PROTEIN TYROSINE KINASE MODULATORS AND METHODS OF USE Russian patent published in 2018 - IPC C07D401/12 C07D401/14 C07D405/12 C07D239/48 A61K31/506 A61P29/00 

FIELD: chemistry.

SUBSTANCE: invention relates to a novel compound of formula I or a pharmaceutically acceptable salt thereof that inhibit kinase activity of the epidermal growth factor receptor (EGFR) or mutant forms thereof, selected from (i) L858R, (ii) T790M, (iii) L858R and T790M, (iv) delE746_A750 or (v) delE746_A750 and T790M, or ALK activity. Cancer caused by EGFR is non-small cell lung cancer (NSCLS), glioblastoma, pancreatic cancer, cancer of the head and neck (for example, squamous cell carcinoma), breast cancer, colorectal cancer, epithelial cancer, cancer of the ovaries, prostate cancer or adenocarcinoma. In the formula I

,

X is NR₁₆; R₁₆ is H; Y is halogen or unsubstituted or halogen substituted C_1-6alkyl; Z is O or CR₂₀R₂₁; and each R₂₀ or R₂₁ independently represents H; R₁ is hydroxy, N(R₈)(R₉), C(O)OR₈, C_1-4alkyl, 5-6 membered saturated heterocyclyl containing 1-2 heteroatoms selected from nitrogen or nitrogen and oxygen; each R₈ and R₉ is independently H, C₁-C₄alkyl, hydroxy-C_1-4alkyl, di(C₁-C₄alkyl)amino-C₁-C₄alkyl, 4-6 membered saturated heterocyclyl containing 1-2 heteroatoms selected from nitrogen which may be substituted with C₂alkenyl carbonyl group, C₃-C₆-cycloalkyl; R₂ is H; R₃ is H; R₄ is H, C_1-6alkoxy, halogen, 5-6-membered -O-heterocyclyl with 1 or 2 heteroatoms, selected from nitrogen and oxygen or -NR₂₄(CH₂)_PNR₂₄R₂₅; and P is 0, 1, 2 or 3, and each R₂₄ or R₂₅ independently represents H, unsubstituted C_1-6alkyl; R₅ is H, F, C_1-6alkyl, haloalkyl, C_1-6alkoxy, halogen C_1-6alkoxy, (diC₁-C₄alkyl) aminoC_1-6alkoxy, -NR₁₅C(O)(CH₂)_nCR₁₇=CR₁₈R₁₉, -NR₁₅C(O)(CH₂)_nCR₁₇=CH(CH₂)_mNR₁₈R₁₉, m or n is independently 0; and each of R₁₅, R₁₇, R₁₈ or R₁₉ is independently absent, is -H; R₇ is H, halogen, C_1-6alkyl, C_1-6alkoxy, -NR₂₂C(O)CR₂₃=CR₁₀R₁₁, -NR₂₂C(O)CR₂₃(CH₂)_sCHR₁₀R_l1,

,

where n=0, m=1, one of R₁₈ and R₁₉ is independently absent, and the other is a 3-6-membered nitrogen-containing saturated heterocyclyl or an amino group substituted with C₁-C₄alkyl; -NR₂₂C(O)CR₂₃=CR₁₀(CH₂)_sR₁₁, -NR₂₂C(O)CR₂₃(CH₂)_sNR₁₀(CH₂)_tNR₁₀R₁₁ or -NR₂₂C(O)(CH₂)_sCR₂₃=CH(CH₂)_tNR₁₀R₁₁, each s is 0, 1 or t is independently 1, 2; each of R₁₀, R₁₁, R₂₂ or R₂₃ independently represents H, C_1-4alkyl; or is a 5- or 6-membered heterocyclic ring containing 1, 2 heteroatoms independently selected from N or O, wherein the heterocyclic ring is unsubstituted or substituted with C₁-C₄alkyl, C₁-C₃alkylcarbonyl, di (C₁-C₄alkyl) amino group; or R₁₀ and R₁₁ together with the atoms to which they are attached, combine to form a 3-, 4-, 5- or 6-membered saturated heterocyclic ring, optionally containing an additional oxygen atom that is unsubstituted or substituted; and each s or t is independently 0, 1, 2 or 3; or R₆ merges with R₇ to form a 6-membered heterocyclic ring with a nitrogen and oxygen atom which may be substituted on the nitrogen atom by an acryloyl group; or R₆ is H, halogen, 4-6 membered heterocyclyl with 1 to 2 heteroatoms in the ring selected from nitrogen and oxygen, optionally substituted C₁-C₄acyl group, an acryloyl group, di(C₁-C₄alkyl) amino group; or R₆ represents -OR₁₃, -O-NR₁₂R₁₃, -NR₁₂R₁₃, -O(CH₂)_rR₁₃, -O(CH₂)_rNR₁₂R₁₃, -NR₁₂(CH₂)_rNR₁₂R₁₃, -NR₁₂(CH₂)_rR₁₃, -(CH₂)_rNR₁₂R₁₃ or -CH₂O(CH₂)_rNR₁₂R₁₃; or R₆ represents

;

and each R₁₂, R₁₃ independently represents H, C₁-C₄alkyl, C₃-C₆cycloalkyl, optionally substituted with a di(C₁-C₄alkyl) amino group, 4-6 membered heterocyclyl with 1 to 2 heteroatoms, selected from nitrogen and oxygen, and optionally with substituted halogen-C₁-C₄alkyl; r is 0, 1, 2, or 3; each A₁ or A₂ independently is CH or N; and R₁₄ is C₁-C₄alkyl.

EFFECT: compounds can be used to treat, prevent, or slow down or prevent onset, or progression of cancer, metastasis of cancer, cardiovascular disease, immunological disorder or ocular disorder.

54 cl, 3 tbl, 150 ex