Synthesis of heterocyclic compounds

Patent metadata

Field	Value
Publication number	US-9994567-B2
Application number	US-201715705097-A
Country	US
Kind code	B2
Filing date	Sep 14, 2017
Priority date	May 22, 2015
Publication date	Jun 12, 2018
Grant date	Jun 12, 2018

Abstract

Provided herein are intermediates and processes useful for facile synthesis of compounds of formula (I):

or a pharmaceutically acceptable salt, a solvate, a tautomer, an isomer or a deuterated analog thereof, wherein Q, P 1 and P 2 are as defined in this disclosure.

First claim

What is claimed is:

1. A method for preparing a compound of formula (I):

or a pharmaceutically acceptable salt, a solvate or a tautomer thereof, said method comprising:
contacting a compound of formula (Ia):

with L 2 -P 1 under conditions sufficient to form the compound of formula (I), wherein:
Q is F or H;
P 2 is —C(O)—R 3 or —C(O)—OR 4 ;
P 1 is

R 1 is H or halogen;
n is 0, 1 or 2;
m is 1 or 2;
R 3 is C 1-6 alkyl, aryl, heteroaryl, aryl-C 1-2 alkyl, heteroaryl-C 1-2 alkyl, C 3-10 cycloalkyl, C 3-10 cycloalkyl-C 1-2 alkyl, ethynyl or vinyl, each of which is optionally substituted with 1-3 R a groups;
R 4 is C 1-6 alkyl, aryl, heteroaryl, aryl-C 1-2 alkyl, heteroaryl-C 1-2 alkyl, C 3-10 cycloalkyl, C 3-10 cycloalkyl-C 1-2 alkyl, ethynyl or vinyl, each of which is optionally substituted with 1-3 R a groups;
L 2 is Br, Cl, I, tosyl-O—, mesyl-O—, trifluoromethanesulfonyl-O—, —C(O)—O—CF 3 or —C(O)—O—CH 3 ; and
each R a group is independently halogen, C 1-6 alkyl, fluoro substituted C 1-6 alkyl, fluoro substituted C 1-6 alkoxy, aryl, heteroaryl, C 1-6 alkoxy, —CN, —NO 2 , —OH, —C(O)—O—C 1-6 alkyl, or —SiMe 3 , wherein the aliphatic or aromatic portion of R a is further optionally substituted with from 1-3 R b groups, wherein each R b group is independently halogen, C 1-6 alkyl, C 1-6 alkoxy, —CN, —NO 2 or —OH.

2. The method of claim 1 , wherein the contacting of L 2 -P 1 with the compound of formula (Ia) is carried out in pyridine and a solvent selected from the group consisting of dichloromethane, tetrahydrofuran, acetonitrile, toluene, dioxane, 2-methyl-tetrahydrofuran, and a mixture thereof.

3. The method of claim 1 , wherein L 2 is Br.

4. The method of claim 3 , wherein P 2 is —C(O)—R 3 and R 3 is 2,6-dichlorophenyl.

5. The method of claim 4 , wherein Q is F.

6. The method of claim 5 , wherein P 1 is:

7. The method of claim 1 , wherein L 2 is Br, P 2 is —C(O)—R 3 , R 3 is 2,6-dichlorophenyl, Q is F, and P 1 is

Assignees

• Plexxikon Inc

Inventors

• Ibrahim Prabha N
• Lin Jack
• Spevak Wayne
• Zhang Jiazhong

Classifications

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title

• A61P9/10

  for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis · CPC title

• A61P35/04

  specific for metastasis · CPC title

• A61P9/04

  Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure · CPC title

• A61P37/06

  Immunosuppressants, e.g. drugs for graft rejection · CPC title