Pyrazole compounds and pharmaceutical compositions comprising the compound

Abstract

The present invention provides a novel compound having an excellent JNK inhibitory effect. That is, it provides a compound represented by the following formula, a salt thereof or a hydrate of them. Wherein R 1 designates —(CO) h —(NR a ) j —(CR b ═CR c ) k —Ar (wherein R a , R b and R c each independently designate a hydrogen atom, a halogen atom, hydroxyl group, an optionally substituted C 1-6 alkyl group or the like; Cy designates a 5- or 6-membered heteroaryl; and V each independently designate the formula -L-X—Y (wherein L designates a single bond, an optionally substituted C 1-6 alkylene group or the like; X designates a single bond or the formula -A- (wherein A designates NR 2 , O, CO, S, SO or SO 2 ) and so on; and Y designates a hydrogen atom, a halogen atom, nitro group or the like).

1 . A compound represented by the formula (III), a salt thereof or a hydrate thereof: 
     
       
         
         
             
             
         
       
       wherein R 1  represents a group represented by the formula —(CO) h —(NR a ) j —(CR b ═CR c ) k —Ar (wherein R a , R b  and R c  each independently represents a hydrogen atom, halogen atom, hydroxyl group, an optionally substituted C 1-6  alkyl group, an optionally substituted C 2-6  alkenyl group, an optionally substituted C 1-6  alkoxy group, an optionally substituted C 2-6  alkenyloxy group, an optionally substituted C 1-6  alkylthio group, an optionally substituted C 2-6  alkenylthio group, an optionally substituted C 3-8  cycloalkenyl group, an optionally substituted 4- to 14-membered non-aromatic heterocyclic group, an optionally substituted C 6-14  aryl group or an optionally substituted 5- to 14-membered heteroaryl group; Ar represents an optionally substituted C 6-14  aryl group or an optionally substituted 5- to 14-membered heteroaryl group; h and j each independently is 0 or 1, and k is 1); 
       R d  and R f  each independently represents a hydrogen atom, 
       R e  represents a halogen atom, 
       L represents a single bond, an optionally substituted C 1-6  alkylene group, an optionally substituted C 2-6  alkenylene group or an optionally substituted C 2-6  alkynylene group; 
       X represents a single bond, or a group represented by —CO—NR 8 -Z-, —NR 8 —CO-Z-, —NR 8 —C(O)O—, —NR 9 —CO—NR 10 —, —OC(O)—NR 14 — or —CH 2 —NR 8 —COR 7 — (wherein R 8 , R 9 , R 10  and R 14  each independently represents a hydrogen atom, halogen atom, hydroxyl group, an optionally substituted C 1-6  alkyl group, an optionally substituted C 2-6  alkenyl group, an optionally substituted C 2-6  alkynyl group, an optionally substituted C 1-6  alkoxy group, an optionally substituted C 2-6  alkenyloxy group, an optionally substituted C 1-6  alkylthio group, an optionally substituted C 2-6  alkenylthio group, an optionally substituted C 3-8  cycloalkyl group, an optionally substituted C 3-8  cycloalkenyl group, an optionally substituted 4- to 14-membered non-aromatic heterocyclic group, an optionally substituted C 6-14  aryl group or an optionally substituted 5- to 14-membered heteroaryl group, Z represents a single bond or an optionally substituted C 1-6  alkylene group, and m designates 0, 1 or 2); and 
       Y represents any one group selected from the group consisting of a hydrogen atom, halogen atom, nitro group, hydroxyl group, cyano group, carboxyl group or an optionally substituted C 1-6  alkyl group, an optionally substituted C 2-6  alkenyl group, an optionally substituted C 2-6  alkynyl group, an optionally substituted C 1-6  alkoxy group, an optionally substituted C 3-8  cycloalkyl group, an optionally substituted C 3-8  cycloalkenyl group, an optionally substituted 4- to 14-membered non-aromatic heterocyclic group, an optionally substituted C 6-14  aryl group, an optionally substituted 5- to 14-membered heteroaryl group, an optionally substituted amino group and a group represented by the formula —W—R 15  (wherein W designates CO or SO 2 ; and R 15  represents an optionally substituted C 1-6  alkyl group, an optionally substituted amino group, an optionally substituted C 6-14  aryl group or an optionally substituted 5- to 14-membered heteroaryl group). 
     
   
   
       2 . The compound according  claim 1 , a salt thereof or a hydrate thereof, wherein at least one of R b  and R c  is not a hydrogen atom, and L is a single bond, an optionally substituted C 2-6  alkenylene group or an optionally substituted C 2-6  alkynylene group, provided that, when L is a single bond, the case where X is a single bond, and Y is an optionally substituted C 1-6  alkyl group, an optionally substituted C 3-8  cycloalkyl group, an optionally substituted C 3-8  cycloalkenyl group, an optionally substituted 4- to 14-membered non-aromatic heterocyclic group, an optionally substituted C 6-14  aryl group or an optionally substituted 5- to 14-membered heteroaryl group is excluded. 
   
   
       3 . The compound according to  claim 1 , a salt thereof or a hydrate thereof, wherein at least either h or j is 1. 
   
   
       4 . The compound according to  claim 1 , a salt thereof or a hydrate thereof, wherein h and j are 0. 
   
   
       5 . The compound according to any one of  claims 3  and  4 , a salt thereof or a hydrate thereof, wherein R b  and/or R c  are(is) a hydrogen atom. 
   
   
       6 . The compound according to  claim 5 , a salt thereof or a hydrate thereof, wherein R b  and R c  are a hydrogen atom. 
   
   
       7 . The compound according to  claim 1 , a salt thereof or a hydrate thereof, wherein Ar is a C 6-14  aryl group or a 5- to 14-membered heteroaryl group, and Ar is a group which may be substituted with 1 to 3 group(s) selected from the following substituent group (a):
 the group consisting of (1) each optionally substituted (a) C 1-6  alkyl groups, (b) C 1-6  alkoxy groups, (c) C 1-7  acyl groups, (d) amide group, (e) amino group, (f) C 3-8  cycloalkyl groups, (2) halogen atom, (3) hydroxyl group, (4) nitro group, (5) cyano group, and (6) carboxyl group.   
   
   
       8 . The compound according to  claim 7 , a salt thereof or a hydrate thereof, wherein Ar is a phenyl group, naphthyl group or a 5- to 10-membered heteroaryl group, and Ar is a group optionally substituted with 1 to 3 group(s) selected from substituent group (a). 
   
   
       9 . The compound according to  claim 7 , a salt thereof or a hydrate thereof, wherein Ar is a phenyl group, 2-naphthyl group, pyridyl group, 2-thienyl group, 2-furyl group, 2-benzofuryl group, 2-quinolyl group or 2-benzothienyl group, and Ar is a group optionally substituted with 1 to 3 group(s) selected from substituent group (a). 
   
   
       10 . The compound according to  claim 7 , a salt thereof or a hydrate thereof, wherein Ar is a phenyl group, pyridyl group, 2-thienyl group or 2-furyl group, and Ar is a group optionally substituted with 1 to 3 group(s) selected from substituent group (a). 
   
   
       11 . The compound according to  claim 7 , a salt thereof or a hydrate thereof, wherein Ar is a 2-naphthyl group, 2-benzofuryl group, 2-quinolyl group or 2-benzothienyl group, and Ar is a group optionally substituted with 1 to 3 group(s) selected from substituent group (a). 
   
   
       12 . The compound according to any one of  claims 7  to  11 , a salt thereof or a hydrate thereof, wherein substituent group (a) is the group consisting of (1) C 1-6  alkyl groups each optionally substituted with 1 to 3 group(s) selected from the group consisting of a halogen atom, hydroxyl group and cyano group, (2) C 1-6  alkoxy groups optionally substituted with 1 to 3 group(s) selected from the group consisting of a halogen atom, hydroxyl group and cyano group, (3) halogen atom, (4) hydroxyl group, (5) cyano group, and (6) C 1-7  acyl groups. 
   
   
       13 . The compound according to any one of  claims 7  to  11 , a salt thereof or a hydrate thereof, wherein the substituent in substituent group (a) is a halogen atom. 
   
   
       14 . The compound according to  claim 1 , a salt thereof or a hydrate thereof, wherein L is a single bond or methylene group. 
   
   
       15 . The compound according to  claim 14 , a salt thereof or a hydrate thereof, wherein L is a single bond. 
   
   
       16 . The compound according to  claim 1 , a salt thereof or a hydrate thereof, wherein X is —CO—NR 8 -Z- or —NR 8 —CO-Z-. 
   
   
       17 . The compound according to  claim 16 , a salt thereof or a hydrate thereof, wherein R 8  is a hydrogen atom. 
   
   
       18 . The compound according to  claim 1 , a salt thereof or a hydrate thereof, wherein X is —CO—NR 8 -Z-. 
   
   
       19 . The compound according to  claim 1 , a salt thereof or a hydrate thereof, wherein X is —NR 8 —CO-Z-. 
   
   
       20 . The compound according to  claim 1 , a salt thereof or a hydrate thereof, wherein X is a single bond. 
   
   
       21 . The compound according to  claim 1 , a salt thereof or a hydrate thereof, wherein Y is a C 1-6  alkyl group, a C 6-14  aryl group, a C 1-6  alkoxy group, a C 3-8  cycloalkyl group, a 4- to 14-membered non-aromatic heterocyclic group or a 5- to 14-membered heteroaryl group, and Y is a group optionally substituted with 1 to 3 group(s) selected from the following substituent group a2:
 the group consisting of (1) each optionally substituted with at least one selected from the group consisting of (a) C 1-6  alkyl groups, (b) C 2-6  alkenyl groups, (c) C 2-6 -alkynyl groups, (d) C 1-6  alkoxy groups, (e) C 2-7  acyl groups, (f) amide group, (g) amino group, (h) C 3-8  cycloalkyl groups, (i) C 3-8  cycloalkenyl groups, (j) C 6-14  aryl groups, (k) 5- to 14-membered heteroaryl groups, (l) C 6-14  aryloxy groups, and (m) 4- to 14-membered non-aromatic heterocyclic groups, (2) halogen atom, (3) hydroxyl group, (4) nitro group, (5) cyano group, and (6) carboxyl group.   
   
   
       22 . The compound according to  claim 21 , a salt thereof or a hydrate thereof, wherein Y is a C 3-8  cycloalkyl group, phenyl group, a 5- or 6-membered non-aromatic heterocyclic group, or a 5- or 6-membered heteroaryl group, and Y is a group optionally substituted with 1 to 3 group(s) selected from substituent group a2. 
   
   
       23 . The compound according to  claim 21 , a salt thereof or a hydrate thereof, wherein Y is a furyl group, thienyl group, pyrrolyl group, phenyl group, pyridyl group, C 3-8  cycloalkyl group, tetrahydrofuran-yl group, tetrahydrothiophene-yl group, pyrrolidinyl group, tetrahydrofuran-2-on-yl group, pyrrolidine-2-on-yl group or a group represented by the formula: 
     
       
         
         
             
             
         
       
       (wherein Y 2a  designates a group represented by —CONH 2  or —CH 2 OH, Y 2b  and Y 2c  each independently designate a hydrogen atom, an optionally substituted phenyl group or an optionally substituted C 1-6  alkyl group), and Y is a group optionally substituted with 1 to 3 group(s) selected from substituent group a2. 
     
   
   
       24 . The compound according to  claim 21 , a salt thereof or a hydrate thereof, wherein Y is a furyl group or thienyl group, and Y is a group optionally substituted with 1 to 3 group(s) selected from substituent group a2. 
   
   
       25 . The compound according to any one of  claims 21  to  24 , a salt thereof or a hydrate thereof, wherein Substituent group a2 is the group consisting of (1) (a) C 1-6  alkyl groups, (b) C 1-6  alkoxy groups, (c) C 1-7  acyl groups, (d) amide group, (e) amino group, (f) C 3-8  cycloalkyl groups, each of which may be substituted with 1 to 3 group(s) selected from the following Substituent group b2, (2) halogen atom, (3) hydroxyl group, (4) nitro group, (5) cyano group, and (6) carboxyl group, and substituent group b2 is:
 the group consisting of C 1-6  alkyl groups, halogen atom, hydroxyl group, nitro group, cyano group and carboxyl group.   
   
   
       26 . The compound according to any one of  claims 21  to  24 , a salt thereof or a hydrate thereof, wherein substituent group a2 is the group consisting of (1) C 1-6  alkoxy groups, (2) halogen atoms and (3) cyano groups. 
   
   
       27 . The compound according to  claim 21 , a salt thereof or a hydrate thereof, wherein L and X are a single bond, Y is a 5- to 6-membered heteroaryl group, and Y is a group optionally substituted with 1 to 3 group(s) selected from substituent group a2. 
   
   
       28 . A pharmaceutical composition comprising:
 the compound according to  claim 1 ,  7 ,  16  or  21 , a salt thereof or a hydrate thereof, and   a pharmaceutically acceptable carrier.   
   
   
       29 . A method for treating or preventing a disease based on JNK 3 action against which inhibition of a c-Jun amino-terminal kinase 3 (JNK 3) is effective for prevention or treatment, immunological diseases, inflammatory diseases, metabolic disorders and/or neurodegenerative diseases, which comprises:
 administering_a pharmacologically effective amount of the compound according to  claim 1 ,  7 ,  16  or  21 , a salt thereof or a hydrate thereof to a patient in need thereof.   
   
   
       30 . A method for treating or preventing a disease based on JNK action against which inhibition of a c-Jun amino-terminal kinase (JNK) is effective for prevention or treatment, immunological diseases, inflammatory diseases, metabolic disorders or neurodegenerative diseases, which comprises:
 administering a pharmacologically effective amount of the compound according to  claim 1 ,  7 ,  16  or  21 , a salt thereof or a hydrate thereof to a patient in need thereof.   
   
   
       31 . The method according to  claim 30 , wherein the disease is Alzheimer's disease, Parkinson's disease, Huntington's chorea, amyotrophic lateral sclerosis, multiple sclerosis or spinocerebellar degeneration.