# US 8,772,277 B2 · Nitrogen-containing heterocyclic compound

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- Number: US 8,772,277 B2
- Document ID: US8772277B2
- Status: Granted
- Kind: B2
- Application number: 13/566,091
- Filed: 2012-08-03
- Published: 2013-03-21
- Granted: 2014-07-08
- Earliest claimed: 2011-08-04
- Assignees: Takeda Pharmaceutical Company Limited
- Applicants: Shigemitsu Matsumoto; Koji Ono; Yusuke Tominari; Taisuke Katoh; Kazuhiro Miwa; Atsushi Hasuoka; Shinichi Imamura
- Inventors: Shigemitsu Matsumoto; Koji Ono; Yusuke Tominari; Taisuke Katoh; Kazuhiro Miwa; Atsushi Hasuoka; Shinichi Imamura
- Web page: https://patentgrep.com/patent/US8772277B2

## CPC

- C07D 417/14: containing three or more hetero rings
- A61P 35/00: Antineoplastic agents
- C07D 417/06: linked by a carbon chain containing only aliphatic carbon atoms
- C07D 451/02: containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

The present invention provides a novel compound having a superior activity as an ERR-α modulator and useful as an agent for the prophylaxis or treatment of ERR-α associated diseases. The present invention relates to a compound represented by the formula wherein each symbol is as defined in the specification, or a salt thereof.

## Claims

### Claim 1

A compound represented by the formula
wherein
A is a cyclic group optionally having substituent(s);
La is a bond, —O—, —CO—, —S—, —SO—, —SO2—, —NRL1— or —NRL1—CO—;
Lb is a bond or a C1-3 alkylene group optionally having substituent(s);
Lc is a bond, —CO—, —O—CO—, —NRL2—CO—, —SO2— or —NRL2—SO2—;
RL1 and RL2 are each independently a hydrogen atom, a hydrocarbon group optionally having substituent(s), a heterocyclic group optionally having substituent(s), a hydroxy group optionally having a substituent, an amino group optionally having substituent(s), or an acyl group;
ring G is a 4- to 10-membered saturated heterocycle containing one nitrogen atom as a ring-constituting hetero atom, which is optionally bridged and optionally has substituent(s); and
E is a group represented by the formula
wherein
X is —S—, —O— or —NRX—; and
R1, R2 and RX are each independently a hydrogen atom, a hydrocarbon group optionally having substituent(s), a heterocyclic group optionally having substituent(s), a hydroxy group optionally having a substituent, an amino group optionally having substituent(s), or an acyl group, or
R1 and R2 in combination optionally form, together with the adjacent nitrogen atom, a nitrogen-containing heterocycle optionally having substituent(s),
or a salt thereof.

### Claim 2

A compound represented by the formula
wherein
A is a cyclic group optionally having substituent(s);
La is a bond, —O—, —CO—, —S—, —SO—, —SO2—, —NRL1— or —NRL1—CO—;
Lb is a bond or a C1-3 alkylene group optionally having substituent(s);
Lc is a bond, —CO—, —O—CO—, —NRL2—CO—, —SO2— or —NRL2—SO2—;
RL1 and RL2 are each independently a hydrogen atom, a hydrocarbon group optionally having substituent(s), a heterocyclic group optionally having substituent(s), a hydroxy group optionally having a substituent, an amino group optionally having substituent(s), or an acyl group;
ring G is a 4- to 10-membered saturated heterocycle containing one nitrogen atom as a ring-constituting hetero atom, which is optionally bridged and optionally has substituent(s); and
E is a group represented by the formula
wherein
X is —S—, —O— or —NRX—; and
R1, R2 and RX are each independently a hydrogen atom, a hydrocarbon group optionally having substituent(s), a heterocyclic group optionally having substituent(s), a hydroxy group optionally having a substituent, an amino group optionally having substituent(s), or an acyl group, or
R1 and R2 in combination optionally form, together with the adjacent nitrogen atom, a nitrogen-containing heterocycle optionally having substituent(s),
or a salt thereof.

### Claim 3 (depends on 1)

The compound or salt of claim 1, wherein A is a C6-10 aryl group, an aromatic heterocyclic group or a C3-10 cycloalkyl group, each optionally having substituent(s).

### Claim 4 (depends on 1)

The compound or salt of claim 1, wherein the substituent of the cyclic group optionally having substituent(s) for A is selected from
(a) a halogen atom,
(b) a cyano group,
(c) a C1-6 alkyl group optionally substituted by 1 to 3 halogen atoms,
(d) a C1-6 alkoxy group optionally substituted by 1 to 3 halogen atoms,
(e) a hydroxy group, and
(f) a pentafluorosulfanyl group.

### Claim 5 (depends on 1)

The compound or salt of claim 1, wherein
La is a bond;
Lb is a bond or a C1-3 alkylene group optionally substituted by 1 to 3C1-6 alkyl groups; and
Lc is a bond or —CO—.

### Claim 6 (depends on 1)

The compound or salt of claim 1, wherein ring G is an azetidine ring, a pyrrolidine ring, a piperidine ring, an azepane ring, a 3-azabicyclo[3.1.0]hexane ring, a 8-azabicyclo[3.2.1]octane ring, a 3-azabicyclo[3.3.1]nonane ring or a 3-azabicyclo[3.3.0]octane ring, each optionally having substituent(s).

### Claim 7 (depends on 1)

The compound or salt of claim 1, wherein E is a group represented by the formula
wherein
X is —S—, —O— or —NRX—;
RX is a C1-6 alkyl group;
R1 is
(1) a hydrogen atom;
(2) a C1-6 alkyl group optionally substituted by 1 to 5 substituents selected from
(a) an amino group optionally mono- or di-substituted by C1-6 alkyl group(s) optionally substituted by 1 to 3 hydroxy groups,
(b) a hydroxy group,
(c) a C1-6 alkoxy group optionally substituted by 1 to 3 substituents selected from a hydroxy group, a C1-6 alkoxy group and a mono- or di-C1-6 alkylamino group,
(d) a carboxy group,
(e) a halogen atom,
(f) a C1-6 alkoxy-carbonyl group,
(g) a carbamoyl group optionally mono- or di-substituted by substituent(s) selected from
(i) a C1-6 alkyl group optionally substituted by 1 to 3 substituents selected from a hydroxy group and a C1-6 alkoxy group,
(ii) a C3-10 cycloalkyl group, and
(iii) a 4- to 6-membered non-aromatic heterocyclic group,
(h) a C1-6 alkylsulfonyl group,
(i) a C6-14 aryl group,
(j) a 5- or 6-membered aromatic heterocyclic group,
(k) a 4- to 6-membered non-aromatic heterocyclic group optionally substituted by 1 to 3 substituents selected from
(i) an oxo group, and
(ii) a C1-6 alkyl group optionally substituted by 1 to 3 hydroxy groups, and
(l) a 4- to 6-membered non-aromatic heterocyclylcarbonyl group optionally substituted by 1 to 3 substituents selected from
(i) a hydroxy group, and
(ii) a C1-6 alkyl group;
(3) a C2-6 alkenyl group optionally substituted by 1 to 3 mono- or di-C1-6 alkylamino groups;
(4) a C2-6 alkynyl group optionally substituted by 1 to 3 substituents selected from
(a) a mono- or di-C1-6 alkylamino group,
(b) a C3-10 cycloalkyl group, and
(c) a hydroxy group;
(5) a C3-10 cycloalkyl group optionally substituted by 1 to 3 substituents selected from
(a) a halogen atom, and
(b) a hydroxy group;
(6) a C3-10 cycloalkyl-C1-6 alkyl group optionally substituted by 1 to 3 substituents selected from
(a) a hydroxy group,
(b) a C1-6 alkyl group optionally substituted by 1 to 3 hydroxy groups, and
(c) a carbamoyl group optionally mono- or di-substituted by C1-6 alkyl group(s); or
(7) a 4- to 6-membered non-aromatic heterocyclic group optionally substituted by 1 to 3 substituents selected from
(a) a C1-6 alkyl group,
(b) a hydroxy group, and
(c) an oxo group; and
R2 is a hydrogen atom; or
R1 and R2 in combination form, together with the adjacent nitrogen atom, a 4- to 7-membered nitrogen-containing heterocycle optionally substituted by 1 to 3 substituents selected from
(1) a hydroxy group, and
(2) a carbamoyl group optionally mono- or di-substituted by C1-6 alkyl group(s).

### Claim 8 (depends on 1)

The compound or salt of claim 1, wherein
A is a phenyl group, a naphthyl group, a benzofuryl group, an indolyl group, a benzimidazolyl group or a C3-10 cycloalkyl group, each optionally substituted by 1 to 3 substituents selected from
(a) a halogen atom,
(b) a cyano group,
(c) a C1-6 alkyl group optionally substituted by 1 to 3 halogen atoms,
(d) a C1-6 alkoxy group optionally substituted by 1 to 3 halogen atoms,
(e) a hydroxy group, and
(f) a pentafluorosulfanyl group;
La is a bond;
Lb is a bond or a C1-3 alkylene group optionally substituted by 1 to 3C1-6 alkyl groups;
Lc is a bond or —CO—;
ring G is an azetidine ring, a pyrrolidine ring, a piperidine ring, an azepane ring, a 3-azabicyclo[3.1.0]hexane ring, a 8-azabicyclo[3.2.1]octane ring, a 3-azabicyclo[3.3.1]nonane ring or a 3-azabicyclo[3.3.0]octane ring, each optionally substituted by 1 to 3C1-6 alkyl groups or one oxo group; and
E is a group represented by the formula
wherein
X is —S—, —O— or —NRX—;
RX is a C1-6 alkyl group;
R1 is
(1) a hydrogen atom;
(2) a C1-6 alkyl group optionally substituted by 1 to 5 substituents selected from
(a) a halogen atom,
(b) an amino group optionally mono- or di-substituted by C1-6 alkyl group(s) optionally substituted by 1 to 3 hydroxy groups,
(c) a hydroxy group,
(d) a C1-6 alkoxy group optionally substituted by 1 to 3 substituents selected from a hydroxy group, a C1-6 alkoxy group and a di-C1-6 alkylamino group,
(e) a carbamoyl group optionally mono- or di-substituted by substituent(s) selected from
(i) a C1-6 alkyl group optionally substituted by 1 to 3 substituents selected from a hydroxy group and a C1-6 alkoxy group,
(ii) a C1-6 cycloalkyl group, and
(iii) an oxetanyl group,
(f) a carboxy group,
(g) a C1-6 alkoxy-carbonyl group,
(h) a pyrrolidylcarbonyl group optionally substituted by hydroxy group(s),
(i) a morpholinylcarbonyl group,
(j) a piperazinylcarbonyl group substituted by C1-6 alkyl group(s),
(k) a dioxanyl group,
(l) a tetrahydropyranyl group substituted by C1-6 alkyl group(s) substituted by hydroxy group(s),
(m) an oxopyrrolidinyl group,
(n) an oxazolyl group,
(o) an isoxazolyl group,
(p) a phenyl group, and
(q) a C1-6 alkylsulfonyl group;
(3) a C2-6 alkenyl group optionally substituted by 1 to 3 di-C1-6 alkylamino groups;
(4) a C2-6 alkynyl group optionally substituted by 1 to 3 substituents selected from
(a) a di-C1-6 alkylamino group,
(b) a C3-10 cycloalkyl group, and
(c) a hydroxy group;
(5) a C3-10 cycloalkyl group optionally substituted by 1 to 3 substituents selected from
(a) a halogen atom, and
(b) a hydroxy group;
(6) a C3-10 cycloalkyl-C1-6 alkyl group optionally substituted by 1 to 3 substituents selected from
(a) a hydroxy group,
(b) a C1-6 alkyl group substituted by hydroxy group(s), and
(c) a di-C1-6 alkyl-carbamoyl group;
(7) an oxetanyl group;
(8) a tetrahydrofuryl group optionally substituted by hydroxy group(s);
(9) a tetrahydropyranyl group optionally substituted by hydroxy group(s);
(10) a pyrrolidinyl group optionally substituted by 1 to 3 substituents selected from a C1-6 alkyl group and an oxo group; or
(11) a piperidyl group optionally substituted by 1 to 3 substituents selected from a C1-6 alkyl group and an oxo group; and
R2 is a hydrogen atom; or
R1 and R2 in combination form, together with the adjacent nitrogen atom,
(1) a pyrrolidine ring optionally substituted by 1 to 3 hydroxy groups or carbamoyl group(s) di-substituted by C1-6 alkyl groups; or
(2) an azetidine ring substituted by carbamoyl group(s) di-substituted by C1-6 alkyl groups.

### Claim 9 (depends on 1)

The compound or salt of claim 1, wherein
A is a phenyl group optionally substituted by 1 to 3 substituents selected from
(a) a halogen atom,
(b) a cyano group, and
(c) a C1-6 alkyl group optionally substituted by 1 to 3 halogen atoms;
La is a bond;
Lb is a C1-3 alkylene group;
Lc is a bond;
ring G is pyrrolidine ring, a piperidine ring or a 8-azabicyclo[3.2.1]octane ring; and
E is a group represented by the formula
wherein
X is —S— or —NRX—;
RX is a C1-6 alkyl group;
R1 is
(1) a C1-6 alkyl group optionally substituted by 1 to 3 substituents selected from
(a) an amino group di-substituted by C1-6 alkyl groups optionally substituted by 1 to 3 hydroxy groups,
(b) a hydroxy group,
(c) a C1-6 alkoxy group substituted by 1 to 3 substituents selected from a hydroxy group, a C1-6 alkoxy group and a di-C1-6 alkylamino group, and
(d) a carbamoyl group di-substituted by C1-6 alkyl groups;
(2) a C2-6 alkynyl group;
(3) a C3-10 cycloalkyl-C1-6 alkyl group;
(4) an oxetanyl group; or
(5) a tetrahydrofuryl group; and
R2 is a hydrogen atom.

### Claim 10 (depends on 1)

The compound or salt of claim 1, wherein
A is a phenyl group substituted by 1 to 3 substituents selected from a C1-6 alkyl group optionally substituted by 1 to 3 halogen atoms;
La is a bond;
Lb is a C1-3 alkylene group;
Lc is a bond;
ring G is a piperidine ring; and
E is a group represented by the formula
wherein
R1 is
(1) a C1-6 alkyl group optionally substituted by 1 to 3 substituents selected from
(a) a hydroxy group,
(b) a C1-6 alkoxy group substituted by 1 to 3 hydroxy groups, and
(c) a carbamoyl group di-substituted by C1-6 alkyl groups; or
(2) a C2-6 alkynyl group; and
R2 is a hydrogen atom.

### Claim 11

(5Z)-5-({1-[2,4-bis(trifluoromethyl)benzyl]piperidin-4-yl}methylidene)-4-(prop-2-yn-1-ylamino)-1,3-thiazol-2(5H)-one or a salt thereof.

### Claim 12

(5Z)-5-({1-[2,4-bis(trifluoromethyl)benzyl]piperidin-4-yl}methylidene)-4-[(2-hydroxy-2-methylpropyl)amino]-1,3-thiazol-2(5H)-one or a salt thereof.

### Claim 13

(5Z)-5-({1-[2,4-bis(trifluoromethyl)benzyl]piperidin-4-yl}methylidene)-4-[(3-hydroxy-2,2-dimethylpropyl)amino]-1,3-thiazol-2(5H)-one or a salt thereof.

### Claim 14

N2-[(5Z)-5-({1-[2,4-bis(trifluoromethyl)benzyl]piperidin-4-yl}methylidene)-2-oxo-2,5-dihydro-1,3-thiazol-4-yl]-N,N-dimethylglycinamide or a salt thereof.

### Claim 15

N2-[(5Z)-5-({1-[2,4-bis(trifluoromethyl)benzyl]piperidin-4-yl}methylidene)-2-oxo-2,5-dihydro-1,3-thiazol-4-yl]-N,N-dimethyl-D-serinamide or a salt thereof.

### Claim 16

(5Z)-5-({1-[2,4-bis(trifluoromethyl)benzyl]piperidin-4-yl}methylidene)-4-{[2-(2-hydroxyethoxy)ethyl]amino}-1,3-thiazol-2(5H)-one or a salt thereof.

### Claim 17 (depends on 1)

A medicament comprising the compound or salt of claim 1.

### Claim 18 (depends on 17)

The medicament of claim 17, which is an ERR-α inverse agonist.

### Claim 19 (depends on 17)

The medicament of claim 17, which is an agent for the treatment of cancer.

### Claim 20 (depends on 1)

A method of inversing ERR-α in a mammal in need thereof, which comprises administering an effective amount of the compound or salt of claim 1 to the mammal.

### Claim 21 (depends on 1)

A method for the treatment of cancer in a mammal in need thereof, which comprises administering an effective amount of the compound or salt of claim 1 to the mammal.

### Claim 22 (depends on 19)

The medicament of claim 19, wherein the cancer is selected from the group consisting of breast cancer, malignant lymphoma, multiple myeloma, prostate cancer, colorectal cancer, lung cancer, ovarian cancer and endometrial carcinoma.

### Claim 23 (depends on 21)

The method of claim 21, wherein the cancer is selected from the group consisting of breast cancer, malignant lymphoma, multiple myeloma, prostate cancer, colorectal cancer, lung cancer, ovarian cancer and endometrial carcinoma.