# US 10,864,196 B2 · Modulators of the integrated stress pathway

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- Number: US 10,864,196 B2
- Document ID: US10864196B2
- Status: Granted
- Kind: B2
- Application number: 16/098,950
- Filed: 2017-05-05
- Published: 2019-05-16
- Granted: 2020-12-15
- Earliest claimed: 2016-05-05
- Assignees: Calico Life Sciences LLC; AbbVie Inc.
- Applicants: Calico Life Sciences LLC; AbbVie Inc.
- Inventors: Marina Pliushchev; Jennifer M. Frost; Lawrence A. Black; Xiangdong Xu; Ramzi Farah Sweis; Lei Shi; Qingwei I. Zhang; Yunsong Tong; Charles W. Hutchins; Seungwon Chung; Michael J. Dart
- Web page: https://patentgrep.com/patent/US10864196B2

## CPC

- A61K 31/42: Oxazoles
- A61P 3/08: for glucose homeostasis (pancreatic hormones A61P5/48)
- A61P 9/00: Drugs for disorders of the cardiovascular 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 233/64: with substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine
- C07D 271/06: 1,2,4-Oxadiazoles; Hydrogenated 1,2,4-oxadiazoles
- C07D 271/10: 1,3,4-Oxadiazoles; Hydrogenated 1,3,4-oxadiazoles
- C07D 401/12: linked by a chain containing hetero atoms as chain links
- C07D 413/12: linked by a chain containing hetero atoms as chain links
- C07D 471/04: Ortho-condensed systems
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)

## Abstract

Provided herein are compounds, compositions, and methods useful for modulating the integrated stress response (ISR) and for treating related diseases; disorders and conditions.

## Claims

### Claim 1

A compound of Formula (I):
or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, wherein:
D is
L1 is CH2O—* or CH2OCH2—*, L2 is selected from CH2O—*, CH2OCH2—*, or —O—, and “-*” indicates the attachment point to A or Z, respectively;
R1 is hydrogen or C1-C6 alkyl;
A and W are each independently phenyl or 5-6-membered heteroaryl, wherein each phenyl or 5-6-membered heteroaryl is optionally substituted with 1-5 RY;
Z is hydrogen, phenyl, or 5-6-membered heteroaryl, wherein each phenyl or 5-6-membered heteroaryl is optionally substituted with 1-5 RY;
each RX is independently selected from the group consisting of C1-C6 alkyl, hydroxy-C1-C6 alkyl, halo-C1-C6 alkyl, amino-C1-C6 alkyl, cyano-C1-C6 alkyl, oxo, halo, cyano, —ORA, —NRBRC, —NRBC(O)RD, —C(O)NRBRC, —C(O)RD, —C(O)OH, —C(O)ORD, —SRE, —S(O)RD, and —S(O)2RD;
each RY is independently selected from the group consisting of hydrogen, C1-C6 alkyl, hydroxy-C1-C6 alkyl, halo-C1-C6 alkyl, halo-C1-C6 alkoxy, amino-C1-C6 alkyl, cyano-C1-C6 alkyl, oxo, halo, cyano, —ORA, —NRBRC, —NRBC(O)RD, —C(O)NRBRC, —C(O)RD, —C(O)OH, —C(O)ORD, —S(RF)m, —S(O)RD, —S(O)2RD, and G1; or
2 RY groups on adjacent atoms, together with the atoms to which they are attached form a 3-7-membered fused cycloalkyl, 3-7-membered fused heterocyclyl, aryl, or 5-6 membered fused heteroaryl optionally substituted with 1-5 RX;
each G1 is independently 3-7-membered cycloalkyl, 3-7-membered heterocyclyl, aryl, or 5-6-membered heteroaryl, wherein each 3-7-membered cycloalkyl, 3-7-membered heterocyclyl, aryl, or 5-6-membered heteroaryl is optionally substituted with 1-3 RZ;
each RZ is independently selected from the group consisting of C1-C6 alkyl, hydroxy-C1-C6 alkyl, halo-C1-C6 alkyl, halo, cyano, —ORA, —NRBRC, —NRBC(O)RD, —C(O)NRBRC, —C(O)RD, —C(O)OH, —C(O)ORD, and —S(O)2RD;
RA is, at each occurrence, independently hydrogen, C1-C6 alkyl, halo-C1-C6 alkyl, —C(O)NRBRC, —C(O)RD, —C(O)OH, or —C(O)ORD;
each of RB and RC is independently hydrogen or C1-C6 alkyl; or
RB and RC together with the atom to which they are attached form a 3-7-membered heterocyclyl ring optionally substituted with 1-3 RZ;
each RD is independently C1-C6 alkyl or halo-C1-C6 alkyl;
each RE is independently hydrogen C1-C6 alkyl, or halo-C1-C6 alkyl;
each RF is independently hydrogen, C1-C6 alkyl, or halo; and
m is 1, 3, or 5.

### Claim 2 (depends on 1)

The compound of claim 1, wherein D is substituted with 0 RX.

### Claim 3 (depends on 1)

The compound of claim 1, wherein D is

### Claim 4 (depends on 1)

The compound of claim 1, wherein D is substituted with 1 RX.

### Claim 5 (depends on 4)

The compound of claim 4, wherein D is

### Claim 6 (depends on 5)

The compound of claim 5, wherein RX is oxo or OH.

### Claim 7 (depends on 1)

The compound of claim 1, wherein RX is hydrogen.

### Claim 8 (depends on 1)

The compound of claim 1, wherein A is phenyl, pyridyl, or isoxazolyl, each of which is optionally substituted with 1-2 RY groups.

### Claim 9 (depends on 1)

The compound of claim 1, wherein A is selected from:

### Claim 10 (depends on 1)

The compound of claim 1, wherein W is oxadiazolyl, imidazolyl, or triazolyl.

### Claim 11 (depends on 1)

The compound of claim 1, wherein W is selected from:

### Claim 12 (depends on 1)

The compound of claim 1, wherein Z is phenyl or pyridyl, each of which is optionally substituted with 1-2 RY groups.

### Claim 13 (depends on 1)

The compound of claim 1, wherein Z is selected from:

### Claim 14 (depends on 1)

The compound of claim 1, wherein Z is hydrogen.

### Claim 15 (depends on 1)

The compound of claim 1, wherein each RY is independently selected from the group consisting of chloro, fluoro, CF3, CH3, CH2CH3, CH(CH3)2, OCH3, OCH(CH3)2, CN, and G1, wherein G1 is cyclopropyl; or
2 RY groups on adjacent atoms, together with the atoms to which they are attached, form a 3-7 membered fused heterocyclyl or 5-6 membered fused heteroaryl ring optionally substituted with 1-5 RX.

### Claim 16 (depends on 15)

The compound of claim 15, wherein the 2 RY together with the atoms to which they are attached form a furanyl, pyrrolyl, or dioxolanyl ring, each of which is optionally substituted with 1-5 RX.

### Claim 17 (depends on 16)

The compound of claim 16, wherein each RX is independently fluoro.

### Claim 18

A compound represented by Formula (I-a):
or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof,
wherein:
D is bicyclo[1.1.1]pentanyl optionally substituted with 1-4 RX groups;
L1 and L2 are each independently CH2O—*, CH2OCH2—*, or —O—, and “-*” indicates the attachment point to A or Z, respectively;
R1 is hydrogen;
A and W are each independently phenyl, pyridyl, oxadiazolyl, imidazolyl, triazolyl, or isoxazolyl, each of which is optionally substituted with 1-5 RY groups;
Z is hydrogen, phenyl, or pyridyl, wherein phenyl or pyridyl is optionally substituted with 1-5 RY groups;
each RX is fluoro, oxo, or OH;
each RY is independently chloro, fluoro, CF3, CH3, CH2CH3, CH(CH3)2, OCH3, OCH(CH3)2, CN, or G1; or
2 RY groups on adjacent atoms, together with the atoms to which they are attached form a furanyl, pyrrolyl, or dioxolanyl ring, each of which is optionally substituted with 1-2 RX; and
G1 is cyclopropyl.

### Claim 19

A compound selected from the group consisting of:
and a pharmaceutically acceptable salt thereof.

### Claim 20 (depends on 1)

A pharmaceutically acceptable composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier.

### Claim 21 (depends on 1)

A composition for use in treating a neurodegenerative disease, a leukodystrophy, cancer, an inflammatory disease, a musculoskeletal disease, or a metabolic disease in a subject in need thereof, wherein the composition comprises a compound of claim 1 or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof.

### Claim 22 (depends on 21)

The composition of claim 21, further comprising a second agent, wherein the second agent is selected from the group consisting of an agent for treating a cancer, an agent for treating a neurodegenerative disease, an agent for treating a leukodystrophy, an agent for treating an inflammatory disease, an agent for treating a musculoskeletal disease, an agent for treating a metabolic disease, and an agent for treating a disease or disorder associated with impaired function of eIF2B, eIF2α, or a component of the eIF2 pathway or ISR pathway.