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

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.

Claims8

Dependent claims

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.

7 more elements

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.

22 more elements

Dependencies are inferred from the claim text.

Facts

Application

15/574,947Filed 19 May 2016

Priority

GB 1508864.422 May 2015

Published

US 2018/0170920 A121 Jun 2018

Granted

2 Apr 2019

Term ends

Not estimatedThe source records don’t support an estimate.

Classification33 codes

C07D 413/12
Containing two hetero rings: 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
Drugs for disorders of the alimentary tract or the digestive system: for liver or gallbladder disorders, e.g. hepatoprotective agents,…
A61P 1/18
Drugs for disorders of the alimentary tract or the digestive system: for pancreatic disorders, e.g. pancreatic enzymes

3-(6-chloro-3-oxo-3,4-dihydro-(2H)-1,4-benzoxazin-4-yl) propanoic acid derivatives and their use as KMO inhibitors

Life of this patent

3-(6-chloro-3-oxo-3,4-dihydro-(2H)-1,4-benzoxazin-4-yl) propanoic acid derivatives and their use as KMO inhibitors

Life of this patent

Abstract

Claims8