Compounds and therapeutical uses thereof

Abstract

Disclosed are 4-arylamino-quinazolines and analogs thereof that are effective as activators of caspases and inducers of apoptosis. The compounds of this invention are useful in the treatment of a variety of clinical conditions in which uncontrolled growth and spread of abnormal cells occurs.

1 . A compound having a structure according to Formula IVb: 
       
         
           
           
               
               
           
         
         or pharmaceutically-acceptable salts thereof, wherein: 
         R 1  is methyl or ethyl; 
         R 2 -R 17  are independently H, halo, N 3 , OH, thiol, nitro, CN, NH 2 , C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, C 1-6  alkoxy, C 1-6  alkylthiol, halo-C 1-6  alkyl, C 2-6  alkenyl-O—, C 2-6  alkynyl-O—, hydroxy-C 1-6  alkyl, C 1-6  alkoxy-C 1-6  alkyl, C 1-6  acyl, C 1-6  acyloxy, —C 1-6  alkyl-C(O)O—C 1-6  alkyl, —C(O)O—C 1-6  alkyl, C 1-6  alkyl-C(O)O—C 1-6  alkyl-, C 1-6  acylamido, —N(R a )(R b ), —C 1-6  alkyl-C(O)N(R a )(R b ), —C(O)N(R a )(R b ), N(R a )(R b )—C 1-6  alkyl-, 3, 4, 5, or 6-membered carbocycle, heterocycle, aryl, or heteroaryl, wherein R a  and R b  are independently H, OH(R a  and R b  are not both OH), C 2-6  hydroxyalkyl, or C 1-6  alkyl, or R a  and R b  together with the nitrogen atom to which they are both linked form a 3, 4, 5 or 6-membered heterocycle (e.g., piperidinyl, pyrrolidinyl, and morpholinyl); wherein any of the groups is optionally substituted with 1-3 substituents wherein each substituent is independently halo, N 3 , OH, thiol, nitro, CN, C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, C 1-6  alkoxy, C 1-6  alkylthiol, C 2-6  alkenyl-O—, C 2-6  alkynyl-O—, hydroxy-C 1-6  alkyl, C 1-6  alkoxy-C 1-6  alkyl, C 1-6  acyl, C 1-6  acyloxy, —C 1-6  alkyl-C(O)O—C 1-6  alkyl, —C(O)O—C 1-6  alkyl, C 1-6  alkyl-C(O)O—C 1-6  alkyl-, C 1-6  acylamido, —N(R a )(R b ), —C 1-6  alkyl-C(O)N(R a )(R b ), —C(O)N(R a )(R b ), N(R a )(R b )—C 1-6  alkyl-, wherein R a  and R b  are independently H, OH(R a  and R b  are not both OH), C 2-6  hydroxyalkyl, or C 1-6  alkyl or R a  and R b  together with the nitrogen atom to which they are both linked form a 3, 4, 5 or 6-membered heterocycle, wherein optionally any two adjacent R 7 -R 11  groups together form a 3, 4, 5 or 6-membered carbocycle or heterocycle; and 
         B and D are independently C or N, provided that at least one of B and D is N,
 and when B or D is N then there is no substituent at the N; 
 
         with the proviso that said compound is not 2-amino-4-(N-ethylanilino)-5,6,7,8-tetrahydro-quinazoline. 
       
     
     
         2 . The compound of  claim 1 , wherein both B and D are Nitrogen. 
     
     
         3 . The compound of  claim 1 , wherein when R 1  is ethyl then at least one of R 8 , R 9 , and R 10  is not H. 
     
     
         4 . The compound of  claim 1 , wherein when R 1  is ethyl then R 9  is not H. 
     
     
         5 . The compound of  claim 1 , wherein:
 R 1  is methyl or ethyl;   R 3 -R 6 , R 12 -R 17  are as defined above;   R 2  is a member of the group consisting of H, halo, N 3 , C 1-4  alkoxy, C 1-4  alkylthiol,
 hydroxyC 1-4  alkyl, C 1-4  alkyl, and —N(R a )(R b ) wherein R a  and R b  are independently H, OH (R a  and R b  are not both OH), C 2-4  hydroxyalkyl, or C 1-4  alkyl or R a  and R b  together with the nitrogen atom to which they are both linked form a 3, 4, 5 or 6-membered heterocycle; each of the member being optionally substituted by 1-4 substituents wherein each substituent is independently halo, OH, or C 1-4  alkyl; 
   R 7  and R 11  are independently H, halo (preferably F), CH 3 , or OCH 3 ;   R 8  and R 10  are independently H, halo (preferably F or Cl), C 1-3  alkyl (preferably CH 3 ) optionally substituted with halo (preferably 1-3 F), C 1-3  alkoxy (preferably OCH 3 ), or C 1-3  alkylthiol (preferably —S—CH 3 );   R 9  is OH, C 1 , N 3 , C 1-4  alkoxy, C 1-4  alkylthiol, hydroxyC 1-4  alkyl, C 1-4  alkyl,
 —COOR c  wherein R c  is C 1-3  alkyl, or —N(R a )(R b ) wherein R a  and R b  are independently H, OH (R a  and R b  are not both OH), C 2-4  hydroxyalkyl, or C 1-4  alkyl or R a  and R b  together with the nitrogen atom to which they are both linked form a 3, 4, 5 or 6-membered heterocycle; each of the member being optionally substituted by 1-4 substituents wherein each substituent is independently halo, OH, or C 1-4  alkyl; and optionally two adjacent R 8 , R 9 , and R 10  groups may together form a 3, 4, 5, or 6-membered carbocycle, heterocycle, preferably heterocyle; and 
   B and D are independently C or N, and at least one of B and D is N.   
     
     
         6 . The compound of  claim 1 , wherein
 R 9  is selected from:
 —OR 9a , wherein R 9a  is methyl, ethyl, fluoromethyl, fluoroethyl; —N 3 ; —N(CH 3 ) 2 ; —NHCH 3 ; and —COOR 9b , wherein R 9b  is H or C 1-2  alkyl. 
   
     
     
         7 . A compound of  claim 1 , wherein the compound is:
 (2-Chloro-5,6,7,8-tetrahydro-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine;   (4-Methoxy-phenyl)-methyl-(2-methyl-5,6,7,8-tetrahydro-quinazolin-4-yl)-amine;   N-{4-[(4-Methoxy-phenyl)-methyl-amino]-5,6,7,8-tetrahydro-quinazolin-2-yl}-O-methyl-hydroxylamine;   {4-[(4-Methoxy-phenyl)-methyl-amino]-5,6,7,8-tetrahydro-quinazolin-2-ylamino}-acetic acid ethyl ester;   N 4 -(4-Methoxy-phenyl)-N 2 ,N 4 -dimethyl-5,6,7,8-tetrahydro-quinazoline-2,4-diamine;   2-{4-[(4-Methoxy-phenyl)-methyl-amino]-5,6,7,8-tetrahydro-quinazolin-2-ylamino}-ethanol; or   (5,6,7,8-Tetrahydro-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine.   
     
     
         8 . A compound having a structure according to: 
       
         
           
           
               
               
           
         
         and pharmaceutically-acceptable salts thereof, wherein: 
         R 1  is methyl or ethyl; 
         R 2 -R 5  and R 7 -R 16  are independently H, halo, N 3 , OH, thiol, nitro, CN, NH 2 , C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, C 1-6  alkoxy, C 1-6  alkylthiol, halo-C 1-6  alkyl, C 2-6  alkenyl-O—, C 2-6  alkynyl-O—, hydroxy-C 1-6  alkyl, C 1-6  alkoxy-C 1-6  alkyl, C 1-6  acyl, C 1-6  acyloxy, —C 1-6  alkyl-C(O)O—C 1-6  alkyl, —C(O)O—C 1-6  alkyl, C 1-6  alkyl-C(O)O—C 1-6  alkyl-, C 1-6  acylamido, —N(R a )(R b ), —C 1-6  alkyl-C(O)N(R a )(R b ), —C(O)N(R a )(R b ), N(R a )(R b )—C 1-6  alkyl-, 3, 4, 5, or 6-membered carbocycle, heterocycle, aryl, or heteroaryl, wherein R a  and R b  are independently H, OH(R a  and R b  are not both OH), C 2-6  hydroxyalkyl, or C 1-6  alkyl, or R a  and R b  together with the nitrogen atom to which they are both linked form a 3, 4, 5 or 6-membered heterocycle; wherein any of the groups is optionally substituted with 1-3 substituents wherein each substituent is independently halo, N 3 , OH, thiol, nitro, CN, C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, C 1-6  alkoxy, C 1-6  alkylthiol, C 2-6  alkenyl-O—C 2-6  alkynyl-O—, hydroxy-C 1-6  alkyl, C 1-6  alkoxy-C 1-6  alkyl, C 1-6  acyl, C 1-6  acyloxy, —C 1-6  alkyl-C(O)O—C 1-6  alkyl, —C(O)O—C 1-6  alkyl, C 1-6  alkyl-C(O)O—C 1-6  alkyl-, C 1-6  acylamido, —N(R a )(R b ), —C 1-6  alkyl-C(O)N(R a )(R b ), —C(O)N(R a )(R b ), N(R a )(R b )—C 1-6  alkyl-, wherein R a  and R b  are independently H, OH(R a  and R b  are not both OH), C 2-6  hydroxyalkyl, or C 1-6  alkyl or R a  and R b  together with the nitrogen atom to which they are both linked form a 3, 4, 5 or 6-membered heterocycle, wherein optionally any two adjacent R 7 -R 11  groups together form a 3, 4, 5 or 6-membered carbocycle or heterocycle; 
         the bonds between Q, T, and U are single, double, or aromatic bonds, provided that both bonds are not double bonds; 
         T is C; 
         Q and U are independently C, N, or S, provided that when Q or U is S, then there are no substituents on the S and the bond with T is a single or aromatic bond, and provided that when Q or U is N and the bond with T is an aromatic bond or double bond, then there are no substituents on the N, and provided that when Q or U is N and the bond with T is a single bond, then there is one substituent on the N; and 
         B and D are independently C or N, provided that at least one of B and D is N, and when B or D is N then there is no substituent on the N. 
       
     
     
         9 . The compound of  claim 8 , wherein both B and D are Nitrogen. 
     
     
         10 . The compound of  claim 8 , wherein at least one of R 8 , R 9 , and R 10  is not H. 
     
     
         11 . The compound of  claim 8 , wherein R 9  is not H. 
     
     
         12 . The compound of  claim 8 , wherein when R 9  is H and R 8  or R 10  or both are independently selected from the group OH; N 3 ; amido; N-dimethylamido; —XR 8a  wherein X is S or O and R 8a  is C 1-6  alkyl optionally substituted with OH or halo; C 1-3  alkyl optionally substituted with halo; —N(R a )(R b ) wherein R a  and R b  are independently H, OH(R a  and R b  are not both OH), or C 1-6  alkyl optionally substituted with OH or halo, and wherein optionally R a  and R b  may together form a 3-6 membered heterocycle; and —C(O)OR c  wherein R c  is C 1-6  alkyl. 
     
     
         13 . The compound of  claim 8 , wherein:
 R 1  is methyl or ethyl;   R 3 -R 5 , R 12 -R 16  are as defined above;   R 2  is a member of the group consisting of H, halo, N 3 , C 1-4  alkoxy, C 1-4  alkylthiol,
 hydroxyC 1-4  alkyl, C 1-4  alkyl, and —N(R a )(R b ) wherein R a  and R b  are independently H, OH (R a  and R b  are not both OH), C 2-4  hydroxyalkyl, or C 1-4  alkyl or R a  and R b  together with the nitrogen atom to which they are both linked form a 3, 4, 5 or 6-membered heterocycle; 
   wherein each R 2  substituent is optionally substituted by 1-4 substituents wherein each substituent is independently halo, OH, or C 1-4  alkyl;   R 7  and R 11  are independently H, halo (preferably F), CH 3 , or OCH 3 ;   R 8  and R 10  are independently H, halo (preferably F or Cl), C 1-3  alkyl (preferably CH 3 ) optionally substituted with halo (preferably 1-3 F), C 1-3  alkoxy (preferably OCH 3 ), or C 1-3  alkylthiol (preferably —S—CH 3 );   R 9  is OH, C 1 , N 3 , C 1-4  alkoxy, C 1-4  alkylthiol, hydroxyC 1-4  alkyl, C 1-4  alkyl, —COOR c  wherein R c  is C 1-3  alkyl, or —N(R a )(R b ) wherein R a  and R b  are independently H, OH (R a  and R b  are not both OH), C 2-4  hydroxyalkyl, or C 1-4  alkyl or R a  and R b  together with the nitrogen atom to which they are both linked form a 3, 4, 5 or 6-membered heterocycle; each of the member being optionally substituted by 1-4 substituents wherein each substituent is independently halo, OH, or C 1-4  alkyl; and optionally two adjacent R 8 , R 9 , and R 10  groups may together form a 3, 4, 5, or 6-membered carbocycle, heterocycle, preferably heterocyle; and   B and D are independently C or N, and at least one of B and D is N.   
     
     
         14 . The compound of  claim 8 , wherein
 R 9  is selected from the group:
 —OR 9a , wherein R 9a  is methyl, ethyl, fluoromethyl, fluoroethyl; —N 3 ; —N(CH 3 ) 2 ; —NHCH 3 ; and —COOR 9b , wherein R 9b  is H or C 1-2  alkyl. 
   
     
     
         15 . The compound of  claim 8 , wherein
 R 2  is selected from the group:
 H, halo, N 3 , C 1-4  alkoxy, C 1-4  alkylthiol, hydroxyC 1-4  alkyl, C 1-4  alkyl, and —N(R a )(R b ) wherein R a  and R b  are independently H, OH(R a  and R b  are not both OH), C 2-4  hydroxyalkyl, C 1-4  alkoxy, —C 1-4  alkyl-C(O)O—C 1-4  alkyl, or C 1-4  alkyl. 
   
     
     
         16 . The compound of  claim 8 , wherein the compound has the structure: 
       
         
           
           
               
               
           
         
       
     
     
         17 . The compound of  claim 16 , wherein
 R 9  is selected from the group:
 —OR 9a , wherein R 9a  is methyl, ethyl, fluoromethyl, fluoroethyl; —N 3 ; —N(CH 3 ) 2 ; —NHCH 3 ; and —COOR 9b , wherein R 9b  is H or C 1-2  alkyl. 
   
     
     
         18 . The compound of  claim 16 , wherein
 R 2  is selected from the group:
 H, halo, N 3 , C 1-4  alkoxy, C 1-4  alkylthiol, hydroxyC 1-4  alkyl, C 1-4  alkyl, and —N(R a )(R b ) wherein R a  and R b  are independently H, OH(R a  and R b  are not both OH), C 2-4  hydroxyalkyl, C 1-4  alkoxy, —C 1-4  alkyl-C(O)O—C 1-4  alkyl, or C 1-4  alkyl. 
   
     
     
         19 . The compound of  claim 8 , wherein the compound is:
 N-{4-[(4-M ethoxy-phenyl)-methyl-amino]-6,7-dihydro-5H-cyclopentapyrimidin-2-yl}-O-methyl-hydroxylamine;   N 4 -(4-Methoxy-phenyl)-N 2 ,N 4 -dimethyl-6,7-dihydro-5H-cyclopentapyrimidine-2,4-diamine;   {4-[(4-Methoxy-phenyl)-methyl-amino]-6,7-dihydro-5H-cyclopentapyrimidin-2-ylamino}-acetic acid ethyl ester;   (4-Methoxy-phenyl)-methyl-(2-methyl-thieno[2,3-d]pyrimidin-4-yl)-amine;   (4-Methoxy-phenyl)-methyl-(2-methyl-thieno[3,2-d]pyrimidin-4-yl)-amine;   N 6 -(4-Methoxy-phenyl)-N 6 -methyl-9H-purine-2,6-diamine; or   (2-Chloro-9H-purin-6-yl)-(4-methoxy-phenyl)-methyl-amine.   
     
     
         20 . A method of inhibiting tubulin, inhibiting topoisomerase II, activating caspase, and/or inducing apoptosis in a mammal, said method comprising administering to said mammal an effective amount of a compound according to Formula I: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein: 
         Ar is aryl or heteroaryl; each of which is optionally substituted by one or more substituents wherein each substituent is independently halo, hydroxy, hydroxy-C 1-6  alkyl-, C 1-6  alkyl-C(O)O—, amino, nitro, cyano, C 1-6  alkyl, C 2-4  alkenyl, C 2-4  alkynyl, C 1-6  acylamino, C 1-6  acyloxy, C 1-6  alkoxy, or C 1-6  alkylthiol; 
         R 1  is C 1-6  alkyl; 
         A is an aromatic, heteroaromatic, heterocyclic, or carbocyclic ring; each of which is optionally substituted by one or more substituents wherein each substituent is as defined for Ar; 
         R 2  is H, halo, nitro, cyano, azido, hydroxy, thiol, or a member of the group consisting of: amino, alkoxy, C 1-6  alkyl, halo-C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, hydroxyalkyl, amino-C 1-6  alkyl, carboxy-C 1-6  alkyl, nitro, cyano, acylamido, acyloxy, carboxy, carbonylamido, alkylthiol; each of which is optionally substituted by one or more substituents wherein each substituent is as defined for Ar; 
         L is (CR 11 R 12 ) n  or NR 11 CO wherein R 11  and R 12  independently are hydrogen or alkyl optionally substituted by R 1a , R 1b , or R 1c ; wherein R 1a , R 1b , and R 1c  are as defined for Ar; 
         n is 0, 1 or 2; 
         B and D are independently nitrogen or CR 13 , wherein R 13  is hydrogen, halo, nitro, cyano, azido, hydroxy, thiol, or a member of the group consisting of amino, alkoxy, C 1-6  alkyl, halo-C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, hydroxyalkyl, amino-C 1-6  alkyl, carboxy-C 1-6  alkyl, nitro, cyano, acylamido, acyloxy, carboxy, carbonylamido, alkylthiol; each of which is optionally substituted by one or more substituents wherein each substituent is as defined for Ar; and 
         with the proviso that at least one of B and D is nitrogen.