Pyrazolo-quinazoline derivatives, process for their preparation and their use as kinase inhibitors

Patent metadata

Field	Value
Publication number	US-2021300935-A1
Application number	US-202017084862-A
Country	US
Kind code	A1
Filing date	Oct 30, 2020
Priority date	May 22, 2003
Publication date	Sep 30, 2021
Grant date	—

Abstract

Pyrazolo-quinazoline derivatives of formula (Ia) or (Ib) as defined in the specification, and pharmaceutically acceptable salts thereof, processes for their preparation and pharmaceutical compositions comprising them are disclosed; the compounds of the invention may be useful, in therapy, in the treatment of diseases associated with a disregulated protein kinase activity, like cancer.

First claim

1 . A pyrazolo-quinazoline derivative of formula (Ia).

or a pharmaceutically acceptable salt thereof, wherein
R is substituted or unsubstituted phenyl;
X is —NH—;
R 1 is an optionally substituted straight or branched C 1 -C 6 alkyl;
R 2 is —NR″R′″, wherein
R″ is hydrogen or an optionally substituted straight or branched C 1 -C 6 alkyl;
R′″ is hydrogen or an optionally substituted group selected from phenyl and straight or branched C 1 -C 6 alkyl; and

A is —(CH 2 ) 2 —, —CH 2 —C(CH 3 ) 2 —, or —C(CH 3 ) 2 —CH 2 —.

2 . The compound of claim 1 , wherein R is phenyl substituted with heterocyclyl or heterocyclylalkyl.

3 . The compound of claim 2 , wherein the heterocyclyl is selected from piperazinyl, morpholinyl, and imidazolyl.

4 . The compound of claim 1 , wherein R is phenyl substituted with one or more groups independently selected from halogen, hydroxy, polyfluorinated alkyl, and aminocarbonyl.

5 . The compound of claim 1 , wherein R 1 is straight or branched C 1 -C 6 alkyl substituted with one or more groups independently selected from halogen and hydroxy.

6 . The compound of claim 1 , wherein R 1 is unsubstituted straight or branched C 1 -C 6 alkyl.

7 . The compound of claim 1 , wherein R 1 is methyl.

8 . The compound of claim 1 , wherein R′″ is unsubstituted straight or branched C 1 -C 6 alkyl or straight or branched C 1 -C 6 alkyl substituted with one or more groups independently selected from halogen, hydroxy, aryl, heterocyclyl, and di-(C 1 -C 6 alkyl)amino.

9 . The compound of claim 8 , wherein the aryl is phenyl.

10 . The compound of claim 8 , wherein the heterocyclyl is pyridyl.

11 . The compound of claim 1 , wherein A is —CH 2 —C(CH 3 ) 2 —.

12 . A method for treating a disease selected from the group consisting of ovarian cancer, acute myeloid leukemia, prostate cancer, breast cancer, liver cancer, melanoma, colon cancer, non-small lung cancer, pancreatic cancer, and pancreatic adenocarcinoma, comprising administering to a mammal in need thereof an effective amount of a compound of claim 1 .

13 . The method of claim 12 , wherein the compound is:

or a pharmaceutically acceptable salt thereof.

14 . A method for inhibiting Aurora 2 activity, comprising administering to a mammal in need thereof an effective amount of a compound of claim 1 .

15 . The method of claim 14 , wherein the compound is:

or a pharmaceutically acceptable salt thereof.

16 . A method for inhibiting cell cycle dependent kinase activity, comprising administering to a mammal in need thereof an effective amount of a compound of claim 1 .

17 . The method of claim 16 , wherein the compound is:

or a pharmaceutically acceptable salt thereof.

18 . A process for preparing the compound of claim 1 , or a pharmaceutically acceptable salt thereof, comprising:
(1) when A is —(CH 2 ) 2 —:
st.1) reacting 2-ethoxy-2-cyclohexen-1-one with diethyl oxalate, in the presence of lithium (bis-trimethylsilyl) amide [LiN(TMS) 2 ], to obtain a compound of formula (II)

and treating the compound of formula (II) with a hydrazine derivative of formula (III)
R 1 —NHNH 2   (III)

according to step st.2a) or st.2b):
st.2a) in the presence of a lower alcohol to obtain a mixture of compounds of formulae (IVa) and (IVb)

and isolating the compound of formula (IVa) from the mixture;
st.2b) in the presence of acetic acid to obtain a compound of formula (IVa);
st.3) reacting the compound of formula (IVa) prepared according to step st.2a) or
st.2b) with dimethylformamide-di-tert-butylacetate to obtain a compound of formula (Va)

and reacting the compound of formula (Va) according to step st.4:
with a guanidine derivative of formula (VI)
R—NH—C(═NH)NH 2   (VI)

so as to obtain a compound of formula (Ia′)

wherein R 2 is ethoxy; and converting the compound of formula (Ia′) into the compound of formula (Ia);

(2) when A is —C(CH 3 ) 2 —CH 2 —:
st.5) reacting 2-methoxy-4,4-dimethyl-2-cyclohexen-1-one with diethyl oxalate, in the presence of [LiN(TMS) 2 ], to obtain a compound of formula (VIII)

st.6) reacting the compound of formula (VIII) with a hydrazine derivative of formula (III) according to step st.2a) or st.2b) to obtain a compound of formula (IXa)

st.7) reacting the compound of formula (IXa) with ethyl formate under basic conditions, to obtain a compound of formula (Xa)

st.8) reacting the compound of formula (Xa) with a guanidine derivative of formula (VI) to obtain a compound of formula (Ia′)

wherein R 2 is ethoxy; and converting the compound of formula (Ia′) into the compound of formula (Ia);

(3) when A is —CH 2 —C(CH 3 ) 2 —:
st.9) reacting 2-methoxy-5,5-dimethyl-2-cyclohexen-1-one with diethyl oxalate in the presence of sodium hydride, to obtain a compound of formula (XI)

st.10) reacting the compound of formula (XI) with a hydrazine derivative of formula (III) according to previous step st.2a) or st.2b) to obtain a compound of formula (XIIa)

st.11) reacting the compound of formula (XIIa) with dimethylformamide-di-tert-butylacetale to obtain a compound of formula (XIIIa)

st.12) reacting the compound of formula (XIIIa) with a guanidine derivative of formula (VI) to obtain a compound of formula (Ia′)

wherein R 2 is ethoxy; and converting the compound of formula (Ia′) into a compound of formula (Ia).

Assignees

• Nerviano Medical Sciences Srl

Inventors

• Traquandi Gabriella
• Brasca Maria Gabriella
• D'Alessio Roberto
• Polucci Paolo
• Roletto Fulvia
• Vulpetti Anna
• Pevarello Paolo
• Panzeri Achille
• Quartieri Francesca
• Ferguson Ron
• Vianello Paola
• Fancelli Daniele

Classifications

• A61K31/5377

  not condensed and containing further heterocyclic rings, e.g. timolol · CPC title

• A61P29/00

  Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] · CPC title

• A61P11/00

  Drugs for disorders of the respiratory system · CPC title

• A61P17/14

  for baldness or alopecia · CPC title

• A61K31/519

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