Substituted chromenones as modulators of protein kinases

Patent metadata

Field	Value
Publication number	US-10322130-B2
Application number	US-201715677614-A
Country	US
Kind code	B2
Filing date	Aug 15, 2017
Priority date	May 4, 2011
Publication date	Jun 18, 2019
Grant date	Jun 18, 2019

Abstract

The present invention provides PI3K protein kinase modulators of formula

wherein R, Cy 1 , R 1 , R 2 , L 1 and Cy 2 are as defined herein. The present invention also relates to methods of preparing compounds of formula (I) to pharmaceutical compositions containing them and to methods of treatment, prevention and/or amelioration of kinase mediated diseases or disorders with them.

First claim

We claim:

1. A compound of formula (I)

or a pharmaceutically acceptable salt, N-oxide or tautomer thereof,
wherein:
each occurrence of R is independently selected from hydroxy, halogen, carboxy, cyano, nitro, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenylalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, —COOR x , —C(O)R x , —C(S)R x , —C(O)NR x R y , —C(O)ONR x R y , —NR x R y , —NR x CONR x R y , —N(R x )SOR x , —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 x R y , —SONR x R y —, —SO 2 NR x R y —, —OR x , —OR x C(O)NR x R y , —OR x C(O)OR x —, —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 x R y , —R x C(O)R y , —R x OC(O)R y , —SR x , —SOR x , —SO 2 R x , or —ONO 2 , wherein R x , R y and R z in each of the above groups is 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 heteroaryl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted heterocyclyl, substituted heterocyclylalkyl ring, or substituted or unsubstituted amino, or (i) any two of R x and R y may be joined to form a substituted or unsubstituted, saturated or unsaturated 3-14 membered ring, which may optionally include heteroatoms which may be the same or different and are selected from O, NR z or S, or (ii) any two of R x and R y join to form (═O), (—S) or (═NR f ) (wherein R f is hydrogen or substituted or unsubstituted alkyl);
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, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkylalkyl, and substituted or unsubstituted heterocyclyl, or both R 1 and R 2 directly bound to a common atom, may be joined to form (═O);
Cy 1 is selected from substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl;
Cy 2 is selected from a substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl;
L 1 is absent or selected from —(CR a R b ) q —, —O—, —S(═O) q —, —NR a — or —C(═Y)—;
each occurrence of R a and R b may be the same or different and are independently 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, or (C 1-6 )alkoxy) and —OR c (wherein R c is substituted or unsubstituted (C 1-6 )alkyl) or when R a and R b are directly bound to a common atom, they may be joined to form (═O) or form a substituted or unsubstituted, saturated or unsaturated 3-10 member ring (including the common atom to which R a and R b are directly bound), which may optionally include one or more heteroatoms which may be the same or different and are selected from O, NR d (wherein R d is hydrogen or substituted or unsubstituted (C 1-6 )alkyl) or S;
Y is selected from O, S, and NR a ; and
q is 0, 1 or 2;

wherein the term “substituted” refers to substitution by any one or more of the following substituents, which may be the same or different, and are independently selected from hydroxy, halogen, cyano, A alkyl, alkoxy, fluorinated alkoxy, heteroaryl, heterocyclyl, alkylheterocyclyl, —NH 2 , —NH(alkyl), N(alkyl) 2 , —NHC(O)(alkyl), —S(alkyl), —SO 2 NH 2 , —SO 2 NH(alkyl), —SO 2 N(alkyl) 2 , —SO 2 NH(cycloalkyl), —SO 2 N(cycloalkyl) 2 , —C(O)NH 2 , —C(O)NH(alkyl), —C(O)N(alkyl) 2 , —O-heterocyclyl, —O-heterocyclyl-alkylaryl, —SO 2 NH(cycloalkyl), and —CO 2 (alkyl).

2. The compound of claim 1 , wherein the compound has the formula (IA-1), formula (IA-II), formula (IA-III), formula (IA-IV), formula (IA-V), formula (IA-Ia), formula (IA-IIa), formula (IA-IIIa), formula (IA-Ib) or formula (IA-IIb):

or a pharmaceutically acceptable salt, N-oxide or tautomer thereof,
wherein:
R is selected from halogen, hydroxy, substituted or unsubstituted alkoxy, cyano, 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 heterocyclyl;
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 (═O);
Cy 1 is a monocyclic group selected from substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl;
X is CR 3 ;
each occurrence of R 3 is independently selected from hydrogen, hydroxy, halogen, carboxy, cyano, nitro, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted heterocyclic ring, substituted or unsubstituted heterocyclylalkyl ring, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, 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 y R z , —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 , or —ONO 2 ;
each occurrence of R′ and R″ is independently selected from hydrogen, hydroxy, halogen, carboxy, 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 cycloalkenyl, substituted or unsubstituted heteroaryl, substituted or unsubs

Assignees

• Rhizen Pharmaceuticals Sa

Inventors

• Nagarathnam Dhanapalan
• Vakkalanka Swaroop K
• Muthuppalaniappan Meyyappan
• Viswanadha Srikant
• Babu Govindarajulu
• Bhavar Prashant K

Classifications

• A61P43/00

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

• A61P37/08

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

• A61P37/06

  Immunosuppressants, e.g. drugs for graft rejection · CPC title

• A61P37/02

  Immunomodulators · CPC title

• A61P37/00

  Drugs for immunological or allergic disorders · CPC title