# US 11,897,898 B2 · Pyridine macrocycle compounds as 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 11,897,898 B2
- Document ID: US11897898B2
- Status: Granted
- Kind: B2
- Application number: 17/265,986
- Filed: 2019-08-13
- Published: 2021-09-30
- Granted: 2024-02-13
- Earliest claimed: 2018-08-14
- Assignees: Biogen MA Inc.
- Applicants: Biogen Ma Inc.
- Inventors: Felix Gonzalez Lopez de Turiso
- Web page: https://patentgrep.com/patent/US11897898B2

## CPC

- C07D 498/22: in which the condensed system contains four or more hetero rings
- 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 519/00: Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

Provided are compounds of Formula (I′), including compounds of Formulas (I), (II), (III), (IIIA) and (IIIB), wherein L, R1, R3 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 (F):
or a pharmaceutically acceptable salt thereof, wherein:
n is selected from 0, 1 and 2;
L is selected from C3-5 alkylene and C3-5 alkenylene, wherein said C3-5 alkylene and C3-5 alkenylene are optionally substituted with one or two R2;
R1 in each occurrence is independently selected from C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 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 C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, carbocyclyl, and heterocyclyl, are optionally and independently substituted with one or more R10;
R1a in each occurrence is independently selected from H, C1-6 alkyl, C2-6 alkenyl, C2-6alkynyl, carbocyclyl, and heterocyclyl, wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted with one or more R10;
R10 in each occurrence is independently selected from C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 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 C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted with one or more 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)2RR10a, —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, C2-6 alkenyl, C2-6alkynyl, carbocyclyl, and heterocyclyl;
R2 in each occurrence is independently selected from C1-6alkyl, —CN, —C(O)R2a, —C(O)OR2a, —C(O)N(R2a)2, —NO2, —N(R2a)2, —N(R2a)C(O)R2a, —N(R2a)C(O)OR2a, —N(R2a)C(O)N(R2a)2, —N(R2a)S(O)2R2a, —OR2a, —OC(O)R2a, —OC(O)N(R2a)2, —SR2a, —S(O)R2a, —S(O)2R2a, —S(O)N(R2a)2, and —S(O)2N(R1a)2, wherein said C1-6 alkyl is optionally substituted with one or more R20;
R2a in each occurrence is independently selected from H, C1-6 alkyl, C2-6 alkenyl, C2-6alkynyl, carbocyclyl, and heterocyclyl wherein said C1-6 alkyl, C2-6 alkenyl, C2-6alkynyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted with one or more R20; and
R20 in each occurrence is independently selected from C1-6 alkyl, halo and —OR20a;
R20a in each occurrence is independently selected from H, C1-6 alkyl, C2-6 alkenyl, C2-6alkynyl, carbocyclyl, and heterocyclyl; and
R3 is H or C1-4 alkyl.

### Claim 2 (depends on 1)

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

### Claim 3 (depends on 1)

The compound of claim 1, wherein L is C3-5 alkylene optionally substituted with one or two R2.

### Claim 4 (depends on 1)

The compound of claim 1, wherein L is C4alkylene optionally substituted with one or two R2.

### Claim 5 (depends on 1)

The compound of claim 1, wherein:
R2 in each occurrence is independently selected from C1-6 alkyl, —CN, —C(O)R2a, —C(O)OR2a, —C(O)N(R2a)2, —NO2, —N(R2a)2, —N(R2a)C(O)R2a, —N(R2a)C(O)OR2a, —OR2a, —OC(O)R2a, and —OC(O)N(R2a)2, wherein said C1-6 alkyl is optionally substituted with one to four R20;
R2a in each occurrence is independently H or C1-6 alkyl, wherein said C1-6 alkyl in each occurrence is optionally and independently substituted with one to three R20; and
R20 in each occurrence is independently halo or —R20a; and
R20a in each occurrence is independently H or C1-6 alkyl.

### Claim 6 (depends on 5)

The compound of claim 5, wherein R2 is C1-4 alkyl.

### Claim 7 (depends on 5)

The compound of claim 5, wherein R2 is methyl.

### Claim 8 (depends on 1)

The compound of claim 1, wherein L is —(CH2)3—, —(CH2)4—, —CH(CH3)—CH2—CH2—CH2—, —CH2—CH(CH3)—CH2—CH2—, —CH2—CH2—CH(CH3)—CH2—, —CH2—CH2—CH2—CH(CH3)—, or —(CH2)5—.

### Claim 9 (depends on 1)

The compound of claim 1, wherein L is —CH2—CH2—CH2—CH(CH3)—.

### Claim 10 (depends on 1)

The compound of claim 1, wherein n is 0.

### Claim 11 (depends on 1)

The compound of claim 1, wherein:
R1 in each occurrence is independently selected from C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, 4- to 7-membered monocyclic non-aromatic heterocyclyl, 5- to 6-membered N-containing heteroaryl, 6- to 8-membered spiro or bridged bicyclic heterocyclyl, halo, —CN, —C(O)R1a, —C(O)OR1a, —C(O)N(R1a)2, —N(R1a)2, —OR1a, —S(O)2R1a, and —S(O)2N(R1a)2, wherein said C1-6alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, 4- to 7-membered monocyclic non-aromatic heterocyclyl, 5- to 6-membered N-containing heteroaryl, and 6- to 8-membered spiro or bridged bicyclic heterocyclyl are optionally substituted with one to four R10;
R1a in each occurrence is independently selected from H, C1-6 alkyl, and 4- to 7-membered monocyclic N-containing non-aromatic heterocyclyl, wherein said C1-6 alkyl, and 4- to 7-membered monocyclic N-containing non-aromatic heterocycly are optionally and independently substituted with one to three R10; and
R10 in each occurrence is independently selected from C1-6 alkyl, halo, —N(R10a)2, —OR10a, —C(O)OR1a, —CN, C3-6 cycloalkyl, and 4- to 7-membered monocyclic non-aromatic heterocyclyl, wherein said C1-6 alkyl, C3-6 cyloalkyl, and 4- to 7-membered monocyclic non-aromatic heterocyclyl are optionally substituted with one to three 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)2RR10a, —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; and
R10a in each occurrence is independently H or C1-4 alkyl.

### Claim 12 (depends on 1)

The compound of claim 1, wherein:
R1 in each occurrence is independently selected from C1-6 alkyl; C2-6 alkenyl; C2-6 alkynyl; C3-6 cycloalkyl selected from cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl; 4- to 7-membered monocyclic heterocyclyl selected from azetidinyl, pyrrolidinyl, tetrahydrofuranyl, thiolanyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, oxetanyl, isothiazolidinyl, dioxolanyl, dithiolanyl, oxathiolanyl, piperidinyl, tetrahydropyranyl, thianyl, piperazinyl, morpholinyl, thiomorpholinyl, dioxanyl, dithianyl, trioxanyl, trithianyl, azepanyl, oxepanyl, thiepanyl, dihydrofuranyl, imidazolinyl, dihydropyranyl, pyrrolyl, furanyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, furazanyl, oxadiazolyl, thiadiazolyl, dithiazolyl, triazolyl, tetrazolyl, pyridinyl, tetrahydropyridinyl, pyranyl, thiopyranyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazinyl, thiazinyl, dioxinyl, dithiinyl, oxathianyl, triazinyl, tetrazinyl, azepinyl, oxepinyl, thiepinyl, diazepinyl, and thiazepinyl; 6- to 8-membered spiro or bridged bicyclic heterocyclyl selected from 3-azabicyclo[3.1.0]hexanyl, 3-azabicyclo[3.1.1]heptanyl, 2-azaspiro[3.3]heptanyl, 2-oxa-6-azaspiro[3.3]heptanyl, 3-oxa-8-azabicyclo[3.2.1]octanyl, 6-oxa-3-azabicyclo[3.1.1]heptanyl, 8-oxa-3-azabicyclo[3.2.1]octanyl, 3-oxa-6-azabicyclo[3.1.1]heptanyl, 5-azaspiro[2.3]hexanyl, and 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazinyl; halo; —CN; —OR1a; —NHR1a; —C(O)R1a; and —S(O)2R1a; wherein said C1-6 alkyl, C2-6alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, 4- to 7-membered monocyclic heterocyclyl, and 6- to 8-membered spiro or bridged bicyclic heterocyclyl are optionally substituted with one to four R10;
R1a in each occurrence is H, C1-6 alkyl or 4- to 7-membered monocyclic heterocyclyl selected from azetidinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, piperidinyl, piperazinyl, morpholinyl, and azepinyl, wherein said C1-6 alkyl or 4- to 7-membered monocyclic heterocyclyl is independently optionally substituted with one to three R10; and
R10 in each occurrence is independently selected from C1-6 alkyl, C3-6 cycloalkyl selected from cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl, oxetanyl, —OR10a, —N(R10a)2, —C(O)OR10a, and halo, wherein C1-6 alkyl and C3-6 cycloalkyl are optionally substituted with one to three substituents independently selected from halo and —N(R10a)2; and
R10a is H or C1-4 alkyl.

### Claim 13 (depends on 1)

The compound of claim 1, wherein:
n is 1;
R1 is C1-4 alkyl, C2-4 alkynyl, C3-6 cycloalkyl selected from cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl, heterocyclyl selected from azetidinyl, piperidinyl, oxetanyl, piperazinyl, morpholinyl, imidazolyl, pyrazolyl, tetrahydropyridinyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, and 6-oxa-3-azabicyclo[3.1.1]heptanyl, halo, —CN, —OR10a, and —S(O)2R1a, wherein said C1-4 alkyl, C2-4 alkynyl, C3-6 cycloalkyl and heterocyclyl is optionally substituted with one to three R10;
R1a is H or C1-4 alkyl optionally substituted with one to three R10;
R10 in each occurrence is independently selected from C1-3 alkyl, C3-6 cycloalkyl, —OR10a, —C(O2)R10a, —N(R10a)2, and halo, wherein said C1-3 alkyl and C3-6 cycloalkyl are optionally substituted with one to three substituents independently selected from halo and —N(R10a)2, and R10a is H or C1-4 alkyl.

### Claim 14 (depends on 1)

The compound of claim 1, wherein:
n is 1;
R1 is selected from —CF3, —C≡CH, cyclopropyl, —C(CH3)2OH, —C(CH3)2OCH3, heterocyclyl selected from azetidinyl, piperidinyl, oxetanyl, piperazinyl, morpholinyl, imidazolyl, pyrazolyl, tetrahydropyridinyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, 6-oxa-3-azabicyclo[3.1.1]heptanyl, —Br, —CN, —OR1a and —S(O)2R1a, wherein said heterocyclyl is optionally substituted with one to three R10 and said —CCH is optionally substituted one R10;
R1a in each occurrence is —CH3 or —CH2CH2N(CH3)2; and
R10 in each occurrence is independently selected from —CH3, —CF3, cyclopropyl, —CH2CH2N(CH3)2, and —F.

### Claim 15 (depends on 1)

The compound of claim 1, wherein the compound is represented by the Formula (III):
or a pharmaceutically acceptable salt thereof, wherein:
n is 0 or 1;
R1 is —CN or heterocyclyl selected from imidazolyl, azetidinyl, piperazinyl and oxetanyl, wherein said heterocyclyl is optionally substituted with one or two R10; and
R10 in each occurrence is independently C1-4 alkyl or C3-6 cycloalkyl.

### Claim 16 (depends on 15)

The compound of claim 15, wherein R1 is —CN, or heterocyclyl selected from the following:
wherein R10 in each occurrence is independently C1-4 alkyl or C3-6 cycloalkyl.

### Claim 17 (depends on 16)

The compound of claim 16, wherein R10 is —CH3 or cyclopropyl.

### 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 an autoimmune disorder.

### Claim 21 (depends on 20)

The method of claim 20, wherein the autoimmune disorder is multiple sclerosis.