# US 2023/0054411 A1 · 7-, 8-, and 10-SUBSTITUTED AMINO TRIAZOLO QUINAZOLINE DERIVATIVES AS ADENOSINE RECEPTOR ANTAGONISTS, PHARMACEUTICAL COMPOSITIONS AND THEIR USE

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- Number: US 2023/0054411 A1
- Document ID: US20230054411A1
- Status: Published application
- Kind: A1
- Application number: 17/294,836
- Filed: 2019-11-26
- Published: 2023-02-23
- Earliest claimed: 2018-11-30
- Assignees: Merck Sharp & Dohme Corp.
- Applicants: Merck Sharp & Dohme Corp.
- Inventors: Yonglian Zhang; Amjad Ali; Jared Cumming; Duane DeMong; Qiaolin Deng; Thomas H. Graham; Elisabeth Hennessy; Matthew A. Larsen; Kun Liu; Ping Liu; Umar Faruk Mansoor; Jianping Pan; Christopher W. Plummer; Aaron Sather; Uma Swaminathan; Huijun Wang
- Web page: https://patentgrep.com/patent/US20230054411A1

## CPC

- A61K 31/519: ortho- or peri-condensed with heterocyclic rings
- A61K 31/55: having seven-membered rings, e.g. azelastine, pentylenetetrazole
- A61K 39/3955: {against proteinaceous materials, e.g. enzymes, hormones, lymphokines}
- 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)
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)

## Abstract

In its many embodiments, the present invention provides certain 7-, 8-, and 10-substituted amino triazolo quinazoline derivatives of Formula (I): or a pharmaceutically acceptable salt thereof, wherein ring A, R1, R2, and R4 are as defined herein, pharmaceutical compositions comprising one or more such compounds (alone and in combination with one or more other therapeutic agents), and methods for their preparation and use, alone and in combination with other therapeutic agents, as antagonists of A2a and/or A2b receptors, and their use in the treatment of a variety of diseases, conditions, or disorders that are mediated, at least in part, by the adenosine A2a receptor and/or the adenosine A2b receptor.

## Claims

### Claim 1

A compound having a structural Formula (I):
or a pharmaceutically acceptable salt thereof, wherein:
R1 is selected from H, F, Cl, Br, CN, OH, (C1-C6)alkyl, O(C1-C6)alkyl, and O(C1-C6)haloalkyl;
R2 is selected from H, F, Cl, Br, CN, OH, (C1-C6)alkyl, (C1-C6)haloalkyl, O(C1-C6)alkyl, O(C1-C6)haloalkyl, (C3-C4)cycloalkyl, S(O)2(C1-C6)alkyl, S(O)2(C1-C6)haloalkyl, and 4-5 membered monocyclic heterocycloalkyl comprising 1 or 2 ring nitrogen atoms;
R4 is selected form H, F, Cl, Br, (C1-C6)alkyl, and (C1-C6)haloalkyl,
with the proviso that at least one of R1, R2, or R4 is not H; and
ring A is a moiety selected from:
wherein:
R3 is selected from: pyrazolyl, pyridinyl, pyrazinyl, phenyl, oxadiazolyl, thiazolyl, triazolyl, pyrimidinyl, pyridazinyl, and imidazolyl,
wherein said pyridinyl, said pyrazinyl, and said phenyl are substituted with 1, 2, 3, or 4 R3A groups
wherein said pyrazolyl, pyridazinyl, imidazolyl, and said pyrimidinyl are substituted with 1, 2, or 3 R3A groups,
wherein said triazolyl and said thiazolyl are substituted with 1 or 2 R3A groups, and
wherein said oxadiazolyl is substituted with 1 R3A group;
each R3A is independently selected from H, F, Cl, (C1-C6)alkyl, (C1-C6)alkyl-OH, (C1-C6)haloalkyl, (C1-C6)alkylNH2, O(C1-C6)alkyl, O(C1-C6)haloalkyl, C(O)(C1-C3)alkyl, (C1-C4)alkylC(O)(C1-C3)alkyl, (C1-C4)alkylO(C1-C3)alkyl, (C1-C4)alkylCH(OH)(C1-C3)alkyl, (C1-C4)alkylS(O)2(C1-C3)alkyl, (C1-C6)alkylC(O)NH(C1-C6)alkyl, (C1-C6)alkylC(O)OH, (C1-C6)alkylC(O)NH(C3-C6)cycloalkyl,
—(CH2)n(C3-C7)cycloalkyl, and —(CH2)n4-7 membered monocyclic heterocycloalkyl comprising 1 or 2 ring heteroatoms selected from O, N, S, and S(O)2,
wherein said (C3-C7)cycloalkyl, and said 4-7 membered monocyclic heterocycloalkyl are each unsubstituted or substituted with 1, 2, or 3 groups independently selected from F, Cl, OH, oxo, (C1-C6)alkyl, O(C1-C6)alkyl, (C1-C6)haloalkyl, and O(C1-C6)haloalkyl;
n is 0, 1, or 2;
each R3Aa is independently selected from H, (C1-C4)alkyl, O(C1-C4)alkyl, (C1-C4)haloalkyl, O(C1-C4)haloalkyl, and (C3-C4)cycloalkyl;
RA1 is selected from H, and (C1-C4)alkyl;
each RA2 is independently selected from H, F, and (C1-C4)alkyl;
RA3 is selected from H, F, and (C1-C4)alkyl;
RA4 is selected from H and OH; and
RA5 is selected from H, F, and (C1-C4)alkyl.

### Claim 2 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein said compounds have the structural Formula (I.1):
wherein R1 is selected from F, Cl, Br, CN, OH, CH3, CH2CH3, OCH3 OCH2CH3 and O(C1-C6)haloalkyl.

### Claim 3 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein said compounds have the structural Formula (I.2):
wherein R2 is selected from F, Cl, Br, CN, OH, CH3, CHF2, CF3, CH2CH3, OCH3, OCH2CH3, OCHF, S(O)2CH3,

### Claim 4 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein said compounds have the structural Formula (I.3):
wherein R4 is selected from F, Cl, Br, (C1-C6)alkyl, and (C1-C6)haloalkyl.

### Claim 5 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein said compounds have the structural Formula (1.4):
wherein R1 is selected from F, Cl, Br, CN, OH, CH3, OCH3, and CF3; and
R2 is selected from F, Cl, Br, CN, OH, CH3, OCH3, and CF3.

### Claim 6 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein said compounds have the structural Formula (I.5):
wherein R1 is selected from F, Cl, Br, CN, OH, CH3, OCH3, and CF3; and
R4 is selected from F, Cl, Br, CN, OH, CH3, OCH3, and CF3.

### Claim 7 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein:
ring A is:

### Claim 8 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein:
ring A is:

### Claim 9 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein:
ring A is:

### Claim 10 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein:
ring A is:

### Claim 11 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein:
ring A is a moiety selected from:

### Claim 12 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein:
ring A is:

### Claim 13 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein:
R3 is a moiety selected from:

### Claim 14 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein said compound is selected from:

### Claim 15 (depends on 1)

A pharmaceutical composition comprising a compound of claim 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

### Claim 16 (depends on 1)

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

### Claim 17 (depends on 16)

The method of claim 16, wherein said cancer is selected from melanoma, head and neck cancer, classical Hodgkin lymphoma, urothelial carcinoma, gastric cancer, cervical cancer, primary mediastinal large-B-cell lymphoma, microsatellite instability-high cancer, non-small cell lung cancer, hepatocellular carcinoma, clear cell kidney cancer, colorectal cancer, breast cancer, squamous cell lung cancer, basal carcinoma, sarcoma, bladder cancer, endometrial cancer, pancreatic cancer, liver cancer, gastrointestinal cancer, multiple myeloma, renal cancer, mesothelioma, ovarian cancer, anal cancer, biliary tract cancer, esophageal cancer, salivary cancer, and prostate cancer, and metastatic castration resistant prostate cancer.

### Claim 18 (depends on 17)

The method of claim 17, wherein said compound, or a pharmaceutically acceptable salt thereof, is administered in combination with another therapeutic agent.

### Claim 19 (depends on 18)

The method of claim 18, wherein said additional therapeutic agent is a PD-1 antagonist.

### Claim 20 (depends on 19)

The method of claim 19, wherein said additional therapeutic agent is selected from pembrolizumab, nivolumab, atezolizumab, dunvalumab, and avelumab.

### Claim 21 (depends on 19)

The method of claim 19, wherein said additional therapeutic agent is pembrolizumab.