Carbazole compounds and therapeutic uses of the compounds

Abstract

Compounds of the general structural formula (I) and (II) and use of the compounds and salts and hydrates thereof, as therapeutic agents are disclosed. Treatable diseases and conditions include cancers, inflammatory diseases and conditions, and immunodeficiency diseases. (I), (II).

1 . A compound having a structural formula: 
       
         
           
           
               
               
           
         
         wherein R a  is selected from the group consisting of hydrogen, C 1-6  alkyl, C 1-6  haloalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, OR e , N(R e ) 2 , and SR e ; alternatively, either R a  and R 1  or NR e  and R 1  together with the carbon atoms to which they are attached form a five or six-membered aliphatic carbocyclic or heterocyclic ring; 
         R b  is selected from the group consisting of hydrogen, C 1-6  alkyl, C 1-6  haloalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, OR e , N(Re) 2 , and SR e , alternatively, either R b  and R 6  or NR e  and R 6  together with the carbon atoms to which they are attached form a five or six-membered aliphatic carbocyclic ring or a five or six-membered aliphatic carbocyclic or heterocyclic ring; 
         R c  is selected from the group consisting of hydrogen, C 1-6  alkyl, C 1-6 hydroxyalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, and C(═O)R e , or R c  and R d  are taken together to form a five, six, or seven-membered aliphatic ring, optionally containing an oxygen atom; 
         R d  is selected from the group consisting of hydrogen, C 1-6  alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, and C(═O)R e , or R d  and R 7  together with the atoms to which they are attached form a five or six-membered aliphatic ring; 
         R e , independently, is selected from the group consisting of hydrogen, C 1-6  alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, or two R e  groups taken together with a nitrogen to which they are attached to form a five or six-membered aliphatic ring; 
         R 1 , R 2 , R 3 , R 4 , R 5 , and R 6 , independently, are selected from the group consisting of hydrogen, C 1-6  alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, halo, OR e , C(═O)R e , C(═O)OR e , OC(═O)R e , C(═O)N(R e ) 2 , C(═O)NR e SO 2 R e , N(R e ) 2 , NR e C(═O)R e , 
         R e C(═O)N(R e ) 2 , CN, NO 2 , CF 3 , OCF 3 , SR e , SOR e , SO 2 R e , SO 2 N(R e ) 2 , and OSO 2 CF 3 ; 
         R 7  is selected from the group consisting of hydrogen, C 1-6  alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl; and 
         n is 0, 1, 2, 3, 4, or 5, 
         or a pharmaceutically acceptable salt or hydrate thereof. 
       
     
     
         2 . The compound of  claim 1  wherein the compound has a general structural formula (Ia): 
       
         
           
           
               
               
           
         
         wherein R a  is C 1-3  alkyl, C 1-4  haloalkyl, C 3-5  cycloalkyl, N(R e ) 2 , or OR e , or R a  and R 1  together with the carbon atoms to which they are attached form a five or six-membered aliphatic carbocyclic ring; 
         R b  is C 1-4  alkyl, C 1-4  haloalkyl, C 3-5  cycloalkyl, N(R e ) 2 , or OR e , or R b  and R 6  together with the carbon atoms to which they are attached form a five or six-membered aliphatic carbocyclic ring or a five or six-membered aliphatic ring containing one nitrogen atom; 
         R c  is C 1-6  alkyl, C 3-5 cycloalky, or C 1-3 hydroxyalkyl; 
         R d  is hydrogen, C 1-4  alkyl, or C 3-5  cycloalkyl, or R d  and R 7  together with the atoms to which they are attached form a five or six-membered aliphatic ring containing one nitrogen atom, or R c  and R d  are taken together to form a six- or seven-membered aliphatic ring, optionally containing an oxygen atom; 
         R e , independently, is hydrogen or C 1-3  alkyl; 
         R 1  is hydrogen or C 1-3  alkyl; 
         R 2  is hydrogen, hydroxy, or C 1-3  alkoxy; 
         R 3  and R 4 , independently, are hydrogen or C 1-3  alkyl; 
         R 5  is hydrogen, hydroxy, C 1-3 alkoxy, or halo; 
         R 6  is hydrogen, C 1-3 alkyl, C 1-3 alkoxy, or halo; 
         R 7  is hydrogen or C 1-3  alkyl; and 
         n is 0, 1, 2, 3, 4, or 5, 
         or a pharmaceutically acceptable salt or hydrate thereof. 
       
     
     
         3 . The compound of  claim 1  wherein the compound has a general structural formula (Ib): 
       
         
           
           
               
               
           
         
         wherein R a  is methyl, ethyl, n-propyl, cyclopropyl, NH(CH 3 ), or OCH 3 , or R a  and R 1  together with the carbon atoms to which they are attached form a five-membered aliphatic carbocyclic ring; 
         R b  is methyl, ethyl, n-propyl, cyclopropyl, NH(CH 3 ), or OCH 3 , or R b  and R 6  together with the carbon atoms to which they are attached form a five-membered aliphatic carbocyclic ring or a five-membered aliphatic ring containing one nitrogen atom; 
         R c  is methyl, ethyl, n-propyl, isopropyl, cyclobutyl, or 2-hydroxyethyl; 
         R d  is hydrogen, methyl, ethyl, or cyclobutyl, or R d  and R 7  together with the atoms to which they are attached form a five-membered aliphatic ring containing one nitrogen atom; or R c  and R d  are taken together to form a morpholino moiety; a tetrahydrofuryl moiety; a piperidinyl moiety; a 
       
       
         
           
           
               
               
           
         
       
       moiety, or a 
       
         
           
           
               
               
           
         
       
       moiety;
 R 1  is hydrogen; 
 R 2  is hydrogen, hydroxy, or methoxy; 
 R 3  and R 4  are hydrogen; 
 R 5  is hydrogen, hydroxy, methoxy, or fluoro; 
 R 6  is hydrogen, methyl, methoxy or fluoro; 
 R 7  is hydrogen; and 
 n is 1 or 2, 
 or a pharmaceutically acceptable salt or hydrate thereof. 
 
     
     
         4 . A compound having a structural formula: 
       
         
           
           
               
               
           
         
         wherein R 1  is selected from the group consisting of hydrogen, C 1-6  alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, and C(═O)R h , or R f  and R g  are taken together to form a five, six, or seven-membered aliphatic ring optionally containing an oxygen atom; 
         R 8  is selected from the group consisting of hydrogen, C 1-6  alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, and C(═O)R h , or R g  and R 8  together with the atoms to which they are attached form a five or six-membered aliphatic ring; 
         R h , independently, is selected from the group consisting of hydrogen, C 1-6  alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, or two R h  groups taken together with a nitrogen to which they are attached to form a five or six-membered aliphatic ring; 
         R 8  is selected from the group consisting of hydrogen, C  1-6  alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl; 
         R 9 , R 10 , R 11 , R 12 , R 13 , and R 14 , independently, are selected from the group consisting of hydrogen, C 1-6  alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, halo, OR h , C(═O)R h , C(═O)OR h , OC(═O)R h , C(═O)N(R h ) 2 , C(═O)NR h SO 2 R h , N(R h ) 2 , NR e C(═O)R h , NR h C(═O)N(R h ) 2 , CN, NO 2 , CF 3 , OCF 3 , SR h , SOR h , SO 2 R h , SO 2 N(R h ) 2 , and OSO 2 CF 3 ; 
         p is 0, 1, 2, 3, 4, or 5, 
         with the proviso that when p is 2, one of R f  and R g  is different from ethyl, 
         or a pharmaceutically acceptable salt or hydrate thereof. 
       
     
     
         5 . The compound of  claim 4  wherein the compound has a general structural formula (IIa): 
       
         
           
           
               
               
           
         
         wherein R f  is C 1-6  alkyl; 
         R g  is hydrogen or C 1-4  alkyl, or R g  and R 8  together with the atoms to which they are attached form a five or six-membered aliphatic ring containing one nitrogen atom; 
         R 9  is hydrogen or C 1-3  alkyl; 
         R 10  is hydrogen, hydroxy, or C 1-3  alkoxy; 
         R 11  and R 12 , independently, are hydrogen or C 1-3  alkyl; 
         R 13  is hydrogen, hydroxy, C 1-3 alkoxy, or halo; 
         R 14  is hydrogen, C 1-3 alkyl, or C 1-3 alkoxy; 
         R 8  is hydrogen or C 1-3  alkyl; and 
         p is 0, 1, 2, 3, 4, or 5, 
         with the proviso that when p is 2, one of R f  and R g  is different from ethyl, 
         or a pharmaceutically acceptable salt or hydrate thereof. 
       
     
     
         6 . The compound of  claim 4  wherein the compound has a structural formula (IIb): 
       
         
           
           
               
               
           
         
         wherein R f  is methyl or ethyl; 
         R g  is hydrogen or methyl or R g  and R 8  together with the atoms to which they are attached form a five-membered aliphatic ring containing one nitrogen atom; 
         R 8  is hydrogen; and 
         p is 1 or 2, 
         or a pharmaceutically acceptable salt or hydrate thereof. 
       
     
     
         7 . The compound of  claim 1  wherein R a  is methyl, ethyl, NH(CH 3 ), OCH 3 , or forms a five-membered aliphatic ring with R 1 , R b  is methyl, ethyl, NH(CH 3 ), OCH 3 , forms a five-membered aliphatic ring with R 6 , or forms a five-membered, nitrogen containing, aliphatic ring with R 6 , and R d  is hydrogen, methyl, ethyl, or forms a five-membered aliphatic ring with R 7 . 
     
     
         8 . The compound of  claim 1  wherein R 1  is hydrogen or forms a five-membered aliphatic ring with R a , R 2  is hydrogen or hydroxy, R 3  is hydrogen, R 4  is hydrogen, R 5  is hydrogen or hydroxy, R 6  is hydrogen, forms a five-membered aliphatic ring with R b , or forms a five-membered, nitrogen-containing aliphatic ring with R b , R 7  is hydrogen or forms a five-membered ring with R d , and n is 2 or 3. 
     
     
         9 . The compound of  claim 4  wherein R f  is methyl or ethyl, R g  is hydrogen, methyl, ethyl, or forms a five-membered, nitrogen containing aliphatic ring with R f  and R 8 , or R 8  is hydrogen; R 9 , R 10 , R 11 , R 12 , R 13 , and R 14  are hydrogen, p is 2 or 3. 
     
     
         10 . A compound having a structure formula: 
       
         
           
           
               
               
           
         
       
     
     
         11 . The compound of  claim 1  or  4  having an EC 50  value for p53 activation of less than about 1.35 μM. 
     
     
         12 . A compound selected from the group disclosed in paragraph [0238] herein. 
     
     
         13 . A method of treating a cancer comprising administering a therapeutically effective amount of a compound of  claim 1 ,  4 , or  10 , or Compound 100, to an individual in need thereof. 
     
     
         14 . The method of  claim 13  wherein the cancer is selected from a cancer disclosed in paragraphs [0270], [0273], [0274], and [0275] herein. 
     
     
         15 . The method of  claim 13  wherein the compound of  claim 1 ,  4 , or  10 , or Compound 100, is administering in conjunction with a chemotherapeutic agent, radiation therapy, a microtubule affecting agent, a cytostatic agent, a TNF polypeptide, and mixtures thereof. 
     
     
         16 . A method of treating an inflammatory disease comprising administering a therapeutically effective amount of a compound of  claim 1 ,  4 , or  10 , or Compound 100, to an individual in need thereof. 
     
     
         17 . The method of  claim 16  wherein the inflammatory disease is selected from a disease disclosed in paragraph [0277] herein. 
     
     
         18 . The method of  claim 16  wherein the compound of  claim 1 ,  4 , or  10 , or Compound 100, is administered in conjunction with an immunosuppressive drug. 
     
     
         19 . A method of treating a microbial infection, a protozoan infection, or a viral infection comprising administering a therapeutically effective amount of a compound of  claim 1 ,  4 , or  10 , or Compound 100, to an individual in need thereof. 
     
     
         20 . The method of  claim 19  wherein the disease is malaria. 
     
     
         21 . A method of treating a disease or condition selected from the group consisting of the diseases and conditions disclosed in paragraph [0278] herein.