Substituted chromenes as kinase modulators

Patent metadata

Field	Value
Publication number	US-9018375-B2
Application number	US-201314090517-A
Country	US
Kind code	B2
Filing date	Nov 26, 2013
Priority date	Nov 5, 2009
Publication date	Apr 28, 2015
Grant date	Apr 28, 2015

Abstract

The present invention provides PI3K protein kinase modulators of formula (I): wherein R, R1, R2, L1, Cy1, Cy2 and n are as described herein, methods of preparing them, pharmaceutical compositions containing them and methods of treatment, prevention and/or amelioration of kinase mediated diseases or disorders with them.

First claim

We claim:

1. A method for the treatment of chronic lymphocytic leukemia (CLL), non-Hodgkin's lymphoma (NHL), acute myeloid leukemia (AML), multiple myeloma (MM), or small lymphocytic lymphoma (SLL), comprising the step of administering to a subject in need thereof an effective amount of compound of the formula

or a tautomer thereof, N-oxide thereof, pharmaceutically acceptable ester thereof, prodrug thereof, or pharmaceutically acceptable salt thereof, wherein
each occurrence of R is independently selected from hydrogen, halogen, —OR f (wherein R f is substituted or unsubstituted (C 1-6 )alkyl), CN, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 alkynyl, substituted or unsubstituted C 3-8 cycloalkyl, and substituted or unsubstituted heterocyclic group;
R 1 and R 2 may be the same or different and are independently selected from hydrogen, halogen, and substituted or unsubstituted C 1-6 alkyl, or both R 1 and R 2 directly bound to a common atom, may be joined to form a substituted or unsubstituted saturated or unsaturated 3-10 member ring (including the carbon atom to which R 1 and R 2 are bound), which may optionally include one or more heteroatoms which may be the same or different and are selected from O, NR a and S;
Cy 1 is a monocyclic group selected from substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclic group, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl;
Cy 2 is selected from a substituted or unsubstituted heterocyclic group, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl;
L 1 is selected from —S(═O) q — and —NR a —;
each occurrence of R a is selected from hydrogen, halogen, hydroxy, cyano, substituted or unsubstituted (C 1-6 )alkyl, —NR c R d (wherein R c and R d are independently hydrogen, halogen, hydroxy, cyano, substituted or unsubstituted (C 1-6 )alkyl, and (C 1-6 )alkoxy) and —OR c (wherein R c is substituted or unsubstituted (C 1-6 )alkyl);
n is an integer from 1 to 4; and
q is 0, 1 or 2.

2. The method of claim 1 , where the compound of formula (I) is selected from the group consisting of:
2-((9H-Purin-6-ylthio)methyl)-3-phenyl-4H-chromen-4 -one;
2-[(9H-Purin-6-ylthio)methyl]-6-bromo-3-phenyl-4H-chromen-4-one;
2-(1-(9H-Purin-6-ylthio)ethyl)-6-bromo-3-phenyl-4H-chromen-4-one;
(S)-2-(1 -(9H-purin-6-ylamino)ethyl)-6-bromo-3-phenyl-4H-chromen-4-one;
2-((9H-purin-6-ylamino)methyl)-6-bromo-3-phenyl-4H-chromen-4-one;
2-((9H-purin-6-ylamino)methyl)-3-phenyl-4H-chromen-4-one;
2-((9H-purin-6-ylamino)methyl)-3-(2-fluorophenyl)-4H-chromen-4-one;
2-((9H-purin-6-ylamino)methyl)-3-(3-fluorophenyl)-4H-chromen-4-one;
(S)-2-(1-(9H-purin-6-ylamino)ethyl)-3-(3 -fluorophenyl)-4H-chromen-4-one;
(R)-2-(1-(9H-purin-6-ylamino)ethyl)-3-(3-fluorophenyl)-4H-chromen-4-one;
(S)-2-(1-(9H-purin-6-ylamino)ethyl)-6-fluoro-3-phenyl-4H-chromen-4-one;
(S)-2-(1-(9H-purin-6-ylamino)ethyl)-3-phenyl-4H-chromen-4-one;
(S)-2-(1-(9H-purin-6-ylamino)ethyl)-6-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one;
2-((9H-purin-6-ylamino)methyl)-6-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one;
2-((9H-purin-6-ylamino)methyl)-6-fluoro-3-phenyl-4H-chromen-4-one;
(R)-2-(1-(9H-purin-6-ylamino)ethyl)-6-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one;
6-Fluoro-3-(3-fluorophenyl)-2-(1-(4-methoxyphenylamino)ethyl)-4H-chromen-4-one, and pharmaceutically acceptable salts thereof.

3. A method for the treatment of a chronic lymphocytic leukemia (CLL), non-Hodgkin's lymphoma (NHL), acute myeloid leukemia (AML), multiple myeloma (MM), or small lymphocytic lymphoma (SLL), comprising the step of administering to a subject in need thereof an effective amount of compound of the formula

or a tautomer thereof, N-oxide thereof, pharmaceutically acceptable ester thereof, prodrug thereof, or pharmaceutically acceptable salt thereof, wherein
each occurrence of R is independently selected from hydrogen, halogen, —OR f (wherein R f is substituted or unsubstituted (C 1-6 )alkyl), substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 alkynyl, substituted or unsubstituted C 3-8 cycloalkyl, and substituted or unsubstituted heterocyclic group;
R 1 and R 2 may be the same or different and are independently selected from hydrogen, halogen, and substituted or unsubstituted C 1-6 alkyl, or both R 1 and R 2 directly bound to a common atom, may be joined to form a substituted or unsubstituted saturated or unsaturated 3-10 member ring (including the carbon atom to which R 1 and R 2 are bound), which may optionally include one or more heteroatoms which may be the same or different and are selected from O, NR a and S;
Cy l is a monocyclic group selected from substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclic group, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl;
Cy 2 is selected from a substituted or unsubstituted heterocyclic group, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl;
L 1 is selected from —S(═O) q — and —NR a —;
each occurrence of R a is selected from hydrogen, halogen, hydroxy, cyano, and substituted or unsubstituted (C 1-6 )alkyl;
n is an integer from 1 to 4; and
q is 0, 1 or 2.

4. The method of claim 1 , wherein the non-Hodgkin's lymphoma is indolent non-Hodgkin's lymphoma (I-NHL).

5. The method of claim 3 , wherein the non-Hodgkin's lymphoma is indolent non-Hodgkin's lymphoma (I-NHL).

Assignees

• Rhizen Pharmaceuticals Sa

Inventors

• Muthuppalaniappan Meyyappan
• Viswanadha Srikant
• Babu Govindarajulu
• Vakkalanka Swaroop Kumar V S

Classifications

• A61P7/02

  Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors · CPC title

• A61P7/00

  Drugs for disorders of the blood or the extracellular fluid · 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

• A61P7/06

  Antianaemics · CPC title

• A61P43/00

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