# US 11,077,113 B2 · 6-aryl-4-morpholin-1-ylpyridone compounds useful for the treatment of cancer and diabetes

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- Number: US 11,077,113 B2
- Document ID: US11077113B2
- Status: Granted
- Kind: B2
- Application number: 15/999,530
- Filed: 2017-02-17
- Published: 2021-05-06
- Granted: 2021-08-03
- Earliest claimed: 2016-02-19
- Assignees: Sprint Bioscience AB
- Applicants: Sprint Bioscience AB
- Inventors: Jessica Martinsson; Martin Andersson; Johan Lindström; Rickard Forsblom; Fredrik Rahm; Tobias Ginman; Jenny Viklund
- Web page: https://patentgrep.com/patent/US11077113B2

## CPC

- A61K 31/5377: not condensed and containing further heterocyclic rings, e.g. timolol
- C07D 213/76: to which a second hetero atom is attached (nitro radicals C07D213/61)
- A61K 31/4745: condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines (yohimbine derivatives, vinblastine A61K31/475; ergoline derivatives A61K31/48)
- A61K 33/243: Platinum; Compounds thereof
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61P 3/00: Drugs for disorders of the metabolism (of the blood or the extracellular fluid A61P7/00)
- A61P 3/10: for hyperglycaemia, e.g. antidiabetics
- A61P 9/00: Drugs for disorders of the cardiovascular system
- A61P 25/00: Drugs for disorders of the nervous system
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A61P 31/12: Antivirals
- A61P 35/00: Antineoplastic agents
- C07D 213/74: Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
- C07D 413/04: directly linked by a ring-member-to-ring-member bond
- C07D 413/12: linked by a chain containing hetero atoms as chain links
- C07D 413/14: containing three or more hetero rings
- 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)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

The invention provides novel 6-aryl or 6-heteroaryl 4-morpholin-4-yl-pyhdine-2-one compounds of formula (I), pharmaceutical compositions containing such compounds, and methods for using such compounds in treatment of diseases including cancer, diabetes, inflammatory diseases, neurodegenerative disorders, cardiovascular disorders and viral infections; wherein R1, R2, R3 and R4 are as defined in the specification.

## Claims

### Claim 1

A compound of formula (I)
wherein
R1 is aryl or heteroaryl, said aryl and said heteroaryl being mono- or bicyclic and optionally substituted with one or more of R5, R6, R7 and R8;
R2, R3 and R4 are independently selected from hydrogen, C1-C3haloalkyl and C1-C3alkyl;
R5, R6, R7 and R8 are independently selected from halogen, C1-C6alkyl, C1-C6alkoxy, C1-C6haloalkyl, amino, —NHSO2R9, hydroxy, phenyl and a monocyclic heteroaryl;
R9 is C1-C3haloalkyl or C1-C3alkyl;
and pharmaceutically acceptable salts, tautomers and stereoisomers thereof.

### Claim 2 (depends on 1)

The compound according to claim 1, wherein R4 is C1-C3alkyl.

### Claim 3 (depends on 1)

The compound according to claim 1, wherein R2 is selected from hydrogen and methyl.

### Claim 4 (depends on 1)

The compound according to claim 1, wherein R3 is hydrogen.

### Claim 5 (depends on 1)

The compound according to claim 1, wherein R4 is methyl.

### Claim 6 (depends on 1)

The compound according to claim 1, wherein R2 is hydrogen.

### Claim 7 (depends on 1)

The compound according to claim 1, wherein R1 is selected from phenyl, furyl, thienyl, pyridyl, pyrimidinyl, naphtyl, quinolinyl, indazolyl, indolyl, 4-azaindolyl, benzoxazolyl, benzimidazolyl, benzothiophenyl, each optionally substituted with one or more of R5, R6, R7 and R8; and
R5, R6, R7 and R8 are independently selected from halogen, C1-C3alkyl, C1-C3haloalkyl, phenyl, amino, —NHSO2CH3, hydroxy, imidazolyl and pyrazolyl.

### Claim 8 (depends on 1)

The compound according to claim 1, wherein R1 is selected from phenyl, furyl, thienyl, pyridyl, pyrimidinyl and quinolinyl, each optionally substituted with R5 and/or R6; and R5 and R6 are independently selected from chlorine, fluorine, trifluoromethyl, methyl, phenyl, —NHSO2CH3 and pyrazolyl.

### Claim 9 (depends on 1)

The compound according to claim 1, wherein R1 is selected from
wherein R5 and R6 are independently selected from halogen, C1-C3alkyl, C1-C3haloalkyl, phenyl, pyrazolyl, and —NHSO2CH3.

### Claim 10 (depends on 1)

The compound according to claim 1, wherein R1 is a monocyclic aryl or heteroaryl.

### Claim 11 (depends on 1)

The compound according to claim 1, wherein R1 is selected from phenyl and pyridyl, each optionally substituted with R5 and/or R6; and R5 and R6 are independently selected from chlorine, fluorine and trifluoromethyl.

### Claim 12 (depends on 1)

The compound according to claim 1, wherein R1 is selected from
R4 is C1-C3alkyl;
and R5 and R6 are independently selected from chlorine, fluorine and trifluoromethyl.

### Claim 13 (depends on 1)

The compound according to claim 1, wherein R1 is selected from
R2 is hydrogen; and
R5 is selected from chlorine and trifluoromethyl.

### Claim 14 (depends on 1)

The compound according to claim 1, wherein R1 is selected from
R2 is hydrogen;
R4 is C1-C3alkyl; and
R5 and R6 are independently selected from chlorine, fluorine and trifluoromethyl.

### Claim 15 (depends on 1)

The compound according to claim 1, wherein
R1 is selected from
R2 is hydrogen or methyl;
R3 is hydrogen;
R4 is methyl;
R5 and R6 are selected from chlorine, fluorine, trifluoromethyl, methyl, phenyl pyrazolyl and —NHSO2CH3; and
pharmaceutically acceptable salts and stereoisomers thereof.

### Claim 16 (depends on 1)

The compound according to claim 1, said compound being selected from:
6-(2-chlorophenyl)-4-morpholino-1H-pyridin-2-one;
6-(2-chlorophenyl)-1-methyl-4-morpholino-pyridin-2-one;
6-(2-chlorophenyl)-4-(3-methylmorpholin-4-yl)-1H-pyridin-2-one;
6-(2-chlorophenyl)-1-methyl-4-(3-methylmorpholin-4-yl)pyridin-2-one;
4-(3-methylmorpholin-4-yl)-6-(4-methyl-3-pyridyl)-1H-pyridin-2-one;
4-(3-methylmorpholin-4-yl)-6-pyrimidin-5-yl-1H-pyridin-2-one;
4-(3-methylmorpholin-4-yl)-6-(2-phenylphenyl)-1H-pyridin-2-one;
6-(2-chloro-5-fluoro-phenyl)-4-[(3R)-3-methylmorpholin-4-yl]-1H-pyridin-2-one;
4-[(3R)-3-methylmorpholin-4-yl]-6-(o-tolyl)-1H-pyridin-2-one;
4-[(3R)-3-methylmorpholin-4-yl]-6-[2-(trifluoromethyl)-3-pyridyl]-1H-pyridin-2-one;
6-(2-chlorophenyl)-4-[(3R)-3-methylmorpholin-4-yl]-1H-pyridin-2-one;
4-[(3R)-3-methylmorpholin-4-yl]-6-[2-(trifluoromethyl)phenyl]-1H-pyridin-2-one;
6-(3-furyl)-4-[(3R)-3-methylmorpholin-4-yl]-1H-pyridin-2-one;
4-[(3R)-3-methylmorpholin-4-yl]-6-(4-methyl-3-thienyl)-1H-pyridin-2-one;
N-[2-[4-[(3R)-3-methylmorpholin-4-yl]-6-oxo-1H-pyridin-2-yl]phenyl]methanesulfonamide;
4-[(3R)-3-methylmorpholin-4-yl]-6-(6-methyl-5-quinolyl)-1H-pyridin-2-one;
4-[(3R)-3-methylmorpholin-4-yl]-6-[4-(1H-pyrazol-5-yl)phenyl]-1H-pyridin-2-one;
and pharmaceutically acceptable salts, tautomers and stereoisomers thereof.

### Claim 17 (depends on 1)

A method of treating cancer, comprising administering a therapeutically effective amount of a compound according to claim 1 to a patient in need thereof.

### Claim 18 (depends on 17)

The method of claim 17, wherein said cancer is selected from triple negative breast cancer, pancreas cancer, leukemia, melanoma and lung cancer.

### Claim 19 (depends on 1)

A method of treating diabetes, comprising administering a therapeutically effective amount of a compound according to claim 1 to a patient in need thereof.

### Claim 20 (depends on 19)

The method of claim 19, wherein said diabetes is type II diabetes.

### Claim 21 (depends on 1)

A method of treating a disease, comprising administering a therapeutically effective amount of a compound according to claim 1 to a patient in need thereof, said disease being selected from inflammatory diseases, neurodegenerative disorders, cardiovascular disorders and viral infections.

### Claim 22 (depends on 1)

A pharmaceutical composition comprising a compound according to claim 1 and a pharmaceutically acceptable diluent, carrier and/or excipient.

### Claim 23 (depends on 1)

A pharmaceutical composition, comprising a therapeutically effective amount of a compound according to claim 1, and another anticancer agent selected from alkylating agents, antimetabolites, anticancer camptothecin derivatives, plan-derived anticancer agents, antibiotics, enzymes, platinum coordination complexes, tyrosine kinase inhibitors, hormones, hormone antagonists, monoclonal antibodies, interferons, and biological response modifiers.