# US 11,998,545 B2 · Substituted pyrazolo[1,5-a]pyridine compounds as RET kinase inhibitors

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- Number: US 11,998,545 B2
- Document ID: US11998545B2
- Status: Granted
- Kind: B2
- Application number: 18/342,314
- Filed: 2023-06-27
- Published: 2024-02-29
- Granted: 2024-06-04
- Earliest claimed: 2016-10-10
- Assignees: Array BioPharma Inc.
- Applicants: Array BioPharma, Inc.
- Inventors: Steven W. Andrews; Sean Aronow; James F. Blake; Barbara J. Brandhuber; Adam Cook; Julia Haas; Yutong Jiang; Gabrielle R. Kolakowski; Elizabeth A. McFaddin; Megan L. McKenney; Oren T. McNulty; Andrew T. Metcalf; David A. Moreno; Tony P. Tang; Li Ren
- Web page: https://patentgrep.com/patent/US11998545B2

## CPC

- A61K 31/496: Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
- A61K 31/444: containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
- A61K 31/4985: Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
- A61K 31/4995: Pyrazines or piperazines forming part of bridged ring systems
- A61K 31/506: not condensed and containing further heterocyclic rings
- A61K 31/5377: not condensed and containing further heterocyclic rings, e.g. timolol
- A61K 31/551: having two nitrogen atoms, e.g. dilazep
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61P 1/12: Antidiarrhoeals
- A61P 35/00: Antineoplastic agents
- A61P 35/02: specific for leukemia
- A61P 35/04: specific for metastasis
- C07D 471/04: Ortho-condensed systems
- C07D 519/00: Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)

## 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.

## Claims

### Claim 1

A process for preparing a compound of Formula I:
or pharmaceutically acceptable salt or solvate thereof, wherein
X1, X2, X3 and X4 are independently CH, CF, CCH3 or N, wherein zero, one or two of X1, X2, X3 and X4 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) (R1R2N)C1-C6 alkyl- wherein said alkyl portion is optionally substituted with OH and wherein R1 and R2 are independently H or C1-C6 alkyl (optionally substituted with 1-3 fluoros);
(g) hetAr1C1-C3 alkyl-, wherein hetAr1 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) (hetCyca)C1-C3 alkyl-,
(j) hetCyca-,
(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) (R1R2N)C(═O)C1-C6 alkyl-, wherein R1 and R2 are independently H or C1-C6 alkyl (optionally substituted with 1-3 fluoros);
hetCyca- 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 hetCyca 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 RgRhN— substituent wherein Rg and Rh 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) Ar1C1-C6 alkyl-,
(i) Ar1(C1-C6 alkyl)C(═O)—, wherein said alkyl portion is optionally substituted with OH, hydroxyC1-C6 alkyl-, C1-C6 alkoxy, RmRnN— or RmRnN—CH2—, wherein each Rm and Rn is independently H or C1-C6 alkyl,
(j) hetAr2C1-C6 alkyl-, wherein said alkyl portion is optionally substituted with 1-3 fluoros,
(k) hetAr2(C1-C6 alkyl)C(═O)— wherein said alkyl portion is optionally substituted with OH, hydroxyC1-C6 alkyl- or C1-C6 alkoxy,
(l) hetAr2C(═O)—,
(m) hetCyc1C(═O)—,
(n) hetCyc1C1-C6 alkyl-,
(o) R3R4NC(═O)—,
(p) Ar1N(R3)C(═O)—,
(q) hetAr2N(R3)C(═O)—,
(r) (C1-C6 alkyl)SO2—, wherein the alkyl portion is optionally substituted with 1-3 fluoros,
(s) Ar1SO2—,
(t) hetAr2SO2—,
(u) N—(C1-C6 alkyl)pyridinonyl,
(v) Ar1C(═O)—;
(w) Ar1O—C(═O)—,
(x) (C3-C6 cycloalkyl)(C1-C6 alkyl)C(═O)—,
(y) (C3-C6 cycloalkyl)(C1-C6 alkyl)SO2—, wherein the alkyl portion is optionally substituted with 1-3 fluoros,
(z) Ar1(C1-C6 alkyl)SO2—,
(aa) hetCyc1-O—C(═O)—,
(bb) hetCyc1CH2C(═O)—,
(cc) hetAr2, or
(dd) C3-C6 cycloalkyl;
Ar1 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), ReRfN— wherein Re and Rf are independently H, C1-C6 alkyl, (RpRqN)C1-C6 alkoxy- wherein Rp and Rq are independently H or C1-C6 alkyl, and (hetAra)C1-C6 alkyl- wherein hetAra is a 5-6 membered heteroaryl ring having 1-2 ring nitrogen atoms, or Ar1 is a phenyl ring fused to a 5-6 membered heterocyclic ring having 1-2 ring heteroatoms independently selected from N and O;
hetAr2 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 hetAr2 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), ReRfN— wherein Re and Rf are independently H or C1-C6 alkyl, OH, (C1-C6 alkoxy)C1-C6 alkoxy- and C3-C6 cycloalkyl;
hetCyc1 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;
R3 is H or C1-C6 alkyl; and
R4 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.

### Claim 2 (depends on 1)

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

### Claim 3 (depends on 1)

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; Ar1C1-C6 alkyl-, or hetAr2C1-C6 alkyl- wherein the alkyl portion is optionally substituted with 1-3 fluoros, or hetCyc1C1-C6 alkyl-).

### Claim 4 (depends on 1)

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; Ar1(C1-C5 alkyl)C(═O)H; hetAr2(C1-C5 alkyl)C(═O)H; or hetCyc1(C1-C5 alkyl)-C(═O)H.

### Claim 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.

### Claim 6 (depends on 5)

The process according to claim 5, wherein the solvent comprises 1,2-dichloroethane.

### Claim 7 (depends on 5)

The process according to claim 5, wherein the reducing agent comprises NaBH(OAc)3.

### Claim 8 (depends on 5)

The process according to claim 5, wherein the solvent comprises 1,2-dichloroethane, and the reducing agent comprises NaBH(OAc)3.

### Claim 9 (depends on 1)

The process according to claim 1, wherein the compound of Formula 12 is prepared by deprotecting a compound of Formula 11a:
Wherein P1 is an amino protecting group.

### Claim 10 (depends on 9)

The process according to claim 9, wherein the amino protecting group is a Boc group.

### Claim 11 (depends on 10)

The process according to claim 10, wherein deprotecting the compounds of Formula 11a comprises treating the compounds of Formula 11a with an acid.

### Claim 12 (depends on 1)

The process according to claim 1, wherein the compound of Formula 12 is prepared by deprotecting a compound of Formula 11a
Wherein P1 is an amino protecting group.

### Claim 13 (depends on 12)

The process according to claim 12, wherein the amino protecting group is a Boc group.

### Claim 14 (depends on 12)

The process according to claim 12, wherein deprotecting the compounds of Formula 11 comprises treating the compounds of Formula 11 with an acid.