# US 11,999,715 B2 · ASK1 inhibiting agents

> Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt

- Number: US 11,999,715 B2
- Document ID: US11999715B2
- Status: Granted
- Kind: B2
- Application number: 17/267,631
- Filed: 2019-08-13
- Published: 2021-10-14
- Granted: 2024-06-04
- Earliest claimed: 2018-08-14
- Assignees: Biogen MA Inc.
- Applicants: Biogen Ma Inc.
- Inventors: Felix Gonzalez Lopez de Turiso; Zhili Xin; Martin Himmelbauer; John H. Jones
- Web page: https://patentgrep.com/patent/US11999715B2

## CPC

- C07D 401/12: linked by a chain containing hetero atoms as chain links
- C07D 401/14: containing three or more hetero rings
- A61P 3/00: Drugs for disorders of the metabolism (of the blood or the extracellular fluid A61P7/00)
- 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 37/00: Drugs for immunological or allergic disorders
- C07D 405/12: linked by a chain containing hetero atoms as chain links
- C07D 405/14: containing three or more hetero rings
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

Provided are compounds of Formula (I): Formula (I), including compounds of Formulas (II), (III), (IV), (V) and (VI), wherein X, R1, R2, R3, R4 and n are as defined herein, and pharmaceutically acceptable salts thereof, and methods for their use and production. These compounds can be useful, e.g., in the treatment of disorders responsive to the inhibition of apoptosis signal-regulating kinase 1 (ASK1).

## Claims

### Claim 1

A compound of Formula (I):
or a pharmaceutically acceptable salt thereof, wherein:
X is CH or N;
n is 1 or 2;
R1 in each occurrence is independently selected from H, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, carbocyclyl, heterocyclyl, halo, —CN, —C(O)R1a, —C(O)OR1a, —C(O)N(R1a)2, —N(R1a)2, —N(R1a)C(O)R1a, —N(R1a)C(O)OR1a, —N(R1a)C(O)N(R1a)2, —N(R1a)S(O)2R1a, —OR1a, —OC(O)R1a, —OC(O)N(R1a)2, —SR1a, —S(O)R1a, —S(O)2R1a, —S(O)N(R1a)2, and —S(O)2N(R1a)2, wherein said C1-6alkyl, C2-6alkenyl, C2-6alkynyl, carbocyclyl, and heterocyclyl are optionally substituted with one or more R10;
R1a in each occurrence is independently selected from H, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, carbocyclyl, and heterocyclyl, wherein said C1-6alkyl, C2-6alkenyl, C2-6alkynyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted with one or more R10;
R10 in each occurrence is independently selected from C1-6alkyl, C2-6alkenyl, C2-6alkynyl, carbocyclyl, heterocyclyl, halo, —CN, —C(O)R10a, —C(O)OR10a, —C(O)N(R10a)2, —N(R10a)2, —N(R10a)C(O)R10a, —N(R10a)C(O)OR10a, —N(R10a)C(O)N(R10a)2, —N(R10a)S(O)2R10a, —OR10a, —OC(O)R10a, —OC(O)N(R10a)2, —SR10a, —S(O)R10a, —S(O)2R10a, —S(O)N(R10a)2, and —S(O)2N(R10a)2, wherein said C1-6alkyl, C2-6alkenyl, C2-6alkynyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted with one or more substituents independently selected from halo, —CN, —C(O)R10a, —C(O)OR10a, —C(O)N(R10a)2, —N(R10a)2, —N(R10a)C(O)R10a, —N(R10a)C(O)OR10a, —N(R10a)C(O)N(R10a)2, —N(R10a)S(O)2R10a, —OR10a, —OC(O)R10a, —OC(O)N(R10a)2, —SR10a, —S(O)R10a, —S(O)2R10a, —S(O)N(R10a)2, and —S(O)2N(R10a)2;
R10a in each occurrence is independently selected from H, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, carbocyclyl, and heterocyclyl;
R2 is selected from H, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, carbocyclyl, and heterocyclyl, wherein said C1-6alkyl, C2-6alkenyl, C2-6alkynyl, carbocyclyl, and heterocyclyl are optionally and independently substituted with one or more R20;
R20 in each occurrence is independently selected from C1-6alkyl, C2-6alkenyl, C2-6alkynyl, carbocyclyl, heterocyclyl, halo, —CN, —C(O)R20a, —C(O)OR20a, —C(O)N(R20a)2, —N(R20a)2, —N(R20a)C(O)R20a, —N(R20a)C(O)OR20a, —N(R20a)C(O)N(R20a)2, —N(R20a)S(O)2R20a, —OR20a, —OC(O)R20a, —OC(O)N(R20a)2, —SR20a, —S(O)R20a, —S(O)2R20a, —S(O)N(R20a)2, and —S(O)2N(R20a)2, wherein said C1-6alkyl, C2-6alkenyl, C2-6alkynyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted with one or more substituents independently selected from halo, —CN, —C(O)R20a, —C(O)OR20a, —C(O)N(R20a)2, —N(R2)2, —N(R20a)C(O)R20a, —N(R20a)C(O)OR20a, —N(R20a)C(O)N(R20a)2, —N(R20a)S(O)2R20a, —OR20a, —OC(O)R20a, —OC(O)N(R20a)2, —SR20a, —S(O)R20a, —S(O)2R20a, —S(O)N(R20a)2, and —S(O)2N(R20a)2;
R20a in each occurrence is independently selected from H, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, carbocyclyl, and heterocyclyl;
R3 is selected from H, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, carbocyclyl, and heterocyclyl, wherein said C1-6alkyl, C2-6alkenyl, C2-6alkynyl, carbocyclyl, and heterocyclyl are optionally substituted with one or more R30;
R30 in each occurrence is independently selected from C1-6alkyl, C2-6alkenyl, C2-6alkynyl, carbocyclyl, heterocyclyl, halo, —CN, —C(O)R30a, —C(O)OR30a, —C(O)N(R30a)2, —N(R30a)2, —N(R30a)C(O)R30a, —N(R30a)C(O)OR30a, —N(R30a)C(O)N(R30a)2, —N(R30a)S(O)2R30a, —OR30a, —OC(O)R30a, —OC(O)N(R30a)2, —SR30a, —S(O)R30a, —S(O)2R30a, —S(O)N(R30a)2, and —S(O)2N(R30a)2, wherein said C1-6alkyl, C2-6alkenyl, C2-6alkynyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted with one or more substituents independently selected from halo, —CN, —C(O)R30a, —C(O)OR30a, —C(O)N(R30a)2, —N(R30a)2, —N(R30a)C(O)R30a, —N(R30a)C(O)OR30a, —N(R30a)C(O)N(R30a)2, —N(R30a)S(O)2R30a, —OR30a, —OC(O)R30a, —OC(O)N(R30a)2, —SR30a, —S(O)R30a, —S(O)2R30a, —S(O)N(R30a)2, and —S(O)2N(R30a)2;
R30a in each occurrence is independently selected from H, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, carbocyclyl, and heterocyclyl, wherein said carbocyclyl, and heterocyclyl are each optionally substituted with C1-4alkyl or halo; and
R4 is H or C1-6alkyl.

### Claim 2 (depends on 1)

The compound of claim 1, wherein the compound is represented by Formula (III):
or a pharmaceutically acceptable salt thereof.

### Claim 3 (depends on 1)

The compound of claim 1, wherein the compound is represented by Formula (IV):
or a pharmaceutically acceptable salt thereof.

### Claim 4 (depends on 1)

The compound of claim 1, wherein:
R1 is H, C1-6alkyl or —OR1a, wherein said C1-6alkyl is optionally substituted with one to three R10;
R1a in each occurrence is independently H or C1-6alkyl;
R10 in each occurrence is independently halo or —OR1a.

### Claim 5 (depends on 4)

The compound of claim 4, wherein R1 is H, —OCH3, —OCH2CH3, —CH2OCH3, —CF3, or —CHF2.

### Claim 6 (depends on 1)

The compound of claim 1, wherein:
R2 is selected from H, C1-6alkyl, C2-6alkenyl, C3-6 cycloalkyl, phenyl, and 5- or 6-membered heteroaryl, wherein said C1-6alkyl, C2-6alkenyl, C3-6cycloalkyl, phenyl, and 5- or 6-membered heteroaryl are optionally and independently substituted with one to three R20;
R20 in each occurrence is independently selected from C1-4alkyl, C2-4alkenyl, C3-6cycloalkyl, phenyl, 4- to 7-membered monocyclic saturated heterocyclyl, 5- or 6-membered heteroaryl, halo, —CN, —C(O)R20a, —C(O)OR20a, —C(O)N(R20a)2, —N(R20a)2, —N(R20a)C(O)R20a, —N(R20a)C(O)OR20a, —N(R20a)C(O)N(R20a)2, —N(R20a)S(O)2R20a, —OR20a, —OC(O)R20a, —OC(O)N(R20a)2, —SR20a, —S(O)R20a, —S(O)2R20a, —S(O)N(R20a)2, and —S(O)2N(R20a)2, wherein said C1-4alkyl, C2-4alkenyl, C3-6cycloalkyl, phenyl, 4- to 7-membered monocyclic saturated heterocyclyl, 5- or 6-membered heteroaryl in each occurrence are optionally and independently substituted with one or more substituents independently selected from halo, —CN, —C(O)R20a, —C(O)OR20a, —C(O)N(R20a)2, —N(R20a)2, —N(R20a)C(O)R20a, —N(R20a)C(O)OR20a, —N(R20a)C(O)N(R20a)2, —N(R20a)S(O)2R20a, —OR20a, —OC(O)R20a, —OC(O)N(R20a)2, —SR20a, —S(O)R20a, —S(O)2R20a, —S(O)N(R20a)2, and —S(O)2N(R20a)2;
R20a in each occurrence is independently H or C1-4alkyl.

### Claim 7 (depends on 6)

The compound of claim 6, wherein:
R2 is selected from H, C1-6alkyl, C2-6alkenyl, C3-6cycloalkyl, phenyl, and 5- or 6-membered heteroaryl, wherein said C1-6alkyl, C2-6alkenyl, C3-6cycloalkyl, phenyl, and 5- or 6-membered heteroaryl are optionally and independently substituted with one to three R20;
R20 in each occurrence is independently selected from C1-4alkyl, C2-4alkenyl, C3-6cycloalkyl, phenyl, 4- to 7-membered monocyclic saturated heterocyclyl, 5- or 6-membered heteroaryl, halo, —CN, —N(R20a)2, and —OR20a;
R20a in each occurrence is independently H or C1-4alkyl.

### Claim 8 (depends on 6)

The compound of claim 6, wherein the 5- or 6-membered heteroaryl is selected from pyridinyl, pyrimidinyl, pyrazinyl, and pyridazinyl.

### Claim 9 (depends on 7)

The compound of claim 7, wherein the 4- to 7-membered monocyclic saturated heterocyclyl is selected from azetidinyl, piperidinyl, oxetanyl, piperazinyl and morpholinyl.

### Claim 10 (depends on 6)

The compound of claim 6, wherein R2 is —CH3, —CH2CH3, —CH2CF3, —C(CH3)3, —CH2CH2OCH3, —CH2CH(CH3)2, —CH2CH2N(CH3)2, —CH2CH═CH2, —CH2CH2CH3,

### Claim 11 (depends on 1)

The compound of claim 1, wherein:
R3 is selected from H, C1-6alkyl, C3-6cycloalkyl, and 4 to 7-membered monocyclic saturated heterocyclyl, wherein said C1-6alkyl, C3-6cycloalkyl, and 4 to 7-membered monocyclic saturated heterocyclyl are optionally substituted with one to three R30;
R30 in each occurrence is independently selected from C1-6alkyl, halo, —CN, —C(O)R30a, —C(O)OR30a, —C(O)N(R30a)2, —N(R30a)2, —N(R30a)C(O)R30a, —N(R30a)C(O)OR30a, —N(R30a)C(O)N(R30a)2, —N(R30a)S(O)2R30a, —OR30a, —OC(O)R30a, —OC(O)N(R30a)2, —SR30a, —S(O)R30a, —S(O)2R30a, —S(O)N(R30a)2, and —S(O)2N(R30a)2, wherein said C1-6alkyl in each occurrence are optionally and independently substituted with one to three substituents independently selected from halo;
R30a in each occurrence is independently selected from H and C1-6alkyl, wherein C1-6alkyl is optionally substituted with one to three substituents independently selected from C1-4alkyl and halo.

### Claim 12 (depends on 11)

The compound of claim 11, wherein:
R3 is C1-6alkyl, C3-6cycloalkyl, or 4 to 7-membered monocyclic saturated heterocyclyl, wherein said C1-6alkyl, C3-6cycloalkyl, and 4 to 7-membered monocyclic saturated heterocyclyl are each optionally substituted with one to three R30;
R30 in each occurrence is independently C1-3alkyl, halo, —C(O)OR30a, or —OR30a, wherein said C1-3alkyl is optionally substituted with one to three halo; and
R30a in each occurrence is independently H or C1-4alkyl.

### Claim 13 (depends on 12)

The compound of claim 12, wherein:
R3 is —CH(CH3)2, —CH(CH3)CF3, —C(CH3)3, —CH(CH3)CHF2, —CH(CH3)CH(CH3)2, —CH(CH3)CH2OCH3, —CH(CH3)CH2OH,

### Claim 14 (depends on 1)

The compound of claim 1, wherein R4 is H or —CH3.

### Claim 15 (depends on 14)

The compound of claim 14, wherein R4 is H.

### Claim 16 (depends on 1)

The compound of claim 1, wherein the compound is represented by Formula (V) or (VI):
or a pharmaceutically acceptable salt thereof, wherein:
R1 is C1-4alkyl or —OR1a, wherein said C1-4alkyl is optionally substituted with one to three halo;
R1a in each occurrence is independently H or C1-4alkyl;
R2 is C1-4alkyl, C2-4alkenyl or 5- or 6-membered heteroaryl, wherein said C1-4alkyl, C2-4alkenyl and 5- or 6-membered heteroaryl are optionally and independently substituted with one to three R20;
R20 in each occurrence is independently selected from C3-6cycloalkyl, halo and —OR20a;
R20a in each occurrence is independently H or C1-4alkyl;
R3 is C1-4alkyl or C3-6cycloalkyl, wherein said C1-4alkyl and C3-6cycloalkyl are each optionally substituted with one to three R30; and
R30 in each occurrence is independently C1-3alkyl or halo, wherein said C1-3alkyl is optionally substituted with one to three halo.

### Claim 17 (depends on 16)

The compound of claim 16, wherein:
R1 is —OCH3, —OCH2CH3, or —CHF2;
R2 is —CH3, —CH2CH3, —CH2CH2OCH3, —CH2CF3, —CH2CH═CH2,
R3 is —CH(CH3)2, —CH(CH3)CF3, —CH(CH3)CHF2,

### Claim 18 (depends on 1)

A pharmaceutical composition comprising a compound of claim 1 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

### Claim 19 (depends on 1)

A method of treating a disorder responsive to inhibition of apoptosis signal-regulating kinase 1 (ASK1) in a subject, the method comprising administering to the subject an effective amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof.

### Claim 20 (depends on 19)

The method of claim 19, wherein the disorder is neurodegenerative disorder, cardiovascular disease, metabolic disorder, inflammatory disease, autoimmune disorder, destructive bone disorder, polyglutamine disease, glutamate neurotoxicity, pain, traumatic brain injury, hemorrhagic stroke, ischemia, acute hypoxia, kidney fibrosis (renal fibrosis), kidney injury, diabetic kidney disease, diabetic nephropathy, non-alcoholic steatohepatitis (NASH), pulmonary arterial hypertension (PAH), optic neuritis, liver disease, respiratory disease, heart reperfusion injury, cardiac hypertrophy, cardiac fibrosis, energy metabolic disorder, or cancer.