Quinazolines and azaquinazolines as dual inhibitors of RAS/RAF/MEK/ERK and PI3K/AKT/PTEN/mTOR pathways

Patent metadata

Field	Value
Publication number	US-9757382-B2
Application number	US-201615290788-A
Country	US
Kind code	B2
Filing date	Oct 11, 2016
Priority date	Apr 12, 2013
Publication date	Sep 12, 2017
Grant date	Sep 12, 2017

Abstract

The present application provides novel quinazolines and azaquinazolines and pharmaceutically acceptable salts thereof. Also provided are methods for preparing these compounds. These compounds are useful in for co-regulating RAS/RAF/MEK/ERK and PI3K/AKT/PTEN/mTOR pathways by administering a therapeutically effective amount of one or more of the compounds of formula (I), wherein X, Y, T and R 4 , and R 6 to R 8′ are defined herein, to a patient. By doing so, these compounds are effective in treating conditions associated with the dysregulation of the RAS/RAF/MEK/ERK and PI3K/AKT/PTEN/mTOR pathways. A variety of conditions can be treated using these compounds and include diseases which are characterized by abnormal cellular proliferation. In one embodiment, the disease is cancer.

First claim

What is claimed is:

1. A method for co-regulating RAS/RAF/MEK/ERK and PI3K/AKT/PTEN/mTOR, said method comprising administering a therapeutically effective amount of a compound of formula (I) to a patient in need thereof:

wherein:
X is CH or N;
Y is H, optionally substituted C 1 -C 6 alkyl, OR 1 or NR 2 R 3 ;
T is H or C 1 -C 6 alkoxy;
R 1 is optionally substituted C 1 -C 6 alkyl, optionally substituted (C 1 -C 6 alkyl)OH, optionally substituted (C 1 -C 6 alkyl)OC 1 -C 6 alkyl, optionally substituted C 3 -C 8 cycloalkyl, optionally substituted (C 1 -C 6 alkyl)NH 2 , optionally substituted (C 1 -C 6 alkyl)CO 2 H, or optionally substituted (C 1 -C 6 alkyl)CONH 2 ;
R 2 and R 3 are joined to form an optionally substituted heterocycle;
R 4 is optionally substituted morpholine;
R 6 is optionally substituted aryl or optionally substituted heteroaryl;
R 7 is optionally substituted aryl, optionally substituted C 1 -C 6 alkyl, or optionally substituted heteroaryl;
R 8 is H or halogen; and
R 8′ is halogen.

2. The method according to claim 1 ,
wherein:
R 4 is morpholine substituted by C 1 -C 6 alkyl;
R 6 is:

wherein:
M is N or CR 10 ;
Q is N or CR 13 ;
Z is N or CR 14 ;
R 10 is H, C 1 -C 6 alkyl, halogen, CN or CF 3 ;
R 12 to R 14 are, independently, H, halogen, C 1 -C 6 alkyl, or CF 3 ;
R 17 is NHC(O)NHNR 9 , H, C 1 -C 6 alkyl, (C 1 -C 6 alkyl)-NH 2 or (C 1 -C 6 alkyl)-OH, (C 1 -C 6 alkyl)-O—(C 1 -C 6 alkyl), CO(C 1 -C 6 alkyl) or SO 2 (C 1 -C 6 alkyl); or
R 13 and R 17 or R 14 and R 17 are joined to form an optionally unsaturated ring;
R 9 is C 1 -C 6 alkyl, C 1 -C 6 hydroxyalkyl, or heteroaryl; and
R 15 is C 1 -C 6 fluoroalkyl or C 1 -C 6 hydroxyalkyl; and

R 7 is phenyl substituted by one or more halogen, C 1 -C 6 alkyl optionally substituted by one or more F, or thiophene.

3. The method according to claim 1 , wherein R 6 is:

wherein:
Z is CH or N; and
R 9 is C 1 -C 6 alkyl, C 1 -C 6 hydroxyalkyl, or heteroaryl.

4. The method according to claim 1 , wherein R 6 is an optionally substituted pyrimidine, optionally substituted pyridine, optionally substituted pyrrole[2,3-b]pyridine, optionally substituted indazole or optionally substituted benzimidazole.

5. The method according to claim 1 , wherein R 6 is:

wherein:
R 10 is H, C 1 -C 6 alkyl or CF 3 ; and
R 17 is H, C 1 -C 6 alkyl, (C 1 -C 6 alkyl)-NH 2 or (C 1 -C 6 alkyl)-OH.

6. The method according to claim 1 , wherein R 6 is:

wherein:
R 10 , R 12 and R 13 are, independently, H, halogen, C 1 -C 6 alkyl, CN or CF 3 ; and
R 17 is H, C 1 -C 6 alkyl, (C 1 -C 6 alkyl)-NH 2 or (C 1 -C 6 alkyl)-OH; or
R 13 and R 17 are joined to form an optionally unsaturated 5-membered ring.

7. The method according to claim 1 , wherein the compound is selected from the group consisting of:
2,6-difluoro-N-(2-fluoro-3-(8-methoxy-2-(4-(3-methylureido)phenyl)-4-morpholinoquinazolin-6-yl)phenyl)benzenesulfonamide;
N-(3-(2-(1H-indazol-4-yl)-8-methoxy-4-morpholinoquinazolin-6-yl)-2-fluorophenyl)propane-1-sulfonamide;
N-(3-(2-(6-((2-aminoethyl)amino)pyridin-3-yl)-8-methoxy-4-morpholinoquinazolin-6-yl)-2-fluorophenyl)propane-1-sulfonamide;
N-(3-(2-(6-aminopyridin-3-yl)-8-(2-hydroxyethoxy)-4-morpholinoquinazolin-6-yl)-2-fluorophenyl)propane-1-sulfonamide;
N-(3-(2-(6-aminopyridin-3-yl)-4,8-dimorpholinoquinazolin-6-yl)-2-fluorophenyl)-3-fluoropropane-1-sulfonamide;
N-(3-(2-(2-aminopyrimidin-5-yl)-8-methoxy-4-morpholinoquinazolin-6-yl)-2,4-difluorophenyl)propane-1-sulfonamide;
N-(3-(2-(2-aminopyrimidin-5-yl)-4-morpholinopyrido[3,2-d]pyrimidin-6-yl)-2-fluorophenyl)propane-1-sulfonamide;
N-(3-(2-(6-aminopyridin-3-yl)-8-methyl-4-morpholinoquinazolin-6-yl)-2-fluorophenyl)propane-1-sulfonamide;
N-(3-(2-(2-(difluoromethyl)-1H-benzo[d]imidazol-1-yl)-8-methoxy-4-morpholinoquinazolin-6-yl)-2-fluorophenyl)propane-1-sulfonamide;
N-(2-fluoro-3-(2-(2-(hydroxymethyl)-1H-benzo[d]imidazol-1-yl)-8-methoxy-4-morpholinoquinazolin-6-yl)phenyl)propane-1-sulfonamide;
N-(3-(2-(2-aminopyrimidin-5-yl)-7-methoxy-4-morpholinoquinazolin-6-yl)-2-fluorophenyl)-3-fluoropropane-1-sulfonamide;
2,6-difluoro-N-(2-fluoro-3-(2-(4-(3-(2-hydroxyethyl)ureido)phenyl)-8-methoxy-4-morpholinoquinazolin-6-yl)phenyl)benzenesulfonamide;
N-(3-(2-(2-aminopyrimidin-5-yl)-8-methoxy-4-morpholinoquinazolin-6-yl)-2-fluorophenyl)-2,6-difluorobenzenesulfonamide;
N-(2-fluoro-3-(8-methoxy-2-(4-(3-methylureido)phenyl)-4-morpholinoquinazolin-6-yl)phenyl)propane-1-sulfonamide;
N-(3-(2-(2-aminopyrimidin-5-yl)-8-methoxy-4-morpholinoquinazolin-6-yl)-2-fluorophenyl)propane-1-sulfonamide;
2,6-difluoro-N-(2-fluoro-3-(8-methoxy-4-morpholino-2-(1H-pyrrolo[2,3-b]pyridin-5-yl)quinazolin-6-yl)phenyl)benzenesulfonamide;
N-(3-(2-(6-aminopyridin-3-yl)-8-methoxy-4-morpholinoquinazolin-6-yl)-2-fluorophenyl)propane-1-sulfonamide;
N-(3-(2-(6-amino-2-fluoropyridin-3-yl)-8-methoxy-4-morpholinoquinazolin-6-yl)-2-fluorophenyl)propane-1-sulfonamide;
N-(3-(2-(6-aminopyridin-3-yl)-8-methoxy-4-morpholinoquinazolin-6-yl)-2-fluorophenyl)-2,6-difluorobenzenesulfonamide;
N-(3-(2-(2-aminopyrimidin-5-yl)-8-methoxy-4-morpholinoquinazolin-6-yl)-2-fluorophenyl)-2-methylpropane-1-sulfonamide;
N-(3-(2-(2-aminopyrimidin-5-yl)-8-methoxy-4-morpholinoquinazolin-6-yl)-2-fluorophenyl)ethanesulfonamide;
N-(3-(2-(2-aminopyrimidin-5-yl)-8-methoxy-4-morpholinoquinazolin-6-yl)-2-fluorophenyl)-2,5-difluorobenzenesulfonamide;
N-(3-(2-(2-aminopyrimidin-5-yl)-8-methoxy-4-morpholinoquinazolin-6-yl)-2-fluorophenyl)butane-1-sulfonamide;
N-(3-(2-(2-aminopyrimidin-5-yl)-8-methoxy-4-morpholinoquinazolin-6-yl)-2-fluorophenyl)-2,4-difluorobenzenesulfonamide;
N-(3-(2-(6-amino-4-(trifluoromethyl)pyridin-3-yl)-8-methoxy-4-morpholinoquinazolin-6-yl)-2-fluorophenyl)propane-1-sulfonamide;
N-(3-(2-(6-amino-5-methylpyridin-3-yl)-8-methoxy-4-morpholinoquinazolin-6-yl)-2-fluorophenyl)propane-1-sulfonamide;
N-(3-(2-(2-aminopyrimidin-5-yl)-8-methoxy-4-morpholinoquinazolin-6-yl)-2-fluorophenyl)-3-fluoropropane-1-sulfonamide;
N-(3-(2-(6-aminopyridin-3-yl)-8-methoxy-4-morpholinoquinazolin-6-yl)-2-fluorophenyl)-2,5-difluorobenzenesulfonamide;
N-(3-(2-(6-aminopyridin-3-yl)-8-methoxy-4-morpholinoquinazolin-6-yl)-2-fluorophenyl)-2-fluorobenzenesulfonamide;
N-(3-(2-(6-aminopyridin-3-yl)-8-methoxy-4-morpholinoquinazolin-6-yl)-2-fluorophenyl)-3-fluoropropane-1-sulfonamide;
N-(3-(2-(6-aminopyridin-3-yl)-8-methoxy-4-morpholinoquinazolin-6-yl)-2-fluorophenyl)-3,3,3-trifluoropropane-1-sulfonamide;
3-fluoro-N-(2-fluoro-3-(8-methoxy-2-(4-(3-methylureido)phenyl)-4-morpholinoquinazolin-6-yl)phenyl)propane-1-sulfonamide;
N-(3-(2-(6-aminopyridin-3-yl)-8-methoxy-4-morpholinoquinazolin-6-yl)-2-fluorophenyl)propane-2-sulfonamide;
N-(2-fluoro-3-(8-methoxy-4-morpholino-2-(4-(3-(pyridin-4-yl)ureido)phenyl)quinazolin-6-yl)phenyl)propane-1-sulfonamide;
N-(3-(2-(2-amino-4-methylpyrimidin-5-yl)-8-methoxy-4-morpholinoquinazolin-6-yl)-2-fluorophenyl)-3-fluoropropane-1-sulfonamide;
N-(3-(2-(6-amino-4-(trifluoromethyl)pyridin-3-yl)-8-methoxy-4-morpholinoquinazolin-6-yl)-2-fluorophenyl)-3-fluoropropane-1-sulfonamide;
N-(3-(2-(1H-indazol-4-yl)-8-methoxy-4-morpholinoquinazolin

Assignees

• Asana Biosciences Llc

Inventors

• Thompson Scott K
• Smith Roger A
• Reddy Sanjeeva
• John Tyler M
• Nyavanandi Vijay Kumar
• Subramanya Hosahalli
• Potluri Vijay
• Panigrahi Sunil Kumar
• Nadipalli Prabhakara Rao
• Sengupta Saumitra

Classifications

• A61P43/00

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

• A61P35/02

  specific for leukemia · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• G01N33/57595

  involving intracellular compounds · CPC title

• C07D239/94

  Nitrogen atoms · CPC title