# US 7,612,092 B2 · Nitrogen-containing aromatic derivatives

> Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt

- Number: US 7,612,092 B2
- Document ID: US7612092B2
- Status: Granted
- Kind: B2
- Application number: 11/293,785
- Filed: 2005-12-02
- Published: 2006-11-02
- Granted: 2009-11-03
- Earliest claimed: 2000-10-20
- Assignees: Eisai R&D Management Co., Ltd.
- Inventors: Yasuhiro Funahashi; Akihiko Tsuruoka; Masayuki Matsukura; Toru Haneda; Yoshio Fukuda; Junichi Kamata; Keiko Takahashi; Tomohiro Matsushima; Kazuki Miyazaki; Ken-ichi Nomoto; Tatsuo Watanabe; Hiroshi Obaishi; Atsumi Yamaguchi; Sachi Suzuki; Katsuji Nakamura; Fusayo Mimura; Yuji Yamamoto; Junji Matsui
- Web page: https://patentgrep.com/patent/US7612092B2

## CPC

- C07D 213/73: Unsubstituted amino or imino radicals
- A61K 31/4706: 4-Aminoquinolines; 8-Aminoquinolines, e.g. chloroquine, primaquine
- A61K 31/4745: condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines (yohimbine derivatives, vinblastine A61K31/475; ergoline derivatives A61K31/48)
- A61K 31/517: ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
- A61K 31/519: ortho- or peri-condensed with heterocyclic rings
- A61P 3/10: for hyperglycaemia, e.g. antidiabetics
- A61P 9/00: Drugs for disorders of the cardiovascular system
- A61P 9/10: for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
- A61P 17/06: Antipsoriatics
- A61P 19/02: for joint disorders, e.g. arthritis, arthrosis
- A61P 27/02: Ophthalmic agents
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A61P 35/00: Antineoplastic agents
- A61P 35/04: specific for metastasis
- A61P 37/00: Drugs for immunological or allergic disorders
- A61P 37/06: Immunosuppressants, e.g. drugs for graft rejection
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07D 207/34: with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D 213/26: Radicals substituted by halogen atoms or nitro radicals
- C07D 213/68: attached in position 4
- C07D 213/74: Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
- C07D 213/75: Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates
- C07D 213/81: Amides; Imides
- C07D 213/82: in position 3
- C07D 215/18: Halogen atoms or nitro radicals
- C07D 215/233: only one oxygen atom which is attached in position 4
- C07D 215/36: Sulfur atoms (C07D215/24 takes precedence)
- C07D 215/38: Nitrogen atoms (nitro radicals C07D215/18)
- C07D 215/48: Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
- C07D 239/34: One oxygen atom
- C07D 239/42: One nitrogen atom (nitro radicals C07D239/30)
- C07D 239/47: One nitrogen atom and one oxygen or sulfur atom, e.g. cytosine
- C07D 239/88: Oxygen atoms
- C07D 249/04: 1,2,3-Triazoles; Hydrogenated 1,2,3-triazoles
- C07D 261/14: Nitrogen atoms
- C07D 277/48: by radicals derived from carbonic acid, or sulfur or nitrogen analogues thereof, e.g. carbonylguanidines
- C07D 307/68: Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
- C07D 319/06: not condensed with other rings
- C07D 401/04: directly linked by a ring-member-to-ring-member bond
- C07D 401/12: linked by a chain containing hetero atoms as chain links
- C07D 401/14: containing three or more hetero rings
- C07D 405/12: linked by a chain containing hetero atoms as chain links
- C07D 405/14: containing three or more hetero rings
- C07D 409/12: linked by a chain containing hetero atoms as chain links
- C07D 413/12: linked by a chain containing hetero atoms as chain links
- C07D 417/12: linked by a chain containing hetero atoms as chain links
- C07D 417/14: containing three or more hetero rings
- C07D 471/04: Ortho-condensed systems
- C07D 487/04: Ortho-condensed systems
- C07D 491/04: Ortho-condensed systems
- C07D 495/04: 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

Compounds represented by the following general formula: [wherein Ag is an optionally substituted 5- to 14-membered heterocyclic group, etc.; Xg is —O—, —S—, etc.; Yg is an optionally substituted C6-14 aryl group, an optionally substituted 5- to 14-membered heterocyclic group, etc.; and Tg1 is a group represented by the following general formula: (wherein Eg is a single bond or —N(Rg2)—, Rg1 and Rg2 each independently represent a hydrogen atom, an optionally substituted C1-6 alkyl group, etc. and Zg represents a C1-8 alkyl group, a C3-8 alicyclic hydrocarbon group, a C6-14 aryl group, etc.)], salts thereof or hydrates of the foregoing.

## Claims

### Claim 1

A method of treating cancer comprising administering a compound represented by the formula:
or a pharmacologically acceptable salt thereof;
wherein:
R1 and R2 are each independently a hydrogen atom, an optionally substituted C1-6 alkyl group, an optionally substituted C2-6 alkenyl group, an optionally substituted C2-6 alkynyl group, an optionally substituted C3-8 alicyclic hydrocarbon group, an optionally substituted C2-7 acyl group or an optionally substituted C2-7 alkoxycarbonyl group;
Z12 is a hydrogen atom, an optionally substituted C1-6 alkyl group, an optionally substituted C2-6 alkenyl group, an optionally substituted C2-6 alkynyl group, an optionally substituted C3-8 alicyclic hydrocarbon group, an optionally substituted C6-14 aryl group, an optionally substituted 5- to 14-membered heterocyclic group, an optionally substituted 5- to 14-membered aromatic heterocyclic group or a group represented by the formula:
wherein Z31, Z33 and Z34 are each independently a methylene group, —CO—, —NH— or —O—, and Z32 is a single bond, a methylene group, —CO—, —NH— or —O—; and
wherein Z12 is not pyrazolyl;
Ya1 is a group represented by the formula:
wherein W31 and W32 are each independently an optionally substituted carbon atom or a nitrogen atom;
R300 and R301 are each independently a hydrogen atom, a halogen atom, a cyano group, a nitro group, an amino group, an optionally substituted C1-6 alkyl group, an optionally substituted C3-8 alicyclic hydrocarbon group, an optionally substituted C1-6 alkoxy group, an optionally substituted C2-7 alkoxycarbonyl group, a formyl group, a group represented by the formula
wherein V300 and V301 are each independently a hydrogen atom or an optionally substituted C1-6 alkyl group, or an optionally substituted C2-7 acyl group;
Ra11 is a group represented by the formula —Va21—Va22—Va23, wherein:
Va21 is an optionally substituted C1-6 alkylene group, a single bond or a group represented by the formula:
Va22 is a single bond, an oxygen atom, a sulfur atom, —CO—, —SO—, —SO2—, —CONRa14—, —SO2NRa14—, —NRa14SO2—, —NRa14CO— or —NRa14—;
wherein Ra14 is a hydrogen atom, an optionally substituted C1-6 alkyl group or an optionally substituted C3-8 alicyclic hydrocarbon group; and
Va23 is a hydrogen atom, an optionally substituted C1-6 alkyl group, an optionally substituted C2-6 alkenyl group, an optionally substituted C2-6 alkynyl group, an optionally substituted C3-8 alicyclic hydrocarbon group, an optionally substituted C6-14 aryl group, an optionally substituted 5- to 14-membered heterocyclic group or an optionally substituted 5- to 14-membered aromatic heterocyclic group; and
Ra12 is a cyano group or a group represented by the formula:
wherein:
Va11 is —CO— or —SO2—; and
Va12, Va13 and Va14 are each independently a hydrogen atom, an optionally substituted C1-6 alkyl group, an optionally substituted C2-6 alkenyl group, an optionally substituted C2-6 alkynyl group, an optionally substituted C3-8 alicyclic hydrocarbon group, an optionally substituted C6-14 aryl group, an optionally substituted 5- to 14-membered heterocyclic group or an optionally substituted 5- to 14-membered aromatic heterocyclic group;
with the exception that the compound is not:
(1) a compound wherein Ra12 is a group represented by the formula:
wherein:
Va12 and Va13 are each independently a hydrogen atom, an optionally substituted C1-6 alkyl group, an optionally substituted C2-6 alkenyl group, an optionally substituted C2-6 alkynyl group, an optionally substituted C3-8 alicyclic hydrocarbon group, an optionally substituted C6-14 aryl group, an optionally substituted 5- to 14-membered heterocyclic group or an optionally substituted 5- to 14-membered aromatic heterocyclic group;
R1 and R2 are hydrogen atoms; and
Z12 is a C6-14 aryl group, a 6- to 14-membered heterocyclic group or a 6- to 14-membered aromatic heterocyclic group; or
(2) a compound wherein Ra12 is a group selected from the group consisting of the formulae:
wherein:
Va11 is —CO— or —SO2—;
Va12, Va13 and Va14 are each independently a hydrogen atom, an optionally substituted C1-6 alkyl group, an optionally substituted C2-6 alkenyl group, an optionally substituted C2-6 alkynyl group, an optionally substituted C3-8 alicyclic hydrocarbon group, an optionally substituted C6-14 aryl group, an optionally substituted 5- to 14-membered heterocyclic group or an optionally substituted 5- to 14-membered aromatic heterocyclic group;
R2 is a hydrogen atom; and
Z12 is (a) a C6-14 aryl group, (b) a 5- to 14-membered heterocyclic group, (c) a 5- to 14-membered aromatic heterocyclic group, (d) a C1-6 alkyl group substituted with a 5- to 10-membered heterocyclic group or a C5-10 alicyclic hydrocarbon group, (e) a C2-6 alkenyl group substituted with a 5- to 10-membered heterocyclic group or a C5-10 alicyclic hydrocarbon group, (f) a C2-6 alkynyl group substituted with a 5- to 10-membered heterocyclic group or a C5-10 alicyclic hydrocarbon group, or (g) a C3-8 alicyclic hydrocarbon group substituted with a 5- to 10-membered heterocyclic group or a C5-10 alicyclic hydrocarbon group,
or a pharmacologically acceptable salt thereof.

### Claim 2 (depends on 1)

The method according to claim 1, wherein Ra11 is a methyl group, a 2-methoxyethyl group or a group represented by the formula:
wherein:
Ra53 is a methyl group, a cyclopropylmethyl group or a cyanomethyl group;
R51 is a hydrogen atom, a fluorine atom or a hydroxyl group; and
Ra52 is a 1-pyrrolidinyl group, a 1-piperidinyl group, a 4-morpholinyl group, a dimethylamino group or a diethylamino group.

### Claim 3 (depends on 1)

The method according to claim 1, wherein Z12 is a methyl group, an ethyl group, a cyclopropyl group, a 2-thiazolyl group or a 4-fluorophenyl group.

### Claim 4 (depends on 1)

The method according to claim 1, wherein Ya1 is a group represented by the formula:
wherein Ra61 is a hydrogen atom, a methyl group, a trifluoromethyl group, a chlorine atom or a fluorine atom.

### Claim 5 (depends on 1)

The method according to claim 1, wherein Ra12 is a cyano group or a group represented by the formula —CONHRa62, wherein Ra62 is a hydrogen atom, an optionally substituted C1-6 alkyl group, an optionally substituted C3-8 alicyclic hydrocarbon group, an optionally substituted C1-6 alkoxy group or an optionally substituted C3-8 cycloalkoxy group.

### Claim 6 (depends on 1)

The method according to claim 1, wherein the compound is 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide, or a pharmacologically acceptable salt thereof.

### Claim 7 (depends on 1)

The method according to claim 1, wherein the compound is 4-(3-chloro-4-(ethylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide, or a pharmacologically acceptable salt thereof.

### Claim 8 (depends on 1)

The method according to claim 1, wherein the compound is N6-methoxy-4-(3-chloro-4-(((cyclopropylamino)carbonyl)amino)phenoxy)-7-methoxy-6-quinolinecarboxamide, or a pharmacologically acceptable salt thereof.

### Claim 9 (depends on 1)

The method according to claim 1, wherein the compound is N6-methoxy-4-(3-chloro-4-(((ethylamino)carbonyl)amino)phenoxy)-7-methoxy-6-quinolinecarboxamide, or a pharmacologically acceptable salt thereof.

### Claim 10 (depends on 1)

The method according to claim 1, wherein cancer is pancreatic cancer, gastric cancer, colon cancer, breast cancer, prostate cancer, lung cancer, renal cancer, brain tumor, blood cancer or ovarian cancer.

### Claim 11 (depends on 10)

The method according to claim 10, wherein Ra11 is a methyl group, a 2-methoxyethyl group or a group represented by the formula:
wherein:
Ra53 is a methyl group, a cyclopropylmethyl group or a cyanomethyl group;
Ra51 is a hydrogen atom, a fluorine atom or a hydroxyl group; and
Ra52 is a 1-pyrrolidinyl group, a 1-piperidinyl group, a 4-morpholinyl group, a dimethylamino group or a diethylamino group.

### Claim 12 (depends on 10)

The method according to claim 10, wherein Z12 is a methyl group, an ethyl group, a cyclopropyl group, a 2-thiazolyl group or a 4-fluorophenyl group.

### Claim 13 (depends on 10)

The method according to claim 10, wherein Ya1 is a group represented by the formula:
wherein Ra61 is a hydrogen atom, a methyl group, a trifluoromethyl group, a chlorine atom or a fluorine atom.

### Claim 14 (depends on 10)

The method according to claim 10, wherein Ra12 is a cyano group or a group represented by the formula —CONHRa62, wherein Ra62 is a hydrogen atom, an optionally substituted C1-6 alkyl group, an optionally substituted C3-8 alicyclic hydrocarbon group, an optionally substituted C1-6 alkoxy group or an optionally substituted C3-8 cycloalkoxy group.

### Claim 15 (depends on 10)

The method according to claim 10, wherein the compound is 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide, or a pharmacologically acceptable salt thereof.

### Claim 16 (depends on 10)

The method according to claim 10, wherein the compound is 4-(3-chloro-4-(ethylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide, or a pharmacologically acceptable salt thereof.

### Claim 17 (depends on 10)

The method according to claim 10, wherein the compound is N6-methoxy-4-(3-chloro-4-(((cyclopropylamino)carbonyl)amino)phenoxy)-7-methoxy-6-quinolinecarboxamide, or a pharmacologically acceptable salt thereof.

### Claim 18 (depends on 10)

The method according to claim 10, wherein the compound is N6-methoxy-4-(3-chloro-4-(((ethylamino)carbonyl)amino)phenoxy)-7-methoxy-6-quinolinecarboxamide, or a pharmacologically acceptable salt thereof.