Multi-targeting degrader and use thereof

Abstract

The present application relates to the field of pharmaceutical chemistry. Provided are a multi-targeting degrader and the use thereof, and particularly provided are a compound as shown in formula (IA), and a stereoisomer, N-oxide, deuterated derivative and pharmaceutically acceptable salt thereof, wherein the definition of each substituent in the formula is detailed in the description. The compound of formula (IA) can degrade the BTK protein and / or IRAK4 protein, can simultaneously degrade the BTK and IRAK4 proteins in various tumor cells and efficiently inhibit tumor cell proliferation and induce tumor cell apoptosis, and can provide a new drug for treating cancers and other autoimmune diseases.

Description

A multi-target degradation agent and its use

[0001] This application claims priority to Chinese patent application 2024101782052 filed on February 8, 2024, Chinese patent application 2024106069292 filed on May 15, 2024, and Chinese patent application 2025100793872 filed on January 17, 2025, the entire contents of the above Chinese patent applications are incorporated herein by reference. Technical Field

[0002] 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

[0003] 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.

[0004] 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.

[0005] 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.

[0006] 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

[0007] The present invention achieves the degradation of BTK and IRAK4 dual-target proteins through protein targeted degradation technology, 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.

[0008] 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.

[0009] The present invention uses protein targeted degradation technology to achieve the degradation of BTK and IRAK4 dual-target proteins, with good degradation activity and high selectivity. The degradation activity of the target proteins 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, high bioavailability and drug exposure, providing a more sufficient material basis for the potential application of this type of compound in clinical practice.

[0010] Specifically, one aspect of the present invention provides a compound of formula (IA), its stereoisomers, N-oxides, deuterated derivatives, pharmaceutically acceptable salts or prodrugs thereof:

[0011] Where,

[0012] Ring B is

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

[0014] W1, W2, W3, and W4 are each independently C═O, CH, CH2, O, N, or CR 1 or NR 1 ;

[0015] W5, W6, and W7 are each independently N or CH;

[0016] R 1 For hydrogen, halogen, C 1-6 Alkyl or C 1-6 alkyl halide;

[0017] R x For hydrogen, C 1-6 Alkoxy, -C(O)NR x1 R x2, 4 to 8 membered nitrogen-containing heterocycloalkyl, 5 or 6 membered heteroaryl or C 6-8 Aryl, the C 1-6 The alkoxy group is optionally replaced by one or more C 3-6 The 4 to 8-membered nitrogen-containing heterocycloalkyl, 5 or 6-membered heteroaryl or C 6-8 Aryl is optionally substituted by one or more selected from halogen, hydroxy, C 1-6 Alkyl or hydroxy substituted C 1-6 The 4- to 8-membered nitrogen-containing heterocycloalkyl group contains at least one nitrogen atom and 0 to 3 heteroatoms independently selected from N, O or S as ring atoms;

[0018] R x1 、R x2 are each independently hydrogen or C 1-6 alkyl;

[0019] Lx is -C(O)NH- or -CH2-NH-;

[0020] Ring A is:

[0021] (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;

[0022] (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;

[0023] (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;

[0024] (iv) a 5- or 6-membered monoheteroaryl group; or

[0025] (v)C 6-8 aryl;

[0026] or,

[0027] Ring A is:

[0028] wherein S1, S2, S3, S4, S5, S6, S7, and S8 are each independently selected from CH2, CH, NH, N, O, or S;

[0029] S9, S 10 are each independently selected from N or CH; q1 and q2 are each independently 0, 1 or 2;

[0030] R y For hydrogen, halogen, hydroxyl, =O, C 1-6 Alkyl, C1-6 Alkoxy, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl, -OR a -、-NR b R c , 4 to 8 membered nitrogen-containing heterocycloalkyl, 5 or 6 membered heteroaryl or C 6-8 Aryl, wherein the C 1-6 Alkyl, 5 or 6 membered heteroaryl, C 6-8 The aryl group is optionally substituted with one or more R 1 replace;

[0031] R 1 Halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 3-6 Cycloalkyl, -OC(O)-C 1-6 Alkyl, -OP(O)(OH)2 or 4 to 12 membered heterocycloalkyl, the C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 3-6 Cycloalkyl or 4 to 12 membered heterocycloalkyl is optionally substituted by one or more selected from halogen, C 1-6 Alkyl, C 1-6 Haloalkyl or C 1-6 Substitution of alkoxy groups;

[0032] Preferably, R 1 Halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 3-6 Cycloalkyl, -OC(O)-C 1-6 alkyl, -OP(O)(OH)2 or 4 to 12 membered heterocycloalkyl, the 4 to 12 membered heterocycloalkyl being optionally substituted by one or more selected from halogen, C 1-6 Alkyl, C 1-6 Haloalkyl or C 1-6 Substitution of alkoxy groups;

[0033] R a C 1-6 Alkyl or C 6-8 aryl;

[0034] R b 、R c are each independently hydrogen or C 1-3 alkyl;

[0035] y is 0, 1, 2, 3, or 4;

[0036] L is in, The position shown indicates connection with E3. The position shown indicates connection with ring B;

[0037] Q1, Q2, and Q3 are each independently a 4- to 12-membered nitrogen-containing heterocycloalkyl group or a C 3-10 Cycloalkyl, the 4 to 12-membered nitrogen-containing heterocycloalkyl contains at least one nitrogen atom as a ring atom; the 4 to 12-membered nitrogen-containing heterocycloalkyl or C 3-10 Cycloalkyl is optionally substituted with one or more substituents selected from halogen and hydroxy;

[0038] L1, L2, L3, and L4 are each independently -CR L1 R L2 -、-NR L3 -、-CR L1 R L2 -NR L3 -、-NR L3 -CR L1 R L2 -OR L4 ;

[0039] R L1 、R L2 、R L3 、R L4 are independently hydrogen, halogen, =O, C 1-6 Alkyl or C 1-6 Haloalkyl or C 2-6 Alkynyl;

[0040] m1, m2, m3, m4, m5, m6, and m7 are each independently 0 or 1;

[0041] E3 is the ubiquitin ligase binding group.

[0042] In one embodiment, L is in, The position shown indicates connection with E3. The position shown indicates connection with ring B;

[0043] Q1, Q2, and Q3 are each independently a 4- to 12-membered nitrogen-containing heterocycloalkyl group or a C 3-10 Cycloalkyl, the 4 to 12-membered nitrogen-containing heterocycloalkyl contains at least one nitrogen atom as a ring atom; the 4 to 12-membered nitrogen-containing heterocycloalkyl or C 3-10 Cycloalkyl is optionally substituted with one or more substituents selected from halogen and hydroxy;

[0044] L1, L2, L3, and L4 are each independently -CR L1 R L2 -、-NR L3 -、-CR L1 R L2 -NR L3 -、-NR L3 -CR L1 R L2 -OR L4 ;

[0045] R L1 、R L2 、R L3 、R L4 are independently hydrogen, halogen, =O, C 1-6 Alkyl or C 1-6 Haloalkyl or C 2-6 Alkynyl;

[0046] m1, m2, m3, m4, and m5 are each independently 0 or 1;

[0047] E3 is the ubiquitin ligase binding group.

[0048] In one aspect of the present invention, there is provided a compound of formula (I), its stereoisomers, N-oxides, deuterated derivatives, pharmaceutically acceptable salts or prodrugs thereof:

[0049] Where,

[0050] is a single bond or a double bond;

[0051] W1, W2, W3, and W4 are each independently C═O, CH, CH2, O, N, or CR 1 or NR 1 ;

[0052] R 1 For hydrogen, halogen, C 1-6 Alkyl or C 1-6 alkyl halide;

[0053] 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;

[0054] Lx is -C(O)NH- or -CH2-NH-;

[0055] Ring A is:

[0056] (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;

[0057] (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;

[0058] (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;

[0059] (iv) a 5- or 6-membered monoheteroaryl group; or

[0060] (v)C 6-8 aryl;

[0061] 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;

[0062] 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;

[0063] R a C 1-6 Alkyl or C 6-8 aryl;

[0064] R b 、R c are each independently hydrogen or C 1-3 alkyl;

[0065] y is 0, 1, 2, 3, or 4;

[0066] L is in, The position shown indicates connection with E3. The position shown indicates connection with ring B;

[0067] Q1, Q2, and Q3 are each independently a 4- to 12-membered nitrogen-containing heterocycloalkyl group or a C3-10 Cycloalkyl, the 4 to 12-membered nitrogen-containing heterocycloalkyl contains at least one nitrogen atom as a ring atom; the 4 to 12-membered nitrogen-containing heterocycloalkyl or C 3-10 Cycloalkyl is optionally substituted with one or more substituents selected from halogen and hydroxy;

[0068] L1, L2, L3, and L4 are each independently -CR L1 R L2 -、-NR L3 -、-CR L1 R L2 -NR L3 -、-NR L3 -CR L1 R L2 -OR L4 ;

[0069] R L1 、R L2 、R L3 、R L4 are independently hydrogen, halogen, =O, C 1-6 Alkyl, C 1-6 Haloalkyl or C 2-6 Alkynyl;

[0070] m1, m2, m3, m4, and m5 are each independently 0 or 1;

[0071] E3 is the ubiquitin ligase binding group.

[0072] In one aspect of the present invention, there is provided a compound of formula (I-1), its stereoisomers, N-oxides, deuterated derivatives, pharmaceutically acceptable salts or prodrugs thereof:

[0073] Where,

[0074] R x For hydrogen, C 1-6 Alkoxy, -C(O)NR x1 R x2 , 4 to 8 membered nitrogen-containing heterocycloalkyl, 5 or 6 membered heteroaryl or C 6-8 Aryl, the C 1-6 The alkoxy group is optionally replaced by one or more C 3-6 The 4 to 8-membered nitrogen-containing heterocycloalkyl, 5 or 6-membered heteroaryl or C 6-8 Aryl is optionally substituted by one or more selected from halogen, hydroxy, C 1-6 Alkyl or hydroxy substituted C 1-6 The 4- to 8-membered nitrogen-containing heterocycloalkyl group contains at least one nitrogen atom and 0 to 3 heteroatoms independently selected from N, O or S as ring atoms;

[0075] R x1 、R x2 are each independently hydrogen or C 1-6 alkyl;

[0076] Lx is -C(O)NH- or -CH2-NH-;

[0077] Ring A is:

[0078] (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;

[0079] (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;

[0080] (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;

[0081] (iv) a 5- or 6-membered monoheteroaryl group; or

[0082] (v)C 6-8 aryl;

[0083] or,

[0084] Ring A is:

[0085] wherein S1, S2, S3, S4, S5, S6, S7, and S8 are each independently selected from CH2, CH, NH, N, O, or S;

[0086] S9, S 10 are each independently selected from N or CH; q1 and q2 are each independently 0, 1 or 2;

[0087] R y For hydrogen, halogen, hydroxyl, =O, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl, -OR a -、-NR b R c , 4 to 8 membered nitrogen-containing heterocycloalkyl, 5 or 6 membered heteroaryl or C 6-8 Aryl, wherein the C 1-6 Alkyl, 5 or 6 membered heteroaryl, C 6-8 The aryl group is optionally substituted with one or more R 1 replace;

[0088] R1 Halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 3-6 Cycloalkyl, -OC(O)-C 1-6 Alkyl, -OP(O)(OH)2 or 4 to 12 membered heterocycloalkyl, the C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 3-6 Cycloalkyl or 4 to 12 membered heterocycloalkyl is optionally substituted by one or more selected from halogen, C 1-6 Alkyl, C 1-6 Haloalkyl or C 1-6 Substitution of alkoxy groups;

[0089] Preferably, R 1 Halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 3-6 Cycloalkyl, -OC(O)-C 1-6 alkyl, -OP(O)(OH)2 or 4 to 12 membered heterocycloalkyl, the 4 to 12 membered heterocycloalkyl being optionally substituted by one or more selected from halogen, C 1-6 Alkyl, C 1-6 Haloalkyl or C 1-6 Substitution of alkoxy groups;

[0090] R a C 1-6 Alkyl or C 6-8 aryl;

[0091] R b 、R c are each independently hydrogen or C 1-3 alkyl;

[0092] y is 0, 1, 2, 3, or 4;

[0093] L is in, The position shown indicates connection with E3. The position shown indicates connection with ring B;

[0094] Q1, Q2, and Q3 are each independently a 4- to 12-membered nitrogen-containing heterocycloalkyl group or a C 3-10Cycloalkyl, the 4 to 12-membered nitrogen-containing heterocycloalkyl contains at least one nitrogen atom as a ring atom; the 4 to 12-membered nitrogen-containing heterocycloalkyl or C 3-10 Cycloalkyl is optionally substituted with one or more substituents selected from halogen and hydroxy;

[0095] L1, L2, L3, and L4 are each independently -CR L1 R L2 -、-NR L3 -、-CR L1 R L2 -NR L3 -、-NR L3 -CR L1 R L2 -OR L4 ;

[0096] R L1 、R L2 、R L3 、R L4 are independently hydrogen, halogen, =O, C 1-6 Alkyl or C 1-6 Haloalkyl or C 2-6 Alkynyl;

[0097] m1, m2, m3, m4, m5, m6, and m7 are each independently 0 or 1;

[0098] E3 is the ubiquitin ligase binding group.

[0099] 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):

[0100] 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 Ry .

[0101] 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):

[0102] 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 .

[0103] 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):

[0104] 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;

[0105] R P1 、R P2 、R P3 、R P4 are each independently hydrogen or R y .

[0106] 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):

[0107] Where 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 CRV6 ; 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 .

[0108] In one embodiment, the 8- to 10-membered biheteroaryl group formed by condensing a 5- or 6-membered monoheteroaryl ring and a 5- or 6-membered monocyclic heterocycloalkyl ring in Ring A is a structure represented by Formula (A7), Formula (A8), (A9), (A10) or (A11):

[0109] 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 ;

[0110] G1 is N, O, S or CRG1 ; 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 、R G6c are each independently hydrogen or R y .

[0111] 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 monocyclic heterocycloalkyl ring is a structure represented by formula (A12) or formula (A13):

[0112] Where M1 is N or CR M1 ; M2 is N or CR M2 ; M3 is N or CR M3 ;M4 is NR M4 ;M5 is NR M5a , O, S or CR M5b R M5c ;M6 is NR M6a , O, S or CR M6b R M6c ;M7 is NR M7a , O, S or CR M7b R M7c ;M8 is NR M8a , O, S or CR M8b R M8c ; R M1 、RM2 、R M3 、R M4 、R M5a 、R M5b 、R M5c 、R M6a 、R M6b 、R M6c 、R M7a 、R M7b 、R M7c 、R M8a 、R M8b 、R M8c are each independently hydrogen or R y ; p1 and p2 are each independently 0, 1 or 2.

[0113] In one embodiment, in the 8- to 10-membered biheteroaryl group formed by condensing a 5- or 6-membered monoheteroaryl ring and a 5- or 6-membered monoheteroaryl ring in Ring A, two of the 5- or 6-membered monoheteroaryl rings are independently selected from the following groups: The group is optionally replaced by one or more R y replace; The attached carbon atoms or heteroatoms represented are adjacent pairs of carbon atoms or heteroatoms that are shared when fused to other rings.

[0114] In one embodiment, in 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, the 5- or 6-membered monoheteroaryl ring is selected from the following group: The group is optionally replaced by one or more R y replace; The attached carbon atoms or heteroatoms represented are adjacent pairs of carbon atoms or heteroatoms that are shared when fused to other rings.

[0115] In one embodiment, in the 8- to 10-membered biheteroaryl group formed by condensing a 5- or 6-membered monoheteroaryl ring and a 5- or 6-membered monocyclic heterocycloalkyl ring in Ring A, the 5- or 6-membered monocyclic heterocycloalkyl ring is selected from the following group: The group is optionally replaced by one or more R y replace; The attached carbon atoms or heteroatoms represented are adjacent pairs of carbon atoms or heteroatoms that are shared when fused to other rings.

[0116] 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:

[0117] 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.

[0118] In one embodiment, when Ring A is a 5- or 6-membered monoheteroaryl group, the 5- or 6-membered monoheteroaryl group is selected from the following group: The group is optionally replaced by one or more R y replace; The position shown indicates connection with Lx.

[0119] In one embodiment, Ring A is C 6-8 When the C 6-8 Aryl is selected from phenyl or naphthyl, said group being optionally substituted by one or more R y replace.

[0120] In one embodiment, Ring A is:

[0121] wherein S1, S2, S3, S4, S5, S6, S7, and S8 are each independently selected from CH2, CH, NH, N, O, or S; wherein the ring A comprises at least 1, 2, 3, 4, or 5 N atoms;

[0122] S9, S 10 are each independently selected from N or CH; q1 and q2 are each independently 0, 1 or 2.

[0123] In one embodiment, Ring A is:

[0124] In one embodiment, Ring B is

[0125] In one embodiment, Ring B is

[0126] In one embodiment, Ring B is

[0127] In one embodiment, Ring B is

[0128] In one embodiment, R ySelected from: halogen, =O, hydroxy, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, methoxy, ethoxy, propoxy, isopropyloxy, butoxy, tert-butoxy, -NH2, -NHCH3, -N(CH3)2, -CH2-OC(O)(CH3)3, -CH2-OP(O)(OH)2, fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl, trifluoroethyl, thienyl, N-alkylpyrrolidonyl, furyl, morpholinyl, piperazinyl, 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-triazolyl, -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, imidazole Oxazolyl, 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 are optionally substituted with one or more F, Cl, Br, I, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, fluoromethyl, difluoromethyl, trifluoromethyl.

[0129] In one embodiment, R ySelected from: halogen, =O, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, methoxy, ethoxy, propoxy, isopropyloxy, butoxy, tert-butoxy, -NH2, -NHCH3, -N(CH3)2, -CH2-OC(O)(CH3)3, -CH2-OP(O)(OH)2, fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl, trifluoroethyl, thienyl, N-alkylpyrrolidonyl, furyl, morpholinyl, piperazinyl, thiazolyl, isothiazolyl, imidazolyl, oxazolyl, pyrrolyl, pyrazolyl, trifluoromethyl ... oxazolyl, 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-triazolyl, -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-alkane phenyl, naphthyl, pyrrolidonyl, furanyl, 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.

[0130] In one embodiment, R ySelected from: halogen, =0, 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 oxazolyl, 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, -O-thienyl, -ON-alkylpyrrolidonyl, -O-furyl, -O-thiazolyl, -O-isothiazolyl, -O-imidazolyl, -O-oxazolyl, -O-pyrrolyl, -O-pyrazolyl, -O-triazolyl, -O-1,2,3- triazolyl, -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 are optionally substituted with one or more F, Cl, Br, I, methyl or ethyl.

[0131] In one embodiment, R ySelected from: halogen, =O, hydroxy, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, methoxy, ethoxy, propoxy, isopropyloxy, butoxy, tert-butoxy, -NH2, -NHCH3, -N(CH3)2, -CH2-OC(O)(CH3)3, -CH2-OP(O)(OH)2, fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl, trifluoroethyl, 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 The 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-phenyl; the imidazolyl, oxazolyl, pyrrolyl, pyrazolyl, triazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 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, ethyl, propyl, isopropyl, methoxy, ethoxy, fluoromethyl, difluoromethyl, trifluoromethyl.

[0132] In one embodiment, R y Selected from: halogen, =O, methyl, ethyl, propyl, isopropyl, tert-butyl, methoxy, ethoxy, -NH2, -NHCH3, -N(CH3)2, -CH2-OC(O)(CH3)3, -CH2-OP(O)(OH)2, fluoromethyl, difluoromethyl, trifluoromethyl, imidazolyl, oxazolyl, pyrrolyl, pyrazolyl, triazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, phenyl, naphthyl, -O-phenyl; the imidazolyl, oxazolyl, pyrrolyl, pyrazolyl, triazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, phenyl, naphthyl are optionally substituted with one or more F, Cl, Br, I, methyl, ethyl, propyl, isopropyl.

[0133] In one embodiment, R ySelected from: halogen, =O, methyl, ethyl, isopropyl, tert-butyl, methoxy, -NH2, -NHCH3, -N(CH3)2, -CH2-OC(O)(CH3)3, -CH2-OP(O)(OH)2, fluoromethyl, difluoromethyl, trifluoromethyl, pyrazolyl, imidazolyl, pyrrolyl, pyridinyl, pyridazinyl, pyrimidinyl, phenyl, -O-phenyl; the pyrazolyl, imidazolyl, pyrrolyl, pyridinyl, pyridazinyl, pyrimidinyl, phenyl are optionally substituted with one or more F, Cl, Br, methyl, ethyl.

[0134] In one embodiment, R y Selected from: halogen, methyl, tert-butyl, methoxy, -NH2, -NHCH3, -N(CH3)2, -CH2-OC(O)(CH3)3, -CH2-OP(O)(OH)2, difluoromethyl, trifluoromethyl, pyrazolyl, pyridyl, pyrimidinyl, phenyl, -O-phenyl; the pyrazolyl, pyridyl, pyrimidinyl, phenyl are optionally substituted with one or more F, Cl, methyl.

[0135] In one embodiment, R y Selected from: halogen, hydroxy, =O, amino, methylamino, dimethylamino, methyl, tert-butyl, trifluoromethyl, methoxy, -CH2-OC(O)(CH3)3, -CH2-OP(O)(OH)2, morpholinyl,

[0136] In one embodiment, R y Selected from: halogen, hydroxy, amino, methyl, tert-butyl, trifluoromethyl, methoxy,

[0137] In one embodiment, Ring A is selected from the following groups: The group is optionally replaced by one or more R y replace.

[0138] In one embodiment, Ring A is selected from: The group is optionally replaced by one or more R y replace.

[0139] In one embodiment, Ring A is selected from: The group is optionally replaced by one or more R y replace.

[0140] In one embodiment, Ring A is selected from the following groups: The group is optionally replaced by one or more R y replace.

[0141] In one embodiment, Ring A is selected from:

[0142] In one embodiment, Ring A is selected from:

[0143] In one embodiment, Ring A is selected from:

[0144] In one embodiment, Ring A is selected from:

[0145] In one embodiment, Ring A is selected from:

[0146] In one embodiment, Ring A is

[0147] In one embodiment, R x For hydrogen, C 1-6 Alkoxy, -C(O)NR x1 R x2 , 4 to 8 membered nitrogen-containing heterocycloalkyl, 5 or 6 membered heteroaryl or C 6-8 Aryl, the C 1-6 The alkoxy group is optionally replaced by one or more C 3-6 The 4 to 8-membered nitrogen-containing heterocycloalkyl, 5 or 6-membered heteroaryl or C 6- 8 aryl groups are optionally substituted by one or more selected from halogen, hydroxyl, C 1-6 Alkyl, hydroxy substituted C 1-6 Alkyl or halogen substituted C 1-6 The 4- to 8-membered nitrogen-containing heterocycloalkyl group contains at least one N atom and 0 to 3 heteroatoms independently selected from N, O or S as ring atoms.

[0148] In one embodiment, R x For hydrogen, C 1-6 Alkoxy, -C(O)NR x1 R x2 , 4 to 8 membered nitrogen-containing heterocycloalkyl, 5 or 6 membered heteroaryl or C 6-8 Aryl, the C 1-6 The alkoxy group is optionally replaced by one or more C 3-6The 4 to 8-membered nitrogen-containing heterocycloalkyl, 5 or 6-membered heteroaryl or C 6- 8 aryl groups are optionally substituted by one or more selected from halogen, hydroxyl, C 1-6 Alkyl or hydroxy substituted C 1-6 The 4- to 8-membered nitrogen-containing heterocycloalkyl group contains at least one N atom and 0 to 3 heteroatoms independently selected from N, O or S as ring atoms.

[0149] In one embodiment, R x1 、R x2 Each is independently hydrogen or methyl, ethyl or propyl.

[0150] In one embodiment, R x1 、R x2 are each independently hydrogen or methyl.

[0151] In one embodiment, R x For hydrogen, C 1-6 Alkoxy, 4 to 8 membered nitrogen-containing heterocycloalkyl, 5 or 6 membered heteroaryl or C 6-8 Aryl, the C 1-6 The alkoxy group is optionally replaced by one or more C 3-6 The 4 to 8-membered nitrogen-containing heterocycloalkyl, 5 or 6-membered heteroaryl or C 6-8 Aryl is optionally substituted by one or more selected from halogen, hydroxy, C 1-6 Alkyl, hydroxy substituted C 1-6 Alkyl or halogen substituted C 1-6 The 4- to 8-membered nitrogen-containing heterocycloalkyl group contains at least one N atom and 0 to 3 heteroatoms independently selected from N, O or S as ring atoms.

[0152] In one embodiment, R x is hydrogen, methoxy, ethoxy, 4 to 8 membered nitrogen-containing heterocycloalkyl, 5 or 6 membered heteroaryl or C 6-8 Aryl is optionally substituted by one or more selected from halogen, hydroxy, C 1-6 Alkyl, hydroxy substituted C 1-6 Alkyl or halogen substituted C 1-6 The 4- to 8-membered nitrogen-containing heterocycloalkyl group contains at least one N atom and 0 to 3 heteroatoms independently selected from N, O or S as ring atoms.

[0153] In one embodiment, R x Methoxy, ethoxy, -C(O)N(CH3)2, -C(O)NH2, wherein the methoxy and ethoxy groups are optionally substituted by one or more cyclopropyl groups, Optionally substituted with one or more substituents selected from hydroxy, F, Cl, Br, methyl, ethyl, propyl, isopropyl, hydroxymethyl, hydroxyethyl, hydroxypropyl.

[0154] In one embodiment, R x Methoxy, -C(O)NH2, In fact, the methoxy group is optionally substituted by one or more cyclopropyl groups. Optionally substituted with one or more substituents selected from hydroxy, F, Cl, Br, hydroxyethyl.

[0155] In one embodiment, R x Methoxy, -C(O)NH2,

[0156] In one embodiment, R x Methoxy,

[0157] In one embodiment, R x for

[0158] In one embodiment, R x is a 4- to 8-membered nitrogen-containing heterocycloalkyl group containing 1 or 2 nitrogen atoms.

[0159] In one embodiment, the 4- to 8-membered nitrogen-containing heterocycloalkyl group is selected from:

[0160] In one embodiment, Lx is selected from *-C(O)NH-**, *-CH2-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.

[0161] In one embodiment, Lx is selected from *-C(O)NH-**, *-CH2-NH-**; wherein the position indicated by "*" indicates connection to ring A, and the position indicated by "**" indicates connection to the other side group of Lx. In one embodiment, Lx is selected from *-C(O)NH-**; wherein the position indicated by "*" indicates connection to ring A, and the position indicated by "**" indicates connection to the other side group of Lx.

[0162] In one embodiment, the compound is a compound represented by formula (IA1) or formula (IA2):

[0163] Where, E3, L, W1, W2, W3, W4, R X , L X , Ring A are defined as above;

[0164] 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 ;

[0165] 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 .

[0166] In one embodiment, the compound is a compound represented by formula (IA1-1) or formula (IA2-1):

[0167] Where, E3, L, R X , L X , Ring A are defined as above;

[0168] 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 ;

[0169] K1 is NR K1 or CR K2 ; K2 is N or CR K2 ; K3 is N or CRK3 ; 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 .

[0170] In one embodiment, the compound is represented by Formula (IB1), Formula (IB2), Formula (IB3), Formula (IB4) or Formula (IB5):

[0171] Where, E3, L, W1, W2, W3, W4, R X , L X 、R y , y are defined as before.

[0172] In one embodiment, the compound is represented by Formula (IB1-1), Formula (IB2-1), Formula (IB3-1), Formula (IB4-1) or Formula (IB5-1):

[0173] Where, E3, L, R X , L X 、R y , y are defined as before.

[0174] In one embodiment, the 4- to 12-membered nitrogen-containing heterocycloalkyl group is selected from:

[0175] X1, X2, X3, and X4 are each independently N or -CR d ;

[0176] X5 is a single bond, -O-, -S-, or -NR a -or-NR e R f -;

[0177] n1, n2, n3, n4, n5, and n6 are each independently 0, 1, 2, or 3;

[0178] Among them, R d 、R e 、R f are independently hydrogen, hydroxy, halogen, -CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6Alkoxy, C 1-6 Haloalkoxy or C 3-6 Cycloalkyl.

[0179] In one embodiment, L is selected from:

[0180] in,

[0181] X1, X2, X3, X4, X 11 、X 12 、X 21 、X 22 、X 31 、X 32 、X 41 、X 42 Each independently is N or -CR d ;

[0182] Among them, R d For hydrogen, hydroxyl, halogen, -CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy or C 3-6 Cycloalkyl;

[0183] n1, n2, n3, n4, n11, n12, n21, n22, n31, n32 are each independently 0, 1, 2 or 3;

[0184] 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 -OR L4 ;

[0185] R L1 、R L2 、R L3 、R L4 are independently =O, hydrogen, halogen, C 1-6 Alkyl or C 1-6 alkyl halide;

[0186] m1, m2, m3, and m4 are each independently 0 or 1;

[0187] in, The position shown indicates connection with E3. The position shown indicates attachment to ring B.

[0188] In one embodiment, L is selected from:

[0189] in,

[0190] X1, X2, X3, X4, n1, n2, n3, and n4 are independently defined as above;

[0191] L1, L2, L3, and L4 are each independently -CR L1 R L2 -、-NR L3 -、-CR L1 R L2 -NR L3 -、-NR L3 -CR L1 R L2 -OR L4 ;

[0192] R L1 、R L2 、R L3 are independently =O, hydrogen, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl or C 2-6 Alkynyl;

[0193] m1, m2, m3, and m4 are each independently 0 or 1;

[0194] in, The position shown indicates connection with E3. The position shown indicates attachment to ring B.

[0195] In one embodiment, L is selected from: in, The position shown indicates connection with E3. The position shown indicates attachment to ring B.

[0196] In one embodiment, L is selected from:

[0197] in, The position shown indicates connection with E3. The position shown indicates attachment to ring B.

[0198] In one embodiment, L is selected from: in, The position shown indicates connection with E3. The position shown indicates attachment to ring B.

[0199] In one embodiment, L is selected from: in, The position shown indicates connection with E3. The position shown indicates attachment to ring B.

[0200] In one embodiment, L is selected from: in, The position shown indicates connection with E3. The position shown indicates attachment to ring B.

[0201] In one embodiment, E3 has the structure represented by the following formula (C1), (C2), (C3), (C4), (C5), (C6), (C7), (C8) or (C9):

[0202] wherein T1, T2, T3, T4, and T5 are each independently CH, C, or N;

[0203] T is CH2, CH(C 1-6 alkyl), C=O, SO2, NH or N(C 1-6 alkyl);

[0204] R2, R5, R6, R8, and R9 are each independently hydrogen, C 1-6 Alkyl or C 1-6 Alkoxy, the C 1-6 The alkyl group is optionally replaced by one or more C 1-6 Alkoxy or -OC(O)-C 1-6 Alkyl substitution;

[0205] Preferably, R2, R5, R6, R8, and R9 are each independently hydrogen or C 1-6 alkyl;

[0206] R3 is hydrogen, hydroxy or C 1-6 alkyl;

[0207] R4, R7, R 10 are independently hydrogen, halogen, C 1-6 Alkyl, C 1-6 Alkoxy or halogenated C 1-6 alkyl;

[0208] Preferably, R4, R7, R 10 are independently hydrogen, halogen, C 1-6 Alkyl or halogenated C 1-6 alkyl;

[0209] m7, m8, m9, and m10 are each independently 0, 1, 2, or 3.

[0210] In one embodiment, E3 is R7 is hydrogen, halogen, C 1-6 Alkyl, C 1-6 Alkoxy or halogenated C 1- 6 alkyl; R5 is hydrogen, C 1-6 Alkyl or C 1-6 Alkoxy, the C 1-6 The alkyl group is optionally replaced by one or more C 1-6 Alkoxy or -OC(O)-C 1-6 Alkyl substituted; m9 is 1, 2 or 3.

[0211] In one embodiment, E3 is R7 is hydrogen, halogen, C 1-6 Alkyl, C 1-6 Alkoxy or halogenated C 1-6 Alkyl; R5 is hydrogen, C 1-6 Alkyl or C 1-6 Alkoxy, the C 1-6 The alkyl group is optionally replaced by one or more C 1-6 Alkoxy or -OC(O)-C 1-6 Alkyl substituted; m9 is 1, 2 or 3;

[0212] In one embodiment, E3 is R7 is hydrogen, halogen, C 1-6 Alkyl, C 1-6 Alkoxy or halogenated C 1-6 Alkyl; R5 is hydrogen, C 1-6 Alkyl or C 1-6 Alkoxy, the C 1-6 The alkyl group is optionally replaced by one or more C 1-6 Alkoxy or -OC(O)-C 1-6 Alkyl substituted; m9 is 1, 2 or 3;

[0213] In one embodiment, R7 is hydrogen, F, Cl, Br, methyl, methoxy or trifluoromethyl.

[0214] In one embodiment, R5 is hydrogen or -CH2-O(O)(CH3)3.

[0215] In one embodiment, E3 is

[0216] In one embodiment, E3 is

[0217] In one embodiment, E3 is

[0218] In one embodiment, E3 is

[0219] In one embodiment, E3 is

[0220] In one embodiment, E3 is

[0221] In one embodiment, E3 is

[0222] In one embodiment, the compound is a compound of Table A, Table B, Table C, Table D, or a compound of the Examples of Table E.

[0223] In one embodiment, the compound is capable of degrading BTK protein and / or IRAK4 protein.

[0224] In one embodiment, the compound is capable of degrading both BTK and IRAK4 proteins.

[0225] 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.

[0226] 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.

[0227] 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.

[0228] 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.

[0229] 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.

[0230] 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 lesions, proliferative disorders, infectious diseases, conditions associated with cell death, thrombin-induced platelet aggregation, liver diseases, pathological immune conditions mediated by T cell activation, cardiovascular disorders and CNS disorders.

[0231] 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, multiple myeloma (including chronic or indolent forms), hematologic malignancies, myeloid leukemia (acute and chronic), acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative disorders, 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, a hematologic cancer selected from the group consisting of leukemia, diffuse large B-cell lymphoma (DLBCL), activated B-cell-like diffuse large B-cell lymphoma (ABC), and leukemia. 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, plasmacytoma, or intravascular large B-cell lymphoma.

[0232] 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;

[0233] 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.

[0234] 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, Graves' disease, ease), 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 diseases, endometriosis, leptospiral nephropathy, glaucoma, retinal diseases, 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 ( disease), incontinentia pigmenti, Paget's disease, pancreatitis, hereditary periodic fever syndromes, asthma (allergic, nonallergic, mild, moderate, severe, bronchitis, or exercise-induced), acute lung injury, acute respiratory distress syndrome, eosinophilia, anaphylaxis, 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 transplant rejection, colitis, conjunctivitis, cystitis, dacryoadenitis, dermatitis, dermatomyositis, encephalitis, endocarditis, subepidermis 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, polymyositis, proctitis, prostatitis, pyelonephritis, rhinitis, eustachian tube inflammation, 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.

[0235] 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, autoimmune retinopathy, axonal and neuronal neuropathy (AMAN), Baló disease, Behçet disease, '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, coxsackiemyocarditis, CR EST 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 ssyndrome), 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

[0236] FIG1 shows the degradation activity of the compound in Test Example 3 on BTK and IRAK4 in TMD8 cells at different concentrations, with an action time of 16 hours. DETAILED DESCRIPTION

[0237] I. Definition

[0238] 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.

[0239] 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.

[0240] 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.

[0241] 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.

[0242] 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).

[0243] 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.

[0244] 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 (C 1-20Alkyl), 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.

[0245] As used herein, the term "alkynyl" refers to a straight or branched aliphatic hydrocarbon group containing at least one C≡C triple bond. The triple bond can be located at any possible position of the hydrocarbon chain. As used herein, the term "C 2-6The term "alkynyl" refers to an alkynyl group containing 2 to 6 carbon atoms, such as ethynyl, propynyl, butynyl, pentynyl, hexynyl, etc. The alkynyl group may be optionally substituted with one or more suitable substituents.

[0246] 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 (C 3-6 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.

[0247] 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.

[0248] 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.

[0249] In one embodiment of the present invention, non-limiting examples of the 5- or 6-membered monocyclic heterocycloalkyl group include:

[0250] 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.

[0251] In some embodiments of the present invention, "heterocycloalkyl" refers to polycyclic heterocycloalkyl, including spiroheterocycloalkyl, fused heterocycloalkyl, and bridged heterocycloalkyl.

[0252] 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:

[0253] 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:

[0254] 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:

[0255] In the present invention, the various 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.

[0256] 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.

[0257] 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.

[0258] 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.

[0259] 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.

[0260] 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.

[0261] 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.

[0262] 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.

[0263] 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.

[0264] 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.

[0265] 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.

[0266] 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).

[0267] 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:

[0268] 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.

[0269] 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.

[0270] 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.

[0271] 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.

[0272] 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.

[0273] 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.

[0274] 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.

[0275] 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.

[0276] 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.

[0277] 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.

[0278] 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.

[0279] 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.

[0280] As used herein, the term "hydroxy" refers to -OH.

[0281] 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.

[0282] 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.

[0283] "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.

[0284] "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.

[0285] 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.

[0286] 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 L2They 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).

[0287] 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.

[0288] In this paper, C 1-6 It can be preferably C 1-4 More preferably C 1-3 .

[0289] 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.

[0290] 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.

[0291] In one embodiment of the present invention, in any group, the 5- or 6-membered monocyclic heteroaryl group is selected from:

[0292] 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.

[0293] 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.

[0294] The "pharmaceutically acceptable salt" includes pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.

[0295] "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.

[0296] "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.

[0297] 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.

[0298] 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.

[0299] 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.).

[0300] 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.

[0301] 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.

[0302] 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.

[0303] 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).

[0304] 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.

[0305] 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.

[0306] 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.

[0307] 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 of the present invention), and the other end is a ligand that binds to intracellular proteins (such as the BTK binding portion of the present invention). These two ligands are then connected by a linker (such as the L of 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.

[0308] 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.

[0309] 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.

[0310] 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.

[0311] II. Examples

[0312] 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.

[0313] 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.

[0314] 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.

[0315] Synthesis of intermediate B1

[0316] Step 1: Synthesis of methyl 4-(4-(dimethoxymethyl)piperidin-1-yl)-2-fluorobenzoate

[0317] 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 replaced with nitrogen three times, heated to 80°C, and stirred for 2 hours. The reaction mixture was cooled to room temperature, quenched with water, and extracted twice with ethyl acetate. 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 3.5 g of the title compound as a white solid in a 49% yield. MS (ESI) m / z = 312.0 [M+H] + .

[0318] Step 2: Synthesis of 4-(4-(dimethoxymethyl)piperidin-1-yl)-2-fluorobenzoic acid

[0319] 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 water was added to dilute the mixture. With stirring, dilute hydrochloric acid was added dropwise until a large amount of precipitate formed. 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. MS (ESI) m / z = 298.1 [M+H] + .

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

[0321] 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. The mixture was quenched with water, washed with ethyl acetate, and filtered to obtain the title compound as a pale yellow solid (17 g, 73.0% yield). MS (ESI) m / z = 408.3 [M+H] + .

[0322] Step 4: Synthesis of N-(2,6-dioxopiperidin-3-yl)-2-fluoro-4-(4-formylpiperidin-1-yl)benzamide

[0323] 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 organic phase was extracted with dichloromethane and dried to afford 12 g of the title compound as an off-white solid in a 79% yield. MS (ESI) m / z = 362.1 [M+H] + .

[0324] 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),4.76–4.72(m,1H ),3.82–3.76(m,2H),3.06-3.02(m,2H),2.79-2.73(m,1H),2.50–2.52(m,2H),2.19–1.97(m,2H),1.93–1.86(m,2H),1.57–1.51(m,2H).

[0325] Referring to the synthetic route and method of intermediate B1, the following intermediate structure was synthesized:

[0326] Synthesis of intermediate B31

[0327] Step 1: Synthesis of tert-butyl 4-(3-fluoro-4-(carbomethoxy)phenyl)piperazine-1-carboxylate

[0328] 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, quenched with water, and extracted twice with ethyl acetate. 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 3.3 g of the title compound as a white solid in a 41.5% yield. MS (ESI) m / z = 339.1 [M+H] + .

[0329] Step 2: Synthesis of 4-(4-(tert-butoxycarbonyl)piperazin-1-yl)-2-fluorobenzoic acid

[0330] A 20 mL solution of lithium hydroxide monohydrate (1.58 g, 37.6 mmol) was slowly added to a 20 mL solution of tert-butyl 4-(3-fluoro-4-(carbomethoxycarbonyl)phenyl)piperazine-1-carboxylate (3.3 g, 9.7 mmol) in methanol. The mixture was heated to 50°C and stirred for 1 hour. The methanol was removed by rotary evaporation under reduced pressure, and the reaction mixture was diluted with water. 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. MS (ESI) m / z = 325.1 [M+H] + .

[0331] Step 3: Synthesis of tert-butyl (S)-4-(4-((2,6-dicarbonylpiperidin-3-yl)carbamoyl)-3-fluorophenyl)piperazine-1-carboxylate

[0332] 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 was added to quench the mixture, and the mixture was washed with ethyl acetate. 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 3.0 g of the title compound as a white solid in an 83.4% yield. MS (ESI) m / z = 435.2 [M+H] + .

[0333] Step 4: Synthesis of (S)-N-(2,6-dicarbonylpiperidin-3-yl)-2-fluoro-4-(piperazin-1-yl)benzamide hydrochloride

[0334] 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 evaporated under reduced pressure to afford 2.2 g of the title compound as an off-white solid in a 95% yield. MS (ESI) m / z = 335.1 [M+H] + .

[0335] Referring to the synthetic route and method of intermediate B31, the following intermediate structure was synthesized:

[0336] Synthesis of intermediate B33

[0337] Step 1: Synthesis of 3-(6-bromo-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[0338] 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). Glacial acetic acid (19.76 g, 0.33 mol) was then added dropwise. Methyl 5-bromo-2-formylbenzoate (8 g, 33 mmol) was then added, followed by sodium cyanoborohydride (4.13 g, 65.8 mmol). The system was heated to 35°C and stirred for 16 hours. Water was added dropwise to the reaction solution, and the methanol was removed by rotary evaporation under reduced pressure. Water was added, the mixture was filtered, and the filter cake was dried to afford 8.3 g of the title compound as a white solid in a 78.1% yield. MS (ESI) m / z = 323.0 / 325.0 [M+H] + .

[0339] Step 2: Synthesis of 3-(6-(4-(dimethoxymethyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[0340] (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 atmosphere was replaced with nitrogen, and the mixture 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 column chromatography to obtain 0.9 g of the title compound as a yellow solid in a 35.5% yield. MS (ESI) m / z = 402.0 [M+H] + .

[0341] Step 3: Synthesis of 1-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)piperidine-4-carboxaldehyde trifluoroacetate

[0342] 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 reaction mixture was evaporated to dryness under reduced pressure to afford 0.83 g of the title compound as a gray solid in a 72.7% yield. MS (ESI) m / z = 356.2 [M+H] + . 1H-NMR (400MHz, DMSO) δ10.98(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),2.96–2.85(m,3H),2.61 -2.52(m,2H),2.43–2.32(m,1H),2.04–1.90(m,3H),1.66–1.56(m,2H).

[0343] Referring to the synthetic route and method of intermediate B33, the following intermediate structure was synthesized:

[0344] Synthesis of intermediate B42

[0345] Step 1: Synthesis of 2-(2,6-dicarbonylpiperidin-3-yl)-5-(4-(hydroxymethyl)piperidin-1-yl)isoindoline-1,3-dione

[0346] 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. After the reaction was complete, the residue was concentrated under reduced pressure and purified by C18 column chromatography to afford 2.2 g of the title compound as a yellow solid in a 90% yield. MS (ESI) m / z = 372.1 [M+H] + .

[0347] Step 2: Synthesis of 1-(2-(2,6-dicarbonylpiperidin-3-yl)-1,3-dicarbonylisoindolin-5-yl)piperidine-4-carboxaldehyde

[0348] 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. Pyridinium chlorochromate (5.80 g, 26.93 mmol) was added portionwise to the reaction solution, which was then stirred at room temperature for 2 hours. The reaction solution was filtered, and the filtrate was dried to obtain the crude product. After separation and purification, 668 mg of the title compound was obtained as a yellow solid in a 32.4% yield. MS (ESI) m / z = 370.0 [M+H] + . 1H-NMR (400MHz, DMSO) δ11.09(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),2.92–2.85(m,1H),2.70–2.51(m,3H),2.05–1.86(m,3H),1.59–1.50(m,2H).

[0349] Referring to the synthetic route and method of intermediate B42, the following intermediate structure was synthesized:

[0350] Synthesis of intermediate B47

[0351] Step 1: Synthesis of tert-butyl 4-(1-(2-(2,6-dicarbonylpiperidin-3-yl)-1,3-dicarbonylisoindolin-5-yl)azetidin-3-yl)piperazine-1-carboxylate

[0352] 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 reaction solution was concentrated under reduced pressure to obtain a residue which was purified by column chromatography to afford 1.2 g of the title compound as a yellow solid in a yield of 69.8%.

[0353] MS (ESI) m / z = 498.2 [M+H] + .

[0354] Step 2: Synthesis of 2-(2,6-dicarbonylpiperidin-3-yl)-5-(3-(piperazin-1-yl)azetidin-1-yl)isoindoline-1,3-dione hydrochloride

[0355] A 4M hydrochloric acid solution in dioxane (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. MS (ESI) m / z = 398.1 [M+H] + .

[0356] Referring to the synthetic route and method of intermediate B47, the following intermediate structure was synthesized:

[0357] Synthesis of intermediate B50

[0358] Step 1: Synthesis of (1-(4-(2,4-dicarbonyltetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)methyl acetate

[0359] Glacial acetic acid (4.70 g, 78.2 mmol) was added 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 h. After the reaction was completed and cooled to room temperature, a solution of urea (9.91 g, 0.165 mmol) in glacial acetic acid (70 ml) was added, the nitrogen was purged, and the system was heated to 120°C and stirred for 20 h. After the reaction was complete, hydrochloric acid (14 ml) was added, and the system was heated to 120°C and stirred for 1 h. After the reaction was completed, the system was cooled to room temperature, diluted with water, and the pH was adjusted to 8. The system was extracted with ethyl acetate. 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 column chromatography to obtain 5 g of the title compound as a pink solid in a 23% yield. MS (ESI) m / z = 346.3 [M+H] + .

[0360] Step 2: Synthesis of 1-(4-(4-(hydroxymethyl)piperidin-1-yl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione

[0361] 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, then heated to 100°C and stirred for 16h. After completion, the reaction was cooled to room temperature, diluted with water, and the pH was adjusted to 8. The mixture was extracted with ethyl acetate. 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 column chromatography to afford 3g of the title compound as a pink solid in a 68% yield. MS (ESI) m / z = 304.3 [M+H] + .

[0362] Step 3: Synthesis of 1-(4-(2,4-dicarbonyltetrahydropyrimidin-1(2H)-yl)phenyl)piperidine-4-carboxaldehyde trifluoroacetate

[0363] Dess-Martin periodinane (5.09 g, 12 mmol, 10%) was added 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 atmosphere was purged with nitrogen three times, and the mixture was stirred at 25°C for 2 hours. After completion of the reaction, the mixture was diluted with water, filtered, and the filtrate was concentrated under reduced pressure and purified by column chromatography to afford 347 mg of the title compound as a brown solid in a 31.4% yield. MS (ESI) m / z = 302.1 [M+H] + . 1 H-NMR (400MHz, DMSO) δ10.33(s,1H),9.64(s,1H),7.21(t,J=22.7Hz,4H),3.72(t,J=6.7Hz,2H),3.67–3.5 5(m,2H),3.03(s,2H),2.68(t,J=6.7Hz,2H),2.57(t,J=10.6Hz,1H),2.04–1.96(m,2H),1.72–1.62(m,2H).

[0364] Referring to the synthetic route and method of intermediate B50, the following intermediate structure was synthesized:

[0365] Synthesis of intermediate B58

[0366] Step 1: Synthesis of 3-((4-bromo-2,6-difluorophenyl)amino)propionic acid

[0367] Tetrabutylammonium bromide (0.700 g, 2.18 mmol) was added portionwise to a mixture of 4-bromo-2,6-difluoroaniline (4.51 g, 21.8 mmol) and acrylic acid (1.73 g, 23.9 mmol) in dilute hydrochloric acid (48 mL, 2 mol / L). The mixture was heated to 100°C and stirred for 16 hours. The reaction solution was cooled to room temperature, evaporated to dryness under reduced pressure, and purified by column chromatography to afford 3.25 g of the title compound as a yellow solid in a 53.5% yield. MS (ESI) m / z = 280.0 / 282.0 [M+H] + .

[0368] Step 2: Synthesis of 1-(4-bromo-2,6-difluorophenyl)dihydropyrimidine-2,4(1H,3H)-dione

[0369] Sodium cyanate (3.67 g, 0.0565 mol) was added to a solution of 3-((4-bromo-2,6-difluorophenyl)amino)propionic acid (3.3 g, 0.0113 mol) in acetic acid (33 mL). The mixture was heated to 120°C and stirred for 16 hours. The reaction mixture was evaporated to dryness under reduced pressure, and ice water was added to produce a precipitate. The precipitate was filtered and the filter cake dried to afford 1.98 g of the title compound as a gray solid in a 62.8% yield. MS (ESI) m / z = 305.0 / 307.0 [M+H] + .

[0370] Step 3: Synthesis of tert-butyl 1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-3,5-difluorophenyl)piperidine-4-carboxylate

[0371] Methanesulfonic acid (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium(II) (544.18 mg, 0.650 mmol) was added to a mixture of 1-(4-bromo-2-fluoro-6-methoxyphenyl)dihydropyrimidine-2,4(1H,3H)-dione (1.32 g, 4.33 mmol), tert-butyl piperidine-4-carboxylate (801 mg, 4.33 mmol), 2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl (303 mg, 0.650 mmol) and sodium tert-butoxide (4.23 g, 13.0 mmol) in dioxane (50 mL), the atmosphere was replaced with nitrogen, the system was heated to 100°C and stirred for 1 hour. The reaction solution was dried under reduced pressure and then purified by column chromatography to obtain 377.4 mg of the title compound as a yellow solid, with a yield of 21.3%. MS (ESI) m / z = 410.2 [M+H] + .

[0372] Step 4: Synthesis of 1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-3,5-difluorophenyl)piperidine-4-carboxylic acid

[0373] Trifluoroacetic acid (3 mL) was added to a solution of tert-butyl 1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-3,5-difluorophenyl)piperidine-4-carboxylate (377.4 mg, 0.92 mmol) in dichloromethane (9 mL). The mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure and purified by column chromatography to afford 211.8 mg of the title compound as a blue solid in a 65.2% yield. MS (ESI) m / z = 354.1 [M+H] + .

[0374] Referring to the synthetic route and method of intermediate B58, the following intermediate structure was synthesized:

[0375] Synthesis of intermediate B60

[0376] Step 1: Synthesis of tert-butyl 1-(4-(2,6-di(benzyloxy)pyridin-3-yl)-3,5-difluorophenyl)piperidine-4-carboxylate

[0377] (Dibenzylideneacetone)dipalladium (570 mg, 0.622 mmol) was added to a mixture of 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (593 mg, 1.24 mmol), 2,6-di(benzyloxy)-3-(4-bromo-2,6-difluorophenyl)pyridine (3.00 g, 6.22 mmol), tert-butyl piperidinium 4-carboxylate (1.73 g, 9.33 mmol), and sodium tert-butoxide (1.20 g, 12.4 mmol) in dioxane (30 mL). The atmosphere was replaced with nitrogen, heated to 100°C, and stirred for 1 hour. The reaction mixture was evaporated to dryness under reduced pressure and purified by column chromatography to obtain 1.30 g of the compound as a light yellow oil in a 35.6% yield. MS (ESI) m / z = 587.1 [M+H] + .

[0378] Step 2: Synthesis of tert-butyl 1-(4-(2,6-dicarbonylpiperidin-3-yl)-3,5-difluorophenyl)piperidine-4-carboxylate

[0379] Palladium-carbon catalyst (0.65 g, 50% wt) was added to a solution of tert-butyl 1-(4-(2,6-di(benzyloxy)pyridin-3-yl)-3,5-difluorophenyl)piperidine-4-carboxylate (1.30 g, 2.22 mmol) in ethyl acetate (50 ml). The hydrogen atmosphere was replaced with water and the mixture was stirred at room temperature. After completion of the reaction, the reaction mixture was filtered through celite and the filtrate was concentrated under reduced pressure to obtain 700 mg of the title compound as a blue solid in a 77.3% yield. MS (ESI) m / z = 408.9 [M+H] + .

[0380] Step 3: Synthesis of 1-(4-(2,6-dicarbonylpiperidin-3-yl)-3,5-difluorophenyl)piperidine-4-carboxylic acid

[0381] Trifluoroacetic acid (2 mL) was added to a solution of tert-butyl 1-(4-(2,6-dicarbonylpiperidin-3-yl)-3,5-difluorophenyl)piperidine-4-carboxylate (700 mg, 3.80 mmol) in dichloromethane (10 mL). The mixture was stirred at room temperature for 2 hours. The reaction solution was rotary evaporated under reduced pressure and purified by column chromatography to afford 532 mg of the title compound as a bluish-gray solid in a 66.6% yield.

[0382] MS (ESI) m / z = 353.0 [M+H] + . 1 H-NMR (400MHz, DMSO-d6) δ12.23(s,1H),10.87(s,1H),6.63(d,J=12.8Hz,2H),4.04(dd,J=12.2,4.6Hz,1H),3.69(d,J=12. 6Hz,2H),2.93-2.70(m,3H),2.48-2.38(m,1H),2.18-2.03(m,1H),2.01-1.91(m,1H),1.90-1.79(m,2H),1.65-1.49(m,2H).

[0383] Referring to the synthetic route and method of intermediate B60, the following intermediate structure was synthesized:

[0384] Synthesis of intermediate B68

[0385] Step 1: Synthesis of 2,6-bis(benzyloxy)-3-(4-bromo-2-fluoro-6-methoxyphenyl)pyridine

[0386] Tetrakistriphenylphosphine palladium (0.89 g, 0.77 mmol) was added to a solution of 5-bromo-1-fluoro-2-iodo-3-methoxybenzene (2.54 g, 7.7 mmol), 2,6-bis(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) in dioxane (40 mL). Water (10 mL) was added, the atmosphere was replaced with nitrogen, and the mixture was heated to 90°C and stirred for 16 hours. Upon completion of the reaction, the mixture was diluted with water and extracted with ethyl acetate. 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 column chromatography to afford 2.0 g of the title compound as a white solid in an 85.7% yield. MS (ESI) m / z = 494.1 [M+H] + .

[0387] Step 2: Synthesis of 2,6-bis(benzyloxy)-3-(4-(4-(dimethoxymethyl)piperidin-1-yl)-2-fluoro-6-methoxyphenyl)pyridine

[0388] Tris(dibenzylideneacetone)dipalladium (354.36 mg, 0.39 mmol), 2-dicyclohexylphosphino-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 atmosphere was replaced with nitrogen, and the mixture was heated to 110°C and stirred for 10 h. The mixture was cooled to room temperature, diluted with water, and extracted with ethyl acetate. 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 column chromatography to afford 956.7 mg of the title compound as a yellow oil in a 43.2% yield. MS (ESI) m / z = 573.3 [M+H] + .

[0389] Step 3: Synthesis of 3-(4-(4-(dimethoxymethyl)piperidin-1-yl)-2-fluoro-6-methoxyphenyl)piperidine-2,6-dione

[0390] 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 mixture was replaced with hydrogen and stirred at room temperature. Upon completion of the reaction, the reaction mixture was filtered through celite and the filtrate was concentrated under reduced pressure to yield 497.0 mg of a blue solid (75.5% yield).

[0391] MS (ESI) m / z = 395.2 [M+H] + .

[0392] Step 4: Synthesis of 1-(4-(2,6-dicarbonylpiperidin-3-yl)-3-fluoro-5-methoxyphenyl)piperidine-4-carbaldehyde

[0393] 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 room temperature for 2 hours. The solvent was removed by rotary evaporation under reduced pressure, and the mixture was purified by column chromatography to obtain 170 mg of an off-white solid in a 38.9% yield. MS (ESI) m / z = 349.1 [M+H] + .

[0394] Synthesis of intermediate B69

[0395] Step 1: Synthesis of 3-[4-(3-{[4-(hydroxymethyl)cyclohexyl]oxy}prop-1-yn-1-yl)-3-methyl-2-carbonyl-1,3-benzodiazol-1-yl]piperidine-2,6-dione

[0396] Bisacetonitrile palladium dichloride (13.04 mg, 0.06 mmol) was added to a solution of [4-(prop-2-yn-1-oxy)cyclohexyl]methanol (1691.51 mg, 10.0 mmol), 3-(4-bromo-3-methyl-2-carbonyl-1,3-benzodiazol-1-yl)piperidine-2,6-dione (1700 mg, 5.02 mmol), cesium carbonate (4.91 g, 15.08 mmol), cuprous iodide (9.57 mg, 0.06 mmol) and 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl (47.93 mg, 0.1 mmol) in N,N-dimethylformamide (60 mL), and the system was heated to 80 ° C and stirred under nitrogen for 1 hour. The reaction solution was cooled, filtered, and the filtrate was concentrated under reduced pressure and purified by column chromatography to obtain 720 mg of a white solid with a yield of 34.0%. MS (ESI) m / z = 426.1 [M+H] + .

[0397] Step 2: Synthesis of 4-({3-[1-(2,6-dicarbonylpiperidin-3-yl)-3-methyl-2-carbonyl-1,3-benzodiazol-4-yl]prop-2-yn-1-yl}oxy)cyclohexane-1-carbaldehyde

[0398] Dess-Martin reagent (837.35 mg, 1.97 mmol) was added portionwise to a solution of 3-[4-(3-{[4-(hydroxymethyl)cyclohexyl]oxy}prop-1-yn-1-yl)-3-methyl-2-carbonyl-1,3-benzodiazol-1-yl]piperidine-2,6-dione (700 mg, 1.65 mmol) in dichloromethane (10 mL). The mixture was stirred at room temperature for 2 hours. The reaction mixture was evaporated to dryness under reduced pressure and purified by column chromatography to obtain 261.0 mg of a white solid in a 37.4% yield. MS (ESI) m / z = 424.2 [M+H] + . 1H-NMR (400MHz, DMSO) δ11.09 (s, 1H), 9.53 (s, 1H), 7.13 (d, J = 7.8Hz, 1H), 7.08 ( d,J=6.8Hz,1H),6.99(t,J=7.9Hz,1H),5.43–5.26(m,1H),4.49–4.31(m,2H),3.6 0(s,3H),3.52–3.37(m,1H),2.94–2.78(m,1H),2.76–2.52(m,2H),2.22(s,1H), 2.09–1.94(m,3H),1.90(d,J=12.3Hz,1H),1.73–1.48(m,1H),1.40–1.01(m,4H).

[0399] Referring to the synthetic route and method of intermediate B69, the following intermediate structure was synthesized:

[0400] Synthesis of intermediate B71

[0401] Step 1: Synthesis of 1-(2,6-dicarbonylpiperidin-3-yl)-3-methyl-2-carbonyl-2,3-dihydro-1H-benzo[d]imidazole-4-carbaldehyde

[0402] 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 was heated to 120°C in a carbon monoxide atmosphere 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 column chromatography to yield 870 mg of a light yellow solid. MS (ESI) m / z = 288.1 [M+H] + .

[0403] Step 2: Synthesis 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.

[0404] 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 column chromatography to yield 600 mg of a light yellow solid in a 40.8% yield. MS (ESI) m / z = 486.1 [M+H] + .

[0405] Step 3: Synthesis 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.

[0406] 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) at room temperature and stirred for 1 hour. The reaction solution was evaporated under reduced pressure to obtain a crude product, which was purified by column chromatography to afford 310 mg of the title compound as a yellow solid in a 58.4% yield. MS (ESI) m / z = 386.1 [M+H] + .

[0407] Synthesis of intermediate B72

[0408] Step 1: Synthesis of tert-butyl 2-(1-(3-(2,4-dicarbonyltetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)-4-hydroxypiperidin-4-yl)acetate

[0409] Methanesulfonic acid (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium(II) (544.2 mg, 0.65 mmol) was added to a mixture of 1-(6-bromo-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (1.4 g, 4.33 mmol), tert-butyl 2-(4-hydroxypiperidin-4-yl)acetate (932.7 mg, 4.33 mmol), 2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl (303.2 mg, 0.65 mmol) and cesium carbonate (4.23 g, 13.0 mmol) in dioxane (50 mL), the atmosphere was replaced with nitrogen, the mixture was heated to 100°C and stirred for 16 hours. The reaction solution was dried under reduced pressure and then purified by column chromatography to obtain 550 mg of a yellow solid with a yield of 27.7%. MS (ESI) m / z = 458.0 [M+H] + .

[0410] Step 2: Synthesis of 2-(1-(3-(2,4-dicarbonyltetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)-4-hydroxypiperidin-4-yl)acetic acid

[0411] Trifluoroacetic acid (3 mL) was added dropwise to a solution of tert-butyl 2-(1-(3-(2,4-dicarbonyltetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)-4-hydroxypiperidin-4-yl) acetate (550 mg, 1.2 mmol) in dichloromethane (3 mL). The system was stirred at room temperature for 2 hours. The reaction solution was rotary evaporated under reduced pressure and purified by carbon column chromatography to obtain 441 mg of a white solid in a 90.2% yield. MS (ESI) m / z = 402.2 [M+H] + . 1H-NMR (400MHz, DMSO) δ10.53 (s, 1H), 7.53 (d, J = 8.8Hz, 1H), 7.14–7.01 (m, 2H), 3.95–3.82 (m, 5H), 3.5 8–3.47(m,2H),3.31(s,2H),2.74(t,J=6.7Hz,2H),2.43(s,2H),1.95-1.84(m,2H),1.79–1.71(m,2H).

[0412] Referring to the synthetic route and method of intermediate B72, the following intermediate structure was synthesized:

[0413] Synthesis of intermediate B74

[0414] Step 1: Synthesis of 1-(6-(4-(dimethoxymethyl)piperidin-1-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

[0415] Cesium carbonate (7.53 g, 23.1 mmol), 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 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 atmosphere was replaced with nitrogen, and the mixture was heated to 100°C and stirred for 16 hours. After the reaction was complete, the mixture was cooled to room temperature, diluted with water, and extracted with ethyl acetate. 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 column chromatography to obtain 1.1 g of a yellow oily compound in a yield of 20.8%. MS (ESI) m / z = 402.0 [M+H] + .

[0416] Step 2: Synthesis of 1-(3-(2,4-dicarbonyltetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperidine-4-carboxaldehyde trifluoroacetate

[0417] 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 room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure at low temperature and purified by column chromatography to afford 534.8 mg of the title compound as a white solid in a 58.2% yield. MS (ESI) m / z = 356.1 [M+H] + . 1 H-NMR (400MHz, DMSO) δ10.51(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),3.7 0(dd,J=8.9,3.8Hz,2H),2.97(s,2H),2.73(t,J=6.7Hz,2H),2.58–2.55(m,1H),2.04-1.97(m,2H),1.72–1.62(m,2H).

[0418] Synthesis of intermediate B75

[0419] Step 1: Synthesis of 3-[2,6-di(benzyloxy)pyridin-3-yl]-6-[4-(dimethoxymethyl)piperidin-1-yl]-1-methylindazole

[0420] Palladium acetate (197.4 mg, 0.799 mmol) was added to a 20 mL toluene solution of 3-[2,6-di(benzyloxy)pyridin-3-yl]-6-bromo-1-methylindazole (2.0 g, 3.99 mmol), 4-(dimethoxymethyl)piperidine (636.4 mg, 3.99 mmol), cesium carbonate (3.90 g, 11.99 mmol), and 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (497.7 mg, 0.799 mmol). The mixture was heated to 100°C and stirred under nitrogen for 15 hours. The mixture was extracted with ethyl acetate, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the residue obtained by rotary evaporation under reduced pressure was purified by column chromatography to yield 1.3 g of a yellow solid in a 56.2% yield. MS (ESI) m / z = 579.2 [M+H] + .

[0421] Step 2: Synthesis of 3-{6-[4-(dimethoxymethyl)piperidin-1-yl]-1-methylindazol-3-yl}piperidine-2,6-dione

[0422] Palladium-on-carbon catalyst (441.3 mg, 0.415 mmol, 10%) was added to a solution of 3-[2,6-di(benzyloxy)pyridin-3-yl]-6-[4-(dimethoxymethyl)piperidin-1-yl]-1-methylindazole (1.2 g, 2.07 mmol) in ethyl acetate. The hydrogen atmosphere was replaced with water, and the mixture was stirred at room temperature for 16 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure and purified by column chromatography to afford 600 mg of the title compound as a yellow solid in a 61.4% yield. MS (ESI) m / z = 401.2 [M+H] + .

[0423] Step 3: Synthesis of 1-[3-(2,6-dicarbonylpiperidin-3-yl)-1-methylindazol-6-yl]piperidine-4-carboxaldehyde

[0424] Trifluoroacetic acid (5 mL) was added dropwise to a solution of 3-{6-[4-(dimethoxymethyl)piperidin-1-yl]-1-methylindazol-3-yl}piperidine-2,6-dione (550 mg, 1.37 mmol) in dichloromethane (10 mL). The mixture was stirred at room temperature for 2 hours. The reaction mixture was dried under reduced pressure and purified by column chromatography to afford 432.5 mg of a white solid in an 87.8% yield. MS (ESI) m / z = 355.2 [M+H] + . 1 H-NMR (400MHz, DMSO) δ10.89(s,1H),9.66(s,1H),7.58(d,J=8.9Hz,1H),7.11(s,1H),7.02(d,J=8.8Hz,1H),4.29(dd,J=9.5,5.0Hz,1H),3.92(s,3 H),3.70(d,J=12.5Hz,2H),3.07(t,J=11.2Hz,2H),2.72–2.54(m,3H),2. 39–2.25(m,1H),2.22–2.10(m,1H),2.07–1.98(m,2H),1.79–1.63(m,2H).

[0425] Synthesis of intermediate B76

[0426] Step 1: Synthesis of 7-(4-nitro-2-(trifluoromethyl)phenyl)-7-azaspiro[3.5]nonan-2-one

[0427] N,N-Diisopropylethylamine (6.63 g, 51.3 mmol) was added to a solution of 7-azaspiro[3.5]nonan-2-one hydrochloride (3.0 g, 17.1 mmol) and 1-fluoro-4-nitro-2-(trifluoromethyl)benzene (3.59 g, 17.1 mmol) in dimethyl sulfoxide (30 mL). The atmosphere was replaced with nitrogen and the mixture was heated to 120°C and stirred for 16 hours. After completion of the reaction, the mixture was cooled to room temperature, diluted with water, and extracted with dichloromethane. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by column chromatography to afford 3.2 g of the title compound as a brown solid in a 56.7% yield. MS (ESI) m / z = 329.1 [M+H] + .

[0428] Step 2: Synthesis of 7-(4-amino-2-(trifluoromethyl)phenyl)-7-azaspiro[3.5]nonan-2-one

[0429] Palladium-carbon catalyst (0.32 g, 10% wt) was added to a solution of 7-(4-nitro-2-(trifluoromethyl)phenyl)-7-azaspiro[3.5]nonan-2-one (3.2 g, 9.7 mmol) in methanol (50 mL). The hydrogen atmosphere was replaced, and the mixture was stirred at 25°C for 16 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to provide 2.2 g of the title compound as a brown solid, in a 49.5% yield. MS (ESI) m / z = 299.1 [M+H] + .

[0430] Step 3: Synthesis of 7-(4-((2,6-di(benzyloxy)pyridin-3-yl)amino)-2-(trifluoromethyl)phenyl)-7-azaspiro[3.5]nonan-2-one

[0431] Tris(dibenzylideneacetone)dipalladium (0.68 g, 0.74 mmol) was added to a mixture of 7-(4-amino-2-(trifluoromethyl)phenyl)-7-azaspiro[3.5]nonan-2-one (2.2 g, 7.4 mmol), 2,6-di(benzyloxy)-3-bromopyridine (3.29 g, 8.9 mmol), 2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl (0.35 g, 0.74 mmol) and cesium carbonate (7.23 g, 22.2 mmol) in tert-butanol (100 mL), the atmosphere was replaced with nitrogen, the system was heated to 100°C and stirred for 16 hours. The reaction mixture was cooled to room temperature, water was added, and extraction was performed with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The residue obtained by rotary evaporation under reduced pressure was separated and purified by column chromatography to obtain 1.2 g of a white solid, with a yield of 25.7%. MS (ESI) m / z = 588.2 [M+H] + .

[0432] Step 4: Synthesis of 3-((4-(2-carbonyl-7-azaspiro[3.5]nonan-7-yl)-3-(trifluoromethyl)phenyl)amino)piperidine-2,6-dione

[0433] Palladium-on-carbon catalyst (0.36 g, 30% wt) was added to a solution of 7-(4-((2,6-di(benzyloxy)pyridin-3-yl)amino)-2-(trifluoromethyl)phenyl)-7-azaspiro[3.5]nonan-2-one (1.2 g, 2.0 mmol) in ethyl acetate (100 ml). The hydrogen atmosphere was replaced with the solution and stirred overnight at room temperature. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to yield 0.3 g of a white solid (35.0% yield). MS (ESI) m / z = 410.1 [M+H] + . 1H-NMR(400MHz,DMSO)δ10.79(s,1H),7.28(d,J=8.7Hz,1H),6.94–6.85(m,2H),4.71(brs,1H),4.38(dd,J=11.5,4.8 Hz,1H),2.92-2.71(m,4H),2.78–2.66(m,5H),2.63–2.53(m,1H),2.12–2.03(m,1H),1.95–1.86(m,1H),1.79–1.68(m 4H).

[0434] Referring to the synthetic route and method of intermediate B76, the following intermediate structure was synthesized:

[0435] Synthesis of intermediate B78

[0436] Step 1: Synthesis of tert-butyl 4-(3-amino-4-cyano-1H-pyrazol-1-yl)piperidine-1-carboxylate

[0437] 3-Amino-1H-pyrazole-4-carbonitrile (4.0 g, 37 mmol), tert-butyl 4-((methylsulfonyl)oxy)piperidine-1-carboxylate (15.52 g, 55.5 mmol), and cesium carbonate (24.1 g, 74 mmol) were dissolved in DMF (100 mL) and stirred at 80°C overnight. The mixture was quenched with water and extracted with EA. The organic phase was dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography to obtain the title compound (5.2 g, yellow solid, 48.2% yield). MS (ESI) m / z: 236.1 [M-56+H] +

[0438] Step 2: Synthesis of tert-butyl 4-(3-amino-4-carbamoyl-1H-pyrazol-1-yl)piperidine-1-carboxylate

[0439] In an ice-water bath, 30% hydrogen peroxide (3.5 mL, 34.4 mmol) was added dropwise to a reaction mixture containing tert-butyl 4-(3-amino-4-cyano-1H-pyrazol-1-yl)piperidine-1-carboxylate (5.0 g, 17.2 mmol), potassium carbonate (470 mg, 3.44 mmol), and DMSO (50 mL). The mixture was stirred at room temperature for 4 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 obtain the target compound (2.63 g, white solid, yield 48.6%). MS (ESI) m / z: 332.1 [M+Na] + . 1 H-NMR (400MHz, DMSO-d6) δ: 7.96 (s, 1H), 7.17 (s, 1H), 6.72 (s, 1H), 5.37 (s, 2H), 3 .90-4.12(m,3H),2.88(s,2H),1.90-2.00(m,2H),1.54-1.68(m,2H),1.41(s,9H).

[0440] Referring to the synthetic route and method of intermediate C1, the following intermediate structure was synthesized:

[0441] Synthesis of intermediate C3

[0442] Step 1: 5-nitro-4-(piperidin-1-yl)pyridin-2-amine

[0443] 4-Chloro-5-nitropyridin-2-amine (20.0 g, 115.2 mmol), DIEA (29.5 g, 345.6 mmol), and piperidine (29.5 g, 345.6 mmol) were dissolved in THF (250 mL). The mixture was stirred at 70°C overnight. The mixture was quenched with water and extracted with EA. The organic phase was dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography to obtain 20.5 g of a yellow solid (80.1% yield). MS (ESI) m / z: 223.1 [M+H] +

[0444] Step 2: tert-Butyl 4-(6-nitro-7-(piperidin-1-yl)imidazo[1,2-a]pyridin-2-yl)piperidine-1-carboxylate

[0445] Dissolve 5-nitro-4-(piperidin-1-yl)pyridin-2-amine (6.0 g, 27.00 mmol) in ethanol (100 mL), then add tert-butyl 4-(2-bromoacetyl)piperidine-1-carboxylate (5.82 g, 29.7 mmol). Stir the reaction mixture at 120°C for 40 hours. Pour the mixture into water and extract with dichloromethane. The organic phase is dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue is separated and purified by column chromatography to obtain 3.5 g of the target compound as a red solid in a 30.2% yield. MS (ESI) m / z: 430.2 [M+H] + .

[0446] Step 3: Synthesis of tert-butyl 4-(6-amino-7-(piperidin-1-yl)imidazo[1,2-a]pyridin-2-yl)piperidine-1-carboxylate

[0447] Tert-butyl 4-(6-nitro-7-(piperidin-1-yl)imidazo[1,2-a]pyridin-2-yl)piperidine-1-carboxylate (3.5 g, 8.14 mmol) was dissolved in methanol (100 mL), followed by the addition of Pd / C (400 mg). The reaction mixture was stirred at room temperature under hydrogen for 16 hours. The reaction mixture was filtered and concentrated under reduced pressure to obtain 2.0 g of a yellow solid with a yield of 61.4%. MS (ESI) m / z: 400.2 [M+H] +

[0448] Referring to the synthetic route and method of intermediate C3, the following intermediate structure was synthesized:

[0449] Synthesis of intermediate C5

[0450] Step 1: Synthesis of 2-azido-4-chloro-5-nitrobenzaldehyde

[0451] Sodium azide (2.52 g, 38.8 mmol) was added to a reaction solution containing 4-chloro-2-fluoro-5-nitrobenzaldehyde (7.9 g, 38.8 mmol) and DMSO (50 mL). Stir at 30°C for 1 h. The reaction solution 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 and filtered to yield 5.0 g of a yellow solid (56.9% yield).

[0452] Step 2: Synthesis of 2-azido-5-nitro-4-(piperidin-1-yl)benzaldehyde

[0453] To the reaction mixture containing 2-azido-4-chloro-5-nitrobenzaldehyde (4.5 g, 19.9 mmol) and DMSO (100 mL) was added piperidine (5.1 g, 59.7 mmol). 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 afford 5.2 g of a brown solid (94.9% yield). MS (ESI) m / z: 276.1 [M+H] +

[0454] Step 3: Synthesis of tert-butyl 4-(5-nitro-6-(piperidin-1-yl)-2H-indazol-2-yl)piperidine-1-carboxylate

[0455] A reaction mixture containing 2-azido-5-nitro-4-(piperidin-1-yl)benzaldehyde (5.2 g, 18.89 mmol), tert-butyl 4-aminopiperidine-1-carboxylate (3.78 g, 18.89 mmol), trimethyl orthoformate (6.0 g, 56.67 mmol), and DCM (100 mL) was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure and purified by column chromatography to yield 3.5 g of the target compound as a yellow solid in a 43.2% yield. MS (ESI) m / z: 430.2 [M+H] + .

[0456] Step 4: Synthesis of tert-butyl 4-(5-amino-6-(piperidin-1-yl)-2H-indazol-2-yl)piperidine-1-carboxylate

[0457] To the reaction mixture containing tert-butyl 4-(5-nitro-6-(piperidin-1-yl)-2H-indazol-2-yl)piperidine-1-carboxylate (1.40 g, 3.26 mmol) and methanol (15 mL) was added Pd / C (0.2 g). The atmosphere was replaced with hydrogen and stirred at room temperature overnight. The reaction mixture was filtered and concentrated under reduced pressure to obtain the title compound (1.15 g, gray solid, 88% yield). MS (ESI) m / z: 400.3 [M+H] + . 1 H-NMR (400MHz, CDCl3) δ: 7.62 (s, 1H), 7.25 (s, 1H), 6.80 (s, 1H), 4.47-4.28 ( m,5H),2.91-2.85(m,6H),2.19-2.03(m,4H),1.79-1.61(m,6H),1.45(s,9H)

[0458] Referring to the synthetic route and method of intermediate C5, the following intermediate structure was synthesized:

[0459] Synthesis of intermediate C19

[0460] Step 1: Synthesis of tert-butyl 4-(6-chloro-5-nitro-2H-indazol-2-yl)piperidine-1-carboxylate

[0461] To 100 mL of a DCM solution of 2-azido-4-chloro-5-nitrobenzaldehyde was added toluene (200 mL), followed by tert-butyl 4-aminopiperidine-1-carboxylate (8.84 g, 44.13 mmol) and trimethyl orthoformate (14.05 g, 132.39 mmol), and the mixture was stirred at room temperature for 3 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by column chromatography to obtain 12.1 g of a yellow solid (72.0% yield). MS (ESI) m / z: 325.0 [M-56+H] + .

[0462] Step 2: Synthesis of tert-butyl 4-(5-nitro-6-phenyl-2H-indazol-2-yl)piperidine-1-carboxylate

[0463] Tert-butyl 4-(6-chloro-5-nitro-2H-indazol-2-yl)piperidine-1-carboxylate (12.0 g, 31.51 mmol) was dissolved in toluene (210 mL), and phenylboronic acid (19.21 g, 157.56 mmol), potassium carbonate (34.84 g, 252.10 mmol), palladium acetate (2.4 g), and water (150 mL) were added. The reaction solution was stirred at 100°C for 16 hours. After completion of the reaction, water was added to quench the reaction, and the mixture was extracted with ethyl acetate. The organic phase was dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was separated and purified by column chromatography to obtain 7.0 g of the target compound as an orange solid in a yield of 52.6%. MS (ESI) m / z: 423.2 [M+H] + .

[0464] Step 3: Synthesis of tert-butyl 4-(5-amino-6-phenyl-2H-indazol-2-yl)piperidine-1-carboxylate

[0465] Dissolve tert-butyl 4-(5-nitro-6-phenyl-2H-indazol-2-yl)piperidine-1-carboxylate (3.0 g, 7.10 mmol) in methanol (60 mL). Add Pd / C (400 mg). Stir the reaction mixture at room temperature for 16 hours. Filter the mixture and dry it under reduced pressure to obtain 2.4 g of a white solid (85.9% yield). MS (ESI) m / z: 393.2 [M+H] + . 1H-NMR (400MHz, CDCl3) δ: 7.71 (s, 1H), 7.50-7.36 (m, 6H), 6.86 (s, 1H), 4.54-4.46 (m, 1H), 4.30 ( s,2H),3.59-3.48(m,2H),2.95-2.90(m,2H),2.23-2.20(m,2H),2.12-2.02(m,2H),1.48(s,9H).

[0466] Referring to the synthetic route and method of intermediate C19, the following intermediate structure was synthesized:

[0467] Synthesis of intermediate C26

[0468] Step 1: Synthesis of methyl 4-methyl-6-nitro-[1,1'-biphenyl]-3-carboxylate

[0469] Methyl 5-chloro-2-methyl-4-nitrobenzoate (5.0 g, 21.78 mmol) was dissolved in 1,4-dioxane (100 mL). Water (20 mL), phenylboronic acid (5.31 g, 43.55 mmol), potassium carbonate (9.03 g, 65.33 mmol), and Pd(dppf)Cl2 (700 mg) were added. The mixture was heated at 100°C and stirred under nitrogen for 16 hours. The reaction mixture was poured into water and extracted with dichloromethane. The organic phase was dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography to obtain 4.2 g of a yellow solid in a 72.8% yield.

[0470] Step 2: Synthesis of methyl 4-(bromomethyl)-6-nitro-[1,1'-biphenyl]-3-carboxylate

[0471] Dissolve methyl 4-methyl-6-nitro-[1,1'-biphenyl]-3-carboxylate (4.2 g, 15.48 mmol) in carbon tetrachloride (80 mL), add N-bromosuccinimide (2.76 g, 15.48 mmol) and azobisisobutyronitrile (500 mg). Stir the reaction mixture at 80°C for 16 hours. Pour the mixture into water and extract with dichloromethane. The organic phase is dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue is purified by column chromatography to obtain 2.9 g of the target compound as a yellow oil in a 52.2% yield.

[0472] Step 3: Synthesis of tert-butyl 4-(5-nitro-1-oxo-6-phenylisoindol-2-yl)piperidine-1-carboxylate

[0473] Methyl 4-(bromomethyl)-6-nitro-[1,1'-biphenyl]-3-carboxylate (2.9 g, 8.28 mmol) was dissolved in methanol (50 mL), and tert-butyl 4-aminopiperidine-1-carboxylate (1.99 g, 9.94 mmol) and DIEA (2.14 g, 16.56 mmol) were added. The reaction mixture was stirred at 60°C for 16 hours. The reaction mixture was poured into water and extracted with dichloromethane. The organic phase was dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was separated and purified by column chromatography to obtain 3.1 g of a yellow solid with a yield of 85.6%. MS (ESI) m / z: 382.1 [M-56+H] + .

[0474] Step 4: Synthesis of tert-butyl 4-(5-amino-1-oxo-6-phenylisoindol-2-yl)piperidine-1-carboxylate

[0475] Dissolve tert-butyl 4-(5-nitro-1-oxo-6-phenylisoindol-2-yl)piperidine-1-carboxylate (3.0 g, 6.86 mmol) in ethyl acetate (60 mL). Add Pd / C (700 mg) to displace the hydrogen atmosphere. Stir at room temperature for 4 hours. The reaction mixture is filtered and dried under reduced pressure to yield 2.1 g of a white solid (75.2% yield). MS (ESI) m / z: 352.2 [M-56+H]. + . 1 H-NMR (400MHz, CDCl3) δ: 7.61 (s, 1H), 7.47-7.35 (m, 5H), 6.80 (s, 1H), 4.40-4.36 (m, 1 H),4.26(s,4H),2.89-2.83(m,2H),1.83-1.80(m,2H),1.67-1.64(m,2H),1.48(s,9H).

[0476] Referring to the synthetic route and method of intermediate C26, the following intermediate structure was synthesized:

[0477] Synthesis of intermediate C29

[0478] Step 1: Synthesis of 5-chlorooxazolo[4,5-b]pyridine-2-thiol

[0479] 2-Amino-6-chloropyridin-3-ol (50.0 g, 347.2 mmol) was dissolved in pyridine (400 mL), and potassium O-ethylcarbonyldisulfide (83.5 g, 520.8 mmol) was added. The reaction mixture was stirred at 120°C for 8 hours. The reaction mixture was concentrated, diluted with water, and the pH was adjusted to 2. The solid was filtered and dried under reduced pressure to obtain 44.0 g of a yellow solid with a yield of 67.9%. MS (ESI) m / z: 187.0 [M+H]+ .

[0480] Step 2: Synthesis of tert-butyl 4-(5-chlorooxazolo[4,5-b]pyridin-2-yl)piperazine-1-carboxylate

[0481] 5-Chlorooxazolo[4,5-b]pyridine-2-thiol (38.0 g, 203.6 mmol) was dissolved in xylene (200 mL), and tert-butyl piperazine-1-carboxylate (41.7 g, 223.98 mmol) and DIEA (52.6 g, 407.2 mmol) were added. The reaction mixture was stirred at 120°C for 16 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The organic phase was dried over Na2SO4, filtered, and concentrated under reduced pressure. The product was separated and purified by column chromatography and dried under reduced pressure to obtain 44.0 g of a white solid with a yield of 63.7%. MS (ESI) m / z: 339.1 [M+H] + .

[0482] Step 3: Synthesis of 5-chloro-6-nitro-2-(piperazin-1-yl)oxazolo[4,5-b]pyridine

[0483] Dissolve tert-butyl 4-(5-chlorooxazolo[4,5-b]pyridin-2-yl)piperazine-1-carboxylate (22.3 g, 65.8 mmol) in concentrated sulfuric acid (100 ml). Add KNO3 (26.6 g, 263.3 mmol). Stir the reaction mixture at room temperature for 16 hours. Pour the reaction mixture into ice water, adjust the pH to 8 with sodium bicarbonate, and proceed directly to the next step.

[0484] Step 4: Synthesis of tert-butyl 4-(5-chloro-6-nitrooxazolo[4,5-b]pyridin-2-yl)piperazine-1-carboxylate

[0485] 5-Chloro-6-nitro-2-(piperazin-1-yl)oxazolo[4,5-b]pyridine (21.3 g, 75.0 mmol) was dissolved in dichloromethane (100 mL). Boc2O (32.78 g, 150.17 mmol) was added, and the reaction mixture was stirred at room temperature for half an hour. The reaction mixture was filtered, and the filtrate was extracted with dichloromethane. The organic phase was dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography to obtain 20 g of the target compound as a yellow solid in a 71.4% yield. MS (ESI) m / z: 384.1 [M+H] + .

[0486] Step 5: Synthesis of tert-butyl (S)-4-(5-(3-hydroxypyrrolidin-1-yl)-6-nitrooxazolo[4,5-b]pyridin-2-yl)piperazine-1-carboxylate

[0487] Tert-butyl 4-(5-chloro-6-nitrooxazolo[4,5-b]pyridin-2-yl)piperazine-1-carboxylate (10.0 g, 26.06 mmol) was dissolved in tetrahydrofuran (200 mL), and (S)-pyrrolidin-3-ol (4.54 g, 52.11 mmol) was added. The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was poured into water and extracted with dichloromethane. The organic phase was dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography to obtain 9.0 g of a yellow solid in a yield of 79.5%. MS (ESI) m / z: 435.2 [M+H] + .

[0488] Step 6: Synthesis of (S)-tert-butyl 4-(6-amino-5-(3-hydroxypyrrolidin-1-yl)oxazolo[4,5-b]pyridin-2-yl)piperazine-1-carboxylate

[0489] (S)-tert-Butyl 4-(5-(3-hydroxypyrrolidin-1-yl)-6-nitrooxazolo[4,5-b]pyridin-2-yl)piperazine-1-carboxylate (9.0 g, 20.72 mmol) was dissolved in ethyl acetate (200 ml) and palladium-carbon catalyst (1.5 g) was added. The reaction mixture was stirred at room temperature under a hydrogen atmosphere for 16 hours. The reaction mixture was filtered and the resulting liquid was concentrated under reduced pressure to give 6.5 g of a solid with a yield of 77.6%. MS (ESI) m / z: 405.2 [M+H] + .

[0490] Referring to the synthetic route and method of intermediate C29, the following intermediate structure was synthesized:

[0491] Synthesis of intermediate C34

[0492] Step 1: Synthesis of 5-nitro-6-(piperidin-1-yl)-2-(piperidin-4-yl)-2-hydrogen-indazole hydrochloride

[0493] 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) in dichloromethane (40 mL) was added a 4M 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. MS (ESI) m / z: 330.2 [M+H] + .

[0494] Step 2: Synthesis of N-(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

[0495] Azo-(2,6-dicarbonylpiperidin-3-yl)-2-fluoro-4-(4-formylpiperidin-1-yl)benzamide (2.0 g, 5.54 mmol) 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) in N,N-dimethylacetamide (40 mL). Glacial acetic acid (0.58 ml, 10.08 mmol) was added dropwise and stirred at room temperature for 5 hours. Then, sodium triacetoxyborohydride (2.14 g, 10.08 mmol) was added and stirred for 2 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The organic phase was dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography to yield 3.02 g of a reddish-brown solid in an 88.8% yield. MS (ESI) m / z = 675.3 [M+H] + .

[0496] Step 3: Synthesis 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

[0497] 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 methanol (30 ml), followed by the addition of 5% palladium on carbon (150 mg). The hydrogen atmosphere was replaced three times, and the reaction system was stirred at room temperature for 16 hours. The reaction solution was filtered, and the filtrate was dried to give 1.23 g of a gray-brown solid (yield 85.4%). MS (ESI) m / z = 645.4 [M+H] + .

[0498] Referring to the synthetic route and method of intermediate C34, the following intermediate structure was synthesized:

[0499] Synthesis of intermediate C43

[0500] Step 1: Synthesis of 8-bromoimidazo[1,2-c]pyrimidin-5(6H)-one

[0501] Dissolve 4-amino-5-bromopyrimidin-2(1H)-one (10.0 g, 52.63 mmol) in water (200 mL), add NaOAc (12.95 g, 157.89 mmol) and 2-chloroacetaldehyde (40% aqueous solution) (20.66 g, 105.26 mmol). Stir at 80°C for 12 h. Quench with water, extract with ethyl acetate, and the organic phase is dried and purified by column chromatography to obtain 8.0 g of a light yellow solid in a 71.0% yield. MS (ESI) m / z: 214.1 [M+H] +

[0502] Step 2: Synthesis of methyl 5-oxo-5,6-dihydroimidazo[1,2-c]pyrimidine-8-carboxylate

[0503] Dissolve 8-bromoimidazo[1,2-c]pyrimidin-5(6H)-one (4 g, 18.8 mmol) in methanol (50 mL), add triethylamine (6.45 g, 63.8 mmol) and Pd(dppf)Cl2 (1.2 g). Stir at 100°C under carbon monoxide for 18 hours. The reaction mixture is concentrated and purified by column chromatography to obtain the title compound as a light red solid (2.5 g, 69.1% yield). MS (ESI) m / z: 194.1 [M+H] +

[0504] Step 3: Synthesis of 5-oxo-5,6-dihydroimidazo[1,2-c]pyrimidine-8-carboxylic acid

[0505] Methyl 5-oxo-5,6-dihydroimidazo[1,2-c]pyrimidine-8-carboxylate (1 g, 5.18 mmol) was dissolved in 10 mL of water and 10 mL of methanol, and lithium hydroxide monohydrate (497 mg, 20.7 mmol) was added. The mixture was stirred at 50°C for 6 hours. The reaction mixture was concentrated and adjusted to pH 4 with 2M hydrochloric acid until solids formed. The mixture was filtered and concentrated under reduced pressure to yield 720 mg of a light yellow solid (77.6% yield). MS (ESI) m / z: 180.0 [M+H] + . 1 H-NMR (400MHz, DMSO) δ: 8.05 (s, 1H), 7.84 (d, J = 1.6 Hz, 1H), 7.47 (d, J = 1.6 Hz, 1H).

[0506] Referring to the synthetic route and method of intermediate C43, the following intermediate structure was synthesized:

[0507] Synthesis of intermediate C49

[0508] Step 1: Synthesis of ethyl 5-methylimidazo[1,2-a]pyrimidine-7-carboxylate

[0509] Ethyl 2-amino-6-methylpyrimidine-4-carboxylate (7.0 g, 38.63 mmol) was dissolved in DCM (150 mL), and 40% chloroacetaldehyde solution (11.38 g, 57.95 mmol) was added. The reaction mixture was stirred at 90°C for 4 hours. The reaction mixture was poured into water and extracted with dichloromethane. The organic phase was concentrated under reduced pressure, and the residue was purified by column chromatography to obtain 900 mg of the title compound as a white solid in a 9.3% yield. MS (ESI) m / z: 206.1 [M+H] + .

[0510] Step 2: Synthesis of 5-methylimidazo[1,2-a]pyrimidine-7-carboxylic acid

[0511] Ethyl 5-methylimidazo[1,2-a]pyrimidine-7-carboxylate (800 mg, 3.90 mmol) was dissolved in THF (20 mL) and water (5 mL). Lithium hydroxide monohydrate (491 mg, 11.7 mmol) was added and the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was spin-dried, water was added, and 3M citric acid was slowly added dropwise until the pH reached 5. The mixture was filtered and the filter cake was dried to obtain 435 mg of a white solid (63.0% yield). MS (ESI) m / z: 178.1 [M+H] + . 1 H-NMR (400MHz, DMSO) δ: 13.37 (brs, 1H), 8.08 (s, 1H), 8.01 (s, 1H), 7.55 (s, 1H), 2.76 (s, 3H).

[0512] Referring to the synthetic route and method of intermediate C49, the following intermediate structure was synthesized:

[0513] Synthesis of intermediate C51

[0514] Step 1: Synthesis of ethyl 7-(pyridin-4-yl)thieno[2,3-b]pyrazine-6-carboxylate

[0515] To a solution of ethyl 7-bromothieno[2,3-b]pyrazine-6-carboxylate (4.0 g, 13.93 mmol) in 1,4-dioxane (100 mL) and water (20 mL) were added pyridin-4-ylboronic acid (3.42 g, 27.86 mmol), sodium bicarbonate (3.51 g, 41.79 mmol), and PdCl2(dppf) (0.5 g). Stirred under nitrogen at 80°C for 16 h. The reaction mixture was poured into water and extracted with ethyl acetate. The organic phase was concentrated and purified by column chromatography to afford 1.8 g of a white solid in a 45.3% yield. MS (ESI) m / z: 286.0 [M+H] +

[0516] Step 2: Synthesis of 7-(pyridin-4-yl)thieno[2,3-b]pyrazine-6-carboxylic acid

[0517] Ethyl 7-(pyridin-4-yl)thieno[2,3-b]pyrazine-6-carboxylate (1.8 g, 6.31 mmol) was dissolved in methanol (50 mL), and sodium hydroxide (0.5 g, 12.62 mmol) and water (5 mL) were added. The reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure and the pH was adjusted to 5 with 2M HCl. A solid precipitated and was filtered. The filter cake was dried to obtain 1.3 g of a white solid, with a yield of 80.1%. MS (ESI) m / z: 258.0 [M+H] + . 1 H-NMR (400MHz, DMSO) δ: 14.11 (brs, 1H), 8.85-8.83 (m, 2H), 8.69-8.67 (m, 2H), 7.55-7.53 (m, 2H).

[0518] Referring to the synthetic route and method of intermediate C51, the following intermediate structure was synthesized:

[0519] Synthesis of intermediate C54

[0520] Step 1: Synthesis of methyl imidazo[1,2-b]pyridazine-7-carboxylate

[0521] Methyl 6-aminopyridazine-4-carboxylate (730 mg, 4.77 mmol) was dissolved in isopropanol (30 mL) and 40% chloroacetaldehyde (2.81 g, 14.31 mmol) was added. The reaction mixture was stirred at 100°C for 16 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The organic phase was dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography to obtain 600 mg of a white solid in a 71.1% yield. MS (ESI) m / z: 178.1 [M+H] +

[0522] Step 2: Synthesis of imidazo[1,2-b]pyridazine-7-carboxylic acid

[0523] Methyl imidazo[1,2-b]pyridazine-7-carboxylate (600 mg, 3.39 mmol) was dissolved in THF (20 mL) and water (5 mL), and LiOH-H2O (427 mg, 10.16 mmol) was added. The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated, 3M hydrochloric acid was added dropwise to pH = 5, filtered, and the filter cake was dried to obtain 20 mg of a white solid (76.1% yield). MS (ESI) m / z: 164.1 [M+H] + . 1 H-NMR (400MHz, DMSO) δ: 8.87 (s, 1H), 8.55 (s, 1H), 8.51 (s, 1H), 8.01 (s, 1H).

[0524] Synthesis of intermediate C55

[0525] Step 1: Synthesis of methyl 6-((4-methoxybenzyl)amino)pyridazine-4-carboxylate

[0526] Methyl 6-chloropyridazine-4-carboxylate (5.0 g, 28.97 mmol) was dissolved in DMSO (50 mL), and (4-methoxyphenyl)methanamine (4.77 g, 34.77 mmol) and DIEA (11.23 g, 86.92 mmol) were added. The reaction mixture was stirred at 120°C for 2.5 hours. The reaction mixture was filtered, the filtrate poured into water, and extracted with ethyl acetate. The organic phase was dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was separated and purified by column chromatography to obtain 2.3 g of the title compound as a yellow solid in a 31.6% yield. MS (ESI) m / z: 274.1 [M+H] +

[0527] Step 2: Synthesis of methyl 6-aminopyridazine-4-carboxylate

[0528] Methyl 6-((4-methoxybenzyl)amino)pyridazine-4-carboxylate (2.3 g, 8.42 mmol) was dissolved in trifluoroacetic acid (40 mL), and the reaction mixture was stirred at 80°C for 16 hours. The reaction mixture was spin-dried, poured into aqueous sodium bicarbonate, and extracted with dichloromethane. The organic phase was dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography to yield 730 mg of a yellow solid in a 56.7% yield. MS (ESI) m / z: 154.1 [M+H] +

[0529] Step 3: Synthesis of 6-aminopyridazine-4-carboxylic acid

[0530] Methyl 6-aminopyridazine-4-carboxylate (1.05 g, 6.53 mmol) was dissolved in concentrated hydrochloric acid (20 mL). The reaction mixture was stirred at 100°C for 16 hours. The reaction mixture was concentrated under reduced pressure to obtain 906 mg of a brown solid with a yield of 94.9%. MS (ESI) m / z: 140.1 [M+H] + . 1 H-NMR (400MHz, DMSO) δ: 9.00 (br s, 2H), 8.66 (s, 1H), 7.98 (s, 1H).

[0531] Synthesis of intermediate C56

[0532] Step 1: Synthesis of 2-chloro-5-fluoro-4-(furan-2-yl)pyrimidine

[0533] Dissolve 2,4-dichloro-5-fluoropyrimidine (10.0 g, 59.8 mmol) in 1,4-dioxane (120 mL) and water (30 mL). Add furan-2-ylboronic acid (8.0 g, 71.8 mmol), sodium carbonate (19.0 g, 179.4 mmol), and trisdibenzylideneacetone dipalladium (1.0 g). Stir at 80°C for 24 h. The reaction mixture is quenched with water and extracted with ethyl acetate. The organic phase is purified by z-column chromatography to afford 10.2 g of a yellow solid in an 85.7% yield. MS (ESI) m / z: 199.1 [M+H] +

[0534] Step 2: Synthesis of 5-fluoro-4-(furan-2-yl)pyrimidin-2-amine

[0535] 2-Chloro-5-fluoro-4-(furan-2-yl)pyrimidine (5.0 g, 25.1 mmol) was dissolved in ammonia methanol (7 M, 50 mL). The reaction mixture was stirred in a sealed container at 90°C for 60 hours. The organic phase was purified by column chromatography to yield the title compound (1.8 g) as a yellow solid, yielding a 40.0% yield. MS (ESI) m / z: 180.1 [M+H] +

[0536] Step 3: Synthesis of 2-amino-5-fluoropyrimidine-4-carboxylic acid

[0537] 5-Fluoro-4-(furan-2-yl)pyrimidin-2-amine (1.8 g, 10.0 mmol) was dissolved in acetonitrile (15 mL) and water (15 mL), and potassium permanganate (9.5 g, 60.0 mmol) was added. The reaction mixture was stirred at 25°C for 16 hours. The reaction mixture was filtered and the filtrate was purified to obtain the title compound (1.2 g) as a white solid in a 76.0% yield. MS (ESI) m / z: 158.1 [M+H] + .1 H-NMR (400MHz, DMSO-d6) δ: 7.98-7.96 (m, 1H), 6.19 (brs, 2H).

[0538] Synthesis of intermediate C57

[0539] Step 1: Synthesis of methyl 2-chloro-3-carboxamidoisonicotinate

[0540] Formic acid (2.96 g, 64.31 mmol) and acetic anhydride (3.28 g, 32.15 mmol) were poured into a bottle and stirred at 50°C for one hour. Methyl 3-amino-2-chloroisonicotinate (3.0 g, 16.08 mmol) was dissolved in dichloromethane (100 mL) and poured into the reaction mixture under an ice bath. The reaction mixture was stirred at 40°C for 18 hours. The reaction mixture was poured into sodium bicarbonate and extracted with dichloromethane. The organic phase was washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography to obtain 3.0 g of a white solid in an 86.9% yield. MS (ESI) m / z: 215.1 [M+H] + .

[0541] Step 2: Synthesis of methyl thiazolo[5,4-b]pyridine-7-carboxylate

[0542] Methyl 2-chloro-3-carboxamidoisonicotinate (3.3 g, 15.37 mmol) was dissolved in tetrahydrofuran (100 mL), and Lawesson's Reagent (6.22 g, 15.37 mmol) was added. The reaction mixture was stirred at 80°C for 16 hours. The reaction mixture was poured into aqueous sodium bicarbonate and extracted with dichloromethane. The organic phase was washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by reverse-phase column chromatography to obtain the title compound as a light yellow solid (1.2 g) in a 44.2% yield. MS (ESI) m / z: 195.0 [M+H] + .

[0543] Step 3: Synthesis of Thiazolo[5,4-b]pyridine-7-carboxylic acid

[0544] Thiazolo[5,4-b]pyridine-7-carboxylic acid methyl ester (1.2 g, 6.18 mmol) was dissolved in tetrahydrofuran (20 mL) and water (5 mL). Lithium hydroxide monohydrate (777 mg, 18.54 mmol) was added and the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated, and 3M hydrochloric acid was slowly added dropwise until the pH reached 5. The mixture was filtered and the filter cake was dried to obtain 1.03 g of a yellow solid (92.5% yield). MS (ESI) m / z: 181.1 [M+H] + . 1H-NMR (400MHz, DMSO) δ: 13.82 (brs, 1H), 9.68 (s, 1H), 8.81 (d, J = 4.8Hz, 1H), 7.87 (d, J = 4.8Hz, 1H).

[0545] Synthesis of intermediate C58

[0546] Step 1: Synthesis of 7-bromothiazolo[5,4-c]pyridine

[0547] Dissolve 7-bromothiazolo[5,4-c]pyridin-2-amine (2.2 g, 9.6 mmol) in tetrahydrofuran (200 mL) and add tert-butyl nitrite (5.6 g, 48.0 mmol). Stir the reaction mixture at 90°C for 16 hours. Cool the reaction mixture, extract with ethyl acetate, and concentrate the organic phase. Purify the mixture by column chromatography to obtain 1.1 g of a yellow solid in a 53.6% yield. MS (ESI) m / z: 215.0, 217.0 [M+H] +

[0548] Step 2: Synthesis of methyl thiazolo[5,4-c]pyridine-7-carboxylate

[0549] 7-Bromothiazolo[5,4-c]pyridine (1.1 g, 5.1 mmol) was dissolved in methanol (20 mL), and triethylamine (1.6 g, 15.4 mmol) and Pd(dppf)Cl2 (187 mg, 0.26 mmol) were added. The reaction mixture was stirred at 100°C under a CO atmosphere for 16 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by column chromatography to obtain 780 mg of a light yellow solid in a 75% yield. MS (ESI) m / z: 195.1 [M+H] +

[0550] Step 3: Synthesis of Thiazolo[5,4-c]pyridine-7-carboxylic acid

[0551] Thiazolo[5,4-c]pyridine-7-carboxylic acid methyl ester (500 mg, 2.56 mmol) was dissolved in tetrahydrofuran (10 mL) and water (5 mL). Lithium hydroxide monohydrate (420 mg, 10.2 mmol) was added at 0°C, and the reaction mixture was stirred at 0°C for 1 hour. 3M citric acid was added dropwise until the pH reached 4. The mixture was extracted with ethyl acetate, and the organic phase was concentrated. The crude product was purified by reverse-phase column chromatography to obtain 100 mg of a white solid in a 21% yield. MS (ESI) m / z: 181.1 [M+H] + . 1 H-NMR (400MHz, DMSO) δ: 13.45 (br, 1H), 9.80 (s, 1H), 9.64 (s, 1H), 9.02 (s, 1H).

[0552] Synthesis of intermediate C59

[0553] Step 1: Synthesis of ethyl 1-(2-methylpyridin-4-yl)-1H-pyrazole-4-carboxylate

[0554] (1S,2S)-N1,N2-dimethylcyclohexane-1,2-diamine (1.02 g, 7.1 mmol) was added to a mixture of ethyl 1H-pyrazole-4-carboxylate (5 g, 35.7 mmol), 4-bromo-2-methylpyridine (7.37 g, 42.8 mmol), cuprous iodide (0.34 g, 1.7 mmol), and potassium carbonate (9.87 g, 71.4 mmol) in anhydrous toluene (100 mL). The atmosphere was replaced with nitrogen, heated to 110°C, and stirred for 24 hours. Water was added and extracted with ethyl acetate. 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 column chromatography to yield 2.6 g of a white solid in a 31.4% yield. MS (ESI) m / z = 232.1 [M+H] + .

[0555] Step 2: Synthesis of 1-(2-methylpyridin-4-yl)-1H-pyrazole-4-carboxylic acid

[0556] A solution of lithium hydroxide monohydrate (1.89 g, 44.97 mmol) in water (30 mL) was slowly added to a solution of ethyl 1-(2-methylpyridin-4-yl)-1H-pyrazole-4-carboxylate (2.6 g, 11.24 mmol) in tetrahydrofuran (30 mL). The mixture was heated to 50°C and stirred for 1 hour. The mixture was evaporated under reduced pressure, diluted with water, and diluted hydrochloric acid (1 mol / L) was added dropwise until a precipitate formed. The filter cake was washed with water and dried to yield 2.05 g of a light pink solid (88.8% yield). MS (ESI) m / z = 204.2 [M+H] + . 1 H-NMR (400MHz, DMSO) δ12.81(s,1H),9.21(s,1H),8.53(d,J=5.6Hz,1H),8.16(s,1H),7.87(d,J=1.8Hz,1H),7.76(dd,J=5.5,2.0Hz,1H),2.53(s,3H).

[0557] Referring to the synthetic route and method of intermediate C59, the following intermediate structure was synthesized:

[0558] Synthesis of intermediate C61

[0559] Step 1: Synthesis of methylpyrrolo[1,2-a]pyrimidine-8-carboxylate

[0560] To the reaction mixture containing methyl 2-(pyrimidin-2-yl)acetate (1.8 g, 11.8 mmol) and acetone (30 mL) were added sodium bicarbonate (4.1 g, 48.4 mmol), lithium bromide (1.0 g, 11.8 mmol), and 2-chloroacetaldehyde (4.6 g, 59.1 mmol) (40% aqueous solution). Stir at 60°C for 16 h. Pour the reaction mixture into water and extract with ethyl acetate. The organic phase was purified on a silica gel column to obtain 0.9 g of a yellow oil, with a yield of 91.4%.

[0561] Step 2: Synthesis of pyrrolo[1,2-a]pyrimidine-8-carboxylic acid

[0562] Methylpyrrolo[1,2-a]pyrimidine-8-carboxylate (1.9 g, 10.8 mmol) was dissolved in tetrahydrofuran (20 mL), and lithium hydroxide monohydrate (2.3 g, 53.9 mmol) and water (5 mL) were added. The reaction mixture was stirred at room temperature until the reaction was complete. The pH was adjusted to approximately pH 4 with 2M hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic phase was dried, filtered, and concentrated to afford 850 mg of a yellow solid in a 46.8% yield. MS (ESI) m / z: 145.1 [MH] - . 1 H-NMR (400MHz, DMSO) δ: 11.77 (s, 1H), 8.87-8.85 (m, 1H), 8.43-8.42 (m, 1H), 7.54-7.53 (m, 1H), 7.30 -7.29 (m, 1H), 6.97-6.95 (m, 1H).

[0563] General Synthesis Method A:

[0564] 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.

[0565] General Synthesis Method B:

[0566] 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.

[0567] General Synthesis Method C:

[0568] 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.

[0569] General Synthesis Method D:

[0570] 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.

[0571] General Synthesis Method E:

[0572] 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). The reaction mixture is stirred at room temperature for 4 hours. Water is added to the reaction mixture, and the mixture is extracted 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 yield the title compound.

[0573] 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.

[0574] 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.

[0575] General Synthesis Method F:

[0576] 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). The reaction mixture is stirred at room temperature for 4 hours. Water is added to the reaction mixture, and the mixture is extracted 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 yield the title compound.

[0577] 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.

[0578] 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.

[0579] General Synthesis Method G:

[0580] 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). The reaction mixture is stirred at room temperature for 4 hours. Water is added to the reaction mixture, and the mixture is extracted 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 yield the title compound.

[0581] 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 title compound, which is used directly in the next step.

[0582] Step 3: Dissolve the product from Step 2 (1.0 eq) and carboxylic acid intermediate B (1.0 eq) in DMF, and add DIPEA (3.0 eq) and HATU (1.2 eq) sequentially. The reaction mixture is stirred at room temperature for 4 hours. Water is added to the reaction mixture, and the mixture is extracted 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 yield the title compound.

[0583] 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

[0584] Using 7-azaindole-4-carboxylic acid as raw material, compound 1 can be prepared according to the general synthesis method A. Mass spectrum [M+H] + :789.4

[0585] 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

[0586] Using 1H-benzimidazole-6-carboxylic acid as raw material, compound 2 can be prepared according to the general synthesis method A. Mass spectrum [M+H] + :789.4

[0587] 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

[0588] Using 8-isoquinolinecarboxylic acid as raw material, compound 3 can be prepared according to the general synthesis method A. Mass spectrum [M+H] + :800.4

[0589] 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

[0590] Using 7-azaindole-5-carboxylic acid as raw material, compound 4 can be prepared according to the general synthesis method A. Mass spectrum [M+H] + :789.4

[0591] 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

[0592] Using quinoxaline-5-carboxylic acid as raw material, compound 5 can be prepared according to the general synthesis method A. Mass spectrum [M+H] + :801.4

[0593] 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

[0594] Using 2,1,3-benzothiadiazole-4-carboxylic acid as raw material, compound 6 can be prepared according to the general synthesis method A. Mass spectrum [M+H] + :807.3

[0595] 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

[0596] Using 2-methyl-6-imidazo[2,1-a]pyridinecarboxylic acid as raw material, compound 7 can be prepared according to the general synthesis method A. Mass spectrum [M+H] + :803.4

[0597] 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

[0598] Using 7-carboxybenzothiazole as raw material, compound 8 can be prepared according to the general synthesis method A. Mass spectrum [M+H] + :806.3

[0599] 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

[0600] Using 1-(4-fluorophenyl)-5-methyl-1H-pyrazole-4-carboxylic acid as raw material, compound 9 can be prepared according to the general synthesis method A. Mass spectrum [M+H] + :847.4

[0601] 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

[0602] Using 1-methyl-3-trifluoromethyl-1H-pyrazole-4-carboxylic acid as raw material, compound 10 can be prepared according to the general synthetic method A. Mass spectrum [M+H] + :821.4

[0603] 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

[0604] Using 1-methyl-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid as raw material, compound 11 can be prepared according to the general synthetic method A. Mass spectrum [M+H] + :821.4

[0605] 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

[0606] Using [1,2,4]triazolo[4,3-a]pyridine-8-carboxylic acid as raw material, compound 12 can be prepared according to the general synthesis method A. Mass spectrum [M+H] + :790.4

[0607] 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

[0608] Using [1,2,4]triazolo[4,3-a]pyridine-7-carboxylic acid as raw material, compound 13 can be prepared according to the general synthetic method A. Mass spectrum [M+H] + :790.4

[0609] 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

[0610] Using 1-phenyl-3-trifluoromethyl-1H-pyrazole-4-carboxylic acid as raw material, compound 14 can be prepared according to the general synthesis method A. Mass spectrum [M+H] + :883.4

[0611] 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

[0612] Using indole-5-carboxylic acid as the starting material, compound 15 can be prepared according to the general synthetic method A. Mass spectrum [M+H] + :788.4

[0613] 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

[0614] Using indole-4-carboxylic acid as a raw material, compound 16 can be prepared according to the general synthesis method A. Mass spectrum [M+H] + :788.4

[0615] 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

[0616] Using quinoline-6-carboxylic acid as the raw material, compound 17 can be prepared according to the general synthesis method A. Mass spectrum [M+H] + :800.4

[0617] 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

[0618] Using 1-benzothiophene-3-carboxylic acid as raw material, compound 18 can be prepared according to the general synthesis method A. Mass spectrum [M+H] + :805.3

[0619] 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

[0620] Using 1-methyl-5-phenyl-1H-pyrazole-4-carboxylic acid as raw material, compound 19 can be prepared according to the general synthesis method A. Mass spectrum [M+H] + :829.4

[0621] 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

[0622] Using isoquinoline-5-carboxylic acid as the starting material, compound 20 can be prepared according to the general synthetic method A. Mass spectrum [M+H] + :800.4

[0623] 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

[0624] Using imidazo[1,2-b]pyridazine-6-carboxylic acid as raw material, compound 21 can be prepared according to the general synthetic method A. Mass spectrum [M+H] + :790.4

[0625] 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

[0626] Using 1,5-naphthyridine-3-carboxylic acid as raw material, compound 22 can be prepared according to the general synthesis method A. Mass spectrum [M+H] + :801.4

[0627] 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

[0628] Using quinoline-4-carboxylic acid as the raw material, compound 23 can be prepared according to the general synthesis method A. Mass spectrum [M+H] + :800.4

[0629] 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

[0630] Using imidazo[1,2-a]pyridine-6-carboxylic acid as raw material, compound 24 can be prepared according to the general synthesis method A. Mass spectrum [M+H] + :789.4

[0631] 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

[0632] Using imidazo[1,2-a]pyridine-7-carboxylic acid as raw material, compound 25 can be prepared according to the general synthesis method A. Mass spectrum [M+H] + :789.4

[0633] 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

[0634] Using 4H-thieno[3,2-b]pyrrole-5-carboxylic acid as raw material, compound 26 can be prepared according to the general synthesis method A. Mass spectrum [M+H] + :794.3

[0635] 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

[0636] Using quinoline-5-carboxylic acid as raw material, compound 27 can be prepared according to the general synthesis method A. Mass spectrum [M+H] + :800.4

[0637] 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

[0638] Using imidazo[1,5-a]pyridine-8-carboxylic acid as raw material, compound 28 can be prepared according to the general synthesis method A. Mass spectrum [M+H] +:789.4

[0639] Example 29: Preparation of 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

[0640] Using 3H-imidazo[4,5-b]pyridine-5-carboxylic acid as raw material, compound 29 can be prepared according to the general synthetic method B. Mass spectrum [M+H] + :802.4

[0641] 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

[0642] Using 2-methyl-1H-benzimidazole-5-carboxylic acid as raw material, compound 30 can be prepared according to the general synthetic method A. Mass spectrum [M+H] + :803.4

[0643] 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

[0644] Using imidazo[1,2-a]pyridine-8-carboxylic acid as raw material, compound 31 can be prepared according to the general synthetic method B. Mass spectrum [M+H] + :789.4

[0645] 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

[0646] Using 3-methylimidazo[1,2-a]pyridine-6-carboxylic acid as raw material, compound 32 can be prepared according to the general synthetic method B. Mass spectrum [M+H] + :803.4

[0647] 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

[0648] Using benzimidazole-4-carboxylic acid as raw material, compound 33 can be prepared according to the general synthesis method A. Mass spectrum [M+H] + :789.4

[0649] 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

[0650] Compound 34 was prepared using 1-(3-methoxyphenyl)pyrazole-4-carboxylic acid as the starting material and following the general synthetic method C. Mass spectrum [M+H] + :845.4

[0651] 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

[0652] Compound 35 was prepared using 2,1,3-benzothiadiazole-5-carboxylic acid as the starting material according to the general synthesis method C. Mass spectrum [M+H] + :807.3

[0653] 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

[0654] Using thieno[3,2-d]pyrimidine-4-carboxylic acid as raw material, compound 36 can be prepared according to the general synthetic method C. Mass spectrum [M+H] + :807.3

[0655] 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

[0656] Using thieno[2,3-c]pyridine-2-carboxylic acid as raw material, compound 37 can be prepared according to the general synthetic method C. Mass spectrum [M+H] + :806.3

[0657] 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

[0658] Using 4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-3-carboxylic acid as raw material, compound 38 can be prepared according to the general synthetic method D. Mass spectrum [M+H] + :793.4

[0659] 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

[0660] Using pyrazolo[1,5-a]pyridine-3-carboxylic acid as raw material, compound 39 can be prepared according to the general synthetic method A. Mass spectrum [M+H] + :789.4

[0661] 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

[0662] Using 4-aminothieno[3,2-d]pyrimidine-7-carboxylic acid as the starting material, compound 40 can be prepared according to the general synthetic method A. Mass spectrum [M+H] + :822.3

[0663] 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

[0664] Using 5-methyl-1-phenyl-1H-pyrazole-4-carboxylic acid as raw material, compound 41 can be prepared according to the general synthetic method A. Mass spectrum [M+H] + :829.4

[0665] 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

[0666] Using imidazo[1,2-b]pyridazine-2-carboxylic acid as raw material, compound 42 can be prepared according to the general synthetic method D. Mass spectrum [M+H] + :790.4

[0667] 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

[0668] Using imidazo[1,2-a]pyrazine-3-carboxylic acid as raw material, compound 43 can be prepared according to the general synthetic method D. Mass spectrum [M+H] + :790.4

[0669] 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

[0670] Using 5-azaindole-7-carboxylic acid as the starting material, compound 44 can be prepared according to the general synthetic method B. Mass spectrum [M+H] + :789.4

[0671] 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

[0672] Using pyrazolo[1,5-b]pyridazine-3-carboxylic acid as raw material, compound 45 can be prepared according to the general synthetic method A. Mass spectrum [M+H] + :790.4

[0673] 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

[0674] Using 6-indolecarboxylic acid as the raw material, compound 46 can be prepared according to the general synthesis method A. Mass spectrum [M+H] + :788.4

[0675] 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

[0676] Using pyrazolo[1,5-a]pyridine-3-carboxylic acid as raw material, compound 47 can be prepared according to the general synthetic method A. Mass spectrum [M+H] + :789.4

[0677] 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

[0678] Using 7-indolecarboxylic acid as the starting material, compound 48 can be prepared according to the general synthetic method C. Mass spectrum [M+H] + :788.4

[0679] 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

[0680] Using imidazo[1,5-a]pyridine-8-carboxylic acid as raw material, compound 49 can be prepared according to the general synthetic method C. Mass spectrum [M+H] + :789.4

[0681] 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

[0682] Using 1H-pyrrolo[2,3-c]pyridine-3-carboxylic acid as raw material, compound 50 can be prepared according to the general synthetic method C. Mass spectrum [M+H] + :789.4

[0683] 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

[0684] Using 3H-imidazo[4,5-b]pyridine-7-carboxylic acid as raw material, compound 51 can be prepared according to the general synthesis method A. Mass spectrum [M+H] + :790.4

[0685] 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

[0686] Using 7H-pyrrolo[2,3-d]pyrimidine-4-carboxylic acid as raw material, compound 52 can be prepared according to the general synthesis method B. Mass spectrum [M+H] + :790.4

[0687] 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

[0688] Using 3H-imidazo[4,5-c]pyridine-7-carboxylic acid as raw material, compound 53 can be prepared according to the general synthesis method A. Mass spectrum [M+H] + :790.4

[0689] 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

[0690] Using pyrazolo[1,5-a]pyrimidine-6-carboxylic acid as raw material, compound 54 can be prepared according to the general synthetic method A. Mass spectrum [M+H] + :790.4

[0691] 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

[0692] Using 1H-pyrazolo[4,3-c]pyridine-4-carboxylic acid as the starting material, compound 55 can be prepared according to the general synthetic method D. Mass spectrum [M+H] + :790.4

[0693] 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

[0694] Using imidazo[1,2-a]pyridine-3-carboxylic acid as raw material, compound 56 can be prepared according to the general synthetic method C. Mass spectrum [M+H] + :801.4

[0695] 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

[0696] Compound 57 was prepared using 2-(2-methylpyridin-4-yl)thiazole-4-carboxylic acid as the starting material and referring to the general synthesis method A. Mass spectrum [M+H] + :859.4

[0697] 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

[0698] Compound 58 was prepared using 2-(pyrimidin-2-yl)oxazole-4-carboxylic acid as the starting material and following the general synthesis method A. Mass spectrum [M+H] + :830.4

[0699] 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

[0700] Compound 59 was prepared using 1-(pyrimidin-2-yl)-1H-imidazole-4-carboxylic acid as the starting material and following the general synthetic method C. Mass spectrum [M+H] + :829.4

[0701] 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

[0702] Using 1-(4-fluorophenyl)-5-methyl-1H-pyrazole-4-carboxylic acid as raw material, compound 60 can be prepared according to the general synthetic method A. Mass spectrum [M+H] + :859.4

[0703] 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

[0704] Using 2-(1-methyl-1H-pyrazol-4-yl)oxazole-4-carboxylic acid as raw material, compound 61 can be prepared according to the general synthetic method D. Mass spectrum [M+H] + :832.4

[0705] 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

[0706] Using 1-(2-methylpyridin-4-yl)-1H-pyrazole-4-carboxylic acid as raw material, compound 62 can be prepared according to the general synthetic method D. Mass spectrum [M+H] + :842.4

[0707] 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

[0708] Using 4-phenoxybenzoic acid as the starting material, compound 63 can be prepared according to the general synthesis method A. Mass spectrum [M+H] + :853.4

[0709] 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

[0710] Using 2-phenyl-1,3-thiazole-4-carboxylic acid as raw material, compound 64 can be prepared according to the general synthetic method B. Mass spectrum [M+H] + :844.4

[0711] 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

[0712] Using 1-(pyridin-3-yl)-1H-pyrazole-4-carboxylic acid as the starting material, compound 65 can be prepared according to the general synthetic method A. Mass spectrum [M+H] + :828.4

[0713] 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)benzofuran-7-carboxamide Compound 66

[0714] Using benzofuran-7-carboxylic acid as the starting material, compound 66 can be prepared according to the general synthetic method B. Mass spectrum [M+H] + :801.4

[0715] 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

[0716] Using benzofuran-3-carboxylic acid as the starting material, compound 67 can be prepared according to the general synthesis method A. Mass spectrum [M+H] + :801.4

[0717] 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

[0718] Using pyrazolo[1,5-a]4,5,6,7-tetrahydropyridine-2-carboxylic acid as raw material, compound 68 can be prepared according to the general synthetic method A. Mass spectrum [M+H] + :805.4

[0719] 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

[0720] Using 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-2-carboxylic acid as raw material, compound 69 can be prepared according to the general synthesis method A. Mass spectrum [M+H] + :791.4

[0721] 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

[0722] Compound 70 was prepared using 4,5,6,7-tetrahydro-1H-indazole-3-carboxylic acid as the starting material and following the general synthetic method C. Mass spectrum [M+H] + :805.4

[0723] 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

[0724] Compound 71 was prepared using 1,4,5,6-tetrahydrocyclopenta-pyrazole-3-carboxylic acid as the starting material and following the general synthetic method D. Mass spectrum [M+H] + :791.4

[0725] 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

[0726] Compound 72 was prepared using 1-methyl-1,4,5,6-tetrahydrocyclopenta[c]pyrazole-3-carboxylic acid as the starting material according to the general synthesis method B. Mass spectrum [M+H] + :805.4

[0727] 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

[0728] Using 7-carboxybenzothiazole as a raw material, compound 73 can be prepared according to the general synthesis method A. Mass spectrum [M+H] + :800.3

[0729] 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

[0730] Using 1-(4-fluorophenyl)-5-methyl-1H-pyrazole-4-carboxylic acid as raw material, compound 74 can be prepared according to the general synthesis method A. Mass spectrum [M+H] + :841.4

[0731] 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

[0732] Using 1-methyl-3-trifluoromethyl-1H-pyrazole-4-carboxylic acid as the starting material, compound 75 can be prepared according to the general synthetic method A. Mass spectrum [M+H] + :815.4

[0733] 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

[0734] Using 4H-thieno[3,2-b]pyrrole-5-carboxylic acid as raw material, compound 76 can be prepared according to the general synthesis method A. Mass spectrum [M+H] + :788.3

[0735] 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

[0736] Using quinoline-4-carboxylic acid as the starting material, compound 77 can be prepared according to the general synthetic method B. Mass spectrum [M+H] + :794.4

[0737] 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

[0738] Using quinoline-5-carboxylic acid as the starting material, compound 78 can be prepared according to the general synthetic method B. Mass spectrum [M+H] + :794.4

[0739] 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

[0740] Using imidazo[1,2-a]pyridine-6-carboxylic acid as raw material, compound 79 can be prepared according to the general synthetic method D. Mass spectrum [M+H] + :783.4

[0741] 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

[0742] Using imidazo[1,2-a]pyridine-7-carboxylic acid as raw material, compound 80 can be prepared according to the general synthesis method A. Mass spectrum [M+H] + :783.4

[0743] 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

[0744] Compound 81 was prepared using 1,5-naphthyridine-3-carboxylic acid as the starting material according to the general synthesis method C. Mass spectrum [M+H] + :795.4

[0745] 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

[0746] Using 7-azaindole-4-carboxylic acid as the starting material, compound 82 can be prepared according to the general synthetic method A. Mass spectrum [M+H] + :783.4

[0747] 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

[0748] Using 8-isoquinolinecarboxylic acid as the starting material, compound 83 can be prepared according to the general synthesis method A. Mass spectrum [M+H] + :794.4

[0749] 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

[0750] Using quinoxaline-5-carboxylic acid as the starting material, compound 84 can be prepared according to the general synthetic method B. Mass spectrum [M+H] + :795.4

[0751] 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

[0752] Using 7-azaindole-5-carboxylic acid as the starting material, compound 85 can be prepared according to the general synthetic method C. Mass spectrum [M+H] + :783.4

[0753] 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

[0754] Using 2-methyl-6-imidazo[2,1-a]pyridinecarboxylic acid as raw material, compound 86 can be prepared according to the general synthetic method C. Mass spectrum [M+H] + :797.4

[0755] 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

[0756] Compound 87 was prepared using 2,1,3-benzothiadiazole-4-carboxylic acid as the starting material according to the general synthesis method A. Mass spectrum [M+H] + :801.3

[0757] 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

[0758] Using imidazo[1,2-a]pyridine-3-carboxylic acid as raw material, compound 88 can be prepared according to the general synthesis method A. Mass spectrum [M+H] + :789.4

[0759] 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

[0760] Using 4-azaindole-3-carboxylic acid as the starting material, compound 89 can be prepared according to the general synthetic method D. Mass spectrum [M+H] + :789.4

[0761] 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

[0762] Compound 90 was prepared using 2-(2-methylpyridin-4-yl)thiazole-4-carboxylic acid as the starting material and referring to the general synthetic method A. Mass spectrum [M+H] + :847.3

[0763] 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

[0764] Compound 91 was prepared using 2-(pyrimidin-2-yl)oxazole-4-carboxylic acid as the starting material and following the general synthetic method D. Mass spectrum [M+H] + :818.4

[0765] 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

[0766] Compound 92 was prepared using 1-(pyrimidin-2-yl)-1H-imidazole-4-carboxylic acid as the starting material and following the general synthesis method A. Mass spectrum [M+H] + :817.4

[0767] 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

[0768] Compound 93 was prepared using 2-(1-methyl-1H-pyrazol-4-yl)oxazole-4-carboxylic acid as the starting material according to the general synthetic method C. Mass spectrum [M+H] + :820.4

[0769] 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

[0770] Compound 94 was prepared using 1-(2-methylpyridin-4-yl)-1H-pyrazole-4-carboxylic acid as the starting material and following the general synthesis method A. Mass spectrum [M+H] + :830.4

[0771] 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

[0772] Using 4-phenoxybenzoic acid as the starting material, compound 95 can be prepared according to the general synthetic method D. Mass spectrum [M+H] + :841.4

[0773] 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

[0774] Using 2-phenyl-1,3-thiazole-4-carboxylic acid as the starting material, compound 96 can be prepared according to the general synthetic method A. Mass spectrum [M+H] + :832.3

[0775] 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

[0776] Compound 97 was prepared using 1-(pyridin-3-yl)-1H-pyrazole-4-carboxylic acid as the starting material and following the general synthetic method B. Mass spectrum [M+H] + :816.4

[0777] 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)benzofuran-7-carboxamide Compound 98

[0778] Compound 98 was prepared by using benzofuran-7-carboxylic acid as the starting material and referring to the general synthesis method B. Mass spectrum [M+H] + :789.4

[0779] 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

[0780] Using benzofuran-3-carboxylic acid as the starting material, compound 99 can be prepared according to the general synthetic method A. Mass spectrum [M+H] + :789.4

[0781] 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

[0782] Using pyrazolo[1,5-a]4,5,6,7-tetrahydropyridine-2-carboxylic acid as raw material, compound 100 can be prepared according to the general synthetic method A. Mass spectrum [M+H] + :793.4

[0783] 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

[0784] Using 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-2-carboxylic acid as raw material, compound 101 can be prepared according to the general synthetic method A. Mass spectrum [M+H] + :779.4

[0785] 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

[0786] Compound 102 was prepared using 4,5,6,7-tetrahydro-1H-indazole-3-carboxylic acid as the starting material and following the general synthetic method C. Mass spectrum [M+H] + :793.4

[0787] 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

[0788] Compound 103 was prepared using 1,4,5,6-tetrahydrocyclopenta-pyrazole-3-carboxylic acid as the starting material according to the general synthesis method A. Mass spectrum [M+H] + :779.4

[0789] 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

[0790] Compound 104 was prepared using 1-methyl-1,4,5,6-tetrahydrocyclopenta[c]pyrazole-3-carboxylic acid as the starting material according to the general synthetic method D. Mass spectrum [M+H] + :793.4

[0791] 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

[0792] Compound 105 was prepared using 1H-benzimidazole-6-carboxylic acid as the starting material according to the general synthesis method C. Mass spectrum [M+H] + :789.3

[0793] 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

[0794] Using imidazo[1,2-b]pyridazine-3-carboxylic acid as the starting material, compound 106 was prepared according to the general synthetic method A. Mass spectrum [M+H] + :790.4

[0795] 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

[0796] Using 7-carboxybenzothiazole as the starting material, compound 107 can be prepared according to the general synthesis method A. Mass spectrum [M+H] + :814.3

[0797] 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

[0798] Compound 108 was prepared using 1-(4-fluorophenyl)-5-methyl-1H-pyrazole-4-carboxylic acid as the starting material and following the general synthetic method B. Mass spectrum [M+H] + :855.4

[0799] 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

[0800] Compound 109 was prepared using 1-methyl-3-trifluoromethyl-1H-pyrazole-4-carboxylic acid as the starting material according to the general synthetic method A. The mass spectrum was [M+H] + :829.3

[0801] 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

[0802] Using 4H-thieno[3,2-b]pyrrole-5-carboxylic acid as the starting material, compound 110 was prepared according to the general synthetic method B. Mass spectrum [M+H] + :802.3

[0803] 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

[0804] Using quinoline-4-carboxylic acid as the starting material, compound 111 can be prepared according to the general synthetic method A. Mass spectrum [M+H] + :808.4

[0805] 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

[0806] Using quinoline-5-carboxylic acid as the starting material, compound 112 was prepared according to the general synthetic method D. Mass spectrum [M+H] + :808.4

[0807] 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

[0808] Using imidazo[1,2-a]pyridine-6-carboxylic acid as raw material, compound 113 can be prepared according to the general synthesis method A. Mass spectrum [M+H] + :797.4

[0809] 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

[0810] Using imidazo[1,2-a]pyridine-7-carboxylic acid as raw material, compound 114 can be prepared according to the general synthetic method C. Mass spectrum [M+H] + :797.4

[0811] 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

[0812] Compound 115 was prepared using 1H-benzimidazole-6-carboxylic acid as the starting material according to the general synthesis method A. The mass spectrum [M+H] + :797.4

[0813] 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

[0814] Compound 116 was prepared using 1,5-naphthyridine-3-carboxylic acid as the starting material according to the general synthesis method B. Mass spectrum [M+H] + :809.4

[0815] 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

[0816] Using 7-azaindole-4-carboxylic acid as the starting material, compound 117 was prepared according to the general synthetic method D. Mass spectrum [M+H] + :797.4

[0817] 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

[0818] Using 8-isoquinolinecarboxylic acid as the starting material, compound 118 can be prepared according to the general synthesis method A. Mass spectrum [M+H] + :808.4

[0819] 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

[0820] Using quinoxaline-5-carboxylic acid as the starting material, compound 119 was prepared according to the general synthesis method A. Mass spectrum [M+H] + :809.4

[0821] 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

[0822] Using 7-azaindole-5-carboxylic acid as the starting material, compound 120 can be prepared according to the general synthetic method D. Mass spectrum [M+H] + :797.4

[0823] 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

[0824] Compound 121 was prepared using 2-methyl-6-imidazo[2,1-a]pyridinecarboxylic acid as the starting material according to the general synthesis method A. Mass spectrum [M+H] + :811.4

[0825] 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

[0826] Compound 122 was prepared using 2,1,3-benzothiadiazole-4-carboxylic acid as the starting material according to the general synthesis method B. Mass spectrum [M+H] + :815.3

[0827] 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

[0828] Using indole-4-carboxylic acid as the starting material, compound 123 can be prepared according to the general synthetic method A. Mass spectrum [M+H] + :796.4

[0829] 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

[0830] Using indole-5-carboxylic acid as the starting material, compound 124 was prepared according to the general synthetic method B. Mass spectrum [M+H] + :796.4

[0831] 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

[0832] Using quinoline-6-carboxylic acid as the starting material, compound 125 can be prepared according to the general synthetic method A. Mass spectrum [M+H] + :808.4

[0833] 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

[0834] Using 1-benzothiophene-3-carboxylic acid as the starting material, compound 126 can be prepared according to the general synthetic method B. Mass spectrum [M+H] + :813.3

[0835] 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

[0836] Using isoquinoline-5-carboxylic acid as the starting material, compound 127 can be prepared according to the general synthetic method B. Mass spectrum [M+H] + :808.4

[0837] 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

[0838] Using imidazo[1,2-b]pyridazine-6-carboxylic acid as raw material, compound 128 can be prepared according to the general synthetic method B. Mass spectrum [M+H] + :798.4

[0839] 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

[0840] Using imidazo[1,5-a]pyridine-8-carboxylic acid as raw material, compound 129 can be prepared according to the general synthetic method B. Mass spectrum [M+H] + :797.4

[0841] 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

[0842] Compound 130 was prepared using 2-methyl-1H-benzimidazole-5-carboxylic acid as the starting material according to the general synthesis method A. The mass spectrum was [M+H] + :811.4

[0843] 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

[0844] Using imidazo[1,2-a]pyridine-8-carboxylic acid as raw material, compound 131 can be prepared according to the general synthesis method A. Mass spectrum [M+H] + :797.4

[0845] 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

[0846] Using 3-methylimidazo[1,2-a]pyridine-6-carboxylic acid as raw material, compound 132 can be prepared according to the general synthetic method C. Mass spectrum [M+H] + :811.4

[0847] 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

[0848] Compound 133 was prepared by using benzimidazole-4-carboxylic acid as the starting material and referring to the general synthetic method C. Mass spectrum [M+H] + :797.4

[0849] 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

[0850] Compound 134 was prepared using 1-(3-methoxyphenyl)pyrazole-4-carboxylic acid as the starting material and following the general synthetic method C. Mass spectrum [M+H] + :853.4

[0851] 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

[0852] Compound 135 was prepared using 2,1,3-benzothiadiazole-5-carboxylic acid as the starting material according to the general synthesis method A. Mass spectrum [M+H] + :815.3

[0853] 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

[0854] Using thieno[3,2-d]pyrimidine-4-carboxylic acid as the starting material, compound 136 can be prepared according to the general synthetic method D. Mass spectrum [M+H] + :815.3

[0855] 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

[0856] Using thieno[2,3-c]pyridine-2-carboxylic acid as raw material, compound 137 can be prepared according to the general synthetic method A. Mass spectrum [M+H] + :814.3

[0857] 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

[0858] Compound 138 was prepared using 1-methyl-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid as the starting material according to the general synthetic method D. Mass spectrum [M+H] + :829.3

[0859] 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

[0860] Using [1,2,4]triazolo[4,3-a]pyridine-8-carboxylic acid as raw material, compound 139 can be prepared according to the general synthetic method D. Mass spectrum [M+H] + :798.4

[0861] 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

[0862] Compound 140 was prepared using [1,2,4]triazolo[4,3-a]pyridine-7-carboxylic acid as the starting material according to the general synthetic method D. Mass spectrum [M+H] + :798.4

[0863] 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

[0864] Using 1-phenyl-3-trifluoromethyl-1H-pyrazole-4-carboxylic acid as the starting material, compound 141 can be prepared according to the general synthetic method D. Mass spectrum [M+H] + :891.4

[0865] 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

[0866] Compound 142 was prepared using 4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-3-carboxylic acid as the starting material according to the general synthetic method A. The mass spectrum [M+H] + :801.4

[0867] 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

[0868] Using 7-carboxybenzothiazole as a raw material, compound 143 can be prepared according to the general synthesis method A. Mass spectrum [M+H] + :800.3

[0869] 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

[0870] Using imidazo[1,2-a]pyridine-7-carboxylic acid as raw material, compound 144 can be prepared according to the general synthetic method B. Mass spectrum [M+H] + :783.4

[0871] 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

[0872] Compound 145 was prepared using 1,5-naphthyridine-3-carboxylic acid as the starting material according to the general synthesis method A. Mass spectrum [M+H] + :795.4

[0873] 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

[0874] Using imidazo[1,2-a]pyridine-8-carboxylic acid as raw material, compound 146 can be prepared according to the general synthetic method B. Mass spectrum [M+H] + :783.4

[0875] 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

[0876] Compound 147 was prepared by using benzimidazole-4-carboxylic acid as the starting material and referring to the general synthesis method B. Mass spectrum [M+H] + :783.4

[0877] 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

[0878] Using pyrazolo[1,5-a]pyridine-3-carboxylic acid as raw material, compound 148 can be prepared according to the general synthetic method C. Mass spectrum [M+H] + :783.4

[0879] 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

[0880] Compound 149 was prepared by using 4-phenoxybenzoic acid as the starting material and referring to the general synthesis method A. The mass spectrum [M+H] + :835.4

[0881] 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

[0882] Using imidazo[1,2-b]pyridazine-6-carboxylic acid as the starting material, compound 150 can be prepared according to the general synthetic method A. Mass spectrum [M+H] + :784.4

[0883] 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

[0884] Using [1,2,4]triazolo[4,3-a]pyridine-8-carboxylic acid as raw material, compound 151 can be prepared according to the general synthetic method A. Mass spectrum [M+H] + :784.4

[0885] 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

[0886] Compound 152 was prepared using [1,2,4]triazolo[4,3-a]pyridine-7-carboxylic acid as the starting material according to the general synthetic method B. Mass spectrum [M+H] + :784.4

[0887] 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

[0888] Compound 153 was prepared using 4-aminothieno[3,2-d]pyrimidine-7-carboxylic acid as the starting material according to the general synthetic method D. Mass spectrum [M+H] + :816.3

[0889] 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

[0890] Using imidazo[1,2-b]pyridazine-2-carboxylic acid as the starting material, compound 154 was prepared according to the general synthetic method D. Mass spectrum [M+H] + :784.4

[0891] 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

[0892] Using 3H-imidazo[4,5-b]pyridine-7-carboxylic acid as raw material, compound 155 can be prepared according to the general synthetic method A. Mass spectrum [M+H] + :784.4

[0893] 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

[0894] Using 3H-imidazo[4,5-c]pyridine-7-carboxylic acid as the starting material, compound 156 was prepared according to the general synthetic method A. The mass spectrum [M+H] + :784.4

[0895] 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

[0896] Compound 157 was prepared using 2-(2-methylpyridin-4-yl)thiazole-4-carboxylic acid as the starting material and following the general synthetic method D. Mass spectrum [M+H] + :841.4

[0897] 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

[0898] Compound 158 was prepared using 2-(pyrimidin-2-yl)oxazole-4-carboxylic acid as the starting material and following the general synthetic method B. Mass spectrum [M+H] + :812.4

[0899] 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

[0900] Compound 159 was prepared using 2-(1-methyl-1H-pyrazol-4-yl)oxazole-4-carboxylic acid as the starting material according to the general synthetic method D. Mass spectrum [M+H] + :814.4

[0901] 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

[0902] Compound 160 was prepared using 2-phenyl-1,3-thiazole-4-carboxylic acid as the starting material and following the general synthetic method D. Mass spectrum [M+H] + :826.4

[0903] 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)benzofuran-7-carboxamide Compound 161

[0904] Compound 161 was prepared by using benzofuran-7-carboxylic acid as the starting material and referring to the general synthesis method A. The mass spectrum [M+H] + :783.4

[0905] 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

[0906] Compound 162 was prepared by using benzofuran-3-carboxylic acid as the starting material and referring to the general synthesis method A. The mass spectrum [M+H] + :783.4

[0907] 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

[0908] Using pyrazolo[1,5-a]4,5,6,7-tetrahydropyridine-2-carboxylic acid as raw material, compound 163 can be prepared according to the general synthetic method A. Mass spectrum [M+H] + :787.4

[0909] 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

[0910] Compound 164 was prepared using 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-2-carboxylic acid as the starting material according to the general synthesis method A. The mass spectrum [M+H] + :773.4

[0911] 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

[0912] Compound 165 was prepared using 4,5,6,7-tetrahydro-1H-indazole-3-carboxylic acid as the starting material and following the general synthetic method A. Mass spectrum [M+H] + :787.4

[0913] 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

[0914] Compound 166 was prepared using 2-(4-pyridyl)thiazole-4-carboxylic acid as the starting material and following the general synthesis method A. Mass spectrum [M+H] + :827.3

[0915] 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

[0916] Using imidazo[1,2-b]pyridazine-6-carboxylic acid as raw material, compound 167 can be prepared according to the general synthetic method A. Mass spectrum [M+H] + :784.4

[0917] 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

[0918] Using imidazo[1,2-a]pyridine-8-carboxylic acid as the starting material, compound 168 can be prepared according to the general synthetic method D. Mass spectrum [M+H] + :783.4

[0919] 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

[0920] Compound 169 was prepared by using benzimidazole-4-carboxylic acid as the starting material and referring to the general synthesis method A. Mass spectrum [M+H] + :783.4

[0921] 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

[0922] Compound 170 was prepared using [1,2,4]triazolo[4,3-a]pyridine-8-carboxylic acid as the starting material according to the general synthetic method B. Mass spectrum [M+H] + :784.4

[0923] 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

[0924] Compound 171 was prepared using [1,2,4]triazolo[4,3-a]pyridine-7-carboxylic acid as the starting material according to the general synthesis method A. The mass spectrum [M+H] + :784.4

[0925] 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

[0926] Using pyrazolo[1,5-a]pyridine-3-carboxylic acid as the starting material, compound 172 was prepared according to the general synthetic method D. Mass spectrum [M+H] + :783.4

[0927] 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

[0928] Compound 173 was prepared using 4-aminothieno[3,2-d]pyrimidine-7-carboxylic acid as the starting material according to the general synthesis method A. Mass spectrum [M+H] + :816.3

[0929] 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

[0930] Using imidazo[1,2-b]pyridazine-2-carboxylic acid as the starting material, compound 174 was prepared according to the general synthetic method D. Mass spectrum [M+H] + :784.4

[0931] 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

[0932] Using 3H-imidazo[4,5-b]pyridine-7-carboxylic acid as raw material, compound 175 can be prepared according to the general synthetic method A. Mass spectrum [M+H] + :784.4

[0933] 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

[0934] Compound 176 was prepared using 2-(2-methylpyridin-4-yl)thiazole-4-carboxylic acid as the starting material and following the general synthetic method D. Mass spectrum [M+H] + :841.4

[0935] 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

[0936] Compound 177 was prepared using 2-(pyrimidin-2-yl)oxazole-4-carboxylic acid as the starting material according to the general synthesis method A. Mass spectrum [M+H] + :812.4

[0937] 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

[0938] Compound 178 was prepared using 2-(1-methyl-1H-pyrazol-4-yl)oxazole-4-carboxylic acid as the starting material according to the general synthetic method D. Mass spectrum [M+H] + :814.4

[0939] 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

[0940] Compound 179 was prepared using 4-phenoxybenzoic acid as the starting material according to the general synthesis method A. Mass spectrum [M+H] + :835.4

[0941] 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

[0942] Compound 180 was prepared using 2-phenyl-1,3-thiazole-4-carboxylic acid as the starting material according to the general synthesis method A. Mass spectrum [M+H] + :826.3

[0943] 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)benzofuran-7-carboxamide Compound 181

[0944] Compound 181 was prepared by using benzofuran-7-carboxylic acid as the starting material and referring to the general synthetic method B. Mass spectrum [M+H] + :783.4

[0945] 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

[0946] Compound 182 was prepared by using benzofuran-3-carboxylic acid as the starting material and referring to the general synthetic method B. Mass spectrum [M+H] + :783.4

[0947] 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

[0948] Using pyrazolo[1,5-a]4,5,6,7-tetrahydropyridine-2-carboxylic acid as raw material, compound 183 can be prepared according to the general synthetic method B. Mass spectrum [M+H] + :787.4

[0949] 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

[0950] Compound 184 was prepared using 4,5,6,7-tetrahydro-1H-indazole-3-carboxylic acid as the starting material according to the general synthetic method A. Mass spectrum [M+H] + :787.4

[0951] 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

[0952] Using 7-carboxybenzothiazole as the starting material, compound 185 can be prepared according to the general synthetic method A. Mass spectrum [M+H] + :818.3

[0953] 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

[0954] Compound 186 was prepared using 1-methyl-3-trifluoromethyl-1H-pyrazole-4-carboxylic acid as the starting material and following the general synthetic method A. The mass spectrum was [M+H] + :833.4

[0955] 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

[0956] Compound 187 was prepared using 4H-thieno[3,2-b]pyrrole-5-carboxylic acid as the starting material according to the general synthetic method C. Mass spectrum [M+H] + :806.3

[0957] 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

[0958] Using quinoline-4-carboxylic acid as the starting material, compound 188 can be prepared according to the general synthetic method A. Mass spectrum [M+H] + :812.4

[0959] 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

[0960] Using quinoline-5-carboxylic acid as the starting material, compound 189 can be prepared according to the general synthetic method A. Mass spectrum [M+H] + :812.4

[0961] 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

[0962] Using imidazo[1,2-a]pyridine-6-carboxylic acid as the starting material, compound 190 can be prepared according to the general synthetic method C. Mass spectrum [M+H] + :801.4

[0963] 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

[0964] Using imidazo[1,2-a]pyridine-7-carboxylic acid as raw material, compound 191 can be prepared according to the general synthetic method C. Mass spectrum [M+H] + :801.4

[0965] 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

[0966] Compound 192 was prepared using 1,5-naphthyridine-3-carboxylic acid as the starting material according to the general synthesis method A. Mass spectrum [M+H] + :813.4

[0967] 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

[0968] Compound 193 was prepared using 7-azaindole-4-carboxylic acid as the starting material according to the general synthesis method A. Mass spectrum [M+H] + :801.4

[0969] 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

[0970] Compound 194 was prepared using 2,1,3-benzothiadiazole-4-carboxylic acid as the starting material according to the general synthesis method B. Mass spectrum [M+H] + :819.3

[0971] 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

[0972] Using indole-4-carboxylic acid as the starting material, compound 195 can be prepared according to the general synthetic method A. Mass spectrum [M+H] + :800.4

[0973] 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

[0974] Using indole-5-carboxylic acid as the starting material, compound 196 was prepared according to the general synthetic method B. Mass spectrum [M+H] + :800.4

[0975] 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

[0976] Using quinoline-6-carboxylic acid as the starting material, compound 197 can be prepared according to the general synthetic method C. Mass spectrum [M+H] + :812.4

[0977] 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

[0978] Compound 198 was prepared using 1-benzothiophene-3-carboxylic acid as the starting material according to the general synthesis method A. Mass spectrum [M+H] + :817.4

[0979] 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

[0980] Compound 199 was prepared using 1-methyl-5-phenyl-1H-pyrazole-4-carboxylic acid as the starting material according to the general synthetic method A. The mass spectrum was [M+H] + :841.4

[0981] 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

[0982] Using imidazo[1,2-b]pyridazine-6-carboxylic acid as the starting material, compound 200 can be prepared according to the general synthetic method C. Mass spectrum [M+H] + :802.4

[0983] 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

[0984] Using imidazo[1,5-a]pyridine-8-carboxylic acid as raw material, compound 201 can be prepared according to the general synthetic method C. Mass spectrum [M+H] + :801.4

[0985] 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

[0986] Using imidazo[1,2-a]pyridine-8-carboxylic acid as the starting material, compound 202 can be prepared according to the general synthetic method C. Mass spectrum [M+H] + :801.4

[0987] 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

[0988] Using 8-isoquinolinecarboxylic acid as the starting material, compound 203 can be prepared according to the general synthetic method C. Mass spectrum [M+H] + :812.4

[0989] 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

[0990] Using quinoxaline-5-carboxylic acid as the starting material, compound 204 was prepared according to the general synthetic method A. Mass spectrum [M+H] + :813.4

[0991] 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

[0992] Using 7-azaindole-5-carboxylic acid as the starting material, compound 205 was prepared according to the general synthetic method A. Mass spectrum [M+H] + :801.4

[0993] 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

[0994] Compound 206 was prepared using 2-methyl-6-imidazo[2,1-a]pyridinecarboxylic acid as the starting material according to the general synthetic method D. Mass spectrum [M+H] + :815.4

[0995] 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

[0996] Using isoquinoline-5-carboxylic acid as the starting material, compound 207 can be prepared according to the general synthetic method A. Mass spectrum [M+H] + :812.4

[0997] 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

[0998] Compound 208 was prepared using 3-methylimidazo[1,2-a]pyridine-6-carboxylic acid as the starting material according to the general synthetic method D. Mass spectrum [M+H] + :815.4

[0999] 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

[1000] Compound 209 was prepared by using benzimidazole-4-carboxylic acid as the starting material and referring to the general synthesis method A. Mass spectrum [M+H] + :801.4

[1001] 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

[1002] Compound 210 was prepared using 1-(3-methoxyphenyl)pyrazole-4-carboxylic acid as the starting material and following the general synthetic method D. Mass spectrum [M+H] + :857.4

[1003] 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

[1004] Using 2,1,3-benzothiadiazole-5-carboxylic acid as raw material, compound 211 can be prepared according to the general synthesis method A. Mass spectrum [M+H] + :819.3

[1005] 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

[1006] Compound 212 was prepared using 4-aminothieno[3,2-d]pyrimidine-7-carboxylic acid as the starting material according to the general synthesis method A. Mass spectrum [M+H] + :834.3

[1007] 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

[1008] Using 5-methyl-1-phenyl-1H-pyrazole-4-carboxylic acid as raw material, compound 213 can be prepared according to the general synthetic method B. Mass spectrum [M+H] + :841.4

[1009] 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

[1010] Using imidazo[1,2-b]pyridazine-2-carboxylic acid as the starting material, compound 214 was prepared according to the general synthetic method A. Mass spectrum [M+H] + :802.4

[1011] 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

[1012] Using imidazo[1,2-a]pyrazine-3-carboxylic acid as raw material, compound 215 can be prepared according to the general synthetic method A. Mass spectrum [M+H] + :802.4

[1013] 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

[1014] Compound 216 was prepared using 5-azaindole-7-carboxylic acid as the starting material according to the general synthetic method D. Mass spectrum [M+H] + :801.4

[1015] 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

[1016] Using pyrazolo[1,5-b]pyridazine-3-carboxylic acid as raw material, compound 217 can be prepared according to the general synthetic method A. Mass spectrum [M+H] + :802.4

[1017] 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

[1018] Compound 218 was prepared using 6-indolecarboxylic acid as the starting material according to the general synthetic method C. Mass spectrum [M+H] + :800.42

[1019] 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

[1020] Using 3H-imidazo[4,5-b]pyridine-7-carboxylic acid as the starting material, compound 219 was prepared according to the general synthetic method C. Mass spectrum [M+H] + :802.4

[1021] 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

[1022] Compound 220 was prepared using 7H-pyrrolo[2,3-d]pyrimidine-4-carboxylic acid as the starting material according to the general synthetic method C. Mass spectrum [M+H] + :802.4

[1023] 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

[1024] Using 3H-imidazo[4,5-c]pyridine-7-carboxylic acid as raw material, compound 221 can be prepared according to the general synthetic method A. Mass spectrum [M+H] + :802.4

[1025] 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

[1026] Using pyrazolo[1,5-a]pyrimidine-6-carboxylic acid as raw material, compound 222 can be prepared according to the general synthetic method D. Mass spectrum [M+H] + :802.4

[1027] 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

[1028] Compound 223 was prepared using 1H-pyrazolo[4,3-c]pyridine-4-carboxylic acid as the starting material according to the general synthesis method A. The mass spectrum [M+H] + :802.4

[1029] 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

[1030] Compound 224 was prepared using 2-(4-pyridyl)thiazole-4-carboxylic acid as the starting material and following the general synthetic method A. Mass spectrum [M+H] + :845.3

[1031] 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

[1032] Compound 225 was prepared by using benzofuran-4-carboxylic acid as the starting material and referring to the general synthesis method A. The mass spectrum [M+H] + :801.4

[1033] 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

[1034] Using imidazo[1,2-b]pyridazine-3-carboxylic acid as raw material, compound 226 can be prepared according to the general synthetic method A. Mass spectrum [M+H] + :802.4

[1035] 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

[1036] Compound 227 was prepared using 1-(4-fluorophenyl)-5-methyl-1H-pyrazole-4-carboxylic acid as the starting material according to the general synthesis method A. Mass spectrum [M+H] + :841.4

[1037] 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

[1038] Using 1-methyl-3-trifluoromethyl-1H-pyrazole-4-carboxylic acid as the starting material, compound 228 can be prepared according to the general synthetic method A. Mass spectrum [M+H] + :815.4

[1039] 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

[1040] Using 4H-thieno[3,2-b]pyrrole-5-carboxylic acid as the starting material, compound 229 was prepared according to the general synthetic method A. The mass spectrum [M+H] + :788.3

[1041] 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

[1042] Using quinoline-4-carboxylic acid as the starting material, compound 230 can be prepared according to the general synthetic method A. Mass spectrum [M+H] + :794.4

[1043] 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

[1044] Using quinoline-5-carboxylic acid as the starting material, compound 231 can be prepared according to the general synthetic method A. Mass spectrum [M+H] + :794.4

[1045] 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

[1046] Using imidazo[1,2-a]pyridine-6-carboxylic acid as raw material, compound 232 can be prepared according to the general synthetic method B. Mass spectrum [M+H] + :783.4

[1047] 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

[1048] Compound 233 was prepared using 1H-benzimidazole-6-carboxylic acid as the starting material according to the general synthesis method B. Mass spectrum [M+H] + :783.4

[1049] 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

[1050] Using 7-azaindole-4-carboxylic acid as the starting material, compound 234 was prepared according to the general synthetic method B. Mass spectrum [M+H] + :783.4

[1051] 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

[1052] Using 8-isoquinolinecarboxylic acid as the starting material, compound 235 can be prepared according to the general synthesis method A. Mass spectrum [M+H] + :794.4

[1053] 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

[1054] Using quinoxaline-5-carboxylic acid as the starting material, compound 236 can be prepared according to the general synthetic method A. Mass spectrum [M+H] + :795.4

[1055] 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

[1056] Using 7-azaindole-5-carboxylic acid as the starting material, compound 237 can be prepared according to the general synthetic method A. Mass spectrum [M+H] + :783.4

[1057] 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

[1058] Compound 238 was prepared using 2-methyl-6-imidazo[2,1-a]pyridinecarboxylic acid as the starting material according to the general synthetic method D. Mass spectrum [M+H] + :797.4

[1059] 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

[1060] Compound 239 was prepared using 2,1,3-benzothiadiazole-4-carboxylic acid as the starting material according to the general synthetic method D. Mass spectrum [M+H] + :801.3

[1061] 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

[1062] Using indole-4-carboxylic acid as the starting material, compound 240 can be prepared according to the general synthetic method D. Mass spectrum [M+H] + :782.4

[1063] 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

[1064] Using indole-5-carboxylic acid as the starting material, compound 241 can be prepared according to the general synthetic method A. Mass spectrum [M+H] + :782.4

[1065] 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

[1066] Using quinoline-6-carboxylic acid as the starting material, compound 242 can be prepared according to the general synthetic method D. Mass spectrum [M+H] + :794.4

[1067] 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

[1068] Using 1-benzothiophene-3-carboxylic acid as the starting material, compound 243 can be prepared according to the general synthetic method A. Mass spectrum [M+H] + :799.3

[1069] 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

[1070] Using isoquinoline-5-carboxylic acid as the starting material, compound 244 can be prepared according to the general synthetic method A. Mass spectrum [M+H] + :794.4

[1071] 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

[1072] Using imidazo[1,5-a]pyridine-8-carboxylic acid as raw material, compound 245 can be prepared according to the general synthetic method A. Mass spectrum [M+H] + :783.4

[1073] 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

[1074] Compound 246 was prepared using 1H-benzimidazole-6-carboxylic acid as the starting material according to the general synthetic method D. Mass spectrum [M+H] + :801.4

[1075] 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

[1076] Compound 247 was prepared using 2-methyl-1H-benzimidazole-5-carboxylic acid as the starting material according to the general synthetic method D. Mass spectrum [M+H] + :815.4

[1077] 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

[1078] Using thieno[3,2-d]pyrimidine-4-carboxylic acid as raw material, compound 248 can be prepared according to the general synthetic method A. Mass spectrum [M+H] + :819.3

[1079] 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

[1080] Using thieno[2,3-c]pyridine-2-carboxylic acid as raw material, compound 249 can be prepared according to the general synthetic method A. Mass spectrum [M+H] + :818.3

[1081] 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

[1082] Compound 250 was prepared using 1-methyl-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid as the starting material according to the general synthetic method A. The mass spectrum was [M+H] + :833.4

[1083] 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

[1084] Using [1,2,4]triazolo[4,3-a]pyridine-8-carboxylic acid as raw material, compound 251 can be prepared according to the general synthetic method C. Mass spectrum [M+H] + :802.4

[1085] 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

[1086] Compound 252 was prepared using [1,2,4]triazolo[4,3-a]pyridine-7-carboxylic acid as the starting material according to the general synthetic method C. Mass spectrum [M+H] + :802.4

[1087] 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

[1088] Compound 253 was prepared using 1-phenyl-3-trifluoromethyl-1H-pyrazole-4-carboxylic acid as the starting material and following the general synthetic method C. Mass spectrum [M+H] + :895.4

[1089] 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

[1090] Compound 254 was prepared using 4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-3-carboxylic acid as the starting material according to the general synthetic method A. Mass spectrum [M+H] + :805.4

[1091] 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

[1092] Using pyrazolo[1,5-a]pyridine-3-carboxylic acid as raw material, compound 255 can be prepared according to the general synthetic method A. Mass spectrum [M+H] + :801.4

[1093] 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

[1094] Using 7-indolecarboxylic acid as the starting material, compound 256 can be prepared according to the general synthesis method A. Mass spectrum [M+H] + :800.4

[1095] 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

[1096] Using imidazo[1,5-a]pyridine-8-carboxylic acid as raw material, compound 257 can be prepared according to the general synthetic method C. Mass spectrum [M+H] + :801.4

[1097] 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

[1098] Compound 258 was prepared using 2-methyl-1H-benzimidazole-5-carboxylic acid as the starting material according to the general synthesis method A. The mass spectrum was [M+H] + :797.4

[1099] 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

[1100] Compound 259 was prepared using 3-methylimidazo[1,2-a]pyridine-6-carboxylic acid as the starting material according to the general synthetic method C. Mass spectrum [M+H] + :797.4

[1101] 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

[1102] Compound 260 was prepared using 1-(3-methoxyphenyl)pyrazole-4-carboxylic acid as the starting material and following the general synthetic method B. Mass spectrum [M+H] + :839.4

[1103] Example 261: 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-5-carboxamide Compound 261

[1104] Using 2,1,3-benzothiadiazole-5-carboxylic acid as raw material, compound 261 can be prepared according to the general synthesis method A. Mass spectrum [M+H] + :801.3

[1105] Example 262: 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)thieno[3,2-d]pyrimidine-4-carboxamide Compound 262

[1106] Using thieno[3,2-d]pyrimidine-4-carboxylic acid as the starting material, compound 262 can be prepared according to the general synthetic method B. Mass spectrum [M+H] + :801.3

[1107] Example 263: 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)thieno[2,3-c]pyridine-2-carboxamide Compound 263

[1108] Using thieno[2,3-c]pyridine-2-carboxylic acid as raw material, compound 263 can be prepared according to the general synthetic method B. Mass spectrum [M+H] + :800.3

[1109] Example 264: 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-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide Compound 264

[1110] Compound 264 was prepared using 1-methyl-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid as the starting material according to the general synthetic method D. Mass spectrum [M+H] + :815.4

[1111] Example 265: 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-phenyl-3-(trifluoromethyl)-1H-pyrazole-4-carboxamide Compound 265

[1112] Compound 265 was prepared using 1-phenyl-3-trifluoromethyl-1H-pyrazole-4-carboxylic acid as the starting material and following the general synthetic method D. Mass spectrum [M+H] + :877.4

[1113] Example 266: 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-3-carboxamide Compound 266

[1114] Compound 266 was prepared using 4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-3-carboxylic acid as the starting material according to the general synthesis method A. The mass spectrum [M+H] + :787.4

[1115] Example 267: 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-methyl-1-phenyl-1H-pyrazole-4-carboxamide Compound 267

[1116] Using 5-methyl-1-phenyl-1H-pyrazole-4-carboxylic acid as the starting material, compound 267 can be prepared according to the general synthetic method A. Mass spectrum [M+H] + :823.4

[1117] Example 268: 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]pyrazine-3-carboxamide Compound 268

[1118] Using imidazo[1,2-a]pyrazine-3-carboxylic acid as raw material, compound 268 can be prepared according to the general synthetic method D. Mass spectrum [M+H] + :784.4

[1119] Example 269: 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-7-carboxamide Compound 269

[1120] Compound 269 was prepared using 5-azaindole-7-carboxylic acid as the starting material according to the general synthetic method D. Mass spectrum [M+H] + :783.4

[1121] Example 270: 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-b]pyridazine-3-carboxamide Compound 270

[1122] Using pyrazolo[1,5-b]pyridazine-3-carboxylic acid as the starting material, compound 270 can be prepared according to the general synthetic method A. Mass spectrum [M+H] + :784.4

[1123] Example 271: 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-6-carboxamide Compound 271

[1124] Using 6-indolecarboxylic acid as the starting material, compound 271 can be prepared according to the general synthetic method B. Mass spectrum [M+H] + :782.4

[1125] Example 272: 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-7-carboxamide Compound 272

[1126] Using 7-indolecarboxylic acid as the starting material, compound 272 can be prepared according to the general synthetic method A. Mass spectrum [M+H] + :782.4

[1127] Example 273: 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 273

[1128] Using imidazo[1,5-a]pyridine-8-carboxylic acid as raw material, compound 273 can be prepared according to the general synthesis method A. Mass spectrum [M+H] + :783.4

[1129] Example 274: 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-d]pyrimidine-4-carboxamide Compound 274

[1130] Compound 274 was prepared using 7H-pyrrolo[2,3-d]pyrimidine-4-carboxylic acid as the starting material according to the general synthesis method A. Mass spectrum [M+H] + :784.4

[1131] Example 275: 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]pyrimidine-6-carboxamide Compound 275

[1132] Using pyrazolo[1,5-a]pyrimidine-6-carboxylic acid as raw material, compound 275 can be prepared according to the general synthetic method A. Mass spectrum [M+H] + :784.4

[1133] Example 276: 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-pyrazolo[4,3-c]pyridine-4-carboxamide Compound 276

[1134] Compound 276 was prepared using 1H-pyrazolo[4,3-c]pyridine-4-carboxylic acid as the starting material according to the general synthesis method A. The mass spectrum [M+H] + :784.4

[1135] Example 277: 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-3-carboxamide Compound 277

[1136] Using imidazo[1,2-a]pyridine-3-carboxylic acid as raw material, compound 277 can be prepared according to the general synthesis method A. Mass spectrum [M+H] + :783.4

[1137] Example 278: 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-(pyrimidin-2-yl)-1H-imidazole-4-carboxamide Compound 278

[1138] Compound 278 was prepared using 1-(pyrimidin-2-yl)-1H-imidazole-4-carboxylic acid as the starting material according to the general synthesis method A. Mass spectrum [M+H] + :811.4

[1139] Example 279: 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-methylpyridin-4-yl)-1H-pyrazole-4-carboxamide Compound 279

[1140] Compound 279 was prepared using 1-(2-methylpyridin-4-yl)-1H-pyrazole-4-carboxylic acid as the starting material according to the general synthesis method A. Mass spectrum [M+H] + :824.4

[1141] Example 280: 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-(pyridin-3-yl)-1H-pyrazole-4-carboxamide Compound 280

[1142] Compound 280 was prepared using 1-(pyridin-3-yl)-1H-pyrazole-4-carboxylic acid as the starting material and following the general synthetic method C. Mass spectrum [M+H] + :810.4

[1143] Example 281: 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)-1,4,5,6-tetrahydrocyclopenta[c]pyrazole-3-carboxamide Compound 281

[1144] Compound 281 was prepared using 1,4,5,6-tetrahydrocyclopenta-pyrazole-3-carboxylic acid as the starting material according to the general synthesis method A. Mass spectrum [M+H] + :773.4

[1145] Example 282: Preparation of N-(2-(1-((1-(2-...

Claims

1. A compound of formula (IA), its stereoisomers, N-oxides, deuterated derivatives, pharmaceutically acceptable salts or prodrugs thereof: Where, Ring B is in, 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 ; W5, W6, and W7 are each independently N or CH; R 1 For hydrogen, halogen, C 1-6 Alkyl or C 1-6 alkyl halide; R x For hydrogen, C 1-6 Alkoxy, -C(O)NR x1 R x2 , 4 to 8 membered nitrogen-containing heterocycloalkyl, 5 or 6 membered heteroaryl or C 6-8 Aryl, the C 1-6 The alkoxy group is optionally replaced by one or more C 3-6 The 4 to 8-membered nitrogen-containing heterocycloalkyl, 5 or 6-membered heteroaryl or C 6-8 Aryl is optionally substituted by one or more selected from halogen, hydroxy, C 1-6 Alkyl or hydroxy substituted C 1-6 The 4- to 8-membered nitrogen-containing heterocycloalkyl group contains at least one nitrogen atom and 0 to 3 heteroatoms independently selected from N, O or S as ring atoms; R x1 、R x2 are each independently hydrogen or C 1-6 alkyl; Lx is -C(O)NH- or -CH2-NH-; 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; (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; or, Ring A is: wherein S1, S2, S3, S4, S5, S6, S7, and S8 are each independently selected from CH2, CH, NH, N, O, or S; S9, S 10 are each independently selected from N or CH; q1 and q2 are each independently 0, 1 or 2; R y For hydrogen, halogen, hydroxyl, =O, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl, -OR a -、-NR b R c , 4 to 8 membered nitrogen-containing heterocycloalkyl, 5 or 6 membered heteroaryl or C 6-8 Aryl, wherein the C 1-6 Alkyl, 5 or 6 membered heteroaryl, 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 Halogenated alkoxy, C 3-6 Cycloalkyl, -OC(O)-C 1-6 Alkyl, -OP(O)(OH)2 or 4 to 12 membered heterocycloalkyl, the C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 3-6 Cycloalkyl or 4 to 12 membered heterocycloalkyl is optionally substituted by one or more selected from halogen, C 1-6 Alkyl, C 1-6 Haloalkyl or C 1-6 Substitution of alkoxy groups; 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 with ring B; Q1, Q2, and Q3 are each independently a 4- to 12-membered nitrogen-containing heterocycloalkyl group or a C 3-10 Cycloalkyl, the 4 to 12-membered nitrogen-containing heterocycloalkyl contains at least one nitrogen atom as a ring atom; the 4 to 12-membered nitrogen-containing heterocycloalkyl or C 3-10 Cycloalkyl 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 -、-NR L3 -CR L1 R L2 -OR L4 ; R L1 、R L2 、R L3 、R L4 are independently hydrogen, halogen, =O, C 1-6 Alkyl, C 1-6 Haloalkyl or C 2-6 Alkynyl; m1, m2, m3, m4, m5, m6, and m7 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): Where 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), (A10) or (A11): 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, O, S 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 、R G6c are each independently hydrogen or R y ; 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 is a structure represented by formula (A12) or formula (A13): Where M1 is N or CR M1 ; M2 is N or CR M2 ; M3 is N or CR M3 ;M4 is NR M4 ;M5 is NR M5a , O, S or CR M5b R M5c ;M6 is NR M6a , O, S or CR M6b R M6c ;M7 is NR M7a , O, S or CR M7b R M7c ;M8 is NR M8a , O, S or CR M8b R M8c ; R M1 、R M2 、R M3 、R M4 、R M5a 、R M5b 、R M5c 、R M6a 、R M6b 、R M6c 、R M7a 、R M7b 、R M7c 、R M8a 、R M8b 、R M8c are each independently hydrogen or R y ; p1 and p2 are each independently 0, 1 or 2.

7. The compound according to claim 1, its stereoisomer, N-oxide, deuterated derivative, pharmaceutically acceptable salt or prodrug thereof: wherein, In the 8- to 10-membered biheteroaryl group formed by condensing a 5- or 6-membered monoheteroaryl ring and a 5- or 6-membered monoheteroaryl ring in Ring A, the two 5- or 6-membered monoheteroaryl rings are independently selected from the following groups: The group is optionally replaced by one or more R y replace; The attached carbon atoms or heteroatoms represented are adjacent pairs of carbon atoms or heteroatoms that are shared when fused with other rings; Preferably, in the 8- to 10-membered biheteroaryl group formed by condensing a 5- or 6-membered monoheteroaryl ring and a 5- or 6-membered monocyclic heterocycloalkyl ring in Ring A, the 5- or 6-membered monoheteroaryl ring is selected from the following group: The group is optionally replaced by one or more R y replace; The attached carbon atoms or heteroatoms represented are adjacent pairs of carbon atoms or heteroatoms that are shared when fused with other rings; Preferably, in the 8- to 10-membered biheteroaryl group formed by condensing a 5- or 6-membered monoheteroaryl ring and a 5- or 6-membered monocyclic heterocycloalkyl ring in Ring A, the 5- or 6-membered monocyclic heterocycloalkyl ring is selected from the following group: The group is optionally replaced by one or more R y replace; The attached carbon atoms or heteroatoms represented are adjacent pairs of carbon atoms or heteroatoms that are shared when fused with other rings; Preferably, 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: in, R D is hydrogen or R y ; The two carbon atoms represented are connected to each other as a pair of adjacent carbon atoms shared when fused to other rings; Preferably, when ring A is a 5- or 6-membered monoheteroaryl group, the 5- or 6-membered monoheteroaryl group is selected from the following group: The group is optionally replaced by one or more R y replace; The position shown indicates connection with Lx; Preferably, ring A is C 6-8 When the C 6-8 Aryl is selected from phenyl or naphthyl, said group being optionally substituted by one or more R y replace.

8. The compound according to any one of claims 1 to 7, its stereoisomer, N-oxide, deuterated derivative, pharmaceutically acceptable salt or prodrug thereof: wherein, Ring B is Preferably, ring B is 9. The compound according to any one of claims 1 to 8, its stereoisomer, N-oxide, deuterated derivative, pharmaceutically acceptable salt or prodrug thereof: wherein, The compound of formula (IA) has the structure shown in the following formula (I): In the formula, ring A, E3, L, W1, W2, W3, W4, R X , L X 、R y , y are as defined above; Preferably, the compound of formula (I) has the structure shown in the following formula (I-1): In the formula, ring A, E3, L, R X , L X 、R y , y are defined as before.

10. The compound according to any one of claims 1 to 9, its stereoisomer, N-oxide, deuterated derivative, pharmaceutically acceptable salt or prodrug thereof: wherein, R y Selected from: halogen, =O, hydroxy, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, methoxy, ethoxy, propoxy, isopropyloxy, butoxy, tert-butoxy, -NH2, -NHCH3, -N(CH3)2, -CH2-OC(O)(CH3)3, -CH2-OP(O)(OH)2, fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl, trifluoroethyl, thienyl, N-alkylpyrrolidonyl, furyl, morpholinyl, piperazinyl, 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-triazolyl, -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, imidazole oxazolyl, 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, ethyl, propyl, isopropyl, methoxy, ethoxy, fluoromethyl, difluoromethyl, trifluoromethyl; Preferably, R y Selected from: halogen, hydroxy, =O, amino, methylamino, dimethylamino, methyl, tert-butyl, trifluoromethyl, methoxy, -CH2-OC(O)(CH3)3, -CH2-OP(O)(OH)2, morpholinyl, 11. The compound according to any one of claims 1 to 10, 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 replace; Preferably, Ring A is selected from:

12. The compound according to any one of claims 1 to 10, its stereoisomer, N-oxide, deuterated derivative, pharmaceutically acceptable salt or prodrug thereof: wherein, R x For hydrogen, C 1-6 Alkoxy, -C(O)NR x1 R x2 , 4 to 8 membered nitrogen-containing heterocycloalkyl, 5 or 6 membered heteroaryl or C 6-8 Aryl, the C 1- 6 alkoxy is optionally replaced by one or more C 3-6 The 4 to 8-membered nitrogen-containing heterocycloalkyl, 5 or 6-membered heteroaryl or C 6-8 Aryl is optionally substituted by one or more selected from halogen, hydroxy, C 1-6 Alkyl, hydroxy substituted C 1-6 Alkyl or halogen substituted C 1-6 The 4- to 8-membered nitrogen-containing heterocycloalkyl group contains at least one nitrogen atom and 0 to 3 heteroatoms independently selected from N, O or S as ring atoms; R x1 、R x2 are each independently hydrogen or methyl, ethyl or propyl; Preferably, R x Methoxy, ethoxy, -C(O)N(CH3)2, -C(O)NH2, wherein the methoxy and ethoxy groups are optionally substituted by one or more cyclopropyl groups, optionally substituted with one or more substituents selected from hydroxy, F, Cl, Br, methyl, ethyl, propyl, isopropyl, hydroxymethyl, hydroxyethyl, hydroxypropyl; Preferably, R x Methoxy, -C(O)NH2, 13. The compound according to any one of claims 1 to 12, its stereoisomer, N-oxide, deuterated derivative, pharmaceutically acceptable salt or prodrug thereof: wherein, Lx is selected from *-C(O)NH-**, *-CH2-NH-** or *-NH-C(O)-**; preferably, Lx is selected from *-C(O)NH-**, *-CH2-NH-**; wherein the position indicated by "*" indicates connection to ring A, and the position indicated by "**" indicates connection to the other side group of Lx.

14. The compound according to any one of claims 1 to 13, 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 ; Preferably, the compound is a compound represented by formula (IA1-1) or formula (IA2-1): Where, E3, L, 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 .

15. 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 above; Preferably, the compound is a compound represented by formula (IB1-1), formula (IB2-1), formula (IB3-1), formula (IB4-1) or formula (IB5-1): Where, E3, L, R X , L X 、R y , y are defined as before.

16. 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, and n6 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.

17. The compound according to any one of claims 1 to 16, its stereoisomer, N-oxide, deuterated derivative, pharmaceutically acceptable salt or prodrug thereof: wherein, L is selected from: in, X1, X2, X3, X4, X 11 、X 12 、X 21 、X 22 、X 31 、X 32 、X 41 、X 42 Each independently is N or -CR d ; Among them, R d For hydrogen, hydroxyl, halogen, -CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy or C 3-6 Cycloalkyl; n1, n2, n3, n4, n11, n12, n21, n22, n31, n32 are each independently 0, 1, 2 or 3; L1, L2, L3, and L4 are each independently -CR L1 R L2 -、-NR L3 -、-CR L1 R L2 -NR L3 -、-NR L3 -CR L1 R L2 -OR L4 ; R L1 、R L2 、R L3 、R L4 are independently =O, hydrogen, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl or C 2-6 Alkynyl; m1, m2, m3, and m4 are each independently 0 or 1; in, The position shown indicates connection with E3. The position shown indicates attachment to ring B.

18. The compound according to any one of claims 1 to 17, its stereoisomer, N-oxide, deuterated derivative, pharmaceutically acceptable salt or prodrug thereof: wherein, L is selected from: in, The position shown indicates connection with E3. The position indicated by " indicates connection with ring B.

19. The compound according to any one of claims 1 to 18, its stereoisomer, N-oxide, deuterated derivative, pharmaceutically acceptable salt or prodrug thereof: wherein, E3 has a structure represented by the following formula (C1), (C2), (C3), (C4), (C5), (C6), (C7), (C8) or (C9): wherein T1, T2, T3, T4, and T5 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, C 1-6 Alkyl or C 1-6 Alkoxy, the C 1-6 The alkyl group is optionally replaced by one or more C 1-6 Alkoxy or -OC(O)-C 1-6 Alkyl substitution; R3 is hydrogen, hydroxy or C 1-6 alkyl; R4, R7, R 10 are independently hydrogen, halogen, C 1-6 Alkyl, C 1-6 Alkoxy or halogenated C 1-6 alkyl; m7, m8, m9, and m10 are each independently 0, 1, 2, or 3.

20. The compound according to claim 1, its stereoisomer, N-oxide, deuterated derivative, pharmaceutically acceptable salt or prodrug thereof: wherein, E3 is R7 is hydrogen, halogen, C 1-6 Alkyl, C 1-6 Alkoxy or halogenated C 1-6 Alkyl; R5 is hydrogen, C 1-6 Alkyl or C 1-6 Alkoxy, the C 1-6 The alkyl group is optionally replaced by one or more C 1-6 Alkoxy or -OC(O)-C 1-6 Alkyl substituted; m9 is 1, 2 or 3; Preferably, R7 is hydrogen, F, Cl, Br, methyl, methoxy or trifluoromethyl; Preferably, R5 is hydrogen or -CH2-O(O)(CH3)3; Preferably, E3 is 21. The compound of claim 1, its stereoisomer, N-oxide, deuterated derivative, pharmaceutically acceptable salt, or prodrug thereof, wherein the compound is selected from Table A, Table B, Table C, Table D, or Table E.

22. The compound of formula (I) according to any one of claims 1 to 21, 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.

23. A pharmaceutical composition, wherein The composition comprises a compound according to any one of claims 1 to 21, a stereoisomer, an N-oxide, a deuterated derivative, a pharmaceutically acceptable salt, or a prodrug thereof.

24. Use of the compound of any one of claims 1 to 21, its stereoisomers, N-oxides, deuterated derivatives, pharmaceutically acceptable salts or prodrugs thereof, or the pharmaceutical composition of claim 23 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 lesions, proliferative disorders, infectious diseases, conditions associated with cell death, thrombin-induced platelet aggregation, liver diseases, pathological immune conditions mediated by T cell activation, cardiovascular disorders and CNS disorders.

25. Use of the compound of any one of claims 1-21, 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.

26. 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 21, its stereoisomers, N-oxides, deuterated derivatives, pharmaceutically acceptable salts or prodrugs thereof, or the pharmaceutical composition of claim 20.

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