# US 2023/0271925 A1 · Novel tnf activity inhibitor compound, and pharmaceutically acceptable salt thereof

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- Number: US 2023/0271925 A1
- Document ID: US20230271925A1
- Status: Published application
- Kind: A1
- Application number: 18/004,564
- Filed: 2021-06-28
- Published: 2023-08-31
- Earliest claimed: 2020-07-07
- Assignees: ILAb
- Applicants: Ilab
- Inventors: Kyung Yeon Park
- Web page: https://patentgrep.com/patent/US20230271925A1

## CPC

- C07D 215/233: only one oxygen atom which is attached in position 4
- C07D 215/56: with oxygen atoms in position 4
- A61K 31/352: condensed with carbocyclic rings, e.g. methantheline {(cannabinoids A61K31/658)}
- A61P 11/00: Drugs for disorders of the respiratory system
- A61P 17/00: Drugs for dermatological disorders
- A61P 19/00: Drugs for skeletal disorders
- A61P 25/00: Drugs for disorders of the nervous system
- A61P 31/00: Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P 35/00: Antineoplastic agents
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07D 311/22: with oxygen or sulfur atoms directly attached in position 4
- C07D 311/30: not hydrogenated in the hetero ring, e.g. flavones
- Y02A 50/30: Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
- 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
- Y02A: TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE

## Abstract

The present invention relates to a novel TNF activity inhibitor compound and a pharmaceutically acceptable salt thereof, a method for prevention, alleviation or treatment comprising administering the compound of the present invention, a method for preparing the compound of the present invention, and a pharmaceutical composition comprising the compound.

## Claims

### Claim 1

The compound of Formula I below or a pharmaceutically acceptable salt thereof:
wherein,
X is —C(R3)2—, —N(R3)—, —O— or —S—,
Y is —ORa, —SRa, —C(O)Ra, —C(O)ORa, —C(O)N(Ra)(Rb), —N(Ra)(Rb), —N(Ra)C(O)Rb, —N(Ra)C(O)ORb, or —N(Ra)S(O)ORb,
A is C3-C8 cycloalkyl; 4- to 10-membered heterocycloalkyl containing 1 to 4 heteroatoms independently selected from the group consisting of N, O and S; C6-C10 aryl; or 5- to 10-membered heteroaryl containing 1 to 4 heteroatoms independently selected from the group consisting of N, O and S,
R1, R2 and R3 may be the same or different and are each independently H, halo, cyano, —ORc, nitro, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, —SRc, —C(O)Rc, —C(O)ORc, —C(O)N(Rc)(Rd), —N(Rc)(Rd), —N(Rc)C(O)Rd, —N(Rc)C(O)ORd, or —N(Rc)S(O)ORd,
Ra, Rb, Rc and Rd may be the same or different and are each independently H or C1-C6 alkyl, and
m and n are each independently an integer from 0 to 4.

### Claim 2 (depends on 1)

The compound or pharmaceutically acceptable salt thereof according to claim 1, wherein X is —N(R3)— or —O—, and R3 is H or C1-C6 alkyl.

### Claim 3 (depends on 1)

The compound or pharmaceutically acceptable salt thereof according to claim 1, wherein Y is —ORa, —C(O)Ra, —C(O)ORa, or —C(O)N(Ra)(Rb).

### Claim 4 (depends on 1)

The compound or pharmaceutically acceptable salt thereof according to claim 1, wherein A is phenyl.

### Claim 5 (depends on 1)

The compound or pharmaceutically acceptable salt thereof according to claim 1, wherein R1 and R2 are the same or different, and are each independently H, halo or —ORc.

### Claim 6 (depends on 1)

The compound or pharmaceutically acceptable salt thereof according to claim 1, wherein the compound is a compound of Formula II below:
wherein,
X is —N(R3)— or —O—,
Y is —ORa, —C(O)Ra, —C(O)ORa, or —C(O)N(Ra)(Rb),
R1 and R2 can be the same or different, and are each independently H, halo, or —ORc,
R3 is H or C1-C6 alkyl,
Ra, Rb and Rc can be the same or different, and are each independently H or C1-C6 alkyl, and
m and n are each independently an integer 1 or 2.

### Claim 7 (depends on 1)

The compound or pharmaceutically acceptable salt thereof according to claim 1, wherein the compound is selected from the group consisting of:
(1) 2-(2,4-difluorophenyl)-3-carboxy-7-chloro-4-(1H)-quinolone;
(2) 2-(2,5-difluorophenyl)-3-carboxy-7-chloro-4-(1H)-quinolone;
(3) 2-(3,4-difluorophenyl)-3-carboxy-7-chloro-4-(1H)-quinolone;
(4) 2-(3,5-difluorophenyl)-3-carboxy-7-chloro-4-(1H)-quinolone;
(5) 2-(2,6-difluorophenyl)-3-carboxy-7-chloro-4-(1H)-quinolone;
(6) 2-(2,5-difluorophenyl)-3-carboxy-6-chloro-4-(1H)-quinolone;
(7) 2-(3,4-difluorophenyl)-3-carboxy-6-chloro-4-(1H)-quinolone;
(8) 2-(3,5-difluorophenyl)-3-carboxy-6-chloro-4-(1H)-quinolone;
(9) 2-(2,6-difluorophenyl)-3-carboxy-6-chloro-4-(1H)-quinolone;
(10) 2-(2,5-difluorophenyl)-3-carboxy-8-chloro-4-(1H)-quinolone;
(11) 2-(2,5-difluorophenyl)-3-carboxy-7-bromo-4-(1H)-quinolone;
(12) 2-(3,4-difluorophenyl)-3-carboxy-7-bromo-4-(1H)-quinolone;
(13) 2-(3,5-difluorophenyl)-3-carboxy-7-bromo-4-(1H)-quinolone;
(14) 2-(2,6-difluorophenyl)-3-carboxy-7-bromo-4-(1H)-quinolone;
(15) 2-(2,5-difluorophenyl)-3-carboxy-7-methoxy-4-(1H)-quinolone;
(16) 2-(3,5-difluorophenyl)-3-carboxy-7-methoxy-4-(1H)-quinolone;
(17) 2-(2,6-difluorophenyl)-3-carboxy-7-methoxy-4-(1H)-quinolone;
(18) 2-(2,5-difluorophenyl)-3-carboxy-7-fluoro-4-(1H)-quinolone;
(19) 1-methyl-2-(2,4-difluorophenyl)-3-carboxy-7-chloro-4-(1H)-quinolone;
(20) 1-methyl-2-(2,5-difluorophenyl)-3-carboxy-7-chloro-4-(1H)-quinolone;
(21) 1-methyl-2-(3,4-difluorophenyl)-3-carboxy-7-chloro-4-(1H)-quinolone;
(22) 1-methyl-2-(3,5-difluorophenyl)-3-carboxy-7-chloro-4-(1H)-quinolone;
(23) 1-methyl-2-(2,6-difluorophenyl)-3-carboxy-7-chloro-4-(1H)-quinolone;
(24) 1-methyl-2-(2,5-difluorophenyl)-3-carboxy-6-chloro-4-(1H)-quinolone;
(25) 1-methyl-2-(3,4-difluorophenyl)-3-carboxy-6-chloro-4-(1H)-quinolone;
(26) 1-methyl-2-(3,5-difluorophenyl)-3-carboxy-6-chloro-4-(1H)-quinolone;
(27) 1-methyl-2-(2,6-difluorophenyl)-3-carboxy-6-chloro-4-(1H)-quinolone;
(28) 1-methyl-2-(2,5-difluorophenyl)-3-carboxy-8-chloro-4-(1H)-quinolone;
(29) 1-methyl-2-(2,5-difluorophenyl)-3-carboxy-7-bromo-4-(1H)-quinolone;
(30) 1-methyl-2-(3,5-difluorophenyl)-3-carboxy-7-bromo-4-(1H)-quinolone;
(31) 1-methyl-2-(2,6-difluorophenyl)-3-carboxy-7-bromo-4-(1H)-quinolone;
(32) 7-chloro-2-(2,5-difluorophenyl)-3-hydroxy-4H-chromen-4-one;
(33) 7-chloro-2-(3,5-difluorophenyl)-3-hydroxy-4H-chromen-4-one;
(34) 7-chloro-2-(3,4-difluorophenyl)-3-hydroxy-4H-chromen-4-one;
(35) 2-(2,5-difluorophenyl)-7-fluoro-3-hydroxy-4H-chromen-4-one;
(36) 2-(3,5-difluorophenyl)-7-fluoro-3-hydroxy-4H-chromen-4-one;
(37) 2-(2,3-difluorophenyl)-7-fluoro-3-hydroxy-4H-chromen-4-one;
(38) 2-(2,5-difluorophenyl)-3-hydroxy-7-methoxy-4H-chromen-4-one;
(39) 2-(3,5-difluorophenyl)-3-hydroxy-7-methoxy-4H-chromen-4-one;
(40) 7-chloro-2-(2,5-difluorophenyl)-3-methoxy-4H-chromen-4-one;
(41) 7-chloro-2-(3,5-difluorophenyl)-3-methoxy-4H-chromen-4-one;
(42) 2-(2,5-difluorophenyl)-7-fluoro-3-methoxy-4H-chromen-4-one;
(43) 2-(2,4-difluorophenyl)-7-fluoro-3-methoxy-4H-chromen-4-one;
(44) 2-(3,5-difluorophenyl)-7-fluoro-3-methoxy-4H-chromen-4-one;
(45) 2-(2,5-difluorophenyl)-3,7-dimethoxy-4H-chromen-4-one;
(46) 2-(3,5-difluorophenyl)-3,7-dimethoxy-4H-chromen-4-one; and
(47) 2-(2,4-difluorophenyl)-3,7-dimethoxy-4H-chromen-4-one,
or a pharmaceutically acceptable salt thereof.

### Claim 8

A compound of Formula III below or a pharmaceutically acceptable salt thereof:
M1-L-M2 [Formula III]
wherein,
M1 and M2 may be the same or different, and are each independently a monomer radical of Formula Ia, and
L is a linking group covalently bonding M1 and M2, and is selected from the following Formulas IVa to IVc,
(wherein,
X is —C(R3)2—, —N(R3)—, —O— or —S—,
Y is —ORa, —SRa, —C(O)Ra, —C(O)ORa, —C(O)N(Ra)(Rb), —N(Ra)(Rb), —N(Ra)C(O)Rb, —N(Ra)C(O)ORb, or —N(Ra)S(O)ORb,
A is C3-C8 cycloalkyl; 4- to 10-membered heterocycloalkyl containing 1 to 4 heteroatoms independently selected from the group consisting of N, O and S; C6-C10 aryl; or 5- to 10-membered heteroaryl containing 1 to 4 heteroatoms independently selected from the group consisting of N, O and S,
R1, R2 and R3 may be the same or different and each independently H, halo, cyano, —ORc, nitro, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, —SRc, —C(O)Rc, —C(O)ORc, —C(O)N(Rc)(Rd), —N(Rc)(Rd), —N(Rc)C(O)Rd, —N(Rc)C(O)ORd, or —N(Rc)S(O)ORd,
Ra, Rb, Rc and Rd may be the same or different and are each independently H or C1-C6 alkyl,
m and n are each independently an integer of 0 to 4,
the monomer unit M1 or M2 is bonded to the linking group L through a bonding site * located in either Y or R2, and
when Y or R2 has the above bonding site *, Y or R2 contains N, O or S atoms, and at the bonding site *, —C(O)—, —NH—, —N(C1-C6 alkyl)-, —O— or —S— radical is located),
(wherein,
* represents a bonding site between the monomer unit M1 or M2 and the linking group L,
R or R′ is each independently C1-C10 alkylene, C2-C10 alkenylene, or C2-C10 alkynylene;
Z is a single bond; —O—; —S—; —NH—; —N(C1-C6 alkyl)-; C3-C8 cycloalkylene; 4- to 10-membered heterocycloalkyl containing 1 to 4 heteroatoms independently selected from the group consisting of N, O and S; C6-C10 aryl; or 5- to 10-membered heteroaryl containing 1 to 4 heteroatoms independently selected from the group consisting of N, O and S;
p is an integer from 1 to 5, and
q1 and q2 are each independently an integer from 0 to 5, but q1 and q2 are not 0 at the same time).

### Claim 9 (depends on 8)

The compound or pharmaceutically acceptable salt thereof according to claim 8, wherein M1 and M2 may be the same or different, and are each independently a monomer radical of Formula IIa below or a pharmaceutically acceptable salt thereof:
wherein,
X is N—R3 or O,
Y is —ORa, —C(O)ORa, or —C(O)N(Ra)(Rb),
R1 and R2 can be the same or different, and are each independently H, halo, or —ORc,
R3 is H or C1-C6 alkyl,
Ra, Rb and Rc can be the same or different, and are each independently H or C1-C6 alkyl, and
m and n are each independently an integer 1 or 2.

### Claim 10 (depends on 8)

The compound or pharmaceutically acceptable salt thereof according to claim 8, wherein L is C2-C4 alkylene, —(CH2)2—O—(CH2)2—, or

### Claim 11 (depends on 8)

The compound or pharmaceutically acceptable salt thereof according to claim 8, wherein the compound is selected from the group consisting of:
(48) 2,2′-((ethane-1,2-diylbis(oxy))bis(2-fluoro-4,1-phenylene))bis(7-chloro-4-oxo-4H-chloromene-3-carboxylic acid);
(49) 2,2′-((propane-1,3-diylbis(oxy))bis(2-fluoro-4,1-phenylene))bis(7-chloro-4-oxo-4H-chloromene-3-carboxylic acid);
(50) 2,2′-((butane-1,4-diylbis(oxy))bis(2-fluoro-4,1-phenylene))bis(7-chloro-4-oxo-4H-chloromene-3-carboxylic acid);
(51) 2,2′-(((oxybis(ethane-2,1-diyl))bis(oxy))bis(2-fluoro-4,1-phenylene))bis(7-chloro-4-oxo-4H-chromene-3-carboxylic acid);
(52) N,N′-(ethane-1,2-diyl)bis(7-chloro-2-(2,5-difluorophenyl)-4-oxo-4H-chromene-3-carboxamide);
(53) N,N′-(propane-1,3-diyl)bis(7-chloro-2-(2,5-difluorophenyl)-4-oxo-4H-chromene-3-carboxamide);
(54) N,N′-(butane-1,4-diyl)bis(7-chloro-2-(2,5-difluorophenyl)-4-oxo-4H-chromene-3-carboxamide); and
(55) 3,3′-(piperazine-1,4-dicarbonyl)bis(7-chloro-2-(2,5-difluorophenyl)-4H-chromene-4-one),
or a pharmaceutically acceptable salt thereof.

### Claim 12 (depends on 1)

A pharmaceutical composition for preventing or treating a TNF-related disease, comprising the compound or pharmaceutically acceptable salt thereof according to claim 1, as an active ingredient.

### Claim 13 (depends on 12)

The pharmaceutical composition according to claim 12, wherein the TNF-related disease is selected from the group consisting of rheumatoid arthritis, juvenile rheumatoid arthritis, inflammatory bowel disease, Crohn's disease, ulcerative colitis, psoriasis, plaque psoriasis, pediatric plaque psoriasis, psoriatic arthritis, polyarticular juvenile idiopathic arthritis, Behcet's enteritis, ankylosing spondylitis, axial spondylarthritis, pediatric osteochondritis-related arthritis, polymyalgia rheumatica, multiple sclerosis, thyroiditis, delayed hypersensitivity, allergy, contact dermatitis, atopic dermatitis, systemic lupus erythematosus, systemic sclerosis, adult-onset Still's disease, asthma, autoimmune thyroid disorder, Sjogren's syndrome, Kawasaki disease, pancreatitis, nephritis, hepatitis, pneumonia, chronic obstructive pulmonary disease, otitis media, angioproliferative nephritis, myelodysplastic syndrome, osteoarthritis, sarcoidosis, granuloma annulus, Wegener's granulomatosis, lupus, hemolytic uremic syndrome, arteriosclerosis, vasculitis, heart failure, stroke, myocardial infarction, myocardial ischemia-reperfusion injury, sexual dysfunction, obesity, hypertension, diabetes and diabetic complications, hyperlipidemia, preeclampsia, kidney disease, liver disease, kidney damage, liver damage, snake bite, allograft rejection, organ transplantation, graft-versus-host disease, dementia, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, pain, central nervous system disease, uveitis, Behcet's disease, diabetic macular edema, macular degeneration, orbitopathy, glaucoma, hidradenitis suppurativa, multicentral reticulocytosis, pityriasis rubra pilaris, eosinophilic fasciitis, panniculitis, necrobiosis lipoidica diabeticorum, cicatricial pemphigoid, pyoderma gangrenosum, Sweet's syndrome, subcorneal pustular dermatosis, scleroderma, neutrophilic dermatosis, toxic epidermal necrolysis, pustular dermatosis, dermatomyositis, polymyositis, bullous dermatosis, erythema nodosum, alopecia, depression, bipolar disorder, anxiety disorder, tuberculosis, viral infection, bacterial infection, fungal infection, protozoan infection, cerebral malaria, sepsis, septic shock, prostate cancer, skin cancer, colorectal cancer, kidney cancer, pancreatic cancer, ovarian cancer, breast cancer, bladder cancer, prostate cancer, lymphoma, glioma, osteosarcoma, leukemia, multiple myeloma and cachexia.

### Claim 14

(canceled)

### Claim 15

(canceled)

### Claim 16 (depends on 8)

A pharmaceutical composition for preventing or treating a TNF-related disease, comprising the compound or pharmaceutically acceptable salt thereof according to claim 8, as an active ingredient.

### Claim 17 (depends on 16)

The pharmaceutical composition according to claim 16, wherein the TNF-related disease is selected from the group consisting of rheumatoid arthritis, juvenile rheumatoid arthritis, inflammatory bowel disease, Crohn's disease, ulcerative colitis, psoriasis, plaque psoriasis, pediatric plaque psoriasis, psoriatic arthritis, polyarticular juvenile idiopathic arthritis, Behcet's enteritis, ankylosing spondylitis, axial spondylarthritis, pediatric osteochondritis-related arthritis, polymyalgia rheumatica, multiple sclerosis, thyroiditis, delayed hypersensitivity, allergy, contact dermatitis, atopic dermatitis, systemic lupus erythematosus, systemic sclerosis, adult-onset Still's disease, asthma, autoimmune thyroid disorder, Sjogren's syndrome, Kawasaki disease, pancreatitis, nephritis, hepatitis, pneumonia, chronic obstructive pulmonary disease, otitis media, angioproliferative nephritis, myelodysplastic syndrome, osteoarthritis, sarcoidosis, granuloma annulus, Wegener's granulomatosis, lupus, hemolytic uremic syndrome, arteriosclerosis, vasculitis, heart failure, stroke, myocardial infarction, myocardial ischemia-reperfusion injury, sexual dysfunction, obesity, hypertension, diabetes and diabetic complications, hyperlipidemia, preeclampsia, kidney disease, liver disease, kidney damage, liver damage, snake bite, allograft rejection, organ transplantation, graft-versus-host disease, dementia, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, pain, central nervous system disease, uveitis, Behcet's disease, diabetic macular edema, macular degeneration, orbitopathy, glaucoma, hidradenitis suppurativa, multicentral reticulocytosis, pityriasis rubra pilaris, eosinophilic fasciitis, panniculitis, necrobiosis lipoidica diabeticorum, cicatricial pemphigoid, pyoderma gangrenosum, Sweet's syndrome, subcorneal pustular dermatosis, scleroderma, neutrophilic dermatosis, toxic epidermal necrolysis, pustular dermatosis, dermatomyositis, polymyositis, bullous dermatosis, erythema nodosum, alopecia, depression, bipolar disorder, anxiety disorder, tuberculosis, viral infection, bacterial infection, fungal infection, protozoan infection, cerebral malaria, sepsis, septic shock, prostate cancer, skin cancer, colorectal cancer, kidney cancer, pancreatic cancer, ovarian cancer, breast cancer, bladder cancer, prostate cancer, lymphoma, glioma, osteosarcoma, leukemia, multiple myeloma and cachexia.