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RU-2025138686-A - Heteroaryl derivatives as DDR inhibitors

RU2025138686ARU 2025138686 ARU2025138686 ARU 2025138686ARU-2025138686-A

Inventors

  • КАРДЗАНИГА, Лаура
  • ФУМАГАЛЛИ, Габриэле
  • ЙОТТИ, Николо
  • ДЖУЛИАНИ, Марта
  • СТИМПСОН, Дин Элфи
  • Ранкати, Фабио
  • СПЕНСЕР, Джонатан Эндрю
  • УИТТАКЕР, Бенджамин Пол
  • ХАМАСОВА, Зузана
  • Рицци, Андреа
  • МАДЗУКАТО, Роберта
  • ЛЕВАНТО, Стефано
  • ЧАПМАН, Роберт Стюарт Лори

Assignees

  • КЬЕЗИ ФАРМАЧЕУТИЧИ С.п.А.

Dates

Publication Date
20260506
Application Date
20240606
Priority Date
20230607

Claims (20)

  1. 1. Compound of formula (I)
  2. Where
  3. A is a ring selected from the group consisting of:
  4. Where indicates a direct connection with NH;
  5. W1, W2 and W3 are ring A substituents independently selected from the group consisting of hydrogen, (C 1 -C 4 )alkyl, (C 1 -C 4 )haloalkyl, (C 1 -C 4 )halogenhydroxyalkyl, (C 1 -C 4 )alkoxy, (C 1 -C 4 )alkoxy-(C 1 -C 4 )alkyl, (C 1 -C 4 )haloalkoxy, (C 1 -C 4 )hydroxyalkyl, halogen, cyano, SF 5 , NR1R2-(C 1 -C 4 )alkyl, CONR1R2, NHCOR1, NR1R2, heterocycloalkyl, (C 3 -C 7 )cycloalkyl, (C 1 -C 4 )alkyl-heterocycloalkyl, (C 1 -C 4 )alkyl-heterocycloalkyl-(C 1 -C 4 )alkyl, (C 1 -C 4 )haloalkyl-cycloalkyl, (C 1 -C 4 )alkyl-(C 3 -C 7 )cycloalkyl, heterocycloalkyl-(C 1 -C 4 )alkyl, heterocycloalkyl-NH-(C 1 -C 4 )alkyl, (C 3 -C 7 )cycloalkyl-(C 1 -C 4 )alkyl, heterocycloalkyl-(C 1 -C 4 )alkoxy, (C 1 -C 4 )alkyl-CO-heterocycloalkyl-oxy, (C 3 -C 7 )cycloalkyl-(C 1 -C 4 )alkoxy, heterocycloalkyl-oxy, (C 3 -C 7 )cycloalkyl-oxy, (C 1 -C 4 )alkyl-heterocycloalkyl-carbonyl, monocyclic (C 1 -C 4 )alkyl-heteroaryl, (C 1 -C 4 )alkyl-sulfonyl, (C 1 -C 4 )haloalkyl sulfonyl, (C 1 -C 4 )haloalkyl-sulfonylamino, (C 1 -C 4 )haloalkyl-sulfinyl, (C 1 -C 4 )haloalkyl-thio, (C 1 -C 4 )alkyl-thio-(C 1 -C 4 )alkyl, (C 1 -C 4 )alkyl-sulfonyl-(C 1 -C 4 )alkyl and (C 1 -C 4 )alkyl-sulfinyl-(C 1 -C 4 )alkyl; or, where W1 and W2 are in adjacent positions on ring A, W1 and W2 form (C 5 -C 6 )cycloalkyl or 5- or 6-membered heterocycloalkyl, where (C 5 -C 6 )cycloalkyl or 5- or 6-membered heterocycloalkyl optionally substituted with 1 to 3 halogen atoms;
  6. L is selected from CO and CH2 or is absent;
  7. L1 is selected from NR, CH2 and O, where R is selected from the group consisting of hydrogen, ( C1 - C4 )alkyl, ( C1 - C4 )hydroxyalkyl, ( C1 - C4 )haloalkyl, ( C3 - C7 )cycloalkyl, ( C3 - C7 )cycloalkyl-( C1 - C4 )alkyl and deuterated ( C1 - C4 )alkyl;
  8. R S is selected from hydrogen and methyl when L1 is NR;
  9. R S is hydrogen when L1 is CH 2 or O;
  10. B is a mono- or bicyclic heteroaryl ring or a bicyclic semi-saturated heteroaryl ring;
  11. Y1 and Y2 are ring B substituents independently selected from the group consisting of hydrogen, (C 1 -C 4 )alkyl, deuterated (C 1 -C 4 )alkyl, (C 1 -C 4 )haloalkyl, (C 1 -C 4 )alkoxy, (C 1 -C 4 )haloalkoxy, (C 1 -C 4 )hydroxyalkyl, halogen, cyano, SF 5 , (C 1 -C 4 )cyanoalkyl, (C 1 -C 4 )alkyl-sulfonyl, (C 1 -C 4 )haloalkyl sulfonyl, CONR1R2, NHCOR1, NR1R2, NR1R2-(C 1 -C 4 )alkyl, heterocycloalkyl optionally substituted with 1-3 halogens, heterocycloalkyl-NH-(C 1 -C 4 )alkyl, (C 3 -C 7 )cycloalkyl, (C 1 -C 4 )alkyl-heterocycloalkyl, (C 1 -C 4 )alkyl-(C 3 -C 7 )cycloalkyl, heterocycloalkyl-(C 1 -C 4 )alkyl, (C 3 -C 7 )cycloalkyl-(C 1 -C 4 )alkyl, heterocycloalkyl-(C 1 -C 4 )alkoxy, (C 3 -C 7 )cycloalkyl-(C 1 -C 4 )alkoxy, heterocycloalkyl-oxy, (C 3 -C 7 )cycloalkyl-oxy, phenyl, (C 1 -C 4 )alkoxy-substituted phenyl, (C 1 -C 4 )alkyl-thio-(C 1 -C 4 )alkyl, (C 1 -C 4 )alkyl-sulfonyl-(C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxy-(C 1 -C 4 )alkyl, (C 1 -C 4 )haloalkyl-cycloalkyl, (C 1 -C 4 )alkyl-heterocycloalkyl-carbonyl and monocyclic heteroaryl optionally substituted with 1-3 groups selected from the group consisting of (C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxy and (C 1 -C 4 )alkoxy-(C 1 -C 4 )alkyl;
  12. R1 and R2 are independently selected from the group consisting of hydrogen, (C 1 -C 4 )alkyl, (C 1 -C 4 )hydroxyalkyl, (C 1 -C 4 )alkoxy-(C 1 -C 4 )alkyl, (C 1 -C 4 )alkylamino-(C 1 -C 4 )alkyl, di-(C 1 -C 4 )alkylamino-(C 1 -C 4 )alkyl, optionally substituted (C 3 -C 7 )cycloalkyl, optionally substituted heterocycloalkyl, and optionally substituted heterocycloalkyl-(C 1 -C 4 )alkoxy, wherein the optional substituents are from 1 to 3 and are selected from the group consisting of (C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxy, (C 1 -C 4 )haloalkyl, (C 1 -C 4 )haloalkoxy and carbamoyl;
  13. R3 is selected from the group consisting of (C 1 -C 4 )alkyl, (C 1 -C 4 )haloalkyl, (C 1 -C 4 )alkylphenyl and monocyclic heteroaryl;
  14. or its stereoisomer, tautomer, solvate and pharmaceutically acceptable salt;
  15. wherein the compound of formula (I) is not 1-(3,5-dichlorophenyl)-3-(2-(2-methylpyridin-4-yl)-2-azaspiro[3.3]heptan-6-yl)urea.
  16. 2. The compound according to claim 1, wherein, when ring A is phenyl and L1 is NH,
  17. W1, W2 and W3 are ring A substituents independently selected from the group consisting of hydrogen, (C 1 -C 4 )alkyl, (C 1 -C 4 )haloalkyl, (C 1 -C 4 )halogenhydroxyalkyl, (C 1 -C 4 )alkoxy, (C 1 -C 4 )alkoxy-(C 1 -C 4 )alkyl, (C 1 -C 4 )haloalkoxy, (C 1 -C 4 )hydroxyalkyl, fluorine, bromine, iodine, cyano, SF 5 , NR1R2-(C 1 -C 4 )alkyl, CONR1R2, NHCOR1, NR1R2, heterocycloalkyl, (C 3 -C 7 )cycloalkyl, (C 1 -C 4 )alkyl-heterocycloalkyl, (C 1 -C 4 )alkyl-heterocycloalkyl-(C 1 -C 4 )alkyl, (C 1 -C 4 )haloalkyl-cycloalkyl, (C 1 -C 4 )alkyl-(C 3 -C 7 )cycloalkyl, heterocycloalkyl-(C 1 -C 4 )alkyl, heterocycloalkyl-NH-(C 1 -C 4 )alkyl, (C 3 -C 7 )cycloalkyl-(C 1 -C 4 )alkyl, heterocycloalkyl-(C 1 -C 4 )alkoxy, (C 1 -C 4 )alkyl-CO-heterocycloalkyl-oxy, (C 3 -C 7 )cycloalkyl-(C 1 -C 4 )alkoxy, heterocycloalkyl-oxy, (C 3 -C 7 )cycloalkyl-oxy, (C 1 -C 4 )alkyl-heterocycloalkyl-carbonyl, monocyclic (C 1 -C 4 )alkyl-heteroaryl, (C 1 -C 4 )alkyl-sulfonyl, (C 1 -C 4 )haloalkyl sulfonyl, (C 1 -C 4 )haloalkyl-sulfonylamino, (C 1 -C 4 )haloalkyl-sulfinyl, (C 1 -C 4 )haloalkyl-thio, (C 1 -C 4 )alkyl-thio-(C 1 -C 4 )alkyl, (C 1 -C 4 )alkyl-sulfonyl-(C 1 -C 4 )alkyl and (C 1 -C 4 )alkyl-sulfinyl-(C 1 -C 4 )alkyl; or, where W1 and W2 are in adjacent positions on ring A, W1 and W2 form (C 5 -C 6 )cycloalkyl or 5- or 6-membered heterocycloalkyl, where (C 5 -C 6 )cycloalkyl or 5- or 6-membered heterocycloalkyl are optionally substituted with 1-3 halogen atoms; and wherein preferably the 6-membered heterocycloalkyl is a pyranyl ring;
  18. or its stereoisomer, tautomer, solvate and pharmaceutically acceptable salt.
  19. 3. The connection according to item 1 or 2, where
  20. W1, W2 and W3 are ring A substituents independently selected from the group consisting of hydrogen, (C 1 -C 4 )alkyl, (C 1 -C 4 )haloalkyl, (C 1 -C 4 )halogenhydroxyalkyl, (C 1 -C 4 )alkoxy, (C 1 -C 4 )alkoxy-(C 1 -C 4 )alkyl, (C 1 -C 4 )haloalkoxy, (C 1 -C 4 )hydroxyalkyl, fluorine, bromine, iodine, cyano, SF 5 , NR1R2-(C 1 -C 4 )alkyl, CONR1R2, NHCOR1, NR1R2, heterocycloalkyl, (C 3 -C 7 )cycloalkyl, (C 1 -C 4 )alkyl-heterocycloalkyl, (C 1 -C 4 )alkyl-heterocycloalkyl-(C 1 -C 4 )alkyl, (C 1 -C 4 )haloalkyl-cycloalkyl, (C 1 -C 4 )alkyl-(C 3 -C 7 )cycloalkyl, heterocycloalkyl-(C 1 -C 4 )alkyl, heterocycloalkyl-NH-(C 1 -C 4 )alkyl, (C 3 -C 7 )cycloalkyl-(C 1 -C 4 )alkyl, heterocycloalkyl-(C 1 -C 4 )alkoxy, (C 1 -C 4 )alkyl-CO-heterocycloalkyl-oxy, (C 3 -C 7 )cycloalkyl-(C 1 -C 4 )alkoxy, heterocycloalkyl-oxy, (C 3 -C 7 )cycloalkyl-oxy, (C 1 -C 4 )alkyl-heterocycloalkyl-carbonyl, monocyclic (C 1 -C 4 )alkyl-heteroaryl, (C 1 -C 4 )alkyl-sulfonyl, (C 1 -C 4 )haloalkyl sulfonyl, (C 1 -C 4 )haloalkyl-sulfonylamino, (C 1 -C 4 )haloalkyl-sulfinyl, (C 1 -C 4 )haloalkyl-thio, (C 1 -C 4 )alkyl-thio-(C 1 -C 4 )alkyl, (C 1 -C 4 )alkyl-sulfonyl-(C 1 -C 4 )alkyl and (C 1 -C 4 )alkyl-sulfinyl-(C 1 -C 4 )alkyl; or, where W1 and W2 are in adjacent positions on ring A, W1 and W2 form (C 5 -C 6 )cycloalkyl or 5- or 6-membered heterocycloalkyl, where (C 5 -C 6 )cycloalkyl or 5- or 6-membered heterocycloalkyl are optionally substituted with 1-3 halogen atoms; and wherein preferably the 6-membered heterocycloalkyl is a pyranyl ring;