# US 12,180,207 B2 · Substituted pyrazolo[1,5-a]pyridine compounds as inhibitors of FGFR tyrosine kinases

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- Number: US 12,180,207 B2
- Document ID: US12180207B2
- Status: Granted
- Kind: B2
- Application number: 17/416,117
- Filed: 2019-12-13
- Published: 2022-03-17
- Granted: 2024-12-31
- Earliest claimed: 2018-12-19
- Assignees: Array BioPharma Inc.
- Applicants: Array Biopharma Inc.
- Inventors: James F. Blake; David A. Moreno; Li Ren; Tony P. Tang; Shane M. Walls
- Web page: https://patentgrep.com/patent/US12180207B2

## CPC

- C07D 471/04: Ortho-condensed systems
- A61P 35/00: Antineoplastic agents
- 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
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

Provided herein are compounds of the general Formula I: and stereoisomers and pharmaceutically acceptable salts or solvates thereof, in which Ring A, Ring B, Ring C, R1, R2, L, Y, and W have the meanings given in the specification, which are inhibitors of FGFR1, FGFR2, FGFR3 and/or FGFR4 and are useful in the treatment and prevention of diseases which can be treated with an FGFR inhibitor, including diseases or disorders mediated by FGFR1, FGFR2, FGFR3 and/or FGFR4.

## Claims

### Claim 1

A compound of Formula I
wherein:
R1 is CN or Cl;
R2 is C1-C6 alkoxy, C1-C6 alkyl, C3-C6 cycloalkoxy, or phenyl optionally substituted with 1-2 groups independently selected from halogen and (C3-C6 cycloalkyl) C(═O)NH—;
Ring A is Ar1 or hetAr1;
Ar1 is phenyl optionally substituted with 1-2 groups independently selected from halogen, C1-C6 alkyl, fluoroC1-C6 alkyl, and C1-C6 alkoxy;
hetAr1 is a 5-6 membered heteroaryl ring having 1-3 ring nitrogen atoms and optionally substituted with 1-2 independently selected halogen, C1-C6 alkyl, fluoroC1-C6 alkyl, or C1-C6 alkoxy substituents;
Ring B is a 4-8 membered monocyclic heterocyclic ring having 1-2 ring nitrogen atoms, a 7-11 membered bridged heterocyclic ring having 1-2 ring nitrogen atoms, a 7-12 membered spiroheterocyclic ring having 2 ring nitrogen atoms, or absent;
L is —C(═O)—,—CH2—, —SO2—, —C(═O)NH*, or absent, wherein the asterisk indicates the point of attachment to Ring C;
Ring C is Cyc1, Cyc2, hetCyc1, hetCyc2, hetCyc3, Ar3, or absent;
Cyc1 is 4-8 membered cycloalkyl ring optionally substituted with halo, CN, OH, C1-C6 alkyl, fluoroC1-C6 alkyl, and C1-C6 alkoxy;
Cyc2 is a 5-11 membered bridged cycloalkyl ring;
hetCyc1 is a 4-6 membered heterocyclic ring having 1-2 ring nitrogen atoms and optionally substituted with 1-4 substituents independently selected from halogen, CN, OH, C1-C6 alkyl, C1-C6 alkoxy, and cyanoC1-C6 alkyl;
hetCyc2 is a 7-11 membered bridged heterocyclic ring having 1-3 ring heteroatoms independently selected from N and O;
hetCyc3 is a 7-12 membered spiroheterocyclic ring having 1-2 ring nitrogen atoms;
Ar3 is phenyl optionally substituted with C1-C6 alkyl or C1-C6 alkoxy;
Y is —NH—, —N(C1-C3 alkyl)-, or absent;
W is R3R4C═CR5C(═O)—, R6R7NCH2CH═CHC(═O)—, H2C═CHSO2— or R8C═C≡C(═O)—;
R3 is hydrogen;
R4 is hydrogen, CF3 or Z (C1-C6 alkyl)-wherein Z is H, F, Cl, Br, HO—, or C1-C6 alkoxy, and
R5 is hydrogen, C1-C3 alkyl, or halogen,
or R4 and R5 together with the carbon atoms to which they are attached form a 4-8-membered carbocyclic ring;
each of R6 and R7 is independently C1-C6 alkyl, or R6 and R7 together with the nitrogen atom to which they are attached form a 5-6 membered heterocyclic ring optionally having an additional ring heteroatom which is O, wherein said ring is optionally substituted with halogen;
R8 is hydrogen, C1-C3 alkyl, HO-C1-C3 alkyl or R′R″NCH2—; and
R′ and R″ are each independently hydrogen or C1-C6 alkyl,
or a pharmaceutically acceptable salt thereof.

### Claim 2 (depends on 1)

The compound according to claim 1, wherein Ring A is
or unsubstituted phenyl, wherein the asterisk indicates point of attachment to Ring B, and pharmaceutically acceptable salts thereof.

### Claim 3 (depends on 1)

The compound according to claim 1, wherein Ring B is
wherein the asterisk indicates point of attachment to L, and pharmaceutically acceptable salts thereof.

### Claim 4 (depends on 1)

The compound of claim 1, wherein L is —C(═O)— or —CH2—.

### Claim 5 (depends on 1)

The compound according to claim 1, wherein Ring C is
wherein the asterisk indicates point of attachment to —Y—W, and pharmaceutically acceptable salts thereof.

### Claim 6 (depends on 1)

The compound of claim 1, wherein the compound is at least about 3-fold more selective for FGFR3 than FGFR1, and wherein the compound forms a covalent bond with a cysteine in a FGFR protein.

### Claim 7 (depends on 1)

The compound of claim 1, wherein the compound is at least about 3-fold more selective for FGFR2 than FGFR1, and wherein the compound forms a covalent bond with a cysteine in a FGFR protein.

### Claim 8 (depends on 1)

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

### Claim 9 (depends on 1)

A method for treating an FGFR-associated cancer in a subject in need thereof, the method comprising administering to the subject a pharmaceutical composition comprising a therapeutically effective amount of a compound according to claim 1 or a pharmaceutically acceptable salt thereof.

### Claim 10 (depends on 9)

The method of claim 9, wherein the FGFR-associated cancer is selected from the group consisting of: bladder cancer, brain cancer, breast cancer, cholangiocarcinoma, head and neck cancer, lung cancer, multiple myeloma, rhabdomyosarcoma, urethral cancer, and uterine cancer.

### Claim 11 (depends on 9)

The method of claim 9, wherein the FGFR-associated cancer is a FGFR fusion lung cancer, a FGFR fusion breast cancer, a FGFR fusion bladder cancer, a FGFR fusion biliary tract cancer, a FGFR fusion urethral cancer, a FGFR fusion head and neck cancer, or a FGFR fusion multiple myeloma.

### Claim 12 (depends on 9)

The method of claim 9, wherein the FGFR-associated cancer is lung cancer, and the lung cancer is small cell lung carcinoma, non-small cell lung cancer, squamous cell lung cancer, or lung adenocarcinoma.

### Claim 13 (depends on 9)

The method of claim 9, wherein the compound or a pharmaceutically acceptable salt thereof is orally administered.

### Claim 14 (depends on 9)

The method of claim 9, wherein the method further comprises administering an additional therapy or therapeutic agent to the subject.