# US 10,766,881 B2 · 2-aryl- and 2-heteroaryl-substituted 2-pyridazin-3(2H)-one compounds as inhibitors of FGFR tyrosine kinases

> Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt

- Number: US 10,766,881 B2
- Document ID: US10766881B2
- Status: Granted
- Kind: B2
- Application number: 16/276,326
- Filed: 2019-02-14
- Published: 2019-10-03
- Granted: 2020-09-08
- Earliest claimed: 2015-10-23
- Assignees: Array BioPharma Inc.
- Applicants: Array BioPharma Inc.
- Inventors: Steven W. Andrews; James F. Blake; Adam Cook; Indrani W. Gunawardana; Kevin W. Hunt; Andrew T. Metcalf; David Moreno; Li Ren; Tony P. Tang
- Web page: https://patentgrep.com/patent/US10766881B2

## CPC

- C07D 403/14: containing three or more hetero rings
- A61K 31/501: not condensed and containing further heterocyclic rings
- A61K 31/5377: not condensed and containing further heterocyclic rings, e.g. timolol
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61P 35/00: Antineoplastic agents
- C07D 401/14: containing three or more hetero rings
- C07D 413/14: containing three or more hetero rings
- C12Q 1/6886: for cancer (immunoassay for cancer G01N33/575)
- G01N 33/575: for cancer
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- 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
- C12Q: MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS (immunoassay G01N33/53); COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
- G01N: INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES (measuring or testing apparatus or processes other than immunoassay, involving enzymes or microorganisms C12M, C12Q)

## Abstract

Provided herein are compounds of the general Formula I: and stereoisomers and pharmaceutically acceptable salts or solvates thereof, in which X, R1, R2, R3, Ring A and z 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 method for treating cancer in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of a compound of general Formula I:
and pharmaceutically acceptable salts thereof, wherein:
X is N or CH;
Ring A is a 5-membered heteroaryl ring having 1-2 ring nitrogen atoms;
z is 1, 2 or 3;
each R1 is independently selected from the group consisting of:
(a) hydrogen;
(b) C1-C6 alkyl optionally substituted with 1-3 fluoros,
(c) hydroxy(C1-C6 alkyl)- optionally substituted with 1-3 fluoros,
(d) dihydroxy(C1-C6 alkyl)- optionally substituted with 1-3 fluoros,
(e) cyano(C1-C6 alkyl)-,
(f) RaRbN(C1-C6 alkyl)-,
(g) (C1-C3 alkoxy)C1-C6 alkyl- optionally substituted with 1-3 fluoros,
(h) (C3-C6 cycloalkyl)(CH2)n— where n is 0-3 and said cycloalkyl is optionally substituted with CN, OH, RaRbN—, (1-3C)alkyl, or (1-3C)alkoxy;
(i) hetCyc1(CH2)m— where m is 0-3,
(j) hetCyc2(CH2)p— where p is 0 or 1,
(k) hetAr1(CH2)q— where q is 1 or 2,
(l) halogen, and
(m) hetCyc1C(═O)CH2—;
hetCyc1 is a 4-7 membered saturated heterocyclic ring having 1-2 ring heteroatoms independently selected from N and 0, wherein said heterocyclic ring is optionally substituted with one or more substituents independently selected from the group consisting of fluoro, HO, C1-C6 alkyl (optionally substituted with 1-3 fluoros), (C1-C6 alkoxy)C1-C6 alkyl- (optionally substituted with 1-3 fluoros), (C3-C6 cycloalkoxy)C1-C6 alkyl-, hydroxy(C1-C6 alkyl)-, RcRdN— and (C1-C6 alkyl)C(═O)-;
hetCyc2 is a 7-10 membered heterospirocyclic ring having 1-2 ring heteroatoms independently selected from N and 0, wherein said heterospirocyclic ring is optionally substituted with one or more substituents independently selected from the group consisting of C1-C6 alkyl (optionally substituted with 1-3 fluoros), (C1-C6 alkoxy)C1-C6 alkyl- (optionally substituted with 1-3 fluoros), (C3-C6 cycloalkoxy)C1-C6 alkyl-, hydroxy(C1-C6 alkyl)-, RcRdN— and (C1-C6 alkyl) C(═O)-;
hetAr1 is a 6-membered heteroaryl ring having 1-2 ring nitrogen atoms, wherein said ring is optionally substituted with one or more substituents independently selected from C1-C6 alkyl and halogen;
R2 is Ar1 or hetAr2;
Ar1 is phenyl substituted with one or more groups independently selected from halogen, cyano, C1-C3 alkyl, C1-C3 alkoxy, (C1-C3 alkyl)NHC(═O)—, (C1-C3 alkyl)C(═O)NH—, (cyclopropyl)C(═O)NH— and (cyclopropyl)NHC(═O)—, wherein each of said C1-C3 alkyl and C1-C3 alkoxy portions is optionally substituted with 1-3 fluoros;
hetAr2 is a 6-10 membered heteroaryl ring having 1-2 ring nitrogen atoms, wherein said ring is optionally substituted with one or more groups independently selected from halogen, C1-C3 alkyl, C1-C3 alkoxy, (C1-C3 alkyl)NHC(═O)—, (C1-C3 alkyl)C(═O)NH—, (C3-C4 cycloalkyl)C(═O)NH- and (C3-C4 cycloalkyl)NHC(═O)—, wherein each of said C1-C3 alkyl and C1-C3 alkoxy portions is optionally substituted with 1-3 fluoros;
R3 is H, C1-C4 alkyl or (C3-C4)cycloalkyl; and
Ra, Rb, Rc and Rd are independently hydrogen or C1-C6 alkyl optionally substituted with F, OH or C1-C6 alkoxy.

### Claim 2

A method of treating an FGFR-associated cancer in a patient, the method comprising:
determining if the cancer in the patient is an FGFR-associated cancer; and
administering to a patient determined to have an FGFR-associated cancer a therapeutically effective amount of a compound of general Formula I:
and pharmaceutically acceptable salts thereof, wherein:
X is N or CH;
Ring A is a 5-membered heteroaryl ring having 1-2 ring nitrogen atoms;
z is 1, 2 or 3;
each R1 is independently selected from the group consisting of:
(a) hydrogen;
(b) C1-C6 alkyl optionally substituted with 1-3 fluoros,
(c) hydroxy(C1-C6 alkyl)- optionally substituted with 1-3 fluoros,
(d) dihydroxy(C1-C6 alkyl)- optionally substituted with 1-3 fluoros,
(e) cyano(C1-C6 alkyl)-,
(f) RaRbN(C1-C6 alkyl)-,
(g) (C1-C3 alkoxy)C1-C6 alkyl- optionally substituted with 1-3 fluoros,
(h) (C3-C6 cycloalkyl)(CH2)n— where n is 0-3 and said cycloalkyl is optionally substituted with CN, OH, RaRbN—, (1-3C)alkyl, or (1-3C)alkoxy;
(i) hetCyc1(CH2)m— where m is 0-3,
(j) hetCyc2(CH2)p— where p is 0 or 1,
(k) hetAr1(CH2)q— where q is 1 or 2,
(l) halogen, and
(m) hetCyc1C(═O)CH2—;
hetCyc1 is a 4-7 membered saturated heterocyclic ring having 1-2 ring heteroatoms independently selected from N and 0, wherein said heterocyclic ring is optionally substituted with one or more substituents independently selected from the group consisting of fluoro, HO, C1-C6 alkyl (optionally substituted with 1-3 fluoros), (C1-C6 alkoxy)C1-C6 alkyl- (optionally substituted with 1-3 fluoros), (C3-C6 cycloalkoxy)C1-C6 alkyl-, hydroxy(C1-C6 alkyl)-, RcRdN— and (C1-C6 alkyl)C(═O)—;
hetCyc2 is a 7-10 membered heterospirocyclic ring having 1-2 ring heteroatoms independently selected from N and 0, wherein said heterospirocyclic ring is optionally substituted with one or more substituents independently selected from the group consisting of C1-C6 alkyl (optionally substituted with 1-3 fluoros), (C1-C6 alkoxy)C1-C6 alkyl- (optionally substituted with 1-3 fluoros), (C3-C6 cycloalkoxy)C1-C6 alkyl-, hydroxy(C1-C6 alkyl)-, RcRdN— and (C1-C6 alkyl) C(═O)—;
hetAr1 is a 6-membered heteroaryl ring having 1-2 ring nitrogen atoms, wherein said ring is optionally substituted with one or more substituents independently selected from C1-C6 alkyl and halogen;
R2 is Ar1 or hetAr2;
Ar1 is phenyl substituted with one or more groups independently selected from halogen, cyano, C1-C3 alkyl, C1-C3 alkoxy, (C1-C3 alkyl)NHC(═O)—, (C1-C3 alkyl)C(═O)NH—, (cyclopropyl)C(═O)NH— and (cyclopropyl)NHC(═O)—, wherein each of said C1-C3 alkyl and C1-C3 alkoxy portions is optionally substituted with 1-3 fluoros;
hetAr2 is a 6-10 membered heteroaryl ring having 1-2 ring nitrogen atoms, wherein said ring is optionally substituted with one or more groups independently selected from halogen, C1-C3 alkyl, C1-C3 alkoxy, (C1-C3 alkyl)NHC(═O)—, (C1-C3 alkyl)C(═O)NH—, (C3-C4 cycloalkyl)C(═O)NH— and (C3-C4 cycloalkyl)NHC(═O)—, wherein each of said C1-C3 alkyl and C1-C3 alkoxy portions is optionally substituted with 1-3 fluoros;
R3 is H, C1-C4 alkyl or (C3-C4)cycloalkyl; and
Ra, Rb, Rc and Rd are independently hydrogen or C1-C6 alkyl optionally substituted with F, OH or C1-C6 alkoxy.

### Claim 3 (depends on 2)

The method of claim 2, wherein the step of determining if the cancer in the patient is an FGFR-associated cancer includes performing an assay to detect dysregulation in a FGFR gene, a FGFR protein, or expression or activity or level of any of the same in a sample from the patient.

### Claim 4 (depends on 3)

The method of claim 3, wherein the dysregulation in a FGFR gene, a FGFR protein, or expression or activity or level of any of the same is one or more point mutations in the FGFR gene.

### Claim 5 (depends on 3)

The method of claim 3, wherein the dysregulation in a FGFR gene, a FGFR protein, or expression or activity or level of any of the same, is a chromosome translocation that results in the expression of a FGFR fusion protein.

### Claim 6 (depends on 2)

The method of claim 2, wherein the FGFR-associated cancer is selected from the group consisting of: urothelial carcinoma, breast carcinoma or cancer, endometriod endometrial cancer or endometrial cancer, ovarian carcinoma or cancer, brain cancer, cholangiocarcinoma or intrahepatic cholangiocarinoma, gastric or stomach cancer, gastrointestinal stromal tumors, lung cancer, pancreatic cancer, prostate cancer, colorectal carcinoma or cancer, rectal cancer, renal cell carcinoma, neuroendocrine carcinoma, head and neck (squamous) carcinoma or head and neck adenoid cystic carcinoma, skin cancer, leiomyosarcoma, sarcoma, osteosarcoma, bladder cancer, rhabdomyosarcoma or embryonal rhabdosarcoma, esophageal cancer, hepatocellular carcinoma or liver cancer, salivary gland tumors, glioblatoma multiforme, myxoid lipocarcinoma, oral cancer, thyroid cancer or carcinoma, anaplastic thyroid carcinoma, adenoid cystic carcinoma, glioblastoma multiforme, myeloproliferative disorder/hematological malignancy, phosphaturic mesenchymal tumor, cervical cancer, biliary tract cancer, gallbladder cancer, spermatocytic seminoma, seborrheic keratosis, testicular cancer, fallopian tube carcinoma, carcinoma of unknown primary, gastroesophageal junction carcinoma, anal squamous cell carcinoma, hemangioendothelioma, uterine carcinosarcoma or uterine cancer, carcinoid, peritoneal carcinoma, adrenal carcinoma, bone cancer, peripheral nerve sheath tumor, glioma or paraganglioma, rosette forming glioneural tumor, lymphoepithelioma, mesothelioma, dysembryoplastic neuroepithelial tumor, and dedifferentiated liposarcoma.

### Claim 7 (depends on 1)

The method of claim 1, wherein X is N.

### Claim 8 (depends on 1)

The method of claim 1, wherein X is CH.

### Claim 9 (depends on 1)

The method of claim 1, wherein R2 is Ar1.

### Claim 10 (depends on 1)

The method of claim 1, wherein R2 is HetAr2.

### Claim 11 (depends on 1)

The method of claim 1, wherein Ring A is pyrazolyl.

### Claim 12 (depends on 1)

The method of claim 1, wherein R3 is hydrogen.

### Claim 13 (depends on 1)

The method of claim 1, wherein the compound of general Formula I is selected from any one of Examples 1-83 or a pharmaceutically acceptable salt thereof.

### Claim 14 (depends on 1)

The method of claim 1, wherein the cancer is selected from the group consisting of: urothelial carcinoma, breast carcinoma or cancer, endometriod endometrial cancer or endometrial cancer, ovarian carcinoma or cancer, brain cancer, cholangiocarcinoma or intrahepatic cholangiocarinoma, gastric or stomach cancer, gastrointestinal stromal tumors, lung cancer, pancreatic cancer, prostate cancer, colorectal carcinoma or cancer, rectal cancer, renal cell carcinoma, neuroendocrine carcinoma, head and neck (squamous) carcinoma or head and neck adenoid cystic carcinoma, skin cancer, leiomyosarcoma, sarcoma, osteosarcoma, bladder cancer, rhabdomyosarcoma or embryonal rhabdosarcoma, esophageal cancer, hepatocellular carcinoma or liver cancer, salivary gland tumors, glioblatoma multiforme, myxoid lipocarcinoma, oral cancer, thyroid cancer or carcinoma, anaplastic thyroid carcinoma, adenoid cystic carcinoma, glioblastoma multiforme, myeloproliferative disorder/hematological malignancy, phosphaturic mesenchymal tumor, cervical cancer, biliary tract cancer, gallbladder cancer, spermatocytic seminoma, seborrheic keratosis, testicular cancer, fallopian tube carcinoma, carcinoma of unknown primary, gastroesophageal junction carcinoma, anal squamous cell carcinoma, hemangioendothelioma, uterine carcinosarcoma or uterine cancer, carcinoid, peritoneal carcinoma, adrenal carcinoma, bone cancer, peripheral nerve sheath tumor, glioma or paraganglioma, rosette forming glioneural tumor, lymphoepithelioma, mesothelioma, dysembryoplastic neuroepithelial tumor, and dedifferentiated liposarcoma.

### Claim 15 (depends on 2)

The method of claim 2, wherein X is N.

### Claim 16 (depends on 2)

The method of claim 2, wherein X is CH.

### Claim 17 (depends on 2)

The method of claim 2, wherein R2 is Ar1.

### Claim 18 (depends on 2)

The method of claim 2, wherein R2 is HetAr2.

### Claim 19 (depends on 2)

The method of claim 2, wherein Ring A is pyrazolyl.

### Claim 20 (depends on 2)

The method of claim 2, wherein R3 is hydrogen.

### Claim 21 (depends on 2)

The method of claim 2, wherein the compound of general Formula I is selected from any one of Examples 1-83 or a pharmaceutically acceptable salt thereof.