Multi-target degradation agent and application thereof

Abstract

The invention provides a stereoisomer, an N-oxide, a deuterated derivative and a pharmaceutically acceptable salt of the compound shown in the formula (I), the compound can degrade BTK protein and / or IRAK4 protein, BTK and IRAK4 protein can be degraded in various tumor cells at the same time, proliferation of the tumor cells is efficiently inhibited, tumor cell apoptosis is induced, and the compound has a good application prospect. Meanwhile, a novel treatment medicine can be provided for cancers and self-immune diseases thereof.

Description

Technical Field

[0001] The present invention relates to the field of medicinal chemistry, and in particular to a multi-target degradation agent, a preparation method thereof, and uses thereof. Background Art

[0002] Interleukin-1 receptor kinase 4 (IRAK4) is a serine / threonine-specific protein kinase. As a key mediator at the intersection of interleukin (IL)-1 family receptors and Toll-like receptors (TLR) signaling, IRAK4 has a wide range of physiological functions. IRAK4 undergoes autophosphorylation and activates the activity of other IRAKs, leading to the activation of downstream signaling pathways (such as NF-κB, JNK, and p38), thereby promoting inflammatory cytokine secretion and immune cell proliferation and differentiation. IRAK4 plays a connecting role in this entire signaling pathway, altering its activity through conformational changes and post-translational modifications. Within the myddosome, IRAK4 is activated through trans-autophosphorylation, which then activates IRAK1 / 2 through phosphorylation, further activating downstream signaling pathways and producing pro-inflammatory cytokines. Previous pharmacological studies have shown that IRAK4 activity plays a key role in various inflammatory diseases, such as arthritis, atherosclerosis, Alzheimer's disease, gout, systemic lupus erythematosus, and psoriasis. Some studies have shown therapeutic effects on inflammatory diseases (such as septic shock, SLE, cardiovascular disease, and Alzheimer's disease) by mutating IRAK4 or inhibiting its activity in animal models. Therefore, IRAK4 has become an important target for drug development, and inhibiting IRAK4 activity can achieve the treatment of various diseases such as inflammatory diseases, autoimmune diseases, and tumors.

[0003] Bruton's tyrosine kinase (BTK) is a non-receptor cytoplasmic tyrosine kinase in the Tec family. In B lymphocytes, BTK activity is crucial for B cell receptor (BCR)-mediated activation, which can lead to cell development, antibody and cytokine production, and the expression of co-stimulatory molecules. BTK is a key kinase that connects BCR signaling, FcR signaling, TLR signaling, and chemokine receptor signaling. BTK's central role in B cell signaling and function makes it an important drug development target for B cell malignancies, as well as autoimmune and inflammatory diseases. Currently, several BTK inhibitors are approved primarily for the treatment of chronic lymphocytic leukemia (CLL), mantle cell lymphoma (MCL), and other B cell malignancies, as well as graft-versus-host disease (GvHD). Currently, a variety of inflammatory or autoimmune diseases driven by B cells or myeloid cells are gradually becoming important indications for BTK inhibitor clinical research, and multiple BTK molecules have entered clinical research. However, to date, no BTK inhibitors have been approved for inflammatory or autoimmune diseases.

[0004] Currently, research on activated B-cell-like diffuse large B-cell lymphoma (ABC-DLBCL) has found that patients with the MyD88L265P mutation in ABC-DLBCL have a poor response to BCR inhibitors due to abnormal MyD88 signaling pathways. Furthermore, extensive research data from Bayer, Nimbus, and AstraZeneca demonstrate that the combination of an IRAK4 inhibitor and a BTK inhibitor significantly enhances the in vivo efficacy of ibrutinib in ABC-DLBCL xenograft animal models. Effectively inhibiting both the BCR and MyD88 pathways would be a more effective approach for treating ABC-DLBCL. Therefore, developing inhibitors that dually target RAK4 and BTK could achieve dual benefits in blocking the NF-κB pathway. This is a highly effective and efficient strategy based on therapeutic mechanisms, providing a potentially effective new treatment for ABC-DLBCL patients.

[0005] PROTAC (Proteolysis Targeting Chimeras) technology, also known as protein-targeted degradation technology, is an emerging chemical probe or drug discovery method that uses the ubiquitin-proteasome system to induce the degradation of target proteins. PROTAC technology uses bifunctional small molecules to simultaneously bind to target proteins and E3 ligases, allowing the target proteins to be recognized by the E3 ligase and ubiquitinated, and then degraded by the proteasome. These bifunctional compounds offer the possibility of temporarily controlling protein expression and have been widely used in the research and treatment of diseases including tumors, autoimmune diseases, and anti-infection. Summary of the Invention

[0006] The present invention uses protein targeted degradation technology to achieve the degradation of multiple target proteins such as BTK and IRAK4, with good degradation activity and high selectivity. The corresponding bifunctional compounds can achieve efficient degradation of the two target proteins. At the same time, the molecules have better drugability, high bioavailability and drug exposure, providing a more sufficient material basis for the potential application of such compounds in clinical practice.

[0007] The present invention discovered a series of structurally diverse carboxylic acid fragments that have efficient degradation activity against target proteins such as IRAK4 and BTK. This type of carboxylic acid fragment has not been clearly reported in the prior art, which is the innovation of the PROTAC drug part, which is the main innovation. In addition, the combination of the E3 part and the linker part is also different, which is a secondary innovation.

[0008] The present invention uses protein targeted degradation technology to achieve the degradation of multiple target proteins such as BTK and IRAK4, with good degradation activity and high selectivity. The degradation activity of the target protein shows a good concentration-dependent relationship with the compound concentration. The corresponding bifunctional compound can achieve efficient degradation of the two target proteins. At the same time, the molecule has better drugability, higher bioavailability and drug exposure, providing a more sufficient material basis for the potential application of this type of compound in clinical practice.

[0009] Specifically, one aspect of the present invention provides a compound of formula (I), its stereoisomers, N-oxides, deuterated derivatives, pharmaceutically acceptable salts or prodrugs thereof:

[0010]

[0011] Where,

[0012] is a single bond or a double bond;

[0013] W1, W2, W3, and W4 are each independently C═O, CH, CH2, O, N, or CR 1 or NR 1 ;

[0014] R 1 For hydrogen, halogen, C 1-6 Alkyl or C 1-6 alkyl halide;

[0015] R x is hydrogen or a 4- to 8-membered nitrogen-containing heterocycloalkyl group containing at least one nitrogen atom and 0 to 3 heteroatoms independently selected from N, O or S as ring atoms;

[0016] Lx is selected from *-C(O)NH-** or *-NH-C(O)-**; wherein the position indicated by "*" indicates connection with ring A, and the position indicated by "**" indicates connection with the other side group of Lx;

[0017] Ring A is:

[0018] (i) an 8- to 10-membered biheteroaryl group; the 8- to 10-membered biheteroaryl group is formed by condensing a 5- or 6-membered monoheteroaryl ring with a 5- or 6-membered monoheteroaryl ring;

[0019] (ii) an 8- to 10-membered biheteroaryl group; the 8- to 10-membered biheteroaryl group is formed by condensing a 5- or 6-membered monoheteroaryl ring with a 5- or 6-membered monocyclic heterocycloalkyl ring;

[0020] (iii) a 9- or 10-membered biheteroaryl group; the 9- or 10-membered biheteroaryl group is formed by condensing a benzene ring with a 5- or 6-membered monoheteroaryl ring;

[0021] (iv) a 5- or 6-membered monoheteroaryl group; or

[0022] (v)C 6-8 aryl;

[0023] R y For hydrogen, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl, -OR a -、-NR b R c , 5- or 6-membered heteroaryl or C 6-8 Aryl, wherein the 5 or 6 membered monoheteroaryl, C 6-8 The aryl group is optionally substituted with one or more R 1 replace;

[0024] R 1 Halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy or C 3-6 Cycloalkyl;

[0025] R a C 1-6 Alkyl or C 6-8 aryl;

[0026] R b 、R c are each independently hydrogen or C 1-3 alkyl;

[0027] y is 0, 1, 2, 3, or 4;

[0028] L is in, The position shown indicates connection with E3. The position shown indicates connection to ring A;

[0029] Q1, Q2, and Q3 are each independently a 4- to 12-membered nitrogen-containing heterocycloalkyl group, wherein the 4- to 12-membered nitrogen-containing heterocycloalkyl group contains at least one nitrogen atom as a ring atom; the 4- to 12-membered nitrogen-containing heterocycloalkyl group is optionally substituted with one or more substituents selected from halogen and hydroxy;

[0030] L1, L2, L3, and L4 are each independently -CR L1 R L2 -、-NR L3 -、-CR L1 R L2 -NR L3 -or-NR L3-CR L1 R L2 -;

[0031] R L1 、R L2 、R L3 are independently hydrogen, halogen, C 1-6 Alkyl or C 1-6 alkyl halide;

[0032] m1, m2, m3, m4, and m5 are each independently 0 or 1;

[0033] E3 is the ubiquitin ligase binding group.

[0034] In one embodiment, the 8- to 10-membered biheteroaryl group formed by condensing a 5- or 6-membered monoheteroaryl ring with a 5- or 6-membered monoheteroaryl ring in Ring A is a structure represented by Formula (A1) or Formula (A2):

[0035]

[0036] Among them, U1 is N or CR U1 ; U2 is N or CR U2 ; U3 is N or CR U3 ; U4 is N or CR U4 ; U5 is N or CR U5 ; U6 is N or CR U6 ; U7 is N or CR U7 ; U8 is N or CR U8 ; and at least one of U1, U2, U3, U4, U5, U6, U7, U8 is N; R U1 、R U2 、R U3 、R U4 、R U5 、R U6 、R U7 、R U8 are each independently hydrogen or R y .

[0037] In one embodiment, the 8- to 10-membered biheteroaryl group formed by condensing a 5- or 6-membered monoheteroaryl ring with a 5- or 6-membered monoheteroaryl ring in Ring A is a structure represented by Formula (A3) or Formula (A4):

[0038]

[0039] Where Z1 is N or CR Z1 ; Z2 is NR Z2 , O or S; Z3 is N or CR Z3 ; Z4 is N or CR Z4 ; Z5 is N or CRZ5 ; Z6 is N or CR Z6 ; and at least one of Z3, Z4, Z5, and Z6 is N; R Z0 、R Z1 、R Z2 、R Z3 、R Z4 、R Z5 、R Z6 are each independently hydrogen or R y .

[0040] In one embodiment, the 8- to 10-membered biheteroaryl group formed by condensing a 5- or 6-membered monoheteroaryl ring with a 5- or 6-membered monoheteroaryl ring in Ring A is a structure represented by Formula (A5):

[0041]

[0042] Among them, P1 is NR P1 , O or S; P2 is NR P2 , O or S; P3 is N or CR P3 ; P4 is N or CR P4 ; and at least one of P3 and P4 is N;

[0043] R P1 、R P2 、R P3 、R P4 are each independently hydrogen or R y .

[0044] In one embodiment, the 8- to 10-membered biheteroaryl group formed by condensing a 5- or 6-membered monoheteroaryl ring with a 5- or 6-membered monoheteroaryl ring in Ring A is a structure represented by Formula (A6):

[0045]

[0046] Among them, V1 is N or CR V1 ; V2 is N or CR V2 ; V3 is N or CR V3 ; V4 is N or CR V4 ; V5 is N or CR V5 ; V6 is N or CR V6 ; V7 is N or CR V7 ; V8 is N or CR V8 ; V9 is N or CR V9 ; and at least one of V1, V2, V3, V4, V5, V6, V7, V8, and V9 is N; R V1 、R V2 、R V3 、R V4 、R V5 、RV6 、R V7 、R V8 、R V9 are each independently hydrogen or R y .

[0047] In one embodiment, the 8- to 10-membered biheteroaryl group in Ring A, which is formed by condensing a 5- or 6-membered monoheteroaryl ring with a 5- or 6-membered monocyclic heterocycloalkyl ring, is represented by Formula (A7), Formula (A8), (A9) or (A10):

[0048]

[0049] Where H1 is N or CR H1 ; H2 is N or CR H2 ; H3 is N or CR H3 ; H4 is NR H4a , O, S or CR H4b R H4c ; H5 is NR H5a , O, S or CR H5b R H5c ; H6 is NR H6a , O, S or CR H6b R H6c ; H7 is NR H7a , O, S or CR H7b R H7c ; R H0 、R H1 、R H2 、R H3 、R H4a 、R H4b 、R H4c 、R H5a 、R H5b 、R H5c 、R H6a 、R H6b 、R H6c 、R H7a 、R H7b 、R H7c are each independently hydrogen or R y ;

[0050] G1 is N or CR G1 ; G2 is NR G2a , O, S or CR G2b R G2c ; G3 is NR G3a , O, S or CR G3b R G3c ; G4 is NR G4a , O, S or CR G4b R G4c ; G5 is NRG5a , O, S or CR G5b R G5c ; G6 is NR G6a , O, S or CR G6b R G6c ; R G0 、R G1 、R G2a 、R G2b 、R G2c 、R G3a 、R G3b 、R G3c 、R G4a 、R G4b 、R G4c 、R G5a 、R G5b 、R G5c 、R G6a 、R G6b are each independently hydrogen or R y .

[0051] In one embodiment, in the 9- or 10-membered biheteroaryl group formed by condensing a benzene ring with a 5- or 6-membered monoheteroaryl ring in Ring A, the 5- or 6-membered monoheteroaryl ring is selected from the following group:

[0052]

[0053] Among them, R D is hydrogen or R y ; The two carbon atoms represented as being connected are adjacent pairs of carbon atoms that are shared when fused to other rings.

[0054] In one embodiment, R ySelected from: halogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, methoxy, ethoxy, propoxy, isopropyloxy, butoxy, tert-butoxy, -NH2, -NHCH3, -N(CH3)2, fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl, trifluoroethyl, thienyl, N-alkylpyrrolidonyl, furyl, thiazolyl, isothiazolyl, imidazolyl, oxazolyl, pyrrolyl, pyrazolyl, triazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, tetrazolyl, isoxazolyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, phenyl, naphthyl, -O-thienyl, -ON-alkylpyrrolidonyl, -O-furyl, -O-thiazolyl, -O-isothiazolyl, -O-imidazolyl, -O-oxazolyl, -O-pyrrolyl, -O-pyrazolyl, -O-triazolyl, -O-1,2,3-triazole yl, -O-1,2,4-triazolyl, -O-1,2,5-triazolyl, -O-1,3,4-triazolyl, -O-tetrazolyl, -O-isoxazolyl, -O-oxadiazolyl, -O-1,2,3-oxadiazolyl, -O-1,2,4-oxadiazolyl, -O-1,2,5-oxadiazolyl, -O-1,3,4-oxadiazolyl, -O-thiadiazolyl, -O-pyridinyl, -O-pyridazinyl, -O-pyrimidinyl, -O-pyrazinyl, -O-phenyl; the thienyl, N-alkylpyrrolidonyl, furyl, Thiazolyl, isothiazolyl, imidazolyl, oxazolyl, pyrrolyl, pyrazolyl, triazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, tetrazolyl, isoxazolyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, phenyl, naphthyl are optionally substituted with one or more F, Cl, Br, I, methyl or ethyl. In one embodiment, R y Selected from: halogen, amino, methyl, tert-butyl, trifluoromethyl, methoxy

[0055] In one embodiment, Ring A is selected from the following groups:

[0056]

[0057]

[0058] The group is optionally replaced by one or more R y In one embodiment, ring A is selected from:

[0059]

[0060] In one embodiment, Ring A is selected from:

[0061]

[0062] In one embodiment, Ring A is selected from:

[0063]

[0064] In one embodiment, Ring A is selected from:

[0065]

[0066]

[0067] In one embodiment, Ring A is

[0068] In one embodiment, R x is a 4- to 8-membered nitrogen-containing heterocycloalkyl group containing 1 or 2 nitrogen atoms.

[0069] In one embodiment, the 4- to 8-membered nitrogen-containing heterocycloalkyl group is selected from:

[0070]

[0071] In one embodiment, Lx is selected from *-C(O)NH-**; wherein the position indicated by "*" is connected to ring A, and the position indicated by "**" is connected to the other side group of Lx.

[0072] In one embodiment, the compound is a compound represented by formula (IA1) or formula (IA2):

[0073]

[0074]

[0075] Where, E3, L, W1, W2, W3, W4, R X 、L X , Ring A are defined as above;

[0076] F1 is NR F1 , O or S; F2 is N or CR F2 ; F3 is N or CR F3 ; F4 is N or CR F4 ; and at least one of F1, F2, F3, F4 is N; R F1 、RF2 、R F3 、R F4 are each independently hydrogen or R 1 ;

[0077] K1 is NR K1 or CR K2 ; K2 is N or CR K2 ; K3 is N or CR K3 ; K4 is N or CR K4 ; K5 is N or CR K5 ; and at least one of K1, K2, K3, K4, K5 is N; R K1 、R K2 、R K3 、R K4 、R K5 are each independently hydrogen or R 1 .

[0078] In one embodiment, the compound is represented by Formula (IB1), Formula (IB2), Formula (IB3), Formula (IB4) or Formula (IB5):

[0079]

[0080]

[0081] Where, E3, L, W1, W2, W3, W4, R X , L X 、R y , y are defined as before.

[0082] In one embodiment, the 4- to 12-membered nitrogen-containing heterocycloalkyl group is selected from:

[0083]

[0084] X1, X2, X3, and X4 are each independently N or -CR d ;

[0085] X5 is a single bond, -O-, -S-, or -NR a -or-NR e R f -;

[0086] n1, n2, n3, n4, n5 are each independently 0, 1, 2 or 3;

[0087] Among them, R d 、R e 、R f are independently hydrogen, hydroxy, halogen, -CN, C 1-6 Alkyl, C 1-6Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy or C 3-6 Cycloalkyl.

[0088] In one embodiment, L is selected from:

[0089]

[0090]

[0091] in,

[0092] X1, X2, X3, X4, n1, n2, n3, and n4 are independently defined as above;

[0093] L1, L2, L3, and L4 are each independently -CR L1 R L2 -、-NR L3 -、-CR L1 R L2 -NR L3 -or-NR L3 -CR L1 R L2 -;R L1 、R L2 、R L3 are independently =O, hydrogen, halogen, C 1-6 Alkyl or C 1-6 alkyl halide;

[0094] m1, m2, m3, and m4 are each independently 0 or 1.

[0095] In one embodiment, L is selected from:

[0096]

[0097] In one embodiment, E3 has the structure shown in the following formula (C1), (C2), (C3), (C4) or (C5):

[0098]

[0099]

[0100] Wherein, T1, T2, T3, T4 are each independently CH, C or N; T is CH2, CH(C 1-6 alkyl), C=O, SO2, NH or N(C 1-6 alkyl); R2, R5, R6, R8, R9 are each independently hydrogen or C 1-6 alkyl;

[0101] R3 is hydrogen, hydroxy or C 1-6 alkyl;

[0102] R4, R7, R 10 are independently hydrogen, halogen, C 1-6 Alkyl or halogenated C 1-6 alkyl;

[0103] m7, m8, m9, and m10 are each independently 0, 1, 2, or 3.

[0104] In one embodiment, E3 is

[0105] In one embodiment, the compound is capable of degrading BTK protein and / or IRAK4 protein.

[0106] In one embodiment, the compound is capable of degrading both BTK and IRAK4 proteins.

[0107] In another aspect of the present invention, a pharmaceutical composition is provided, comprising the aforementioned compound, its stereoisomers, N-oxides, deuterated derivatives, pharmaceutically acceptable salts or prodrugs thereof.

[0108] In another aspect of the present invention, there is provided a use of the aforementioned compound, its stereoisomers, N-oxides, deuterated derivatives, pharmaceutically acceptable salts or prodrugs thereof, or the aforementioned pharmaceutical composition in the preparation of a drug for treating a disease mediated by BTK protein and / or IRAK4 protein in a patient.

[0109] In another aspect of the present invention, there is provided a use of the aforementioned compound, its stereoisomers, N-oxides, deuterated derivatives, pharmaceutically acceptable salts or prodrugs thereof, or the aforementioned pharmaceutical composition in the preparation of a BTK and / or IRAK4 degrader; preferably, the degrader is a simultaneous degrader of BTK and IRAK4.

[0110] In another aspect of the present invention, a method for simultaneously degrading BTK and / or IRAK4 proteins in a biological sample is provided, which comprises contacting the biological sample with the aforementioned compound, its stereoisomers, N-oxides, deuterated derivatives, pharmaceutically acceptable salts or prodrugs thereof, or the aforementioned pharmaceutical composition.

[0111] In another aspect of the present invention, a method for treating a disease mediated by BTK protein and / or IRAK4 protein in a patient in need thereof is provided, comprising administering to the patient a therapeutically effective amount of the aforementioned compound, its stereoisomers, N-oxides, deuterated derivatives, pharmaceutically acceptable salts or prodrugs thereof, or the aforementioned pharmaceutical composition.

[0112] In one embodiment, the IRAK and / or BTK mediated disorder is selected from the group consisting of cancer, neurodegenerative diseases, viral diseases, autoimmune diseases, inflammatory disorders, genetic disorders, hormone-related diseases, metabolic disorders, conditions associated with organ transplantation, immunodeficiency disorders, destructive bone diseases, proliferative disorders, infectious diseases, conditions associated with cell death, thrombin-induced platelet aggregation, liver diseases, pathological immune conditions involving T cell activation, cardiovascular disorders, and CNS disorders.

[0113] In one embodiment, the cancer or proliferative disorder is selected from the group consisting of a benign or malignant tumor, a solid tumor, brain cancer, kidney cancer, liver cancer, adrenal cancer, bladder cancer, breast cancer, stomach cancer, gastric tumor, ovarian cancer, colon cancer, rectal cancer, prostate cancer, pancreatic cancer, lung cancer, vaginal cancer, cervical cancer, testicular cancer, genitourinary tract cancer, esophageal cancer, laryngeal cancer, skin cancer, bone cancer or thyroid cancer, sarcoma, glioblastoma, neuroblastoma, multiple myeloma, gastrointestinal cancer, colon cancer, colorectal adenoma, tumors of the neck and head, epidermal hyperplasia, psoriasis, prostatic hyperplasia, neoplasia, neoplasia of epithelial characteristics, adenoma, adenocarcinoma, keratoacanthoma, epidermoid carcinoma, large cell carcinoma, non-small cell lung cancer, lymphoma, Hodgkin's or non-Hodgkin's lymphoma, breast carcinoma, follicular carcinoma, undifferentiated tumor, papillary carcinoma, seminoma, melanoma, IL-11 1 driven disorder, MyD88 driven disorder, mild or indolent multiple myeloma and hematologic malignancies, myeloid leukemias (acute and chronic), acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative disorders, multiple myeloma, myelodysplastic syndrome, Hodgkin's disease, non-Hodgkin's lymphoma (malignant lymphoma) hairy cell, mantle cell lymphoma, Waldenstrom's macroglobulinemia, marginal zone lymphoma, and follicular lymphoma, wherein the hematologic malignancy is selected from the group consisting of leukemia, diffuse large B-cell lymphoma (DLBCL), ABC DLBCL, chronic lymphocytic leukemia (CLL), chronic lymphocytic lymphoma, primary effusion lymphoma, Burkitt lymphoma / leukemia, acute lymphocytic leukemia, B-cell prolymphocytic leukemia, lymphoplasmacytic lymphoma, Waldenstrom's macroglobulinemia (WM), splenic marginal zone lymphoma, multiple myeloma, plasmacytoma, or intravascular large B-cell lymphoma.

[0114] In one embodiment, the MyD88-driven disorder is selected from the group consisting of: ABC DLBCL, Waldenstrom's macroglobulinemia, Hodgkin's lymphoma, primary cutaneous T-cell lymphoma, and chronic lymphocytic leukemia;

[0115] In one embodiment, the neurodegenerative disease is selected from the group consisting of Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease, cerebral ischemia, and neurodegenerative diseases caused by traumatic injury, glutamate neurotoxicity, hypoxia, epilepsy, diabetes treatment, metabolic syndrome, obesity, organ transplantation, and graft-versus-host disease.

[0116] In one embodiment, the inflammatory disorder is selected from the group consisting of: ocular allergy, conjunctivitis, dry eye, vernal conjunctivitis; allergic rhinitis, hemolytic anemia, aplastic anemia, pure red cell anemia, idiopathic thrombocytopenia or another inflammatory disease in which an autoimmune reaction is involved or has an autoimmune component or etiology, systemic lupus erythematosus, rheumatoid arthritis, polychondritis, scleroderma, Wegener's granulomatosis, dermatomyositis, chronic active hepatitis, myasthenia gravis, Stevens-Johnson syndrome, idiopathic steatorrhea, ulcerative colitis , Crohn's disease or another autoimmune inflammatory bowel disease, irritable bowel syndrome, celiac disease, periostitis, hyaline membrane disease, kidney disease, glomerular disease, alcoholic liver disease, endocrine eye disease, Grave's disease, sarcoidosis, alveolitis, chronic hypersensitivity pneumonitis, multiple sclerosis, primary biliary cirrhosis, uveitis (anterior and posterior), Sjögren's syndrome, vernal keratoconjunctivitis, interstitial pulmonary fibrosis, psoriatic arthritis, systemic juvenile idiopathic arthritis, nephritis, diverticulitis, interstitial cystitis, glomerulonephritis (with or without nephrotic syndrome),Optionally including idiopathic nephrotic syndrome or minimal change nephropathy), chronic granulomatous disease, endometriosis, leptospiral nephropathy, glaucoma, retinal disease, aging, headache, pain, complex regional pain syndrome, cardiac hypertrophy, muscle atrophy, catabolic disorders, obesity, fetal growth retardation, hypercholesterolemia, heart disease, chronic heart failure, mesothelioma, anhidrotic ectodermal dysplasia, Behçet's disease, incontinentia pigmenti, Paget's disease, pancreatitis, hereditary periodic fever syndrome, asthma (allergic, non-allergic, mild, moderate, severe, bronchitis or exercise-induced ), acute lung injury, acute respiratory distress syndrome, eosinophilia, allergic reaction, anaphylaxis, sinusitis, silica-induced disease, COPD (damage, airway inflammation, bronchial hyperresponsiveness, remodeling, or decreased disease progression), lung disease, cystic fibrosis, acid-induced lung injury, pulmonary hypertension, polyneuropathy, cataracts, muscle inflammation along with systemic sclerosis, inclusion body myositis, myasthenia gravis, thyroiditis, Addison's disease, lichen planus, type 1 diabetes, type 2 diabetes, appendicitis, atopic dermatitis, allergies, blepharitis, bronchiolitis, bronchitis , bursitis, cervicitis, cholangitis, cholecystitis, chronic graft rejection, colitis, conjunctivitis, cystitis, dacryoadenitis, dermatitis, dermatomyositis, encephalitis, endocarditis, endometritis, enteritis, enterocolitis, epicondylitis, epididymitis, fasciitis, fibrositis, gastritis, gastroenteritis, Henlein-Schönlein purpura, hepatitis, hidradenitis suppurativa, immunoglobulin A nephropathy, interstitial lung disease, laryngitis, mastitis, meningitis, myelitis, myocarditis, myositis, nephritis, oophoritis, orchitis, osteitis, otitis, pancreatitis, mumps, pericarditis, peritonitis, pharyngitis, pleurisy, phlebitis, pneumonia, multiple Myositis, proctitis, prostatitis, pyelonephritis, rhinitis, eustachianitis, sinusitis, stomatitis, synovitis, tendonitis, tonsillitis, vaginitis, vasculitis, vulvitis, alopecia areata, erythema multiforme, dermatitis herpetiformis, scleroderma, vitiligo, hypersensitivity vasculitis, urticaria, bullous pemphigoid, pemphigus vulgaris, pemphigus foliaceus, paraneoplastic pemphigus, epidermolysis bullosa acquisita, acute and chronic gout, chronic gouty arthritis, psoriasis, psoriatic arthritis, rheumatoid arthritis, juvenile rheumatoid arthritis, cryptopyrin-associated periodic syndrome (CAPS), and osteoarthritis.

[0117] In one embodiment, the autoimmune disease is selected from the group consisting of urticaria, graft-versus-host disease, pemphigus vulgaris, achalasia, Addison's disease, Adult Still's disease, agammaglobulinemia, alopecia areata, amyloidosis, ankylosing spondylitis, anti-GBM / anti-TBM nephritis, antiphospholipid syndrome, autoimmune angioedema, autoimmune familial dysautonomia, autoimmune encephalomyelitis, autoimmune hepatitis, autoimmune inner ear disease (AIED), autoimmune myocarditis, autoimmune oophoritis, autoimmune orchitis, autoimmune pancreatitis, and autoimmune retinopathy. , axonal and neuronal neuropathy (AMAN), Baló disease, Behcet's disease, benign mucous membrane pemphigoid, bullous pemphigoid, Castleman disease (CD), celiac disease, Chagas disease, chronic inflammatory demyelinating polyneuropathy (CIDP), chronic recurrent multifocal osteomyelitis (CRMO), allergic granulomatosis with polyangiitis (CSS) or eosinophilic granulomatosis with polyangiitis (EGPA), cicatricial pemphigoid, Cogan's syndrome, cold agglutinin disease, congenital heart block, Coxsackie disease Toxic myocarditis (coxsackiemycarditis), CREST syndrome, Crohn's disease, dermatitis herpetiformis, dermatomyositis, Devic's disease (neuromyelitis optica), discoid lupus, Dressler's syndrome, endometriosis, eosinophilic esophagitis (EoE), eosinophilic fasciitis, erythema nodosum, mixed cryoglobulinemia, Evans syndrome, fibromyalgia, fibrosing alveolitis, giant cell arteritis (temporal arteritis), giant cell myocarditis, glomerulonephritis, Goodpasture's syndrome Goodpasture's syndrome, granulomatosis with polyangiitis, Graves' disease, Guillain-Barre syndrome, Hashimoto's thyroiditis, hemolytic anemia, Henoch-Schonlein purpura (HSP), herpes gestationis or pemphigoid gestationis (PG), hidradenitis suppurativa (HS) (acne inversa), hypogammaglobulinemia, IgA nephropathy, IgG4-related sclerosing disease, immune thrombocytopenic purpura (ITP), inclusion body myositis (IBM),Interstitial cystitis (IC), juvenile arthritis, juvenile diabetes mellitus (type 1 diabetes), juvenile myositis (JM), Kawasaki disease, Lambert Eaton syndrome, leukocytoclastic vasculitis, lichen planus, lichen sclerosus atrophicus, woody conjunctivitis, linear IgA disease (LAD), lupus, chronic Lyme disease, Meniere's disease, microscopic polyangiitis (MPA), mixed connective tissue disease (MCTD), Mooren's ulcer, Mucha-Habermas disease nndisease), multifocal motor neuropathy (MMN) or MMNCB, multiple sclerosis, myasthenia gravis, myositis, narcolepsy, neonatal lupus, neuromyelitis optica, neutropenia, ocular cicatricial pemphigoid, optic neuritis, relapsing rheumatic disease (PR), PANDAS, paraneoplastic cerebellar degeneration (PCD), paroxysmal nocturnal hemoglobinuria (PNH), Parry Romberg syndrome, pars planitis (peripheral uveitis), Parsonnage Turner syndrome, pemphigus, peripheral neuropathy, perivenous encephalomyelitis pernicious anemia (PA), POEMS syndrome, polyarteritis nodosa, polyglandular syndrome type I, II, and III, polymyalgia rheumatica, polymyositis, post-myocardial infarction syndrome, postpericardiotomy syndrome, primary biliary cirrhosis, primary sclerosing cholangitis, progesterone-induced dermatitis, psoriasis, psoriatic arthritis, pure red cell aplasia (PRCA), pyoderma gangrenosum, Raynaud's phenomenon, reactive arthritis, reflex sympathetic dystrophy, relapsing polychondritis, restless legs syndrome (RLS), retroperitoneal fibrosis, rheumatic fever, rheumatoid arthritis, sarcoidosis, Schmidt syndrome syndrome), scleritis, scleroderma, Sjögren's syndrome, sperm and testicular autoimmune diseases, stiff-man syndrome (SPS), subacute bacterial endocarditis (SBE), Susac's syndrome, sympathetic ophthalmia (SO), Takayasu's arteritis, temporal arteritis (giant cell arteritis), thrombocytopenic purpura (TTP), painful ophthalmoplegia syndrome (Tolosa-Hunt syndrome, THS), transverse myelitis, type 1 diabetes, ulcerative colitis (UC), undifferentiated connective tissue disease (UCTD), uveitis, vasculitis, vitiligo,Vogt-Koyanagi-Harada disease and Wegener's granulomatosis (GPA). BRIEF DESCRIPTION OF THE DRAWINGS

[0118] Figure 1 To test the degradation activity of the compound in Example 3 on BTK and IRAK4 in TMD8 cells at different concentrations, the action time was 16 hours. DETAILED DESCRIPTION

[0119] I. Definition

[0120] Unless otherwise indicated, scientific and technical terms used herein have the meanings commonly understood by those skilled in the art. Furthermore, the relevant terms and laboratory procedures used herein are those widely used in the relevant fields and routine procedures. To facilitate a better understanding of the present invention, definitions and explanations of relevant terms are provided below.

[0121] As used herein and unless otherwise indicated, the term "about" or "approximately" means within plus or minus 10% of a given value or range. Where an integer is required, the term means within plus or minus 10% of a given value or range, rounded up or down to the nearest integer.

[0122] In the description herein, references to “some embodiments,” “some implementation schemes,” or “some implementation plans” describe a subset of all possible embodiments, but it will be understood that “some embodiments” may be the same subset or different subsets of all possible embodiments and may be combined with each other without conflict.

[0123] As used herein and unless otherwise specified, the terms "comprises," "includes," "has," "contains," and their grammatical equivalents should generally be understood as open-ended and non-limiting, e.g., not excluding other unlisted elements or steps.

[0124] As used herein, the term "heteroatom" is selected from nitrogen, oxygen or sulfur. Among them, nitrogen can be optionally substituted; sulfur can also be optionally substituted, such as oxo, i.e., forming S(O) t3 (where t3 is an integer from 0 to 2).

[0125] As used herein, when a group such as an alkyl group is located in the middle of a structural formula, the group is a substituent. For example, an alkyl group is an alkylene group, etc.

[0126] As used herein, the term "alkyl" refers to a chain (straight or branched) saturated aliphatic hydrocarbon group. The term "alkyl" may be a straight or branched chain alkyl group (C1-20 Alkyl), preferably an alkyl group containing 1 to 12 carbon atoms (C 1-12 Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2, 3-dimethylpentyl, 2,4-dimethylpentyl, 2,2-dimethylpentyl, 3,3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2,5-dimethylhexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2,2-diethylpentyl, n-decyl, 3,3-diethylhexyl, 2,2-diethylhexyl, and various branched chain isomers thereof. More preferred are lower alkyl groups (C1-6) containing 1 to 6 carbon atoms. 1-6 Alkyl), non-limiting examples of which include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, and the like. More preferred are lower alkyl (C 2-4) groups containing 1 to 3 carbon atoms. 1-3 Alkyl), non-limiting examples include methyl, ethyl, n-propyl, isopropyl, etc. The alkyl group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more groups described in this application.

[0127] As used herein, the terms "cycloalkyl" and "cycloalkyl ring" are used interchangeably to refer to saturated or partially unsaturated monocyclic or polycyclic hydrocarbon groups. The term "cycloalkyl" may be a cycloalkyl group (C 3-20 Cycloalkyl), typically containing 3 to 6 carbon atoms (C3-6 Cycloalkyl) is a monocyclic cycloalkyl (C 3-6 As used herein, "3 to 6 membered monocyclic ring", "3 to 6 membered monocyclic ring cycloalkyl", "C 3-6 Monocyclic cycloalkyl" and "C 3-6 "Cycloalkyl" is used interchangeably to refer to a saturated or partially unsaturated all-carbon monocyclic ring containing 3 to 6 ring atoms. The ring carbon atoms of the monocyclic ring may be optionally substituted with 1, 2 or 3 oxo groups to form a cyclic ketone structure. Examples of 3 to 6 membered monocyclic rings include (but are not limited to): cyclopropyl ring, cyclobutyl ring, cyclopentyl ring, cyclopentenyl ring, cyclohexyl ring, cyclohexenyl ring, cyclohexadienyl ring, cyclobutanone, cyclobutane-1,2-dione, cyclopentanone, cyclopentane-1,3-dione, cyclohexanone, cyclohexane-1,3-dione, etc.

[0128] As used herein, the terms "heterocycloalkyl" and "heterocycloalkyl ring" are used interchangeably to refer to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon group, wherein one or more (preferably 1 to 4 or 1 to 3 or 1 to 2) ring atoms are selected from nitrogen, oxygen or S(O) t3 (wherein t3 is an integer from 0 to 2) heteroatoms, but excluding the ring portion of -OO-, -OS- or -SS-, the remaining ring atoms are carbon. The term "heterocycloalkyl" may be a heterocycloalkyl containing 3 to 20 ring atoms (i.e., 3 to 20 members); preferably a 3 to 12-membered heterocycloalkyl; more preferably a 3 to 10-membered heterocycloalkyl, more preferably a 3 to 6-membered heterocycloalkyl; wherein one or more (preferably 1 to 4) ring atoms are selected from nitrogen, oxygen or S(O) t3 wherein t3 is an integer from 0 to 2, excluding the ring portion of -OO-, -OS- or -SS-, and the remaining ring atoms are carbon. The nitrogen atom may be substituted or unsubstituted (i.e., N or NR, R is hydrogen or any substituent defined herein). The ring carbon atoms of the heterocycloalkyl group may optionally be substituted with 1, 2 or 3 oxo groups to form a cyclic ketone, cyclic lactone or cyclic lactam structure.

[0129] In some embodiments of the present invention, "heterocycloalkyl" refers to a monocyclic heterocycloalkyl group, which is saturated or partially unsaturated, preferably comprising 3 to 8 ring atoms (i.e., 3 to 8 members), of which 1, 2, or 3 are heteroatoms. More preferably, it is a monocyclic heterocycloalkyl group comprising 3 to 6 ring atoms (i.e., 3 to 6 members), of which 1, 2, or 3 are heteroatoms. Most preferably, it is a monocyclic heterocycloalkyl group comprising 5 or 6 ring atoms (i.e., 5 or 6 members), of which 1, 2, or 3 are heteroatoms. As used herein, the terms "3 to 6 membered heterocycloalkyl" and "3 to 6 membered monocyclic heterocycloalkyl" are used interchangeably, and the terms "5 or 6 membered heterocycloalkyl" and "5 or 6 membered monocyclic heterocycloalkyl" are used interchangeably. When the heteroatom is a nitrogen atom, the nitrogen atom may be substituted or unsubstituted (i.e., N or NR, R is hydrogen or other substituents as defined herein). When the heteroatom is a sulfur atom, the sulfur atom may be optionally oxidized (ie, S(O) t3, t3 is an integer from 0 to 2). The ring carbon atoms of the monocyclic heterocycloalkyl group may be optionally substituted by 1, 2 or 3 oxo groups to form a cyclic ketone, cyclic lactone or cyclic lactam structure. Non-limiting examples of monocyclic heterocycloalkyl groups include: aziridine, oxirane, azetidine, azetidine-2-one, oxetane, oxetane-2-one, oxazolidine, pyrrolidone-2-one, pyrrolidine-2,5-dione, 1,3-dioxolane, dihydrofuran-2(3H)-one, dihydrofuran-2,5-dione, piperidine-2-one, piperidine-2,6-dione, tetrahydro-2H-pyran-2-one, imidazolidine, tetrahydrofuran, tetrahydrothiophene, tetrahydropyrrole, 1,3-dioxolane-2-one, oxazolidin-2-one, imidazolidin-2-one, piperidine, piperazine, piperazin-2-one, morpholine, morpholin-3-one, morpholin-2-one, thiophene, Morpholin-3-one 1,1-dioxide, thiomorpholine, thiomorpholine-1,1-dioxide, tetrahydropyran, 1,2-dihydroazetadiene, 1,2-dihydrooxetadiene, 2,5-dihydro-1H-pyrrole, 2,5-dihydrofuran, 2,3-dihydrofuran, 2,3-dihydro-1H-pyrrole, 3,4-dihydro-2H-pyran, 1,2,3,4-tetrahydropyridine, 3,6-dihydro-2H-pyran, 1,2,3,6-tetrahydropyridine, 1,3-oxazinane, hexahydropyrimidine, 1,4-dioxane, tetrahydropyrimidin-2(1H)-one, 1,4-dioxane-2-one, 5,6-dihydro-2H-pyran-2-one, 5,6-dihydropyrimidin-4(3H)-one, 3,4-dihydropyridin-2(1H)-one, 5,6-dihydropyridin-2(1H)-one, 5,6-dihydropyrimidin-4(1H)-one, pyrimidin-4(3H)-one, pyrimidin-4(1H)-one, 4,5-dihydro-1H-imidazole, 2,3-dihydro-1H-imidazole, 2,3-dihydrooxazole, 1,3-dioxole, 2,3-dihydrothiophene, 2,5-dihydrothiophene, 3,4-dihydro-2H-1,4-oxazine, 3,4-dihydro-2H-1,4-thiazine 1,1-dioxide, 1,2,3,4-tetrahydropyrazine, 1,3-dihydro-2H-pyrrole-2- Ketone, 1,5-dihydro-2H-pyrrol-2-one, 1H-pyrrole-2,5-dione, furan-2(3H)-one, furan-2(5H)-one, 1,3-dioxol-2-one, oxazole-2(3H)-one, 1,3-dihydro-2H-imidazole-2-one, furan-2,5-dione, 3,6-dihydropyridine-2(1H)-one, pyridine-2,6-(1H,3H)-dione, 5,6-dihydro-2H-pyran-2-one, 3,6-dihydro-2H-pyran-2-one, 3,4-dihydro-2H-1,3-oxazine, 3,6-dihydro-2H-1,3-oxazine, 1,2,3,4-tetrahydropyrimidine, etc.

[0130] In one embodiment of the present invention, non-limiting examples of the 5- or 6-membered monocyclic heterocycloalkyl group include:

[0131] The two connected ring atoms of the above monocyclic heterocycloalkyl group, including CC and NC, may be optionally fused with a 5- or 6-membered monocyclic heteroaryl ring as defined in the present invention to form a fused polycyclic ring.

[0132] In some embodiments of the present invention, "heterocycloalkyl" refers to polycyclic heterocycloalkyl, including spiroheterocycloalkyl, fused heterocycloalkyl, and bridged heterocycloalkyl.

[0133] As used herein, the term "spiroheterocycloalkyl" refers to a saturated or partially unsaturated polycyclic heterocycloalkyl group, wherein the single rings in the system share one atom (called a spiro atom), wherein one or more (e.g., 1 to 4 or 1 to 3 or 1 to 2) ring atoms are selected from nitrogen, oxygen or S(O) t4 (wherein t4 is an integer from 0 to 2) of heteroatoms, and the remaining ring atoms are carbon. The term "saturated spiroheterocycloalkyl" means that there are no unsaturated bonds in the spiroheterocycloalkyl system. The term "partially unsaturated spiroheterocycloalkyl" means that one or more rings in the spiroheterocycloalkyl system may contain one or more double bonds, but no ring has a completely conjugated π electron system. The term "spiroheterocycloalkyl" may be a spiroheterocycloalkyl comprising 5 to 20 ring atoms (i.e., 5 to 20 members), wherein the 3 to 8 membered (i.e., comprising 3 to 8 ring atoms) monocyclic rings share an atom (called a spiro atom), preferably a 6 to 14 membered spiroheterocycloalkyl, more preferably a 7 to 11 membered spiroheterocycloalkyl; wherein one or more ring atoms are selected from nitrogen, oxygen or S(O) t4 (wherein t4 is an integer 0 to 2) heteroatoms, and the remaining ring atoms are carbon. When the heteroatom is a nitrogen-atom, the nitrogen-atom can be substituted or unsubstituted (i.e. N or NR, R is hydrogen or other substituents defined herein). Each monocycle can contain one or more double bonds, but no ring has a completely conjugated π electron system. According to the number of shared spiral atoms between the rings, spiral heterocycloalkyl is divided into single spiral heterocycloalkyl, double spiral heterocycloalkyl or multiple spiral heterocycloalkyl, preferably single spiral heterocycloalkyl and double spiral heterocycloalkyl. More preferably 7 yuan (4 yuan monocycle / 4 yuan monocycle), 8 yuan (4 yuan monocycle / 5 yuan monocycle), 9 yuan (4 yuan monocycle / 6 yuan monocycle, 5 yuan monocycle / 5 yuan monocycle), 10 yuan (5 yuan monocycle / 6 yuan monocycle) or 11 yuan (6 yuan monocycle / 6 yuan monocycle) single spiral heterocycloalkyl. Non-limiting examples of spiral heterocycloalkyl include:

[0134]

[0135] As used herein, the term "fused heterocycloalkyl" refers to a saturated or partially unsaturated polycyclic heterocycloalkyl group, each ring in the system shares a pair of adjacent atoms with other rings in the system, and one or more (e.g., 1 to 4 or 1 to 3 or 1 to 2) ring atoms in the system are selected from nitrogen, oxygen or S(O) t4 (wherein t4 is an integer from 0 to 2) of heteroatoms, and the remaining ring atoms are carbon. The term "saturated fused heterocycloalkyl" means that there is no unsaturated bond in the fused heterocycloalkyl system. The term "partially unsaturated fused heterocycloalkyl" means that one or more rings in the fused heterocycloalkyl system may contain one or more double bonds, but no ring has a completely conjugated π electron system. The term "fused heterocycloalkyl" may be a fused heterocycloalkyl containing 5 to 20 ring atoms (i.e., 5 to 20 members), preferably a 6 to 14-membered fused heterocycloalkyl, more preferably a 6 to 10-membered fused heterocycloalkyl, more preferably an 8 to 10-membered fused heterocycloalkyl; one or more ring atoms in the system are selected from nitrogen, oxygen or S(O) t4 (wherein t4 is an integer 0 to 2) heteroatoms, and the remaining ring atoms are carbon. When the heteroatom is a nitrogen-atom, the nitrogen-atom can be substituted or unsubstituted (i.e. N or NR, R is hydrogen or other substituents defined herein). According to the number of the rings, bicyclic, tricyclic, tetracyclic or polycyclic condensed heterocycloalkyls can be divided, preferably bicyclic or tricyclic, more preferably 8 yuan (5 yuan monocycles are fused with 5 yuan monocycles), 9 yuan (5 yuan monocycles are fused with 6 yuan monocycles) or 10 yuan (6 yuan monocycles are fused with 6 yuan monocycles) bicyclic condensed heterocycloalkyls. Non-limiting examples of condensed heterocycloalkyls include:

[0136] As used herein, the term "bridged heterocycloalkyl" refers to a saturated or partially unsaturated polycyclic heterocycloalkyl group, wherein any two rings in the system share two atoms that are not directly connected, wherein one or more (e.g., 1 to 4 or 1 to 3 or 1 to 2) ring atoms are selected from nitrogen, oxygen or S(O) t3 wherein t3 is an integer (0 to 2) of heteroatoms, and the remaining ring atoms are carbon. The term "saturated bridged heterocycloalkyl" refers to a bridged heterocycloalkyl system without any unsaturated bonds. The term "partially unsaturated bridged heterocycloalkyl" refers to a bridged heterocycloalkyl system in which one or more rings may contain one or more double bonds, but no ring has a completely conjugated π electron system. The term "bridged heterocycloalkyl" may be a bridged heterocycloalkyl containing 5 to 20 ring atoms (i.e., 5 to 20 members), preferably a 6 to 14-membered bridged heterocycloalkyl, more preferably a 7 to 10-membered bridged heterocycloalkyl; wherein one or more (e.g., 1 to 4 or 1 to 3 or 1 to 2) ring atoms are selected from nitrogen, oxygen or S(O) t3Wherein t3 is an integer (0 to 2) of heteroatoms, and the remaining ring atoms are carbon. According to the number of constituent rings, they can be classified as bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocycloalkyl groups, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of bridged heterocycloalkyl groups include:

[0137]

[0138] In the present invention, the various types of heterocycloalkyl groups mentioned above may be optionally substituted or unsubstituted. When substituted, the substituents are preferably one or more groups described in the present application.

[0139] As used herein, in the "spiroheterocycloalkyl", "bridged heterocycloalkyl" or "fused heterocycloalkyl", when the ring containing a heteroatom is a 3-membered ring and contains only one heteroatom as a ring atom, the heteroatom is not a nitrogen atom.

[0140] As used herein, the terms "aryl", "aryl ring" and "aromatic ring" are used interchangeably to refer to a fully unsaturated aliphatic hydrocarbon group. 6-14 ) is an all-carbon monocyclic, all-carbon polycyclic (rings are connected by covalent bonds and are not fused) or all-carbon fused polycyclic (i.e., rings that share adjacent carbon atom pairs) group, at least one ring in the ring system is aromatic, i.e., has a conjugated π electron system. Preferably, it contains 6 to 10 ring atoms (i.e., 6 to 10 members or C 6-10 Each ring in the ring system contains 5 or 6 ring atoms.

[0141] In some embodiments of the present invention, "aryl" refers to a monoaryl or polyaryl ring, non-limiting examples of which include phenyl, biphenyl, and the like.

[0142] In some embodiments of the present invention, "aryl" refers to an aromatic fused polycyclic ring, which is a polycyclic group in which a single aromatic ring is fused to one or more single aromatic rings. Non-limiting examples of the aromatic fused polycyclic ring include naphthyl, anthracenyl, and the like.

[0143] In some embodiments of the present invention, the aryl ring described herein (e.g., a single aryl ring, preferably a phenyl group) may be fused with one or more non-aromatic rings to form a polycyclic group, wherein the ring connected to the parent structure is an aromatic ring or a non-aromatic ring, and the non-aromatic ring includes but is not limited to: a 3- to 6-membered monocyclic heterocycloalkyl ring, preferably a 5- or 6-membered monocyclic heterocycloalkyl ring (the ring carbon atoms of the monocyclic heterocycloalkyl ring may be substituted by 1 to 2 oxo groups to form a cyclic lactam or cyclic lactone structure), a 3- to 6-membered monocyclic cycloalkyl ring, preferably a 5- or 6-membered monocyclic cycloalkyl ring (the ring carbon atoms of the monocyclic cycloalkyl ring may be substituted by 1 or 2 oxo groups to form a cyclic ketone structure), etc. The polycyclic group in which the above-mentioned single aryl ring is fused with one or more non-aromatic rings may be connected to other groups or the parent structure through a nitrogen atom or a carbon atom, and the ring connected to the parent structure is a single aryl ring or a non-aromatic ring.

[0144] As used herein, the phenyl group fused with a 5- or 6-membered monocyclic heterocycloalkyl ring to form a 9- or 10-membered bicyclic ring refers to a fused 5- or 6-membered monocyclic heterocycloalkyl ring formed by two adjacent substituent groups on the phenyl group and the ring atoms to which they are attached. The 5- or 6-membered monocyclic heterocycloalkyl ring is as defined herein, and the formed 9- or 10-membered bicyclic ring may also be referred to as a 9- or 10-membered phenylheterocycloalkyl ring.

[0145] As used herein, the phenyl group fused with a 5- or 6-membered monocyclic cycloalkyl ring to form a 9- or 10-membered bicyclic ring refers to a fused 5- or 6-membered monocyclic cycloalkyl ring formed by two adjacent substituent groups on the phenyl group and the ring atoms to which they are attached. The 5- or 6-membered monocyclic cycloalkyl ring is as defined herein, and the formed 9- or 10-membered bicyclic ring may also be referred to as a 9- or 10-membered phenylcycloalkyl ring.

[0146] In the present invention, the above-mentioned various aryl groups may be substituted or unsubstituted. When substituted, the substituent is preferably one or more groups described in this application.

[0147] As used herein, the terms "heteroaryl", "heteroaryl ring" and "heteroaromatic ring" are used interchangeably and refer to fully unsaturated aliphatic hydrocarbon groups containing heteroatoms. They can be monocyclic or fused polycyclic (i.e., rings that share adjacent carbon atoms or heteroatoms) groups having 5 to 14 ring atoms (i.e., 5 to 14 members), preferably 5 to 10 ring atoms (i.e., 5 to 10 members), more preferably 5, 6, 8, 9 or 10 ring atoms, wherein 1 to 4 heteroatoms are selected from oxygen, sulfur and nitrogen as ring atoms. The nitrogen and sulfur atoms may be optionally oxidized, and the nitrogen atom may be optionally quaternized. The heteroaryl group preferably has 6, 10 or 14 shared π electrons in the ring system. At least one ring in the ring system is aromatic.

[0148] In some embodiments of the present invention, "heteroaryl" refers to a monocyclic heteroaryl ring (preferably a 5- or 6-membered monocyclic heteroaryl ring). Non-limiting examples of monocyclic heteroaryl groups include: thiophene, N-alkylpyrrolidone, furan, thiazole, isothiazole, imidazole, oxazole, pyrrole, pyrazole, triazole, 1,2,3-triazole, 1,2,4-triazole, 1,2,5-triazole, 1,3,4-triazole, tetrazole, isoxazole, oxadiazole, 1,2,3-oxadiazole, 1,2,4-oxadiazole, 1,2,5-oxadiazole, 1,3,4-oxadiazole, thiadiazole, pyridine, pyridazine, pyrimidine, pyrazine, and the like.

[0149] In some embodiments of the present invention, "heteroaryl" refers to a fused polyheteroaryl ring (preferably an 8- to 10-membered bicyclic heteroaryl ring). The fused polyheteroaryl ring includes a polycyclic group (preferably a 9- or 10-membered bicyclic heteroaryl ring) fused with a monocyclic aryl ring (preferably a 5- or 6-membered monocyclic heteroaryl ring), and a polycyclic group (preferably an 8- to 10-membered bicyclic heteroaryl ring) fused with a monocyclic heteroaryl group (preferably a 5- or 6-membered monocyclic heteroaryl group).

[0150] In some embodiments of the present invention, non-limiting examples of monocyclic heteroaryl rings (preferably 5- or 6-membered monocyclic heteroaryl rings) that form fused polycyclic rings include:

[0151] Non-limiting examples of fused polyheteroaryl rings include: benzo[d]isoxazole, 1H-indole, isoindole, 1H-benzo[d]imidazole, benzo[d]isothiazole, 1H-benzo[d][1,2,3]triazole, benzo[d]oxazole, benzo[d]thiazole, indazole, benzofuran, benzo[b]thiophene, quinoline, isoquinoline, quinazoline, quinoxaline, cinnoline, pyrido[3,2-d]pyrimidine, pyrido[2,3-d]pyrimidine, pyrido[3,4-d]pyrimidine, pyrido[4,3-d]pyrimidine, 1,8-naphthyridine, 1,7-naphthyridine, 1,6-naphthyridine, 1,5-naphthyridine, pyrazolo[1,5-a]pyrimidine, imidazo[1,2-b]pyridazine, and the like.

[0152] In some embodiments of the present invention, the heteroaryl ring described in the present invention (e.g., a monocyclic heteroaryl ring, preferably a 5- or 6-membered monocyclic heteroaryl ring) can be fused with one or more non-aromatic rings to form a polycyclic group, wherein the ring connected to the parent structure is a heteroaryl ring or a non-aromatic ring, and the non-aromatic ring includes but is not limited to: a 3- to 6-membered (preferably 5- or 6-membered) monocyclic heterocycloalkyl ring (the ring carbon atoms of the monocyclic heterocycloalkyl ring can be substituted by 1 to 2 oxo groups to form a cyclic lactam or cyclic lactone structure), a 3- to 6-membered (preferably 5- or 6-membered) monocyclic cycloalkyl ring (the ring carbon atoms of the monocyclic cycloalkyl ring can be substituted by 1 or 2 oxo groups to form a cyclic ketone structure), etc.

[0153] The above-mentioned polycyclic group in which the monocyclic heteroaryl ring is fused with one or more non-aromatic rings can be connected to other groups or the parent structure through nitrogen atoms or carbon atoms, and the ring connected to the parent structure is a heteroaryl ring or a non-aromatic ring.

[0154] As used herein, the 5- or 6-membered monocyclic heteroaryl group fused with a 5- or 6-membered monocyclic heterocycloalkyl ring to form an 8- to 10-membered biheterocyclic ring refers to a fused 5- or 6-membered monocyclic heterocycloalkyl ring formed by two adjacent substituent groups on the 5- or 6-membered monocyclic heteroaryl group and the ring atoms to which they are attached. The 5- or 6-membered monocyclic heterocycloalkyl ring is as defined herein, and the 8- to 10-membered biheterocyclic ring formed may also be referred to as an 8- to 10-membered heteroarylheterocycloalkyl ring.

[0155] As used herein, the 5- or 6-membered monocyclic heteroaryl group fused with a 5- or 6-membered monocyclic cycloalkyl ring to form an 8- to 10-membered biheterocyclic ring refers to a fused 5- or 6-membered monocyclic cycloalkyl ring formed by two adjacent substituent groups on the 5- or 6-membered monocyclic heteroaryl group and the ring atoms to which they are attached. The 5- or 6-membered monocyclic cycloalkyl ring is as defined herein, and the 8- to 10-membered biheterocyclic ring formed may also be referred to as an 8- to 10-membered heteroarylcycloalkyl ring.

[0156] In the present invention, the above-mentioned various heteroaryl groups may be substituted or unsubstituted. When substituted, the substituent is preferably one or more groups described in the present application.

[0157] As used herein, the term "C 1-6 "Alkoxy" refers to -O-(C 1-6 alkyl), wherein alkyl is as defined above. Preferably C 1-3 Alkoxy. Non-limiting examples include methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy, isobutoxy, pentoxy, and the like. Alkoxy may be optionally substituted or unsubstituted. When substituted, the substituent is preferably one or more of the groups described herein.

[0158] As used herein, "deuterated" refers to a group in which one or more (eg, 1, 2, 3, 4, or 5) or all hydrogen atoms are replaced by deuterium atoms.

[0159] For example, "deuterated C 1-6 "Alkyl" refers to an alkyl group in which one or more (such as 1, 2, 3, 4 or 5) or all hydrogen atoms are replaced by deuterium atoms, wherein the definition of alkyl is as described above. Preferably, deuterated C 1-3 For example, the deuterated methyl group may be a monodeuterated methyl group, a dideuterated methyl group, or a perdeuterated methyl group.

[0160] As used herein, "halo" refers to a group in which one or more (eg, 1, 2, 3, 4, or 5) hydrogen atoms are replaced by a halogen.

[0161] For example, "halogenated C 1-6 "Alkyl" refers to an alkyl group substituted by one or more (such as 1, 2, 3, 4 or 5) halogens, wherein the definition of alkyl is as described above. Preferably, the alkyl group is halogenated. 1-3 Alkyl. Halogenated C 1-6 Examples of alkyl groups include, but are not limited to, monochloromethyl, dichloromethyl, trichloromethyl, monochloroethyl, 1,2-dichloroethyl, trichloroethyl, monobromoethyl, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoroethyl, difluoroethyl, trifluoroethyl, and the like.

[0162] For example, "halogenated C 1-6 "Alkoxy" refers to an alkoxy group substituted by one or more (such as 1, 2, 3, 4 or 5) halogens, wherein the definition of alkoxy is as described above. Preferably, the halogenated C 1-3 Alkoxy groups include, but are not limited to, trifluoromethoxy, trifluoroethoxy, monofluoromethoxy, monofluoroethoxy, difluoromethoxy, difluoroethoxy, and the like.

[0163] As used herein, the term "hydroxy" refers to -OH.

[0164] Herein, a wavy line on a group is represented Regardless of the form it appears in, it indicates that this is the point where it connects to other parts of the molecule. If there is no wavy line on the group, it means that any position in the group may connect to other positions in the molecule.

[0165] A chemical bond on a ring means that the chemical bond can be connected to any ring atom on the ring, for example include wait.

[0166] "Optional" or "optionally" means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where the event or circumstance occurs and instances where it does not. For example, "a heterocycloalkyl group optionally substituted with an alkyl group" means that the alkyl group may but need not be present, and that the description includes instances where the heterocycloalkyl group is substituted with an alkyl group and instances where the heterocycloalkyl group is not substituted with an alkyl group.

[0167] "Substituted" means that one or more hydrogen atoms, preferably up to 5, more preferably 1 to 3 hydrogen atoms, in a group are replaced independently of one another by a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and a person skilled in the art can determine (by experiment or theory) which substitutions are possible or impossible without undue effort. For example, an amino or hydroxyl group with free hydrogen may be unstable when combined with a carbon atom with an unsaturated (e.g., olefinic) bond.

[0168] Unless otherwise defined, when a group described in the present invention is substituted by a substituent, it means that all the same groups appearing in the present invention can be substituted by a substituent, that is, the group can be substituted when it exists alone, and it also means that the group can be substituted when it exists in combination with other groups. For example, R is -C 1-6 Alkyl, C 6-10 Aryl, C 3-6 Monocyclic cycloalkyl, -C(O)C 1-6 Alkyl, -C 1-4 Alkyl-C 6-10 Aryl or -S(O)2-C 3-6 Monocyclic cycloalkyl, wherein the C 1-6 Alkyl, C 6-10 Aryl, C 3-6 Monocyclic cycloalkyl groups are optionally substituted; this description also includes -C(O)C 1-6 Alkyl, -C 1-4 Alkyl-C 6-10 Aryl and -S(O)2-C 3-6 C in monocyclic cycloalkyl 1-6 Alkyl, C 6-10 Aryl and C 3-6 Monocyclic cycloalkyl groups are optionally substituted.

[0169] Unless otherwise defined, the phrase "...same or different, and each independently is..." in the present invention means that when there are more than one identical substituent group in the general formula, the substituent group may be the same or different and are each independent species. For example, L is (CR L1 R L2 ) s , when s is 2, that is, L is (CR L1 R L2 )-(CR L1 R L2 ), where two R L1 or R L2 They can be the same or different and are independent species. For example, L can be C(CH3)(CN)-C(CH2CH3)(OH), C(CH3)(CN)-C(CH3)(OH) or C(CN)(CH2CH3)-C(OH)(CH2CH3).

[0170] Unless otherwise defined, the "substituents independently selected from..." described in the present invention means that when more than one hydrogen on a group is replaced by a substituent, the substituents may be the same or different, and the substituents selected are independently of each other.

[0171] In this paper, C 1-6 It can be preferably C 1-4 More preferably C 1-3 .

[0172] In one embodiment of the present invention, in any group, the C 3-6 The cycloalkyl group is selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

[0173] In one embodiment of the present invention, in any group, the 5- or 6-membered monocyclic heteroaryl group is selected from the group consisting of thiophene, N-alkylpyrrolidone, furan, thiazole, isothiazole, imidazole, oxazole, pyrrole, pyrazole, triazole, 1,2,3-triazole, 1,2,4-triazole, 1,2,5-triazole, 1,3,4-triazole, tetrazole, isoxazole, oxadiazole, 1,2,3-oxadiazole, 1,2,4-oxadiazole, 1,2,5-oxadiazole, 1,3,4-oxadiazole, thiadiazole, pyridine, pyridazine, pyrimidine, and pyrazine.

[0174] In one embodiment of the present invention, in any group, the 5- or 6-membered monocyclic heteroaryl group is selected from:

[0175]

[0176] In one embodiment of the present invention, in any group, the 8- to 10-membered bicyclic heteroaryl is selected from the group consisting of benzoxazole, benzisoxazole, benzimidazole, benzothiazole, benzisothiazole, benzotriazole, benzofuran, benzothiophene, indole, indazole, isoindole, quinoline, isoquinoline, quinazoline, quinoxaline, cinnoline, pyridopyrimidine, and naphthyridine.

[0177] A "pharmaceutical composition" refers to a mixture containing one or more compounds described herein, or their physiologically / pharmaceutically acceptable salts or prodrugs, together with other chemical components, as well as other components such as physiologically / pharmaceutically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration to an organism, facilitating absorption of the active ingredient and thereby exerting its biological activity.

[0178] The "pharmaceutically acceptable salt" includes pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.

[0179] "Pharmaceutically acceptable acid addition salt" refers to a salt formed with an inorganic acid or an organic acid that retains the biological effectiveness of the free base without other side effects.

[0180] "Pharmaceutically acceptable base addition salts" include, but are not limited to, salts of inorganic bases such as sodium salts, potassium salts, calcium salts and magnesium salts, and salts of organic bases such as ammonium salts, triethylamine salts, lysine salts, arginine salts, and the like.

[0181] As used herein, "solvates" refer to complexes formed between a compound of the present invention and a solvent. These complexes are formed by reacting in the solvent or by precipitating or crystallizing from the solvent. For example, a complex formed with water is referred to as a "hydrate." Solvates of the compound of formula (I) of the present invention are also encompassed within the scope of the present invention.

[0182] The compounds represented by formula (I) of the present invention may contain one or more chiral centers and exist in different optically active forms. When the compound contains one chiral center, the compound contains enantiomers. The present invention includes these two isomers and mixtures of isomers, such as racemic mixtures. Enantiomers can be resolved by methods known in the art, such as crystallization and chiral chromatography. When the compound represented by formula (I) contains more than one chiral center, diastereomers may exist. The present invention includes resolved optically pure specific isomers and mixtures of diastereomers. Diastereomers can be resolved by methods known in the art, such as crystallization and preparative chromatography. The "stereoisomers" described in the present invention include (but are not limited to) enantiomers, diastereomers, etc.

[0183] The present invention includes prodrugs of the above-mentioned compounds. The prodrugs include known amino protecting groups and carboxyl protecting groups, which are hydrolyzed under physiological conditions or released via enzymatic reactions to yield the parent compound. Specific methods for preparing the prodrugs can be found in (Saulnier, MG; Frennesson, DB; Deshpande, MS; Hansel, SB and Vysa, DM Bioorg. Med. Chem Lett. 1994, 4, 1985-1990; and Greenwald, RB; Choe, YH; Conover, CD; Shum, K.; Wu, D.; Royzen, MJ Med. Chem. 2000, 43, 475.).

[0184] Generally, the compounds of the present invention, their stereoisomers, N-oxides, deuterated derivatives, pharmaceutically acceptable salts, or prodrugs thereof, can be combined with one or more pharmaceutical carriers to form suitable dosage forms for administration. These dosage forms are suitable for oral, rectal, topical, oral, and other parenteral administrations (e.g., subcutaneous, intramuscular, intravenous, etc.). For example, dosage forms suitable for oral administration include capsules, tablets, granules, and syrups. The compounds of the present invention contained in these formulations can be solid powders or granules; solutions or suspensions in aqueous or non-aqueous liquids; water-in-oil or oil-in-water emulsions, etc. The above dosage forms can be prepared from the active compound and one or more carriers or excipients using common pharmaceutical methods. The above carriers need to be compatible with the active compound or other excipients. For solid preparations, commonly used non-toxic carriers include, but are not limited to, mannitol, lactose, starch, magnesium stearate, cellulose, glucose, sucrose, etc. Carriers for liquid preparations include water, physiological saline, aqueous glucose solution, ethylene glycol, and polyethylene glycol. The active compound can form a solution or suspension with the above carriers.

[0185] The compositions of the present invention are formulated, dosed and administered in a manner consistent with standard medical practice. The "therapeutically effective amount" of the compound administered is determined by factors such as the specific condition to be treated, the individual being treated, the cause of the condition, the target of the drug, and the mode of administration.

[0186] As used herein, "therapeutically effective amount" refers to the amount of the compound of the present invention that will elicit a biological or medical response in a subject, such as reducing or inhibiting enzyme or protein activity or improving symptoms, alleviating symptoms, slowing or delaying disease progression, or preventing disease.

[0187] The therapeutically effective amount of the compound of the present invention or its pharmaceutically acceptable salt, solvate, or stereoisomer contained in the pharmaceutical composition of the present invention is preferably 0.1 mg to 5 g / kg (body weight).

[0188] As used herein, "pharmaceutically acceptable carrier" refers to a non-toxic, inert, solid, semi-solid substance or liquid filler, diluent, encapsulating material or auxiliary formulation or any type of excipient that is compatible with a patient, preferably a mammal, more preferably a human, and is suitable for delivering an active agent to a target site without terminating the activity of the agent.

[0189] As used herein, "patient" refers to an animal, preferably a mammal, more preferably a human. The term "mammal" refers to warm-blooded vertebrate mammals, including cats, dogs, rabbits, bears, foxes, wolves, monkeys, deer, mice, pigs and humans.

[0190] As used herein, "treat" refers to alleviating, slowing the progression, attenuating, preventing, or maintaining an existing disease or condition (eg, cancer). Treatment also includes curing, preventing the development of, or alleviating to some extent, one or more symptoms of a disease or condition.

[0191] As used herein, the term "protein degradation targeting chimera" or PROTAC (proteolysis targeting chimeras) is a chemical molecule containing different ligands at both ends, one end is a ligand that binds to the E3 ligase (such as the ULM portion described in the present invention), and the other end is a ligand that binds to intracellular proteins (such as the BTK binding portion described in the present invention). These two ligands are then connected by a linker (such as the L described in the present invention). Such a chemical molecule can bind to both E3 ubiquitin ligase and intracellular proteins, and achieves polyubiquitination of the targeted protein by recruiting the targeted protein to the vicinity of the E3 ubiquitin ligase, and finally degraded by the proteasome. PROTAC can be recycled and is not degraded by the proteasome.

[0192] As used herein, the term "capable of degrading BTK protein" refers to a degradation capacity of not less than 10% (degradation percentage ≥ 10%) for BTK protein, and "capable of degrading IRAK4 protein" refers to a degradation capacity of not less than 30% (degradation percentage ≥ 30%) for IRAK4 protein. The term "capable of simultaneously degrading BTK protein and IRAK4 protein" refers to a degradation capacity of not less than 10%, or even not less than 30%, or 50%, or more than 90% for both target proteins.

[0193] The term "treating" includes inhibiting, alleviating, preventing or eliminating one or more symptoms or side effects associated with the disease, condition or disorder being treated.

[0194] As used herein, the term "ubiquitin ligase" refers to a family of proteins that facilitate the transfer of ubiquitin to specific substrate proteins, targeting the substrate proteins for degradation. For example, cereblon is an E3 ubiquitin ligase protein that, alone or in combination with an E2 ubiquitin conjugating enzyme, causes the attachment of ubiquitin to lysine on a target protein and subsequently targets a specific protein substrate for degradation by the proteasome. Therefore, an E3 ubiquitin ligase, alone or in combination with an E2 ubiquitin conjugating enzyme, is responsible for the transfer of ubiquitin to the target protein. Generally speaking, ubiquitin ligases involve polyubiquitination, where a second ubiquitin is attached to a first ubiquitin; a third ubiquitin is attached to a second ubiquitin, and so on. Polyubiquitination marks a protein for degradation by the proteasome. However, there are some ubiquitination events that are limited to monoubiquitination, in which only a single ubiquitin is added to the substrate molecule by the ubiquitin ligase. Monoubiquitinated proteins are not targeted for degradation by the proteasome, but can be altered in their cellular location or function, for example, by binding to other proteins with domains capable of binding ubiquitin. To complicate matters further, different lysines on ubiquitin can be targeted by E3s to make chains. The most common lysine is Lys48 on the ubiquitin chain. This is the lysine used to make polyubiquitin that is recognized by the proteasome.

[0195] Example

[0196] In order to make the purpose, technical solutions and advantages of the present invention clearer, the present invention will be further described in detail below. The described embodiments should not be regarded as limiting the present invention. All other embodiments obtained by ordinary technicians in this field without making creative work are within the scope of protection of the present invention.

[0197] Before further explaining the embodiments of the present invention in detail, the nouns and terms involved in the embodiments of the present invention are explained. The nouns and terms involved in the embodiments of the present invention are subject to the following interpretations.

[0198] The raw materials and equipment used in the specific embodiments of the present disclosure are all known products and are obtained by purchasing commercially available products.

[0199] Preparation Example

[0200] Synthesis of intermediate B1

[0201]

[0202] Step 1: Synthesis of methyl 4-(4-(dimethoxymethyl)piperidin-1-yl)-2-fluorobenzoate

[0203] A mixture of 4-(dimethoxymethyl)piperidine (5.5 g, 34.9 mmol), methyl 2,4-difluorobenzoate (4 g, 23.3 mmol), and potassium carbonate (6.4 g, 46.6 mmol) in DMSO (40 mL) was purged with nitrogen three times, heated to 80°C, and stirred for 2 hours. The reaction mixture was cooled to room temperature, water (300 mL) was added, and extracted twice with ethyl acetate (200 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the residue obtained by rotary evaporation under reduced pressure was isolated and purified by flash silica gel column chromatography (petroleum ether-ethyl acetate, 95-90%) to afford 3.5 g of the title compound as a white solid in a 49% yield.

[0204] LCMS: Rt=2.551min, MS(ESI)m / z=312.0[M+H] + .

[0205] 1 H NMR(400MHz,DMSO-d6)δ7.86–7.76ppm(m,1H),6.63(dt,J=9.4,2.6Hz,1H),6.51(dt,J=14.8,2.6Hz,1H),4.20–4.01(m,1H),3 .93–3.84(m,5H),3.39(q,J=1.3Hz,6H),3.02–2.71(m,2H),1.86(dt,J=10.7,3.5Hz,3H),1.74–1.55(m,1H),1.52–1.23(m,2H)

[0206] Step 2: Synthesis of 4-(4-(dimethoxymethyl)piperidin-1-yl)-2-fluorobenzoic acid

[0207] A solution of lithium hydroxide monohydrate (7.9 g, 329.8 mmol) in water (60 mL) was slowly added to a solution of methyl 4-(4-(dimethoxymethyl)piperidin-1-yl)-2-fluorobenzoate (25.4 g, 82.5 mmol) in methanol (60 mL). The mixture was heated to 50°C and stirred for 1 hour. The methanol was removed by rotary evaporation under reduced pressure, and the mixture was diluted with water (60 mL). Diluted aqueous hydrochloric acid (1 mol / L) was added dropwise with stirring until a large amount of precipitate formed and the pH was approximately 6. The mixture was filtered, the filter cake was washed with water, and dried to obtain 20 g of the title compound as a white solid in an 87.0% yield.

[0208] LCMS: Rt=2.391min, MS(ESI)m / z=298.0[M+H] + .

[0209] 1H NMR(400MHz,DMSO-d6)δ10.93ppm(s,1H),9.82(d,J=7.0Hz,1H),7.97–7.76(m ,1H),7.29–7.08(m,1H),6.99(td,J=8.3,2.3Hz,1H),4.85–4.68(m,1H),4.50 (s,1H),3.16(s,2H),2.88–2.62(m,3H),2.24(d,J=12.6Hz,1H),2.12–1.91(m ,1H),1.77(d,J=11.5Hz,2H),1.45(d,J=12.3Hz,3H),1.27(d,J=17.1Hz,1H).

[0210] Step 3: Synthesis of 4-(4-(dimethoxymethyl)piperidin-1-yl)-N-(2,6-dicarbonylpiperidin-3-yl)-2-fluorobenzamide

[0211] 2-(7-Azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (32.3 g, 85.5 mmol) was added all at once to a solution of 4-(4-(dimethoxymethyl)piperidin-1-yl)-2-fluorobenzoic acid (17 g, 57 mmol), 3-aminopiperidine-2,6-dione hydrochloride (9.35 g, 57 mmol), and diisopropylethylamine (22.1 g, 171 mmol) in dimethylformamide (1700 mL). The mixture was stirred at room temperature for 1 hour. Water (1000 mL) was added to the mixture, which was washed with ethyl acetate (200 mL). The filter cake was filtered to obtain the relatively pure title compound. The mixture was slurried in a mixture of DCM:EA = 1:10 to afford 17 g of the title compound as a pale yellow solid in a 73.0% yield.

[0212] LCMS: Rt=1.12min, MS(ESI)m / z=408.3[M+H] + .

[0213] 1H NMR (400MHz, DMSO-d6) δ10.85(s,1H),8.01(t,J=7.3Hz,1H),7.62(t,J=9.1Hz,1H), 6.95–6.67(m,2H),4.83–4.67(m,1H),4.07(d,J=6.9Hz,1H),3.90(dd,J=13.2,3.4Hz ,2H),3.27(s,6H),2.78(tdd,J=13.5,9.6,4.1Hz,3H),2.19–1.93(m,2H),1.83(dtt, J=11.4,7.3,3.6Hz,1H),1.68(dd,J=13.4,3.7Hz,2H),1.26(qd,J=12.4,4.1Hz,2H).

[0214] Step 4: Synthesis of N-(2,6-dioxopiperidin-3-yl)-2-fluoro-4-(4-formylpiperidin-1-yl)benzamide 2,2,2-trifluoroacetate: Trifluoroacetic acid (17 mL) was added dropwise to a solution of 4-(4-(dimethoxymethyl)piperidin-1-yl)-N-(2,6-dicarbonylpiperidin-3-yl)-2-fluorobenzamide (17 g, 2.9 mmol) in dichloromethane (170 mL). The mixture was stirred at room temperature for 4 hours. The reaction mixture was evaporated under reduced pressure to obtain a residue, which was then adjusted to a weakly alkaline pH with saturated sodium bicarbonate solution. The mixture was extracted once with 1.5 L of DCM. The organic phase was washed three times with water and dried to afford 12 g of the title compound as an off-white solid in a 79% yield.

[0215] LCMS: Rt=0.967min, MS(ESI)m / z=362.0[M+H] + .

[0216] 1 H NMR (400MHz, DMSO-d6) δ = 10.85ppm (s, 1H), 1H NMR (400MHz, DMSO-d6) δ10.85(s,1H),9.62(s,1H),8.03(t,J=7.2Hz,1H),7.63(t,J=9. 1Hz,1H),6.97–6.64(m,2H),4.73(ddd,J=12.7,7.7,5.4Hz,1H),3.02(ddd,J=13.5,10.9 ,3.0Hz,2H),2.78(ddd,J=17.2,13.3,5.6Hz,1H),2.59(dtd,J=12.2,8.2,7.3,4.0Hz,1H ),2.19–1.97(m,2H),1.90(dt,J=12.4,3.8Hz,2H),1.54(dtd,J=14.4,10.8,3.9Hz,2H).

[0217] Synthesis of intermediate B2

[0218]

[0219] Step 1: Preparation of methyl 4-(4-(dimethoxymethyl)piperidin-1-yl)-2-methoxybenzoate

[0220] Palladium acetate (640 mg, 2.86 mmol), 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (3810 mg, 6.12 mmol), and cesium carbonate (26.59 g, 81.61 mmol) were added to a mixture of methyl 4-bromo-2-methoxybenzoate (10.00 g, 40.81 mmol) and 4-(dimethoxymethyl)piperidine (7.15 g, 44.89 mmol) in 1,4-dioxane (150 mL). The argon atmosphere was replaced three times, and the mixture was stirred at 100°C under argon for 8 hours. After the reaction, the mixture was filtered through Celite and washed with ethyl acetate. The filtrate was dried and the resulting crude product was purified by a normal flow silica gel column (ethyl acetate / petroleum ether = 1 / 10 to 3 / 1) to afford 8.0 g of the crude title compound as a pale yellow solid in a yield of 60.63%.

[0221] LCMS: MS (ESI) m / z = 324.2 [M+H] + .

[0222] Step 2: Preparation of 4-(4-(dimethoxymethyl)piperidin-1-yl)-2-methoxybenzoic acid

[0223] Dissolve methyl 4-(4-(dimethoxymethyl)piperidin-1-yl)-2-methoxybenzoate (8.0 g, 24.74 mmol) in 40 mL of tetrahydrofuran and 40 mL of methanol. Add 40 mL of a prepared aqueous solution of lithium hydroxide (4.15 g, 98.95 mmol) and stir at room temperature for 16 hours. After the reaction, spin dry, add 100 mL of water, and extract twice with ethyl acetate (60 mL x 2). Adjust the pH of the aqueous phase to 4-5 with 1N hydrochloric acid. A large amount of solid precipitates, which is filtered to yield 6.0 g of the title compound as a pale yellow solid in a 78.40% yield.

[0224] LCMS: MS (ESI) m / z = 310.2 [M+H] + .

[0225] Step 3: Preparation of (S)-4-(4-(dimethoxymethyl)piperidin-1-yl)-N-(2,6-dicarbonylpiperidin-3-yl)-2-methoxybenzamide Under ice bath, (S)-3-aminopiperidine-2,6-dione hydrochloric acid (3.35 g, 20.37 mmol) and diisopropylethylamine (7.52 g, 58.19 mmol) were added to a mixed solution of 4-(4-(dimethoxymethyl)piperidin-1-yl)-2-methoxybenzoic acid (6.0 g, 19.40 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (8.85 g, 23.27 mmol) in N,N-dimethylformamide (30 mL) and dichloromethane (120 mL), and the system was stirred at 25 ° C for 16 hours. The dichloromethane and diisopropylethylamine were removed by rotary evaporation under reduced pressure, and the reaction solution was added dropwise to 200 mL of water with stirring. After stirring for 1 hour, the mixture was filtered and the filter cake was washed with water. After the filter cake was dried, the mixture was rotary evaporation under reduced pressure to obtain 7.8 g of the title compound as a white solid with a yield of 95.87%.

[0226] LCMS: MS (ESI) m / z = 420.2 [M+H] + .

[0227] Step 4: Preparation of (S)-N-(2,6-dicarbonylpiperidin-3-yl)-4-(4-formylpiperidin-1-yl)-2-methoxybenzamide trifluoroacetate: Dissolve (S)-4-(4-(dimethoxymethyl)piperidin-1-yl)-N-(2,6-dicarbonylpiperidin-3-yl)-2-methoxybenzamide (7.80 g, 18.59 mmol) in 30 mL of dichloromethane, add 30 mL of trifluoroacetic acid, and stir at room temperature for 3 hours. After the reaction, the reaction solution was dried and the crude product was separated by a normal silica gel column (methanol / dichloromethane = 1 / 20 to 10 / 1) to obtain 3.90 g of the title compound as a light yellow solid, in a yield of 46.01%.

[0228] LCMS: MS (ESI) m / z = 374.2 [M+H] + .

[0229] Synthesis of intermediate B3

[0230]

[0231] Step 1: Preparation of 3-(6-bromo-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[0232] Sodium acetate (5.4 g, 65.8 mmol) was added to a methanol solution (160 mL) of 3-amino-2,6-piperidinedione hydrochloride (5.69 g, 36.2 mmol). The resulting turbid solution was stirred at 15°C for 10 minutes. Glacial acetic acid (19.76 g, 0.33 mol) was then added dropwise, followed by methyl 5-bromo-2-formylbenzoate (8 g, 33 mmol). The system was stirred at 15°C for 20 minutes. Sodium cyanoborohydride (4.13 g, 65.8 mmol) was then added portionwise. The system was heated to 35°C and stirred for 16 hours. Water (20 mL) was added dropwise to the reaction solution, and the methanol was removed by rotary evaporation under reduced pressure. Water (500 mL) was added, filtered, and the filter cake dried to afford 8.3 g of the title compound as a white solid in a yield of 78.12%.

[0233] LCMS: Rt=1.07min, MS(ESI)m / z=323.0 / 325.0[M+H] + .

[0234] Step 2: Preparation of 3-(6-(4-(dimethoxymethyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (SP-4-1)-[1,3-bis[2,6-bis(1-propylbutyl)phenyl]-4,5-dichloro-1,3-dihydro-2H-imidazol-2-ylidene]dichloro(3-chloropyridine-κN)-palladium (0.3 g, 0.3 mmol) was added to a mixture of 3-(6-bromo-1-oxoisoindolin-2-yl)piperidine-2,6-dione (2 g, 6.2 mmol), 4-(dimethoxymethyl)piperidine (1.28 g, 8.1 mmol) and cesium carbonate (6.06 g, 18.6 mmol) in dioxane (40 mL), the nitrogen was replaced three times, the system was heated to 100°C and stirred for 3 hours. The reaction solution was cooled to room temperature, diluted with ethyl acetate and filtered. The filtrate was dried under reduced pressure and purified by silica gel column chromatography (methanol / dichloromethane, 0-10%) to obtain 0.9 g of the title compound as a yellow solid in a yield of 35.48%.

[0235] LCMS: Rt=0.98min, MS(ESI)m / z=402.0[M+H]+ .

[0236] Step 3: Preparation of 1-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)piperidine-4-carbaldehyde trifluoroacetate.

[0237] Trifluoroacetic acid (6 mL) was added dropwise to a dichloromethane solution (20 mL) of 3-(6-(4-(dimethoxymethyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (0.9 g, 2.2 mmol). The mixture was stirred at room temperature for 2 hours. The solvent was removed by rotary evaporation under reduced pressure, and ether (30 mL) was added. The mixture was sonicated for 10 minutes, filtered, and the filter cake dried to afford 0.83 g of the title compound as a gray solid in a yield of 72.73%. LCMS: Rt = 0.88 min, MS (ESI) m / z = 356.2 [M+H] + .

[0238] 1 H NMR(400MHz,DMSO)δppm 10.98(s,1H),9.64(s,1H),7.43(d,J=8.4Hz,1H),7.27(m,2H),5.10(dd,J=13.3,5.1Hz,1H),4.34(d,J=16.7Hz,1H),4.20(d ,J=16.8Hz,1H),3.67(d,J=12.6Hz,2H),2.91(m,3H),2.56(m,2H),2.37(m,1H),1.97(dd,J=12.9,10.7Hz,3H),1.61(m,2H).

[0239] Synthesis of intermediate B4

[0240]

[0241] Step 1: Preparation of 3-(5-bromo-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[0242] Sodium acetate (670 mg, 8.2 mmol) was added to a methanol solution (20 mL) of 3-amino-2,6-piperidinedione hydrochloride (0.74 g, 4.5 mmol). The resulting turbid solution was stirred at 15°C for 10 minutes. Glacial acetic acid (2.46 g, 41 mmol) was then added dropwise, followed by methyl 4-bromo-2-formylbenzoate (1 g, 4.1 mmol). The system was stirred at 15°C for 20 minutes. Sodium cyanoborohydride (0.52 g, 8.2 mmol) was then added portionwise. The system was heated to 35°C and stirred for 16 hours. Water (5 mL) was added dropwise to the reaction solution, and the methanol was removed by rotary evaporation under reduced pressure. Water (50 mL) was added, the mixture was filtered, and the filter cake was dried to afford 1.2 g of the title compound as a white solid in an 81.11% yield.

[0243] LCMS: Rt=1.03min, MS(ESI)m / z=322.9 / 324.9[M+H] + .

[0244] Step 2: Preparation of 3-(5-(4-(dimethoxymethyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (SP-4-1)-[1,3-bis[2,6-bis(1-propylbutyl)phenyl]-4,5-dichloro-1,3-dihydro-2H-imidazol-2-ylidene]dichloro(3-chloropyridine-κN)-palladium (0.3 g, 0.3 mmol) was added to a mixture of 3-(5-bromo-1-oxoisoindolin-2-yl)piperidine-2,6-dione (2 g, 6.2 mmol), 4-(dimethoxymethyl)piperidine (1.28 g, 8.1 mmol) and cesium carbonate (6.06 g, 18.6 mmol) in dioxane (40 mL), the nitrogen was replaced three times, the system was heated to 100°C and stirred for 3 hours. The reaction solution was cooled to room temperature, diluted with ethyl acetate and filtered. The filtrate was dried under reduced pressure and purified by silica gel column chromatography (methanol / dichloromethane, 0-10%) to obtain 1.5 g of the title compound as a yellow solid in a yield of 59.68%.

[0245] LCMS: Rt=1.17min, MS(ESI)m / z=402.0[M+H] + .

[0246] Step 3: Preparation of 1-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperidine-4-carboxaldehyde trifluoroacetate: Trifluoroacetic acid (10 mL) was added dropwise to a solution of 3-(5-(4-(dimethoxymethyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (1.5 g, 3.7 mmol) in dichloromethane (30 mL). The mixture was stirred at room temperature for 2 hours. The solvent was removed by vacuum drying, and ether (50 mL) was added. The mixture was sonicated for 10 minutes, filtered, and the filter cake dried to afford 1.35 g of the title compound as a green solid in a yield of 70.27%.

[0247] 1H NMR(400MHz,DMSO)δppm 10.95(s,1H),9.62(s,1H),7.51(d,J=8.4Hz,1H),7.07(d,J=10.4Hz,2H),5.05(dd,J=13.3,5.1Hz,1H),4.26(dd,J=49.5,16.8Hz,2H),3.7 8(m,2H),3.02(m,2H),2.90(m,1H),2.58(dd,J=11.0,4.0Hz,2H),2.36(dt,J=13.3,8.9Hz,1H),1.94(m,3H),1.57(qd,J=11.0,3.7Hz,2H).

[0248] LCMS: Rt=0.97min, MS(ESI)m / z=356.1[M+H] +

[0249] Synthesis of intermediate B5

[0250]

[0251] Step 1: Preparation of methyl 4-bromo-2-(bromomethyl)-5-fluorobenzoate

[0252] Bromosuccinimide (3.95 g, 22.2 mmol) was added portionwise to a 1,2-dichloroethane solution (100 mL) of methyl 4-bromo-5-fluoro-2-methylbenzoate (5 g, 20.2 mmol) and azobisisobutyronitrile (0.33 g, 2.0 mmol). The mixture was stirred at 85°C for 16 hours. The reaction mixture was cooled to room temperature, washed with water (100 mL) and saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was dried under reduced pressure to give 5.5 g of the crude yellow oily title compound in a yield of 75.25%. This product was used directly in the next step.

[0253] 1H NMR (400MHz, DMSO) δppm 8.07 (d, J = 6.8Hz, 1H), 7.81 (d, J = 9.3Hz, 1H), 4.98 (s, 2H), 3.88 (s, 3H). LCMS: Rt = 1.37min, MS (ESI) m / z = no MS signal.

[0254] Step 2: Preparation of 3-(5-bromo-6-fluoro-1-carbonylisoindolin-2-yl)piperidine-2,6-dione

[0255] Methyl 4-bromo-2-(bromomethyl)-5-fluorobenzoate (5.5 g, 15.2 mol) was added to a solution of 3-amino-2,6-piperidinedione hydrochloride (3.75 g, 22.8 mmol) and diisopropylethylamine (5.89 g, 45.6 mol) in dimethylformamide (100 mL). The system was stirred at 100°C for 10 hours. The cooled reaction solution was added to water (300 mL) and filtered. The filter cake was dissolved in a mixture of ethyl acetate (30 mL) and petroleum ether (150 mL), stirred at room temperature for 10 minutes, filtered, and dried to afford 3.7 g of the title compound as a brown solid in a yield of 70.39%.

[0256] 1H NMR(400MHz,DMSO)δppm 11.01(s,1H),7.74–7.65(m,2H),5.11(dd,J=13.3,5.1Hz,1H),4.41(dd,J=51.4,17.7Hz,2H),2.91(dd d,J=13.5,12.4,5.4Hz,1H),2.64–2.55(m,1H),2.39(ddd,J=26.6,13.3,4.5Hz,1H),2.06–1.95(m,1H).

[0257] LCMS: Rt=1.04min, MS(ESI)m / z=341.0,343.0[M+H] + .

[0258] Step 3: Preparation of 3-(5-(4-(dimethoxymethyl)piperidin-1-yl)-6-fluoro-1-carbonylisoindolin-2-yl)piperidine-2,6-dione

[0259] (SP-4-1)-[1,3-bis[2,6-bis(1-propylbutyl)phenyl]-4,5-dichloro-1,3-dihydro-2H-imidazol-2-ylidene]dichloro(3-chloropyridine-κN)-palladium (0.58 g, 0.6 mmol) was added to a mixture of 3-(5-bromo-6-fluoro-1-carbonylisoindolin-2-yl)piperidine-2,6-dione (3.4 g, 10.0 mmol), 4-(dimethoxymethyl)piperidine (2.39 g, 15.0 mmol) and cesium carbonate (9.77 g, 30.0 mmol) in dioxane (80 mL), the atmosphere was replaced with nitrogen three times, and the system was heated to 100°C and stirred for 3 hours. The reaction solution was cooled to room temperature, diluted with dioxane and filtered. The filtrate was dried under reduced pressure and purified by silica gel column chromatography (methanol / dichloromethane, 0-10%) to obtain 1.9 g of the title compound as a brown solid in a yield of 45.00%.

[0260] LCMS: Rt=1.07min, MS(ESI)m / z=420.0[M+H] + .

[0261] 1 H NMR(400MHz,DMSO)δppm 10.89(s,1H),7.40(d,J=11.6Hz,1H),7.22(d,J=7.6Hz,1H),5.02(dd,J=13.3,5.1 Hz,1H),4.28(dd,J=45.0,17.1Hz,2H),4.12(d,J=6.5Hz,1H),3.48(s,2H),3.28(s ,6H),2.91–2.80(m,1H),2.70(t,J=11.6Hz,2H),2.56(d,J=17.6Hz,1H),2.40–2.2 8(m,1H),2.02–1.93(m,1H),1.74(d,J=9.7Hz,3H),1.41(dd,J=21.6,12.2Hz,2H).

[0262] Step 4: 1-(2-(2,6-dicarbonylpiperidin-3-yl)-6-fluoro-1-carbonylisoindolin-5-yl)piperidine-4-carbaldehyde

[0263] Trifluoroacetic acid (10 mL) was added dropwise to a dichloromethane solution (30 mL) of 3-(5-(4-(dimethoxymethyl)piperidin-1-yl)-6-fluoro-1-carbonylisoindolin-2-yl)piperidine-2,6-dione (1.9 g, 4.5 mmol). The mixture was stirred at room temperature for 1 hour. The solvent was removed from the reaction mixture by vacuum drying. The resulting residue was purified by C18 column chromatography (water (0.1% trifluoroacetic acid)-acetonitrile, 0-35%) to afford 1.54 g of the title compound as a white solid in a 66.67% yield.

[0264] LCMS: Rt=1.01min, MS(ESI)m / z=374.0[M+H] + .

[0265] 1 H NMR(400MHz,DMSO)δppm 10.98(s,1H),9.66(s,1H),7.42(d,J=11.5Hz,1H),7.25(d,J=7.6Hz,1H),5.07(dd,J=13.3,5.1Hz,1H),4.29(dd,J=49.0,17.1Hz,2H),3 .40(dd,J=11.8,4.8Hz,2H),3.00–2.79(m,3H),2.56(dd,J=18.2,11.5Hz,2H),2.44–2.29(m,1H),2.01–1.95(m,2H),1.77–1.57(m,2H).

[0266] Synthesis of intermediate B6

[0267]

[0268] Step 1: Preparation of methyl 4-bromo-2-(bromomethyl)-3-fluorobenzoate

[0269] Bromosuccinimide (3.95 g, 22.2 mmol) was added portionwise to a solution of methyl 4-bromo-3-fluoro-2-methylbenzoate (5 g, 20.2 mmol) and azobisisobutyronitrile (0.33 g, 2.0 mmol) in carbon tetrachloride (50 mL). The system was stirred at 80°C for 16 hours. The reaction solution was cooled to room temperature, diluted with dichloromethane (100 mL), washed sequentially with water (100 mL) and saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was dried under reduced pressure and purified by flash silica gel column chromatography (ethyl acetate / petroleum ether, 0-10%) to afford 3 g of the title compound as a white solid in a yield of 45.54%.

[0270] 1H NMR (400MHz, DMSO) δppm, 7.87 (dd, J = 8.4, 7.0Hz, 1H), 7.68 (dd, J = 8.5, 1.0Hz, 1H), 4.98 (d, J = 2.0Hz, 2H), 3.89 (s, 3H).

[0271] Step 2: Preparation of 3-(5-bromo-4-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[0272] Methyl 4-bromo-2-(bromomethyl)-3-fluorobenzoate (2.8 g, 8.6 mol) was added to a solution of 3-amino-2,6-piperidinedione hydrochloride (1.42 g, 8.6 mmol) and diisopropylethylamine (5.56 g, 43 mol) in dimethylformamide (50 mL). The mixture was stirred at 100°C for 2 hours. The solvent was removed by rotary evaporation under reduced pressure, and water (200 mL) was added. The mixture was ultrasonically shaken for 10 minutes, filtered, and the filter cake was dried to obtain 2.5 g of the title compound as a blue solid in a yield of 84.88%.

[0273] LCMS: Rt=1.09min, MS(ESI)m / z=340.9.0 / 342.9[M+H] + .

[0274] Step 3: Preparation of 3-(5-(4-(dimethoxymethyl)piperidin-1-yl)-4-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[0275] (SP-4-1)-[1,3-bis[2,6-bis(1-propylbutyl)phenyl]-4,5-dichloro-1,3-dihydro-2H-imidazol-2-ylidene]dichloro(3-chloropyridine-κN)-palladium (0.29 g, 0.3 mmol) was added to a mixture of 3-(5-bromo-4-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione (2 g, 5.9 mmol), 4-(dimethoxymethyl)piperidine (1.22 g, 7.7 mmol) and cesium carbonate (5.77 g, 17.7 mmol) in dioxane (40 mL), the atmosphere was replaced with nitrogen three times, the system was heated to 100°C and stirred for 3 hours. The reaction solution was cooled to room temperature, diluted with dioxane and filtered. The filtrate was dried under reduced pressure and purified by silica gel column chromatography (methanol / dichloromethane, 0-10%) to obtain 1.4 g of the title compound as a yellow solid in a yield of 45.76%.

[0276] LCMS: Rt=1.10min, MS(ESI)m / z=420.0[M+H] + .

[0277] Step 4: 1-(2-(2,6-dioxopiperidin-3-yl)-4-fluoro-1-oxoisoindolin-5-yl)piperidine-4-carbaldehyde: Trifluoroacetic acid (10 mL) was added dropwise to a solution of 3-(5-(4-(dimethoxymethyl)piperidin-1-yl)-4-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione (1.4 g, 3.3 mmol) in dichloromethane (30 mL). The mixture was stirred at room temperature for 2 hours. The solvent was removed by vacuum drying, and ether (50 mL) was added. The mixture was sonicated for 10 minutes, filtered, and the filter cake was dried to afford 1.0 g of the title compound as a gray solid in a yield of 75.76%.

[0278] LCMS: Rt=1.02min, MS(ESI)m / z=374.1[M+H] + .

[0279] 1 H NMR(400MHz,DMSO)δppm 10.99(s,1H),9.66(s,1H),7.47(d,J=8.1Hz,1H),7.18(t,J=7.9Hz,1H),5.08(dd,J=13.3,5.1Hz,1H),4.48(d,J=17.0Hz,1H),4.31 (d,J=17.0Hz,1H),3.41(dd,J=9.9,6.0Hz,2H),2.90(m,3H),2.56(dd,J=19.1,11.9Hz,2H),2.40(m,1H),1.98(m,3H),1.67(m,2H).

[0280] Synthesis of intermediate B7

[0281]

[0282] Step 1: Preparation of methyl 5-bromo-2-(bromomethyl)-3-fluorobenzoate

[0283] To a solution of methyl 5-bromo-3-fluoro-2-methylbenzoate (5 g, 20.2 mmol) in 1,2-dichloroethane (50 mL) was added N-bromosuccinimide (4.31 g, 24.2 mmol) and azobisisobutyronitrile (0.17 g, 1.01 mmol). The reaction mixture was heated to 70°C and stirred for 4 hours. After completion of the reaction, the mixture was cooled to room temperature, concentrated under reduced pressure, and purified by flash silica gel column chromatography (petroleum ether / ethyl acetate, 100%) to afford 6 g of the title compound as a colorless oil in a 91.09% yield.

[0284] LCMS: Rt=1.41min, MS(ESI)m / z 326.1[M+H] + .

[0285] Step 2: Preparation of 3-(6-bromo-4-fluoro-1-carbonylisoindolin-2-yl)piperidine-2,6-dione

[0286] 3-Aminopiperidine-2,6-dione hydrochloride (3.03 g, 18.4 mmol) was added to a solution of methyl 5-bromo-2-(bromomethyl)-3-fluorobenzoate (6 g, 18.4 mmol) and N,N-diisopropylethylamine (11.89 g, 92 mmol) in N,N-dimethylformamide (60 mL). The mixture was heated to 100°C and stirred for 11.5 hours. After cooling to room temperature, the mixture was concentrated under reduced pressure, diluted with water (200 mL), filtered, and the filter cake was washed with petroleum ether / ethyl acetate (4 / 1) solution. The filter cake was concentrated under reduced pressure and lyophilized to obtain 4.6 g of the title compound as a gray solid in a yield of 73.37%.

[0287] LCMS: Rt=1.10min, MS(ESI)m / z 340.9,342.8[M+H] + .

[0288] Step 3: Preparation of 3-(6-(4-(dimethoxymethyl)piperidin-1-yl)-4-fluoro-1-carbonylisoindolin-2-yl)piperidine-2,6-dione

[0289] (SP-4-1)-[1,3-bis[2,6-bis(1-propylbutyl)phenyl]-4,5-dichloro-1,3-dihydro-2H-imidazol-2-ylidene]dichloro(3-chloropyridine-κN)-palladium (0.66 g, 0.675 mmol) was added to a mixture of 3-(6-bromo-4-fluoro-1-carbonylisoindolin-2-yl)piperidine-2,6-dione (4.6 g, 0.0135 mol), 4-(dimethoxymethyl)piperidine (3.22 g, 20.25 mmol) and cesium carbonate (13.2 g, 40.5 mmol) in dioxane (60 mL), the atmosphere was replaced with nitrogen three times, and the system was heated to 100°C and stirred for 3 hours. The reaction mixture was cooled to room temperature, diluted with ethyl acetate, and filtered. The filtrate was evaporated to dryness under reduced pressure and purified by silica gel column chromatography (methanol / dichloromethane, 0-10%) to afford 2 g of the title compound as a yellow solid in a yield of 35.56%. LCMS: Rt = 1.09 min, MS (ESI) m / z = 420.0 [M+H] + .

[0290] Step 4: Preparation of 1-(2-(2,6-dicarbonylpiperidin-3-yl)-7-fluoro-3-carbonylisoindolin-5-yl)piperidine-4-carbaldehyde.

[0291] Trifluoroacetic acid (5 mL) was added dropwise to a dichloromethane solution (20 mL) of 3-(6-(4-(dimethoxymethyl)piperidin-1-yl)-4-fluoro-1-carbonylisoindolin-2-yl)piperidine-2,6-dione (2 g, 0.0048 mol). The mixture was stirred at room temperature for 1 hour. The solvent was removed by vacuum drying. The reaction mixture was then purified by C18 column chromatography (water-acetonitrile, 10-90%, 0.1% trifluoroacetic acid) to afford 752.2 mg of the title compound as an off-white solid in a 39.88% yield.

[0292] LCMS: Rt=1.07min, MS(ESI)m / z=374.0[M+H] +

[0293] 1 H NMR(400MHz,DMSO)δppm 10.99(s,1H),9.63(s,1H),7.12–7.03(m,2H),5.10(dd,J=13.3,5.0Hz,1H),4.42( d,J=16.7Hz,1H),4.25(d,J=16.6Hz,1H),3.73(d,J=12.7Hz,2H),2.97(dd,J=17.2 ,6.4Hz,2H),2.89(dd,J=13.5,5.1Hz,1H),2.60(dd,J=32.5,14.0Hz,2H),2.41(dt ,J=13.2,8.8Hz,1H),2.04–1.96(m,1H),1.92(d,J=10.0Hz,2H),1.62–1.52(m,2H).

[0294] Synthesis of intermediate B8

[0295]

[0296] Step 1: Preparation of 2-(2,6-dicarbonylpiperidin-3-yl)-5-(4-(hydroxymethyl)piperidin-1-yl)isoindoline-1,3-dione

[0297] N,N-Diisopropylethylamine (4.21 g, 32.58 mmol) was added to a mixture of 2-(2,6-dicarbonylpiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (1.80 g, 6.52 mmol) and piperidin-4-ylmethanol (0.83 g, 7.17 mmol) in dimethyl sulfoxide (15 mL). The mixture was heated to 120°C and stirred for 2 hours. The N,N-diisopropylethylamine was removed by rotary evaporation under reduced pressure, and the resulting residue was separated by C18 column chromatography (water-acetonitrile, 0.1% formic acid, 95-50%). The resulting preparative solution was adjusted to pH 9 with saturated sodium bicarbonate solution and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to dryness to afford 2.2 g of the title compound as a yellow solid in an 89.99% yield.

[0298] LCMS: Rt=1.04min, MS(ESI)m / z=372.1[M+H] + .

[0299] 1 H NMR(400MHz,DMSO)δppm 11.09(s,1H),7.64(d,J=8.6Hz,1H),7.30(d,J=2.1Hz,1H),7.23(dd,J=8.7,2.3Hz,1H),5.06(dd,J=12.9,5.4Hz,1H),4.51(t,J=5.3Hz,1H),4.1 1–4.03(m,2H),3.26(t,J=5.7Hz,2H),3.02–2.81(m,3H),2.56(dd,J=17. 8,10.6Hz,3H),2.05–1.99(m,1H),1.77–1.60(m,3H),1.25–1.19(m,1H).

[0300] Step 2: Preparation of 1-(2-(2,6-dicarbonylpiperidin-3-yl)-1,3-dicarbonylisoindolin-5-yl)piperidine-4-carbaldehyde.

[0301] 2-(2,6-dicarbonylpiperidin-3-yl)-5-(4-(hydroxymethyl)piperidin-1-yl)isoindoline-1,3-dione (2.00 g, 5.39 mmol) was dissolved in dichloromethane (50 mL) at room temperature under nitrogen. Pyridinium chlorochromate (5.80 g, 26.93 mmol) was added portionwise to the reaction mixture, which was then stirred at room temperature for 2 hours. The reaction mixture was filtered, and the filter cake was rinsed with dichloromethane. The filtrate was dried to obtain the crude product. The crude product was purified by combi-flash separation (ethyl acetate:petroleum ether = 3:2) to afford 668 mg of the title compound as a yellow solid in a 32.44% yield.

[0302] LCMS: Rt=1.07min, MS(ESI)m / z=370.0[M+H] + .

[0303] 1H NMR(400MHz,DMSO)δppm 11.09(s,1H),9.62(s,1H),7.66(d,J=8.5Hz,1H),7.34(d,J=2.1Hz,1H),7.25(dd,J=8.6,2.2Hz,1H),5.07(dd,J=12.9,5.4Hz,1H),3.94(d, J=13.4Hz,2H),3.23–3.11(m,2H),2.88(ddd,J=17.3,14.2,5.4Hz,1H),2.70–2.51(m,3H),2.05–1.86(m,3H),1.55(qd,J=10.8,3.7Hz,2H).

[0304] Synthesis of intermediate B9

[0305]

[0306] Step 1: Synthesis of (S)-4-(4-(dimethoxymethyl)piperidin-1-yl)-N-(2,6-dicarbonylpiperidin-3-yl)-2-fluorobenzamide

[0307] 2-(7-Azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (32.3 g, 85.5 mmol) was added all at once to a solution of 4-(4-(dimethoxymethyl)piperidin-1-yl)-2-fluorobenzoic acid (17 g, 57 mmol), 3-aminopiperidine-2,6-dione hydrochloride (9.35 g, 57 mmol), and diisopropylethylamine (22.1 g, 171 mmol) in dimethylformamide (1700 mL). The mixture was stirred at room temperature for 1 hour. Water (1000 mL) was added and the mixture was washed with ethyl acetate (200 mL). A white solid precipitated, which was insoluble in both the aqueous and organic phases. Filtration afforded the filter cake, which was the relatively pure title compound. The mixture was slurried in DCM:EA (1:10) to afford 17 g of the title compound as a pale yellow solid in a 73.0% yield.

[0308] LCMS: Rt=1.072min, MS(ESI)m / z=408.2[M+H] + .

[0309] Step 2: Synthesis of (S)-N-(2,6-dioxopiperidin-3-yl)-2-fluoro-4-(4-formylpiperidin-1-yl)benzamide trifluoroacetate: Trifluoroacetic acid (17 mL) was added dropwise to a solution of (S)-4-(4-(dimethoxymethyl)piperidin-1-yl)-N-(2,6-dicarbonylpiperidin-3-yl)-2-fluorobenzamide (17 g, 2.9 mmol) in dichloromethane (170 mL). The system was stirred at 45°C for 4 hours. The reaction solution was evaporated under reduced pressure to obtain a residue, which was then adjusted to a weakly alkaline pH with saturated sodium bicarbonate solution. The mixture was extracted once with 1.5 L of DCM, and the dichloromethane layer was dried to afford 12 g of the title compound as an off-white solid in a 79% yield.

[0310] LCMS: Rt=0.967min, MS(ESI)m / z=362.0[M+H] + .

[0311] 1 H NMR (400MHz, DMSO-d6) δ10.85(s,1H),9.62(s,1H),8.03(t,J=7.2Hz,1H),7.63(t,J=9. 1Hz,1H),6.97–6.64(m,2H),4.73(ddd,J=12.7,7.7,5.4Hz,1H),3.02(ddd,J=13.5,10.9 ,3.0Hz,2H),2.78(ddd,J=17.2,13.3,5.6Hz,1H),2.59(dtd,J=12.2,8.2,7.3,4.0Hz,1H ),2.19–1.97(m,2H),1.90(dt,J=12.4,3.8Hz,2H),1.54(dtd,J=14.4,10.8,3.9Hz,2H).

[0312] Synthesis of intermediate B10

[0313]

[0314] Step 1: Synthesis of methyl 4-(4-(dimethoxymethyl)piperidin-1-yl)-2-chlorobenzoate

[0315] A mixture of 4-(dimethoxymethyl)piperidine (5.5 g, 34.9 mmol), methyl 2-chloro-4-fluorobenzoate (4.4 g, 23.3 mmol), and potassium carbonate (6.4 g, 46.6 mmol) in DMSO (40 mL) was purged with nitrogen three times, heated to 80°C, and stirred for 2 hours. The reaction mixture was cooled to room temperature, water (300 mL) was added, and extracted twice with ethyl acetate (200 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the residue obtained by rotary evaporation under reduced pressure was purified by flash silica gel column chromatography (petroleum ether-ethyl acetate, 95-90%) to afford 3.9 g of the title compound as a white solid in a 51% yield.

[0316] LCMS: MS (ESI) m / z = 328.1 [M+H] + .

[0317] Step 2: Synthesis of 4-(4-(dimethoxymethyl)piperidin-1-yl)-2-chlorobenzoic acid

[0318] A solution of lithium hydroxide monohydrate (2.0 g, 47.6 mmol) in water (30 mL) was slowly added to a solution of methyl 4-(4-(dimethoxymethyl)piperidin-1-yl)-2-chlorobenzoate (3.9 g, 11.9 mmol) in methanol (30 mL). The mixture was heated to 50°C and stirred for 1 hour. The methanol was removed by rotary evaporation under reduced pressure, and the mixture was diluted with water (60 mL). Diluted aqueous hydrochloric acid (1 mol / L) was added dropwise with stirring until a large amount of precipitate formed. The mixture was filtered, the filter cake was washed with water, and dried to obtain 3.4 g of the title compound as a white solid in a yield of 91.0%.

[0319] LCMS: MS (ESI) m / z = 314.1 [M+H] + .

[0320] Step 3: Synthesis of (S)-2-chloro-4-(4-(dimethoxymethyl)piperidin-1-yl)-N-(2,6-dicarbonylpiperidin-3-yl)benzamide

[0321] 2-(7-Azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (3.23 g, 8.55 mmol) was added all at once to a solution of 4-(4-(dimethoxymethyl)piperidin-1-yl)-2-chlorobenzoic acid (1.78 g, 5.7 mmol), (S)-3-aminopiperidine-2,6-dione hydrochloride (935 mg, 5.7 mmol), and diisopropylethylamine (2.21 g, 17.1 mmol) in dimethylformamide (20 mL). The system was stirred at room temperature for 1 hour. Water (200 mL) was added to the system, and the mixture was washed with ethyl acetate (50 mL). A white solid precipitated, which was filtered to obtain 1.8 g of the title compound as a pale yellow solid, in a yield of 75.0%.

[0322] LCMS: MS (ESI) m / z = 424.1 [M+H] + .

[0323] Step 4: Synthesis of (S)-2-chloro-N-(2,6-dicarbonylpiperidin-3-yl)-4-(4-formylpiperidin-1-yl)benzamide trifluoroacetate

[0324] Trifluoroacetic acid (1.7 mL) was added dropwise to a dichloromethane solution (17 mL) of (S)-2-chloro-4-(4-(dimethoxymethyl)piperidin-1-yl)-N-(2,6-dicarbonylpiperidin-3-yl)benzamide (1.7 g, 4.0 mmol). The mixture was stirred at room temperature for 4 hours. The reaction mixture was evaporated under reduced pressure to obtain a residue, which was then adjusted to a weakly alkaline pH with saturated sodium bicarbonate solution. The dichloromethane layer was extracted with dichloromethane and dried to afford 1.2 g of the title compound as an off-white solid in a 78.5% yield.

[0325] LCMS: MS (ESI) m / z = 378.1 [M+H] + .

[0326] Synthesis of intermediate B11

[0327]

[0328] Step 1: Synthesis of methyl 5-(4-(hydroxymethyl)piperidin-1-yl)methylpicolinate

[0329] A solution of methyl 5-fluoromethylpyridinate (5.0 g, 32.23 mmol), piperidin-4-ylmethanol (3.3 g, 32.23 mmol), and triethylamine (8.1 g, 80.58 mmol) in DMSO (40 mL) was heated to 90°C and stirred for 2 hours. The reaction mixture was cooled to room temperature, water (300 mL) was added, and the mixture was extracted twice with ethyl acetate (200 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the residue was purified by flash silica gel column chromatography (petroleum ether-ethyl acetate, 95-90%) to afford 3.24 g of a yellow oily compound in a 42.6% yield. MS (ESI) m / z = 251.1 [M+H] + .

[0330] Step 2: Synthesis of 5-(4-(hydroxymethyl)piperidin-1-yl)-1-picolinic acid

[0331] A solution of lithium hydroxide monohydrate (1.32 g, 54.72 mmol) in water (10 mL) was slowly added to a solution of methyl 5-(4-(hydroxymethyl)piperidin-1-yl)methylpicolinate (3.23 g, 13.68 mmol) in methanol (10 mL). The mixture was heated to 60°C and stirred for 2 hours. The methanol was removed by rotary evaporation under reduced pressure, and the mixture was diluted with water (60 mL). Diluted aqueous hydrochloric acid (1 mol / L) was added dropwise with stirring until a large amount of precipitate formed. The mixture was filtered, the filter cake was washed with water, and dried to obtain 3.0 g of the title compound as a yellow solid in a yield of 98.7%.

[0332] MS (ESI) m / z = 237.1 [M+H] + .

[0333] Step 3: Synthesis of (S)-N-(2,6-dicarbonylpiperidin-3-yl)-5-(4-(hydroxymethyl)piperidin-1-yl)methylpicolinamide

[0334] 2-(7-Azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (3.27 g, 8.6 mmol) was added all at once to a solution of 5-(4-(hydroxymethyl)piperidin-1-yl)-1-picolinic acid (1.34 g, 5.7 mmol), (S)-3-aminopiperidine-2,6-dione hydrochloride (935 mg, 5.7 mmol), and diisopropylethylamine (2.2 g, 17.1 mmol) in dimethylformamide (20 mL). The mixture was stirred at room temperature for 1 hour. Water (100 mL) was added, and the mixture was extracted twice with ethyl acetate (200 mL). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the residue was purified by flash silica gel column chromatography (dichloromethane-methanol, 0-10%) to afford 864 mg of a yellow oily compound in a yield of 43.8%.

[0335] MS (ESI) m / z = 347.1 [M+H] + .

[0336] Step 4: Synthesis of (S)-N-(2,6-dicarbonylpiperidin-3-yl)-5-(4-formylpiperidin-1-yl)methylpicolinamide

[0337] IBX (46% wt, 840 mg, 3.0 mmol) was added to a solution of (S)-N-(2,6-dicarbonylpiperidin-3-yl)-5-(4-(hydroxymethyl)piperidin-1-yl)methylpicolinamide (864 mg, 2.5 mmol) in acetonitrile (10 mL) and 1,2-dichloromethane (10 mL). The mixture was heated to 60°C and stirred for 2 hours. The reaction was monitored for completion by TLC. The mixture was cooled to room temperature and filtered. The filter cake was washed with DCM. The filtrate was then dried to give a residue which was purified by flash silica gel column chromatography (dichloromethane-methanol, 0-10%) to afford 354.4 mg of a yellow solid compound in a 41.2% yield.

[0338] MS (ESI) m / z = 345.1 [M+H] + .

[0339] Synthesis of intermediate B12

[0340]

[0341] Step 1: Synthesis of methyl 2-fluoro-4-(3-(hydroxymethyl)azetidin-1-yl)benzoate

[0342] A solution of methyl 2,4-difluorobenzoate (3.44 g, 20.0 mmol), 3-methylhydroxyazetidine hydrochloride (2.46 g, 20.0 mmol), and diisopropylethylamine (7.74 g, 60.0 mmol) in DMSO (20 mL) was heated to 90°C and stirred for 6 hours. The reaction mixture was cooled to room temperature, water (300 mL) was added, and the mixture was extracted twice with ethyl acetate (200 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the residue obtained by rotary evaporation under reduced pressure was separated and purified by flash silica gel column chromatography (dichloromethane-methanol, 95-10%) to obtain 1.3 g of a white solid compound in a yield of 27.6%.

[0343] MS (ESI) m / z = 240.1 [M+H] + .

[0344] Step 2: Synthesis of 2-fluoro-4-(3-(hydroxymethyl)azetidin-1-yl)benzoic acid

[0345] A solution of lithium hydroxide monohydrate (521 mg, 21.76 mmol) in water (10 mL) was slowly added to a solution of methyl 2-fluoro-4-(3-(hydroxymethyl)azetidin-1-yl)benzoate (1.3 g, 5.44 mmol) in methanol (10 mL). The mixture was heated to 60°C and stirred for 2 hours. The methanol was removed by rotary evaporation under reduced pressure, and the mixture was diluted with water (60 mL). Diluted aqueous hydrochloric acid (1 mol / L) was added dropwise with stirring until a large amount of precipitate formed. The mixture was filtered, the filter cake was washed with water, and dried to obtain 1.0 g of the title compound as a yellow solid in an 81.7% yield.

[0346] MS (ESI) m / z = 226.1 [M+H] + .

[0347] Step 3: Synthesis of (S)-N-(2,6-dicarbonylpiperidin-3-yl)-2-fluoro-4-(3-(hydroxymethyl)azetidin-1-yl)benzamide

[0348] 2-(7-Azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (2.02 g, 5.33 mmol) was added all at once to a solution of 2-fluoro-4-(3-(hydroxymethyl)azetidin-1-yl)benzoic acid (1.0 g, 4.44 mmol), (S)-3-aminopiperidine-2,6-dione hydrochloride (805 mg, 4.89 mmol), and diisopropylethylamine (1.72 g, 13.33 mmol) in dimethylformamide (10 mL). The mixture was stirred at room temperature for 1 hour. Water (50 mL) was added, and the mixture was extracted twice with ethyl acetate (150 mL). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the residue was purified by flash silica gel column chromatography (dichloromethane-methanol, 0-10%) to afford 1.3 g of a white solid compound in a yield of 87.4%. MS (ESI) m / z = 336.1 [M+H] + .

[0349] Step 4: Synthesis of (S)-N-(2,6-dicarbonylpiperidin-3-yl)-2-fluoro-4-(3-formylazetidin-1-yl)benzamide

[0350] IBX (46% wt, 1.3 g, 3.88 mmol) was added to a solution of (S)-N-(2,6-dicarbonylpiperidin-3-yl)-2-fluoro-4-(3-(hydroxymethyl)azetidin-1-yl)benzamide (864 mg, 2.5 mmol) in DMSO (10 mL). The system was heated to 60°C and stirred for 2 hours. The reaction was monitored for completion by TLC. The mixture was cooled to room temperature, and water (80 mL) was added. The mixture was extracted twice with dichloromethane (150 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The residue was purified by flash silica gel column chromatography (methanol:dichloromethane, 0-10%) to afford 340 mg of the compound as a white solid in a yield of 26.3%.

[0351] MS (ESI) m / z = 334.1 [M+H] + .

[0352] Synthesis of intermediate B13

[0353]

[0354] Step 1: Preparation of methyl 2-fluoro-4-[3-(hydroxymethyl)tetrahydro-1H-pyrrol-1-yl]benzoate

[0355] Methyl 2,4-difluorobenzoate (3.44 g, 20.00 mmol) and tetrahydro-1H-pyrrol-3-ylmethanol (2.02 g, 20.00 mmol) were dissolved in dimethyl sulfoxide (15 mL). Triethylamine (5.05 g, 50.00 mmol) was added and stirred at 90°C for 1 hour. After the reaction was completed, the temperature was cooled to room temperature and ethyl acetate (200 mL) was added to the reaction solution. The mixture was washed three times with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was dried and the resulting crude product was separated by a normal silica gel column (ethyl acetate / petroleum ether = 1 / 5 to 1 / 1) to obtain 1.43 g of the crude title compound as a pale yellow solid in a yield of 28.1%.

[0356] LCMS: MS (ESI) m / z = 254.2 [M+H] + .

[0357] Step 2: Preparation of 2-fluoro-4-[3-(hydroxymethyl)tetrahydro-1H-pyrrol-1-yl]benzoic acid

[0358] Dissolve methyl 2-fluoro-4-[3-(hydroxymethyl)tetrahydro-1H-pyrrol-1-yl]benzoate (1.43 g, 5.65 mmol) in tetrahydrofuran (20 mL) and methanol (5 mL). Add 10 mL of a prepared aqueous solution of lithium hydroxide (541 mg, 22.60 mmol) and stir at room temperature for 16 hours. After the reaction, spin dry the mixture and adjust the pH to 2-3 with 1N hydrochloric acid. A solid precipitates and is filtered to obtain 1.14 g of the title compound as a pale yellow solid in an 84.4% yield.

[0359] LCMS: MS (ESI) m / z = 240.1 [M+H] + .

[0360] Step 3: Preparation of N-((S)-2,6-dicarbonylpiperidin-3-yl)-2-fluoro-4-(3-(hydroxymethyl)pyrrolidin-1-yl)benzamide

[0361] Under ice, (S)-3-aminopiperidine-2,6-dione hydrochloride (864 mg, 5.25 mmol) and diisopropylethylamine (1.85 g, 14.31 mmol) were added to a solution of 2-fluoro-4-[3-(hydroxymethyl)tetrahydro-1H-pyrrol-1-yl]benzoic acid (1.14 g, 4.77 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (2.17 g, 5.72 mmol) in N,N-dimethylformamide (10 mL). The mixture was stirred at 25°C for 2 hours. The diisopropylethylamine was removed by rotary evaporation under reduced pressure, and the reaction solution was added dropwise to 100 mL of water with stirring. After stirring for 0.5 hour, the mixture was filtered and the filter cake was washed with water. After draining, the filter cake was evaporated under reduced pressure to give 1.4 g of the crude title compound as a pale yellow solid in an 85.2% yield.

[0362] LCMS: MS (ESI) m / z = 350.2 [M+H] + .

[0363] Step 4: Preparation of N-((S)-2,6-dicarbonylpiperidin-3-yl)-2-fluoro-4-(3-formylpyrrolidin-1-yl)benzamide

[0364] N-((S)-2,6-dicarbonylpiperidin-3-yl)-2-fluoro-4-(3-(hydroxymethyl)pyrrolidin-1-yl)benzamide (1.85 g, 5.30 mmol) was dissolved in N,N-dimethylformamide (5 mL) and dichloromethane (50 mL). Dess-Martin periodinane (2.70 g, 6.36 mmol) was added and stirred at room temperature for 2 hours. After the reaction, water (50 mL) was added and the mixture was extracted twice with dichloromethane. The organic phases were combined, washed three times with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was dried to dryness. The resulting crude product was separated on a silica gel column (methanol / dichloromethane = 1 / 50 to 10 / 1) to obtain 500 mg of the crude product. The crude product was purified by thin-layer preparative chromatography to yield 180 mg of the title compound as a white solid, in a 9.8% yield.

[0365] LCMS: MS (ESI) m / z = 348.1 [M+H] + .

[0366] Synthesis of intermediate B14

[0367]

[0368] Step 1: Synthesis of methyl 2-fluoro-4-(4-fluoro-4-(hydroxymethyl)piperidin-1-yl)benzoate

[0369] A mixture of 4-fluoro-4-piperidinemethanol hydrochloride (5.9 g, 34.9 mmol), methyl 2,4-difluorobenzoate (4 g, 23.3 mmol), and potassium carbonate (6.4 g, 46.6 mmol) in DMSO (40 mL) was purged with nitrogen three times, heated to 80°C, and stirred for 2 hours. The reaction mixture was cooled to room temperature, water (300 mL) was added, and extracted twice with ethyl acetate (200 mL). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the residue obtained by rotary evaporation under reduced pressure was isolated and purified by flash silica gel column chromatography (petroleum ether-ethyl acetate, 95-90%) to afford 1.7 g of the title compound as a white solid in a 25.7% yield.

[0370] MS (ESI) m / z = 286.1 [M+H] + .

[0371] Step 2: Synthesis of 2-fluoro-4-(4-fluoro-4-(hydroxymethyl)piperidin-1-yl)benzoic acid

[0372] A solution of lithium hydroxide monohydrate (991 mg, 23.6 mmol) in water (20 mL) was slowly added to a solution of methyl 2-fluoro-4-(4-fluoro-4-(hydroxymethyl)piperidin-1-yl)benzoate (1.7 g, 5.9 mmol) in methanol (20 mL). The mixture was heated to 50°C and stirred for 1 hour. The methanol was removed by rotary evaporation under reduced pressure, and the mixture was diluted with water (60 mL). Diluted aqueous hydrochloric acid (1 mol / L) was added dropwise with stirring until a large amount of precipitate formed. The mixture was filtered, the filter cake was washed with water, and dried to obtain 1.4 g of the title compound as a white solid, in an 87.0% yield.

[0373] MS (ESI) m / z = 272.1 [M+H] + .

[0374] Step 3: Synthesis of (S)-N-(2,6-dicarbonylpiperidin-3-yl)-2-fluoro-4-(4-fluoro-4-(hydroxymethyl)piperidin-1-yl)benzamide. 2-(7-Azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (2.96 g, 7.8 mmol) was added to a dimethylformamide solution (25 mL) of 2-fluoro-4-(4-fluoro-4-(hydroxymethyl)piperidin-1-yl)benzoic acid (1.4 g, 5.2 mmol), (S)-3-aminopiperidine-2,6-dione hydrochloride (853 mg, 5.2 mmol) and diisopropylethylamine (2.01 g, 15.6 mmol), and the system was stirred at room temperature for 1 hour. Water (100 mL) was added to the system and washed with ethyl acetate (50 mL x 2). A white solid precipitated, which was insoluble in both the aqueous and organic phases. Filtration afforded 1.49 g of the title compound as a light yellow solid, with a yield of 75.1%.

[0375] MS (ESI) m / z = 382.1 [M+H] + .

[0376] Step 4: Synthesis of (S)-N-(2,6-dicarbonylpiperidin-3-yl)-2-fluoro-4-(4-fluoro-4-formylpiperidin-1-yl)benzamide trifluoroacetate

[0377] Dess-Martin reagent (2.48 g, 5.85 mmol) was added to a dichloromethane solution (20 mL) of (S)-N-(2,6-dicarbonylpiperidin-3-yl)-2-fluoro-4-(4-fluoro-4-(hydroxymethyl)piperidin-1-yl)benzamide (1.49 g, 3.9 mmol). The mixture was stirred at room temperature for 2 hours. After the reaction, the mother liquor was filtered, the solvent was removed under vacuum, and the product was purified by silica gel column chromatography (methanol / dichloromethane = 0-10%) to afford 674 mg of the title compound as a yellow solid in a 45.6% yield.

[0378] MS (ESI) m / z = 380.1 [M+H] + .

[0379] Synthesis of intermediate B15

[0380]

[0381] Step 1: Synthesis of methyl 2-fluoro-4-(3-fluoro-3-(hydroxymethyl)azetidin-1-yl)benzoate

[0382] A mixture of (3-fluoroazetidin-3-yl)methanol hydrochloride (4.9 g, 34.9 mmol), methyl 2,4-difluorobenzoate (4 g, 23.3 mmol), and potassium carbonate (6.4 g, 46.6 mmol) in DMSO (40 mL) was purged with nitrogen three times, heated to 80°C, and stirred for 2 hours. The reaction mixture was cooled to room temperature, added with water (300 mL), and extracted twice with ethyl acetate (200 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the residue obtained by rotary evaporation under reduced pressure was purified by flash silica gel column chromatography (petroleum ether-ethyl acetate, 95-90%) to afford 1.4 g of the title compound as a white solid in a yield of 23.4%.

[0383] MS (ESI) m / z = 258.0 [M+H] + .

[0384] Step 2: Synthesis of 2-fluoro-4-(3-fluoro-3-(hydroxymethyl)azetidin-1-yl)benzoic acid

[0385] A solution of lithium hydroxide monohydrate (907 mg, 21.6 mmol) in water (20 mL) was slowly added to a solution of methyl 2-fluoro-4-(3-fluoro-3-(hydroxymethyl)azetidin-1-yl)benzoate (1.4 g, 5.4 mmol) in methanol (20 mL). The mixture was heated to 50°C and stirred for 1 hour. The methanol was removed by rotary evaporation under reduced pressure, and the mixture was diluted with water (60 mL). Diluted aqueous hydrochloric acid (1 mol / L) was added dropwise with stirring until a large amount of precipitate formed. The mixture was filtered, the filter cake was washed with water, and dried to obtain 1.1 g of the title compound as a white solid, in an 87.0% yield.

[0386] MS (ESI) m / z = 244.0 [M+H] + .

[0387] Step 3: Synthesis of (S)-N-(2,6-dicarbonylpiperidin-3-yl)-2-fluoro-4-(3-fluoro-3-(hydroxymethyl)azetidin-1-yl)benzamide

[0388] 2-(7-Azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (2.56 g, 6.7 mmol) was added to a solution of 2-fluoro-4-(3-fluoro-3-(hydroxymethyl)azetidin-1-yl)benzoic acid (1.1 g, 4.5 mmol), (S)-3-aminopiperidine-2,6-dione hydrochloride (738 mg, 5.2 mmol), and diisopropylethylamine (1.74 g, 13.5 mmol) in dimethylformamide (10 mL). The mixture was stirred at room temperature for 1 hour. Water (50 mL) was added, and the mixture was extracted with ethyl acetate (30 mL x 2). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the residue was purified by flash silica gel column chromatography (petroleum ether-ethyl acetate, 95-90%) to afford 1.2 g of the title compound as a white solid in a yield of 77.3%.

[0389] MS (ESI) m / z = 354.1 [M+H] + .

[0390] Step 4: Synthesis of (S)-N-(2,6-dicarbonylpiperidin-3-yl)-2-fluoro-4-(3-fluoro-3-formylazetidin-1-yl)benzamide trifluoroacetate

[0391] Dess-Martin reagent (2.16 g, 5.09 mmol) was added to a dichloromethane solution (20 mL) of (S)-N-(2,6-dicarbonylpiperidin-3-yl)-2-fluoro-4-(3-fluoro-3-(hydroxymethyl)azetidin-1-yl)benzamide (1.2 g, 3.4 mmol). The mixture was stirred at room temperature for 2 hours. After the reaction, the mother liquor was filtered, the solvent was removed under vacuum, and the product was purified by silica gel column chromatography (methanol / dichloromethane = 0-10%) to afford 462 mg of the compound as a yellow solid, in a 38.7% yield.

[0392] MS (ESI) m / z = 352.1 [M+H] + .

[0393] Synthesis of intermediate B16

[0394]

[0395] Step 1: Synthesis of methyl 2-fluoro-4-(4-hydroxy-4-(hydroxymethyl)piperidin-1-yl)benzoate

[0396] A mixture of 4-hydroxy-4-piperidinemethanol hydrochloride (5.8 g, 34.9 mmol), methyl 2,4-difluorobenzoate (4 g, 23.3 mmol), and potassium carbonate (6.4 g, 46.6 mmol) in DMSO (40 mL) was purged with nitrogen three times, heated to 80°C, and stirred for 2 hours. The reaction mixture was cooled to room temperature, added with water (300 mL), and extracted twice with ethyl acetate (200 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the resulting residue was purified by flash silica gel column chromatography (petroleum ether-ethyl acetate, 95-90%) to afford 2.4 g of the title compound as a white solid in a 36.2% yield.

[0397] MS (ESI) m / z = 284.1 [M+H] + .

[0398] Step 2: Synthesis of 2-fluoro-4-(4-hydroxy-4-(hydroxymethyl)piperidin-1-yl)benzoic acid

[0399] A solution of lithium hydroxide monohydrate (1.43 g, 34 mmol) in water (20 mL) was slowly added to a solution of methyl 2-fluoro-4-(4-hydroxy-4-(hydroxymethyl)piperidin-1-yl)benzoate (2.4 g, 8.5 mmol) in methanol (20 mL). The mixture was heated to 50°C and stirred for 1 hour. The methanol was removed by rotary evaporation under reduced pressure, and the mixture was diluted with water (60 mL). Diluted aqueous hydrochloric acid (1 mol / L) was added dropwise with stirring until a large amount of precipitate formed. The mixture was filtered, the filter cake was washed with water, and dried to obtain 1.9 g of the title compound as a white solid, in an 84.0% yield.

[0400] MS (ESI) m / z = 270.1 [M+H] + .

[0401] Step 3: Synthesis of (S)-N-(2,6-dicarbonylpiperidin-3-yl)-2-fluoro-4-(4-hydroxy-4-(hydroxymethyl)piperidin-1-yl)benzamide

[0402] 2-(7-Azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (4.02 g, 10.5 mmol) was added to a solution of 2-fluoro-4-(4-hydroxy-4-(hydroxymethyl)piperidin-1-yl)benzoic acid (1.9 g, 7.0 mmol), (S)-3-aminopiperidine-2,6-dione hydrochloride (1.15 g, 7.0 mmol), and diisopropylethylamine (2.01 g, 15.6 mmol) in dimethylformamide (30 mL). The mixture was stirred at room temperature for 1 hour. Water (100 mL) was added, and the mixture was washed with ethyl acetate (50 mL x 2). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the residue was purified by flash silica gel column chromatography (petroleum ether-ethyl acetate, 95-90%) to afford 1.97 g of the title compound as a white solid in a yield of 74.3%.

[0403] MS (ESI) m / z = 380.1 [M+H] + .

[0404] Step 4: Synthesis of (S)-N-(2,6-dicarbonylpiperidin-3-yl)-2-fluoro-4-(4-hydroxy-4-formylpiperidin-1-yl)benzamide trifluoroacetate

[0405] Dess-Martin reagent (3.3 g, 7.8 mmol) was added to a dichloromethane solution (20 mL) of (S)-N-(2,6-dicarbonylpiperidin-3-yl)-2-fluoro-4-(4-hydroxy-4-(hydroxymethyl)piperidin-1-yl)benzamide (1.97 g, 5.2 mmol). The mixture was stirred at room temperature for 2 hours. After the reaction, the mother liquor was filtered, the solvent was removed under vacuum, and the product was purified by silica gel column chromatography (methanol / dichloromethane = 0-10%) to afford 702 mg of the compound as a yellow solid in a 35.8% yield.

[0406] MS (ESI) m / z = 378.1 [M+H] + .

[0407] Synthesis of intermediate B17

[0408]

[0409] Step 1: Synthesis of tert-butyl 4-(3-fluoro-4-(carbomethoxy)phenyl)piperazine-1-carboxylate

[0410] A mixture of tert-butylpiperazine-1-carboxylate (6.5 g, 34.9 mmol), methyl 2,4-difluorobenzoate (4 g, 23.3 mmol), and potassium carbonate (6.4 g, 46.6 mmol) in DMSO (40 mL) was purged with nitrogen three times, heated to 80°C, and stirred for 2 hours. The reaction mixture was cooled to room temperature, water (300 mL) was added, and extracted twice with ethyl acetate (200 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the residue obtained by rotary evaporation under reduced pressure was purified by flash silica gel column chromatography (petroleum ether-ethyl acetate, 95-90%) to afford 3.3 g of the title compound as a white solid in a 41.5% yield.

[0411] MS (ESI) m / z = 339.1 [M+H] + .

[0412] Step 2: Synthesis of 4-(4-(tert-butoxycarbonyl)piperazin-1-yl)-2-fluorobenzoic acid

[0413] A solution of lithium hydroxide monohydrate (1.58 g, 37.6 mmol) in water (20 mL) was slowly added to a solution of tert-butyl 4-(3-fluoro-4-(carbomethoxycarbonyl)phenyl)piperazine-1-carboxylate (3.3 g, 9.7 mmol) in methanol (20 mL). The mixture was heated to 50°C and stirred for 1 hour. The methanol was removed by rotary evaporation under reduced pressure, and the mixture was diluted with water (60 mL). Diluted aqueous hydrochloric acid (1 mol / L) was added dropwise with stirring until a large amount of precipitate formed. The mixture was filtered, the filter cake was washed with water, and dried to obtain 2.7 g of the title compound as a white solid in an 85.9% yield.

[0414] MS (ESI) m / z = 325.1 [M+H] + .

[0415] Step 3: Synthesis of tert-butyl (S)-4-(4-((2,6-dicarbonylpiperidin-3-yl)carbamoyl)-3-fluorophenyl)piperazine-1-carboxylate

[0416] 2-(7-Azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (4.7 g, 12.5 mmol) was added to a solution of 4-(4-(tert-butoxycarbonyl)piperazin-1-yl)-2-fluorobenzoic acid (2.7 g, 8.3 mmol), (S)-3-aminopiperidine-2,6-dione hydrochloride (1.36 g, 8.3 mmol), and diisopropylethylamine (3.22 g, 24.9 mmol) in dimethylformamide (30 mL). The mixture was stirred at room temperature for 1 hour. Water (100 mL) was added, and the mixture was washed with ethyl acetate (50 mL x 2). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the residue was purified by flash silica gel column chromatography (petroleum ether-ethyl acetate, 95-90%) to afford 3.0 g of the title compound as a white solid in a yield of 83.4%.

[0417] MS (ESI) m / z = 435.2 [M+H] + .

[0418] Step 4: Synthesis of (S)-N-(2,6-dicarbonylpiperidin-3-yl)-2-fluoro-4-(piperazin-1-yl)benzamide hydrochloride

[0419] A 4M solution of dioxane hydrochloride (6 mL) was added dropwise to a solution of tert-butyl (S)-4-(4-((2,6-dicarbonylpiperidin-3-yl)carbamoyl)-3-fluorophenyl)piperazine-1-carboxylate (3.0 g, 6.9 mmol) in dichloromethane (30 mL). The mixture was stirred at room temperature for 4 hours. The reaction mixture was rotary evaporated under reduced pressure to afford 2.2 g of the title compound as an off-white solid in a 95% yield.

[0420] MS (ESI) m / z = 335.1 [M+H] + .

[0421] Synthesis of intermediate B18

[0422]

[0423] Step 1: Preparation of 2-(2,6-dicarbonylpiperidin-3-yl)-5-(2-(hydroxymethyl)-7-azaspiro[3.5]nonan-7-yl)isoindoline-1,3-dione

[0424] N,N-Diisopropylethylamine (1.87 g, 14.48 mmol) was added to a mixture of 2-(2,6-dicarbonylpiperidin-3-yl)-5-fluoroisoindole-1,3-dione (1 g, 3.6 mmol) and (7-azaspiro[3.5]nonan-2-yl)methanol (0.76 g, 3.98 mmol) in dimethyl sulfoxide (10 mL). The mixture was heated to 120°C and stirred for 2 hours. The N,N-diisopropylethylamine was removed by rotary evaporation under reduced pressure. The resulting residue was purified by C18 column chromatography (water-acetonitrile, 5-70%) to afford 1.2 g of the title compound as a yellow solid in a yield of 80.56%.

[0425] LCMS: Rt=1.12min, MS(ESI)m / z=412.1[M+H] + .

[0426] Step 2: Preparation of 7-(2-(2,6-dicarbonylpiperidin-3-yl)-1,3-dicarbonylisoindolin-5-yl)-7-azaspiro[3.5]nonane-2-carbaldehyde.

[0427] Dess-Martin periodinane (1.42 g, 3.35 mmol) was added portionwise to a dichloromethane solution (50 mL) of 2-(2,6-dicarbonylpiperidin-3-yl)-5-(2-(hydroxymethyl)-7-azaspiro[3.5]nonan-7-yl)isoindoline-1,3-dione (1.15 g, 2.79 mmol). The mixture was stirred at 25°C for 1 hour. The mixture was diluted with dichloromethane, and the organic phase was washed sequentially with aqueous triethylamine (100 mL, 2%) and saturated brine, dried, filtered, and dried under reduced pressure. The mixture was then purified by C18 column chromatography (water-acetonitrile, 5-70%, 0.1% trifluoroacetic acid) to afford 310 mg of the title compound as a yellow solid in an 18.31% yield.

[0428] LCMS: Rt=1.20min, MS(ESI)m / z=410.1[M+H] + .

[0429] 1H NMR(400MHz,DMSO)δppm 11.09(s,1H),9.70(d,J=1.6Hz,1H),7.65(d,J=8.6Hz,1H),7.33(d,J=2.0Hz,1H),7.24(dd,J=8.6,2.2Hz,1H),5.07(dd,J=12 .9,5.4Hz,1H),3.42(m,4H),3.22(m,1H),2.88(m,1H),2.56(dd,J=18.1,10.7Hz,2H),1.99(m,5H),1.68(m,2H),1.50(m,2H).

[0430] Synthesis of intermediate B19

[0431]

[0432] Step 1: Preparation of methyl 2-fluoro-4-(4-carbonylpiperidin-1-yl)benzoate

[0433] Palladium acetate (352.5 mg, 1.57 mmol) was added to a mixture of piperidin-4-one (1.6 g, 15.7 mmol), methyl 4-bromo-2-fluorobenzoate (3.66 g, 15.7 mmol), 1,1'-binaphthyl-2,2'-bis(diphenylphosphine) (0.98 g, 1.57 mmol), and cesium carbonate (15.35 g, 47.1 mmol) in anhydrous toluene (50 mL). The atmosphere was replaced with nitrogen three times, and the mixture was heated to 110°C and stirred for 16 hours. The reaction mixture was cooled to room temperature, water (300 mL) was added, and the mixture was extracted twice with ethyl acetate (200 mL). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the residue was purified by flash silica gel column chromatography (petroleum ether-ethyl acetate, 10-50%) to afford 1.2 g of the compound as a yellow solid in a yield of 30.5%. LCMS: Rt=1.18min, MS(ESI)m / z=252.1[M+H] + .

[0434] Step 2: Preparation of 2-fluoro-4-(4-carbonylpiperidin-1-yl)benzoic acid

[0435] A solution of lithium hydroxide monohydrate (0.81 g, 19.2 mmol) in water (20 mL) was slowly added to a solution of methyl 2-fluoro-4-(4-carbonylpiperidin-1-yl)benzoate (1.2 g, 4.8 mmol) in tetrahydrofuran (20 mL). The mixture was heated to 50°C and stirred for 1 hour. The tetrahydrofuran was removed by rotary evaporation under reduced pressure, and the mixture was diluted with water (20 mL). Diluted aqueous hydrochloric acid (1 mol / L) was added dropwise with stirring until a large amount of precipitate formed. The mixture was filtered, the filter cake was washed with water, and dried to obtain 949 mg of the compound as a white solid, with a yield of 83.3%.

[0436] LCMS: Rt=1.17min, MS(ESI)m / z=238.1[M+H] + .

[0437] Step 3: Preparation of (S)-N-(2,6-dicarbonylpiperidin-3-yl)-2-fluoro-4-(4-carbonylpiperidin-1-yl)benzamide

[0438] 2-(7-Azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (2.28 g, 6 mmol) was added all at once to a solution of 2-fluoro-4-(4-carbonylpiperidin-1-yl)benzoic acid (949 mg, 4 mmol), (S)-3-aminopiperidine-2,6-dione hydrochloride (0.66 g, 4 mmol), and diisopropylethylamine (1.55 g, 12 mmol) in dimethylformamide (20 mL). The mixture was stirred at room temperature for 1 hour. Water (300 mL) was added, and the mixture was extracted twice with ethyl acetate (100 mL). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the residue was purified by flash silica gel column chromatography (methanol / dichloromethane, 0-10%) to afford 1.02 g of the title compound as a yellow solid in a yield of 73.8%. LCMS: Rt=1.605min, MS(ESI)m / z=348.1[M+H] + .

[0439] Synthesis of intermediate B20

[0440]

[0441] Step 1: Preparation of tert-butyl 4-(1-((benzyloxy)carbonyl)azetidin-3-yl)piperazine-1-carboxylate

[0442] N,N-Diisopropylethylamine (18.87 g, 0.15 mol) was added to a solution of tert-butylpiperazine-1-carboxylate (13.5 g, 0.073 mol) and benzyl 3-carbonylazetidine-1-carboxylate (14.98 g, 0.073 mol) in tetrahydrofuran (100 mL). The mixture was stirred at 25°C for 10 minutes. Sodium triacetoxyborohydride (46.41 g, 0.22 mol) was then added portionwise to the reaction mixture, and the mixture was stirred at 25°C for 4 hours. The N,N-diisopropylethylamine was removed by rotary evaporation under reduced pressure. The resulting residue was purified by flash silica gel column chromatography (petroleum ether-ethyl acetate, 95-90%) to afford 7.6 g of the title compound as an off-white solid in a 27.8% yield.

[0443] MS (ESI) m / z = 376.2 [M+H] + .

[0444] Step 2: Preparation of tert-butyl 4-(azetidin-3-yl)piperazine-1-carboxylate

[0445] Under a hydrogen atmosphere, 10% palladium on carbon (2.02 g) was added to a solution of tert-butyl 4-(1-((benzyloxy)carbonyl)azetidin-3-yl)piperazine-1-carboxylate (7.6 g, 20.2 mmol) in methanol (80 mL). The mixture was stirred at room temperature for 2 hours. The reaction mixture was filtered, the filter cake rinsed with methanol, and the filtrate was dried to afford 4.5 g of the title compound as a colorless oil (92.3% yield), which was used directly in the next step.

[0446] MS (ESI) m / z = 242.1 [M+H] + .

[0447] Step 3: Preparation of tert-butyl 4-(1-(2-(2,6-dicarbonylpiperidin-3-yl)-1,3-dicarbonylisoindolin-5-yl)azetidin-3-yl)piperazine-1-carboxylate.

[0448] N,N-Diisopropylethylamine (2.34 g, 18.10 mmol) was added to a solution of 2-(2,6-dicarbonylpiperidin-3-yl)-5-fluoroisoindole-1,3-dione (1.00 g, 3.62 mmol) and tert-butyl 4-(azetidin-3-yl)piperazine-1-carboxylate (2.09 g, 8.69 mmol) in dimethyl sulfoxide (10 mL). The mixture was heated to 120°C and stirred for 2 hours. The N,N-diisopropylethylamine was removed by rotary evaporation under reduced pressure. The resulting residue was purified by C18 column chromatography (water (0.1% formic acid)-acetonitrile, 100-50%) to afford 1.2 g of the title compound as a yellow solid in a 69.8% yield.

[0449] MS (ESI) m / z = 498.2 [M+H]+ .

[0450] Step 4: Preparation of 2-(2,6-dicarbonylpiperidin-3-yl)-5-(3-(piperazin-1-yl)azetidin-1-yl)isoindoline-1,3-dione hydrochloride

[0451] A 4M solution of dioxane hydrochloride (4 mL) was added dropwise to a solution of tert-butyl 4-(1-(2-(2,6-dicarbonylpiperidin-3-yl)-1,3-dicarbonylisoindolin-5-yl)azetidin-3-yl)piperazine-1-carboxylate (1.2 g, 2.4 mmol) in dichloromethane (20 mL). The mixture was stirred at room temperature for 4 hours. The reaction mixture was concentrated under reduced pressure to yield 2.2 g of a yellow solid.

[0452] MS (ESI) m / z = 398.1 [M+H] + .

[0453] Synthesis of intermediate B21

[0454]

[0455] Step 1: Preparation of tert-butyl 8-(2-(2,6-dicarbonylpiperidin-3-yl)-1,3-dicarbonylisoindolin-5-yl)-2,8-diazaspiro[4.5]decane-2-carboxylate

[0456] N,N-Diisopropylethylamine (2.34 g, 18.10 mmol) was added to a solution of 2-(2,6-dicarbonylpiperidin-3-yl)-5-fluoroisoindole-1,3-dione (1.00 g, 3.62 mmol) and tert-butyl 2,8-diazaspiro[4.5]decane-2-carboxylate (2.08 g, 8.69 mmol) in dimethyl sulfoxide (10 mL). The mixture was heated to 120°C and stirred for 2 hours. The N,N-diisopropylethylamine was removed by rotary evaporation under reduced pressure. The resulting residue was purified by C18 column chromatography (water (0.1% formic acid)-acetonitrile, 100-50%) to afford 1.35 g of the title compound as a yellow solid in a 75.2% yield.

[0457] MS (ESI) m / z = 497.2 [M+H] +

[0458] Step 2: Preparation of 2-(2,6-dicarbonylpiperidin-3-yl)-5-(2,8-diazaspiro[4.5]decane-8-yl)isoindoline-1,3-dione

[0459] A 4 M solution of dioxane hydrochloride (4 mL) was added dropwise to a solution of tert-butyl 8-(2-(2,6-dicarbonylpiperidin-3-yl)-1,3-dicarbonylisoindolin-5-yl)-2,8-diazaspiro[4.5]decane-2-carboxylate (1.35 g, 2.7 mmol) in dichloromethane (20 mL). The mixture was stirred at room temperature for 4 hours. The reaction mixture was concentrated under reduced pressure to yield 1.1 g of a yellow solid.

[0460] MS (ESI) m / z = 397.2 [M+H] + .

[0461] Synthesis of intermediate B22

[0462]

[0463] Step 1: Preparation of (1-(4-nitrophenyl)piperidin-4-yl)methanol

[0464] Potassium carbonate (8.81 g, 63.75 mmol) was added to a solution of 1-fluoro-4-nitrobenzene (6 g, 42.5 mmol) and piperidin-4-ylmethanol (4.89 g, 42.5 mmol) in N,N-dimethylformamide (60 mL). The system was purged with nitrogen three times and heated to 90°C with stirring for 5 hours. After completion of the reaction, the mixture was cooled to room temperature, diluted with water (100 mL), and extracted with ethyl acetate (50 mL x 3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure and purified by flash silica gel column chromatography (petroleum ether / ethyl acetate, 40-60%) to afford 8.9 g of the title compound as an orange solid in an 86.59% yield.

[0465] LCMS: Rt=1.14min, MS(ESI)m / z=237.2[M+H] + .

[0466] Step 2: Preparation of (1-(4-aminophenyl)piperidin-4-yl)methanol

[0467] Palladium-on-carbon catalyst (7.83 g, 7.36 mmol, 10%) was added to a solution of (1-(4-nitrophenyl)piperidin-4-yl)methanol (8.7 g, 36.8 mmol) in methanol (200 mL). The system was purged with hydrogen three times, and then stirred at 25°C for 4 hours. The reaction solution was filtered through celite, and the filtrate was concentrated under reduced pressure to obtain 6.8 g of the title compound as a pink solid, with a yield of 86.41%.

[0468] LCMS: Rt=0.22min, MS(ESI)m / z=207.2[M+H] + .

[0469] Step 3: Preparation of (1-(4-(2,4-dicarbonyltetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)methyl acetate

[0470] Add glacial acetic acid (4.70 g, 78.2 mmol) to a solution of (1-(4-aminophenyl)piperidin-4-yl)methanol (6.8 g, 33.0 mmol) and acrylic acid (2.38 g, 33 mmol) in water (8 ml). The system was purged with nitrogen three times, then heated to 105°C and stirred for 20 hours. After the reaction was complete and cooled to room temperature, a solution of urea (9.91 g, 0.165 mmol) in glacial acetic acid (70 ml) was added. The system was purged with nitrogen three times, then heated to 120°C and stirred for 20 hours. After the reaction was complete, the system was cooled to room temperature, hydrochloric acid (14 ml) was added, and the mixture was heated to 120°C and stirred for 1 hour. After completion of the reaction, the mixture was cooled to room temperature, diluted with water (100 ml), adjusted to pH 8 with saturated sodium bicarbonate solution, and extracted with ethyl acetate (100 mL*3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure and purified by flash silica gel column chromatography (ethyl acetate / petroleum ether, 40-60%) to give 5 g of the title compound as a pink solid in a yield of 23.03%.

[0471] LCMS: Rt=0.92min, MS(ESI)m / z=346.3[M+H] + .

[0472] Step 4: Preparation of 1-(4-(4-(hydroxymethyl)piperidin-1-yl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione

[0473] A solution of (1-(4-(2,4-dicarbonyltetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)methyl acetate (5g, 0.0072mol) in hydrochloric acid (50ml, 2mol / L) was purged with nitrogen three times, then heated to 100°C and stirred for 16h. After completion of the reaction, the mixture was cooled to room temperature, diluted with water (50ml), and the pH was adjusted to 8 with saturated sodium bicarbonate solution. The mixture was extracted with ethyl acetate (100mL*3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by flash silica gel column chromatography (ethyl acetate / petroleum ether, 40-60%) to obtain 3g of the title compound as a pink solid in a yield of 68.06%.

[0474] LCMS: Rt=0.37min, MS(ESI)m / z=304.3[M+H] + .

[0475] Step 5: Preparation of 1-(4-(2,4-dicarbonyltetrahydropyrimidin-1(2H)-yl)phenyl)piperidine-4-carboxaldehyde trifluoroacetate

[0476] Dess-Martin periodinane (5.09 g, 12 mmol, 10%) was added portionwise over one hour to a solution of 1-(4-(4-(hydroxymethyl)piperidin-1-yl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione (1.2 g, 0.004 mol) in N,N-dimethylformamide (30 mL). The system was purged with nitrogen three times, and then stirred at 25°C for 2 hours. After completion of the reaction, the mixture was diluted with water (100 ml), filtered, and the filter cake was concentrated under reduced pressure. Purification followed by C18 column chromatography (water-acetonitrile, 7-93%, 0.1% trifluoroacetic acid) afforded 347 mg of the title compound as a brown solid in a 31.44% yield.

[0477] LCMS: Rt=0.72min, MS(ESI)m / z=302.1[M+H] + .

[0478] 1 H NMR(400MHz,DMSO)δppm 10.33(s,1H),9.64(s,1H),7.21(t,J=22.7Hz,4H),3.72(t,J=6.7Hz,2H),3.67–3.55(m,2H),3.03(s,2H ),2.68(t,J=6.7Hz,2H),2.57(t,J=10.6Hz,1H),2.00(d,J=11.1Hz,2H),1.67(dd,J=21.2,10.7Hz,2H).

[0479] Synthesis of intermediate B23

[0480]

[0481] Step 1: tert-Butyl 4-(4-chloro-2-fluorophenyl)-3,6-dihydropyridine-1(2H)-carboxylate

[0482] Tetrakistriphenylphosphine palladium (0.89 g, 0.77 mmol) was added to a dioxane (40 mL) solution of 1-bromo-4-chloro-2-fluorobenzene (1.6 g, 7.7 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (3.57 g, 11.6 mmol) and sodium carbonate (2.45 g, 23.1 mmol), water (10 mL) was added, the system was replaced with nitrogen three times, and then heated to 90 ° C and stirred for 16 hours. The reaction solution was cooled to room temperature, and dioxane was removed by rotary evaporation under reduced pressure. Water (150 mL) was added for dilution, and the mixture was extracted with ethyl acetate (100 mL*2). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure and purified by flash silica gel column chromatography (ethyl acetate / petroleum ether, 0-20%) to obtain 2.0 g of the title compound as a white solid in a yield of 85.7%.

[0483] MS (ESI) m / z = 312.1 [M+H] + .

[0484] Step 2: tert-Butyl 4-(4-((2,6-di(benzyloxy)pyridin-3-yl)amino)-2-fluorophenyl)-3,6-dihydropyridine-1(2H)-carboxylate

[0485] Tris(dibenzylideneacetone)dipalladium (354.36 mg, 0.39 mmol), 2-dicyclohexylphosphine-2',6'-dimethoxybiphenyl (238.29 mg, 0.58 mmol), and cesium carbonate (3.78 g, 11.6 mmol) were added sequentially to a solution of tert-butyl 4-(4-chloro-2-fluorophenyl)-3,6-dihydropyridine-1(2H)-carboxylate (1.2 g, 3.87 mmol) and 2,6-di(benzyloxy)pyridin-3-amine (1.18 g, 3.87 mmol) in dimethylformamide (50 mL). The system was replaced with nitrogen three times, then heated to 110°C and stirred for 10 h. The system was cooled to room temperature, diluted with water (500 mL), and extracted with ethyl acetate (200 mL*2). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure and purified by flash silica gel column chromatography (ethyl acetate / petroleum ether, 0-20%) to obtain 1.48 g of the title compound as a yellow oil in a yield of 65.7%.

[0486] MS (ESI) m / z = 582.2 [M+H] + .

[0487] Step 3: tert-Butyl 4-(4-((2,6-dicarbonylpiperidin-3-yl)amino)-2-fluorophenyl)piperidine-1-carboxylate

[0488] Palladium-carbon catalyst (510 mg, 0.48 mmol, 10%) was added to a solution of tert-butyl 4-(4-((2,6-di(benzyloxy)pyridin-3-yl)amino)-2-fluorophenyl)-3,6-dihydropyridine-1(2H)-carboxylate (1.4 g, 2.4 mmol) in ethyl acetate (50 mL). The system was purged with hydrogen three times and then stirred at 25°C for 60 hours. The reaction solution was filtered through celite, and the filtrate was concentrated under reduced pressure to obtain 882 mg of the title compound as a blue solid in a yield of 90.5%. MS (ESI) m / z = 406.2 [M+H + .

[0489] Step 4: Preparation of 3-((4-(piperidin-4-yl)-3-fluorophenyl)amino)piperidine-2,6-dione trifluoroacetate

[0490] Trifluoroacetic acid (1 mL) was added dropwise to a solution of tert-butyl 4-(4-((2,6-dicarbonylpiperidin-3-yl)amino)-2-fluorophenyl)piperidine-1-carboxylate (882 mg, 2.1 mmol) in dichloromethane (10 mL). The mixture was stirred at 25°C for 2 hours. The solvent was removed by rotary evaporation under reduced pressure, and the reaction solution was isolated and purified by C18 column chromatography (water-acetonitrile, 5-50%, 0.1% trifluoroacetic acid) to afford 690 mg of the title compound as an off-white solid in a 54.3% yield.

[0491] MS (ESI) m / z = 306.1 [M+H] + .

[0492] Synthesis of intermediate B24

[0493]

[0494] Step 1: Preparation of 2,6-bis(benzyloxy)-3-(4-bromo-2-fluoro-6-methoxyphenyl)pyridine

[0495] Tetrakistriphenylphosphine palladium (0.89 g, 0.77 mmol) was added to a dioxane (40 mL) solution of 5-bromo-1-fluoro-2-iodo-3-methoxybenzene (2.54 g, 7.7 mmol), 2,6-di(benzyloxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (4.84 g, 11.6 mmol) and sodium carbonate (2.45 g, 23.1 mmol), water (10 mL) was added, the system was replaced with nitrogen three times, and then heated to 90 ° C and stirred for 16 hours. The reaction solution was cooled to room temperature, and dioxane was removed by rotary evaporation under reduced pressure. Water (150 mL) was added for dilution, and the mixture was extracted with ethyl acetate (100 mL*2). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure and purified by flash silica gel column chromatography (ethyl acetate / petroleum ether, 0-20%) to obtain 2.0 g of the title compound as a white solid in a yield of 85.7%.

[0496] MS (ESI) m / z = 494.1 [M+H] + .

[0497] Step 2: Preparation of 2,6-bis(benzyloxy)-3-(4-(4-(dimethoxymethyl)piperidin-1-yl)-2-fluoro-6-methoxyphenyl)pyridine

[0498] Tris(dibenzylideneacetone)dipalladium (354.36 mg, 0.39 mmol), 2-dicyclohexylphosphine-2',6'-dimethoxybiphenyl (238.29 mg, 0.58 mmol), and cesium carbonate (3.78 g, 11.6 mmol) were added sequentially to a solution of 2,6-di(benzyloxy)-3-(4-bromo-2-fluoro-6-methoxyphenyl)pyridine (1.9 g, 3.87 mmol) and 4-(dimethoxymethyl)piperidine (615.7 mg, 3.87 mmol) in dimethylformamide (50 mL). The system was replaced with nitrogen three times, then heated to 110 °C and stirred for 10 h. The system was cooled to room temperature, diluted with water (500 mL), extracted with ethyl acetate (200 mL*2), and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure and purified by flash silica gel column chromatography (ethyl acetate / petroleum ether, 0-20%) to obtain 956.7 mg of the title compound as a yellow oil, with a yield of 43.2%.

[0499] MS (ESI) m / z = 573.3 [M+H] + .

[0500] Step 3: Preparation of 3-(4-(4-(dimethoxymethyl)piperidin-1-yl)-2-fluoro-6-methoxyphenyl)piperidine-2,6-dione

[0501] 10% palladium-on-carbon catalyst (96 mg) was added to a solution of 2,6-bis(benzyloxy)-3-(4-(4-(dimethoxymethyl)piperidin-1-yl)-2-fluoro-6-methoxyphenyl)pyridine (956.7 mg, 1.67 mmol) in ethyl acetate (50 mL). The system was purged with hydrogen three times, and then stirred at 25°C for 60 hours. The reaction solution was filtered through celite, and the filtrate was concentrated under reduced pressure to provide 497.0 mg of the title compound as a blue solid, in a yield of 75.5%.

[0502] MS (ESI) m / z = 395.2 [M+H] + .

[0503] Step 4: Preparation of 1-(4-(2,6-dicarbonylpiperidin-3-yl)-3-fluoro-5-methoxyphenyl)piperidine-4-carbaldehyde

[0504] Trifluoroacetic acid (2 mL) was added dropwise to a solution of 3-(4-(4-(dimethoxymethyl)piperidin-1-yl)-2-fluoro-6-methoxyphenyl)piperidine-2,6-dione (497 mg, 1.26 mmol) in dichloromethane (10 mL). The mixture was stirred at 25°C for 2 hours. The solvent was removed by rotary evaporation under reduced pressure. The reaction solution was then purified by C18 column chromatography (water-acetonitrile, 5-50%, 0.1% trifluoroacetic acid) to afford 170 mg of the title compound as an off-white solid in a 38.9% yield. MS (ESI) m / z = 349.1 [M+H] + .

[0505] Synthesis of intermediate B25

[0506]

[0507] Step 1: Preparation of 1-(2,6-dicarbonylpiperidin-3-yl)-3-methyl-2-carbonyl-2,3-dihydro-1H-benzo[d]imidazole-4-carbaldehyde

[0508] 3-(4-Bromo-3-methyl-2-carbonyl-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (1.40 g, 4.14 mmol) was dissolved in N,N-dimethylformamide (60 mL). Triethylamine (1.26 g, 12.42 mmol), triethylsilane (1.44 g, 12.42 mmol), and Pd(dppf)Cl2 (1.20 g, 1.66 mmol) were added sequentially. The reaction mixture was heated to 120°C under a carbon monoxide atmosphere (50 psi) and stirred for 16 hours. The reaction mixture was filtered, and the filtrate was evaporated under reduced pressure to obtain a residue, which was purified by C18 column chromatography (water (0.1% formic acid)-acetonitrile, 5-40%) to afford 870 mg of the title compound as a pale yellow solid.

[0509] LCMS: Rt=0.97min, MS(ESI)m / z=288.1[M+H] + .

[0510] Step 2: Preparation of tert-butyl (1-((1-(2,6-dicarbonylpiperidin-3-yl)-3-methyl-2-carbonyl-2,3-dihydro-1H-benzo[d]imidazol-4-yl)methyl)piperidin-4-yl)(methyl)carbamate.

[0511] Tetraisopropyl titanate (1205 mg, 4.24 mmol) was added to a solution of 1-(2,6-dicarbonylpiperidin-3-yl)-3-methyl-2-carbonyl-2,3-dihydro-1H-benzo[d]imidazole-4-carbaldehyde (870 mg, 2.12 mmol) and tert-butylmethyl(piperidin-4-yl)carbamate (1363 mg, 6.36 mmol) in N,N-dimethylformamide (70 mL) and tetrahydrofuran (70 mL). The reaction was heated to 50°C and stirred for 16 hours. Sodium triacetoxyborohydride (1348 mg, 6.36 mmol) was then added to the reaction mixture and stirred at room temperature for 0.5 hours. The reaction mixture was evaporated to dryness under reduced pressure, and the resulting residue was purified by C18 column chromatography (water (0.1% trifluoroacetic acid)-acetonitrile, 5-40%) to afford 600 mg of the crude title compound as a pale yellow solid in a 40.8% yield. LCMS: Rt=0.96min, MS(ESI)m / z=486.1[M+H] + .

[0512] Step 3: Preparation of 3-(3-methyl-4-((4-(methylamino)piperidin-1-yl)methyl)-2-carbonyl-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione trifluoroacetate.

[0513] At room temperature, tert-butyl (1-((1-(2,6-dicarbonylpiperidin-3-yl)-3-methyl-2-carbonyl-2,3-dihydro-1H-benzo[d]imidazol-4-yl)methyl)piperidin-4-yl)(methyl)carbamate (600 mg, 0.87 mmol) was dissolved in dichloromethane (10 mL) and trifluoroacetic acid (2 mL). Under nitrogen protection, the solution was stirred at 25°C for 1 hour. The reaction solution was evaporated under reduced pressure to obtain a crude product, which was directly separated and purified by C18 column chromatography (water (0.1% trifluoroacetic acid)-acetonitrile, 100-88%) to obtain the crude product. The crude product was further separated and purified by C18 column chromatography (water (0.1% trifluoroacetic acid)-acetonitrile, 0-6%) to obtain 310 mg of the title compound as a yellow solid, with a yield of 58.36%.

[0514] LCMS: Rt=0.32min, MS(ESI)m / z=386.1[M+H] + .

[0515] 1 H NMR(400MHz,DMSO)δppm 11.14(s,1H),9.85(s,1H),9.02(s,2H),7.34–7.03(m,3H),5.44(dd,J=12.5,5.2Hz,1H),4.60(s,2H),3.66–3.37( m,5H),3.21(s,3H),2.89(dd,J=20.8,9.5Hz,1H),2.81–2.53(m,5H),2.21(s,2H),2.05–1.95(m,1H),1.72(s,2H).

[0516] Synthesis of intermediate B26

[0517]

[0518] Step 1: Preparation of 1-(6-(4-(dimethoxymethyl)piperidin-1-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

[0519] Cesium carbonate (7.53 g, 23.1 mmol) was added to a solution of 1-(6-bromo-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (2.5 g, 7.7 mmol) and 4-(dimethoxymethyl)piperidine (1.23 g, 7.7 mmol) in 1,4-dioxane (30 mL). The mixture was stirred at room temperature for 15 minutes. Methanesulfonic acid (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium(II) (0.97 g, 1.1 mmol) and 2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl (0.54 g, 1.1 mmol) were added. The system was purged with nitrogen three times and heated to 100°C with stirring for 16 hours. After completion of the reaction, the mixture was cooled to room temperature, diluted with water (100 mL), and extracted with ethyl acetate (100 mL*3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure and purified by flash silica gel column chromatography (petroleum ether / ethyl acetate, 30-70%) to obtain 1.1 g of the title compound as a yellow oil in a yield of 20.78%.

[0520] LCMS: Rt=1.00min, MS(ESI)m / z=402.0[M+H] + .

[0521] Step 2: Preparation of 1-(3-(2,4-dicarbonyltetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperidine-4-carboxaldehyde trifluoroacetate

[0522] Trifluoroacetic acid (2 mL) was added to a solution of 1-(6-(4-(dimethoxymethyl)piperidin-1-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (1 g, 2.5 mmol) in dichloromethane (10 mL). The mixture was stirred at 25°C for 1 hour. The reaction solution was concentrated under reduced pressure at low temperature and then purified by C18 column chromatography (water-acetonitrile, 20-80%, 0.1% trifluoroacetic acid) to afford 534.8 mg of the title compound as a white solid in a 58.2% yield. LCMS: Rt = 0.90 min, MS (ESI) m / z = 356.1 [M+H] + .

[0523] 1H NMR(400MHz,DMSO)δppm 10.51(s,1H),9.66(s,1H),7.47(d,J=8.7Hz,1H),6.94(d,J=8.1Hz,2H),3.91–3.87(m,5H),3.70(dd,J=8.9,3.8H z,2H),2.97(s,2H),2.73(t,J=6.7Hz,2H),2.55(d,J=10.4Hz,1H),1.98(d,J=12.8Hz,2H),1.67(t,J=10.8Hz,2H).

[0524] Synthesis of intermediate B27

[0525]

[0526] Step 1: Preparation of 2-(2,6-dicarbonylpiperidin-3-yl)-5-(3-(hydroxymethyl)azetidin-1-yl)isoindoline-1,3-dione

[0527] N,N-Diisopropylethylamine (2.52 g, 19.55 mmol) was added to a solution of 2-(2,6-dicarbonylpiperidin-3-yl)-5-fluoroisoindole-1,3-dione (1.8 g, 6.51 mmol) and azetidin-3-ylmethanol hydrochloride (805.32 mg, 6.51 mmol) in dimethyl sulfoxide (15 mL). The mixture was heated to 120°C and stirred for 2 hours. Water (90 mL, 50 V) was poured into the reaction solution, and the mixture was extracted three times with ethyl acetate (90 mL, 50 V). The organic phases were combined, the solvent removed under vacuum, and the product was isolated and purified by silica gel column chromatography (methanol / dichloromethane = 0-10%) to obtain 1.5 g of the target compound as a yellow solid in a yield of 65.03%. MS (ESI) m / z = 344.1 [M+H] + .

[0528] Step 2: 1-(2-(2,6-dicarbonylpiperidin-3-yl)-1,3-dicarbonylisoindolin-5-yl)azetidine-3-carbaldehyde

[0529] Dess-Martin reagent (3.21 g, 7.57 mmol) was added to a solution of 2-(2,6-dicarbonylpiperidin-3-yl)-5-(3-(hydroxymethyl)azetidin-1-yl)isoindoline-1,3-dione (1.3 g, 3.79 mmol) in dichloromethane (20 mL). The mixture was allowed to react at room temperature for 2 hours. After completion of the reaction, the mother liquor was filtered, the solvent removed under vacuum, and the product was purified by silica gel column chromatography (methanol / dichloromethane = 0-10%, 1‰ triethylamine) to afford 619.8 mg of the target compound as a yellow solid, in a yield of 44.89%.

[0530] LCMS: Rt=0.979min, MS(ESI)m / z=342.1[M+H] + .

[0531] 1H NMR(400MHz,DMSO)δppm 11.05(s,1H),9.80(d,J=1.7Hz,1H),7.66–7.60(m,1H),6.82(d,J=2.0Hz,1H),6.68(dd,J=8.3,2.1Hz,1H),5.02(dt,J=10.8,5.4Hz, 1H),4.18–4.09(m,4H),3.70–3.61(m,1H),2.84(ddd,J=17.4,14.1,5.5Hz,1H),2.51(ddd,J=9.6,8.5,2.4Hz,2H),2.01–1.93(m,1H).

[0532] Synthesis of intermediate B28

[0533]

[0534] Step 1: Preparation of methyl 3-bromo-6-(bromomethyl)-2-fluorobenzoate

[0535] Bromosuccinimide (3.95 g, 22.2 mmol) was added portionwise to a solution of methyl 3-bromo-2-fluoro-6-methylbenzoate (5 g, 20.2 mmol) and azobisisobutyronitrile (0.33 g, 2.0 mmol) in 1,2-dichloroethane (100 mL). The mixture was stirred at 85°C for 16 hours. The reaction mixture was cooled to room temperature, washed sequentially with water (100 mL) and saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to dryness under reduced pressure to afford 5.5 g of the crude title compound as a yellow oil, in a yield of 77.4%.

[0536] MS (ESI) m / z = no MS signal.

[0537] Step 2: Preparation of 3-(6-bromo-7-fluoro-1-carbonylisoindolin-2-yl)piperidine-2,6-dione

[0538] Methyl 3-bromo-6-(bromomethyl)-2-fluorobenzoate (5.5 g, 15.2 mol) was added to a solution of 3-amino-2,6-piperidinedione hydrochloride (3.75 g, 22.8 mmol) and diisopropylethylamine (5.89 g, 45.6 mol) in dimethylformamide (100 mL). The mixture was stirred at 100°C for 10 hours. The cooled reaction mixture was added to water (300 mL) and filtered. The filter cake was dissolved in a mixture of ethyl acetate (30 mL) and petroleum ether (150 mL), stirred at room temperature for 10 minutes, filtered, and dried to afford 3.7 g of the title compound as a brown solid in a yield of 70.4%.

[0539] MS (ESI) m / z = 341.0, 343.0 [M+H] + .

[0540] Step 3: Preparation of 3-(6-(4-(dimethoxymethyl)piperidin-1-yl)-7-fluoro-1-carbonylisoindolin-2-yl)piperidine-2,6-dione

[0541] (SP-4-1)-[1,3-bis[2,6-bis(1-propylbutyl)phenyl]-4,5-dichloro-1,3-dihydro-2H-imidazol-2-ylidene]dichloro(3-chloropyridine-κN)-palladium (0.58 g, 0.6 mmol) was added to a mixture of 3-(6-bromo-7-fluoro-1-carbonylisoindolin-2-yl)piperidine-2,6-dione (3.4 g, 10.0 mmol), 4-(dimethoxymethyl)piperidine (2.39 g, 15.0 mmol) and cesium carbonate (9.77 g, 30.0 mmol) in dioxane (80 mL), the atmosphere was replaced with nitrogen three times, and the system was heated to 100°C and stirred for 3 hours. The reaction solution was cooled to room temperature, diluted with dioxane and filtered. The filtrate was dried under reduced pressure and purified by silica gel column chromatography (methanol / dichloromethane, 0-10%) to obtain 1.9 g of the title compound as a brown solid in a yield of 45.0%.

[0542] MS (ESI) m / z = 420.2 [M+H] + .

[0543] Step 4: Preparation of 1-(2-(2,6-dicarbonylpiperidin-3-yl)-4-fluoro-3-carbonylisoindolin-5-yl)piperidine-4-carbaldehyde

[0544] Trifluoroacetic acid (10 mL) was added dropwise to a dichloromethane solution (30 mL) of 3-(6-(4-(dimethoxymethyl)piperidin-1-yl)-7-fluoro-1-carbonylisoindolin-2-yl)piperidine-2,6-dione (1.9 g, 4.5 mmol). The mixture was stirred at room temperature for 1 hour. The solvent was removed from the reaction mixture by vacuum drying. The resulting residue was purified by C18 column chromatography (water (0.1% trifluoroacetic acid)-acetonitrile, 0-35%) to afford 1.54 g of the title compound as a white solid in a 66.7% yield.

[0545] MS (ESI) m / z = 374.1 [M+H] + .

[0546] Synthesis of intermediate B29

[0547]

[0548] Step 1: Preparation of 2-(2,6-dicarbonylpiperidin-3-yl)-5-(3-(hydroxymethyl)pyrrolidin-1-yl)isoindoline-1,3-dione

[0549] N,N-Diisopropylethylamine (2.52 g, 19.55 mmol) was added to a solution of 2-(2,6-dicarbonylpiperidin-3-yl)-5-fluoroisoindole-1,3-dione (1.8 g, 6.51 mmol) and pyrrolidin-3-ylmethanol (659.12 mg, 6.51 mmol) in dimethyl sulfoxide (15 mL). The mixture was heated to 120°C and stirred for 2 hours. Water (90 mL, 50 V) was poured into the reaction solution, and the mixture was extracted three times with ethyl acetate (90 mL, 50 V). The organic phases were combined, the solvent removed under vacuum, and the product was isolated and purified by silica gel column chromatography (methanol / dichloromethane = 0-10%) to obtain 1.5 g of the target compound as a yellow solid in a yield of 64.41%.

[0550] MS (ESI) m / z = 358.1 [M+H] + .

[0551] Step 2: Preparation of 1-(2-(2,6-dicarbonylpiperidin-3-yl)-1,3-dicarbonylisoindolin-5-yl)pyrrolidine-3-carbaldehyde.

[0552] Dess-Martin reagent (3.08 g, 7.27 mmol) was added to a solution of 2-(2,6-dicarbonylpiperidin-3-yl)-5-(3-(hydroxymethyl)pyrrolidin-1-yl)isoindoline-1,3-dione (1.3 g, 3.63 mmol) in dichloromethane (20 mL) and allowed to react at room temperature for 2 hours. The mother liquor was filtered, the solvent removed under vacuum, and the product was isolated and purified by silica gel column chromatography (methanol / dichloromethane = 0-10%, 1‰ triethylamine) to afford 287 mg of the title compound as a yellow solid in a 21.5% yield.

[0553] LCMS: Rt=1.023min, MS(ESI)m / z=356.1[M+H] + .

[0554] 1H NMR(400MHz,DMSO)δppm 11.05(s,1H),9.80(d,J=1.7Hz,1H),7.66–7.60(m,1H),6.82(d,J=2.0Hz,1H),6.68(dd,J=8.3,2.1Hz,1H),5.02(dt,J=10.8,5.4Hz, 1H),4.18–4.09(m,4H),3.70–3.61(m,1H),2.84(ddd,J=17.4,14.1,5.5Hz,1H),2.51(ddd,J=9.6,8.5,2.4Hz,2H),2.01–1.93(m,1H).

[0555] Synthesis of intermediate B30

[0556]

[0557] Step 1: Synthesis of 1-(4-bromo-2,6-difluorophenyl)dihydropyrimidine-2,4(1H,3H)-dione

[0558] Add glacial acetic acid (4.70 g, 0.0782 mol) to a solution of 4-bromo-2,6-difluoroaniline (6.83 g, 0.0330 mol) and acrylic acid (2.38 g, 0.033 mol) in water (8 ml). The system was purged with nitrogen three times, then heated to 105°C and stirred for 20 hours. After the reaction was complete and cooled to room temperature, a solution of urea (9.91 g, 0.165 mol) in glacial acetic acid (70 ml) was added. The system was purged with nitrogen three times, then heated to 120°C and stirred for 20 hours. After the reaction was complete, the system was cooled to room temperature, hydrochloric acid (14 ml) was added, and the mixture was heated to 120°C and stirred for 1 hour. After completion of the reaction, the mixture was cooled to room temperature, diluted with water (100 ml), adjusted to pH 8 with saturated sodium bicarbonate solution, and extracted with ethyl acetate (100 mL*3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure and purified by flash silica gel column chromatography (ethyl acetate / petroleum ether, 40-60%) to give 2.7 g of the title compound as a yellow solid in a yield of 27.2%.

[0559] LCMS: MS (ESI) m / z=305.1, 307.1[M+H] +

[0560] Step 2: Synthesis of 1-(4-(4-(dimethoxymethyl)piperidin-1-yl)-2,6-difluorophenyl)dihydropyrimidine-2,4(1H,3H)-dione

[0561] Cesium carbonate (7.14 g, 0.0219 mol) was added to a solution of 1-(4-bromo-2,6-difluorophenyl)dihydropyrimidine-2,4(1H,3H)-dione (2.2 g, 0.0073 mol) and 4-(dimethoxymethyl)piperidine (1.36 g, 0.0073 mol) in 1,4-dioxane (30 mL). After stirring at room temperature for 15 minutes, methanesulfonic acid ( 2-Dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium(II) (0.92 g, 0.0011 mol) and 2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl (0.51 g, 0.0011 mol) were added. The system was purged with nitrogen three times, heated to 100°C, and stirred for 16 hours. After completion of the reaction, the mixture was cooled to room temperature, diluted with water (100 mL), and extracted with ethyl acetate (50 mL*3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure and purified by flash silica gel column chromatography (petroleum ether / ethyl acetate, 30-70%) to obtain 872.7 mg of the title compound as a yellow solid, in a yield of 31.2%.

[0562] LCMS: MS (ESI) m / z = 384.2 [M+H] +

[0563] Step 3: Synthesis of 1-(4-(2,4-dicarbonyltetrahydropyrimidin-1(2H)-yl)-3,5-difluorophenyl)piperidine-4-carbaldehyde

[0564] Trifluoroacetic acid (10 mL) was added dropwise to a dichloromethane solution (10 mL) of 1-(4-(4-(dimethoxymethyl)piperidin-1-yl)-2,6-difluorophenyl)dihydropyrimidine-2,4(1H,3H)-dione (1.1 g, 2.9 mmol). The mixture was stirred at room temperature for 2 hours. The reaction solution was rotary evaporated under reduced pressure and purified by C18 column chromatography (water-acetonitrile, 15%-85%, 0.1% trifluoroacetic acid) to afford 696.7 mg of the title compound as a white solid in a 62.7% yield. LCMS: MS (ESI) m / z = 338.1 [M+H] +

[0565] Synthesis of intermediate B31

[0566]

[0567] Step 1: Synthesis of 2,6-bis(benzyloxy)-3-(4-bromophenyl)pyridine

[0568] Potassium carbonate (3.65 g, 26.4 mmol) and 1,1-bis(diphenylphosphino)ferrocenepalladium dichloride (0.97 g, 1.32 mmol) were added sequentially to a dioxane (50 mL) solution of 1-bromo-4-iodobenzene (2.5 g, 8.8 mmol) and 2,6-di(benzyloxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (4.41 g, 10.56 mmol), water (10 mL) was added, the system was replaced with nitrogen three times, and then heated to 90 ° C and stirred for 16 hours. The reaction solution was cooled to room temperature, and dioxane was removed by rotary evaporation under reduced pressure. Water (150 mL) was added for dilution, and the mixture was extracted with ethyl acetate (100 mL*2). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure and purified by flash silica gel column chromatography (ethyl acetate / petroleum ether, 0-10%) to obtain 3.5 g of the title compound as a white solid in a yield of 79.5%.

[0569] LCMS:MS(ESI)m / z=446.1 / 448.1[M+H] + .

[0570] Step 2: Synthesis of methyl 1-(4-(2,6-di(benzyloxy)pyridin-3-yl)phenyl)piperidine-4-carboxylate

[0571] Tris(dibenzylideneacetone)dipalladium (0.36 g, 0.39 mmol), 2-dicyclohexylphosphino-2,4,6-triisopropylbiphenyl (0.37 g, 0.78 mmol), and cesium carbonate (5.08 g, 15.6 mmol) were added sequentially to a dioxane (50 mL) solution of 2,6-di(benzyloxy)-3-(4-bromophenyl)pyridine (3.5 g, 7.8 mmol) and methyl 4-piperidinate (1.67 g, 11.7 mmol). The system was replaced with nitrogen three times, then heated to 100 ° C and stirred for 16 h. The system was evaporated under reduced pressure to remove the solvent, diluted with water (200 mL), extracted with ethyl acetate (100 mL*2), and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure and then separated and purified by flash silica gel column chromatography (ethyl acetate / petroleum ether, 0-10%) to obtain 2.3 g of the title compound as a yellow solid, with a yield of 57.2%.

[0572] LCMS: MS (ESI) m / z = 509.1 [M+H] + .

[0573] Step 3: Synthesis of 1-(4-(2,6-di(benzyloxy)pyridin-3-yl)phenyl)piperidine-4-carboxylic acid

[0574] A solution of lithium hydroxide monohydrate (516 mg, 12.30 mmol) in water (30 mL) was added to a mixed solution of methyl 1-(4-(2,6-di(benzyloxy)pyridin-3-yl)phenyl)piperidine-4-carboxylate (2.1 g, 4.10 mmol) in tetrahydrofuran (30 mL) and methanol (30 mL). The mixture was stirred at 50°C for 2 hours. The solvent was removed by rotary evaporation under reduced pressure, and the mixture was diluted to 200 mL with water. The pH was adjusted to approximately 5 with dilute hydrochloric acid (30 mL, 1 mol / L), and the mixture was extracted with ethyl acetate (100 mL x 2). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was rotary evaporation under reduced pressure to obtain 1.9 g of the title compound as a yellow solid in a yield of 94.8%.

[0575] LCMS: MS (ESI) m / z = 495.2 [M+H] + .

[0576] Step 4: Synthesis of 1-(4-(2,6-dicarbonylpiperidin-3-yl)phenyl)piperidine-4-carboxylic acid

[0577] Palladium-on-carbon catalyst (418.48 mg, 0.39 mmol, 10%) was added to a mixture of 1-(4-(2,6-di(benzyloxy)pyridin-3-yl)phenyl)piperidine-4-carboxylic acid (1.94 g, 3.93 mmol) in methanol and tetrahydrofuran (1:1, 60 mL). The system was purged with hydrogen three times, and then stirred at 25°C for 16 hours. The reaction solution was filtered through celite, and the filtrate was concentrated under reduced pressure and purified by C18 column chromatography (water-acetonitrile, 5-70%, 0.1% trifluoroacetic acid) to afford 1.24 g (trifluoroacetate salt) of the title compound as a white solid in a 60.4% yield.

[0578] LCMS: MS (ESI) m / z = 317.1 [M+H] + .

[0579] Synthesis of intermediate B32

[0580]

[0581] Step 1: Synthesis of 1-(4-bromo-2-fluoro-6-methoxyphenyl)dihydropyrimidine-2,4(1H,3H)-dione

[0582] Add glacial acetic acid (4.70 g, 0.0782 mol) to a solution of 4-bromo-2-fluoro-6-methoxyaniline (10.42 g, 0.0330 mol) and acrylic acid (2.38 g, 0.033 mol) in water (8 ml). The system was purged with nitrogen three times, then heated to 105°C and stirred for 20 hours. After the reaction was complete and cooled to room temperature, a solution of urea (9.91 g, 0.165 mol) in glacial acetic acid (70 ml) was added. The system was purged with nitrogen three times, then heated to 120°C and stirred for 20 hours. After the reaction was complete, the system was cooled to room temperature, hydrochloric acid (14 ml) was added, and the mixture was heated to 120°C and stirred for 1 hour. After completion of the reaction, the mixture was cooled to room temperature, diluted with water (100 ml), adjusted to pH 8 with saturated sodium bicarbonate solution, and extracted with ethyl acetate (100 mL*3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure and purified by flash silica gel column chromatography (ethyl acetate / petroleum ether, 40-60%) to give 2.3 g of the title compound as a yellow solid in a yield of 21.8%.

[0583] LCMS: MS (ESI) m / z=317.0, 319.0[M+H] +

[0584] Step 2: Synthesis of 1-(4-(4-(dimethoxymethyl)piperidin-1-yl)-2-fluoro-6-methoxyphenyl)dihydropyrimidine-2,4(1H,3H)-dione

[0585] Tris(dibenzylideneacetone)dipalladium (0.36 g, 0.39 mmol), 2-dicyclohexylphosphino-2,4,6-triisopropylbiphenyl (0.37 g, 0.78 mmol), and cesium carbonate (5.08 g, 15.6 mmol) were added sequentially to a dioxane (50 mL) solution of 1-(4-bromo-2-fluoro-6-methoxyphenyl)dihydropyrimidine-2,4(1H,3H)-dione (2.46 g, 7.8 mmol) and 4-(dimethoxymethyl)piperidine (1.86 g, 11.7 mmol). The system was replaced with nitrogen three times, then heated to 100 ° C and stirred for 16 h. The system was evaporated under reduced pressure to remove the solvent, diluted with water (200 mL), extracted with ethyl acetate (100 mL*2), and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure and then separated and purified by flash silica gel column chromatography (ethyl acetate / petroleum ether, 0-10%) to obtain 1.2 g of the title compound as a yellow solid, with a yield of 37.9%.

[0586] LCMS: MS (ESI) m / z = 396.1 [M+H] + .

[0587] Step 3: Synthesis of 1-(4-(2,4-dicarbonyltetrahydropyrimidin-1(2H)-yl)-3-fluoro-5-methoxyphenyl)piperidine-4-carbaldehyde

[0588] Trifluoroacetic acid (10 mL) was added dropwise to a dichloromethane solution (10 mL) of 1-(4-(4-(dimethoxymethyl)piperidin-1-yl)-2-fluoro-6-methoxyphenyl)dihydropyrimidine-2,4(1H,3H)-dione (1.2 g, 3.0 mmol). The mixture was stirred at room temperature for 2 hours. The reaction solution was rotary evaporated under reduced pressure and purified by C18 column chromatography (water-acetonitrile, 15%-85%, 0.1% trifluoroacetic acid) to afford 562.4 mg of the title compound as an off-white solid in a 53.7% yield.

[0589] LCMS: MS (ESI) m / z = 350.1 [M+H] +

[0590] Synthesis of intermediate B33

[0591]

[0592] Step 1: Synthesis of 2,6-bis(benzyloxy)-3-(4-bromo-2-fluoro-6-methoxyphenyl)pyridine

[0593] Potassium carbonate (3.65 g, 26.4 mmol) and 1,1-bis(diphenylphosphino)ferrocenepalladium dichloride (0.97 g, 1.32 mmol) were added sequentially to a dioxane (50 mL) solution of 5-bromo-1-fluoro-2-iodo-3-methoxybenzene (2.9 g, 8.8 mmol) and 2,6-di(benzyloxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (4.41 g, 10.56 mmol), water (10 mL) was added, the system was replaced with nitrogen three times, and then heated to 90 ° C and stirred for 16 hours. The reaction solution was cooled to room temperature, and dioxane was removed by rotary evaporation under reduced pressure. Water (150 mL) was added for dilution, and the mixture was extracted with ethyl acetate (100 mL*2). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure and purified by flash silica gel column chromatography (ethyl acetate / petroleum ether, 0-10%) to obtain 3.1 g of the title compound as a white solid in a yield of 71.6%.

[0594] LCMS:MS(ESI)m / z=494.1 / 496.1[M+H] + .

[0595] Step 2: Synthesis of methyl 1-(4-(2,6-di(benzyloxy)pyridin-3-yl)-3-fluoro-5-methoxyphenyl)piperidine-4-carboxylate

[0596] Tris(dibenzylideneacetone)dipalladium (0.36 g, 0.39 mmol), 2-dicyclohexylphosphino-2,4,6-triisopropylbiphenyl (0.37 g, 0.78 mmol), and cesium carbonate (5.08 g, 15.6 mmol) were added sequentially to a dioxane (50 mL) solution of 2,6-di(benzyloxy)-3-(4-bromo-2-fluoro-6-methoxyphenyl)pyridine (3.8 g, 7.8 mmol) and methyl 4-piperidinate (2.16 g, 11.7 mmol). The system was replaced with nitrogen three times, then heated to 100 ° C and stirred for 16 h. The system was evaporated under reduced pressure to remove the solvent, diluted with water (200 mL), extracted with ethyl acetate (100 mL*2), and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure and then separated and purified by flash silica gel column chromatography (ethyl acetate / petroleum ether, 0-10%) to obtain 2.1 g of the title compound as a yellow solid, with a yield of 47.5%.

[0597] LCMS: MS (ESI) m / z = 557.2 [M+H] + .

[0598] Step 3: Synthesis of 1-(4-(2,6-di(benzyloxy)pyridin-3-yl)-3-fluoro-5-methoxyphenyl)piperidine-4-carboxylic acid

[0599] A solution of lithium hydroxide monohydrate (516 mg, 12.30 mmol) in water (30 mL) was added to a mixed solution of methyl 1-(4-(2,6-di(benzyloxy)pyridin-3-yl)phenyl)piperidine-4-carboxylate (2.3 g, 4.10 mmol) in tetrahydrofuran (30 mL) and methanol (30 mL). The mixture was stirred at 50°C for 2 hours. The solvent was removed by rotary evaporation under reduced pressure, and the mixture was diluted to 200 mL with water. The pH was adjusted to approximately 5 with dilute hydrochloric acid (30 mL, 1 mol / L), and the mixture was extracted with ethyl acetate (100 mL x 2). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was rotary evaporation under reduced pressure to obtain 2.1 g of the title compound as a yellow solid in a yield of 94.8%.

[0600] LCMS: MS (ESI) m / z = 543.2 [M+H] + .

[0601] Step 4: Synthesis of 1-(4-(2,6-dicarbonylpiperidin-3-yl)-3-fluoro-5-methoxyphenyl)piperidine-4-carboxylic acid

[0602] Palladium-on-carbon catalyst (418.48 mg, 0.39 mmol, 10%) was added to a mixture of 1-(4-(2,6-di(benzyloxy)pyridin-3-yl)-3-fluoro-5-methoxyphenyl)piperidine-4-carboxylic acid (2.1 g, 3.93 mmol) in methanol and tetrahydrofuran (1:1, 60 mL). The system was purged with hydrogen three times, and then stirred at 25°C for 16 hours. The reaction solution was filtered through celite, and the filtrate was concentrated under reduced pressure and purified by C18 column chromatography (water-acetonitrile, 5-70%, 0.1% trifluoroacetic acid) to afford 732.6 mg (trifluoroacetate salt) of the title compound as a white solid in a 51.2% yield.

[0603] LCMS: MS (ESI) m / z = 365.1 [M+H] + .

[0604] Synthesis of intermediate B1-1

[0605]

[0606] Step 1: Synthesis of 4-chloro-2-fluoro-5-nitrobenzaldehyde

[0607] Dissolve 4-chloro-2-fluorobenzaldehyde (14.5 g, 91.45 mmol, 1.0 eq) in concentrated sulfuric acid (100 mL) and add potassium nitrate (13.87 g, 137.175 mmol, 1.5 eq). Stir at room temperature for 1 h. Pour the reaction mixture into ice water (300 mL) to quench the mixture and filter to obtain the target compound, 4-chloro-2-fluoro-5-nitrobenzaldehyde (16.9 g, yellow solid, 91.0% yield).

[0608] 1 H NMR (400MHz, CDCl3) δ: 7.48 (d, J = 11.6Hz, 1H), 8.46 (d, J = 6.4Hz, 1H), 10.31 (s, 1H)

[0609] Step 2: Synthesis of 2-azido-4-chloro-5-nitrobenzaldehyde

[0610] Sodium azide (2.52 g, 38.8 mmol, 1.0 eq) was added to a reaction mixture containing 4-chloro-2-fluoro-5-nitrobenzaldehyde (7.9 g, 38.8 mmol, 1.0 eq) in DMSO (50 mL). The mixture was stirred at 30°C for 1 h. The reaction mixture was poured into water and extracted with EA. The organic phase was washed with water, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was slurried with PE / EA (10 / 1) and filtered to yield the target compound, 2-azido-4-chloro-5-nitrobenzaldehyde (5.0 g, yellow solid, 56.9% yield).

[0611] Step 3: Synthesis of 2-azido-5-nitro-4-(piperidin-1-yl)benzaldehyde

[0612] To the reaction mixture containing 2-azido-4-chloro-5-nitrobenzaldehyde (4.5 g, 19.9 mmol, 1.0 eq) and DMSO (100 mL) was added piperidine (5.1 g, 59.7 mmol, 3.0 eq). The mixture was stirred at 50°C for 3 h. The reaction mixture was poured into water and extracted with DCM. The organic phase was washed with water, dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the target compound, 2-azido-5-nitro-4-(piperidin-1-yl)benzaldehyde (5.2 g, brown solid, 94.9% yield).

[0613] LC-MS (ESI) m / z: 276.1 [M+H] +

[0614] Step 4: Synthesis of tert-butyl 4-(5-nitro-6-(piperidin-1-yl)-2H-indazol-2-yl)piperidine-1-carboxylate

[0615] A reaction mixture containing 2-azido-5-nitro-4-(piperidin-1-yl)benzaldehyde (5.2 g, 18.89 mmol, 1.0 eq), tert-butyl 4-aminopiperidine-1-carboxylate (3.78 g, 18.89 mmol, 1.0 eq), trimethyl orthoformate (6.0 g, 56.67 mmol, 3.0 eq), and DCM (100 mL) was stirred at room temperature overnight. Toluene (100 mL) was then added and the temperature was raised to 130°C. The DCM was removed using a water separator and stirred for 3 h. The reaction mixture was concentrated under reduced pressure and purified on a silica gel column (PE / EA = 4 / 1) to yield the target compound, tert-butyl 4-(5-nitro-6-(piperidin-1-yl)-2H-indazol-2-yl)piperidine-1-carboxylate (3.5 g, yellow solid, 43.2% yield).

[0616] LC-MS (ESI) m / z: 430.2 [M+H] + .

[0617] Step 5: Synthesis of 5-nitro-6-(piperidin-1-yl)-2-(piperidin-4-yl)-2-hydrogen-indazole hydrochloride

[0618] To a reaction mixture containing tert-butyl 4-(5-nitro-6-(piperidin-1-yl)-2H-indazol-2-yl)piperidine-1-carboxylate (3.5 g, 8.09 mmol, 1.0 eq) in dichloromethane (40 mL) was added a 4 M hydrochloric acid solution in dioxane (20 mL). The mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure to yield the title compound.

[0619] LC-MS (ESI) m / z: 330.2 [M+H] + .

[0620] Step 6: Preparation of nitrogen-(2,6-dicarbonylpiperidin-3-yl)-2-fluoro-4-(4-((4-(5-nitro-6-(piperidin-1-yl)-2hydro-indazol-2-yl)piperidin-1-yl)methyl)piperidin-1-yl)benzamide.

[0621] Nitrogen-(2,6-dicarbonylpiperidin-3-yl)-2-fluoro-4-(4-formylpiperidin-1-yl)benzamide (2.0 g, 5.54 mmol, 1.1 eq) was added to a solution of 5-nitro-6-(piperidin-1-yl)-2-(piperidin-4-yl)-2-hydro-indazole (1.66 g, 5.04 mmol, 1.0 eq) in N,N-dimethylacetamide (40 mL). The reaction solution was stirred at 25 ° C for 5 minutes, and glacial acetic acid (0.58 ml, 10.08 mmol, 2.0 eq) was added dropwise. The mixture was stirred at 4°C for 5 hours, and then sodium triacetoxyborohydride (2.14 g, 10.08 mmol, 2.0 eq) was added in two batches at an interval of 30 minutes, with 1 eq added in each batch. The system was stirred at 25°C for 16 hours. The reaction was completed under TLC monitoring. 150 ml of n-butanol was added to the system to dilute the reaction solution, and then washed with 100 ml*5 of saturated NaCl(aq). The n-butanol was spin-dried and separated and purified by silica gel column chromatography (methanol / dichloromethane, 0-10%) to obtain 3.02 g of the title compound as a reddish-brown solid in a yield of 88.82%.

[0622] LCMS: Rt=4.302min, MS(ESI)m / z=675.3[M+H] + .

[0623] Step 7: Preparation of 4-(4-((4-(5-amino-6-(piperidin-1-yl)-2-hydrogen-indazol-2-yl)piperidin-1-yl)methyl)piperidin-1-yl)-nitrogen-(2,6-dicarbonylpiperidin-3-yl)-2-fluorobenzamide.

[0624] Azo-(2,6-piperidin-3-yl)-2-fluoro-4-(4-((4-(5-nitro-6-(piperidin-1-yl)-2-hydrogen-indazol-2-yl)piperidin-1-yl)methyl)piperidin-1-yl)benzamide (1.51 g, 2.24 mmol) was added to THF (60 ml) / MeOH (60 ml). 5% palladium on carbon (1 g) was then added to displace the hydrogen three times. The reaction system was stirred at 25°C for 16 hours and monitored for completion by TLC. The reaction solution was diluted with THF (60 ml) / MeOH (60 ml), and the filtrate was filtered through celite and dried to afford 1.23 g of the title compound as a gray-brown solid in an 85.42% yield.

[0625] LCMS: Rt=1.356min, MS(ESI)m / z=645.4[M+H] + .

[0626] Synthesis of intermediate B2-1

[0627]

[0628] Step 1: Preparation of (S)-nitro-(2,6-dicarbonylpiperidin-3-yl)-2-methoxy-4-(4-((4-(5-nitro-6-(piperidin-1-yl)-2hydro-indazol-2-yl)piperidin-1-yl)methyl)piperidin-1-yl)benzamide.

[0629] N-(2,6-dicarbonylpiperidin-3-yl)-2-methoxy-4-(4-formylpiperidin-1-yl)benzamide (3.2 g, 6.57 mmol, 1.2 eq) was added to a solution of 5-nitro-6-(piperidin-1-yl)-2-(piperidin-4-yl)-2-hydrogen-indazole dihydrochloride (2.31 g, 5.47 mmol, 1.0 eq) in N,N-dimethylacetamide (60 mL). The reaction solution was stirred at 25 ° C for 5 minutes, and triethylamine (1.5 ml, 10.94 mmol, 2.0 eq) and 2-nitro-3-piperidin-1-yl)-2-methoxy-4-(4-formylpiperidin-1-yl)benzamide were added dropwise. The mixture was stirred at 5°C for 5 hours, and then sodium triacetoxyborohydride (2.32 g, 10.94 mmol, 2.0 eq) was added in two batches at an interval of 30 minutes, with 1 eq added in each batch. The system was stirred at 25°C for 16 hours. The reaction was completed under TLC monitoring. 150 ml of n-butanol was added to the system to dilute the reaction solution, and then washed with 100 ml*5 of saturated NaCl(aq). The n-butanol was spin-dried and separated and purified by silica gel column chromatography (methanol / dichloromethane, 0-10%) to obtain 3.40 g of the title compound as a reddish-brown solid in a yield of 90.42%.

[0630] LCMS: Rt=1.639min, MS(ESI)m / z=687.4[M+H] + .

[0631] Step 2: Preparation of (S)-4-(4-((4-(5-amino-6-(piperidin-1-yl)-2-hydrogen-indazol-2-yl)piperidin-1-yl)methyl)piperidin-1-yl)-nitrogen-(2,6-dicarbonylpiperidin-3-yl)-2-methoxybenzamide

[0632] Azo-(2,6-dicarbonylpiperidin-3-yl)-2-methoxy-4-(4-((4-(5-nitro-6-(piperidin-1-yl)-2-hydrogen-indazol-2-yl)piperidin-1-yl)methyl)piperidin-1-yl)benzamide (1.70 g, 2.47 mmol) was added to THF (60 ml) / MeOH (60 ml). 5% palladium on carbon (1.1 g) was then added to displace the hydrogen atmosphere three times. The reaction system was stirred at 25°C for 16 hours and monitored for completion by TLC. The reaction solution was diluted with THF (60 ml) / MeOH (60 ml), and the filtrate was filtered through celite and dried to afford 1.35 g of the title compound as a gray-brown solid in an 83.33% yield.

[0633] LCMS: Rt=1.374min, MS(ESI)m / z=657.4[M+H] + .

[0634] Synthesis of intermediate B3-1

[0635]

[0636] Step 1: Preparation of 3-(6-(4-((4-(5-nitro-6-(piperidin-1-yl)-2-hydrogen-indazol-2-yl)piperidin-1-yl)methyl)piperidin-1-yl)-1-carbonylisoindolin-2-yl)piperidine-2,6-dione.

[0637] 1-(2-(2,6-dicarbonylpiperidin-3-yl)-3-carbonylisoindole-5-yl)piperidine-4-carboxaldehyde (2.4 g, 5.19 mmol, 1.2 eq) was added to a solution of 5-nitro-6-(piperidin-1-yl)-2-(piperidin-4-yl)-2-hydro-indazole dihydrochloride (1.69 g, 4.32 mmol, 1.0 eq) in N,N-dimethylacetamide (40 mL). The reaction mixture was stirred at 25 ° C for 5 minutes, and triethylamine (1.8 ml, 12.96 mmol, 3.0 eq) was added dropwise. The mixture was stirred at 25°C for 5 hours, and then sodium triacetoxyborohydride (1.83 g, 8.64 mmol, 2.0 eq) was added in two batches at an interval of 30 minutes, with 1 eq added in each batch. The system was stirred at 25°C for 16 hours. The reaction was completed under TLC monitoring. 120 ml of n-butanol was added to the system to dilute the reaction solution, and then washed with 100 ml*5 of saturated NaCl(aq). The n-butanol was spin-dried and separated and purified by silica gel column chromatography (methanol / dichloromethane, 0-10%) to obtain 2.6 g of the title compound as a reddish-brown solid in a yield of 89.96%.

[0638] LCMS: Rt=3.305min, MS(ESI)m / z=669.3[M+H] + .

[0639] Step 2: Preparation of 3-(6-(4-((4-(5-amino-6-(piperidin-1-yl)-2-hydrogen-indazol-2-yl)piperidin-1-yl)methyl)piperidin-1-yl)-1-carbonylisoindolin-2-yl)piperidine-2,6-dione.

[0640] 3-(6-(4-((4-(5-nitro-6-(piperidin-1-yl)-2-hydro-indazol-2-yl)piperidin-1-yl)methyl)piperidin-1-yl)-1-carbonylisoindolin-2-yl)piperidine-2,6-dione (1.30 g, 1.94 mmol) was added to THF (60 ml) / MeOH (60 ml), followed by the addition of 5% palladium on carbon (1.0 g). The hydrogen atmosphere was replaced three times. The reaction system was stirred at 25°C for 16 hours and the reaction was monitored for completion by TLC. The reaction solution was diluted with THF (60 ml) / MeOH (60 ml), and the filtrate was filtered through celite and dried to afford 1.05 g of the title compound as a gray-brown solid in an 84.67% yield.

[0641] LCMS: Rt=2.962min, MS(ESI)m / z=639.4[M+H] + .

[0642] Synthesis of intermediate B4-1

[0643]

[0644] Step 1: Preparation of 3-(5-(4-((4-(5-nitro-6-(piperidin-1-yl)-2-hydrogen-indazol-2-yl)piperidin-1-yl)methyl)piperidin-1-yl)-1-carbonylisoindolin-2-yl)piperidine-2,6-dione.

[0645] 1-(2-(2,6-dicarbonylpiperidin-3-yl)-1-carbonylisoindolin-5-yl)piperidine-4-carboxaldehyde (2.97 g, 6.33 mmol, 1.1 eq) was added to a solution of 5-nitro-6-(piperidin-1-yl)-2-(piperidin-4-yl)-2-hydro-indazole dihydrochloride (2.47 g, 5.75 mmol, 1.0 eq) in N,N-dimethylacetamide (50 mL). The reaction mixture was stirred at 25 ° C for 5 minutes, and triethylamine (2.4 ml, 17.25 mmol, 3.0 eq) was added dropwise. The mixture was stirred at 25°C for 5 hours, and then sodium triacetoxyborohydride (2.44 g, 11.50 mmol, 2.0 eq) was added in two batches at 30-min intervals, with 1 eq added in each batch. The system was stirred at 25°C for 16 hours. The reaction was monitored to be complete by TLC. 120 ml of n-butanol was added to the system to dilute the reaction solution, and then washed with 100 ml*5 of saturated NaCl(aq). The n-butanol was spin-dried and separated and purified by silica gel column chromatography (methanol / dichloromethane, 0-10%) to give 3.5 g of the title compound as a reddish-brown solid in a yield of 90.91%.

[0646] LCMS: Rt=3.381min, MS(ESI)m / z=669.3[M+H] + .

[0647] Step 2: Preparation of 3-(5-(4-((4-(5-amino-6-(piperidin-1-yl)-2-hydrogen-indazol-2-yl)piperidin-1-yl)methyl)piperidin-1-yl)-1-carbonylisoindolin-2-yl)piperidine-2,6-dione.

[0648] 3-(5-(4-((4-(5-nitro-6-(piperidin-1-yl)-2-hydro-indazol-2-yl)piperidin-1-yl)methyl)piperidin-1-yl)-1-carbonylisoindolin-2-yl)piperidine-2,6-dione (1.75 g, 2.61 mmol) was added to THF (60 ml) / MeOH (60 ml), followed by the addition of 5% palladium on carbon (1.1 g). The hydrogen atmosphere was replaced three times. The reaction system was stirred at 25°C for 16 hours and the reaction was monitored for completion by TLC. The reaction solution was diluted with THF (60 ml) / MeOH (60 ml), and the filtrate was filtered through celite and dried to afford 1.45 g of the title compound as a gray-brown solid in an 86.82% yield.

[0649] LCMS: Rt=2.967min, MS(ESI)m / z=639.4[M+H] + .

[0650] Synthesis of intermediate B5-1

[0651]

[0652] Step 1: Preparation of 3-(6-fluoro-5-(4-((4-(5-nitro-6-(piperidin-1-yl)-2-hydrogen-indazol-2-yl)piperidin-1-yl)methyl)piperidin-1-yl)-1-carbonylisoindolin-2-yl)piperidine-2,6-dione.

[0653] 1-(2-(2,6-dicarbonylpiperidin-3-yl)-6-fluoro-1-carbonylisoindolin-5-yl)piperidine-4-carboxaldehyde (945 mg, 1.94 mmol, 1.1 eq) was added to a solution of 5-nitro-6-(piperidin-1-yl)-2-(piperidin-4-yl)-2-hydro-indazole (581 mg, 1.76 mmol, 1.0 eq) in N,N-dimethylacetamide (40 mL). The reaction mixture was stirred at 25°C for 5 minutes, and glacial acetic acid (0.2 ml, 3.52 mmol, 3.0 eq) was added dropwise. The mixture was stirred at 25°C for 5 hours, and then sodium triacetoxyborohydride (746 mg, 3.52 mmol, 2.0 eq) was added in two batches at an interval of 30 minutes, with 1 eq added in each batch. The system was stirred at 25°C for 16 hours. The reaction was monitored by TLC to be complete. 80 ml of n-butanol was added to the system to dilute the reaction solution, and then washed with 80 ml*5 of saturated NaCl(aq). The n-butanol was spin-dried and purified by silica gel column chromatography (methanol / dichloromethane, 0-10%) to give 1.02 g of the title compound as a reddish-brown solid in a yield of 84.29%.

[0654] LCMS: Rt=3.449min, MS(ESI)m / z=687.3[M+H] + .

[0655] Step 2: Preparation of 3-(5-(4-((4-(5-amino-6-(piperidin-1-yl)-2-hydrogen-indazol-2-yl)piperidin-1-yl)methyl)piperidin-1-yl)-6-fluoro-1-carbonylisoindolin-2-yl)piperidine-2,6-dione.

[0656] 3-(6-Fluoro-5-(4-((4-(5-nitro-6-(piperidin-1-yl)-2-hydrogen-indazol-2-yl)piperidin-1-yl)methyl)piperidin-1-yl)-1-carbonylisoindolin-2-yl)piperidine-2,6-dione (1.02 g, 1.49 mmol) was added to THF (60 ml) / MeOH (60 ml), followed by the addition of 5% palladium on carbon (800 mg). The hydrogen atmosphere was replaced three times. The reaction system was stirred at 25°C for 16 hours and the reaction was monitored for completion by TLC. The reaction solution was diluted with THF (60 ml) / MeOH (60 ml), and the filtrate was filtered through celite and dried to afford 850 mg of the title compound as a gray-brown solid in an 87.17% yield.

[0657] LCMS: Rt=3.032min, MS(ESI)m / z=657.4[M+H] + .

[0658] Synthesis of intermediate B6-1

[0659]

[0660] Step 1: Preparation of 3-(4-fluoro-5-(4-((4-(5-nitro-6-(piperidin-1-yl)-2H-indazol-2-yl)piperidin-1-yl)methyl)piperidin-1-yl)-1-carbonylisoindolin-2-yl)piperidine-2,6-dione.

[0661] 1-(2-(2,6-dicarbonylpiperidin-3-yl)-4-fluoro-1-carbonylisoindolin-5-yl)piperidine-4-carboxaldehyde (2.97 g, 6.1 mmol, 1.15 eq) was added to a solution of 5-nitro-6-(piperidin-1-yl)-2-(piperidin-4-yl)-2-hydro-indazole (1.75 g, 5.3 mmol, 1.0 eq) in N,N-dimethylacetamide (50 mL). The reaction mixture was stirred at 25 ° C for 5 minutes, and glacial acetic acid (0.61 ml, 10.6 mmol, 2.0 eq) was added dropwise. The mixture was stirred at 25°C for 5 hours, and then sodium triacetoxyborohydride (2.25 g, 10.6 mmol, 2.0 eq) was added in two batches at an interval of 30 minutes, with 1 eq added in each batch. The system was stirred at 25°C for 16 hours. The reaction was monitored to be complete by TLC. 120 ml of n-butanol was added to the system to dilute the reaction solution, and then washed with 100 ml*5 of saturated NaCl(aq). The n-butanol was spin-dried and separated and purified by silica gel column chromatography (methanol / dichloromethane, 0-10%) to give 2.9 g of the title compound as a reddish-brown solid in a yield of 79.73%.

[0662] LCMS: Rt=1.679min, MS(ESI)m / z=687.3[M+H] +.

[0663] Step 2: Preparation of 3-(5-(4-((4-(5-amino-6-(piperidin-1-yl)-2H-indazol-2-yl)piperidin-1-yl)methyl)piperidin-1-yl)-4-fluoro-1-carbonylisoindolin-2-yl)piperidine-2,6-dione.

[0664] 3-(4-Fluoro-5-(4-((4-(5-nitro-6-(piperidin-1-yl)-2H-indazol-2-yl)piperidin-1-yl)methyl)piperidin-1-yl)-1-carbonylisoindolin-2-yl)piperidine-2,6-dione (1.55 g, 2.26 mmol) was added to THF (60 ml) / MeOH (60 ml), followed by the addition of 5% palladium on carbon (1.1 g). The hydrogen atmosphere was replaced three times, and the reaction system was stirred at 25°C for 16 hours. The reaction was monitored for completion by TLC. The reaction solution was diluted with THF (60 ml) / MeOH (60 ml), and the filtrate was filtered through celite and dried to afford 1.15 g of the title compound as a gray-brown solid in a 77.70% yield.

[0665] LCMS: Rt=3.922min, MS(ESI)m / z=657.4[M+H] + .

[0666] Synthesis of intermediate B7-1

[0667]

[0668] Step 1: Preparation of 3-(4-fluoro-6-(4-((4-(5-nitro-6-(piperidin-1-yl)-2-hydrogen-indazol-2-yl)piperidin-1-yl)methyl)piperidin-1-yl)-1-carbonylisoindolin-2-yl)piperidine-2,6-dione.

[0669] 1-(2-(2,6-dicarbonylpiperidin-3-yl)-7-fluoro-3-carbonylisoindolin-5-yl)piperidine-4-carboxaldehyde (2.97 g, 6.1 mmol, 1.15 eq) was added to a solution of 5-nitro-6-(piperidin-1-yl)-2-(piperidin-4-yl)-2-hydro-indazole (1.75 g, 5.3 mmol, 1.0 eq) in N,N-dimethylacetamide (50 mL). The reaction mixture was stirred at 25 ° C for 5 minutes, and glacial acetic acid (0.61 ml, 10.6 mmol, 2.0 eq) was added dropwise. The mixture was stirred at 25°C for 5 hours, and then sodium triacetoxyborohydride (2.25 g, 10.6 mmol, 2.0 eq) was added in two batches at an interval of 30 minutes, with 1 eq added in each batch. The system was stirred at 25°C for 16 hours. The reaction was monitored to be complete by TLC. 120 ml of n-butanol was added to the system to dilute the reaction solution, and then washed with 100 ml*5 of saturated NaCl(aq). The n-butanol was spin-dried and separated and purified by silica gel column chromatography (methanol / dichloromethane, 0-10%) to obtain 3.1 g of the title compound as a reddish-brown solid in a yield of 86.11%.

[0670] LCMS: Rt=1.687min, MS(ESI)m / z=687.3[M+H] + .

[0671] Step 2: Preparation of 3-(6-(4-((4-(5-amino-6-(piperidin-1-yl)-2-hydrogen-indazol-2-yl)piperidin-1-yl)methyl)piperidin-1-yl)-4-fluoro-1-carbonylisoindolin-2-yl)piperidine-2,6-dione.

[0672] 3-(4-Fluoro-6-(4-((4-(5-nitro-6-(piperidin-1-yl)-2-hydrogen-indazol-2-yl)piperidin-1-yl)methyl)piperidin-1-yl)-1-carbonylisoindolin-2-yl)piperidine-2,6-dione (1.55 g, 2.26 mmol) was added to THF (60 ml) / MeOH (60 ml), followed by the addition of 5% palladium on carbon (1.1 g). The hydrogen atmosphere was replaced three times. The reaction system was stirred at 25°C for 16 hours and the reaction was monitored for completion by TLC. The reaction solution was diluted with THF (60 ml) / MeOH (60 ml), and the filtrate was filtered through celite and dried to afford 1.25 g of the title compound as a gray-brown solid in an 84.46% yield.

[0673] LCMS: Rt=3.914min, MS(ESI)m / z=657.4[M+H] + .

[0674] Synthesis of intermediate B8-1

[0675]

[0676] Step 1: Preparation of 2-(2,6-dicarbonylpiperidin-3-yl)-5-(4-((4-(5-nitro-6-(piperidin-1-yl)-2-hydro-indazol-2-yl)piperidin-1-yl)methyl)piperidin-1-yl)isoindoline-1,3-dione.

[0677] 1-(2-(2,6-dicarbonylpiperidin-3-yl)-1,3-dicarbonylisoindole-5-yl)piperidine-4-carboxaldehyde (2.05 g, 5.56 mmol, 1.1 eq) was added to a solution of 5-nitro-6-(piperidin-1-yl)-2-(piperidin-4-yl)-2-hydro-indazole dihydrochloride (2.17 g, 5.05 mmol, 1.0 eq) in N,N-dimethylacetamide (50 mL). The reaction mixture was stirred at 25 ° C for 5 minutes, and triethylamine (1.41 ml, 10.1 mmol, 2.0 eq) was added dropwise. ), stirred at 25°C for 5 hours, then sodium triacetoxyborohydride (2.14 g, 10.1 mmol, 2.0 eq) was added in two batches at an interval of 30 min, 1 eq was added in each batch, and the system was stirred at 25°C for 16 hours. The reaction was monitored by TLC to be complete. 120 ml of n-butanol was added to the system to dilute the reaction solution, and then washed with 100 ml*5 of saturated NaCl (aq). The n-butanol was spin-dried and separated and purified by silica gel column chromatography (methanol / dichloromethane, 0-10%) to obtain 3.1 g of the title compound as a reddish-brown solid in a yield of 89.85%.

[0678] LCMS: Rt=3.051min, MS(ESI)m / z=683.3[M+H] + .

[0679] Step 2: Preparation of 5-(4-((4-(5-amino-6-(piperidin-1-yl)-2-hydrogen-indazol-2-yl)piperidin-1-yl)methyl)piperidin-1-yl)-2-(2,6-dicarbonylpiperidin-3-yl)isoindoline-1,3-dione.

[0680] 2-(2,6-dicarbonylpiperidin-3-yl)-5-(4-((4-(5-nitro-6-(piperidin-1-yl)-2-hydro-indazol-2-yl)piperidin-1-yl)methyl)piperidin-1-yl)isoindole-1,3-dione (1.55 g, 2.27 mmol) was added to THF (60 ml) / MeOH (60 ml). 5% palladium on carbon (1.1 g) was then added to replace the hydrogen atmosphere three times. The reaction system was stirred at 25°C for 16 hours and monitored for completion by TLC. The reaction solution was diluted with THF (60 ml) / MeOH (60 ml), and the filtrate was filtered through celite and dried to afford 1.3 g of the title compound as a gray-brown solid in an 87.83% yield.

[0681] LCMS: Rt=3.131min, MS(ESI)m / z=653.3[M+H] + .

[0682] Synthesis of intermediate B9-1

[0683]

[0684] Step 1: Preparation of (S)-nitro-(2,6-dicarbonylpiperidin-3-yl)-2-fluoro-4-(4-((4-(5-nitro-6-(piperidin-1-yl)-2-hydrogen-indazol-2-yl)piperidin-1-yl)methyl)piperidin-1-yl)benzamide.

[0685] (S)-nitro-(2,6-dicarbonylpiperidin-3-yl)-2-fluoro-4-(4-formylpiperidin-1-yl)benzamide (2.0 g, 5.54 mmol, 1.1 eq) was added to a solution of 5-nitro-6-(piperidin-1-yl)-2-(piperidin-4-yl)-2-hydrogen-indazole dihydrochloride (2.13 g, 5.04 mmol, 1.0 eq) in N,N-dimethylacetamide (40 mL). The reaction mixture was stirred at 25 ° C for 5 minutes, and triethylamine (1.4 ml, 10.08 mmol, 2.0 eq) was added dropwise. The mixture was stirred at 25°C for 5 hours, and then sodium triacetoxyborohydride (2.14 g, 10.08 mmol, 2.0 eq) was added in two batches at an interval of 30 minutes, with 1 eq added in each batch. The system was stirred at 25°C for 16 hours. The reaction was monitored to be complete by TLC. 150 ml of n-butanol was added to the system to dilute the reaction solution, and then washed with 100 ml*5 of saturated NaCl(aq). The n-butanol was spin-dried and the product was separated and purified by silica gel column chromatography (methanol / dichloromethane, 0-10%) to give 3.05 g of the title compound as a reddish-brown solid in a yield of 89.71%.

[0686] LCMS: Rt=1.614min, MS(ESI)m / z=675.3[M+H] +.

[0687] Step 2: Preparation of (S)-4-(4-((4-(5-amino-6-(piperidin-1-yl)-2-hydrogen-indazol-2-yl)piperidin-1-yl)methyl)piperidin-1-yl)-nitrogen-(2,6-dicarbonylpiperidin-3-yl)-2-fluorobenzamide.

[0688] (S)-nitrogen-(2,6-dicarbonylpiperidin-3-yl)-2-fluoro-4-(4-((4-(5-nitro-6-(piperidin-1-yl)-2-hydrogen-indazol-2-yl)piperidin-1-yl)methyl)piperidin-1-yl)benzamide (1.52 g, 2.25 mmol) was added to THF (60 ml) / MeOH (60 ml). 5% palladium on carbon (1 g) was then added to displace the hydrogen atmosphere three times. The reaction system was stirred at 25°C for 16 hours and monitored for completion by TLC. The reaction solution was diluted with THF (60 ml) / MeOH (60 ml), and the filtrate was filtered through celite and dried to afford 1.26 g of the title compound as a gray-brown solid in an 86.89% yield.

[0689] LCMS: Rt=1.358min, MS(ESI)m / z=645.3[M+H] + .

[0690] Synthesis of intermediate C1

[0691]

[0692] Step 1: Synthesis of methyl (1r,4r)-4-(5-nitro-6-(piperidin-1-yl)-2H-indazol-2-yl)cyclohexane-1-carboxylate

[0693] A reaction mixture containing 2-azido-5-nitro-4-(piperidin-1-yl)benzaldehyde (30.0 g, 108.98 mmol, 1.0 eq), methyl (1r,4r)-4-aminocyclohexane-1-carboxylate (17.1 g, 108.98 mmol, 1.0 eq), trimethyl orthoformate (34.7 g, 326.95 mmol, 3.0 eq), and DCM (200 mL) was stirred at room temperature for 10 min. Toluene (500 mL) was then added and the temperature was raised to 120°C. The DCM was removed using a water separator and stirred for 3 h. The reaction solution was concentrated under reduced pressure and purified by silica gel column chromatography (PE / EA = 4 / 1) to obtain the target compound (1r, 4r)-4-(5-nitro-6-(piperidin-1-yl)-2H-indazol-2-yl)cyclohexane-1-carboxylic acid methyl ester (20.5 g, yellow solid, yield 48.7%).

[0694] LC-MS (ESI) m / z: 387.2 [M+H] +

[0695] Step 2: Synthesis of methyl (1r,4r)-4-(5-amino-6-(piperidin-1-yl)-2H-indazol-2-yl)cyclohexane-1-carboxylate

[0696] Pd / C (2.1 g) was added to a reaction mixture containing methyl (1r,4r)-4-(5-nitro-6-(piperidin-1-yl)-2H-indazol-2-yl)cyclohexane-1-carboxylate (20.5 g) and methanol (800 mL). The mixture was stirred at room temperature overnight under hydrogen. The reaction mixture was filtered and concentrated under reduced pressure to obtain the target compound, methyl (1r,4r)-4-(5-amino-6-(piperidin-1-yl)-2H-indazol-2-yl)cyclohexane-1-carboxylate (15.0 g, brown solid, 79.3% yield).

[0697] LC-MS (ESI) m / z: 357.2 [M+H] +

[0698] Step 3: Synthesis of ((1r,4r)-4-(5-amino-6-(piperidin-1-yl)-2H-indazol-2-yl)cyclohexyl)methanol

[0699] To a reaction mixture containing methyl (1r,4r)-4-(5-amino-6-(piperidin-1-yl)-2H-indazol-2-yl)cyclohexane-1-carboxylate (15.0 g, 42.08 mmol, 1.0 eq), THF (600 mL), and MeOH (80 mL) was added LiBH4 (4.58 g, 210.4 mmol, 5.0 eq). The mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure and purified on a silica gel column (PE / EA = 1 / 1) to obtain the target compound ((1r,4r)-4-(5-amino-6-(piperidin-1-yl)-2H-indazol-2-yl)cyclohexyl)methanol (12.0 g, white solid, yield 86.8%).

[0700] LC-MS (ESI) m / z: 329.2 [M+H] +

[0701] Synthesis of intermediate C2

[0702]

[0703] Step 1: Preparation of (1r,4r)-N-methyl-4-(5-nitro-6-(piperidin-1-yl)-2H-indazol-2-yl)cyclohexane-1-amine

[0704] A reaction mixture containing 2-azido-5-nitro-4-(piperidin-1-yl)benzaldehyde (10.0 g, 36.3 mmol), (1r,4r)-N1-methylcyclohexane-1,4-diamine (4.65 g, 36.3 mmol), trimethyl orthoformate (34.7 g, 108.9 mmol), and DCM (70 mL) was stirred at room temperature for 10 minutes. Toluene (170 mL) was then added and the temperature was raised to 120°C. The DCM was removed using a water separator and stirred for 3 hours. The reaction mixture was concentrated under reduced pressure and purified on a silica gel column (PE / EA = 4 / 1) to yield the title compound (5.4 g, yellow solid, 42.2% yield).

[0705] LC-MS (ESI) m / z: 358.2 [M+H] +

[0706] Step 2: Preparation of 2-((1r,4r)-4-(methylamino)cyclohexyl)-6-(piperidin-1-yl)-2H-indazol-5-amine

[0707] To a reaction mixture containing (1r,4r)-N-methyl-4-(5-nitro-6-(piperidin-1-yl)-2H-indazol-2-yl)cyclohexane-1-amine (5.4 g, 15.1 mmol) and methanol (100 mL) was added Pd / C (0.6 g). The mixture was stirred at room temperature overnight under hydrogen. The reaction mixture was filtered and concentrated under reduced pressure to obtain the title compound (4.1 g, brown solid, 82.4% yield).

[0708] LC-MS (ESI) m / z: 328.2 [M+H] +

[0709] Example

[0710] Synthesis route Synthesis route A:

[0711] The amine compound (1.0 equiv.) and the carboxylic acid compound (1.0 equiv.) were dissolved in DMF, followed by the addition of DIPEA (3.0 equiv.) and HATU (1.2 equiv.). The reaction mixture was stirred at room temperature for 4 hours. Water was added to the reaction mixture, and the mixture was extracted with DCM. The organic phases were combined, dried over Na2SO4, and filtered. The filtrate was concentrated under reduced pressure and further purified by preparative TLC (DCM:MeOH = 10:1) to yield the title compound.

[0712] Synthetic Route B:

[0713] The amine compound (1.0 equiv.) and the carboxylic acid compound (1.0 equiv.) were dissolved in dry DMF, followed by the addition of DIPEA (3.0 equiv.) and T3P (1.5 equiv.). The reaction mixture was stirred at room temperature for 2 hours. Water was added to the reaction mixture, and the mixture was extracted with DCM. The organic phases were combined, dried over Na2SO4, and filtered. The filtrate was concentrated under reduced pressure and further purified by preparative TLC (DCM:MeOH = 10:1) to yield the title compound.

[0714] Synthetic Route C:

[0715] The amine compound (1.0 equiv.) and the carboxylic acid compound (1.0 equiv.) were dissolved in dry DMF, followed by the addition of DIPEA (3.0 equiv.) and PyBOP (1.5 equiv.). The reaction mixture was stirred at room temperature for 2 hours. Water was added to the reaction mixture, and the mixture was extracted with DCM. The organic phases were combined, dried over Na2SO4, and filtered. The filtrate was concentrated under reduced pressure and further purified by preparative TLC (DCM:MeOH = 10:1) to yield the title compound.

[0716] Synthetic Route D:

[0717] The amine compound (1.0 equiv.) and the carboxylic acid compound (1.0 equiv.) were dissolved in dry DMF, followed by the addition of DIPEA (3.0 equiv.) and EDCI (1.5 equiv.). The reaction mixture was stirred at room temperature for 4 hours. Water was added to the reaction mixture, and the mixture was extracted with DCM. The organic phases were combined, dried over Na2SO4, and filtered. The filtrate was concentrated under reduced pressure and further purified by preparative TLC (DCM:MeOH = 10:1) to yield the title compound.

[0718] Synthetic Route E:

[0719] Step 1: Dissolve the amine intermediate C (1.0 eq) and the carboxylic acid compound (1.0 eq) in DMF, then add DIPEA (3.0 eq) and HATU (1.2 eq). Stir the reaction mixture at room temperature for 4 hours. Add water to the reaction mixture and extract with DCM. The organic phases are combined, dried over Na2SO4, and filtered. The filtrate is concentrated under reduced pressure and purified by silica gel column chromatography (methanol / dichloromethane, 0-10%) to obtain the title compound.

[0720] Step 2: Add trifluoroacetic acid (10 mL) dropwise to a solution of the product from Step 1 (1.0 equiv.) in dichloromethane (30 mL). Stir at room temperature for 1 hour. Remove the solvent from the reaction mixture under reduced pressure and spin dry to obtain the desired compound, which is used directly in the next reaction.

[0721] Step 3: Add the aldehyde compound intermediate B (1.1 eq) to the N,N-dimethylformamide solution (10 mL) of the amine compound (1.0 eq) in the above step 2, stir at room temperature for 5 minutes, add triethylamine (2.0 eq) dropwise, stir at room temperature for 5 hours, then add sodium triacetoxyborohydride (2.0 eq) in two batches, and stir the system at room temperature for 16 hours. The reaction is monitored by TLC to be complete. 15 ml of n-butanol is added to the system to dilute the reaction solution, and then washed with saturated NaCl (aq) 100 ml * 5. The organic phases are combined, dried over Na2SO4 and filtered. The filtrate is concentrated under reduced pressure and further purified by preparative TLC (DCM:MeOH = 10:1) to obtain the target compound.

[0722] Synthesis Route F:

[0723] Step 1: Dissolve the amine intermediate C (1.0 eq) and the carboxylic acid compound (1.0 eq) in DMF, then add DIPEA (3.0 eq) and HATU (1.2 eq). Stir the reaction mixture at room temperature for 4 hours. Add water to the reaction mixture and extract with DCM. The organic phases are combined, dried over Na2SO4, and filtered. The filtrate is concentrated under reduced pressure and purified by silica gel column chromatography (methanol / dichloromethane, 0-10%) to obtain the title compound.

[0724] Step 2: Dissolve the product from Step 1 (1.0 eq) in DMF, add Dess-Martin (1.5 eq), and stir at room temperature until the reaction is complete. Add water to the reaction mixture and extract with ethyl acetate. The organic phases are combined, dried over Na2SO4, and filtered. The filtrate is concentrated under reduced pressure and purified by silica gel column chromatography (methanol / dichloromethane, 0-5%) to obtain the title compound.

[0725] Step 3: Add the aldehyde compound intermediate B (1.1 eq) to the N,N-dimethylformamide solution (10 mL) of the amine compound (1.0 eq) in the above step 2, stir at room temperature for 5 minutes, add triethylamine (2.0 eq) dropwise, stir at room temperature for 5 hours, then add sodium triacetoxyborohydride (2.0 eq) in two batches, and stir the system at room temperature for 16 hours. The reaction is monitored by TLC to be complete. 15 ml of n-butanol is added to the system to dilute the reaction solution, and then washed with saturated NaCl (aq) 100 ml * 5. The organic phases are combined, dried over Na2SO4 and filtered. The filtrate is concentrated under reduced pressure and further purified by preparative TLC (DCM:MeOH = 10:1) to obtain the target compound.

[0726] Example 1: Preparation of N-(2-(1-((1-(4-((2,6-dicarbonylpiperidin-3-yl)carbamoyl)-3-fluorophenyl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-1-yl)-2H-indazol-5-yl)-7H-pyrrolo[2,3-b]pyridine-4-carboxamide Compound 1

[0727] Referring to the synthetic route A, compound 1 can be prepared, mass spectrum (M+H): 789.4

[0728] Example 2: Preparation of N-(2-(1-((1-(4-((2,6-dicarbonylpiperidin-3-yl)carbamoyl)-3-fluorophenyl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-1-yl)-2H-indazol-5-yl)-1H-benzo[d]imidazole-6-carboxamide Compound 2

[0729] Referring to the synthetic route A, compound 2 can be prepared, mass spectrum (M+H): 789.4

[0730] Example 3: Preparation of N-(2-(1-((1-(4-((2,6-dicarbonylpiperidin-3-yl)carbamoyl)-3-fluorophenyl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-1-yl)-2H-indazol-5-yl)isoquinoline-8-carboxamide Compound 3

[0731] Referring to the synthetic route A, compound 3 can be prepared, mass spectrum (M+H): 800.4

[0732] Example 4: Preparation of N-(2-(1-((1-(4-((2,6-dicarbonylpiperidin-3-yl)carbamoyl)-3-fluorophenyl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-1-yl)-2H-indazol-5-yl)-7H-pyrrolo[2,3-b]pyridine-5-carboxamide Compound 4

[0733] Referring to the synthetic route A, compound 4 can be prepared, mass spectrum (M+H): 789.4

[0734] Example 5: Preparation of N-(2-(1-((1-(4-((2,6-dicarbonylpiperidin-3-yl)carbamoyl)-3-fluorophenyl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-1-yl)-2H-indazol-5-yl)quinoxaline-5-carboxamide Compound 5

[0735] Referring to the synthetic route A, compound 5 can be prepared, mass spectrum (M+H): 801.4

[0736] Example 6: Preparation of N-(2-(1-((1-(4-((2,6-dicarbonylpiperidin-3-yl)carbamoyl)-3-fluorophenyl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-1-yl)-2H-indazol-5-yl)benzo[c][1,2,5]thiadiazole-4-carboxamide Compound 6

[0737] Referring to the synthetic route A, compound 6 can be prepared, mass spectrum (M+H): 807.3

[0738] Example 7: Preparation of N-(2-(1-((1-(4-((2,6-dicarbonylpiperidin-3-yl)carbamoyl)-3-fluorophenyl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-1-yl)-2H-indazol-5-yl)-2-methylimidazo[1,2-a]pyridine-6-carboxamide Compound 7

[0739] Referring to the synthetic route A, compound 7 can be prepared, mass spectrum (M+H): 803.4

[0740] Example 8: Preparation of N-(2-(1-((1-(4-((2,6-dicarbonylpiperidin-3-yl)carbamoyl)-3-fluorophenyl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-1-yl)-2H-indazol-5-yl)benzo[d]thiazole-7-carboxamide Compound 8

[0741] Referring to the synthetic route A, compound 8 can be prepared, mass spectrum (M+H): 806.3

[0742] Example 9: Preparation of N-(2-(1-((1-(4-((2,6-dicarbonylpiperidin-3-yl)carbamoyl)-3-fluorophenyl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-1-yl)-2H-indazol-5-yl)-1-(4-fluorophenyl)-5-methyl-1H-pyrazole-4-carboxamide Compound 9

[0743] Referring to the synthetic route A, compound 9 can be prepared, mass spectrum (M+H): 847.4

[0744] Example 10: Preparation of N-(2-(1-((1-(4-((2,6-dicarbonylpiperidin-3-yl)carbamoyl)-3-fluorophenyl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-1-yl)-2H-indazol-5-yl)-1-methyl-3-(trifluoromethyl)-1H-pyrazole-4-carboxamide Compound 10

[0745] Referring to the synthetic route A, compound 10 can be prepared, mass spectrum (M+H): 821.4

[0746] Example 11: Preparation of N-(2-(1-((1-(4-((2,6-dicarbonylpiperidin-3-yl)carbamoyl)-3-fluorophenyl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-1-yl)-2H-indazol-5-yl)-1-methyl-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide Compound 11

[0747] Referring to the synthetic route A, compound 11 can be prepared, mass spectrum (M+H): 821.4

[0748] Example 12: Preparation of N-(2-(1-((1-(4-((2,6-dicarbonylpiperidin-3-yl)carbamoyl)-3-fluorophenyl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-1-yl)-2H-indazol-5-yl)-[1,2,4]triazolo[4,3-a]pyridine-8-carboxamide Compound 12

[0749] Referring to the synthetic route A, compound 12 can be prepared, mass spectrum (M+H): 790.4

[0750] Example 13: Preparation of N-(2-(1-((1-(4-((2,6-dicarbonylpiperidin-3-yl)carbamoyl)-3-fluorophenyl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-1-yl)-2H-indazol-5-yl)-[1,2,4]triazolo[4,3-a]pyridine-7-carboxamide Compound 13

[0751] Referring to the synthetic route A, compound 13 can be prepared, mass spectrum (M+H): 790.4

[0752] Example 14: Preparation of N-(2-(1-((1-(4-((2,6-dicarbonylpiperidin-3-yl)carbamoyl)-3-fluorophenyl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-1-yl)-2H-indazol-5-yl)-1-phenyl-3-(trifluoromethyl)-1H-pyrazole-4-carboxamide Compound 14

[0753] Referring to the synthetic route A, compound 14 can be prepared, mass spectrum (M+H): 883.4

[0754] Example 15: Preparation of N-(2-(1-((1-(4-((2,6-dicarbonylpiperidin-3-yl)carbamoyl)-3-fluorophenyl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-1-yl)-2H-indazol-5-yl)-1H-indole-5-carboxamide Compound 15

[0755] Referring to the synthetic route A, compound 15 can be prepared, mass spectrum (M+H): 788.4

[0756] Example 16: Preparation of N-(2-(1-((1-(4-((2,6-dicarbonylpiperidin-3-yl)carbamoyl)-3-fluorophenyl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-1-yl)-2H-indazol-5-yl)-1H-indole-4-carboxamide Compound 16

[0757] Referring to the synthetic route A, compound 16 can be prepared, mass spectrum (M+H): 788.4

[0758] Example 17: Preparation of N-(2-(1-((1-(4-((2,6-dicarbonylpiperidin-3-yl)carbamoyl)-3-fluorophenyl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-1-yl)-2H-indazol-5-yl)quinoline-6-carboxamide Compound 17

[0759] Referring to the synthetic route A, compound 17 can be prepared, mass spectrum (M+H): 800.4

[0760] Example 18: Preparation of N-(2-(1-((1-(4-((2,6-dicarbonylpiperidin-3-yl)carbamoyl)-3-fluorophenyl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-1-yl)-2H-indazol-5-yl)benzo[b]thiophene-3-carboxamide Compound 18

[0761] Referring to the synthetic route A, compound 18 can be prepared, mass spectrum (M+H): 805.3

[0762] Example 19: Preparation of N-(2-(1-((1-(4-((2,6-dicarbonylpiperidin-3-yl)carbamoyl)-3-fluorophenyl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-1-yl)-2H-indazol-5-yl)-1-methyl-5-phenyl-1H-pyrazole-4-carboxamide Compound 19

[0763] Referring to the synthetic route A, compound 19 can be prepared, mass spectrum (M+H): 829.4

[0764] Example 20: Preparation of N-(2-(1-((1-(4-((2,6-dicarbonylpiperidin-3-yl)carbamoyl)-3-fluorophenyl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-1-yl)-2H-indazol-5-yl)isoquinoline-5-carboxamide Compound 20

[0765] Referring to the synthetic route A, compound 20 can be prepared, mass spectrum (M+H): 800.4

[0766] Example 21: Preparation of N-(2-(1-((1-(4-((2,6-dicarbonylpiperidin-3-yl)carbamoyl)-3-fluorophenyl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-1-yl)-2H-indazol-5-yl)imidazo[1,2-b]pyridazine-6-carboxamide Compound 21

[0767] Referring to the synthetic route A, compound 21 can be prepared, mass spectrum (M+H): 790.4

[0768] Example 22: Preparation of N-(2-(1-((1-(4-((2,6-dicarbonylpiperidin-3-yl)carbamoyl)-3-fluorophenyl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-1-yl)-2H-indazol-5-yl)-1,5-naphthyridine-3-carboxamide Compound 22

[0769] Referring to the synthetic route A, compound 22 can be prepared, mass spectrum (M+H): 801.4

[0770] Example 23: Preparation of N-(2-(1-((1-(4-((2,6-dicarbonylpiperidin-3-yl)carbamoyl)-3-fluorophenyl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-1-yl)-2H-indazol-5-yl)quinoline-4-carboxamide Compound 23

[0771] Referring to the synthetic route A, compound 23 can be prepared, mass spectrum (M+H): 800.4

[0772] Example 24: Preparation of N-(2-(1-((1-(4-((2,6-dicarbonylpiperidin-3-yl)carbamoyl)-3-fluorophenyl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-1-yl)-2H-indazol-5-yl)imidazo[1,2-a]pyridine-6-carboxamide Compound 24

[0773] Referring to the synthetic route A, compound 24 can be prepared, mass spectrum (M+H): 789.4

[0774] Example 25: Preparation of N-(2-(1-((1-(4-((2,6-dicarbonylpiperidin-3-yl)carbamoyl)-3-fluorophenyl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-1-yl)-2H-indazol-5-yl)imidazo[1,2-a]pyridine-7-carboxamide Compound 25

[0775] Referring to the synthetic route A, compound 25 can be prepared, mass spectrum (M+H): 789.4

[0776] Example 26: Preparation of N-(2-(1-((1-(4-((2,6-dicarbonylpiperidin-3-yl)carbamoyl)-3-fluorophenyl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-1-yl)-2H-indazol-5-yl)-4H-thieno[3,2-b]pyrrole-5-carboxamide Compound 26

[0777] Referring to the synthetic route A, compound 26 can be prepared, mass spectrum (M+H): 794.3

[0778] Example 27: Preparation of N-(2-(1-((1-(4-((2,6-dicarbonylpiperidin-3-yl)carbamoyl)-3-fluorophenyl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-1-yl)-2H-indazol-5-yl)quinoline-5-carboxamide Compound 27

[0779] Referring to the synthetic route A, compound 27 can be prepared, mass spectrum (M+H): 800.4

[0780] Example 28: Preparation of N-(2-(1-((1-(4-((2,6-dicarbonylpiperidin-3-yl)carbamoyl)-3-fluorophenyl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-1-yl)-2H-indazol-5-yl)imidazo[1,5-a]pyridine-8-carboxamide Compound 28

[0781] Referring to the synthetic route A, compound 28 can be prepared, mass spectrum (M+H): 789.4

[0782] Example 29: Preparation of (S)-N-(2-(1-((1-(4-((2,6-dicarbonylpiperidin-3-yl)carbamoyl)-3-methoxyphenyl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-1-yl)-2H-indazol-5-yl)-3H-imidazo[4,5-b]pyridine-5-carboxamide Compound 29

[0783] Referring to the synthetic route B, compound 29 can be prepared, mass spectrum (M+H): 802.4

[0784] Example 30: Preparation of N-(2-(1-((1-(4-((2,6-dicarbonylpiperidin-3-yl)carbamoyl)-3-fluorophenyl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-1-yl)-2H-indazol-5-yl)-2-methyl-1H-benzo[d]imidazole-5-carboxamide Compound 30

[0785] Referring to the synthetic route A, compound 30 can be prepared, mass spectrum (M+H): 803.4

[0786] Example 31: Preparation of N-(2-(1-((1-(4-((2,6-dicarbonylpiperidin-3-yl)carbamoyl)-3-fluorophenyl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-1-yl)-2H-indazol-5-yl)imidazo[1,2-a]pyridine-8-carboxamide Compound 31

[0787] Referring to the synthetic route B, compound 31 can be prepared, mass spectrum (M+H): 789.4

[0788] Example 32: Preparation of N-(2-(1-((1-(4-((2,6-dicarbonylpiperidin-3-yl)carbamoyl)-3-fluorophenyl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-1-yl)-2H-indazol-5-yl)-3-methylimidazo[1,2-a]pyridine-6-carboxamide Compound 32

[0789] Referring to the synthetic route B, compound 32 can be prepared, mass spectrum (M+H): 803.4

[0790] Example 33: Preparation of N-(2-(1-((1-(4-((2,6-dicarbonylpiperidin-3-yl)carbamoyl)-3-fluorophenyl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-1-yl)-2H-indazol-5-yl)-1H-benzo[d]imidazole-4-carboxamide Compound 33

[0791] Referring to the synthetic route A, compound 33 can be prepared, mass spectrum (M+H): 789.4

[0792] Example 34: Preparation of N-(2-(1-((1-(4-((2,6-dicarbonylpiperidin-3-yl)carbamoyl)-3-fluorophenyl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-1-yl)-2H-indazol-5-yl)-1-(3-methoxyphenyl)-1H-pyrazole-4-carboxamide Compound 34

[0793] Referring to the synthetic route C, compound 34 can be prepared, mass spectrum (M+H): 845.4

[0794] Example 35: Preparation of N-(2-(1-((1-(4-((2,6-dicarbonylpiperidin-3-yl)carbamoyl)-3-fluorophenyl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-1-yl)-2H-indazol-5-yl)benzo[c][1,2,5]thiadiazole-5-carboxamide Compound 35

[0795] Referring to the synthetic route C, compound 35 can be prepared, mass spectrum (M+H): 807.3

[0796] Example 36: Preparation of N-(2-(1-((1-(4-((2,6-dicarbonylpiperidin-3-yl)carbamoyl)-3-fluorophenyl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-1-yl)-2H-indazol-5-yl)thieno[3,2-d]pyrimidine-4-carboxamide Compound 36

[0797] Referring to the synthetic route C, compound 36 can be prepared, mass spectrum (M+H): 807.3

[0798] Example 37: Preparation of N-(2-(1-((1-(4-((2,6-dicarbonylpiperidin-3-yl)carbamoyl)-3-fluorophenyl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-1-yl)-2H-indazol-5-yl)thieno[2,3-c]pyridine-2-carboxamide Compound 37

[0799] Referring to the synthetic route C, compound 37 can be prepared, mass spectrum (M+H): 806.3

[0800] Example 38: Preparation of N-(2-(1-((1-(4-((2,6-dicarbonylpiperidin-3-yl)carbamoyl)-3-fluorophenyl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-1-yl)-2H-indazol-5-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-3-carboxamide Compound 38

[0801] Referring to the synthetic route D, compound 38 can be prepared, mass spectrum (M+H): 793.4

[0802] Example 39: Preparation of N-(2-(1-((1-(4-((2,6-dicarbonylpiperidin-3-yl)carbamoyl)-3-fluorophenyl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-1-yl)-2H-indazol-5-yl)pyrazolo[1,5-a]pyridine-3-carboxamide Compound 39

[0803] Referring to the synthetic route A, compound 39 can be prepared, mass spectrum (M+H): 789.4

[0804] Example 40: Preparation of 4-amino-N-(2-(1-((1-(4-((2,6-dicarbonylpiperidin-3-yl)carbamoyl)-3-fluorophenyl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-1-yl)-2H-indazol-5-yl)thieno[3,2-d]pyrimidine-7-carboxamide Compound 40

[0805] Referring to the synthetic route A, compound 40 can be prepared, mass spectrum (M+H): 822.3

[0806] Example 41: Preparation of N-(2-(1-((1-(4-((2,6-dicarbonylpiperidin-3-yl)carbamoyl)-3-fluorophenyl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-1-yl)-2H-indazol-5-yl)-5-methyl-1-phenyl-1H-pyrazole-4-carboxamide Compound 41

[0807] Referring to the synthetic route A, compound 41 can be prepared, mass spectrum (M+H): 829.4

[0808] Example 42: Preparation of N-(2-(1-((1-(4-((2,6-dicarbonylpiperidin-3-yl)carbamoyl)-3-fluorophenyl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-1-yl)-2H-indazol-5-yl)imidazo[1,2-b]pyridazine-2-carboxamide Compound 42

[0809] Referring to the synthetic route D, compound 42 can be prepared, mass spectrum (M+H): 790.4

[0810] Example 43: Preparation of N-(2-(1-((1-(4-((2,6-dicarbonylpiperidin-3-yl)carbamoyl)-3-fluorophenyl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-1-yl)-2H-indazol-5-yl)imidazo[1,2-a]pyrazine-3-carboxamide Compound 43

[0811] Referring to the synthetic route D, compound 43 can be prepared, mass spectrum (M+H): 790.4

[0812] Example 44: Preparation of N-(2-(1-((1-(4-((2,6-dicarbonylpiperidin-3-yl)carbamoyl)-3-fluorophenyl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-1-yl)-2H-indazol-5-yl)-1H-pyrrolo[3,2-c]pyridine-7-carboxamide Compound 44

[0813] Referring to the synthetic route B, compound 44 can be prepared, mass spectrum (M+H): 789.4

[0814] Example 45: Preparation of N-(2-(1-((1-(4-((2,6-dicarbonylpiperidin-3-yl)carbamoyl)-3-fluorophenyl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-1-yl)-2H-indazol-5-yl)pyrazolo[1,5-b]pyridazine-3-carboxamide Compound 45

[0815] Referring to the synthetic route A, compound 45 can be prepared, mass spectrum (M+H): 790.4

[0816] Example 46: Preparation of N-(2-(1-((1-(4-((2,6-dicarbonylpiperidin-3-yl)carbamoyl)-3-fluorophenyl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-1-yl)-2H-indazol-5-yl)-1H-indole-6-carboxamide Compound 46

[0817] Referring to the synthetic route A, compound 46 can be prepared, mass spectrum (M+H): 788.4

[0818] Example 47: Preparation of N-(2-(1-((1-(4-((2,6-dicarbonylpiperidin-3-yl)carbamoyl)-3-fluorophenyl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-1-yl)-2H-indazol-5-yl)pyrazolo[1,5-a]pyridine-3-carboxamide Compound 47

[0819] Referring to the synthetic route A, compound 47 can be prepared, mass spectrum (M+H): 789.4

[0820] Example 48: Preparation of N-(2-(1-((1-(4-((2,6-dicarbonylpiperidin-3-yl)carbamoyl)-3-fluorophenyl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-1-yl)-2H-indazol-5-yl)-1H-indole-7-carboxamide Compound 48

[0821] Referring to the synthetic route C, compound 48 can be prepared, mass spectrum (M+H): 788.4

[0822] Example 49: Preparation of N-(2-(1-((1-(4-((2,6-dicarbonylpiperidin-3-yl)carbamoyl)-3-fluorophenyl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-1-yl)-2H-indazol-5-yl)imidazo[1,5-a]pyridine-8-carboxamide Compound 49

[0823] Referring to the synthetic route C, compound 49 can be prepared, mass spectrum (M+H): 789.4

[0824] Example 50: Preparation of N-(2-(1-((1-(4-((2,6-dicarbonylpiperidin-3-yl)carbamoyl)-3-fluorophenyl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-1-yl)-2H-indazol-5-yl)-1H-pyrrolo[2,3-c]pyridine-3-carboxamide Compound 50

[0825] Referring to the synthetic route C, compound 50 can be prepared, mass spectrum (M+H): 789.4

[0826] Example 51: Preparation of N-(2-(1-((1-(4-((2,6-dicarbonylpiperidin-3-yl)carbamoyl)-3-fluorophenyl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-1-yl)-2H-indazol-5-yl)-3H-imidazo[4,5-b]pyridine-7-carboxamide Compound 51

[0827] Referring to the synthetic route A, compound 51 can be prepared, mass spectrum (M+H): 790.4

[0828] Example 52: Preparation of N-(2-(1-((1-(4-((2,6-dicarbonylpiperidin-3-yl)carbamoyl)-3-fluorophenyl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-1-yl)-2H-indazol-5-yl)-7H-pyrrolo[2,3-d]pyrimidine-4-carboxamide Compound 52

[0829] Referring to the synthetic route B, compound 52 can be prepared, mass spectrum (M+H): 790.4

[0830] Example 53: Preparation of N-(2-(1-((1-(4-((2,6-dicarbonylpiperidin-3-yl)carbamoyl)-3-fluorophenyl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-1-yl)-2H-indazol-5-yl)-3H-imidazo[4,5-c]pyridine-7-carboxamide Compound 53

[0831] Referring to the synthetic route A, compound 53 can be prepared, mass spectrum (M+H): 790.4

[0832] Example 54: Preparation of N-(2-(1-((1-(4-((2,6-dicarbonylpiperidin-3-yl)carbamoyl)-3-fluorophenyl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-1-yl)-2H-indazol-5-yl)pyrazolo[1,5-a]pyrimidine-6-carboxamide Compound 54

[0833] Referring to the synthetic route A, compound 54 can be prepared, mass spectrum (M+H): 790.4

[0834] Example 55: Preparation of N-(2-(1-((1-(4-((2,6-dicarbonylpiperidin-3-yl)carbamoyl)-3-fluorophenyl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-1-yl)-2H-indazol-5-yl)-1H-pyrazolo[4,3-c]pyridine-4-carboxamide Compound 55

[0835] Referring to the synthetic route D, compound 55 can be prepared, mass spectrum (M+H): 790.4

[0836] Example 56: Preparation of (S)-N-(2-(1-((1-(4-((2,6-dicarbonylpiperidin-3-yl)carbamoyl)-3-methoxyphenyl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-1-yl)-2H-indazol-5-yl)imidazo[1,2-a]pyridine-3-carboxamide Compound 56

[0837] Referring to the synthetic route C, compound 56 can be prepared, mass spectrum (M+H): 801.4

[0838] Example 57: Preparation of (S)-N-(2-(1-((1-(4-((2,6-dicarbonylpiperidin-3-yl)carbamoyl)-3-methoxyphenyl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-1-yl)-2H-indazol-5-yl)-2-(2-methylpyridin-4-yl)thiazole-4-carboxamide Compound 57

[0839] Referring to the synthetic route A, compound 57 can be prepared, mass spectrum (M+H): 859.4

[0840] Example 58: Preparation of (S)-N-(2-(1-((1-(4-((2,6-dicarbonylpiperidin-3-yl)carbamoyl)-3-methoxyphenyl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-1-yl)-2H-indazol-5-yl)-2-(pyrimidin-2-yl)oxazole-4-carboxamide Compound 58

[0841] Referring to the synthetic route A, compound 58 can be prepared, mass spectrum (M+H): 830.4

[0842] Example 59: Preparation of (S)-N-(2-(1-((1-(4-((2,6-dicarbonylpiperidin-3-yl)carbamoyl)-3-methoxyphenyl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-1-yl)-2H-indazol-5-yl)-1-(pyrimidin-2-yl)-1H-imidazole-4-carboxamide Compound 59

[0843] Referring to the synthetic route C, compound 59 can be prepared, mass spectrum (M+H): 829.4

[0844] Example 60: Preparation of (S)-N-(2-(1-((1-(4-((2,6-dicarbonylpiperidin-3-yl)carbamoyl)-3-methoxyphenyl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-1-yl)-2H-indazol-5-yl)-1-(4-fluorophenyl)-5-methyl-1H-pyrazole-4-carboxamide Compound 60

[0845] Referring to the synthetic route A, compound 60 can be prepared, mass spectrum (M+H): 859.4

[0846] Example 61: Preparation of (S)-N-(2-(1-((1-(4-((2,6-dicarbonylpiperidin-3-yl)carbamoyl)-3-methoxyphenyl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-1-yl)-2H-indazol-5-yl)-2-(1-methyl-1H-pyrazol-4-yl)oxazole-4-carboxamide Compound 61

[0847] Referring to the synthetic route D, compound 61 can be prepared, mass spectrum (M+H): 832.4

[0848] Example 62: Preparation of (S)-N-(2-(1-((1-(4-((2,6-dicarbonylpiperidin-3-yl)carbamoyl)-3-methoxyphenyl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-1-yl)-2H-indazol-5-yl)-1-(2-methylpyridin-4-yl)-1H-pyrazole-4-carboxamide Compound 62

[0849] Referring to the synthetic route D, compound 62 can be prepared, mass spectrum (M+H): 842.4

[0850] Example 63: Preparation of (S)-N-(2,6-dicarbonylpiperidin-3-yl)-2-methoxy-4-(4-((4-(5-(4-phenoxybenzamido)-6-(piperidin-1-yl)-2H-indazol-2-yl)piperidin-1-yl)methyl)piperidin-1-yl)benzamide Compound 63

[0851] Referring to the synthetic route A, compound 63 can be prepared, mass spectrum (M+H): 853.4

[0852] Example 64: Preparation of (S)-N-(2-(1-((1-(4-((2,6-dicarbonylpiperidin-3-yl)carbamoyl)-3-methoxyphenyl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-1-yl)-2H-indazol-5-yl)-2-phenylthiazole-4-carboxamide Compound 64

[0853] Referring to the synthetic route B, compound 64 can be prepared, mass spectrum (M+H): 844.4

[0854] Example 65: Preparation of (S)-N-(2-(1-((1-(4-((2,6-dicarbonylpiperidin-3-yl)carbamoyl)-3-methoxyphenyl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-1-yl)-2H-indazol-5-yl)-1-(pyridin-3-yl)-1H-pyrazole-4-carboxamide Compound 65

[0855] Referring to the synthetic route A, compound 65 can be prepared, mass spectrum (M+H): 828.4

[0856] Example 66: Preparation of (S)-N-(2-(1-((1-(4-((2,6-dicarbonylpiperidin-3-yl)carbamoyl)-3-methoxyphenyl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-1-yl)-2H-indazol-5-yl)-1H-pyrrolo[3,2-c]pyridine-3-carboxamide Compound 66

[0857] Referring to the synthetic route B, compound 66 can be prepared, mass spectrum (M+H): 801.4

[0858] Example 67: Preparation of (S)-N-(2-(1-((1-(4-((2,6-dicarbonylpiperidin-3-yl)carbamoyl)-3-methoxyphenyl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-1-yl)-2H-indazol-5-yl)benzofuran-3-carboxamide Compound 67

[0859] Referring to the synthetic route A, compound 67 can be prepared, mass spectrum (M+H): 801.4

[0860] Example 68: Preparation of (S)-N-(2-(1-((1-(4-((2,6-dicarbonylpiperidin-3-yl)carbamoyl)-3-methoxyphenyl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-1-yl)-2H-indazol-5-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-2-carboxamide Compound 68

[0861] Referring to the synthetic route A, compound 68 can be prepared, mass spectrum (M+H): 805.4

[0862] Example 69: Preparation of (S)-N-(2-(1-((1-(4-((2,6-dicarbonylpiperidin-3-yl)carbamoyl)-3-methoxyphenyl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-1-yl)-2H-indazol-5-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-2-carboxamide Compound 69

[0863] Referring to the synthetic route A, compound 69 can be prepared, mass spectrum (M+H): 791.4

[0864] Example 70: Preparation of (S)-N-(2-(1-((1-(4-((2,6-dicarbonylpiperidin-3-yl)carbamoyl)-3-methoxyphenyl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-1-yl)-2H-indazol-5-yl)-4,5,6,7-tetrahydro-1H-indazole-3-carboxamide Compound 70

[0865] Referring to the synthetic route C, compound 70 can be prepared, mass spectrum (M+H): 805.4

[0866] Example 71: Preparation of (S)-N-(2-(1-((1-(4-((2,6-dicarbonylpiperidin-3-yl)carbamoyl)-3-methoxyphenyl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-1-yl)-2H-indazol-5-yl)-1,4,5,6-tetrahydrocyclopenta[c]pyrazole-3-carboxamide Compound 71

[0867] Referring to the synthetic route D, compound 71 can be prepared, mass spectrum (M+H): 791.4

[0868] Example 72: Preparation of (S)-N-(2-(1-((1-(4-((2,6-dicarbonylpiperidin-3-yl)carbamoyl)-3-methoxyphenyl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-1-yl)-2H-indazol-5-yl)-1-methyl-1,4,5,6-tetrahydrocyclopenta[c]pyrazole-3-carboxamide Compound 72

[0869] Referring to the synthetic route B, compound 72 can be prepared, mass spectrum (M+H): 805.4

[0870] Example 73: Preparation of N-(2-(1-((1-(2-(2,6-dicarbonylpiperidin-3-yl)-1-carbonylisoindolin-5-yl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-1-yl)-2H-indazol-5-yl)benzo[d]thiazole-7-carboxamide Compound 73

[0871] Referring to the synthetic route A, compound 73 can be prepared, mass spectrum (M+H): 800.3

[0872] Example 74: Preparation of N-(2-(1-((1-(2-(2,6-dicarbonylpiperidin-3-yl)-1-carbonylisoindolin-5-yl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-1-yl)-2H-indazol-5-yl)-1-(4-fluorophenyl)-5-methyl-1H-pyrazole-4-carboxamide Compound 74

[0873] Referring to the synthetic route A, compound 74 can be prepared, mass spectrum (M+H): 841.4

[0874] Example 75: Preparation of N-(2-(1-((1-(2-(2,6-dicarbonylpiperidin-3-yl)-1-carbonylisoindolin-5-yl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-1-yl)-2H-indazol-5-yl)-1-methyl-3-(trifluoromethyl)-1H-pyrazole-4-carboxamide Compound 75

[0875] Referring to the synthetic route A, compound 75 can be prepared, mass spectrum (M+H): 815.4

[0876] Example 76: Preparation of N-(2-(1-((1-(2-(2,6-dicarbonylpiperidin-3-yl)-1-carbonylisoindolin-5-yl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-1-yl)-2H-indazol-5-yl)-4H-thieno[3,2-b]pyrrole-5-carboxamide Compound 76

[0877] Referring to the synthetic route A, compound 76 can be prepared, mass spectrum (M+H): 788.3

[0878] Example 77: Preparation of N-(2-(1-((1-(2-(2,6-dicarbonylpiperidin-3-yl)-1-carbonylisoindolin-5-yl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-1-yl)-2H-indazol-5-yl)quinoline-4-carboxamide Compound 77

[0879] Referring to the synthetic route B, compound 77 can be prepared, mass spectrum (M+H): 794.4

[0880] Example 78: Preparation of N-(2-(1-((1-(2-(2,6-dicarbonylpiperidin-3-yl)-1-carbonylisoindolin-5-yl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-1-yl)-2H-indazol-5-yl)quinoline-5-carboxamide Compound 78

[0881] Referring to the synthetic route B, compound 78 can be prepared, mass spectrum (M+H): 794.4

[0882] Example 79: Preparation of N-(2-(1-((1-(2-(2,6-dicarbonylpiperidin-3-yl)-1-carbonylisoindolin-5-yl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-1-yl)-2H-indazol-5-yl)imidazo[1,2-a]pyridine-6-carboxamide Compound 79

[0883] Referring to the synthetic route D, compound 79 can be prepared, mass spectrum (M+H): 783.4

[0884] Example 80: Preparation of N-(2-(1-((1-(2-(2,6-dicarbonylpiperidin-3-yl)-1-carbonylisoindolin-5-yl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-1-yl)-2H-indazol-5-yl)imidazo[1,2-a]pyridine-7-carboxamide Compound 80

[0885] Referring to the synthetic route A, compound 80 can be prepared, mass spectrum (M+H): 783.4

[0886] Example 81: Preparation of N-(2-(1-((1-(2-(2,6-dicarbonylpiperidin-3-yl)-1-carbonylisoindolin-5-yl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-1-yl)-2H-indazol-5-yl)-1,5-naphthyridine-3-carboxamide Compound 81

[0887] Referring to the synthetic route C, compound 81 can be prepared, mass spectrum (M+H): 795.4

[0888] Example 82: Preparation of N-(2-(1-((1-(2-(2,6-dicarbonylpiperidin-3-yl)-1-carbonylisoindolin-5-yl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-1-yl)-2H-indazol-5-yl)-7H-pyrrolo[2,3-b]pyridine-4-carboxamide Compound 82

[0889] Referring to the synthetic route A, compound 82 can be prepared, mass spectrum (M+H): 783.4

[0890] Example 83: Preparation of N-(2-(1-((1-(2-(2,6-dicarbonylpiperidin-3-yl)-1-carbonylisoindolin-5-yl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-1-yl)-2H-indazol-5-yl)isoquinoline-8-carboxamide Compound 83

[0891] Referring to the synthetic route A, compound 83 can be prepared, mass spectrum (M+H): 794.4

[0892] Example 84: Preparation of N-(2-(1-((1-(2-(2,6-dicarbonylpiperidin-3-yl)-1-carbonylisoindolin-5-yl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-1-yl)-2H-indazol-5-yl)quinoxaline-5-carboxamide Compound 84

[0893] Referring to the synthetic route B, compound 84 can be prepared, mass spectrum (M+H): 795.4

[0894] Example 85: Preparation of N-(2-(1-((1-(2-(2,6-dicarbonylpiperidin-3-yl)-1-carbonylisoindolin-5-yl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-1-yl)-2H-indazol-5-yl)-7H-pyrrolo[2,3-b]pyridine-5-carboxamide Compound 85

[0895] Referring to the synthetic route C, compound 85 can be prepared, mass spectrum (M+H): 783.4

[0896] Example 86: Preparation of N-(2-(1-((1-(2-(2,6-dicarbonylpiperidin-3-yl)-1-carbonylisoindolin-5-yl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-1-yl)-2H-indazol-5-yl)-2-methylimidazo[1,2-a]pyridine-6-carboxamide Compound 86

[0897] Referring to the synthetic route C, compound 86 can be prepared, mass spectrum (M+H): 797.4

[0898] Example 87: Preparation of N-(2-(1-((1-(2-(2,6-dicarbonylpiperidin-3-yl)-1-carbonylisoindolin-5-yl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-1-yl)-2H-indazol-5-yl)benzo[c][1,2,5]thiadiazole-4-carboxamide Compound 87

[0899] Referring to the synthetic route A, compound 87 can be prepared, mass spectrum (M+H): 801.3

[0900] Example 88: Preparation of N-(2-(1-((1-(4-((2,6-dicarbonylpiperidin-3-yl)carbamoyl)-3-fluorophenyl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-1-yl)-2H-indazol-5-yl)imidazo[1,2-a]pyridine-3-carboxamide Compound 88

[0901] Referring to the synthetic route A, compound 88 can be prepared, mass spectrum (M+H): 789.4

[0902] Example 89: Preparation of N-(2-(1-((1-(4-((2,6-dicarbonylpiperidin-3-yl)carbamoyl)-3-fluorophenyl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-1-yl)-2H-indazol-5-yl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide Compound 89

[0903] Referring to the synthetic route D, compound 89 can be prepared, mass spectrum (M+H): 789.4

[0904] Example 90: Preparation of N-(2-(1-((1-(4-((2,6-dicarbonylpiperidin-3-yl)carbamoyl)-3-fluorophenyl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-1-yl)-2H-indazol-5-yl)-2-(2-methylpyridin-4-yl)thiazole-4-carboxamide Compound 90

[0905] Referring to the synthetic route A, compound 90 can be prepared, mass spectrum (M+H): 847.3

[0906] Example 91: Preparation of N-(2-(1-((1-(4-((2,6-dicarbonylpiperidin-3-yl)carbamoyl)-3-fluorophenyl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-1-yl)-2H-indazol-5-yl)-2-(pyrimidin-2-yl)oxazole-4-carboxamide Compound 91

[0907] Referring to the synthetic route D, compound 91 can be prepared, mass spectrum (M+H): 818.4

[0908] Example 92: Preparation of N-(2-(1-((1-(4-((2,6-dicarbonylpiperidin-3-yl)carbamoyl)-3-fluorophenyl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-1-yl)-2H-indazol-5-yl)-1-(pyrimidin-2-yl)-1H-imidazole-4-carboxamide Compound 92

[0909] Referring to the synthetic route A, compound 92 can be prepared, mass spectrum (M+H): 817.4

[0910] Example 93: Preparation of N-(2-(1-((1-(4-((2,6-dicarbonylpiperidin-3-yl)carbamoyl)-3-fluorophenyl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-1-yl)-2H-indazol-5-yl)-2-(1-methyl-1H-pyrazol-4-yl)oxazole-4-carboxamide Compound 93

[0911] Referring to the synthetic route C, compound 93 can be prepared, mass spectrum (M+H): 820.4

[0912] Example 94: Preparation of N-(2-(1-((1-(4-((2,6-dicarbonylpiperidin-3-yl)carbamoyl)-3-fluorophenyl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-1-yl)-2H-indazol-5-yl)-1-(2-methylpyridin-4-yl)-1H-pyrazole-4-carboxamide Compound 94

[0913] Referring to the synthetic route A, compound 94 can be prepared, mass spectrum (M+H): 830.4

[0914] Example 95: Preparation of N-(2,6-dicarbonylpiperidin-3-yl)-2-fluoro-4-(4-((4-(5-(4-phenoxybenzamido)-6-(piperidin-1-yl)-2H-indazol-2-yl)piperidin-1-yl)methyl)piperidin-1-yl)benzamide Compound 95

[0915] Referring to the synthetic route D, compound 95 can be prepared, mass spectrum (M+H): 841.4

[0916] Example 96: Preparation of N-(2-(1-((1-(4-((2,6-dicarbonylpiperidin-3-yl)carbamoyl)-3-fluorophenyl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-1-yl)-2H-indazol-5-yl)-2-phenylthiazole-4-carboxamide Compound 96

[0917] Referring to the synthetic route A, compound 96 can be prepared, mass spectrum (M+H): 832.3

[0918] Example 97: Preparation of N-(2-(1-((1-(4-((2,6-dicarbonylpiperidin-3-yl)carbamoyl)-3-fluorophenyl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-1-yl)-2H-indazol-5-yl)-1-(pyridin-3-yl)-1H-pyrazole-4-carboxamide Compound 97

[0919] Referring to the synthetic route B, compound 97 can be prepared, mass spectrum (M+H): 816.4

[0920] Example 98: Preparation of N-(2-(1-((1-(4-((2,6-dicarbonylpiperidin-3-yl)carbamoyl)-3-fluorophenyl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-1-yl)-2H-indazol-5-yl)-1H-pyrrolo[3,2-c]pyridine-3-carboxamide Compound 98

[0921] Referring to the synthetic route B, compound 98 can be prepared, mass spectrum (M+H): 789.4

[0922] Example 99: Preparation of N-(2-(1-((1-(4-((2,6-dicarbonylpiperidin-3-yl)carbamoyl)-3-fluorophenyl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-1-yl)-2H-indazol-5-yl)benzofuran-3-carboxamide Compound 99

[0923] Referring to the synthetic route A, compound 99 can be prepared, mass spectrum (M+H): 789.4

[0924] Example 100: Preparation of N-(2-(1-((1-(4-((2,6-dicarbonylpiperidin-3-yl)carbamoyl)-3-fluorophenyl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-1-yl)-2H-indazol-5-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-2-carboxamide Compound 100

[0925] Referring to the synthetic route A, compound 100 can be prepared, mass spectrum (M+H): 793.4

[0926] Example 101: Preparation of N-(2-(1-((1-(4-((2,6-dicarbonylpiperidin-3-yl)carbamoyl)-3-fluorophenyl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-1-yl)-2H-indazol-5-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-2-carboxamide Compound 101

[0927] Referring to the synthetic route A, compound 101 can be prepared, mass spectrum (M+H): 779.4

[0928] Example 102: Preparation of N-(2-(1-((1-(4-((2,6-dicarbonylpiperidin-3-yl)carbamoyl)-3-fluorophenyl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-1-yl)-2H-indazol-5-yl)-4,5,6,7-tetrahydro-1H-indazole-3-carboxamide Compound 102

[0929] Referring to the synthetic route C, compound 102 can be prepared, mass spectrum (M+H): 793.4

[0930] Example 103: Preparation of N-(2-(1-((1-(4-((2,6-dicarbonylpiperidin-3-yl)carbamoyl)-3-fluorophenyl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-1-yl)-2H-indazol-5-yl)-1,4,5,6-tetrahydrocyclopenta[c]pyrazole-3-carboxamide Compound 103

[0931] Referring to the synthetic route A, compound 103 can be prepared, mass spectrum (M+H): 779.4

[0932] Example 104: Preparation of N-(2-(1-((1-(4-((2,6-dicarbonylpiperidin-3-yl)carbamoyl)-3-fluorophenyl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-1-yl)-2H-indazol-5-yl)-1-methyl-1,4,5,6-tetrahydrocyclopenta[c]pyrazole-3-carboxamide Compound 104

[0933] Referring to the synthetic route D, compound 104 can be prepared, mass spectrum (M+H): 793.4

[0934] Example 105: Preparation of N-(2-(1-((1-(4-((2,6-dicarbonylpiperidin-3-yl)carbamoyl)-3-fluorophenyl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-1-yl)-2H-indazol-5-yl)benzofuran-4-carboxamide Compound 105

[0935] Referring to the synthetic route C, compound 105 can be prepared, mass spectrum (M+H): 789.3

[0936] Example 106: Preparation of N-(2-(1-((1-(4-((2,6-dicarbonylpiperidin-3-yl)carbamoyl)-3-fluorophenyl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-1-yl)-2H-indazol-5-yl)imidazo[1,2-b]pyridazine-3-carboxamide Compound 106

[0937] Referring to the synthetic route A, compound 106 can be prepared, mass spectrum (M+H): 790.4

[0938] Example 107: Preparation of N-(2-(1-((1-(2-(2,6-dicarbonylpiperidin-3-yl)-1,3-dicarbonylisoindolin-5-yl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-1-yl)-2H-indazol-5-yl)benzo[d]thiazole-7-carboxamide Compound 107

[0939] Referring to the synthetic route A, compound 107 can be prepared, mass spectrum (M+H): 814.3

[0940] Example 108: Preparation of N-(2-(1-((1-(2-(2,6-dicarbonylpiperidin-3-yl)-1,3-dicarbonylisoindolin-5-yl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-1-yl)-2H-indazol-5-yl)-1-(4-fluorophenyl)-5-methyl-1H-pyrazole-4-carboxamide Compound 108

[0941] Referring to the synthetic route B, compound 108 can be prepared, mass spectrum (M+H): 855.4

[0942] Example 109: Preparation of N-(2-(1-((1-(2-(2,6-dicarbonylpiperidin-3-yl)-1,3-dicarbonylisoindolin-5-yl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-1-yl)-2H-indazol-5-yl)-1-methyl-3-(trifluoromethyl)-1H-pyrazole-4-carboxamide Compound 109

[0943] Referring to the synthetic route A, compound 109 can be prepared, mass spectrum (M+H): 829.3

[0944] Example 110: Preparation of N-(2-(1-((1-(2-(2,6-dicarbonylpiperidin-3-yl)-1,3-dicarbonylisoindolin-5-yl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-1-yl)-2H-indazol-5-yl)-4H-thieno[3,2-b]pyrrole-5-carboxamide Compound 110

[0945] Referring to the synthetic route B, compound 110 can be prepared, mass spectrum (M+H): 802.3

[0946] Example 111: Preparation of N-(2-(1-((1-(2-(2,6-dicarbonylpiperidin-3-yl)-1,3-dicarbonylisoindolin-5-yl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-1-yl)-2H-indazol-5-yl)quinoline-4-carboxamide Compound 111

[0947] Referring to the synthetic route A, compound 111 can be prepared, mass spectrum (M+H): 808.4

[0948] Example 112: Preparation of N-(2-(1-((1-(2-(2,6-dicarbonylpiperidin-3-yl)-1,3-dicarbonylisoindolin-5-yl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-1-yl)-2H-indazol-5-yl)quinoline-5-carboxamide Compound 112

[0949] Referring to the synthetic route D, compound 112 can be prepared, mass spectrum (M+H): 808.4

[0950] Example 113: Preparation of N-(2-(1-((1-(2-(2,6-dicarbonylpiperidin-3-yl)-1,3-dicarbonylisoindolin-5-yl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-1-yl)-2H-indazol-5-yl)imidazo[1,2-a]pyridine-6-carboxamide Compound 113

[0951] Referring to the synthetic route A, compound 113 can be prepared, mass spectrum (M+H): 797.4

[0952] Example 114: Preparation of N-(2-(1-((1-(2-(2,6-dicarbonylpiperidin-3-yl)-1,3-dicarbonylisoindolin-5-yl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-1-yl)-2H-indazol-5-yl)imidazo[1,2-a]pyridine-7-carboxamide Compound 114

[0953] Referring to the synthetic route C, compound 114 can be prepared, mass spectrum (M+H): 797.4

[0954] Example 115: Preparation of N-(2-(1-((1-(2-(2,6-dicarbonylpiperidin-3-yl)-1,3-dicarbonylisoindolin-5-yl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-1-yl)-2H-indazol-5-yl)-1H-benzo[d]imidazole-6-carboxamide Compound 115

[0955] Referring to the synthetic route A, compound 115 can be prepared, mass spectrum (M+H): 797.4

[0956] Example 116: Preparation of N-(2-(1-((1-(2-(2,6-dicarbonylpiperidin-3-yl)-1,3-dicarbonylisoindolin-5-yl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-1-yl)-2H-indazol-5-yl)-1,5-naphthyridine-3-carboxamide Compound 116

[0957] Referring to the synthetic route B, compound 116 can be prepared, mass spectrum (M+H): 809.4

[0958] Example 117: Preparation of N-(2-(1-((1-(2-(2,6-dicarbonylpiperidin-3-yl)-1,3-dicarbonylisoindolin-5-yl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-1-yl)-2H-indazol-5-yl)-7H-pyrrolo[2,3-b]pyridine-4-carboxamide Compound 117

[0959] Referring to the synthetic route D, compound 117 can be prepared, mass spectrum (M+H): 797.4

[0960] Example 118: Preparation of N-(2-(1-((1-(2-(2,6-dicarbonylpiperidin-3-yl)-1,3-dicarbonylisoindolin-5-yl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-1-yl)-2H-indazol-5-yl)isoquinoline-8-carboxamide Compound 118

[0961] Referring to the synthetic route A, compound 118 can be prepared, mass spectrum (M+H): 808.4

[0962] Example 119: Preparation of N-(2-(1-((1-(2-(2,6-dicarbonylpiperidin-3-yl)-1,3-dicarbonylisoindolin-5-yl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-1-yl)-2H-indazol-5-yl)quinoxaline-5-carboxamide Compound 119

[0963] Referring to the synthetic route A, compound 119 can be prepared, mass spectrum (M+H): 809.4

[0964] Example 120: Preparation of N-(2-(1-((1-(2-(2,6-dicarbonylpiperidin-3-yl)-1,3-dicarbonylisoindolin-5-yl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-1-yl)-2H-indazol-5-yl)-7H-pyrrolo[2,3-b]pyridine-5-carboxamide Compound 120

[0965] Referring to the synthetic route D, compound 120 can be prepared, mass spectrum (M+H): 797.4

[0966] Example 121: Preparation of N-(2-(1-((1-(2-(2,6-dicarbonylpiperidin-3-yl)-1,3-dicarbonylisoindolin-5-yl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-1-yl)-2H-indazol-5-yl)-2-methylimidazo[1,2-a]pyridine-6-carboxamide Compound 121

[0967] Referring to the synthetic route A, compound 121 can be prepared, mass spectrum (M+H): 811.4

[0968] Example 122: Preparation of N-(2-(1-((1-(2-(2,6-dicarbonylpiperidin-3-yl)-1,3-dicarbonylisoindolin-5-yl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-1-yl)-2H-indazol-5-yl)benzo[c][1,2,5]thiadiazole-4-carboxamide Compound 122

[0969] Referring to the synthetic route B, compound 122 can be prepared, mass spectrum (M+H): 815.3

[0970] Example 123: Preparation of N-(2-(1-((1-(2-(2,6-dicarbonylpiperidin-3-yl)-1,3-dicarbonylisoindolin-5-yl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-1-yl)-2H-indazol-5-yl)-1H-indole-4-carboxamide Compound 123

[0971] Referring to the synthetic route A, compound 123 can be prepared, mass spectrum (M+H): 796.4

[0972] Example 124: Preparation of N-(2-(1-((1-(2-(2,6-dicarbonylpiperidin-3-yl)-1,3-dicarbonylisoindolin-5-yl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-1-yl)-2H-indazol-5-yl)-1H-indole-5-carboxamide Compound 124

[0973] Referring to the synthetic route B, compound 124 can be prepared, mass spectrum (M+H): 796.4

[0974] Example 125: Preparation of N-(2-(1-((1-(2-(2,6-dicarbonylpiperidin-3-yl)-1,3-dicarbonylisoindolin-5-yl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-1-yl)-2H-indazol-5-yl)quinoline-6-carboxamide Compound 125

[0975] Referring to the synthetic route A, compound 125 can be prepared, mass spectrum (M+H): 808.4

[0976] Example 126: Preparation of N-(2-(1-((1-(2-(2,6-dicarbonylpiperidin-3-yl)-1,3-dicarbonylisoindolin-5-yl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-1-yl)-2H-indazol-5-yl)benzo[b]thiophene-3-carboxamide Compound 126

[0977] Referring to the synthetic route B, compound 126 can be prepared, mass spectrum (M+H): 813.3

[0978] Example 127: Preparation of N-(2-(1-((1-(2-(2,6-dicarbonylpiperidin-3-yl)-1,3-dicarbonylisoindolin-5-yl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-1-yl)-2H-indazol-5-yl)isoquinoline-5-carboxamide Compound 127

[0979] Referring to the synthetic route B, compound 127 can be prepared, mass spectrum (M+H): 808.4

[0980] Example 128: Preparation of N-(2-(1-((1-(2-(2,6-dicarbonylpiperidin-3-yl)-1,3-dicarbonylisoindolin-5-yl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-1-yl)-2H-indazol-5-yl)imidazo[1,2-b]pyridazine-6-carboxamide Compound 128

[0981] Referring to the synthetic route B, compound 128 can be prepared, mass spectrum (M+H): 798.4

[0982] Example 129: Preparation of N-(2-(1-((1-(2-(2,6-dicarbonylpiperidin-3-yl)-1,3-dicarbonylisoindolin-5-yl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-1-yl)-2H-indazol-5-yl)imidazo[1,5-a]pyridine-8-carboxamide Compound 129

[0983] Referring to the synthetic route B, compound 129 can be prepared, mass spectrum (M+H): 797.4

[0984] Example 130: Preparation of N-(2-(1-((1-(2-(2,6-dicarbonylpiperidin-3-yl)-1,3-dicarbonylisoindolin-5-yl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-1-yl)-2H-indazol-5-yl)-2-methyl-1H-benzo[d]imidazole-5-carboxamide Compound 130

[0985] Referring to the synthetic route A, compound 130 can be prepared, mass spectrum (M+H): 811.4

[0986] Example 131: Preparation of N-(2-(1-((1-(2-(2,6-dicarbonylpiperidin-3-yl)-1,3-dicarbonylisoindolin-5-yl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-1-yl)-2H-indazol-5-yl)imidazo[1,2-a]pyridine-8-carboxamide Compound 131

[0987] Referring to the synthetic route A, compound 131 can be prepared, mass spectrum (M+H): 797.4

[0988] Example 132: Preparation of N-(2-(1-((1-(2-(2,6-dicarbonylpiperidin-3-yl)-1,3-dicarbonylisoindolin-5-yl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-1-yl)-2H-indazol-5-yl)-3-methylimidazo[1,2-a]pyridine-6-carboxamide Compound 132

[0989] Referring to the synthetic route C, compound 132 can be prepared, mass spectrum (M+H): 811.4

[0990] Example 133: Preparation of N-(2-(1-((1-(2-(2,6-dicarbonylpiperidin-3-yl)-1,3-dicarbonylisoindolin-5-yl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-1-yl)-2H-indazol-5-yl)-1H-benzo[d]imidazole-4-carboxamide Compound 133

[0991] Referring to the synthetic route C, compound 133 can be prepared, mass spectrum (M+H): 797.4

[0992] Example 134: Preparation of N-(2-(1-((1-(2-(2,6-dicarbonylpiperidin-3-yl)-1,3-dicarbonylisoindolin-5-yl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-1-yl)-2H-indazol-5-yl)-1-(3-methoxyphenyl)-1H-pyrazole-4-carboxamide Compound 134

[0993] Referring to the synthetic route C, compound 134 can be prepared, mass spectrum (M+H): 853.4

[0994] Example 135: Preparation of N-(2-(1-((1-(2-(2,6-dicarbonylpiperidin-3-yl)-1,3-dicarbonylisoindolin-5-yl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-1-yl)-2H-indazol-5-yl)benzo[c][1,2,5]thiadiazole-5-carboxamide Compound 135

[0995] Referring to the synthetic route A, compound 135 can be prepared, mass spectrum (M+H): 815.3

[0996] Example 136: Preparation of N-(2-(1-((1-(2-(2,6-dicarbonylpiperidin-3-yl)-1,3-dicarbonylisoindolin-5-yl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-1-yl)-2H-indazol-5-yl)thieno[3,2-d]pyrimidine-4-carboxamide Compound 136

[0997] Referring to the synthetic route D, compound 136 can be prepared, mass spectrum (M+H): 815.3

[0998] Example 137: Preparation of N-(2-(1-((1-(2-(2,6-dicarbonylpiperidin-3-yl)-1,3-dicarbonylisoindolin-5-yl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-1-yl)-2H-indazol-5-yl)thieno[2,3-c]pyridine-2-carboxamide Compound 137

[0999] Referring to the synthetic route A, compound 137 can be prepared, mass spectrum (M+H): 814.3

[1000] Example 138: Preparation of N-(2-(1-((1-(2-(2,6-dicarbonylpiperidin-3-yl)-1,3-dicarbonylisoindolin-5-yl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-1-yl)-2H-indazol-5-yl)-1-methyl-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide Compound 138

[1001] Referring to the synthetic route D, compound 138 can be prepared, mass spectrum (M+H): 829.3

[1002] Example 139: Preparation of N-(2-(1-((1-(2-(2,6-dicarbonylpiperidin-3-yl)-1,3-dicarbonylisoindolin-5-yl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-1-yl)-2H-indazol-5-yl)-[1,2,4]triazolo[4,3-a]pyridine-8-carboxamide Compound 139

[1003] Referring to the synthetic route D, compound 139 can be prepared, mass spectrum (M+H): 798.4

[1004] Example 140: Preparation of N-(2-(1-((1-(2-(2,6-dicarbonylpiperidin-3-yl)-1,3-dicarbonylisoindolin-5-yl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-1-yl)-2H-indazol-5-yl)-[1,2,4]triazolo[4,3-a]pyridine-7-carboxamide Compound 140

[1005] Referring to the synthetic route D, compound 140 can be prepared, mass spectrum (M+H): 798.4

[1006] Example 141: Preparation of N-(2-(1-((1-(2-(2,6-dicarbonylpiperidin-3-yl)-1,3-dicarbonylisoindolin-5-yl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-1-yl)-2H-indazol-5-yl)-1-phenyl-3-(trifluoromethyl)-1H-pyrazole-4-carboxamide Compound 141

[1007] Referring to the synthetic route D, compound 141 can be prepared, mass spectrum (M+H): 891.4

[1008] Example 142: Preparation of N-(2-(1-((1-(2-(2,6-dicarbonylpiperidin-3-yl)-1,3-dicarbonylisoindolin-5-yl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-1-yl)-2H-indazol-5-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-3-carboxamide Compound 142

[1009] Referring to the synthetic route A, compound 142 can be prepared, mass spectrum (M+H): 801.4

[1010] Example 143: Preparation of N-(2-(1-((1-(2-(2,6-dicarbonylpiperidin-3-yl)-3-carbonylisoindolin-5-yl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-1-yl)-2H-indazol-5-yl)benzo[d]thiazole-7-carboxamide Compound 143

[1011] Referring to the synthetic route A, compound 143 can be prepared, mass spectrum (M+H): 800.3

[1012] Example 144: Preparation of N-(2-(1-((1-(2-(2,6-dicarbonylpiperidin-3-yl)-3-carbonylisoindolin-5-yl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-1-yl)-2H-indazol-5-yl)imidazo[1,2-a]pyridine-7-carboxamide Compound 144

[1013] Referring to the synthetic route B, compound 144 can be prepared, mass spectrum (M+H): 783.4

[1014] Example 145: Preparation of N-(2-(1-((1-(2-(2,6-dicarbonylpiperidin-3-yl)-3-carbonylisoindolin-5-yl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-1-yl)-2H-indazol-5-yl)-1,5-naphthyridine-3-carboxamide Compound 145

[1015] Referring to the synthetic route A, compound 145 can be prepared, mass spectrum (M+H): 795.4

[1016] Example 146: Preparation of N-(2-(1-((1-(2-(2,6-dicarbonylpiperidin-3-yl)-3-carbonylisoindolin-5-yl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-1-yl)-2H-indazol-5-yl)imidazo[1,2-a]pyridine-8-carboxamide Compound 146

[1017] Referring to the synthetic route B, compound 146 can be prepared, mass spectrum (M+H): 783.4

[1018] Example 147: Preparation of N-(2-(1-((1-(2-(2,6-dicarbonylpiperidin-3-yl)-3-carbonylisoindolin-5-yl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-1-yl)-2H-indazol-5-yl)-1H-benzo[d]imidazole-4-carboxamide Compound 147

[1019] Referring to the synthetic route B, compound 147 can be prepared, mass spectrum (M+H): 783.4

[1020] Example 148: Preparation of N-(2-(1-((1-(2-(2,6-dicarbonylpiperidin-3-yl)-3-carbonylisoindolin-5-yl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-1-yl)-2H-indazol-5-yl)pyrazolo[1,5-a]pyridine-3-carboxamide Compound 148

[1021] Referring to the synthetic route C, compound 148 can be prepared, mass spectrum (M+H): 783.4

[1022] Example 149: Preparation of N-(2-(1-((1-(2-(2,6-dicarbonylpiperidin-3-yl)-3-carbonylisoindolin-5-yl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-1-yl)-2H-indazol-5-yl)-4-phenoxybenzamide Compound 149

[1023] Referring to the synthetic route A, compound 149 can be prepared, mass spectrum (M+H): 835.4

[1024] Example 150: Preparation of N-(2-(1-((1-(2-(2,6-dicarbonylpiperidin-3-yl)-3-carbonylisoindolin-5-yl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-1-yl)-2H-indazol-5-yl)imidazo[1,2-b]pyridazine-6-carboxamide Compound 150

[1025] Referring to the synthetic route A, compound 150 can be prepared, mass spectrum (M+H): 784.4

[1026] Example 151: Preparation of N-(2-(1-((1-(2-(2,6-dicarbonylpiperidin-3-yl)-3-carbonylisoindolin-5-yl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-1-yl)-2H-indazol-5-yl)-[1,2,4]triazolo[4,3-a]pyridine-8-carboxamide Compound 151

[1027] Referring to the synthetic route A, compound 151 can be prepared, mass spectrum (M+H): 784.4

[1028] Example 152: Preparation of N-(2-(1-((1-(2-(2,6-dicarbonylpiperidin-3-yl)-3-carbonylisoindolin-5-yl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-1-yl)-2H-indazol-5-yl)-[1,2,4]triazolo[4,3-a]pyridine-7-carboxamide Compound 152

[1029] Referring to the synthetic route B, compound 152 can be prepared, mass spectrum (M+H): 784.4

[1030] Example 153: Preparation of 4-amino-N-(2-(1-((1-(2-(2,6-dicarbonylpiperidin-3-yl)-3-carbonylisoindolin-5-yl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-1-yl)-2H-indazol-5-yl)thieno[3,2-d]pyrimidine-7-carboxamide Compound 153

[1031] Referring to the synthetic route D, compound 153 can be prepared, mass spectrum (M+H): 816.3

[1032] Example 154: Preparation of N-(2-(1-((1-(2-(2,6-dicarbonylpiperidin-3-yl)-3-carbonylisoindolin-5-yl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-1-yl)-2H-indazol-5-yl)imidazo[1,2-b]pyridazine-2-carboxamide Compound 154

[1033] Referring to the synthetic route D, compound 154 can be prepared, mass spectrum (M+H): 784.4

[1034] Example 155: Preparation of N-(2-(1-((1-(2-(2,6-dicarbonylpiperidin-3-yl)-3-carbonylisoindolin-5-yl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-1-yl)-2H-indazol-5-yl)-3H-imidazo[4,5-b]pyridine-7-carboxamide Compound 155

[1035] Referring to the synthetic route A, compound 155 can be prepared, mass spectrum (M+H): 784.4

[1036] Example 156: Preparation of N-(2-(1-((1-(2-(2,6-dicarbonylpiperidin-3-yl)-3-carbonylisoindolin-5-yl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-1-yl)-2H-indazol-5-yl)-3H-imidazo[4,5-c]pyridine-7-carboxamide Compound 156

[1037] Referring to the synthetic route A, compound 156 can be prepared, mass spectrum (M+H): 784.4

[1038] Example 157: Preparation of N-(2-(1-((1-(2-(2,6-dicarbonylpiperidin-3-yl)-3-carbonylisoindolin-5-yl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-1-yl)-2H-indazol-5-yl)-2-(2-methylpyridin-4-yl)thiazole-4-carboxamide Compound 157

[1039] Referring to the synthetic route D, compound 157 can be prepared, mass spectrum (M+H): 841.4

[1040] Example 158: Preparation of N-(2-(1-((1-(2-(2,6-dicarbonylpiperidin-3-yl)-3-carbonylisoindolin-5-yl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-1-yl)-2H-indazol-5-yl)-2-(pyrimidin-2-yl)oxazole-4-carboxamide Compound 158

[1041] Referring to the synthetic route B, compound 158 can be prepared, mass spectrum (M+H): 812.4

[1042] Example 159: Preparation of N-(2-(1-((1-(2-(2,6-dicarbonylpiperidin-3-yl)-3-carbonylisoindolin-5-yl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-1-yl)-2H-indazol-5-yl)-2-(1-methyl-1H-pyrazol-4-yl)oxazole-4-carboxamide Compound 159

[1043] Referring to the synthetic route D, compound 159 can be prepared, mass spectrum (M+H): 814.4

[1044] Example 160: Preparation of N-(2-(1-((1-(2-(2,6-dicarbonylpiperidin-3-yl)-3-carbonylisoindolin-5-yl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-1-yl)-2H-indazol-5-yl)-2-phenylthiazole-4-carboxamide Compound 160

[1045] Referring to the synthetic route D, compound 160 can be prepared, mass spectrum (M+H): 826.4

[1046] Example 161: Preparation of N-(2-(1-((1-(2-(2,6-dicarbonylpiperidin-3-yl)-3-carbonylisoindolin-5-yl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-1-yl)-2H-indazol-5-yl)-1H-pyrrolo[3,2-c]pyridine-3-carboxamide Compound 161

[1047] Referring to the synthetic route A, compound 161 can be prepared, mass spectrum (M+H): 783.4

[1048] Example 162: Preparation of N-(2-(1-((1-(2-(2,6-dicarbonylpiperidin-3-yl)-3-carbonylisoindolin-5-yl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-1-yl)-2H-indazol-5-yl)benzofuran-3-carboxamide Compound 162

[1049] Referring to the synthetic route A, compound 162 can be prepared, mass spectrum (M+H): 783.4

[1050] Example 163: Preparation of N-(2-(1-((1-(2-(2,6-dicarbonylpiperidin-3-yl)-3-carbonylisoindolin-5-yl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-1-yl)-2H-indazol-5-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-2-carboxamide Compound 163

[1051] Referring to the synthetic route A, compound 163 can be prepared, mass spectrum (M+H): 787.4

[1052] Example 164: Preparation of N-(2-(1-((1-(2-(2,6-dicarbonylpiperidin-3-yl)-3-carbonylisoindolin-5-yl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-1-yl)-2H-indazol-5-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-2-carboxamide Compound 164

[1053] Referring to the synthetic route A, compound 164 can be prepared, mass spectrum (M+H): 773.4

[1054] Example 165: Preparation of N-(2-(1-((1-(2-(2,6-dicarbonylpiperidin-3-yl)-3-carbonylisoindolin-5-yl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-1-yl)-2H-indazol-5-yl)-4,5,6,7-tetrahydro-1H-indazole-3-carboxamide Compound 165

[1055] Referring to the synthetic route A, compound 165 can be prepared, mass spectrum (M+H): 787.4

[1056] Example 166: Preparation of N-(2-(1-((1-(2-(2,6-dicarbonylpiperidin-3-yl)-1-carbonylisoindolin-5-yl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-1-yl)-2H-indazol-5-yl)-2-(pyridin-4-yl)thiazole-4-carboxamide Compound 166

[1057] Referring to the synthetic route A, compound 166 can be prepared, mass spectrum (M+H): 827.3

[1058] Example 167: Preparation of N-(2-(1-((1-(2-(2,6-dicarbonylpiperidin-3-yl)-1-carbonylisoindolin-5-yl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-1-yl)-2H-indazol-5-yl)imidazo[1,2-b]pyridazine-6-carboxamide Compound 167

[1059] Referring to the synthetic route A, compound 167 can be prepared, mass spectrum (M+H): 784.4

[1060] Example 168: Preparation of N-(2-(1-((1-(2-(2,6-dicarbonylpiperidin-3-yl)-1-carbonylisoindolin-5-yl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-1-yl)-2H-indazol-5-yl)imidazo[1,2-a]pyridine-8-carboxamide Compound 168

[1061] Referring to the synthetic route D, compound 168 can be prepared, mass spectrum (M+H): 783.4

[1062] Example 169: Preparation of N-(2-(1-((1-(2-(2,6-dicarbonylpiperidin-3-yl)-1-carbonylisoindolin-5-yl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-1-yl)-2H-indazol-5-yl)-1H-benzo[d]imidazole-4-carboxamide Compound 169

[1063] Referring to the synthetic route A, compound 169 can be prepared, mass spectrum (M+H): 783.4

[1064] Example 170: Preparation of N-(2-(1-((1-(2-(2,6-dicarbonylpiperidin-3-yl)-1-carbonylisoindolin-5-yl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-1-yl)-2H-indazol-5-yl)-[1,2,4]triazolo[4,3-a]pyridine-8-carboxamide Compound 170

[1065] Referring to the synthetic route B, compound 170 can be prepared, mass spectrum (M+H): 784.4

[1066] Example 171: Preparation of N-(2-(1-((1-(2-(2,6-dicarbonylpiperidin-3-yl)-1-carbonylisoindolin-5-yl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-1-yl)-2H-indazol-5-yl)-[1,2,4]triazolo[4,3-a]pyridine-7-carboxamide Compound 171

[1067] Referring to the synthetic route A, compound 171 can be prepared, mass spectrum (M+H): 784.4

[1068] Example 172: Preparation of N-(2-(1-((1-(2-(2,6-dicarbonylpiperidin-3-yl)-1-carbonylisoindolin-5-yl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-1-yl)-2H-indazol-5-yl)pyrazolo[1,5-a]pyridine-3-carboxamide Compound 172

[1069] Referring to the synthetic route D, compound 172 can be prepared, mass spectrum (M+H): 783.4

[1070] Example 173: Preparation of 4-amino-N-(2-(1-((1-(2-(2,6-dicarbonylpiperidin-3-yl)-1-carbonylisoindolin-5-yl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-1-yl)-2H-indazol-5-yl)thieno[3,2-d]pyrimidine-7-carboxamide Compound 173

[1071] Referring to the synthetic route A, compound 173 can be prepared, mass spectrum (M+H): 816.3

[1072] Example 174: Preparation of N-(2-(1-((1-(2-(2,6-dicarbonylpiperidin-3-yl)-1-carbonylisoindolin-5-yl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-1-yl)-2H-indazol-5-yl)imidazo[1,2-b]pyridazine-2-carboxamide Compound 174

[1073] Referring to the synthetic route D, compound 174 can be prepared, mass spectrum (M+H): 784.4

[1074] Example 175: Preparation of N-(2-(1-((1-(2-(2,6-dicarbonylpiperidin-3-yl)-1-carbonylisoindolin-5-yl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-1-yl)-2H-indazol-5-yl)-3H-imidazo[4,5-b]pyridine-7-carboxamide Compound 175

[1075] Referring to the synthetic route A, compound 175 can be prepared, mass spectrum (M+H): 784.4

[1076] Example 176: Preparation of N-(2-(1-((1-(2-(2,6-dicarbonylpiperidin-3-yl)-1-carbonylisoindolin-5-yl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-1-yl)-2H-indazol-5-yl)-2-(2-methylpyridin-4-yl)thiazole-4-carboxamide Compound 176

[1077] Referring to the synthetic route D, compound 176 can be prepared, mass spectrum (M+H): 841.4

[1078] Example 177: Preparation of N-(2-(1-((1-(2-(2,6-dicarbonylpiperidin-3-yl)-1-carbonylisoindolin-5-yl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-1-yl)-2H-indazol-5-yl)-2-(pyrimidin-2-yl)oxazole-4-carboxamide Compound 177

[1079] Referring to the synthetic route A, compound 177 can be prepared, mass spectrum (M+H): 812.4

[1080] Example 178: Preparation of N-(2-(1-((1-(2-(2,6-dicarbonylpiperidin-3-yl)-1-carbonylisoindolin-5-yl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-1-yl)-2H-indazol-5-yl)-2-(1-methyl-1H-pyrazol-4-yl)oxazole-4-carboxamide Compound 178

[1081] Referring to the synthetic route D, compound 178 can be prepared, mass spectrum (M+H): 814.4

[1082] Example 179: Preparation of N-(2-(1-((1-(2-(2,6-dicarbonylpiperidin-3-yl)-1-carbonylisoindolin-5-yl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-1-yl)-2H-indazol-5-yl)-4-phenoxybenzamide Compound 179

[1083] Referring to the synthetic route A, compound 179 can be prepared, mass spectrum (M+H): 835.4

[1084] Example 180: Preparation of N-(2-(1-((1-(2-(2,6-dicarbonylpiperidin-3-yl)-1-carbonylisoindolin-5-yl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-1-yl)-2H-indazol-5-yl)-2-phenylthiazole-4-carboxamide Compound 180

[1085] Referring to the synthetic route A, compound 180 can be prepared, mass spectrum (M+H): 826.3

[1086] Example 181: Preparation of N-(2-(1-((1-(2-(2,6-dicarbonylpiperidin-3-yl)-1-carbonylisoindolin-5-yl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-1-yl)-2H-indazol-5-yl)-1H-pyrrolo[3,2-c]pyridine-3-carboxamide Compound 181

[1087] Referring to the synthetic route B, compound 181 can be prepared, mass spectrum (M+H): 783.4

[1088] Example 182: Preparation of N-(2-(1-((1-(2-(2,6-dicarbonylpiperidin-3-yl)-1-carbonylisoindolin-5-yl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-1-yl)-2H-indazol-5-yl)benzofuran-3-carboxamide Compound 182

[1089] Referring to the synthetic route B, compound 182 can be prepared, mass spectrum (M+H): 783.4

[1090] Example 183: Preparation of N-(2-(1-((1-(2-(2,6-dicarbonylpiperidin-3-yl)-1-carbonylisoindolin-5-yl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-1-yl)-2H-indazol-5-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-2-carboxamide Compound 183

[1091] Referring to the synthetic route B, compound 183 can be prepared, mass spectrum (M+H): 787.4

[1092] Example 184: Preparation of N-(2-(1-((1-(2-(2,6-dicarbonylpiperidin-3-yl)-1-carbonylisoindolin-5-yl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-1-yl)-2H-indazol-5-yl)-4,5,6,7-tetrahydro-1H-indazole-3-carboxamide Compound 184

[1093] Referring to the synthetic route A, compound 184 can be prepared, mass spectrum (M+H): 787.4

[1094] Example 185: Preparation of (S)-N-(2-(1-((1-(4-((2,6-dicarbonylpiperidin-3-yl)carbamoyl)-3-methoxyphenyl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-1-yl)-2H-indazol-5-yl)benzo[d]thiazole-7-carboxamide Compound 185

[1095] Referring to the synthetic route A, compound 185 can be prepared, mass spectrum (M+H): 818.3

[1096] Example 186: Preparation of (S)-N-(2-(1-((1-(4-((2,6-dicarbonylpiperidin-3-yl)carbamoyl)-3-methoxyphenyl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-1-yl)-2H-indazol-5-yl)-1-methyl-3-(trifluoromethyl)-1H-pyrazole-4-carboxamide Compound 186

[1097] Referring to the synthetic route A, compound 186 can be prepared, mass spectrum (M+H): 833.4

[1098] Example 187: Preparation of (S)-N-(2-(1-((1-(4-((2,6-dicarbonylpiperidin-3-yl)carbamoyl)-3-methoxyphenyl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-1-yl)-2H-indazol-5-yl)-4H-thieno[3,2-b]pyrrole-5-carboxamide Compound 187

[1099] Referring to the synthetic route C, compound 187 can be prepared, mass spectrum (M+H): 806.3

[1100] Example 188: Preparation of (S)-N-(2-(1-((1-(4-((2,6-dicarbonylpiperidin-3-yl)carbamoyl)-3-methoxyphenyl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-1-yl)-2H-indazol-5-yl)quinoline-4-carboxamide Compound 188

[1101] Referring to the synthetic route A, compound 188 can be prepared, mass spectrum (M+H): 812.4

[1102] Example 189: Preparation of (S)-N-(2-(1-((1-(4-((2,6-dicarbonylpiperidin-3-yl)carbamoyl)-3-methoxyphenyl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-1-yl)-2H-indazol-5-yl)quinoline-5-carboxamide Compound 189

[1103] Referring to the synthetic route A, compound 189 can be prepared, mass spectrum (M+H): 812.4

[1104] Example 190: Preparation of (S)-N-(2-(1-((1-(4-((2,6-dicarbonylpiperidin-3-yl)carbamoyl)-3-methoxyphenyl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-1-yl)-2H-indazol-5-yl)imidazo[1,2-a]pyridine-6-carboxamide Compound 190

[1105] Referring to the synthetic route C, compound 190 can be prepared, mass spectrum (M+H): 801.4

[1106] Example 191: Preparation of (S)-N-(2-(1-((1-(4-((2,6-dicarbonylpiperidin-3-yl)carbamoyl)-3-methoxyphenyl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-1-yl)-2H-indazol-5-yl)imidazo[1,2-a]pyridine-7-carboxamide Compound 191

[1107] Referring to the synthetic route C, compound 191 can be prepared, mass spectrum (M+H): 801.4

[1108] Example 192: Preparation of (S)-N-(2-(1-((1-(4-((2,6-dicarbonylpiperidin-3-yl)carbamoyl)-3-methoxyphenyl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-1-yl)-2H-indazol-5-yl)-1,5-naphthyridine-3-carboxamide Compound 192

[1109] Referring to the synthetic route A, compound 192 can be prepared, mass spectrum (M+H): 813.4

[1110] Example 193: Preparation of (S)-N-(2-(1-((1-(4-((2,6-dicarbonylpiperidin-3-yl)carbamoyl)-3-methoxyphenyl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-1-yl)-2H-indazol-5-yl)-7H-pyrrolo[2,3-b]pyridine-4-carboxamide Compound 193

[1111] Referring to the synthetic route A, compound 193 can be prepared, mass spectrum (M+H): 801.4

[1112] Example 194: Preparation of (S)-N-(2-(1-((1-(4-((2,6-dicarbonylpiperidin-3-yl)carbamoyl)-3-methoxyphenyl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-1-yl)-2H-indazol-5-yl)benzo[c][1,2,5]thiadiazole-4-carboxamide Compound 194

[1113] Referring to the synthetic route B, compound 194 can be prepared, mass spectrum (M+H): 819.3

[1114] Example 195: Preparation of (S)-N-(2-(1-((1-(4-((2,6-dicarbonylpiperidin-3-yl)carbamoyl)-3-methoxyphenyl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-1-yl)-2H-indazol-5-yl)-1H-indole-4-carboxamide Compound 195

[1115] Referring to the synthetic route A, compound 195 can be prepared, mass spectrum (M+H): 800.4

[1116] Example 196: Preparation of (S)-N-(2-(1-((1-(4-((2,6-dicarbonylpiperidin-3-yl)carbamoyl)-3-methoxyphenyl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-1-yl)-2H-indazol-5-yl)-1H-indole-5-carboxamide Compound 196

[1117] Referring to the synthetic route B, compound 196 can be prepared, mass spectrum (M+H): 800.4

[1118] Example 197: Preparation of (S)-N-(2-(1-((1-(4-((2,6-dicarbonylpiperidin-3-yl)carbamoyl)-3-methoxyphenyl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-1-yl)-2H-indazol-5-yl)quinoline-6-carboxamide Compound 197

[1119] Referring to the synthetic route C, compound 197 can be prepared, mass spectrum (M+H): 812.4

[1120] Example 198: Preparation of (S)-N-(2-(1-((1-(4-((2,6-dicarbonylpiperidin-3-yl)carbamoyl)-3-methoxyphenyl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-1-yl)-2H-indazol-5-yl)benzo[b]thiophene-3-carboxamide Compound 198

[1121] Referring to the synthetic route A, compound 198 can be prepared, mass spectrum (M+H): 817.4

[1122] Example 199: Preparation of (S)-N-(2-(1-((1-(4-((2,6-dicarbonylpiperidin-3-yl)carbamoyl)-3-methoxyphenyl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-1-yl)-2H-indazol-5-yl)-1-methyl-5-phenyl-1H-pyrazole-4-carboxamide Compound 199

[1123] Referring to the synthetic route A, compound 199 can be prepared, mass spectrum (M+H): 841.4

[1124] Example 200: Preparation of (S)-N-(2-(1-((1-(4-((2,6-dicarbonylpiperidin-3-yl)carbamoyl)-3-methoxyphenyl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-1-yl)-2H-indazol-5-yl)imidazo[1,2-b]pyridazine-6-carboxamide Compound 200

[1125] Referring to the synthetic route C, compound 200 can be prepared, mass spectrum (M+H): 802.4

[1126] Example 201: Preparation of (S)-N-(2-(1-((1-(4-((2,6-dicarbonylpiperidin-3-yl)carbamoyl)-3-methoxyphenyl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-1-yl)-2H-indazol-5-yl)imidazo[1,5-a]pyridine-8-carboxamide Compound 201

[1127] Referring to the synthetic route C, compound 201 can be prepared, mass spectrum (M+H): 801.4

[1128] Example 202: Preparation of (S)-N-(2-(1-((1-(4-((2,6-dicarbonylpiperidin-3-yl)carbamoyl)-3-methoxyphenyl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-1-yl)-2H-indazol-5-yl)imidazo[1,2-a]pyridine-8-carboxamide Compound 202

[1129] Referring to the synthetic route C, compound 202 can be prepared, mass spectrum (M+H): 801.4

[1130] Example 203: Preparation of (S)-N-(2-(1-((1-(4-((2,6-dicarbonylpiperidin-3-yl)carbamoyl)-3-methoxyphenyl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-1-yl)-2H-indazol-5-yl)isoquinoline-8-carboxamide Compound 203

[1131] Referring to the synthetic route C, compound 203 can be prepared, mass spectrum (M+H): 812.4

[1132] Example 204: Preparation of (S)-N-(2-(1-((1-(4-((2,6-dicarbonylpiperidin-3-yl)carbamoyl)-3-methoxyphenyl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-1-yl)-2H-indazol-5-yl)quinoxaline-5-carboxamide Compound 204

[1133] Referring to the synthetic route A, compound 204 can be prepared, mass spectrum (M+H): 813.4

[1134] Example 205: Preparation of (S)-N-(2-(1-((1-(4-((2,6-dicarbonylpiperidin-3-yl)carbamoyl)-3-methoxyphenyl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-1-yl)-2H-indazol-5-yl)-7H-pyrrolo[2,3-b]pyridine-5-carboxamide Compound 205

[1135] Referring to the synthetic route A, compound 205 can be prepared, mass spectrum (M+H): 801.4

[1136] Example 206: Preparation of (S)-N-(2-(1-((1-(4-((2,6-dicarbonylpiperidin-3-yl)carbamoyl)-3-methoxyphenyl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-1-yl)-2H-indazol-5-yl)-2-methylimidazo[1,2-a]pyridine-6-carboxamide Compound 206

[1137] Referring to the synthetic route D, compound 206 can be prepared, mass spectrum (M+H): 815.4

[1138] Example 207: Preparation of (S)-N-(2-(1-((1-(4-((2,6-dicarbonylpiperidin-3-yl)carbamoyl)-3-methoxyphenyl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-1-yl)-2H-indazol-5-yl)isoquinoline-5-carboxamide Compound 207

[1139] Referring to the synthetic route A, compound 207 can be prepared, mass spectrum (M+H): 812.4

[1140] Example 208: Preparation of (S)-N-(2-(1-((1-(4-((2,6-dicarbonylpiperidin-3-yl)carbamoyl)-3-methoxyphenyl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-1-yl)-2H-indazol-5-yl)-3-methylimidazo[1,2-a]pyridine-6-carboxamide Compound 208

[1141] Referring to the synthetic route D, compound 208 can be prepared, mass spectrum (M+H): 815.4

[1142] Example 209: Preparation of (S)-N-(2-(1-((1-(4-((2,6-dicarbonylpiperidin-3-yl)carbamoyl)-3-methoxyphenyl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-1-yl)-2H-indazol-5-yl)-1H-benzo[d]imidazole-4-carboxamide Compound 209

[1143] Referring to the synthetic route A, compound 209 can be prepared, mass spectrum (M+H): 801.4

[1144] Example 210: Preparation of (S)-N-(2-(1-((1-(4-((2,6-dicarbonylpiperidin-3-yl)carbamoyl)-3-methoxyphenyl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-1-yl)-2H-indazol-5-yl)-1-(3-methoxyphenyl)-1H-pyrazole-4-carboxamide Compound 210

[1145] Referring to the synthetic route D, compound 210 can be prepared, mass spectrum (M+H): 857.4

[1146] Example 211: Preparation of (S)-N-(2-(1-((1-(4-((2,6-dicarbonylpiperidin-3-yl)carbamoyl)-3-methoxyphenyl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-1-yl)-2H-indazol-5-yl)benzo[c][1,2,5]thiadiazole-5-carboxamide Compound 211

[1147] Referring to the synthetic route A, compound 211 can be prepared, mass spectrum (M+H): 819.3

[1148] Example 212: Preparation of (S)-4-amino-N-(2-(1-((1-(4-((2,6-dicarbonylpiperidin-3-yl)carbamoyl)-3-methoxyphenyl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-1-yl)-2H-indazol-5-yl)thieno[3,2-d]pyrimidine-7-carboxamide Compound 212

[1149] Referring to the synthetic route A, compound 212 can be prepared, mass spectrum (M+H): 834.3

[1150] Example 213: Preparation of (S)-N-(2-(1-((1-(4-((2,6-dicarbonylpiperidin-3-yl)carbamoyl)-3-methoxyphenyl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-1-yl)-2H-indazol-5-yl)-5-methyl-1-phenyl-1H-pyrazole-4-carboxamide Compound 213

[1151] Referring to the synthetic route B, compound 213 can be prepared, mass spectrum (M+H): 841.4

[1152] Example 214: Preparation of (S)-N-(2-(1-((1-(4-((2,6-dicarbonylpiperidin-3-yl)carbamoyl)-3-methoxyphenyl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-1-yl)-2H-indazol-5-yl)imidazo[1,2-b]pyridazine-2-carboxamide Compound 214

[1153] Referring to the synthetic route A, compound 214 can be prepared, mass spectrum (M+H): 802.4

[1154] Example 215: Preparation of (S)-N-(2-(1-((1-(4-((2,6-dicarbonylpiperidin-3-yl)carbamoyl)-3-methoxyphenyl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-1-yl)-2H-indazol-5-yl)imidazo[1,2-a]pyrazine-3-carboxamide Compound 215

[1155] Referring to the synthetic route A, compound 215 can be prepared, mass spectrum (M+H): 802.4

[1156] Example 216: Preparation of (S)-N-(2-(1-((1-(4-((2,6-dicarbonylpiperidin-3-yl)carbamoyl)-3-methoxyphenyl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-1-yl)-2H-indazol-5-yl)-1H-pyrrolo[3,2-c]pyridine-7-carboxamide Compound 216

[1157] Referring to the synthetic route D, compound 216 can be prepared, mass spectrum (M+H): 801.4

[1158] Example 217: Preparation of (S)-N-(2-(1-((1-(4-((2,6-dicarbonylpiperidin-3-yl)carbamoyl)-3-methoxyphenyl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-1-yl)-2H-indazol-5-yl)pyrazolo[1,5-b]pyridazine-3-carboxamide Compound 217

[1159] Referring to the synthetic route A, compound 217 can be prepared, mass spectrum (M+H): 802.4

[1160] Example 218: Preparation of (S)-N-(2-(1-((1-(4-((2,6-dicarbonylpiperidin-3-yl)carbamoyl)-3-methoxyphenyl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-1-yl)-2H-indazol-5-yl)-1H-indole-6-carboxamide Compound 218

[1161] Referring to the synthetic route C, compound 218 can be prepared, mass spectrum (M+H): 800.42

[1162] Example 219: Preparation of (S)-N-(2-(1-((1-(4-((2,6-dicarbonylpiperidin-3-yl)carbamoyl)-3-methoxyphenyl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-1-yl)-2H-indazol-5-yl)-3H-imidazo[4,5-b]pyridine-7-carboxamide Compound 219

[1163] Referring to the synthetic route C, compound 219 can be prepared, mass spectrum (M+H): 802.4

[1164] Example 220: Preparation of (S)-N-(2-(1-((1-(4-((2,6-dicarbonylpiperidin-3-yl)carbamoyl)-3-methoxyphenyl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-1-yl)-2H-indazol-5-yl)-7H-pyrrolo[2,3-d]pyrimidine-4-carboxamide Compound 220

[1165] Referring to the synthetic route C, compound 220 can be prepared, mass spectrum (M+H): 802.4

[1166] Example 221: Preparation of (S)-N-(2-(1-((1-(4-((2,6-dicarbonylpiperidin-3-yl)carbamoyl)-3-methoxyphenyl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-1-yl)-2H-indazol-5-yl)-3H-imidazo[4,5-c]pyridine-7-carboxamide Compound 221

[1167] Referring to the synthetic route A, compound 221 can be prepared, mass spectrum (M+H): 802.4

[1168] Example 222: Preparation of (S)-N-(2-(1-((1-(4-((2,6-dicarbonylpiperidin-3-yl)carbamoyl)-3-methoxyphenyl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-1-yl)-2H-indazol-5-yl)pyrazolo[1,5-a]pyrimidine-6-carboxamide Compound 222

[1169] Referring to the synthetic route D, compound 222 can be prepared, mass spectrum (M+H): 802.4

[1170] Example 223: Preparation of (S)-N-(2-(1-((1-(4-((2,6-dicarbonylpiperidin-3-yl)carbamoyl)-3-methoxyphenyl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-1-yl)-2H-indazol-5-yl)-1H-pyrazolo[4,3-c]pyridine-4-carboxamide Compound 223

[1171] Referring to the synthetic route A, compound 223 can be prepared, mass spectrum (M+H): 802.4

[1172] Example 224: Preparation of (S)-N-(2-(1-((1-(4-((2,6-dicarbonylpiperidin-3-yl)carbamoyl)-3-methoxyphenyl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-1-yl)-2H-indazol-5-yl)-2-(pyridin-4-yl)thiazole-4-carboxamide Compound 224

[1173] Referring to the synthetic route A, compound 224 can be prepared, mass spectrum (M+H): 845.3

[1174] Example 225: Preparation of (S)-N-(2-(1-((1-(4-((2,6-dicarbonylpiperidin-3-yl)carbamoyl)-3-methoxyphenyl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-1-yl)-2H-indazol-5-yl)benzofuran-4-carboxamide Compound 225

[1175] Referring to the synthetic route A, compound 225 can be prepared, mass spectrum (M+H): 801.4

[1176] Example 226: Preparation of (S)-N-(2-(1-((1-(4-((2,6-dicarbonylpiperidin-3-yl)carbamoyl)-3-methoxyphenyl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-1-yl)-2H-indazol-5-yl)imidazo[1,2-b]pyridazine-3-carboxamide Compound 226

[1177] Referring to the synthetic route A, compound 226 can be prepared, mass spectrum (M+H): 802.4

[1178] Example 227: Preparation of N-(2-(1-((1-(2-(2,6-dicarbonylpiperidin-3-yl)-3-carbonylisoindolin-5-yl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-1-yl)-2H-indazol-5-yl)-1-(4-fluorophenyl)-5-methyl-1H-pyrazole-4-carboxamide Compound 227

[1179] Referring to the synthetic route A, compound 227 can be prepared, mass spectrum (M+H): 841.4

[1180] Example 228: Preparation of N-(2-(1-((1-(2-(2,6-dicarbonylpiperidin-3-yl)-3-carbonylisoindolin-5-yl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-1-yl)-2H-indazol-5-yl)-1-methyl-3-(trifluoromethyl)-1H-pyrazole-4-carboxamide Compound 228

[1181] Referring to the synthetic route A, compound 228 can be prepared, mass spectrum (M+H): 815.4

[1182] Example 229: Preparation of N-(2-(1-((1-(2-(2,6-dicarbonylpiperidin-3-yl)-3-carbonylisoindolin-5-yl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-1-yl)-2H-indazol-5-yl)-4H-thieno[3,2-b]pyrrole-5-carboxamide Compound 229

[1183] Referring to the synthetic route A, compound 229 can be prepared, mass spectrum (M+H): 788.3

[1184] Example 230: Preparation of N-(2-(1-((1-(2-(2,6-dicarbonylpiperidin-3-yl)-3-carbonylisoindolin-5-yl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-1-yl)-2H-indazol-5-yl)quinoline-4-carboxamide Compound 230

[1185] Referring to the synthetic route A, compound 230 can be prepared, mass spectrum (M+H): 794.4

[1186] Example 231: Preparation of N-(2-(1-((1-(2-(2,6-dicarbonylpiperidin-3-yl)-3-carbonylisoindolin-5-yl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-1-yl)-2H-indazol-5-yl)quinoline-5-carboxamide Compound 231

[1187] Referring to the synthetic route A, compound 231 can be prepared, mass spectrum (M+H): 794.4

[1188] Example 232: Preparation of N-(2-(1-((1-(2-(2,6-dicarbonylpiperidin-3-yl)-3-carbonylisoindolin-5-yl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-1-yl)-2H-indazol-5-yl)imidazo[1,2-a]pyridine-6-carboxamide Compound 232

[1189] Referring to the synthetic route B, compound 232 can be prepared, mass spectrum (M+H): 783.4

[1190] Example 233: Preparation of N-(2-(1-((1-(2-(2,6-dicarbonylpiperidin-3-yl)-3-carbonylisoindolin-5-yl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-1-yl)-2H-indazol-5-yl)-1H-benzo[d]imidazole-6-carboxamide Compound 233

[1191] Referring to the synthetic route B, compound 233 can be prepared, mass spectrum (M+H): 783.4

[1192] Example 234: Preparation of N-(2-(1-((1-(2-(2,6-dicarbonylpiperidin-3-yl)-3-carbonylisoindolin-5-yl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-1-yl)-2H-indazol-5-yl)-7H-pyrrolo[2,3-b]pyridine-4-carboxamide Compound 234

[1193] Referring to the synthetic route B, compound 234 can be prepared, mass spectrum (M+H): 783.4

[1194] Example 235: Preparation of N-(2-(1-((1-(2-(2,6-dicarbonylpiperidin-3-yl)-3-carbonylisoindolin-5-yl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-1-yl)-2H-indazol-5-yl)isoquinoline-8-carboxamide Compound 235

[1195] Referring to the synthetic route A, compound 235 can be prepared, mass spectrum (M+H): 794.4

[1196] Example 236: Preparation of N-(2-(1-((1-(2-(2,6-dicarbonylpiperidin-3-yl)-3-carbonylisoindolin-5-yl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-1-yl)-2H-indazol-5-yl)quinoxaline-5-carboxamide Compound 236

[1197] Referring to the synthetic route A, compound 236 can be prepared, mass spectrum (M+H): 795.4

[1198] Example 237: Preparation of N-(2-(1-((1-(2-(2,6-dicarbonylpiperidin-3-yl)-3-carbonylisoindolin-5-yl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-1-yl)-2H-indazol-5-yl)-7H-pyrrolo[2,3-b]pyridine-5-carboxamide Compound 237

[1199] Referring to the synthetic route A, compound 237 can be prepared, mass spectrum (M+H): 783.4

[1200] Example 238: Preparation of N-(2-(1-((1-(2-(2,6-dicarbonylpiperidin-3-yl)-3-carbonylisoindolin-5-yl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-1-yl)-2H-indazol-5-yl)-2-methylimidazo[1,2-a]pyridine-6-carboxamide Compound 238

[1201] Referring to the synthetic route D, compound 238 can be prepared, mass spectrum (M+H): 797.4

[1202] Example 239: Preparation of N-(2-(1-((1-(2-(2,6-dicarbonylpiperidin-3-yl)-3-carbonylisoindolin-5-yl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-1-yl)-2H-indazol-5-yl)benzo[c][1,2,5]thiadiazole-4-carboxamide Compound 239

[1203] Referring to the synthetic route D, compound 239 can be prepared, mass spectrum (M+H): 801.3

[1204] Example 240: Preparation of N-(2-(1-((1-(2-(2,6-dicarbonylpiperidin-3-yl)-3-carbonylisoindolin-5-yl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-1-yl)-2H-indazol-5-yl)-1H-indole-4-carboxamide Compound 240

[1205] Referring to the synthetic route D, compound 240 can be prepared, mass spectrum (M+H): 782.4

[1206] Example 241: Preparation of N-(2-(1-((1-(2-(2,6-dicarbonylpiperidin-3-yl)-3-carbonylisoindolin-5-yl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-1-yl)-2H-indazol-5-yl)-1H-indole-5-carboxamide Compound 241

[1207] Referring to the synthetic route A, compound 241 can be prepared, mass spectrum (M+H): 782.4

[1208] Example 242: Preparation of N-(2-(1-((1-(2-(2,6-dicarbonylpiperidin-3-yl)-3-carbonylisoindolin-5-yl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-1-yl)-2H-indazol-5-yl)quinoline-6-carboxamide Compound 242

[1209] Referring to the synthetic route D, compound 242 can be prepared, mass spectrum (M+H): 794.4

[1210] Example 243: Preparation of N-(2-(1-((1-(2-(2,6-dicarbonylpiperidin-3-yl)-3-carbonylisoindolin-5-yl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-1-yl)-2H-indazol-5-yl)benzo[b]thiophene-3-carboxamide Compound 243

[1211] Referring to the synthetic route A, compound 243 can be prepared, mass spectrum (M+H): 799.3

[1212] Example 244: Preparation of N-(2-(1-((1-(2-(2,6-dicarbonylpiperidin-3-yl)-3-carbonylisoindolin-5-yl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-1-yl)-2H-indazol-5-yl)isoquinoline-5-carboxamide Compound 244

[1213] Referring to the synthetic route A, compound 244 can be prepared, mass spectrum (M+H): 794.4

[1214] Example 245: Preparation of N-(2-(1-((1-(2-(2,6-dicarbonylpiperidin-3-yl)-3-carbonylisoindolin-5-yl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-1-yl)-2H-indazol-5-yl)imidazo[1,5-a]pyridine-8-carboxamide Compound 245

[1215] Referring to the synthetic route A, compound 245 can be prepared, mass spectrum (M+H): 783.4

[1216] Example 246: Preparation of (S)-N-(2-(1-((1-(4-((2,6-dicarbonylpiperidin-3-yl)carbamoyl)-3-methoxyphenyl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-1-yl)-2H-indazol-5-yl)-1H-benzo[d]imidazole-6-carboxamide Compound 246

[1217] Referring to the synthetic route D, compound 246 can be prepared, mass spectrum (M+H): 801.4

[1218] Example 247: Preparation of (S)-N-(2-(1-((1-(4-((2,6-dicarbonylpiperidin-3-yl)carbamoyl)-3-methoxyphenyl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-1-yl)-2H-indazol-5-yl)-2-methyl-1H-benzo[d]imidazole-5-carboxamide Compound 247

[1219] Referring to the synthetic route D, compound 247 can be prepared, mass spectrum (M+H): 815.4

[1220] Example 248: Preparation of (S)-N-(2-(1-((1-(4-((2,6-dicarbonylpiperidin-3-yl)carbamoyl)-3-methoxyphenyl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-1-yl)-2H-indazol-5-yl)thieno[3,2-d]pyrimidine-4-carboxamide Compound 248

[1221] Referring to the synthetic route A, compound 248 can be prepared, mass spectrum (M+H): 819.3

[1222] Example 249: Preparation of (S)-N-(2-(1-((1-(4-((2,6-dicarbonylpiperidin-3-yl)carbamoyl)-3-methoxyphenyl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-1-yl)-2H-indazol-5-yl)thieno[2,3-c]pyridine-2-carboxamide Compound 249

[1223] Referring to the synthetic route A, compound 249 can be prepared, mass spectrum (M+H): 818.3

[1224] Example 250: Preparation of (S)-N-(2-(1-((1-(4-((2,6-dicarbonylpiperidin-3-yl)carbamoyl)-3-methoxyphenyl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-1-yl)-2H-indazol-5-yl)-1-methyl-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide Compound 250

[1225] Referring to the synthetic route A, compound 250 can be prepared, mass spectrum (M+H): 833.4

[1226] Example 251: Preparation of (S)-N-(2-(1-((1-(4-((2,6-dicarbonylpiperidin-3-yl)carbamoyl)-3-methoxyphenyl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-1-yl)-2H-indazol-5-yl)-[1,2,4]triazolo[4,3-a]pyridine-8-carboxamide Compound 251

[1227] Referring to the synthetic route C, compound 251 can be prepared, mass spectrum (M+H): 802.4

[1228] Example 252: Preparation of (S)-N-(2-(1-((1-(4-((2,6-dicarbonylpiperidin-3-yl)carbamoyl)-3-methoxyphenyl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-1-yl)-2H-indazol-5-yl)-[1,2,4]triazolo[4,3-a]pyridine-7-carboxamide Compound 252

[1229] Referring to the synthetic route C, compound 252 can be prepared, mass spectrum (M+H): 802.4

[1230] Example 253: Preparation of (S)-N-(2-(1-((1-(4-((2,6-dicarbonylpiperidin-3-yl)carbamoyl)-3-methoxyphenyl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-1-yl)-2H-indazol-5-yl)-1-phenyl-3-(trifluoromethyl)-1H-pyrazole-4-carboxamide Compound 253

[1231] Referring to the synthetic route C, compound 253 can be prepared, mass spectrum (M+H): 895.4

[1232] Example 254: Preparation of (S)-N-(2-(1-((1-(4-((2,6-dicarbonylpiperidin-3-yl)carbamoyl)-3-methoxyphenyl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-1-yl)-2H-indazol-5-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-3-carboxamide Compound 254

[1233] Referring to the synthetic route A, compound 254 can be prepared, mass spectrum (M+H): 805.4

[1234] Example 255: Preparation of (S)-N-(2-(1-((1-(4-((2,6-dicarbonylpiperidin-3-yl)carbamoyl)-3-methoxyphenyl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-1-yl)-2H-indazol-5-yl)pyrazolo[1,5-a]pyridine-3-carboxamide Compound 255

[1235] Referring to the synthetic route A, compound 255 can be prepared, mass spectrum (M+H): 801.4

[1236] Example 256: Preparation of (S)-N-(2-(1-((1-(4-((2,6-dicarbonylpiperidin-3-yl)carbamoyl)-3-methoxyphenyl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-1-yl)-2H-indazol-5-yl)-1H-indole-7-carboxamide Compound 256

[1237] Referring to the synthetic route A, compound 256 can be prepared, mass spectrum (M+H): 800.4

[1238] Example 257: Preparation of (S)-N-(2-(1-((1-(4-((2,6-dicarbonylpiperidin-3-yl)carbamoyl)-3-methoxyphenyl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-1-yl)-2H-indazol-5-yl)imidazo[1,5-a]pyridine-8-carboxamide Compound 257

[1239] Referring to the synthetic route C, compound 257 can be prepared, mass spectrum (M+H): 801.4

[1240] Example 258: Preparation of N-(2-(1-((1-(2-(2,6-dicarbonylpiperidin-3-yl)-3-carbonylisoindolin-5-yl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-1-yl)-2H-indazol-5-yl)-2-methyl-1H-benzo[d]imidazole-5-carboxamide Compound 258

[1241] Referring to the synthetic route A, compound 258 can be prepared, mass spectrum (M+H): 797.4

[1242] Example 259: Preparation of N-(2-(1-((1-(2-(2,6-dicarbonylpiperidin-3-yl)-3-carbonylisoindolin-5-yl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-1-yl)-2H-indazol-5-yl)-3-methylimidazo[1,2-a]pyridine-6-carboxamide Compound 259

[1243] Referring to the synthetic route C, compound 259 can be prepared, mass spectrum (M+H): 797.4

[1244] Example 260: Preparation of N-(2-(1-((1-(2-(2,6-dicarbonylpiperidin-3-yl)-3-carbonylisoindolin-5-yl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-1-yl)-2H-indazol-5-yl)-1-(3-methoxyphenyl)-1H-pyrazole-4-carboxamide Compound 260 [1245...

Claims

1. A compound of formula (I), its stereoisomers, N-oxides, deuterated derivatives, pharmaceutically acceptable salts or prodrugs thereof: Where, is a single bond or a double bond; W1, W2, W3, and W4 are each independently C═O, CH, CH2, O, N, or CR 1 or NR 1 ; R 1 For hydrogen, halogen, C 1-6 Alkyl or C 1-6 alkyl halide; R x is hydrogen or a 4- to 8-membered nitrogen-containing heterocycloalkyl group containing at least one nitrogen atom and 0 to 3 heteroatoms independently selected from N, O or S as ring atoms; Lx is selected from *-C(O)NH-** or *-NH-C(O)-**; wherein, The position indicated by "*" indicates that it is connected to ring A, and the position indicated by "**" indicates that it is connected to the other side group of Lx; Ring A is: (i) an 8- to 10-membered biheteroaryl group; the 8- to 10-membered biheteroaryl group is formed by condensing a 5- or 6-membered monoheteroaryl ring with a 5- or 6-membered monoheteroaryl ring; (ii) an 8- to 10-membered biheteroaryl group; the 8- to 10-membered biheteroaryl group is formed by condensing a 5- or 6-membered monoheteroaryl ring with a 5- or 6-membered monocyclic heterocycloalkyl ring; or (iii) a 9- or 10-membered biheteroaryl group; the 9- or 10-membered biheteroaryl group is formed by condensing a benzene ring with a 5- or 6-membered monoheteroaryl ring; (iv) a 5- or 6-membered monoheteroaryl group; or (v)C 6-8 aryl; R y For hydrogen, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl, -OR a -、-NR b R c , 5- or 6-membered heteroaryl or C 6-8 Aryl, wherein the 5 or 6 membered monoheteroaryl, C 6-8 The aryl group is optionally substituted with one or more R 1 replace; R 1 Halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy or C 3-6 Cycloalkyl; R a C 1-6 Alkyl or C 6-8 aryl; R b 、R c are each independently hydrogen or C 1-3 alkyl; y is 0, 1, 2, 3, or 4; L is in, The position shown indicates connection with E3. The position shown indicates connection to ring A; Q1, Q2, and Q3 are each independently a 4- to 12-membered nitrogen-containing heterocycloalkyl group, wherein the 4- to 12-membered nitrogen-containing heterocycloalkyl group contains at least one nitrogen atom as a ring atom; the 4- to 12-membered nitrogen-containing heterocycloalkyl group is optionally substituted with one or more substituents selected from halogen and hydroxy; L1, L2, L3, and L4 are each independently -CR L1 R L2 -、-NR L3 -、-CR L1 R L2 -NR L3 -or-NR L3 -CR L1 R L2 -; R L1 、R L2 、R L3 are independently hydrogen, halogen, C 1-6 Alkyl or C 1-6 alkyl halide; m1, m2, m3, m4, and m5 are each independently 0 or 1; E3 is the ubiquitin ligase binding group.

2. The compound according to claim 1, its stereoisomer, N-oxide, deuterated derivative, pharmaceutically acceptable salt or prodrug thereof: wherein, The 8- to 10-membered biheteroaryl group formed by condensing a 5- or 6-membered monoheteroaryl ring with a 5- or 6-membered monoheteroaryl ring in Ring A has a structure represented by Formula (A1) or Formula (A2): Among them, U1 is N or CR U1 ; U2 is N or CR U2 ; U3 is N or CR U3 ; U4 is N or CR U4 ; U5 is N or CR U5 ; U6 is N or CR U6 ; U7 is N or CR U7 ; U8 is N or CR U8 ; and at least one of U1, U2, U3, U4, U5, U6, U7, U8 is N; R U1 、R U2 、R U3 、R U4 、R U5 、R U6 、R U7 、R U8 are each independently hydrogen or R y .

3. The compound according to claim 1, its stereoisomer, N-oxide, deuterated derivative, pharmaceutically acceptable salt or prodrug thereof: wherein, The 8- to 10-membered biheteroaryl group formed by condensing a 5- or 6-membered monoheteroaryl ring with a 5- or 6-membered monoheteroaryl ring in Ring A has a structure represented by Formula (A3) or Formula (A4): Where Z1 is N or CR Z1 ; Z2 is NR Z2 , O or S; Z3 is N or CR Z3 ; Z4 is N or CR Z4 ; Z5 is N or CR Z5 ; Z6 is N or CR Z6 ; and at least one of Z3, Z4, Z5, and Z6 is N; R Z0 、R Z1 、R Z2 、R Z3 、R Z4 、R Z5 、R Z6 are each independently hydrogen or R y .

4. The compound according to claim 1, its stereoisomer, N-oxide, deuterated derivative, pharmaceutically acceptable salt or prodrug thereof: wherein, The 8- to 10-membered biheteroaryl group formed by condensing a 5- or 6-membered monoheteroaryl ring with a 5- or 6-membered monoheteroaryl ring in Ring A has a structure represented by formula (A5): Among them, P1 is NR P1 , O or S; P2 is NR P2 , O or S; P3 is N or CR P3 ; P4 is N or CR P4 ; and at least one of P3 and P4 is N; R P1 、R P2 、R P3 、R P4 are each independently hydrogen or R y .

5. The compound according to claim 1, its stereoisomers, N-oxides, deuterated derivatives, pharmaceutically acceptable salts or prodrugs thereof: wherein, The 8- to 10-membered biheteroaryl group formed by condensing a 5- or 6-membered monoheteroaryl ring with a 5- or 6-membered monoheteroaryl ring in Ring A has a structure represented by formula (A6): Among them, V1 is N or CR V1 ; V2 is N or CR V2 ; V3 is N or CR V3 ; V4 is N or CR V4 ; V5 is N or CR V5 ; V6 is N or CR V6 ; V7 is N or CR V7 ; V8 is N or CR V8 ; V9 is N or CR V9 ; and at least one of V1, V2, V3, V4, V5, V6, V7, V8, and V9 is N; R V1 、R V2 、R V3 、R V4 、R V5 、R V6 、R V7 、R V8 、R V9 are each independently hydrogen or R y .

6. The compound according to claim 1, its stereoisomer, N-oxide, deuterated derivative, pharmaceutically acceptable salt or prodrug thereof: wherein, The 8- to 10-membered biheteroaryl group formed by condensing a 5- or 6-membered monoheteroaryl ring with a 5- or 6-membered monocyclic heterocycloalkyl ring in Ring A is represented by Formula (A7), Formula (A8), (A9) or (A10): Where H1 is N or CR H1 ; H2 is N or CR H2 ; H3 is N or CR H3 ; H4 is NR H4a , O, S or CR H4b R H4c ; H5 is NR H5a , O, S or CR H5b R H5c ; H6 is NR H6a , O, S or CR H6b R H6c ; H7 is NR H7a , O, S or CR H7b R H7c ; R H0 、R H1 、R H2 、R H3 、R H4a 、R H4b 、R H4c 、R H5a 、R H5b 、R H5c 、R H6a 、R H6b 、R H6c 、R H7a 、R H7b 、R H7c are each independently hydrogen or R y ; G1 is N or CR G1 ; G2 is NR G2a , O, S or CR G2b R G2c ; G3 is NR G3a , O, S or CR G3b R G3c ; G4 is NR G4a , O, S or CR G4b R G4c ; G5 is NR G5a , O, S or CR G5b R G5c ; G6 is NR G6a , O, S or CR G6b R G6c ; R G0 、R G1 、R G2a 、R G2b 、R G2c 、R G3a 、R G3b 、R G3c 、R G4a 、R G4b 、R G4c 、R G5a 、R G5b 、R G5c 、R G6a 、R G6b are each independently hydrogen or R y .

7. The compound according to claim 1, its stereoisomer, N-oxide, deuterated derivative, pharmaceutically acceptable salt or prodrug thereof: wherein, In the 9- or 10-membered biheteroaryl group formed by condensing a benzene ring with a 5- or 6-membered monoheteroaryl ring in Ring A, the 5- or 6-membered monoheteroaryl ring is selected from the following group: Among them, R D is hydrogen or R y ; The two carbon atoms represented as being connected are adjacent pairs of carbon atoms that are shared when fused to other rings.

8. The compound according to claim 1, its stereoisomer, N-oxide, deuterated derivative, pharmaceutically acceptable salt or prodrug thereof: wherein, R y Selected from: halogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, methoxy, ethoxy, propoxy, isopropyloxy, butoxy, tert-butoxy, -NH2, -NHCH3, -N(CH3)2, fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl, trifluoroethyl, thienyl, N-alkylpyrrolidonyl, furyl, thiazolyl, isothiazolyl, imidazolyl, oxazolyl, pyrrolyl, pyrazolyl, triazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, tetrazolyl, isoxazolyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, phenyl, naphthyl, -O-thienyl, -ON-alkylpyrrolidonyl, -O-furyl, -O-thiazolyl, -O-isothiazolyl, -O-imidazolyl, -O-oxazolyl, -O-pyrrolyl, -O-pyrazolyl, -O-triazolyl, -O-1,2,3-triazole yl, -O-1,2,4-triazolyl, -O-1,2,5-triazolyl, -O-1,3,4-triazolyl, -O-tetrazolyl, -O-isoxazolyl, -O-oxadiazolyl, -O-1,2,3-oxadiazolyl, -O-1,2,4-oxadiazolyl, -O-1,2,5-oxadiazolyl, -O-1,3,4-oxadiazolyl, -O-thiadiazolyl, -O-pyridinyl, -O-pyridazinyl, -O-pyrimidinyl, -O-pyrazinyl, -O-phenyl; the thienyl, N-alkylpyrrolidonyl, furyl, thiazolyl, isothiazolyl, imidazolyl, oxazolyl, pyrrolyl, pyrazolyl, triazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, tetrazolyl, isoxazolyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, phenyl, naphthyl, optionally substituted with one or more F, Cl, Br, I, methyl or ethyl; Preferably, R y Selected from: halogen, amino, methyl, tert-butyl, trifluoromethyl, methoxy, 9. The compound according to claim 1, its stereoisomer, N-oxide, deuterated derivative, pharmaceutically acceptable salt or prodrug thereof: wherein, Ring A is selected from the following groups: The group is optionally replaced by one or more R y Substituted; preferably, Ring A is selected from:

10. The compound according to claim 1, its stereoisomer, N-oxide, deuterated derivative, pharmaceutically acceptable salt or prodrug thereof: wherein, R x is a 4- to 8-membered nitrogen-containing heterocycloalkyl group containing 1 or 2 nitrogen atoms.

11. The compound according to claim 1, its stereoisomer, N-oxide, deuterated derivative, pharmaceutically acceptable salt or prodrug thereof: wherein, Lx is selected from *-C(O)NH-**; wherein the position indicated by "*" indicates connection with ring A, and the position indicated by "**" indicates connection with the other side group of Lx.

12. The compound according to claim 1, its stereoisomer, N-oxide, deuterated derivative, pharmaceutically acceptable salt or prodrug thereof: wherein, The compound is a compound represented by formula (IA1) or formula (IA2): Where, E3, L, W1, W2, W3, W4, R X 、L X , Ring A are defined as above; F1 is NR F1 , O or S; F2 is N or CR F2 ; F3 is N or CR F3 ; F4 is N or CR F4 ; and at least one of F1, F2, F3, F4 is N; R F1 、R F2 、R F3 、R F4 are each independently hydrogen or R 1 ; K1 is NR K1 or CR K2 ; K2 is N or CR K2 ; K3 is N or CR K3 ; K4 is N or CR K4 ; K5 is N or CR K5 ; and at least one of K1, K2, K3, K4, K5 is N; R K1 、R K2 、R K3 、R K4 、R K5 are each independently hydrogen or R 1 .

13. The compound according to claim 1, its stereoisomer, N-oxide, deuterated derivative, pharmaceutically acceptable salt or prodrug thereof: wherein, The compound is a compound represented by formula (IB1), formula (IB2), formula (IB3), formula (IB4) or formula (IB5): Where, E3, L, W1, W2, W3, W4, R X 、L X 、R y , y are defined as before.

14. The compound according to claim 1, its stereoisomer, N-oxide, deuterated derivative, pharmaceutically acceptable salt or prodrug thereof: wherein, The 4 to 12-membered nitrogen-containing heterocycloalkyl group is selected from: X1, X2, X3, and X4 are each independently N or -CR d ; X5 is a single bond, -O-, -S-, or -NR a -or-NR e R f -; n1, n2, n3, n4, n5 are each independently 0, 1, 2 or 3; Among them, R d 、R e 、R f are independently hydrogen, hydroxy, halogen, -CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy or C 3-6 Cycloalkyl.

15. The compound according to claim 1, its stereoisomer, N-oxide, deuterated derivative, pharmaceutically acceptable salt or prodrug thereof: wherein, L is selected from: in, X1, X2, X3, X4, n1, n2, n3, and n4 are independently defined as above; L1, L2, L3, and L4 are each independently -CR L1 R L2 -、-NR L3 -、-CR L1 R L2 -NR L3 -or-NR L3 -CR L1 R L2 -; R L1 、R L2 、R L3 are independently =O, hydrogen, halogen, C 1-6 Alkyl or C 1-6 alkyl halide; m1, m2, m3, and m4 are each independently 0 or 1.

16. The compound according to claim 1, its stereoisomer, N-oxide, deuterated derivative, pharmaceutically acceptable salt or prodrug thereof: wherein, L is selected from:

17. The compound according to claim 1, its stereoisomer, N-oxide, deuterated derivative, pharmaceutically acceptable salt or prodrug thereof: wherein, E3 has the structure represented by the following formula (C1), (C2), (C3), (C4) or (C5): wherein T1, T2, T3, and T4 are each independently CH, C, or N; T is CH2, CH(C 1-6 alkyl), C=O, SO2, NH or N(C 1-6 alkyl); R2, R5, R6, R8, and R9 are each independently hydrogen or C 1-6 alkyl; R3 is hydrogen, hydroxy or C 1-6 alkyl; R4, R7, R 10 are independently hydrogen, halogen, C 1-6 Alkyl or halogenated C 1-6 alkyl; m7, m8, m9, and m10 are each independently 0, 1, 2, or 3.

18. The compound according to claim 1, its stereoisomer, N-oxide, deuterated derivative, pharmaceutically acceptable salt or prodrug thereof: wherein, E3 is 19. The compound according to claim 1, its stereoisomer, N-oxide, deuterated derivative, pharmaceutically acceptable salt or prodrug thereof, wherein the compound is selected from Table A, Table B or Table C.

20. The compound of formula (I) according to any one of claims 1 to 19, its stereoisomers, N-oxides, deuterated derivatives, pharmaceutically acceptable salts or prodrugs thereof: wherein, The compound can degrade BTK protein and / or IRAK4 protein. Preferably, the compound can degrade BTK and IRAK4 proteins simultaneously.

21. A pharmaceutical composition, wherein The composition comprises a compound according to any one of claims 1 to 19, a stereoisomer, an N-oxide, a deuterated derivative, a pharmaceutically acceptable salt, or a prodrug thereof.

22. Use of the compound of any one of claims 1 to 19, its stereoisomers, N-oxides, deuterated derivatives, pharmaceutically acceptable salts or prodrugs thereof, or the pharmaceutical composition of claim 20 in the preparation of a medicament for treating a condition mediated by BTK protein and / or IRAK4 protein in a patient; Preferably, the IRAK and / or BTK mediated disorder is selected from the group consisting of cancer, neurodegenerative diseases, viral diseases, autoimmune diseases, inflammatory disorders, genetic disorders, hormone-related diseases, metabolic disorders, conditions associated with organ transplantation, immunodeficiency disorders, destructive bone diseases, proliferative disorders, infectious diseases, conditions associated with cell death, thrombin-induced platelet aggregation, liver diseases, pathological immune conditions involving T cell activation, cardiovascular disorders and CNS disorders.

23. Use of the compound of any one of claims 1-19, its stereoisomers, N-oxides, deuterated derivatives, pharmaceutically acceptable salts or prodrugs thereof, or the pharmaceutical composition of claim 20 in the preparation of a BTK and / or IRAK4 degrader; preferably, the degrader is a simultaneous BTK and IRAK4 degrader.

24. A method for simultaneously degrading BTK and / or IRAK4 proteins in a biological sample, comprising contacting the biological sample with the compound of any one of claims 1 to 19, its stereoisomers, N-oxides, deuterated derivatives, pharmaceutically acceptable salts or prodrugs thereof, or the pharmaceutical composition of claim 20.

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