# US 10,766,899 B2 · Methods for preparing substituted imidazo[4,5-b]pyrazines

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- Number: US 10,766,899 B2
- Document ID: US10766899B2
- Status: Granted
- Kind: B2
- Application number: 14/246,230
- Filed: 2014-04-07
- Published: 2014-10-09
- Granted: 2020-09-08
- Earliest claimed: 2006-08-02
- Assignees: Cytokinetics, Inc.
- Applicants: Cytokinetics, Inc.
- Inventors: Bradley P. Morgan; David J. Morgans, Jr.; Alex Muci
- Web page: https://patentgrep.com/patent/US10766899B2

## CPC

- C07D 487/04: Ortho-condensed systems
- A61P 21/00: Drugs for disorders of the muscular or neuromuscular system
- A61P 21/04: for myasthenia gravis
- A61P 25/00: Drugs for disorders of the nervous system
- 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 methods of preparing compounds of Formula 201:

## Claims

### Claim 1

A method of producing a compound of Formula 201:
wherein:
R1 is selected from halogen, mesyloxy, p-nitrobenzenesulfonyloxy and tosyloxy;
R4 is hydrogen; and
R2 is selected from pentan-3-yl, heptan-4-yl, 4-methyl-1-morpholinopentan-2-yl, isobutyl, cyclohexyl, cyclopropyl, sec-butyl, tert-butyl, isopropyl, 1-hydroxybutan-2-yl, tetrahydro-2H-pyran-4-yl, 1-methoxybutan-2-yl, 1-aminobutan-2-yl and 1-morpholinobutan-2-yl;
the method comprising:
(a) treating a compound of Formula 101:
wherein X is halogen;
with an amine of formula R2—NH2 in a suitable solvent to produce a compound of Formula 102:
and
(b) treating the compound of Formula 102 with a di-activated carbonyl equivalent selected from carbonyl diimidazole, phosgene and triphosgene in a suitable solvent to produce the compound of Formula 201.

### Claim 2 (depends on 1)

The method of claim 1, wherein R1 is halogen.

### Claim 3 (depends on 2)

The method of claim 2, wherein R1 is bromo.

### Claim 4 (depends on 3)

The method of claim 3, wherein R2 is pentan-3-yl.

### Claim 5 (depends on 3)

The method of claim 3, wherein X is bromo.

### Claim 6 (depends on 1)

The method of claim 1, wherein R1 is mesyloxy.

### Claim 7 (depends on 1)

The method of claim 1, wherein R1 is p-nitrobenzenesulfonyloxy.

### Claim 8 (depends on 1)

The method of claim 1, wherein R1 is tosyloxy.

### Claim 9 (depends on 1)

The method of claim 1, wherein R2 is pentan-3-yl.

### Claim 10 (depends on 1)

The method of claim 1, wherein R2 is isobutyl.

### Claim 11 (depends on 1)

The method of claim 1, wherein R2 is cyclopropyl.

### Claim 12 (depends on 1)

The method of claim 1, wherein R2 is cyclohexyl.

### Claim 13 (depends on 1)

The method of claim 1, wherein X is bromo.

### Claim 14 (depends on 1)

The method of claim 1, wherein the amine of formula R2-NH2 is present in excess of the compound of Formula 101.

### Claim 15 (depends on 14)

The method of claim 14, wherein R2 is pentan-3-yl.

### Claim 16 (depends on 14)

The method of claim 14, wherein the amine of formula R2-NH2 is present in about 2-fold to about 20-fold excess of the compound of Formula 101.

### Claim 17 (depends on 14)

The method of claim 14, wherein the mixture of the compound of Formula 101 and the amine of formula R2-NH2 is heated.

### Claim 18 (depends on 17)

The method of claim 17, wherein R2 is pentan-3-yl.

### Claim 19 (depends on 17)

The method of claim 17, wherein the mixture of the compound of Formula 101 and the amine of formula R2-NH2 is heated to 110° C. to 190° C.

### Claim 20 (depends on 17)

The method of claim 17, wherein the mixture of the compound of Formula 101 and the amine of formula R2-NH2 is heated to 110° C. to 190° C. with microwave irradiation.

### Claim 21 (depends on 17)

The method of claim 17, wherein the mixture of the compound of Formula 101 and the amine of formula R2-NH2 is heated to 110° C. to 190° C. over 20 to 40 minutes.

### Claim 22 (depends on 17)

The method of claim 17, wherein the mixture of the compound of Formula 101 and the amine of formula R2-NH2 is heated to 110° C. to 190° C. over 20 to 40 minutes, with microwave irradiation.

### Claim 23 (depends on 1)

The method of claim 1, wherein the compound of Formula 102 is isolated.

### Claim 24 (depends on 23)

The method of claim 23, wherein the compound of Formula 102 is purified.

### Claim 25 (depends on 1)

The method of claim 1, wherein the di-activated carbonyl equivalent is carbonyl diimidazole.

### Claim 26 (depends on 1)

The method of claim 1, wherein the di-activated carbonyl equivalent is carbonyl diimidazole.

### Claim 27 (depends on 1)

The method of claim 1, wherein the di-activated carbonyl equivalent is triphosgene.

### Claim 28 (depends on 1)

The method of claim 1, wherein the compound of Formula 201 is isolated.

### Claim 29 (depends on 28)

The method of claim 28, wherein the compound of Formula 201 is purified.