Quinazolinone Compounds as Anticancer Agents

Abstract

Quinazolinone compounds, pharmaceutically acceptable salts, and prodrugs thereof; compositions that include a pharmaceutically acceptable carrier and one or more of the quinazolinone compounds, either alone or in combination with at least one additional therapeutic agent. Methods of using the quinazolinone compounds, either alone or in combination with at least one additional therapeutic agent, in the prophylaxis or treatment of proliferative diseases.

1 . A compound having the formula: 
       
         
           
           
               
               
           
         
         or a stereoisomer, tautomer, pharmaceutically acceptable salt, or prodrug thereof, wherein 
         X is O or S; 
         R 1  is selected from the group consisting of
 (1) hydrogen, 
 (2) substituted or unsubstituted alkyl, 
 (3) substituted or unsubstituted alkenyl, 
 (4) substituted or unsubstituted alkynyl, 
 (5) substituted or unsubstituted aryl, 
 (6) substituted or unsubstituted heteroaryl, 
 (7) substituted or unsubstituted heterocyclyl, 
 (8) substituted or unsubstituted alkylsulfonyl, and 
 (9) substituted or unsubstituted arylsulfonyl; 
 
         R 2  is selected from the group consisting of
 (1) hydrogen, 
 (2) substituted or unsubstituted alkyl, 
 (3) substituted or unsubstituted alkenyl, and 
 (4) substituted or unsubstituted alkynyl; 
 
         R 3  is selected from the group consisting of
 (1) CO 2 R 10 , 
 (2) COR 10 , 
 (3) CONR 11 R 12 , 
 (4) S(O) m R 13 , and 
 (5) SO 2 NR 14 R 15 ; or 
 
         R 2  and R 3  taken together with the carbon atom to which they are attached form a 3- to 7-membered carbocyclic or heterocyclic ring; 
         with the proviso that when R 4  and R 5  are taken together to form a 5- to 12-membered heterocyclic ring, R 3  is CONR 11 R 12  or R 2  and R 3  taken together with the carbon atom to which they are attached form a 3- to 7-membered carbocyclic or heterocyclic ring; 
         R 4  is selected from the group consisting of
 (1) hydrogen, 
 (2) substituted or unsubstituted alkyl, 
 (3) substituted or unsubstituted alkenyl, 
 (4) substituted or unsubstituted alkynyl, 
 (5) substituted or unsubstituted aryl, 
 (6) substituted or unsubstituted heteroaryl, and 
 (7) substituted or unsubstituted heterocyclyl; 
 
         R 5  is selected from the group consisting of
 (1) hydrogen, 
 (2) substituted or unsubstituted alkyl, 
 (3) substituted or unsubstituted alkoxy, 
 (4) substituted or unsubstituted aryl, 
 (5) substituted or unsubstituted heteroaryl, 
 (6) substituted or unsubstituted heterocyclyl, 
 (7) COR 17 , 
 (8) CO 2 R 18 , 
 (9) CONR 19 R 20 , and 
 (10) SO 2 R 21 ; or 
 
         R 4  and R 5  are taken together with the nitrogen atom to which they are attached form a heteroaryl or heterocyclyl ring, wherein the heteroaryl ring contains one or two ring heteroatoms, wherein the heterocyclyl ring contains one or two ring heteroatoms, and wherein the heteroaryl or heterocyclyl ring is optionally substituted with a halogen, alkyl, hydroxy, amino, cyano, alkylamino, dialkylamino, alkylaminoalkyl, dialkylaminoalkyl, alkoxy, aryl, aryloxy, heteroaryl, arylalkyl, heterocycle, aminocarbonyl, carbonylamino, alkylcarbonyl, alkylcarboxy, alkylaminocarbonyl, alkylcarbonylamino, carbocycle, or heteroarylalkyl group; with the proviso that when R 4  and R 5  taken together with the nitrogen atom to which they are attached form a 5-membered heterocyclic ring, the heterocyclic ring is not a 2,4-dioxo-3-oxazolidinyl ring, a 2,5-dioxo-1-imidazolidinyl ring, or a 2,4,5-trioxo-1-imidazolidinyl ring; 
         R 6 , R 7 , R 8 , and R 9  are independently selected from the group consisting of
 (1) hydrogen, 
 (2) halogen, 
 (3) hydroxy, 
 (4) nitro, 
 (5) amino, 
 (6) cyano, 
 (7) alkoxy, 
 (8) alkylthio, 
 (9) methylenedioxy, 
 (10) haloalkoxy, 
 (11) CO 2 R 10 , 
 (12) COR 10 , 
 (13) OR 10 , 
 (14) CONR 11 R 12 , 
 (15) substituted or unsubstituted alkyl, 
 (16) substituted or unsubstituted aryl, 
 (17) substituted or unsubstituted heteroaryl, 
 (18) substituted or unsubstituted alkylamino, 
 (19) substituted or unsubstituted dialkylamino, 
 (20) substituted or unsubstituted alkylsulfonyl, 
 (21) substituted or unsubstituted arylsulfonyl, 
 (22) substituted or unsubstituted alkylcarboxy, 
 (23) substituted or unsubstituted carboxamido, 
 (24) substituted or unsubstituted carboxyamino, 
 (25) substituted or unsubstituted aminocarboxy, 
 (26) substituted or unsubstituted aminocarbonyl, and 
 (27) substituted or unsubstituted alkylsulfonamido; 
 
         R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 17 , R 18 , R 19 , R 20 , and R 21  are independently selected from the group consisting of
 (1) hydrogen, 
 (2) substituted or unsubstituted alkyl, 
 (3) substituted or unsubstituted alkenyl, 
 (4) substituted or unsubstituted alkynyl, 
 (5) substituted or unsubstituted aryl, 
 (6) substituted or unsubstituted heteroaryl, and 
 (7) substituted or unsubstituted heterocyclyl; or 
 
         R 11  and R 12 , R 14  and R 15 , or R 19  and R 20  taken together form a 3- to 7-membered carbocyclic or heterocyclic ring; and 
         m=0, 1, or 2. 
       
     
     
         2 . A compound of  claim 1 , wherein substituted alkyl comprises arylalkyl, heteroarylalkyl, heterocyclyalkyl, aminoalkyl, alkylaminoalkyl, dialkyaminoalkyl, or sulfonamidoalkyl. 
     
     
         3 . A compound of  claim 1 , wherein X is O. 
     
     
         4 . A compound of  claim 1 , wherein R 1  is substituted or unsubstituted arylalkyl. 
     
     
         5 . A compound of  claim 4 , wherein R 1  is benzyl. 
     
     
         6 . A compound of  claim 4 , wherein R 1  is substituted benzyl. 
     
     
         7 . A compound of  claim 6 , wherein R 1  is a halo-substituted benzyl. 
     
     
         8 . A compound of  claim 7 , wherein R 1  is 3-chlorobenzyl. 
     
     
         9 . A compound of  claim 7 , wherein R 1  is 3-fluorobenzyl. 
     
     
         10 . A compound of  claim 7 , wherein R 1  is 3-methoxybenzyl. 
     
     
         11 . A compound of  claim 7 , wherein R 1  is 3-trifluoromethylbenzyl. 
     
     
         12 . A compound of  claim 7 , wherein R 1  is 3-trifluoromethoxybenzyl. 
     
     
         13 . A compound of  claim 6 , wherein R 1  is 3,5-dimethylbenzyl. 
     
     
         14 . A compound of  claim 1 , wherein R 1  is 2-naphthylmethyl. 
     
     
         15 . A compound of  claim 1 , wherein R 2  is hydrogen and R 3  is CO 2 R 10 . 
     
     
         16 . A compound of  claim 15 , wherein R 10  is alkyl. 
     
     
         17 . A compound of  claim 1 , wherein R 2  is hydrogen and R 3  is CONR 11 R 12 . 
     
     
         18 . A compound of  claim 17 , wherein R 11  and R 12  are alkyl. 
     
     
         19 . A compound of  claim 18 , wherein R 11  and R 12  are methyl. 
     
     
         20 . A compound of  claim 17 , wherein R 11  and R 12  taken together with the nitrogen atom to which they are attached from a 3- to 7-membered heterocyclic ring. 
     
     
         21 . A compound of  claim 1 , wherein R 4  is amino-substituted alkyl. 
     
     
         22 . A compound of  claim 21 , wherein R 4  is 3-aminopropyl. 
     
     
         23 . A compound of  claim 1 , wherein R 5  is hydrogen, alkyl, aryl, or COR 17 . 
     
     
         24 . A compound of  claim 23 , wherein R 5  is COR 17 . 
     
     
         25 . A compound of  claim 24 , wherein R 17  is aryl, arylalkyl, alkyl-substituted aryl, or halogen-substituted aryl. 
     
     
         26 . A compound of  claim 25 , wherein aryl is phenyl 
     
     
         27 . A compound of  claim 1 , wherein R 6 , R 8 , and R 9  are hydrogen. 
     
     
         28 . A compound of  claim 1 , wherein R 7  is a halogen. 
     
     
         29 . A compound of  claim 1  selected from the group consisting of:
 ethyl(3-benzyl-7-chloro-4-oxo-3,4-dihydroquinazolin-2-yl){(4-bromobenzoyl)[3-(dimethylamino)propyl]amino}acetate; 
 ethyl[(3-aminopropyl)(4-methylbenzoyl)amino] (3-benzyl-7-chloro-4-oxo-3,4-dihydroquinazolin-2-yl)acetate; 
 isopropyl(3-benzyl-7-chloro-4-oxo-3,4-dihydroquinazolin-2-yl) [[3-(dimethylamino)propyl](4-methylbenzoyl)amino]acetate; 
 isopropyl[(3-aminopropyl)(4-bromobenzoyl)amino] (3-benzyl-7-chloro-4-oxo-3,4-dihydroquinazolin-2-yl)acetate; 
 isopropyl [(3-aminopropyl)(4-methylbenzoyl)amino](3-b enzyl-7-chloro-4-oxo-3,4-dihydroquinazolin-2-yl)acetate; 
 N-(3-aminopropyl)-N-[1-(3-benzyl-7-chloro-4-oxo-3,4-dihydroquinazolin-2-yl)-2-(diethylamino)-2-oxoethyl]-4-bromobenzamide; 
 N-(3-aminopropyl)-N-[1-(3-benzyl-7-chloro-4-oxo-3,4-dihydroquinazolin-2-yl)-2-(diethylamino)-2-oxoethyl]-4-methylbenzamide; 
 N-(3-aminopropyl)-N-[1-(3-benzyl-7-chloro-4-oxo-3,4-dihydroquinazolin-2-yl)-2-oxo-2-pyrrolidin-1-ylethyl]-4-bromobenzamide; 
 N-(3-aminopropyl)-N-[1-(3-benzyl-7-chloro-4-oxo-3,4-dihydroquinazolin-2-yl)-2-oxo-2-pyrrolidin-1-ylethyl]-4-chlorobenzamide; 
 N-(3-aminopropyl)-N-[1-(3-benzyl-7-chloro-4-oxo-3,4-dihydroquinazolin-2-yl)-2-morpholin-4-yl-2-oxoethyl]-4-bromobenzamide; 
 N-(3-aminopropyl)-N-[1-(3-benzyl-7-chloro-4-oxo-3,4-dihydroquinazolin-2-yl)-2-morpholin-4-yl-2-oxoethyl]-4-chlorobenzamide; 
 N-(3-aminopropyl)-N-[1-(3-benzyl-7-chloro-4-oxo-3,4-dihydroquinazolin-2-yl)-2-(dimethylamino)-2-oxoethyl]-4-bromobenzamide; 
 N-(3-aminopropyl)-N-[1-(3-benzyl-7-chloro-4-oxo-3,4-dihydroquinazolin-2-yl)-2-(dimethylamino)-2-oxoethyl]-4-chlorobenzamide; 
 N-(3-aminopropyl)-N-[1-(3-benzyl-7-chloro-4-oxo-3,4-dihydroquinazolin-2-yl)-2-oxo-2-pyrrolidin-1-ylethyl]-4-methylbenzamide; 
 N-(3-aminopropyl)-N-[1-(3-benzyl-7-chloro-4-oxo-3,4-dihydroquinazolin-2-yl)-2-(dimethylamino)-2-oxoethyl]-4-methylbenzamide; 
 N-(3-aminopropyl)-N-[1-[7-chloro-3-(3-chlorobenzyl)-4-oxo-3,4-dihydroquinazolin-2-yl]-2-(dimethylamino)-2-oxoethyl]-4-methylbenzamide; 
 N-(3-aminopropyl)-N-[1-[7-chloro-3-(3-fluorobenzyl)-4-oxo-3,4-dihydroquinazolin-2-yl]-2-(dimethylamino)-2-oxoethyl]-4-methylbenzamide; 
 N-(3-aminopropyl)-N-[1-[7-chloro-3-(3-methylbenzyl)-4-oxo-3,4-dihydroquinazolin-2-yl]-2-(dimethylamino)-2-oxoethyl]-4-methylbenzamide; 
 N-(3-aminopropyl)-N-[1-{7-chloro-4-oxo-3-[4-(trifluoromethoxy)benzyl]-3,4-dihydroquinazolin-2-yl}-2-(dimethylamino)-2-oxoethyl]-4-methylbenzamide; 
 N-(3-aminopropyl)-N-[1-[7-chloro-3-(4-chlorobenzyl)-4-oxo-3,4-dihydroquinazolin-2-yl]-2-(dimethylamino)-2-oxoethyl]-4-methylbenzamide; 
 N-(3-aminopropyl)-N-[1-[7-chloro-3-(3-methoxybenzyl)-4-oxo-3,4-dihydroquinazolin-2-yl]-2-(dimethylamino)-2-oxoethyl]-4-methylbenzamide; 
 N-(3-aminopropyl)-N-[1-[7-chloro-3-(2-naphthylmethyl)-4-oxo-3,4-dihydroquinazolin-2-yl]-2-(dimethylamino)-2-oxoethyl]-4-methylbenzamide; 
 N-(3-aminopropyl)-N-[1-{7-chloro-4-oxo-3-[3-(trifluoromethyl)benzyl]-3,4-dihydroquinazolin-2-yl}-2-(dimethylamino)-2-oxoethyl]-4-methylbenzamide; 
 N-(3-aminopropyl)-N-[1-{7-chloro-4-oxo-3-[3-(trifluoromethoxy)benzyl]-3,4-dihydroquinazolin-2-yl}-2-(dimethylamino)-2-oxoethyl]-4-methylbenzamide; 
 N-(3-aminopropyl)-N-[1-[7-chloro-3-(3-hydroxybenzyl)-4-oxo-3,4-dihydroquinazolin-2-yl]-2-(dimethylamino)-2-oxoethyl]-4-methylbenzamide; 
 N-(3-aminopropyl)-N-[1-[7-chloro-3-(3,5-dimethylbenzyl)-4-oxo-3,4-dihydroquinazolin-2-yl]-2-(dimethylamino)-2-oxoethyl]-4-methylbenzamide; 
 N-(3-aminopropyl)-N-[1-[3-(1,1′-biphenyl-3-ylmethyl)-7-chloro-4-oxo-3,4-dihydroquinazolin-2-yl]-2-(dimethylamino)-2-oxoethyl]-4-methylbenzamide; 
 N-(3-aminopropyl)-N-[1-[7-chloro-3-(3-cyanobenzyl)-4-oxo-3,4-dihydroquinazolin-2-yl]-2-(dimethylamino)-2-oxoethyl]-4-methylbenzamide; 
 N-(3-aminopropyl)-N-[1-[7-chloro-3-(3-nitrobenzyl)-4-oxo-3,4-dihydroquinazolin-2-yl]-2-(dimethylamino)-2-oxoethyl]-4-methylbenzamide; 
 N-(3-aminopropyl)-N-[1-[7-chloro-3-(3,4-dichlorobenzyl)-4-oxo-3,4-dihydroquinazolin-2-yl]-2-(dimethylamino)-2-oxoethyl]-4-methylbenzamide; 
 N-(3-aminopropyl)-N-{1-(3-benzyl-7-chloro-4-oxo-3,4-dihydroquinazolin-2-yl)-2-[ethyl(methyl)amino]-2-oxoethyl}-4-methylbenzamide; 
 N-(3-aminopropyl)-N-{1-[7-chloro-3-(3,5-dimethylbenzyl)-4-oxo-3,4-dihydroquinazolin-2-yl]-2-[ethyl(methyl)amino]-2-oxoethyl}-4-methylbenzamide; 
 N-(3-aminopropyl)-N-{1-[7-chloro-3-(3,5-dimethylbenzyl)-4-oxo-3,4-dihydroquinazolin-2-yl]-2-[ethyl(methyl)amino]-2-oxoethyl}-4-methylbenzamide; 
 N-(3-aminopropyl)-N-{1-[7-chloro-3-(3-methoxybenzyl)-4-oxo-3,4-dihydroquinazolin-2-yl]-2-[ethyl(methyl)amino]-2-oxoethyl}-4-methylbenzamide; 
 N-(3-aminopropyl)-N-[1-[7-chloro-3-(3,5-difluorobenzyl)-4-oxo-3,4-dihydroquinazolin-2-yl]-2-(dimethylamino)-2-oxoethyl]-4-methylbenzamide; 
 N-(3-aminopropyl)-N-[1-{7-chloro-3-[(6-chloropyridin-2-yl)methyl]-4-oxo-3,4-dihydroquinazolin-2-yl}-2-(dimethylamino)-2-oxoethyl]-4-methylbenzamide; 
 N-(3-aminopropyl)-N-[1-{7-chloro-3-[(2-chloropyridin-4-yl)methyl]-4-oxo-3,4-dihydroquinazolin-2-yl}-2-(dimethylamino)-2-oxoethyl]-4-methylbenzamide; and 
 N-(3-aminopropyl)-N-[1-[7-chloro-4-oxo-3-(quinolin-2-ylmethyl)-3,4-dihydroquinazolin-2-yl]-2-(dimethylamino)-2-oxoethyl]-4-methylbenzamide. 
 
     
     
         30 . A composition, comprising a pharmaceutically acceptable carrier and an amount of a compound of  claim 1  effective to inhibit KSP activity in a human or animal subject when administered thereto. 
     
     
         31 . The composition of  claim 30  further comprising at least one additional agent for the treatment of cancer. 
     
     
         32 . The composition of  claim 31 , wherein the at least one additional agent for the treatment of cancer is selected from irinotecan, topotecan, gemcitabine, gleevec, herceptin, 5-fluorouracil, leucovorin, carboplatin, cisplatin, taxanes, tezacitabine, cyclophosphamide, vinca alkaloids, imatinib, anthracyclines, rituximab, and trastuzumab. 
     
     
         33 . A method for treating a condition by modulation of KSP protein activity comprising administering to a human or animal subject in need of such treatment an effective amount of a compound of  claim 1 . 
     
     
         34 . The method of  claim 33 , wherein the compound has an 1050 value of less than about 50 μM in a cell proliferation assay. 
     
     
         35 . The method of  claim 33 , wherein the condition is cancer. 
     
     
         36 . A method for inhibiting KSP activity in a human or animal subject, comprising administering to the human or animal subject a composition comprising an amount of a compound of  claim 1  effective to inhibit KSP activity the human or animal subject. 
     
     
         37 . A method for treating a cancer disorder in a human or animal subject, comprising administering to the human or animal subject a composition comprising an amount of a compound of  claim 1  effective to inhibit KSP activity the human or animal subject. 
     
     
         38 . The method of  claim 37  further comprising administering to the human or animal subject at least one additional agent for the treatment of cancer. 
     
     
         39 . The method of  claim 38 , wherein the at least one additional agent for the treatment of cancer is selected from irinotecan, topotecan, gemcitabine, gleevec, herceptin, 5-fluorouracil, leucovorin, carboplatin, cisplatin, taxanes, tezacitabine, cyclophosphamide, vinca alkaloids, imatinib, anthracyclines, rituximab, and trastuzumab. 
     
     
         40 . A compound of  claim 1  for use in the treatment of cancer.