Purine and 3-deazapurine analogues as choline kinase inhibitors

Patent metadata

Field	Value
Publication number	US-10683292-B2
Application number	US-201716319951-A
Country	US
Kind code	B2
Filing date	Jul 19, 2017
Priority date	Jul 25, 2016
Publication date	Jun 16, 2020
Grant date	Jun 16, 2020

Abstract

There are provided substituted purine and 3-deazapurine analogues, which modulate the activity of Choline Kinase (ChoK). The compounds of this invention are therefore useful in treating diseases caused by an altered choline metabolism, such as cancer, cell proliferative disorders, infectious diseases of different origin, immune-related disorders and neurodegenerative disorders. The present invention also provides methods for preparing these compounds, pharmaceutical compositions comprising these compounds, and methods of treating diseases utilizing pharmaceutical compositions comprising these compounds.

First claim

The invention claimed is:

1. A compound of formula (I):

wherein:
X is CH or nitrogen;
A is a 6- or 7-membered cycloalkyl or a 6- or 7-membered nitrogen-containing heterocyclyl, or A is a 7- to 9-membered carbon bicyclic system, in which one ring carbon is optionally replaced by nitrogen;
R1 is linked:
either
1) to any A ring carbon, in which case R1 is fluorine, an optionally substituted (C 3 -C 7 )cycloalkyl, —COR6, —COOR4, —CONR4R5, —NR4COOR6, —NR4COR5, —NR4R5, —NR4CONR4R5, —NR4CSNR4R5, or —NR4SO 2 R6;
or
2) to the A ring nitrogen, if present, in which case R1 is an optionally substituted (C 1 -C 6 )alkyl or (C 3 -C 7 )cycloalkyl, —COR5, —COOR6, —CONR4R5, —CSNR4R5, or —SO 2 R6;
wherein:
R4 and R5 are independently hydrogen or an optionally substituted group selected from (C 1 -C 6 )alkyl, (C 3 -C 7 )cycloalkyl, heterocyclyl, aryl, aryl(C 1 -C 6 )alkyl, heteroaryl and heteroaryl(C 1 -C 6 )alkyl; or R4 and R5, taken together with the nitrogen atom to which they are bonded, may form an optionally substituted 5- or 6-membered heterocyclyl group optionally containing one additional heteroatom selected from N, O and S;
R6 is an optionally substituted group selected from (C 1 -C 6 )alkyl, (C 3 -C 7 )cycloalkyl, heterocyclyl, aryl, aryl(C 1 -C 6 )alkyl, heteroaryl and heteroaryl(C 1 -C 6 )alkyl;

n is 0, 1 or 2;
R2 is linked to any A ring atom and is selected from the group consisting of fluorine, an optionally substituted (C 1 -C 6 )alkyl or (C 3 -C 7 )cycloalkyl, and NR4R5;
provided that
when R2 is fluorine or NR4R5, then R2 is linked to a ring carbon;
when n is 2, then the R2 groups are not necessarily the same;

wherein the R1 and R2 groups can be linked to the same ring carbon;
R3 is hydrogen, halogen, cyano or an optionally substituted group selected from (C 1 -C 6 )alkyl, polyfluorinated (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 3 -C 7 )cycloalkyl, heterocyclyl, aryl, heteroaryl, —OR6, —SR6, —SO 2 R6, —NR4R5 or —CONR4R5, wherein R4, R5 and R6 are as defined above;
provided that
when X is nitrogen, then R3 is not hydrogen and not NR4R5, wherein R4 is an optionally substituted aryl and R5 hydrogen; and that and also provided that
when X is nitrogen, then R1 and R2 may be optionally substituted by one or more groups but not hydroxy and hydroxy(C 1 -C 6 )alkyl groups;

or a pharmaceutically acceptable salt thereof.

2. A compound or pharmaceutically acceptable salt according to claim 1 , wherein:
X is CH or nitrogen;
A is a 6- or 7-membered cycloalkyl or a 6- or 7-membered nitrogen-containing heterocyclyl, or A is a 7- to 9-membered carbon bicyclic system, in which one ring carbon is optionally replaced by a nitrogen;
R1 is linked:
either
1) to any A ring carbon, in which case R1 is fluorine, —COOR4, —CONR4R5, —NR4COOR6, —NR4COR5, —NR4R5, —NR4CONR4R5, —NR4CSNR4R5, or —NR4SO 2 R6;
or
2) to the A ring nitrogen, if present, in which case R1 is —COR5, —COOR6, —CONR4R5, —CSNR4R5, or —SO 2 R6;
wherein:
R4 and R5 are independently hydrogen or an optionally substituted group selected from (C 1 -C 6 )alkyl, (C 3 -C 7 )cycloalkyl, heterocyclyl, aryl, aryl(C 1 -C 6 )alkyl, heteroaryl and heteroaryl(C 1 -C 6 )alkyl; or R4 and R5, taken together with the nitrogen atom to which they are bonded, may form an optionally substituted 5- or 6-membered heterocyclyl group optionally containing one additional heteroatom selected from N, O and S;
R6 is an optionally substituted group selected from (C 1 -C 6 )alkyl, (C 3 -C 7 )cycloalkyl, heterocyclyl, aryl, aryl(C 1 -C 6 )alkyl, heteroaryl and heteroaryl(C 1 -C 6 )alkyl;

n is 0, 1 or 2;
R2 is linked to any A ring atom and is selected from the group consisting of fluorine, an optionally substituted (C 1 -C 6 )alkyl and NR4R5;
provided that
when R2 is fluorine or NR4R5, then R2 is linked to a ring carbon;
when n is 2, then the R2 groups are not necessarily the same;

wherein the R1 and R2 groups can be linked to the same ring carbon;
R3 is hydrogen, halogen, cyano or an optionally substituted group selected from polyfluorinated (C 1 -C 6 )alkyl, (C 3 -C 7 )cycloalkyl, (C 2 -C 6 )alkynyl, heterocyclyl, aryl, heteroaryl, —OR6 or —CONR4R5, wherein R4, R5 and R6 are as defined above;
when X is nitrogen, then R3 is not hydrogen.

3. A compound or pharmaceutically acceptable salt according to claim 2 , wherein:
X is CH or nitrogen;
A is a 6-membered cycloalkyl or a 6-membered nitrogen-containing heterocyclyl;
R1 is linked:
either
1) to any A ring carbon, in which case R1 is —CONR4R5, —NR4COR5, —NR4CONR4R5, —NR4CSNR4R5, or —NR4SO 2 R6,
or
2) to the A ring nitrogen, in which case R1 is —COR5, —CONR4R5, —CSNR4R5 or —SO 2 R6;
wherein:
R4 and R5 are independently hydrogen or an optionally substituted group selected from (C 1 -C 6 )alkyl, aryl and heteroaryl, and;
R6 is an optionally substituted group selected from (C 1 -C 6 )alkyl, aryl and heteroaryl;

n is 0, 1 or 2;
R2 is an optionally substituted (C 1 -C 6 )alkyl;
provided that
when n is 2 the R2 groups are not necessarily the same;
wherein the R1 and R2 groups can be linked to the same ring carbon;

R3 is halogen, cyano or an optionally substituted group selected from polyfluorinated(C 1 -C 6 )alkyl, (C 2 -C 6 )alkynyl, aryl, heteroaryl, —OR6 and —CONR4R5, wherein R4, R5 and R6 are as defined above.

4. A compound or pharmaceutically acceptable salt according to claim 3 , represented by formula (I)′ below:

wherein:
X is nitrogen;
A is a 6-membered cycloalkyl, wherein A has a cis-1,4-disubstituted configuration;
R1 is linked:
to an A ring carbon, and is —CONR4R5, —NR4COR5, —NR4CONR4R5;
wherein R4 and R5 are independently hydrogen or an optionally substituted group selected from aryl and heteroaryl;
n is 0;
R3 is halogen, cyano or an optionally substituted group selected from (C 2 -C 6 )alkynyl, aryl, heteroaryl and —OR6, wherein R6 is an optionally substituted (C 1 -C 6 )alkyl.

5. A compound (cpd), or pharmaceutically acceptable salt according to claim 1 , selected from the group consisting of:
cis-4-(6-amino-2-chloro-9H-purin-9-yl)-N-(3-methoxyphenyl)cyclohexanecarboxamide (cpd 3),
cis-4-[6-amino-2-(pyridin-3-yl)-9H-purin-9-yl]-N-(3-methoxyphenyl)cyclohexanecarboxamide (cpd 4),
cis-4-[6-amino-2-(pyridin-4-yl)-9H-purin-9-yl]-N-(3-methoxyphenyl)cyclohexanecarboxamide (cpd 9),
cis-4-[6-amino-2-(2-fluoropyridin-4-yl)-9H-purin-9-yl]-N-(3-methoxyphenyl)cyclohexanecarboxamide (cpd 15),
cis-4-[6-amino-2-(4-hydroxyphenyl)-9H-purin-9-yl]-N-(3-methoxyphenyl)cyclohexanecarboxamide (cpd 17),
cis-4-[6-amino-2-(3-hydroxyphenyl)-9H-purin-9-yl]-N-(3-methoxyphenyl)cyclohexanecarboxamide (cpd 18),
cis-4-[6-amino-2-(6-fluoropyridin-3-yl)-9H-purin-9-yl]-N-(3-methoxyphenyl)cyclohexanecarboxamide (cpd 19),
cis-4-[6-amino-2-(2-methoxypyridin-4-yl)-9H-purin-9-yl]-N-(3-methoxyphenyl)cyclohexanecarboxamide (cpd 21),
3-(6-amino-9-{cis-4-[(3-methoxyphenyl)carbamoyl]cyclohexyl}-9H-purin-2-yl)benzamide (cpd 26),
cis-4-(6-amino-2-chloro-9H-purin-9-yl)-N-{4-[(trifluoromethyl)sulfonyl]phenyl}cyclohexanecarboxamide (cpd 27),
4-(6-amino-9-{cis-4-[(3-methoxyphenyl)carbamoyl]cyclohexyl}-9H-purin-2-yl)-N-{4-[(4-methylpiperazin-1-yl)methyl]phenyl}benzamide (cpd 29),
3-(6-amino-9-{cis-4-[(3-methoxyphenyl)carbamoyl]cyclohexyl}-9H-purin-2-yl)-N-{4-[(4-methylpiperazin-1-yl)methyl]phenyl}benzamide (cpd 30),
3-(6-amino-9-{cis-4-[(3-methoxyphenyl)carbamoyl]cyclohexyl}-9H-purin-2

Assignees

• Nerviano Medical Sciences Srl

Inventors

• Casale Elena
• Corti Emiliana
• Gnocchi Paola
• Nesi Marcella
• Orrenius Sten Christian
• Quartieri Francesca
• Riccardi Sirtori Federico

Classifications

• C07D513/04

  Ortho-condensed systems · CPC title

• C07D513/14

  Ortho-condensed systems · CPC title

• C07D473/40 Primary

  with halogen atoms or perhalogeno-alkyl radicals directly attached in position 2 or 6 · CPC title

• C07D471/04

  Ortho-condensed systems · CPC title

• A61P35/00

  Antineoplastic agents · CPC title