# US 11,896,592 B2 · Certain triazolopyridines and triazolopyrazines, compositions thereof and methods of use therefor

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- Number: US 11,896,592 B2
- Document ID: US11896592B2
- Status: Granted
- Kind: B2
- Application number: 17/248,688
- Filed: 2021-02-03
- Published: 2021-05-27
- Granted: 2024-02-13
- Earliest claimed: 2009-12-31
- Assignees: Hutchison Medipharma Limited
- Applicants: Hutchison Medipharma Limited
- Inventors: Wei-Guo Su; Hong Jia; Guangxiu Dai
- Web page: https://patentgrep.com/patent/US11896592B2

## CPC

- A61K 31/4985: Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
- A61K 31/437: the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
- A61K 31/4375: the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
- A61K 31/4545: containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
- A61K 31/4709: Non-condensed quinolines and containing further heterocyclic rings
- A61K 31/5025: ortho- or peri-condensed with heterocyclic ring systems
- A61K 31/519: ortho- or peri-condensed with 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
- A61P 35/02: specific for leukemia
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07D 471/04: Ortho-condensed systems
- C07D 487/04: 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 are certain triazolopyridines and triazolopyrazines of Formula 1, wherein X, Y, R1, R2, R3, R4 and R5 have any of the meanings described herein; processes for their preparation, pharmaceutical compositions containing them, and their use in the treatment of cell proliferative disorders.

## Claims

### Claim 1

A method of treating cancer responsive to inhibition of c-Met, wherein the cancer is selected from lung cancer, stomach cancer, colorectal cancer, esophageal cancer, hepatocellular cancer, breast cancer, kidney cancer and ovarian cancer, comprising administering to a subject in recognized need thereof an effective amount of at least one compound of formula 1:
and/or at least one pharmaceutically acceptable salt thereof, wherein:
X is N, Y is absent and R1 is a fused bicyclic heteroaryl selected from:
optionally substituted with one or more groups selected from halo, —CF3, —CF2H, cycloalkyl, —C(O)R11, —C(O)OR11, —CN, —C(O)NR13R14, —NR13R14, —NR13C(O)R11, —NR13S(O)nR12, —NR13S(O)nNR13R14, —NR13C(O)OR12, —NR13C(O)NR13R14, —NO2, —S(O)nR12, —S(O)nNR13R14, heterocycle, heteroaryl, aryl, alkenyl, alkynyl, lower alkyl, lower alkyl substituted with hydroxy, lower alkyl substituted with lower alkoxy, lower alkyl substituted with —NR13R14, and lower alkyl substituted with heterocycle;
R2 and R3 are independently selected from hydrogen, and alkyl, or R2 and R3, together with the carbon to which they are attached, form a ring chosen from 3- to 7-membered cycloalkyl and 3- to 7-membered heterocycle;
R4 is selected from halo, alkyl, cycloalkyl, heterocycle, aryl and heteroaryl, each of which, except for halo, is optionally substituted with one or more groups selected from:
(i) lower alkyl optionally substituted with one or more groups selected from hydroxy, lower alkoxy, cyano, halo, —C(O)OR11, —C(O)NR13R14, —NR13R14, —OC(O)R11, —NR13C(O)R11, —NR13S(O)nR12, —NR13S(O)nR13R14, —N13C(O)OR12, and —NR13C(O)NR13R14;
(ii) lower alkoxy optionally substituted with one or more groups selected from halo, hydroxy, and lower alkoxy;
(iii) cycloalkoxy optionally substituted with one or more groups selected from halo, hydroxy, and lower alkoxy;
(iv) heterocycloalkoxy optionally substituted with one or more groups selected from halo, hydroxy, and lower alkoxy;
(v) heterocycle optionally substituted with one or more groups selected from lower alkyl, halo, hydroxy, and lower alkoxy;
(vi) heteroaryloxy optionally substituted with one or more groups selected from lower alkyl, halo, hydroxy, and lower alkoxy;
(viii) aryl optionally substituted with one or more groups selected from lower alkyl, halo, hydroxy, and lower alkoxy;
(ix) heteroaryl optionally substituted with one or more groups selected from lower alkyl, halo, hydroxy, and lower alkoxy;
(x) halo;
(xi) cyano;
(xii) —C(O)R11;
(xiii) —C(O)OR11;
(xiv) —NR13R14;
(xv) —NR13C(O)R11;
(xvi) —NR13S(O)nR12;
(xvii) —NR13S(O)nNR13R14;
(xviii) —NR13C(O)OR12;
(xix) —NR13C(O)NR13R14;
(xx) —C(O)NR13R14,
(xxi) —S(O)nR12; and
(xxii) —S(O)nNR13R14;
R5 is selected from hydrogen, halo, OH, NH2, CF3, —CF2H, alkyl, alkenyl, and alkynyl;
each n is independently 0, 1, or 2;
R11, R12, R13, and R14 are independently selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, and heterocycle, each of which except for hydrogen, is optionally substituted with one or more groups selected from halo, lower alkyl, hydroxy, and lower alkoxy, or R13 and R14, with the nitrogen to which they are attached, combine to form a heterocycle ring, which is optionally substituted with one or more groups selected from halo, lower alkyl, hydroxy, and lower alkoxy and further optionally includes one or two additional heteroatoms in the heterocycle ring wherein the one or two additional heteroatoms are selected from —O—, —S—, and —N(R15)—; and
R15 is selected from hydrogen, lower alkyl, —C(O)R11, —C(O)OR11, —C(O)NR13R14, —S(O)nR12, and —S(O)nNR13R14;
provided that:
when R2 is hydrogen or methyl and R3 and R5 are hydrogen, then R1 is not 3-quinazolin-6-yl;
wherein said at least one compound of formula (I), and/or at least one pharmaceutically acceptable salt thereof, is administered in conjunction with a protein tyrosine kinase inhibitor.

### Claim 2 (depends on 1)

The method of treating cancer according to claim 1, comprising administering to a subject in recognized need thereof an effective amount of at least one compound of formula 1 selected from:
and/or at least one pharmaceutically acceptable salt thereof.

### Claim 3 (depends on 1)

The method of treating cancer according to claim 1, comprising administering to a subject in recognized need thereof an effective amount of at least one compound of formula 1 which is selected from:
and/or at least one pharmaceutically acceptable salt thereof.

### Claim 4 (depends on 1)

The method of treating cancer according to claim 1, comprising administering to a subject in recognized need thereof an effective amount of at least one compound of formula 1 which is selected from:
and/or at least one pharmaceutically acceptable salt thereof.

### Claim 5 (depends on 1)

The method of treating cancer according to claim 1, comprising administering to a subject in recognized need thereof an effective amount of at least one compound of formula 1 which is:
and/or at least one pharmaceutically acceptable salt thereof.

### Claim 6 (depends on 1)

The method of treating cancer according to claim 1, comprising administering to a subject in recognized need thereof an effective amount of at least one compound of formula 1 which is:

### Claim 7 (depends on 1)

The method of treating cancer according to claim 1, where the cancer is lung cancer.

### Claim 8 (depends on 1)

The method of treating cancer according to claim 1, where the cancer is stomach cancer.

### Claim 9 (depends on 1)

The method of treating cancer according to claim 1, where the cancer is kidney cancer.

### Claim 10 (depends on 1)

The method of treating cancer according to claim 1, where the cancer is colorectal cancer.

### Claim 11 (depends on 1)

The method of treating cancer according to claim 1, wherein the protein tyrosine kinase inhibitor is selected from imatinib mesylate and gefitinib.

### Claim 12 (depends on 1)

The method of treating cancer according to claim 1, wherein the protein tyrosine kinase inhibitor is gefitinib.