Isoxazolo-quinazolines as modulators of protein kinase activity

Patent metadata

Field	Value
Publication number	US-9333205-B2
Application number	US-201113813200-A
Country	US
Kind code	B2
Filing date	Jul 20, 2011
Priority date	Jul 30, 2010
Publication date	May 10, 2016
Grant date	May 10, 2016

Abstract

The present invention relates to substituted isoxazolo-quinazolines which modulate the activity of protein kinases and are therefore useful in treating diseases caused by dysregulated protein kinase activity, in particular human MPS1 and PERK. The present invention also provides methods for preparing these compounds, pharmaceutical compositions comprising these compounds, and methods of treating diseases utilizing such these compounds or the pharmaceutical compositions containing them.

First claim

The invention claimed is:

1. A compound of formula (I):

wherein:
Y is O and Z is N, or Y is N and Z is O;
X is NH;
R1 is a phenyl that is optionally substituted with a first 1 to 6 groups, independently selected from: C 1 -C 6 alkyl, polyfluorinated alkyl, polyfluorinated alkoxy, hydroxyalkyl, heterocyclyl, C 3 -C 7 cycloalkyl, hydroxy, alkoxy, amino, alkylamino, dialkylamino, arylamino, diarylamino, heterocyclylamino, formylamino, alkylcarbonylamino, arylcarbonylamino, heterocyclylcarbonylamino, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, heterocyclylaminocarbonyl, alkylcarbonyl, cycloalkylcarbonyl, and heterocyclylcarbonyl, wherein heterocyclyl is a 3 to 7 membered saturated carbocyclic ring wherein 1 to 3 carbon atoms are replaced with nitrogen, wherein the first 1 to 6 groups is further optionally substituted with a second 1 to 6 groups independently selected from C 1 -C 6 alkyl, polyfluorinated alkyl, polyfluorinated alkoxy, hydroxyalkyl, heterocyclyl, C 3 -C 7 cycloalkyl, hydroxy, alkoxy, amino, alkylamino, dialkylamino, arylamino, diarylamino, heterocyclylamino, formylamino, alkylcarbonylamino, arylcarbonylamino, heterocyclylcarbonylamino, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, heterocyclylaminocarbonyl, alkylcarbonyl, cycloalkylcarbonyl, and heterocyclylcarbonyl, wherein heterocyclyl is a 3 to 7 membered saturated carbocyclic ring wherein 1 to 3 carbon atoms are replaced with nitrogen;
R2 is —NR′R″, wherein R′ is hydrogen and R″ is hydrogen or a group, selected from straight or branched C 1 -C 6 alkyl and phenyl, that is optionally substituted with 1 to 6 groups, independently selected from: C 1 -C 6 alkyl, phenyl, amino, alkylamino and dialkylamino;
A is a divalent group selected from —(CH 2 ) 2 —, —CH 2 —C(CH 3 ) 2 —, and —C(CH 3 ) 2 —CH 2 —;
and the pharmaceutically acceptable salts thereof.

2. A compound of formula (I) or a pharmaceutically acceptable salt thereof as defined in claim 1 which is selected from the group consisting of:
N-(2,6-diethylphenyl)-8-{[2-methoxy-4-(4-methylpiperazin-1-yl)phenyl]amino}-4,5-dihydroisoxazolo[4,3-h]quinazoline-3-carboxamide,
8-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-4,5-dihydroisoxazolo[4,3-h]quinazoline-3-carboxamide,
N-(2,6-diethylphenyl)-8-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-4,5-dihydroisoxazolo[4,3-h]quinazoline-3-carboxamide,
N-(2,6-diethylphenyl)-8-({4-[4-(2-hydroxyethyl)piperazin-1-yl]-2-methoxyphenyl}amino)-4,5-dihydroisoxazolo[4,3-h]quinazoline-3-carboxamide,
N-(2,6-diethylphenyl)-8-{[2-methoxy-4-(4-pyrrolidin-1-ylpiperidin-1-yl)phenyl]amino}-4,5-dihydroisoxazolo[4,3-h]quinazoline-3-carboxamide,
8-{[2-methoxy-4-(4-methylpiperazin-1-yl)phenyl]amino}-4,5-dihydroisoxazolo[4,3-h]quinazoline-3-carboxamide,
5,5-dimethyl-8-{[4-(4-methylpiperazin-1-yl)-2-(trifluoromethoxy)phenyl]amino}-4,5-dihydroisoxazolo[4,3-h]quinazoline-3-carboxamide,
N-(2,6-diethylphenyl)-8-[(4-{[2-(dimethylamino)ethyl]carbamoyl}-2-methoxyphenyl)amino]-4,5-dihydroisoxazolo[4,3-h]quinazoline-3-carboxamide,
N-(2,6-diethylphenyl)-8-[(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}-2-methoxyphenyl)amino]-4,5-dihydroisoxazolo[4,3-h]quinazoline-3-carboxamide,
N-(2,6-diethylphenyl)-8-[(2-methoxy-4-{[(2S)-2-(pyrrolidin-1-ylmethyl)pyrrolidin-1-yl]carbonyl}phenyl)amino]-4,5-dihydroisoxazolo[4,3-h]quinazoline-3-carboxamide,
N-(2,6-diethylphenyl)-8-[(2-methoxy-4-{[(2R)-2-(pyrrolidin-1-ylmethyl)pyrrolidin-1-yl]carbonyl}phenyl)amino]-4,5-dihydroisoxazolo[4,3-h]quinazoline-3-carboxamide,
N-(2,6-diethylphenyl)-8-{[4-(4-methylpiperazin-1-yl)-2-(trifluoromethoxy)phenyl]amino}-4,5-dihydroisoxazolo[4,3-h]quinazoline-3-carboxamide,
8-{[4-(4-methylpiperazin-1-yl)-2-(trifluoromethoxy)phenyl]amino}-4,5-dihydroisoxazolo[4,3-h]quinazoline-3-carboxamide,
N-(2,6-diethylphenyl)-8-({4-[4-(dimethylamino)piperidin-1-yl]-2-methoxyphenyl}amino)-4,5-dihydroisoxazolo[4,3-h]quinazoline-3-carboxamide,
N-(2,6-diethylphenyl)-8-[(4-{[2-(dimethylamino)ethyl](methyl)amino}-2-methoxyphenyl)amino]-4,5-dihydroisoxazolo[4,3-h]quinazoline-3-carboxamide,
5,5-dimethyl-8-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-4,5-dihydroisoxazolo[4,3-h]quinazoline-3-carboxamide,
8-({2-methoxy-4-[(1-methylpiperidin-4-yl)carbamoyl]phenyl}amino)-4,4-dimethyl-4,5-dihydroisoxazolo[4,3-h]quinazoline-3-carboxamide,
8-({2-methoxy-4-[(1-methylpiperidin-4-yl)carbamoyl]phenyl}amino)-5,5-dimethyl-4,5-dihydroisoxazolo[4,3-h]quinazoline-3-carboxamide,
N-[(1S)-2-amino-1-phenylethyl]-8-({2-methoxy-4-[(1-methylpiperidin-4-yl)carbamoyl]phenyl}amino)-5,5-dimethyl-4,5-dihydroisoxazolo[4,3-h]quinazoline-3-carboxamide,
N-[(1S)-2-amino-1-phenylethyl]-8-({2-methoxy-4-[(1-methylpiperidin-4-yl)carbamoyl]phenyl}amino)-4,4-dimethyl-4,5-dihydroisoxazolo[4,3-h]quinazoline-3-carboxamide,
N-(2,6-diethylphenyl)-8-{[2-methoxy-4-(4-methylpiperazin-1-yl)phenyl]amino}-4,5-dihydroisoxazolo[4,5-h]quinazoline-3-carboxamide,
8-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-4,5-dihydroisoxazolo[4,5-h]quinazoline-3-carboxamide,
N-(2,6-diethylphenyl)-8-{[2-methoxy-4-(4-pyrrolidin-1-ylpiperidin-1-yl)phenyl]amino}-4,5-dihydroisoxazolo[4,5-h]quinazoline-3-carboxamide,
N-(2,6-diethylphenyl)-8-({4-[4-(2-hydroxyethyl)piperazin-1-yl]-2-methoxyphenyl}amino)-4,5-dihydroisoxazolo[4,5-h]quinazoline-3-carboxamide,
N-(2,6-diethylphenyl)-8-({4-[4-(dimethylamino)piperidin-1-yl]-2-methoxyphenyl}amino)-4,5-dihydroisoxazolo[4,5-h]quinazoline-3-carboxamide,
N-(2,6-diethylphenyl)-8-[(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}-2-methoxyphenyl)amino]-4,5-dihydroisoxazolo[4,5-h]quinazoline-3-carboxamide,
5,5-dimethyl-8-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-4,5-dihydroisoxazolo[4,5-h]quinazoline-3-carboxamide,
8-{[4-(4-methylpiperazin-1-yl)-2-(trifluoromethoxy)phenyl]amino}-4,5-dihydroisoxazolo[4,5-h]quinazoline-3-carboxamide,
N-(2,6-diethylphenyl)-8-{[4-(4-methylpiperazin-1-yl)-2-(trifluoromethoxy)phenyl]amino}-4,5-dihydroisoxazolo[4,5-h]quinazoline-3-carboxamide,
8-({2-methoxy-4-[(1-methylpiperidin-4-yl)carbamoyl]phenyl}amino)-5,5-dimethyl-4,5-dihydroisoxazolo[4,5-h]quinazoline-3-carboxamide,
N-[(2R)-2-amino-2-phenylethyl]-8-({2-methoxy-4-[(1-methylpiperidin-4-yl)carbamoyl]phenyl}amino)-5,5-dimethyl-4,5-dihydroisoxazolo[4,5-h]quinazoline-3-carboxamide,
N-[(1R)-2-amino-1-phenylethyl]-8-({2-methoxy-4-[(1-methylpiperidin-4-yl)carbamoyl]phenyl}amino)-5,5-dimethyl-4,5-dihydroisoxazolo[4,5-h]quinazoline-3-carboxamide and
5,5-dimethyl-8-{[4-(4-methylpiperazin-1-yl)-2-(trifluoromethoxy)phenyl]amino}-4,5-dihydroisoxazolo[4,5-h]quinazoline-3-carboxamide.

3. A process for preparing a compound of formula (I) or the pharmaceutically acceptable salts thereof, as defined in claim 1 , which process comprises:
st.A1) reacting a compound of the formula (II):

wherein R2 is O—(C 1 -C 4 alkyl), A is a divalent group selected from —(CH 2 ) 2 —, —CH 2 —C(CH 3 ) 2 — and —C(CH 3 ) 2 —CH 2 —, with hydroxylamine HO—NH 2 HCl, optionally in the presence of a C 1 -C 4 alkyl alcohol, and separating the resultant compounds (IIIa) and (IIIb):

wherein R2 and A are as defined above;
or
st.A1/a) reacting a compound of the formula (II-) as defined above, with hydroxylamine HO—NH 2 .H 2 O in acetic acid and a C 1 -C 4 alkyl alcohol, then separating the single compounds, (IIa) and (IIb);
st.A1/b) dehydrating in acidic conditions the resultant compound of formula (IIa) and (IIb):

wherein R2 and A

Assignees

• Caldarelli Marina
• Beria Italo
• Colombo Nicoletta
• Piutti Claudia
• Salsa Matteo
• Traquandi Gabriella
• Nerviano Medical Sciences Srl

Inventors

• Caldarelli Marina
• Beria Italo
• Colombo Nicoletta
• Piutti Claudia
• Salsa Matteo
• Traquandi Gabriella

Classifications

• C07D498/04

  Ortho-condensed systems · CPC title

• C07D498/02

  in which the condensed system contains two hetero rings · CPC title

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61K31/519 Primary

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

• A61N5/10

  X-ray therapy; Gamma-ray therapy; Particle-irradiation therapy (A61N5/01 takes precedence) · CPC title