Aminoquinazoline derivatives and their salts and methods of use thereof

Patent metadata

Field	Value
Publication number	US-9556191-B2
Application number	US-201414774702-A
Country	US
Kind code	B2
Filing date	Apr 28, 2014
Priority date	Apr 28, 2013
Publication date	Jan 31, 2017
Grant date	Jan 31, 2017

Abstract

Provided herein are aminoquinazoline compounds, salts and uses thereof. The compounds have Formula (I), or a stereoisomer, a geometric isomer, a tautomer, an N-oxide, a hydrate, a solvate, a metabolite, a pharmaceutically acceptable salt or a prodrug thereof. Also provided herein are pharmaceutical compositions containing the compounds disclosed herein, and uses of the compounds or the compositions for preventing, managing, treating or lessening the severity of a proliferative disorder in a patient and for modulating the protein tyrosine kinase activity.

First claim

What is claimed is:

1. A compound having Formula (I):

or a stereoisomer, a geometric isomer, a tautomer, a hydrate, a solvate, or a pharmaceutically acceptable salt thereof, wherein
R is

wherein each X and X 1a is independently O, S, S(═O), S(═O) 2 or NR a ;
X 1b is O, S, S(═O), or S(═O) 2 ;
X 1c is S, S(═O) or S(═O) 2 ;
each Y, Y 1 , and Y 2 is independently O, S, S(═O), S(═O) 2 , NR a or CR b R b′ ;
Y 1a is O, S, S(═O), S(═O) 2 , or CR b R b′ ;
each Y 3 is independently CR b″ or N;
wherein each R a is independently H, D or C 1-3 alkyl;
each R b , R b′ and R b″ is independently H, D, F, Cl, Br, I, —OH, —NO 2 , —NH 2 , —CN, C 1-3 alkyl, C 1-3 alkoxy or C 1-3 alkylamino;
each R 7 is independently H, D, F, Cl, Br, I, —OH, —SH, —NO 2 , —NH 2 , —CN, —COOH, C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 alkylamino, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, C 2-10 heterocyclyl, C 6-10 aryl, C 6-10 aryl-C 1-6 -alkyl, C 6-10 aryloxy, C 6-10 aryl-C 1-6 -alkoxy or C 1-9 heteroaryl;
each d is independently 0, 1, 2, 3, 4 or 5;
e is 0, 1, 2, or 3;
f is 0 or 1;
L is a bond, O or S;
R 1 is H, D, F, Cl, Br, I, —OH, —NO 2 , —NH 2 , —CN, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy-C 1-6 -alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkylamino-C 1-6 -alkyl, C 3-8 cycloalkyl, C 3-8 cycloalkyl-C 16 -alkyl, C 3-8 cycloalkyl-C 2-6 -alkenyl, C 3-8 cycloalkyl-C 2-6 -alkynyl, C 3-8 cycloalkyloxy-C 2-6 -alkynyl, C 2-10 heterocyclyl, C 2-10 heterocyclyl-C 1-6 -alkyl, C 2-10 heterocyclyl-C 2-6 -alkenyl, C 2-10 heterocyclyl-C 2-6 -alkynyl, C 5-12 fused bicyclyl, C 5-12 fused bicyclyl-C 1-6 -alkyl, C 5-12 fused bicyclyl-C 2-6 -alkenyl, C 5-12 fused bicyclyl-C 2-6 -alkynyl, C 5-12 fused heterobicyclyl, C 5-12 fused heterobicyclyl-C 1-6 -alkyl, C 5-12 fused heterobicyclyl-C 2-6 -alkenyl, C 5-12 fused heterobicyclyl-C 2-6 -alkynyl, C 5-12 spiro bicyclyl, C 5-12 spiro bicyclyl-C 1-6 -alkyl, C 5-12 spiro bicyclyl-C 2-6 -alkenyl, C 5-12 spiro bicyclyl-C 2-6 -alkynyl, C 5-12 spiro heterobicyclyl, C 5-12 spiro heterobicyclyl-C 1-6 -alkyl, C 5-12 spiro heterobicyclyl-C 2-6 -alkenyl, C 5-12 spiro heterobicyclyl-C 2-6 -alkynyl, C 6-10 aryl, C 6-10 aryl-C 1-6 -alkyl, C 1-9 heteroaryl or C 1-9 heteroaryl-C 1-6 -alkyl;
R 2 is H, F, Cl, Br, I, —NH 2 , —NO 2 , —CN or C 1-6 alkyl;
each of R 3 and R 4 is independently H, D or C 1-4 alkyl;
R 5 is H;
Ar is

wherein each R 6 is independently H, D, F, Cl, Br, I, C 2-6 alkynyl, C 6-10 aryl-C 1-6 -alkoxy, or C 1-9 heteroaryl-C 1-6 -alkoxy;
k is 0, 1, 2, 3, 4 or 5; and
R y is H or C 6-10 aryl-C 1-6 -alkyl,
wherein optionally each of alkyl, alkoxy, alkoxyalkyl, alkylamino, alkylaminoalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkylalkynyl, cycloalkyloxyalkynyl, heterocyclyl, heterocyclylalkyl, heterocyclylalkenyl, heterocyclylalkynyl, fused bicyclyl, fused bicyclylalkyl, fused bicyclylalkenyl, fused bicyclylalkynyl, fused heterobicyclyl, fused heterobicyclylalkyl, fused heterobicyclylalkenyl, fused heterobicyclylalkynyl, spiro bicyclyl, spiro bicyclylalkyl, spiro bicyclylalkenyl, spiro bicyclylalkynyl, spiro heterobicyclyl, spiro heterobicyclylalkyl, spiro heterobicyclylalkenyl, spiro heterobicyclylalkynyl, aryl, aryloxy, arylalkyl, arylalkoxy, arylamino, heteroaryl, heteroarylalkyl, heteroarylalkoxy, heteroaryloxy, alkylthio, alkylcarbonyl, alkylacylamino, alkylsulfonyl, haloalkyl and alkylsulfinyl is independently substituted with one or more substituents independently selected from D, F, Cl, Br, I, —OH, —NO 2 , —NH 2 , —CN, —COOH, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 alkylamino, C 1-3 alkylthio, C 6-10 aryl, C 6-10 aryloxy, C 6-10 arylamino, C 1-9 heteroaryl, C 1-9 heteroaryloxy, C 3-8 cycloalkyl, C 3-8 cycloalkyloxy, C 2-10 heterocyclyl and C 5-12 fused heterobicyclyl, and wherein optionally each of C 1-3 alkyl, C 1-3 alkoxy, C 1-3 alkylamino, C 1-3 alkylthio, C 6-10 aryl, C 6-10 aryloxy, C 6-10 arylamino, C 1-9 heteroaryl, C 1-9 heteroaryloxy, C 3-8 cycloalkyl, C 3-8 cycloalkyloxy, C 2-10 heterocyclyl and C 5-12 fused heterobicyclyl is independently substituted with one or more substituents independently selected from D, F, Cl, Br, I, —OH, —NO 2 , —NH 2 , —CN, —COOH, C 1-3 alkyl, deuterated C 1-3 alkyl, C 1-3 haloalkyl and hydroxy-substituted C 1-3 alkyl.

2. The compound according to claim 1 , wherein R is

3. The compound according to claim 2 , wherein R is

4. The compound according to claim 1 , wherein R 1 is H, D, F, Cl, Br, I, —OH, —NO 2 , —NH 2 , —CN, C 1-6 alkyl, C 2-6 alkynyl or C 1-6 alkoxy-C 1-6 -alkyl, and wherein optionally each of C 1-6 alkyl, C 2-6 alkynyl and C 1-6 alkoxy-C 1-6 -alkyl is independently substituted with one or more substituents independently selected from D, F, Cl, Br, I, —OH, —NO 2 , —NH 2 , —CN, —COOH, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkylamino, C 1-3 alkoxy, C 6-10 aryl, C 1-9 heteroaryl, C 3-8 cycloalkyl, C 3-8 cycloalkyloxy and C 2-10 heterocyclyl, or R 1 is

wherein each A, G, E and J is independently CR b R b′ , NR a , O, S, S(═O) or S(═O) 2 ;
each K is independently NR a , O, S, S(═O) or S(═O) 2 ;
each L is independently a bond, C 1-4 alkylene, C 2-4 alkenylene or C 2-4 alkynylene, wherein optionally each of C 1-4 alkylene, C 2-4 alkenylene and C 2-4 alkynylene is independently substituted with one or more substituents independently selected from D, F, Cl, Br, I, —OH, —NO 2 , —NH 2 , —CN, —COOH and C 1-3 alkyl;
each R 8 is independently H, D, F, Cl, Br, I, —OH, —SH, —NO 2 , —NH 2 , —CN, —COOH, C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 alkylamino, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, C 2-10 heterocyclyl or C 5-12 fused heterobicyclyl, wherein optionally each of C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 alkylamino, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, C 2-10 heterocyclyl and C 5-12 fused heterobicyclyl is independently substituted with one or more substituents independently selected from D, F, Cl, Br, I, —OH, —SH, —NO 2 , —NH 2 , —CN, —COOH, C 1-3 alkyl and C 1-3 haloalkyl;
each g is independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 or 13;
m is 0, 1, 2, 3 or 4;
each n is independently 0, 1 or 2; and
each p is independently 1 or 2.

5. The compound according to claim 4 , wherein R 1 is H, D, F, Cl, Br, I, —OH, —NO 2 , —NH 2 , —CN, C 1-3 alkyl, C 2-3 alkynyl or C 1-3 alkoxy-C 13 -alkyl, and wherein optionally each of C 1-3 alkyl, C 2-3 alkynyl and C 1-3 alkoxy-C 1-3 -alkyl is independently substit

Assignees

• Sunshine Lake Pharma Co Ltd
• Sunshine Lake Pharma Co Ltd

Inventors

• Zhang Yingjun
• Liu Bing
• Liu Jinlei
• Zhang Jiancun
• Cheng Changchung

Classifications

• A61P35/02

  specific for leukemia · CPC title

• A61P35/04

  specific for metastasis · CPC title

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · 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

• A61P7/00

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