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JP-7856673-B2 - Triazolone, tetrazolon, and imidazolon, or salts thereof, and pharmaceutical compositions containing them.

JP7856673B2JP 7856673 B2JP7856673 B2JP 7856673B2JP-7856673-B2

Inventors

  • タク， ヒ ジェ
  • キム， ウン キョン
  • チョ， ヒョク ジュン
  • リム， チョル ヒ

Assignees

  • ユハン コーポレーション

Dates

Publication Date
20260511
Application Date
20220421
Priority Date
20210422

Claims (18)

  1. Compound of formula 1, or a pharmaceutically acceptable salt thereof During the ceremony, (i) X is N and Y is N or CR 2' , or (ii) X is CR 3 and Y is N or CR 2 , or (iii) X and Y are both N. R1 is hydrogen or fluorocarbon. R2 is hydrogen, C1-3 alkyl, halogen, phenyl, or benzyl. R 2' is a C1-3 alkyl, halogen, phenyl, or benzyl. R3 is hydrogen, C1-3 alkyl, or phenyl. n is either 0 or 1, A is a C6 - C10 aryl group or a 5-10 membered heteroaryl group, wherein the heteroaryl group has 1-5 heteroatom ring members independently selected from O, N, and S, and the aryl group or heteroaryl group is optionally substituted with 1 or 2 substituents independently selected from the group consisting of C1 -C3 alkyl, halogen, and -R. R is a compound or a pharmaceutically acceptable salt thereof, in which R is a substituted or unsubstituted cyclic ring optionally containing 1 to 5 heteroatom ring members independently selected from O, N, and S, wherein the cyclic ring is aromatic or unaromatic.
  2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein A is a C6 - C10 aryl group optionally substituted with one or two substituents independently selected from the group consisting of C1-3 alkyl, halogen, and -R.
  3. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein A is a phenyl compound optionally substituted with one or two substituents independently selected from the group consisting of C1-3 alkyl, halogen, and -R.
  4. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein A is a 5-10 membered heteroaryl group having 1-5 heteroatom ring members independently selected from O, N, or S, and the heteroaryl group is optionally substituted with 1 or 2 substituents independently selected from the group consisting of C1-3 alkyl, halogen, and -R.
  5. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein A is thiophenyl or pyridinyl and optionally substituted with one or two substituents independently selected from the group consisting of C1-3 alkyl, halogen and -R.
  6. R is, It is a substituted or unsubstituted phenyl. A compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, which is a substituted or unsubstituted 5 to 10-membered heteroaryl having 1 to 5 heteroatom ring members independently selected from O, N, and S, or a substituted or unsubstituted non-aromatic 3 to 12-membered heterocycle having 1 to 5 heteroatom ring members independently selected from O, N, and S.
  7. The compound according to any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof, wherein R is a cyclic ring selected from the group consisting of phenyl, pyridinyl, pyrazolyl, pyridine-2-onyl, benzodioxolyl, benzoxadiazolyl, 3,4- dihydroquinoline -2- onyl, and triazolo[1,5-a]pyridinyl, and the cyclic ring is optionally substituted with 1 to 3 substituents independently selected from the group consisting of C1-6 alkyl, mono -C1-6 alkylamino, di-C1-6 alkylamino, C1-6 alkylsulfonyl, piperazinyl, and morpholinyl.
  8. Compound of formula 15, or a pharmaceutically acceptable salt thereof During the ceremony, R1 is hydrogen or fluorocarbon. R 2' is a C1-3 alkyl, halogen, phenyl, or benzyl. n is either 0 or 1, A is a C6 - C10 aryl group or a 5-10 membered heteroaryl group, wherein the heteroaryl group has 1-5 heteroatom ring members independently selected from O, N, and S, and the aryl group or heteroaryl group is optionally substituted with 1 or 2 substituents independently selected from the group consisting of C1 -C3 alkyl, halogen, and -R. R is a compound or a pharmaceutically acceptable salt thereof, in which R is a substituted or unsubstituted cyclic ring optionally containing 1 to 5 heteroatom ring members independently selected from O, N, and S, wherein the cyclic ring is aromatic or unaromatic.
  9. Compound of formula 16, or a pharmaceutically acceptable salt thereof During the ceremony, R1 is hydrogen or fluorocarbon. n is either 0 or 1, A is a C6 - C10 aryl group or a 5-10 membered heteroaryl group, wherein the heteroaryl group has 1-5 heteroatom ring members independently selected from O, N, and S, and the aryl group or heteroaryl group is optionally substituted with 1 or 2 substituents independently selected from the group consisting of C1 -C3 alkyl, halogen, and -R. R is a compound or a pharmaceutically acceptable salt thereof, in which R is a substituted or unsubstituted cyclic ring optionally containing 1 to 5 heteroatom ring members independently selected from O, N, and S, wherein the cyclic ring is aromatic or unaromatic.
  10. Compound of formula 17, or a pharmaceutically acceptable salt thereof During the ceremony, R1 is hydrogen and fluoro, n is either 0 or 1, A is a C6 - C10 aryl group or a 5-10 membered heteroaryl group, wherein the heteroaryl group has 1-5 heteroatom ring members independently selected from O, N, or S, and the aryl group or heteroaryl group is optionally substituted with 1 or 2 substituents independently selected from the group consisting of C1 -C3 alkyl, halogen, and -R. R is a compound or a pharmaceutically acceptable salt thereof, in which R is a substituted or unsubstituted cyclic ring optionally containing 1 to 5 heteroatom ring members independently selected from O, N, and S, wherein the cyclic ring is aromatic or unaromatic.
  11. The aforementioned compound, The compound according to claim 1 or a pharmaceutically acceptable salt thereof.
  12. A pharmaceutical composition comprising a compound according to any one of claims 1 to 5 and 8 to 11, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.
  13. A composition for use in inhibiting vascular adhesion protein-1 (VAP-1), comprising a compound according to any one of claims 1 to 5 and 8 to 11, or a pharmaceutically acceptable salt thereof.
  14. A composition for use in the treatment of diseases mediated by VAP-1, wherein the composition comprises a compound described in any one of claims 1 to 5 and 8 to 11 or a pharmaceutically acceptable salt thereof, wherein the diseases mediated by VAP-1 are conditions or diseases resulting from chronic fatty and fibrous degeneration of organs due to lipid disorders, lipoprotein disorders, accumulation of lipids, particularly triglycerides, and subsequent activation of fibrotic progressive pathways; type I or type II diabetes mellitus; clinical complications of type I and type II diabetes mellitus; chronic intrahepatic cholestasis; extrahepatic cholestasis; hepatic fibrosis; acute intrahepatic cholestasis; obstructive or chronic inflammatory diseases resulting from inappropriate bile composition; and reduced intake of dietary fats and fat-soluble dietary vitamins. A composition selected from the group consisting of: gastrointestinal conditions, inflammatory bowel disease, obesity, metabolic syndromes, dyslipidemia, diabetes and abnormally high obesity index, persistent infection by intracellular bacteria or parasitic protists, non-malignant hyperproliferative disorder, malignant hyperproliferative disorder, colorectal adenocarcinoma and hepatocellular carcinoma, fatty liver disease or related syndromes, hepatitis B infection, hepatitis C infection, cholestasis and fibrosis associated with alcoholic cirrhosis or viral hepatitis, hepatic failure or impaired hepatic function as a result of chronic liver disease or surgical hepatectomy, acute myocardial infarction, acute stroke, chronic obstructive arteriosclerosis, osteoarthritis, rheumatoid arthritis, psoriasis, and thrombosis (alone or in combination thereof) occurring as an endpoint of cerebral infarction.
  15. Formula 1a A compound of, or a pharmaceutically acceptable salt thereof, wherein, (i) X is N and Y is N or CR 2' , or (ii) X is CR 3 and Y is N or CR 2 , or (iii) X and Y are both N. R1 is hydrogen or fluorocarbon. R2 is hydrogen, C1-3 alkyl, halogen, phenyl, or benzyl. R 2' is a C1-3 alkyl, halogen, phenyl, or benzyl. R3 is hydrogen, C1-3 alkyl, or phenyl. n is either 0 or 1, A' is a C6 - C10 aryl group or a 5-10 membered heteroaryl group, wherein the heteroaryl group has 1-5 heteroatom ring members independently selected from O, N, and S. R' is selected from the group consisting of C1-3 alkyl, halogen, and -R. A method for preparing a compound or a pharmaceutically acceptable salt thereof, wherein R is a substituted or unsubstituted cyclic ring optionally containing 1 to 5 heteroatom ring members independently selected from O, N, and S, and the cyclic ring is aromatic or non-aromatic, The aforementioned method, (a) A compound of formula 2, In the formula, PG is an amino protecting group, and the compound is The compound of formula 3, Z-R' (Formula 3) In the formula, Z is -B(OH) 2 , -B( C1-3 alkoxy) 2 , or The compound is reacted with the compound, To obtain the compound of formula 1aa, (b) a method comprising removing PG from the compound of formula 1aa under reaction conditions to obtain the compound of formula 1a or a pharmaceutically acceptable salt thereof.
  16. X is N, Y is CR 2' , n is 1, and the compound of formula 2 is, (a) The compound of formula 4, React with the compound in formula 5, Obtaining the compound of formula 6, (b) The compound of formula 6 is the compound of formula 11, The compound of formula 12, In the formula, Q is a halogen, and the compound is... The method according to claim 15, which is obtained by reacting under reaction conditions to obtain the compound of formula 2.
  17. Both X and Y are N, and the compound of formula 2 is, (a) The compound of formula 7, By reacting with trimethylsilyl azide under cyclization conditions, the compound of formula 8 is obtained. (b) The compound of formula 8 is the compound of formula 11, The compound of formula 12, In the formula, Q is a halogen, and the compound is... The method according to claim 15, which is obtained by reacting under reaction conditions to obtain the compound of formula 2.
  18. X is CH, Y is CH, n is 1, and the compound of formula 2 is, The compound of formula 9, Compound of formula 11, The compound of formula 12, In the formula, Q is a halogen, and the compound is... The method according to claim 15, which is obtained by reacting under reaction conditions to obtain the compound of formula 2.

Description

(Cross-reference of related applications) This application claims priority to Korean Patent Application No. 10-2021-0052441, filed on 22 April 2021, the entirety of which is incorporated herein by reference. (Field of invention) This technology relates to triazolone, tetrazolon, and imidazolone, or pharmaceutically acceptable salts thereof, which have inhibitory activity against vascular adhesion protein (VAP-1), a process for preparing them, pharmaceutical compositions containing them, and their use. Vascular adhesion protein-1 (VAP-1) is a semicarbazide-sensitive amine oxidase (SSAO) abundant in human plasma. VAP-1 is an ectoenzyme containing a short cytoplasmic end, a single transmembrane domain, and a large, highly glycosylated extracellular domain containing the active site. VAP-1 exists not only as a membrane-bound form in the endothelium but also as a soluble form in serum (soluble VAP-1, sVAP-1). This soluble form has been shown to be a cleavage product of membrane-bound VAP-1 and appears to have similar characteristics to its tissue-bound form. Furthermore, while VAP-1 is normally stored in intracellular granules within endothelial cells, it has been reported that in response to inflammatory stimuli, it migrates to the cell membrane, its expression is upregulated, and therefore, it is expressed more strongly in inflamed tissue than in normal tissue. The substrates of VAP-1 include endogenous methylamine and aminoacetone, as well as several xenobiotic amines such as tyramine and benzylamine. VAP-1 possesses two physiological functions: firstly, amine oxidase activity, as previously described in this section, and secondly, cell adhesion activity. These two activities demonstrate that VAP-1 acts as a leukocyte adhesion protein at inflammatory sites, playing a crucial role in the leakage of inflammatory cells [Trends Immunol. (2001) 22:211]. VAP-1-deficient transgenic mice are healthy, develop normally, are fertile, and exhibit a normal phenotype, but show a marked reduction in inflammatory responses to various inflammatory stimuli [Immunity. (2005) 22:105]. In addition, the inhibitory activity of VAP-1 by antibodies or small molecules in several animal models of human diseases (e.g., carrageenan-induced peditis, oxazolone-induced colitis, lipopolysaccharide-induced pneumonia, collagen-induced arthritis, endotoxin-induced uveitis) has been shown to prevent leukocyte rolling, adhesion, and leakage, reduce levels of inflammatory cytokines and chemokines, and thereby reduce disease severity [Eur J Immunol. (2005) 35:3119, J Pharmacol Exp Ther. (2005) 315:553, Annu Rep Med Chem. (2007) 42:229, FASEB J. (2008) 22:1094]. Inflammation is the immune system's initial response to infection or irritation, and in this process, the migration of leukocytes into tissues through the circulation is a crucial step. Leukocytes first bind to adhesion proteins, then adhere to the endothelium, and then begin to traverse the blood vessel wall. VAP-1 is highly expressed in endothelial venules (HEVs), such as high endothelial venules in lymphoid organs, as well as in hepatic sinusoidal endothelial cells (HSECs), smooth muscle cells, and adipocytes. VAP-1 expression on the cell surface of endothelial cells is tightly regulated and increases during inflammation. VAP-1 activates NF-κB when present in the substrate, and NF-κB is activated within HSECs, while other adhesion molecules, E-selectin and the chemokine IL-8, are upregulated ex vivo. This suggests that VAP-1 may be a key factor in regulating the inflammatory response, and therefore, VAP-1 inhibitors appear likely to be effective anti-inflammatory agents in a wide range of human diseases. Non-alcoholic fatty liver disease (NAFLD) histologically includes simple steatosis, non-alcoholic steatohepatitis (NASH), and cirrhosis. Among these, NASH differs from simple steatosis (non-alcoholic fatty liver, NAFL) in that it can progress to cirrhosis and hepatocellular carcinoma. In NASH, insulin resistance, along with oxidative stress, inflammatory cascades, and fibrosis, is known to play a significant role in disease progression. Elevated sVAP-1 levels have been found in NAFLD patients, and carbon tetrachloride-induced hepatic fibrosis was reduced in VAP-1 knockout (K/O) mice compared to wild-type animals. Furthermore, improvement in hepatic fibrosis by VAP-1 inhibition after administration of VAP-1 antibodies was identified by histological changes [J Clin Invest (2015) 125:501]. Therefore, VAP-1 has been found to be associated with NASH in clinical trials and animal disease models. The inhibitory activity of VAP-1 in carbon tetrachloride-induced animal models is thought to be due to a decrease in the infiltration of leukocytes such as T cells, B cells, NKT cells, and NK cells observed in hepatic fibrosis, suggesting that VAP-1 inhibitors may have the potential to treat fibrotic diseases. Therefore, substances that inhibit VAP-1 can be applied to the prevention and treatment of var