# US 9,751,884 B2 · N-aryl unsaturated fused ring tertiary amine compounds, preparation method and anti-tumor applications thereof

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- Number: US 9,751,884 B2
- Document ID: US9751884B2
- Status: Granted
- Kind: B2
- Application number: 14/403,750
- Filed: 2013-05-30
- Published: 2015-05-21
- Granted: 2017-09-05
- Earliest claimed: 2012-05-31
- Assignees: Institute of Pharmacology and Toxicology Academy of Military Medical Sciences P.L.A. China
- Applicants: Institute of Pharmacology and Toxicology Academy of Military Medical Sciences P.L.A. China
- Inventors: Lan Xie; Xiaofeng Wang; Kuo-Hsiung Lee
- Web page: https://patentgrep.com/patent/US9751884B2

## CPC

- C07D 473/40: with halogen atoms or perhalogeno-alkyl radicals directly attached in position 2 or 6
- A61P 35/00: Antineoplastic agents
- A61P 35/02: specific for leukemia
- C07D 215/20: Oxygen atoms
- C07D 401/04: directly linked by a ring-member-to-ring-member bond
- C07D 403/04: directly linked by a ring-member-to-ring-member bond
- C07D 413/04: directly linked by a ring-member-to-ring-member bond
- C07D 473/00: Heterocyclic compounds containing purine ring systems
- C07D 473/32: Nitrogen atom
- C07D 473/34: attached in position 6, e.g. adenine
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

The present invention relates to a compound of Formula I or a pharmaceutically acceptable salt thereof, its preparation method, a pharmaceutical composition comprising the compound, and its use in manufacture of a medicament for treatment of a disease or disorder, wherein R1, R2, R5, R6, X, Y, Q, W, n1 and n2 are defined as those stated in the description.

## Claims

### Claim 1

A compound of Formula I or a pharmaceutically acceptable salt thereof:
wherein,
X is —NR′—, and Y is —C(O)—, —CHOR′—, or —CR′R″—; wherein R′ and R″ each independently are H, C1-6 alkyl, C1-6 alkoxyl, C1-6 alkylamino, or hydroxyl;
R1 represents 1 or 2 substituents optionally existing on the benzene ring, independently being C1-6 alkyl, C1-6 alkoxyl, halogen, hydroxyl, cyano, amino, or C1-6alkylamino;
R2 is C1-6 alkyl, C1-6 alkoxyl, halogen, acyl, alkenyl, alkynyl, hydroxyl, cyano, alkylamino, dialkylamino, acylamino, alkylthio, cycloalkyl, cyano alkyl, heterocycloalkyl or aryl;
Q and W each independently are N;
R5 and R6 together with carbon atoms linked to them form 6-membered aromatic ring forming a conjugated system, wherein the aromatic ring is optionally substituted with 1 or 2 R3;
R3 independently is H, C1-6 alkyl, C1-6 alkoxyl, fluorine, chlorine, bromine, iodine, acyl, hydroxyl, cyano, amino, C1-6 alkylamino, C1-6dialkylamino, acylamino, C1-6 alkylthio, or C3-6 cycloalkyl;
n1=1; and
n2=0.

### Claim 2

A compound selected from the group consisting of:
N1-[4-(2-chloro)quinazolinyl]-6-methoxy-1,2,3,4-tetrahydroquinoline (Compound 1),
N1-[4-(2-methyl)quinazolinyl]-6-methoxy-1,2,3,4-tetrahydroquinoline (Compound 2),
N1-[4-(2-methoxy)quinazolinyl]-6-methoxy-1,2,3,4-tetrahydroquinoline (Compound 3),
N1-[4-(2-methylamino)quinazolinyl]-6-methoxy-1,2,3,4-tetrahydroquinoline (Compound 4),
2-methyl-4-(6-methoxy-7-fluoro-3,4-dihydroquinolin-1(2H)-yl)quinazoline (Compound 5),
N1-[4-(2-methyl)quinazolinyl]-6-methyl-1,2,3,4-tetrahydroquinoline (Compound 6),
N1-[4-(2-methyl)quinazolinyl]-6-bromo-1,2,3,4-tetrahydroquinoline (Compound 7),
N2-[4-(2-methyl)quinazolinyl]-7-methoxy-2,3,4,5-tetrahydro-1H-benzo[c]azepine (Compound 9),
N1-[4-(2-chloro)quinazolinyl]-7-methoxy-2,3,4,5-tetrahydro-1H-benzo[b]azepine (Compound 10),
N1-[4-(2-methyl)quinazolinyl]-4-hydroxyl-6-methoxy-1,2,3,4-tetrahydroquinoline (Compound 11),
N1-[4-(2-chloro)quinazolinyl]-4-ethoxy-6-methoxy-1,2,3,4-tetrahydroquinoline (Compound 12),
N4-[4-(2-chloro)quinazolinyl]-7-methoxy-3,4-dihydro-2H-benzo[b][1,4]oxazine (Compound 13),
N4-[4-(2-methyl)quinazolinyl]-6-fluoro-7-methoxy-3,4-dihydro-2H-benzo[b][1,4]oxazine (Compound 14),
4-(2-chloroquinazolin-4-yl)-7-methoxy-3,4-dihydro-2H-benzo[b][1,4]thiazine (Compound 15),
4-(2-chloroquinazolin-4-yl)-7-methoxy-3,4-dihydro-2H-benzo[b][1,4]-1-oxythiazine (Compound 16),
4-(2-chloroquinazolin-4-yl)-7-methoxy-3,4-dihydro-2H-benzo[b][1,4]-1,1-dioxythiazine (Compound 17),
N1-[4-(2-chloro)quinazolinyl]-6-methoxy-2,3-dihydroquinolin-4(1H)-one (Compound 18),
N4-[4-(2-methyl)quinazolinyl]-7-methoxy-3,4-dihydroquinoxalin-2(1H)-one (Compound 19),
6-methoxy-2′-methyl-3,4-dihydro-2H-1,4′-biquinoline (Compound 20),
2-methyl-4-(6-methoxy-3,4-dihydroquinolin-1(2H)-yl)pyrido[2,3-d]pyrimidine (Compound 21),
2-methyl-4-(6-methoxy-3,4-dihydroquinolin-1(2H)-yl)pyrido[3,4-d]pyrimidine (Compound 22),
2-methyl-4-(6-methoxy-3,4-dihydroquinolin-1(2H)-yl)pyrido[4,3-d]pyrimidine (Compound 23),
2-methyl-4-(6-methoxy-3,4-dihydroquinolin-1(2H)-yl)pyrido[3,2-d]pyrimidine (Compound 24),
2-methyl-4-(6-methoxy-3,4-dihydroquinolin-1(2H)-yl)pteridine (Compound 25),
N1-[(3-bromo-5-methoxycarbonyl)phenyl]-6-methoxy-1,2,3,4-tetrahydroquinoline (Compound 26),
N1-[(3-bromo-5-carboxyl)phenyl]-6-methoxy-1,2,3,4-tetrahydroquinoline (Compound 27),
N1-[(3-bromo-5-methylaminoacyl)phenyl]-6-methoxy-1,2,3,4-tetrahydroquinoline (Compound 28),
N1-[3-bromo-5-(N-cyclopropylaminoacyl)phenyl]-6-methoxy-1,2,3,4-tetrahydroquinoline (Compound 29),
N1-[4-(2-amino-6-chloro)pyrimidinyl]-6-methoxy-1,2,3,4-tetrahydroquinoline (Compound 30),
N1-methyl-N4-[4-(2-methyl)quinazolinyl]-7-methoxy-3,4-dihydroquinoxalin-2(1H)-one (Compound 31),
2-(N-methylmethylamino)-4-(6-methoxy-1,2,3,4-tetrahydro-1-quinolyl)quinazoline (Compound 32),
2-cyclopropylamino-4-(6-methoxy-1,2,3,4-tetrahydro-1-quinolyl)quinazoline (Compound 33),
2-cyclopentylamino-4-(6-methoxy-1,2,3,4-tetrahydro-1-quinolyl)quinazoline (Compound 34),
2-(3-hydroxylpropylamino)-4-(6-methoxy-1,2,3,4-tetrahydro-1-quinolyl)quinazoline (Compound 35),
4-(6-methoxy-1,2,3,4-tetrahydro-1-quinolyl)quinazoline (Compound 36),
4-(6-methoxy-1,2,3,4-tetrahydro-1-quinolyl)naphthalene (Compound 37),
4-(6-methoxy-1,2,3,4-tetrahydro-1-quinolyl)quinoline (Compound 38),
1-(6-methoxy-1,2,3,4-tetrahydro-1-quinolyl)isoquinoline (Compound 39),
4-(6-methoxy-1,2,3,4-tetrahydro-1-quinolyl)isoquinoline (Compound 40),
8-(6-methoxy-1,2,3,4-tetrahydro-1-quinolyl)quinoline (Compound 41),
6-(6-methoxy-1,2,3,4-tetrahydro-1-quinolyl)purine (Compound 42),
2-fluoro-6-(6-methoxy-1,2,3,4-tetrahydro-1-quinolyl)purine (Compound 43), and
2-amino-6-(6-methoxy-1,2,3,4-tetrahydro-1-quinolyl)purine (Compound 44); or
a pharmaceutically acceptable salt thereof.

### Claim 3 (depends on 1, 2)

A pharmaceutical composition, comprising the compound according to any one of claims 2 and 1, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers or excipients.

### Claim 4 (depends on 1)

A method for preparing the compound of claim 1 or a pharmaceutically acceptable salt thereof, the method comprising:
in the presence of an alkali or acid, reacting a substituted halide of Formula III with a substituted amine compound of Formula II in a solvent to afford a compound of Formula I,
wherein R1, R2, R5, R6, X, Y, Q, W, n1 and n2 are defined as in claim 1, and
optionally, converting the obtained compound of Formula I into a pharmaceutically acceptable salt thereof.

### Claim 5 (depends on 1, 2)

A method for treatment of a disease or disorder or alleviating severity of the disease or disorder, the method comprising administering to a patient in need of such treatment a therapeutically effective amount if at least one compound according to any one of claims 2 and 1 or a pharmaceutically acceptable salt thereof, wherein the disease or disorder is selected from lung cancer, prostate cancer, and nasopharyngeal cancer.