Substituted quinobenzoxazine analogs

Abstract

The present invention relates to quinobenzoxazines analogs having the general formula: and pharmaceutically acceptable salts, esters and prodrugs thereof; wherein A, U, V, W, X and Z are substituents. The present invention also relates to methods for using such compounds.

1 . A compound having formula 1, 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof;
 wherein V is H, halo, NR 1 R 2 or NR 1 —(CR 1   2 ) n —NR 3 R 4 ; 
 A is H, fluoro, or NR 1   2 ; 
 Z is S, NR 1  or CH 2 ; 
 U is selected from the group consisting of NR 1 —(CR 1   2 ) n —NR 3 R 4  and NR 1 R; 
 X is OR 2 , NR 1 R 2 , halo, azido, or SR 2 ; 
 n is 1-6; 
 R is an optionally substituted 5-14 membered heterocyclic ring containing one or more N, O or S; or a C 1-10  alkyl or C 2-10  alkenyl optionally containing one or more non-adjacent heteroatoms selected from N, O, and S, and optionally substituted with an optionally substituted carbocyclic or heterocyclic ring; 
 R 1  and R 3  are independently H or a C 1-6  alkyl; 
 R 2  and R 4  are independently H or a C 1-10  alkyl or C 2-10  alkenyl optionally containing one or more non-adjacent heteroatoms selected from N, O, and S, and optionally substituted with an optionally substituted carbocyclic or heterocyclic ring;
 wherein R 1  and R 2  together with N in NR 1 R 2 , and/or R 3  and R 4  together with N in NR 3 R 4 , and/or R 1  and R together with N in NR 1 R may independently form an optionally substituted 5-6 membered ring containing N, and optionally O or S; 
 
 W is selected from the group consisting of 
 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           wherein Q, Q 1 , Q 2 , and Q 3  are independently CH or N; 
           Y is independently O, CH, C═O or NR 1 ; 
           and R 5  is a substituent at any position on the fused ring; and is H, OR 2 , C 1-6  alkyl, C 2-6  alkenyl, each optionally substituted by halo, ═O or one or more heteroatoms; or R 5  is an inorganic substituent; or two adjacent R 5  is linked to obtain a 5-6 membered substituted or unsubstituted carbocyclic or heterocyclic ring, optionally fused to an additional substituted or unsubstituted carbocyclic or heterocyclic ring; 
         
         provided that U is not morpholinyl or 2,4-difluoroaniline when X is F or pyrrolidinyl; A is F; Z is O; and W is phenylene. 
       
     
     
         2 . The compound of  claim 1 , wherein A and X are independently halo. 
     
     
         3 . The compound of  claim 2 , wherein said halo is fluoro. 
     
     
         4 . The compound of  claim 1 , where V is H. 
     
     
         5 . The compound of  claim 1 , wherein U is NR 1 R and X is NR 1 R 2 . 
     
     
         6 . The compound of  claim 5 , wherein R 1  is H and- R and R 2  are independently a C 1-10  alkyl optionally containing one or more heteroatoms, and optionally substituted with a C 3-6  cycloalkyl, aryl or a 5-14 membered heterocyclic ring containing one or more N, O or S, each of which is optionally substituted. 
     
     
         7 . The compound of  claim 6 , wherein said 5-14 membered heterocyclic ring is selected from the group consisting of tetrahydrofuran, 1,3-dioxolane, 2,3-dihydrofuran, tetrahydropyran, benzofuran, isobenzofuran, 1,3-dihydro-isobenzofuran, isoxazole, 4,5-dihydroisoxazole, piperidine, pyrrolidine, pyrrolidin-2-one, pyrrole, pyridine, pyrimidine, octahydro-pyrrolo[3,4-b]pyridine, piperazine, pyrazine, morpholine, thiomorpholine, imidazole, imidazolidine-2,4-dione, benzimidazole, 1,3-dihydrobenzimidazol-2-one, indole, thiazole, benzothiazole, thiadiazole, thiophene, tetrahydro-thiophene 1,1-dioxide, diazepine, triazole, guanidine, diazabicyclo[2.2.1]heptane, 2,5-diazabicyclo[2.2.1]heptane, and 2,3,4,4a,9,9a-hexahydro-1H-β-carboline. 
     
     
         8 . The compound of  claim 5 , wherein R 1  is H and R 2  is an aryl or a 5-14 membered heterocyclic ring containing one or more N, O or S, each optionally substituted with an amino or another heterocyclic ring. 
     
     
         9 . The compound of  claim 8 , wherein said 5-14 membered heterocyclic ring is selected from the group consisting of tetrahydrofuran, 1,3-dioxolane, 2,3-dihydrofuran, tetrahydropyran, benzofuran, isobenzofuran, 1,3-dihydro-isobenzofuran, isoxazole, 4,5-dihydroisoxazole, piperidine, pyrrolidine, pyrrolidin-2-one, pyrrole, pyridine, pyrimidine, octahydro-pyrrolo[3,4-b]pyridine, piperazine, pyrazine, morpholine, thiomorpholine, imidazole, imidazolidine-2,4-dione, benzimidazole, 1,3-dihydrobenzimidazol-2-one, indole, thiazole, benzothiazole, thiadiazole, thiophene, tetrahydro-thiophene 1,1-dioxide, diazepine, triazole, guanidine, diazabicyclo[2.2.1]heptane, 2,5-diazabicyclo[2.2.1]heptane, and 2,3,4,4a,9,9a-hexahydro-1H-β-carboline. 
     
     
         10 . The compound of  claim 5 , wherein R 1  and R 2  in NR 1 R 2  form an optionally substituted 5-14 membered ring containing one or more N, O or S. 
     
     
         11 . The compound of  claim 10 , where NR 1 R 2  is morpholine, thiomorpholine, piperazine, piperidine or diazepine. 
     
     
         12 . The compound of  claim 1 , wherein U and X independently have the formula
   NR 1 —(CR 1   2 ) n —NR 3 R 4   (2)
   wherein R 1  and R 3  are independently H or C 1-6  alkyl;   n is 1-6; and   R 4  is H or a C 1-10  alkyl or C 2-10  alkenyl optionally containing one or more non-adjacent heteroatoms selected from N, O and S, and optionally substituted with a carbocyclic or heterocyclic ring; and   wherein R 3  and R 4  in NR 3 R 4  may form an optionally substituted ring.   
     
     
         13 . The compound of  claim 12 , wherein n is 2-3. 
     
     
         14 . The compound of  claim 12 , wherein NR 3 R 4  is an acyclic amine, or guanidinyl or a tautomer thereof; or R 3  and R 4  form a substituted ring containing one or more N, O or S. 
     
     
         15 . The compound of  claim 12 , wherein NR 3 R 4  is morpholine, thiomorpholine, imidazole, pyrrolidine, piperazine, pyridine or piperidine. 
     
     
         16 . The compound of  claim 1 , wherein X is NR 1 R 2 ; and U has the formula
   NR 1 —(CR 1   2 ) n —NR 3 R 4   (2)
   wherein R 1  and R 2  are as defined in  claim 1 ;   R 3  is H or C 1-6  alkyl;   n is 1-6; and   R 4  is H or a C 1-10  alkyl or C 2-10  alkenyl optionally containing one or more non-adjacent heteroatoms selected from N, O and S, and optionally substituted with a carbocyclic or heterocyclic ring; and   wherein R 1  and R 2  in NR 1 R 2 ; and R 3  and R 4  in NR 3 R 4  each independently may form a substituted ring.   
     
     
         17 . The compound of  claim 16 , wherein R 1  and R e in NR 1 R 2 ; and R 3  and R 4  in NR 3 R 4  each independently form a substituted ring containing one or more N, O or S. 
     
     
         18 . The compound of  claim 17 , wherein X is optionally substituted with amino, carbamate, a C 1-10  alkyl containing one or more non-adjacent N, O or S, and optionally substituted with a heterocyclic ring; aryl or a saturated or unsaturated heterocyclic ring, each of which is optionally substituted. 
     
     
         19 . The compound of  claim 17 , wherein X is substituted with a heterocyclic ring selected from the group consisting of tetrahydrofuran, 1,3-dioxolane, 2,3-dihydrofuran, tetrahydropyran, benzofuran, isobenzofuran, 1,3-dihydro-isobenzofuran, isoxazole, 4,5-dihydroisoxazole, piperidine, pyrrolidine, pyrrolidin-2-one, pyrrole, pyridine, pyrimidine, octahydro-pyrrolo[3,4-b]pyridine, piperazine, pyrazine, morpholine, thiomorpholine, imidazole, imidazolidine-2,4-dione, benzimidazole, 1,3-dihydrobenzimidazol-2-one, indole, thiazole, benzothiazole, thiadiazole, thiophene, tetrahydro-thiophene 1,1-dioxide, diazepine, triazole, guanidine, diazabicyclo[2.2.1]heptane, 2,5-diazabicyclo[2.2.1]heptane, and 2,3,4,4a,9,9a-hexahydro-1H-β-carboline. 
     
     
         20 . The compound of  claim 17 , wherein X and NR 3 R 4  are independently morpholine, thiomorpholine, imidazole, pyrrolidine, piperazine, pyridine or piperidine. 
     
     
         21 . The compound of  claim 20 , wherein X and NR 3 R 4  are independently pyrrolidine. 
     
     
         22 . The compound of  claim 21 , wherein X is substituted with pyrazine. 
     
     
         23 . The compound of  claim 22 , wherein W is naphthalenyl. 
     
     
         24 . The compound of  claim 1 , wherein W is benzene, pyridine, biphenyl, naphthalene, phenanthrene, quinoline, isoquinoline, quinazoline, cinnoline, phthalazine, quinoxaline, indole, benzimidazole, benzoxazole, benzthiazole, benzofuran, anthrone, xanthone, acridone, fluorenone, carbazolyl, pyrimido[4,3-b]furan, pyrido[4,3-b]indole, pyrido[2,3-b]indole, dibenzofuran, acridine or acridizine. 
     
     
         25 . The compound of  claim 1 , wherein each optionally substituted moiety is substituted with one or more halo, OR 2 , NR 1 R 2 , carbamate, C 1-10  alkyl, C 2-10  alkenyl, each optionally substituted by halo, ═O, aryl or one or more heteroatoms; inorganic substituents, aryl, carbocyclic or a heterocyclic ring. 
     
     
         26 . The compound of  claim 1 , wherein said compound is chiral. 
     
     
         27 . A pharmaceutical composition comprising the compound of  claim 1  and a pharmaceutically acceptable excipient. 
     
     
         28 . A method for ameliorating a cell proliferative disorder, comprising administering to a subject in need thereof an effective amount of the compound of  claim 1  or a pharmaceutical composition thereof, thereby ameliorating said cell-proliferative disorder. 
     
     
         29 . The method of  claim 28 , wherein said cell proliferative disorder is cancer. 
     
     
         30 . The method of  claim 28 , wherein cell proliferation is reduced, or cell death is induced. 
     
     
         31 . The method of  claim 28 , wherein said subject is human or an animal. 
     
     
         32 . A method for reducing cell proliferation or inducing cell death, comprising contacting a system with an effective amount of the compound of  claim 1  or a pharmaceutical composition thereof, thereby reducing cell proliferation or inducing cell death in said system. 
     
     
         33 . The method of  claim 32 , wherein said system is a cell or tissue. 
     
     
         34 . A method for reducing microbial titers, comprising contacting a system with an effective amount of the compound of  claim 1  or a pharmaceutical composition thereof, thereby reducing microbial titers. 
     
     
         35 . The method of  claim 34 , where the system is a cell or tissue. 
     
     
         36 . The method of  claim 34 , wherein the microbial titers are viral, bacterial or fungal titers. 
     
     
         37 . A method for ameliorating a microbial infection, comprising administering to a subject in need thereof an effective amount of the compound of  claim 1  or a pharmaceutical composition thereof, thereby ameliorating said microbial infection. 
     
     
         38 . The method of  claim 37 , where the subject is a human or an animal. 
     
     
         39 . The method of  claim 37 , wherein said microbial infection is viral, bacterial or fungal. 
     
     
         40 . The compound of  claim 1 , wherein V is NH 2  or NR 1 —(CR 1   2 ) n —NR 3 R 4 ;
 wherein R 1  and R 3  are independently H or C 1-6  alkyl; 
 n is 1-6; and 
 R 4  is H, C 1-6  alkyl optionally substituted with a carbocyclic or heterocyclic ring, or aryl; and wherein R 3  and R 4  in NR 3 R 4  may form an optionally substituted ring. 
 
     
     
         41 . The compound of  claim 16 , wherein V is H. 
     
     
         42 . The compound of  claim 16 , wherein A is fluoro. 
     
     
         43 . The compound of  claim 16 , wherein W is naphthalenyl. 
     
     
         44 . The compound of  claim 23 , wherein V is H and A is fluoro. 
     
     
         45 . The compound of  claim 1 , wherein Z is NR 1 . 
     
     
         46 . The compound of  claim 45 , wherein U is NR 1 R, where R is a C 1-10  alkyl or C 2-10  alkenyl optionally containing one or more non-adjacent heteroatoms selected from N, O, and S, and optionally substituted with an optionally substituted carbocyclic or heterocyclic ring. 
     
     
         47 . The compound of  claim 45 , wherein X is NR 1 R 2 , wherein R 1  and R 2  in NR 1 R form an optionally substituted 5-6 membered ring containing N, and optionally O or S. 
     
     
         48 . The compound of  claim 45 , wherein W is optionally substituted naphthalenyl.