Quinoline derivative

Abstract

A compound represented by general formula (I) has a strong Axl inhibitory activity by introducing a distinctive bicyclic structure in which a saturated carbon ring is fused to a pyridone ring, and can be a therapeutic agent for Axl-related diseases, for example, cancer such as acute myeloid leukemia, melanoma, breast cancer, pancreatic cancer, and glioma, kidney diseases, immune system diseases, and circulatory system diseases

1 . A compound of formula (1-A): 
       
         
           
           
               
               
           
         
         wherein 
         R 1  represents (1) a C1-8 alkyl group optionally substituted with one to five R 11 , (2) a C3-7 carbon ring optionally substituted with one to five R 12 , or (3) a 4- to 7-membered heterocycle optionally substituted with one to five R 13 , wherein when the C1-8 alkyl group represented by R 1  is a branched alkyl group, the C1-3 alkyl group branched from the same carbon atom, together with the carbon atom bound thereto, optionally forms a saturated C3-7 carbon ring, 
         R 3  represents (1) a C1-4 alkyl group, (2) a halogen atom, or (3) a C1-4 haloalkyl group, 
         R 4  represents (1) a C1-4 alkoxy group, (2) a C1-4 haloalkyl group, (3) an —OR 41  group, (4) a C1-4 alkyl group, (5) a C2-4 alkenyloxy group, or (6) a C2-4 alkynyloxy group, 
         R 5  represents (1) a hydrogen atom, (2) a C1-4 alkyl group, (3) a halogen atom, (4) a C1-4 haloalkyl group, or (5) an —OR 21  group, 
         R 11  represents (1) an —OR 101  group, (2) an SO 2 R 102  group, (3) an NR 103 R 104  group, or (4) a C3-7 carbon ring optionally substituted with one to three halogen atoms, 
         R 12  represents (1) a C1-8 alkyl group optionally substituted with a hydroxyl group, or (2) a halogen atom, 
         R 13  represents (1) a C1-8 alkyl group optionally substituted with a hydroxyl group, or (2) a halogen atom, 
         R 21  represents (1) a hydrogen atom, or (2) a C1-4 alkyl group, 
         R 41  represents 
         (1) a hydrogen atom; 
         (2) a C1-8 alkyl group substituted with one to two substituents selected from the group consisting of (a) 5- to 7-membered cyclic group optionally substituted with one to two substituents selected from the group consisting of (i) a C1-4 alkyl group, (ii) a C1-4 haloalkyl group, and (iii) a halogen atom, (b) NR 401 R 402 , (c) a hydroxyl group, and (d) an SO 2 R 403  group; 
         (3) a C2-8 alkenyl group substituted with one to two substituents selected from the group consisting of (a) 5- to 7-membered cyclic group optionally substituted with one to two substituents selected from the group consisting of (i) a C1-4 alkyl group, (ii) a C1-4 haloalkyl group, and (iii) a halogen atom, (b) NR 401 R 402 , (c) a hydroxyl group, and (d) an SO 2 R 403  group; or 
         (4) a C2-8 alkynyl group substituted with one to two substituents selected from the group consisting of (a) 5- to 7-membered cyclic group optionally substituted with one to two substituents selected from the group consisting of (i) a C1-4 alkyl group, (ii) a C1-4 haloalkyl group, and (iii) a halogen atom, (b) NR 401 R 402 , (c) a hydroxyl group, and (d) an SO 2 R 403  group, 
         R 101  represents (1) a hydrogen atom, or (2) a C1-4 alkyl group, 
         R 102  represents (1) a hydrogen atom, or (2) a C1-4 alkyl group, 
         R 103  and R 104  each independently represents (1) a hydrogen atom, or (2) a C1-4 alkyl group, 
         R 401  and R 402  each independently represents (1) a hydrogen atom, or (2) a C1-4 alkyl group, 
         R 403  represents (1) a hydrogen atom, or (2) a C1-4 alkyl group, 
         A represents (1) CH, or (2) a nitrogen atom, 
         ring 1 represents a 5- to 7-membered cyclic group, 
         n is an integer from 0 to 5, 
         p is an integer from 0 to 2, 
         q is an integer from 0 to 4, 
         when n is two or more, a plurality of R 3  may be the same as or different from each other, and when q is two or more, a plurality of R 4  may be the same as or different from each other, 
         a salt thereof, a solvate thereof, an N-oxide thereof, or a prodrug thereof. 
       
     
     
         2 . The compound according to  claim 1 , wherein the ring 1 is benzene or pyridine,
 or a salt thereof, a solvate thereof, an N-oxide thereof, or a prodrug thereof.   
     
     
         3 . The compound according to  claim 1 , wherein R 1  represents a C1-8 alkyl group optionally substituted with one to five R 11 ,
 a salt thereof, a solvate thereof, an N-oxide thereof, or a prodrug thereof.   
     
     
         4 . The compound according to  claim 1 , wherein R 1  represents a C3-7 carbon ring optionally substituted with one to five R 12 ,
 a salt thereof, a solvate thereof, an N-oxide thereof, or a prodrug thereof.   
     
     
         5 . The compound according to  claim 1 , wherein q is an integer of 1 or 2; and
 R 4  is a C1-4 alkoxy group or an —OR 41  group,   a salt thereof, a solvate thereof, an N-oxide thereof, or a prodrug thereof.   
     
     
         6 . The compound according to  claim 2 , wherein q is an integer of 1 or 2; and
 R 4  is a C1-4 alkoxy group or an —OR 41  group,   a salt thereof, a solvate thereof, an N-oxide thereof, or a prodrug thereof.   
     
     
         7 . The compound according to  claim 3 , wherein q is an integer of 1 or 2; and
 R 4  is a C1-4 alkoxy group or an —OR 41  group,   a salt thereof, a solvate thereof, an N-oxide thereof, or a prodrug thereof.   
     
     
         8 . The compound according to  claim 4 , wherein q is an integer of 1 or 2; and
 R 4  is a C1-4 alkoxy group or an —OR 41  group,   a salt thereof, a solvate thereof, an N-oxide thereof, or a prodrug thereof.   
     
     
         9 . A composition containing a compound of formula (I-A) as defined in  claim 1 , or a salt thereof, a solvate thereof, an N-oxide thereof, or a prodrug thereof. 
     
     
         10 . A method for preventing and/or treating an Axl-related disease, the method comprising administering an effective amount of a compound of formula (I-A) as defined in  claim 1 , or a salt thereof, a solvate thereof, an N-oxide thereof, or a prodrug thereof, to a mammal. 
     
     
         11 . The method according to  claim 10 , wherein the Axl-related disease is a cancer, a kidney disease, an immune system disease, or a circulatory system disease. 
     
     
         12 . The method according to  claim 11 , wherein the cancer is acute myeloid leukemia, chronic myeloid leukemia, acute lymphatic leukemia, melanoma, breast cancer, pancreatic cancer, glioma, esophageal adenocarcinoma, large intestine cancer, renal cell carcinoma, thyroid cancer, non-small cell lung cancer, prostate cancer, stomach cancer, liver cancer, uveal malignant melanoma, ovarian cancer, endometrial cancer, lymphoma, head and neck cancer, or sarcoma. 
     
     
         13 . The method according to  claim 12 , wherein the cancer is a metastatic cancer. 
     
     
         14 . A method of suppressing an activity of Axl in a subject, the method comprising administering a compound of formula (I-A) as defined in  claim 1 , or a salt thereof, a solvate thereof, an N-oxide thereof, or a prodrug thereof, to the subject. 
     
     
         15 . A method of preparing a compound of formula (I-A) as defined in  claim 1  or a salt thereof, the method comprising the following steps (i) to (iii):
 step (i): subjecting a compound of the formula (a)′: 
 
       
         
           
           
               
               
           
         
         wherein all symbols have the same meanings as defined in  claim 1  or a salt thereof, 
         and a compound of the formula (V): 
       
       
         
           
           
               
               
           
         
         wherein X 2  represents a halogen atom, and the other symbols have the same meanings as defined in  claim 1  or a salt thereof, to an aromatic nucleophilic substitution reaction to produce a compound of the formula (b)′: 
       
       
         
           
           
               
               
           
         
         wherein all symbols have the same meanings as defined in  claim 1  or a salt thereof; 
         step (ii): subjecting the compound of formula (b)′ or a salt thereof obtained in the step (i) to a reduction reaction of the nitro group thereof to produce a compound of the formula (c): 
       
       
         
           
           
               
               
           
         
         wherein all symbols have the same meanings as defined in  claim 1  or a salt thereof; and 
         step (iii): subjecting the compound of the formula (c) or a salt thereof obtained in the step (ii) and a compound of the formula (f): 
       
       
         
           
           
               
               
           
         
         wherein all symbols have the same meanings as defined in  claim 1  or a salt thereof, 
         to an amidation reaction to produce the compound of the formula (I-A) or a salt thereof.