# US 11,028,097 B2 · Thienopyrimidine compounds

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- Number: US 11,028,097 B2
- Document ID: US11028097B2
- Status: Granted
- Kind: B2
- Application number: 16/726,308
- Filed: 2019-12-24
- Published: 2020-05-07
- Granted: 2021-06-08
- Earliest claimed: 2007-09-21
- Assignees: Vernalis (R&D) Ltd
- Applicants: Vernalis (R&D) Limited
- Inventors: Allan Jordan; Simon Bedford; Klenke Burkhard; Ian Yule; Karine Poullennec
- Web page: https://patentgrep.com/patent/US11028097B2

## CPC

- C07D 495/04: Ortho-condensed systems
- A61K 31/519: ortho- or peri-condensed with heterocyclic rings
- A61P 3/10: for hyperglycaemia, e.g. antidiabetics
- A61P 11/00: Drugs for disorders of the respiratory system
- A61P 11/06: Antiasthmatics
- A61P 25/04: Centrally acting analgesics, e.g. opioids
- A61P 27/02: Ophthalmic agents
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A61P 35/00: Antineoplastic agents
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07D 495/14: Ortho-condensed systems
- 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

## Abstract

Compounds of formula (I) are A2B receptor antagonists: Wherein R1 is optionally substituted aryl or an optionally substituted 5- or 6-membered heteroaryl ring; R2 and R3 are independently selected from hydrogen, C1-C6 alkyl, C3-C8 cycloalkyl, C3-C8 cycloalkyl-(C1-C6)-alkyl, aryl-(C1-C6)-alkyl optionally substituted in the ring part thereof, a 5- or 6-membered monocyclic heterocyclic group optionally linked via a C1-C6 alkylene chain and optionally substituted in the ring part thereof, benzimidazol-2-yl-methyl, pyrid-3-yl-carbonyl, or (1-methyl-piperidin-4-yl)-carbonyl-methyl; or R2 and R3 taken together with the nitrogen atom to which they are attached form an optionally substituted 5- or 6-membered ring; R4 is C1-C3 alkyl, C2-C3 alkenyl, —N(—R5)—R6, or optionally substituted heteroarylmethylamino; and R5 and R6 are independently selected from hydrogen or C1-C3 alkyl; or R5 and R6 taken together with the nitrogen atom to which they are attached form an optionally substituted 4- to 6-membered saturated ring.

## Claims

### Claim 1

A method of treating a disorder which is responsive to antagonism of the adenosine A2B receptor in a subject in need thereof, the method comprising administering to the subject a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) is:
wherein:
R1 is optionally substituted aryl or an optionally substituted 5- or 6-membered heteroaryl ring;
R2 and R3 are independently selected from hydrogen, C1-C6 alkyl, C3-C8 cycloalkyl, C3-C8 cycloalkyl-(C1-C6)-alkyl, aryl-(C1-C6)-alkyl optionally substituted in the ring part thereof, a 5- or 6-membered monocyclic heterocyclic group optionally linked via a C1-C6 alkylene chain and optionally substituted in the ring part thereof, benzimidazol-2-yl-methyl, pyrid-3-yl-carbonyl, or (1-methyl-piperidin-4-yl)-carbonyl-methyl; or R2 and R3 taken together with the nitrogen atom to which they are attached form an optionally substituted 5- or 6-membered ring;
R4 is C1-C3 alkyl, C2-C3 alkenyl, —N(—R5)—R6, or optionally substituted heteroarylmethylamino; and
R5 and R6 are independently selected from hydrogen or C1-C3 alkyl; or R5 and R6 taken together with the nitrogen atom to which they are attached form an optionally substituted 4- to 6-membered saturated ring.

### Claim 2 (depends on 1)

The method of claim 1, wherein the disorder is an inflammatory disease.

### Claim 3 (depends on 2)

The method of claim 2, wherein the inflammatory disease is rheumatoid arthritis, multiple sclerosis, lupus, psoriasis, or inflammatory bowel disease.

### Claim 4 (depends on 1)

The method of claim 1, wherein the disorder is nociception, asthma, chronic obstructive pulmonary disease, diabetes, or diabetic retinopathy.

### Claim 5 (depends on 1)

The method of claim 1, comprising orally administering to the subject the compound of formula (I) or the pharmaceutically acceptable salt thereof.

### Claim 6 (depends on 5)

The method of claim 5, wherein R1 is an optionally substituted 5- or 6-membered heteroaryl ring.

### Claim 7 (depends on 1)

The method of claim 1, wherein R1 is an optionally substituted 5-membered heteroaryl ring.

### Claim 8 (depends on 1)

The method of claim 1, wherein R1 is thienyl optionally substituted by fluoro, chloro, bromo, cyano, methyl, trifluoromethyl, ethyl, hydroxyl, hydroxymethyl, or hydroxyethyl.

### Claim 9 (depends on 1)

The method of claim 1, wherein R2 is hydrogen or a 5- or 6-membered monocyclic heterocyclic group optionally linked via a C1-C6 alkylene chain and optionally substituted in the ring part thereof.

### Claim 10 (depends on 1)

The method of claim 1, wherein R2 is an optionally substituted 5- or 6-membered monocyclic heteroaryl group linked via a C1-C6 alkylene chain.

### Claim 11 (depends on 1)

The method of claim 1, wherein R2 is a 5- or 6-membered monocyclic heteroaryl group linked via a C1-C6 alkylene chain and optionally substituted in the ring part thereof by fluoro, chloro, bromo, cyano, methyl, trifluoromethyl, ethyl, hydroxyl, hydroxymethyl, or hydroxyethyl.

### Claim 12 (depends on 1)

The method of claim 1, wherein R3 is hydrogen or a 5- or 6-membered monocyclic heterocyclic group optionally linked via a C1-C6 alkylene chain and optionally substituted in the ring part thereof.

### Claim 13 (depends on 1)

The method of claim 1, wherein R3 is an optionally substituted 5- or 6-membered monocyclic heteroaryl group linked via a C1-C6 alkylene chain.

### Claim 14 (depends on 1)

The method of claim 1, wherein R4 is amino, methylamino, ethylamino, or ethyl.

### Claim 15

A method of treating a disorder which is responsive to antagonism of the adenosine A2B receptor in a subject in need thereof, the method comprising administering to the subject a compound of formula (II) or a pharmaceutically acceptable salt thereof, wherein the compound of formula (II) is:
wherein:
R1 is optionally substituted aryl or an optionally substituted 5- or 6-membered heteroaryl ring;
R2 and R3 are independently selected from hydrogen, C1-C6 alkyl, C3-C8 cycloalkyl, C3-C8 cycloalkyl-(C1-C6)-alkyl, aryl-(C1-C6)-alkyl optionally substituted in the ring part thereof; a 5- or 6-membered monocyclic heterocyclic group optionally linked via a C1-C6 alkylene chain and optionally substituted in the ring part thereof, benzimidazol-2-yl-methyl, pyrid-3-yl-carbonyl, or (1-methyl-piperidin-4-yl)-carbonyl-methyl; or R2 and R3 taken together with the nitrogen atom to which they are attached form an optionally substituted 5- or 6-membered ring; and
R4 is hydrogen or C1-C3 alkyl.

### Claim 16 (depends on 15)

The method of claim 15, wherein the disorder is an inflammatory disease.

### Claim 17 (depends on 16)

The method of claim 16, wherein the inflammatory disease is rheumatoid arthritis, multiple sclerosis, lupus, psoriasis, or inflammatory bowel disease.

### Claim 18 (depends on 15)

The method of claim 15, wherein the disorder is nociception, asthma, chronic obstructive pulmonary disease, diabetes, or diabetic retinopathy.

### Claim 19 (depends on 15)

The method of claim 15, comprising orally administering to the subject the compound of formula (I) or the pharmaceutically acceptable salt thereof.

### Claim 20 (depends on 15)

The method of claim 15, wherein R1 is thien-2-yl, R2 is hydrogen, and R3 is pyrid-3-yl-methyl, and R4 is hydrogen or methyl.