TYROSINE KINASE INHIBITORS
The present disclosure provides compounds and pharmaceutically acceptable salts thereof that are tyrosine kinase inhibitors, in particular BLK, BMX, EGFR, HER2, HER4, ITK, TEC, BTK, and TXK and are therefore useful for the treatment of diseases treatable by inhibition of tyrosine kinases such as cancer and inflammatory diseases such as arthritis, and the like. Also provided are pharmaceutical compositions containing such compounds and pharmaceutically acceptable salts thereof and processes for preparing such compounds and pharmaceutically acceptable salts thereof.
1 - 47 . (canceled)
48 . A compound of Formula (Id) or a pharmaceutically acceptable salt thereof:
wherein:
Z 2 is —N— or CR 2 where R 2 is hydrogen or alkyl;
R 3 is methyl, chloro, fluoro, cyclopropyl, hydroxy, methoxy, cyano, trifluoromethyl or trifluoromethoxy;
R 4 is hydrogen, methyl, chloro, fluoro, cyclopropyl, hydroxy, methoxy, cyano, trifluoromethyl or trifluoromethoxy;
R 6 and R 7 are independently hydrogen, methyl, methoxy, fluoro, chloro, trifluoromethyl, trifluoromethoxy, or cyano;
—Z-EWG- is -(alkylene)-NR′CO—, -(alkylene)-NR′SO 2 —,
each ring optionally substituted with one or two substituents independently selected from alkyl, hydroxy, and halo and the carbonyl and sulfonyl group in -(alkylene)-NR′CO—, -(alkylene)-NR′SO 2 —,
is attached to —C(CN)═CHR c ; and each R′ is independently hydrogen or alkyl; and
R c is a cycloalkyl or 3 to 6 membered saturated monocyclic heterocyclyl containing one or two heteroatoms selected from N, O, and S and optionally substituted with one or two substituents selected from hydroxy, alkyl and fluoro,
or a mixture of R and S isomers thereof;
or an individual (E) or (Z) isomer of any of the foregoing compounds;
or a pharmaceutically acceptable salt of any of the foregoing compounds.
49 . The compound or a pharmaceutically acceptable salt thereof of claim 48 wherein:
R c is a 3 to 6 membered saturated monocyclic heterocyclyl containing one or two heteroatoms selected from N, O, and S and optionally substituted with one or two substituents selected from hydroxy, alkyl and fluoro; and
is:
50 . The compound or a pharmaceutically acceptable salt thereof of claim 48 wherein R c is a 3 to 6 membered saturated monocyclic heterocyclyl containing one or two heteroatoms selected from N, O, and S and optionally substituted with one or two substituents selected from hydroxy, alkyl and fluoro; and
51 . The compound or a pharmaceutically acceptable salt thereof of claim 49 wherein:
is a ring of formula
52 . The compound or a pharmaceutically acceptable salt thereof of claim 49 wherein:
is a ring of formula:
53 . The compound or a pharmaceutically acceptable salt thereof of claim 49 wherein:
is a ring of formula
is a ring of formula:
54 . The compound or a pharmaceutically acceptable salt thereof of claim 53 wherein
is a ring of formula
55 . The compound or a pharmaceutically acceptable salt thereof of claim 49 wherein:
—Z-EWG- is
optionally substituted with one or two substituents independently selected from alkyl, hydroxy, and halo.
56 . The compound or a pharmaceutically acceptable salt thereof of claim 55 wherein R c is
X is O, S, SO 2 , NH, or N-alkyl, and each of the ring is optionally substituted with one or two substituents selected from hydroxy, alkyl and fluoro.
57 . The compound or a pharmaceutically acceptable salt thereof of claim 55 wherein:
R c is 2-pyrrolidinyl, 3- or 4-piperidinyl, 1-methylpiperidin-4-yl, 1-methylpiperidin-3-yl, or 4-tetrahydropyranyl, and each of the heterocyclic ring is optionally substituted with one or two substituents selected from hydroxy, alkyl and fluoro.
58 . The compound or a pharmaceutically acceptable salt thereof of claim 57 wherein R c is 4-tetrahydropyranyl optionally substituted with one or two substituents selected from hydroxy, alkyl and fluoro.
59 . The compound or a pharmaceutically acceptable salt thereof of claim 49 wherein:
—Z-EWG- is
optionally substituted with one or two substituents independently selected from alkyl, hydroxy, and halo.
60 . The compound or a pharmaceutically acceptable salt thereof of claim 59 wherein R c is
X is O, S, SO 2 , NH, or N-alkyl, and each of the ring is optionally substituted with one or two substituents selected from hydroxy, alkyl and fluoro.
61 . The compound or a pharmaceutically acceptable salt thereof of claim 60 wherein:
R c is 2-pyrrolidinyl, 3- or 4-piperidinyl, 1-methylpiperidin-4-yl, 1-methylpiperidin-3-yl, or 4-tetrahydropyranyl, and each of the heterocyclic ring is optionally substituted with one or two substituents selected from hydroxy, alkyl and fluoro.
62 . The compound or a pharmaceutically acceptable salt thereof of claim 61 wherein R c is 4-tetrahydropyranyl optionally substituted with one or two substituents selected from hydroxy, alkyl and fluoro.
63 . The compound or a pharmaceutically acceptable salt thereof of claim 49 wherein:
—Z-EWG- is
which is optionally substituted with one or two substituents independently selected from alkyl, hydroxy, and halo.
64 . The compound or a pharmaceutically acceptable salt thereof of claim 63 wherein R c is
X is O, S, SO 2 , NH, or N-alkyl, and each of the ring is optionally substituted with one or two substituents selected from hydroxy, alkyl and fluoro.
65 . The compound or a pharmaceutically acceptable salt thereof of claim 64 wherein R c is 2-pyrrolidinyl, 3- or 4-piperidinyl, 1-methylpiperidin-4-yl, 1-methylpiperidin-3-yl, or 4-tetrahydropyranyl, and each of the heterocyclic ring is optionally substituted with one or two substituents selected from hydroxy, alkyl and fluoro.
66 . The compound or a pharmaceutically acceptable salt thereof of claim 65 wherein R c is 4-tetrahydropyranyl optionally substituted with one or two substituents selected from hydroxy, alkyl and fluoro.
67 . A pharmaceutical composition comprising a compound or a pharmaceutically acceptable salt thereof of claim 48 , and a pharmaceutically acceptable excipient.