Substituted pyrimidinyl and pyridinyl-pyrrolopyridinones, process for their preparation and their use as kinase inhibitors

Patent metadata

Field	Value
Publication number	US-9604980-B2
Application number	US-201314647940-A
Country	US
Kind code	B2
Filing date	Oct 31, 2013
Priority date	Nov 7, 2012
Publication date	Mar 28, 2017
Grant date	Mar 28, 2017

Abstract

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

First claim

The invention claimed is:

1. A compound of formula (I),

wherein
X is CH or N;
R 1 is H or NHR 3 , wherein R 3 is H, an optionally substituted group selected from straight or branched C 1 -C 6 alkyl, heterocyclyl and COR′, wherein R′ is an optionally substituted group selected from straight or branched C 1 -C 6 alkyl, a C 3 -C 6 carbocyclyl, aryl and heteroaryl;
L 1 is CH 2 —CH 2 , CH═CH or C≡C;
Q is an optionally substituted group selected from aryl and heteroaryl;
L 2 is C(RaRb)NRa, C(RaRb)C(RaRb)NRa, C(RaRb)NRaC(RaRb), NRaC(RaRb), NRaC(RaRb)C(RaRb), COO, C(RaRb)COO, C(RaRb)C(RaRb)COO, SO 2 NRa, C(RaRb)SO 2 NRa, CONRa, C(RaRb)CONRa, C(RaRb)C(RaRb)CONRa, CONRaC(RaRb), CONRaC(RaRb)C(RaRb), C(RaRb)NRaCO, C(RaRb)C(RaRb)NRaCO, NRaCOC(RaRb),NRaCOC(RaRb)C(RaRb), OC(RaRb)CONRa, C(RaRb)OC(RaRb), OC(RaRb)(C(RaRb))nC(RaRb),

wherein Ra and Rb are independently H or an optionally substituted straight or branched C 1 -C 6 alkyl and n is 0 or 1;
T is H or an optionally substituted group selected from straight or branched C 1 -C 6 alkyl, C 3 -C 6 carbocyclyl, heterocyclyl, aryl and heteroaryl;
R 2 is H or an optionally substituted group selected from straight or branched C 1 -C 6 alkyl, C 3 -C 6 carbocyclyl, heterocyclyl, aryl and heteroaryl;
or pharmaceutically acceptable salts thereof.

2. A compound of formula (I), according to claim 1 , wherein
R 1 is H or NHR 3 , wherein R 3 is H, an optionally substituted group selected from straight or branched C 1 -C 3 alkyl, heterocyclyl and COR′;
L 1 is C≡C;
Q is an optionally substituted group selected from aryl and heteroaryl, wherein the heteroaryl is monocyclic or bicyclic, and said bicyclic heteroaryl contains a nitrogen atom which the L 2 group is attached to.

3. A compound of formula (I), according to claim 1 , wherein Q is an optionally substituted aryl or heteroaryl selected from:

wherein Rc is selected from methyl and halogen;
L 2 is CONRa, C(RaRb)CONRa, C(RaRb)C(RaRb)CONRa, CONRaC(RaRb), OC(RaRb)CONRa, SO 2 NRa or C(RaRb)SO 2 NRa, wherein Ra and Rb are both hydrogen;
T is a substituted aryl of formula J:

wherein
Rd is halogen, optionally substituted straight or branched C 1 -C 4 alkyl, C 3 -C 6 cycloalkyl or trifluoromethyl;
L 3 is direct linkage, O, NH, NCH 3 , CH 2 , CH 2 NH, CH 2 NCH 3 or C═O;
Re is
an optionally substituted heterocyclyl or
an optionally substituted straight or branched C 1 -C 6 alkyl chain, wherein from 1 to 3 carbon atoms of said alkyl may be substituted independently by N or O, or
NRfRg, wherein Rf and Rg are each independently hydrogen or an optionally substituted straight or branched C 1 -C 6 alkyl chain, wherein from 1 to 3 carbon atoms of said alkyl may be substituted independently by N or O, or Rf and Rg joined together with the nitrogen atom might represent a heterocyclic ring.

4. A compound of formula (I), according to claim 1 , wherein L 2 is C(RaRb)NRaC(RaRb), C(RaRb)OC(RaRb), and OC(RaRb)(C(RaRb))nC(RaRb), wherein Ra and Rb are both hydrogen and n is 0 or 1.

5. A compound or a pharmaceutically acceptable salt thereof according to claim 1 , which is selected from the group consisting of:
6-[2-Amino-4-(1-methyl-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridin-2-yl)-pyrimidin-5-ylethynyl]-2,3-dihydro-indole-1-carboxylic acid [4-(4-ethyl-piperazin-1-ylmethyl)-3-trifluoromethyl-phenyl]-amide (Cmpd 44),
5-[2-Amino-4-(1-methyl-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridin-2-yl)-pyrimidin-5-ylethynyl]-2,3-dihydro-indole-1-carboxylic acid [4-(4-ethyl-piperazin-1-ylmethyl)-3-trifluoromethyl-phenyl]-amide (Cmpd 45),
3-[2-Amino-4-(1-methyl-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridin-2-yl)-pyrimidin-5-ylethynyl]-N-[4-(4-ethyl-piperazin-1-ylmethyl)-3-trifluoromethyl-phenyl]-benzamide (Cmpd 48),
N-[4-(4-Ethyl-piperazin-1-ylmethyl)-3-trifluoromethyl-phenyl]-3-[2-methylamino-4-(1-methyl-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridin-2-yl)-pyrimidin-5-ylethynyl]-benzamide (Cmpd 49),
3-[2-Amino-4-(1-methyl-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridin-2-yl)-pyrimidin-5-ylethynyl]-N-[4-(4-ethyl-piperazin-1-ylmethyl)-3-trifluoromethyl-phenyl]-4-methyl-benzamide (Cmpd 50),
5-[2-Amino-4-(1-methyl-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridin-2-yl)-pyrimidin-5-ylethynyl]-thiophene-2-carboxylic acid [4-(4-ethyl-piperazin-1-ylmethyl)-3-trifluoromethyl-phenyl]-amide (Cmpd 51),
2-[2-Amino-4-(1-methyl-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridin-2-yl)-pyrimidin-5-ylethynyl]-thiazole-5-carboxylic acid [4-(4-ethyl-piperazin-1-ylmethyl)-3-trifluoromethyl-phenyl]-amide (Cmpd 52),
N-{3-[2-Amino-4-(1-methyl-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridin-2-yl)-pyrimidin-5-ylethynyl]-phenyl}-4-trifluoromethyl-benzamide (Cmpd 57),
N-{3-[2-Amino-4-(1-methyl-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridin-2-yl)-pyrimidin-5-ylethynyl]-phenyl}-2-(4-trifluoromethyl-phenyl)-acetamide (Cmpd 58),
2-{3-[2-Amino-4-(1-methyl-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridin-2-yl)-pyrimidin-5-ylethynyl]-phenoxy}-N-phenyl-acetamide hydrochloride (Cmpd 59),
N-{3-[2-Amino-4-(1-methyl-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridin-2-yl)-pyrimidin-5-ylethynyl]-phenyl}-3-(3-trifluoromethyl-phenyl)-propionamide hydrochloride (Cmpd 73),
3-[2-Amino-4-(1-methyl-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridin-2-yl)-pyrimidin-5-ylethynyl]-N-(3-trifluoromethyl-benzyl)-benzamide hydrochloride (Cmpd 74),
2-{3-[2-Amino-4-(1-methyl-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridin-2-yl)-pyrimidin-5-ylethynyl]-phenyl}-N-[4-(4-ethyl-piperazin-1-ylmethyl)-3-trifluoromethyl-phenyl]-acetamide (Cmpd 77),
N-[4-(4-Ethyl-piperazin-1-ylmethyl)-3-trifluoromethyl-phenyl]-2-{3-[2-methylamino-4-(1-methyl-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridin-2-yl)-pyrimidin-5-ylethynyl]-phenyl}-acetamide (Cmpd 78),
2-{3-[2-Amino-4-(1-methyl-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridin-2-yl)-pyrimidin-5-ylethynyl]-phenyl}-N-[3-(4-ethyl-piperazin-1-ylmethyl)-4-trifluoromethyl-phenyl]-acetamide (Cmpd 82),
2-{3-[2-Amino-4-(1-methyl-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridin-2-yl)-pyrimidin-5-ylethynyl]-phenyl}-N-indan-5-yl-acetamide (Cmpd 100),
2-{3-[2-Amino-4-(1-methyl-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridin-2-yl)-pyrimidin-5-ylethynyl]-phenyl}-N-benzothiazol-6-yl-acetamide (Cmpd 102),
2-{3-[2-Amino-4-(1-methyl-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridin-2-yl)-pyrimidin-5-ylethynyl]-phenyl}-N-(5-tert-butyl-2-methyl-2H-pyrazol-3-yl)-acetamide (Cmpd 105),
2-{3-[2-Amino-4-(1-methyl-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridin-2-yl)-pyrimidin-5-ylethynyl]-phenyl}-N-quinolin-3-yl-acetamide (Cmpd 106),
2-{3-[2-Amino-4-(1-methyl-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridin-2-yl)-pyrimidin-5-ylethynyl]-phenyl}-N-(3-trifluoromethyl-benzyl)-acetamide (Cmpd 111),
2-{3-[2-Amino-4-(1-methyl-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridin-2-yl)-pyrimidin-5-ylethynyl]-phenyl}-N-[4-(4-ethyl-piperazin-1-ylmethyl)-3-fluoro-phenyl]-acetamide (Cmpd 120),
2-{5-[2-Amino-4-(1-methyl-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridin-2-yl)-pyrimidin-5-ylethynyl]-pyridin-3-yl}-N-[4-(4-ethyl-piperazin-1-ylmethyl)-3-trifluoromethyl-phenyl]-acetamide (Cmpd 122),
2-{4-[2-Amino-4-(1-methyl-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridin-2-yl

Assignees

• Nerviano Medical Sciences Srl
• Nerviano Medical Sciences Srl

Inventors

• Menichincheri Maria
• Angiolini Mauro
• Bertrand Jay Aaron
• Caruso Michele
• Polucci Paolo
• Quartieri Francesca
• Salom Barbara
• Salsa Matteo
• Zuccotto Fabio

Classifications

• A61P35/00

  Antineoplastic agents · 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

• A61P31/12

  Antivirals · CPC title

• A61P35/02

  specific for leukemia · CPC title

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title