# US 10,246,447 B2 · 3-(6-chloro-3-oxo-3,4-dihydro-(2H)-1,4-benzoxazin-4-yl) propanoic acid derivatives and their use as KMO inhibitors

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- Number: US 10,246,447 B2
- Document ID: US10246447B2
- Status: Granted
- Kind: B2
- Application number: 15/574,947
- Filed: 2016-05-19
- Published: 2018-06-21
- Granted: 2019-04-02
- Earliest claimed: 2015-05-22
- Assignees: GlaxoSmithKline Intellectual Property Development Limited
- Applicants: Glaxosmithkline Intellectual Property Development Limited
- Inventors: Anne Marie Jeanne Bouillot; Alexis Denis; John Liddle; Olivier Mirguet; Ann Louise Walker
- Web page: https://patentgrep.com/patent/US10246447B2

## CPC

- C07D 413/12: linked by a chain containing hetero atoms as chain links
- A61P 1/00: Drugs for disorders of the alimentary tract or the digestive system
- A61P 1/16: for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
- A61P 1/18: for pancreatic disorders, e.g. pancreatic enzymes
- A61P 3/04: Anorexiants; Antiobesity agents
- A61P 3/06: Antihyperlipidemics
- A61P 9/00: Drugs for disorders of the cardiovascular system
- A61P 9/04: Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
- A61P 9/10: for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
- A61P 9/12: Antihypertensives
- A61P 11/00: Drugs for disorders of the respiratory system
- A61P 13/12: of the kidneys
- A61P 17/02: for treating wounds, ulcers, burns, scars, keloids, or the like
- A61P 21/00: Drugs for disorders of the muscular or neuromuscular system
- A61P 25/00: Drugs for disorders of the nervous system
- A61P 25/08: Antiepileptics; Anticonvulsants
- A61P 25/14: for treating abnormal movements, e.g. chorea, dyskinesia
- A61P 25/16: Anti-Parkinson drugs
- A61P 25/18: Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
- A61P 25/24: Antidepressants
- A61P 25/28: for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
- A61P 25/30: for treating abuse or dependence
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A61P 31/00: Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P 31/04: Antibacterial agents
- A61P 31/12: Antivirals
- A61P 31/18: for HIV
- A61P 33/00: Antiparasitic agents
- A61P 35/00: Antineoplastic agents
- A61P 37/06: Immunosuppressants, e.g. drugs for graft rejection
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

Compounds of formula (I) wherein: R1 is heteroaryl optionally substituted by methyl, ethyl, halo or ═O; and R2 is H, methyl or ethyl. and salts thereof are KMO inhibitors and may be useful in the treatment of various disorders, for example acute pancreatitis, chronic kidney disease, other conditions associated with systemic inflammatory response syndrome (SIRS), Huntington's disease, Alzheimer's disease, spinocerebellar ataxias, Parkinson's disease, AIDS-dementia complex, HIV infection, amylotrophic lateral sclerosis (ALS), depression, schizophrenia, sepsis, cardiovascular shock, severe trauma, acute lung injury, acute respiratory distress syndrome, acute cholecystitis, severe burns, pneumonia, extensive surgical procedures, ischemic bowel disease, severe acute hepatic disease, severe acute hepatic encephalopathy or acute renal failure.

## Claims

### Claim 1

A compound of Formula (I):
wherein:
R1 is heteroaryl optionally substituted by methyl, ethyl, or halo; and
R2 is H, methyl or ethyl;
wherein:
heteroaryl as defined for R1 is selected from the group consisting of oxazolyl, pyridinyl, pyrimidinyl, pyridazinyl and imidazolyl,
wherein:
the oxazolyl, pyridinyl, pyrimidinyl, and pyridazinyl, respectively, is optionally substituted by methyl, ethyl, chloro or fluoro; or
a pharmaceutically acceptable salt thereof.

### Claim 2 (depends on 1)

A compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein R1 is pyridinyl optionally substituted by ethyl, methyl, chloro or fluoro.

### Claim 3 (depends on 1)

A compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein R2 is ethyl.

### Claim 4

A compound which is:
(3-(6-chloro-7-(1-(5-chloropyridin-2-yl)propoxy)-3-oxo-2H-benzo[b][1 ,4]oxazin-4(3H)-yl)propanoic acid;
3-{6-chloro-3-oxo-7-[1-(pyridin-2-yl)ethoxy]-3,4-dihydro-2H-1,4-benzoxazin-4-yl}propanoic acid;
3-{6-chloro-7-[1 -(2-methyl-1,3-oxazol-5-yl)ethoxy]-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-4-yl}propanoic acid ;
3-{6-chloro-7-[1 -(1,3-oxazol-2-yl)ethoxy]-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-4-yl}propanoic acid ;
3-{6-chloro-7-[1-(1 H-imidazol-2-yl)ethoxy]-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-4-yl}propanoic acid;
3-{6-chloro-3-oxo-7-[1- (pyrimidin-2-yl)ethoxy]-3,4-dihydro-2H-1,4-benzoxazin-4-yl}propanoic acid;
3-[chloro-3-oxo-7-(pyridin-2-ylmethoxy)-3,4-dihydro-2H-1,4-benzoxazin-4-yl]propanoic acid;
3-{6-chloro-7-[1 -(5-methylpyridin-2-yl)ethoxy]-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-4yl}propanoic acid;
3-{6-chloro-7-[1 -(5-chloropyridin-2-yl)ethoxy]-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-4-yl}propanoic acid;
3-{6-chloro-7-[1 -(5-fluoropyridin-2-yl)ethoxy]-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-4-yl}propanoic acid;
3-{6-chloro-3-oxo-7-[1 -(pyridazin-3-yl)ethoxy]-3,4-dihydro-2H-1,4-benzoxazin-4-yl}propanoic acid;
3-{6-chloro-7-[(6-methylpyridazin-3-yl)methoxy]-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-4-yl}propanoic acid;
3-{6-chloro-7-[1 -(6-methylpyridazin-3-yl)ethoxy]-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-4-yl}propanoic acid;
3-{6-chloro-7-[1 -(5-methylpyridin-2-yl)propoxy]-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-4-yl}propanoic acid;
3-{6-chloro-3-oxo-7[1-(pyridin-2-yl)propoxy]-3,4-dihydro-2H-1,4-benzoxazin-4-yl}propanoic acid;
3-{6-chloro-7-[(5-chloropyridin-2-yl)methoxy]-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-4-yl}propanoic acid;
3-{6-chloro-7-[(5-methylpyridin-2-yl)methoxy]-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-4-yl}propanoic acid;
3-{6-chloro-7-[1 -(5-ethylpyridin-2-yl)ethoxy]-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-4-yl}propanoic acid;
3-{6-chloro-3-oxo-7-[1 -(pyrimidin-2-yl)propoxy]-3,4-dihydro-2H-1,4-benzoxazin-4-yl}propanoic acid ;
3-{6-chloro-7-[1 -(5-methylpyrimidin-2-yl)propoxy]-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-4-yl}propanoic acid;
3-{6-chloro-7-[1 -(5-chloropyrim idin-2-yl)propoxy]-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-4-yl}propanoic acid;
3-{6-chloro-3-oxo-7-[1-(pyridazin-3-yl)propoxy]-3,4-dihydro-2H-1,4-benzoxazin-4-yl}propanoic acid; and
3-{6-chloro-7[1-(6-methylpyridazin-3-yl)propoxy]-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-4-yl}propanoic acid; or a pharmaceutically acceptable salt thereof.

### Claim 5

A compound which is (R)-3-(6-chloro-7-(1-(5-chloropyridin-2-yl)propoxy)-3-oxo-2H-benzo[b][1,4]oxazin-4(3H)-yl)propanoic acid as shown below:
or
a pharmaceutically acceptable salt thereof.

### Claim 6 (depends on 5)

The compound according to claim 5 which is (R)-3-(6-chloro-7-(1-(5-chloropyridin-2-yl)propoxy)-3-oxo-2H-benzo[b][1,4]oxazin-4(3H)-yl)propanoic acid as shown below:

### Claim 7 (depends on 1)

A pharmaceutical composition comprising:
a) a therapeutically effective amount of a compound or pharmaceutically acceptable salt as defined in claim 1; and
b) at least one pharmaceutically acceptable excipient(s).

### Claim 8 (depends on 4)

A pharmaceutical composition, comprising:
a) a therapeutically effective amount of a compound or pharmaceutically acceptable salt as defined in claim 4; and
b) at least one pharmaceutically acceptable excipient(s).