Substituted quinoline derivatives

Abstract

The present invention relates to new substituted quinoline compounds and pharmaceutically acceptable salts, esters or prodrugs thereof, compositions of the new compounds together with pharmaceutically acceptable carriers, and uses of the new compounds. The compounds of the invention have the following general formula:

1 . A compound of formula I: 
     
       
         
         
             
             
         
       
       wherein: 
       m is an integer from 0 to 3; 
       R 1  is selected from the group consisting of acylamino, carboxyl ester, and C 1  to C 5  alkyl optionally substituted with hydroxy, or halo; 
       R 2  is hydrogen or C 1  to C 5  alkyl; 
       R 3  is —C(═X)-A, wherein A is selected from the group consisting of aryl, heteroaryl, heterocyclic, and cycloalkyl, all of which may be optionally substituted with 1 to 4 substituents selected from the group consisting of C 1  to C 4  alkyl, C 1  to C 4  alkoxy, halo, hydroxy, and nitro and X is oxygen or sulfur; 
       R 4  is -alkylene-heterocyclic or -alkylene-NR 7 R 8  wherein alkylene is a C 1  to C 4  straight chained alkylene; R 7  and R 8  are independently selected from the group consisting of hydrogen, C 1  to C 4  alkyl, arylalkyl, heteroarylalkyl, cycloalkyl and cycloalkylalkyl; 
       R 5  is selected from the group consisting of L-A 1 , wherein A 1  is selected from the group consisting of aryl, heteroaryl, heterocyclic, and cycloalkyl, all of which may be optionally substituted with 1 to 4 substituents selected from the group consisting of C 1  to C 4  alkyl, C 1  to C 4  alkoxy, halo, hydroxy, and nitro and wherein L is selected from the group consisting of oxygen, —NR 9  where R 9  is hydrogen or alkyl, —S(O) q — where q is zero, one or two, and C 1  to C 8  alkylene, optionally substituted with hydroxy, halo, or acylamino; and 
       R 6  is selected from the group consisting of C 1  to C 5  alkyl, C 2  to C 8  alkenyl, C 2  to C 5  alkynyl, —CF 3 , C 1  to C 5  alkoxy, halo, and hydroxy; 
       or pharmaceutically acceptable salts, esters or prodrugs thereof. 
     
   
   
       2 . The compound of  claim 1 , wherein the compound is represented by formula II: 
     
       
         
         
             
             
         
       
     
     wherein:
 A 2  and A 3  are independently selected from the group consisting of aryl, heteroaryl, heterocyclic, and cycloalkyl, all of which may be optionally substituted with 1 to 4 substituents selected from the group consisting of C 1  to C 4  alkyl, C 1  to C 4  alkoxy, halo, hydroxy, and nitro; 
 each R 6  is independently selected from the group consisting of C 1  to C 5  alkyl, C 2  to C 8  alkenyl, C 2  to C 8  alkynyl, —CF 3 , C 1  to C 8  alkoxy, halo and hydroxyl; 
 R 11  is C 2  to C 3  alkyl; 
 R 12  and R 13  are independently selected from the group consisting of hydrogen, C 1  to C 4  alkyl, arylalkyl, heteroarylalkyl, cycloalkyl and cycloalkylalkyl; 
 m is an integer equal to 0 to 2; 
 n is an integer equal to 1 to 3; and 
 p is an integer equal to 1 to 4; 
 or pharmaceutically acceptable salts, esters and prodrugs thereof. 
 
   
   
       3 . The compound of  claim 1 , wherein the compound is represented by formula III: 
     
       
         
         
             
             
         
       
       wherein: 
       A 2  and A 3  are independently selected from the group consisting of aryl, heteroaryl, heterocyclic, and cycloalkyl, all of which may be optionally substituted with 1 to 4 substituents selected from the group consisting of C 1  to C 4  alkyl, C 1  to C 4  alkoxy, halo, hydroxy, and nitro; 
       R 12  and R 13  are independently selected from the group consisting of hydrogen, C 1  to C 4  alkyl, arylalkyl, heteroarylalkyl, cycloalkyl and cycloalkylalkyl; 
       p is an integer equal to 1 to 4; 
       or pharmaceutically acceptable salts, esters and prodrugs thereof. 
     
   
   
       4 . The compound of  claim 1 , wherein R 1  is C 1  to C 5  alkyl. 
   
   
       5 . The compound of  claim 1 , wherein R 1  is isopropyl or t-butyl. 
   
   
       6 . The compound of  claim 1 , wherein R 2  is hydrogen or methyl. 
   
   
       7 . The compound of  claim 1 , wherein X is oxygen. 
   
   
       8 . The compound of  claim 1 , wherein A is aryl. 
   
   
       9 . The compound of  claim 1 , wherein A is phenyl or naphthyl. 
   
   
       10 . The compound of  claim 1 , wherein A is heteroaryl. 
   
   
       11 . The compound of  claim 1 , wherein A is selected from the group consisting of pyridinyl, imidazolyl, furanyl, pyrazolyl, and thiazolyl. 
   
   
       12 . The compound of  claim 1 , wherein A is cycloalkyl. 
   
   
       13 . The compound of  claim 1 , wherein A is cyclohexyl. 
   
   
       14 . The compound of  claim 1 , wherein A is substituted with 1 to 4 substituents selected from the group consisting of chloro, methyl, bromo, fluoro, nitro, —CF 3 , methoxy, and t-butyl. 
   
   
       15 . The compound of  claim 1 , wherein —C(O)-A is selected from the group consisting of:
 (2-chloro-6-methylpyridin-4-yl)carbonyl;   (5-methylimidazol-4-yl)carbonyl;   (naphth-2-yl)carbonyl;   (pyridin-3-yl)carbonyl;   (pyridin-4-yl)carbonyl;   
     3,4-difluorobenzoyl; 
     3,4-dimethylbenzoyl; 
     3,5-dimethylpyrazol-3-ylcarbonyl; 
     2-(3-aminopropanamido)-4-methylbenzoyl; 
     2,4-difluorobenzoyl; 
     2,6-difluorobenzoyl; 
     2-chlorobenzoyl; 
     2-chloropyridin-3-ylcarbonyl; 
     2-chloropyridin-5-ylcarbonyl; 
     2-fluorobenzoyl; 
     2-methoxybenzoyl; 
     3,4-dichlorobenzoyl; 
     3-chlorobenzoyl; 
     3-fluoro-4-methylbenzoyl; 
     4-bromobenzoyl; 
     4-chlorobenzoyl; 
     4-hydroxybenzoyl; 
     4-methoxybenzoyl; 
     4-methyl-3-fluorobenzoyl; 
     4-methylbenzoyl; 
     4-nitrobenzoyl; 
     4-t-butylbenzoyl; 
     4-trifluoromethylbenzoyl;
 benzoyl; 
 cyclohexylcarbonyl; 
 
     furan-3-ylcarbonyl; 
     pyridin-2-ylcarbonyl; and 
     thiazol-4-ylcarbonyl. 
   
   
       16 . The compound of  claim 15 , wherein —C(O)-A is selected from the group consisting of 4-methyl-3-fluorobenzoyl, 4-methylbenzoyl, and 3,4-dimethylbenzoyl. 
   
   
       17 . The compound of  claim 1 , wherein R 4  is selected from the group consisting of: 
     3-(benzylamino)propyl; 
     3-(cyclobutylamino)propyl; 
     3-(cyclohexylmethylamino)propyl; 
     3-(diethylamino)propyl; 
     3-(isopropylamino)propyl; 
     3-[(3-trifluoromethylpyridin-6-yl)amino]propyl; 
     3-aminopropyl; 
     2-aminoethyl; 
     piperidin-3-ylmethyl; and 
     pyrrolidin-3-ylmethyl. 
   
   
       18 . The compound of  claim 1 , wherein R 4  is 3-aminopropyl. 
   
   
       19 . The compound of  claim 1 , wherein R 5  is alkylene-A 1  and A 1  is aryl. 
   
   
       20 . The compound of  claim 19 , wherein R 5  is selected from the group consisting of: 
     benzyl; 
     2-methylbenzyl; 
     3,5-difluorobenzyl; 
     3-acetylaminobenzyl; 
     3-fluorobenzyl; 
     3-hydroxybenzyl; 
     4-chlorobenzyl; 
     4-difluorobenzyl; and 
     4-methylbenzyl. 
   
   
       21 . The compound of  claim 1 , wherein R 6  is selected from the group consisting of hydrogen, fluoro, chloro, methyl, bromo, ethyl, vinyl, methoxy, phenyl, ethynyl, and —CF 3 . 
   
   
       22 . The compound of  claim 2 , wherein m is 1 and n is 1. 
   
   
       23 . The compound of  claim 2 , wherein R 11  is isopropyl. 
   
   
       24 . The compound of  claim 2 , wherein p is 3. 
   
   
       25 . The compound of  claim 2 , wherein R 12  and R 13  are hydrogen. 
   
   
       26 . The compound of  claim 2 , wherein A 2  is phenyl. 
   
   
       27 . The compound of  claim 3 , wherein A 2  is phenyl. 
   
   
       28 . The compound of  claim 3 , wherein p is 3. 
   
   
       29 . The compound of  claim 3 , wherein R 12  and R 13  are hydrogen. 
   
   
       30 . A compound selected from the group consisting of: 
     N-(3-aminopropyl)-N-[1-(3-benzylquinolin-2-yl)-2-methylpropyl]-3-fluoro-4-methylbenzamide; 
     N-(3-aminopropyl)-N-[1-(3-benzylquinolin-2-yl)-2-methylpropyl]-4-methylbenzamide; 
     N-(3-aminopropyl)-N-[1-(3-benzylquinolin-2-yl)-2-methylpropyl]-3,4-dimethylbenzamide; 
     N-(3-aminopropyl)-N-[1-(3-benzyl-7-chloroquinolin-2-yl)-2-methylpropyl]-4-methylbenzamide; 
     N-(3-aminopropyl)-N-[1-(3-benzyl-7-chloroquinolin-2-yl)-2-methylpropyl]-3-fluoro-4-methylbenzamide; and
 pharmaceutically acceptable salts, esters and prodrugs thereof. 
 
   
   
       31 . A pharmaceutical composition comprising a therapeutically effective amount of a compound of  claim 1  and a pharmaceutically acceptable carrier. 
   
   
       32 . The composition of  claim 31  further comprising at least one additional agent for the treatment of cancer. 
   
   
       33 . The composition of  claim 31 , wherein the additional agent for the treatment of cancer is selected from the group consisting of irinotecan, topotecan, gemcitabine, imatinib, trastuzumab, 5-fluorouracil, leucovorin, carboplatin, cisplatin, docetaxel, paclitaxel, tezacitabine, cyclophosphamide, vinca alkaloids, anthracyclines, rituximab, and trastuzumab. 
   
   
       34 . A method of treating a disorder mediated, at least in part, by KSP in a mammalian patient comprising administering to a mammalian patient in need of such treatment a therapeutically effective amount of a composition of  claim 31 . 
   
   
       35 . The method of  claim 34 , wherein the disorder is a cellular proliferative disease. 
   
   
       36 . The method of  claim 35 , wherein the cellular proliferative disease is cancer. 
   
   
       37 . The method of  claim 36 , wherein the cancer is selected from the group consisting of lung and bronchus; prostate; breast; pancreas; colon and rectum; thyroid; stomach; liver and intrahepatic bile duct; kidney and renal pelvis; urinary bladder; uterine corpus; uterine cervix; ovary; multiple myeloma; esophagus; acute myelogenous leukemia; chronic myelognous leukemia; lymphocytic leukemia; myeloid leukemia; brain; oral cavity and pharynx; larynx; small intestine; non-hodgkin lymphoma; melanoma; and villous colon adenoma. 
   
   
       38 . The method of  claim 34  further comprising administering to the mammalian patient one additional agent for the treatment of cancer. 
   
   
       39 . The method of  claim 38 , wherein the additional agent for the treatment of cancer is selected from the group consisting of irinotecan, topotecan, gemcitabine, imatinib, trastuzumab, 5-fluorouracil, leucovorin, carboplatin, cisplatin, docetaxel, paclitaxel, tezacitabine, cyclophosphamide, vinca alkaloids, anthracyclines, rituximab, and trastuzumab. 
   
   
       40 . Use of the composition of  claim 31  in the manufacture of a medicament for the treatment of cancer.