Substituted pyrazolo[4,3-h]quinazolines as choline kinase inhibitors

Patent metadata

Field	Value
Publication number	US-11117901-B2
Application number	US-201816630208-A
Country	US
Kind code	B2
Filing date	Jul 3, 2018
Priority date	Jul 11, 2017
Publication date	Sep 14, 2021
Grant date	Sep 14, 2021

Abstract

The present invention relates to substituted pyrazolo-quinazoline derivatives 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. The compounds of this disclosure include those of formula (I):

First claim

The invention claimed is:

1. A compound of formula (I):

or a pharmaceutically acceptable salt thereof,
wherein:
A is (C 3 -C 7 )cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein the (C 3 -C 7 )cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more independently selected substituents;
L is C(O)NR6aR7a, —C(O)NR8-, NR8C(O)R6a, or —NR8C(O)—;
R1 is hydrogen, or (C 1 -C 6 )alkyl;
R2 is hydrogen, (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 ) alkynyl, (C 3 -C 7 )cycloalkyl, or heterocyclyl, wherein the (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 ) alkynyl, (C 3 -C 7 )cycloalkyl, or heterocyclyl is optionally substituted with one or more independently selected substituents;
R3 is hydrogen or (C 1 -C 6 )alkyl;
R4 is hydrogen or (C 1 -C 6 )alkyl;
R3′ is hydrogen or (C 1 -C 6 )alkyl;
R4′ is hydrogen or (C 1 -C 6 )alkyl;
R5 is C(O)R6, C(O)NR6R7, C(O)OR6, NR6R7, NR7C(O)R6, NR7C(O)NR6R7, NR7C(O)OR9, or OR6;
R6 is hydrogen, (C 1 -C 6 )alkyl, aryl(C 1 -C 6 )alkyl, heteroaryl(C 1 -C 6 )alkyl, (C 3 -C 7 )cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein the (C 1 -C 6 )alkyl, aryl(C 1 -C 6 )alkyl, heteroaryl(C 1 -C 6 )alkyl, (C 3 -C 7 )cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more independently selected substituents;
each R7 is independently hydrogen, (C 1 -C 6 )alkyl, aryl(C 1 -C 6 )alkyl, heteroaryl(C 1 -C 6 )alkyl, (C 3 -C 7 )cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein each (C 1 -C 6 )alkyl, aryl(C 1 -C 6 )alkyl, heteroaryl(C 1 -C 6 )alkyl, (C 3 -C 7 )cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally and independently substituted with one or more independently selected substituents; or
R6 and R7, taken together with the nitrogen atom to which they are bonded, form a 5- or 6-membered heterocyclyl, wherein the 5- or 6-membered heterocyclyl optionally contains one additional heteroatom selected from the group consisting of nitrogen, oxygen, and sulfur, and further wherein the 5- or 6-membered heterocyclyl is optionally substituted with one or more independently selected substituents;
R6a is hydrogen, (C 1 -C 6 )alkyl, aryl(C 1 -C 6 )alkyl, heteroaryl(C 1 -C 6 )alkyl, (C 3 -C 7 )cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein the (C 1 -C 6 )alkyl, aryl(C 1 -C 6 )alkyl, heteroaryl(C 1 -C 6 )alkyl, (C 3 -C 7 )cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more independently selected substituents;
R7a is hydrogen, (C 1 -C 6 )alkyl, aryl(C 1 -C 6 )alkyl, heteroaryl(C 1 -C 6 )alkyl, (C 3 -C 7 )cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein the (C 1 -C 6 )alkyl, aryl(C 1 -C 6 )alkyl, heteroaryl(C 1 -C 6 )alkyl, (C 3 -C 7 )cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more independently selected substituents; or
R6a and R7a, taken together with the nitrogen atom to which they are bonded, form a 5- or 6-membered heterocyclyl, wherein the 5- or 6-membered heterocyclyl optionally contains one additional heteroatom selected from the group consisting of nitrogen, oxygen, and sulfur, and further wherein the 5- or 6-membered heterocyclyl is optionally substituted with one or more independently selected substituents;
R8 is hydrogen or (C 1 -C 6 )alkyl, wherein the (C 1 -C 6 ) alkyl is optionally substituted with one or more independently selected substituents;
R9 is (C 1 -C 6 )alkyl, aryl(C 1 -C 6 )alkyl, heteroaryl(C 1 -C 6 ) alkyl, (C 3 -C 7 )cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein the (C 1 -C 6 )alkyl, aryl(C 1 -C 6 )alkyl, heteroaryl(C 1 -C 6 ) alkyl, (C 3 -C 7 )cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more independently selected substituents;
Ra is hydrogen, fluoro, or (C 1 -C 6 )alkyl, wherein the (C 1 -C 6 ) alkyl is optionally substituted with one or more independently selected substituents;
Rb is hydrogen, fluoro, or (C 1 -C 6 )alkyl, wherein the (C 1 -C 6 ) alkyl is optionally substituted with one or more independently selected substituents; or
Ra and Rb, taken together with the carbon atom to which they are bonded, form a 3-membered cycloalkyl;
Rc is hydrogen, fluoro, or (C 1 -C 6 )alkyl, wherein the (C 1 -C 6 ) alkyl is optionally substituted with one or more independently selected substituents;
Rd is hydrogen, fluoro, or (C 1 -C 6 )alkyl, wherein the (C 1 -C 6 ) alkyl is optionally substituted with one or more independently selected substituents; or
Rc and Rd, taken together with the carbon atom to which they are bonded, form a 3-membered cycloalkyl;
y is 0 or 1;
n is 0, 1, or 2; and
z is 0, 1, or 2;
wherein the optional substituents for A, R2, R5, R6, R6a, R7, R7a, R6 and R7, R6a and R7a, R8, R9, Ra, Rb, Rc, Rd, Ra and Rb, and Rc and Rd, are independently selected from the group consisting halogen, cyano, nitro, oxo, (C 1 -C 6 )alkyl, polyfluorinated (C 1 -C 6 )alkyl, C(O)NHaryl(C 1 -C 6 )alkyl, C(O)heterocyclyl(C 1 -C 6 )alkyl, amino(C 1 -C 6 )alkyl, hydroxy(C 1 -C 6 )alkyl, (C 3 -C 7 )cycloalkyl(C 1 -C 6 )alkyl, heterocyclyl(C 1 -C 6 )alkyl, (C 1 -C 6 )alkylheterocyclyl(C 1 -C 6 )alkyl, di(C 1 -C 6 )alkylaminoheterocyclyl(C 1 -C 6 )alkyl, aryl(C 1 -C 6 )alkyl, heteroaryl(C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, C(NH)O(C 1 -C 6 )alkyl, C(O)H, C(O)(C 1 -C 6 )alkyl, C(O)NH 2 , C(O)NH(C 1 -C 6 )alkyl, C(O)N((C 1 -C 6 )alkyl) 2 , CO)NHOH, C(O)NHheterocyclyl, C(O)NHaryl, C(O)NHheteroaryl, C(O)OH, C(O)O(C 1 -C 6 )alkyl, C(O)O(C 3 -C 7 )cycloalkyl, C(O)Oaryl, C(O)(C 3 -C 7 )cycloalkyl, C(O)heterocyclyl, C(O)aryl, NH 2 , NH(C 1 -C 6 )alkyl, N((C 1 -C 6 )alkyl) 2 , NHC(O)H, NHC(O)(C 1 -C 6 )alkyl, NHC(O)NH 2 , NHC(O)NH(C 1 -C 6 )alkyl, NHC(O)O(C 1 -C 6 )alkyl, NHC(O)O(C 1 -C 6 )alkyl(heterocyclyl), NHC(O)(C 3 -C 7 )cycloalkyl, NHC(O)heterocyclyl, NHC(O)aryl, NHS(O) 2 (C 1 -C 6 )alkyl, NHS(O) 2 heterocyclyl, NHS(O) 2 aryl, NHheterocyclyl, NHaryl, N(aryl) 2 , OH, —OCH 2 O—, O(C 1 -C 6 )alkyl, (polyfluorinated) O(C 1 -C 6 )alkyl, (aryl) O(C 1 -C 6 )alkyl, O(C 1 -C 6 )alkylideneamino, OC(O)(C 1 -C 6 )alkyl, OC(O)heterocyclyl, OC(O)aryl, O(C 3 -C 7 )cycloalkenyl, Oheterocyclyl, Oaryl, tri(C 1 -C 6 )alkylsilyl, S(C 1 -C 6 )alkyl, Saryl, S(O) 2 (C 1 -C 6 )alkyl, polyfluorinated S(O) 2 (C 1 -C 6 )alkyl, S(O) 2 NH 2 , S(O) 2 NH(C 1 -C 6 )alkyl, S(O) 2 N((C 1 -C 6 )alkyl) 2 , S(O) 2 NHheterocyclyl, S(O) 2 NHaryl, S(O) 2 aryl, (C 3 -C 7 )cycloalkyl, heterocyclyl, polyfluorinated heterocyclyl, (C 1 -C 6 )alkylheterocyclyl, aryl, (C 1 -C 6 )alkylaryl, heteroaryl, and (C 1 -C 6 )alkylheteroaryl;

with provisos that:
(1) when y is 0, L is C(O)NR6aR7a or NR8C(O)R6a;
(2) when y is 1, L is —C(O)NR8- or —NR8C(O)—;
(3) R3, R4, R3′, and R4′ are not simultaneously hydrogen; and
(4) the following compounds of formula (I) are excluded:

2. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof,
wherein:
A is aryl or heteroaryl, wherein the aryl or heteroaryl is optionally substituted with one or more independently selected substituents;
R2 is hydrogen, (C 1 -C 6 )alkyl, (C 3 -C 7 )cycloalkyl, or heterocyclyl, wherein the (C 1 -C 6 )alkyl, (C 3 -C 7 )cycloalkyl, or heterocyclyl is optionally substituted with one or more independently selected substituents;
R5 is C(O)NR6R7, NR6R7, NR7C(O)R6, NR7C(O)NR6R7, or OR6;
n is 0 or 1; and
z is 0 or 1.

3. The compound according to claim 2 , or a pharmaceutically acceptable salt thereof,
wherein:
L is C(O)NR6aR7a, —C(O)NR8-, NR8C(O)R6a, or —NR8C(O)—;
R2 is hydrogen or (C 1 -C 6 )alkyl, wherein the (C 1 -C 6 )alkyl is optionally substituted with one or more independently sel

Assignees

• Nerviano Medical Sciences Srl

Inventors

• Badari Alessandra
• Casale Elena
• Nesi Marcella
• Quartieri Francesca

Classifications

• A61K31/519

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

• A61P35/00

  Antineoplastic agents · CPC title

• C07D487/04 Primary

  Ortho-condensed systems · CPC title