Multiheteroaryl compounds as inhibitors of h-pgds and their use for treating prostaglandin d2 mediated diseases

Abstract

Multiheteroaryl compounds, their preparation, pharmaceutical compositions comprising these compounds, and their pharmaceutical use in the prevention and treatment of prostaglandin D 2 mediated diseases and conditions that may be modulated by the inhibition of hematopoietic prostaglandin D synthase (H-PGDS).

1 .- 60 . (canceled) 
     
     
         61 . A compound of Formula (II): 
       
         
           
           
               
               
           
         
       
       wherein:
 R 1  is (C 1 -C 6 )-alkyl, (C 3 -C 6 )-cycloalkyl, phenyl, 2-pyridyl, 3-pyridyl, or 4-pyridyl; wherein each phenyl, 2-pyridyl, 3-pyridyl, or 4-pyridyl of R 1  may be optionally substituted with no more than two of each or a combination of fluoro, hydroxy, —CH 2 OH, carboxy, carboxymethyl, or carboxyethyl; 
 R 2  is —(CH 2 ) n Z 1  or —(CH 2 ) n Z 2 ; 
 n is 0, 1, 2, 3, or 4; 
 Z 1  is hydrogen, OR 3 , C(O)R 3 , CO 2 R 3 , C(O)NR 4 R 5 , SO 2 NR 4 R 5 , SO 2 R 3 , (C 1 -C 6 )-alkyl, (C 3 -C 6 )-cycloalkyl, (C 3 -C 6 )-alkenyl, (C 3 -C 6 )-alkynyl, (C 6 -C 14 )-aryl, (CH 2 ) p CF 3 , a five- to ten-membered heteroaryl, 
 
       
         
           
           
               
               
           
         
       
       or a three- to ten-membered heterocycle; wherein any one nitrogen atom of any heterocycle containing one or more nitrogen atoms that may be substituted with a non-ring atom are substituted with —(CH 2 ) q Q;
 Z 2  is cyano, trifluoromethyl, (CF 2 ) p CF 3 , SR 3 , NR 4 R 5 , N(H)C(O)R 3 , N(H)CO 2 R 3 , N(H)C(O)NR 4 R 5 , N(H)SO 2 R 3 , vinyl, or ethynyl when n is 1, 2, 3 or 4; 
 Z 2  may also be cyano, trifluoromethyl, (CF 2 ) p CF 3 , SR 3 , NR 4 R 5 , N(H)C(O)R 3 , N(H)CO 2 R 3 , N(H)C(O)NR 4 R 5 , N(H)SO 2 R 3 , vinyl, or ethynyl when n is 0, except when R 2  is covalently bonded to a U 1 , U 2 , U 3 , or U 4  that is a nitrogen atom; 
 R 3  is hydrogen, (C 1 -C 6 )-alkyl, trifluoromethyl, (C 3 -C 6 )-alkenyl, (C 3 -C 6 )-alkynyl, (CH 2 ) m (C 3 -C 6 )-cycloalkyl, (CH 2 ) m phenyl, (CH 2 ) m -(five- to ten-membered heteroaryl), or (CH 2 ) m (three- to ten-membered heterocycle); wherein any one nitrogen atom of any heterocycle containing one or more nitrogen atoms that may be substituted with a non-ring atom are substituted with —(CH 2 ) q Q; 
 m is 0, 1, 2, 3, or 4; 
 q is 0, 1, 2, 3, or 4; 
 Q is hydrogen, (C 1 -C 6 )-alkyl, (CH 2 ) p CF 3 , (C 3 -C 6 )-alkenyl, (C 3 -C 6 )-alkynyl, (C 3 -C 6 )-cycloalkyl, (C 6 -C 14 )-aryl, C(O)R 3 , CO 2 R 3 , C(O)NR 4 R 5 , a three- to six-membered heterocycle, or a five- to ten-membered heteroaryl when q is 0, 1, 2, 3, or 4; 
 Q may also be cyano, trifluoromethyl, or SO 2 NR 4 R 5  when q is 1, 2, 3, or 4; 
 Q may also be hydroxy, (C 1 -C 6 )-alkoxy, sulfhydryl, —S—(C 1 -C 6 )-alkyl, or NR 4 R 5  when q is 2, 3, or 4; 
 p is 1, 2, or 3; 
 R 3  may also be vinyl or ethynyl when R 3  is not covalently bonded to an N or O atom; 
 R 3  may also be vinyl or ethynyl when R 3  is not covalently bonded to an S atom possessing a −2 (minus 2) oxidation state; 
 R 4  and R 5  are independently hydrogen, (C 1 -C 6 )-alkyl, (C 3 -C 6 )-alkenyl, (C 3 -C 6 )-alkynyl, (CH 2 ) m (C 3 -C 6 )-cycloalkyl, (CH 2 ) m phenyl, (CH 2 ) m -(three- to ten-membered heterocycyl), or (CH 2 ) m -(five- to ten-membered heteroaryl); 
 the NR 4 R 5  group of any C(O)NR 4 R 5 , SO 2 NR 4 R 5 , NR 4 R 5 , or N(H)C(O)NR 4 R 5  may also form a pyrrolidine, a piperidine, a morpholine, a thiomorpholine, or a thiomorpholine S-dioxide; 
 the NR 4 R 5  group of any C(O)NR 4 R 5 , SO 2 NR 4 R 5 , NR 4 R 5 , or N(H)C(O)NR 4 R 5  may also form a piperazine ring, wherein the other nitrogen atom of the piperazine ring is substituted with hydrogen, (C 1 -C 6 )-alkyl, CH 2 CF 3 , (C 3 -C 6 )-cycloalkyl, CH 2 (C 3 -C 6 )-cycloalkyl, phenyl, benzyl, hydroxyethyl, or hydroxypropyl; 
 phenyl or heteroaryl rings of Z 1  and Z 2  are optionally substituted with one-to-three of any one or combination of the following: halo, hydroxy, sulfhydryl, (C 1 -C 3 )-alkoxy, (C 1 -C 3 )-alkyl, (C 1 -C 3 )-alkylthio, trifluoromethyl, trifluoromethoxy, cyano, carboxy, carboxy(C 1 -C 3 )-alkyl, carbamoyl, or sulfamoyl; 
 W is a covalent bond, O, S, SO, SO 2 , CH 2 , CHOH, CO, or NH; 
 U 1 , U 2 , U 3 , U 4 , and a carbon atom form a five-membered heteroaryl ring; wherein one of U 1 , U 2 , U 3 , and U 4  of the five-membered heteroaryl ring is covalently bonded to the R 2  group; wherein the U 1 , U 2 , U 3 , or U 4  that is covalently bonded to the R 2  group is a carbon atom or a nitrogen atom; wherein when the U 1 , U 2 , U 3 , or U 4  that is covalently bonded to the R 2  group is a nitrogen atom, one, two, or all of the other three of the group consisting of U 1 , U 2 , U 3 , and U 4  is N and each remaining of the group consisting of U 1 , U 2 , U 3 , and U 4  that is not N is C—R 6 ; wherein when the U 1 , U 2 , U 3 , or U 4  that is covalently bonded to the R 2  group is a carbon atom, one of the other three of the group consisting of U 1 , U 2 , U 3 , and U 4  is N—R 6 , O, or S, and each of remaining of the group consisting of U 1 , U 2 , U 3 , and U 4  is C—R 6  or N; 
 Y 4  is O, S, or N—R 7 ; 
 each R 6  is independently hydrogen, methyl, trifluoromethyl, or amino; and 
 each R 7  is independently hydrogen or methyl. 
 
     
     
         62 . A compound of  claim 61 , wherein Y 4  is S. 
     
     
         63 . A compound of  claim 62 , wherein W is a covalent bond. 
     
     
         64 . A pharmaceutical composition comprising a compound of  claim 61 , or an equivalent thereof. 
     
     
         65 . A method of treating a disease or condition mediated at least in part by prostaglandin D 2  produced by H-PGDS, in a subject in need of such treatment, comprising administering to the subject a therapeutically effective amount of a compound of  claim 61 . 
     
     
         66 . The method of  claim 65  wherein the disease or condition is allergy or allergic inflammation. 
     
     
         67 . The method of  claim 65  wherein the disease or condition is asthma. 
     
     
         68 . The method of  claim 65  wherein the disease or condition is Duchenne muscular dystrophy. 
     
     
         69 . A pharmaceutical composition comprising a compound of  claim 61 , and a second pharmacologically active compound.