JP-2025515096-A5 -

Dates

Publication Date

20260511

Application Date

20230503

Description

Assays for the efficacy of TRPA1 channel inhibitors: In some embodiments, the compounds described herein are tested for their activity against the TRPA1 channel. In some embodiments, the compounds described herein are tested for their TRPA1 channel electrophysiology. In some embodiments, the compounds described herein are tested for their hERG electrophysiology. The present specification includes the following embodiments. Item 1: Compounds of formula I, or pharmaceutically acceptable salts thereof, or tautomers thereof: (In the formula, Y is N or CR2 ; Z is N or CR 3 ; R1 is H, D, halogen, alkyl, cycloalkyl, alkyl halide, cycloalkyl halide, saturated heterocycle, CN, OR a , SR a , or NR a R b ; R2 is H, D, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, halogenated alkyl, halogenated alkenyl, halogenated alkynyl, halogenated cycloalkyl, saturated heterocycle, partially saturated heterocycle, aryl, heteroaryl, alkylaryl, alkylheteroaryl, CN, -C 1-4 alkyl-CN, OR a , SR a , NR a R b , (C=O)NR a R b , NR b (C=O)R a , (C=O)R a , (C=O)OR a , -C 1-4 alkyl-OR a , -C 1-4 alkyl-SR a , -C 1-4 alkyl-NR a R b , -C 1-4 alkyl-COOR a , -C 1-4 alkyl-CONR a R b , -C 1-4 alkyl-NR a COR b , O-C 1-4 alkyl-R a , or NR a -C 1-4 alkyl-R b ; R3 is H, D, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, halogenated alkyl, halogenated alkenyl, halogenated alkynyl, halogenated cycloalkyl, saturated heterocycle, partially saturated heterocycle, aryl, heteroaryl, alkylaryl, alkylheteroaryl, CN, -C 1-4 alkyl-CN, OR a , SR a , NR a R b , (C=O)NR a R b , NR b (C=O)R a , (C=O)R a , (C=O)OR a , -C 1-4 alkyl-OR a , -C 1-4 alkyl-SR a , -C 1-4 alkyl-NR a R b , -C 1-4 alkyl-COOR a , -C 1-4 alkyl-CONR a R b , -C 1-4 alkyl-NR a COR b , O-C 1-4 alkyl-R a , or NR a -C 1-4 alkyl-R b ; R4 is H, D, halogen, alkyl, cycloalkyl, alkyl halide, cycloalkyl halide, aryl, heteroaryl, saturated heterocycle, CN, OR a , SR a , -C 1-4 alkyl-OR a , or NR a R b ; This is an aryl or heteroaryl molecule that is optionally substituted with 1 to 5 substituents independently selected from the group consisting of H, D, halogen, alkyl, cycloalkyl, halogenated cycloalkyl, halogenated alkyl, alkenyl, alkynyl, aryl, heteroaryl, CN, OR a , SR a , NR a R b , -C 1-4 alkyl-SR a , or -C 1-4 alkyl-OR a ; L1 is - ( CR5R6 ) n- ; Each appearance of R 5 is independently H, D, alkyl, halogen, alkyl halide, cycloalkyl, cycloalkyl halide, CN, OR a , or -C 1-4 alkyl-OR a ; Each appearance of R 6 is independently H, D, alkyl, halogen, alkyl halide, cycloalkyl, cycloalkyl halide, CN, OR a , or -C1-4 alkyl-OR a ; n is either 2 or 3; L2 is -CR7R8- ; R7 is H, D, alkyl, alkyl halide, cycloalkyl, cycloalkyl halide, CN, or -C1-4 alkyl- ORa ; R8 is H, D, alkyl, alkyl halide, cycloalkyl, cycloalkyl halide, CN, or -C1-4 alkyl- ORa ; Each appearance of Ra a and R b is independently a saturated heterocycle, aryl, or heteroaryl comprising one to three heteroatoms selected from the group consisting of H, alkyl, (C=O)R x , (C=O)N(R x ) 2 , SO 2 R x , NR x (C=O)NR x 2 , cycloalkyl, alkyl halide, heteroalkyl, heteroalkyl halide, cycloalkyl halide, N, O, and S; or alternatively, Ra a and R b , together with the carbon or nitrogen atom to which they are bonded, form a cycloalkyl, or a saturated heterocycle comprising the nitrogen atom and 0 to 3 additional heteroatoms selected from the group consisting of N, O, and S; Where applicable, the alkyl, alkenyl, alkynyl, cycloalkyl, saturated heterocycle, partially saturated heterocycle , aryl, heteroaryl, alkylaryl, and alkylheteroaryl in R1, R2 , R3 , R4 , R5 , R6 , R7 , R8 , Ra , or Rb are optionally substituted, where valency allows, with one to four substituents independently selected from the group consisting of alkyl, cycloalkyl, halogenated cycloalkyl, halogenated alkyl , halogen, CN, OR x , -(CH2) 1-2 OR x , N(R x ) 2 , -( CH2 ) 1-2 N(R x ) 2 , (C=O)R x , (C= O ) N (R x)2, NR x (C=O)R x , and oxo; Each R x occurrence is independently a heterocycle substituted with H, D, alkyl, or optionally; or alternatively, two R x groups, along with the nitrogen atom to which they are bonded, are optionally substituted with alkyl, forming a heterocycle comprising the nitrogen atom and 0 to 3 additional heteroatoms selected from the group consisting of N, O, and S; However, when Z is N, R 4 is not OH. Item 2: The compound described in item 1, wherein Y is CR2 . Item 3: The compound described in item 1, wherein Y is N. Item 4: A compound according to any one of items 1 to 3, wherein Z is CR3 . Item 5: A compound according to any one of items 1 to 3, wherein Z is N. Item 6: A compound according to any one of items 1 to 5, wherein n is 2. Item 7: The compound according to any one of claims 1 to 6, wherein each appearance of R 5 is independently a cycloalkyl, a halogenated cycloalkyl, -C1-4alkyl -OR a , or CN. Item 8: The compound according to any one of claims 1 to 6, wherein each appearance of R 5 is independently H, D, alkyl, halogen, OR a , or fluorinated alkyl. Item 9: The