ARYLPYRAZOLE ETHERS AS INHIBITORS OF LEUKOTRIENE A4 HYDROLASE

摘要

The present invention relates to compounds of formula I or a pharmaceutically acceptable salt thereof, wherein A1, A2, A3, L1, L2 and D are as defined herein. The compounds of formula (I) are useful as inhibitors of leukotriene A4 hydrolase (LTA4H) and treating LTA4H related disorder. The present invention also relates to pharmaceutical compositions comprising the Compounds of formula (I), methods of using these compounds in the treatment of various diseases and disorders, and processes for preparing these compounds.;

主权项

1. A compound of formula (I): or a pharmaceutically acceptable salt thereof, wherein: A1, A2 and A3 are each independently CH or N; L1 is a linker selected from —O— and —CH2—; L2 is absent or a —(C1-C6)alkylene- linker; wherein said —(C1-C6)alkylene- linker is optionally substituted with one to three groups selected from —OH, halo, —(C1-C6)alkyl; D is a ring selected from
(a) —(C3-C7)cycloalkyl, (C6-C10)aryl, and -(5- to 11-membered)heteroaryl;(b) -(4- to 11-membered)heterocycloalkyl, comprising an O or S ring atom and optionally 1 to 3 additional ring heteroatoms selected from N, O, and S;(c) 4-8 member monocyclic heterocyclic comprising a N ring atom and 1 to 3 additional ring heteroatoms selected from N, O, and S;(d) a 6 to 11-membered fused bicyclic, bridged bicyclic or spirocyclic heterocyclic radical comprising a N ring atom and optionally 1 to 3 additional ring heteroatoms selected from N, O, and S; and(e) a group selected from 2-oxo-pyrrolidin-1-yl, 2-oxo-pyrrolidin-3-yl, 2-oxo-pyrrolidin-5-yl, 1-methyl-2-oxo-pyrrolidin-4-yl, and 2-oxo-piperidin-5-yl wherein each of said D rings is optionally substituted with one to three R1 groups; and wherein each of said D rings is further optionally substituted, where possible, by one or two groups independently selected from (═O) and (═S); each R1 is independently selected from halo, —OH, —CF3, —CN, —(C1-C6)alkyl, —O(C1-C6)alkyl, —C(O)R2, —C(O)OR2, —C(O)N(R2)2, —N(R2)2, —N(R2)C(O)R2, —S(O)2R2, —N(R2)—S(O)2—R2, —(C3-C6)cycloalkyl, -(5- to 11-membered)heterocycloalkyl, —(C6-C10)aryl, and -(5- to 11-membered)heteroaryl; wherein each of said, —(C1-C6)alkyl, —(C1-C6)alkyl, —(C3-C6)cycloalkyl, -(5- to 11-membered)heterocycloalkyl, —(C6-C10)aryl, and -(5- to 11-membered)heteroaryl of said R1 group is optionally substituted with one to three groups selected from halo, —OH, —CF3, —(C1-C6)alkyl, —C(O)OH, —C(O)OC1-C6)alkyl, —C(O)(C1-C6)alkyl), —NH2, —NH(C1-C6)alkyl, N((C1-C6)alkyl)2 and —CN; each R2 is independently selected from the group consisting of —H, —(C1-C6)alkyl, —(C3-C6)cycloalkyl, -(5- to 11-membered)heterocycloalkyl, —(C6-C10)aryl, and -(5- to 11-membered)heteroaryl; wherein each of said, —(C1-C6)alkyl, —O(C1-C6)alkyl, —(C3-C6)cycloalkyl, -(5- to 11-membered)heterocycloalkyl, —(C6-C10)aryl, and -(5- to 11-membered)heteroaryl of said R2 group is optionally independently substituted by one to three groups selected from halo, —OH, —CF3, —(C1-C6)alkyl, —NH2, —NH(C1-C6)alkyl, —N((C1-C6)alkyl)2 and —CN.