# US 11,299,485 B2 · Thiophene derivative and use thereof

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- Number: US 11,299,485 B2
- Document ID: US11299485B2
- Status: Granted
- Kind: B2
- Application number: 16/962,218
- Filed: 2019-01-25
- Published: 2021-03-04
- Granted: 2022-04-12
- Earliest claimed: 2018-01-25
- Assignees: Fujimoto Co., Ltd.
- Applicants: Fujimoto Co., Ltd.
- Inventors: Mayumi Watanabe; Takashi Ando; Yasuyuki Ueda; Kenya Matsushita; Yasuhiko Mizutani; Jun Takahashi; Mitsuo Yamada; Hironori Yokoyama; Daiki Kanaoka; Kazunori Urabe; Takafumi Ishii
- Web page: https://patentgrep.com/patent/US11299485B2

## CPC

- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- C07D 409/14: containing three or more hetero rings
- A61P 35/00: Antineoplastic agents
- A61P 35/02: specific for leukemia
- A61P 37/02: Immunomodulators
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07D 495/04: Ortho-condensed systems
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)

## Abstract

The present invention relates to thiophene derivatives represented by the following formula (I): wherein each symbol is as defined in the DESCRIPTION, or a salt thereof, which has TNF-α production suppressive activity and hematologic cancer cell proliferation inhibitory activity, and is useful for the treatment of rheumatoid arthritis, Crohn's disease, ulcerative colitis, and further, hematologic cancer.

## Claims

### Claim 1

A compound represented by the following general formula (I):
wherein:
R1 is hydrogen or halogen;
R in the number of m are each independently halogen, C1-6 alkyl, C1-6 hydroxyalkyl, C1-6 alkoxy optionally having a substituent, C1-6 alkoxycarbonyl, or C1-6 alkylcarbonyl, or
two R on adjacent ring carbon atoms are bonded to each other to form, together with the two adjacent ring carbon atoms linked thereto, a 5- or 6-membered ring containing 1-2 oxygen atoms; and
m is 0, 1, 2 or 3,
or a salt thereof.

### Claim 2 (depends on 1)

The compound according to claim 1 or a salt thereof, wherein the compound represented by the general formula (I) is a compound represented by the following general formula (IA) or (IB):
wherein:
R1 is hydrogen or halogen;
R2 is hydrogen, halogen, C1-6 alkyl, C1-6 hydroxyalkyl, C1-6 alkoxy, C1-6 alkoxycarbonyl, or C1-6 alkylcarbonyl;
R3 is hydrogen, halogen, C1-6 alkyl, or C1-6 alkoxy optionally having a substituent;
R4 is hydrogen, halogen, C1-6 alkyl, C1-6 hydroxyalkyl, C1-6 alkoxy, C1-6 alkoxycarbonyl, or C1-6 alkylcarbonyl;
R5 is hydrogen, halogen, C1-6 alkyl, C1-6 hydroxyalkyl, C1-6 alkoxy, C1-6 alkoxycarbonyl, or C1-6 alkylcarbonyl;
R6 is hydrogen, halogen, C1-6 alkyl, C1-6 hydroxyalkyl, C1-6 alkoxy, C1-6 alkoxycarbonyl, or C1-6 alkylcarbonyl, or
R5 and R6 are bonded to each other to form, together with a carbon atom linked thereto, a 5- or 6-membered ring containing 1-2 oxygen atoms; and
R7 is hydrogen, halogen, C1-6 alkyl, C1-6 hydroxyalkyl, C1-6 alkoxy, C1-6 alkoxycarbonyl, or C1-6 alkylcarbonyl.

### Claim 3 (depends on 2)

The compound according to claim 2 or a salt thereof, wherein
R1 is hydrogen or halogen;
R2 is hydrogen, halogen, or C1-6 alkoxy;
R3 is hydrogen, halogen, C1-6 alkyl, or C1-6 alkoxy optionally having a substituent;
R4 is hydrogen, halogen, C1-6 alkyl, C1-6 hydroxyalkyl, C1-6 alkoxy, or C1-6 alkoxycarbonyl;
R5 and R6 are each hydrogen, or
R5 and R6 are bonded to each other to form, together with a carbon atom linked thereto, a 5- or 6-membered ring containing 1-2 oxygen atoms; and
R7 is hydrogen, halogen, C1-6 alkyl, or C1-6 alkylcarbonyl.

### Claim 4 (depends on 1)

The compound according to claim 1, or a salt thereof, wherein the C1-6 alkoxy optionally having a substituent for R is C1-6 chain alkoxy, C3-6 cycloalkoxy, or alkoxy represented by the formula: —O—X—Y
wherein:
X is a linear or branched chain C1-6 alkylene; and
Y is C3-6 cycloalkyl, or pyridine, naphthalene or benzothiophene, each of which optionally has a substituent, or a substituent represented by the general formula (II):
Z is hydrogen, C1-6 alkoxy, C1-6 alkoxymethyl, halogen, or a substituent represented by the following general formula (III), (IV), (V) or (VI):
wherein Z1 and Z2 are each independently hydrogen or C1-6 alkyl, or
Z1 and Z2 are bonded to each other to form, together with a nitrogen atom linked thereto, a 5- or 6-membered ring; and
n is 1 or 2

### Claim 5 (depends on 4)

The compound according to claim 4, wherein X is CH2, CH(CH3) or CH2CH2, or a salt thereof.

### Claim 6 (depends on 2)

The compound according to claim 2, or an acid addition salt thereof, wherein
R1 is hydrogen, iodo, bromo or chloro;
R2 is hydrogen, bromo or methoxy;
R3 is hydrogen, bromo, chloro, methyl, methoxy, ethoxy, propoxy, isopropoxy, butoxy, cyclopentyloxy, cyclopropylmethoxy, cyclopentylmethoxy, cyclohexylmethoxy, benzyloxy, 1-phenylethoxy, pyridin-2-ylmethoxy, pyridin-3-ylmethoxy, pyridin-4-ylmethoxy, benzo[b]thiophen-2-ylmethoxy, 4-methoxybenzyl oxy, 4-(methoxymethyl)benzyloxy, 4-chlorobenzyloxy, 4-(pyrrolidin-1-ylmethyl)benzyloxy, 4-(piperidin-1-ylmethyl)benzyloxy, 4-[(dimethylamino)methyl]benzyloxy, 4-(2-morpholinoethyl)benzyloxy, 2-(morpholinomethyl)benzyloxy, 3-(morpholinomethyl)benzyloxy, 4-(morpholinomethyl)benzyloxy or 4-{[(2S,6R)-2,6-dimethylmorpholino]methyl}benzyloxy;
R4 is hydrogen, bromo, chloro, methyl, hydroxymethyl, methoxy, ethoxy or methoxycarbonyl;
R5 and R6 are each hydrogen, or
R5 and R6 are bonded to each other to form, together with a carbon atom linked thereto, a 6-membered ring containing two oxygen atoms; and
R7 is hydrogen, chloro, bromo, methyl or acetyl.

### Claim 7 (depends on 1)

The compound according to claim 1, or a salt thereof, wherein the compound or the salt is selected from
3-[4-(4-bromothiophen-3-yl)-1H-1,2,3-triazol-1-yl]piperidine-2,6-dione,
3-[4-(thiophen-3-yl)-1H-1,2,3-triazol-1-yl]piperidine-2,6-dione,
3-[4-(thiophen-2-yl)-1H-1,2,3-triazol-1-yl]piperidine-2,6-dione,
3-[5-chloro-4-(thiophen-3-yl)-1H-1,2,3-triazol-1-yl]piperidine-2,6-dione,
3-[4-(5-methylthiophen-2-yl)-1H-1,2,3-triazol-1-yl]piperidine-2,6-dione,
3-[4-(5-methylthiophen-3-yl)-1H-1,2,3-triazol-1-yl]piperidine-2,6-dione,
3-[4-(4-methylthiophen-3-yl)-1H-1,2,3-triazol-1-yl]piperidine-2,6-dione,
3-[4-(5-acetylthiophen-2-yl)-1H-1,2,3-triazol-1-yl]piperidine-2,6-dione,
3-{4-[5-(hydroxymethyl)thiophen-3-yl]-1H-1,2,3-triazol-1-yl}piperidine-2,6-dione,
3-[4-(2,3-dihydrothieno[3,4-b][1,4]dioxin-5-yl)-1H-1,2,3-triazol-1-yl]piperidine-2,6-dione,
3-[4-(5-chlorothiophen-2-yl)-1H-1,2,3-triazol-1-yl]piperidine-2,6-dione,
3-[4-(5-bromothiophen-2-yl)-1H-1,2,3-triazol-1-yl]piperidine-2,6-dione,
3-[4-(2,5-dibromothiophen-3-yl)-1H-1,2,3-triazol-1-yl]piperidine-2,6-dione,
3-[4-(4-chlorothiophen-3-yl)-1H-1,2,3-triazol-1-yl]piperidine-2,6-dione,
3-[4-(4-methoxy-5-methylthiophen-3-yl)-1H-1,2,3-triazol-1-yl]piperidine-2,6-dione,
methyl 4-[1-(2,6-dioxopiperidin-3-yl)-1H-1,2,3-triazol-4-yl]-3-methoxythiophene-2-carboxylate,
3-[4-(4-ethoxythiophen-3-yl)-1H-1,2,3-triazol-1-yl]piperidine-2,6-dione,
3-[4-(2-methoxythiophen-3-yl)-1H-1,2,3-triazol-1-yl]piperidine-2,6-dione,
3-[4-(4-methoxythiophen-3-yl)-1H-1,2,3-triazol-1-yl]piperidine-2,6-dione,
3-[4-(5-methoxythiophen-3-yl)-1H-1,2,3-triazol-1-yl]piperidine-2,6-dione,
3-[4-(4-propoxythiophen-3-yl)-1H-1,2,3-triazol-1-yl]piperidine-2,6-dione,
3-[4-(5-chloro-4-methoxythiophen-3-yl)-1H-1,2,3-triazol-1-yl]piperidine-2,6-dione,
3-[4-(5-bromo-4-methoxythiophen-3-yl)-1H-1,2,3-triazol-1-yl]piperidine-2,6-dione,
3-[4-(5-ethoxythiophen-3-yl)-1H-1,2,3-triazol-1-yl]piperidine-2,6-dione,
3-[4-(4-butoxythiophen-3-yl)-1H-1,2,3-triazol-1-yl]piperidine-2,6-dione,
3-[4-(4-isopropoxythiophen-3-yl)-1H-1,2,3-triazol-1-yl]piperidine-2,6-dione,
3-{4-[4-(cyclopentyloxy)thiophen-3-yl]-1H-1,2,3-triazol-1-yl}piperidine-2,6-dione,
3-{4-[4-(cyclopropylmethoxy)thiophen-3-yl]-1H-1,2,3-triazol-1-yl}piperidine-2,6-dione,
3-{4-[4-(cyclopentylmethoxy)thiophen-3-yl]-1H-1,2,3-triazol-1-yl}piperidine-2,6-dione,
3-{4-[4-(cyclohexylmethoxy)thiophen-3-yl]-1H-1,2,3-triazol-1-yl}piperidine-2,6-dione,
3-{4-[4-(4-methoxybenzyloxy)thiophen-3-yl]-1H-1,2,3-triazol-1-yl}piperidine-2,6-dione,
3-{4-[4-(benzyloxy)thiophen-3-yl]-1H-1,2,3-triazol-1-yl}piperidine-2,6-dione,
3-{4-[4-(pyridin-4-ylmethoxy)thiophen-3-yl]-1H-1,2,3-triazol-1-yl}piperidine-2,6-dione,
3-{4-[4-(pyridin-2-ylmethoxy)thiophen-3-yl]-1H-1,2,3-triazol-1-yl}piperidine-2,6-dione,
3-{4-[4-(pyridin-3-ylmethoxy)thiophen-3-yl]-1H-1,2,3-triazol-1-yl}piperidine-2,6-dione,
3-(4-{4-[4-(morpholinomethyl)benzyloxy]thiophen-3-yl}-1H-1,2,3-triazol-1-yl)piperidine-2,6-dione,
3-(4-{4-[4-(methoxymethyl)benzyloxy]thiophen-3-yl}-1H-1,2,3-triazol-1-yl)piperidine-2,6-dione,
3-{4-[4-(4-{[(2S,6R)-2,6-dimethylmorpholino]methyl}benzyloxy)thiophen-3-yl]-1H-1,2,3-triazol-1-yl}piperidine-2,6-dione,
3-(4-{4-[3-(morpholinomethyl)benzyloxy]thiophen-3-yl}-1H-1,2,3-triazol-1-yl)piperidine-2,6-dione,
3-(4-{4-[2-(morpholinomethyl)benzyloxy]thiophen-3-yl}-1H-1,2,3-triazol-1-yl)piperidine-2,6-dione,
3-(4-{4-[4-(pyrrolidin-1-ylmethyl)benzyloxy]thiophen-3-yl}-1H-1,2,3-triazol-1-yl)piperidine-2,6-dione,
3-(4-{4-[4-(piperidin-1-ylmethyl)benzyloxy]thiophen-3-yl}-1H-1,2,3-triazol-1-yl)piperidine-2,6-dione,
3-{4-[4-(4-chlorobenzyloxy)thiophen-3-yl]-1H-1,2,3-triazol-1-yl}piperidine-2,6-dione,
3-{4-[4-(1-phenylethoxy)thiophen-3-yl]-1H-1,2,3-triazol-1-yl}piperidine-2,6-dione,
3-(4-{4-[4-(2-morpholinoethyl)benzyloxy]thiophen-3-yl}-1H-1,2,3-triazol-1-yl)piperidine-2,6-dione,
3-[4-(4-{4-[(dimethylamino)methyl]benzyloxy}thiophen-3-yl)-1H-1,2,3-triazol-1-yl]piperidine-2,6-dione,
3-{4-[4-(benzo[b]thiophen-2-ylmethoxy)thiophen-3-yl]-1H-1,2,3-triazol-1-yl}piperidine-2,6-dione,
3-[5-bromo-4-(thiophen-3-yl)-1H-1,2,3-triazol-1-yl]piperidine-2,6-dione, and
3-[5-iodo-4-(4-methoxythiophen-3-yl)-1H-1,2,3-triazol-1-yl]piperidine-2,6-dione, and
acid addition salts thereof.

### Claim 8 (depends on 2)

The compound according to claim 2 or a salt thereof, wherein the compound represented by the general formula (I) is a compound represented by the following general formula (IA):
wherein:
R1 is hydrogen;
R2 is hydrogen;
R3 is hydrogen or C1-6 alkoxy optionally having a substituent; and
R4 is hydrogen, C1-6 alkoxy or halogen.

### Claim 9 (depends on 8)

The compound according to claim 8 or a salt thereof, wherein R3 is hydrogen, C1-6 chain alkoxy, or alkoxy represented by the formula: —O—X—Y
wherein:
X is linear C1-6 alkylene; and
Y is benzothiophene, pyridine or a substituent represented by the general formula (II):
wherein Z is hydrogen, C1-6 chain alkoxymethyl, or a substituent represented by the following general formula (III), (IV), (V) or (VI):
wherein Z1 and Z2 are each C1-6 chain alkyl, or
Z1 and Z2 are bonded to each other to form, together with a nitrogen atom linked thereto, a 5- or 6-membered ring; and
n is 1 or 2;
and
R4 is hydrogen.

### Claim 10 (depends on 1)

The compound according to claim 1, or a salt thereof, wherein the compound or the salt is selected from
3-[4-(5-methoxythiophen-3-yl)-1H-1,2,3-triazol-1-yl]piperidine-2,6-dione,
3-[4-(5-bromo-4-methoxythiophen-3-yl)-1H-1,2,3-triazol-1-yl]piperidine-2,6-dione,
3-[4-(4-methoxythiophen-3-yl)-1H-1,2,3-triazol-1-yl]piperidine-2,6-dione,
3-{4-[4-(benzyloxy)thiophen-3-yl]-1H-1,2,3-triazol-1-yl}piperidine-2,6-dione,
3-(4-{4-[4-(methoxymethyl)benzyloxy]thiophen-3-yl}-1H-1,2,3-triazol-1-yl)piperidine-2,6-dione,
3-{4-[4-(4-{[(2S,6R)-2,6-dimethylmorpholino]methyl}benzyloxy)thiophen-3-yl]-1H-1,2,3-triazol-1-yl}piperidine-2,6-dione,
3-(4-{4-[4-(pyrrolidin-1-ylmethyl)benzyloxy]thiophen-3-yl}-1H-1,2,3-triazol-1-yl)piperidine-2,6-dione,
3-(4-{4-[4-(piperidin-1-ylmethyl)benzyloxy]thiophen-3-yl}-1H-1,2,3-triazol-1-yl)piperidine-2,6-dione,
3-(4-{4-[4-(2-morpholinoethyl)benzyloxy]thiophen-3-yl}-1H-1,2,3-triazol-1-yl)piperidine-2,6-dione,
3-[4-(4-{4-[(dimethylamino)methyl]benzyloxy}thiophen-3-yl)-1H-1,2,3-triazol-1-yl]piperidine-2,6-dione, and
3-{4-[4-(benzo[b]thiophen-2-ylmethoxy)thiophen-3-yl]-1H-1,2,3-triazol-1-yl}piperidine-2,6-dione and
acid addition salts thereof.

### Claim 11 (depends on 1)

The compound according to claim 1, or a salt thereof, wherein the compound or the salt is selected from
3-[4-(5-methoxythiophen-3-yl)-1H-1,2,3-triazol-1-yl]piperidine-2,6-dione,
3-[4-(4-methoxythiophen-3-yl)-1H-1,2,3-triazol-1-yl]piperidine-2,6-dione,
3-(4-{4-[4-(methoxymethyl)benzyloxy]thiophen-3-yl}-1H-1,2,3-triazol-1-yl)piperidine-2,6-dione,
3-{4-[4-(4-{[(2S,6R)-2,6-dimethylmorpholino]methyl}benzyloxy)thiophen-3-yl]-1H-1,2,3-triazol-1-yl}piperidine-2,6-dione, and
3-(4-{4-[4-(piperidin-1-ylmethyl)benzyloxy]thiophen-3-yl}-1H-1,2,3-triazol-1-yl)piperidine-2,6-dione, and
acid addition salts thereof.

### Claim 12 (depends on 1)

The compound according to claim 1 or a salt thereof for use in the treatment of an inflammatory disease, an autoimmune disease, or a hematologic cancer.

### Claim 13 (depends on 1)

A medicament comprising the compound according to claim 1 or a salt thereof as an active ingredient.

### Claim 14 (depends on 13)

The medicament according to claim 13, wherein the medicament is a TNF-α production suppressor.

### Claim 15 (depends on 13)

The medicament according to claim 13, wherein the medicament is a therapeutic agent for an inflammatory disease, an autoimmune disease, or a hematologic cancer.

### Claim 16 (depends on 15)

The medicament according to claim 15, wherein the autoimmune disease is rheumatoid arthritis, Crohn's disease or ulcerative colitis.

### Claim 17 (depends on 15)

The medicament according to claim 15, wherein the hematologic cancer is leukemia, malignant lymphoma, or multiple myeloma.

### Claim 18 (depends on 15)

The medicament according to claim 15, wherein the hematologic cancer is multiple myeloma.

### Claim 19 (depends on 15)

The medicament according to claim 15, wherein the hematologic cancer is malignant lymphoma.

### Claim 20 (depends on 15)

The medicament according to claim 15, wherein the hematologic cancer is leukemia.

### Claim 21 (depends on 17)

The medicament according to claim 17, wherein the malignant lymphoma is non-Hodgkin's lymphoma.

### Claim 22 (depends on 21)

The medicament according to claim 21, wherein the non-Hodgkin's lymphoma is precursor lymphoid neoplasms or mature B-cell neoplasms.

### Claim 23 (depends on 1)

A pharmaceutical composition comprising the compound according to claim 1 or a salt thereof as an active ingredient together with a pharmaceutically acceptable carrier.

### Claim 24 (depends on 1)

A method for suppressing TNF-α production in a mammal, comprising administering an effective amount of the compound according to claim 1 or a salt thereof to the mammal.

### Claim 25 (depends on 1)

A method for treating an inflammatory disease, an autoimmune disease, or a hematologic cancer, comprising administering a therapeutically effective amount of the compound according to claim 1 or a salt thereof to a mammal in need of the administration thereof.