# US 11,306,077 B2 · Compounds, compositions and methods

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- Number: US 11,306,077 B2
- Document ID: US11306077B2
- Status: Granted
- Kind: B2
- Application number: 17/334,587
- Filed: 2021-05-28
- Published: 2021-09-23
- Granted: 2022-04-19
- Earliest claimed: 2019-02-13
- Assignees: Denali Therapeutics Inc.
- Applicants: Denali Therapeutics Inc.
- Inventors: Robert A. Craig, II; Javier de Vicente Fidalgo; Anthony A. Estrada; Jianwen A. Feng; Brian M. Fox; Maksim Osipov; Arun Thottumkara
- Web page: https://patentgrep.com/patent/US11306077B2

## CPC

- C07D 413/04: directly linked by a ring-member-to-ring-member bond
- A61P 25/00: Drugs for disorders of the nervous system
- 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 35/00: Antineoplastic agents
- C07D 271/113: with oxygen, sulfur or nitrogen atoms, directly attached to ring carbon atoms, the nitrogen atoms not forming part of a nitro radical
- C07D 413/12: linked by a chain containing hetero atoms as chain links
- C07D 413/14: containing three or more hetero rings
- C07D 417/04: directly linked by a ring-member-to-ring-member bond
- C07D 417/14: containing three or more hetero rings
- C07D 493/08: Bridged systems
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## 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.

## Claims

### Claim 1

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, —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 R21 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.

### Claim 2 (depends on 1)

The compound 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 R14.

### Claim 3 (depends on 1)

The compound 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 R14.

### Claim 4 (depends on 1)

The compound 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 four halo.

### Claim 5 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, wherein ring B is

### Claim 6 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, wherein ring B is

### Claim 7

A compound of Formula II:
or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, wherein:
p is 0, 1, 2, 3, 4, 5, or 6;
ring B is
or
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, 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.

### Claim 8 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, wherein R2 is —CHF2, —CF3, or —CH2CF3.

### Claim 9 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, wherein Q1 is O.

### Claim 10 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, wherein Q1 is NR15, and Q2 is O.

### Claim 11 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, wherein Q1 and Q2 are each O.

### Claim 12 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, wherein L is —CH2CH2—.

### Claim 13 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, wherein the moiety —Q1—L—Q2—R2 is —OCH2CH2OCF3 or —NR15CH2CH2OCF3.

### Claim 14 (depends on 7)

The compound of claim 7, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, wherein the moiety —Q1—L—Q2—R2 is —OCH2CH2OCF3.

### Claim 15 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, wherein X1 is O.

### Claim 16 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, wherein R3 is C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is optionally substituted with one to five R11.

### Claim 17 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, wherein R3 is C3-10 cycloalkyl, aryl, or heteroaryl, each of which is optionally substituted with one to five R11.

### Claim 18 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, wherein R3 is aryl or heteroaryl, each of which is optionally substituted with one to five R11.

### Claim 19 (depends on 14)

The compound of claim 14, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, wherein R3 is aryl or heteroaryl, each of which is optionally substituted with one to five R11.

### Claim 20 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, wherein R3 is aryl or heteroaryl, each of which is optionally substituted with chloro, fluoro, —CF3, or a combination thereof.

### Claim 21 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, wherein R3 is
each of which is optionally substituted with one to five R11.

### Claim 22 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, wherein R4 and R5 are hydrogen.

### Claim 23 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, wherein R1 is hydrogen.

### Claim 24

A compound, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, selected from the group consisting of:

### Claim 25 (depends on 1)

A pharmaceutical composition comprising a compound of claim 1, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or prodrug thereof, and a pharmaceutically acceptable carrier.

### Claim 26 (depends on 25)

A method for treating a disease or condition mediated, at least in part, by eukaryotic initiation factor 2B, the method comprising administering an effective amount of the pharmaceutical composition of claim 25 to a subject in need thereof, 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.

### Claim 27 (depends on 26)

The method of claim 26, wherein the disease is amyotrophic lateral sclerosis (ALS).

### Claim 28

A compound having the structure:
or a pharmaceutically acceptable salt thereof.

### Claim 29 (depends on 28)

A pharmaceutical composition comprising a compound of claim 28, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

### Claim 30

A compound having the structure:
or a pharmaceutically acceptable salt thereof.

### Claim 31 (depends on 30)

A pharmaceutical composition comprising a compound of claim 30, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

### Claim 32

A compound having the structure:
or a pharmaceutically acceptable salt thereof.

### Claim 33 (depends on 32)

A pharmaceutical composition comprising a compound of claim 32, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

### Claim 34

A compound having the structure:
or a pharmaceutically acceptable salt thereof.

### Claim 35 (depends on 34)

A pharmaceutical composition comprising a compound of claim 34, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

### Claim 36

A compound having the structure:
or a pharmaceutically acceptable salt thereof.

### Claim 37 (depends on 36)

A pharmaceutical composition comprising a compound of claim 36, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

### Claim 38

A compound having the structure:
or a pharmaceutically acceptable salt thereof.

### Claim 39 (depends on 38)

A pharmaceutical composition comprising a compound of claim 38, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

### Claim 40

A compound having the structure:
or a pharmaceutically acceptable salt thereof.

### Claim 41 (depends on 40)

A pharmaceutical composition comprising a compound of claim 40, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

### Claim 42

A compound having the structure:
or a pharmaceutically acceptable salt thereof.

### Claim 43 (depends on 42)

A pharmaceutical composition comprising a compound of claim 42, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

### Claim 44

A compound having the structure:
or a pharmaceutically acceptable salt thereof.

### Claim 45 (depends on 44)

A pharmaceutical composition comprising a compound of claim 44, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

### Claim 46

A compound having the structure:
or a pharmaceutically acceptable salt thereof.

### Claim 47 (depends on 46)

A pharmaceutical composition comprising a compound of claim 46, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.