Kinase modulators

Patent metadata

Field	Value
Publication number	US-9421209-B2
Application number	US-201514642423-A
Country	US
Kind code	B2
Filing date	Mar 9, 2015
Priority date	Nov 5, 2009
Publication date	Aug 23, 2016
Grant date	Aug 23, 2016

Abstract

The present invention provides PI3K protein kinase modulators, 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 of inhibiting a catalytic activity of a PI3 kinase present in a cell, comprising contacting the cell with an effective amount of a 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 a , 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 an oxo group (═O) or 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 1, 2, 3 or 4; and
q is 0, 1 or 2.

2. The method of claim 1 , wherein the inhibition takes place in a subject suffering from lymphocytic leukemia (CLL), non-Hodgkin's lymphoma (NHL), acute myeloid leukemia (AML), multiple myeloma (MM), small lymphocytic lymphoma (SLL) or indolent non-Hodgkin's lymphoma (I-NHL).

3. The method of claim 1 , further comprising the step of administering simultaneously or sequentially to a subject in need thereof at least one other anti-cancer agent, anti-inflammatory agent, immunosuppressive agent, steroid, non-steroidal anti-inflammatory agent, antihistamine, analgesic, or a mixture thereof.

4. 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.

5. The method of claim 1 , wherein the compound has the formula:

or a tautomer thereof, N-oxide thereof, pharmaceutically acceptable ester thereof, prodrug thereof, or pharmaceutically acceptable salt thereof, wherein
Cy 2 is selected from substituted or unsubstituted heterocyclic group and substituted or unsubstituted heteroaryl.

6. The method of claim 1 , wherein the compound has the formula (IA-III), or (IA-IV):

or a tautomer thereof, N-oxide thereof, pharmaceutically acceptable ester thereof, prodrug thereof, or pharmaceutically acceptable salt thereof, wherein
each occurrence of X is independently selected from CR 3 or N; and
each occurrence of R 3 is independently selected from hydrogen, hydroxy, halogen, carboxyl, cyano, nitro, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenylalkyl substituted or unsubstituted cycloalkenyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted heterocyclic ring, substituted heterocyclylalkyl ring, substituted or unsubstituted guanidine, —COOR x , —C(O)R x , —C(S)R x , —C(O)NR x R y , —C(O)ONR x R y , —NR x CONR y R z , —N(R x )SOR y , —N(R x )SO 2 R y , —(═N—N(R x )R y ), —NR x C(O)OR y , —NR x R y , —NR x C(O)R y —, —NR x C(S)R y —NR x C(S)NR y R z , —SONR x R y —, —SO 2 NR x R y —, —OR x , —OR x C(O)NR y R z , —OR x C(O)OR y —, —OC(O)R x , —OC(O)NR x R y , —R x NR y C(O)R z , —R x OR y , —R x C(O)OR y , —R x C(O)NR y R z , —R x C(O)R x , —R x OC(O)R y , —SR x , —SOR x , —SO 2 R x , and —ONO 2 , wherein R x , R y and R z in each of the above groups can be hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted heterocyclic ring, substituted or unsubstituted heterocyclylalkyl ring, or substituted or unsubstituted amino, or any two of R x , R y and R z may be joined to form a substituted or unsubstituted saturated or unsaturated 3-10 membered ring, which may optionally include heteroatoms which may be the same or different and are selected from 0, NR W (wherein R W is hydrogen or substituted or unsubstituted alkyl) or S.

7. The method of claim 1 , wherein
Cy 1 is substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl;
Cy 2 is

wherein X is CR 3 ;
R 3 is independently selected from hydrogen, hydroxy, halogen, carboxyl, cyano, nitro, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted heteroaryl, substituted heterocyclylalkyl ring, substituted or unsubstituted heteroarylalkyl, subs

Assignees

• Rhizen Pharmaceuticals Sa

Inventors

• Muthuppalaniappan Meyyappan
• Viswanadha Srikant
• Babu Govindarajulu
• Vakkalanka Swaroop K

Classifications

• A61P35/04

  specific for metastasis · CPC title

• A61P37/08

  Antiallergic agents (antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14) · CPC title

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title

• A61P7/00

  Drugs for disorders of the blood or the extracellular fluid · CPC title

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title