CONDENSED RING HETEROARYL COMPOUNDS AND USE THEREOF AS TRK INHIBITORS Russian patent published in 2019 - IPC C07D487/04 A61P35/00 A61P29/00 A61P17/00 A61P11/06 

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of general formula I or a pharmaceutically acceptable salt thereof. In a compound of formula I

,

IR1 is a phenyl ring substituted with one or more substituents independently selected from a group consisting of fluorine, methoxy and ethoxy; R2 is H; X is selected from a group consisting of -CH2- and -CH(Z)-, where Z is halogen; and Q is selected from a group consisting of -CH=CR3C(O)NR4R5, -C≡CC (O) NR4R5 and

; where R3 is H, where -NR4R5 either forms 4–7-member heterocyclic ring or does not form a ring structure, wherein the heterocyclic ring is 4–7-member heterocycloalkyl ring, where when -NR4R5 forms 4- to 7-member heterocyclic ring, 4–7 membered heterocyclic ring optionally includes a second heteroatom selected from N or O in addition to nitrogen in -NR4R5, and is optionally substituted with one or more substituents, independently selected from a group consisting of linear C1-C6 alkyl, branched C1-C6 alkyl, hydroxyl, where when -NR4R5 does not form a ring structure, then R4 is selected from a group consisting of hydrogen, linear C1-C6 alkyl and branched C1-C6 alkyl, linear C1-C6 hydroxyalkyl and branched C1-C6 hydroxyalkyl, and R5 is selected from H, methyl, ethyl, isopropyl, cyclopropyl, tert-butyl, methoxyethyl and hydroxyethyl, where each of Y1, Y2, Y3 and Y4 is independently selected from a group consisting of -CH, N, O, S, -CR6 and -NR6, provided that three of Y1, Y2, Y3 and Y4 are selected from N or NR6, or one of Y1, Y2, Y3 and Y4 is O or S, and one or two of Y1, Y2, Y3 and Y4 are N or NR6, where R6 is selected from a group consisting of hydrogen, linear C1-C4 alkyl, branched C1-C4 alkyl, 5-member heteroaryl ring having 2 nitrogen atoms in the ring, 5–7-member heterocycloalkyl ring having 1 to 2 nitrogen atoms and/or oxygen in ring, 3–7-member cycloalkyl ring, -NHCO- (phenyl ring) and -CH2CO- (6-member heterocyclic ring having 1–2 heteroatoms selected from nitrogen and oxygen); or R1 is a pyridine ring substituted with at least one substitute selected from a group consisting of fluorine and methoxy; R2 is H; X is selected from a group consisting of -CH2- and -CH(Z)-, where Z is halogen; and Q is selected from a group consisting of -CH=CR3C(O)NR4R5, -C≡CC (O) NR4R5 and

, where R3 is H, where -NR4R5 either forms 4–7-member heterocyclic ring or does not form a ring structure, wherein the heterocyclic ring is 4–7-membered heterocycloalkyl ring, where when -NR4R5 forms 4- to 7-member heterocyclic ring, 4–7 membered heterocyclic ring includes an optional second heteroatom selected from N or O, in addition to nitrogen in -NR4R5, and it is optionally substituted with one or more substitutes independently selected from a group consisting of linear C1-C6 alkyl, branched C1-C6 alkyl, hydroxyl, where when -NR4R5 does not form an annular structure, then R4 is selected from a group consisting of hydrogen, linear C1-C6 alkyl and branched C1-C6 alkyl, linear C1-C6 hydroxyalkyl and branched C1-C6 hydroxyalkyl, and R5 is selected from a group consisting of H, methyl, ethyl, isopropyl, cyclopropyl, tert-butyl, methoxyethyl and hydroxyethyl, with the proviso that R4 and R5 are not simultaneously hydrogen, where each of Y1, Y2, Y3 and Y4 is independently selected from a group consisting of -CH, N, O, S, -CR6 and -NR6, provided that three of Y1, Y2, Y3 and Y4 are selected from N or NR6, or one of Y1, Y2, Y3 and Y4 is O or S, and one or two of Y1, Y2, Y3 and Y4 are N or NR6, where R6 is selected from a group consisting of hydrogen, linear C1-C4 alkyl, branched C1-C4 alkyl, 5-member heteroaryl ring with 2 nitrogen atoms in the ring, 5–7 membered heterocycloalkyl ring having 1 to 2 nitrogen and/or oxygen atoms in the ring, 3–7-membered cycloalkyl ring, -NHCO- (phenyl ring) and -CH2CO- (6-member heterocyclic ring having 1–2 heteroatoms selected from nitrogen and oxygen); or the compound is (R, E)-4-(3-(5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl)acryloyl)piperazin-2-one (chemical compound 51) or (E)-3-(5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl)-1-(3-(2-hydroxypropan-2-yl)piperazin-1-yl)prop-2-en-1-one (chemical compound 52).

EFFECT: compounds have the properties of a Trk inhibitor and can be used to treat a TRK-mediated disease selected from a group consisting of papillary thyroid carcinoma, pancreatic cancer, lung cancer, colon cancer, breast carcinoma, neuroblastoma, pain, cachexia, dermatitis and asthma.

17 cl, 1 tbl, 74 ex