Substituted pyrazolo[1,5-a]pyridine compounds as RET kinase inhibitors

Patent metadata

Field	Value
Publication number	US-11998545-B2
Application number	US-202318342314-A
Country	US
Kind code	B2
Filing date	Jun 27, 2023
Priority date	Oct 10, 2016
Publication date	Jun 4, 2024
Grant date	Jun 4, 2024

Abstract

Provided herein are compounds of the Formula I:and stereoisomers and pharmaceutically acceptable salts or solvates thereof, in which A, B, X1, X2, X3, X4, Ring D, and E have the meanings given in the specification, which are inhibitors of RET kinase and are useful in the treatment and prevention of diseases which can be treated with a RET kinase inhibitor, including RET-associated diseases and disorders.

First claim

What is claimed is:

1. A process for preparing a compound of Formula I:

or pharmaceutically acceptable salt or solvate thereof, wherein
X 1 , X 2 , X 3 and X 4 are independently CH, CF, CCH 3 or N, wherein zero, one or two of X 1 , X 2 , X 3 and X 4 is N;
A is CN;
B is
(a) hydrogen,
(b) C1-C6 alkyl optionally substituted with 1-3 fluoros,
(c) hydroxyC2-C6 alkyl-, wherein the alkyl portion is optionally substituted with 1-3 fluoros or a C3-C6 cycloalkylidene ring,
(d) dihydroxyC3-C6 alkyl-, wherein the alkyl portion is optionally substituted with a C3-C6 cycloalkylidene ring,
(e) (C1-C6 alkoxy)C1-C6 alkyl- optionally substituted with 1-3 fluoros,
(f) (R 1 R 2 N)C1-C6 alkyl- wherein said alkyl portion is optionally substituted with OH and wherein R 1 and R 2 are independently H or C1-C6 alkyl (optionally substituted with 1-3 fluoros);
(g) hetAr 1 C1-C3 alkyl-, wherein hetAr 1 is a 5-6 membered heteroaryl ring having 1-3 ring heteroatoms independently selected from N, O and S and is optionally substituted with one or more independently selected C1-C6 alkyl substituents;
(h) (C3-C6 cycloalkyl)C1-C3 alkyl-, wherein said cycloalkyl is optionally substituted with OH,
(i) (hetCyc a )C1-C3 alkyl-,
(j) hetCyc a -,
(k) C3-C6 cycloalkyl-, wherein said cycloalkyl is optionally substituted with OH,
(l) (C1-C4 alkyl)C(═O)O—C1-C6 alkyl-, wherein each of the C1-C4 alkyl and C1-C6 alkyl portions is optionally and independently substituted with 1-3 fluoros, or
(m) (R 1 R 2 N)C(═O)C1-C6 alkyl-, wherein R 1 and R 2 are independently H or C1-C6 alkyl (optionally substituted with 1-3 fluoros);
hetCyc a - is a 4-6 membered heterocyclic ring having 1-2 ring heteroatoms independently selected from N and O and optionally substituted with one or more substituents independently selected from OH, C1-C6 alkyl (optionally substituted with 1-3 fluoros), hydroxyC1-C6 alkyl-, C1-C6 alkoxy, (C1-C6 alkyl)C(═O)—, (C1-C6 alkoxy)C1-C6 alkyl-, and fluoro, or wherein hetCyc a is substituted with oxo;

Ring D is (i) a saturated 4-7 membered heterocyclic ring having two ring nitrogen atoms, (ii) a saturated 7-8 membered bridged heterocyclic ring having two ring nitrogen atoms and optionally having a third ring heteroatom which is oxygen, (iii) a saturated 7-11 membered heterospirocyclic ring having two ring nitrogen atoms, or (iv) a saturated 9-10 membered bicyclic fused heterocyclic ring having two ring nitrogen atoms, wherein each of said rings is optionally substituted with (a) one to four groups independently selected from halogen, OH, C1-C3 alkyl which is optionally substituted with 1-3 fluoros, or C1-C3 alkoxy which is optionally substituted with 1-3 fluoros, (b) a C3-C6 cycloalkylidene ring, or (c) an oxo group;
E is
(a) hydrogen,
(b) C1-C6 alkyl optionally substituted with 1-3 fluoros,
(c) (C1-C6 alkoxy)C1-C6 alkyl- optionally substituted with 1-3 fluoros,
(d) (C1-C6 alkyl)C(═O)—, wherein said alkyl portion is optionally substituted with 1-3 fluoros or with a R g R h N— substituent wherein R g and R h are independently H or C1-C6 alkyl,
(e) (hydroxyC2-C6 alkyl)C(═O)— optionally substituted with 1-3 fluoros,
(f) (C1-C6 alkoxy)C(═O)—,
(g) (C3-C6 cycloalkyl)C(═O)—, wherein said cycloalkyl is optionally substituted with one or more substituents independently selected from C1-C6 alkyl, C1-C6 alkoxy, OH, and (C1-C6 alkoxy)C1-C6 alkyl-, or said cycloalkyl is substituted with a 5-6 membered heteroaryl ring having 1-3 ring heteroatoms independently selected from N and O,
(h) Ar 1 C1-C6 alkyl-,
(i) Ar 1 (C1-C6 alkyl)C(═O)—, wherein said alkyl portion is optionally substituted with OH, hydroxyC1-C6 alkyl-, C1-C6 alkoxy, R m R n N— or R m R n N—CH 2 —, wherein each R m and R n is independently H or C1-C6 alkyl,
(j) hetAr 2 C1-C6 alkyl-, wherein said alkyl portion is optionally substituted with 1-3 fluoros,
(k) hetAr 2 (C1-C6 alkyl)C(═O)— wherein said alkyl portion is optionally substituted with OH, hydroxyC1-C6 alkyl- or C1-C6 alkoxy,
(l) hetAr 2 C(═O)—,
(m) hetCyc 1 C(═O)—,
(n) hetCyc 1 C1-C6 alkyl-,
(o) R 3 R 4 NC(═O)—,
(p) Ar 1 N(R 3 )C(═O)—,
(q) hetAr 2 N(R 3 )C(═O)—,
(r) (C1-C6 alkyl)SO 2 —, wherein the alkyl portion is optionally substituted with 1-3 fluoros,
(s) Ar 1 SO 2 —,
(t) hetAr 2 SO 2 —,
(u) N—(C1-C6 alkyl)pyridinonyl,
(v) Ar 1 C(═O)—;
(w) Ar 1 O—C(═O)—,
(x) (C3-C6 cycloalkyl)(C1-C6 alkyl)C(═O)—,
(y) (C3-C6 cycloalkyl)(C1-C6 alkyl)SO 2 —, wherein the alkyl portion is optionally substituted with 1-3 fluoros,
(z) Ar 1 (C1-C6 alkyl)SO 2 —,
(aa) hetCyc 1 -O—C(═O)—,
(bb) hetCyc 1 CH 2 C(═O)—,
(cc) hetAr 2 , or
(dd) C3-C6 cycloalkyl;
Ar 1 is phenyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, CN, C1-C6 alkyl (optionally substituted with 1-3 fluoros), C1-C6 alkoxy (optionally substituted with 1-3 fluoros), R e R f N— wherein R e and R f are independently H, C1-C6 alkyl, (R p R q N)C1-C6 alkoxy- wherein R p and R q are independently H or C1-C6 alkyl, and (hetAr a )C1-C6 alkyl- wherein hetAr a is a 5-6 membered heteroaryl ring having 1-2 ring nitrogen atoms, or Ar 1 is a phenyl ring fused to a 5-6 membered heterocyclic ring having 1-2 ring heteroatoms independently selected from N and O;
hetAr 2 is a 5-6 membered heteroaryl ring having 1-3 ring heteroatoms independently selected from N, O and S or a 9-10 membered bicyclic heteroaryl ring having 1-3 ring nitrogen atoms, wherein hetAr 2 is optionally substituted with one or more substituents independently selected from the group consisting of halogen, CN, C1-C6 alkyl (optionally substituted with 1-3 fluoros), C1-C6 alkoxy (optionally substituted with 1-3 fluoros), (C1-C6 alkoxy)C1-C6 alkyl- (optionally substituted with 1-3 fluoros), R e R f N— wherein R e and R f are independently H or C1-C6 alkyl, OH, (C1-C6 alkoxy)C1-C6 alkoxy- and C3-C6 cycloalkyl;
hetCyc 1 is a 4-6 membered saturated heterocyclic ring having 1-2 ring heteroatoms independently selected from N, O and S wherein said heterocyclic ring is optionally substituted with one or more substituents independently selected from C1-C6 alkoxy and halogen;

R 3 is H or C1-C6 alkyl; and
R 4 is C1-C6 alkyl,
the process comprising reacting a compound of Formula 12,

wherein and E is H,
with an aldehyde, in the presence of a reducing agent.

2. The process according to claim 1 , wherein the reducing agent is NaBH(AcO) 3 .

3. The process according to claim 1 , wherein in Formula I, E is C1-C6 alkyl optionally substituted with one to three fluoros; (C1-C6 alkoxy)C1-C6 alkyl- optionally substituted with 1-3 fluoros; Ar 1 C1-C6 alkyl-, or hetAr 2 C1-C6 alkyl- wherein the alkyl portion is optionally substituted with 1-3 fluoros, or hetCyc 1 C1-C6 alkyl-).

4. The process according to claim 1 , wherein the aldehyde is (C1-C5 alkyl(C═O)H optionally substituted with one to three fluoros; (C1-C6 alkoxy)(C1-C5 alkyl)C(═O)H optionally substituted with one to three fluoros; Ar 1 (C1-C5 alkyl)C(═O)H; hetAr 2 (C1-C5 alkyl)C(═O)H; or hetCyc 1 (C1-C5 alkyl)-C(═O)H.

5. A process for preparing a compound of the formula:

the process comprising reacting a compound of the formula:

with 6-methoxynicotinaldehyde and a reducing agent, in the presence of a solvent.

6. The process ac

Assignees

• Array Biopharma Inc

Inventors

• Andrews Steven W
• Aronow Sean
• Blake James F
• Brandhuber Barbara J
• Cook Adam
• Haas Julia
• Jiang Yutong
• Kolakowski Gabrielle R
• Mcfaddin Elizabeth A
• Mckenney Megan L
• Mcnulty Oren T
• Metcalf Andrew T
• Moreno David A
• Tang Tony P
• Ren Li

Classifications

• A61K31/496 Primary

  Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin · CPC title

• A61K31/444

  containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone · CPC title

• A61K31/4985 Primary

  Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems · CPC title

• A61K31/4995

  Pyrazines or piperazines forming part of bridged ring systems · CPC title

• A61K31/506

  not condensed and containing further heterocyclic rings · CPC title