# US 10,501,473 B2 · Fused heterocyclic ring compounds and method of treating retinal disease using same

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- Number: US 10,501,473 B2
- Document ID: US10501473B2
- Status: Granted
- Kind: B2
- Application number: 15/417,724
- Filed: 2017-01-27
- Published: 2017-06-01
- Granted: 2019-12-10
- Earliest claimed: 2014-07-28
- Assignees: The Industry & Academic Cooperation in Chungnam National University (IAC)
- Applicants: The Industry & Academic Cooperation In Chungnam National University (Iac)
- Inventors: Eunhee Kim; Sung-Eun Yoo; Nam Sook Kang; Tae-Sung Koo; Min-Young Park; Young-Hoon Kim; Hyun-Ju Bae; Jin-Woo Kim; Tae-Kyu In; Choun-Ki Joo
- Web page: https://patentgrep.com/patent/US10501473B2

## CPC

- C07D 495/04: Ortho-condensed systems
- A23L 33/16: Inorganic salts, minerals or trace elements
- A23L 33/40: {Complete food formulations for specific consumer groups or specific purposes, e.g. infant formula}
- A61K 31/5377: not condensed and containing further heterocyclic rings, e.g. timolol
- A61P 27/02: Ophthalmic agents
- A61P 27/06: Antiglaucoma agents or miotics
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07D 209/42: Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D 235/24: 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 in position 2
- C07D 307/85: attached in position 2
- C07D 333/58: Radicals substituted by nitrogen atoms
- C07D 333/60: Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D 333/74: Naphthothiophenes
- C07D 409/04: directly linked by a ring-member-to-ring-member bond
- C07D 409/06: linked by a carbon chain containing only aliphatic carbon atoms
- C07D 413/06: linked by a carbon chain containing only aliphatic carbon atoms
- A23V 2002/00: Food compositions, function of food ingredients or processes for food or foodstuffs
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A23L: FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES, NOT OTHERWISE PROVIDED FOR; PREPARATION OR TREATMENT THEREOF (preservation thereof A23B)
- 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
- A23V: INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION

## Abstract

The present invention relates to a novel indene derivative, a preparation method for the same, and a pharmaceutical composition for treating retinal disease comprising the same as an active ingredient. The novel indene derivative of the present invention, the optional isomer of the same, or the pharmaceutically acceptable salts of the same have excellent inhibitory efficiency of receptor-interacting serine-threonine-protein kinase 1 (RIPK1). Therefore, the composition containing the same as an active ingredient can be effectively used as a pharmaceutical composition for treating retinal disease.

## Claims

### Claim 1

A compound, an optical isomer, or a pharmaceutically acceptable salt of the same, wherein the compound is selected from the group consisting of:
(1) (4-bromo-7-chlorothieno[2,3-c]pyridine-2-yl)(morpholino)methanone;
(2) (4-(4-fluorophenyl)thieno[2,3-c]pyridine-2-yl)(morpholino)methanone;
(3) (4-bromothieno[2,3-c]pyridine-2-yl)(morpholino)methanone;
(4) (4-(4-fluorophenyl)thieno[2,3-b]pyridine-2-yl)(morpholino)methanone;
(5) (7-chloro-4-(4-fluorophenyl)thieno[2,3-c]pyridine-2-yl)(morpholino)methanone;
(7) 4-((4-(4-fluorophenyl)benzo[b]thiophene-2-yl)methyl)morpholine;
(8) 4-(4-(4-fluorophenyl)benzo[b]thiophene-2-carbonyl)morpholine-3-carboxylic acid;
(9) (4-(1H-indole-5-yl)benzo[b]thiophene-2-yl)(morpholino)methanone;
(10) N-(4-(2-(morpholine-4-carbonyl)benzo[b]thiophene-4-yl)phenyl)acetamide;
(14) (5-bromo-1H-benzo[d]imidazole-2-yl)(morpholino)methanone;
(17) (4,6-dimethylbenzo[b]thiophene-2-yl)(morpholino)methanone;
(18) (6,7-dimethylbenzo[b]thiophene-2-yl)(morpholino)methanone;
(19) (6-methoxybenzo[b]thiophene-2-yl)(morpholino)methanone;
(20) N,N-diethyl-2-(morpholine-4-carbonyl)benzo[b]thiophene-4-carboxamide;
(24) (5-methoxy-1H-benzo[d]imidazole-2-yl)(morpholino)methanone;
(27) (6-methylbenzofuran-2-yl)(morpholino)methanone;
(29) (7-bromobenzo[b]thiophene-2-yl)(morpholino)methanone;
(30) (4-(2-fluorophenyl)benzo[b]thiophene-2-yl)(morpholino)methanone;
(31) (4-(biphenyl-4-yl)benzo[b]thiophene-2-yl)(morpholino)methanone;
(32) morpholino(4-p-tolylbenzo[b]thiophene-2-yl)methanone;
(33) 4-(2-(morpholine-4-carbonyl)benzo[b]thiophene-4-yl)benzoic acid;
(34) (4-(4-methoxyphenyl)benzo[b]thiophene-2-yl)(morpholino)methanone;
(35) (4-(4-fluorophenyl)benzo[b]thiophene-2-yl)(pyrrolidine-1-yl)methanone;
(36) (4-(3-fluorophenyl)benzo[b]thiophene-2-yl)(morpholino)methanone;
(37) (4-aminopiperidine-1-yl)(4-(4-fluorophenyl)benzo[b]thiophene-2-yl)methanone hydrochloride;
(38) (4-(4-fluorophenyl)benzo[b]thiophene-2-yl)(piperazine-1-yl)methanone hydrochloride;
(39) (4-(4-fluorophenyl)benzo[b]thiophene-2-yl)(morpholino)methanone;
(40) (5-(4-fluorophenyl)benzo[b]thiophene-2-yl)(morpholino)methanone;
(41) (4-(biphenyl-3-yl)benzo[b]thiophene-2-yl)(morpholino)methanone;
(42) (4-(3-aminophenyl)benzo[b]thiophene-2-yl)(morpholino)methanone;
(43) 4-(2-(morpholine-4-carbonyl)benzo[b]thiophene-4-yl)benzamide;
(44) (4-(4-hydroxyphenyl)benzo[b]thiophene-2-yl)(morpholino)methanone;
(45) morpholino(4-(4-(trifluoromethoxy)phenyl)benzo[b]thiophene-2-yl)methanone;
(46) (4-(4-fluorophenyl)benzo[b]thiophene-2-yl)(oxazolidine-3-yl)ethanone;
(47) (4-(4-fluorophenyl)benzo[b]thiophene-2-yl)(piperidine-1-yl)methanone;
(48) (4-(4-fluorophenyl)benzo[b]thiophene-2-yl)(4-hydroxypiperidine-1-yl)methanone;
(49) (4-(4-fluorophenyl)benzo[b]thiophene-2-yl)(4-methylpiperazine-1-yl)methanone hydrochloride;
(50) (4-(4-(methylthio)phenyl)benzo[b]thiophene-2-yl)(morpholino)methanone;
(51) (4-(4-fluorophenyl)benzo[b]thiophene-2-yl)(thiomorpholino)methanone;
(52) (4-(4-fluorophenyl)benzo[b]thiophene-2-yl)(1,4-oxazepane-4-yl)ethanone;
(53) (7-chloro-4-(4-fluorophenyl)benzo[b]thiophene-2-yl)(morpholino)methanone;
(54) (4-(4-bromophenyl)benzo[b]thiophene-2-yl)(morpholino)methanone;
(55) (4-(6-methoxypyridine-3-yl)benzo[b]thiophene-2-yl)(morpholino)methanone;
(56) (4-(3-fluorobenzyl)benzo[b]thiophene-2-yl)(morpholino)methanone;
(57) (4-(2,4-difluorobenzyl)benzo[b]thiophene-2-yl)(morpholino)methanone;
(58) (4-(2,4-difluorophenylamino)benzo[b]thiophene-2-yl)(morpholino)methanone;
(59) (4-(4-fluorophenoxy)benzo[b]thiophene-2-yl)(morpholino)methanone;
(60) (4-(4-fluorophenethyl)benzo[b]thiophene-2-yl)(morpholino)methanone;
(61) (4-(4-fluorobenzyloxy)benzo[b]thiophene-2-yl)(morpholino)methanone;
(62) (4-(4-fluorobenzylsulfonyl)benzo[b]thiophene-2-yl)(morpholino)methanone;
(63) (4-(2,4-difluorophenyl)benzo[b]thiophene-2-yl)(morpholino)methanone;
(64) methyl 4-(2-(morpholine-4-carbonyl)benzo[b]thiophene-4-yl)benzene sulfiante;
(65) (7-(4-fluorophenyl)benzo[b]thiophene-2-yl)(morpholino)methanone;
(66) (4-(6-fluoropyridine-3-yl)benzo[b]thiophene-2-yl)(morpholino)methanone hydrochloride;
(67) (4-(4-fluorobenzyl)benzo[b]thiophene-2-yl)(morpholino)methanone;
(68) (4-(4-fluorophenylamino)benzo[b]thiophene-2-yl)(morpholino)methanone;
(69) (4-((4-fluorophenyl)(methyl)amino)benzo[b]thiophene-2-yl)(morpholino)methanone;
(70) 4-fluoro-N-(2-(morpholine-4-carbonyl)benzo[b]thiophene-4-yl)benzenesulfonamide;
(71) (4-(4-fluorobenzylthio)benzo[b]thiophene-2-yl)(morpholino)methanone;
(72) 1-methyl-5-(2-(morpholine-4-carbonyl)benzo[b]thiophene-4-yl)-1H-pyrrole-2-carbonitrile;
(73) (4-(1-methyl-1H-pyrazol-4-yl)benzo[b]thiophene-2-yl)(morpholino)methanone;
(74) morpholino(4-(thiophene-2-yl)benzo[b]thiophene-2-yl)methanone;
(75) (4-(furan-3-yl)benzo[b]thiophene-2-yl)(morpholino)methanone; and
(76) morpholino(4-(thiophene-3-yl)benzo[b]thiophene-2-yl)methanone.

### Claim 2 (depends on 1)

A pharmaceutical composition for the treatment of retinal disease comprising the compound of claim 1, the optical isomer thereof, or the pharmaceutically acceptable salt of the same as an active ingredient, and a pharmaceutical acceptable carrier.

### Claim 3 (depends on 2)

The pharmaceutical composition for the treatment of retinal disease according to claim 2, wherein the compound is characterized by inhibiting receptor-interacting serine/threonine-protein kinase 1.

### Claim 4 (depends on 2)

The pharmaceutical composition for the treatment of retinal disease according to claim 2, wherein the retinal disease is selected from the group consisting of retinitis pigmentosa (RP), Leber congenital amaurosis (LCA), Stargardts disease, Usher syndrome, choroideremia, rod-cone or cone-rod dystrophy, ciliopathy, mitochondrial disorders, progressive retinal atrophy, degenerative retinal diseases, age-related macular degeneration (AMD), wet AMD, dry AMD, geographical atrophy, inherited or acquired macular degeneration, retinal photoreceptor diseases, retinal pigment epithelial diseases, diabetic retinopathy, cystic macular edema, uveitis, retinal detachment, traumatic retinal injury, iatrogenic retinal injury, macular holes, macular capillarectasia, ganglion cell diseases, optic nerve diseases, glaucoma, optic neuropathy, ischemic retinal diseases, retinopathy of prematurity, occlusion of retinal vessels, inherited macroaneurysm, retinal vascular diseases, ophthalmic vascular diseases, glaucomatous retinal neurodegeneration, and ischemic optic neuropathy.

### Claim 5

A method of treating retinal disease in a subject, comprising administering to the subject an effective amount of a compound, an optical isomer, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of:
(1) (4-bromo-7-chlorothieno[2,3-c]pyridine-2-yl)(morpholino)methanone;
(2) (4-(4-fluorophenyl)thieno[2,3-c]pyridine-2-yl)(morpholino)methanone;
(3) (4-bromothieno[2,3-c]pyridine-2-yl)(morpholino)methanone;
(4) (4-(4-fluorophenyl)thieno[2,3-b]pyridine-2-yl)(morpholino)methanone;
(5) (7-chloro-4-(4-fluorophenyl)thieno[2,3-c]pyridine-2-yl)(morpholino)methanone;
(6) morpholino(naphtho[1,2-b]thiophene-2-yl)methanone;
(7) 4-((4-(4-fluorophenyl)benzo[b]thiophene-2-yl)methyl)morpholine;
(8) 4-(4-(4-fluorophenyl)benzo[b]thiophene-2-carbonyl)morpholine-3-carboxylic acid;
(9) (4-(1H-indole-5-yl)benzo[b]thiophene-2-yl)(morpholino)methanone;
(10) N-(4-(2-(morpholine-4-carbonyl)benzo[b]thiophene-4-yl)phenyl)acetamide;
(11) (5-hydroxy-1H-indole-2-yl)(morpholino)methanone;
(12) (5-chloro-1H-indole-2-yl)(morpholino)methanone;
(13) (5-methyl-1H-benzo[d]imidazole-2-yl)(morpholino)methanone;
(14) (5-bromo-1H-benzo[d]imidazole-2-yl)(morpholino)methanone;
(15) benzofuran-2-yl(morpholino)methanone;
(16) (5-bromobenzofuran-2-yl)(morpholino)methanone;
(17) (4,6-dimethylbenzo[b]thiophene-2-yl)(morpholino)methanone;
(18) (6,7-dimethylbenzo[b]thiophene-2-yl)(morpholino)methanone;
(19) (6-methoxybenzo[b]thiophene-2-yl)(morpholino)methanone;
(20) N,N-diethyl-2-(morpholine-4-carbonyl)benzo[b]thiophene-4-carboxamide;
(21) (5-methyl-1H-indole-2-yl)(morpholino)methanone;
(22) (5-methoxy-1H-indole-2-yl)(morpholino)methanone;
(23) (1H-benzo[d]imidazole-2-yl)(morpholino)methanone;
(24) (5-methoxy-1H-benzo[d]imidazole-2-yl)(morpholino)methanone;
(25) (1-methyl-1H-indole-2-yl)(morpholino)methanone;
(26) (5-methoxybenzofuran-2-yl)(morpholino)methanone;
(27) (6-methylbenzofuran-2-yl)(morpholino)methanone;
(28) (5-aminobenzo[b]thiophene-2-yl)(morpholino)methanone;
(29) (7-bromobenzo[b]thiophene-2-yl)(morpholino)methanone;
(30) (4-(2-fluorophenyl)benzo[b]thiophene-2-yl)(morpholino)methanone;
(31) (4-(biphenyl-4-yl)benzo[b]thiophene-2-yl)(morpholino)methanone;
(32) morpholino(4-p-tolylbenzo[b]thiophene-2-yl)methanone;
(33) 4-(2-(morpholine-4-carbonyl)benzo[b]thiophene-4-yl)benzoic acid;
(34) (4-(4-methoxyphenyl)benzo[b]thiophene-2-yl)(morpholino)methanone;
(35) (4-(4-fluorophenyl)benzo[b]thiophene-2-yl)(pyrrolidine-1-yl)methanone;
(36) (4-(3-fluorophenyl)benzo[b]thiophene-2-yl)(morpholino)methanone;
(37) (4-am inopiperidine-1-yl)(4-(4-fluorophenyl)benzo[b]thiophene-2-yl)methanone hydrochloride;
(38) (4-(4-fluorophenyl)benzo[b]thiophene-2-yl)(piperazine-1-yl)methanone hydrochloride;
(39) (4-(4-fluorophenyl)benzo[b]thiophene-2-yl)(morpholino)methanone;
(40) (5-(4-fluorophenyl)benzo[b]thiophene-2-yl)(morpholino)methanone;
(41) (4-(biphenyl-3-yl)benzo[b]thiophene-2-yl)(morpholino)methanone;
(42) (4-(3-aminophenyl)benzo[b]thiophene-2-yl)(morpholino)methanone;
(43) 4-(2-(morpholine-4-carbonyl)benzo[b]thiophene-4-yl)benzamide;
(44) (4-(4-hydroxyphenyl)benzo[b]thiophene-2-yl)(morpholino)methanone;
(45) morpholino(4-(4-(trifluoromethoxy)phenyl)benzo[b]thiophene-2-yl)methanone;
(46) (4-(4-fluorophenyl)benzo[b]thiophene-2-yl)(oxazolidine-3-yl)methanone;
(47) (4-(4-fluorophenyl)benzo[b]thiophene-2-yl)(piperidine-1-yl)methanone;
(48) (4-(4-fluorophenyl)benzo[b]thiophene-2-yl)(4-hydroxypiperidine-1-yl)methanone;
(49) (4-(4-fluorophenyl)benzo[b]thiophene-2-yl)(4-methylpiperazine-1-yl)methanone hydrochloride;
(50) (4-(4-(methylthio)phenyl)benzo[b]thiophene-2-yl)(morpholino)methanone;
(51) (4-(4-fluorophenyl)benzo[b]thiophene-2-yl)(thiomorpholino)methanone;
(52) (4-(4-fluorophenyl)benzo[b]thiophene-2-yl)(1,4-oxazepane-4-yl)methanone;
(53) (7-chloro-4-(4-fluorophenyl)benzo[b]thiophene-2-yl)(morpholino)methanone;
(54) (4-(4-bromophenyl)benzo[b]thiophene-2-yl)(morpholino)methanone;
(55) (4-(6-methoxypyridine-3-yl)benzo[b]thiophene-2-yl)(morpholino)methanone;
(56) (4-(3-fluorobenzyl)benzo[b]thiophene-2-yl)(morpholino)methanone;
(57) (4-(2,4-difluorobenzyl)benzo[b]thiophene-2-yl)(morpholino)methanone;
(58) (4-(2,4-difluorophenylamino)benzo[b]thiophene-2-yl)(morpholino)methanone;
(59) (4-(4-fluorophenoxy)benzo[b]thiophene-2-yl)(morpholino)methanone;
(60) (4-(4-fluorophenethyl)benzo[b]thiophene-2-yl)(morpholino)methanone;
(61) (4-(4-fluorobenzyloxy)benzo[b]thiophene-2-yl)(morpholino)methanone;
(62) (4-(4-fluorobenzylsulfonyl)benzo[b]thiophene-2-yl)(morpholino)methanone;
(63) (4-(2,4-difluorophenyl)benzo[b]thiophene-2-yl)(morpholino)methanone;
(64) methyl 4-(2-(morpholine-4-carbonyl)benzo[b]thiophene-4-yl)benzene sulfiante;
(65) (7-(4-fluorophenyl)benzo[b]thiophene-2-yl)(morpholino)methanone;
(66) (4-(6-fluoropyridine-3-yl)benzo[b]thiophene-2-yl)(morpholino)methanone hydrochloride;
(67) (4-(4-fluorobenzyl)benzo[b]thiophene-2-yl)(morpholino)methanone;
(68) (4-(4-fluorophenylamino)benzo[b]thiophene-2-yl)(morpholino)methanone;
(69) (4-((4-fluorophenyl)(methyl)amino)benzo[b]thiophene-2-yl)(morpholino)methanone;
(70) 4-fluoro-N-(2-(morpholine-4-carbonyl)benzo[b]thiophene-4-yl)benzenesulfonamide;
(71) (4-(4-fluorobenzylthio)benzo[b]thiophene-2-yl)(morpholino)methanone;
(72) 1-methyl-5-(2-(morpholine-4-carbonyl)benzo[b]thiophene-4-yl)-1H-pyrrole-2-carbonitrile;
(73) (4-(1-methyl-1H-pyrazol-4-yl)benzo[b]thiophene-2-yl)(morpholino)methanone;
(74) morpholino(4-(thiophene-2-yl)benzo[b]thiophene-2-yl)methanone;
(75) (4-(furan-3-yl)benzo[b]thiophene-2-yl)(morpholino)methanone; and
(76) morpholino(4-(thiophene-3-yl)benzo[b]thiophene-2-yl)methanone.

### Claim 6 (depends on 5)

The method of treating retinal disease according to claim 5, wherein the compound is characterized by inhibiting receptor-interacting serine/threonine-protein kinase 1.

### Claim 7 (depends on 5)

The method of treating retinal disease according to claim 5, wherein the retinal disease is selected from the group consisting of retinitis pigmentosa (RP), Leber congenital amaurosis (LCA), Stargardts disease, Usher syndrome, choroideremia, rod-cone or cone-rod dystrophy, ciliopathy, mitochondrial disorders, progressive retinal atrophy, degenerative retinal diseases, age-related macular degeneration (AMD), wet AMD, dry AMD, geographical atrophy, inherited or acquired macular degeneration, retinal photoreceptor diseases, retinal pigment epithelial diseases, diabetic retinopathy, cystic macular edema, uveitis, retinal detachment, traumatic retinal injury, iatrogenic retinal injury, macular holes, macular capillarectasia, ganglion cell diseases, optic nerve diseases, glaucoma, optic neuropathy, ischemic retinal diseases, retinopathy of prematurity, occlusion of retinal vessels, inherited macroaneurysm, retinal vascular diseases, ophthalmic vascular diseases, glaucomatous retinal neurodegeneration, and ischemic optic neuropathy.