Substituted pyrroles active as kinases inhibitors

Patent metadata

Field	Value
Publication number	US-10071986-B2
Application number	US-201715598976-A
Country	US
Kind code	B2
Filing date	May 18, 2017
Priority date	Aug 2, 2012
Publication date	Sep 11, 2018
Grant date	Sep 11, 2018

Abstract

The present invention relates to substituted pyrrole compounds which modulate the activity of protein kinases and are therefore useful in treating diseases caused by dysregulated protein kinase activity, in particular Jak family kinases. The present invention also provides methods for preparing these compounds, pharmaceutical compositions comprising these compounds, and methods of treating diseases utilizing such compounds or the pharmaceutical compositions containing them.

First claim

The invention claimed is:

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

wherein:
Ring W is a pyrrole;
R1 is a substituted aryl;
R2 is CONR6R7 wherein R6 and R7 are independently hydrogen or an optionally substituted group selected from straight or branched C 1 -C 6 alkyl, straight or branched C 2 -C 6 alkenyl, straight or branched C 2 -C 6 alkynyl, C 3 -C 7 cycloalkyl, cycloalkyl-alkyl, aryl, aryl-alkyl, heteroaryl, heteroaryl-alkyl, heterocyclyl and heterocyclyl-alkyl, or R6 and R7, taken together with the nitrogen atom to which they are bonded, may form an optionally substituted 5 to 7 membered heterocyclyl group optionally containing one additional heteroatom selected from N, O and S;
R3 is hydrogen, halo or an optionally substituted group selected from straight or branched C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, cycloalkyl-alkyl, heterocyclyl and heterocyclyl-alkyl;
R4 is an optionally substituted group

wherein:
R8 is hydrogen or an optionally substituted group selected from straight or branched C 1 -C 6 alkyl, straight or branched C 2 -C 6 alkenyl, straight or branched C 2 -C 6 alkynyl, C 3 -C 7 cycloalkyl, cycloalkyl-alkyl, aryl, aryl-alkyl, heteroaryl, heteroaryl-alkyl, heterocyclyl and heterocyclyl-alkyl, COR9, CONR10R11 and SO 2 R12,
wherein:
R9 is a group optionally substituted selected from straight or branched C 1 -C 6 alkyl, straight or branched C 2 -C 6 alkenyl, straight or branched C 2 -C 6 alkynyl, C 3 -C 7 cycloalkyl, cycloalkyl-alkyl, aryl, aryl-alkyl, heteroaryl, heteroaryl-alkyl, heterocyclyl and heterocyclyl-alkyl;
R10 and R11 are independently hydrogen or an optionally substituted group selected from straight or branched C 1 -C 6 alkyl, straight or branched C 2 -C 6 alkenyl, straight or branched C 2 -C 6 alkynyl, C 3 -C 7 cycloalkyl, cycloalkyl-alkyl, aryl, aryl-alkyl, heteroaryl, heteroaryl-alkyl, heterocyclyl and heterocyclyl-alkyl, or R10 and R11, taken together with the nitrogen atom to which they are bonded, may form an optionally substituted 5 to 7 membered heterocyclyl group optionally containing one additional heteroatom selected from N, O and S;
R12 is a group optionally substituted selected from straight or branched C 1 -C 6 alkyl, straight or branched C 2 -C 6 alkenyl, straight or branched C 2 -C 6 alkynyl, C 3 -C 7 cycloalkyl, cycloalkyl-alkyl, aryl, aryl-alkyl, heteroaryl, heteroaryl-alkyl, heterocyclyl and heterocyclyl-alkyl;

R5 is hydrogen, halo or an optionally substituted group selected from straight or branched C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, cycloalkyl-alkyl, heterocyclyl and heterocyclyl-alkyl;
or the pharmaceutically acceptable salts thereof,
said process comprising:
Step 1: reaction of a compound of formula (II)

wherein R1 and R3 are as defined above and PG is a protecting group selected from benzenesulfonyl with 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxyborolane;
alternatively:
Step 1a: reaction of a compound of formula (III)

wherein each of R1 and R3 are as defined above, X is halogen, and PG is a protecting group selected from the group consisting of 2-(trimethylsilyl)ethoxymethyl or tert-butyloxycarbonyl,
with 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxyborolane;
Step 2: metal-catalyzed coupling reaction of the resultant compound of formula (IV)

wherein each of R1 and R3 are as defined above and PG is a protecting group selected from the group consisting of 2-(trimethylsilyl)ethoxymethyl, tert-butyloxycarbonyl, benzenesulfonyl with a compound of formula (V)
R4-X  (V)

wherein R4 is as defined above and X is halogen;
Step 3: deprotection of the resultant compound of formula (VI)

wherein each of R1, R3 and R4 are as defined above and PG is a protecting group selected from the group consisting of 2-(trimethylsilyl)ethoxymethyl, tert-butyloxycarbonyl or benzenesulfonyl to give a compound of formula (Ia)

wherein each of R1, R3 and R4 are as defined above, R2 is CN and R5 is hydrogen;
alternatively
Step 4: reaction of a compound of formula (VII)

wherein R1 and R3 are as defined above and PG is a protecting group selected from the group consisting of benzenesulfonyl with 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxyborolane;
Step 5: metal-catalyzed coupling reaction of the resultant compound of formula (VIII)

wherein R1 and R3 are as defined above and PG is a protecting group selected from benzenesulfonyl with a compound of formula (V), as defined above;
Step 6: hydrolysis under basic conditions of the resultant carboxylic ester of formula (IX)

wherein each of R1, R3 and R4 and PG are as defined above;
Step 7: amidation of the resultant carboxylic acid of formula (X)

wherein each of R1, R3 and R4 are as defined above, through reaction with a compound of formula (XI)
NHR6R7  (XI)

wherein R6 and R7 are as defined above, to give a compound of formula (Ia)

wherein R2 is CONR6R7, R5 is hydrogen, and wherein each of R1, R3, R4, R6 and R7 are as defined above;
alternatively
Step 11: reaction of a compound of formula (XV)

wherein R1 and R5 are as defined above and PG is a protecting group selected from benzenesulfonyl with 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxyborolane;
Step 12: metal-catalyzed coupling reaction of the resultant compound of formula (XVI)

wherein R1 and R5 are as defined above and PG is a protecting group selected from benzenesulfonyl with a compound of formula (V), as defined above;
Step 13: hydrolysis under basic conditions of the resultant carboxylic ester of formula (XVII)

wherein R1, R4 and R5 are as defined above and PG is a protecting group;
Step 14: amidation of the resultant carboxylic acid of formula (XVIII)

wherein R1, R4 and R5 are as defined above, through reaction with a compound of formula (XI), as defined above, to give a compound of formula (Id)

wherein R1, R2,

Assignees

• Nerviano Medical Sciences Srl

Inventors

• Brasca Maria Gabriella
• Bindi Simona
• Caldarelli Marina
• Nesi Marcella
• Orrenius Sten Christian
• Panzeri Achille

Classifications

• C07F5/04

  Esters of boric acids · CPC title

• A61P37/06

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

• A61K45/06

  Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca · CPC title

• C07D473/00

  Heterocyclic compounds containing purine ring systems · CPC title

• A61K31/519

  ortho- or peri-condensed with heterocyclic rings · CPC title