Nitrogen-containing spiro cyclic compounds and pharmaceutical uses thereof

Abstract

A compound of the following general formula [I]:wherein each symbol has the same meaning as defined herein, or a pharmaceutically acceptable salt thereof, or a solvate thereof, and a pharmaceutical use of the same in treating organ transplant rejection, graft versus host reaction after transplantation, autoimmune disease, allergic disease and chronic myeloproliferative disease.

1 . A compound of formula [I]: 
       
         
           
           
               
               
           
         
         wherein R a  is the same or different and each is: 
         (1) C 1-6  alkyl, or 
         (2) halogen atom,
 n1 is an integer selected from 0 to 4, 
 R b  is the same or different and each is: 
 
         (1) C 1-6  alkyl, or 
         (2) halogen atom,
 n2 is an integer selected from 0 to 4, 
 m1 is an integer selected from 0 to 3, 
 m2 is an integer selected from 1 to 4, 
 X a ═X b  is: 
 
         (1) CH═CH, 
         (2) N═CH, or 
         (3) CH═N,
 X is: 
 
         (1) nitrogen atom, or 
         (2) C—R d  wherein R d  is hydrogen atom or halogen atom,
 R c  is a group selected from the following (1) to (6): 
 
         (1) hydrogen atom, 
         (2) C 1-6  alkyl optionally substituted by the same or different 1 to 5 substituents selected from the following Group A, 
         (3) —C(═O)—R c1 , 
         (4) —C(═O)—O—R c2    
         (5) —C(═O)—NR c3 R c4    
         in which R c1 , R c2 , R c3  and R c4  are the same or different and each is: 
         (i) hydrogen atom, or 
         (ii) C 1-6  alkyl optionally substituted by the same or different 1 to 5 substituents selected from the following Group A, and 
         (6) a group of formula: 
       
       
         
           
           
               
               
           
         
         in which Y a  is a group selected from the following (i) to (iii): 
         (i) C 1-6  alkylene, 
         (ii) —C(═O)—, and 
         (iii) —C(═O)—O—,
 Ring T is: 
 
         (i) C 6-10  aryl, 
         (ii) C 3-10  cycloalkyl, or 
         (iii) saturated monoheterocyclyl wherein the saturated monoheterocyclyl comprises 1 to 4 heteroatoms selected from nitrogen atom, oxygen atom or sulfur atom as well as carbon atoms and the number of the constituent ring atoms is 3 to 7,
 R c5  is the same or different and each is: 
 
         (i) cyano, or 
         (ii) nitro,
 p is an integer selected from 0 to 4, 
 Group A is selected from the group consisting of: 
 
         (a) hydroxyl, 
         (b) C 1-6  alkoxy, 
         (c) cyano, 
         (d) C 1-6  alkoxycarbonyl, 
         (e) C 1-6  alkylcarbonyloxy, and 
         (f) C 2-6  alkenyloxy, or a pharmaceutically acceptable salt thereof, or a solvate of the compound or salt thereof, provided that when X a ═X b  is CH═CH, then X is C—R d  wherein R d  is hydrogen atom or halogen atom. 
       
     
     
         2 . The compound as claimed in  claim 1 , wherein,
 n1 is an integer selected from 0 to 2,   n2 is an integer selected from 0 to 2,   m1 is an integer selected from 0 to 3,   m2 is an integer selected from 1 to 3,   X is:   (1) nitrogen atom, or   (2) C—R d  wherein R d  is halogen atom,
 R c  is a group selected from the following (1) to (6): 
   (1) hydrogen atom,   (2) C 1-6  alkyl substituted by one substituent selected from the following Group A,   (3) —C(═O)—R c1 ,   (4) —C(═O)—O—R c2 ,   (5) —C(═O)—NR c3 R c4      in which R c1  is C 1-6  alkyl optionally substituted by one substituent selected from the following Group A,
 R c2  is C 1-6  alkyl, 
 R c3  is C 1-6  alkyl optionally substituted by one substituent selected from the following Group A, 
 R c4  is 
   (i) hydrogen atom, or   (ii) C 1-6  alkyl, and   (6) a group of formula:   
       
         
           
           
               
               
           
         
         in which Y a  is a group selected from the following (i) to (iii): 
         (i) C 1-6  alkylene, 
         (ii) —C(═O)—, and 
         (iii) —C(═O)—O—,
 Ring T is: 
 
         (i) phenyl, 
         (ii) C 3-6  cycloalkyl, or 
         (iii) pyrrolidinyl,
 R c5  is 
 
         (i) cyano, or 
         (ii) nitro,
 p is an integer selected from 0 or 1, 
 Group A is selected from the group consisting of: 
 
         (a) hydroxyl, 
         (b) C 1-6  alkoxy, 
         (c) cyano, 
         (d) C 1-6  alkoxycarbonyl, 
         (e) C 1-6  alkylcarbonyloxy, and 
         (f) C 2-6  alkenyloxy, or a pharmaceutically acceptable salt thereof, or a solvate of the compound or salt thereof. 
       
     
     
         3 . The compound as claimed in  claim 1 , wherein m1 is an integer of 0 or 1 and m2 is an integer of 1 or 2, or a pharmaceutically acceptable salt thereof, or a solvate of the compound or salt thereof. 
     
     
         4 . The compound as claimed in  claim 3 , wherein m1 is 1 and m2 is 2, which is a compound of formula [II]: 
       
         
           
           
               
               
           
         
         wherein each symbol has the same meaning as defined in  claim 1 , or a pharmaceutically acceptable salt thereof, or a solvate of the compound or salt thereof. 
       
     
     
         5 . The compound as claimed in  claim 3 , wherein m1 is 0 and m2 is 2, which is a compound of formula [III]: 
       
         
           
           
               
               
           
         
         wherein each symbol has the same meaning as defined in  claim 1 , or a pharmaceutically acceptable salt thereof, or a solvate of the compound or salt thereof. 
       
     
     
         6 . The compound as claimed in  claim 3 , wherein m1 is 0 and m2 is 1, which is a compound of the general formula [IV]: 
       
         
           
           
               
               
           
         
         wherein each symbol has the same meaning as defined in  claim 1 , or a pharmaceutically acceptable salt thereof, or a solvate of the compound or salt thereof. 
       
     
     
         7 . The compound as claimed in  claim 1 , wherein m1 is 0 and m2 is 3, or m1 is 2 and m2 is 1, or m1 is 2 and m2 is 2, or m1 is 3 and m2 is 2, or a pharmaceutically acceptable salt thereof, or a solvate of the compound or salt thereof. 
     
     
         8 . (canceled) 
     
     
         9 . The compound as claimed in  claim 1 , wherein n1 is 0 and n2 is 0, or a pharmaceutically acceptable salt thereof, or a solvate of the compound or salt thereof. 
     
     
         10 . The compound as claimed in  claim 1 , wherein n1 is 1 and n2 is 0, or a pharmaceutically acceptable salt thereof, or a solvate of the compound or salt thereof. 
     
     
         11 . The compound as claimed in  claim 1 , wherein n1 is 0 and n2 is 1, or a pharmaceutically acceptable salt thereof, or a solvate of the compound or salt thereof. 
     
     
         12 . The compound as claimed in  claim 1 , wherein n1 is 2 and n2 is 0, or a pharmaceutically acceptable salt thereof, or a solvate of the compound or salt thereof. 
     
     
         13 . The compound as claimed in  claim 1 , wherein n1 is 0 and n2 is 2, or a pharmaceutically acceptable salt thereof, or a solvate of the compound or salt thereof. 
     
     
         14 . The compound as claimed in  claim 10 , wherein R a  is methyl or fluorine atom, or a pharmaceutically acceptable salt thereof, or a solvate of the compound or salt thereof. 
     
     
         15 . The compound as claimed in  claim 1 , wherein R c  is —C(═O)—R c1 , or a pharmaceutically acceptable salt thereof, or a solvate of the compound or salt thereof. 
     
     
         16 . The compound as claimed in  claim 15 , wherein R c1  is C 1-6  alkyl substituted by one hydroxyl or cyano group, or a pharmaceutically acceptable salt thereof, or a solvate of the compound or salt thereof. 
     
     
         17 . The compound as claimed in  claim 1 , wherein R c  is —C(═O)—NR c3 R c4 , or a pharmaceutically acceptable salt thereof, or a solvate of the compound or salt thereof. 
     
     
         18 . The compound as claimed in  claim 17 , wherein R c3  is C 1-6  alkyl substituted by one cyano group, and R c4  is hydrogen, or a pharmaceutically acceptable salt thereof, or a solvate of the compound or salt thereof. 
     
     
         19 .- 20 . (canceled) 
     
     
         21 . A pharmaceutical composition, comprising the compound as claimed in  claim 1  or a pharmaceutically acceptable salt thereof, or a solvate of the compound or salt thereof, and a pharmaceutically acceptable carrier. 
     
     
         22 .- 27 . (canceled) 
     
     
         28 . A method for inhibiting Janus kinase 2 or Janus kinase 3, comprising administering to a mammal in need thereof a pharmaceutically effective amount of the compound as claimed in  claim 1  or a pharmaceutically acceptable salt thereof, or a solvate of the compound or salt thereof. 
     
     
         29 . The method as claimed in  claim 28 , wherein the Janus kinase is Janus kinase 3. 
     
     
         30 . The method as claimed in  claim 28 , wherein the Janus kinase is Janus kinase 2. 
     
     
         31 . A method for treating or preventing a disease selected from the group consisting of organ transplant rejection and graft versus host reaction after transplantation, comprising administering to a mammal in need thereof a pharmaceutically effective amount of the compound as claimed in  claim 1  or a pharmaceutically acceptable salt thereof, or a solvate of the compound or salt thereof. 
     
     
         32 . A method for treating rheumatoid arthritis, comprising administering to a mammal in need thereof a pharmaceutically effective amount of the compound as claimed in  claim 1  or a pharmaceutically acceptable salt thereof, or a solvate of the compound or salt thereof. 
     
     
         33 . A method for treating psoriasis, comprising administering to a mammal in need thereof a pharmaceutically effective amount of the compound as claimed in  claim 1  or a pharmaceutically acceptable salt thereof, or a solvate of the compound or salt thereof. 
     
     
         34 .- 39 . (canceled) 
     
     
         40 . A method for treating atopic dermatitis, comprising administering to a mammal in need thereof a pharmaceutically effective amount of the compound as claimed in  claim 1  or a pharmaceutically acceptable salt thereof, or a solvate of the compound or salt thereof. 
     
     
         41 . A method for treating dry eye, comprising administering to a mammal in need thereof a pharmaceutically effective amount of the compound as claimed in  claim 1  or a pharmaceutically acceptable salt thereof, or a solvate of the compound or salt thereof.