Patent ID: 11958840
Assignee: DENALI THERAPEUTICS INC.
Field: Organic fine chemistry (Chemistry)
Classification: CPC C  A | IPC C

Claim 0:
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 C3-10 cycloalkyl or heterocyclyl, provided ring A is not bicyclo[1.1.1]pentanyl or bicyclo[2.1.1]hexanyl; wherein the C3-10 cycloalkyl or heterocyclyl is optionally substituted with one to six R14;
ring B is, Q1 and Q2 are each independently O, S, or NR15;
L is a C1-6 alkylene linker, optionally substituted with one to three substituents independently selected from halo, cyano, nitro, —OR6, —SR6, —SF5, —NR6R7, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, —C(O)R6, —C(O)OR6, —OC(O)OR6, —OC(O)R6, —C(O)NR6R7, —OC(O)NR6R7, —NR6C(O)NR7R8, —S(O)1-2R6, —S(O)1-2NR6R7, —NR6S(O)1-2R7, —NR6S(O)1-2NR7R8, —NR6C(O)R7, and —NR6C(O)OR7;
z is 0 or 1;
X1 is O, NR9, or a bond;
R1 is hydrogen, C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, C3-10 cycloalkyl, or heterocyclyl, each of which, other than hydrogen, is optionally substituted with one to three R11;
R2 is C1-6 haloalkyl;
R3 is hydrogen, C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which, other than hydrogen, is optionally substituted with one to five R11;
R4 and R5 are independently hydrogen, C1-12 alkyl, C2-12 alkenyl, or C2-12 alkynyl, each of which, other than hydrogen, is independently optionally substituted with one to five R11;
or R3 and R4, together with the atoms to which they are attached, join to form a C3-10 cycloalkyl or heterocyclyl, each of which is optionally substituted with one to five R11;
or R4 and R5, together with the atoms to which they are attached, join to form a C3-10 cycloalkyl or heterocyclyl, each of which is optionally substituted with one to five R11;
each of R6, R7, and R8 is independently hydrogen, C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, C3-10 cycloalkyl, heterocyclyl, aryl, heteroaryl, —C(O)R20, —C(O)OR20, —C(O)NR20R21, —S(O)1-2R20, or —S(O)1-2NR20R21, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl of R6, R7, and R8 is independently optionally substituted with one to five R12; or two of R6, R7, and R8 are taken together with the atoms to which they are attached to form heterocyclyl independently optionally substituted by one to three halo, oxo, or C1-12 alkyl independently optionally substituted by one to three oxo, halo, hydroxyl, or amino;
R9 is hydrogen, C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, C3-10 cycloalkyl, or heterocyclyl, each of which, other than hydrogen, is optionally substituted with one to three R11;
each R11 is independently halo, cyano, nitro, oxo, —OR6, —SR6, —SF5, —NR6R7, C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, C3-10 cycloalkyl, heterocyclyl, aryl, heteroaryl, —C(O)R6, —C(O)OR6, —OC(O)OR6, —OC(O)R6, —C(O)NR6R7, —OC(O)NR6R7, —NR6C(O)NR7R8, —S(O)1-2R6, —S(O)1-2NR6R7, —NR6S(O)1-2R7, —NR6S(O)1-2NR7R8, —NR6C(O)R7, or —NR6C(O)OR7, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl of R11 is independently optionally substituted with one to five R12;
each R12 is independently halo, cyano, nitro, oxo, —OR30, —SR30, —SF5, —NR30R31, C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, C3-10 cycloalkyl, heterocyclyl, aryl, heteroaryl, —C(O)R30, —C(O)OR30, —OC(O)OR30, —OC(O)R30, —C(O)NR30R31, —OC(O)NR30R31, —NR30C(O)NR30R31, —S(O)1-2R30, —S(O)1-2NR30R31, —NR30S(O)1-2R31, —NR30S(O)1-2NR30R31, —NR30C(O)R31, or —NR30C(═O)OR31, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl of R12 is independently optionally substituted with one to three halo or C1-12 alkyl independently optionally substituted by one to three oxo, halo, hydroxyl, or amino;
each R14 is independently halo, cyano, —NR6R7, C1-6 alkyl, C1-6 alkoxy, or C1-6 haloalkyl, or two R14 together with the atoms to which they are attached form a ring or a C═O;
each R15 is independently hydrogen, C1-6 alkyl, or C1-6 haloalkyl;
each R20 and R21 is independently hydrogen or C1-12 alkyl independently optionally substituted with one to three oxo, halo, hydroxyl, or amino; or R20 and R21 are taken together with the atoms to which they are attached to form heterocyclyl independently optionally substituted by one to three halo or C1-12 alkyl independently optionally substituted by one to three oxo, halo, hydroxyl, or amino; and
each R30 and R31 is independently hydrogen or C1-12 alkyl independently optionally substituted with one to three oxo, halo, hydroxyl, or amino; or R30 and R31 are taken together with the atoms to which they are attached to form heterocyclyl independently optionally substituted by one to three halo or C1-12 alkyl independently optionally substituted by one to three oxo, halo, hydroxyl, or amino;
to a subject in need thereof.