WO2022057928A1 - 一种羰基杂环类化合物及其应用 - Google Patents

一种羰基杂环类化合物及其应用 Download PDF

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WO2022057928A1
WO2022057928A1 PCT/CN2021/119377 CN2021119377W WO2022057928A1 WO 2022057928 A1 WO2022057928 A1 WO 2022057928A1 CN 2021119377 W CN2021119377 W CN 2021119377W WO 2022057928 A1 WO2022057928 A1 WO 2022057928A1
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membered
independently
heterocycloalkyl
aryl
group
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French (fr)
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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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Priority to EP21868750.7A priority Critical patent/EP4215526A1/en
Priority to US18/026,862 priority patent/US20240101552A1/en
Priority to JP2023517967A priority patent/JP2023542908A/ja
Publication of WO2022057928A1 publication Critical patent/WO2022057928A1/zh

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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 I 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;
  • Z 1 -L 1 - is (ie L 1 is the connecting key) or (The q-terminal indicates that it is connected to a carbonyl group);
  • the carbon atom with "*" means that when it is a chiral carbon atom, it is in S configuration, R configuration or a mixture thereof;
  • Ring Q 1 It is a 6-10-membered cyclic heterocycloalkyl, a 6-12-membered spirocyclic heterocycloalkyl or a 6-10-membered bridged heterocycloalkyl; in Q 1 , it contains 1 to 3 N atoms;
  • M is 6-10-membered heterocyclic aryl, 6-10-membered heterocyclic aryl substituted by R 4 , 5-10-membered heterocyclic alkenyl, oxo substituted 5-10-membered heterocyclic Alkenyl or 5-10-membered cycloalkyl substituted by R 5 ; heteroatoms in the 6-10-membered heterocyclic aryl group, 6-10-membered cyclic aryl substituted by R 4
  • G is S or O
  • A', A 1a , A 1b and A 1c are independently NO 2 , -OR 8 , C 6-14 aryl or H;
  • Y 3 , Y 3a , Y 3b , Y 4 , Y 4a , Y 4b , Y 5 , Y 5a , Y 5b and Y 5c are independently CH or N;
  • R 6 is halogen
  • R 7 is H or C 1-6 alkyl
  • R 8 is C 6-14 aryl
  • R 3 is C 1-6 alkyl or halogen
  • R 4 is C 1-6 alkyl
  • R 5 is a C 6-14 aryl group or a C 6-14 aryl group substituted by halogen.
  • 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, For example phenyl.
  • the 6-10-membered cyclic heterocycloalkyl is a 6-8-membered cyclic heterocyclic ring Alkyl, containing 1 or 2 N atoms (for example, the N atom attached to the carbonyl group and the ring atoms other than Z 1 are carbon), and may also be a 5-membered N-heterocycloalkyl and a heterocycle of a three-membered cycloalkyl group Alkyl or 5-membered N-heterocycloalkyl and 5-membered N-heterocycloalkyl, such as
  • Q 1 is a 6-12-membered spirocyclic heterocycloalkyl
  • the 6-12-membered spirocyclic heterocycloalkyl is a 7-11-membered spirocyclic heterocycle Alkyl, containing 1 or 2 N atoms (e.g.
  • spiro[5,5]undecaheterocycloalkyl spiro[5,4]decacycloalkyl, spiro[4,4]nonanecycloalkane base or spiro[3,3]heptacycloalkyl
  • the outer ring atoms are all carbon), and it can also be azaspiro[5,5]undecacycloalkyl, azaspiro[5,4]decanecycloalkyl or azaspiro[4, 4] Nonheterocycloalkyl such as (also for example ), (also for example ), (The b terminal represents the connected).
  • the 6-10-membered bridged heterocycloalkyl is a 7-membered bridged heterocycloalkyl , containing 1 to 2 N atoms (for example, the N atom connected to the carbonyl group and the ring atoms other than Z 1 are carbon), for example,
  • Y 3 , Y 3a , Y 3b , Y 4 , Y 4a , Y 4b and Y 5b are independently CH or N.
  • the number of R 3 is 1, 2 or 3; for example, 1 or 2.
  • 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-butyl or tert-butyl, eg methyl.
  • the halogen is F, Cl, Br or I, eg, F or Cl.
  • the 6-10-membered heterocyclic aryl group is independently a 9- to 10-membered cyclic heterocyclic aryl, and the heteroatoms are N and/or S, and the number is 1 or 2 (for example, the 5-membered N heteroaryl acene Heterocyclic aryl, heterocyclic aryl of 6-membered N-heteroarylacyl, 5-membered N-heteroaryl and heterocyclic aryl of 6-membered N-heteroaryl), such as indolyl Quinolinyl isoindolyl or imidazopyridyl
  • R 4 when R 4 is a C 1-6 alkyl group, the C 1-6 alkyl group is methyl, ethyl, n-propyl, isopropyl, n-butyl , isobutyl, sec-butyl or tert-butyl, eg methyl.
  • M is a 6-10-membered heterocyclic aryl group substituted by R 4
  • the 6-10-membered heterocyclic aryl group substituted by R 4 is
  • M is a 5-10-membered heterocyclenyl group or an oxo-substituted 5-10-membered heterocyclenyl group
  • the 5-10-membered heterocyclenyl group is 6-membered heterocycloalkenyl
  • the heteroatom is N, and the number is 2, for example
  • M is an oxo-substituted 5-10-membered heterocycloalkenyl
  • the oxo-substituted 5-10-membered heterocycloalkenyl is
  • M is a 4-10-membered cycloalkyl group substituted by R 5
  • the 4-10-membered cycloalkyl group is cyclopentyl, cyclohexyl or cycloheptyl, for example cyclohexyl.
  • R 5 is a C 6-14 aryl group or a C 6-14 aryl group substituted by halogen
  • the C 6-14 aryl group is independently phenyl, Naphthyl, anthracenyl or phenanthryl, eg phenyl.
  • halogen is F, Cl , Br or I, eg Cl.
  • R 5 is a halogen-substituted C 6-14 aryl group
  • the halogen-substituted C 6-14 aryl group is a chlorophenyl group, such as
  • M is a 4-10-membered cycloalkyl substituted by R 5
  • the 4-10-membered cycloalkyl substituted by R 5 is
  • R6 when R6 is halogen, said halogen is F, Cl , Br or I, eg F.
  • R 7 when R 7 is a C 1-6 alkyl group, the C 1-6 alkyl group is methyl, ethyl, n-propyl, isopropyl, n-butyl , isobutyl, sec-butyl or tert-butyl, eg methyl.
  • A', A 1a , A 1b and A 1c are independently C 6-14 aryl groups
  • the C 6-14 aryl groups are independently phenyl, naphthalene group, anthracenyl or phenanthrenyl, such as phenyl.
  • R 8 when R 8 is a C 6-14 aryl group, the C 6-14 aryl group is independently phenyl, naphthyl, anthracenyl or phenanthrenyl, such as phenyl .
  • A', A 1a , A 1b and A 1c are independently selected from the following structures:
  • one of R 1 and R 2 is H, and the other is a C 6-14 aryl group.
  • Y 2 is CH.
  • Q 1 is a 6-10 membered cyclic heterocycloalkyl or a 6-12 membered spirocyclic heterocycloalkyl.
  • Q 1 is a 6-10-membered cyclic heterocycloalkyl
  • Z 1 -L 1 - is
  • Q is
  • Q 1 is a 6-10-membered cyclic heterocycloalkyl
  • Z 1 -L 1 - is
  • Q is
  • Q 1 is a 6-12-membered spirocyclic heterocycloalkyl
  • Z 1 -L 1 - is
  • Q 1 is a 6-10-membered bridged heterocycloalkyl
  • Z 1 -L 1 - is
  • 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 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;
  • the carbon atom with "*" means that when it is a chiral carbon atom, it is in S configuration, R configuration or a mixture thereof;
  • Ring Q 1 is a 6-10-membered cyclic heterocycloalkyl, a 6-12-membered spirocyclic heterocycloalkyl or a 6-10-membered bridged heterocycloalkyl; Q 1 contains 1 to 3 N atom;
  • M is 6-10-membered heterocyclic aryl, 6-10-membered heterocyclic aryl substituted by R 4 , 5-10-membered heterocyclic alkenyl, oxo substituted 5-10-membered heterocyclic Alkenyl or 5-10-membered cycloalkyl substituted by R 5 ; heteroatoms in the 6-10-membered heterocyclic aryl group, 6-10-membered cyclic aryl substituted by R 4
  • the heteroatom in the heterocyclic aryl group, the heteroatom in the 5-10 membered heterocyclic alkenyl group and the heteroatom in the oxo-substituted 5-10 membered heterocyclic alkenyl group are independently N, S and O One or more of them, the number of which is independently 1, 2 or 3;
  • G is S and O
  • A', A 1a , A 1b and A 1c are independently NO 2 , -OR 8 , C 6-14 aryl or H;
  • Y 5 , Y 5a and Y 5c are independently CH or N;
  • R 6 is halogen
  • R 7 is C 1-6 alkyl
  • R 8 is C 6-14 aryl
  • R 3 is C 1-6 alkyl or halogen
  • R 4 is C 1-6 alkyl
  • R 5 is a C 6-14 aryl group or a C 6-14 aryl group substituted by halogen.
  • 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;
  • the carbon atom with "*" means that when it is a chiral carbon atom, it is in S configuration, R configuration or a mixture thereof;
  • Ring Q 1 It is a 6-10-membered cyclic heterocycloalkyl or a 6-12-membered spirocyclic heterocycloalkyl; in Q 1 , it contains 1 to 3 N atoms;
  • M is 6-10-membered heterocyclic aryl, 6-10-membered heterocyclic aryl substituted by R 4 , 5-10-membered heterocyclic alkenyl, oxo substituted 5-10-membered heterocyclic Alkenyl or 5-10 membered cycloalkyl substituted by R 5 ;
  • G is S and O
  • a 1a , A 1b and A 1c are independently -OR 8 , C 6-14 aryl or H;
  • Y 5 , Y 5a and Y 5b are independently CH or N;
  • R 6 is halogen
  • R 7 is C 1-6 alkyl
  • R 8 is C 6-14 aryl
  • R 3 is C 1-6 alkyl or halogen
  • R 4 is C 1-6 alkyl
  • R 5 is a C 6-14 aryl group or a C 6-14 aryl group substituted by halogen.
  • Y 2 is CH
  • Ring Q 1 is a 5-membered N-heterocycloalkyl and a heterocycloalkyl of three-membered cycloalkyl (for example e end with attached) or spiro[5,5]undecaheterocycloalkyl (e.g. );
  • M is Or a 6-10-membered heterocyclic aryl group
  • a ' and A 1b independently are NO 2 ,
  • A is or -NR 1 R 2 ;
  • R 1 and R 2 are independently H or C 6-14 aryl
  • Y 1 and Y 2 are independently CH or N;
  • Ring Q 1 is a 6-10-membered heterocyclic alkyl group; in Q 1 , it contains 1 or 2 N atoms;
  • M is 6-10-membered heterocyclic aryl, 6-10-membered heterocyclic aryl substituted by R 4 , 5-10-membered heterocyclic alkenyl, oxo substituted 5-10-membered heterocyclic Alkenyl or 4-10 membered cycloalkyl substituted by R ;
  • G is S
  • A' and A 1c are independently -OR 8 , C 6-14 aryl or H;
  • Y 5 , Y 5a and Y 5b are independently CH or N;
  • R 6 is halogen
  • R 7 is C 1-6 alkyl
  • R 8 is C 6-14 aryl
  • R 3 is C 1-6 alkyl or halogen
  • R 4 is C 1-6 alkyl
  • R 5 is a C 6-14 aryl group or a C 6-14 aryl group substituted by halogen.
  • A is or -NR 1 R 2 ;
  • R 1 and R 2 are independently H or C 6-14 aryl
  • Y 1 and Y 2 are independently CH or N;
  • Ring Q 1 is a 6-12-membered spirocyclic heterocycloalkyl; in Q 1 , it contains 2 N atoms;
  • M is 6-10-membered heterocyclic aryl, 6-10-membered heterocyclic aryl substituted by R 4 , 5-10-membered heterocyclic alkenyl, oxo substituted 5-10-membered heterocyclic Alkenyl or 4-10 membered cycloalkyl substituted by R ;
  • A', A 1a , A 1b and A 1c are independently NO 2 ,
  • Y 5 and Y 5b are independently CH or N.
  • the carbonyl heterocyclic compound shown in formula I is shown in formula I-1:
  • Y 1 and Y 2 are independently CH or N;
  • Z 1 -L 1 - is (ie L 1 is the connecting key) or (The q-terminal indicates that it is connected to a carbonyl group);
  • Ring Q 1 It is a 6-10-membered cyclic heterocycloalkyl, a 6-12-membered spirocyclic heterocycloalkyl or a 6-10-membered bridged heterocycloalkyl; in Q 1 , it contains 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.
  • the 6-10-membered cyclic heterocycloalkyl is a 6-8-membered cyclic heterocycloalkyl, containing 1 to 2 N Atoms (for example, the N atom attached to the carbonyl group and the ring atoms other than Z 1 are carbon); for example
  • the 6-12-membered spirocyclic heterocycloalkyl is a 9-11-membered spirocyclic heterocycloalkyl, containing 1 to 2 N Atoms (for example, the N atom attached to the carbonyl group and the ring atoms other than Z 1 are carbon); for example (also for example ), (also for example )or (The b-terminal indicates that it is attached to the left carbonyl group).
  • the 6-10-membered bridged heterocycloalkyl is a 7-membered bridged heterocycloalkyl, containing 1 to 2 N atoms ( For example, the N atom connected to the carbonyl group and the ring atoms other than Z 1 are carbon); for example,
  • A' is selected from the following structures:
  • A is the same as A';
  • A' is or NO 2 ; for example
  • Y 1 and Y 2 are independently CH or N; for example for
  • Q is Q 1 is 6-10-membered ring heterocycloalkyl, 6-12-membered spirocyclic heterocycloalkyl or 6-10-membered bridged ring heterocycloalkyl, Z 1 -L 1 - is Or, Q 1 is a 6-10-membered ring heterocycloalkyl, and Z 1 -L 1 - is
  • Y 3 and Y 4 are independently CH or N; for example for
  • A' is or NO 2 ;
  • Y 5 is CH or N.
  • Y 1 and Y 2 are independently CH or N;
  • Q is Q 1 is independently a 6-10-membered cyclic heterocycloalkyl or a 6-12-membered spirocyclic heterocycloalkyl; Z 1 -L 1 - is Or, Q 1 is a 6-10-membered ring heterocycloalkyl, and Z 1 -L 1 - is
  • Y 3 and Y 4 are independently CH or N;
  • A' is or NO 2 ;
  • Y 5 is CH or N.
  • Q is Q 1 is independently a 6- to 10-membered ring heterocycloalkyl; Z 1 -L 1 - is
  • A' is or NO 2 ;
  • Y 5 is CH or N.
  • Q is Q 1 is independently a 6-12-membered spirocyclic heterocycloalkyl; Z 1 -L 1 - is
  • A' is or NO 2 .
  • carbonyl heterocyclic compounds shown in formula I are selected from the group consisting of:
  • the carbonyl heterocyclic compounds represented by formula I or pharmaceutically acceptable salts thereof have 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 compounds represented by formula I or their pharmaceutically acceptable salts, if there are stereoisomers, 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 I or their pharmaceutically acceptable salts described in the present invention 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 raw materials or reagents for preparing the carbonyl heterocyclic compounds represented by formula I 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 I or a pharmaceutically acceptable salt thereof can also be prepared by the carbonyl heterocyclic compound represented by formula I 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 I 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 I unless otherwise specified.
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising the above-mentioned carbonyl heterocyclic compound represented by formula I or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers.
  • the amount of the carbonyl heterocyclic compound represented by formula I 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 a carbonyl heterocyclic compound represented by formula I, a pharmaceutically acceptable salt thereof or the above-mentioned pharmaceutical composition in the preparation of a lanthionine C-like protein 2 (LANCL2) agonist applications in .
  • 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 shown in formula I, its pharmaceutically acceptable salt or the above-mentioned pharmaceutical composition in the preparation of 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 shown in formula I or a pharmaceutically acceptable salt thereof in the preparation of a medicine; the medicine can be used for prevention and/or treatment of itself Drugs for immune, 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 dose of said carbonyl group of formula I
  • LANCL2 lanthionine C-like protein 2
  • Another aspect of the present invention relates to a method of treating, preventing and/or treating autoimmune, chronic inflammatory or infectious diseases, comprising administering to a patient a therapeutically effective dose of said carbonyl heterocycle of formula I compound, its pharmaceutically acceptable salt or the above-mentioned pharmaceutical composition.
  • Another aspect of the present invention relates to a medicament for lanthionine C-like protein 2 (LANCL2), which comprises the carbonyl heterocyclic compound represented by formula I, 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
  • 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 said carbonyl heterocyclic compound of formula I or a pharmaceutically acceptable salt thereof or a pharmaceutical composition as described above corresponding to this amount will depend 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 usually 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 performance testing of light-emitting devices.
  • the description mode "...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 positive improvement effect of the present invention is that: the carbonyl heterocyclic compounds provided by the present invention are compounds with targeting lanthionine synthase C-like protein 2 pathway; the compounds can be used to treat various conditions, 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-Pyridinylamino)pyrimidine-4-carboxylic acid (40mg, 0.18mmol) was dissolved in 2ml 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

提供了式(I)所示的羰基杂环类化合物或其药学上可接受的盐，其可作为具有靶向羊毛硫氨酸合成酶C样蛋白质2路径的化合物，用于治疗多种病状，包括传染性疾病、自身免疫性疾病、糖尿病以及慢性发炎性疾病。

Description

一种羰基杂环类化合物及其应用
本申请要求申请日为2020/9/18的中国专利申请2020109893021的优先权，申请日为2021/2/10的中国专利申请2021101847890的优先权。本申请引用上述中国专利申请的全文。
技术领域
本发明涉及一种羰基杂环类化合物及其应用。
背景技术
羊毛硫氨酸C样蛋白质2(LANCL2)(也称为“羊毛硫氨酸合成酶C样蛋白质2”或“羊毛硫氨酸合成酶组分C样蛋白质2”是所表达免疫细胞、胃肠道、神经元、睾丸和胰脏的信号传导路径蛋白质。使LANCL2路径活化增加胰岛素敏感性并且减少与各种自身免疫、发炎性和代谢病状相关联的炎症。小鼠中体内和体外测试的结果展示，与对照组相比，使用靶向此路径的化合物在葡萄糖耐量测试中降低葡萄糖水平2倍并且提供与处方
Figure PCTCN2021119377-appb-000001
(英格兰布伦特福德的葛兰素史克公司(GlaxoSmithKline plc，Brentford，England))，是有效治疗但具有显著副作用。靶向LANCL2路径还使肠道炎症减少90％，并且使病变数量相应减少4倍。所述路径的此测试和其它验证的结果已被多篇文章提及。
在自身免疫相关炎症的类别内，目前存在自身免疫性病症全球大流行，如发炎性肠病(IBD)、全身性狼疮、类风湿性关节炎、1型糖尿病、牛皮癣、多发性硬化症。还存在慢性代谢发炎性疾病大流行，包括代谢综合征、肥胖、前驱糖尿病、心血管疾病和2型糖尿病。目前的治疗是适度有效的，但昂贵并且具有严重副作用。对自身免疫性疾病最有效的治疗(如抗TNF抗体)的投药途径是经由IV或皮下注射，因而要求访问诊所/手术和频繁监测。LANCL2的独特作用模式提供与抗TNF抗体同样有效但不具有副作用和高成本的口服投与的治疗剂。鉴于发炎性和自身免疫性疾病整体的流行性，LANCL2路径具有显著影响数百万患者的潜能。
脱落酸(“ABA”)是在原始筛选过程中发现的结合于LANCL2的一种天然化合物。
在合成有机化学领域中描述大量化合物。各种化合物由以下参考文献提供：Diana等人的W01997/036866、Sun等人的WO 2006/053109、Kim等人的WO 2006/080821、Nunes等人的WO 2007/019417、Singh等人的WO 2009/067600和WO 2009/067621、Adams等人的WO2008/079277、Urasoe等人的JP 2008/056615、Stoessel等人的WO 2011/066898、 Bassaganya-Riera等人的US 2013/0142825以及Bassaganya-Riera等人的美国专利7,741,367。国际专利申请WO2016064445公开了一种靶向羊毛硫氨酸合成酶C样蛋白质2路径的化合物，所述化合物可以用于治疗多种病状，包括传染性疾病、自身免疫性疾病、糖尿病以及慢性发炎性疾病。
已知描述于这些参考文献中的化合物中的一些使LANCL2路径活化，而另一些不使之活化。需要研发LANCL2路径的新颖配位体以允许治疗针对个别疾病进行特异性定制并潜在地使其功效达到最大。
发明内容
本发明所要解决的技术问题是为了克服现有技术中基于羊毛硫氨酸合成酶C样2的治疗剂缺乏的问题；而提供了一种羰基杂环类化合物及其应用。本发明提供的羰基杂环类化合物为具有靶向羊毛硫氨酸合成酶C样蛋白质2路径的化合物；所述化合物可结合于LANCL2蛋白质、并且在各种疾病病状中实现有益反应，其可以用于治疗多种病状，包括代谢和传染性疾病、自身免疫性疾病、糖尿病以及慢性发炎性疾病。
本发明是通过下述技术方案来解决上述技术问题的。
本发明提供了一种如式I所示的羰基杂环类化合物或其药学上可接受的盐；
Figure PCTCN2021119377-appb-000002
其中，A为
Figure PCTCN2021119377-appb-000003
或-NR 1R 2；
R 1和R 2独立地为H或C 6-18的芳基；
Y 1和Y 2独立地为CH或N；
Q为
Figure PCTCN2021119377-appb-000004
(包括
Figure PCTCN2021119377-appb-000005
)；
Z 1-L 1-为
Figure PCTCN2021119377-appb-000006
(即L 1为连接键)或
Figure PCTCN2021119377-appb-000007
(q端表示与羰基相连)；
带“*”碳原子表示当为手性碳原子时，为S构型、R构型或它们的混合物；
环Q 1
Figure PCTCN2021119377-appb-000008
为6-10元并环的杂环烷基、6-12元螺环的杂环烷基或6-10元桥环的杂环烷基；Q 1中，含有1到3个N原子；
M为
Figure PCTCN2021119377-appb-000009
Figure PCTCN2021119377-appb-000010
6-10元并环的杂环芳基、被R 4取代的6-10元并环的杂环芳基、5-10元的杂环烯基、被氧代的5-10元的杂环烯基或被R 5取代的5-10元的环烷基；所述的6-10元并环的杂环芳基中的杂原子、所述的被R 4取代的6-10元并环的杂环芳基中的杂原子、5-10元的杂环烯基中的杂原子和被氧代取代的5-10元的杂环烯基中的杂原子独立地为N、S和O中的一种或多种，个数独立地为1个、2个或3个；R 3为的个数为1个、2个或3个；(c端表示与所示C＝O连接)
G为S或O；
A’、A 1a、A 1b和A 1c独立地为
Figure PCTCN2021119377-appb-000011
NO 2、
Figure PCTCN2021119377-appb-000012
-OR 8、C 6-14的芳基或H；
Y 3、Y 3a、Y 3b、Y 4、Y 4a、Y 4b、Y 5、Y 5a、Y 5b和Y 5c独立地为CH或N；
R 6为卤素；
R 7为H或C 1-6的烷基；
R 8为C 6-14的芳基；
R 3为C 1-6的烷基或卤素；
R 4为C 1-6的烷基；
R 5为C 6-14的芳基或被卤素取代的C 6-14的芳基。
在本发明某些优选实施方案中，所述的如式I所示的羰基杂环类化合物、其药学上可接受的盐、其溶剂化物或其溶剂化物的盐中的某些基团如下定义(未提及的基团同本申请任一方案所述)，以下简称在在本发明某些优选实施方案中。
本发明某些优选实施方案中，
Figure PCTCN2021119377-appb-000013
为
Figure PCTCN2021119377-appb-000014
Figure PCTCN2021119377-appb-000015
例如
Figure PCTCN2021119377-appb-000016
又例如
Figure PCTCN2021119377-appb-000017
(a端表示与A连接的位置)。
本发明某些优选实施方案中，当R 1和R 2独立地为C 6-18的芳基时，所述的C 6-14的芳基为苯基、萘基、菲基或蒽基，例如苯基。
本发明某些优选实施方案中，当Q 1为6-10元并环的杂环烷基时，所述的6-10元并环的杂环烷基为6-8元并环的杂环烷基，含有1或2个N原子(例如与羰基连接的N原子和Z 1之外的环原子均为碳)，还可以为5元N杂环烷基并三元环烷基的杂环烷基或5元N杂环烷基并5元N杂环烷基的杂环烷基，例如
Figure PCTCN2021119377-appb-000018
Figure PCTCN2021119377-appb-000019
本发明某些优选实施方案中，当Q 1为6-12元螺环的杂环烷基时，所述的6-12元螺环的杂环烷基为7-11元螺环的杂环烷基，含有1或2个N原子(例如螺环[5,5]十一杂环烷基、螺环[5,4]癸杂环烷基、螺环[4,4]壬杂环烷基或螺环[3,3]庚杂环烷基)，还可为9-11元螺环的杂环烷基，含有1或2个N原子(例如与羰基连接的N原子及Z 1a之外的环原子均为碳)，还可以为氮杂螺环[5,5]十一杂环烷基、氮杂螺环[5,4]癸杂环烷基或氮杂螺环[4,4]壬杂环烷基，例如
Figure PCTCN2021119377-appb-000020
(又例如
Figure PCTCN2021119377-appb-000021
)、
Figure PCTCN2021119377-appb-000022
Figure PCTCN2021119377-appb-000023
(又例如
Figure PCTCN2021119377-appb-000024
)、
Figure PCTCN2021119377-appb-000025
(b端表示与
Figure PCTCN2021119377-appb-000026
相连)。
本发明某些优选实施方案中，当Q 1为6-10元桥环的杂环烷基时，所述的6-10元桥环的杂环烷基为7元桥环的杂环烷基，含有1到2个N原子(例如与羰基连接的N原子 及Z 1之外的环原子均为碳)，例如，
Figure PCTCN2021119377-appb-000027
本发明某些优选实施方案中，Y 3、Y 3a、Y 3b、Y 4、Y 4a、Y 4b和Y 5b独立地为CH或N。
本发明某些优选实施方案中，R 3为的个数为1个、2个或3个；例如1个或2个。
本发明某些优选实施方案中，当M为
Figure PCTCN2021119377-appb-000028
时，
Figure PCTCN2021119377-appb-000029
Figure PCTCN2021119377-appb-000030
为
Figure PCTCN2021119377-appb-000031
本发明某些优选实施方案中，当M为
Figure PCTCN2021119377-appb-000032
时，
Figure PCTCN2021119377-appb-000033
Figure PCTCN2021119377-appb-000034
为
Figure PCTCN2021119377-appb-000035
本发明某些优选实施方案中，当M为
Figure PCTCN2021119377-appb-000036
时，
Figure PCTCN2021119377-appb-000037
为
Figure PCTCN2021119377-appb-000038
本发明某些优选实施方案中，当R 3为C 1-6的烷基时，所述的C 1-6的烷基为甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基，例如甲基。
本发明某些优选实施方案中，当R 3为卤素时，所述的卤素为F、Cl、Br或I，例如F或Cl。
本发明某些优选实施方案中，当M为
Figure PCTCN2021119377-appb-000039
时，
Figure PCTCN2021119377-appb-000040
Figure PCTCN2021119377-appb-000041
为
Figure PCTCN2021119377-appb-000042
Figure PCTCN2021119377-appb-000043
本发明某些优选实施方案中，当M为
Figure PCTCN2021119377-appb-000044
时，
Figure PCTCN2021119377-appb-000045
Figure PCTCN2021119377-appb-000046
为
Figure PCTCN2021119377-appb-000047
本发明某些优选实施方案中，当M为
Figure PCTCN2021119377-appb-000048
时，
Figure PCTCN2021119377-appb-000049
Figure PCTCN2021119377-appb-000050
为
Figure PCTCN2021119377-appb-000051
本发明某些优选实施方案中，当M为6-10元并环的杂环芳基或被R 4取代的6-10元并环的杂环芳基时，所述的6-10元并环的杂环芳基独立地为9-10元并环的杂环芳基，杂原子为N和/或S，个数为1个或2个(例如5元N杂芳基并苯基的杂环芳基、6元N杂芳基并苯基的杂环芳基、5元N杂芳基并6元N杂芳基的杂环芳基)，例如吲哚基
Figure PCTCN2021119377-appb-000052
喹啉基
Figure PCTCN2021119377-appb-000053
异吲哚基
Figure PCTCN2021119377-appb-000054
或咪唑并吡啶基
Figure PCTCN2021119377-appb-000055
本发明某些优选实施方案中，当R 4为C 1-6的烷基时，所述的C 1-6的烷基为甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基，例如甲基。
本发明某些优选实施方案中，当M为被R 4取代的6-10元并环的杂环芳基时，所述的被R 4取代的6-10元并环的杂环芳基为
Figure PCTCN2021119377-appb-000056
本发明某些优选实施方案中，当M为5-10元的杂环烯基或被氧代的5-10元的杂环烯基时，所述的5-10元的杂环烯基为6元的杂环烯基，杂原子为N，个数为2个，例如
Figure PCTCN2021119377-appb-000057
本发明某些优选实施方案中，当M为被氧代的5-10元的杂环烯基时，所述的被氧代的5-10元的杂环烯基为
Figure PCTCN2021119377-appb-000058
本发明某些优选实施方案中，当M为R 5取代的4-10元的环烷基时，所述的4-10元的环烷基为环戊基、环己基或环庚基，例如环己基。
本发明某些优选实施方案中，当R 5为C 6-14的芳基或被卤素取代的C 6-14的芳基时，所述的C 6-14的芳基独立地为苯基、萘基、蒽基或菲基，例如苯基。
本发明某些优选实施方案中，当R 5为被卤素取代的C 6-14的芳基时，所述的卤素为F、Cl、Br或I，例如Cl。
本发明某些优选实施方案中，当R 5为被卤素取代的C 6-14的芳基时，所述的卤素取代的C 6-14的芳基为氯苯基，例如
Figure PCTCN2021119377-appb-000059
本发明某些优选实施方案中，当M为R 5取代的4-10元的环烷基时，所述的R 5取代的4-10元的环烷基为
Figure PCTCN2021119377-appb-000060
本发明某些优选实施方案中，当A’、A 1a、A 1b和A 1c独立地为
Figure PCTCN2021119377-appb-000061
时，
Figure PCTCN2021119377-appb-000062
为
Figure PCTCN2021119377-appb-000063
本发明某些优选实施方案中，当A’、A 1a、A 1b和A 1c独立地为
Figure PCTCN2021119377-appb-000064
时，
Figure PCTCN2021119377-appb-000065
为
Figure PCTCN2021119377-appb-000066
本发明某些优选实施方案中，当R 6为卤素时，所述的卤素为F、Cl、Br或I，例如F。
本发明某些优选实施方案中，当A’、A 1a、A 1b和A 1c独立地为
Figure PCTCN2021119377-appb-000067
时，
Figure PCTCN2021119377-appb-000068
为
Figure PCTCN2021119377-appb-000069
本发明某些优选实施方案中，当A’、A 1a、A 1b和A 1c独立地为
Figure PCTCN2021119377-appb-000070
时，
Figure PCTCN2021119377-appb-000071
为
Figure PCTCN2021119377-appb-000072
本发明某些优选实施方案中，当R 7为C 1-6的烷基时，所述的C 1-6的烷基为甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基，例如甲基。
本发明某些优选实施方案中，当A’、A 1a、A 1b和A 1c独立地为
Figure PCTCN2021119377-appb-000073
时，
Figure PCTCN2021119377-appb-000074
为
Figure PCTCN2021119377-appb-000075
本发明某些优选实施方案中，当A’、A 1a、A 1b和A 1c独立地为C 6-14的芳基时，所述的C 6-14的芳基独立地为苯基、萘基、蒽基或菲基，例如苯基。
本发明某些优选实施方案中，当R 8为C 6-14的芳基时，所述的C 6-14的芳基独立地为苯基、萘基、蒽基或菲基，例如苯基。
本发明某些优选实施方案中，A’、A 1a、A 1b和A 1c独立地选自如下结构：
NO 2、
Figure PCTCN2021119377-appb-000076
Figure PCTCN2021119377-appb-000077
本发明某些优选实施方案中，
Figure PCTCN2021119377-appb-000078
为
Figure PCTCN2021119377-appb-000079
Figure PCTCN2021119377-appb-000080
本发明某些优选实施方案中，R 1和R 2中一个H，另一个为C 6-14的芳基。
本发明某些优选实施方案中，Y 2为CH。
本发明某些优选实施方案中，Q 1为6-10元并环的杂环烷基或6-12元螺环的杂环烷基。
本发明某些优选实施方案中，Q 1为6-10元并环的杂环烷基，Z 1-L 1-为
Figure PCTCN2021119377-appb-000081
例如Q为
Figure PCTCN2021119377-appb-000082
Figure PCTCN2021119377-appb-000083
本发明某些优选实施方案中，Q 1为6-10元并环的杂环烷基，Z 1-L 1-为
Figure PCTCN2021119377-appb-000084
例如Q为
Figure PCTCN2021119377-appb-000085
本发明某些优选实施方案中，Q 1为6-12元螺环的杂环烷基，Z 1-L 1-为
Figure PCTCN2021119377-appb-000086
本发明某些优选实施方案中，Q 1为6-10元桥环的杂环烷基，Z 1-L 1-为
Figure PCTCN2021119377-appb-000087
本发明某些优选实施方案中，
Figure PCTCN2021119377-appb-000088
为
Figure PCTCN2021119377-appb-000089
Figure PCTCN2021119377-appb-000090
本发明某些优选实施方案中，Q为
Figure PCTCN2021119377-appb-000091
Figure PCTCN2021119377-appb-000092
本发明某些优选实施方案中，
Figure PCTCN2021119377-appb-000093
为
Figure PCTCN2021119377-appb-000094
Figure PCTCN2021119377-appb-000095
本发明某些优选实施方案中，
Figure PCTCN2021119377-appb-000096
为
Figure PCTCN2021119377-appb-000097
Figure PCTCN2021119377-appb-000098
本发明某些优选实施方案中，
Figure PCTCN2021119377-appb-000099
为
Figure PCTCN2021119377-appb-000100
本发明某些优选实施方案中，
Figure PCTCN2021119377-appb-000101
为
Figure PCTCN2021119377-appb-000102
在本发明某些优选实施方案中，A为
Figure PCTCN2021119377-appb-000103
在本发明某些优选实施方案中，A为
Figure PCTCN2021119377-appb-000104
本发明某些优选实施方案中，
其中，A为
Figure PCTCN2021119377-appb-000105
或-NR 1R 2；
R 1和R 2独立地为H或C 6-18的芳基；
Y 1和Y 2独立地为CH或N；
Q为
Figure PCTCN2021119377-appb-000106
Z 1-L 1-为
Figure PCTCN2021119377-appb-000107
带“*”碳原子表示当为手性碳原子时，为S构型、R构型或它们的混合物；
环Q 1为6-10元并环的杂环烷基、6-12元螺环的杂环烷基或6-10元桥环的杂环烷基； Q 1中，含有1到3个N原子；
M为
Figure PCTCN2021119377-appb-000108
Figure PCTCN2021119377-appb-000109
6-10元并环的杂环芳基、被R 4取代的6-10元并环的杂环芳基、5-10元的杂环烯基、被氧代的5-10元的杂环烯基或被R 5取代的5-10元的环烷基；所述的6-10元并环的杂环芳基中的杂原子、所述的被R 4取代的6-10元并环的杂环芳基中的杂原子、5-10元的杂环烯基中的杂原子和被氧代取代的5-10元的杂环烯基中的杂原子独立地为N、S和O中的一种或多种，个数独立地为1个、2个或3个；
G为S和O；
A’、A 1a、A 1b和A 1c独立地为
Figure PCTCN2021119377-appb-000110
NO 2、
Figure PCTCN2021119377-appb-000111
-OR 8、C 6-14的芳基或H；
Y 5、Y 5a和Y 5c独立地为CH或N；
R 6为卤素；
R 7为C 1-6的烷基；
R 8为C 6-14的芳基；
R 3为C 1-6的烷基或卤素；
R 4为C 1-6的烷基；
R 5为C 6-14的芳基或被卤素取代的C 6-14的芳基。
本发明某些优选实施方案中，A为
Figure PCTCN2021119377-appb-000112
或-NR 1R 2；
R 1和R 2独立地为H或C 6-18的芳基；
Y 1和Y 2独立地为CH或N；
Q为
Figure PCTCN2021119377-appb-000113
Z 1-L 1-为
Figure PCTCN2021119377-appb-000114
带“*”碳原子表示当为手性碳原子时，为S构型、R构型或它们的混合物；
环Q 1
Figure PCTCN2021119377-appb-000115
为6-10元并环的杂环烷基或6-12元螺环的杂环烷基；Q 1中，含有1到3个N原子；
M为
Figure PCTCN2021119377-appb-000116
Figure PCTCN2021119377-appb-000117
6-10元并环的杂环芳基、被R 4取代的6-10元并环的杂环芳基、5-10元的杂环烯基、被氧代的5-10元的杂环烯基或被R 5取代的5-10元的环烷基；
G为S和O；
A 1a、A 1b和A 1c独立地为
Figure PCTCN2021119377-appb-000118
Figure PCTCN2021119377-appb-000119
-OR 8、C 6-14的芳基或H；
Y 5、Y 5a和Y 5b独立地为CH或N；
R 6为卤素；
R 7为C 1-6的烷基；
R 8为C 6-14的芳基；
R 3为C 1-6的烷基或卤素；
R 4为C 1-6的烷基；
R 5为C 6-14的芳基或被卤素取代的C 6-14的芳基。
在本发明某些优选实施方案中，
其中，A为
Figure PCTCN2021119377-appb-000120
Y 2为CH；
Q为
Figure PCTCN2021119377-appb-000121
Z 1-L 1-为
Figure PCTCN2021119377-appb-000122
环Q 1为5元N杂环烷基并三元环烷基的杂环烷基(例如
Figure PCTCN2021119377-appb-000123
Figure PCTCN2021119377-appb-000124
e端与
Figure PCTCN2021119377-appb-000125
相连)或螺环[5,5]十一杂环烷基(例如
Figure PCTCN2021119377-appb-000126
)；
M为
Figure PCTCN2021119377-appb-000127
或6-10元并环的杂环芳基；
A ’和A 1b独立地为
Figure PCTCN2021119377-appb-000128
NO 2、
Figure PCTCN2021119377-appb-000129
本发明某些优选实施方案中，
A为
Figure PCTCN2021119377-appb-000130
或-NR 1R 2；
R 1和R 2独立地为H或C 6-14的芳基；
Y 1和Y 2独立地为CH或N；
Q为
Figure PCTCN2021119377-appb-000131
Z 1-L 1-为
Figure PCTCN2021119377-appb-000132
环Q 1为6-10元并环的杂环烷基；Q 1中，含有1或2个N原子；
M为
Figure PCTCN2021119377-appb-000133
6-10元并环的杂环芳基、被R 4取代的6-10元并环的杂环芳基、5-10元的杂环烯基、被氧代的5-10元的杂环烯基或被R 5取代的4-10元的环烷基；
G为S；
A’和A 1c独立地为
Figure PCTCN2021119377-appb-000134
Figure PCTCN2021119377-appb-000135
-OR 8、C 6-14的芳基或H；
Y 5、Y 5a和Y 5b独立地为CH或N；
R 6为卤素；
R 7为C 1-6的烷基；
R 8为C 6-14的芳基；
R 3为C 1-6的烷基或卤素；
R 4为C 1-6的烷基；
R 5为C 6-14的芳基或被卤素取代的C 6-14的芳基。
本发明某些优选实施方案中，
A为
Figure PCTCN2021119377-appb-000136
或-NR 1R 2；
R 1和R 2独立地为H或C 6-14的芳基；
Y 1和Y 2独立地为CH或N；
Q为
Figure PCTCN2021119377-appb-000137
Z 1-L 1-为
Figure PCTCN2021119377-appb-000138
环Q 1为6-12元螺环的杂环烷基；Q 1中，含有2个N原子；
M为
Figure PCTCN2021119377-appb-000139
Figure PCTCN2021119377-appb-000140
6-10元并环的杂环芳基、被R 4取代的6-10元并环的杂环芳基、5-10元的杂环烯基、被氧代的5-10元的杂环烯基或被R 5取代的4-10元的环烷基；
A’、A 1a、A 1b和A 1c独立地为
Figure PCTCN2021119377-appb-000141
NO 2、
Figure PCTCN2021119377-appb-000142
Y 5和Y 5b独立地为CH或N。
本发明某些优选实施方案中，所述的如式I所示的羰基杂环类化合物为式I-1所示：
Figure PCTCN2021119377-appb-000143
其中，A为
Figure PCTCN2021119377-appb-000144
Y 1和Y 2独立地为CH或N；
Q为
Figure PCTCN2021119377-appb-000145
(包括
Figure PCTCN2021119377-appb-000146
)；
Z 1-L 1-为
Figure PCTCN2021119377-appb-000147
(即L 1为连接键)或
Figure PCTCN2021119377-appb-000148
(q端表示与羰基相连)；
环Q 1
Figure PCTCN2021119377-appb-000149
为6-10元并环的杂环烷基、6-12元螺环的杂环烷基或6-10元桥环的杂环烷基；Q 1中，含有1到3个N原子；
Y 3和Y 4独立地为CH或N；
A’为
Figure PCTCN2021119377-appb-000150
或NO 2；
Y 5为CH或N；
带“*”碳原子表示当为手性碳原子时，为S构型、R构型或它们的混合物。
在本发明某些优选实施方案中，所述的如式I所示的羰基杂环类化合物或其药学上可接受的盐中的某些基团如下定义(未提及的基团同本申请任一方案所述)，
Figure PCTCN2021119377-appb-000151
为
Figure PCTCN2021119377-appb-000152
例如
Figure PCTCN2021119377-appb-000153
Figure PCTCN2021119377-appb-000154
又例如
Figure PCTCN2021119377-appb-000155
(a端表示与A连接的位置)
在本发明某些优选实施方案中，所述的如式I所示的羰基杂环类化合物或其药学上可接受的盐中的某些基团如下定义(未提及的基团同本申请任一方案所述)，
当Q 1为6-10元并环的杂环烷基时，所述的6-10元并环的杂环烷基为6-8元并环的杂环烷基，含有1到2个N原子(例如与羰基连接的N原子及Z 1之外的环原子均为碳)；例如
Figure PCTCN2021119377-appb-000156
在本发明某些优选实施方案中，所述的如式I所示的羰基杂环类化合物或其药学上可接受的盐中的某些基团如下定义(未提及的基团同本申请任一方案所述)，
当Q 1为6-12元螺环的杂环烷基时，所述的6-12元螺环的杂环烷基为9-11元螺环的杂环烷基，含有1到2个N原子(例如与羰基连接的N原子及Z 1之外的环原子均为碳)；例如
Figure PCTCN2021119377-appb-000157
(又例如
Figure PCTCN2021119377-appb-000158
)、
Figure PCTCN2021119377-appb-000159
(又例如
Figure PCTCN2021119377-appb-000160
)或
Figure PCTCN2021119377-appb-000161
(b端表示与左侧羰基相连)。
在本发明某些优选实施方案中，所述的如式I所示的羰基杂环类化合物或其药学上可接受的盐中的某些基团如下定义(未提及的基团同本申请任一方案所述)，
当Q 1为6-10元桥环的杂环烷基时，所述的6-10元桥环的杂环烷基为7元桥环的杂环烷基，含有1到2个N原子(例如与羰基连接的N原子及Z 1之外的环原子均为碳)； 例如，
Figure PCTCN2021119377-appb-000162
在本发明某些优选实施方案中，所述的如式I所示的羰基杂环类化合物或其药学上可接受的盐中的某些基团如下定义(未提及的基团同本申请任一方案所述)，
Figure PCTCN2021119377-appb-000163
为
Figure PCTCN2021119377-appb-000164
在本发明某些优选实施方案中，所述的如式I所示的羰基杂环类化合物或其药学上可接受的盐中的某些基团如下定义(未提及的基团同本申请任一方案所述)，
当A’为
Figure PCTCN2021119377-appb-000165
时，
Figure PCTCN2021119377-appb-000166
为
Figure PCTCN2021119377-appb-000167
在本发明某些优选实施方案中，所述的如式I所示的羰基杂环类化合物或其药学上可接受的盐中的某些基团如下定义(未提及的基团同本申请任一方案所述)，
A’选自如下结构：
NO 2、
Figure PCTCN2021119377-appb-000168
在本发明某些优选实施方案中，所述的如式I所示的羰基杂环类化合物或其药学上可接受的盐中的某些基团如下定义(未提及的基团同本申请任一方案所述)，
A与A’相同；
和/或，
Figure PCTCN2021119377-appb-000169
与
Figure PCTCN2021119377-appb-000170
相同(当M为
Figure PCTCN2021119377-appb-000171
时)。
在本发明某些优选实施方案中，所述的如式I所示的羰基杂环类化合物或其药学上可接受的盐中的某些基团如下定义(未提及的基团同本申请任一方案所述)，
Figure PCTCN2021119377-appb-000172
为
Figure PCTCN2021119377-appb-000173
在本发明某些优选实施方案中，所述的如式I所示的羰基杂环类化合物或其药学上可接受的盐中的某些基团如下定义(未提及的基团同本申请任一方案所述)，
Q选自如下结构：
Figure PCTCN2021119377-appb-000174
Figure PCTCN2021119377-appb-000175
(b端表示与B相连)。
在本发明某些优选实施方案中，所述的如式I所示的羰基杂环类化合物或其药学上可接受的盐中的某些基团如下定义(未提及的基团同本申请任一方案所述)，
Figure PCTCN2021119377-appb-000176
选自如下结构：
Figure PCTCN2021119377-appb-000177
在本发明某些优选实施方案中，所述的如式I所示的羰基杂环类化合物或其药学上可接受的盐中的某些基团如下定义(未提及的基团同本申请任一方案所述)，
A’为
Figure PCTCN2021119377-appb-000178
或NO 2；例如
Figure PCTCN2021119377-appb-000179
在本发明某些优选实施方案中，所述的如式I所示的羰基杂环类化合物或其药学上可接受的盐中的某些基团如下定义(未提及的基团同本申请任一方案所述)，
其中，A为
Figure PCTCN2021119377-appb-000180
Y 1和Y 2独立地为CH或N；例如
Figure PCTCN2021119377-appb-000181
为
Figure PCTCN2021119377-appb-000182
Q为
Figure PCTCN2021119377-appb-000183
Q 1为6-10元并环的杂环烷基、6-12元螺环的杂环烷基或6-10元桥环的杂环烷基，Z 1-L 1-为
Figure PCTCN2021119377-appb-000184
或者，Q 1为6-10元并环的杂环烷基，Z 1-L 1-为
Figure PCTCN2021119377-appb-000185
Y 3和Y 4独立地为CH或N；例如
Figure PCTCN2021119377-appb-000186
为
Figure PCTCN2021119377-appb-000187
Figure PCTCN2021119377-appb-000188
A’为
Figure PCTCN2021119377-appb-000189
或NO 2；
Y 5为CH或N。
在本发明某些优选实施方案中，所述的如式I所示的羰基杂环类化合物或其药学上可接受的盐中的某些基团如下定义(未提及的基团同本申请任一方案所述)，
其中，A为
Figure PCTCN2021119377-appb-000190
Y 1和Y 2独立地为CH或N；
Q为
Figure PCTCN2021119377-appb-000191
Q 1独立地为6-10元并环的杂环烷基或6-12元螺环的杂环烷基；Z 1-L 1-为
Figure PCTCN2021119377-appb-000192
或者，Q 1为6-10元并环的杂环烷基，Z 1-L 1-为
Figure PCTCN2021119377-appb-000193
Y 3和Y 4独立地为CH或N；
A’为
Figure PCTCN2021119377-appb-000194
或NO 2；
Y 5为CH或N。
在本发明某些优选实施方案中，所述的如式I所示的羰基杂环类化合物或其药学上可接受的盐中的某些基团如下定义(未提及的基团同本申请任一方案所述)，
其中，A为
Figure PCTCN2021119377-appb-000195
Figure PCTCN2021119377-appb-000196
为
Figure PCTCN2021119377-appb-000197
Q为
Figure PCTCN2021119377-appb-000198
Q 1独立地为6-10元并环的杂环烷基；Z 1-L 1-为
Figure PCTCN2021119377-appb-000199
Figure PCTCN2021119377-appb-000200
Figure PCTCN2021119377-appb-000201
为
Figure PCTCN2021119377-appb-000202
A’为
Figure PCTCN2021119377-appb-000203
或NO 2；
Y 5为CH或N。
在本发明某些优选实施方案中，所述的如式I所示的羰基杂环类化合物或其药学上可接受的盐中的某些基团如下定义(未提及的基团同本申请任一方案所述)，
其中，A为
Figure PCTCN2021119377-appb-000204
Figure PCTCN2021119377-appb-000205
为
Figure PCTCN2021119377-appb-000206
Q为
Figure PCTCN2021119377-appb-000207
Q 1独立地为6-12元螺环的杂环烷基；Z 1-L 1-为
Figure PCTCN2021119377-appb-000208
Figure PCTCN2021119377-appb-000209
为
Figure PCTCN2021119377-appb-000210
A’为
Figure PCTCN2021119377-appb-000211
或NO 2。
在本发明某些优选实施方案中，所述的如式I所示的羰基杂环类化合物选自下组：
Figure PCTCN2021119377-appb-000212
Figure PCTCN2021119377-appb-000213
Figure PCTCN2021119377-appb-000214
Figure PCTCN2021119377-appb-000215
本发明中，所述的如式I所示的羰基杂环类化合物或其药学上可接受的盐具有一个或多个手性碳原子，因此可以分离得到光学纯度异构体，例如纯的对映异构体，或者外消旋体，或者混合异构体。可以通过本领域的分离方法来获得纯的单一异构体，如手性结晶成盐，或者手性制备柱分离得到。
本发明中，所述的如式I所示的羰基杂环类化合物或其药学上可接受的盐如存在立体异构体，则可以以单一的立体异构体或它们的混合物(例如外消旋体)的形式存在。术语“立体异构体”是指顺反异构体或旋光异构体。这些立体异构体可以通过不对称合成方法或手性分离法(包括但不限于薄层色谱、旋转色谱、柱色谱、气相色谱、高压液相色谱等)分离、纯化及富集，还可以通过与其它手性化合物成键(化学结合等)或成盐(物理结合等)等方式进行手性拆分获得。术语“单一的立体异构体”是指本发明化合物的一种立体异构体相对于该化合物的所有立体异构体的质量含量不低于95％。
本发明所述的如式I所示的羰基杂环类化合物或其药学上可接受的盐可通过包括与化学领域公知方法相似的方法合成，其步骤和条件可参考本领域类似反应的步骤和条件，特别是根据本文说明进行合成。起始原料通常是来自商业来源，例如Aldrich或可使用本领域技术人员公知的方法(通过SciFinder、Reaxys联机数据库得到)容易地制备。
用于制备如式I所示的羰基杂环类化合物或其药学上可接受的盐的必要原料或试剂可以商购获得，或者通过本领域已知的合成方法制备。如下实验部分所描述的方法，可 以制备游离碱或者其加酸所成盐的本发明的化合物。术语药学上可接受的盐指的是本文所定义的药学上可接受的盐，并且具有母体化合物所有的作用。药学上可接受的盐可以通过在有机碱的合适的有机溶剂中加入相应的酸，根据常规方法处理来制备药学上可接受的盐。
成盐实例包括：对于碱加成盐，有可能通过在水性介质中使用碱金属或碱土金属氢氧化物或醇盐(例如乙醇盐或甲醇盐)或适当碱性有机胺(例如二乙醇胺、胆碱或葡甲胺)处理具有适当酸性质子的本发明化合物来制备碱金属(如钠、钾或锂)或碱土金属(如铝、镁、钙、锌或铋)的盐。
或者，对于酸加成盐，与无机酸成盐，如盐酸、氢溴酸、硫酸、硝酸、磷酸；和有机酸所形成的盐，如醋酸、苯磺酸、苯甲酸、樟脑磺酸、柠檬酸、乙磺酸、富马酸、葡庚糖酸、谷氨酸、乙醇酸、羟基萘甲酸、2-羟基乙磺酸、乳酸、马来酸、苹果酸、草酸、丙酮酸、丙二酸、扁桃酸、甲磺酸、2-萘磺酸、丙酸、水杨酸、琥铂酸、酒石酸、柠檬酸、肉桂酸、对甲苯磺酸或三甲基乙酸。
本发明中，所述的如式I所示的羰基杂环类化合物或其药学上可接受的盐，也可以通过已制备得到的所述的如式I所示的羰基杂环类化合物或其药学上可接受的盐，采用本领域常规方法，经外周修饰进而得到其他所述的如式I所示的羰基杂环类化合物或其药学上可接受的盐。
一般地，本发明的化合物可以通过本发明所描述的方法制备得到，除非有进一步的说明，其中取代基的定义如式I所示。
本发明还提供了一种药物组合物，其包括如上所述的如式I所示的羰基杂环类化合物或其药学上可接受的盐、和一种或多种药学上可接受的载体。在所述的药物组合物中，所述的如式I所示的羰基杂环类化合物或其药学上可接受的盐的用量可为治疗有效量。
所述的药学上可接受的载体(药用辅料)可为药物生产领域中广泛采用的那些辅料。辅料主要用于提供一个安全、稳定和功能性的药物组合物，还可以提供方法，使受试者接受给药后活性成分以所期望速率溶出，或促进受试者接受组合物给药后活性成分得到有效吸收。所述的药用辅料可以是惰性填充剂，或者提供某种功能，例如稳定该组合物的整体pH值或防止组合物活性成分的降解。所述的药用辅料可以包括下列辅料中的一种或多种：粘合剂、助悬剂、乳化剂、稀释剂、填充剂、成粒剂、胶粘剂、崩解剂、润滑剂、抗粘着剂、助流剂、润湿剂、胶凝剂、吸收延迟剂、溶解抑制剂、增强剂、吸附剂、缓冲剂、螯合剂、防腐剂、着色剂、矫味剂和甜味剂。
本发明的药物组合物可根据公开的内容使用本领域技术人员已知的任何方法来制备。 例如，常规混合、溶解、造粒、乳化、磨细、包封、包埋或冻干工艺。
本发明所述的药物组合物可以任何形式给药，包括注射(静脉内)、粘膜、口服(固体和液体制剂)、吸入、眼部、直肠、局部或胃肠外(输注、注射、植入、皮下、静脉内、动脉内、肌内)给药。本发明的药物组合物还可以是控释或延迟释放剂型(例如脂质体或微球)。固体口服制剂的实例包括但不限于粉末、胶囊、囊片、软胶囊剂和片剂。口服或粘膜给药的液体制剂实例包括但不限于悬浮液、乳液、酏剂和溶液。局部用制剂的实例包括但不限于乳剂、凝胶剂、软膏剂、乳膏剂、贴剂、糊剂、泡沫剂、洗剂、滴剂或血清制剂。胃肠外给药的制剂实例包括但不限于注射用溶液、可以溶解或悬浮在药学上可接受载体中的干制剂、注射用悬浮液和注射用乳剂。所述的药物组合物的其它合适制剂的实例包括但不限于滴眼液和其他眼科制剂；气雾剂：如鼻腔喷雾剂或吸入剂；适于胃肠外给药的液体剂型；栓剂以及锭剂。
本发明还提供了一种所述的如式I所示的羰基杂环类化合物、其药学上可接受的盐或上述的药物组合物在制备羊毛硫氨酸C样蛋白质2(LANCL2)激动剂中的应用。在所述的应用中，所述的羊毛硫氨酸C样蛋白质2(LANCL2)激活剂可用于哺乳动物生物体内；也可用于生物体外，主要作为实验用途，例如：作为标准样或对照样提供比对，或按照本领域常规方法制成试剂盒，为羊毛硫氨酸C样蛋白质2(LANCL2)的激活效果提供快速检测。
本发明还提供了一种所述的如式I所示的羰基杂环类化合物、其药学上可接受的盐或上述的药物组合物在制备药物中的应用；所述的药物可为用于预防和/或治疗与羊毛硫氨酸C样蛋白质2(LANCL2)有关的疾病的药物。所述的与羊毛硫氨酸C样蛋白质2(LANCL2)有关的疾病可为自身免疫性、慢性发炎性、慢性代谢性和传染性疾病中的一种或多种。
本发明还提供了一种所述的如式I所示的羰基杂环类化合物或其药学上可接受的盐在制备药物中的应用；所述的药物可为用于预防和/或治疗自身免疫性、慢性发炎性、慢性代谢性或传染性疾病的药物。
本发明的另一方面涉及一种预防和/或治疗羊毛硫氨酸C样蛋白质2(LANCL2)有关的疾病的方法，其包括向患者施用治疗有效剂量的所述的如式I所示的羰基杂环类化合物或其药学上可接受的盐或如上所述的包含其的药物组合物。
本发明的另一方面涉及一种治疗预防和/或治疗自身免疫性、慢性发炎性或传染性疾病的方法，其包括向患者施用治疗有效剂量的所述的如式I所示的羰基杂环类化合物、其药学上可接受的盐或上述的药物组合物。
本发明的另一方面涉及一种用于羊毛硫氨酸C样蛋白质2(LANCL2)的药物，其包括所述的如式I所示的羰基杂环类化合物、其药学上可接受的盐或上述的药物组合物。
如上所述的自身免疫性病症可为发炎性肠病(IBD)(包括溃疡性结肠炎和/或克罗恩氏病(Crohn’s disease))、全身性狼疮、类风湿性关节炎、1型糖尿病、牛皮癣、多发性硬化症。
如上所述的慢性代谢性疾病可为代谢综合征、肥胖、前驱糖尿病、心血管疾病和2型糖尿病。
如上所述的传染性疾病可为病毒性疾病，如流感感染。
第二方面，本发明还提供了一种羰基杂环类化合物或其药学上可接受的盐，包含其的药物组合物，以及其应用。
具体地，本发明提供了一种羰基杂环类化合物或其药学上可接受的盐，所述的羰基杂环类化合物选自下组：
Figure PCTCN2021119377-appb-000216
Figure PCTCN2021119377-appb-000217
Figure PCTCN2021119377-appb-000218
本发明提供了一种药物组合物，其包括如上(第二方面)所述的羰基杂环类化合物或其药学上可接受的盐、和一种或多种药学上可接受的载体。在所述的药物组合物中，所述的羰基杂环类化合物或其药学上可接受的盐的用量可为治疗有效量。
本发明还提供了一种如上(第二方面)所述的羰基杂环类化合物、其药学上可接受的盐或上述的药物组合物在制备羊毛硫氨酸C样蛋白质2(LANCL2)激动剂中的应用。在所述的应用中，所述的羊毛硫氨酸C样蛋白质2(LANCL2)激活剂可用于哺乳动物生物体内；也可用于生物体外，主要作为实验用途，例如：作为标准样或对照样提供比对，或按照本领域常规方法制成试剂盒，为羊毛硫氨酸C样蛋白质2(LANCL2)的激活效果提供快 速检测。
本发明还提供了一种如上(第二方面)所述的羰基杂环类化合物、其药学上可接受的盐或上述的药物组合物在制备药物中的应用；所述的药物可为用于预防和/或治疗与羊毛硫氨酸C样蛋白质2(LANCL2)有关的疾病的药物。所述的与羊毛硫氨酸C样蛋白质2(LANCL2)有关的疾病可为自身免疫性、慢性发炎性、慢性代谢性和传染性疾病中的一种或多种。
本发明还提供了一种如上(第二方面)所述的羰基杂环类化合物或其药学上可接受的盐在制备药物中的应用；所述的药物可为用于预防和/或治疗自身免疫性、慢性发炎性、慢性代谢性或传染性疾病的药物。
本发明还提供了一种预防和/或治疗羊毛硫氨酸C样蛋白质2(LANCL2)有关的疾病的方法，其包括向患者施用治疗有效剂量的如上(第二方面)所述的羰基杂环类化合物或其药学上可接受的盐或如上所述的包含其的药物组合物。
本发明还提供了一种治疗预防和/或治疗自身免疫性、慢性发炎性或传染性疾病的方法，其包括向患者施用治疗有效剂量的如上(第二方面)所述的羰基杂环类化合物、其药学上可接受的盐或上述的药物组合物。
本发明还提供了一种用于羊毛硫氨酸C样蛋白质2(LANCL2)的药物，其包括如上(第二方面)所述的羰基杂环类化合物、其药学上可接受的盐或上述的药物组合物。
如上所述的自身免疫性病症可为发炎性肠病(IBD)(包括溃疡性结肠炎和/或克罗恩氏病(Crohn’s disease))、全身性狼疮、类风湿性关节炎、1型糖尿病、牛皮癣、多发性硬化症。如上所述的慢性代谢性疾病可为代谢综合征、肥胖、前驱糖尿病、心血管疾病和2型糖尿病。如上所述的传染性疾病可为病毒性疾病，如流感感染。
本发明还提供用本文所描述化合物中的任何一种或多种治疗动物中的病状的方法。所述方法包含向动物投与有效量的本文所描述化合物中的一种或多种。所述病状可以选自由以下组成的群组：传染性疾病、自身免疫性疾病、糖尿病以及慢性发炎性疾病。在一些方法中，传染性疾病包含病毒性疾病，如流感感染。在一些方法中，自身免疫性疾病包含自身免疫性发炎性疾病，如发炎性肠病，包括溃疡性结肠炎和/或克罗恩氏病(Crohn’s disease)。在一些方法中，糖尿病选自由1型糖尿病和2型糖尿病组成的群组。在一些方法中，慢性发炎性疾病包含代谢综合征。在一些方法中，所述方法包含投与一定量的有效增加LANCL2活性、减少炎症和/或增加抗炎作用的化合物。
本发明还提供用于用本文所描述化合物中的任何一种或多种治疗动物中的病状的化合物。用于此类用途的化合物包括本文所描述的任何化合物。使用可以包含向动物投与 有效量的本文所描述化合物中的一种或多种，其中病状选自由以下组成的群组：传染性疾病、自身免疫性疾病、糖尿病以及慢性发炎性疾病。在一些型式中，传染性疾病包含病毒性疾病，如流感感染。在一些型式中，自身免疫性疾病包含自身免疫性发炎性疾病，如发炎性肠病，包括溃疡性结肠炎和/或克罗恩氏病。在一些型式中，糖尿病选自由1型糖尿病和2型糖尿病组成的群组。在一些型式中，慢性发炎性疾病包含代谢综合征。在一些型式中，化合物有效增加LANCL2活性、减少炎症和/或增加抗炎作用。
术语“药学上可接受的”是指盐、溶剂、辅料等一般无毒、安全，并且适合于患者使用。所述的“患者”优选哺乳动物，更优选为人类。
术语“药学上可接受的盐”是指本发明化合物与相对无毒的、药学上可接受的酸制备得到的盐。
“治疗”意味着对哺乳动物体内疾病的任何治疗，包括：(1)防止疾病，即造成临床疾病的症状不发展；(2)抑制疾病，即阻止临床症状的发展；(3)减轻疾病，即造成临床症状的消退。
“有效量”是指当向需要治疗的患者给予化合物时，其量足以(i)治疗相关疾病，(ii)减弱、改善或消除特定疾病或病症的一种或多种症状，或(iii)延迟本文所述的特定疾病或病症的一种或多种症状的发作。对应于该量的所述的如式I所示的羰基杂环类化合物或其药学上可接受的盐或者如上所述的药物组合物的量将根据例如特定化合物、疾病状况及其严重性、需要治疗的患者的特征(例如体重)等因素而变化，但是尽管如此仍然可以由本领域技术人员常规地确定。
本发明所述的“预防”是指获得或发生疾病或障碍的风险降低。
本发明所述的“药物组合物”，指一种或多种本发明的化合物或其盐与在本领域中通常接受的用于将生物活性化合物输送至有机体(例如人)的载体的制剂。药物组合物的目的是有利于对有机体给药输送。
术语“药学上可接受的载体”，指与活性成份共同给药的、且有利于活性成份给药的物质，包括但不限于国家食品药品监督管理局许可的可接受的用于人或动物(例如家畜)的任何助流剂、增甜剂、稀释剂、防腐剂、染料/着色剂、矫味增强剂、表面活性剂、润湿剂、分散剂、崩解剂、助悬剂、稳定剂、等渗剂、溶剂或乳化剂。例如包括但不限于碳酸钙、磷酸钙、各种糖和各类淀粉、纤维素衍生物、明胶、植物油和聚乙二醇。
本发明所述的药物组合物，可配制成固态、半固态、液态或气态制剂，如片剂、丸剂、胶囊剂、粉剂、颗粒剂、膏剂、乳剂、悬浮剂、溶液剂、栓剂、注射剂、吸入剂、凝胶剂、微球及气溶胶等等。
本发明所述的药物组合物，可以采用本领域熟知的方法制造，如常规的混合法、溶解法、制粒法、制糖衣药丸法、磨细法、乳化法、冷冻干燥法等。
本发明所述的化合物或其药学上可接受的盐或其药物组合物的给药途径，包括但不限于口服、直肠、透黏膜、经肠给药，或者局部、经皮、吸入、肠胃外、舌下、阴道内、鼻内、眼内、腹膜内、肌内、皮下、静脉内给药。优选的给药途径是口服给药。
对于口服给药，可以通过将活性化合物与本领域熟知的药学上可接受的载体混合，来配制该药物组合物。这些载体能使本发明的化合物被配制成片剂、丸剂、锭剂、糖衣剂、胶囊剂、液体、凝胶剂、浆剂、悬浮剂等，以用于对患者的口服给药。例如，用于口服给药的药物组合物，可采用如下方式获得片剂：将活性成分与一种或多种固体载体合并，如果需要将所得混合物制粒，并且如果需要加入少量的赋形剂加工成混合物或颗粒，以形成片剂或片芯。片芯可与任选适合肠溶的包衣材料结合，加工成更有利于有机体(例如人)吸收的包衣制剂形式。
除非另外说明，应当应用本文所使用的下列定义。出于本发明的目的，化学元素与元素周期表CAS版，和《化学和物理手册》，第75版，1994一致。此外，有机化学一般原理可参考"Organic Chemistry",Thomas Sorrell,University Science Books,Sausalito:1999,和"March's Advanced Organic Chemistry”by Michael B.Smith and Jerry March,John Wiley&Sons,New York:2007中的描述，其全部内容通过引用并入本文。
在本说明书中，可由本领域技术人员选择基团及其取代基以提供稳定的结构部分和化合物。当通过从左向右书写的常规化学式描述取代基时，该取代基也同样包括从右向左书写结构式时所得到的在化学上等同的取代基。
在本文中定义的某些化学基团前面通过简化符号来表示该基团中存在的碳原子总数。例如，C 1-C 6烷基是指具有总共1、2、3、4、5或6个碳原子的如下文所定义的烷基。简化符号中的碳原子总数不包括可能存在于所述基团的取代基中的碳。
在本文中，取代基中定义的数值范围如0至4、1-4、1至3等表明该范围内的整数，如1-6为1、2、3、4、5、6。
除前述以外，当用于本申请的说明书及权利要求书中时，除非另外特别指明，否则以下术语具有如下所示的含义。
术语“包括”为开放式表达，即包括本发明所指明的内容，但并不排除其他方面的内容。
术语“被取代的”是指特定原子上的任意一个或多个氢原子被取代基取代，包括重氢和氢的变体，只要特定原子的价态是正常的并且取代后的化合物是稳定的。
一般而言，术语“取代的”表示所给结构中的一个或多个氢原子被具体取代基所取代。进一步地，当该基团被1个以上所述取代基取代时，所述取代基之间是相互独立，即，所述的1个以上的取代基可以是互不相同的，也可以是相同的。除非其他方面表明，一个取代基团可以在被取代基团的各个可取代的位置进行取代。当所给出的结构式中不只一个位置能被选自具体基团的一个或多个取代基所取代，那么取代基可以相同或不同地在各个位置取代。
术语“一种(个)或多种(个)”或“一种(个)或两种(个)以上”是指即1、2、3、4、5、6、7、8、9或更多；例如1、2、3、4或5。
在本申请中，作为基团或是其它基团的一部分，除非另有规定，术语“环烷基”意指仅由碳原子和氢原子组成的饱和的单环、多环或者桥接碳环取代基，且其可经由任何适宜的碳原子通过单键与分子的其余部分连接；当为多环时，可为并环连接或螺环连接(即，碳原子上的两个偕氢被亚烷基取代)的螺环体系或桥环体系。
在本申请中，作为基团或是其它基团的一部分，术语“杂环烷基”意指由2-11个碳原子以及1-5个选自氮、氧和硫的杂原子组成的稳定的3元至16元饱和环状基团。除非本说明书中另外特别指明，否则杂环烷基基团或者可以是单环的(“单环的杂环烷基”)，或者是双环、三环或更多环的环体系，其可包括融合的(并环)、桥联的(桥环)或螺的(螺环)环系统(例如二环系统(“二环的杂环烷基”)。杂环烷基二环的环系统可以在一个或两个环中包括一个或多个杂原子；并且是饱和的。
本文所用术语“部分”、“结构部分”、“化学部分”、“基团”、“化学基团”是指分子中的特定片段或官能团。化学部分通常被认为是嵌入或附加到分子上的化学实体。
当所列举的取代基中没有指明其通过哪一个原子连接到化学结构通式中包括但未具体提及的化合物时，这种取代基可以通过其任何原子相键合。取代基和/或其变体的组合只有在这样的组合会产生稳定的化合物的情况下才是被允许的。
当所列举的基团中没有明确指明其具有取代基时，这种基团仅指未被取代。例如当“C 1～C 4烷基”前没有“取代或未取代的”的限定时，仅指“C 1～C 4烷基”本身或“未取代的C 1～C 4烷基”。
在本发明的各部分，描述了连接取代基。当该结构清楚地需要连接基团时，针对该基团所列举的马库什变量应理解为连接基团。例如，如果该结构需要连接基团并且针对该变量的马库什基团定义列举了“烷基”或“芳基”，则应该理解，该“烷基”或“芳基”分别代表连接的亚烷基基团或亚芳基基团。
在一些具体的结构中，当烷基基团清楚地表示为连接基团时，则该烷基基团代表连 接的亚烷基基团，例如，基团“卤代-C 1-C 6烷基”中的C 1-C 6烷基应当理解为C 1-C 6亚烷基。
除非另有规定，本文使用的所有技术术语和科学术语具有要求保护主题所属领域的标准含义。倘若对于某术语存在多个定义，则以本文定义为准。
应该理解，在本发明中使用的单数形式，如“一种”，包括复数指代，除非另有规定。此外，术语“包括”是开放性限定并非封闭式，即包括本发明所指明的内容，但并不排除其他方面的内容。
除非另有说明，本发明采用质谱、元素分析的传统方法，各步骤和条件可参照本领域常规的操作步骤和条件。
除非另有指明，本发明采用分析化学、有机合成化学和光学的标准命名及标准实验室步骤和技术。在某些情况下，标准技术被用于化学合成、化学分析、发光器件性能检测。
另外，需要说明的是，除非以其他方式明确指出，在本发明中所采用的描述方式“…独立地为”应做广义理解，是指所描述的各个个体之间是相互独立的，可以独立地为相同或不同的具体基团。更详细地，描述方式“…独立地为”既可以是指在不同基团中，相同符号之间所表达的具体选项之间互相不影响；也可以表示在相同的基团中，相同符号之间所表达的具体选项之间互相不影响。
本领域技术人员可以理解，根据本领域中使用的惯例，本申请描述基团的结构式中所使用的
Figure PCTCN2021119377-appb-000219
是指，相应的基团通过该位点与化合物中的其它片段、基团进行连接。
在不违背本领域常识的基础上，上述各优选条件，可任意组合，即得本发明各较佳实例。
本发明所用试剂和原料均市售可得。
本发明的积极进步效果在于：本发明提供的羰基杂环类化合物为具有靶向羊毛硫氨酸合成酶C样蛋白质2路径的化合物；所述化合物可以用于治疗多种病状，包括传染性疾病、自身免疫性疾病、糖尿病以及慢性发炎性疾病。
附图说明
图1为化合物L7-LANCL2结合曲线
图2为化合物L8-LANCL2结合曲线
图3为化合物L12-LANCL2结合曲线
图4为化合物L17-LANCL2结合曲线
图5为化合物L22-LANCL2结合曲线
图6为化合物L28-LANCL2结合曲线
图7为化合物L29-LANCL2结合曲线
图8为化合物L30-LANCL2结合曲线
图9为化合物L32-LANCL2结合曲线
图10为化合物L37-LANCL2结合曲线
图11为化合物L44-LANCL2结合曲线
图12为化合物L56-LANCL2结合曲线
图13为小鼠体重变化及DAI评分(化合物L30、化合物L56及对照组)，其中，A)体重变化数据曲线，B)DAI评分数据
图14为小鼠结肠重量与长度比值变化(化合物L30、化合物L56及对照组)，其中，A)结肠重量与长度比值，B)结肠长度，C)结肠重量
图15为肠形态(化合物L30、化合物L56及对照组)
图16为小鼠体重变化及DAI评分(化合物L11、化合物L25、化合物L84、化合物L77、化合物L101、化合物L10、化合物L23及对照组)，其中，A)体重变化数据曲线，B)DAI评分数据
图17为小鼠拉稀与便血评分(化合物L11、化合物L25、化合物L84、化合物L77、化合物L101、化合物L10、化合物L23及对照组)，其中，A)小鼠的拉稀变化，B)便血情况变化
图18为小鼠结肠重量与长度比值变化(化合物L11、化合物L25、化合物L10及对照组)，其中，A)结肠长度，B)结肠重量，C)结肠重量与长度比值
图19为肠形态(化合物L11、化合物L10及对照组)
具体实施方式
下面通过实施例的方式进一步说明本发明，但并不因此将本发明限制在所述的实施例范围之中。下列实施例中未注明具体条件的实验方法，按照常规方法和条件，或按照商品说明书选择。
实施例1：6-(1H-苯并[d]咪唑-2-基)-N-(3-(3-(3-(咪唑偶氮[1,2-a]吡啶-2-基)苯甲酰基)-3-氮杂二环[3.1.0]己烷-6-基)吡啶酰胺(L-1)
Figure PCTCN2021119377-appb-000220
一、3-(咪唑并[1,2-a]吡啶-2-基)苯甲酸甲酯的合成
Figure PCTCN2021119377-appb-000221
室温下，将2-氨基吡啶(1.6g,17mmol)，3-乙酰基甲酸甲酯(2.3g,14mmol)和碘化亚铜(0.5g,2.8mmol)溶于1,4-二氧六环50mL中，反应液加热至回流反应过夜，LC-MS监测至反应结束。减压浓缩后加入水50mL，乙酸乙酯萃取(50mL x 3)，合并有机相，无水硫酸钠干燥，减压浓缩得到残余物，经柱层析(洗脱剂：石油醚/乙酸乙酯＝5/1)分离纯化，得到白色固体(1.8g,7.4mmol)，收率52％。LC-MS：[M+1] +:253.09
二、3-(咪唑并[1,2-a]吡啶-2-基)苯甲酸的合成
Figure PCTCN2021119377-appb-000222
室温下，将3-(咪唑并[1,2-a]吡啶-2-基)苯甲酸甲酯(1.8g，7.4mmol)和氢氧化锂(0.88g,37mmol)溶于乙醇和水(v/v＝10:1)20mL中，加热回流，LC-MS监测反应至结束。反应液减压浓缩，浓缩液硅胶柱层析得白色固体(1.6g,0.67mmol)，收率90％。LC-MS：238.07。
三、N，N’-(1,2-苯胺)双(3-(咪唑并[1,2-a]吡啶-2-基)苯甲酰胺的合成
Figure PCTCN2021119377-appb-000223
冰浴下，将3-(咪唑并[1,2-a]吡啶-2-基)苯甲酸(0.12g,0.5mmol)，1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(0.1g,0.52mmol)，1-羟基苯并三唑(0.07g,0.52mmol)和N，N-二 异丙基乙胺(0.14g,1.13mmol)溶于N,N-二甲基甲酰胺6mL中，搅拌0.5h后加入邻苯二胺(0.024g,0.228mmol),继续搅拌0.5小时后回复至室温反应过夜。反应液倒入20mL水中，并用乙酸乙酯(20mL x 3)萃取，饱和食盐水洗涤，合并有机相，无水硫酸钠干燥，减圧浓缩硅胶柱层析(DCM:MeOH＝20:1)得到类白色固体(15mg,2.7μmol)，收率5.4％。LC-MS:m/z:(M+H)+＝549。
1H NMR(400MHz,Chloroform-d)δ9.42(s,2H),8.54(t,J＝1.8Hz,2H),8.27(m,2H),8.04(m,4H),7.93–7.87(m,2H),7.66–7.56(m,6H),7.20–7.08(m,4H),6.73(m,2H).
实施例2 6-(1H-苯并[d]咪唑-2-基)-N-(3-(3-(3-(咪唑偶氮[1,2-a]吡啶-2-基)苯甲酰基)-3-氮杂二环[3.1.0]己烷-6-基)吡啶酰胺(L-2)
Figure PCTCN2021119377-appb-000224
冰浴下，将3-(咪唑并[1,2-a]吡啶-2-基)苯甲酸(0.12g,0.5mmol)，1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(0.1g,0.52mmol)，1-羟基苯并三唑(0.07g,0.52mmol)和N，N-二异丙基乙胺(0.14g,1.13mmol)溶于N,N-二甲基甲酰胺6mL中，搅拌0.5h后加入6-(1H-苯并[d]咪唑-2-基)-N-(3-氮杂双环[3.1.0]己烷-6-基)吡啶酰胺(0.16g,0.5mmol)，继续搅拌0.5小时后回复至室温反应过夜。反应液倒入20mL水中，并用乙酸乙酯(20mL x 3)萃取，饱和食盐水洗涤，合并有机相，无水硫酸钠干燥，减圧浓缩硅胶柱层析(DCM:MeOH＝20:1)得到类白色固体(20mg,37μmol)，收率7.4％。LC-MS m/z:(M+H)+＝540。
1H NMR(400MHz,Chloroform-d)δ14.50(s,1H),8.91(s,1H),8.60(dd,J＝7.9,1.1Hz,1H),8.25(d,J＝6.8Hz,1H),8.19(dd,J＝7.7,1.0Hz,1H),8.09–7.98(m,3H),7.91(q,J＝8.0Hz,2H),7.59(d,J＝9.1Hz,1H),7.50(t,J＝7.7Hz,1H),7.42–7.36(m,1H),7.26–7.12(m,4H),6.88(m,1H),3.98(d,J＝12.3Hz,1H),3.39(d,J＝11.6Hz,2H),3.19(d,J＝12.8Hz,1H),1.79(s,1H),1.33(s,1H),1.06(s,1H).
实施例3:(9-(3-(1h-苯并[d]咪唑-2-基)苯甲酰基)-3,9-二氮杂螺[5.5]十一烷-3-基)(3-(咪唑[1,2-a]吡啶-2-基)苯基)甲酮(L-3)
Figure PCTCN2021119377-appb-000225
冰浴下，将3-(咪唑并[1,2-a]吡啶-2-基)苯甲酸(0.12g,0.5mmol)，1-(3-二甲氨基丙基)- 3-乙基碳二亚胺盐酸盐(0.1g,0.52mmol)，1-羟基苯并三唑(0.07g,0.52mmol)和N，N-二异丙基乙胺(0.14g,1.13mmol)溶于N,N-二甲基甲酰胺6mL中，搅拌0.5h后加入6-(1H-苯并[d]咪唑-2-基)-N-(3-氮杂双环[3.1.0]己烷-6-基)吡啶酰胺(0.18g,0.5mmol)，继续搅拌0.5小时后回复至室温反应过夜。反应液倒入20mL水中，并用乙酸乙酯(20mL x 3)萃取，饱和食盐水洗涤，合并有机相，无水硫酸钠干燥，减圧浓缩硅胶柱层析(DCM:MeOH＝20:1)得到类白色固体(30mg,50μmol)，收率10％。LC-MS m/z:(M+H)+＝596。
1H NMR(400MHz,Chloroform-d)δ10.53(s,1H),8.49(dd,J＝7.9,1.1Hz,1H),8.15(m,1H),8.06–7.94(m,3H),7.89(d,J＝14.0Hz,2H),7.65(d,J＝9.1Hz,1H),7.60(m,1H),7.51(m,2H),7.35(m,3H),7.21(m,1H),6.82(m,1H),3.84(s,4H),3.52(s,4H),1.74(s,4H),1.58(s,4H).
实施例4(1S，4S)-5-(6-(1H-苯并[d]咪唑-2-基)吡啶基)-2,5-二氮杂双环[2.2.1]庚烷-2-基)(3-(咪唑偶氮[1,2-a]吡啶-2-基)苯基)甲酮(L-4)
Figure PCTCN2021119377-appb-000226
冰浴下，将3-(咪唑并[1,2-a]吡啶-2-基)苯甲酸(0.12g,0.5mmol)，1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(0.1g,0.52mmol)，1-羟基苯并三唑(0.07g,0.52mmol)和N，N-二异丙基乙胺(0.14g,1.13mmol)溶于N,N-二甲基甲酰胺6mL中，搅拌0.5h后加入(6-(1H-苯并[d]咪唑-2-基)吡啶-2-基)(1S，4S)-2,5-二氮杂双环[2.2.1]庚-2-基)甲酮(0.18g,0.5mmol)，继续搅拌0.5小时后回复至室温反应过夜。反应液倒入20mL水中，并用乙酸乙酯(20mL x 3)萃取，饱和食盐水洗涤，合并有机相，无水硫酸钠干燥，减圧浓缩硅胶柱层析(DCM:MeOH＝20:1)得到类白色固体(25mg,46μmol)，收率9％。LC-MS m/z:(M+H)+＝540。
1H NMR(400MHz,Chloroform-d)δ10.80(d,J＝23.5Hz,1H),8.57(d,J＝7.3Hz,1H),8.21–8.09(m,2H),8.02(m,3H),7.91(d,J＝10.4Hz,2H),7.73–7.62(m,2H),7.56(m,3H),7.37(s,1H),7.16(s,1H),6.85–6.75(m,1H),4.85–4.61(m,2H),4.08–3.74(m,4H),2.03(s,2H).
实施例5 N-(1-(6-(1H-苯并[d]咪唑-2-基)吡啶酰)哌啶-4-基)-3-(咪唑[1,2-a]吡啶-2-基)苯甲酰胺(L-5)
Figure PCTCN2021119377-appb-000227
一、叔丁基(1-(6-(1H-苯并[d]咪唑-2-基)吡啶啉基)哌啶-4-基)氨基甲酸酯的合成
Figure PCTCN2021119377-appb-000228
冰浴下，将6-(1H-苯并[d]咪唑-2-基)吡啶甲酸(1g,4.2mmol)，1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(0.96g,5mmol)，1-羟基苯并三唑(0.66g,5mmol)和N，N-二异丙基乙胺(1.19g,9.2mmol)溶于N,N-二甲基甲酰胺20mL中，搅拌0.5h后加入叔丁基哌啶-4-基氨基甲酸酯(0.92g,4.6mmol)，继续搅拌0.5小时后回复至室温反应过夜。反应液倒入80mL水中，并用乙酸乙酯(80mL x 3)萃取，饱和食盐水洗涤，合并有机相，无水硫酸钠干燥，减圧浓缩硅胶柱层析(PE:EA＝5:1)得到类白色固体(1.3g,3mmol)，收率73％。LC-MS m/z:(M+H)+＝421。
二、6-(1H-苯并[d]咪唑-2-基)吡啶-2-基)(4-氨基哌啶-1-基)甲酮的合成
Figure PCTCN2021119377-appb-000229
冰浴下，叔丁基(1-(6-(1H-苯并[d]咪唑-2-基)吡啶啉基)哌啶-4-基)氨基甲酸酯(1.3g,3mmol)溶于二氯甲烷20mL中，加入饱和1,4-二氧六环的盐酸溶液(2mL,8mmol)，继续搅拌0.5小时后回复至室温反应过夜。反应液减压浓缩，所得固体直接用于下步反应。收率>90％。LC-MS：321[M+1] +
N-(1-(6-(1H-苯并[d]咪唑-2-基)吡啶酰)哌啶-4-基)-3-(咪唑[1,2-a]吡啶-2-基)苯甲酰胺的合成
Figure PCTCN2021119377-appb-000230
三、冰浴下，将3-(咪唑并[1,2-a]吡啶-2-基)苯甲酸(0.12g,0.5mmol)，1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(0.1g,0.52mmol)，1-羟基苯并三唑(0.07g,0.52mmol)和N，N-二异丙基乙胺(0.14g,1.13mmol)溶于N,N-二甲基甲酰胺6mL中，搅拌0.5h后加入(6-(1H-苯并[d]咪唑-2-基)吡啶-2-基)(4-氨基哌啶-1-基)甲酮(0.18g,0.5mmol)，继续搅拌0.5小时后回复至室温反应过夜。反应液倒入20mL水中，并用乙酸乙酯(20mL x 3)萃取，饱和食盐水洗涤，合并有机相，无水硫酸钠干燥，减圧浓缩硅胶柱层析(DCM:MeOH＝20:1)得到类白色固体(15mg,27μmol)，收率5.5％。LC-MS m/z:(M+H)+＝542。
1H NMR(400MHz,Chloroform-d)δ11.87(s,1H),8.56(dd,J＝7.9,1.1Hz,1H),8.40(t,J＝1.7Hz,1H),8.21(m,1H),8.07–7.94(m,3H),7.90–7.80(m,2H),7.69(d,J＝9.1Hz,1H),7.61(dd,J＝7.7,1.1Hz,1H),7.48(m,2H),7.28–7.17(m,3H),6.87(m,1H),6.25(d,J＝7.9Hz,1H),4.68(d,J＝13.7Hz,1H),4.25(dd,J＝7.7,3.9Hz,1H),3.85(d,J＝13.9Hz,1H),3.19(t,J＝12.6Hz,1H),3.02–2.91(m,1H),2.12(s,1H),1.92(d,J＝12.8Hz,2H),1.61(m,1H).
实施例6 6-(1H-苯并[d]咪唑-2-基)-N-(1-(3-(咪唑[1,2-a]吡啶-2-基)苯甲酰基)吡咯烷-3-基)吡啶酰胺(L-6)
Figure PCTCN2021119377-appb-000231
冰浴下，将3-(咪唑并[1,2-a]吡啶-2-基)苯甲酸(0.12g,0.5mmol)，1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(0.1g,0.52mmol)，1-羟基苯并三唑(0.07g,0.52mmol)和N，N-二异丙基乙胺(0.14g,1.13mmol)溶于N,N-二甲基甲酰胺6mL中，搅拌0.5h后加入6-(1H-苯并[d]咪唑-2-基)-N-(吡咯烷-3-基)吡啶酰胺(0.14g,0.5mmol)，继续搅拌0.5小时后回复至室温反应过夜。反应液倒入20mL水中，并用乙酸乙酯(20mL x 3)萃取，饱和食盐水洗涤，合并有机相，无水硫酸钠干燥，减圧浓缩硅胶柱层析(DCM:MeOH＝20:1)得到类白色固体(18mg,34μmol)，收率5.5％。
LC-MS m/z:(M+H)+＝528， 1H NMR(400MHz,Chloroform-d)δ8.64–8.44(m,2H),8.08(d,J＝6.9Hz,1H),8.02–7.67(m,7H),7.62–7.44(m,3H),7.28–7.11(m,4H),6.83(t, J＝6.6Hz,1H),5.40–5.34(m,1H),4.92(d,J＝17.1Hz,1H),4.69–4.61(m,1H),4.09(m,1H),4.02–3.72(m,3H).
实施例7 N，N'-(1,2-亚苯基)双(6-(1H-苯并[d]咪唑-2-基)吡啶啉酰胺)(L-7)
Figure PCTCN2021119377-appb-000232
一、6-(1H-苯并[d]咪唑-2-基)吡啶甲酸的合成
Figure PCTCN2021119377-appb-000233
将吡啶2，6-二羧酸(5g，21.919mmol)加入到邻苯基二胺(3.5g，32mmol)的丙二醇(100mL)溶液中，所得混合物加热回流24h，然后冷却至室温。向反应液中加入冰水(50mL)，搅拌析出棕色固体，沉淀收集并溶于热甲醇中，用活性炭过滤溶液。所得滤液缓慢蒸发除去溶剂，得到6-(1H-苯并咪唑-2-)吡啶羧酸。收率52％。LC-MS：[M+1] +:240.1
二、N，N'-(1,2-亚苯基)双(6-(1H-苯并[d]咪唑-2-基)吡啶啉酰胺)的合成
Figure PCTCN2021119377-appb-000234
冰浴下，将6-(1H-苯并咪唑-2-)吡啶羧酸(0.12g,0.5mmol)，1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(0.1g,0.52mmol)，1-羟基苯并三唑(0.07g,0.52mmol)和N，N-二异丙基乙胺(0.14g,1.13mmol)溶于N,N-二甲基甲酰胺6mL中，搅拌0.5h后加入邻苯二胺(0.024g,0.228mmol),继续搅拌0.5小时后回复至室温反应过夜。反应液倒入20mL水中，并用乙酸乙酯(20mL x 3)萃取，饱和食盐水洗涤，合并有机相，无水硫酸钠干燥，减圧浓缩硅胶柱层析(DCM:MeOH＝20:1)得到类白色固体(30mg,5.4μmol)，收率11％。LC-MS:m/z:(M+H)+＝550.98, 1H NMR(400MHz,DMSO)δ12.58(s,2H),11.01(s,2H),8.20(d,J＝7.3Hz,2H),8.07–7.80(m,6H),7.67–7.53(m,2H),7.43(dd,J＝5.7,3.6Hz,2H), 7.25–7.09(m,4H),7.03(d,J＝5.5Hz,2H).
实施例8 N，N'-(环己烷-1,2-二基)双(6-(1H-苯并[d]咪唑-2-基)吡啶啉酰胺)(L-8)
Figure PCTCN2021119377-appb-000235
N，N'-(环己烷-1,2-二基)双(6-(1H-苯并[d]咪唑-2-基)吡啶啉酰胺)
操作同L-7，环己烷-1,2-二胺购于国药试剂
LC-MS:m/z:(M+H)+＝557.26, 1H NMR(400MHz,CDCl 3)δ8.83(s,2H),8.42(d,J＝7.8Hz,2H),8.03(d,J＝7.7Hz,2H),7.79(t,J＝7.8Hz,6H),7.32(dd,J＝5.8,3.1Hz,2H),4.13(d,J＝16.6Hz,2H),2.35(d,J＝11.4Hz,2H),1.94–1.37(m,6H).
实施例9(3,9-二氮杂螺[5.5]十一烷-3,9-二基)双((6-(1H-苯并[d]咪唑-2-基)吡啶-2-基)甲酮)(L-9)
Figure PCTCN2021119377-appb-000236
一、9-(6-(1H-苯并[d]咪唑-2-基)吡啶啉基)-3,9-二氮杂螺[5.5]十一烷-3-羧酸叔丁酯的合成
Figure PCTCN2021119377-appb-000237
冰浴下，将6-(1H-苯并咪唑-2-)吡啶羧酸(1g,4.2mmol)，1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(0.96g,5mmol)，1-羟基苯并三唑(0.66g,5mmol)和N，N-二异丙基乙胺(1.19g,9.2mmol)溶于N,N-二甲基甲酰胺20mL中，搅拌0.5h后加入3,9-二氮杂螺[5.5]十一烷-3-羧酸叔丁酯(0.92g,4.6mmol)，继续搅拌0.5小时后回复至室温反应过夜。反应液倒入80mL水中，并用乙酸乙酯(80mL x 3)萃取，饱和食盐水洗涤，合并有机相，无水 硫酸钠干燥，减圧浓缩硅胶柱层析(PE:EA＝5:1)得到类白色固体(1.3g,3mmol)，收率73％。LC-MS m/z:(M+H)+＝476。
二、(6-(1H-苯并[d]咪唑-2-基)吡啶-2-基)(3,9-二氮杂螺[5.5]十一烷-3-基)甲酮的合成
Figure PCTCN2021119377-appb-000238
冰浴下，9-(6-(1H-苯并[d]咪唑-2-基)吡啶啉基)-3,9-二氮杂螺[5.5]十一烷-3-羧酸叔丁酯(1.3g,3mmol)溶于二氯甲烷20mL中，加入饱和1,4-二氧六环的盐酸溶液(2mL,8mmol)，继续搅拌0.5小时后回复至室温反应过夜。反应液减压浓缩，所得固体直接用于下步反应。收率>90％。LC-MS：376[M+1] +。
三、(3,9-二氮杂螺[5.5]十一烷-3,9-二基)双((6-(1H-苯并[d]咪唑-2-基)吡啶-2-基)甲酮)的合成
Figure PCTCN2021119377-appb-000239
冰浴下，将6-(1H-苯并咪唑-2-)吡啶羧酸(0.14g,0.27mmol)和N，N-二异丙基乙胺(0.12g,1.0mmol)溶于N,N-二甲基甲酰胺6mL中，搅拌0.5h后加入(6-(1H-苯并[d]咪唑-2-基)吡啶-2-基)(3,9-二氮杂螺[5.5]十一烷-3-基)甲酮(0.089g,0.27mmol)，继续搅拌0.5小时后回复至室温反应过夜。反应液倒入20mL水中，并用乙酸乙酯(20mL x 3)萃取，饱和食盐水洗涤，合并有机相，无水硫酸钠干燥，减圧浓缩硅胶柱层析(DCM:MeOH＝20:1)得到类白色固体(20mg,38μmol)，收率14.3％。
LC-MS:m/z:(M+H)+＝598.1, 1H NMR(400MHz,CDCl 3)δ10.70(s,2H),8.49(d,J＝7.9Hz,2H),7.93(dd,J＝25.5,17.6Hz,4H),7.56(t,J＝8.1Hz,5H),7.38–7.30(m,5H),3.84(s,3H),3.51(s,5H),1.65(d,J＝67.9Hz,8H).
实施例10(四氢吡咯并[3,4-c]吡咯-2,5(1H，3H)-二基)双((6-(1H-苯并[d]咪唑-2-基]吡啶-2-基)甲酮)(L-10)
Figure PCTCN2021119377-appb-000240
一、5-(6-(1H-苯并[d]咪唑-2-基)吡啶啉基)叔氢吡咯并[3,4-c]吡咯-2(1H)-羧酸叔丁酯的合成
Figure PCTCN2021119377-appb-000241
冰浴下，将6-(1H-苯并咪唑-2-)吡啶羧酸(1g,4.2mmol)，1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(0.96g,5mmol)，1-羟基苯并三唑(0.66g,5mmol)和N，N-二异丙基乙胺(1.19g,9.2mmol)溶于N,N-二甲基甲酰胺20mL中，搅拌0.5h后加入叔丁基六氢吡咯并[3,4-c]吡咯-2(1H)-羧酸盐(0.92g,4.6mmol)，继续搅拌0.5小时后回复至室温反应过夜。反应液倒入80mL水中，并用乙酸乙酯(80mL x 3)萃取，饱和食盐水洗涤，合并有机相，无水硫酸钠干燥，减圧浓缩硅胶柱层析(PE:EA＝5:1)得到类白色固体(1.3g,3mmol)，收率73％。LC-MS m/z:(M+H)+＝434。
二、(6-(1H-苯并[d]咪唑-2-基)吡啶-2-基)(六氢吡咯并[3,4-c]吡咯-2(1H)-基)甲酮的合成
Figure PCTCN2021119377-appb-000242
冰浴下，5-(6-(1H-苯并[d]咪唑-2-基)吡啶啉基)叔氢吡咯并[3,4-c]吡咯-2(1H)-羧酸叔丁酯(1.3g,3mmol)溶于二氯甲烷20mL中，加入饱和1,4-二氧六环的盐酸溶液(2mL,8mmol)，继续搅拌0.5小时后回复至室温反应过夜。反应液减压浓缩，所得固体直接用于下步反应。收率>90％。LC-MS m/z:(M+H)+＝334。
三、(四氢吡咯并[3,4-c]吡咯-2,5(1H，3H)-二基)双((6-(1H-苯并[d]咪唑-2-基]吡啶-2-基)甲酮)的合成
Figure PCTCN2021119377-appb-000243
操作同L-9
(四氢吡咯并[3,4-c]吡咯-2,5(1H，3H)-二基)双((6-(1H-苯并[d]咪唑-2-基]吡啶-2-基)甲酮)
LC-MS:m/z:(M+H)+＝555.61, 1H NMR(400MHz,MeOD)δ8.49–8.29(m,3H),8.23–8.04(m,3H),8.03–7.93(m,1H),7.86(dd,J＝7.0,5.6Hz,1H),7.71(dd,J＝6.0,3.1Hz,1H),7.64–7.54(m,2H),7.50(dd,J＝8.1,5.7Hz,2H),7.41–7.28(m,2H),7.26–7.17(m,1H),7.01–6.87(m,1H),4.23–3.55(m,8H),3.27–3.04(m,2H).
实施例11 N-(3-(6-(1H-苯并[d]咪唑-2-基)吡啶啉基)-3-氮杂双环[3.1.0]己-6-基)-6-(1H-苯并[d]咪唑-2-基)吡啶甲酸酰胺(L-11)
Figure PCTCN2021119377-appb-000244
一、叔丁基(3-(6-(1H-苯并[d]咪唑-2-基)吡啶啉基)-3-氮杂双环[3.1.0]己基-6-基)氨基甲酸酯的合成
Figure PCTCN2021119377-appb-000245
冰浴下，将6-(1H-苯并咪唑-2-)吡啶羧酸(1g,4.2mmol)，1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(0.96g,5mmol)，1-羟基苯并三唑(0.66g,5mmol)和N，N-二异丙基乙胺(1.19g,9.2mmol)溶于N,N-二甲基甲酰胺20mL中，搅拌0.5h后加入(3-氮杂双环[3.1.0]己-6基)氨基甲酸叔丁酯(0.92g,4.6mmol)，继续搅拌0.5小时后回复至室温反应过夜。反应液倒入80mL水中，并用乙酸乙酯(80mL x 3)萃取，饱和食盐水洗涤，合并有机相，无水硫酸钠干燥，减圧浓缩硅胶柱层析(PE:EA＝5:1)得到类白色固体(1.3g,3mmol)，收 率73％。LC-MS m/z:(M+H)+＝421。
二、(6-(1H-苯并[d]咪唑-2-基)吡啶-2-基)(6-氨基-3-氮杂双环[3.1.0]己-3-基)甲酮的合成
Figure PCTCN2021119377-appb-000246
冰浴下，叔丁基(3-(6-(1H-苯并[d]咪唑-2-基)吡啶啉基)-3-氮杂双环[3.1.0]己基-6-基)氨基甲酸酯(1.3g,3mmol)溶于二氯甲烷20mL中，加入饱和1,4-二氧六环的盐酸溶液(2mL,8mmol)，继续搅拌0.5小时后回复至室温反应过夜。反应液减压浓缩，所得固体直接用于下步反应。收率>90％。LC-MS m/z:(M+H)+＝321。
三、N-(3-(6-(1H-苯并[d]咪唑-2-基)吡啶啉基)-3-氮杂双环[3.1.0]己-6-基)-6-(1H-苯并[d]咪唑-2-基)吡啶甲酸酰胺的合成
Figure PCTCN2021119377-appb-000247
操作同L-9
LC-MS:m/z:(M+H)+＝541.20, 1H NMR(400MHz,CDCl 3)δ13.25(s,1H),12.09(s,1H),8.68(s,1H),8.48(d,J＝7.6Hz,1H),8.26(d,J＝7.6Hz,1H),8.01(d,J＝7.5Hz,1H),7.81(t,J＝7.8Hz,4H),7.50(dt,J＝20.7,5.8Hz,3H),7.38–7.30(m,4H),4.58(d,J＝11.3Hz,1H),4.45–4.22(m,2H),3.64–3.43(m,3H),2.63(s,1H),2.00(s,9H),1.60(s,2H).
实施例12(2,5-二氮杂双环[2.2.1]庚烷-2,5-二基)双((6-(1H-苯并[d]咪唑-2-基)吡啶-2-基)甲酮)(L-12)
Figure PCTCN2021119377-appb-000248
(2,5-二氮杂双环[2.2.1]庚烷-2,5-二基)双((6-(1H-苯并[d]咪唑-2-基)吡啶-2-基)甲酮)
操作同L-7
LC-MS:m/z:(M+H)+＝541.59, 1H NMR(400MHz,CDCl 3)δ12.67(s,1H),8.13–7.82(m,4H),7.54–7.33(m,4H),7.26(d,J＝7.6Hz,2H),4.54(d,J＝11.9Hz,3H),4.04(t,J＝15.9Hz,3H),1.85(s,1H),1.77(s,1H).
实施例13 N，N'-(1,2-亚苯基)双(2-吗啉基嘧啶-4-羧酰胺)(L-13)
Figure PCTCN2021119377-appb-000249
一、2-吗啉嘧啶-4-羧酸的合成
将2-氯嘧啶-4-羧酸(500mg,3.15mmol)溶于15ml四氢呋喃和15ml二氧六环中,加入2ml吗啡啉，反应液在70℃搅拌18小时。反应液冷却至室温，过滤。将固体溶于20ml水中，用1N盐酸酸化至pH＝1，溶液用二氯甲烷/甲醇＝10:1(20mL*3)萃取。合并的有机相用无水硫酸钠干燥，过滤，浓缩得到白色固体580mg，收率为87.9％。LC-MS:m/z:(M+H) +＝210.0。
1H NMR(400MHz,CD3OD)δ8.57(d,J＝4.8Hz,1H),7.20(d,J＝4.8Hz,1H),3.93–3.83(m,4H),3.76(m,4H).
二、N，N'-(1,2-亚苯基)双(2-吗啉基嘧啶-4-羧酰胺)的合成
将2-吗啉基嘧啶-4-羧酸(100mg，0.48mmol)(如式3所示的化合物)悬浮于2ml N,N-二甲基甲酰胺中，加入1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(137mg，0.72mmol)，1-羟基苯并三氮唑(97mg，0.72)和N,N-二异丙基乙胺(185mg,1.4340mmol)。反应液搅拌20分钟后加入邻苯二胺(25.8mg，0.24mmol),反应液在15℃下搅拌16h。向反应液中加入10ml水，并用乙酸乙酯(10mL*2)萃取。合并的有机层经无水硫酸钠干燥，过滤并浓缩，得到粗产物。将所得粗产品通过薄层层析板纯化(二氯甲烷∶甲醇＝10∶1)，得到的产物用二甲亚砜(3mL)和甲醇(2mL)混合溶液打浆，过滤，固体用甲醇洗涤、干燥，得到所需产物23mg的白色固体，收率为9.81％。
LC-MS:m/z:(M+H)+＝491.0, 1H NMR(400MHz,DMSO-d6)δ10.46(s,2H),8.70(d,J＝4.8Hz,2H),7.78(dd,J＝6.0,3.6Hz,2H),7.36(dd,J＝6.0,3.6Hz,2H),7.26(d,J＝4.8Hz,2H),3.90–3.69(m,4H),3.60(d,J＝4.4Hz,4H).
实施例14 N-(3-(6-(1H-苯并[d]咪唑-2-基]吡啶啉基)-3-氮杂双环[3.1.0]己基-6-基)-2-吗啉基嘧啶-4-羧酰胺(L-14)
Figure PCTCN2021119377-appb-000250
N-(3-(6-(1H-苯并[d]咪唑-2-基]吡啶啉基)-3-氮杂双环[3.1.0]己基-6-基)-2-吗啉基嘧啶-4-羧酰胺
将2-吗啉基嘧啶-4-羧酸(100mg，0.48mmol)(如式3所示的化合物)悬浮于2ml N,N-二甲基甲酰胺中，加入1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(137mg，0.72mmol)，1-羟基苯并三氮唑(97mg，0.72)和N,N-二异丙基乙胺(185mg,1.4340mmol)。反应液搅拌20分钟后加入(6-氨基-3-氮杂双环[3.1.0]己-3-基)-[6-(1H-苯并咪唑-2-基)-2-吡啶基]甲酮(76mg，0.24mmol),反应液在15℃下搅拌16h。向反应液中加入10ml水，并用乙酸乙酯(10mL*2)萃取。合并的有机层经无水硫酸钠干燥，过滤并浓缩，得到粗产物。将所得粗产品通过薄层层析板纯化(二氯甲烷∶甲醇＝10∶1)，得到所需产物38mg的白色固体,收率为31.14％。
LC-MS:m/z:(M+H)+＝511.0, 1H NMR(400MHz,DMSO-d6)δ8.75(s,1H),8.61(d,J＝7.8Hz,1H),8.35(d,J＝4.8Hz,1H),8.22(t,J＝13.6Hz,1H),7.99(t,J＝7.8Hz,1H),7.63(s,2H),7.31(dd,J＝6.6,3.5Hz,1H),6.78(d,J＝4.8Hz,1H),4.33(d,J＝12.5Hz,1H),4.20–4.10(m,2H),3.98(dd,J＝11.8,4.4Hz,1H),3.72(dd,J＝12.9,4.8Hz,9H),2.56(d,J＝2.1Hz,1H),2.12(d,J＝2.5Hz,1H),2.04(d,J＝4.7Hz,1H).
实施例15 9-(6-(1-H-苯并[d]咪唑-2-基)吡啶啉基)-3,9-二氮杂螺[5.5]十一烷-3-基)(2-吗啉代嘧啶-4-基)甲酮(L-15)
Figure PCTCN2021119377-appb-000251
(9-(6-(1-H-苯并[d]咪唑-2-基)吡啶啉基)-3,9-二氮杂螺[5.5]十一烷-3-基)(2-吗啉代嘧啶-4-基)甲酮
操作同L-14
LC-MS:m/z:(M+H)+＝567.0, 1H NMR(400MHz,CD 3OD)δ8.53(d,J＝7.8Hz,1H),8.44(d,J＝4.8Hz,1H),7.97(t,J＝7.8Hz,1H),7.73(s,2H),7.59(dd,J＝7.7,0.9Hz,1H),7.39 –7.31(m,2H),6.70(d,J＝4.8Hz,1H),3.90-3.76(m,12H),3.51(d,J＝6.9Hz,4H),1.75-1.69(m,4H),1.59-1.57(m,4H).
实施例16(5-(6-(1-(1-H-苯并[d]咪唑-2-基]吡啶啉基)六氢吡咯并[3,4-c]吡咯-2(1H)-基)(2-吗啉代嘧啶丁-4-基)甲酮(L-16)
Figure PCTCN2021119377-appb-000252
(5-(6-(1-(1-H-苯并[d]咪唑-2-基]吡啶啉基)六氢吡咯并[3,4-c]吡咯-2(1H)-基)(2-吗啉代嘧啶丁-4-基)甲酮
操作同L-14
LC-MS:m/z:(M+H)+＝525.0, 1H NMR(400MHz,CDCl 3)δ8.60–8.37(m,2H),8.00(dd,J＝17.8,9.9Hz,1H),7.81(ddd,J＝14.2,8.7,2.6Hz,2H),7.65(d,J＝4.6Hz,1H),7.33(dd,J＝6.0,3.1Hz,2H),6.97(dd,J＝10.5,4.8Hz,1H),4.25–3.56(m,16H),3.21–2.81(m,2H).
实施例17 N，N'-(环己烷-1,2-二基)双(2-吗啉基嘧啶-4-羧酰胺)(L-17)
Figure PCTCN2021119377-appb-000253
N，N'-(环己烷-1,2-二基)双(2-吗啉基嘧啶-4-羧酰胺)
操作同L-7
LC-MS:m/z:(M+H)+＝497.0, 1H NMR(400MHz,CD 3OD)δ8.48(d,J＝4.8Hz,2H),8.14–7.99(m,2H),7.18(d,J＝4.8Hz,2H),3.96(s,2H),3.82–3.80(m,16H),2.24(d,J＝6.8Hz,2H),1.85(s,2H),1.45(d,J＝5.2Hz,4H).
实施例18(5-(6-(1H-苯并[d]咪唑-2-基)吡啶啉基)-2,5-二氮杂双环[2.2.1]庚-2-基)(2-吗啉代嘧啶-4-基)甲酮(L-18)
Figure PCTCN2021119377-appb-000254
(5-(6-(1H-苯并[d]咪唑-2-基)吡啶啉基)-2,5-二氮杂双环[2.2.1]庚-2-基)(2-吗啉代嘧啶-4-基)甲酮
操作同L-14
LC-MS:m/z:(M+H)+＝511.0, 1H NMR(400MHz,CDCl3)δ8.67–8.41(m,2H),8.06–7.87(m,4H),7.38–7.35(m,2H),7.19–6.98(m,1H),5.33–5.00(m,2H),4.20–3.41(m,12H),2.11–1.98(m,2H).
实施例19(N-(1-(1-(6-(1H-苯并[d]咪唑-2-基]吡啶啉基]哌啶-4-基)-2-(苯氨基)嘧啶-4-羧酰胺(L-19)
Figure PCTCN2021119377-appb-000255
一、2-(苯氨基)嘧啶-4-羧酸
将2-氯嘧啶-4-羧酸(500mg,3.15mmol)溶于15ml二氧六环中,加入苯胺(881mg,9.46mmol)，反应液在70℃搅拌18小时。反应液冷却至室温，加入20ml水和10ml 1N氢氧化钠，反应液用用乙酸乙酯萃取二次(20ml*2)。将水相用1N盐酸酸化至pH＝3，固体过滤干燥得到白色固体500mg，收率为73.67％。LC-MS:m/z:(M+H)+＝216.0。
二、叔丁基(1-(6-(1H-苯并[d]咪唑-2-基)吡啶啉基)哌啶-4-基)氨基甲酸酯的合成
Figure PCTCN2021119377-appb-000256
冰浴下，将6-(1H-苯并咪唑-2-)吡啶羧酸(1g,4.2mmol)，1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(0.96g,5mmol)，1-羟基苯并三唑(0.66g,5mmol)和N，N-二异丙基乙胺(1.19g,9.2mmol)溶于N,N-二甲基甲酰胺20mL中，搅拌0.5h后加入哌啶-4-基氨基甲 酸叔丁酯(0.92g,4.6mmol)，继续搅拌0.5小时后回复至室温反应过夜。反应液倒入80mL水中，并用乙酸乙酯(80mL x 3)萃取，饱和食盐水洗涤，合并有机相，无水硫酸钠干燥，减圧浓缩硅胶柱层析(PE:EA＝5:1)得到类白色固体(1.3g,3mmol)，收率73％。LC-MS m/z:(M+H)+＝421。
三、(6-(1H-苯并[d]咪唑-2-基)吡啶-2-基)(4-氨基哌啶-1-基)甲酮的合成
Figure PCTCN2021119377-appb-000257
冰浴下，叔丁基(1-(6-(1H-苯并[d]咪唑-2-基)吡啶啉基)哌啶-4-基)氨基甲酸酯(1.3g,3mmol)溶于二氯甲烷20mL中，加入饱和1,4-二氧六环的盐酸溶液(2mL,8mmol)，继续搅拌0.5小时后回复至室温反应过夜。反应液减压浓缩，所得固体直接用于下步反应。收率>90％。LC-MS：321[M+1] +。
四、(N-(1-(1-(6-(1H-苯并[d]咪唑-2-基]吡啶啉基]哌啶-4-基)-2-(苯氨基)嘧啶-4-羧酰胺
操作同L-14
LC-MS:m/z:(M+H)+＝519.0,1H NMR(400MHz,CD3OD)δ8.64(d,J＝4.9Hz,1H),8.40(dd,J＝8.0,1.0Hz,1H),8.13(t,J＝7.9Hz,1H),7.76–7.58(m,5H),7.40–7.26(m,5H),7.08–6.99(m,1H),4.64(d,J＝13.6Hz,1H),4.27–4.15(m,1H),3.85(d,J＝14.1Hz,1H),3.43(dd,J＝18.3,7.0Hz,1H),3.31–3.20(m,1H),2.19(d,J＝11.0Hz,1H),2.00(s,1H),1.72-1.79(m,10.0Hz,2H).
实施例20(N-(1-(1-(6-(1H-苯并[d]咪唑-2-基]吡啶啉基)哌啶-4-基]-3-(1H-苯并[d]咪唑-2-基)环己烷-1-羧酰胺(L-20)
Figure PCTCN2021119377-appb-000258
一、3-(1H-苯并[d]咪唑-2-基)环己烷-1-甲酸
将1,3-环己二甲酸(1g，5.8mmol)和领苯二胺(628mg，5.8mmol)溶于10ml N,N-二甲基甲酰胺中，加入2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(2.43g，6.34mmol)和N,N-二异丙基乙胺(2.25g,17.4 0mmol)。反应液在15℃下搅拌16h。向反应 液中加入50ml水，并用乙酸乙酯(50mL*3)萃取。水相浓缩得到3g黑色油状物，将油状物溶于20ml乙酸中，55℃下搅拌4h浓缩，柱层析纯化得到所需产物1.3g,收率为93％。LC-MS:m/z:(M+H)+＝245.0。
二、(N-(1-(1-(6-(1H-苯并[d]咪唑-2-基]吡啶啉基)哌啶-4-基]-3-(1H-苯并[d]咪唑-2-基)环己烷-1-羧酰胺
操作同L-14
LC-MS:m/z:(M+H)+＝519.0,1H NMR(400MHz,CD3OD)δ8.40(d,J＝7.9Hz,1H),8.13(t,J＝7.8Hz,1H),7.65(dd,J＝7.7,0.9Hz,3H),7.54(d,J＝2.5Hz,2H),7.32(dd,J＝6.1,3.1Hz,2H),7.27–7.16(m,2H),4.62(d,J＝9.1Hz,1H),4.05–3.95(m,1H),3.81(d,J＝13.9Hz,1H),3.50–3.42(m,1H),3.39(s,1H),3.18(dd,J＝15.3,9.6Hz,1H),2.64(s,1H),2.43–2.29(m,1H),2.24–2.04(m,3H),1.94(dd,J＝13.8,10.6Hz,2H),1.74(dd,J＝11.1,5.5Hz,3H),1.66–1.45(m,3H).
实施例21 N-(1-(1-(6-(1H-苯并[d]咪唑-2-基]吡啶啉基)哌啶-4-基]-2-(吡啶-2-基氨基)嘧啶-4-羧酰胺(L-21)
Figure PCTCN2021119377-appb-000259
一、2-(吡啶-2-基氨基)嘧啶-4-羧酸
将吡啶-2-胺(534mg，5.67mmol)溶于1ml N,N-二甲基甲酰胺中,20℃下加入60％NaH(227mg，5.6768mmol)。反应液在20℃下搅拌1h。加入2-氯嘧啶-4-羧酸(300mg，1.89mmol)，反应液在70℃下搅拌18h。将反应液降至室温并加入20mL水，反应液用二氯甲烷(20mL*2)萃取。水相用1N盐酸酸化至pH＝5后浓缩。将残渣溶解在5mL N,N-二甲基甲酰胺中，并搅拌10分钟,过滤、浓缩得到黄色固体80mg，收率为19.5％。LC-MS:m/z:(M+H)+＝217.0。
二、(N-(1-(1-(6-(1H-苯并[d]咪唑-2-基]吡啶啉基)哌啶-4-基]-2-(吡啶-2-基氨基)嘧啶-4-羧酰胺
操作同L-14
LC-MS:m/z:(M+H)+＝520.0, 1H NMR(400MHz,CDCl3)δ8.74(d,J＝4.9Hz,1H),8.50(t,J＝9.1Hz,2H),8.36(s,1H),8.27(d,J＝4.7Hz,1H),8.04(d,J＝8.2Hz,1H),7.95(t,J＝7.8Hz,1H),7.84(t,J＝7.4Hz,1H),7.65(ddd,J＝17.5,9.1,5.3Hz,3H),7.28–7.25 (m,1H),7.12–7.01(m,1H),4.68(d,J＝13.3Hz,1H),4.37–4.13(m,1H),3.87(d,J＝13.5Hz,1H),3.28(t,J＝11.8Hz,1H),3.14(t,J＝11.5Hz,1H),2.15(d,J＝11.2Hz,1H),2.01(d,J＝10.6Hz,1H),1.79(dd,J＝21.2,11.4Hz,2H).
实施例22(N-(1-(1-(6-(1H-苯并[d]咪唑-2-基]吡啶啉基)哌啶-4-基]-2-吗啉基嘧啶-4-羧酰胺(L-22)
Figure PCTCN2021119377-appb-000260
(N-(1-(1-(6-(1H-苯并[d]咪唑-2-基]吡啶啉基)哌啶-4-基]-2-吗啉基嘧啶-4-羧酰胺
操作同L-14
LC-MS:m/z:(M+H)+＝513.0,1H NMR(400MHz,CDCl3)δ8.57(d,J＝4.8Hz,1H),8.52(d,J＝7.8Hz,1H),7.95(t,J＝7.8Hz,1H),7.75(d,J＝8.2Hz,2H),7.63–7.58(m,1H),7.39–7.32(m,3H),4.78(d,J＝13.5Hz,1H),4.26(dt,J＝10.9,9.5Hz,1H),3.92(d,J＝13.9Hz,1H),3.88–3.76(m,8H),3.34(t,J＝11.9Hz,1H),3.12(t,J＝11.6Hz,1H),2.21(d,J＝9.7Hz,1H),2.07(d,J＝11.7Hz,1H),1.81–1.63(m,2H).
实施例23 N-(3-(6-(1H-苯并[d]咪唑-2-基)吡啶啉基)-3-氮杂双环[3.1.0]己基-6-基)-2-(苯氨基)嘧啶-4-羧酰胺(L-23)
Figure PCTCN2021119377-appb-000261
N-(3-(6-(1H-苯并[d]咪唑-2-基)吡啶啉基)-3-氮杂双环[3.1.0]己基-6-基)-2-(苯氨基)嘧啶-4-羧酰胺
操作同L-14
LC-MS:m/z:(M+H)+＝517.0,1H NMR(400MHz,CDCl3)δ8.61–8.52(m,2H),8.48(d,J＝4.9Hz,1H),8.24(d,J＝6.9Hz,1H),7.98(t,J＝7.8Hz,1H),7.63(d,J＝7.7Hz,3H),7.46(s,1H),7.37(t,J＝8.0Hz,2H),7.30(d,J＝3.2Hz,1H),7.09(t,J＝7.4Hz,1H),6.97 (d,J＝4.9Hz,1H),4.24(d,J＝12.6Hz,1H),4.08(d,J＝11.7Hz,1H),3.87(dd,J＝11.7,4.4Hz,1H),3.69(dd,J＝12.1,4.5Hz,2H),3.14(dt,J＝11.7,7.3Hz,1H),2.56(d,J＝2.2Hz,1H),1.97(dd,J＝18.6,4.3Hz,2H).
实施例24(5-(6-(1-(1-H-苯并[d]咪唑-2-基]吡啶啉基)六氢吡咯并[3,4-c]吡咯-2(1H)-基)(2-(苯基氨基)嘧啶-4-基)甲酮(L-24)
Figure PCTCN2021119377-appb-000262
(5-(6-(1-(1-H-苯并[d]咪唑-2-基]吡啶啉基)六氢吡咯并[3,4-c]吡咯-2(1H)-基)(2-(苯基氨基)嘧啶-4-基)甲酮
操作同L-14
LC-MS:m/z:(M+H)+＝531.0,1H NMR(400MHz,CDCl3)δ8.60–8.44(m,2H),8.02–7.92(m,1H),7.79(dd,J＝6.3,3.1Hz,2H),7.75–7.62(m,2H),7.51(d,J＝7.7Hz,1H),7.41–7.30(m,3H),7.27–7.16(m,1H),7.09(dd,J＝9.6,6.2Hz,1H),4.05-3.79(m,4H),3.78-3.68(m,4H),3.07(s,2H).
实施例25(N-(3-(6-(1H-苯并[d]咪唑-2-基)吡啶啉基)-3-氮杂双环[3.1.0]己基-6-基)-2-(吡啶-2-基氨基)嘧啶-4-羧酰胺(L-25)
Figure PCTCN2021119377-appb-000263
(N-(3-(6-(1H-苯并[d]咪唑-2-基)吡啶啉基)-3-氮杂双环[3.1.0]己基-6-基)-2-(吡啶-2-基氨基)嘧啶-4-羧酰胺
操作同L-14
LC-MS:m/z:(M+H)+＝518.0,1H NMR(400MHz,CD3OD)δ8.71(d,J＝4.9Hz,1H),8.41(dd,J＝7.6,1.3Hz,1H),8.31(dd,J＝9.5,4.8Hz,2H),8.21–8.08(m,2H),8.07-7.82(m,1H),7.68(s,2H),7.40–7.28(m,2H),7.17(d,J＝4.9Hz,1H),7.05(ddd,J＝7.2,5.0,0.9Hz,1H),4.24(d,J＝12.5Hz,1H),4.14(d,J＝11.5Hz,1H),3.99(dd,J＝11.5,4.3Hz,1H),3.75(dt,J＝13.2,5.1Hz,1H),2.71(t,J＝2.4Hz,1H),2.17–2.05(m,2H).
实施例26((5-(6-(1H-苯并[d]咪唑-2-基]吡啶啉基)六氢吡咯并[3,4-c]吡咯-2(1H)-基)(2-(吡啶-2-基氨基)嘧啶-4-基)甲酮(L-26)
Figure PCTCN2021119377-appb-000264
((5-(6-(1H-苯并[d]咪唑-2-基]吡啶啉基)六氢吡咯并[3,4-c]吡咯-2(1H)-基)(2-(吡啶-2-基氨基)嘧啶-4-基)甲酮
将2-(2-吡啶基氨基)嘧啶-4-羧酸(40mg，0.18mmol)溶于2ml N,N-二甲基甲酰胺中，加入1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(145mg，0.28mmol)和N,N-二异丙基乙胺(72mg,0.56mmol)。反应液搅拌20分钟后加入2,3,3a，4,6,6a-六氢-1H-吡咯并[3,4-c]吡咯-5-基-[6-(1H-苯并咪唑-加入2-基)-2-吡啶基]甲酮(62mg，0.18mmol),反应液在15℃下搅拌16h。向反应液中加入10ml水，过滤，得到的固体通过薄层层析板纯化(二氯甲烷∶甲醇＝10∶1)，得到白色固体15mg,收率为15.25％。
LC-MS:m/z:(M+H)+＝532.0,1H NMR(400MHz,CD3OD)δ8.68(dd,J＝26.6,5.0Hz,1H),8.63-8.61(m,1H),8.32–8.22(m,1H),8.19–8.07(m,2H),7.92–7.51(m,4H),7.36–7.26(m,2H),7.20(dd,J＝14.8,5.0Hz,1H),6.84-6.82(m,1H),4.29–3.65(m,8H),3.17–3.03(m,2H).
实施例27(9-(6-(1H-苯并[d]咪唑-2-基)吡啶啉基)-3,9-二氮杂螺[5.5]十一烷-3-基)(2-(苯氨基)嘧啶-4-基)甲酮(L-27)
Figure PCTCN2021119377-appb-000265
(9-(6-(1H-苯并[d]咪唑-2-基)吡啶啉基)-3,9-二氮杂螺[5.5]十一烷-3-基)(2-(苯氨基)嘧啶-4-基)甲酮
操作同L-26
LC-MS:m/z:(M+H)+＝573.0,1H NMR(400MHz,DMSO-d6)δ12.96(s,1H),9.82(s,1H),8.59(d,J＝4.9Hz,1H),8.38(dd,J＝7.9,1.0Hz,1H),8.11(t,J＝7.8Hz,1H),7.75–7.72(m,3H),7.62-7.56(m,2H),7.31-7.21(m,4H),6.96(t,J＝7.3Hz,1H),6.88(d,J＝4.9Hz,1H),3.78–3.54(m,4H),3.35(s,4H),1.72–1.31(m,8H).
实施例28 6-(1H-苯并[d]咪唑-2-基)-N-(1-(2-(苯氨基)嘧啶-4-羰基)吡咯烷-3-基)吡啶啉酰胺(L-28)
Figure PCTCN2021119377-appb-000266
6-(1H-苯并[d]咪唑-2-基)-N-(1-(2-(苯氨基)嘧啶-4-羰基)吡咯烷-3-基)吡啶啉酰胺
操作同L-26
LC-MS:m/z:(M+H)+＝505.0,1H NMR(400MHz,CD3OD)δ8.62(dd,J＝30.1,4.9Hz,1H),8.41(t,J＝7.9Hz,1H),8.12(q,J＝7.8Hz,1H),7.86(d,J＝7.7Hz,1H),7.75–7.54(m,4H),7.41–7.22(m,5H),6.97(dd,J＝12.5,7.3Hz,1H),4.72–4.52(m,1H),4.34-3.54(m,4H),2.42(dd,J＝12.9,5.7Hz,1H),2.20(d,J＝5.5Hz,1H).
实施例29 6-(1H-苯并[d]咪唑-2-基)-N-(1-(2-(吡啶-2-基氨基)嘧啶-4-羰基)吡咯烷-3-基)吡啶啉酰胺(L-29)
Figure PCTCN2021119377-appb-000267
6-(1H-苯并[d]咪唑-2-基)-N-(1-(2-(吡啶-2-基氨基)嘧啶-4-羰基)吡咯烷-3-基)吡啶啉酰胺
操作同L-26
LC-MS:m/z:(M+H)+＝506.0,1H NMR(400MHz,CD3OD)δ8.73(dd,J＝33.7,4.9Hz,1H),8.48–8.35(m,1H),8.32–8.00(m,3H),7.87(ddd,J＝7.8,2.1,1.0Hz,1H),7.75-7.73(m,2H),7.61(s,1H),7.46(dd,J＝43.3,4.9Hz,1H),7.36–7.23(m,2H),6.99(dd,J＝7.3,5.0Hz,1H),4.78–4.30(m,2H),4.09-4.01(m,1H),4.02–3.77(m,2H),2.49–2.12(m,2H).
实施例30 N-(1-(1-(6-(1H-苯并[d]咪唑-2-基)吡啶啉基)哌啶-4-基)-6-(1H-苯并[d]咪唑-2-基)吡啶啉酰胺(L-30)
Figure PCTCN2021119377-appb-000268
N-(1-(1-(6-(1H-苯并[d]咪唑-2-基)吡啶啉基)哌啶-4-基)-6-(1H-苯并[d]咪唑-2-基)吡啶啉酰胺
操作同L-5
LC-MS:m/z:(M+H)+＝543.22, 1H NMR(400MHz,CDCl 3)δ8.49(d,J＝7.2Hz,2H),8.07–7.86(m,2H),7.72(s,4H),7.58(dd,J＝7.7,1.0Hz,2H),7.38–7.31(m,4H),4.69(d,J＝13.1Hz,2H),4.55(d,J＝7.8Hz,2H),3.83(d,J＝13.8Hz,4H),3.15(dt,J＝22.4,11.4Hz,4H),2.06(dd,J＝56.4,13.3Hz,4H).
实施例31 N-(4-(9-甲基-3,9-二氮杂螺[5.5]十一烷-3-基)苯基)-1-(2-(苯基氨基)嘧啶-4-羰基)吡咯烷-3-羧酰胺(L-31)
Figure PCTCN2021119377-appb-000269
N-(4-(9-甲基-3,9-二氮杂螺[5.5]十一烷-3-基)苯基)-1-(2-(苯基氨基)嘧啶-4-羰基)吡咯烷-3-羧酰胺
操作同L-5
4-(9-甲基-3,9-二氮杂螺[5.5]十一烷-3-基)苯胺购于毕得医药
LC-MS:m/z:(M+H)+＝554.23, 1H NMR(400MHz,MeOD)δ8.50–8.34(m,1H),8.19–8.07(m,1H),7.83(t,J＝13.8Hz,1H),7.69(s,2H),7.49(d,J＝9.0Hz,1H),7.42–7.27(m,2H),6.97(dd,J＝28.4,9.0Hz,2H),4.21–3.87(m,4H),3.77(dt,J＝12.3,7.7Hz,1H),3.19–3.06(m,4H),2.83(s,4H),2.57(d,J＝5.6Hz,3H),2.44–2.26(m,2H).
实施例32 N-(1-(1-(6-(1H-苯并[d]咪唑-2-基)吡啶啉基)吡咯烷-3-基)-6-(1H-苯并[d]咪唑-2-基)吡啶啉酰胺(L-32)
Figure PCTCN2021119377-appb-000270
N-(1-(1-(6-(1H-苯并[d]咪唑-2-基)吡啶啉基)吡咯烷-3-基)-6-(1H-苯并[d]咪唑-2-基)吡啶啉酰胺
操作同L-6
LC-MS:m/z:(M+H)+＝529.5, 1H NMR(400MHz,CDCl 3)δ8.70(s,2H),8.57(d,J＝23.6Hz,1H),8.46(d,J＝7.9Hz,1H),8.34(d,J＝6.2Hz,2H),8.16(dd,J＝22.0,7.1Hz,2H),7.86(dd,J＝17.5,9.7Hz,2H),7.80–7.50(m,4H),7.36–7.16(m,4H),4.61(d,J＝5.9Hz,2H),4.41(s,1H),4.03(dd,J＝11.5,6.2Hz,1H),3.78(dd,J＝58.9,16.7Hz,4H),3.53(s,3H),2.18(dd,J＝12.9,6.3Hz,1H),1.93(dd,J＝39.9,18.0Hz,2H),1.74–1.50(m,2H),1.32(dt,J＝14.2,10.8Hz,4H).
实施例33环己烷-1,4-二基双((5-(4-硝基苯基)六氢吡咯并[3,4-c]吡咯-2(1H)-基)甲酮)(L-33)
Figure PCTCN2021119377-appb-000271
环己烷-1,4-二基双((5-(4-硝基苯基)六氢吡咯并[3,4-c]吡咯-2(1H)-基)甲酮)
操作同L-8
2-(4-硝基苯基)八氢吡咯并[3,4-c]吡咯购于毕得医药
LC-MS:m/z:(M+H)+＝603.21, 1H NMR(400MHz,CDCl 3)δ8.15(d,J＝8.1Hz,4H),6.50(d,J＝8.6Hz,4H),4.00–3.65(m,8H),3.65–3.27(m,8H),3.15(d,J＝34.2Hz,4H),2.39(s,2H),2.07–1.72(m,4H),1.59(dd,J＝25.9,13.6Hz,4H),1.45–1.20(m,4H).
实施例34 1,4-亚苯基双((5-(4-硝基苯基)六氢吡咯并[3,4-c]吡咯-2(1H)-基)甲酮)(L-34)
Figure PCTCN2021119377-appb-000272
1,4-亚苯基双((5-(4-硝基苯基)六氢吡咯并[3,4-c]吡咯-2(1H)-基)甲酮)
操作同L-8
LC-MS:m/z:(M+H)+＝597.21, 1H NMR(400MHz,CDCl 3)δ8.15(t,J＝8.8Hz,4H),8.01–7.86(m,4H),6.61–6.43(m,4H),4.28–3.88(m,4H),3.84–3.51(m,8H),3.51–3.38(m,2H),3.38–3.21(m,2H),3.21–2.81(m,4H).
实施例35 1-(6-(1H-苯并[d]咪唑-2-基)吡啶啉基)-N-(4-(9-甲基-3,9-二氮杂螺[5.5]十一烷-3-基)苯基)吡咯烷-3-羧酰胺(L-35)
Figure PCTCN2021119377-appb-000273
1-(6-(1H-苯并[d]咪唑-2-基)吡啶啉基)-N-(4-(9-甲基-3,9-二氮杂螺[5.5]十一烷-3-基)苯基)吡咯烷-3-羧酰胺
操作同L-6
LC-MS:m/z:(M+H)+＝578.31, 1H NMR(400MHz,MeOD)δ8.59(d,J＝4.7Hz,1H),7.66(dd,J＝15.3,8.1Hz,2H),7.44(dd,J＝15.0,8.9Hz,2H),7.36–7.25(m,2H),7.04(ddd,J＝30.4,15.7,6.8Hz,4H),4.16–3.76(m,5H),3.70(s,4H),3.27–3.05(m,4H),2.80(s,3H),2.54(s,2H),2.27(d,J＝5.2Hz,2H),1.69(s,5H).
实施例36哌嗪-1,4-二基双((3-(咪唑[1,2-a]吡啶-2-基)苯基)甲酮)(L-36)
Figure PCTCN2021119377-appb-000274
冰浴下，将3-(咪唑并[1,2-a]吡啶-2-基)苯甲酸(0.12g,0.5mmol)，六氟磷酸苯并三唑-1-基-氧基三吡咯烷基磷(0.28g,0.55mmol)和N，N-二异丙基乙胺(0.14g,1.1mmol)溶于N,N-二甲基甲酰胺6mL中，搅拌0.5h后加入哌嗪(0.04g,0.5mmol)，继续搅拌0.5小时后回复至室温反应过夜。反应液倒入20mL水中，并用乙酸乙酯(20mL x 3)萃取，饱和食盐水洗涤，合并有机相，无水硫酸钠干燥，减圧浓缩硅胶柱层析(DCM:MeOH＝20:1)得到类白色固体(12mg,22μmol)，收率4.5％。LC-MS m/z:(M+H)+＝527。
1H NMR(400MHz,Chloroform-d)δ8.15(d,2H),8.08–8.00(m,4H),7.91(s,2H),7.65(d,J＝9.1Hz,2H),7.56–7.46(m,2H),7.39(d,J＝7.6Hz,2H),7.21(m,2H),6.82(m,2H),3.73(d,J＝89.9Hz,8H).
实施例37 6-(1H-苯并[d]咪唑-2-基)-N-(1-(3-硝基苯甲基)吡咯烷-3-基)吡啶酰胺(L-37)
Figure PCTCN2021119377-appb-000275
冰浴下，将间硝基苯甲酸(0.08g,0.48mmol)，六氟磷酸苯并三唑-1-基-氧基三吡咯烷基磷(0.30g,0.58mmol)和N，N-二异丙基乙胺(0.16g,1.3mmol)溶于N,N-二甲基甲酰胺6mL中，搅拌0.5h后加入6-(1H-苯并[d]咪唑-2-基)-N-(吡咯烷-3-基)吡啶酰胺(0.15g,0.48mmol)， 继续搅拌0.5小时后回复至室温反应过夜。反应液倒入20mL水中，并用乙酸乙酯(20mL x 3)萃取，饱和食盐水洗涤，合并有机相，无水硫酸钠干燥，减圧浓缩硅胶柱层析(DCM:MeOH＝20:1)得到类白色固体(15mg,32μmol)，收率6.8％。LC-MS m/z:(M+H)+＝457。
实施例38：N-(1-(6-(1H-苯并[d]咪唑-2-基)吡啶酰)哌啶-4-基)-3-硝基苯甲酰胺(L-38)
Figure PCTCN2021119377-appb-000276
冰浴下，将(6-1H-苯并[d]咪唑-2-基)吡啶-2-基)(4-氨基哌啶-1-基)甲酮(0.088g,0.27mmol)，六氟磷酸苯并三唑-1-基-氧基三吡咯烷基磷(0.15g,0.3mmol)和N，N-二异丙基乙胺(0.12g,1.0mmol)溶于N,N-二甲基甲酰胺6mL中，搅拌0.5h后加入间硝基苯甲酸(0.04g,0.27mmol)，继续搅拌0.5小时后回复至室温反应过夜。反应液倒入20mL水中，并用乙酸乙酯(20mL x 3)萃取，饱和食盐水洗涤，合并有机相，无水硫酸钠干燥，减圧浓缩硅胶柱层析(DCM:MeOH＝20:1)得到类白色固体(11mg,32μmol)，收率8.6％。LC-MS m/z:(M+H)+＝471。
实施例39：(1-(3-(咪唑[1,2-a]吡啶-2-基)苯甲酰基)吡咯烷-2-基)(5-(4-硝基苯基)六氢吡咯[3,4-c]吡咯-2(1H)-基)甲酮的合成(L-39)
Figure PCTCN2021119377-appb-000277
冰浴下，将3-(咪唑并[1,2-a]吡啶-2-基)苯甲酸(0.1g,0.4mmol)，六氟磷酸苯并三唑-1-基-氧基三吡咯烷基磷(0.24g,0.44mmol)和N，N-二异丙基乙胺(0.12g,1.0mmol)溶于N,N-二甲基甲酰胺6mL中，搅拌0.5h后加入2-(4-硝基苯基)-5-脯酰八氢吡咯[3,4-c]吡咯(0.13g,0.4mmol)，继续搅拌0.5小时后回复至室温反应过夜。反应液倒入20mL水中，并用乙酸乙酯(20mL x 3)萃取，饱和食盐水洗涤，合并有机相，无水硫酸钠干燥，减圧浓缩硅胶柱层析(DCM:MeOH＝20:1)得到类白色固体(16mg,μmol)，收率7.2％。LC-MS m/z:(M+H)+＝551。
1H NMR(400MHz,Chloroform-d)δ8.20–7.99(m,5H),7.90(d,J＝9.8Hz,1H),7.64(t,J＝8.8Hz,1H),7.53–7.45(m,2H),7.21(m,1H),6.82(m,1H),6.57–6.38(m,2H),3.81(m,7H),3.62–3.06(m,8H),2.25(m,2H).
实施例40：(9-(3-(1H-苯并[d]咪唑-2-基)苯甲酰基)-3,9-二氮杂螺环[5.5条]十一碳-3-基)(3-硝基苯基)甲酮(L-40)
Figure PCTCN2021119377-appb-000278
冰浴下，将间硝基苯甲酸(0.041g,0.25mmol)，六氟磷酸苯并三唑-1-基-氧基三吡咯烷基磷(0.14g,0.27mmol)和N，N-二异丙基乙胺(0.12g,1.0mmol)溶于N,N-二甲基甲酰胺6mL中，搅拌0.5h后加入(6-(1H-苯并[d]咪唑-2-基)吡啶-2-基)(3,9-二氮螺环[5.5]十一烷-3-基)美沙酮(0.093g,0.25mmol)，继续搅拌0.5小时后回复至室温反应过夜。反应液倒入20mL水中，并用乙酸乙酯(20mL x 3)萃取，饱和食盐水洗涤，合并有机相，无水硫酸钠干燥，减圧浓缩硅胶柱层析(DCM:MeOH＝20:1)得到类白色固体(17mg,μmol)，收率12.9％。LC-MS m/z:(M+H)+＝525。
1H NMR(400MHz,Chloroform-d)δ10.74(s,1H),8.48(dd,J＝8.0,1.1Hz,1H),8.34–8.27(m,2H),7.97(t,J＝7.8Hz,1H),7.87(d,J＝6.9Hz,1H),7.77(m,1H),7.64(t,J＝7.9Hz,1H),7.57(m,2H),7.37–7.32(m,2H),3.94–3.74(m,4H),3.52(s,2H),3.42(s,2H),1.59(m,8H).
实施例41：(5-(6-(1H-苯并[d]咪唑-2-基)吡啶酰)六氢吡咯[3,4-c]吡咯-2(1H)-基)(3-硝基苯基)甲酮的合成(L-41)
Figure PCTCN2021119377-appb-000279
冰浴下，将间硝基苯甲酸(0.041g,0.25mmol)，六氟磷酸苯并三唑-1-基-氧基三吡咯烷基磷(0.14g,0.27mmol)和N，N-二异丙基乙胺(0.12g,1.0mmol)溶于N,N-二甲基甲酰胺6mL中，搅拌0.5h后加入(6-(1H-苯并[d]咪唑-2-基)吡啶-2-基)(六氢吡咯[3,4-c]吡咯-2(1H)-基)甲酮(0.083g,0.25mmol)，继续搅拌0.5小时后回复至室温反应过夜。反应液倒入20mL水中，并用乙酸乙酯(20mL x 3)萃取，饱和食盐水洗涤，合并有机相，无水硫酸钠干燥，减圧浓缩硅胶柱层析(DCM:MeOH＝20:1)得到类白色固体(17mg,μmol)，收率12.9％。LC-MS m/z:(M+H)+＝483。
1H NMR(400MHz,Chloroform-d)δ11.58(s,1H),8.52(dd,J＝28.6,7.9Hz,1H),8.38(s,1H),8.30(t,J＝9.1Hz,1H),8.04–7.49(m,6H),7.32(m 2H),4.22(m,1H),4.09–4.00(m, 1H),3.91–3.32(m,6H),3.05(m,2H).
实施例42：N-(1-(3-(咪唑并[1,2-a]吡啶-2-基)苯甲酰基)哌啶-4-基)-2-(苯胺基)嘧啶-4-甲酰胺(L-42)
Figure PCTCN2021119377-appb-000280
一、叔丁基(1-(3-(咪唑[1,2-a]吡啶-2-基)苯甲酰基)哌啶-4-基)氨基甲酸酯的合成
Figure PCTCN2021119377-appb-000281
冰浴下，将3-(咪唑并[1,2-a]吡啶-2-基)苯甲酸(1g,4.2mmol)，1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(0.96g,5mmol)，1-羟基苯并三唑(0.66g,5mmol)和N，N-二异丙基乙胺(1.19g,9.2mmol)溶于N,N-二甲基甲酰胺20mL中，搅拌0.5h后加入叔丁基哌啶-4-基氨基甲酸酯(0.92g,4.6mmol)，继续搅拌0.5小时后回复至室温反应过夜。反应液倒入80mL水中，并用乙酸乙酯(80mL x 3)萃取，饱和食盐水洗涤，合并有机相，无水硫酸钠干燥，减圧浓缩硅胶柱层析(PE:EA＝5:1)得到类白色固体(1.3g,3mmol)，收率73％。LC-MS m/z:(M+H)+＝421。
二、(4-氨基哌啶-1-基)(3-(咪唑并[1,2-a]吡啶-2-基)苯基)甲酮的合成
Figure PCTCN2021119377-appb-000282
冰浴下，叔丁基(1-(3-(咪唑[1,2-a]吡啶-2-基)苯甲酰基)哌啶-4-基)氨基甲酸酯(1.3g,3mmol)溶于二氯甲烷20mL中，加入饱和1,4-二氧六环的盐酸溶液(2mL,8mmol)，继续搅拌0.5小时后回复至室温反应过夜。反应液减压浓缩，所得固体直接用于下步反应。收率>90％。LC-MS m/z:(M+H)+＝321。
三、N-(1-(3-(咪唑并[1,2-a]吡啶-2-基)苯甲酰基)哌啶-4-基)-2-(苯胺基)嘧啶-4-甲酰胺的合成
Figure PCTCN2021119377-appb-000283
冰浴下，将2-(苯胺基)嘧啶-4-羧酸(0.060g,0.27mmol)，六氟磷酸苯并三唑-1-基-氧基三吡咯烷基磷(0.14g,0.27mmol)和N，N-二异丙基乙胺(0.12g,1.0mmol)溶于N,N-二甲基甲酰胺6mL中，搅拌0.5h后加入(4-氨基哌啶-1-基)(3-(咪唑并[1,2-a]吡啶-2-基)苯基)甲酮(0.089g,0.27mmol)，继续搅拌0.5小时后回复至室温反应过夜。反应液倒入20mL水中，并用乙酸乙酯(20mL x 3)萃取，饱和食盐水洗涤，合并有机相，无水硫酸钠干燥，减圧浓缩硅胶柱层析(DCM:MeOH＝20:1)得到类白色固体(20mg,38μmol)，收率14.3％。LC-MS m/z:(M+H)+＝518。
1H NMR(400MHz,Chloroform-d)δ8.65(d,J＝4.8Hz,1H),8.22(d,J＝6.7Hz,1H),7.97(m,4H),7.65(m,3H),7.52–7.44(m,2H),7.43–7.30(m,5H),7.13(t,J＝7.3Hz,1H),6.92(t,J＝6.7Hz,1H),4.70(s,1H),4.27(s,1H),3.84(s,1H),3.20(m，2H),1.67(s,2H),1.31(m,2H).
实施例43 N-(1-(3-(咪唑并[1,2-a]吡啶-2-基)苯甲酰基)哌啶-4-基)-2-(苯胺基)嘧啶-4-甲酰胺(L-43)
Figure PCTCN2021119377-appb-000284
一、叔丁基5-(3-(咪唑并[1,2-a]吡啶-2-基)苯甲酰基)六氢吡咯吡咯-2(1H)-羧酸盐的合成
Figure PCTCN2021119377-appb-000285
冰浴下，将3-(咪唑并[1,2-a]吡啶-2-基)苯甲酸(1g,4.2mmol)，1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(0.96g,5mmol)，1-羟基苯并三唑(0.66g,5mmol)和N，N-二异丙基乙胺(1.19g,9.2mmol)溶于N,N-二甲基甲酰胺20mL中，搅拌0.5h后加入叔丁基哌啶-4-基氨基甲酸酯(0.98g,4.6mmol)，继续搅拌0.5小时后回复至室温反应过夜。反应液倒入 80mL水中，并用乙酸乙酯(80mL x 3)萃取，饱和食盐水洗涤，合并有机相，无水硫酸钠干燥，减圧浓缩硅胶柱层析(PE:EA＝5:1)得到类白色固体(1.26g,2.9mmol)，收率72％。LC-MS m/z:(M+H)+＝433。
二、(六氢吡咯[3,4-c]吡咯-2(1H)-基)(3-(咪唑并[1,2-a]吡啶-2-基)苯基)甲酮的合成
Figure PCTCN2021119377-appb-000286
冰浴下，叔丁基5-(3-(咪唑并[1,2-a]吡啶-2-基)苯甲酰基)六氢吡咯吡咯-2(1H)-羧酸盐(1.3g,3mmol)溶于二氯甲烷20mL中，加入饱和1,4-二氧六环的盐酸溶液(2mL,8mmol)，继续搅拌0.5小时后回复至室温反应过夜。反应液减压浓缩，所得固体直接用于下步反应。收率>90％。LC-MS m/z:(M+H)+＝333。
三、N-(1-(3-(咪唑并[1,2-a]吡啶-2-基)苯甲酰基)哌啶-4-基)-2-(苯胺基)嘧啶-4-甲酰胺的合成
Figure PCTCN2021119377-appb-000287
冰浴下，将2-(苯胺基)嘧啶-4-羧酸(0.060g,0.27mmol)，六氟磷酸苯并三唑-1-基-氧基三吡咯烷基磷(0.14g,0.27mmol)和N，N-二异丙基乙胺(0.12g,1.0mmol)溶于N,N-二甲基甲酰胺6mL中，搅拌0.5h后加入(六氢吡咯[3,4-c]吡咯-2(1H)-基)(3-(咪唑并[1,2-a]吡啶-2-基)苯基)甲酮(0.092g,0.27mmol)，继续搅拌0.5小时后回复至室温反应过夜。反应液倒入20mL水中，并用乙酸乙酯(20mL x 3)萃取，饱和食盐水洗涤，合并有机相，无水硫酸钠干燥，减圧浓缩硅胶柱层析(DCM:MeOH＝20:1)得到类白色固体(12mg,22μmol)，收率8.4％。LC-MS m/z:(M+H)+＝530。
1H NMR(400MHz,Chloroform-d)δ8.57(d,J＝13.0Hz,1H),8.12(d,2H),8.03(d,J＝7.0Hz,1H),7.90(d,J＝8.8Hz,1H),7.66–7.36(m,7H),7.27–6.95(m,4H),6.81(t,J＝6.8Hz,1H),4.04–3.40(m,8H),3.01(d,2H).
实施例44 N-(3-(6-(1H-苯并[d]咪唑-2-基)吡啶啉基)-3-氮杂双环[3.1.0]己基-6-基)-6-(苯氨基)吡啶啉酰胺(L-44)
Figure PCTCN2021119377-appb-000288
一、6-(苯基氨基)吡啶甲酸
将6-溴吡啶-2-甲酸甲酯(2g,9.26mmol)溶于50ml二氧六环中,加入苯胺(826mg,9.26mmol)，三(二亚苄基丙酮)二钯(424mg,0.46mmol),4,5-双二苯基膦-9,9-二甲基氧杂蒽(536mg,0.92mmol)和碳酸铯(7.54g,23.1mmol)，反应液在95℃氮气保护下搅拌15小时。反应液冷却至室温，过滤、浓缩得到黄色固体。将固体溶于15ml四氢呋喃、10ml甲醇和15ml水中,加入氢氧化钠(1.2g,29mmol)，反应液在20℃搅拌15小时。反应液用乙酸乙酯萃取三次(20ml*3)。将水相用2N盐酸酸化至pH＝1，水相用乙酸乙酯萃取三次(20ml*3)，再用饱和碳酸氢钠水溶液中和至pH＝1，固体过滤干燥得到白色固体500mg，收率为25.2％。LC-MS:m/z:(M+H)+＝215.0。
二、N-(3-(6-(1H-苯并[d]咪唑-2-基)吡啶啉基)-3-氮杂双环[3.1.0]己基-6-基)-6-(苯氨基)吡啶啉酰胺
操作同L-14
LC-MS:m/z:(M+H)+＝516.0,1H NMR(400MHz,CD3OD)δ8.47(dd,J＝7.4,1.5Hz,1H),8.26–8.13(m,2H),7.85–7.54(m,5H),7.45–7.23(m,4H),7.08(dd,J＝7.3,0.8Hz,1H),6.99-6.92(m,2H),4.29(d,J＝12.4Hz,1H),4.20(d,J＝11.7Hz,1H),3.97(dd,J＝11.7,4.2Hz,1H),3.75(dd,J＝12.4,4.4Hz,1H),2.74(t,J＝2.4Hz,1H),2.15–2.05(m,2H).
实施例45(9-(6-(1-H-苯并[d]咪唑-2-基)吡啶啉基)-3,9-二氮杂螺[5.5]十一烷-3-基)(6-(苯氨基)吡啶-2-基)甲酮(L-45)
Figure PCTCN2021119377-appb-000289
(9-(6-(1-H-苯并[d]咪唑-2-基)吡啶啉基)-3,9-二氮杂螺[5.5]十一烷-3-基)(6-(苯氨基)吡啶-2-基)甲酮
操作同L-14
LC-MS:m/z:(M+H)+＝572.0,1H NMR(400MHz,CD3OD)δ8.40(dd,J＝8.0,1.0Hz,1H),8.13(t,J＝7.9Hz,1H),7.86–7.53(m,6H),7.33(d,J＝5.1Hz,2H),7.29–7.20(m,2H),6.94(t,J＝7.4Hz,1H),6.91–6.82(m,2H),3.77(dd,J＝28.2,21.3Hz,4H),3.62–3.47(m,4H),1.70(d,J＝37.8Hz,8H).
实施例46(5-(6-(1H-苯并[d]咪唑-2-基)吡啶啉基)六氢吡咯并[3,4-c]吡咯-2(1H)-基)(6-(苯基氨基)吡啶-2-基)甲酮(L-46)
Figure PCTCN2021119377-appb-000290
(5-(6-(1H-苯并[d]咪唑-2-基)吡啶啉基)六氢吡咯并[3,4-c]吡咯-2(1H)-基)(6-(苯基氨基)吡啶-2-基)甲酮
操作同L-14
LC-MS:m/z:(M+H)+＝530.0,1H NMR(400MHz,CD3OD)δ8.43(ddd,J＝7.9,5.4,0.9Hz,1H),8.15(dd,J＝15.4,7.7Hz,1H),7.92–7.81(m,1H),7.79–7.27(m,7H),7.23–6.52(m,5H),4.25–3.62(m,8H),3.20–3.03(m,2H).
实施例47 N-(1-(1-(6-(1H-苯并[d]咪唑-2-基]吡啶啉基)哌啶-4-基]-6-(苯基氨基)吡啶啉酰胺(L-47)
Figure PCTCN2021119377-appb-000291
N-(1-(1-(6-(1H-苯并[d]咪唑-2-基]吡啶啉基)哌啶-4-基]-6-(苯基氨基)吡啶啉酰胺
操作同L-14
LC-MS:m/z:(M+H)+＝518.0,1H NMR(400MHz,CD3OD)δ8.41(dd,J＝8.0,0.9Hz,1H),8.15(t,J＝7.9Hz,1H),7.84–7.57(m,4H),7.56–7.42(m,3H),7.41–7.16(m,4H),7.04–6.91(m,2H),4.54(d,J＝13.7Hz,1H),4.24–4.17(m,1H),3.82(d,J＝13.8Hz,1H),3.50-3.21(m,2H),2.23(d,J＝10.1Hz,1H),2.05(d,J＝10.1Hz,1H),1.75(dt,J＝19.7,10.2Hz,2H).
实施例48 N-(6-(5-(6-(1H-苯并[d]咪唑-2-基]吡啶啉基)八氢吡咯并[3,4-c]吡咯-2-羰基)吡啶-2-基)乙酰胺(L-48)
Figure PCTCN2021119377-appb-000292
操作同L-14
6-乙酰氨基吡啶甲酸购于毕得医药
LC-MS:m/z:(M+H)+＝496.2, 1H NMR(400MHz,MeOD)δ8.43(dd,J＝13.6,7.8Hz,1H),8.15(dd,J＝17.8,8.1Hz,1H),7.96–7.82(m,2H),7.67(dd,J＝41.3,19.9Hz,2H),7.53–7.41(m,1H),7.31(dt,J＝21.6,7.7Hz,3H),4.24–3.83(m,5H),3.80–3.57(m,3H),3.50(s,1H),3.13(d,J＝20.5Hz,2H),2.20(dd,J＝15.6,8.0Hz,2H),2.05(d,J＝15.3Hz,2H),1.63(s,1H).
实施例50 N-(1-(3-(咪唑并[1,2-a]吡啶-2-基)苯甲酰基)哌啶-4-基)-2-(苯胺基)吡啶-4-甲酰胺(L-50)
Figure PCTCN2021119377-appb-000293
N-(1-(3-(咪唑并[1,2-a]吡啶-2-基)苯甲酰基)哌啶-4-基)-2-(苯胺基)吡啶-4-甲酰胺的合成
冰浴下，将2-(苯胺基)吡啶-4-羧酸(0.060g,0.27mmol)，六氟磷酸苯并三唑-1-基-氧基三吡咯烷基磷(0.14g,0.27mmol)和N，N-二异丙基乙胺(0.12g,1.0mmol)溶于N,N-二甲基甲酰胺6mL中，搅拌0.5h后加入(4-氨基哌啶-1-基)(3-(咪唑并[1,2-a]吡啶-2-基)苯基)甲酮(0.089g,0.27mmol)，继续搅拌0.5小时后回复至室温反应过夜。反应液倒入20mL水中，并用乙酸乙酯(20mL x 3)萃取，饱和食盐水洗涤，合并有机相，无水硫酸钠干燥，减圧浓缩硅胶柱层析(DCM:MeOH＝20:1)得到类白色固体(18mg,34μmol)，收率12.8％。LC-MS m/z:(M+H)+＝517。
1H NMR(400MHz,Chloroform-d)δ8.14(m,1H),8.05–7.99(m,2H),7.96(d,J＝8.2Hz,1H),7.89(d,J＝0.7Hz,1H),7.65–7.60(m,3H),7.48(m,1H),7.40–7.34(m,5H),7.19(m,1H),7.14–7.08(m,1H),7.04(s,1H),7.00–6.94(m,1H),6.80(m,1H),4.62(s,1H),4.29–4.14(m,1H),3.82(s,1H),3.31–3.08(m,2H),2.02(m,2H),1.57(d,2H).
实施例51 N-(1-(3-(咪唑并[1,2-a]吡啶-2-基)苯甲酰基)哌啶-4-基)-2-(苯胺基)吡啶-4-甲酰胺(L-51)
Figure PCTCN2021119377-appb-000294
N-(1-(3-(咪唑并[1,2-a]吡啶-2-基)苯甲酰基)哌啶-4-基)-2-(苯胺基)吡啶-4-甲酰胺的合成
冰浴下，将2-(苯胺基)吡啶-4-羧酸(0.060g,0.27mmol)，六氟磷酸苯并三唑-1-基-氧基三吡咯烷基磷(0.14g,0.27mmol)和N，N-二异丙基乙胺(0.12g,1.0mmol)溶于N,N-二甲基甲酰胺6mL中，搅拌0.5h后加入(六氢吡咯[3,4-c]吡咯-2(1H)-基)(3-(咪唑并[1,2-a]吡啶-2-基)苯基)甲酮(0.092g,0.27mmol)，继续搅拌0.5小时后回复至室温反应过夜。反应液倒入20mL水中，并用乙酸乙酯(20mL x 3)萃取，饱和食盐水洗涤，合并有机相，无水硫酸钠干燥，减圧浓缩硅胶柱层析(DCM:MeOH＝20:1)得到类白色固体(16mg,30μmol)，收率11.2％。LC-MS m/z:(M+H)+＝529。
1H NMR(400MHz,Chloroform-d)δ8.09(td,J＝20.1,18.0,6.8Hz,3H),7.89(d,J＝14.3Hz,1H),7.54(dt,J＝53.5,7.3Hz,4H),7.36(d,J＝4.4Hz,2H),7.32–7.05(m,5H),6.99–6.85(m,2H),6.83–6.75(m,1H),4.09–3.50(m,8H),3.06–2.85(m,2H).
实施例52 N-(3-(6-(1H-苯并[d]咪唑-2-基)吡啶啉基)-3-氮杂双环[3.1.0]己基-6-基)-6-(吡啶-2-基氨基)吡啶啉酰胺(L-52)
Figure PCTCN2021119377-appb-000295
一、6-(吡啶-2-基氨基)吡啶甲酸甲酯
将6-溴吡啶-2-甲酸甲酯(2g,9.26mmol)溶于50ml二氧六环中,加入2-氨基吡啶(871mg,9.26mmol)，三(二亚苄基丙酮)二钯(424mg,0.46mmol),4,5-双二苯基膦-9,9-二甲基氧杂蒽(536mg,0.92mmol)和碳酸铯(7.54g,23.1mmol)，反应液在95℃氮气保护下搅拌15小时。反应液冷却至室温，过滤、浓缩得到黄色固体。将固体溶于15ml四氢呋喃、10ml甲醇和15ml水中,加入氢氧化钠(0.94g,24mmol)，反应液在20℃搅拌15小时。反应液用乙酸乙酯萃取三次(20ml*3)。将水相用2N盐酸酸化至pH＝1，水相用乙酸乙酯萃取三次(20ml*3)，再用饱和碳酸氢钠水溶液中和至pH＝1，水相浓缩得到固体，将固体加入50mLN,N-二甲基甲酰胺中，20℃搅拌2小时，过滤浓缩得到白色固体460mg，收率为23.0％。LC-MS:m/z:(M+H)+＝216.0。
二、N-(3-(6-(1H-苯并[d]咪唑-2-基)吡啶啉基)-3-氮杂双环[3.1.0]己基-6-基)-2-(吡啶-2-基氨基)异烟酰胺
操作同L-51
LC-MS:m/z:(M+H)+＝517.0,1H NMR(400MHz,CD3OD)δ8.45(dd,J＝7.5,1.4Hz,1H),8.27–8.11(m,3H),7.92–7.56(m,6H),7.36(dd,J＝6.1,3.1Hz,2H),7.24(d,J＝7.0Hz,1H),7.02–6.88(m,1H),4.25(dd,J＝21.8,12.0Hz,2H),3.99(dd,J＝11.6,4.4Hz,1H),3.76(dd,J＝12.4,4.5Hz,1H),2.74(t,J＝2.2Hz,1H),2.17–2.06(m,2H).
实施例53(5-(6-(1H-苯并[d]咪唑-2-基)吡啶啉基)六氢吡咯并[3,4-c]吡咯-2(1H)-基)(2-(吡啶-2-基氨基)吡啶-4-基)甲酮(L-53)
Figure PCTCN2021119377-appb-000296
(5-(6-(1H-苯并[d]咪唑-2-基)吡啶啉基)六氢吡咯并[3,4-c]吡咯-2(1H)-基)(2-(吡啶-2-基氨基)吡啶-4-基)甲酮
操作同L-14
LC-MS:m/z:(M+H)+＝531.0,1H NMR(400MHz,CD3OD)δ8.46–8.35(m,1H),8.27–8.08(m,2H),7.99–6.66(m,11H),4.31–3.53(m,8H),3.13(dt,J＝13.3,7.1Hz,2H).
实施例54(5-(6-(咪唑并[1,2-a]吡啶-2-基]吡啶啉基)六氢吡咯并[3,4-c]吡咯-2(1H)-基)(2-(吡啶-2-基氨基)吡啶-4-基)甲酮(L-54)
Figure PCTCN2021119377-appb-000297
(5-(6-(咪唑并[1,2-a]吡啶-2-基]吡啶啉基)六氢吡咯并[3,4-c]吡咯-2(1H)-基)(2-(吡啶-2-基氨基)吡啶-4-基)甲酮
操作同L-14
LC-MS:m/z:(M+H)+＝531.0,1H NMR(400MHz,CD3OD)δ8.43(dd,J＝13.1,6.8Hz,1H),8.25(d,J＝32.8Hz,1H),8.09(d,J＝21.0Hz,2H),7.67–7.47(m,5H),7.40–7.28(m,2H),7.13(dt,J＝8.0,5.8Hz,2H),6.88(ddt,J＝35.3,14.7,7.3Hz,3H),4.11–3.41(m,8H),3.17–2.96(m,2H).
实施例55(5-(6-(1-(1H-苯并[d]咪唑-2-基]吡啶啉基)六氢吡咯并[3,4-c]吡咯-2 (1H)-基)(3-(咪唑并[1,2-a]吡啶-2-基)苯基)甲酮(L-55)
Figure PCTCN2021119377-appb-000298
操作同L-53
(5-(6-(1-(1H-苯并[d]咪唑-2-基]吡啶啉基)六氢吡咯并[3,4-c]吡咯-2(1H)-基)(3-(咪唑并[1,2-a]吡啶-2-基)苯基)甲酮
LC-MS:m/z:(M+H)+＝554.63, 1H NMR(400MHz,CDCl 3)δ12.67(s,1H),8.13–7.82(m,4H),7.54–7.33(m,4H),7.26(d,J＝7.6Hz,2H),4.54(d,J＝11.9Hz,3H),4.04(t,J＝15.9Hz,3H),1.85(s,1H),1.77(s,1H).
实施例56 6-(1h-苯并[d]咪唑-2-基)-n-(1-(3-(咪唑并[1,2-a]吡啶-2-基)苯甲酰基)哌啶-4-基)吡啶酰胺(L-56)
Figure PCTCN2021119377-appb-000299
将6-(1h-苯并[d]咪唑-2-基)吡啶甲酸2(15mg,0.063mmol)溶于N,N-二甲基甲酰胺(5ml)中,加入1H-苯并三唑-1-基氧三吡咯烷基六氟磷酸盐(65mg,0.13mmol)和N,N-二异丙基乙胺(0.02ml)，共同室温搅拌15分钟。再将(4-氨基哌啶-1-基)(3-(咪唑并[1,2-a]吡啶-2-基)苯基)甲酮1(20mg,0.063mmol)加入反应液，反应液在室温条件下搅拌16小时。反应液浓缩，得到的固体用薄层层析板分离两次(二氯甲烷:甲醇＝10:1)得到白色固体8mg,收率24％。
LC-MS m/z:(M+H)+＝542.0，1H NMR(400MHz,Chloroform-d)δ8.68(dd,J＝7.9,1.1Hz,1H),8.40(d,J＝6.8Hz,1H),8.31(dd,J＝7.7,1.1Hz,1H),8.24(s,2H),8.01(t,J＝7.8Hz,1H),7.93(d,J＝7.8Hz,1H),7.82(d,J＝9.0Hz,1H),7.45(t,J＝7.7Hz,1H),7.39–7.31(m,2H),7.21(s,2H),7.03(t,J＝6.7Hz,1H),4.59(s,1H),4.18(s,1H),3.55(s,1H),2.93–2.55(m,3H).
实施例57(4-(1h-苯并[d]咪唑-2-基)哌啶-1-基)(6-(1h-苯并[d]咪唑-2-基)吡啶-2-基)甲酮(L-57)
Figure PCTCN2021119377-appb-000300
化合物1到2的同实例42中脱Boc保护的操作，化合物2到L-57操作同L-56
(4-(1h-苯并[d]咪唑-2-基)哌啶-1-基)(6-(1h-苯并[d]咪唑-2-基)吡啶-2-基)甲酮
LC-MS m/z:(M+H)+＝422.9，1H NMR(400MHz,Methanol-d4)δ8.43(dd,J＝8.0,1.0Hz,1H),8.16(t,J＝7.9Hz,1H),7.72(d,J＝1.1Hz,1H),7.71–7.67(m,2H),7.60–7.53(m,2H),7.34(dd,J＝6.1,3.1Hz,2H),7.27(dd,J＝6.1,3.1Hz,2H),3.96(d,J＝13.7Hz,1H),3.53–3.38(m,2H),3.21(dd,J＝12.8,2.8Hz,1H),2.33(d,J＝12.9Hz,1H),2.26–2.02(m,4H).
实施例58(2,9-二氮杂螺[5.5]十一烷-2,9-二基)双(6-(1h-苯并[d]咪唑-2-基)吡啶-2-基)甲酮(L-58)
Figure PCTCN2021119377-appb-000301
操作同L-43
2,9-二氮杂螺[5.5]十一烷-2-甲酸叔丁酯2购于毕得医药
(2,9-二氮杂螺[5.5]十一烷-2,9-二基)双(6-(1h-苯并[d]咪唑-2-基)吡啶-2-基)甲酮
LC-MS m/z:(M+H)+＝597.1，1H NMR(400MHz,Methanol-d4)δ8.44–8.36(m,2H),8.21–8.14(m,1H),8.12–8.06(m,1H),7.78(q,J＝7.7Hz,1H),7.71–7.68(m,2H),7.64–7.60(m,2H),7.32(dt,J＝6.6,3.1Hz,4H),7.29–7.25(m,1H),4.23–4.11(m,1H),3.95(dd,J＝12.2,6.4Hz,1H),3.83(d,J＝21.5Hz,1H),3.74(dt,J＝13.3,6.7Hz,3H),3.68–3.58(m,2H),3.47(s,2H),1.92–1.83(m,1H),1.80(d,J＝11.9Hz,2H),1.66–1.57(m,2H),1.54(d,J＝4.5Hz,1H).
实施例59(2,8-二氮杂[4.5]癸烷-2,8-二基)双(6-(1h-苯并[d]咪唑-2-基)吡啶-2-基) 甲酮(L-59)
Figure PCTCN2021119377-appb-000302
操作同L-43
2,9-二氮杂螺[5.5]十一烷-2-甲酸叔丁酯2购于毕得医药
(2,8-二氮杂[4.5]癸烷-2,8-二基)双(6-(1h-苯并[d]咪唑-2-基)吡啶-2-基)甲酮
LC-MS m/z:(M+H)+＝583.1，1H NMR(400MHz,Methanol-d4)δ8.45–8.39(m,2H),8.35(dd,J＝7.9,1.1Hz,1H),8.17–8.09(m,2H),8.06(td,J＝8.0,2.6Hz,1H),7.82(ddd,J＝12.1,7.8,1.0Hz,2H),7.70(d,J＝1.1Hz,1H),7.58(dd,J＝7.7,1.0Hz,1H),7.35–7.31(m,3H),7.28(dd,J＝6.1,3.1Hz,1H),3.97(dd,J＝15.2,7.7Hz,2H),3.80(dd,J＝12.5,5.2Hz,3H),3.66–3.58(m,2H),2.08–1.97(m,3H),1.91(dd,J＝7.6,4.9Hz,1H),1.79(t,J＝6.1Hz,2H),1.69(d,J＝5.1Hz,1H).
实施例60(7-(6-(1h-苯并[d]咪唑-2-基)烟酰基)-2,7-二氮螺[4.4]壬烷-2-基)(6-(1h-苯并[d]咪唑-2-基)吡啶-2-基)甲酮(L-60)
Figure PCTCN2021119377-appb-000303
操作同L-43
2,9-二氮杂螺[5.5]十一烷-2-甲酸叔丁酯2购于毕得医药
(7-(6-(1h-苯并[d]咪唑-2-基)烟酰基)-2,7-二氮螺[4.4]壬烷-2-基)(6-(1h-苯并[d]咪唑-2-基)吡啶-2-基)甲酮
LC-MS m/z:(M+H)+＝569.1，1H NMR(400MHz,Methanol-d4)δ8.44(dt,J＝8.0,1.1 Hz,1H),8.37(ddd,J＝17.3,7.9,1.0Hz,1H),8.16(t,J＝7.8Hz,1H),8.06(dt,J＝10.2,7.9Hz,1H),7.88(ddd,J＝10.2,7.8,1.0Hz,1H),7.80–7.72(m,2H),7.66(s,2H),7.50(s,1H),7.34(d,J＝6.0Hz,1H),7.30(dq,J＝5.6,3.0,2.3Hz,3H),4.20–3.97(m,2H),3.89(dd,J＝13.2,6.2Hz,2H),3.85–3.76(m,2H),3.78–3.64(m,2H),2.30–2.15(m,2H),2.07(dt,J＝13.7,7.1Hz,2H).
实施例49 BT-11
Figure PCTCN2021119377-appb-000304
BT-11参考CN107108573A中的实施例2制备所得。
实施例61(8-(6-(1H-苯并[d]咪唑-2-基)吡啶酰基)-2,8-二氮螺环[4.5]癸-2-基)(6-(苯胺基)吡啶-2-基)甲酮(化合物L-61)
Figure PCTCN2021119377-appb-000305
操作同实施例82中化合物L-82的制备。
LC-MS m/z:(M+H)+＝558.1。
1H NMR(400MHz,Methanol-d4)δ8.40(ddd,J＝11.2,8.0,1.0Hz,1H),8.13(dt,J＝13.7,7.8Hz,1H),7.76–7.62(m,3H),7.60(dd,J＝7.7,1.0Hz,1H),7.58–7.50(m,2H),7.39–7.28(m,2H),7.22(dtd,J＝16.2,7.3,1.9Hz,2H),7.08(ddd,J＝7.0,6.1,0.9Hz,1H),6.97–6.81(m,2H),4.10–3.91(m,1H),3.95–3.78(m,2H),3.73(dt,J＝13.3,8.0Hz,2H),3.64–3.54(m,2H),3.44(dt,J＝11.3,5.5Hz,1H),2.03–1.91(m,2H),1.75(td,J＝12.5,12.1,5.9Hz,2H),1.62(t,J＝5.9Hz,2H).
实施例62(8-(6-(1H-苯并[d]咪唑-2-基)吡啶酰基)-2,8-二氮螺环[4.5]癸-2-基)(2-(苯胺基)嘧啶-4-基)甲酮(化合物L-62)
Figure PCTCN2021119377-appb-000306
操作同实施例82中化合物L-82的制备。
LC-MS m/z:(M+H)+＝559.1。
1H NMR(400MHz,Methanol-d4)δ8.61–8.56(m,1H),8.40(ddd,J＝9.1,7.9,1.0Hz,1H),8.14(dt,J＝10.8,7.9Hz,1H),7.74–7.67(m,2H),7.66(d,J＝1.1Hz,1H),7.65–7.61(m,2H),7.34(tt,J＝7.0,2.8Hz,2H),7.31–7.23(m,2H),7.05–7.02(m,1H),7.01–6.94(m,1H),3.85(dq,J＝10.6,6.2,5.1Hz,2H),3.76–3.70(m,2H),3.61–3.55(m,1H),3.48(d,J＝5.9Hz,1H),2.04–1.96(m,2H),1.76(s,2H),1.67–1.60(m,2H).
实施例63(9-(6-(1H-苯并[d]咪唑-2-基)吡啶酰基)-2,9-二氮螺环[5.5]十一烷-2-基)(6-(苯胺基)吡啶-2-基)甲酮(化合物L-63)
Figure PCTCN2021119377-appb-000307
操作同实施例82中化合物L-82的制备。
LC-MS m/z:(M+H)+＝587.7。
1H NMR(400MHz,Chloroform-d)δ8.68(s,1H),8.56(d,J＝8.0Hz,1H),7.98(t,J＝7.8Hz,1H),7.80–7.74(m,2H),7.48–7.40(m,1H),7.31(dd,J＝6.1,3.2Hz,2H),7.28–7.20(m,1H),7.13(dt,J＝7.4,4.5Hz,2H),4.04–3.81(m,2H),3.86–3.72(m,2H),3.74–3.48(m,4H),3.01(s,2H),2.36(s,3H).
实施例64(9-(6-(1H-苯并[d]咪唑-2-基)吡啶酰基)-2,9-二氮螺环[5.5]十一烷-2-基)(2-(苯胺基)嘧啶-4-基)甲酮(化合物L-64)
Figure PCTCN2021119377-appb-000308
操作同实施例82中化合物L-82的制备。
LC-MS m/z:(M+H)+＝572.9。
1H NMR(400MHz,Methanol-d4)δ8.58(d,J＝4.9Hz,1H),8.43–8.36(m,1.5H),8.26(d,J＝4.9Hz,0.5H),8.12(td,J＝7.9,1.4Hz,1.5H),7.72–7.68(m,2H),7.64(dd,J＝7.8,1.0Hz,2H),7.58–7.54(m,1.5H),7.33(tq,J＝7.5,2.6Hz,5H),7.19(dd,J＝8.6,7.3Hz,1H),7.04(tt,J＝7.4,1.2Hz,1H),6.91(d,J＝4.9Hz,1H),6.55(d,J＝4.9Hz,0.5H),4.10(dt,J＝13.8,4.9Hz,1H),3.88–3.74(m,3H),3.64(tdd,J＝13.8,9.6,3.8Hz,4H),3.47(d,J＝5.3Hz,2H), 3.42(d,J＝1.7Hz,1H),1.80(d,J＝16.3Hz,2H),1.64(dd,J＝9.7,4.8Hz,3H).
实施例65(7-(6-(1H-苯并[d]咪唑-2-基)吡啶酰基)-2,7-二氮螺环[4.4]壬-2-基)(6-(苯胺基)吡啶-2-基)甲酮(化合物L-65)
Figure PCTCN2021119377-appb-000309
操作同实施例82中化合物L-82的制备。
LC-MS m/z:(M+H)+＝554.1。
1H NMR(400MHz,Methanol-d4)δ8.49–8.42(m,1H),8.38(d,J＝7.5Hz,1H),8.32(s,1H),8.21–8.18(m,1H),8.17–8.05(m,2H),7.86(ddd,J＝7.8,5.4,1.1Hz,1H),7.71(dt,J＝7.1,3.5Hz,1H),7.61–7.55(m,2H),7.52–7.48(m,1H),7.40–7.27(m,2H),7.22(dt,J＝6.2,3.6Hz,1H),6.95(dtd,J＝11.7,6.8,1.2Hz,1H),4.18–3.59(m,8H),3.24–3.04(m,2H).
实施例66(7-(6-(1H-苯并[d]咪唑-2-基)吡啶酰基)-2,7-二氮螺环[4.4]壬-2-基)(4-(苯胺基)嘧啶-2-基)甲酮(化合物L-66)
Figure PCTCN2021119377-appb-000310
操作同实施例82中化合物L-82的制备。
LC-MS m/z:(M+H)+＝544.9。
1H NMR(400MHz,Chloroform-d)δ8.62–8.57(m,1H),8.57–8.53(m,1H),8.01–7.91(m,1H),7.82–7.77(m,1H),7.75-7.68(s,1H),7.71(s,1H),7.68–7.61(m,2H),7.47(ddd,J＝8.5,3.6,1.2Hz,1H),7.36–7.30(m,2H),7.27–7.22(m,1H),7.12–7.08(m,1H),7.05–6.96(m,1H),3.96–3.68(m,6H),3.69–3.53(m,2H),2.02–1.88(m,4H).
实施例67 N-(3-(6-(1H-苯并[d]咪唑-2-基)吡啶酰基)-3-氮杂双环[3.1.0]己-6-基)-6-甲基-1H-吲哚-2-甲酰胺(化合物L-67)
Figure PCTCN2021119377-appb-000311
操作同实施例82中化合物L-82的制备。
LC-MS m/z:(M+H)+＝476.9。
1H NMR(400MHz,DMSO-d6)δ13.20(s,1H),11.43(d,J＝2.1Hz,1H),9.33(d,J＝3.1Hz,1H),8.46(dd,J＝7.7,1.2Hz,1H),8.18(t,J＝7.7Hz,1H),8.11(dd,J＝7.7,1.2Hz,1H),7.77(dd,J＝7.9,1.1Hz,1H),7.73–7.64(m,1H),7.55(d,J＝8.2Hz,1H),7.35(ddd,J＝8.2,7.2,1.2Hz,1H),7.28(ddd,J＝8.3,7.2,1.3Hz,1H),7.25(dd,J＝1.6,0.8Hz,1H),6.96(dd,J＝2.3,0.9Hz,1H),6.90(dd,J＝8.2,1.5Hz,1H),4.17(s,3H),3.74(s,1H),2.62(q,J＝2.7Hz,1H),2.41(s,3H),2.21(s,1H),2.09(s,1H).
实施例68 N-(3-(6-(1H-苯并[d]咪唑-2-基)吡啶酰基)-3-氮杂双环[3.1.0]己-6-基)喹啉-2-甲酰胺(化合物L-68)
Figure PCTCN2021119377-appb-000312
操作同实施例82中化合物L-82的制备。
LC-MS m/z:(M+H)+＝476.1。
1H NMR(400MHz,DMSO)δ13.18(s,1H),9.31(s,1H),8.50(dd,J＝28.7,8.2Hz,1H),8.32–8.01(m,2H),7.98–7.81(m,1H),7.82–7.66(m,2H),7.40–7.22(m,2H),4.16(d,J＝12.5Hz,1H),3.77(d,J＝12.2Hz,1H),3.62(s,1H),3.18(d,J＝5.2Hz,1H),2.10(s,1H).
实施例69(5-(6-(1H-苯并[d]咪唑-2-基)吡啶酰基)六氢吡咯[3,4-c]吡咯-2(1H)-基)(喹啉-2-基)甲酮(化合物L-69)
Figure PCTCN2021119377-appb-000313
将(6-(1H-苯并[d]咪唑-2-基)吡啶-2-基)(六氢吡咯[3,4-c]吡咯-2(1H)-基)甲酮(33mg，0.1mmol)和喹啉-2-羧酸(17mg，0.1mmol)悬浮于N,N-二甲基甲酰胺(3mL)中，加入N,N-二异丙基乙胺(26mg,0.2mmol)和1-丙基磷酸酐(41mg,0.13mmol)。反应液在25℃下搅拌16h。反应液浓缩得到粗产物，将所得粗产品通过薄层层析板纯化(二氯甲烷∶甲醇＝15∶1)，得到淡黄色固体(15mg，31％)。LC-MS:m/z:(M+H) +＝488.9； 1H NMR(400MHz,DMSO-d6)δ12.93(d,J＝6.3Hz,1H),8.61–8.34(m,2H),8.14–8.03(m,3H),7.96–7.53(m,6H),7.38–7.17(m,2H),4.21–3.56(m,8H),3.06(s,2H).
实施例70(5-(6-(1H-苯并[d]咪唑-2-基)吡啶酰基)六氢吡咯[3,4-c]吡咯-2(1H) -基)(6-甲基-1H-吲哚-2-基)甲酮(化合物L-70)
Figure PCTCN2021119377-appb-000314
操作同实施例82中化合物L-82的制备。
LC-MS:m/z:(M+H)+＝491.1； 1H NMR(400MHz,DMSO-d 6)δ12.91(s,1H),11.42(s,1H),8.42(d,J＝7.9Hz,1H),8.13(t,J＝7.8Hz,1H),7.77(dd,J＝27.7,7.7Hz,2H),7.59(d,J＝7.4Hz,1H),7.54–7.38(m,1H),7.35–7.15(m,3H),6.92(t,J＝20.7Hz,2H),4.20–3.56(m,8H),3.09(d,J＝40.8Hz,2H),2.40(s,3H).
实施例71(5-(6-(1H-苯并[d]咪唑-2-基)吡啶酰基)六氢吡咯[3,4-c]吡咯-2(1H)-基)(2-甲基-1H-吲哚-3-基)甲酮(化合物L-71)
Figure PCTCN2021119377-appb-000315
操作同实施例82中化合物L-82的制备。
LC-MS m/z:(M+H)+＝491.1。
1H NMR(400MHz,CDCl3)δ8.68(s,1H),8.56(d,J＝7.7Hz,1H),7.98(t,J＝7.8Hz,1H),7.77(d,J＝7.4Hz,3H),7.51–7.40(m,1H),7.38–7.27(m,4H),7.18–7.06(m,2H),3.96–3.54(m,6H),3.01(s,2H),2.37(s,3H),2.03(d,J＝5.9Hz,1H),1.66(s,1H).
实施例72(9-(3-(咪唑并[1,2-a]吡啶-2-基)苯甲酰基)-3,9-二氮螺环[5.5]十一烷-3-基)(6-(苯胺基)吡啶-2-基)甲酮(化合物L-72)
Figure PCTCN2021119377-appb-000316
操作同实施例82中化合物L-82的制备。
LC-MS:m/z:(M+H) +＝433.2；1H NMR(400MHz,Methanol-d4)δ8.46(d,J＝6.8Hz, 1H),8.31(s,1H),8.06(d,J＝7.8Hz,1H),8.00(s,1H),7.66–7.54(m,5H),7.45–7.33(m,2H),7.27(t,J＝7.9Hz,2H),6.96(td,J＝6.8,4.4Hz,2H),6.88(t,J＝7.2Hz,2H),3.79(d,J＝16.7Hz,4H),3.54(s,5H),1.73(s,3H),1.63(s,5H).
实施例73(3,9-二氮螺环[5.5]十一烷-3,9-二基)双((3-(咪唑并[1,2-a]吡啶-2-基)苯基)甲酮)(化合物L-73)
Figure PCTCN2021119377-appb-000317
操作同实施例82中化合物L-82的制备。
LC-MS:m/z:(M+H) +/2＝298.2；1H NMR(400MHz,Methanol-d4)δ8.45(d,J＝6.8Hz,2H),8.30(s,2H),8.05(d,J＝7.9Hz,2H),8.00(d,J＝1.8Hz,2H),7.66–7.53(m,4H),7.46–7.31(m,4H),6.95(t,J＝6.8Hz,2H),3.83(s,4H),3.52(s,4H),1.69(d,J＝46.5Hz,9H).
实施例74(四氢吡咯[3,4-c]吡咯-2,5(1H，3H)-二基)双((3-(咪唑并[1,2-a]吡啶-2-基)苯基)甲酮)(化合物L-74)
Figure PCTCN2021119377-appb-000318
操作同实施例82中化合物L-82的制备。
LC-MS:m/z:(M+H) +＝553.2；1H NMR(400MHz,Methanol-d4)δ8.43(dd,J＝24.7,6.9Hz,2H),8.36–8.22(m,2H),8.10(dd,J＝29.2,20.1Hz,4H),7.57(dd,J＝25.5,8.6Hz,6H),7.34(dt,J＝17.0,8.2Hz,2H),6.94(dt,J＝13.9,6.8Hz,2H),4.05–3.50(m,9H),3.24–3.01(m,2H).
实施例75(4-(2-羟乙基)哌嗪-1-基)(3-(咪唑并[1,2-a]吡啶-2-基)苯基)甲酮(化合物L-75)
Figure PCTCN2021119377-appb-000319
操作同实施例82中化合物L-82的制备。
LC-MS:m/z:(M+H) +＝351.2；1H NMR(400MHz,Methanol-d4)δ8.46(dt,J＝6.9,1.2Hz,1H),8.30(s,1H),8.06(dt,J＝7.9,1.4Hz,1H),8.00(d,J＝1.7Hz,1H),7.64–7.54(m,2H),7.45–7.33(m,2H),6.96(td,J＝6.8,1.2Hz,1H),3.85(s,2H),3.72(t,J＝5.8Hz,2H),3.56(s,2H),2.75–2.51(m,6H).
实施例76(6-(1H-苯并[d]咪唑-2-基)吡啶-2-基)(4-(2-羟乙基)哌嗪-1-基)甲酮(化合物L-76)
Figure PCTCN2021119377-appb-000320
操作同实施例82中化合物L-82的制备。
LC-MS:m/z:(M+H) +＝352.2；1H NMR(400MHz,Methanol-d4)δ8.40(dd,J＝8.0,0.9Hz,1H),8.14(t,J＝7.9Hz,1H),7.75(s,1H),7.68(dd,J＝7.8,1.0Hz,1H),7.63(d,J＝7.2Hz,1H),7.33(d,J＝6.0Hz,2H),3.89(t,J＝5.2Hz,2H),3.72(t,J＝5.8Hz,2H),3.62(t,J＝5.1Hz,2H),2.71(t,J＝5.2Hz,2H),2.60(dt,J＝12.0,5.5Hz,4H).
实施例77 6-(1H-苯并[d]咪唑-2-基)-N-(3-(3-(苯并[d]噻唑-2-基)苯甲酰基)-3-氮杂双环[3.1.0]己烷-6-基)吡啶酰胺(化合物L-77)
Figure PCTCN2021119377-appb-000321
一、3-(苯并[d]噻唑-2-基)苯甲酸甲酯
2-溴-1,3-苯并噻唑(1.07g，5.0mmol)，(3-甲氧羰基苯基)硼酸(0.9g，5.0mmol)，K 2CO 3(1.38g，10.0mmol)和[1,1'-双(二苯基膦基)二茂铁]二氯化钯(0.1g，0.5mmol)在二恶烷(50mL)和水(10mL)中的溶液，在80℃搅拌4小时。将反应浓缩至干燥，并通过快速色谱法(二氧化硅)(石油醚:乙酸乙酯＝3:1)纯化，得到白色固体3-(1,3-苯 并噻唑-2-基)苯甲酸甲酯(1.0g，74.3％)。
二、3-(苯并[d]噻唑-2-基)苯甲酸
将3-(1,3-苯并噻唑-2-基)苯甲酸甲酯(54mg，0.2mmol)存于MeOH(5mL)和水(1mL)中，添加LiOH(24mg，1.0mmol)，反应液在80℃下搅拌1h。将反应浓缩至干燥得到粗品，并直接用于下一反应。
三、6-(1H-苯并[d]咪唑-2-基)-N-(3-(3-(苯并[d]噻唑-2-基)苯甲酰基)-3-氮杂双环[3.1.0]己烷-6-基)吡啶酰胺
操作同实施例82中化合物L-82的制备。
LC-MS:m/z:(M+H) +＝557.2；1H NMR(400MHz,DMSO-d6)δ13.18(s,1H),9.29(d,J＝3.1Hz,1H),8.46(dd,J＝7.8,1.2Hz,1H),8.24–8.15(m,4H),8.13–8.08(m,2H),7.83–7.65(m,4H),7.59(td,J＝8.2,7.7,1.3Hz,1H),7.55–7.47(m,1H),7.31(s,2H),4.17(d,J＝12.1Hz,1H),4.00–3.85(m,1H),3.71–3.61(m,2H),2.07(s,2H).
实施例78(3,9-二氮杂螺[5.5]十一烷-3,9-二基)双((2-(苯氨基)嘧啶-4-基)甲酮)(化合物L-78)
Figure PCTCN2021119377-appb-000322
一、9-(2-(2-(苯基氨基)嘧啶-4-羰基)-3,9-二氮杂螺[5.5]十一烷-3-羧酸叔丁酯
将3,9-二氮杂螺[5.5]十一烷-3-羧酸叔丁酯(100mg，0.39mmol)(如式2所示的化合物)和2-苯胺基嘧啶-4-羧酸(85mg，0.39mmol)(如式1所示的化合物)悬浮于3ml N,N-二甲基甲酰胺中，加入N,N-二异丙基乙胺(101mg,0.78mmol)和2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(179mg,0.47mmol)。反应液在30℃下搅拌16h。向反应液中加入10ml冰水，搅拌五分钟，过滤，固体干燥得到粗产物为175mg的棕色固体,收率为98.58％。LC-MS:m/z:(M+H)+＝452.0。
二、(2-(苯氨基)嘧啶-4-基)(3,9-二氮杂螺[5.5]十一烷-3-基)甲酮
将9-(2-(2-(苯基氨基)嘧啶-4-羰基)-3,9-二氮杂螺[5.5]十一烷-3-羧酸叔丁酯(175mg，0.39mmol)(如式3所示的化合物)溶于3ml甲醇中，加入盐酸二氧六环溶液(3mL,4M,12mmol)。反应液在15℃下搅拌2h。反应液浓缩,干燥得到粗产物为136mg的棕色 固体,收率为99.87％。LC-MS:m/z:(M+H)+＝352.0。
三、(3,9-二氮杂螺[5.5]十一烷-3,9-二基)双((2-(苯氨基)嘧啶-4-基)甲酮)
操作同实施例82中化合物L-82的制备。
LC-MS:m/z:(M+H)+＝549.0,1H NMR(400MHz,CD 3OD)δ8.55(d,J＝4.9Hz,2H),7.67(dd,J＝8.6,1.0Hz,4H),7.36–7.26(m,4H),7.03(t,J＝7.4Hz,2H),6.87(d,J＝4.9Hz,2H),3.77(dd,J＝11.7,5.6Hz,4H),3.50(dd,J＝11.1,5.3Hz,4H),1.77–1.57(m,8H).
实施例79 2-(苯基氨基)-N-(1-(2-(2-(苯基氨基)嘧啶-4-羰基)哌啶-4-基)嘧啶-4-羧酰胺(化合物L-79)
Figure PCTCN2021119377-appb-000323
一、(1-(2-(苯氨基)嘧啶-4-羰基)哌啶-4-基)氨基甲酸叔丁酯
将叔丁基哌啶-4-基氨基甲酸酯(100mg，0.50mmol)(如式2所示的化合物)和2-苯胺基嘧啶-4-羧酸(107mg，0.50mmol)(如式1所示的化合物)悬浮于3ml N,N-二甲基甲酰胺中，加入N,N-二异丙基乙胺(129mg,1.0mmol)和2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(228mg,0.60mmol)。反应液在30℃下搅拌16h。向反应液中加入10ml冰水，搅拌五分钟，过滤，固体干燥得到粗产物为185mg的棕色固体,收率为93.21％。LC-MS:m/z:(M+H)+＝498.0。
二、(4-氨基哌啶-1-基)(2-(苯基氨基)嘧啶-4-基)甲酮
将(1-(2-(苯氨基)嘧啶-4-羰基)哌啶-4-基)氨基甲酸叔丁酯(185mg，0.47mmol)(如式3所示的化合物)溶于3ml甲醇中，加入盐酸二氧六环溶液(3mL,4M,12mmol)。反应液在15℃下搅拌2h。反应液浓缩,干燥得到粗产物为138mg的棕色固体,收率为99.70％。LC-MS:m/z:(M+H)+＝298.0。
三、2-(苯基氨基)-N-(1-(2-(2-(苯基氨基)嘧啶-4-羰基)哌啶-4-基)嘧啶-4-羧酰胺
操作同实施例82中化合物L-82的制备。
LC-MS:m/z:(M+H)+＝495.0,1H NMR(400MHz,CD 3OD)δ8.66(d,J＝4.9Hz,1H),8.57(d,J＝4.9Hz,1H),7.74–7.60(m,4H),7.41–7.24(m,5H),7.04(dt,J＝20.0,7.4Hz,2H),6.91(d,J＝4.9Hz,1H),4.56(d,J＝14.7Hz,1H),4.26–4.15(m,1H),3.98–3.89(m,1H),3.41 –3.34(m,1H),3.23–3.13(m,1H),2.19–2.08(m,1H),2.02(dd,J＝9.1,4.0Hz,1H),1.79–1.63(m,2H).
实施例80(9-(6-(苯基氨基)吡啶啉基)-3,9-二氮杂螺[5.5]十一烷-3-基)(2-(苯基氨基)嘧啶-4-基)甲酮(化合物L-80)
Figure PCTCN2021119377-appb-000324
操作同实施例82中化合物L-82的制备。
LC-MS:m/z:(M+H)+＝548.0,1H NMR(400MHz,CD3OD)δ(d,J＝4.9Hz,1H),7.64(ddd,J＝11.8,9.4,6.1Hz,5H),7.29(dt,J＝12.4,7.9Hz,4H),6.99(dt,J＝26.9,7.4Hz,2H),6.88(dd,J＝9.5,5.7Hz,3H),3.77(dt,J＝11.6,5.7Hz,4H),3.61–3.44(m,4H),1.83–1.50(m,8H).
实施例81 6-(苯氨基)-N-(1-(2-(苯氨基)嘧啶-4-羰基)哌啶-4-基)吡啶啉酰胺(化合物L-81)
Figure PCTCN2021119377-appb-000325
操作同实施例82中化合物L-82的制备。
LC-MS:m/z:(M+H)+＝494.0,1H NMR(400MHz,CD3OD)δ8.57(d,J＝4.9Hz,1H),7.69(dd,J＝16.7,8.2Hz,3H),7.49(dd,J＝18.9,7.5Hz,3H),7.31(dt,J＝24.3,7.9Hz,4H),7.07–6.96(m,3H),6.91(d,J＝4.9Hz,1H),4.46(d,J＝13.3Hz,1H),4.19(ddd,J＝14.0,9.9,4.0Hz,1H),3.86(d,J＝13.4Hz,1H),3.43–3.36(m,1H),3.27(dd,J＝13.6,3.0Hz,1H),2.23–2.11(m,1H),2.09–1.97(m,1H),1.76–1.60(m,2H).
实施例82(5-(6-(1H-苯并[d]咪唑-2-基)吡啶啉基)六氢吡咯并[3,4-c]吡咯-2(1H)-基)(2-(((4-氟苯基)氨基)嘧啶-4-基)甲酮(化合物L-82)
Figure PCTCN2021119377-appb-000326
一、2-((4-氟苯基)氨基)嘧啶-4-羧酸
将2-氯嘧啶-4-羧酸(500mg,3.15mmol)溶于15ml二氧六环中,加入对氟苯胺(881mg,9.46mmol)，反应液在70℃搅拌18小时。反应液冷却至室温，加入20ml水和10ml 1N氢氧化钠，反应液用用乙酸乙酯萃取二次(20ml*2)。将水相用1N盐酸酸化至pH＝3，固体过滤干燥得到白色固体500mg，收率为67.98％。LC-MS:m/z:(M+H)+＝234.0。
二、(5-(6-(1H-苯并[d]咪唑-2-基)吡啶啉基)六氢吡咯并[3,4-c]吡咯-2(1H)-基)(2-(((4-氟苯基)氨基)嘧啶-4-基)甲酮
将2,3,3a，4,6,6a-六氢-1H-吡咯并[3,4-c]吡咯-5-基-[6-(1H-苯并咪唑-2-基)-2-吡啶基(40mg，0.12mmol)(如式4所示的化合物)和2-((4-氟苯基)氨基)嘧啶-4-羧酸(28mg，0.12mmol)(如式3所示的化合物)悬浮于5ml N,N-二甲基甲酰胺中，加入N,N-二异丙基乙胺(62mg,0.48mmol)和1-丙基磷酸酐(115mg,0.18mmol)。反应液在15℃下搅拌16h。反应液浓缩得到粗产物，将所得粗产品通过薄层层析板纯化(二氯甲烷∶甲醇＝10∶1)，得到所需产物20mg的白色固体,收率为30.39％。
LC-MS:m/z:(M+H)+＝549.0,1H NMR(400MHz,CDCl3)δ8.48(ddd,J＝39.8,21.6,6.4Hz,2H),8.03–7.54(m,6H),7.49–7.30(m,2H),7.26–6.93(m,3H),4.31–3.67(m,8H),3.12–2.91(m,2H).
实施例83(四氢吡咯并[3,4-c]吡咯-2,5(1H，3H)-二基)双((2-(苯基氨基)嘧啶-4-基)甲酮)(化合物L-83)
Figure PCTCN2021119377-appb-000327
一、5-(2-(苯氨基)嘧啶-4-羰基)六氢吡咯并[3,4-c]吡咯-2(1H)-羧酸叔丁酯
将2,3,3a，4,6,6a-六氢-1H-吡咯并[3,4-c]吡咯-5-羧酸叔丁酯(100mg，0.47mmol)(如式2所示的化合物)和2-苯胺基嘧啶-4-羧酸(101mg，0.47mmol)(如式1所示的化合物)悬浮于3ml N,N-二甲基甲酰胺中，加入N,N-二异丙基乙胺(122mg,0.94mmol)和1-丙基磷酸酐(449mg,0.71mmol)。反应液在15℃下搅拌16h。向反应液中加入10ml冰水，搅拌五分钟，过滤，固体干燥得到粗产物为180mg的棕色固体,收率为93.31％。LC-MS:m/z:(M+H)+＝410.0。
二、(六氢吡咯并[3,4-c]吡咯-2(1H)-基)(2-(苯氨基)嘧啶-4-基)甲酮
将5-(2-(苯氨基)嘧啶-4-羰基)六氢吡咯并[3,4-c]吡咯-2(1H)-羧酸叔丁酯(180mg，0.44mmol)(如式3所示的化合物)溶于于3ml甲醇中，加入盐酸二氧六环溶液(3mL,4M,12mmol)。反应液在15℃下搅拌2h。反应液浓缩，固体用乙酸乙酯(10mL)洗涤，干燥得到粗产物为120mg的棕色固体,收率为88.24％。LC-MS:m/z:(M+H)+＝310.0。
三、(四氢吡咯并[3,4-c]吡咯-2,5(1H，3H)-二基)双((2-(苯基氨基)嘧啶-4-基)甲酮)
操作同实施例82中化合物L-82的制备。
LC-MS:m/z:(M+H)+＝507.0,1H NMR(400MHz,CDCl3)δ8.56–8.42(m,2H),7.53(dd,J＝19.5,8.3Hz,4H),7.18(dt,J＝30.7,7.3Hz,4H),7.03–6.79(m,4H),3.93–3.46(m,8H),2.94(d,J＝7.4Hz,2H).
实施例84(2-(苯基氨基)-N-(3-(2-(2-(苯基氨基)嘧啶-4-羰基)-3-氮杂双环[3.1.0]己6-基)嘧啶-4-羧酰胺(化合物L-84)
Figure PCTCN2021119377-appb-000328
一、((1R，5S，6s)-6-(2-(苯基氨基)嘧啶-4-羧酰胺基)-3-氮杂双环[3.1.0]己烷-3-羧酸叔丁酯
将(1R，5S，6s)-6-氨基-3-氮杂双环[3.1.0]己烷-3-羧酸叔丁酯(100mg，0.50mmol)(如式2所示的化合物)和2-苯胺基嘧啶-4-羧酸(108mg，0.51mmol)(如式1所示的化合物)悬浮于3ml N,N-二甲基甲酰胺中，加入N,N-二异丙基乙胺(130mg,1.0mmol)和1-丙基磷酸酐(480mg,0.75mmol)。反应液在15℃下搅拌16h。向反应液中加入10ml冰水，搅拌五分钟，过滤，固体干燥得到粗产物为180mg的棕色固体,收率为90.28％。LC-MS:m/z:(M+H)+＝396.0。
二、N-((1R，5S，6s)-3-氮杂双环[3.1.0]己-6-基)-2-(苯氨基)嘧啶-4-羧酰胺
将((1R，5S，6s)-6-(2-(苯基氨基)嘧啶-4-羧酰胺基)-3-氮杂双环[3.1.0]己烷-3-羧酸叔丁酯(180mg，0.45mmol)(如式3所示的化合物)溶于于3ml甲醇中，加入盐酸二氧六环溶液(3mL,4M,12mmol)。反应液在15℃下搅拌2h。反应液浓缩，固体用乙酸 乙酯(10mL)洗涤，干燥得到粗产物为120mg的棕色固体,收率为89.27％。LC-MS:m/z:(M+H)+＝296.0。
三、(2-(苯基氨基)-N-(3-(2-(2-(苯基氨基)嘧啶-4-羰基)-3-氮杂双环[3.1.0]己6-基)嘧啶-4-羧酰胺
操作同实施例82中化合物L-82的制备。
LC-MS:m/z:(M+H)+＝493.0,1H NMR(400MHz,DMSO-d6)δ9.80(d,J＝28.2Hz,1H),8.70-8.62(m,2H),7.76-7.74(m,4H),7.32-7.25(m,4H),7.01-6.97(3,3H),4.04–3.96(m,1H),3.87(d,J＝11.3Hz,1H),3.79(dd,J＝11.4,3.9Hz,1H),3.59(dd,J＝12.3,4.0Hz,1H),2.66(d,J＝2.2Hz,1H),1.98(d,J＝5.9Hz,2H).
实施例85(2-(苯基氨基)嘧啶-4-基)(哌嗪-1-基)甲酮哌嗪-1,4-二基双((2-(苯基氨基)嘧啶-4-基)甲酮)(化合物L-85)
Figure PCTCN2021119377-appb-000329
一、4-(2-(苯氨基)嘧啶-4-羰基)哌嗪-1-甲酸叔丁酯
将1-叔丁氧羰基-哌嗪(100mg，0.54mmol)(如式2所示的化合物)和2-苯胺基嘧啶-4-羧酸(115m，0.54mmol)(如式1所示的化合物)悬浮于3ml N,N-二甲基甲酰胺中，加入N,N-二异丙基乙胺(139mg,1.07mmol)和2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(245mg,0.64mmol)。反应液在30℃下搅拌16h。向反应液中加入10ml冰水，搅拌五分钟，过滤，固体干燥得到粗产物为190mg的棕色固体,收率为92％。LC-MS:m/z:(M+H)+＝384.0。
二、((2-(苯氨基)嘧啶-4-基)(哌嗪-1-基)甲酮
将4-(2-(苯氨基)嘧啶-4-羰基)哌嗪-1-甲酸叔丁酯(190mg，0.49mmol)(如式3所示的化合物)溶于3ml甲醇中，加入盐酸二氧六环溶液(3mL,4M,12mmol)。反应液在15℃下搅拌2h。反应液浓缩,干燥得到粗产物为139mg的棕色固体,收率为99.01％。LC-MS:m/z:(M+H)+＝284.0。
三、(2-(苯基氨基)嘧啶-4-基)(哌嗪-1-基)甲酮哌嗪-1,4-二基双((2-(苯基氨基)嘧啶-4-基)甲酮)
操作同实施例82中化合物L-82的制备。
LC-MS:m/z:(M+H)+＝481.0,1H NMR(400MHz,DMSO-d6)δ9.84(d,J＝21.0Hz,2H),8.74–8.51(m,2H),7.71(dd,J＝20.8,7.4Hz,4H),7.50–7.21(m,4H),7.13–6.78(m,4H),3.62(dd,J＝76.7,37.7Hz,8H).
实施例86哌嗪-1,4-二基双((6-(苯氨基)吡啶-2-基)甲酮)(化合物L-86)
Figure PCTCN2021119377-appb-000330
一、4-(6-(苯基氨基)吡啶啉基)哌嗪-1-羧酸叔丁酯
将1-叔丁氧羰基-哌嗪(100mg，0.54mmol)(如式2所示的化合物)和6-(苯基氨基)吡啶甲酸(115mg，0.54mmol)(如式1所示的化合物)悬浮于3ml N,N-二甲基甲酰胺中，加入N,N-二异丙基乙胺(139mg,1.07mmol)和2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(245mg,0.64mmol)。反应液在30℃下搅拌16h。向反应液中加入10ml冰水，搅拌五分钟，过滤，固体干燥得到粗产物为190mg的棕色固体,收率为92％。LC-MS:m/z:(M+H)+＝383.0。
二、(6-(苯基氨基)吡啶-2-基)(哌嗪-1-基)甲酮
将4-(6-(苯基氨基)吡啶啉基)哌嗪-1-羧酸叔丁酯(190mg，0.49mmol)(如式3所示的化合物)溶于3ml甲醇中，加入盐酸二氧六环溶液(3mL,4M,12mmol)。反应液在15℃下搅拌2h。反应液浓缩,干燥得到粗产物为139mg的棕色固体,收率为99.12％。LC-MS:m/z:(M+H)+＝283.0。
三、哌嗪-1,4-二基双((6-(苯氨基)吡啶-2-基)甲酮)
操作同实施例82中化合物L-82的制备。
LC-MS:m/z:(M+H)+＝479.0,1H NMR(400MHz,DMSO-d6)δ9.21(d,J＝26.7Hz,2H),7.81–7.50(m,6H),7.26(dt,J＝44.9,7.5Hz,4H),7.03–6.70(m,6H),3.83–3.44(m,8H).
实施例87(2,6-二氮螺环[3.3]庚烷-2,6-二基)双((6-(1H-苯并[d]咪唑-2-基)吡啶-2-基)甲酮)(化合物L-87)
Figure PCTCN2021119377-appb-000331
操作同实施例82中化合物L-82的制备。
LC-MS m/z:(M+H)+＝542.2。
1H NMR(400MHz,DMSO-d6)δ8.45(dd,J＝7.9,1.1Hz,2H),8.16(t,J＝7.8Hz,2H),8.00(dd,J＝7.8,1.1Hz,2H),7.70(s,4H),7.28(d,J＝6.5Hz,4H),5.10(d,J＝10.7Hz,2H),5.01(d,J＝10.8Hz,2H),4.46–4.39(m,4H).
实施例88 3-(咪唑并[1,2-a]吡啶-2-基)-N-(1-(3-(咪唑并[1,2-a]吡啶-2-基)苯甲酰基)哌啶-4-基)苯甲酰胺(化合物L-88)
Figure PCTCN2021119377-appb-000332
操作同实施例82中化合物L-82的制备。
LC-MS m/z:(M+H)+＝542.2。
1H NMR(400MHz,Chloroform-d)δ8.53(s,1H),8.20(t,J＝7.8Hz,2H),8.03(dd,J＝12.9,7.2Hz,4H),7.97(s,1H),7.90(d,J＝7.7Hz,1H),7.74(d,J＝9.0Hz,1H),7.68(d,J＝9.1Hz,1H),7.51(q,J＝8.0Hz,2H),7.39(d,J＝7.6Hz,1H),7.35–7.30(m,1H),7.22(dd,J＝9.1,6.7Hz,1H),6.99(d,J＝7.8Hz,1H),6.92(t,J＝6.8Hz,1H),6.83(t,J＝6.7Hz,1H),4.74(d,J＝28.3Hz,1H),4.33(d,J＝10.0Hz,1H),3.89(s,1H),3.23(s,1H),3.05(s,1H),2.66(s,3H),2.23(t,J＝7.7Hz,1H).
实施例89 3-(咪唑并[1,2-a]吡啶-2-基)-N-((1R，5S，6s)-3-(咪唑并[1,2-a]吡啶-2-基)苯甲酰基)-3-氮杂双环[3.1.0]己-6-基)苯甲酰胺(化合物L-89)
Figure PCTCN2021119377-appb-000333
操作同实施例82中化合物L-82的制备。
LC-MS m/z:(M+H)+＝539.2。
1H NMR(400MHz,Chloroform-d)δ8.36(d,J＝1.8Hz,1H),8.14(ddd,J＝7.8,6.7,3.3Hz,2H),8.06–8.01(m,2H),8.02–7.98(m,2H),7.81(dt,J＝7.8,1.5Hz,1H),7.63(t,J＝9.2Hz,2H),7.47(t,J＝7.7Hz,2H),7.39(dt,J＝7.7,1.5Hz,1H),7.20(tdd,J＝9.3,7.4,1.3Hz,2H),7.06(d,J＝2.7Hz,1H),6.84–6.78(m,2H),4.32(d,J＝12.4Hz,1H),3.83–3.75(m,2H),3.64(dd,J＝12.4,4.3Hz,1H),2.70(q,J＝2.5Hz,1H),1.91(d,J＝29.8Hz,2H).
实施例90 3-(咪唑并[1,2-a]吡啶-2-基)-N-(((1R，5S，6s)-3-(6-(苯基氨基)吡啶啉基)-3-氮杂双环[3.1.0]己-6-基)苯甲酰胺(化合物L-90)
Figure PCTCN2021119377-appb-000334
操作同实施例82中化合物L-82的制备。
LC-MS m/z:(M+H)+＝515.2。
1H NMR(400MHz,Chloroform-d)δ8.42(s,1H),8.17(d,J＝6.8Hz,1H),8.01(d,J＝7.7Hz,1H),7.94(s,1H),7.85(d,J＝7.8Hz,1H),7.69(d,J＝9.1Hz,1H),7.58(t,J＝7.9Hz,1H),7.51(t,J＝7.8Hz,1H),7.37(s,2H),7.26(s,1H),7.20(d,J＝7.4Hz,1H),7.10(q,J＝5.1,4.3Hz,1H),6.90(dt,J＝15.0,7.7Hz,3H),6.78(s,1H),4.29(d,J＝12.4Hz,1H),4.20(d,J＝11.8Hz,1H),3.94(dd,J＝11.8,4.1Hz,1H),3.77–3.65(m,2H),2.71(d,J＝2.7Hz,1H),2.03(s,1H).
实施例91 6-(1H-苯并[d]咪唑-2-基)-N-(3-((1,4-二氧基-1,4-二氢萘-2-基)氨基)-4-甲基苯甲酰基)-3-氮杂双环[3.1.0]己烷-6-基)吡啶酰胺(化合物L-91)
Figure PCTCN2021119377-appb-000335
一、将3-氨基-4-甲基-苯甲酸(1.5g，9.9mmol)、萘-1,4-二酮(1.6g，9.9mmol)和乙酸铜(0.2g，0.99mmol)溶解在AcOH(50mL)中，在60℃搅拌16h。将反应浓缩至干燥，并用EtOH(10mL)重结晶，并干燥得到红色固体3-[(1，4-二氧基-2-萘基)氨基]-4-甲基-苯甲酸(2g，66％)。
二、操作同实施例82中化合物L-82的制备。
LC-MS:m/z:(M+H) +＝609.3；1H NMR(400MHz,Methanol-d4)δ8.45(dd,J＝7.2,1.7Hz,1H),8.25–8.13(m,3H),8.04(dd,J＝7.6,1.3Hz,1H),7.79(dtd,J＝25.1,7.4,1.4Hz,3H),7.63(d,J＝7.4Hz,1H),7.54–7.44(m,3H),7.36(s,2H),5.60(s,1H),4.31(d,J＝12.3Hz,1H),3.99–3.82(m,2H),3.71(dd,J＝12.3,4.5Hz,1H),2.72(t,J＝2.5Hz,1H),2.36(s,3H),2.19–2.12(m,1H),2.07(d,J＝9.9Hz,1H).
实施例92(9-(3-(咪唑并[1,2-a]吡啶-2-基)苯甲酰基)-3,9-二氮螺环[5.5]十一烷-3-基)(3-(4-甲基-1H-咪唑-1-基)苯基)甲酮(化合物L-92)
Figure PCTCN2021119377-appb-000336
操作同实施例82中化合物L-82的制备。
LC-MS:m/z:(M+H) +/2＝280.2；1H NMR(400MHz,Methanol-d4)δ8.46(dt,J＝6.8,1.2Hz,1H),8.30(d,J＝0.7Hz,1H),8.11(d,J＝1.4Hz,1H),8.05(dt,J＝7.9,1.3Hz,1H),8.00(t,J＝1.6Hz,1H),7.72–7.54(m,5H),7.46–7.30(m,4H),6.96(td,J＝6.8,1.2Hz,1H),3.82(s,4H),3.50(d,J＝1.6Hz,4H),2.27(d,J＝1.1Hz,3H),1.68(d,J＝48.3Hz,8H).
实施例93 6-(1H-苯并[d]咪唑-2-基)-N-(3-(3-(4-甲基-1H-咪唑-1-基)苯甲酰基)-3-氮杂双环[3.1.0]己烷-6-基)吡啶酰胺(化合物L-93)
Figure PCTCN2021119377-appb-000337
一、将(3-甲氧羰基苯基)硼酸(1.8g，10mmol)、4-甲基-1H-咪唑(0.82g，10mmol)、吡啶(0.81mL，10mmol)和乙酸铜(0.4g，2.0mmol)溶解在DCM(50mL)中，反应在室温下搅拌16小时。将反应浓缩至干燥并通过快速色谱法(二氧化硅)(石油醚：乙酸乙酯＝2:1)纯化，得到白色固体3-(4-甲基咪唑-1-基)苯甲酸甲酯(1g，46％)。
二、将3-(4-甲基咪唑-1-基)苯甲酸甲酯(43mg，0.2mmol)溶解于THF(5mL) 和水(1mL)中，反应液加入LiOH(24mg，1.0mmol)后，在80℃下搅拌2h。将反应浓缩至干燥并直接用于下一反应。
三、操作同实施例82中化合物L-82的制备。
LC-MS:m/z:(M+H) +＝504.2；1H NMR(400MHz,Methanol-d4)δ8.46(dd,J＝7.3,1.6Hz,1H),8.26–8.12(m,3H),7.81–7.62(m,5H),7.53(dt,J＝7.5,1.4Hz,1H),7.45–7.32(m,3H),4.32(d,J＝12.3Hz,1H),3.90(dd,J＝11.0,4.5Hz,1H),3.82(d,J＝10.9Hz,1H),3.75(dd,J＝12.4,4.7Hz,1H),2.76(t,J＝2.4Hz,1H),2.29(d,J＝1.0Hz,3H),2.18(d,J＝4.6Hz,1H),2.08(d,J＝12.6Hz,1H).
实施例94(9-(3-(苯并[d]噻唑-2-基)苯甲酰基)-3,9-二氮螺环[5.5]十一烷-3-基)(3-(咪唑并[1,2-a]吡啶-2-基)苯基)甲酮(化合物L-94)
Figure PCTCN2021119377-appb-000338
操作同实施例82中化合物L-82的制备。
LC-MS:m/z:(M+H) +＝612.3；1H NMR(400MHz,Methanol-d4)δ8.46(dt,J＝6.9,1.2Hz,1H),8.30(d,J＝0.7Hz,1H),8.21(dt,J＝7.8,1.4Hz,1H),8.19–8.16(m,1H),8.06(ddt,J＝6.8,5.2,1.0Hz,3H),8.02–7.99(m,1H),7.73–7.64(m,1H),7.64–7.54(m,4H),7.48(ddd,J＝8.3,7.2,1.2Hz,1H),7.44–7.33(m,2H),6.96(td,J＝6.8,1.2Hz,1H),3.84(s,4H),3.52(s,4H),1.70(d,J＝48.3Hz,8H).
实施例95 2-((5-(9-(3-(咪唑并[1,2-a]吡啶-2-基)苯甲酰基)-3,9-二氮螺环[5.5]十一碳-3-羰基)-2-甲基苯基)氨基)萘-1,4-二酮(化合物L-95)
Figure PCTCN2021119377-appb-000339
操作同实施例82中化合物L-82的制备。
LC-MS:m/z:(M+H) +＝664.3；1H NMR(400MHz,Chloroform-d)δ8.14(ddd,J＝15.6,7.3,2.1Hz,3H),8.04(d,J＝7.9Hz,1H),7.99(d,J＝1.8Hz,1H),7.91(s,1H),7.79(td,J＝7.6,1.4Hz,1H),7.74–7.62(m,2H),7.50(t,J＝7.7Hz,1H),7.43–7.33(m,4H),7.28–7.18(m,2H),6.83(t,J＝6.7Hz,1H),5.98(s,1H),3.79(s,4H),3.50(s,4H),2.34(s,3H),1.61(d,J＝ 57.2Hz,8H).
实施例96 3-(4-(9-(3-(咪唑并[1,2-a]吡啶-2-基)苯甲酰基)-3,9-二氮螺环[5.5]十一碳-3-羰基)苯甲酰胺基)噻吩-2-甲酰胺(化合物L-96)
Figure PCTCN2021119377-appb-000340
一、将3-氨基噻吩-2-甲酰胺(1.4g，9.8mmol)和N,N-二异丙基乙胺(2.5g，20mmol)溶解在四氢呋喃(200mL)中，添加3-氯羰基苯甲酸甲酯(2.0g，9.8mmol)，在25℃搅拌16h。将反应浓缩至干燥并通过快速色谱纯化(二氧化硅)(石油醚：乙酸乙酯＝50：50)洗脱，得到黄色固体的3-[(2-氨甲酰基-3-噻吩基)氨甲酰基]苯甲酸甲酯(1g，33％)。
二、将3-[(2-氨甲酰基-3-噻吩基)氨甲酰基]苯甲酸甲酯(180mg，0.6mmol)溶解于MeOH(5mL)和水(1mL)中，添加NaOH(71mg，3.0mmol)后，在100℃下搅拌5天。将反应浓缩至干燥，并向粗品中添加水(5mL)，用1N稀盐酸调节PH＝5,过滤得黄色固体3-[(2-氨甲酰基-3-噻吩基)氨甲酰基]苯甲酸(90mg，52％)。
三、操作同实施例82中化合物L-82的制备。
LC-MS:m/z:(M+H) +＝647.3；1H NMR(400MHz,Methanol-d4)δ8.47(dd,J＝6.8,1.3Hz,1H),8.31(d,J＝1.4Hz,1H),8.12–8.08(m,2H),8.07–8.03(m,1H),8.00(d,J＝1.7Hz,1H),7.66–7.56(m,4H),7.44–7.34(m,3H),7.03–6.93(m,2H),3.82(s,4H),3.48(d,J＝30.4Hz,4H),1.68(d,J＝50.0Hz,8H).
实施例97((2-(苯氨基)嘧啶-4-基)(9-(2-(吡啶-2-基氨基)嘧啶-4-羰基)-3,9-二氮杂螺[5.5]十一烷-3-基)甲酮(化合物L-97)
Figure PCTCN2021119377-appb-000341
操作同实施例82中化合物L-82的制备。
LC-MS:m/z:(M+H)+＝482.0,1H NMR(400MHz,DMSO-d6)δ10.08(d,J＝26.4Hz,1H),9.86(d,J＝20.0Hz,1H),8.66(ddd,J＝20.0,14.7,4.9Hz,2H),8.23(ddd,J＝29.4,21.0,6.0Hz,2H),7.86–7.63(m,3H),7.29(dt,J＝21.7,8.0Hz,2H),7.18–6.88(m,4H),3.79–3.46(m,8H).
实施例98((2-(苯氨基)嘧啶-4-基)(9-(2-(吡啶-2-基氨基)嘧啶-4-羰基)-3,9-二氮杂螺[5.5]十一烷-3-基)甲酮(化合物L-98)
Figure PCTCN2021119377-appb-000342
操作同实施例82中化合物L-82的制备。
LC-MS:m/z:(M+H)+＝550.0,1H NMR(400MHz,CDCl 3)δ8.66(d,J＝4.9Hz,1H),8.57(d,J＝4.9Hz,1H),8.39(d,J＝8.5Hz,2H),7.72(t,J＝8.5Hz,1H),7.62(d,J＝8.1Hz,2H),7.56(s,1H),7.35(t,J＝7.8Hz,2H),7.08(t,J＝7.3Hz,1H),7.00(dd,J＝13.2,5.9Hz,2H),6.92(d,J＝4.9Hz,1H),3.86–3.67(m,4H),3.50(d,J＝4.0Hz,4H),1.73–1.52(m,8H).
实施例99(N-(1-(2-(苯基氨基)嘧啶-4-羰基)哌啶-4-基)-2-(吡啶-2-基氨基)嘧啶-4-羧酰胺(E100124-081)(化合物L-99)
Figure PCTCN2021119377-appb-000343
操作同实施例82中化合物L-82的制备。
LC-MS:m/z:(M+H)+＝495.2,1H NMR(400MHz,CDCl 3)δ9.31(s,1H),8.76(d,J＝4.9Hz,1H),8.59(d,J＝4.9Hz,1H),8.41(d,J＝4.8Hz,1H),8.33(d,J＝8.4Hz,1H),8.09(s,1H),7.86(d,J＝8.2Hz,1H),7.79–7.72(m,1H),7.62(dd,J＝14.3,6.4Hz,3H),7.34(t,J＝7.8Hz,2H),7.10–7.00(m,2H),6.95(d,J＝4.9Hz,1H),4.63(d,J＝13.5Hz,1H),4.32–4.18(m,1H),3.98(d,J＝13.8Hz,1H),3.27(t,J＝11.4Hz,1H),3.11–3.03(m,1H),2.09(dd,J＝38.8,10.9Hz,2H),1.69–1.56(m,2H).
实施例100(四氢吡咯并[3,4-c]吡咯-2,5(1H，3H)-二基)双((6-(苯基氨基)吡啶-2-基)甲酮)(化合物L-100)
Figure PCTCN2021119377-appb-000344
一、5-(6-(苯基氨基)吡啶啉基)六氢吡咯并[3,4-c]吡咯-2(1H)-羧酸叔丁酯
将六氢吡咯并[3,4-c]吡咯-2(1H)-羧酸叔丁酯(100mg，0.47mmol)(如式2所示的化合物)和6-(苯基氨基)吡啶甲酸(101mg，0.47mmol)(如式1所示的化合物)悬浮于3ml N,N-二甲基甲酰胺中，加入N,N-二异丙基乙胺(122mg,0.94mmol)和1-丙基磷酸酐(449mg,0.71mmol)。反应液在30℃下搅拌16h。向反应液中加入10ml冰水，搅拌五分钟，过滤，固体干燥得到粗产物为190mg的棕色固体,收率为98.96％。LC-MS:m/z:(M+H)+＝409.0。
二、(六氢吡咯并[3,4-c]吡咯-2(1H)-基)(6-(苯氨基)吡啶-2-基)甲酮
将5-(6-(苯基氨基)吡啶啉基)六氢吡咯并[3,4-c]吡咯-2(1H)-羧酸叔丁酯(190mg，0.47mmol)(如式3所示的化合物)溶于3ml甲醇中，加入盐酸二氧六环溶液(3mL,4M,12mmol)。反应液在15℃下搅拌2h。反应液浓缩,干燥得到粗产物为150mg的棕色固体,收率为94.38％。LC-MS:m/z:(M+H)+＝309.0。
三、(四氢吡咯并[3,4-c]吡咯-2,5(1H，3H)-二基)双((6-(苯基氨基)吡啶-2-基)甲酮)
操作同实施例82中化合物L-82的制备。
LC-MS:m/z:(M+H)+＝505.0,1H NMR(400MHz,CDCl3)δ7.62(td,J＝8.1,3.4Hz,2H),7.41–7.30(m,8H),7.08(ddd,J＝12.8,9.9,5.5Hz,2H),6.97–6.73(m,4H),4.05(ddd,J＝13.8,9.7,4.8Hz,3H),3.91–3.65(m,5H),2.98(s,2H).
实施例101 6-(苯氨基)-N-(((1R，5S，6s)-3-(6-(苯氨基)吡啶啉基)-3-氮杂双环[3.1.0]己-6基)吡啶啉酰胺(化合物L-101)
Figure PCTCN2021119377-appb-000345
一、(1R，5S，6s)-6-(6-(苯氨基)吡啶甲酰氨基)-3-氮杂双环[3.1.0]己烷-3-羧酸叔丁酯(E100124-067)
将(1R，5S，6s)-6-氨基-3-氮杂双环[3.1.0]己烷-3-羧酸叔丁酯(100mg，0.50mmol)(如式2所示的化合物)和6-(苯基氨基)吡啶甲酸(108mg，0.50mmol)(如式1所示的化合物)悬浮于3ml N,N-二甲基甲酰胺中，加入N,N-二异丙基乙胺(130mg,1.01mmol)和1-丙基磷酸酐(481mg,0.76mmol)。反应液在30℃下搅拌16h。向反应液中加入10ml冰水，搅拌五分钟，过滤，固体干燥得到粗产物为198mg的棕色固体,收率为99.6％。LC-MS:m/z:(M+H)+＝395.0。
二、N-(((1R，5S，6s)-3-氮杂双环[3.1.0]己-6基)-6-(苯氨基)吡啶啉酰胺
将(1R，5S，6s)-6-(6-(苯氨基)吡啶甲酰氨基)-3-氮杂双环[3.1.0]己烷-3-羧酸叔丁酯(198mg，0.50mmol)(如式3所示的化合物)溶于3ml甲醇中，加入盐酸二氧六环溶液(3mL,4M,12mmol)。反应液在15℃下搅拌2h。反应液浓缩,干燥得到粗产物为148mg的棕色固体,收率为99.1％。LC-MS:m/z:(M+H)+＝295.0。
三、6-(苯氨基)-N-(((1R，5S，6s)-3-(6-(苯氨基)吡啶啉基)-3-氮杂双环[3.1.0]己-6基)吡啶啉酰胺
操作同实施例82中化合物L-82的制备。
LC-MS:m/z:(M+H)+＝491.0,1H NMR(400MHz,CDCl 3)δ7.98(s,1H),7.68–7.57(m,3H),7.45–7.30(m,8H),7.21–7.08(m,3H),7.03–6.89(m,3H),6.70(s,1H),4.30(d,J＝12.5Hz,1H),4.18(d,J＝11.6Hz,1H),3.98(d,J＝11.6Hz,1H),3.76–3.68(m,1H),2.69(d,J＝2.0Hz,1H),1.91(s,2H).
实施例102(5-(6-(苯基氨基)吡啶基)六氢吡咯并[3,4-c]吡咯-2(1H)-基)(2-(苯基氨基)嘧啶-4-基)甲酮(化合物L-102)
Figure PCTCN2021119377-appb-000346
操作同实施例82中化合物L-82的制备。
LC-MS:m/z:(M+H)+＝506.0,1H NMR(400MHz,CD3OD)δ8.57(dd,J＝12.9,4.9Hz,1H),7.70–7.61(m,2H),7.59–7.42(m,3H),7.36–6.71(m,9H),4.01–3.46(m,8H),3.11–2.92(m,2H).
实施例103(2-(苯基氨基)-N-(((1R，5S，6s)-3-(6-(苯基氨基)吡啶基)-3-氮杂双环[3.1.0]己-6-基)嘧啶-4-羧酰胺(化合物L-103)
Figure PCTCN2021119377-appb-000347
操作同实施例82中化合物L-82的制备。
LC-MS:m/z:(M+H)+＝492.0,1H NMR(400MHz,CD3OD)δ8.61(d,J＝4.9Hz,1H),7.69–7.54(m,5H),7.32(dt,J＝16.2,4.8Hz,5H),7.08–6.86(m,4H),4.20(d,J＝12.5Hz,1H),4.12(d,J＝11.7Hz,1H),3.88(dd,J＝11.8,4.3Hz,1H),3.72–3.63(m,1H),2.60(t,J＝2.3Hz,1H),2.01–1.89(m,2H).
实施例104 N-((1R，5S，6s)-3-(3-(1H-吡咯-1-基)噻吩-2-羰基)-3-氮杂双环[3.1.0]己-6-基)-3-(咪唑并[1,2-a]吡啶-2-基)苯甲酰胺(化合物L-104)
Figure PCTCN2021119377-appb-000348
操作同实施例82中化合物L-82的制备。
LC-MS:m/z:(M+H)+＝494.2。
1H NMR(400MHz,Chloroform-d)δ8.38(s,1H),8.18(d,J＝6.7Hz,1H),7.99(d,J＝ 7.8Hz,1H),7.
94(s,1H),7.82(d,J＝7.8Hz,1H),7.68(d,J＝9.1Hz,1H),7.50(t,J＝7.7Hz,1H),7.44(d,J＝5.3Hz,1H),7.27(s,1H),7.06(d,J＝5.3Hz,1H),6.90–6.85(m,1H),6.74(s,1H),6.33(t,J＝2.2Hz,2H),4.25(d,J＝12.5Hz,1H),3.53(d,J＝13.3Hz,1H),3.32(d,J＝11.0Hz,1H),2.70–2.61(m,1H),2.45(t,J＝2.5Hz,1H),1.86(s,1H).
实施例105 3-(咪唑并[1,2-a]吡啶-2-基)-N-((1R，5S，6s)-3-(2-苯氧基烟酰胺基)-3-氮杂双环[3.1.0]己-6-基)苯甲酰胺(化合物L-105)
Figure PCTCN2021119377-appb-000349
操作同实施例82中化合物L-82的制备。
LC-MS:m/z:(M+H)+＝516.2。
1H NMR(400MHz,Chloroform-d)δ8.47(s,1H),8.21(dt,J＝5.1,2.4Hz,2H),8.00(d,J＝7.7Hz,1H),7.87(d,J＝7.7Hz,1H),7.77–7.68(m,2H),7.53(t,J＝7.7Hz,1H),7.44(t,J＝7.8Hz,2H),7.37–7.30(m,1H),7.26–7.18(m,3H),7.08(dd,J＝7.4,4.9Hz,1H),6.93(t,J＝7.2Hz,2H),4.31(d,J＝12.4Hz,1H),3.88–3.80(m,1H),3.76(d,J＝10.8Hz,1H),3.69(dd,J＝12.4,4.5Hz,1H),2.76(d,J＝2.6Hz,1H),2.03(d,J＝7.6Hz,1H),1.97(d,J＝4.1Hz,1H).
实施例106 N-((1R，5S，6s)-3-(1H-吲唑-3-羰基)-3-氮杂双环[3.1.0]己-6-基)-3-(咪唑并[1,2-a]吡啶-2-基)苯甲酰胺(化合物L-106)
Figure PCTCN2021119377-appb-000350
操作同实施例82中化合物L-82的制备。
LC-MS:m/z:(M+H)+＝463.1。
1H NMR(400MHz,DMSO-d6)δ13.60(s,1H),8.73(d,J＝3.9Hz,1H),8.57(d,J＝6.7Hz,1H),8.47(s,1H),8.42(d,J＝1.9Hz,1H),8.16(d,J＝8.2Hz,1H),8.11(dd,J＝7.7,1.7Hz,1H),7.80–7.75(m,1H),7.65–7.58(m,2H),7.54(t,J＝7.8Hz,1H),7.45–7.41(m,1H),7.29(s,1H),7.24(t,J＝7.5Hz,1H),6.94(s,1H),4.49(d,J＝11.7Hz,1H),4.10(d,J＝12.3Hz,1H),4.04–4.00(m,1H),3.70–3.62(m,2H),2.04(s,1H),1.97(s,1H).
实施例107 4-丁氧基-N-(1-(3-(咪唑并[1,2-a]吡啶-2-基)苯甲酰基)哌啶-4-基)苯甲酰胺(化合物L-107)
Figure PCTCN2021119377-appb-000351
操作同实施例82中化合物L-82的制备。
LC-MS:m/z:(M+H)+＝497.3。
1H NMR(400MHz,Chloroform-d)δ8.17(d,J＝6.8Hz,1H),8.04–7.98(m,2H),7.91(s,1H),7.79–7.73(m,2H),7.70(d,J＝9.1Hz,1H),7.49(t,J＝7.6Hz,1H),7.37(d,J＝7.6Hz,1H),7.25(t,J＝8.0Hz,1H),6.94–6.89(m,2H),6.85(t,J＝6.7Hz,1H),6.30(d,J＝7.9Hz,1H),4.75(s,1H),4.28(d,J＝6.9Hz,1H),3.86(s,1H),3.22(s,1H),3.02(s,1H),2.29(s,2H),2.03(s,1H),1.79(p,J＝6.8Hz,2H),1.50(hept,J＝6.8,6.2Hz,4H),1.02–0.95(m,3H).
实施例108(4-(6-(1H-苯并[d]咪唑-2-基]吡啶啉基)哌嗪-1-基)(喹啉-3-基)甲酮(化合物L-108)
Figure PCTCN2021119377-appb-000352
操作同实施例82中化合物L-82的制备。
LC-MS:m/z:(M+H)+＝463.0,1H NMR(400MHz,CDCl 3)δ9.01(s,1H),8.63(s,1H),8.32(s,1H),8.17(d,J＝8.1Hz,1H),8.02(t,J＝7.6Hz,1H),7.95–7.80(m,2H),7.79–7.63(m,3H),7.38(dd,J＝6.0,3.0Hz,2H),3.85(d,J＝72.4Hz,8H).
实施例109(4-(6-(1H-苯并[d]咪唑-2-基]吡啶啉基)哌嗪-1-基)(4-甲基吡啶-3-基)甲酮(化合物L-109)
Figure PCTCN2021119377-appb-000353
操作同实施例82中化合物L-82的制备。
LC-MS:m/z:(M+H)+＝427.0,1H NMR(400MHz,CDCl 3)δ8.78–8.43(m,3H),8.04(d,J＝7.4Hz,1H),7.74(d,J＝22.5Hz,3H),7.39(s,2H),7.21(s,1H),4.01–3.29(m,8H),2.40(s,3H).
实施例110(4-(6-(1H-苯并[d]咪唑-2-基)吡啶啉基)哌嗪-1-基)(1H-吲唑-3-基)甲酮(化合物L-110)
Figure PCTCN2021119377-appb-000354
操作同实施例82中化合物L-82的制备。
LC-MS:m/z:(M+H)+＝452.0,1H NMR(400MHz,CDCl 3)δ11.00(d,J＝117.6Hz,2H),8.52(s,1H),8.11(s,1H),7.97(t,J＝7.8Hz,1H),7.69(d,J＝6.8Hz,3H),7.49(d,J＝8.4Hz,1H),7.45–7.30(m,3H),7.22(s,1H),4.44–3.58(m,8H).
实施例111 6-(4-(6-(1H-苯并[d]咪唑-2-基)吡啶啉基)哌嗪-1-羰基)-4,5-二氢哒嗪-3(2H)-酮(化合物L-111)
Figure PCTCN2021119377-appb-000355
操作同实施例82中化合物L-82的制备。
LC-MS:m/z:(M+H)+＝432.0,1H NMR(400MHz,CDCl 3)δ8.91(s,1H),8.57(s,1H),7.99(t,J＝7.8Hz,1H),7.86–7.60(m,3H),7.41–7.32(m,2H),4.00–3.61(m,8H),2.91(s,2H),2.62(s,2H).
实施例112(4-(6-(1H-苯并[d]咪唑-2-基]吡啶啉基)哌嗪-1-基)(噻吩-2-基)甲酮(化合物L-112)
Figure PCTCN2021119377-appb-000356
操作同实施例82中化合物L-82的制备。
LC-MS:m/z:(M+H)+＝418.0,1H NMR(400MHz,CDCl 3)δ8.57(d,J＝7.8Hz,1H),8.01(dd,J＝15.8,8.0Hz,1H),7.71(t,J＝8.5Hz,3H),7.50(d,J＝5.0Hz,1H),7.41–7.32(m, 3H),7.11–7.05(m,1H),4.09–3.67(m,8H).
实施例113(3,9-二氮杂螺[5.5]十一烷-3,9-二基)双((6-(苯氨基)吡啶-2-基)甲酮)(化合物L-113)
Figure PCTCN2021119377-appb-000357
一、9-(6-(6-(苯基氨基)吡啶啉基)-3,9-二氮杂螺[5.5]十一烷-3-羧酸叔丁酯
将3,9-二氮杂螺[5.5]十一烷-3-羧酸叔丁酯(187mg，0.74mmol)(如式2所示的化合物)和6-(苯基氨基)吡啶甲酸(150mg，0.70mmol)(如式1所示的化合物)悬浮于3ml N,N-二甲基甲酰胺中，加入N,N-二异丙基乙胺(181mg,1.40mmol)和1-丙基磷酸酐(668mg,1.05mmol)。反应液在15℃下搅拌16h。向反应液中加入10ml冰水，搅拌五分钟，过滤，固体干燥得到粗产物为220mg的棕色固体,收率为69.73％。LC-MS:m/z:(M+H)+＝451.0。
二、(6-(苯基氨基)吡啶-2-基)(3,9-二氮杂螺[5.5]十一烷-3-基)甲酮
将9-(6-(6-(苯基氨基)吡啶啉基)-3,9-二氮杂螺[5.5]十一烷-3-羧酸叔丁酯(175mg，0.33mmol)(如式3所示的化合物)溶于5ml甲醇中，加入盐酸二氧六环溶液(5mL,4M,20mmol)。反应液在15℃下搅拌2h。反应液浓缩,干燥得到粗产物为115mg的棕色固体,收率为98.56％。LC-MS:m/z:(M+H)+＝351.0。
三、(3,9-二氮杂螺[5.5]十一烷-3,9-二基)双((6-(苯氨基)吡啶-2-基)甲酮)
操作同实施例82中化合物L-82的制备。
LC-MS:m/z:(M+H)+＝547.0,1H NMR(400MHz,CDCl 3)δ8.04(s,1H),7.64–7.56(m,2H),7.39–7.33(m,7H),7.11(dt,J＝8.5,3.5Hz,2H),6.99(d,J＝7.2Hz,2H),6.91(d,J＝8.4Hz,3H),3.67(d,J＝96.1Hz,8H),1.75–1.51(m,8H).
实施例114 6-(苯基氨基)-N-(1-(6-(6-(苯基氨基)吡啶啉基)哌啶-4-基)吡啶啉酰胺(化合物L-114)
Figure PCTCN2021119377-appb-000358
一、(1-(6-(苯基氨基)吡啶啉基)哌啶-4-基)氨基甲酸叔丁酯
将叔丁基哌啶-4-基氨基甲酸酯(147mg，0.74mmol)(如式2所示的化合物)和6-(苯基氨基)吡啶甲酸(150mg，0.70mmol)(如式1所示的化合物)悬浮于3ml N,N-二甲基甲酰胺中，加入N,N-二异丙基乙胺(181mg,1.4mmol)和1-丙基磷酸酐(668mg,1.05mmol)。反应液在30℃下搅拌16h。向反应液中加入10ml冰水，搅拌五分钟，过滤，固体干燥得到粗产物为230mg的棕色固体,收率为82.34％。LC-MS:m/z:(M+H)+＝397.0。
二、(4-氨基哌啶-1-基)(6-(苯基氨基)吡啶-2-基)甲酮
将(1-(2-(苯氨基)嘧啶-4-羰基)哌啶-4-基)氨基甲酸叔丁酯(150mg，0.38mmol)(如式3所示的化合物)溶于5ml甲醇中，加入盐酸二氧六环溶液(5mL,4M,20mmol)。反应液在15℃下搅拌2h。反应液浓缩,干燥得到粗产物为110mg的棕色固体,收率为98.10％。LC-MS:m/z:(M+H)+＝297.0。
三、6-(苯基氨基)-N-(1-(6-(6-(苯基氨基)吡啶啉基)哌啶-4-基)吡啶啉酰胺
操作同实施例82中化合物L-82的制备。
LC-MS:m/z:(M+H)+＝493.0,1H NMR(400MHz,CDCl 3)δ8.06–7.99(m,1H),7.72–7.61(m,3H),7.38(dt,J＝13.4,8.0Hz,8H),7.15(t,J＝7.1Hz,2H),6.98(dd,J＝21.4,7.9Hz,3H),4.61(s,1H),4.28(d,J＝8.2Hz,1H),3.96(s,1H),3.37–3.14(m,2H),2.12(d,J＝28.1Hz,2H),1.73(d,J＝10.2Hz,2H).
实施例115 3-(4-(4-(6-(1H-苯并[d]咪唑-2-基)吡啶基)哌嗪-1-羰基)苯甲酰胺基)噻吩-2-甲酰胺(化合物L-115)
Figure PCTCN2021119377-appb-000359
操作同实施例82中化合物L-82的制备。
LC-MS:m/z:(M+H) +＝579.8；1H NMR(400MHz,Methanol-d4)δ8.41(s,1H),8.14(s,3H),7.81–7.61(m,5H),7.36(d,J＝16.9Hz,3H),6.98(s,1H),3.95(d,J＝36.7Hz,4H),3.67(t,J＝29.0Hz,4H).
实施例116 2-((5-(4-(6-(1H-苯并[d]咪唑-2-基)吡啶酰基)哌嗪-1-羰基)-2-甲基苯基)氨基)萘-1,4-二酮(化合物L-116)
Figure PCTCN2021119377-appb-000360
操作同实施例82中化合物L-82的制备。
LC-MS:m/z:(M+H) +＝596.8；1H NMR(400MHz,Chloroform-d)δ8.58(s,1H),8.40–7.92(m,3H),7.72(s,5H),7.55–7.19(m,7H),6.03(s,1H),3.85(d,J＝36.6Hz,8H),2.34(s,3H).
实施例117(4-(6-(1H-苯并[d]咪唑-2-基)吡啶酰基)哌嗪-1-基)(3-(4-甲基-1H-咪唑-1-基)苯基)甲酮(化合物L-117)
Figure PCTCN2021119377-appb-000361
操作同实施例82中化合物L-82的制备。
LC-MS:m/z:(M+H) +＝419.9；1H NMR(400MHz,Methanol-d4)δ8.41(s,1H),8.14 (d,J＝8.1Hz,2H),7.89–7.54(m,6H),7.48(s,1H),7.34(s,3H),4.19–3.48(m,8H),2.27(s,3H).
实施例118 4-(6-(1H-苯并[d]咪唑-2-基)吡啶酰基)-N-(3-(咪唑[1,2-a]吡啶-2-基)苯基)哌嗪-1-甲酰胺(化合物L-118)
Figure PCTCN2021119377-appb-000362
将3-咪唑并[1,2-a]吡啶-2-基苯胺(42mg，0.2mmol)溶解于无水二氯甲烷(5mL)中，添加三光气(20mg，0.067mmol)，在25℃下搅拌16h。将反应浓缩至干燥并直接用于下一步反应。
将[6-(1H-苯并咪唑-2-基)-2-吡啶基]-哌嗪-1-基-甲酮(63mg，0.2mmol)和N,N-二异丙基乙胺(79mg，0.6mmol)溶解在N,N-二甲基甲酰胺(1mL)中，添加2-(3-异氰酸酯基苯基)咪唑并[1,2-a]吡啶(48mg，0.2mmol)，反应液在25℃下搅拌2小时。将反应浓缩至干燥，并用快速色谱法(二氧化硅)纯化(二氯甲烷：甲醇＝20：1)，得到黄色固体4-[6-(1H-苯并咪唑-2-基)吡啶-2-羰基]-N-(3-咪唑并[1,2-a]吡啶-2-基苯基)哌嗪-1-甲酰胺(35mg，32％)。
LC-MS:m/z:(M+H) +/2＝272.0；1H NMR(400MHz,Methanol-d4)δ8.47–8.40(m,2H),8.20–8.12(m,2H),7.91(t,J＝1.8Hz,1H),7.75(dd,J＝7.8,1.0Hz,2H),7.62(dt,J＝7.4,1.5Hz,2H),7.56(d,J＝9.1Hz,1H),7.46–7.29(m,5H),6.93(td,J＝6.8,1.2Hz,1H),3.95(t,J＝5.2Hz,2H),3.81(d,J＝5.5Hz,2H),3.71(s,4H).
实施例119 1,3-双(3-(咪唑并[1,2-a]吡啶-2-基)苯基)脲(化合物L-119)
Figure PCTCN2021119377-appb-000363
操作同实施例118中化合物L-118的制备。
LC-MS:m/z:(M+H) +/2＝223.0；1H NMR(400MHz,Methanol-d4)δ8.27(dt,J＝6.8,1.2Hz,1H),8.04(s,1H),7.92(t,J＝1.9Hz,1H),7.64–7.51(m,3H),7.38(t,J＝7.9Hz,1H),7.30(ddd,J＝9.1,6.8,1.2Hz,1H),6.90(td,J＝6.8,1.1Hz,1H).
实施例120(5-(6-(1H苯并[d]咪唑-2-基)吡啶酰)六氢吡咯[3,4-c]吡咯-2(1H) -基)(1H-吲唑-3-基)甲酮的合成(化合物L-120)
Figure PCTCN2021119377-appb-000364
一、(6-(1H苯并[d]咪唑-2-基)吡啶-2-基)(六氢吡咯[3,4-c]吡咯-2(1H)-基)甲酮盐酸盐的合成
操作：将原料5-(6-(1H苯并[d]咪唑-2-基)吡啶酰)六氢吡咯[3,4-c]吡咯-2(1H)-羧酸叔丁酯540mg投入反应瓶中，加入甲醇40ml，搅拌加入4M/L的盐酸/1,4-二氧六环溶液20ml，室温搅拌过夜。次日，LC-MS显示反应完全。直接减压浓缩除去溶剂。得500mg收率：100％
LC-MS:m/z:(M+H)+＝369.9。
二、(5-(6-(1H苯并[d]咪唑-2-基)吡啶酰)六氢吡咯[3,4-c]吡咯-2(1H)-基)(1H-吲唑-3-基)甲酮的合成。
操作：将原料(6-(1H苯并[d]咪唑-2-基)吡啶-2-基)(六氢吡咯[3,4-c]吡咯-2(1H)-基)甲酮盐酸盐60mg(1eq)投至反应瓶中，加入2ml无水DMF，加入原料1H-吲唑-3-羧酸26.25mg(1eq),搅拌加入T3P103.2mg(50％EA溶液，1.5eq)，DIPEA 83.7mg(3eq),30℃搅拌过夜，次日，LC-MS反应完。后处理：将反应液倒入20ml冰水中搅拌，加入二氯甲烷50ml*3次萃取，合并有机层，饱和盐水萃取，无水硫酸钠干燥。过滤浓缩至干，得残余物经过柱(DCM:MEOH＝0---5％)得到产物，再经厚层析板分离(DCM:MEOH＝95：5)得纯产物32.5mg。收率：41.9％。
LC-MS:m/z:(M+H)+＝478.2。
1H NMR(400MHz,Methanol-d 4)δ8.46–8.37(m,1H),8.20(d,J＝8.2Hz,1H),8.12(dt,J＝10.1,7.9Hz,1H),7.88–7.81(m,1H),7.77–7.52(m,3H),7.48–7.39(m,1H),7.37–7.19(m,3H),4.49–3.67(m,8H),3.17(ttd,J＝15.6,7.3,3.4Hz,2H).
实施例121 6-(5-(6-(1H苯并[d]咪唑-2-基)吡啶酰)八氢吡咯[3,4-c]吡咯-2-羰基)-4,5-二氢哒嗪-3(2H)-酮的合成(化合物L-121)
Figure PCTCN2021119377-appb-000365
操作：将原料(6-(1H苯并[d]咪唑-2-基)吡啶-2-基)(六氢吡咯[3,4-c]吡咯-2(1H)-基)甲酮盐酸盐60mg(1eq)投至反应瓶中，加入2ml无水DMF，加入原料6-氧代- 1,4,5,6-四氢哒嗪-3-羧酸23.04mg(1eq),搅拌加入T3P103.2mg(50％EA溶液，1.5eq)，DIPEA 83.7mg(3eq),30℃搅拌过夜，次日，LC-MS反应完。后处理：将反应液倒入20ml冰水中搅拌，加入二氯甲烷50ml*3次萃取，合并有机层，饱和盐水萃取，无水硫酸钠干燥。过滤浓缩至干，得残余物经过柱(DCM:MEOH＝0---5％)得到产物，再经厚层析板分离(DCM:MEOH＝95：5)得纯产物19.6mg。收率：26.4％。
LC-MS:m/z:(M+H)+＝458.2。
1H NMR(400MHz,Methanol-d 4)δ8.42(ddd,J＝7.9,4.6,0.9Hz,1H),8.14(td,J＝7.9,1.0Hz,1H),7.88–7.82(m,1H),7.69(d,J＝40.9Hz,2H),7.34(d,J＝4.9Hz,2H),4.24–3.52(m,8H),3.12(dddd,J＝14.9,12.4,4.0,2.1Hz,2H),2.91–2.79(m,2H),2.61–2.45(m,2H).
实施例122(5-(6-(1H苯并[d]咪唑-2-基)吡啶酰)六氢吡咯[3,4-c]吡咯-2(1H)-基)(喹啉-3-基)甲酮的合成(化合物L-122)
Figure PCTCN2021119377-appb-000366
操作：将原料(6-(1H苯并[d]咪唑-2-基)吡啶-2-基)(六氢吡咯[3,4-c]吡咯-2(1H)-基)甲酮盐酸盐60mg(1eq)投至反应瓶中，加入2ml无水DMF，加入原料喹啉-3-羧酸28.08mg(1eq),搅拌加入T3P103.2mg(50％EA溶液，1.5eq)，DIPEA 83.7mg(3eq),30℃搅拌过夜，次日，LC-MS反应完。后处理：将反应液倒入20ml冰水中搅拌，加入二氯甲烷50ml*3次萃取，合并有机层，饱和盐水萃取，无水硫酸钠干燥。过滤浓缩至干，得残余物经过柱(DCM:MEOH＝0---5％)得到产物，再经厚层析板分离(DCM:MEOH＝95：5)得纯产物41.8mg。收率：52.8％。
LC-MS:m/z:(M+H)+＝489.2。
1H NMR(400MHz,Methanol-d 4)δ9.04(d,J＝17.9Hz,1H),8.59(d,J＝27.0Hz,1H),8.41(dd,J＝22.3,7.9Hz,1H),8.18–7.82(m,5H),7.69(dt,J＝32.4,7.4Hz,3H),7.33(s,2H),4.28–4.04(m,2H),3.96(tt,J＝13.6,8.3Hz,2H),3.88–3.56(m,4H),3.29–3.05(m,2H).
实施例123(5-(6-(1H苯并[d]咪唑-2-基)吡啶酰)六氢吡咯[3,4-c]吡咯-2(1H)-基)(4-甲基吡啶-3-基)甲酮的合成(化合物L-123)
Figure PCTCN2021119377-appb-000367
操作：将原料(6-(1H苯并[d]咪唑-2-基)吡啶-2-基)(六氢吡咯[3,4-c]吡咯-2(1H)-基)甲酮盐酸盐60mg(1eq)投至反应瓶中，加入2ml无水DMF，加入原料4-甲基烟酸22.2mg(1eq),搅拌加入T3P103.2mg(50％EA溶液，1.5eq)，DIPEA 83.7mg(3eq),30℃搅拌过夜，次日，LC-MS反应完。后处理：将反应液倒入20ml冰水中搅拌，加入二氯甲烷50ml*3次萃取，合并有机层，饱和盐水萃取，无水硫酸钠干燥。过滤浓缩至干，得残余物经过柱(DCM:MEOH＝0---5％)得到产物，再经厚层析板分离(DCM:MEOH＝95：5)得纯产物49.1mg。收率：67％。
LC-MS:m/z:(M+H)+＝453.2。
1H NMR(400MHz,Methanol-d 4)δ8.50(d,J＝5.5Hz,1H),8.47–8.37(m,2H),8.14(dt,J＝10.7,7.8Hz,1H),7.90–7.81(m,1H),7.72(s,2H),7.46–7.29(m,3H),4.25–3.85(m,4H),3.81–3.49(m,4H),3.20–3.06(m,2H),2.38(d,J＝29.1Hz,3H).
实施例124(5-(6-(1H苯并[d]咪唑-2-基)吡啶酰)六氢吡咯[3,4-c]吡咯-2(1H)-基)(3-氯-4-氟苯基)甲酮的合成(化合物L-124)
Figure PCTCN2021119377-appb-000368
操作：将原料(6-(1H苯并[d]咪唑-2-基)吡啶-2-基)(六氢吡咯[3,4-c]吡咯-2(1H)-基)甲酮盐酸盐80mg(1eq)投至反应瓶中，加入2ml无水DMF，加入原料3-氯-4-氟苯甲酸37.76mg(1eq),搅拌加入T3P137.6mg(50％EA溶液，1.5eq)，DIPEA 111.6mg(3eq),30℃搅拌过夜，次日，LC-MS反应完。后处理：将反应液倒入20ml冰水中搅拌，加入二氯甲烷50ml*3次萃取，合并有机层，饱和盐水萃取，无水硫酸钠干燥。过滤浓缩至干，得残余物经过柱(DCM:MEOH＝0---5％)得到产物，再经厚层析板分离(DCM:MEOH＝95：5)得纯产物55mg。收率：51.88％。
LC-MS:m/z:(M+H)+＝489.8。
1H NMR(400MHz,DMSO-d 6)δ12.92(s,1H),8.41(t,J＝7.6Hz,1H),8.13(q,J＝7.5Hz,1H),7.83–7.77(m,2H),7.73(t,J＝6.9Hz,1H),7.59(q,J＝7.5,6.9Hz,2H),7.48(dt,J＝32.4,8.9Hz,1H),7.26(dq,J＝14.6,7.7,7.2Hz,2H),4.18–3.35(m,8H),3.11–2.90(m,2H).
实施例125(5-(6-(1H苯并[d]咪唑-2-基)吡啶酰)六氢吡咯[3,4-c]吡咯-2(1H)-基)(2-甲基喹啉-6-基)甲酮的合成(化合物L-125)
Figure PCTCN2021119377-appb-000369
操作：将原料(6-(1H苯并[d]咪唑-2-基)吡啶-2-基)(六氢吡咯[3,4-c]吡咯-2(1H)-基)甲酮盐酸盐80mg(1eq)投至反应瓶中，加入2ml无水DMF，加入原料2-甲基喹啉-6-羧酸40.48mg(1eq),搅拌加入T3P137.6mg(50％EA溶液，1.5eq)，DIPEA 111.6mg(3eq),30℃搅拌过夜，次日，LC-MS反应完。后处理：将反应液倒入20ml冰水中搅拌，加入二氯甲烷50ml*3次萃取，合并有机层，饱和盐水萃取，无水硫酸钠干燥。过滤浓缩至干，得残余物经过柱(DCM:MEOH＝0---5％)得到产物，再经厚层析板分离(DCM:MEOH＝95：5)得纯产物70mg。收率：64.5％。
LC-MS:m/z:(M+H)+＝502.9。
1H NMR(400MHz,DMSO-d 6)δ12.93(s,1H),8.46–8.24(m,2H),8.20–8.07(m,2H),7.94(dd,J＝29.9,8.9Hz,1H),7.86(d,J＝8.6Hz,1H),7.80(d,J＝7.6Hz,1H),7.73(dd,J＝11.9,7.9Hz,1H),7.61(dd,J＝16.2,7.9Hz,1H),7.48(dd,J＝26.5,8.6Hz,1H),7.26(dq,J＝14.1,7.1Hz,2H),4.19–3.47(m,8H),3.12–2.91(m,2H),2.72–2.62(m,3H).
实施例126(5-(6-(1H苯并[d]咪唑-2-基)吡啶酰)六氢吡咯[3,4-c]吡咯-2(1H)-基)(4-(4-氯苯基)环己基)甲酮的合成(化合物L-126)
Figure PCTCN2021119377-appb-000370
操作：将原料(6-(1H苯并[d]咪唑-2-基)吡啶-2-基)(六氢吡咯[3,4-c]吡咯-2(1H)-基)甲酮盐酸盐80mg(1eq)投至反应瓶中，加入2ml无水DMF，加入原料4-(4-氯苯基)环己烷-1-羧酸51.6mg(1eq),搅拌加入T3P137.6mg(50％EA溶液，1.5eq)，DIPEA 111.6mg(3eq),30℃搅拌过夜，次日，LC-MS反应完。后处理：将反应液倒入20ml冰水中搅拌，加入二氯甲烷50ml*3次萃取，合并有机层，饱和盐水萃取，无水硫酸钠干燥。过滤浓缩至干，得残余物经过柱(DCM:MEOH＝0---5％)得到产物，再经厚层析板分离(DCM:MEOH＝95：5)得纯产物53mg。收率：44.2％。
LC-MS:m/z:(M+H)+＝553.8。
1H NMR(400MHz,DMSO-d 6)δ12.93(d,J＝22.3Hz,1H),8.41(d,J＝7.9Hz,1H),8.17 –8.08(m,1H),7.82–7.69(m,2H),7.59(t,J＝6.7Hz,1H),7.28(ddd,J＝30.5,16.0,7.3Hz,6H),4.16–3.33(m,8H),3.11–2.87(m,2H),2.43(t,J＝10.0Hz,2H),1.94–1.70(m,4H),1.61–1.39(m,4H).
实施例127(5-(6-(1H苯并[d]咪唑-2-基)吡啶酰)六氢吡咯[3,4-c]吡咯-2(1H)-基)([1,1'-联苯]-4-基)甲酮的合成(化合物L-127)
Figure PCTCN2021119377-appb-000371
操作：将原料(6-(1H苯并[d]咪唑-2-基)吡啶-2-基)(六氢吡咯[3,4-c]吡咯-2(1H)-基)甲酮盐酸盐80mg(1eq)投至反应瓶中，加入2ml无水DMF，加入原料[1,1'-联苯]-4-羧酸43mg(1eq),搅拌加入T3P137.6mg(50％EA溶液，1.5eq)，DIPEA 111.6mg(3eq)，30℃搅拌过夜，次日，LC-MS反应完。后处理：将反应液倒入20ml冰水中搅拌，加入二氯甲烷50ml*3次萃取，合并有机层，饱和盐水萃取，无水硫酸钠干燥。过滤浓缩至干，得残余物经过柱(DCM:MEOH＝0---5％)得到产物，再经厚层析板分离(DCM:MEOH＝95：5)得纯产物32mg。收率：28.8％。
LC-MS:m/z:(M+H)+＝513.9。
1H NMR(400MHz,DMSO-d 6)δ12.94(s,1H),8.41(dd,J＝13.3,8.0Hz,1H),8.13(q,J＝7.9Hz,1H),7.83–7.70(m,4H),7.70–7.57(m,5H),7.46(ddt,J＝25.7,13.0,6.6Hz,3H),7.27(dt,J＝13.4,6.5Hz,2H),4.14–3.36(m,8H),3.13–2.91(m,2H).
受体结合实例:LANCL2结合实例
1.实验材料
1.1试剂材料
配体：LANCL2
运行缓冲液：20mM MES,150mM NaCl,0.05％P20,pH 6.5,1％DMSO
1.2仪器设备
仪器名称：Biacore S200
芯片类型：CM5(29-1496-03)
2.实验方法
2.1配体偶联
固定LANCL2蛋白，使用pH为4.0的醋酸钠溶液稀释蛋白至50μg/ml。
进样条件：使用EDC/NHS的混合液对CM5芯片表面进行活化处理，流速10μl/min.进样时间：420s；随即进行LANCL2进样，流速5μl/min，进样时间：2000s，单次配体偶联量大约1800RU；最后使用乙醇胺对芯片表面进行封闭，乙醇胺进样流速10μl/min，进样时间：420s。
偶联缓冲液：20mM MES,150mM NaCl,0.05％P20,pH 6.5。
2.2实验条件
分析物：所有小分子化合物样品分析物从50μM浓度2倍稀释至0.78μM浓度，最后配得化合物溶液含1％DMSO。
小分子化合物进样条件：流速30μl/min，结合时间60s，解离时间300s。
运行缓冲液：20mM MES,150mM NaCl,0.05％P20,pH 6.5,1％DMSO。
样品室温度：25℃；分析温度：25℃。
方法
LANCL2-小分子相互作用的动力学测定。BIACORE S200用于测定小分子BT-11和L-1～60(被分析物)与LANCL2(配位体)结合发动力学参数。以剂量依赖性(5-8个滴定点)方式一式三份地产生数据，并且加以分析以确定结合模型(朗格缪尔(Langmuir)、构象偏移等)、实时缔合与解离常数以及平衡解离常数。SPR技术允许验证特异性LANCL2-植物化学成分相互作用以及增加对结合机制和速率的金标准深刻理解。实验通过由胺偶合共价附接LANCL2在羧基甲基聚葡萄糖(CM5)传感器芯片上执行。用BIACORE S200T200评估软件(版本1)分析数据以使用1:1结合模型确定亲和力结合常数(KD)。
结果
本发明的化合物强结合于LANCL2。为了确认化合物与LANCL2蛋白质的结合，我们在BIACORE S200仪器中执行SPR分析。用于检测分子相互作用的光学技术SPR用于测量LANCL2与其配位体(待测化合物)之间的结合亲和力。我们将经过纯化的重组LANCL2蛋白质固定在BIACORE传感器芯片上，并且使用仪器微流体系统将小分子注射到蛋白质表面上。测量芯片表面上的总质量的变化，其对应于与蛋白质的小结合。通过注射一系列小分子浓度，我们能够计算待测化合物结合于LANCL2的结合信号，解离信号，计算化合物的稳态结合亲和力以及化合物在不同浓度下的结合信号曲线(本专利中的部分不好计算亲和力的化合物，将其不同浓度下的结合信号曲线放置在本专利中作为化合物具有结合活性的证据)。结合传感图展示典型小分子蛋白质相互作用，其具有极快缔合速率和极快解离速率。这些快速相互作用超出仪器的技术能力。因此，未确定可靠缔合速率常数(ka)和解离速率常数(kd)。平衡解离常数(Kd)常用以描述配位体与蛋白质 之间的亲和力，如配位体结合于特定蛋白质的紧密程度。配位体-蛋白质亲和力受两个分子之间的非共价分子间相互作用影响，所述相互作用如氢键结、静电相互作用、疏水力和范德华力。通过针对化合物浓度绘制平衡结合水平，我们能够测量每一相互作用的稳态亲和力(Kd)。本发明的化合物与LANCL2蛋白质的具有良好的结合性，甚至本发明的部分化合物如(L-2,L-9,L-11,L-15,L-25,L-40,L-52,L-77,L-89,L-95,L-96,L-106)，其结合活性优于阳性参照化合物BT-ll。
具体数据如下表所示。
序号 化合物编号 KD(M) Rmax(RU) 序号 化合物编号 KD(M) Rmax(RU)
  BT-11 4.46E-06 3.6   BT-11 4.46E-06 3.6
1 L-1 4.46E-06 3.6 65 L-65 2.60E-05 6.5
2 L-2 7.19E-07 9.6 66 L-66 3.18E-05 7.2
3 L-3 6.92E-06 3 67 L-67 N/A N/A
4 L-4 4.00E-05 8 68 L-68 N/A N/A
5 L-5 1.70E-05 7.3 69 L-69 2.17E-05 6.1
6 L-6 / / 70 L-70 N/A N/A
7 L-7 / / 71 L-71 4.06E-05 5.9
8 L-8 / / 72 L-72 6.93E-06 5.3
9 L-9 3.44E-06 3.9 73 L-73 8.73E-06 4.5
10 L-10 1.84E-05 5.3 74 L-74 2.58E-05 0.102
11 L-11 3.67E-06 4.2 75 L-77 1.90E-06 7.3
12 L-12 / / 76 L-78 8.15E-05 14.4
13 L-13 3.83E-05 1.5 77 L-79 2.48E-05 13
14 L-14 2.11E-05 7.1 78 L-80 2.84E-05 8.5
15 L-15 2.30E-06 3.2 79 L-81 2.30E-05 10.5
16 L-16 8.49E-05 6.9 80 L-82 4.23E-05 9.4
17 L-17 / / 81 L-83 5.37E-05 9.6
18 L-18 1.27E-04 5.2 82 L-84 / /
19 L-19 2.53E-05 9.7 83 L-85 / /
20 L-20 4.33E-05 5.3 84 L-86 / /
21 L-21 9.88E-06 7.3 85 L-87 / /
22 L-22 / / 86 L-88 1.64E-05 9.7
23 L-23 1.03E-05 7.5 87 L-89 2.53E-06 3.9
24 L-24 5.73E-05 12.7 88 L-90 9.50E-06 6.5
25 L-25 2.01E-06 8.1 89 L-91 1.71E-06 5.2
26 L-26 6.58E-05 10.7 90 L-92 5.88E-05 11
27 L-27 1.33E-05 6.5 91 L-93 5.84E-06 8
28 L-28 / / 92 L-95 2.09E-06 5.2
29 L-29 / / 93 L-96 1.91E-06 2.3
30 L-30 / / 94 L-97 / /
31 L-32 / / 95 L-98 1.22E-05 3.2
32 L-35 6.61E-05 14.4 96 L-99 5.41E-06 5.1
33 L-37 / / 97 L-100 3.85E-05 7.8
34 L-38 9.09E-06 10.9 98 L-101 2.33E-05 5.5
35 L-39 6.33E-06 8.5 99 L-102 2.95E-05 7.5
36 L-40 3.21E-06 3.1 100 L-103 2.41E-05 6
37 L-41 2.76E-05 6.3 101 L-104 1.25E-05 9.7
38 L-42 1.32E-05 12 102 L-105 1.75E-05 8.6
39 L-43 4.92E-05 15.1 103 L-106 4.32E-06 6.4
40 L-44 / / 104 L-107 6.19E-06 4.5
41 L-45 8.31E-06 6.3 105 L-108 4.84E-05 13.7
42 L-46 3.04E-05 10.6 106 L-109 / /
43 L-47 1.33E-05 11.1 107 L-110 2.62E-05 15
45 L-50 7.04E-06 7.5 108 L-111 / /
46 L-51 1.64E-05 7.5 109 L-112 2.48E-05 12.7
47 L-52 2.83E-06 3.9 110 L-113 / /
48 L-53 3.60E-05 6.2 111 L-114 1.08E-05 24
49 L-54 2.78E-05 8.4 112 L-115 1.77E-05 20.8
50 L-55 1.68E-05 6.8 113 L-116 1.48E-05 32.5
51 L-56 / / 114 L-117 2.70E-05 3.2
52 L-57 8.02E-06 8 115 L-118 8.73E-06 74.9
53 L-58 2.15E-05 3.3 116 L-119 6.78E-06 10.8
54 L-59 1.49E-05 3.6 117 L-120 2.21E-05 8.9
55 L-60 2.74E-05 3.6 118 L-121 2.08E-05 2.3
56 L-31 N/A N/A 119 L-122 1.03E-05 7
57 L-33 N/A N/A 120 L-123 1.83E-05 3.9
58 L-34 N/A N/A 121 L-124 8.79E-06 4.8
59 L-36 N/A N/A a 122 L-125 2.35E-05 5.2
60 L-48 N/A N/A 123 L-126 4.05E-05 3.3
61 L-61 2.32E-05 5.8 124 L-127 9.38E-06 5.1
62 L-62 2.93E-05 5.7 125 L-75 N/A N/A
63 L-63 5.35E-05 7.6 126 L-76 N/A N/A
64 L-64 4.88E-05 6.1 127 L-94 N/A N/A
KD(M)表示结合力(单位mol)；Rmax(RU)表示最大结合力；N/A表示无结合活性；“/”表示检查结果不方便计算KD，此部分将以结合曲线的形式展现其结合活性，图中展示了化合物在不同浓度下的结合信号强度；a表示溶解性差。部分化合物的结合曲线见图1至12。
本发明化合物对TNBS诱导的小鼠肠炎的缓解作用研究(一)
1.研究背景
IBD属于一类自身免疫性疾病，可分为克罗恩病和溃烂性结肠炎。本项目利用TNBS诱导的小鼠的结肠炎模型来模拟克罗恩病，并对相应化合物的疗效作出评估，以期开发成治疗克罗恩病的药物。
2.研究目的
本项目旨在测试代表性化合物对TNBS诱导的小鼠结肠炎的缓解作用。
3.试剂
Reagents Vendor Cat
DPBS Corning 21-031-CVR
TNBS 北京偶合科技有限公司 2508-19-2
无水乙醇 Aladdin(阿拉丁) 64-17-5
美沙拉嗪(成品药) Losan Pharma GmbH NA
氯化钠注射液 山东科伦药业有限公司 NA
1.25％阿佛丁 南京爱贝生物科技有限公 M2910
  司  
4.仪器
Equipment Vendor Model
电子天平 常州之天平 YH-2000
电子分析天平 Mettle Toledo 585310
5.实验方法
5.1化合物的溶解与保藏
L56的配制方法：称取适量的L56化合物至棕色样品瓶中，加入一定体积的溶媒95％(20％HP-β-CD)+5％(10％苯甲酸钠)，涡旋1分钟，超声促进溶解。化合物每天配置一次。
L30的配制方法：称取适量的L30化合物至棕色样品瓶中，加入一定体积的溶媒95％(20％HP-β-CD)+5％(10％苯甲酸钠)，涡旋1分钟，超声促进溶解。化合物每天配置一次。
Mesa(Mesalamine)的配制方法：称取适量的美拉沙嗪(Selleck)化合物至棕色样品瓶中，加入一定体积的溶媒0.5％CMC-Na，涡旋1分钟，超声促进溶解。化合物每天配置一次。
5.2化合物的给药途径与频率
雌性Balb/c小鼠56只，体重18g左右，8-10周龄，随机分成7组，6个模型组和1个Sham对照组。于Day-1开始给药至Day7结束，化合物每天配置一次，具体给药途径和频率详见表1，化合物配置与给药体积参见表2。
表1动物分组及给药方案
组别 动物数(只) 给药剂量(mg/kg) 给药途径 给药频率 给药周期
Sham组 5 - - - -
溶剂对照组 5 - PO BID 9days
L56组 5 50mpk PO BID 9days
L30组 6 50mpk PO BID 9days
Mesa 5 100mpk PO QD 9days
注：阳性药为Mesalamine(Mesa)
表2给药体积和药物终浓度
组别 给药剂量 给药体积(mL) 药物终浓度(mg/mL) 给药频率
溶剂对照组 --- 0.2 0 BID
L56组 50mpk 0.2 5 BID
L30组 50mpk 0.2 5 BID
Mesa 100mpk 0.2 10 QD
注：小鼠进行称重给药，上表是按照20克小鼠计算的给药体积。
5.3 TNBS诱导的小鼠肠炎模型构建
Day0，体重18-20克左右Balb/c小鼠用0.25毫升的1.25％阿佛丁麻药进行麻醉。模型组小鼠直肠灌注150微升1％TNBS溶液(终浓度50％乙醇)。Sham对照组小鼠Day0直肠灌注50％乙醇。
5.4小鼠结肠组织的固定
小鼠的结肠进行拍照，测量长度，去除内容物后进行称重，然后将每只小鼠的结肠1/2处纵切开，采取瑞士卷(Swiss-roll)的方法按照统一方向进行卷曲并放入中性多聚甲醛中进行固定。
5.5 DAI评分标准
DAI评分由3部分组成，采取体重变化、粪便和便血混合评分的方式，具体的DAI评分标准如表3所示。整个实验过程中，所有小鼠的DAI评分由同一人完成，保证评分的尺度一致性。
表3 DAI评分标准
评分 体重降低％ 大便性状 隐血或血便
0 0 正常 隐血阴性
1 1～5 软便 隐血弱阳性
2 6～10 松散便 隐血阳性
3 11～20 稀便 血便
4 >20 极稀便 大量血便
5.6结肠组织病理评分标准
小鼠结肠组织病理评分由5部分组成，具体的评分标准如表4所示。病理评分采取双盲法由临床病理平台专业的病理医生进行。
表4结肠组织病理评分标准
Figure PCTCN2021119377-appb-000372
Figure PCTCN2021119377-appb-000373
5.7统计学分析
实验数据采用ANOVA方法进行统计学分析，阳性药Mesalamine(PO,100mpk,QD)组，L56(PO,50mpk,BID)组，L30(PO,50mpk,BID)组，*p<0.05，**p<0.01，***p<0.005，****p<0.0001
6.结果与分析
6.1小鼠体重变化及DAI评分
收集各组小鼠10天(Day-1到Day8)的体重数据并进行相应的DAI评分，数据的分析采用Two way ANOVA的方法。如图13A的数据表明，相比于Vehicle组，L56(PO,50mpk,BID)组，Mesalamine(PO,100mpk,QD)组小鼠的体重下降程度明显减缓，而L30(PO,50mpk,BID)组小鼠，相比于Vehicle组小鼠的体重在Day5到Day8下降程度明显减缓。如图13B的DAI评分数据同样可以看出相比于Vehicle组，L30(PO，50mpk,BID)组，L56(PO,50mpk,BID)组，Mesalamine(PO,100mpk,QD)组小鼠的DAI评分明显更低。综合体重变化和DAI评分，我们发现L30(PO，50mpk,BID)，L56(PO,50mpk,BID)，能有效缓解TNBS诱导结肠炎造成的小鼠体重降低。
注：图13中，模型组及其它组小鼠体重变化及疾病活动指数的统计学分析采取two way ANOVA方法，与模型组相比，假造模组:*p<0.05**p<0.01***p<0.005****p<0.0001；美沙拉嗪组:#p<0.05##p<0.01###p<0.005####p<0.0001；L56 50mg/kg组:^p<0.05^^p<0.01^^^p<0.005^^^^p<0.0001；L30 50mg/kg组：$p<0.05$$p<0.01$$$p<0.005$$$$p<0.0001.two way-ANOVA采用Dunnett’s方法进行多组比较。
6.2小鼠结肠重量与长度比值变化
一般来说，炎症会造成结肠缩短和结肠重量的增加。如图14A的数据表明，相比于vehicle组小鼠，L30(PO，50mpk,BID)组，L56(PO,50mpk,BID)组，Mesalamine(PO,100mpk,QD)组小鼠的结肠重量与长度比值要明显更低，具有统计学上的明显差异。如图14B的数据表明，相比于vehicle组小鼠，L56(PO,50mpk,BID)组，Mesalamine(PO,100mpk,QD)组小鼠的结肠明显更长一些。如图14C的数据表明，相比于vehicle组小鼠，L30(PO，50mpk,BID)组，L56(PO,50mpk,BID)组，Mesalamine(PO,100mpk,QD)组小鼠的结肠更低一些，跟Sham组小鼠的结肠重量接近。这些数据进一步说明L30(PO，50mpk,BID)，L56(PO,50mpk,BID)能够很多缓解TNBS诱导的小鼠的结肠炎。
注：图14中，模型组与其它组的小鼠结肠重量与长度比值统计学分析采取one way  ANOVA方法，与模型组相比，*p<0.05**p<0.01***p<0.005****p<0.0001,one way-ANOVA采用采用Dunnett’s方法进行多组比较。
6.3小鼠结肠组织HE染色与病理评分
进而我们对7组小鼠的结肠组织进行HE染色并由病理医生进行评分。相比于Vehicle组小鼠，L56(PO,50mpk,BID)组，Mesalamine(PO,100mpk,QD)组小鼠结肠组织的病理评分要低一些，具有统计学上的明显差异。进一步说明L56(PO,50mpk,BID)，能够有效缓解TNBS模型小鼠肠炎的发生。
结论
结合In-life实验及病理分析的数据可知，L56(PO,50mpk,BID)能够很好地减缓TNBS诱导的小鼠肠炎。
肠形态如图15(Sham组&Vehicle组、Mesalamine(PO,100mpk,QD)组&L56(PO,50mpk,BID)组及L30(PO,50mpk,BID)组。
本发明化合物对TNBS诱导的小鼠肠炎的缓解作用研究(二)
1.研究背景
IBD属于一类自身免疫性疾病，可分为克罗恩病和溃烂性结肠炎。本项目利用TNBS诱导的小鼠的结肠炎模型来模拟克罗恩病，并对相应化合物的疗效作出评估，以期开发成治疗克罗恩病的药物。
2.研究目的
本项目旨在测试代表性化合物对TNBS诱导的小鼠结肠炎的缓解作用。
3.试剂
Reagents Vendor Cat
DPBS Corning 21-031-CVR
TNBS 北京偶合科技有限公司 2508-19-2
无水乙醇 Aladdin(阿拉丁) 64-17-5
美沙拉嗪(成品药) Losan Pharma GmbH NA
氯化钠注射液 山东科伦药业有限公司 NA
1.25％阿佛丁 南京爱贝生物科技有限公司 M2910
4.仪器
Equipment Vendor Model
电子天平 常州之天平 YH-2000
电子分析天平 Mettle Toledo 585310
5.实验方法
5.1化合物的溶解与保藏
BT-11的配制方法：称取适量的BT11化合物至棕色样品瓶中，加入一定体积的溶媒0.5％CMC-Na，涡旋1分钟，超声促进溶解。化合物每天配置一次。
L11的配制方法：称取适量的L11化合物至棕色样品瓶中，加入一定体积的溶媒0.5％CMC-Na，涡旋1分钟，超声促进溶解。化合物每天配置一次。
L25的配制方法：称取适量的L25化合物至棕色样品瓶中，加入一定体积的溶媒0.5％CMC-Na，涡旋1分钟，超声促进溶解。化合物每天配置一次。
L84的配制方法：称取适量的L84化合物至棕色样品瓶中，加入一定体积的溶媒0.5％CMC-Na，涡旋1分钟，超声促进溶解。化合物每天配置一次。
L77的配制方法：称取适量的L77化合物至棕色样品瓶中，加入一定体积的溶媒0.5％CMC-Na，涡旋1分钟，超声促进溶解。化合物每天配置一次。
L101的配制方法：称取适量的L101化合物至棕色样品瓶中，加入一定体积的氯化钠注射液(生理盐水)，涡旋1分钟，超声促进溶解。化合物每天配置一次。
L10的配制方法：称取适量的L10化合物至棕色样品瓶中，加入一定体积的溶媒0.5％CMC-Na，涡旋1分钟，超声促进溶解。化合物每天配置一次。
L23的配制方法：称取适量的L23化合物至棕色样品瓶中，加入一定体积的溶媒0.5％CMC-Na，涡旋1分钟，超声促进溶解。化合物每天配置一次。
Mesa(Mesalamine)的配制方法：称取适量的美拉沙嗪(Selleck)化合物至棕色样品瓶中，加入一定体积的溶媒0.5％CMC-Na，涡旋1分钟，超声促进溶解。化合物每天配置一次。
5.2化合物的给药途径与频率
雌性Balb/c小鼠60只，体重18g左右，8-10周龄，随机分成12组，11个模型组和1个Sham对照组。于Day-1开始给药至Day7结束，化合物每天配置一次，具体给药途径和频率详见表1，化合物配置与给药体积参见表2。
表1动物分组及给药方案
Figure PCTCN2021119377-appb-000374
Figure PCTCN2021119377-appb-000375
表2给药体积和药物终浓度
Figure PCTCN2021119377-appb-000376
注：小鼠进行称重给药，上表是按照20克小鼠计算的给药体积。溶剂组是模型对照组。
5.3 TNBS诱导的小鼠肠炎模型构建
Day0，体重18-20克左右Balb/c小鼠用0.25毫升的1.25％阿佛丁麻药进行麻醉。模型组小鼠直肠灌注150微升1％TNBS溶液(终浓度50％乙醇)。Sham对照组小鼠Day0直肠灌注50％乙醇。
5.4小鼠结肠组织的固定
小鼠的结肠进行拍照，测量长度，去除内容物后进行称重，然后将每只小鼠的结肠1/2处纵切开，采取瑞士卷(Swiss-roll)的方法按照统一方向进行卷曲并放入中性多聚甲 醛中进行固定。
5.5小鼠结肠新鲜组织的收集
剩余的1/2的结肠组织，再沿着1/2处纵向剪开，分装成两管，液氮速冻，-80℃保存，干冰运输，用于后续实验。
5.6小鼠肠系膜淋巴结的收集
采集小鼠的肠系膜淋巴结，4度保存，待所有样本采集完后，立即转送给客户进行流式分析。
5.7 DAI评分标准
DAI评分由3部分组成，采取体重变化、粪便和便血混合评分的方式，具体的DAI评分标准如表3所示。整个实验过程中，所有小鼠的DAI评分由同一人完成，保证评分的尺度一致性。
表3 DAI评分标准
评分 体重降低％ 大便性状 隐血或血便
0 0 正常 隐血阴性
1 1～5 软便 隐血弱阳性
2 6～10 松散便 隐血阳性
3 11～20 稀便 血便
4 >20 极稀便 大量血便
5.8统计学分析
实验数据采用ANOVA方法进行统计学分析，其它组与Vehicle(PO,QD)组数据进行Dunnett’s检测来比较多组数据，*p<0.05，**p<0.01，***p<0.005，****p<0.0001
6.结果与分析
6.1小鼠体重变化及DAI评分
收集各组小鼠10天(Day-1到Day8)的体重数据并进行相应的DAI评分，数据的分析采用Two way ANOVA的方法。如图16A的数据表明，相比于Vehicle组，9种测试化合物组小鼠中L11(PO,50mpk,BID)组和L10(PO,50mpk,BID)组小鼠的体重下降程度明显减缓。除了L84(PO,50mpk,BID)组和BT11(PO,50mpk,BID)组小鼠的体重下降程度与Vehicle组小鼠相比较，未见明显减缓。其它5种测试化合物在缓解小鼠的体重下降方面都具有明显的作用，但没有L11和L10作用那么明显。在如图16B的DAI评分数据同样可以看出相比于Vehicle组，9种测试化合物组小鼠中L11(PO,50mpk,BID)组和L10(PO,50mpk,BID)组小鼠的DAI评分明显更低。其它7种测试化合物在改善DAI 评分方面都具有明显的作用，但没有L11和L10作用那么明显。综合体重变化和DAI评分，我们发现L11(PO,50mpk,BID)和L10(PO,50mpk,BID)能有效缓解TNBS诱导结肠炎造成的小鼠体重降低。更有意思的是，L10(PO,50mpk,BID)与阳性药Mesalamine(PO,100mpk,QD)药效相当。
6.2小鼠拉稀与便血评分
同样，采用Two way ANOVA的方法分析单独的拉稀和便血评分。如图17A，相比于Vehicle组，9种测试化合物组小鼠中L11(PO,50mpk,BID)组和L10(PO,50mpk,BID)组小鼠的拉稀情况明显减缓。其它7种测试化合物在改善肠炎小鼠拉稀方面都具有明显的作用，但没有L11和L10作用那么明显。如图17B，相比于Vehicle组，9种测试化合物组小鼠中L11(PO,50mpk,BID)组和L10(PO,50mpk,BID)组小鼠的便血情况明显减缓。其它7种测试化合物在改善肠炎小鼠便血方面都具有明显的作用，但没有L11和L10作用那么明显。因此，我们发现L11(PO,50mpk,BID)和L10(PO,50mpk,BID)能够很好的缓解TNBS模型小鼠拉稀和便血的症状。
6.3小鼠结肠重量与长度比值变化
一般来说，炎症会造成结肠缩短和结肠重量的增加。终点收样时，挑选了药效比较显著的L10(PO,50mpk,BID)组、L25(PO,50mpk,BID)组、L11(PO,50mpk,BID)组小鼠进行结肠拍照、测量长度和称重。如图18C的数据表明，相比于vehicle组小鼠，L10(PO,50mpk,BID)组、L25(PO,50mpk,BID)组、L11(PO,50mpk,BID)组和Mesalazine(PO,100mpk,QD)组小鼠的结肠重量与长度比值要明显更低，具有统计学上的明显差异。如图18A的数据表明，相比于vehicle组小鼠，L10(PO,50mpk,BID)组、L25(PO,50mpk,BID)组、L11(PO,50mpk,BID)组小鼠的结肠明显更长一些。如图18B的数据表明，相比于vehicle组小鼠，L10(PO,50mpk,BID)组、L25(PO,50mpk,BID)组、L11(PO,50mpk,BID)组和Mesalazine(PO,100mpk,QD)组小鼠的结肠更低一些。这些数据进一步说明L11(PO,50mpk,BID)和L10(PO,50mpk,BID)能够很多缓解TNBS肠炎小鼠的炎症发生。
7.结论
结合In-life实验的数据可知，L11(PO,50mpk,BID)和L10(PO,50mpk,BID)能够很好地减缓TNBS诱导的小鼠肠炎。
肠形态如图19。
虽然以上描述了本发明的具体实施方式，但是本领域的技术人员应当理解，这些仅是举例说明，在不背离本发明的原理和实质的前提下，可以对这些实施方式做出多种变更或修改。因此，本发明的保护范围由所附权利要求书限定。

Claims (11)

  1. 一种如式I所示的羰基杂环类化合物或其药学上可接受的盐；
    Figure PCTCN2021119377-appb-100001
    其中，A为
    Figure PCTCN2021119377-appb-100002
    或-NR 1R 2；
    R 1和R 2独立地为H或C 6-18的芳基；
    Y 1和Y 2独立地为CH或N；
    Q为
    Figure PCTCN2021119377-appb-100003
    Z 1-L 1-为
    Figure PCTCN2021119377-appb-100004
    带“*”碳原子表示当为手性碳原子时，为S构型、R构型或它们的混合物；
    环Q 1为6-10元并环的杂环烷基、6-12元螺环的杂环烷基或6-10元桥环的杂环烷基；Q 1中，含有1到3个N原子；
    M为
    Figure PCTCN2021119377-appb-100005
    6-10元并环的杂环芳基、被R 4取代的6-10元并环的杂环芳基、5-10元的杂环烯基、被氧代的5-10元的杂环烯基或被R 5取代的5-10元的环烷基；所述的6-10元并环的杂环芳基中的杂原子、所述的被R 4取代的6-10元并环的杂环芳基中的杂原子、5-10元的杂环烯基中的杂原子和被氧代取代的5-10元的杂环烯基中的杂原子独立地为N、S和O中的一种或多种，个数独立地为1个、2个或3个；R 3为的个数为1个、2个或3个；c端表示与所示C＝O连接；
    G为S或O；
    A’、A 1a、A 1b和A 1c独立地为
    Figure PCTCN2021119377-appb-100006
    NO 2、
    Figure PCTCN2021119377-appb-100007
    -OR 8、C 6-14的芳基或H；
    Y 3、Y 3a、Y 3b、Y 4、Y 4a、Y 4b、Y 5、Y 5a、Y 5b和Y 5c独立地为CH或N；
    R 6为卤素；
    R 7为H或C 1-6的烷基；
    R 8为C 6-14的芳基；
    R 3为C 1-6的烷基或卤素；
    R 4为C 1-6的烷基；
    R 5为C 6-14的芳基或被卤素取代的C 6-14的芳基。
  2. 如权利要求1所述的如式I所示的羰基杂环类化合物或其药学上可接受的盐，其特征在于，
    Figure PCTCN2021119377-appb-100008
    为
    Figure PCTCN2021119377-appb-100009
    a端表示与A连接的位置；
    和/或，当Q 1为6-10元并环的杂环烷基时，所述的6-10元并环的杂环烷基为6-8元并环的杂环烷基，含有1到2个N原子,还可以为5元N杂环烷基并三元环烷基的杂环烷基或5元N杂环烷基并5元N杂环烷基的杂环烷基，例如
    Figure PCTCN2021119377-appb-100010
    Figure PCTCN2021119377-appb-100011
    和/或，当Q 1为6-12元螺环的杂环烷基时，所述的6-12元螺环的杂环烷基为7-11元螺环的杂环烷基，含有1或2个N原子，还可为9-11元螺环的杂环烷基，含有1或2个N原子，又可以为氮杂螺环[5,5]十一杂环烷基、氮杂螺环[5,4]癸杂环烷基或氮杂螺环[4,4]壬杂环烷基，例如
    Figure PCTCN2021119377-appb-100012
    和/或，当Q 1为6-10元桥环的杂环烷基时，所述的6-10元桥环的杂环烷基为7元桥环的杂环烷基；例如，
    Figure PCTCN2021119377-appb-100013
    和/或，当M为
    Figure PCTCN2021119377-appb-100014
    时，
    Figure PCTCN2021119377-appb-100015
    为
    Figure PCTCN2021119377-appb-100016
    和/或，当M为
    Figure PCTCN2021119377-appb-100017
    时，
    Figure PCTCN2021119377-appb-100018
    为
    Figure PCTCN2021119377-appb-100019
    和/或，当M为
    Figure PCTCN2021119377-appb-100020
    时，
    Figure PCTCN2021119377-appb-100021
    为
    Figure PCTCN2021119377-appb-100022
    和/或，当M为
    Figure PCTCN2021119377-appb-100023
    时，
    Figure PCTCN2021119377-appb-100024
    为
    Figure PCTCN2021119377-appb-100025
    和/或，当M为6-10元并环的杂环芳基或被R 4取代的6-10元并环的杂环芳基时，所述的6-10元并环的杂环芳基独立地为9-10元并环的杂环芳基，杂原子为N和/或S，个数为1个或2个，例如吲哚基、喹啉基、异吲哚基或咪唑并吡啶基；
    和/或，当M为5-10元的杂环烯基或被氧代的5-10元的杂环烯基时，所述的5-10元的杂环烯基为6元的杂环烯基，杂原子为N，个数为2个，例如
    Figure PCTCN2021119377-appb-100026
    和/或，当M为R 5取代的4-10元的环烷基时，所述的4-10元的环烷基为环戊基、环己基或环庚基，例如环己基；
    和/或，当A’、A 1a、A 1b和A 1c独立地为
    Figure PCTCN2021119377-appb-100027
    时，
    Figure PCTCN2021119377-appb-100028
    为
    Figure PCTCN2021119377-appb-100029
    和/或，当A’、A 1a、A 1b和A 1c独立地为
    Figure PCTCN2021119377-appb-100030
    时，
    Figure PCTCN2021119377-appb-100031
    为
    Figure PCTCN2021119377-appb-100032
    和/或，当A’、A 1a、A 1b和A 1c独立地为
    Figure PCTCN2021119377-appb-100033
    时，
    Figure PCTCN2021119377-appb-100034
    为
    Figure PCTCN2021119377-appb-100035
    Figure PCTCN2021119377-appb-100036
    和/或，当A’、A 1a、A 1b和A 1c独立地为C 6-14的芳基时，所述的C 6-14的芳基独立地为苯基、萘基、蒽基或菲基；
    和/或，当R 6为卤素时，所述的卤素为F、Cl、Br或I，例如F；
    和/或，当R 7为C 1-6的烷基时，所述的C 1-6的烷基为甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基，例如甲基；
    和/或，当R 8为C 6-14的芳基时，所述的C 6-14的芳基独立地为苯基、萘基、蒽基或菲基，例如苯基；
    和/或，当R 3为C 1-6的烷基时，所述的C 1-6的烷基为甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基，例如甲基；
    和/或，当R 3为卤素时，所述的卤素为F、Cl、Br或I，例如F或Cl；
    和/或，当R 4为C 1-6的烷基时，所述的C 1-6的烷基为甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基，例如甲基；
    和/或，当R 5为C 6-14的芳基或被卤素取代的C 6-14的芳基时，所述的C 6-14的芳基独立地为苯基、萘基、蒽基或菲基，例如苯基；
    和/或，当R 5为被卤素取代的C 6-14的芳基时，所述的卤素为F、Cl、Br或I，例如Cl。
  3. 如权利要求2所述的如式I所示的羰基杂环类化合物或其药学上可接受的盐，其特征在于，当M为被R 4取代的6-10元并环的杂环芳基时，所述的被R 4取代的6-10元并环的杂环芳基为
    Figure PCTCN2021119377-appb-100037
    和/或，当M为被氧代的5-10元的杂环烯基时，所述的被氧代的5-10元的杂环烯基为
    Figure PCTCN2021119377-appb-100038
    和/或，当M为R 5取代的4-10元的环烷基时，所述的R 5取代的4-10元的环烷基为
    Figure PCTCN2021119377-appb-100039
    和/或，当A’、A 1a、A 1b和A 1c独立地为
    Figure PCTCN2021119377-appb-100040
    时，
    Figure PCTCN2021119377-appb-100041
    为
    Figure PCTCN2021119377-appb-100042
    和/或，当A’、A 1a、A 1b和A 1c独立地为
    Figure PCTCN2021119377-appb-100043
    时，
    Figure PCTCN2021119377-appb-100044
    为
    Figure PCTCN2021119377-appb-100045
  4. 如权利要求1所述的如式I所示的羰基杂环类化合物或其药学上可接受的盐，其特征在于，R 1和R 2中一个H，另一个为C 6-14的芳基；
    和/或，Y 2为CH；
    和/或，当Q 1为6-10元并环的杂环烷基时，Z 1-L 1-为
    Figure PCTCN2021119377-appb-100046
    或，当Q 1为6-10元并环的杂环烷基时，Z 1-L 1-为
    Figure PCTCN2021119377-appb-100047
    和/或，当Q 1为6-12元螺环的杂环烷基时，Z 1-L 1-为
    Figure PCTCN2021119377-appb-100048
    和/或，Q 1为6-10元桥环的杂环烷基，Z 1-L 1-为
    Figure PCTCN2021119377-appb-100049
    和/或，A’为
    Figure PCTCN2021119377-appb-100050
    或NO 2；
    和/或，A与A’相同；
    和/或，
    Figure PCTCN2021119377-appb-100051
    与
    Figure PCTCN2021119377-appb-100052
    相同。
  5. 如权利要求1所述的如式I所示的羰基杂环类化合物或其药学上可接受的盐，其特征在于，
    Figure PCTCN2021119377-appb-100053
    为
    Figure PCTCN2021119377-appb-100054
    Figure PCTCN2021119377-appb-100055
    Figure PCTCN2021119377-appb-100056
    还可以为
    Figure PCTCN2021119377-appb-100057
    Figure PCTCN2021119377-appb-100058
    和/或，Q为
    Figure PCTCN2021119377-appb-100059
    Figure PCTCN2021119377-appb-100060
    Figure PCTCN2021119377-appb-100061
    还可以为
    Figure PCTCN2021119377-appb-100062
    和/或，
    Figure PCTCN2021119377-appb-100063
    为
    Figure PCTCN2021119377-appb-100064
    Figure PCTCN2021119377-appb-100065
    Figure PCTCN2021119377-appb-100066
    还可以为
    Figure PCTCN2021119377-appb-100067
    Figure PCTCN2021119377-appb-100068
    和/或，
    Figure PCTCN2021119377-appb-100069
    为
    Figure PCTCN2021119377-appb-100070
    和/或，
    Figure PCTCN2021119377-appb-100071
    为
    Figure PCTCN2021119377-appb-100072
    和/或，
    Figure PCTCN2021119377-appb-100073
    为
    Figure PCTCN2021119377-appb-100074
  6. 如权利要求1所述的如式I所示的羰基杂环类化合物或其药学上可接受的盐，其特征在于，所述的如式I所示的羰基杂环类化合物为如下任一方案：
    方案1：
    A为
    Figure PCTCN2021119377-appb-100075
    或-NR 1R 2；
    R 1和R 2独立地为H或C 6-18的芳基；
    Y 1和Y 2独立地为CH或N；
    Q为
    Figure PCTCN2021119377-appb-100076
    Z 1-L 1-为
    Figure PCTCN2021119377-appb-100077
    带“*”碳原子表示当为手性碳原子时，为S构型、R构型或它们的混合物；
    环Q 1为6-10元并环的杂环烷基或6-12元螺环的杂环烷基；Q 1中，含有1到3个N原子；
    M为
    Figure PCTCN2021119377-appb-100078
    6-10元并环的杂环芳基、被R 4取代的6-10元并环的杂环芳基、5-10元的杂环烯基、被氧代的5-10元的杂环烯基或被R 5取代的5-10元的环烷基；
    G为S和O；
    A 1a、A 1b和A 1c独立地为
    Figure PCTCN2021119377-appb-100079
    Figure PCTCN2021119377-appb-100080
    -OR 8、C 6-14的芳基或H；
    Y 5、Y 5a和Y 5b独立地为CH或N；
    R 6为卤素；
    R 7为C 1-6的烷基；
    R 8为C 6-14的芳基；
    R 3为C 1-6的烷基或卤素；
    R 4为C 1-6的烷基；
    R 5为C 6-14的芳基或被卤素取代的C 6-14的芳基
    方案2：
    A为
    Figure PCTCN2021119377-appb-100081
    Y 2为CH；
    Q为
    Figure PCTCN2021119377-appb-100082
    Z 1-L 1-为
    Figure PCTCN2021119377-appb-100083
    环Q 1为5元N杂环烷基并三元环烷基的杂环烷基或螺环[5,5]十一杂环烷基(例如
    Figure PCTCN2021119377-appb-100084
    )；
    M为
    Figure PCTCN2021119377-appb-100085
    或6-10元并环的杂环芳基；
    A ’和A 1b独立地为
    Figure PCTCN2021119377-appb-100086
    NO 2、
    Figure PCTCN2021119377-appb-100087
    方案3：
    A为
    Figure PCTCN2021119377-appb-100088
    或-NR 1R 2；
    R 1和R 2独立地为H或C 6-14的芳基；
    Y 1和Y 2独立地为CH或N；
    Q为
    Figure PCTCN2021119377-appb-100089
    Z 1-L 1-为
    Figure PCTCN2021119377-appb-100090
    环Q 1为6-10元并环的杂环烷基；Q 1中，含有1或2个N原子；
    M为
    Figure PCTCN2021119377-appb-100091
    6-10元并环的杂环芳基、被R 4取代的6-10元并环的杂环芳基、5-10元的杂环烯基、被氧代的5-10元的杂环烯基或被R 5取代的4-10元的环烷基；
    G为S；
    A’和A 1c独立地为
    Figure PCTCN2021119377-appb-100092
    Figure PCTCN2021119377-appb-100093
    -OR 8、C 6-14的芳基或H；
    Y 5、Y 5a和Y 5b独立地为CH或N；
    R 6为卤素；
    R 7为C 1-6的烷基；
    R 8为C 6-14的芳基；
    R 3为C 1-6的烷基或卤素；
    R 4为C 1-6的烷基；
    R 5为C 6-14的芳基或被卤素取代的C 6-14的芳基；
    方案4：
    A为
    Figure PCTCN2021119377-appb-100094
    或-NR 1R 2；
    R 1和R 2独立地为H或C 6-14的芳基；
    Y 1和Y 2独立地为CH或N；
    Q为
    Figure PCTCN2021119377-appb-100095
    Z 1-L 1-为
    Figure PCTCN2021119377-appb-100096
    环Q 1为6-12元螺环的杂环烷基；Q 1中，含有2个N原子；
    M为
    Figure PCTCN2021119377-appb-100097
    6-10元并环的杂环芳基、被R 4取代的6-10元并环的杂环芳基、5-10元的杂环烯基、被氧代的5-10元的杂环烯基或被R 5取代的4-10元的环烷基；
    A’、A 1a、A 1b和A 1c独立地为
    Figure PCTCN2021119377-appb-100098
    NO 2、
    Figure PCTCN2021119377-appb-100099
    Y 5和Y 5b独立地为CH或N；
    方案5：
    所述的如式I所示的羰基杂环类化合物为式I-1所示：
    Figure PCTCN2021119377-appb-100100
    其中，A为
    Figure PCTCN2021119377-appb-100101
    Y 1和Y 2独立地为CH或N；
    Q为
    Figure PCTCN2021119377-appb-100102
    Z 1-L 1-为
    Figure PCTCN2021119377-appb-100103
    环Q 1为6-10元并环的杂环烷基、6-12元螺环的杂环烷基或6-10元桥环的杂环烷基；Q 1中，含有1到3个N原子；
    Y 3和Y 4独立地为CH或N；
    A’为
    Figure PCTCN2021119377-appb-100104
    或NO 2；
    Y 5为CH或N；
    带“*”碳原子表示当为手性碳原子时，为S构型、R构型或它们的混合物；
    方案6：
    A为
    Figure PCTCN2021119377-appb-100105
    Y 1和Y 2独立地为CH或N；
    Q为
    Figure PCTCN2021119377-appb-100106
    Q 1为6-10元并环的杂环烷基、6-12元螺环的杂环烷基或6-10元桥环的杂环烷基，Z 1-L 1-为
    Figure PCTCN2021119377-appb-100107
    或者，Q 1为6-10元并环的杂环烷基，Z 1-L 1-为
    Figure PCTCN2021119377-appb-100108
    Y 3和Y 4独立地为CH或N；
    A’为
    Figure PCTCN2021119377-appb-100109
    或NO 2；
    Y 5为CH或N；
    方案7：
    A为
    Figure PCTCN2021119377-appb-100110
    Y 1和Y 2独立地为CH或N；
    Q为
    Figure PCTCN2021119377-appb-100111
    Q 1独立地为6-10元并环的杂环烷基或6-12元螺环的杂环烷基；Z 1-L 1-为
    Figure PCTCN2021119377-appb-100112
    或者，Q 1为6-10元并环的杂环烷基，Z 1-L 1-为
    Figure PCTCN2021119377-appb-100113
    Y 3和Y 4独立地为CH或N；
    A’为
    Figure PCTCN2021119377-appb-100114
    或NO 2；
    Y 5为CH或N；
    方案8：
    A为
    Figure PCTCN2021119377-appb-100115
    Figure PCTCN2021119377-appb-100116
    为
    Figure PCTCN2021119377-appb-100117
    Q为
    Figure PCTCN2021119377-appb-100118
    Q 1独立地为6-10元并环的杂环烷基；Z 1-L 1-为
    Figure PCTCN2021119377-appb-100119
    Figure PCTCN2021119377-appb-100120
    Figure PCTCN2021119377-appb-100121
    为
    Figure PCTCN2021119377-appb-100122
    A’为
    Figure PCTCN2021119377-appb-100123
    或NO 2；
    Y 5为CH或N；
    方案9：
    A为
    Figure PCTCN2021119377-appb-100124
    Figure PCTCN2021119377-appb-100125
    为
    Figure PCTCN2021119377-appb-100126
    Q为
    Figure PCTCN2021119377-appb-100127
    Q 1独立地为6-12元螺环的杂环烷基；Z 1-L 1-为
    Figure PCTCN2021119377-appb-100128
    Figure PCTCN2021119377-appb-100129
    为
    Figure PCTCN2021119377-appb-100130
    A’为
    Figure PCTCN2021119377-appb-100131
    或NO 2；
    方案10：
    A为
    Figure PCTCN2021119377-appb-100132
    Figure PCTCN2021119377-appb-100133
    为
    Figure PCTCN2021119377-appb-100134
    Q为
    Figure PCTCN2021119377-appb-100135
    Q 1为6-10元桥环的杂环烷基；Z 1-L 1-为
    Figure PCTCN2021119377-appb-100136
    Figure PCTCN2021119377-appb-100137
    为
    Figure PCTCN2021119377-appb-100138
    A’为
    Figure PCTCN2021119377-appb-100139
  7. 如权利要求1所述的如式I所示的羰基杂环类化合物或其药学上可接受的盐，其特征在于，所述的如式I所示的羰基杂环类化合物选自下组：
    Figure PCTCN2021119377-appb-100140
    Figure PCTCN2021119377-appb-100141
    Figure PCTCN2021119377-appb-100142
    Figure PCTCN2021119377-appb-100143
  8. 一种药物组合物，其包括如权利要求1-7中任一项所述的如式I所示的羰基杂环类化合物或其药学上可接受的盐、和一种或多种药学上可接受的载体。
  9. 一种如权利要求1-7中任一项所述的如式I所示的羰基杂环类化合物、其药学上可接受的盐、或如权利要求8所述的药物组合物在制备羊毛硫氨酸C样蛋白质2激动剂中的应用。
  10. 一种如权利要求1-7中任一项所述的如式I所示的羰基杂环类化合物、其药学上可接受的盐、或如权利要求8所述的药物组合物在制备药物中的应用；所述的药物可为用于预防和/或治疗与羊毛硫氨酸C样蛋白质2有关的疾病的药物，和/或，所述的药物可为用于预防和/或治疗自身免疫性、慢性发炎性、慢性代谢性或传染性疾病的药物。
  11. 如权利要求10所述的应用，其特征在于，
    所述的与羊毛硫氨酸C样蛋白质2有关的疾病为自身免疫性、慢性发炎性、慢性代谢性和传染性疾病中的一种或多种；
    和/或，所述的自身免疫性病症为发炎性肠病、全身性狼疮、类风湿性关节炎、1型糖尿病、牛皮癣、多发性硬化症；
    和/或，所述的慢性代谢性疾病为代谢综合征、肥胖、前驱糖尿病、心血管疾病和2型糖尿病；
    和/或，所述的传染性疾病为病毒性疾病。
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