Substituted pyrroles active as kinases inhibitors

Patent metadata

Field	Value
Publication number	US-10479779-B2
Application number	US-201816055396-A
Country	US
Kind code	B2
Filing date	Aug 6, 2018
Priority date	Aug 2, 2012
Publication date	Nov 19, 2019
Grant date	Nov 19, 2019

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 method for treating a disease selected from the group consisting of acute megakaryoblastic leukemia; transplant rejection, rheumatoid arthritis, psoriasis, Crohn's disease, ulcerative colitis, atopic dermatitis, solid tumors, myelofibrosis, myeloproliferative disorders, Polycythemia Vera (PV), Essential Thrombocythemia (ET), acute myeloid leukemia (AML), chronic myelogenous leukemia (CML), and acute lymphoblastic leukemia (ALL), the method comprising administering to a mammal in need thereof an effective amount of 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.

2. The method according to claim 1 wherein the mammal in need thereof is a human.

3. The method according to claim 1 provides tumor angiogenesis and metastasis inhibition.

4. The method according to claim 1 further comprising subjecting the mammal in need thereof to a radiation therapy or chemotherapy regimen in combination with at least one cytostatic or cytotoxic agent.

5. An in vitro method for inhibiting the JAK family kinase protein activity which comprises contacting the said protein with an effective amount of 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.

Assignees

• Nerviano Medical Sciences Srl

Inventors

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

Classifications

• C07D487/04

  Ortho-condensed systems · CPC title

• A61P19/02

  for joint disorders, e.g. arthritis, arthrosis · CPC title

• C07D403/04 Primary

  directly linked by a ring-member-to-ring-member bond · CPC title

• A61P35/04

  specific for metastasis · CPC title

• C07D473/00

  Heterocyclic compounds containing purine ring systems · CPC title