HETEROCYCLIC PYRIMIDINE ANALOGUES AS TYK2 INHIBITORS Russian patent published in 2018 - IPC C07D401/14 C07D403/12 A61K31/506 A61P31/00 

FIELD: pharmacology.

SUBSTANCE: compounds possess the properties of the inhibitor of the non-responsive tyrosine Tyk2 kinase and selective inhibitory action against JAK1, JAK2, JAK3 Janus kinases. The compounds can be used in a method for treatment or prevention of immunological, inflammatory, autoimmune, allergic disorder or graft rejection or graft-versus-host diseases. In the formula (I)

,

R¹ is H; C_1-6 alkyl, where C_1-6 alkyl is optionally substituted by one or more R³, which are the same or different. At that, C _1-6 alkyl containing a hydroxy group may be deuterated; R³ represents halogen; CN; C(O)OR⁴; OR⁴; C(O)R⁴; (O)N(R⁴R^4a); S(O)₂R⁴; S(O)R⁴; or T¹; R⁴, R^4a, R^4b are independently selected from the group consisting of H; T¹; C_1-6 alkyl, where C_1-6 alkyl is optionally substituted by one or more R⁵, which are the same or different; R⁵ represents halogen; CN; OR⁶; or T¹; R⁶ is H; T¹ is C_3-7 cycloalkyl; 4-7 membered heterocyclyl with 1 to 2 heteroatoms in the ring selected from nitrogen, oxygen or sulfur; or a 7-8 membered heterobicyclyl, optionally spyrocondensed, with two heteroatoms in the cycle, selected from nitrogen or nitrogen and oxygen, where T¹ is optionally substituted by one or more R⁷ , which are the same or different; R⁷ is halogen; CN; C(O)OR⁸ ; oxo (= O), wherein the ring is at least partially saturated; C _1-6 alkyl; R ⁸ are independently selected from the group consisting of H; C_1-6 alkyl; X¹ is C(R^11a) or N; X² is C(R^11b) or N; X³ is C(R^11c) or N; X⁴ is C(R^11d) or N; X⁵ is C(R^11e) or N, provided that no more than two of X¹, X², X³, X⁴, X⁵ are N; R^11a, R^11c, R^11e are independently selected from the group consisting of H; halogen; CN; OR¹²; C(O)N(R¹² R^12a); S(O)₂N (R¹²R^12a); S(O)₂R¹²; T²; C_1-6 alkyl, where C_1-6 alkyl is optionally substituted by one or more R¹³, which are the same or different; R^11b, R^11d are independently selected from the group consisting of H; halogen; CN; OR¹²; S(O)₂N (R¹²R^12a); S(O)R¹²; C_1-6 alkyl, where C_1-6 alkyl is optionally substituted by one or more R¹³, which are the same or different; R¹², R^12a are independently selected from the group consisting of H and C_1-6 alkyl, where C_1-6 alkyl is optionally substituted by one or more R¹³, which are the same or different; T² is a 5-membered heterocycle with two nitrogen atoms in the ring; R¹³ is halogen; CN; OR¹⁴; C(O)N (R¹⁴R^14a); S(O)₂N(R¹⁴R^14a); S(O)₂R¹⁴; S(O) R¹⁴; N(R¹⁴) S(O)₂N(R^14aR^14b); N(R¹⁴)S(O)N(R^14aR^14b); SR¹⁴; N(R¹⁴R^14a); NO₂; OC(O)R¹⁴; N(R¹⁴)S(O)₂R^14a; R¹⁴, R^14a, R^14b are independently selected from the group consisting of H or C_1-6 alkyl, where C_1-6 alkyl is optionally substituted by one or more R¹⁵, which are the same or different; R¹⁵ is halogen.

EFFECT: increased efficiency.

18 cl, 13 tbl, 480 ex