Bicyclic compound and use thereof

Patent metadata

Field	Value
Publication number	US-2022402902-A1
Application number	US-202117378957-A
Country	US
Kind code	A1
Filing date	Jul 19, 2021
Priority date	Oct 2, 2019
Publication date	Dec 22, 2022
Grant date	—

Abstract

The present disclosure relates to a compound derivative containing a 6-7 bicyclic ring and use thereof. The compound according to the present invention can be effectively used in the prevention or treatment of diseases caused by PRMT5 by acting as a PRMT5 inhibitor.

First claim

1 .- 20 . (canceled)

21 . A method for treating a disease associated with protein arginine methyltransferase 5 (PRMT5) inhibition, comprising:
administering to a subject in need thereof a therapeutically effective amount of the compound of Formula 1 or a pharmaceutically acceptable salt thereof:

wherein
X 1 and X 2 are each independently carbon or nitrogen;
Y is carbon, oxygen or nitrogen;
Z is carbon;
n is an integer of 0 or 1;
m is an integer of 0 to 2;
is a single bond or a double bond;
R 1 is -D-R 10 ; wherein D is a direct bond, —O—, —C(═O)—, —C≡C— or —CR 11 R 12 —; R 10 is hydrogen, halo, hydroxy, cyano, alkyl, hydroxyalkyl, haloalkyl, haloalkylsulfonate, dialkylamino, alkylaminoalkyl, dialkylaminoalkyl, dialkylaminocarbonylalkyl, saturated or unsaturated carbocyclyl, saturated or unsaturated heterocyclyl, saturated or unsaturated carbocyclyl-alkyl, or saturated or unsaturated heterocyclyl-alkyl; R 11 and R 12 are each independently hydrogen, hydroxy or alkyl; the carbocycle or heterocycle is optionally substituted with one or more substituents selected from hydroxy, halo, oxo, formyl (—CHO), nitrile, alkyl, alkoxy, hydroxyalkyl, hydroxyhaloalkyl, alkoxyalkyl, haloalkyl, nitrilealkyl, alkylcarbonyl, alkylthiocarbonyl, alkoxycarbonyl, haloalkylcarbonyl, carbocyclyl, carbocyclylcarbonyl, (alkyl)(haloalkyl)amino, (alkyl)(heterocyclyl)amino, heterocyclyl and heterocyclyl-alkyl;
R 2 is hydrogen or alkyl;
R 3 is hydrogen or alkyl;
R 4 , R 5 , R 6 and R 7 are each independently hydrogen or alkyl;
R 8 is hydrogen, halo, alkyl, alkoxy or amino; and
R 9 is hydrogen, halo or alkyl; and
wherein the disease associated with PRMT5 inhibition is selected from the group consisting of blood disease, autoimmune disease, inflammatory disease and neurodegenerative disease.

22 . The method according to claim 21 , wherein the blood disease is hemoglobinemia or sickle cell anemia.

23 . The method according to claim 21 , wherein the autoimmune disease is selected from the group consisting of rheumatoid arthritis, spinal arthritis, gouty arthritis, degenerative joint disease, osteoarthritis, systemic lupus erythematosus, multiple sclerosis, psoriatic arthritis, juvenile arthritis, asthma, atherosclerosis, osteoporosis, bronchitis, tendinitis, psoriasis, eczema, burns, dermatitis, pruritus, enuresis, eosinophilic disease, peptic ulcer, localized enteritis, diverticulitis, gastrointestinal bleeding, eosinophilic esophagitis, eosinophilic gastritis, eosinophilic gastroenteritis and eosinophilic colitis.

24 . The method according to claim 21 , wherein the inflammatory disease is selected from the group consisting of acne-related inflammation, aplastic anemia, hemolytic autoimmune anemia, rhinitis, asthma, polyarteritis, temporal arteritis, periarteritis nodosa , Takayasu's arteritis, crystalline arthritis, osteoarthritis, psoriatic arthritis, gouty arthritis, reactive arthritis, rheumatoid arthritis, amyotrophic lateral sclerosis, autoimmune disease, allergic or allergic reaction, atherosclerosis, bronchitis, bursitis, chronic prostatitis, conjunctivitis, chronic obstructive pulmonary disease, dermatomyositis, type I diabetes, type 2 diabetes, psoriasis, eczema, eczema hypersensitivity reaction, burn, dermatitis, pruritus, endometriosis, infection, ischemic heart disease, glomerulonephritis, gingivitis, irritability, migraine, tension headache, postoperative intestinal obstruction, intestinal obstruction during sepsis, idiopathic thrombocytopenia purpura, bladder pain syndrome, peptic ulcer, localized enteritis, diverticulitis, gastric bleeding, eosinophilic esophagitis, eosinophilic gastritis, eosinophilic gastroenteritis, eosinophilic colitis, gastritis, diarrhea, gastroesophageal reflux disease, Crohn's disease, ulcerative colitis, collagenous colitis, lymphocytic colitis, ischemic colitis, bypass colitis, Behcet's syndrome, indeterminate colitis, inflammatory bowel syndrome (IBS), lupus, ecchymosis, myasthenia gravis and myocardial ischemia.

25 . The method according to claim 21 , wherein the neurodegenerative disease is selected from the group consisting of motor neuron disease, Pick's disease, Alzheimer's disease, AIDS-related dementia, Parkinson's disease, amyotrophic lateral sclerosis, retinal pigmentation, spinal muscular atrophy and cerebellar degeneration.

26 . The method according to claim 21 , wherein
X 1 and X 2 are each independently CH or N; Y is CH 2 , O or NH, when n is 0; Y is CH or N, when n is 1; Z is CH 2 or CH, when m is 0; Z is CH or C, when m is 1; Z is C, when m is 2; and is a single bond or a double bond.

27 . The method according to claim 21 , wherein
R 1 is -D-R 10 ; wherein D is a direct bond, —O—, —C(═O)—, —C≡C— or —CR 11 R 12 —; R 10 is hydrogen, halo, hydroxy, cyano, C 1 -C 7 alkyl, hydroxy-C 1 -C 7 alkyl, halo-C 1 -C 7 alkyl, halo-C 1 -C 7 alkylsulfonate, di(C 1 -C 7 alkyl)amino, C 1 -C 7 alkylamino-C 1 -C 7 alkyl, di(C 1 -C 7 alkyl)amino-C 1 -C 7 alkyl, di(C 1 -C 7 alkyl)aminocarbonyl-C 1 -C 7 alkyl, saturated or unsaturated C 3 -C 10 carbocyclyl, saturated or unsaturated, 4- to 10-membered heterocyclyl, saturated or unsaturated C 3 -C 10 carbocyclyl-C 1 -C 7 alkyl, or saturated or unsaturated, 4- to 10-membered heterocyclyl-alkyl; and R 11 and R 12 are each independently hydrogen, hydroxy or C 1 -C 7 alkyl.

28 . The method according to claim 21 , wherein
the carbocycle or heterocycle is optionally substituted with 1 to 5 substituents selected from hydroxy, halo, oxo, formyl, nitrile, C 1 -C 7 alkyl, C 1 -C 7 alkoxy, hydroxy-C 1 -C 7 alkyl, hydroxyhalo-C 1 -C 7 alkyl, C 1 -C 7 alkoxy-C 1 -C 7 alkyl, halo-C 1 -C 7 alkyl, nitrile-C 1 -C 7 alkyl, C 1 -C 7 alkylcarbonyl, C 1 -C 7 alkylthiocarbonyl, C 1 -C 7 alkoxycarbonyl, halo-C 1 -C 7 alkylcarbonyl, saturated or unsaturated C 3 -C 10 carbocyclyl, saturated or unsaturated C 3 -C 10 carbocyclylcarbonyl, (C 1 -C 7 alkyl)(halo-C 1 -C 7 alkyl)amino, (C 1 -C 7 alkyl)(saturated or unsaturated, 4- to 10-membered heterocyclyl)amino, saturated or unsaturated, 4- to 10-membered heterocyclyl and saturated or unsaturated, 4- to 10-membered heterocyclyl-C 1 -C 7 alkyl.

29 . The method according to claim 21 , wherein
the carbocycle or heterocycle is optionally substituted with 1 to 5 substituents selected from hydroxy, halo, formyl, C 1 -C 7 alkyl, hydroxy-C 1 -C 7 alkyl, C 1 -C 7 alkoxy-C 1 -C 7 alkyl, halo-C 1 -C 7 alkyl, C 1 -C 7 alkylcarbonyl, C 1 -C 7 alkoxycarbonyl, halo-C 1 -C 7 alkylcarbonyl, saturated or unsaturated C 3 -C 10 carbocyclyl, saturated or unsaturated C 3 -C 10 carbocyclylcarbonyl, (C 1 -C 7 alkyl)(halo-C 1 -C 7 alkyl)amino, (C 1 -C 7 alkyl)(saturated or unsaturated, 4- to 10-membered heterocyclyl)amino and saturated or unsaturated, 4- to 10-membered heterocyclyl-C 1 -C 7 alkyl.

30 . The method according to claim 21 , wherein the heterocycle is optionally substituted with 1 or 2 substituents selected from hydroxy, halo, formyl, C 1 -C 7 alkyl, hydroxy-C 1 -C 7 alkyl, C 1 -C 7 alkoxy-C 1 -C 7 alkyl, halo-C 1 -C 7 alkyl, C 1 -C 7 alkylcarbonyl, C 1 -C 7 alkoxycarbonyl, halo-C 1 -C 7 alkylcarbonyl, saturated or unsaturated C 3 -C 10 carbocyclyl, saturated or unsaturated C 3 -C 10 carbocyclylcarbonyl and saturated or unsaturated, 4- to 10-membered heterocyclyl-C 1 -C 7 alkyl.

31 . The method according to claim 21 , wherein the carbocycle is optionally substituted with 1 or 2 substituents selected f

Assignees

• Sk Biopharmaceuticals Co Ltd

Inventors

• Shin Yong Je
• Kim Jin Hee
• Lee Jun
• Park Sook Kyung
• Lee Ho Yeon
• Choi Hyun Suk
• Kim Se Hyuk
• Kang Eun Ji
• Lee Ho Youl
• Jung Soo Yeon

Classifications

• C07D413/14

  containing three or more hetero rings · CPC title

• A61K31/553

  having at least one nitrogen and one oxygen as ring hetero atoms, e.g. loxapine, staurosporine · CPC title

• C07D491/107

  with only one oxygen atom as ring hetero atom in the oxygen-containing ring · CPC title

• C07D487/04

  Ortho-condensed systems · CPC title

• A61P35/00

  Antineoplastic agents · CPC title