# US 12,600,720 B2 · Modulators of the integrated stress response pathway

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- Number: US 12,600,720 B2
- Document ID: US12600720B2
- Status: Granted
- Kind: B2
- Application number: 18/033,317
- Filed: 2021-10-21
- Published: 2023-11-30
- Granted: 2026-04-14
- Earliest claimed: 2020-10-22
- Assignees: Evotec International GmbH
- Applicants: Evotec International GmbH
- Inventors: Holly Victoria Atton; Mohamad Sabbah
- Web page: https://patentgrep.com/patent/US12600720B2

## CPC

- C07D 471/04: Ortho-condensed systems
- 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 413/04: directly linked by a ring-member-to-ring-member bond
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

The present invention relates to compounds of formula (I) or pharmaceutically acceptable salts, solvates, hydrates, tautomers or stereoisomers thereof, wherein R1, R2, R2a, R3, R4, R4a, R4b, R4c, R4d, R4e, R5, R6 have the meaning as indicated in the description and claims. The invention further relates to pharmaceutical compositions comprising said compounds, their use as medicament and in a method for treating or preventing of one or more diseases or disorders associated with integrated stress response.

## Claims

### Claim 1

A compound of formula (I)
or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein:
R1 is H or C1-4 alkyl, wherein C1-4 alkyl is optionally substituted with one or more halogen, which are the same or different;
R2 is H, F or C1-4 alkyl, wherein C1-4 alkyl is optionally substituted with one or more halogen, which are the same or different;
R2a is H;
R3 is phenyl or 6 membered aromatic heterocyclyl, wherein R3 is optionally substituted with one or more R7, which are the same or different;
R7 is halogen, CN, C(O)OR8, OR8, C(O)R8, C(O)N(R8R8a), S(O)2N(R8R8a), S(O)N(R8R8a), S(O)2R8, S(O)R8, N(R8)S(O)2N(R8aR8b), SR8, N(R8R8a), NO2, OC(O)R8, N(R8)C(O)R8a, N(R8)S(O)2R8a, N(R8)S(O)R8a, N(R8)C(O)OR8a, N(R8)C(O)N(R8aR8b), OC(O)N(R8R8a), C1-6 alkyl, C2-6 alkenyl or C2-6 alkynyl, wherein C1-6 alkyl, C2-6 alkenyl and C2-6 alkynyl are optionally substituted with one or more R9, which are the same or different;
R8, R8a, R8b are independently selected from the group consisting of H, C1-6 alkyl, C2-6 alkenyl and C2-6 alkynyl, wherein C1-6 alkyl, C2-6 alkenyl and C2-6 alkynyl are optionally substituted with one or more halogen, which are the same or different;
R9 is halogen, CN, C(O)OR10, OR10, C(O)R10, C(O)N(R10R10a), S(O)2N(R10R10a), S(O)N(R10R10a), S(O)2R10, S(O)R10, N(R10)S(O)2N(R10aR10b), SR10, N(R10R10a), NO2, OC(O)R10, N(R10)C(O)R10a, N(R10)SO2R10a, N(R10)S(O)R10a, N(R10)C(O)N(R10aR10b), N(R10)C(O)OR10a or OC(O)N(R10R10a);
R10, R10a, R10b are independently selected from the group consisting of H, C1-6 alkyl, C2-6 alkenyl and C2-6 alkynyl, wherein C1-6 alkyl, C2-6 alkenyl and C2-6 alkynyl are optionally substituted with one or more halogen, which are the same or different;
R4 is H, C(O)OC1-4 alkyl or C1-4 alkyl, wherein C(O)OC1-4 alkyl and C1-4 alkyl are optionally substituted with one or more substituents selected from the group consisting of halogen, OH and O—C1-3 alkyl, wherein the substituents are the same or different;
R4a, R4b, R4c, R5 are independently selected from the group consisting of H, halogen and C1-4 alkyl; and
R4d, R4e are independently selected from the group consisting of H, OH, OC1-4 alkyl, halogen and C1-4 alkyl;
or R4 and one of R4d and R4e form a methylene or ethylene group;
or R4 and R4c form an ethylene group;
or R4b and R4d form a covalent single bond;
R6 is 7 to 12 membered heterobicyclyl, wherein R6 is optionally substituted with one or more R11, which are the same or different;
R11 is R12, OH, OR12, halogen or CN;
R12 is cyclopropyl, C1-6 alkyl, C2-6 alkenyl or C2-6 alkynyl, wherein R12 is optionally substituted with one or more R13, which are the same or different;
R13 is halogen, CN or OR14; and
R14 is H or C1-4 alkyl, wherein C1-4 alkyl is optionally substituted with one or more halogen, which are the same or different.

### Claim 2 (depends on 1)

The compound of claim 1 or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein R4 is H, CH3, CH2CH3, or CH2CH2OCH3.

### Claim 3 (depends on 1)

The compound of claim 1 or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein R4a, R4b, R4c, R5 are independently selected from the group consisting of H, halogen and C1-4 alkyl and R4d, R4e are independently selected from the group consisting of H, OH, OC1-4 alkyl, halogen and C1-4 alkyl.

### Claim 4 (depends on 1)

The compound of claim 1 or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein R1 is H or CH3.

### Claim 5 (depends on 1)

The compound of claim 1 or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein R2 is H, F or CH3.

### Claim 6 (depends on 1)

The compound of claim 1 or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein R1, R2, R2a, R4, R4a, R4b, R4c, R5, R4d, R4e in formula (I) are H to give formula (Ia):

### Claim 7 (depends on 1)

The compound of claim 1 or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein R3 is phenyl or pyridyl wherein R3 is optionally substituted with one or more R7, which are the same or different.

### Claim 8 (depends on 1)

The compound of claim 1 or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein R3 is substituted with one, two or three R7, which are the same or different.

### Claim 9 (depends on 1)

The compound of claim 1 or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein R7 is F, Cl, Br, CN, CHF2, CF3, OCH3, OCF3, CH═O, CH2OH or CH3.

### Claim 10 (depends on 1)

The compound of claim 1 or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein R1, R2, R2a, R3, R4, R4a, R4b, R4c, R4d, R4e, R5 in formula (I) are selected to give formula (Ib):
wherein each R7 is independently selected from the group consisting of halogen and CF3.

### Claim 11 (depends on 1)

The compound of claim 1 or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein R6 is quinazolinyl, pyrrolo[1,2-a]pyrazinyl, 1,3-benzoxazolyl, pyrido[2,3-d]pyrimidinyl, pyrido[3,4-d]pyrimidinyl, pyrimido[5,4-d]pyrimidinyl, 1,2,3,4-tetrahydroquinolinyl, chromanyl, oxazolo[4,5-c]pyridinyl, imidazo[1,2-a]pyridinyl, [1,2,4]triazolo[1,5-a]pyridinyl, imidazo[1,2-b]pyridazinyl or 6,7-dihydro-4H-pyrano[4,3-d]oxazolyl, wherein R6 is optionally substituted with one or more R11, which are the same or different.

### Claim 12 (depends on 1)

The compound of claim 1 or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein R6 is unsubstituted or substituted with one or two R11, which are the same or different.

### Claim 13 (depends on 1)

The compound of claim 1 or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein R11 is Cl, CH3, CF3, CH2CF3, OCF3, OCHF2 or OCH2CF3.

### Claim 14 (depends on 1)

The compound of claim 1 or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein R1, R2, R2a, R4, R4a, R4b, R4c, R4d, R4e, R3, R5, R6 in formula (I) are selected to give:
tert-butyl (2R,5S)-2-(6-chloro-1,3-benzoxazol-2-yl)-5-[2-(4-chloro-3-fluorophenoxy)acetamido]piperidine-1-carboxylate;
N-[(3S,6R)-6-(6-chloro-1,3-benzoxazol-2-yl)piperidin-3-yl]-2-(4-chloro-3-fluorophenoxy)acetamide;
tert-butyl (2R,5S)-2-(5-chloro-1,3-benzoxazol-2-yl)-5-[2-(4-chloro-3-fluorophenoxy)acetamido]piperidine-1-carboxylate;
N-[(3S,6R)-6-(5-chloro-1,3-benzoxazol-2-yl)piperidin-3-yl]-2-(4-chloro-3-fluorophenoxy)acetamide;
tert-butyl (2R,5S)-5-[[2-(4-chloro-3-fluoro-phenoxy)acetyl]amino]-2-[6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl]piperidine-1-carboxylate;
2-(4-chloro-3-fluoro-phenoxy)-N-[(3S,6R)-6-[6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl]-3-piperidyl]acetamide;
tert-butyl (2R,5S)-5-[2-(4-chloro-3-fluorophenoxy)acetamido]-2-[7-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl]piperidine-1-carboxylate or 2-(4-chloro-3-fluoro-phenoxy)-N-[(3S,6R)-6-[7-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl]-3-piperidyl]acetamide;
tert-butyl (2R,5S)-2-(7-chloro-1,3-benzoxazol-2-yl)-5-[2-(4-chloro-3-fluorophenoxy)acetamido]piperidine-1-carboxylate;
N-[(3S,6R)-6-(7-chloro-1,3-benzoxazol-2-yl)piperidin-3-yl]-2-(4-chloro-3-fluorophenoxy)acetamide;
tert-butyl (2R,5S)-5-[2-(4-chloro-3-fluorophenoxy)acetamido]-2-[6-(trifluoromethoxy)-1,3-benzoxazol-2-yl]piperidine-1-carboxylate;
2-(4-chloro-3-fluorophenoxy)-N-[(3S,6R)-6-[6-(trifluoromethoxy)-1,3-benzoxazol-2-yl]piperidin-3-yl]acetamide;
tert-butyl (2R,5S)-5-[2-(4-chloro-3-fluorophenoxy)acetamido]-2-[6-(difluoromethoxy)-1,3-benzoxazol-2-yl]piperidine-1-carboxylate;
2-(4-chloro-3-fluorophenoxy)-N-[(3S,6R)-6-[6-(difluoromethoxy)-1,3-benzoxazol-2-yl]piperidin-3-yl]acetamide;
tert-butyl (2R,5S)-5-[2-(4-chloro-3-fluorophenoxy)acetamido]-2-[6-(trifluoromethyl)-1,3-benzoxazol-2-yl]piperidine-1-carboxylate;
2-(4-chloro-3-fluorophenoxy)-N-[(3S,6R)-6-[6-(trifluoromethyl)-1,3-benzoxazol-2-yl]piperidin-3-yl]acetamide;
tert-butyl (2R,5S)-2-(4-chloro-1,3-benzoxazol-2-yl)-5-[2-(4-chloro-3-fluorophenoxy)acetamido]piperidine-1-carboxylate; or
N-[(3S,6R)-6-(4-chloro-1,3-benzoxazol-2-yl)piperidin-3-yl]-2-(4-chloro-3-fluorophenoxy)acetamide.

### Claim 15 (depends on 1)

The compound of claim 1 or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein formula (I) has a stereochemistry as shown in formula (Ic):

### Claim 16 (depends on 1)

A pharmaceutical composition comprising at least one compound or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof of claim 1 together with a pharmaceutically acceptable carrier, optionally in combination with one or more other bioactive compounds or pharmaceutical compositions.

### Claim 17 (depends on 1)

A method of treating of one or more diseases or disorders associated with integrated stress response comprising administering to a subject in need a compound or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof of claim 1 or a pharmaceutical composition thereof.

### Claim 18 (depends on 17)

The method of claim 17, wherein the diseases or disorders are selected from the group consisting of leukodystrophies, intellectual disability syndrome, neurodegenerative diseases and disorders, neoplastic diseases, infectious diseases, inflammatory diseases, musculoskeletal diseases, metabolic diseases, ocular diseases, organ fibrosis, chronic and acute diseases of the liver, chronic and acute diseases of the lung, chronic and acute diseases of the kidney, myocardial infarction, cardiovascular disease, arrhythmias, atherosclerosis, spinal cord injury, ischemic stroke, and neuropathic pain.