Compounds and therapeutical use thereof

Abstract

Disclosed are 4-arylamino-quinazolines and analogs thereof 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 - 54 . (canceled). 
     
     
         55 . A compound according to Formula Vlb: 
       
         
           
           
               
               
           
         
         or pharmaceutically acceptable salts thereof, wherein: 
         R 1  is methyl or ethyl; 
         R 5  is H or F; 
         R 2  is 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, 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 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; and 
         R 3 , R 4 , and R 6 -R 11  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  al kyl-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 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; 
         provided that R 9  is not —O(C 1-6  alkyl)C(O)O(C 1-6  alkyl), and when R 9  is H then R 8  and R 10  are not both H or one H and the other halo. 
       
     
     
         56 . The compound of  claim 55 , wherein when R 9  is H then at least one of R 8  and R 10  is not H or halo or C 1-6  alkyl. 
     
     
         57 . The compound of  claim 55 , wherein R 9  is selected from the group consisting of H, Cl, N 3 ,
 C 1-6  alkyl optionally substituted with 1, 2 or 3 substituents, each substituent being independently OH, halo, C 1-3  alkoxy, (halo)C 1-3  alkoxy, —N(R a )(R b ) where R a  and R b  are independently H, OH (R a  and R b  are not both OH), C 2-4  hydroxyalkyl, or C 1-3  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;   —XR c  wherein X is S or O and R c  is C 1-6  alkyl optionally substituted with 1, 2 or 3 substituents, each substituent being independently OH, halo, C 1-3  alkoxy, or (halo)C 1-3  alkoxy;   —(C 0-3  alkyl)CO 2 R d  where R d  is C 1-6  alkyl;   —N(R a )(R b ) where R a  and R b  are independently H, OH (R a  and R b  are not both OH), C 2-4  hydroxyalkyl, C 1-3  alkyl, or —N(R e )(R f ) where R e  and R f  are independently H, OH (R c  and R f  are not both OH), or C 1-3  alkyl; wherein optionally 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, and optionally le and R f  together with the nitrogen atom to which they both are linked form a 3, 4, 5 or 6-membered heterocycle; and   —(Co -3  alkyl)C(O)N(R a )(R b ) where R a  and R b  are independently H or C 1-3  alkyl; and optionally R 9  and one of R 8  and R 10  together form a 3, 4, 5, or 6-membered heterocycle.   
     
     
         58 . The compound of  claim 55 , wherein R 9  is H; OH; Cl; N 3 ; C 1-3  alkyl; C 1-3  haloalkyl; —OR 9a  where R 9a  is C 1-4  alkyl or C 1-3  haloalkyl; —NH(R a ) or —N(R a )(R b ) where R a  and R b  are independently C 1-3  alkyl; or —COOR 9b  where R 9b  is C 1-3  alkyl; and optionally R 9  and one of R 8  and R 10  together form a 3, 4, 5, or 6-membered heterocycle. 
     
     
         59 . The compound of  claim 55 , wherein when R 9  is H, then R 8  or R 10  or both are independently OH; N 3 ; —XR 9a , where X is O or S and R 9a  is C 1-4  alkyl or C 1-3  haloalkyl; —NH(R a ) or —N(R a )(R b ) where R a  and R b  are independently C 1-3  alkyl; or —COOR 9b  wherein R 9b  is C 1-3  alkyl. 
     
     
         60 . The compound of  claim 55 , wherein when R 9  is H, then R 8  or R 10  or both are independently N 3 ; —OR 9a  where R 9a  is C 1-4  alkyl or C 1-3  haloalkyl; —N(R a )(R b ) where R a  and R b  are independently C 1-3  alkyl; or —COOR 9b  where R 9b  is C 1-3  alkyl. 
     
     
         61 . The compound of  claim 55 , wherein when R 8  is H, then R 8  or R 10  or both are C 1-3  alkoxy or C 1-3  halo alkoxy. 
     
     
         62 . The compound of  claim 55 , wherein R 9  is N 3 ; —OR 9a , wherein R 9a  is C 1-3  alkyl optionally substituted with 1-7 F; —N(R a )(R b ) where R a  and R b  are independently C 1-3  alkyl; or —COOR 9b  where R 9b  is C 1-3  alkyl. 
     
     
         63 . The compound of  claim 55 , wherein R 1  is CH 3 ; R 2  is methyl, ethyl, Cl, F, fluoromethyl, CH 2 OH, NH 2 , NHCH 3 , N(CH 3 ) 2 , —NHCH 2 CH 2 OH, OCH 3 , or SCH 3 ; R 3  is H, CH 3 , OCH 3 , F, or Cl; R 4  and R 6  are independently H, CH 3 , NH 2 , F, or Cl; R 5  is H; R 7  and R 11  are independently H, F, or OCH 3 ; R 8  and R 10  are independently H, F, Cl, or OCH 3 ; and R 9  is selected from the group consisting of —OR 12  where R 12  is methyl, ethyl, fluoromethyl or fluoroethyl, —NHCH 3 , N(CH 3 ) 2 , N 3 , and —COOR D  where R 13  is methyl or ethyl. 
     
     
         64 . A compound according to Formula VIb: 
       
         
           
           
               
               
           
         
         or pharmaceutically acceptable salts thereof, wherein: 
         R 1  is methyl or ethyl; 
         R 5  is H or F; 
         R 2 -R 4 , R 6 -R 11  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, 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 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; 
         provided that R 9  is H; OH; Cl; N 3 ; C 1-3  alkyl; C 1-3  haloalkyl; —OR 9a  where R 9a  is C 1-4  alkyl or C 1-3  haloalkyl; —NH(R a ) or —N(R a )(R b ) where R a  and R b  are independently C 1-3  alkyl; or —COOR 9b  where R 9b  is C 1-3  alkyl; and optionally R 9  and one of R 8  and R 10  together form a 3, 4, 5, or 6-membered heterocycle; and 
         provided that when R 9  is H then R 8  and R 10  are not both H or one H and the other halo. 
       
     
     
         65 . The compound of  claim 64 , wherein:
 R 2  is H; halo; N 3 , C 1-6  alkyl optionally substituted with 1-4 substituents which are independently OH or halo; —XR 2a  where X is S or O, and R 2a  is C 1-6  alkyl optionally substituted with OH or halo; —CO 2 —R 2f , where R 2f  is C 1-6 ; or —N(R 2b )(R 2c ) where R 2b  and R 2c  are independently H, OH, C 1-6  alkyl, C 1-6  hydroxyalkyl, or C 1-6  alkyl that is optionally substituted with —N(R 2a )(R 2e ) where R 2d  and R 2e  are independently H, OH, C 1-3  alkyl, or C 2-3  hydroxyalkyl, and wherein R 2b  and R 2c  together with the nitrogen atom to which they are both linked may form a 3, 4, 5 or 6-membered heterocycle, and wherein R 2b  and R 2c  are not both OH, R 2d  and R 2e  are not both OH;   R 3  is H; halo; C 1-3  alkyl; or C 1-3  alkoxy;   R 4  and R 6  are independently H; halo; N 3  C 1-3  alkyl; C 1-3  alkoxy; or —N(R 2b )(R 2c ) wherein R 2b  and R 2c  are independently H, OH, CH3, and optionally R 2b  and R 2c  together may form a 3, 4, 5 or 6-membered heterocycle, and where R 2b  and R 2c  are not both OH;   R 5  is H;   R 7  and R 11  are independently H, halo, CH 3 , or OCH 3 ;   R 8  and R 10  are independently H; halo; C 1-3  alkyl; C 1-3  alkoxy; —XR 9a , where X is O or S, and R 9 a is C 1-4  alkyl or C 1-3  haloalkyl; —N(R a )(R b ) where R a  and R b  are independently C 1-3  alkyl; or —COOR 9b , wherein R 9b  is C 1-3  alkyl; and   R 9  is selected from the group consisting of H; hydroxy; Cl; N 3 ; C 1-3  alkyl or C 1-3  haloalkyl; —OR 9a , wherein R 12  is C 1-3  alkyl or C 1-3  haloalkyl; —N(R 2b )(R 2c ) where R 2b  and R 2c  are independently H, C 1-3  alkyl, or C 1-3  haloalkyl; or —COOR 9b , wherein R 9b  is C 1-3  alkyl; and optionally R 9  and one of R g  and R 10  together form a 3, 4, 5, or 6-membered heterocycle.   
     
     
         66 . The compound of  claim 64 , wherein:
 R 2  is H; halo; N 3 , C 1-6  alkyl optionally substituted with 1-4 substituents that are OH or halo; —XR 2a  where X is S or O, and R 2a  is C 1-6  alkyl optionally substituted with OH or halo; or —N(R 2b )(R 2c ) where R 2b  and R 2c  are independently H, OH, C 1-6  alkyl, C 1-6  hydroxyalkyl, or R 2b  and R 2c  together with the nitrogen atom to which they are both linked form a 3, 4, 5 or 6-membered heterocycle;   R 3  is H; halo; C 1-3  alkyl; or C 1-3  alkoxy;   R 4  and R 6  are independently H; halo; N 3 , C 1-3  alkyl; C 1-3  alkoxy; or —N(R 2b )(R 2c ) wherein R 2b  and R 2c  are independently H, OH (R 2b  and R 2c  are not both OH), CH 3 , or R 2b  and R 2c  together form a 3, 4, 5 or 6-membered heterocycle;   R 5  is H;   R 7 , R 8 , R 10  and R 11  are independently H, halo, C 1-3  alkyl, C 1-3  alkoxy, or C 1-3  alkylthiol;   R 9  is selected from the group consisting of H; OH; Cl; N 3 ; C 1-3  alkyl; C 1-3  haloalkyl; —OR 9a  where R 9a  is C 1-3  alkyl or C 1-3  haloalkyl; N(R 2b )(R 2c ) where R 2b  and R 2c  are independently C 1-3  alkyl; or —COOR 9b  where R 9b  is C 1-3  alkyl; and optionally R 9  and one of R 8  and R 10  together form a 3, 4, 5, or 6-membered heterocycle.   
     
     
         67 . The compound of  claim 64 , wherein R 1  is methyl or ethyl; R 2  is H, methyl, ethyl, Cl, F, fluoromethyl, C 1-3  hydroxyalkyl, NH 2 , NH 2 OH, NHCH 2 CH 2 OH, NHCH 3 , N(CH 3 ) 2 , N 3 , morpholino, OCH 3 , OC 2 H 5 , or SCH 3 ; R 3  is H, CH 3 , OCH 3 , F, or Cl; R 4  and R 6  are independently H, CH 3 , NH 2 , N 3 , F, or Cl; R 5  is H; R 7  and R 11  are independently H, F, or OCH 3 ; R g  and R 10  are independently H, F, Cl, or OCH 3 ; and R 9  is selected from the group consisting of H, OH, N 3 , Cl, C 1-3  alkyl, C 1-3  haloalkyl, or —OR 9a  where R 9a  is C 1-3  alkyl or C 1-3  haloalkyl, —N(R 2b )(R 2c ) wherein R 2b  and R 2c  are independently C 1-3  alkyl, or —COOR 9b  where R 9b  is C 1-3  alkyl, and optionally R 8  and R 9  together form a 3, 4, 5, or 6-membered heterocycle; provided that when R 9  is H, at least one of R 8  and R 10  is OCH 3 , and when R 9  is C 1-3  alkyl or C 1-3  haloalkyl or Cl, R 2  is Cl or methyl or ethyl. 
     
     
         68 . The compound of  claim 64 , wherein R 2  is H; halo; N 3 , C 1-6  alkyl optionally substituted with OH or halo; —XR 2a  wherein X is S or O, and R 2a  is C 1-6  alkyl optionally substituted with OH or halo; —CO 2 R d  wherein R d  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 1-6  alkyl, C 1-6  hydroxyalkyl, or C 1-6  alkyl that is optionally substituted with —N(R e )(R f ) wherein R e  and R f  are independently H, OH (R e  and R f  are not both OH), C 1-3  alkyl, or C 2-3  hydroxyalkyl, and wherein optionally R a  and R b  together with the nitrogen atom to which they are both linked may form a 3, 4, 5 or 6-membered heterocycle. 
     
     
         69 . The compound of  claim 64 , wherein R 2  is H; halo; C 1-3  alkyl optionally substituted with OH or halo; —XR 2a  wherein X is S or O and R 2a  is C 1-3  alkyl optionally substituted with halo; 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 1-3  alkyl, C 2-3  hydroxyalkyl. 
     
     
         70 . The compound of  claim 64 , wherein R 1  is CH 3 ; R 2  is H, methyl, ethyl, Cl, F, fluoromethyl, CH 2 OH, NH 2 , NHCH 3 , N(CH 3 ) 2 , —NHCH 2 CH 2 OH, OCH 3 , or SCH 3 ; R 3  is H, CH 3 , OCH3, F, or Cl; R 4  and R 6  are independently H, CH 3 , NH 2 , F, or Cl; R 5  is H; R 7  and R 11  are independently H, F, or OCH 3 ; R 8  and R 10  are independently H, F, Cl, or OCH 3 ; and R 9  is selected from the group consisting of —OR 12  where R 12  is methyl, ethyl, fluoromethyl or fluoroethyl, —NHCH 3 , N(CH 3 ) 2 , N 3 , and —COOR D  where R 13  is methyl or ethyl. 
     
     
         71 . A pharmaceutical composition comprising a pharmaceutically acceptable carrier and an effective amount of a compound according to  claim 55 . 
     
     
         72 . A pharmaceutical composition comprising a pharmaceutically acceptable carrier and an effective amount of a compound according to  claim 64 . 
     
     
         73 . A method of treating cancer, comprising treating a patient in need thereof with a therapeutically-effective amount of a compound according to  claim 55 . 
     
     
         74 . A method of treating cancer, comprising treating a patient in need thereof with a therapeutically-effective amount of a compound according to  claim 64 .