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

Patent metadata

Field	Value
Publication number	US-10226468-B2
Application number	US-201715581330-A
Country	US
Kind code	B2
Filing date	Apr 28, 2017
Priority date	Apr 12, 2013
Publication date	Mar 12, 2019
Grant date	Mar 12, 2019

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 dosing regimen comprising the step of:
administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I):

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,
or a pharmaceutically acceptable salt thereof.

2. The dosing regimen according to claim 1 , wherein the administration of the compound regulates at least one of RAS/RAF/MEK/ERK and PI3K/AKT/PTEN/mTOR pathways.

3. The dosing regimen according to claim 1 , wherein the compound is administered to the patient orally, by injection, inhalation, ocularly, transdermally, intravascularly, subcutaneously, intramuscularly, sublingually, intracranially, epidurally, rectally, or vaginally.

4. The dosing regimen according to claim 1 , wherein the compound is administered to the patient about every 2 hours, about every 6 hours, about every 8 hours, about every 12 hours, about every 24 hours, about every 36 hours, about every 48 hours, about every 72 hours, about every week, about every two weeks, about every three weeks, about every month, or about every two months.

5. The dosing regimen 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.

6. The dosing regimen 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.

7. The dosing regimen 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.

8. The dosing regimen 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.

9. The dosing regimen 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.

10. The dosing regimen 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

Assignees

• Asana Biosciences Llc

Inventors

• Thompson Scott K
• Smith Roger A
• Reddy Sanjeeva
• John Tyler M
• Nyavanandi Vijay Kumar
• Hoshalli Subramanya
• 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

• C07D401/14

  containing three or more hetero rings · CPC title