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US 2024/0174666 A1Published application
PYRAZOLO[3,4-b]PYRIDINE COMPOUNDS AS INHIBITORS OF TAM AND MET KINASES
AssigneeArray BioPharma Inc.
InventorsRonald Jay Hinklin, Shelley Allen, Patrick Michael Doerner Barbour, Adam Wade Cook, Joshua Ryan Dahlke, John Joseph Gaudino, Ellen Ruth Laird, Oren Teague McNulty, Qian Zhao
Life of this patent
Estimating the term…
Abstract
Provided herein are compounds of the Formula I: and stereoisomers, tautomers and pharmaceutically acceptable salts thereof, wherein R1, R2, R9, X1 and G are as defined herein, which are inhibitors of one or more TAM kinases and/or c-Met kinase, and are useful in the treatment and prevention of diseases which can be treated with a TAM kinase inhibitor and/or a c-Met kinase inhibitor.
Claims17
A compound of Formula I
- and stereoisomers, tautomers and pharmaceutically acceptable salts thereof, wherein:
- X1 is CH or N;
- R1 is hydrogen or C1-C6 alkyl;
- R2 is
- (a) hydrogen,
- (b) C1-C6 alkyl,
- (c) hydroxyC1-C6 alkyl,
- (d) dihydroxyC2-C6 alkyl,
- (e) C1-C6 fluoroalkyl optionally substituted with OH,
- (f) (di-C1-C6 alkoxy)C2-C6 alkyl-,
- (g) (C1-C6 alkoxy)C1-C6 alkyl- wherein said alkyl portion is optionally substituted with OH,
- (h) Cyc1,
- (i) Cyc2,
- (j) (hetCyc1)C1-C6 alkyl- wherein said alkyl portion is optionally substituted with OH,
- (k) (Ar1)C1-C6 alkyl- wherein said alkyl portion is optionally substituted with OH,
- (l) (hetAr1)C1-C6 alkyl- wherein said alkyl portion is optionally substituted with OH, or
- (m) (HOSO3)C1-C6 alkyl-;
- Cyc1 is a 3-4 membered cycloalkyl ring optionally substituted with 1-2 substituents independently selected from halogen, hydroxy, C1-C3 alkyl, hydroxyC1-C3 alkyl, C1-C3 alkoxy, (C1-C3 alkoxy)C1-C3 alkyl- and R′R″NC(═O)—;
- R′ and R″ are independently hydrogen or C1-C6 alkyl;
- Cyc2 is a 5-membered cycloalkyl ring substituted with 1-2 substituents independently selected from C1-C3 alkyl, (C1-C3 alkoxy)C1-C63 alkyl- and hydroxyC1-C3 alkyl-;
- hetCyc1 is a 5-6 membered saturated heterocyclic ring having 1-2 ring heteroatoms independently selected from O, N, S and SO2, wherein said ring is optionally substituted with oxo;
- Ar1 is phenyl;
- hetAr1 is pyridyl;
- G is
- X2 is C or N;
- Ring A, including the atoms at the points of attachment, is a 5-6 membered heterocyclic ring optionally having an additional 1-2 ring nitrogen atoms when X2 is N and having one ring nitrogen atom when X2 is C;
- R3 is hydrogen, methyl, or absent;
- R6 is hydrogen, halogen, C1-C6 alkyl, C1-C6 alkoxy, hydroxyC1-C6 alkyl, C3-C6 cycloalkyl, (C3-C6 cycloalkyl)C1-C6 alkyl- or hetCyc2, provided that when R6 is halogen and is on the ring carbon atom adjacent to the carbon linked to the —NHC(═O)— moiety of Formula I, then R6 is not halogen, and
- R7 is hydrogen, C1-C6 alkyl, oxo or thioxo,
- or optionally when R6 and R7 are on the same carbon atom, R6 and R7 together with the carbon atom to which they are attached form a cyclopropyl ring;
- hetCyc2 is a 4-6 membered saturated heterocyclic ring having a ring nitrogen atom and optionally substituted with C1-C6 alkyl;
- Ring B, including the atoms at the points of attachment, is a 6-membered saturated carbocyclic optionally substituted with oxo or a 6-membered aromatic carbocyclic ring optionally substituted with OH;
- R8 is Ar2, hetAr2, C3-C6 cycloalkyl, hetCyc3 or C1-C6 alkyl;
- Ar2 is phenyl optionally substituted with one or more substituents independently selected from halogen, C1-C2 alkyl and C1-C2 alkoxy;
- hetAr2 is a 5-6 membered heteroaryl having 1-2 ring nitrogen atoms and optionally substituted with one or more substituents independently selected from halogen, C1-C2 alkyl and C1-C2 alkoxy;
- hetCyc3 is a 5-6 membered heterocyclic ring having a ring oxygen atom;
- and
- R9 is hydrogen or halogen.
35 more elements
A compound of Formula I-A
- and stereoisomers, tautomers and pharmaceutically acceptable salts thereof, wherein:
- X1 is CH or N;
- R1 is hydrogen or C1-C6 alkyl;
- R2 is
- (a) hydrogen,
- (b) C1-C6 alkyl,
- (c) hydroxyC1-C6 alkyl,
- (g) (C1-C6 alkoxy)C1-C6 alkyl- wherein said alkyl portion is optionally substituted with OH, or
- (h) Cyc1;
- Cyc1 is a 3-4 membered cycloalkyl ring optionally substituted with 1-2 substituents independently selected from halogen, hydroxy, C1-C3 alkyl, hydroxyC1-C3 alkyl, C1-C3 alkoxy, (C1-C3 alkoxy)C1-C3 alkyl- and R′R″NC(═O)—;
- X2 is N, R3 is absent, Ring A is a 6-membered heterocyclic ring having one additional ring nitrogen atom, and R7 is oxo, wherein G has the formula A-1
- R6 is C1-C6 alkyl, hydroxyC1-C6 alkyl, C3-C6 cycloalkyl, (C3-C6 cycloalkyl)C1-C6 alkyl- or hetCyc2;
- hetCyc2 is a 4-6 membered saturated heterocyclic ring having a ring nitrogen atom and optionally substituted with C1-C6 alkyl;
- R8 is Ar2, hetAr2, C3-C6 cycloalkyl, hetCyc3 or C1-C6 alkyl;
- Ar2 is phenyl optionally substituted with one or more substituents independently selected from halogen, C1-C2 alkyl and C1-C2 alkoxy;
- hetAr2 is a 5-6 membered heteroaryl having 1-2 ring nitrogen atoms and optionally substituted with one or more substituents independently selected from halogen, C1-C2 alkyl and C1-C2 alkoxy;
- hetCyc3 is a 5-6 membered heterocyclic ring having a ring oxygen atom;
- and
- R9 is hydrogen or halogen.
16 more elements
Dependencies are inferred from the claim text.