# US 8,772,283 B2 · Imidazo-oxazine compound or salt thereof

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- Number: US 8,772,283 B2
- Document ID: US8772283B2
- Status: Granted
- Kind: B2
- Application number: 14/004,446
- Filed: 2012-04-05
- Published: 2014-01-02
- Granted: 2014-07-08
- Earliest claimed: 2011-04-06
- Assignees: Taiho Pharmaceutical Co., Ltd.
- Applicants: Masayuki Nakamura; Kenji Niiyama; Kaori Kamijo; Mitsuru Ohkubo; Toshiyasu Shimomura
- Inventors: Masayuki Nakamura; Kenji Niiyama; Kaori Kamijo; Mitsuru Ohkubo; Toshiyasu Shimomura
- Web page: https://patentgrep.com/patent/US8772283B2

## CPC

- C07D 498/04: Ortho-condensed systems
- A61K 31/5365: ortho- or peri-condensed with heterocyclic ring systems
- A61P 35/00: Antineoplastic agents
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07D 498/14: Ortho-condensed systems
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

The present invention provides an imidazooxazine compound represented by Formula (I) or a salt thereof, wherein A, B, C, and D are as defined in the specification.

## Claims

### Claim 1

An imidazooxazine compound represented by Formula (I) or a salt thereof,
wherein
A, B, C, and D represent an N atom or C—R1a, an N atom or C—R1b, an N atom or C—R1c, and an N atom or C—R1d, respectively;
R1a, R1b, R1c, and R1d are the same or different, and each represents hydrogen, halogen, cyano, optionally substituted C1-6 alkyl, optionally substituted C1-6 alkoxy, substituted carbonyl, or an optionally substituted unsaturated heterocyclic group;
R2 represents optionally substituted aryl or an optionally substituted unsaturated heterocyclic group; and
R3 and R4 are the same or different, and each represents hydrogen, hydroxy, optionally substituted C1-6 alkyl, or optionally substituted C3-7 cycloalkyl, and
wherein a substituent of the substituted carbonyl is selected from the group consisting of: hydroxyl, amino, optionally substituted mono- or di-(C1-6 alkyl)amino, and mono- or di-(C1-6 alkoxy)amino; and
wherein a substituent of the optionally substituted groups is selected from the group consisting of: halogen, hydroxyl, cyano, amino, nitro, oxo, carboxy, carbamoyl, alkyl, cycloalkyl, alkenyl, alkynyl, alkoxy, acyl, acyloxy, alkoxycarbonyl, saturated heterocyclic group, an unsaturated heterocyclic group, aryl, halogenoalkyl, aralkyl, saturated heterocyclic alkyl, alkylamino, acylamino, and aralkyloxy.

### Claim 2 (depends on 1)

The imidazooxazine compound according to claim 1 or a salt thereof, wherein
A, B, C, and D represent an N atom or C—R1a, an N atom or C—R1b, an N atom or C—R1c, and an N atom or C—R1d, respectively;
R1a, R1b, R1c, and R1d are the same or different, and each represents hydrogen, halogen, cyano, optionally substituted C1-6 alkyl, C1-6 alkoxy, substituted carbonyl, or an optionally substituted unsaturated heterocyclic group;
R2 represents C6-10 aryl or a 5- to 6-membered monocyclic unsaturated heterocyclic group having 1 to 4 hetero atoms selected from the group consisting of N, S, and O;
R3 represents hydrogen, optionally substituted C1-6 alkyl, or optionally substituted C3-7 cycloalkyl; and
R4 represents hydrogen or hydroxyl, and
wherein a substituent of the substituted carbonyl is selected from the group consisting of: hydroxyl, amino, optionally substituted mono- or di-(C1-6 alkyl)amino, and mono- or di-(C1-6 alkoxy)amino; and
wherein a substituent of the optionally substituted groups is selected from the group consisting of: halogen, hydroxyl, cyano, amino, nitro, oxo, carboxy, carbamoyl, alkyl, cycloalkyl, alkenyl, alkynyl, alkoxy, acyl, acyloxy, alkoxycarbonyl, saturated heterocyclic group, an unsaturated heterocyclic group, aryl, halogenoalkyl, aralkyl, saturated heterocyclic alkyl, alkylamino, acylamino, and aralkyloxy.

### Claim 3 (depends on 1)

The imidazooxazine compound according to claim 1 or a salt thereof, wherein
A, B, C, and D represent C—R1a, C—R1b, C—R1c, and C—R1d, respectively, or one or two of A, B, C, and D represent an N atom;
at least two of R1a, R1b, R1c, and R1d represent hydrogen, and the other(s) represent(s) halogen, cyano, C1-6 alkyl that may have hydroxyl group(s) as substituent(s), C1-6 alkoxy, carbonyl having hydroxyl, amino, or mono- or di-(C1-6 alkoxy)amino as a substituent, optionally substituted mono- or di-(C1-6 alkyl)aminocarbonyl, or an unsaturated heterocyclic group;
R2 represents phenyl, pyridyl, or thienyl;
R3 represents hydrogen, methyl, ethyl, or cyclopropyl; and
R4 represents hydrogen or hydroxy, and
wherein a substituent of the optionally substituted groups is selected from the group consisting of: halogen, hydroxyl, cyano, amino, nitro, oxo, carboxy, carbamoyl, alkyl, cycloalkyl, alkenyl, alkynyl, alkoxy, acyl, acyloxy, alkoxycarbonyl, saturated heterocyclic group, an unsaturated heterocyclic group, aryl, halogenoalkyl, aralkyl, saturated heterocyclic alkyl, alkylamino, acylamino, and aralkyloxy.

### Claim 4 (depends on 1)

The imidazooxazine compound according to claim 1 or a salt thereof, wherein
A, B, C, and D represent C—R1a, C—R1b, C—R1c, and C—R1d, respectively, or one or two of A, B, C, and D represent an N atom;
at least two of R1a, R1b, R1c, and R1d represent hydrogen, and the other(s) represent(s) chlorine, fluorine, cyano, methyl, hydroxymethyl, methoxy, ethoxy, amino, carboxyl, carbamoyl, methylaminocarbonyl, dimethylaminocarbonyl, ethylaminocarbonyl, hydroxyethylaminocarbonyl, ethoxyaminocarbonyl, or pyrazolyl;
R2 represents phenyl, pyridyl, or thienyl;
R3 represents hydrogen, methyl, ethyl, or cyclopropyl; and
R4 represents hydrogen or hydroxy.

### Claim 5

An imidazooxazine compound selected from the group consisting of the following (a) to (t), or a salt thereof:
(a) trans-3-amino-1-cyclopropyl-3-(4-(10-fluoro-3-phenyl-5H-benzo[e]imidazo[1,2-c][1,3]oxazin-2-yl)phenyl)cyclobutanol,
(b) trans-3-amino-1-cyclopropyl-3-(4-(10-fluoro-3-(pyridine-4-yl)-5H-benzo[e]imidazo[1,2-c][1,3]oxazin-2-yl)phenyl)cyclobutanol,
(c) trans-3-amino-1-cyclopropyl-3-(4-(3-phenyl-5H-benzo[e]imidazo[1,2-c][1,3]oxazin-2-yl)phenyl)cyclobutanol,
(d) trans-3-amino-1-cyclopropyl-3-(4-(10-methoxy-3-phenyl-5H-benzo[e]imidazo[1,2-c][1,3]oxazin-2-yl)phenyl)cyclobutanol,
(e) trans-3-amino-1-cyclopropyl-3-(4-(9-methoxy-3-phenyl-5H-benzo[e]imidazo[1,2-c][1,3]oxazin-2-yl)phenyl)cyclobutanol,
(f) trans-3-amino-1-cyclopropyl-3-(4-(8-methoxy-3-phenyl-5H-benzo[e]imidazo[1,2-c][1,3]oxazin-2-yl)phenyl)cyclobutanol,
(g) trans-3-amino-1-cyclopropyl-3-(4-(3-phenyl-5H-imidazo[1,2-c]pyrido[2,3-e][1,3]oxazin-2-yl)phenyl)cyclobutanol,
(h) trans-3-amino-1-methyl-3-(4-(3-phenyl-5H-imidazo[1,2-c]pyrido[2,3-e][1,3]oxazin-2-yl)phenyl)cyclobutanol,
(i) trans-3-amino-1-ethyl-3-(4-(3-phenyl-5H-imidazo[1,2-c]pyrido[2,3-e][1,3]oxazin-2-yl)phenyl)cyclobutanol,
(j) trans-3-amino-1-cyclopropyl-3-(4-(3-phenyl-5H-imidazo[1,2-c]pyrido[3,4-e][1,3]oxazin-2-yl)phenyl)cyclobutanol,
(k) trans-3-amino-1-methyl-3-(4-(3-phenyl-5H-imidazo[1,2-c]pyrido[3,4-e][1,3]oxazin-2-yl)phenyl)cyclobutanol,
(1) trans-3-amino-1-cyclopropyl-3-(4-(3-phenyl-5H-imidazo[1,2-c]pyrido[4,3-e][1,3]oxazin-2-yl)phenyl)cyclobutanol,
(m) trans-3-amino-1-methyl-3-(4-(3-phenyl-5H-imidazo[1,2-c]pyrido[4,3-e][1,3]oxazin-2-yl)phenyl)cyclobutanol,
(n) trans-3-amino-1-cyclopropyl-3-(4-(3-phenyl-5H-imidazo[1,2-c]pyrido[3,2-e][1,3]oxazin-2-yl)phenyl)cyclobutanol,
(o) trans-3-amino-1-cyclopropyl-3-(4-(3-phenyl-5H-imidazo[1,2-c]pyrazino[2,3-e][1,3]oxazin-2-yl)phenyl)cyclobutanol,
(p) trans-3-amino-3-(4-(9-(hydroxymethyl)-3-phenyl-5H-benzo[e]imidazo[1,2-c][1,3]oxazin-2-yl)phenyl)-1-methylcyclobutanol,
(q) 2-(4-(trans-1-amino-3-hydroxy-3-methylcyclobutyl)phenyl)-3-phenyl-5H-benzo[e]imidazo[1,2-c][1,3]oxazine-9-carbonitrile,
(r) trans-3-amino-1-methyl-3-(4-(3-phenyl-9-(1H-pyrazol-5-yl)-5H-benzo[e]imidazo[1,2-c][1,3]oxazin-2-yl)phenyl)cyclobutanol,
(s) 2-(4-(trans-1-amino-3-hydroxy-3-methylcyclobutyl)phenyl)-N-methyl-3-phenyl-5H-benzo[e]imidazo[1,2-c][1,3]oxazine-8-carboxamide, and
(t) 2-(4-(trans-1-amino-3-hydroxy-3-methylcyclobutyl)phenyl)-N-ethoxy-3-phenyl-5H-benzo[e]imidazo[1,2-c][1,3]oxazine-8-carboxamide.

### Claim 6 (depends on 1)

A pharmaceutical composition comprising an effective amount of the imidazooxazine compound according to claim 1 or a salt thereof, and a pharmaceutical carrier.

### Claim 7 (depends on 6)

The pharmaceutical composition of claim 6, wherein the pharmaceutical composition has antitumor properties.

### Claim 8 (depends on 1)

A method for treating a cancer, comprising administering, to a mammal, the imidazooxazine compound according to claim 1 or a salt thereof in an effective amount for cancer treatment, wherein the cancer is selected from the group consisting of breast cancer, pancreatic cancer, liver cancer, prostatic cancer, stomach cancer, lung cancer, ovarian cancer, head and neck cancer, urinary tract cancer, and endometrial cancer.