# US 2020/0399279 A1 · SUBSTITUTED PYRAZOLO[3,4-d]PYRIMIDINE COMPOUNDS AS RET KINASE INHIBITORS

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- Number: US 2020/0399279 A1
- Document ID: US20200399279A1
- Status: Published application
- Kind: A1
- Application number: 16/961,973
- Filed: 2019-01-18
- Published: 2020-12-24
- Earliest claimed: 2018-01-18
- Assignees: Array BioPharma Inc.
- Applicants: Array Biopharma Inc.
- Inventors: James F. BLAKE; Donghua DAI; Julia HAAS; Yutong JIANG; Gabrielle R. KOLAKOWSKI; Andrew T. METCALF; David A. MORENO; Brett PRIGARO; Li REN
- Web page: https://patentgrep.com/patent/US20200399279A1

## CPC

- A61P 35/00: Antineoplastic agents
- C07D 487/04: Ortho-condensed systems
- 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 tautomers and pharmaceutically acceptable salts and solvates thereof, wherein R1 and R2 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 compound of Formula I:
and pharmaceutically acceptable salts thereof, wherein:
R1 is a 5-membered heteroaryl ring having 2-3 ring heteroatoms independently selected from N, O and S, wherein R1 is optionally substituted with 1-3 substituents independently selected from halogen, C1-C6 alkyl, fluoroC1-C6 alkyl, hydroxyC1-C6 alkyl, (C1-C6 alkoxy)C1-C6 alkyl-, C2-C6 alkenyl, Cyc1, hetCyc1, Ar1, hetAr1, (C1-C6 alkyl)C(═O)—, (C1-C6 alkyl)2-P(═O)—, and R′R″NC(═O)— wherein R′ is hydrogen and R″ is hydrogen, C1-C alkyl or Cyc2,
provided that when R1 is an isoxazolyl ring, then R1 is substituted with 2 substituents independently selected from halogen, C1-C6 alkyl, fluoroC1-C6 alkyl, hydroxyC1-C6 alkyl, (C1-C6 alkoxy)C1-C6 alkyl-, C2-C6 alkenyl, Cyc1, hetCyc1, Ar1, hetAr1, (C1-C6 alkyl)C(═O)—, (C1-C6 alkyl)2-P(═O)—, and R′R″NC(═O)— wherein R′ is hydrogen and R″ is hydrogen, C1-C alkyl or Cyc2;
Cyc1 is a 3-6 membered saturated or partially unsaturated cycloalkyl ring optionally substituted with one or more substituents independently selected from hydroxy, C1-C6 alkyl and oxo;
hetCyc1 is a 4-6 membered saturated or partially unsaturated heterocyclic ring having 1-2 ring heteroatoms independently selected from N and O and optionally substituted with one or more substituents independently selected from C1-C6 alkyl, hydroxy, and oxo;
Ar1 is phenyl optionally substituted with one or more substituents independently selected from C1-C6 alkyl, fluoroC1-C6 alkyl, halogen, and hydroxy;
Cyc2 is C3-C6 cycloalkyl optionally substituted with hydroxy;
hetAr1 is a 5-6 membered heteroaryl ring having 1-3 ring nitrogen atoms and optionally substituted with one or more substituents independently selected from C1-C6 alkyl, fluoroC1-C6 alkyl, halogen, hydroxy, and benzyl; and
R2 is hydrogen, C1-C6 alkyl, fluoroC1-C6 alkyl, cyanoC1-C6 alkyl-, hydroxyC1-C6 alkyl, C3-C6 cycloalkyl or (C3-C6 cycloalkyl)C1-C6 alkyl-.

### Claim 2 (depends on 1)

The compound or pharmaceutically acceptably salt thereof according to claim 1, wherein R1 is an isoxazolyl ring substituted with 2 substituents independently selected from halogen, C1-C6 alkyl, fluoroC1-C6 alkyl, hydroxyC1-C6 alkyl, (C1-C6 alkoxy)C1-C6 alkyl-, C2-C6 alkenyl, Cyc1, hetCyc1, Ar1, hetAr1, (C1-C6 alkyl)C(═O)—, (C1-C6 alkyl)2-P(═O)—, and R′R″NC(═O)— wherein R′ is hydrogen and R″ is hydrogen, C1-C alkyl or Cyc2.

### Claim 3 (depends on 2)

The compound or pharmaceutically acceptably salt thereof according to claim 2, wherein R1 is an isoxazolyl ring substituted with 2 substituents independently selected from halogen, hydroxyC1-C6 alkyl, Cyc1, hetCyc1, Ar1 and hetAr1.

### Claim 4 (depends on 3)

The compound or pharmaceutically acceptably salt thereof according to claim 3, wherein R1 is
wherein:
Ra is cyclopropyl; and
Rb is halogen,

### Claim at position 5

-11. (canceled)

### Claim 12 (depends on 1)

The compound or pharmaceutically acceptably salt thereof according to claim 1, wherein R1 is

### Claim 13 (depends on 1)

The compound or pharmaceutically acceptably salt thereof according to claim 1, wherein R1 is
wherein:
Rc is hydrogen, C1-C6 alkyl, fluoroC1-C6 alkyl, C2-C6 alkenyl, Cyc1, or Ar1;
Rd is C1-C6 alkyl, Cyc1 or hetCyc1; and
Re is hydrogen or C1-C6 alkyl.

### Claim at position 8

-24. (canceled)

### Claim 25 (depends on 13)

The compound or pharmaceutically acceptably salt thereof according to claim 13, wherein R2 is C1-C6 alkyl.

### Claim 26 (depends on 1)

The compound or pharmaceutically acceptably salt thereof according to claim 1, selected from Examples 1-35.

### Claim 27 (depends on 1)

A pharmaceutical composition, comprising a compound or pharmaceutically acceptably salt thereof according to claim 1 in admixture with a pharmaceutically acceptable diluent or carrier.

### Claim 28

(canceled)

### Claim 29 (depends on 1)

A method for treating cancer in a patient in need thereof, the method comprising administering to the patient an effective amount of a compound of claim 1, or a pharmaceutically acceptable salt thereof.

### Claim at position 14

-50. (canceled)

### Claim 51 (depends on 29)

The method of claim 29 wherein the cancer is selected from the group consisting of: lung cancer, papillary thyroid cancer, medullary thyroid cancer, differentiated thyroid cancer, recurrent thyroid cancer, refractory differentiated thyroid cancer, multiple endocrine neoplasia type 2A or 2B (MEN2A or MEN2B, respectively), pheochromocytoma, parathyroid hyperplasia, breast cancer, colorectal cancer, papillary renal cell carcinoma, ganglioneuromatosis of the gastroenteric mucosa, and cervical cancer.

### Claim 52 (depends on 51)

The method of claim 51, wherein the lung cancer is RET fusion lung cancer or the cancer is medullary thyroid cancer.

### Claim at position 17

53-169. (canceled)