Compounds, compositions and methods

Patent metadata

Field	Value
Publication number	US-12180211-B2
Application number	US-202117350581-A
Country	US
Kind code	B2
Filing date	Jun 17, 2021
Priority date	Dec 9, 2016
Publication date	Dec 31, 2024
Grant date	Dec 31, 2024

Abstract

The present disclosure relates generally to methods and compositions for preventing or arresting cell death and/or inflammation.

First claim

The invention claimed is:

1. A method for treating a necrotic cell disease, the method comprising administering an effective amount of a compound of Formula I,

or a pharmaceutically acceptable salt, stereoisomer, or mixture of stereoisomers thereof to a subject in need thereof, wherein:
Y is N or CH;
n is 1 or 2;
m is 0, 1, 2, 3, 4, or 5;
p is 0, 1, 2, or 3;
A is aryl, heteroaryl, C 3-10 cycloalkyl, or heterocyclyl;
each of R 1 and R 2 is independently hydrogen, deuterium, halo, C 1-12 alkyl, C 1-12 alkenyl, C 1-12 alkynyl, C 1-12 alkoxy, C 1-12 haloalkyl, C 1-12 haloalkoxy, C 3-10 cycloalkyl, heterocyclyl, heteroaryl or aryl;
wherein each C 1-12 alkyl, C 1-12 alkenyl, C 1-12 alkynyl, C 1-12 alkoxy, C 1-12 haloalkyl, C 1-12 haloalkoxy, C 3-10 cycloalkyl, heterocyclyl, heteroaryl, and aryl is optionally substituted with one, two, three, four, or five Z 1 ; or
R 1 and R 2 taken together with the atoms to which they are attached form a C 3-10 cycloalkyl;
wherein the C 3-10 cycloalkyl is optionally substituted with one, two, three, four, or five Z 2 ;
R 3 in each instance is independently deuterium, halo, hydroxy, cyano, nitro, azido, oxo, C 1-12 alkyl, —OR 5 , C 1-12 alkoxy, C 2-12 alkenyl, C 2-12 alkynyl, C 1-12 haloalkyl, C 1-12 haloalkoxy, C 3-10 cycloalkyl, heterocyclyl, aryl, heteroaryl, —C(═O)R 4 , —C(═O)OR 4 , —OC(═O)OR 4 , —OC(═O)R 4 , —C(═O)NR 4 R 5 , —OC(═O)NR 4 R 5 , —NR 4 C(═O)NR 5 R 6 , —S(═O) 1-2 R 4 , —S(═O) 1-2 OR 4 , —OS(═O) 1-2 R 4 , —S(═O) 1-2 NR 4 , —NR 4 S(═O) 1-2 R 5 , —NR 4 S(═O) 1-2 NR 4 R 5 , —NR 4 R 5 , —NR 4 C(═O)R 5 , or —NR 4 C(═O)OR 5 ;
wherein each C 1-12 alkyl, C 1-12 alkoxy, C 2-12 alkenyl, C 2-12 alkynyl, C 1-12 haloalkyl, C 1-12 haloalkoxy, C 3-10 cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one, two, three, four, or five Z 3 ;
R 4 , R 5 , and R 6 in each instance are independently C 1-12 alkyl, C 1-12 alkenyl, C 1-12 alkynyl, C 1-12 haloalkyl, C 3-10 cycloalkyl, heterocyclyl, heteroaryl, or aryl;
wherein each C 1-12 alkyl, C 1-12 alkenyl, C 1-12 alkynyl, C 1-12 haloalkyl, C 3-10 cycloalkyl, heterocyclyl, heteroaryl, and aryl is optionally substituted with one, two, three, four, or five Z 4 ; or
two of R 4 , R 5 , and R 6 taken together with the atoms to which they are attached form a heterocyclyl;
wherein the heterocyclyl is optionally substituted with one, two, three, four, or five Z 5 ;
R 14 is bonded to either ring of the fused bicyclic ring and, in each instance, is independently halo or haloalkyl, or two R 14 bonded to the same carbon atom may be taken together with the atom to which they are attached to form a C 3-10 cycloalkyl or heterocyclyl;
wherein the C 3-10 cycloalkyl or heterocyclyl is optionally substituted with one, two, three, four, or five Z 6 ;
each of Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , and Z 6 are independently deuterium, halo, hydroxy, cyano, nitro, azido, C 1-12 alkyl, C 1-12 alkenyl, C 1-12 alkynyl, C 1-12 alkoxy, C 1-12 haloalkyl, C 1-12 haloalkoxy, C 3-10 cycloalkyl, heterocyclyl, aryl, heteroaryl, —C(═O)R 11 , —C(═O)OR 11 , —OC(═O)OR 11 , —OC(═O)R 11 , —C(═O)NR 11 R 12 , —OC(═O)NR 11 R 12 , —NR 11 C(═O)NR 12 R 13 , —S(═O) 1-2 R 11 , —S(═O) 1-2 OR 11 , —S(═O) 1-2 NR 11 , —NR 11 S(═O) 1-2 R 12 , —NR 11 S(═O) 1-2 NR 12 R 13 , —NR 11 R 12 , —NR 11 C(═O)R 12 , or —NR 11 C(═O)OR 12 ;
wherein each C 1-12 alkyl, C 1-12 alkenyl, C 1-12 alkynyl, C 1-12 alkoxy, C 1-12 haloalkyl, C 1-12 haloalkoxy, C 3-10 cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one, two, or three substituents independently selected from deuterium, halo, hydroxy, cyano, amino, nitro, azido, oxo, C 1-12 alkyl, C 1-12 alkoxy, C 1-12 haloalkyl, C 1-12 haloalkoxy, C 2-12 alkenyl, C 2-12 alkynyl, C 3-10 cycloalkyl, heterocyclyl, aryl, and heteroaryl; and
R 11 , R 12 , and R 13 in each instance are independently C 1-12 alkyl, C 1-12 alkenyl, C 1-12 alkynyl, C 1-12 alkoxy, C 3-10 cycloalkyl, heterocyclyl, heteroaryl, or aryl;
wherein each C 1-12 alkyl, C 1-12 alkenyl, C 1-12 alkynyl, C 1-12 alkoxy, C 3-10 cycloalkyl, heterocyclyl, heteroaryl, and aryl is optionally substituted with one, two, three, four, or five Z 11 ; or
two of R 11 , R 12 , and R 13 are taken together with the atoms to which they are attached to form a heterocyclyl; wherein the heterocyclyl is optionally substituted with one, two, three, four or five Z 12 ;
wherein each of Z 11 and Z 12 is independently deuterium, halo, hydroxy, cyano, oxo, amino or C 1-12 alkyl; wherein the C 1-12 alkyl is optionally substituted with one, two or three halo, hydroxyl, amino or oxo, provided that
when n is 1, Y is CH, and both of R 1 and R 2 are hydrogen, then A is not heterocyclyl substituted with oxo; and
when n is 2, Y is CH, and one of R 1 or R 2 is iodo, or both of R 1 or R 2 are hydrogen, then A is not 4-chlorophenyl, 2,6-difluoropyridin-3-yl, phenyl, or phenyl substituted with 1, 2 or 3 fluoro; and
the compound is not chosen from (3R,8aR)-6-chloro-3-(4-fluorophenyl)hexahydroindolizin-5(1H)one: (3R,6S,8aS)-6-methyl-3-phenylhexahydroindolizin-5(1H)-one; hexahydro-6-methyl-3-phenyl-5(1H)-indolizinone; and 6-[(2-bromo-1H-indol-3-yl)methyl]hexahydro-3-(4-hydroxyphenyl)-5(1H)-indolizinone.

2. The method of claim 1 , wherein the necrotic cell disease is selected from at least one of trauma, ischemia, stroke, cardiac infarction, infection, Gaucher's disease, Krabbe disease, sepsis, Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis, Huntington's disease, HIV-associated dementia, retinal degenerative disease, glaucoma, age-related macular degeneration, rheumatoid arthritis, psoriasis, psoriatic arthritis, and inflammatory bowel disease.

3. A method for treating an inflammatory disorder, the method comprising administering an effective amount of a compound of Formula I,

or a pharmaceutically acceptable salt, stereoisomer, or mixture of stereoisomers thereof to a subject in need thereof, wherein:
Y is N or CH;
n is 1 or 2;
m is 0, 1, 2, 3, 4, or 5;
p is 0, 1, 2, or 3;
A is aryl, heteroaryl, C3-10 cycloalkyl, or heterocyclyl;
each of R 1 and R 2 is independently hydrogen, deuterium, halo, C 1-12 alkyl, C 1-12 alkenyl, C 1-12 alkynyl, C 1-12 alkoxy, C 1-12 haloalkyl, C 1-12 haloalkoxy, C 3-10 cycloalkyl, heterocyclyl, heteroaryl or aryl;
wherein each C 1-12 alkyl, C 1-12 alkenyl, C 1-12 alkynyl, C 1-12 alkoxy, C 1-12 haloalkyl, C 1-12 haloalkoxy, C 3-10 cycloalkyl, heterocyclyl, heteroaryl, and aryl is optionally substituted with one, two, three, four, or five Z 1 ; or
R 1 and R 2 taken together with the atoms to which they are attached form a C3-10 cycloalkyl; wherein the C3-10 cycloalkyl is optionally substituted with one, two, three, four, or five Z 2 ;
R 3 in each instance is independently deuterium, halo, hydroxy, cyano, nitro, azido, oxo, C 1-12 alkyl, —OR 5 , C 1-12 alkoxy, C 2-12 alkenyl, C 2-12 alkynyl, C 1-12 haloalkyl, C 1-12 haloalkoxy, C 3-10 cycloalkyl, heterocyclyl, aryl, heteroaryl, —C(═O)R 4 , —C(═O)OR 4 , —OC(═O)OR 4 , —OC(═O)R 4 , —C(═O)NR 4 R 5 , —OC(═O)NR 4 R 5 , —NR 4 C(═O)NR 5 R 6 , —S(═O) 1-2 R 4 , —S(═O) 1-2 OR 4 , —OS(═O) 1-2 R 4 , —S(═O) 1-2 NR 4 , —NR 4 S(═O) 1-2 R 5 , —NR 4 S(═O) 1-2 NR 4 R 5 , —NR 4 R 5 , —NR 4 C(═O)R 5 , or —NR 4 C(═O)OR 5 ;
wherein each C 1-12 alkyl, C 1-12 alkoxy, C 2-12 alkenyl, C 2-12 alkynyl, C 1-12 haloalkyl, C 1-12 haloalkoxy, C 3-10 cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one, two, three, four, or five Z 3 ;
R 4 , R 5 , and R 6 in each instance are

Assignees

• Denali Therapeutics Inc

Inventors

• Estrada Anthony A
• Feng Jianwen A
• Fox Brian
• Hu Cheng
• Osipov Maksim
• Sweeney Zachary K
• De Vicente Fidalgo Javier
• Thottumkara Arun

Classifications

• G01N33/575 Primary

  for cancer · CPC title

• A61P31/04

  Antibacterial agents · CPC title

• A61P31/00

  Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics · CPC title

• A61P27/06

  Antiglaucoma agents or miotics · CPC title

• A61P27/02

  Ophthalmic agents · CPC title