Quinobenzoxazine analogs and methods of using thereof

Abstract

The present invention relates to quinobenzoxazines analogs having the general formula: and pharmaceutically acceptable salts, esters and prodrugs thereof; wherein A, U, W, X, Z, B, L, R 1 , R 3 , R 4 and R 5 are substituents. The present invention also relates to methods for using such compounds.

1 . A compound having formula 1 
       
         
           
           
               
               
           
         
         and pharmaceutically acceptable salts, esters and prodrugs thereof, 
         wherein X is H, OR 2 , NR 1 R 2 , halogen, azido, SR 2  or CH 2 R; 
         A is H, halogen, NR 1 R 2 , SR 2 , OR 2 , CH 2 R, azido or NR 1 —(CR 1   2 ) n —NR 3 R 4 ; 
         Z is S, NR 1  or CH 2 ; 
         U is NR 1 R 2  or NR 1 —(CR 1   2 ) n —NR 3 R 4  provided U is not H; 
         W is an optionally substituted aryl or heteroaryl, which may be monocyclic or fused with a single or multiple ring optionally containing a heteroatom; 
         wherein R 1  and R 2  together with N in NR 1 R 2 , and R 3  and R 4  together with N in NR 3 R 4  may independently form an optionally substituted 5-6 membered ring containing N, and optionally O or S; 
         R 1  and R 3  are independently H or a C 1-6  alkyl; and 
         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 a substituted or unsubstituted aryl, heteroaryl, carbocyclic, or heterocyclic ring; or R 2  is an optionally substituted cycloalkyl, heterocyclic ring, aryl or heteroaryl; 
         R 5  is a substituent at any position of W and is H, halo, cyano, azido, —CONHR 1 , OR 2 , or C 1-6  alkyl or C 2-6  alkenyl, each optionally substituted by halo, ═O or one or more heteroatoms; 
         provided X and A both are not H, and further provided that R 5  is cyano or —CONHR 1  when A is H, halogen or NR 1 R 2 ; 
         or a compound having formula (1A) 
       
       
         
           
           
               
               
           
         
         and pharmaceutically acceptable salts, esters and prodrugs thereof; 
         A is H, halogen, azido, SR 2 , OR 2 , CH 2 R 2 , NR 1 R 2 , or NR 1 —(CR 1   2 ) n —NR 3 R 4 ; 
         Z, U, W, R 1 , R 2 , R 3  and R 4  are as defined in formula 1; and 
         R 5  is a substituent at any position of W and is H, halo, cyano, azido, —CONHR 1 , OR 2 , or C 1-6  alkyl or C 2-6  alkenyl, each optionally substituted by halo, ═O or one or more heteroatoms; 
         wherein each optionally substituted moiety in formula 1 and 1A is substituted with one or more halo, cyano, azido, acetyl, amido, 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 selected from N, O and S; or is substituted with an aryl, a carbocyclic or a heterocyclic ring. 
       
     
     
         2 . The compound of  claim 1 , wherein each W is independently 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, ═O or NR 1 ; and 
         R 5  is as defined in  claim 1 . 
       
     
     
         3 . The compound of  claim 1 , wherein each W is an optionally substituted phenyl, 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. 
     
     
         4 . The compound of  claim 1  having formula 1, wherein A is SR 2  and X is H. 
     
     
         5 . The compound of  claim 1 , wherein each A is NR 1 —(CR 1   2 ) n —NR 3 R 4 , or an optionally substituted 5-14 membered heterocyclic ring containing N and optionally O or S. 
     
     
         6 . The compound of  claim 5 , wherein said 5-14 membered heterocyclic ring is an optionally substituted tetrahydrofuran, 1,3-dioxolane, 2,3-dihydrofuran, tetrahydropyran, benzofuran, isobenzofuran, 1,3-dihydro-isobenzofuran, isoxazole, 4,5-dihydroisoxazole, piperidine, piperidin-2-one, pyrrolidine, pyrrolidin-2-one, pyrrole, pyridine, pyrimidine, octahydro-pyrrolo[3,4-b]pyridine, piperazine, piperazin-2-one, 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, or 2,3,4,4a,9,9a-hexahydro-1H-β-carboline. 
     
     
         7 . The compound of  claim 5 , wherein said 5-14 membered heterocyclic ring is an optionally substituted morpholine, thiomorpholine, imidazole, pyrrolidine, pyrrolidin-2-one, piperazine, piperazin-2-one, pyridine, piperidine, or piperidin-2-one. 
     
     
         8 . The compound of  claim 1 , wherein U is NR 1 —(CR 1   2 ) n —NR 3 R 4 . 
     
     
         9 . The compound of  claim 8 , wherein n is 2-3. 
     
     
         10 . The compound of  claim 8 , wherein R 3  and R 4  together with N form an optionally substituted ring containing N, and optionally O or S. 
     
     
         11 . The compound of  claim 8 , wherein NR 3 R 4  is an optionally substituted morpholine, thiomorpholine, imidazole, pyrrolidine, piperazine, pyridine or piperidine. 
     
     
         12 . The compound of  claim 1 , wherein A is an optionally substituted 5-14 membered heterocyclic ring and X is H or halogen. 
     
     
         13 . The compound of  claim 12 , wherein W is an optionally substituted phenyl. 
     
     
         14 . The compound of  claim 12 , wherein A is an optionally substituted morpholine, thiomorpholine, imidazole, pyrrolidine, pyrrolidin-2-one, piperazine, piperazin-2-one, pyridine, piperidine, or piperidin-2-one. 
     
     
         15 . The compound of  claim 14 , wherein A is an optionally substituted piperazine. 
     
     
         16 . The compound of  claim 12 , wherein U is NR 1 —(CR 1   2 ) n —NR 3 R 4 . 
     
     
         17 . The compound of  claim 16 , wherein NR 3 R 4  is morpholine, thiomorpholine, imidazole, pyrrolidine, piperazine, pyridine or piperidine. 
     
     
         18 . A pharmaceutical composition comprising the compound of  claim 1  and a pharmaceutically acceptable excipient. 
     
     
         19 . A compound having formula 2 
       
         
           
           
               
               
           
         
         and pharmaceutically acceptable salts, esters and prodrugs thereof; 
         wherein A is NR 1 R 2 ; 
         Z is S, NR 1  or CH 2 ; and 
         U is NR 1 R 2  or NR 1 —(CR 1   2 )—NR 3 R 4 ; 
         B is a 5-6 membered aryl or heteroaryl; 
         R 1  and R 2  together with N in NR 1 R 2 , and R 3  and R 4  together with N in NR 3 R 4  may independently form an optionally substituted 5-6 membered ring containing N, and optionally O or S; 
         R 1  and R 3  are independently H or a C 1-6  alkyl; and 
         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 a substituted or unsubstituted aryl, heteroaryl, carbocyclic, or heterocyclic ring; or R 2  is an optionally substituted cycloalkyl, heterocyclic ring, aryl or heteroaryl; 
         R 5  is a substituent at any position of W and is H, halo, cyano, azido, —CONHR 1 , OR 2 , or C 1-6  alkyl or C 2-6  alkenyl, each optionally substituted by halo, ═O or one or more heteroatoms; 
         wherein each optionally substituted moiety is substituted with one or more halo, cyano, azido, acetyl, amido, 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 selected from N, O and S; or is substituted with an aryl, a carbocyclic or a heterocyclic ring. 
       
     
     
         20 . The compound of  claim 19 , wherein R 5  is halo. 
     
     
         21 . The compound of  claim 19 , wherein B is phenyl. 
     
     
         22 . The compound of  claim 19 , wherein NR 1 R 2  and NR 3 R 4  are independently an optionally substituted morpholine, thiomorpholine, imidazole, pyrrolidine, piperazine, pyridine or piperidine. 
     
     
         23 . A pharmaceutical composition comprising the compound of  claim 19  and a pharmaceutically acceptable excipient. 
     
     
         24 . A compound having formula 3 
       
         
           
           
               
               
           
         
         and pharmaceutically acceptable salts, esters and prodrugs thereof; 
         wherein A is H or F; 
         X is H, halo or NR 1 R 2 ; 
         Z is S, NR 1  or CH 2 ; 
         L is a C 1-10  alkyl optionally substituted with N, O or S; 
         B is 5-6 membered aryl or heteroaryl; 
         R 1  and R 3  are independently H or a C 1-6  alkyl; 
         R 2  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 substituted or unsubstituted aryl, heteroaryl, carbocyclic, or heterocyclic ring; or R 2  is an optionally substituted cycloalkyl, heterocyclic ring, aryl or heteroaryl; 
         R 5  is a substituent at any position of W and is H, halo, cyano, —CONHR 1 , OR 2 , or C 1-6  alkyl or C 2-6  alkenyl, each optionally substituted by halo, ═O or one or more heteroatoms; 
         wherein each optionally substituted moiety is substituted with one or more halo, cyano, azido, acetyl, amido, 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 selected from N, O and S; or is substituted with an aryl, a carbocyclic or a heterocyclic ring. 
       
     
     
         25 . The compound of  claim 24 , wherein L is a C 2-4  alkyl. 
     
     
         26 . The compound of  claim 24 , wherein X is NR 1 R 2 , and R 2  is an optionally substituted cyclopropyl, phenyl, or imidazole, or a C 1-6  alkyl optionally substituted with a cyclopropyl or OR 1 . 
     
     
         27 . The compound of  claim 24 , wherein each NR 1 R 2  and NR 3 R 4  are independently an optionally substituted morpholine, thiomorpholine, imidazole, pyrrolidine, piperazine, pyridine or piperidine. 
     
     
         28 . The compound of  claim 24 , wherein A is F and R 5  is halo, cyano, amido or azido. 
     
     
         29 . The compound of  claim 24 , wherein W is phenyl or pyridyl. 
     
     
         30 . A pharmaceutical composition comprising the compound of  claim 24  and a pharmaceutically acceptable excipient. 
     
     
         31 . A method for ameliorating a cell proliferative disorder, comprising administering to a subject in need thereof an effective amount of the compound of  claim 24  or a pharmaceutical composition thereof and optionally with a chemotherapeutic agent, thereby ameliorating said cell-proliferative disorder. 
     
     
         32 . The method of  claim 31 , wherein said cell proliferative disorder is a tumor or cancer. 
     
     
         33 . The method of  claim 31 , wherein said subject is human or an animal. 
     
     
         34 . A method for reducing cell proliferation or inducing cell death, comprising contacting a system with an effective amount of the compound of  claim 24  or a pharmaceutical composition thereof and optionally with a chemotherapeutic agent, thereby reducing cell proliferation or inducing cell death in said system. 
     
     
         35 . The method of  claim 34 , wherein said system is a cell or tissue. 
     
     
         36 . A method for reducing microbial titers or for ameliorating a microbial infection, comprising contacting a system or a subject with an effective amount of the compound of  claim 24  or a pharmaceutical composition thereof and optionally with an antimicrobial agent, thereby reducing microbial titers in said system or ameliorating said microbial infection in said subject. 
     
     
         37 . The method of  claim 36 , where the system is a cell or tissue, and said subject is animal or human. 
     
     
         38 . The method of  claim 36 , wherein the microbial titers or microbial infection are viral, bacterial or fungal. 
     
     
         39 . A method for inducing apoptosis, comprising administering to a system or a subject in need thereof an effective amount of a composition comprising a compound in  claim 24 , or a pharmaceutical composition thereof and optionally with a chemotherapeutic agent. 
     
     
         40 . The method of  claim 39 , wherein said subject is human or an animal, and said system is a cell or tissue. 
     
     
         41 . A method for treating or ameliorating a disorder mediated by c-Myc overexpression, comprising administering to a system or a subject in need thereof an effective amount of a compound in  claim 24 , or a pharmaceutical composition thereof and optionally with a chemotherapeutic agent. 
     
     
         42 . A method for determining interaction selectivity between a compound of  claim 1  and nucleic acids capable of forming a quadruplex structure, comprising:
 a) contacting a compound in the absence of a competitor molecule with three or more nucleic acids capable of forming a quadruplex structure, wherein each nucleic acid is not a telomere nucleic acid;   b) measuring a direct interaction between the compound and said three or more nucleic acids; and   c) determining interaction selectivity from a comparison of the interaction measurements.   
     
     
         43 . The method of  claim 42 , wherein said three or more nucleic acids comprise a nucleotide sequence located 5′ of an oncogene nucleotide sequence. 
     
     
         44 . The method of  claim 43 , wherein said oncogene is MYC, HIF, VEGF, ABL, TGF, PDGFα, MYB, SPARC, HER, VAV, RET, H-RAS, EGF, SRC, BCL-1, BCL-2, DHFR, or HMGA. 
     
     
         45 . The method of  claim 42 , wherein the compound is separately contacted with each of said three or more nucleic acids in a different vessel. 
     
     
         46 . The method of  claim 42 , wherein interaction selectivity is determined from a comparison of IC50 values. 
     
     
         47 . The method of  claim 42 , wherein the compound binds and/or stabilizes a propeller quadrupled a chair-eller quadruplex, or a basket quadruplex or BCL-2. 
     
     
         48 . The method of  claim 42 , wherein the compound binds and/or stabilizes BCL-2, H-RAS, RET, BCL-1, DHFR, TGF-β, HIF-1α, VEGF, c-Myc, or PDGFα.