A compound containing a heterocyclic ring, its application and composition containing the same

Abstract

The present invention discloses a heterocyclic compound, its application and a composition containing the heterocyclic compound. The present invention provides a compound as shown in Formula XII or a pharmaceutically acceptable salt thereof. The compound has a novel structure and has good STAT5 inhibitory activity. #imgabs0#

Description

Technical Field

[0001] The present invention relates to a heterocyclic compound, application thereof and a composition containing the heterocyclic compound. Background Art

[0002] Rheumatoid arthritis is a chronic, systemic autoimmune disease characterized by inflammation of the synovial membranes of the joints. Its incidence rate is approximately 1% of the adult population. Its primary manifestation is symmetrical, multiple, recurrent arthritis, with the small joints of the hands and feet being most affected. In the early or acute stages of the disease, joints often present with redness, swelling, heat, pain, and impaired mobility. In the late stages, it can lead to joint destruction, stiffness, deformity, and loss of function, as well as osteoporosis and skeletal muscle atrophy. Throughout the course of the disease, it may be accompanied by fever, anemia, weight loss, vasculitis, and subcutaneous nodules. It can also affect multiple organs throughout the body, resulting in a highly disabling disease with a significantly increased mortality rate. The pathogenesis of rheumatoid arthritis is still not fully understood, and there is currently no complete cure, resulting in a heavy health and financial burden on patients worldwide.

[0003] Over the past two decades, people have gained a deeper understanding of the pathogenesis of arthritis. They believe that overactivation of immune cells and increased inflammatory cytokines lead to symptoms in the joints and other parts of the body. As a result, significant progress has been made in its treatment, and a series of drugs against rheumatic factors have been developed and produced, including methotrexate, tumor necrosis factor (TNFα) antibodies, interleukin (IL) 1, interleukin-6 antibodies, and JAK kinase inhibitors.

[0004] These anti-rheumatic drugs can control the progression of the disease to a certain extent and improve the patient's living conditions. However, their sustained effects are not ideal, and they are only effective for a small number of patients, and are accompanied by side effects of varying degrees of severity. For example, methotrexate, as an anti-cancer drug, has significant non-specific cytotoxicity and is very harmful to the gastrointestinal tract and liver and kidney organs. Due to insufficient efficacy or strong adverse reactions, about half of the patients will stop taking the drug within one year of starting treatment. Anti-TNFα antibodies are only effective for 30-40% of patients, and are also accompanied by the risk of random infection and cancer. There are reports that they increase the risk of multiple sclerosis, and long-term use can produce neutralizing antibodies in the body, leading to loss of efficacy [Ann Rheum Dis. 2014 Mar; 73 (3): 529-35]. We urgently need to find new disease pathogenesis and develop targeted and better products.

[0005] The pathogenesis of rheumatoid arthritis manifests as severely dysregulated innate and adaptive immune responses, leading to chronic inflammation. Helper T cells play a crucial role in both the initiation and progression of arthritis. When dysfunctional, T lymphocytes are persistently activated and proliferate abnormally, leading to a corresponding proliferation of fibroblasts in joint tissue, resulting in the symptoms of arthritis. The JAK-STAT pathway plays an important role in regulating T cells and other immune cells. STAT5, in particular, plays a key role in the development and maturation of multiple T cell subtypes.

[0006] Our team recently discovered a new type of helper T cell, named Th-GM. This cell plays a driving role in many inflammatory diseases and represents a novel mechanism of inflammatory pathogenesis. Th-GM cells are characterized by the activation of the STAT5 signaling pathway by interleukin-7, leading to high expression of downstream colony-stimulating factor (GM-CSF) and interleukin-3. RNA sequencing experiments also revealed that Th-GM cells exhibit a unique gene expression profile, distinct from the established Th-1 and Th-17 helper T cell types. Genetic experiments have also demonstrated that knocking out the STAT5 gene significantly reduces neurological inflammation and arthritis severity in multiple sclerosis mice (references CN107002037A, PCT / US2018 / 031217). Given the critical regulatory role of STAT5 in Th-GM cells, and the possibility of its role in other inflammatory cells, we believe that STAT5 inhibitors will be very promising drug candidates for the treatment of arthritis.

[0007] In this patent, we describe the design and synthesis of a series of novel STAT5 inhibitors and their validation evidence for the treatment of rheumatoid arthritis. Summary of the Invention

[0008] The technical problem to be solved by the present invention is the defect that the existing STAT5 inhibitors have a relatively simple structure. To this end, the present invention provides a heterocyclic compound, its application and a composition containing the same. The structure of this type of compound is novel and has better STAT5 inhibitory activity.

[0009] The present invention provides a compound as shown in Formula XII or a pharmaceutically acceptable salt thereof;

[0010]

[0011] Wherein, W is any of the following groups:

[0012] (1)

[0013] in is a single bond or a double bond;

[0014] when in When Y is a single bond, 1 C(=O), O, NH, N-OH, or NR 3 , R 3 is CH2COOH or C1-C4 alkyl, Y 2 is C(=N-CO-Ph), C(=N-CO-CH3), NH, S(=O)2, C=O or C=S;

[0015] when in When it is a double bond, Y 1 N, Y 2 is C-NH2, C-NH-CN or CO-CH3;

[0016] Y 3 N or CH;

[0017] X 1 N or CR 2 , X 2 N or CR 4 , X 3 N or CR 5 , X 4 N or CR 6 ;

[0018] R 2 、R 4 、R 5 and R 6 independently hydrogen, halogen, hydroxy, amino, carboxyl, cyano, nitro, C1-C4 alkyl, C1-C4 alkyl substituted with one or more halogens, C1-C4 alkoxy, C3-C6 cycloalkyl, phenyl, "5-7 membered heterocycloalkyl containing 1, 2 or 3 independently selected from N, O and S", -S(=O)2-R 2-1 、-NH-S(=O)2-R 2-2 、-S(=O)2-NR 2-3 R 2-4 、-C(=O)-R 2-5 、-NH-C(=O)-R 2-6 , or, -C(=O)-NR 2-7 R 2-8 ;

[0019] R 2-1 、R 2-2 、R 2-3 、R 2-4 、R 2-5 、R 2-6 、R2-7 and R 2-8 are independently hydrogen, C1-C4 alkyl, or one or more halogen-substituted C1-C4 alkyl;

[0020] (2)

[0021] Y 4-1 is -NH-C(=O)-CH2- or NH;

[0022] Y 5 N or CR 7 , R 7 is a halogen;

[0023] X 5 N or CR 8 , X 6 N or CR 9 , X 7 N or CR 10 , X 8 N or CR 11 ;

[0024] R 8 、R 9 、R 10 and R 11 are independently hydrogen, halogen, hydroxy, amino, carboxyl, cyano, nitro, C1-C4 alkyl, C1-C4 alkyl substituted with one or more halogens, C1-C4 alkoxy, C3-C6 cycloalkyl, phenyl, "5-7 membered heterocycloalkyl containing 1, 2 or 3 groups independently selected from N, O and S", -S(=O)2-NH2, or -C(=O)-NH2;

[0025] (3)

[0026] Y 6 is NC(=O)-CH3, CH2 or NH;

[0027] Y 7 is NH, CH2, C(=O), C(=S) or C(=N-OH);

[0028] Y 8 is CH2, CH2CH2, CH(CH3) or C(=O);

[0029] Y 9 N or CH;

[0030] X 9 N or CR 12 , X 10 N or CR 13 , X 11N or CR 14 , X 12 N or CR 15 ;

[0031] R 12 、R 13 、R 14 and R 15 are independently hydrogen, halogen, hydroxy, amino, carboxyl, cyano, nitro, C1-C4 alkyl, C1-C4 alkyl substituted with one or more halogens, C1-C4 alkoxy, C3-C6 cycloalkyl, phenyl, "5-7 membered heterocycloalkyl containing 1, 2 or 3 groups independently selected from N, O and S", -S(=O)2-NH2, or -C(=O)-NH2;

[0032] (4)

[0033] Y 10 for NH;

[0034] Y 11 is C(=O);

[0035] Y 12 N or CH;

[0036] Y 13 is CH2;

[0037] X 13 N or CR 16 , X 14 N or CR 17 , X 15 N or CR 18 , X 16 N or CR 19 ;

[0038] R 16 、R 17 、R 18 and R 19 are independently hydrogen, halogen, hydroxy, amino, carboxyl, cyano, nitro, C1-C4 alkyl, C1-C4 alkyl substituted with one or more halogens, C1-C4 alkoxy, C3-C6 cycloalkyl, phenyl, "5-7 membered heterocycloalkyl containing 1, 2 or 3 groups independently selected from N, O and S", -S(=O)2-NH2, or -C(=O)-NH2;

[0039] (5)

[0040] Y 14 for NH;

[0041] Y 15 is C(=O);

[0042] Y 16 N or CH;

[0043] X 17 N or CR 20 , X 18 N or CR 21 , X 19 N or CR 22 ;

[0044] R 20 、R 21 and R 22 are independently hydrogen, halogen, hydroxy, amino, carboxyl, cyano, nitro, C1-C4 alkyl, C1-C4 alkyl substituted with one or more halogens, C1-C4 alkoxy, C3-C6 cycloalkyl, phenyl, "5-7 membered heterocycloalkyl containing 1, 2 or 3 groups independently selected from N, O and S", -S(=O)2-NH2, or -C(=O)-NH2;

[0045] (6)

[0046] Y 17 for NH;

[0047] X 20 N or CR 23 , X 21 N or CR 24 , X 22 N or CR 25 , X 23 N or CR 26 ;

[0048] R 23 、R 24 、R 25 and R 26 are independently hydrogen, halogen, hydroxy, amino, carboxyl, cyano, nitro, C1-C4 alkyl, C1-C4 alkyl substituted with one or more halogens, C1-C4 alkoxy, C3-C6 cycloalkyl, phenyl, "5-7 membered heterocycloalkyl containing 1, 2 or 3 groups independently selected from N, O and S", -S(=O)2-NH2, or -C(=O)-NH2;

[0049] (7)

[0050] Y 18 is NH or CH2;

[0051] Y 19 is C(=O) or NH;

[0052] Y 20 is CH2 or C(=O);

[0053] X 24 N or CR 27 , X 25 N or CR 28 , X 26 N or CR 29 ;

[0054] R 27 、R 28 and R 29 are independently hydrogen, halogen, hydroxy, amino, carboxyl, cyano, nitro, C1-C4 alkyl, C1-C4 alkyl substituted with one or more halogens, C1-C4 alkoxy, C3-C6 cycloalkyl, phenyl, "5-7 membered heterocycloalkyl containing 1, 2 or 3 groups independently selected from N, O and S", -S(=O)2-NH2, or -C(=O)-NH2;

[0055] (8)

[0056] Y 21 is C(=O);

[0057] Y 22 for NH;

[0058] Y 23 is CH2 or C(=O);

[0059] Y 24 NR 30 , R 30 is hydrogen or phenyl;

[0060] (9)

[0061] Y 25 for NH;

[0062] Y 26 is C(=O);

[0063] Y 27 is a single bond, O or NH;

[0064] X 27 N or CR 31 , X 28 N or CR 32 , X 29 N or CR 33 , X 30 N or CR 34 ;

[0065] R 31 、R 32 、R 33 and R34 are independently hydrogen, halogen, hydroxy, amino, carboxyl, cyano, nitro, C1-C4 alkyl, C1-C4 alkyl substituted with one or more halogens, C1-C4 alkoxy, C3-C6 cycloalkyl, phenyl, "5-7 membered heterocycloalkyl containing 1, 2 or 3 groups independently selected from N, O and S", -S(=O)2-NH2, or -C(=O)-NH2;

[0066] (10)

[0067] Y 28 for NH;

[0068] Y 29 is C(=O);

[0069] Y 30 is CH or N;

[0070] (11)

[0071] Y 31 is O, NH or NC(=O)-CH3;

[0072] Y 32 is CH or N;

[0073] X 31 N or CR 35 , X 32 N or CR 36 , X 33 N or CR 37 , X 34 N or CR 38 ;

[0074] R 35 、R 36 、R 37 and R 38 are independently hydrogen, halogen, hydroxy, amino, carboxyl, cyano, nitro, C1-C4 alkyl, C1-C4 alkyl substituted with one or more halogens, C1-C4 alkoxy, C3-C6 cycloalkyl, phenyl, "5-7 membered heterocycloalkyl containing 1, 2 or 3 groups independently selected from N, O and S", -S(=O)2-NH2, or -C(=O)-NH2;

[0075] (12)

[0076] Y 33 for NH;

[0077] Y 34 is C(=O);

[0078] Y35 is CH or N;

[0079] X 35 N or CR 39 , X 36 N or CR 40 , X 37 N or CR 41 , X 38 N or CR 42 ;

[0080] R 39 、R 40 、R 41 and R 42 are independently hydrogen, halogen, hydroxy, amino, carboxyl, cyano, nitro, C1-C4 alkyl, C1-C4 alkyl substituted with one or more halogens, C1-C4 alkoxy, C3-C6 cycloalkyl, phenyl, "5-7 membered heterocycloalkyl containing 1, 2 or 3 groups independently selected from N, O and S", -S(=O)2-NH2, or -C(=O)-NH2;

[0081] (13)

[0082] Y 36 for NH;

[0083] Y 37 is C(=O);

[0084] Y 38 is CH or N;

[0085] X 39 N or CR 43 , X 40 N or CR 44 , X 41 N or CR 45 , X 42 N or CR 46 ;

[0086] R 43 、R 44 、R 45 and R 46 are independently hydrogen, halogen, hydroxy, amino, carboxyl, cyano, nitro, C1-C4 alkyl, C1-C4 alkyl substituted with one or more halogens, C1-C4 alkoxy, C3-C6 cycloalkyl, phenyl, "5-7 membered heterocycloalkyl containing 1, 2 or 3 groups independently selected from N, O and S", -S(=O)2-NH2, or -C(=O)-NH2;

[0087] (14)

[0088] Y 39 for NH;

[0089] Y 40 is C(=O);

[0090] Y 41 is CH or N;

[0091] X 43 N or CR 47 , X 44 N or CR 48 , X 45 N or CR 49 , X 46 N or CR 50 ;

[0092] R 47 、R 48 、R 49 and R 50 are independently hydrogen, halogen, hydroxy, amino, carboxyl, cyano, nitro, C1-C4 alkyl, C1-C4 alkyl substituted with one or more halogens, C1-C4 alkoxy, C3-C6 cycloalkyl, phenyl, "5-7 membered heterocycloalkyl containing 1, 2 or 3 groups independently selected from N, O and S", -S(=O)2-NH2, or -C(=O)-NH2;

[0093] and, (15)

[0094] Z is any of the following fragments:

[0095] (1) m is 1 or 2, n is 1, 2 or 3;

[0096] (2) u is 1 or 2, t is 1 or 2;

[0097] (3)

[0098] (4) p is 1 or 2, q is 1 or 2;

[0099] (5) a2 is 1 or 2, b2 is 1 or 2;

[0100] (6) a3 is 1 or 2, b3 is 1 or 2;

[0101] (7)

[0102] (8) -C(=O)-;

[0103] (9)

[0104] R 1 C2-C4 alkyl, C2-C4 alkyl substituted with one or more halogens, -(CH2) s -R 1-1 、-NH-R 1-2 、 s is 0, 1, or 2;

[0105] R 1-1 、R 1-2 、R 1-3 、R 1-4 and R 1-5 Independently C7-C 10 Cycloalkyl, one or more R 1-1-3 Substituted C3-C6 cycloalkyl, one or more R 1-1-6 Substituted "5-6 membered heterocycloalkyl containing 1, 2 or 3 independently selected from N, O and S", one or more R 1-1-1 Substituted C6-C 10 Aryl, naphthyl, "a 5- or 10-membered heteroaryl group containing 1, 2 or 3 groups independently selected from N, O and S", pyridyl, or, one or more R 1-1-2 Substituted "5- to 10-membered heteroaryl containing 1, 2 or 3 groups independently selected from N, O and S";

[0106] R 1-1-1 、R 1-1-2 、R 1-1-3 , and, R 1-1-6 independently carboxyl, hydroxyl, halogen, C1-C4 alkyl, one or more halogen-substituted C1-C4 alkyl, one or more halogen-substituted C1-C4 alkoxy, C3-C6 cycloalkyl, "5-6 membered heterocycloalkyl containing 1, 2 or 3 independently selected from N, O and S", -N(R 1-1-1-1 )(R 1-1-1-2 ), or, phenyl;

[0107] R 1-1-1-1 and R 1-1-1-2 are independently hydrogen or C1-C4 alkyl;

[0108] R 1-1-7 、R 1-1-8 , and, R 1-1-9 are independently C1-C4 alkyl;

[0109] R 1-1-10 are independently C1-C4 alkoxy;

[0110] R 1-1-11 and R 1-1-12 are independently hydrogen or halogen.

[0111] In a certain embodiment, in the compound of Formula XII or a pharmaceutically acceptable salt thereof, the compound of Formula XII is a compound of Formula II;

[0112]

[0113] in, in is a single bond or a double bond;

[0114] when in When Y is a single bond, 1 is NH, or N-OH, Y 2 C=O;

[0115] when in When it is a double bond, Y 1 N, Y 2 is C-NH2, C-NH-CN or CO-CH3;

[0116] Y 3 is N;

[0117] X 1 CR 2 , X 2 CR 4 , X 3 CR 5 , X 4 CR 6 ;

[0118] R 2 、R 4 、R 5 and R 6 are independently hydrogen, halogen, hydroxy, amino, carboxyl, cyano, nitro, C1-C4 alkyl, C1-C4 alkyl substituted with one or more halogens, C1-C4 alkoxy, C3-C6 cycloalkyl, phenyl, -S(=O)2-R 2-1 、-NH-S(=O)2-R 2 -2 、-S(=O)2-NR 2-3 R 2-4 、-C(=O)-R 2-5 、-NH-C(=O)-R 2-6 , or, -C(=O)-NR 2-7 R 2-8 ;

[0119] R 2-1 、R 2-2 、R 2-3 、R 2-4 、R 2-5 、R 2-6 、R 2-7 and R 2-8 are independently C1-C4 alkyl, or one or more halogen-substituted C1-C4 alkyl;

[0120] Z is m is 1 or 2, n is 1 or 2; u is 1 or 2, t is 1 or 2;

[0121] R 1 -(CH2) s -R 1-1 ;s is 0, 1 or 2;

[0122] R 1-1 C6-C 10 Aryl, one or more R 1-1-1 Substituted C6-C 10 Aryl, "5-10 membered heteroaryl containing 1, 2 or 3 independently selected from N, O and S", or one or more R 1-1-2 Substituted "5- to 10-membered heteroaryl containing 1, 2 or 3 groups independently selected from N, O and S";

[0123] R 1-1-1 and R 1-1-2 Independently C1-C4 alkyl, one or more halogen-substituted C1-C4 alkyl, C3-C6 cycloalkyl, or phenyl.

[0124] In one embodiment, in the compound of Formula II or a pharmaceutically acceptable salt thereof, the definitions of certain groups may be as follows, and the definitions of the remaining groups are as described in any of the above embodiments:

[0125] When R 2 、R 4 、R 5 and R 6 When independently a C1-C4 alkyl group, the C1-C4 alkyl group is a tert-butyl group.

[0126] In one embodiment, in the compound of Formula II or a pharmaceutically acceptable salt thereof, the definitions of certain groups may be as follows, and the definitions of the remaining groups are as described in any of the above embodiments:

[0127] When R 2 、R 4 、R 5 and R 6When the C1-C4 alkyl group is independently substituted with multiple halogens, the multiple halogens are 2 or 3.

[0128] In one embodiment, in the compound of Formula II or a pharmaceutically acceptable salt thereof, the definitions of certain groups may be as follows, and the definitions of the remaining groups are as described in any of the above embodiments:

[0129] When R 2 、R 4 、R 5 and R 6 When the C1-C4 alkyl group is independently substituted by one or more halogens, the halogen is fluorine.

[0130] In one embodiment, in the compound of Formula II or a pharmaceutically acceptable salt thereof, the definitions of certain groups may be as follows, and the definitions of the remaining groups are as described in any of the above embodiments:

[0131] When R 2 、R 4 、R 5 and R 6 When the C1-C4 alkyl group is independently substituted by one or more halogens, the C1-C4 alkyl group is methyl.

[0132] In one embodiment, in the compound of Formula II or a pharmaceutically acceptable salt thereof, the definitions of certain groups may be as follows, and the definitions of the remaining groups are as described in any of the above embodiments:

[0133] When R 2 、R 4 、R 5 and R 6 When the multiple halogen-substituted C1-C4 alkyl groups are independently multiple halogen-substituted C1-C4 alkyl groups, the multiple halogen-substituted C1-C4 alkyl groups are trifluoromethyl groups.

[0134] In one embodiment, in the compound of Formula II or a pharmaceutically acceptable salt thereof, the definitions of certain groups may be as follows, and the definitions of the remaining groups are as described in any of the above embodiments:

[0135] When R 2 、R 4 、R 5 and R 6 When independently a C1-C4 alkoxy group, the C1-C4 alkoxy group is a methoxy group.

[0136] In one embodiment, in the compound of Formula II or a pharmaceutically acceptable salt thereof, the definitions of certain groups may be as follows, and the definitions of the remaining groups are as described in any of the above embodiments:

[0137] When R 2 、R4 、R 5 and R 6 When independently a C3-C6 cycloalkyl group, the C3-C6 cycloalkyl group is a cyclopropyl group.

[0138] In one embodiment, in the compound of Formula II or a pharmaceutically acceptable salt thereof, the definitions of certain groups may be as follows, and the definitions of the remaining groups are as described in any of the above embodiments:

[0139] When R 2-1 、R 2-2 、R 2-3 、R 2-4 、R 2-5 、R 2-6 、R 2-7 and R 2-8 When independently a C1-C4 alkyl group, the C1-C4 alkyl group is a methyl group or a tert-butyl group.

[0140] In one embodiment, in the compound of Formula II or a pharmaceutically acceptable salt thereof, the definitions of certain groups may be as follows, and the definitions of the remaining groups are as described in any of the above embodiments:

[0141] When R 2-1 、R 2-2 、R 2-3 、R 2-4 、R 2-5 、R 2-6 、R 2-7 and R 2-8 When the C1-C4 alkyl group is independently substituted with multiple halogens, the multiple halogens are 2 or 3.

[0142] In one embodiment, in the compound of Formula II or a pharmaceutically acceptable salt thereof, the definitions of certain groups may be as follows, and the definitions of the remaining groups are as described in any of the above embodiments:

[0143] When R 2-1 、R 2-2 、R 2-3 、R 2-4 、R 2-5 、R 2-6 、R 2-7 and R 2-8 When the C1-C4 alkyl group is independently substituted by one or more halogens, the halogen is fluorine.

[0144] In one embodiment, in the compound of Formula II or a pharmaceutically acceptable salt thereof, the definitions of certain groups may be as follows, and the definitions of the remaining groups are as described in any of the above embodiments:

[0145] When R 2-1 、R2-2 、R 2-3 、R 2-4 、R 2-5 、R 2-6 、R 2-7 and R 2-8 When the C1-C4 alkyl group is independently substituted by one or more halogens, the C1-C4 alkyl group is methyl.

[0146] In one embodiment, in the compound of Formula II or a pharmaceutically acceptable salt thereof, the definitions of certain groups may be as follows, and the definitions of the remaining groups are as described in any of the above embodiments:

[0147] When R 2-1 、R 2-2 、R 2-3 、R 2-4 、R 2-5 、R 2-6 、R 2-7 and R 2-8 When the C1-C4 alkyl group is independently substituted with multiple halogens, the C1-C4 alkyl group is trifluoromethyl.

[0148] In one embodiment, in the compound of Formula II or a pharmaceutically acceptable salt thereof, the definitions of certain groups may be as follows, and the definitions of the remaining groups are as described in any of the above embodiments:

[0149] When Z is When m is 1 and n is 1.

[0150] In one embodiment, in the compound of Formula II or a pharmaceutically acceptable salt thereof, the definitions of certain groups may be as follows, and the definitions of the remaining groups are as described in any of the above embodiments:

[0151] When Z is When m is 2 and n is 2.

[0152] In one embodiment, in the compound of Formula II or a pharmaceutically acceptable salt thereof, the definitions of certain groups may be as follows, and the definitions of the remaining groups are as described in any of the above embodiments:

[0153] When Z is When for Its b end and R 1 connect.

[0154] In one embodiment, in the compound of Formula II or a pharmaceutically acceptable salt thereof, the definitions of certain groups may be as follows, and the definitions of the remaining groups are as described in any of the above embodiments:

[0155] When Z is When m is 1, n is 1, and for Its b end and R 1 connect.

[0156] In one embodiment, in the compound of Formula II or a pharmaceutically acceptable salt thereof, the definitions of certain groups may be as follows, and the definitions of the remaining groups are as described in any of the above embodiments:

[0157] When Z is When m is 2, n is 2, and for Its b end and R 1 connect.

[0158] In one embodiment, in the compound of Formula II or a pharmaceutically acceptable salt thereof, the definitions of certain groups may be as follows, and the definitions of the remaining groups are as described in any of the above embodiments:

[0159] When Z is When , u is 1 and t is 1.

[0160] In one embodiment, in the compound of Formula II or a pharmaceutically acceptable salt thereof, the definitions of certain groups may be as follows, and the definitions of the remaining groups are as described in any of the above embodiments:

[0161] When Z is When u is 2 and t is 2.

[0162] In one embodiment, in the compound of Formula II or a pharmaceutically acceptable salt thereof, the definitions of certain groups may be as follows, and the definitions of the remaining groups are as described in any of the above embodiments:

[0163] When Z is When for Its f end and R 1 connect;

[0164] It can also be Its f end and R 1 connect.

[0165] In one embodiment, in the compound of Formula II or a pharmaceutically acceptable salt thereof, the definitions of certain groups may be as follows, and the definitions of the remaining groups are as described in any of the above embodiments:

[0166] When Z is When for Its f end and R 1 connection, u is 1, t is 1;

[0167] It can also be Its f end and R 1 connection, u is 1, t is 1.

[0168] In one embodiment, in the compound of Formula II or a pharmaceutically acceptable salt thereof, the definitions of certain groups may be as follows, and the definitions of the remaining groups are as described in any of the above embodiments:

[0169] When Z is When for Its f end and R 1 Connection, said u is 2, t is 2;

[0170] It can also be Its f end and R 1 Connection, u is 2, t is 2.

[0171] In one embodiment, in the compound of Formula II or a pharmaceutically acceptable salt thereof, the definitions of certain groups may be as follows, and the definitions of the remaining groups are as described in any of the above embodiments:

[0172] When Z is When for Its d end and R 1 connect.

[0173] In one embodiment, in the compound of Formula II or a pharmaceutically acceptable salt thereof, the definitions of certain groups may be as follows, and the definitions of the remaining groups are as described in any of the above embodiments:

[0174] When Z is When for Its w end and R 1 connect.

[0175] In one embodiment, in the compound of Formula II or a pharmaceutically acceptable salt thereof, the definitions of certain groups may be as follows, and the definitions of the remaining groups are as described in any of the above embodiments:

[0176] When R 1-1 C6-C 10 When the C6-C 10 Aryl is phenyl or naphthyl.

[0177] In one embodiment, in the compound of Formula II or a pharmaceutically acceptable salt thereof, the definitions of certain groups may be as follows, and the definitions of the remaining groups are as described in any of the above embodiments:

[0178] When R 1-1For one or more R 1-1-1 Substituted C6-C 10 When the C6-C 10 Aryl is phenyl or naphthyl.

[0179] In one embodiment, in the compound of Formula II or a pharmaceutically acceptable salt thereof, the definitions of certain groups may be as follows, and the definitions of the remaining groups are as described in any of the above embodiments:

[0180] When R 1-1 For one or more R 1-1-1 Substituted C6-C 10 Aryl, the C6-C 10 When the aryl group is a phenyl group, the R 1-1-1 With the "-(CH2) s - or -NH-" may be in the ortho, meta or para position, and may also be in the para position.

[0181] In one embodiment, in the compound of Formula II or a pharmaceutically acceptable salt thereof, the definitions of certain groups may be as follows, and the definitions of the remaining groups are as described in any of the above embodiments:

[0182] When R 1-1 When it is a 5- to 10-membered heteroaryl group containing 1, 2 or 3 groups independently selected from N, O and S, the 5- to 10-membered heteroaryl group containing 1, 2 or 3 groups independently selected from N, O and S may be a 5- to 6-membered heteroaryl group containing 1 group selected from N, O and S, an indolyl group, an isoquinolyl group or a quinolyl group, or may be a 5- to 6-membered heteroaryl group containing 1 group selected from N, O and S.

[0183] The 5- to 6-membered heteroaryl group containing one selected from N, O and S is, for example, furyl, thienyl or pyridyl.

[0184] In one embodiment, in the compound of Formula II or a pharmaceutically acceptable salt thereof, the definitions of certain groups may be as follows, and the definitions of the remaining groups are as described in any of the above embodiments:

[0185] When R 1-1 For one or more R 1-1-2 When the substituted “5- to 10-membered heteroaryl group containing 1, 2 or 3 groups independently selected from N, O and S” is used, the 5- to 10-membered heteroaryl group containing 1, 2 or 3 groups independently selected from N, O and S may be a 5- to 6-membered heteroaryl group containing 1 group selected from N, O and S, an indolyl group, an isoquinolyl group or a quinolyl group, or a 5- to 6-membered heteroaryl group containing 1 group selected from N, O and S.

[0186] The 5- to 6-membered heteroaryl group containing one selected from N, O and S is, for example, furyl, thienyl or pyridyl.

[0187] In one embodiment, in the compound of Formula II or a pharmaceutically acceptable salt thereof, the definitions of certain groups may be as follows, and the definitions of the remaining groups are as described in any of the above embodiments:

[0188] When R 1-1 For one or more R 1-1-2 When the substituted "5- to 10-membered heteroaryl group containing 1, 2 or 3 independently selected from N, O and S" is a 5-membered heteroaryl group containing 1 selected from N, O and S, the R 1-1-2 With the "-(CH2) s - or -NH-" can be in the ortho or meta position relative to each other.

[0189] In one embodiment, in the compound of Formula II or a pharmaceutically acceptable salt thereof, the definitions of certain groups may be as follows, and the definitions of the remaining groups are as described in any of the above embodiments:

[0190] When R 1-1 For one or more R 1-1-2 When the substituted "5- to 10-membered heteroaryl group containing 1, 2 or 3 independently selected from N, O and S" is a 6-membered heteroaryl group containing 1 selected from N, O and S, the R 1-1-2 With the "-(CH2) s - or -NH-" may be in the ortho, meta or para position, and may also be in the para position.

[0191] In one embodiment, in the compound of Formula II or a pharmaceutically acceptable salt thereof, the definitions of certain groups may be as follows, and the definitions of the remaining groups are as described in any of the above embodiments:

[0192] When R 1-1-1 and R 1-1-2 When they are independently C1-C4 alkyl, the C1-C4 alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl.

[0193] In one embodiment, in the compound of Formula II or a pharmaceutically acceptable salt thereof, the definitions of certain groups may be as follows, and the definitions of the remaining groups are as described in any of the above embodiments:

[0194] When R 1-1-1 and R 1-1-2 When the plurality of halogen-substituted C1-C4 alkyl groups are independently multiple, the plurality is 2 or 3.

[0195] In one embodiment, in the compound of Formula II or a pharmaceutically acceptable salt thereof, the definitions of certain groups may be as follows, and the definitions of the remaining groups are as described in any of the above embodiments:

[0196] When R 1-1-1 and R 1-1-2 When the C1-C4 alkyl group is independently substituted by one or more halogens, the halogen is fluorine.

[0197] In one embodiment, in the compound of Formula II or a pharmaceutically acceptable salt thereof, the definitions of certain groups may be as follows, and the definitions of the remaining groups are as described in any of the above embodiments:

[0198] When R 1-1-1 and R 1-1-2 When the C1-C4 alkyl group is independently substituted by one or more halogens, the C1-C4 alkyl group is methyl or ethyl.

[0199] In one embodiment, in the compound of Formula II or a pharmaceutically acceptable salt thereof, the definitions of certain groups may be as follows, and the definitions of the remaining groups are as described in any of the above embodiments:

[0200] When R 1-1-1 and R 1-1-2 When the C1-C4 alkyl groups are independently multiple halogen-substituted, the multiple halogen-substituted C1-C4 alkyl groups are trifluoromethyl.

[0201] In one embodiment, in the compound of Formula II or a pharmaceutically acceptable salt thereof, the definitions of certain groups may be as follows, and the definitions of the remaining groups are as described in any of the above embodiments:

[0202] When R 1-1-1 and R 1-1-2 When independently a C3-C6 cycloalkyl group, the C3-C6 cycloalkyl group is a cyclopropyl group.

[0203] In one embodiment, in the compound of Formula II or a pharmaceutically acceptable salt thereof, the definitions of certain groups may be as follows, and the definitions of the remaining groups are as described in any of the above embodiments:

[0204] for

[0205] In one embodiment, in the compound of Formula II or a pharmaceutically acceptable salt thereof, the definitions of certain groups may be as follows, and the definitions of the remaining groups are as described in any of the above embodiments:

[0206] R 1-1 is naphthyl, one or more R 1-1-1 Substituted C6-C 10Aryl, "a 10-membered heteroaryl group containing 1, 2 or 3 groups independently selected from N, O and S", or one or more R 1-1-2 The substituted "5- to 10-membered heteroaryl group containing 1, 2 or 3 groups independently selected from N, O and S".

[0207] In one embodiment, in the compound of Formula II or a pharmaceutically acceptable salt thereof, the definitions of certain groups may be as follows, and the definitions of the remaining groups are as described in any of the above embodiments:

[0208] R 1-1 It is naphthyl.

[0209] In one embodiment, in the compound of Formula II or a pharmaceutically acceptable salt thereof, the definitions of certain groups may be as follows, and the definitions of the remaining groups are as described in any of the above embodiments:

[0210] R 1-1 For one or more R 1-1-1 Substituted C6-C 10 Aryl.

[0211] In one embodiment, in the compound of Formula II or a pharmaceutically acceptable salt thereof, the definitions of certain groups may be as follows, and the definitions of the remaining groups are as described in any of the above embodiments:

[0212] R 1-1 is a "10-membered heteroaryl group containing 1, 2 or 3 independently selected from N, O and S", or one or more R 1-1-2 The substituted "5- to 10-membered heteroaryl group containing 1, 2 or 3 groups independently selected from N, O and S".

[0213] In one embodiment, in the compound of Formula II or a pharmaceutically acceptable salt thereof, the definitions of certain groups may be as follows, and the definitions of the remaining groups are as described in any of the above embodiments:

[0214] in For a single bond.

[0215] In one embodiment, in the compound of Formula II or a pharmaceutically acceptable salt thereof, the definitions of certain groups may be as follows, and the definitions of the remaining groups are as described in any of the above embodiments:

[0216] in is a single bond, Y 1 is NH, or N-OH, Y 2 It is C=O.

[0217] In one embodiment, in the compound of Formula II or a pharmaceutically acceptable salt thereof, the definitions of certain groups may be as follows, and the definitions of the remaining groups are as described in any of the above embodiments:

[0218] in is a single bond, Y 1 NH, Y 2 It is C=O.

[0219] In one embodiment, in the compound of Formula II or a pharmaceutically acceptable salt thereof, the definitions of certain groups may be as follows, and the definitions of the remaining groups are as described in any of the above embodiments:

[0220] R 2 、R 4 、R 5 and R 6 At least one of them is halogen, hydroxy, amino, carboxyl, cyano, nitro, C1-C4 alkyl, one or more halogen-substituted C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 alkoxy, C3-C6 cycloalkyl, phenyl, -S(=O)2-R 2-1 、-NH-S(=O)2-R 2-2 、-S(=O)2-NR 2-3 R 2-4 、-C(=O)-R 2-5 、-NH-C(=O)-R 2-6 , or, -C(=O)-NR 2-7 R 2-8 ; R 2-1 、R 2-2 、R 2-3 、R 2-4 、R 2-5 、R 2-6 、R 2-7 and R 2-8 are independently C1-C4 alkyl, or C1-C4 alkyl substituted with one or more halogens, and the rest are hydrogen.

[0221] In one embodiment, in the compound of Formula II or a pharmaceutically acceptable salt thereof, the definitions of certain groups may be as follows, and the definitions of the remaining groups are as described in any of the above embodiments:

[0222] R 2 、R 4 、R 5 and R 6wherein one of the following is halogen, hydroxy, amino, carboxyl, cyano, nitro, C1-C4 alkyl, C1-C4 alkyl substituted with one or more halogens, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 alkoxy, C3-C6 cycloalkyl, phenyl, -S(=O)2-R 2-1 、-NH-S(=O)2-R 2-2 、-S(=O)2-NR 2-3 R 2-4 、-C(=O)-R 2-5 、-NH-C(=O)-R 2-6 , or, -C(=O)-NR 2-7 R 2-8 ; R 2-1 、R 2-2 、R 2-3 、R 2-4 、R 2-5 、R 2-6 、R 2-7 and R 2-8 are independently C1-C4 alkyl, or C1-C4 alkyl substituted with one or more halogens, and the rest are hydrogen.

[0223] In one embodiment, in the compound of Formula II or a pharmaceutically acceptable salt thereof, the definitions of certain groups may be as follows, and the definitions of the remaining groups are as described in any of the above embodiments:

[0224] R 2 、R 4 、R 5 and R 6 One of them is cyano and the rest are hydrogen.

[0225] In one embodiment, in the compound of Formula II or a pharmaceutically acceptable salt thereof, the definitions of certain groups may be as follows, and the definitions of the remaining groups are as described in any of the above embodiments:

[0226] X 1 CH, X 2 CH; R 5 and R 6 wherein one of the following is halogen, hydroxy, amino, carboxyl, cyano, nitro, C1-C4 alkyl, C1-C4 alkyl substituted with one or more halogens, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 alkoxy, C3-C6 cycloalkyl, phenyl, -S(=O)2-R 2-1 、-NH-S(=O)2-R 2-2 、-S(=O)2-NR 2-3 R 2-4 、-C(=O)-R 2-5 、-NH-C(=O)-R 2-6, or, -C(=O)-NR 2-7 R 2-8 ; R 2-1 、R 2-2 、R 2-3 、R 2-4 、R 2-5 、R 2-6 、R 2-7 and R 2-8 are independently C1-C4 alkyl, or one or more halogen-substituted C1-C4 alkyl, and the other is hydrogen.

[0227] In one embodiment, in the compound of Formula II or a pharmaceutically acceptable salt thereof, the definitions of certain groups may be as follows, and the definitions of the remaining groups are as described in any of the above embodiments:

[0228] X 1 CH, X 2 CH; R 5 and R 6 One of them is cyano and the other is hydrogen.

[0229] In one embodiment, in the compound of Formula II or a pharmaceutically acceptable salt thereof, the definitions of certain groups may be as follows, and the definitions of the remaining groups are as described in any of the above embodiments:

[0230] s is 1 or 2.

[0231] In one embodiment, in the compound of Formula XII or a pharmaceutically acceptable salt thereof, the compound of Formula XII is a compound of Formula IV;

[0232]

[0233] Among them, Y 4 for

[0234] Z is m is 1 or 2, n is 1 or 2; u is 1 or 2, t is 1 or 2;

[0235] R 1 -(CH2) s -R 1-1 ;s is 0, 1 or 2;

[0236] R 1-1 C6-C 10 Aryl, one or more R 1-1-1 Substituted C6-C 10 Aryl, "5-10 membered heteroaryl containing 1, 2 or 3 independently selected from N, O and S", or one or more R1-1-2 Substituted "5- to 10-membered heteroaryl containing 1, 2 or 3 groups independently selected from N, O and S";

[0237] R 1-1-1 and R 1-1-2 Independently C1-C4 alkyl, one or more halogen-substituted C1-C4 alkyl, C3-C6 cycloalkyl, or phenyl.

[0238] In one embodiment, in the compound of Formula IV or a pharmaceutically acceptable salt thereof, the definitions of certain groups may be as follows, and the definitions of the remaining groups are as described in any of the above embodiments:

[0239] When Z is When m is 1 and n is 1.

[0240] In one embodiment, in the compound of Formula IV or a pharmaceutically acceptable salt thereof, the definitions of certain groups may be as follows, and the definitions of the remaining groups are as described in any of the above embodiments:

[0241] When Z is When m is 2 and n is 2.

[0242] In one embodiment, in the compound of Formula IV or a pharmaceutically acceptable salt thereof, the definitions of certain groups may be as follows, and the definitions of the remaining groups are as described in any of the above embodiments:

[0243] When Z is When for Its b end and R 1 connect.

[0244] In one embodiment, in the compound of Formula IV or a pharmaceutically acceptable salt thereof, the definitions of certain groups may be as follows, and the definitions of the remaining groups are as described in any of the above embodiments:

[0245] When Z is When m is 1, n is 1, and for Its b end and R 1 connect.

[0246] In one embodiment, in the compound of Formula IV or a pharmaceutically acceptable salt thereof, the definitions of certain groups may be as follows, and the definitions of the remaining groups are as described in any of the above embodiments:

[0247] When Z is When m is 2, n is 2, and for Its b end and R 1 connect.

[0248] In one embodiment, in the compound of Formula IV or a pharmaceutically acceptable salt thereof, the definitions of certain groups may be as follows, and the definitions of the remaining groups are as described in any of the above embodiments:

[0249] When Z is When , u is 1 and t is 1.

[0250] In one embodiment, in the compound of Formula IV or a pharmaceutically acceptable salt thereof, the definitions of certain groups may be as follows, and the definitions of the remaining groups are as described in any of the above embodiments:

[0251] When Z is When u is 2 and t is 2.

[0252] In one embodiment, in the compound of Formula IV or a pharmaceutically acceptable salt thereof, the definitions of certain groups may be as follows, and the definitions of the remaining groups are as described in any of the above embodiments:

[0253] When Z is When for Its f end and R 1 connect;

[0254] It can also be Its f end and R 1 connect.

[0255] In one embodiment, in the compound of Formula IV or a pharmaceutically acceptable salt thereof, the definitions of certain groups may be as follows, and the definitions of the remaining groups are as described in any of the above embodiments:

[0256] When Z is When for Its f end and R 1 connection, u is 1, t is 1;

[0257] It can also be Its f end and R 1 connection, u is 1, t is 1.

[0258] In one embodiment, in the compound of Formula IV or a pharmaceutically acceptable salt thereof, the definitions of certain groups may be as follows, and the definitions of the remaining groups are as described in any of the above embodiments:

[0259] When Z is When for Its f end and R 1 Connection, said u is 2, t is 2;

[0260] It can also be Its f end and R 1 Connection, u is 2, t is 2.

[0261] In one embodiment, in the compound of Formula IV or a pharmaceutically acceptable salt thereof, the definitions of certain groups may be as follows, and the definitions of the remaining groups are as described in any of the above embodiments:

[0262] When Z is When for Its d end and R 1 connect.

[0263] In one embodiment, in the compound of Formula IV or a pharmaceutically acceptable salt thereof, the definitions of certain groups may be as follows, and the definitions of the remaining groups are as described in any of the above embodiments:

[0264] When Z is When for Its w end and R 1 connect.

[0265] In one embodiment, in the compound of Formula IV or a pharmaceutically acceptable salt thereof, the definitions of certain groups may be as follows, and the definitions of the remaining groups are as described in any of the above embodiments:

[0266] When R 1-1 C6-C 10 When the C6-C 10 Aryl is phenyl or naphthyl.

[0267] In one embodiment, in the compound of Formula IV or a pharmaceutically acceptable salt thereof, the definitions of certain groups may be as follows, and the definitions of the remaining groups are as described in any of the above embodiments:

[0268] When R 1-1 For one or more R 1-1-1 Substituted C6-C 10 When the C6-C 10 Aryl is phenyl or naphthyl.

[0269] In one embodiment, in the compound of Formula IV or a pharmaceutically acceptable salt thereof, the definitions of certain groups may be as follows, and the definitions of the remaining groups are as described in any of the above embodiments:

[0270] When R 1-1 For one or more R 1-1-1 Substituted C6-C 10 Aryl, the C6-C 10When the aryl group is a phenyl group, the R 1-1-1 With the "-(CH2) s - or -NH-" may be in the ortho, meta or para position, and may also be in the para position.

[0271] In one embodiment, in the compound of Formula IV or a pharmaceutically acceptable salt thereof, the definitions of certain groups may be as follows, and the definitions of the remaining groups are as described in any of the above embodiments:

[0272] When R 1-1 When it is a 5- to 10-membered heteroaryl group containing 1, 2 or 3 groups independently selected from N, O and S, the 5- to 10-membered heteroaryl group containing 1, 2 or 3 groups independently selected from N, O and S may be a 5- to 6-membered heteroaryl group containing 1 group selected from N, O and S, an indolyl group, an isoquinolyl group or a quinolyl group, or may be a 5- to 6-membered heteroaryl group containing 1 group selected from N, O and S.

[0273] The 5- to 6-membered heteroaryl group containing one selected from N, O and S is, for example, furyl, thienyl or pyridyl.

[0274] In one embodiment, in the compound of Formula IV or a pharmaceutically acceptable salt thereof, the definitions of certain groups may be as follows, and the definitions of the remaining groups are as described in any of the above embodiments:

[0275] When R 1-1 For one or more R 1-1-2 When the substituted “5- to 10-membered heteroaryl group containing 1, 2 or 3 groups independently selected from N, O and S” is used, the 5- to 10-membered heteroaryl group containing 1, 2 or 3 groups independently selected from N, O and S may be a 5- to 6-membered heteroaryl group containing 1 group selected from N, O and S, an indolyl group, an isoquinolyl group or a quinolyl group, or a 5- to 6-membered heteroaryl group containing 1 group selected from N, O and S.

[0276] The 5- to 6-membered heteroaryl group containing one selected from N, O and S is, for example, furyl, thienyl or pyridyl.

[0277] In one embodiment, in the compound of Formula IV or a pharmaceutically acceptable salt thereof, the definitions of certain groups may be as follows, and the definitions of the remaining groups are as described in any of the above embodiments:

[0278] When R 1-1 For one or more R 1-1-2 When the substituted "5- to 10-membered heteroaryl group containing 1, 2 or 3 independently selected from N, O and S" is a 5-membered heteroaryl group containing 1 selected from N, O and S, the R 1-1-2 With the "-(CH2) s - or -NH-" can be in the ortho or meta position relative to each other.

[0279] In one embodiment, in the compound of Formula IV or a pharmaceutically acceptable salt thereof, the definitions of certain groups may be as follows, and the definitions of the remaining groups are as described in any of the above embodiments:

[0280] When R 1-1 For one or more R 1-1-2 When the substituted "5- to 10-membered heteroaryl group containing 1, 2 or 3 independently selected from N, O and S" is a 6-membered heteroaryl group containing 1 selected from N, O and S, the R 1-1-2 With the "-(CH2) s - or -NH-" may be in the ortho, meta or para position, and may also be in the para position.

[0281] In one embodiment, in the compound of Formula IV or a pharmaceutically acceptable salt thereof, the definitions of certain groups may be as follows, and the definitions of the remaining groups are as described in any of the above embodiments:

[0282] When R 1-1-1 and R 1-1-2 When they are independently C1-C4 alkyl, the C1-C4 alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl.

[0283] In one embodiment, in the compound of Formula IV or a pharmaceutically acceptable salt thereof, the definitions of certain groups may be as follows, and the definitions of the remaining groups are as described in any of the above embodiments:

[0284] When R 1-1-1 and R 1-1-2 When the plurality of halogen-substituted C1-C4 alkyl groups are independently multiple, the plurality is 2 or 3.

[0285] In one embodiment, in the compound of Formula IV or a pharmaceutically acceptable salt thereof, the definitions of certain groups may be as follows, and the definitions of the remaining groups are as described in any of the above embodiments:

[0286] When R 1-1-1 and R 1-1-2 When the C1-C4 alkyl group is independently substituted by one or more halogens, the halogen is fluorine.

[0287] In one embodiment, in the compound of Formula IV or a pharmaceutically acceptable salt thereof, the definitions of certain groups may be as follows, and the definitions of the remaining groups are as described in any of the above embodiments:

[0288] When R 1-1-1 and R 1-1-2When the C1-C4 alkyl group is independently substituted by one or more halogens, the C1-C4 alkyl group is methyl or ethyl.

[0289] In one embodiment, in the compound of Formula IV or a pharmaceutically acceptable salt thereof, the definitions of certain groups may be as follows, and the definitions of the remaining groups are as described in any of the above embodiments:

[0290] When R 1-1-1 and R 1-1-2 When the C1-C4 alkyl groups are independently multiple halogen-substituted, the multiple halogen-substituted C1-C4 alkyl groups are trifluoromethyl.

[0291] In one embodiment, in the compound of Formula IV or a pharmaceutically acceptable salt thereof, the definitions of certain groups may be as follows, and the definitions of the remaining groups are as described in any of the above embodiments:

[0292] When R 1-1-1 and R 1-1-2 When independently a C3-C6 cycloalkyl group, the C3-C6 cycloalkyl group is a cyclopropyl group.

[0293] In one embodiment, in the compound of Formula IV or a pharmaceutically acceptable salt thereof, the definitions of certain groups may be as follows, and the definitions of the remaining groups are as described in any of the above embodiments:

[0294] for

[0295] In one embodiment, in the compound of Formula IV or a pharmaceutically acceptable salt thereof, the definitions of certain groups may be as follows, and the definitions of the remaining groups are as described in any of the above embodiments:

[0296] Y 4 for

[0297] In one embodiment, in the compound of Formula IV or a pharmaceutically acceptable salt thereof, the definitions of certain groups may be as follows, and the definitions of the remaining groups are as described in any of the above embodiments:

[0298] Y 4 for

[0299] In one embodiment, in the compound of Formula IV or a pharmaceutically acceptable salt thereof, the definitions of certain groups may be as follows, and the definitions of the remaining groups are as described in any of the above embodiments:

[0300] Y 4 for

[0301] In one embodiment, in the compound of Formula IV or a pharmaceutically acceptable salt thereof, the definitions of certain groups may be as follows, and the definitions of the remaining groups are as described in any of the above embodiments:

[0302] Y 4 for

[0303] In one embodiment, in the compound of Formula IV or a pharmaceutically acceptable salt thereof, the definitions of certain groups may be as follows, and the definitions of the remaining groups are as described in any of the above embodiments:

[0304] Y 4 for

[0305] In one embodiment, in the compound of Formula IV or a pharmaceutically acceptable salt thereof, the definitions of certain groups may be as follows, and the definitions of the remaining groups are as described in any of the above embodiments:

[0306] s is 1 or 2.

[0307] In one embodiment, in the compound of Formula XII or a pharmaceutically acceptable salt thereof, the compound of Formula XII is a compound of Formula VI;

[0308]

[0309] Among them, R 1 -(CH2) s -R 1-1 ;s is 0, 1 or 2;

[0310] R 1-1 C6-C 10 Aryl, one or more R 1-1-1 Substituted C6-C 10 Aryl, "5-10 membered heteroaryl containing 1, 2 or 3 independently selected from N, O and S", or one or more R 1-1-2 Substituted "5- to 10-membered heteroaryl containing 1, 2 or 3 groups independently selected from N, O and S";

[0311] R 1-1-1 and R 1-1-2 Independently C1-C4 alkyl, one or more halogen-substituted C1-C4 alkyl, C3-C6 cycloalkyl, or phenyl.

[0312] In one embodiment, in the compound of Formula VI or a pharmaceutically acceptable salt thereof, the definitions of certain groups may be as follows, and the definitions of the remaining groups are as described in any of the above embodiments:

[0313] When R 1-1C6-C 10 When the C6-C 10 Aryl is phenyl or naphthyl.

[0314] In one embodiment, in the compound of Formula VI or a pharmaceutically acceptable salt thereof, the definitions of certain groups may be as follows, and the definitions of the remaining groups are as described in any of the above embodiments:

[0315] When R 1-1 For one or more R 1-1-1 Substituted C6-C 10 When the C6-C 10 Aryl is phenyl or naphthyl.

[0316] In one embodiment, in the compound of Formula VI or a pharmaceutically acceptable salt thereof, the definitions of certain groups may be as follows, and the definitions of the remaining groups are as described in any of the above embodiments:

[0317] When R 1-1 For one or more R 1-1-1 Substituted C6-C 10 Aryl, the C6-C 10 When the aryl group is a phenyl group, the R 1-1-1 With the "-(CH2) s - or -NH-" may be in the ortho, meta or para position, and may also be in the para position.

[0318] In one embodiment, in the compound of Formula VI or a pharmaceutically acceptable salt thereof, the definitions of certain groups may be as follows, and the definitions of the remaining groups are as described in any of the above embodiments:

[0319] When R 1-1 When it is a 5- to 10-membered heteroaryl group containing 1, 2 or 3 groups independently selected from N, O and S, the 5- to 10-membered heteroaryl group containing 1, 2 or 3 groups independently selected from N, O and S may be a 5- to 6-membered heteroaryl group containing 1 group selected from N, O and S, an indolyl group, an isoquinolyl group or a quinolyl group, or may be a 5- to 6-membered heteroaryl group containing 1 group selected from N, O and S.

[0320] The 5- to 6-membered heteroaryl group containing one selected from N, O and S is, for example, furyl, thienyl or pyridyl.

[0321] In one embodiment, in the compound of Formula VI or a pharmaceutically acceptable salt thereof, the definitions of certain groups may be as follows, and the definitions of the remaining groups are as described in any of the above embodiments:

[0322] When R 1-1 For one or more R 1-1-2When the substituted “5- to 10-membered heteroaryl group containing 1, 2 or 3 groups independently selected from N, O and S” is used, the 5- to 10-membered heteroaryl group containing 1, 2 or 3 groups independently selected from N, O and S may be a 5- to 6-membered heteroaryl group containing 1 group selected from N, O and S, an indolyl group, an isoquinolyl group or a quinolyl group, or a 5- to 6-membered heteroaryl group containing 1 group selected from N, O and S.

[0323] The 5- to 6-membered heteroaryl group containing one selected from N, O and S is, for example, furyl, thienyl or pyridyl.

[0324] In one embodiment, in the compound of Formula VI or a pharmaceutically acceptable salt thereof, the definitions of certain groups may be as follows, and the definitions of the remaining groups are as described in any of the above embodiments:

[0325] When R 1-1 For one or more R 1-1-2 When the substituted "5- to 10-membered heteroaryl group containing 1, 2 or 3 independently selected from N, O and S" is a 5-membered heteroaryl group containing 1 selected from N, O and S, the R 1-1-2 With the "-(CH2) s - or -NH-" can be in the ortho or meta position relative to each other.

[0326] In one embodiment, in the compound of Formula VI or a pharmaceutically acceptable salt thereof, the definitions of certain groups may be as follows, and the definitions of the remaining groups are as described in any of the above embodiments:

[0327] When R 1-1 For one or more R 1-1-2 When the substituted "5- to 10-membered heteroaryl group containing 1, 2 or 3 independently selected from N, O and S" is a 6-membered heteroaryl group containing 1 selected from N, O and S, the R 1-1-2 With the "-(CH2) s - or -NH-" may be in the ortho, meta or para position, and may also be in the para position.

[0328] In one embodiment, in the compound of Formula VI or a pharmaceutically acceptable salt thereof, the definitions of certain groups may be as follows, and the definitions of the remaining groups are as described in any of the above embodiments:

[0329] When R 1-1-1 and R 1-1-2 When they are independently C1-C4 alkyl, the C1-C4 alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl.

[0330] In one embodiment, in the compound of Formula VI or a pharmaceutically acceptable salt thereof, the definitions of certain groups may be as follows, and the definitions of the remaining groups are as described in any of the above embodiments:

[0331] When R 1-1-1 and R 1-1-2 When the C1-C4 alkyl group is independently substituted with multiple halogens, the multiple halogens are 2 or 3.

[0332] In one embodiment, in the compound of Formula VI or a pharmaceutically acceptable salt thereof, the definitions of certain groups may be as follows, and the definitions of the remaining groups are as described in any of the above embodiments:

[0333] When R 1-1-1 and R 1-1-2 When the C1-C4 alkyl group is independently substituted by one or more halogens, the halogen is fluorine.

[0334] In one embodiment, in the compound of Formula VI or a pharmaceutically acceptable salt thereof, the definitions of certain groups may be as follows, and the definitions of the remaining groups are as described in any of the above embodiments:

[0335] When R 1-1-1 and R 1-1-2 When the C1-C4 alkyl group is independently substituted by one or more halogens, the C1-C4 alkyl group is methyl or ethyl.

[0336] In one embodiment, in the compound of Formula VI or a pharmaceutically acceptable salt thereof, the definitions of certain groups may be as follows, and the definitions of the remaining groups are as described in any of the above embodiments:

[0337] When R 1-1-1 and R 1-1-2 When the multiple halogen-substituted C1-C4 alkyl groups are independently multiple halogen-substituted C1-C4 alkyl groups, the multiple halogen-substituted C1-C4 alkyl groups are trifluoromethyl groups.

[0338] In one embodiment, in the compound of Formula VI or a pharmaceutically acceptable salt thereof, the definitions of certain groups may be as follows, and the definitions of the remaining groups are as described in any of the above embodiments:

[0339] When R 1-1-1 and R 1-1-2 When independently a C3-C6 cycloalkyl group, the C3-C6 cycloalkyl group is a cyclopropyl group.

[0340] In one embodiment, in the compound of Formula VI or a pharmaceutically acceptable salt thereof, the definitions of certain groups may be as follows, and the definitions of the remaining groups are as described in any of the above embodiments:

[0341] s is 1 or 2.

[0342] In one embodiment, in the compound of Formula XII or a pharmaceutically acceptable salt thereof, the definitions of certain groups may be as follows, and the definitions of the remaining groups are as described in any of the above embodiments:

[0343] W is any of the following groups:

[0344] (1)

[0345] in is a single bond or a double bond;

[0346] when in When Y is a single bond, 1 C(=O), O, NH, N-OH, or NR 3 , R 3 is CH2COOH or C1-C4 alkyl, Y 2 is C(=N-CO-Ph), C(=N-CO-CH3), NH, S(=O)2, C=O or C=S;

[0347] when in When it is a double bond, Y 1 N, Y 2 is C-NH2 or C-NH-CN;

[0348] Y 3 N or CH;

[0349] X 1 N or CR 2 , X 2 N or CR 4 , X 3 N or CR 5 , X 4 N or CR 6 ;

[0350] R 2 、R 4 、R 5 and R 6 independently hydrogen, halogen, hydroxy, amino, carboxyl, cyano, nitro, C1-C4 alkyl, C1-C4 alkyl substituted with one or more halogens, C1-C4 alkoxy, C3-C6 cycloalkyl, phenyl, "5-7 membered heterocycloalkyl containing 1, 2 or 3 independently selected from N, O and S", -S(=O)2-NR 2-3 R 2-4 , or, -C(=O)-NR 2-7 R 2-8 ;

[0351] R 2-3 、R 2-4 、R 2-7 and R 2-8 are independently hydrogen;

[0352] (2)

[0353] Y 4-1 is -NH-C(=O)-CH2- or NH;

[0354] Y 5 N or CR 7 , R 7 is a halogen;

[0355] X 5 CR 8 , X 6 CR 9 , X 7 CR 10 , X 8 CR 11 ;

[0356] R 8 、R 9 、R 10 and R 11 are independently hydrogen;

[0357] (3)

[0358] Y 6 is NC(=O)-CH3, CH2 or NH;

[0359] Y 7 is NH, CH2, C(=O), C(=S) or C(=N-OH);

[0360] Y 8 is CH2, CH2CH2, CH(CH3) or C(=O);

[0361] Y 9 is N;

[0362] X 9 CR 12 , X 10 CR 13 , X 11 CR 14 , X 12 CR 15 ;

[0363] R 12 、R 13 、R 14 and R15 are independently hydrogen, nitro, or one or more halogen-substituted C1-C4 alkyl groups;

[0364] (4)

[0365] Y 10 for NH;

[0366] Y 11 is C(=O);

[0367] Y 12 is N;

[0368] Y 13 is CH2;

[0369] X 13 CR 16 , X 14 CR 17 , X 15 CR 18 , X 16 CR 19 ;

[0370] R 16 、R 17 、R 18 and R 19 are independently hydrogen;

[0371] (5)

[0372] Y 14 for NH;

[0373] Y 15 is C(=O);

[0374] Y 16 is N;

[0375] X 17 CR 20 , X 18 CR 21 , X 19 CR 22 ;

[0376] R 20 、R 21 and R 22 are independently hydrogen;

[0377] (6)

[0378] Y 17 for NH;

[0379] X 20CR 23 , X 21 CR 24 , X 22 CR 25 , X 23 CR 26 ;

[0380] R 23 、R 24 、R 25 and R 26 are independently hydrogen;

[0381] (7)

[0382] Y 18 is NH or CH2;

[0383] Y 19 is C(=O) or NH;

[0384] Y 20 is CH2 or C(=O);

[0385] X 24 CR 27 , X 25 CR 28 , X 26 CR 29 ;

[0386] R 27 、R 28 and R 29 are independently hydrogen;

[0387] (8)

[0388] Y 21 is C(=O);

[0389] Y 22 for NH;

[0390] Y 23 is CH2 or C(=O);

[0391] Y 24 NR 30 , R 30 is hydrogen or phenyl;

[0392] (9)

[0393] Y 25 for NH;

[0394] Y 26 is C(=O);

[0395] Y 27 is a single bond, O or NH;

[0396] X 27 CR 31 , X 28 CR 32 , X 29 CR 33 , X 30 CR 34 ;

[0397] R 31 、R 32 、R 33 and R 34 are independently hydrogen;

[0398] (10)

[0399] Y 28 for NH;

[0400] Y 29 is C(=O);

[0401] Y 30 is N;

[0402] (11)

[0403] Y 31 is O, NH or NC(=O)-CH3;

[0404] Y 32 is N;

[0405] X 31 CR 35 , X 32 CR 36 , X 33 CR 37 , X 34 CR 38 ;

[0406] R 35 、R 36 、R 37 and R 38 are independently hydrogen;

[0407] (12)

[0408] Y 33 for NH;

[0409] Y 34 is C(=O);

[0410] Y35 is N;

[0411] X 35 CR 39 , X 36 CR 40 , X 37 CR 41 , X 38 CR 42 ;

[0412] R 39 、R 40 、R 41 and R 42 are independently hydrogen;

[0413] (13)

[0414] Y 36 for NH;

[0415] Y 37 is C(=O);

[0416] Y 38 is N;

[0417] X 39 CR 43 , X 40 CR 44 , X 41 CR 45 , X 42 CR 46 ;

[0418] R 43 、R 44 、R 45 and R 46 are independently hydrogen;

[0419] (14)

[0420] Y 39 for NH;

[0421] Y 40 is C(=O);

[0422] Y 41 is N;

[0423] X 43 CR 47 , X 44 CR 48 , X 45 CR 49 , X 46 CR 50 ;

[0424] R 47 、R 48 、R 49 and R 50 are independently hydrogen;

[0425] and, (15)

[0426] In one embodiment, in the compound of Formula XII or a pharmaceutically acceptable salt thereof, the definitions of certain groups may be as follows, and the definitions of the remaining groups are as described in any of the above embodiments:

[0427] W is any of the following groups:

[0428] (1)

[0429] in is a single bond or a double bond;

[0430] when in When Y is a single bond, 1 NH, N-OH, Y 2 is C(=N-CO-Ph), C(=N-CO-CH3), S(=O)2, C=O or C=S;

[0431] when in When it is a double bond, Y 1 N, Y 2 is C-NH2 or C-NH-CN;

[0432] Y 3 N or CH;

[0433] X 1 N or CR 2 , X 2 N or CR 4 , X 3 N or CR 5 , X 4 N or CR 6 ;

[0434] R 2 、R 4 、R 5 and R 6 independently hydrogen, halogen, hydroxy, amino, cyano, nitro, C1-C4 alkyl, C1-C4 alkyl substituted with one or more halogens, C1-C4 alkoxy, C3-C6 cycloalkyl, phenyl, "5-7 membered heterocycloalkyl containing 1, 2 or 3 independently selected from N, O and S", -S(=O)2-NR2-3 R 2-4 , or, -C(=O)-NR 2-7 R 2-8 ;

[0435] R 2-3 、R 2-4 、R 2-7 and R 2-8 are independently hydrogen;

[0436] (2)

[0437] Y 4-1 is -NH-C(=O)-CH2- or NH;

[0438] Y 5 N or CR 7 , R 7 is a halogen;

[0439] X 5 CR 8 , X 6 CR 9 , X 7 CR 10 , X 8 CR 11 ;

[0440] R 8 、R 9 、R 10 and R 11 are independently hydrogen;

[0441] (3)

[0442] Y 6 is NC(=O)-CH3 or NH;

[0443] Y 7 is C(═O), C(═S) or C(═N-OH);

[0444] Y 8 is CH2, or C(=O);

[0445] Y 9 is N;

[0446] X 9 CR 12 , X 10 CR 13 , X 11 CR 14 , X 12 CR 15 ;

[0447] R 12 、R 13 、R 14 and R 15 are independently hydrogen, nitro, or one or more halogen-substituted C1-C4 alkyl groups;

[0448] (4)

[0449] Y 10 for NH;

[0450] Y 11 is C(=O);

[0451] Y 12 is N;

[0452] Y 13 is CH2;

[0453] X 13 CR 16 , X 14 CR 17 , X 15 CR 18 , X 16 CR 19 ;

[0454] R 16 、R 17 、R 18 and R 19 are independently hydrogen;

[0455] (5)

[0456] Y 14 for NH;

[0457] Y 15 is C(=O);

[0458] Y 16 is N;

[0459] X 17 CR 20 , X 18 CR 21 , X 19 CR 22 ;

[0460] R 20 、R 21 and R 22 are independently hydrogen;

[0461] (7)

[0462] Y18 is NH or CH2;

[0463] Y 19 is C(=O) or NH;

[0464] Y 20 is CH2 or C(=O);

[0465] X 24 CR 27 , X 25 CR 28 , X 26 CR 29 ;

[0466] R 27 、R 28 and R 29 are independently hydrogen;

[0467] (8)

[0468] Y 21 is C(=O);

[0469] Y 22 for NH;

[0470] Y 23 is CH2;

[0471] Y 24 NR 30 , R 30 is phenyl;

[0472] (9)

[0473] Y 25 for NH;

[0474] Y 26 is C(=O);

[0475] Y 27 is a single bond, O or NH;

[0476] X 27 CR 31 , X 28 CR 32 , X 29 CR 33 , X 30 CR 34 ;

[0477] R 31 、R 32 、R 33 and R 34 are independently hydrogen;

[0478] (11)

[0479] Y 31 is O, NH or NC(=O)-CH3;

[0480] Y 32 is N;

[0481] X 31 CR 35 , X 32 CR 36 , X 33 CR 37 , X 34 CR 38 ;

[0482] R 35 、R 36 、R 37 and R 38 are independently hydrogen;

[0483] (12)

[0484] Y 33 for NH;

[0485] Y 34 is C(=O);

[0486] Y 35 is N;

[0487] X 35 CR 39 , X 36 CR 40 , X 37 CR 41 , X 38 CR 42 ;

[0488] R 39 、R 40 、R 41 and R 42 are independently hydrogen;

[0489] (13)

[0490] Y 36 for NH;

[0491] Y 37 is C(=O);

[0492] Y 38 is N;

[0493] X 39 CR 43 , X 40 CR 44 , X 41 CR 45 , X 42 CR 46 ;

[0494] R 43 、R 44 、R 45 and R 46 are independently hydrogen;

[0495] and (14)

[0496] Y 39 for NH;

[0497] Y 40 is C(=O);

[0498] Y 41 is N;

[0499] X 43 CR 47 , X 44 CR 48 , X 45 CR 49 , X 46 CR 50 ;

[0500] R 47 、R 48 、R 49 and R 50 are independently hydrogen;

[0501] In one embodiment, in the compound of Formula XII or a pharmaceutically acceptable salt thereof, the definitions of certain groups may be as follows, and the definitions of the remaining groups are as described in any of the above embodiments:

[0502] R 1 -(CH2) s -R 1-1 、-NH-R 1-2 、 s is 0, 1, or 2;

[0503] R 1-1 、R 1-2 、R 1-3 、R 1-4 and R 1-5 independently one or more R 1-1-3 Substituted C3-C6 cycloalkyl, one or more R1-1-1 Substituted C6-C 10 Aryl, naphthyl, "a 5- or 10-membered heteroaryl group containing 1, 2 or 3 groups independently selected from N, O and S", pyridyl, or, one or more R 1-1-2 Substituted "5- to 10-membered heteroaryl containing 1, 2 or 3 groups independently selected from N, O and S";

[0504] R 1-1-1 、R 1-1-2 and R 1-1-3 independently carboxyl, hydroxyl, halogen, C1-C4 alkyl, one or more halogen-substituted C1-C4 alkyl, one or more halogen-substituted C1-C4 alkoxy, C3-C6 cycloalkyl, "5-6 membered heterocycloalkyl containing 1, 2 or 3 independently selected from N, O and S", -N(R 1-1-1-1 )(R 1-1-1-2 ), or, phenyl;

[0505] R 1-1-1-1 and R 1-1-1-2 are independently hydrogen or C1-C4 alkyl;

[0506] R 1-1-7 、R 1-1-8 , and, R 1-1-9 are independently C1-C4 alkyl;

[0507] R 1-1-10 are independently C1-C4 alkoxy;

[0508] R 1-1-11 and R 1-1-12 are independently hydrogen or halogen.

[0509] In one embodiment, in the compound of Formula XII or a pharmaceutically acceptable salt thereof, the definitions of certain groups may be as follows, and the definitions of the remaining groups are as described in any of the above embodiments:

[0510] When W is When Z is any of the following fragments:

[0511] (1) m is 1 or 2, n is 1, 2 or 3;

[0512] (2) u is 1 or 2, t is 1 or 2;

[0513] (3)

[0514] (4) p is 1 or 2, q is 1 or 2;

[0515] (5) a2 is 1 or 2, b2 is 1 or 2;

[0516] (6) a3 is 1 or 2, b3 is 1 or 2;

[0517] (9)

[0518] In one embodiment, in the compound of Formula XII or a pharmaceutically acceptable salt thereof, the definitions of certain groups may be as follows, and the definitions of the remaining groups are as described in any of the above embodiments:

[0519] When W is When Z is

[0520] In one embodiment, in the compound of Formula XII or a pharmaceutically acceptable salt thereof, the definitions of certain groups may be as follows, and the definitions of the remaining groups are as described in any of the above embodiments:

[0521] When W is When Z is -C(=O)-.

[0522] In one embodiment, in the compound of Formula XII or a pharmaceutically acceptable salt thereof, the definitions of certain groups may be as follows, and the definitions of the remaining groups are as described in any of the above embodiments:

[0523] W is any of the following groups:

[0524] (1)

[0525] in is a single bond or a double bond;

[0526] when in When Y is a single bond, 1 C(=O), O, NH, N-OH, or NR 3 , R 3 is CH2COOH or C1-C4 alkyl, Y 2 is C(=N-CO-Ph), C(=N-CO-CH3), NH, S(=O)2, C=O or C=S;

[0527] when in When it is a double bond, Y 1 N, Y 2is C-NH2 or C-NH-CN;

[0528] Y 3 N or CH;

[0529] X 1 N or CR 2 , X 2 N or CR 4 , X 3 N or CR 5 , X 4 N or CR 6 ;

[0530] R 2 、R 4 、R 5 and R 6 independently hydrogen, halogen, hydroxy, amino, carboxyl, cyano, nitro, C1-C4 alkyl, C1-C4 alkyl substituted with one or more halogens, C1-C4 alkoxy, C3-C6 cycloalkyl, phenyl, "5-7 membered heterocycloalkyl containing 1, 2 or 3 independently selected from N, O and S", -S(=O)2-NR 2-3 R 2-4 , or, -C(=O)-NR 2-7 R 2-8 ;

[0531] R 2-3 、R 2-4 、R 2-7 and R 2-8 are independently hydrogen;

[0532] (2)

[0533] Y 4-1 is -NH-C(=O)-CH2- or NH;

[0534] Y 5 N or CR 7 , R 7 is a halogen;

[0535] X 5 CR 8 , X 6 CR 9 , X 7 CR 10 , X 8 CR 11 ;

[0536] R 8 、R 9 、R 10 and R 11 are independently hydrogen;

[0537] (3)

[0538] Y 6 is NC(=O)-CH3, CH2 or NH;

[0539] Y 7 is NH, CH2, C(=O), C(=S) or C(=N-OH);

[0540] Y 8 is CH2, CH2CH2, CH(CH3) or C(=O);

[0541] Y 9 is N;

[0542] X 9 CR 12 , X 10 CR 13 , X 11 CR 14 , X 12 CR 15 ;

[0543] R 12 、R 13 、R 14 and R 15 are independently hydrogen, nitro, or one or more halogen-substituted C1-C4 alkyl groups;

[0544] (4)

[0545] Y 10 for NH;

[0546] Y 11 is C(=O);

[0547] Y 12 is N;

[0548] Y 13 is CH2;

[0549] X 13 CR 16 , X 14 CR 17 , X 15 CR 18 , X 16 CR 19 ;

[0550] R 16 、R 17 、R 18 and R 19are independently hydrogen;

[0551] (5)

[0552] Y 14 for NH;

[0553] Y 15 is C(=O);

[0554] Y 16 is N;

[0555] X 17 CR 20 , X 18 CR 21 , X 19 CR 22 ;

[0556] R 20 、R 21 and R 22 are independently hydrogen;

[0557] (6)

[0558] Y 17 for NH;

[0559] X 20 CR 23 , X 21 CR 24 , X 22 CR 25 , X 23 CR 26 ;

[0560] R 23 、R 24 、R 25 and R 26 are independently hydrogen;

[0561] (7)

[0562] Y 18 is NH or CH2;

[0563] Y 19 is C(=O) or NH;

[0564] Y 20 is CH2 or C(=O);

[0565] X 24 CR 27 , X 25 CR 28 , X 26 CR29 ;

[0566] R 27 、R 28 and R 29 are independently hydrogen;

[0567] (8)

[0568] Y 21 is C(=O);

[0569] Y 22 for NH;

[0570] Y 23 is CH2 or C(=O);

[0571] Y 24 NR 30 , R 30 is hydrogen or phenyl;

[0572] (9)

[0573] Y 25 for NH;

[0574] Y 26 is C(=O);

[0575] Y 27 is a single bond, O or NH;

[0576] X 27 CR 31 , X 28 CR 32 , X 29 CR 33 , X 30 CR 34 ;

[0577] R 31 、R 32 、R 33 and R 34 are independently hydrogen;

[0578] (10)

[0579] Y 28 for NH;

[0580] Y 29 is C(=O);

[0581] Y 30 is N;

[0582] (11)

[0583] Y 31 is O, NH or NC(=O)-CH3;

[0584] Y 32 is N;

[0585] X 31 CR 35 , X 32 CR 36 , X 33 CR 37 , X 34 CR 38 ;

[0586] R 35 、R 36 、R 37 and R 38 are independently hydrogen;

[0587] (12)

[0588] Y 33 for NH;

[0589] Y 34 is C(=O);

[0590] Y 35 is N;

[0591] X 35 CR 39 , X 36 CR 40 , X 37 CR 41 , X 38 CR 42 ;

[0592] R 39 、R 40 、R 41 and R 42 are independently hydrogen;

[0593] (13)

[0594] Y 36 for NH;

[0595] Y 37 is C(=O);

[0596] Y 38 is N;

[0597] X 39 CR 43 , X40 CR 44 , X 41 CR 45 , X 42 CR 46 ;

[0598] R 43 、R 44 、R 45 and R 46 are independently hydrogen;

[0599] (14)

[0600] Y 39 for NH;

[0601] Y 40 is C(=O);

[0602] Y 41 is N;

[0603] X 43 CR 47 , X 44 CR 48 , X 45 CR 49 , X 46 CR 50 ;

[0604] R 47 、R 48 、R 49 and R 50 are independently hydrogen;

[0605] and, (15)

[0606] Z is any of the following fragments:

[0607] (1) m is 1 or 2, n is 1, 2 or 3;

[0608] (2) u is 1 or 2, t is 1 or 2;

[0609] (3)

[0610] (4) p is 1 or 2, q is 1 or 2;

[0611] (5) a2 is 1 or 2, b2 is 1 or 2;

[0612] (6) a3 is 1 or 2, b3 is 1 or 2;

[0613] (7)

[0614] (8) -C(=O)-;

[0615] (9)

[0616] R 1 C2-C4 alkyl, C2-C4 alkyl substituted with one or more halogens, -(CH2) s -R 1-1 、-NH-R 1-2 、 s is 0, 1, or 2;

[0617] R 1-1 、R 1-2 、R 1-3 、R 1-4 and R 1-5 Independently C7-C 10 Cycloalkyl, one or more R 1-1-3 Substituted C3-C6 cycloalkyl, one or more R 1-1-6 Substituted "5-6 membered heterocycloalkyl containing 1, 2 or 3 independently selected from N, O and S", one or more R 1-1-1 Substituted C6-C 10 Aryl, naphthyl, "a 5- or 10-membered heteroaryl group containing 1, 2 or 3 groups independently selected from N, O and S", pyridyl, or, one or more R 1-1-2 Substituted "5- to 10-membered heteroaryl containing 1, 2 or 3 groups independently selected from N, O and S";

[0618] R 1-1-1 、R 1-1-2 、R 1-1-3 , and, R 1-1-6 independently carboxyl, hydroxyl, halogen, C1-C4 alkyl, one or more halogen-substituted C1-C4 alkyl, one or more halogen-substituted C1-C4 alkoxy, C3-C6 cycloalkyl, "5-6 membered heterocycloalkyl containing 1, 2 or 3 independently selected from N, O and S", -N(R 1-1-1-1 )(R 1-1-1-2 ), or, phenyl;

[0619] R 1-1-1-1 and R 1-1-1-2 are independently hydrogen or C1-C4 alkyl;

[0620] R 1-1-7 、R 1-1-8, and, R 1-1-9 are independently C1-C4 alkyl;

[0621] R 1-1-10 are independently C1-C4 alkoxy;

[0622] R 1-1-11 and R 1-1-12 are independently hydrogen or halogen.

[0623] In one embodiment, in the compound of Formula XII or a pharmaceutically acceptable salt thereof, the definitions of certain groups may be as follows, and the definitions of the remaining groups are as described in any of the above embodiments:

[0624] W is any of the following groups:

[0625] (1)

[0626] in is a single bond or a double bond;

[0627] when in When Y is a single bond, 1 NH, N-OH, Y 2 is C(=N-CO-Ph), C(=N-CO-CH3), S(=O)2, C=O or C=S;

[0628] when in When it is a double bond, Y 1 N, Y 2 is C-NH2 or C-NH-CN;

[0629] Y 3 N or CH;

[0630] X 1 N or CR 2 , X 2 N or CR 4 , X 3 N or CR 5 , X 4 N or CR 6 ;

[0631] R 2 、R 4 、R 5 and R 6independently hydrogen, halogen, hydroxy, amino, cyano, nitro, C1-C4 alkyl, C1-C4 alkyl substituted with one or more halogens, C1-C4 alkoxy, C3-C6 cycloalkyl, phenyl, "5-7 membered heterocycloalkyl containing 1, 2 or 3 independently selected from N, O and S", -S(=O)2-NR 2-3 R 2-4 , or, -C(=O)-NR 2-7 R 2-8 ;

[0632] R 2-3 、R 2-4 、R 2-7 and R 2-8 are independently hydrogen;

[0633] (2)

[0634] Y 4-1 is -NH-C(=O)-CH2- or NH;

[0635] Y 5 N or CR 7 , R 7 is a halogen;

[0636] X 5 CR 8 , X 6 CR 9 , X 7 CR 10 , X 8 CR 11 ;

[0637] R 8 、R 9 、R 10 and R 11 are independently hydrogen;

[0638] (3)

[0639] Y 6 is NC(=O)-CH3 or NH;

[0640] Y 7 is C(═O), C(═S) or C(═N-OH);

[0641] Y 8 is CH2, or C(=O);

[0642] Y 9 is N;

[0643] X 9 CR 12 , X10 CR 13 , X 11 CR 14 , X 12 CR 15 ;

[0644] R 12 、R 13 、R 14 and R 15 are independently hydrogen, nitro, or one or more halogen-substituted C1-C4 alkyl groups;

[0645] (4)

[0646] Y 10 for NH;

[0647] Y 11 is C(=O);

[0648] Y 12 is N;

[0649] Y 13 is CH2;

[0650] X 13 CR 16 , X 14 CR 17 , X 15 CR 18 , X 16 CR 19 ;

[0651] R 16 、R 17 、R 18 and R 19 are independently hydrogen;

[0652] (5)

[0653] Y 14 for NH;

[0654] Y 15 is C(=O);

[0655] Y 16 is N;

[0656] X 17 CR 20 , X 18 CR 21 , X 19 CR 22 ;

[0657] R 20、R 21 and R 22 are independently hydrogen;

[0658] (7)

[0659] Y 18 is NH or CH2;

[0660] Y 19 is C(=O) or NH;

[0661] Y 20 is CH2 or C(=O);

[0662] X 24 CR 27 , X 25 CR 28 , X 26 CR 29 ;

[0663] R 27 、R 28 and R 29 are independently hydrogen;

[0664] (8)

[0665] Y 21 is C(=O);

[0666] Y 22 for NH;

[0667] Y 23 is CH2;

[0668] Y 24 NR 30 , R 30 is phenyl;

[0669] (9)

[0670] Y 25 for NH;

[0671] Y 26 is C(=O);

[0672] Y 27 is a single bond, O or NH;

[0673] X 27 CR 31 , X 28 CR 32 , X 29 CR 33 , X 30 CR34 ;

[0674] R 31 、R 32 、R 33 and R 34 are independently hydrogen;

[0675] (11)

[0676] Y 31 is O, NH or NC(=O)-CH3;

[0677] Y 32 is N;

[0678] X 31 CR 35 , X 32 CR 36 , X 33 CR 37 , X 34 CR 38 ;

[0679] R 35 、R 36 、R 37 and R 38 are independently hydrogen;

[0680] (12)

[0681] Y 33 for NH;

[0682] Y 34 is C(=O);

[0683] Y 35 is N;

[0684] X 35 CR 39 , X 36 CR 40 , X 37 CR 41 , X 38 CR 42 ;

[0685] R 39 、R 40 、R 41 and R 42 are independently hydrogen;

[0686] (13)

[0687] Y 36 for NH;

[0688] Y 37 is C(=O);

[0689] Y 38 is N;

[0690] X 39 CR 43 , X 40 CR 44 , X 41 CR 45 , X 42 CR 46 ;

[0691] R 43 、R 44 、R 45 and R 46 are independently hydrogen;

[0692] and (14)

[0693] Y 39 for NH;

[0694] Y 40 is C(=O);

[0695] Y 41 is N;

[0696] X 43 CR 47 , X 44 CR 48 , X 45 CR 49 , X 46 CR 50 ;

[0697] R 47 、R 48 、R 49 and R 50 are independently hydrogen;

[0698] Z is any of the following fragments:

[0699] (1) m is 1 or 2, n is 1, 2 or 3;

[0700] (2) u is 1 or 2, t is 1 or 2;

[0701] (3) or

[0702] (4) p is 1 or 2, q is 1 or 2;

[0703] (5) a2 is 1 or 2, b2 is 1 or 2;

[0704] (6) a3 is 1 or 2, b3 is 1 or 2;

[0705] (7)

[0706] (8) -C(=O)-;

[0707] (9)

[0708] R 1 -(CH2) s -R 1-1 、-NH-R 1-2 、 s is 0, 1, or 2;

[0709] R 1-1 、R 1-2 、R 1-3 、R 1-4 and R 1-5 independently one or more R 1-1-3 Substituted C3-C6 cycloalkyl, one or more R 1-1-1 Substituted C6-C 10 Aryl, naphthyl, "a 5- or 10-membered heteroaryl group containing 1, 2 or 3 groups independently selected from N, O and S", pyridyl, or, one or more R 1-1-2 Substituted "5- to 10-membered heteroaryl containing 1, 2 or 3 groups independently selected from N, O and S";

[0710] R 1-1-1 、R 1-1-2 and R 1-1-3 independently carboxyl, hydroxyl, halogen, C1-C4 alkyl, one or more halogen-substituted C1-C4 alkyl, one or more halogen-substituted C1-C4 alkoxy, C3-C6 cycloalkyl, "5-6 membered heterocycloalkyl containing 1, 2 or 3 independently selected from N, O and S", -N(R 1-1-1-1 )(R 1-1-1-2 ), or, phenyl;

[0711] R 1-1-1-1 and R 1-1-1-2 are independently hydrogen or C1-C4 alkyl;

[0712] R 1-1-7 、R 1-1-8 , and, R 1-1-9are independently C1-C4 alkyl;

[0713] R 1-1-10 are independently C1-C4 alkoxy;

[0714] R 1-1-11 and R 1-1-12 are independently hydrogen or halogen.

[0715] In one embodiment, in the compound of Formula XII or a pharmaceutically acceptable salt thereof, the definitions of certain groups may be as follows, and the definitions of the remaining groups are as described in any of the above embodiments:

[0716] R 1-1 、R 1-2 、R 1-3 、R 1-4 and R 1-5 independently one or more R 1-1-3 Substituted C3-C6 cycloalkyl, one or more R 1-1-6 Substituted "5-6 membered heterocycloalkyl containing 1, 2 or 3 independently selected from N, O and S", one or more R 1-1-1 Substituted C6-C 10 Aryl, or, one or more R 1-1-2 Substituted "5- to 10-membered heteroaryl containing 1, 2 or 3 groups independently selected from N, O and S";

[0717] R 1-1-1 、R 1-1-2 、R 1-1-3 , and, R 1-1-6 independently carboxyl, hydroxyl, halogen, C1-C4 alkyl, one or more halogen-substituted C1-C4 alkyl, one or more halogen-substituted C1-C4 alkoxy, C3-C6 cycloalkyl, "5-6 membered heterocycloalkyl containing 1, 2 or 3 independently selected from N, O and S", -N(R 1-1-1-1 )(R 1-1-1-2 ), or, phenyl.

[0718] In one embodiment, in the compound of Formula XII or a pharmaceutically acceptable salt thereof, the definitions of certain groups may be as follows, and the definitions of the remaining groups are as described in any of the above embodiments:

[0719] R 1-1 、R 1-2 、R 1-3 、R 1-4 and R 1-5 independently one or more R 1-1-3 Substituted C3-C6 cycloalkyl, one or more R 1-1-6Substituted "5-6 membered heterocycloalkyl containing 1, 2 or 3 independently selected from N, O and S", one or more R 1-1-1 Substituted C6-C 10 Aryl, or, one or more R 1-1-2 Substituted "5- to 10-membered heteroaryl containing 1, 2 or 3 groups independently selected from N, O and S";

[0720] R 1-1-1 、R 1-1-2 、R 1-1-3 , and, R 1-1-6 are independently carboxyl.

[0721] In one embodiment, in the compound of Formula XII or a pharmaceutically acceptable salt thereof, the definitions of certain groups may be as follows, and the definitions of the remaining groups are as described in any of the above embodiments:

[0722] R 1-1 、R 1-2 、R 1-3 、R 1-4 and R 1-5 independently one or more R 1-1-3 Substituted C3-C6 cycloalkyl, one or more R 1-1-6 Substituted "5-6 membered heterocycloalkyl containing 1, 2 or 3 independently selected from N, O and S", one or more R 1-1-1 Substituted C6-C 10 Aryl, or, one or more R 1-1-2 Substituted "5- to 10-membered heteroaryl containing 1, 2 or 3 groups independently selected from N, O and S";

[0723] R 1-1-1 、R 1-1-2 、R 1-1-3 , and, R 1-1-6 are independently hydroxyl.

[0724] In one embodiment, in the compound of Formula XII or a pharmaceutically acceptable salt thereof, the definitions of certain groups may be as follows, and the definitions of the remaining groups are as described in any of the above embodiments:

[0725] R 1-1 、R 1-2 、R 1-3 、R 1-4 and R 1-5 independently one or more R 1-1-3 Substituted C3-C6 cycloalkyl, one or more R 1-1-6 Substituted "5-6 membered heterocycloalkyl containing 1, 2 or 3 independently selected from N, O and S", one or more R 1-1-1 Substituted C6-C 10Aryl, or, one or more R 1-1-2 Substituted "5- to 10-membered heteroaryl containing 1, 2 or 3 groups independently selected from N, O and S";

[0726] R 1-1-1 、R 1-1-2 、R 1-1-3 , and, R 1-1-6 are independently halogen.

[0727] In one embodiment, in the compound of Formula XII or a pharmaceutically acceptable salt thereof, the definitions of certain groups may be as follows, and the definitions of the remaining groups are as described in any of the above embodiments:

[0728] R 1-1 、R 1-2 、R 1-3 、R 1-4 and R 1-5 independently one or more R 1-1-3 Substituted C3-C6 cycloalkyl, one or more R 1-1-6 Substituted "5-6 membered heterocycloalkyl containing 1, 2 or 3 independently selected from N, O and S", one or more R 1-1-1 Substituted C6-C 10 Aryl, or, one or more R 1-1-2 Substituted "5- to 10-membered heteroaryl containing 1, 2 or 3 groups independently selected from N, O and S";

[0729] R 1-1-1 、R 1-1-2 、R 1-1-3 , and, R 1-1-6 are independently C1-C4 alkyl or C1-C4 alkyl substituted with one or more halogens.

[0730] In one embodiment, in the compound of Formula XII or a pharmaceutically acceptable salt thereof, the definitions of certain groups may be as follows, and the definitions of the remaining groups are as described in any of the above embodiments:

[0731] R 1-1 、R 1-2 、R 1-3 、R 1-4 and R 1-5 independently one or more R 1-1-3 Substituted C3-C6 cycloalkyl, one or more R 1-1-6 Substituted "5-6 membered heterocycloalkyl containing 1, 2 or 3 independently selected from N, O and S", one or more R 1-1-1 Substituted C6-C 10 Aryl, or, one or more R 1-1-2Substituted "5- to 10-membered heteroaryl containing 1, 2 or 3 groups independently selected from N, O and S";

[0732] R 1-1-1 、R 1-1-2 、R 1-1-3 , and, R 1-1-6 and independently one or more halogen-substituted C1-C4 alkyl groups.

[0733] In one embodiment, in the compound of Formula XII or a pharmaceutically acceptable salt thereof, the definitions of certain groups may be as follows, and the definitions of the remaining groups are as described in any of the above embodiments:

[0734] R 1-1 、R 1-2 、R 1-3 、R 1-4 and R 1-5 independently one or more R 1-1-3 Substituted C3-C6 cycloalkyl, one or more R 1-1-6 Substituted "5-6 membered heterocycloalkyl containing 1, 2 or 3 independently selected from N, O and S", one or more R 1-1-1 Substituted C6-C 10 Aryl, or, one or more R 1-1-2 Substituted "5- to 10-membered heteroaryl containing 1, 2 or 3 groups independently selected from N, O and S";

[0735] R 1-1-1 、R 1-1-2 、R 1-1-3 , and, R 1-1-6 is independently trifluoromethyl.

[0736] In one embodiment, in the compound of Formula XII or a pharmaceutically acceptable salt thereof, the definitions of certain groups may be as follows, and the definitions of the remaining groups are as described in any of the above embodiments:

[0737] R 1-1 、R 1-2 、R 1-3 、R 1-4 and R 1-5 independently one or more R 1-1-3 Substituted C3-C6 cycloalkyl, one or more R 1-1-6 Substituted "5-6 membered heterocycloalkyl containing 1, 2 or 3 independently selected from N, O and S", one or more R 1-1-1 Substituted C6-C 10 Aryl, or, one or more R 1-1-2 Substituted "5- to 10-membered heteroaryl containing 1, 2 or 3 groups independently selected from N, O and S";

[0738] R 1-1-1 、R 1-1-2 、R 1-1-3 , and, R 1-1-6 and C1-C4 alkoxy groups which are independently substituted by one or more halogens.

[0739] In one embodiment, in the compound of Formula XII or a pharmaceutically acceptable salt thereof, the definitions of certain groups may be as follows, and the definitions of the remaining groups are as described in any of the above embodiments:

[0740] R 1-1 、R 1-2 、R 1-3 、R 1-4 and R 1-5 independently one or more R 1-1-3 Substituted C3-C6 cycloalkyl, one or more R 1-1-6 Substituted "5-6 membered heterocycloalkyl containing 1, 2 or 3 independently selected from N, O and S", one or more R 1-1-1 Substituted C6-C 10 Aryl, or, one or more R 1-1-2 Substituted "5- to 10-membered heteroaryl containing 1, 2 or 3 groups independently selected from N, O and S";

[0741] R 1-1-1 、R 1-1-2 、R 1-1-3 , and, R 1-1-6 It is independently a C3-C6 cycloalkyl group or a 5- to 6-membered heterocycloalkyl group containing 1, 2 or 3 groups independently selected from N, O and S.

[0742] In one embodiment, in the compound of Formula XII or a pharmaceutically acceptable salt thereof, the definitions of certain groups may be as follows, and the definitions of the remaining groups are as described in any of the above embodiments:

[0743] R 1-1 、R 1-2 、R 1-3 、R 1-4 and R 1-5 independently one or more R 1-1-3 Substituted C3-C6 cycloalkyl, one or more R 1-1-6 Substituted "5-6 membered heterocycloalkyl containing 1, 2 or 3 independently selected from N, O and S", one or more R 1-1-1 Substituted C6-C 10 Aryl, or, one or more R 1-1-2 Substituted "5- to 10-membered heteroaryl containing 1, 2 or 3 groups independently selected from N, O and S";

[0744] R1-1-1 、R 1-1-2 、R 1-1-3 , and, R 1-1-6 are independently phenyl.

[0745] In one embodiment, in the compound of Formula XII or a pharmaceutically acceptable salt thereof, the definitions of certain groups may be as follows, and the definitions of the remaining groups are as described in any of the above embodiments:

[0746] R 1-1 、R 1-2 、R 1-3 、R 1-4 and R 1-5 independently one or more R 1-1-3 Substituted C3-C6 cycloalkyl, one or more R 1-1-6 Substituted "5-6 membered heterocycloalkyl containing 1, 2 or 3 independently selected from N, O and S", one or more R 1-1-1 Substituted C6-C 10 Aryl, or, one or more R 1-1-2 Substituted "5- to 10-membered heteroaryl containing 1, 2 or 3 groups independently selected from N, O and S";

[0747] R 1-1-1 、R 1-1-2 、R 1-1-3 , and, R 1-1-6 are independently -N(R 1-1-1-1 )(R 1-1-1-2 ).

[0748] In one embodiment, in the compound of Formula XII or a pharmaceutically acceptable salt thereof, the definitions of certain groups may be as follows, and the definitions of the remaining groups are as described in any of the above embodiments:

[0749] R 1-1 、R 1-2 、R 1-3 、R 1-4 and R 1-5 Independently C7-C 10 Cycloalkyl.

[0750] In one embodiment, in the compound of Formula XII or a pharmaceutically acceptable salt thereof, the definitions of certain groups may be as follows, and the definitions of the remaining groups are as described in any of the above embodiments:

[0751] R 1-1 、R 1-2 、R 1-3 、R 1-4 and R 1-5 are independently naphthyl.

[0752] In one embodiment, in the compound of Formula XII or a pharmaceutically acceptable salt thereof, the definitions of certain groups may be as follows, and the definitions of the remaining groups are as described in any of the above embodiments:

[0753] R 1-1 、R 1-2 、R 1-3 、R 1-4 and R 1-5 Independently

[0754] In one embodiment, in the compound of Formula XII or a pharmaceutically acceptable salt thereof, the definitions of certain groups may be as follows, and the definitions of the remaining groups are as described in any of the above embodiments:

[0755] R 1-1 、R 1-2 、R 1-3 、R 1-4 and R 1-5 Independently

[0756] In one embodiment, in the compound of Formula XII or a pharmaceutically acceptable salt thereof, the definitions of certain groups may be as follows, and the definitions of the remaining groups are as described in any of the above embodiments:

[0757] R 1-1 、R 1-2 、R 1-3 、R 1-4 and R 1-5 Independently

[0758] In one embodiment, in the compound of Formula XII or a pharmaceutically acceptable salt thereof, the definitions of certain groups may be as follows, and the definitions of the remaining groups are as described in any of the above embodiments:

[0759] R 1-1 、R 1-2 、R 1-3 、R 1-4 and R 1-5 are independently "a 5- or 10-membered heteroaryl group containing 1, 2 or 3 groups independently selected from N, O and S".

[0760] In one embodiment, in the compound of Formula XII or a pharmaceutically acceptable salt thereof, the definitions of certain groups may be as follows, and the definitions of the remaining groups are as described in any of the above embodiments:

[0761] R 1-1 、R 1-2 、R 1-3 、R 1-4 and R 1-5are independently pyridinyl.

[0762] In one embodiment, in the compound of Formula XII or a pharmaceutically acceptable salt thereof, the definitions of certain groups may be as follows, and the definitions of the remaining groups are as described in any of the above embodiments:

[0763] R 1-1 、R 1-2 、R 1-3 、R 1-4 and R 1-5 Independently

[0764] In one embodiment, in the compound of Formula XII or a pharmaceutically acceptable salt thereof, the definitions of certain groups may be as follows, and the definitions of the remaining groups are as described in any of the above embodiments:

[0765] R 1-1 、R 1-2 、R 1-3 、R 1-4 and R 1-5 Independently

[0766] In one embodiment, in the compound of Formula XII or a pharmaceutically acceptable salt thereof, the definitions of certain groups may be as follows, and the definitions of the remaining groups are as described in any of the above embodiments:

[0767] W is

[0768] In one embodiment, in the compound of Formula XII or a pharmaceutically acceptable salt thereof, the definitions of certain groups may be as follows, and the definitions of the remaining groups are as described in any of the above embodiments:

[0769] W is

[0770] Y 4-1 is -NH-C(=O)-CH2- or NH;

[0771] Y 5 N or CR 7 , R 7 is a halogen;

[0772] X 5 CR 8 , X 6 CR 9 , X 7 CR 10 , X 8 CR 11 ;

[0773] R 8、R 9 、R 10 and R 11 are independently hydrogen.

[0774] In one embodiment, in the compound of Formula XII or a pharmaceutically acceptable salt thereof, the definitions of certain groups may be as follows, and the definitions of the remaining groups are as described in any of the above embodiments:

[0775] W is

[0776] In one embodiment, in the compound of Formula XII or a pharmaceutically acceptable salt thereof, the definitions of certain groups may be as follows, and the definitions of the remaining groups are as described in any of the above embodiments:

[0777] W is

[0778] Y 6 is NC(=O)-CH3, CH2 or NH;

[0779] Y 7 is NH, CH2, C(=O), C(=S) or C(=N-OH);

[0780] Y 8 is CH2, CH2CH2, CH(CH3) or C(=O);

[0781] Y 9 is N;

[0782] X 9 CR 12 , X 10 CR 13 , X 11 CR 14 , X 12 CR 15 ;

[0783] R 12 、R 13 、R 14 and R 15 are independently hydrogen, nitro, or one or more halogen-substituted C1-C4 alkyl groups.

[0784] In one embodiment, in the compound of Formula XII or a pharmaceutically acceptable salt thereof, the definitions of certain groups may be as follows, and the definitions of the remaining groups are as described in any of the above embodiments:

[0785] W is

[0786] In one embodiment, in the compound of Formula XII or a pharmaceutically acceptable salt thereof, the definitions of certain groups may be as follows, and the definitions of the remaining groups are as described in any of the above embodiments:

[0787] W is

[0788] Y 10 for NH;

[0789] Y 11 is C(=O);

[0790] Y 12 is N;

[0791] Y 13 is CH2;

[0792] X 13 CR 16 , X 14 CR 17 , X 15 CR 18 , X 16 CR 19 ;

[0793] R 16 、R 17 、R 18 and R 19 are independently hydrogen.

[0794] In one embodiment, in the compound of Formula XII or a pharmaceutically acceptable salt thereof, the definitions of certain groups may be as follows, and the definitions of the remaining groups are as described in any of the above embodiments:

[0795] W is

[0796] In one embodiment, in the compound of Formula XII or a pharmaceutically acceptable salt thereof, the definitions of certain groups may be as follows, and the definitions of the remaining groups are as described in any of the above embodiments:

[0797] W is

[0798] Y 14 for NH;

[0799] Y 15 is C(=O);

[0800] Y 16 is N;

[0801] X 17 CR 20 , X 18 CR 21, X 19 CR 22 ;

[0802] R 20 、R 21 and R 22 are independently hydrogen.

[0803] In one embodiment, in the compound of Formula XII or a pharmaceutically acceptable salt thereof, the definitions of certain groups may be as follows, and the definitions of the remaining groups are as described in any of the above embodiments:

[0804] W is

[0805] In one embodiment, in the compound of Formula XII or a pharmaceutically acceptable salt thereof, the definitions of certain groups may be as follows, and the definitions of the remaining groups are as described in any of the above embodiments:

[0806] W is

[0807] Y 17 for NH;

[0808] X 20 CR 23 , X 21 CR 24 , X 22 CR 25 , X 23 CR 26 ;

[0809] R 23 、R 24 、R 25 and R 26 are independently hydrogen.

[0810] In one embodiment, in the compound of Formula XII or a pharmaceutically acceptable salt thereof, the definitions of certain groups may be as follows, and the definitions of the remaining groups are as described in any of the above embodiments:

[0811] W is

[0812] In one embodiment, in the compound of Formula XII or a pharmaceutically acceptable salt thereof, the definitions of certain groups may be as follows, and the definitions of the remaining groups are as described in any of the above embodiments:

[0813] W is

[0814] Y 18 is NH or CH2;

[0815] Y 19is C(=O) or NH;

[0816] Y 20 is CH2 or C(=O);

[0817] X 24 CR 27 , X 25 CR 28 , X 26 CR 29 ;

[0818] R 27 、R 28 and R 29 are independently hydrogen.

[0819] In one embodiment, in the compound of Formula XII or a pharmaceutically acceptable salt thereof, the definitions of certain groups may be as follows, and the definitions of the remaining groups are as described in any of the above embodiments:

[0820] W is

[0821] In one embodiment, in the compound of Formula XII or a pharmaceutically acceptable salt thereof, the definitions of certain groups may be as follows, and the definitions of the remaining groups are as described in any of the above embodiments:

[0822] W is

[0823] Y 21 is C(=O);

[0824] Y 22 for NH;

[0825] Y 23 is CH2 or C(=O);

[0826] Y 24 NR 30 , R 30 is hydrogen or phenyl.

[0827] In one embodiment, in the compound of Formula XII or a pharmaceutically acceptable salt thereof, the definitions of certain groups may be as follows, and the definitions of the remaining groups are as described in any of the above embodiments:

[0828] W is

[0829] In one embodiment, in the compound of Formula XII or a pharmaceutically acceptable salt thereof, the definitions of certain groups may be as follows, and the definitions of the remaining groups are as described in any of the above embodiments:

[0830] W is

[0831] Y 25 for NH;

[0832] Y 26 is C(=O);

[0833] Y 27 is a single bond, O or NH;

[0834] X 27 CR 31 , X 28 CR 32 , X 29 CR 33 , X 30 CR 34 ;

[0835] R 31 、R 32 、R 33 and R 34 are independently hydrogen.

[0836] In one embodiment, in the compound of Formula XII or a pharmaceutically acceptable salt thereof, the definitions of certain groups may be as follows, and the definitions of the remaining groups are as described in any of the above embodiments:

[0837] W is

[0838] In one embodiment, in the compound of Formula XII or a pharmaceutically acceptable salt thereof, the definitions of certain groups may be as follows, and the definitions of the remaining groups are as described in any of the above embodiments:

[0839] W is

[0840] Y 28 for NH;

[0841] Y 29 is C(=O);

[0842] Y 30 is N.

[0843] In one embodiment, in the compound of Formula XII or a pharmaceutically acceptable salt thereof, the definitions of certain groups may be as follows, and the definitions of the remaining groups are as described in any of the above embodiments:

[0844] W is

[0845] In one embodiment, in the compound of Formula XII or a pharmaceutically acceptable salt thereof, the definitions of certain groups may be as follows, and the definitions of the remaining groups are as described in any of the above embodiments:

[0846] W is

[0847] Y 31 is O, NH or NC(=O)-CH3;

[0848] Y 32 is N;

[0849] X 31 CR 35 , X 32 CR 36 , X 33 CR 37 , X 34 CR 38 ;

[0850] R 35 、R 36 、R 37 and R 38 are independently hydrogen.

[0851] In one embodiment, in the compound of Formula XII or a pharmaceutically acceptable salt thereof, the definitions of certain groups may be as follows, and the definitions of the remaining groups are as described in any of the above embodiments:

[0852] W is

[0853] In one embodiment, in the compound of Formula XII or a pharmaceutically acceptable salt thereof, the definitions of certain groups may be as follows, and the definitions of the remaining groups are as described in any of the above embodiments:

[0854] W is

[0855] Y 33 for NH;

[0856] Y 34 is C(=O);

[0857] Y 35 is N;

[0858] X 35 CR 39 , X 36 CR 40 , X 37 CR 41 , X 38 CR 42 ;

[0859] R 39 、R 40 、R 41 and R 42 are independently hydrogen.

[0860] In one embodiment, in the compound of Formula XII or a pharmaceutically acceptable salt thereof, the definitions of certain groups may be as follows, and the definitions of the remaining groups are as described in any of the above embodiments:

[0861] W is

[0862] In one embodiment, in the compound of Formula XII or a pharmaceutically acceptable salt thereof, the definitions of certain groups may be as follows, and the definitions of the remaining groups are as described in any of the above embodiments:

[0863] W is

[0864] Y 36 for NH;

[0865] Y 37 is C(=O);

[0866] Y 38 is N;

[0867] X 39 CR 43 , X 40 CR 44 , X 41 CR 45 , X 42 CR 46 ;

[0868] R 43 、R 44 、R 45 and R 46 are independently hydrogen.

[0869] In one embodiment, in the compound of Formula XII or a pharmaceutically acceptable salt thereof, the definitions of certain groups may be as follows, and the definitions of the remaining groups are as described in any of the above embodiments:

[0870] W is

[0871] In one embodiment, in the compound of Formula XII or a pharmaceutically acceptable salt thereof, the definitions of certain groups may be as follows, and the definitions of the remaining groups are as described in any of the above embodiments:

[0872] W is

[0873] Y 39 for NH;

[0874] Y 40 is C(=O);

[0875] Y 41 is N;

[0876] X 43 CR 47 , X 44 CR 48 , X 45 CR 49 , X 46 CR 50 ;

[0877] R 47 、R 48 、R 49 and R 50 are independently hydrogen.

[0878] In one embodiment, in the compound of Formula XII or a pharmaceutically acceptable salt thereof, the definitions of certain groups may be as follows, and the definitions of the remaining groups are as described in any of the above embodiments:

[0879] W is

[0880] In one embodiment, in the compound of Formula XII or a pharmaceutically acceptable salt thereof, the definitions of certain groups may be as follows, and the definitions of the remaining groups are as described in any of the above embodiments:

[0881] W is any of the following groups:

[0882] (1)

[0883] in is a single bond, Y 1 C(=O), O, or NR 3 , R 3 is CH2COOH or C1-C4 alkyl, Y 2 is C(=N-CO-Ph), C(=N-CO-CH3), NH, S(=O)2 or C=S;

[0884] Y 3 N or CH;

[0885] X 1 N or CR 2 , X 2 N or CR 4 , X 3 N or CR 5 , X 4 N or CR 6 ;

[0886] R 2 、R4 、R 5 and R 6 independently hydrogen, halogen, hydroxy, amino, carboxyl, cyano, nitro, C1-C4 alkyl, C1-C4 alkyl substituted with one or more halogens, C1-C4 alkoxy, C3-C6 cycloalkyl, phenyl, "5-7 membered heterocycloalkyl containing 1, 2 or 3 independently selected from N, O and S", -S(=O)2-R 2-1 、-NH-S(=O)2-R 2-2 、-S(=O)2-NR 2-3 R 2-4 、-C(=O)-R 2-5 、-NH-C(=O)-R 2-6 , or, -C(=O)-NR 2-7 R 2-8 ;

[0887] R 2-1 、R 2-2 、R 2-3 、R 2-4 、R 2-5 、R 2-6 、R 2-7 and R 2-8 are independently hydrogen, C1-C4 alkyl, or one or more halogen-substituted C1-C4 alkyl;

[0888] (2)

[0889] Y 4-1 is -NH-C(=O)-CH2- or NH;

[0890] Y 5 N or CR 7 , R 7 is a halogen;

[0891] X 5 N or CR 8 , X 6 N or CR 9 , X 7 N or CR 10 , X 8 N or CR 11 ;

[0892] R 8 、R 9 、R 10 and R 11are independently hydrogen, halogen, hydroxy, amino, carboxyl, cyano, nitro, C1-C4 alkyl, C1-C4 alkyl substituted with one or more halogens, C1-C4 alkoxy, C3-C6 cycloalkyl, phenyl, "5-7 membered heterocycloalkyl containing 1, 2 or 3 groups independently selected from N, O and S", -S(=O)2-NH2, or -C(=O)-NH2;

[0893] (3)

[0894] Y 6 is NC(=O)-CH3, CH2 or NH;

[0895] Y 7 is NH, CH2, C(=O), C(=S) or C(=N-OH);

[0896] Y 8 is CH2, CH2CH2, CH(CH3) or C(=O);

[0897] Y 9 N or CH;

[0898] X 9 N or CR 12 , X 10 N or CR 13 , X 11 N or CR 14 , X 12 N or CR 15 ;

[0899] R 12 、R 13 、R 14 and R 15 are independently hydrogen, halogen, hydroxy, amino, carboxyl, cyano, nitro, C1-C4 alkyl, C1-C4 alkyl substituted with one or more halogens, C1-C4 alkoxy, C3-C6 cycloalkyl, phenyl, "5-7 membered heterocycloalkyl containing 1, 2 or 3 groups independently selected from N, O and S", -S(=O)2-NH2, or -C(=O)-NH2;

[0900] (4)

[0901] Y 10 for NH;

[0902] Y 11 is C(=O);

[0903] Y 12 N or CH;

[0904] Y 13is CH2;

[0905] X 13 N or CR 16 , X 14 N or CR 17 , X 15 N or CR 18 , X 16 N or CR 19 ;

[0906] R 16 、R 17 、R 18 and R 19 are independently hydrogen, halogen, hydroxy, amino, carboxyl, cyano, nitro, C1-C4 alkyl, C1-C4 alkyl substituted with one or more halogens, C1-C4 alkoxy, C3-C6 cycloalkyl, phenyl, "5-7 membered heterocycloalkyl containing 1, 2 or 3 groups independently selected from N, O and S", -S(=O)2-NH2, or -C(=O)-NH2;

[0907] (5)

[0908] Y 14 for NH;

[0909] Y 15 is C(=O);

[0910] Y 16 N or CH;

[0911] X 17 N or CR 20 , X 18 N or CR 21 , X 19 N or CR 22 ;

[0912] R 20 、R 21 and R 22 are independently hydrogen, halogen, hydroxy, amino, carboxyl, cyano, nitro, C1-C4 alkyl, C1-C4 alkyl substituted with one or more halogens, C1-C4 alkoxy, C3-C6 cycloalkyl, phenyl, "5-7 membered heterocycloalkyl containing 1, 2 or 3 groups independently selected from N, O and S", -S(=O)2-NH2, or -C(=O)-NH2;

[0913] (6)

[0914] Y 17 for NH;

[0915] X 20N or CR 23 , X 21 N or CR 24 , X 22 N or CR 25 , X 23 N or CR 26 ;

[0916] R 23 、R 24 、R 25 and R 26 are independently hydrogen, halogen, hydroxy, amino, carboxyl, cyano, nitro, C1-C4 alkyl, C1-C4 alkyl substituted with one or more halogens, C1-C4 alkoxy, C3-C6 cycloalkyl, phenyl, "5-7 membered heterocycloalkyl containing 1, 2 or 3 groups independently selected from N, O and S", -S(=O)2-NH2, or -C(=O)-NH2;

[0917] (7)

[0918] Y 18 is NH or CH2;

[0919] Y 19 is C(=O) or NH;

[0920] Y 20 is CH2 or C(=O);

[0921] X 24 N or CR 27 , X 25 N or CR 28 , X 26 N or CR 29 ;

[0922] R 27 、R 28 and R 29 are independently hydrogen, halogen, hydroxy, amino, carboxyl, cyano, nitro, C1-C4 alkyl, C1-C4 alkyl substituted with one or more halogens, C1-C4 alkoxy, C3-C6 cycloalkyl, phenyl, "5-7 membered heterocycloalkyl containing 1, 2 or 3 groups independently selected from N, O and S", -S(=O)2-NH2, or -C(=O)-NH2;

[0923] (8)

[0924] Y 21 is C(=O);

[0925] Y 22 for NH;

[0926] Y23 is CH2 or C(=O);

[0927] Y 24 NR 30 , R 30 is hydrogen or phenyl;

[0928] (9)

[0929] Y 25 for NH;

[0930] Y 26 is C(=O);

[0931] Y 27 is a single bond, O or NH;

[0932] X 27 N or CR 31 , X 28 N or CR 32 , X 29 N or CR 33 , X 30 N or CR 34 ;

[0933] R 31 、R 32 、R 33 and R 34 are independently hydrogen, halogen, hydroxy, amino, carboxyl, cyano, nitro, C1-C4 alkyl, C1-C4 alkyl substituted with one or more halogens, C1-C4 alkoxy, C3-C6 cycloalkyl, phenyl, "5-7 membered heterocycloalkyl containing 1, 2 or 3 groups independently selected from N, O and S", -S(=O)2-NH2, or -C(=O)-NH2;

[0934] (10)

[0935] Y 28 for NH;

[0936] Y 29 is C(=O);

[0937] Y 30 is CH or N;

[0938] (11)

[0939] Y 31 is O, NH or NC(=O)-CH3;

[0940] Y 32 is CH or N;

[0941] X 31 N or CR 35 , X 32 N or CR 36 , X 33 N or CR 37 , X 34 N or CR 38 ;

[0942] R 35 、R 36 、R 37 and R 38 are independently hydrogen, halogen, hydroxy, amino, carboxyl, cyano, nitro, C1-C4 alkyl, C1-C4 alkyl substituted with one or more halogens, C1-C4 alkoxy, C3-C6 cycloalkyl, phenyl, "5-7 membered heterocycloalkyl containing 1, 2 or 3 groups independently selected from N, O and S", -S(=O)2-NH2, or -C(=O)-NH2;

[0943] (12)

[0944] Y 33 for NH;

[0945] Y 34 is C(=O);

[0946] Y 35 is CH or N;

[0947] X 35 N or CR 39 , X 36 N or CR 40 , X 37 N or CR 41 , X 38 N or CR 42 ;

[0948] R 39 、R 40 、R 41 and R 42 are independently hydrogen, halogen, hydroxy, amino, carboxyl, cyano, nitro, C1-C4 alkyl, C1-C4 alkyl substituted with one or more halogens, C1-C4 alkoxy, C3-C6 cycloalkyl, phenyl, "5-7 membered heterocycloalkyl containing 1, 2 or 3 groups independently selected from N, O and S", -S(=O)2-NH2, or -C(=O)-NH2;

[0949] (13)

[0950] Y 36 for NH;

[0951] Y 37 is C(=O);

[0952] Y 38 is CH or N;

[0953] X 39 N or CR 43 , X 40 N or CR 44 , X 41 N or CR 45 , X 42 N or CR 46 ;

[0954] R 43 、R 44 、R 45 and R 46 are independently hydrogen, halogen, hydroxy, amino, carboxyl, cyano, nitro, C1-C4 alkyl, C1-C4 alkyl substituted with one or more halogens, C1-C4 alkoxy, C3-C6 cycloalkyl, phenyl, "5-7 membered heterocycloalkyl containing 1, 2 or 3 groups independently selected from N, O and S", -S(=O)2-NH2, or -C(=O)-NH2;

[0955] (14)

[0956] Y 39 for NH;

[0957] Y 40 is C(=O);

[0958] Y 41 is CH or N;

[0959] X 43 N or CR 47 , X 44 N or CR 48 , X 45 N or CR 49 , X 46 N or CR 50 ;

[0960] R 47 、R 48 、R 49 and R 50 are independently hydrogen, halogen, hydroxy, amino, carboxyl, cyano, nitro, C1-C4 alkyl, C1-C4 alkyl substituted with one or more halogens, C1-C4 alkoxy, C3-C6 cycloalkyl, phenyl, "5-7 membered heterocycloalkyl containing 1, 2 or 3 groups independently selected from N, O and S", -S(=O)2-NH2, or -C(=O)-NH2;

[0961] and, (15)

[0962] In one embodiment, in the compound of Formula XII or a pharmaceutically acceptable salt thereof, the definitions of certain groups may be as follows, and the definitions of the remaining groups are as described in any of the above embodiments:

[0963] Z is any of the following fragments:

[0964] (1) m is 1 or 2, n is 3;

[0965] (3)

[0966] (4) p is 1 or 2, q is 1 or 2;

[0967] (5) a2 is 1 or 2, b2 is 1 or 2;

[0968] (6) a3 is 1 or 2, b3 is 1 or 2;

[0969] (7)

[0970] (8) -C(=O)-;

[0971] (9)

[0972] In one embodiment, in the compound of Formula XII or a pharmaceutically acceptable salt thereof, the definitions of certain groups may be as follows, and the definitions of the remaining groups are as described in any of the above embodiments:

[0973] R 1 -NH-R 1-2 、

[0974] R 1-2 、R 1-3 、R 1-4 and R 1-5 Independently C7-C 10 Cycloalkyl, one or more R 1-1-3 Substituted C3-C6 cycloalkyl, one or more R 1-1-6 Substituted "5-6 membered heterocycloalkyl containing 1, 2 or 3 independently selected from N, O and S", one or more R 1-1-1 Substituted C6-C 10 Aryl, naphthyl, "a 5- or 10-membered heteroaryl group containing 1, 2 or 3 groups independently selected from N, O and S", pyridyl, or, one or more R 1-1-2 Substituted "5- to 10-membered heteroaryl containing 1, 2 or 3 groups independently selected from N, O and S";

[0975] R 1-1-1 、R 1-1-2 、R 1-1-3 , and, R 1-1-6 independently carboxyl, hydroxyl, halogen, C1-C4 alkyl, one or more halogen-substituted C1-C4 alkyl, one or more halogen-substituted C1-C4 alkoxy, C3-C6 cycloalkyl, "5-6 membered heterocycloalkyl containing 1, 2 or 3 independently selected from N, O and S", -N(R 1-1-1-1 )(R 1-1-1-2 ), or, phenyl;

[0976] R 1-1-1-1 and R 1-1-1-2 are independently hydrogen or C1-C4 alkyl;

[0977] R 1-1-7 、R 1-1-8 , and, R 1-1-9 are independently C1-C4 alkyl;

[0978] R 1-1-10 are independently C1-C4 alkoxy;

[0979] R 1-1-11 and R 1-1-12 are independently hydrogen or halogen.

[0980] In one embodiment, in the compound of Formula XII or a pharmaceutically acceptable salt thereof, the definitions of certain groups may be as follows, and the definitions of the remaining groups are as described in any of the above embodiments:

[0981] R 1 -(CH2) s -R 1-1 ;s is 0, 1 or 2;

[0982] R 1-1 C7-C 10 Cycloalkyl, one or more R 1-1-3 Substituted C3-C6 cycloalkyl, one or more R 1-1-6 Substituted "5-6 membered heterocycloalkyl containing 1, 2 or 3 independently selected from N, O and S", one or more R 1-1-1 Substituted C6-C 10 Aryl,

[0983] R1-1-1 、R 1-1-3 , and, R 1-1-6 are independently carboxyl, hydroxyl, halogen, one or more halogen-substituted C1-C4 alkoxy, "a 5- to 6-membered heterocycloalkyl group containing 1, 2 or 3 independently selected from N, O and S", or -N(R 1-1-1-1 )(R 1-1-1-2 );

[0984] R 1-1-1-1 and R 1-1-1-2 are independently hydrogen or C1-C4 alkyl;

[0985] R 1-1-7 、R 1-1-8 , and, R 1-1-9 are independently C1-C4 alkyl;

[0986] R 1-1-10 are independently C1-C4 alkoxy;

[0987] R 1-1-11 and R 1-1-12 are independently hydrogen or halogen.

[0988] In a certain embodiment, in the compound of Formula XII or a pharmaceutically acceptable salt thereof, if optical isomers exist, the compound of Formula XII may exist in the form of a racemate.

[0989] In one embodiment, the atoms in the compound of Formula XII or a pharmaceutically acceptable salt thereof are present in their natural abundance.

[0990] In one embodiment, in the compound of Formula XII or a pharmaceutically acceptable salt thereof, the definitions of certain groups may be as follows, and the definitions of the remaining groups are as described in any of the above embodiments:

[0991] When R 3 When it is a C1-C4 alkyl group, the C1-C4 alkyl group is a methyl group.

[0992] In one embodiment, in the compound of Formula XII or a pharmaceutically acceptable salt thereof, the definitions of certain groups may be as follows, and the definitions of the remaining groups are as described in any of the above embodiments:

[0993] When R 2 、R 4 、R 5 and R 6 When independently halogen, the halogen is fluorine, chlorine or bromine.

[0994] In one embodiment, in the compound of Formula XII or a pharmaceutically acceptable salt thereof, the definitions of certain groups may be as follows, and the definitions of the remaining groups are as described in any of the above embodiments:

[0995] When R 2 、R 4 、R 5 and R 6 When independently a C1-C4 alkyl group, the C1-C4 alkyl group is a methyl group or a tert-butyl group.

[0996] In one embodiment, in the compound of Formula XII or a pharmaceutically acceptable salt thereof, the definitions of certain groups may be as follows, and the definitions of the remaining groups are as described in any of the above embodiments:

[0997] When R 2 、R 4 、R 5 and R 6 When independently a C1-C4 alkyl group, the C1-C4 alkyl group is a tert-butyl group.

[0998] In one embodiment, in the compound of Formula XII or a pharmaceutically acceptable salt thereof, the definitions of certain groups may be as follows, and the definitions of the remaining groups are as described in any of the above embodiments:

[0999] When R 2 、R 4 、R 5 and R 6 When the C1-C4 alkyl group is independently substituted with multiple halogens, the multiple halogens are 2 or 3.

[1000] In one embodiment, in the compound of Formula XII or a pharmaceutically acceptable salt thereof, the definitions of certain groups may be as follows, and the definitions of the remaining groups are as described in any of the above embodiments:

[1001] When R 2 、R 4 、R 5 and R 6 When the C1-C4 alkyl group is independently substituted by one or more halogens, the halogen is fluorine.

[1002] In one embodiment, in the compound of Formula XII or a pharmaceutically acceptable salt thereof, the definitions of certain groups may be as follows, and the definitions of the remaining groups are as described in any of the above embodiments:

[1003] When R 2 、R 4 、R 5 and R 6When the C1-C4 alkyl group is independently substituted by one or more halogens, the C1-C4 alkyl group is methyl.

[1004] In one embodiment, in the compound of Formula XII or a pharmaceutically acceptable salt thereof, the definitions of certain groups may be as follows, and the definitions of the remaining groups are as described in any of the above embodiments:

[1005] When R 2 、R 4 、R 5 and R 6 When the C1-C4 alkyl groups are independently multiple halogen-substituted, the multiple halogen-substituted C1-C4 alkyl groups are trifluoromethyl.

[1006] In one embodiment, in the compound of Formula XII or a pharmaceutically acceptable salt thereof, the definitions of certain groups may be as follows, and the definitions of the remaining groups are as described in any of the above embodiments:

[1007] When R 2 、R 4 、R 5 and R 6 When independently a C1-C4 alkoxy group, the C1-C4 alkoxy group is a methoxy group.

[1008] In one embodiment, in the compound of Formula XII or a pharmaceutically acceptable salt thereof, the definitions of certain groups may be as follows, and the definitions of the remaining groups are as described in any of the above embodiments:

[1009] When R 2 、R 4 、R 5 and R 6 When independently a C3-C6 cycloalkyl group, the C3-C6 cycloalkyl group is a cyclopropyl group.

[1010] In one embodiment, in the compound of Formula XII or a pharmaceutically acceptable salt thereof, the definitions of certain groups may be as follows, and the definitions of the remaining groups are as described in any of the above embodiments:

[1011] When R 2 、R 4 、R 5 and R 6 When it is independently “a 5- to 7-membered heterocycloalkyl group containing 1, 2 or 3 groups independently selected from N, O and S”, the “a 5- to 7-membered heterocycloalkyl group containing 1, 2 or 3 groups independently selected from N, O and S” may be morpholinyl or morpholin-1-yl.

[1012] In one embodiment, in the compound of Formula XII or a pharmaceutically acceptable salt thereof, the definitions of certain groups may be as follows, and the definitions of the remaining groups are as described in any of the above embodiments:

[1013] When R 2-1 、R 2-2 、R 2-3 、R 2-4 、R 2-5 、R 2-6 、R 2-7 and R 2-8 When independently a C1-C4 alkyl group, the C1-C4 alkyl group is a methyl group or a tert-butyl group.

[1014] In one embodiment, in the compound of Formula XII or a pharmaceutically acceptable salt thereof, the definitions of certain groups may be as follows, and the definitions of the remaining groups are as described in any of the above embodiments:

[1015] When R 2-1 、R 2-2 、R 2-3 、R 2-4 、R 2-5 、R 2-6 、R 2-7 and R 2-8 When the C1-C4 alkyl group is independently substituted with multiple halogens, the multiple halogens are 2 or 3.

[1016] In one embodiment, in the compound of Formula XII or a pharmaceutically acceptable salt thereof, the definitions of certain groups may be as follows, and the definitions of the remaining groups are as described in any of the above embodiments:

[1017] When R 2-1 、R 2-2 、R 2-3 、R 2-4 、R 2-5 、R 2-6 、R 2-7 and R 2-8 When the C1-C4 alkyl group is independently substituted by one or more halogens, the halogen is fluorine.

[1018] In one embodiment, in the compound of Formula XII or a pharmaceutically acceptable salt thereof, the definitions of certain groups may be as follows, and the definitions of the remaining groups are as described in any of the above embodiments:

[1019] When R 2-1 、R 2-2 、R 2-3 、R 2-4 、R 2-5 、R 2-6 、R 2-7 and R2-8 When the C1-C4 alkyl group is independently substituted by one or more halogens, the C1-C4 alkyl group is methyl.

[1020] In one embodiment, in the compound of Formula XII or a pharmaceutically acceptable salt thereof, the definitions of certain groups may be as follows, and the definitions of the remaining groups are as described in any of the above embodiments:

[1021] When R 2-1 、R 2-2 、R 2-3 、R 2-4 、R 2-5 、R 2-6 、R 2-7 and R 2-8 When the C1-C4 alkyl group is independently substituted with multiple halogens, the C1-C4 alkyl group is trifluoromethyl.

[1022] In one embodiment, in the compound of Formula XII or a pharmaceutically acceptable salt thereof, the definitions of certain groups may be as follows, and the definitions of the remaining groups are as described in any of the above embodiments:

[1023] When W is hour, Can

[1024] In one embodiment, in the compound of Formula XII or a pharmaceutically acceptable salt thereof, the definitions of certain groups may be as follows, and the definitions of the remaining groups are as described in any of the above embodiments:

[1025] When Y 4-1 When it is -NH-C(=O)-CH2-, the -CH2- end can be connected with Y 5 connect.

[1026] In one embodiment, in the compound of Formula XII or a pharmaceutically acceptable salt thereof, the definitions of certain groups may be as follows, and the definitions of the remaining groups are as described in any of the above embodiments:

[1027] When W is When Can

[1028] In one embodiment, in the compound of Formula XII or a pharmaceutically acceptable salt thereof, the definitions of certain groups may be as follows, and the definitions of the remaining groups are as described in any of the above embodiments:

[1029] When W is When Can

[1030] In one embodiment, in the compound of Formula XII or a pharmaceutically acceptable salt thereof, the definitions of certain groups may be as follows, and the definitions of the remaining groups are as described in any of the above embodiments:

[1031] When W is When Can

[1032] In one embodiment, in the compound of Formula XII or a pharmaceutically acceptable salt thereof, the definitions of certain groups may be as follows, and the definitions of the remaining groups are as described in any of the above embodiments:

[1033] When W is When Can

[1034] In one embodiment, in the compound of Formula XII or a pharmaceutically acceptable salt thereof, the definitions of certain groups may be as follows, and the definitions of the remaining groups are as described in any of the above embodiments:

[1035] When W is When Can

[1036] In one embodiment, in the compound of Formula XII or a pharmaceutically acceptable salt thereof, the definitions of certain groups may be as follows, and the definitions of the remaining groups are as described in any of the above embodiments:

[1037] When Z is When m is 1 and n is 1.

[1038] In one embodiment, in the compound of Formula XII or a pharmaceutically acceptable salt thereof, the definitions of certain groups may be as follows, and the definitions of the remaining groups are as described in any of the above embodiments:

[1039] When Z is When m is 2 and n is 2.

[1040] In one embodiment, in the compound of Formula XII or a pharmaceutically acceptable salt thereof, the definitions of certain groups may be as follows, and the definitions of the remaining groups are as described in any of the above embodiments:

[1041] When Z is When for Its b end and R 1 connect.

[1042] In one embodiment, in the compound of Formula XII or a pharmaceutically acceptable salt thereof, the definitions of certain groups may be as follows, and the definitions of the remaining groups are as described in any of the above embodiments:

[1043] When Z is When m is 1, n is 1, and for Its b end and R 1 connect.

[1044] In one embodiment, in the compound of Formula XII or a pharmaceutically acceptable salt thereof, the definitions of certain groups may be as follows, and the definitions of the remaining groups are as described in any of the above embodiments:

[1045] When Z is When m is 2, n is 2, and for Its b end and R 1 connect.

[1046] In one embodiment, in the compound of Formula XII or a pharmaceutically acceptable salt thereof, the definitions of certain groups may be as follows, and the definitions of the remaining groups are as described in any of the above embodiments:

[1047] When Z is When , u is 1 and t is 1.

[1048] In one embodiment, in the compound of Formula XII or a pharmaceutically acceptable salt thereof, the definitions of certain groups may be as follows, and the definitions of the remaining groups are as described in any of the above embodiments:

[1049] When Z is When u is 2 and t is 2.

[1050] In one embodiment, in the compound of Formula XII or a pharmaceutically acceptable salt thereof, the definitions of certain groups may be as follows, and the definitions of the remaining groups are as described in any of the above embodiments:

[1051] When Z is When for Its f end and R 1 connect;

[1052] It can also be Its f end and R 1 connect.

[1053] In one embodiment, in the compound of Formula XII or a pharmaceutically acceptable salt thereof, the definitions of certain groups may be as follows, and the definitions of the remaining groups are as described in any of the above embodiments:

[1054] When Z is When for Its f end and R 1 connection, u is 1, t is 1;

[1055] It can also be Its f end and R 1 connection, u is 1, t is 1.

[1056] In one embodiment, in the compound of Formula XII or a pharmaceutically acceptable salt thereof, the definitions of certain groups may be as follows, and the definitions of the remaining groups are as described in any of the above embodiments:

[1057] When Z is When for Its f end and R 1 Connection, said u is 2, t is 2;

[1058] It can also be Its f end and R 1 Connection, u is 2, t is 2.

[1059] In one embodiment, in the compound of Formula XII or a pharmaceutically acceptable salt thereof, the definitions of certain groups may be as follows, and the definitions of the remaining groups are as described in any of the above embodiments:

[1060] When Z is When the carbonyl end can be connected with R 1 connect.

[1061] In one embodiment, in the compound of Formula XII or a pharmaceutically acceptable salt thereof, the definitions of certain groups may be as follows, and the definitions of the remaining groups are as described in any of the above embodiments:

[1062] When Z is When p is 2 and q is 2.

[1063] In one embodiment, in the compound of Formula XII or a pharmaceutically acceptable salt thereof, the definitions of certain groups may be as follows, and the definitions of the remaining groups are as described in any of the above embodiments:

[1064] When Z is When for Its L2 end and R 1 connect.

[1065] In one embodiment, in the compound of Formula XII or a pharmaceutically acceptable salt thereof, the definitions of certain groups may be as follows, and the definitions of the remaining groups are as described in any of the above embodiments:

[1066] When Z is When p is 2, q is 2, and for Its L2 end and R 1 connect.

[1067] In one embodiment, in the compound of Formula XII or a pharmaceutically acceptable salt thereof, the definitions of certain groups may be as follows, and the definitions of the remaining groups are as described in any of the above embodiments:

[1068] When Z is When a2 is 2 and b2 is 2.

[1069] In one embodiment, in the compound of Formula XII or a pharmaceutically acceptable salt thereof, the definitions of certain groups may be as follows, and the definitions of the remaining groups are as described in any of the above embodiments:

[1070] When Z is When for Its L6 end and R 1 connect.

[1071] In one embodiment, in the compound of Formula XII or a pharmaceutically acceptable salt thereof, the definitions of certain groups may be as follows, and the definitions of the remaining groups are as described in any of the above embodiments:

[1072] When Z is When a2 is 2, b2 is 2, and for Its L6 end and R 1 connect.

[1073] In one embodiment, in the compound of Formula XII or a pharmaceutically acceptable salt thereof, the definitions of certain groups may be as follows, and the definitions of the remaining groups are as described in any of the above embodiments:

[1074] When Z is When a3 is 2 and b3 is 2.

[1075] In one embodiment, in the compound of Formula XII or a pharmaceutically acceptable salt thereof, the definitions of certain groups may be as follows, and the definitions of the remaining groups are as described in any of the above embodiments:

[1076] When Z is When for Its L8 end and R 1 connect.

[1077] In one embodiment, in the compound of Formula XII or a pharmaceutically acceptable salt thereof, the definitions of certain groups may be as follows, and the definitions of the remaining groups are as described in any of the above embodiments:

[1078] When Z is When a3 is 2, b3 is 2, and for Its L8 end and R 1 connect.

[1079] In one embodiment, in the compound of Formula XII or a pharmaceutically acceptable salt thereof, the definitions of certain groups may be as follows, and the definitions of the remaining groups are as described in any of the above embodiments:

[1080] When Z is When for Its L4 end and R 1 connect.

[1081] In one embodiment, in the compound of Formula XII or a pharmaceutically acceptable salt thereof, the definitions of certain groups may be as follows, and the definitions of the remaining groups are as described in any of the above embodiments:

[1082] When Z is When for Its d end and R 1 connect.

[1083] In one embodiment, in the compound of Formula XII or a pharmaceutically acceptable salt thereof, the definitions of certain groups may be as follows, and the definitions of the remaining groups are as described in any of the above embodiments:

[1084] When Z is When for Its w end and R 1 connect.

[1085] In one embodiment, in the compound of Formula XII or a pharmaceutically acceptable salt thereof, the definitions of certain groups may be as follows, and the definitions of the remaining groups are as described in any of the above embodiments:

[1086] When R 1 When it is a C2-C4 alkyl group, the C2-C4 alkyl group is an ethyl group.

[1087] In one embodiment, in the compound of Formula XII or a pharmaceutically acceptable salt thereof, the definitions of certain groups may be as follows, and the definitions of the remaining groups are as described in any of the above embodiments:

[1088] When R 1 When the C2-C4 alkyl group is substituted with multiple halogens, the multiple halogens are 2 or 3.

[1089] In one embodiment, in the compound of Formula XII or a pharmaceutically acceptable salt thereof, the definitions of certain groups may be as follows, and the definitions of the remaining groups are as described in any of the above embodiments:

[1090] When R 1 When the C2-C4 alkyl group is substituted with one or more halogens, the halogen is fluorine.

[1091] In one embodiment, in the compound of Formula XII or a pharmaceutically acceptable salt thereof, the definitions of certain groups may be as follows, and the definitions of the remaining groups are as described in any of the above embodiments:

[1092] When R 1 When it is a C2-C4 alkyl group substituted with one or more halogens, the C2-C4 alkyl group is an ethyl group.

[1093] In one embodiment, in the compound of Formula XII or a pharmaceutically acceptable salt thereof, the definitions of certain groups may be as follows, and the definitions of the remaining groups are as described in any of the above embodiments:

[1094] When R 1 When it is a C2-C4 alkyl group substituted with multiple halogens, the C2-C4 alkyl group substituted with multiple halogens is 2,2,2-trifluoroethyl.

[1095] In one embodiment, in the compound of Formula XII or a pharmaceutically acceptable salt thereof, the definitions of certain groups may be as follows, and the definitions of the remaining groups are as described in any of the above embodiments:

[1096] When R 1-1 、R 1-2 、R 1-3 、R 1-4 and R 1-5 independently one or more R 1-1-1 Substituted C6-C 10 When the C6-C 10 Aryl is phenyl or naphthyl.

[1097] In one embodiment, in the compound of Formula XII or a pharmaceutically acceptable salt thereof, the definitions of certain groups may be as follows, and the definitions of the remaining groups are as described in any of the above embodiments:

[1098] When R 1-1 、R 1-2 、R 1-3 、R 1-4 and R 1-5 independently one or more R 1-1-1 When the phenyl group is substituted, the R 1-1-1 With the "-(CH2) s -、-NH-、 or carbonyl" may be in ortho, meta or para position, or in para position.

[1099] In one embodiment, in the compound of Formula XII or a pharmaceutically acceptable salt thereof, the definitions of certain groups may be as follows, and the definitions of the remaining groups are as described in any of the above embodiments:

[1100] R 1-1 、R 1-2 、R 1-3 、R 1-4 and R 1-5 is independently 4-trifluoromethylphenyl.

[1101] In one embodiment, in the compound of Formula XII or a pharmaceutically acceptable salt thereof, the definitions of certain groups may be as follows, and the definitions of the remaining groups are as described in any of the above embodiments:

[1102] When R 1-1 、R 1-2 、R 1-3 、R 1-4 and R 1-5 independently one or more R 1-1-2 When the substituted 5- to 10-membered heteroaryl group contains 1, 2 or 3 independently selected from N, O and S, the 5- to 10-membered heteroaryl group containing 1, 2 or 3 independently selected from N, O and S may be a 5- to 6-membered heteroaryl group containing 1 selected from N, O and S, an indolyl group, an isoquinolyl group or a quinolyl group, or may be a 5- to 6-membered heteroaryl group containing 1 selected from N, O and S.

[1103] The 5- to 6-membered heteroaryl group containing one selected from N, O and S is, for example, furyl, thienyl or pyridyl, and is also exemplified by pyridin-2-yl, pyridin-3-yl or pyridin-4-yl.

[1104] In one embodiment, in the compound of Formula XII or a pharmaceutically acceptable salt thereof, the definitions of certain groups may be as follows, and the definitions of the remaining groups are as described in any of the above embodiments:

[1105] When R 1-1 、R 1-2 、R 1-3 、R 1-4 and R1-5 independently one or more R 1-1-2 When the substituted "5- to 10-membered heteroaryl group containing 1, 2 or 3 independently selected from N, O and S" is a 5-membered heteroaryl group containing 1 selected from N, O and S, the R 1-1-2 With the "-(CH2) s -、-NH-、 or carbonyl groups" may be in ortho or meta positions relative to each other.

[1106] In one embodiment, in the compound of Formula XII or a pharmaceutically acceptable salt thereof, the definitions of certain groups may be as follows, and the definitions of the remaining groups are as described in any of the above embodiments:

[1107] When R 1-1 、R 1-2 、R 1-3 、R 1-4 and R 1-5 independently one or more R 1-1-2 When the substituted "5- to 10-membered heteroaryl group containing 1, 2 or 3 independently selected from N, O and S" and the 5- to 10-membered heteroaryl group containing 1, 2 or 3 independently selected from N, O and S is a 6-membered heteroaryl group containing 1 N, the R 1-1-2 With the "-(CH2) s -、-NH-、 or carbonyl" may be in ortho, meta or para position, or in para position.

[1108] In one embodiment, in the compound of Formula XII or a pharmaceutically acceptable salt thereof, the definitions of certain groups may be as follows, and the definitions of the remaining groups are as described in any of the above embodiments:

[1109] When R 1-1 、R 1-2 、R 1-3 、R 1-4 and R 1-5 independently one or more R 1-1-2 When the pyridyl group is substituted, the R 1 -1-2 With the "-(CH2) s -、-NH-、 or carbonyl" may be in ortho, meta or para position, or in para position.

[1110] In one embodiment, in the compound of Formula XII or a pharmaceutically acceptable salt thereof, the definitions of certain groups may be as follows, and the definitions of the remaining groups are as described in any of the above embodiments:

[1111] When R1-1 、R 1-2 、R 1-3 、R 1-4 and R 1-5 independently one or more R 1-1-3 In the case of a substituted C3-C6 cycloalkyl group, the C3-C6 cycloalkyl group is, for example, cyclohexyl.

[1112] In one embodiment, in the compound of Formula XII or a pharmaceutically acceptable salt thereof, the definitions of certain groups may be as follows, and the definitions of the remaining groups are as described in any of the above embodiments:

[1113] When R 1-1 、R 1-2 、R 1-3 、R 1-4 and R 1-5 independently one or more R 1-1-6 When the substituted "5- to 6-membered heterocycloalkyl group containing 1, 2 or 3 groups independently selected from N, O and S" is used, the "5- to 6-membered heterocycloalkyl group containing 1, 2 or 3 groups independently selected from N, O and S" is, for example, piperidinyl, and another example is piperidin-1-yl.

[1114] In one embodiment, in the compound of Formula XII or a pharmaceutically acceptable salt thereof, the definitions of certain groups may be as follows, and the definitions of the remaining groups are as described in any of the above embodiments:

[1115] When R 1-1 、R 1-2 、R 1-3 、R 1-4 and R 1-5 Independently C7-C 10 When cycloalkyl, the C7-C 10 The cycloalkyl group may be C7-C 10 The bridged cycloalkyl group may also be an adamantyl group.

[1116] In one embodiment, in the compound of Formula XII or a pharmaceutically acceptable salt thereof, the definitions of certain groups may be as follows, and the definitions of the remaining groups are as described in any of the above embodiments:

[1117] When R 1-1 、R 1-2 、R 1-3 、R 1-4 and R 1-5 When independently naphthyl, the naphthyl may be naphthalene-2-yl.

[1118] In one embodiment, in the compound of Formula XII or a pharmaceutically acceptable salt thereof, the definitions of certain groups may be as follows, and the definitions of the remaining groups are as described in any of the above embodiments:

[1119] When R 1-1 、R 1-2 、R 1-3 、R 1-4 and R 1-5 When independently pyridyl, the pyridyl may be pyridin-4-yl.

[1120] In one embodiment, in the compound of Formula XII or a pharmaceutically acceptable salt thereof, the definitions of certain groups may be as follows, and the definitions of the remaining groups are as described in any of the above embodiments:

[1121] When R 1-1 、R 1-2 、R 1-3 、R 1-4 and R 1-5 When the "5- or 10-membered heteroaryl group containing 1, 2 or 3 groups independently selected from N, O and S" is independently "a 5- or 10-membered heteroaryl group containing 1, 2 or 3 groups independently selected from N, O and S", the "5- or 10-membered heteroaryl group containing 1, 2 or 3 groups independently selected from N, O and S" may be "a 10-membered heteroaryl group containing 1 or 2 groups independently selected from N, O and S", or may be quinolyl (e.g. ),

[1122] In one embodiment, in the compound of Formula XII or a pharmaceutically acceptable salt thereof, the definitions of certain groups may be as follows, and the definitions of the remaining groups are as described in any of the above embodiments:

[1123] When R 1-1-1 、R 1-1-2 、R 1-1-3 , and, R 1-1-6 When they are independently C1-C4 alkyl, the C1-C4 alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl.

[1124] In one embodiment, in the compound of Formula XII or a pharmaceutically acceptable salt thereof, the definitions of certain groups may be as follows, and the definitions of the remaining groups are as described in any of the above embodiments:

[1125] When R 1-1-1 、R 1-1-2 、R 1-1-3 , and, R 1-1-6 When independently a C1-C4 alkyl group, the C1-C4 alkyl group is a methyl group or a tert-butyl group.

[1126] In one embodiment, in the compound of Formula XII or a pharmaceutically acceptable salt thereof, the definitions of certain groups may be as follows, and the definitions of the remaining groups are as described in any of the above embodiments:

[1127] When R 1-1-1 、R1-1-2 、R 1-1-3 , and, R 1-1-6 When the plurality of halogen-substituted C1-C4 alkyl groups are independently multiple, the plurality is 2 or 3.

[1128] In one embodiment, in the compound of Formula XII or a pharmaceutically acceptable salt thereof, the definitions of certain groups may be as follows, and the definitions of the remaining groups are as described in any of the above embodiments:

[1129] When R 1-1-1 、R 1-1-2 、R 1-1-3 , and, R 1-1-6 When the C1-C4 alkyl group is independently substituted by one or more halogens, the halogen is fluorine.

[1130] In one embodiment, in the compound of Formula XII or a pharmaceutically acceptable salt thereof, the definitions of certain groups may be as follows, and the definitions of the remaining groups are as described in any of the above embodiments:

[1131] When R 1-1-1 、R 1-1-2 、R 1-1-3 , and, R 1-1-6 When the C1-C4 alkyl group is independently substituted by one or more halogens, the C1-C4 alkyl group is methyl or ethyl.

[1132] In one embodiment, in the compound of Formula XII or a pharmaceutically acceptable salt thereof, the definitions of certain groups may be as follows, and the definitions of the remaining groups are as described in any of the above embodiments:

[1133] When R 1-1-1 、R 1-1-2 、R 1-1-3 , and, R 1-1-6 When the C1-C4 alkyl groups are independently multiple halogen-substituted, the multiple halogen-substituted C1-C4 alkyl groups are trifluoromethyl.

[1134] In one embodiment, in the compound of Formula XII or a pharmaceutically acceptable salt thereof, the definitions of certain groups may be as follows, and the definitions of the remaining groups are as described in any of the above embodiments:

[1135] When R 1-1-1 、R 1-1-2 、R 1-1-3 , and, R 1-1-6 When independently a C3-C6 cycloalkyl group, the C3-C6 cycloalkyl group is a cyclopropyl group.

[1136] In one embodiment, in the compound of Formula XII or a pharmaceutically acceptable salt thereof, the definitions of certain groups may be as follows, and the definitions of the remaining groups are as described in any of the above embodiments:

[1137] When R 1-1-1 、R 1-1-2 、R 1-1-3 , and, R 1-1-6 When independently halogen, the halogen is fluorine, chlorine or bromine.

[1138] In one embodiment, in the compound of Formula XII or a pharmaceutically acceptable salt thereof, the definitions of certain groups may be as follows, and the definitions of the remaining groups are as described in any of the above embodiments:

[1139] When R 1-1-1 、R 1-1-2 、R 1-1-3 , and, R 1-1-6 When the C1-C4 alkoxy group is independently substituted with multiple halogens, the multiple halogens are 2 or 3.

[1140] In one embodiment, in the compound of Formula XII or a pharmaceutically acceptable salt thereof, the definitions of certain groups may be as follows, and the definitions of the remaining groups are as described in any of the above embodiments:

[1141] When R 1-1-1 、R 1-1-2 、R 1-1-3 , and, R 1-1-6 When the C1-C4 alkoxy group is independently substituted by one or more halogens, the halogen is fluorine.

[1142] In one embodiment, in the compound of Formula XII or a pharmaceutically acceptable salt thereof, the definitions of certain groups may be as follows, and the definitions of the remaining groups are as described in any of the above embodiments:

[1143] When R 1-1-1 、R 1-1-2 、R 1-1-3 , and, R 1-1-6 When the C1-C4 alkoxy group is independently substituted by one or more halogens, the C1-C4 alkoxy group is a methoxy group or an ethoxy group.

[1144] In one embodiment, in the compound of Formula XII or a pharmaceutically acceptable salt thereof, the definitions of certain groups may be as follows, and the definitions of the remaining groups are as described in any of the above embodiments:

[1145] When R 1-1-1 、R 1-1-2 、R 1-1-3 , and, R 1-1-6When the C1-C4 alkoxy groups are independently multiple halogen-substituted C1-C4 alkoxy groups, the multiple halogen-substituted C1-C4 alkoxy groups are trifluoromethoxy groups.

[1146] In one embodiment, in the compound of Formula XII or a pharmaceutically acceptable salt thereof, the definitions of certain groups may be as follows, and the definitions of the remaining groups are as described in any of the above embodiments:

[1147] When R 1-1-1 、R 1-1-2 、R 1-1-3 , and, R 1-1-6 The term "5- to 6-membered heterocycloalkyl group containing 1, 2 or 3 groups independently selected from N, O and S" refers to a morpholinyl group or a morpholin-1-yl group.

[1148] In one embodiment, in the compound of Formula XII or a pharmaceutically acceptable salt thereof, the definitions of certain groups may be as follows, and the definitions of the remaining groups are as described in any of the above embodiments:

[1149] When R 1-1-1-1 and R 1-1-1-2 are independently C1-C4 alkyl, wherein the C1-C4 alkyl is methyl or ethyl.

[1150] In one embodiment, in the compound of Formula XII or a pharmaceutically acceptable salt thereof, the definitions of certain groups may be as follows, and the definitions of the remaining groups are as described in any of the above embodiments:

[1151] When R 1-1-7 、R 1-1-8 , and, R 1-1-9 When independently a C1-C4 alkyl group, the C1-C4 alkyl group is a methyl group or an ethyl group.

[1152] In one embodiment, in the compound of Formula XII or a pharmaceutically acceptable salt thereof, the definitions of certain groups may be as follows, and the definitions of the remaining groups are as described in any of the above embodiments:

[1153] When R 1-1-10 When independently a C1-C4 alkoxy group, the C1-C4 alkoxy group is a methoxy group or an ethoxy group.

[1154] In one embodiment, in the compound of Formula XII or a pharmaceutically acceptable salt thereof, the definitions of certain groups may be as follows, and the definitions of the remaining groups are as described in any of the above embodiments:

[1155] When R 1-1-11 and R 1-1-12 When independently halogen, the halogen is fluorine.

[1156] In one embodiment, in the compound of Formula XII or a pharmaceutically acceptable salt thereof, the definitions of certain groups may be as follows, and the definitions of the remaining groups are as described in any of the above embodiments:

[1157] for

[1158] In one embodiment, the compound represented by Formula XII or a pharmaceutically acceptable salt thereof is any of the following structures:

[1159]

[1160]

[1161]

[1162]

[1163]

[1164]

[1165]

[1166]

[1167]

[1168]

[1169]

[1170]

[1171]

[1172]

[1173]

[1174]

[1175]

[1176] The present invention also provides a pharmaceutical composition comprising substance Y and pharmaceutical excipients;

[1177] The substance Y is the compound represented by the above formula XII or a pharmaceutically acceptable salt thereof.

[1178] The dosage form of the pharmaceutical composition can be an oral dosage form.

[1179] In the pharmaceutical composition, the substance Y may be the compound shown in Formula II or a pharmaceutically acceptable salt thereof, the compound shown in Formula IV or a pharmaceutically acceptable salt thereof, or the compound shown in Formula VI or a pharmaceutically acceptable salt thereof.

[1180] The present invention also provides a use of a substance Y in the preparation of a STAT5 inhibitor;

[1181] The substance Y is the compound represented by the above formula XII or a pharmaceutically acceptable salt thereof.

[1182] In the application, the substance Y may be the compound shown in Formula II or a pharmaceutically acceptable salt thereof, the compound shown in Formula IV or a pharmaceutically acceptable salt thereof, or the compound shown in Formula VI or a pharmaceutically acceptable salt thereof.

[1183] The present invention also provides a use of a substance Y in preparing a medicine;

[1184] The substance Y is the compound represented by formula XII or a pharmaceutically acceptable salt thereof;

[1185] The drug is a drug for treating and / or preventing diseases related to STAT5, or a drug for treating and / or preventing rheumatoid arthritis.

[1186] In the application, the substance Y may be the compound shown in Formula II or a pharmaceutically acceptable salt thereof, the compound shown in Formula IV or a pharmaceutically acceptable salt thereof, or the compound shown in Formula VI or a pharmaceutically acceptable salt thereof.

[1187] Unless otherwise specified, the terms used in this invention have the following meanings:

[1188] The term "plurality" refers to 2, 3, 4 or 5.

[1189] The term "pharmaceutically acceptable" means that salts, solvents, excipients, etc. are generally non-toxic, safe, and suitable for use by patients. The "patient" is preferably a mammal, more preferably a human.

[1190] The term "pharmaceutically acceptable salt" refers to a salt prepared from a compound of the present invention with a relatively nontoxic, pharmaceutically acceptable acid or base. When the compound of the present invention contains a relatively acidic functional group, a base addition salt can be obtained by contacting the neutral form of such compound with a sufficient amount of a pharmaceutically acceptable base in a pure solution or a suitable inert solvent. Pharmaceutically acceptable base addition salts include, but are not limited to, lithium salts, sodium salts, potassium salts, calcium salts, aluminum salts, magnesium salts, zinc salts, bismuth salts, ammonium salts, and diethanolamine salts. When the compound of the present invention contains a relatively basic functional group, an acid addition salt can be obtained by contacting the neutral form of such compound with a sufficient amount of a pharmaceutically acceptable acid in a pure solution or a suitable inert solvent. The pharmaceutically acceptable acid includes inorganic acids, including, but not limited to, hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, carbonic acid, phosphoric acid, phosphorous acid, sulfuric acid, and the like. The pharmaceutically acceptable acid includes organic acids, including but not limited to acetic acid, propionic acid, oxalic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, salicylic acid, tartaric acid, methanesulfonic acid, isonicotinic acid, acid citric acid, oleic acid, tannic acid, pantothenic acid, bitartrate, ascorbic acid, gentisic acid, fumaric acid, gluconic acid, sugar acid, formic acid, ethanesulfonic acid, pamoic acid (i.e., 4,4'-methylene-bis(3-hydroxy-2-naphthoic acid)), amino acids (e.g., glutamic acid, arginine), etc. When the compounds of the present invention contain relatively acidic and relatively basic functional groups, they can be converted into base addition salts or acid addition salts. For details, see Berge et al., "Pharmaceutical Salts", Journal of Pharmaceutical Science 66: 1-19 (1977), or Handbook of Pharmaceutical Salts: Properties, Selection, and Use (P. Heinrich Stahl and Camille G. Wermuth, ed., Wiley-VCH, 2002).

[1191] The terms "compound" and "pharmaceutically acceptable salt" may exist in crystalline or amorphous forms. The term "crystalline form" refers to a compound in which the ions or molecules are arranged in a strictly periodic pattern in three-dimensional space, with a regular pattern of recurring appearance at intervals. Due to differences in this periodic arrangement, multiple crystalline forms can exist, also known as polymorphism. The term "amorphous form" refers to a compound in which the ions or molecules are distributed in a disordered manner, i.e., the ions or molecules do not have a regular periodic arrangement.

[1192] The terms "compound" and "pharmaceutically acceptable salt" may exist as a single stereoisomer or a mixture thereof (e.g., a racemate) if stereoisomers exist. The term "stereoisomer" refers to cis-trans isomers or optical isomers. These stereoisomers can be separated, purified, and enriched by asymmetric synthesis methods or chiral separation methods (including but not limited to thin layer chromatography, rotary chromatography, column chromatography, gas chromatography, high pressure liquid chromatography, etc.), and can also be obtained by chiral resolution by bonding with other chiral compounds (chemical bonding, etc.) or salt formation (physical bonding, etc.). The term "single stereoisomer" means that the mass content of one stereoisomer of the compound of the present invention relative to all stereoisomers of the compound is not less than 95%.

[1193] The terms "compound" and "pharmaceutically acceptable salt" may exist as a single tautomer or a mixture thereof, if tautomers exist, preferably in a form in which the more stable tautomer predominates.

[1194] The atoms in the terms "compound" and "pharmaceutically acceptable salt" may exist in their natural abundance or in a non-natural abundance form. For example, hydrogen atoms in their natural abundance form are approximately 99.985% protium and approximately 0.015% deuterium; and in their non-natural abundance form are approximately 95% deuterium. That is, one or more atoms in the terms "compound," "pharmaceutically acceptable salt," "solvate," and "solvate of a pharmaceutically acceptable salt" may be atoms that exist in a non-natural abundance form.

[1195] When any variable (such as R 1-1-1 ) appears multiple times in the definition of a compound, the definition of each position of the variable is independent of the definition of the other positions, and their meanings are independent of each other and do not affect each other. Therefore, if a group is replaced by 1, 2 or 3 R 1-1-1 group substituted, that is, the group may be replaced by up to 3 R 1-1-1 Replace, the position R 1-1-1 Definition and other positions R 1-1-1 In addition, combinations of substituents and / or variables are permissible only if such combinations result in stable compounds.

[1196] The term "halogen" refers to fluorine, chlorine, bromine or iodine.

[1197] The term "alkyl" refers to a straight or branched chain alkyl group having the specified number of carbon atoms. Examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, and the like.

[1198] The term "alkoxy" refers to the group -ORX , where R X is an alkyl group as defined above.

[1199] The term "cycloalkyl" refers to a monovalent saturated cyclic alkyl group, preferably having 3-7 ring carbon atoms, more preferably 3-6 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. The cycloalkyl group can be monocyclic or polycyclic (e.g., bridged ring, spirocyclic).

[1200] The term "heterocycloalkyl" refers to a saturated monocyclic group having heteroatoms, preferably a 3-7 membered saturated monocyclic ring containing 1, 2 or 3 ring heteroatoms independently selected from N, O and S. Examples of heterocycloalkyl groups are pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothienyl, tetrahydropyridinyl, tetrahydropyrrolyl, azetidinyl, thiazolidinyl, oxazolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, azepanyl, diazepanyl, oxazepanyl and the like. Preferred heterocycloalkyl groups are morpholin-4-yl, piperidin-1-yl, pyrrolidin-1-yl, thiomorpholin-4-yl and 1,1-dioxo-thiomorpholin-4-yl.

[1201] The term "aryl" refers to phenyl or naphthyl.

[1202] The term "heteroaryl" refers to an aromatic group containing heteroatoms, preferably an aromatic 5-6 membered monocyclic ring or a 9-10 membered bicyclic ring containing 1, 2 or 3 groups independently selected from nitrogen, oxygen and sulfur, such as furanyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, thienyl, isoxazolyl, oxazolyl, oxadiazolyl, imidazolyl, pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, isothiazolyl, thiadiazolyl, benzimidazolyl, indolyl, indazolyl, benzothiazolyl, benzisothiazolyl, benzoxazolyl, benzisoxazolyl, quinolyl, isoquinolyl, etc. At least one ring in the heteroaryl group has aromaticity.

[1203] The term "pharmaceutical excipients" refers to excipients and additives used in the production of pharmaceuticals and the preparation of prescriptions. They are all substances contained in pharmaceutical preparations, in addition to the active ingredients. For a complete list, please refer to the Pharmacopoeia of the People's Republic of China (2015 Edition), Part IV, or the Handbook of Pharmaceutical Excipients (Raymond C Rowe, 2009, Sixth Edition).

[1204] The term "treat" refers to therapeutic treatment. When referring to a specific condition, treatment means: (1) alleviating the disease or one or more biological manifestations of the condition, (2) interfering with (a) one or more points in the biological cascade that leads to or causes the condition or (b) one or more biological manifestations of the condition, (3) ameliorating one or more symptoms, effects, or side effects associated with the condition or one or more symptoms, effects, or side effects associated with the condition or its treatment, or (4) slowing the progression of the condition or one or more biological manifestations of the condition.

[1205] The term "prevent" refers to the reduction of the risk of acquiring or developing a disease or disorder.

[1206] The term "STAT5 inhibitor" refers to a substance that can specifically inhibit STAT5 activity in vivo.

[1207] Without violating the common sense in the art, the above-mentioned preferred conditions can be arbitrarily combined to obtain preferred embodiments of the present invention.

[1208] The reagents and raw materials used in the present invention are commercially available.

[1209] The positive progress of the present invention is that the compounds have novel structures and better STAT5 inhibitory activity. DETAILED DESCRIPTION

[1210] The present invention is further illustrated by way of examples below, but the present invention is not limited to the scope of the examples. Experimental methods in the following examples where specific conditions are not specified were performed according to conventional methods and conditions, or selected according to the product specifications.

[1211] Example 1. 3-(1-Propanylpiperidin-4-yl)benzo[d]oxazol-2(3H)-one (P1)

[1212]

[1213] Step 1.1. Synthesis of tert-butyl 4-(2-oxobenzo[d]oxazol-3(2H)-yl)piperidine-1-carboxylate

[1214]

[1215] To a stirred solution of tert-butyl 4-oxopipecotate (20 g, 100 mmol) and 2-aminophenol (11 g, 100 mmol) in CH2Cl2 (300 mL) at room temperature under nitrogen was added NaBH(OAc)3 (32.4 g, 151 mmol). The mixture was stirred at room temperature for 14 h. The mixture was diluted with CH2Cl2 (1000 mL) and saturated NaHCO3 (1500 mL), and the layers were separated. The aqueous layer was extracted with CH2Cl2 (2 x 500 mL), and the combined organic layers were washed with brine, dried over Na2SO4, and the solvent was removed under reduced pressure. The crude material was diluted with CH2Cl2 (300 mL), carbonyldiimidazole (18 g, 110 mmol) was added, and the mixture was stirred for 16 h. The mixture was diluted with CH2Cl2 (1 L) and 1N HCl (1 L), and the layers were separated. The aqueous layer was extracted with CH2Cl2 (2 x 500 mL), and the combined organic layers were washed with brine, dried over Na2SO4, and the solvent was removed under reduced pressure. Purification by silica gel column chromatography (PE:EA=15:1) gave a yellow solid (18.4 g, yield 38%). MS (ESI) m / z 319.0 [M+H] + .

[1216] Step 1.2. Synthesis of 3-(piperidin-4-yl)benzo[d]oxazol-2(3H)-one

[1217]

[1218] tert-Butyl 4-(2-oxobenzo[d]oxazol-3(2H)-yl)piperidine-1-carboxylate (16.0 g, 50.3 mmol) was added to a solution of CH2Cl2 (24 ml), and TFA (24 ml) was slowly added at 0°C. The reaction mixture was concentrated. The residue was treated with saturated NaHCO3 (200 mL) and CH2Cl2 (1000 mL). The separated organic layer was washed with brine, dried over Na2SO4, and the solvent was removed under reduced pressure to give the desired compound (11 g, yield: 100%) as a yellow solid. MS (ESI) m / z 218.9 [M+H] + .

[1219] Step 1.3. Synthesis of 3-(1-propionylpiperidin-4-yl)benzo[d]oxazol-2(3H)-one (P1)

[1220]

[1221] To a solution of 3-(piperidin-4-yl)benzo[d]oxazol-2(3H)-one (1.92 g, 8.8 mmol) and DIEA (1.50 g, 11.6 mmol) in DCM (25 ml) was added propionyl chloride (1.05 g, 11.4 mmol) dropwise at 0°C. The reaction mixture was stirred at room temperature for 2 hours, diluted with DCM (100 mL), and washed with aqueous NH4Cl (200 mL). The separated organic layer was dried over Na2SO4 and concentrated under reduced pressure to afford the crude product, which was then purified by silica gel column chromatography (PE:EA:DCM = 4:1:1 to 1:1:1) to afford the desired product as a white solid (1.1 g, 46% yield). 1 H NMR (400MHz, CDCl3): δ7.30-7.08(m,4H),4.93(d,J=13.2Hz,1H),4.42-4.36(m,1H),4.10(d,J=13.6Hz,1H),3.20(t,J=12.8H z,1H),2.68(t,J=12.8Hz,1H),2.43(q,J=7.6Hz,2H),2.31-2.24(m,2H),2.01-1.95(m,2H),1.22(t,J=7.6Hz,3H).MS(ESI)m / z 275.0[M+H] + .

[1222] Example 2. 3-(1-(3,3,3-trifluoropropionyl)piperidin-4-yl)benzo[d]oxazol-2(3H)-one (P2)

[1223]

[1224] Step 2.1. 3-(1-(3,3,3-trifluoropropionyl)piperidin-4-yl)benzo[d]oxazol-2(3H)-one (P2)

[1225]

[1226] 3-(Piperidin-4-yl)benzo[d]oxazol-2(3H)-one (1.5 g, 6.88 mmol) and KCO (1.99 g, 13.8 mmol) were added to DCM (15 ml). 3,3,3-trifluoropropyl chloride (1.05 g, 11.4 mmol) was added dropwise at 0°C. The reaction mixture was stirred at room temperature for 4 hours. The reaction mixture was filtered and the filtrate was concentrated. The product was purified by silica gel column chromatography (PE:EA:DCM = 1:1:1) to obtain the desired product as a white solid (1.75 g, 77% yield). 1H NMR (400MHz, CDCl3): δ7.23 (dd, J=5.2, 1.2Hz, 1H), 7.21-7.12 (m, 2H), 7.04 (dd, J=8.0, 1.2Hz, 1H), 4.94-4.89 (m, 1H), 4.4 4-4.37(m,1H),4.01-3.97(m,1H),3.38-3.27(m,3H),2.78-2.70(m,1H),2.37-2.23(m,2H),2.04-1.98(m,2H).MS(ESI)m / z 329.1[M+H] + .

[1227] Example 3. 3-(1-(2-(pyridin-4-yl)acetyl)piperidin-4-yl)benzo[d]oxazol-2(3H)-one (P3)

[1228]

[1229] Step 3.1. Synthesis of 3-(1-(2-(pyridin-4-yl)acetyl)piperidin-4-yl)benzo[d]oxazol-2(3H)-one (P3)

[1230]

[1231] To a solution of 3-(piperidin-4-yl)benzo[d]oxazol-2(3H)-one (1.5 g, 6.88 mmol) and K2CO3 (2.8 g, 20.6 mmol) in DCM (20 ml) was added 2-(pyridin-4-yl)acetyl chloride hydrochloride (2.0 g, 10.3 mmol) dropwise at 0°C. The reaction mixture was stirred at room temperature for 4 hours, filtered, and the filtrate concentrated. The product was purified by HPLC (20-95% CH3CN in water) to give a white solid (1.07 g, 46% yield). 1 H NMR (400MHz, DMSO-d6): δ8.51(d,J=6.0Hz,2H),7.35-7.29(m,4H),7.23-7.19(m,1H),7.15-7.11(m,1H),4.57(d,J=13.2Hz,1H),4.43-4 .35(m,1H),4.09(d,J=14.4Hz,1H),3.85(s,2H),3.23-3.16(m,1H),2.76-2.69(m,1H),2.09-1.98(m,2H),1.86-1.81(m,2H).MS(ESI)m / z 338.0[M+H] + .

[1232] Example 4. 3-(1-(2-phenylacetyl)piperidin-4-yl)benzo[d]oxazol-2(3H)-one (P4)

[1233]

[1234] Step 4.1. Synthesis of 3-(1-(2-phenylacetyl)piperidin-4-yl)benzo[d]oxazol-2(3H)-one (P4)

[1235]

[1236] 3-(Piperidin-4-yl)benzo[d]oxazol-2(3H)-one (1.5 g, 6.88 mmol) and triethylamine (2.1 g, 20.6 mmol) were added to DCM (15 ml). 2-Phenylacetyl chloride (1.6 g, 10.3 mmol) was added dropwise at 0°C. The reaction mixture was stirred at room temperature for 1 hour and then concentrated. The product was purified by silica gel column chromatography (PE:EA:DCM = 1:1:1) to obtain the desired product as a white solid (1.16 g, 50% yield). 1 H NMR (400MHz, CDCl3) δ7.39-7.35(m,4H),7.29-7.26(m,1H),7.20-7.18(m ,1H),7.11-7.09(m,2H),6.79-6.75(m,1H),4.91-4.88(m,1H),4.39-4.30 (m,1H),4.08-4.04(m,1H),3.82(s,2H),3.16-3.08(m,1H),2.70-2.63(m, 1H),2.18-2.09(m,1H),1.91-1.78(m,1H),1.77-1.73(m,2H).MS(ESI)m / z 337.2[M+H] + .

[1237] Example 5. 4-(2-oxo-2-(4-(2-oxobenzo[d]oxazol-3(2H)-yl)piperidin-1-yl)ethyl)benzoic acid (P6)

[1238]

[1239] Step 5.1. 4-(2-Oxo-2-(4-(2-oxobenzo[d]oxazol-3(2H)-yl)piperidin-1-yl)ethyl)benzoic acid (P6)

[1240]

[1241] 3-(Piperidin-4-yl)benzo[d]oxazol-2(3H)-one (1.5 g, 6.88 mmol), 2-(4-(methoxycarbonyl)phenyl)acetic acid (1.42 g, 7.33 mmol) and HATU (3.9 g, 10.2 mmol) were added to DCM (20 ml), and DIEA (2.67 g, 20 mmol) was added at 0° C. The reaction mixture was stirred at room temperature under nitrogen for 2 hours, diluted with DCM (150 mL), and washed with aqueous NH4Cl solution (200 mL). The separated organic layer was dried over Na2SO4 and concentrated under reduced pressure to yield the crude product, which was then purified by silica gel column chromatography (MeOH:DCM = 1:20 to 1:10) to afford methyl 4-(2-oxo-2-(4-(2-oxobenzo[d]oxazol-3(2H)-yl)piperidin-1-yl)ethyl)benzoate (2.5 g, 82% yield) as a brown solid. Methyl 4-(2-oxo-2-(4-(2-oxobenzo[d]oxazol-3(2H)-yl)piperidin-1-yl)ethyl)benzoate (2.0 g, 5.08 mmol) and lithium hydroxide monohydrate (352 mg, 8.2 mmol) were added to THF (80 mL) and H2O (20 mL). The mixture was stirred at room temperature for 16 h. After removal of the organic solvent, the aqueous layer was adjusted to pH 2 with the addition of 2N HCl and extracted with EtOAc (3 x 200 mL). The organic layer was dried over Na 2 SO 4 and concentrated under reduced pressure to give a crude product, which was purified by silica gel column chromatography (MeOH:DCM=1:60-1:40) to give the desired brown solid (1.01 g, yield: 53%). 1 H NMR (400MHz, DMSO-d6): δ12.78(brs,1H),7.92(d,J=8.0Hz,2H),7.42(d,J=8.0Hz,2H),7.33(d,J=7.6Hz,1H),7.18-7.10(m,3H),4.58(d,J=13 .2Hz,1H),4.42-4.36(m,1H),4.10(d,J=13.6Hz,1H),3.94-3.83(m,2H),3.21-3.15(m,1H),2.75-2.68(m,1H),2.00-1.76(m,4H).MS(ESI)m / z 381.2[M+H] + .

[1242] Example 6. 3-(1-(2-(p-Tolyl)acetyl)piperidin-4-yl)benzo[d]oxazol-2(3H)-one (P7)

[1243]

[1244] Step 6.1. Synthesis of 3-(1-(2-(p-methylphenyl)acetyl)piperidin-4-yl)benzo[d]oxazol-2(3H)-one (P7)

[1245]

[1246] To a solution of 3-(piperidin-4-yl)benzo[d]oxazol-2(3H)-one (1.5 g, 6.88 mmol), 2-(p-tolyl)acetic acid (1.1 g, 7.32 mmol), and HATU (3.9 g, 10.2 mmol) in DCM (20 ml) was added DIEA (2.67 g, 20 mmol) at 0°C. The reaction mixture was stirred at room temperature under nitrogen for 2 hours, diluted with DCM (150 mL), and rinsed with aqueous NH4Cl (200 mL). The separated organic layer was dried over Na2SO4 and concentrated under reduced pressure to afford the desired product, which was purified by silica gel column chromatography (MeOH:DCM = 1:25 to 1:10) to afford the desired product as a white solid (1.2 g, 50% yield). 1 H NMR (400MHz, CDCl3): δ7.26-7.08(m,7H),6.77-6.75(m,1H),4.90-4.87(m,1H),4.39-4.31(m,1H),4.08-4.04(m,1H),3.77(s ,2H),3.15-3.07(m,1H),2.68-2.62(m,1H),2.32(s,3H),2.13-2.07(m,1H),1.93-1.82(m,1H),1.74-1.64(m,2H).MS(ESI)m / z 351.2[M+H] + .

[1247] Example 7. 3-(1-(2-(4-(trifluoromethyl)phenyl)acetyl)piperidin-4-yl)benzo[d]oxazol-2(3H)-one (P8)

[1248]

[1249] Step 7.1. Synthesis of 3-(1-(2-(4-(trifluoromethyl)phenyl)acetyl)piperidin-4-yl)benzo[d]oxazol-2(3H)-one (P8)

[1250]

[1251] 3-(Piperidin-4-yl)benzo[d]oxazol-2(3H)-one (2.0 g, 9.17 mmol), 2-(4-(trifluoromethyl)phenyl)acetic acid (2.24 g, 9.17 mmol), and HATU (5.2 g, 13.8 mmol) were added to DCM (27 mL). DIEA (3.56 g, 27.5 mmol) was added at 0°C. The reaction mixture was stirred at room temperature under N2 for 1 h, diluted with DCM (150 mL), and rinsed with aqueous NH4Cl (200 mL). The separated organic layer was dried over Na2SO4 and concentrated under reduced pressure to give the crude product, which was purified by silica gel column chromatography (MeOH:DCM = 1:30) to give the desired white solid (1.28 g, 40% yield). 1 H NMR (400MHz, CDCl3): δ7.63 (d, J = 8.0 Hz, 2H), 7.44 (d, J = 7.6 Hz, 2H), 7.23-7. 19(m,1H),7.14-7.09(m,2H),6.85-6.83(m,1H),4.88(d,J=13.2Hz,1H),4.3 8-4.32(m,1H),4.05(d,J=14.0Hz,1H),3.86(s,2H),3.22-3.14(m,1H),2.73 -2.66(m,1H),2.21-2.17(m,1H),1.99-1.84(m,3H).MS(ESI)m / z405.2[M+H] + .

[1252] Example 8. 3-(2-(4-Fluorobenzyl)-4-oxo-4H-quinolizin-8-yl)benzo[d]oxazol-2(3H)-one (P9)

[1253]

[1254] Step 8.1. Synthesis of 4-methoxypyridinecarboxaldehyde

[1255]

[1256] Ethyl 4-methoxypicolinate (94.3 g, 560 mmol) was added to toluene (1.70 L). DIBAL-H (408 mL, 1.0 M hexane) was then added dropwise at -78°C under nitrogen. After thorough mixing, the mixture was stirred at this temperature for 3 hours. The reaction was monitored by thin-layer chromatography. Excess DIBAL-H was quenched with methanol before the addition of aqueous sodium hydroxide (2.0 M, 1.5 L). The reaction mixture was allowed to reach room temperature. The mixture was extracted with DCM (4 × 1 L). The combined organic layers were dried and concentrated to yield the crude product, which was then purified by silica gel column chromatography (PE / EA = 5:1) to afford the desired product as a yellow gel (42.5 g, yield: 57%). MS (ESI) m / z 138.1 [M+H] + .

[1257] Step 8.2. Synthesis of ethyl 8-methoxy-4-oxo-4H-quinolizine-2-carboxylate

[1258]

[1259] A suspension of potassium tert-butoxide (1.12 g, 10 mmol, 25 mL of tert-butanol) was added to a mixture of 4-methoxypyridinaldehyde (685 mg, 5.0 mmol) and diethyl succinate (1.74 g, 10.0 mmol). The reaction mixture was stirred at 50°C for 0.5 h, then 15% aqueous acetic acid (40 mL) was added and extracted with EA (2 x 30 mL). This was repeated 61 times. The EA layers were combined and concentrated. The mixture was stored at room temperature for 2 days until the cyclization reaction was complete. The product was purified by silica gel column chromatography (PE:EA = 2:1) to yield the desired yellow solid (11.5 g, 15% yield). 1 H NMR (400MHz, DMSO-d6): δ8.96(d,J=8.0Hz,1H),7.48(d,J=2.4Hz,1H),7.13(d,J=2.4Hz,1H),7.07(dd,J=8.0Hz,2. 8Hz,1H),6.55(d,J=2.0Hz,1H),4.34(q,J=7.2Hz,2H),3.94(s,3H),1.35(t,J=7.2Hz,3H).MS(ESI)m / z248.1[M+H] + .

[1260] Step 8.3. Synthesis of 2-(hydroxymethyl)-8-methoxy-4H-quinolizin-4-one

[1261]

[1262] A slurry of ethyl 8-methoxy-4-oxo-4-H-quinolizine-2-carboxylate (5.0 g, 20.2 mmol) was added to THF (300 mL), and LiBH4 (1.77 g, 80.4 mmol) was gradually added. The reaction mixture was stirred at room temperature for 24 hours. The reaction mixture was quenched with 15% aqueous acetic acid. After removal of the solvent, the precipitate was collected by filtration and concentrated to the desired compound (3.3 g, yield: 79%) as a light yellow solid. 1 H NMR (400MHz, DMSO-d6): δ8.84(d,J=8.0Hz,1H),7.11(d,J=2.8Hz,1H),6.85(dd,J=7.6Hz,2.4Hz,1H ),6.58(s,1H),6.13(s,1H),5.39(t,J=5.6Hz,1H),4.90(d,J=2.8Hz,2H),3.90(s,3H).MS(ESI)m / z 206.1[M+H] + .

[1263] Step 8.4. Synthesis of (8-methoxy-4-oxo-4H-quinolin-2-yl)methyl methanesulfonate

[1264]

[1265] 2-(Hydroxymethyl)-8-methoxy-4H-quinolizin-4-one (3.3 g, 16.0 mmol) and Et3N (9.69 g, 96.0 mmol) were added to DCM (1.0 L). MsCl (7.36 g, 64.0 mmol) was added dropwise at 0°C and stirred at 0°C for 1 h. Water was added and the DCM layer was separated. The mixture was washed with brine, dried over Na2SO4, and concentrated to give a crude product (5.35 g), which was used directly in the next step. MS (ESI) m / z 284.0 [M+H] + .

[1266] Step 8.5. Synthesis of 2-(bromomethyl)-8-methoxy-4H-quinolizin-4-one

[1267]

[1268] Lithium bromide (8.35 g, 96.0 mmol) was added to a solution of methyl (8-methoxy-4-oxo-4H-quinolizin-2-yl)methyl methanesulfonate (5.35 g, 16.0 mmol) in acetone (240 mL). The mixture was stirred at 35°C overnight under nitrogen. After removing the acetone, the residue was dissolved in EA and water. The organic layer was separated, washed with brine, dried over Na2SO4, and concentrated to give the crude product (3.5 g) as a yellow solid, which was used directly in the next step. MS (ESI) m / z 267.9 and 269.9 [M+H] + .

[1269] Step 8.6. Synthesis of 2-(4-fluorobenzyl)-8-methoxy-4H-quinolizin-4-one

[1270]

[1271] 2-(Bromomethyl)-8-methoxy-4H-quinolizin-4-one (3.5 g, crude product, <16.0 mmol), (4-fluorophenyl)boronic acid (3.36 g, 24.0 mmol), Cs2CO3 (10.4 g, 32.0 mmol), and PdCl2(PPh3)2 (1.12 g, 1.60 mmol) were added to dioxane (350 mL) and stirred at 100°C for 1 hour. The reaction mixture was extracted with EA. The organic layer was washed with brine, dried over Na2SO4, and concentrated, then purified by silica gel column chromatography (DCM:EA = 10:1) to afford a light yellow solid (2.77 g, 48% yield over four steps). 1 H NMR (400MHz, CDCl3): δ8.90(d,J=8.0Hz,1H),7.15-7.08(m,2H),6.96-6.89(m,2H),6.57(dd,J=8.4H z,2.8Hz,1H),6.47(d,J=2.8Hz,1H),6.19(s,1H),6.16(s,1H),3.81(s,3H),3.81(s,2H).MS(ESI)m / z 284.0[M+H] + .

[1272] Step 8.7. Synthesis of 2-(4-fluorobenzyl)-8-hydroxy-4H-quinolizin-4-one

[1273]

[1274] To a cooled solution of 2-(4-fluorobenzyl)-8-methoxy-4H-quinolizin-4-one (2.77 g, 9.75 mmol) in dichloromethane was added 55 ml (55.0 mmol) of 1N boron tribromide solution. The mixture was then stirred at 35°C for 16 hours. The reaction mixture was concentrated, and the residue was treated with 20 mL of acetonitrile in water at 0°C. After removing the acetonitrile, the precipitate was collected by filtration to yield 2.60 g (99% yield) of a yellow solid. 1 H NMR (400MHz, DMSO-d6): δ11.25(s,1H),8.86(d,J=7.6Hz,1H),7.36-7.28(m,2H),7.17-7.08(m ,2H),6.83-6.75(m,2H),6.38(d,J=1.2Hz,1H),5.94(d,J=1.6Hz,1H),3.83(s,2H).MS(ESI)m / z 270.0[M+H] + .

[1275] Step 8.8. Synthesis of 2-(4-fluorobenzyl)-4-oxo-4H-quinoxalin-8-yl trifluoromethanesulfonate

[1276]

[1277] To a solution of 2-(4-fluorobenzyl)-8-hydroxy-4H-quinolizin-4-one (2.60 g, 9.63 mmol) in DMF (13 ml) was added Et3N (1.46 g, 14.4 mmol) and Tf2NPh (4.13 g, 11.6 mmol). Under nitrogen, the mixture was stirred at room temperature for 3 hours. 40 mL of 0°C water was added to the reaction mixture and stirred vigorously. The precipitate was collected by filtration to obtain yellow crystals (3.43 g, yield: 89%). MS (ESI) m / z 402.0 [M+H] + .

[1278] Step 8.9. Synthesis of trimethyl(2-((2-nitrophenoxy)methoxy)ethyl)silane

[1279]

[1280] SEM-Cl (6.6 g, 39.6 mmol) was added to a cooled solution of 2-nitrophenol (5.0 g, 36.0 mmol) and Et3N (5.4 g, 54.0 mmol) in DCM (50 mL). The reaction mixture was stirred at room temperature for 3 hours. The mixture was washed with water and aqueous NH4Cl, dried over Na2SO4, and concentrated to yield the crude product. Column chromatography afforded the desired product as a yellow oil (5.0 g, 70% yield). 1H NMR (400MHz, CDCl3): δ7.81 (dd, J=8.0Hz, 1.6Hz, 1H), 7.54-7.46 (m, 1H), 7.35 (dd, J=8.4Hz, 0. 8Hz,1H),7.10-7.03(m,1H),5.34(s,2H),3.84-3.77(m,2H),0.90-0.93(m,2H),-0.001(s,9H).

[1281] Step 8.10. Synthesis of 2-((2-(trimethylsilyl)ethoxy)methoxy)aniline

[1282]

[1283] A mixture of trimethyl(2-((2-nitrophenoxy)methoxy)ethyl)silane (5.0 g, 18.6 mmol) and 10% Pd / C (2.5 g) in MeOH (50 mL) was stirred at room temperature under H₂ for 16 h. The reaction mixture was filtered through Celite and concentrated and used directly in the next reaction. MS (ESI) m / z 240.1 [M+H] + .

[1284] Step 8.11. Synthesis of 2-(4-fluorobenzyl)-8-((2-((2-(trimethylsilyl)ethoxy)methoxy)phenyl)amino)-4H-quinolizin-4-one

[1285]

[1286] A solution of 2-(4-fluorobenzyl)-4-oxo-4H-quinazolin-8-yl trifluoromethanesulfonate (2.46 g, 6.11 mmol), 2-((2-(trimethylsilyl)ethoxy)methoxy)aniline (2.20 g, 9.17 mmol), Cs2CO3 (3.98 g, 12.2 mmol), BINAP (380 mg, 0.611 mmol), and Pd2(dba)3 (279 mg, 0.305 mmol) in dioxane (88 mL) was stirred at 90°C under N2 for 2 hours. The reaction mixture was purified by silica gel column chromatography (PE:EA from 3:1 to 1:1) to give the desired product (2.25 g, 76% yield) as a yellow solid. MS (ESI) m / z 491.2 [M+H] + .

[1287] Step 8.12. Synthesis of 2-(4-fluorobenzyl)-8-((2-hydroxyphenyl)amino)-4H-quinolizin-4-one

[1288]

[1289] 2-(4-Fluorobenzyl)-8-((2-((2-(trimethylsilyl)ethoxy)methoxy)phenyl)amino)-4H-quinolizin-4-one (2.25 g, 4.59 mmol) was added dropwise to a mixture of MeOH (90 mL) and THF (90 mL). A solution of HSO (4.60 mL con HSO in 90 mL MeOH) was added. The mixture was stirred at room temperature for 2 hours. The reaction mixture was neutralized with ice-cold aqueous NaHCO and extracted with EA. The EA layer was concentrated (1.81 g, crude product) and used directly in the next step. MS (ESI) m / z 361.1 [M+H] + .

[1290] Step 8.13. Synthesis of 3-(2-(4-fluorobenzyl)-4-oxo-4H-quinolizin-8-yl)benzo[d]oxazol-2(3H)-one (P9)

[1291]

[1292] Methyl chloroformate (0.95 g, 10.0 mmol) was slowly added dropwise to a cooled solution of 2-(4-fluorobenzyl)-8-((2-hydroxyphenyl)amino)-4H-quinolizin-4-one (1.81 g, 5.0 mmol) and Cs2CO3 (3.26 g, 10.0 mmol) in dioxane (250 mL). The mixture was stirred at room temperature overnight. The reaction mixture was then stirred at 80°C for an additional 20 hours. The resulting mixture was stirred at 100°C for 3 hours. LCMS indicated complete consumption of the starting material. The reaction mixture was diluted with EA and washed with water and brine. The organic layer was dried and concentrated over Na2SO4. The crude product was purified by silica gel column chromatography (PE / EA, 10:1 to 3:1) to obtain the title compound (1.20 g, 63% yield). 1 H NMR(400MHz, DMSO-d6)δ8.99(d,J=8.0Hz,1H),7.95(d,J=2.4Hz,1H),7.52-7.46(m,1H),7.46–7.40(m,2H),7.40 –7.33(m,2H),7.33–7.24(m,2H),7.20–7.11(m,2H),6.83(s,1H),6.38(d,J=1.6Hz,1H),3.97(s,2H).MS(ESI)m / z 387.1[M+H] + ,Purity:99.2%@254nm,99.3%@214nm.

[1293] Example 9. 1-(1-Propanylpiperidin-4-yl)-1H-benzo[d]imidazol-2(3H)-one (X1)

[1294]

[1295] Step 9.1. Synthesis of 1-(1-propionylpiperidin-4-yl)-1H-benzo[d]imidazol-2(3H)-one (X1)

[1296]

[1297] 1-(Piperidin-4-yl)-1H-benzo[d]imidazol-2(3H)-one hydrochloride (1.40 g, 5.52 mmol) and pyridine (1.74 g, 22.1 mmol) were added to DCM (40 ml), and propionyl chloride (1.53 g, 16.5 mmol) was added dropwise at 0°C. The reaction mixture was stirred at room temperature for 16 h, diluted with water, and extracted with DCM. The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure to afford the crude product, which was purified by HPLC (20-95% CH3CN in water) to afford the desired product as a white solid (1.18 g, 69% yield). 1 H NMR (400MHz, DMSO-d6): δ10.84(s,1H),7.25-7.19(m,1H),7.00-6.97(m,3 H),4.58(d,J=13.2Hz,1H),4.45-4.37(m,1H),4.01(d,J=13.6Hz,1H),3.18 -3.07(m,1H),2.67-2.59(m,1H),2.42-2.39(m,2H),2.37-2.20(m,1H),2. 18-2.06(m,1H),1.71(t,J=12.8Hz,2H),1.02(m,J=7.6Hz,3H).MS(ESI)m / z 274.2[M+H] + ,Purity:99.6%@254nm,99.9%@214nm.

[1298] Example 10. 1-(1-(3,3,3-trifluoropropionyl)piperidin-4-yl)-1H-benzo[d]imidazol-2(3H)-one (X2)

[1299]

[1300] Step 10.1. Synthesis of 1-(1-(3,3,3-trifluoropropionyl)piperidin-4-yl)-1H-benzo[d]imidazol-2(3H)-one (X2)

[1301]

[1302] 1-(Piperidin-4-yl)-1H-benzo[d]imidazol-2(3H)-one hydrochloride (1.50 g, 5.90 mmol) and DIEA (3.04 g, 23.6 mmol) were added to DCM (20 ml), and 3,3,3-trifluoropropyl chloride (1.30 g, 8.86 mmol) was added dropwise at 0°C. The reaction mixture was stirred at room temperature for 2 hours, then concentrated. The product was purified by HPLC (10-95% CH3CN in water) to give the desired product as a white solid (1.21 g, 63% yield). 1 H NMR (400MHz, DMSO-d6): δ10.85(s,1H),7.24-7.21(m,1H),7.00-6.97(m,3H),4.62-4.53(m,1H),4.49-4.37(m,1H),4.03-3.93(m, 1H),3.76-3.68(m,2H),3.25-3.14(m,1H),2.75-2.68(m,1H),2.42-2.28(m,1H),2.21-2.07(m,1H),1.78-1.68(m,2H).MS(ESI)m / z 328.1[M+H] + ,Purity:94.5%@254nm,99.1%@214nm.

[1303] Example 11. 1-(1-(2-(pyridin-4-yl)acetyl)piperidin-4-yl)-1H-benzo[d]imidazol-2(3H)-one (X3)

[1304]

[1305] Step 11.1. Synthesis of 1-(1-(2-(pyridin-4-yl)acetyl)piperidin-4-yl)-1H-benzo[d]imidazol-2(3H)-one (X3)

[1306]

[1307] 1-(Piperidin-4-yl)-1H-benzo[d]imidazol-2(3H)-one hydrochloride (1.50 g, 5.90 mmol), 2-(pyridin-4-yl)acetic acid hydrochloride (1.55 g, 8.90 mmol), and HATU (6.76 g, 17.8 mmol) were added to DCM (20 mL), and DIEA (3.81 g, 29.5 mmol) was added dropwise at 0°C. The reaction mixture was stirred at room temperature under N2 for 2 hours, and then concentrated. The product was purified by HPLC (10-95% CH3CN in water) to give the desired white solid (1.27 g, yield: 64%). 1H NMR (400MHz, DMSO-d6): δ10.84(s,1H),8.72-8.35(m,2H),7.31(d,J=3.6Hz,2H),7.15-7.06(m,1H),7.02-6.89(m,3H),4.57(d,J=13.2Hz,1H),4.4 5-4.38(m,1H),4.08(d,J=13.6Hz,1H),3.91-3.79(m,2H),3.23-3.11(m, 1H),2.78-2.64(m,1H),2.19-2.05(m,2H),1.73-1.62(m,2H).MS(ESI)m / z 337.1[M+H] + ,Purity:99.8%@254m,99.9%@214nm.

[1308] Example 12. 1-(1-(2-phenylacetyl)piperidin-4-yl)-1H-benzo[d]imidazol-2(3H)-one (X4)

[1309]

[1310] Step 12.1. Synthesis of 1-(1-(2-phenylacetyl)piperidin-4-yl)-1H-benzo[d]imidazol-2(3H)-one (X4)

[1311]

[1312] 1-(Piperidin-4-yl)-1H-benzo[d]imidazol-2(3H)-one hydrochloride (1.50 g, 5.90 mmol) and pyridine (1.87 g, 23.6 mmol) were added to DCM (40 ml), and 2-phenylacetyl chloride (2.28 g, 14.8 mmol) was added dropwise at 0°C. The reaction mixture was stirred at room temperature for 16 h, diluted with water, and extracted with DCM. The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure to afford the crude product, which was purified by HPLC (10-95% CH3CN in water) to afford the desired product as a white solid (1.46 g, 63% yield). 1H NMR (400MHz, CDCl3) δ10.82(s,1H),7.38-7.21(m,5H),6.96-6.95(m,4H),4.57(d,J=13.2Hz,1H),4.45-4.35(m,1H),4.09(d ,J=13.6Hz,1H),3.84-3.74(m,2H),3.19-3.08(m,1H),2.73-2.62(m,1H),2.11-1.88(m,2H),1.72-1.54(m,2H).MS(ESI)m / z 336.1[M+H] + ,Purity:97.9%@254nm,99.9%@214nm.

[1313] Example 13. 4-(2-oxo-2-(4-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidin-1-yl)ethyl)benzoic acid (X6)

[1314]

[1315] Step 13.1. 4-(2-Oxo-2-(4-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidin-1-yl)ethyl)benzoic acid (X6)

[1316]

[1317] 1-(Piperidin-4-yl)-1H-benzo[d]imidazol-2(3H)-one hydrochloride (2.40 g, 8.43 mmol), 2-(4-(methoxycarbonyl)phenyl)acetic acid (1.80 g, 9.28 mmol) and HATU (4.80 g, 12.6 mmol) were added to DCM (50 mL), and DIEA (3.26 g, 25.3 mmol) was added at 0° C. The reaction mixture was stirred at room temperature under N2 for 2 h, diluted with DCM (200 mL), and washed with aqueous NH4Cl (200 mL). The separated organic layer was dried over Na2SO4 and concentrated under reduced pressure to give a crude product, which was purified by high performance liquid chromatography (25-95% CH3CN aqueous solution) to give methyl 4-(2-oxo-2-(4-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidin-1-yl)benzoate (1.6 g, yield 37%) as a white solid. 4-(2-oxo-2-(4-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidin-1-yl)benzoate was added to THF (20 ml) and H2O (20 ml). Methyl 2-(4-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidin-1-yl)benzoate (1.6 g, 4.07 mmol) and LiOH.H2O (855 mg, 2.04 mmol) were stirred at room temperature for 3 hours. After removing the organic solvent, the aqueous layer was adjusted to pH 2 by adding 2N hydrochloric acid. The precipitate was collected and dried to yield the desired product (1.15 g, 75% yield) as a white solid. 1 H NMR (400MHz, DMSO-d6): δ12.89(brs,1H),10.83(s,1H),7.93(d,J=7.2Hz,2H),7.43(d,J=7.2Hz,2H),6.95(s,4H),4.57(d,J=12.0Hz,1H),4.50- 4.32(m,1H),4.10(d,J=12.8Hz,1H),3.96-3.82(m,2H),3.25-3.12(m,1 H),2.75-2.62(m,1H),2.13-1.88(m,2H),1.80-1.53(m,2H).MS(ESI)m / z 380.0[M+H] + ,Purity:95.9%@254nm,98.9%@214nm.

[1318] Example 14. 1-(1-(2-(p-Tolyl)acetyl)piperidin-4-yl)-1H-benzo[d]imidazol-2(3H)-one (X7)

[1319]

[1320] Step 14.1. Synthesis of 1-(1-(2-(p-methylphenyl)acetyl)piperidin-4-yl)-1H-benzo[d]imidazol-2(3H)-one (X7)

[1321]

[1322] 1-(Piperidin-4-yl)-1H-benzo[d]imidazol-2(3H)-one hydrochloride (1.50 g, 5.90 mmol), 2-(p-tolyl)acetic acid (1.34 g, 8.90 mmol), and HATU (6.76 g, 17.8 mmol) were added to DCM (20 ml). DIEA (3.81 g, 29.5 mmol) was added dropwise at 0°C. The reaction mixture was concentrated. The product was purified by HPLC (10-95% CH3CN in water) to give the desired product as a white solid (1.16 g, 56% yield). 1 H NMR (400MHz, CDCl3): δ10.83(s,1H),7.21-7.15(m,4H),6.96-6.90(m,4H),4. 57(d,J=13.2Hz,1H),4.45-4.32(m,1H),4.07(d,J=14.0Hz,1H),3.82-3.67(m ,2H),3.18-3.07(m,1H),2.72-2.62(m,1H),2.27(s,3H),2.08-1.96(m,1H),1 .95-1.80(m,1H),1.66(d,J=10.8Hz,1H),1.57(d,J=10.8Hz,1H).MS(ESI)m / z 350.2[M+H] + ,Purity:96.8%@254nm,99.6%@214nm.

[1323] Example 15. 1-(1-(2-(4-(trifluoromethyl)phenyl)acetyl)piperidin-4-yl)-1H-benzo[d]imidazol-2(3H)-one (X8)

[1324]

[1325] Step 15.1. Synthesis of 1-(1-(2-(4-(trifluoromethyl)phenyl)acetyl)piperidin-4-yl)-1H-benzo[d]imidazol-2(3H)-one (X8)

[1326]

[1327] 1-(Piperidin-4-yl)-1H-benzo[d]imidazol-2(3H)-one hydrochloride (1.50 g, 5.90 mmol), 2-(4-(trifluoromethyl)phenyl)acetic acid (1.45 g, 7.09 mmol), and HATU (3.37 g, 8.87 mmol) were added to DCM (50 mL). DIEA (3.81 g, 29.6 mmol) was added at 0°C. The reaction mixture was stirred at room temperature under N2 for 3 h. The reaction mixture was diluted with DCM (100 mL) and washed with aqueous NH4Cl (100 mL). The separated organic layer was dried over Na2SO4 and concentrated under reduced pressure to afford the crude product, which was purified by HPLC (10-50% CH3CN in water) to afford the desired product as a white solid (1.75 g, 74% yield). 1 H NMR (400MHz, CDCl3): δ10.84 (s, 1H), 7.71 (d, J = 8.0Hz, 2H), 7.53 (d, J = 8.0Hz, 2H),7.09-7.03(m,1H),6.98-6.92(m,3H),4.57(d,J=13.2Hz,1H),4.45-4.32 (m,1H),4.13(d,J=14.0Hz,1H),3.98-3.85(m,2H),3.19(t,J=12.0Hz,1H),2. 71(t,J=12.0Hz,1H),2.16-2.01(m,2H),1.68(m,t,J=12.0Hz,2H).MS(ESI)m / z 404.1[M+H] + ,Purity:92.4%@254nm,99.7%@214nm.

[1328] Example 16. 2-(4-Fluorobenzyl)-8-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-4H-quinolizin-4-one (X9)

[1329]

[1330] Step 16.1. Synthesis of 2-(4-fluorobenzyl)-8-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-4H-quinolizin-4-one (X9)

[1331]

[1332] 2-(4-Fluorobenzyl)-4-oxo-4H-quinolizin-8-yl trifluoromethanesulfonate (2.54 g, 6.32 mmol), tert-butyl (2-aminophenyl)carbamate (1.97 g, 9.48 mmol), Cs2CO3 (4.12 g, 9.11 mmol), BINAP (390 mg, 0.63 mmol), and Pd2(dba)3 (270 mg, 0.32 mmol) were stirred in dioxane (70 mL) at 90°C under nitrogen for 2 hours. The reaction mixture was diluted with dioxane (0.02 M) and stirred at 110°C for 5 hours. The reaction mixture was cooled to rt, the solvent was filtered off, and the filter cake was dissolved in EA and rinsed with water. The EA layer was dried and concentrated to give the crude product, which was recrystallized from EA to obtain the desired compound (1.57 g, 64% yield) as a yellow solid. 1 H NMR (400MHz, DMSO-d6) δ11.41(s,1H),8.97(d,J=8.0Hz,1H),7.89(d,J=2.4Hz,1H),7.44(dd,J=8.0,2.4H z,1H),7.41–7.26(m,3H),7.21–7.00(m,5H),6.79(s,1H),6.33(d,J=1.2Hz,1H),3.95(s,2H).MS(ESI)m / z 386.1[M+H] + ,Purity:98.3%@254nm,98.9%@214nm.

[1333] Example 17. 4-(Trifluoromethyl)-1-(1-(2-(4-(trifluoromethyl)phenyl)acetyl)piperidin-4-yl)-1H-benzo[d]imidazol-2(3H)-one (GEN1-001)

[1334]

[1335] Step 17.1. Synthesis of tert-butyl 4-((2-nitro-3-(trifluoromethyl)phenyl)amino)piperidine-1-carboxylate (GEN1-001-1)

[1336]

[1337] 1-Fluoro-2-nitro-3-(trifluoromethyl)benzene (1.50 g, 6.60 mmol), tert-butyl 4-aminopiperidine-1-carboxylate (1.60 g, 8.00 mmol), K2CO3 (1.80 g, 130 mmol), and KI (12 mg, 0.07 mmol) were suspended in DMF (12 mL) and stirred at 120°C for 20 hours. The reaction mixture was cooled, poured into 60 mL of water, and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with 30 mL of brine, dried over MgSO4, and concentrated. The crude product was purified by silica gel column chromatography (PE:EtOAc = 5:1 to 3:1) to afford the desired compound (360 mg, 14% yield) as an orange solid. MS (ESI) Rt = 1.85 min, m / z no [M+H] + found, purity: 100%@254nm, 76.33%@214nm.

[1338] Step 17.2. Synthesis of tert-butyl 4-((2-amino-3-(trifluoromethyl)phenyl)amino)piperidine-1-carboxylate (GEN1-001-2)

[1339]

[1340] A suspension of tert-butyl 4-((2-nitro-3-(trifluoromethyl)phenyl)amino)piperidine-1-carboxylate (360 mg, 0.924 mmol), zinc powder (362 mg, 5.54 mmol), and NH4Cl (494 mg, 9.23 mmol) was stirred in methanol (5 ml) at 55°C overnight. The reaction mixture was filtered and the filtrate was concentrated. The residue was partitioned between water (30 ml) and ethyl acetate (30 ml). The aqueous layer was extracted with EtOAc (30 ml x 3), and the combined organic layers were washed with brine (30 ml), dried over MgSO4, filtered, and concentrated to give the desired compound (320 mg, 96% yield) as a brown solid. 1 HNMR (400MHz, CDCl3): δ7.01 (d, J = 8.0Hz, 1H), 6.85-6.77 (m, 2H), 4.14-3.98 (m, 2H), 3.94 (s, 2H), 3. 42-3.32(m,1H),3.14(s,1H),2.98-2.92(m,2H),2.02-1.99(m,2H),1.47(s,9H),1.41-1.35(m,2H).

[1341] Step 17.3. Synthesis of tert-butyl 4-(2-oxo-4-(trifluoromethyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-1-carboxylate (GEN1-001-3)

[1342]

[1343] To a suspension of tert-butyl 4-((2-amino-3-(trifluoromethyl)phenyl)amino)piperidine-1-carboxylate (260 mg, 0.723 mmol) and NaHCO₃ (182 mg, 2.17 mmol) in DCM (10 ml) was added triphosgene (215 mg, 0.723 mmol) under ice-cooling. The resulting mixture was stirred overnight. The reaction mixture was poured into 50 mL of water and extracted with DCM (30 mL x 3). The combined organic layers were washed with brine (30 mL), dried over MgSO₄, filtered, and concentrated to afford the desired compound (210 mg, 75% yield) as a brown solid. MS (ESI) Rt = 1.66 min, m / z 286.0 [M+H-Boc] + ,Purity:34%@254nm,49%@214nm.

[1344] Step 17.4. Synthesis of 1-(piperidin-4-yl)-4-(trifluoromethyl)-1H-benzo[d]imidazol-2(3H)-one (GEN1-001-4)

[1345]

[1346] Tert-butyl 4-(2-oxo-4-(trifluoromethyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-1-carboxylate (210 mg, 0.545 mmol) was added to DCM (4.5 mL), and TFA (1.5 mL) was added at room temperature and stirred overnight. The reaction mixture was concentrated, and the residue was dissolved in DCM (10 mL). Na2CO3 (sat., 20 mL) was added to the solution and stirred for 15 min. The mixture was extracted with DCM (20 mL x 3). The combined organic layers were dried over MgSO4, filtered, and concentrated to afford the desired compound (76 mg, 49% yield) as a brown oil. MS (ESI) Rt = 1.29 min, m / z 286.2 [M+H] + ,Purity:41%@254nm,81%@214nm.

[1347] Step 17.5. Synthesis of 4-(trifluoromethyl)-1-(1-(2-(4-(trifluoromethyl)phenyl)acetyl)piperidin-4-yl)-1H-benzo[d]imidazol-2(3H)-one (GEN1-001)

[1348]

[1349] To a solution of 1-(piperidin-4-yl)-4-(trifluoromethyl)-1H-benzo[d]imidazol-2(3H)-one (76 mg, 0.27 mmol), 2-(4-(trifluoromethyl)phenyl)acetic acid (55 mg, 0.27 mmol), and DIEA (105 mg, 0.810 mmol) in DMF (2 mL) was added HATU (156 mg, 0.410 mmol) portionwise at room temperature. The resulting mixture was stirred at room temperature for 1.5 hours. The reaction mixture was poured into 50 mL of water and extracted with EtOAc (25 mL 3). The combined organic layers were washed with brine (25 mL), dried over MgSO4, filtered, and concentrated. The crude product was purified by pre-treatment thin-layer chromatography (DCM:MeOH = 15:1) to afford the desired compound (32.6 mg, 26% yield) as a white solid. 1 H NMR (400MHz, CDCl3) δ8.43 (s, 1H), 7.64 (d, J = 8.0Hz, 2H), 7.46 (d, J = 8.0Hz, 2H), 7.28-7. 26(m,1H),7.11(t,J=8.0Hz,1H),6.99(d,J=8.0Hz,1H),4.91-4.88(m,1H),4.56-4.47(m, 1H),4.08-4.05(m,1H),3.87(s,2H),3.24-3.16(m,1H),2.75-2.68(m,1H),2.29-2.18(m ,1H),2.06-1.95(m,1H),1.91-1.88(m,1H),1.82-1.79(m,1H).MS(ESI)Rt=3.942min,m / z 472.2[M+H] + ,Purity:95.72@254nm,99.61%@214nm.

[1350] Example 18. 4-Methoxy-1-(1-(2-(4-(trifluoromethyl)phenyl)acetyl)piperidin-4-yl)-1H-benzo[d]imidazol-2(3H)-one (GEN1-003)

[1351]

[1352] Step 18.1. Synthesis of tert-butyl 4-((3-methoxy-2-nitrophenyl)amino)piperidine-1-carboxylate (GEN1-003-1)

[1353]

[1354] To a solution of 1-fluoro-3-methoxy-2-nitrobenzene (1.00 g, 5.85 mmol) and tert-butyl 4-aminopiperidine-1-carboxylate (1.29 g, 6.43 mmol) in DMSO (20 mL) was added KCO (1.61 g, 11.7 mmol). The mixture was stirred at 100°C overnight, cooled, poured into 150 mL of water, stirred for 10 minutes, and extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine (20 mL), dried over NaSO, and concentrated to yield the desired red solid (1.88 g, 92% yield). MS (ESI) Rt = 1.712 min, m / z 374.1 [M+Na] + ,purity:62.4%@214nm.

[1355] Step 18.2. Synthesis of tert-butyl 4-((2-amino-3-methoxyphenyl)amino)piperidine-1-carboxylate (GEN1-003-2)

[1356]

[1357] Tert-butyl 4-((3-methoxy-2-nitrophenyl)amino)piperidine-1-carboxylate (1.85 g, 5.27 mmol) was added to a solution of THF (15 ml) and methanol (15 ml), and Pd / C (10%, 200 mg) was added. The mixture was stirred at 50° C. under a hydrogen balloon for 5 hours. The mixture was then filtered through celite. The filtrate was concentrated to the desired brown oil (1.69 g, 100% yield). MS (ESI) Rt=1.660 min, m / z 322.2 [M+H] + ,purity:68.6%@214nm.

[1358] Step 18.3. Synthesis of tert-butyl 4-(4-methoxy-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-1-carboxylate (GEN1-003-3)

[1359]

[1360] To a solution of tert-butyl 4-((2-amino-3-methoxyphenyl)amino)piperidine-1-carboxylate (1.65 g, 5.14 mmol) in DCM (50 ml) was added NaHCO 3 (4.32 g, 51.4 mmol). The mixture was cooled to 0 degrees Celsius. Then 760 mg, 2.57 mmol of triphosgene was added. The mixture was stirred at room temperature overnight. The mixture was then poured into water (50 ml) and extracted with DCM (2 x 50 ml). The combined organic layers were washed with brine (20 mL), dried over Na 2 SO 4, and concentrated. The residue was purified by silica gel column chromatography (PE:EA=3:1 to 1:1) to obtain the desired compound (1.22 g, 69% yield) as a yellow solid. 1 HNMR (400MHz, CDCl3): δ8.75-8.72(m,1H),6.99(t,J=8.4Hz,1H),6.79(d,J=8.0Hz,1H),6.63(d,J=8.0Hz,1H),4.48(t,J=8.4Hz,1H),4.36 -4.24(m,2H),3.92(s,3H),2.89-2.84(m,2H),2.34-2.26(m,2H),1.85-1.82(m,2H),1.50(s,9H).MS(ESI),Rt=1.543min,m / z370.2[M+Na] + Purity: 84.7% @ 214nm.

[1361] Step 18.4. Synthesis of 4-methoxy-1-(piperidin-4-yl)-1H-benzo[d]imidazol-2(3H)-one (GEN1-003-4)

[1362]

[1363] Tert-butyl 4-(4-methoxy-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-1-carboxylate (200 mg, 0.58 mmol) and TFA (1 mL) were added to DCM (2 mL). The mixture was stirred at 30°C for 1 hour. The mixture was concentrated. The residue was diluted with water (2 mL) and aqueous Na2CO3 solution (sat., 5 mL) was added. The mixture was extracted with DCM:MeOH = 10:1 (4 x 10 mL). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, and concentrated to the desired compound (110 mg, yield: 77%) as a white solid. MS (ESI) Rt = 1.048 min, m / z 248.1 [M+H] + ,Purity:95.5%@214nm.

[1364] Step 18.5. Synthesis of 4-methoxy-1-(1-(2-(4-(trifluoromethyl)phenyl)acetyl)piperidin-4-yl)-1H-benzo[d]imidazol-2(3H)-one (GEN1-003)

[1365]

[1366] To a solution of 2-(4-(trifluoromethyl)phenyl)acetic acid (100 mg, 0.490 mmol) in DCM (2 mL) was added DMF (1 drop) followed by SOCl2 (106 mg, 0.89 mmol). After stirring at 20°C for 30 minutes, the mixture was concentrated. The residue was dissolved in DCM (1 mL) and used in the next step. 4-Methoxy-1-(piperidin-4-yl)-1H-benzo[d]imidazol-2(3H)-one (110 mg, 0.450 mmol) and DIEA (287 mg, 2.23 mmol) were stirred at room temperature for 10 minutes in DCM (2 mL), and the previous solution was added dropwise. The mixture was stirred at room temperature for 2 hours. The mixture was poured into water (10 mL) and extracted with DCM (3×10 mL). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, and concentrated. The crude product was purified by high performance liquid chromatography (Xbridge C18, 5um, 19x 150mm, 20-70% B, A:H2O (0.1% NH4HCO3), B:CH3CN, uv=214nm, F=15mL / min) to give the desired compound (110mg, yield 57%) as a white solid. 1 H NMR (400MHz, CDCl3): δ8.19(s,1H),7.63(d,J=8.0Hz,2H),7.45(d,J=8.0Hz,2H),6.95(t,J=8.4 Hz,1H),6.63(d,J=8.4Hz,2H),6.50(d,J=8.0Hz,2H),4.87(d,J=13.2Hz,1H),4.54-4.58(m,1H) ,4.04(d,J=13.6Hz,1H),3.90(s,3H),3.86(s,2H),3.22-3.15(m,H),2.74-2.67(m,1H),2.28-2 .17(m,1H),2.05-1.95(m,1H),1.90-1.87(m,1H),1.80-1.78(m,1H).MS(ESI)Rt=3.448min,m / z 434.2[M+H] + ,Purity:99.0%@254nm,99.6%@214nm.

[1367] Example 19. 5-(Trifluoromethyl)-1-(1-(2-(4-(trifluoromethyl)phenyl)acetyl)piperidin-4-yl)-1H-benzo[d]imidazol-2(3H)-one (GEN1-005)

[1368]

[1369]

[1370] Step 19.1. Synthesis of tert-butyl 4-((2-nitro-4-(trifluoromethyl)phenyl)amino)piperidine-1-carboxylate (GEN1-005-1)

[1371]

[1372] 1-Fluoro-2-nitro-4-(trifluoromethyl)benzene (1.00 g, 4.80 mmol), tert-butyl 4-aminopiperidine-1-carboxylate (961 mg, 4.80 mmol), and KCO (995 mg, 7.20 mmol) were suspended in DMF (10 mL) and stirred at 85°C for 2 hours. After cooling to room temperature, the reaction mixture was poured into water (50 mL) and extracted with EtOAc (25 mL x 3). The combined organic layers were washed with water (25 mL), brine (25 mL), dried over MgSO, and concentrated to yield the desired compound (1.86 g, 100% yield) as a yellow solid. 1 HNMR (400MHz, CDCl3): δ8.48(d,J=1.2Hz,1H),8.31(d,J=7.6Hz,1H),7.61(dd,J=9.2,2.0Hz,1H),6.97(d,J=9.2Hz ,1H),4.06-4.03(m,2H),3.76-3.67(m,1H),3.09-3.04(m,2H),2.09-2.04(m,2H),1.61-1.54(m,2H),1.48(s,9H).

[1373] Step 19.2. Synthesis of tert-butyl 4-((2-amino-4-(trifluoromethyl)phenyl)amino)piperidine-1-carboxylate (GEN1-005-2)

[1374]

[1375] Tert-butyl 4-((2-nitro-4-(trifluoromethyl)phenyl)amino)piperidine-1-carboxylate (1.86 g, 4.78 mmol) was suspended in methanol (15 ml) and Pd / C (10%, 186 mg) was added under a nitrogen atmosphere. The resulting mixture was stirred at 35°C under a hydrogen atmosphere overnight. The reaction mixture was filtered and the filtrate was concentrated to provide the desired compound (1.60 g, 93% yield) as a gray solid. 1 HNMR (400MHz, CDCl3): δ7.08-7.06(m,1H),6.94(d,J=2.0Hz,1H),6.65(d,J=8.4Hz,1H),4.06-4.0 4(m,2H),3.70-3.24(m,4H),3.00-2.94(m,2H),2.06-2.02(m,2H),1.47(s,9H),1.47-1.36(m,2H).

[1376] Step 19.3. Synthesis of tert-butyl 4-(2-oxo-5-(trifluoromethyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-1-carboxylate (GEN1-005-3)

[1377]

[1378] To a suspension of tert-butyl 4-((2-amino-4-(trifluoromethyl)phenyl)amino)piperidine-1-carboxylate (500 mg, 1.39 mmol) and NaHCO₃ (584 mg, 6.95 mmol) in DCM (25 ml) was added triphosgene (206 mg, 0.694 mmol). The resulting mixture was stirred for 2 hours. The reaction mixture was poured into water (50 mL) and extracted with DCM (25 mL 3). The combined organic layers were washed with brine (25 mL), dried over MgSO₄, and concentrated to afford the desired compound (530 mg, 99% yield) as a white solid. 1 HNMR (400MHz, CDCl3): δ9.87(s,1H),7.38(s,1H),7.35(d,J=8.8Hz,1H),7.20(d,J=8.4Hz,1H),4.54- 4.45(m,1H),4.36-4.33(m,2H),2.92-2.85(m,2H),2.38-2.27(m,2H),1.87-1.84(m,2H),1.52(s,9H).

[1379] Step 19.4. Synthesis of 1-(piperidin-4-yl)-5-(trifluoromethyl)-1H-benzo[d]imidazol-2(3H)-one (GEN1-005-4)

[1380]

[1381] tert-Butyl 4-(2-oxo-5-(trifluoromethyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-1-carboxylate (530 mg, 1.38 mmol) was added to DCM (6 mL), and TFA (2 mL) was added at room temperature. The resulting mixture was stirred overnight. The reaction mixture was concentrated, and the residue was dissolved in DCM (10 mL). Na2CO3 (10 mL) was added to the solution and stirred for 20 minutes. The mixture was extracted with DCM (25 mL x 3). The combined organic layers were washed with brine (25 mL), dried over MgSO4, and concentrated to give the desired compound (368 mg, 93% yield) as a white solid. 1 HNMR (400MHz, CDCl3): δ7.39-7.36(m,3H),4.52-4.42(m,1H),3.34-3.31(m,2H),2.88-2.82(m,2H),2.46-2.35(m,2H),1.89-1.86(m,2H).

[1382] Step 19.5. Synthesis of 5-(trifluoromethyl)-1-(1-(2-(4-(trifluoromethyl)phenyl)acetyl)piperidin-4-yl)-1H-benzo[d]imidazol-2(3H)-one (GEN1-005)

[1383]

[1384] 1-(Piperidin-4-yl)-5-(trifluoromethyl)-1H-benzo[d]imidazol-2(3H)-one (70 mg, 0.25 mmol), 2-[4-(trifluoromethyl)phenyl]acetic acid (60 mg, 0.29 mmol), and DIEA (95 mg, 0.74 mmol) were added to DMF (2 mL). HATU (140 mg, 0.368 mmol) was added gradually at room temperature. The resulting mixture was stirred at room temperature for 1.5 hours. The reaction mixture was purified by HPLC (Xbridge C18 5μm 19*150 mm; B, A: H2O (0.1% NH4HCO3), B: CH3CN; UV: 214 nm, flow rate: 15 ml / min) to afford the desired compound (37.2 mg, 32% yield) as a white solid. 1H NMR (400MHz, CDCl3) δ7.94(s,1H),7.64(d,J=8.0Hz,2H),7.46(d,J=8.0Hz,2H),7.34(s,1H) ,7.31(d,J=8.4Hz,1H),6.93(d,J=8.4Hz,1H),4.93-4.90(m,1H),4.59-4.47(m,1H),4.10-4. 06(m,1H),3.88(s,2H),3.22(t,J=12.8Hz,1H),2.73(t,J=12.8Hz,1H),2.32-2.21(m,1H),2. 09-1.98(m,1H),1.92-1.89(m,1H),1.84-1.81(m,1H).MS(ESI)Rt=3.296min,m / z472.1[M+H] + ,Purity:98.62@254nm,99.24%@214nm.

[1385] Example 20. 2-Oxo-1-(1-(2-(4-(trifluoromethyl)phenyl)acetyl)piperidin-4-yl)-2,3-dihydro-1H-benzo[d]imidazole-5-carbonitrile (GEN1-006)

[1386]

[1387]

[1388] Step 20.1. Synthesis of tert-butyl 4-((4-cyano-2-nitrophenyl)amino)piperidine-1-carboxylate (GEN1-006-1)

[1389]

[1390] To a solution of 4-chloro-3-nitrobenzonitrile (1.00 g, 5.50 mmol), tert-butyl 4-aminopiperidine-1-carboxylate (1.1 g, 5.50 mmol), and KCO (1.14 g, 8.25 mmol) in DMF (20 mL) was added KI (40 mg, 0.275 mmol). After stirring at 95°C for 12 hours, the mixture was cooled to room temperature and poured into water (50 ml). EtOAc (30 x 2 ml) was added to extract the desired compound. The combined organic layers were washed with brine, dried over NaSO, and concentrated to give the desired compound (1.7 g, 90% yield) as a yellow solid. 1H NMR (400MHz, CDCl3): δ8.52(d,J=2.0Hz,1H),8.43(d,J=7.6Hz,1H),7.60(dd,J=8.8,1.6Hz,1H),6.94(d,J=9.2Hz,1 H), 4.05 (d, J = 12.0Hz, 2H), 3.73-3.70 (m, 1H), 3.07-3.02 (m, 2H), 2.08-2.04 (m, 2H), 1.63-1.60 (m, 2H), 1.55 (s, 9H).

[1391] Step 20.2. Synthesis of tert-butyl 4-((4-cyano-2-aminophenyl)amino)piperidine-1-carboxylate (GEN1-006-2)

[1392]

[1393] Zinc powder (416 mg, 6.40 mmol) was added to a solution of tert-butyl 4-((4-cyano-2-nitrophenyl)amino)piperidine-1-carboxylate (560 mg, 1.60 mmol) and NH4Cl (428 mg, 8 mmol) in MeOH (5 mL). The reaction mixture was stirred at 35°C for 12 hours. The reaction mixture was then filtered, and the filtrate was concentrated to afford the desired product (482 mg, 94% yield) as a red oil. 1 HNMR (400MHz, CDCl3): δ7.15 (dd, J=8.4, 2.0Hz, 2H), 6.95 (d, J=1.6Hz, 1H), 6.60 (d, J=8.0Hz, 1H), 4 .11-4.06(m,3H),3.48(s,1H),3.28(s,2H),2.96(t,J=11.2Hz,2H),2.05-2.03(m,2H),1.49(s,9H).

[1394] Step 20.3. Synthesis of tert-butyl 4-(5-cyano-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-1-carboxylate (GEN1-006-3)

[1395]

[1396] tert-Butyl 4-((4-cyano-2-aminophenyl)amino)piperidine-1-carboxylate (482 mg, 1.50 mmol) and NaHCO 3 (639 mg, 1.5 mmol) were added to DCM (6 ml), and triphosgene (452 ​​mg, 1.50 mmol) was added and reacted under ice bath. The reaction mixture was stirred at room temperature for 2 hours. The mixture was then poured into water (10 ml) and extracted with DCM (10 x 2 ml). The combined organic layers were rinsed with brine, dried over Na 2 SO 4 , and concentrated to give the desired compound (314 mg, 60% yield) as a gray solid. MS (ESI): Rt = 0.32 min, m / z 243.0 [M + H-Boc] + Purity: 90% @ 254nm, 85% @ 214nm.

[1397] Step 20.4. Synthesis of 2-oxo-1-(piperidin-4-yl)-2,3-dihydro-1H-benzo[d]imidazole-5-carbonitrile (GEN1-006-4)

[1398]

[1399] tert-Butyl 4-(5-cyano-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-1-carboxylate (314 mg, 0.920 mmol) and TFA (1 mL) were added to DCM (2 ml). The reaction mixture was stirred at room temperature for 12 hours. The mixture was concentrated to give a crude product. Water (2 ml) was added and the pH was adjusted to 9 with saturated aqueous Na2CO3 solution (5 ml). The mixture was extracted with DCM (10 x 4 mL). The combined organic layers were dried and concentrated to give the desired product (80 mg, 36% yield) as a white solid. MS (ESI) Rt = 0.87 min, m / z 243.0, [M+H] + Purity: 76% @ 254nm, 81% @ 214nm.

[1400] Step 20.5. Synthesis of 2-oxo-1-(1-(2-(4-(trifluoromethyl)phenyl)acetyl)piperidin-4-yl)-2,3-dihydro-1H-benzo[d]imidazole-5-carbonitrile (GEN1-006)

[1401]

[1402] To a solution of 2-oxo-1-(piperidin-4-yl)-2,3-dihydro-1H-benzo[d]imidazole-5-carbonitrile (75 mg, 0.31 mmol), 2-(4-(trifluoromethyl)phenyl)acetic acid (63 mg, 0.31 mmol), and HATU (175 mg, 0.46 mmol) in DMF (3 mL) was added DIEA (120 mg, 0.93 mmol). The reaction mixture was stirred at room temperature for 12 hours. Purification was performed directly on a C18 column (CH3CN:water = 5% to 50%) to afford the desired product (70 mg, 53% yield) as a yellow solid. 1 H NMR (400MHz, CDCl3): δ8.96(s,1H),7.63(d,J=8.0Hz,2H),7.44(d,J=8.0Hz,2H),7.36(dd ,J=8.0,1.2Hz,1H),7.32(d,J=1.2Hz,1H),6.93(d,J=8.0Hz,1H),4.93-4.89(m,1H),4.53 -4.44(m,1H),4.10-4.06(m,1H),3.87(s,2H),3.20(t,J=13.6Hz,1H),2.72(t,J=13.6Hz, 1H),2.30-2.19(m,1H),2.09-1.97(m,1H),1.90-1.80(m,2H).MS(ESI),Rt=3.748min,m / z 429.1[M+H] + ,Purity:92.24%@254nm,95.70%@214nm.

[1403] Example 21. 5-Methoxy-1-(1-(2-(4-(trifluoromethyl)phenyl)acetyl)piperidin-4-yl)-1H-benzo[d]imidazol-2(3H)-one (GEN1-007)

[1404]

[1405] Step 21.1. Synthesis of tert-butyl 4-((4-methoxy-2-nitrophenyl)amino)piperidine-1-carboxylate (GEN1-007-1)

[1406]

[1407] To a solution of 1-fluoro-4-methoxy-2-nitrobenzene (1.00 g, 5.85 mmol) and tert-butyl 4-aminopiperidine-1-carboxylate (1.29 g, 6.43 mmol) in DMSO (15 mL) was added KCO (1.61 g, 11.7 mmol). After stirring at 90°C for 15 hours, the mixture was cooled to room temperature, poured into 100 mL of water, stirred for 10 minutes, and extracted with ethyl acetate (3 x 30 mL). The combined organic layers were washed with aqueous hydrochloric acid (1 M, 30 mL) and brine (30 mL), dried over NaSO, and concentrated to afford the desired compound (1.98 g, 97% yield) as a red solid. MS (ESI) Rt = 1.746 min, m / z 296.1 [Mt-Bu+2H] + , purity: 78.6%@214nm.

[1408] Step 21.2. Synthesis of tert-butyl 4-((2-amino-4-methoxyphenyl)amino)piperidine-1-carboxylate (GEN1-007-2)

[1409]

[1410] To a solution of tert-butyl 4-((4-methoxy-2-nitrophenyl)amino)piperidine-1-carboxylate (1.95 g, 5.56 mmol) in THF (15 ml) and methanol (15 ml) was added Pd / C (10%, 200 mg). The mixture was stirred under a hydrogen balloon at 50°C for 5 hours and filtered through Celite. The filtrate was concentrated to give the desired compound (1.78 g, yield: 100%) as a brown oil. MS (ESI) Rt = 1.598 min, m / z 322.2 [M+H] + ,purity:71.4%@214nm.

[1411] Step 21.3. Synthesis of tert-butyl 4-(5-methoxy-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-1-carboxylate (GEN1-007-3)

[1412]

[1413] To a solution of tert-butyl 4-((2-amino-4-methoxyphenyl)amino)piperidine-1-carboxylate (1.75 g, 5.45 mmol) in DCM (50 ml) was added NaHCO 3 (4.58 g, 54.5 mmol). The mixture was cooled to 0 degrees Celsius. Triphosgene (810 mg, 2.73 mmol) was added stepwise. The mixture was stirred at room temperature overnight. The mixture was poured into water (50 ml) and extracted with DCM (3×20 ml). The combined organic layers were washed with brine (20 mL), dried over Na 2 SO 4, and concentrated. The residue was purified by silica gel column chromatography (PE:EA=2:1~1:1) to give the desired compound (1.05 g, yield 56%) as a yellow solid. 1 HNMR (400MHz, CDCl3): δ10.21-9.96(m,1H),7.01(d,J=8.8Hz,1H),6.74(d,J=2.0Hz,1H),6.62(dd,J=8.8,2.4Hz,1H),4.50-4.41(m,1H),4. 33-4.31(m,2H),3.80(s,3H),2.90-2.85(m,2H),2.35-2.24(m,2H),1.85-1.82(m,2H),1.51(s,9H).MS(ESI)Rt=1.508min,m / z370.2[M+Na] + ,purity:54.9%@214nm.

[1414] Step 21.4. Synthesis of 5-methoxy-1-(piperidin-4-yl)-1H-benzo[d]imidazol-2(3H)-one (GEN1-007-4)

[1415]

[1416] Tert-butyl 4-(5-methoxy-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-1-carboxylate (200 mg, 0.58 mmol) and TFA (1 mL) were added to DCM (2 mL). The mixture was stirred at 30°C for 1 hour. The mixture was concentrated. The residue was diluted with water (2 mL) and an aqueous Na2CO3 solution (sat., 5 mL) was added. The mixture was extracted with DCM:MeOH = 10:1 (4 x 20 mL). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, and concentrated to the desired yellow solid (120 mg, 85% yield). MS (ESI) Rt = 0.767 min, m / z 248.1 [M+H] + ,Purity:95.7%@214nm.

[1417] Step 21.5. Synthesis of 5-methoxy-1-(1-(2-(4-(trifluoromethyl)phenyl)acetyl)piperidin-4-yl)-1H-benzo[d]imidazol-2(3H)-one (GEN1-007)

[1418]

[1419] To a solution of 2-(4-(trifluoromethyl)phenyl)acetic acid (109 mg, 0.53 mmol) in DCM (2 mL) was added DMF (1 drop). SOCl2 (116 mg, 0.97 mmol) was added. After stirring at 20 ° C for 30 minutes, the mixture was concentrated. The residue was dissolved in DCM (1 ml) and used in the next step. 5-Methoxy-1-(piperidin-4-yl)-1H-benzo[d]imidazol-2(3H)-one (120 mg, 0.490 mmol) and DIEA (313 mg, 2.43 mmol) were stirred at room temperature for 5 minutes in DCM (2 ml), and the previous solution was added dropwise. The mixture was stirred at room temperature for 2 hours. The mixture was poured into water (20 ml) and extracted with DCM (3×10 ml). The combined organic layers were washed with brine (10 ml), dried over Na2SO4, and concentrated. The residue was purified by high performance liquid chromatography (Xbridge C18, 5um, 19x 150mm, 20-70% B, A:H2O (0.1% NH4HCO3), B:CH3CN, uv=214nm, F=15mL / min) to give the desired compound (105mg, yield 50%) as a white solid. 1 H NMR (400MHz, CDCl3): δ9.53 (s, 1H), 7.63 (d, J = 8.0Hz, 2H), 7.46 (d, J = 8.4Hz, 2H), 6.7 3-6.69(m,2H),6.59-6.56(m,1H),4.88(d,J=13.6Hz,1H),4.52-4.46(m,1H),4.05(d ,J=14.4Hz,1H),3.87(s,2H),3.79(s,3H),3.23-3.17(m,1H),2.75-2.69(m,1H),2.2 6-2.17(m,1H),2.04-1.95(m,1H),1.90-1.87(m,1H),1.82-1.78(m,1H).MS(ESI)m / z 434.2[M+H] + ,Rt=3.553min,Purity:98.6%@254nm,99.6%@214nm.

[1420] Example 22. 2-Oxo-3-(1-(2-(4-(trifluoromethyl)phenyl)acetyl)piperidin-4-yl)-2,3-dihydro-1H-benzo[d]imidazole-5-carbonitrile (GEN1-010)

[1421]

[1422] Step 22.1. Synthesis of tert-butyl 4-((5-cyano-2-nitrophenyl)amino)piperidine-1-carboxylate (GEN1-010-1)

[1423]

[1424] To a mixture of 3-fluoro-4-nitrobenzonitrile (1.0 g, 6.0 mmol), tert-butyl 4-aminopiperidine-1-carboxylate (1.1 g, 6.0 mmol), and K2CO3 (2.4 g, 18 mmol) in DMF (15 mL) was added KI (50 mg, 0.3 mmol). The resulting mixture was stirred at 95°C for 12 hours. The mixture was cooled to room temperature, poured into water (50 mL), and extracted with EtOAc (30 x 2 mL). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated to the desired yellow solid (2.0 g, 95% yield). 1 H NMR (400MHz, CDCl3): δ8.27(d,J=8.8Hz,1H),8.06(d,J=7.6Hz,1H),7.17(d,J=1.2Hz,1H),6.87(dd,J=8.8,1.6Hz,1 H),4.11-4.05(m,2H),3.69-3.60(m,1H),3.06(t,J=11.2Hz,2H),2.08-2.04(m,2H),1.58-1.52(m,2H),1.48(s,9H).

[1425] Step 22.2. Synthesis of tert-butyl 4-((2-amino-5-cyanophenyl)amino)piperidine-1-carboxylate (GEN1-010-2)

[1426]

[1427] Zinc powder (905 mg, 13.9 mmol) was added to a solution of tert-butyl 4-((5-cyano-2-nitrophenyl)amino)piperidine-1-carboxylate (1.1 g, 3.5 mmol) and NH4Cl (910 mg, 17.4 mmol) in MeOH (15 mL). The reaction mixture was stirred at 35°C for 12 hours. The reaction mixture was filtered, and the filtrate was concentrated to the desired product (930 mg, 93% yield) as a red solid. MS (ESI): Rt = 1.58 min, m / z 217.1, [M+H–Boc] + Purity: 91% @ 254nm, 86% @ 214nm

[1428] Step 22.3. Synthesis of tert-butyl 4-(6-cyano-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-1-carboxylate (GEN1-010-3)

[1429]

[1430] To tert-butyl 4-((2-amino-5-cyano)amino)piperidine-1-carboxylate (500 mg, 1.58 mmol) and NaHCO₃ (1.32 g, 15.8 mmol) in DCM (10 ml) was added portionwise under ice-cooling conditions. The reaction mixture was stirred at room temperature for 2 hours. The mixture was poured into 10 mL of water and extracted with DCM (10 × 2 mL). The combined organic layers were washed with brine, dried over Na₂SO₄, and concentrated to the desired compound (480 mg, 88% yield) as a white solid. MS (ESI): Rt = 1.48 min, m / z 243.0, [M+H–Boc] + Purity: 100% @ 254nm, 100% @ 214nm.

[1431] Step 22.4. 2-Oxo-3-(piperidin-4-yl)-2,3-dihydro-1H-benzo[d]imidazole-5-carbonitrile (GEN1-010-4)

[1432]

[1433] Tert-butyl 4-(6-cyano-2-oxy-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-1-carboxylate (480 mg, 1.40 mmol) and TFA (1 mL) were added to DCM (4 ml). The reaction mixture was stirred at room temperature for 12 hours. The mixture was concentrated and the residue was dissolved in water (2 ml). The aqueous solution was basified to pH = 9 with aqueous Na2CO3 solution (sat., 5 ml) and extracted with DCM (10 × 4 ml). The combined organic layers were dried over Na2SO4 and concentrated to the desired white solid (125 mg, 37% yield). MS (ESI): Rt = 0.73 min m / z 243.0, [M+H] + Purity: 100% @ 254nm, 100% @ 214nm.

[1434] Step 22.5. Synthesis of 2-oxo-3-(1-(2-(4-(trifluoromethyl)phenyl)acetyl)piperidin-4-yl)-2,3-dihydro-1H-benzo[d]imidazole-5-carbonitrile (GEN1-010)

[1435]

[1436] To a solution of 2-oxo-3-(piperidin-4-yl)-2,3-dihydro-1H-benzo[d]imidazole-5-carbonitrile (75 mg, 0.31 mmol), 2-(4-(trifluoromethyl)phenyl)acetic acid (63 mg, 0.31 mmol), and HATU (175 mg, 0.460 mmol) in DMF (3 mL) was added DIEA (120 mg, 0.929 mmol). The reaction mixture was stirred at room temperature for 12 hours. The mixture was purified using a C18 column (CH3CN:water = 5% to 50%) to obtain the desired compound (80 mg, 60% yield) as a white solid. 1 H NMR (400MHz, DMSO-d6): δ11.44(s,1H),7.73-7.68(m,3H),7.51(d,J=8.4Hz,2H),7.44(dd,J=8.0,1.2Hz,1H),7.11(d,J=8.0Hz,1H),4.58(d,J=1 3.6Hz,1H),4.48-4.42(m,1H),4.11(d,J=13.2Hz,1H),3.92-3.91(m,2H ),3.16(t,J=12.8Hz,1H),2.72-2.67(m,1H),2.21-2.12(m,2H),1.72(br s,2H).MS(ESI):Rt=3.55min,m / z 429.2[M+H] + ,Purity:97.98%@254nm,99.10%@214nm.

[1437] Example 23. 6-Methoxy-1-(1-(2-(4-(trifluoromethyl)phenyl)acetyl)piperidin-4-yl)-1H-benzo[d]imidazol-2(3H)-one (GEN1-011)

[1438]

[1439] Step 23.1. Synthesis of tert-butyl 4-((5-methoxy-2-nitrophenyl)amino)piperidine-1-carboxylate (GEN1-011-1)

[1440]

[1441] A solution of 2-fluoro-4-methoxy-1-nitrobenzene (500 mg, 2.92 mmol) and tert-butyl 4-aminopiperidine-1-carboxylate (702 mg, 3.51 mmol) was added to DMSO (15 ml), followed by the addition of K2CO3 (807 mg, 5.85 mmol). After stirring at 90°C for 6 hours, the mixture was cooled and poured into water (100 ml). After stirring for 10 minutes, the mixture was filtered. The filter cake was washed with water (2 x 20 ml) and dissolved in ethyl acetate (50 ml). The organic solution was washed with aqueous hydrochloric acid (1 M, 20 mL) and brine (20 mL), dried over Na2SO4, and concentrated to give the desired compound (1.01 g, 98% yield) as a yellow solid. 1 H NMR (300MHz, CDCl3): δ8.34(d,J=7.2Hz,1H),8.17(d,J=9.6Hz,1H),6.25(dd,J=9.6,1.5Hz,1H),6.18(s,1H),4.02-3. 98(m,2H),3.87(s,3H),3.66-3.58(m,1H),3.08(t,J=11.7Hz,2H),2.08-2.04(m,2H),1.55-1.51(m,2H),1.48(s,9H).

[1442] Step 23.2. Synthesis of tert-butyl 4-((2-amino-5-methoxyphenyl)amino)piperidine-1-carboxylate (GEN1-011-2)

[1443]

[1444] Pd / C (10%, 200 mg) was added to a solution of tert-butyl 4-((5-methoxy-2-nitrophenyl)amino)piperidine-1-carboxylate (1.00 g, 2.85 mmol) in THF (5 mL) and methanol (15 mL). The mixture was stirred at 50°C under a hydrogen balloon for 6 hours. The mixture was filtered through Celite. The filtrate was concentrated to provide the desired compound (910 mg, 100% yield) as a brown solid. 1 H NMR (400MHz, CDCl3): δ6.67(d,J=8.4Hz,1H),6.25(d,J=2.4Hz,1H),6.18(dd,J=8.0,2.4Hz,1H),4.02-3.99( m,2H),3.75(s,3H),3.40-3.35(m,1H),2.95-2.92(m,2H),2.05-2.02(m,2H),1.47(s,9H),1.43-1.26(m,4H).

[1445] Step 23.3. Synthesis of tert-butyl 4-(6-methoxy-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-1-carboxylate (GEN1-011-3)

[1446]

[1447] To a solution of tert-butyl 4-((2-amino-5-methoxyphenyl)amino)piperidine-1-carboxylate (900 mg, 2.80 mmol) in DCM (50 ml) was added NaHCO₃ (2.36 g, 28.0 mmol). The mixture was cooled to 0°C. Then, 500 mg, 1.68 mmol of triphosgene was added. The mixture was stirred at room temperature overnight. The mixture was poured into water (50 ml) and extracted with DCM (2 x 30 ml). The combined organic layers were washed with brine (20 mL), dried over Na₂SO₄, and concentrated. The residue was purified by silica gel column chromatography (PE:EA=1:1) to obtain 820 mg of crude product. Further purification was performed by C18 column chromatography (30-60% CH₃CN aqueous solution) to obtain the desired yellow solid (510 mg, yield 52%). MS (ESI) Rt=1.532 min, m / z 370.2 [M+H] + , purity: 82.8%@214nm.

[1448] Step 23.4. Synthesis of 6-methoxy-1-(piperidin-4-yl)-1H-benzo[d]imidazol-2(3H)-one (GEN1-011-4)

[1449]

[1450] Tert-butyl 4-(6-methoxy-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-1-carboxylate (500 mg, 1.44 mmol) and TFA (1 mL) were added to DCM (2 mL). The mixture was stirred at room temperature for 3 hours. The mixture was then concentrated. The residue was diluted with 5 mL of water and 10 mL of aqueous Na2CO3. The mixture was extracted with DCM:MeOH = 10:1 (4 x 20 mL). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, and concentrated to the desired product (200 mg, 56% yield) as a brown solid. MS (ESI) Rt = 1.042 min, m / z 248.1 [M+H] + ,purity:96.1%@214nm.

[1451] Step 23.5. Synthesis of 6-methoxy-1-(1-(2-(4-(trifluoromethyl)phenyl)acetyl)piperidin-4-yl)-1H-benzo[d]imidazol-2(3H)-one (GEN1-011)

[1452]

[1453] DMF (2 drops) was added to a solution of 2-(4-(trifluoromethyl)phenyl)acetic acid in DCM (3 mL), followed by the addition of SOCl2 (193 mg, 1.62 mmol). After stirring at 20 ° C for 30 minutes, the mixture was concentrated. The concentrate was dissolved in DCM (1 ml) and directly put into the next step. 6-Methoxy-1-(piperidin-4-yl)-1H-benzo[d]imidazole-2(3H)-one (200 mg, 0.81 mmol) and DIEA (522 mg, 4.05 mmol) were stirred at room temperature for 5 minutes in DCM (2 mL), and the previous solution was added dropwise. The mixture was stirred at room temperature for 1 hour. The mixture was poured into water (20 ml) and extracted with DCM (2 x 20 ml). The combined organic layers were rinsed with brine (20 mL), dried over Na2SO4, and concentrated. The crude product was purified by high performance liquid chromatography (Xbridge C18, 5um, 19x 150mm, 20-70% B, A: H2O (0.1% NH4HCO3), B: CH3CN, uv = 214nm, F = 15mL / min) to give the desired white solid (135mg, yield 39%). 1H NMR (400MHz, CDCl3): δ9.46 (s, 1H), 7.65 (d, J = 8.0Hz, 2H), 7.45 (d, J = 8.0Hz, 2H),6.97(d,J=8.8Hz,1H),6.61(dd,J=8.8,2.4Hz,1H),6.52(d,J=2.4Hz,1H) ,4.90(d,J=13.6Hz,1H),4.51-4.45(m,1H),4.03(d,J=14.0Hz,1H),3.87(s,2 H),3.81(s,3H),3.19(t,J=12.0Hz,1H),2.71(t,J=12.0Hz,1H),2.31-2.26(m 1H),2.04-2.00(m,1H),1.90-1.87(m,1H),1.79-1.72(m,1H).MS(ESI)Rt=2.995min,m / z 434.2[M+H] + ,Purity:99.4%@254nm,99.8%@214nm.

[1454] Example 24. 7-(Trifluoromethyl)-1-(1-(2-(4-(trifluoromethyl)phenyl)acetyl)piperidin-4-yl)-1H-benzo[d]imidazol-2(3H)-one (GEN1-013)

[1455]

[1456] Step 24.1. Synthesis of tert-butyl 4-((2-nitro-6-(trifluoromethyl)phenyl)amino)piperidine-1-carboxylate (GEN1-013-1)

[1457]

[1458] 2-Fluoro-1-nitro-3-(trifluoromethyl)benzene (1.00 g, 4.80 mmol), tert-butyl 4-aminopiperidine-1-carboxylate (961 mg, 4.80 mmol), and K2CO3 (995 mg, 7.20 mmol) were suspended in DMF (10 mL) and stirred at 85°C for 2 hours. After cooling to room temperature, the reaction mixture was poured into water (50 mL) and extracted with EA (25 mL x 3). The combined organic layers were washed with water (25 mL), brine (25 mL), dried over MgSO4, and concentrated to yield the desired compound (1.86 g, 100% yield) as a yellow solid. 1HNMR (400MHz, CDCl3): δ8.08 (dd, J=8.0, 1.2Hz, 1H), 7.78 (dd, J=7.6, 1.2Hz, 1H), 6.96 (t, J=8.0Hz, 1H), 5.93 (d, J=9. 6Hz,1H),4.10-3.93(m,2H),3.46-3.36(m,1H),2.84-2.78(m,2H),1.94-1.91(m,2H),1.45(s,9H),1.39-1.29(m,2H).

[1459] Step 24.2. Synthesis of tert-butyl 4-((2-amino-6-(trifluoromethyl)phenyl)amino)piperidine-1-carboxylate (GEN1-013-2)

[1460]

[1461] Pd / C (10%, 186 mg) was added to a solution of tert-butyl 4-((2-nitro-6-(trifluoromethyl)phenyl)amino)piperidine-1-carboxylate (1.86 g, 4.78 mmol) in methanol (20 mL) under an N atmosphere. The resulting mixture was degassed with H and stirred overnight under a hydrogen atmosphere at 35°C. The reaction mixture was filtered, and the filtrate was concentrated to afford the desired compound (1.66 g, 97% yield) as a brown oil. 1 HNMR (400MHz, CDCl3): δ6.97 (dd, J=7.6, 1.6Hz, 1H), 6.92 (t, J=8.0Hz, 1H), 6.86 (dd, J=8.0, 1.6Hz, 1H), 4.11 (br s,2H),3.88(s,2H),3.38-3.24(m,2H),2.73-2.66(m,2H),1.84-1.81(m,2H),1.46(s,9H),1.40-1.31(m,2H).

[1462] Step 24.3. Synthesis of tert-butyl 4-(2-oxo-7-(trifluoromethyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-1-carboxylate (GEN1-013-3)

[1463]

[1464] To a suspension of tert-butyl 4-((2-amino-6-(trifluoromethyl)phenyl)amino)piperidine-1-carboxylate (500 mg, 1.39 mmol) and NaHCO₃ (584 mg, 6.95 mmol) in DCM (25 ml) at 7°C was added triphosgene (206 mg, 0.694 mmol). The mixture was stirred for 2 hours. The reaction mixture was poured into water (50 mL) and extracted with DCM (25 mL x 3). The combined organic layers were washed with brine (25 mL), dried over MgSO₄, and concentrated to afford the desired compound (510 mg, 95% yield) as a white solid. 1 HNMR (400MHz, CDCl3): δ10.16(s,1H),7.40(d,J=8.0Hz,1H),7.30(d,J=7.6Hz,1H),7.14 (t,J=8.0Hz,1H),4.42-4.25(m,3H),2.82-2.70(m,4H),1.76-1.73(m,2H),1.50(s,9H).

[1465] Step 24.4. Synthesis of 1-(piperidin-4-yl)-7-(trifluoromethyl)-1H-benzo[d]imidazol-2(3H)-one (GEN1-013-4)

[1466]

[1467] tert-Butyl 4-(2-oxo-7-(trifluoromethyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-1-carboxylate (510 mg, 1.32 mmol) was added to DCM (6 ml), and TFA (2 ml) was added at room temperature. The mixture was stirred at room temperature overnight. The reaction mixture was concentrated, and the residue was dissolved in DCM (10 ml). Na2CO3 (sat., 10 mL) was added to the solution, and stirred for 20 minutes. The mixture was filtered and the filter cake dried to give the desired compound (340 mg, 67% yield) as a white solid. 1 HNMR(400MHz,DMSO-d6):δ8.41(br s,1H),7.37(d,J=8.0Hz,1H),7.31(d,J=7.2Hz,1H),7.18(t,J=8.0Hz,1H),4.29-4.18(m ,1H),3.43-3.40(m,2H),2.97-2.80(m,4H),1.88-1.85(m,2H).MS(ESI)Rt=1.50min,m / z 286.3[M+H] + ,Purity:98%@254nm,100%@214nm.

[1468] Step 24.5. Synthesis of 7-(trifluoromethyl)-1-(1-(2-(4-(trifluoromethyl)phenyl)acetyl)piperidin-4-yl)-1H-benzo[d]imidazol-2(3H)-one (GEN1-013)

[1469]

[1470] 1-(Piperidin-4-yl)-7-(trifluoromethyl)-1H-benzo[d]imidazol-2(3H)-one (70 mg, 0.25 mmol), 2-[4-(trifluoromethyl)phenyl]acetic acid (60 mg, 0.29 mmol), and DIEA (95 mg, 0.74 mmol) were added to DMF (2 mL). HATU (140 mg, 0.368 mmol) was added gradually at room temperature. The resulting mixture was stirred at room temperature for 1.5 hours. The reaction mixture was purified by C18 (CH3CN:water = 5% to 50%) to afford the desired compound (53.1 mg, 46% yield) as a white solid. 1 HNMR(400MHz, CDCl3)δ9.66(s,1H),7.60(d,J=8.0Hz,2H),7.42-7.40(m,3H),7.28-7.26(m,1H),7.15(t,J=8.0Hz,1H),4.91-4.88(m,1H ),4.47-4.40(m,1H),4.05-4.02(m,1H),3.85(s,2H),3.13-3.06(m,1H),2.82-2.60(m,3H),1.85-1.80(m,2H).MS(ESI)Rt=3.437min,m / z 472.2[M+H] + ,Purity:94.12%@254nm,99.57%@214nm.

[1471] Example 25. 2-Oxo-3-(1-(2-(4-(trifluoromethyl)phenyl)acetyl)piperidin-4-yl)-2,3-dihydro-1H-benzo[d]imidazole-4-carbonitrile (GEN1-014)

[1472]

[1473] Step 25.1. Synthesis of tert-butyl 4-((2-cyano-6-nitrophenyl)amino)piperidine-1-carboxylate (GEN1-014-1)

[1474]

[1475] 2-Chloro-3-nitrobenzonitrile (875 mg, 4.80 mmol), tert-butyl 4-aminopiperidine-1-carboxylate (958 mg, 4.80 mmol), K2CO3 (993 mg, 7.18 mmol), and KI (50 mg, 0.30 mmol) were added to DMF (15 mL). The resulting mixture was stirred at 95°C for 12 hours. The mixture was cooled to room temperature, poured into water (50 mL), and extracted with EtOAc (30 × 2 mL). The organic layer was washed with brine, dried over Na2SO4, and concentrated to the desired product (1.3 g, 81% yield) as a yellow solid. 1 H NMR (400MHz, CDCl3): δ8.46 (d, J=8.4Hz, 1H), 8.41 (dd, J=8.4, 1.6Hz, 1H), 7.75 (dd, J=7.6, 2.0Hz, 1H), 6.78-6.74 (m, 1H),4.56-4.51(m,1H),4.08-4.05(m,2H),3.04(t,J=11.6Hz,2H),2.17-2.13(m,2H),1.55-1.51(m,2H),1.47(s,9H).

[1476] Step 25.2. Synthesis of tert-butyl 4-((2-amino-6-cyanophenyl)amino)piperidine-1-carboxylate (GEN1-014-2)

[1477]

[1478] To a solution of tert-butyl 4-((2-cyano-6-nitrophenyl)amino)piperidine-1-carboxylate (1.3 g, 3.8 mmol) and NH4Cl (0.81 g, 15 mmol) in MeOH (15 mL) was added Zn powder (0.73 g, 11 mmol). The reaction mixture was stirred at 35°C for 12 hours. The reaction mixture was filtered, and the filtrate was concentrated to afford the desired compound (900 mg, 76% yield) as a red oil. 1 HNMR(400MHz, CDCl3): δ6.98-6.95(m,1H),6.90-6.88(m,2H),4.23-4.00(m,2H),3.84(s,2H), 3.43-3.31(m,2H),2.77(t,J=12.4Hz,2H),1.93-1.90(m,2H),1.46(s,9H),1.43-1.36(m,2H).

[1479] Step 25.3. Synthesis of tert-butyl 4-(7-cyano-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-1-carboxylate (GEN1-014-3)

[1480]

[1481] tert-Butyl 4-((2-amino-6-cyano)amino)piperidine-1-carboxylate (900 mg, 2.85 mmol) and NaHCO₃ (2.40 g, 28.5 mmol) were added to DCM (12 ml), followed by the addition of triphosgene (592 mg, 2.28 mmol) under ice-cooling conditions. The reaction mixture was stirred at room temperature for 2 hours. The mixture was poured into 10 mL of water and extracted with DCM (10 × 2 mL). The organic layer was washed with brine, dried over Na₂SO₄, and concentrated to the desired yellow solid (680 mg, 70% yield). MS (ESI): Rt = 1.69 min, m / z 243.2 [M+H–Boc] + Purity: 100% @ 254nm, 94% @ 214nm.

[1482] Step 25.4. Synthesis of 2-oxo-3-(piperidin-4-yl)-2,3-dihydro-1H-benzo[d]imidazole-4-carbonitrile (GEN1-014-4)

[1483]

[1484] 4-(7-cyano-2-oxy-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-1-carboxylic acid tert-butyl ester (680 mg, 2.09 mmol) and TFA (5 mL) were added to DCM (10 ml). The reaction mixture was stirred at room temperature for 12 hours. The mixture was concentrated to give a crude product. The crude product was dissolved in water (2 ml) and basified to pH = 9 with aqueous Na2CO3 solution (sat.5 mL). It was extracted with DCM (10×4 mL). The combined organic layers were dried and concentrated to give the desired (170 mg, 36% yield) gray solid. MS (ESI): Rt=1.10 min, m / z 243.1, [M+H] + Purity: 100% @ 254nm, 98% @ 214nm.

[1485] Step 25.5. Synthesis of 2-oxo-3-(1-(2-(4-(trifluoromethyl)phenyl)acetyl)piperidin-4-yl)-2,3-dihydro-1H-benzo[d]imidazole-4-carbonitrile (GEN1-014)

[1486]

[1487] To a solution of 2-oxo-3-(piperidin-4-yl)-2,3-dihydro-1H-benzo[d]imidazole-4-carbonitrile (80 mg, 0.33 mmol), 2-(4-(trifluoromethyl)phenyl)acetic acid (67 mg, 0.33 mmol), and HATU (190 mg, 0.50 mmol) in DMF (3 mL) was added DIEA (129 mg, 0.998 mmol). The reaction mixture was stirred at room temperature for 12 hours. The mixture was purified using a C18 column (CH3CN:water = 5% to 50%) to afford the desired compound (80 mg, 57% yield) as a white solid. 1 H NMR (400MHz, CDCl3): δ9.79 (s, 1H), 7.59 (d, J = 8.0Hz, 2H), 7.40 (d, J = 7.6Hz, 2 H),7.35(d,J=7.6Hz,1H),7.29-7.26(m,1H),7.15(t,J=8.0Hz,1H),4.93(t,J= 14.4Hz,2H),4.05(d,J=13.6Hz,1H),3.86(s,2H),3.23(t,J=12.4Hz,1H),2.79 -2.69(m,2H),2.69-2.58(m,1H),1.97-1.94(m,2H).MS(ESI):Rt=3.71min,m / z 403.2,[M+H] + ,Purity:96.17%@254nm,93.93%@214nm.

[1488] Example 26. 7-Methoxy-1-(1-(2-(4-(trifluoromethyl)phenyl)acetyl)piperidin-4-yl)-1H-benzo[d]imidazol-2(3H)-one (GEN1-015)

[1489]

[1490]

[1491] Step 26.1. Synthesis of tert-butyl 4-((2-methoxy-6-nitrophenyl)amino)piperidine-1-carboxylate (GEN1-015-1)

[1492]

[1493] To a solution of 2-chloro-1-methoxy-3-nitrobenzene (1.50 g, 7.98 mmol) and tert-butyl 4-aminopiperidine-1-carboxylate (4.79 g, 23.9 mmol) in DMSO (25 mL) was added KCO (3.30 g, 23.9 mmol). The mixture was stirred at 140°C overnight. After cooling, it was poured into 150 mL of water and stirred for 10 minutes. The mixture was then extracted with ethyl acetate (3 x 30 mL). The combined organic layers were washed with brine (20 mL), dried over NaSO, and concentrated. The product was purified by silica gel column chromatography (PE:EA = 20:1 to 10:1) to obtain the desired compound (788 mg, 28% yield). 1 H NMR (300MHz, CDCl3): δ7.74(d,J=8.7Hz,1H),7.51(d,J=8.4Hz,1H),6.95(d,J=8.1Hz,1H),6.71(t,J=8.4Hz,1H),4.14- 4.08(m,1H),3.99-3.95(m,2H),3.88(s,3H),2.93(t,J=8.7Hz,2H),1.96-1.93(m,2H),1.46(s,9H),1.43-1.34(m,2H).

[1494] Step 26.2. Synthesis of tert-butyl 4-((2-amino-6-methoxyphenyl)amino)piperidine-1-carboxylate (GEN1-015-2)

[1495]

[1496] tert-Butyl 4-((2-methoxy-6-nitrophenyl)amino)piperidine-1-carboxylate (1.15 g, 3.28 mmol) and Pd / C (10%, 100 mg) were added to methanol (15 ml). The mixture was stirred at 40°C under a hydrogen balloon for 5 hours. The mixture was filtered through celite. The filtrate was concentrated, and the residue was purified by silica gel column chromatography (PE:EA = 10:1 to 5:1) to obtain the desired compound (500 mg, 48% yield) as a yellow oil. MS (ESI) Rt = 1.536 min, m / z 322.2 [M+H] + ,purity:47.9%@214nm.

[1497] Step 26.3. Synthesis of tert-butyl 4-(7-methoxy-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-1-carboxylate (GEN1-015-3)

[1498]

[1499] Tert-butyl 4-((2-amino-6-methoxyphenyl)amino)piperidine-1-carboxylate (500 mg, 1.56 mmol) and triethylamine (1.57 g, 15.6 mmol) were placed in THF (30 mL) and cooled to 0°C. Triphosgene (463 mg, 1.56 mmol) was added portionwise. The mixture was stirred at room temperature overnight. The mixture was concentrated, and the residue was diluted with ethyl acetate (20 mL) and water (20 mL). Ethyl acetate (3 × 20 mL) was added to extract the desired compound. The combined organic layers were washed with brine (20 mL), dried over Na2SO4, and concentrated. The residue was purified by C18 column chromatography (50-70% CH3CN in water) to obtain the desired compound (150 mg, 28% yield) as a yellow solid. MS (ESI) Rt = 1.650 min, m / z 370.2 [M+Na] + ,Purity:99.1%@214nm.

[1500] Step 26.4. Synthesis of 7-methoxy-1-(piperidin-4-yl)-1H-benzo[d]imidazol-2(3H)-one (GEN1-015-4)

[1501]

[1502] Tert-butyl 4-(7-methoxy-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-1-carboxylate (150 mg, 0.430 mmol) and TFA (2 mL) were added to DCM (4 mL). The mixture was stirred at room temperature for 3 hours. The mixture was concentrated and the residue was diluted with DCM (10 mL) and aqueous Na2CO3 solution (sat., 10 mL). Extraction was performed with DCM (2×20 mL). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, and concentrated to give the desired compound (80 mg, 75% yield) as a yellow solid. MS (ESI) Rt=1.101 min, m / z 248.1 [M+H] + ,Purity:94.5%@214nm.

[1503] Step 26.5. Synthesis of 7-methoxy-1-(1-(2-(4-(trifluoromethyl)phenyl)acetyl)piperidin-4-yl)-1H-benzo[d]imidazol-2(3H)-one (GEN1-015)

[1504]

[1505] DMF (1 drop) was added to a solution of 2-(4-(trifluoromethyl)phenyl)acetic acid (73 mg, 0.36 mmol) in DCM (1 mL). SOCl2 (96 mg, 0.81 mmol) was added. After stirring at room temperature for 30 minutes, the mixture was concentrated. The residue was dissolved in DCM (1 ml) and used in the next step. 7-methoxy-1-(piperidin-4-yl)-1H-benzo[d]imidazole-2(3H)-one (80 mg, 0.32 mmol) and DIEA (209 mg, 1.62 mmol) were stirred at room temperature for 5 minutes in DCM (4 ml), and the previous solution was added dropwise. The mixture was stirred at room temperature for 1 hour. The mixture was poured into water (10 ml) and extracted with DCM (20 ml). The organic layer was dried over Na2SO4 and concentrated. The residue was purified by high performance liquid chromatography (Xbridge C18, 5um, 19x 150mm, 20-70% B, A:H2O (0.1% NH4HCO3), B:CH3CN, uv=214nm, F=15mL / min) to give the desired compound (50mg, yield 36%) as a white solid. 1 H NMR (400 MHz, CDCl3): δ 8.63 (br s,1H),7.61(d,J=8.0Hz,2H),7.45(d,J=7.6Hz,2H),7.01(t,J=8.0Hz,1H),6 .72(d,J=8.0Hz,1H),6.63(d,J=8.0Hz,1H),4.87-4.81(m,2H),4.05(d,J=14. 0Hz,1H),3.84(s,2H),3.74(s,3H),3.18(t,J=12.4Hz,1H),2.70(td,J=13.2 ,2.0Hz,1H),2.47-2.41(m,2H),1.83-1.81(m,2H).MS(ESI)Rt=3.174min,m / z 434.2[M+H] + ,Purity:98.9%@254nm,99.7%@214nm.

[1506] Example 27. 1-(1-(4-(Trifluoromethyl)benzoyl)piperidin-4-yl)-1H-benzo[d]imidazol-2(3H)-one (GEN1-017)

[1507]

[1508] Step 27.1. Synthesis of 1-(1-(4-(trifluoromethyl)benzoyl)piperidin-4-yl)-1H-benzo[d]imidazol-2(3H)-one (GEN1-017)

[1509]

[1510] 1-(Piperidin-4-yl)-1H-benzo[d]imidazol-2(3H)-one (114 mg, 0.526 mmol), 4-(trifluoromethyl)benzoic acid (100 mg, 0.562 mmol), HATU (300 mg, 0.843 mmol), and DIEA (217 mg, 1.69 mmol) were added to DMF (3 mL). The reaction mixture was stirred at room temperature for 12 hours. The mixture was directly purified using a C18 column (CH3CN:water = 5% to 50%) to obtain the desired compound (100 mg, 50% yield) as a gray solid. 1 H NMR (400MHz, DMSO-d6): δ10.87(s,1H),7.84(d,J=8.0Hz,2H),7.70(d,J=8.0Hz,2H),7.38-7.36(m,1H),7.03-6.98(m,3H),4.70-4.67(m,1H), 4.51-4.45(m,1H),3.61-3.59(m,1H),3.28-3.21(m,1H),3.02-2.89(m,1H),2.37-2.27(m,2H),1.83-1.65(m,2H).MS(ESI):Rt=3.647min,m / z 390.1[M+H] + ,Purity:99.21%@254nm,99.95%@214nm.

[1511] Example 28. 1-(1-(3-(4-(Trifluoromethyl)phenyl)propionyl)piperidin-4-yl)-1H-benzo[d]imidazol-2(3H)-one (GEN1-018)

[1512]

[1513] Step 28.1. Synthesis of 1-(1-(3-(4-(trifluoromethyl)phenyl)propionyl)piperidin-4-yl)-1H-benzo[d]imidazol-2(3H)-one (GEN1-018)

[1514]

[1515] 1-(Piperidin-4-yl)-1H-benzo[d]imidazol-2(3H)-one (100 mg, 0.460 mmol), 3-(4-(trifluoromethyl)phenyl)propanoic acid (100 mg, 0.460 mmol), HATU (262 mg, 0.690 mmol), and DIEA (177 mg, 1.37 mmol) were added to DMF (3 mL). The reaction mixture was stirred at room temperature for 12 hours. The mixture was directly purified using a C18 column (CH3CN:water = 5% to 50%) to obtain the desired compound (100 mg, 50% yield) as a white solid. 1 H NMR (400MHz, DMSO-d6): δ10.85(s,1H),7.64(d,J=8.0Hz,2H),7.52(d,J=8.0Hz,2H) ,7.21-7.19(m,1H),6.97-6.96(m,3H),4.58(d,J=12.8Hz,1H),4.44-4.37(m,1H),4. 04(d,J=12.8Hz,1H),3.13(t,J=13.2Hz,1H),2.97-2.93(m,2H),2.73-2.71(m,2H), 2.70-2.63(m,1H),2.20-2.06(m,2H),1.71-1.68(m,2H).MS(ESI):Rt=3.748min,m / z 418.2[M+H] + ,Purity:98.23%@254nm,99.39%@214nm.

[1516] Example 29. 1-Methyl-3-(1-(2-(4-(trifluoromethyl)phenyl)acetyl)piperidin-4-yl)-1H-benzo[d]imidazol-2(3H)-one (GEN1-020)

[1517]

[1518]

[1519] Step 29.1. Synthesis of tert-butyl 4-((2-nitrophenyl)amino)piperidine-1-carboxylate (GEN1-020-1)

[1520]

[1521] A suspension of 1-fluoro-2-nitrobenzene (3.50 g, 25.0 mmol), tert-butyl 4-aminopiperidine-1-carboxylate (5.0 g, 25 mmol), K2CO3 (5.1 g, 37 mmol), and KI (42 mg, 0.25 mmol) was stirred in DMF (35 mL) at 80°C overnight. After cooling to room temperature, the reaction mixture was poured into water (200 mL) and extracted with EtOAc (70 mL x 3). The combined organic layers were washed with water (70 mL), brine (70 mL), dried over MgSO4, and concentrated to yield the desired compound (7.2 g, 90% yield) as an orange oil. 1 HNMR (400MHz, CDCl3): δ8.18(dd,J=8.8,1.2Hz,1H),8.10(d,J=7.2Hz,1H),7.45-7.41(m,1H),6.87(d,J=8.8Hz,1H),6.67 -6.63(m,1H),4.09-3.94(m,2H),3.74-3.64(m,1H),3.08-3.03(m,2H),2.08-2.05(m,2H),1.61-1.51(m,2H),1.48(s,9H).

[1522] Step 29.2. Synthesis of tert-butyl 4-((2-aminophenyl)amino)piperidine-1-carboxylate (GEN1-020-2)

[1523]

[1524] 4-tert-Butyl((2-nitrophenyl)amino)piperidine-1-carboxylate (7.20 g, 220 mmol) was dissolved in methanol (40 mL) and, under a nitrogen atmosphere, palladium / carbon (10%, 720 mg) was added. The resulting mixture was degassed with H₂ and stirred at 35°C under an H₂ atmosphere overnight. The reaction mixture was filtered, and the filtrate was concentrated to afford the desired compound (6.5 g, 100% yield) as a brown oil. MS (ESI) Rt = 1.81 min, m / z 292.1, purity: 98% @ 254 nm, 93% @ 214 nm.

[1525] Step 29.3. Synthesis of tert-butyl 4-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-1-carboxylate (GEN1-020-3)

[1526]

[1527] To a suspension of tert-butyl 4-((2-aminophenyl)amino)piperidine-1-carboxylate (500 mg, 1.72 mmol) and NaHCO₃ (1.44 g, 17.2 mmol) in DCM (5 ml) was added triphosgene (510 mg, 1.72 mmol) portionwise in an ice bath. After stirring overnight at room temperature, the reaction mixture was poured into water (50 mL) and extracted with DCM (30 mL x 3). The combined organic layers were washed with brine (30 mL), dried over MgSO₄, and concentrated. The crude product was purified by silica gel column chromatography (DCM:MeOH = 50:1) to afford the desired compound (360 mg, 66% yield) as a pink solid. 1 HNMR(300MHz, CDCl3): δ9.50(s,1H),7.19-7.08(m,4H),4.60-4.47(m,1H),4.43-4 .23(m,2H),2.96-2.87(m,2H),2.45-2.31(m,2H),1.90-1.86(m,2H),1.55(s,9H).

[1528] Step 29.4. Synthesis of tert-butyl 4-(3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-1-carboxylate (GEN1-020-4)

[1529]

[1530] To tert-butyl 4-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-1-carboxylate (100 mg, 0.315 mmol) in DMF (2 mL) was added NaH (60%, 25 mg in mineral oil, 0.63 mmol) in an ice bath under nitrogen. The mixture was stirred for 15 minutes, and then CH₃I (50 mg, 0.35 mmol) was added dropwise in an ice bath. The resulting mixture was then stirred at room temperature for 1.5 hours. The reaction mixture was poured into water (30 mL) and extracted with EtOAc (20 mL x 3). The combined organic layers were washed with water (30 mL) and brine (30 mL), dried over MgSO₄, and concentrated to afford the desired compound (130 mg, crude) as a yellow solid. 1 HNMR (400MHz, CDCl3): δ7.13-7.04(m,3H),7.00-6.98(m,1H),4.53-4.44(m,1H),4.38-4.22 (m,2H),3.41(s,3H),2.92-2.79(m,2H),2.37-2.26(m,2H),1.82-1.79(m,2H),1.50(s,9H).

[1531] Step 29.5. Synthesis of 1-methyl-3-(piperidin-4-yl)-1H-benzo[d]imidazol-2(3H)-one (GEN1-020-5)

[1532]

[1533] To a solution of tert-butyl 4-(3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-1-carboxylate (130 mg, 0.315 mmol) in DCM (3 mL) was added TFA (1 mL) at room temperature. The mixture was stirred overnight. The reaction mixture was concentrated, and the residue was dissolved in DCM (15 mL). Na2CO3 (saturated solution, 15 mL) was added to the solution, and the mixture was stirred for 20 minutes. The mixture was extracted with DCM (15 mL x 2). The combined organic layers were dried over MgSO4 and concentrated to yield the desired compound (70 mg, 96% yield, last two steps) as a white solid. MS (ESI) Rt = 1.12 min, m / z 232.2 [M+H] + ,Purity:98%@254nm,98%@214nm.

[1534] Step 29.6. Synthesis of 1-methyl-3-(1-(2-(4-(trifluoromethyl)phenyl)acetyl)piperidin-4-yl)-1H-benzo[d]imidazol-2(3H)-one (GEN1-020)

[1535]

[1536] 1-Methyl-3-(piperidin-4-yl)-1H-benzo[d]imidazol-2(3H)-one (70 mg, 0.30 mmol), 2-(4-(trifluoromethyl)phenyl)acetic acid (74 mg, 0.36 mmol), and DIEA (117 mg, 0.909 mmol) were added to DMF (2 mL). HATU (173 mg, 0.455 mmol) was added at room temperature. The resulting mixture was stirred at room temperature for 1.5 hours. The reaction mixture was directly purified via a C18 column (CH3CN:water = 5% to 45%) to afford the desired compound (53.3 mg, 42% yield) as a white solid. 1HNMR(400MHz, CDCl3) δ7.63(d,J=8.0Hz,2H),7.45(d,J=8.0Hz,2H),7.10(t,J=7.6Hz,1H),7.03 (t,J=7.6Hz,1H),6.99(t,J=8.0Hz,1H),6.86(t,J=8.0Hz,1H),4.89-4.86(m,1H),4.59-4.49(m ,1H),4.06-4.02(m,1H),3.86(s,2H),3.40(s,3H),3.23-3.16(m,1H),2.75-2.68(m,1H),2.31- 2.20(m,1H),2.09-1.98(m,1H),1.88-1.85(m,1H),1.80-1.76(m,1H).MS(ESI)Rt=3.629min,m / z 418.1[M+H] + ,Purity:91.32%@254nm,99.57%@214nm.

[1537] Example 30. cis-N-(4-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)cyclohexyl)-2-(4-(trifluoromethyl)phenyl)acetamide (GEN1-021)

[1538]

[1539] Step 30.1. Synthesis of tert-butyl cis-(4-((2-nitrophenyl)amino)cyclohexyl)carbamate (GEN1-021-1)

[1540]

[1541] To a solution of 1-fluoro-2-nitrobenzene (500 mg, 3.55 mmol) and tert-butyl cis-(4-aminocyclohexyl)carbamate (911 mg, 4.26 mmol) in DMF (15 ml) was added KCO (734 mg, 5.32 mmol). Stir at 90°C for 2 hours, then cool, pour into 60 ml of water, stir for 10 minutes, and filter. The filter cake was washed with water (2 x 10 ml) and then dissolved in ethyl acetate (50 ml). The organic solution was dried over NaSO and concentrated to yield the desired compound (1.15 g, 97% yield) as an orange solid. 1HNMR (400MHz, CDCl3): δ8.31-8.29(m,1H),8.19-8.17(m,1H),7.44-7.40(m,1H),6.85(d,J=8.4Hz,1H),6.65-6.61(m,1H),4.58(br s,1H),3.76(br s,1H),3.63(s,1H),1.86-1.82(m,6H),1.60-1.52(m,2H),1.45(s,9H).

[1542] Step 30.2. Synthesis of tert-butyl cis-(4-((2-aminophenyl)amino)cyclohexyl)carbamate (GEN1-021-2)

[1543]

[1544] Dissolve tert-butyl cis-(4-((2-nitrophenyl)amino)cyclohexyl)carbamate (500 mg, 1.49 mmol) in methanol (15 mL) and add Pd / C (10%, 50 mg). Stir the mixture at 30°C under a hydrogen balloon for 5 hours. Filter the mixture through Celite. Concentrate the filtrate to yield the desired compound (450 mg, 99% yield) as a brown oil. 1 H NMR (400MHz, CDCl3): δ6.83-6.79(m,1H),6.74-6.72(m,1H),6.69-6.65(m,2H),4.58(br s,1H),3.65(br s,1H),3.44(s,1H),3.31(br s,2H),1.85-1.72(m,4H),1.67-1.61(m,4H),1.45(s,9H).

[1545] Step 30.3. Synthesis of tert-butyl cis-(4-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)cyclohexyl)carbamate (GEN1-021-3)

[1546]

[1547] To a solution of tert-butyl cis-(4-((2-aminophenyl)amino)cyclohexyl)carbamate (450 mg, 1.48 mmol) in DCM (50 mL) was added NaHCO₃ (1.24 g, 14.8 mmol). The mixture was cooled to 5 degrees Celsius. Triphosgene (438 mg, 1.48 mmol) was added stepwise. The mixture was stirred at room temperature for 5 hours. The mixture was poured into water (50 mL) and extracted with DCM (2×20 mL). The combined organic layers were washed with brine (20 mL), dried over Na₂SO₄, and concentrated. The residue was purified by C18 column chromatography (40-70% CH₃CN in water) to give the desired compound (310 mg, 64% yield). 1 H NMR (400MHz, CDCl3): δ9.19 (br s, 1H), 7.11-7.06 (m, 4H), 4.99 (d, J = 8.8Hz, 1H), 4.19 (br s,1H),3.93(s,1H),2.43-2.33(m,2H),2.05-2.01(m,2H),1.78-1.68(m,4H),1.50(s,9H).

[1548] Step 30.4. Synthesis of cis-1-(4-aminocyclohexyl)-1H-benzo[d]imidazol-2(3H)-one (GEN1-021-4)

[1549]

[1550] tert-Butyl cis-(4-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)cyclohexyl)carbamate (300 mg, 0.91 mmol) and TFA (2 ml) were added to DCM (4 ml). The mixture was stirred at room temperature for 3 hours. The mixture was concentrated. The residue was diluted with DCM (10 ml) and aqueous Na2CO3 (sat., 5 mL). Extraction was performed with DCM (2 x 20 mL). The combined organic layers were washed with brine (5 ml), dried over Na2SO4, and concentrated to yield the desired compound (130 mg, 62% yield) as a yellow solid. MS (ESI) Rt = 1.14 min, m / z 232.1 [M+H] + ,Purity:96.5%@214nm.

[1551] Step 30.5. Synthesis of cis-N-(4-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)cyclohexyl)-2-(4-(trifluoromethyl)phenyl)acetamide (GEN1-021)

[1552]

[1553] A mixture of 2-(4-(trifluoromethyl)phenyl)acetic acid (74mg, 0.36mmol) in DCM (1ml) was added DMF (1 drop). SOCl2 (82mg, 0.69mmol) was added. After stirring at 20°C for 20 minutes, the mixture was concentrated. The residue was dissolved in DCM (1 ml) and used in the next step. Cis-1-(4-aminocyclohexyl)-1H-benzo[d]imidazole-2(3H)-one (80mg, 0.35mmol) and DIEA (223mg, 1.73mmol) were stirred at room temperature for 10min in DCM (4mL), and the previous solution was added dropwise. The mixture was stirred at room temperature for 1 hour. The mixture was poured into water (20 ml) and extracted with DCM (2x 20 ml). The combined organic layer was rinsed with brine (20mL) and dried over Na2SO4 and concentrated. The residue was purified by high performance liquid chromatography (Xbridge C18, 5um, 19x 150mm, 30-60% B, A:H2O (0.1% NH4HCO3), B:CH3CN, uv=214nm, F=15mL / min) to give the desired compound (30mg, yield: 21%) as a white solid. 1 H NMR (400MHz, CDCl3): δ10.83(s,1H),8.26(d,J=6.0Hz,1H),7.68(d,J=8.0Hz,2H),7. 56(d,J=8.0Hz,2H),7.33-7.32(m,1H),7.04-6.94(m,3H),4.22-4.16(m,1H),3.91(br s,1H),3.68(s,2H),2.38-2.27(m,2H),1.92-1.89(m,2H),1.68-1.60(m,2H),1.52-1.49(m,2H).MS(ESI)Rt=3.826min,m / z 418.1[M+H] + ,Purity:95.6%@254nm,99.3%@214nm.

[1554] Example 31. trans-N-(4-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)cyclohexyl)-2-(4-(trifluoromethyl)phenyl)acetamide (GEN1-022)

[1555]

[1556] Step 31.1. Synthesis of tert-butyl trans-(4-((2-nitrophenyl)amino)cyclohexyl)carbamate (GEN1-022-1)

[1557]

[1558] To a solution of 1-fluoro-2-nitrobenzene (500 mg, 3.55 mmol) and tert-butyl trans-(4-aminocyclohexyl)carbamate (911 mg, 4.26 mmol) in DMF (15 mL) was added KCO (734 mg, 5.32 mmol). After stirring at 90°C for 2 hours, the mixture was cooled, poured into 60 mL of water, stirred for 10 minutes, and filtered. The filter cake was dissolved in ethyl acetate (50 mL). The organic solution was washed with aqueous hydrochloric acid (0.5 M, 2 x 10 mL) and brine (20 mL), dried over NaSO, and concentrated. Trituration with petroleum ether (10 mL) afforded the desired yellow solid (1.02 g, 86% yield). MS (ESI) Rt = 1.869 min, m / z 336.2 [M+H] + ,Purity:98.4%@214nm.

[1559] Step 31.2. Synthesis of tert-butyl trans-(4-((2-aminophenyl)amino)cyclohexyl)carbamate (GEN1-022-2)

[1560]

[1561] tert-Butyl trans-(4-((2-nitrophenyl)amino)cyclohexyl)carbamate (500 mg, 1.49 mmol) was dissolved in methanol (15 mL) and Pd / C (10%, 50 mg) was added. The mixture was stirred at 30°C under a hydrogen balloon for 5 hours. The mixture was filtered through Celite. The filtrate was concentrated to give the desired compound (450 mg, 99% yield) as a brown solid. MS (ESI) Rt = 1.677 min, m / z 306.2 [M+H] + ,Purity:93.5%@214nm.

[1562] Step 31.3. Synthesis of tert-butyl trans-(4-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)cyclohexyl)carbamate (GEN1-022-3)

[1563]

[1564] To a solution of tert-butyl trans-(4-((2-aminophenyl)amino)cyclohexyl)carbamate (450 mg, 1.48 mmol) in DCM (50 ml) was added NaHCO₃ (1.24 g, 14.8 mmol). The mixture was cooled to 5 degrees Celsius. Triphosgene (438 mg, 1.48 mmol) was added stepwise. The mixture was stirred at room temperature overnight. The mixture was poured into water (60 mL) and extracted with DCM:CH₃OH = 10:1 (3 x 30 mL). The combined organic layers were rinsed with water (20 ml), dried over Na₂SO₄, and concentrated. The residue was triturated with PE:EA = 1:1 (10 mL) to give the desired compound (410 mg, 84% yield) as a pink solid. 1 HNMR(400MHz,DMSO-d6): δ10.80(br s,1H),7.32-7.30(m,1H),6.99-6.92(m,3H),6.78(d,J=7.6Hz,1H),4.14-4.07(m,1H),3.47-3.33 (m,1H),2.26-2.16(m,2H),1.99-1.89(m,2H),1.68-1.65(m,2H),1.40(s,9H),1.37-1.30(m,2H).

[1565] Step 31.4. Synthesis of trans-1-(4-aminocyclohexyl)-1H-benzo[d]imidazol-2(3H)-one (GEN1-022-4)

[1566]

[1567] tert-Butyl trans-(4-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)cyclohexyl)carbamate (400 mg, 1.21 mmol) and TFA (2 ml) were added to DCM (4 ml). The mixture was stirred at room temperature for 3 hours. The mixture was concentrated. The residue was diluted with DCM (10 ml) and aqueous Na2CO3 (sat., 10 ml). The mixture was extracted with DCM:CH3OH = 10:1 (3 x 30 mL), and the combined organic layers were concentrated. The residue was dissolved in DCM (50 mL) and filtered. The filtrate was concentrated to give the desired compound (150 mg, 54% yield) as a yellow solid. MS (ESI) Rt = 1.051 min, m / z 232.1 [M+H] + ,purity:88.9%@214nm.

[1568] Step 31.5. Synthesis of trans-N-(4-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)cyclohexyl)-2-(4-(trifluoromethyl)phenyl)acetamide (GEN1-022)

[1569]

[1570] (4-(Trifluoromethyl)phenyl)acetic acid (46 mg, 0.23 mmol) and DMF (1 drop) were added to DCM (1 mL). SOCl2 (52 mg, 0.43 mmol) was added. After stirring at 20 ° C for 20 minutes, the mixture was concentrated. The residue was dissolved in DCM (1 ml) for the next step. Trans-1-(4-aminocyclohexyl)-1H-benzo [d] imidazole-2 (3H) -one (50 mg, 0.22 mmol) and DIEA (140 mg, 1.08 mmol) were stirred at room temperature for 10 minutes in DCM (4 mL), and the previous solution was added dropwise. The mixture was stirred at room temperature for 3 hours. The mixture was poured into water (20 mL) and extracted with DCM: CH3OH = 10: 1 (2 x 20 mL). The mixed organic layer was rinsed with brine (20 ml) and concentrated. The residue was purified by high performance liquid chromatography (Xbridge C18, 5um, 19x 150mm, 30-60% B, A:H2O (0.1% NH4HCO3), B:CH3CN, uv=214nm, F=15mL / min) to give the desired compound (15mg, yield 17%) as a white solid. H NMR (400MHz, DMSO-d6): δ10.80(s,1H),8.12(d,J=7.6Hz,1H),7.67(d,J=8 .4Hz,2H),7.59(d,J=8.0Hz,2H),7.36-7.30(m,1H),6.97-6.95(m,3H),4.2 2-4.13(m,1H),3.76-3.64(m,1H),3.52(s,2H),2.29-2.19(m,2H),1.95-1. 92(m,2H),1.70-1.68(m,2H),1.43-1.33(m,2H).MS(ESI)Rt=3.376min,m / z 418.1[M+H] + ,Purity:95.1%@254nm,98.6%@214nm.

[1571] Example 32. 1-(1-(2-(4-(Trifluoromethyl)phenyl)acetyl)azetidin-3-yl)-1H-benzo[d]imidazol-2(3H)-one (GEN1-023)

[1572]

[1573]

[1574] Step 32.1. Synthesis of tert-butyl 3-((2-nitrophenyl)amino)azetidine-1-carboxylate (GEN1-023-1)

[1575]

[1576] 1-Fluoro-2-nitrobenzene (1.0 g, 7.1 mmol), tert-butyl 3-aminoazetidine-1-carboxylate (1.3 g, 7.8 mmol), K2CO3 (1.9 g, 14 mmol), and KI (40 mg, 0.28 mmol) were added to DMF (20 mL). After stirring at 95°C for 12 hours, the mixture was cooled to room temperature, poured into 50 mL of water, and extracted with EtOAc (30 × 2 mL). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated to obtain the desired product (2.1 g, 97% yield) as a yellow solid. 1 H NMR (400MHz, DMSO-d6): δ8.22-8.20(m,2H),7.46(t,J=7.2Hz,1H),6.76(t,J=7.2 Hz, 1H), 6.53 (d, J = 8.4Hz, 1H), 4.40-4.33 (m, 3H), 3.90-3.87 (m, 2H), 1.43 (s, 9H).

[1577] Step 32.2. Synthesis of tert-butyl 3-((2-aminophenyl)amino)azetidine-1-carboxylate (GEN1-023-2)

[1578]

[1579] To a solution of tert-butyl 3-((2-nitrophenyl)amino)azetidine-1-carboxylate (1.0 g, 3.4 mmol) and NH4Cl (890 mg, 17.1 mmol) in MeOH (15 mL) was added Zn powder (890 mg, 13.7 mmol). The reaction mixture was stirred at 35°C for 12 hours. The reaction mixture was filtered, and the filtrate was concentrated to the desired compound (600 mg, 67% yield) as a red solid. MS (ESI): Rt = 1.54 min, m / z 164.0, [M+H–Boc] + Purity: 95% @ 254nm, 98% @ 214nm.

[1580] Step 32.3. Synthesis of tert-butyl 3-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)azetidine-1-carboxylate (GEN1-023-3)

[1581]

[1582] To a mixture of tert-butyl 3-((2-aminophenyl)amino)azetidine-1-carboxylate (600 mg, 2.30 mmol) and NaHCO₃ (1.9 g, 2.3 mmol) in DCM (10 ml) was added triphosgene (541 mg, 1.80 mmol) under ice-cooling. The reaction mixture was stirred at room temperature for 2 hours. The mixture was poured into 10 mL of water and extracted with DCM (10×2 mL). The combined organic layers were washed with brine, dried over Na₂SO₄, and concentrated to the desired compound (598 mg, 91% yield) as a red solid. MS (ESI): Rt=1.55 min, m / z 234.1, [M+2H–t-Bu] + Purity: 100% @ 254nm, 88% @ 214nm.

[1583] Step 32.4. Synthesis of 1-(azetidin-3-yl)-1H-benzo[d]imidazol-2(3H)-one (GEN1-023-4)

[1584]

[1585] 3-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-azetidine-1-carboxylic acid tert-butyl ester (598 mg, 2.07 mmol) and TFA (1 ml) were added to DCM (4 ml). The reaction mixture was stirred at room temperature for 12 hours. The mixture was concentrated to give a crude product. The crude product was dissolved in water (2 ml) and basified to pH = 9 with aqueous Na2CO3 solution (sat., 5 ml). It was extracted with DCM (10×4 mL). The combined organic layers were dried over Na2SO4 and concentrated to the desired (352 mg, 90% yield) white solid. MS (ESI): Rt=0.39 min, m / z 190.0, [M+H] + Purity: 95% @ 254nm, 90% @ 214nm.

[1586] Step 32.5. Synthesis of 1-(1-(2-(4-(trifluoromethyl)phenyl)acetyl)azetidin-3-yl)-1H-benzo[d]imidazol-2(3H)-one (GEN1-023)

[1587]

[1588] 1-(Azetidin-3-yl)-1H-benzo[d]imidazol-2(3H)-one (75 mg, 0.40 mmol), 2-(4-(trifluoromethyl)phenyl)acetic acid (81 mg, 0.40 mmol), HATU (227 mg, 0.597 mmol), and DIEA (154 mg, 1.20 mmol) were added to DMF (1.5 mL). The reaction mixture was stirred at room temperature for 12 hours. The mixture was purified using a C18 column (CH3CN:water = 5% to 50%) to obtain the desired product (30 mg, 20% yield) as a white solid. 1 H NMR (400MHz, CDCl3): δ8.83(s,1H),7.62(d,J=7.6Hz,2H),7.48(d,J=8.4Hz,2H),7.13-7.08(m,2H),7.01-6.94(m,2H ),5.37-5.33(m,1H),4.72-4.69(m,1H),4.60-4.54(m,2H),4.54-4.47(m,1H),3.65(s,2H).MS(ESI):Rt=3.45min,m / z 376.2[M+H] + ,Purity:95.48%@254nm,99.19%@214nm.

[1589] Example 33. 1-(1-(2-(6-(Trifluoromethyl)pyridin-3-yl)acetyl)piperidin-4-yl)-1H-benzo[d]imidazol-2(3H)-one (GEN1-027)

[1590]

[1591] Step 33.1. Synthesis of 1-(1-(2-(6-(trifluoromethyl)pyridin-3-yl)acetyl)piperidin-4-yl)-1H-benzo[d]imidazol-2(3H)-one (GEN1-027)

[1592]

[1593] 1-(Piperidin-4-yl)-1H-benzo[d]imidazol-2(3H)-one (60 mg, 0.28 mmol), 2-(6-(trifluoromethyl)pyridin-3-yl)acetic acid (64 mg, 0.31 mmol), and DIEA (109 mg, 0.844 mmol) were added to DMF (2 mL). HATU (160 mg, 0.421 mmol) was then added at room temperature. The resulting mixture was stirred at room temperature for 1.5 hours. The reaction mixture was directly purified via a C18 column (CH3CN:water = 5% to 45%) to afford the desired compound (65.5 mg, 58% yield) as a white solid. 1H NMR (400MHz, DMSO-d6): δ10.85(s,1H),8.66(s,1H),7.97(d,J=8.0Hz,1H),7.88(d,J= 7.6Hz,1H),7.20-7.18(m,1H),7.01-6.93(m,3H),4.86-4.55(m,1H),4.49-4.41(m,1H) ,4.19-4.16(m,1H),4.00(dd,J=22.0,16.0Hz,2H),3.28-3.22(m,1H),2.77-2.71(m,1 H),2.34-2.23(m,1H),2.20-2.09(m,1H),1.78-1.71(m,2H).MS(ESI)Rt=3.236min,m / z 405.2[M+H] + ,Purity:98.70%@254nm,99.59%@214nm.

[1594] Example 34. 1-(1-(2-(5-(Trifluoromethyl)pyridin-2-yl)acetyl)piperidin-4-yl)-1H-benzo[d]imidazol-2(3H)-one (GEN1-028)

[1595]

[1596] Step 34.1. Synthesis of 1-(1-(2-(5-(trifluoromethyl)pyridin-2-yl)acetyl)piperidin-4-yl)-1H-benzo[d]imidazol-2(3H)-one (GEN1-028)

[1597]

[1598] 1-(Piperidin-4-yl)-1H-benzo[d]imidazol-2(3H)-one (60 mg, 0.28 mmol), 2-(5-(trifluoromethyl)pyridin-2-yl)acetic acid (64 mg, 0.31 mmol), and DIEA (109 mg, 0.844 mmol) were added to DMF (1.5 mL). HATU (160 mg, 0.421 mmol) was then added at room temperature. The resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was directly purified via a C18 column (CH3CN:water = 5% to 45%) to afford the desired compound (20.4 mg, 18% yield) as a white solid. 1H NMR (400MHz, CDCl3): δ9.46 (s, 1H), 8.83 (s, 1H), 7.95 (dd, J = 8.0, 2.0Hz, 1H), 7.5 7(d,J=8.4Hz,1H),7.11-6.99(m,4H),4.89-4.86(m,1H),4.62-4.53(m,1H),4.34- 4.30(m,1H),4.14(d,J=14.4Hz,1H),4.04(d,J=14.4Hz,1H),3.29-3.22(m,1H),2 .78-2.71(m,1H),2.37-2.25(m,2H),1.92-1.89(m,2H).MS(ESI)Rt=3.048min,m / z 405.2[M+H] + ,Purity:98.20%@254nm,99.61%@214nm.

[1599] Example 35. 1-(1-(2-(3-(Trifluoromethyl)phenyl)acetyl)piperidin-4-yl)-1H-benzo[d]imidazol-2(3H)-one (GEN1-029)

[1600]

[1601] Step 35.1. Synthesis of 1-(1-(2-(3-(trifluoromethyl)phenyl)acetyl)piperidin-4-yl)-1H-benzo[d]imidazol-2(3H)-one (GEN1-029)

[1602]

[1603] 1-(Piperidin-4-yl)-1H-benzo[d]imidazol-2(3H)-one (106 mg, 0.490 mmol), 2-(3-(trifluoromethyl)phenyl)acetic acid (100 mg, 0.490 mmol), HATU (280 mg, 0.735 mmol), and DIEA (190 mg, 1.47 mmol) were added to DMF (3 mL). The reaction mixture was stirred at room temperature for 12 hours. The mixture was directly purified using a C18 column (CH3CN:water = 5% to 50%) to obtain the desired compound (100 mg, 49% yield) as a white solid. 1H NMR (400MHz, CDCl3): δ8.58(s,1H),7.59-7.48(m,4H),7.07-7.01(m,3H),6.90-6 .88(m,1H),4.90(d,J=13.2Hz,1H),4.57-4.50(m,1H),4.05(d,J=14.8Hz,1H),3. 87(s,2H),3.24-3.18(m,1H),2.76-2.70(m,1H),2.30-2.26(m,1H),2.05-2.01(m ,1H),1.90(d,J=11.6Hz,1H),1.81(d,J=11.6Hz,1H).MS(ESI):Rt=3.573min,m / z 404.2[M+H] + ,Purity:97.12%@254nm,99.27%@214nm.

[1604] Example 36. 1-(1-(2-(2-(trifluoromethyl)phenyl)acetyl)piperidin-4-yl)-1H-benzo[d]imidazol-2(3H)-one (GEN1-030)

[1605]

[1606] Step 36.1. Synthesis of 1-(1-(2-(2-(trifluoromethyl)phenyl)acetyl)piperidin-4-yl)-1H-benzo[d]imidazol-2(3H)-one (GEN1-030)

[1607]

[1608] 1-(Piperidin-4-yl)-1H-benzo[d]imidazol-2(3H)-one (106 mg, 0.490 mmol), 2-(2-(trifluoromethyl)phenyl)acetic acid (100 mg, 0.490 mmol), HATU (280 mg, 0.735 mmol), and DIEA (190 mg, 1.47 mmol) were added to DMF (3 mL). The reaction mixture was stirred at room temperature for 12 hours. The mixture was purified using a C18 column (CH3CN:water = 5% to 50%) to obtain the desired compound (100 mg, 49% yield) as a white solid. 1H NMR (400MHz, CDCl3): δ8.91 (s, 1H), 7.67 (d, J = 7.2Hz, 1H), 7.60-7.56 (m, 1H), 7.46 ( d,J=8.0Hz,1H),7.42-7.38(m,1H),7.09-7.05(m,4H),4.91(d,J=12.8Hz,1H),4.59 -4.53 (m, 1H), 4.06-4.02 (m, 2H), 3.92-3.88 (m, 1H), 3.22 (t, J = 11.6 Hz, 1H), 2.75 (t, J = 11.6 Hz, 1H), 2.37-2.22 (m, 2H), 1.93-1.85 (m, 2H). MS (ESI): Rt = 3.546 min purity, m / z 404.2 [M+H] + ,93.25%@254nm,99.04%@214nm.

[1609] Example 37. 1-(1-(2-(4-(tert-Butyl)phenyl)acetyl)piperidin-4-yl)-1H-benzo[d]imidazol-2(3H)-one (GEN1-031)

[1610]

[1611] Step 37.1. Synthesis of 1-(1-(2-(4-(tert-butyl)phenyl)acetyl)piperidin-4-yl)-1H-benzo[d]imidazol-2(3H)-one (GEN1-031)

[1612]

[1613] 1-(Piperidin-4-yl)-1H-benzo[d]imidazol-2(3H)-one (60 mg, 0.28 mmol), 2-(4-(tert-butyl)phenyl)acetic acid (54 mg, 0.28 mmol), and DIEA (109 mg, 0.844 mmol) were added to DMF (2 mL). HATU (160 mg, 0.421 mmol) was then added at room temperature. The resulting mixture was stirred at room temperature for 1.5 hours. The reaction mixture was directly purified via a C18 column (CH3CN:water = 5% to 45%) to afford the desired compound (24 mg, 22% yield) as a white solid. 1H NMR (400MHz, CDCl3): δ8.95(s,1H),7.40-7.38(m,2H),7.27-7.25(m,2H),7.08 -6.99(m,3H),6.90-6.88(m,1H),4.91-4.88(m,1H),4.57-4.48(m,1H),4.09-4. 06(m,1H),3.79(s,2H),3.18-3.11(m,1H),2.73-2.65(m,1H),2.30-2.19(m,1H ),1.94-1.84(m,2H),1.73-1.69(m,1H),1.29(s,9H).MS(ESI)Rt=2.519min,m / z 392.2[M+H] + ,Purity:71.40%@254nm,97.55%@214nm.

[1614] Example 38. 1-(1-(2-(4-cyclopropylphenyl)acetyl)piperidin-4-yl)-1H-benzo[d]imidazol-2(3H)-one (GEN1-032)

[1615]

[1616] Step 38.1. Synthesis of 1-(1-(2-(4-cyclopropylphenyl)acetyl)piperidin-4-yl)-1H-benzo[d]imidazol-2(3H)-one (GEN1-032)

[1617]

[1618] 1-(Piperidin-4-yl)-1H-benzo[d]imidazol-2(3H)-one hydrochloride (100 mg, 0.390 mmol) and DIEA (152 mg, 1.18 mmol) in DMF (1 mL) were stirred at room temperature for 20 minutes. The solution was used directly in the next step. HATU (224 mg, 0.59 mmol) was added to a solution of 2-(4-cyclopropylphenyl)acetic acid (76 mg, 0.43 mmol) and DIEA (102 mg, 0.79 mmol) in DMF (2 mL). After stirring at room temperature for 20 minutes, the previous solution was added. The mixture was stirred at room temperature for 1 hour. The mixture was then poured into 15 mL of water and extracted with ethyl acetate (2 x 20 mL). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, and concentrated. The residue was purified by high performance liquid chromatography (Xbridge C18, 5um, 19x 150mm, 30-60% B, A:H2O (0.1% NH4HCO3), B:CH3CN, uv=214nm, F=15mL / min) to give the desired compound (50mg, yield 34%) as a white solid. 1 H NMR (400MHz, CDCl3): δ8.58(s,1H),7.23-7.21(m,2H),7.08-7.00(m,5H),6.83-6.81 (m,1H),4.88(d,J=13.6Hz,1H),4.58-4.48(m,1H),4.05(d,J=13.6Hz,1H),3.77(s,2H ),3.13(t,J=13.2Hz,1H),2.67(t,J=13.2Hz,1H),2.25-2.14(m,1H),1.90-1.82(m,3H ),1.70-1.67(m,1H),0.95-0.92(m,2H),0.66-0.64(m,2H).MS(ESI)Rt=3.548min,m / z 376.2[M+H] + ,Purity:99.1%@254nm,99.6%@214nm.

[1619] Example 39. 1-(1-(2-([1,1'-biphenyl]-4-yl)acetyl)piperidin-4-yl)-1H-benzo[d]imidazol-2(3H)-one (GEN1-033)

[1620]

[1621] Step 39.1. Synthesis of 1-(1-(2-([1,1'-biphenyl]-4-yl)acetyl)piperidin-4-yl)-1H-benzo[d]imidazol-2(3H)-one (GEN1-033)

[1622]

[1623] To a solution of 2-([1,1'-biphenyl]-4-yl)acetic acid (73 mg, 0.35 mmol) in DCM (2 mL) was added DMF (1 drop). SOCl2 (75 mg, 0.63 mmol) was added. After stirring at 40 ° C for 20 minutes, the mixture was concentrated. The residue was dissolved in DCM (1 ml) for the next step. 1-(Piperidin-4-yl)-1H-benzo[d]imidazol-2(3H)-one hydrochloride (80 mg, 0.31 mmol) and DIEA (203 mg, 1.57 mmol) were stirred at room temperature for 10 minutes in DCM (3 ml), and the previous solution was added dropwise. The resulting mixture was stirred for 2 hours. The mixture was poured into water (20 ml) and extracted with DCM (2 x 20 ml). The combined organic layer was rinsed with brine (20 mL), dried over Na2SO4, and concentrated. The residue was purified by high performance liquid chromatography (Xbridge C18, 5um, 19x 150mm, 35-65% B, A: H2O (0.1% NH4HCO3), B: CH3CN, uv = 214nm, F = 15mL / min) to give the desired compound (50mg, yield 39%) as a white solid. 1 H NMR (400MHz, CDCl3): δ9.39(s,1H),7.61-7.59(m,2H),7.57-7.55(m,2H),7.44-7.40(m,4H),7.35-7.32( m,1H),7.07-7.05(m,1H),7.00(t,J=7.6Hz,1H),6.95-6.91(m,1H),6.88-6.86(m,1H),4.92(d,J=13.6Hz, 1H),4.56-4.50(m,1H),4.11(d,J=13.2Hz,1H),3.87(s,2H),3.19(t,J=12.4Hz,1H),2.72(t,J=12.8Hz,1 H),2.31-2.21(m,1H),2.03-1.94(m,1H),1.89-1.86(m,1H),1.77-1.74(m,1H).MS(ESI)Rt=3.475min,m / z 412.2[M+H] + ,Purity:98.1%@254nm,98.7%@214nm.

[1624] Example 40. 1-(1-(2-(4-morpholinophenyl)acetyl)piperidin-4-yl)-1H-benzo[d]imidazol-2(3H)-one (GEN1-034)

[1625]

[1626] Step 40.1. Synthesis of ethyl 2-(4-morpholinophenyl)acetate (GEN1-034-1)

[1627]

[1628] To a mixture of ethyl 2-(4-bromophenyl)acetate (1.00 g, 4.12 mmol), morpholine (430 mg, 4.94 mmol), Cs2CO3 (2.68 g, 8.23 ​​mmol), and Xphos (196 mg, 0.41 mmol) in toluene (15 ml) was added Pd(OAc)2 (92 mg, 0.41 mmol). The mixture was refluxed under a nitrogen atmosphere for 2 hours, cooled, and filtered. The filtrate was concentrated. The residue was purified by silica gel column chromatography (PE:EA = 10:1 to 5:1) to obtain the desired compound (630 mg, 62% yield) as a yellow oil. 1 HNMR (400MHz, CDCl3): δ7.19 (d, J = 8.4Hz, 2H), 6.87 (d, J = 8.8Hz, 2H), 4.13 (q, J = 7.2Hz, 2H), 3.85 (t ,J=4.8Hz,4H),3.53(s,2H),3.14(t,J=4.8Hz,4H),1.25(t,J=7.2Hz,3H).MS(ESI)Rt=1.584min,m / z 250.1[M+H] + ,purity:69.9%@214nm.

[1629] Step 40.2. Synthesis of 2-(4-morpholinophenyl)acetic acid (GEN1-034-2)

[1630]

[1631] To a solution of ethyl 2-(4-morpholinophenyl)acetate (300 mg, 1.20 mmol) in methanol (4 ml) was added a solution of lithium hydroxide hydrate (152 mg, 3.61 mmol) in water (2 ml). After stirring at 30°C for 2 hours, the mixture was concentrated. The residue was diluted with water (10 ml). 10% aqueous HCl was added dropwise until the pH was 2-3. Extraction was performed with DCM (3 x 20 mL). The combined organic layers were rinsed with brine (20 ml), dried over Na2SO4, and concentrated to yield the desired compound (180 mg, 68% yield) as a yellow solid. 1H NMR (400MHz, CDCl3): δ7.19 (d, J = 8.8Hz, 2H), 6.88 (d, J = 8.8Hz, 2H), 3.86 (t, J = 4.8Hz, 4H), 3.57 (s, 2H), 3.14 (t, J = 4.8Hz, 4H).

[1632] Step 40.3. Synthesis of 1-(1-(2-(4-morpholinophenyl)acetyl)piperidin-4-yl)-1H-benzo[d]imidazol-2(3H)-one (GEN1-034)

[1633]

[1634] DMF (1 drop) was added to a DCM (2 mL) solution of 2-(4-morpholinophenyl)acetic acid (96 mg, 0.43 mmol). SOCl2 (94 mg, 0.79 mmol) was added. After stirring at 25 ° C for 30 minutes, the mixture was concentrated. The residue was dissolved in DCM (1 ml) and used for the next step. 1-(piperidin-4-yl)-1H-benzo [d] imidazole-2 (3H) -one hydrochloride (100 mg, 0.390 mmol) and DIEA (254 mg, 1.97 mmol) were stirred at room temperature for 30 min in DCM (3 ml), and the previous solution was added dropwise. The resulting mixture was stirred at room temperature for 3 hours. The mixture was poured into water (20 ml) and extracted with DCM (2x 20 ml). The combined organic layer was rinsed with brine (20 mL) and dried over Na2SO4 and concentrated. The residue was purified by high performance liquid chromatography (Xbridge C18, 5um, 19x 150mm, 25-40% B, A:H2O (0.1% NH4HCO3), B:CH3CN, uv=214nm, F=15mL / min) to give the desired compound (60mg, yield 36%) as a white solid. 1 H NMR (400MHz, CDCl3): δ9.27 (s, 1H), 7.24 (d, J = 8.4Hz, 2H), 7.09-6.98 (m, 3H), 6.91 (d, J=8.8Hz,2H),6.86-6.84(m,1H),4.88(d,J=13.6Hz,1H),4.55-4.49(m,1H),4.07(d,J =14.0Hz,1H),3.84(t,J=4.8Hz,4H),3.75(s,2H),3.17-3.11(m,2H),2.71-2.65(m,1H ),2.28-2.18(m,1H),1.94-1.84(m,2H),1.73-1.69(m,1H).MS(ESI)Rt=2.726min,m / z 421.2[M+H]+ ,Purity:97.5%@254nm,99.2%@214nm.

[1635] Example 41. 1-(4-(2-amino-1H-benzo[d]imidazol-1-yl)piperidin-1-yl)-2-(4-(trifluoromethyl)phenyl)ethanone (GEN1-055)

[1636]

[1637] Step 41.1. Synthesis of tert-butyl 4-((2-nitrophenyl)amino)piperidine-1-carboxylate (GEN1-055-1)

[1638]

[1639] To a solution of 1-fluoro-2-nitrobenzene (2.0 g, 14 mmol), tert-butyl 4-aminopiperidine-1-carboxylate (2.8 g, 14 mmol), and K2CO3 (3.0 g, 21 mmol) in DMF (30 mL) was added KI (50 mg, 0.30 mmol). The resulting mixture was stirred at 95°C for 12 hours. The mixture was cooled to room temperature, poured into water (50 mL), and extracted with EtOAc (30 mL x 2). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated to the desired yellow oil (4 g, 87% yield). MS (ESI): Rt = 1.75 min, m / z 266.1 [M+2H-t-Bu] + Purity: 93% @ 254nm, 100% @ 214nm.

[1640] Step 41.2. Synthesis of N-(2-nitrophenyl)piperidin-4-amine (GEN1-055-2)

[1641]

[1642] TFA (15 mL) was added to a solution of tert-butyl 4-((2-nitrophenyl)amino)piperidine-1-carboxylate (4.0 g, 12 mmol) in DCM (30 mL). The reaction mixture was stirred at room temperature for 12 hours. The mixture was concentrated and the residue was dissolved in water (50 ml). The aqueous solution was basified to pH = 9 with aqueous Na2CO3 solution (saturated solution, 50 ml) and extracted with DCM (50 mL × 3). The combined organic layers were dried over Na2SO4 and concentrated to the desired yellow solid (2.5 g, yield 91%). 1H NMR (400MHz, CDCl3): δ8.18-8.12(m,2H),7.41(t,J=8.4Hz,1H),6.88(d,J=8.4Hz,1H),6.62(t,J=8.4Hz,1H) ,3.65-3.63(m,1H),3.18-3.15(m,2H),2.81-2.75(m,2H),2.17(s,1H),2.11-2.08(m,2H),1.58-1.51(m,2H).

[1643] Step 41.3. Synthesis of 1-(4-((2-nitrophenyl)amino)piperidin-1-yl)-2-(4-(trifluoromethyl)phenyl)ethanone (GEN1-055-3)

[1644]

[1645] To a solution of N-(2-nitrophenyl)piperidin-4-amine (1.0 g, 4.5 mmol), 2-(4-(trifluoromethyl)phenyl)acetic acid (830 mg, 4.01 mmol), EDCI (1.1 g, 5.8 mmol), and HOBT (790 mg, 5.85 mmol) in DMF (30 mL) was added DIEA (1.74 g, 13.5 mmol). The reaction mixture was stirred at room temperature for 12 hours. The mixture was purified using a C18 column (CH3CN:water = 5% to 50%) to obtain the desired product (1.2 g, 74% yield) as a yellow solid. MS (ESI): Rt = 1.60 min, m / z 408.3 [M+H] + ,Purity:97%@254nm,100%@214nm.

[1646] Step 41.4. Synthesis of 1-(4-((2-aminophenyl)amino)piperidin-1-yl)-2-(4-(trifluoromethyl)phenyl)ethanone (GEN1-055-4)

[1647]

[1648] To a solution of 1-(4-((2-nitrophenyl)amino)piperidin-1-yl)-2-(4-(trifluoromethyl)phenyl)ethanone (1.2 g, 2.9 mmol) in MeOH (10 mL) was added Pd / C (10%, 100 mg) under H2. The reaction mixture was stirred at room temperature for 12 hours. The mixture was filtered and the filtrate was concentrated to the desired product (900 mg, 82% yield) as a gray solid. MS (ESI): Rt = 1.62 min, m / z 378.3 [M+H] + ,Purity:91%@254nm,76%@214nm.

[1649] Step 41.5. Synthesis of 1-(4-(2-amino-1H-benzo[d]imidazol-1-yl)piperidin-1-yl)-2-(4-(trifluoromethyl)phenyl)ethanone (GEN1-055)

[1650]

[1651] To a solution of 1-(4-((2-aminophenyl)amino)piperidin-1-yl)-2-(4-(trifluoromethyl)phenyl)ethanone (100 mg, 0.265 mmol) in methanol (1 mL) and water (0.1 mL) was added cyanogen bromide (140 mg, 1.32 mmol). The mixture was stirred at room temperature for two hours and then concentrated and purified using a C18 column (CH3CN:water = 5% to 45%) to obtain the desired compound (60 mg, 55% yield) as a white solid. 1 H NMR (400MHz, CDCl3): δ7.64(d,J=8.0Hz,2H),7.46-7.42(m,3H),7.15-7.11(m,1H),7.03-7.02(m,2H),4.95-4.92(m,1H),4.54(br s,2H),4.21-4.07(m,2H),3.88(s,2H),3.18(t,J=12.8Hz,1H),2.70(t,J=1 3.6Hz,1H),2.34-2.22(m,1H),2.12-1.85(m,3H).MS(ESI):Rt=3.46min,m / z 403.2[M+H] + ,Purity:99.48%@254nm,98.24%@214nm.

[1652] Example 42: 6-(Trifluoromethyl)-1-(1-(2-(4-(trifluoromethyl)phenyl)acetyl)piperidin-4-yl)-1H-benzo[d]imidazol-2(3H)-one (GEN1-009)

[1653]

[1654]

[1655] Step 1. Synthesis of tert-butyl 4-((2-nitro-5-(trifluoromethyl)phenyl)amino)piperidine-1-carboxylate (GEN1-009-1)

[1656]

[1657] A mixture of 2-chloro-1-nitro-4-(trifluoromethyl)benzene (676 mg, 3.00 mmol), KCO (828 mg, 5.99 mmol) and tert-butyl 4-aminopiperidine-1-carboxylate (630 mg, 3.15 mmol) in DMF (5 mL) was stirred at 90° C. for 6 hours. After cooling to room temperature, the reaction mixture was poured into water (50 mL) and extracted with EtOAc (50 mL×2). The combined organic layers were washed with water (25 mL) and brine (25 mL), dried over MgSO and concentrated. The residue was purified by flash chromatography on silica gel (petroleum:ethyl acetate=10:1) to give the desired compound (512 mg, 43% yield) as a yellow oil. 1 HNMR (400MHz, DMSO-d6): δ8.25(d,J=8.8Hz,1H),7.95(d,J=8.0Hz,1H),7.44(s,1H),6.96(dd,J=8.8,1.2Hz,1H ),4.06-3.96(m,1H),3.91-3.88(m,2H),3.32-3.09(m,2H),1.93-1.90(m,2H),1.53-1.44(m,2H),1.41(s,9H).

[1658] Step 2. Synthesis of tert-butyl 4-((2-amino-5-(trifluoromethyl)phenyl)amino)piperidine-1-carboxylate (GEN1-009-2)

[1659]

[1660] To a suspension of tert-butyl 4-((2-nitro-5-(trifluoromethyl)phenyl)amino)piperidine-1-carboxylate (512 mg, 1.31 mmol) in methanol (3 mL), Pd / C (10%, 50 mg) was added under a N2 atmosphere. The resulting mixture was degassed with hydrogen and stirred overnight under a hydrogen atmosphere at 20 degrees Celsius. The reaction mixture was filtered and the filtrate was concentrated to afford the desired compound (418 mg, 77% yield) as a gray solid. MS (ESI): Rt = 1.677 min, m / z 304.1 [M+H] + Purity: 86.28% @ 254nm

[1661] Step 3. Synthesis of tert-butyl 4-(2-oxo-6-(trifluoromethyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-1-carboxylate (GEN1-009-3)

[1662]

[1663] Triphosgene (210 mg, 0.708 mmol) was added to a DCM solution (10 mL) of tert-butyl 4-((2-amino-5-(trifluoromethyl)phenyl)amino)piperidine-1-carboxylate (318 mg, 0.885 mmol) and NaHCO₃ (743 mg, 8.85 mmol) and stirred at 0°C for 2 hours. The reaction mixture was poured into water (50 mL) and extracted with DCM (25 mL x 3). The combined organic layers were washed with brine (25 mL), dried over MgSO₄, and concentrated to afford the desired compound (342 mg, 95% yield) as a red oil. MS (ESI): Rt = 1.450 min, m / z 330.2 [M+H] + Purity: 81.59% @ 254nm

[1664] Step 4. Synthesis of 1-(piperidin-4-yl)-6-(trifluoromethyl)-1H-benzo[d]imidazol-2(3H)-one (GEN1-009-4)

[1665]

[1666] tert-Butyl 4-(2-oxo-6-(trifluoromethyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-1-carboxylate (342 mg, 0.887 mmol) was added to HCl / EA (6 M, 4 ml) and stirred at room temperature for 2 hours. The reaction mixture was concentrated to the desired white solid (256 mg, 64% yield). MS (ESI): Rt = 1.287 min, m / z 286.1 [M+H] + Purity: 71.38% @ 254nm.

[1667] Step 5. Synthesis of 6-(trifluoromethyl)-1-(1-(2-(4-(trifluoromethyl)phenyl)acetyl)piperidin-4-yl)-1H-benzo[d]imidazol-2(3H)-one (GEN1-009)

[1668]

[1669] A solution of 2-(4-(trifluoromethyl)phenyl)acetic acid (146 mg, 0.717 mmol) and DIEA (253 mg, 1.96 mmol) was added to DMF (4 ml). HATU (298 mg, 0.782 mmol) was then added separately at 0°C. After stirring for 10 minutes, 1-(piperidin-4-yl)-6-(trifluoromethyl)-1H-benzo[d]imidazol-2(3H)-one (186 mg, 0.652 mmol) was added. The mixture was stirred at room temperature for 4 hours. The reaction mixture was purified by preparative HPLC (Xbridge C18 5μm 19*150mm; B: 40-80%, A: H2O (0.1% NH4HCO3), B: CH3CN; UV: 214 nm, flow rate: 15 mL / min) to afford the desired compound (34 mg, 11% yield) as a white solid. 1 H NMR (400MHz, DMSO-d6): δ11.32(s,1H),7.68(d,J=8.0Hz,2H),7.51-7.49(m,3H),7.34(d,J=8.4Hz,1H),7.13(d,J=8.0Hz,1H),4.59-4.47(m ,2H),4.4-4.11(m,1H),3.92(s,2H),3.21-3.15(m,1H),2.75-2.68(m,1H),2.22-2.13(m,2H),1.75-1.73(m,2H).MS(ESI):Rt=3.047min,m / z 472.1[M+H] + Purity: 89.46% @ 254nm, 98.72% @ 214nm.

[1670] Example 43: 6-Hydroxy-1-(1-(2-(4-(trifluoromethyl)phenyl)acetyl)piperidin-4-yl)-1H-benzo[d]imidazol-2(3H)-one (GEN1-012)

[1671]

[1672]

[1673] Step 1. Synthesis of tert-butyl 4-((5-hydroxy-2-nitrophenyl)amino)piperidine-1-carboxylate (GEN1-012-1)

[1674]

[1675] To a solution of compound 3-fluoro-4-nitrophenol (1.0 g, 6.4 mmol) and tert-butyl 4-aminopiperidine-1-carboxylate (1.53 g, 7.64 mmol) in DMSO (20 mL) was added K2CO3 (2.20 g, 15.9 mmol). The mixture was stirred at 100 ° C overnight. TLC showed that 80% of the starting material remained. The mixture was stirred at 140 ° C overnight. TLC showed that 40% of the starting material remained. The reaction mixture was cooled to room temperature and diluted with water (100 mL). EtOAc (20 mL) was added and stirred for 5 minutes. The organic layer was discarded and the aqueous layer was acidified to pH = 2 with 1M HCl. The aqueous layer was extracted with EtOAc (50 mL×2). The combined organic phases were washed with brine, dried over anhydrous Na2SO4 and concentrated to give a residue. The residue was purified by column chromatography on silica gel (petroleum oil:ethyl acetate=20:1 to 10:1) to give the desired compound (800 mg, yield 35%) as a yellow solid. 1 H NMR (400MHz, CDCl3): δ8.31(d,J=7.2Hz,1H),8.13(d,J=9.6Hz,1H),6.69(s,1H),6.21-6.20(m,1H),6.19-6.16(m,1 H),4.02-3.99(m,2H),3.61-3.55(m,1H),3.06(t,J=10.4Hz,2H),2.07-2.04(m,2H),1.60-1.52(m,2H),1.48(s,9H).

[1676] Step 2. Synthesis of tert-butyl 4-((5-((tert-butyldimethylsilyl)oxy)-2-nitrophenyl)amino)piperidine-1-carboxylate (GEN1-012-2)

[1677]

[1678] To a solution of tert-butyl 4-((5-hydroxy-2-nitrophenyl)amino)piperidine-1-carboxylate (800 mg, 2.37 mmol) and TEA (480 mg, 4.74 mmol) in DCM (10 mL) was added dropwise at room temperature a solution of tert-butylchlorodimethylsilane (357 mg, 2.37 mmol) in DCM (2 mL). After stirring overnight, the reaction mixture was diluted with water (10 mL) and the phases were separated. The organic phase was washed with brine, dried over Na2SO4 and concentrated. The residue was purified by silica gel column chromatography (PE: EA = 10: 1) to give the desired compound (500 mg, 47% yield) as a yellow solid. MS (ESI) Rt = 1.851 min, m / z 396.0 [M+H-56] +Purity: 89.2% @ 214nm.

[1679] Step 3. Synthesis of tert-butyl 4-((2-amino-5-((tert-butyldimethylsilyl)oxy)phenyl)amino)piperidine-1-carboxylate (GEN1-012-3)

[1680]

[1681] tert-Butyl 4-((5-((tert-butyldimethylsilyl)oxy)-2-nitrophenyl)amino)piperidine-1-carboxylate (500 mg, 1.11 mmol) was added to a solution of THF (3 ml) and MeOH (3 ml), followed by the addition of Pd / C (10%, 150 mg). The mixture was hydrogenated under a hydrogen balloon at 50° C. for 5 hours. The mixture was filtered through celite and concentrated to afford the desired compound (460 mg, 91% yield), which was used directly in the next step. MS (ESI) Rt=1.916 min, m / z 422 [M+H] + Purity: 92% @ 214nm.

[1682] Step 4. Synthesis of tert-butyl 4-(6-(((tert-butyldimethylsilyl)oxy)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-ylpiperidine-1-carboxylate (GEN1-012-4)

[1683]

[1684] To a mixture of tert-butyl 4-[2-amino-5-[tert-butyl(dimethyl)silyl]oxy-anilino]piperidine-1-carboxylate (460 mg, 1.00 mmol) and NaHCO (843.16 mg, 10.04 mmol) was added triphosgene (119 mg, 0.41 mmol) in DCM (50 mL) at room temperature in portions. After stirring at room temperature for 1 hour, the reaction mixture was diluted with water (30 mL) and the phases were separated. The organic phase was washed with brine, dried over Na SO and concentrated. The residue was purified by column chromatography on silica gel (PE: EA = 5: 1 to 1: 1) to give the desired compound (450 mg, 92% yield) as a white solid. 1H NMR (400MHz, DMSO-d6): δ10.66(s,1H),6.82(d,J=8.0Hz,1H),6.60(d,J=1.6Hz,1H),6.47(dd,J=8.0,2.0Hz,1H),4.38-4.29(m,1H),4.08 -4.06(m,2H),2.92-2.84(m,2H),2.16-2.06(m,2H),1.68-1.65(m,2H),1.44(s,9H),0.95(s,9H),0.16(s,6H).MS(ESI),Rt=1.703min,m / z 392.3[M+H-56] + Purity: 91.6% @ 214nm.

[1685] Step 5. Synthesis of 6-hydroxy-1-(piperidin-4-yl)-1H-benzo[d]imidazol-2(3H)-one (GEN1-012-5)

[1686]

[1687] tert-Butyl 4-(6-(((tert-Butyldimethylsilyl)oxy)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-ylpiperidine-1-carboxylate (200 mg, 0.41 mmol) was added to a mixed solution of MeOH (3 ml) and hydrochloric acid (1 ml). The mixture was stirred at room temperature for 2 hours. A 5% aqueous NaOH solution was added to the mixture, and the pH was 7-8. The mixture was concentrated to dryness to give the desired compound (140 mg, yield 99%). MS (ESI) Rt = 0.50 min, m / z 234.1 [M+H] + Purity: 90% @ 214nm, 85% @ 254nm.

[1688] Step 6. Synthesis of 6-hydroxy-1-(1-(2-(4-(trifluoromethyl)phenyl)acetyl)piperidin-4-yl)-1H-benzo[d]imidazol-2(3H)-one (GEN1-012)

[1689]

[1690] In a solution of 6-hydroxy-1-(piperidin-4-yl)-1H-benzo[d]imidazole-2(3H)-one (98 mg, 0.41 mmol), 2-(4-(trifluoromethyl)phenyl)acetic acid (92 mg, 0.45 mmol) and DIEA (264 mg, 2.04 mmol) were dissolved in DMF (5 mL). To this mixture were added HOBT (83 mg, 0.61 mmol) and EDCI (117 mg, 0.61 mmol) and the mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with water (10 mL) and extracted with DCM (5 mL × 3). The combined organic phases were dried over anhydrous NaSO and concentrated. The residue was purified by preparative HPLC [gilson-2, Xbridge C18, 5um, 19x150mm, 30-60%B, A: H2O (0.1%TFA), B: ACN, F=15mL / min, uv purification=214nm] to give the desired compound (55mg, 32% yield) as a white solid. 1 H NMR (400MHz, CDCl3): δ8.65(s,1H),7.63(d,J=8.0Hz,2H),7.45(d,J=7.6Hz,2H ),6.84(d,J=8.4Hz,1H),6.58(d,J=1.6Hz,1H),6.55(d,J=2.0Hz,1H),6.31(br s,1H),4.85(d,J=12.4Hz,1H),4.55-4.47(m,1H),4.02(d,J=12.4Hz,1H),3.89(s,2H),3.20(t,J=12.0Hz,1H ),2.71(t,J=12.0Hz,1H),2.28-2.17(m,1H),2.01-1.92(m,1H),1.78-1.74(m,2H).MS(ESI)Rt=3.202min,m / z 420.2[M+H] + Purity: 99.5% @ 254nm, 99.9% @ 214nm.

[1691] Example 44: 7-Hydroxy-1-(1-(2-(4-(trifluoromethyl)phenyl)acetyl)piperidin-4-yl)-1H-benzo[d]imidazol-2(3H)-one (GEN1-016)

[1692]

[1693]

[1694] Step 1. Synthesis of tert-butyl 4-((2-methoxy-6-nitrophenyl)amino)piperidine-1-carboxylate (GEN1-016-1)

[1695]

[1696] To a solution of 2-chloro-1-methoxy-3-nitrobenzene (3.0 g, 16 mmol) and tert-butyl 4-aminopiperidine-1-carboxylate (6.41 g, 32.0 mmol) in DMF (30 mL) was added K2CO3 (4.42 g, 32.0 mmol), followed by stirring at 120°C for 24 hours. After cooling to room temperature, the resulting mixture was poured into water (300 mL) and extracted with EtOAc (150 mL × 3). The combined organic layers were washed with brine (150 mL), dried over anhydrous Na2SO4, and purified by silica gel column chromatography (PE: EA = 10: 1) to give the desired compound (1.56 g, 26% yield) as a red oil. 1 HNMR (400MHz, CDCl3): δ7.74(dd,J=8.8,1.2Hz,1H),7.50(t,J=8.0,1H),6.95(dd,J=8.0,1.2Hz,1H),6.71(t,J=8.4Hz,1H),4.15-4.06(m,1H),4. 02-3.91(m,2H),3.87(s,3H),2.93(t,J=11.6Hz,2H),1.96-1.92(m,2H), 1.46(s,9H),1.41-1.37(m,2H).MS(ESI)Rt=1.77min,m / z296.2[M+1-56] + Purity: 100% @ 254nm, 94% @ 214nm.

[1697] Step 2. Synthesis of tert-butyl 4-((2-amino-6-methoxyphenyl)amino)piperidine-1-carboxylate (GEN1-016-2)

[1698]

[1699] To a solution of tert-butyl 4-(2-methoxy-6-nitro-anilino)piperidine-1-carboxylate (1.06 g, 3.02 mmol) in MeOH (20 mL) was added Pd / C (321 mg, 0.302 mmol, 10% purity). The mixture was stirred at room temperature under a hydrogen atmosphere for 1 hour. The resulting mixture was filtered and the filtrate was concentrated to give the desired compound (533 mg, 52% yield) as a yellow oil. MS (ESI): Rt = 1.12 min, m / z 322.3 [M+H] + Purity: 91% @ 254nm, 94% @ 214nm.

[1700] Step 3. Synthesis of tert-butyl 4-(7-methoxy-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-1-carboxylate (GEN1-016-3)

[1701]

[1702] NaHCO3 (1.39 g, 16.6 mmol) was added to a solution of tert-butyl 4-(2-amino-6-methoxy-anilino)piperidine-1-carboxylate (533 mg, 1.66 mmol) in DCM (50 mL) at 0°C. Triphosgene (246 mg, 0.829 mmol) was then added portionwise. After stirring at 0°C for 2 hours, the resulting mixture was concentrated and diluted with water (20 mL). EtOAc (50 mL×3) was then added to extract the desired compound. The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4, and purified by a C18 column (50-70% B; A: H2O, B: CH3CN) to give the desired product (530 mg, 75% yield). It was obtained as a white solid. MS (ESI): Rt=1.52 min, m / z 348.3 [M+H] + Purity: 82% @ 254nm, 100% @ 214nm.

[1703] Step 4. Synthesis of 7-hydroxy-1-(piperidin-4-yl)-1H-benzo[d]imidazol-2(3H)-one (GEN1-016-4)

[1704]

[1705] Tert-butyl 4-(7-methoxy-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-1-carboxylate (200 mg, 0.576 mmol) was dissolved in HI (45% in water, 5 mL) and stirred at 130°C for 3 hours. The mixture was cooled to room temperature and DIEA (5 mL) was added. The mixture was concentrated to give the compound (3.06 g crude) as a white solid. MS (ESI): Rt = 0.48 min, m / z 234.1 [M+H] + Purity: 100% @ 254nm, 100% @ 214nm.

[1706] Step 5. Synthesis of 7-hydroxy-1-(1-(2-(4-(trifluoromethyl)phenyl)acetyl)piperidin-4-yl)-1H-benzo[d]imidazol-2(3H)-one (GEN1-016)

[1707]

[1708] 7-Hydroxy-1-(piperidin-4-yl)-1H-benzo[d]imidazol-2(3H)-one (135 mg, crude), 2-[4-(trifluoromethyl)phenyl]acetic acid (177 mg, 0.867 mmol), HATU (440 mg, 1.16 mmol), and DIEA (224 mg, 1.73 mmol) were dissolved in DMF (6 mL) and stirred at room temperature for 16 hours. The resulting mixture was purified by preparative HPLC (RP-PREP-1 Xbridge C18 5 μm 19*150 mm, 20%-65% B; A: H2O (0.1% NH4HCO3), B: CH3CN; UV: 254 nm, flow rate: 15 mL / min) to afford the desired product (110 mg, 45% yield over two steps) as a white solid. 1 HNMR (400MHz, DMSO-d6): δ10.75(s,1H),9.87(s,1H),7.69(d,J=8.0Hz,2H),7.47(d,J=8.0Hz, 2H),6.79(t,J=8.0Hz,1H),6.51-6.45(m,2H),4.80-4.66(m,1H),4.55(d,J=13.6Hz,1H),4.09( d,J=14.0Hz,1H),3.93(d,J=15.6Hz,1H),3.83(d,J=15.6Hz,1H),3.12(t,J=12.4Hz,1H),2.64( t,J=12.0Hz,1H),2.47-2.35(m,2H),1.67-1.64(m,2H).MS(ESI):Rt=3.344min,m / z420.1[M+H] + Purity: 94.81% @ 254nm, 99.63% @ 214nm.

[1709] Example 45: N-((1s,3s)-3-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)cyclobutyl)-2-(4-(trifluoromethyl)phenyl)acetamide

[1710]

[1711]

[1712] Step 1. Synthesis of tert-butyl ((1s,3s)-3-((2-nitrophenyl)amino)cyclobutyl)carbamate (GEN1-024-1)

[1713]

[1714] To a solution of tert-butyl ((1s, 3s)-3-aminocyclobutyl)carbamate (500 mg, 2.68 mmol) and 1-fluoro-2-nitrobenzene (455 mg, 3.22 mmol) in DMF (10 mL) was added KCO (557 mg, 4.03 mmol). After stirring overnight at 80 ° C, the resulting mixture was cooled to room temperature and poured into water (25 mL). EtOAc (80 mL × 4) was added to extract the desired compound. The combined organic layer was washed with brine (20 mL), dried over anhydrous NaSO and filtered. The filtrate was concentrated and the residue was purified by C18 column (CHCN: water = 55-75%) to give the desired compound (758 mg, yield 92%) as a yellow solid. MS (ESI): Rt = 1.66 min, m / z 252.2 [M + H-56] + Purity: 100% @ 254nm, 16% @ 214nm.

[1715] Step 2. Synthesis of tert-butyl ((1s,3s)-3-((2-aminophenyl)amino)cyclobutyl)carbamate (GEN1-024-2)

[1716]

[1717] To a solution of tert-butyl ((1s,3s)-3-(((2-nitrophenyl)amino)cyclobutyl)carbamate (758 mg, 2.47 mmol) in MeOH (30 mL) was added Pd / C (10%, 262 mg, 0.246 mmol). After stirring at room temperature for 3 hours under a hydrogen atmosphere, the resulting mixture was filtered. The filtrate was concentrated to give the desired compound (666 mg, 97% yield) as a brown solid. MS (ESI): Rt = 1.54 min, m / z 278.4 [M+H] + Purity: 100% @ 254nm, 100% @ 214nm.

[1718] Step 3. Synthesis of tert-butyl ((1s,3s)-3-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)cyclobutyl)carbamate (GEN1-024-3)

[1719]

[1720] To a suspension of tert-butyl ((1s,3s)-3-(((2-aminophenyl)amino)cyclobutyl)carbamate and NaHCO (2.02 g, 24.0 mmol) in DCM (30 mL) was added triphosgene (356 mg, 1.20 mmol). After stirring at 0° C. for 1 hour, the resulting mixture was filtered. The filtrate was concentrated and the residue was purified by C18 column (CHCN:water=45-65%) to give the desired compound (619 mg, 85% yield) as a white solid. MS (ESI): Rt=1.44 min, m / z 304.2 [M+H-100] + Purity: 100% @ 254nm, 100% @ 214nm.

[1721] Step 4. Synthesis of 1-((1s,3s)-3-aminocyclobutyl)-1H-benzo[d]imidazole-2(3H)-one (GEN1-024-4)

[1722]

[1723] To tert-butyl ((1s, 3s)-3-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)cyclobutyl)carbamate (250 mg, 824 umol) was added DCM (5 mL) and TFA (1 mL). The resulting mixture was stirred at room temperature for 2 hours. The resulting mixture was basified to pH = 8-10 with aqueous Na2CO3 solution. The mixture was then separated and the organic layer was concentrated. The residue was purified by C18 column (CH3CN:water = 20-40%) to give the desired compound (140 mg, yield 84%) as a light yellow oil. MS (ESI): Rt = 0.70 min, m / z 204.2 [M+H] + Purity: 100% @ 254nm, 100% @ 214nm.

[1724] Step 5. Synthesis of N-((1s,3s)-3-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)cyclobutyl)-2-(4-(trifluoromethyl)phenyl)acetamide (GEN1-024)

[1725]

[1726] 1-((1s,3s)-3-Aminocyclobutyl)-1H-benzo[d]imidazole-2(3H)-one (140 mg, 0.689 mmol), EDCI (198 mg, 1.03 mmol), HOBT (140 mg, 1.04 mmol), and DIEA (267 mg, 2.07 mmol) were dissolved in DMF (2 mL), and 2-[4-(trifluoromethyl)phenyl]acetic acid (155 mg, 0.759 mmol) was added. The mixture was stirred at room temperature overnight. The mixture was then purified by preparative HPLC (Prep 5 Xbridge C18 5um 19*150mm, 30-70% B; A: H2O (0.1% NH4HCO3), B: CH3CN; 214 nm; flow rate: 15 mL / min) to afford the desired compound (104 mg, 38% yield) as a white solid. 1 HNMR (400MHz, DMSO-d6): δ10.86(s,1H),8.64(d,J=7.6Hz,1H),7.68(d,J=8.0Hz,2H),7.50(d,J=8.0Hz,2H),7.42-7.39(m,1H),7.0 5-6.97(m,3H),4.57-4.48(m,1H),4.11-4.01(m,1H),3.55(s,2H),2.81-2.73(m,2H),2.63-2.56(m,2H).MS(ESI):Rt=3.486min,m / z 390.1[M+H] + Purity: 97.40% @ 254nm, 98.82% @ 214nm.

[1727] Example 46: N-((1r,3r)-3-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)cyclobutyl)-2-(4-(trifluoromethyl)phenyl)acetamide

[1728]

[1729]

[1730] Step 1. Synthesis of tert-butyl ((1r,3r)-3-(((2-nitrophenyl)amino)cyclobutyl)carbamate (GEN1-025-1)

[1731]

[1732] To a solution of 1-fluoro-2-nitrobenzene (273 mg, 1.93 mmol) and tert-butyl ((1r, 3r)-3-aminocyclobutyl) carbamate (300 mg, 1.61 mmol) in DMF (4 mL) was added K CO (334 mg, 2.42 mmol). The mixture was stirred at 80° C. for 16 hours. The mixture was filtered and the filtrate was purified by C18 column (CH CN:water=55-75%) to give the desired compound (466 mg, 94% yield) as a yellow solid. 1 HNMR (400MHz, CDCl3): δ8.18 (dd, J=8.8, 1.6Hz, 1H), 8.11 (br s,1H),7.42(t,J=6.8Hz,1H),6.70-6.66(m,1H),6.60(d,J=8.0Hz,1H),4.79(b rs,1H),4.33-4.31(m,1H),4.16-4.09(m,1H),2.45-2.40(m,4H),1.46(s,9H).

[1733] Step 2. Synthesis of tert-butyl ((1r,3r)-3-((2-aminophenyl)amino)cyclobutyl)carbamate (GEN1-025-2)

[1734]

[1735] To a solution of tert-butyl ((1r,3r)-3-(((2-nitrophenyl)amino)cyclobutyl)carbamate (416 mg, 1.35 mmol) in MeOH (20 mL) was added Pd / C (10%, 144 mg, 0.135 mmol). The mixture was stirred at room temperature under a hydrogen atmosphere for 2 hours. The resulting mixture was filtered and the filtrate was concentrated. The residue was purified by C18 column (CH3CN:water=50-70%) to give the desired compound (357 mg, 95% yield) as a brown solid. MS (ESI): Rt=1.51 min, m / z 222.2 [M+H-56] + Purity: 100% @ 254nm, 100% @ 214nm.

[1736] Step 3. Synthesis of tert-butyl ((1r,3r)-3-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)cyclobutyl)carbamate (GEN1-025-3)

[1737]

[1738] To a suspension of (tert-butyl)((1r,3r)-3-((2-aminophenyl)amino)cyclobutyl)carbamate (350 mg, 1.26 mmol) and NaHCO 3 (1.06 g, 12.6 mmol) in dichloromethane (25 mL) was added triphosgene (187 mg, 0.630 mmol). After stirring at 0° C. for 1 hour, the resulting mixture was filtered. The filtrate was concentrated and the residue was purified by C18 column (CH 3 CN:water=50-70%) to give the desired compound (344 mg, 90% yield) as a gray solid. MS (ESI): Rt=1.46 min, m / z 248.2 [M+H-56] + Purity: 100% @ 254nm, 100% @ 214nm.

[1739] Step 4. Synthesis of 1-((1R,3R)-3-aminocyclobutyl)-1H-benzo[d]imidazol-2(3H)-one (GEN1-025-4)

[1740]

[1741] To a solution of tert-butyl ((1r, 3r)-3-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)cyclobutyl)carbamate (395 mg, 1.30 mmol) was added DCM (5 mL) and TFA (1 mL). The mixture was stirred at room temperature for 2 hours. The resulting mixture was basified to pH = 8-10 with aqueous Na2CO3 solution. The mixture was then separated and the organic layer was concentrated. The residue was purified by C18 column (CH3CN:water = 15-35%) to give the desired compound (179 mg, 61% yield) as a white solid. MS (ESI): Rt = 0.31 min, m / z 204.1 [M+H] + Purity: 99% @ 254nm, 76% @ 214nm.

[1742] Step 5. Synthesis of N-((1r,3r)-3-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)cyclobutyl)-2-(4-(trifluoromethyl)phenyl)acetamide (GEN1-025)

[1743]

[1744] To a solution of 1-((1r,3r)-3-aminocyclobutyl)-1H-benzo[d]imidazol-2(3H)-one (100 mg, 0.492 mmol), HATU (281 mg, 0.739 mmol), and DIEA (191 mg, 1.48 mmol) in DMF (2 mL) was added 2-[4-(trifluoromethyl)phenyl]acetic acid (121 mg, 0.593 mmol). After the addition was complete, the mixture was stirred at room temperature for 16 hours. The resulting mixture was purified by preparative HPLC (prep-5 Xbridge C18 5um 19*150mm, 30%-70% B; A: H2O (0.1% NH4HCO3), B: CH3CN; 214 nm, flow rate: 15 mL / min) to afford the desired compound (68 mg, 34% yield) as a white solid. 1 HNMR (400MHz, DMSO-d6): δ10.86(s,1H),8.73(d,J=6.8Hz,1H),7.68(d,J=8.0Hz,2H),7.51(d,J=8.0Hz,2H),7.32-7.30(m,1H),7.03-6.9 7(m,3H),5.16-5.07(m,1H),4.37-4.35(m,1H),3.57(s,2H),3.12-3.04(m,2H),2.31-2.24(m,2H).MS(ESI):Rt=3.723min,m / z390.2[M+H] + Purity: 86.87% @ 254nm, 96.20% @ 214nm.

[1745] Example 47: 1-(1-(2-(4-(trifluoromethyl)phenyl)acetyl)piperidin-4-yl)-1H-imidazo[4,5-b]pyridin-2(3H)-one

[1746]

[1747] Step 1. Synthesis of tert-butyl 4-((2-aminopyridin-3-yl)amino)piperidine-1-carboxylate (GEN1-041-1)

[1748]

[1749] To a suspension of tert-butyl 4-oxopiperidine-1-formate (1.00 g, 5.04 mmol) in acetonitrile (10 mL), pyridine-2,3-diamine (500 mg, 4.58 mmol) was added. After stirring at room temperature for 30 minutes, all solid matter was completely dissolved. The reaction mixture was cooled to 0 ° C, and TFA (0.7 mL) was added dropwise within 1 minute. The reaction mixture was stirred for another 30 minutes, and sodium triacetoxyborohydride (1.46 g, 6.87 mmol) was added. The mixture was then stirred at room temperature for another 30 minutes. The mixture was cooled to 0 ° C, and alkalized to pH = 13 with a NaOH aqueous solution (4 M). The mixture was stirred for another 30 minutes and diluted with ice water (50 mL). The mixture was extracted with DCM (50 mL × 3). The combined organic layer was washed with brine (50 mL) and dried over anhydrous Na2SO4. The solution was concentrated, and the residue was purified by column chromatography on silica gel (DCM (0.1% TEA): MeOH = 40:1) and further purified by C18 (50-70% B; A: H2O B: CH3CN). The desired compound (382 mg, 25% yield) was obtained as a light brown solid. MS (ESI): Rt = 1.45 min, m / z 293.4 [M+H] + Purity: 87% @ 254nm, 89% @ 214nm.

[1750] Step 2. Synthesis of tert-butyl 4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)piperidine-1-carboxylate (GEN1-041-2)

[1751]

[1752] To a solution of tert-butyl 4-((2-aminopyridin-3-yl)amino)piperidine-1-carboxylate (367 mg, 1.26 mmol) and TEA (254 mg, 2.51 mmol) in THF (10 mL) was slowly added triphosgene (372 mg, 1.25 mmol) in an ice-water bath. After completion of the addition, the mixture was stirred at room temperature for 2 hours. The resulting mixture was concentrated and basified to pH = 8-10 with saturated Na2CO3. DCM (30 mL×3) was added to extract the desired compound. The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4 and concentrated. The residue was purified by C18 column (45-65% B; A: H2O B: CH3CN) to give the desired compound (159 mg, 37% yield) as a yellow solid.

[1753] MS(ESI):Rt=1.38min,m / z 317.4[MH] - Purity: 94% @ 254nm, 100% @ 214nm.

[1754] Step 3. Synthesis of 1-(piperidin-4-yl)-1H-imidazo[4,5-b]pyridine-2(3H)-monohydrochloride (GEN1-041-3)

[1755]

[1756] A solution of tert-butyl 4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)piperidine-1-carboxylate (159 mg, 0.499 mmol) in HCl / MeOH (4 M, 5 mL) was stirred at room temperature for 3 hours. Concentration afforded the desired compound (173 mg, 67% yield) as a light yellow solid. MS (ESI): Rt = 0.30 min, m / z 219.3 [M+H] + Purity: 94% @ 254nm, 100% @ 214nm.

[1757] Step 4. Synthesis of 1-(1-(2-(4-(trifluoromethyl)phenyl)acetyl)piperidin-4-yl)-1H-imidazo[4,5-b]pyridin-2(3H)-one (GEN1-041)

[1758]

[1759] To 1-(piperidin-4-yl)-1H-imidazo[4,5-b]pyridine-2(3H)-monohydrochloride (173 mg, 0.594 mmol), DIEA (384 mg, 2.97 mmol), EDCI (171 mg, 0.892 mmol), HOBT (120 mg, 0.888 mmol) and 2-(4-(trifluoromethyl)phenyl)acetic acid (146 mg, 0.715 mmol) was stirred in DMF (2 mL) at room temperature overnight. The resulting mixture was purified by C18 (45-65% B; A: H2O B: CH3CN) to give the desired compound (70 mg, 29% yield) as a white solid. 1HNMR (400MHz, CDCl3): δ10.18(s,1H),8.05(dd,J=5.6,1.2Hz,1H),7.64(d,J=8.0Hz,2 H),7.46(d,J=8.0Hz,2H),7.03(dd,J=7.6,1.2Hz,1H),6.97-6.93(m,1H),4.89(d,J=1 3.6Hz,1H),4.60-4.51(m,1H),4.06(d,J=13.6Hz,1H),3.87(s,2H),3.24-3.16(m,1H) ,2.75-2.67(m,1H),2.19-2.08(m,1H),1.93-1.84(m,3H).MS(ESI):Rt=3.263min,m / z 405.1[M+H] + Purity: 96.18% @ 254nm, 98.61% @ 214nm.

[1760] Example 48: 1-(1-(2-(4-(trifluoromethyl)phenyl)acetyl)piperidin-4-yl)-1H-imidazo[4,5-c]pyridin-2(3H)-one

[1761]

[1762] Step 1. Synthesis of tert-butyl 4-((3-nitropyridin-4-yl)amino)piperidine-1-carboxylate (GEN1-228-1)

[1763]

[1764] To a solution of 4-chloro-3-nitropyridine (500 mg, 3.15 mmol) and tert-butyl 4-aminopiperidine-1-carboxylate (695 mg, 3.47 mmol) in DMF (5 mL) was added TEA (479 mg, 4.73 mmol). The resulting mixture was stirred at room temperature overnight. The reaction mixture was poured into water (50 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (30 mL), dried over MgSO4, filtered and concentrated to give the desired compound (1.1 g, yield 98%) as a yellow oil. MS (ESI): Rt = 1.57 min, m / z 323.3 [M+H] + Purity: 91% @ 254nm, 81% @ 214nm.

[1765] Step 2. Synthesis of tert-butyl 4-((3-aminopyridin-4-yl)amino)piperidine-1-carboxylate (GEN1-042-1)

[1766]

[1767] To a solution of tert-butyl 4-((3-nitropyridin-4-yl)amino)piperidine-1-carboxylate (400 mg, 1.24 mmol, see the final report of GEN1-228-1 for the synthesis procedure) in MeOH (10 mL) was added Pd / C (10%, 132 mg). The mixture was stirred at room temperature under hydrogen for 2 hours. The resulting mixture was filtered, and the filtrate was concentrated to obtain the desired compound (360 mg, 99% yield) as a gray solid. MS (ESI): Rt = 1.36 min, m / z 293.4 [M+H] + Purity: 100% @ 254nm, 100% @ 214nm.

[1768] Step 3. Synthesis of tert-butyl 4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)piperidine-1-carboxylate (GEN1-042-2)

[1769]

[1770] To a solution of tert-butyl 4-((3-aminopyridin-4-yl)amino)piperidine-1-carboxylate (310 mg, 1.06 mmol) and TEA (215 mg, 2.12 mmol) in THF (15 mL) was added triphosgene (378 mg, 1.27 mmol). After addition, the mixture was stirred at room temperature for 1 hour. The mixture was then basified to pH = 7-8 with saturated NaHCO 3 . DCM (40 mL×3) was added to extract the desired compound. The combined organic phases were washed with brine (50 mL), dried over anhydrous Na 2 SO 4 and purified by C18 (40-60% B; A: H 2 OB: CH 3 CN) to give the desired compound (243 mg, yield 72%) as a light yellow solid. MS (ESI): Rt=1.34 min, m / z 319.4 [M+H] + Purity: 100% @ 254nm, 100% @ 214nm.

[1771] Step 4. Synthesis of 1-(piperidin-4-yl)-1H-imidazo[4,5-c]pyridine-2(3H)-monohydrochloride (GEN1-042-3)

[1772]

[1773] A solution of tert-butyl 4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)piperidine-1-carboxylate (150 mg, 0.471 mmol) in HCl / MeOH (2 M, 10 mL) was stirred at room temperature for 4 hours. The resulting mixture was concentrated to afford the desired compound (119 mg, 100% yield) as a white solid. MS (ESI): Rt = 0.29 min, m / z 219.2 [M+H] + Purity: 100% @ 254nm, 100% @ 214nm.

[1774] Step 5. Synthesis of 1-(1-(2-(4-(trifluoromethyl)phenyl)acetyl)piperidin-4-yl)-1H-imidazo[4,5-c]pyridin-2(3H)-one (GEN1-042)

[1775]

[1776] To 1-(piperidin-4-yl)-1H-imidazo[4,5-c]pyridine-2-(3H)-monohydrochloride (119 mg, 0.470 mmol) and DIEA (353 mg, 2.73 mmol) was added EDCI (157 mg, 0.819 mmol), HOBT (111 mg, 0.821 mmol), and 2-(4-(trifluoromethyl)phenyl)acetic acid (123 mg, 0.603 mmol) dissolved in DMF (3 mL) and stirred overnight at room temperature. The mixture was then purified by preparative HPLC (water 3 sunfire C18 5um 19*150mm, 10-40% B; A: H2O (0.1% TFA), B: CH3CN; 214 nm; flow rate: 15 mL / min) to give the desired compound (120 mg, 63% yield) as a white solid. 1 H NMR (400MHz, CDCl3): δ9.50 (s, 1H), 8.37 (s, 1H), 8.26 (d, J = 6.0Hz, 1H), 7.64 (d, J = 8.0Hz, 2H),7.45(d,J=8.0Hz,2H),6.83(d,J=4.8Hz,1H),4.91(d,J=13.2Hz,1H),4.54-4.46(m,1H ),4.07(d,J=13.2Hz,1H),3.88(s,2H),3.24-3.18(m,1H),2.75-2.69(m,1H),2.27-2.16( m,1H),2.03-1.94(m,1H),1.93-1.90(m,1H),1.85-1.82(m,1H).MS(ESI)Rt=3.486min,m / z 405.2[M+H]+ Purity: 98.96% @ 254nm, 98.42% @ 214nm.

[1777] Example 49: 3-(1-(2-(4-(trifluoromethyl)phenyl)acetyl)piperidin-4-yl)-1H-imidazo[4,5-c]pyridin-2(3H)-one (GEN1-043)

[1778]

[1779] Step 1. Synthesis of tert-butyl 4-((4-aminopyridin-3-yl)amino)piperidine-1-carboxylate (GEN1-043-1)

[1780]

[1781] To a solution of pyridine 3,4-diamine (1.0 g, 9.2 mmol), tert-butyl 4-oxopiperidine-1-carboxylate (3.10 g, 15.6 mmol) and acetic acid (10.5 g, 174 mmol) in 1,2-dichloroethane (10 mL) was added NaBH(OAc)3 (3.69 g, 17.4 mmol). The resulting mixture was stirred at room temperature for 3 days. The resulting mixture was concentrated and saturated Na2CO3 (50 mL) was added. The mixture was extracted with DCM (100 mL×5), and the combined organic layers were dried over anhydrous Na2SO4 and concentrated. The crude product was purified by silica gel column (DCM:MeOH=10:1) to give the desired compound (620 mg, yield 23%) as a yellow solid. MS (ESI) Rt=1.32 min, m / z 293.3 [M+H] + Purity: 100% @ 254nm, 100% @ 214nm.

[1782] Step 2. Synthesis of 3-(piperidin-4-yl)-1H-imidazo[4,5-c]pyridin-2(3H)-one (GEN1-043-2)

[1783]

[1784] To a solution of tert-butyl 4-((4-aminopyridin-3-yl)amino)piperidine-1-carboxylate (450 mg, 1.54 mmol) and TEA (312 mg, 3.08 mmol) in THF (7.50 mL) was added triphosgene (457 mg, 1.54 mmol) at 0°C. The mixture was then stirred at room temperature for 1 hour. Water (5 mL) was then added, and the mixture was stirred at 55°C for another 15 minutes. The resulting mixture was concentrated, and the mixture was purified by C18 (5-25% B; A: H2O, B: CH3CN) to give the desired compound (234 mg, 70% yield) as a white solid. MS (ESI): Rt = 0.29 min, m / z 219.2 [M+H] + Purity: 100% @ 254nm, 100% @ 214nm.

[1785] Step 3. Synthesis of 3-(1-(2-(4-(trifluoromethyl)phenyl)acetyl)piperidin-4-yl)-1H-imidazo[4,5-c]pyridin-2(3H)-one (GEN1-043)

[1786]

[1787] 3-(4-Piperidinyl)-1H-imidazo[4,5-c]pyridin-2-one (100 mg, 0.458 mumol), 2-[4-(trifluoromethyl)phenyl]acetic acid (113 mg, 0.554 mmol), HOBt (99 mg, 0.73 mmol), DIEA (296 mg, 2.29 mmol), and EDCI (141 mg, 0.736 mmol) were dissolved in DMF (3 mL). The mixture was stirred at room temperature for 16 hours. The resulting mixture was purified by preparative HPLC (prep-5 Xbridge C18 5um 19*150mm, 15-55...

Claims

1. A compound as shown in Formula XII or a pharmaceutically acceptable salt thereof; in, W is any of the following groups: (1) In is a single bond or a double bond; when In When Y is a single bond, 1 is C(=O), O, NH, or NR 3 , R 3 is CH2COOH or C1-C4 alkyl, Y 2 is NH, C=O or C=S; when In When Y is a double bond, 1 N, Y 2 is C-NH2, C-NH-CN or CO-CH3; Y 3 N or CH; X 1 N or CR 2 , X 2 N or CR 4 , X 3 CR 5 , X 4 N or CR 6 ; R 2 , R 4 , R 5 and R 6 are independently hydrogen, halogen, hydroxy, amino, carboxyl, cyano, nitro, C1-C4 alkyl, C1-C4 alkyl substituted with one or more halogens, C1-C4 alkoxy, C3-C6 cycloalkyl, phenyl, -S(=O)2-R 2-1 、-NH-S(=O)2-R 2-2 、-S(=O)2-NR 2-3 R 2-4 , -C(=O)-R 2-5 or -NH-C(=O)-R 2-6 ; R 2-1 , R 2-2 , R 2-3 , R 2-4 , R 2-5 and R 2-6 are independently hydrogen, C1-C4 alkyl, or C1-C4 alkyl substituted with one or more halogens; Z is the following fragment: (1) m is 1 or 2, n is 1, 2 or 3; R 1 -(CH2) s -R 1-1 ;s is 1; R 1-1 is “a 5- or 10-membered heteroaryl group containing 1, 2 or 3 groups independently selected from N, O and S”; the “a 5- or 10-membered heteroaryl group containing 1, 2 or 3 groups independently selected from N, O and S” is quinolyl.

2. The compound of formula XII or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that: R 2 , R 4 , R 5 and R 6 At least one of them is halogen, hydroxyl, amino, carboxyl, cyano, nitro, C1-C4 alkyl, C1-C4 alkyl substituted with one or more halogens, C1-C4 alkoxy, C3-C6 cycloalkyl, phenyl, -S(=O)2-R 2-1 、-NH-S(=O)2-R 2-2 、-S(=O)2-NR 2-3 R 2-4 , -C(=O)-R 2-5 , or, -NH-C(=O)-R 2-6 ; R 2-1 , R 2-2 , R 2-3 , R 2-4 , R 2-5 and R 2-6 are independently C1-C4 alkyl, or C1-C4 alkyl substituted with one or more halogens, and the rest are hydrogen.

3. The compound of formula XII or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that: W is any of the following groups: (1) In is a single bond or a double bond; when In When Y is a single bond, 1 is C(=O), O, NH, or NR 3 , R 3 is CH2COOH or C1-C4 alkyl, Y 2 is NH, C=O or C=S; when In When Y is a double bond, 1 N, Y 2 is C-NH2 or C-NH-CN; Y 3 N or CH; X 1 N or CR 2 , X 2 N or CR 4 , X 3 CR 5 , X 4 N or CR 6 ; R 2 , R 4 , R 5 and R 6 independently hydrogen, halogen, hydroxyl, amino, carboxyl, cyano, nitro, C1-C4 alkyl, C1-C4 alkyl substituted with one or more halogens, C1-C4 alkoxy, C3-C6 cycloalkyl, phenyl, or -S(=O)2-NR 2-3 R 2-4 ; R 2-3 and R 2-4 are independently hydrogen.

4. The compound of formula XII or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, characterized in that: When R 3 When it is a C1-C4 alkyl group, the C1-C4 alkyl group is a methyl group; and / or, when R 2 , R 4 , R 5 and R 6 When independently halogen, the halogen is fluorine, chlorine or bromine; and / or, when R 2 , R 4 , R 5 and R 6 When they are independently C1-C4 alkyl, the C1-C4 alkyl is methyl or tert-butyl; and / or, when R 2 , R 4 , R 5 and R 6 When the plurality of halogen-substituted C1-C4 alkyl groups are independently substituted, the plurality is 2 or 3; and / or, when R 2 , R 4 , R 5 and R 6 When they are independently C1-C4 alkyl substituted with one or more halogens, the halogen is fluorine; and / or, when R 2 , R 4 , R 5 and R 6 When independently one or more halogen-substituted C1-C4 alkyl groups, the C1-C4 alkyl group is methyl; and / or, when R 2 , R 4 , R 5 and R 6 When they are independently C1-C4 alkoxy, the C1-C4 alkoxy is methoxy; and / or, when R 2 , R 4 , R 5 and R 6 When they are independently C3-C6 cycloalkyl, the C3-C6 cycloalkyl is cyclopropyl; and / or, when R 2-1 , R 2-2 , R 2-3 , R 2-4 , R 2-5 and R 2-6 When they are independently C1-C4 alkyl, the C1-C4 alkyl is methyl or tert-butyl; and / or, when R 2-1 , R 2-2 , R 2-3 , R 2-4 , R 2-5 and R 2-6 When the plurality of halogen-substituted C1-C4 alkyl groups are independently substituted, the plurality is 2 or 3; and / or, when R 2-1 , R 2-2 , R 2-3 , R 2-4 , R 2-5 and R 2-6 When they are independently C1-C4 alkyl substituted with one or more halogens, the halogen is fluorine; and / or, when R 2-1 , R 2-2 , R 2-3 , R 2-4 , R 2-5 and R 2-6 When independently one or more halogen-substituted C1-C4 alkyl groups, the C1-C4 alkyl group is methyl; And / or, when W is hour, for And / or, when Z is When m is 1 and n is 1, or m is 2 and n is 2; And / or, when Z is When for Its b end and R 1 connect.

5. The compound of formula XII or a pharmaceutically acceptable salt thereof according to claim 4, characterized in that: When R 2 , R 4 , R 5 and R 6 When they are independently C1-C4 alkyl, the C1-C4 alkyl is tert-butyl; and / or, when R 2 , R 4 , R 5 and R 6 When they are independently multiple halogen-substituted C1-C4 alkyl groups, the multiple halogen-substituted C1-C4 alkyl groups are trifluoromethyl groups; and / or, when R 2-1 , R 2-2 , R 2-3 , R 2-4 , R 2-5 and R 2-6 When they are independently C1-C4 alkyl, the C1-C4 alkyl is methyl or tert-butyl; and / or, when R 2-1 , R 2-2 , R 2-3 , R 2-4 , R 2-5 and R 2-6 When they are independently multiple halogen-substituted C1-C4 alkyl groups, the multiple halogen-substituted C1-C4 alkyl groups are trifluoromethyl groups.

6. The compound of formula XII or a pharmaceutically acceptable salt thereof according to claim 5, characterized in that: The "5- or 10-membered heteroaryl group containing 1, 2 or 3 independently selected from N, O and S" is 7. A compound or a pharmaceutically acceptable salt thereof, characterized in that: The compound is any of the following structures:

8. A pharmaceutical composition comprising substance Y and a pharmaceutical excipient; The substance Y is a compound represented by formula XII or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 6, or a compound or a pharmaceutically acceptable salt thereof according to claim 7.

9. Use of a substance Y in the preparation of a STAT5 inhibitor; The substance Y is a compound represented by formula XII or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 6, or a compound or a pharmaceutically acceptable salt thereof according to claim 7.

10. Use of a substance Y in the preparation of a drug; The medicine is a medicine for treating and / or preventing rheumatoid arthritis.

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