# US 8,785,459 B2 · Quinazoline compounds as kinase inhibitors

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- Number: US 8,785,459 B2
- Document ID: US8785459B2
- Status: Granted
- Kind: B2
- Application number: 13/337,863
- Filed: 2011-12-27
- Published: 2013-06-27
- Granted: 2014-07-22
- Earliest claimed: 2011-12-27
- Assignees: Development Center for Biotechnology
- Applicants: Jiann-Jyh Huang; Chu-Bin Liao; Pao-Nien Chen
- Inventors: Jiann-Jyh Huang; Chu-Bin Liao; Pao-Nien Chen
- Web page: https://patentgrep.com/patent/US8785459B2

## CPC

- C12N 9/99: Enzyme inactivation by chemical treatment
- A61P 3/10: for hyperglycaemia, e.g. antidiabetics
- A61P 13/12: of the kidneys
- A61P 19/02: for joint disorders, e.g. arthritis, arthrosis
- A61P 35/00: Antineoplastic agents
- A61P 35/02: specific for leukemia
- A61P 37/00: Drugs for immunological or allergic disorders
- C07D 239/94: Nitrogen atoms
- C12Y 207/00: Transferases transferring phosphorus-containing groups (2.7)
- C12N: MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA (microbiological testing media C12Q1/00)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- C12Y: ENZYMES

## Abstract

A compound for treating protein kinase-related disease or disorder having a structure of formula (A): wherein X is N or CH; Y is NH, O, or CH2; Z is an aryl or a heteroaryl; and R1, R2, R3, and R4 are independently H, halo, nitro, cyano, aryl, heteroaryl, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, —ORa, —C(O)Ra, —C(O)NRaRb, —NRaC(O)Rb, —NRaRb, —S(O)2Ra, —S(O)2NRaRb, —NRaS(O)2Rb, —N═CRaRb, or —NRaC(O)NHRb, wherein each of Ra and Rb, independently, is H, alkyl, alkenyl, alkynyl, aryl, aryloxy, alkoxy, hydroxy, heteroaryl, cycloalkyl, heterocycloalkyl, cycloalkenyl, or heterocycloalkenyl, or Ra and Rb, together with the nitrogen atom to which they are bonded, form heteroaryl, heterocycloalkyl, or heterocycloalkenyl; or R3 and R4 are as defined above, and R1 and R2 together with the carbons, to which they are attached, form a heterocycloalkenyl or heteroaryl.

## Claims

### Claim 1

A compound having a structure represented by formula (II)
wherein X is N; Y is NH;
wherein the heteroaryl attached to Y is selected from:
wherein each of R5, R6, and R7, independently, is H, halo, nitro, cyano, aryl, heteroaryl, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, —ORa, —C(O)Ra, —C(O)NRaRb, —NRaC(O)Rb, —NRaRb, —S(O)2Ra, —S(O)2NRaRb, —NRaS(O)2Rb, —N═CRaRb, or —NRaC(O)NHRb, wherein each of Ra and Rb, independently, is H, alkyl, alkenyl, alkynyl, aryl, aryloxy, alkoxy, hydroxy, heteroaryl, cycloalkyl, heterocycloalkyl, cycloalkenyl, or heterocycloalkenyl, or Ra and Rb, together with the nitrogen atom to which they are bonded, form heteroaryl, heterocycloalkyl, or heterocycloalkenyl;
one of R1 and R2 is —OH or —ORa and the other of R1 and R2 is —H, OH, or —ORa,
R3, and R4 are independently H or —ORa, wherein Ra is alkyl.

### Claim 2

A compound having a structure represented by formula (II)
wherein X is CH; Y is NH;
wherein the heteroaryl attached to Y is selected from:
wherein each of R5, R6, and R7, independently, is H, halo, nitro, cyano, aryl, heteroaryl, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, —ORa, —C(O)Ra, —C(O)NRaRb, —NRaC(O)Rb, —NRaRb, —S(O)2Ra, —S(O)2NRaRb, —NRaS(O)2Rb, —N═CRaRb, or —NRaC(O)NHRb, wherein each of Ra and Rb, independently, is H, alkyl, alkenyl, alkynyl, aryl, aryloxy, alkoxy, hydroxy, heteroaryl, cycloalkyl, heterocycloalkyl, cycloalkenyl, or heterocycloalkenyl, or Ra and Rb, together with the nitrogen atom to which they are bonded, form heteroaryl, heterocycloalkyl, or heterocycloalkenyl;
one of R and R2 is —OH or —ORa and the other of R1 and R2 is —H, OH, or —ORa,
R3, and R4 are independently H or —ORa, wherein Ra is alkyl.

### Claim 3

A compound of Formula (A),
wherein X is N; Y is NH:
Z is
or a heteroaryl selected from
wherein each of R5, R6, and R7, independently, is H, halo, nitro, cyano, aryl, heteroaryl, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, —ORa, —C(O)Ra, —C(O)NRaRb, —NRaC(O)Rb, —NRaRb, —S(O)2Ra, —S(O)2NRaRb, —NRaS(O)2Rb, —N═CRaRb, or —NRaC(O)NHRb, wherein each of Ra and Rb, independently, is H, alkyl, alkenyl, alkynyl, aryl, aryloxy, alkoxy, hydroxy, heteroaryl, cycloalkyl heterocycloalkyl, cycloalkenyl, or heterocycloalkenyl, or Ra and Rb, together with the nitrogen atom to which they are bonded, form heteroaryl, heterocycloalkyl, or heterocycloalkenyl;
one of R1 and R2 is —OH or —ORa and the other of R1 and R2 is —H, OH, or —ORa,
R3, and R4 are independently H or —ORa, wherein Ra is alkyl,
wherein the compound is:
2-methoxy-4-(4-(phenylamino)quinazolin-6-yl)phenol;
6-(3-fluoro-4-methoxyphenyl)-N-phenylquinazolin-4-amine;
6-(3-methoxyphenyl)-N-phenylquinazolin-4-amine;
4-(4-(phenylamino)quinazolin-6-yl)phenol;
6-(4-aminophenyl)-N-phenylquinazolin-4-amine;
2-methoxy-4-(4-(phenylamino)quinazolin-6-yl)phenyl phenylcarbamate;
4-(4-(3-hydroxyphenylamino)quinazolin-6-yl)-2-methoxyphenol;
2-methoxy-4-(4-(phenylamino)quinazolin-6-yl)phenyl ethylcarbamate;
6-(4-methoxyphenyl)-N-phenylquinazolin-4-amine;
4-(4-(3,4-dimethoxyphenylamino)quinazolin-6-yl)-2-methoxyphenol;
4-(4-(3-chloro-4-fluorophenylamino)quinazolin-6-yl)-2-methoxyphenol;
4-(4-(4-fluorophenylamino)quinazolin-6-yl)-2-methoxyphenol;
4-(4-(4-chloro-2-fluorophenylamino)quinazolin-6-yl)-2-methoxyphenol;
4-(4-(2-fluoro-4-methylphenylamino)quinazolin-6-yl)-2-methoxyphenol;
2-methoxy-4-(4-(3-(trifluoromethyl)phenylamino)quinazolin-6-yl)phenol;
4-(4-(4-hydroxyphenylamino)quinazolin-6-yl)-2-methoxyphenol;
4-(4-(2,4-difluorophenylamino)quinazolin-6-yl)-2-methoxyphenol;
4-(4-(4-chloro-2-hydroxyphenylamino)quinazolin-6-yl)-2-methoxyphenol;
2-methoxy-4-(4-(3-methoxyphenylamino)quinazolin-6-yl)phenol;
4-(4-(2-hydroxyphenylamino)quinazolin-6-yl)-2-methoxyphenol;
N-(4-(4-(phenylamino)quinazolin-6-yl)phenyl)ethanesulfonamide;
4-(4-(3-hydroxy-4-methoxyphenylamino)quinazolin-6-yl)-2-methoxyphenol;
3-(6-(4-hydroxy-3-methoxyphenyl)quinazolin-4-ylamino)benzene sulfonamide;
4-(4-(3-hydroxy-4-methylphenylamino)quinazolin-6-yl)-2-methoxyphenol;
2-methoxy-4-(7-methoxy-4-(phenylamino)quinazolin-6-yl)phenol;
4-(4-(3-hydroxyphenylamino)-7-methoxyquinazolin-6-yl)-2-methoxyphenol;
3-(6-(4-hydroxy-3-methoxyphenyl)quinazolin-4-ylamino)benzoic acid;
2-(6-(4-hydroxy-3-methoxyphenyl)quinazolin-4-ylamino)benzamide;
3-hydroxy-4-(6-(4-hydroxy-3-methoxyphenyl)quinazolin-4-ylamino)benzoic acid;
3-(6-(4-hydroxy-3-methoxyphenyl)quinazolin-4-ylamino)benzamide;
2-methoxy-4-(4-(3-nitrophenylamino)quinazolin-6-yl)phenol;
4-(4-(3-aminophenylamino)quinazolin-6-yl)-2-methoxyphenol;
4-(4-(benzo[d][1,3]dioxol-5-ylamino)quinazolin-6-yl)-2-methoxyphenol;
4-(4-(1H-indazol-6-ylamino)quinazolin-6-yl)-2-methoxyphenol;
4-(4-(1H-indol-6-ylamino)quinazolin-6-yl)-2-methoxyphenol;
4-(4-(3-hydroxy-4-methylphenylamino)-7-methoxyquinazolin-6-yl)-2-methoxyphenol;
4-(4-(3-hydroxy-4-methoxyphenylamino)-7-methoxyquinazolin-6-yl)-2-methoxyphenol;
4-(4-(2-chloro-5-hydroxyphenylamino)-7-methoxyquinazolin-6-yl)-2-methoxyphenol;
N-(3-(6-(4-hydroxy-3-methoxyphenyl)quinazolin-4-ylamino)phenyl)acetamide;
2,2,2-trifluoro-N-(3-(6-(4-hydroxy-3-methoxyphenyl)quinazolin-4-ylamino)phenyl)acetamide;
4-(6-(4-hydroxy-3-methoxyphenyl)quinazolin-4-ylamino)benzenesulfonamide;
4-(6-(4-hydroxy-3-methoxyphenyl)quinazolin-4-ylamino)benzamide;
2-(6-(4-hydroxy-3-methoxyphenyl)quinazolin-4-ylamino)-4-methoxybenzoic acid;
3-(6-(4-hydroxyphenyl)-7-methoxyquinazolin-4-ylamino)phenol;
2-(6-(4-hydroxy-3-methoxyphenyl)quinazolin-4-ylamino)benzoic acid;
4-(4-(1H-indazol-4-ylamino)quinazolin-6-yl)-2-methoxyphenol;
4-(4-(3-fluorophenylamino)quinazolin-6-yl)-2-methoxyphenol;
3-(6-(4-hydroxy-3-methoxyphenyl)quinazolin-4-ylamino)-2-methylphenol;
4-(4-(1H-benzo[d]imidazol-6-ylamino)quinazolin-6-yl)-2-methoxyphenol;
4-(4-(5-hydroxy-2-methoxyphenylamino)quinazolin-6-yl)-2-methoxyphenol;
N-(3-(6-(4-hydroxy-3-methoxyphenyl)quinazolin-4-ylamino)phenyl)methanesulfonamide;
4-(6-(4-hydroxy-3-methoxyphenyl)quinazolin-4-ylamino)benzoic acid;
4-(4-(2-fluoro-5-hydroxyphenylamino)quinazolin-6-yl)-2-methoxyphenol;
4-(4-(2-chloro-5-hydroxyphenylamino)quinazolin-6-yl)-2-methoxyphenol;
2-chloro-3-(6-(4-hydroxy-3-methoxyphenyl)quinazolin-4-ylamino)phenol;
2,4-dichloro-5-(6-(4-hydroxy-3-methoxyphenyl)quinazolin-4-ylamino)phenol;
3-(6-(4-hydroxyphenyl)quinazolin-4-ylamino)phenol;
3-(6-(3-hydroxyphenyl)quinazolin-4-ylamino)phenol;
3-(6-(4-methoxyphenyl)quinazolin-4-ylamino)phenol;
1,1,1-trifluoro-N-(3-(6-(4-hydroxy-3-methoxyphenyl)quinazolin-4-ylamino)phenyl)methanesulfonamide;
4-(4-(1H-benzo[d][1,2,3]triazol-5-ylamino)quinazolin-6-yl)-2-methoxyphenol;
3-(6-(3-methoxyphenyl)quinazolin-4-ylamino)phenol;
6-(2-fluoro-3-methoxyphenyl)-N-(1H-indazol-4-yl)quinazolin-4-amine;
6-(3-fluoro-4-methoxyphenyl)-N-(1H-indazol-4-yl)quinazolin-4-amine;
6-(3-chloro-4-methoxyphenyl)-N-(1H-indazol-4-yl)quinazolin-4-amine;
N-(1H-indazol-4-yl)-6-(4-methoxy-2-methylphenyl)quinazolin-4-amine;
N-(1H-indazol-4-yl)-6-(4-methoxy-3-methylphenyl)quinazolin-4-amine;
4-(4-(1H-benzo[d][1,2,3]triazol-4-ylamino)quinazolin-6-yl)-2-methoxyphenol;
4-(4-(1H-indol-4-ylamino)quinazolin-6-yl)-2-methoxyphenol;
6-(4-fluoro-3-methoxyphenyl)-N-(1H-indazol-4-yl)quinazolin-4-amine;
6-(3,4-dimethoxyphenyl)-N-(1H-indazol-4-yl)quinazolin-4-amine;
6-(4-ethoxyphenyl)-N-(1H-indazol-4-yl)quinazolin-4-amine;
5-(4-(1H-indazol-4-ylamino)quinazolin-6-yl)-2-methoxybenzaldehyde;
2-methoxy-4-(4-(1-methyl-1H-indazol-4-ylamino)quinazolin-6-yl)phenol;
4-(4-(3-hydroxyphenylamino)quinolin-6-yl)-2-methoxyphenol;
4-(4-(2-fluoro-5-hydroxyphenylamino)quinolin-6-yl)-2-methoxyphenol;
4-(4-(1H-indazol-4-ylamino)quinolin-6-yl)-2-methoxyphenol;
6-(2,3-dimethoxyphenyl)-N-(1H-indazol-4-yl)quinazolin-4-amine;
6-(2-fluoro-3-methoxyphenyl)-N-(1H-indazol-4-yl)quinolin-4-amine;
6-(3-fluoro-4-methoxyphenyl)-N-(1H-indazol-4-yl)quinolin-4-amine;
6-(3,4-dimethoxyphenyl)-N-(1H-indazol-4-yl)quinolin-4-amine;
6-(3-chloro-4-methoxyphenyl)-N-(1H-indazol-4-yl)quinolin-4-amine;
5-(4-(1H-indazol-4-ylamino)quinolin-6-yl)-2-methoxybenzaldehyde;
4-(4-(3-(difluoromethoxy)phenylamino)quinazolin-6-yl)-2-methoxyphenol;
4-(4-(2-fluorophenylamino)quinazolin-6-yl)-2-methoxyphenol;
N-(1H-indazol-4-yl)-6-(4-(methylsulfonyl)phenyl)quinolin-4-amine;
N-(1H-indazol-4-yl)-6-(3-methoxyphenyl)quinolin-4-amine;
4-(4-(1H-indazol-4-ylamino)quinolin-6-yl)phenol;
4-(4-(3-chloro-1H-indazol-4-ylamino)quinazolin-6-yl)-2-methoxyphenol;
4-(6-(4-hydroxy-3-methoxyphenyl)quinazolin-4-ylamino)-1H-benzo[d]imidazol-2(3H)-one;
N-(4-fluoro-3-(6-(4-hydroxy-3-methoxyphenyl)quinolin-4-ylamino)phenyl)methanesulfonamide;
N-(4-fluoro-3-(6-(4-hydroxy-3-methoxyphenyl)quinazolin-4-ylamino)phenyl)methanesulfonamide;
N-(2-fluoro-5-(6-(4-hydroxy-3-methoxyphenyl)quinazolin-4-ylamino)phenyl)methanesulfonamide;
4-(4-(1H-indazol-4-ylamino)quinazolin-6-yl)phenol;
3-(6-phenylquinazolin-4-ylamino)phenol;
4-(4-(2,6-difluorophenylamino)quinazolin-6-yl)-2-methoxyphenol;
4-(1H-indazol-4-ylamino)-6-(4-hydroxy-3-methoxyphenyl)quinoline-3-carbonitrile;
4-(4-(5-fluoro-1H-indazol-4-ylamino)quinazolin-6-yl)-2-methoxyphenol;
N-(4-chloro-3-(6-(4-hydroxy-3-methoxyphenyl)quinazolin-4-ylamino)phenyl)methanesulfonamide;
N-(2-chloro-5-(6-(4-hydroxy-3-methoxyphenyl)quinazolin-4-ylamino)phenyl)methanesulfonamide;
N-(2-chloro-5-(6-(4-hydroxy-3-methoxyphenyl)quinolin-4-ylamino)phenyl)methanesulfonamide;
3-(4-(1H-indazol-4-ylamino)quinazolin-6-yl)phenol;
N-(1H-indazol-4-yl)-6-(3-methoxyphenyl)quinazolin-4-amine;
N-(2-fluoro-5-(6-(4-hydroxy-3-methoxyphenyl)quinolin-4-ylamino)phenyl)methanesulfonamide;
N-(1H-indazol-4-yl)-6-(3-methoxyphenyl)quinolin-4-amine;
N-(1H-indazol-4-yl)-6-(4-methoxyphenyl)quinazolin-4-amine;
3-(4-(1H-indazol-4-ylamino)quinolin-6-yl)phenol;
4-(4-(5-fluoro-1H-indazol-4-ylamino)quinazolin-6-yl)-2-methoxyphenol;
N-(2,4-difluoro-5-(6-(4-hydroxy-3-methoxyphenyl)quinazolin-4-ylamino)phenyl)methanesulfonamide;
N-(3-ethynylphenyl)-6-(4-methoxyphenyl)quinazolin-4-amine;
3-(6-(4-methoxyphenyl)quinazolin-4-yloxy)phenol;
4-(4-(5-hydroxy-2-methylphenylamino)quinazolin-6-yl)-2-methoxyphenol;
2-methoxy-4-(4-(5-methyl-1H-indazol-4-ylamino)quinazolin-6-yl)phenol;
4-fluoro-5-(6-(4-hydroxy-3-methoxyphenyl)quinazolin-4-ylamino)-2-methylphenol;
4-(4-(4-chloro-3-hydroxyphenylamino)quinazolin-6-yl)-2-methoxyphenol;
2,4-difluoro-5-(6-(4-hydroxy-3-methoxyphenyl)quinazolin-4-ylamino)phenol;
2-chloro-4-fluoro-5-(6-(4-hydroxy-3-methoxyphenyl)quinazolin-4-ylamino)phenol;
5-(6-(4-chlorophenyl)quinazolin-4-ylamino)-2,4-difluorophenol;
4-(4-(4-fluoro-3-hydroxyphenylamino)quinazolin-6-yl)-2-methoxyphenol;
2,6-difluoro-3-(6-(4-hydroxy-3-methoxyphenyl)quinazolin-4-ylamino)phenol;
3-(6-(1H-indazol-5-yl)quinazolin-4-ylamino)-2,6-difluorophenol; or
3-(6-(4-chlorophenyl)quinazolin-4-ylamino)-2,6-difluorophenol.