Multi-target degradation agent and application thereof

Abstract

The invention provides a multi-target degradation agent and application thereof, relates to the field of medicinal chemistry, and particularly provides a stereoisomer, N-oxide, deuterated derivative and pharmaceutically acceptable salt of the multi-target degradation agent shown in the formula (IA), all substituent groups in the formula are defined in the specification, and the compound can degrade BTK protein and / or IRAK4 protein. According to the present invention, the BTK and IRAK4 protein can be simultaneously degraded in a variety of tumor cells, the proliferation of the tumor cells can be efficiently inhibited, the apoptosis of the tumor cells can be induced, and the new treatment drug can be provided for cancers and other self-immune diseases.

Description

TECHNICAL FIELD

[0001] The present application relates to the field of pharmaceutical chemistry, in particular to a multi-target degrading agent and a preparation method and use thereof. BACKGROUND

[0002] Interleukin-1-receptor kinase 4 (IRAK4) is a serine / threonine-specific protein kinase. IRAK4, as an important mediator located at the intersection of interleukin (IL)-1 family receptor and Toll-like receptor (TLR) signaling, has very wide physiological functions. IRAK4 undergoes autophosphorylation and activates the kinase activity of other IRAKs, completes the activation of downstream related signaling pathways (NF-κB, JNK, p38, etc.), and then promotes the secretion of inflammatory cytokines and the proliferation and differentiation of immune cells. IRAK4 plays a role in the whole signaling pathway, and changes its activity through conformational change and post-translational modification. In Myddosome, IRAK4 is activated by trans-autophosphorylation, then activates IRAK1 / 2 through phosphorylation, and then activates the downstream signaling pathway to produce pro-inflammatory factors. Previous pharmacological research results show that IRAK4 activity plays a key role in various inflammatory diseases, such as arthritis, atherosclerosis, Alzheimer's disease, gout, systemic lupus erythematosus, psoriasis, etc. Some studies show that the mutation or inhibition of IRAK4 activity in animal models shows therapeutic effects on inflammatory diseases (such as septic shock, SLE, cardiovascular disease, Alzheimer's disease). Therefore, IRAK4 has become an important drug development target, and by inhibiting the activity of IRAK4, the treatment of various diseases such as inflammatory diseases, autoimmune diseases and tumors can be achieved.

[0003] Bruton's tyrosine kinase (BTK) is a non-receptor cytoplasmic tyrosine kinase in the Tec family. In B lymphocytes, BTK activity is essential for B cell receptor (BCR)-mediated activation, which can cause cell development, antibody and cytokine production, and co-stimulatory molecule expression. BTK is a key kinase that links BCR signals, FcR signals, TLR signals, and chemokine receptor signals. The central role of BTK in B cell signaling and function makes it an important drug development target for B cell malignancies and autoimmune and inflammatory diseases. Currently, several BTK inhibitors have been approved for the treatment of chronic lymphocytic leukemia (CLL), mantle cell lymphoma (MCL) and other B cell malignancies, and graft-versus-host disease (GvHD). Currently, a variety of inflammatory diseases or autoimmune diseases driven by B cells or bone marrow cells have gradually become important indications for clinical research of BTK inhibitors, and several BTK molecules have entered clinical research, but so far no BTK inhibitor has been approved for use in inflammatory or autoimmune diseases.

[0004] Currently, in the research process of activated B-cell-like diffuse large B-cell lymphoma (ABC-DLBCL), it is found that ABC-DLBCL patients with MyD88L265P mutation have poor response to BCR inhibitors due to abnormal MyD88 signaling pathway, and a large number of research data of Bayer, Nimbus and AstraZeneca show that the combination of IRAK4 inhibitor and BTK inhibitor can significantly improve the in vivo efficacy of Ibrutinib in an ABC-DLBCL xenograft animal model. If the abnormal BCR pathway and MyD88 pathway can be effectively inhibited at the same time, it will be a more effective way to treat ABC-DLBCL, and therefore the development of RAK4 and BTK dual-target inhibitors can obtain double benefits in blocking the NF-KB pathway, which is a very efficient and effective strategy from the treatment mechanism, and provides a potential effective new treatment method for ABC-DLBCL patients.

[0005] PROTAC (Proteolysis Targeting Chimeras) technology, i.e. protein targeting degradation technology, is a new chemical probe or drug discovery means for inducing degradation of target proteins by ubiquitin-proteasome system. PROTAC technology combines target proteins and E3 ligase through bifunctional small molecules, so that the target proteins are recognized by E3 ligase and tagged with ubiquitination, and then degraded by proteasome. These bifunctional compounds provide 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

[0006] The present application realizes the degradation of multiple target proteins of BTK and IRAK4 by protein targeting degradation technology, has good degradation activity and high selectivity, and the corresponding bifunctional compound can realize efficient degradation of two target proteins, and the molecule has better drugability, higher bioavailability and drug exposure, thereby providing more sufficient material basis for the potential application of the compound in clinic.

[0007] The present application finds a series of carboxylic acid fragments with diverse structures, which have high degradation activity for IRAK4 and BTK target proteins. The carboxylic acid fragments have not been reported in the prior art, which is a new PROTAC drug part, and the combination of E3 part and linker part is also different, which is a secondary innovation point.

[0008] The present application realizes the degradation of multiple target proteins of BTK and IRAK4 through the protein targeted degradation technology, has good degradation activity and high selectivity, the degradation activity of the target protein presents a good concentration dependence on the compound concentration, the corresponding bifunctional compound can realize efficient degradation of two target proteins, meanwhile, the molecule has better drugability, has higher bioavailability and drug exposure, and provides more sufficient material basis for the potential application of the compound in clinic.

[0009] Specifically, in one aspect of the present application, a compound of formula (IA), a stereoisomer, an N-oxide, a deuterated derivative, a pharmaceutically acceptable salt or a prodrug thereof is provided:

[0010]

[0011] in the formula,

[0012] ring B is

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

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

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

[0016] R 1 is hydrogen, halogen, C 1-6 alkyl or C 1-6 haloalkyl;

[0017] R x is hydrogen, C 1-6 alkoxy, -C(O)NR x1 R x2 , 4- to 8-membered nitrogen-containing heterocycloalkyl, 5- or 6-membered monoheteroaryl or C 6-8 aryl, said C 1-6 alkoxy is optionally substituted with one or more C 3-6 cycloalkyl; said 4- to 8-membered nitrogen-containing heterocycloalkyl, 5- or 6-membered monoheteroaryl or C 6-8 aryl is optionally substituted with one or more C 1-6 alkyl or hydroxy-substituted C 1-6 alkyl; said 4- to 8-membered nitrogen-containing heterocycloalkyl contains at least one N atom, and contains 0-3 heteroatoms independently selected from N, O or S as ring atoms;

[0018] R x1 , R x2each independently hydrogen or C 1-6 alkyl;

[0019] Lx is selected from *-C(O)NH-** or *-NH-C(O)-**; wherein the position indicated by "*" represents the attachment to ring A and the position indicated by "**" represents the attachment to the other group of Lx;

[0020] ring A is:

[0021] (i) 8- to 10-membered biheteroaryl; said 8- to 10-membered biheteroaryl is formed by the fusion of a 5- or 6-membered monoheteroaryl ring with a 5- or 6-membered monoheteroaryl ring;

[0022] (ii) 8- to 10-membered biheteroaryl; said 8- to 10-membered biheteroaryl is formed by the fusion of a 5- or 6-membered monoheteroaryl ring with a 5- or 6-membered monocyclic heterocycloalkyl ring;

[0023] (iii) 9- or 10-membered biheteroaryl; said 9- or 10-membered biheteroaryl is formed by the fusion of a phenyl ring with a 5- or 6-membered monoheteroaryl ring;

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

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

[0026] or,

[0027] ring A is:

[0028] wherein S1, S2, S3, S4, S5, S6, S7, S8are each independently selected from CH2, CH, NH, N, O or S;

[0029] S9, S 10 are each independently selected from N or CH; q1, q2are each independently 0, 1 or 2;

[0030] R y is hydrogen, halogen, =O, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 3-6 cycloalkyl, -O-R a -, -NR b R c , 4- to 8-membered nitrogen-containing heterocycloalkyl, 5- or 6-membered monoheteroaryl or C 6-8 aryl, wherein said C 1-6 alkyl, 5- or 6-membered monoheteroaryl, C 6-8 aryl is optionally substituted with one or more R 1 ;

[0031] R 1halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-6 cycloalkyl, -OC(O)-C 1-6 alkyl, -OP(O)(OH)2, or 4- to 12-membered heterocycloalkyl, which C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-6 cycloalkyl or 4- to 12-membered heterocycloalkyl, which are optionally substituted by one or more substituents selected from the group consisting of halogen, C 1-6 alkyl, C 1-6 haloalkyl or C 1-6 alkoxy;

[0032] R 1 is halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-6 cycloalkyl, -OC(O)-C 1-6 alkyl, -OP(O)(OH)2, or 4- to 12-membered heterocycloalkyl, which C 1-6 alkyl, C 1-6 haloalkyl or C 1-6 alkoxy;

[0033] R a is 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 wherein, the position indicated represents the attachment to E3, the position indicated represents the attachment to ring A;

[0037] Q1, Q2, Q3are each independently 4- to 12-membered nitrogen-containing heterocycloalkyl, which contains at least one N atom as ring atom; which 4- to 12-membered nitrogen-containing heterocycloalkyl is optionally substituted by one or more substituents selected from the group consisting of halogen and hydroxyl;

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

[0039] R L1 , R L2 , R L3 are each independently hydrogen, halogen, C 1-6 alkyl or C 1-6 haloalkyl;

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

[0041] E3 is a ubiquitin ligase binding group.

[0042] Preferably, L is wherein, the position indicated is connected to E3, the position indicated is connected to ring A;

[0043] Q1, Q2, Q3 are each independently a 4- to 12-membered nitrogen-containing heterocycloalkyl group, which contains at least one N atom as ring atom; which 4- to 12-membered nitrogen-containing heterocycloalkyl group is optionally substituted by one or more substituents selected from the group consisting of halogen and hydroxyl;

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

[0045] R L1 , R L2 , R L3 are each independently hydrogen, halogen, C 1-6 alkyl or C 1-6 haloalkyl;

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

[0047] E3 is a ubiquitin ligase binding group.

[0048] In one aspect of the present application, there is provided a compound of Formula (I), a stereoisomer, N-oxide, deuterated derivative, pharmaceutically acceptable salt, or prodrug thereof:

[0049]

[0050] wherein,

[0051] is a single or double bond;

[0052] W1, W2, W3, W4are each independently C=O, CH, CH2, O, N, CR 1 or NR 1 ;

[0053] R 1 is hydrogen, halogen, C 1-6 alkyl or C 1-6 haloalkyl;

[0054] R x is hydrogen or 4- to 8-membered nitrogen-containing heterocycloalkyl, said 4- to 8-membered nitrogen-containing heterocycloalkyl containing at least one N atom and containing from 0 to 3 heteroatoms independently selected from N, O or S as ring atoms;

[0055] Lxis selected from *-C(O)NH-** or *-NH-C(O)-**; wherein the position indicated by “*” represents the attachment to ring A and the position indicated by “**” represents the attachment to the other group of Lx;

[0056] ring A is:

[0057] (i) 8- to 10-membered biheteroaryl; said 8- to 10-membered biheteroaryl is formed by the fusion of a 5- or 6-membered monoheteroaryl ring with a 5- or 6-membered monoheteroaryl ring;

[0058] (ii) 8- to 10-membered biheteroaryl; said 8- to 10-membered biheteroaryl is formed by the fusion of a 5- or 6-membered monoheteroaryl ring with a 5- or 6-membered monocyclic heterocycloalkyl ring;

[0059] (iii) 9- or 10-membered biheteroaryl; said 9- or 10-membered biheteroaryl is formed by the fusion of a phenyl ring with a 5- or 6-membered monoheteroaryl ring;

[0060] (iv) 5- or 6-membered monoheteroaryl; or,

[0061] (v) C 6-8 aryl;

[0062] R y is hydrogen, halogen, C 1-6 alkyl, C 1-6haloalkyl, C 3-6 cycloalkyl, -O-R a -, -NR b R c , 5- or 6-membered mono- or bicyclic heteroaryl, or C 6-8 aryl, wherein said 5- or 6-membered mono- or bicyclic heteroaryl, or C 6-8 aryl is optionally substituted by one or more R 1 ;

[0063] R 1 is halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, or C 3-6 cycloalkyl;

[0064] R a is C 1-6 alkyl or C 6-8 aryl;

[0065] R b , R c each independently is hydrogen or C 1-3 alkyl;

[0066] y is 0, 1, 2, 3 or 4;

[0067] L is wherein, the position indicated means being attached to E3, the position indicated means being attached to ring A;

[0068] Q1, Q2, Q3are each independently a 4- to 12-membered nitrogen-containing heterocycloalkyl, said 4- to 12-membered nitrogen-containing heterocycloalkyl containing at least one N atom as ring atom; said 4- to 12-membered nitrogen-containing heterocycloalkyl being optionally substituted by one or more substituents selected from the group consisting of halogen and hydroxy;

[0069] L1, L2, L3, L4are each independently -CR L1 R L2 -, -NR L3 -, -CR L1 R L2 -NR L3 - or -NR L3 -CR L1 R L2 -;

[0070] R L1 , R L2 , R L3 are each independently hydrogen, halogen, C 1-6 alkyl or C 1-6 haloalkyl;

[0071] each of ml, m2, m3, m4, m5 is independently 0 or 1 ;

[0072] E3 is a ubiquitin ligase binding group.

[0073] In one embodiment, the 8- to 10-membered biheteroaryl formed by the fusion of a 5- or 6-membered monoheteroaryl ring with a 5- or 6-membered monoheteroaryl ring in Ring A is a structure according to Formula (A1) or Formula (A2):

[0074]

[0075] wherein U1is N or CR U1 ; U2is N or CR U2 ; U3is N or CR U3 ; U4is N or CR U4 ; U5is N or CR U5 ; U6is N or CR U6 ; U7is N or CR U7 ; U8is N or CR U8 ; and at least one of U1, U2, U3, U4, U5, U6, U7, U8is N; each R U1 , each R U2 , each R U3 , each R U4 , each R U5 , each R U6 , each R U7 , each R U8 is independently hydrogen or R y .

[0076] In one embodiment, the 8- to 10-membered biheteroaryl formed by the fusion of a 5- or 6-membered monoheteroaryl ring with a 5- or 6-membered monoheteroaryl ring in Ring A is a structure according to Formula (A3) or Formula (A4):

[0077]

[0078] wherein Z1is N or CR Z1 ; Z2is NR Z2 , O or S; Z3is N or CR Z3 ; Z4is N or CR Z4 ; Z5is N or CR Z5 ; Z6is N or CR Z6 ; and at least one of Z3, Z4, Z5, Z6is N; each R Z0 , each R Z1 , each R Z2 , each R Z3 , each R Z4 , each R Z5 , each R Z6each independently hydrogen or R y .

[0079] In one embodiment, the 8- to 10-membered biheteroaryl formed by the fusion of 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):

[0080]

[0081] wherein P1is NR P1 , O or S; P2is NR P2 , O or S; P3is N or CR P3 ; P4is N or CR P4 ; and at least one of P3, P4is N;

[0082] R P1 , R P2 , R P3 , R P4 each independently hydrogen or R y .

[0083] In one embodiment, the 8- to 10-membered biheteroaryl formed by the fusion of 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):

[0084]

[0085] wherein V1is N or CR V1 ; V2is N or CR V2 ; V3is N or CR V3 ; V4is N or CR V4 ; V5is N or CR V5 ; V6is N or CR V6 ; V7is N or CR V7 ; V8is N or CR V8 ; V9is N or CR V9 ; and at least one of V1, V2, V3, V4, V5, V6, V7, V8, V9is N; R V1 , R V2 , R V3 , R V4 , R V5 , R V6 , R V7 , R V8 , R V9 each independently hydrogen or R y .

[0086] In one embodiment, the 8- to 10-membered biheteroaryl formed by the fusion of a 5- or 6-membered, single heteroaryl ring with a 5- or 6-membered, single ring heterocycloalkyl ring in Ring A is of the structure of Formula (A7), Formula (A8), (A9), or (A10):

[0087]

[0088] wherein H1is N or CR H1 ; H2is N or CR H2 ; H3is N or CR H3 ; H4is NR H4a , O, S, or CR H4b R H4c ; H5is NR H5a , O, S, or CR H5b R H5c ; H6is NR H6a , O, S, or CR H6b R H6c ; H7is 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 each independently is hydrogen or R y ;

[0089] G1is N or CR G1 ; G2is NR G2a , O, S, or CR G2b R G2c ; G3is NR G3a , O, S, or CR G3b R G3c ; G4is NR G4a , O, S, or CR G4b R G4c ; G5is NR G5a , O, S, or CR G5b R G5c ; G6is NR G6a , O, S, or CR G6b R G6c ; RG0 , 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 each independently is hydrogen or R y .

[0090] In one embodiment, the 8- to 10-membered biheteroaryl formed by the fusion of a 5- or 6-membered monoheteroaryl ring with a 5- or 6-membered monocyclic heterocycloalkyl ring is of the structure of Formula (A11) or Formula (A12):

[0091]

[0092] wherein M1is N or CR M1 ; M2is N or CR M2 ; M3is N or CR M3 ; M4is NR M4 ; M5is NR M5a , O, S, or CR M5b R M5c ; M6is NR M6a , O, S, or CR M6b R M6c ; M7is NR M7a , O, S, or CR M7b R M7c ; M8is 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 each independently is hydrogen or R y; each p1, p2 is independently 0, 1 or 2.

[0093] In one embodiment, in the 9- or 10-membered biheteroaryl ring formed by the fusion of 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 group consisting of:

[0094]

[0095]

[0096] wherein R D is hydrogen or R y ; represents the two carbon atoms to which the attached groups are adjacent carbon atom pair shared when fused with other rings.

[0097] In one embodiment, ring A is:

[0098] wherein each S1, S2, S3, S4, S5, S6, S7, S8 is independently selected from CH2, CH, NH, N, O or S; wherein said ring A comprises at least 1, 2, 3, 4 or 5 N atoms;

[0099] each S9, S 10 is independently selected from N or CH; each q1, q2 is independently 0, 1 or 2.

[0100] In one embodiment, ring A is:

[0101] In one embodiment, ring B is

[0102] In one embodiment, ring B is

[0103] In one embodiment, R yselected from: halogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, methoxy, ethoxy, propoxy, isopropoxy, 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-alkylpyrrolidinonyl, furanyl, 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, -O-N-alkylpyrrolidinonyl, -O-furanyl, -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-pyridyl, -O-pyridazinyl, -O-pyrimidinyl, -O-pyrazinyl, -O-phenyl; said thienyl, N-alkylpyrrolidinonyl, 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, 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.

[0104] In one embodiment, R y selected from: a compound according to any one of claims 1-9, a stereoisomer, a N-oxide, a deuterated derivative, a pharmaceutically acceptable salt or a prodrug thereof: wherein R yselected from the group consisting of: halogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, methoxy, ethoxy, propoxy, isopropoxy, 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-alkylpyrrolidinonyl, furanyl, 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, -O-N-alkylpyrrolidinonyl, -O-furanyl, -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-pyridyl, -O-pyridazinyl, -O-pyrimidinyl, -O-pyrazinyl, -O-phenyl; said thienyl, N-alkylpyrrolidinonyl, 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, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, phenyl, naphthyl being optionally substituted with one or more F, Cl, Br, I, methyl or ethyl.

[0105] In one embodiment, R yselected from: halogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy, -NH2, -NHCH3, -N(CH3)2, fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl, trifluoroethyl, thienyl, N-alkylpyrrolidinonyl, 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, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, phenyl, naphthyl, -O-thienyl, -O-N-alkylpyrrolidinonyl, -O-furanyl, -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-pyridyl, -O-pyridazinyl, -O-pyrimidinyl, -O-pyrazinyl, -O-phenyl; said thienyl, N-alkylpyrrolidinonyl, 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, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, phenyl, naphthyl being optionally substituted with one or more F, Cl, Br, I, methyl or ethyl.

[0106] In one embodiment, R y selected from: halogen, =0, amino, methyl, tert-butyl, trifluoromethyl, methoxy,

[0107] In one embodiment, R y selected from: halogen, =0, amino, methyl, tert-butyl, trifluoromethyl, methoxy,

[0108] In one embodiment, ring A is selected from the following groups:

[0109]

[0110] The group is optionally surrounded by one or more R y replace.

[0111] In one embodiment, ring A is selected from the following groups:

[0112] The group is optionally surrounded by one or more R y replace.

[0113] In one implementation scheme, ring A is selected from:

[0114]

[0115]

[0116] In one implementation scheme, ring A is selected from:

[0117]

[0118] In one implementation scheme, ring A is selected from:

[0119] In one implementation scheme, ring A is selected from:

[0120]

[0121]

[0122] In one implementation scheme, ring A is selected from:

[0123]

[0124] In one implementation scheme, ring A is

[0125] In one implementation scheme, R x For hydrogen, C 1-6 Alkoxy, -C(O)NR x1 R x2 4 to 8-membered nitrogen-containing heterocyclic alkyl groups, 5 or 6-membered mono-heteroaryl groups, or C 6-8 Aryl, the C 1-6 Alkyl groups are optionally surrounded by one or more C groups. 3-6 Cycloalkyl substituted; the 4 to 8-membered nitrogen-containing heterocycloalkyl, 5 or 6-membered monoheteroaryl or C 6-8 The aryl group is optionally surrounded by one or more elements selected from halogens, hydroxyl groups, and C.1-6 alkyl, hydroxy-substituted C 1-6 alkyl or halogen-substituted C 1-6 alkyl; said 4- to 8-membered nitrogen-containing heterocycloalkyl group contains at least one N atom and contains 0 to 3 heteroatoms independently selected from N, O or S as ring atoms.

[0126] In one embodiment, R x is hydrogen, C 1-6 alkoxy, -C(O)NR x1 R x2 , 4- to 8-membered nitrogen-containing heterocycloalkyl, 5- or 6-membered monoheteroaryl or C 6-8 aryl, said C 1-6 alkoxy is optionally substituted with one or more C 3-6 cycloalkyl; said 4- to 8-membered nitrogen-containing heterocycloalkyl, 5- or 6-membered monoheteroaryl or C 6-8 aryl is optionally substituted with one or more substituents selected from halogen, hydroxy, C 1-6 alkyl or hydroxy-substituted C 1-6 alkyl; said 4- to 8-membered nitrogen-containing heterocycloalkyl group contains at least one N atom and contains 0 to 3 heteroatoms independently selected from N, O or S as ring atoms.

[0127] In one embodiment, R x1 , R x2 each independently is hydrogen or methyl, ethyl or propyl.

[0128] In one embodiment, R x1 , R x2 each independently is hydrogen or methyl.

[0129] In one embodiment, R x is methoxy, ethoxy, -C(O)N(CH3)2, -C(O)NH2, wherein said methoxy, ethoxy is optionally substituted with one or more cyclopropyl, said optionally substituted with one or more substituents selected from hydroxy, F, Cl, Br, methyl, ethyl, propyl, isopropyl, hydroxymethyl, hydroxyethyl, hydroxypropyl.

[0130] In one embodiment, R x is methoxy, -C(O)NH2, wherein said methoxy is optionally substituted with one or more cyclopropyl, said optionally substituted with one or more substituents selected from hydroxy, F, Cl, Br, hydroxyethyl;

[0131] In one embodiment, Rx is methoxy, -C(O)NH2,

[0132] In one embodiment, R x is a 4- to 8-membered nitrogen-containing heterocycloalkyl group containing one or two N atoms.

[0133] In one embodiment, the 4- to 8-membered nitrogen-containing heterocycloalkyl group is selected from:

[0134]

[0135] In one embodiment, Lxis selected from -C(O)NH-**; wherein the position marked with "*" indicates the attachment to ring A and the position marked with "**" indicates the attachment to the other group of Lx.

[0136] In one embodiment, the compound is a compound of formula (IA1) or formula (IA2):

[0137]

[0138] wherein E3, L, W1, W2, W3, W4, R X , L X , and ring A are each as defined above;

[0139] F1is NR F1 , O, or S; F2is N or CR F2 ; F3is N or CR F3 ; F4is N or CR F4 ; and at least one of F1, F2, F3, F4is N; R F1 , R F2 , R F3 , R F4 is each independently hydrogen or R 1 ;

[0140] K1is NR K1 or CR K2 ; K2is N or CR K2 ; K3is N or CR K3 ; K4is N or CR K4 ; K5is N or CR K5 ; and at least one of K1, K2, K3, K4, K5is N; R K1 , R K2 , R K3 , R K4 , R K5 is each independently hydrogen or R 1 .

[0141] In one embodiment, the compound is a compound of Formula (IB1), Formula (IB2), Formula (IB3), Formula (IB4), or Formula (IB5):

[0142]

[0143]

[0144] wherein E3, L, W1, W2, W3, W4, R X , L X , R y , y are each as previously defined.

[0145] In one embodiment, the 4- to 12-membered nitrogen-containing heterocycloalkyl is selected from:

[0146]

[0147] X1, X2, X3, X4are each independently N or -CR d ;

[0148] X5is a single bond, -O-, -S-, -NR a , or -NR e R f ;

[0149] n1, n2, n3, n4, n5, n6are each independently 0, 1, 2, or 3;

[0150] wherein R d , R e , R f are each independently hydrogen, hydroxyl, halogen, -CN, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, or C 3-6 cycloalkyl.

[0151] In one embodiment, L is selected from:

[0152]

[0153] wherein,

[0154] X1, X2, X3, X4, X 11 , X 12 , X 21 , X 22 , X 31 , X 32 , X 41 , X 42 are each independently N or -CR d ;

[0155] Among them, R d Hydrogen, hydroxyl, halogen, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy or C 3-6 cycloalkyl;

[0156] n1, n2, n3, n4, n11, n12, n21, n22, n31, and n32 are each independently 0, 1, 2, or 3;

[0157] 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 -;

[0158] R L1 R L2 R L3 Each is independently represented by O, hydrogen, halogen, and C. 1-6 Alkyl or C 1-6 Halogenated alkyl groups;

[0159] m1, m2, m3, and m4 are each independently 0 or 1.

[0160] In one implementation scheme, L is selected from:

[0161]

[0162] in,

[0163] X1, X2, X3, X4, X 11 X 12 X 21 X 22 X 31 X 32 X 41 X 42 Each is independently N or -CR d ;

[0164] Among them, R d Hydrogen, hydroxyl, halogen, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy or C3-6 cycloalkyl;

[0165] n1, n2, n3, n4, n11, n12, n21, n22, n31, and n32 are each independently 0, 1, 2, or 3;

[0166] 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 -;

[0167] R L1 R L2 R L3 Each is independently represented by O, hydrogen, halogen, and C. 1-6 Alkyl or C 1-6 Halogenated alkyl groups;

[0168] m1, m2, m3, and m4 are each independently 0 or 1.

[0169] In one implementation scheme, L is selected from:

[0170]

[0171] in,

[0172] X1, X2, X3, X4, n1, n2, n3, and n4 are each defined independently as before;

[0173] 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 -;

[0174] R L1 R L2 R L3 Each is independently represented by O, hydrogen, halogen, and C. 1-6 Alkyl or C 1-6 Halogenated alkyl groups;

[0175] m1, m2, m3, and m4 are each independently 0 or 1.

[0176] In one embodiment, L is selected from:

[0177]

[0178] In one embodiment, L is selected from:

[0179]

[0180] In one embodiment, E3 has the structure according to formula (C1), (C2), (C3), (C4), (C5) or (C6):

[0181]

[0182]

[0183] wherein T1, T2, T3, T4 are each independently CH, C or N;

[0184] T is CH2, CH(C 1-6 alkyl), C=0, SO2, NH or N(C 1-6 alkyl);

[0185] R2, R5, R6, R8, R9 are each independently hydrogen, C 1-6 alkyl or C 1-6 alkoxy, said C 1-6 alkyl being optionally substituted by one or more C 1-6 alkoxy or -OC(O)-C 1-6 alkyl;

[0186] Preferably, R2, R5, R6, R8, R9 are each independently hydrogen or C 1-6 alkyl;

[0187] R3 is hydrogen, hydroxyl or C 1-6 alkyl;

[0188] R4, R7, R 10 are each independently hydrogen, halogen, C 1-6 alkyl, C 1-6 alkoxy or halogenated C 1-6 alkyl;

[0189] Preferably, R4, R7, R 10 are each independently hydrogen, halogen, C 1-6 alkyl or halogenated C 1-6 alkyl;

[0190] m7, m8, m9, m10 are each independently 0, 1, 2 or 3.

[0191] 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, said C 1-6 alkyl is optionally substituted with one or more C 1-6 alkoxy or -OC(O)-C 1-6 alkyl; m9 is 1, 2 or 3.

[0192] In one embodiment, R7 is hydrogen, F, Cl, Br, methyl, methoxy or trifluoromethyl.

[0193] In one embodiment, R5 is hydrogen or -CH2-O(O)(CH3)3.

[0194] In one embodiment, E3 is

[0195]

[0196] In one embodiment, E3 is

[0197] In one embodiment, E3 is

[0198] In one embodiment, the compound is a compound of Table A, Table B, Table C, Table D or an example compound.

[0199] In one embodiment, the compound is capable of degrading BTK protein and / or IRAK4 protein.

[0200] In one embodiment, the compound is capable of simultaneously degrading BTK and IRAK4 proteins.

[0201] In still another aspect of the present application, there is provided a pharmaceutical composition comprising a compound, stereoisomer, N-oxide, deuterated derivative, pharmaceutically acceptable salt or prodrug thereof as previously described.

[0202] In still another aspect of the present application, there is provided a use of a compound, stereoisomer, N-oxide, deuterated derivative, pharmaceutically acceptable salt or prodrug thereof as previously described or a pharmaceutical composition as previously described in the manufacture of a medicament for treating a disorder mediated by BTK protein and / or IRAK4 protein in a patient.

[0203] In still another aspect of the present application, there is provided a use of the aforementioned compound, stereoisomer, N-oxide, deuterated derivative, pharmaceutically acceptable salt or prodrug thereof, or the aforementioned pharmaceutical composition in the preparation of a BTK and / or IRAK4 degrader; preferably, the degrader is a simultaneous BTK and IRAK4 degrader.

[0204] In still another aspect of the present application, there is provided a method of simultaneously degrading BTK and / or IRAK4 protein in a biological sample, comprising contacting the biological sample with the aforementioned compound, stereoisomer, N-oxide, deuterated derivative, pharmaceutically acceptable salt or prodrug thereof, or the aforementioned pharmaceutical composition.

[0205] In still another aspect of the present application, there is provided a method of treating a disorder mediated by BTK protein and / or IRAK4 protein in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of the aforementioned compound, stereoisomer, N-oxide, deuterated derivative, pharmaceutically acceptable salt or prodrug thereof, or the aforementioned pharmaceutical composition.

[0206] In one embodiment, the IRAK and / or BTK mediated disorder is selected from the group consisting of: cancer, neurodegenerative disease, viral disease, autoimmune disease, inflammatory disorder, genetic disorder, hormone-related disease, metabolic disorder, condition associated with organ transplantation, immunodeficiency disorder, destructive bone disorder, proliferative disorder, infectious disease, condition associated with cell death, thrombin-induced platelet aggregation, liver disease, T cell activation-mediated pathological immune condition, cardiovascular disorder, and CNS disorder.

[0207] In an embodiment, the cancer or proliferative disorder is selected from the group consisting of a benign or malignant tumor, a solid tumor, a brain cancer, a kidney cancer, a liver cancer, an adrenal cancer, a bladder cancer, a breast cancer, a stomach cancer, a gastric tumor, an ovarian cancer, a colon cancer, a rectal cancer, a prostate cancer, a pancreatic cancer, a lung cancer, a vaginal cancer, a cervical cancer, a testicular cancer, a urogenital tract cancer, an esophageal cancer, a laryngeal cancer, a skin cancer, a bone cancer or a thyroid cancer, a sarcoma, a glioblastoma, a neuroblastoma, a multiple myeloma, a gastrointestinal cancer, a colon cancer, a colorectal adenoma, a tumor of the neck and head, an epidermal hyperproliferation, a psoriasis, a prostate hyperplasia, a neoplasia, a neoplasia of epithelial character, an adenoma, an adenocarcinoma, a keratoacanthoma, an epidermoid carcinoma, a large cell carcinoma, a non-small cell lung cancer, a lymphoma, a Hodgkin's or non-Hodgkin's lymphoma, a mammary carcinoma, a follicular carcinoma, an anaplastic carcinoma, a papillary carcinoma, a seminoma, a melanoma, an IL1 -driven disorder, a MyD88-driven disorder, a multiple myeloma (including indolent or smoldering type), a hematological malignancy, a myeloid leukemia (acute and chronic), an acute lymphoblastic leukemia, a chronic lymphocytic leukemia, a myeloproliferative disease, a myelodysplastic syndrome, a Hodgkin's disease, a non-Hodgkin's lymphoma (malignant lymphoma) hairy cell, mantle cell lymphoma, macroglobulinemia, marginal zone lymphoma, and a hematological cancer of follicular lymphoma, the hematological malignancy is selected from the group consisting of a leukemia, a diffuse large B-cell lymphoma (DLBCL), an activated B-cell-like diffuse large B-cell lymphoma (ABC DLBCL), a chronic lymphocytic leukemia (CLL), a chronic lymphocytic lymphoma, a primary effusion lymphoma, a Burkitt's lymphoma / leukemia, an acute lymphoblastic leukemia, a B-cell prolymphocytic leukemia, a lymphoplasmacytic lymphoma, a Waldenstrom's macroglobulinemia (WM), a splenic marginal zone lymphoma, a plasmacytoma or an intravascular large B-cell lymphoma.

[0208] In an embodiment, the MyD88-driven disorder is selected from the group consisting of an ABC DLBCL, a Waldenstrom's macroglobulinemia, a Hodgkin's lymphoma, a primary cutaneous T-cell lymphoma and a chronic lymphocytic leukemia;

[0209] In an 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.

[0210] In an embodiment, the inflammatory condition 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 granulomatosis, dermatomyositis, chronic active hepatitis, myasthenia gravis, Steven-Johnson syndrome, idiopathic sprue, ulcerative colitis, Crohn's disease or another autoimmune inflammatory bowel disease, irritable bowel syndrome, celiac disease, periodontal disease, hyaline membrane disease, nephrosis, glomerular disease, alcoholic liver disease, endocrine ophthalmopathy, Graves' disease, sarcoidosis, alveolitis, hypersensitivity pneumonitis, multiple sclerosis, primary biliary cirrhosis, uveitis (anterior and posterior), Sjogren's syndrome, vernal keratoconjunctivitis, interstitial lung fibrosis, psoriatic arthritis, systemic juvenile idiopathic arthritis, nephritis, diverticulitis, interstitial cystitis, glomerulonephritis (with or without nephrotic syndrome, optionally including idiopathic nephrotic syndrome or minimal change nephropathy), chronic granulomatous disease, endometriosis, leptospiral nephritis, glaucoma, retinal disease, aging, headache, pain, complex regional pain syndrome, cardiac hypertrophy, muscle atrophy, catabolic conditions, obesity, fetal growth retardation, hypercholesterolemia, heart disease, chronic heart failure, mesothelioma, anhidrotic ectodermal dysplasia, Behcet's disease disease), pigmentary disorders, Paget's disease, pancreatitis, hereditary periodic fever syndrome, asthma (allergic, non-allergic, mild, moderate, severe, bronchitic or exercise-induced), acute lung injury, acute respiratory distress syndrome, eosinophilia, anaphylaxis, systemic anaphylaxis, sinusitis, silica-induced disease, COPD (damage, airway inflammation, bronchial hyper-reactivity, remodelling or disease progression reduction), 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, allergy, blepharitis, bronchiolitis, bronchitis, bursitis, cervicitis, cholangitis, cholecystitis, chronic graft rejection, colitis, conjunctivitis, cystitis, dacryadenitis, dermatitis, dermatomyositis, encephalitis, endocarditis, endometritis, enteritis, enterocolitis, epicondylitis, epididymitis, fasciitis, fibrositis, gastritis, gastroenteritis, Henoch-Schonlein purpura, hepatitis, hidradenitis suppurativa, immunoglobulin A nephropathy, interstitial lung disease, laryngitis, mastitis, meningitis, myelitis myocarditis, myositis, nephritis, oophoritis, orchitis, osteitis, otitis, pancreatitis, parotitis, pericarditis, peritonitis, pharyngitis, pleuritis, phlebitis, pneumonitis, polymyositis, proctitis, prostatitis, pyelonephritis, rhinitis, salpingitis, 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, acquired epidermolysis bullosa, acute and chronic gout, chronic gouty arthritis, psoriasis, psoriatic arthritis, rheumatoid arthritis, juvenile rheumatoid arthritis, cryopyrin-associated periodic syndromes (CAPS), and osteoarthritis.

[0211] In an embodiment, the autoimmune disease is selected from the group consisting of: urticaria, graft versus host disease, pemphigus vulgaris, adrenoleukodystrophy, 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, Behcet’s disease, benign mucosal pemphigoid, bullous pemphigoid, Castleman disease (CD), celiac disease, Chagas disease, chronic inflammatory demyelinating polyneuropathy (CIDP), chronic recurrent multifocal osteomyelitis (CRMO), Churg-Strauss syndrome (CSS) or Eosinophilic Granulomatosis with Polyangiitis (EGPA), cicatricial pemphigoid, Cogan’s syndrome, cold agglutinin disease, congenital heart block, coxsackie myocarditis, CREST syndrome, Crohn’s disease, dermatitis herpetiformis, dermatomyositis, Devic’s disease (neuromyelitis optica), discoid lupus, Dressler’s syndrome, endometriosis, eosinophilic esophagitis (EoE), eosinophilic fasciitis, erythema nodosum, mixed cryoglobulinemia, Evans syndrome, fibromyalgia, fibrosing alveolitis, giant cell arteritis (temporal arteritis), giant cell myocarditis, glomerulonephritis, goodpasture’s syndrome, 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), hypogammalglobulinemia, IgA nephropathy, IgG4-related sclerosing disease, immune thrombocytopenic purpura (ITP), inclusion body myositis (IBM), idiopathic inflammatory demyelinating diseases of the central nervous system (e.g., multiple sclerosis), idiopathic pulmonary fibrosis, idiopathic sprue, idiopathic thrombocytopenic purpura, immune checkpoint inhibitor associated colitis, immune checkpoint inhibitor associated pneumonitis, immune checkpoint inhibitor associated myocarditis, immune checkpoint inhibitor associated hepatitis, inclusion body myositis, inclusion body myositis, inclusion body myositis, inclusion body myositis, inclusion body myositis, inclusion body myositis, inclusion body myositis, inclusion body myositis, inclusion body myositis, inclusion body myositis, inclusion body myositis, inclusion body myositis, inclusion body myositis, inclusion body myositis, inclusion body myositis, inclusion body myositis, inclusion body myositis, inclusion body myositis, inclusion body myositis, inclusion body myositis, inclusion body myositis, inclusion body myositis, inclusion body myositis, inclusion body myositis, inclusion body myositis, inclusion body myositis, inclusion body myositis, inclusion body myositis, inclusion body myositis, inclusion body myositis, inclusion body myositis, inclusion body myositis, inclusion body myositis, inclusion body myositis, inclusion body myositis, inclusion body myositis, inclusion body myositis, inclusion body myositis, inclusion body myositis, inclusion body myositis, inclusion body myositis, inclusion body myositis, inclusion body myositis, inclusion body myositis, inclusion body myositis, inclusion body myositis, inclusion body myositis, inclusion body myositis, inclusion body myositis, inclusion body myositis, inclusion body myositis, inclusion body myositis, inclusion body myositis, inclusion body myositis, inclusion body myositis, inclusion body myositis, inclusion body myositis, inclusion body myositis, inclusion body myositis, inclusion body myositis, inclusion body myositis, inclusion body myositis, inclusion body myositis, inclusion body myositis, inclusion body myositis, inclusion body myositis, inclusion body myositis, inclusion body myositis, inclusion body myositis, inclusion body myositis, inclusion body myositis, inclusion body myositis, inclusion body myositis, inclusion body myositis, inclusion body myositis, inclusion body myositis, inclusion body myositis, inclusion body myositis, inclusion body myositis, inclusion body myositis, inclusion body myositis, inclusion body myositis, inclusion body myositis, inclusion body myositis, inclusion body myositis, inclusion body myositis, inclusion body myositis, inclusion body myositis, inclusion body myositis, inclusion body myositis, inclusion body myositis, inclusion body myositis, inclusion body myositis, inclusion body myositis, inclusion body myositis, inclusion body myositis, inclusion body myositis, inclusion body myositis, inclusion body myositis, inclusion body myositis, inclusion body myositis, inclusion body myositis, inclusion body myositis, inclusion body myositis, inclusion body myositis, inclusion body myositis, inclusion body myositis, inclusion body myositis, inclusion body myositis, inclusion body myositis, inclusion body myositis, inclusion body myositis, inclusion body myositis, inclusion body myositis, inclusion body myositis, inclusion body myositis, inclusion body myositis, inclusion body myositis, inclusion body myositis, inclusion body myositis, inclusion body myositis, inclusion body myositis, inclusion body myositis, inclusion body myositis, inclusion body myositis, inclusion body myositis, inclusion body myositis, inclusion body myositis, inclusion body myositis, inclusion body myositis, inclusion body myositis, inclusion body myositis, inclusion body myositis, inclusion body myositis, inclusion body myositis, inclusion body myositis, inclusion body myositis, inclusion body myositis, inclusion body myositis, inclusion body myositis, inclusion body myositis, inclusion body myositis, inclusion body myositis, inclusion body myositis, inclusion body myositis, inclusion body myositis, inclusion body myositis, inclusion body myositis, inclusion body myositis, inclusion body myositis, inclusion body myositis, inclusion body myositis, inclusion body myositis, inclusion body myositis, inclusion body myositis, inclusion body myositis, inclusion body myositis, inclusion body myositis, inclusion body myositis, inclusion body myositis, inclusion body myositis, inclusion body myositis, inclusion body myositis, inclusion body myositis, inclusion body myositis, inclusion body myositis, inclusion body myositis, inclusion body myositis, inclusion body myositis, inclusion body myositis, inclusion body myositis, inclusion body myositis, inclusion body myositis, inclusion body myositis, inclusion body myositis, inclusion body myositis, inclusion body myositis, inclusion body myositis, inclusion body myositis, inclusion body myositis, inclusion body myositis, inclusion body myositis, inclusion body myositis, inclusion body myositis, inclusion body myositis, inclusion body myositis, inclusion body myositis, inclusion body myositis, inclusion body myositis, inclusion body myositis, inclusion body myositis, inclusion body myositis, inclusion body myositis, inclusion body myositis, inclusion body myositis, inclusion body myositis, inclusion body myositis, inclusion body myositis, inclusion body myositis, inclusion body myositis, inclusion body myositis, inclusion body myositis, inclusion body myositis, inclusion body myositis, inclusion body myositis, inclusion body myositis, inclusion body myositis, inclusion body myositis, inclusion body myositis, inclusion body myositis, inclusion body myositis, inclusion body myositis, inclusion body myositis, inclusion body myositis, inclusion body myositis, inclusion body myositis, inclusion body myositis, inclusion body myositis, inclusion body myositis, inclusion body myositis, inclusion body myositis, inclusion body myositis, inclusion body myositis, inclusion body myositis, inclusion body myositis, inclusion body myositis, inclusion body myositis, inclusion body myositis, inclusion body myositis, inclusion body myositis, inclusion body myositis, inclusion body myositis, inclusion body myositis, inclusion body myositis, inclusion body myositis, inclusion body myositis, inclusion body myositis, inclusion body myositis, inclusion body myositis, inclusion body myositis, inclusion body myositis,interstitial cystitis (IC), juvenile arthritis, juvenile diabetes (type 1 diabetes), juvenile myositis (JM), Kawasaki disease, Lambert-Eaton syndrome, leukocytoclastic vasculitis, lichen planus, lichen sclerosus et atrophicus, ligneous conjunctivitis, linear IgA disease (LAD), lupus, chronic Lyme disease, Meniere's disease, microscopic polyangiitis (MPA), mixed connective tissue disease (MCTD), Mooren's ulcer, Mucha-Habermann disease, multifocal motor neuropathy (MMN) or MMNCB, multiple sclerosis, myasthenia gravis, myositis, narcolepsy, neonatal lupus, neuromyelitis optica, neutropenia, ocular cicatricial pemphigoid, optic neuritis, palindromic rheumatism (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 syndromes type I, type II, type III, polymyalgia rheumatica, polymyositis, post myocardial infarction syndrome, post pericardiotomy syndrome, primary biliary cirrhosis, primary sclerosing cholangitis, progesterone dermatitis, psoriasis, psoriatic arthritis, pure red cell anemia (PRCA), pyoderma gangrenosum, Raynaud's phenomenon, reactive arthritis, reflex sympathetic dystrophy, relapsing polychondritis, restless leg syndrome (RLS), retroperitoneal fibrosis, rheumatic fever, rheumatoid arthritis, sarcoidosis, Schmid syndrome, scleritis, scleroderma, Sjogren's syndrome, sperm and testicular autoimmune disease, stiff person syndrome (SPS), subacute bacterial endocarditis (SBE), Susac's syndrome, sympathetic ophthalmia (SO), Takayasu's arteritis, temporal arteritis (giant cell arteritis), thrombocytopenic purpura (TTP), 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 (or granulomatous polyangiitis (GPA)). Attached Figure Description

[0212] Figure 1 To test the degradation activity of the compound in Example 3 on BTK and IRAK4 in TMD8 cells at different concentrations, the treatment time was 16 hours. Detailed Implementation

[0213] I. Definition

[0214] In this invention, unless otherwise stated, the scientific and technical terms used herein have the meanings commonly understood by those skilled in the art. Furthermore, the related terms and laboratory procedures used herein are all widely used terms and routine procedures in the respective fields. To better understand this invention, definitions and explanations of related terms are provided below.

[0215] As used herein and unless otherwise stated, the terms “about” or “approximately” mean within 10% of a given value or range. Where an integer is required, the term means within 10% of a given value or range, rounded up or down to the nearest integer.

[0216] In the description herein, references to “some embodiments,” “some implementations,” or “some implementation schemes” describe a subset of all possible embodiments. However, it is 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.

[0217] As used herein and unless otherwise stated, the terms “comprising,” “including,” “having,” “containing,” and their grammatical equivalents, including their grammatical equivalents, should generally be understood as open-ended and non-restrictive, e.g., not excluding other unlisted elements or steps.

[0218] As used herein, the term "heteroatom" is selected from nitrogen, oxygen, or sulfur. Nitrogen may optionally be substituted; sulfur may also optionally be substituted, for example, by oxidation, thus forming S(O). t3 (where t3 is an integer from 0 to 2).

[0219] As used herein, when an alkyl group or similar group is located in the middle of a structural formula, that group is a subunit. For example, an alkyl group can be an alkylene group or similar.

[0220] As used herein, the term "alkyl" refers to a chain-like (straight-chain or branched) saturated aliphatic hydrocarbon group. The term "alkyl" can refer to a straight-chain or branched alkyl group containing 1 to 20 carbon atoms.1-20 alkyl) containing 1 to 12 carbon atoms, preferably lower alkyl (C 1-12 Non-limiting examples include methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, s-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 isomers thereof, and the like. More preferred is lower alkyl (C 1-6 Non-limiting examples include methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, s-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 is lower alkyl (C 1-3 Non-limiting examples include methyl, ethyl, n-propyl, i-propyl, and the like. The alkyl group can be substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups recited herein.

[0221] As used herein, the terms "cycloalkyl" and "cycloalkyl ring" are used interchangeably to refer to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon radical. The term "cycloalkyl" can be a cycloalkyl radical (C 3-20 cycloalkyl) typically containing 3 to 6 carbon atoms, cycloalkyl (C3-6 cycloalkyl) is a monocyclic cycloalkyl (C 3-6 monocyclic cycloalkyl). As used herein, "3- to 6-membered monocyclic," "3- to 6-membered monocyclic cycloalkyl," "C 3-6 monocyclic cycloalkyl" and "C 3-6 cycloalkyl" are 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 can optionally be 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: a cyclopropyl ring, a cyclobutyl ring, a cyclopentyl ring, a cyclopentenyl ring, a cyclohexyl ring, a cyclohexenyl ring, a cyclohexadienyl ring, a cyclobutanone, a cyclobutane-1,2-dione, a cyclopentanone, a cyclopentane-1,3-dione, a cyclohexanone, a cyclohexane-1,3-dione, and the like.

[0222] As used herein, the terms "heterocycloalkyl" and "heterocycloalkyl ring" are used interchangeably to refer to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon radical and wherein one or more (preferably 1 to 4 or 1 to 3 or 1 to 2) ring atoms are a heteroatom selected from nitrogen, oxygen, or S(O) t3 (where t3 is an integer from 0 to 2) but excluding ring moieties of -0-0-, -0-S-, or -S-S-, the remaining ring atoms being carbon. The term "heterocycloalkyl" can be a heterocycloalkyl group containing 3 to 20 ring atoms (i.e., 3- to 20-membered); preferably 3- to 12-membered; more preferably 3- to 10-membered, more preferably 3- to 6-membered; wherein one or more (preferably 1 to 4) ring atoms are a heteroatom selected from nitrogen, oxygen, or S(O) t3 (where t3 is an integer from 0 to 2) but excluding ring moieties of -0-0-, -0-S-, or -S-S-, the remaining ring atoms being carbon. The nitrogen atom can be substituted or unsubstituted (i.e., N or NR, R being hydrogen or any one of the substituents already defined herein). The ring carbon atoms of the heterocycloalkyl group can optionally be substituted with 1, 2, or 3 oxo groups to form a cyclic ketone, cyclic lactone, or cyclic lactam structure.

[0223] In some embodiments of the invention, "heterocyclic alkyl" refers to a monocyclic heterocyclic alkyl group that is saturated or partially unsaturated, preferably comprising 3 to 8 ring atoms (i.e., 3 to 8 members), wherein one, two, or three of the ring atoms are heteroatoms. More preferably, it comprises 3 to 6 ring atoms (i.e., 3 to 6 members), wherein one, two, or three of the ring atoms are heteroatoms. Most preferably, it comprises 5 or 6 ring atoms (i.e., 5 or 6 members), wherein one, two, or three of the ring atoms are heteroatoms. As used herein, the terms "3 to 6 membered heterocyclic alkyl" and "3 to 6 membered monocyclic heterocyclic alkyl" are used interchangeably, as are the terms "5 or 6 membered heterocyclic alkyl" and "5 or 6 membered monocyclic heterocyclic alkyl". When the heteroatom is a nitrogen atom, the nitrogen atom may be substituted or unsubstituted (i.e., N or NR, where R is hydrogen or another substituent as defined herein). When the heteroatom is a sulfur atom, the sulfur atom can be optionally oxidized (i.e., S(O)). t3, t3 is an integer from 0 to 2). The ring carbon atoms of the monocyclic heterocycloalkyl group can optionally be substituted with 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, azetidin-2-one, oxetane, oxetane-2-one, oxazolidine, pyrrolidine-2-one, pyrrolidine-2,5-dione, 1,3-dioxolane, dihydrofuran-2(3H)-one, dihydrofuran-2,5-dione, piperidin-2-one, piperidin-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, morpholine-3-one, morpholine-2-one, thiomorpholine-3-one 1,1-dioxide, thiomorpholine, thiomorpholine-1,1-dioxide, tetrahydropyran, 1,2-dihydroazetidine, 1,2-dihydrooxetane, 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-dioxan-2-one, 5,6-dihydro-2H-pyran-2-one, 5,6-dihydro-pyrimidin-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-pyrrol-2-one, 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, oxazol-2(3H)-one, 1,3-dihydro-2H-imidazol-2-one, furan-2,5-dione, 3,6-dihydropyridin-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, and the like.

[0224] In an embodiment of the application, non-limiting examples of said 5- or 6-membered monocyclic heteroaryl groups include:

[0225]

[0226] The 2 ring atoms attached to the monocyclic heterocycloalkyl group described above, including C-C, N-C, can optionally be fused to a 5- or 6-membered monocyclic heteroaryl ring as defined in the present application to form a fused polycyclic ring.

[0227] In some embodiments of the application, "heterocycloalkyl" refers to polycyclic heterocycloalkyl groups, including spiroheterocycloalkyl, fused heterocycloalkyl and bridged heterocycloalkyl groups.

[0228] As used herein, the term "spiroheterocycloalkyl" refers to a saturated or partially unsaturated polycyclic heterocycloalkyl group in which the single rings share one atom (referred to as a spiro atom) in the system, wherein one or more (e.g., 1 to 4 or 1 to 3 or 1 to 2) ring atoms are heteroatoms selected from nitrogen, oxygen or S(O) t4 (wherein t4 is an integer from 0 to 2) and the remaining ring atoms are carbon. The term "saturated spiroheterocycloalkyl" refers to a spiroheterocycloalkyl system that does not have any unsaturated bonds. The term "partially unsaturated spiroheterocycloalkyl" refers to a spiroheterocycloalkyl system in which one or more rings can contain one or more double bonds, but no ring has a fully conjugated pi-electron system. The term "spiroheterocycloalkyl" can be a spiroheterocycloalkyl group comprising from 5 to 20 ring atoms (i.e., 5- to 20-membered), in which 3- to 8-membered (i.e., comprising 3 to 8 ring atoms) single rings share one atom (referred to as a spiro atom), preferably a 6- to 14-membered spiroheterocycloalkyl group, more preferably a 7- to 11-membered spiroheterocycloalkyl group; wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen or S(O) t4 (wherein t4 is an integer from 0 to 2) 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 being hydrogen or other substituents as already defined herein). Each single ring can contain one or more double bonds, but no ring has a fully conjugated pi-electron system. The spiroheterocycloalkyl groups are classified as mono-, bi- or polyspiroheterocycloalkyl groups, preferably mono- and bi-spiroheterocycloalkyl groups, depending on the number of spiro atoms shared between the rings. More preferably, the spiroheterocycloalkyl groups are 7-membered (4-membered single ring / 4-membered single ring), 8-membered (4-membered single ring / 5-membered single ring), 9-membered (4-membered single ring / 6-membered single ring, 5-membered single ring / 5-membered single ring), 10-membered (5-membered single ring / 6-membered single ring) or 11-membered (6-membered single ring / 6-membered single ring) mono-spiroheterocycloalkyl groups. Non-limiting examples of spiroheterocycloalkyl groups include:

[0229]

[0230] As used herein, the term "fused heterocycloalkyl" refers to a saturated or partially unsaturated polycyclic heterocycloalkyl group, each ring in the system shares an adjacent pair of 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 is a heteroatom selected from nitrogen, oxygen, or S(O) t4 (where t4 is an integer from 0 to 2) and the remaining ring atoms are carbon. The term "saturated fused heterocycloalkyl" means that there are no unsaturated bonds in the fused heterocycloalkyl system. The term "partially unsaturated fused heterocycloalkyl" means that one or more rings in the fused heterocycloalkyl system can contain one or more double bonds, but no ring has a fully conjugated pi-electron system. The term "fused heterocycloalkyl" can be a fused heterocycloalkyl group comprising 5 to 20 ring atoms (i.e., 5 to 20 membered), preferably 6 to 14 membered fused heterocycloalkyl, more preferably 6 to 10 membered fused heterocycloalkyl, more preferably 8 to 10 membered fused heterocycloalkyl; one or more (e.g., 1 to 4 or 1 to 3 or 1 to 2) ring atoms in the system is a heteroatom selected from nitrogen, oxygen, or S(O) t4 (where t4 is an integer from 0 to 2) 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 being hydrogen or other substituents as defined herein). It can be a bicyclic, tricyclic, tetracyclic, or polycyclic fused heterocycloalkyl depending on the number of rings comprising the ring system, preferably bicyclic or tricyclic, more preferably 8 membered (5 membered monocycle fused to 5 membered monocycle), 9 membered (5 membered monocycle fused to 6 membered monocycle), or 10 membered (6 membered monocycle fused to 6 membered monocycle) bicyclic fused heterocycloalkyl. Non-limiting examples of fused heterocycloalkyl groups include:

[0231] As used herein, the term "bridged heterocycloalkyl" refers to a saturated or partially unsaturated polycyclic heterocycloalkyl group, any two rings in the system share two non-adjacent atoms, wherein one or more (e.g., 1 to 4 or 1 to 3 or 1 to 2) ring atoms is a heteroatom selected from nitrogen, oxygen, or S(O) t3 (where t3 is an integer from 0 to 2) and the remaining ring atoms are carbon. The term "saturated bridged heterocycloalkyl" means that there are no unsaturated bonds in the bridged heterocycloalkyl system. The term "partially unsaturated bridged heterocycloalkyl" means that one or more rings in the bridged heterocycloalkyl system can contain one or more double bonds, but no ring has a fully conjugated pi-electron system. The term "bridged heterocycloalkyl" can be a bridged heterocycloalkyl group comprising 5 to 20 ring atoms (i.e., 5 to 20 membered), preferably 6 to 14 membered bridged heterocycloalkyl, more preferably 7 to 10 membered bridged heterocycloalkyl; one or more (e.g., 1 to 4 or 1 to 3 or 1 to 2) ring atoms in the system is a heteroatom selected from nitrogen, oxygen, or S(O) t3wherein t3 is an integer from 0 to 2, the remaining ring atoms are carbon. Depending on the number of rings, bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocycloalkyl groups are distinguished, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of bridged heterocycloalkyl groups include:

[0232]

[0233] In the present application, each of the above-mentioned heterocycloalkyl groups can be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups described herein.

[0234] As used herein, in "spiroheterocycloalkyl", "bridged heterocycloalkyl" or "fused heterocycloalkyl", when the ring containing the heteroatom is a 3-membered ring and contains only one heteroatom as a ring atom, the heteroatom is not a nitrogen atom.

[0235] As used herein, the terms "aryl", "aryl ring" and "aromatic ring" are used interchangeably to refer to a fully unsaturated aliphatic hydrocarbon group. It can be a fully carbon monocyclic, fully carbon polycyclic (rings connected by covalent bonds, not fused) or fully carbon fused polycyclic (that is, rings sharing pairs of adjacent carbon atoms) group comprising 6 to 14 ring atoms (i.e., 6 to 14 membered or C 6-14 ) ring atoms, at least one ring in the ring system is aromatic, that is, has a conjugated pi electron system. Preferably, the aryl group comprises 6 to 10 ring atoms (i.e., 6 to 10 membered or C 6-10 ) ring atoms. Each ring in the ring system comprises 5 or 6 ring atoms.

[0236] In some embodiments of the present application, "aryl" refers to a mono- or poly- aryl ring, non-limiting examples of which include: phenyl, biphenyl, and the like.

[0237] In some embodiments of the present application, "aryl" refers to an aromatic fused polycyclic ring, the aromatic fused polycyclic ring being a polycyclic group in which a mono- aryl ring is fused to one or more mono- aryl rings, non-limiting examples of which include: naphthyl, anthryl, and the like.

[0238] In some embodiments of the present application, the aryl ring (e.g., a monoaryl ring, preferably a phenyl ring) described herein can be fused with one or more non-aromatic rings to form a polycyclic group, wherein the rings connected together with the parent structure are aromatic or non-aromatic, including but 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 can be substituted with 1 to 2 oxo groups to form a cyclic amide or cyclic ester 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 can be substituted with 1 or 2 oxo groups to form a cyclic ketone structure), and the like. The polycyclic group formed by the above-mentioned monoaryl ring fused with one or more non-aromatic rings can be connected to other groups or the parent structure through a nitrogen atom or a carbon atom, and the rings connected together with the parent structure are a monoaryl ring or a non-aromatic ring.

[0239] In the present context, the phenyl group fused with a 5- or 6-membered monocyclic heterocycloalkyl ring to form a 9- or 10-membered bicyclic ring means that the two adjacent substituents on the phenyl group form a fused 5- or 6-membered monocyclic heterocycloalkyl ring with the ring atoms to which they are attached, and the 5- or 6-membered monocyclic heterocycloalkyl ring is as defined herein. The 9- or 10-membered bicyclic ring formed can also be referred to as a 9- or 10-membered phenylheterocycloalkyl ring.

[0240] In the present context, the phenyl group fused with a 5- or 6-membered monocyclic cycloalkyl ring to form a 9- or 10-membered bicyclic ring means that the two adjacent substituents on the phenyl group form a fused 5- or 6-membered monocyclic cycloalkyl ring with the ring atoms to which they are attached, and the 5- or 6-membered monocyclic cycloalkyl ring is as defined herein. The 9- or 10-membered bicyclic ring formed can also be referred to as a 9- or 10-membered phenylcycloalkyl ring.

[0241] In the present application, the above-mentioned various aryl groups can be substituted or unsubstituted. When substituted, the substituents are preferably one or more groups described in the present application.

[0242] As used herein, the terms "heteroaryl", "heteroaryl ring" and "heteroaromatic ring" are used interchangeably and refer to a fully unsaturated aliphatic hydrocarbon group containing heteroatoms. It can be a monocyclic or a fused polycyclic (i.e., sharing adjacent pairs of carbon atoms or heteroatoms of the rings) group having 5 to 14 ring atoms (i.e., 5- to 14-membered), preferably 5 to 10 ring atoms (i.e., 5- to 10-membered), more preferably 5, 6, 8, 9, or 10 ring atoms, wherein 1 to 4 heteroatoms are included as ring atoms, the heteroatoms being selected from oxygen, sulfur, and nitrogen. The nitrogen and sulfur atoms can optionally be oxidized, and the nitrogen atoms can optionally be quaternized. The heteroaryl group preferably has 6, 10, or 14 π electrons shared in a cyclic arrangement. At least one ring in the ring system is aromatic.

[0243] In some embodiments of the application, "heteroaryl" refers to a monocyclic heteroaryl ring (preferably a 5- or 6-membered monocyclic heteroaryl ring). Non-limiting examples of monocyclic heteroaryls include: thiophene, N-alkylpyrrolidine, 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.

[0244] In some embodiments of the application, "heteroaryl" refers to a fused polycyclic heteroaryl ring (preferably an 8- to 10-membered bicyclic heteroaryl ring). The fused polycyclic heteroaryl ring includes both polycyclic groups (preferably 9- or 10-membered bicyclic heteroaryl rings) in which a monocyclic aryl ring (preferably a phenyl ring) is fused to a monocyclic heteroaryl ring (preferably a 5- or 6-membered monocyclic heteroaryl ring), and polycyclic groups (preferably 8- to 10-membered bicyclic heteroaryl rings) in which a monocyclic heteroaryl ring (preferably a 5- or 6-membered monocyclic heteroaryl ring) is fused to a monocyclic heteroaryl ring (preferably a 5- or 6-membered monocyclic heteroaryl ring).

[0245] In some embodiments of the application, non-limiting examples of monocyclic heteroaryl rings (preferably 5- or 6-membered monocyclic heteroaryl rings) that form fused polycyclic rings include:

[0246] Non-limiting examples of fused polycyclic heteroaryl 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, indazol, 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.

[0247] In some embodiments of the present invention, the heteroaryl ring (e.g., a monocyclic heteroaryl ring, preferably a 5- or 6-membered monocyclic heteroaryl ring) described in the present invention 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: 3 to 6-membered (preferably 5 or 6-membered) monocyclic heterocyclic alkyl rings (the ring carbon atom of the monocyclic heterocyclic alkyl ring can be replaced by 1 to 2 oxo groups to form a cyclic lactam or cyclic lactone structure), 3 to 6-membered (preferably 5 or 6-membered) monocyclic cycloalkyl rings (the ring carbon atom of the monocyclic cycloalkyl ring can be replaced by 1 or 2 oxo groups to form a cyclic ketone structure), etc.

[0248] The polycyclic groups fused with the aforementioned monocyclic heteroaryl ring and one or more non-aromatic rings can be connected to other groups or parent structures through nitrogen or carbon atoms. The ring connected to the parent structure is a heteroaryl ring or a non-aromatic ring.

[0249] In this document, the fusion of a 5- or 6-membered monocyclic heteroaryl group with a 5- or 6-membered monocyclic heterocyclic alkyl ring to form an 8- to 10-membered bicyclic heterocycle refers to the formation of a fused 5- or 6-membered monocyclic heterocyclic alkyl ring by two adjacent substituents on a 5- or 6-membered monocyclic heterocyclic alkyl group and the ring atom to which they are attached. The 5- or 6-membered monocyclic heterocyclic alkyl ring is as defined herein, and the resulting 8- to 10-membered bicyclic heterocycle can also be referred to as an 8- to 10-membered heteroaryl heterocyclic alkyl ring.

[0250] In this document, the fusion of a 5- or 6-membered monocyclic heteroaryl group with a 5- or 6-membered monocyclic cycloalkyl ring to form an 8- or 10-membered biheterocyclic ring refers to the formation of a fused 5- or 6-membered monocyclic cycloalkyl ring by two adjacent substituents on a 5- or 6-membered monocyclic heteroaryl group and the ring atom to which they are attached. The 5- or 6-membered monocyclic cycloalkyl ring is as defined herein, and the resulting 8- or 10-membered biheterocyclic ring can also be referred to as an 8- or 10-membered heteroaryl cycloalkyl ring.

[0251] In this invention, the various heteroaryl groups described above can be substituted or unsubstituted. When substituted, the substituent is preferably one or more groups described in this application.

[0252] As used in this article, the term "C" 1-6 "Alkoxy" refers to -O-(C 1-6 Alkyl group), wherein the definition of alkyl group is as described above. Preferably C 1-3 Alkoxy groups. Non-limiting examples include methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy, isobutoxy, pentoxy, etc. Alkoxy groups may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups described in this application.

[0253] As used in this article, "deuteration" refers to the substitution of one or more (e.g., 1, 2, 3, 4, or 5) or all of the hydrogen atoms in a group by a deuterium atom.

[0254] For example, "deuterated C 1-6 alkyl" means that one or more (such as 1, 2, 3, 4, or 5) or all hydrogens of an alkyl group are replaced by deuterium atoms, wherein alkyl is as defined above. Preferably, deuterated C 1-3 alkyl. For example, deuterated methyl can be monodeuterated methyl, dideuterated methyl, or perdeuterated methyl.

[0255] As used herein, "halo" means that one or more (such as 1, 2, 3, 4, or 5) hydrogens of a group are replaced by a halogen.

[0256] For example, "halo C 1-6 alkyl" means that an alkyl group is substituted with one or more (such as 1, 2, 3, 4, or 5) halogens, wherein alkyl is as defined above. Preferably, halo C 1-3 alkyl. Examples of halo C 1-6 alkyl include, but are not limited to, monochloromethyl, dichloromethyl, trichloromethyl, monochloroethyl, 1,2-dichloroethyl, trichloroethyl, monobromoethyl, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoroethyl, difluoroethyl, trifluoroethyl, and the like.

[0257] For example, "halo C 1-6 alkoxy" means that an alkoxy group is substituted with one or more (such as 1, 2, 3, 4, or 5) halogens, wherein alkoxy is as defined above. Preferably, halo C 1-3 alkoxy. Examples include, but are not limited to, trifluoromethoxy, trifluoroethoxy, monofluoromethoxy, monofluoroethoxy, difluoromethoxy, difluoroethoxy, and the like.

[0258] As used herein, the term "hydroxyl" means -OH.

[0259] Herein, a wavy line represents the point of attachment to the rest of the molecule, regardless of the form in which it appears. If no wavy line is noted on a group, it is intended that the group can be attached anywhere on the molecule.

[0260] A chemical bond to a ring means that the bond can be to any ring atom of the ring, for example including and the like.

[0261] "Optional" or "optionally" means that the subsequently described event or circumstance can or can not occur, and that the description includes instances where the event or circumstance occurs and instances where it does not. For example, "heterocycloalkyl optionally substituted with alkyl" means that alkyl can or can not be present, and that the description includes instances in which the heterocycloalkyl group is substituted with alkyl and instances in which the heterocycloalkyl group is not substituted with alkyl.

[0262] "substituted" means that one or more hydrogen atoms, preferably up to 5, more preferably 1 to 3, of the group are independently of each other replaced with a corresponding number of substituents. It is understood that substituents are only in their possible chemical positions and that a person skilled in the art can determine (experimentally or theoretically) what is possible or not possible to substitute without undue effort. For example, an amino or hydroxy group with a free hydrogen can be unstable when bound to a carbon atom with an unsaturated (e.g. olefinic) bond.

[0263] Unless otherwise defined, when a certain group described in the present application is substituted with a substituent, it is meant that all the same groups occurring in the present application can be substituted with the substituent, i.e. it is meant that the group can be substituted when it is present in isolation and it is also meant that the group can be substituted when it is present 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 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 optionally substituted.

[0264] Unless otherwise defined, "the same or different, and each independently" as described in the present application means that when there is more than one identical substituent group in the general formula, the group can be the same or different, and each independently of the kind. For example L is (CR L1 R L2 ) s when s is 2, i.e. L is (CR L1 R L2 )-(CR L1 R L2 ), wherein two R L1 or R L2L can be C(CH3)(CN)-C(CH2CH3)(OH), C(CH3)(CN)-C(CH3)(OH) or C(CN)(CH2CH3)-C(OH)(CH2CH3).

[0265] Unless otherwise defined, "substituents selected independently from each other" as used herein means that when more than one hydrogen on a group is replaced by a substituent, the substituent species can be the same or different, and the substituents selected are each independent species.

[0266] In the present application, C 1-6 may be preferably C 1-4 ; more preferably C 1-3 .

[0267] In one embodiment of the present application, in any group, the C 3-6 cycloalkyl is selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl.

[0268] In one embodiment of the present application, in any group, the 5- or 6-membered monocyclic heteroaryl is selected from the group consisting of thiophene, N-alkylpyrrolidine, 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.

[0269] In one embodiment of the present application, in any group, the 5- or 6-membered monocyclic heteroaryl is selected from the group consisting of:

[0270]

[0271] In one embodiment of the present application, 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, pyrido-pyrimidine, naphthridine.

[0272] "Pharmaceutical composition" means a mixture of one or more compounds described herein or physiologically / pharmaceutically acceptable salts or prodrugs thereof with other chemical components, such as physiologically / pharmaceutically acceptable carriers and excipients. The goal of a pharmaceutical composition is to facilitate administration to an organism and to facilitate absorption of the active ingredient(s) to elicit the biological activity.

[0273] The "pharmaceutically acceptable salts" include pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.

[0274] The "pharmaceutically acceptable acid addition salts" means salts with inorganic acids or organic acids, which retain the biological effectiveness of the free bases and have no other undesired side effects.

[0275] The "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, etc. The "pharmaceutically acceptable base addition salts" include, but are not limited to, salts of organic bases such as ammonium salts, triethylamine salts, lysine salts, arginine salts, etc.

[0276] The "solvate" mentioned in the present application means a complex of the compound of the present application with a solvent. They are either reacted in the solvent or precipitated out of the solvent or crystallized out of the solvent. For example, a complex with water is called "hydrate". The solvate of the compound of formula (I) of the present application is within the scope of the present application.

[0277] The compound of formula (I) of the present application can contain one or more chiral centers and exist in different optically active forms. When the compound contains one chiral center, the compound comprises enantiomers. The present application includes both the isomers and mixtures of the isomers, such as racemic mixtures. The enantiomers can be separated by methods known in the art, such as crystallization and chiral chromatography, etc. When the compound of formula (I) contains more than one chiral center, diastereomers can exist. The present application includes the separated optically pure specific isomers and mixtures of diastereomers. The diastereomers can be separated by methods known in the art, such as crystallization and preparative chromatography. The "stereoisomer" described in the present application includes, but is not limited to, enantiomers, diastereomers, etc.

[0278] The present application includes prodrugs of the above-mentioned compounds. The prodrugs include known amino protecting groups and carboxyl protecting groups, which are hydrolyzed or released to obtain the parent compounds under physiological conditions or via enzymatic reactions. The specific prodrug preparation methods can refer to (Saulnier, M. G.; Frennesson, D. B.; Deshpande, M. S.; Hansel, S. B and Vysa, D. M. Bioorg. Med. Chem Lett. 1994, 4, 1985-1990; and Greenwald, R. B.; Choe, Y. H.; Conover, C. D.; Shum, K.; Wu, D.; Royzen, M. J. Med. Chem. 2000, 43, 475.).

[0279] In general, the compounds of the present application, their stereoisomers, N-oxides, deuterated derivatives, pharmaceutically acceptable salts or prodrugs thereof can be administered in a form suitable for oral, rectal, topical, buccal or other non-gastrointestinal administration (e.g., subcutaneous, intramuscular, intravenous, etc.) in need of treatment. For example, suitable dosage forms for oral administration include capsules, tablets, granules, syrups and the like. The compounds of the present application contained in these formulations can be in the form of a solid powder or granules; a solution or suspension in aqueous or non-aqueous liquids; an oil-in-water or water-in-oil emulsion, etc. The above-mentioned dosage forms can be prepared by conventional pharmaceutical methods using the active compound and one or more carriers or excipients. The above-mentioned 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, etc. The active compound can form a solution or suspension with the above-mentioned carriers.

[0280] The compositions of the present application are formulated, dosed and administered in a fashion consistent with good medical practice. A "therapeutically effective amount" of a compound is the amount that will elicit the biological or medical response of a subject, for example, reduction or inhibition of an enzyme or a protein activity, or ameliorate symptoms, alleviate conditions, slow or delay disease progression, or prevent a disease, etc.

[0281] As used herein, "therapeutically effective amount" means the amount of the compound of the present application that will elicit the biological or medical response of a subject, for example, reduction or inhibition of an enzyme or a protein activity, or ameliorate symptoms, alleviate conditions, slow or delay disease progression, or prevent a disease, etc.

[0282] A therapeutically effective amount of the compound of the present application, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a stereoisomer thereof, contained in the pharmaceutical composition of the present application is preferably 0.1 mg to 5 g / kg (body weight).

[0283] As used herein, "pharmaceutically acceptable carrier" means a non-toxic, inert, solid, semi-solid or liquid material or gel, diluent, encapsulating material, or auxiliary ingredient, or any type of auxiliary ingredient, which is compatible with the patient, preferably a mammal, more preferably a human, and is suitable for safe delivery of the active agent to the target site without terminating the activity of the agent.

[0284] As used herein, "patient" means an animal, preferably a mammal, more preferably a human. The term "mammal" refers to warm-blooded vertebrates, including, for example, cats, dogs, rabbits, bears, foxes, wolves, monkeys, deer, mice, pigs and humans.

[0285] As used herein, "treatment" refers to reducing, delaying the progression of, attenuating, preventing, or maintaining an existing disease or condition (e.g., cancer). Treatment also includes curing, preventing the development of, or reducing to some extent one or more symptoms of a disease or condition.

[0286] As used herein, the term "proteolysis targeting chimera" or "PROTAC" is a chemical molecule with two different ligands at two ends, one end is a ligand binding to E3 ligase (e.g., the ULM moiety described in the present application), the other end is a ligand binding to intracellular protein (e.g., the BTK binding moiety described in the present application), and the two ligands are connected by a linker (e.g., the L described in the present application). Such a chemical molecule can bind to both E3 ubiquitin ligase and intracellular protein, recruit the targeted protein to the vicinity of E3 ubiquitin ligase to achieve polyubiquitination of the targeted protein, and finally be degraded by proteasome. PROTAC can be recycled and is not degraded by proteasome.

[0287] As used herein, the term "can degrade BTK protein" refers to a degradation ability of no less than 10% (degradation percentage ≥ 10%) to BTK protein, "can degrade IRAK4 protein" refers to a degradation ability of no less than 30% (degradation percentage ≥ 30%) to IRAK4 protein. The term "can simultaneously degrade BTK protein and IRAK4 protein" refers to a degradation ability of no less than 10%, even no less than 30% or 50% or more than 90% to both of the two target proteins.

[0288] The term "treatment" includes inhibiting, alleviating, preventing, or eliminating one or more symptoms or side effects associated with the disease, condition, or disorder being treated.

[0289] As used herein, the term "ubiquitin ligase" refers to a family of proteins that facilitate the transfer of ubiquitin to a particular substrate protein, targeting the substrate protein 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 lysines on a target protein and subsequently targets the particular protein substrate for degradation by the proteasome. Thus, the E3 ubiquitin ligase, alone or in complex with an E2 ubiquitin conjugating enzyme, is responsible for the transfer of ubiquitin to the target protein. In general, ubiquitin ligases are involved in polyubiquitination, such that a second ubiquitin is attached to the first; a third ubiquitin is attached to the second, and so on. Polyubiquitination marks the protein for degradation by the proteasome. However, there are some ubiquitination events that are limited to mono-ubiquitination, in which only a single ubiquitin is added to the substrate molecule by the ubiquitin ligase. Mono-ubiquitinated proteins are not targeted to the proteasome for degradation, but rather can be altered in their cellular location or function, for example, via binding to other proteins that have domains capable of binding ubiquitin. More complex, different lysines of 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, which is recognized by the proteasome.

[0290] II. Examples

[0291] In order to make the objects, technical solutions and advantages of the present application clearer, the present application will be further described in detail in the following. The described embodiments should not be regarded as limiting the present application, and all other embodiments obtained by those of ordinary skill in the art without creative work fall within the scope of protection of the present application.

[0292] Before the embodiments of the present application are further described in detail, the terms and phrases involved in the embodiments of the present application are described, and the terms and phrases involved in the embodiments of the present application are applicable to the following explanations.

[0293] The raw materials and equipment used in the specific embodiments of the present disclosure are known products, which are obtained by purchasing commercially available products.

[0294] Preparation Example

[0295] Synthesis of Intermediate B1

[0296]

[0297] Step 1: Synthesis of methyl 4-(4-(dimethoxymethyl)piperidin-1-yl)-2-fluorobenzoate

[0298] A mixture of 4-(dimethoxymethyl)piperidine (5.5 g, 34.9 mmol), methyl 2,4-difluorobenzoate (4 g, 23.3 mmol), and potassium carbonate (6.4 g, 46.6 mmol) in DMSO (40 mL) was purged with nitrogen three times, heated to 80 °C, and stirred for 2 hours. The reaction mixture was cooled to room temperature, and water (300 mL) was added. The mixture was extracted twice with ethyl acetate (200 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the residue obtained by rotary evaporation under reduced pressure was purified by rapid silica gel column chromatography (petroleum ether-ethyl acetate, 95–90%) to give 3.5 g of the title compound as a white solid, in 49% yield.

[0299] LCMS: Rt=2.551min, MS(ESI)m / z=312.0[M+H] + .

[0300] 1 H NMR(400MHz,DMSO-d6)δ7.86–7.76ppm(m,1H),6.63(dt,J=9.4,2.6Hz,1H),6.51(dt,J=14.8,2.6Hz,1H),4.20–4.01(m,1H),3 .93–3.84(m,5H),3.39(q,J=1.3Hz,6H),3.02–2.71(m,2H),1.86(dt,J=10.7,3.5Hz,3H),1.74–1.55(m,1H),1.52–1.23(m,2H)

[0301] Step 2: Synthesis of 4-(4-(dimethoxymethyl)piperidin-1-yl)-2-fluorobenzoic acid

[0302] An aqueous solution (60 mL) of lithium hydroxide monohydrate (7.9 g, 329.8 mmol) was slowly added to a methanol solution (60 mL) of methyl 4-(4-(dimethoxymethyl)piperidin-1-yl)-2-fluorobenzoate (25.4 g, 82.5 mmol). The system was heated to 50 °C and stirred for 1 h. The methanol was removed by rotary evaporation under reduced pressure, and the solution was diluted with water (60 mL). A dilute aqueous hydrochloric acid solution (1 mol / L) was added dropwise with stirring until a large amount of precipitate formed, and the pH was approximately 6. The solution was filtered, the filter cake was washed with water, and dried to give 20 g of the title compound as a white solid, with a yield of 87.0%.

[0303] LCMS: Rt=2.391min, MS(ESI)m / z=298.0[M+H] + .

[0304] 1H NMR (400 MHz, DMSO-d6) δ 10.93 ppm (s, 1H), 9.82 (d, J = 7.0 Hz, 1H), 7.97 - 7.76 (m, 1H), 7.29 - 7.08 (m, 1H), 6.99 (td, J = 8.3, 2.3 Hz, 1H), 4.85 - 4.68 (m, 1H), 4.50 (s, 1H), 3.16 (s, 2H), 2.88 - 2.62 (m, 3H), 2.24 (d, J = 12.6 Hz, 1H), 2.12 - 1.91 (m, 1H), 1.77 (d, J = 11.5 Hz, 2H), 1.45 (d, J = 12.3 Hz, 3H), 1.27 (d, J = 17.1 Hz, 1H).

[0305] Step 3: Synthesis of 4-(4-(dimethoxymethyl)piperidin-l-yl)-N-(2,6-dicarbonylpiperidin-3-yl)-2-fluorobenzamide

[0306] To a solution of 4-(4-(dimethoxymethyl)piperidin-l-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) was added 2-(7-azobenzotriazol)-N,N,N',N'-tetramethyluronium hexafluorophosphate (32.3 g, 85.5 mmol) in one portion. The mixture was stirred at room temperature for 1 h. Water (1000 mL) was added to the mixture, which was extracted with ethyl acetate (200 mL). The filtrate was obtained by filtration. The filtrate was washed with DCM:EA = 1:10 to give 17 g of the title compound as a light yellow solid in 73.0% yield.

[0307] LCMS: Rt = 1.12 min, MS (ESI) m / z = 408.3 [M+H] + .

[0308] 1H NMR (400 MHz, DMSO-d6) δ 10.85 (s, 1H), 8.01 (t, J = 7.3 Hz, 1H), 7.62 (t, J = 9.1 Hz, 1H), 6.95 - 6.67 (m, 2H), 4.83 - 4.67 (m, 1H), 4.07 (d, J = 6.9 Hz, 1H), 3.90 (dd, J = 13.2, 3.4 Hz, 2H), 3.27 (s, 6H), 2.78 (tdd, J = 13.5, 9.6, 4.1 Hz, 3H), 2.19 - 1.93 (m, 2H), 1.83 (dtt, J = 11.4, 7.3, 3.6 Hz, 1H), 1.68 (dd, J = 13.4, 3.7 Hz, 2H), 1.26 (qd, J = 12.4, 4.1 Hz, 2H).

[0309] Step 4: Synthesis of N-(2,6-dioxopiperidin-3-yl)-2-fluoro-4-(4-formylpiperidin-1- yl)benzamide 2,2,2-trifluoroacetate

[0310] Trifluoroacetic acid (17 mL) was added dropwise to a solution of 4-(4- (dimethoxymethyl)piperidin-l-yl)-N-(2,6-dioxopiperidin-3-yl)-2-fluorobenzamide (17 g, 2.9 mmol) in dichloromethane (170 mL) and the system was stirred at room temperature for 4 hours. The reaction was concentrated under reduced pressure to give a residue which was adjusted to weak alkaline with saturated sodium bicarbonate solution and extracted with DCM 1.5 L once. The organic phase was washed with water 3 times and concentrated to give 12 g of the title compound as a white solid with a yield of 79%.

[0311] LCMS: Rt = 0.967 min, MS (ESI) m / z = 362.0 [M+H] + .

[0312] 1 1H NMR (400 MHz, DMSO-d6) δ = 10.85 ppm (s, 1H), 1H NMR (400 MHz, DMSO-d6) δ 10.85 (s, 1H), 9.62 (s, 1H), 8.03 (t, J = 7.2 Hz, 1H), 7.63 (t, J = 9.1 Hz, 1H), 6.97 - 6.64 (m, 2H), 4.73 (ddd, J = 12.7, 7.7, 5.4 Hz, 1H), 3.02 (ddd, J = 13.5, 10.9, 3.0 Hz, 2H), 2.78 (ddd, J = 17.2, 13.3, 5.6 Hz, 1H), 2.59 (dtd, J = 12.2, 8.2, 7.3, 4.0 Hz, 1H), 2.19 - 1.97 (m, 2H), 1.90 (dt, J = 12.4, 3.8 Hz, 2H), 1.54 (dtd, J = 14.4, 10.8, 3.9 Hz, 2H).

[0313] Synthesis of intermediate B2

[0314]

[0315] Step 1: Preparation of methyl 4-(4-(dimethoxymethyl)piperidin-l-yl)-2- methoxybenzoate

[0316] Palladium acetate (640 mg, 2.86 mmol), 1,1'-binaphthalene-2,2'-diphenylphosphine (3810 mg, 6.12 mmol), cesium carbonate (26.59 g, 81.61 mmol) were added to a mixture of methyl 4-bromo-2-methoxybenzoate (10.00 g, 40.81 mmol) and 4-(dimethoxymethyl)piperidine (7.15 g, 44.89 mmol) in 1,4-dioxane (150 mL), replaced with argon for 3 times, stirred at 100 °C for 8 hours under argon protection. After the reaction was completed, the reaction mixture was filtered through celite and washed with ethyl acetate, and the filtrate was rotary evaporated to give 8.0 g of the crude title compound as a light yellow solid, with a yield of 60.63%.

[0317] LCMS: MS (ESI) m / z = 324.2 [M+H] + .

[0318] Step 2: Preparation of 4-(4-(dimethoxymethyl)piperidin-l-yl)-2-methoxybenzoic acid

[0319] Methyl 4-(4-(dimethoxymethyl)piperidin-l-yl)-2-methoxybenzoate (8.0 g, 24.74 mmol) was dissolved in 40 mL of tetrahydrofuran and 40 mL of methanol, and a prepared lithium hydroxide (4.15 g, 98.95 mmol) aqueous solution 40 mL was added, and stirred at room temperature for 16 hours. After the reaction was completed, it was spin-dried, and 100 mL of water was added again, and extracted twice with 60 mL*2 of ethyl acetate, and the water phase was adjusted to pH 4-5 with 1 N hydrochloric acid, and a large amount of solid was precipitated, and filtration was performed to obtain 6.0 g of a yellowish solid title compound with a yield of 78.40%.

[0320] LCMS: MS (ESI) m / z = 310.2 [M+H] + .

[0321] Step 3: Preparation of (S)-4-(4-(dimethoxymethyl)piperidin-l-yl)-N-(2,6-dicarbonylpiperidin-3-yl)-2-methoxybenzamide

[0322] (S)-3-aminopiperidine-2,6-dione hydrochloride (3.35 g, 20.37 mmol) and diisopropylethylamine (7.52 g, 58.19 mmol) were added to a mixture of 4-(4-(dimethoxymethyl)piperidin-l-yl)-2-methoxybenzoic acid (6.0 g, 19.40 mmol) and O-(7-azabenzotriazol-l-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (8.85 g, 23.27 mmol) in N,N-dimethylformamide (30 mL) and dichloromethane (120 mL) under ice bath, and the system was stirred at 25°C for 16 hours. Dichloromethane and diisopropylethylamine were removed by rotary evaporation under reduced pressure, and the reaction solution was added dropwise to 200 mL of water under stirring, and after stirring for 1 hour, filtration was performed, and the filter cake was washed with water, and after the filter cake was spin-dried, 7.8 g of a white solid title compound was obtained with a yield of 95.87%.

[0323] LCMS: MS (ESI) m / z = 420.2 [M+H] + .

[0324] Step 4: Preparation of (S)-N-(2,6-dicarbonylpiperidin-3-yl)-4-(4-formylpiperidin-l-yl)-2-methoxybenzamide trifluoroacetate

[0325] (S)-4-(4-(dimethoxymethyl)piperidin-l-yl)-N-(2,6-dicarbomylpiperidin-3-yl)-2- methoxybenzamide (7.80 g, 18.59 mmol) was dissolved in 30 mL of dichloromethane, 30 mL of trifluoroacetic acid was added, and the mixture was stirred at room temperature for 3 hours. After the reaction was completed, the reaction solution was spin-dried, and the resulting crude product was separated on a normal silica gel column (methanol / dichloromethane = 1 / 20 ~ 10 / 1) to obtain 3.90 g of the title compound as a light yellow solid at a yield of 46.01%.

[0326] LCMS: MS (ESI) m / z = 374.2 [M+H] + .

[0327] Synthesis of Intermediate B3

[0328]

[0329] Step 1: Preparation of 3-(6-bromo-l-oxoisoindolin-2-yl)piperidine-2,6-dione

[0330] Sodium acetate (5.4 g, 65.8 mmol) was added to a solution of 3-amino-2,6-piperidine dione hydrochloride (5.69 g, 36.2 mmol) in methanol (160 mL), and the resulting turbid solution was stirred at 15°C for 10 minutes. Glacial acetic acid (19.76 g, 0.33 mol) was added dropwise, followed by the addition of 5-bromo-2-formylbenzoic acid methyl ester (8 g, 33 mmol). The system was stirred at 15°C for 20 minutes, and sodium cyanoborohydride (4.13 g, 65.8 mmol) was added portionwise. The system was heated to 35°C and stirred for 16 hours. Water (20 mL) was added dropwise to the reaction solution, and then methanol was removed by spin-drying under reduced pressure. Water (500 mL) was added, and the mixture was filtered and the filter cake was dried to obtain 8.3 g of the title compound as a white solid at a yield of 78.12%.

[0331] LCMS: Rt = 1.07 min, MS (ESI) m / z = 323.0 / 325.0 [M+H] + .

[0332] Step 2: Preparation of 3-(6-(4-(dimethoxymethyl)piperidin-l-yl)-l-oxoisoindolin-2- yl)piperidine-2,6-dione

[0333] To a mixture of (SP-4-1)-[1,3-bis[2,6-bis(1 -propylbutyl)phenyl]-4,5-dichloro- 1,3-dihydro-2H-imidazol-2-ylidene]dichloropalladium (0.3 g, 0.3 mmol) in 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) was replaced with nitrogen three times, the mixture was heated to 100 °C and stirred for 3 h. The reaction was cooled to room temperature, diluted with ethyl acetate and filtered, the filtrate was concentrated under reduced pressure and purified by column chromatography on silica gel (methanol / dichloromethane, 0-10%) to give 0.9 g of the title compound as a yellow solid in 35.48% yield.

[0334] LCMS: Rt = 0.98 min, MS (ESI) m / z = 402.0 [M+H] + .

[0335] Step 3: Preparation of 1 -(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)piperidine- 4-carbaldehyde trifluoroacetate salt.

[0336] Trifluoroacetic acid (6 mL) was added dropwise to a solution of 3-(6-(4- (dimethoxymethyl)piperidin-1 -yl)-1 -oxoisoindolin-2-yl)piperidine-2,6-dione (0.9 g, 2.2 mmol) in dichloromethane (20 mL), the mixture was stirred at room temperature for 2 h. The reaction was concentrated under reduced pressure to remove the solvent, added diethyl ether (30 mL), sonicated for 10 min, filtered and the filter cake was dried to give 0.83 g of the title compound as a grey solid in 72.73% yield.

[0337] LCMS: Rt = 0.88 min, MS (ESI) m / z = 356.2 [M+H] + .

[0338] 1H NMR (400 MHz, DMSO) δ ppm 10.98 (s, 1 H), 9.64 (s, 1 H), 7.43 (d, J = 8.4 Hz, 1 H), 7.27 (m, 2 H), 5.10 (dd, J = 13.3, 5.1 Hz, 1 H), 4.34 (d, J = 16.7 Hz, 1 H), 4.20 (d, J = 16.8 Hz, 1 H), 3.67 (d, J = 12.6 Hz, 2 H), 2.91 (m, 3 H), 2.56 (m, 2 H), 2.37 (m, 1 H), 1.97 (dd, J = 12.9, 10.7 Hz, 3 H), 1.61 (m, 2 H).

[0339] Synthesis of intermediate B4

[0340]

[0341] Step 1 : Preparation of 3-(5-bromo-l-oxoisoindolin-2-yl)piperidine-2,6-dione

[0342] Sodium acetate (670 mg, 8.2 mmol) was added to a solution of 3-amino-2,6- piperidinedione hydrochloride (0.74 g, 4.5 mmol) in methanol (20 mL) and the resulting cloudy solution was stirred at 15 °C for 10 minutes, glacial acetic acid (2.46 g, 41 mmol) was added dropwise followed by 4-bromo-2-formylbenzoic acid methyl ester (1 g, 4.1 mmol) and the system was stirred at 15 °C for 20 minutes, sodium cyanoborohydride (0.52 g, 8.2 mmol) was added in portions and the system was heated to 35 °C and stirred for 16 hours. Water (5 mL) was added dropwise to the reaction and the methanol was removed by rotary evaporation under reduced pressure, water (50 mL) was added and the mixture was filtered and the filter cake was dried to give 1.2 g of the title compound as a white solid in 81.11% yield.

[0343] LCMS: Rt = 1.03 min, MS (ESI) m / z = 322.9 / 324.9 [M+H] + .

[0344] Step 2: Preparation of 3-(5-(4-(dimethoxymethyl)piperidin-l-yl)-l-oxoisoindolin-2- yl)piperidine-2,6-dione

[0345] To a mixture of (SP-4-1)-[1,3-bis[2,6-bis(1 -propylbutyl)phenyl]-4,5-dichloro- 1,3-dihydro-2H-imidazol-2-ylidene]dichloropalladium (0.3 g, 0.3 mmol) in dioxane (40 mL) was added 3-(5-bromo-1 -oxoisoindolin-2-yl)piperidine-2,6-dione (2 g, 6.2 mmol), 4-(dimethoxymethyl)piperidine (1.28 g, 8.1 mmol) and cesium carbonate (6.06 g, 18.6 mmol). The mixture was purged with nitrogen three times, heated to 100 °C and stirred for 3 h. The reaction was cooled to room temperature, diluted with ethyl acetate and filtered. The filtrate was concentrated under reduced pressure and purified by column chromatography on silica gel (methanol / dichloromethane, 0-10%) to give 1.5 g of the title compound as a yellow solid in 59.68% yield.

[0346] LCMS: Rt = 1.17 min, MS (ESI) m / z = 402.0 [M+H] + .

[0347] Step 3: Preparation of 1 -(2-(2,6-dioxopiperidin-3-yl)-1 -oxoisoindolin-5-yl)piperidine- 4-carbaldehyde trifluoroacetate salt

[0348] Trifluoroacetic acid (10 mL) was added dropwise to a solution of 3-(5-(4- (dimethoxymethyl)piperidin-1 -yl)-1 -oxoisoindolin-2-yl)piperidine-2,6-dione (1.5 g, 3.7 mmol) in dichloromethane (30 mL) and the mixture was stirred at room temperature for 2 h. The solvent was removed under reduced pressure and ethyl ether (50 mL) was added. The mixture was sonicated for 10 min, filtered and the filter cake was dried to give 1.35 g of the title compound as a green solid in 70.27% yield.

[0349] 1H NMR (400 MHz, DMSO) d ppm 10.95 (s, 1 H), 9.62 (s, 1 H), 7.51 (d, J = 8.4 Hz, 1 H), 7.07 (d, J = 10.4 Hz, 2 H), 5.05 (dd, J = 13.3, 5.1 Hz, 1 H), 4.26 (dd, J = 49.5, 16.8 Hz, 2 H), 3.78 (m, 2 H), 3.02 (m, 2 H), 2.90 (m, 1 H), 2.58 (dd, J = 11.0, 4.0 Hz, 2 H), 2.36 (dt, J = 13.3, 8.9 Hz, 1 H), 1.94 (m, 3 H), 1.57 (qd, J = 11.0, 3.7 Hz, 2 H).

[0350] LCMS: Rt = 0.97 min, MS (ESI) m / z = 356.1 [M+H]+

[0351] Synthesis of intermediate B5

[0352]

[0353] Step 1 : Preparation of methyl 4-bromo-2-(bromomethyl)-5-fluorobenzoate

[0354] Bromosuccinimide (3.95 g, 22.2 mmol) was added portionwise to a solution of methyl 4-bromo-5-fluoro-2-methylbenzoate (5 g, 20.2 mmol) and azobisisobutyronitrile (0.33 g, 2.0 mmol) in 1,2-dichloroethane (100 mL) and the system was stirred at 85 °C for 16 h. The reaction was cooled to room temperature and washed successively with water (100 mL) and saturated brine, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure to give 5.5 g of the crude title compound as a yellow oil in 75.25% yield. It was used directly in the next step.

[0355] 1H NMR (400 MHz, DMSO) δ ppm 8.07 (d, J = 6.8 Hz, 1H), 7.81 (d, J = 9.3 Hz, 1H), 4.98 (s, 2H), 3.88 (s, 3H).

[0356] LCMS: Rt = 1.37 min, MS (ESI) m / z = no MS signal.

[0357] Step 2: Preparation of 3-(5-bromo-6-fluoro-1 -oxoisoindolin-2-yl)piperidine-2,6- dione

[0358] Methyl 4-bromo-2-(bromomethyl)-5-fluorobenzoate (5.5 g, 15.2 mol) was added to a solution of 3-amino-2,6-piperidinedione hydrochloride (3.75 g, 22.8 mmol) and diisopropylethylamine (5.89 g, 45.6 mol) in dimethylformamide (100 mL) and the system was stirred at 100 °C for 10 h. The cooled reaction was added to water (300 mL) and filtered, the filter cake was dissolved in a mixture of ethyl acetate (30 mL) and petroleum ether (150 mL) and stirred at room temperature for 10 min, filtered and the filter cake was dried to give 3.7 g of the title compound as a brown solid in 70.39% yield.

[0359] 1H NMR (400 MHz, DMSO) δ ppm 11.01 (s, 1H), 7.74 - 7.65 (m, 2H), 5.11 (dd, J=13.3, 5.1 Hz, 1H), 4.41 (dd, J=51.4, 17.7 Hz, 2H), 2.91 (ddd, J=13.5, 12.4, 5.4 Hz, 1H), 2.64 - 2.55 (m, 1H), 2.39 (ddd, J=26.6, 13.3, 4.5 Hz, 1H), 2.06 - 1.95 (m, 1H).

[0360] LCMS: Rt = 1.04 min, MS (ESI) m / z = 341.0, 343.0 [M+H] + .

[0361] Step 3: Preparation of 3-(5-(4-(dimethoxymethyl)piperidin-l-yl)-6-fluoro-l- carbonylisochroman-2-yl)piperidine-2,6-dione

[0362] (SP-4-1)-[1,3-bis[2,6-bis(1 -propylbutyl)phenyl]-4,5-dichloro-1,3-dihydro-2H- imidazol-2-ylidene]dichloropalladium (0.58 g, 0.6 mmol) was added to a mixture of 3-(5-bromo-6-fluoro-l-carbonylisochroman-2-yl)piperidine-2,6-dione (3.4 g, 10.0 mmol), 4-(dimethoxymethyl)piperidine (2.39 g, 15.0 mmol) and cesium carbonate (9.77 g, 30.0 mmol) in dioxane (80 mL), the system was replaced with nitrogen three times, heated to 100 °C and stirred for 3 hours. The reaction was cooled to room temperature, diluted with dioxane and filtered, the filtrate was rotary evaporated under reduced pressure and separated and purified by silica gel column chromatography (methanol / dichloromethane, 0-10%) to give 1.9 g of the title compound as a brown solid, yield 45.00%.

[0363] LCMS: Rt = 1.07 min, MS (ESI) m / z = 420.0 [M+H] + .

[0364] 1H NMR (400 MHz, DMSO) δ ppm 10.89 (s, 1 H), 7.40 (d, J=11.6 Hz, 1 H), 7.22 (d, J=7.6 Hz, 1 H), 5.02 (dd, J=13.3, 5.1 Hz, 1 H), 4.28 (dd, J=45.0, 17.1 Hz, 2 H), 4.12 (d, J=6.5 Hz, 1 H), 3.48 (s, 2 H), 3.28 (s, 6 H), 2.91 - 2.80 (m, 1 H), 2.70 (t, J=11.6 Hz, 2 H), 2.56 (d, J=17.6 Hz, 1 H), 2.40 - 2.28 (m, 1 H), 2.02 - 1.93 (m, 1 H), 1.74 (d, J=9.7 Hz, 3 H), 1.41 (dd, J=21.6, 12.2 Hz, 2 H).

[0365] Step 4: 1-(2-(2,6-dicarbonylpiperidin-3-yl)-6-fluoro-1-oxoisoindolin-5-yl)piperidine-4- carbaldehyde

[0366] Trifluoroacetic acid (10 mL) was added dropwise to a solution of 3-(5-(4- (dimethoxymethyl)piperidin-1-yl)-6-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione (1.9 g, 4.5 mmol) in dichloromethane (30 mL) and the system was stirred at room temperature for 1 hour. The reaction was concentrated under reduced pressure to remove the solvent to give a residue which was separated and purified by column chromatography on carbon 18 (water (0.1% trifluoroacetic acid) - acetonitrile, 0-35%) to give 1.54 g of the title compound as a white solid in a yield of 66.67%.

[0367] LCMS: Rt = 1.01 min, MS (ESI) m / z = 374.0 [M+H] + .

[0368] 1 H NMR (400 MHz, DMSO) δ ppm 10.98 (s, 1 H), 9.66 (s, 1 H), 7.42 (d, J=11.5 Hz, 1 H), 7.25 (d, J=7.6 Hz, 1 H), 5.07 (dd, J=13.3, 5.1 Hz, 1 H), 4.29 (dd, J=49.0, 17.1 Hz, 2 H), 3.40 (dd, J=11.8, 4.8 Hz, 2 H), 3.00 - 2.79 (m, 3 H), 2.56 (dd, J=18.2, 11.5 Hz, 2 H), 2.44 - 2.29 (m, 1 H), 2.01 - 1.95 (m, 2 H), 1.77 - 1.57 (m, 2 H).

[0369] Synthesis of Intermediate B6

[0370]

[0371] Step 1: Preparation of methyl 4-bromo-2-(bromomethyl)-3-fluorobenzoate

[0372] Bromosuccinimide (3.95 g, 22.2 mmol) was added portionwise to a solution of methyl 4-bromo-3-fluoro-2-methylbenzoate (5 g, 20.2 mmol) and azobisisobutyronitrile (0.33 g, 2.0 mmol) in carbon tetrachloride (50 mL) and the mixture was stirred at 80 °C for 16 h. The reaction was cooled to room temperature, diluted with dichloromethane (100 mL), washed sequentially with water (100 mL) and saturated brine, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (ethyl acetate / petroleum ether, 0-10%) to give 3 g of the title compound as a white solid in 45.54% yield.

[0373] 1 H NMR (400 MHz, DMSO) δ ppm, 7.87 (dd, J = 8.4, 7.0 Hz, 1 H), 7.68 (dd, J = 8.5, 1.0 Hz, 1 H), 4.98 (d, J = 2.0 Hz, 2 H), 3.89 (s, 3 H).

[0374] Step 2: Preparation of 3-(5-bromo-4-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[0375] Methyl 4-bromo-2-(bromomethyl)-3-fluorobenzoate (2.8 g, 8.6 mol) was added to a solution of 3-amino-2,6-piperidinedione hydrochloride (1.42 g, 8.6 mmol) and diisopropylethylamine (5.56 g, 43 mol) in dimethylformamide (50 mL) and the mixture was stirred at 100 °C for 2 h. The solvent was removed by rotary evaporation under reduced pressure and water (200 mL) was added. The mixture was sonicated for 10 min and filtered to give the title compound as a blue solid in 84.88% yield.

[0376] LCMS: Rt = 1.09 min, MS (ESI) m / z = 340.9.0 / 342.9 [M+H] + .

[0377] Step 3: Preparation of 3-(5-(4-(dimethoxymethyl)piperidin-1-yl)-4-fluoro-1- oxoisoindolin-2-yl)piperidine-2,6-dione

[0378] (SP-4-1)-[1,3-bis[2,6-bis(1-propylbutyl)phenyl]-4,5-dichloro-1,3-dihydro-2H-imidazol-2-ylidene]dichloro(3-chloropyridin-κN)-palladium (0.29 g, 0.3 mmol) was added to a mixture of 3-(5-bromo-4-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione (2 g, 5.9 mmol), 4-(dimethoxymethyl)piperidine (1.22 g, 7.7 mmol), and cesium carbonate (5.77 g, 17.7 mmol) in dioxane (40 mL). Nitrogen gas was purged three times, and the system was heated to 100 °C and stirred for 3 hours. The reaction solution was cooled to room temperature, diluted with dioxane, and filtered. The filtrate was evaporated to dryness under reduced pressure and purified by silica gel column chromatography (methanol / dichloromethane, 0–10%) to obtain 1.4 g of the title compound as a yellow solid, with a yield of 45.76%.

[0379] LCMS: Rt=1.10min, MS(ESI)m / z=420.0[M+H] + .

[0380] Step 4: 1-(2-(2,6-dioxopiperidin-3-yl)-4-fluoro-1-oxoisoindololin-5-yl)piperidin-4-carboxaldehyde was added dropwise with trifluoroacetic acid (10 mL) to a dichloromethane solution (30 mL) of 3-(5-(4-(dimethoxymethyl)piperidin-1-yl)-4-fluoro-1-oxoisoindololin-2-yl)piperidin-2,6-dione (1.4 g, 3.3 mmol). The system was stirred at room temperature for 2 hours. The reaction solution was evaporated under reduced pressure to remove the solvent, and diethyl ether (50 mL) was added. The mixture was sonicated for 10 minutes, filtered, and the filter cake was dried to give 1.0 g of the title compound as a gray solid, with a yield of 75.76%.

[0381] LCMS: Rt=1.02min, MS(ESI)m / z=374.1[M+H] + .

[0382] 1 H NMR(400MHz,DMSO)δppm 10.99(s,1H),9.66(s,1H),7.47(d,J=8.1Hz,1H),7.18(t,J=7.9Hz,1H),5.08(dd,J=13.3,5.1Hz,1H),4.48(d,J=17.0Hz,1H),4.31 (d,J=17.0Hz,1H),3.41(dd,J=9.9,6.0Hz,2H),2.90(m,3H),2.56(dd,J=19.1,11.9Hz,2H),2.40(m,1H),1.98(m,3H),1.67(m,2H).

[0383] Synthesis of intermediate B7

[0384]

[0385] Step 1: Preparation of methyl 5-bromo-2-(bromomethyl)-3-fluorobenzoate

[0386] To a solution of methyl 5-bromo-3-fluoro-2-methylbenzoate (5 g, 20.2 mmol) in 1,2-dichloroethane (50 mL) was added N-bromosuccinimide (4.31 g, 24.2 mmol) and azobisisobutyronitrile (0.17 g, 1.01 mmol). The reaction mixture was heated to 70 °C and stirred for 4 h. Upon completion of the reaction, the mixture was cooled to room temperature, concentrated under reduced pressure and purified by flash column chromatography on silica gel (petroleum ether / ethyl acetate, 100%) to give 6 g of the title compound as colorless oil in 91.09% yield.

[0387] LCMS: Rt = 1.41 min, MS (ESI) m / z 326.1 [M+H] + .

[0388] Step 2: Preparation of 3-(6-bromo-4-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[0389] To a solution of 3-aminopiperidine-2,6-dione hydrochloride (3.03 g, 18.4 mmol) in N,N-dimethylformamide (60 mL) was added methyl 5-bromo-2-(bromomethyl)-3-fluorobenzoate (6 g, 18.4 mmol) and N,N-diisopropylethylamine (11.89 g, 92 mmol) and heated to 100 °C and stirred for 11.5 h. Upon cooling to room temperature, it was concentrated under reduced pressure, diluted with water (200 mL), filtered, the filter cake was washed with petroleum ether / ethyl acetate (4 / 1) solution, concentrated under reduced pressure and lyophilized to give 4.6 g of the title compound as a grey solid in 73.37% yield.

[0390] LCMS: Rt = 1.10 min, MS (ESI) m / z 340.9, 342.8 [M+H] + .

[0391] Step 3: Preparation of 3-(6-(4-(dimethoxymethyl)piperidin-1-yl)-4-fluoro-1- oxoisoindolin-2-yl)piperidine-2,6-dione

[0392] To a mixture of (SP-4-1)-[1,3-bis[2,6-bis(1 -propylbutyl)phenyl]-4,5-dichloro-1,3- dihydro-2H-imidazol-2-ylidene]dichloropalladium (0.66 g, 0.675 mmol) in a mixture of 3-(6-bromo-4-fluoro-1 -oxoisoindolin-2-yl)piperidine-2,6-dione (4.6 g, 0.0135 mol), 4-(dimethoxymethyl)piperidine (3.22 g, 20.25 mmol) and cesium carbonate (13.2 g, 40.5 mmol) in dioxane (60 mL) was substituted with nitrogen three times, the system was heated to 100 °C and stirred for 3 hours. The reaction was cooled to room temperature, diluted with ethyl acetate and filtered, the filtrate was rotary evaporated under reduced pressure and separated and purified by silica gel column chromatography (methanol / dichloromethane, 0-10%) to give 2 g of the title compound as a yellow solid in 35.56% yield.

[0393] LCMS: Rt = 1.09 min, MS (ESI) m / z = 420.0 [M+H] + .

[0394] Step 4: Preparation of 1 -(2-(2,6-dicarbonylpiperidin-3-yl)-7-fluoro-3- oxoisoindolin-5-yl)piperidine-4-carbaldehyde.

[0395] Trifluoroacetic acid (5 mL) was added dropwise to a solution of 3-(6-(4- (dimethoxymethyl)piperidin-1 -yl)-4-fluoro-1 -oxoisoindolin-2-yl)piperidine-2,6-dione (2 g, 0.0048 mol) in dichloromethane (20 mL), the system was stirred at room temperature for 1 hour. The reaction was rotary evaporated under reduced pressure to remove the solvent and separated and purified by carbon 18 column chromatography (water-acetonitrile, 10-90%, 0.1 % trifluoroacetic acid) to give 752.2 mg of the title compound as a white solid in 39.88% yield.

[0396] LCMS: Rt = 1.07 min, MS (ESI) m / z = 374.0 [M+H] +

[0397] 1H NMR (400 MHz, DMSO) δ ppm 10.99 (s, 1 H), 9.63 (s, 1 H), 7.12 - 7.03 (m, 2 H), 5.10 (dd, J=13.3, 5.0 Hz, 1 H), 4.42 (d, J=16.7 Hz, 1 H), 4.25 (d, J=16.6 Hz, 1 H), 3.73 (d, J=12.7 Hz, 2 H), 2.97 (dd, J=17.2, 6.4 Hz, 2 H), 2.89 (dd, J=13.5, 5.1 Hz, 1 H), 2.60 (dd, J=32.5, 14.0 Hz, 2 H), 2.41 (dt, J=13.2, 8.8 Hz, 1 H), 2.04 - 1.96 (m, 1 H), 1.92 (d, J=10.0 Hz, 2 H), 1.62 - 1.52 (m, 2 H).

[0398] Synthesis of intermediate B8

[0399]

[0400] Step 1 : Preparation of 2-(2,6-dicarbonylpiperidin-3-yl)-5-(4- (hydroxymethyl)piperidin-1 -yl)isoindoline-1,3-dione

[0401] 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), heated to 120 °C and stirred for 2 hours. The reaction was concentrated under reduced pressure to remove N,N-diisopropylethylamine and the resulting residue was separated by carbon 18 column chromatography (water-acetonitrile, 0.1 % formic acid, 95-50%) and the resulting preparation was adjusted to pH = 9 with saturated sodium bicarbonate solution and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure to give 2.2 g of the title compound as a yellow solid in 89.99% yield.

[0402] LCMS: Rt = 1.04 min, MS (ESI) m / z = 372.1 [M+H] + .

[0403] 1H NMR (400 MHz, DMSO) δ ppm 11.09 (s, 1 H), 7.64 (d, J = 8.6 Hz, 1 H), 7.30 (d, J = 2.1 Hz, 1 H), 7.23 (dd, J = 8.7, 2.3 Hz, 1 H), 5.06 (dd, J = 12.9, 5.4 Hz, 1 H), 4.51 (t, J = 5.3 Hz, 1 H), 4.11 - 4.03 (m, 2 H), 3.26 (t, J = 5.7 Hz, 2 H), 3.02 - 2.81 (m, 3 H), 2.56 (dd, J = 17.8, 10.6 Hz, 3 H), 2.05 - 1.99 (m, 1 H), 1.77 - 1.60 (m, 3 H), 1.25 - 1.19 (m, 1 H).

[0404] Step 2: Preparation of 1-(2-(2,6-dicarbonylpiperidin-3-yl)-1,3-dicarbonylisatine-5- yl)piperidine-4-carbaldehyde.

[0405] Step 2: Preparation of 1-(2-(2,6-dicarbonylpiperidin-3-yl)-1,3-dicarbonylisatine-5- yl)piperidine-4-carbaldehyde.

[0406] LCMS: Rt = 1.07 min, MS (ESI) m / z = 370.0 [M+H] + .

[0407] 1H NMR (400 MHz, DMSO) δ ppm 11.09 (s, 1 H), 9.62 (s, 1 H), 7.66 (d, J = 8.5 Hz, 1 H), 7.34 (d, J = 2.1 Hz, 1 H), 7.25 (dd, J = 8.6, 2.2 Hz, 1 H), 5.07 (dd, J = 12.9, 5.4 Hz, 1 H), 3.94 (d, J = 13.4 Hz, 2 H), 3.23 - 3.11 (m, 2 H), 2.88 (ddd, J = 17.3, 14.2, 5.4 Hz, 1 H), 2.70 - 2.51 (m, 3 H), 2.05 - 1.86 (m, 3 H), 1.55 (qd, J = 10.8, 3.7 Hz, 2 H).

[0408] Synthesis of Intermediate B9

[0409]

[0410] Step 1: Synthesis of (S)-4-(4-(dimethoxymethyl)piperidin-l-yl)-N-(2,6-dioxopiperidin-3-yl)-2-fluorobenzamide

[0411] To a solution of 4-(4-(dimethoxymethyl)piperidin-l-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) was added 2-(7-azabenzotriazol-l-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (32.3 g, 85.5 mmol) in one portion. The mixture was stirred at room temperature for 1 h. Water (1000 mL) was added to the mixture and the mixture was extracted with ethyl acetate (200 mL). White solid was precipitated and the mixture was filtered. The filtrate was washed with ethyl acetate (200 mL). The solid was collected by filtration to give the title compound as a light yellow solid (17 g, 73.0% yield).

[0412] LCMS: Rt = 1.072 min, MS (ESI) m / z = 408.2 [M+H] + .

[0413] Step 2: Synthesis of (S)-N-(2,6-dioxopiperidin-3-yl)-2-fluoro-4-(4-formylpiperidin-l-yl)benzamide trifluoroacetate

[0414] To a solution of (S)-4-(4-(dimethoxymethyl)piperidin-l-yl)-N-(2,6-dioxopiperidin-3-yl)-2-fluorobenzamide (17 g, 2.9 mmol) in dichloromethane (170 mL) was added trifluoroacetic acid (17 mL) dropwise. The mixture was stirred at 45 °C for 4 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was adjusted to weak alkaline with saturated sodium bicarbonate solution and extracted with DCM (1.5 L) once. The mixture was concentrated under reduced pressure to give the title compound as a white solid (12 g, 79% yield).

[0415] LCMS: Rt = 0.967 min, MS (ESI) m / z = 362.0 [M+H] + .

[0416] 1H NMR (400 MHz, DMSO-d6) δ 10.85 (s, 1H), 9.62 (s, 1H), 8.03 (t, J = 7.2 Hz, 1H), 7.63 (t, J = 9.1 Hz, 1H), 6.97 - 6.64 (m, 2H), 4.73 (ddd, J = 12.7, 7.7, 5.4 Hz, 1H), 3.02 (ddd, J = 13.5, 10.9, 3.0 Hz, 2H), 2.78 (ddd, J = 17.2, 13.3, 5.6 Hz, 1H), 2.59 (dtd, J = 12.2, 8.2, 7.3, 4.0 Hz, 1H), 2.19 - 1.97 (m, 2H), 1.90 (dt, J = 12.4, 3.8 Hz, 2H), 1.54 (dtd, J = 14.4, 10.8, 3.9 Hz, 2H).

[0417] Synthesis of intermediate B10

[0418]

[0419] Step 1: Synthesis of methyl 4-(4-(dimethoxymethyl)piperidin-l-yl)-2- chlorobenzoate

[0420] A mixture of 4-(dimethoxymethyl)piperidine (5.5 g, 34.9 mmol), methyl 2-chloro-4-fluorobenzoate (4.4 g, 23.3 mmol) and potassium carbonate (6.4 g, 46.6 mmol) in DMSO (40 mL) was purged with nitrogen three times, heated to 80 °C and stirred for 2 hours. The reaction was cooled to room temperature, water (300 mL) was added, extracted with ethyl acetate (200 mL) twice, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and the residue obtained by rotary evaporation under reduced pressure was separated and purified by flash silica gel column chromatography (petroleum ether-ethyl acetate, 95-90%) to give 3.9 g of the title compound as a white solid with a yield of 51%.

[0421] LCMS: MS (ESI) m / z = 328.1 [M+H] + .

[0422] Step 2: Synthesis of 4-(4-(dimethoxymethyl)piperidin-l-yl)-2-chlorobenzoic acid

[0423] A solution of lithium hydroxide monohydrate (2.0 g, 47.6 mmol) in water (30 mL) was added slowly to a solution of methyl 4-(4-(dimethoxymethyl)piperidin-l-yl)-2-chlorobenzoate (3.9 g, 11.9 mmol) in methanol (30 mL), the system was warmed to 50 °C and stirred for 1 h. The reaction was concentrated under reduced pressure to remove methanol, diluted with water (60 mL), and diluted with dilute aqueous hydrochloric acid (1 mol / L) dropwise with stirring until a large amount of precipitate was formed. The precipitate was filtered, washed with water, and dried to give 3.4 g of the title compound as a white solid in 91.0% yield.

[0424] LCMS: MS (ESI) m / z = 314.1 [M+H] + .

[0425] Step 3: Synthesis of (S)-2-chloro-4-(4-(dimethoxymethyl)piperidin-l-yl)-N-(2,6-dicarb oxypiperidin-3-yl)benzamide

[0426] A solution of 2-(7-azobenzotriazol)-N,N,N',N'-tetramethyluronium hexafluorophosphate (3.23 g, 8.55 mmol) was added in one portion to a solution of 4-(4- (dimethoxymethyl)piperidin-l-yl)-2-chlorobenzoic acid (1.78 g, 5.7 mmol), (S)-3- aminopiperidine-2,6-dione hydrochloride (935 mg, 5.7 mmol), and diisopropylethylamine (2.21 g, 17.1 mmol) in dimethylformamide (20 mL), the system was stirred at room temperature for 1 h. Water (200 mL) was added to the system, which was washed with ethyl acetate (50 mL), at this time a white solid was precipitated, which was filtered to give 1.8 g of the title compound as a light yellow solid in 75.0% yield.

[0427] LCMS: MS (ESI) m / z = 424.1 [M+H] + .

[0428] Step 4: Synthesis of (S)-2-chloro-N-(2,6-dicarb oxypiperidin-3-yl)-4-(4-formylpiperidin- 1-yl)benzamide trifluoroacetate

[0429] Trifluoroacetic acid (1.7 mL) was added dropwise to a solution of (S)-2-chloro-4-(4- (dimethoxymethyl)piperidin-l-yl)-N-(2,6-dicarb oxypiperidin-3-yl)benzamide (1.7 g, 4.0 mmol) in dichloromethane (17 mL), the system was stirred at room temperature for 4 h. The reaction was concentrated under reduced pressure to give a residue, which was adjusted to weak alkalinity with a saturated sodium bicarbonate solution, and extracted with DCM. The dichloromethane layer was concentrated under reduced pressure to give 1.2 g of the title compound as a white solid in 78.5% yield.

[0430] LCMS: MS (ESI) m / z = 378.1 [M+H] + .

[0431] Synthesis of intermediate B11

[0432]

[0433] Step 1: Synthesis of methyl 5-(4-(hydroxymethyl)piperidin-l-yl)methyl pyridine carboxylate

[0434] A mixture of methyl 5-fluoromethyl pyridine carboxylate (5.0 g, 32.23 mmol), piperidin-4-ylmethanol (3.3 g, 32.23 mmol) and triethylamine (8.1 g, 80.58 mmol) in DMSO (40 mL) was heated to 90 °C and stirred for 2 h. The reaction was cooled to room temperature, water (300 mL) was added, and the mixture was extracted twice with ethyl acetate (200 mL). The combined 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 flash column chromatography on silica gel (petroleum ether-ethyl acetate, 95-90%) to give 3.24 g of the compound as a yellow oil in 42.6% yield.

[0435] MS (ESI) m / z = 251.1 [M+H] + .

[0436] Step 2: Synthesis of 5-(4-(hydroxymethyl)piperidin-l-yl)picolinic acid

[0437] A solution of lithium hydroxide monohydrate (1.32 g, 54.72 mmol) in water (10 mL) was slowly added to a solution of methyl 5-(4-(hydroxymethyl)piperidin-l-yl)methyl pyridine carboxylate (3.23 g, 13.68 mmol) in methanol (10 mL), and the mixture was warmed to 60 °C and stirred for 2 h. The reaction was rotary evaporated under reduced pressure to remove methanol, diluted with water (60 mL), and a dilute aqueous hydrochloric acid solution (1 mol / L) was added dropwise with stirring until a large amount of precipitate was formed. The precipitate was filtered, washed with water, and dried to give 3.0 g of the title compound as a yellow solid in 98.7% yield.

[0438] MS (ESI) m / z = 237.1 [M+H] + .

[0439] Step 3: Synthesis of (S)-N-(2,6-dicarbonylpiperidin-3-yl)-5-(4- (hydroxymethyl)piperidin-l-yl)methyl pyridine amide

[0440] To a solution of 2-(7-azobenzotriazol)-N,N,N',N'-tetramethyluronium hexafluorophosphate (3.27 g, 8.6 mmol) in dimethylformamide (20 mL) was added 5-(4- (hydroxymethyl)piperidin-l-yl)picolinic acid (1.34 g, 5.7 mmol), (S)-3-aminopiperidine-2,6- dione hydrochloride (935 mg, 5.7 mmol) and diisopropylethylamine (2.2 g, 17.1 mmol) in one portion. The mixture was stirred at room temperature for 1 h. Water (100 mL) was added to the mixture, which was extracted with ethyl acetate (200 mL) twice. The organic phase was combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (dichloromethane-methanol, 0-10%) to give 864 mg of the compound as a yellow oil in 43.8% yield.

[0441] MS (ESI) m / z = 347.1 [M+H] + .

[0442] Step 4: Synthesis of (S)-N-(2,6-dicarbonylpiperidin-3-yl)-5-(4-formylpiperidin-l- yl)methylpicolinamide

[0443] IBX (46% wt, 840 mg, 3.0 mmol) was added to a solution of (S)-N-(2,6-dicarbonylpiperidin-3- yl)-5-(4-(hydroxymethyl)piperidin-l-yl)methylpicolinamide (864 mg, 2.5 mmol) in acetonitrile (10 mL) and 1,2-dichloromethane (10 mL). The mixture was heated to 60 °C and stirred for 2 h. The reaction was monitored by TLC. The mixture was cooled to room temperature, filtered and the filter cake was washed with DCM. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (dichloromethane-methanol, 0-10%) to give 354.4 mg of the compound as a yellow solid in 41.2% yield.

[0444] MS (ESI) m / z = 345.1 [M+H] + .

[0445] Synthesis of Intermediate B12

[0446]

[0447] Step 1: Synthesis of methyl 2-fluoro-4-(3-(hydroxymethyl)azetidin-l-yl)benzoate

[0448] A mixture of methyl 2,4-difluorobenzoate (3.44 g, 20.0 mmol), 3- methoxyazetidine hydrochloride (2.46 g, 20.0 mmol), and diisopropylethylamine (7.74 g, 60.0 mmol) in DMSO (20 mL) was heated to 90 °C and stirred for 6 h. The reaction was cooled to room temperature, water (300 mL) was added, and the mixture was extracted twice with ethyl acetate (200 mL). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the resulting residue was isolated and purified by flash column chromatography on silica gel (dichloromethane-methanol, 95-10%) to give 1.3 g of the compound as a white solid in 27.6% yield.

[0449] MS (ESI) m / z = 240.1 [M+H] + .

[0450] Step 2: Synthesis of 2-fluoro-4-(3-(hydroxymethyl)azetidin-l-yl)benzoic acid

[0451] A solution of lithium hydroxide monohydrate (521 mg, 21.76 mmol) in water (10 mL) was slowly added to a solution of methyl 2-fluoro-4-(3-(hydroxymethyl)azetidin-l- yl)benzoate (1.3 g, 5.44 mmol) in methanol (10 mL), and the mixture was warmed to 60 °C and stirred for 2 h. The reaction was concentrated under reduced pressure to remove methanol, diluted with water (60 mL), and diluted with dilute aqueous hydrochloric acid (1 mol / L) dropwise with stirring until a large amount of precipitate was formed. The mixture was filtered, and the filter cake was washed with water and dried to give 1.0 g of the title compound as a yellow solid in 81.7% yield.

[0452] MS (ESI) m / z = 226.1 [M+H] + .

[0453] Step 3: Synthesis of (S)-N-(2,6-dicarbonylpiperidin-3-yl)-2-fluoro-4-(3- (hydroxymethyl)azetidin-l-yl)benzamide

[0454] To a solution of 2-(7-azobenzotriazol)-N,N,N',N'-tetramethyluronium hexafluorophosphate (2.02 g, 5.33 mmol) in dimethylformamide (10 mL) was added (S)-3- aminopiperidine-2,6-dione hydrochloride (805 mg, 4.89 mmol) and diisopropylethylamine (1.72 g, 13.33 mmol) in one portion. The mixture was stirred at room temperature for 1 h. Water (50 mL) was added to the mixture, which was extracted with ethyl acetate (150 mL) twice. The organic phase was combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (dichloromethane-methanol, 0-10%) to give 1.3 g of the compound as a white solid in 87.4% yield. MS (ESI) m / z = 336.1 [M+H] + .

[0455] Step 4: Synthesis of (S)-N-(2,6-dicarbonylpiperidin-3-yl)-2-fluoro-4-(3- formylazetidin-1-yl)benzamide

[0456] IBX (46% wt, 1.3 g, 3.88 mmol) was added to a solution of (S)-N-(2,6-dicarbonylpiperidin-3-yl)-2-fluoro-4-(3-(hydroxymethyl)azetidin-1-yl)benzamide (864 mg, 2.5 mmol) in DMSO (10 mL) and the mixture was heated to 60 °C and stirred for 2 h. The reaction was monitored by TLC. The mixture was cooled to room temperature and water (80 mL) was added. The mixture was extracted with dichloromethane (150 mL) twice. The organic phase was combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (methanol:dichloromethane, 0-10%) to give 340 mg of the compound as a white solid in 26.3% yield.

[0457] MS (ESI) m / z = 334.1 [M+H] + .

[0458] Synthesis of Intermediate B13

[0459]

[0460] Step 1: Preparation of methyl 2-fluoro-4-[3-(hydroxymethyl)tetrahydro-1H-pyrrol-1- yl]benzoate

[0461] Methyl 2,4-difluorobenzoate (3.44 g, 20.00 mmol), tetrahydro-lH-pyrrol-3- ylmethanol (2.02 g, 20.00 mmol) were dissolved in dimethyl sulfoxide (15 mL), triethylamine (5.05 g, 50.00 mmol) was added, and the mixture was stirred at 90 °C for 1 h. After the reaction was completed, the mixture was cooled to room temperature, ethyl acetate (200 mL) was added, and the mixture was washed with saturated brine three times, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated by normal silica gel column chromatography (ethyl acetate / petroleum ether = 1 / 5 ~ 1 / 1) to give 1.43 g of the title compound as a yellow solid in 28.1% yield.

[0462] LCMS: MS (ESI) m / z = 254.2 [M+H] + .

[0463] Step 2: Preparation of 2-fluoro-4-[3-(hydroxymethyl)tetrahydro-lH-pyrrol-l- yl]benzoic acid

[0464] Methyl 2-fluoro-4-[3-(hydroxymethyl)tetrahydro-lH-pyrrol-l-yl]benzoate (1.43 g, 5.65 mmol) was dissolved in tetrahydrofuran (20 mL) and methanol (5 mL), and a prepared lithium hydroxide (541 mg, 22.60 mmol) aqueous solution (10 mL) was added. The mixture was stirred at room temperature for 16 h. After the reaction was completed, the mixture was concentrated under reduced pressure, and the pH was adjusted to 2 ~ 3 with 1 N hydrochloric acid. A solid was precipitated, and the mixture was filtered to give 1.14 g of the title compound as a yellow solid in 84.4% yield.

[0465] LCMS: MS (ESI) m / z = 240.1 [M+H]+.

[0466] Step 3: Preparation of N-((S)-2,6-dicarbonylpiperidin-3-yl)-2-fluoro-4-(3- (hydroxymethyl)pyrrolidin-l-yl)benzamide

[0467] (S)-3-aminopiperidine-2,6-dione hydrochloride (864 mg, 5.25 mmol) and diisopropylethylamine (1.85 g, 14.31 mmol) were added to a solution of 2-fluoro-4-[3- (hydroxymethyl)tetrahydro-lH-pyrrol-l-yl]benzoic acid (1.14 g, 4.77 mmol) and O-(7- azabenzotriazol-l-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (2.17 g, 5.72 mmol) in N,N-dimethylformamide (10 mL) under ice bath. The mixture was stirred at 25 °C for 2 h. Diisopropylethylamine was removed under reduced pressure, and the reaction mixture was added dropwise to 100 mL of water with stirring. After stirring for 0.5 h, the mixture was filtered, and the filter cake was washed with water. The filter cake was dried under reduced pressure, and the residue was concentrated under reduced pressure to give 1.4 g of the title compound as a yellow solid in 85.2% yield.

[0468] LCMS: MS (ESI) m / z = 350.2 [M+H] + .

[0469] Step 4: Preparation of N-((S)-2,6-dicarbonylpiperidin-3-yl)-2-fluoro-4-(3- formylpyrrolidin-1-yl)benzamide

[0470] N-((S)-2,6-dicarbonylpiperidin-3-yl)-2-fluoro-4-(3-(hydroxymethyl)pyrrolidin-1- yl)benzamide (1.85 g, 5.30 mmol) was dissolved in N,N-dimethylformamide (5 mL) and dichloromethane (50 mL), and Dess-Martin oxidant (2.70 g, 6.36 mmol) was added, and stirred at room temperature for 2 hours. After the reaction was completed, water (50 mL) was added, and extracted with dichloromethane twice, and the organic phase was combined, washed with saturated brine three times, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained crude product was separated by silica gel column (methanol / dichloromethane = 1 / 50 ~ 10 / 1) to obtain 500 mg of crude product. The crude product was subjected to thin layer preparative chromatography to obtain 180 mg of the title compound as a white solid in a yield of 9.8%.

[0471] LCMS: MS (ESI) m / z = 348.1 [M+H] + .

[0472] Synthesis of Intermediate B14

[0473]

[0474] Step 1: Synthesis of methyl 2-fluoro-4-(4-fluoro-4-(hydroxymethyl)piperidin-1- yl)benzoate

[0475] A mixture of 4-fluoro-4-piperidinemethanol hydrochloride (5.9 g, 34.9 mmol), methyl 2,4-difluorobenzoate (4 g, 23.3 mmol), and potassium carbonate (6.4 g, 46.6 mmol) in DMSO (40 mL) was replaced with nitrogen three times, heated to 80°C, and stirred for 2 hours. The reaction solution was cooled to room temperature, water (300 mL) was added, extracted with ethyl acetate (200 mL) twice, the organic phase was combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the obtained residue was separated and purified by flash silica gel column chromatography (petroleum ether-ethyl acetate, 95 ~ 90%) to obtain 1.7 g of the title compound as a white solid in a yield of 25.7%.

[0476] MS (ESI) m / z = 286.1 [M+H] + .

[0477] Step 2: Synthesis of 2-fluoro-4-(4-fluoro-4-(hydroxymethyl)piperidin-l- yl)benzoic acid

[0478] A solution of lithium hydroxide monohydrate (991 mg, 23.6 mmol) in water (20 mL) was added slowly to a solution of methyl 2-fluoro-4-(4-fluoro-4- (hydroxymethyl)piperidin-l-yl)benzoate (1.7 g, 5.9 mmol) in methanol (20 mL), the system was warmed to 50 °C and stirred for 1 h. The reaction was concentrated under reduced pressure to remove methanol, diluted with water (60 mL), and diluted with dilute aqueous hydrochloric acid (1 mol / L) dropwise with stirring until a large amount of precipitate was formed, filtered, and the filter cake was washed with water and dried to give 1.4 g of the title compound as a white solid in 87.0% yield.

[0479] MS (ESI) m / z = 272.1 [M+H] + .

[0480] Step 3: Synthesis of (S)-N-(2,6-dicarbonylpiperidin-3-yl)-2-fluoro-4-(4-fluoro-4- (hydroxymethyl)piperidin-l-yl)benzamide

[0481] 2-(7-Azobenzotriazolyl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (2.96 g, 7.8 mmol) was added to a solution of 2-fluoro-4-(4-fluoro-4- (hydroxymethyl)piperidin-l-yl)benzoic acid (1.4 g, 5.2 mmol), (S)-3-aminopiperidine- 2,6-dione hydrochloride (853 mg, 5.2 mmol), and diisopropylethylamine (2.01 g, 15.6 mmol) in dimethylformamide (25 mL), and the system was stirred at room temperature for 1 h. Water (100 mL) was added to the system, which was washed with ethyl acetate (50 mL x 2), at which time a white solid was precipitated, and the water phase and organic phase were both insoluble. The title compound was filtered as a light yellow solid in 75.1% yield (1.49 g).

[0482] MS (ESI) m / z = 382.1 [M+H] + .

[0483] Step 4: Synthesis of (S)-N-(2,6-dicarbonylpiperidin-3-yl)-2-fluoro-4-(4-fluoro-4- (hydroxymethyl)piperidin-l-yl)benzamide trifluoroacetate

[0484] Dess-Martin reagent (2.48 g, 5.85 mmol) was added to a solution of (S)-N-(2,6-dicarbonylpiperidin-3-yl)-2-fluoro-4-(4-fluoro-4-(hydroxymethyl)piperidin-1-yl)benzamide (1.49 g, 3.9 mmol) in dichloromethane (20 mL) and the mixture was stirred at room temperature for 2 hours. After the reaction was completed, the mother liquor was obtained by suction filtration, the solvent was removed under vacuum and the product was isolated and purified by silica gel column chromatography (methanol / dichloromethane = 0-10%) to give 674 mg of the target compound as a yellow solid in a yield of 45.6%.

[0485] MS (ESI) m / z = 380.1 [M+H]+.

[0486] Synthesis of intermediate B15

[0487]

[0488] Step 1: Synthesis of methyl 2-fluoro-4-(3-fluoro-3-(hydroxymethyl)azetidin-1-yl)benzoate

[0489] A mixture of (3-fluoroazetidin-3-yl)methanol hydrochloride (4.9 g, 34.9 mmol), methyl 2,4-difluorobenzoate (4 g, 23.3 mmol), and potassium carbonate (6.4 g, 46.6 mmol) in DMSO (40 mL) was purged with nitrogen three times, heated to 80 °C and stirred for 2 hours. The reaction was cooled to room temperature, water (300 mL) was added, and the mixture was extracted twice with ethyl acetate (200 mL), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the residue obtained by rotary evaporation under reduced pressure was isolated and purified by flash silica gel column chromatography (petroleum ether-ethyl acetate, 95-90%) to give 1.4 g of the title compound as a white solid in a yield of 23.4%.

[0490] MS (ESI) m / z = 258.0 [M+H] + .

[0491] Step 2: Synthesis of 2-fluoro-4-(3-fluoro-3-(hydroxymethyl)azetidin-1-yl)benzoic acid

[0492] A solution of lithium hydroxide monohydrate (907 mg, 21.6 mmol) in water (20 mL) was added slowly to a solution of methyl 2-fluoro-4-(3-fluoro-3- (hydroxymethyl)azetidin-l-yl)benzoate (1.4 g, 5.4 mmol) in methanol (20 mL), the system was warmed to 50 °C and stirred for 1 h. The reaction was concentrated under reduced pressure to remove methanol, diluted with water (60 ml), and diluted with dilute aqueous hydrochloric acid (1 mol / L) dropwise with stirring until a large amount of precipitate was precipitated, filtered, and the filter cake was washed with water and dried to give 1.1 g of the title compound as a white solid in a yield of 87.0%.

[0493] MS (ESI) m / z = 244.0 [M+H] + .

[0494] Step 3: Synthesis of (S)-N-(2,6-dicarbonylpiperidin-3-yl)-2-fluoro-4-(3-fluoro-3- (hydroxymethyl)azetidin-l-yl)benzamide

[0495] 2-(7-Azobenzotriazolyl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (2.56 g, 6.7 mmol) was added to a solution of 2-fluoro-4-(3-fluoro-3- (hydroxymethyl)azetidin-l-yl)benzoic acid (1.1 g, 4.5 mmol), (S)-3-aminopiperidine- 2,6-dione hydrochloride (738 mg, 5.2 mmol), and diisopropylethylamine (1.74 g, 13.5 mmol) in dimethylformamide (10 mL), and the system was stirred at room temperature for 1 h. Water (50 mL) was added to the system, extracted with ethyl acetate (30 mL x 2), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the residue obtained by rotary evaporation under reduced pressure was separated and purified by flash silica gel column chromatography (petroleum ether-ethyl acetate, 95-90%) to give 1.2 g of the title compound as a white solid in a yield of 77.3%.

[0496] MS (ESI) m / z = 354.1 [M+H] + .

[0497] Step 4: Synthesis of (S)-N-(2,6-dicarbonylpiperidin-3-yl)-2-fluoro-4-(3-fluoro-3- formylazetidin-l-yl)benzamide trifluoroacetate

[0498] Dess-Martin reagent (2.16 g, 5.09 mmol) was added to a solution of (S)-N-(2,6-dicarbonylpiperidin-3-yl)-2-fluoro-4-(3-fluoro-3-(hydroxymethyl)azetidin-1-yl)benzamide (1.2 g, 3.4 mmol) in dichloromethane (20 mL) and the system was stirred at room temperature for 2 hours. After the reaction was completed, the mother liquor was obtained by suction filtration, the solvent was removed under vacuum and the product was isolated and purified by silica gel column chromatography (methanol / dichloromethane = 0-10%) to obtain 462 mg of the compound as a yellow solid, with a yield of 38.7%.

[0499] MS (ESI) m / z = 352.1 [M+H] + .

[0500] Synthesis of intermediate B16

[0501]

[0502] Step 1: Synthesis of methyl 2-fluoro-4-(4-hydroxy-4-(hydroxymethyl)piperidin-1-yl)benzoate

[0503] A mixture of 4-hydroxy-4-piperidinemethanol hydrochloride (5.8 g, 34.9 mmol), methyl 2,4-difluorobenzoate (4 g, 23.3 mmol) and potassium carbonate (6.4 g, 46.6 mmol) in DMSO (40 mL) was replaced with nitrogen three times, the system was heated to 80°C and stirred for 2 hours. The reaction liquid was cooled to room temperature, water (300 mL) was added, extracted with ethyl acetate (200 mL) twice, the organic phase was combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the residue obtained by rotary evaporation under reduced pressure was separated and purified by flash silica gel column chromatography (petroleum ether-ethyl acetate, 95-90%) to obtain 2.4 g of the title compound as a white solid, with a yield of 36.2%.

[0504] MS (ESI) m / z = 284.1 [M+H] + .

[0505] Step 2: Synthesis of 2-fluoro-4-(4-hydroxy-4-(hydroxymethyl)piperidin-1-yl)benzoic acid

[0506] A solution of lithium hydroxide monohydrate (1.43 g, 34 mmol) in water (20 mL) was added slowly to a solution of methyl 2-fluoro-4-(4-hydroxy-4- (hydroxymethyl)piperidin-1-yl)benzoate (2.4 g, 8.5 mmol) in methanol (20 mL), the system was warmed to 50 °C and stirred for 1 h. The reaction was concentrated under reduced pressure to remove methanol, diluted with water (60 ml), and diluted with dilute aqueous hydrochloric acid (1 mol / L) dropwise with stirring until a large amount of precipitate was formed, filtered, and the filter cake was washed with water and dried to give 1.9 g of the title compound as a white solid in 84.0% yield.

[0507] MS (ESI) m / z = 270.1 [M+H] + .

[0508] Step 3: Synthesis of (S)-N-(2,6-dicarbonylpiperidin-3-yl)-2-fluoro-4-(4- hydroxy-4-(hydroxymethyl)piperidin-1-yl)benzamide

[0509] 2-(7-Azobenzotriazolyl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (4.02 g, 10.5 mmol) was added to a solution of 2-fluoro-4-(4-hydroxy-4- (hydroxymethyl)piperidin-1-yl)benzoic acid (1.9 g, 7.0 mmol), (S)-3-aminopiperidine- 2,6-dione hydrochloride (1.15 g, 7.0 mmol) and diisopropylethylamine (2.01 g, 15.6 mmol) in dimethylformamide (30 mL), the system was stirred at room temperature for 1 h. Water (100 mL) was added to the system, washed with ethyl acetate (50 mL x 2), the combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the residue obtained by rotary evaporation under reduced pressure was separated and purified by flash silica gel column chromatography (petroleum ether-ethyl acetate, 95-90%) to give 1.97 g of the title compound as a white solid in 74.3% yield.

[0510] MS (ESI) m / z = 380.1 [M+H] + .

[0511] Step 4: Synthesis of (S)-N-(2,6-dicarbonylpiperidin-3-yl)-2-fluoro-4-(4-hydroxy-4- formylpiperidin-1-yl)benzamide trifluoroacetate

[0512] Dess-Martin reagent (3.3 g, 7.8 mmol) was added to a solution of (S)-N-(2,6-dicarbonylpiperidin-3-yl)-2-fluoro-4-(4-hydroxy-4-(hydroxymethyl)piperidin-1-yl)benzamide (1.97 g, 5.2 mmol) in dichloromethane (20 mL) and the mixture was stirred at room temperature for 2 hours. After the reaction was completed, the mother liquor was obtained by suction filtration, the solvent was removed under vacuum and the product was isolated and purified by silica gel column chromatography (methanol / dichloromethane = 0-10%) to give 702 mg of the compound as a yellow solid in a yield of 35.8%.

[0513] MS (ESI) m / z = 378.1 [M+H] + .

[0514] Synthesis of intermediate B17

[0515]

[0516] Step 1: Synthesis of tert-butyl 4-(3-fluoro-4-(methylcarbomoyl)phenyl)piperazine-1- carboxylate

[0517] A mixture of tert-butyl piperazine-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 was cooled to room temperature, water (300 mL) was added, and the mixture was extracted twice with ethyl acetate (200 mL), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the residue obtained by rotary evaporation under reduced pressure was isolated and purified by flash silica gel column chromatography (petroleum ether-ethyl acetate, 95-90%) to give 3.3 g of the title compound as a white solid in a yield of 41.5%.

[0518] MS (ESI) m / z = 339.1 [M+H] + .

[0519] Step 2: Synthesis of 4-(4-(tert-butoxycarbonyl)piperazin-1-yl)-2-fluorobenzoic acid

[0520] A solution of lithium hydroxide monohydrate (1.58 g, 37.6 mmol) in water (20 mL) was added slowly to a solution of tert-butyl 4-(3-fluoro-4-(methylcarbomoyl)phenyl)piperazine-1- carboxylate (3.3 g, 9.7 mmol) in methanol (20 mL), the system was warmed to 50 °C and stirred for 1 h. The reaction was concentrated under reduced pressure to remove methanol, diluted with water (60 mL), and diluted with dilute aqueous hydrochloric acid (1 mol / L) dropwise with stirring until a large amount of precipitate was formed, filtered, the filter cake was washed with water, and dried to give 2.7 g of the title compound as a white solid in 85.9% yield.

[0521] MS (ESI) m / z = 325.1 [M+H] + .

[0522] Step 3: Synthesis of tert-butyl (S)-4-(4-((2,6-dicarbonylpiperidin-3-yl)carbamoyl)-3- fluorophenyl)piperazine-1-carboxylate

[0523] A solution of 2-(7-azobenzotriazol)-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 system was stirred at room temperature for 1 h. Water (100 mL) was added to the system, washed with ethyl acetate (50 mL x 2), the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the residue obtained by rotary evaporation under reduced pressure was separated and purified by flash column chromatography on silica gel (petroleum ether-ethyl acetate, 95-90%) to give 3.0 g of the title compound as a white solid in 83.4% yield.

[0524] MS (ESI) m / z = 435.2 [M+H] + .

[0525] Step 4: Synthesis of (S)-N-(2,6-dicarbonylpiperidin-3-yl)-2-fluoro-4-piperazin-1- yl)benzamide hydrochloride

[0526] A 4M hydrochloric acid solution in dioxane (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 system was stirred at room temperature for 4 h. The reaction was concentrated under reduced pressure to give 2.2 g of the title compound as a white solid in 95% yield.

[0527] MS (ESI) m / z = 335.1 [M+H] + .

[0528] Synthesis of intermediate B18

[0529]

[0530] Step 1: Preparation of 2-(2,6-dicarbonylpiperidin-3-yl)-5-(2-(hydroxymethyl)-7- azaspiro[3.5]nonan-7-yl)isoindole-1,3-dione

[0531] N,N-diisopropylethylamine (1.87 g, 14.48 mmol) was added to a mixture solution of 2-(2,6-dicarbonylpiperidin-3-yl)-5-fluoroisoindole-1,3-dione (1 g, 3.6 mmol) and (7-azaspiro[3.5]nonan-2-yl)methanol (0.76 g, 3.98 mmol) in dimethyl sulfoxide (10 mL), the system was warmed to 120 °C and stirred for 2 hours. The reaction solution was concentrated under reduced pressure to remove N,N-diisopropylethylamine, the obtained residue was separated and purified by carbon 18 column chromatography (water-acetonitrile, 5-70%) to give 1.2 g of the title compound as a yellow solid with a yield of 80.56%.

[0532] LCMS: Rt = 1.12 min, MS (ESI) m / z = 412.1 [M+H] + .

[0533] Step 2: Preparation of 7-(2-(2,6-dicarbonylpiperidin-3-yl)-1,3-dicarbonylisochromen-5-yl)-7- azaspiro[3.5]nonane-2-carbaldehyde.

[0534] Dess-Martin periodinane (1.42 g, 3.35 mmol) was added portionwise to a solution of 2-(2,6-dicarbonylpiperidin-3-yl)-5-(2-(hydroxymethyl)-7-azaspiro[3.5]nonan-7-yl)isoindole-1,3-dione (1.15 g, 2.79 mmol) in dichloromethane (50 mL), the system was stirred at 25 °C for 1 hour. The system was diluted with dichloromethane, the organic phase was washed successively with aqueous triethylamine (100 mL, 2%) and saturated brine, dried, filtered and concentrated under reduced pressure. The obtained residue was separated and purified by carbon 18 column chromatography (water-acetonitrile, 5-70%, 0.1% trifluoroacetic acid) to give 310 mg of the title compound as a yellow solid with a yield of 18.31%.

[0535] LCMS: Rt = 1.20 min, MS (ESI) m / z = 410.1 [M+H] + .

[0536] 1H NMR (400 MHz, DMSO) δ ppm 11.09 (s, 1H), 9.70 (d, J = 1.6 Hz, 1H), 7.65 (d, J = 8.6 Hz, 1H), 7.33 (d, J = 2.0 Hz, 1H), 7.24 (dd, J = 8.6, 2.2 Hz, 1H), 5.07 (dd, J = 12.9, 5.4 Hz, 1H), 3.42 (m, 4H), 3.22 (m, 1H), 2.88 (m, 1H), 2.56 (dd, J = 18.1, 10.7 Hz, 2H), 1.99 (m, 5H), 1.68 (m, 2H), 1.50 (m, 2H).

[0537] Synthesis of intermediate B19

[0538]

[0539] Step 1 : Preparation of methyl 2-fluoro-4-(4-oxopiperidin-1 -yl)benzoate

[0540] Palladium acetate (352.5 mg, 1.57 mmol) was added to a mixture of piperidin-4-one (1.6 g, 15.7 mmol), methyl 4-bromo-2-fluorobenzoate (3.66 g, 15.7 mmol), 1,1 '-binaphthalene-2,2'-diphenylphosphine (0.98 g, 1.57 mmol) and cesium carbonate (15.35 g, 47.1 mmol) in dry toluene (50 mL), the system was replaced with nitrogen three times, heated to 1 10 °C and stirred for 16 hours. The reaction was cooled to room temperature, water (300 mL) was added, extracted with ethyl acetate (200 mL) twice, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the residue obtained by rotary evaporation under reduced pressure was separated and purified by flash silica gel column chromatography (petroleum ether-ethyl acetate, 10-50%) to give 1.2 g of compound as a yellow solid, with a yield of 30.5%.

[0541] LCMS: Rt = 1.18 min, MS (ESI) m / z = 252.1 [M+H] + .

[0542] Step 2: Preparation of 2-fluoro-4-(4-oxopiperidin-1-yl)benzoic acid

[0543] A solution of lithium hydroxide monohydrate (0.81 g, 19.2 mmol) in water (20 mL) was added slowly to a solution of methyl 2-fluoro-4-(4-oxopiperidin-1-yl)benzoate (1.2 g, 4.8 mmol) in tetrahydrofuran (20 mL), the system was warmed to 50 °C and stirred for 1 h. The reaction was concentrated under reduced pressure to remove tetrahydrofuran, diluted with water (20 ml), and diluted with dilute aqueous hydrochloric acid (1 mol / L) dropwise with stirring until a large amount of precipitate was formed, filtered, the filter cake was washed with water, and dried to give 949 mg of the compound as a white solid in 83.3% yield.

[0544] LCMS: Rt = 1.17 min, MS (ESI) m / z = 238.1 [M+H] + .

[0545] Step 3: Preparation of (S)-N-(2,6-dicarbonylpiperidin-3-yl)-2-fluoro-4-(4- carbonylpiperidin-1-yl)benzamide

[0546] 2-(7-Azobenzotriazol)-N,N,N',N'-tetramethyluronium hexafluorophosphate (2.28 g, 6 mmol) was added in one portion to a solution of 2-fluoro-4-(4-oxopiperidin-1-yl)benzoic acid (949 mg, 4 mmol), (S)-3-aminopiperidine-2,6-dione hydrochloride (0.66 g, 4 mmol), and diisopropylethylamine (1.55 g, 12 mmol) in dimethylformamide (20 mL), the system was stirred at room temperature for 1 h. Water (300 mL) was added to the system, extracted twice with ethyl acetate (100 mL), the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the residue obtained by rotary evaporation under reduced pressure was separated and purified by flash column chromatography on silica gel (methanol / dichloromethane, 0-10%) to give 1.02 g of the title compound as a yellow solid in 73.8% yield.

[0547] LCMS: Rt = 1.605 min, MS (ESI) m / z = 348.1 [M+H] + .

[0548] Synthesis of Intermediate B20

[0549]

[0550] Step 1: Preparation of tert-butyl 4-(1-((benzyloxy)carbonyl)azetidin-3-yl)piperazine-1- carboxylate

[0551] N,N-diisopropylethylamine (18.87 g, 0.15 mol) was added to a solution of tert-butyl piperazine-1 -carboxylate (13.5 g, 0.073 mol) and benzyl 3-oxobutane-1 -carboxylate (14.98 g, 0.073 mol) in tetrahydrofuran (100 mL) and stirred at 25 °C for 10 min. Sodium triacetoxyborohydride (46.41 g, 0.22 mol) was then added portionwise to the reaction and stirred at 25 °C for 4 h. The reaction was concentrated under reduced pressure to remove N,N-diisopropylethylamine and the resulting residue was purified by flash column chromatography on silica gel (petroleum ether-ethyl acetate, 95-90%) to give 7.6 g of the title compound as an off-white solid in 27.8% yield.

[0552] MS (ESI) m / z = 376.2 [M+H] + .

[0553] Step 2: Preparation of tert-butyl 4-(azetidin-3-yl)piperazine-1-carboxylate

[0554] Palladium on carbon (2.02 g, 10%) was added to a solution of tert-butyl 4-(1- ((benzyloxy)carbonyl)azetidin-3-yl)piperazine-1-carboxylate (7.6 g, 20.2 mmol) in methanol (80 mL) under a hydrogen atmosphere and stirred at room temperature for 2 h. The reaction was filtered and the filter cake was rinsed with methanol and the filtrate was concentrated under reduced pressure to give 4.5 g of the title compound as a colourless oil in 92.3% yield which was used directly in the next step.

[0555] MS (ESI) m / z = 242.1 [M+H] + .

[0556] Step 3: Preparation of tert-butyl 4-(1-(2-(2,6-dicarbonylpiperidin-3-yl)-1,3- dicarbonylisobenzofuran-5-yl)azetidin-3-yl)piperazine-1-carboxylate.

[0557] 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) and heated to 120 °C and stirred for 2 h. The reaction was concentrated under reduced pressure to remove N,N-diisopropylethylamine and the resulting residue was purified by column chromatography on carbon 18 (water (0.1% formic acid)-acetonitrile, 100-50%) to give 1.2 g of the title compound as a yellow solid in 69.8% yield.

[0558] MS (ESI) m / z = 498.2 [M+H]+ .

[0559] Step 4: Preparation of 2-(2,6-dicarbonylpiperidin-3-yl)-5-(3-(piperazin-l- yl)azetidin-l-yl)isoindole-l,3-dione hydrochloride

[0560] To a solution of tert-butyl 4-(l-(2-(2,6-dicarbonylpiperidin-3-yl)-l,3-dicarbonylisoindol-5- yl)azetidin-3-yl)piperazine-l-carboxylate (1.2 g, 2.4 mmol) in dichloromethane (20 mL) was added dropwise a 4 M hydrochloric acid solution in dioxane (4 mL) at 0 °C, and the mixture was stirred at room temperature for 4 h. The reaction solution was concentrated under reduced pressure to give 2.2 g of a yellow solid.

[0561] The system was stirred at room temperature for 4 h. The reaction solution was concentrated under reduced pressure to give 2.2 g of a yellow solid.

[0562] MS (ESI) m / z = 398.1 [M+H] + .

[0563] Synthesis of Intermediate B21

[0564]

[0565] Step 1: Preparation of tert-butyl 8-(2-(2,6-dicarbonylpiperidin-3-yl)-l,3-dicarbonylisoindol-5-yl)- 2,8-diazaspiro[4.5]decane-2-carboxylate

[0566] To a solution of 2-(2,6-dicarbonylpiperidin-3-yl)-5-fluoroisoindole-l,3-dione (1.00 g, 3.62 mmol) and tert-butyl 2,8-diazaspiro[4.5]decane-2-carboxylate (2.08 g, 8.69 mmol) in dimethyl sulfoxide (10 mL) was added N,N-diisopropylethylamine (2.34 g, 18.10 mmol) and the mixture was heated to 120 °C and stirred for 2 h. The reaction solution was concentrated under reduced pressure to remove N,N-diisopropylethylamine and the resulting residue was separated and purified by column chromatography on carbon 18 (water (0.1% formic acid) - acetonitrile, 100-50%) to give 1.35 g of the title compound as a yellow solid in a yield of 75.2%.

[0567] MS (ESI) m / z = 497.2 [M+H] +

[0568] Step 2: Preparation of 2-(2,6-dicarbonylpiperidin-3-yl)-5-(2,8-diazaspiro[4.5]dec-8-yl)isoindole- 1,3-dione

[0569] To a solution of tert-butyl 8-(2-(2,6-dicarbamoylpiperidin-3-yl)-l,3- dicarbamoylisindolin-5-yl)-2,8-diazaspiro[4.5]decane-2-carboxylate (1.35 g, 2.7 mmol) in dichloromethane (20 mL) was added dropwise 4M hydrochloric acid in dioxane (4 mL) and the mixture was stirred at room temperature for 4 hours. The solution was concentrated under reduced pressure to give 1.1 g of a yellow solid.

[0570] MS (ESI) m / z = 397.2 [M+H] + .

[0571] Synthesis of intermediate B22

[0572]

[0573] Step 1: Preparation of (l-(4-nitrophenyl)piperidin-4-yl)methanol

[0574] Potassium carbonate (8.81 g, 63.75 mmol) was added to a solution of l-fluoro-4- nitrobenzene (6 g, 42.5 mmol) and piperidin-4-ylmethanol (4.89 g, 42.5 mmol) in N,N- dimethylformamide (60 mL), the system was replaced with nitrogen three times, heated to 90 °C and stirred for 5 hours. After the reaction was completed, it was cooled to room temperature, diluted with water (100 mL), extracted with ethyl acetate (50 mL*3), the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and then separated and purified by flash silica gel column chromatography (petroleum ether / ethyl acetate, 40-60%) to give 8.9 g of the title compound as an orange solid in a yield of 86.59%.

[0575] LCMS: Rt = 1.14 min, MS (ESI) m / z = 237.2 [M+H] + .

[0576] Step 2: Preparation of (l-(4-aminophenyl)piperidin-4-yl)methanol

[0577] Palladium on carbon catalyst (7.83 g, 7.36 mmol, 10%) was added to a solution of (l-(4-nitrophenyl)piperidin-4-yl)methanol (8.7 g, 36.8 mmol) in methanol (200 mL), the system was replaced with hydrogen three times, and then stirred at 25 °C for 4 hours. The reaction solution was filtered through diatomite, and the filtrate was concentrated under reduced pressure to give 6.8 g of the title compound as a pink solid in a yield of 86.41%.

[0578] LCMS: Rt = 0.22 min, MS (ESI) m / z = 207.2 [M+H] + .

[0579] Step 3: Preparation of (1-(4-(2,4-dicarbonyltetrahydro pyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)methyl acetate

[0580] 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) was added glacial acetic acid (4.70 g, 78.2 mmol), the system was replaced 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 system was replaced with nitrogen three times, then heated to 120°C and stirred for 20 h. After the reaction was completed and cooled to room temperature, hydrochloric acid (14 ml) was added, heated to 120°C and stirred for 1 h. After the reaction was completed and cooled to room temperature, water (100 ml) was added to dilute, the pH was adjusted to 8 with saturated sodium bicarbonate solution, extracted with ethyl acetate (100 mL*3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by flash silica gel column chromatography (ethyl acetate / petroleum ether, 40-60%) to give 5 g of the title compound as a pink solid with a yield of 23.03%.

[0581] LCMS: Rt = 0.92 min, MS (ESI) m / z = 346.3 [M+H] + .

[0582] Step 4: Preparation of 1-(4-(4-(hydroxymethyl)piperidin-1-yl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione

[0583] A solution of (1-(4-(2,4-dicarbonyltetrahydro pyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)methyl acetate (5 g, 0.0072 mol) in hydrochloric acid (50 ml, 2 mol / L) was prepared, the system was replaced with nitrogen three times, then heated to 100°C and stirred for 16 h. After the reaction was completed and cooled to room temperature, water (50 ml) was added to dilute, the pH was adjusted to 8 with saturated sodium bicarbonate solution, extracted with ethyl acetate (100 mL*3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by flash silica gel column chromatography (ethyl acetate / petroleum ether, 40-60%) to give 3 g of the title compound as a pink solid with a yield of 68.06%.

[0584] LCMS: Rt = 0.37 min, MS (ESI) m / z = 304.3 [M+H] + .

[0585] Step 5: Preparation of 1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidine- 4-carbaldehyde trifluoroacetate salt

[0586] Dess-Martin periodinane (5.09 g, 12 mmol, 10%) was added portionwise over a period of one hour to a solution of 1-(4-(4-(hydroxymethyl)piperidin-1-yl)phenyl)dihydropyrimidine- 2,4(1H,3H)-dione (1.2 g, 0.004 mol) in N,N-dimethylformamide (30 mL) and the system was purged with nitrogen three times, then stirred at 25 °C for 2 hours. After the reaction was completed, water (100 ml) was added for dilution, and the filter cake was concentrated under reduced pressure and separated and purified by carbon 18 column chromatography (water-acetonitrile, 7-93%, 0.1% trifluoroacetic acid) to obtain 347 mg of the title compound as a brown solid, with a yield of 31.44%.

[0587] LCMS: Rt = 0.72 min, MS (ESI) m / z = 302.1 [M+H] + .

[0588] 1 H NMR (400 MHz, DMSO) δ ppm 10.33 (s, 1H), 9.64 (s, 1H), 7.21 (t, J = 22.7 Hz, 4H), 3.72 (t, J = 6.7 Hz, 2H), 3.67 - 3.55 (m, 2H), 3.03 (s, 2H), 2.68 (t, J = 6.7 Hz, 2H), 2.57 (t, J = 10.6 Hz, 1H), 2.00 (d, J = 11.1 Hz, 2H), 1.67 (dd, J = 21.2, 10.7 Hz, 2H).

[0589] Synthesis of Intermediate B23

[0590]

[0591] Step 1: tert-Butyl 4-(4-chloro-2-fluorophenyl)-3,6-dihydropyridine-1(2H)-carboxylate

[0592] Tetrakis(triphenylphosphine)palladium (0.89 g, 0.77 mmol) was added to a solution of 1-bromo-4-chloro-2-fluorobenzene (1.6 g, 7.7 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-l(2H)- carboxylate (3.57 g, 11.6 mmol) and sodium carbonate (2.45 g, 23.1 mmol) in dioxane (40 mL), water (10 mL) was added, the system was purged with nitrogen three times, then heated to 90 °C and stirred for 16 h. The reaction was cooled to room temperature, dioxane was removed by rotary evaporation under reduced pressure, diluted with water (150 mL), extracted with ethyl acetate (100 mL*2), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (ethyl acetate / petroleum ether, 0-20%) to give the title compound as a white solid (2.0 g, 85.7% yield).

[0593] MS (ESI) m / z = 312.1 [M+H] + .

[0594] Step 2: tert-Butyl 4-(4-((2,6-bis(benzyloxy)pyridin-3-yl)amino)-2-fluorophenyl)-3,6- dihydropyridine-l(2H)-carboxylate

[0595] Tetrakis(triphenylphosphine)palladium (0.89 g, 0.77 mmol) was added to a solution of 1-bromo-4-chloro-2-fluorobenzene (1.6 g, 7.7 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-l(2H)- carboxylate (3.57 g, 11.6 mmol) and sodium carbonate (2.45 g, 23.1 mmol) in dioxane (40 mL), water (10 mL) was added, the system was purged with nitrogen three times, then heated to 90 °C and stirred for 16 h. The reaction was cooled to room temperature, dioxane was removed by rotary evaporation under reduced pressure, diluted with water (150 mL), extracted with ethyl acetate (100 mL*2), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (ethyl acetate / petroleum ether, 0-20%) to give the title compound as a white solid (2.0 g, 85.7% yield).

[0596] MS (ESI) m / z = 582.2 [M+H] + .

[0597] Step 3: tert-Butyl 4-(4-((2,6-dicarbonylpiperidin-3-yl)amino)-2-fluorophenyl)piperidine-l- carboxylate

[0598] Palladium on carbon catalyst (510 mg, 0.48 mmol, 10%) was added to a solution of tert-butyl 4-(4-((2,6-di(benzyloxy)pyridin-3-yl)amino)-2-fluorophenyl)-3,6- dihydropyridine-1(2H)-carboxylate (1.4 g, 2.4 mmol) in ethyl acetate (50 mL), the system was purged with hydrogen three times, then stirred at 25 °C for 60 hours. The reaction was filtered through celite, the filtrate was concentrated under reduced pressure to give 882 mg of the title compound as a blue solid, with a yield of 90.5%.

[0599] MS (ESI) m / z = 406.2 [M+H + .

[0600] Step 4: Preparation of 3-((4-(piperidin-4-yl)-3-fluorophenyl)amino)piperidine- 2,6-dione trifluoroacetate salt

[0601] Trifluoroacetic acid (1 mL) was added dropwise to a solution of tert-butyl 4-(4-((2,6-dicarbonylpiperidin-3-yl)amino)-2-fluorophenyl)piperidine-1- carboxylate (882 mg, 2.1 mmol) in dichloromethane (10 mL), the system was stirred at 25 °C for 2 hours. The reaction was concentrated under reduced pressure to remove the solvent, and separated and purified by carbon 18 column chromatography (water-acetonitrile, 5-50%, 0.1% trifluoroacetic acid) to give 690 mg of the title compound as an off-white solid, with a yield of 54.3%.

[0602] MS (ESI) m / z = 306.1 [M+H] + .

[0603] Synthesis of intermediate B24

[0604]

[0605] Step 1: Preparation of 2,6-di(benzyloxy)-3-(4-bromo-2-fluoro-6- methoxyphenyl)pyridine

[0606] 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) was added tetrakis(triphenylphosphine)palladium (0.89 g, 0.77 mmol), water (10 mL) was added, the system was purged with nitrogen three times, then heated to 90 °C and stirred for 16 h. The reaction was cooled to room temperature, dioxane was removed by rotary evaporation under reduced pressure, diluted with water (150 mL), extracted with ethyl acetate (100 mL*2), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (ethyl acetate / petroleum ether, 0-20%) to give 2.0 g of the title compound as a white solid in 85.7% yield.

[0607] MS (ESI) m / z = 494.1 [M+H] + .

[0608] Step 2: Preparation of 2,6-bis(benzyloxy)-3-(4-(4-(dimethoxymethyl)piperidin-1-yl)-2- fluoro-6-methoxyphenyl)pyridine

[0609] To a solution of 2,6-bis(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) were added successively tris(dibenzylideneacetone)dipalladium (354.36 mg, 0.39 mmol), 2-bis(cyclohexylphosphino)-2',6'-dimethoxybiphenyl (238.29 mg, 0.58 mmol), and cesium carbonate (3.78 g, 11.6 mmol), the system was purged with nitrogen three times, then heated to 110 °C and stirred for 10 h. The system was cooled to room temperature, diluted with water (500 mL), extracted with ethyl acetate (200 mL*2), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (ethyl acetate / petroleum ether, 0-20%) to give 956.7 mg of the title compound as a yellow oil in 43.2% yield.

[0610] MS (ESI) m / z = 573.3 [M+H] + .

[0611] Step 3: Preparation of 3-(4-(4-(dimethoxymethyl)piperidin-1-yl)-2-fluoro-6- methoxyphenyl)piperidine-2,6-dione

[0612] A 10% palladium carbon catalyst (96 mg) was added to a solution of 2,6-di(benzyloxy)-3-(4-(4-(dimethoxymethyl)piperidin-l-yl)-2-fluoro-6-methoxyphenyl)pyridine (956.7 mg, 1.67 mmol) in ethyl acetate (50 mL), the system was purged with hydrogen three times, then stirred at 25 °C for 60 hours. The reaction was filtered through celite, the filtrate was concentrated under reduced pressure to obtain 497.0 mg of the title compound as a blue solid, with a yield of 75.5%.

[0613] MS (ESI) m / z = 395.2 [M+H] + .

[0614] Step 4: Preparation of l-(4-(2,6-dicarbonylpiperidin-3-yl)-3-fluoro-5- methoxyphenyl)piperidine-4-carbaldehyde

[0615] Trifluoroacetic acid (2 mL) was added dropwise to a solution of 3-(4-(4- (dimethoxymethyl)piperidin-l-yl)-2-fluoro-6-methoxyphenyl)piperidine-2,6-dione (497 mg, 1.26 mmol) in dichloromethane (10 mL), the system was stirred at 25 °C for 2 hours. The reaction was concentrated under reduced pressure to remove the solvent, and separated and purified by carbon 18 column chromatography (water-acetonitrile, 5-50%, 0.1% trifluoroacetic acid) to obtain 170 mg of the title compound as an off-white solid, with a yield of 38.9%.

[0616] MS (ESI) m / z = 349.1 [M+H] + .

[0617] Synthesis of intermediate B25

[0618]

[0619] Step 1: Preparation of l-(2,6-dicarbonylpiperidin-3-yl)-3-methyl-2-oxo-2,3- dihydro-lH-benzo[d]imidazole-4-carbaldehyde

[0620] To a solution of 3-(4-bromo-3-methyl-2-oxo-2,3-dihydro-lH-benzo[d]imidazol-l- yl)piperidine-2,6-dione (1.40 g, 4.14 mmol) in N,N-dimethylformamide (60 mL) was added triethylamine (1.26 g, 12.42 mmol), triethylsilane (1.44 g, 12.42 mmol) and Pd(dppf)Cl2(1.20 g, 1.66 mmol) sequentially. The reaction was heated to 120 °C under carbon monoxide (50 Psi) for 16 h. The reaction was filtered and the filtrate was evaporated under reduced pressure to give a residue which was purified by column chromatography on carbon 18 (water (0.1% formic acid) - acetonitrile, 5-40%) to give 870 mg of the title compound as a light yellow solid.

[0621] LCMS: Rt = 0.97 min, MS (ESI) m / z = 288.1 [M+H] + .

[0622] Step 2: Preparation of tert-butyl (l-((l-(2,6-dicarbonylpiperidin-3-yl)-3-methyl-2- oxo-2,3-dihydro-lH-benzo[d]imidazol-4-yl)methyl)piperidin-4-yl)(methyl)carbamate.

[0623] To a solution of l-(2,6-dicarbonylpiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-lH- benzo[d]imidazole-4-carbaldehyde (870 mg, 2.12 mmol) and tert-butyl methyl(piperidin-4- yl)carbamate (1363 mg, 6.36 mmol) in N,N-dimethylformamide (70 mL) and tetrahydrofuran (70 mL) was added tetraisopropyl titanate (1205 mg, 4.24 mmol) and the reaction was heated to 50 °C for 16 h. Sodium triacetoxyborohydride (1348 mg, 6.36 mmol) was then added to the reaction and stirred at room temperature for 0.5 h. The reaction was evaporated under reduced pressure to give a residue which was purified by column chromatography on carbon 18 (water (0.1% trifluoroacetic acid) - acetonitrile, 5-40%) to give 600 mg of the title compound as a light yellow solid in 40.8% yield.

[0624] LCMS: Rt = 0.96 min, MS (ESI) m / z = 486.1 [M+H] + .

[0625] Step 3: Preparation of 3-(3-methyl-4-((4-(methylamino)piperidin-l-yl)methyl)-2- oxo-2,3-dihydro-lH-benzo[d]imidazol-l-yl)piperidine-2,6-dione trifluoroacetate salt.

[0626] tert-Butyl (1-((1-(2,6-dicarbomylpiperidin-3-yl)-3-methyl-2-carbomyl-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, the solution was stirred at 25 °C for 1 hour under nitrogen protection. The reaction solution was rotary evaporated under reduced pressure to get the crude product, which was separated and purified by carbon 18 column chromatography (water (0.1 trifluoroacetic acid) - acetonitrile, 100-88%) to get the crude product, and then separated and purified by carbon 18 column chromatography (water (0.1 trifluoroacetic acid) - acetonitrile, 0-6%) to get 310 mg of the title compound as a yellow solid, with a yield of 58.36%.

[0627] LCMS: Rt = 0.32 min, MS (ESI) m / z = 386.1 [M+H] + .

[0628] 1 H NMR (400 MHz, DMSO) δ ppm 11.14 (s, 1H), 9.85 (s, 1H), 9.02 (s, 2H), 7.34 - 7.03 (m, 3H), 5.44 (dd, J = 12.5, 5.2 Hz, 1H), 4.60 (s, 2H), 3.66 - 3.37 (m, 5H), 3.21 (s, 3H), 2.89 (dd, J = 20.8, 9.5 Hz, 1H), 2.81 - 2.53 (m, 5H), 2.21 (s, 2H), 2.05 - 1.95 (m, 1H), 1.72 (s, 2H).

[0629] Synthesis of intermediate B26

[0630]

[0631] Step 1: Preparation of 1-(6-(4-(dimethoxymethyl)piperidin-1-yl)-1-methyl-1H-indazol-3-yl) dihydropyrimidine-2,4(1H,3H)-dione

[0632] Cesium carbonate (7.53 g, 23.1 mmol) was added to a solution of 1-(6-bromo-1- methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (2.5 g, 7.7 mmol) and 4-(dimethoxymethyl)piperidine (1.23 g, 7.7 mmol) in 1,4-dioxane (30 mL), stirred at room temperature for 15 min, then added methylsulfonic 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-dicyclohexylphospho-2',6'- diisopropoxy-1,1'-biphenyl (0.54 g, 1.1 mmol), the system was replaced with nitrogen three times, heated to 100 °C and stirred for 16 h. After the reaction was completed, it was cooled to room temperature, diluted with water (100 mL), extracted with ethyl acetate (100 mL*3), the combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, then separated and purified by flash silica gel column chromatography (petroleum ether / ethyl acetate, 30-70%) to give 1.1 g of the title compound as a yellow oil, with a yield of 20.78%.

[0633] LCMS: Rt = 1.00 min, MS (ESI) m / z = 402.0 [M+H] + .

[0634] Step 2: Preparation of 1-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H- indazol-6-yl)piperidine-4-carbaldehyde trifluoroacetate

[0635] 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 system was stirred at 25 °C for 1 h. The reaction was concentrated under reduced pressure at low temperature, then separated and purified by carbon 18 column chromatography (water-acetonitrile, 20-80%, 0.1% trifluoroacetic acid) to give 534.8 mg of the title compound as a white solid, with a yield of 58.2%.

[0636] LCMS: Rt = 0.90 min, MS (ESI) m / z = 356.1 [M+H] + .

[0637] 1H NMR (400 MHz, DMSO) δ ppm 10.51 (s, 1H), 9.66 (s, 1H), 7.47 (d, J = 8.7 Hz, 1H), 6.94 (d, J = 8.1 Hz, 2H), 3.91 - 3.87 (m, 5H), 3.70 (dd, J = 8.9, 3.8 Hz, 2H), 2.97 (s, 2H), 2.73 (t, J = 6.7 Hz, 2H), 2.55 (d, J = 10.4 Hz, 1H), 1.98 (d, J = 12.8 Hz, 2H), 1.67 (t, J = 10.8 Hz, 2H).

[0638] Synthesis of intermediate B27

[0639]

[0640] Step 1: Preparation of 2-(2,6-dicarbonylpiperidin-3-yl)-5-(3- (hydroxymethyl)azetidin-l-yl)isoindole-l,3-dione

[0641] N,N-diisopropylethylamine (2.52 g, 19.55 mmol) was added to a solution of 2-(2,6-dicarbonylpiperidin-3-yl)-5-fluoroisoindole-l,3-dione (1.8 g, 6.51 mmol) and azetidin-3-ylmethanol hydrochloride (805.32 mg, 6.51 mmol) in dimethyl sulfoxide (15 mL) and heated to 120 °C with stirring for 2 hours. Water (90 ml, 50V) was poured into the reaction liquid and extracted with ethyl acetate (90 ml, 50V) three times, the organic phase was combined, the solvent was removed under vacuum and purified by silica gel column chromatography (methanol / dichloromethane = 0-10%) to obtain 1.5 g of the target compound as a yellow solid with a yield of 65.03%.

[0642] MS (ESI) m / z = 344.1 [M+H] + .

[0643] Step 2: l-(2-(2,6-dicarbonylpiperidin-3-yl)-l,3-dicarbonylisochromen-5-yl)azetidine-3- carbaldehyde

[0644] Dess-Martin reagent (3.21 g, 7.57 mmol) was added to a solution of 2-(2,6-dicarbonylpiperidin-3-yl)-5-(3-(hydroxymethyl)azetidin-l-yl)isoindole-l,3-dione (1.3 g, 3.79 mmol) in dichloromethane (20 mL) and reacted at room temperature for 2 hours. After the reaction was completed, the mother liquor was obtained by suction filtration, the solvent was removed under vacuum and purified by silica gel column chromatography (methanol / dichloromethane = 0-10%, 1% triethylamine) to obtain 619.8 mg of the target compound as a yellow solid with a yield of 44.89%.

[0645] LCMS: Rt = 0.979 min, MS (ESI) m / z = 342.1 [M+H] + .

[0646] 1H NMR (400 MHz, DMSO) δ ppm 11.05 (s, 1H), 9.80 (d, J = 1.7 Hz, 1H), 7.66 - 7.60 (m, 1H), 6.82 (d, J = 2.0 Hz, 1H), 6.68 (dd, J = 8.3, 2.1 Hz, 1H), 5.02 (dt, J = 10.8, 5.4 Hz, 1H), 4.18 - 4.09 (m, 4H), 3.70 - 3.61 (m, 1H), 2.84 (ddd, J = 17.4, 14.1, 5.5 Hz, 1H), 2.51 (ddd, J = 9.6, 8.5, 2.4 Hz, 2H), 2.01 - 1.93 (m, 1H).

[0647] Synthesis of intermediate B28

[0648]

[0649] Step 1: Preparation of methyl 3-bromo-6-(bromomethyl)-2-fluorobenzoate

[0650] Bromosuccinimide (3.95 g, 22.2 mmol) was added portionwise to a solution of methyl 3-bromo-2-fluoro-6-methylbenzoate (5 g, 20.2 mmol) and azodiisobutyronitrile (0.33 g, 2.0 mmol) in 1,2-dichloroethane (100 mL) and the system was stirred at 85 °C for 16 h. The reaction was cooled to room temperature and washed successively with water (100 mL) and saturated brine, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure to give 5.5 g of the crude title compound as a yellow oil in 77.4% yield.

[0651] MS (ESI) m / z = no MS signal.

[0652] Step 2: Preparation of 3-(6-bromo-7-fluoro-1-carboxyisoindolin-2-yl)piperidine-2,6- dione

[0653] Methyl 3-bromo-6-(bromomethyl)-2-fluorobenzoate (5.5 g, 15.2 mmol) was added to a solution of 3-amino-2,6-piperidinedione hydrochloride (3.75 g, 22.8 mmol) and diisopropylethylamine (5.89 g, 45.6 mmol) in dimethylformamide (100 mL) and the system was stirred at 100 °C for 10 h. The cooled reaction solution was added to water (300 mL) and filtered, the filter cake was dissolved in a mixture of ethyl acetate (30 mL) and petroleum ether (150 mL), stirred at room temperature for 10 min, filtered and the filter cake was dried to give 3.7 g of the title compound as a brown solid in 70.4% yield.

[0654] MS (ESI) m / z = 341.0, 343.0 [M+H] + .

[0655] Step 3: Preparation of 3-(6-(4-(dimethoxymethyl)piperidin-l-yl)-7-fluoro-l- carbonylisochromane-2-yl)piperidine-2,6-dione

[0656] (SP-4-1)-[l,3-bis[2,6-bis(l-propylbutyl)phenyl]-4,5-dichloro-l,3-dihydro-2H- imidazol-2-ylidene]dichloropalladium (0.58 g, 0.6 mmol) was added to a mixture of 3-(6-bromo-7-fluoro-l-carbonylisochromane-2-yl)piperidine-2,6-dione (3.4 g, 10.0 mmol), 4-(dimethoxymethyl)piperidine (2.39 g, 15.0 mmol) and cesium carbonate (9.77 g, 30.0 mmol) in dioxane (80 mL), the system was purged with nitrogen three times, heated to 100 °C and stirred for 3 h. The reaction solution was cooled to room temperature, diluted with dioxane and filtered, the filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (methanol / dichloromethane, 0-10%) to give 1.9 g of the title compound as a brown solid in 45.0% yield.

[0657] MS (ESI) m / z = 420.2 [M+H] + .

[0658] Step 4: Preparation of l-(2-(2,6-dicarbonylpiperidin-3-yl)-4-fluoro-3- carbonylisochromane-5-yl)piperidine-4-carbaldehyde

[0659] Trifluoroacetic acid (10 mL) was added dropwise to a solution of 3-(6-(4- (dimethoxymethyl)piperidin-l-yl)-7-fluoro-l-oxoisoindolin-2-yl)piperidine-2,6-dione (1.9 g, 4.5 mmol) in dichloromethane (30 mL) and the system was stirred at room temperature for 1 hour. The reaction was concentrated under reduced pressure to remove the solvent to give a residue which was separated and purified by column chromatography on carbon 18 (water (0.1% trifluoroacetic acid) - acetonitrile, 0-35%) to give 1.54 g of the title compound as a white solid in a yield of 66.7%.

[0660] MS (ESI) m / z = 374.1 [M+H] + .

[0661] Synthesis of intermediate B29

[0662]

[0663] Step 1: Preparation of 2-(2,6-dicarbonylpiperidin-3-yl)-5-(3- (hydroxymethyl)pyrrolidin-l-yl)isoindole-l,3-dione

[0664] N,N-diisopropylethylamine (2.52 g, 19.55 mmol) was added to a solution of 2-(2,6-dicarbonylpiperidin-3-yl)-5-fluoroisoindole-l,3-dione (1.8 g, 6.51 mmol) and pyrrolidin-3-ylmethanol (659.12 mg, 6.51 mmol) in dimethyl sulfoxide (15 mL) and heated to 120 °C and stirred for 2 hours. Water (90 ml, 50V) was poured into the reaction and extracted with ethyl acetate (90 ml, 50V) three times, the organic phases were combined, the solvent was removed under vacuum and separated and purified by column chromatography on silica gel (methanol / dichloromethane = 0-10%) to give 1.5 g of the target compound as a yellow solid in a yield of 64.41%.

[0665] MS (ESI) m / z = 358.1 [M+H] + .

[0666] Step 2: Preparation of l-(2-(2,6-dicarbonylpiperidin-3-yl)-l,3-dicarbonylisoindol-5- yl)pyrrolidin-3-formaldehyde.

[0667] Dess-Martin reagent (3.08 g, 7.27 mmol) was added to a solution of 2-(2,6-dicarbonylpiperidin-3-yl)-5-(3-(hydroxymethyl)pyrrolidin-1-yl)isoindole-1,3-dione (1.3 g, 3.63 mmol) in dichloromethane (20 mL) and reacted at room temperature for 2 hours. After the end of the reaction, the mother liquor was extracted by suction filtration, the solvent was removed under vacuum and the product was isolated and purified by column chromatography on silica gel (methanol / dichloromethane = 0-10%, 1% triethylamine) to obtain 287 mg of the target compound as a yellow solid with a yield of 21.5%.

[0668] LCMS: Rt = 1.023 min, MS (ESI) m / z = 356.1 [M+H] + .

[0669] 1H NMR (400 MHz, DMSO) δ ppm 11.05 (s, 1H), 9.80 (d, J = 1.7 Hz, 1H), 7.66 - 7.60 (m, 1H), 6.82 (d, J = 2.0 Hz, 1H), 6.68 (dd, J = 8.3, 2.1 Hz, 1H), 5.02 (dt, J = 10.8, 5.4 Hz, 1H), 4.18 - 4.09 (m, 4H), 3.70 - 3.61 (m, 1H), 2.84 (ddd, J = 17.4, 14.1, 5.5 Hz, 1H), 2.51 (ddd, J = 9.6, 8.5, 2.4 Hz, 2H), 2.01 - 1.93 (m, 1H).

[0670] Synthesis of intermediate B30

[0671]

[0672] Step 1: Synthesis of 1-(4-bromo-2,6-difluorophenyl)dihydropyrimidine-2,4(1H,3H)-dione

[0673] To a solution of 4-bromo-2,6-difluoroaniline (6.83 g, 0.0330 mol) and acrylic acid (2.38 g, 0.033 mol) in water (8 ml) was added glacial acetic acid (4.70 g, 0.0782 mol) and 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 mol) in glacial acetic acid (70 ml) was added, the system was purged with nitrogen three times, then heated to 120°C and stirred for 20 h. After the reaction was completed and cooled to room temperature, hydrochloric acid (14 ml) was added, heated to 120°C and stirred for 1 h. After the reaction was completed and cooled to room temperature, water (100 ml) was added to dilute, the pH was adjusted to 8 with saturated sodium bicarbonate solution, extracted with ethyl acetate (100 mL*3), the organic phase was combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by flash column chromatography on silica gel (ethyl acetate / petroleum ether, 40-60%) to give 2.7 g of the title compound as a yellow solid, with a yield of 27.2%.

[0674] LCMS: MS (ESI) m / z = 305.1, 307.1 [M+H] +

[0675] Step 2: Synthesis of 1-(4-(4-(dimethoxymethyl)piperidin-1-yl)-2,6-difluorophenyl) dihydropyrimidine-2,4(1H,3H)-dione

[0676] To a solution of 1-(4-bromo-2,6-difluorophenyl) dihydropyrimidine-2,4(1H,3H)-dione (2.2 g, 0.0073 mol) and 4-(dimethoxymethyl)piperidine (1.36 g, 0.0073 mol) in 1,4-dioxane (30 ml) was added cesium carbonate (7.14 g, 0.0219 mol), stirred at room temperature for 15 min, then added methyl sulfonic acid (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl) (2-amino-1,1'-biphenyl-2-yl) palladium (II) (0.92 g, 0.0011 mol) and 2-dicyclohexylphosphine-2',6'-diisopropoxy-1,1'-biphenyl (0.51 g, 0.0011 mol), the system was purged with nitrogen three times, heated to 100°C and stirred for 16 h. After the reaction was completed and cooled to room temperature, water (100 ml) was added to dilute, extracted with ethyl acetate (50 ml*3), the organic phase was combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by flash column chromatography on silica gel (petroleum ether / ethyl acetate, 30-70%) to give 872.7 mg of the title compound as a yellow solid, with a yield of 31.2%.

[0677] LCMS: MS (ESI) m / z = 384.2 [M+H]+

[0678] Step 3: Synthesis of 1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-3,5- difluorophenyl)piperidine-4-carbaldehyde

[0679] Trifluoroacetic acid (10 mL) was added dropwise to a solution of 1-(4-(4- (dimethoxymethyl)piperidin-1-yl)-2,6-difluorophenyl)dihydropyrimidine-2,4(1H,3H)- dione (1.1 g, 2.9 mmol) in dichloromethane (10 mL) and the system was stirred at room temperature for 2 hours. After the reaction solution was rotary evaporated under reduced pressure, it was separated and purified by carbon 18 column chromatography (water-acetonitrile, 15%~85%, 0.1% trifluoroacetic acid) to give 696.7 mg of the title compound as a white solid in a yield of 62.7%.

[0680] LCMS: MS (ESI) m / z = 338.1 [M+H] +

[0681] Synthesis of Intermediate B31

[0682]

[0683] Step 1: Synthesis of 2,6-bis(benzyloxy)-3-(4-bromophenyl)pyridine

[0684] Potassium carbonate (3.65 g, 26.4 mmol) and 1,1-bis(diphenylphosphino) ferrocene palladium dichloride (0.97 g, 1.32 mmol) were added to a solution of 1-bromo-4- iodobenzene (2.5 g, 8.8 mmol) and 2,6-bis(benzyloxy)-3-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)pyridine (4.41 g, 10.56 mmol) in dioxane (50 mL) in turn, water (10 mL) was added, the system was replaced with nitrogen three times, then heated to 90°C and stirred for 16 hours. The reaction solution was cooled to room temperature, dioxane was removed by rotary evaporation under reduced pressure, diluted with water (150 mL), extracted with ethyl acetate (100 mL*2), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and then separated and purified by flash silica gel column chromatography (ethyl acetate / petroleum ether, 0~10%) to give 3.5 g of the title compound as a white solid in a yield of 79.5%.

[0685] LCMS: MS (ESI) m / z = 446.1 / 448.1 [M+H] + .

[0686] Step 2: Synthesis of methyl 1-(4-(2,6-bis(benzyloxy)pyridin-3-yl)phenyl)piperidine-4- carboxylate

[0687] Tris(dibenzylideneacetone)dipalladium (0.36 g, 0.39 mmol), 2-dicyclohexylphosphino-2,4,6-triisopropylbiphenyl (0.37 g, 0.78 mmol), cesium carbonate (5.08 g, 15.6 mmol) were added successively to a solution of 2,6-bis(benzyloxy)-3-(4-bromophenyl)pyridine (3.5 g, 7.8 mmol) and methyl 4-piperidinecarboxylate (1.67 g, 11.7 mmol) in dioxane (50 mL), the system was replaced with nitrogen for three times, then heated to 100 °C and stirred for 16 h. The solvent was removed by rotary evaporation under reduced pressure, diluted with water (200 mL), extracted with ethyl acetate (100 mL*2), the combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, then purified by flash silica gel column chromatography (ethyl acetate / petroleum ether, 0~10%) to give 2.3 g of the title compound as a yellow solid in a yield of 57.2%.

[0688] LCMS: MS (ESI) m / z = 509.1 [M+H] + .

[0689] Step 3: Synthesis of 1-(4-(2,6-di(benzyloxy)pyridin-3-yl)phenyl)piperidine-4- carboxylic acid

[0690] A solution of lithium hydroxide monohydrate (516 mg, 12.30 mmol) in water (30 mL) was added to a mixture of methyl 1-(4-(2,6-di(benzyloxy)pyridin-3-yl)phenyl)piperidine-4- carboxylate (2.1 g, 4.10 mmol) in tetrahydrofuran (30 mL) and methanol (30 mL), the system was stirred at 50 °C for 2 h. The solvent was removed by rotary evaporation under reduced pressure, diluted with water to 200 mL, adjusted to pH about 5 with dilute hydrochloric acid (30 mL, 1 mol / L), extracted with ethyl acetate (100 mL*2), the combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated by rotary evaporation under reduced pressure to give 1.9 g of the title compound as a yellow solid in a yield of 94.8%.

[0691] LCMS: MS (ESI) m / z = 495.2 [M+H] + .

[0692] Step 4: Synthesis of 1-(4-(2,6-dicarbonylpiperidin-3-yl)phenyl)piperidine-4-carboxylic acid

[0693] Palladium on carbon catalyst (418.48 mg, 0.39 mmol, 10%) was added to a mixture of 1-(4-(2,6-di(benzyloxy)pyridin-3-yl)phenyl)piperidine-4-carboxylic acid (1.94 g, 3.93 mmol) in methanol and tetrahydrofuran (1 : 1, 60 mL), the system was replaced with hydrogen three times, then stirred at 25 °C for 16 h. The reaction solution was filtered through celite, the filtrate was concentrated under reduced pressure, then separated and purified by carbon 18 column chromatography (water-acetonitrile, 5-70%, 0.1% trifluoroacetic acid) to give 1.24 g (trifluoroacetate) of the title compound as a white solid, with a yield of 60.4%.

[0694] LCMS: MS (ESI) m / z = 317.1 [M+H] + .

[0695] Synthesis of intermediate B32

[0696]

[0697] Step 1: Synthesis of 1-(4-bromo-2-fluoro-6-methoxyphenyl)dihydropyrimidine- 2,4(lH,3H)-dione

[0698] Glacial acetic acid (4.70 g, 0.0782 mol) was added to a solution of 4-bromo-2-fluoro-6-methoxyaniline (10.42 g, 0.0330 mol) and acrylic acid (2.38 g, 0.033 mol) in water (8 ml), the system was replaced 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 mol) in glacial acetic acid (70 ml) was added, the system was replaced with nitrogen three times, then heated to 120 °C and stirred for 20 h. After the reaction was completed, it was cooled to room temperature, hydrochloric acid (14 ml) was added, heated to 120 °C and stirred for 1 h. After the reaction was completed, it was cooled to room temperature, diluted with water (100 ml), adjusted to pH = 8 with saturated sodium bicarbonate solution, extracted with ethyl acetate (100 mL*3), the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, then separated and purified by flash silica gel column chromatography (ethyl acetate / petroleum ether, 40-60%) to give 2.3 g of the title compound as a yellow solid, with a yield of 21.8%.

[0699] LCMS: MS (ESI) m / z = 317.0, 319.0 [M+H] +

[0700] Step 2: Synthesis of 1-(4-(4-(dimethoxymethyl)piperidin-l-yl)-2-fluoro-6- methoxyphenyl)dihydropyrimidine-2,4(lH,3H)-dione

[0701] ​

[0702] Tris(dibenzylideneacetone)dipalladium (0.36 g, 0.39 mmol), 2-dicyclohexylphosphino-2,4,6-triisopropylbiphenyl (0.37 g, 0.78 mmol), cesium carbonate (5.08 g, 15.6 mmol) were added successively to a solution of 1-(4-bromo-2-fluoro-6-methoxyphenyl)dihydropyrimidine-2,4(lH,3H)-dione (2.46 g, 7.8 mmol) and 4-(dimethoxymethyl)piperidine (1.86 g, 11.7 mmol) in dioxane (50 mL), the system was replaced with nitrogen for three times, then heated to 100 °C and stirred for 16 h. The solvent was removed by rotary evaporation under reduced pressure, diluted with water (200 mL), extracted with ethyl acetate (100 mL*2), the combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, then purified by flash silica gel column chromatography (ethyl acetate / petroleum ether, 0~10%) to give 1.2 g of the title compound as a yellow solid, with a yield of 37.9%.

[0703] LCMS: MS (ESI) m / z = 396.1 [M+H] + .

[0704] Step 3: Synthesis of l-(4-(2,4-dioxotetrahydropyrimidin-l(2H)-yl)-3-fluoro-5- methoxyphenyl)piperidine-4-carbaldehyde

[0705] Trifluoroacetic acid (10 mL) was added dropwise to a solution of l-(4-(4- (dimethoxymethyl)piperidin-l-yl)-2-fluoro-6-methoxyphenyl)dihydropyrimidine-2,4(lH,3H)- dione (1.2 g, 3.0 mmol) in dichloromethane (10 mL), the system was stirred at room temperature for 2 h. The reaction solution was rotary evaporated under reduced pressure, then purified by carbon 18 column chromatography (water-acetonitrile, 15%~85%, 0.1% trifluoroacetic acid) to give 562.4 mg of the title compound as a white solid, with a yield of 53.7%.

[0706] LCMS: MS (ESI) m / z = 350.1 [M+H] +

[0707] Synthesis of intermediate B33

[0708]

[0709] Step 1: Synthesis of 2,6-bis(benzyloxy)-3-(4-bromo-2-fluoro-6-methoxyphenyl)pyridine

[0710] Potassium carbonate (3.65 g, 26.4 mmol) and 1,1-bis(diphenylphosphino) ferrocene palladium dichloride (0.97 g, 1.32 mmol) were added successively to a solution of 5-bromo-1-fluoro-2-iodo-3-methoxybenzene (2.9 g, 8.8 mmol) and 2,6-bis(benzyloxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (4.41 g, 10.56 mmol) in dioxane (50 mL), water (10 mL) was added, the system was replaced with nitrogen three times, then heated to 90 °C and stirred for 16 h. The reaction was cooled to room temperature, dioxane was removed by rotary evaporation under reduced pressure, diluted with water (150 mL), extracted with ethyl acetate (100 mL*2), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and then separated and purified by flash column chromatography on silica gel (ethyl acetate / petroleum ether, 0-10%) to give 3.1 g of the title compound as a white solid in a yield of 71.6%.

[0711] LCMS: MS (ESI) m / z = 494.1 / 496.1 [M+H] + .

[0712] Step 2: Synthesis of methyl 1-(4-(2,6-di(benzyloxy)pyridin-3-yl)-3-fluoro-5- methoxyphenyl)piperidine-4-carboxylate

[0713] Tris(dibenzylideneacetone)dipalladium (0.36 g, 0.39 mmol), 2-dicyclohexylphosphino-2,4,6-triisopropylbiphenyl (0.37 g, 0.78 mmol), cesium carbonate (5.08 g, 15.6 mmol) were added successively to a solution of 2,6-di(benzyloxy)-3-(4-bromo-2-fluoro-6-methoxyphenyl)pyridine (3.8 g, 7.8 mmol) and methyl 4-piperidinecarboxylate (2.16 g, 11.7 mmol) in dioxane (50 mL), the system was replaced with nitrogen three times, then heated to 100 °C and stirred for 16 h. The solvent was removed by rotary evaporation under reduced pressure, diluted with water (200 mL), extracted with ethyl acetate (100 mL*2), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and then separated and purified by flash column chromatography on silica gel (ethyl acetate / petroleum ether, 0-10%) to give 2.1 g of the title compound as a yellow solid in a yield of 47.5%.

[0714] LCMS: MS (ESI) m / z = 557.2 [M+H] + .

[0715] Step 3: Synthesis of 1-(4-(2,6-di(benzyloxy)pyridin-3-yl)-3-fluoro-5-methoxyphenyl)piperidine-4-carboxylic acid

[0716] A solution of lithium hydroxide monohydrate (516 mg, 12.30 mmol) in water (30 mL) was added to a mixture of methyl 1-(4-(2,6-di(benzyloxy)pyridin-3-yl)phenyl)piperidine-4-carboxylate (2.3 g, 4.10 mmol) in tetrahydrofuran (30 mL) and methanol (30 mL), and the system was stirred at 50 °C for 2 h. The reaction solution was concentrated under reduced pressure to remove the solvent, diluted with water to 200 mL, adjusted to pH about 5 with dilute hydrochloric acid (30 mL, 1 mol / L), extracted with ethyl acetate (100 mL*2), the combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give 2.1 g of the title compound as a yellow solid, with a yield of 94.8%.

[0717] LCMS: MS (ESI) m / z = 543.2 [M+H] + .

[0718] Step 4: Synthesis of 1-(4-(2,6-dicarbonylpiperidin-3-yl)-3-fluoro-5- methoxyphenyl)piperidine-4-carboxylic acid

[0719] Palladium on carbon catalyst (418.48 mg, 0.39 mmol, 10%) was added to a mixture of 1-(4-(2,6-di(benzyloxy)pyridin-3-yl)-3-fluoro-5-methoxyphenyl)piperidine-4-carboxylic acid (2.1 g, 3.93 mmol) in methanol and tetrahydrofuran (1:1, 60 mL), the system was replaced with hydrogen three times, and then stirred at 25 °C for 16 h. The reaction solution was filtered through diatomite, and the filtrate was concentrated under reduced pressure, and then separated and purified by carbon 18 column chromatography (water-acetonitrile, 5-70%, 0.1% trifluoroacetic acid) to give 732.6 mg (trifluoroacetate) of the title compound as a white solid, with a yield of 51.2%.

[0720] LCMS: MS (ESI) m / z = 365.1 [M+H] + .

[0721] Synthesis of intermediate B1-1

[0722]

[0723] Step 1: Synthesis of 4-chloro-2-fluoro-5-nitrobenzaldehyde

[0724] To a solution of 4-chloro-2-fluorobenzaldehyde (14.5 g, 91.45 mmol, 1.0 eq) in concentrated sulfuric acid (100 mL) was added potassium nitrate (13.87 g, 137.175 mmol, 1.5 eq). It was stirred at room temperature for 1 h. The reaction was quenched by pouring into ice water (300 mL), filtered to give the target compound 4-chloro-2-fluoro-5-nitrobenzaldehyde (16.9 g, yellow solid, yield 91.0%).

[0725] 1 H NMR (400 MHz, CDC13) δ: 7.48 (d, J = 11.6 Hz, 1H), 8.46 (d, J = 6.4 Hz, 1H), 10.31 (s, 1H)

[0726] Step 2: Synthesis of 2-azido-4-chloro-5-nitrobenzaldehyde

[0727] To a solution of 4-chloro-2-fluoro-5-nitrobenzaldehyde (7.9 g, 38.8 mmol, 1.0 eq) in DMSO (50 mL) was added sodium azide (2.52 g, 38.8 mmol, 1.0 eq). It was stirred at 30 °C for 1 h. The reaction was quenched by pouring into water, extracted with EA. The organic phase was washed with water, dried over Na2S04, filtered, concentrated under reduced pressure, the residue was swabbed with (PE / EA, 10 / 1), filtered to give the target compound 2-azido-4-chloro-5-nitrobenzaldehyde (5.0 g, yellow solid, yield 56.9%).

[0728] Step 3: Synthesis of 2-azido-5-nitro-4-(piperidin-l-yl)benzaldehyde

[0729] To a solution of 2-azido-4-chloro-5-nitrobenzaldehyde (4.5 g, 19.9 mmol, 1.0 eq) in DMSO (100 mL) was added piperidine (5.1 g, 59.7 mmol, 3.0 eq). It was stirred at 50 °C for 3 h. The reaction was quenched by pouring into water, extracted with DCM. The organic phase was washed with water, dried over Na2S04, filtered, concentrated under reduced pressure to give the target compound 2-azido-5-nitro-4-(piperidin-l-yl)benzaldehyde (5.2 g, brown solid, yield 94.9%)

[0730] LC-MS (ESI) m / z: 276.1 [M+H] +

[0731] Step 4: Synthesis of tert-butyl 4-(5-nitro-6-(piperidin-l-yl)-2H-indazol-2-yl)piperidine-l- carboxylate

[0732] A reaction solution containing 2-azido-5-nitro-4-(piperidin-l-yl)benzaldehyde (5.2 g, 18.89 mmol, 1.0 eq), tert-butyl 4-aminopiperidine-l-carboxylate (3.78 g, 18.89 mmol, 1.0 eq), trimethyl orthoformate (6.0 g, 56.67 mmol, 3.0 eq), DCM (100 mL) was stirred at room temperature overnight. Then toluene (100 mL) was added and warmed to 130 °C. DCM was distilled out with a water trap, stirred for 3 h. The reaction solution was concentrated under reduced pressure, purified by silica gel column (PE / EA = 4 / 1) to give the target compound tert-butyl 4-(5-nitro-6-(piperidin-l-yl)-2H-indazol-2-yl)piperidine-l-carboxylate (3.5 g, yellow solid, yield 43.2%).

[0733] LC-MS (ESI) m / z: 430.2 [M+H] + .

[0734] Step 5: Synthesis of 5-nitro-6-(piperidin-l-yl)-2-(piperidin-4-yl)-2H-indazole hydrochloride

[0735] To a reaction solution containing tert-butyl 4-(5-nitro-6-(piperidin-l-yl)-2H-indazol-2- yl)piperidine-l-carboxylate (3.5 g, 8.09 mmol, 1.0 eq) in dichloromethane (40 mL) was added 4M hydrochloric acid in dioxane (20 mL). Stirred at room temperature overnight. The reaction solution was concentrated under reduced pressure to give the target compound.

[0736] LC-MS (ESI) m / z: 330.2 [M+H] + .

[0737] Step 6: Preparation of N-(2,6-dicarbonylpiperidin-3-yl)-2-fluoro-4-(4-((4-(5-nitro-6-(piperidin-l- yl)-2H-indazol-2-yl)piperidin-l-yl)methyl)piperidin-l-yl)benzamide.

[0738] To a solution of 5-nitro-6-(piperidin-l-yl)-2-(piperidin-4-yl)-2H-indazole (1.66 g, 5.04 mmol, 1.0 eq) in N,N-dimethylacetamide (40 mL) was added nitrogen-(2,6-dicarbonylpiperidin-3-yl)-2-fluoro-4-(4-formylpiperidin-l-yl)benzamide (2.0 g, 5.54 mmol, 1.1 eq) and the reaction was stirred at 25 °C for 5 min. Acetic acid (0.58 mL, 10.08 mmol, 2.0 eq) was added dropwise and the reaction was stirred at 25 °C for 5 h. Sodium triacetoxyborohydride (2.14 g, 10.08 mmol, 2.0 eq) was added in two portions, 1 eq per portion, with 30 min intervals. The reaction was stirred at 25 °C for 16 h. The reaction was diluted with 150 mL of n-butanol and washed with 100 mL of saturated NaCl(aq) 5 times. The n-butanol was dried and purified by silica gel column chromatography (methanol / dichloromethane, 0-10%) to give 3.02 g of the title compound as a red-brown solid in 88.82% yield.

[0739] LCMS: Rt = 4.302 min, MS (ESI) m / z = 675.3 [M+H] + .

[0740] Step 7: Preparation of 4-(4-((4-(5-amino-6-(piperidin-l-yl)-2H-indazol-2-yl)piperidin-l- yl)methyl)piperidin-l-yl)-nitrogen-(2,6-dicarbonylpiperidin-3-yl)-2-fluorobenzamide.

[0741] To a solution of nitrogen-(2,6-dicarbonylpiperidin-3-yl)-2-fluoro-4-(4-((4-(5-nitro-6- (piperidin-l-yl)-2H-indazol-2-yl)piperidin-l-yl)methyl)piperidin-l-yl)benzamide (1.51 g, 2.24 mmol) in THF (60 mL) / MeOH (60 mL) was added 5% palladium on carbon (1 g) and the reaction was stirred at 25 °C for 16 h. The reaction was diluted with THF (60 mL) / MeOH (60 mL) and the filtrate was filtered through celite. The filtrate was dried to give 1.23 g of the title compound as a gray-brown solid in 85.42% yield.

[0742] LCMS: Rt = 1.356 min, MS (ESI) m / z = 645.4 [M+H] + .

[0743] Synthesis of Intermediate B2-1

[0744]

[0745] Step 1: Preparation of (S)-N-(2,6-dicarbonylpiperidin-3-yl)-2-methoxy-4-(4-((4-(5-nitro-6-(piperidin-l-yl)-2H-indazol-2-yl)piperidin-l-yl)methyl)piperidin-l-yl)benzamide

[0746] N-(2,6-dicarbonylpiperidin-3-yl)-2-methoxy-4-(4-formylpiperidin-l-yl)benzamide (3.2 g, 6.57 mmol, 1.2 eq) was added to a solution of 5-nitro-6-(piperidin-l-yl)-2-(piperidin-4-yl)-2H-indazole dihydrochloride (2.31 g, 5.47 mmol, 1.0 eq) in N,N-dimethylacetamide (60 mL), the reaction was stirred at 25 °C for 5 min, triethylamine (1.5 ml, 10.94 mmol, 2.0 eq) was added dropwise, stirred at 25 °C for 5 h, then sodium triacetoxyborohydride (2.32 g, 10.94 mmol, 2.0 eq) was added in two batches with an interval of 30 min, 1 eq per batch, the system was stirred at 25 °C for 16 h, TLC monitored the completion of the reaction, 150 ml of n-butanol was added to dilute the reaction solution, then washed with saturated NaCl (aq) 100 ml*5, spin dry n-butanol, separated and purified by silica gel column chromatography (methanol / dichloromethane, 0~10%) to obtain 3.40 g of the title compound as a red-brown solid, with a yield of 90.42%.

[0747] LCMS: Rt = 1.639 min, MS (ESI) m / z = 687.4 [M+H] + .

[0748] Step 2: Preparation of (S)-4-(4-((4-(5-amino-6-(piperidin-l-yl)-2H-indazol-2-yl)piperidin-l-yl)methyl)piperidin-l-yl)-N-(2,6-dicarbonylpiperidin-3-yl)-2-methoxybenzamide

[0749] N-(2,6-dicarbonylpiperidin-3-yl)-2-methoxy-4-(4-((4-(5-nitro-6-(piperidin-l-yl)-2H-indazol-2-yl)piperidin-l-yl)methyl)piperidin-l-yl)benzamide (1.70 g, 2.47 mmol) was added to THF (60 ml) / MeOH (60 ml), then 5% palladium on carbon (1.1 g) was added, replaced with hydrogen three times, the reaction system was stirred at 25 °C for 16 h, TLC monitored the completion of the reaction. The reaction solution was diluted with THF (60 ml) / MeOH (60 ml), and the filtrate was filtered through celite. The filtrate was spin dried to obtain 1.35 g of the title compound as a gray-brown solid, with a yield of 83.33%.

[0750] LCMS: Rt = 1.374 min, MS (ESI) m / z = 657.4 [M+H] + .

[0751] Synthesis of Intermediate B3-1

[0752]

[0753] Step 1: Preparation of 3-(6-(4-((4-(5-nitro-6-(piperidin-l-yl)-2-hydro-indazol-2- yl)piperidin-l-yl)methyl)piperidin-l-yl)-l-oxoisoindolin-2-yl)piperidine-2,6-dione.

[0754] To a solution of 1-(2-(2,6-dicarbonylpiperidin-3-yl)-3-oxoisoindolin-5-yl)piperidine- 4-carbaldehyde (2.4 g, 5.19 mmol, 1.2 eq) in N,N-dimethylacetamide (40 mL) was added 5-nitro-6-(piperidin-l-yl)-2-(piperidin-4-yl)-2H-indazole dihydrochloride (1.69 g, 4.32 mmol, 1.0 eq), the reaction was stirred at 25 °C for 5 min, triethylamine (1.8 ml, 12.96 mmol, 3.0 eq) was added dropwise, stirred at 25 °C for 5 h, then sodium triacetoxyborohydride (1.83 g, 8.64 mmol, 2.0 eq) was added in two batches, 30 min interval, 1 eq per batch, the system was stirred at 25 °C for 16 h, TLC monitored the completion of the reaction, 120 ml of n-butanol was added to dilute the reaction solution, then washed with saturated NaCl (aq) 100 ml*5, the n-butanol was spin-dried, separated and purified by silica gel column chromatography (methanol / dichloromethane, 0~10%) to obtain 2.6 g of the title compound as a red-brown solid, with a yield of 89.96%.

[0755] LCMS: Rt = 3.305 min, MS (ESI) m / z = 669.3 [M+H] + .

[0756] Step 2: Preparation of 3-(6-(4-((4-(5-amino-6-(piperidin-l-yl)-2-hydro-indazol-2- yl)piperidin-l-yl)methyl)piperidin-l-yl)-l-oxoisoindolin-2-yl)piperidine-2,6-dione.

[0757] To a solution of 3-(6-(4-((4-(5-nitro-6-(piperidin-1-yl)-2H-indazol-2-yl)piperidin-1- yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (1.30 g, 1.94 mmol) in THF (60 ml) / MeOH (60 ml) was added 5% palladium on carbon (1.0 g) and the reaction was stirred at 25 °C for 16 h under a hydrogen atmosphere. The reaction was monitored by TLC. The reaction mixture was diluted with THF (60 ml) / MeOH (60 ml) and filtered through celite. The filtrate was concentrated to give 1.05 g of the title compound as a grey brown solid in 84.67% yield.

[0758] LCMS: Rt = 2.962 min, MS (ESI) m / z = 639.4 [M+H] + .

[0759] Synthesis of intermediate B4-1

[0760]

[0761] Step 1: Preparation of 3-(5-(4-((4-(5-nitro-6-(piperidin-1-yl)-2H-indazol-2-yl)piperidin-1- yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione.

[0762] To a solution of 1-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperidine-4-carbaldehyde (2.97 g, 6.33 mmol, 1.1 eq) in N,N-dimethylacetamide (50 mL) was added 5-nitro-6-(piperidin-1-yl)-2-(piperidin-4-yl)-2H-indazole dihydrochloride (2.47 g, 5.75 mmol, 1.0 eq) and the reaction was stirred at 25 °C for 5 min. Triethylamine (2.4 ml, 17.25 mmol, 3.0 eq) was added dropwise and the reaction was stirred at 25 °C for 5 h. Sodium triacetoxyborohydride (2.44 g, 11.50 mmol, 2.0 eq) was added in two portions at 30 min intervals and the reaction was stirred at 25 °C for 16 h. The reaction was monitored by TLC. The reaction mixture was diluted with 120 mL of n-butanol and washed with saturated NaCl (aq) 100 mL x 5. The n-butanol was concentrated and purified by column chromatography on silica gel (methanol / dichloromethane, 0-10%) to give 3.5 g of the title compound as a red brown solid in 90.91% yield.

[0763] LCMS: Rt = 3.381 min, MS (ESI) m / z = 669.3 [M+H] + .

[0764] Step 2: Preparation of 3-(5-(4-((4-(5-amino-6-(piperidin-l-yl)-2H-indazol-2-yl)piperidin-l- yl)methyl)piperidin-l-yl)-l-oxoisoindolin-2-yl)piperidine-2,6-dione.

[0765] To 3-(5-(4-((4-(5-nitro-6-(piperidin-l-yl)-2H-indazol-2-yl)piperidin-l-yl)methyl)piperidin- 1-yl)-l-oxoisoindolin-2-yl)piperidine-2,6-dione (1.75 g, 2.61 mmol) in THF (60 ml) / MeOH (60 ml) was added 5% palladium on carbon (1.1 g), displaced with hydrogen three times, and the reaction stirred at 25 °C for 16 h. The reaction was monitored by TLC. The reaction was diluted with THF (60 ml) / MeOH (60 ml) and the filtrate was filtered through celite. The filtrate was concentrated to give 1.45 g of the title compound as a grey-brown solid in 86.82% yield.

[0766] LCMS: Rt = 2.967 min, MS (ESI) m / z = 639.4 [M+H] + .

[0767] Synthesis of Intermediate B5-1

[0768]

[0769] Step 1: Preparation of 3-(6-fluoro-5-(4-((4-(5-nitro-6-(piperidin-l-yl)-2H-indazol-2-yl)piperidin- 1-yl)methyl)piperidin-l-yl)-l-oxoisoindolin-2-yl)piperidine-2,6-dione.

[0770] To a solution of 5-nitro-6-(piperidin-l-yl)-2-(piperidin-4-yl)-2H-indazole (581 mg, 1.76 mmol, 1.0 eq) in N,N-dimethylacetamide (40 mL) was added l-(2-(2,6-dicarbonylpiperidin-3-yl)-6-fluoro-l- carbonylisatine-5-yl)piperidine-4-carbaldehyde (945 mg, 1.94 mmol, 1.1 eq) and the reaction was stirred at 25 °C for 5 min. Acetic acid (0.2 mL, 3.52 mmol, 3.0 eq) was added dropwise and the reaction was stirred at 25 °C for 5 h. Sodium triacetoxyborohydride (746 mg, 3.52 mmol, 2.0 eq) was added in two portions with 30 min intervals and the reaction was stirred at 25 °C for 16 h. The reaction was diluted with n-butanol (80 mL) and washed with saturated NaCl (aq) (80 mL x 5). The n-butanol was evaporated and the residue was purified by silica gel column chromatography (methanol / dichloromethane, 0-10%) to give the title compound as a red-brown solid (1.02 g, 84.29% yield).

[0771] LCMS: Rt = 3.449 min, MS (ESI) m / z = 687.3 [M+H] + .

[0772] Step 2: Preparation of 3-(5-(4-((4-(5-amino-6-(piperidin-l-yl)-2-hydro-indazol-2- yl)piperidin-l-yl)methyl)piperidin-l-yl)-6-fluoro-l-carbonylisatine-2-yl)piperidine-2,6- dione.

[0773] To a solution of 3-(6-fluoro-5-(4-((4-(5-nitro-6-(piperidin-l-yl)-2-hydro-indazol-2- yl)piperidin-l-yl)methyl)piperidin-l-yl)-l-carbonylisatine-2-yl)piperidine-2,6-dione (1.02 g, 1.49 mmol) in THF (60 mL) / MeOH (60 mL) was added 5% palladium on carbon (800 mg) and the reaction was stirred at 25 °C for 16 h. The reaction was diluted with THF (60 mL) / MeOH (60 mL) and the filtrate was filtered through celite. The filtrate was evaporated to give the title compound as a grey-brown solid (850 mg, 87.17% yield).

[0774] LCMS: Rt = 3.032 min, MS (ESI) m / z = 657.4 [M+H] + .

[0775] Synthesis of Intermediate B6-1

[0776]

[0777] Step 1: Preparation of 3-(4-fluoro-5-(4-((4-(5-nitro-6-(piperidin-l-yl)-2H-indazol-2- yl)piperidin-l-yl)methyl)piperidin-l-yl)-l-oxoisoindolin-2-yl)piperidine-2,6-dione.

[0778] To a solution of 1-(2-(2,6-dicarbonylpiperidin-3-yl)-4-fluoro-l-oxoisoindolin-5-yl)piperidine- 4-carbaldehyde (2.97 g, 6.1 mmol, 1.15 eq) in N,N-dimethylacetamide (50 mL) was added 5- nitro-6-(piperidin-l-yl)-2-(piperidin-4-yl)-2H-indazole (1.75 g, 5.3 mmol, 1.0 eq), stirred at 25 °C for 5 min, then acetic acid (0.61 ml, 10.6 mmol, 2.0 eq) was added dropwise, stirred at 25 °C for 5 h, then sodium triacetoxyborohydride (2.25 g, 10.6 mmol, 2.0 eq) was added in two portions with 30 min interval, 1 eq per portion, the system was stirred at 25 °C for 16 h, TLC monitored the reaction was complete, then the reaction solution was diluted with 120 ml of n-butanol, washed with saturated NaCl (aq) 100 ml*5, n-butanol was rotary evaporated, separated and purified by silica gel column chromatography (methanol / dichloromethane, 0~10%) to give 2.9 g of the title compound as a red-brown solid, with a yield of 79.73%.

[0779] LCMS: Rt = 1.679 min, MS (ESI) m / z = 687.3 [M+H] + .

[0780] Step 2: Preparation of 3-(5-(4-((4-(5-amino-6-(piperidin-l-yl)-2H-indazol-2-yl)piperidin-l- yl)methyl)piperidin-l-yl)-4-fluoro-l-oxoisoindolin-2-yl)piperidine-2,6-dione.

[0781] To a solution of 3-(4-fluoro-5-(4-((4-(5-nitro-6-(piperidin-l-yl)-2H-indazol-2-yl)piperidin-l- yl)methyl)piperidin-l-yl)-l-oxoisoindolin-2-yl)piperidine-2,6-dione (1.55 g, 2.26 mmol) in THF (60 ml) / MeOH (60 ml) was added 5% palladium on carbon (1.1 g), replaced with hydrogen three times, the reaction system was stirred at 25 °C for 16 h, TLC monitored the reaction was complete. The reaction solution was diluted with THF (60 ml) / MeOH (60 ml), the filtrate was filtered through celite, and the filtrate was rotary evaporated to give 1.15 g of the title compound as a gray-brown solid, with a yield of 77.70%.

[0782] LCMS: Rt = 3.922 min, MS (ESI) m / z = 657.4 [M+H] + .

[0783] Synthesis of intermediate B7-1

[0784]

[0785] Step 1: Preparation of 3-(4-fluoro-6-(4-((4-(5-nitro-6-(piperidin-l-yl)-2- hydro-indazol-2-yl)piperidin-l-yl)methyl)piperidin-l-yl)-l-oxoisoindolin-2-yl)piperidine- 2,6-dione.

[0786] To a solution of 1-(2-(2,6-dicarbonylpiperidin-3-yl)-7-fluoro-3-oxoisoindolin-5-yl)piperidine- 4-carbaldehyde (2.97 g, 6.1 mmol, 1.15 eq) in N,N-dimethylacetamide (50 mL) was added 5-nitro-6-(piperidin-l-yl)-2-(piperidin-4-yl)-2-hydro-indazole (1.75 g, 5.3 mmol, 1.0 eq), the reaction was stirred at 25 °C for 5 min, then acetic acid (0.61 ml, 10.6 mmol, 2.0 eq) was added dropwise, stirred at 25 °C for 5 h, then sodium triacetoxyborohydride (2.25 g, 10.6 mmol, 2.0 eq) was added in two batches with an interval of 30 min, 1 eq per batch, the system was stirred at 25 °C for 16 h, TLC monitoring showed that the reaction was complete, 120 ml of n-butanol was added to dilute the reaction solution, then washed with saturated NaCl (aq) 100 ml*5, the n-butanol was rotary evaporated, and the product was separated and purified by silica gel column chromatography (methanol / dichloromethane, 0-10%) to give 3.1 g of the title compound as a red-brown solid, with a yield of 86.11%.

[0787] LCMS: Rt = 1.687 min, MS (ESI) m / z = 687.3 [M+H] + .

[0788] Step 2: Preparation of 3-(6-(4-((4-(5-amino-6-(piperidin-l-yl)-2-hydro-indazol-2- yl)piperidin-l-yl)methyl)piperidin-l-yl)-4-fluoro-l-oxoisoindolin-2-yl)piperidine-2,6-dione.

[0789] To a solution of 3-(4-fluoro-6-(4-((4-(5-nitro-6-(piperidin-1-yl)-2H-indazol-2-yl)piperidin-1- yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (1.55 g, 2.26 mmol) in THF (60 ml) / MeOH (60 ml) was added 5% palladium on carbon (1.1 g) and the reaction was stirred at 25 °C for 16 h under a hydrogen atmosphere. The reaction was monitored by TLC. The reaction mixture was diluted with THF (60 ml) / MeOH (60 ml) and filtered through celite. The filtrate was concentrated to give 1.25 g of the title compound as a grey brown solid in 84.46% yield.

[0790] LCMS: Rt = 3.914 min, MS (ESI) m / z = 657.4 [M+H] + .

[0791] Synthesis of intermediate B8-1

[0792]

[0793] Step 1: Preparation of 2-(2,6-dicarbonylpiperidin-3-yl)-5-(4-((4-(5-nitro-6-(piperidin-1-yl)-2H- indazol-2-yl)piperidin-1-yl)methyl)piperidin-1-yl)isoindoline-1,3-dione.

[0794] To a solution of 1-(2-(2,6-dicarbonylpiperidin-3-yl)-1,3-dicarbonylisoindolin-5-yl)piperidine-4- carbaldehyde (2.05 g, 5.56 mmol, 1.1 eq) in N,N-dimethylacetamide (50 mL) was added 5-nitro-6- (piperidin-1-yl)-2-(piperidin-4-yl)-2H-indazole dihydrochloride (2.17 g, 5.05 mmol, 1.0 eq) and the reaction was stirred at 25 °C for 5 min. Triethylamine (1.41 ml, 10.1 mmol, 2.0 eq) was added dropwise and the reaction was stirred at 25 °C for 5 h. Sodium triacetoxyborohydride (2.14 g, 10.1 mmol, 2.0 eq) was added in two portions at 30 min intervals and the reaction was stirred at 25 °C for 16 h. The reaction was monitored by TLC. The reaction mixture was diluted with 120 ml of n-butanol and washed with saturated NaCl (aq) 100 ml*5. The n-butanol was concentrated and purified by silica gel column chromatography (methanol / dichloromethane, 0-10%) to give 3.1 g of the title compound as a red brown solid in 89.85% yield.

[0795] LCMS: Rt = 3.051 min, MS (ESI) m / z = 683.3 [M+H]+ .

[0796] Step 2: Preparation of 5-(4-((4-(5-amino-6-(piperidin-l-yl)-2H-indazol-2-yl)piperidin-l- yl)methyl)piperidin-l-yl)-2-(2,6-dicarbonylpiperidin-3-yl)isoindole-l,3-dione.

[0797] To a solution of 2-(2,6-dicarbonylpiperidin-3-yl)-5-(4-((4-(5-nitro-6-(piperidin-l-yl)-2H- indazol-2-yl)piperidin-l-yl)methyl)piperidin-l-yl)isoindole-l,3-dione (1.55 g, 2.27 mmol) in THF (60 ml) / MeOH (60 ml) was added 5% palladium on carbon (1.1 g) and the reaction was stirred at 25 °C for 16 h under 3 times hydrogen replacement. The reaction was monitored by TLC. The reaction mixture was diluted with THF (60 ml) / MeOH (60 ml) and the filtrate was filtered through celite. The filtrate was evaporated to give 1.3 g of the title compound as a grey brown solid in 87.83% yield.

[0798] LCMS: Rt = 3.131 min, MS (ESI) m / z = 653.3 [M+H] + .

[0799] Synthesis of Intermediate B9-1

[0800]

[0801] Step 1: Preparation of (S)-N-(2,6-dicarbonylpiperidin-3-yl)-2-fluoro-4-(4-((4-(5-nitro-6- (piperidin-l-yl)-2H-indazol-2-yl)piperidin-l-yl)methyl)piperidin-l-yl)benzamide.

[0802] (S)-N-(2,6-dicarboxypiperidin-3-yl)-2-fluoro-4-(4-formylpiperidin-1-yl)benzamide (2.0 g, 5.54 mmol, 1.1 eq) was added to a solution of 5-nitro-6-(piperidin-1-yl)-2-(piperidin-4-yl)-2H-indazole dihydrochloride (2.13 g, 5.04 mmol, 1.0 eq) in N,N-dimethylacetamide (40 mL), the reaction was stirred at 25 °C for 5 min, triethylamine (1.4 ml, 10.08 mmol, 2.0 eq) was added dropwise, stirred at 25 °C for 5 h, then sodium triacetoxyborohydride (2.14 g, 10.08 mmol, 2.0 eq) was added in two batches, 30 min interval, 1 eq per batch, the system was stirred at 25 °C for 16 h, TLC monitored the completion of the reaction, 150 ml of n-butanol was added to dilute the reaction solution, then washed with saturated NaCl (aq) 100 ml*5, spin dry n-butanol, separated and purified by silica gel column chromatography (methanol / dichloromethane, 0~10%) to obtain 3.05 g of the title compound as a red-brown solid, with a yield of 89.71%.

[0803] LCMS: Rt = 1.614 min, MS (ESI) m / z = 675.3 [M+H] + .

[0804] Step 2: Preparation of (S)-4-(4-((4-(5-amino-6-(piperidin-1-yl)-2-hydro-indazol-2-yl)piperidin-1-yl)methyl)piperidin-1-yl)-N-(2,6-dicarboxypiperidin-3-yl)-2-fluorobenzamide.

[0805] (S)-N-(2,6-dicarboxypiperidin-3-yl)-2-fluoro-4-(4-((4-(5-nitro-6-(piperidin-1-yl)-2-hydro-indazol-2-yl)piperidin-1-yl)methyl)piperidin-1-yl)benzamide (1.52 g, 2.25 mmol) was added to THF (60 ml) / MeOH (60 ml), then 5% palladium on carbon (1 g) was added, replaced with hydrogen three times, the reaction system was stirred at 25 °C for 16 h, TLC monitored the completion of the reaction. The reaction solution was diluted with THF (60 ml) / MeOH (60 ml), the filtrate was filtered through celite, and the filtrate was spin dried to obtain 1.26 g of the title compound as a gray-brown solid, with a yield of 86.89%.

[0806] LCMS: Rt = 1.358 min, MS (ESI) m / z = 645.3 [M+H] + .

[0807] Synthesis of Intermediate C1

[0808]

[0809] Step 1: Synthesis of methyl (lr,4r)-4-(5-nitro-6-(piperidin-l-yl)-2H-indazol-2- yl)cyclohexane- 1 -carboxylate

[0810] A reaction containing 2-azido-5-nitro-4-(piperidin-l-yl)benzaldehyde (30.0 g, 108.98 mmol, 1.0 eq), methyl (lr,4r)-4-aminocyclohexane-l-carboxylate (17.1 g, 108.98 mmol, 1.0 eq), trimethyl orthoformate (34.7 g, 326.95 mmol, 3.0 eq), DCM (200 mL) was stirred at room temperature for 10 min. Then toluene (500 mL) was added and warmed to 120 °C. DCM was distilled out with a water trap, stirred for 3 h. The reaction was concentrated under reduced pressure, purified by silica gel column (PE / EA = 4 / 1) to give the target compound methyl (lr,4r)-4-(5-nitro-6-(piperidin-l-yl)-2H-indazol-2-yl)cyclohexane-l-carboxylate (20.5 g, yellow solid, yield 48.7%).

[0811] LC-MS (ESI) m / z: 387.2 [M+H] +

[0812] Step 2: Synthesis of methyl (lr,4r)-4-(5-amino-6-(piperidin-l-yl)-2H-indazol-2- yl)cyclohexane- 1 -carboxylate

[0813] To a reaction containing methyl (lr,4r)-4-(5-nitro-6-(piperidin-l-yl)-2H-indazol-2- yl)cyclohexane- 1 -carboxylate (20.5 g), methanol (800 mL) was added Pd / C (2.1 g). Stirred at room temperature under hydrogen overnight. The reaction was filtered, concentrated under reduced pressure to give the target compound methyl (lr,4r)-4-(5-amino-6-(piperidin-l-yl)-2H-indazol-2-yl)cyclohexane-l-carboxylate (15.0 g, brown solid, yield 79.3%).

[0814] LC-MS (ESI) m / z: 387.2 [M+H] +

[0815] Step 3: Synthesis of ((lr,4r)-4-(5-amino-6-(piperidin-l-yl)-2H-indazol-2-yl)cyclohexyl) methanol

[0816] To the reaction solution containing (1r,4r)-4-(5-amino-6-(piperidin-1-yl)-2H- indazol-2-yl)cyclohexane-1-carboxylate (15.0 g, 42.08 mmol, 1.0 eq), THF (600 mL), MeOH (80 mL) was added LiBH4(4.58 g, 210.4 mmol, 5.0 eq). Stirred at room temperature overnight. The reaction solution was concentrated under reduced pressure, purified by silica gel column (PE / EA = 1 / 1) to give the target compound ((1r,4r)-4-(5-amino-6-(piperidin-1-yl)-2H-indazol-2-yl)cyclohexyl)methanol (12.0 g, white solid, yield 86.8%).

[0817] LC-MS (ESI) m / z: 329.2 [M+H] +

[0818] Synthesis of intermediate C2

[0819]

[0820] Step 1: Preparation of (1r,4r)-N-methyl-4-(5-nitro-6-(piperidin-1-yl)-2H-indazol-2- yl)cyclohexan-1-amine

[0821] The reaction solution containing 2-azido-5-nitro-4-(piperidin-1-yl)benzaldehyde (10.0 g, 36.3 mmol), (1r,4r)-N1-methylcyclohexane-1,4-diamine (4.65 g, 36.3 mmol), trimethyl orthoformate (34.7 g, 108.9 mmol), DCM (70 mL) was stirred at room temperature for 10 min. Then toluene (170 mL) was added and warmed to 120 °C. DCM was distilled out with a water trap, stirred for 3 h. The reaction solution was concentrated under reduced pressure, purified by silica gel column (PE / EA = 4 / 1) to give the target compound (5.4 g, yellow solid, yield 42.2%).

[0822] LC-MS (ESI) m / z: 358.2 [M+H] +

[0823] Step 2: Preparation of 2-((1r,4r)-4-(methylamino)cyclohexyl)-6-(piperidin-1-yl)-2H- indazol-5-amine

[0824] To the reaction solution containing (1r,4r)-N-methyl-4-(5-nitro-6-(piperidin-1-yl)- 2H-indazol-2-yl)cyclohexan-1-amine (5.4 g, 15.1 mmol), methanol (100 mL) was added Pd / C (0.6 g). It was stirred at room temperature under hydrogen overnight. The reaction solution was filtered and concentrated under reduced pressure to obtain the target compound (4.1 g, brown solid, yield 82.4%).

[0825] LC-MS (ESI) m / z: 328.2 [M+H] +

[0826] Example

[0827] Synthetic route Synthetic route A:

[0828] The amine compound (1.0 equiv.), carboxylic acid compound (1.0 equiv.) was dissolved in DMF, DIPEA (3.0 equiv.) and HATU (1.2 equiv.) were added successively. The reaction mixture was stirred at room temperature for 4 hours. Water was added to the post-reaction system and extracted with DCM. The organic phases were combined, dried over Na2SO4 and filtered, and the filtrate was concentrated under reduced pressure and further purified by preparative TLC (DCM:MeOH=10:1) to obtain the target compound.

[0829] Synthetic route B:

[0830] The amine compound (1.0 equiv.), carboxylic acid compound (1.0 equiv.) was dissolved in dry DMF, DIPEA (3.0 equiv.) and T3P (1.5 equiv.) were added successively. The reaction mixture was stirred at room temperature for 2 hours. Water was added to the post-reaction system and extracted with DCM. The organic phases were combined, dried over Na2SO4 and filtered, and the filtrate was concentrated under reduced pressure and further purified by preparative TLC (DCM:MeOH=10:1) to obtain the target compound.

[0831] Synthetic route C:

[0832] The amine compound (1.0 equiv.), carboxylic acid compound (1.0 equiv.) was dissolved in dry DMF, DIPEA (3.0 equiv.) and PyBOP (1.5 equiv.) were added successively. The reaction mixture was stirred at room temperature for 2 hours. Water was added to the post-reaction system and extracted with DCM. The organic phases were combined, dried over Na2SO4 and filtered, and the filtrate was concentrated under reduced pressure and further purified by preparative TLC (DCM:MeOH=10:1) to obtain the target compound.

[0833] Synthetic route D:

[0834] The amine compound (1.0 equiv.), carboxylic acid compound (1.0 equiv.) was dissolved in dry DMF, DIPEA (3.0 equiv.) and EDCI (1.5 equiv.) were added successively. The reaction mixture was stirred at room temperature for 4 hours. Water was added to the post-reaction system and extracted with DCM. The organic phases were combined, dried over Na2SO4and filtered, and the filtrate was concentrated under reduced pressure and further purified by preparative TLC (DCM:MeOH=10:1) to obtain the target compound.

[0835] Synthetic Route E:

[0836] Step 1: The amine compound intermediate C (1.0 eq), carboxylic acid compound (1.0 eq) was dissolved in DMF, DIPEA (3.0 eq) and HATU (1.2 eq) were added successively. The reaction mixture was stirred at room temperature for 4 hours. Water was added to the post-reaction system and extracted with DCM. The organic phases were combined, dried over Na2SO4and filtered, and the filtrate was concentrated under reduced pressure and separated and purified by silica gel column chromatography (methanol / dichloromethane, 0-10%) to obtain the target compound.

[0837] Step 2: Trifluoroacetic acid (10 mL) was added dropwise to a dichloromethane solution (30 mL) of the product of Step 1 above (1.0 equiv.), and the system was stirred at room temperature for 1 hour. The reaction solution was rotary evaporated under reduced pressure to remove the solvent to obtain the target compound, which was directly used in the next reaction.

[0838] Step 3: The aldehyde compound intermediate B (1.1 eq) was added to a N,N- dimethylformamide solution (10 mL) of the amine compound of Step 2 above (1.0 eq), stirred at room temperature for 5 minutes, and triethylamine (2.0 eq) was added dropwise, stirred at room temperature for 5 hours, then sodium triacetoxyborohydride (2.0 eq) was added in two batches, the system was stirred at room temperature for 16 hours, and the reaction was monitored by TLC. 15 ml of n-butanol was added to dilute the reaction solution, and then it was washed with saturated NaCl (aq) 100 ml*5. The organic phases were combined, dried over Na2SO4and filtered, and the filtrate was concentrated under reduced pressure and further purified by preparative TLC (DCM:MeOH=10:1) to obtain the target compound.

[0839] Synthetic Route F:

[0840] Step 1: Dissolve amine intermediate C (1.0 eq), carboxylic acid (1.0 eq) in DMF, add DIPEA (3.0 eq) and HATU (1.2 eq) sequentially. Stir the reaction mixture at room temperature for 4 hours. Add water to the reaction mixture and extract with DCM. Combine the organic phases, dry over Na2SO4, filter and concentrate the filtrate under reduced pressure. Purify the residue by silica gel column chromatography (methanol / dichloromethane, 0-10%) to give the target compound.

[0841] Step 2: Dissolve the product of 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. Combine the organic phases, dry over Na2SO4, filter and concentrate the filtrate under reduced pressure. Purify the residue by silica gel column chromatography (methanol / dichloromethane, 0-5%) to give the target compound.

[0842] Step 3: Add aldehyde intermediate B (1.1 eq) to a solution of the amine from Step 2 (1.0 eq) in N,N-dimethylformamide (10 mL) and stir at room temperature for 5 minutes. Add triethylamine (2.0 eq) dropwise and stir at room temperature for 5 hours. Add sodium triacetoxyborohydride (2.0 eq) in two portions and stir the mixture at room temperature for 16 hours. Monitor the reaction by TLC. Dilute the reaction mixture with 15 mL of n-butanol and wash with 100 mL of saturated NaCl(aq) five times. Combine the organic phases, dry over Na2SO4, filter and concentrate the filtrate under reduced pressure. Purify the residue by preparative TLC (DCM:MeOH = 10:1) to give the target compound.

[0843] 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

[0844] Referring to synthetic route A, Compound 1 can be prepared, Mass (M+H): 789.4

[0845] 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

[0846] Referring to synthetic route A, Compound 2 can be prepared, Mass (M+H): 789.4

[0847] Example 3: Preparation of N-(2-(l-((l-(4-((2,6-dicarbonylpiperidin-3-yl) carbamoyl)-3-fluorophenyl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-l- yl)-2H-indazol-5-yl)isoquinoline-8-carboxamide Compound 3

[0848] Compound 3 can be prepared according to synthetic Scheme A, mass (M+H): 800.4

[0849] Example 4: Preparation of N-(2-(l-((l-(4-((2,6-dicarbonylpiperidin-3-yl) carbamoyl)-3-fluorophenyl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-l- yl)-2H-indazol-5-yl)-7H-pyrrolo[2,3-b]pyridine-5-carboxamide Compound 4

[0850] Compound 4 can be prepared according to synthetic Scheme A, mass (M+H): 789.4

[0851] Example 5: Preparation of N-(2-(l-((l-(4-((2,6-dicarbonylpiperidin-3-yl) carbamoyl)-3-fluorophenyl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-l- yl)-2H-indazol-5-yl)quinoxaline-5-carboxamide Compound 5

[0852] Compound 5 can be prepared according to synthetic Scheme A, mass (M+H): 801.4

[0853] Example 6: Preparation of N-(2-(l-((l-(4-((2,6-dicarbonylpiperidin-3-yl) carbamoyl)-3-fluorophenyl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-l- yl)-2H-indazol-5-yl)benzo[c][l,2,5]thiadiazole-4-carboxamide Compound 6

[0854] Compound 6 can be prepared according to synthetic Scheme A, mass (M+H): 807.3

[0855] Example 7: Preparation of N-(2-(l-((l-(4-((2,6-dicarbonylpiperidin-3-yl) carbamoyl)-3-fluorophenyl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-l- yl)-2H-indazol-5-yl)-2-methylimidazo[l,2-a]pyridine-6-carboxamide Compound 7

[0856] Compound 7 can be prepared according to synthetic Scheme A, mass (M+H): 803.4

[0857] Example 8: Preparation of N-(2-(l-((l-(4-((2,6-dicarbonylpiperidin-3-yl)carbamoyl)-3- fluorophenyl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-l-yl)-2H-indazol-5-yl)benzo[d]thiazole- 7-carboxamide Compound 8

[0858] Compound 8 can be prepared according to Scheme A, Mass Spec (M+H): 806.3

[0859] Example 9: Preparation of N-(2-(l-((l-(4-((2,6-dicarbonylpiperidin-3-yl)carbamoyl)-3- fluorophenyl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-l-yl)-2H-indazol-5-yl)-l-(4- fluorophenyl)-5-methyl-lH-pyrazole-4-carboxamide Compound 9

[0860] Compound 9 can be prepared according to Scheme A, Mass Spec (M+H): 847.4

[0861] Example 10: Preparation of N-(2-(l-((l-(4-((2,6-dicarbonylpiperidin-3-yl)carbamoyl)-3- fluorophenyl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-l-yl)-2H-indazol-5-yl)-l-methyl-3- (trifluoromethyl)-lH-pyrazole-4-carboxamide Compound 10

[0862] Compound 10 can be prepared according to Scheme A, Mass Spec (M+H): 821.4

[0863] Example 11: Preparation of N-(2-(l-((l-(4-((2,6-dicarbonylpiperidin-3-yl)carbamoyl)-3- fluorophenyl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-l-yl)-2H-indazol-5-yl)-l-methyl-5- (trifluoromethyl)-lH-pyrazole-4-carboxamide Compound 11

[0864] Compound 11 can be prepared according to Scheme A, Mass Spec (M+H): 821.4

[0865] Example 12: Preparation of N-(2-(l-((l-(4-((2,6-dicarbonylpiperidin-3-yl)carbamoyl)-3- fluorophenyl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-l-yl)-2H-indazol-5-yl)-[l,2,4]triazolo[4,3- a]pyridine-8-carboxamide Compound 12

[0866] Compound 12 can be prepared according to Scheme A, Mass Spec (M+H): 790.4

[0867] Example 13: Preparation of N-(2-(l-((l-(4-((2,6-dicarbonylpiperidin-3- yl)carbamoyl)-3-fluorophenyl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-l- yl)-2H-indazol-5-yl)-[l,2,4]triazolo[4,3-a]pyridine-7-carboxamide Compound 13

[0868] Compound 13 can be prepared according to Scheme A, mass spectrum (M+H): 790.4

[0869] Example 14: Preparation of N-(2-(l-((l-(4-((2,6-dicarbonylpiperidin-3- yl)carbamoyl)-3-fluorophenyl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-l- yl)-2H-indazol-5-yl)-l-phenyl-3-(trifluoromethyl)-lH-pyrazole-4-carboxamide Compound 14

[0870] Compound 14 can be prepared according to Scheme A, mass spectrum (M+H): 883.4

[0871] Example 15: Preparation of N-(2-(l-((l-(4-((2,6-dicarbonylpiperidin-3- yl)carbamoyl)-3-fluorophenyl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-l- yl)-2H-indazol-5-yl)-lH-indole-5-carboxamide Compound 15

[0872] Compound 15 can be prepared according to Scheme A, mass spectrum (M+H): 788.4

[0873] Example 16: Preparation of N-(2-(l-((l-(4-((2,6-dicarbonylpiperidin-3- yl)carbamoyl)-3-fluorophenyl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-l- yl)-2H-indazol-5-yl)-lH-indole-4-carboxamide Compound 16

[0874] Compound 16 can be prepared according to Scheme A, mass spectrum (M+H): 788.4

[0875] Example 17: Preparation of N-(2-(l-((l-(4-((2,6-dicarbonylpiperidin-3- yl)carbamoyl)-3-fluorophenyl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-l- yl)-2H-indazol-5-yl)quinoline-6-carboxamide Compound 17

[0876] Compound 17 can be prepared according to Scheme A, mass spectrum (M+H): 800.4

[0877] Example 18: Preparation of N-(2-(l-((l-(4-((2,6-dicarbonylpiperidin-3- yl)carbamoyl)-3-fluorophenyl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-l- yl)-2H-indazol-5-yl)benzo[b]thiophene-3-carboxamide Compound 18

[0878] Compound 18 can be prepared according to Scheme A, mass spectrum (M+H): 805.3

[0879] Example 19: Preparation of N-(2-(l-((l-(4-((2,6-dicarbonylpiperidin-3- yl)carbamoyl)-3-fluorophenyl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-l- yl)-2H-indazol-5-yl)-l-methyl-5-phenyl-lH-pyrazole-4-carboxamide Compound 19

[0880] Compound 19 can be prepared according to Scheme A, mass spectrum (M+H): 829.4

[0881] Example 20: Preparation of N-(2-(l-((l-(4-((2,6-dicarbonylpiperidin-3- yl)carbamoyl)-3-fluorophenyl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-l- yl)-2H-indazol-5-yl)isoquinoline-5-carboxamide Compound 20

[0882] Compound 20 can be prepared according to Scheme A, mass spectrum (M+H): 800.4

[0883] Example 21: Preparation of N-(2-(l-((l-(4-((2,6-dicarbonylpiperidin-3- yl)carbamoyl)-3-fluorophenyl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-l- yl)-2H-indazol-5-yl)imidazo[l,2-b]pyridazine-6-carboxamide Compound 21

[0884] Compound 21 can be prepared according to Scheme A, mass spectrum (M+H): 790.4

[0885] Example 22: Preparation of N-(2-(l-((l-(4-((2,6-dicarbonylpiperidin-3- yl)carbamoyl)-3-fluorophenyl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-l- yl)-2H-indazol-5-yl)-l,5-naphthyridine-3-carboxamide Compound 22

[0886] Compound 22 can be prepared according to Scheme A, mass spectrum (M+H): 801.4

[0887] Example 23: Preparation of N-(2-(l-((l-(4-((2,6-dicarbonylpiperidin-3- yl)carbamoyl)-3-fluorophenyl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-l- yl)-2H-indazol-5-yl)quinoline-4-carboxamide Compound 23

[0888] Compound 23 can be prepared according to Scheme A, mass spectrum (M+H): 800.4

[0889] Example 24: Preparation of N-(2-(l-((l-(4-((2,6-dicarbonylpiperidin-3- yl)carbamoyl)-3-fluorophenyl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-l- yl)-2H-indazol-5-yl)imidazo[l,2-a]pyridine-6-carboxamide Compound 24

[0890] Compound 24 can be prepared according to Scheme A, mass spectrum (M+H): 789.4

[0891] Example 25: Preparation of N-(2-(l-((l-(4-((2,6-dicarbonylpiperidin-3- yl)carbamoyl)-3-fluorophenyl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-l- yl)-2H-indazol-5-yl)imidazo[l,2-a]pyridine-7-carboxamide Compound 25

[0892] Compound 25 can be prepared according to Scheme A, mass spectrum (M+H): 789.4

[0893] Example 26: Preparation of N-(2-(l-((l-(4-((2,6-dicarbonylpiperidin-3- yl)carbamoyl)-3-fluorophenyl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-l- yl)-2H-indazol-5-yl)-4H-thieno[3,2-b]pyrrole-5-carboxamide Compound 26

[0894] Compound 26 can be prepared according to Scheme A, mass spectrum (M+H): 794.3

[0895] Example 27: Preparation of N-(2-(l-((l-(4-((2,6-dicarbonylpiperidin-3- yl)carbamoyl)-3-fluorophenyl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-l- yl)-2H-indazol-5-yl)quinoline-5-carboxamide Compound 27

[0896] Compound 27 can be prepared according to Scheme A, mass spectrum (M+H): 800.4

[0897] Example 28: Preparation of N-(2-(l-((l-(4-((2,6-dicarbonylpiperidin-3- yl)carbamoyl)-3-fluorophenyl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-l-yl)- 2H-indazol-5-yl)imidazo[l,5-a]pyridine-8-carboxamide Compound 28

[0898] Compound 28 can be prepared according to Scheme A, Mass Spec (M+H): 789.4

[0899] Example 29: Preparation of (S)-N-(2-(l-((l-(4-((2,6-dicarbonylpiperidin-3- yl)carbamoyl)-3-methoxyphenyl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-l-yl)- 2H-indazol-5-yl)-3H-imidazo[4,5-b]pyridine-5-carboxamide Compound 29

[0900] Compound 29 can be prepared according to Scheme B, Mass Spec (M+H): 802.4

[0901] Example 30: Preparation of N-(2-(l-((l-(4-((2,6-dicarbonylpiperidin-3- yl)carbamoyl)-3-fluorophenyl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-l-yl)- 2H-indazol-5-yl)-2-methyl-lH-benzo[d]imidazole-5-carboxamide Compound 30

[0902] Compound 30 can be prepared according to Scheme A, Mass Spec (M+H): 803.4

[0903] Example 31: Preparation of N-(2-(l-((l-(4-((2,6-dicarbonylpiperidin-3- yl)carbamoyl)-3-fluorophenyl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-l-yl)- 2H-indazol-5-yl)imidazo[l,2-a]pyridine-8-carboxamide Compound 31

[0904] Compound 31 can be prepared according to Scheme B, Mass Spec (M+H): 789.4

[0905] Example 32: Preparation of N-(2-(l-((l-(4-((2,6-dicarbonylpiperidin-3- yl)carbamoyl)-3-fluorophenyl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-l-yl)- 2H-indazol-5-yl)-3-methylimidazo[l,2-a]pyridine-6-carboxamide Compound 32

[0906] Compound 32 can be prepared according to Scheme B, Mass Spec (M+H): 803.4

[0907] Example 33: Preparation of N-(2-(l-((l-(4-((2,6-dicarbonylpiperidin-3- yl)carbamoyl)-3-fluorophenyl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-l- yl)-2H-indazol-5-yl)-lH-benzo[d]imidazole-4-carboxamide Compound 33

[0908] Compound 33 can be prepared according to synthetic route A, mass spectrum (M+H): 789.4

[0909] Example 34: Preparation of N-(2-(l-((l-(4-((2,6-dicarbonylpiperidin-3- yl)carbamoyl)-3-fluorophenyl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-l- yl)-2H-indazol-5-yl)-l-(3-methoxyphenyl)-lH-pyrazole-4-carboxamide Compound 34

[0910] Compound 34 can be prepared according to synthetic route C, mass spectrum (M+H): 845.4

[0911] Example 35: Preparation of N-(2-(l-((l-(4-((2,6-dicarbonylpiperidin-3- yl)carbamoyl)-3-fluorophenyl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-l- yl)-2H-indazol-5-yl)benzo[c][l,2,5]thiadiazole-5-carboxamide Compound 35

[0912] Compound 35 can be prepared according to synthetic route C, mass spectrum (M+H): 807.3

[0913] Example 36: Preparation of N-(2-(l-((l-(4-((2,6-dicarbonylpiperidin-3- yl)carbamoyl)-3-fluorophenyl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-l- yl)-2H-indazol-5-yl)thieno[3,2-d]pyrimidine-4-carboxamide Compound 36

[0914] Compound 36 can be prepared according to synthetic route C, mass spectrum (M+H): 807.3

[0915] Example 37: Preparation of N-(2-(l-((l-(4-((2,6-dicarbonylpiperidin-3- yl)carbamoyl)-3-fluorophenyl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-l- yl)-2H-indazol-5-yl)thieno[2,3-c]pyridine-2-carboxamide Compound 37

[0916] Compound 37 can be prepared according to synthetic route C, mass spectrum (M+H): 806.3

[0917] Example 38: Preparation of N-(2-(l-((l-(4-((2,6-dicarbonylpiperidin-3- yl)carbamoyl)-3-fluorophenyl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-l-yl)- 2H-indazol-5-yl)-4,5,6,7-tetrahydropyrazolo[l,5-a]pyridine-3-carboxamide Compound 38

[0918] Compound 38 can be prepared according to synthetic route D, mass spectrum (M+H): 793.4

[0919] Example 39: Preparation of N-(2-(l-((l-(4-((2,6-dicarbonylpiperidin-3- yl)carbamoyl)-3-fluorophenyl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-l-yl)- 2H-indazol-5-yl)pyrazolo[l,5-a]pyridine-3-carboxamide Compound 39

[0920] Compound 39 can be prepared according to synthetic route A, mass spectrum (M+H): 789.4

[0921] Example 40: Preparation of 4-amino-N-(2-(l-((l-(4-((2,6-dicarbonylpiperidin-3- yl)carbamoyl)-3-fluorophenyl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-l-yl)- 2H-indazol-5-yl)thieno[3,2-d]pyrimidine-7-carboxamide Compound 40

[0922] Compound 40 can be prepared according to synthetic route A, mass spectrum (M+H): 822.3

[0923] Example 41: Preparation of N-(2-(l-((l-(4-((2,6-dicarbonylpiperidin-3- yl)carbamoyl)-3-fluorophenyl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-l-yl)- 2H-indazol-5-yl)-5-methyl-l-phenyl-lH-pyrazole-4-carboxamide Compound 41

[0924] Compound 41 can be prepared according to synthetic route A, mass spectrum (M+H): 829.4

[0925] Example 42: Preparation of N-(2-(l-((l-(4-((2,6-dicarbonylpiperidin-3- yl)carbamoyl)-3-fluorophenyl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-l-yl)- 2H-indazol-5-yl)imidazo[l,2-b]pyridazine-2-carboxamide Compound 42

[0926] Compound 42 can be prepared according to synthetic route D, mass spectrum (M+H): 790.4

[0927] Example 43: Preparation of N-(2-(l-((l-(4-((2,6-dicarbonylpiperidin-3- yl)carbamoyl)-3-fluorophenyl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-l-yl)- 2H-indazol-5-yl)imidazo[l,2-a]pyrazine-3-carboxamide Compound 43

[0928] Compound 43 can be prepared according to Scheme D, Mass Spec (M+H): 790.4

[0929] Example 44: Preparation of N-(2-(l-((l-(4-((2,6-dicarbonylpiperidin-3- yl)carbamoyl)-3-fluorophenyl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-l-yl)- 2H-indazol-5-yl)-lH-pyrrolo[3,2-c]pyridine-7-carboxamide Compound 44

[0930] Compound 44 can be prepared according to Scheme B, Mass Spec (M+H): 789.4

[0931] Example 45: Preparation of N-(2-(l-((l-(4-((2,6-dicarbonylpiperidin-3- yl)carbamoyl)-3-fluorophenyl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-l-yl)- 2H-indazol-5-yl)pyrazolo[l,5-b]pyridazine-3-carboxamide Compound 45

[0932] Compound 45 can be prepared according to Scheme A, Mass Spec (M+H): 790.4

[0933] Example 46: Preparation of N-(2-(l-((l-(4-((2,6-dicarbonylpiperidin-3- yl)carbamoyl)-3-fluorophenyl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-l-yl)- 2H-indazol-5-yl)-lH-indole-6-carboxamide Compound 46

[0934] Compound 46 can be prepared according to Scheme A, Mass Spec (M+H): 788.4

[0935] Example 47: Preparation of N-(2-(l-((l-(4-((2,6-dicarbonylpiperidin-3- yl)carbamoyl)-3-fluorophenyl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-l-yl)- 2H-indazol-5-yl)pyrazolo[l,5-a]pyridine-3-carboxamide Compound 47

[0936] Compound 47 can be prepared according to Scheme A, Mass Spec (M+H): 789.4

[0937] Example 48: Preparation of N-(2-(l-((l-(4-((2,6-dicarbonylpiperidin-3- yl)carbamoyl)-3-fluorophenyl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-l- yl)-2H-indazol-5-yl)-lH-indole-7-carboxamide Compound 48

[0938] Compound 48 can be prepared according to Scheme C, Mass Spec (M+H): 788.4

[0939] Example 49: Preparation of N-(2-(l-((l-(4-((2,6-dicarbonylpiperidin-3- yl)carbamoyl)-3-fluorophenyl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-l- yl)-2H-indazol-5-yl)imidazo[l,5-a]pyridine-8-carboxamide Compound 49

[0940] Compound 49 can be prepared according to Scheme C, Mass Spec (M+H): 789.4

[0941] Example 50: Preparation of N-(2-(l-((l-(4-((2,6-dicarbonylpiperidin-3- yl)carbamoyl)-3-fluorophenyl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-l- yl)-2H-indazol-5-yl)-lH-pyrrolo[2,3-c]pyridine-3-carboxamide Compound 50

[0942] Compound 50 can be prepared according to Scheme C, Mass Spec (M+H): 789.4

[0943] Example 51: Preparation of N-(2-(l-((l-(4-((2,6-dicarbonylpiperidin-3- yl)carbamoyl)-3-fluorophenyl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-l- yl)-2H-indazol-5-yl)-3H-imidazo[4,5-b]pyridine-7-carboxamide Compound 51

[0944] Compound 51 can be prepared according to Scheme A, Mass Spec (M+H): 790.4

[0945] Example 52: Preparation of N-(2-(l-((l-(4-((2,6-dicarbonylpiperidin-3- yl)carbamoyl)-3-fluorophenyl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-l- yl)-2H-indazol-5-yl)-7H-pyrrolo[2,3-d]pyrimidine-4-carboxamide Compound 52

[0946] Compound 52 can be prepared according to Scheme B, Mass Spec (M+H): 790.4

[0947] Example 53: Preparation of N-(2-(l-((l-(4-((2,6-dicarbonylpiperidin-3- yl)carbamoyl)-3-fluorophenyl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-l-yl)- 2H-indazol-5-yl)-3H-imidazo[4,5-c]pyridine-7-carboxamide Compound 53

[0948] Compound 53 can be prepared according to Scheme A, Mass Spec (M+H): 790.4

[0949] Example 54: Preparation of N-(2-(l-((l-(4-((2,6-dicarbonylpiperidin-3- yl)carbamoyl)-3-fluorophenyl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-l-yl)- 2H-indazol-5-yl)pyrazolo[l,5-a]pyrimidine-6-carboxamide Compound 54

[0950] Compound 54 can be prepared according to Scheme A, Mass Spec (M+H): 790.4

[0951] Example 55: Preparation of N-(2-(l-((l-(4-((2,6-dicarbonylpiperidin-3- yl)carbamoyl)-3-fluorophenyl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-l-yl)- 2H-indazol-5-yl)-lH-pyrazolo[4,3-c]pyridine-4-carboxamide Compound 55

[0952] Compound 55 can be prepared according to Scheme D, Mass Spec (M+H): 790.4

[0953] Example 56: Preparation of (S)-N-(2-(l-((l-(4-((2,6-dicarbonylpiperidin-3- yl)carbamoyl)-3-methoxyphenyl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-l-yl)- 2H-indazol-5-yl)imidazo[l,2-a]pyridine-3-carboxamide Compound 56

[0954] Compound 56 can be prepared according to Scheme C, Mass Spec (M+H): 801.4

[0955] Example 57: Preparation of (S)-N-(2-(l-((l-(4-((2,6-dicarbonylpiperidin-3- yl)carbamoyl)-3-methoxyphenyl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-l-yl)- 2H-indazol-5-yl)-2-(2-methylpyridin-4-yl)thiazole-4-carboxamide Compound 57

[0956] Compound 57 can be prepared according to Scheme A, Mass Spec (M+H): 859.4

[0957] Example 58: Preparation of (S)-N-(2-(l-((l-(4-((2,6-dicarbonylpiperidin-3- yl)carbamoyl)-3-methoxyphenyl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-l- yl)-2H-indazol-5-yl)-2-(pyrimidin-2-yl)oxazole-4-carboxamide Compound 58

[0958] Compound 58 can be prepared according to Scheme A, mass spectrum (M+H): 830.4

[0959] Example 59: Preparation of (S)-N-(2-(l-((l-(4-((2,6-dicarbonylpiperidin-3- yl)carbamoyl)-3-methoxyphenyl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-l- yl)-2H-indazol-5-yl)-l-(pyrimidin-2-yl)-lH-imidazole-4-carboxamide Compound 59

[0960] Compound 59 can be prepared according to Scheme C, mass spectrum (M+H): 829.4

[0961] Example 60: Preparation of (S)-N-(2-(l-((l-(4-((2,6-dicarbonylpiperidin-3- yl)carbamoyl)-3-methoxyphenyl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-l- yl)-2H-indazol-5-yl)-l-(4-fluorophenyl)-5-methyl-lH-pyrazole-4-carboxamide Compound 60

[0962] Compound 60 can be prepared according to Scheme A, mass spectrum (M+H): 859.4

[0963] Example 61: Preparation of (S)-N-(2-(l-((l-(4-((2,6-dicarbonylpiperidin-3- yl)carbamoyl)-3-methoxyphenyl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-l- yl)-2H-indazol-5-yl)-2-(l-methyl-lH-pyrazol-4-yl)oxazole-4-carboxamide Compound 61

[0964] Compound 61 can be prepared according to Scheme D, mass spectrum (M+H): 832.4

[0965] Example 62: Preparation of (S)-N-(2-(l-((l-(4-((2,6-dicarbonylpiperidin-3- yl)carbamoyl)-3-methoxyphenyl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-l- yl)-2H-indazol-5-yl)-l-(2-methylpyridin-4-yl)-lH-pyrazole-4-carboxamide Compound 62

[0966] Compound 62 can be prepared according to Scheme D, Mass Spec (M+H): 842.4

[0967] Example 63: Preparation of (S)-N-(2,6-dicarbonylpiperidin-3-yl)-2-methoxy-4-(4-((4-(5-(4- phenoxybenzamido)-6-(piperidin-l-yl)-2H-indazol-2-yl)piperidin-l-yl)methyl)piperidin- 1-yl)benzamide Compound 63

[0968] Compound 63 can be prepared according to Scheme A, Mass Spec (M+H): 853.4

[0969] Example 64: Preparation of (S)-N-(2-(l-((l-(4-((2,6-dicarbonylpiperidin-3-yl)carbamoyl)-3- methoxyphenyl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-l-yl)-2H-indazol-5-yl)-2- phenylthiazole-4-carboxamide Compound 64

[0970] Compound 64 can be prepared according to Scheme B, Mass Spec (M+H): 844.4

[0971] Example 65: Preparation of (S)-N-(2-(l-((l-(4-((2,6-dicarbonylpiperidin-3-yl)carbamoyl)-3- methoxyphenyl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-l-yl)-2H-indazol-5-yl)-l- (pyridin-3-yl)-lH-pyrazole-4-carboxamide Compound 65

[0972] Compound 65 can be prepared according to Scheme A, Mass Spec (M+H): 828.4

[0973] Example 66: Preparation of (S)-N-(2-(l-((l-(4-((2,6-dicarbonylpiperidin-3-yl)carbamoyl)-3- methoxyphenyl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-l-yl)-2H-indazol-5-yl)-lH- pyrrolo[3,2-c]pyridine-3-carboxamide Compound 66

[0974] Compound 66 can be prepared according to Scheme B, Mass Spec (M+H): 801.4

[0975] Example 67: Preparation of (S)-N-(2-(l-((l-(4-((2,6-dicarbonylpiperidin-3-yl)carbamoyl)-3- methoxyphenyl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-l-yl)-2H-indazol-5-yl)benzofuran- 3-carboxamide Compound 67

[0976] Referring to synthetic scheme A, compound 67 can be prepared, mass spectrum (M+H): 801.4

[0977] Example 68: Preparation of (S)-N-(2-(l-((l-(4-((2,6-dicarbonylpiperidin-3- yl)carbamoyl)-3-methoxyphenyl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-l- yl)-2H-indazol-5-yl)-4,5,6,7-tetrahydropyrazolo[l,5-a]pyridine-2-carboxamide compound 68

[0978] Referring to synthetic scheme A, compound 68 can be prepared, mass spectrum (M+H): 805.4

[0979] Example 69: Preparation of (S)-N-(2-(l-((l-(4-((2,6-dicarbonylpiperidin-3- yl)carbamoyl)-3-methoxyphenyl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-l- yl)-2H-indazol-5-yl)-5,6-dihydro-4H-pyrrolo[l,2-b]pyrazole-2-carboxamide compound 69

[0980] Referring to synthetic scheme A, compound 69 can be prepared, mass spectrum (M+H): 791.4

[0981] Example 70: Preparation of (S)-N-(2-(l-((l-(4-((2,6-dicarbonylpiperidin-3- yl)carbamoyl)-3-methoxyphenyl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-l- yl)-2H-indazol-5-yl)-4,5,6,7-tetrahydro-lH-indazole-3-carboxamide compound 70

[0982] Referring to synthetic scheme C, compound 70 can be prepared, mass spectrum (M+H): 805.4

[0983] Example 71: Preparation of (S)-N-(2-(l-((l-(4-((2,6-dicarbonylpiperidin-3- yl)carbamoyl)-3-methoxyphenyl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-l- yl)-2H-indazol-5-yl)-l,4,5,6-tetrahydrocyclopenta[c]pyrazole-3-carboxamide compound 71

[0984] Referring to synthetic scheme D, compound 71 can be prepared, mass spectrum (M+H): 791.4

[0985] Example 72: Preparation of (S)-N-(2-(l-((l-(4-((2,6-dicarbonylpiperidin-3- yl)carbamoyl)-3-methoxyphenyl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-l- yl)-2H-indazol-5-yl)-l-methyl-l,4,5,6-tetrahydrocyclopenta[c]pyrazole-3-carboxamide Compound 72

[0986] Compound 72 can be prepared according to Scheme B, mass spectrum (M+H): 805.4

[0987] Example 73: Preparation of N-(2-(l-((l-(2-(2,6-dicarbonylpiperidin-3-yl)-l- carbonylisochromane-5-yl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-l-yl)-2H- indazol-5-yl)benzo[d]thiazole-7-carboxamide Compound 73

[0988] Compound 73 can be prepared according to Scheme A, mass spectrum (M+H): 800.3

[0989] Example 74: Preparation of N-(2-(l-((l-(2-(2,6-dicarbonylpiperidin-3-yl)-l- carbonylisochromane-5-yl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-l-yl)-2H- indazol-5-yl)-l-(4-fluorophenyl)-5-methyl-lH-pyrazole-4-carboxamide Compound 74

[0990] Compound 74 can be prepared according to Scheme A, mass spectrum (M+H): 841.4

[0991] Example 75: Preparation of N-(2-(l-((l-(2-(2,6-dicarbonylpiperidin-3-yl)-l- carbonylisochromane-5-yl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-l-yl)-2H- indazol-5-yl)-l-methyl-3-(trifluoromethyl)-lH-pyrazole-4-carboxamide Compound 75

[0992] Compound 75 can be prepared according to Scheme A, mass spectrum (M+H): 815.4

[0993] Example 76: Preparation of N-(2-(l-((l-(2-(2,6-dicarbonylpiperidin-3-yl)-l- carbonylisochromane-5-yl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-l-yl)-2H- indazol-5-yl)-4H-thieno[3,2-b]pyrrole-5-carboxamide Compound 76

[0994] Compound 76 can be prepared according to Scheme A, mass spectrum (M+H): 788.3

[0995] Example 77: Preparation of N-(2-(l-((l-(2-(2,6-dicarbonylpiperidin-3-yl)-l- carbonylisochromane-5-yl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-l-yl)-2H- indazol-5-yl)quinoline-4-carboxamide Compound 77

[0996] Compound 77 can be prepared according to Synthetic Route B, mass spectrum (M+H): 794.4

[0997] Example 78: Preparation of N-(2-(l-((l-(2-(2,6-dicarbonylpiperidin-3-yl)-l- carbonylisochromane-5-yl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-l-yl)-2H- indazol-5-yl)quinoline-5-carboxamide Compound 78

[0998] Compound 78 can be prepared according to Synthetic Route B, mass spectrum (M+H): 794.4

[0999] Example 79: Preparation of N-(2-(l-((l-(2-(2,6-dicarbonylpiperidin-3-yl)-l- carbonylisochromane-5-yl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-l-yl)-2H- indazol-5-yl)imidazo[l,2-a]pyridine-6-carboxamide Compound 79

[1000] Compound 79 can be prepared according to Synthetic Route D, mass spectrum (M+H): 783.4

[1001] Example 80: Preparation of N-(2-(l-((l-(2-(2,6-dicarbonylpiperidin-3-yl)-l- carbonylisochromane-5-yl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-l-yl)-2H- indazol-5-yl)imidazo[l,2-a]pyridine-7-carboxamide Compound 80

[1002] Compound 80 can be prepared according to Synthetic Route A, mass spectrum (M+H): 783.4

[1003] Example 81: Preparation of N-(2-(l-((l-(2-(2,6-dicarbonylpiperidin-3-yl)-l- carbonylisochromane-5-yl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-l-yl)-2H- indazol-5-yl)-l,5-naphthyridine-3-carboxamide Compound 81

[1004] Compound 81 can be prepared according to Synthetic Route C, mass spectrum (M+H): 795.4

[1005] Example 82: Preparation of N-(2-(l-((l-(2-(2,6-dicarbonylpiperidin-3-yl)-l- carbonylisochromane-5-yl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-l-yl)-2H- indazol-5-yl)-7H-pyrrolo[2,3-b]pyridine-4-carboxamide Compound 82

[1006] Compound 82 can be prepared according to Scheme A, mass spectrum (M+H): 783.4

[1007] Example 83: Preparation of N-(2-(l-((l-(2-(2,6-dicarbonylpiperidin-3-yl)-l- carbonylisochromane-5-yl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-l-yl)-2H- indazol-5-yl)isoquinoline-8-carboxamide Compound 83

[1008] Compound 83 can be prepared according to Scheme A, mass spectrum (M+H): 794.4

[1009] Example 84: Preparation of N-(2-(l-((l-(2-(2,6-dicarbonylpiperidin-3-yl)-l- carbonylisochromane-5-yl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-l-yl)-2H- indazol-5-yl)quinoxaline-5-carboxamide Compound 84

[1010] Compound 84 can be prepared according to Scheme B, mass spectrum (M+H): 795.4

[1011] Example 85: Preparation of N-(2-(l-((l-(2-(2,6-dicarbonylpiperidin-3-yl)-l- carbonylisochromane-5-yl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-l-yl)-2H- indazol-5-yl)-7H-pyrrolo[2,3-b]pyridine-5-carboxamide Compound 85

[1012] Compound 85 can be prepared according to Scheme C, mass spectrum (M+H): 783.4

[1013] Example 86: Preparation of N-(2-(l-((l-(2-(2,6-dicarbonylpiperidin-3-yl)-l- carbonylisochromane-5-yl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-l-yl)-2H- indazol-5-yl)-2-methylimidazo[l,2-a]pyridine-6-carboxamide Compound 86

[1014] Compound 86 can be prepared according to Scheme C, mass spectrum (M+H): 797.4

[1015] Example 87: Preparation of N-(2-(l-((l-(2-(2,6-dicarbonylpiperidin-3-yl)-l- carbonylisodiindol-5-yl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-l-yl)-2H- indazol-5-yl)benzo[c][l,2,5]thiadiazole-4-carboxamide Compound 87

[1016] Compound 87 can be prepared according to Scheme A, Mass Spec (M+H): 801.3

[1017] Example 88: Preparation of N-(2-(l-((l-(4-((2,6-dicarbonylpiperidin-3-yl)carbamoyl)- 3-fluorophenyl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-l-yl)-2H-indazol-5- yl)imidazo[l,2-a]pyridine-3-carboxamide Compound 88

[1018] Compound 88 can be prepared according to Scheme A, Mass Spec (M+H): 789.4

[1019] Example 89: Preparation of N-(2-(l-((l-(4-((2,6-dicarbonylpiperidin-3-yl)carbamoyl)- 3-fluorophenyl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-l-yl)-2H-indazol-5- yl)-lH-pyrrolo[3,2-b]pyridine-3-carboxamide Compound 89

[1020] Compound 89 can be prepared according to Scheme D, Mass Spec (M+H): 789.4

[1021] Example 90: Preparation of N-(2-(l-((l-(4-((2,6-dicarbonylpiperidin-3-yl)carbamoyl)- 3-fluorophenyl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-l-yl)-2H-indazol-5- yl)-2-(2-methylpyridin-4-yl)thiazole-4-carboxamide Compound 90

[1022] Compound 90 can be prepared according to Scheme A, Mass Spec (M+H): 847.3

[1023] Example 91: Preparation of N-(2-(l-((l-(4-((2,6-dicarbonylpiperidin-3-yl)carbamoyl)- 3-fluorophenyl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-l-yl)-2H-indazol-5- yl)-2-(pyrimidin-2-yl)oxazole-4-carboxamide Compound 91

[1024] Compound 91 can be prepared according to Scheme D, Mass Spec (M+H): 818.4

[1025] Example 92: Preparation of N-(2-(l-((l-(4-((2,6-dicarbonylpiperidin-3- yl)carbamoyl)-3-fluorophenyl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-l- yl)-2H-indazol-5-yl)-l-(pyrimidin-2-yl)-lH-imidazole-4-carboxamide Compound 92

[1026] Compound 92 can be prepared according to Scheme A, mass spectrum (M+H): 817.4

[1027] Example 93: Preparation of N-(2-(l-((l-(4-((2,6-dicarbonylpiperidin-3- yl)carbamoyl)-3-fluorophenyl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-l- yl)-2H-indazol-5-yl)-2-(l-methyl-lH-pyrazol-4-yl)oxazole-4-carboxamide Compound 93

[1028] Compound 93 can be prepared according to Scheme C, mass spectrum (M+H): 820.4

[1029] Example 94: Preparation of N-(2-(l-((l-(4-((2,6-dicarbonylpiperidin-3- yl)carbamoyl)-3-fluorophenyl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-l- yl)-2H-indazol-5-yl)-l-(2-methylpyridin-4-yl)-lH-pyrazole-4-carboxamide Compound 94

[1030] Compound 94 can be prepared according to Scheme A, mass spectrum (M+H): 830.4

[1031] Example 95: Preparation of N-(2,6-dicarbonylpiperidin-3-yl)-2-fluoro-4-(4-((4-(5-(4- phenoxybenzamido)-6-(piperidin-l-yl)-2H-indazol-2-yl)piperidin-l-yl)methyl)piperidin- 1-yl)benzamide Compound 95

[1032] Compound 95 can be prepared according to Scheme D, mass spectrum (M+H): 841.4

[1033] Example 96: Preparation of N-(2-(l-((l-(4-((2,6-dicarbonylpiperidin-3- yl)carbamoyl)-3-fluorophenyl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-l- yl)-2H-indazol-5-yl)-2-phenylthiazole-4-carboxamide Compound 96

[1034] Compound 96 can be prepared according to Scheme A, mass spectrum (M+H): 832.3

[1035] Example 97: Preparation of N-(2-(l-((l-(4-((2,6-dicarbonylpiperidin-3- yl)carbamoyl)-3-fluorophenyl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-l-yl)- 2H-indazol-5-yl)-l-(pyridin-3-yl)-lH-pyrazole-4-carboxamide Compound 97

[1036] Compound 97 can be prepared according to synthetic route B, mass spectrum (M+H): 816.4

[1037] Example 98: Preparation of N-(2-(l-((l-(4-((2,6-dicarbonylpiperidin-3- yl)carbamoyl)-3-fluorophenyl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-l-yl)- 2H-indazol-5-yl)-lH-pyrrolo[3,2-c]pyridine-3-carboxamide Compound 98

[1038] Compound 98 can be prepared according to synthetic route B, mass spectrum (M+H): 789.4

[1039] Example 99: Preparation of N-(2-(l-((l-(4-((2,6-dicarbonylpiperidin-3- yl)carbamoyl)-3-fluorophenyl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-l-yl)- 2H-indazol-5-yl)benzofuran-3-carboxamide Compound 99

[1040] Compound 99 can be prepared according to synthetic route A, mass spectrum (M+H): 789.4

[1041] Example 100: Preparation of N-(2-(l-((l-(4-((2,6-dicarbonylpiperidin-3- yl)carbamoyl)-3-fluorophenyl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-l-yl)- 2H-indazol-5-yl)-4,5,6,7-tetrahydropyrrolo[l,5-a]pyridine-2-carboxamide Compound 100

[1042] Compound 100 can be prepared according to synthetic route A, mass spectrum (M+H): 793.4

[1043] Example 101: Preparation of N-(2-(l-((l-(4-((2,6-dicarbonylpiperidin-3- yl)carbamoyl)-3-fluorophenyl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-l-yl)- 2H-indazol-5-yl)-5,6-dihydro-4H-pyrrolo[l,2-b]pyrazole-2-carboxamide Compound 101

[1044] Compound 101 can be prepared according to synthetic route A, mass spectrum (M+H): 779.4

[1045] Example 102: Preparation of N-(2-(l-((l-(4-((2,6-dicarbonylpiperidin-3- yl)carbamoyl)-3-fluorophenyl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-l- yl)-2H-indazol-5-yl)-4,5,6,7-tetrahydro-lH-indazole-3-carboxamide Compound 102

[1046] Compound 102 can be prepared according to synthetic route C, mass spectrum (M+H): 793.4

[1047] Example 103: Preparation of N-(2-(l-((l-(4-((2,6-dicarbonylpiperidin-3- yl)carbamoyl)-3-fluorophenyl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-l- yl)-2H-indazol-5-yl)-l,4,5,6-tetrahydrocyclopenta[c]pyrazole-3-carboxamide Compound 103

[1048] Compound 103 can be prepared according to synthetic route A, mass spectrum (M+H): 779.4

[1049] Example 104: Preparation of N-(2-(l-((l-(4-((2,6-dicarbonylpiperidin-3- yl)carbamoyl)-3-fluorophenyl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-l- yl)-2H-indazol-5-yl)-l-methyl-l,4,5,6-tetrahydrocyclopenta[c]pyrazole-3-carboxamide Compound 104

[1050] Compound 104 can be prepared according to synthetic route D, mass spectrum (M+H): 793.4

[1051] Example 105: Preparation of N-(2-(l-((l-(4-((2,6-dicarbonylpiperidin-3- yl)carbamoyl)-3-fluorophenyl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-l- yl)-2H-indazol-5-yl)benzofuran-4-carboxamide Compound 105

[1052] Compound 105 can be prepared according to synthetic route C, mass spectrum (M+H): 789.3

[1053] Example 106: Preparation of N-(2-(l-((l-(4-((2,6-dicarbonylpiperidin-3- yl)carbamoyl)-3-fluorophenyl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-l- yl)-2H-indazol-5-yl)imidazo[l,2-b]pyridazine-3-carboxamide Compound 106

[1054] Compound 106 can be prepared according to synthetic route A, mass spectrum (M+H): 790.4

[1055] Example 107: Preparation of N-(2-(l-((l-(2-(2,6-dicarbonylpiperidin-3-yl)-l,3- dicarbonylisatindoline-5-yl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-l-yl)- 2H-indazol-5-yl)benzo[d]thiazole-7-carboxamide Compound 107

[1056] Compound 107 can be prepared according to Synthetic Route A, Mass Spec (M+H): 814.3

[1057] Example 108: Preparation of N-(2-(l-((l-(2-(2,6-dicarbonylpiperidin-3-yl)-l,3- dicarbonylisatindoline-5-yl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-l-yl)- 2H-indazol-5-yl)-l-(4-fluorophenyl)-5-methyl-lH-pyrazole-4-carboxamide Compound 108

[1058] Compound 108 can be prepared according to Synthetic Route B, Mass Spec (M+H): 855.4

[1059] Example 109: Preparation of N-(2-(l-((l-(2-(2,6-dicarbonylpiperidin-3-yl)-l,3- dicarbonylisatindoline-5-yl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-l-yl)- 2H-indazol-5-yl)-l-methyl-3-(trifluoromethyl)-lH-pyrazole-4-carboxamide Compound 109

[1060] Compound 109 can be prepared according to Synthetic Route A, Mass Spec (M+H): 829.3

[1061] Example 110: Preparation of N-(2-(l-((l-(2-(2,6-dicarbonylpiperidin-3-yl)-l,3- dicarbonylisatindoline-5-yl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-l-yl)- 2H-indazol-5-yl)-4H-thieno[3,2-b]pyrrole-5-carboxamide Compound 110

[1062] Compound 110 can be prepared according to Synthetic Route B, Mass Spec (M+H): 802.3

[1063] Example 111: Preparation of N-(2-(l-((l-(2-(2,6-dicarbonylpiperidin-3-yl)-l,3- dicarbonylisatindoline-5-yl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-l-yl)- 2H-indazol-5-yl)quinoline-4-carboxamide Compound 111

[1064] Referring to synthetic scheme A, compound 111 can be prepared, mass spectrum (M+H): 808.4

[1065] Example 112: Preparation of N-(2-(l-((l-(2-(2,6-dicarbonylpiperidin-3-yl)-l,3- dicarbonylisatindoline-5-yl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-l-yl)-2H- indazol-5-yl)quinoline-5-carboxamide compound 112

[1066] Referring to synthetic scheme D, compound 112 can be prepared, mass spectrum (M+H): 808.4

[1067] Example 113: Preparation of N-(2-(l-((l-(2-(2,6-dicarbonylpiperidin-3-yl)-l,3- dicarbonylisatindoline-5-yl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-l-yl)-2H- indazol-5-yl)imidazo[l,2-a]pyridine-6-carboxamide compound 113

[1068] Referring to synthetic scheme A, compound 113 can be prepared, mass spectrum (M+H): 797.4

[1069] Example 114: Preparation of N-(2-(l-((l-(2-(2,6-dicarbonylpiperidin-3-yl)-l,3- dicarbonylisatindoline-5-yl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-l-yl)-2H- indazol-5-yl)imidazo[l,2-a]pyridine-7-carboxamide compound 114

[1070] Referring to synthetic scheme C, compound 114 can be prepared, mass spectrum (M+H): 797.4

[1071] Example 115: Preparation of N-(2-(l-((l-(2-(2,6-dicarbonylpiperidin-3-yl)-l,3- dicarbonylisatindoline-5-yl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-l-yl)-2H- indazol-5-yl)-lH-benzo[d]imidazole-6-carboxamide compound 115

[1072] Referring to synthetic scheme A, compound 115 can be prepared, mass spectrum (M+H): 797.4

[1073] Example 116: Preparation of N-(2-(l-((l-(2-(2,6-dicarbonylpiperidin-3-yl)-l,3- dicarbonylisatindoline-5-yl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-l-yl)-2H- indazol-5-yl)-l,5-naphthyridine-3-carboxamide compound 116

[1074] Referring to synthetic scheme B, compound 116 can be prepared, mass spectrum (M+H): 809.4

[1075] Example 117: Preparation of N-(2-(l-((l-(2-(2,6-dicarbonylpiperidin-3-yl)-l,3- dicarbonylisatindoline-5-yl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-l-yl)-2H- indazol-5-yl)-7H-pyrrolo[2,3-b]pyridine-4-carboxamide compound 117

[1076] Referring to synthetic scheme D, compound 117 can be prepared, mass spectrum (M+H): 797.4

[1077] Example 118: Preparation of N-(2-(l-((l-(2-(2,6-dicarbonylpiperidin-3-yl)-l,3- dicarbonylisatindoline-5-yl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-l-yl)-2H- indazol-5-yl)isoquinoline-8-carboxamide compound 118

[1078] Referring to synthetic scheme A, compound 118 can be prepared, mass spectrum (M+H): 808.4

[1079] Example 119: Preparation of N-(2-(l-((l-(2-(2,6-dicarbonylpiperidin-3-yl)-l,3- dicarbonylisatindoline-5-yl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-l-yl)-2H- indazol-5-yl)quinoxaline-5-carboxamide compound 119

[1080] Referring to synthetic scheme A, compound 119 can be prepared, mass spectrum (M+H): 809.4

[1081] Example 120: Preparation of N-(2-(l-((l-(2-(2,6-dicarbonylpiperidin-3-yl)-l,3- dicarbonylisatindoline-5-yl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-l-yl)-2H- indazol-5-yl)-7H-pyrrolo[2,3-b]pyridine-5-carboxamide compound 120

[1082] Referring to synthetic scheme D, compound 120 can be prepared, mass spectrum (M+H): 797.4

[1083] Example 121: Preparation of N-(2-(l-((l-(2-(2,6-dicarbonylpiperidin-3-yl)-l,3- dicarbonylisatindoline-5-yl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-l-yl)-2H- indazol-5-yl)-2-methylimidazo[l,2-a]pyridine-6-carboxamide compound 121

[1084] Compound 121 can be prepared according to Scheme A, Mass Spec (M+H): 811.4

[1085] Example 122: Preparation of N-(2-(l-((l-(2-(2,6-dicarbonylpiperidin-3-yl)-l,3- dicarbonylisatindin-5-yl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-l-yl)-2H- indazol-5-yl)benzo[c][l,2,5]thiadiazole-4-carboxamide Compound 122

[1086] Compound 122 can be prepared according to Scheme B, Mass Spec (M+H): 815.3

[1087] Example 123: Preparation of N-(2-(l-((l-(2-(2,6-dicarbonylpiperidin-3-yl)-l,3- dicarbonylisatindin-5-yl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-l-yl)-2H- indazol-5-yl)-lH-indole-4-carboxamide Compound 123

[1088] Compound 123 can be prepared according to Scheme A, Mass Spec (M+H): 796.4

[1089] Example 124: Preparation of N-(2-(l-((l-(2-(2,6-dicarbonylpiperidin-3-yl)-l,3- dicarbonylisatindin-5-yl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-l-yl)-2H- indazol-5-yl)-lH-indole-5-carboxamide Compound 124

[1090] Compound 124 can be prepared according to Scheme B, Mass Spec (M+H): 796.4

[1091] Example 125: Preparation of N-(2-(l-((l-(2-(2,6-dicarbonylpiperidin-3-yl)-l,3- dicarbonylisatindin-5-yl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-l-yl)-2H- indazol-5-yl)quinoline-6-carboxamide Compound 125

[1092] Compound 125 can be prepared according to Scheme A, Mass Spec (M+H): 808.4

[1093] Example 126: Preparation of N-(2-(l-((l-(2-(2,6-dicarbonylpiperidin-3-yl)-l,3- dicarbonylisatindin-5-yl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-l-yl)-2H- indazol-5-yl)benzo[b]thiophene-3-carboxamide Compound 126

[1094] Compound 126 can be prepared according to Scheme B, Mass Spec (M+H): 813.3

[1095] Example 127: Preparation of N-(2-(l-((l-(2-(2,6-dicarbonylpiperidin-3-yl)-l,3- dicarbonylisochromane-5-yl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-l-yl)- 2H-indazol-5-yl)isoquinoline-5-carboxamide Compound 127

[1096] Compound 127 can be prepared according to Scheme B, Mass Spec (M+H): 808.4

[1097] Example 128: Preparation of N-(2-(l-((l-(2-(2,6-dicarbonylpiperidin-3-yl)-l,3- dicarbonylisochromane-5-yl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-l-yl)- 2H-indazol-5-yl)imidazo[l,2-b]pyridazine-6-carboxamide Compound 128

[1098] Compound 128 can be prepared according to Scheme B, Mass Spec (M+H): 798.4

[1099] Example 129: Preparation of N-(2-(l-((l-(2-(2,6-dicarbonylpiperidin-3-yl)-l,3- dicarbonylisochromane-5-yl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-l-yl)- 2H-indazol-5-yl)imidazo[l,5-a]pyridine-8-carboxamide Compound 129

[1100] Compound 129 can be prepared according to Scheme B, Mass Spec (M+H): 797.4

[1101] Example 130: Preparation of N-(2-(l-((l-(2-(2,6-dicarbonylpiperidin-3-yl)-l,3- dicarbonylisochromane-5-yl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-l-yl)- 2H-indazol-5-yl)-2-methyl-lH-benzo[d]imidazole-5-carboxamide Compound 130

[1102] Compound 130 can be prepared according to Scheme A, Mass Spec (M+H): 811.4

[1103] Example 131 : Preparation of N-(2-(l-((l-(2-(2,6-dicarbonylpiperidin-3-yl)-l,3- dicarbonylisatindin-5-yl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-l-yl)-2H- indazol-5-yl)imidazo[l,2-a]pyridine-8-carboxamide Compound 131

[1104] Compound 131 can be prepared according to Scheme A, mass spectrum (M+H): 797.4

[1105] Example 132: Preparation of N-(2-(l-((l-(2-(2,6-dicarbonylpiperidin-3-yl)-l,3- dicarbonylisatindin-5-yl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-l-yl)-2H- indazol-5-yl)-3-methylimidazo[l,2-a]pyridine-6-carboxamide Compound 132

[1106] Compound 132 can be prepared according to Scheme C, mass spectrum (M+H): 811.4

[1107] Example 133: Preparation of N-(2-(l-((l-(2-(2,6-dicarbonylpiperidin-3-yl)-l,3- dicarbonylisatindin-5-yl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-l-yl)-2H- indazol-5-yl)-lH-benzo[d]imidazole-4-carboxamide Compound 133

[1108] Compound 133 can be prepared according to Scheme C, mass spectrum (M+H): 797.4

[1109] Example 134: Preparation of N-(2-(l-((l-(2-(2,6-dicarbonylpiperidin-3-yl)-l,3- dicarbonylisatindin-5-yl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-l-yl)-2H- indazol-5-yl)-l-(3-methoxyphenyl)-lH-pyrazole-4-carboxamide Compound 134

[1110] Compound 134 can be prepared according to Scheme C, mass spectrum (M+H): 853.4

[1111] Example 135: Preparation of N-(2-(l-((l-(2-(2,6-dicarbonylpiperidin-3-yl)-l,3- dicarbonylisatindin-5-yl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-l-yl)-2H- indazol-5-yl)benzo[c][l,2,5]thiadiazole-5-carboxamide Compound 135

[1112] Referring to synthetic scheme A, compound 135 can be prepared, Mass (M+H): 815.3

[1113] Example 136: Preparation of N-(2-(l-((l-(2-(2,6-dicarbonylpiperidin-3-yl)-l,3- dicarbonylisatindin-5-yl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-l-yl)-2H- indazol-5-yl)thieno[3,2-d]pyrimidine-4-carboxamide compound 136

[1114] Referring to synthetic scheme D, compound 136 can be prepared, Mass (M+H): 815.3

[1115] Example 137: Preparation of N-(2-(l-((l-(2-(2,6-dicarbonylpiperidin-3-yl)-l,3- dicarbonylisatindin-5-yl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-l-yl)-2H- indazol-5-yl)thieno[2,3-c]pyridine-2-carboxamide compound 137

[1116] Referring to synthetic scheme A, compound 137 can be prepared, Mass (M+H): 814.3

[1117] Example 138: Preparation of N-(2-(l-((l-(2-(2,6-dicarbonylpiperidin-3-yl)-l,3- dicarbonylisatindin-5-yl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-l-yl)-2H- indazol-5-yl)-l-methyl-5-(trifluoromethyl)-lH-pyrazole-4-carboxamide compound 138

[1118] Referring to synthetic scheme D, compound 138 can be prepared, Mass (M+H): 829.3

[1119] Example 139: Preparation of N-(2-(l-((l-(2-(2,6-dicarbonylpiperidin-3-yl)-l,3- dicarbonylisatindin-5-yl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-l-yl)-2H- indazol-5-yl)-[l,2,4]triazolo[4,3-a]pyridine-8-carboxamide compound 139

[1120] Referring to synthetic scheme D, compound 139 can be prepared, Mass (M+H): 798.4

[1121] Example 140: Preparation of N-(2-(l-((l-(2-(2,6-dicarbonylpiperidin-3-yl)-l,3- dicarbonylisatindoline-5-yl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-l-yl)-2H- indazol-5-yl)-[l,2,4]triazolo[4,3-a]pyridine-7-carboxamide Compound 140

[1122] Compound 140 can be prepared according to Scheme D, Mass Spec (M+H): 798.4

[1123] Example 141: Preparation of N-(2-(l-((l-(2-(2,6-dicarbonylpiperidin-3-yl)-l,3- dicarbonylisatindoline-5-yl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-l-yl)-2H- indazol-5-yl)-l-phenyl-3-(trifluoromethyl)-lH-pyrazole-4-carboxamide Compound 141

[1124] Compound 141 can be prepared according to Scheme D, Mass Spec (M+H): 891.4

[1125] Example 142: Preparation of N-(2-(l-((l-(2-(2,6-dicarbonylpiperidin-3-yl)-l,3- dicarbonylisatindoline-5-yl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-l-yl)-2H- indazol-5-yl)-4,5,6,7-tetrahydropyrazolo[l,5-a]pyridine-3-carboxamide Compound 142

[1126] Compound 142 can be prepared according to Scheme A, Mass Spec (M+H): 801.4

[1127] Example 143: Preparation of N-(2-(l-((l-(2-(2,6-dicarbonylpiperidin-3-yl)-3- carbonylisatindoline-5-yl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-l-yl)-2H- indazol-5-yl)benzo[d]thiazole-7-carboxamide Compound 143

[1128] Compound 143 can be prepared according to Scheme A, Mass Spec (M+H): 800.3

[1129] Example 144: Preparation of N-(2-(l-((l-(2-(2,6-dicarbonylpiperidin-3-yl)-3- carbonylisatindoline-5-yl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-l-yl)-2H- indazol-5-yl)imidazo[l,2-a]pyridine-7-carboxamide Compound 144

[1130] Referring to synthetic scheme B, compound 144 can be prepared, mass spectrum (M+H): 783.4

[1131] Example 145: Preparation of N-(2-(l-((l-(2-(2,6-dicarbonylpiperidin-3-yl)-3- carbonylisochromane-5-yl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-l-yl)-2H- indazol-5-yl)-l,5-naphthyridine-3-carboxamide compound 145

[1132] Referring to synthetic scheme A, compound 145 can be prepared, mass spectrum (M+H): 795.4

[1133] Example 146: Preparation of N-(2-(l-((l-(2-(2,6-dicarbonylpiperidin-3-yl)-3- carbonylisochromane-5-yl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-l-yl)-2H- indazol-5-yl)imidazo[l,2-a]pyridine-8-carboxamide compound 146

[1134] Referring to synthetic scheme B, compound 146 can be prepared, mass spectrum (M+H): 783.4

[1135] Example 147: Preparation of N-(2-(l-((l-(2-(2,6-dicarbonylpiperidin-3-yl)-3- carbonylisochromane-5-yl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-l-yl)-2H- indazol-5-yl)-lH-benzo[d]imidazole-4-carboxamide compound 147

[1136] Referring to synthetic scheme B, compound 147 can be prepared, mass spectrum (M+H): 783.4

[1137] Example 148: Preparation of N-(2-(l-((l-(2-(2,6-dicarbonylpiperidin-3-yl)-3- carbonylisochromane-5-yl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-l-yl)-2H- indazol-5-yl)pyrazolo[l,5-a]pyridine-3-carboxamide compound 148

[1138] Referring to synthetic scheme C, compound 148 can be prepared, mass spectrum (M+H): 783.4

[1139] Example 149: Preparation of N-(2-(l-((l-(2-(2,6-dicarbonylpiperidin-3-yl)-3- carbonylisochromane-5-yl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-l-yl)-2H- indazol-5-yl)-4-phenoxybenzamide compound 149

[1140] Referring to synthetic scheme A, compound 149 can be prepared, mass spectrum (M+H): 835.4

[1141] Example 150: Preparation of N-(2-(l-((l-(2-(2,6-dicarbonylpiperidin-3-yl)-3- carbonylisochromane-5-yl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-l-yl)-2H- indazol-5-yl)imidazo[l,2-b]pyridazine-6-carboxamide compound 150

[1142] Referring to synthetic scheme A, compound 150 can be prepared, mass spectrum (M+H): 784.4

[1143] Example 151: Preparation of N-(2-(l-((l-(2-(2,6-dicarbonylpiperidin-3-yl)-3- carbonylisochromane-5-yl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-l-yl)-2H- indazol-5-yl)-[l,2,4]triazolo[4,3-a]pyridine-8-carboxamide compound 151

[1144] Referring to synthetic scheme A, compound 151 can be prepared, mass spectrum (M+H): 784.4

[1145] Example 152: Preparation of N-(2-(l-((l-(2-(2,6-dicarbonylpiperidin-3-yl)-3- carbonylisochromane-5-yl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-l-yl)-2H- indazol-5-yl)-[l,2,4]triazolo[4,3-a]pyridine-7-carboxamide compound 152

[1146] Referring to synthetic scheme B, compound 152 can be prepared, mass spectrum (M+H): 784.4

[1147] Example 153: Preparation of 4-amino-N-(2-(l-((l-(2-(2,6-dicarbonylpiperidin-3-yl)-3- carbonylisochromane-5-yl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-l-yl)-2H- indazol-5-yl)thieno[3,2-d]pyrimidine-7-carboxamide compound 153

[1148] Referring to synthetic scheme D, compound 153 can be prepared, mass spectrum (M+H): 816.3

[1149] Example 154: Preparation of N-(2-(l-((l-(2-(2,6-dicarbonylpiperidin-3-yl)-3- carbonylisochromane-5-yl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-l-yl)-2H- indazol-5-yl)imidazo[l,2-b]pyridazine-2-carboxamide compound 154

[1150] Compound 154 can be prepared according to Scheme D, Mass Spec (M+H): 784.4

[1151] Example 155: Preparation of N-(2-(l-((l-(2-(2,6-dicarbonylpiperidin-3-yl)-3- carbonylisochromane-5-yl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-l-yl)-2H- indazol-5-yl)-3H-imidazo[4,5-b]pyridine-7-carboxamide Compound 155

[1152] Compound 155 can be prepared according to Scheme A, Mass Spec (M+H): 784.4

[1153] Example 156: Preparation of N-(2-(l-((l-(2-(2,6-dicarbonylpiperidin-3-yl)-3- carbonylisochromane-5-yl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-l-yl)-2H- indazol-5-yl)-3H-imidazo[4,5-c]pyridine-7-carboxamide Compound 156

[1154] Compound 156 can be prepared according to Scheme A, Mass Spec (M+H): 784.4

[1155] Example 157: Preparation of N-(2-(l-((l-(2-(2,6-dicarbonylpiperidin-3-yl)-3- carbonylisochromane-5-yl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-l-yl)-2H- indazol-5-yl)-2-(2-methylpyridin-4-yl)thiazole-4-carboxamide Compound 157

[1156] Compound 157 can be prepared according to Scheme D, Mass Spec (M+H): 841.4

[1157] Example 158: Preparation of N-(2-(l-((l-(2-(2,6-dicarbonylpiperidin-3-yl)-3- carbonylisochromane-5-yl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-l-yl)-2H- indazol-5-yl)-2-(pyrimidin-2-yl)oxazole-4-carboxamide Compound 158

[1158] Compound 158 can be prepared according to Scheme B, Mass Spec (M+H): 812.4

[1159] Example 159: Preparation of N-(2-(l-((l-(2-(2,6-dicarbonylpiperidin-3-yl)-3- carbonylisochromane-5-yl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-l-yl)-2H- indazol-5-yl)-2-(l-methyl-lH-pyrazol-4-yl)oxazole-4-carboxamide Compound 159

[1160] Compound 159 can be prepared according to Scheme D, mass spectrum (M+H): 814.4

[1161] Example 160: Preparation of N-(2-(l-((l-(2-(2,6-dicarbonylpiperidin-3-yl)-3- carbonylisochromane-5-yl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-l-yl)-2H- indazol-5-yl)-2-phenylthiazole-4-carboxamide Compound 160

[1162] Compound 160 can be prepared according to Scheme D, mass spectrum (M+H): 826.4

[1163] Example 161: Preparation of N-(2-(l-((l-(2-(2,6-dicarbonylpiperidin-3-yl)-3- carbonylisochromane-5-yl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-l-yl)-2H- indazol-5-yl)-lH-pyrrolo[3,2-c]pyridine-3-carboxamide Compound 161

[1164] Compound 161 can be prepared according to Scheme A, mass spectrum (M+H): 783.4

[1165] Example 162: Preparation of N-(2-(l-((l-(2-(2,6-dicarbonylpiperidin-3-yl)-3- carbonylisochromane-5-yl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-l-yl)-2H- indazol-5-yl)benzofuran-3-carboxamide Compound 162

[1166] Compound 162 can be prepared according to Scheme A, mass spectrum (M+H): 783.4

[1167] Example 163: Preparation of N-(2-(l-((l-(2-(2,6-dicarbonylpiperidin-3-yl)-3- carbonylisochromane-5-yl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-l-yl)-2H- indazol-5-yl)-4,5,6,7-tetrahydropyrazolo[l,5-a]pyridine-2-carboxamide Compound 163

[1168] Compound 163 can be prepared according to Scheme A, mass spectrum (M+H): 787.4

[1169] Example 164: Preparation of N-(2-(l-((l-(2-(2,6-dicarbonylpiperidin-3-yl)-3- carbonylisochroman-5-yl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-l-yl)-2H- indazol-5-yl)-5,6-dihydro-4H-pyrrolo[l,2-b]pyrazole-2-carboxamide Compound 164

[1170] Compound 164 can be prepared according to Scheme A, mass spectrum (M+H): 773.4

[1171] Example 165: Preparation of N-(2-(l-((l-(2-(2,6-dicarbonylpiperidin-3-yl)-3- carbonylisochroman-5-yl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-l-yl)-2H- indazol-5-yl)-4,5,6,7-tetrahydro-lH-indazole-3-carboxamide Compound 165

[1172] Compound 165 can be prepared according to Scheme A, mass spectrum (M+H): 787.4

[1173] Example 166: Preparation of N-(2-(l-((l-(2-(2,6-dicarbonylpiperidin-3-yl)-l- carbonylisochroman-5-yl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-l-yl)-2H- indazol-5-yl)-2-(pyridin-4-yl)thiazole-4-carboxamide Compound 166

[1174] Compound 166 can be prepared according to Scheme A, mass spectrum (M+H): 827.3

[1175] Example 167: Preparation of N-(2-(l-((l-(2-(2,6-dicarbonylpiperidin-3-yl)-l- carbonylisochroman-5-yl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-l-yl)-2H- indazol-5-yl)imidazo[l,2-b]pyridazine-6-carboxamide Compound 167

[1176] Compound 167 can be prepared according to Scheme A, mass spectrum (M+H): 784.4

[1177] Example 168: Preparation of N-(2-(l-((l-(2-(2,6-dicarbonylpiperidin-3-yl)-l- carbonylisochroman-5-yl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-l-yl)-2H- indazol-5-yl)imidazo[l,2-a]pyridine-8-carboxamide Compound 168

[1178] Compound 168 can be prepared according to Scheme D, Mass (M+H): 783.4

[1179] Example 169: Preparation of N-(2-(l-((l-(2-(2,6-dicarbonylpiperidin-3-yl)-l- carbonylisochromane-5-yl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-l-yl)-2H- indazol-5-yl)-lH-benzo[d]imidazole-4-carboxamide Compound 169

[1180] Compound 169 can be prepared according to Scheme A, Mass (M+H): 783.4

[1181] Example 170: Preparation of N-(2-(l-((l-(2-(2,6-dicarbonylpiperidin-3-yl)-l- carbonylisochromane-5-yl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-l-yl)-2H- indazol-5-yl)-[l,2,4]triazolo[4,3-a]pyridine-8-carboxamide Compound 170

[1182] Compound 170 can be prepared according to Scheme B, Mass (M+H): 784.4

[1183] Example 171: Preparation of N-(2-(l-((l-(2-(2,6-dicarbonylpiperidin-3-yl)-l- carbonylisochromane-5-yl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-l-yl)-2H- indazol-5-yl)-[l,2,4]triazolo[4,3-a]pyridine-7-carboxamide Compound 171

[1184] Compound 171 can be prepared according to Scheme A, Mass (M+H): 784.4

[1185] Example 172: Preparation of N-(2-(l-((l-(2-(2,6-dicarbonylpiperidin-3-yl)-l- carbonylisochromane-5-yl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-l-yl)-2H- indazol-5-yl)pyrazolo[l,5-a]pyridine-3-carboxamide Compound 172

[1186] Compound 172 can be prepared according to Scheme D, Mass (M+H): 783.4

[1187] Example 173: Preparation of 4-amino-N-(2-(l-((l-(2-(2,6-dicarbonylpiperidin-3-yl)-l- carbonylisochromane-5-yl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-l-yl)-2H- indazol-5-yl)thieno[3,2-d]pyrimidine-7-carboxamide Compound 173

[1188] Compound 173 can be prepared according to Scheme A, Mass Spec (M+H): 816.3

[1189] Example 174: Preparation of N-(2-(l-((l-(2-(2,6-dicarbonylpiperidin-3-yl)-l- carbonylisochromane-5-yl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-l-yl)-2H- indazol-5-yl)imidazo[l,2-b]pyridazine-2-carboxamide Compound 174

[1190] Compound 174 can be prepared according to Scheme D, Mass Spec (M+H): 784.4

[1191] Example 175: Preparation of N-(2-(l-((l-(2-(2,6-dicarbonylpiperidin-3-yl)-l- carbonylisochromane-5-yl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-l-yl)-2H- indazol-5-yl)-3H-imidazo[4,5-b]pyridine-7-carboxamide Compound 175

[1192] Compound 175 can be prepared according to Scheme A, Mass Spec (M+H): 784.4

[1193] Example 176: Preparation of N-(2-(l-((l-(2-(2,6-dicarbonylpiperidin-3-yl)-l- carbonylisochromane-5-yl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-l-yl)-2H- indazol-5-yl)-2-(2-methylpyridin-4-yl)thiazole-4-carboxamide Compound 176

[1194] Compound 176 can be prepared according to Scheme D, Mass Spec (M+H): 841.4

[1195] Example 177: Preparation of N-(2-(l-((l-(2-(2,6-dicarbonylpiperidin-3-yl)-l- carbonylisochromane-5-yl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-l-yl)-2H- indazol-5-yl)-2-(pyrimidin-2-yl)oxazole-4-carboxamide Compound 177

[1196] Compound 177 can be prepared according to Scheme A, Mass Spec (M+H): 812.4

[1197] Example 178: Preparation of N-(2-(l-((l-(2-(2,6-dicarbonylpiperidin-3-yl)-l- carbonylisochromane-5-yl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-l-yl)-2H- indazol-5-yl)-2-(l-methyl-lH-pyrazol-4-yl)oxazole-4-carboxamide Compound 178

[1198] Compound 178 can be prepared according to Scheme D, mass spectrum (M+H): 814.4

[1199] Example 179: Preparation of N-(2-(l-((l-(2-(2,6-dicarbonylpiperidin-3-yl)-l- carbonylisochromane-5-yl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-l-yl)-2H- indazol-5-yl)-4-phenoxybenzamide Compound 179

[1200] Compound 179 can be prepared according to Scheme A, mass spectrum (M+H): 835.4

[1201] Example 180: Preparation of N-(2-(l-((l-(2-(2,6-dicarbonylpiperidin-3-yl)-l- carbonylisochromane-5-yl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-l-yl)-2H- indazol-5-yl)-2-phenylthiazole-4-carboxamide Compound 180

[1202] Compound 180 can be prepared according to Scheme A, mass spectrum (M+H): 826.3

[1203] Example 181: Preparation of N-(2-(l-((l-(2-(2,6-dicarbonylpiperidin-3-yl)-l- carbonylisochromane-5-yl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-l-yl)-2H- indazol-5-yl)-lH-pyrrolo[3,2-c]pyridine-3-carboxamide Compound 181

[1204] Compound 181 can be prepared according to Scheme B, mass spectrum (M+H): 783.4

[1205] Example 182: Preparation of N-(2-(l-((l-(2-(2,6-dicarbonylpiperidin-3-yl)-l- carbonylisochromane-5-yl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-l-yl)-2H- indazol-5-yl)benzofuran-3-carboxamide Compound 182

[1206] Compound 182 can be prepared according to Scheme B, mass spectrum (M+H): 783.4

[1207] Example 183: Preparation of N-(2-(l-((l-(2-(2,6-dicarbonylpiperidin-3-yl)-l- carbonylisodiindol-5-yl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-l-yl)-2H- indazol-5-yl)-4,5,6,7-tetrahydropyrazolo[l,5-a]pyridine-2-carboxamide Compound 183

[1208] Compound 183 can be prepared according to Scheme B, mass spectrum (M+H): 787.4

[1209] Example 184: Preparation of N-(2-(l-((l-(2-(2,6-dicarbonylpiperidin-3-yl)-l- carbonylisodiindol-5-yl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-l-yl)-2H- indazol-5-yl)-4,5,6,7-tetrahydro-lH-indazole-3-carboxamide Compound 184

[1210] Compound 184 can be prepared according to Scheme A, mass spectrum (M+H): 787.4

[1211] Example 185: Preparation of (S)-N-(2-(l-((l-(4-((2,6-dicarbonylpiperidin-3-yl) carbamoyl)-3-methoxyphenyl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-l-yl)- 2H-indazol-5-yl)benzo[d]thiazole-7-carboxamide Compound 185

[1212] Compound 185 can be prepared according to Scheme A, mass spectrum (M+H): 818.3

[1213] Example 186: Preparation of (S)-N-(2-(l-((l-(4-((2,6-dicarbonylpiperidin-3-yl) carbamoyl)-3-methoxyphenyl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-l-yl)- 2H-indazol-5-yl)-l-methyl-3-(trifluoromethyl)-lH-pyrazole-4-carboxamide Compound 186

[1214] Compound 186 can be prepared according to Scheme A, mass spectrum (M+H): 833.4

[1215] Example 187: Preparation of (S)-N-(2-(l-((l-(4-((2,6-dicarbonylpiperidin-3-yl) carbamoyl)-3-methoxyphenyl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-l-yl)- 2H-indazol-5-yl)-4H-thieno[3,2-b]pyrrole-5-carboxamide Compound 187

[1216] Compound 187 can be prepared according to Scheme C, Mass (M+H): 806.3

[1217] Example 188: Preparation of (S)-N-(2-(l-((l-(4-((2,6-dicarbonylpiperidin-3- yl)carbamoyl)-3-methoxyphenyl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-l- yl)-2H-indazol-5-yl)quinoline-4-carboxamide Compound 188

[1218] Compound 188 can be prepared according to Scheme A, Mass (M+H): 812.4

[1219] Example 189: Preparation of (S)-N-(2-(l-((l-(4-((2,6-dicarbonylpiperidin-3- yl)carbamoyl)-3-methoxyphenyl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-l- yl)-2H-indazol-5-yl)quinoline-5-carboxamide Compound 189

[1220] Compound 189 can be prepared according to Scheme A, Mass (M+H): 812.4

[1221] Example 190: Preparation of (S)-N-(2-(l-((l-(4-((2,6-dicarbonylpiperidin-3- yl)carbamoyl)-3-methoxyphenyl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-l- yl)-2H-indazol-5-yl)imidazo[l,2-a]pyridine-6-carboxamide Compound 190

[1222] Compound 190 can be prepared according to Scheme C, Mass (M+H): 801.4

[1223] Example 191: Preparation of (S)-N-(2-(l-((l-(4-((2,6-dicarbonylpiperidin-3- yl)carbamoyl)-3-methoxyphenyl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-l- yl)-2H-indazol-5-yl)imidazo[l,2-a]pyridine-7-carboxamide Compound 191

[1224] Compound 191 can be prepared according to Scheme C, Mass (M+H): 801.4

[1225] Example 192: Preparation of (S)-N-(2-(l-((l-(4-((2,6-dicarbonylpiperidin-3- yl)carbamoyl)-3-methoxyphenyl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-l- yl)-2H-indazol-5-yl)-l,5-naphthyridine-3-carboxamide Compound 192

[1226] Referring to synthetic scheme A, compound 192 can be prepared, mass spectrum (M+H): 813.4

[1227] Example 193: Preparation of (S)-N-(2-(l-((l-(4-((2,6-dicarbonylpiperidin-3- yl)carbamoyl)-3-methoxyphenyl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-l- yl)-2H-indazol-5-yl)-7H-pyrrolo[2,3-b]pyridine-4-carboxamide compound 193

[1228] Referring to synthetic scheme A, compound 193 can be prepared, mass spectrum (M+H): 801.4

[1229] Example 194: Preparation of (S)-N-(2-(l-((l-(4-((2,6-dicarbonylpiperidin-3- yl)carbamoyl)-3-methoxyphenyl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-l- yl)-2H-indazol-5-yl)benzo[c][l,2,5]thiadiazole-4-carboxamide compound 194

[1230] Referring to synthetic scheme B, compound 194 can be prepared, mass spectrum (M+H): 819.3

[1231] Example 195: Preparation of (S)-N-(2-(l-((l-(4-((2,6-dicarbonylpiperidin-3- yl)carbamoyl)-3-methoxyphenyl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-l- yl)-2H-indazol-5-yl)-lH-indole-4-carboxamide compound 195

[1232] Referring to synthetic scheme A, compound 195 can be prepared, mass spectrum (M+H): 800.4

[1233] Example 196: Preparation of (S)-N-(2-(l-((l-(4-((2,6-dicarbonylpiperidin-3- yl)carbamoyl)-3-methoxyphenyl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-l- yl)-2H-indazol-5-yl)-lH-indole-5-carboxamide compound 196

[1234] Referring to synthetic scheme B, compound 196 can be prepared, mass spectrum (M+H): 800.4

[1235] Example 197: Preparation of (S)-N-(2-(l-((l-(4-((2,6-dicarbonylpiperidin-3- yl)carbamoyl)-3-methoxyphenyl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-l- yl)-2H-indazol-5-yl)quinoline-6-carboxamide compound 197

[1236] Referring to synthetic scheme C, compound 197 can be prepared, Mass Spec (M+H): 812.4

[1237] Example 198: Preparation of (S)-N-(2-(l-((l-(4-((2,6-dicarbonylpiperidin-3- yl)carbamoyl)-3-methoxyphenyl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-l- yl)-2H-indazol-5-yl)benzo[b]thiophene-3-carboxamide compound 198

[1238] Referring to synthetic scheme A, compound 198 can be prepared, Mass Spec (M+H): 817.4

[1239] Example 199: Preparation of (S)-N-(2-(l-((l-(4-((2,6-dicarbonylpiperidin-3- yl)carbamoyl)-3-methoxyphenyl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-l- yl)-2H-indazol-5-yl)-l-methyl-5-phenyl-lH-pyrazole-4-carboxamide compound 199

[1240] Referring to synthetic scheme A, compound 199 can be prepared, Mass Spec (M+H): 841.4

[1241] Example 200: Preparation of (S)-N-(2-(l-((l-(4-((2,6-dicarbonylpiperidin-3- yl)carbamoyl)-3-methoxyphenyl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-l- yl)-2H-indazol-5-yl)imidazo[l,2-b]pyridazine-6-carboxamide compound 200

[1242] Referring to synthetic scheme C, compound 200 can be prepared, Mass Spec (M+H): 802.4

[1243] Example 201: Preparation of (S)-N-(2-(l-((l-(4-((2,6-dicarbonylpiperidin-3- yl)carbamoyl)-3-methoxyphenyl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-l- yl)-2H-indazol-5-yl)imidazo[l,5-a]pyridine-8-carboxamide compound 201

[1244] Referring to synthetic scheme C, compound 201 can be prepared, Mass Spec (M+H): 801.4

[1245] Example 202: Preparation of (S)-N-(2-(l-((l-(4-((2,6-dicarbonylpiperidin-3- yl)carbamoyl)-3-methoxyphenyl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-l- yl)-2H-indazol-5-yl)imidazo[l,2-a]pyridine-8-carboxamide Compound 202

[1246] Compound 202 can be prepared according to Scheme C, Mass Spec (M+H): 801.4

[1247] Example 203: Preparation of (S)-N-(2-(l-((l-(4-((2,6-dicarbonylpiperidin-3- yl)carbamoyl)-3-methoxyphenyl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-l- yl)-2H-indazol-5-yl)isoquinoline-8-carboxamide Compound 203

[1248] Compound 203 can be prepared according to Scheme C, Mass Spec (M+H): 812.4

[1249] Example 204: Preparation of (S)-N-(2-(l-((l-(4-((2,6-dicarbonylpiperidin-3- yl)carbamoyl)-3-methoxyphenyl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-l- yl)-2H-indazol-5-yl)quinoxaline-5-carboxamide Compound 204

[1250] Compound 204 can be prepared according to Scheme A, Mass Spec (M+H): 813.4

[1251] Example 205: Preparation of (S)-N-(2-(l-((l-(4-((2,6-dicarbonylpiperidin-3- yl)carbamoyl)-3-methoxyphenyl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-l- yl)-2H-indazol-5-yl)-7H-pyrrolo[2,3-b]pyridine-5-carboxamide Compound 205

[1252] Compound 205 can be prepared according to Scheme A, Mass Spec (M+H): 801.4

[1253] Example 206: Preparation of (S)-N-(2-(l-((l-(4-((2,6-dicarbonylpiperidin-3- yl)carbamoyl)-3-methoxyphenyl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-l- yl)-2H-indazol-5-yl)-2-methylimidazo[l,2-a]pyridine-6-carboxamide Compound 206

[1254] Compound 206 can be prepared according to Scheme D, Mass Spec (M+H): 815.4

[1255] Example 207: Preparation of (S)-N-(2-(l-((l-(4-((2,6-dicarbonylpiperidin-3- yl)carbamoyl)-3-methoxyphenyl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-l- yl)-2H-indazol-5-yl)isoquinoline-5-carboxamide Compound 207

[1256] Compound 207 can be prepared according to Scheme A, mass spectrum (M+H): 812.4

[1257] Example 208: Preparation of (S)-N-(2-(l-((l-(4-((2,6-dicarbonylpiperidin-3- yl)carbamoyl)-3-methoxyphenyl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(piperidin-l- yl)-2H-indazol-5-yl)-3-methylimidazo[l,2-a]pyridine-6-carboxamide Compound 208

[1258] Compound 208 can be prepared according to Scheme D, mass spectrum (M+H): 815.4

[1259] Example 209: Preparation of (S)-N-(2-(l-((l-(4-((2,6-di...

Claims

1. Compounds of formula (IA), their stereoisomers, N-oxides, deuterated derivatives, pharmaceutically acceptable salts or prodrugs thereof: In the formula, Ring B is in, It can be a single bond or a double bond; W1, W2, W3, and W4 are each independently C=O, CH, CH2, O, N, and 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 Halogenated alkyl groups; R x For hydrogen, C 1-6 Alkoxy, -C(O)NR x1 R x2 4 to 8-membered nitrogen-containing heterocyclic alkyl groups, 5 or 6-membered mono-heteroaryl groups, or C 6-8 Aryl, the C 1-6 Alkyl groups are optionally surrounded by one or more C groups. 3-6 Cycloalkyl substituted; the 4 to 8-membered nitrogen-containing heterocycloalkyl, 5 or 6-membered monoheteroaryl or C 6-8 The aryl group is optionally surrounded by one or more elements selected from halogens, hydroxyl groups, and C. 1-6 alkyl or hydroxy substituted C 1-6 The alkyl group is substituted; the 4 to 8-membered nitrogen-containing heterocyclic alkyl group contains at least one N atom and contains 0 to 3 heteroatoms independently selected from N, O or S as ring atoms; R x1 R x2 Each is independently hydrogen or C 1-6 alkyl; Lx is selected from *-C(O)NH-** or *-NH-C(O)-**; where "*" indicates the position connected to ring A, and "**" indicates the position connected to the group on the other side of Lx; Ring A is: (i) 8 to 10 bis-heteroaryl; wherein the 8 to 10 bis-heteroaryl is formed by fusion of a 5 or 6 bis-heteroaryl ring with a 5 or 6 bis-heteroaryl ring; (ii) 8 to 10-membered diheteroaryl; wherein the 8 to 10-membered diheteroaryl is formed by the fusion of a 5 or 6-membered monoheteroaryl ring with a 5 or 6-membered monocyclic heterocyclic alkyl ring; (iii) A 9- or 10-membered diheteroaryl group; wherein the 9- or 10-membered diheteroaryl group is formed by the fusion of a benzene ring with a 5- or 6-membered monoheteroaryl ring; (iv) 5- or 6-membered mono-heteroaryl groups; or, (v)C 6-8 Aryl; or, Ring A is: Among them, S1, S2, S3, S4, S5, S6, S7, and S8 are each independently selected from CH2, CH, NH, N, O, or S; S9, S 10 Each is independently selected from N or CH; q1 and q2 are independently 0, 1 or 2; R y Hydrogen, halogen, =O, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 3-6 cycloalkyl, -OR a -、-NR b R c 4 to 8-membered nitrogen-containing heterocyclic alkyl groups, 5 or 6-membered mono-heteroaryl groups, or C 6-8 Aryl, wherein the C 1-6 Alkyl, 5- or 6-membered monoheteroaryl, C 6-8 Aryl group is optionally bounded by one or more R 1 replace; R 1 Halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 3-6 Cycloalkyl, -OC(O)-C 1-6 Alkyl, -OP(O)(OH)2 or 4 to 12-membered heterocyclic alkyl, wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 3-6 Cycloalkyl or 4- to 12-membered heterocycloalkyl groups are optionally surrounded by one or more elements selected from halogens, C 1-6 Alkyl, C 1-6 Halogenated alkyl or C 1-6 Substitution of alkoxy groups; R a C 1-6 Alkyl or C 6-8 Aryl; R b R c Each is independently hydrogen or C 1-3 alkyl; y is 0, 1, 2, 3 or 4; L is in, The location shown indicates a connection to E3. The position shown indicates a connection to ring A; Q1, Q2, and Q3 are each independently a 4- to 12-membered nitrogen-containing heterocyclic alkyl group, wherein the 4- to 12-membered nitrogen-containing heterocyclic alkyl group contains at least one N atom as a ring atom; the 4- to 12-membered nitrogen-containing heterocyclic alkyl group is optionally substituted by one or more substituents selected from halogens and hydroxyl groups; L1, L2, L3, and L4 are each independently -CR L1 R L2 -、-NR L3 -、-CR L1 R L2 -NR L3 -or-NR L3 -CR L1 R L2 -; R L1 R L2 R L3 Each is independently hydrogen, halogen, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups; m1, m2, m3, m4, m5, m6, and m7 are each independently 0 or 1; E3 is the ubiquitin ligase binding group.

2. The compound, its stereoisomer, N-oxide, deuterated derivative, pharmaceutically acceptable salt, or prodrug according to claim 1: wherein, The 8- to 10-membered diheteroaryl ring formed by the fusion of a 5- or 6-membered monoheteroaryl ring with another 5- or 6-membered monoheteroaryl ring in ring A has the structure shown in formula (A1) or formula (A2): Where 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, and U8 is N; R U1 R U2 R U3 R U4 R U5 R U6 R U7 R U8 Each independently is either hydrogen or R y .

3. The compound, its stereoisomer, N-oxide, deuterated derivative, pharmaceutically acceptable salt, or prodrug according to claim 1: wherein, The 8- to 10-membered bis-heteroaryl ring formed by the fusion of a 5- or 6-membered mono ... 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 either 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 Each independently is either hydrogen or R y .

4. The compound, its stereoisomer, N-oxide, deuterated derivative, pharmaceutically acceptable salt, or prodrug according to claim 1: wherein, The 8- to 10-membered diheteroaryl ring formed by the fusion of a 5- or 6-membered monoheteroaryl ring with another 5- or 6-membered monoheteroaryl ring in ring A has the structure shown in formula (A5): Where 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 Each independently is either 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 diheteroaryl ring formed by the fusion of a 5- or 6-membered monoheteroaryl ring with another 5- or 6-membered monoheteroaryl ring in ring A has the structure shown in formula (A6): Where V1 is N or CR V1 V2 is N or CR V2 V3 is N or CR V3 V4 is either N or CR V4 V5 is either N or CR V5 V6 is either N or CR V6 V7 is either N or CR V7 V8 is either N or CR V8 V9 is either 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 Each independently is either hydrogen or R y .

6. The compound, its stereoisomer, N-oxide, deuterated derivative, pharmaceutically acceptable salt, or prodrug according to claim 1: wherein, The 8- to 10-membered diheteroaryl group formed by the fusion of a 5- or 6-membered monoheteroaryl ring with a 5- or 6-membered monocyclic heterocyclic alkyl ring in ring A has the structure shown in formula (A7), (A8), (A9), or (A10): Where H1 is N or CR H1 H2 is N or CR H2 H3 is N or CR H3 H4 is NR H4a O, S or CR H4b R H4c H5 is NR H5a O, S or CR H5b R H5c H6 is NR H6a O, S or CR H6b R H6c H7 is NR H7a O, S or CR H7b R H7c ;R H0 R H1 R H2 R H3 R H4a R H4b R H4c R H5a R H5b R H5c R H6a R H6b R H6c R H7a R H7b R H7c Each independently is either hydrogen or R y ; G1 is N or CR G1 G2 is NR G2a O, S or CR G2b R G2c G3 is NR G3a O, S or CR G3b R G3c G4 is NR G4a O, S or CR G4b R G4c G5 is NR G5a O, S or CR G5b R G5c G6 is NR G6a O, S or CR G6b R G6c ;R G0 R G1 R G2a R G2b R G2c R G3a R G3b R G3c R G4a R G4b R G4c R G5a R G5b R G5c R G6a R G6b R G6c Each independently is either hydrogen or R y ; The 8- to 10-membered diheteroaryl group formed by the fusion of a 5- or 6-membered monoheteroaryl ring with a 5- or 6-membered monocyclic heterocyclic alkyl ring has the structure shown in formula (A11) or formula (A12): 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 Each independently is either hydrogen or R y p1 and p2 are each independently 0, 1 or 2.

7. The compound according to claim 1, its stereoisomers, N-oxides, deuterated derivatives, pharmaceutically acceptable salts, or prodrugs thereof: wherein, In ring A, the 9- or 10-membered diheteroaryl group formed by the fusion of a benzene ring and a 5- or 6-membered monoheteroaryl ring is selected from the group consisting of: Among them, R D For hydrogen or R y ; The two carbon atoms connected to represent adjacent carbon atom pairs shared when fused with other rings.

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

10. The compound, its stereoisomer, N-oxide, deuterated derivative, pharmaceutically acceptable salt, or prodrug according to any one of claims 1-9: wherein, R y Selected from: halogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy, -NH2, -NHCH3, -N(CH3)2, -CH2-OC(O)(CH3)3, -CH2-OP(O)(OH)2, fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl, trifluoroethyl, thiophene, N-alkylpyrrolidone, furanyl, morpholinyl, piperazine, thiazolyl, isothiazolyl, imidazole, 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, pyrimidinyl, pyrazinyl, phenyl, naphthyl, -O-thiophene, -ON-alkylpyrrolidone, -O-furanyl, -O-thiazolyl, -O-isothiazolyl, -O-imidazolyl, -O-oxazolyl, -O-pyrroleyl, -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-tetrazole, -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-pyrimidinyl, -O-pyrazinyl, -O-phenyl; thiophene, N-alkylpyrrolidone, furanyl, thiazolyl, isothiazolyl, imidazole The radical, oxazolyl, pyrroleyl, 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, pyrimidinyl, pyrazinyl, phenyl, naphthyl are optionally substituted by one or more F, Cl, Br, I, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, fluoromethyl, difluoromethyl, trifluoromethyl; Preferably, R y Selected from: halogen, =O, amino, methylamino, dimethylamino, methyl, tert-butyl, trifluoromethyl, methoxy, -CH2-OC(O)(CH3)3, -CH2-OP(O)(OH)2, morpholinyl, 11. The compound, its stereoisomer, N-oxide, deuterated derivative, pharmaceutically acceptable salt, or prodrug according to any one of claims 1-10: wherein, Ring A is selected from the following groups: The group is optionally surrounded by one or more R y replace; Preferably, ring A is selected from:

12. The compound, its stereoisomer, N-oxide, deuterated derivative, pharmaceutically acceptable salt, or prodrug according to any one of claims 1-10: wherein, R x For hydrogen, C 1-6 Alkoxy, -C(O)NR x1 R x2 4 to 8-membered nitrogen-containing heterocyclic alkyl groups, 5 or 6-membered mono-heteroaryl groups, or C 6-8 Aryl, the C 1-6 Alkyl groups are optionally surrounded by one or more C groups. 3-6 Cycloalkyl substituted; the 4 to 8-membered nitrogen-containing heterocycloalkyl, 5 or 6-membered monoheteroaryl or C 6-8 The aryl group is optionally surrounded by one or more elements selected from halogens, hydroxyl groups, and C. 1-6 Alkyl, hydroxyl substituted C 1-6 alkyl or halogen-substituted C 1-6 Alkyl groups are substituted; the 4 to 8-membered nitrogen-containing heterocyclic alkyl groups contain at least one N atom and 0 to 3 heteroatoms independently selected from N, O or S as ring atoms; R x1 R x2 Each can be independently hydrogen or methyl, ethyl or propyl; Preferably, R x For methoxy, ethoxy, -C(O)N(CH3)2, -C(O)NH2, The methoxy and ethoxy groups are optionally substituted with one or more cyclopropyl groups, wherein... Optionally substituted with one or more substituents selected from hydroxyl, F, Cl, Br, methyl, ethyl, propyl, isopropyl, hydroxymethyl, hydroxyethyl, and hydroxypropyl; Preferably, R x It is methoxy, -C(O)NH2, 13. The compound, its stereoisomer, N-oxide, deuterated derivative, pharmaceutically acceptable salt, or prodrug according to any one of claims 1-12: wherein, Lx is selected from *-C(O)NH-**; where "*" indicates the position connected to ring A, and "**" indicates the position connected to the group on the other side of Lx.

14. The compound, its stereoisomer, N-oxide, deuterated derivative, pharmaceutically acceptable salt, or prodrug according to any one of claims 1-13: wherein, The compound is a compound of formula (IA1) or formula (IA2): In the formula, E3, L, W1, W2, W3, W4, R X L X The definitions for ring A and ring B are the same as before; 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, and F4 is N; R F1 R F2 R F3 R F4 Each independently is either 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, and K5 is N; R K1 R K2 R K3 R K4 R K5 Each independently is either hydrogen or R 1 .

15. The compound according to claim 1, its stereoisomers, N-oxides, deuterated derivatives, pharmaceutically acceptable salts, or prodrugs thereof: wherein, The compound is one of the compounds represented by formula (IB1), (IB2), (IB3), (IB4), or (IB5): In the formula, E3, L, W1, W2, W3, W4, R X L X R y The definitions for 'y' and 'y' are the same as before.

16. The compound, its stereoisomer, N-oxide, deuterated derivative, pharmaceutically acceptable salt, or prodrug according to claim 1: wherein, The 4- to 12-membered nitrogen-containing heterocyclic alkyl groups are selected from: X1, X2, X3, and X4 are each independently N or -CR d ; X5 represents 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 Each is independently hydrogen, hydroxyl, halogen, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy or C 3-6 Cycloalkyl.

17. The compound, its stereoisomer, N-oxide, deuterated derivative, pharmaceutically acceptable salt, or prodrug according to any one of claims 1-16: 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 is independently N or -CR d ; Among them, R d Hydrogen, hydroxyl, halogen, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy or C 3-6 cycloalkyl; n1, n2, n3, n4, n11, n12, n21, n22, n31, and 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 -or-NR L3 -CR L1 R L2 -; R L1 R L2 R L3 Each is independently represented by O, hydrogen, halogen, and C. 1-6 Alkyl or C 1-6 Halogenated alkyl groups; m1, m2, m3, and m4 are each independently 0 or 1.

18. The compound, its stereoisomer, N-oxide, deuterated derivative, pharmaceutically acceptable salt, or prodrug according to any one of claims 1-17: wherein, L is selected from:

19. The compound, its stereoisomer, N-oxide, deuterated derivative, pharmaceutically acceptable salt, or prodrug according to any one of claims 1-18: wherein, E3 has the structure shown in the following formulas (C1), (C2), (C3), (C4), (C5), or (C6): Among them, T1, T2, T3, and T4 are each independently CH, C, or N; T represents CH2 and 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 and C. 1-6 Alkyl or C 1-6 Alkoxy, the C 1-6 Alkyl groups are optionally surrounded by one or more Cs 1-6 Alkyl group or -OC(O)-C 1-6 Alkyl substitution; R3 is hydrogen, hydroxyl group, or C. 1-6 alkyl; R4, R7, R 10 Each is 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, its stereoisomer, N-oxide, deuterated derivative, pharmaceutically acceptable salt, or prodrug according to claim 1: wherein, E3 is R7 represents hydrogen, halogen, and 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 Alkyl groups are optionally surrounded by one or more Cs 1-6 Alkyl group or -OC(O)-C 1-6 Alkyl substitution; 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 Preferably, E3 is 21. The compound of claim 1, its stereoisomers, N-oxides, deuterated derivatives, pharmaceutically acceptable salts or prodrugs thereof, wherein the compound is selected from Table A, Table B, Table C or Table D.

22. The compound of formula (I) according to any one of claims 1-21, its stereoisomers, N-oxides, deuterated derivatives, pharmaceutically acceptable salts or prodrugs thereof: wherein, The compound is capable of degrading BTK protein and / or IRAK4 protein, preferably, the compound is capable of degrading BTK and IRAK4 proteins simultaneously.

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

24. The use of any compound of claims 1-21, its stereoisomers, N-oxides, deuterated derivatives, pharmaceutically acceptable salts or their prodrugs, or the pharmaceutical composition of claim 23 in the preparation of a medicament for treating a patient with a condition mediated by BTK protein and / or IRAK4 protein; Preferably, the IRAK and / or BTK-mediated conditions are selected from: cancer, neurodegenerative diseases, viral diseases, autoimmune diseases, inflammatory diseases, hereditary diseases, hormone-related diseases, metabolic diseases, organ transplant-related conditions, immunodeficiency diseases, destructive bone diseases, proliferative diseases, infectious diseases, cell death-related conditions, thrombin-induced platelet aggregation, liver diseases, T-cell activation-mediated pathological immune conditions, cardiovascular diseases, and CNS diseases.

25. The use of the compound of any one of claims 1-21, its stereoisomers, N-oxides, deuterated derivatives, pharmaceutically acceptable salts or their prodrugs, or the pharmaceutical composition of claim 20 in the preparation of a BTK and / or IRAK4 degrading agent; preferably, the degrading agent is a BTK and IRAK4 simultaneous degrading agent.

26. A method for simultaneously degrading BTK and / or IRAK4 proteins in a biological sample, comprising contacting the biological sample with a compound of any one of claims 1-21, its stereoisomers, N-oxides, deuterated derivatives, pharmaceutically acceptable salts or their prodrugs, or a pharmaceutical composition of claim 20.

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