Process for the preparation of kinase inhibitors and intermediates thereof

Patent metadata

Field	Value
Publication number	US-10550087-B2
Application number	US-201515776762-A
Country	US
Kind code	B2
Filing date	Nov 17, 2015
Priority date	Nov 17, 2015
Publication date	Feb 4, 2020
Grant date	Feb 4, 2020

Abstract

Described are processes for the synthesis of certain compounds, useful for treating diseases, e.g. eye disease, such as glaucoma and ocular hypertension, in a subject.

First claim

What is claimed is:

1. A method for the synthesis of a compound of Formula (I):

or a pharmaceutically acceptable salt thereof; wherein A is cyclohexyl or phenyl, substituted with 0-3 substituents independently selected from alkyl, halogen, alkoxy, or cyano;

the method comprising
(a) reacting a compound of Formula (II), wherein PG is a nitrogen protecting group,

with 6-aminoisoquinoline to form a compound of Formula (III)

wherein A is cyclohexyl or phenyl, substituted with 0-3 substituents independently selected from alkyl, halogen, alkoxy, or cyano; and
(b) removing the nitrogen protecting group to form the compound of Formula (I);

further comprising:
(c) reacting a compound of Formula (IV),

wherein A is cyclohexyl or phenyl, substituted with 0-3 substituents independently selected from alkyl, halogen, alkoxy, or cyano; and T is a chiral auxiliary; with

wherein PG is a nitrogen protecting group;

to form a compound of Formula (V):

wherein A is cyclohexyl or phenyl, substituted with 0-3 substituents independently selected from alkyl, halogen, alkoxy, or cyano; and T is a chiral auxiliary; and
(d) removing the chiral auxiliary to form the compound of Formula (II).

2. The method of claim 1 , further comprising converting a compound of Formula (VIII):

wherein A is cyclohexyl or phenyl, substituted with 0-3 substituents independently selected from alkyl, halogen, alkoxy, or cyano; and R 1 is halogen, OR a , OC(O)R b , SR a , or SC(O)R b ; wherein R a is H, alkyl or aryl, and R b is alkyl or aryl;
to the compound of Formula (IV):

wherein A is cyclohexyl or phenyl, substituted with 0-3 substituents independently selected from alkyl, halogen, alkoxy, or cyano; and T is a chiral auxiliary.

3. The method of claim 2 , wherein the compound of Formula (II) is synthesized by a method comprising:
(a) reacting

with a compound of Formula (VI),

wherein A is cyclohexyl or phenyl, substituted with 0-3 substituents independently selected from alkyl, halogen, alkoxy, or cyano;
to form a compound of formula (VII-a),

wherein A is cyclohexyl or phenyl, substituted with 0-3 substituents independently selected from alkyl, halogen, alkoxy, or cyano; and
(b) converting the compound of Formula (VII) into the compound of Formula (VIII).

4. The method of claim 1 , wherein T is

wherein
Z is S or O;
B is S or O;
R c is hydrogen, C 1-4 alkyl, or aryl; and
R d is C 1-4 alkyl, C 3-7 branched alkyl; arylalkyl or aryl.

5. The method of claim 4 , wherein T is

wherein
Z is S or O;
B is S or O;
R c is hydrogen or aryl; and
R d is C 1-4 alkyl, arylalkyl or aryl.

6. The method of claim 5 , wherein T is selected from:

7. The method of claim 6 , wherein T is

Assignees

• Aerie Pharmaceuticals Inc

Inventors

• Sturdivant Jill Marie
• Delong Mitchell A
• Chambournier Gilles
• Pamment Michael G
• Fedij Victor

Classifications

• C07C271/22

  to carbon atoms of hydrocarbon radicals substituted by carboxyl groups · CPC title

• C07D217/02 Primary

  with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines · CPC title

• C07D277/14

  Oxygen atoms · CPC title

• C07C69/78

  Benzoic acid esters · CPC title

• C07D249/18

  Benzotriazoles · CPC title