AR094550A1 - BTK INHIBITORS - Google Patents

Abstract

Pharmaceutical compositions comprising these compounds and their use in therapy. In particular, it refers to the use of Btk inhibitor compounds in the treatment of Btk mediated disorders. Claim 1: A compound according to formula (1), or a pharmaceutically acceptable salt thereof, wherein: A¹, A², A³ and A⁴ are independently C, CH, CR¹¹ or N and the bicyclic ring system EG is selected from group consisting of the remains of the group of formulas (2), where R¹¹ is independently selected from the group consisting of: a) deuterium, b) H, c) halogen, d) cyano, e) C²H₃, f) -COOH, g) -CO₂-C₁₋₆ alkyl, h) -CO-C₁₋₆ alkyl, i) -CONH-C₁₋₆ alkoxy, j) -CONH-C₁₋₆ alkyl, k) -CON-C₁₋₆ dialkyl, ₗ₎ ₐₗqᵘⁱₗₒ C₁₋₆, ₘ₎ ᶜⁱᶜₗₒₐₗqᵘⁱₗₒ C₃₋₇, n) C₁₋₆ alkoxy, o) aryl, p) C₁₋₅ heteroaryl, q) C₂₋₆ alkenyl, r) C₂₋₆ alkynyl, and s) C₄ heterocycloalkyl ₋₇, R¹¹ is optionally substituted with one or more groups selected from: halogen, C₁₋₆ alkyl, C₁₋₅ alkoxy, hydroxyl or oxo; R¹² is independently selected from the group consisting of: H, C₁₋₃ alkyl. C₁₋₃-NHC (O) alkyl, C₁₋₃-OC (O) alkyl and C₁₋₃-C (O) alkyl; R¹³ is independently selected from the group consisting of: H and C₁₋₄ alkoxy; wherein in the aromatic ring K: B¹ is N or C (R⁷); B² is N or C (R⁸); B³ is N or C (R⁹); B⁴ is N or C (R¹⁰); R⁷ is H, halogen, OH, C₁₋₃ alkyl, C₁₋₆ alkoxy, C₃₋₆ cycloalkoxy, C₁₋₅ heterocycloalkoxy, C₁₋₃ haloalkyl or CN; wherein R⁷ may be optionally substituted with one, two or three halogens, OH, C₂₋₄ alkynyl, -C (O) NH₂, -C (O) OH or -C (O) C₁₋₄ alkyl; R⁸ is H, halogen, OH, C₁₋₃ alkyl, C₁₋₆ alkoxy, C₃₋₆ cycloalkoxy, C₁₋₅ heterocycloalkoxy, C₁₋₃ haloalkyl or CN; wherein R⁸ may be optionally substituted with one, two or three halogens, OH, C₂₋₄ alkynyl, -C (O) NH₂, -C (O) OH or -C (O) C₁₋₄ alkyl; R⁹ is H, halogen, OH, C₁₋₃ alkyl, C₁₋₆ alkoxy, C₃₋₆ cycloalkoxy, C₁₋₅ heterocycloalkoxy, C₁₋₃ haloalkyl or CN; wherein R⁹ may be optionally substituted with one, two or three halogens, OH, C₂₋₄ alkynyl, -C (O) NH₂, -C (O) OH or -C (O) C₁₋₄ alkyl; R¹⁰ is H, halogen, OH, C₁₋₃ alkyl, C₁₋₆ alkoxy, C₃₋₆ cycloalkoxy, C₁₋₅ heterocycloalkoxy, C₁₋₃ haloalkyl or CN; wherein R¹⁰ may be optionally substituted with one, two or three halogens, OH, C₂₋₄ alkynyl, -C (O) NH₂, -C (O) OH or -C (O) C₁₋₄ alkyl; wherein in the heteroaromatic ring L: W is CH, N or S; X is C (R⁶ᵃ), N, O or S; Y is C (R⁶), N (R⁶ᵇ), O or S; Z is C (R⁶ᵃ), N or a bond; R⁵ is H, halogen, cyano, C₁₋₄ alkyl, C₁₋₅ alkoxy, C₃₋₆ cycloalkyl, C₃₋₆ cycloalkoxy or -C (O) O-C₁₋₃ alkyl; wherein R⁵ may be optionally substituted with one, two or three halogens, OH or C₁₋₃ alkoxy; or R⁵ is C₆₋₁₀ aryl, C₁₋₅ heteroaryl or C₂₋₆ heterocycloalkyl, in which R⁵ may be optionally substituted with halogen, C₁₋₆ alkyl or C₁₋₃ alkoxy; R⁶ is H, halogen, cyano, C₁₋₆ alkyl or C₁₋₆ alkoxy; wherein R⁶ may be optionally substituted with one, two or three halogens or cyano; R⁶ᵃ is H, C₁₋₄ alkyl or C₃₋₆ cycloalkyl; R⁶ᵇ is H, C₁₋₃ alkyl, C₃₋₆ cycloalkyl or -C (O) O-C₁₋₄ alkyl; or R⁵ and R⁶ can together form a 5 to 6 carbocyclic or heterocyclic ring, and optionally be unsaturated or aromatic; or R⁵ and R⁶ can together form C₃₋₇ cycloalkenyl or C₂₋₆ heterocycloalkenyl; each optionally substituted with C₁₋₃ alkyl or with one or more halogens; Q is C = O, C (Rᶠ) ₂ or C = N (Rʰ); T is C (Rᵉ) ₂, O, NRᵉ or a bond; U is C (Rᵈ) ₂, O or NRᵈ; V is C (Rᵍ) ₂, O or a link; Rᶜ, Rᵈ, Rᵉ and Rᶠ are each independently selected from H, halogen, C₁₋₆ alkyl, hydroxyl, C₁₋₆ or -C (O) Rᶻ alkenyl, wherein Rᶻ is independently selected from C₁₋₅ heteroaryl, aryl and hydroxyl, any alkyl group of Rᶜ, Rᵈ, Rᵉ or Rᶠ may be optionally substituted with hydroxy, -C (O) C₁₋₃ alkoxy or -C (O) OH; Rᵍ is independently selected from H, halogen, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkyl or hydroxyl; Rʰ is independently selected from H or CN; with the proviso that: 1) up to 2 atoms of X, Y and Z can simultaneously be a heteroatom; 2) when an atom selected from X or Y is O or S, then Z is a bond and the other atom selected from X or Y cannot be O or S; 3) when Z is CH or N, then Y is C (R⁶) or N and X is CH or N; 4) in ring K, up to 2 of B¹, B², B³ and B⁴ can be N; 5) when Q is C (Rᶠ) ₂, then T is C (Rᵉ) ₂; 6) when T is NRᵉ, then Rᵉ is not halogen; and 7) when U is NRᵈ, then Rᵈ is not halogen.