WO2022057932A1 - Composé hétérocyclique carbonyle et son application - Google Patents

Composé hétérocyclique carbonyle et son application Download PDF

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WO2022057932A1
WO2022057932A1 PCT/CN2021/119427 CN2021119427W WO2022057932A1 WO 2022057932 A1 WO2022057932 A1 WO 2022057932A1 CN 2021119427 W CN2021119427 W CN 2021119427W WO 2022057932 A1 WO2022057932 A1 WO 2022057932A1
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membered
independently
compound
mmol
group
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PCT/CN2021/119427
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Chinese (zh)
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张朝欣
夏广新
向志军
柯樱
楼江松
赵蒙浩
郝利军
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上海医药集团股份有限公司
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Publication of WO2022057932A1 publication Critical patent/WO2022057932A1/fr

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    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/407—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with other heterocyclic ring systems, e.g. ketorolac, physostigmine
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    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
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    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
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    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
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    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/18—Benzimidazoles; Hydrogenated benzimidazoles with aryl radicals directly attached in position 2
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    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
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    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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Definitions

  • the present invention relates to a carbonyl heterocyclic compound and its application.
  • Lanthionine C-like protein 2 (also known as “lanthionine synthase C-like protein 2" or “lanthionine synthase component C-like protein 2” is expressed by immune cells, gastrointestinal Signaling pathway protein of the tract, neurons, testis and pancreas. Activating the LANCL2 pathway increases insulin sensitivity and reduces inflammation associated with various autoimmune, inflammatory and metabolic conditions. Results of in vivo and in vitro tests in mice demonstrated that using a compound targeting this pathway reduced glucose levels by a factor of 2 in the glucose tolerance test compared to controls and provided the same (GlaxoSmithKline plc, Brentford, England), is an effective treatment but has significant side effects. Targeting the LANCL2 pathway also reduced intestinal inflammation by 90% and a corresponding 4-fold reduction in the number of lesions. The results of this and other validations of the pathway have been mentioned in several articles.
  • autoimmune-related inflammation there is currently a global pandemic of autoimmune disorders such as inflammatory bowel disease (IBD), systemic lupus, rheumatoid arthritis, type 1 diabetes, psoriasis, multiple sclerosis.
  • IBD inflammatory bowel disease
  • pandemic including metabolic syndrome, obesity, prediabetes, cardiovascular disease, and type 2 diabetes.
  • Current treatments are moderately effective, but expensive and have serious side effects.
  • the route of administration for the most effective treatments for autoimmune diseases eg, anti-TNF antibodies
  • LANCL2 provides an orally administered therapeutic that is as effective as anti-TNF antibodies but without the side effects and high cost. Given the overall prevalence of inflammatory and autoimmune diseases, the LANCL2 pathway has the potential to significantly affect millions of patients.
  • Abscisic acid is a natural compound found to bind to LANCL2 during the original screening process.
  • the technical problem to be solved by the present invention is to overcome the problem of lack of therapeutic agents based on lanthionine synthase C-like 2 in the prior art, and to provide a carbonyl heterocyclic compound and its application.
  • the carbonyl heterocyclic compounds provided by the present invention are compounds with a targeting lanthionine synthase C-like protein 2 pathway; the compounds can bind to the LANCL2 protein and achieve beneficial responses in various disease conditions, which can be used with It is used to treat a variety of conditions, including metabolic and infectious diseases, autoimmune diseases, diabetes, and chronic inflammatory diseases.
  • the present invention solves the above-mentioned technical problems through the following technical solutions.
  • the present invention provides a carbonyl heterocyclic compound as shown in formula II or a pharmaceutically acceptable salt thereof;
  • A is or NR 1 R 2 ;
  • R 1 and R 2 are independently H or C 6-18 aryl
  • Y 1 and Y 2 are independently CH or N;
  • T is a connecting bond or -NH-
  • Q is or -NH-
  • L 1 -Z 1 and Z 2 -L 2 are independently (ie L 1 and L 2 are independently connecting bonds) or (the b-terminal represents connecting with carbonyl or B'), and not both
  • Ring Q 2 is a 5-7 membered cycloalkyl or a 5-7 membered monocyclic heterocycloalkyl; the 5-7 membered monocyclic heterocycloalkyl contains 1 to 3 N atoms;
  • Y 3 and Y 4 are independently CH or N;
  • Y 3a and Y 4a are independently CH or N;
  • R 3 is C 1-6 alkyl
  • A' is NO 2 , -OC 1-6 alkyl, C 1-6 alkyl, or H;
  • Y 5 is CH or N
  • the carbon atom with "*" means that when it is a chiral carbon atom, it is in S configuration, R configuration or a mixture thereof;
  • certain groups in the carbonyl heterocyclic compounds represented by formula I, pharmaceutically acceptable salts thereof, solvates or salts of solvates thereof are defined as follows (The unmentioned groups are the same as those described in any scheme of this application), hereinafter referred to as in some preferred embodiments of the present invention.
  • R 1 and R 2 are independently a C 6-18 aryl group
  • the C 6-14 aryl group is phenyl, naphthyl, phenanthryl or anthracenyl , such as phenyl.
  • Z 1 and Z 2 are in ortho, meta or para positions.
  • the 5-7 membered cycloalkyl group is cyclopentyl, cyclohexyl or cycloheptyl; such as cyclohexyl, and E.g
  • the 5-7 membered monocyclic heterocycloalkyl group is N heterocyclopentyl or N heterocyclopentyl Cyclohexyl; e.g. (The b-terminal indicates that it is connected to a carbonyl group)
  • B' when B' is hour, can be E.g (The a' end indicates that it is connected to A').
  • the 5-7 membered heterocyclenyl is a heterocycle Hexenyl, containing 2 N atoms, e.g.
  • R 3 when R 3 is a C 1-6 alkyl group, the C 1-6 alkyl group is methyl, ethyl, n-propyl, isopropyl, n-butyl , isobutyl, sec- or tert-butyl, eg methyl.
  • A is a compound having the same in certain preferred embodiments of the present invention.
  • A is a compound having the same in certain preferred embodiments of the present invention.
  • A is a compound having the same in certain preferred embodiments of the present invention.
  • A is -NR 1 R 2 .
  • A is the same as A'; and/or, Same as B'.
  • Q is Q 2 is a 5-7 membered cycloalkyl
  • L 1 -Z 1 and Z 2 -L 2 are independently E.g for
  • Q is When Q 2 is a 5-7 membered monocyclic heterocycloalkyl, one of L 1 -Z 1 and Z 2 -L 2 is another for E.g for (The b-terminal represents the attachment to the carbonyl group).
  • Q is or -NH-.
  • B' is a linkage
  • A' is
  • B' is A' is NO 2 , -OC 1-6 alkyl, C 1-6 alkyl, or H, can also be or NO 2 .
  • A' is
  • B' is A' is H.
  • B'-A' is the following structure:
  • A is or NR 1 R 2 ;
  • R 1 and R 2 are independently H or C 6-18 aryl
  • Y 1 and Y 2 are independently CH or N;
  • T is a connecting bond or -NH-
  • Q is or -NH-
  • L 1 -Z 1 and Z 2 -L 2 are independently and not at the same time
  • Ring Q 2 is a 5-7-membered monocyclic heterocycloalkyl; the 5-7-membered monocyclic heterocycloalkyl contains 1 to 3 N atoms;
  • Y 3 and Y 4 are independently CH or N;
  • Y 3a and Y 4a are independently CH or N;
  • R 3 is C 1-6 alkyl
  • A' is -OC 1-6 alkyl, C 1-6 alkyl, or H;
  • Y 5 is CH or N
  • the carbon atom with "*" means that when it is a chiral carbon atom, it is in S configuration, R configuration or a mixture thereof;
  • A is or NR 1 R 2 ;
  • R 1 and R 2 are independently H or C 6-18 aryl
  • Y 1 and Y 2 are independently CH or N;
  • T is a connecting bond or -NH-
  • Q is or -NH-
  • L 1 -Z 1 and Z 2 -L 2 are independently and not at the same time
  • Ring Q 2 is a 5-7 membered cycloalkyl or a 5-7 membered monocyclic heterocycloalkyl; the 5-7 membered monocyclic heterocycloalkyl contains 1 to 3 N atoms;
  • Y 3 and Y 4 are independently CH or N;
  • A' is Alkyl of NO 2 or -OC 1-6 ;
  • Y 5 is CH or N
  • a carbon atom with "*" means that when it is a chiral carbon atom, it is in S configuration, R configuration or a mixture thereof.
  • A is or NR 1 R 2 ;
  • R 1 and R 2 are independently H or C 6-18 aryl
  • Y 1 and Y 2 are independently CH or N;
  • T is a connecting bond or -NH-
  • Q is or -NH-
  • L 1 -Z 1 and Z 2 -L 2 are independently and not at the same time
  • Ring Q 2 is a 5-7 membered cycloalkyl or a 5-7 membered monocyclic heterocycloalkyl; the 5-7 membered monocyclic heterocycloalkyl contains 1 to 3 N atoms;
  • Y 3 and Y 4 are independently CH or N;
  • A' is Alkyl of NO 2 or -OC 1-6 ;
  • Y 5 is CH or N
  • a carbon atom with "*" means that when it is a chiral carbon atom, it is in S configuration, R configuration or a mixture thereof.
  • A is or NR 1 R 2 ;
  • R 1 and R 2 are independently H or C 6-18 aryl
  • Y 1 and Y 2 are independently CH or N;
  • T is the connection key
  • Y 3 and Y 4 are independently CH or N;
  • Y 3a and Y 4a are independently CH or N;
  • R 3 is C 1-6 alkyl
  • A' is C 1-6 alkyl, or H
  • Y 5 is CH or N
  • the carbon atom with "*" means that when it is a chiral carbon atom, it is in S configuration, R configuration or a mixture thereof;
  • Y 1 and Y 2 are independently CH or N;
  • T is the connection key
  • T is the connection key
  • A is or NR 1 R 2 ;
  • R 1 and R 2 are independently H or C 6-18 aryl
  • Y 1 and Y 2 are independently CH or N;
  • T is the connection key
  • L 1 -Z 1 and Z 2 -L 2 are independently and not at the same time
  • Ring Q 2 is a 5-7 membered monocyclic heterocycloalkyl
  • Y 3 and Y 4 are independently CH or N.
  • A' is NO 2. or -OC 1-6 alkyl
  • Y 5 is CH or N
  • a carbon atom with "*" means that when it is a chiral carbon atom, it is in S configuration, R configuration or a mixture thereof.
  • A is or NR 1 R 2 ;
  • R 1 and R 2 are independently H or C 6-18 aryl
  • Y 1 and Y 2 are independently CH or N;
  • T is the connection key
  • L 1 -Z 1 and Z 2 -L 2 are independently and not at the same time
  • Ring Q 2 is a 5-7 membered monocyclic heterocycloalkyl
  • Y 3 and Y 4 are independently CH or N.
  • A' is or -OC 1-6 alkyl
  • Y 5 is CH or N
  • a carbon atom with "*" means that when it is a chiral carbon atom, it is in S configuration, R configuration or a mixture thereof.
  • A is E.g.
  • Y 1 and Y 2 are independently CH or N;
  • Y 3 and Y 4 are independently CH or N;
  • A' is E.g
  • A is the same as A';
  • the carbonyl heterocyclic compound shown in formula II is shown in formula II-a:
  • Y 1 and Y 2 are independently CH or N;
  • L 1 -Z 1 and Z 2 -L 2 are independently (ie L 1 and L 2 are independently connecting bonds) or (the b-terminal is connected to a carbonyl group), and not at the same time
  • Ring Q 2 is a 5-7 membered cycloalkyl or a 5-7 membered monocyclic heterocycloalkyl; the 5-7 membered monocyclic heterocycloalkyl contains 1 to 3 N atoms;
  • 6-10-membered and cyclic heterocycloalkyl there are 1 to 3 N atoms;
  • Y 3 and Y 4 are independently CH or N;
  • A' is or NO 2 ;
  • Y 5 is CH or N
  • a carbon atom with "*" means that when it is a chiral carbon atom, it is in S configuration, R configuration or a mixture thereof.
  • B' is A' is or NO 2 .
  • B'-A' is the following structure:
  • A is a compound having the same in certain preferred embodiments of the present invention.
  • Y 1 and Y 2 are independently CH or N;
  • L 1 -Z 1 and Z 2 -L 2 are independently (ie L 1 and L 2 are independently connecting bonds) or (the b-terminal is connected to a carbonyl group), and not at the same time
  • Q 2 is a 5-7-membered cycloalkyl or a 5-7-membered monocyclic heterocycloalkyl; the 5-7-membered monocyclic heterocycloalkyl contains 1 to 3 N atoms; for example, except Z 1 and Z Ring atoms other than 2 are carbon;
  • the 6-10-membered heterocycloalkyl group with a ring it contains 1 to 3 N atoms; for example, the ring atoms other than the N atom connected with the carbonyl group or A' are all carbons;
  • Y 3 and Y 4 are independently CH or N;
  • A' is or NO 2 ;
  • Y 5 is CH or N.
  • A' is or NO 2 ;
  • Y 5 is CH or N.
  • the carbonyl heterocyclic compound represented by formula II is any of the following structures:
  • the carbonyl heterocyclic compound represented by formula II or a pharmaceutically acceptable salt thereof has one or more chiral carbon atoms, so optically pure isomers can be isolated, such as pure parabens. Enantiomers, or racemates, or mixed isomers. Pure single isomers can be obtained by separation methods in the art, such as chiral crystallization into salts, or chiral preparative column separation.
  • the carbonyl heterocyclic compound represented by formula II or a pharmaceutically acceptable salt thereof, if there is a stereoisomer can be used as a single stereoisomer or a mixture thereof (for example, elimination vortex) in the form of.
  • stereoisomer refers to a cis-trans isomer or an optical isomer.
  • stereoisomers can be separated, purified and enriched by asymmetric synthesis methods or chiral separation methods (including but not limited to thin layer chromatography, spin chromatography, column chromatography, gas chromatography, high pressure liquid chromatography, etc.) It can be obtained by chiral resolution by forming bonds with other chiral compounds (chemical bonding, etc.) or forming salts (physical bonding, etc.).
  • single stereoisomer means that the mass content of one stereoisomer of the compound of the present invention relative to all stereoisomers of the compound is not less than 95%.
  • the carbonyl heterocyclic compounds represented by formula II of the present invention or their pharmaceutically acceptable salts can be synthesized by methods similar to those known in the chemical field, and the steps and conditions can refer to the steps and conditions of similar reactions in the art. conditions, in particular the synthesis was carried out according to the description herein. Starting materials are typically from commercial sources such as Aldrich or can be readily prepared using methods well known to those skilled in the art (obtained via SciFinder, Reaxys online database).
  • Necessary starting materials or reagents for the preparation of carbonyl heterocyclic compounds represented by formula II or pharmaceutically acceptable salts thereof can be obtained commercially, or prepared by synthetic methods known in the art.
  • Compounds of the invention can be prepared as free bases or as acid salts thereof as described in the experimental section below.
  • the term pharmaceutically acceptable salt refers to a pharmaceutically acceptable salt as defined herein, and has all the effects of the parent compound.
  • Pharmaceutically acceptable salts can be prepared by treating the organic base in a suitable organic solvent with the corresponding acid according to conventional methods.
  • salt formation examples include: for base addition salts, it is possible by using alkali metal or alkaline earth metal hydroxides or alkoxides (such as ethoxide or methoxide) or suitable basic organic amines (such as diethanolamine, bile Alkali (eg, sodium, potassium, or lithium) or alkaline earth (eg, aluminum, magnesium, calcium, zinc, or bismuth) salts are prepared by treating compounds of the invention with appropriate acidic protons with a base or meglumine.
  • alkali metal or alkaline earth metal hydroxides or alkoxides such as ethoxide or methoxide
  • suitable basic organic amines such as diethanolamine, bile Alkali (eg, sodium, potassium, or lithium)
  • alkaline earth salts eg, aluminum, magnesium, calcium, zinc, or bismuth
  • salts are formed with inorganic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid; and salts formed with organic acids, such as acetic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, lemon acid, ethanesulfonic acid, fumaric acid, glucoheptonic acid, glutamic acid, glycolic acid, hydroxynaphthoic acid, 2-hydroxyethanesulfonic acid, lactic acid, maleic acid, malic acid, oxalic acid, pyruvic acid, malonic acid , mandelic acid, methanesulfonic acid, 2-naphthalenesulfonic acid, propionic acid, salicylic acid, succinic acid, tartaric acid, citric acid, cinnamic acid, p-toluenesulfonic acid or trimethylacetic acid.
  • inorganic acids such as hydrochloric acid
  • the carbonyl heterocyclic compound represented by formula II or a pharmaceutically acceptable salt thereof can also be prepared by the carbonyl heterocyclic compound represented by formula II or its pharmaceutically acceptable salt.
  • the pharmaceutically acceptable salts are subjected to peripheral modification using conventional methods in the art to obtain other described carbonyl heterocyclic compounds represented by formula II or pharmaceutically acceptable salts thereof.
  • the compounds of the present invention can be prepared by the methods described in the present invention, wherein the substituents are as defined in formula II unless otherwise specified.
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising the above-mentioned carbonyl heterocyclic compound represented by formula II or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers.
  • the amount of the carbonyl heterocyclic compound represented by formula II or a pharmaceutically acceptable salt thereof may be a therapeutically effective amount.
  • the pharmaceutically acceptable carriers can be those excipients widely used in the field of pharmaceutical production. Excipients are mainly used to provide a safe, stable and functional pharmaceutical composition, and can also provide a method to enable the subject to dissolve the active ingredient at a desired rate after administration, or to promote the activity of the subject after the composition is administered. The ingredients are effectively absorbed.
  • the pharmaceutical excipients can be inert fillers, or provide some function, such as stabilizing the overall pH of the composition or preventing degradation of the active ingredients of the composition.
  • Described pharmaceutical adjuvants may include one or more of the following adjuvants: binders, suspending agents, emulsifiers, diluents, fillers, granulating agents, adhesives, disintegrating agents, lubricants, anti-sticking agents Agents, glidants, wetting agents, gelling agents, absorption delaying agents, dissolution inhibitors, enhancers, adsorbents, buffers, chelating agents, preservatives, colorants, flavors and sweeteners.
  • adjuvants may include one or more of the following adjuvants: binders, suspending agents, emulsifiers, diluents, fillers, granulating agents, adhesives, disintegrating agents, lubricants, anti-sticking agents Agents, glidants, wetting agents, gelling agents, absorption delaying agents, dissolution inhibitors, enhancers, adsorbents, buffers, chelating agents, preservatives, colorants, flavors and sweeten
  • compositions of the present invention can be prepared in light of the disclosure using any method known to those skilled in the art. For example, conventional mixing, dissolving, granulating, emulsifying, attenuating, encapsulating, entrapping or lyophilizing processes.
  • compositions of the present invention may be administered in any form, including injection (intravenous), mucosal, oral (solid and liquid formulations), inhalation, ophthalmic, rectal, topical or parenteral (infusion, injection, implant Intradermal, subcutaneous, intravenous, intraarterial, intramuscular) administration.
  • the pharmaceutical compositions of the present invention may also be in controlled release or delayed release dosage forms (eg, liposomes or microspheres).
  • solid oral formulations include, but are not limited to, powders, capsules, caplets, softgels, and tablets.
  • liquid formulations for oral or mucosal administration include, but are not limited to, suspensions, emulsions, elixirs, and solutions.
  • topical formulations include, but are not limited to, creams, gels, ointments, creams, patches, pastes, foams, lotions, drops, or serum formulations.
  • formulations for parenteral administration include, but are not limited to, solutions for injection, dry formulations that can be dissolved or suspended in a pharmaceutically acceptable carrier, suspensions for injection, and emulsions for injection.
  • suitable formulations of the pharmaceutical compositions include, but are not limited to, eye drops and other ophthalmic formulations; aerosols: such as nasal sprays or inhalants; liquid dosage forms suitable for parenteral administration; suppositories and lozenges agent.
  • the present invention also provides the use of the carbonyl heterocyclic compound represented by formula II or a pharmaceutically acceptable salt thereof in the preparation of a lanthionine C-like protein 2 (LANCL2) agonist.
  • the lanthionine C-like protein 2 (LANCL2) activator can be used in mammalian organisms; it can also be used in vitro, mainly for experimental purposes, such as: providing as a standard sample or a control sample
  • the comparison, or the kit prepared according to the conventional method in the art provides a rapid detection for the activation effect of lanthionine C-like protein 2 (LANCL2).
  • the present invention also provides a use of the carbonyl heterocyclic compound represented by formula II or a pharmaceutically acceptable salt thereof in the preparation of a medicament; the medicament can be used for prevention and/or treatment and Drugs for lanthionine C-like protein 2 (LANCL2)-related diseases.
  • the disease associated with lanthionine C-like protein 2 (LANCL2) may be one or more of autoimmune, chronic inflammatory, chronic metabolic and infectious diseases.
  • the present invention also provides the use of the carbonyl heterocyclic compound shown in formula II, a pharmaceutically acceptable salt thereof or the above composition in the preparation of medicine; the medicine can be used for prevention and/or drugs for the treatment of autoimmune, chronic inflammatory, chronic metabolic or infectious diseases.
  • Another aspect of the present invention relates to a method of preventing and/or treating lanthionine C-like protein 2 (LANCL2)-related diseases, comprising administering to a patient a therapeutically effective amount of said carbonyl group of formula II Heterocyclic compounds, pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising the same as described above.
  • LANCL2 lanthionine C-like protein 2
  • Another aspect of the present invention pertains to a method of therapeutically preventing and/or treating an autoimmune, chronic inflammatory, chronic metabolic or infectious disease comprising administering to a patient a therapeutically effective amount of said formula II as described
  • the carbonyl heterocyclic compound, its pharmaceutically acceptable salt or the above-mentioned composition is administered to a patient a therapeutically effective amount of said formula II as described.
  • Another aspect of the present invention relates to a medicament for lanthionine C-like protein 2 (LANCL2), comprising the carbonyl heterocyclic compound represented by formula II, a pharmaceutically acceptable salt thereof or The above composition.
  • LANCL2 lanthionine C-like protein 2
  • the autoimmune disorder as described above may be inflammatory bowel disease (IBD) (including ulcerative colitis and/or Crohn's disease), systemic lupus, rheumatoid arthritis, type 1 diabetes , psoriasis, multiple sclerosis.
  • IBD inflammatory bowel disease
  • Crohn's disease including ulcerative colitis and/or Crohn's disease
  • systemic lupus including ulcerative colitis and/or Crohn's disease
  • rheumatoid arthritis rheumatoid arthritis
  • type 1 diabetes psoriasis
  • psoriasis multiple sclerosis.
  • the chronic metabolic disease as described above can be metabolic syndrome, obesity, prediabetes, cardiovascular disease and type 2 diabetes.
  • the infectious disease as described above may be a viral disease, such as an influenza infection.
  • the present invention also provides a carbonyl heterocyclic compound or a pharmaceutically acceptable salt thereof, a pharmaceutical composition comprising the same, and an application thereof.
  • the present invention provides a carbonyl heterocyclic compound or a pharmaceutically acceptable salt thereof, wherein the carbonyl heterocyclic compound is selected from the following group:
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising the carbonyl heterocyclic compound or a pharmaceutically acceptable salt thereof as described above (the second aspect), and one or more pharmaceutically acceptable carriers.
  • the amount of the carbonyl heterocyclic compound or a pharmaceutically acceptable salt thereof may be a therapeutically effective amount.
  • the present invention also provides a lanthionine C-like protein 2 (LANCL2) agonist using the carbonyl heterocyclic compound, its pharmaceutically acceptable salt or the above pharmaceutical composition as described above (second aspect) applications in .
  • LANCL2 lanthionine C-like protein 2
  • the lanthionine C-like protein 2 (LANCL2) activator can be used in mammalian organisms; it can also be used in vitro, mainly for experimental purposes, such as: providing as a standard sample or a control sample
  • the comparison, or the kit prepared according to the conventional method in the art provides a rapid detection for the activation effect of lanthionine C-like protein 2 (LANCL2).
  • the present invention also provides the use of the carbonyl heterocyclic compound described above (the second aspect), a pharmaceutically acceptable salt thereof or the above-mentioned pharmaceutical composition in the preparation of a medicine; the medicine can be used for Drugs for the prevention and/or treatment of diseases associated with lanthionine C-like protein 2 (LANCL2).
  • the disease associated with lanthionine C-like protein 2 (LANCL2) may be one or more of autoimmune, chronic inflammatory, chronic metabolic and infectious diseases.
  • the present invention also provides a use of the carbonyl heterocyclic compound or a pharmaceutically acceptable salt thereof as described above (the second aspect) in the preparation of a medicament; the medicament can be used for prevention and/or treatment of itself Drugs for immune, chronic inflammatory, chronic metabolic or infectious diseases.
  • the present invention also provides a method for preventing and/or treating lanthionine C-like protein 2 (LANCL2) related diseases, comprising administering to a patient a therapeutically effective dose of the carbonyl heterocycle as described above (second aspect) A compound or a pharmaceutically acceptable salt thereof or a pharmaceutical composition comprising the same as described above.
  • LANCL2 lanthionine C-like protein 2
  • the present invention also provides a method of treating, preventing and/or treating autoimmune, chronic inflammatory or infectious diseases, comprising administering to a patient a therapeutically effective dose of the carbonyl heterocyclic compound as described above (the second aspect) , its pharmaceutically acceptable salt or the above-mentioned pharmaceutical composition.
  • the present invention also provides a medicament for lanthionine C-like protein 2 (LANCL2), which comprises the carbonyl heterocyclic compound as described above (the second aspect), a pharmaceutically acceptable salt thereof or the above-mentioned pharmaceutical composition.
  • LANCL2 lanthionine C-like protein 2
  • the autoimmune disorder as described above may be inflammatory bowel disease (IBD) (including ulcerative colitis and/or Crohn's disease), systemic lupus, rheumatoid arthritis, type 1 diabetes , psoriasis, multiple sclerosis.
  • IBD inflammatory bowel disease
  • the chronic metabolic disease as described above can be metabolic syndrome, obesity, prediabetes, cardiovascular disease and type 2 diabetes.
  • the infectious disease as described above may be a viral disease, such as an influenza infection.
  • the present invention also provides methods of treating a condition in an animal with any one or more of the compounds described herein.
  • the methods comprise administering to an animal an effective amount of one or more of the compounds described herein.
  • the condition may be selected from the group consisting of infectious diseases, autoimmune diseases, diabetes, and chronic inflammatory diseases.
  • the infectious disease comprises a viral disease, such as influenza infection.
  • the autoimmune disease comprises an autoimmune inflammatory disease, such as inflammatory bowel disease, including ulcerative colitis and/or Crohn's disease.
  • the diabetes is selected from the group consisting of type 1 diabetes and type 2 diabetes.
  • the chronic inflammatory disease comprises metabolic syndrome.
  • the methods comprise administering an amount of a compound effective to increase LANCL2 activity, reduce inflammation, and/or increase anti-inflammatory effects.
  • the present invention also provides compounds for use in treating a condition in an animal with any one or more of the compounds described herein.
  • Compounds for such use include any of the compounds described herein. Use may comprise administering to an animal an effective amount of one or more of the compounds described herein, wherein the condition is selected from the group consisting of infectious disease, autoimmune disease, diabetes, and chronic inflammatory disease.
  • infectious diseases include viral diseases, such as influenza infection.
  • the autoimmune disease comprises an autoimmune inflammatory disease, such as inflammatory bowel disease, including ulcerative colitis and/or Crohn's disease.
  • the diabetes is selected from the group consisting of type 1 diabetes and type 2 diabetes.
  • the chronic inflammatory disease comprises metabolic syndrome.
  • the compounds are effective to increase LANCL2 activity, reduce inflammation, and/or increase anti-inflammatory effects.
  • pharmaceutically acceptable means that salts, solvents, excipients, etc. are generally non-toxic, safe, and suitable for patient use.
  • patient is preferably a mammal, more preferably a human.
  • pharmaceutically acceptable salts refers to salts prepared from compounds of the present invention with relatively non-toxic, pharmaceutically acceptable acids.
  • Treatment means any treatment of a disease in a mammal, including: (1) preventing the disease, i.e. causing the symptoms of the clinical disease not to develop; (2) inhibiting the disease, i.e. preventing the development of the clinical symptoms; (3) alleviating the disease, This results in the subsidence of clinical symptoms.
  • an “effective amount” refers to an amount of a compound sufficient to (i) treat the associated disease, (ii) reduce, ameliorate, or eliminate one or more symptoms of a particular disease or disorder, or (iii) when administered to a patient in need of treatment. Delay the onset of one or more symptoms of a particular disease or disorder described herein.
  • the amount of the carbonyl heterocyclic compound of formula II, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition as described above, corresponding to this amount will vary depending on, for example, the particular compound, the disease state and its severity, The characteristics of the patient in need of treatment (eg, weight) and other factors vary, but can nonetheless be routinely determined by those skilled in the art.
  • Prevention refers to a reduction in the risk of acquiring or developing a disease or disorder.
  • a "pharmaceutical composition” as used herein refers to a formulation of one or more compounds of the present invention or salts thereof and a carrier generally accepted in the art for delivering a biologically active compound to an organism (eg, a human).
  • the purpose of a pharmaceutical composition is to facilitate administration and delivery to an organism.
  • pharmaceutically acceptable carrier refers to a substance that is co-administered with the active ingredient and facilitates the administration of the active ingredient, including but not limited to those acceptable for use in humans or animals approved by the State Food and Drug Administration (such as livestock) any glidants, sweeteners, diluents, preservatives, dyes/colorants, flavor enhancers, surfactants, wetting agents, dispersing agents, disintegrating agents, suspending agents, stabilizers , isotonic agents, solvents or emulsifiers. Examples include, but are not limited to, calcium carbonate, calcium phosphate, various sugars and various types of starch, cellulose derivatives, gelatin, vegetable oils, and polyethylene glycols.
  • the pharmaceutical composition of the present invention can be formulated into solid, semi-solid, liquid or gaseous preparations, such as tablets, pills, capsules, powders, granules, ointments, emulsions, suspensions, solutions, suppositories, injections, Inhalants, gels, microspheres and aerosols, etc.
  • the pharmaceutical composition of the present invention can be manufactured by methods well known in the art, such as conventional mixing method, dissolving method, granulation method, sugar-coated pill method, grinding method, emulsification method, freeze-drying method and the like.
  • routes of administration of the compounds of the present invention or their pharmaceutically acceptable salts or their pharmaceutical compositions include but are not limited to oral, rectal, transmucosal, enteral administration, or topical, transdermal, inhalation, parenteral administration , sublingual, intravaginal, intranasal, intraocular, intraperitoneal, intramuscular, subcutaneous, intravenous administration.
  • the preferred route of administration is oral administration.
  • the pharmaceutical compositions can be formulated by admixing the active compound with pharmaceutically acceptable carriers well known in the art. These carriers enable the compounds of the present invention to be formulated as tablets, pills, dragees, dragees, capsules, liquids, gels, slurries, suspensions and the like for oral administration to a patient.
  • tablets may be obtained by combining the active ingredient with one or more solid carriers, granulating the resulting mixture, if desired, and adding minor amounts of excipients if desired. Processed into mixtures or granules to form tablets or cores.
  • the tablet core can be combined with an optional enteric coating material and processed into a coated formulation that is more conducive to absorption by an organism (eg, a human).
  • C1 - C6 alkyl refers to an alkyl group as defined below having a total of 1, 2, 3, 4, 5 or 6 carbon atoms.
  • the total number of carbon atoms in the simplified notation does not include carbons that may be present in the substituents of the group.
  • substituted means that any one or more hydrogen atoms on a specified atom are replaced by a substituent, including deuterium and hydrogen variants, as long as the valence of the specified atom is normal and the substituted compound is stable .
  • substituted means that one or more hydrogen atoms in a given structure have been replaced with a specified substituent.
  • the substituents are independent of each other, that is, the one or more substituents may be different from each other or the same of.
  • a substituent group may be substituted at various substitutable positions of the substituted group. When more than one position in a given formula can be substituted with one or more substituents selected from a particular group, the substituents can be substituted identically or differently at each position.
  • one(s) or more(s) or "one(s) or two(s) or more” means i.e. 1, 2, 3, 4, 5, 6, 7, 8, 9 or More; such as 1, 2, 3, 4, or 5.
  • cycloalkyl as part of a group or other group, unless otherwise specified, means a saturated monocyclic, polycyclic or bridged carbocyclic substituted consisting solely of carbon and hydrogen atoms is attached to the rest of the molecule by a single bond via any suitable carbon atom; when polycyclic, it may be a copular or spiro (i.e., two geminal hydrogens on a carbon atom are linked by an alkylene substituted) spiro or bridged ring systems.
  • heterocycloalkyl as a group or part of another group means a stable compound consisting of 2-11 carbon atoms and 1-5 heteroatoms selected from nitrogen, oxygen and sulfur 3- to 16-membered saturated cyclic group.
  • a heterocycloalkyl group may be either monocyclic ("monocyclic heterocycloalkyl"), or a bicyclic, tricyclic or more cyclic ring system, which may include Fused (paracyclic), bridged (bridged), or spiro (spiro) ring systems (eg, bicyclic ring systems ("bicyclic heterocycloalkyl").
  • Heterocycloalkyl bicyclic ring systems can be Include one or more heteroatoms in one or both rings; and be saturated.
  • moiety refers to a specific fragment or functional group in a molecule.
  • a chemical moiety is generally thought of as a chemical entity embedded or attached to a molecule.
  • linking substituents are described.
  • the Markush variables listed for that group should be understood to be the linking group.
  • the Markush group definition for that variable recites “alkyl” or “aryl”, it should be understood that the “alkyl” or “aryl” respectively represents the linking An alkylene group or an arylene group.
  • alkyl group when an alkyl group is clearly represented as a linking group, then the alkyl group represents the alkylene group to which it is attached, eg, the group "halo- C1 - C6alkane” C 1 -C 6 alkyl in "radical” is to be understood as C 1 -C 6 alkylene.
  • each step and condition may refer to the conventional operation steps and conditions in the art.
  • the present invention employs standard nomenclature and standard laboratory procedures and techniques of analytical chemistry, synthetic organic chemistry, and optics. In some cases, standard techniques are used for chemical synthesis, chemical analysis, and light-emitting device performance testing.
  • the description method "...independently” used in the present invention should be understood in a broad sense, meaning that the described individuals are independent of each other and may be independent of each other. are the same or different specific groups.
  • the description mode "...independently” can either mean that in different groups, the specific options expressed between the same symbols do not affect each other; it can also mean that in the same group, the same symbols are The specific options expressed between them do not affect each other.
  • the reagents and raw materials used in the present invention are all commercially available.
  • the carbonyl heterocyclic compounds provided by the present invention are compounds with a targeting lanthionine synthase C-like protein 2 pathway; the compounds can be used for the treatment of various pathologies, including infectious diseases , autoimmune diseases, diabetes, and chronic inflammatory diseases.
  • Figure 1 shows the binding curve of compound L7-LANCL2
  • Figure 2 shows the binding curve of compound L8-LANCL2
  • Figure 3 shows the binding curve of compound L12-LANCL2
  • Figure 4 shows the binding curve of compound L17-LANCL2
  • Figure 5 is the binding curve of compound L22-LANCL2
  • Figure 6 shows the binding curve of compound L28-LANCL2
  • Figure 7 is the binding curve of compound L29-LANCL2
  • Figure 8 is the binding curve of compound L30-LANCL2
  • Figure 9 is the binding curve of compound L32-LANCL2
  • Figure 10 is the binding curve of compound L37-LANCL2
  • Figure 11 is the binding curve of compound L44-LANCL2
  • Figure 12 is the binding curve of compound L56-LANCL2
  • Figure 13 is the weight change and DAI score of mice (compound L30, compound L56 and control group), wherein, A) body weight change data curve, B) DAI score data
  • Figure 14 is the change in the ratio of colon weight to length in mice (Compound L30, Compound L56 and control group), wherein, A) colon weight to length ratio, B) colon length, C) colon weight
  • Figure 15 shows intestinal morphology (compound L30, compound L56 and control group)
  • Figure 16 is the weight change and DAI score of mice (Compound L11, Compound L25, Compound L84, Compound L77, Compound L101, Compound L10, Compound L23 and control group), wherein, A) body weight change data curve, B) DAI score data
  • FIG 17 shows the scores of diarrhea and blood in the stool in mice (Compound L11, Compound L25, Compound L84, Compound L77, Compound L101, Compound L10, Compound L23 and the control group), wherein, A) changes in diarrhea in mice, B) changes in blood in stool
  • Figure 18 shows the changes in the ratio of colon weight to length in mice (Compound L11, Compound L25, Compound L10 and the control group), wherein A) colon length, B) colon weight, and C) colon weight and length ratio
  • Figure 19 shows intestinal morphology (compound L11, compound L10 and control group)
  • 6-(1H-benzimidazole-2-)pyridinecarboxylic acid (0.12g, 0.5mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride Salt (0.1 g, 0.52 mmol), 1-hydroxybenzotriazole (0.07 g, 0.52 mmol) and N,N-diisopropylethylamine (0.14 g, 1.13 mmol) in N,N-dimethyl
  • o-phenylenediamine 0.024 g, 0.228 mmol
  • 6-(1H-benzimidazole-2-)pyridinecarboxylic acid (1 g, 4.2 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.96g, 5mmol), 1-hydroxybenzotriazole (0.66g, 5mmol) and N,N-diisopropylethylamine (1.19g, 9.2mmol) were dissolved in N,N-dimethylformamide 20mL 3,9-diazaspiro[5.5]undecane-3-carboxylate tert-butyl ester (0.92 g, 4.6 mmol) was added to the mixture after stirring for 0.5 h, and the mixture was stirred for 0.5 h and returned to room temperature for overnight reaction.
  • tert-butyl 9-(6-(1H-benzo[d]imidazol-2-yl)pyridinyl)-3,9-diazaspiro[5.5]undecan-3-carboxylate (1.3 g, 3 mmol) was dissolved in 20 mL of dichloromethane, a saturated hydrochloric acid solution of 1,4-dioxane (2 mL, 8 mmol) was added, and the mixture was stirred for 0.5 hours and then returned to room temperature to react overnight. The reaction solution was concentrated under reduced pressure, and the obtained solid was directly used in the next reaction. Yield >90%.
  • 6-(1H-benzimidazole-2-)pyridinecarboxylic acid (1 g, 4.2 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.96g, 5mmol), 1-hydroxybenzotriazole (0.66g, 5mmol) and N,N-diisopropylethylamine (1.19g, 9.2mmol) were dissolved in N,N-dimethylformamide 20mL
  • tert-butylhexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (0.92 g, 4.6 mmol) was added, stirring was continued for 0.5 h, and the reaction was returned to room temperature overnight.
  • 6-(1H-benzimidazole-2-)pyridinecarboxylic acid (1 g, 4.2 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.96g, 5mmol), 1-hydroxybenzotriazole (0.66g, 5mmol) and N,N-diisopropylethylamine (1.19g, 9.2mmol) were dissolved in N,N-dimethylformamide 20mL
  • tert-butyl (3-azabicyclo[3.1.0]hex-6yl)carbamate (0.92 g, 4.6 mmol) was added, and the mixture was stirred for 0.5 h and returned to room temperature for overnight reaction.
  • 2-Morpholinylpyrimidine-4-carboxylic acid 100 mg, 0.48 mmol (a compound of formula 3) was suspended in 2 ml of N,N-dimethylformamide, and 1-(3-dimethylamino was added propyl)-3-ethylcarbodiimide hydrochloride (137 mg, 0.72 mmol), 1-hydroxybenzotriazole (97 mg, 0.72) and N,N-diisopropylethylamine (185 mg, 1.4340 mmol). After the reaction solution was stirred for 20 minutes, o-phenylenediamine (25.8 mg, 0.24 mmol) was added, and the reaction solution was stirred at 15° C. for 16 h.
  • 2-Morpholinylpyrimidine-4-carboxylic acid 100 mg, 0.48 mmol (a compound of formula 3) was suspended in 2 ml of N,N-dimethylformamide, and 1-(3-dimethylamino was added propyl)-3-ethylcarbodiimide hydrochloride (137 mg, 0.72 mmol), 1-hydroxybenzotriazole (97 mg, 0.72) and N,N-diisopropylethylamine (185 mg, 1.4340 mmol).
  • 6-(1H-benzimidazole-2-)pyridinecarboxylic acid (1 g, 4.2 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.96g, 5mmol), 1-hydroxybenzotriazole (0.66g, 5mmol) and N,N-diisopropylethylamine (1.19g, 9.2mmol) were dissolved in N,N-dimethylformamide 20mL
  • tert-butyl piperidin-4-ylcarbamate (0.92 g, 4.6 mmol) was added, and stirring was continued for 0.5 h, then returned to room temperature and reacted overnight.
  • tert-butyl(1-(6-(1H-benzo[d]imidazol-2-yl)pyridinyl)piperidin-4-yl)carbamate (1.3 g, 3 mmol) was dissolved in In 20 mL of dichloromethane, a saturated hydrochloric acid solution of 1,4-dioxane (2 mL, 8 mmol) was added, and the mixture was stirred for 0.5 hours, and then returned to room temperature to react overnight. The reaction solution was concentrated under reduced pressure, and the obtained solid was directly used in the next reaction. Yield >90%.
  • 2-(2-Pyridylamino)pyrimidine-4-carboxylic acid 40 mg, 0.18 mmol was dissolved in 2 ml of N,N-dimethylformamide and 1-(3-dimethylaminopropyl)-3 was added - Ethylcarbodiimide hydrochloride (145 mg, 0.28 mmol) and N,N-diisopropylethylamine (72 mg, 0.56 mmol).
  • tert-butyl (1-(3-(imidazo[1,2-a]pyridin-2-yl)benzoyl)piperidin-4-yl)carbamate (1.3 g, 3 mmol) was dissolved in In 20 mL of dichloromethane, a saturated hydrochloric acid solution of 1,4-dioxane (2 mL, 8 mmol) was added, and the mixture was stirred for 0.5 hours and then returned to room temperature to react overnight. The reaction solution was concentrated under reduced pressure, and the obtained solid was directly used in the next reaction. Yield >90%.
  • LC-MS m/z: (M+H)+ 321.
  • 2-(anilino)pyrimidine-4-carboxylic acid (0.060 g, 0.27 mmol), benzotriazol-1-yl-oxytripyrrolidinophosphorus hexafluorophosphate (0.14 g, 0.27 mmol) ) and N,N-diisopropylethylamine (0.12g, 1.0mmol) were dissolved in N,N-dimethylformamide 6mL, stirred for 0.5h and then added (4-aminopiperidin-1-yl)( 3-(imidazo[1,2-a]pyridin-2-yl)phenyl)methanone (0.089 g, 0.27 mmol) was stirred for 0.5 hours and then returned to room temperature to react overnight.
  • 2-(anilino)pyrimidine-4-carboxylic acid (0.060 g, 0.27 mmol), benzotriazol-1-yl-oxytripyrrolidinophosphorus hexafluorophosphate (0.14 g, 0.27 mmol) ) and N,N-diisopropylethylamine (0.12g, 1.0mmol) were dissolved in N,N-dimethylformamide 6mL, stirred for 0.5h and then added (hexahydropyrrole[3,4-c]pyrrole -2(1H)-yl)(3-(imidazo[1,2-a]pyridin-2-yl)phenyl)methanone (0.092 g, 0.27 mmol), continued to stir for 0.5 hours and then returned to room temperature to react overnight .
  • Methyl 6-bromopyridine-2-carboxylate (2g, 9.26mmol) was dissolved in 50ml of dioxane, aniline (826mg, 9.26mmol), tris(dibenzylideneacetone)dipalladium (424mg, 0.46mmol) were added ), 4,5-bisdiphenylphosphine-9,9-dimethylxanthene (536mg, 0.92mmol) and cesium carbonate (7.54g, 23.1mmol), the reaction solution was stirred at 95°C under nitrogen protection for 15 hours . The reaction solution was cooled to room temperature, filtered and concentrated to obtain a yellow solid.
  • the solid was dissolved in 15 ml of tetrahydrofuran, 10 ml of methanol and 15 ml of water, sodium hydroxide (1.2 g, 29 mmol) was added, and the reaction solution was stirred at 20° C. for 15 hours.
  • the reaction solution was extracted three times with ethyl acetate (20ml*3).
  • LC-MS: m/z: (M+H)+ 215.0.
  • 6-Acetylaminopicolinic acid was purchased from Bide Pharmaceuticals
  • 2-(anilino)pyridine-4-carboxylic acid (0.060 g, 0.27 mmol), benzotriazol-1-yl-oxytripyrrolidinophosphorus hexafluorophosphate (0.14 g, 0.27 mmol) ) and N,N-diisopropylethylamine (0.12g, 1.0mmol) were dissolved in N,N-dimethylformamide 6mL, stirred for 0.5h and then added (hexahydropyrrole[3,4-c]pyrrole -2(1H)-yl)(3-(imidazo[1,2-a]pyridin-2-yl)phenyl)methanone (0.092 g, 0.27 mmol), continued to stir for 0.5 hours and then returned to room temperature to react overnight .
  • Methyl 6-bromopyridine-2-carboxylate (2g, 9.26mmol) was dissolved in 50ml of dioxane, 2-aminopyridine (871mg, 9.26mmol), tris(dibenzylideneacetone)dipalladium (424mg) were added , 0.46mmol), 4,5-bisdiphenylphosphine-9,9-dimethylxanthene (536mg, 0.92mmol) and cesium carbonate (7.54g, 23.1mmol), the reaction solution was at 95°C under nitrogen protection Stir for 15 hours. The reaction solution was cooled to room temperature, filtered and concentrated to obtain a yellow solid.
  • the solid was dissolved in 15 ml of tetrahydrofuran, 10 ml of methanol and 15 ml of water, sodium hydroxide (0.94 g, 24 mmol) was added, and the reaction solution was stirred at 20° C. for 15 hours. The reaction solution was extracted three times with ethyl acetate (20ml*3).
  • LC-MS: m/z: (M+H)+ 216.0.
  • 6-(1h-Benzo[d]imidazol-2-yl)picolinic acid 2 (15mg, 0.063mmol) was dissolved in N,N-dimethylformamide (5ml), 1H-benzotriazole- 1-yloxytripyrrolidinyl hexafluorophosphate (65 mg, 0.13 mmol) and N,N-diisopropylethylamine (0.02 ml) were stirred together at room temperature for 15 minutes.
  • BT-11 was prepared with reference to Example 2 in CN107108573A.
  • Methyl 3-(1,3-benzothiazol-2-yl)benzoate (54 mg, 0.2 mmol) was dissolved in MeOH (5 mL) and water (1 mL), LiOH (24 mg, 1.0 mmol) was added, and the reaction solution was Stir at 80°C for 1 h. The reaction was concentrated to dryness to give the crude product, which was used directly in the next reaction.
  • reaction solution was stirred at 15°C for 16h.
  • Hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate tert-butyl ester (100 mg, 0.47 mmol) (a compound of formula 2) and 6-(phenylamino)picolinic acid ( 101 mg, 0.47 mmol) (the compound shown in formula 1) was suspended in 3 ml of N,N-dimethylformamide, and N,N-diisopropylethylamine (122 mg, 0.94 mmol) and 1-propyl ethylamine were added. Phosphoric anhydride (449 mg, 0.71 mmol). The reaction solution was stirred at 30°C for 16h.
  • tert-Butylpiperidin-4-ylcarbamate (147 mg, 0.74 mmol) (compound of formula 2) and 6-(phenylamino)picolinic acid (150 mg, 0.70 mmol) (compound of formula 1) were combined
  • the compound shown was suspended in 3 ml of N,N-dimethylformamide, and N,N-diisopropylethylamine (181 mg, 1.4 mmol) and 1-propylphosphoric anhydride (668 mg, 1.05 mmol) were added.
  • the reaction solution was stirred at 30°C for 16h.

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Abstract

L'invention concerne un composé hétérocyclique carbonyle représenté par la formule II ou un sel pharmaceutiquement acceptable de ce dernier. Le composé hétérocyclique carbonyle peut être utilisé en tant que composé comportant une voie de protéine 2 de type lanthionine synthétase C ciblée ; et le composé peut être utilisé pour traiter de multiples états pathologiques, y compris une maladie infectieuse, une maladie auto-immune, le diabète et une maladie inflammatoire chronique.
PCT/CN2021/119427 2020-09-18 2021-09-18 Composé hétérocyclique carbonyle et son application WO2022057932A1 (fr)

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WO2021127472A1 (fr) * 2019-12-20 2021-06-24 Landos Biopharma, Inc. Ligands de la protéine 2 de type lanthionine c, cellules préparées avec ceux-ci, et thérapies les utilisant

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Publication number Priority date Publication date Assignee Title
JP2022525249A (ja) * 2019-12-20 2022-05-11 ランドス バイオファーマ インコーポレイテッド ランチオニンｃ様タンパク質２リガンド、それを用いて調製される細胞、およびそれを使用する療法
US11377437B2 (en) 2019-12-20 2022-07-05 Landos Biopharma, Inc. Lanthionine C-like protein 2 ligands, cells prepared therewith, and therapies using same
JP7430852B2 (ja) 2019-12-20 2024-02-14 エヌイミューン バイオファーマ インコーポレイテッド ランチオニンｃ様タンパク質２リガンド、それを用いて調製される細胞、およびそれを使用する療法

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