A carbonyl heterocyclic compound and application thereof

Abstract

The application discloses a carbonyl heterocyclic compound and application thereof. The application provides a carbonyl heterocyclic compound as shown in formula II or a pharmaceutically acceptable salt thereof; the compound can be used as a compound with a targeted lipoamide synthetase C-like protein 2 path; and the compound can be used for treating various conditions, including infectious diseases, autoimmune diseases, diabetes and chronic inflammatory diseases.

Description

TECHNICAL FIELD

[0001] The present invention relates to a carbonyl heterocyclic compound and its use. BACKGROUND

[0002] Lanthionine C-like protein 2 (LANCL2), also known as "lathionine synthetase C-like protein 2" or "lathionine synthetase component C-like protein 2" is a signaling pathway protein of expressed immune cells, gastrointestinal tract, neurons, testes, and pancreas. Activation of the LANCL2 pathway increases insulin sensitivity and reduces inflammation associated with various autoimmune, inflammatory, and metabolic conditions. Results of in vivo and in vitro testing in mice show that using compounds targeting this pathway reduces glucose levels 2-fold in glucose tolerance tests and provides a 4-fold reduction in lesion number compared to controls (ELZULOX® (GlaxoSmithKline pic, Brentford, England)) is an effective treatment but has significant side effects. Targeting the LANCL2 pathway also reduces intestinal inflammation by 90% and correspondingly reduces lesion number by 4-fold. Results of this and other validation of the pathway have been mentioned in multiple articles.

[0003] Within the category of 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. There is also a pandemic of chronic metabolic inflammatory diseases including metabolic syndrome, obesity, prediabetes, cardiovascular disease, and type 2 diabetes. Current treatments are moderately effective but expensive and have serious side effects. The most effective treatments for autoimmune diseases, such as anti-TNF antibodies, are administered via IV or subcutaneous injection, thus requiring access to a clinic / surgery and frequent monitoring. The unique mode of action of LANCL2 provides an orally administered therapeutic as effective as anti-TNF antibodies but without side effects and high cost. Given the overall prevalence of inflammatory and autoimmune diseases, the LANCL2 pathway has the potential to significantly impact millions of patients.

[0004] Abscisic acid ("ABA") is a natural compound that binds to LANCL2 that was discovered in the original screening process.

[0005] A large number of compounds are described in the field of synthetic organic chemistry. Various compounds are provided by the following references: WO 1997 / 036866 by Diana et al., WO 2006 / 053109 by Sun et al., WO 2006 / 080821 by Kim et al., WO 2007 / 019417 by Nunes et al., WO 2009 / 067600 and WO 2009 / 067621 by Singh et al., WO 2008 / 079277 by Adams et al., JP 2008 / 056615 by Urasoe et al., WO 2011 / 066898 by Stoessel et al., US 2013 / 0142825 by Bassaganya-Riera et al., and U.S. Patent 7,741,367 by Bassaganya-Riera et al. International patent application WO2016064445 discloses a compound targeting the lanthionine synthetase C-like 2 pathway that can be used to treat a variety of conditions, including infectious diseases, autoimmune diseases, diabetes, and chronic inflammatory diseases. Some of the compounds known described in these references activate the LANCL2 pathway, while others do not. There is a need to develop novel ligands of the LANCL2 pathway to allow for specific customization of the treatment to the individual disease and potentially maximize its efficacy. SUMMARY

[0006] The technical problem to be solved by the present application is to overcome the problem of the lack of lanthionine synthetase C-like 2-based therapeutic agents in the prior art; and to provide a carbonyl heterocyclic compound and applications thereof. The carbonyl heterocyclic compound provided by the present application is a compound targeting the lanthionine synthetase C-like protein 2 pathway; the compound can bind to the LANCL2 protein and achieve a beneficial response in various disease conditions, which can be used to treat a variety of conditions, including metabolic and infectious diseases, autoimmune diseases, diabetes, and chronic inflammatory diseases.

[0007] The present application solves the above technical problem by the following technical scheme.

[0008] The present application provides a carbonyl heterocyclic compound as shown in Formula II or a pharmaceutically acceptable salt thereof;

[0009]

[0010] wherein A is or NR 1 R 2 ;

[0011] R 1 and R 2 are independently H or C6-18 aryl;

[0012] Y 1 and Y 2 Independently CH or N;

[0013] T represents a linker bond or -NH-;

[0014] Q is Or -NH-;

[0015] L 1 -Z 1 and Z 2 -L 2 Independently (i.e. L) 1 and L 2 (independently for connection keys) or (The b-terminus indicates that it is attached to a carbonyl group or B'), and not simultaneously...

[0016] Q Ring 2 It is a 5-7 membered cycloalkyl or a 5-7 membered monocyclic heterocyclic alkyl; the 5-7 membered monocyclic heterocyclic alkyl contains 1 to 3 N atoms;

[0017] B' is a connector key. -C(=O)-(5-7 membered cycloalkyl)-(right side is attached to A'), -C(=O)-(6-10 membered fused heterocyclic alkyl)-(right side is attached to A'), -C(=O)-(oxo-substituted 5-7 membered heterocyclic alkenyl)-(right side is attached to A'), Or -C(=O)-(7-10 fused heteroaryl)- (the right side is connected to A'); the 6-10 fused heterocyclic alkyl contains 1 to 3 N atoms; the C(=O)-(oxo-substituted 5-7 fused heterocyclic alkenyl)- contains 1 to 3 N atoms; the -C(=O)-(7-10 fused heteroaryl)- contains 1 to 3 N atoms;

[0018] Z 3 -L 3 Z 3a -L 3a For connecting bonds, -C(=O)- or -C(=O)-NH-;

[0019] Y 3 and Y 4 Independently CH or N;

[0020] Y 3a and Y 4a Independently CH or N;

[0021] R 3 C1-6 Alkyl groups;

[0022] A' is

[0023] NO2, -OC 1-6 alkyl, C 1-6 alkyl, Or H;

[0024] Y 5 For CH or N;

[0025] A carbon atom marked with an asterisk (*) indicates that when it is a chiral carbon atom, it is in the S configuration, R configuration, or a mixture thereof.

[0026] When Q is A is At that time, A and A' are different.

[0027] In certain preferred embodiments of the present invention, certain groups in the carbonyl heterocyclic compounds represented by Formula I, their pharmaceutically acceptable salts, their solvates, or salts of their solvates are defined as follows (groups not mentioned are as described in any embodiment of this application), hereinafter referred to as in certain preferred embodiments of the present invention.

[0028] In certain preferred embodiments of the present invention, when R 1 and R 2 Independently for C 6-18 When the aryl group is present, the C 6-14 The aryl group is phenyl, naphthyl, phenanthryl or anthracene, such as phenyl.

[0029] In certain preferred embodiments of the present invention for For example For example (End 'a' indicates the position connected to A)

[0030] In certain preferred embodiments of the present invention, when T is -NH-, for

[0031] In certain preferred embodiments of the present invention (When T is the connection key) is For example For example (End 'a' indicates the position connected to A)

[0032] In certain preferred embodiments of the present invention, Q 2 In the middle, Z 1 and Z 2 It is located adjacent, intermediate, or opposite.

[0033] In certain preferred embodiments of the application, when Q 2 When Q is 5-7 membered cycloalkyl, said 5-7 membered cycloalkyl is cyclopentyl, cyclohexyl or cycloheptyl; for example cyclohexyl, and alternatively, -C(=O)- is located at the ortho, meta or para position of A'; for example the meta position; and alternatively, -C(=O)-(5-7 membered cycloalkyl)- is

[0034] In certain preferred embodiments of the application, when Q 2 When Q is 5-7 membered monocyclic heterocycloalkyl, said 5-7 membered monocyclic heterocycloalkyl is N-heterocyclopentyl or N-heterocyclohexyl; for example (b end denotes attachment to the carbonyl group)

[0035] In certain preferred embodiments of the application, when B' is then, may be for example (a' end denotes attachment to A').

[0036] In certain preferred embodiments of the application, when B' is -C(=O)-(5-7 membered cycloalkyl)-, said 5-7 membered cycloalkyl is cyclopentyl, cyclohexyl or cycloheptyl; for example cyclohexyl, and alternatively, -C(=O)- is located at the ortho, meta or para position of A'; for example the meta position; and alternatively, -C(=O)-(5-7 membered cycloalkyl)- is

[0037] In certain preferred embodiments of the application, when B' is -C(=O)-(6-10 membered annulated heterocycloalkyl)-, said 6-10 membered annulated heterocycloalkyl is 8-10 membered annulated heterocycloalkyl, wherein the N atoms are 1 or 2, and one N atom is attached to -C(=O)-; for example -C(=O)-(6-10 membered annulated heterocycloalkyl)- is

[0038] In certain preferred embodiments of the application, when B' is -C(=O)-(oxo 5-7 membered heterocycloalkenyl), said 5-7 membered heterocycloalkenyl is heterocyclohexenyl, containing 2 N atoms; for example

[0039] In certain preferred embodiments of the application, when B' is -C(=O)-(oxo 5-7 membered heterocycloalkenyl), said -C(=O)-(oxo 5-7 membered heterocycloalkenyl is

[0040] In certain preferred embodiments of the application, when B' is -C(=O)-(7-10 membered annulated heteroaryl)-, said -C(=O)-(7-10 membered annulated heteroaryl)- is 6 membered heteroaryl annulated phenyl or 5 membered heteroaryl annulated phenyl, and alternatively quinolinyl (for example ) or indolyl (e.g. ).

[0041] In certain preferred embodiments of the application, when R 3 is alkyl, said alkyl is methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl or t-butyl, e.g. methyl. 1-6 1-6

[0042] In certain preferred embodiments of the application, Z 3a -L 3a is a bond, -C(=O)- or -C(=O)-NH-; e.g. -C(=O)-.

[0043] In certain preferred embodiments of the application, when B' is , may be e.g. e.g.

[0044] In certain preferred embodiments of the application, when A' is , is

[0045] In certain preferred embodiments of the application, A is

[0046] In certain preferred embodiments of the application, A is

[0047] In certain preferred embodiments of the application, A is

[0048] In certain preferred embodiments of the application, A is -NR 1 R 2 .

[0049] In certain preferred embodiments of the application, A is the same as A'; and / or, B' is the same as B.

[0050] In certain preferred embodiments of the application, (when T is a bond) is of the following structure: may also be

[0051] In certain preferred embodiments of the application, Q is Q 2 is 5-7 membered cycloalkyl, L​​1 -Z 1 and Z 2 -L 2 are independently for example is

[0052] In certain preferred embodiments of the application, Q is

[0053] Q is when Q 2 -L 1 -Z 1 and Z 2 -L 2 one is the other is for example is (b denotes attachment to the carbonyl group).

[0054] In certain preferred embodiments of the application, Q is or -NH-.

[0055] In certain preferred embodiments of the application, B' is a bond and A' is

[0056] In certain preferred embodiments of the application, B' is A' is NO2, -O-C 1-6 alkyl, C 1-6 alkyl, or H, and also or NO2.

[0057] In certain preferred embodiments of the application, B' is -C(=O)-(5-7 membered cycloalkyl)- and A' is

[0058] In certain preferred embodiments of the application, B' is -C(=O)-(6-10 membered annelated heterocycloalkyl)- and A' is

[0059] In certain preferred embodiments of the application, B' is -C(=O)-(oxo-5-7 membered heterocycloalkenyl)- and A' is H.

[0060] In certain preferred embodiments of the application, B' is A' is

[0061] In certain preferred embodiments of the application, B' is A' is H.

[0062] In certain preferred embodiments of the application, B' is -C(=O)-(7-10 membered annulated heteroaryl)-, and A' is H.

[0063] In certain preferred embodiments of the application, B'-A' is of the structure:

[0064]

[0065] In certain preferred embodiments of the application,

[0066] wherein A is or NR 1 R 2 ;

[0067] R 1 and R 2 are independently H or C 6-18 aryl;

[0068] Y 1 and Y 2 are independently CH or N;

[0069] T is a bond or -NH-;

[0070] Q is or -NH-;

[0071] L 1 -Z 1 and Z 2 -L 2 are independently and not simultaneously ring Q 2 is 5-7 membered monocyclic heterocycloalkyl; 5-7 membered monocyclic heterocycloalkyl containing from 1 to 3 N atoms;

[0072] B' is -C(=O)-(oxo 5-7 membered heterocycloalkenyl)-, or -C(=O)-(7-10 membered annulated heteroaryl)-;

[0073] Z 3 -L 3 , Z 3a -L 3a is a bond, -C(=O)- or -C(=O)-NH-;

[0074] Y 3 and Y 4independently CH or N;

[0075] Y 3a and Y 4a independently CH or N;

[0076] R 3 is C 1-6 alkyl;

[0077] A' is -O-C 1-6 alkyl, C 1-6 alkyl, or H;

[0078] Y 5 is CH or N;

[0079] the carbon atom marked with "*" represents S configuration, R configuration or mixture thereof when it is a chiral carbon atom;

[0080] when Q is A is A and A' are different.

[0081] In certain preferred embodiments of the present application,

[0082] wherein A is or NR 1 R 2 ;

[0083] R 1 and R 2 independently H or C 6-18 aryl;

[0084] Y 1 and Y 2 independently CH or N;

[0085] T is a bond or -NH-;

[0086] Q is or -NH-;

[0087] L 1 -Z 1 and Z 2 -L 2 independently and are not simultaneously

[0088] the ring Q 2 is 5-7 membered cycloalkyl or 5-7 membered monocyclic heterocycloalkyl; in the 5-7 membered monocyclic heterocycloalkyl, there are 1 to 3 N atoms;

[0089] B' is a bond, -C(=O)-(5-7 membered cycloalkyl)- or -C(=O)-(6-10 membered annulated heterocycloalkyl)-;

[0090] Z 3 -L 3 is a bond, -C(=O)- or -C(=O)-NH-;

[0091] Y 3 and Y 4 are independently CH or N;

[0092] A' is

[0093] NO2or -O-C 1-6 alkyl;

[0094] Y 5 is CH or N;

[0095] the carbon atom marked with an "*" represents the S configuration, the R configuration or a mixture thereof when it is a chiral carbon atom.

[0096] In certain preferred embodiments of the application,

[0097] wherein A is or NR 1 R 2 ;

[0098] R 1 and R 2 are independently H or C 6-18 aryl;

[0099] Y 1 and Y 2 are independently CH or N;

[0100] T is a bond or -NH-;

[0101] Q is or -NH-;

[0102] L 1 -Z 1 and Z 2 -L 2 are independently and are not simultaneously

[0103] the ring Q 2 is 5-7 membered cycloalkyl or 5-7 membered monocyclic heterocycloalkyl; in the 5-7 membered monocyclic heterocycloalkyl, there are 1 to 3 N atoms;

[0104] B' is a bond, -C(=O)-(5-7 membered cycloalkyl)- or -C(=O)-(6-10 membered fused heterocyclic alkyl)-;

[0105] Z 3 -L 3 For connecting bonds, -C(=O)- or -C(=O)-NH-;

[0106] Y 3 and Y 4 Independently CH or N;

[0107] A' is NO2 or -OC 1-6 Alkyl groups;

[0108] Y 5 For CH or N;

[0109] A carbon atom marked with an asterisk (*) indicates that, when it is a chiral carbon atom, it is in the S configuration, R configuration, or a mixture thereof.

[0110] In certain preferred embodiments of the present invention

[0111] Where A is or NR 1 R 2 ;

[0112] R 1 and R 2 Independently H or C 6-18 aryl;

[0113] Y 1 and Y 2 Independently CH or N;

[0114] T stands for connection key;

[0115] Q is

[0116] B' is a connector key. -C(=O)-(oxo-substituted 5-7 membered heterocyclic alkenyl)-, Or -C(=O)-(7-10 fused heteroaryl groups)-;

[0117] Z 3 -L 3 Z 3a -L 3a For connecting bonds, -C(=O)- or -C(=O)-NH-;

[0118] Y 3 and Y 4 Independently CH or N;

[0119] Y 3a and Y 4a is independently CH or N;

[0120] R 3 is C 1-6 alkyl;

[0121] A' is C 1-6 alkyl, or H;

[0122] Y 5 is CH or N;

[0123] the carbon atom with "*" indicates S configuration, R configuration or mixture thereof when it is a chiral carbon atom;

[0124] when Q is A is A and A' are different.

[0125] In certain preferred embodiments of the present application,

[0126] wherein A is Y 1 and Y 2 is independently CH or N;

[0127] T is a bond;

[0128] Q is

[0129] B'-A' is the following structure:

[0130] when A is A and A' are different.

[0131] In certain preferred embodiments of the present application,

[0132] wherein A is

[0133] T is a bond;

[0134] Q is

[0135] B'-A' is the following structure:

[0136] In certain preferred embodiments of the present application,

[0137] A is or NR 1 R2 ;

[0138] R 1 and R 2 are independently H or C 6-18 aryl

[0139] Y 1 and Y 2 are independently CH or N;

[0140] T is a bond;

[0141] Q is

[0142] L 1 -Z 1 and Z 2 -L 2 are independently and are not simultaneously

[0143] ring Q 2 is 5-7 membered monocyclic heterocycloalkyl;

[0144] B' is a bond, -C(=O)-(5-7 membered cycloalkyl)- or -C(=O)-(6-10 membered annulated heterocycloalkyl)-;

[0145] Z 3 -L 3 is a bond, -C(=O)- or -C(=O)-NH-;

[0146] Y 3 and Y 4 are independently CH or N.

[0147] A' is

[0148] NO2, or -O-C 1-6 alkyl;

[0149] Y 5 is CH or N;

[0150] the carbon atom marked with an "*" represents the S configuration, the R configuration or a mixture thereof when it is a chiral carbon atom.

[0151] In certain preferred embodiments of the present application,

[0152] A is or NR 1 R 2 ;

[0153] R 1 and R2 Independently H or C 6-18 aryl;

[0154] Y 1 and Y 2 Independently CH or N;

[0155] T stands for connection key;

[0156] Q is

[0157] L 1 -Z 1 and Z 2 -L 2 Independently And not at the same time

[0158] Q Ring 2 It is a 5-7 membered monocyclic heterocyclic alkyl group;

[0159] B' is Or -C(=O)-(5-7 membered cycloalkyl)-;

[0160] Z 3 -L 3 For connecting bonds, -C(=O)- or -C(=O)-NH-;

[0161] Y 3 and Y 4 Independently, it can be CH or N.

[0162] A' is or -OC 1-6 Alkyl groups;

[0163] Y 5 For CH or N;

[0164] A carbon atom marked with an asterisk (*) indicates that, when it is a chiral carbon atom, it is in the S configuration, R configuration, or a mixture thereof.

[0165] In certain preferred embodiments of the present invention

[0166] A is For example

[0167] Y 1 and Y 2 Independently CH or N;

[0168] Q is

[0169] B' is

[0170] Z 3-L 3 is -C(=O)-;

[0171] Y 3 and Y 4 independently is CH or N;

[0172] A' is for example

[0173] Preferably, is

[0174] and / or, B' is

[0175] More preferably, A is the same as A';

[0176] and / or, the same as B'.

[0177] In certain preferred embodiments of the present application, the carbonyl heterocyclic compound of Formula II is of Formula II-a:

[0178]

[0179] wherein A is

[0180] Y 1 and Y 2 independently is CH or N;

[0181] Q is

[0182] L 1 -Z 1 and Z 2 -L 2 independently is (i.e., L 1 and L 2 independently is a bond) or (b end indicates attachment to carbonyl group), and is not simultaneously

[0183] ring Q 2 is 5-7 membered cycloalkyl or 5-7 membered monocyclic heterocycloalkyl; the 5-7 membered monocyclic heterocycloalkyl contains from 1 to 3 N atoms;

[0184] B' is a bond, -C(=O)-(5-7 membered cycloalkyl)- or -C(=O)-(6-10 membered fused heterocycloalkyl)-(right side indicates attachment to A'); the 6-10 membered fused heterocycloalkyl contains from 1 to 3 N atoms;

[0185] Z 3 -L 3 is a bond, -C(=O)- or -C(=O)-NH-;

[0186] Y 3 and Y 4 are independently CH or N;

[0187] A' is or NO2.

[0188] Y 5 is CH or N;

[0189] the carbon atom marked with an "*" represents, when a chiral carbon atom, the S configuration, the R configuration or a mixture thereof.

[0190] In certain preferred embodiments of the application, is the following structure:

[0191] In certain preferred embodiments of the application, B' is A' is or NO2.

[0192] In certain preferred embodiments of the application, B'-A' is the following structure: In certain preferred embodiments of the application, A is Y 1 and Y 2 are independently CH or N;

[0193] Q is

[0194] L 1 -Z 1 and Z 2 -L 2 are independently (i.e. L 1 and L 2 are independently a bond) or (b denotes attachment to the carbonyl group) and are not simultaneously

[0195] Q 2 is 5-7 membered cycloalkyl or 5-7 membered monocyclic heterocycloalkyl; in the 5-7 membered monocyclic heterocycloalkyl, there are 1 to 3 N atoms; for example, in addition to Z 1 and Z 2 are carbon;

[0196] B' is a bond, -C(=O)-(5-7 membered cycloalkyl)- or -C(=O)-(6-10 membered annulated heterocycloalkyl)- (right side is attached to A'); said 6-10 membered annulated heterocycloalkyl contains from 1 to 3 N atoms; for example, the ring atoms other than the N atom attached to the carbonyl or A' are carbon;

[0197] Z 3 -L 3 is a bond, -C(=O)- or -C(=O)-NH-;

[0198] Y 3 and Y 4 are independently CH or N;

[0199] A' is or NO2;

[0200] Y 5 is CH or N.

[0201] In certain preferred embodiments of the application, the carbonyl heterocyclic compound of Formula II is any one of the following:

[0202] A is

[0203] is

[0204] Q is

[0205] B' is a bond,

[0206] A' is or NO2; Y 5 is CH or N.

[0207] In certain preferred embodiments of the application, the carbonyl heterocyclic compound of Formula II is any one of the following:

[0208]

[0209]

[0210]

[0211] In the present application, the carbonyl heterocyclic compound of Formula II or a pharmaceutically acceptable salt thereof has one or more chiral carbon atoms, and therefore can be isolated as optically pure isomers, such as pure enantiomers, or as racemates, or as mixtures of isomers. Pure single isomers can be obtained by separation methods known in the art, such as chiral crystallization of a salt, or separation on a chiral preparative column.

[0212] In the present application, the carbonyl heterocyclic compounds of Formula II or pharmaceutically acceptable salts thereof, if present as stereoisomers, can exist in the form of a single stereoisomer or a mixture thereof (e.g., racemate). The term "stereoisomer" refers to cis-trans isomers or optical isomers. These stereoisomers can be separated, purified and enriched by asymmetric synthesis methods or chiral separation methods (including but not limited to thin layer chromatography, rotary chromatography, column chromatography, gas chromatography, high pressure liquid chromatography, etc.), and can also be obtained by chiral resolution through bonding (chemical combination, etc.) or salification (physical combination, etc.) with other chiral compounds. The term "single stereoisomer" refers to the mass content of one stereoisomer of the compound of the present application relative to all stereoisomers of the compound is not less than 95%.

[0213] The carbonyl heterocyclic compounds of Formula II or pharmaceutically acceptable salts thereof described in the present application can be synthesized by methods including methods known in the art, and the steps and conditions can refer to the steps and conditions of similar reactions in the art, and are particularly synthesized according to the description herein. The starting materials are usually obtained from commercial sources, such as Aldrich, or can be easily prepared by methods known to those skilled in the art (obtained by SciFinder, Reaxys online database).

[0214] The necessary raw materials or reagents for preparing the carbonyl heterocyclic compounds of Formula II or pharmaceutically acceptable salts thereof can be commercially available, or prepared by known synthesis methods in the art. As described in the experimental section below, the compounds of the present application can be prepared as free bases or their acid salts. The term "pharmaceutically acceptable salt" refers to a pharmaceutically acceptable salt as defined herein, and has all the effects of the parent compound. The pharmaceutically acceptable salt can be prepared by adding the corresponding acid to the organic base in a suitable organic solvent, and treating according to conventional methods to prepare the pharmaceutically acceptable salt.

[0215] Examples of salt formation include: for base addition salts, it is possible to prepare alkali metal (such as sodium, potassium or lithium) or alkaline earth metal (such as aluminum, magnesium, calcium, zinc or bismuth) salts by treating the compounds of the present application with alkali metal or alkaline earth metal hydroxides or alkoxides (such as ethanolate or methanolate) or appropriate basic organic amines (such as diethanolamine, choline or meglumine) in aqueous media.

[0216] or, for acid addition salts, salts 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, camphorsulfonic acid, citric acid, ethanesulfonic acid, fumaric acid, glucoheptonic acid, glutamic acid, glycolic acid, hydroxynaphthalene carboxylic 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, cinnamic acid, p-toluenesulfonic acid or trimethylacetic acid.

[0217] In the present application, the carbonyl heterocyclic compound of formula II or a pharmaceutically acceptable salt thereof can also be obtained by peripherally modifying the already prepared carbonyl heterocyclic compound of formula II or a pharmaceutically acceptable salt thereof using conventional methods in the art to obtain other carbonyl heterocyclic compounds of formula II or a pharmaceutically acceptable salt thereof.

[0218] Generally, the compounds of the present application can be prepared by the methods described herein, unless otherwise indicated, wherein the substituents are as defined in formula II.

[0219] The present application also provides a pharmaceutical composition comprising a carbonyl heterocyclic compound of formula II or a pharmaceutically acceptable salt thereof as described above, and one or more pharmaceutically acceptable carriers. In the pharmaceutical composition, the carbonyl heterocyclic compound of formula II or a pharmaceutically acceptable salt thereof can be present in a therapeutically effective amount.

[0220] The pharmaceutically acceptable carriers (pharmaceutical excipients) can be those commonly used in the pharmaceutical production field. The excipients are mainly used to provide a safe, stable and functional pharmaceutical composition, and can also provide a method for allowing the active ingredient to be dissolved at a desired rate after administration to a subject, or to facilitate effective absorption of the active ingredient after administration of the composition to a subject. The pharmaceutical excipients can be inert fillers, or provide certain functions, such as stabilizing the overall pH of the composition or preventing degradation of the active ingredients of the composition. The pharmaceutical excipients can include one or more of the following excipients: binders, suspending agents, emulsifiers, diluents, fillers, granulating agents, adhesives, disintegrants, lubricants, anti-adherents, glidants, wetting agents, gelling agents, absorption delaying agents, dissolution inhibitors, enhancers, adsorbents, buffers, chelating agents, preservatives, colorants, flavorings and sweeteners.

[0221] The pharmaceutical composition of the present application can be prepared according to the disclosure using any method known to those skilled in the art. For example, conventional mixing, dissolving, granulating, emulsifying, dragee-making, encapsulating, entrapping or lyophilizing processes.

[0222] The pharmaceutical compositions described herein can be administered in any form including injection (intravenous), mucosal, oral (solid and liquid formulations), inhalation, ocular, rectal, topical, or parenteral (infusion, injection, implantation, subcutaneous, intravenous, intra-arterial, intramuscular) administration. The pharmaceutical compositions of the present application can also be in a controlled or delayed release dosage form (e.g., liposome or microsphere). Examples of solid oral formulations include, but are not limited to, powders, capsules, caplets, soft capsules, and tablets. Examples of liquid formulations for oral or mucosal administration include, but are not limited to, suspensions, emulsions, elixirs, and solutions. Examples of topical formulations include, but are not limited to, emulsions, gels, ointments, creams, patches, pastes, foams, lotions, drops, or serums. Examples of 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. Examples of other suitable formulations of the pharmaceutical compositions described herein include, but are not limited to, eye drops and other ophthalmic formulations; aerosols: such as nasal sprays or inhalers; liquid dosage forms suitable for parenteral administration; suppositories; and lozenges.

[0223] The present application also provides a use of the carbonyl heterocyclic compound of Formula II or a pharmaceutically acceptable salt thereof in the preparation of a lantibiotic-like protein 2 (LANCL2) agonist. In the use, the lantibiotic-like protein 2 (LANCL2) activator can be used in vivo in a mammalian organism; can also be used in vitro, mainly as a standard or control sample for comparison, or prepared into a kit according to the conventional method in the art, to provide a rapid detection of the activation effect of lantibiotic-like protein 2 (LANCL2).

[0224] The present application also provides a use of the carbonyl heterocyclic compound of Formula II or a pharmaceutically acceptable salt thereof in the preparation of a medicament; the medicament can be a medicament for preventing and / or treating a disease related to lantibiotic-like protein 2 (LANCL2). The disease related to lantibiotic-like protein 2 (LANCL2) can be one or more of autoimmune, chronic inflammatory, chronic metabolic, and infectious diseases.

[0225] The present application also provides a use of the carbonyl heterocyclic compound of Formula II, a pharmaceutically acceptable salt thereof, or the above-mentioned composition in the preparation of a medicament; the medicament can be a medicament for preventing and / or treating autoimmune, chronic inflammatory, chronic metabolic, or infectious diseases.

[0226] Another aspect of the present application relates to a method of preventing and / or treating a lanthionine C-like protein 2 (LANCL2) related disease comprising administering to a patient a therapeutically effective amount of said carbonyl heterocyclic compound of Formula II, a pharmaceutically acceptable salt thereof or a pharmaceutical composition comprising the same as described above.

[0227] Another aspect of the present application relates to a method of treating a method of preventing and / or treating an autoimmune, a chronic inflammatory, a chronic metabolic or an infectious disease comprising administering to a patient a therapeutically effective amount of said carbonyl heterocyclic compound of Formula II, a pharmaceutically acceptable salt thereof or a composition as described above.

[0228] Another aspect of the present application relates to a medicament for lanthionine C-like protein 2 (LANCL2) comprising said carbonyl heterocyclic compound of Formula II, a pharmaceutically acceptable salt thereof or a composition as described above.

[0229] The autoimmune disorder as described above can be inflammatory bowel disease (IBD) (including ulcerative colitis and / or Crohn’s disease), systemic lupus, rheumatoid arthritis, type 1 diabetes, psoriasis, multiple sclerosis.

[0230] The chronic metabolic disease as described above can be metabolic syndrome, obesity, prediabetes, cardiovascular disease and type 2 diabetes.

[0231] The infectious disease as described above can be a viral disease, such as influenza infection.

[0232] The present application 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 the animal an effective amount of one or more of the compounds described herein. The condition can be selected from the group consisting of an infectious disease, an autoimmune disease, diabetes, and a chronic inflammatory disease. In some methods, the infectious disease comprises a viral disease, such as influenza infection. In some methods, the autoimmune disease comprises an autoimmune inflammatory disease, such as inflammatory bowel disease, including ulcerative colitis and / or Crohn’s disease. In some methods, the diabetes is selected from the group consisting of type 1 diabetes and type 2 diabetes. In some methods, the chronic inflammatory disease comprises metabolic syndrome. In some methods, the methods comprise administering an amount of a compound effective to increase LANCL2 activity, reduce inflammation, and / or increase anti-inflammatory effects.

[0233] The present disclosure 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 can comprise administering to the animal an effective amount of one or more of the compounds described herein, wherein the condition is selected from the group consisting of an infectious disease, an autoimmune disease, diabetes, and a chronic inflammatory disease. In some versions, the infectious disease comprises a viral disease, such as an influenza infection. In some versions, the autoimmune disease comprises an autoimmune inflammatory disease, such as an inflammatory bowel disease, including ulcerative colitis and / or Crohn’s disease. In some versions, the diabetes is selected from the group consisting of type 1 diabetes and type 2 diabetes. In some versions, the chronic inflammatory disease comprises metabolic syndrome. In some versions, the compound is effective to increase LANCL2 activity, reduce inflammation, and / or increase anti-inflammatory effects.

[0234] The term "pharmaceutically acceptable" means that the salt, solvent, adjuvant, etc. is not toxic or safe and appropriate for patient use. The "patient" is preferably a mammal, more preferably a human.

[0235] The term "pharmaceutically acceptable salt" means a salt of a compound of the present disclosure prepared from a relatively non-toxic, pharmaceutically acceptable acid.

[0236] "Treatment" means any treatment of a disease in a mammal, including: (1) preventing the disease, that is, causing the clinical symptoms of the disease not to develop; (2) inhibiting the disease, that is, arresting the development of clinical symptoms; and (3) relieving the disease, that is, causing the regression of clinical symptoms.

[0237] "Effective amount" means the amount of a compound that, when administered to a patient in need of treatment, is sufficient to (i) treat the relevant disease, (ii) attenuate, ameliorate, or eliminate one or more symptoms of a particular disease or condition, or (iii) delay the onset of one or more symptoms of a particular disease or condition described herein. The amount of the carbonyl heterocycle compound of Formula II or a pharmaceutically acceptable salt thereof or a pharmaceutical composition as described above that corresponds to such an amount will vary depending, for example, on the particular compound, the disease condition and its severity, the identity (e.g., weight) of the patient in need of treatment, and other factors, but can nevertheless be routinely determined by a person of ordinary skill in the art.

[0238] "Prevention" as described herein means a reduction in the risk of acquiring or developing a disease or disorder.

[0239] "Pharmaceutical composition" as described herein means a preparation of one or more compounds of the present disclosure or salts thereof with a carrier that is commonly accepted in the art for delivery of biologically active compounds to an organism (e.g., a human). The purpose of a pharmaceutical composition is to facilitate administration of delivery to an organism.

[0240] The term "pharmaceutically acceptable carrier" means a material which is not biologically or otherwise undesirable, with which the active ingredients are combined for administration of the active ingredients, including but not limited to any of the adjuvants, diluents, preservatives, dyes, colorings, flavorings, surface-active or wetting agents, dispersing agents, or emulsifying agents, suspending or stabilizing agents, isotonic, or absorption delaying agents, and the like that are approved by the State Food and Drug Administration for use in humans or animals (e.g., domestic animals) that are well-known in the art. These can include but are not limited to calcium carbonate, calcium phosphate, various sugars and types of starch, cellulose derivatives, gelatin, vegetable oils, and polyethylene glycols.

[0241] The pharmaceutical composition described in the present application can be formulated into solid, semi-solid, liquid or gaseous preparations such as tablets, pills, capsules, powders, granules, pastes, emulsions, suspensions, solutions, suppositories, injections, inhalants, gels, microspheres, aerosols, and the like.

[0242] The pharmaceutical composition described in the present application can be manufactured by methods well known in the art, such as conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, freeze-drying, or the like.

[0243] The route of administration of the compound described in the present application or its pharmaceutically acceptable salt or its pharmaceutical composition includes but is not limited to oral, rectal, transmucosal, enteral administration, or topical, transdermal, inhalation, parenteral, sublingual, intravaginal, intranasal, intraocular, intraperitoneal, intramuscular, subcutaneous, intravenous administration. The preferred route of administration is oral administration.

[0244] For oral administration, the pharmaceutical composition can be formulated by mixing the active compound with a pharmaceutically acceptable carrier well known in the art. These carriers can enable the compound of the present application to be formulated into tablets, pills, dragees, capsules, liquids, gels, slurries, suspensions, and the like, for oral administration to a patient. For example, the pharmaceutical composition for oral administration can be obtained in the form of tablets by combining the active ingredient with one or more solid carriers, if desired, granulating and then processing the mixture or granules, if desired, with little amounts of excipients to form a tablet or a tablet core. The tablet cores can be combined with optional enteric coatings, which are suitable for the intestinal tract, to form coated tablet formulations that are more advantageous for absorption by an organism (e.g., a human).

[0245] The following definitions shall apply unless otherwise indicated. For the purposes of the present application, the chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, and the American Chemical Society. Additionally, general principles of organic chemistry are described in "Organic Chemistry", Thomas Sorrell, University Science Books, Sausalito: 1999, and "March's Advanced Organic Chemistry" by Michael B. Smith and Jerry March, John Wiley & Sons, New York: 2007, the entire contents of which are incorporated herein by reference.

[0246] In this specification, groups of substituents can be chosen by one skilled in the art to provide stable moieties and compounds. When describing substituents by their conventional chemical formulae, it is understood that these are meant to describe the substituents alone and not in combination. For example, the description "alkyl" is understood to describe an alkyl group alone and not in combination with another substituent unless the description is specifically recited otherwise to form a substituent group, e.g., "alkylcarbonyl."

[0247] In this specification, certain chemical groups are defined herein before which a shorthand notation is used to indicate the total number of carbon atoms present in the group. For example, C1-C6alkyl 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 shorthand notation does not include carbon atoms that can be present in substituents of the group.

[0248] In this specification, numerical ranges are defined as including the integers within the range. For example, the range 1 -6 is defined as including the integers 1, 2, 3, 4, 5, and 6.

[0249] In addition to the foregoing, the following terms, as used in the specification and claims, shall have the meanings indicated below, unless explicitly stated otherwise.

[0250] The term "comprising" is a open term, i.e. including, but not excluding, other elements.

[0251] The term "substituted" means that any one or more hydrogen atoms on the particular atom is replaced with a substituent group, including deuterium and variants of hydrogen, as long as the valency of the particular atom is not normally changed and the resulting compound is stable.

[0252] In general, the term "substituted" means that one or more hydrogen atoms in a given structure are replaced by a particular substituent. Further, when a group is substituted with more than one of such substituents, the substituents are independent of each other, i.e., the substituents can be the same or different. Unless otherwise indicated, a substituent group can be substituted at any available unsaturated carbon atom. When more than one position in a given structure is available for substitution, the substituents can be the same or different at each available position. When a given structure is substituted with more than one substituent, the substituents are independent of each other, i.e., the substituents can be the same or different.

[0253] The terms "one or more" or "one or more than two" mean 1, 2, 3, 4, 5, 6, 7, 8, 9, or more; for example, 1, 2, 3, 4, or 5.

[0254] In the present application, the term "cycloalkyl", as a group or part of a group, means a saturated monocyclic, polycyclic, or bridged carbocyclic substituent consisting solely of carbon and hydrogen atoms, and which can be attached to the rest of the molecule through a single bond via any available carbon atom; when polycyclic, can be a spiro system or a bridged system of fused (annular) or bridged (bicyclic) ring systems (i.e., two geminal hydrogens on a carbon atom are replaced by an alkylene group).

[0255] In the present application, the term "heterocycloalkyl", as a group or part of a group, means a stable 3- to 16-membered saturated cyclic radical consisting of 2-11 carbon atoms and 1-5 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. Unless otherwise specifically indicated herein, a heterocycloalkyl group can be monocyclic ("monocyclic heterocycloalkyl") or a bicyclic, tricyclic, or more ring system, which can include fused (annular), bridged (bicyclic), or spiro (spirocyclic) ring systems (e.g., a bicyclic system ("bicyclic heterocycloalkyl"). A heterocycloalkyl bicyclic ring system can include one or more heteroatoms in one or both rings; and is saturated.

[0256] The terms "moiety", "structural moiety", "chemical moiety", "group", "chemical group" as used herein refer to a specific fragment or functional group in a molecule. A chemical moiety is generally considered to be a chemical entity that is embedded in or appended to a molecule.

[0257] When an enumerated substituent does not specify through which atom of the chemical structure formula it is attached to the compound included but not specifically named, the substituent can be bonded through any atom thereof. Combinations of substituents and / or variables are permissible only if such combinations result in stable compounds.

[0258] When a group is recited without explicit indication that it bears a substituent, the group refers only to the unsubstituted version of the group. For example, when "C1-C4alkyl" is recited without the qualifier "substituted or unsubstituted," it refers only to the "C1-C4alkyl" group itself or "unsubstituted C1-C4alkyl."

[0259] In various portions of the application, connecting substituents are described. When the structure clearly requires a connecting group, the Markush variable recited for that group should be understood to be a connecting group. For example, if the structure requires a connecting group and the Markush group definition recited for that variable recites "alkyl" or "aryl," then it should be understood that the "alkyl" or "aryl" represents a connected alkylene group or arylene group, respectively.

[0260] In some specific structures, when an alkyl group is clearly indicated to be a connecting group, then the alkyl group represents a connected alkylene group, for example, the C1-C6alkyl in the group "halo-C1-C6alkyl" should be understood to be C1-C6alkylene.

[0261] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as is commonly understood by one of ordinary skill in the art to which the claimed subject matter belongs. In the event that there is a plurality of definitions for a term herein, those in this section prevail.

[0262] It should be understood that, as used in the present application, the singular form "a", "an", and "the" include plural references unless otherwise stated. In addition, the term "comprising" is an open term not a closed one, i.e., it includes the explicitly identified items, but not excluding other items.

[0263] Unless otherwise indicated, the present application employs the conventional methods of mass spectroscopy, elemental analysis, and the conventional procedures of the art for each of the steps and conditions.

[0264] Unless otherwise indicated, the present application employs standard nomenclature used in analytical chemistry, organic synthesis chemistry, and optics, and standard laboratory procedures and techniques. In certain instances, standard techniques are used for chemical synthesis, chemical analysis, and testing of luminescent device performance.

[0265] In addition, it should be noted that, unless otherwise explicitly indicated, the description "independently" employed in the present application should be interpreted broadly, i.e., it means that each individual described is independent of the other, and can be the same or different specific group. In more detail, the description "independently" can mean that the specific options expressed by the same symbol in different groups are independent of each other; or it can mean that the specific options expressed by the same symbol in the same group are independent of each other.

[0266] As will be understood by those skilled in the art, the use of the following terms in the structural formulae of the groups described in the present application is in accordance with the conventions used in the art: This refers to the fact that the corresponding group is connected to other fragments or groups in the compound through this site.

[0267] Without violating common sense in the field, the above-mentioned preferred conditions can be combined arbitrarily to obtain various preferred embodiments of the present invention.

[0268] The reagents and raw materials used in this invention are all commercially available.

[0269] The positive and progressive effects of this invention are as follows: the carbonyl heterocyclic compounds provided by this invention are compounds that target the lanthanine synthase C-like protein 2 pathway; the compounds can be used to treat a variety of conditions, including infectious diseases, autoimmune diseases, diabetes, and chronic inflammatory diseases. Attached Figure Description

[0270] Figure 1 Binding curve of compound L7-LANCL2

[0271] Figure 2 Binding curve of compound L8-LANCL2

[0272] Figure 3 Binding curve of compound L12-LANCL2

[0273] Figure 4 Binding curve of compound L17-LANCL2

[0274] Figure 5 Binding curve of compound L22-LANCL2

[0275] Figure 6 Binding curve of compound L28-LANCL2

[0276] Figure 7 Binding curve of compound L29-LANCL2

[0277] Figure 8 Binding curve of compound L30-LANCL2

[0278] Figure 9 Binding curve of compound L32-LANCL2

[0279] Figure 10 Binding curve of compound L37-LANCL2

[0280] Figure 11 Binding curve of compound L44-LANCL2

[0281] Figure 12 Binding curve of compound L56-LANCL2

[0282] Figure 13 Mouse weight change and DAI score (Compound L30, Compound L56 and control group), wherein, A) weight change data curve, B) DAI score data

[0283] Figure 14 Mouse colon weight to length ratio change (Compound L30, Compound L56 and control group), wherein, A) colon weight to length ratio, B) colon length, C) colon weight

[0284] Figure 15 Intestinal morphology (Compound L30, Compound L56 and control group)

[0285] Figure 16 Mouse weight change and DAI score (Compound L11, Compound L25, Compound L84, Compound L77, Compound L101, Compound L10, Compound L23 and control group), wherein, A) weight change data curve, B) DAI score data

[0286] Figure 17 Mouse diarrhea and blood stool score (Compound L11, Compound L25, Compound L84, Compound L77, Compound L101, Compound L10, Compound L23 and control group), wherein, A) mouse diarrhea change, B) blood stool change

[0287] Figure 18 Mouse colon weight to length ratio change (Compound L11, Compound L25, Compound L10 and control group), wherein, A) colon length, B) colon weight, C) colon weight to length ratio

[0288] Figure 19 Intestinal morphology (Compound L11, Compound L10 and control group) DETAILED DESCRIPTION

[0289] The present application is further illustrated by the following examples, but the present application is not limited to the examples. The experimental methods in the following examples, unless otherwise specified, are selected according to the conventional methods and conditions, or according to the product instructions.

[0290] Example 1: 6-(1H-benzo[d]imidazol-2-yl)-N-(3-(3-(3-(imidazoleazo[1,2-a]pyridin-2-yl)benzoyl)-3-azabicyclo[3.1.0]hexan-6-yl)picolinamide (L-1)

[0291]

[0292] I. Synthesis of methyl 3-(imidazo[1,2-a]pyridine-2-yl)benzoate

[0293]

[0294] Methyl 3-(imidazo[l,2-a]pyridin-2-yl)benzoate (1.8 g, 7.4 mmol) and lithium hydroxide (0.88 g, 37 mmol) were dissolved in ethanol and water (v / v = 10: 1) 20 mL at room temperature, heated to reflux, LC-MS monitored the reaction to end. The reaction was concentrated under reduced pressure, the concentrated solution was column chromatography on silica gel to give white solid (1.6 g, 0.67 mmol), the yield was 90%. LC-MS: 238.07. + : 253.09

[0295] II. Synthesis of 3-(imidazo[l,2-a]pyridin-2-yl)benzoic acid

[0296]

[0297] Methyl 3-(imidazo[l,2-a]pyridin-2-yl)benzoate (1.8 g, 7.4 mmol) and lithium hydroxide (0.88 g, 37 mmol) were dissolved in ethanol and water (v / v = 10: 1) 20 mL at room temperature, heated to reflux, LC-MS monitored the reaction to end. The reaction was concentrated under reduced pressure, the concentrated solution was column chromatography on silica gel to give white solid (1.6 g, 0.67 mmol), the yield was 90%. LC-MS: 238.07.

[0298] III. Synthesis of N,N'-(l,2-phenylenediamine)bis(3-(imidazo[l,2-a]pyridin-2- yl)benzamide

[0299]

[0300] To a solution of 3-(imidazo[l,2-a]pyridin-2-yl)benzoic acid (0.12 g, 0.5 mmol), l-(3- dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (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-dimethylformamide 6 mL was added o-phenylenediamine (0.024 g, 0.228 mmol) under ice bath. The mixture was stirred for 0.5 h and then allowed to warm to room temperature and stirred overnight. The reaction mixture was poured into 20 mL of water and extracted with ethyl acetate (20 mL x 3), washed with saturated brine, combined organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (DCM:MeOH = 20: 1) to give white solid (15 mg, 2.7 μmol) in 5.4% yield. LC-MS: m / z: (M+H)+= 549.

[0301] 1 H NMR (400 MHz, Chloroform-d) δ 9.42 (s, 2H), 8.54 (t, J = 1.8 Hz, 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).

[0302] Example 2 6-(lH-Benzo[d]imidazol-2-yl)-N-(3-(3-(3-(imidazo[l,2-a]pyridin-2- yl)benzoyl)-3-azabicyclo[3.1.0]hexan-6-yl)pyridine amide (L-2)

[0303]

[0304] To a stirred solution of 3-(imidazo[l,2-a]pyridin-2-yl)benzoic acid (0.12 g, 0.5 mmol), l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (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-dimethylformamide 6 mL, 6-(lH-benzo[d]imidazol-2-yl)-N-(3-azabicyclo[3.1.0]hexan-6-yl)picolinamide (0.16 g, 0.5 mmol) was added after stirring for 0.5 h and the reaction was continued for 0.5 h before returning to room temperature overnight. The reaction was poured into 20 mL of water and extracted with ethyl acetate (20 mL x 3), washed with saturated brine, the organic phases were combined, dried over anhydrous sodium sulfate and concentrated under reduced pressure and purified by silica gel column chromatography (DCM:MeOH = 20: 1) to give a white solid (20 mg, 37 pmol), 7.4% yield. LC-MS m / z: (M+H)+= 540.

[0305] 1 H NMR (400 MHz, Chloroform-d) δ 14.50 (s, 1H), 8.91 (s, 1H), 8.60 (dd, J = 7.9, 1.1 Hz, 1H), 8.25 (d, J = 6.8 Hz, 1H), 8.19 (dd, J = 7.7, 1.0 Hz, 1H), 8.09 - 7.98 (m, 3H), 7.91 (q, J = 8.0 Hz, 2H), 7.59 (d, J = 9.1 Hz, 1H), 7.50 (t, J = 7.7 Hz, 1H), 7.42 - 7.36 (m, 1H), 7.26 - 7.12 (m, 4H), 6.88 (m, 1H), 3.98 (d, J = 12.3 Hz, 1H), 3.39 (d, J = 11.6 Hz, 2H), 3.19 (d, J = 12.8 Hz, 1H), 1.79 (s, 1H), 1.33 (s, 1H), 1.06 (s, 1H).

[0306] Example 3: (9-(3-(lH-benzo[d]imidazol-2-yl)benzoyl)-3,9-diazaspiro[5.5]undecan-3-yl)(3-(imidazo[l,2-a]pyridin-2-yl)phenyl)methanone (L-3)

[0307]

[0308] To a stirred solution of 3-(imidazo[l,2-a]pyridin-2-yl)benzoic acid (0.12 g, 0.5 mmol), l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (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-dimethylformamide 6 mL, 6-(lH-benzo[d]imidazol-2-yl)-N-(3-azabicyclo[3.1.0]hexan-6-yl)picolinamide (0.18 g, 0.5 mmol) was added after stirring for 0.5 h and the reaction was continued for 0.5 h before returning to room temperature overnight. The reaction was poured into 20 mL of water and extracted with ethyl acetate (20 mL x 3), washed with saturated brine, the organic phases were combined, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (DCM:MeOH = 20: 1) to give a white solid (30 mg, 50 μmol) in 10% yield. LC-MS m / z: (M+H)+= 596.

[0309] 1 H NMR (400 MHz, Chloroform-d) δ 10.53 (s, 1H), 8.49 (dd, J = 7.9, 1.1 Hz, 1H), 8.15 (m, 1H), 8.06 - 7.94 (m, 3H), 7.89 (d, J = 14.0 Hz, 2H), 7.65 (d, J = 9.1 Hz, 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).

[0310] Example 4 (IS,4S)-5-(6-(lH-benzo[d]imidazol-2-yl)pyridyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)(3-(imidazo[l,2-a]pyridin-2-yl)phenyl)methanone (L-4)

[0311]

[0312] To a stirred solution of (6-(lH-benzo[d]imidazol-2-yl)pyridin-2-yl)(lS,4S)-2,5- diazabicyclo[2.2.1]heptan-2-yl)methanone (0.18 g, 0.5 mmol) in N,N- dimethylformamide (6 mL) was added 3-(imidazo[l,2-a]pyridin-2-yl)benzoic acid (0.12 g, 0.5 mmol), l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.1 g, 0.52 mmol), 1-hydroxybenzotriazole (0.07 g, 0.52 mmol) and N,N- diisopropylethylamine (0.14 g, 1.13 mmol). The reaction mixture was stirred for 0.5 h before being cooled in an ice bath. N,N-Dimethylformamide (6 mL) was added to the reaction mixture, which was stirred for 0.5 h before being returned to room temperature and allowed to react overnight. The reaction mixture was poured into 20 mL of water and extracted with ethyl acetate (20 mL x 3), washed with saturated brine, the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (DCM:MeOH = 20: 1) to give a white solid (25 mg, 46 μmol) in 9% yield. LC-MS m / z: (M+H)+= 540.

[0313] 1 H NMR (400 MHz, Chloroform-d) δ 10.80 (d, J = 23.5 Hz, 1H), 8.57 (d, J = 7.3 Hz, 1H), 8.21 - 8.09 (m, 2H), 8.02 (m, 3H), 7.91 (d, J = 10.4 Hz, 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).

[0314] Example 5 N-(l-(6-(lH-benzo[d]imidazol-2-yl)pyridinecarbonyl)piperidin-4-yl)-3- (imidazo[l,2-a]pyridin-2-yl)benzamide (L-5)

[0315]

[0316] Example 1 Synthesis of tert-butyl (l-(6-(lH-benzo[d]imidazol-2-yl)pyridinyl)piperidin-4- yl)carbamate

[0317]

[0318] Under ice-bath, 6-(lH-benzo[d]imidazol-2-yl)picolinic acid (1 g, 4.2 mmol), l-(3- dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.96 g, 5 mmol), 1- hydroxybenzotriazole (0.66 g, 5 mmol) and N, N-diisopropylethylamine (1.19 g, 9.2 mmol) were dissolved in N, N-dimethylformamide 20 mL, after stirring for 0.5 h, tert-butyl piperidin-4-ylcarbamate (0.92 g, 4.6 mmol) was added, after stirring for 0.5 h, the reaction was returned to room temperature and reacted overnight. The reaction was poured into 80 mL of water and extracted with ethyl acetate (80 mL x 3), washed with saturated brine, the organic phase was combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure and purified by silica gel column chromatography (PE:EA = 5: 1) to obtain a white solid (1.3 g, 3 mmol), yield 73%. LC-MS m / z: (M+H)+= 421.

[0319] II. Synthesis of 6-(lH-benzo[d]imidazol-2-yl)pyridin-2-yl)(4-aminopiperidin-l- yl)methanone

[0320]

[0321] Under ice-bath, tert-butyl (l-(6-(lH-benzo[d]imidazol-2-yl)pyridinyl)piperidin-4- yl)carbamate (1.3 g, 3 mmol) was dissolved in dichloromethane 20 mL, saturated 1,4- dioxane hydrochloric acid solution (2 mL, 8 mmol) was added, after stirring for 0.5 h, the reaction was returned to room temperature and reacted overnight. The reaction was concentrated under reduced pressure, and the obtained solid was directly used in the next step. Yield >90%. LC-MS: 321 [M+1] +

[0322] Synthesis of N-(l-(6-(lH-benzo[d]imidazol-2-yl)pyridinoyl)piperidin-4-yl)-3- (imidazo[l,2-a]pyridin-2-yl)benzamide

[0323]

[0324] III. To a stirred solution of 3-(imidazo[l,2-a]pyridin-2-yl)benzoic acid (0.12 g, 0.5 mmol), l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (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-dimethylformamide 6 mL was added (6-(lH-benzo[d]imidazol-2-yl)pyridin-2-yl)(4- aminopiperidin-l-yl)methanone (0.18 g, 0.5 mmol) after stirring for 0.5 h. The reaction mixture was stirred at room temperature overnight. The reaction mixture was poured into 20 mL of water and extracted with ethyl acetate (20 mL x 3), washed with saturated brine, the organic phase was combined, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (DCM:MeOH = 20: 1) to give a white solid (15 mg, 27 μmol) in 5.5% yield. LC-MS m / z: (M+H)+= 542.

[0325] 1 H NMR (400 MHz, Chloroform-d) δ 11.87 (s, 1H), 8.56 (dd, J = 7.9, 1.1 Hz, 1H), 8.40 (t, J = 1.7 Hz, 1H), 8.21 (m, 1H), 8.07 - 7.94 (m, 3H), 7.90 - 7.80 (m, 2H), 7.69 (d, J = 9.1 Hz, 1H), 7.61 (dd, J = 7.7, 1.1 Hz, 1H), 7.48 (m, 2H), 7.28 - 7.17 (m, 3H), 6.87 (m, 1H), 6.25 (d, J = 7.9 Hz, 1H), 4.68 (d, J = 13.7 Hz, 1H), 4.25 (dd, J = 7.7, 3.9 Hz, 1H), 3.85 (d, J = 13.9 Hz, 1H), 3.19 (t, J = 12.6 Hz, 1H), 3.02 - 2.91 (m, 1H), 2.12 (s, 1H), 1.92 (d, J = 12.8 Hz, 2H), 1.61 (m, 1H).

[0326] Example 6 6-(lH-benzo[d]imidazol-2-yl)-N-(l-(3-(imidazo[l,2-a]pyridin-2-yl)benzoyl)pyrrolidin-3-yl)picolinamide (L-6)

[0327]

[0328] To a stirred solution of 6-(lH-benzo[d]imidazol-2-yl)-N-(pyrrolidin-3-yl)picolinamide (0.14 g, 0.5 mmol) in N,N-dimethylformamide (6 mL) was added 3-(imidazo[l,2-a]pyridin-2-yl)benzoic acid (0.12 g, 0.5 mmol), l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.1 g, 0.52 mmol), 1-hydroxybenzotriazole (0.07 g, 0.52 mmol) and N,N-diisopropylethylamine (0.14 g, 1.13 mmol). The reaction mixture was stirred for 0.5 h and then cooled to 0 °C. The reaction mixture was stirred for 0.5 h and then warmed to room temperature and stirred overnight. The reaction mixture was poured into 20 mL of water and extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (DCM:MeOH = 20: 1) to give a white solid (18 mg, 34 μmol) in 5.5% yield.

[0329] LC-MS m / z: (M+H)+= 528, 1 H NMR (400 MHz, Chloroform-d) δ 8.64 - 8.44 (m, 2H), 8.08 (d, J = 6.9

[0330] Hz, 1H), 8.02 - 7.67 (m, 7H), 7.62 - 7.44 (m, 3H), 7.28 - 7.11 (m, 4H), 6.83 (t, J = 6.6 Hz, 1H), 5.40 - 5.34 (m, 1H), 4.92 (d, J = 17.1 Hz, 1H), 4.69 - 4.61 (m, 1H), 4.09 (m, 1H), 4.02 - 3.72 (m, 3H).

[0331] Example 7 N,N'-(l,2-phenylene)bis(6-(lH-benzo[d]imidazol-2-yl)pyridinamide) (L-7)

[0332]

[0333] I. Synthesis of 6-(lH-benzo[d]imidazol-2-yl)picolinic acid

[0334]

[0335] Pyridine 2,6-dicarboxylic acid (5 g, 21.919 mmol) was added to a solution of o- phenylenediamine (3.5 g, 32 mmol) in propylene glycol (100 mL) and the resulting mixture was heated to reflux for 24 h, then cooled to room temperature. Ice water (50 mL) was added to the reaction and a brown solid was precipitated upon stirring. The precipitate was collected and dissolved in hot methanol and the solution was filtered through activated carbon. The resulting filtrate was slowly evaporated to remove the solvent to give 6-(lH-benzimidazol-2-yl)pyridine carboxylic acid. Yield 52%. LC-MS: [M+1] + : 240.1

[0336] II. Synthesis of N,N'-(l,2-phenylene)bis(6-(lH-benzo[d]imidazol-2-yl)pyridin- amide)

[0337]

[0338] To a solution of 6-(lH-benzimidazol-2-yl)pyridine carboxylic acid (0.12 g, 0.5 mmol), l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (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-dimethylformamide 6 mL was added o-phenylenediamine (0.024 g, 0.228 mmol) under ice bath. The reaction was stirred for 0.5 h and then allowed to warm to room temperature and stirred overnight. The reaction was poured into 20 mL of water and extracted with ethyl acetate (20 mL x 3), washed with saturated brine, the organic phases were combined, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (DCM:MeOH = 20: 1) to give a white solid (30 mg, 5.4 μmol), yield 11%. LC-MS: m / z: (M+H)+= 550.98, 1 H NMR (400 MHz, DMSO) δ 12.58 (s, 2H), 11.01 (s, 2H), 8.20 (d, J = 7.3 Hz, 2H), 8.07 - 7.80 (m, 6H), 7.67 - 7.53 (m, 2H), 7.43 (dd, J = 5.7, 3.6 Hz, 2H), 7.25 - 7.09 (m, 4H), 7.03 (d, J = 5.5 Hz, 2H).

[0339] Example 8 N,N'-(Cyclohexane-l,2-diyl)bis(6-(lH-benzo[d]imidazol-2-yl)pyridin- amide) (L-8)

[0340]

[0341] N,N'-(cyclohexane-1,2-diyl)bis(6-(1H-benzo[d]imidazol-2-yl)pyridin-2-amine)

[0342] Operation as L-7, cyclohexane-1,2-diamine purchased from National Pharmaceutical Reagent

[0343] LC-MS: m / z: (M+H)+= 557.26, 1 H NMR (400 MHz, CDC13) δ 8.83 (s, 2H), 8.42 (d, J = 7.8 Hz,

[0344] 2H), 8.03 (d, J = 7.7 Hz, 2H), 7.79 (t, J = 7.8 Hz, 6H), 7.32 (dd, J = 5.8, 3.1 Hz, 2H), 4.13 (d, J = 16.6 Hz, 2H), 2.35 (d, J = 11.4 Hz, 2H), 1.94 - 1.37 (m, 6H).

[0345] Example 9 (3,9-diazaspiro[5.5]undecane-3,9-diyl)bis((6-(1H-benzo[d]imidazol-2- yl)pyridin-2-yl)methanone) (L-9)

[0346]

[0347] I. Synthesis of tert-butyl 9-(6-(1H-benzo[d]imidazol-2-yl)pyridin-2-yl)-3,9- diazaspiro[5.5]undecane-3-carboxylate

[0348]

[0349] Under ice bath, 6-(1H-benzoimidazol-2-)pyridine carboxylic acid (1 g, 4.2 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.96 g, 5 mmol), 1-hydroxybenzotriazole (0.66 g, 5 mmol) and N,N-diisopropyl ethylamine (1.19 g, 9.2 mmol) were dissolved in N,N-dimethylformamide 20 mL, stirred for 0.5 h, then tert-butyl 3,9-diazaspiro[5.5]undecane-3-carboxylate (0.92 g, 4.6 mmol) was added, and continued to stir for 0.5 h, then returned to room temperature and reacted overnight. The reaction solution was poured into 80 mL of water, and extracted with ethyl acetate (80 mL x 3), washed with saturated brine, the organic phase was combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (PE:EA = 5:1) to obtain a white solid (1.3 g, 3 mmol), with a yield of 73%. LC-MS m / z: (M+H)+= 476.

[0350] II. Synthesis of (6-(lH-benzo[d]imidazol-2-yl)pyridin-2-yl)(3,9- diazaspiro[5.5]undecan-3-yl)methanone

[0351]

[0352] tert-Butyl 9-(6-(lH-benzo[d]imidazol-2-yl)pyridin-2-yl)-3,9- diazaspiro[5.5]undecane-3-carboxylate (1.3 g, 3 mmol) was dissolved in dichloromethane 20 mL under ice bath, saturated 1,4-dioxane hydrochloric acid solution (2 mL, 8 mmol) was added, after stirring for 0.5 h, it was returned to room temperature and reacted overnight. The reaction solution was concentrated under reduced pressure, and the obtained solid was directly used in the next step. Yield >90%. LC-MS: 376 [M+1] + .

[0353] III. Synthesis of (3,9-diazaspiro[5.5]undecane-3,9-diyl)bis((6-(lH-benzo[d]imidazol-2- yl)pyridin-2-yl)methanone)

[0354]

[0355] 6-(lH-benzoimidazol-2-)pyridine carboxylic acid (0.14 g, 0.27 mmol) and N,N- diisopropylethylamine (0.12 g, 1.0 mmol) were dissolved in N,N-dimethylformamide 6 mL under ice bath, after stirring for 0.5 h, (6-(lH-benzo[d]imidazol-2-yl)pyridin-2-yl)(3,9- diazaspiro[5.5]undecan-3-yl)methanone (0.089 g, 0.27 mmol) was added, after stirring for 0.5 h, it was returned to room temperature and reacted overnight. The reaction solution was poured into 20 mL of water, and extracted with ethyl acetate (20 mL x 3), washed with saturated brine, the combined organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and column chromatography on silica gel (DCM:MeOH=20:1) to obtain a white solid (20 mg, 38 μmol), yield 14.3%.

[0356] LC-MS: m / z: (M+H)+= 598.1, 1 H NMR (400 MHz, CDCl3) δ 10.70 (s, 2H), 8.49 (d, J = 7.9 Hz, 2H),

[0357] 7.93 (dd, J = 25.5, 17.6 Hz, 4H), 7.56 (t, J = 8.1 Hz, 5H), 7.38 - 7.30 (m, 5H), 3.84 (s, 3H), 3.51 (s, 5H), 1.65 (d, J = 67.9 Hz, 8H).

[0358] Example 10 (Tetrahydropyrrolo[3,4-c]pyrrole-2,5(lH,3H)-diyl)bis((6-(lH- benzo[d]imidazol-2-yl]pyridin-2-yl)methanone) (L-10)

[0359]

[0360] I. Synthesis of tert-butyl 5-(6-(lH-benzo[d]imidazol-2-yl)pyridinyl)terahydro- pyrrolo[3,4-c]pyrrole-2(lH)-carboxylate

[0361] Under ice-bath, 6-(lH-benzoimidazol-2-)pyridine carboxylic acid (1 g, 4.2 mmol), l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.96 g, 5 mmol), 1-hydroxybenzotriazole (0.66 g, 5 mmol) and N,N-diisopropylethylamine (1.19 g, 9.2 mmol) were dissolved in N,N-dimethylformamide 20 mL, after stirring for 0.5 h, tert-butyl hexahydropyrrolo[3,4-c]pyrrole-2(lH)-carboxylate (0.92 g, 4.6 mmol) was added, continue stirring for 0.5 h, then return to room temperature and react overnight. The reaction solution was poured into 80 mL of water, and extracted with ethyl acetate (80 mL x 3), washed with saturated brine, the organic phase was combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (PE:EA = 5: 1) to obtain white solid (1.3 g, 3 mmol), yield 73%. LC-MS m / z: (M+H)+= 434.

[0362] II. Synthesis of (6-(lH-benzo[d]imidazol-2-yl)pyridin-2-yl)(hexahydropyrrolo[3,4- c]pyrrol-2(lH)-yl)methanone

[0363]

[0364] Under ice-bath, tert-butyl 5-(6-(lH-benzo[d]imidazol-2-yl)pyridinyl)terahydro- pyrrolo[3,4-c]pyrrole-2(lH)-carboxylate (1.3 g, 3 mmol) was dissolved in dichloromethane 20 mL, saturated 1,4-dioxane hydrochloric acid solution (2 mL, 8 mmol) was added, continue stirring for 0.5 h, then return to room temperature and react overnight. The reaction solution was concentrated under reduced pressure, the obtained solid was directly used in the next step. Yield >90%. LC-MS m / z: (M+H)+= 334.

[0365] III. Synthesis of (Tetrahydropyrrolo[3,4-c]pyrrole-2,5(lH,3H)-diyl)bis((6-(lH- benzo[d]imidazol-2-yl]pyridin-2-yl)methanone)

[0366]

[0367] Operation as L-9

[0368] (Tetrahydropyrrolo[3,4-c]pyrrole-2,5(lH,3H)-diyl)bis((6-(lH-benzo[d]imidazol-2- yl]pyridin-2-yl)methanone)

[0369] LC-MS: m / z: (M+H)+ = 555.61, 1 H NMR (400 MHz, MeOD) δ 8.49 - 8.29 (m, 3H), 8.23 - 8.04

[0370] (m, 3H), 8.03 - 7.93 (m, 1H), 7.86 (dd, J = 7.0, 5.6 Hz, 1H), 7.71 (dd, J = 6.0, 3.1 Hz, 1H), 7.64 - 7.54 (m, 2H), 7.50 (dd, J = 8.1, 5.7 Hz, 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).

[0371] Example 11 N-(3-(6-(lH-benzo[d]imidazol-2-yl)pyridinyl)-3-azabicyclo[3.1.0]hex-6-yl)-6-(lH- benzo[d]imidazol-2-yl)picolinamide (L-11)

[0372]

[0373] I. Synthesis of tert-butyl (3-(6-(lH-benzo[d]imidazol-2-yl)pyridinyl)-3-azabicyclo[3.1.0]hexyl-6- yl)carbamate

[0374]

[0375] Under ice-bath, 6-(1H-benzimidazol-2-yl)pyridinecarboxylic acid (1 g, 4.2 mmol), 1-(3- dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.96 g, 5 mmol), 1-hydroxybenzotriazole (0.66 g, 5 mmol) and N,N-diisopropylethylamine (1.19 g, 9.2 mmol) were dissolved in N,N-dimethylformamide 20 mL, after stirring for 0.5 h, tert-butyl (3-(6-(1H- benzimidazol-2-yl)pyridinyl)-3-azabicyclo[3.1.0]hexan-6-yl)carbamate (0.92 g, 4.6 mmol) was added, after stirring for 0.5 h, the reaction was returned to room temperature and reacted overnight. The reaction was poured into 80 mL of water, and extracted with ethyl acetate (80 mL x 3), washed with saturated brine, the organic phase was combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (PE:EA = 5:1) to obtain a white solid (1.3 g, 3 mmol), with a yield of 73%. LC-MS m / z: (M+H)+= 421.

[0376] II. Synthesis of (6-(1H-benzo[d]imidazol-2-yl)pyridin-2-yl)(6-amino-3-azabicyclo[3.1.0]hexan-3-yl)methanone

[0377]

[0378] Under ice-bath, tert-butyl (3-(6-(1H-benzo[d]imidazol-2-yl)pyridinyl)-3-azabicyclo[3.1.0]hexan-6-yl)carbamate (1.3 g, 3 mmol) was dissolved in dichloromethane 20 mL, saturated 1,4-dioxane hydrochloric acid solution (2 mL, 8 mmol) was added, after stirring for 0.5 h, the reaction was returned to room temperature and reacted overnight. The reaction was concentrated under reduced pressure, and the obtained solid was directly used in the next step. The yield was >90%. LC-MS m / z: (M+H)+= 321.

[0379] III. Synthesis of N-(3-(6-(1H-benzo[d]imidazol-2-yl)pyridinyl)-3-azabicyclo[3.1.0]hexan-6-yl)-6-(1H-benzo[d]imidazol-2-yl)pyridinecarboxamide

[0380]

[0381] The operation was the same as L-9

[0382] LC-MS: m / z: (M+H)+= 541.20, 1 H NMR (400 MHz, CDCl3) δ 13.25 (s, 1H), 12.09 (s, 1H), 8.68 (s,

[0383] 1H), 8.48 (d, J = 7.6 Hz, 1H), 8.26 (d, J = 7.6 Hz, 1H), 8.01 (d, J = 7.5 Hz, 1H), 7.81 (t, J = 7.8 Hz, 4H), 7.50 (dt, J = 20.7, 5.8 Hz, 3H), 7.38 - 7.30 (m, 4H), 4.58 (d, J = 11.3 Hz, 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).

[0384] Example 12 (2,5-Diazabicyclo[2.2.1]heptane-2,5-diyl)bis((6-(1H-benzo[d]imidazol-2- yl)pyridin-2-yl)methanone) (L-12)

[0385]

[0386] (2,5-Diazabicyclo[2.2.1]heptane-2,5-diyl)bis((6-(1H-benzo[d]imidazol-2- yl)pyridin-2-yl)methanone)

[0387] Procedure same as L-7

[0388] LC-MS: m / z: (M+H)+= 541.59, 1 H NMR (400 MHz, CDC13) δ 12.67 (s, 1H), 8.13 - 7.82 (m, 4H), 7.54 - 7.33 (m, 4H), 7.26 (d, J = 7.6 Hz, 2H), 4.54 (d, J = 11.9 Hz, 3H), 4.04 (t, J = 15.9 Hz, 3H), 1.85 (s, 1H), 1.77 (s, 1H).

[0389] Example 13 N,N'-(1,2-Phenylene)bis(2-morpholino-pyrimidine-4-carboxamide) (L-13)

[0390]

[0391] I. Synthesis of 2-morpholino-pyrimidine-4-carboxylic acid

[0392] Dissolve 2-chloropyrimidine-4-carboxylic acid (500 mg, 3.15 mmol) in 15 ml tetrahydrofuran and 15 ml dioxane, add 2 ml morpholine, stir the reaction at 70 °C for 18 hours. Cool the reaction to room temperature, filter. Dissolve the solid in 20 ml water, acidify with 1 N hydrochloric acid to pH = 1, extract the solution with dichloromethane / methanol = 10:1 (20 mL*3). Dry the combined organic phase over anhydrous sodium sulfate, filter, concentrate to give 580 mg of white solid, yield 87.9%. LC-MS: m / z: (M+H) + = 210.0.

[0393] 1H NMR (400 MHz, CD3OD) δ 8.57 (d, J = 4.8 Hz, 1H), 7.20 (d, J = 4.8 Hz, 1H), 3.93 - 3.83 (m, 4H), 3.76 (m, 4H).

[0394] II. Synthesis of N,N'-(1,2-phenylene)bis(2-morpholinopyrimidine-4-carboxamide)

[0395] Dissolve 2-morpholinopyrimidine-4-carboxylic acid (100 mg, 0.48 mmol) (compound as shown in formula 3) in 2 ml N,N-dimethylformamide, add 1-(3- dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (137 mg, 0.72 mmol), 1- hydroxybenzotriazole (97 mg, 0.72) and N,N-diisopropylethylamine (185 mg, 1.4340 mmol). Stir the reaction for 20 minutes, add o-phenylenediamine (25.8 mg, 0.24 mmol), stir the reaction at 15 °C for 16 h. Add 10 ml water to the reaction, extract with ethyl acetate (10 mL*2). Dry the combined organic layer over anhydrous sodium sulfate, filter and concentrate to give the crude product. Purify the crude product by thin layer chromatography plate (dichloromethane:methanol = 10:1), slurry the product obtained with a mixture of dimethyl sulfoxide (3 mL) and methanol (2 mL), filter, wash the solid with methanol, dry to give the desired product 23 mg of white solid, yield 9.81%.

[0396] LC-MS: m / z: (M+H)+ = 491.0, 1 1H NMR (400 MHz, DMSO-d6) δ 10.46 (s, 2H), 8.70 (d, J = 4.8 Hz, 2H), 7.78 (dd, J = 6.0, 3.6 Hz, 2H), 7.36 (dd, J = 6.0, 3.6 Hz, 2H), 7.26 (d, J = 4.8 Hz, 2H), 3.90 - 3.69 (m, 4H), 3.60 (d, J = 4.4 Hz, 4H).

[0397] Example 14 N-(3-(6-(1H-Benzo[d]imidazol-2-yl]pyridinyl)-3-azabicyclo[3.1.0]hexyl-6-yl)-2-morpholinopyrimidine-4-carboxamide (L-14)

[0398]

[0399] N-(3-(6-(1H-Benzo[d]imidazol-2-yl]pyridinyl)-3-azabicyclo[3.1.0]hexyl-6-yl)-2-morpholinopyrimidine-4-carboxamide

[0400] To 2-morpholinopyrimidine-4-carboxylic acid (100 mg, 0.48 mmol) (compound as shown in formula 3) was suspended in 2 ml of N,N-dimethylformamide, 1-(3- dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (137 mg, 0.72 mmol), 1- hydroxybenzotriazole (97 mg, 0.72) and N,N-diisopropylethylamine (185 mg, 1.4340 mmol) were added. After the reaction solution was stirred for 20 minutes, (6-amino-3- azabicyclo[3.1.0]hex-3-yl)-[6-(1H-benzoimidazol-2-yl)-2-pyridyl]methanone (76 mg, 0.24 mmol) was added, and the reaction solution was stirred at 15°C for 16 hours. 10 ml of water was added to the reaction solution, and extracted with ethyl acetate (10 mL*2). The combined organic layer was dried over anhydrous sodium sulfate, filtered and concentrated to obtain a crude product. The obtained crude product was purified by a thin layer chromatography plate (dichloromethane:methanol = 10:1) to obtain 38 mg of the desired product as a white solid, with a yield of 31.14%.

[0401] LC-MS: m / z: (M+H)+= 511.0, 1 H NMR (400 MHz, DMSO-d6) δ 8.75 (s, 1H), 8.61 (d, J = 7.8 Hz, 1H), 8.35 (d, J = 4.8 Hz, 1H), 8.22 (t, J = 13.6 Hz, 1H), 7.99 (t, J = 7.8 Hz, 1H), 7.63 (s, 2H), 7.31 (dd, J = 6.6, 3.5 Hz, 1H), 6.78 (d, J = 4.8 Hz, 1H), 4.33 (d, J = 12.5 Hz, 1H), 4.20 - 4.10 (m, 2H), 3.98 (dd, J = 11.8, 4.4 Hz, 1H), 3.72 (dd, J = 12.9, 4.8 Hz, 9H), 2.56 (d, J = 2.1 Hz, 1H), 2.12 (d, J = 2.5 Hz, 1H), 2.04 (d, J = 4.7 Hz, 1H).

[0402] Example 15 9-(6-(l-H-benzo[d]imidazol-2-yl)pyridinyl)-3,9-diazaspiro[5.5]undecan- 3-yl)(2-morpholinopyrimidin-4-yl)methanone (L-15)

[0403]

[0404] (9-(6-(l-H-benzo[d]imidazol-2-yl)pyridinyl)-3,9-diazaspiro[5.5]undecan- 3-yl)(2-morpholinopyrimidin-4-yl)methanone

[0405] Procedure same as L-14

[0406] LC-MS: m / z: (M+H)+ = 567.0, 1 H NMR (400 MHz, CD3OD) δ 8.53 (d, J = 7.8 Hz, 1H), 8.44 (d, J = 4.8 Hz, 1H), 7.97 (t, J = 7.8 Hz, 1H), 7.73 (s, 2H), 7.59 (dd, J = 7.7, 0.9 Hz, 1H), 7.39 - 7.31 (m, 2H), 6.70 (d, J = 4.8 Hz, 1H), 3.90 - 3.76 (m, 12H), 3.51 (d, J = 6.9 Hz, 4H), 1.75 - 1.69 (m, 4H), 1.59 - 1.57 (m, 4H).

[0407] Example 16 (5-(6-(l-(l-H-benzo[d]imidazol-2-yl]pyridinyl)hexahydropyrrolo[3,4- c]pyrrol-2(lH)-yl)(2-morpholinopyrimidin-4-yl)methanone (L-16)

[0408]

[0409] (5-(6-(l-(l-H-benzo[d]imidazol-2-yl]pyridinyl)hexahydropyrrolo[3,4- c]pyrrol-2(lH)-yl)(2-morpholinopyrimidin-4-yl)methanone

[0410] Procedure same as L-14

[0411] LC-MS: m / z: (M+H)+ = 525.0, 1H NMR (400 MHz, CDC13) δ 8.60 - 8.37 (m, 2H), 8.00 (dd, J = 17.8, 9.9 Hz, 1H), 7.81 (ddd, J = 14.2, 8.7, 2.6 Hz, 2H), 7.65 (d, J = 4.6 Hz, 1H), 7.33 (dd, J = 6.0, 3.1 Hz, 2H), 6.97 (dd, J = 10.5, 4.8 Hz, 1H), 4.25 - 3.56 (m, 16H), 3.21 - 2.81 (m, 2H).

[0412] Example 17 N,N'-(cyclohexane-1,2-diyl)bis(2-morpholino pyrimidine-4- carboxamide) (L-17)

[0413]

[0414] N,N'-(cyclohexane-1,2-diyl)bis(2-morpholino pyrimidine-4-carboxamide)

[0415] Procedure same as L-7

[0416] LC-MS: m / z: (M+H)+ = 497.0, 1 H NMR (400 MHz, CDC13) δ 8.60 - 8.37 (m, 2H), 8.00 (dd, J = 17.8, 9.9 Hz, 1H), 7.81 (ddd, J = 14.2, 8.7, 2.6 Hz, 2H), 7.65 (d, J = 4.6 Hz, 1H), 7.33 (dd, J = 6.0, 3.1 Hz, 2H), 6.97 (dd, J = 10.5, 4.8 Hz, 1H), 4.25 - 3.56 (m, 16H), 3.21 - 2.81 (m, 2H).

[0417] Example 18 (5-(6-(1H-benzo[d]imidazol-2-yl)pyridinyl)-2,5-diazabicyclo[2.2.1]heptan- 2-yl)(2-morpholino pyrimidin-4-yl)methanone (L-18)

[0418]

[0419] (5-(6-(1H-benzo[d]imidazol-2-yl)pyridinyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)(2- morpholino pyrimidin-4-yl)methanone

[0420] Procedure same as L-14

[0421] LC-MS: m / z: (M+H)+ = 511.0, 1H NMR (400 MHz, CDC13) δ 8.67 - 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).

[0422] Example 19 (N-(l-(l-(6-(lH-benzo[d]imidazol-2-yl]pyridinyl]piperidin-4-yl)-2- (phenylamino)pyrimidine-4-carboxamide (L-19)

[0423]

[0424] I. 2-(phenylamino)pyrimidine-4-carboxylic acid

[0425] Dissolve 2-chloropyrimidine-4-carboxylic acid (500 mg, 3.15 mmol) in 15 ml of dioxane, add aniline (881 mg, 9.46 mmol), and stir the reaction solution at 70°C for 18 hours. Cool the reaction solution to room temperature, add 20 ml of water and 10 ml of IN sodium hydroxide, and extract the reaction solution twice with ethyl acetate (20 ml x 2). Acidify the aqueous phase with IN hydrochloric acid to pH = 3, filter the solid, and dry to obtain 500 mg of a white solid with a yield of 73.67%. LC-MS: m / z: (M+H)+= 216.0.

[0426] II. Synthesis of tert-butyl (l-(6-(lH-benzo[d]imidazol-2-yl)pyridinyl)piperidin-4- yl)carbamate

[0427]

[0428] Dissolve 6-(lH-benzimidazol-2-)pyridine carboxylic acid (1 g, 4.2 mmol), l-(3- dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.96 g, 5 mmol), 1- hydroxybenzotriazole (0.66 g, 5 mmol), and N,N-diisopropylethylamine (1.19 g, 9.2 mmol) in N,N-dimethylformamide 20 mL, stir for 0.5 h, then add tert-butyl piperidin-4- ylcarbamate (0.92 g, 4.6 mmol), continue stirring for 0.5 h, then return to room temperature and react overnight. Pour the reaction solution into 80 mL of water, extract with ethyl acetate (80 mL x 3), wash with saturated brine, combine the organic phases, dry over anhydrous sodium sulfate, concentrate under reduced pressure, and purify by silica gel column chromatography (PE:EA = 5: 1) to obtain a white solid (1.3 g, 3 mmol) with a yield of 73%. LC-MS m / z: (M+H)+= 421.

[0429] III. Synthesis of (6-(1H-benzo[d]imidazol-2-yl)pyridin-2-yl)(4-aminopiperidin-1- yl)methanone

[0430]

[0431] tert-butyl (1-(6-(1H-benzo[d]imidazol-2-yl)pyridinyl)piperidin-4-yl)carbamate (1.3 g, 3 mmol) was dissolved in dichloromethane 20 mL, saturated 1,4-dioxane hydrochloric acid solution (2 mL, 8 mmol) was added, and stirring was continued for 0.5 h before returning to room temperature overnight. The reaction was concentrated under reduced pressure, and the resulting solid was used directly in the next step. Yield >90%. LC-MS: 321 [M+1] + .

[0432] IV. (N-(1-(1-(6-(1H-benzo[d]imidazol-2-yl]pyridinyl)piperidin-4-yl)-2- (phenylamino)pyrimidine-4-carboxamide was prepared according to the procedure for L-14

[0433] LC-MS: m / z: (M+H)+= 519.0, ¾ NMR (400 MHz, CD3OD) δ 8.64 (d, J = 4.9 Hz, 1H), 8.40 (dd, J = 8.0, 1.0 Hz, 1H), 8.13 (t, J = 7.9 Hz, 1H), 7.76 - 7.58 (m, 5H), 7.40 - 7.26 (m, 5H), 7.08 - 6.99 (m, 1H), 4.64 (d, J = 13.6 Hz, 1H), 4.27 - 4.15 (m, 1H), 3.85 (d, J = 14.1 Hz, 1H), 3.43 (dd, J = 18.3, 7.0 Hz, 1H), 3.31 - 3.20 (m, 1H), 2.19 (d, J = 11.0 Hz, 1H), 2.00 (s, 1H), 1.72 - 1.79 (m, 10.0 Hz, 2H).

[0434] Example 20 (N-(1-(1-(6-(1H-benzo[d]imidazol-2-yl]pyridinyl)piperidin-4-yl]-3-(1H- benzo[d]imidazol-2-yl)cyclohexane-1-carboxamide (L-20)

[0435]

[0436] I. 3-(1H-benzo[d]imidazol-2-yl)cyclohexane-1-carboxylic acid

[0437] To a solution of 1,3-cyclohexanedicarboxylic acid (1 g, 5.8 mmol) and benzene-1,2-diamine (628 mg, 5.8 mmol) in 10 mL of N,N-dimethylformamide was added 2-(7-azobenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (2.43 g, 6.34 mmol) and N,N-diisopropylethylamine (2.25 g, 17.40 mmol). The reaction was stirred at 15 °C for 16 h. To the reaction was added 50 mL of water and extracted with ethyl acetate (50 mL*3). The aqueous phase was concentrated to give 3 g of black oil. The oil was dissolved in 20 mL of acetic acid, stirred at 55 °C for 4 h, concentrated, and purified by column chromatography to give the desired product 1.3 g, in a yield of 93%. LC-MS: m / z: (M+H)+= 245.0.

[0438] II, N-(1-(1-(6-(1H-benzo[d]imidazol-2-yl]pyridinyl)piperidin-4-yl]-3-(1H- benzo[d]imidazol-2-yl)cyclohexan-1-carboxamide

[0439] The operation is the same as L-14

[0440] LC-MS: m / z: (M+H)+= 519.0, 1H NMR (400 MHz, CD3OD) δ 8.40 (d, J = 7.9 Hz, 1H), 8.13 (t, J = 7.8 Hz, 1H), 7.65 (dd, J = 7.7, 0.9 Hz, 3H), 7.54 (d, J = 2.5 Hz, 2H), 7.32 (dd, J = 6.1, 3.1 Hz, 2H), 7.27 - 7.16 (m, 2H), 4.62 (d, J = 9.1 Hz, 1H), 4.05 - 3.95 (m, 1H), 3.81 (d, J = 13.9 Hz, 1H), 3.50 - 3.42 (m, 1H), 3.39 (s, 1H), 3.18 (dd, J = 15.3, 9.6 Hz, 1H), 2.64 (s, 1H), 2.43 - 2.29 (m, 1H), 2.24 - 2.04 (m, 3H), 1.94 (dd, J = 13.8, 10.6 Hz, 2H), 1.74 (dd, J = 11.1, 5.5 Hz, 3H), 1.66 - 1.45 (m, 3H).

[0441] Example 21 N-(1-(1-(6-(1H-benzo[d]imidazol-2-yl]pyridinyl)piperidin-4-yl]-2-(pyridin-2- ylamino)pyrimidine-4-carboxamide (L-21)

[0442]

[0443] I, 2-(pyridin-2-ylamino)pyrimidine-4-carboxylic acid

[0444] Pyridin-2-amine (534 mg, 5.67 mmol) was dissolved in 1 ml of N,N-dimethylformamide, and 60% NaH (227 mg, 5.6768 mmol) was added at 20 °C. The reaction solution was stirred at 20 °C for 1 h. 2-Chloropyrimidine-4-carboxylic acid (300 mg, 1.89 mmol) was added, and the reaction solution was stirred at 70 °C for 18 h. The reaction solution was reduced to room temperature and 20 mL of water was added, and the reaction solution was extracted with dichloromethane (20 mL*2). The aqueous phase was acidified with 1N hydrochloric acid to pH = 5 and concentrated. The residue was dissolved in 5 mL of N,N-dimethylformamide and stirred for 10 minutes, filtered, and concentrated to obtain 80 mg of a yellow solid with a yield of 19.5%. LC-MS: m / z: (M+H)+= 217.0.

[0445] II, N-(1-(1-(6-(1H-benzo[d]imidazol-2-yl]pyridinyl)piperidin-4-yl]-2-(pyridin-2-ylamino)pyrimidine-4-carboxamide

[0446] The operation was the same as L-14

[0447] LC-MS: m / z: (M+H)+= 520.0, 1 H NMR (400 MHz, CDCl3) δ 8.74 (d, J = 4.9 Hz, 1H), 8.50 (t, J = 9.1 Hz, 2H), 8.36 (s, 1H), 8.27 (d, J = 4.7 Hz, 1H), 8.04 (d, J = 8.2 Hz, 1H), 7.95 (t, J = 7.8 Hz, 1H), 7.84 (t, J = 7.4 Hz, 1H), 7.65 (ddd, J = 17.5, 9.1, 5.3 Hz, 3H), 7.28 - 7.25 (m, 1H), 7.12 - 7.01 (m, 1H), 4.68 (d, J = 13.3 Hz, 1H), 4.37 - 4.13 (m, 1H), 3.87 (d, J = 13.5 Hz, 1H), 3.28 (t, J = 11.8 Hz, 1H), 3.14 (t, J = 11.5 Hz, 1H), 2.15 (d, J = 11.2 Hz, 1H), 2.01 (d, J = 10.6 Hz, 1H), 1.79 (dd, J = 21.2, 11.4 Hz, 2H).

[0448] Example 22 N-(1-(1-(6-(1H-benzo[d]imidazol-2-yl]pyridinyl)piperidin-4-yl]-2-morpholypyrimidine-4-carboxamide (L-22)

[0449]

[0450] N-(3-(6-(lH-benzo[d]imidazol-2-yl)pyridinyl)-3-azabicyclo[3.1.0]hex-6-yl)-2- morpholino pyrimidine-4-carboxamide

[0451] Operate as L-14

[0452] LC-MS: m / z: (M+H)+ = 513.0, 1H NMR (400 MHz, CDC13) δ 8.57 (d, J = 4.8 Hz, 1H), 8.52 (d, J = 7.8 Hz, 1H), 7.95 (t, J = 7.8 Hz, 1H), 7.75 (d, J = 8.2 Hz, 2H), 7.63 - 7.58 (m, 1H), 7.39 - 7.32 (m, 3H), 4.78 (d, J = 13.5 Hz, 1H), 4.26 (dt, J = 10.9, 9.5 Hz, 1H), 3.92 (d, J = 13.9 Hz, 1H), 3.88 - 3.76 (m, 8H), 3.34 (t, J = 11.9 Hz, 1H), 3.12 (t, J = 11.6 Hz, 1H), 2.21 (d, J = 9.7 Hz, 1H), 2.07 (d, J = 11.7 Hz, 1H), 1.81 - 1.63 (m, 2H).

[0453] Example 23 N-(3-(6-(lH-benzo[d]imidazol-2-yl)pyridinyl)-3-azabicyclo[3.1.0]hex-6-yl)-2- morpholino pyrimidine-4-carboxamide (L-23)

[0454]

[0455] N-(3-(6-(lH-benzo[d]imidazol-2-yl)pyridinyl)-3-azabicyclo[3.1.0]hex-6-yl)-2- morpholino pyrimidine-4-carboxamide

[0456] Operate as L-14

[0457] ​LC-MS: m / z: (M+H)+ = 517.0, 1H NMR (400 MHz, CDC13) δ 8.61 - 8.52 (m, 2H), 8.48 (d, J = 4.9 Hz, 1H), 8.24 (d, J = 6.9 Hz, 1H), 7.98 (t, J = 7.8 Hz, 1H), 7.63 (d, J = 7.7 Hz, 3H), 7.46 (s, 1H), 7.37 (t, J = 8.0 Hz, 2H), 7.30 (d, J = 3.2 Hz, 1H), 7.09 (t, J = 7.4 Hz, 1H), 6.97 (d, J = 4.9 Hz, 1H), 4.24 (d, J = 12.6 Hz, 1H), 4.08 (d, J = 11.7 Hz, 1H), 3.87 (dd, J = 11.7, 4.4 Hz, 1H), 3.69 (dd, J = 12.1, 4.5 Hz, 2H), 3.14 (dt, J = 11.7, 7.3 Hz, 1H), 2.56 (d, J = 2.2 Hz, 1H), 1.97 (dd, J = 18.6, 4.3 Hz, 2H).

[0458] Example 24 (5-(6-(1-(1-H-benzo[d]imidazol-2-yl]pyridinyl)hexahydropyrrolo[3,4- c]pyrrol-2(1H)-yl)(2-(phenylamino)pyrimidin-4-yl)methanone (L-24)

[0459]

[0460] (5-(6-(1-(1-H-benzo[d]imidazol-2-yl]pyridinyl)hexahydropyrrolo[3,4- c]pyrrol-2(1H)-yl)(2-(phenylamino)pyrimidin-4-yl)methanone

[0461] Procedure same as L-14

[0462] LC-MS: m / z: (M+H)+ = 531.0, 1H NMR (400 MHz, CDC13) δ 8.60 - 8.44 (m, 2H), 8.02 - 7.92 (m, 1H), 7.79 (dd, J = 6.3, 3.1 Hz, 2H), 7.75 - 7.62 (m, 2H), 7.51 (d, J = 7.7 Hz, 1H), 7.41 - 7.30 (m, 3H), 7.27 - 7.16 (m, 1H), 7.09 (dd, J = 9.6, 6.2 Hz, 1H), 4.05 - 3.79 (m, 4H), 3.78 - 3.68 (m, 4H), 3.07 (s, 2H).

[0463] Example 25 (N-(3-(6-(lH-benzo[d]imidazol-2-yl)pyridinyl)-3-azabicyclo[3.1.0]hexyl-6-yl)-2-(pyridin-2-ylamino)pyrimidine-4-carboxamide (L-25)

[0464]

[0465] (N-(3-(6-(lH-benzo[d]imidazol-2-yl)pyridinyl)-3-azabicyclo[3.1.0]hexyl-6-yl)-2-(pyridin-2-ylamino)pyrimidine-4-carboxamide

[0466] Procedure same as L-14

[0467] LC-MS: m / z: (M+H)+= 518.0, 1H NMR (400 MHz, CD3OD) δ 8.71 (d, J = 4.9 Hz, 1H), 8.41 (dd, J = 7.6, 1.3 Hz, 1H), 8.31 (dd, J = 9.5, 4.8 Hz, 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 = 4.9 Hz, 1H), 7.05 (ddd, J = 7.2, 5.0, 0.9 Hz, 1H), 4.24 (d, J = 12.5 Hz, 1H), 4.14 (d, J = 11.5 Hz, 1H), 3.99 (dd, J = 11.5, 4.3 Hz, 1H), 3.75 (dt, J = 13.2, 5.1 Hz, 1H), 2.71 (t, J = 2.4 Hz, 1H), 2.17 - 2.05 (m, 2H).

[0468] Example 26 ((5-(6-(lH-benzo[d]imidazol-2-yl]pyridinyl)hexahydropyrrolo[3,4-c]pyrrol-2(lH)-yl)(2-(pyridin-2-ylamino)pyrimidin-4-yl)methanone (L-26)

[0469]

[0470] ((5-(6-(lH-benzo[d]imidazol-2-yl]pyridinyl)hexahydropyrrolo[3,4-c]pyrrol-2(lH)-yl)(2-(pyridin-2-ylamino)pyrimidin-4-yl)methanone

[0471] To a solution of 2-(2-pyridylamino)pyrimidine-4-carboxylic acid (40 mg, 0.18 mmol) in 2 ml of N,N-dimethylformamide was added l-(3-dimethylaminopropyl)-3- ethylcarbodiimide hydrochloride (145 mg, 0.28 mmol) and N,N-diisopropylethylamine (72 mg, 0.56 mmol). After the reaction was stirred for 20 minutes, 2,3,3a,4,6,6a-hexahydro-lH-pyrrolo[3,4-c]pyrrol-5-yl-[6-(lH-benzoimidazol-2-yl)-2- pyridyl]methanone (62 mg, 0.18 mmol) was added and the reaction was stirred at 15 °C for 16 h. To the reaction was added 10 ml of water and the resulting solid was purified by thin layer chromatography (dichloromethane:methanol = 10:1) to give 15 mg of a white solid in a yield of 15.25%.

[0472] LC-MS: m / z: (M+H)+= 532.0, 1H NMR (400 MHz, CD3OD) δ 8.68 (dd, J = 26.6, 5.0 Hz, 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, 5.0 Hz, 1H), 6.84 - 6.82 (m, 1H), 4.29 - 3.65 (m, 8H), 3.17 - 3.03 (m, 2H).

[0473] Example 27 (9-(6-(lH-benzo[d]imidazol-2-yl)pyridinyl)-3,9-diazaspiro[5.5]undecan-3-yl)(2-(phenylamino)pyrimidin-4-yl)methanone (L-27)

[0474]

[0475] (9-(6-(lH-benzo[d]imidazol-2-yl)pyridinyl)-3,9-diazaspiro[5.5]undecan-3-yl)(2-(phenylamino)pyrimidin-4-yl)methanone

[0476] The procedure was the same as L-26

[0477] LC-MS: m / z: (M+H)+ = 573.0, ¾ NMR (400 MHz, DMSO-d6) δ 12.96 (s, 1H), 9.82 (s, 1H), 8.59 (d, J = 4.9 Hz, 1H), 8.38 (dd, J = 7.9, 1.0 Hz, 1H), 8.11 (t, J = 7.8 Hz, 1H), 7.75 - 7.72 (m, 3H), 7.62 - 7.56 (m, 2H), 7.31 - 7.21 (m, 4H), 6.96 (t, J = 7.3 Hz, 1H), 6.88 (d, J = 4.9 Hz, 1H), 3.78 - 3.54 (m, 4H), 3.35 (s, 4H), 1.72 - 1.31 (m, 8H).

[0478] Example 28 6-(lH-Benzo[d]imidazol-2-yl)-N-(l-(2-(phenylamino)pyrimidine-4- carbonyl)pyrrolidin-3-yl)pyridinamide (L-28)

[0479]

[0480] 6-(lH-Benzo[d]imidazol-2-yl)-N-(l-(2-(phenylamino)pyrimidine-4-carbonyl)pyrrolidin- 3-yl)pyridinamide

[0481] Procedure same as L-26

[0482] LC-MS: m / z: (M+H)+ = 505.0, ¾ NMR (400 MHz, CD3OD) δ 8.62 (dd, J = 30.1, 4.9 Hz, 1H), 8.41 (t, J = 7.9 Hz, 1H), 8.12 (q, J = 7.8 Hz, 1H), 7.86 (d, J = 7.7 Hz, 1H), 7.75 - 7.54 (m, 4H), 7.41 - 7.22 (m, 5H), 6.97 (dd, J = 12.5, 7.3 Hz, 1H), 4.72 - 4.52 (m, 1H), 4.34 - 3.54 (m, 4H), 2.42 (dd, J = 12.9, 5.7 Hz, 1H), 2.20 (d, J = 5.5 Hz, 1H).

[0483] Example 29 6-(lH-Benzo[d]imidazol-2-yl)-N-(l-(2-(pyridin-2-ylamino)pyrimidine-4- carbonyl)pyrrolidin-3-yl)pyridinamide (L-29)

[0484]

[0485] 6-(1H-benzo[d]imidazol-2-yl)-N-(1-(2-(pyridin-2-ylamino)pyrimidine-4- carbonyl)pyrrolidin-3-yl)pyridinamide was prepared according to the procedures described in L-26

[0486] LC-MS: m / z: (M+H)+= 506.0, 1H NMR (400 MHz, CD3OD) δ 8.73 (dd, J = 33.7, 4.9 Hz, 1H), 8.48 - 8.35 (m, 1H), 8.32 - 8.00 (m, 3H), 7.87 (ddd, J = 7.8, 2.1, 1.0 Hz, 1H), 7.75 - 7.73 (m, 2H), 7.61 (s, 1H), 7.46 (dd, J = 43.3, 4.9 Hz, 1H), 7.36 - 7.23 (m, 2H), 6.99 (dd, J = 7.3, 5.0 Hz, 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).

[0487] Example 30 N-(1-(1-(6-(1H-benzo[d]imidazol-2-yl)pyridinyl)piperidin-4-yl)-6-(1H- benzo[d]imidazol-2-yl)pyridinamide (L-30)

[0488]

[0489] N-(1-(1-(6-(1H-benzo[d]imidazol-2-yl)pyridinyl)piperidin-4-yl)-6-(1H- benzo[d]imidazol-2-yl)pyridinamide

[0490] Prepared according to the procedures described in L-5

[0491] LC-MS: m / z: (M+H)+= 543.22, 1 H NMR (400 MHz, CDCl3) δ 8.49 (d, J = 7.2 Hz, 2H), 8.07 - 7.86

[0492] (m, 2H), 7.72 (s, 4H), 7.58 (dd, J = 7.7, 1.0 Hz, 2H), 7.38 - 7.31 (m, 4H), 4.69 (d, J = 13.1 Hz, 2H), 4.55 (d, J = 7.8 Hz, 2H), 3.83 (d, J = 13.8 Hz, 4H), 3.15 (dt, J = 22.4, 11.4 Hz, 4H), 2.06 (dd, J = 56.4, 13.3 Hz, 4H).

[0493] Example 31 N-(4-(9-methyl-3,9-diazaspiro[5.5]undecan-3-yl)phenyl)-1-(2- (phenylamino)pyrimidine-4-carbonyl)pyrrolidine-3-carboxamide (L-31)

[0494]

[0495] N-(4-(9-methyl-3,9-diazaspiro[5.5]undecan-3-yl)phenyl)-1-(2- (phenylamino)pyrimidine-4-carbonyl)pyrrolidine-3-carboxamide

[0496] Procedure same as L-5

[0497] 4-(9-methyl-3,9-diazaspiro[5.5]undecan-3-yl)aniline was purchased from Bide Pharm

[0498] LC-MS: m / z: (M+H)+= 554.23, 1 H NMR (400 MHz, MeOD) δ 8.50 - 8.34 (m, 1H), 8.19 - 8.07 (m,

[0499] 1H), 7.83 (t, J = 13.8 Hz, 1H), 7.69 (s, 2H), 7.49 (d, J = 9.0 Hz, 1H), 7.42 - 7.27 (m, 2H), 6.97 (dd, J = 28.4, 9.0 Hz, 2H), 4.21 - 3.87 (m, 4H), 3.77 (dt, J = 12.3, 7.7 Hz, 1H), 3.19 - 3.06 (m, 4H), 2.83 (s, 4H), 2.57 (d, J = 5.6 Hz, 3H), 2.44 - 2.26 (m, 2H).

[0500] Example 32 N-(1-(1-(6-(1H-benzo[d]imidazol-2-yl)pyridinyl)piperidin-3-yl)-6-(1H- benzo[d]imidazol-2-yl)pyridinamide (L-32)

[0501]

[0502] N-(1-(1-(6-(1H-benzo[d]imidazol-2-yl)pyridinyl)piperidin-3-yl)-6-(1H- benzo[d]imidazol-2-yl)pyridinamide

[0503] Procedure same as L-6

[0504] LC-MS: m / z: (M+H)+= 529.5, 1H NMR (400 MHz, CDC13) δ 8.70 (s, 2H), 8.57 (d, J = 23.6 Hz, 1H),

[0505] 8.46 (d, J = 7.9 Hz, 1H), 8.34 (d, J = 6.2 Hz, 2H), 8.16 (dd, J = 22.0, 7.1 Hz, 2H), 7.86 (dd, J = 17.5, 9.7 Hz, 2H), 7.80 - 7.50 (m, 4H), 7.36 - 7.16 (m, 4H), 4.61 (d, J = 5.9 Hz, 2H), 4.41 (s, 1H), 4.03 (dd, J = 11.5, 6.2 Hz, 1H), 3.78 (dd, J = 58.9, 16.7 Hz, 4H), 3.53 (s, 3H), 2.18 (dd, J = 12.9, 6.3 Hz, 1H), 1.93 (dd, J = 39.9, 18.0 Hz, 2H), 1.74 - 1.50 (m, 2H), 1.32 (dt, J = 14.2, 10.8 Hz, 4H).

[0506] Example 33 Cyclohexane-1,4-diyl bis((5-(4-nitrophenyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)- yl)methanone) (L-33)

[0507]

[0508] Cyclohexane-1,4-diyl bis((5-(4-nitrophenyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)- yl)methanone)

[0509] Procedure same as L-8

[0510] 2-(4-nitrophenyl)octahydropyrrolo[3,4-c]pyrrole was purchased from Bide Pharm

[0511] LC-MS: m / z: (M+H)+ = 603.21, 1 H NMR (400 MHz, CDC13) δ 8.70 (s, 2H), 8.57 (d, J = 23.6 Hz, 1H),

[0512] Example 34 1,4-Phenylene bis((5-(4-nitrophenyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)- yl)methanone) (L-34)

[0513]

[0514] 1,4-phenylene bis((5-(4-nitrophenyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)methanone)

[0515] Operate as L-8

[0516] LC-MS: m / z: (M+H)+= 597.21, 1 H NMR (400 MHz, CDC13) δ 8.15 (t, J = 8.8 Hz, 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).

[0517] Example 35 1-(6-(1H-benzo[d]imidazol-2-yl)pyridinyl)-N-(4-(9-methyl-3,9-diazaspiro[5.5]undecan-3- yl)phenyl)pyrrolidine-3-carboxamide (L-35)

[0518]

[0519] 1-(6-(1H-benzo[d]imidazol-2-yl)pyridinyl)-N-(4-(9-methyl-3,9-diazaspiro[5.5]undecan-3- yl)phenyl)pyrrolidine-3-carboxamide

[0520] Operate as L-6

[0521] LC-MS: m / z: (M+H)+= 578.31, 1 H NMR (400 MHz, MeOD) δ 8.59 (d, J = 4.7 Hz, 1H), 7.66 (dd, J = 15.3, 8.1 Hz, 2H), 7.44 (dd, J = 15.0, 8.9 Hz, 2H), 7.36 - 7.25 (m, 2H), 7.04 (ddd, J = 30.4, 15.7, 6.8 Hz, 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 = 5.2 Hz, 2H), 1.69 (s, 5H).

[0522] Example 36 Piperazine-1,4-diyl bis((3-(imidazo[1,2-a]pyridin-2-yl)phenyl)methanone) (L-36)

[0523]

[0524] To a stirred solution of 3-(imidazo[l,2-a]pyridin-2-yl)benzoic acid (0.12 g, 0.5 mmol), benzotriazole- 1 -yl-oxytris-pyrrolidino-phosphonium hexafluorophosphate (0.28 g, 0.55 mmol) and N,N- diisopropylethylamine (0.14 g, 1.1 mmol) in N,N-dimethylformamide 6 mL was added piperazine (0.04 g, 0.5 mmol) after stirring for 0.5 h and the reaction mixture was stirred for another 0.5 h before returning to room temperature overnight. The reaction mixture was poured into 20 mL of water and extracted with ethyl acetate (20 mL x 3), washed with saturated brine, the organic phases were combined, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (DCM:MeOH = 20: 1) to give a white solid (12 mg, 22 μmol) in 4.5% yield. LC-MS m / z: (M+H)+= 527.

[0525] 1 H NMR (400 MHz, Chloroform-d) δ 8.15 (d, 2H), 8.08 - 8.00 (m, 4H), 7.91 (s, 2H), 7.65 (d, J = 9.1 Hz, 2H), 7.56 - 7.46 (m, 2H), 7.39 (d, J = 7.6 Hz, 2H), 7.21 (m, 2H), 6.82 (m, 2H), 3.73 (d, J = 89.9 Hz, 8H).

[0526] Example 37 6-(lH-Benzo[d]imidazol-2-yl)-N-(l-(3-nitrobenzyl)pyrrolidin-3-yl)picolinamide (L-37)

[0527]

[0528] Under ice-bath, 6-(lH-benzo[d]imidazol-2-yl)-N-(pyrrolidin-3-yl)picolinamide (0.15 g, 0.48 mmol), benzotriazole-1 -yl-oxytris-(dimethylamino)-phosphonium hexafluorophosphate (0.30 g, 0.58 mmol) and N,N-diisopropyl ethylamine (0.16 g, 1.3 mmol) were dissolved in N,N-dimethylformamide 6 mL, after stirring for 0.5 h, 3-nitrobenzoic acid (0.08 g, 0.48 mmol) was added, continue stirring for 0.5 h, then let it return to room temperature and react overnight. The reaction solution was poured into 20 mL water, and extracted with ethyl acetate (20 mL x 3), washed with saturated brine, combined organic phase, dried over anhydrous sodium sulfate, concentrated under reduced pressure, silica gel column chromatography (DCM:MeOH = 20:1) to get white solid (15 mg, 32 μmol), yield 6.8%. LC-MS m / z: (M+H)+= 457.

[0529] Example 38: N-(l-(6-(lH-benzo[d]imidazol-2-yl)picolinoyl)piperidin-4-yl)-3- nitrobenzamide (L-38)

[0530]

[0531] Under ice-bath, (6-1H-benzo[d]imidazol-2-yl)pyridin-2-yl)(4-aminopiperidin-1- yl)methanone (0.088 g, 0.27 mmol), benzotriazole-1 -yl-oxytris-(dimethylamino)- phosphonium hexafluorophosphate (0.15 g, 0.3 mmol) and N,N-diisopropyl ethylamine (0.12 g, 1.0 mmol) were dissolved in N,N-dimethylformamide 6 mL, after stirring for 0.5 h, 3-nitrobenzoic acid (0.04 g, 0.27 mmol) was added, continue stirring for 0.5 h, then let it return to room temperature and react overnight. The reaction solution was poured into 20 mL water, and extracted with ethyl acetate (20 mL x 3), washed with saturated brine, combined organic phase, dried over anhydrous sodium sulfate, concentrated under reduced pressure, silica gel column chromatography (DCM:MeOH = 20:1) to get white solid (11 mg, 32 μmol), yield 8.6%. LC-MS m / z: (M+H)+= 471.

[0532] Example 39: Synthesis of (1-(3-(imidazo[1,2-a]pyridin-2-yl)benzoyl)pyrrolidin-2-yl)(5-(4- nitrophenyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)methanone (L-39)

[0533]

[0534] To a stirred solution of 3-(imidazo[l,2-a]pyridin-2-yl)benzoic acid (0.1 g, 0.4 mmol), benzotriazole- 1 -yl-oxytris-pyrrolidino-phosphonium hexafluorophosphate (0.24 g, 0.44 mmol) and N,N- diisopropylethylamine (0.12 g, 1.0 mmol) in N,N-dimethylformamide 6 mL was added 2-(4- nitrophenyl)-5-prolyloctahydropyrrolo[3,4-c]pyrrole (0.13 g, 0.4 mmol) after stirring for 0.5 h. The reaction mixture was stirred for another 0.5 h and then allowed to warm to room temperature and stirred overnight. The reaction mixture was poured into 20 mL of water and extracted with ethyl acetate (20 mL x 3), washed with saturated brine, the organic phases were combined, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (DCM:MeOH = 20: 1) to give a white solid (16 mg, pmol), 7.2% yield. LC-MS m / z: (M+H)+= 551.

[0535] 1H NMR (400 MHz, Chloroform-d) δ 8.20 - 7.99 (m, 5H), 7.90 (d, J = 9.8 Hz, 1H), 7.64 (t, J = 8.8 Hz, 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).

[0536] Example 40: (9-(3-(lH-benzo[d]imidazol-2-yl)benzoyl)-3,9-diazaspiro[5.5- tri]undecan-3-yl)(3-nitrophenyl)methanone (L-40)

[0537]

[0538] To a stirred solution of (6-(lH-benzo[d]imidazol-2-yl)pyridin-2-yl)(3,9- diazaspiro[5.5]undecan-3-yl)methanone (0.1 g, 0.25 mmol) in N,N- dimethylformamide (6 mL) was added 3-bromopropanoic acid (0.05 g, 0.27 mmol) and N,N-diisopropylethylamine (0.12 g, 1.0 mmol) under ice-bath cooling. The mixture was stirred for 0.5 h, and then the reaction mixture was allowed to stand at room temperature overnight. The reaction mixture was poured into 20 mL of water and extracted with ethyl acetate (20 mL x 3). The combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (DCM:MeOH = 20: 1) to give a white solid (0.05 g, 0.15 mmol) in 60.0% yield. LC-MS m / z: (M+H)+= 521.

[0539] 1 H NMR (400 MHz, Chloroform-d) δ 10.74 (s, 1H), 8.48 (dd, J = 8.0, 1.1 Hz, 1H), 8.34 - 8.27 (m, 2H), 7.97 (t, J = 7.8 Hz, 1H), 7.87 (d, J = 6.9 Hz, 1H), 7.77 (m, 1H), 7.64 (t, J = 7.9 Hz, 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).

[0540] Example 41: Synthesis of (5-(6-(lH-benzo[d]imidazol-2-yl)pyridinecarbonyl)hexahydropyrrolo[3,4-c]pyrrol-2(lH)-yl)(3-nitrophenyl)methanone (L-41)

[0541]

[0542] To a stirred solution of (6-(lH-benzo[d]imidazol-2-yl)pyridin-2-yl)(hexahydropyrrolo[3,4- c]pyrrol-2(lH)-yl)methanone (0.083 g, 0.25 mmol) in N,N-dimethylformamide (6 mL) was added 3-(trifluoromethyl)benzoic acid (0.041 g, 0.25 mmol), benzotriazole- 1 -yl-oxytris-(dimethylamino)-phosphonium hexafluorophosphate (0.14 g, 0.27 mmol) and N,N- diisopropylethylamine (0.12 g, 1.0 mmol) under ice-bath cooling. The mixture was stirred for 0.5 h and then allowed to stand at room temperature overnight. The reaction mixture was poured into 20 mL of water and extracted with ethyl acetate (20 mL x 3). The combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (DCM:MeOH = 20: 1) to give a white solid (17 mg, pmol) in 12.9% yield. LC-MS m / z: (M+H)+= 483.

[0543] 1H NMR (400 MHz, Chloroform-d) δ 11.58 (s, 1H), 8.52 (dd, J = 28.6, 7.9 Hz, 1H), 8.38 (s, 1H), 8.30 (t, J = 9.1 Hz, 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).

[0544] Example 42: N-(l-(3-(imidazo[l,2-a]pyridin-2-yl)benzoyl)piperidin-4-yl)-2- (anilino)pyrimidine-4-carboxamide (L-42)

[0545]

[0546] I. Synthesis of tert-butyl (l-(3-(imidazo[l,2-a]pyridin-2-yl)benzoyl)piperidin-4-yl)carbamate

[0547]

[0548] Under ice bath, 3-(imidazo[l,2-a]pyridin-2-yl)benzoic acid (1 g, 4.2 mmol), l-(3- dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.96 g, 5 mmol), 1- hydroxybenzotriazole (0.66 g, 5 mmol) and N,N-diisopropylethylamine (1.19 g, 9.2 mmol) were dissolved in N,N-dimethylformamide 20 mL, after stirring for 0.5 h, tert-butyl piperidin-4-ylcarbamate (0.92 g, 4.6 mmol) was added, after stirring for 0.5 h, the reaction was returned to room temperature and reacted overnight. The reaction was poured into 80 mL of water and extracted with ethyl acetate (80 mL x 3), washed with saturated brine, the organic phase was combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure and purified by silica gel column chromatography (PE:EA = 5: 1) to obtain a white solid (1.3 g, 3 mmol), yield 73%. LC-MS m / z: (M+H)+= 421.

[0549] II. Synthesis of (4-aminopiperidin-l-yl)(3-(imidazo[l,2-a]pyridin-2- yl)phenyl)methanone

[0550]

[0551] Under ice bath, tert-butyl (l-(3-(imidazo[l,2-a]pyridin-2-yl)benzoyl)piperidin-4- yl)carbamate (1.3 g, 3 mmol) was dissolved in dichloromethane 20 mL, saturated 1,4- dioxane hydrochloric acid solution (2 mL, 8 mmol) was added, after stirring for 0.5 h, the reaction was returned to room temperature and reacted overnight. The reaction was concentrated under reduced pressure, and the obtained solid was directly used in the next step. Yield >90%. LC-MS m / z: (M+H)+= 321.

[0552] III. Synthesis of N-(l-(3-(imidazo[l,2-a]pyridin-2-yl)benzoyl)piperidin-4-yl)-2- (phenylamino)pyrimidine-4-carboxamide

[0553]

[0554] To a stirred solution of 2-(phenylamino)pyrimidine-4-carboxylic acid (0.060 g, 0.27 mmol), benzotriazol-1 -yl-oxytripyrrolidinophosphonium hexafluorophosphate (0.14 g, 0.27 mmol) and N,N-diisopropylethylamine (0.12 g, 1.0 mmol) in N,N-dimethylformamide 6 mL was added (4-aminopiperidin-1-yl)(3-(imidazo[1,2-a]pyridin-2-yl)phenyl)methanone (0.089 g, 0.27 mmol) after stirring for 0.5 h. The reaction mixture was stirred for another 0.5 h and then allowed to warm to room temperature and stirred overnight. The reaction mixture was poured into 20 mL of water and extracted with ethyl acetate (20 mL x 3), washed with saturated brine, the organic phases were combined, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (DCM:MeOH = 20:1) to give a white solid (20 mg, 38 μmol) in 14.3% yield. LC-MS m / z: (M+H)+= 518.

[0555] 1 H NMR (400 MHz, Chloroform-d) δ 8.65 (d, J = 4.8 Hz, 1H), 8.22 (d, J = 6.7 Hz, 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 = 7.3 Hz, 1H), 6.92 (t, J = 6.7 Hz, 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).

[0556] Example 43 N-(1-(3-(imidazo[1,2-a]pyridin-2-yl)benzoyl)piperidin-4-yl)-2-(phenylamino)pyrimidine-4-carboxamide (L-43)

[0557]

[0558] Example 1 Synthesis of tert-butyl 5-(3-(imidazo[1,2-a]pyridin-2-yl)benzoyl)hexahydropyrrolopyrrole-2(1 H)-carboxylate

[0559]

[0560] Under ice-bath, 3-(imidazo[l,2-a]pyridin-2-yl)benzoic acid (1 g, 4.2 mmol), l-(3- dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.96 g, 5 mmol), 1- hydroxybenzotriazole (0.66 g, 5 mmol) and N,N-diisopropylethylamine (1.19 g, 9.2 mmol) were dissolved in N,N-dimethylformamide 20 mL, after stirring for 0.5 h, tert-butyl piperidin-4-ylcarbamate (0.98 g, 4.6 mmol) was added, after stirring for 0.5 h, the reaction was returned to room temperature and reacted overnight. The reaction was poured into 80 mL of water and extracted with ethyl acetate (80 mL x 3), washed with saturated brine, the organic phase was combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure and purified by silica gel column chromatography (PE:EA = 5: 1) to obtain a white solid (1.26 g, 2.9 mmol), yield 72%. LC-MS m / z: (M+H)+= 433.

[0561] II. Synthesis of (hexahydropyrrolo[3,4-c]pyrrol-2(lH)-yl)(3-(imidazo[l,2-a]pyridin-2- yl)phenyl)methanone

[0562]

[0563] Under ice-bath, tert-butyl 5-(3-(imidazo[l,2-a]pyridin-2-yl)benzoyl)hexahydropyrrolo pyrrole-2(lH)-carboxylate (1.3 g, 3 mmol) was dissolved in dichloromethane 20 mL, saturated 1,4-dioxane hydrochloric acid solution (2 mL, 8 mmol) was added, after stirring for 0.5 h, the reaction was returned to room temperature and reacted overnight. The reaction was concentrated under reduced pressure, and the obtained solid was directly used in the next step. Yield >90%. LC-MS m / z: (M+H)+= 333.

[0564] III. Synthesis of N-(l-(3-(imidazo[l,2-a]pyridin-2-yl)benzoyl)piperidin-4-yl)-2- (phenylamino)pyrimidine-4-carboxamide

[0565]

[0566] To a stirred solution of 6-(phenylamino)picolinic acid (0.060 g, 0.27 mmol), benzotriazol-1 -yl-oxytripyrrolidinophosphonium hexafluorophosphate (0.14 g, 0.27 mmol) and N,N-diisopropylethylamine (0.12 g, 1.0 mmol) in N,N-dimethylformamide 6 mL was added (hexahydropyrrolo[3,4-c]pyrrol-2(1 H)-yl)(3-(imidazo[1,2-a]pyridin-2- yl)phenyl)methanone (0.092 g, 0.27 mmol) and stirred for 0.5 h. The reaction mixture was allowed to warm to room temperature and stirred overnight. The reaction mixture was poured into 20 mL of water and extracted with ethyl acetate (20 mL x 3), washed with saturated brine, the organic phases were combined, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (DCM:MeOH = 20:1 ) to give a white solid (12 mg, 22 μmol), 8.4% yield. LC-MS m / z: (M+H)+= 530.

[0567] 1 H NMR (400 MHz, Chloroform-d) δ 8.57 (d, J = 13.0 Hz, 1 H), 8.12 (d, 2H), 8.03 (d, J = 7.0 Hz, 1 H), 7.90 (d, J = 8.8 Hz, 1 H), 7.66 - 7.36 (m, 7H), 7.27 - 6.95 (m, 4H), 6.81 (t, J = 6.8 Hz, 1 H), 4.04 - 3.40 (m, 8H), 3.01 (d, 2H).

[0568] Example 44 N-(3-(6-(1 H-benzo[d]imidazol-2-yl)pyridinyl)-3-azabicyclo[3.1.0]hexyl-6-yl)-6-(phenylamino)pyridinamide (L-44)

[0569]

[0570] I. 6-(phenylamino)picolinic acid

[0571] Methyl 6-bromopyridine-2-carboxylate (2 g, 9.26 mmol) was dissolved in 50 ml of dioxane, aniline (826 mg, 9.26 mmol) was added, tris(dibenzylideneacetone)dipalladium (424 mg, 0.46 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (536 mg, 0.92 mmol) and cesium carbonate (7.54 g, 23.1 mmol) were added, and 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 with ethyl acetate three times (20 ml*3). The aqueous phase was acidified to pH = 1 with 2N hydrochloric acid, and the aqueous phase was extracted with ethyl acetate three times (20 ml*3), and then neutralized to pH = 1 with saturated aqueous sodium bicarbonate solution. The solid was filtered and dried to obtain a white solid 500 mg, with a yield of 25.2%. LC-MS: m / z: (M+H)+= 215.0.

[0572] II. N-(3-(6-(1H-benzo[d]imidazol-2-yl)pyridinyl)-3-azabicyclo[3.1.0]hexyl-6-yl)-6- (phenylamino)pyridinamide

[0573] The operation is the same as L-14

[0574] LC-MS: m / z: (M+H)+= 516.0, 1H NMR (400 MHz, CD3OD) δ 8.47 (dd, J = 7.4, 1.5 Hz, 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, 0.8 Hz, 1H), 6.99 - 6.92 (m, 2H), 4.29 (d, J = 12.4 Hz, 1H), 4.20 (d, J = 11.7 Hz, 1H), 3.97 (dd, J = 11.7, 4.2 Hz, 1H), 3.75 (dd, J = 12.4, 4.4 Hz, 1H), 2.74 (t, J = 2.4 Hz, 1H), 2.15 - 2.05 (m, 2H).

[0575] Example 45 (9-(6-(1-H-benzo[d]imidazol-2-yl)pyridinyl)-3,9-diazaspiro[5.5]undec-3-yl)(6- (phenylamino)pyridin-2-yl)methanone (L-45)

[0576]

[0577] (9-(6-(1-H- benzimidazol-2-yl)pyridinyl)-3,9-diazaspiro[5.5]undec-3-yl)(6-(phenylamino)pyridin-2-yl)methanone

[0578] Procedure same as L-14

[0579] LC-MS: m / z: (M+H)+ = 572.0, ¾ NMR (400 MHz, CD3OD) δ 8.40 (dd, J = 8.0, 1.0 Hz, 1H), 8.13 (t, J = 7.9 Hz, 1H), 7.86 - 7.53 (m, 6H), 7.33 (d, J = 5.1 Hz, 2H), 7.29 - 7.20 (m, 2H), 6.94 (t, J = 7.4 Hz, 1H), 6.91 - 6.82 (m, 2H), 3.77 (dd, J = 28.2, 21.3 Hz, 4H), 3.62 - 3.47 (m, 4H), 1.70 (d, J = 37.8 Hz, 8H).

[0580] Example 46 (5-(6-(1H-benzimidazol-2-yl)pyridinyl)hexahydropyrrolo[3,4-c]pyrrol-2(lH)-yl)(6-(phenylamino)pyridin-2-yl)methanone (L-46)

[0581]

[0582] (5-(6-(1H-benzimidazol-2-yl)pyridinyl)hexahydropyrrolo[3,4-c]pyrrol-2(lH)-yl)(6-(phenylamino)pyridin-2-yl)methanone

[0583] Procedure same as L-14

[0584] LC-MS: m / z: (M+H)+ = 572.0, ¾ NMR (400 MHz, CD3OD) δ 8.40 (dd, J = 8.0, 1.0 Hz, 1H), 8.13 (t, J = 7.9 Hz, 1H), 7.86 - 7.53 (m, 6H), 7.33 (d, J = 5.1 Hz, 2H), 7.29 - 7.20 (m, 2H), 6.94 (t, J = 7.4 Hz, 1H), 6.91 - 6.82 (m, 2H), 3.77 (dd, J = 28.2, 21.3 Hz, 4H), 3.62 - 3.47 (m, 4H), 1.70 (d, J = 37.8 Hz, 8H).

[0585] Example 47 N-(l-(l-(6-(lH-benzimidazol-2-yl]pyridinyl)piperidin-4-yl]-6-(phenylamino)pyridinamide (L-47)

[0586]

[0587] N-(1-(1-(6-(1H-benzo[d]imidazol-2-yl]pyridinyl)piperidin-4-yl]-6-(phenylamino)pyridinylamide

[0588] Operate as L-14

[0589] LC-MS: m / z: (M+H)+ = 518.0, 1H NMR (400 MHz, CD3OD) δ 8.41 (dd, J = 8.0, 0.9 Hz, 1H), 8.15 (t, J = 7.9 Hz, 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 = 13.7 Hz, 1H), 4.24 - 4.17 (m, 1H), 3.82 (d, J = 13.8 Hz, 1H), 3.50 - 3.21 (m, 2H), 2.23 (d, J = 10.1 Hz, 1H), 2.05 (d, J = 10.1 Hz, 1H), 1.75 (dt, J = 19.7, 10.2 Hz, 2H).

[0590] Example 48 N-(6-(5-(6-(1H-benzo[d]imidazol-2-yl]pyridinyl)octahydropyrrolo[3,4-c]pyrrole-2-carbonyl)pyridin-2-yl)acetamide (L-48)

[0591]

[0592] Operate as L-14

[0593] 6-acetamidopicolinic acid was purchased from Bide Pharm

[0594] LC-MS: m / z: (M+H)+ = 496.2, 1 H NMR (400 MHz, MeOD) δ 8.43 (dd, J = 13.6, 7.8 Hz, 1H), 8.15

[0595] (dd, J = 17.8, 8.1 Hz, 1H), 7.96 - 7.82 (m, 2H), 7.67 (dd, J = 41.3, 19.9 Hz, 2H), 7.53 - 7.41 (m, 1H), 7.31 (dt, J = 21.6, 7.7 Hz, 3H), 4.24 - 3.83 (m, 5H), 3.80 - 3.57 (m, 3H), 3.50 (s, 1H), 3.13 (d, J = 20.5 Hz, 2H), 2.20 (dd, J = 15.6, 8.0 Hz, 2H), 2.05 (d, J = 15.3 Hz, 2H), 1.63 (s, 1H).

[0596] Example 50 N-(l-(3-(imidazo[l,2-a]pyridin-2-yl)benzoyl)piperidin-4-yl)-2- (anilino)pyridine-4-carboxamide (L-50)

[0597]

[0598] Synthesis of N-(l-(3-(imidazo[l,2-a]pyridin-2-yl)benzoyl)piperidin-4-yl)-2- (anilino)pyridine-4-carboxamide

[0599] To a solution of 2-(anilino)pyridine-4-carboxylic acid (0.060 g, 0.27 mmol), benzotriazole-l-yl-oxytris-pyrrolidinophosphonium hexafluorophosphate (0.14 g, 0.27 mmol) and N,N-diisopropylethylamine (0.12 g, 1.0 mmol) in N,N-dimethylformamide 6 mL was stirred for 0.5 h before (4-aminopiperidin-l-yl)(3- (imidazo[l,2-a]pyridin-2-yl)phenyl)methanone (0.089 g, 0.27 mmol) was added. The reaction was stirred for 0.5 h before being returned to room temperature and left to react overnight. The reaction was poured into 20 mL of water and extracted with ethyl acetate (20 mL x 3), washed with saturated brine, the organic phases were combined, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (DCM:MeOH = 20: 1) to give a white solid (18 mg, 34 μmol) in 12.8% yield. LC-MS m / z: (M+H)+= 517.

[0600] 1 H NMR (400 MHz, Chloroform-d) δ 8.14 (m, 1H), 8.05 - 7.99 (m, 2H), 7.96 (d, J = 8.2 Hz, 1H), 7.89 (d, J = 0.7 Hz, 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).

[0601] Example 51 N-(l-(3-(imidazo[l,2-a]pyridin-2-yl)benzoyl)piperidin-4-yl)-2- (anilino)pyridine-4-carboxamide (L-50)

[0602]

[0603] Synthesis of N-(l-(3-(imidazo[l,2-a]pyridin-2-yl)benzoyl)piperidin-4-yl)-2- (phenylamino)pyridine-4-carboxamide

[0604] To a stirred solution of 2-(phenylamino)pyridine-4-carboxylic acid (0.060 g, 0.27 mmol), benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate (0.14 g, 0.27 mmol) and N,N-diisopropylethylamine (0.12 g, 1.0 mmol) in N,N-dimethylformamide 6 mL was added (hexahydropyrrolo[3,4-c]pyrrol-2(lH)-yl)(3-(imidazo[l,2-a]pyridin-2-yl)phenyl)methanone (0.092 g, 0.27 mmol) under ice bath. After stirring for 0.5 h, the mixture was allowed to warm to room temperature and stirred overnight. The reaction mixture was poured into 20 mL of water and extracted with ethyl acetate (20 mL x 3). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (DCM:MeOH = 20: 1) to give a white solid (16 mg, 30 μmol) in 11.2% yield. LC-MS m / z: (M+H)+= 529.

[0605] 1 H NMR (400 MHz, Chloroform-d) δ 8.09 (td, J = 20.1, 18.0, 6.8 Hz, 3H), 7.89 (d, J = 14.3 Hz, 1H), 7.54 (dt, J = 53.5, 7.3 Hz, 4H), 7.36 (d, J = 4.4 Hz, 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).

[0606] Example 52 N-(3-(6-(lH-benzo[d]imidazol-2-yl)pyridinyl)-3-azabicyclo[3.1.0]hexyl-6-yl)-6-(pyridin-2-ylamino)pyridinecarboxamide (L-52)

[0607]

[0608] I. Methyl 6-(pyridin-2-ylamino)picolinic acid

[0609] Methyl 6-bromopyridine-2-carboxylate (2 g, 9.26 mmol) was dissolved in 50 ml of dioxane, 2-aminopyridine (871 mg, 9.26 mmol), tris(dibenzylideneacetone)dipalladium (424 mg, 0.46 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (536 mg, 0.92 mmol) and cesium carbonate (7.54 g, 23.1 mmol) were added, and the reaction was stirred at 95 °C under nitrogen protection for 15 hours. The reaction 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 was stirred at 20 °C for 15 hours. The reaction was extracted with ethyl acetate three times (20 ml*3). The aqueous phase was acidified to pH = 1 with 2N hydrochloric acid, and the aqueous phase was extracted with ethyl acetate three times (20 ml*3), and then neutralized to pH = 1 with saturated aqueous sodium bicarbonate solution. The aqueous phase was concentrated to obtain a solid, which was added to 50 ml of N,N-dimethylformamide, stirred at 20 °C for 2 hours, filtered and concentrated to obtain a white solid 460 mg, with a yield of 23.0%. LC-MS: m / z: (M+H)+= 216.0.

[0610] II. N-(3-(6-(1H-benzo[d]imidazol-2-yl)pyridinyl)-3-azabicyclo[3.1.0]hexyl-6-yl)-2-(pyridin-2- ylamino)isonicotinamide

[0611] The operation was the same as L-51

[0612] LC-MS: m / z: (M+H)+= 517.0, 1H NMR (400 MHz, CD3OD) δ 8.45 (dd, J = 7.5, 1.4 Hz, 1H), 8.27 - 8.11 (m, 3H), 7.92 - 7.56 (m, 6H), 7.36 (dd, J = 6.1, 3.1 Hz, 2H), 7.24 (d, J = 7.0 Hz, 1H), 7.02 - 6.88 (m, 1H), 4.25 (dd, J = 21.8, 12.0 Hz, 2H), 3.99 (dd, J = 11.6, 4.4 Hz, 1H), 3.76 (dd, J = 12.4, 4.5 Hz, 1H), 2.74 (t, J = 2.2 Hz, 1H), 2.17 - 2.06 (m, 2H).

[0613] Example 53 (5-(6-(1H-benzo[d]imidazol-2-yl)pyridinyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)(2-(pyridin-2-ylamino)pyridin-4-yl)methanone (L-53)

[0614]

[0615] (5-(6-(1H-benzo[d]imidazol-2-yl)pyridinyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)(2-(pyridin-2-ylamino)pyridin-4-yl)methanone

[0616] Operate as L-14

[0617] LC-MS: m / z: (M+H)+ = 531.0, ¾ NMR (400 MHz, CD3OD) δ 8.46 - 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, 7.1 Hz, 2H).

[0618] Example 54 (5-(6-(imidazo[l,2-a]pyridin-2-yl]pyridinyl)hexahydropyrrolo[3,4-c]pyrrol-2(lH)-yl)(2-(pyridin-2-ylamino)pyridin-4-yl)methanone (L-54)

[0619]

[0620] (5-(6-(imidazo[l,2-a]pyridin-2-yl]pyridinyl)hexahydropyrrolo[3,4-c]pyrrol-2(lH)-yl)(2-(pyridin-2-ylamino)pyridin-4-yl)methanone

[0621] Operate as L-14

[0622] LC-MS: m / z: (M+H)+ = 531.0, ¾ NMR (400 MHz, CD3OD) δ 8.46 - 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, 7.1 Hz, 2H).

[0623] Example 55 (5-(6-(l-(lH-benzo[d]imidazol-2-yl]pyridinyl)hexahydropyrrolo[3,4-c]pyrrol-2(lH)-yl)(3-(imidazo[l,2-a]pyridin-2-yl)phenyl)methanone (L-55)

[0624]

[0625] Operate as L-53

[0626] (5-(6-(1-(1H-benzo[d]imidazol-2-yl]pyridinyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)(3-(imidazo[1,2-a]pyridin-2-yl)phenyl)methanone

[0627] LC-MS: m / z: (M+H)+= 554.63, 1 H NMR (400 MHz, CDC13) δ 12.67 (s, 1H), 8.13 - 7.82 (m, 4H), 7.54 - 7.33 (m, 4H), 7.26 (d, J = 7.6 Hz, 2H), 4.54 (d, J = 11.9 Hz, 3H), 4.04 (t, J = 15.9 Hz, 3H), 1.85 (s, 1H), 1.77 (s, 1H).

[0628] Example 56 6-(1h-benzo[d]imidazol-2-yl)-n-(1-(3-(imidazo[1,2-a]pyridin-2-yl)benzoyl)piperidin-4-yl)picolinamide (L-56)

[0629]

[0630] Example 56 6-(1h-benzo[d]imidazol-2-yl)-n-(1-(3-(imidazo[1,2-a]pyridin-2-yl)benzoyl)piperidin-4-yl)picolinamide (L-56)

[0631] LC-MS m / z: (M+H)+ = 542.0, 1H NMR (400 MHz, Chloroform-d) δ 8.68 (dd, J = 7.9, 1.1 Hz, 1H), 8.40 (d, J = 6.8 Hz, 1H), 8.31 (dd, J = 7.7, 1.1 Hz, 1H), 8.24 (s, 2H), 8.01 (t, J = 7.8 Hz, 1H), 7.93 (d, J = 7.8 Hz, 1H), 7.82 (d, J = 9.0 Hz, 1H), 7.45 (t, J = 7.7 Hz, 1H), 7.39 - 7.31 (m, 2H), 7.21 (s, 2H), 7.03 (t, J = 6.7 Hz, 1H), 4.59 (s, 1H), 4.18 (s, 1H), 3.55 (s, 1H), 2.93 - 2.55 (m, 3H).

[0632] Example 57 (4-(1h-benzo[d]imidazol-2-yl)piperidin-1-yl)(6-(1h-benzo[d]imidazol-2- yl)pyridin-2-yl)methanone (L-57)

[0633]

[0634] Following the procedure for de-Boc protection of Example 42 for compounds 1-2, operate compounds 2 to L-57 as for L-56

[0635] (4-(1h-benzo[d]imidazol-2-yl)piperidin-1-yl)(6-(1h-benzo[d]imidazol-2- yl)pyridin-2-yl)methanone

[0636] LC-MS m / z: (M+H)+ = 422.9, 1H NMR (400 MHz, Methanol-d4) δ 8.43 (dd, J = 8.0, 1.0 Hz, 1H), 8.16 (t, J = 7.9 Hz, 1H), 7.72 (d, J = 1.1 Hz, 1H), 7.71 - 7.67 (m, 2H), 7.60 - 7.53 (m, 2H), 7.34 (dd, J = 6.1, 3.1 Hz, 2H), 7.27 (dd, J = 6.1, 3.1 Hz, 2H), 3.96 (d, J = 13.7 Hz, 1H), 3.53 - 3.38 (m, 2H), 3.21 (dd, J = 12.8, 2.8 Hz, 1H), 2.33 (d, J = 12.9 Hz, 1H), 2.26 - 2.02 (m, 4H).

[0637] Example 58 (2,9-diazaspiro[5.5]undecane-2,9-diyl)bis(6-(1h-benzo[d]imidazol-2- yl)pyridin-2-yl)methanone (L-58)

[0638]

[0639] Operate as L-43

[0640] 2,9-diazaspiro[5.5]undecane-2-carboxylic acid tert-butyl ester 2 was purchased from Bide Pharmatech Co., Ltd.

[0641] (2,9-diazaspiro[5.5]undecane-2,9-diyl)bis(6-(1h-benzo[d]imidazol-2-yl)pyridin-2- yl)methanone

[0642] LC-MS m / z: (M+H)+= 597.1, 1H NMR (400 MHz, Methanol-d4) δ 8.44 - 8.36 (m, 2H), 8.21 - 8.14 (m, 1H), 8.12 - 8.06 (m, 1H), 7.78 (q, J=7.7 Hz, 1H), 7.71 - 7.68 (m, 2H), 7.64 - 7.60 (m, 2H), 7.32 (dt, J=6.6, 3.1 Hz, 4H), 7.29 - 7.25 (m, 1H), 4.23 - 4.11 (m, 1H), 3.95 (dd, J=12.2, 6.4 Hz, 1H), 3.83 (d, J=21.5 Hz, 1H), 3.74 (dt, J=13.3, 6.7 Hz, 3H), 3.68 - 3.58 (m, 2H), 3.47 (s, 2H), 1.92 - 1.83 (m, 1H), 1.80 (d, J=11.9 Hz, 2H), 1.66 - 1.57 (m, 2H), 1.54 (d, J=4.5 Hz, 1H).

[0643] Example 59 (2,8-diaza[4.5]decane-2,8-diyl)bis(6-(1h-benzo[d]imidazol-2-yl)pyridin-2- yl)methanone (L-59)

[0644]

[0645] Operate as L-43

[0646] 2,9-diazaspiro[5.5]undecane-2-carboxylic acid tert-butyl ester 2 was purchased from Bide Pharmatech Co., Ltd.

[0647] (2,8-diaza[4.5]decane-2,8-diyl)bis(6-(1h-benzo[d]imidazol-2-yl)pyridin-2- yl)methanone

[0648] LC-MS m / z: (M+H)+= 583.1, 1H NMR (400 MHz, Methanol-d4) δ 8.45 - 8.39 (m, 2H), 8.35 (dd, J=7.9, 1.1 Hz, 1H), 8.17 - 8.09 (m, 2H), 8.06 (td, J=8.0, 2.6 Hz, 1H), 7.82 (ddd, J=12.1, 7.8, 1.0 Hz, 2H), 7.70 (d, J=1.1 Hz, 1H), 7.58 (dd, J=7.7, 1.0 Hz, 1H), 7.35 - 7.31 (m, 3H), 7.28 (dd, J=6.1, 3.1 Hz, 1H), 3.97 (dd, J=15.2, 7.7 Hz, 2H), 3.80 (dd, J=12.5, 5.2 Hz, 3H), 3.66 - 3.58 (m, 2H), 2.08 - 1.97 (m, 3H), 1.91 (dd, J=7.6, 4.9 Hz, 1H), 1.79 (t, J=6.1 Hz, 2H), 1.69 (d, J=5.1 Hz, 1H).

[0649] Example 60 (7-(6-(1h-benzo[d]imidazol-2-yl)nicotinoyl)-2,7-diazaspiro[4.4]nonan-2-yl)(6-(1h-benzo[d]imidazol-2-yl)pyridin-2-yl)methanone (L-60)

[0650]

[0651] Procedure same as L-43

[0652] 2,9-Diazaspiro[5.5]undecane-2-carboxylic acid tert-butyl ester 2 was purchased from Bide Pharmachem

[0653] (7-(6-(1h-benzo[d]imidazol-2-yl)nicotinoyl)-2,7-diazaspiro[4.4]nonan-2-yl)(6-(1h-benzo[d]imidazol-2-yl)pyridin-2-yl)methanone

[0654] LC-MS m / z: (M+H)+ = 569.1, 1H NMR (400 MHz, Methanol-d4) δ 8.44 (dt, J = 8.0, 1.1 Hz, 1H), 8.37 (ddd, J = 17.3, 7.9, 1.0 Hz, 1H), 8.16 (t, J = 7.8 Hz, 1H), 8.06 (dt, J = 10.2, 7.9 Hz, 1H), 7.88 (ddd, J = 10.2, 7.8, 1.0 Hz, 1H), 7.80 - 7.72 (m, 2H), 7.66 (s, 2H), 7.50 (s, 1H), 7.34 (d, J = 6.0 Hz, 1H), 7.30 (dq, J = 5.6, 3.0, 2.3 Hz, 3H), 4.20 - 3.97 (m, 2H), 3.89 (dd, J = 13.2, 6.2 Hz, 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, 7.1 Hz, 2H).

[0655] Example 49 BT-11

[0656]

[0657] BT-11 was prepared as described in Example 2 of CN107108573A.

[0658] Example 61 (8-(6-(1H-benzo[d]imidazol-2-yl)pyridinoyl)-2,8-diazaspiro[4.5]dec-2-yl)(6- (anilino)pyridin-2-yl)methanone (Compound L-61)

[0659]

[0660] The procedure was the same as the preparation of Compound L-82 in Example 82.

[0661] LC-MS m / z: (M+H)+ = 558.1.

[0662] 1H NMR (400 MHz, Methanol-d4) δ 8.40 (ddd, J = 11.2, 8.0, 1.0 Hz, 1H), 8.13 (dt, J = 13.7, 7.8 Hz, 1H), 7.76 - 7.62 (m, 3H), 7.60 (dd, J = 7.7, 1.0 Hz, 1H), 7.58 - 7.50 (m, 2H), 7.39 - 7.28 (m, 2H), 7.22 (dtd, J = 16.2, 7.3, 1.9 Hz, 2H), 7.08 (ddd, J = 7.0, 6.1, 0.9 Hz, 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, 8.0 Hz, 2H), 3.64 - 3.54 (m, 2H), 3.44 (dt, J = 11.3, 5.5 Hz, 1H), 2.03 - 1.91 (m, 2H), 1.75 (td, J = 12.5, 12.1, 5.9 Hz, 2H), 1.62 (t, J = 5.9 Hz, 2H).

[0663] Example 62 (8-(6-(lH-Benzo[d]imidazol-2-yl)pyridinoyl)-2,8-diazaspiro[4.5]dec-2-yl)(2- (phenylamino)pyrimidin-4-yl)methanone (Compound L-62)

[0664]

[0665] The procedure was same as preparation of Compound L-82 in Example 82.

[0666] LC-MS m / z: (M+H)+= 559.1.

[0667] 1H NMR (400 MHz, Methanol-d4) δ 8.61 - 8.56 (m, 1H), 8.40 (ddd, J = 9.1, 7.9, 1.0 Hz, 1H), 8.14 (dt, J = 10.8, 7.9 Hz, 1H), 7.74 - 7.67 (m, 2H), 7.66 (d, J = 1.1 Hz, 1H), 7.65 - 7.61 (m, 2H), 7.34 (tt, J = 7.0, 2.8 Hz, 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, 5.1 Hz, 2H), 3.76 - 3.70 (m, 2H), 3.61 - 3.55 (m, 1H), 3.48 (d, J = 5.9 Hz, 1H), 2.04 - 1.96 (m, 2H), 1.76 (s, 2H), 1.67 - 1.60 (m, 2H).

[0668] Example 63 (9-(6-(lH-Benzo[d]imidazol-2-yl)pyridinoyl)-2,9-diazaspiro[5.5]undecan- 2-yl)(6-(anilino)pyridin-2-yl)methanone (Compound L-63)

[0669]

[0670] Procedure same as the preparation of Compound L-82 in Example 82.

[0671] LC-MS m / z: (M+H)+= 587.7.

[0672] 1H NMR (400 MHz, Chloroform-d) δ 8.68 (s, 1H), 8.56 (d, J = 8.0 Hz, 1H), 7.98 (t, J = 7.8 Hz, 1H), 7.80 - 7.74 (m, 2H), 7.48 - 7.40 (m, 1H), 7.31 (dd, J = 6.1, 3.2 Hz, 2H), 7.28 - 7.20 (m, 1H), 7.13 (dt, J = 7.4, 4.5 Hz, 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).

[0673] Example 64 (9-(6-(lH-Benzo[d]imidazol-2-yl)pyridinoyl)-2,9-diazaspiro[5.5]undecan- 2-yl)(2-(anilino)pyrimidin-4-yl)methanone (Compound L-64)

[0674]

[0675] Procedure same as the preparation of Compound L-82 in Example 82.

[0676] LC-MS m / z: (M+H)+= 572.9.

[0677] 1H NMR (400 MHz, Methanol-d4) δ 8.58 (d, J = 4.9 Hz, 1H), 8.43 - 8.36 (m, 1.5H), 8.26 (d, J = 4.9 Hz, 0.5H), 8.12 (td, J = 7.9, 1.4 Hz, 1.5H), 7.72 - 7.68 (m, 2H), 7.64 (dd, J = 7.8, 1.0 Hz, 2H), 7.58 - 7.54 (m, 1.5H), 7.33 (tq, J = 7.5, 2.6 Hz, 5H), 7.19 (dd, J = 8.6, 7.3 Hz, 1H), 7.04 (tt, J = 7.4, 1.2 Hz, 1H), 6.91 (d, J = 4.9 Hz, 1H), 6.55 (d, J = 4.9 Hz, 0.5H), 4.10 (dt, J = 13.8, 4.9 Hz, 1H), 3.88 - 3.74 (m, 3H), 3.64 (tdd, J = 13.8, 9.6, 3.8 Hz, 4H), 3.47 (d, J = 5.3 Hz, 2H), 3.42 (d, J = 1.7 Hz, 1H), 1.80 (d, J = 16.3 Hz, 2H), 1.64 (dd, J = 9.7, 4.8 Hz, 3H).

[0678] Example 65 (7-(6-(lH-Benzo[d]imidazol-2-yl)pyridinoyl)-2,7-diazaspiro[4.4]nonan-2- yl)(6-(anilino)pyridin-2-yl)methanone (Compound L-65)

[0679]

[0680] The procedure was the same as in the preparation of Compound L-82 in Example 82.

[0681] LC-MS m / z: (M+H)+= 554.1.

[0682] 1H NMR (400 MHz, Methanol-d4) δ 8.49 - 8.42 (m, 1H), 8.38 (d, J = 7.5 Hz, 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, 1.1 Hz, 1H), 7.71 (dt, J = 7.1, 3.5 Hz, 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, 3.6 Hz, 1H), 6.95 (dtd, J = 11.7, 6.8, 1.2 Hz, 1H), 4.18 - 3.59 (m, 8H), 3.24 - 3.04 (m, 2H).

[0683] Example 66 (7-(6-(lH-Benzo[d]imidazol-2-yl)pyridinoyl)-2,7-diazaspiro[4.4]nonan-2- yl)(4-(anilino)pyrimidin-2-yl)methanone (Compound L-66)

[0684]

[0685] Procedure similar to the preparation of Compound L-82 in Example 82.

[0686] LC-MS m / z: (M+H)+ = 544.9.

[0687] 1H NMR (400 MHz, Chloroform-d) δ 8.62 - 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, 1.2 Hz, 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).

[0688] Example 67 N-(3-(6-(lH-Benzo[d]imidazol-2-yl)pyridinoyl)-3-azabicyclo[3.1.0]hexan-6-yl)-6- methyl-lH-indole-2-carboxamide (Compound L-67)

[0689]

[0690] Procedure similar to the preparation of Compound L-82 in Example 82.

[0691] LC-MS m / z: (M+H)+ = 476.9.

[0692] 1H NMR (400 MHz, DMSO-d6) δ 13.20 (s, 1H), 11.43 (d, J = 2.1 Hz, 1H), 9.33 (d, J = 3.1 Hz, 1H), 8.46 (dd, J = 7.7, 1.2 Hz, 1H), 8.18 (t, J = 7.7 Hz, 1H), 8.11 (dd, J = 7.7, 1.2 Hz, 1H), 7.77 (dd, J = 7.9, 1.1 Hz, 1H), 7.73 - 7.64 (m, 1H), 7.55 (d, J = 8.2 Hz, 1H), 7.35 (ddd, J = 8.2, 7.2, 1.2 Hz, 1H), 7.28 (ddd, J = 8.3, 7.2, 1.3 Hz, 1H), 7.25 (dd, J = 1.6, 0.8 Hz, 1H), 6.96 (dd, J = 2.3, 0.9 Hz, 1H), 6.90 (dd, J = 8.2, 1.5 Hz, 1H), 4.17 (s, 3H), 3.74 (s, 1H), 2.62 (q, J = 2.7 Hz, 1H), 2.41 (s, 3H), 2.21 (s, 1H), 2.09 (s, 1H).

[0693] Example 68 N-(3-(6-(lH-Benzo[d]imidazol-2-yl)pyridinecarbonyl)-3- azabicyclo[3.1.0]hexan-6-yl)quinoline-2-carboxamide (Compound L-68)

[0694]

[0695] The procedure was same as preparation of compound L-82 in example 82.

[0696] LC-MS m / z: (M+H)+= 476.1.

[0697] 1H NMR (400 MHz, DMSO) δ 13.18 (s, 1H), 9.31 (s, 1H), 8.50 (dd, J = 28.7, 8.2 Hz, 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 = 12.5 Hz, 1H), 3.77 (d, J = 12.2 Hz, 1H), 3.62 (s, 1H), 3.18 (d, J = 5.2 Hz, 1H), 2.10 (s, 1H).

[0698] Example 69 (5-(6-(lH-Benzo[d]imidazol-2-yl)pyridinecarbonyl)hexahydropyrrolo[3,4- c]pyrrol-2(lH)-yl)(quinolin-2-yl)methanone (Compound L-69)

[0699] LC-MS m / z: (M+H)+= 476.1.

[0700] (6-(lH-benzo[d]imidazol-2-yl)pyridin-2-yl)(hexahydropyrrolo[3,4-c]pyrrol-2(lH)- yl)methanone (33 mg, 0.1 mmol) and quinoline-2-carboxylic acid (17 mg, 0.1 mmol) were suspended in N,N-dimethylformamide (3 mL), N,N-diisopropylethylamine (26 mg, 0.2 mmol) and 1-propylphosphonic anhydride (41 mg, 0.13 mmol) were added. The reaction was stirred at 25 °C for 16 h. The reaction was concentrated to give the crude product, which was purified by thin layer chromatography plate (dichloromethane:methanol = 15:1) to give a yellow solid (15 mg, 31%). LC-MS: m / z: (M+H)+= 488.9. + 1 H NMR (400 MHz, DMSO-d6) δ 12.93 (d, J = 6.3 Hz, 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).

[0701] Example 70 (5-(6-(lH-benzo[d]imidazol-2-yl)pyridinecarbonyl)hexahydropyrrolo[3,4- c]pyrrol-2(lH)-yl)(6-methyl-lH-indol-2-yl)methanone (Compound L-70)

[0702]

[0703] The procedure was the same as the preparation of Compound L-82 in Example 82.

[0704] LC-MS: m / z: (M+H)+= 491.1. 1 H NMR (400 MHz, DMSO-d6) δ 12.91 (s, 1H), 11.42 (s, 1H), 8.42 (d, J = 7.9 Hz, 1H), 8.13 (t, J = 7.8 Hz, 1H), 7.77 (dd, J = 27.7, 7.7 Hz, 2H), 7.59 (d, J = 7.4 Hz, 1H), 7.54 - 7.38 (m, 1H), 7.35 - 7.15 (m, 3H), 6.92 (t, J = 20.7 Hz, 2H), 4.20 - 3.56 (m, 8H), 3.09 (d, J = 40.8 Hz, 2H), 2.40 (s, 3H).

[0705] ​Example 71 (5-(6-(lH-benzo[d]imidazol-2-yl)picolinoyl)hexahydropyrrolo[3,4- c]pyrrol-2(lH)-yl)(2-methyl-lH-indol-3-yl)methanone (Compound L-71)

[0706]

[0707] The procedure was same as the preparation of Compound L-82 in Example 82.

[0708] LC-MS m / z: (M+H)+= 491.1.

[0709] 1H NMR (400 MHz, CDCl3) d 8.68 (s, 1H), 8.56 (d, J = 7.7 Hz, 1H), 7.98 (t, J = 7.8 Hz, 1H), 7.77 (d, J = 7.4 Hz, 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 = 5.9 Hz, 1H), 1.66 (s, 1H).

[0710] Example 72 (9-(3-(imidazo[l,2-a]pyridin-2-yl)benzoyl)-3,9-diazaspiro[5.5]undecan- 3-yl)(6-(anilino)pyridin-2-yl)methanone (Compound L-72)

[0711]

[0712] The procedure was same as the preparation of Compound L-82 in Example 82.

[0713] LC-MS: m / z: (M+H) + = 433.2; 1H NMR (400 MHz, Methanol-d4) d 8.46 (d, J = 6.8 Hz, 1H), 8.31 (s, 1H), 8.06 (d, J = 7.8 Hz, 1H), 8.00 (s, 1H), 7.66 - 7.54 (m, 5H), 7.45 - 7.33 (m, 2H), 7.27 (t, J = 7.9 Hz, 2H), 6.96 (td, J = 6.8, 4.4 Hz, 2H), 6.88 (t, J = 7.2 Hz, 2H), 3.79 (d, J = 16.7 Hz, 4H), 3.54 (s, 5H), 1.73 (s, 3H), 1.63 (s, 5H).

[0714] Example 73 (3,9-diazaspiro[5.5]undecane-3,9-diyl)bis((3-(imidazo[l,2- a]pyridin-2-yl)phenyl)methanone) (Compound L-73)

[0715]

[0716] The procedure was same as the preparation of compound L-82 in Example 82.

[0717] LC-MS: m / z: (M+H) + = 553.2; 1H NMR (400 MHz, Methanol-d4) δ 8.43 (dd, J = 24.7, 6.9 Hz, 2H), 8.36 - 8.22 (m, 2H), 8.10 (dd, J = 29.2, 20.1 Hz, 4H), 7.57 (dd, J = 25.5, 8.6 Hz, 6H), 7.34 (dt, J = 17.0, 8.2 Hz, 2H), 6.94 (dt, J = 13.9, 6.8 Hz, 2H), 4.05 - 3.50 (m, 9H), 3.24 - 3.01 (m, 2H).

[0718] Example 74 (Tetrahydropyrrolo[3,4-c]pyrrole-2,5(lH,3H)-diyl)bis((3-(imidazo[l,2- a]pyridin-2-yl)phenyl)methanone) (Compound L-74)

[0719]

[0720] The procedure was same as the preparation of compound L-82 in Example 82.

[0721] LC-MS: m / z: (M+H) + = 553.2; 1H NMR (400 MHz, Methanol-d4) δ 8.43 (dd, J = 24.7, 6.9 Hz, 2H), 8.36 - 8.22 (m, 2H), 8.10 (dd, J = 29.2, 20.1 Hz, 4H), 7.57 (dd, J = 25.5, 8.6 Hz, 6H), 7.34 (dt, J = 17.0, 8.2 Hz, 2H), 6.94 (dt, J = 13.9, 6.8 Hz, 2H), 4.05 - 3.50 (m, 9H), 3.24 - 3.01 (m, 2H).

[0722] Example 75 (4-(2-hydroxyethyl)piperazin-l-yl)(3-(imidazo[l,2-a]pyridin-2- yl)phenyl)methanone (Compound L-75)

[0723]

[0724] The procedure is the same as that used in the preparation of compound L-82 in Example 82.

[0725] 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).

[0726] Example 76 (6-(1H-benzo[d]imidazol-2-yl)pyridin-2-yl)(4-(2-hydroxyethyl)piperazin-1-yl)methyl ketone (compound L-76)

[0727]

[0728] The procedure is the same as that used in the preparation of compound L-82 in Example 82.

[0729] 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).

[0730] Example 77 6-(1H-benzo[d]imidazol-2-yl)-N-(3-(3-(benzo[d]thiazol-2-yl)benzoyl)-3-azabicyclo[3.1.0]hexane-6-yl)pyridine amide (compound L-77)

[0731]

[0732] 1. Methyl 3-(benzo[d]thiazo-2-yl)benzoate

[0733] A solution of 2-bromo-1,3-benzothiazole (1.07 g, 5.0 mmol), (3-methoxycarbonylphenyl)boronic acid (0.9 g, 5.0 mmol), K₂CO₃ (1.38 g, 10.0 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (0.1 g, 0.5 mmol) in dioxane (50 mL) and water (10 mL) was stirred at 80 °C for 4 hours. The reaction mixture was concentrated to dryness and purified by rapid chromatography (silica) (petroleum ether:ethyl acetate = 3:1) to give a white solid methyl 3-(1,3-benzothiazole-2-yl)benzoate (1.0 g, 74.3%).

[0734] II. 3-(benzo[d]thiazolyl)benzoic acid

[0735] Methyl 3-(1,3-benzothiazol-2-yl)benzoate (54 mg, 0.2 mmol) was placed in MeOH (5 mL) and water (1 mL), and LiOH (24 mg, 1.0 mmol) was added. The reaction mixture was stirred at 80 °C for 1 h. The reaction mixture was concentrated to dryness to obtain a crude product, which was then used directly in the next reaction.

[0736] III. 6-(1H-benzo[d]imidazol-2-yl)-N-(3-(3-(benzo[d]thiazol-2-yl)benzoyl)-3-azabicyclo[3.1.0]hexane-6-yl)pyridine amide

[0737] The procedure is the same as that used in the preparation of compound L-82 in Example 82.

[0738] 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,4 H),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).

[0739] Example 78 (3,9-diazaspiro[5.5]undecane-3,9-diyl)bis((2-(phenylamino)pyrimidin-4-yl)methyl ketone) (Compound L-78)

[0740]

[0741] I. 9-(2-(2-(phenylamino)pyrimidine-4-carbonyl)-3,9-diazaspiro[5.5]undecane-3- carboxylic acid tert-butyl ester

[0742] tert-Butyl 3,9-diazaspiro[5.5]undecane-3-carboxylate (100 mg, 0.39 mmol) (compound as shown in Formula 2) and 2-anilinopyrimidine-4-carboxylic acid (85 mg, 0.39 mmol) (compound as shown in Formula 1) were suspended in 3 ml of N,N-dimethylformamide, N,N-diisopropylethylamine (101 mg, 0.78 mmol) and 2-(7-azobenzotriazol)-N,N,N',N'-tetramethyluronium hexafluorophosphate (179 mg, 0.47 mmol) were added. The reaction was stirred at 30 °C for 16 h. 10 ml of ice water was added to the reaction, stirred for five minutes, filtered, and the solid was dried to give the crude product as 175 mg of brown solid with a yield of 98.58%. LC-MS: m / z: (M+H)+= 452.0.

[0743] II. (2-(phenylamino)pyrimidin-4-yl)(3,9-diazaspiro[5.5]undecan-3-yl)methanone

[0744] tert-Butyl 9-(2-(2-(phenylamino)pyrimidine-4-carbonyl)-3,9-diazaspiro[5.5]undecane-3- carboxylate (175 mg, 0.39 mmol) (compound as shown in Formula 3) was dissolved in 3 ml of methanol, and hydrochloric acid dioxane solution (3 mL, 4 M, 12 mmol) was added. The reaction was stirred at 15 °C for 2 h. The reaction was concentrated and dried to give the crude product as 136 mg of brown solid with a yield of 99.87%. LC-MS: m / z: (M+H)+= 352.0.

[0745] III. (3,9-diazaspiro[5.5]undecane-3,9-diyl)bis((2-(phenylamino)pyrimidin-4-yl)methanone)

[0746] The operation was the same as the preparation of compound L-82 in Example 82.

[0747] LC-MS: m / z: (M+H)+= 549.0, 1H NMR (400 MHz, CD3OD) δ 8.55 (d, J = 4.9 Hz, 2H), 7.67 (dd, J = 8.6, 1.0 Hz, 4H), 7.36 - 7.26 (m, 4H), 7.03 (t, J = 7.4 Hz, 2H), 6.87 (d, J = 4.9 Hz, 2H), 3.77 (dd, J = 11.7, 5.6 Hz, 4H), 3.50 (dd, J = 11.1, 5.3 Hz, 4H), 1.77 - 1.57 (m, 8H).

[0748] Example 79 2-(phenylamino)-N-(1-(2-(2-(phenylamino)pyrimidine-4-carbonyl)piperidin-4- yl)pyrimidine-4-carboxamide (Compound L-79)

[0749]

[0750] One, tert-butyl (1-(2-(phenylamino)pyrimidine-4-carbonyl)piperidin-4-yl)carbamate

[0751] Tert-butyl piperidin-4-ylcarbamate (100 mg, 0.50 mmol) (compound as shown in Formula 2) and 2-anilinopyrimidine-4-carboxylic acid (107 mg, 0.50 mmol) (compound as shown in Formula 1) were suspended in 3 ml of N,N-dimethylformamide, N,N-diisopropylethylamine (129 mg, 1.0 mmol) and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (228 mg, 0.60 mmol) were added. The reaction was stirred at 30 °C for 16 h. 10 ml of ice water was added to the reaction, stirred for five minutes, filtered, and the solid was dried to give the crude product as 185 mg of brown solid, with a yield of 93.21%. LC-MS: m / z: (M+H)+= 498.0.

[0752] Two, (4-aminopiperidin-1-yl)(2-(phenylamino)pyrimidin-4-yl)methanone

[0753] Tert-butyl (1-(2-(phenylamino)pyrimidine-4-carbonyl)piperidin-4-yl)carbamate (185 mg, 0.47 mmol) (compound as shown in Formula 3) was dissolved in 3 ml of methanol, and a hydrochloric acid dioxane solution (3 mL, 4 M, 12 mmol) was added. The reaction was stirred at 15 °C for 2 h. The reaction was concentrated and dried to give the crude product as 138 mg of brown solid, with a yield of 99.70%. LC-MS: m / z: (M+H)+= 298.0.

[0754] Three, 2-(phenylamino)-N-(1-(2-(2-(phenylamino)pyrimidine-4-carbonyl)piperidin-4-yl)pyrimidine-4-carboxamide

[0755] The operation was the same as the preparation of compound L-82 in Example 82.

[0756] LC-MS: m / z: (M+H)+ = 495.0, 1H NMR (400 MHz, CD3OD) δ 8.66 (d, J = 4.9 Hz, 1H), 8.57 (d, J = 4.9 Hz, 1H), 7.74 - 7.60 (m, 4H), 7.41 - 7.24 (m, 5H), 7.04 (dt, J = 20.0, 7.4 Hz, 2H), 6.91 (d, J = 4.9 Hz, 1H), 4.56 (d, J = 14.7 Hz, 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, 4.0 Hz, 1H), 1.79 - 1.63 (m, 2H).

[0757] Example 80 (9-(6-(phenylamino)pyridinyl)-3,9-diazaspiro[5.5]undec-3-yl)(2- (phenylamino)pyrimidin-4-yl)methanone (Compound L-80)

[0758]

[0759] The procedure was same as the preparation of compound L-82 in Example 82.

[0760] LC-MS: m / z: (M+H)+ = 548.0, 1H NMR (400 MHz, CD3OD) δ (d, J = 4.9 Hz, 1H), 7.64 (ddd, J = 11.8, 9.4, 6.1 Hz, 5H), 7.29 (dt, J = 12.4, 7.9 Hz, 4H), 6.99 (dt, J = 26.9, 7.4 Hz, 2H), 6.88 (dd, J = 9.5, 5.7 Hz, 3H), 3.77 (dt, J = 11.6, 5.7 Hz, 4H), 3.61 - 3.44 (m, 4H), 1.83 - 1.50 (m, 8H).

[0761] Example 81 6-(phenylamino)-N-(1-(2-(phenylamino)pyrimidine-4-carbonyl)piperidin-4- yl)pyridinamide (Compound L-81)

[0762]

[0763] The procedure was same as the preparation of compound L-82 in Example 82.

[0764] LC-MS: m / z: (M+H)+ = 494.0, 1H NMR (400 MHz, CD3OD) δ 8.57 (d, J = 4.9 Hz, 1H), 7.69 (dd, J = 16.7, 8.2 Hz, 3H), 7.49 (dd, J = 18.9, 7.5 Hz, 3H), 7.31 (dt, J = 24.3, 7.9 Hz, 4H), 7.07 - 6.96 (m, 3H), 6.91 (d, J = 4.9 Hz, 1H), 4.46 (d, J = 13.3 Hz, 1H), 4.19 (ddd, J = 14.0, 9.9, 4.0 Hz, 1H), 3.86 (d, J = 13.4 Hz, 1H), 3.43 - 3.36 (m, 1H), 3.27 (dd, J = 13.6, 3.0 Hz, 1H), 2.23 - 2.11 (m, 1H), 2.09 - 1.97 (m, 1H), 1.76 - 1.60 (m, 2H).

[0765] Example 82 (5-(6-(1H-benzo[d]imidazol-2-yl)pyridinyl)hexahydropyrrolo[3,4- c]pyrrol-2(1H)-yl)(2-(((4-fluorophenyl)amino)pyrimidin-4-yl)methanone (Compound L-82)

[0766]

[0767] I. 2-((4-Fluorophenyl)amino)pyrimidine-4-carboxylic acid

[0768] Dissolve 2-chloropyrimidine-4-carboxylic acid (500 mg, 3.15 mmol) in 15 ml dioxane, add p-fluoroaniline (881 mg, 9.46 mmol), and stir the reaction at 70 °C for 18 hours. Cool the reaction to room temperature, add 20 ml water and 10 ml 1 N sodium hydroxide, and extract the reaction twice with 20 ml ethyl acetate. Acidify the aqueous phase with 1 N hydrochloric acid to pH = 3, filter the solid, and dry to yield 500 mg of a white solid with a yield of 67.98%. LC-MS: m / z: (M+H)+ = 234.0.

[0769] II. (5-(6-(1H-benzo[d]imidazol-2-yl)pyridinyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)- yl)(2-(((4-fluorophenyl)amino)pyrimidin-4-yl)methanone

[0770] To a solution of 2,3,3a,4,6,6a-hexahydro-lH-pyrrolo[3,4-c]pyrrol-5-yl-[6-(lH- benzimidazol-2-yl)-2-pyridyl] (40 mg, 0.12 mmol) and 2-((4-fluorophenyl)amino)pyrimidine- 4-carboxylic acid (28 mg, 0.12 mmol) in 5 mL of N,N-dimethylformamide, N,N- diisopropylethylamine (62 mg, 0.48 mmol) and 1-propylphosphonic anhydride (115 mg, 0.18 mmol) were added. The reaction was stirred at 15 °C for 16 h. The reaction was concentrated to get the crude product. The crude product was purified by thin layer chromatography plate (dichloromethane:methanol = 10:1) to get the desired product 20 mg as a white solid with 30.39% yield.

[0771] LC-MS: m / z: (M+H)+= 549.0, ¾ NMR (400 MHz, CDC13) δ 8.48 (ddd, J = 39.8, 21.6, 6.4 Hz, 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).

[0772] Example 83 (Tetrahydropyrrolo[3,4-c]pyrrole-2,5(lH,3H)-diyl)bis((2-(phenylamino)pyrimidin-4- yl)methanone) (Compound L-83)

[0773]

[0774] Example 1 1 (2-(phenylamino)pyrimidin-4-yl)(2,3,3a,4,6,6a-hexahydro-lH-pyrrolo[3,4-c]pyrrol-5- yl)methanone (Compound L-11)

[0775] To a solution of 2,3,3a,4,6,6a-hexahydro-lH-pyrrolo[3,4-c]pyrrol-5-carboxylic acid tert-butyl ester (100 mg, 0.47 mmol) and 2-anilinopyrimidine-4-carboxylic acid (101 mg, 0.47 mmol) in 3 mL of N,N-dimethylformamide, N,N-diisopropylethylamine (122 mg, 0.94 mmol) and 1-propylphosphonic anhydride (449 mg, 0.71 mmol) were added. The reaction was stirred at 15 °C for 16 h. To the reaction, 10 mL of ice water was added, stirred for five minutes, filtered, and the solid was dried to get the crude product as 180 mg of brown solid with 93.31% yield. LC-MS: m / z: (M+H)+= 410.0.

[0776] II. (Hexahydropyrrolo[3,4-c]pyrrol-2(lH)-yl)(2-(phenylamino)pyrimidin-4- yl)methanone

[0777] tert-Butyl 5-(2-(phenylamino)pyrimidine-4-carbonyl)hexahydropyrrolo[3,4- c]pyrrole-2(lH)-carboxylate (180 mg, 0.44 mmol) (compound as shown in Formula 3) was dissolved in 3 mL of methanol, and a hydrochloric acid dioxane solution (3 mL, 4 M, 12 mmol) was added. The reaction solution was stirred at 15 °C for 2 h. The reaction solution was concentrated, and the solid was washed with ethyl acetate (10 mL) and dried to obtain 120 mg of a brown solid as a crude product at a yield of 88.24%. LC-MS: m / z: (M+H)+= 310.0.

[0778] III. (Tetrahydropyrrolo[3,4-c]pyrrol-2,5(lH,3H)-diyl)bis((2-(phenylamino)pyrimidin-4- yl)methanone)

[0779] The operation was the same as the preparation of compound L-82 in Example 82.

[0780] LC-MS: m / z: (M+H)+= 507.0, 1H NMR (400 MHz, CDCl3) δ 8.56 - 8.42 (m, 2H), 7.53 (dd, J = 19.5, 8.3 Hz, 4H), 7.18 (dt, J = 30.7, 7.3 Hz, 4H), 7.03 - 6.79 (m, 4H), 3.93 - 3.46 (m, 8H), 2.94 (d, J = 7.4 Hz, 2H).

[0781] Example 84 (2-(phenylamino)-N-(3-(2-(2-(phenylamino)pyrimidine-4-carbonyl)-3- azabicyclo[3.1.0]hex-6-yl)pyrimidine-4-carboxamide (compound L-84)

[0782]

[0783] I. tert-Butyl ((lR,5S,6s)-6-(2-(phenylamino)pyrimidine-4-carboxamido)-3- azabicyclo[3.1.0]hexane-3-carboxylate

[0784] (1R,5S,6s)-6-amino-3-azabicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester (100 mg, 0.50 mmol) (compound as shown in Formula 2) and 2-anilinopyrimidine-4-carboxylic acid (108 mg, 0.51 mmol) (compound as shown in Formula 1) were suspended in 3 ml of N,N-dimethylformamide, N,N-diisopropylethylamine (130 mg, 1.0 mmol) and 1-propylphosphonic anhydride (480 mg, 0.75 mmol) were added. The reaction was stirred at 15 °C for 16 h. To the reaction was added 10 ml of ice water, stirred for five minutes, filtered, and the solid was dried to give the crude product as 180 mg of brown solid in 90.28% yield. LC-MS: m / z: (M+H)+= 396.0.

[0785] II. N-((1R,5S,6s)-3-azabicyclo[3.1.0]hexan-6-yl)-2-(phenylamino)pyrimidine-4- carboxamide

[0786] ((1R,5S,6s)-6-(2-(phenylamino)pyrimidine-4-carboxamido)-3-azabicyclo[3.1.0]hexane- 3-carboxylic acid tert-butyl ester (180 mg, 0.45 mmol) (compound as shown in Formula 3) was dissolved in 3 ml of methanol, hydrochloric acid dioxane solution (3 mL, 4 M, 12 mmol) was added. The reaction was stirred at 15 °C for 2 h. The reaction was concentrated, the solid was washed with ethyl acetate (10 mL), and dried to give the crude product as 120 mg of brown solid in 89.27% yield. LC-MS: m / z: (M+H)+= 296.0.

[0787] III. (2-(phenylamino)-N-(3-(2-(2-(phenylamino)pyrimidine-4-carbonyl)-3-azabicyclo[3.1.0]hex-6-yl)pyrimidine-4-carboxamide

[0788] The procedure was the same as the preparation of compound L-82 in Example 82.

[0789] LC-MS: m / z: (M+H)+= 493.0, 1H NMR (400 MHz, DMSO-d6) δ 9.80 (d, J = 28.2 Hz, 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 = 11.3 Hz, 1H), 3.79 (dd, J = 11.4, 3.9 Hz, 1H), 3.59 (dd, J = 12.3, 4.0 Hz, 1H), 2.66 (d, J = 2.2 Hz, 1H), 1.98 (d, J = 5.9 Hz, 2H).

[0790] Example 85 (2-(phenylamino)pyrimidin-4-yl)(piperazin-l-yl)methanone piperazine- 1,4-diyl bis((2-(phenylamino)pyrimidin-4-yl)methanone) (Compound L-85)

[0791]

[0792] I. 4-(2-(phenylamino)pyrimidine-4-carbonyl)piperazine- 1 -carboxylic acid tert-butyl ester

[0793] Example 1 1 1 (2-(phenylamino)pyrimidin-4-yl)(piperazin-l-yl)methanone piperazine- 1,4-diyl bis((2-(phenylamino)pyrimidin-4-yl)methanone) (Compound L-82)

[0794] II. (2-(phenylamino)pyrimidin-4-yl)(piperazin-l-yl)methanone

[0795] Example 1 1 1 (2-(phenylamino)pyrimidin-4-yl)(piperazin-l-yl)methanone piperazine- 1,4-diyl bis((2-(phenylamino)pyrimidin-4-yl)methanone) (Compound L-82)

[0796] III. (2-(phenylamino)pyrimidin-4-yl)(piperazin-l-yl)methanone piperazine- 1,4-diyl bis((2-(phenylamino)pyrimidin-4-yl)methanone)

[0797] The procedure was the same as the preparation of Compound L-82 in Example 82.

[0798] LC-MS: m / z: (M+H)+ = 481.0, 1H NMR (400 MHz, DMSO-d6) δ 9.84 (d, J = 21.0 Hz, 2H), 8.74 - 8.51 (m, 2H), 7.71 (dd, J = 20.8, 7.4 Hz, 4H), 7.50 - 7.21 (m, 4H), 7.13 - 6.78 (m, 4H), 3.62 (dd, J = 76.7, 37.7 Hz, 8H).

[0799] Example 86 Piperazine-1, 4-diyl bis ((6- (phenylamino) pyridin-2-yl) methanone) (Compound L-86)

[0800]

[0801] I. tert-Butyl 4-(6-(phenylamino)pyridinyl)piperazine-1-carboxylate

[0802] tert-Butyl 4-(6-(phenylamino)pyridinyl)piperazine-1-carboxylate (190 mg, 0.49 mmol) (compound as shown in formula 3) was dissolved in 3 ml of methanol, and a hydrochloric acid dioxane solution (3 mL, 4 M, 12 mmol) was added. The reaction solution was stirred at 15 °C for 2 h. The reaction solution was concentrated and dried to obtain a crude product of 139 mg of brown solid with a yield of 99.12%. LC-MS: m / z: (M+H)+ = 283.0.

[0803] II. (6-(phenylamino)pyridin-2-yl)(piperazin-1-yl)methanone

[0804] tert-Butyl 4-(6-(phenylamino)pyridinyl)piperazine-1-carboxylate (190 mg, 0.49 mmol) (compound as shown in formula 3) was dissolved in 3 ml of methanol, and a hydrochloric acid dioxane solution (3 mL, 4 M, 12 mmol) was added. The reaction solution was stirred at 15 °C for 2 h. The reaction solution was concentrated and dried to obtain a crude product of 139 mg of brown solid with a yield of 99.12%. LC-MS: m / z: (M+H)+ = 283.0.

[0805] III. Piperazine-1, 4-diyl bis ((6-(phenylamino)pyridin-2-yl) methanone)

[0806] The operation was the same as the preparation of compound L-82 in Example 82.

[0807] LC-MS: m / z: (M+H)+ = 479.0, 1H NMR (400 MHz, DMSO-d6) δ 9.21 (d, J = 26.7 Hz, 2H), 7.81 - 7.50 (m, 6H), 7.26 (dt, J = 44.9, 7.5 Hz, 4H), 7.03 - 6.70 (m, 6H), 3.83 - 3.44 (m, 8H).

[0808] Example 87 (2,6-diazaspiro[3.3]heptane-2,6-diyl)bis((6-(1H-benzo[d]imidazol-2- yl)pyridin-2-yl)methanone) (Compound L-87)

[0809]

[0810] The procedure was same as the preparation of compound L-82 in Example 82.

[0811] LC-MS m / z: (M+H)+ = 542.2.

[0812] 1H NMR (400 MHz, DMSO-d6) δ 8.45 (dd, J = 7.9, 1.1 Hz, 2H), 8.16 (t, J = 7.8 Hz, 2H), 8.00 (dd, J = 7.8, 1.1 Hz, 2H), 7.70 (s, 4H), 7.28 (d, J = 6.5 Hz, 4H), 5.10 (d, J = 10.7 Hz, 2H), 5.01 (d, J = 10.8 Hz, 2H), 4.46 - 4.39 (m, 4H).

[0813] Example 88 3-(Imidazo[1,2-a]pyridin-2-yl)-N-(1-(3-(imidazo[1,2-a]pyridin-2- yl)benzoyl)piperidin-4-yl)benzamide (Compound L-88)

[0814]

[0815] The procedure was same as the preparation of compound L-82 in Example 82.

[0816] LC-MS m / z: (M+H)+ = 542.2.

[0817] 1H NMR (400 MHz, Chloroform-d) δ 8.53 (s, 1H), 8.20 (t, J = 7.8 Hz, 2H), 8.03 (dd, J = 12.9, 7.2 Hz, 4H), 7.97 (s, 1H), 7.90 (d, J = 7.7 Hz, 1H), 7.74 (d, J = 9.0 Hz, 1H), 7.68 (d, J = 9.1 Hz, 1H), 7.51 (q, J = 8.0 Hz, 2H), 7.39 (d, J = 7.6 Hz, 1H), 7.35 - 7.30 (m, 1H), 7.22 (dd, J = 9.1, 6.7 Hz, 1H), 6.99 (d, J = 7.8 Hz, 1H), 6.92 (t, J = 6.8 Hz, 1H), 6.83 (t, J = 6.7 Hz, 1H), 4.74 (d, J = 28.3 Hz, 1H), 4.33 (d, J = 10.0 Hz, 1H), 3.89 (s, 1H), 3.23 (s, 1H), 3.05 (s, 1H), 2.66 (s, 3H), 2.23 (t, J = 7.7 Hz, 1H).

[0818] Example 89 3-(Imidazo[l,2-a]pyridin-2-yl)-N-((lR,5S,6s)-3-(imidazo[l,2-a]pyridin-2- yl)benzoyl)-3-azabicyclo[3.1.0]hex-6-yl)benzamide (Compound L-89)

[0819]

[0820] The procedure was same as the preparation of Compound L-82 in Example 82.

[0821] LC-MS m / z: (M+H)+= 539.2.

[0822] 1H NMR (400 MHz, Chloroform-d) δ 8.36 (d, J = 1.8 Hz, 1H), 8.14 (ddd, J = 7.8, 6.7, 3.3 Hz, 2H), 8.06 - 8.01 (m, 2H), 8.02 - 7.98 (m, 2H), 7.81 (dt, J = 7.8, 1.5 Hz, 1H), 7.63 (t, J = 9.2 Hz, 2H), 7.47 (t, J = 7.7 Hz, 2H), 7.39 (dt, J = 7.7, 1.5 Hz, 1H), 7.20 (tdd, J = 9.3, 7.4, 1.3 Hz, 2H), 7.06 (d, J = 2.7 Hz, 1H), 6.84 - 6.78 (m, 2H), 4.32 (d, J = 12.4 Hz, 1H), 3.83 - 3.75 (m, 2H), 3.64 (dd, J = 12.4, 4.3 Hz, 1H), 2.70 (q, J = 2.5 Hz, 1H), 1.91 (d, J = 29.8 Hz, 2H).

[0823] Example 90 3-(Imidazo[l,2-a]pyridin-2-yl)-N-(((lR,5S,6s)-3-(6-(phenylamino)pyridinyl)-3- azabicyclo[3.1.0]hex-6-yl)benzamide (Compound L-90)

[0824]

[0825] The procedure was same as the preparation of Compound L-82 in Example 82.

[0826] LC-MS m / z: (M+H)+= 515.2.

[0827] 1H NMR (400 MHz, Chloroform-d) δ 8.42 (s, 1H), 8.17 (d, J = 6.8 Hz, 1H), 8.01 (d, J = 7.7 Hz, 1H), 7.94 (s, 1H), 7.85 (d, J = 7.8 Hz, 1H), 7.69 (d, J = 9.1 Hz, 1H), 7.58 (t, J = 7.9 Hz, 1H), 7.51 (t, J = 7.8 Hz, 1H), 7.37 (s, 2H), 7.26 (s, 1H), 7.20 (d, J = 7.4 Hz, 1H), 7.10 (q, J = 5.1, 4.3 Hz, 1H), 6.90 (dt, J = 15.0, 7.7 Hz, 3H), 6.78 (s, 1H), 4.29 (d, J = 12.4 Hz, 1H), 4.20 (d, J = 11.8 Hz, 1H), 3.94 (dd, J = 11.8, 4.1 Hz, 1H), 3.77 - 3.65 (m, 2H), 2.71 (d, J = 2.7 Hz, 1H), 2.03 (s, 1H).

[0828] Example 91 6-(1H-Benzo[d]imidazol-2-yl)-N-(3-((1,4-dioxo-1,4-dihydronaphthalen-2-yl)amino)-4-methylbenzoyl)-3-azabicyclo[3.1.0]hexan-6-yl)picolinamide (Compound L-91)

[0829]

[0830] One, 3-amino-4-methyl-benzoic acid (1.5 g, 9.9 mmol), naphthalene-1,4-dione (1.6 g, 9.9 mmol) and copper acetate (0.2 g, 0.99 mmol) were dissolved in AcOH (50 mL) and stirred at 60 °C for 16 h. The reaction was concentrated to dryness and recrystallized with EtOH (10 mL) and dried to get red solid 3-[(1,4-dioxo-2-naphthyl)amino]-4-methyl-benzoic acid (2 g, 66%).

[0831] Two, the procedure was same as the preparation of compound L-82 in Example 82.

[0832] LC-MS: m / z: (M+H) += 609.3; 1H NMR (400 MHz, Methanol-d4) δ 8.45 (dd, J = 7.2, 1.7 Hz, 1H), 8.25 - 8.13 (m, 3H), 8.04 (dd, J = 7.6, 1.3 Hz, 1H), 7.79 (dtd, J = 25.1, 7.4, 1.4 Hz, 3H), 7.63 (d, J = 7.4 Hz, 1H), 7.54 - 7.44 (m, 3H), 7.36 (s, 2H), 5.60 (s, 1H), 4.31 (d, J = 12.3 Hz, 1H), 3.99 - 3.82 (m, 2H), 3.71 (dd, J = 12.3, 4.5 Hz, 1H), 2.72 (t, J = 2.5 Hz, 1H), 2.36 (s, 3H), 2.19 - 2.12 (m, 1H), 2.07 (d, J = 9.9 Hz, 1H).

[0833] Example 92 (9-(3-(Imidazo[l,2-a]pyridin-2-yl)benzoyl)-3,9-diazaspiro[5.5]undecan-3-yl)(3-(4-methyl-lH-imidazol-l-yl)phenyl)methanone (Compound L-92)

[0834]

[0835] The procedure was same as the preparation of Compound L-82 in Example 82.

[0836] LC-MS: m / z: (M+H) + = 609.3; 1H NMR (400 MHz, Methanol-d4) δ 8.45 (dd, J = 7.2, 1.7 Hz, 1H), 8.25 - 8.13 (m, 3H), 8.04 (dd, J = 7.6, 1.3 Hz, 1H), 7.79 (dtd, J = 25.1, 7.4, 1.4 Hz, 3H), 7.63 (d, J = 7.4 Hz, 1H), 7.54 - 7.44 (m, 3H), 7.36 (s, 2H), 5.60 (s, 1H), 4.31 (d, J = 12.3 Hz, 1H), 3.99 - 3.82 (m, 2H), 3.71 (dd, J = 12.3, 4.5 Hz, 1H), 2.72 (t, J = 2.5 Hz, 1H), 2.36 (s, 3H), 2.19 - 2.12 (m, 1H), 2.07 (d, J = 9.9 Hz, 1H).

[0837] Example 93 6-(lH-Benzo[d]imidazol-2-yl)-N-(3-(3-(4-methyl-lH-imidazol-l-yl)benzoyl)-3- azabicyclo[3.1.0]hexan-6-yl)picolinamide (Compound L-93)

[0838]

[0839] One, (3-methoxycarbonylphenyl)boronic acid (1.8 g, 10 mmol), 4-methyl-lH- imidazole (0.82 g, 10 mmol), pyridine (0.81 mL, 10 mmol) and copper acetate (0.4 g, 2.0 mmol) were dissolved in DCM (50 mL) and the reaction was stirred at room temperature for 16 h. The reaction was concentrated to dryness and purified by flash chromatography (silica) (petroleum ether: ethyl acetate = 2: 1) to give methyl 3-(4-methylimidazol-l-yl)benzoate (1 g, 46%) as a white solid.

[0840] Two, Methyl 3-(4-methylimidazol-l-yl)benzoate (43 mg, 0.2 mmol) was dissolved in THF (5 mL) and water (1 mL) and the reaction was stirred at 80 °C for 2 h after the addition of LiOH (24 mg, 1.0 mmol). The reaction was concentrated to dryness and used directly in the next reaction.

[0841] Three, The procedure was the same as the preparation of compound L-82 in Example 82.

[0842] LC-MS: m / z: (M+H) + = 504.2; 1H NMR (400 MHz, Methanol-d4) δ 8.46 (dd, J = 7.3, 1.6 Hz, 1H), 8.26 - 8.12 (m, 3H), 7.81 - 7.62 (m, 5H), 7.53 (dt, J = 7.5, 1.4 Hz, 1H), 7.45 - 7.32 (m, 3H), 4.32 (d, J = 12.3 Hz, 1H), 3.90 (dd, J = 11.0, 4.5 Hz, 1H), 3.82 (d, J = 10.9 Hz, 1H), 3.75 (dd, J = 12.4, 4.7 Hz, 1H), 2.76 (t, J = 2.4 Hz, 1H), 2.29 (d, J = 1.0 Hz, 3H), 2.18 (d, J = 4.6 Hz, 1H), 2.08 (d, J = 12.6 Hz, 1H).

[0843] Example 94 (9-(3-(Benz[d]thiazol-2-yl)benzoyl)-3,9-diazaspiro[5.5]undec-3-yl)(3-(imidazo[l,2- a]pyridin-2-yl)phenyl)methanone (Compound L-94)

[0844]

[0845] The procedure was the same as the preparation of compound L-82 in Example 82.

[0846] LC-MS: m / z: (M+H) += 612.3; 1H NMR (400 MHz, Methanol-d4) δ 8.46 (dt, J = 6.9, 1.2 Hz, 1H), 8.30 (d, J = 0.7 Hz, 1H), 8.21 (dt, J = 7.8, 1.4 Hz, 1H), 8.19 - 8.16 (m, 1H), 8.06 (ddt, J = 6.8, 5.2, 1.0 Hz, 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, 1.2 Hz, 1H), 7.44 - 7.33 (m, 2H), 6.96 (td, J = 6.8, 1.2 Hz, 1H), 3.84 (s, 4H), 3.52 (s, 4H), 1.70 (d, J = 48.3 Hz, 8H).

[0847] Example 95 2-((5-(9-(3-(imidazo[l,2-a]pyridin-2-yl)benzoyl)-3,9-diazaspiro[5.5]undecane-3- carboxyl)-2-methylphenyl)amino)naphthalene- 1,4-dione (Compound L-95)

[0848]

[0849] The procedure was same as the preparation of Compound L-82 in Example 82.

[0850] LC-MS: m / z: (M+H) + = 664.3; 1H NMR (400 MHz, Chloroform-d) δ 8.14 (ddd, J = 15.6, 7.3, 2.1 Hz, 3H), 8.04 (d, J = 7.9 Hz, 1H), 7.99 (d, J = 1.8 Hz, 1H), 7.91 (s, 1H), 7.79 (td, J = 7.6, 1.4 Hz, 1H), 7.74 - 7.62 (m, 2H), 7.50 (t, J = 7.7 Hz, 1H), 7.43 - 7.33 (m, 4H), 7.28 - 7.18 (m, 2H), 6.83 (t, J = 6.7 Hz, 1H), 5.98 (s, 1H), 3.79 (s, 4H), 3.50 (s, 4H), 2.34 (s, 3H), 1.61 (d, J = 57.2 Hz, 8H).

[0851] Example 96 3-(4-(9-(3-(imidazo[l,2-a]pyridin-2-yl)benzoyl)-3,9-diazaspiro[5.5]undecane-3- carboxyl)benzamido)thiophene-2-carboxamide (Compound L-96)

[0852]

[0853] 1. 3-Aminothiophene-2-carboxamide (1.4 g, 9.8 mmol) and N,N-diisopropylethylamine (2.5 g, 20 mmol) were dissolved in tetrahydrofuran (200 mL), and methyl 3-chlorocarbonylbenzoate (2.0 g, 9.8 mmol) was added. The mixture was stirred at 25 °C for 16 h. The reaction mixture was concentrated to dryness and purified by rapid chromatography (silica) (petroleum ether: ethyl acetate = 50:50) to give a yellow solid of methyl 3-[(2-carbamoyl-3-thienyl)carbamoyl]benzoate (1 g, 33%).

[0854] 2. Methyl 3-[(2-carbamoyl-3-thienyl)carbamoyl]benzoate (180 mg, 0.6 mmol) was dissolved in MeOH (5 mL) and water (1 mL). NaOH (71 mg, 3.0 mmol) was added, and the mixture was stirred at 100 °C for 5 days. The reaction mixture was concentrated to dryness, and water (5 mL) was added to the crude product. The pH was adjusted to 5 with 1 N dilute hydrochloric acid, and the mixture was filtered to obtain a yellow solid 3-[(2-carbamoyl-3-thienyl)carbamoyl]benzoic acid (90 mg, 52%).

[0855] III. The procedure is the same as that for the preparation of compound L-82 in Example 82.

[0856] 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).

[0857] Example 97 ((2-(phenylamino)pyrimidin-4-yl)(9-(2-(pyridin-2-ylamino)pyrimidin-4-carbonyl)-3,9-diazaspiro[5.5]undecane-3-yl) methyl ketone (compound L-97)

[0858]

[0859] The procedure is the same as that used in the preparation of compound L-82 in Example 82.

[0860] LC-MS: m / z: (M+H)+ = 482.0, 1H NMR (400 MHz, DMSO-d6) δ 10.08 (d, J = 26.4 Hz, 1H), 9.86 (d, J = 20.0 Hz, 1H), 8.66 (ddd, J = 20.0, 14.7, 4.9 Hz, 2H), 8.23 (ddd, J = 29.4, 21.0, 6.0 Hz, 2H), 7.86 - 7.63 (m, 3H), 7.29 (dt, J = 21.7, 8.0 Hz, 2H), 7.18 - 6.88 (m, 4H), 3.79 - 3.46 (m, 8H).

[0861] Example 98 ((2-(phenylamino)pyrimidin-4-yl)(9-(2-(pyridin-2-ylamino)pyrimidine-4- carbonyl)-3,9-diazaspiro[5.5]undec-3-yl)methanone (Compound L-98)

[0862]

[0863] The procedure was same as the preparation of compound L-82 in Example 82.

[0864] LC-MS: m / z: (M+H)+ = 550.0, 1H NMR (400 MHz, CDCl3) δ 8.66 (d, J = 4.9 Hz, 1H), 8.57 (d, J = 4.9 Hz, 1H), 8.39 (d, J = 8.5 Hz, 2H), 7.72 (t, J = 8.5 Hz, 1H), 7.62 (d, J = 8.1 Hz, 2H), 7.56 (s, 1H), 7.35 (t, J = 7.8 Hz, 2H), 7.08 (t, J = 7.3 Hz, 1H), 7.00 (dd, J = 13.2, 5.9 Hz, 2H), 6.92 (d, J = 4.9 Hz, 1H), 3.86 - 3.67 (m, 4H), 3.50 (d, J = 4.0 Hz, 4H), 1.73 - 1.52 (m, 8H).

[0865] Example 99 (N-(l-(2-(phenylamino)pyrimidine-4-carbonyl)piperidin-4-yl)-2-(pyridin-2- ylamino)pyrimidine-4-carboxamide (E100124-081) (Compound L-99)

[0866]

[0867] The procedure was same as the preparation of compound L-82 in Example 82.

[0868] LC-MS: m / z: (M+H)+ = 495.2, 1H NMR (400 MHz, CDC13) δ 9.31 (s, 1H), 8.76 (d, J = 4.9 Hz, 1H), 8.59 (d, J = 4.9 Hz, 1H), 8.41 (d, J = 4.8 Hz, 1H), 8.33 (d, J = 8.4 Hz, 1H), 8.09 (s, 1H), 7.86 (d, J = 8.2 Hz, 1H), 7.79 - 7.72 (m, 1H), 7.62 (dd, J = 14.3, 6.4 Hz, 3H), 7.34 (t, J = 7.8 Hz, 2H), 7.10 - 7.00 (m, 2H), 6.95 (d, J = 4.9 Hz, 1H), 4.63 (d, J = 13.5 Hz, 1H), 4.32 - 4.18 (m, 1H), 3.98 (d, J = 13.8 Hz, 1H), 3.27 (t, J = 11.4 Hz, 1H), 3.11 - 3.03 (m, 1H), 2.09 (dd, J = 38.8, 10.9 Hz, 2H), 1.69 - 1.56 (m, 2H).

[0869] Example 100 (Tetrahydropyrrolo[3,4-c]pyrrole-2,5(lH,3H)-diyl)bis((6-(phenylamino)pyridin-2-yl)methanone) (Compound L-100)

[0870]

[0871] One, tert-butyl 5-(6-(phenylamino)pyridinyl)hexahydropyrrolo[3,4-c]pyrrole-2(lH)- carboxylate

[0872] tert-Butyl hexahydropyrrolo[3,4-c]pyrrole-2(lH)-carboxylate (100 mg, 0.47 mmol) (compound as shown in Formula 2) and 6-(phenylamino)picolinic acid (101 mg, 0.47 mmol) (compound as shown in Formula 1) were suspended in 3 ml of N,N-dimethylformamide, and N,N-diisopropylethylamine (122 mg, 0.94 mmol) and 1-propylphosphonic anhydride (449 mg, 0.71 mmol) were added. The reaction was stirred at 30 °C for 16 h. 10 ml of ice water was added to the reaction, stirred for five minutes, filtered, and the solid was dried to obtain 190 mg of brown solid as a crude product, with a yield of 98.96%. LC-MS: m / z: (M+H)+ = 409.0.

[0873] Two, (hexahydropyrrolo[3,4-c]pyrrol-2(lH)-yl)(6-(phenylamino)pyridin-2-yl)methanone

[0874] tert-Butyl 5-(6-(phenylamino)pyridinyl)hexahydropyrrolo[3,4-c]pyrrole-2(lH)- carboxylate (190 mg, 0.47 mmol) (compound as shown in Formula 3) was dissolved in 3 mL of methanol, and a hydrochloric acid dioxane solution (3 mL, 4 M, 12 mmol) was added. The reaction solution was stirred at 15 °C for 2 h. The reaction solution was concentrated and dried to obtain 150 mg of a brown solid as a crude product, with a yield of 94.38%. LC-MS: m / z: (M+H)+= 309.0.

[0875] III. (Tetrahydropyrrolo[3,4-c]pyrrole-2,5(lH,3H)-diyl)bis((6-(phenylamino)pyridin-2- yl)methanone)

[0876] The operation was the same as the preparation of compound L-82 in Example 82.

[0877] LC-MS: m / z: (M+H)+= 505.0, 1H NMR (400 MHz, CDCl3) δ 7.62 (td, J = 8.1, 3.4 Hz, 2H), 7.41 - 7.30 (m, 8H), 7.08 (ddd, J = 12.8, 9.9, 5.5 Hz, 2H), 6.97 - 6.73 (m, 4H), 4.05 (ddd, J = 13.8, 9.7, 4.8 Hz, 3H), 3.91 - 3.65 (m, 5H), 2.98 (s, 2H).

[0878] Example 101 6-(phenylamino)-N-(((lR,5S,6s)-3-(6-(phenylamino)pyridinyl)-3- azabicyclo[3.1.0]hex-6-yl)pyridinamide (compound L-101)

[0879]

[0880] I. tert-Butyl (lR,5S,6s)-6-(6-(phenylamino)picolinamido)-3-azabicyclo[3.1.0]hexane-3- carboxylate (E100124-067)

[0881] (1R,5S,6s)-6-amino-3-azabicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester (100 mg, 0.50 mmol) (compound as shown in Formula 2) and 6-(phenylamino)picolinic acid (108 mg, 0.50 mmol) (compound as shown in Formula 1) were suspended in 3 ml of N,N-dimethylformamide, N,N-diisopropylethylamine (130 mg, 1.01 mmol) and 1-propylphosphonic anhydride (481 mg, 0.76 mmol) were added. The reaction was stirred at 30 °C for 16 h. 10 ml of ice water was added to the reaction, stirred for five minutes, filtered, and the solid was dried to give the crude product as 198 mg of brown solid, with a yield of 99.6%. LC-MS: m / z: (M+H)+= 395.0.

[0882] II. N-(((1R,5S,6s)-3-azabicyclo[3.1.0]hex-6-yl)-6-(phenylamino)pyridinamide

[0883] (1R,5S,6s)-6-(6-(phenylamino)pyridinecarboxamido)-3-azabicyclo[3.1.0]hexane-3- carboxylic acid tert-butyl ester (198 mg, 0.50 mmol) (compound as shown in Formula 3) was dissolved in 3 ml of methanol, and a hydrochloric acid dioxane solution (3 mL, 4 M, 12 mmol) was added. The reaction was stirred at 15 °C for 2 h. The reaction was concentrated and dried to give the crude product as 148 mg of brown solid, with a yield of 99.1%. LC-MS: m / z: (M+H)+= 295.0.

[0884] III. 6-(phenylamino)-N-(((1R,5S,6s)-3-(6-(phenylamino)pyridinyl)-3-azabicyclo[3.1.0]hex- 6-yl)pyridinamide

[0885] The operation was the same as the preparation of compound L-82 in Example 82.

[0886] LC-MS: m / z: (M+H)+= 491.0, 1H NMR (400 MHz, CDCl3) δ 7.98 (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 = 12.5 Hz, 1H), 4.18 (d, J = 11.6 Hz, 1H), 3.98 (d, J = 11.6 Hz, 1H), 3.76 - 3.68 (m, 1H), 2.69 (d, J = 2.0 Hz, 1H), 1.91 (s, 2H).

[0887] Example 102 (5-(6-(phenylamino)pyridinyl)hexahydropyrrolo[3,4-c]pyrrol-2(lH)-yl)(2- (phenylamino)pyrimidin-4-yl)methanone (Compound L-102)

[0888]

[0889] The procedure was same as the preparation of compound L-82 in Example 82.

[0890] LC-MS: m / z: (M+H)+= 506.0, 1H NMR (400 MHz, CD3OD) δ 8.57 (dd, J = 12.9, 4.9 Hz, 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).

[0891] Example 103 (2-(phenylamino)-N-(((lR,5S,6s)-3-(6-(phenylamino)pyridinyl)-3- azabicyclo[3.1.0]hexan-6-yl)pyrimidine-4-carboxamide (Compound L-103)

[0892]

[0893] The procedure was same as the preparation of compound L-82 in Example 82.

[0894] LC-MS: m / z: (M+H)+= 492.0, 1H NMR (400 MHz, CD3OD) δ 8.61 (d, J = 4.9 Hz, 1H), 7.69 - 7.54 (m, 5H), 7.32 (dt, J = 16.2, 4.8 Hz, 5H), 7.08 - 6.86 (m, 4H), 4.20 (d, J = 12.5 Hz, 1H), 4.12 (d, J = 11.7 Hz, 1H), 3.88 (dd, J = 11.8, 4.3 Hz, 1H), 3.72 - 3.63 (m, 1H), 2.60 (t, J = 2.3 Hz, 1H), 2.01 - 1.89 (m, 2H).

[0895] Example 104 N-((lR,5S,6s)-3-(3-(lH-pyrrol-l-yl)thiophene-2-carbonyl)-3- azabicyclo[3.1.0]hexan-6-yl)-3-(imidazo[l,2-a]pyridin-2-yl)benzamide (Compound L-104)

[0896]

[0897] The procedure was same as the preparation of compound L-82 in Example 82.

[0898] LC-MS: m / z: (M+H)+ = 494.2.

[0899] 1H NMR (400 MHz, Chloroform-d) δ 8.38 (s, 1H), 8.18 (d, J = 6.7 Hz, 1H), 7.99 (d, J = 7.8 Hz, 1H), 7.

[0900] 94 (s, 1H), 7.82 (d, J = 7.8 Hz, 1H), 7.68 (d, J = 9.1 Hz, 1H), 7.50 (t, J = 7.7 Hz, 1H), 7.44 (d, J = 5.3 Hz, 1H), 7.27 (s, 1H), 7.06 (d, J = 5.3 Hz, 1H), 6.90 - 6.85 (m, 1H), 6.74 (s, 1H), 6.33 (t, J = 2.2 Hz, 2H), 4.25 (d, J = 12.5 Hz, 1H), 3.53 (d, J = 13.3 Hz, 1H), 3.32 (d, J = 11.0 Hz, 1H), 2.70 - 2.61 (m, 1H), 2.45 (t, J = 2.5 Hz, 1H), 1.86 (s, 1H).

[0901] Example 105 3-(Imidazo[l,2-a]pyridin-2-yl)-N-((lR,5S,6s)-3-(2-phenoxy nicotinamido)-3- azabicyclo[3.1.0]hexan-6-yl)benzamide (Compound L-105)

[0902]

[0903] The procedure was same as the preparation of Compound L-82 in Example 82.

[0904] LC-MS: m / z: (M+H)+ = 516.2.

[0905] 1H NMR (400 MHz, Chloroform-d) δ 8.47 (s, 1H), 8.21 (dt, J = 5.1, 2.4 Hz, 2H), 8.00 (d, J = 7.7 Hz, 1H), 7.87 (d, J = 7.7 Hz, 1H), 7.77 - 7.68 (m, 2H), 7.53 (t, J = 7.7 Hz, 1H), 7.44 (t, J = 7.8 Hz, 2H), 7.37 - 7.30 (m, 1H), 7.26 - 7.18 (m, 3H), 7.08 (dd, J = 7.4, 4.9 Hz, 1H), 6.93 (t, J = 7.2 Hz, 2H), 4.31 (d, J = 12.4 Hz, 1H), 3.88 - 3.80 (m, 1H), 3.76 (d, J = 10.8 Hz, 1H), 3.69 (dd, J = 12.4, 4.5 Hz, 1H), 2.76 (d, J = 2.6 Hz, 1H), 2.03 (d, J = 7.6 Hz, 1H), 1.97 (d, J = 4.1 Hz, 1H).

[0906] Example 106 N-((1R,5S,6s)-3-(1H-indazole-3-carbonyl)-3-azabicyclo[3.1.0]hexan-6-yl)-3- (imidazo[1,2-a]pyridin-2-yl)benzamide (Compound L-106)

[0907]

[0908] The procedure was same as in the preparation of Compound L-82 in Example 82.

[0909] LC-MS: m / z: (M+H)+= 463.1.

[0910] 1H NMR (400 MHz, DMSO-d6) δ 13.60 (s, 1H), 8.73 (d, J = 3.9 Hz, 1H), 8.57 (d, J = 6.7 Hz, 1H), 8.47 (s, 1H), 8.42 (d, J = 1.9 Hz, 1H), 8.16 (d, J = 8.2 Hz, 1H), 8.11 (dd, J = 7.7, 1.7 Hz, 1H), 7.80 - 7.75 (m, 1H), 7.65 - 7.58 (m, 2H), 7.54 (t, J = 7.8 Hz, 1H), 7.45 - 7.41 (m, 1H), 7.29 (s, 1H), 7.24 (t, J = 7.5 Hz, 1H), 6.94 (s, 1H), 4.49 (d, J = 11.7 Hz, 1H), 4.10 (d, J = 12.3 Hz, 1H), 4.04 - 4.00 (m, 1H), 3.70 - 3.62 (m, 2H), 2.04 (s, 1H), 1.97 (s, 1H).

[0911] Example 107 4-butoxy-N-(l-(3-(imidazo[l,2-a]pyridin-2-yl)benzoyl)piperidin-4- yl)benzamide (Compound L-107)

[0912]

[0913] The procedure was same as the preparation of Compound L-82 in Example 82.

[0914] LC-MS: m / z: (M+H)+= 497.3.

[0915] 1H NMR (400 MHz, Chloroform-d) δ 8.17 (d, J = 6.8 Hz, 1H), 8.04 - 7.98 (m, 2H), 7.91 (s, 1H), 7.79 - 7.73 (m, 2H), 7.70 (d, J = 9.1 Hz, 1H), 7.49 (t, J = 7.6 Hz, 1H), 7.37 (d, J = 7.6 Hz, 1H), 7.25 (t, J = 8.0 Hz, 1H), 6.94 - 6.89 (m, 2H), 6.85 (t, J = 6.7 Hz, 1H), 6.30 (d, J = 7.9 Hz, 1H), 4.75 (s, 1H), 4.28 (d, J = 6.9 Hz, 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 = 6.8 Hz, 2H), 1.50 (hept, J = 6.8, 6.2 Hz, 4H), 1.02 - 0.95 (m, 3H).

[0916] Example 108 (4-(6-(lH-benzo[d]imidazol-2-yl]pyridinyl)piperazin-l-yl)(quinolin-3- yl)methanone (Compound L-108)

[0917]

[0918] The procedure was same as the preparation of Compound L-82 in Example 82.

[0919] LC-MS: m / z: (M+H)+ = 463.0, 1H NMR (400 MHz, CDC13) δ 9.01 (s, 1H), 8.63 (s, 1H), 8.32 (s, 1H), 8.17 (d, J = 8.1 Hz, 1H), 8.02 (t, J = 7.6 Hz, 1H), 7.95 - 7.80 (m, 2H), 7.79 - 7.63 (m, 3H), 7.38 (dd, J = 6.0, 3.0 Hz, 2H), 3.85 (d, J = 72.4 Hz, 8H).

[0920] Example 109 (4-(6-(lH-Benzo[d]imidazol-2-yl]pyridinyl)piperazin-l-yl)(4- methylpyridin-3-yl)methanone (Compound L-109)

[0921]

[0922] The procedure was same as the preparation of Compound L-82 in Example 82.

[0923] LC-MS: m / z: (M+H)+ = 427.0, 1H NMR (400 MHz, CDC13) δ 8.78 - 8.43 (m, 3H), 8.04 (d, J = 7.4 Hz, 1H), 7.74 (d, J = 22.5 Hz, 3H), 7.39 (s, 2H), 7.21 (s, 1H), 4.01 - 3.29 (m, 8H), 2.40 (s, 3H).

[0924] Example 110 (4-(6-(lH-Benzo[d]imidazol-2-yl]pyridinyl)piperazin-l-yl)(lH- indazol-3-yl)methanone (Compound L-110)

[0925]

[0926] The procedure was same as the preparation of Compound L-82 in Example 82.

[0927] LC-MS: m / z: (M+H)+ = 452.0, 1H NMR (400 MHz, CDC13) δ 11.00 (d, J = 117.6 Hz, 2H), 8.52 (s, 1H), 8.11 (s, 1H), 7.97 (t, J = 7.8 Hz, 1H), 7.69 (d, J = 6.8 Hz, 3H), 7.49 (d, J = 8.4 Hz, 1H), 7.45 - 7.30 (m, 3H), 7.22 (s, 1H), 4.44 - 3.58 (m, 8H).

[0928] Example 111 6-(4-(6-(1H-Benzo[d]imidazol-2-yl)pyridinyl)piperazin-1- ylcarbonyl)-4,5-dihydropyridazin-3(2H)-one (Compound L-111)

[0929]

[0930] The procedure was same as the preparation of compound L-82 in Example 82.

[0931] LC-MS: m / z: (M+H)+= 432.0, 1H NMR (400 MHz, CDCl3) δ 8.91 (s, 1H), 8.57 (s, 1H), 7.99 (t, J = 7.8 Hz, 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).

[0932] Example 112 (4-(6-(1H-Benzo[d]imidazol-2-yl]pyridinyl)piperazin-1-yl)(thiophen-2- yl)methanone (Compound L-112)

[0933]

[0934] The procedure was same as the preparation of compound L-82 in Example 82.

[0935] LC-MS: m / z: (M+H)+= 418.0, 1H NMR (400 MHz, CDCl3) δ 8.57 (d, J = 7.8 Hz, 1H), 8.01 (dd, J = 15.8, 8.0 Hz, 1H), 7.71 (t, J = 8.5 Hz, 3H), 7.50 (d, J = 5.0 Hz, 1H), 7.41 - 7.32 (m, 3H), 7.11 - 7.05 (m, 1H), 4.09 - 3.67 (m, 8H).

[0936] Example 113 (3,9-Diazaspiro[5.5]undecane-3,9-diyl)bis((6-(phenylamino)pyridin-2- yl)methanone) (Compound L-113)

[0937]

[0938] Example 113 (3,9-Diazaspiro[5.5]undecane-3,9-diyl)bis((6-(phenylamino)pyridin-2- yl)methanone) (Compound L-113)

[0939] tert-Butyl 3,9-diazaspiro[5.5]undecane-3-carboxylate (187 mg, 0.74 mmol) (compound as shown in Formula 2) and 6-(phenylamino)picolinic acid (150 mg, 0.70 mmol) (compound as shown in Formula 1) were suspended in 3 ml of N,N-dimethylformamide, N,N-diisopropylethylamine (181 mg, 1.40 mmol) and 1-propylphosphonic anhydride (668 mg, 1.05 mmol) were added. The reaction was stirred at 15 °C for 16 h. 10 ml of ice water was added to the reaction, stirred for five minutes, filtered, and the solid was dried to give the crude product as 220 mg of brown solid, with a yield of 69.73%. LC-MS: m / z: (M+H)+= 451.0.

[0940] II. (6-(phenylamino)pyridin-2-yl)(3,9-diazaspiro[5.5]undecan-3-yl)methanone

[0941] tert-Butyl 9-(6-(6-(phenylamino)pyridinyl)-3,9-diazaspiro[5.5]undecane-3-carboxylate (175 mg, 0.33 mmol) (compound as shown in Formula 3) was dissolved in 5 ml of methanol, and a hydrochloric acid dioxane solution (5 mL, 4 M 20 mmol) was added. The reaction was stirred at 15 °C for 2 h. The reaction was concentrated and dried to give the crude product as 115 mg of brown solid, with a yield of 98.56%. LC-MS: m / z: (M+H)+= 351.0.

[0942] III. (3,9-diazaspiro[5.5]undecane-3,9-diyl)bis((6-(phenylamino)pyridin-2-yl)methanone)

[0943] The operation was the same as the preparation of compound L-82 in Example 82.

[0944] LC-MS: m / z: (M+H)+= 547.0, 1H NMR (400 MHz, CDCl3) δ 8.04 (s, 1H), 7.64-7.56 (m, 2H), 7.39-7.33 (m, 7H), 7.11 (dt, J = 8.5, 3.5 Hz, 2H), 6.99 (d, J = 7.2 Hz, 2H), 6.91 (d, J = 8.4 Hz, 3H), 3.67 (d, J = 96.1 Hz, 8H), 1.75-1.51 (m, 8H).

[0945] Example 114 6-(phenylamino)-N-(1-(6-(6-(phenylamino)pyridinyl)piperidin-4-yl)pyridinamide (compound L-114)

[0946]

[0947] I. tert-Butyl (1-(6-(phenylamino)pyridinyl)piperidin-4-yl)carbamate

[0948] tert-Butyl piperidin-4-ylcarbamate (147 mg, 0.74 mmol) (compound as shown in Formula 2) and 6-(phenylamino)picolinic acid (150 mg, 0.70 mmol) (compound as shown in Formula 1) were suspended in 3 ml of N,N-dimethylformamide, N,N-diisopropyl ethylamine (181 mg, 1.4 mmol) and 1-propyl phosphonic anhydride (668 mg, 1.05 mmol) were added. The reaction was stirred at 30 °C for 16 h. 10 ml of ice water was added to the reaction, stirred for five minutes, filtered, and the solid was dried to give the crude product as 230 mg of brown solid, with a yield of 82.34%. LC-MS: m / z: (M+H)+= 397.0.

[0949] II. (4-Aminopiperidin-1-yl)(6-(phenylamino)pyridin-2-yl)methanone

[0950] tert-Butyl (1-(2-(phenylamino)pyrimidine-4-carbonyl)piperidin-4-yl)carbamate (150 mg, 0.38 mmol) (compound as shown in Formula 3) was dissolved in 5 ml of methanol, and a hydrochloric acid dioxane solution (5 mL, 4 M, 20 mmol) was added. The reaction was stirred at 15 °C for 2 h. The reaction was concentrated and dried to give the crude product as 110 mg of brown solid, with a yield of 98.10%. LC-MS: m / z: (M+H)+= 297.0.

[0951] III. 6-(phenylamino)-N-(1-(6-(6-(phenylamino)pyridinyl)piperidin-4-yl)pyridinamide

[0952] The operation was the same as the preparation of compound L-82 in Example 82.

[0953] LC-MS: m / z: (M+H)+= 493.0, 1H NMR (400 MHz, CDCl3) δ 8.06 - 7.99 (m, 1H), 7.72 - 7.61 (m, 3H), 7.38 (dt, J = 13.4, 8.0 Hz, 8H), 7.15 (t, J = 7.1 Hz, 2H), 6.98 (dd, J = 21.4, 7.9 Hz, 3H), 4.61 (s, 1H), 4.28 (d, J = 8.2 Hz, 1H), 3.96 (s, 1H), 3.37 - 3.14 (m, 2H), 2.12 (d, J = 28.1 Hz, 2H), 1.73 (d, J = 10.2 Hz, 2H).

[0954] Example 115 3-(4-(4-(6-(lH-Benzo[d]imidazol-2-yl)pyridinyl)piperazine- 1-carbonyl)benzamido)thiophene-2-carboxamide (Compound L-115)

[0955]

[0956] Procedure same as the preparation of Compound L-82 in Example 82.

[0957] LC-MS: m / z: (M+H) + = 579.8; 1H NMR (400 MHz, Methanol-d4) δ 8.41 (s, 1H), 8.14 (s, 3H), 7.81 - 7.61 (m, 5H), 7.36 (d, J = 16.9 Hz, 3H), 6.98 (s, 1H), 3.95 (d, J = 36.7 Hz, 4H), 3.67 (t, J = 29.0 Hz, 4H).

[0958] Example 116 2-((5-(4-(6-(lH-Benzo[d]imidazol-2-yl)pyridinoyl)piperazine- 1-carbonyl)-2-methylphenyl)amino)naphthalene-1,4-dione (Compound L-116)

[0959]

[0960] Procedure same as the preparation of Compound L-82 in Example 82.

[0961] LC-MS: m / z: (M+H) + = 596.8; 1H NMR (400 MHz, Chloroform-d) δ 8.58 (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 = 36.6 Hz, 8H), 2.34 (s, 3H).

[0962] Example 117 (4-(6-(lH-Benzo[d]imidazol-2-yl)pyridinoyl)piperazin- 1-yl)(3-(4-methyl-lH-imidazol-l-yl)phenyl)methanone (Compound L-117)

[0963]

[0964] Procedure same as the preparation of Compound L-82 in Example 82.

[0965] LC-MS: m / z: (M+H) += 419.9; 1H NMR (400 MHz, Methanol-d4) δ 8.41 (s, 1H), 8.14 (d, J = 8.1 Hz, 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).

[0966] Example 118 4-(6-(1H-Benzo[d]imidazol-2-yl)pyridinecarbonyl)-N-(3-(imidazo[1,2- a]pyridin-2-yl)phenyl)piperazine-1-carboxamide (Compound L-118)

[0967]

[0968] Dissolve 3-imidazo[1,2-a]pyridin-2-yl aniline (42 mg, 0.2 mmol) in anhydrous dichloromethane (5 mL), add triphosgene (20 mg, 0.067 mmol), stir at 25 °C for 16 h. Concentrate the reaction to dryness and use directly in the next step.

[0969] Dissolve [6-(1H-benzimidazol-2-yl)-2-pyridyl]-piperazin-1-yl-methanone (63 mg, 0.2 mmol) and N,N-diisopropylethylamine (79 mg, 0.6 mmol) in N,N-dimethylformamide (1 mL), add 2-(3-isocyanatophenyl)imidazo[1,2-a]pyridine (48 mg, 0.2 mmol), stir the reaction at 25 °C for 2 h. Concentrate the reaction to dryness and purify with flash chromatography (silica) (dichloromethane:methanol = 20:1) to give 4-[6-(1H-benzimidazol-2-yl)pyridine-2-carbonyl]-N-(3-imidazo[1,2-a]pyridin-2- ylphenyl)piperazine-1-carboxamide (35 mg, 32%) as a yellow solid.

[0970] LC-MS: m / z: (M+H) + LC-MS: m / z: (M+H) LC-MS: m / z: (M+H)

[0971] Example 119 1,3-Bis(3-(imidazo[l,2-a]pyridin-2-yl)phenyl)urea (Compound L-119)

[0972]

[0973] The operation is the same as the preparation of compound L-118 in Example 118.

[0974] LC-MS: m / z: (M+H)+ = 369.9. + LC-MS: m / z: (M+H)+ = 369.9.

[0975] Example 120 Synthesis of (5-(6-(lH-benzo[d]imidazol-2-yl)pyridinecarbonyl)hexahydropyrrolo[3,4-c]pyrrol-2(lH)-yl)(lH-indazol-3-yl)methanone (Compound L-120)

[0976]

[0977] I. Synthesis of (6-(lH-benzo[d]imidazol-2-yl)pyridin-2-yl)(hexahydropyrrolo[3,4- c]pyrrol-2(lH)-yl)methanone hydrochloride

[0978] Operation: The starting material 5-(6-(lH-benzo[d]imidazol-2-yl)pyridinecarbonyl)hexahydropyrrolo[3,4-c]pyrrol-2(lH)-carboxylic acid tert-butyl ester 540 mg was put into a reaction bottle, methanol 40 ml was added, 4M / L hydrochloric acid / 1,4-dioxane solution 20 ml was added with stirring, and it was stirred at room temperature overnight. The next day, LC-MS showed that the reaction was complete. The solvent was directly removed by concentration under reduced pressure. Yield: 500 mg, 100%

[0979] LC-MS: m / z: (M+H)+ = 369.9.

[0980] II. Synthesis of (5-(6-(lH-benzo[d]imidazol-2-yl)pyridinecarbonyl)hexahydropyrrolo[3,4- c]pyrrol-2(lH)-yl)(lH-indazol-3-yl)methanone.

[0981] Procedure: Put the starting material (6-(lH-benzo[d]imidazol-2-yl)pyridin-2-yl)(hexahydropyrrolo[3,4-c]pyrrol-2(lH)-yl)methanone hydrochloride 60 mg (1 eq) into a reaction bottle, add 2 ml of anhydrous DMF, add the starting material lH-indazole-3-carboxylic acid 26.25 mg (1 eq), stir in T3P 103.2 mg (50% EA solution, 1.5 eq), DIPEA 83.7 mg (3 eq), stir at 30 °C overnight, the next day, LC-MS reaction is complete. Work-up: pour the reaction liquid into 20 ml of ice water, stir, add dichloromethane 50 ml * 3 times of extraction, combine the organic layer, saturated brine extraction, dry over anhydrous sodium sulfate. Filter and concentrate to dryness, get the residue through column (DCM: MEOH = 0-5%) to get the product, then separate by thick layer chromatography plate (DCM: MEOH = 95:5) to get the pure product 32.5 mg. Yield: 41.9%.

[0982] LC-MS: m / z: (M+H)+= 478.2.

[0983] 1 H NMR (400 MHz, Methanol-d4) δ 8.46 - 8.37 (m, 1H), 8.20 (d, J = 8.2 Hz, 1H), 8.12 (dt, J = 10.1, 7.9 Hz, 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, 3.4 Hz, 2H).

[0984] Example 121 Synthesis of 6-(5-(6-(lH-benzo[d]imidazol-2-yl)pyridinecarbonyl)hexahydropyrrolo[3,4-c]pyrrole-2-carbonyl)-4,5-dihydropyridazine-3(2H)-one (Compound L-121)

[0985]

[0986] Procedure: Put the starting material (6-(lH-benzo[d]imidazol-2-yl)pyridin-2-yl)(hexahydropyrrolo[3,4-c]pyrrol-2(lH)-yl)methanone hydrochloride 60 mg (1 eq) into the reaction bottle, add 2 ml of anhydrous DMF, add the starting material 6-oxo-l,4,5,6-tetrahydropyridazine-3-carboxylic acid 23.04 mg (1 eq), stir in T3P 103.2 mg (50% EA solution, 1.5 eq), DIPEA 83.7 mg (3 eq), stir at 30°C overnight, the next day, LC-MS reaction is complete. Work-up: pour the reaction liquid into 20 ml of ice water, stir, add dichloromethane 50 ml*3 times of extraction, combine the organic layer, saturated brine extraction, dry over anhydrous sodium sulfate. Filter and concentrate to dryness, get the residue through column (DCM:MEOH=0-5%) to get the product, then separate by thick layer chromatography plate (DCM:MEOH=95:5) to get the pure product 19.6 mg. Yield: 26.4%.

[0987] LC-MS: m / z: (M+H)+= 458.2.

[0988] 1 H NMR (400 MHz, Methanol-d4) δ 8.42 (ddd, J = 7.9, 4.6, 0.9 Hz, 1H), 8.14 (td, J = 7.9, 1.0 Hz, 1H), 7.88 - 7.82 (m, 1H), 7.69 (d, J = 40.9 Hz, 2H), 7.34 (d, J = 4.9 Hz, 2H), 4.24 - 3.52 (m, 8H), 3.12 (dddd, J = 14.9, 12.4, 4.0, 2.1 Hz, 2H), 2.91 - 2.79 (m, 2H), 2.61 - 2.45 (m, 2H).

[0989] Example 122 Synthesis of (5-(6-(lH-benzo[d]imidazol-2-yl)pyridinecarbonyl)hexahydropyrrolo[3,4-c]pyrrol-2(lH)-yl)(quinolin-3-yl)methanone (Compound L-122)

[0990]

[0991] Procedure: Put the starting material (6-(lH-benzo[d]imidazol-2-yl)pyridin-2-yl)(hexahydropyrrolo[3,4-c]pyrrol-2(lH)-yl)methanone hydrochloride 60 mg (1 eq) into a reaction bottle, add 2 ml of anhydrous DMF, add the starting material quinoline-3-carboxylic acid 28.08 mg (1 eq), stir in T3P 103.2 mg (50% EA solution, 1.5 eq), DIPEA 83.7 mg (3 eq), stir at 30°C overnight, the next day, LC-MS reaction is complete. Work-up: pour the reaction liquid into 20 ml of ice water, stir, add dichloromethane 50 ml*3 times of extraction, combine the organic layer, saturated brine extraction, dry over anhydrous sodium sulfate. Filter and concentrate to dryness, get the residue through column (DCM:MEOH=0-5%) to get the product, then separate by thick layer chromatography plate (DCM:MEOH=95:5) to get the pure product 41.8 mg. Yield: 52.8%.

[0992] LC-MS: m / z: (M+H)+= 489.2.

[0993] 1 H NMR (400 MHz, Methanol-d4) δ 9.04 (d, J = 17.9 Hz, 1H), 8.59 (d, J = 27.0 Hz, 1H), 8.41 (dd, J = 22.3, 7.9 Hz, 1H), 8.18 - 7.82 (m, 5H), 7.69 (dt, J = 32.4, 7.4 Hz, 3H), 7.33 (s, 2H), 4.28 - 4.04 (m, 2H), 3.96 (tt, J = 13.6, 8.3 Hz, 2H), 3.88 - 3.56 (m, 4H), 3.29 - 3.05 (m, 2H).

[0994] Example 123 Synthesis of (5-(6-(lH-benzo[d]imidazol-2-yl)pyridinecarbonyl)hexahydropyrrolo[3,4-c]pyrrol-2(lH)-yl)(4-methylpyridin-3-yl)methanone (Compound L-123)

[0995]

[0996] Procedure: Put raw material (6-(lH-benzo[d]imidazol-2-yl)pyridin-2-yl)(hexahydropyrrolo[3,4- c]pyrrol-2(lH)-yl)methanone hydrochloride 60 mg (1 eq) into a reaction bottle, add 2 ml of anhydrous DMF, add raw material 4-methylnicotinic acid 22.2 mg (1 eq), stir in T3P 103.2 mg (50% EA solution, 1.5 eq), DIPEA 83.7 mg (3 eq), stir at 30°C overnight, the next day, LC-MS reaction is complete. Work-up: pour the reaction into 20 ml of ice water, stir, add dichloromethane 50 ml*3 times, extract the combined organic layers, extract with saturated brine, dry over anhydrous sodium sulfate. Filter and concentrate to dryness, get the residue through column (DCM:MEOH=0-5%) to get the product, then separate by thick layer chromatography plate (DCM:MEOH=95:5) to get the pure product 49.1 mg. Yield: 67%.

[0997] LC-MS: m / z: (M+H)+= 453.2.

[0998] 1 H NMR (400 MHz, Methanol-d4) δ 8.50 (d, J = 5.5 Hz, 1H), 8.47 - 8.37 (m, 2H), 8.14 (dt, J = 10.7, 7.8 Hz, 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 = 29.1 Hz, 3H).

[0999] Example 124 Synthesis of (5-(6-(lH-benzo[d]imidazol-2-yl)pyridinecarbonyl)hexahydropyrrolo[3,4- c]pyrrol-2(lH)-yl)(3-chloro-4-fluorophenyl)methanone (Compound L-124)

[1000]

[1001] Procedure: Put the starting material (6-(lH-benzo[d]imidazol-2-yl)pyridin-2-yl)(hexahydropyrrolo[3,4-c]pyrrol-2(lH)-yl)methanone hydrochloride 80 mg (1 eq) into a reaction bottle, add 2 ml of anhydrous DMF, add the starting material 3-chloro-4-fluorobenzoic acid 37.76 mg (1 eq), stir in T3P 137.6 mg (50% EA solution, 1.5 eq), DIPEA 111.6 mg (3 eq), stir at 30°C overnight, the next day, LC-MS reaction is complete. Work-up: pour the reaction liquid into 20 ml of ice water, stir, add dichloromethane 50 ml*3 times, extract, combine the organic layers, extract with saturated brine, dry over anhydrous sodium sulfate. Filter and concentrate to dryness, get the residue through column (DCM:MEOH=0-5%) to get the product, then separate by thick layer chromatography plate (DCM:MEOH=95:5) to get the pure product 55 mg. Yield: 51.88%.

[1002] LC-MS: m / z: (M+H)+= 489.8.

[1003] 1 H NMR (400 MHz, DMSO-d6) δ 12.92 (s, 1H), 8.41 (t, J = 7.6 Hz, 1H), 8.13 (q, J = 7.5 Hz, 1H), 7.83 - 7.77 (m, 2H), 7.73 (t, J = 6.9 Hz, 1H), 7.59 (q, J = 7.5, 6.9 Hz, 2H), 7.48 (dt, J = 32.4, 8.9 Hz, 1H), 7.26 (dq, J = 14.6, 7.7, 7.2 Hz, 2H), 4.18 - 3.35 (m, 8H), 3.11 - 2.90 (m, 2H).

[1004] Example 125 Synthesis of (5-(6-(lH-benzo[d]imidazol-2-yl)pyridinecarbonyl)hexahydropyrrolo[3,4-c]pyrrol-2(lH)-yl)(2-methylquinolin-6-yl)methanone (Compound L-125)

[1005]

[1006] Procedure: Put the starting material (6-(lH-benzo[d]imidazol-2-yl)pyridin-2-yl)(hexahydropyrrolo[3,4-c]pyrrol-2(lH)-yl)methanone hydrochloride 80 mg (1 eq) into the reaction bottle, add 2 ml of anhydrous DMF, add the starting material 2-methylquinoline-6-carboxylic acid 40.48 mg (1 eq), stir in T3P 137.6 mg (50% EA solution, 1.5 eq), DIPEA 111.6 mg (3 eq), stir at 30°C overnight, the next day, LC-MS reaction is complete. Work-up: pour the reaction liquid into 20 ml of ice water, stir, add dichloromethane 50 ml*3 times of extraction, combine the organic layer, saturated brine extraction, anhydrous sodium sulfate drying. Filter and concentrate to dryness, get the residue through column (DCM:MEOH=0-5%) to get the product, then separate by thick layer chromatography plate (DCM:MEOH=95:5) to get the pure product 70 mg. Yield: 64.5%.

[1007] LC-MS: m / z: (M+H)+= 502.9.

[1008] 1 H NMR (400 MHz, DMSO-d6) δ 12.93 (s, 1H), 8.46 - 8.24 (m, 2H), 8.20 - 8.07 (m, 2H), 7.94 (dd, J = 29.9, 8.9 Hz, 1H), 7.86 (d, J = 8.6 Hz, 1H), 7.80 (d, J = 7.6 Hz, 1H), 7.73 (dd, J = 11.9, 7.9 Hz, 1H), 7.61 (dd, J = 16.2, 7.9 Hz, 1H), 7.48 (dd, J = 26.5, 8.6 Hz, 1H), 7.26 (dq, J = 14.1, 7.1 Hz, 2H), 4.19 - 3.47 (m, 8H), 3.12 - 2.91 (m, 2H), 2.72 - 2.62 (m, 3H).

[1009] Example 126 Synthesis of (5-(6-(lH-benzo[d]imidazol-2-yl)pyridinecarbonyl)hexahydropyrrolo[3,4-c]pyrrol-2(lH)-yl)(4-(4-chlorophenyl)cyclohexyl)methanone (Compound L-126)

[1010]

[1011] Procedure: Put the starting material (6-(lH-benzo[d]imidazol-2-yl)pyridin-2-yl)(hexahydropyrrolo[3,4-c]pyrrol-2(lH)-yl)methanone hydrochloride 80 mg (1 eq) into the reaction bottle, add 2 ml of anhydrous DMF, add the starting material 4-(4-chlorophenyl)cyclohexane-l -carboxylic acid 51.6 mg (1 eq), stir in T3P 137.6 mg (50% EA solution, 1.5 eq), DIPEA 111.6 mg (3 eq), stir at 30 °C overnight, the next day, LC-MS reaction is complete. Work-up: pour the reaction liquid into 20 ml of ice water, stir, add dichloromethane 50 ml * 3 times of extraction, combine the organic layer, saturated brine extraction, dry over anhydrous sodium sulfate. Filter and concentrate to dryness, get the residue through column (DCM: MEOH = 0-5%) to get the product, then separate by thick layer chromatography plate (DCM: MEOH = 95:5) to get the pure product 53 mg. Yield: 44.2%.

[1012] LC-MS: m / z: (M+H)+= 553.8.

[1013] 1 H NMR (400 MHz, DMSO-d6) δ 12.93 (d, J = 22.3 Hz, 1H), 8.41 (d, J = 7.9 Hz, 1H), 8.17 - 8.08 (m, 1H), 7.82 - 7.69 (m, 2H), 7.59 (t, J = 6.7 Hz, 1H), 7.28 (ddd, J = 30.5, 16.0, 7.3 Hz, 6H), 4.16 - 3.33 (m, 8H), 3.11 - 2.87 (m, 2H), 2.43 (t, J = 10.0 Hz, 2H), 1.94 - 1.70 (m, 4H), 1.61 - 1.39 (m, 4H).

[1014] Example 127 Synthesis of (5-(6-(lH-benzo[d]imidazol-2-yl)pyridinecarbonyl)hexahydropyrrolo[3,4-c]pyrrol-2(lH)-yl)([l,l'-biphenyl]-4-yl)methanone (Compound L-127)

[1015]

[1016] Procedure: Put raw material (6-(1H-benzo[d]imidazol-2-yl)pyridin-2-yl)(hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)methanone hydrochloride 80 mg (1 eq) into the reaction bottle, add 2 ml of anhydrous DMF, add raw material [1,1'-biphenyl]-4-carboxylic acid 43 mg (1 eq), stir and add T3P 137.6 mg (50% EA solution, 1.5 eq), DIPEA 111.6 mg (3 eq), stir at 30°C overnight, the next day, LC-MS reaction is complete. Work-up: pour the reaction into 20 ml of ice water, stir, add dichloromethane 50 ml*3 times, extract, combine the organic layers, extract with saturated brine, dry over anhydrous sodium sulfate. Filter and concentrate to dryness, get the residue through column (DCM:MEOH=0-5%) to get the product, then separate the pure product 32 mg by thick layer chromatography plate (DCM:MEOH=95:5). Yield: 28.8%.

[1017] LC-MS: m / z: (M+H)+= 513.9.

[1018] 1 H NMR (400 MHz, DMSO-d6) δ 12.94 (s, 1H), 8.41 (dd, J = 13.3, 8.0 Hz, 1H), 8.13 (q, J = 7.9 Hz, 1H), 7.83 - 7.70 (m, 4H), 7.70 - 7.57 (m, 5H), 7.46 (ddt, J = 25.7, 13.0, 6.6 Hz, 3H), 7.27 (dt, J = 13.4, 6.5 Hz, 2H), 4.14 - 3.36 (m, 8H), 3.13 - 2.91 (m, 2H).

[1019] Receptor binding example: LANCL2 binding example

[1020] 1. Experimental materials

[1021] 1.1 Reagent materials

[1022] Ligand: LANCL2

[1023] Running buffer: 20 mM MES, 150 mM NaCl, 0.05% P20, pH 6.5, 1% DMSO

[1024] 1.2 Instrument equipment

[1025] Instrument name: Biacore S200

[1026] Chip type: CM5 (29-1496-03)

[1027] 2. Experimental method

[1028] 2.1 Ligand coupling

[1029] Immobilization of LANCL2 protein, dilution of protein to 50 pg / ml using sodium acetate solution at pH 4.0.

[1030] Injection conditions: Activation of the CM5 chip surface with a mixture of EDC / NHS, flow rate 10 pl / min. Injection time: 420 s; followed by injection of LANCL2, flow rate 5 pl / min, injection time: 2000 s, approximately 1800 RU of ligand coupled per injection; finally the chip surface was blocked using ethanolamine, ethanolamine injection flow rate 10 pl / min, injection time: 420 s.

[1031] Coupling buffer: 20 mM MES, 150 mM NaCl, 0.05% P20, pH 6.5.

[1032] 2.2 Experimental conditions

[1033] Analyte: All small molecule compound analytes were 2-fold diluted from a concentration of 50 mM to a concentration of 0.78 mM, resulting in a final compound solution containing 1% DMSO.

[1034] Small molecule compound injection conditions: flow rate 30 pl / min, association time 60 s, dissociation time 300 s.

[1035] Running buffer: 20 mM MES, 150 mM NaCl, 0.05% P20, pH 6.5, 1% DMSO.

[1036] Sample chamber temperature: 25 °C; assay temperature: 25 °C.

[1037] Method

[1038] Kinetic determination of LANCL2-small molecule interactions. BIACORE S200 was used to determine the kinetic parameters of the binding of small molecules BT-11 and L-1-60 (analytes) to LANCL2 (ligand). Data were generated in triplicate in a dose-dependent (5-8 titration points) manner and analyzed to determine the binding model (Langmuir, conformational shift, etc.), the on- and off-rate constants, and the equilibrium dissociation constant. SPR technology allows the verification of specific LANCL2-phytochemical interactions and increases the gold standard in-depth understanding of the binding mechanism and rate. The experiments were performed by covalently attaching LANCL2 on a carboxymethyl dextran (CM5) sensor chip via amine coupling. Data were analyzed with BIACORE S200 T200 Evaluation Software (version 1) to determine the affinity binding constant (KD) using a 1 : 1 binding model.

[1039] Results

[1040] The compounds of the present invention strongly bind to LANCL2. To confirm the binding of the compounds to the LANCL2 protein, we performed SPR analysis in a BIACORE S200 instrument. The optical technique SPR for detecting molecular interactions was used to measure the binding affinity between LANCL2 and its ligand (the test compound). We immobilized the purified recombinant LANCL2 protein on a BIACORE sensor chip, and used the instrument microfluidic system to inject small molecules onto the protein surface. The change in the total mass on the chip surface was measured, which corresponds to the small binding to the protein. By injecting a series of small molecule concentrations, we were able to calculate the binding signal of the test compound binding to LANCL2, the dissociation signal, calculate the steady-state binding affinity of the compound, and the binding signal curve of the compound at different concentrations (the part of the patent that is not good to calculate the affinity, the binding signal curve of the compound at different concentrations is placed in the patent as evidence that the compound has binding activity). The binding sensor exhibits typical small molecule protein interactions, which have very fast association rates and very fast dissociation rates. These fast interactions are beyond the technical capabilities of the instrument. Therefore, reliable association rate constants (ka) and dissociation rate constants (kd) were not determined. The equilibrium dissociation constant (Kd) is commonly used to describe the affinity between a ligand and a protein, such as the tightness of the ligand binding to a specific protein. Ligand-protein affinity is affected by non-covalent intermolecular interactions between the two molecules, such as hydrogen bonding, electrostatic interactions, hydrophobic forces, and van der Waals forces. By plotting the equilibrium binding level against the compound concentration, we were able to measure the steady-state affinity (Kd) of each interaction. The compounds of the present invention have good binding to the LANCL2 protein, and even some of the compounds of the present invention, such as (L-2, L-9, L-11, L-15, L-25, L-40, L-52, L-77, L-89, L-95, L-96, L-106), have better binding activity than the positive reference compound BT-ll.

[1041] The specific data are shown in the following table.

[1042]

[1043]

[1044]

[1045] KD (M) indicates the binding force (unit mol); Rmax (RU) indicates the maximum binding force; N / A indicates no binding activity; " / " indicates that the check result is not convenient to calculate KD, this part will show its binding activity in the form of binding curve, Figures 1 to 12The binding signal intensity of some compounds at different concentrations is shown in the figure; a represents poor solubility.

[1046] Study on the alleviating effect of the compounds of the present application on TNBS-induced colitis in mice (I)

[1047] 1. Background

[1048] IBD belongs to a class of autoimmune diseases, which can be divided into Crohn's disease and ulcerative colitis. This project uses a TNBS-induced mouse colitis model to simulate Crohn's disease, and evaluates the therapeutic effect of the corresponding compounds, with a view to developing drugs for treating Crohn's disease.

[1049] 2. Purpose

[1050] The present project aims to test the alleviating effect of representative compounds on TNBS-induced colitis in mice.

[1051] 3. Reagents

[1052] Reagents Vendor Cat DPBS Corning 21-031-CVR TNBS Beijing Coupling Technology Co., Ltd. 2508-19-2 Anhydrous ethanol Aladdin 64-17-5 Mesalazine (finished drug) Losan Pharma GmbH NA Sodium chloride injection Shandong Kelun Pharmaceutical Co., Ltd. NA 1.25% Avicel Nanjing Aibei Biological Technology Co., Ltd. M2910

[1053] 4. Instruments

[1054] Equipment Vendor Model Electronic balance Changzhou Zhi Balance YH-2000 Electronic analytical balance Mettle Toledo 585310

[1055] 5. Experimental methods

[1056] 5.1 Solubilization and preservation of compounds

[1057] Preparation method of L56: weigh an appropriate amount of L56 compound into a brown sample bottle, add a certain volume of solvent 95% (20% HP-β-CD) + 5% (10% sodium benzoate), vortex for 1 minute, and promote dissolution by ultrasonic. The compound is prepared once a day.

[1058] Preparation method of L30: weigh an appropriate amount of L30 compound into a brown sample bottle, add a certain volume of solvent 95% (20% HP-β-CD) + 5% (10% sodium benzoate), vortex for 1 minute, and promote dissolution by ultrasonic. The compound is prepared once a day.

[1059] Preparation method of Mesa (Mesalamine): weigh an appropriate amount of mesalamine (Selleck) compound into a brown sample bottle, add a certain volume of solvent 0.5% CMC-Na, vortex for 1 minute, and promote dissolution by ultrasonic. The compound is prepared once a day.

[1060] 5.2 Administration route and frequency of compounds

[1061] Female Balb / c mice, 56, 8-10 weeks old, 18g in weight, were randomly divided into 7 groups, 6 model groups and 1 Sham control group. The dosing started on Day-1 and ended on Day 7. The compounds were prepared once a day. The specific dosing route and frequency were shown in Table 1. The compound preparation and dosing volume were shown in Table 2.

[1062] Table 1 Animal grouping and dosing regimen

[1063] Group Number of animals (n) Dose (mg / kg) Route of administration Frequency of administration Period of administration Sham group 5 - - - - Solvent control group 5 - PO BID 9 days L56 group 5 50mpk PO BID 9 days L30 group 6 50mpk PO BID 9 days Mesa 5 100mpk PO QD 9 days

[1064] Note: The positive drug is Mesalamine (Mesa)

[1065] Table 2 Dosing volume and final drug concentration

[1066] Group Dose Volume of administration (mL) Final concentration of drug (mg / mL) Frequency of administration Solvent control group --- 0.2 0 BID L56 group 50mpk 0.2 5 BID L30 group 50mpk 0.2 5 BID Mesa 100mpk 0.2 10 QD

[1067] Note: The mice were weighed before dosing. The above table was calculated according to the dosing volume of 20g mice.

[1068] 5.3 Construction of TNBS-induced mouse colitis model

[1069] Day 0, Balb / c mice with a weight of 18-20g were anesthetized with 0.25ml of 1.25% atropine. The model group mice were rectally perfused with 150ul of 1% TNBS solution (final concentration 50% ethanol). The Sham control group mice were rectally perfused with 50% ethanol on Day 0.

[1070] 5.4 Fixation of mouse colon tissue

[1071] The colon of the mice was photographed, the length was measured, and the contents were removed before weighing. Then, the colon of each mouse was cut longitudinally at 1 / 2, rolled in the same direction according to the Swiss-roll method, and placed in neutral paraformaldehyde for fixation.

[1072] 5.5 DAI scoring criteria

[1073] The DAI score was composed of 3 parts, and the mixed score of body weight change, feces and blood in stool was taken. The specific DAI scoring criteria were shown in Table 3. During the entire experimental process, the DAI score of all mice was completed by the same person to ensure the consistency of the scale.

[1074] Table 3 DAI scoring criteria

[1075]

[1076]

[1077] 5.6 Histopathological scoring criteria of colon tissue

[1078] The mouse colon histopathology score is composed of 5 parts, and the specific scoring criteria are shown in Table 4. The pathological score was conducted by a professional pathologist of the clinical pathology platform in a double-blind manner.

[1079] Table 4. Colon histopathology score criteria

[1080]

[1081] 5.7 Statistical analysis

[1082] The experimental data was statistically analyzed by ANOVA method, and the positive drug Mesalamine (PO, 100 mpk, QD) group, L56 (PO, 50 mpk, BID) group, L30 (PO, 50 mpk, BID) group, *p < 0.05, **p < 0.01, ***p < 0.005, ****p < 0.0001

[1083] 6. Results and analysis

[1084] 6.1 Changes in mouse body weight and DAI score

[1085] The body weight data of mice in each group was collected for 10 days (Day-1 to Day8) and the corresponding DAI score was performed, and the data was analyzed by Two way ANOVA method. As shown in Figure 1A, compared with the Vehicle group, the body weight of mice in the L56 (PO, 50 mpk, BID) group and the Mesalamine (PO, 100 mpk, QD) group decreased significantly, while the body weight of mice in the L30 (PO, 50 mpk, BID) group decreased significantly compared with the Vehicle group. Figure 13 The DAI score data in Figure 1B also shows that compared with the Vehicle group, the DAI score of mice in the L30 (PO, 50 mpk, BID) group, the L56 (PO, 50 mpk, BID) group, and the Mesalamine (PO, 100 mpk, QD) group was significantly lower. In summary, the changes in body weight and DAI score show that L30 (PO, 50 mpk, BID) and L56 (PO, 50 mpk, BID) can effectively alleviate the decrease in body weight of mice induced by TNBS-induced colitis. Figure 13

[1086] Note: Figure 13 ​In the statistical analysis of body weight changes and disease activity index in the model group and other groups of mice, the two-way ANOVA method was used. Compared with the model group, the results were as follows: *p<0.05**p<0.01***p<0.005****p<0.0001; mesalazine group: #p<0.05##p<0.01###p<0.005####p<0.0001; L56 50mg / kg group: ^p<0.05^^p<0.01^^^p<0.005^^^^p<0.0001; L30 50mg / kg group: $p<0.05$$p<0.01$$$p<0.005$$$$p<0.0001. The two-way ANOVA method was used for multiple group comparisons.

[1087] 6.2 Changes in the ratio of colon weight to length in mice

[1088] Generally, inflammation causes the colon to shorten and its weight to increase. For example... Figure 14 Data A in the study showed that, compared to the vehicle group mice, the colon weight to length ratios in the L30 (PO, 50 mpk, BID), L56 (PO, 50 mpk, BID), and Mesalamine (PO, 100 mpk, QD) groups were significantly lower, exhibiting statistically significant differences. Figure 14 Data from group B indicates that, compared to the vehicle group mice, the colons of the Mesalamine (PO, 100 mpk, QD) group mice were significantly longer. Figure 14 The data from C indicate that, compared to the vehicle group mice, the colon weights of the L30 (PO, 50 mpk, BID), L56 (PO, 50 mpk, BID), and Mesalamine (PO, 100 mpk, QD) groups were slightly lower, similar to those of the Sham group mice. These data further suggest that L30 (PO, 50 mpk, BID) and L56 (PO, 50 mpk, BID) can significantly alleviate TNBS-induced colitis in mice.

[1089] Note: Figure 14 In the statistical analysis of the ratio of colon weight to length in mice in the model group and other groups, the one-way ANOVA method was used. Compared with the model group, *p<0.05**p<0.01***p<0.005****p<0.0001. One-way ANOVA was performed using Dunnett's method for multiple group comparisons.

[1090] 6.3 HE staining and pathological scoring of mouse colon tissue

[1091] Further, we performed HE staining on colon tissues of 7 groups of mice and scored by pathologists. Compared with Vehicle group mice, L56 (PO, 50 mpk, BID) group, Mesalamine (PO, 100 mpk, QD) group mice colon tissue pathological score is lower, with statistically significant difference. Further illustrate L56 (PO, 50 mpk, BID), can effectively alleviate the occurrence of TNBS model mice intestinal inflammation.

[1092] Conclusion

[1093] Combined with the data of in-life experiment and pathological analysis, it can be known that L56 (PO, 50 mpk, BID) can well slow down the TNBS-induced intestinal inflammation of mice.

[1094] Intestinal morphology Figure 15 (Sham group & Vehicle group, Mesalamine (PO, 100 mpk, QD) group & L56 (PO, 50 mpk, BID) group and L30 (PO, 50 mpk, BID) group.

[1095] Study on the alleviating effect of the compound of the application on TNBS-induced intestinal inflammation of mice (two)

[1096] 1. Research background

[1097] IBD belongs to a kind of autoimmune diseases, which can be divided into Crohn's disease and ulcerative colitis. The colon inflammation model of mice induced by TNBS is used to simulate Crohn's disease in this project, and the therapeutic effect of the corresponding compound is evaluated, so as to develop a drug for treating Crohn's disease.

[1098] 2. Research purpose

[1099] The purpose of this project is to test the alleviating effect of representative compounds on TNBS-induced intestinal inflammation of mice.

[1100] 3. Reagents

[1101]

[1102]

[1103] 4. Instruments

[1104] Equipment Vendor Model Electronic balance Changzhou Zhi Balance YH-2000 Electronic analytical balance Mettle Toledo 585310

[1105] 5. Experimental method

[1106] 5.1 Dissolution and preservation of compounds

[1107] Preparation method of BT-11: Take an appropriate amount of BT-11 compound into a brown sample bottle, add a certain volume of solvent 0.5% CMC-Na, vortex for 1 min, and promote dissolution by ultrasonic. The compound is prepared once a day.

[1108] Preparation method of L11: Take an appropriate amount of L11 compound into a brown sample bottle, add a certain volume of solvent 0.5% CMC-Na, vortex for 1 min, and promote dissolution by ultrasonic. The compound is prepared once a day.

[1109] Preparation method of L25: Take an appropriate amount of L25 compound into a brown sample bottle, add a certain volume of solvent 0.5% CMC-Na, vortex for 1 min, and promote dissolution by ultrasonic. The compound is prepared once a day.

[1110] Preparation method of L84: Take an appropriate amount of L84 compound into a brown sample bottle, add a certain volume of solvent 0.5% CMC-Na, vortex for 1 min, and promote dissolution by ultrasonic. The compound is prepared once a day.

[1111] Preparation method of L77: Take an appropriate amount of L77 compound into a brown sample bottle, add a certain volume of solvent 0.5% CMC-Na, vortex for 1 min, and promote dissolution by ultrasonic. The compound is prepared once a day.

[1112] Preparation method of L101: Take an appropriate amount of L101 compound into a brown sample bottle, add a certain volume of sodium chloride injection (normal saline), vortex for 1 min, and promote dissolution by ultrasonic. The compound is prepared once a day.

[1113] Preparation method of L10: Take an appropriate amount of L10 compound into a brown sample bottle, add a certain volume of solvent 0.5% CMC-Na, vortex for 1 min, and promote dissolution by ultrasonic. The compound is prepared once a day.

[1114] Preparation method of L23: Take an appropriate amount of L23 compound into a brown sample bottle, add a certain volume of solvent 0.5% CMC-Na, vortex for 1 min, and promote dissolution by ultrasonic. The compound is prepared once a day.

[1115] Preparation method of Mesa (Mesalamine): Take an appropriate amount of mesalamine (Selleck) compound into a brown sample bottle, add a certain volume of solvent 0.5% CMC-Na, vortex for 1 min, and promote dissolution by ultrasonic. The compound is prepared once a day.

[1116] 5.2 Administration route and frequency of 5.2 compound

[1117] Female Balb / c mice, 60, 18g in weight, 8-10 weeks old, were randomly divided into 12 groups, 11 model groups and 1 Sham control group. The dosing started on Day-1 and ended on Day 7. The compounds were prepared once a day. The specific dosing route and frequency were shown in Table 5. The compound preparation and dosing volume were shown in Table 6.

[1118] Table 5 Animal grouping and dosing schedule

[1119]

[1120]

[1121] Table 6 Dosing volume and final drug concentration

[1122] Group Dose Volume of administration (mL) Final concentration of drug (mg / mL) Frequency of administration Model control group --- 0.2 0 BID Mesalazine group 100mpk 0.2 10 QD L11 group 50mpk 0.2 5 BID L25 group 50mpk 0.2 5 BID L84 group 50mpk 0.2 5 BID L77 group 50mpk 0.2 5 BID L101 group 50mpk 0.2 5 BID L10 group 50mpk 0.2 5 BID L23 group 50mpk 0.2 5 BID BT-11 group 50mpk 0.2 5 BID

[1123] Note: The mice were weighed before dosing. The above table was calculated according to the dosing volume of 20g mice. The solvent group was the model control group.

[1124] 5.3 Construction of TNBS-induced mouse colitis model

[1125] Day 0, Balb / c mice with a weight of 18-20g were anesthetized with 0.25ml of 1.25% Alverdiscus anesthetic. The model group mice were rectally perfused with 150ul of 1% TNBS solution (final concentration 50% ethanol). The Sham control group mice were rectally perfused with 50% ethanol on Day 0.

[1126] 5.4 Fixation of mouse colon tissue

[1127] The colon of the mice was photographed and the length was measured. After removing the contents, the colon was weighed, then the colon of each mouse was cut longitudinally at 1 / 2, rolled in the direction of the Swiss roll, and placed in neutral paraformaldehyde for fixation.

[1128] 5.5 Collection of fresh mouse colon tissue

[1129] The remaining 1 / 2 of the colon tissue was cut longitudinally along the 1 / 2, divided into two tubes, frozen in liquid nitrogen, and stored at -80℃. Dry ice was used for transportation, and the frozen tissue was used for subsequent experiments.

[1130] 5.6 Collection of mouse mesenteric lymph nodes

[1131] The mesenteric lymph nodes of the mice were collected and stored at 4℃. After all the samples were collected, they were immediately sent to the customer for flow cytometry analysis.

[1132] 5.7 DAI scoring criteria

[1133] DAI score was composed of 3 parts, which was a combination of body weight change, stool and blood in stool score. The detailed DAI score criteria was shown in Table 7. The DAI score of all mice was done by the same person to ensure the consistency of the scale.

[1134] Table 7 DAI score criteria

[1135] Score Weight loss % Stool character Hidden blood or bloody stool 0 0 Normal Hidden blood negative 1 1～5 Soft stool Weakly positive hidden blood 2 6～10 Loose stool Hidden blood positive 3 11～20 Diarrhea Bloody stool 4 >20 Very loose stool Massive bloody stool

[1136] 5.8 Statistical analysis

[1137] The experimental data was analyzed by ANOVA method. Dunnett’s test was used to compare the data of other groups with the data of Vehicle (PO, QD) group. *p < 0.05, **p < 0.01, ***p < 0.005, ****p < 0.0001

[1138] 6. Results and analysis

[1139] 6.1 Body weight change and DAI score of mice

[1140] The body weight data of mice in each group was collected for 10 days (Day-1 to Day8) and the corresponding DAI score was done. The data was analyzed by Two way ANOVA method. As shown in the data of A in Figure 16 compared with the Vehicle group, the body weight loss of mice in L11 (PO, 50 mpk, BID) group and L10 (PO, 50 mpk, BID) group was significantly slowed down. Except for L84 (PO, 50 mpk, BID) group and BT11 (PO, 50 mpk, BID) group, the body weight loss of mice in other 5 test compound groups was significantly slowed down. In addition, the body weight loss of mice in L11 (PO, 50 mpk, BID) group and L10 (PO, 50 mpk, BID) group was more significantly slowed down than that in other 5 test compound groups. As shown in the data of B in Figure 16 compared with the Vehicle group, the DAI score of mice in L11 (PO, 50 mpk, BID) group and L10 (PO, 50 mpk, BID) group was significantly lower. The DAI score of mice in other 7 test compound groups was significantly lower than that in the Vehicle group. In addition, the DAI score of mice in L11 (PO, 50 mpk, BID) group and L10 (PO, 50 mpk, BID) group was more significantly lower than that in other 7 test compound groups. In summary, L11 (PO, 50 mpk, BID) and L10 (PO, 50 mpk, BID) could effectively alleviate the body weight loss of mice induced by TNBS-induced colitis. More interestingly, the efficacy of L10 (PO, 50 mpk, BID) was comparable to that of Mesalamine (PO, 100 mpk, QD).

[1141] 6.2 Scoring of diarrhea and bloody stool in mice

[1142] Similarly, a two-way ANOVA method was used to analyze the individual diarrhea and rectal bleeding scores. Figure 17 In group A, compared to the Vehicle group, the diarrhea in mice in the L11 (PO, 50 mpk, BID) and L10 (PO, 50 mpk, BID) groups was significantly reduced among the nine tested compounds. The other seven tested compounds all showed significant effects in improving diarrhea in mice with enteritis, but not as significantly as L11 and L10. Figure 17 In the B group, compared to the Vehicle group, the L11(PO,50mpk,BID) and L10(PO,50mpk,BID) groups of mice tested with the nine compounds showed a significant reduction in fecal bleeding. The other seven compounds also showed significant effects in improving fecal bleeding in mice with enteritis, but not as significantly as L11 and L10. Therefore, we found that L11(PO,50mpk,BID) and L10(PO,50mpk,BID) effectively alleviated diarrhea and fecal bleeding symptoms in TNBS model mice.

[1143] 6.3 Changes in the ratio of colon weight to length in mice

[1144] Generally, inflammation causes colonic shortening and increased colonic weight. At the final sample collection point, mice in the L10 (PO, 50 mpk, BID) group, L25 (PO, 50 mpk, BID) group, and L11 (PO, 50 mpk, BID) group, which showed significant drug efficacy, were selected for colonic photography, length measurement, and weight weighing. For example... Figure 18 Data from group C indicate that, compared to the vehicle group, mice in the L10 (PO, 50 mpk, BID), L25 (PO, 50 mpk, BID), L11 (PO, 50 mpk, BID), and Mesalazine (PO, 100 mpk, QD) groups had significantly lower colon weight to length ratios, showing statistically significant differences. Figure 18 Data A in the study showed that, compared to the vehicle group mice, the colons of the L10 (PO, 50 mpk, BID) group, the L25 (PO, 50 mpk, BID) group, and the L11 (PO, 50 mpk, BID) group mice were significantly longer. Figure 18The data of B in the table showed that the colon of the mice in the L10 (PO, 50 mpk, BID) group, the L25 (PO, 50 mpk, BID) group, the L11 (PO, 50 mpk, BID) group and the Mesalazine (PO, 100 mpk, QD) group was lower than that of the mice in the vehicle group. These data further showed that L11 (PO, 50 mpk, BID) and L10 (PO, 50 mpk, BID) could alleviate the inflammation of the mice with TNBS enteritis.

[1145] 7. Conclusion

[1146] In combination with the data of the in-life experiment, it can be known that L11 (PO, 50 mpk, BID) and L10 (PO, 50 mpk, BID) can well alleviate the TNBS-induced enteritis of the mice.

[1147] The intestinal morphology was as shown in Figure 19 .

Claims

1. A carbonyl heterocyclic compound as shown in Formula II, or a pharmaceutically acceptable salt thereof; in, A is Y 1 and Y 2 Independently CH or N; T stands for connection key; Q is The b-terminus indicates that it is connected to a carbonyl group; B' is Z 3 -L 3 It is -C(=O)-; Y 3 and Y 4 Independently CH or N; A' is 2. The carbonyl heterocyclic compound of formula II as described in claim 1, or a pharmaceutically acceptable salt thereof, characterized in that, for End 'a' indicates the position connected to A.

3. The carbonyl heterocyclic compound of formula II as described in claim 1, or a pharmaceutically acceptable salt thereof, characterized in that, When B' is hour, for 4. The carbonyl heterocyclic compound of formula II as described in claim 3, characterized in that, When B' is hour, for The a' end indicates that it is connected to A'.

5. The carbonyl heterocyclic compound of formula II as described in claim 1, or a pharmaceutically acceptable salt thereof, characterized in that, for 6. The carbonyl heterocyclic compound of formula II as described in claim 1, or a pharmaceutically acceptable salt thereof, characterized in that, B'-A' is 7. A carbonyl heterocyclic compound or a pharmaceutically acceptable salt thereof, characterized in that, The carbonyl heterocyclic compounds are selected from the following group:

8. A pharmaceutical composition comprising a carbonyl heterocyclic compound of formula II as described in any one of claims 1-6 or a pharmaceutically acceptable salt thereof, or a carbonyl heterocyclic compound of formula II as described in claim 7 or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers.

9. The use of a pharmaceutically acceptable salt of a carbonyl heterocyclic compound as shown in Formula II as described in any one of claims 1-6, or a carbonyl heterocyclic compound as described in claim 7, or a pharmaceutically acceptable salt thereof, or a composition as described in claim 8, in the preparation of a lanothioneine C-like protein 2 agonist.

10. The use of a pharmaceutically acceptable salt of a carbonyl heterocyclic compound as shown in Formula II as described in any one of claims 1-6, or a carbonyl heterocyclic compound as described in claim 7, or a pharmaceutically acceptable salt thereof, or a composition as described in claim 8, in the preparation of a medicament; The drug is used to prevent and / or treat diseases related to lanolin-like protein 2.

11. The application as described in claim 10, characterized in that, The aforementioned drugs are used to prevent and / or treat autoimmune, chronic inflammatory, chronic metabolic, or infectious diseases.

12. The application as described in claim 11, characterized in that, The autoimmune diseases mentioned are inflammatory bowel disease, systemic lupus erythematosus, rheumatoid arthritis, type 1 diabetes, psoriasis, and multiple sclerosis.

13. The application as described in claim 11, characterized in that, The chronic metabolic diseases mentioned are metabolic syndrome, obesity, prediabetes, cardiovascular disease, and type 2 diabetes.

14. The application as described in claim 11, characterized in that, The infectious disease mentioned is a viral disease.

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