# US 2018/0022708 A1 · Processes for preparing ask1 inhibitors

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- Number: US 2018/0022708 A1
- Document ID: US20180022708A1
- Status: Published application
- Kind: A1
- Application number: 15/680,024
- Filed: 2017-08-17
- Published: 2018-01-25
- Earliest claimed: 2014-12-23
- Assignees: Gilead Sciences, Inc.
- Applicants: Gilead Sciences, Inc.
- Inventors: Brandon Heath Brown; Troy Reynolds
- Web page: https://patentgrep.com/patent/US20180022708A1

## CPC

- C07D 233/64: with substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine
- A61P 1/16: for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
- A61P 3/00: Drugs for disorders of the metabolism (of the blood or the extracellular fluid A61P7/00)
- A61P 3/10: for hyperglycaemia, e.g. antidiabetics
- A61P 9/00: Drugs for disorders of the cardiovascular system
- A61P 9/12: Antihypertensives
- A61P 11/00: Drugs for disorders of the respiratory system
- A61P 13/12: of the kidneys
- A61P 25/00: Drugs for disorders of the nervous system
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A61P 37/06: Immunosuppressants, e.g. drugs for graft rejection
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07D 233/56: with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
- C07D 401/14: containing three or more hetero rings
- C07B 2200/13: Crystalline forms, e.g. polymorphs
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C07B: GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR (preparation of carboxylic acid esters by telomerisation C07C67/47; telomerisation C08F)

## Abstract

The present disclosure provides processes for the preparation of a compound of formula: which exhibits apoptosis signal-regulating kinase (“ASK1”) inhibitory activity and is thus useful in the treatment of diseases such as kidney disease, diabetic nephropathy and kidney fibrosis. The disclosure also provides compounds that are synthetic intermediates.

## Claims

### Claim 1

A method for preparing a compound of formula (A):
or a salt or solvate thereof,
comprising the steps of:
(a) carboxylating a compound of formula (E) or a salt thereof:
under reaction conditions sufficient to form a compound of formula (D) or a hydrate, solvate, or salt thereof:
(b) chlorinating a compound of formula (D) or a hydrate, solvate or salt thereof under reaction conditions sufficient to form a compound of formula (B) or a salt thereof:
and
(c) contacting a compound of formula (B) or a salt thereof with a compound of formula (C) or a salt thereof:
under reaction conditions sufficient to yield a compound of formula (A).

### Claim 2 (depends on 1)

The method of claim 1, wherein the reaction conditions of step (a) comprise a base.

### Claim 3 (depends on 1)

The method of claim 1, wherein the reaction conditions of step (a) comprise a solvent selected from the group consisting of tetrahydrofuran, 2-methyltetrahydrofuran, methyl-tert-butyl ether, and diethyl ether.

### Claim 4 (depends on 1)

The method of claim 1, wherein the reaction conditions of step (a) comprise a first temperature of about −20° C. to about 40° C. and a second temperature of about −10° C. to about 50° C.

### Claim 5 (depends on 1)

The method of claim 1, wherein the reaction conditions of step (b) comprise a chlorinating reagent.

### Claim 6 (depends on 1)

The method of claim 1, wherein the reaction conditions of step (b) comprise a solvent selected from the group consisting of dichloromethane, acetonitrile, tetrahydrofuran, methyl-tert-butyl ether, and chloroform.

### Claim 7 (depends on 1)

The method of claim 1, wherein the reaction conditions of step (b) comprise a temperature of about −20° C. to about 40° C.

### Claim 8 (depends on 1)

The method of claim 1, wherein the reaction conditions of step (c) comprise an organic base.

### Claim 9 (depends on 1)

The method of claim 1, wherein the reaction conditions of step (c) comprise a solvent selected from the group consisting of dichloromethane, dichloroethane, acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran, toluene, methyl-tert-butyl ether, and chloroform.

### Claim 10 (depends on 1)

The method of claim 1, wherein the reaction conditions of step (c) comprise a temperature of about 0° C. to about 40° C.

### Claim at position 11

-152. (canceled)