A carbonyl heterocyclic compound and application thereof

Abstract

This invention discloses a carbonyl heterocyclic compound and its applications. The invention provides a carbonyl heterocyclic compound as shown in Formula I or a pharmaceutically acceptable salt thereof; it can serve as a compound targeting the lanthanine synthase C-like protein 2 pathway; said compound can be used to treat a variety of conditions, including infectious diseases, autoimmune diseases, diabetes, and chronic inflammatory diseases.

Description

Technical Field

[0001] This invention relates to a carbonyl heterocyclic compound and its applications. Background Technology

[0002] Lanothionine C-like protein 2 (LANCL2) (also known as "lanothionine synthase C-like protein 2" or "lanothionine synthase component C-like protein 2") is a protein expressing signaling pathways in immune cells, the gastrointestinal tract, neurons, the testes, and the pancreas. Activation of the LANCL2 pathway increases insulin sensitivity and reduces inflammation associated with various autoimmune, inflammatory, and metabolic conditions. In vivo and in vitro tests in mice showed that, compared to the control group, the use of compounds targeting this pathway reduced glucose levels by 2-fold in glucose tolerance tests and provided the same level of protection as prescribed. GlaxoSmithKline plc, Brentford, England, is an effective treatment with significant side effects. Targeting the LANCL2 pathway also reduces intestinal inflammation by 90% and correspondingly reduces the number of lesions by 4 times. The results of this test and other validations of this pathway have been mentioned in numerous articles.

[0003] Within the category of autoimmune-related inflammation, there is currently a global pandemic of autoimmune diseases such as inflammatory bowel disease (IBD), systemic lupus erythematosus, rheumatoid arthritis, type 1 diabetes, psoriasis, and 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 clinic / surgical visits and frequent monitoring. LANCL2's unique mode of action provides an orally administered therapeutic agent that is as effective as anti-TNF antibodies but without the side effects and high cost. Given the overall prevalence of inflammatory and autoimmune diseases, the LANCL2 pathway has the significant potential to impact millions of patients.

[0004] Abscisic acid (“ABA”) is a natural compound bound to LANCL2 that was discovered during the initial screening process.

[0005] Numerous compounds are described in the field of synthetic organic chemistry. Various compounds are provided by the following references: Diana et al. WO 1997 / 036866, Sun et al. WO 2006 / 053109, Kim et al. WO 2006 / 080821, Nunes et al. WO 2007 / 019417, Singh et al. WO 2009 / 067600 and WO 2009 / 067621, Adams et al. WO 2008 / 079277, Urasoe et al. JP 2008 / 056615, Stoessel et al. WO 2011 / 066898, Bassaganya-Riera et al. US2013 / 0142825, and Bassaganya-Riera et al. U.S. Patent 7,741,367. International patent application WO2016064445 discloses a compound that targets the lanolin-3-amino acid synthase C-like protein 2 pathway, which can be used to treat a variety of conditions, including infectious diseases, autoimmune diseases, diabetes, and chronic inflammatory diseases.

[0006] Some of the compounds described in these references are known to activate the LANCL2 pathway, while others do not. There is a need to develop novel ligands for the LANCL2 pathway to allow for disease-specific tailoring of treatments and potentially maximize their efficacy. Summary of the Invention

[0007] The technical problem to be solved by this invention is to overcome the lack of therapeutic agents based on lanolin-like protein C2 in the prior art; and to provide a carbonyl heterocyclic compound and its application. The carbonyl heterocyclic compound provided by this invention is a compound that targets the lanolin-like protein C2 pathway; the compound can bind to the LANCL2 protein and achieve beneficial responses in various disease symptoms, and can be used to treat a variety of conditions, including metabolic and infectious diseases, autoimmune diseases, diabetes, and chronic inflammatory diseases.

[0008] The present invention solves the above-mentioned technical problems through the following technical solutions.

[0009] This invention provides a carbonyl heterocyclic compound as shown in Formula I or a pharmaceutically acceptable salt thereof;

[0010]

[0011] Where A is or -NR 1 R 2 ;

[0012] R 1 and R2 Independently H or C 6-18 aryl;

[0013] Y 1 and Y 2 Independently CH or N;

[0014] Q is (include );

[0015] Z 1 -L 1 -for (i.e. L) 1 (for connection key) or (The q-end indicates that it is connected to a carbonyl group);

[0016] 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.

[0017] Q Ring 1 It is a 6-10 membered fused heterocyclic alkyl, a 6-12 membered spirocyclic heterocyclic alkyl, or a 6-10 membered bridged heterocyclic alkyl; Q 1 It contains 1 to 3 N atoms;

[0018] M is 6-10 fused heterocyclic aryl groups, with R 4 Substituted 6-10 fused heterocyclic aryl groups, 5-10 fused heterocyclic alkenyl groups, oxidized 5-10 fused heterocyclic alkenyl groups, or R-substituted heterocyclic alkenyl groups. 5 The substituted 5-10 cyclic alkyl group; the heteroatom in the 6-10 fused heterocyclic aryl group; the R-substituted... 4 The heteroatoms in the substituted 6-10 membered fused heterocyclic aryl groups, the heteroatoms in the 5-10 membered heterocyclic alkenyl groups, and the heteroatoms in the oxo-substituted 5-10 membered heterocyclic alkenyl groups are independently one or more of N, S, and O, and the number of heteroatoms is independently one, two, or three; R 3 The number of is 1, 2, or 3; (the 'c' terminal indicates a connection to the C=O shown).

[0019] G is either S or O;

[0020] A'、A 1a A 1b and A 1c Independently NO2 -OR 8 C 6-14 aryl or H;

[0021] Y 3 Y3a Y 3b Y 4 Y 4a Y 4b Y 5 Y 5a Y 5b and Y 5c Independently CH or N;

[0022] R 6 It is a halogen;

[0023] R 7 For H or C 1-6 Alkyl groups;

[0024] R 8 C 6-14 aryl;

[0025] R 3 C 1-6 Alkyl or halogen;

[0026] R 4 C 1-6 Alkyl groups;

[0027] R 5 C 6-14 aryl or halogenated C 6-14 Aryl groups.

[0028] 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.

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

[0030] In some 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.

[0031] In some preferred embodiments of the present invention, when Q 1 When it is a 6-10 membered fused heterocyclic alkyl group, the 6-10 membered fused heterocyclic alkyl group is a 6-8 membered fused heterocyclic alkyl group containing 1 or 2 N atoms (e.g., N atoms connected to the carbonyl group and Z atoms).1 The ring atoms other than [are all carbon], and can also be a heterocycloalkyl of a 5-membered N-heterocycloalkyl fused to a tricycloalkyl or a heterocycloalkyl of a 5-membered N-heterocycloalkyl fused to a 5-membered N-heterocycloalkyl. For example

[0032] In certain preferred embodiments of the present invention, when Q 1 is a heterocycloalkyl of a 6- to 12-membered spiro ring, the 6- to 12-membered spiro ring heterocycloalkyl is a 7- to 11-membered spiro ring heterocycloalkyl, containing 1 or 2 N atoms (such as spiro[5,5]undecazacycloalkyl, spiro[5,4]decazacycloalkyl, spiro[4,4]nonazacycloalkyl or spiro[3,3]heptazacycloalkyl), and can also be a 9- to 11-membered spiro ring heterocycloalkyl, containing 1 or 2 N atoms (such as the N atom connected to the carbonyl group and the ring atoms other than Z 1a are all carbon), and can also be azaspiro[5,5]undecazacycloalkyl, azaspiro[5,4]decazacycloalkyl or azaspiro[4,4]nonazacycloalkyl. For example (Another example is (Another example is ), (The b end indicates connection to ).

[0033] In certain preferred embodiments of the present invention, when Q 1 is a heterocycloalkyl of a 6- to 10-membered bridged ring, the 6- to 10-membered bridged ring heterocycloalkyl is a 7-membered bridged ring heterocycloalkyl, containing 1 to 2 N atoms (such as the N atom connected to the carbonyl group and the ring atoms other than Z 1 are all carbon). For example,

[0034] In certain preferred embodiments of the present invention, Y 3 , Y 3a , Y 3b , Y 4 , Y 4a , Y 4b and Y 5b are independently CH or N.

[0035] In certain preferred embodiments of the present invention, the number of R 3 is 1, 2 or 3; for example, 1 or 2.

[0036] In certain preferred embodiments of the present invention, when M is , is

[0037] In certain preferred embodiments of the present invention, when M is , for

[0038] In some preferred embodiments of the present invention, when M is hour, for

[0039] In some preferred embodiments of the present invention, when R 3 C 1-6 When alkyl, the C 1-6 The alkyl group is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl, for example, methyl.

[0040] In some preferred embodiments of the present invention, when R 3 When the halogen is halogen, the halogen is F, Cl, Br or I, for example F or Cl.

[0041] In some preferred embodiments of the present invention, when M is hour, for

[0042] In some preferred embodiments of the present invention, when M is hour, for

[0043] In some preferred embodiments of the present invention, when M is hour, for

[0044] In certain preferred embodiments of the present invention, when M is a 6-10 fused heterocyclic aryl group or is converted by R 4 When a 6-10 membered fused heterocyclic aryl group is substituted, the 6-10 membered fused heterocyclic aryl group is independently a 9-10 membered fused heterocyclic aryl group, the heteroatom being N and / or S, and the number being one or two (e.g., a 5-membered N-heteroaryl-phenyl heterocyclic aryl group, a 6-membered N-heteroaryl-phenyl heterocyclic aryl group, a 5-membered N-heteroaryl-6-membered N-heteroaryl heterocyclic aryl group), such as an indole group. Quinolinyl Isoindolyl or imidazopyridyl

[0045] In some preferred embodiments of the present invention, when R 4 C 1-6 When alkyl, the C 1-6The alkyl group is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl, for example, methyl.

[0046] In some preferred embodiments of the present invention, when M is R 4 When the 6-10 fused heterocyclic aryl group is replaced, the R- 4 The substituted 6-10 fused heterocyclic aryl group is

[0047] In certain preferred embodiments of the present invention, when M is a 5-10 member heterocyclic alkenyl group or a 5-10 member heterocyclic alkenyl group substituted with oxygen, the 5-10 member heterocyclic alkenyl group is a 6-membered heterocyclic alkenyl group, the heteroatom is N, and the number is 2, for example...

[0048] In certain preferred embodiments of the present invention, when M is an oxidized 5-10 member heterocyclic alkenyl group, the oxidized 5-10 member heterocyclic alkenyl group is...

[0049] In some preferred embodiments of the present invention, when M is R 5 When the substituted 4-10 cycloalkyl group is used, the 4-10 cycloalkyl group is cyclopentyl, cyclohexyl, or cycloheptyl, for example, cyclohexyl.

[0050] In some preferred embodiments of the present invention, when R 5 C 6-14 aryl or halogenated C 6-14 When the aryl group is present, the C 6-14 The aryl group can be phenyl, naphthyl, anthraceneyl, or phenanthryl, such as phenyl.

[0051] In some preferred embodiments of the present invention, when R 5 C replaced by halogen 6-14 When the aryl group is present, the halogen is F, Cl, Br or I, for example Cl.

[0052] In some preferred embodiments of the present invention, when R 5 C replaced by halogen 6-14 When the aryl group is substituted, the halogenated C 6-14 The aryl group is chlorophenyl, for example...

[0053] In some preferred embodiments of the present invention, when M is R 5 When the 4-10 membered cycloalkyl group is substituted, the R 5 The substituted 4-10 cycloalkyl group is

[0054] In some preferred embodiments of the present invention, when A', A 1aA 1b and A 1c Independently hour, for

[0055] In some preferred embodiments of the present invention, when A', A 1a A 1b and A 1c Independently hour, for

[0056] In some preferred embodiments of the present invention, when R 6 When the halogen is halogen, the halogen is F, Cl, Br or I, for example F.

[0057] In some preferred embodiments of the present invention, when A', A 1a A 1b and A 1c Independently hour, for

[0058] In some preferred embodiments of the present invention, when A', A 1a A 1b and A 1c Independently hour, for

[0059] In some preferred embodiments of the present invention, when R 7 C 1-6 When alkyl, the C 1-6 The alkyl group is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl, for example, methyl.

[0060] In some preferred embodiments of the present invention, when A', A 1a A 1b and A 1c Independently hour, for

[0061] In some preferred embodiments of the present invention, when A', A 1a A 1b and A 1c Independently for C 6-14 When the aryl group is present, the C 6-14 The aryl group can be phenyl, naphthyl, anthraceneyl, or phenanthryl, such as phenyl.

[0062] In some preferred embodiments of the present invention, when R 8 C 6-14 When the aryl group is present, the C 6-14 The aryl group can be phenyl, naphthyl, anthraceneyl, or phenanthryl, such as phenyl.

[0063] In certain preferred embodiments of the present invention, A', A 1a A 1b and A 1c Independently selected from the following structures:

[0064] NO2

[0065] In some preferred embodiments of the present invention, for

[0066] In some preferred embodiments of the present invention, R 1 and R 2 One is H, and the other is C. 6-14 Aryl groups.

[0067] In some preferred embodiments of the present invention, Y 2 For CH.

[0068] In some preferred embodiments of the present invention, Q 1 It is a 6-10 membered fused heterocyclic alkyl group or a 6-12 membered spirocyclic heterocyclic alkyl group.

[0069] In some preferred embodiments of the present invention, Q 1 It is a 6-10 fused heterocyclic alkyl group, Z 1 -L 1 -for For example, Q is

[0070] In some preferred embodiments of the present invention, Q 1 It is a 6-10 fused heterocyclic alkyl group, Z 1 -L 1 -for For example, Q is

[0071] In some preferred embodiments of the present invention, Q 1 It is a heterocyclic alkyl group with a 6-12 membered spirocyclic ring, Z 1 -L 1 -for In some preferred embodiments of the present invention, Q 1 It is a heterocyclic alkyl group with a 6-10 membered bridged ring, Z 1 -L1 -for In some preferred embodiments of the present invention, for

[0072] In some preferred embodiments of the present invention, Q is

[0073] In some preferred embodiments of the present invention, for

[0074] In some preferred embodiments of the present invention, for

[0075] In some preferred embodiments of the present invention, for

[0076] In some preferred embodiments of the present invention, for

[0077] In certain preferred embodiments of the present invention, A is...

[0078] In certain preferred embodiments of the present invention, A is...

[0079] In some preferred embodiments of the present invention,

[0080] Where A is or -NR 1 R 2 ;

[0081] R 1 and R 2 Independently H or C 6-18 aryl;

[0082] Y 1 and Y 2 Independently CH or N;

[0083] Q is

[0084] Z 1 -L 1 -for

[0085] 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.

[0086] Q Ring 1 It is a 6-10 membered fused heterocyclic alkyl, a 6-12 membered spirocyclic heterocyclic alkyl, or a 6-10 membered bridged heterocyclic alkyl; Q 1 It contains 1 to 3 N atoms;

[0087] M is 6-10 fused heterocyclic aryl groups, with R 4 Substituted 6-10 fused heterocyclic aryl groups, 5-10 fused heterocyclic alkenyl groups, oxidized 5-10 fused heterocyclic alkenyl groups, or R-substituted heterocyclic alkenyl groups. 5 The substituted 5-10 cyclic alkyl group; the heteroatom in the 6-10 fused heterocyclic aryl group; the R-substituted... 4 The heteroatoms in the substituted 6-10 fused heterocyclic aryl groups, the heteroatoms in the 5-10 fused heterocyclic alkenyl groups, and the heteroatoms in the oxo-substituted 5-10 fused heterocyclic alkenyl groups are independently one or more of N, S, and O, and the number of them is independently 1, 2, or 3.

[0088] G represents S and O;

[0089] A'、A 1a A 1b and A 1c Independently NO2 -OR 8 C 6-14 aryl or H;

[0090] Y 5 Y 5a and Y 5c Independently CH or N;

[0091] R 6 It is a halogen;

[0092] R 7 C 1-6 Alkyl groups;

[0093] R 8 C 6-14 aryl;

[0094] R 3 C 1-6 Alkyl or halogen;

[0095] R 4 C 1-6 Alkyl groups;

[0096] R 5 C 6-14 aryl or halogenated C 6-14 Aryl groups.

[0097] In some preferred embodiments of the present invention, A is or -NR 1 R 2 ;

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

[0099] Y 1 and Y 2 Independently CH or N;

[0100] Q is Z 1 -L 1 -for

[0101] 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.

[0102] Q Ring 1 It is a 6-10 membered fused heterocyclic alkyl group or a 6-12 membered spirocyclic heterocyclic alkyl group; Q 1 It contains 1 to 3 N atoms;

[0103] M is 6-10 fused heterocyclic aryl groups, with R 4 Substituted 6-10 fused heterocyclic aryl groups, 5-10 fused heterocyclic alkenyl groups, oxidized 5-10 fused heterocyclic alkenyl groups, or R-substituted heterocyclic alkenyl groups. 5 Substituted 5-10 membered cycloalkyl groups;

[0104] G represents S and O;

[0105] A 1a A 1b and A 1c Independently -OR 8 C 6-14 aryl or H;

[0106] Y 5 Y 5a and Y 5b Independently CH or N;

[0107] R 6 It is a halogen;

[0108] R 7 C 1-6 Alkyl groups;

[0109] R8 C 6-14 aryl;

[0110] R 3 C 1-6 Alkyl or halogen;

[0111] R 4 C 1-6 Alkyl groups;

[0112] R 5 C 6-14 aryl or halogenated C 6-14 Aryl groups.

[0113] In certain preferred embodiments of the present invention

[0114] Where A is

[0115] Y 2 For CH;

[0116] Q is

[0117] Z 1 -L 1 -for

[0118] Q Ring 1 Heterocyclic alkyl groups that are 5-membered N-heterocyclic alkyl groups or ternary cyclic alkyl groups (e.g.) e-end and (connected) or spirocyclic [5,5] undecylane (e.g.) );

[0119] M is Or 6-10 fused heterocyclic aryl groups;

[0120] A' and A 1b Independently

[0121] In some preferred embodiments of the present invention,

[0122] A is or -NR 1 R 2 ;

[0123] R 1 and R 2 Independently H or C 6-14 aryl;

[0124] Y 1 and Y 2 Independently CH or N;

[0125] Q is

[0126] Z 1 -L 1 -for

[0127] Q Ring 1 It is a 6-10 membered fused heterocyclic alkyl group; Q 1 It contains one or two N atoms;

[0128] M is 6-10 fused heterocyclic aryl groups, with R 4 Substituted 6-10 fused heterocyclic aryl groups, 5-10 fused heterocyclic alkenyl groups, oxidized 5-10 fused heterocyclic alkenyl groups, or R-substituted heterocyclic alkenyl groups. 5 Substituted 4-10 membered cycloalkyl groups;

[0129] G is S;

[0130] A' and A 1c Independently -OR 8 C 6-14 aryl or H;

[0131] Y 5 Y 5a and Y 5b Independently CH or N;

[0132] R 6 It is a halogen;

[0133] R 7 C 1-6 Alkyl groups;

[0134] R 8 C 6-14 aryl;

[0135] R 3 C 1-6 Alkyl or halogen;

[0136] R 4 C 1-6 Alkyl groups;

[0137] R 5 C 6-14 aryl or halogenated C 6-14 Aryl groups.

[0138] In some preferred embodiments of the present invention,

[0139] A is or -NR1 R 2 ;

[0140] R 1 and R 2 Independently H or C 6-14 aryl;

[0141] Y 1 and Y 2 Independently CH or N;

[0142] Q is

[0143] Z 1 -L 1 -for

[0144] Q Ring 1 It is a heterocyclic alkyl group with a 6-12 membered spirocyclic ring; Q 1 It contains 2 N atoms;

[0145] M is 6-10 fused heterocyclic aryl groups, with R 4 Substituted 6-10 fused heterocyclic aryl groups, 5-10 fused heterocyclic alkenyl groups, oxidized 5-10 fused heterocyclic alkenyl groups, or R-substituted heterocyclic alkenyl groups. 5 Substituted 4-10 membered cycloalkyl groups;

[0146] A'、A 1a A 1b and A 1c Independently NO2

[0147] Y 5 and Y 5b Independently, it can be CH or N.

[0148] In some preferred embodiments of the present invention, the carbonyl heterocyclic compound represented by Formula I is shown in Formula I-1:

[0149]

[0150] Where A is

[0151] Y 1 and Y 2 Independently CH or N;

[0152] Q is (include );

[0153] Z 1 -L 1 -for (i.e. L) 1 (for connection key) or (The q-end indicates that it is connected to a carbonyl group);

[0154] Q Ring 1 It is a 6-10 membered fused heterocyclic alkyl, a 6-12 membered spirocyclic heterocyclic alkyl, or a 6-10 membered bridged heterocyclic alkyl; Q 1 It contains 1 to 3 N atoms;

[0155] Y 3 and Y 4 Independently CH or N;

[0156] A' is Or NO2;

[0157] Y 5 For CH or N;

[0158] 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.

[0159] In certain preferred embodiments of the present invention, certain groups in the carbonyl heterocyclic compounds of Formula I or their pharmaceutically acceptable salts are defined as follows (groups not mentioned are as described in any embodiment of this application).

[0160] for For example For example (End 'a' indicates the position connected to A)

[0161] In certain preferred embodiments of the present invention, certain groups in the carbonyl heterocyclic compounds of Formula I or their pharmaceutically acceptable salts are defined as follows (groups not mentioned are as described in any embodiment of this application).

[0162] When Q 1 When it is a 6-10 membered fused heterocyclic alkyl group, the 6-10 membered fused heterocyclic alkyl group is a 6-8 membered fused heterocyclic alkyl group containing 1 to 2 N atoms (e.g., N atoms connected to the carbonyl group and Z atoms). 1 (All ring atoms except for carbon atoms); for example

[0163] In certain preferred embodiments of the present invention, certain groups in the carbonyl heterocyclic compounds of Formula I or their pharmaceutically acceptable salts are defined as follows (groups not mentioned are as described in any embodiment of this application).

[0164] When Q 1When the heterocyclic alkyl group is a 6-12 membered spirocyclic ring, the 6-12 membered spirocyclic alkyl group is a 9-11 membered spirocyclic alkyl group containing 1 to 2 N atoms (e.g., N atoms connected to the carbonyl group and Z atoms). 1 (All ring atoms except for carbon atoms); for example (For example) ), (For example) )or (The b-end indicates that it is connected to the carbonyl group on the left).

[0165] In certain preferred embodiments of the present invention, certain groups in the carbonyl heterocyclic compounds of Formula I or their pharmaceutically acceptable salts are defined as follows (groups not mentioned are as described in any embodiment of this application).

[0166] When Q 1 When the heterocyclic alkyl group is a 6-10 membered bridged ring, the 6-10 membered bridged ring is a 7-membered bridged ring heterocyclic alkyl group containing 1 to 2 N atoms (e.g., N atoms connected to the carbonyl group and Z atoms). 1 (All ring atoms except for carbon atoms); for example,

[0167] In certain preferred embodiments of the present invention, certain groups in the carbonyl heterocyclic compounds of Formula I or their pharmaceutically acceptable salts are defined as follows (groups not mentioned are as described in any embodiment of this application).

[0168] for

[0169] In certain preferred embodiments of the present invention, certain groups in the carbonyl heterocyclic compounds of Formula I or their pharmaceutically acceptable salts are defined as follows (groups not mentioned are as described in any embodiment of this application).

[0170] When A' is hour, for

[0171] In certain preferred embodiments of the present invention, certain groups in the carbonyl heterocyclic compounds of Formula I or their pharmaceutically acceptable salts are defined as follows (groups not mentioned are as described in any embodiment of this application).

[0172] A' is selected from the following structure:

[0173] NO2

[0174] In certain preferred embodiments of the present invention, certain groups in the carbonyl heterocyclic compounds of Formula I or their pharmaceutically acceptable salts are defined as follows (groups not mentioned are as described in any embodiment of this application).

[0175] A is the same as A';

[0176] And / or, and Same (when M is) hour).

[0177] In certain preferred embodiments of the present invention, certain groups in the carbonyl heterocyclic compounds of Formula I or their pharmaceutically acceptable salts are defined as follows (groups not mentioned are as described in any embodiment of this application).

[0178] for

[0179] In certain preferred embodiments of the present invention, certain groups in the carbonyl heterocyclic compounds of Formula I or their pharmaceutically acceptable salts are defined as follows (groups not mentioned are as described in any embodiment of this application).

[0180] Q is selected from the following structure:

[0181] (b indicates that it is connected to B).

[0182] In certain preferred embodiments of the present invention, certain groups in the carbonyl heterocyclic compounds of Formula I or their pharmaceutically acceptable salts are defined as follows (groups not mentioned are as described in any embodiment of this application).

[0183] Selected from the following structure:

[0184]

[0185] In certain preferred embodiments of the present invention, certain groups in the carbonyl heterocyclic compounds of Formula I or their pharmaceutically acceptable salts are defined as follows (groups not mentioned are as described in any embodiment of this application).

[0186] A' is Or NO2; for example

[0187] In certain preferred embodiments of the present invention, certain groups in the carbonyl heterocyclic compounds of Formula I or their pharmaceutically acceptable salts are defined as follows (groups not mentioned are as described in any embodiment of this application).

[0188] Where A is

[0189] Y 1 and Y 2 Independently CH or N; for example for

[0190] Q is Q 1 It is a 6-10 membered fused heterocyclic alkyl, a 6-12 membered spirocyclic heterocyclic alkyl, or a 6-10 membered bridged heterocyclic alkyl, Z 1 -L 1 -for Or, Q 1 It is a 6-10 fused heterocyclic alkyl group, Z 1 -L 1 -for

[0191] Y 3 and Y 4 Independently CH or N; for example for

[0192] A' is Or NO2;

[0193] Y 5 It can be CH or N.

[0194] In certain preferred embodiments of the present invention, certain groups in the carbonyl heterocyclic compounds of Formula I or their pharmaceutically acceptable salts are defined as follows (groups not mentioned are as described in any embodiment of this application).

[0195] Where A is

[0196] Y 1 and Y 2 Independently CH or N;

[0197] Q is Q 1 Independently a 6-10 membered fused heterocyclic alkyl group or a 6-12 membered spirocyclic heterocyclic alkyl group; Z 1 -L 1 -for Or, Q 1 It is a 6-10 fused heterocyclic alkyl group, Z 1 -L 1 -for

[0198] Y 3 and Y 4 Independently CH or N;

[0199] A' is Or NO2;

[0200] Y 5 It can be CH or N.

[0201] In certain preferred embodiments of the present invention, certain groups in the carbonyl heterocyclic compounds of Formula I or their pharmaceutically acceptable salts are defined as follows (groups not mentioned are as described in any embodiment of this application).

[0202] Where A is

[0203] for

[0204] Q is Q 1 Independently a 6-10 membered fused heterocyclic alkyl group; Z 1 -L 1 -for

[0205] for

[0206] A' is

[0207] Y 5 It can be CH or N.

[0208] In certain preferred embodiments of the present invention, certain groups in the carbonyl heterocyclic compounds of Formula I or their pharmaceutically acceptable salts are defined as follows (groups not mentioned are as described in any embodiment of this application).

[0209] Where A is

[0210] for

[0211] Q is Q 1 Independently, it is a heterocyclic alkyl group consisting of a 6-12 membered spirocyclic ring; Z 1 -L 1 -for

[0212] for

[0213] A' is Or NO2.

[0214] In certain preferred embodiments of the present invention, the carbonyl heterocyclic compounds represented by Formula I are selected from the group consisting of:

[0215]

[0216]

[0217]

[0218]

[0219] In this invention, the carbonyl heterocyclic compound as shown in Formula I or its pharmaceutically acceptable salt has one or more chiral carbon atoms, thus allowing for the isolation of optically pure isomers, such as pure enantiomers, racemates, or mixed isomers. Pure single isomers can be obtained using separation methods in the art, such as chiral crystallization into salts or separation by chiral preparative columns.

[0220] In this invention, the carbonyl heterocyclic compounds represented by Formula I or their pharmaceutically acceptable salts, if stereoisomers exist, may exist as a single stereoisomer or a mixture thereof (e.g., a racemic mixture). The term "stereoisomer" refers to cis-trans isomers or optical isomers. These stereoisomers can be separated, purified, and enriched by asymmetric synthetic methods or chiral separation methods (including but not limited to thin-layer chromatography, rotational chromatography, column chromatography, gas chromatography, high-performance liquid chromatography, etc.), and can also be obtained through chiral resolution by bonding (chemical bonding, etc.) or salt formation (physical bonding, etc.) with other chiral compounds. The term "single stereoisomer" means that the mass content of one stereoisomer of the compound is not less than 95% relative to all stereoisomers of the compound.

[0221] The carbonyl heterocyclic compounds of Formula I or their pharmaceutically acceptable salts described herein can be synthesized by methods similar to those known in the chemical field, with steps and conditions referencing those of similar reactions in the art, particularly those described herein. Starting materials are typically derived from commercial sources, such as Aldrich, or can be readily prepared using methods known to those skilled in the art (obtainable via online databases such as SciFinder and Reaxys).

[0222] The necessary starting materials or reagents for preparing carbonyl heterocyclic compounds of Formula I or their pharmaceutically acceptable salts are commercially available or can be prepared by synthetic methods known in the art. The methods described in the Experimental Section below can be used to prepare compounds of the present invention, either as a free base or as a salt thereof upon addition of acid. The term pharmaceutically acceptable salt refers to a pharmaceutically acceptable salt as defined herein and possesses all the properties of the parent compound. Pharmaceutically acceptable salts can be prepared by adding a suitable acid to a suitable organic solvent containing an organic base, following conventional methods.

[0223] Examples of salt formation include: For alkali addition salts, it is possible to prepare salts of alkali metals (such as sodium, potassium, or lithium) or alkaline earth metals (such as aluminum, magnesium, calcium, zinc, or bismuth) by treating the compounds of the present invention having suitable acidic protons with alkali metal or alkaline earth metal hydroxides or alkoxides (e.g., ethanol or methanol) or suitable basic organic amines (e.g., diethanolamine, choline, or meglumine) in an aqueous medium.

[0224] Alternatively, for acid addition salts, salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid; and salts formed with organic acids such as acetic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, ethanesulfonic acid, fumaric acid, glucoheponic acid, glutamic acid, glycolic acid, hydroxynaphthoic acid, 2-hydroxyethanesulfonic acid, lactic acid, maleic acid, malic acid, oxalic acid, pyruvic acid, malonic acid, mandelic acid, methanesulfonic acid, 2-naphthalenesulfonic acid, propionic acid, salicylic acid, succinic acid, tartaric acid, citric acid, cinnamic acid, p-toluenesulfonic acid, or trimethylacetic acid.

[0225] In this invention, the carbonyl heterocyclic compound or its pharmaceutically acceptable salt as shown in Formula I can also be obtained by peripheral modification of the prepared carbonyl heterocyclic compound or its pharmaceutically acceptable salt using conventional methods in the art.

[0226] Generally, the compounds of the present invention can be prepared by the methods described in the present invention, unless otherwise specified, wherein the substituents are defined as shown in Formula I.

[0227] The present invention also provides a pharmaceutical composition comprising a carbonyl heterocyclic compound of Formula I as described above, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers. In the pharmaceutical composition, the amount of the carbonyl heterocyclic compound of Formula I or a pharmaceutically acceptable salt thereof may be a therapeutically effective amount.

[0228] The pharmaceutically acceptable carrier (pharmaceutical excipient) may be any excipient widely used in the pharmaceutical manufacturing industry. Excipients primarily serve to provide a safe, stable, and functional pharmaceutical composition, and may also provide methods for dissolving the active ingredient at a desired rate after administration to a subject, or for promoting effective absorption of the active ingredient after administration to a subject. The pharmaceutical excipient may be an inert filler, or may provide a function such as stabilizing the overall pH of the composition or preventing degradation of the active ingredient. The pharmaceutical excipient may include one or more of the following: binders, suspending agents, emulsifiers, diluents, fillers, granulators, adhesives, disintegrants, lubricants, anti-adhesion agents, flow aids, wetting agents, gelling agents, absorption delay agents, dissolution inhibitors, enhancers, adsorbents, buffers, chelating agents, preservatives, colorants, flavoring agents, and sweeteners.

[0229] The pharmaceutical compositions of the present invention can be prepared using any method known to those skilled in the art, based on the disclosure. For example, conventional mixing, dissolving, granulation, emulsification, grinding, encapsulation, embedding, or lyophilization processes.

[0230] The pharmaceutical compositions of this invention can be administered in any form, including by 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 this invention can also be controlled-release or delayed-release dosage forms (e.g., liposomes or microspheres). Examples of solid oral formulations include, but are not limited to, powders, capsules, tablets, 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 serum preparations. Examples of parenteral formulations 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 composition include, but are not limited to, eye drops and other ophthalmic preparations; aerosols, such as nasal sprays or inhalers; liquid dosage forms suitable for parenteral administration; suppositories; and tablets.

[0231] This invention also provides the use of the carbonyl heterocyclic compound of Formula I, its pharmaceutically acceptable salt, or the above-described pharmaceutical composition in the preparation of lanathionine C-like protein 2 (LANCL2) agonists. In the described application, the lanathionine C-like protein 2 (LANCL2) activator can be used in mammalian organisms; it can also be used in vitro, primarily for experimental purposes, such as providing a standard or control sample for comparison, or preparing a kit according to conventional methods in the art to provide rapid detection of the activation effect of lanathionine C-like protein 2 (LANCL2).

[0232] The present invention also provides the use of the carbonyl heterocyclic compound of Formula I, its pharmaceutically acceptable salt, or the above-described pharmaceutical composition in the preparation of a medicament; said medicament may be for the prevention and / or treatment of diseases related to lanethionine C-like protein 2 (LANCL2). The diseases related to lanethionine C-like protein 2 (LANCL2) may be one or more of autoimmune, chronic inflammatory, chronic metabolic, and infectious diseases.

[0233] The present invention also provides the use of the carbonyl heterocyclic compound as shown in Formula I or a pharmaceutically acceptable salt thereof in the preparation of a medicament; the medicament may be a medicament for the prevention and / or treatment of autoimmune, chronic inflammatory, chronic metabolic or infectious diseases.

[0234] Another aspect of the invention relates to a method for preventing and / or treating diseases related to lanethionine C-like protein 2 (LANCL2), comprising administering to a patient a therapeutically effective dose of the carbonyl heterocyclic compound of Formula I or a pharmaceutically acceptable salt thereof or a pharmaceutical composition comprising the thereof as described above.

[0235] Another aspect of the invention relates to a method for treating, preventing, and / or treating autoimmune, chronic inflammatory, or infectious diseases, comprising administering to a patient a therapeutically effective dose of the carbonyl heterocyclic compound of Formula I, a pharmaceutically acceptable salt thereof, or the aforementioned pharmaceutical composition.

[0236] Another aspect of the present invention relates to a medicament for lanthanine C-like protein 2 (LANCL2), comprising the carbonyl heterocyclic compound as shown in Formula I, a pharmaceutically acceptable salt thereof, or the aforementioned pharmaceutical composition.

[0237] The autoimmune diseases mentioned above can include inflammatory bowel disease (IBD) (including ulcerative colitis and / or Crohn's disease), systemic lupus erythematosus, rheumatoid arthritis, type 1 diabetes, psoriasis, and multiple sclerosis.

[0238] The chronic metabolic diseases mentioned above can include metabolic syndrome, obesity, prediabetes, cardiovascular disease, and type 2 diabetes.

[0239] The infectious diseases mentioned above can be viral diseases, such as influenza.

[0240] This invention also provides a method for treating a condition in an animal using any one or more of the compounds described herein. The method comprises administering to the animal an effective amount of one or more of the compounds described herein. The condition may be selected from the group consisting of infectious diseases, autoimmune diseases, diabetes, and chronic inflammatory diseases. In some methods, infectious diseases include viral diseases, such as influenza infection. In some methods, autoimmune diseases include autoimmune inflammatory diseases, such as inflammatory bowel disease, including ulcerative colitis and / or Crohn's disease. In some methods, diabetes is selected from the group consisting of type 1 diabetes and type 2 diabetes. In some methods, chronic inflammatory diseases include metabolic syndrome. In some methods, the method comprises administering an effective amount of a compound that increases LANCL2 activity, reduces inflammation, and / or increases anti-inflammatory effects.

[0241] This invention also provides compounds for treating symptoms in animals using any one or more of the compounds described herein. Compounds for such use include any of the compounds described herein. Use may involve administering to an animal an effective amount of one or more of the compounds described herein, wherein the symptoms are selected from the group consisting of infectious diseases, autoimmune diseases, diabetes, and chronic inflammatory diseases. In some forms, infectious diseases include viral diseases, such as influenza infection. In some forms, autoimmune diseases include autoimmune inflammatory diseases, such as inflammatory bowel disease, including ulcerative colitis and / or Crohn's disease. In some forms, diabetes is selected from the group consisting of type 1 diabetes and type 2 diabetes. In some forms, chronic inflammatory diseases include metabolic syndrome. In some forms, the compounds effectively increase LANCL2 activity, reduce inflammation, and / or increase anti-inflammatory effects.

[0242] The term "pharmaceutically acceptable" means that the salts, solvents, excipients, etc., are generally non-toxic, safe, and suitable for patient use. The term "patient" preferably refers to a mammal, and more preferably a human.

[0243] The term "pharmaceutically acceptable salt" refers to a salt prepared from the compound of the present invention with a relatively non-toxic, pharmaceutically acceptable acid.

[0244] “Treatment” means any treatment of disease in a mammal, including: (1) preventing disease, i.e. causing the symptoms of clinical disease to not develop; (2) suppressing disease, i.e. preventing the development of clinical symptoms; and (3) alleviating disease, i.e. causing the clinical symptoms to subside.

[0245] "Effective amount" means that when administered to a patient requiring treatment, the amount of the compound is sufficient to (i) treat the relevant disease, (ii) reduce, improve, 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 corresponding to this amount of the carbonyl heterocyclic compound as shown in Formula I or its pharmaceutically acceptable salt, or the pharmaceutical composition as described above, will vary depending on factors such as the specific compound, the disease condition and its severity, and the characteristics of the patient requiring treatment (e.g., weight), but nonetheless it can be routinely determined by those skilled in the art.

[0246] The "prevention" mentioned in this invention refers to the reduction of the risk of acquiring or developing a disease or disorder.

[0247] The term "pharmaceutical composition" as used in this invention refers to a formulation comprising one or more compounds of the invention or salts thereof, and a carrier commonly accepted in the art for delivering a bioactive compound to an organism (e.g., a human). The purpose of the pharmaceutical composition is to facilitate drug delivery to the organism.

[0248] The term "pharmaceutically acceptable carrier" refers to a substance that is co-administered with the active ingredient and facilitates the administration of the active ingredient. This includes, but is not limited to, any flow aids, sweeteners, diluents, preservatives, dyes / colorants, flavor enhancers, surfactants, wetting agents, dispersants, disintegrants, suspending agents, stabilizers, isotonic agents, solvents, or emulsifiers approved by the National Medical Products Administration for use in humans or animals (e.g., livestock). Examples include, but are not limited to, calcium carbonate, calcium phosphate, various sugars and starches, cellulose derivatives, gelatin, vegetable oils, and polyethylene glycol.

[0249] The pharmaceutical compositions described in this invention can be formulated into solid, semi-solid, liquid, or gaseous preparations, such as tablets, pills, capsules, powders, granules, ointments, emulsions, suspensions, solutions, suppositories, injections, inhalers, gels, microspheres, and aerosols, etc.

[0250] The pharmaceutical composition described in this invention can be manufactured using methods well known in the art, such as conventional mixing, dissolving, granulation, sugar-coated pill making, grinding, emulsification, freeze drying, etc.

[0251] The routes of administration for the compounds or pharmaceutically acceptable salts thereof or pharmaceutical compositions described in this invention include, but are not limited to, oral, rectal, transmucosal, enteral, or local, transdermal, inhalation, parenteral, sublingual, intravaginal, intranasal, intraocular, intraperitoneal, intramuscular, subcutaneous, and intravenous administration. The preferred route of administration is oral administration.

[0252] 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 enable the compounds of the present invention to be formulated into tablets, pills, lozenges, sugar-coated tablets, capsules, liquids, gels, pastes, suspensions, etc., for oral administration to patients. For example, a pharmaceutical composition for oral administration can be obtained as a tablet by combining the active ingredient with one or more solid carriers, granulating the resulting mixture if necessary, and adding a small amount of excipients to process it into a mixture or granules to form a tablet or tablet core. The tablet core can be combined with a coating material optionally suitable for enteric coating to process it into a coated formulation more favorable for absorption by the organism (e.g., human).

[0253] Unless otherwise stated, the following definitions shall apply as used herein. For the purposes of this invention, chemical elements are consistent with the CAS edition of the periodic table and the Handbook of Chemistry and Physics, 75th edition, 1994. Furthermore, general principles of organic chemistry can be found 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.

[0254] In this specification, groups and their substituents may be selected by those skilled in the art to provide stable structural moieties and compounds. When a substituent is described by a conventional chemical formula written from left to right, the substituent also includes chemically equivalent substituents obtained when the structural formula is written from right to left.

[0255] Certain chemical groups defined herein are preceded by simplified symbols to indicate the total number of carbon atoms present in the group. For example, C1-C6 alkyl refers to an alkyl group having a total of 1, 2, 3, 4, 5, or 6 carbon atoms as defined below. The total number of carbon atoms in the simplified symbols does not include carbons that may be present in substituents of the group.

[0256] In this paper, the numerical ranges defined in the substituents, such as 0 to 4, 1-4, 1 to 3, etc., indicate the integers within that range, such as 1-6 being 1, 2, 3, 4, 5, 6.

[0257] Except as otherwise specified, when used in the specification and claims of this application, the following terms shall have the following meanings.

[0258] The term "comprising" is an open-ended expression, meaning it includes the contents specified in this invention, but does not exclude other aspects.

[0259] The term "substituted" refers to the substitution of one or more hydrogen atoms on a particular atom by a substituent, including deuterium and hydrogen variants, provided that the valence state of the particular atom is normal and the substituted compound is stable.

[0260] Generally, the term "substituted" indicates that one or more hydrogen atoms in a given structure are substituted by a specific substituent. Further, when the group is substituted by more than one of the substituents, the substituents are independent of each other; that is, the more than one substituent can be different or the same. Unless otherwise indicated, a substituent can be substituted at each substituted position of the substituted group. When more than one position in a given structural formula can be substituted by one or more substituents selected from a specific group, the substituents can be substituted at the same or different positions.

[0261] The terms “one or more” or “one or more kinds” refer to 1, 2, 3, 4, 5, 6, 7, 8, 9 or more; for example, 1, 2, 3, 4 or 5.

[0262] In this application, as a group or part of other groups, unless otherwise specified, the term "cycloalkyl" means a saturated monocyclic, polycyclic, or bridged carbocyclic substituent consisting only of carbon and hydrogen atoms, which may be connected to the rest of the molecule via a single bond through any suitable carbon atom; when polycyclic, it may be a spirocyclic system or a bridged ring system with fused or spirocyclic linkages (i.e., the two geminal hydrogens on the carbon atom are replaced by alkylene groups).

[0263] In this application, as part of a group or other group, the term "heterocyclic alkyl" means a stable 3- to 16-membered saturated cyclic group consisting of 2-11 carbon atoms and 1-5 heteroatoms selected from nitrogen, oxygen, and sulfur. Unless otherwise specifically indicated in this specification, a heterocyclic alkyl group may be either monocyclic ("monocyclic heterocyclic alkyl") or a bicyclic, tricyclic, or more cyclic system, which may include fused (fused ring), bridged (bridged ring), or spirocyclic (spiro ring) ring systems (e.g., bicyclic systems ("bicyclic heterocyclic alkyl"). A bicyclic alkyl ring system may include one or more heteroatoms in one or both rings; and is saturated.

[0264] The terms “part,” “structural part,” “chemical part,” “group,” and “chemical group” used in this article refer to specific segments or functional groups within a molecule. A chemical part is generally considered to be a chemical entity embedded in or attached to a molecule.

[0265] When a listed substituent does not specify which atom it is attached to in a compound included but not specifically mentioned in the general chemical formula, such a substituent may be bonded to any of its atoms. Combinations of substituents and / or their variants are permitted only if such combinations produce stable compounds.

[0266] When a listed group does not explicitly indicate that it has a substituent, the group refers only to the unsubstituted group. For example, when "C1-C4 alkyl" is not preceded by the qualifier "substituted or unsubstituted", it refers only to "C1-C4 alkyl" itself or "unsubstituted C1-C4 alkyl".

[0267] Linking substituents are described in various parts of this invention. When the structure clearly requires a linking group, the Markush variable listed for that group should be understood as the linking group. For example, if the structure requires a linking group and the Markush group definition for that variable lists "alkyl" or "aryl," it should be understood that "alkyl" or "aryl" represents a linked alkylene group or an arylene group, respectively.

[0268] In some specific structures, when an alkyl group is clearly indicated as a linking group, then the alkyl group represents a linked alkylene group. For example, the C1-C6 alkyl in the group “halogenated-C1-C6 alkyl” should be understood as C1-C6 alkylene.

[0269] Unless otherwise specified, all technical and scientific terms used herein have the standard meaning in the field to which the claimed subject matter pertains. Where multiple definitions exist for a term, the definition herein shall prevail.

[0270] It should be understood that the singular forms used in this invention, such as "a," include plural references unless otherwise specified. Furthermore, the term "comprising" is an open-ended limitation, not a closed one; that is, it includes the contents specified in this invention but does not exclude other aspects.

[0271] Unless otherwise stated, this invention employs traditional methods of mass spectrometry and elemental analysis, and the steps and conditions can be referred to conventional operating procedures and conditions in the field.

[0272] Unless otherwise specified, this invention employs standard nomenclature and standard laboratory procedures and techniques of analytical chemistry, organic synthetic chemistry, and optics. In some cases, standard techniques are used for chemical synthesis, chemical analysis, and performance testing of light-emitting devices.

[0273] Furthermore, it should be noted that, unless otherwise explicitly stated, the descriptive phrase "...independently" used in this invention should be interpreted broadly, meaning that the described entities are independent of each other and can independently be the same or different specific functional groups. More specifically, the descriptive phrase "...independently" can mean either that the specific options expressed by the same symbol in different functional groups do not affect each other, or that the specific options expressed by the same symbol in the same functional group do not affect each other.

[0274] Those skilled in the art will understand that, according to the conventions used in the art, the structural formulas of the descriptive groups described in this application... This refers to the fact that the corresponding group is connected to other fragments or groups in the compound through this site.

[0275] 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.

[0276] The reagents and raw materials used in this invention are all commercially available.

[0277] 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

[0278] Figure 1 Binding curve of compound L7-LANCL2

[0279] Figure 2 Binding curve of compound L8-LANCL2

[0280] Figure 3 Binding curve of compound L12-LANCL2

[0281] Figure 4 Binding curve of compound L17-LANCL2

[0282] Figure 5 Binding curve of compound L22-LANCL2

[0283] Figure 6 Binding curve of compound L28-LANCL2

[0284] Figure 7 Binding curve of compound L29-LANCL2

[0285] Figure 8 Binding curve of compound L30-LANCL2

[0286] Figure 9 Binding curve of compound L32-LANCL2

[0287] Figure 10 Binding curve of compound L37-LANCL2

[0288] Figure 11 Binding curve of compound L44-LANCL2

[0289] Figure 12 Binding curve of compound L56-LANCL2

[0290] Figure 13 The data includes changes in mouse body weight and DAI scores (compound L30, compound L56, and control group). A) Body weight change data curve; B) DAI score data.

[0291] Figure 14 The changes in the colon weight-to-length ratio in mice (compound L30, compound L56, and control group) are shown, where A) colon weight-to-length ratio, B) colon length, and C) colon weight.

[0292] Figure 15 Intestinal morphology (compound L30, compound L56, and control group)

[0293] Figure 16 The study included changes in mouse body weight and DAI scores (compounds L11, L25, L84, L77, L101, L10, L23, and the control group). A) Body weight change data curves; B) DAI score data.

[0294] Figure 17Diarrhea and bloody stool were scored in mice (compounds L11, L25, L84, L77, L101, L10, L23, and the control group), where A) changes in diarrhea and B) changes in bloody stool were scored.

[0295] Figure 18 The changes in the colon weight-to-length ratio in mice (compound L11, compound L25, compound L10, and control group) are shown, where A) colon length, B) colon weight, and C) colon weight-to-length ratio.

[0296] Figure 19 Intestinal morphology (compound L11, compound L10, and control group) Detailed Implementation

[0297] The present invention is further illustrated below by way of embodiments, but the invention is not limited to the scope of the embodiments described herein. Experimental methods in the following embodiments that do not specify specific conditions were performed according to conventional methods and conditions, or as selected according to the product instructions.

[0298] Example 1: 6-(1H-benzo[d]imidazol-2-yl)-N-(3-(3-(3-(imidazoliumazo[1,2-a]pyridin-2-yl)benzoyl)-3-azabicyclo[3.1.0]hexane-6-yl)pyridineamide (L-1)

[0299]

[0300] I. Synthesis of methyl 3-(imidazo[1,2-a]pyridin-2-yl)benzoate

[0301]

[0302] At room temperature, 2-aminopyridine (1.6 g, 17 mmol), methyl 3-acetylcarbamate (2.3 g, 14 mmol), and cuprous iodide (0.5 g, 2.8 mmol) were dissolved in 50 mL of 1,4-dioxane. The reaction mixture was heated to reflux overnight, and the reaction was monitored by LC-MS until completion. After concentration under reduced pressure, 50 mL of water was added, and the mixture was extracted with ethyl acetate (50 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography (eluent: petroleum ether / ethyl acetate = 5 / 1) to give a white solid (1.8 g, 7.4 mmol), in 52% yield. LC-MS: [M+1] + 253.09

[0303] II. Synthesis of 3-(imidazo[1,2-a]pyridin-2-yl)benzoic acid

[0304]

[0305] At room temperature, methyl 3-(imidazo[1,2-a]pyridin-2-yl)benzoate (1.8 g, 7.4 mmol) and lithium hydroxide (0.88 g, 37 mmol) were dissolved in 20 mL of ethanol and water (v / v = 10:1). The mixture was heated to reflux, and the reaction was monitored by LC-MS until completion. The reaction solution was concentrated under reduced pressure, and the concentrate was purified by silica gel column chromatography to give a white solid (1.6 g, 0.67 mmol), in 90% yield. LC-MS: 238.07.

[0306] III. Synthesis of N,N'-(1,2-aniline)bis(3-(imidazo[1,2-a]pyridin-2-yl)benzamide

[0307]

[0308] Under ice bath conditions, 3-(imidazo[1,2-a]pyridin-2-yl)benzoic acid (0.12 g, 0.5 mmol), 1-(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) were dissolved in 6 mL of N,N-dimethylformamide. After stirring for 0.5 h, o-phenylenediamine (0.024 g, 0.228 mmol) was added, and stirring was continued for another 0.5 h. The mixture was then allowed to return to room temperature and reacted overnight. The reaction mixture was poured into 20 mL of water and extracted with ethyl acetate (20 mL x 3). The extract was washed with saturated brine, and the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated by silica gel column chromatography (DCM:MeOH = 20:1) to give an off-white solid (15 mg, 2.7 μmol), yield 5.4%. LC-MS: m / z: (M+H)+ = 549.

[0309] 1 H NMR (400MHz, Chloroform-d) δ9.42 (s, 2H), 8.54 (t, J = 1.8Hz, 2H), 8.27 (m, 2H), 8. 04(m,4H),7.93–7.87(m,2H),7.66–7.56(m,6H),7.20–7.08(m,4H),6.73(m,2H).

[0310] Example 2 6-(1H-benzo[d]imidazol-2-yl)-N-(3-(3-(3-(imidazoliumazo[1,2-a]pyridin-2-yl)benzoyl)-3-azabicyclo[3.1.0]hexane-6-yl)pyridineamide (L-2)

[0311]

[0312] Under ice bath conditions, 3-(imidazo[1,2-a]pyridin-2-yl)benzoic acid (0.12 g, 0.5 mmol), 1-(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) were dissolved in 6 mL of N,N-dimethylformamide. After stirring for 0.5 h, 6-(1H-benzo[d]imidazo-2-yl)-N-(3-azabicyclo[3.1.0]hexane-6-yl)pyridine amide (0.16 g, 0.5 mmol) was added. After stirring for another 0.5 h, the mixture was allowed to return to room temperature and reacted overnight. The reaction mixture was poured into 20 mL of water and extracted with ethyl acetate (20 mL x 3). The extract was washed with saturated brine, and the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated by silica gel column chromatography (DCM:MeOH = 20:1) to give an off-white solid (20 mg, 37 μmol), yield 7.4%. LC-MS m / z: (M+H)+ = 540.

[0313] 1 H NMR(400MHz,Chloroform-d)δ14.50(s,1H),8.91(s,1H),8.60(dd,J=7.9,1.1Hz,1H),8.25(d,J= 6.8Hz,1H),8.19(dd,J=7.7,1.0Hz,1H),8.09–7.98(m,3H),7.91(q,J=8.0Hz,2H),7.59(d,J=9.1 Hz,1H),7.50(t,J=7.7Hz,1H),7.42–7.36(m,1H),7.26–7.12(m,4H),6.88(m,1H),3.98(d,J=12. 3Hz,1H),3.39(d,J=11.6Hz,2H),3.19(d,J=12.8Hz,1H),1.79(s,1H),1.33(s,1H),1.06(s,1H).

[0314] Example 3: (9-(3-(1h-benzo[d]imidazol-2-yl)benzoyl)-3,9-diazaspiro[5.5]undecane-3-yl)(3-(imidazol[1,2-a]pyridin-2-yl)phenyl)methyl ketone (L-3)

[0315]

[0316] Under ice bath conditions, 3-(imidazo[1,2-a]pyridin-2-yl)benzoic acid (0.12 g, 0.5 mmol), 1-(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) were dissolved in 6 mL of N,N-dimethylformamide. After stirring for 0.5 h, 6-(1H-benzo[d]imidazo-2-yl)-N-(3-azabicyclo[3.1.0]hexane-6-yl)pyridine amide (0.18 g, 0.5 mmol) was added. After stirring for another 0.5 h, the mixture was allowed to return to room temperature and reacted overnight. The reaction mixture was poured into 20 mL of water and extracted with ethyl acetate (20 mL x 3). The extract was washed with saturated brine, and the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated by silica gel column chromatography under reduced pressure (DCM:MeOH = 20:1) to give an off-white solid (30 mg, 50 μmol), yield 10%. LC-MS m / z: (M+H)+ = 596.

[0317] 1 H NMR(400MHz,Chloroform-d)δ10.53(s,1H),8.49(dd,J=7.9,1.1Hz,1H),8.15(m,1H),8.06–7.94(m,3H),7.89(d,J=14.0Hz,2H),7.65( d,J=9.1Hz,1H),7.60(m,1H),7.51(m,2H),7.35(m,3H),7.21(m,1H),6.82(m,1H),3.84(s,4H),3.52(s,4H),1.74(s,4H),1.58(s,4H).

[0318] Example 4 (1S,4S)-5-(6-(1H-benzo[d]imidazol-2-yl)pyridyl)-2,5-diazabicyclo[2.2.1]heptane-2-yl)(3-(imidazolium azo[1,2-a]pyridin-2-yl)phenyl)methyl ketone (L-4)

[0319]

[0320] Under ice bath conditions, 3-(imidazo[1,2-a]pyridin-2-yl)benzoic acid (0.12 g, 0.5 mmol), 1-(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) were dissolved in 6 mL of N,N-dimethylformamide. After stirring for 0.5 h, (6-(1H-benzo[d]imidazo-2-yl)pyridin-2-yl)(1S,4S)-2,5-diazabicyclo[2.2.1]hept-2-yl)methyl ketone (0.18 g, 0.5 mmol) was added. After stirring for another 0.5 h, the mixture was allowed to return to room temperature and reacted overnight. The reaction mixture was poured into 20 mL of water and extracted with ethyl acetate (20 mL x 3). The extract was washed with saturated brine, and the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated by silica gel column chromatography (DCM:MeOH = 20:1) to give an off-white solid (25 mg, 46 μmol), yield 9%. LC-MS m / z: (M+H)+ = 540.

[0321] 1 H NMR(400MHz,Chloroform-d)δ10.80(d,J=23.5Hz,1H),8.57(d,J=7.3Hz,1H),8.21–8.09(m,2H),8.02(m,3H),7.91(d,J=10.4Hz,2H ),7.73–7.62(m,2H),7.56(m,3H),7.37(s,1H),7.16(s,1H),6.85–6.75(m,1H),4.85–4.61(m,2H),4.08–3.74(m,4H),2.03(s,2H).

[0322] Example 5: N-(1-(6-(1H-benzo[d]imidazol-2-yl)pyridyl)piperidin-4-yl)-3-(imidazol[1,2-a]pyridin-2-yl)benzamide (L-5)

[0323]

[0324] I. Synthesis of tert-butyl (1-(6-(1H-benzo[d]imidazol-2-yl)pyridinyl)piperidin-4-yl)carbamate

[0325]

[0326] Under ice bath conditions, 6-(1H-benzo[d]imidazol-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 20 mL of N,N-dimethylformamide. After stirring for 0.5 h, tert-butylpiperidin-4-ylcarbamate (0.92 g, 4.6 mmol) was added, and stirring was continued for another 0.5 h. The mixture was then allowed to react overnight at room temperature. The reaction solution was poured into 80 mL of water and extracted with ethyl acetate (80 mL x 3). The extract was washed with saturated brine, and the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated by silica gel column chromatography (PE:EA = 5:1) to give an off-white solid (1.3 g, 3 mmol), in 73% yield. LC-MS m / z:(M+H)+=421.

[0327] II. Synthesis of 6-(1H-benzo[d]imidazol-2-yl)pyridin-2-yl)(4-aminopiperidin-1-yl)methyl ketone

[0328]

[0329] 1.3 g (3 mmol) of tert-butyl(1-(6-(1H-benzo[d]imidazol-2-yl)pyridinyl)piperidin-4-yl)carbamate was dissolved in 20 mL of dichloromethane under ice bath conditions. A saturated hydrochloric acid solution of 1,4-dioxane (2 mL, 8 mmol) was added, and the mixture was stirred for 0.5 hours. The reaction mixture was then allowed to return to room temperature and reacted overnight. The reaction solution was concentrated under reduced pressure, and the resulting solid was used directly in the next reaction step. Yield >90%. LC-MS: 321 [M+1] +

[0330] Synthesis of N-(1-(6-(1H-benzo[d]imidazol-2-yl)pyridyl)piperidin-4-yl)-3-(imidazol[1,2-a]pyridin-2-yl)benzamide

[0331]

[0332] 3. Under ice bath conditions, 3-(imidazo[1,2-a]pyridin-2-yl)benzoic acid (0.12 g, 0.5 mmol), 1-(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) were dissolved in 6 mL of N,N-dimethylformamide. After stirring for 0.5 h, (6-(1H-benzo[d]imidazo-2-yl)pyridin-2-yl)(4-aminopiperidin-1-yl)methyl ketone (0.18 g, 0.5 mmol) was added. After stirring for another 0.5 h, the mixture was allowed to return to room temperature and reacted overnight. The reaction mixture was poured into 20 mL of water and extracted with ethyl acetate (20 mL x 3). The extract was washed with saturated brine, and the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated by silica gel column chromatography (DCM:MeOH = 20:1) to give an off-white solid (15 mg, 27 μmol), yield 5.5%. LC-MS m / z: (M+H)+ = 542.

[0333] 1 H NMR(400MHz,Chloroform-d)δ11.87(s,1H),8.56(dd,J=7.9,1.1Hz,1H),8.40(t,J=1.7Hz,1H),8.21(m,1H), 8.07–7.94(m,3H),7.90–7.80(m,2H),7.69(d,J=9.1Hz,1H),7.61(dd,J=7.7,1.1Hz,1H),7.48(m,2H),7.28– 7.17(m,3H),6.87(m,1H),6.25(d,J=7.9Hz,1H),4.68(d,J=13.7Hz,1H),4.25(dd,J=7.7,3.9Hz,1H),3.85(d ,J=13.9Hz,1H),3.19(t,J=12.6Hz,1H),3.02–2.91(m,1H),2.12(s,1H),1.92(d,J=12.8Hz,2H),1.61(m,1H).

[0334] Example 6 6-(1H-benzo[d]imidazol-2-yl)-N-(1-(3-(imidazol[1,2-a]pyridin-2-yl)benzoyl)pyrrolidine-3-yl)pyridineamide (L-6)

[0335]

[0336] Under ice bath conditions, 3-(imidazo[1,2-a]pyridin-2-yl)benzoic acid (0.12 g, 0.5 mmol), 1-(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) were dissolved in 6 mL of N,N-dimethylformamide. After stirring for 0.5 h, 6-(1H-benzo[d]imidazo-2-yl)-N-(pyrrolidine-3-yl)pyridineamide (0.14 g, 0.5 mmol) was added, and stirring was continued for another 0.5 h. The mixture was then allowed to return 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). The mixture was washed with saturated brine, and the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated by silica gel column chromatography (DCM:MeOH = 20:1) to give an off-white solid (18 mg, 34 μmol), yield 5.5%.

[0337] LC-MS m / z:(M+H)+=528, 1 H NMR(400MHz,Chloroform-d)δ8.64–8.44(m,2H),8.08(d,J=6.9Hz,1H),8.02–7.67(m,7H),7.62–7.44(m,3H),7.28–7.11(m ,4H),6.83(t,J=6.6Hz,1H),5.40–5.34(m,1H),4.92(d,J=17.1Hz,1H),4.69–4.61(m,1H),4.09(m,1H),4.02–3.72(m,3H).

[0338] Example 7 N,N'-(1,2-phenylene)bis(6-(1H-benzo[d]imidazol-2-yl)pyridinelinamide)(L-7)

[0339]

[0340] I. Synthesis of 6-(1H-benzo[d]imidazol-2-yl)pyridinecarboxylic acid

[0341]

[0342] 5 g of pyridine-2,6-dicarboxylic acid (21.919 mmol) was added to a propylene glycol solution of o-phenyldiamine (3.5 g, 32 mmol) in 100 mL. The resulting mixture was heated under reflux for 24 h and then cooled to room temperature. 50 mL of ice water was added to the reaction mixture, and stirring was performed to precipitate a brown solid. The precipitate was collected and dissolved in hot methanol, and the solution was filtered through activated carbon. The solvent was removed by slow evaporation of the filtrate to give 6-(1H-benzimidazole-2-)pyridinecarboxylic acid. Yield: 52%. LC-MS: [M+1] + 240.1

[0343] II. Synthesis of N,N'-(1,2-phenylene)bis(6-(1H-benzo[d]imidazol-2-yl)pyridinium amide)

[0344]

[0345] Under ice bath conditions, 6-(1H-benzimidazole-2-)pyridinecarboxylic acid (0.12 g, 0.5 mmol), 1-(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) were dissolved in 6 mL of N,N-dimethylformamide. After stirring for 0.5 h, o-phenylenediamine (0.024 g, 0.228 mmol) was added, and stirring was continued for another 0.5 h. The mixture was then allowed to return 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). The extract was washed with saturated brine, and the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated by silica gel column chromatography (DCM:MeOH = 20:1) to give an off-white solid (30 mg, 5.4 μmol), yield 11%. LC-MS:m / z:(M+H)+=550.98, 1 H NMR (400MHz, DMSO) δ12.58 (s, 2H), 11.01 (s, 2H), 8.20 (d, J = 7.3Hz, 2H), 8.07–7.80 (m, 6H) ,7.67–7.53(m,2H),7.43(dd,J=5.7,3.6Hz,2H),7.25–7.09(m,4H),7.03(d,J=5.5Hz,2H).

[0346] Example 8 N,N'-(cyclohexane-1,2-diyl)bis(6-(1H-benzo[d]imidazol-2-yl)pyridinelinamide)(L-8)

[0347]

[0348] N,N'-(cyclohexane-1,2-diyl)bis(6-(1H-benzo[d]imidazol-2-yl)pyridinamide)

[0349] The procedure was the same as for L-7; cyclohexane-1,2-diamine was purchased from Sinopharm Reagent Center.

[0350] LC-MS:m / z:(M+H)+=557.26, 1 H NMR (400MHz, CDCl3) δ8.83(s,2H),8.42(d,J=7.8Hz,2H),8.03(d,J=7.7Hz,2H),7.79(t,J=7.8Hz,6 H),7.32(dd,J=5.8,3.1Hz,2H),4.13(d,J=16.6Hz,2H),2.35(d,J=11.4Hz,2H),1.94–1.37(m,6H).

[0351] Example 9 (3,9-diazaspiro[5.5]undecane-3,9-diyl)bis((6-(1H-benzo[d]imidazol-2-yl)pyridin-2-yl)methyl ketone)(L-9)

[0352]

[0353] I. Synthesis of tert-butyl 9-(6-(1H-benzo[d]imidazol-2-yl)pyridinyl)-3,9-diazaspiro[5.5]undecane-3-carboxylic acid

[0354]

[0355] Under ice bath conditions, 6-(1H-benzimidazole-2-)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 20 mL of N,N-dimethylformamide. After stirring for 0.5 h, 3,9-diazaspiro[5.5]undecane-3-carboxylic acid tert-butyl ester (0.92 g, 4.6 mmol) was added, and stirring was continued for another 0.5 h. The mixture was then allowed to return to room temperature and reacted overnight. The reaction mixture was poured into 80 mL of water and extracted with ethyl acetate (80 mL x 3). The extract was washed with saturated brine, and the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated by silica gel column chromatography under reduced pressure (PE:EA = 5:1) to give an off-white solid (1.3 g, 3 mmol), yield 73%. LC-MS m / z: (M+H)+ = 476.

[0356] II. Synthesis of (6-(1H-benzo[d]imidazol-2-yl)pyridin-2-yl)(3,9-diazaspiro[5.5]undecane-3-yl)methyl ketone

[0357]

[0358] 9-(6-(1H-benzo[d]imidazol-2-yl)pyridinyl)-3,9-diazaspiro[5.5]undecane-3-carboxylic acid tert-butyl ester (1.3 g, 3 mmol) was dissolved in 20 mL of dichloromethane under ice bath conditions. A saturated hydrochloric acid solution of 1,4-dioxane (2 mL, 8 mmol) was added, and the mixture was stirred for 0.5 hours. The reaction mixture was then allowed to return to room temperature and reacted overnight. The reaction solution was concentrated under reduced pressure, and the resulting solid was used directly in the next reaction step. Yield >90%. LC-MS: 376 [M+1] + .

[0359] III. Synthesis of (3,9-diazaspiro[5.5]undecane-3,9-diyl)bis((6-(1H-benzis[d]imidazol-2-yl)pyridin-2-yl)methyl ketone)

[0360]

[0361] Under ice bath conditions, 6-(1H-benzimidazol-2-)pyridinecarboxylic acid (0.14 g, 0.27 mmol) and N,N-diisopropylethylamine (0.12 g, 1.0 mmol) were dissolved in 6 mL of N,N-dimethylformamide. After stirring for 0.5 h, (6-(1H-benzimidazol-2-yl)pyridin-2-yl)(3,9-diazaspiro[5.5]undecane-3-yl)methyl ketone (0.089 g, 0.27 mmol) was added, and stirring was continued for another 0.5 h. The mixture was then allowed to react overnight at room temperature. The reaction mixture was poured into 20 mL of water and extracted with ethyl acetate (20 mL x 3). The extract was washed with saturated brine, and the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated by silica gel column chromatography (DCM:MeOH = 20:1) to give an off-white solid (20 mg, 38 μmol), with a yield of 14.3%.

[0362] LC-MS:m / z:(M+H)+=598.1, 1 H NMR (400MHz, CDCl3) δ10.70 (s, 2H), 8.49 (d, J = 7.9Hz, 2H), 7.93 (dd, J = 25.5, 17.6Hz, 4H), 7 .56(t,J=8.1Hz,5H),7.38–7.30(m,5H),3.84(s,3H),3.51(s,5H),1.65(d,J=67.9Hz,8H).

[0363] Example 10 (Tetrahydropyrrolo[3,4-c]pyrrole-2,5(1H,3H)-diyl)bis((6-(1H-benzo[d]imidazol-2-yl]pyridin-2-yl)methyl ketone)(L-10)

[0364]

[0365] I. Synthesis of tert-butyl 5-(6-(1H-benzo[d]imidazol-2-yl)pyridinyl)tert-hydropyrrolo[3,4-c]pyrrolo-2(1H)-carboxylic acid

[0366]

[0367] Under ice bath conditions, 6-(1H-benzimidazole-2-)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 20 mL of N,N-dimethylformamide. After stirring for 0.5 h, tert-butylhexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (0.92 g, 4.6 mmol) was added, and stirring was continued for another 0.5 h. The mixture was then allowed to return to room temperature and reacted overnight. The reaction mixture was poured into 80 mL of water and extracted with ethyl acetate (80 mL x 3). The extract was washed with saturated brine, and the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated by silica gel column chromatography under reduced pressure (PE:EA = 5:1) to give an off-white solid (1.3 g, 3 mmol), yield 73%. LC-MS m / z:(M+H)+ = 434.

[0368] II. Synthesis of (6-(1H-benzo[d]imidazol-2-yl)pyridin-2-yl)(hexahydropyrrolo[3,4-c]pyrrolo-2(1H)-yl) methyl ketone

[0369]

[0370] 1.3 g (3 mmol) of 5-(6-(1H-benzo[d]imidazol-2-yl)pyridinyl)tert-hydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylic acid tert-butyl ester was dissolved in 20 mL of dichloromethane under ice bath conditions. A saturated hydrochloric acid solution of 1,4-dioxane (2 mL, 8 mmol) was added, and the mixture was stirred for 0.5 hours. The reaction mixture was then allowed to return to room temperature overnight. The reaction solution was concentrated under reduced pressure, and the resulting solid was used directly in the next reaction step. Yield >90%. LC-MS m / z: (M+H)+ = 334.

[0371] III. Synthesis of (tetrahydropyrrolo[3,4-c]pyrrolo-2,5(1H,3H)-diyl)bis((6-(1H-benzo[d]imidazol-2-yl]pyridin-2-yl)methyl ketone)

[0372]

[0373] Operation is the same as L-9

[0374] (tetrahydropyrrolo[3,4-c]pyrrole-2,5(1H,3H)-diyl)bis((6-(1H-benzo[d]imidazol-2-yl]pyridin-2-yl)methyl ketone)

[0375] LC-MS:m / z:(M+H)+=555.61, 1 H NMR (400MHz, MeOD) δ8.49–8.29(m,3H),8.23–8.04(m,3H),8.03–7.93(m,1H),7.86(dd,J=7.0,5.6Hz,1H),7.71(dd,J=6.0,3.1Hz,1H),7.6 4–7.54(m,2H),7.50(dd,J=8.1,5.7Hz,2H),7.41–7.28(m,2H),7.26–7.17(m,1H),7.01–6.87(m,1H),4.23–3.55(m,8H),3.27–3.04(m,2H).

[0376] Example 11 N-(3-(6-(1H-benzo[d]imidazol-2-yl)pyridinyl)-3-azabicyclo[3.1.0]hex-6-yl)-6-(1H-benzo[d]imidazol-2-yl)pyridinecarboxamide (L-11)

[0377]

[0378] I. Synthesis of tert-butyl(3-(6-(1H-benzo[d]imidazol-2-yl)pyridinyl)-3-azabicyclo[3.1.0]hexyl-6-yl)carbamate

[0379]

[0380] Under ice bath conditions, 6-(1H-benzimidazole-2-)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 20 mL of N,N-dimethylformamide. After stirring for 0.5 h, tert-butyl (3-azabicyclo[3.1.0]hex-6-yl)carbamate (0.92 g, 4.6 mmol) was added, and stirring was continued for another 0.5 h. The mixture was then allowed to return to room temperature and reacted overnight. The reaction mixture was poured into 80 mL of water and extracted with ethyl acetate (80 mL x 3). The extract was washed with saturated brine, and the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated by silica gel column chromatography under reduced pressure (PE:EA = 5:1) to give an off-white solid (1.3 g, 3 mmol), yield 73%. LC-MS m / z:(M+H)+ = 421.

[0381] II. Synthesis of (6-(1H-benzo[d]imidazol-2-yl)pyridin-2-yl)(6-amino-3-azabicyclo[3.1.0]hex-3-yl) ketone

[0382]

[0383] Under ice bath conditions, tert-butyl(3-(6-(1H-benzo[d]imidazol-2-yl)pyridinyl)-3-azabicyclo[3.1.0]hexyl-6-yl)carbamate (1.3 g, 3 mmol) was dissolved in 20 mL of dichloromethane. A saturated hydrochloric acid solution of 1,4-dioxane (2 mL, 8 mmol) was added, and the mixture was stirred for 0.5 hours. The reaction mixture was then allowed to return to room temperature and reacted overnight. The reaction solution was concentrated under reduced pressure, and the resulting solid was used directly in the next reaction step. Yield >90%. LC-MS m / z: (M+H)+=321.

[0384] III. Synthesis of N-(3-(6-(1H-benzo[d]imidazol-2-yl)pyridinyl)-3-azabicyclo[3.1.0]hexyl-6-yl)-6-(1H-benzo[d]imidazol-2-yl)pyridinecarboxamide

[0385]

[0386] Operation is the same as L-9

[0387] LC-MS:m / z:(M+H)+=541.20, 1H NMR (400MHz, CDCl3) δ13.25(s,1H),12.09(s,1H),8.68(s,1H),8.48(d,J=7 .6Hz,1H),8.26(d,J=7.6Hz,1H),8.01(d,J=7.5Hz,1H),7.81(t,J=7.8Hz,4H ),7.50(dt,J=20.7,5.8Hz,3H),7.38–7.30(m,4H),4.58(d,J=11.3Hz,1H),4 .45–4.22(m,2H),3.64–3.43(m,3H),2.63(s,1H),2.00(s,9H),1.60(s,2H).

[0388] Example 12 (2,5-diazabicyclo[2.2.1]heptane-2,5-diyl)bis((6-(1H-benzo[d]imidazol-2-yl)pyridin-2-yl)methyl ketone)(L-12)

[0389]

[0390] (2,5-diazabicyclo[2.2.1]heptane-2,5-diyl)bis((6-(1H-benzo[d]imidazol-2-yl)pyridin-2-yl)methyl ketone)

[0391] Operation is the same as L-7

[0392] LC-MS:m / z:(M+H)+=541.59, 1 H NMR (400MHz, CDCl3) δ12.67(s,1H),8.13–7.82(m,4H),7.54–7.33(m,4H),7.26(d,J= 7.6Hz, 2H), 4.54 (d, J = 11.9Hz, 3H), 4.04 (t, J = 15.9Hz, 3H), 1.85 (s, 1H), 1.77 (s, 1H).

[0393] Example 13 N,N'-(1,2-phenylene)bis(2-morpholinylpyrimidine-4-carboxamide) (L-13)

[0394]

[0395] I. Synthesis of 2-morpholinopyrimidine-4-carboxylic acid

[0396] 2-Chloroprene-4-carboxylic acid (500 mg, 3.15 mmol) was dissolved in 15 mL of tetrahydrofuran and 15 mL of dioxane, and 2 mL of morpholine was added. The reaction mixture was stirred at 70 °C for 18 hours. The reaction mixture was cooled to room temperature and filtered. The solid was dissolved in 20 mL of water and acidified to pH 1 with 1 N hydrochloric acid. The solution was extracted with dichloromethane / methanol at a ratio of 10:1 (20 mL * 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated to give 580 mg of a white solid, with a yield of 87.9%. LC-MS: m / z: (M+H) + =210.0.

[0397] 1H NMR (400MHz, CD3OD) δ8.57(d,J=4.8Hz,1H),7.20(d,J=4.8Hz,1H),3.93–3.83(m,4H),3.76(m,4H).

[0398] II. Synthesis of N,N'-(1,2-phenylene)bis(2-morpholinylpyrimidine-4-carboxamide)

[0399] 2-Morpholinylpyrimidine-4-carboxylic acid (100 mg, 0.48 mmol) (the compound shown in Formula 3) was suspended in 2 mL of N,N-dimethylformamide, and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (137 mg, 0.72 mmol), 1-hydroxybenzotriazole (97 mg, 0.72 mmol), and N,N-diisopropylethylamine (185 mg, 1.4340 mmol) were added. After stirring the reaction mixture for 20 min, o-phenylenediamine (25.8 mg, 0.24 mmol) was added, and the reaction mixture was stirred at 15 °C for 16 h. 10 mL of water was added to the reaction mixture, and the mixture was extracted with ethyl acetate (10 mL * 2). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated to give the crude product. The crude product was purified by thin-layer chromatography (dichloromethane:methanol = 10:1). The product was then slurried with a mixture of dimethyl sulfoxide (3 mL) and methanol (2 mL), filtered, and the solid was washed with methanol and dried to obtain 23 mg of the desired product as a white solid, with a yield of 9.81%.

[0400] LC-MS:m / z:(M+H)+=491.0, 1 H NMR (400MHz, DMSO-d6) δ10.46(s,2H),8.70(d,J=4.8Hz,2H),7.78(dd,J=6.0,3.6Hz,2H),7 .36(dd,J=6.0,3.6Hz,2H),7.26(d,J=4.8Hz,2H),3.90–3.69(m,4H),3.60(d,J=4.4Hz,4H).

[0401] Example 14 N-(3-(6-(1H-benzo[d]imidazol-2-yl]pyridinyl)-3-azabicyclo[3.1.0]hexyl-6-yl)-2-morpholinylpyrimidine-4-carboxamide (L-14)

[0402]

[0403] N-(3-(6-(1H-benzo[d]imidazol-2-yl]pyridinyl)-3-azabicyclo[3.1.0]hexyl-6-yl)-2-morpholinylpyrimidine-4-carboxamide

[0404] 2-Morpholinylpyrimidine-4-carboxylic acid (100 mg, 0.48 mmol) (the compound shown in Formula 3) was suspended in 2 mL of N,N-dimethylformamide, and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (137 mg, 0.72 mmol), 1-hydroxybenzotriazole (97 mg, 0.72 mmol), and N,N-diisopropylethylamine (185 mg, 1.4340 mmol) were added. After stirring the reaction solution for 20 min, (6-amino-3-azabicyclo[3.1.0]hex-3-yl)-[6-(1H-benzimidazol-2-yl)-2-pyridyl]methyl ketone (76 mg, 0.24 mmol) was added, and the reaction solution was stirred at 15 °C for 16 h. 10 mL of water was added to the reaction solution, and the mixture was extracted with ethyl acetate (10 mL * 2). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated to give the crude product. The crude product was purified by thin-layer chromatography (dichloromethane:methanol = 10:1) to obtain 38 mg of the desired product as a white solid, with a yield of 31.14%.

[0405] LC-MS:m / z:(M+H)+=511.0, 1 H NMR (400MHz, DMSO-d6) δ8.75(s,1H),8.61(d,J=7.8Hz,1H),8.35(d,J=4.8Hz,1H),8.22(t, J=13.6Hz,1H),7.99(t,J=7.8Hz,1H),7.63(s,2H),7.31(dd,J=6.6,3.5Hz,1H),6.78(d,J= 4.8Hz,1H),4.33(d,J=12.5Hz,1H),4.20–4.10(m,2H),3.98(dd,J=11.8,4.4Hz,1H),3.72( dd,J=12.9,4.8Hz,9H),2.56(d,J=2.1Hz,1H),2.12(d,J=2.5Hz,1H),2.04(d,J=4.7Hz,1H).

[0406] Example 15 9-(6-(1-H-benzo[d]imidazol-2-yl)pyridinyl)-3,9-diazaspiro[5.5]undecane-3-yl)(2-morpholinopyrimidin-4-yl) methyl ketone (L-15)

[0407]

[0408] (9-(6-(1-H-benzo[d]imidazol-2-yl)pyridinyl)-3,9-diazaspiro[5.5]undecane-3-yl)(2-morpholinopyrimidin-4-yl)methyl ketone

[0409] Operation is the same as L-14

[0410] LC-MS:m / z:(M+H)+=567.0, 1 H NMR (400MHz, CD3OD) δ8.53(d,J=7.8Hz,1H),8.44(d,J=4.8Hz,1H),7.97(t,J=7.8Hz,1H),7.73(s,2H),7.59(dd,J=7.7,0.9Hz, 1H),7.39–7.31(m,2H),6.70(d,J=4.8Hz,1H),3.90-3.76(m,12H),3.51(d,J=6.9Hz,4H),1.75-1.69(m,4H),1.59-1.57(m,4H).

[0411] Example 16 (5-(6-(1-(1-H-benzo[d]imidazol-2-yl]pyridinyl)hexahydropyrrolo[3,4-c]pyrrolo-2(1H)-yl)(2-morpholinopyrimidin-4-yl)methyl ketone (L-16)

[0412]

[0413] (5-(6-(1-(1-H-benzo[d]imidazol-2-yl]pyridinyl)hexahydropyrrolo[3,4-c]pyrrolo-2(1H)-yl)(2-morpholinopyrimidin-4-yl)methyl ketone

[0414] Operation is the same as L-14

[0415] LC-MS:m / z:(M+H)+=525.0, 1H NMR (400MHz, CDCl3) δ8.60–8.37(m,2H),8.00(dd,J=17.8,9.9Hz,1H),7.81(ddd,J=14.2,8.7,2.6Hz,2H),7.65(d ,J=4.6Hz,1H),7.33(dd,J=6.0,3.1Hz,2H),6.97(dd,J=10.5,4.8Hz,1H),4.25–3.56(m,16H),3.21–2.81(m,2H).

[0416] Example 17 N,N'-(cyclohexane-1,2-diyl)bis(2-morpholinylpyrimidine-4-carboxamide) (L-17)

[0417]

[0418] N,N'-(cyclohexane-1,2-diyl)bis(2-morpholinylpyrimidine-4-carboxamide)

[0419] Operation is the same as L-7

[0420] LC-MS:m / z:(M+H)+=497.0, 1 H NMR(400MHz,CD3OD)δ8.48(d,J=4.8Hz,2H),8.14–7.99(m,2H),7.18(d,J=4.8Hz,2H),3. 96(s,2H),3.82–3.80(m,16H),2.24(d,J=6.8Hz,2H),1.85(s,2H),1.45(d,J=5.2Hz,4H).

[0421] Example 18 (5-(6-(1H-benzo[d]imidazol-2-yl)pyridinyl)-2,5-diazabicyclo[2.2.1]hept-2-yl)(2-morpholinopyrimidin-4-yl) methyl ketone (L-18)

[0422]

[0423] (5-(6-(1H-benzo[d]imidazol-2-yl)pyridinyl)-2,5-diazabicyclo[2.2.1]hept-2-yl)(2-morpholinopyrimidin-4-yl)methyl ketone

[0424] Operation is the same as L-14

[0425] LC-MS:m / z:(M+H)+=511.0, 1H NMR (400MHz, CDCl3) δ8.67–8.41(m,2H),8.06–7.87(m,4H),7.38–7.35(m,2H) ,7.19–6.98(m,1H),5.33–5.00(m,2H),4.20–3.41(m,12H),2.11–1.98(m,2H).

[0426] Example 19 (N-(1-(1-(6-(1H-benzo[d]imidazol-2-yl]pyridinyl]piperidin-4-yl)-2-(phenylamino)pyrimidine-4-carboxamide (L-19)

[0427]

[0428] I. 2-(phenylamino)pyrimidine-4-carboxylic acid

[0429] 2-Chloropremine-4-carboxylic acid (500 mg, 3.15 mmol) was dissolved in 15 mL of dioxane, and aniline (881 mg, 9.46 mmol) was added. The reaction mixture was stirred at 70 °C for 18 hours. The reaction mixture was cooled to room temperature, and 20 mL of water and 10 mL of 1 N sodium hydroxide were added. The reaction mixture was extracted twice with ethyl acetate (20 mL * 2). The aqueous phase was acidified to pH 3 with 1 N hydrochloric acid. The solid was filtered and dried to give 500 mg of a white solid, with a yield of 73.67%. LC-MS: m / z: (M+H)+ = 216.0.

[0430] II. Synthesis of tert-butyl (1-(6-(1H-benzo[d]imidazol-2-yl)pyridinyl)piperidin-4-yl)carbamate

[0431]

[0432] Under ice bath conditions, 6-(1H-benzimidazole-2-)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 20 mL of N,N-dimethylformamide. After stirring for 0.5 h, piperidin-4-ylcarbamate tert-butyl ester (0.92 g, 4.6 mmol) was added, and stirring was continued for another 0.5 h. The mixture was then allowed to react overnight at room temperature. The reaction solution was poured into 80 mL of water and extracted with ethyl acetate (80 mL x 3). The extract was washed with saturated brine, and the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated by silica gel column chromatography (PE:EA = 5:1) to give an off-white solid (1.3 g, 3 mmol), in 73% yield. LC-MS m / z:(M+H)+=421.

[0433] III. Synthesis of (6-(1H-benzo[d]imidazol-2-yl)pyridin-2-yl)(4-aminopiperidin-1-yl)methyl ketone

[0434]

[0435] 1.3 g (3 mmol) of tert-butyl(1-(6-(1H-benzo[d]imidazol-2-yl)pyridinyl)piperidin-4-yl)carbamate was dissolved in 20 mL of dichloromethane under ice bath conditions. A saturated hydrochloric acid solution of 1,4-dioxane (2 mL, 8 mmol) was added, and the mixture was stirred for 0.5 hours. The reaction mixture was then allowed to return to room temperature and reacted overnight. The reaction solution was concentrated under reduced pressure, and the resulting solid was used directly in the next reaction step. Yield >90%. LC-MS: 321 [M+1] + .

[0436] IV. The operation of (N-(1-(1-(6-(1H-benzo[d]imidazol-2-yl]pyridinyl]piperidin-4-yl)-2-(phenylamino)pyrimidine-4-carboxamide is the same as that of L-14.

[0437] LC-MS:m / z:(M+H)+=519.0,1H NMR (400MHz, CD3OD) δ8.64(d,J=4.9Hz,1H),8.40(dd,J=8.0,1.0Hz,1H),8.13(t,J =7.9Hz,1H),7.76–7.58(m,5H),7.40–7.26(m,5H),7.08–6.99(m,1H),4.64(d,J=13 .6Hz,1H),4.27–4.15(m,1H),3.85(d,J=14.1Hz,1H),3.43(dd,J=18.3,7.0Hz,1H), 3.31–3.20(m,1H),2.19(d,J=11.0Hz,1H),2.00(s,1H),1.72-1.79(m,10.0Hz,2H).

[0438] 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)

[0439]

[0440] 1. 3-(1H-benzo[d]imidazol-2-yl)cyclohexane-1-carboxylic acid

[0441] 1,3-Cyclohexanedicarboxylic acid (1 g, 5.8 mmol) and phenylenediamine (628 mg, 5.8 mmol) were dissolved in 10 mL of N,N-dimethylformamide. 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (2.43 g, 6.34 mmol) and N,N-diisopropylethylamine (2.25 g, 17.40 mmol) were added. The reaction mixture was stirred at 15 °C for 16 h. 50 mL of water was added to the reaction mixture, and the mixture was extracted with ethyl acetate (50 mL x 3). The aqueous phase was concentrated to give 3 g of a black oil. The oil was dissolved in 20 mL of acetic acid, stirred at 55 °C for 4 h, and concentrated. Column chromatography purification yielded 1.3 g of the desired product, with a yield of 93%. LC-MS: m / z: (M+H)+=245.0.

[0442] II. (N-(1-(1-(6-(1H-benzo[d]imidazol-2-yl]pyridinyl)piperidin-4-yl]-3-(1H-benzo[d]imidazol-2-yl)cyclohexane-1-carboxamide

[0443] Operation is the same as L-14

[0444] LC-MS:m / z:(M+H)+=519.0,1H NMR (400MHz, CD3OD) δ8.40(d,J=7.9Hz,1H),8.13(t,J=7.8Hz,1H),7.65(dd,J=7.7,0.9Hz,3H),7.54(d,J= 2.5Hz,2H),7.32(dd,J=6.1,3.1Hz,2H),7.27–7.16(m,2H),4.62(d,J=9.1Hz,1H),4.05–3.95(m,1H),3.81 (d,J=13.9Hz,1H),3.50–3.42(m,1H),3.39(s,1H),3.18(dd,J=15.3,9.6Hz,1H),2.64(s,1H),2.43–2.29( m,1H),2.24–2.04(m,3H),1.94(dd,J=13.8,10.6Hz,2H),1.74(dd,J=11.1,5.5Hz,3H),1.66–1.45(m,3H).

[0445] 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)

[0446]

[0447] I. 2-(pyridin-2-ylamino)pyrimidine-4-carboxylic acid

[0448] Pyridine-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 mixture was stirred at 20 °C for 1 h. 2-Chloroprene-4-carboxylic acid (300 mg, 1.89 mmol) was added, and the reaction mixture was stirred at 70 °C for 18 h. The reaction mixture was cooled to room temperature and 20 mL of water was added. The reaction mixture was extracted with dichloromethane (20 mL * 2). The aqueous phase was acidified to pH 5 with 1 N hydrochloric acid and then concentrated. The residue was dissolved in 5 mL of N,N-dimethylformamide and stirred for 10 min. The mixture was filtered and concentrated to give 80 mg of a yellow solid, with a yield of 19.5%. LC-MS: m / z: (M+H)+ = 217.0.

[0449] II. (N-(1-(1-(6-(1H-benzo[d]imidazol-2-yl]pyridinyl)piperidin-4-yl]-2-(pyridin-2-ylamino)pyrimidine-4-carboxamide

[0450] Operation is the same as L-14

[0451] LC-MS:m / z:(M+H)+=520.0, 1 H NMR (400MHz, CDCl3) δ8.74(d,J=4.9Hz,1H),8.50(t,J=9.1Hz,2H),8.36(s,1H),8.27(d,J=4.7Hz,1H),8.04( d,J=8.2Hz,1H),7.95(t,J=7.8Hz,1H),7.84(t,J=7.4Hz,1H),7.65(ddd,J=17.5,9.1,5.3Hz,3H),7.28–7.25( m,1H),7.12–7.01(m,1H),4.68(d,J=13.3Hz,1H),4.37–4.13(m,1H),3.87(d,J=13.5Hz,1H),3.28(t,J=11.8H z,1H),3.14(t,J=11.5Hz,1H),2.15(d,J=11.2Hz,1H),2.01(d,J=10.6Hz,1H),1.79(dd,J=21.2,11.4Hz,2H).

[0452] Example 22 (N-(1-(1-(6-(1H-benzo[d]imidazol-2-yl]pyridinyl)piperidin-4-yl]-2-morpholinylpyrimidine-4-carboxamide (L-22)

[0453]

[0454] (N-(1-(1-(6-(1H-benzo[d]imidazol-2-yl]pyridinyl)piperidin-4-yl]-2-morpholinylpyrimidine-4-carboxamide)

[0455] Operation is the same as L-14

[0456] LC-MS:m / z:(M+H)+=513.0,1H NMR (400MHz, CDCl3) δ8.57(d,J=4.8Hz,1H),8.52(d,J=7.8Hz,1H),7.95(t,J=7.8Hz,1H), 7.75(d,J=8.2Hz,2H),7.63–7.58(m,1H),7.39–7.32(m,3H),4.78(d,J=13.5Hz,1H),4.26( dt,J=10.9,9.5Hz,1H),3.92(d,J=13.9Hz,1H),3.88–3.76(m,8H),3.34(t,J=11.9Hz,1H) ,3.12(t,J=11.6Hz,1H),2.21(d,J=9.7Hz,1H),2.07(d,J=11.7Hz,1H),1.81–1.63(m,2H).

[0457] Example 23 N-(3-(6-(1H-benzo[d]imidazol-2-yl)pyridinyl)-3-azabicyclo[3.1.0]hexyl-6-yl)-2-(phenylamino)pyrimidine-4-carboxamide (L-23)

[0458]

[0459] N-(3-(6-(1H-benzo[d]imidazol-2-yl)pyridinyl)-3-azabicyclo[3.1.0]hexyl-6-yl)-2-(phenylamino)pyrimidine-4-carboxamide

[0460] Operation is the same as L-14

[0461] LC-MS:m / z:(M+H)+=517.0,1H NMR (400MHz, CDCl3) δ8.61–8.52(m,2H),8.48(d,J=4.9Hz,1H),8.24(d,J=6.9Hz,1H),7.98(t,J=7.8Hz,1H ),7.63(d,J=7.7Hz,3H),7.46(s,1H),7.37(t,J=8.0Hz,2H),7.30(d,J=3.2Hz,1H),7.09(t,J=7.4Hz,1H), 6.97(d,J=4.9Hz,1H),4.24(d,J=12.6Hz,1H),4.08(d,J=11.7Hz,1H),3.87(dd,J=11.7,4.4Hz,1H),3.69( dd,J=12.1,4.5Hz,2H),3.14(dt,J=11.7,7.3Hz,1H),2.56(d,J=2.2Hz,1H),1.97(dd,J=18.6,4.3Hz,2H).

[0462] Example 24 (5-(6-(1-(1-H-benzo[d]imidazol-2-yl]pyridinyl)hexahydropyrrolo[3,4-c]pyrrolo-2(1H)-yl)(2-(phenylamino)pyrimidin-4-yl)methyl ketone (L-24)

[0463]

[0464] (5-(6-(1-(1-H-benzo[d]imidazol-2-yl]pyridinyl)hexahydropyrrolo[3,4-c]pyrrolo-2(1H)-yl)(2-(phenylamino)pyrimidin-4-yl)methyl ketone

[0465] Operation is the same as L-14

[0466] LC-MS:m / z:(M+H)+=531.0,1H NMR (400MHz, CDCl3) δ8.60–8.44(m,2H),8.02–7.92(m,1H),7.79(dd,J=6.3,3.1Hz,2H),7.75–7.62(m,2H),7.51(d,J=7.7Hz ,1H),7.41–7.30(m,3H),7.27–7.16(m,1H),7.09(dd,J=9.6,6.2Hz,1H),4.05-3.79(m,4H),3.78-3.68(m,4H),3.07(s,2H).

[0467] Example 25 (N-(3-(6-(1H-benzo[d]imidazol-2-yl)pyridinyl)-3-azabicyclo[3.1.0]hexyl-6-yl)-2-(pyridin-2-ylamino)pyrimidine-4-carboxamide (L-25)

[0468]

[0469] (N-(3-(6-(1H-benzo[d]imidazol-2-yl)pyridinyl)-3-azabicyclo[3.1.0]hexyl-6-yl)-2-(pyridin-2-ylamino)pyrimidine-4-carboxamide

[0470] Operation is the same as L-14

[0471] LC-MS:m / z:(M+H)+=518.0,1H NMR (400MHz, CD3OD) δ8.71(d,J=4.9Hz,1H),8.41(dd,J=7.6,1.3Hz,1H),8.31(dd,J=9.5,4.8H z,2H),8.21–8.08(m,2H),8.07-7.82(m,1H),7.68(s,2H),7.40–7.28(m,2H),7.17(d,J=4.9Hz ,1H),7.05(ddd,J=7.2,5.0,0.9Hz,1H),4.24(d,J=12.5Hz,1H),4.14(d,J=11.5Hz,1H),3.99( dd,J=11.5,4.3Hz,1H),3.75(dt,J=13.2,5.1Hz,1H),2.71(t,J=2.4Hz,1H),2.17–2.05(m,2H).

[0472] Example 26 ((5-(6-(1H-benzo[d]imidazol-2-yl]pyridinyl)hexahydropyrrolo[3,4-c]pyrrolo-2(1H)-yl)(2-(pyridin-2-ylamino)pyrimidin-4-yl)methyl ketone (L-26)

[0473]

[0474] ((5-(6-(1H-benzo[d]imidazol-2-yl]pyridinyl)hexahydropyrrolo[3,4-c]pyrrolo-2(1H)-yl)(2-(pyridin-2-ylamino)pyrimidin-4-yl)methyl ketone

[0475] 2-(2-pyridylamino)pyrimidine-4-carboxylic acid (40 mg, 0.18 mmol) was dissolved in 2 mL of N,N-dimethylformamide, and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (145 mg, 0.28 mmol) and N,N-diisopropylethylamine (72 mg, 0.56 mmol) were added. After stirring the reaction solution for 20 min, 2,3,3a,4,6,6a-hexahydro-1H-pyrrolo[3,4-c]pyrrolo-5-yl-[6-(1H-benzimidazole-added-2-yl)-2-pyridyl] methyl ketone (62 mg, 0.18 mmol) was added, and the reaction solution was stirred at 15 °C for 16 h. 10 mL of water was added to the reaction solution, and the mixture was filtered. The obtained solid was purified by thin-layer chromatography (dichloromethane:methanol = 10:1) to give 15 mg of white solid, with a yield of 15.25%.

[0476] LC-MS:m / z:(M+H)+=532.0,1H NMR (400MHz, CD3OD) δ8.68 (dd, J=26.6, 5.0Hz, 1H), 8.63-8.61 (m, 1H), 8.32–8.22 (m, 1H), 8.19–8.07 (m, 2H), 7.92–7. 51(m,4H),7.36–7.26(m,2H),7.20(dd,J=14.8,5.0Hz,1H),6.84-6.82(m,1H),4.29–3.65(m,8H),3.17–3.03(m,2H).

[0477] Example 27 (9-(6-(1H-benzo[d]imidazol-2-yl)pyridinyl)-3,9-diazaspiro[5.5]undecane-3-yl)(2-(phenylamino)pyrimidin-4-yl)methyl ketone (L-27)

[0478]

[0479] (9-(6-(1H-benzo[d]imidazol-2-yl)pyridinyl)-3,9-diazaspiro[5.5]undecane-3-yl)(2-(phenylamino)pyrimidin-4-yl)methyl ketone

[0480] Operation is the same as L-26

[0481] LC-MS:m / z:(M+H)+=573.0,1H NMR (400MHz, DMSO-d6) δ12.96(s,1H),9.82(s,1H),8.59(d,J=4.9Hz,1H),8.38(dd,J=7.9,1.0Hz,1H),8.11(t,J=7.8Hz,1H),7.75–7.72(m, 3H),7.62-7.56(m,2H),7.31-7.21(m,4H),6.96(t,J=7.3Hz,1H),6.88(d,J=4.9Hz,1H),3.78–3.54(m,4H),3.35(s,4H),1.72–1.31(m,8H).

[0482] Example 28 6-(1H-benzo[d]imidazol-2-yl)-N-(1-(2-(phenylamino)pyrimidin-4-carbonyl)pyrrolidine-3-yl)pyridinelinamide (L-28)

[0483]

[0484] 6-(1H-benzo[d]imidazol-2-yl)-N-(1-(2-(phenylamino)pyrimidin-4-carbonyl)pyrrolidine-3-yl)pyridinelinamide

[0485] Operation is the same as L-26

[0486] LC-MS:m / z:(M+H)+=505.0,1H NMR (400MHz, CD3OD) δ8.62(dd,J=30.1,4.9Hz,1H),8.41(t,J=7.9Hz,1H),8.12(q,J=7.8Hz,1H),7.86(d,J=7.7Hz,1H),7.75–7.54(m,4H), 7.41–7.22(m,5H),6.97(dd,J=12.5,7.3Hz,1H),4.72–4.52(m,1H),4.34-3.54(m,4H),2.42(dd,J=12.9,5.7Hz,1H),2.20(d,J=5.5Hz,1H).

[0487] Example 29 6-(1H-benzo[d]imidazol-2-yl)-N-(1-(2-(pyridin-2-ylamino)pyrimidin-4-carbonyl)pyrrolidine-3-yl)pyridinelinamide (L-29)

[0488]

[0489] 6-(1H-benzo[d]imidazol-2-yl)-N-(1-(2-(pyridin-2-ylamino)pyrimidin-4-carbonyl)pyrrolidine-3-yl)pyridinelinamide is operated as in L-26.

[0490] LC-MS:m / z:(M+H)+=506.0,1H NMR(400MHz,CD3OD)δ8.73(dd,J=33.7,4.9Hz,1H),8.48–8.35(m,1H),8.32–8 .00(m,3H),7.87(ddd,J=7.8,2.1,1.0Hz,1H),7.75-7.73(m,2H),7.61(s,1H) ,7.46(dd,J=43.3,4.9Hz,1H),7.36–7.23(m,2H),6.99(dd,J=7.3,5.0Hz,1H) ,4.78–4.30(m,2H),4.09-4.01(m,1H),4.02–3.77(m,2H),2.49–2.12(m,2H).

[0491] Example 30 N-(1-(1-(6-(1H-benzo[d]imidazol-2-yl)pyridinyl)piperidin-4-yl)-6-(1H-benzo[d]imidazol-2-yl)pyridinylamide (L-30)

[0492]

[0493] N-(1-(1-(6-(1H-benzo[d]imidazol-2-yl)pyridinyl)piperidin-4-yl)-6-(1H-benzo[d]imidazol-2-yl)pyridinamide

[0494] Operation is the same as L-5

[0495] LC-MS:m / z:(M+H)+=543.22, 1 H NMR(400MHz, CDCl3)δ8.49(d,J=7.2Hz,2H),8.07–7.86(m,2H),7.72(s,4H),7.58(dd,J=7.7,1.0Hz,2H),7.38–7.31(m,4H),4.6 9(d,J=13.1Hz,2H), 4.55(d,J=7.8Hz,2H), 3.83(d,J=13.8Hz,4H), 3.15(dt,J=22.4,11.4Hz,4H), 2.06(dd,J=56.4,13.3Hz,4H).

[0496] Example 31 N-(4-(9-methyl-3,9-diazaspiro[5.5]undecane-3-yl)phenyl)-1-(2-(phenylamino)pyrimidin-4-carbonyl)pyrrolidine-3-carboxamide (L-31)

[0497]

[0498] N-(4-(9-methyl-3,9-diazaspiro[5.5]undecane-3-yl)phenyl)-1-(2-(phenylamino)pyrimidin-4-carbonyl)pyrrolidine-3-carboxamide

[0499] Operation is the same as L-5

[0500] 4-(9-methyl-3,9-diazaspiro[5.5]undecane-3-yl)aniline was purchased from Bide Pharmaceuticals.

[0501] LC-MS:m / z:(M+H)+=554.23, 1 H NMR (400MHz, MeOD) δ8.50–8.34(m,1H),8.19–8.07(m,1H),7.83(t,J=13.8Hz,1H),7.69(s,2H),7.49(d,J=9.0Hz,1H),7.42–7.27(m,2H),6.97(d d,J=28.4,9.0Hz,2H),4.21–3.87(m,4H),3.77(dt,J=12.3,7.7Hz,1H),3 .19–3.06(m,4H),2.83(s,4H),2.57(d,J=5.6Hz,3H),2.44–2.26(m,2H).

[0502] Example 32 N-(1-(1-(6-(1H-benzo[d]imidazol-2-yl)pyridinyl)pyrrolidine-3-yl)-6-(1H-benzo[d]imidazol-2-yl)pyridinylamide (L-32)

[0503]

[0504] N-(1-(1-(6-(1H-benzo[d]imidazol-2-yl)pyridinyl)pyrrolidine-3-yl)-6-(1H-benzo[d]imidazol-2-yl)pyridinamide

[0505] Operation is the same as L-6

[0506] LC-MS:m / z:(M+H)+=529.5, 1H NMR (400MHz, CDCl3) δ8.70(s,2H),8.57(d,J=23.6Hz,1H),8.46(d,J=7.9Hz,1H),8.34(d,J=6.2Hz,2H),8 .16(dd,J=22.0,7.1Hz,2H),7.86(dd,J=17.5,9.7Hz,2H),7.80–7.50(m,4H),7.36–7.16(m,4H),4.61(d,J =5.9Hz,2H),4.41(s,1H),4.03(dd,J=11.5,6.2Hz,1H),3.78(dd,J=58.9,16.7Hz,4H),3.53(s,3H),2.18 (dd,J=12.9,6.3Hz,1H),1.93(dd,J=39.9,18.0Hz,2H),1.74–1.50(m,2H),1.32(dt,J=14.2,10.8Hz,4H).

[0507] Example 33 Cyclohexane-1,4-dimethylbis((5-(4-nitrophenyl)hexahydropyrrolo[3,4-c]pyrrolo-2(1H)-yl)methyl ketone)(L-33)

[0508]

[0509] Cyclohexane-1,4-dimethylbis((5-(4-nitrophenyl)hexahydropyrrolo[3,4-c]pyrrolo-2(1H)-yl)methyl ketone)

[0510] Operation is the same as L-8

[0511] 2-(4-nitrophenyl)octahydropyrrolo[3,4-c]pyrrole was purchased from Bid Pharmaceuticals.

[0512] LC-MS:m / z:(M+H)+=603.21, 1 H NMR(400MHz, CDCl3)δ8.15(d,J=8.1Hz,4H),6.50(d,J=8.6Hz,4H),4.00–3.65(m,8H),3.65–3.27(m,8H), 3.15(d,J=34.2Hz,4H),2.39(s,2H),2.07–1.72(m,4H),1.59(dd,J=25.9,13.6Hz,4H),1.45–1.20(m,4H).

[0513] Example 34 1,4-Phenylidene bis((5-(4-nitrophenyl)hexahydropyrrolo[3,4-c]pyrrolo-2(1H)-yl) methyl ketone)(L-34)

[0514]

[0515] 1,4-Phenylidene bis((5-(4-nitrophenyl)hexahydropyrrolo[3,4-c]pyrrolo-2(1H)-yl)methyl ketone)

[0516] Operation is the same as L-8

[0517] LC-MS:m / z:(M+H)+=597.21, 1 H NMR(400MHz, CDCl3)δ8.15(t,J=8.8Hz,4H),8.01–7.86(m,4H),6.61–6.43(m,4H),4.28– 3.88(m,4H),3.84–3.51(m,8H),3.51–3.38(m,2H),3.38–3.21(m,2H),3.21–2.81(m,4H).

[0518] Example 35 1-(6-(1H-benzo[d]imidazol-2-yl)pyridinyl)-N-(4-(9-methyl-3,9-diazaspiro[5.5]undecane-3-yl)phenyl)pyrrolidine-3-carboxamide (L-35)

[0519]

[0520] 1-(6-(1H-benzo[d]imidazol-2-yl)pyridinyl)-N-(4-(9-methyl-3,9-diazaspiro[5.5]undecane-3-yl)phenyl)pyrrolidine-3-carboxamide

[0521] Operation is the same as L-6

[0522] LC-MS:m / z:(M+H)+=578.31, 1 H NMR (400MHz, MeOD) δ8.59(d,J=4.7Hz,1H),7.66(dd,J=15.3,8.1Hz,2H),7.44(dd,J=15.0,8.9Hz,2H),7.36–7.25(m,2H),7.04(ddd,J=3 0.4,15.7,6.8Hz,4H),4.16–3.76(m,5H),3.70(s,4H),3.27–3.05(m,4H),2.80(s,3H),2.54(s,2H),2.27(d,J=5.2Hz,2H),1.69(s,5H).

[0523] Example 36 Piperazine-1,4-dimethylbis((3-(imidazol[1,2-a]pyridin-2-yl)phenyl)methyl ketone)(L-36)

[0524]

[0525] Under ice bath conditions, 0.12 g (0.5 mmol) of 3-(imidazo[1,2-a]pyridin-2-yl)benzoic acid, 0.28 g (0.55 mmol) of benzotriazol-1-yl-oxytripyrrolidinephosphine hexafluorophosphate, and 0.14 g (1.1 mmol) of N,N-dimethylformamide were dissolved in 6 mL of N,N-dimethylformamide. After stirring for 0.5 h, piperazine (0.04 g, 0.5 mmol) was added, and stirring was continued for another 0.5 h. The mixture was then allowed to react overnight at room temperature. The reaction solution was poured into 20 mL of water and extracted with ethyl acetate (20 mL x 3). The extract was washed with saturated brine, and the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated by silica gel column chromatography (DCM:MeOH = 20:1) to give an off-white solid (12 mg, 22 μmol), yield 4.5%. LC-MS m / z: (M+H)+ = 527.

[0526] 1 H NMR(400MHz,Chloroform-d)δ8.15(d,2H),8.08–8.00(m,4H),7.91(s,2H),7.65(d,J=9.1Hz,2 H),7.56–7.46(m,2H),7.39(d,J=7.6Hz,2H),7.21(m,2H),6.82(m,2H),3.73(d,J=89.9Hz,8H).

[0527] Example 37 6-(1H-benzo[d]imidazol-2-yl)-N-(1-(3-nitrobenzyl)pyrrolidine-3-yl)pyridineamide (L-37)

[0528]

[0529] Under ice bath conditions, m-nitrobenzoic acid (0.08 g, 0.48 mmol), benzotriazol-1-yl-oxytripyrrolidinephosphine hexafluorophosphate (0.30 g, 0.58 mmol), and N,N-diisopropylethylamine (0.16 g, 1.3 mmol) were dissolved in 6 mL of N,N-dimethylformamide. After stirring for 0.5 h, 6-(1H-benzo[d]imidazol-2-yl)-N-(pyrrolidine-3-yl)pyridineamide (0.15 g, 0.48 mmol) was added, and stirring was continued for another 0.5 h. The mixture was then allowed to react overnight at room temperature. The reaction solution was poured into 20 mL of water and extracted with ethyl acetate (20 mL x 3). The extract was washed with saturated brine, and the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated by silica gel column chromatography (DCM:MeOH = 20:1) to give an off-white solid (15 mg, 32 μmol), yield 6.8%. LC-MS m / z:(M+H)+=457.

[0530] Example 38: N-(1-(6-(1H-benzo[d]imidazol-2-yl)pyridyl)piperidin-4-yl)-3-nitrobenzamide (L-38)

[0531]

[0532] Under ice bath conditions, (6-1H-benzo[d]imidazol-2-yl)pyridin-2-yl)(4-aminopiperidin-1-yl)methyl ketone (0.088 g, 0.27 mmol), benzotriazol-1-yl-oxytripyrrolidinephosphine hexafluorophosphate (0.15 g, 0.3 mmol), and N,N-diisopropylethylamine (0.12 g, 1.0 mmol) were dissolved in 6 mL of N,N-dimethylformamide. After stirring for 0.5 h, m-nitrobenzoic acid (0.04 g, 0.27 mmol) was added, and stirring was continued for another 0.5 h. The mixture was then allowed to react overnight at room temperature. The reaction solution was poured into 20 mL of water and extracted with ethyl acetate (20 mL x 3). The extract was washed with saturated brine, and the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated by silica gel column chromatography (DCM:MeOH = 20:1) to give an off-white solid (11 mg, 32 μmol), yield 8.6%. LC-MS m / z:(M+H)+=471.

[0533] Example 39: Synthesis of (1-(3-(imidazol[1,2-a]pyridin-2-yl)benzoyl)pyrrolidine-2-yl)(5-(4-nitrophenyl)hexahydropyrrolo[3,4-c]pyrrolo-2(1H)-yl) methyl ketone (L-39)

[0534]

[0535] Under ice bath conditions, 0.1 g (0.4 mmol) of 3-(imidazo[1,2-a]pyridin-2-yl)benzoic acid, 0.24 g (0.44 mmol) of benzotriazol-1-yl-oxytripyrrolylphosphine hexafluorophosphate, and 0.12 g (1.0 mmol) of N,N-dimethylformamide were dissolved in 6 mL of N,N-dimethylformamide. After stirring for 0.5 h, 0.13 g (0.4 mmol) of 2-(4-nitrophenyl)-5-prolyl octahydropyrrole[3,4-c]pyrrole (0.13 g, 0.4 mmol) were added, and stirring was continued for another 0.5 h. The mixture was then allowed to react overnight at room temperature. The reaction mixture was poured into 20 mL of water and extracted with ethyl acetate (20 mL x 3). The extract was washed with saturated brine, and the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated by silica gel column chromatography (DCM:MeOH = 20:1) to give an off-white solid (16 mg, μmol), yield 7.2%. LC-MS m / z:(M+H)+=551.

[0536] 1H NMR(400MHz,Chloroform-d)δ8.20–7.99(m,5H),7.90(d,J=9.8Hz,1H),7.64(t,J=8.8Hz,1H),7.53–7 .45(m,2H),7.21(m,1H),6.82(m,1H),6.57–6.38(m,2H),3.81(m,7H),3.62–3.06(m,8H),2.25(m,2H).

[0537] Example 40: (9-(3-(1H-benzo[d]imidazol-2-yl)benzoyl)-3,9-diazaspirocyclic[5.5]undec-3-yl)(3-nitrophenyl)methyl ketone (L-40)

[0538]

[0539] Under ice bath conditions, m-nitrobenzoic acid (0.041 g, 0.25 mmol), benzotriazol-1-yl-oxytripyrrolidinephosphine hexafluorophosphate (0.14 g, 0.27 mmol), and N,N-diisopropylethylamine (0.12 g, 1.0 mmol) were dissolved in 6 mL of N,N-dimethylformamide. After stirring for 0.5 h, (6-(1H-benzo[d]imidazol-2-yl)pyridin-2-yl)(3,9-diazaspiro[5.5]undecane-3-yl)methadone (0.093 g, 0.25 mmol) was added. After stirring for another 0.5 h, the mixture was allowed to return to room temperature and reacted overnight. The reaction mixture was poured into 20 mL of water and extracted with ethyl acetate (20 mL x 3). The extract was washed with saturated brine, and the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated by silica gel column chromatography (DCM:MeOH = 20:1) to give an off-white solid (17 mg, μmol), yield 12.9%. LC-MS m / z: (M+H)+ = 525.

[0540] 1 H NMR(400MHz,Chloroform-d)δ10.74(s,1H),8.48(dd,J=8.0,1.1Hz,1H),8.34–8.27(m,2H),7.97(t,J=7.8Hz,1H),7.87(d,J=6.9Hz ,1H),7.77(m,1H),7.64(t,J=7.9Hz,1H),7.57(m,2H),7.37–7.32(m,2H),3.94–3.74(m,4H),3.52(s,2H),3.42(s,2H),1.59(m,8H).

[0541] Example 41: Synthesis of (5-(6-(1H-benzo[d]imidazol-2-yl)pyridyl)hexahydropyrrole[3,4-c]pyrrole-2(1H)-yl)(3-nitrophenyl)methyl ketone (L-41)

[0542]

[0543] Under ice bath conditions, m-nitrobenzoic acid (0.041 g, 0.25 mmol), benzotriazol-1-yl-oxytripyrrolylphosphine hexafluorophosphate (0.14 g, 0.27 mmol), and N,N-diisopropylethylamine (0.12 g, 1.0 mmol) were dissolved in 6 mL of N,N-dimethylformamide. After stirring for 0.5 h, (6-(1H-benzo[d]imidazol-2-yl)pyridin-2-yl)(hexahydropyrrolo[3,4-c]pyrrolo-2(1H)-yl)methyl ketone (0.083 g, 0.25 mmol) was added. After stirring for another 0.5 h, the mixture was allowed to return to room temperature and reacted overnight. The reaction mixture was poured into 20 mL of water and extracted with ethyl acetate (20 mL x 3). The extract was washed with saturated brine, and the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated by silica gel column chromatography (DCM:MeOH = 20:1) to give an off-white solid (17 mg, μmol), yield 12.9%. LC-MS m / z:(M+H)+ = 483.

[0544] 1H NMR (400MHz, Chloroform-d) δ11.58(s,1H),8.52(dd,J=28.6,7.9Hz,1H),8.38(s,1H),8.30(t,J=9.1Hz,1H),8.04–7.49(m,6H),7.32(m 2H),4.22(m,1H),4.09–4.00(m,1H),3.91–3.32(m,6H),3.05(m,2H).

[0545] Example 42: N-(1-(3-(imidazo[1,2-a]pyridin-2-yl)benzoyl)piperidin-4-yl)-2-(aniline)pyrimidin-4-carboxamide (L-42)

[0546]

[0547] I. Synthesis of tert-butyl (1-(3-(imidazolium[1,2-a]pyridin-2-yl)benzoyl)piperidin-4-yl)carbamate

[0548]

[0549] Under ice bath conditions, 3-(imidazo[1,2-a]pyridin-2-yl)benzoic 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 20 mL of N,N-dimethylformamide. After stirring for 0.5 h, tert-butylpiperidin-4-ylcarbamate (0.92 g, 4.6 mmol) was added, and stirring was continued for another 0.5 h. The mixture was then allowed to react overnight at room temperature. The reaction solution was poured into 80 mL of water and extracted with ethyl acetate (80 mL x 3). The extract was washed with saturated brine, and the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated by silica gel column chromatography (PE:EA = 5:1) to give an off-white solid (1.3 g, 3 mmol), in 73% yield. LC-MS m / z:(M+H)+=421.

[0550] II. Synthesis of (4-aminopiperidin-1-yl)(3-(imidazo[1,2-a]pyridin-2-yl)phenyl)methyl ketone

[0551]

[0552] 1.3 g (3 mmol) of tert-butyl(1-(3-(imidazolium[1,2-a]pyridin-2-yl)benzoyl)piperidin-4-yl)carbamate was dissolved in 20 mL of dichloromethane under ice bath conditions. A saturated hydrochloric acid solution of 1,4-dioxane (2 mL, 8 mmol) was added, and the mixture was stirred for 0.5 hours. The reaction mixture was then allowed to return to room temperature and reacted overnight. The reaction solution was concentrated under reduced pressure, and the resulting solid was used directly in the next reaction step. Yield >90%. LC-MS m / z: (M+H)+ = 321.

[0553] III. Synthesis of N-(1-(3-(imidazo[1,2-a]pyridin-2-yl)benzoyl)piperidin-4-yl)-2-(aniline)pyrimidine-4-carboxamide

[0554]

[0555] Under ice bath conditions, 2-(anilino)pyrimidine-4-carboxylic acid (0.060 g, 0.27 mmol), benzotriazol-1-yl-oxytripyrrolidinephosphine hexafluorophosphate (0.14 g, 0.27 mmol), and N,N-diisopropylethylamine (0.12 g, 1.0 mmol) were dissolved in 6 mL of N,N-dimethylformamide. After stirring for 0.5 h, (4-aminopiperidin-1-yl)(3-(imidazo[1,2-a]pyridin-2-yl)phenyl)methyl ketone (0.089 g, 0.27 mmol) was added, and stirring was continued for another 0.5 h. The mixture was then allowed to return to room temperature and reacted overnight. The reaction mixture was poured into 20 mL of water and extracted with ethyl acetate (20 mL x 3). The extract was washed with saturated brine, and the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated by silica gel column chromatography (DCM:MeOH = 20:1) to give an off-white solid (20 mg, 38 μmol), yield 14.3%. LC-MS m / z: (M+H)+ = 518.

[0556] 1 H NMR(400MHz,Chloroform-d)δ8.65(d,J=4.8Hz,1H),8.22(d,J=6.7Hz,1H),7.97(m,4H),7.65(m,3H),7.52–7.44(m,2H),7.43–7.30 (m,5H),7.13(t,J=7.3Hz,1H),6.92(t,J=6.7Hz,1H),4.70(s,1H),4.27(s,1H),3.84(s,1H),3.20(m,2H),1.67(s,2H),1.31(m,2H).

[0557] Example 43 N-(1-(3-(imidazo[1,2-a]pyridin-2-yl)benzoyl)piperidin-4-yl)-2-(aniline)pyrimidin-4-carboxamide (L-43)

[0558]

[0559] I. Synthesis of tert-butyl 5-(3-(imidazo[1,2-a]pyridin-2-yl)benzoyl)hexahydropyrrole-2(1H)-carboxylate

[0560]

[0561] Under ice bath conditions, 3-(imidazo[1,2-a]pyridin-2-yl)benzoic 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 20 mL of N,N-dimethylformamide. After stirring for 0.5 h, tert-butylpiperidin-4-ylcarbamate (0.98 g, 4.6 mmol) was added, and stirring was continued for another 0.5 h. The mixture was then allowed to return to room temperature and reacted overnight. The reaction mixture was poured into 80 mL of water and extracted with ethyl acetate (80 mL x 3). The extract was washed with saturated brine, and the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated by silica gel column chromatography under reduced pressure (PE:EA = 5:1) to give an off-white solid (1.26 g, 2.9 mmol), yield 72%. LC-MS m / z: (M+H)+ = 433.

[0562] II. Synthesis of (hexahydropyrrolo[3,4-c]pyrrolo-2(1H)-yl)(3-(imidazo[1,2-a]pyridin-2-yl)phenyl)methyl ketone

[0563]

[0564] Under ice bath conditions, tert-butyl 5-(3-(imidazo[1,2-a]pyridin-2-yl)benzoyl)hexahydropyrrole-2(1H)-carboxylate (1.3 g, 3 mmol) was dissolved in 20 mL of dichloromethane. A saturated hydrochloric acid solution of 1,4-dioxane (2 mL, 8 mmol) was added, and the mixture was stirred for 0.5 hours. The reaction mixture was then allowed to return to room temperature and reacted overnight. The reaction solution was concentrated under reduced pressure, and the resulting solid was used directly in the next reaction step. Yield >90%. LC-MS m / z: (M+H)+=333.

[0565] III. Synthesis of N-(1-(3-(imidazo[1,2-a]pyridin-2-yl)benzoyl)piperidin-4-yl)-2-(aniline)pyrimidine-4-carboxamide

[0566]

[0567] Under ice bath conditions, 2-(anilino)pyrimidine-4-carboxylic acid (0.060 g, 0.27 mmol), benzotriazol-1-yl-oxytripyrrolidinyl phosphate (0.14 g, 0.27 mmol), and N,N-diisopropylethylamine (0.12 g, 1.0 mmol) were dissolved in 6 mL of N,N-dimethylformamide. After stirring for 0.5 h, (hexahydropyrrolo[3,4-c]pyrrolo-2(1H)-yl)(3-(imidazo[1,2-a]pyridin-2-yl)phenyl)methyl ketone (0.092 g, 0.27 mmol) was added. After stirring for another 0.5 h, the mixture was allowed to return to room temperature and reacted overnight. The reaction mixture was poured into 20 mL of water and extracted with ethyl acetate (20 mL x 3). The extract was washed with saturated brine, and the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated by silica gel column chromatography (DCM:MeOH = 20:1) to give an off-white solid (12 mg, 22 μmol), yield 8.4%. LC-MS m / z: (M+H)+ = 530.

[0568] 1 H NMR (400MHz, Chloroform-d) δ8.57(d,J=13.0Hz,1H),8.12(d,2H),8.03(d,J=7.0Hz,1H),7.90(d,J=8. 8Hz,1H),7.66–7.36(m,7H),7.27–6.95(m,4H),6.81(t,J=6.8Hz,1H),4.04–3.40(m,8H),3.01(d,2H).

[0569] Example 44 N-(3-(6-(1H-benzo[d]imidazol-2-yl)pyridinyl)-3-azabicyclo[3.1.0]hexyl-6-yl)-6-(phenylamino)pyridinyl amide (L-44)

[0570]

[0571] 1. 6-(Phenylano)pyridinecarboxylic acid

[0572] Methyl 6-bromopyridine-2-carboxylate (2 g, 9.26 mmol) was dissolved in 50 mL of dioxane, and aniline (826 mg, 9.26 mmol), tris(dibenzylacetone)dipalladium (424 mg, 0.46 mmol), 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene) (536 mg, 0.92 mmol), and cesium carbonate (7.54 g, 23.1 mmol) were added. The reaction mixture was stirred at 95 °C under nitrogen protection for 15 hours. The reaction mixture 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, and sodium hydroxide (1.2 g, 29 mmol) was added. The reaction mixture was stirred at 20 °C for 15 hours. The reaction mixture was extracted three times with ethyl acetate (20 mL * 3). The aqueous phase was acidified to pH 1 with 2N hydrochloric acid, extracted three times with ethyl acetate (20 ml * 3), and then neutralized to pH 1 with saturated sodium bicarbonate aqueous solution. The solid was filtered and dried to give 500 mg of white solid, with a yield of 25.2%. LC-MS: m / z: (M + H) + = 215.0.

[0573] II. N-(3-(6-(1H-benzo[d]imidazol-2-yl)pyridinyl)-3-azabicyclo[3.1.0]hexyl-6-yl)-6-(phenylamino)pyridinylamide

[0574] Operation is the same as L-14

[0575] LC-MS:m / z:(M+H)+=516.0,1H NMR(400MHz,CD3OD)δ8.47(dd,J=7.4,1.5Hz,1H),8.26–8.13(m,2H),7.85– 7.54(m,5H),7.45–7.23(m,4H),7.08(dd,J=7.3,0.8Hz,1H),6.99-6.92(m,2 H),4.29(d,J=12.4Hz,1H),4.20(d,J=11.7Hz,1H),3.97(dd,J=11.7,4.2Hz, 1H), 3.75 (dd, J=12.4, 4.4Hz, 1H), 2.74 (t, J=2.4Hz, 1H), 2.15–2.05 (m, 2H).

[0576] Example 45 (9-(6-(1-H-benzo[d]imidazol-2-yl)pyridinyl)-3,9-diazaspiro[5.5]undecane-3-yl)(6-(phenylamino)pyridin-2-yl) methyl ketone (L-45)

[0577]

[0578] (9-(6-(1-H-benzo[d]imidazol-2-yl)pyridinyl)-3,9-diazaspiro[5.5]undecane-3-yl)(6-(phenylamino)pyridin-2-yl)methyl ketone

[0579] Operation is the same as L-14

[0580] LC-MS:m / z:(M+H)+=572.0,1H NMR(400MHz, CD3OD)δ8.40(dd,J=8.0,1.0Hz,1H),8.13(t,J=7.9Hz,1H),7.86–7.53(m,6H),7.33(d,J=5.1Hz,2H),7.29–7.2 0(m,2H),6.94(t,J=7.4Hz,1H),6.91–6.82(m,2H),3.77(dd,J=28.2,21.3Hz,4H),3.62–3.47(m,4H),1.70(d,J=37.8Hz,8H).

[0581] Example 46 (5-(6-(1H-benzo[d]imidazol-2-yl)pyridinyl)hexahydropyrrolo[3,4-c]pyrrolo-2(1H)-yl)(6-(phenylamino)pyridin-2-yl)methyl ketone (L-46)

[0582]

[0583] (5-(6-(1H-benzo[d]imidazol-2-yl)pyridinyl)hexahydropyrrolo[3,4-c]pyrrolo-2(1H)-yl)(6-(phenylamino)pyridin-2-yl)methyl ketone

[0584] Operation is the same as L-14

[0585] LC-MS:m / z:(M+H)+=530.0,1H NMR(400MHz,CD3OD)δ8.43(ddd,J=7.9,5.4,0.9Hz,1H),8.15(dd,J=15.4,7.7Hz,1H),7.92 –7.81(m,1H),7.79–7.27(m,7H),7.23–6.52(m,5H),4.25–3.62(m,8H),3.20–3.03(m,2H).

[0586] Example 47 N-(1-(1-(6-(1H-benzo[d]imidazol-2-yl]pyridinyl)piperidin-4-yl]-6-(phenylamino)pyridinyl amide (L-47)

[0587]

[0588] N-(1-(1-(6-(1H-benzo[d]imidazol-2-yl]pyridinyl)piperidin-4-yl]-6-(phenylamino)pyridinamide

[0589] Operation is the same as L-14

[0590] LC-MS:m / z:(M+H)+=518.0,1H NMR (400MHz, CD3OD) δ8.41 (dd, J=8.0, 0.9Hz, 1H), 8.15 (t, J=7.9Hz, 1H), 7.84 –7.57(m,4H),7.56–7.42(m,3H),7.41–7.16(m,4H),7.04–6.91(m,2H),4.54(d ,J=13.7Hz,1H),4.24–4.17(m,1H),3.82(d,J=13.8Hz,1H),3.50-3.21(m,2H), 2.23(d,J=10.1Hz,1H), 2.05(d,J=10.1Hz,1H), 1.75(dt,J=19.7,10.2Hz,2H).

[0591] Example 48 N-(6-(5-(6-(1H-benzo[d]imidazol-2-yl]pyridinyl)octahydropyrrolo[3,4-c]pyrrolo-2-carbonyl)pyridin-2-yl)acetamide (L-48)

[0592]

[0593] Operation is the same as L-14

[0594] 6-Acetaminopyridinecarboxylic acid was purchased from Bid Pharmaceuticals.

[0595] LC-MS:m / z:(M+H)+=496.2, 1 H NMR(400MHz,MeOD)δ8.43(dd,J=13.6,7.8Hz,1H),8.15(dd,J=17.8,8.1Hz,1H), 7.96–7.82(m,2H),7.67(dd,J=41.3,19.9Hz,2H),7.53–7.41(m,1H),7.31(dt,J =21.6,7.7Hz,3H),4.24–3.83(m,5H),3.80–3.57(m,3H),3.50(s,1H),3.13(d,J =20.5Hz,2H),2.20(dd,J=15.6,8.0Hz,2H),2.05(d,J=15.3Hz,2H),1.63(s,1H).

[0596] Example 50 N-(1-(3-(imidazo[1,2-a]pyridin-2-yl)benzoyl)piperidin-4-yl)-2-(aniline)pyridin-4-carboxamide (L-50)

[0597]

[0598] Synthesis of N-(1-(3-(imidazo[1,2-a]pyridin-2-yl)benzoyl)piperidin-4-yl)-2-(aniline)pyridin-4-carboxamide

[0599] Under ice bath conditions, 2-(anilino)pyridine-4-carboxylic acid (0.060 g, 0.27 mmol), benzotriazol-1-yl-oxytripyrrolidinephosphine hexafluorophosphate (0.14 g, 0.27 mmol), and N,N-diisopropylethylamine (0.12 g, 1.0 mmol) were dissolved in 6 mL of N,N-dimethylformamide. After stirring for 0.5 h, (4-aminopiperidin-1-yl)(3-(imidazo[1,2-a]pyridin-2-yl)phenyl)methyl ketone (0.089 g, 0.27 mmol) was added, and stirring was continued for another 0.5 h. The mixture was then allowed to return to room temperature and reacted overnight. The reaction mixture was poured into 20 mL of water and extracted with ethyl acetate (20 mL x 3). The extract was washed with saturated brine, and the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated by silica gel column chromatography (DCM:MeOH = 20:1) to give an off-white solid (18 mg, 34 μmol), yield 12.8%. LC-MS m / z: (M+H)+ = 517.

[0600] 1 H NMR(400MHz,Chloroform-d)δ8.14(m,1H),8.05–7.99(m,2H),7.96(d,J=8.2Hz,1 H),7.89(d,J=0.7Hz,1H),7.65–7.60(m,3H),7.48(m,1H),7.40–7.34(m,5H),7.19 (m,1H),7.14–7.08(m,1H),7.04(s,1H),7.00–6.94(m,1H),6.80(m,1H),4.62(s, 1H),4.29–4.14(m,1H),3.82(s,1H),3.31–3.08(m,2H),2.02(m,2H),1.57(d,2H).

[0601] Example 51 N-(1-(3-(imidazo[1,2-a]pyridin-2-yl)benzoyl)piperidin-4-yl)-2-(aniline)pyridin-4-carboxamide (L-51)

[0602]

[0603] Synthesis of N-(1-(3-(imidazo[1,2-a]pyridin-2-yl)benzoyl)piperidin-4-yl)-2-(aniline)pyridin-4-carboxamide

[0604] Under ice bath conditions, 2-(anilino)pyridine-4-carboxylic acid (0.060 g, 0.27 mmol), benzotriazol-1-yl-oxytripyrrolylphosphine hexafluorophosphate (0.14 g, 0.27 mmol), and N,N-diisopropylethylamine (0.12 g, 1.0 mmol) were dissolved in 6 mL of N,N-dimethylformamide. After stirring for 0.5 h, (hexahydropyrrolo[3,4-c]pyrrolo-2(1H)-yl)(3-(imidazo[1,2-a]pyridin-2-yl)phenyl)methyl ketone (0.092 g, 0.27 mmol) was added. After stirring for another 0.5 h, the mixture was allowed to return to room temperature and reacted overnight. The reaction mixture was poured into 20 mL of water and extracted with ethyl acetate (20 mL x 3). The extract was washed with saturated brine, and the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated by silica gel column chromatography (DCM:MeOH = 20:1) to give an off-white solid (16 mg, 30 μmol), yield 11.2%. LC-MS m / z: (M+H)+ = 529.

[0605] 1 H NMR(400MHz,Chloroform-d)δ8.09(td,J=20.1,18.0,6.8Hz,3H),7.89(d,J=14.3Hz,1H),7.54(dt,J=53.5,7.3Hz,4H) ,7.36(d,J=4.4Hz,2H),7.32–7.05(m,5H),6.99–6.85(m,2H),6.83–6.75(m,1H),4.09–3.50(m,8H),3.06–2.85(m,2H).

[0606] Example 52 N-(3-(6-(1H-benzo[d]imidazol-2-yl)pyridinyl)-3-azabicyclo[3.1.0]hexyl-6-yl)-6-(pyridin-2-ylamino)pyridinyl amide (L-52)

[0607]

[0608] 1. Methyl 6-(pyridin-2-ylamino)pyridinecarboxylate

[0609] Methyl 6-bromopyridine-2-carboxylate (2 g, 9.26 mmol) was dissolved in 50 mL of dioxane, and 2-aminopyridine (871 mg, 9.26 mmol), tris(dibenzylacetone)dipalladium (424 mg, 0.46 mmol), 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene) (536 mg, 0.92 mmol), and cesium carbonate (7.54 g, 23.1 mmol) were added. The reaction mixture was stirred at 95 °C under nitrogen protection for 15 hours. The reaction mixture 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, and sodium hydroxide (0.94 g, 24 mmol) was added. The reaction mixture was stirred at 20 °C for 15 hours. The reaction mixture was extracted three times with ethyl acetate (20 mL * 3). The aqueous phase was acidified to pH 1 with 2N hydrochloric acid, extracted three times with ethyl acetate (20 mL * 3), and then neutralized to pH 1 with saturated sodium bicarbonate aqueous solution. The aqueous phase was concentrated to obtain a solid, which was added to 50 mL of N,N-dimethylformamide and stirred at 20 °C for 2 hours. After filtration and concentration, 460 mg of white solid was obtained, 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] Operation is the same as L-51

[0612] LC-MS:m / z:(M+H)+=517.0,1H NMR (400MHz, CD3OD) δ8.45(dd,J=7.5,1.4Hz,1H),8.27–8.11(m,3H),7.92–7.56(m,6H),7.36(dd,J=6.1,3.1Hz,2H),7.24(d,J=7.0Hz,1H),7.02– 6.88(m,1H),4.25(dd,J=21.8,12.0Hz,2H),3.99(dd,J=11.6,4.4Hz,1H),3.76(dd,J=12.4,4.5Hz,1H),2.74(t,J=2.2Hz,1H),2.17–2.06(m,2H).

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

[0614]

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

[0616] Operation is the same as L-14

[0617] LC-MS:m / z:(M+H)+=531.0,1H NMR (400MHz, CD3OD) δ8.46–8.35(m,1H),8.27–8.08(m,2H),7.99–6.66(m,11H),4.31–3.53(m,8H),3.13(dt,J=13.3,7.1Hz,2H).

[0618] Example 54 (5-(6-(imidazo[1,2-a]pyridin-2-yl]pyridinyl)hexahydropyrrolo[3,4-c]pyrrolo-2(1H)-yl)(2-(pyridin-2-ylamino)pyridin-4-yl)methyl ketone (L-54)

[0619]

[0620] (5-(6-(imidazo[1,2-a]pyridin-2-yl]pyridinyl)hexahydropyrrolo[3,4-c]pyrrolo-2(1H)-yl)(2-(pyridin-2-ylamino)pyridin-4-yl)methyl ketone

[0621] Operation is the same as L-14

[0622] LC-MS:m / z:(M+H)+=531.0,1H NMR (400MHz, CD3OD) δ8.43(dd,J=13.1,6.8Hz,1H),8.25(d,J=32.8Hz,1H),8.09(d,J=21.0Hz,2H),7.67–7.47(m,5H),7. 40–7.28(m,2H),7.13(dt,J=8.0,5.8Hz,2H),6.88(ddt,J=35.3,14.7,7.3Hz,3H),4.11–3.41(m,8H),3.17–2.96(m,2H).

[0623] Example 55 (5-(6-(1-(1H-benzo[d]imidazol-2-yl]pyridinyl)hexahydropyrrolo[3,4-c]pyrrolo-2(1H)-yl)(3-(imidazol[1,2-a]pyridin-2-yl)phenyl) methyl ketone (L-55)

[0624]

[0625] Operation is the same as L-53

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

[0627] LC-MS:m / z:(M+H)+=554.63, 1 H NMR (400MHz, CDCl3) δ12.67(s,1H),8.13–7.82(m,4H),7.54–7.33(m,4H),7.26(d,J= 7.6Hz, 2H), 4.54 (d, J = 11.9Hz, 3H), 4.04 (t, J = 15.9Hz, 3H), 1.85 (s, 1H), 1.77 (s, 1H).

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

[0629]

[0630] 6-(1h-benzo[d]imidazol-2-yl)pyridinecarboxylic acid 2 (15 mg, 0.063 mmol) was dissolved in N,N-dimethylformamide (5 ml), and 1H-benzotriazol-1-yloxytripyrrolidinyl hexafluorophosphate (65 mg, 0.13 mmol) and N,N-diisopropylethylamine (0.02 ml) were added. The mixture was stirred at room temperature for 15 minutes. Then, (4-aminopiperidin-1-yl)(3-(imidazol[1,2-a]pyridin-2-yl)phenyl)methyl ketone 1 (20 mg, 0.063 mmol) was added to the reaction solution, and the reaction solution was stirred at room temperature for 16 hours. The reaction solution was concentrated, and the resulting solid was separated twice by thin-layer chromatography (dichloromethane:methanol = 10:1) to give 8 mg of white solid, yield 24%.

[0631] LC-MS m / z:(M+H)+=542.0,1H NMR(400MHz,Chloroform-d)δ8.68(dd,J=7.9,1.1Hz,1H),8.40(d,J=6.8Hz,1H), 8.31(dd,J=7.7,1.1Hz,1H),8.24(s,2H),8.01(t,J=7.8Hz,1H),7.93(d,J=7.8Hz, 1H),7.82(d,J=9.0Hz,1H),7.45(t,J=7.7Hz,1H),7.39–7.31(m,2H),7.21(s,2H) ,7.03(t,J=6.7Hz,1H),4.59(s,1H),4.18(s,1H),3.55(s,1H),2.93–2.55(m,3H).

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

[0633]

[0634] The deBoc protection procedures for compounds 1 and 2 are the same as those in Example 42; the procedures for compounds 2 to L-57 are the same as those in L-56.

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

[0636] LC-MS m / z:(M+H)+=422.9,1H NMR (400MHz, Methanol-d4) δ8.43 (dd, J=8.0, 1.0Hz, 1H), 8.16 (t, J=7.9Hz, 1H ),7.72(d,J=1.1Hz,1H),7.71–7.67(m,2H),7.60–7.53(m,2H),7.34(dd,J=6.1 ,3.1Hz,2H),7.27(dd,J=6.1,3.1Hz,2H),3.96(d,J=13.7Hz,1H),3.53–3.38(m ,2H),3.21(dd,J=12.8,2.8Hz,1H),2.33(d,J=12.9Hz,1H),2.26–2.02(m,4H).

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

[0638]

[0639] Operation is the same as L-43

[0640] 2,9-Diazaspiro[5.5]undecane-2-carboxylic acid tert-butyl ester was purchased from Bide Pharmaceuticals.

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

[0642] LC-MS m / z: (M+H)+=597.1, 1H NMR(400MHz, Methanol-d4)δ8.44–8.36(m,2H),8.21–8.14(m,1H),8.12–8.06(m,1H),7.78(q,J=7.7Hz ,1H),7.71–7.68(m,2H),7.64–7.60(m,2H),7.32(dt,J=6.6,3.1Hz,4H),7.29–7.25(m,1H),4.23–4.11( m,1H),3.95(dd,J=12.2,6.4Hz,1H),3.83(d,J=21.5Hz,1H),3.74(dt,J=13.3,6.7Hz,3H),3.68–3.58(m ,2H),3.47(s,2H),1.92–1.83(m,1H),1.80(d,J=11.9Hz,2H),1.66–1.57(m,2H),1.54(d,J=4.5Hz,1H).

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

[0644]

[0645] Operation is the same as L-43

[0646] 2,9-Diazaspiro[5.5]undecane-2-carboxylic acid tert-butyl ester was purchased from Bide Pharmaceuticals.

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

[0648] LC-MS m / z: (M+H)+=583.1, 1H NMR(400MHz, Methanol-d4)δ8.45–8.39(m,2H),8.35(dd,J=7.9,1.1Hz,1H),8.17–8.09(m,2H),8.06(td,J= 8.0,2.6Hz,1H),7.82(ddd,J=12.1,7.8,1.0Hz,2H),7.70(d,J=1.1Hz,1H),7.58(dd,J=7.7,1.0Hz,1H),7.3 5–7.31(m,3H),7.28(dd,J=6.1,3.1Hz,1H),3.97(dd,J=15.2,7.7Hz,2H),3.80(dd,J=12.5,5.2Hz,3H),3.6 6–3.58(m,2H),2.08–1.97(m,3H),1.91(dd,J=7.6,4.9Hz,1H),1.79(t,J=6.1Hz,2H),1.69(d,J=5.1Hz,1H).

[0649] Example 60 (7-(6-(1h-benzo[d]imidazol-2-yl)nicotinyl)-2,7-diazaspiro[4.4]nonane-2-yl)(6-(1h-benzo[d]imidazol-2-yl)pyridin-2-yl) methyl ketone (L-60)

[0650]

[0651] Operation is the same as L-43

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

[0653] (7-(6-(1h-benzo[d]imidazol-2-yl)nicotinyl)-2,7-diazaspiro[4.4]nonane-2-yl)(6-(1h-benzo[d]imidazol-2-yl)pyridin-2-yl)methyl ketone

[0654] LC-MS m / z: (M+H)+=569.1, 1H NMR (400MHz, Methanol-d4) δ8.44 (dt, J=8.0, 1.1Hz, 1H), 8.37 (ddd, J=17.3, 7.9, 1.0Hz, 1H), 8.16 (t, J= 7.8Hz,1H),8.06(dt,J=10.2,7.9Hz,1H),7.88(ddd,J=10.2,7.8,1.0Hz,1H),7.80–7.72(m,2H),7.66(s, 2H),7.50(s,1H),7.34(d,J=6.0Hz,1H),7.30(dq,J=5.6,3.0,2.3Hz,3H),4.20–3.97(m,2H),3.89(dd,J= 13.2,6.2Hz,2H),3.85–3.76(m,2H),3.78–3.64(m,2H),2.30–2.15(m,2H),2.07(dt,J=13.7,7.1Hz,2H).

[0655] Example 49 BT-11

[0656]

[0657] BT-11 was prepared according to Example 2 in CN107108573A.

[0658] Example 61 (8-(6-(1H-benzo[d]imidazol-2-yl)pyridyl)-2,8-diazaspirocyclic[4.5]dec-2-yl)(6-(anilino)pyridin-2-yl)methyl ketone (compound L-61)

[0659]

[0660] The procedure is the same as that used in the preparation of compound L-82 in Example 82.

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

[0662] 1H NMR(400MHz, Methanol-d4)δ8.40(ddd,J=11.2,8.0,1.0Hz,1H),8.13(dt,J=13.7,7.8Hz,1H),7.76–7.62(m,3H),7. 60(dd,J=7.7,1.0Hz,1H),7.58–7.50(m,2H),7.39–7.28(m,2H),7.22(dtd,J=16.2,7.3,1.9Hz,2H),7.08(ddd,J=7. 0,6.1,0.9Hz,1H),6.97–6.81(m,2H),4.10–3.91(m,1H),3.95–3.78(m,2H),3.73(dt,J=13.3,8.0Hz,2H),3.64–3.5 4(m,2H),3.44(dt,J=11.3,5.5Hz,1H),2.03–1.91(m,2H),1.75(td,J=12.5,12.1,5.9Hz,2H),1.62(t,J=5.9Hz,2H).

[0663] Example 62 (8-(6-(1H-benzo[d]imidazol-2-yl)pyridyl)-2,8-diazaspirocyclic[4.5]dec-2-yl)(2-(anilino)pyrimidin-4-yl)methyl ketone (compound L-62)

[0664]

[0665] The procedure is the same as that used in the preparation of compound L-82 in Example 82.

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

[0667] 1H NMR(400MHz, Methanol-d4)δ8.61–8.56(m,1H),8.40(ddd,J=9.1,7.9,1.0Hz,1H),8.14(dt,J=10.8,7 .9Hz,1H),7.74–7.67(m,2H),7.66(d,J=1.1Hz,1H),7.65–7.61(m,2H),7.34(tt,J=7.0,2.8Hz,2H),7 .31–7.23(m,2H),7.05–7.02(m,1H),7.01–6.94(m,1H),3.85(dq,J=10.6,6.2,5.1Hz,2H),3.76–3.70 (m,2H),3.61–3.55(m,1H),3.48(d,J=5.9Hz,1H),2.04–1.96(m,2H),1.76(s,2H),1.67–1.60(m,2H).

[0668] Example 63 (9-(6-(1H-benzo[d]imidazol-2-yl)pyridyl)-2,9-diazaspirocyclic[5.5]undecane-2-yl)(6-(anilino)pyridin-2-yl) methyl ketone (compound L-63)

[0669]

[0670] The procedure is the same as that used in the preparation of compound L-82 in Example 82.

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

[0672] 1H NMR(400MHz,Chloroform-d)δ8.68(s,1H),8.56(d,J=8.0Hz,1H),7.98(t,J=7.8Hz,1H),7.80–7.74(m,2H),7.48–7.40(m,1H),7.31(dd,J=6.1, 3.2Hz,2H),7.28–7.20(m,1H),7.13(dt,J=7.4,4.5Hz,2H),4.04–3.81( m,2H),3.86–3.72(m,2H),3.74–3.48(m,4H),3.01(s,2H),2.36(s,3H).

[0673] Example 64 (9-(6-(1H-benzo[d]imidazol-2-yl)pyridyl)-2,9-diazaspirocyclic[5.5]undecane-2-yl)(2-(anilino)pyrimidin-4-yl)methyl ketone (compound L-64)

[0674]

[0675] The procedure is the same as that used in the preparation of compound L-82 in Example 82.

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

[0677] 1H NMR (400MHz, Methanol-d4) δ8.58(d,J=4.9Hz,1H),8.43–8.36(m,1.5H),8.26(d,J=4.9Hz,0.5H),8.12(td,J=7.9,1.4Hz,1.5H) ,7.72–7.68(m,2H),7.64(dd,J=7.8,1.0Hz,2H),7.58–7.54(m,1.5H),7.33(tq,J=7.5,2.6Hz,5H),7.19(dd,J=8.6,7.3Hz,1H),7 .04(tt,J=7.4,1.2Hz,1H),6.91(d,J=4.9Hz,1H),6.55(d,J=4.9Hz,0.5H),4.10(dt,J=13.8,4.9Hz,1H),3.88–3.74(m,3H),3.64 (tdd,J=13.8,9.6,3.8Hz,4H),3.47(d,J=5.3Hz,2H),3.42(d,J=1.7Hz,1H),1.80(d,J=16.3Hz,2H),1.64(dd,J=9.7,4.8Hz,3H).

[0678] Example 65 (7-(6-(1H-benzo[d]imidazol-2-yl)pyridyl)-2,7-diazaspirocyclic[4.4]non-2-yl)(6-(anilino)pyridin-2-yl) methyl ketone (compound L-65)

[0679]

[0680] The procedure is the same as that used in the preparation of compound L-82 in Example 82.

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

[0682] 1H NMR (400MHz, Methanol-d4) δ8.49–8.42(m,1H),8.38(d,J=7.5Hz,1H),8.32(s,1H),8. 21–8.18(m,1H),8.17–8.05(m,2H),7.86(ddd,J=7.8,5.4,1.1Hz,1H),7.71(dt,J=7.1 ,3.5Hz,1H),7.61–7.55(m,2H),7.52–7.48(m,1H),7.40–7.27(m,2H),7.22(dt,J=6.2 ,3.6Hz,1H),6.95(dtd,J=11.7,6.8,1.2Hz,1H),4.18–3.59(m,8H),3.24–3.04(m,2H).

[0683] Example 66 (7-(6-(1H-benzo[d]imidazol-2-yl)pyridyl)-2,7-diazaspirocyclic[4.4]non-2-yl)(4-(anilino)pyrimidin-2-yl)methyl ketone (compound L-66)

[0684]

[0685] The procedure is the same as that used in the preparation of compound L-82 in Example 82.

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

[0687] 1H NMR(400MHz,Chloroform-d)δ8.62–8.57(m,1H),8.57–8.53(m,1H),8.01–7.91(m ,1H),7.82–7.77(m,1H),7.75-7.68(s,1H),7.71(s,1H),7.68–7.61(m,2H),7.47 (ddd,J=8.5,3.6,1.2Hz,1H),7.36–7.30(m,2H),7.27–7.22(m,1H),7.12–7.08(m ,1H),7.05–6.96(m,1H),3.96–3.68(m,6H),3.69–3.53(m,2H),2.02–1.88(m,4H).

[0688] Example 67 N-(3-(6-(1H-benzo[d]imidazol-2-yl)pyridyl)-3-azabicyclo[3.1.0]hex-6-yl)-6-methyl-1H-indole-2-carboxamide (compound L-67)

[0689]

[0690] The procedure is the same as that used in the preparation of compound L-82 in Example 82.

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

[0692] 1H NMR (400MHz, DMSO-d6) δ13.20(s,1H),11.43(d,J=2.1Hz,1H),9.33(d,J=3.1Hz,1H),8.46(dd,J=7.7,1.2Hz,1H),8.18( t,J=7.7Hz,1H),8.11(dd,J=7.7,1.2Hz,1H),7.77(dd,J=7.9,1.1Hz,1H),7.73–7.64(m,1H),7.55(d,J=8.2Hz,1H),7.3 5(ddd,J=8.2,7.2,1.2Hz,1H),7.28(ddd,J=8.3,7.2,1.3Hz,1H),7.25(dd,J=1.6,0.8Hz,1H),6.96(dd,J=2.3,0.9Hz,1 H),6.90(dd,J=8.2,1.5Hz,1H),4.17(s,3H),3.74(s,1H),2.62(q,J=2.7Hz,1H),2.41(s,3H),2.21(s,1H),2.09(s,1H).

[0693] Example 68 N-(3-(6-(1H-benzo[d]imidazol-2-yl)pyridyl)-3-azabicyclo[3.1.0]hex-6-yl)quinoline-2-carboxamide (compound L-68)

[0694]

[0695] The procedure is the same as that used in the preparation of compound L-82 in Example 82.

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

[0697] 1H NMR (400MHz, DMSO) δ13.18(s,1H),9.31(s,1H),8.50(dd,J=28.7,8.2Hz,1H),8.32–8.01(m,2H),7.98–7.81(m,1H),7.82–7.6 6(m,2H),7.40–7.22(m,2H),4.16(d,J=12.5Hz,1H),3.77(d,J=12.2Hz,1H),3.62(s,1H),3.18(d,J=5.2Hz,1H),2.10(s,1H).

[0698] Example 69 (5-(6-(1H-benzo[d]imidazol-2-yl)pyridyl)hexahydropyrrolo[3,4-c]pyrrolo-2(1H)-yl)(quinolin-2-yl)methyl ketone (compound L-69)

[0699]

[0700] (6-(1H-benzo[d]imidazol-2-yl)pyridin-2-yl)(hexahydropyrrolo[3,4-c]pyrrolo-2(1H)-yl) methyl ketone (33 mg, 0.1 mmol) and quinoline-2-carboxylic acid (17 mg, 0.1 mmol) were suspended in N,N-dimethylformamide (3 mL), and N,N-diisopropylethylamine (26 mg, 0.2 mmol) and 1-propylphosphoric anhydride (41 mg, 0.13 mmol) were added. The reaction mixture was stirred at 25 °C for 16 h. The reaction mixture was concentrated to obtain a crude product, which was purified by thin-layer chromatography (dichloromethane:methanol = 15:1) to give a pale yellow solid (15 mg, 31%). LC-MS: m / z: (M+H) + =488.9; 1 H NMR(400MHz,DMSO-d6)δ12.93(d,J=6.3Hz,1H),8.61–8.34(m,2H),8.14–8.03 (m,3H),7.96–7.53(m,6H),7.38–7.17(m,2H),4.21–3.56(m,8H),3.06(s,2H).

[0701] Example 70 (5-(6-(1H-benzo[d]imidazol-2-yl)pyridyl)hexahydropyrrolo[3,4-c]pyrrolo-2(1H)-yl)(6-methyl-1H-indol-2-yl)methyl ketone (compound L-70)

[0702]

[0703] The procedure is the same as that used in the preparation of compound L-82 in Example 82.

[0704] LC-MS:m / z:(M+H)+=491.1; 1 H NMR (400MHz, DMSO-d6) δ12.91(s,1H),11.42(s,1H),8.42(d,J=7.9Hz,1H),8.13(t,J=7.8Hz,1H),7.77(dd,J=27.7,7.7Hz,2H),7.59( d,J=7.4Hz,1H),7.54–7.38(m,1H),7.35–7.15(m,3H),6.92(t,J=20.7Hz,2H),4.20–3.56(m,8H),3.09(d,J=40.8Hz,2H),2.40(s,3H).

[0705] Example 71 (5-(6-(1H-benzo[d]imidazol-2-yl)pyridyl)hexahydropyrrolo[3,4-c]pyrrolo-2(1H)-yl)(2-methyl-1H-indol-3-yl)methyl ketone (compound L-71)

[0706]

[0707] The procedure is the same as that used in the preparation of compound L-82 in Example 82.

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

[0709] 1H NMR (400MHz, CDCl3) δ8.68(s,1H),8.56(d,J=7.7Hz,1H),7.98(t,J=7.8Hz,1H),7.77(d,J=7.4Hz,3H),7.51–7.40(m,1H) ,7.38–7.27(m,4H),7.18–7.06(m,2H),3.96–3.54(m,6H),3.01(s,2H),2.37(s,3H),2.03(d,J=5.9Hz,1H),1.66(s,1H).

[0710] Example 72 (9-(3-(imidazo[1,2-a]pyridin-2-yl)benzoyl)-3,9-diazaspiro[5.5]undecane-3-yl)(6-(anilino)pyridin-2-yl) methyl ketone (compound L-72)

[0711]

[0712] The procedure is the same as that used in the preparation of compound L-82 in Example 82.

[0713] LC-MS:m / z:(M+H) + =433.2;1H NMR (400MHz, Methanol-d4) δ8.46(d,J=6.8Hz,1H),8.31(s,1H),8.06(d,J=7.8Hz,1H),8.00(s,1H),7.66–7.54(m,5H),7.45–7.33(m,2H) ,7.27(t,J=7.9Hz,2H),6.96(td,J=6.8,4.4Hz,2H),6.88(t,J=7.2Hz,2H),3.79(d,J=16.7Hz,4H),3.54(s,5H),1.73(s,3H),1.63(s,5H).

[0714] Example 73 (3,9-diazaspirocyclic[5.5]undecane-3,9-diyl)bis((3-(imidazo[1,2-a]pyridin-2-yl)phenyl)methyl ketone) (compound L-73)

[0715]

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

[0717] LC-MS:m / z:(M+H) + / 2=298.2;1H NMR (400MHz, Methanol-d4) δ8.45(d,J=6.8Hz,2H),8.30(s,2H),8.05(d,J=7.9Hz,2H),8.00(d,J=1.8Hz,2H), 7.66–7.53(m,4H),7.46–7.31(m,4H),6.95(t,J=6.8Hz,2H),3.83(s,4H),3.52(s,4H),1.69(d,J=46.5Hz,9H).

[0718] Example 74 (Tetrahydropyrrole[3,4-c]pyrrole-2,5(1H,3H)-diyl)bis((3-(imidazo[1,2-a]pyridin-2-yl)phenyl)methyl ketone) (Compound L-74)

[0719]

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

[0721] LC-MS:m / z:(M+H) + =553.2;1H NMR (400MHz, Methanol-d4) δ8.43(dd,J=24.7,6.9Hz,2H),8.36–8.22(m,2H),8.10(dd,J=29.2,20.1Hz,4H),7.57(dd, J=25.5,8.6Hz,6H),7.34(dt,J=17.0,8.2Hz,2H),6.94(dt,J=13.9,6.8Hz,2H),4.05–3.50(m,9H),3.24–3.01(m,2H).

[0722] Example 75 (4-(2-hydroxyethyl)piperazin-1-yl)(3-(imidazo[1,2-a]pyridin-2-yl)phenyl)methyl ketone (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] 1. 9-(2-(2-(phenylamino)pyrimidin-4-carbonyl)-3,9-diazaspiro[5.5]undecane-3-carboxylic acid tert-butyl ester

[0742] 3,9-diazaspiro[5.5]undecane-3-carboxylic acid tert-butyl ester (100 mg, 0.39 mmol) (the compound shown in Formula 2) and 2-phenylaminopyrimidine-4-carboxylic acid (85 mg, 0.39 mmol) (the compound shown in Formula 1) were suspended in 3 mL of N,N-dimethylformamide. N,N-diisopropylethylamine (101 mg, 0.78 mmol) and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (179 mg, 0.47 mmol) were added. The reaction mixture was stirred at 30 °C for 16 h. 10 mL of ice water was added to the reaction mixture, and the mixture was stirred for five minutes. The mixture was filtered, and the solid was dried to give 175 mg of a 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]undecane-3-yl)methyl ketone

[0744] 9-(2-(2-(phenylamino)pyrimidin-4-carbonyl)-3,9-diazaspiro[5.5]undecane-3-carboxylic acid tert-butyl ester (175 mg, 0.39 mmol) (the compound shown in Formula 3) was dissolved in 3 mL of methanol, and dioxane hydrochloride 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 give a crude product of 136 mg as a 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)methyl ketone)

[0746] The procedure is the same as that used in the preparation of compound L-82 in Example 82.

[0747] LC-MS:m / z:(M+H)+=549.0,1H NMR (400MHz, CD3OD) δ8.55(d,J=4.9Hz,2H),7.67(dd,J=8.6,1.0Hz,4H),7.36–7.26(m,4H),7.03(t,J=7.4H z,2H),6.87(d,J=4.9Hz,2H),3.77(dd,J=11.7,5.6Hz,4H),3.50(dd,J=11.1,5.3Hz,4H),1.77–1.57(m,8H).

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

[0749]

[0750] I. (1-(2-(phenylamino)pyrimidin-4-carbonyl)piperidin-4-yl)tert-butyl carbamate

[0751] Tert-butylpiperidin-4-ylcarbamate (100 mg, 0.50 mmol) (the compound shown in Formula 2) and 2-phenylaminopyrimidine-4-carboxylic acid (107 mg, 0.50 mmol) (the compound 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'-tetramethylurea hexafluorophosphate (228 mg, 0.60 mmol) were added. The reaction mixture was stirred at 30 °C for 16 h. 10 mL of ice water was added to the reaction mixture, and the mixture was stirred for five minutes. The mixture was filtered, and the solid was dried to give 185 mg of a brown solid, with a yield of 93.21%. LC-MS: m / z: (M+H)+=498.0.

[0752] II. (4-aminopiperidin-1-yl)(2-(phenylamino)pyrimidin-4-yl)methyl ketone

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

[0754] III. 2-(phenylamino)-N-(1-(2-(2-(phenylamino)pyrimidin-4-carbonyl)piperidin-4-yl)pyrimidin-4-carboxamide

[0755] The procedure is the same as that used in the preparation of compound L-82 in Example 82.

[0756] LC-MS:m / z:(M+H)+=495.0,1H NMR (400MHz, CD3OD) δ8.66(d,J=4.9Hz,1H),8.57(d,J=4.9Hz,1H),7.74–7.60(m, 4H),7.41–7.24(m,5H),7.04(dt,J=20.0,7.4Hz,2H),6.91(d,J=4.9Hz,1H),4.56 (d,J=14.7Hz,1H),4.26–4.15(m,1H),3.98–3.89(m,1H),3.41–3.34(m,1H),3.23 –3.13(m,1H),2.19–2.08(m,1H),2.02(dd,J=9.1,4.0Hz,1H),1.79–1.63(m,2H).

[0757] Example 80 (9-(6-(phenylamino)pyridinyl)-3,9-diazaspiro[5.5]undecane-3-yl)(2-(phenylamino)pyrimidin-4-yl) methyl ketone (compound L-80)

[0758]

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

[0760] LC-MS: m / z: (M+H)+=548.0,1H NMR (400MHz, 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 =26.9,7.4Hz,2H),6.88(dd,J=9.5,5.7Hz,3H),3.77(dt,J=11.6,5.7Hz,4H),3.61–3.44(m,4H),1.83–1.50(m,8H).

[0761] Example 81 6-(phenylamino)-N-(1-(2-(phenylamino)pyrimidin-4-carbonyl)piperidin-4-yl)pyridinelinamide (compound L-81)

[0762]

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

[0764] LC-MS:m / z:(M+H)+=494.0,1H NMR (400MHz, CD3OD) δ8.57(d,J=4.9Hz,1H),7.69(dd,J=16.7,8.2Hz,3H),7.49(dd,J=18.9 ,7.5Hz,3H),7.31(dt,J=24.3,7.9Hz,4H),7.07–6.96(m,3H),6.91(d,J=4.9Hz,1H),4.46(d ,J=13.3Hz,1H),4.19(ddd,J=14.0,9.9,4.0Hz,1H),3.86(d,J=13.4Hz,1H),3.43–3.36(m, 1H),3.27(dd,J=13.6,3.0Hz,1H),2.23–2.11(m,1H),2.09–1.97(m,1H),1.76–1.60(m,2H).

[0765] Example 82 (5-(6-(1H-benzo[d]imidazol-2-yl)pyridinyl)hexahydropyrrolo[3,4-c]pyrrolo-2(1H)-yl)(2-(((4-fluorophenyl)amino)pyrimidin-4-yl)methyl ketone (compound L-82)

[0766]

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

[0768] 2-Chloropremine-4-carboxylic acid (500 mg, 3.15 mmol) was dissolved in 15 mL of dioxane, and p-fluoroaniline (881 mg, 9.46 mmol) was added. The reaction mixture was stirred at 70 °C for 18 hours. The reaction mixture was cooled to room temperature, and 20 mL of water and 10 mL of 1 N sodium hydroxide were added. The reaction mixture was extracted twice with ethyl acetate (20 mL * 2). The aqueous phase was acidified to pH 3 with 1 N hydrochloric acid. The solid was filtered and dried to give 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]pyrrolo-2(1H)-yl)(2-(((4-fluorophenyl)amino)pyrimidin-4-yl)methyl ketone

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

[0771] LC-MS:m / z:(M+H)+=549.0,1H NMR (400MHz, CDCl3) δ8.48 (ddd, J=39.8, 21.6, 6.4Hz, 2H), 8.03–7.54 (m, 6H) ,7.49–7.30(m,2H),7.26–6.93(m,3H),4.31–3.67(m,8H),3.12–2.91(m,2H).

[0772] Example 83 (Tetrahydropyrrolo[3,4-c]pyrrole-2,5(1H,3H)-diyl)bis((2-(phenylamino)pyrimidin-4-yl)methyl ketone) (Compound L-83)

[0773]

[0774] I. 5-(2-(phenylamino)pyrimidin-4-carbonyl)hexahydropyrrolo[3,4-c]pyrrolo-2(1H)-carboxylic acid tert-butyl ester

[0775] 2,3,3a,4,6,6a-hexahydro-1H-pyrrolo[3,4-c]pyrrole-5-carboxylic acid tert-butyl ester (100 mg, 0.47 mmol) (as shown in Formula 2) and 2-phenylaminopyrimidine-4-carboxylic acid (101 mg, 0.47 mmol) (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-propylphosphoric anhydride (449 mg, 0.71 mmol) were added. The reaction mixture was stirred at 15 °C for 16 h. 10 mL of ice water was added to the reaction mixture, and the mixture was stirred for 5 minutes. The mixture was filtered, and the solid was dried to give 180 mg of a brown solid, with a yield of 93.31%. LC-MS: m / z: (M+H)+=410.0.

[0776] II. (hexahydropyrrolo[3,4-c]pyrrolo-2(1H)-yl)(2-(phenylamino)pyrimidin-4-yl)methyl ketone

[0777] 180 mg (0.44 mmol) of 5-(2-(phenylamino)pyrimidin-4-carbonyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylic acid tert-butyl ester (as shown in Formula 3) was dissolved in 3 mL of methanol, and dioxane hydrochloride solution (3 mL, 4 M, 12 mmol) was added. The reaction mixture was stirred at 15 °C for 2 h. The reaction mixture was concentrated, and the solid was washed with ethyl acetate (10 mL) and dried to give 120 mg of crude product as a brown solid, with a yield of 88.24%. LC-MS: m / z: (M+H)+=310.0.

[0778] III. (Tetrahydropyrrolo[3,4-c]pyrrole-2,5(1H,3H)-diyl)bis((2-(phenylamino)pyrimidin-4-yl)methyl ketone)

[0779] The procedure is the same as that used in the preparation of compound L-82 in Example 82.

[0780] LC-MS: m / z: (M+H)+=507.0,1H NMR (400MHz, CDCl3) δ8.56–8.42(m,2H),7.53(dd,J=19.5,8.3Hz,4H),7.18(dt, J=30.7,7.3Hz,4H),7.03–6.79(m,4H),3.93–3.46(m,8H),2.94(d,J=7.4Hz,2H).

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

[0782]

[0783] I. ((1R,5S,6S)-6-(2-(phenylamino)pyrimidin-4-carboxamido)-3-azabicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester

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

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

[0786] ((1R,5S,6S)-6-(2-(phenylamino)pyrimidin-4-carboxamido)-3-azabicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester (180 mg, 0.45 mmol) (the compound shown in Formula 3) was dissolved in 3 mL of methanol, and dioxane hydrochloride 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, the solid was washed with ethyl acetate (10 mL), and dried to give a crude product of 120 mg as a brown solid, with a yield of 89.27%. LC-MS: m / z: (M+H)+=296.0.

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

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

[0789] LC-MS:m / z:(M+H)+=493.0,1H NMR(400MHz, DMSO-d6)δ9.80(d,J=28.2Hz,1H),8.70-8.62(m,2H),7.76-7.74(m,4H),7.32-7.25(m,4H),7.01-6.97(3,3H),4.04–3.96( m,1H),3.87(d,J=11.3Hz,1H),3.79(dd,J=11.4,3.9Hz,1H),3.59(dd,J=12.3,4.0Hz,1H),2.66(d,J=2.2Hz,1H),1.98(d,J=5.9Hz,2H).

[0790] Example 85 (2-(phenylamino)pyrimidin-4-yl)(piperazin-1-yl)methyl ketone piperazine-1,4-diylbis((2-(phenylamino)pyrimidin-4-yl)methyl ketone) (Compound L-85)

[0791]

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

[0793] 1-tert-butyloxycarbonyl-piperazine (100 mg, 0.54 mmol) (the compound shown in Formula 2) and 2-phenylaminopyrimidine-4-carboxylic acid (115 mg, 0.54 mmol) (the compound shown in Formula 1) were suspended in 3 mL of N,N-dimethylformamide. N,N-diisopropylethylamine (139 mg, 1.07 mmol) and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (245 mg, 0.64 mmol) were added. The reaction mixture was stirred at 30 °C for 16 h. 10 mL of ice water was added to the reaction mixture, and the mixture was stirred for five minutes. The mixture was filtered, and the solid was dried to give 190 mg of a brown solid, with a yield of 92%. LC-MS: m / z: (M+H)+=384.0.

[0794] II. ((2-(phenylamino)pyrimidin-4-yl)(piperazin-1-yl)methyl ketone

[0795] 4-(2-(phenylamino)pyrimidin-4-carbonyl)piperazine-1-carboxylic acid tert-butyl ester (190 mg, 0.49 mmol) (the compound shown in Formula 3) was dissolved in 3 mL of methanol, and dioxane hydrochloride 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 give a crude product of 139 mg as a brown solid, with a yield of 99.01%. LC-MS: m / z: (M+H)+=284.0.

[0796] III. (2-(phenylamino)pyrimidin-4-yl)(piperazin-1-yl)methyl ketone piperazine-1,4-diylbis((2-(phenylamino)pyrimidin-4-yl)methyl ketone)

[0797] The procedure is the same as that used in the preparation of compound L-82 in Example 82.

[0798] LC-MS: m / z: (M+H)+=481.0,1H NMR (400MHz, DMSO-d6) δ9.84 (d, J=21.0Hz, 2H), 8.74–8.51 (m, 2H), 7.71 (dd, J=20. 8,7.4Hz,4H),7.50–7.21(m,4H),7.13–6.78(m,4H),3.62(dd,J=76.7,37.7Hz,8H).

[0799] Example 86 Piperazine-1,4-dimethylbis((6-(phenylamino)pyridin-2-yl)methyl ketone) (Compound L-86)

[0800]

[0801] I. 4-(6-(phenylamino)pyridinyl)piperazine-1-carboxylic acid tert-butyl ester

[0802] 1-tert-butyloxycarbonyl-piperazine (100 mg, 0.54 mmol) (the compound shown in Formula 2) and 6-(phenylamino)pyridinecarboxylic acid (115 mg, 0.54 mmol) (the compound shown in Formula 1) were suspended in 3 mL of N,N-dimethylformamide. N,N-diisopropylethylamine (139 mg, 1.07 mmol) and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (245 mg, 0.64 mmol) were added. The reaction mixture was stirred at 30 °C for 16 h. 10 mL of ice water was added to the reaction mixture, and the mixture was stirred for five minutes. The mixture was filtered, and the solid was dried to give 190 mg of a brown solid, with a yield of 92%. LC-MS: m / z: (M+H)+=383.0.

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

[0804] 4-(6-(phenylamino)pyridinyl)piperazine-1-carboxylic acid tert-butyl ester (190 mg, 0.49 mmol) (the compound shown in Formula 3) was dissolved in 3 mL of methanol, and dioxane hydrochloride 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 give a crude product of 139 mg as a brown solid, with a yield of 99.12%. LC-MS: m / z: (M+H)+=283.0.

[0805] III. Piperazine-1,4-dimethylbis((6-(phenylamino)pyridin-2-yl)methyl ketone)

[0806] The procedure is the same as that used in the preparation of compound L-82 in Example 82.

[0807] LC-MS:m / z:(M+H)+=479.0,1H NMR (400MHz, DMSO-d6) δ9.21(d,J=26.7Hz,2H),7.81–7.50(m,6H),7.26(dt,J=44.9,7.5Hz,4H),7.03–6.70(m,6H),3.83–3.44(m,8H).

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

[0809]

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

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

[0812] 1H NMR (400MHz, DMSO-d6) δ8.45(dd,J=7.9,1.1Hz,2H),8.16(t,J=7.8Hz,2H),8.00(dd,J=7.8,1.1Hz,2H) ,7.70(s,4H),7.28(d,J=6.5Hz,4H),5.10(d,J=10.7Hz,2H),5.01(d,J=10.8Hz,2H),4.46–4.39(m,4H).

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

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

[0817] 1H NMR(400MHz,Chloroform-d)δ8.53(s,1H),8.20(t,J=7.8Hz,2H),8.03(dd,J=12.9,7.2Hz,4H),7.97(s,1H),7.90( d,J=7.7Hz,1H),7.74(d,J=9.0Hz,1H),7.68(d,J=9.1Hz,1H),7.51(q,J=8.0Hz,2H),7.39(d,J=7.6Hz,1H),7.35–7. 30(m,1H),7.22(dd,J=9.1,6.7Hz,1H),6.99(d,J=7.8Hz,1H),6.92(t,J=6.8Hz,1H),6.83(t,J=6.7Hz,1H),4.74(d ,J=28.3Hz,1H),4.33(d,J=10.0Hz,1H),3.89(s,1H),3.23(s,1H),3.05(s,1H),2.66(s,3H),2.23(t,J=7.7Hz,1H).

[0818] Example 89 3-(imidazo[1,2-a]pyridin-2-yl)-N-((1R,5S,6S)-3-(imidazo[1,2-a]pyridin-2-yl)benzoyl)-3-azabicyclo[3.1.0]hex-6-yl)benzamide (compound L-89)

[0819]

[0820] The procedure is the same as that used in the preparation of compound L-82 in Example 82.

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

[0822] 1H NMR(400MHz,Chloroform-d)δ8.36(d,J=1.8Hz,1H),8.14(ddd,J=7.8,6.7,3.3Hz,2H),8.06–8.01(m,2H) ,8.02–7.98(m,2H),7.81(dt,J=7.8,1.5Hz,1H),7.63(t,J=9.2Hz,2H),7.47(t,J=7.7Hz,2H),7.39(dt,J= 7.7,1.5Hz,1H),7.20(tdd,J=9.3,7.4,1.3Hz,2H),7.06(d,J=2.7Hz,1H),6.84–6.78(m,2H),4.32(d,J=12 .4Hz,1H),3.83–3.75(m,2H),3.64(dd,J=12.4,4.3Hz,1H),2.70(q,J=2.5Hz,1H),1.91(d,J=29.8Hz,2H).

[0823] Example 90 3-(imidazo[1,2-a]pyridin-2-yl)-N-(((1R,5S,6S)-3-(6-(phenylamino)pyridinyl)-3-azabicyclo[3.1.0]hex-6-yl)benzamide (Compound L-90)

[0824]

[0825] The procedure is the same as that used in the preparation of compound L-82 in Example 82.

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

[0827] 1H NMR(400MHz,Chloroform-d)δ8.42(s,1H),8.17(d,J=6.8Hz,1H),8.01(d,J=7.7Hz,1H),7.94(s,1H),7.85(d,J =7.8Hz,1H),7.69(d,J=9.1Hz,1H),7.58(t,J=7.9Hz,1H),7.51(t,J=7.8Hz,1H),7.37(s,2H),7.26(s,1H),7.2 0(d,J=7.4Hz,1H),7.10(q,J=5.1,4.3Hz,1H),6.90(dt,J=15.0,7.7Hz,3H),6.78(s,1H),4.29(d,J=12.4Hz,1H ),4.20(d,J=11.8Hz,1H),3.94(dd,J=11.8,4.1Hz,1H),3.77–3.65(m,2H),2.71(d,J=2.7Hz,1H),2.03(s,1H).

[0828] Example 91 6-(1H-benzo[d]imidazol-2-yl)-N-(3-((1,4-dioxy-1,4-dihydronaphthyl-2-yl)amino)-4-methylbenzoyl)-3-azabicyclo[3.1.0]hexane-6-yl)pyridineamide (compound L-91)

[0829]

[0830] 1. 3-Amino-4-methylbenzoic acid (1.5 g, 9.9 mmol), naphthyl-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 mixture was concentrated to dryness and recrystallized from EtOH (10 mL) and dried to give a red solid 3-[(1,4-dioxy-2-naphthyl)amino]-4-methylbenzoic acid (2 g, 66%).

[0831] II. The procedure is the same as that for the preparation of compound L-82 in Example 82.

[0832] LC-MS:m / z:(M+H) +=609.3;1H NMR(400MHz, Methanol-d4)δ8.45(dd,J=7.2,1.7Hz,1H),8.25–8.13(m,3H),8.04(dd,J=7 .6,1.3Hz,1H),7.79(dtd,J=25.1,7.4,1.4Hz,3H),7.63(d,J=7.4Hz,1H),7.54–7.44(m,3 H),7.36(s,2H),5.60(s,1H),4.31(d,J=12.3Hz,1H),3.99–3.82(m,2H),3.71(dd,J=12.3 ,4.5Hz,1H),2.72(t,J=2.5Hz,1H),2.36(s,3H),2.19–2.12(m,1H),2.07(d,J=9.9Hz,1H).

[0833] Example 92 (9-(3-(imidazo[1,2-a]pyridin-2-yl)benzoyl)-3,9-diazaspiro[5.5]undecane-3-yl)(3-(4-methyl-1H-imidazo-1-yl)phenyl) ketone (compound L-92)

[0834]

[0835] The procedure is the same as that used in the preparation of compound L-82 in Example 82.

[0836] LC-MS:m / z:(M+H) + / 2=280.2;1H NMR (400MHz, Methanol-d4) δ8.46(dt,J=6.8,1.2Hz,1H),8.30(d,J=0.7Hz,1H),8.11(d,J=1.4Hz,1H),8.05(dt,J=7.9,1.3Hz,1H),8.00(t,J=1.6Hz,1H ),7.72–7.54(m,5H),7.46–7.30(m,4H),6.96(td,J=6.8,1.2Hz,1H),3.82( s, 4H), 3.50 (d, J = 1.6Hz, 4H), 2.27 (d, J = 1.1Hz, 3H), 1.68 (d, J = 48.3Hz, 8H).

[0837] Example 93 6-(1H-benzo[d]imidazol-2-yl)-N-(3-(3-(4-methyl-1H-imidazol-1-yl)benzoyl)-3-azabicyclo[3.1.0]hexane-6-yl)pyridine amide (compound L-93)

[0838]

[0839] 1. (3-Methoxycarbonylphenyl)boronic acid (1.8 g, 10 mmol), 4-methyl-1H-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 hours. The reaction mixture was concentrated to dryness and purified by rapid chromatography (silica) (petroleum ether: ethyl acetate = 2:1) to give a white solid methyl 3-(4-methylimidazol-1-yl)benzoate (1 g, 46%).

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

[0841] III. The procedure is the same as that for the preparation of compound L-82 in Example 82.

[0842] LC-MS:m / z:(M+H) + =504.2;1H NMR (400MHz, Methanol-d4) δ8.46 (dd, J=7.3, 1.6Hz, 1H), 8.26–8.12 (m, 3H), 7.81–7. 62(m,5H),7.53(dt,J=7.5,1.4Hz,1H),7.45–7.32(m,3H),4.32(d,J=12.3Hz,1H),3.9 0(dd,J=11.0,4.5Hz,1H),3.82(d,J=10.9Hz,1H),3.75(dd,J=12.4,4.7Hz,1H),2.76( t,J=2.4Hz,1H),2.29(d,J=1.0Hz,3H),2.18(d,J=4.6Hz,1H),2.08(d,J=12.6Hz,1H).

[0843] Example 94 (9-(3-(benzo[d]thiazolyl)benzoyl)-3,9-diazaspiro[5.5]undecane-3-yl)(3-(imidazo[1,2-a]pyridin-2-yl)phenyl) ketone (compound L-94)

[0844]

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

[0846] LC-MS:m / z:(M+H) +=612.3;1H NMR(400MHz, Methanol-d4)δ8.46(dt,J=6.9,1.2Hz,1H),8.30(d,J=0.7Hz,1H),8.21(d t,J=7.8,1.4Hz,1H),8.19–8.16(m,1H),8.06(ddt,J=6.8,5.2,1.0Hz,3H),8.02–7.99(m ,1H),7.73–7.64(m,1H),7.64–7.54(m,4H),7.48(ddd,J=8.3,7.2,1.2Hz,1H),7.44–7.3 3(m,2H),6.96(td,J=6.8,1.2Hz,1H),3.84(s,4H),3.52(s,4H),1.70(d,J=48.3Hz,8H).

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

[0848]

[0849] The procedure is the same as that used in the preparation of compound L-82 in Example 82.

[0850] LC-MS:m / z:(M+H) + =664.3; 1H NMR(400MHz,Chloroform-d)δ8.14(ddd,J=15.6,7.3,2.1Hz,3H),8.04(d,J=7.9Hz ,1H),7.99(d,J=1.8Hz,1H),7.91(s,1H),7.79(td,J=7.6,1.4Hz,1H),7.74–7.62(m ,2H),7.50(t,J=7.7Hz,1H),7.43–7.33(m,4H),7.28–7.18(m,2H),6.83(t,J=6.7H z,1H),5.98(s,1H),3.79(s,4H),3.50(s,4H),2.34(s,3H),1.61(d,J=57.2Hz,8H).

[0851] Example 96 3-(4-(9-(3-(imidazo[1,2-a]pyridin-2-yl)benzoyl)-3,9-diazaspiro[5.5]undec-3-carbonyl)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 (400MHz, DMSO-d6) δ10.08(d,J=26.4Hz,1H),9.86(d,J=20.0Hz,1H),8.66(ddd,J=20.0,14.7,4.9Hz,2H),8.23(d dd,J=29.4,21.0,6.0Hz,2H),7.86–7.63(m,3H),7.29(dt,J=21.7,8.0Hz,2H),7.18–6.88(m,4H),3.79–3.46(m,8H).

[0861] Example 98 ((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-98)

[0862]

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

[0864] LC-MS:m / z:(M+H)+=550.0,1H NMR (400MHz, CDCl3) δ8.66(d,J=4.9Hz,1H),8.57(d,J=4.9Hz,1H),8.39(d,J =8.5Hz,2H),7.72(t,J=8.5Hz,1H),7.62(d,J=8.1Hz,2H),7.56(s,1H),7.35 (t,J=7.8Hz,2H),7.08(t,J=7.3Hz,1H),7.00(dd,J=13.2,5.9Hz,2H),6.92( d,J=4.9Hz,1H),3.86–3.67(m,4H),3.50(d,J=4.0Hz,4H),1.73–1.52(m,8H).

[0865] Example 99 (N-(1-(2-(phenylamino)pyrimidin-4-carbonyl)piperidin-4-yl)-2-(pyridin-2-ylamino)pyrimidin-4-carboxamide (E100124-081) (Compound L-99)

[0866]

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

[0868] LC-MS: m / z: (M+H)+=495.2,1H NMR (400MHz, CDCl3) δ9.31(s,1H),8.76(d,J=4.9Hz,1H),8.59(d,J=4.9Hz,1H),8.41(d,J=4.8Hz,1H),8.33( d,J=8.4Hz,1H),8.09(s,1H),7.86(d,J=8.2Hz,1H),7.79–7.72(m,1H),7.62(dd,J=14.3,6.4Hz,3H),7.34(t ,J=7.8Hz,2H),7.10–7.00(m,2H),6.95(d,J=4.9Hz,1H),4.63(d,J=13.5Hz,1H),4.32–4.18(m,1H),3.98(d, J=13.8Hz,1H),3.27(t,J=11.4Hz,1H),3.11–3.03(m,1H),2.09(dd,J=38.8,10.9Hz,2H),1.69–1.56(m,2H).

[0869] Example 100 (Tetrahydropyrrolo[3,4-c]pyrrole-2,5(1H,3H)-diyl)bis((6-(phenylamino)pyridin-2-yl)methyl ketone) (Compound L-100)

[0870]

[0871] I. 5-(6-(phenylamino)pyridinyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylic acid tert-butyl ester

[0872] Hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylic acid tert-butyl ester (100 mg, 0.47 mmol) (the compound shown in Formula 2) and 6-(phenylamino)pyridinecarboxylic acid (101 mg, 0.47 mmol) (the compound shown in Formula 1) were suspended 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 mixture was stirred at 30 °C for 16 h. 10 mL of ice water was added to the reaction mixture, and the mixture was stirred for five minutes. The mixture was filtered, and the solid was dried to give 190 mg of a brown solid, with a yield of 98.96%. LC-MS: m / z: (M+H)+=409.0.

[0873] II. (hexahydropyrrolo[3,4-c]pyrrolo-2(1H)-yl)(6-(phenylamino)pyridin-2-yl) methyl ketone

[0874] 190 mg (0.47 mmol) of 5-(6-(phenylamino)pyridinyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylic acid tert-butyl ester (as shown in Formula 3) was dissolved in 3 mL of methanol, and dioxane hydrochloride solution (3 mL, 4 M, 12 mmol) was added. The reaction mixture was stirred at 15 °C for 2 h. The reaction mixture was concentrated and dried to give 150 mg of crude product as a brown solid, with a yield of 94.38%. LC-MS: m / z: (M+H)+=309.0.

[0875] III. (Tetrahydropyrrolo[3,4-c]pyrrole-2,5(1H,3H)-diyl)bis((6-(phenylamino)pyridin-2-yl)methyl ketone)

[0876] The procedure is the same as that used in the preparation of compound L-82 in Example 82.

[0877] LC-MS:m / z:(M+H)+=505.0,1H NMR (400MHz, CDCl3) δ7.62 (td, J=8.1, 3.4Hz, 2H), 7.41–7.30 (m, 8H), 7.08 (ddd, J=12.8, 9.9, 5. 5Hz,2H),6.97–6.73(m,4H),4.05(ddd,J=13.8,9.7,4.8Hz,3H),3.91–3.65(m,5H),2.98(s,2H).

[0878] Example 101 6-(phenylamino)-N-(((1R,5S,6S)-3-(6-(phenylamino)pyridinyl)-3-azabicyclo[3.1.0]hexyl-6-yl)pyridinyl amide (compound L-101)

[0879]

[0880] I. (1R,5S,6S)-6-(6-(phenylamino)pyridinecarboxylate)-3-azabicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester (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) (the compound shown in Formula 2) and 6-(phenylamino)pyridinecarboxylic acid (108 mg, 0.50 mmol) (the compound 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 mixture was stirred at 30 °C for 16 h. 10 mL of ice water was added to the reaction mixture, and the mixture was stirred for five minutes. The mixture was filtered, and the solid was dried to give 198 mg of a 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]hexyl-6-yl)-6-(phenylamino)pyridinelineamide

[0883] (1R, 5S, 6S)-6-(6-(phenylamino)pyridinecarboxylate)-3-azabicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester (198 mg, 0.50 mmol) (the compound shown in Formula 3) was dissolved in 3 mL of methanol, and dioxane hydrochloride 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 give a crude product of 148 mg as a 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]hexyl-6-yl)pyridinylamide

[0885] The procedure is the same as that used in the preparation of compound L-82 in Example 82.

[0886] LC-MS:m / z:(M+H)+=491.0,1H NMR(400MHz, CDCl3)δ7.98(s,1H),7.68–7.57(m,3H),7.45–7.30(m,8H),7.21–7.08(m,3H),7.03–6.89(m,3H),6.70(s,1H),4 .30(d,J=12.5Hz,1H),4.18(d,J=11.6Hz,1H),3.98(d,J=11.6Hz,1H),3.76–3.68(m,1H),2.69(d,J=2.0Hz,1H),1.91(s,2H).

[0887] Example 102 (5-(6-(phenylamino)pyridyl)hexahydropyrrolo[3,4-c]pyrrolo-2(1H)-yl)(2-(phenylamino)pyrimidin-4-yl)methyl ketone (compound L-102)

[0888]

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

[0890] LC-MS:m / z:(M+H)+=506.0,1H NMR (400MHz, CD3OD) δ8.57(dd,J=12.9,4.9Hz,1H),7.70–7.61(m,2H),7.59–7.42(m,3H),7.36–6.71(m,9H),4.01–3.46(m,8H),3.11–2.92(m,2H).

[0891] Example 103 (2-(phenylamino)-N-(((1R,5S,6S)-3-(6-(phenylamino)pyridyl)-3-azabicyclo[3.1.0]hex-6-yl)pyrimidine-4-carboxamide (compound L-103)

[0892]

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

[0894] LC-MS: m / z: (M+H)+=492.0,1H NMR (400MHz, CD3OD) δ8.61(d,J=4.9Hz,1H),7.69–7.54(m,5H),7.32(dt,J=16.2,4.8Hz,5H),7.08–6.86(m,4H),4.20(d,J=12 .5Hz,1H),4.12(d,J=11.7Hz,1H),3.88(dd,J=11.8,4.3Hz,1H),3.72–3.63(m,1H),2.60(t,J=2.3Hz,1H),2.01–1.89(m,2H).

[0895] Example 104 N-((1R,5S,6S)-3-(3-(1H-pyrrolo-1-yl)thiophene-2-carbonyl)-3-azabicyclo[3.1.0]hex-6-yl)-3-(imidazo[1,2-a]pyridin-2-yl)benzamide (compound L-104)

[0896]

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

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

[0899] 1H NMR (400MHz, Chloroform-d) δ8.38 (s, 1H), 8.18 (d, J = 6.7Hz, 1H), 7.99 (d, J = 7.8Hz, 1H), 7.

[0900] 94(s,1H),7.82(d,J=7.8Hz,1H),7.68(d,J=9.1Hz,1H),7.50(t,J=7.7Hz,1H), 7.44(d,J=5.3Hz,1H),7.27(s,1H),7.06(d,J=5.3Hz,1H),6.90–6.85(m,1H),6. 74(s,1H),6.33(t,J=2.2Hz,2H),4.25(d,J=12.5Hz,1H),3.53(d,J=13.3Hz,1H) ,3.32(d,J=11.0Hz,1H),2.70–2.61(m,1H),2.45(t,J=2.5Hz,1H),1.86(s,1H).

[0901] Example 105 3-(imidazo[1,2-a]pyridin-2-yl)-N-((1R,5S,6S)-3-(2-phenoxynicotinamide)-3-azabicyclo[3.1.0]hex-6-yl)benzamide (compound L-105)

[0902]

[0903] The procedure is the same as that used in the preparation of compound L-82 in Example 82.

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

[0905] 1H NMR(400MHz,Chloroform-d)δ8.47(s,1H),8.21(dt,J=5.1,2.4Hz,2H),8.00(d,J=7.7Hz,1H),7.87(d,J=7.7 Hz,1H),7.77–7.68(m,2H),7.53(t,J=7.7Hz,1H),7.44(t,J=7.8Hz,2H),7.37–7.30(m,1H),7.26–7.18(m,3H ),7.08(dd,J=7.4,4.9Hz,1H),6.93(t,J=7.2Hz,2H),4.31(d,J=12.4Hz,1H),3.88–3.80(m,1H),3.76(d,J=1 0.8Hz,1H),3.69(dd,J=12.4,4.5Hz,1H),2.76(d,J=2.6Hz,1H),2.03(d,J=7.6Hz,1H),1.97(d,J=4.1Hz,1H).

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

[0907]

[0908] The procedure is the same as that used in the preparation of compound L-82 in Example 82.

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

[0910] 1H NMR (400MHz, DMSO-d6) δ13.60(s,1H),8.73(d,J=3.9Hz,1H),8.57(d,J=6.7Hz,1H),8.47(s,1H),8.42( d,J=1.9Hz,1H),8.16(d,J=8.2Hz,1H),8.11(dd,J=7.7,1.7Hz,1H),7.80–7.75(m,1H),7.65–7.58(m,2 H),7.54(t,J=7.8Hz,1H),7.45–7.41(m,1H),7.29(s,1H),7.24(t,J=7.5Hz,1H),6.94(s,1H),4.49(d, J=11.7Hz,1H),4.10(d,J=12.3Hz,1H),4.04–4.00(m,1H),3.70–3.62(m,2H),2.04(s,1H),1.97(s,1H).

[0911] Example 107 4-Butoxy-N-(1-(3-(imidazo[1,2-a]pyridin-2-yl)benzoyl)piperidin-4-yl)benzamide (Compound L-107)

[0912]

[0913] The procedure is the same as that used in the preparation of compound L-82 in Example 82.

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

[0915] 1H NMR(400MHz,Chloroform-d)δ8.17(d,J=6.8Hz,1H),8.04–7.98(m,2H),7.91(s,1H),7.79–7.73(m,2H),7.7 0(d,J=9.1Hz,1H),7.49(t,J=7.6Hz,1H),7.37(d,J=7.6Hz,1H),7.25(t,J=8.0Hz,1H),6.94–6.89(m,2H),6. 85(t,J=6.7Hz,1H),6.30(d,J=7.9Hz,1H),4.75(s,1H),4.28(d,J=6.9Hz,1H),3.86(s,1H),3.22(s,1H),3.0 2(s,1H),2.29(s,2H),2.03(s,1H),1.79(p,J=6.8Hz,2H),1.50(hept,J=6.8,6.2Hz,4H),1.02–0.95(m,3H).

[0916] Example 108 (4-(6-(1H-benzo[d]imidazol-2-yl]pyridinyl)piperazin-1-yl)(quinolin-3-yl)methyl ketone (compound L-108)

[0917]

[0918] The procedure is the same as that used in the preparation of compound L-82 in Example 82.

[0919] LC-MS:m / z:(M+H)+=463.0,1H NMR (400MHz, CDCl3) δ9.01(s,1H),8.63(s,1H),8.32(s,1H),8.17(d,J=8.1Hz,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=6.0,3.0Hz,2H),3.85(d,J=72.4Hz,8H).

[0920] Example 109 (4-(6-(1H-benzo[d]imidazol-2-yl]pyridinyl)piperazin-1-yl)(4-methylpyridin-3-yl)methyl ketone (compound L-109)

[0921]

[0922] The procedure is the same as that used in the preparation of compound L-82 in Example 82.

[0923] LC-MS:m / z:(M+H)+=427.0,1H NMR (400MHz, CDCl3) δ8.78–8.43(m,3H),8.04(d,J=7.4Hz,1H),7.74(d,J=22.5Hz,3H),7.39(s,2H),7.21(s,1H),4.01–3.29(m,8H),2.40(s,3H).

[0924] Example 110 (4-(6-(1H-benzo[d]imidazol-2-yl)pyridinyl)piperazin-1-yl)(1H-indazol-3-yl)methyl ketone (compound L-110)

[0925]

[0926] The procedure is the same as that used in the preparation of compound L-82 in Example 82.

[0927] LC-MS:m / z:(M+H)+=452.0,1H NMR(400MHz, CDCl3)δ11.00(d,J=117.6Hz,2H),8.52(s,1H),8.11(s,1H),7.97(t,J=7.8Hz,1H), 7.69(d,J=6.8Hz,3H),7.49(d,J=8.4Hz,1H),7.45–7.30(m,3H),7.22(s,1H),4.44–3.58(m,8H).

[0928] Example 111 6-(4-(6-(1H-benzo[d]imidazol-2-yl)pyridinyl)piperazine-1-carbonyl)-4,5-dihydropyridazine-3(2H)-one (Compound L-111)

[0929]

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

[0931] LC-MS:m / z:(M+H)+=432.0,1H NMR(400MHz, CDCl3)δ8.91(s,1H),8.57(s,1H),7.99(t,J=7.8Hz,1H),7.86– 7.60(m,3H),7.41–7.32(m,2H),4.00–3.61(m,8H),2.91(s,2H),2.62(s,2H).

[0932] Example 112 (4-(6-(1H-benzo[d]imidazol-2-yl]pyridinyl)piperazin-1-yl)(thiophen-2-yl)methyl ketone (compound L-112)

[0933]

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

[0935] LC-MS:m / z:(M+H)+=418.0,1H NMR (400MHz, CDCl3) δ8.57(d,J=7.8Hz,1H),8.01(dd,J=15.8,8.0Hz,1H),7.71(t,J=8.5 Hz,3H),7.50(d,J=5.0Hz,1H),7.41–7.32(m,3H),7.11–7.05(m,1H),4.09–3.67(m,8H).

[0936] Example 113 (3,9-diazaspiro[5.5]undecane-3,9-diyl)bis((6-(phenylamino)pyridin-2-yl)methyl ketone) (compound L-113)

[0937]

[0938] I. 9-(6-(6-(phenylamino)pyridinyl)-3,9-diazaspiro[5.5]undecane-3-carboxylic acid tert-butyl ester

[0939] 3,9-diazaspiro[5.5]undecane-3-carboxylic acid tert-butyl ester (187 mg, 0.74 mmol) (the compound shown in Formula 2) and 6-(phenylamino)pyridinecarboxylic acid (150 mg, 0.70 mmol) (the compound shown in Formula 1) were suspended in 3 mL of N,N-dimethylformamide, and N,N-diisopropylethylamine (181 mg, 1.40 mmol) and 1-propylphosphonic anhydride (668 mg, 1.05 mmol) were added. The reaction mixture was stirred at 15 °C for 16 h. 10 mL of ice water was added to the reaction mixture, and the mixture was stirred for 5 minutes. The mixture was filtered, and the solid was dried to give 220 mg of a 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]undecane-3-yl)methyl ketone

[0941] 9-(6-(6-(phenylamino)pyridinyl)-3,9-diazaspiro[5.5]undecane-3-carboxylic acid tert-butyl ester (175 mg, 0.33 mmol) (the compound shown in Formula 3) was dissolved in 5 mL of methanol, and dioxane hydrochloride solution (5 mL, 4 M, 20 mmol) was added. The reaction solution was stirred at 15 °C for 2 h. The reaction solution was concentrated and dried to give a crude product of 115 mg as a 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)methyl ketone)

[0943] The procedure is the same as that used in the preparation of compound L-82 in Example 82.

[0944] LC-MS:m / z:(M+H)+=547.0,1H NMR (400MHz, CDCl3) δ8.04(s,1H),7.64–7.56(m,2H),7.39–7.33(m,7H),7.11(dt,J=8.5,3.5H z,2H),6.99(d,J=7.2Hz,2H),6.91(d,J=8.4Hz,3H),3.67(d,J=96.1Hz,8H),1.75–1.51(m,8H).

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

[0946]

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

[0948] Tert-butylpiperidin-4-ylcarbamate (147 mg, 0.74 mmol) (the compound shown in Formula 2) and 6-(phenylamino)pyridinecarboxylic acid (150 mg, 0.70 mmol) (the compound shown in Formula 1) were suspended in 3 mL of N,N-dimethylformamide. N,N-diisopropylethylamine (181 mg, 1.4 mmol) and 1-propylphosphonic anhydride (668 mg, 1.05 mmol) were added. The reaction mixture was stirred at 30 °C for 16 h. 10 mL of ice water was added to the reaction mixture, and the mixture was stirred for five minutes. The mixture was filtered, and the solid was dried to give 230 mg of a 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)methyl ketone

[0950] (150 mg, 0.38 mmol) tert-butyl (1-(2-(phenylamino)pyrimidin-4-carbonyl)piperidin-4-yl)carbamate (as shown in Formula 3) was dissolved in 5 mL of methanol, and dioxane hydrochloride solution (5 mL, 4 M, 20 mmol) was added. The reaction mixture was stirred at 15 °C for 2 h. The reaction mixture was concentrated and dried to give 110 mg of crude product as a 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)pyridinylamide

[0952] The procedure is the same as that used in the preparation of compound L-82 in Example 82.

[0953] LC-MS:m / z:(M+H)+=493.0,1H NMR (400MHz, CDCl3) δ8.06–7.99(m,1H),7.72–7.61(m,3H),7.38(dt,J=13.4,8.0Hz,8H),7.15(t,J=7.1Hz,2H),6.98(dd,J=21.4 ,7.9Hz,3H),4.61(s,1H),4.28(d,J=8.2Hz,1H),3.96(s,1H),3.37–3.14(m,2H),2.12(d,J=28.1Hz,2H),1.73(d,J=10.2Hz,2H).

[0954] Example 115 3-(4-(4-(6-(1H-benzo[d]imidazol-2-yl)pyridyl)piperazine-1-carbonyl)benzamido)thiophene-2-carboxamide (Compound L-115)

[0955]

[0956] The procedure is the same as that used in the preparation of compound L-82 in Example 82.

[0957] LC-MS:m / z:(M+H) + =579.8;1H NMR(400MHz,Methanol-d4)δ8.41(s,1H),8.14(s,3H),7.81–7.61(m,5H),7.36 (d,J=16.9Hz,3H),6.98(s,1H),3.95(d,J=36.7Hz,4H),3.67(t,J=29.0Hz,4H).

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

[0959]

[0960] The procedure is the same as that used in the preparation of compound L-82 in Example 82.

[0961] LC-MS:m / z:(M+H) + =596.8;1H NMR(400MHz,Chloroform-d)δ8.58(s,1H),8.40–7.92(m,3H),7.72(s,5H),7.55–7.19(m,7H),6.03(s,1H),3.85(d,J=36.6Hz,8H),2.34(s,3H).

[0962] Example 117 (4-(6-(1H-benzo[d]imidazol-2-yl)pyridyl)piperazin-1-yl)(3-(4-methyl-1H-imidazol-1-yl)phenyl) methyl ketone (compound L-117)

[0963]

[0964] The procedure is the same as that used in the preparation of compound L-82 in Example 82.

[0965] LC-MS:m / z:(M+H) +=419.9;1H NMR (400MHz, Methanol-d4) δ8.41(s,1H),8.14(d,J=8.1Hz,2H),7.89–7.54(m,6H),7.48(s,1H),7.34(s,3H),4.19–3.48(m,8H),2.27(s,3H).

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

[0967]

[0968] 3-Imidazolo[1,2-a]pyridin-2-ylaniline (42 mg, 0.2 mmol) was dissolved in anhydrous dichloromethane (5 mL), and triphosgene (20 mg, 0.067 mmol) was added. The mixture was stirred at 25 °C for 16 h. The reaction mixture was concentrated to dryness and used directly in the next step.

[0969] [6-(1H-benzimidazol-2-yl)-2-pyridyl]-piperazin-1-yl-methyl ketone (63 mg, 0.2 mmol) and N,N-diisopropylethylamine (79 mg, 0.6 mmol) were dissolved in N,N-dimethylformamide (1 mL), and 2-(3-isocyanophenyl)imidazo[1,2-a]pyridine (48 mg, 0.2 mmol) was added. The reaction mixture was stirred at 25 °C for 2 hours. The reaction mixture was concentrated to dryness and purified by rapid chromatography (silica) (dichloromethane:methanol = 20:1) to give a yellow solid 4-[6-(1H-benzimidazol-2-yl)pyridin-2-carbonyl]-N-(3-imidazo[1,2-a]pyridin-2-ylphenyl)piperazin-1-carboxamide (35 mg, 32%).

[0970] LC-MS:m / z:(M+H) + / 2=272.0;1H NMR (400MHz, Methanol-d4) δ8.47–8.40(m,2H),8.20–8.12(m,2H),7.91(t,J=1.8Hz,1H),7.75(dd,J=7.8,1.0Hz,2H),7.62(dt,J=7.4,1. 5Hz,2H),7.56(d,J=9.1Hz,1H),7.46–7.29(m,5H),6.93(td,J=6.8,1.2Hz,1H),3.95(t,J=5.2Hz,2H),3.81(d,J=5.5Hz,2H),3.71(s,4H).

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

[0972]

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

[0974] LC-MS:m / z:(M+H) + / 2=223.0;1H NMR (400MHz, Methanol-d4) δ8.27(dt,J=6.8,1.2Hz,1H),8.04(s,1H),7.92(t,J=1.9Hz,1H),7.64– 7.51(m,3H),7.38(t,J=7.9Hz,1H),7.30(ddd,J=9.1,6.8,1.2Hz,1H),6.90(td,J=6.8,1.1Hz,1H).

[0975] Example 120 Synthesis of (5-(6-(1H-benzo[d]imidazol-2-yl)pyridyl)hexahydropyrrolo[3,4-c]pyrrolo-2(1H)-yl)(1H-indazol-3-yl) methyl ketone (Compound L-120)

[0976]

[0977] I. Synthesis of (6-(1H-benzo[d]imidazol-2-yl)pyridin-2-yl)(hexahydropyrrolo[3,4-c]pyrrolo-2(1H)-yl)methyl ketone hydrochloride

[0978] Procedure: 540 mg of tert-butyl 5-(6-(1H-benzo[d]imidazol-2-yl)pyridyl)hexahydropyrrole[3,4-c]pyrrole-2(1H)-carboxylic acid was added to a reaction flask, followed by 40 mL of methanol. After stirring, 20 mL of a 4 M / L hydrochloric acid / 1,4-dioxane solution was added, and the mixture was stirred overnight at room temperature. The next day, LC-MS showed that the reaction was complete. The solvent was removed by direct concentration under reduced pressure. 500 mg was obtained. Yield: 100%

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

[0980] II. Synthesis of (5-(6-(1H-benzo[d]imidazol-2-yl)pyridyl)hexahydropyrrolo[3,4-c]pyrrolo-2(1H)-yl)(1H-indazol-3-yl)methyl ketone.

[0981] Procedure: 60 mg (1 eq) of the starting material (6-(1H-benzimidazol-2-yl)pyridin-2-yl)(hexahydropyrrole[3,4-c]pyrrole-2(1H)-yl) methyl ketone hydrochloride) was added to a reaction flask, followed by 2 mL of anhydrous DMF, and then 26.25 mg (1 eq) of the starting material 1H-indazole-3-carboxylic acid. After stirring, 103.2 mg of T3P (1.5 eq) in 50% EA solution and 83.7 mg (3 eq) of DIPEA were added. The mixture was stirred overnight at 30°C. The reaction was completed by LC-MS the next day. Post-treatment: The reaction solution was poured into 20 mL of ice water and stirred. 50 mL of dichloromethane was added and extracted three times. The organic layers were combined, extracted with saturated brine, and dried over anhydrous sodium sulfate. The residue was filtered and concentrated to dryness. The residue was then passed through a column chromatography (DCM:MEOH = 0–5%) to obtain the product, which was further separated by thick-layer chromatography (DCM:MEOH = 95:5) to give 32.5 mg of pure product. Yield: 41.9%.

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

[0983] 1 H NMR (400MHz, Methanol-d4) δ8.46–8.37(m,1H),8.20(d,J=8.2Hz,1H),8.12(dt,J=10.1,7.9Hz,1H),7.88–7.81(m,1 H),7.77–7.52(m,3H),7.48–7.39(m,1H),7.37–7.19(m,3H),4.49–3.67(m,8H),3.17(ttd,J=15.6,7.3,3.4Hz,2H).

[0984] Example 121 Synthesis of 6-(5-(6-(1H-benzo[d]imidazol-2-yl)pyridyl)octahydropyrrole[3,4-c]pyrrole-2-carbonyl)-4,5-dihydropyridazine-3(2H)-one (Compound L-121)

[0985]

[0986] Procedure: 60 mg (1 eq) of the starting material (6-(1H-benzimidazol-2-yl)pyridin-2-yl)(hexahydropyrrolo[3,4-c]pyrrolo-2(1H)-yl) methyl ketone hydrochloride) was added to a reaction flask. 2 mL of anhydrous DMF was added, followed by 23.04 mg (1 eq) of the starting material 6-oxo-1,4,5,6-tetrahydropyridazine-3-carboxylic acid. After stirring, 103.2 mg of T3P (1.5 eq) in 50% EA solution and 83.7 mg (3 eq) of DIPEA were added. The mixture was stirred overnight at 30°C. The reaction was completed by LC-MS the next day. Post-treatment: The reaction solution was poured into 20 mL of ice water and stirred. 50 mL of dichloromethane was added for three extractions. The organic layers were combined, extracted with saturated brine, and dried over anhydrous sodium sulfate. The residue was filtered and concentrated to dryness. The residue was then passed through a column chromatography (DCM:MEOH = 0–5%) to obtain the product, which was further separated by thick-layer chromatography (DCM:MEOH = 95:5) to give 19.6 mg of pure product. Yield: 26.4%.

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

[0988] 1 H NMR(400MHz, Methanol-d4)δ8.42(ddd,J=7.9,4.6,0.9Hz,1H),8.14(td,J=7.9,1.0Hz,1H),7.88–7.82(m,1H),7.69(d,J=40.9Hz ,2H),7.34(d,J=4.9Hz,2H),4.24–3.52(m,8H),3.12(dddd,J=14.9,12.4,4.0,2.1Hz,2H),2.91–2.79(m,2H),2.61–2.45(m,2H).

[0989] Example 122 Synthesis of (5-(6-(1H-benzo[d]imidazol-2-yl)pyridyl)hexahydropyrrolo[3,4-c]pyrrolo-2(1H)-yl)(quinolin-3-yl)methyl ketone (Compound L-122)

[0990]

[0991] Procedure: 60 mg (1 eq) of the starting material (6-(1H-benzis[d]imidazol-2-yl)pyridin-2-yl)(hexahydropyrrole[3,4-c]pyrrole-2(1H)-yl) methyl ketone hydrochloride was added to a reaction flask. 2 mL of anhydrous DMF was added, followed by 28.08 mg (1 eq) of the starting material quinoline-3-carboxylic acid. After stirring, 103.2 mg of T3P (1.5 eq) in 50% EA solution and 83.7 mg (3 eq) of DIPEA were added. The mixture was stirred overnight at 30°C. The reaction was completed by LC-MS the next day. Post-treatment: The reaction solution was poured into 20 mL of ice water and stirred. 50 mL of dichloromethane was added and extracted three times. The organic layers were combined, extracted with saturated brine, and dried over anhydrous sodium sulfate. The residue was filtered and concentrated to dryness. The residue was then passed through a column chromatography (DCM:MEOH = 0–5%) to obtain the product, which was further separated by thick-layer chromatography (DCM:MEOH = 95:5) to give 41.8 mg of pure product. Yield: 52.8%.

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

[0993] 1 H NMR (400MHz, Methanol-d4) δ9.04(d,J=17.9Hz,1H),8.59(d,J=27.0Hz,1H),8.41(dd,J=22.3,7.9Hz,1H),8.18–7.82(m,5H),7. 69(dt,J=32.4,7.4Hz,3H),7.33(s,2H),4.28–4.04(m,2H),3.96(tt,J=13.6,8.3Hz,2H),3.88–3.56(m,4H),3.29–3.05(m,2H).

[0994] Example 123 Synthesis of (5-(6-(1H-benzo[d]imidazol-2-yl)pyridyl)hexahydropyrrolo[3,4-c]pyrrolo-2(1H)-yl)(4-methylpyridin-3-yl)methyl ketone (Compound L-123)

[0995]

[0996] Procedure: 60 mg (1 eq) of the starting material (6-(1H-benzimidazol-2-yl)pyridin-2-yl)(hexahydropyrrole[3,4-c]pyrrole-2(1H)-yl) methyl ketone hydrochloride) was added to a reaction flask. 2 ml of anhydrous DMF was added, followed by 22.2 mg (1 eq) of the starting material 4-methylnicotinic acid. After stirring, 103.2 mg of T3P (1.5 eq) in 50% EA solution and 83.7 mg (3 eq) of DIPEA were added. The mixture was stirred overnight at 30°C. The reaction was completed by LC-MS the next day. Post-treatment: The reaction solution was poured into 20 ml of ice water and stirred. 50 ml of dichloromethane was added for three extractions. The organic layers were combined, extracted with saturated brine, and dried over anhydrous sodium sulfate. The mixture was filtered and concentrated to dryness. The residue was passed through a column chromatography (DCM:MEOH = 0–5%) to obtain the product, which was then separated by thick-layer chromatography (DCM:MEOH = 95:5) to obtain 49.1 mg of pure product. Yield: 67%.

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

[0998] 1 H NMR(400MHz, Methanol-d4)δ8.50(d,J=5.5Hz,1H),8.47–8.37(m,2H),8.14(dt,J=10.7,7.8Hz,1H),7.90–7.81(m,1 H),7.72(s,2H),7.46–7.29(m,3H),4.25–3.85(m,4H),3.81–3.49(m,4H),3.20–3.06(m,2H),2.38(d,J=29.1Hz,3H).

[0999] Example 124 Synthesis of (5-(6-(1H-benzo[d]imidazol-2-yl)pyridyl)hexahydropyrrolo[3,4-c]pyrrolo-2(1H)-yl)(3-chloro-4-fluorophenyl)methyl ketone (Compound L-124)

[1000]

[1001] Procedure: 80 mg (1 eq) of the starting material (6-(1H-benzimidazol-2-yl)pyridin-2-yl)(hexahydropyrrole[3,4-c]pyrrole-2(1H)-yl) methyl ketone hydrochloride) was added to a reaction flask, followed by 2 ml of anhydrous DMF, and then 37.76 mg (1 eq) of the starting material 3-chloro-4-fluorobenzoic acid. After stirring, 137.6 mg of T3P (1.5 eq) in 50% EA solution and 111.6 mg (3 eq) of DIPEA were added. The mixture was stirred overnight at 30°C. The reaction was completed by LC-MS the next day. Post-treatment: The reaction solution was poured into 20 ml of ice water and stirred. 50 ml of dichloromethane was added for extraction three times. The organic layers were combined, extracted with saturated brine, and dried over anhydrous sodium sulfate. The residue was filtered and concentrated to dryness. The residue was then passed through a column chromatography (DCM:MEOH = 0–5%) to obtain the product, which was further separated by thick-layer chromatography (DCM:MEOH = 95:5) to give 55 mg of pure product. Yield: 51.88%.

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

[1003] 1 H NMR (400MHz, DMSO-d6) δ12.92(s,1H),8.41(t,J=7.6Hz,1H),8.13(q,J=7.5Hz,1H),7.83–7.77(m,2H),7.73(t,J=6.9Hz,1H),7. 59(q,J=7.5,6.9Hz,2H),7.48(dt,J=32.4,8.9Hz,1H),7.26(dq,J=14.6,7.7,7.2Hz,2H),4.18–3.35(m,8H),3.11–2.90(m,2H).

[1004] Example 125 Synthesis of (5-(6-(1H-benzo[d]imidazol-2-yl)pyridyl)hexahydropyrrolo[3,4-c]pyrrolo-2(1H)-yl)(2-methylquinoline-6-yl) methyl ketone (Compound L-125)

[1005]

[1006] Procedure: 80 mg (1 eq) of the starting material (6-(1H-benzimidazol-2-yl)pyridin-2-yl)(hexahydropyrrole[3,4-c]pyrrole-2(1H)-yl) methyl ketone hydrochloride) was added to a reaction flask, followed by 2 mL of anhydrous DMF, and then 40.48 mg (1 eq) of the starting material 2-methylquinoline-6-carboxylic acid. After stirring, 137.6 mg of T3P (1.5 eq) in 50% EA solution and 111.6 mg (3 eq) of DIPEA were added. The mixture was stirred overnight at 30°C. The reaction was completed by LC-MS the next day. Post-treatment: The reaction solution was poured into 20 mL of ice water and stirred. 50 mL of dichloromethane was added and extracted three times. The organic layers were combined, extracted with saturated brine, and dried over anhydrous sodium sulfate. The residue was filtered and concentrated to dryness. The residue was then passed through a column chromatography (DCM:MEOH = 0–5%) to obtain the product, which was further separated by thick-layer chromatography (DCM:MEOH = 95:5) to give 70 mg of pure product. Yield: 64.5%.

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

[1008] 1 H NMR(400MHz,DMSO-d6)δ12.93(s,1H),8.46–8.24(m,2H),8.20–8.07(m,2H),7.94 (dd,J=29.9,8.9Hz,1H),7.86(d,J=8.6Hz,1H),7.80(d,J=7.6Hz,1H),7.73(dd,J= 11.9,7.9Hz,1H),7.61(dd,J=16.2,7.9Hz,1H),7.48(dd,J=26.5,8.6Hz,1H),7.26 (dq,J=14.1,7.1Hz,2H),4.19–3.47(m,8H),3.12–2.91(m,2H),2.72–2.62(m,3H).

[1009] Example 126 Synthesis of (5-(6-(1H-benzo[d]imidazol-2-yl)pyridyl)hexahydropyrrole[3,4-c]pyrrole-2(1H)-yl)(4-(4-chlorophenyl)cyclohexyl) ketone (Compound L-126)

[1010]

[1011] Procedure: 80 mg (1 eq) of the starting material (6-(1H-benzimidazol-2-yl)pyridin-2-yl)(hexahydropyrrole[3,4-c]pyrrole-2(1H)-yl) methyl ketone hydrochloride) was added to a reaction flask, followed by 2 mL of anhydrous DMF, and then 51.6 mg (1 eq) of the starting material 4-(4-chlorophenyl)cyclohexane-1-carboxylic acid. After stirring, 137.6 mg of T3P (1.5 eq) in 50% EA solution and 111.6 mg (3 eq) of DIPEA were added. The mixture was stirred overnight at 30°C. The reaction was completed by LC-MS the next day. Post-treatment: The reaction solution was poured into 20 mL of ice water and stirred. 50 mL of dichloromethane was added for extraction three times. The organic layers were combined, extracted with saturated brine, and dried over anhydrous sodium sulfate. The residue was filtered and concentrated to dryness. The residue was then passed through a column chromatography (DCM:MEOH = 0–5%) to obtain the product, which was further separated by thick-layer chromatography (DCM:MEOH = 95:5) to give 53 mg of pure product. Yield: 44.2%.

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

[1013] 1 H NMR (400MHz, DMSO-d6) δ12.93(d,J=22.3Hz,1H),8.41(d,J=7.9Hz,1H),8.17–8.08(m,1H),7.82–7.69(m,2H),7.59(t,J=6.7Hz,1H),7. 28(ddd,J=30.5,16.0,7.3Hz,6H),4.16–3.33(m,8H),3.11–2.87(m,2H),2.43(t,J=10.0Hz,2H),1.94–1.70(m,4H),1.61–1.39(m,4H).

[1014] Example 127 Synthesis of (5-(6-(1H-benzo[d]imidazol-2-yl)pyridyl)hexahydropyrrolo[3,4-c]pyrrolo-2(1H)-yl)([1,1'-biphenyl]-4-yl) methyl ketone (compound L-127)

[1015]

[1016] Procedure: 80 mg (1 eq) of the starting material (6-(1H-benzis[d]imidazol-2-yl)pyridin-2-yl)(hexahydropyrrole[3,4-c]pyrrole-2(1H)-yl) methyl ketone hydrochloride was added to a reaction flask. 2 mL of anhydrous DMF was added, followed by 43 mg (1 eq) of the starting material [1,1'-biphenyl]-4-carboxylic acid. After stirring, 137.6 mg of T3P (1.5 eq) in 50% EA solution and 111.6 mg (3 eq) of DIPEA were added. The mixture was stirred overnight at 30°C. The reaction was completed by LC-MS the next day. Post-treatment: The reaction solution was poured into 20 mL of ice water and stirred. 50 mL of dichloromethane was added and extracted three times. The organic layers were combined, extracted with saturated brine, and dried over anhydrous sodium sulfate. The residue was filtered and concentrated to dryness. The residue was then passed through a column chromatography (DCM:MEOH = 0–5%) to obtain the product, which was further separated by thick-layer chromatography (DCM:MEOH = 95:5) to give 32 mg of pure product. Yield: 28.8%.

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

[1018] 1 H NMR(400MHz, DMSO-d6)δ12.94(s,1H),8.41(dd,J=13.3,8.0Hz,1H),8.13(q,J=7.9Hz,1H),7.83–7.70(m,4H),7.70–7 .57(m,5H),7.46(ddt,J=25.7,13.0,6.6Hz,3H),7.27(dt,J=13.4,6.5Hz,2H),4.14–3.36(m,8H),3.13–2.91(m,2H).

[1019] Receptor binding example: LANCL2 binding example

[1020] 1. Experimental Materials

[1021] 1.1 Reagents and Materials

[1022] Ligand: LANCL2

[1023] Running buffer: 20 mM MES, 150 mM NaCl, 0.05% P2O, pH 6.5, 1% DMSO

[1024] 1.2 Instruments and Equipment

[1025] Instrument Name: Biacore S200

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

[1027] 2. Experimental Methods

[1028] 2.1 Ligand Coupling

[1029] The LANCL2 protein was fixed and diluted to 50 μg / ml using sodium acetate solution at pH 4.0.

[1030] Injection conditions: The CM5 chip surface was activated using an EDC / NHS mixture at a flow rate of 10 μl / min for 420 s. LANCL2 was then injected at a flow rate of 5 μl / min for 2000 s, with a single ligand coupling amount of approximately 1800 RU. Finally, the chip surface was sealed with ethanolamine at a flow rate of 10 μl / min for 420 s.

[1031] Coupling buffer: 20mM MES, 150mM NaCl, 0.05% P2O, pH 6.5.

[1032] 2.2 Experimental Conditions

[1033] Analytes: All small molecule compound samples were diluted 2-fold from 50 μM to 0.78 μM, and the final compound solution contained 1% DMSO.

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

[1035] Run buffer: 20mM MES, 150mM NaCl, 0.05% P2O, pH 6.5, 1% DMSO.

[1036] Sample chamber temperature: 25℃; Analysis temperature: 25℃.

[1037] method

[1038] Kinetic determination of LANCL2-small molecule interactions. The BIACORE S200 was used to determine the binding kinetic parameters of small molecules BT-11 and L-1–60 (analytes) with LANCL2 (ligands). Data were generated in triplicate in a dose-dependent manner (5–8 titration points) and analyzed to determine the binding model (Langmuir, conformational shift, etc.), real-time association and dissociation constants, and equilibrium dissociation constants. SPR technology allows for validation of specific LANCL2-phytochemical interactions and enhances the gold standard understanding of binding mechanisms and rates. Experiments were performed by covalently attaching LANCL2 to a carboxymethyl polyglucose (CM5) sensor chip via amine coupling. Data were analyzed using BIACORE S200T200 evaluation software (version 1) to determine the affinity binding constant (KD) using a 1:1 binding model.

[1039] result

[1040] The compounds of this 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. SPR, an optical technique for detecting molecular interactions, was used to measure the binding affinity between LANCL2 and its ligand (the analyte). We immobilized purified recombinant LANCL2 protein on a BIACORE sensor chip and injected small molecules onto the protein surface using the instrument's microfluidic system. The change in the total mass on the chip surface was measured, corresponding to the small binding with the protein. By injecting a series of small molecule concentrations, we were able to calculate the binding signal and dissociation signal of the analyte to LANCL2, calculate the steady-state binding affinity of the compound, and obtain binding signal curves of the compound at different concentrations (for some compounds whose affinity is difficult to calculate, their binding signal curves at different concentrations are included in this patent as evidence of the compound's binding activity). The binding sensor plots show typical small molecule-protein interactions with extremely fast association and dissociation rates. These rapid interactions are beyond the instrument's technical capabilities. 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 how tightly the ligand binds to a specific protein. Ligand-protein affinity is influenced by non-covalent intermolecular interactions between the two molecules, such as hydrogen bonding, electrostatic interactions, hydrophobic forces, and van der Waals forces. By plotting equilibrium binding levels against compound concentrations, we can measure the steady-state affinity (Kd) of each interaction. The compounds of this invention exhibit good binding to the LANCL2 protein; in fact, some compounds of this 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), show superior binding activity compared to the positive reference compound BT-11.

[1041] The specific data is shown in the table below.

[1042]

[1043]

[1044]

[1045] KD(M) represents binding force (unit: mol); Rmax(RU) represents maximum binding force; N / A indicates no binding activity; " / " indicates that the KD cannot be calculated due to the test results, and the binding activity will be shown as a binding curve in this section. The figure shows the binding signal intensity of the compound at different concentrations; 'a' indicates poor solubility. Binding curves of some compounds are shown below. Figures 1 to 12 .

[1046] Study on the alleviating effect of the compound of this invention on TNBS-induced enteritis in mice (Part 1)

[1047] 1. Research Background

[1048] IBD is a class of autoimmune diseases, which can be divided into Crohn's disease and ulcerative colitis. This project uses a TNBS-induced colitis model in mice to simulate Crohn's disease and evaluates the efficacy of corresponding compounds, with the aim of developing drugs to treat Crohn's disease.

[1049] 2. Research Objectives

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

[1051] 3. Reagents

[1052] DPBS Corning 21-031-CVR TNBS Beijing Ouhe 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% Aphrodine Nanjing Aibei Biotechnology Co., Ltd. M2910

[1053] 4. Instruments

[1054] Electronic balance Changzhou's Balance YH-2000 Electronic analytical balance Mettle Toledo 585310

[1055] 5. Experimental Methods

[1056] 5.1 Dissolution and Preservation of Compounds

[1057] Preparation method of L56: Weigh an appropriate amount of L56 compound into a brown sample vial, add a certain volume of solvent 95% (20% HP-β-CD) + 5% (10% sodium benzoate), vortex for 1 minute, and sonicate to promote dissolution. The compound should be prepared once a day.

[1058] Preparation method of L30: Weigh an appropriate amount of L30 compound into a brown sample vial, add a certain volume of solvent 95% (20% HP-β-CD) + 5% (10% sodium benzoate), vortex for 1 minute, and sonicate to promote dissolution. The compound should be prepared once a day.

[1059] Preparation method of Mesa (Mesalamine): Weigh an appropriate amount of mesalamine (Selleck) compound into a brown sample vial, add a certain volume of 0.5% CMC-Na solvent, vortex for 1 minute, and sonicate to promote dissolution. Prepare the compound once daily.

[1060] 5.2 Route and frequency of compound administration

[1061] Fifty-six female Balb / c mice, weighing approximately 18g and aged 8-10 weeks, were randomly divided into 7 groups: 6 model groups and 1 Sham control group. Drug administration began on Day 1 and ended on Day 7. The compound was prepared once daily. Specific routes and frequencies of administration are detailed in Table 1, and compound preparation and administration volumes are shown in Table 2.

[1062] Table 1 Animal grouping and administration regimen

[1063] 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 control drug is Mesalamine (Mesa).

[1065] Table 2 Dosage volume and final drug concentration

[1066]

[1067]

[1068] Note: Mice were weighed before administration. The table above shows the administration volume calculated based on a 20-gram mouse.

[1069] 5.3 Construction of a TNBS-induced mouse enteritis model

[1070] On Day 0, Balb / c mice weighing approximately 18-20 grams were anesthetized with 0.25 ml of 1.25% aphthylamine. The model group mice were rectally instilled with 150 μL of 1% TNBS solution (final concentration 50% ethanol). The Sham control group mice were rectally instilled with 50% ethanol on Day 0.

[1071] 5.4 Fixation of mouse colon tissue

[1072] The colons of mice were photographed, their length measured, and their contents removed and weighed. Then, the colons of each mouse were longitudinally cut at half length, rolled in a uniform direction using the Swiss-roll method, and fixed in neutral paraformaldehyde.

[1073] 5.5 DAI Scoring Criteria

[1074] The DAI score consists of three parts, using a combined scoring method based on weight change, fecal matter, and blood in the stool. The specific DAI scoring criteria are shown in Table 3. Throughout the experiment, the DAI scores for all mice were completed by the same person to ensure consistency in scoring scales.

[1075] Table 3 DAI Scoring Criteria

[1076] 0 0 normal negative occult blood 1 1～5 soft stool Weak positive for occult blood 2 6～10 loose stool Occult blood positive 3 11～20 loose stool bloody stool 4 >20 extremely loose stools Large amount of bloody stool

[1077] 5.6 Colonic Histopathological Scoring Criteria

[1078] The histopathological scoring of mouse colon tissue consists of five parts, and the specific scoring criteria are shown in Table 4. The histopathological scoring was conducted using a double-blind method by professional pathologists from the clinical pathology platform.

[1079] Table 4. Colonic Tissue Pathology Scoring Criteria

[1080]

[1081] 5.7 Statistical Analysis

[1082] Experimental data were statistically analyzed using ANOVA. For the positive control group (Mesalamine, PO, 100 mpk, QD), the L56 group (PO, 50 mpk, BID), and the L30 group (PO, 50 mpk, BID), the values ​​were *p<0.05, **p<0.01, ***p<0.005, and ****p<0.0001.

[1083] 6. Results and Analysis

[1084] 6.1 Changes in mouse body weight and DAI score

[1085] Body weight data of mice in each group were collected over 10 days (Day-1 to Day-8), and corresponding DAI scores were calculated. Data analysis was performed using a two-way ANOVA method. Figure 13 Data from group A showed that, compared to the Vehicle group, the weight loss of mice in the L56 (PO, 50 mpk, BID) group and the Mesalamine (PO, 100 mpk, QD) group was significantly slower, while the weight loss of mice in the L30 (PO, 50 mpk, BID) group was significantly slower than that of mice in the Vehicle group from Day 5 to Day 8. Figure 13 The DAI score data for mice in group B also showed that, compared to the Vehicle group, the DAI scores of mice in the L30 (PO, 50 mpk, BID), L56 (PO, 50 mpk, BID), and Mesalamine (PO, 100 mpk, QD) groups were significantly lower. Considering both weight change and DAI score, we found that the L30 (PO, 50 mpk, BID) and L56 (PO, 50 mpk, BID) groups effectively alleviated the weight loss in mice caused by TNBS-induced colitis.

[1086] Note: Figure 13In 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 from group A showed that, compared to the vehicle group, 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 showed that, compared to the vehicle group mice, the colons of the Mice in the L56 (PO, 50 mpk, BID) group and the Mesalamine (PO, 100 mpk, QD) group were significantly longer. Figure 14 Data from group C indicate that, compared to the vehicle group mice, the colonic weights of mice in the L30 (PO, 50 mpk, BID) group, L56 (PO, 50 mpk, BID) group, and Mesalamine (PO, 100 mpk, QD) group were slightly lower, similar to those in the Sham group mice. These data further demonstrate 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] We then stained the colon tissues of the seven groups of mice with hematoxylin and eosin (HE) and had them scored by pathologists. Compared to the Vehicle group, the pathological scores of the colon tissues of the L56 (PO, 50 mpk, BID) and Mesalamine (PO, 100 mpk, QD) groups were significantly lower. This further demonstrates that L56 (PO, 50 mpk, BID) can effectively alleviate enteritis in TNBS model mice.

[1092] in conclusion

[1093] Data from in-life experiments and pathological analysis show that L56(PO, 50mpk, BID) can effectively alleviate TNBS-induced enteritis in mice.

[1094] Intestinal morphology as Figure 15 (Sham group & Vehicle group, Mesalamine (PO, 100mpk, QD) group & L56 (PO, 50mpk, BID) group and L30 (PO, 50mpk, BID) group.

[1095] Study on the alleviating effect of the compounds of this invention on TNBS-induced enteritis in mice (Part II)

[1096] 1. Research Background

[1097] IBD is a class of autoimmune diseases, which can be divided into Crohn's disease and ulcerative colitis. This project uses a TNBS-induced colitis model in mice to simulate Crohn's disease and evaluates the efficacy of corresponding compounds, with the aim of developing drugs to treat Crohn's disease.

[1098] 2. Research Objectives

[1099] This project aims to test the alleviating effect of representative compounds on TNBS-induced colitis in mice.

[1100] 3. Reagents

[1101] DPBS Corning 21-031-CVR TNBS Beijing Ouhe 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% Aphrodine Nanjing Aibei Biotechnology Co., Ltd. M2910

[1102] 4. Instruments

[1103] Electronic balance Changzhou's Balance YH-2000 Electronic analytical balance Mettle Toledo 585310

[1104] 5. Experimental Methods

[1105] 5.1 Dissolution and Preservation of Compounds

[1106] Preparation method of BT-11: Weigh an appropriate amount of BT-11 compound into a brown sample vial, add a certain volume of 0.5% CMC-Na solvent, vortex for 1 minute, and sonicate to promote dissolution. Prepare the compound once daily.

[1107] Preparation method of L11: Weigh an appropriate amount of L11 compound into a brown sample vial, add a certain volume of 0.5% CMC-Na solvent, vortex for 1 minute, and sonicate to promote dissolution. Prepare the compound once a day.

[1108] Preparation method of L25: Weigh an appropriate amount of L25 compound into a brown sample vial, add a certain volume of 0.5% CMC-Na solvent, vortex for 1 minute, and sonicate to promote dissolution. The compound should be prepared once a day.

[1109] Preparation method of L84: Weigh an appropriate amount of L84 compound into a brown sample vial, add a certain volume of 0.5% CMC-Na solvent, vortex for 1 minute, and sonicate to promote dissolution. Prepare the compound once a day.

[1110] Preparation method of L77: Weigh an appropriate amount of L77 compound into a brown sample vial, add a certain volume of 0.5% CMC-Na solvent, vortex for 1 minute, and sonicate to promote dissolution. Prepare the compound once a day.

[1111] Preparation method of L101: Weigh an appropriate amount of L101 compound into a brown sample vial, add a certain volume of sodium chloride injection solution (physiological saline), vortex for 1 minute, and sonicate to promote dissolution. The compound should be prepared once a day.

[1112] Preparation method of L10: Weigh an appropriate amount of L10 compound into a brown sample vial, add a certain volume of 0.5% CMC-Na solvent, vortex for 1 minute, and sonicate to promote dissolution. The compound should be prepared once a day.

[1113] Preparation method of L23: Weigh an appropriate amount of L23 compound into a brown sample vial, add a certain volume of 0.5% CMC-Na solvent, vortex for 1 minute, and sonicate to promote dissolution. Prepare the compound once a day.

[1114] Preparation method of Mesa (Mesalamine): Weigh an appropriate amount of mesalamine (Selleck) compound into a brown sample vial, add a certain volume of 0.5% CMC-Na solvent, vortex for 1 minute, and sonicate to promote dissolution. Prepare the compound once daily.

[1115] 5.2 Route and frequency of compound administration

[1116] Sixty female Balb / c mice, weighing approximately 18g and aged 8-10 weeks, were randomly divided into 12 groups: 11 model groups and 1 Sham control group. Drug administration began on Day 1 and ended on Day 7. The compound was prepared once daily. Specific routes and frequencies of administration are detailed in Table 1, and compound preparation and administration volumes are shown in Table 2.

[1117] Table 1 Animal grouping and administration regimen

[1118] Sham Group 5 - - - - Solvent control group 5 - PO BID 9 days Mesalazine Group 5 100mpk PO QD 9 days L11 Group 5 50mpk PO BID 9 days L25 Group 5 50mpk PO BID 9 days L84 Group 5 50mpk PO BID 9 days L77 Group 5 50mpk PO BID 9 days Group L101 5 50mpk PO BID 9 days L10 Group 5 50mpk PO BID 9 days Group L23 5 50mpk PO BID 9 days BT-11 group 5 50mpk PO BID 9 days

[1119] Table 2 Dosage volume and final drug concentration

[1120] 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 Group L101 50mpk 0.2 5 BID L10 Group 50mpk 0.2 5 BID Group L23 50mpk 0.2 5 BID BT-11 group 50mpk 0.2 5 BID

[1121] Note: Mice were weighed before administration; the table above shows the administration volume calculated for a 20-gram mouse. The solvent group served as the model control group.

[1122] 5.3 Construction of a TNBS-induced mouse enteritis model

[1123] On Day 0, Balb / c mice weighing approximately 18-20 grams were anesthetized with 0.25 ml of 1.25% aphthylamine. The model group mice were rectally instilled with 150 μL of 1% TNBS solution (final concentration 50% ethanol). The Sham control group mice were rectally instilled with 50% ethanol on Day 0.

[1124] 5.4 Fixation of mouse colon tissue

[1125] The colons of mice were photographed, their length measured, and their contents removed and weighed. Then, the colons of each mouse were longitudinally cut at half length, rolled in a uniform direction using the Swiss-roll method, and fixed in neutral paraformaldehyde.

[1126] 5.5 Collection of fresh colon tissue from mice

[1127] The remaining half of the colon tissue was cut longitudinally along the halfway point, divided into two tubes, flash-frozen in liquid nitrogen, stored at -80°C, and transported on dry ice for subsequent experiments.

[1128] 5.6 Collection of mesenteric lymph nodes from mice

[1129] Mesenteric lymph nodes were collected from mice and stored at 4 degrees Celsius. Once all samples were collected, they were immediately transferred to the client for flow cytometry analysis.

[1130] 5.7 DAI Scoring Criteria

[1131] The DAI score consists of three parts, using a combined scoring method based on weight change, fecal matter, and blood in the stool. The specific DAI scoring criteria are shown in Table 3. Throughout the experiment, the DAI scores for all mice were completed by the same person to ensure consistency in scoring scales.

[1132] Table 3 DAI Scoring Criteria

[1133] 0 0 normal Occult blood negative 1 1～5 soft stool Weak positive for occult blood 2 6～10 loose stool Occult blood positive 3 11～20 loose stool bloody stool 4 >20 extremely loose stools Large amount of bloody stool

[1134] 5.8 Statistical Analysis

[1135] Experimental data were statistically analyzed using ANOVA. Data from other groups and the Vehicle (PO, QD) group were compared using Dunnett's test. *p<0.05, **p<0.01, ***p<0.005, ****p<0.0001

[1136] 6. Results and Analysis

[1137] 6.1 Changes in mouse body weight and DAI score

[1138] Body weight data of mice in each group were collected over 10 days (Day-1 to Day-8), and corresponding DAI scores were calculated. Data analysis was performed using a two-way ANOVA method. Figure 16 Data from group A showed that, compared to the Vehicle group, the L11 (PO, 50 mpk, BID) and L10 (PO, 50 mpk, BID) groups of mice treated with the nine compounds experienced a significantly slower rate of weight loss. Except for the L84 (PO, 50 mpk, BID) and BT11 (PO, 50 mpk, BID) groups, which showed no significant slowdown in weight loss compared to the Vehicle group, the other five compounds all demonstrated a significant effect in alleviating weight loss in mice, but not as pronounced as L11 and L10. Figure 16 The DAI score data for mice in group B also showed that, compared to the Vehicle group, the DAI scores of mice in the L11 (PO, 50 mpk, BID) and L10 (PO, 50 mpk, BID) groups were significantly lower than those in the other group of mice tested with the nine compounds. The other seven compounds all showed significant effects in improving DAI scores, but not as significantly as L11 and L10. Considering both weight change and DAI score, we found that L11 (PO, 50 mpk, BID) and L10 (PO, 50 mpk, BID) effectively alleviated the weight loss in mice caused by TNBS-induced colitis. Interestingly, L10 (PO, 50 mpk, BID) was comparable in efficacy to the positive control drug Mesalamine (PO, 100 mpk, QD).

[1139] 6.2 Scoring of diarrhea and bloody stool in mice

[1140] Similarly, a two-way ANOVA method was used to analyze the individual diarrhea and rectal bleeding scores. Figure 17 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 Compared to the Vehicle group, mice in the L11 (PO, 50 mpk, BID) and L10 (PO, 50 mpk, BID) groups showed significantly reduced fecal bleeding among the nine tested compounds. The other seven tested compounds all 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, 50 mpk, BID) and L10 (PO, 50 mpk, BID) effectively alleviated diarrhea and fecal bleeding symptoms in TNBS model mice.

[1141] 6.3 Changes in the ratio of colon weight to length in mice

[1142] 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 showed that, compared to the vehicle group, the colon weight to length ratios in the L10 (PO, 50 mpk, BID), L25 (PO, 50 mpk, BID), L11 (PO, 50 mpk, BID), and Mesalazine (PO, 100 mpk, QD) groups were significantly lower, with statistically significant differences. Figure 18 Data from group A indicates that, compared to the vehicle group mice, the colons of mice in the L10 (PO, 50 mpk, BID) group, L25 (PO, 50 mpk, BID) group, and L11 (PO, 50 mpk, BID) group were significantly longer. Figure 18Data from group B showed 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 lower colonic inflammation. These data further demonstrate that L11 (PO, 50 mpk, BID) and L10 (PO, 50 mpk, BID) significantly alleviated inflammation in TNBS-infected mice.

[1143] 7. Conclusion

[1144] Based on data from the in-life experiment, L11(PO,50mpk,BID) and L10(PO,50mpk,BID) can effectively alleviate TNBS-induced enteritis in mice.

[1145] Intestinal morphology as Figure 19 .

Claims

1. A carbonyl heterocyclic compound as shown in Formula I, or a pharmaceutically acceptable salt thereof; ； in, A is , or -NR 1 R 2 ; R 1 is H; R 2 It is phenyl or naphthyl; Y 1 and Y 2 Independently CH or N; Q is ; Z 1 -L 1 -for or The q-terminus indicates that it is connected to a carbonyl group. bring" "The carbon atom indicates that, when it is a chiral carbon atom, it is in the S configuration, R configuration, or a mixture thereof; Q Ring 1 It is a heterocyclic alkyl group consisting of a 5-membered N-heterocyclic alkyl group and a 3-membered cycloalkyl group, or a heterocyclic alkyl group consisting of a 5-membered N-heterocyclic alkyl group and a 5-membered N-heterocyclic alkyl group; M is , , or The c-end indicates a connection to the C=O shown. A'、A 1a A 1b and A 1c Independently , , , or ; Y 3 Y 3a Y 3b Y 4 Y 4a Y 4b Y 5 Y 5a and Y 5b Independently, it is CH or N; G is S or O; or for ; R 6 It is a halogen; R 7 For H or C 1-6 Alkyl groups; R 3 C 1-6 Alkyl or halogen.

2. The carbonyl heterocyclic compound of formula I as described in claim 1, characterized in that, for , or ; End 'a' indicates the position connected to A; And / or, when M is hour, for , or ; And / or, when M is hour, for ; And / or, when M is hour, for ; And / or, when M is hour, for ; And / or, when A', A 1a A 1b and A 1c Independently hour, for or ; And / or, when A', A 1a A 1b and A 1c Independently hour, for or ; And / or, when R 6 When the halogen is halogen, the halogen is F, Cl, Br or I; And / or, when R 7 C 1-6 When alkyl, the C 1-6 The alkyl group is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl; And / or, when R 3 C 1-6 When alkyl, the C 1-6 The alkyl group is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl; And / or, when R 3 When the halogen is halogen, the halogen is F, Cl, Br or I.

3. The carbonyl heterocyclic compound of formula I as described in claim 2, characterized in that, When R 6 When the halogen is halogen, the halogen is F; And / or, when R 7 C 1-6 When alkyl, the C 1-6 The alkyl group is methyl; And / or, when R 3 C 1-6 When alkyl, the C 1-6 The alkyl group is methyl; And / or, when R 3 When the halogen is halogen, the halogen is F or Cl.

4. The carbonyl heterocyclic compound of formula I as described in claim 1, characterized in that, Q 1 for , , or .

5. The carbonyl heterocyclic compound of formula I as described in claim 2, characterized in that, When A', A 1a A 1b and A 1c Independently hour, for ; And / or, when A', A 1a A 1b and A 1c Independently hour, for or .

6. The carbonyl heterocyclic compound of formula I as described in claim 1, characterized in that, Y 2 is CH; And / or, A' is or ; And / or, A is the same as A'; And / or, and same.

7. The carbonyl heterocyclic compound of formula I as described in claim 1, characterized in that, for , , , or ; And / or, Q is , , , , or The b-terminus indicates that it is connected to the carbonyl group on the left. And / or, for , , , , , , , , or ; And / or, for ; And / or, for .

8. The carbonyl heterocyclic compound of formula I as described in claim 1, characterized in that, for , or ; And / or, Q is , , , or The b-terminus indicates that it is connected to the carbonyl group on the left. And / or, for , , , , , or .

9. The carbonyl heterocyclic compound of formula I as described in claim 1, characterized in that, The carbonyl heterocyclic compound represented by Formula I can be any of the following schemes: Option 1: A is , or -NR 1 R 2 ; R 1 For H; R 2 It is phenyl or naphthyl; Y 1 and Y 2 Independently CH or N; Q is Z 1 -L 1 -for or ; bring" "The carbon atom indicates that, when it is a chiral carbon atom, it is in the S configuration, R configuration, or a mixture thereof; Q Ring 1 It is a heterocyclic alkyl group consisting of a 5-membered N-heterocyclic alkyl group and a 3-membered cycloalkyl group, or a heterocyclic alkyl group consisting of a 5-membered N-heterocyclic alkyl group and a 5-membered N-heterocyclic alkyl group; M is , , or ; G represents S and O; A 1a A 1b and A 1c Independently , , , or ; Y 5 Y 5a and Y 5b Independently CH or N; R 6 It is a halogen; R 7 C 1-6 Alkyl groups; R 3 C 1-6 Alkyl or halogen; Option 2: A is or ; Y 2 is CH; Q is ; Z 1 -L 1 -for or ; Q Ring 1 Heterocyclic alkyl groups that are 5-membered N-heterocyclic alkyl groups and ternary cyclic alkyl groups; M is or ; A ’ and A 1b Independently , or ; Option 3: A is , or -NR 1 R 2 ; R 1 For H; R 2 It is phenyl or naphthyl; Y 1 and Y 2 Independently CH or N; Q is ; Z 1 -L 1 -for or ; Q Ring 1 It is a heterocyclic alkyl group consisting of a 5-membered N-heterocyclic alkyl group and a 3-membered cycloalkyl group, or a heterocyclic alkyl group consisting of a 5-membered N-heterocyclic alkyl group and a 5-membered N-heterocyclic alkyl group; M is , or ; G is S; A' and A 1c Independently , , , or ; Y 5 Y 5a and Y 5b Independently CH or N; R 6 It is a halogen; R 7 C 1-6 Alkyl groups; R 3 C 1-6 Alkyl or halogen; Option 4: The carbonyl heterocyclic compound shown in Formula I is as shown in Formula I-1: ； Where A is or ; Y 1 and Y 2 Independently CH or N; Q is ; Z 1 -L 1 -for or ; Q Ring 1 It is a heterocyclic alkyl group consisting of a 5-membered N-heterocyclic alkyl group and a 3-membered cycloalkyl group, or a heterocyclic alkyl group consisting of a 5-membered N-heterocyclic alkyl group and a 5-membered N-heterocyclic alkyl group; Y 3 and Y 4 Independently CH or N; A' is , or ; Y 5 For CH or N; bring" "The carbon atom indicates that, when it is a chiral carbon atom, it is in the S configuration, R configuration, or a mixture thereof; Option 5: A is or ; Y 1 and Y 2 Independently CH or N; Y 3 and Y 4 Independently CH or N; A' is , or ; Y 5 For CH or N; Option 6: A is or ; for or ; for , or ; A' is or ; Y 5 It can be CH or N.

10. The carbonyl heterocyclic compound of formula I as described in claim 1, characterized in that, The carbonyl heterocyclic compounds represented by Formula I are selected from the following group: 。 11. A pharmaceutical composition comprising a carbonyl heterocyclic compound of formula I as described in any one of claims 1-10, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers.

12. The use of a carbonyl heterocyclic compound of formula I as described in any one of claims 1-10, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described in claim 11, in the preparation of a medicament; The aforementioned drug is used for the prevention and / or treatment of inflammatory bowel disease.

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