Condensed imidazole derivatives

Abstract

The present invention is related to compounds represented by the following formula, or salts or hydrates thereof wherein, T 1 represents a 4- to 12-membered heterocyclic group containing one or two nitrogen atoms in the ring, which is a monocyclic or bicyclic structure that may have one or more substituents; X represents a C 1-6 alkyl group which may have one or more substituents, or such; Z 1 and Z 2 each independently represent a nitrogen atom or a group represented by the formula —CR 2 —; R 1 and R 2 independently represent a hydrogen atom, a C 1-6 alkyl group which may have one or more substituents, or a C 1-6 alkoxy group which may have one or more substituents, or such. These are novel compounds that exhibit an excellent DPPIV-inhibiting activity.

1 . A compound represented by the following formula, or a salt or hydrate thereof,  
       
         
           
           
               
               
           
         
       
       wherein, 
 T 1  represents a monocyclic or bicyclic 4- to 12-membered heterocyclic group containing one or two nitrogen atoms in the ring, that may have one or more substituents;  
 X represents a C 1-6  alkyl group which may have one or more substituents, a C 2-6  alkenyl group which may have one or more substituents, a C 2-6  alkynyl group which may have one or more substituents, a C 6-10  aryl group which may have one or more substituents, a 5 to 10-membered heteroaryl group which may have one or more substituents, a C 6-10  aryl C 1-6  alkyl group which may have one or more substituents, or a 5 to 10-membered heteroaryl C 1-6  alkyl group which may have one or more substituents;  
 Z 1  and Z 2  each independently represent a nitrogen atom or a group represented by the formula —CR 2 ═;  
 R 1  and R 2  each independently represent a group according to the formula -A 0 -A 1 -A 2    
  (wherein 
 A 0  represents a single bond or a C 1-6  alkylene group which may have 1 to 3 substituents selected from group B consisting of the substituents described below;  
 A 1  represents a single bond, an oxygen atom, a sulfur atom, a sulfinyl group, a sulfonyl group, a carbonyl group, a group represented by the formula —O—CO—, a group represented by the formula —CO—O—, a group represented by the formula —NR A —, a group represented by the formula —CO—NR A —, a group represented by the formula —NR A —CO—, a group represented by the formula —SO 2 —NR A —, or a group represented by the formula —NR A —SO 2 —;  
 A 2  and R A  each independently represent a hydrogen atom, a halogen atom, a cyano group, a C 1-6  alkyl group, a C 3-8  cycloalkyl group, a C 2-6  alkenyl group, a C 2-6  alkynyl group, C 6-10  aryl group, a 5 to 10-membered heteroaryl group, a 4 to 8-membered heterocyclic group, a 5 to 10-membered heteroaryl C 1-6  alkyl group, a C 6-10  aryl C 1-6  alkyl group, or a C 2-7  alkylcarbonyl group;  
 however, A 2  and R A  each independently may have 1 to 3 substituents selected from the substituent group B described below:  
 
  when Z 2  is a group represented by the formula —CR 2 ═, R 1 , and R 2  may in combination form a 5 to 7-membered ring;  
  except in cases where: [1] R 1  is a hydrogen atom; Z 1  is a nitrogen atom; and Z 2  is —CH═; and [2] Z 1  is a nitrogen atom; and Z 2  is —C(OH)═; 
 <Substituent group B> 
 Substituent group B represents the group consisting of: a hydroxyl group, a mercapto group, a cyano group, a nitro group, a halogen atom, a trifluoromethyl group, a C 1-6  alkyl group which may have one or more substituents, a C 3-8  cycloalkyl group, a C 2-6  alkenyl group, a C 2-6  alkynyl group, a C 6-10  aryl group, a 5 to 10-membered heteroaryl group, a 4 to 8-membered heterocyclic group, a C 1-6  alkoxy group, a C 1-6  alkylthio group, a group represented by the formula —SO 2 —NR B1 —R B2 , a group represented by the formula —NR B1 —CO—R B2 , a group represented by the formula —NR B1 —R B2  (where R B1  and R B2  each independently represent a hydrogen atom or a C 1-6  alkyl group), a group represented by the formula —CO—R B3  (where R B3  represents a 4 to 8-membered heterocyclic group), a group represented by the formula —CO—R B4 —R B5  and a group represented by the formula —CH 2 —CO—R B4 —R B5  (where R B4  represents a single bond, an oxygen atom, or a group represented by the formula —NR B6 ; R B5  and R B6  each independently represent a hydrogen atom, a C 1-6  alkyl group, a C 3-8  cycloalkyl group, a C 2-6  alkenyl group, a C 2-6  alkynyl group, a C 6-10  aryl group, a 5 to 10-membered heteroaryl group, a 4 to 8-membered heterocyclic C 1-6  alkyl group, a C 6-10  aryl C 1-6  alkyl group, or a 5 to 10-membered heteroaryl C 1-6  alkyl group)).  
 
 
     
     
         2 . The compound according to  claim 1 , or a salt or hydrate thereof, wherein T 1  is, 
 a group represented by the following formula:                           (wherein, n and m each independently represent 0 or 1) which may have one or more substituents;    an azetidin-1-yl group which may have one or more substituents;    a pyrrolidin-1-yl group which may have one or more substituents;    a piperidin-1-yl group which may have one or more substituents; or    an azepan-1-yl group which may have one or more substituents.    
     
     
         3 . The compound according to  claim 1 , or a salt or hydrate thereof, wherein T 1  is, 
 a group represented by the following formula                           (where n and m each independently represent 0 or 1);    an azetidin-1-yl group which may have an amino group;    a pyrrolidin-1-yl group which may have an amino group;    a piperidin-1-yl group which may have an amino group; or    an azepan-1-yl group which may have an amino group.    
     
     
         4 . The compound according to  claim 1 , or a salt or hydrate thereof, wherein T 1  is a piperazin-1-yl group or a 3-aminopiperidin-1-yl group.  
     
     
         5 . The compound according to  claim 1 , or a salt or hydrate thereof, wherein T 1  is a piperazin-1-yl group.  
     
     
         6 . The compound according to any one of  claims 1  to  5 , or a salt or hydrate thereof, wherein X is a group represented by the formula —X 1 —X 2  (where X 1  represents a single bond or a methylene group which may have one or more substituents; X 2  represents a C 2-6  alkenyl group which may have one or more substituents, a C 2-6  alkynyl group may have one or more substituents, or a phenyl group which may have one or more substituents).  
     
     
         7 . The compound according to any one of  claims 1  to  5 , or a salt or hydrate thereof, wherein X is a group represented by the formula —X 11 —X 12  (where X 11  represents a single bond or a methylene group; X 12  represents a C 2-6  alkenyl group, a C 2-6  alkynyl group, or a phenyl group which may have one or more substituents).  
     
     
         8 . The compound according to  claim 6  or  7 , or a salt or hydrate thereof, wherein the phenyl group that may have one or more substituents is a phenyl group which may have at the 2-position a substituent selected from the group consisting of a hydroxyl group, a fluorine atom, a chlorine atom, a methyl group, an ethyl group, a fluoromethyl group, a vinyl group, a methoxy group, an ethoxy group, an acetyl group, a cyano group, a formyl group, and a C 2-7  alkoxycarbonyl group.  
     
     
         9 . The compound according to any one of  claims 1  to  5 , or a salt or hydrate thereof, wherein X is a 3-methyl-2-buten-1-yl group, a 2-butyn-1-yl group, a benzyl group, or a 2-chlorophenyl group.  
     
     
         10 . The compound according to any one of  claims 1  to  5 , or a salt or hydrate thereof, wherein X is a 2-butyn-1-yl group.  
     
     
         11 . The compound according to any one of  claims 1  to  10 , or a salt or hydrate thereof, wherein either the Z 1  or Z 2  is a nitrogen atom.  
     
     
         12 . The compound according to any one of  claims 1  to  10 , or a salt or hydrate thereof, wherein, 
 Z 1  is a nitrogen atom; and  
 Z 2  is a group represented by the formula —CR 2 ═
 (where R 2  is as defined above in  claim 1) .  
 
 
     
     
         13 . The compound according to any one of  claims 1  to  10 , or a salt or a hydrate thereof, wherein, 
 Z 2  is a nitrogen atom; and  
 Z 1  is a group represented by the formula —CR 2 ═
 (where R 2  is as defined above in  claim 1) .  
 
 
     
     
         14 . The compound according to any one of  claims 1  to  13 , or a salt or hydrate thereof,  
       wherein R 1  represents a hydrogen atom, or a group represented by the formula -A 10 -A 11 -A 12    
       (where 
 A 10  represents a C 1-6  alkylene group which may have 1 to 3 substituents selected from the substituent group C described below;  
 A 11  represents a single bond, an oxygen atom, a sulfur atom or a carbonyl group;  
 A 12  represents a hydrogen atom, a C 6-10  aryl group which may have 1 to 3 substituents selected from the substituent group C described below, a 5 to 10-membered heteroaryl group which may have 1 to 3 substituents selected from the substituent group C described below, a 5 to 10-membered heteroaryl C 1-6  alkyl group which may have 1 to 3 substituents selected from the substituent group C described below, or a C 6-10  aryl C 1-6  alkyl group which may have 1 to 3 substituents selected from the substituent group C described below:  
 <Substituent group C> 
 Substituent group C represents the group consisting of: a hydroxyl group, a nitro group, a cyano group, a halogen atom, a C 1-6  alkyl group, a C 1-6  alkoxy group, a C 1-6  alkylthio group, a trifluoromethyl group, a group represented by the formula —NR C1 —R C2  (where each of R C1  and R C2  independently represent a hydrogen atom or C 1-6  alkyl group), a group represented by the formula —CO—R C3 —R C4  and a group represented by the formula —CH 2 —CO—R C3 —R C4  (where R C3  represents a single bond, an oxygen atom, or a group represented by the formula —NR C5 —; R C4  and R C5  each independently represent a hydrogen atom or a C 1-6  alkyl group).  
 
     
     
         15 . The compound according to any one of  claims 1  to  13 , or a salt or hydrate thereof,  
       wherein R 1  is a hydrogen atom, a C 1-6  alkyl group which may have 1 to 3 substituents selected from the substituent group C described below, a 5 to 10-membered heteroaryl C 1-6  alkyl group which may have 1 to 3 substituents selected from the substituent group C described below, or a C 6-10  aryl C 1-6  alkyl group which may have 1 to 3 substituents selected from the substituent group C described below: 
 <Substituent group C> 
 Substituent group C represents the group consisting of: a hydroxyl group, a nitro group, a cyano group, a halogen atom, a C 1-6  alkyl group, a C 1-6  alkoxy group, a C 1-6  alkylthio group, a trifluoromethyl group, a group represented by the formula —NR C1 —R C2  (where each of R C1  and R C2  independently represent a hydrogen atom or a C 1-6  alkyl group), a group represented by the formula —CO—R C3 —R C4  and a group represented by the formula —CH 2 —CO—R C3 —R C4  (where R C3  represents a single bond, an oxygen atom, or a group represented by the formula —NR C5 —; R C4  and R C5  each independently represent a hydrogen atom or a C 1-6  alkyl group);  
 
     
     
         16 . The compound according to  claim 14  or  15 , or a salt or hydrate thereof, wherein the substituent group C is a group consisting of a cyano group, a C 1-6  alkoxy group, a C 2-7  alkoxycarbonyl group, and a halogen atom.  
     
     
         17 . The compound according to any one of  claims 1  to  13 , or a salt or hydrate thereof, wherein R 1  is a methyl group, a cyanobenzyl group, a fluorocyanobenzyl group, a phenethyl group, a 2-methoxyethyl group, or a 4-methoxycarbonylpyridin-2-yl group.  
     
     
         18 . The compound according to any one of  claims 1  to  13 , or a salt or hydrate thereof, wherein R 1  is a methyl group or a 2-cyanobenzyl group.  
     
     
         19 . The compound according to any one of  claims 1  to  18 , or a salt or hydrate thereof,  
       wherein R 2  is a hydrogen atom, a cyano group, or a group represented by the formula -A 21 -A 22  
 (where A 21  represents a single bond, an oxygen atom, a sulfur atom, a sulfinyl group, a sulfonyl group, a carbonyl group, a group represented by the formula —O—CO—, a group represented by the formula —CO—O—, a group represented by the formula —NR A2 —, a group represented by the formula —CO—NR A2 —, or a group represented by the formula —NR A2 —CO—;  
 A 22  and R A2  each independently represent a hydrogen atom, a cyano group, a C 1-6  alkyl group, a C 3-8  cycloalkyl group, a C 2-6  alkenyl group, a C 2-6  alkynyl group, a C 6-10  aryl group, a 5- to 10-membered heteroaryl group, a 4- to 8-membered heterocyclic group, a 5to 10-membered heteroaryl C 1-6  alkyl group, or a C 6-10  aryl C 1-6  alkyl group;  
 however, A 22  and R A2  each may independently have 1- to 3 substituents selected from the substituent group D described below: 
 <Substituent group D> 
 Substituent group D represents the group consisting of: a hydroxyl group, a cyano group, a nitro group, a halogen atom, a C 1-6  alkyl group, a C 1-6  alkoxy group, a C 1-6  alkylthio group, a trifluoromethyl group, a group represented by the formula —NR D1 —R D2  (where R D1  and R D2  each independently represent a hydrogen atom or a C 1-6  alkyl group), a group represented by the formula —CO—R D3  (where R D3  represents a 4 to 8-membered heterocyclic group), and a group represented by the formula —CO—R D4 —R D5  (where R D4  represents a single bond, an oxygen atom, or a group represented by the formula —NR D6 —; R D5  and R D6  each independently represent a hydrogen atom, a C 3-8  cycloalkyl group, or a C 1-6  alkyl group)).  
 
 
     
     
         20 . The compound according to any one of  claims 1  to  18 , or a salt or hydrate thereof,  
       wherein R 2  represents a hydrogen atom, a cyano group, a carboxy group, a C 2-7  alkoxycarbonyl group, a C 1-6  alkyl group, a group represented by the formula —CONR D7 R D8  (where R D7  and R D8  each independently represent a hydrogen atom or a C 1-6  alkyl group), or a group represented by the formula -A 23 -A 24    
       (where 
 A 23  represents an oxygen atom, a sulfur atom or a group represented by the formula —NR A3 —;  
 A 24  and R A3  each independently represent a hydrogen atom, a C 1-6  alkyl group which may have a substituent selected from the substituent group D1 described below, a C 3-8  cycloalkyl group which may have a substituent selected from the substituent group D1 described below, a C 2-6  alkenyl group which may have a substituent selected from the substituent group D1 described below, a C 2-6  alkynyl group which may have a substituent selected from the substituent group D1 described below, a phenyl group which may have a substituent selected from the substituent group D1 described below, or a 5 to 10-membered heteroaryl group which may have a substituent selected from the substituent group D1 described below: 
 <Substituent group D1> 
 Substituent group D1 represents the group consisting of: a carboxy group, a C 2-7  alkoxycarbonyl group, a C 1-6  alkyl group, a group represented by the formula —CONR D7 R D8  (where R D7  and R D8  each independently represent a hydrogen atom or C 1-6  alkyl group), a pyrrolidin-1-ylcarbonyl group, a C 1-6  alkyl group, and a C 1-6  alkoxy group).  
 
 
     
     
         21 . The compound according to any one of  claims 1  to  18 , or a salt or hydrate thereof,  
       wherein R represents a hydrogen atom, a cyano group, a C 1-6  alkoxy group, or a group represented by the formula -A 25 -A 26    
       (where 
 A 25  represents an oxygen atom, a sulfur atom, or a group represented by the formula —NR A4 —;  
 A 26  and R A4  each independently represent a hydrogen atom, a C 1-6  alkyl group having a substituent selected from the substituent group D1 described below, a C 3-8  cycloalkyl group having a substituent selected from the substituent group D1 described below, or a phenyl group having a substituent selected from the substituent group D1 described below: 
 <Substituent group D1> 
 Substituent group D1 represents the group consisting of: a carboxy group, a C 2-7  alkoxycarbonyl group, a C 1-6  alkyl group, a group represented by the formula —CONR D7 R D8  (where R D7  and R D8  each independently represent a hydrogen atom or a C 1-6  alkyl group), pyrrolidin-1-ylcarbonyl group, a C 1-6  alkyl group, and a C 1-6  alkoxy group).  
 
 
     
     
         22 . The compound according to any one of  claims 1  to  18 , or a salt or hydrate thereof,  
       wherein R 2  is a hydrogen atom, a cyano group, a methoxy group, a carbamoylphenyloxy group, or a group represented by the following formula:  
       
         
           
           
               
               
           
         
       
       (where A 27  represents an oxygen atom, a sulfur atom, or —NH—; A 28  and A 29  each independently represent a hydrogen atom or a C 1-6  alkyl group).  
     
     
         23 . The compound according to any one of  claims 1  to  18 , or a salt or hydrate thereof, wherein R 2  is a hydrogen atom, a cyano group, or a 2-carbamoylphenyloxy group.  
     
     
         24 . The compound according to  claim 1 , or a salt or hydrate thereof, wherein the compound of formula (I) indicated above is any one selected from the group consisting of: 
 7-(2-butynyl)-2-cyano-1-methyl-8-(piperazin-1-yl)-1,7-dihydropurin-6-one,    3-(2-butynyl)-5-methyl-2-(piperazin-1-yl)-3,5-dihydroimidazo[4,5-d]pyridazin-4-one,    2-(3-aminopiperidin-1-yl)-3-(2-butynyl)-5-methyl-3,5-dihydroimidazo[4,5-d]pyridazin-4-one,    2-[7-(2-butynyl)-1-methyl-6-oxo-8-(piperazin-1-yl)-6,7-dihydro-1H-purin-2-yloxy]benzamide,    7-(2-butynyl)-1-(2-cyanobenzyl)-6-oxo-8-(piperazin-1-yl)-6,7-dihydro-1H-purine-2-carbonitrile, and    2-[3-(2-butynyl)-4-oxo-2-(piperazin-1-yl)-3,4-dihydroimidazo[4,5-d]pyridazin-5-ylmethyl]benzonitrile.    
     
     
         25 . A pharmaceutical agent comprising a compound of  claim 1 .  
     
     
         26 . Adipeptidyl peptidase IV inhibitor comprising a compound of  claim 1 .  
     
     
         27 . A pharmaceutical composition comprising a compound of  claim 1  and an adjuvant useful for formulation.  
     
     
         28 . A preventive or a therapeutic agent for diabetes mellitus, which comprises a compound of  claim 1 .  
     
     
         29 . A preventive or therapeutic agent, which comprises a compound of  claim 1 , for diabetes mellitus, obesity, hyperlipidemia, AIDS, osteoporosis, a gastrointestinal disorder, angiogenesis, infertility, an inflammatory disease, an allergic disease, or cancer.  
     
     
         30 . An immunomodulator, a hormone modulator, or an anti-rheumatic drug, which comprises a compound of  claim 1 .  
     
     
         31 . A therapeutic or preventive method for a disease in which the inhibition of dipeptidyl peptidase IV is effective, wherein the method comprises administering to a patient a compound of  claim 1 , or a salt or hydrate thereof, in a pharmaceutically effective amount.  
     
     
         32 . The use of a compound of  claim 1 , or a salt or hydrate thereof, in producing a pharmaceutical agent.  
     
     
         33 . The use of a compound of  claim 1 , or a salt or hydrate thereof, in producing a therapeutic or preventive agent for a disease in which the inhibition of dipeptidyl peptidase IV is effective.