Alkynl and azido-substituted 4-anilinoquinazolines

Abstract

The invention relates to compounds of the formula and to pharmaceutically acceptable salts thereof, wherein R 1 , R 2 , R 3 , R 4 , n and m are as defined herein. The compounds of formula I are useful in the treatment of hyperproliferative diseases, such as cancer. The invention further relates to processes of making the compounds of formula I and to methods of using such compounds in the treatment of hyperproliferative diseases.

1. A compound of the formula 
                 
 
       or a pharmaceutically acceptable salt thereof wherein:
 m is 1, 2, or 3;  
 each R 1  is independently selected from the group consisting of hydrogen, halo, hydroxy, hydroxyamino, carboxy, nitro, guanidino, ureido, cyano, trifluoromethyl, and -(C 1 -C 4  alkylene)-W-(phenyl) wherein W is a single bond, O, S or NH;  
 or each R 1  is independently selected from R 9  and C 1 -C 4 -alkyl substituted by cyano, wherein R 9  is selected from the group consisting of R 5 , —OR 6 , —NR 6 R 6 , —C(O)R 7 , —NHOR 5 , —OC(O)R 6 , cyano, A and —YR 5 ; R 5  is C 1 -C 4  alkyl; R 6 is independently hydrogen or R 5 ; R 7  is R 5 , —OR 6  or —NR 6 R 6 ; A is selected from piperidino, morpholino, pyrrolidino, 4-R 6 -piperazin-1-yl, imidazol-1-yl, 4-pyridon-1-yl, -(C 1 -C 4  alkylene) (CO 2 H), phenoxy, phenyl, phenylsulfanyl, C 2 -C 4  alkenyl, and -(C 1 -C 4  alkylene)C(O)NR 6 R 6 ; and Y is S, SO, or SO 2 ; wherein the alkyl moieties in R 5 , —OR 6  and —NR 6 R 6  are optionally substituted by one to three halo substituents and the alkyl moieties in R 5 , —OR 6  and —NR 6 R 6  are optionally substituted by 1 or 2 R 9  groups, and wherein the alkyl moieties of said optional substituents are optionally substituted by halo or R 9 , with the proviso that two heteroatoms are not attached to the same carbon atom;  
 or each R 1  is independently selected from —NHSO 2 R 5 , phthalimido-(C 1 -C 4 ) -alkylsulfonylamino, benzamido, benzenesulfonylamino, 3-phenylureido, 2-oxopyrrolidin-1-yl, 2,5-dioxopyrrolidin-1-yl, and R 10 -(C 2 -C 4 ) -alkanoylamino wherein R 10  is selected from halo, —OR 6 , C 2 -C 4  alkanoyloxy, —C(O)R 7 , and —NR 6 R 6 ; and wherein said —NHSO 2 R 5 , phthalimido-(C 1 -C 4 -alkylsulfonylamino, benzamido, benzenesulfonylamino, 3-phenylureido, 2-oxopyrrolidin-1-yl, 2,5-dioxopyrrolidin-1-yl, and R 10 -(C 2 -C 4 )-alkanoylamino R 1  groups are optionally substituted by 1 or 2 substituents independently selected from halo, C 1 -C 4  alkyl, cyano, methanesulfonyl and C 1 -C 4  alkoxy;  
 or two R 1  groups are taken together with the carbons to which they are attached to form a 5-8 membered ring that includes 1 or 2 heteroatoms selected from O, S and N;  
 R 2  is hydrogen or C 1 -C 6  alkyl optionally substituted by 1 to 3 substituents independently selected from halo, C 1 -C 4  alkoxy, —NR 6 R 6 , and —SO 2 R 5 ;  
 n is 1 or 2 and each R 3  is independently selected from hydrogen, halo, hydroxy, C 1 -C 6  alkyl, —NR 6 R 6 , and C 1 -C 4  alkoxy, wherein the alkyl moieties of said R 3  groups are optionally substituted by 1 to 3 substituents independently selected from halo, C 1 -C 4  alkoxy, —NR 6 R 6 , and —SO 2 R 5 ; and,  
 R 4  is azido or -(ethynyl)-R 11  wherein R 11  is hydrogen or C 1 -C 6  alkyl optionally substituted by hydroxy, —OR 6 , or —NR 6 R 6 .  
 
     
     
       2. The compound according to  claim 1  wherein R 2  is hydrogen and R 4  is -(ethynyl)-R 11 . 
     
     
       3. A pharmaceutical composition for the treatment of a hyperproliferative disorder in a mammal which comprises a pharmaceutically effective amount of the compound of  claim 1  and a pharmaceutically acceptable carrier. 
     
     
       4. The compound of  claim 1  wherein each R 1  is independently selected from hydrogen, hydroxy, hydroxyamino, nitro, carbamoyl, ureido, R 5  optionally substituted with halo, —OR 6 , carboxy, or —C(O)NH 2 ; —OR 5  optionally substituted with halo, —OR 6 , —OC(O)R 6 , —NR 6 R 6 , or A; —NR 6 R 6 , —C(O)NR 6 R 6 , —SR 5 , phenyl-(C 2 -C 4 )-alkoxy wherein said phenyl moiety is optionally substituted with 1 or 2 substituents independently selected from halo, R 5  or —OR 5 . 
     
     
       5. The compound according to  claim 1  wherein R 2  is hydrogen and R 4  is azido. 
     
     
       6. The compound of  claim 1  wherein R 3  is halo and R 1  is hydrogen or —OR 5 . 
     
     
       7. The compound of  claim 6  wherein R 1  is methoxy. 
     
     
       8. The compound of  claim 1  selected from the group consisting of:
 (6,7-dimethoxyquinazolin-4-yl)-(3-ethynylphenyl)-amine;  
 (6,7-dimethoxyquinazolin-4-yl)-[3-(3′-hydroxypropyn-1-yl)phenyl]-amine;  
 [3-(2′-(aminomethyl)-ethynyl)phenyl]-(6,7-dimethoxyquinazolin-4-yl)-amine;  
 (3-ethynylphenyl)-(6-nitroquinazolin-4-yl)-amine;  
 (6,7-dimethoxyquinazolin-4-yl)-(4-ethynylphenyl)-amine;  
 (6,7-dimethoxyquinazolin-4-yl)-(3-ethynyl-2-methylphenyl)-amine;  
 (6-aminoquinazolin-4-yl)-(3-ethynylphenyl)-amine;  
 (3-ethynylphenyl)-(6-methanesulfonylaminoquinazolin-4-yl)-amine;  
 (3-ethynylphenyl)-(6,7-methylenedioxyquinazolin-4-yl)-amine;  
 (6,7-dimethoxyquinazolin-4-yl)-(3-ethynyl-6-methylphenyl)-amine;  
 (3-ethynylphenyl)-(7-nitroquinazolin-4-yl)-amine;  
 (3-ethynylphenyl)-[6-(4′-toluenesulfonylamino)quinazolin-4-yl]-amine;  
 (3-ethynylphenyl)-{6-[2′-phthalimido-eth-1′-yl-sulfonylamino]quinazolin-4-yl}-amine;  
 (3-ethynylphenyl)-(6-guanidinoquinazolin-4-yl)-amine;  
 (7-aminoquinazolin-4-yl)-(3-ethynylphenyl)-amine;  
 (3-ethynylphenyl)-(7-methoxyquinazolin-4-yl)-amine;  
 (6-carbomethoxyquinazolin-4-yl)-(3-ethynylphenyl)-amine;  
 (7-carbomethoxyquinazolin-4-yl)-(3-ethynylphenyl)-amine;  
 [6,7-bis(2-methoxyethoxy)quinazolin-4-yl]-(3-ethynylphenyl)-amine;  
 (3-azidophenyl)-(6,7-dimethoxyquinazolin-4-yl)-amine;  
 (3-azido-5-chlorophenyl)-(6,7-dimethoxyquinazolin-4-yl)-amine;  
 (4-azidophenyl)-(6,7-dimethoxyquinazolin-4-yl)-amine;  
 (3-ethynylphenyl)-(6-methansulfonyl-quinazolin-4-yl)-amine;  
 (6-ethansulfanyl-quinazolin-4-yl)-(3-ethynylphenyl)-amine  
 (6,7-dimethoxy-quinazolin-4-yl)-(3-ethynyl-4-fluoro-phenyl)-amine;  
 (6,7-dimethoxy-quinazolin-4-yl)-[3-(propyn-1′-yl)-phenyl]-amine;  
 [6,7-bis-(2-methoxy-ethoxy)-quinazolin-4-yl]-(5-ethynyl-2-methyl-phenyl)-amine;  
 [6,7-bis-(2-methoxy-ethoxy)-quinazolin-4-yl]-(3-ethynyl-4-fluoro-phenyl)-amine;  
 [6,7-bis-(2-chloro-ethoxy)-quinazolin-4-yl]-(3-ethynyl-phenyl)-amine;  
 [6-(2-chloro-ethoxy)-7-(2-methoxy-ethoxy)-quinazolin-4-yl]-(3-ethynyl-phenyl)-amine;  
 [6,7-bis-(2-acetoxy-ethoxy)-quinazolin-4-yl]-(3-ethynyl-phenyl)-amine;  
 2-[4-(3-ethynyl-phenylamino)-7-(2-hydroxy-ethoxy)-quinazolin-6-yloxy]-ethanol;  
 [6-(2-acetoxy-ethoxy)-7-(2-methoxy-ethoxy)-quinazolin-4-yl]-(3-ethynyl-phenyl)-amine;  
 [7-(2-chloro-ethoxy)-6-(2-methoxy-ethoxy)-quinazolin-4-yl]-(3-ethynyl-phenyl)-amine;  
 [7-(2-acetoxy-ethoxy)-6-(2-methoxy-ethoxy)-quinazolin-4-yl]-(3-ethynyl-phenyl)-amine;  
 2-[4-(3-ethynyl-phenylamino)-6-(2-hydroxy-ethoxy)-quinazolin-7-yloxy]-ethanol;  
 2-[4-(3-ethynyl-phenylamino)-7-(2-methoxy-ethoxy)-quinazolin-6-yloxy]-ethanol;  
 2-[4-(3-ethynyl-phenylamino)-6-(2-methoxy-ethoxy)-quinazolin-7-yloxy]-ethanol;  
 [6-(2-acetoxy-ethoxy)-7-(2-methoxy-ethoxy)-quinazolin-4-yl]-(3-ethynyl-phenyl)-amine;  
 (3-ethynyl-phenyl)-{6-(2-methoxy-ethoxy)-7-[2-(4-methyl-piperazin-1-yl)-ethoxy]-quinazolin-4-yl}-amine;  
 (3-ethynyl-phenyl)-[7-(2-methoxy-ethoxy)-6-(2-morpholin-4-yl)-ethoxy)-quinazolin-4-yl]-amine;  
 (6,7-diethoxyquinazolin-1-yl)-(3-ethynylphenyl)-amine;  
 (6,7-dibutoxyquinazolin-1-yl)-(3-ethynylphenyl)-amine;  
 (6,7-diisopropoxyquinazolin-1-yl)-(3-ethynylphenyl)-amine;  
 (6,7-diethoxyquinazolin-1-yl)-(3-ethynyl-2-methyl-phenyl)-amine;  
 [6,7-bis-(2-methoxy-ethoxy)-quinazolin-1-yl]-(3-ethynyl-2-methyl-phenyl)-amine;  
 (3-ethynylphenyl)-[6-(2-hydroxy-ethoxy)-7-(2-methoxy-ethoxy)-quinazolin-1-yl]-amine;  
 [6,7-bis-(2-hydroxy-ethoxy)-quinazolin-1-yl]-(3-ethynylphenyl)-amine; and  
 2-[4-(3-ethynyl-phenylamino)-6-(2-methoxy-ethoxy)-quinazolin-7-yloxy]-ethanol.  that is [ 6 , 7 - bis (   2   - methoxyethoxy ) quinazolin -   4   - yl ]-(   3   - ethynylphenyl )- amine.   
 
     
     
       9. The compound of  claim 1  selected from the group consisting of
 (6,7-dipropoxy-quinazolin-4-yl)-(3-ethynyl-phenyl)-amine;  
 (6,7-diethoxy-quinazolin-4-yl)-(3-ethynyl-5-fluoro-phenyl)-amine;  
 (6,7-diethoxy-quinazolin-4-yl)-(3-ethynyl-4-fluoro-phenyl)-amine;  
 (6,7-diethoxy-quinazolin-4-yl)-(5-ethynyl-2-methyl-phenyl)-amine;  
 (6,7-diethoxy-quinazolin-4-yl)-(3-ethynyl-4-methyl-phenyl)-amine;  
 (6-aminomethyl-7-methoxy-quinazolin-4-yl)-(3-ethynyl-phenyl)-amine;  
 (6-aminomethyl-7-methoxy-quinazolin-4-yl)-(3-ethynylphenyl)-amine;  
 (6-aminocarbonylmethyl-7-methoxy-quinazolin-4-yl)-(3-ethynylphenyl)-amine;  
 (6-aminocarbonylethyl-7-methoxy-quinazolin-4-yl)-(3-ethynylphenyl)-amine;  
 (6-aminocarbonylmethyl-7-ethoxy-quinazolin-4-yl)-(3-ethynylphenyl)-amine;  
 (6-aminocarbonylethyl-7-ethoxy-quinazolin-4-yl)-(3-ethynylphenyl)-amine;  
 (6-aminocarbonylmethyl-7-isopropoxy-quinazolin-4-yl)-(3-ethynylphenyl)-amine;  
 (6-aminocarbonylmethyl-7-propoxy-quinazolin-4-yl)-(3-ethynylphenyl)-amine;  
 (6-aminocarbonylmethyl-7-methoxy-quinazolin-4-yl)-(3-ethynylphenyl)-amine;  
 (6-aminocarbonylethyl-7-isopropoxy-quinazolin-4-yl)-(3-ethynylphenyl)-amine; and  
 (6-aminocarbonylethyl-7-propoxy-quinazolin-4-yl)-(3-ethynylphenyl)-amine.  
 
     
     
       10. The compound of  claim 1  selected from the group consisting of:
 (6,7-diethoxyquinazolin-1-yl)-(3-ethynylphenyl)-amine;    (3-ethynylphenyl)-[6-(2-hydroxy-ethoxy)-7-(2-methoxy-ethoxy)-quinazolin-1-yl]-amine;    [6,7-bis-(2-hydroxy-ethoxy)-quinazolin-1-yl]-(3-ethynylphenyl)-amine;    [6,7-bis-(2-methoxy-ethoxy)-quinazolin-1-yl]-(3-ethynylphenyl)-amine;    (6,7-dimethoxyquinazolin-1-yl)-(3-ethynylphenyl)-amine;    (3-ethynylphenyl)-(6-methanesulfonylamino-quinazolin-1-yl)-amine; and,    (6-amino-quinazolin-1-yl)-(3-ethynylphenyl)-amine.    
     
     
       11. A pharmaceutical composition for the treatment of a hyperproliferative disorder in a mammal which comprises a therapeutically-effective amount of the compound of  claim 1  and a pharmaceutically acceptable carrier. 
     
     
       12. A method of treating a hyperproliferative disorder in a mammal which comprises administering to said mammal a therapeutically-effective amount of the compound of  claim 1 . 
     
     
       13. The method of  claim 12  wherein said hyperproliferative disorder is cancer. 
     
     
       14. The method of  claim 13  wherein said cancer is brain, lung, squamous cell, bladder, gastric, pancreatic, breast, head, neck, oesophageal, gynecological or thyroid cancer. 
     
     
       15. The method of  claim 12  wherein the hyperproliferative disease is noncancerous. 
     
     
       16. The method of  claim 15  wherein said disorder is a benign hyperplasia of the skin or prostate. 
     
     
       17. A process for preparing a compound of the formula 
                 
 
       or a pharmaceutically acceptable salt or prodrug  thereof, wherein:
 m is 1, 2, or 3;  
 each R 1  is independently selected from the group consisting of hydrogen, halo, hydroxy, hydroxyamino, carboxy, nitro, guanidino, ureido, cyano, trifluoromethyl, and -(C 1 -C 4  alkylene)-W-(phenyl) wherein W is a single bond, O, S or NH;  
 or each R 1  is independently selected from R 9  and (C 1 -C 4 )-alkyl substituted by cyano, wherein R 9  is selected from the group consisting of R 5 , —OR 6 , —NR 6 R 6 , —C(O)R 7 , —NHOR 5 , —OC(O)R 6 , cyano, A and —YR 5 ; R 5 is C 1 -C 4  alkyl; R 6  is independently hydrogen or R 5 ; R 7  is R 5 , —OR 6  or —NR 6 R 6 ; A is selected from piperidino, morpholino, pyrrolidino, 4-R 6 -piperazin-1-yl, imidazol-1-yl, 4-pyridon-1-yl, -(C 1 -C 4  alkylene)(CO 2 H), phenoxy, phenyl, phenylsulfanyl, C 2 -C 4  alkenyl, and -(C 1 -C 4  alkylene)C(O)NR 6 R 6 ; and Y is S, SO, or SO 2 ; wherein the alkyl moieties in R 5 , —OR 6  and —NR 6 R 6  are optionally substituted by one to three substituents independently selected from halo and R 9 , and wherein the alkyl moieties of said optional substituents are optionally substituted by halo or R 9 , with the proviso that two heteroatoms are not attached to the same carbon atom, and with the further proviso that no more than three R 9  groups may comprise a single R 1  group;  
 or each R 1  is independently selected from —NHSO 2 R 5 , phthalimido-(C 1 -C 4 )-alkylsulfonylamino, benzamido, benzenesulfonylamino, 3-phenylureido, 2-oxopyrrolidin-1-yl, 2,5-dioxopyrrolidin-1-yl, and R 10 -(C 2 -C 4 )-alkanoylamino wherein R 10  is selected from halo, —OR 6 , C 2 -C 4  alkanoyloxy, —C(O)R 7 , and —NR 6 R 6 ; and wherein the foregoing R 1  groups are optionally substituted by 1 or 2 substituents independently selected from halo, C 1 -C 4  alkyl, cyano, methanesulfonyl and C 1 -C 4  alkoxy;  
 or two R 1  groups are taken together with the carbons to which they are attached to form a 5-8 membered ring that includes 1 or 2 heteroatoms selected from O, S and N;  
 R 2  is hydrogen or C 1 -C 6  alkyl optionally substituted by 1 to 3 substituents independently selected from halo, C 1 -C 4  alkoxy, —NR 6 R 6 , and —SO 2 R 5 ;  
 n is 1 or 2 and each R 3  is independently selected from hydrogen, halo, hydroxy, C 1 -C 6  alkyl, —NR 6 R 6 , and C 1 -C 4  alkoxy, wherein the alkyl moieties of said R 3  groups are optionally substituted by 1 to 3 substituents independently selected from halo, C 1 -C 4  alkoxy, —NR 6 R 6 , and —SO 2 R 5 ; and,  
 R 4  is azido or -(ethynyl)-R 11  wherein R 11  is hydrogen or C 1 -C 6  alkyl optionally substituted by hydroxy, —OR 6 , or —NR 6 R 6 ;  
  which comprises 
 a) treating a compound of the formula 
                 
 
 
  wherein R 1  and m are as defined above, with CCl 4  and (C 6 -C 10 aryl) 3 P, optionally supported on an inert polymer, wherein the aryl moieties of said (C 6 -C 10 aryl) 3 P are optionally substituted by C 1 -C 6  alkyl; and 
 b) treating the product of step a) with a compound of the formula 
                 
 
 
  wherein R 2 , R 3  and n are as defined above, and J is Y or R 4 , wherein R 4  is as defined above and wherein Y is NH 2 , Br, I or trifluoromethanesulfonyloxy, with the proviso that when J is Y then the product of step b) must further be treated with an alkyne where Y is Br, I or trifluoromethanesulfonyloxy, or an azide where Y is NH 2 .  
 
     
     
       18. The process of  claim 17  wherein each aryl group is selected from phenyl, naphth-1-yl and naphth-2-yl. 
     
     
       19. The process of  claim 17  wherein each Ar in (C 6 -C 10 aryl) 3 P is phenyl. 
     
     
       20. The process of  claim 17  wherein said (C 6 -C 10 aryl) 3 P is supported on an inert polymer. 
     
     
       21. The process of  claim 20  wherein said inert polymer is a divinylbenzene-cross-linked polymer of styrene. 
     
     
       22. The composition of  claim 3  wherein said hyperproliferative disorder is cancer. 
     
     
       23. The composition of  claim 22  wherein said cancer is selected from the group consisting of renal, liver, kidney, colorectal, brain, lung, skin, bladder, gastric, pancreatic, breast, head, neck, oesophageal, vulval, gynecological, and thyroid cancer. 
     
     
       24. The composition of  claim 3  wherein said hyperproliferative disorder is benign. 
     
     
       25. The composition of  claim 24  wherein said hyperproliferative disorder is benign hyperplasia of the skin or prostate. 
     
     
       26. The composition of  claim 25  wherein said hyperproliferative disorder is  A pharmaceutical composition for the treatment of psoriasis in a mammal which comprises a therapeutically effective amount of the compound of  claim 1  and a pharmaceutically acceptable carrier. 
     
     
       27. A method of treating a hyperproliferative disorder in a mammal which comprises administering to said mammal a pharmaceutically effective amount of the compound of  claim 1 . 
     
     
       28. The method of  claim 27  wherein said hyperproliferative disorder is cancer. 
     
     
       29. The method of  claim 28  wherein said cancer is selected from the group consisting of renal, liver, kidney, colorectal, brain, lung, skin, bladder, gastric, pancreatic, breast, head, neck, oesophageal, vulval, gynecological, and thyroid cancer. 
     
     
       30. The method of  claim 27  wherein said hyperproliferative disorder is benign. 
     
     
       31. The method of  claim 30  wherein said hyperproliferative disorder is benign hyperplasia of the skin or prostate. 
     
     
       32. The method of  claim 31  wherein said hyperproliferative disorder is  A method of treating psoriasis in a mammal which comprises administering to said mammal a therapeutically effective amount of the compound of  claim 1 . 
     
     
       33. A pharmaceutical composition for the treatment of psoriasis in a mammal which comprises a therapeutically effective amount of the compound of  claim 8  and a pharmaceutically acceptable carrier. 
     
     
       34. A compound that is a pharmaceutically acceptable salt of [ 6 , 7 - bis (   2   - methoxyethoxy ) quinazolin -   4   - yl ]-(   3   - ethynylphenyl )- amine.   
     
     
       35. A compound that is a hydrochloride salt of [ 6 , 7 - bis (   2   - methoxyethoxy ) quinazolin -   4   - yl ]-(   3   - ethynylphenyl )- amine.