-morpholinopyrido[3,2-d]pyrimidin-2-yl)phenol, 3-(4-morpholinopyrido[3,4-d]pyrimidin-2-yl)phenol, 3-(6-methoxy-4-morpholinoquinazolin-2-yl)phenol, 3-(4-morpholinothieno[3,2-d]pyrimidin-2-yl)phenol, 3-(4-morpholinopteridin-2-yl)phenol, and salts thereof.  
     
     
         21 . A pharmaceutical composition comprising a fused heteroaryl derivative or a salt thereof according to  claim 13  or  16 , and a pharmaceutically acceptable carrier.