Compounds, compositions and methods

Patent metadata

Field	Value
Publication number	US-11958840-B2
Application number	US-202217702718-A
Country	US
Kind code	B2
Filing date	Mar 23, 2022
Priority date	Feb 13, 2019
Publication date	Apr 16, 2024
Grant date	Apr 16, 2024

Abstract

The present disclosure relates generally to eukaryotic initiation factor 2B modulators, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or prodrug thereof, and methods of making and using thereof.

First claim

What is claimed is:

1. A method for treating a disease or condition mediated, at least in part, by eukaryotic initiation factor 2B, wherein the disease is Alexander's disease, Alper's disease, Alzheimer's disease, amyotrophic lateral sclerosis, ataxia telangiectasia, Batten disease (also known as Spielmeyer-Vogt-Sjogren-Batten disease), bovine spongiform encephalopathy (BSE), Canavan disease, Cockayne syndrome, Corticobasal degeneration, Creutzfeldt-Jakob disease, frontotemporal dementia, Gerstmann-Straussler-Scheinker syndrome, Huntington's disease, HIV-associated dementia, Kennedy's disease, Krabbe's disease, kuru, Lewy body dementia, Machado-Joseph disease (Spinocerebellar ataxia type 3), multiple sclerosis, multiple system atrophy, narcolepsy, neuroborreliosis, Parkinson's disease, Pelizaeus-Merzbacher Disease, Pick's disease, primary lateral sclerosis, prion disease, Refsum's disease, Sandhoffs disease, Schilder's disease, Subacute combined degeneration of spinal cord secondary to pernicious anemia, schizophrenia, spinocerebellar ataxia (multiple types with varying characteristics), spinal muscular atrophy, Steele-Richardson-Olszewski disease, vanishing white matter (VWM) disease, insulin resistance, or Tabes dorsalis, the method comprising administering an effective amount of a compound of Formula I:

or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, wherein:
ring A is C 3-10 cycloalkyl or heterocyclyl, provided ring A is not bicyclo[1.1.1]pentanyl or bicyclo[2.1.1]hexanyl; wherein the C 3-10 cycloalkyl or heterocyclyl is optionally substituted with one to six R 14 ;
ring B is

Q 1 and Q 2 are each independently O, S, or NR 15 ;
L is a C 1-6 alkylene linker, optionally substituted with one to three substituents independently selected from halo, cyano, nitro, —OR 6 , —SR 6 , —SF 5 , —NR 6 R 7 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, —C(O)R 6 , —C(O)OR 6 , —OC(O)OR 6 , —OC(O)R 6 , —C(O)NR 6 R 7 , —OC(O)NR 6 R 7 , —NR 6 C(O)NR 7 R 8 , —S(O) 1-2 R 6 , —S(O) 1-2 NR 6 R 7 , —NR 6 S(O) 1-2 R 7 , —NR 6 S(O) 1-2 NR 7 R 8 , —NR 6 C(O)R 7 , and —NR 6 C(O)OR 7 ;
z is 0 or 1;
X 1 is O, NR 9 , or a bond;
R 1 is hydrogen, C 1-12 alkyl, C 2-12 alkenyl, C 2-12 alkynyl, C 3-10 cycloalkyl, or heterocyclyl, each of which, other than hydrogen, is optionally substituted with one to three R 11 ;
R 2 is C 1-6 haloalkyl;
R 3 is hydrogen, C 1-12 alkyl, C 2-12 alkenyl, C 2-12 alkynyl, C 3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which, other than hydrogen, is optionally substituted with one to five R 11 ;
R 4 and R 5 are independently hydrogen, C 1-12 alkyl, C 2-12 alkenyl, or C 2-12 alkynyl, each of which, other than hydrogen, is independently optionally substituted with one to five R 11 ;
or R 3 and R 4 , together with the atoms to which they are attached, join to form a C 3-10 cycloalkyl or heterocyclyl, each of which is optionally substituted with one to five R 11 ;
or R 4 and R 5 , together with the atoms to which they are attached, join to form a C 3-10 cycloalkyl or heterocyclyl, each of which is optionally substituted with one to five R 11 ;
each of R 6 , R 7 , and R 8 is independently hydrogen, C 1-12 alkyl, C 2-12 alkenyl, C 2-12 alkynyl, C 3-10 cycloalkyl, heterocyclyl, aryl, heteroaryl, —C(O)R 20 , —C(O)OR 20 , —C(O)NR 20 R 21 , —S(O) 1-2 R 20 , or —S(O) 1-2 NR 20 R 21 , wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl of R 6 , R 7 , and R 8 is independently optionally substituted with one to five R 12 ; or two of R 6 , R 7 , and R 8 are taken together with the atoms to which they are attached to form heterocyclyl independently optionally substituted by one to three halo, oxo, or C 1-12 alkyl independently optionally substituted by one to three oxo, halo, hydroxyl, or amino;
R 9 is hydrogen, C 1-12 alkyl, C 2-12 alkenyl, C 2-12 alkynyl, C 3-10 cycloalkyl, or heterocyclyl, each of which, other than hydrogen, is optionally substituted with one to three R 11 ;
each R 11 is independently halo, cyano, nitro, oxo, —OR 6 , —SR 6 , —SF 5 , —NR 6 R 7 , C 1-12 alkyl, C 2-12 alkenyl, C 2-12 alkynyl, C 3-10 cycloalkyl, heterocyclyl, aryl, heteroaryl, —C(O)R 6 , —C(O)OR 6 , —OC(O)OR 6 , —OC(O)R 6 , —C(O)NR 6 R 7 , —OC(O)NR 6 R 7 , —NR 6 C(O)NR 7 R 8 , —S(O) 1-2 R 6 , —S(O) 1-2 NR 6 R 7 , —NR 6 S(O) 1-2 R 7 , —NR 6 S(O) 1-2 NR 7 R 8 , —NR 6 C(O)R 7 , or —NR 6 C(O)OR 7 , wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl of R 11 is independently optionally substituted with one to five R 12 ;
each R 12 is independently halo, cyano, nitro, oxo, —OR 30 , —SR 30 , —SF 5 , —NR 30 R 31 , C 1-12 alkyl, C 2-12 alkenyl, C 2-12 alkynyl, C 3-10 cycloalkyl, heterocyclyl, aryl, heteroaryl, —C(O)R 30 , —C(O)OR 30 , —OC(O)OR 30 , —OC(O)R 30 , —C(O)NR 30 R 31 , —OC(O)NR 30 R 31 , —NR 30 C(O)NR 30 R 31 , —S(O) 1-2 R 30 , —S(O) 1-2 NR 30 R 31 , —NR 30 S(O) 1-2 R 31 , —NR 30 S(O) 1-2 NR 30 R 31 , —NR 30 C(O)R 31 , or —NR 30 C(═O)OR 31 , wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl of R 12 is independently optionally substituted with one to three halo or C 1-12 alkyl independently optionally substituted by one to three oxo, halo, hydroxyl, or amino;
each R 14 is independently halo, cyano, —NR 6 R 7 , C 1-6 alkyl, C 1-6 alkoxy, or C 1-6 haloalkyl, or two R 14 together with the atoms to which they are attached form a ring or a C═O;
each R 15 is independently hydrogen, C 1-6 alkyl, or C 1-6 haloalkyl;
each R 20 and R 21 is independently hydrogen or C 1-12 alkyl independently optionally substituted with one to three oxo, halo, hydroxyl, or amino; or R 20 and R 21 are taken together with the atoms to which they are attached to form heterocyclyl independently optionally substituted by one to three halo or C 1-12 alkyl independently optionally substituted by one to three oxo, halo, hydroxyl, or amino; and
each R 30 and R 31 is independently hydrogen or C 1-12 alkyl independently optionally substituted with one to three oxo, halo, hydroxyl, or amino; or R 30 and R 31 are taken together with the atoms to which they are attached to form heterocyclyl independently optionally substituted by one to three halo or C 1-12 alkyl independently optionally substituted by one to three oxo, halo, hydroxyl, or amino;
to a subject in need thereof.

2. The method of claim 1 , or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, wherein ring A is monocyclic cycloalkyl, fused bicyclic cycloalkyl, or spiro bicyclic cycloalkyl, wherein each is optionally substituted with one to six R 14 .

3. The method of claim 1 , or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, wherein ring A is heterocyclyl, wherein each is optionally substituted with one to six R 14 .

4. The method of claim 1 , or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, wherein ring A is selected from

wherein each is independently optionally substituted with one to

Assignees

• Denali Therapeutics Inc

Inventors

• Craig Ii Robert A
• De Vicente Fidalgo Javier
• Estrada Anthony A
• Feng Jianwen A
• Fox Brian M
• Osipov Maksim
• Thottumkara Arun

Classifications

• C07D413/04 Primary

  directly linked by a ring-member-to-ring-member bond · CPC title

• C07D271/113

  with oxygen, sulfur or nitrogen atoms, directly attached to ring carbon atoms, the nitrogen atoms not forming part of a nitro radical · CPC title

• C07D413/14

  containing three or more hetero rings · CPC title

• C07D417/04 Primary

  directly linked by a ring-member-to-ring-member bond · CPC title

• C07D417/14

  containing three or more hetero rings · CPC title