Bifunctional chimeric heterocyclic compounds for targeted degradation of the androgen receptor and uses thereof

Abstract

The present invention relates to a bifunctional chimeric heterocyclic compound that targets androgen receptor degradation and its use. Specifically, the present invention provides a compound represented by formula (I), or an isotopic compound thereof, or an optical isomer thereof, or a tautomer thereof, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, or a solvate thereof, wherein ARB is an androgen receptor recognition / binding moiety, L is a binding moiety, and U is a ubiquitin protease recognition / binding moiety, and these three moieties are linked via a chemical bond. The above compound according to the present invention can target androgen receptor in prostate cancer cells, inhibit the proliferation of prostate cancer cells, and exhibit excellent metabolic stability and pharmacokinetic properties. The compound of the present invention is expected to be useful in the production of proteolytically targeted chimeric androgen receptor and in the production of pharmaceuticals for treating androgen receptor-regulated diseases (including prostate cancer, breast cancer, and Kennedy's disease). TIFF2022529339001916.tif3591

Description

[Technical Field]

[0001] The present invention relates to the pharmaceutical field, and more particularly to bifunctional chimeric heterocyclic compounds that target androgen receptor degradation and uses thereof. [Background technology]

[0002] With the global population growing and aging, the incidence of prostate cancer continues to increase, and currently, androgen deprivation therapy is the primary treatment. The androgen receptor (AR) is a member of the nuclear receptor family and a ligand-dependent transcription factor. Abnormal regulation of the AR signaling pathway plays a key role in the development and progression of prostate cancer, and studies have shown that castration-resistant prostate cancer (CRPC) still relies on the role of the AR. The androgen receptor (AR) contains 918 amino acids and shares similar structure and function with other nuclear receptors. It consists of three key structural domains: the DNA-binding domain (DBD), the ligand-binding domain (LBD), and the N-terminal domain (NTD). The DBD and LBD are connected via a hinge region. The LBD, located at the AR's N-terminus, is the site where AR binds to ligands and determines the specificity of ligand-AR binding. Ligand binding to the LBD activates AR. Two transcriptional activation domains have been identified in AR: activation function 1 (AF1) in the NTD structural domain and a highly conserved hydrophobic pocket activation function 2 (AF2) in the LBD structural domain. Before 2010, docetaxel-based chemotherapy was the only treatment that could prolong the survival of patients with metastatic CRPC.

[0003] Protein degradation-targeting chimeras (PROTACs) have attracted widespread attention as small molecules capable of inducing the degradation of target proteins. PROTACs are bifunctional molecules that contain a small molecule compound capable of binding to a protein of interest (POI), with a linking group introduced at an appropriate position, and then linked to a small molecule compound capable of binding to a ubiquitin protease. The resulting small molecule probe can simultaneously bind to the target protein and the ubiquitin protease, thereby promoting the ubiquitination of the target protein and allowing the polyubiquitinated protein to be recognized and degraded by the proteasome.

[0004] Using the PROTACs strategy, a proteolytic targeting chimera that can target and recognize / bind to the androgen receptor can be produced, and the level of the androgen receptor can be regulated via the intracellular ubiquitin-proteasome degradation system, inducing degradation of the androgen receptor, thereby achieving the effect of treating related diseases regulated by the androgen receptor, such as prostate cancer.

[0005] Therefore, bifunctional chimeric molecules have been developed that can target and effectively degrade the androgen receptor, and are expected to be utilized in the treatment of related diseases regulated by the androgen receptor. Summary of the Invention [Problem to be solved by the invention]

[0006] An object of the present invention is to provide a proteolytic target chimera that has a higher target binding ability to the androgen receptor and a higher activity in degrading the androgen receptor. [Means for solving the problem]

[0007] The present invention provides a compound represented by formula (I), or an isotopic compound thereof, or an optical isomer thereof, or a tautomer thereof, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, or a solvate thereof. TIFF0007603609000001.tif3588 (wherein ARB is an androgen receptor recognition / binding moiety, L is a binding moiety, and U is a ubiquitin protease recognition / binding moiety, and these three moieties are linked via a chemical bond; wherein the ARB is selected from the structure of formula (IA): TIFF0007603609000002.tif4191In formula, W 1 is selected from substituted or unsubstituted aryl or heteroaryl groups, 1 The substituents in each of the formula (I) are independently a halogen, a hydroxyl group, an amino group, a mercapto group, a sulfonic acid group, a sulfoxide group, a nitro group, a cyano group, CF3, a heterocyclic group, C 1~6 Alkyl group or its halide or its deuterated group, C 3~6 Cycloalkyl groups, C 1~6 Alkoxy group or its halide or its deuterated derivative, C 1~6 Alkylamino group, C 2~6 Alkenyl group or C 2~6 alkynyl groups, Y 1 , Y 2 , Y 3 , Y 4 are each independently a bond, O, S, or NR 1 , C.R. 2 R 3 , C=O, C=S, SO or SO2, wherein R 1 , R 2 , R 3 are independently H, C 1~6 alkyl groups or their halides or deuterated groups, 3-8 membered cycloalkyl groups or heterocyclic groups containing 0-2 heteroatoms, or R 2 and R 3 are linked to form a 3- to 8-membered ring containing 0 to 2 heteroatoms, Q is 0 to 6 R q a saturated cycloalkyl group, a saturated heterocyclic group, or an aryl or heteroaryl group containing 0 to 4 heteroatoms, each of which is substituted with R qare each independently H, D, OH, halogen, or C 1~6 Alkyl group or its halide, C 1~6 an alkoxy group or a halide thereof, or two substituents are linked to form a 3- to 8-membered ring containing 0 to 2 heteroatoms; W 2 is a bond or 0 to 4 R 4 Alkenyl, alkynyl, C substituted 1~6 Alkyl group, C 1~6 is selected from an alkoxy group, a monocycloalkyl group, a monoheterocyclic group, an aryl group, a heteroaryl group, a bridged cycloalkyl group, a heterobridged ring group, a spirocycloalkyl group, a heterospiro ring group, a fused cycloalkyl group, and a heterofused ring group; R 4 are each independently H, halogen, hydroxyl group, amino group, mercapto group, sulfonic acid group, sulfoxide group, nitro group, cyano group, CF3, C 1~6 Alkyl groups or their halides or their deuterated derivatives, C3-6 cycloalkyl groups, C 1~6 Alkoxy group or its halide or its deuterated derivative, C 1~6 Alkylamino group, C2-6 alkynyl TIFF0007603609000003.tif20156 or S, Or, ARB is selected from the structure of formula (IB): TIFF0007603609000004.tif4183In formula, W 1 is selected from substituted or unsubstituted aryl or heteroaryl groups, 1 The substituents in each of the formula (I) are independently a halogen, a hydroxyl group, an amino group, a mercapto group, a sulfonic acid group, a sulfoxide group, a nitro group, a cyano group, CF3, a heterocyclic group, C 1~6 Alkyl groups or their halides or their deuterated derivatives, C3-6 cycloalkyl groups, C 1~6 Alkoxy group or its halide or its deuterated derivative, C 1~6 Alkylamino group, C 2~6 Alkenyl group or C2~6 alkynyl groups, Y 1 , Y 5 , Y 6 are each independently a bond, O, S, or NR 1 , C.R. 2 R 3 , C=O, C=S, SO, SO2, wherein R 1 , R 2 , R 3 are independently H, C 1~6 alkyl groups or their halides or deuterated groups, 3-8 membered cycloalkyl groups or heterocyclic groups containing 0-2 heteroatoms, or R 2 and R 3 are linked to form a 3- to 8-membered ring containing 0 to 2 heteroatoms, Q is 0 to 6 R q a saturated cycloalkyl group, a saturated heterocyclic group, or an aryl or heteroaryl group containing 0 to 4 heteroatoms, each of which is substituted with R q are each independently H, D, OH, halogen, or C 1~6 Alkyl group or its halide, C 1~6 an alkoxy group or a halide thereof, or two substituents are linked to form a 3- to 8-membered ring containing 0 to 2 heteroatoms; W 2 is a bond or 0 to 3 R 4 Alkenyl, alkynyl, C substituted 1~6 Alkyl group, C 1~6 is selected from an alkoxy group, a monocycloalkyl group, a monoheterocyclic group, an aryl group, a heteroaryl group, a bridged cycloalkyl group, a heterobridged ring group, a spirocycloalkyl group, a heterospiro ring group, a fused cycloalkyl group, and a heterofused ring group; R 4 are each independently H, halogen, hydroxyl group, amino group, mercapto group, sulfonic acid group, sulfoxide group, nitro group, cyano group, CF3, C 1~6 Alkyl group or its halide or its deuterated group, C 3~6 Cycloalkyl groups, C 1~6Alkoxy group or its halide or its deuterated derivative, C 1~6 Alkylamino group, C 2~6 Alkynyl group, C 2~6 alkenyl groups, Or, ARB is selected from the structure of formula (IC), TIFF0007603609000005.tif64104In formula, W 1 is selected from substituted or unsubstituted aryl or heteroaryl groups, 1 The substituents in each of the formula (I) are independently a halogen, a hydroxyl group, an amino group, a mercapto group, a sulfonic acid group, a sulfoxide group, a nitro group, a cyano group, CF3, a heterocyclic group, C 1~6 Alkyl group or its halide or its deuterated group, C 3~6 Cycloalkyl groups, C 1~6 Alkoxy group or its halide or its deuterated derivative, C 1~6 Alkylamino group, C 2~6 Alkenyl group or C 2~6 alkynyl groups, Y 1 is one bond, O, S, NR 1 , C.R. 2 R 3 , C=O, C=S, SO, SO2; Y 7 N, CR 2 is selected from Y 8 is one bond, O, S, NR 1 , C.R. 2 R 3 , C=O, C=S, SO, SO2; Y 7 is W 2 is concatenated to Y 8 together with the group consisting of the formula (I) and (II), forming a 4- to 7-membered ring, and the ring is substituted with 0 to 4 deuterium atoms or halogen atoms, R 1 , R 2 , R 3 are independently H, C 1~6alkyl groups or halides thereof or deuterated groups, 3-8 membered cycloalkyl groups or heterocyclic groups containing 0-2 heteroatoms, or R 2 and R 3 are linked to form a 3- to 8-membered ring containing 0 to 2 heteroatoms, Q is 0 to 6 R q a saturated cycloalkyl group, a saturated heterocyclic group, or an aryl or heteroaryl group containing 0 to 4 heteroatoms, each of which is substituted with R q are each independently H, D, OH, halogen, or C 1~6 Alkyl group or its halide, C 1~6 an alkoxy group or a halide thereof, or two substituents are linked to form a 3- to 8-membered ring containing 0 to 2 heteroatoms; W 2 is a bond or 0 to 3 R 4 Alkenyl, alkynyl, C substituted 1~6 Alkyl group, C 1~6 is selected from an alkoxy group, a monocycloalkyl group, a monoheterocyclic group, an aryl group, a heteroaryl group, a bridged cycloalkyl group, a heterobridged ring group, a spirocycloalkyl group, a heterospiro ring group, a fused cycloalkyl group, and a heterofused ring group; R 4 are each independently H, halogen, hydroxyl group, amino group, mercapto group, sulfonic acid group, sulfoxide group, nitro group, cyano group, CF3, C 1~6 Alkyl group or its halide or its deuterated group, C 3~6 Cycloalkyl groups, C 1~6 Alkoxy group or its halide or its deuterated derivative, C 1~6 Alkylamino group, C 2~6 Alkynyl group, C 2~6 alkenyl groups, Or, ARB is selected from the structure of formula (ID): TIFF0007603609000006.tif4268 formula, W 1 is selected from substituted or unsubstituted aryl or heteroaryl groups,1 The substituents in each of the formula (I) are independently a halogen, a hydroxyl group, an amino group, a mercapto group, a sulfonic acid group, a sulfoxide group, a nitro group, a cyano group, CF3, a heterocyclic group, C 1~6 Alkyl groups or their halides or their deuterated derivatives, C3-6 cycloalkyl groups, C 1~6 Alkoxy group or its halide or its deuterated derivative, C 1~6 Alkylamino group, C 2~6 Alkenyl group or C 2~6 alkynyl groups, Y 9 , Y 10 , Y 11 are each independently selected from CH, O, and S; Y 12 represents one bond or CO, CO2, O, S, NR 1e , N.R. 1e CO, NR 1e SO2, wherein R 1e is H, C 1~6 is selected from an alkyl group, a halide thereof, or a deuterated alkyl group, a 3-8 membered cycloalkyl group or a heterocyclic group containing 0-2 heteroatoms, R q are each independently H, D, OH, halogen, or C 1~6 Alkyl group or its halide, C 1~6 or two R q are linked to form a 3- to 8-membered ring containing 0 to 2 heteroatoms, W 2 is a bond or 0 to 3 R 4 Alkenyl, alkynyl, C substituted 1~6 Alkyl group, C 1~6 R is selected from an alkoxy group, a monocycloalkyl group, a monoheterocyclic group, an aryl group, a heteroaryl group, a bridged cycloalkyl group, a heterobridged ring group, a spirocycloalkyl group, a heterospirocyclic group, a fused cycloalkyl group, and a heterofused ring group; 4are each independently H, halogen, hydroxyl group, amino group, mercapto group, sulfonic acid group, sulfoxide group, nitro group, cyano group, CF3, C 1~6 Alkyl group or its halide or its deuterated group, C 3~6 Cycloalkyl groups, C 1~6 Alkoxy group or its halide or its deuterated derivative, C 1~6 Alkylamino group, C 2~6 Alkynyl group, C 2~6 alkenyl groups.

[0008] moreover, TIFF0007603609000007.tif35155 is represented by the following formula (II-A), (IV-B), (IV-C), (IV-D), (IV-E), (IV-F), (IV-G), or (IV-H). TIFF0007603609000008.tif154136 (in the formula, R q are each independently H, OH, halogen, or C 1~6 Alkyl group or its halide, C 1~6 or two R q are linked to form a 3- to 8-membered ring containing 0 to 2 heteroatoms, a, b, c, and d are each independently selected from integers of 0 to 3.

[0009] moreover, TIFF0007603609000009.tif25149Represented by formula (III-A) or formula (III-B) or formula (III-C) or formula (III-D), TIFF0007603609000010.tif117147Represented by the following formula (III-E), formula (III-F), formula (III-G), formula (III-H), formula (III-I), formula (III-J), formula (III-K), formula (III-L), formula (III-M) or formula (III-N). TIFF0007603609000011.tif119155TIFF0007603609000012.tif45155 (in the formula, R w1, R w2 , R w3 , R w4 , R w5 are each independently a halogen, a hydroxyl group, an amino group, a mercapto group, a sulfone group, a sulfoxide group, a nitro group, a cyano group, CF3, a heterocyclic group, C 1~6 Alkyl group or its halide or its deuterated group, C 3~6 Cycloalkyl groups, C 1~6 Alkoxy group or its halide or its deuterated derivative, C 1~6 Alkylamino group, C 2~6 Alkenyl group or C 2~6 alkynyl groups, the halogen is preferably chlorine or bromine, and the C 1~6 The alkyl group is preferably a methyl group, and 1~6 The alkoxy group is preferably a methoxy group or an ethoxy group; R q are each independently H, OH, halogen, or C 1~6 Alkyl group or its halide, C 1~6 or any two R q are linked to form a 3- to 8-membered ring containing 0 to 2 heteroatoms.

[0010] moreover, TIFF0007603609000013.tif107150TIFF0007603609000014.tif72156

[0011] moreover, The structure of the formula (ID) is shown in the following formula (VD). TIFF0007603609000015.tif3860(in the formula, W 1 , W 2 , Y 12 , R q is as described in formula (ID) above.

[0012] moreover, The ARB is selected from the following structures: TIFF0007603609000016.tif56153TIFF0007603609000017.tif236158TIFF0007603609000 018.tif231154TIFF0007603609000019.tif235157TIFF0007603609000020.tif61154 (in the formula, R w1 , R w2 , R w3 , R w4 , R w5 are each independently a halogen, a hydroxyl group, an amino group, a mercapto group, a sulfonic acid group, a sulfoxide group, a nitro group, a cyano group, a heterocyclic group, CF3, C 1~6 Alkyl group or its halide or its deuterated group, C 3~6 Cycloalkyl groups, C 1~6 Alkoxy group or its halide or its deuterated derivative, C 1~6 Alkylamino group, C 2~6 Alkenyl group or C 2~6 alkynyl groups, the halogen is preferably chlorine or bromine, and the C 1~6 The alkyl group is preferably a methyl group, and 1~6 The alkoxy group is preferably a methoxy group or an ethoxy group; R w6 is H, halogen, hydroxyl group, amino group, mercapto group, sulfonic acid group, sulfoxide group, nitro group, cyano group, CF3, C 1~6 Alkyl group or its halide or its deuterated group, C 3~6 Cycloalkyl groups, C 1~6 Alkoxy group or its halide or its deuterated derivative, C 1~6 Alkylamino group, C 2~6 Alkynyl group, C 2~6 alkenyl groups, R q are each independently H, OH, halogen, or C 1~6 Alkyl group or its halide, C 1~6 or any two R q are linked to form a 3- to 8-membered ring containing 0 to 2 heteroatoms, Y 12 represents one bond or CO, CO2, O, S, NR 1e , N.R. 1e CO, NR 1e SO2, wherein R 1e is H, C 1~6 is selected from an alkyl group, a halide thereof, or a deuterated alkyl group.

[0013] moreover, The ARB is selected from the following structures: TIFF0007603609000021.tif236155TIFF0007603609000022.tif254159TIFF0007603609000023.tif231158TIFF0007603609000024.tif251160TIFF0007603609000025.tif249158TIFF0007603609000026.tif143155Or, the ARB is selected from structures of the following formulas: TIFF0007603609000027.tif74155TIFF0007603609000028.tif231159TIFF0007603609000029.tif243158 TIFF0007603609000030.tif246158TIFF0007603609000031.tif246161TIFF0007603609000032.tif233155 TIFF0007603609000033.tif210158TIFF0007603609000034.tif218158TIFF0007603609000035.tif22115 5TIFF0007603609000036.tif232159TIFF0007603609000037.tif232157TIFF0007603609000038.tif99154

[0014] Furthermore, the L is selected from the structure of the following formula (VIII-A): TIFF0007603609000039.tif4094 (in the formula, L 1 , L 2 , L 3 , L4 , L 5 , L 6 are each independently zero, one bond, O, S, or NR L1 , C.R. L2 R L3 , C=O, C=S, SO, SO2, a substituted or unsubstituted alkenyl group, a substituted or unsubstituted alkynyl group, a substituted or unsubstituted monocycloalkyl group, a substituted or unsubstituted monoheterocyclic group, a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, a substituted or unsubstituted bridged cycloalkyl group, a substituted or unsubstituted heterobridged ring group, a substituted or unsubstituted spirocycloalkyl group, a substituted or unsubstituted heterospirocyclic group, a substituted or unsubstituted fused cycloalkyl group, a substituted or unsubstituted heterofused ring group, The substituent is C 1~6 Alkyl group, -L 7 -OH, halogen, L 7 is selected from 0 to 6 methylene groups; R L1 , R L2 , R L3 are independently H, C 1~6 an alkyl group or a halide thereof or a deuterated alkyl group, a 3-8 membered cycloalkyl group or a heterocyclic group containing 0-2 heteroatoms, or R L2 , R L3 are linked to form a 3- to 8-membered ring containing 0 to 2 heteroatoms, a, b, c, d, e, and f are each independently selected from integers of 0 to 5; L 1 and L 6 can be freely connected to ARB or U, respectively. Alternatively, L is selected from the structure represented by formula (VIII-B). TIFF0007603609000040.tif3068 (wherein ring A and ring B are each independently selected from the following halogenated or non-halogenated structures: TIFF0007603609000041.tif133154TIFF0007603609000042.tif90152X 0 Is, nothing, O, S, SO, SO2、 NR X1 , C.R. X1 R X2 Selected from R X1 , R X2 are each independently selected from H, a halogen, a C1-C6 alkyl group, a C3-C6 cycloalkyl group, a C1-C6 alkyl group substituted with a halogen, a hydroxyl group, or an amino group, a group obtained by replacing a carbon atom in the main chain of a C1-C6 alkyl group with an oxygen atom or a nitrogen atom, a heterocyclic group, an aryl group, a hydroxyl group, and an amino group, or R X1 and R X2 are linked to form a 3- to 7-membered ring, Ring A and ring B can be freely linked to ARB or U, respectively.

[0015] Furthermore, the formula (VIII-A) is selected from the structures shown below. TIFF0007603609000043.tif193153TIFF0007603609000044.tif216155TIFF0007603609000045.tif255158TIFF0007603609000046 .tif231152TIFF0007603609000047.tif206153TIFF0007603609000048.tif213150TIFF0007603609000049.tif205152TIFF000760 3609000050.tif216138TIFF0007603609000051.tif247146TIFF0007603609000052.tif255145TIFF0007603609000053.tif226147TIFF0007603609000054.tif236148TIFF0007603609000055.tif160149 (In the formula, X is selected from H or a halogen, and m and n are each independently selected from integers of 0 to 5.)

[0016] Furthermore, L is selected from the structures shown below: TIFF0007603609000056.tif48153TIFF0007603609000057.tif221156TIFF0007603609000058.tif186155TIFF0007603609000059.tif235159TIFF0007603609000060.tif194158Preferably, L is selected from the following structures: TIFF0007603609000061.tif223157TIFF0007603609000062.tif123156

[0017] Furthermore, U is selected from the structure of the following formula (XA): TIFF0007603609000063.tif5284 (wherein T and Y each independently represent one bond, O, S, NR T1 or CR T2 R T3 is selected from V and J each independently represent one bond, C=O, -SO-, -SO2-, or CR 2 R 3 is selected from R T1 , R T2 , R T3 are independently H, C 1~6 an alkyl group or a halide thereof or a deuterated alkyl group, a 3-8 membered cycloalkyl group or a heterocyclic group containing 0-2 heteroatoms, or R T2 and R T3 are linked to form a 3- to 8-membered ring containing 0 to 2 heteroatoms, R v is H, C 1~6 an alkyl group or a halide thereof or a deuterated alkyl group, a cycloalkyl group or a heterocyclic group containing 0 to 3 heteroatoms, or a halide thereof; or R x and R y are linked to form a 3- to 8-membered ring containing 0 to 2 heteroatoms, g and h are each independently selected from integers of 0 to 3, and g and h are not simultaneously 0; Z is H, hydroxyl group, amino group, C1~6 Alkyl group, C 3~6 C substituted with cycloalkyl, oxygen or halogen 1~6 Alkyl group, -OR Z1 , -NR Z1 R Z2 , -COR Z3 , -CO2R Z3 , -OCOR Z3 , -NHCOR Z3 , -CONHR Z3 , -SO2R Z3 Selected from R Z1 , R Z2 are independently H, C 1~6 is selected from an alkyl group, a halide thereof, or a deuterated alkyl group, a 3-8 membered cycloalkyl group or a heterocyclic group containing 0-2 heteroatoms, R Z3 is a substituted or unsubstituted C 1~6 Alkyl groups, substituted or unsubstituted C 3~6 Cycloalkyl groups, substituted or unsubstituted C 3~6 a heterocyclic group, a substituted or unsubstituted aryl group, or a substituted or unsubstituted heteroaryl group, Z3 The substituents in 1~3 alkyl groups, R x , R y are independently H, C 1~6 Alkyl groups, halogenated C 1~6 C substituted with alkyl groups and heteroatom-containing groups 1~6 Alkyl group, -L y -OH, a cycloalkyl group or a heterocyclic group containing 0 to 3 heteroatoms, or a halide thereof, or R x and R y are bonded to form a 3- to 8-membered ring containing 0 to 2 heteroatoms, and L y is selected from 0 to 5 methylene groups; W 4 , W 5are each independently selected from an aryl group and a heteroaryl group substituted with 0 to 3 substituents, and the substituents are each independently selected from H, a halogen, a hydroxyl group, an amino group, a mercapto group, a sulfone group, a sulfoxide group, a nitro group, a cyano group, CF3, a heterocyclic group, C 1~6 Alkyl group, C 3~6 Cycloalkyl groups, C 1~6 Alkoxy group, C 1~6 Alkylamino group, C 2~6 Alkenyl group, C 2~6 alkynyl groups. Or, The U is selected from the structures of the following formula (XB): TIFF0007603609000064.tif4254 (wherein M is O, S, NR m Selected from R m is H, C 1~6 Alkyl group, C 3~6 S TIFF0007603609000065.tif19119 R m1 is H, C 1~6 Alkyl group, C 3~6 cycloalkyl groups, and X m Is, No, O, S, NR m3 is selected from R m2 , R m3 are independently H, C 1~6 Alkyl group, C 3~6 cycloalkyl groups, TIFF0007603609000066.tif46154C 1~6 alkyl groups, L m is selected from 0 to 5 methylene groups, M a is selected from N, CH, and M b is selected from O, S, CH2, and NH; E and F are independently CO, CS, or NR e1 , O, S, SO2, CH2, CD2, TIFF0007603609000067.tif21156 e2 , R e3 are each independently1~6 selected from alkyl groups, H, halogens, hydroxyl groups, and amino groups; Y 15 , Y 13 , Y 14 are independently H, O, S, and C 1~3 alkyl groups, j and k are each independently selected from integers of 0 to 3, and j and k are not simultaneously 0; G 1 , G 2 , G 3 , G 4 are independently O, S, N, and CR g1 , C.R. g2 , C.R. g3 , C.R. g4 Selected from R g1 , R g2 , R g3 , R g4 are each independently H, halogen, a hydroxyl group, an amino group, a mercapto group, a sulfonic acid group, a sulfoxide group, a nitro group, a cyano group, CF3, a heterocyclic group, or C 1~6 Alkyl group, C 3~6 Cycloalkyl groups, C 1~6 Alkoxy group, C 1~6 Alkylamino group, C 2~6 Alkenyl group, C 2~6 alkynyl groups, R u1 is selected from H and C1 to C6 alkyl groups. Or, The U is selected from the structures of the following formula (XC): TIFF0007603609000068.tif6059

[0018] moreover, The formula (XA) is selected from the structures represented by the following formula (XI-A): TIFF0007603609000069.tif4161 (in the formula, R v , Z, g, h, R x , R y , W 4 , W 5The selection range is the same as that of formula (II-A) above. Or, TIFF0007603609000070.tif29147(XI-D), (XI-E), or (XI-F). TIFF0007603609000071.tif37155 (in the formula, G 1 , G 2 , G 3 , G 4 The selection range is the same as that of the above formula (XB).

[0019] Furthermore, the formula (XI-A) is selected from the structures represented by the following formula (XII-A). TIFF0007603609000072.tif5383 (in the formula, R w7 is H, halogen, hydroxyl group, amino group, mercapto group, sulfone group, sulfoxide group, nitro group, cyano group, CF3, heterocyclic group, C 1~6 Alkyl group, C 3~6 Cycloalkyl groups, C 1~6 Alkoxy group, C 1~6 Alkylamino group, C 2~6 Alkenyl group, C 2~6 alkynyl groups, M 1 , M 2 , M 3 , M 4 are independently O, S, and NR 12 , C(R 12 )2 and R 12 is H, halogen, hydroxyl group, amino group, mercapto group, sulfone group, sulfoxide group, nitro group, cyano group, CF3, heterocyclic group, C 1~6 Alkyl group, C 3~6 Cycloalkyl groups, C 1~6 Alkoxy group, C 1~6 Alkylamino group, C 2~6 Alkenyl group, C 2~6 alkynyl groups, R v , Z, R x , R yThe selection range is the same as that of formula (XI-A) above.

[0020] Furthermore, W in the formula (XI-A) 5 is selected from the following structures: TIFF0007603609000073.tif94156

[0021] Furthermore, U is selected from the following structures: TIFF0007603609000074.tif242155TIFF0007603609000075.tif232157TIFF0007603609000076.tif253157TIFF0007603609000077.tif232156

[0022] Furthermore, the compound is selected from any of the following compounds: TIFF0007603609000078.tif239155TIFF0007603609000079.tif224158TIFF0007603609000080.tif242158 TIFF0007603609000081.tif233157TIFF0007603609000082.tif249157TIFF0007603609000083.tif235157 TIFF0007603609000084.tif245159TIFF0007603609000085.tif234159TIFF0007603609000086.tif255159 TIFF0007603609000087.tif228158TIFF0007603609000088.tif235160TIFF0007603609000089.tif226159 TIFF0007603609000090.tif255158TIFF0007603609000091.tif247162TIFF0007603609000092.tif248159 TIFF0007603609000093.tif240158TIFF0007603609000094.tif255153TIFF0007603609000095.tif239161 TIFF0007603609000096.tif242156TIFF0007603609000097.tif250158TIFF0007603609000098.tif254159 TIFF0007603609000099.tif233157TIFF0007603609000100.tif240158TIFF0007603609000101.tif177157

[0023] The present invention further provides the use of the above-mentioned compound, or an isotopic compound thereof, or an optical isomer thereof, or a tautomer thereof, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, or a solvate thereof, in the manufacture of an androgen receptor proteolytic targeting chimera.

[0024] Furthermore, the proteolytic targeting chimera is capable of targeting and / or binding to the androgen receptor.

[0025] Furthermore, the proteolysis targeted chimera is capable of degrading and / or downregulating the androgen receptor.

[0026] Furthermore, said proteolytic targeting chimeras are active ingredients of pharmaceuticals for treating related diseases regulated by the androgen receptor.

[0027] Furthermore, the disease is selected from prostate cancer, breast cancer, and Kennedy's disease.

[0028] The present invention further provides a pharmaceutical agent for treating an androgen receptor-regulated related disease, the pharmaceutical agent being a formulation containing the above-mentioned compound, or an isotope thereof, or an optical isomer thereof, or a tautomer thereof, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, or a solvate thereof as an active ingredient, in addition to pharmaceutically acceptable auxiliary materials.

[0029] Experiments have demonstrated that the compound of formula (I) of the present invention can target and degrade the androgen receptor in prostate cancer cells, inhibit the proliferation of prostate cancer cells, and also exhibit excellent metabolic stability and pharmacokinetic properties.The compound of the present invention is expected to be used in the manufacture of proteolytic targeting chimeras of androgen receptor and in the manufacture of medicines for treating related diseases regulated by androgen receptor (including prostate cancer, breast cancer, Kennedy's disease).

[0030] Regarding the definitions of terms used in the present invention, unless otherwise specified, the initial definition of a group or term in this specification is applicable to the group or term throughout the specification, and terms not specifically defined in this specification should be given the meaning that a person skilled in the art can assign to them based on the disclosed content and context.

[0031] The minimum and maximum content of carbon atoms in the hydrocarbon group is indicated by a prefix, for example, the prefix C a~b The alkyl group represents any alkyl group containing "a" to "b" carbon atoms. For example, C 1~6Alkyl refers to straight or branched chain alkyl groups containing from 1 to 6 carbon atoms.

[0032] As used herein, "substitution" means that one, two, or more hydrogen atoms in a molecule are replaced with other, different atoms or molecules, including the replacement of one, two, or more isotopic or heterotopic atoms in the molecule.

[0033] The minimum and maximum carbon atom content in hydrocarbon groups herein is indicated by prefixes, e.g., C 1~6 The alkyl group represents any straight or branched chain alkyl group containing 1 to 6 carbon atoms, C 1~6 The alkoxy group represents any straight or branched chain alkoxy group containing 1 to 6 carbon atoms.

[0034] For the purposes of the present invention, the term "aryl group" refers to an all-carbon monocyclic or fused polycyclic (i.e., rings sharing a pair of adjacent carbon atoms) group having a conjugated π-electron system, such as phenyl and naphthyl groups. The aryl ring can be fused to other cyclic groups (including saturated and unsaturated rings), but cannot contain heteroatoms such as nitrogen, oxygen, or sulfur, and the point of attachment to the parent must be on a carbon atom of the ring having a conjugated π-electron system. The aryl group can be substituted or unsubstituted.

[0035] A "heteroaryl group" refers to a heteroaromatic group containing one or more heteroatoms. Heteroatoms include oxygen, sulfur, and nitrogen. Examples include furyl, thienyl, pyridine, pyrazolyl, pyrrolyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, imidazolyl, and tetrazolyl. The heteroaryl ring can be fused to an aryl, heterocyclic, or cycloalkyl ring, and the ring connected to the parent structure is a heteroaryl ring. The heteroaryl group may be substituted or unsubstituted as needed.

[0036] An "alkyl group" is a hydrocarbon group formed by the absence of one hydrogen atom in an alkane molecule, and examples include methyl-CH3 and ethyl-CH3CH2.

[0037] An "alkylamino group" is a group in which one or more hydrogen atoms in an alkyl group are substituted with amino groups.

[0038] An "alkynyl group" refers to an aliphatic hydrocarbon group having at least one carbon-carbon triple bond. The alkynyl group may be linear or branched. When the number of carbon atoms preceding the alkynyl group is limited, for example, "C 2~6 An "alkynyl group" refers to a straight or branched chain alkynyl group having 2 to 6 carbon atoms.

[0039] An "alkenyl group" refers to an aliphatic hydrocarbon group having at least one carbon-carbon double bond. The alkenyl group may be linear or branched. When the number of carbon atoms preceding the alkenyl group is limited, for example, a "C2-6 alkenyl group" refers to a linear or branched alkenyl group having 2 to 6 carbon atoms.

[0040] "Substituted or unsubstituted alkenyl group" means that the alkenyl group can be substituted or unsubstituted.

[0041] A "cycloalkyl group" refers to a saturated or unsaturated cyclic hydrocarbon substituent, which can be monocyclic or polycyclic. For example, a "3- to 8-membered cycloalkyl group" refers to a cycloalkyl group having 3 to 8 carbon atoms.

[0042] A "saturated cycloalkyl group" refers to a saturated cycloalkyl group.

[0043] A "monocycloalkyl group" means that the cycloalkyl group is monocyclic.

[0044] A "bridged cycloalkyl group" refers to a polycyclic cycloalkyl group in which the two rings of the polycyclic cycloalkyl group share two non-adjacent carbon atoms.

[0045] A "spirocycloalkyl group" refers to a polycyclic cycloalkyl group in which the two rings share one carbon atom.

[0046] A "fused cycloalkyl group" refers to a polycyclic cycloalkyl group in which the two rings of the polycyclic cycloalkyl group share two adjacent carbon atoms.

[0047] A "heterocyclic group" refers to a saturated or unsaturated cyclic hydrocarbon substituent, which may be monocyclic or polycyclic and contains at least one ring heteroatom, including but not limited to O, S, or N. For example, a "3- to 8-membered heterocyclic group" refers to a heterocyclic group having 3 to 8 carbon atoms.

[0048] A "saturated heterocyclic group" refers to a saturated heterocyclic group.

[0049] The term "monoheterocyclic group" means that the heterocyclic group is monocyclic.

[0050] A "heterobridged ring group" refers to a polycyclic heterocyclic group whose two rings share two non-adjacent carbon atoms or heteroatoms.

[0051] A "heterospirocyclic group" refers to a polycyclic heterocyclic group, the two rings of which share one carbon atom or heteroatom.

[0052] A "fused heterocyclic group" refers to a polycyclic heterocyclic group whose two rings share two adjacent carbon atoms or heteroatoms.

[0053] Halogen is fluorine, chlorine, bromine or iodine.

[0054] An "isotopic compound" refers to a compound obtained by replacing one or more atoms in a compound with the corresponding isotope. For example, a compound obtained by replacing one or more hydrogen (H) atoms in a compound with deuterium (D) or tritium (T), for example, a compound obtained by replacing one or more carbon atoms in a compound with deuterium (D) or tritium (T).12 The carbon 11 or carbon 13 Examples of compounds include compounds obtained by substituting

[0055] "Pharmaceutically acceptable" means that a particular carrier, cargo, diluent, auxiliary material, and / or formed salt is usually chemically or physically compatible with the other ingredients of a particular pharmaceutical dosage form and physiologically compatible with the recipient.

[0056] "Salt" refers to acidic and / or basic salts formed between a compound or its stereoisomer and inorganic and / or organic acids and / or bases, including not only zwitterionic salts (internal salts) but also quaternary ammonium salts such as alkylammonium salts. These salts may be obtained directly from the final isolation and purification of the compound, or by mixing the compound or its stereoisomer with an appropriate amount of acid or base (e.g., equal amounts). These salts form precipitates in solution and are collected by filtration, recovered after solvent evaporation, or produced by reaction in an aqueous medium followed by lyophilization. The salts described in this invention may be hydrochloride, sulfate, citrate, benzenesulfonate, hydrobromide, hydrofluoride, phosphate, acetate, propionate, butanoate, oxalate, malate, succinate, fumarate, maleate, tartrate, or trifluoroacetate salts of the compound.

[0057] "Solvate thereof" refers to a solvate formed between a compound of the present invention and a solvent, said solvent including, but not limited to, water, ethanol, methanol, isopropanol, propylene glycol, tetrahydrofuran, and dichloromethane.

[0058] In the compounds of the present invention, the ARB is an androgen receptor recognition / binding moiety, which acts as an androgen receptor ligand in the compound.

[0059] In the present invention, "selected from one bond" means that the group or atom is absent, and the linking moieties at both ends are directly connected, for example, as represented by formula (IA): TIFF0007603609000102.tif60155

[0060] TIFF0007603609000103.tif25150 and has a five-membered ring with a conjugated structure.

[0061] "L" in formula (VIII-A) of the present invention 1 and L 6 can be freely connected to ARB or U, respectively, 1 is connected to the ARB, and L 6 is connected to U, or L 1 is connected to U and L 6 is connected to the ARB.

[0062] Similarly, in formula (VIII-B) of the present invention, "ring A and ring B can be freely linked to ARB or U, respectively" means that ring A is linked to ARB and ring B is linked to U, or ring A is linked to U and ring B is linked to ARB.

[0063] For purposes of the present invention, "D" represents deuterium.

[0064] There are several ways to name specific compounds of the present invention, for example, compounds "315", "3", etc. TIFF0007603609000104.tif8153((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)ureido)phenyl)amino)pentyl)oxy)acetamide)- Although the naming methods vary, each specific compound of the present invention can be uniquely identified according to its structure.

[0065] Obviously, according to the above content of the present invention, various other modifications, substitutions or changes can be made according to the common technical knowledge and common means in this field without departing from the above basic technical concept of the present invention.

[0066] The above content of the present invention will be described in more detail below by specific embodiments in the form of examples. However, it should not be understood that the scope of the above subject matter of the present invention is limited to the following examples. All technologies realized based on the above content of the present invention belong to the scope of the present invention. [Brief explanation of the drawings]

[0067] [Figure 1] 1 shows the results of a Western blot experiment using Compound 99 of the present invention at various concentrations. DETAILED DESCRIPTION OF THE INVENTION

[0068] The raw materials and equipment used in the specific embodiments of the present invention are all known products and can be obtained by purchasing them commercially.

[0069] First, synthesis of intermediates TIFF0007603609000106.tif59123SM-A-1:4-((1r,3r)-3-(2-bromo-5-oxy-5,7-dihydro-6H-pyrrole[3,4-b]pyridin-6-yl)-2,2,4,4-tetramethylcyclobutoxy)-2-chlorobenzonitrile TIFF0007603609000107.tif731521.Compound 3-(methoxycarbonyl)-2-methylpyridine-1-oxide The compound methyl 2-methylnicotinate (30.0 g, 199.0 mmol) was dissolved in dichloromethane (500 mL) and metachloroperbenzoic acid (68.7 g, 398.0 mmol) was added in batches. The mixture was stirred overnight at room temperature, filtered, and the filter cake was washed with dichloromethane. 5% sodium sulfite (200 mL) was added to the filtrate and stirred for 30 minutes. The mixture was separated and extracted with dichloromethane (100 mL x 3). The filtrates were combined, dried over anhydrous sodium sulfate, and the solvent was removed by rotary evaporation. The mixture was purified by silica gel column chromatography (dichloromethane:methanol = 100:1 to 20:1) to obtain the white solid compound 3-(methoxycarbonyl)-2-methylpyridine-1-oxide (18 g, 107.8 mmol) in 54% yield. MS: calculated for C8H9NO3 [M+H] + :168.0;found:168.1. 2. Compound 6-chloro-2-methylnicotinic acid methyl ester The compound 3-(methoxycarbonyl)-2-methylpyridine-1-oxide (36.5 g, 218.6 mmol) was added batchwise to phosphorus oxychloride (300 mL) in an ice bath. The temperature was then slowly raised and the reaction mixture was refluxed for 3 hours. The reaction mixture was then decompressed to remove most of the solvent, diluted with ethyl acetate (500 mL), washed with 10% aqueous Na2CO3 (100 mL x 3), and washed with saturated brine (100 mL x 3). The organic layer was dried over anhydrous sodium sulfate, the solvent was removed by rotary evaporation, and the residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 10:1 to 5:1) to obtain a white solid, methyl 6-chloro-2-methylnicotinate (8 g, 43.2 mmol), in a 20% yield. MS: calculated for C8H8ClNO2 [M+H] + :186.0;found:186.1. 3. Compound 6-bromo-2-methylnicotinic acid methyl ester The compound methyl 6-chloro-2-methylnicotinate (8.0 g, 43.2 mmol) was dissolved in acetonitrile (80 mL), trimethylsilyl bromide (19.8 g, 129.7 mmol) was added, and the reaction mixture was heated under reflux overnight. The reaction mixture was reduced in pressure to remove the solvent, and the residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 30:1 to 10:1) to obtain a yellow solid methyl 6-bromo-2-methylnicotinate (7.0 g, TIFF0007603609000108.tif7151C8H8BrNO2[M+H] + :230.0;found:230.1. 4. Compound 2-(bromomethyl)-6-bromonicotinic acid methyl ester The compound methyl 6-bromo-2-methylnicotinate (7.0 g, 30.6 mmol) and N-bromosuccinimide (8.16 g, 45.9 mmol) were added to carbon tetrachloride (100 mL), followed by azobisisobutyronitrile (566 mg, 3.06 mmol). The reaction mixture was refluxed overnight. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 30:1 to 10:1) to obtain crude 2-(bromomethyl)-6-bromonicotinic acid methyl ester (A-1-5). The crude product was dissolved in dichloromethane (60 mL), N,N-diisopropylethylamine (2.36 g, 18.3 mmol) was added, and diethyl phosphite (1.21 g, 8.76 mmol) was added dropwise in an ice bath. The mixture was stirred overnight at room temperature. Water (100 mL) was added to dilute the reaction mixture, and the mixture was extracted with dichloromethane (40 mL x 3). The mixture was washed with saturated brine (50 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, and the solvent was removed by rotary evaporation. The mixture was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 30:1 to 10:1) to give a white solid, 2-(bromomethyl)-6-bromonicotinic acid methyl ester (6.0 g, 19.5 mmol), in 64% yield. MS: calcd. for C8H7Br2NO2 [M+H] + :307.9;found:308.1. 5. Compound 3-carbonyl-2,2,4,4-tetramethylcyclobutanone oxime Hydroxylamine hydrochloride (26.0 g, 374.5 mmol) was dissolved in water (40 mL) and ethanol (250 mL), and tetramethyl-1,3-cyclobutanedione (50 g, 356.7 mmol) and sodium acetate (29.3 g, 356.7 mmol) were added. The reaction mixture was heated to reflux for 2 hours. The ethanol and water were removed by rotary evaporation. The residue was added to toluene (300 mL), refluxed for 3 hours, hot filtered, and the filter cake was washed with toluene (100 mL). The solvent was removed from the filtrate by rotary evaporation to give a white solid, 3-carbonyl-2,2,4,4-tetramethylcyclobutanone oxime (32.0 g, 206.5 mmol), in 59% yield. MS:calcd.for C8H 13 NO2[M+H] + :156.1;found:156.1. 6. Compound 3-hydroxy-2,2,4,4-tetramethylcyclobutanone oxime 3-Carbonyl-2,2,4,4-tetramethylcyclobutanone oxime (110.9 g, 714.6 mmol) was dissolved in isopropanol (715 mL) and sodium borohydride (18.9 g, 500.2 mmol) was added in batches. The reaction was stirred overnight at room temperature. The reaction was controlled at 5 °C and quenched with sodium hydroxide (2000 mL). The mixture was extracted with ethyl acetate (700 mL x 3). The combined organic phases were dried over sodium sulfate, and the solvent was removed by rotary evaporation to give a white solid, 3-hydroxy-2,2,4,4-tetramethylcyclobutanone oxime (100.8 g, 642.0 mmol), in 90% yield. MS:calcd.for C8H 15 NO2[M+H] + :158.1;found:158.1. 7. Compound 3-aminotetramethylcyclobutanone 3-Hydroxy-2,2,4,4-tetramethylcyclobutanone oxime (A-1-7) (35.1 g, 223.3 mmol) was dissolved in tetrahydrofuran (300 mL) and nickel-aluminum alloy (76.5 g, 893.3 mmol) was added under nitrogen protection. The reaction mixture was refluxed for 30 minutes, and 15% sodium hydroxide (300 mL) was added to maintain reflux. After the addition, the mixture was refluxed for 2 hours. After the reaction was complete, the mixture was filtered. The filter cake was washed with tetrahydrofuran (100 mL x 3). The filtrate was extracted with ethyl acetate (200 mL x 3). The combined organic phases were washed with saturated brine (200 mL x 3), dried over sodium sulfate, and the solvent was removed by rotary evaporation to give a pale yellow solid, 3-aminotetramethylcyclobutanone (24.5 g, 171.3 mmol), in 77% yield. MS:calcd.for C8H 17 NO[M+H] + :144.1;found:144.1. 8. Compound tert-butyl 3-hydroxy-2,2,4,4-tetramethylcyclobutylcarbamate 3-Aminotetramethylcyclobutanone (26.9 g, 188.1 mmol) was dissolved in dichloromethane (500 mL), and di-tert-butyl dicarbonate (41.4 g, 190.0 mmol) and triethylamine (38.0 g, 376.2 mmol) were added. The reaction mixture was stirred overnight at room temperature. The reaction mixture was diluted with water (300 mL) and extracted with dichloromethane (100 mL x 3). The combined organic phases were washed with saturated brine (200 mL x 3), dried over sodium sulfate, and purified by silica gel column chromatography (petroleum ether:ethyl acetate = 10:1 to 1:1) to give a pale yellow solid, tert-butyl 3-hydroxy-2,2,4,4-tetramethylcyclobutylcarbamate (30.1 g, 123.9 mmol), in 66% yield. MS:calcd.for C8H 17 NO[M+H] + :244.2;found:244.2. 9. Compound tert-butyl (1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutylcarbamate tert-Butyl 3-hydroxy-2,2,4,4-tetramethylcyclobutylcarbamate (25.0 g, 102.9 mmol) was dissolved in tetrahydrofuran (250 mL), and sodium hydride (60% in mineral oil) (8.23 g, 205.8 mmol) was added in batches under ice bath conditions. The mixture was stirred for 30 minutes in an ice bath. 2-Chloro-4-fluorobenzonitrile (17.6 g, 113.2 mmol) was dissolved in tetrahydrofuran (50 mL) and slowly added dropwise to the reaction mixture. The reaction mixture was heated to 60°C and reacted for 3 hours. The reaction mixture was quenched with water (300 mL) and extracted with ethyl acetate (100 mL x 3). The combined organic phases were washed with saturated brine (200 mL × 3), dried over sodium sulfate, and purified by silica gel column chromatography (petroleum ether:ethyl acetate = 50:1 to 30:1) to give a white solid, tert-butyl (1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutylcarbamate (15.0 g, 39.7 mmol), in 39% yield. MS: calcd. for C 20 H 27 ClN2O3[M+H] + :379.2;found:279.2. 10. Compound 4-((1r,3r)-3-amino-2,2,4,4-tetramethylcyclobutoxy)-2-chlorobenzonitrile trifluoroacetate tert-Butyl (1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutylcarbamate (5.0 g, 13.2 mmol) was dissolved in dichloromethane (50 mL) and trifluoroacetic acid (50 mL) was added in an ice bath. The reaction mixture was stirred at room temperature for 1 hour, and the solvent was removed by rotary evaporation to give crude 4-((1r,3r)-3-amino-2,2,4,4-tetramethylcyclobutoxy)-2-chlorobenzonitrile trifluoroacetate, which was used directly in the next reaction. MS: calcd. for C 17 H 19 ClF3N2O2[M+H] + :376.1;found:279.1. 11. The compound 4-((1r,3r)-3-(2-bromo-5-oxy-5,7-dihydro-6H-pyrrole[3,4-b]pyridin-6-yl)-2,2,4,4-tetramethylcyclobutoxy)-2-chlorobenzonitrile 4-((1r,3r)-3-amino-2,2,4,4-tetramethylcyclobutoxy)-2-chlorobenzonitrile trifluoroacetate (13.2 mmol, crude product obtained from the previous step) was dissolved in acetonitrile (240 mL), and N,N-diisopropylethylamine (8.51 g, 66.0 mmol) and the compound 2-(bromomethyl)-6-bromonicotinic acid methyl ester (4.0 g, 13.2 mmol) were added. The reaction was also heated to reflux overnight. The solvent was removed from the reaction by rotary evaporation, and toluene (50 mL) was added and refluxed overnight. The reaction was cooled and filtered, the filter cake was washed with toluene, and the filter cake was dried to give the target compound as a white solid (3.95 g, 8.3 mmol) in 63% yield for the two steps. MS: calcd. for C 22 H 21 BrClN3O2[M+H] + :474.0;foud:474.0.

[0070] SM-A-2, SM-A-3, SM-A-4, and SM-A-5 were produced by the same method as SM-A-1.

[0071] TIFF0007603609000109.tif15152(methylcyclobutoxy)benzonitrile TIFF0007603609000110.tif36104TIFF0007603609000111.tif6147-2-Chlorobenzonitrile (527 mg, 1.89 mmol), potassium carbonate (392 mg, 2.84 mmol), and 10 mL of DMF were added sequentially. After stirring uniformly under nitrogen protection, a DMF solution of methyl 2-(bromomethyl)-6-chloronicotinate (500 mg, 1.89 mmol) was added dropwise and stirred at room temperature for 2 h. The reaction endpoint was determined by TLC. The reaction mixture was then added with water, extracted three times with ethyl acetate, dried over anhydrous sodium sulfate, extracted and washed three times with saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed by rotary evaporation to obtain the crude product. The intermediate was isolated by silica gel column chromatography. DIEA (734 mg, 1.48 mmol) and 5 mL of 1,4-dioxane were added to the intermediate, and the reaction was carried out at 100°C for 2 days. The end point of the reaction was determined by TLC, and the reaction product was analyzed by silica gel column chromatography. TIFF0007603609000112.tif151534,4-Tetramethylcyclobutoxy)benzonitrile (536 mg, 1.25 mmol) was obtained in 66% yield. LC / MS (ESI+) calculation for C 22 H 21 C 12 N3O2(M+H + ) m / z, 430.1; found, 430.1.

[0072] SM-A-3: Synthesis of 4-((1r,3r)-3-(5-bromo-1-isoindolin-2-yl)-2,2,4,4-tetramethylcyclobutyl ether)-2-chlorobenzonitrile TIFF0007603609000113.tif37100 Compound 4-((1r,3r)-3-amino-2,2,4,4-tetramethylcyclobutylether)-2-chlorobenzonitrile (1.0 g, 3.59 mmol) and K2CO3 (743.0 mg, 5.38 mmol) were added to 20 mL of DMF, and methyl 4-bromo-2-(bromomethyl)benzoate (1.10 g, 3.59 mmol) was added to the reaction mixture in batches. The mixture was stirred at room temperature for 1 hour and monitored for completion by TLC, generating a new point. The mixture was extracted with ethyl acetate and saturated brine. The organic layer was washed twice with saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed by rotary evaporation. The mixture was purified by silica gel column chromatography to give 1.2 g of an oily liquid. 10 mL of toluene and 1 mL of triethylamine were added, heated to reflux, and stirred for 16 h. The solvent was removed by rotary evaporation, a small amount of petroleum ether and ethyl acetate (4:1) was added, and the solid was suction filtered and dried to give a white solid, 4-((1r,3r)-3-(5-bromo-1-isoindolin-2-yl)-2,2,4,4-tetramethylcyclobutylether)-2-chlorobenzonitrile (900.0 mg, 1.9 mmol), in 52.9% yield.

[0073] SM-A-4: 4-(((1r,4r)-4-(5-bromo-1-oxoisoindolin-2-yl)cyclohexyl)oxy)-2-chlorobenzonitrile TIFF0007603609000114.tif32145 Step 1, Synthesis of 4-(((1r,4r)-4-aminocyclohexyl)oxy)-2-chlorobenzonitrile The compound trans-p-aminocyclohexanol hydrochloride (26.8 g, 177 mmol) was dissolved in 0.8 L of DMF. Under the protection of N2, NaH (22.3 g, 531 mmol) was added in batches in an ice bath. The mixture was allowed to react at 0°C for 1 hour. The compound 2-chloro-4-fluorobenzonitrile was dissolved in 200 mL of DMF and slowly added dropwise to the reaction mixture. The mixture was then heated at 0°C for 0.5 hours, returned to room temperature, stirred for 3 hours, and analyzed by thin-layer chromatography to confirm the complete reaction. EA and water were added for extraction. The EA was washed twice with saturated brine and dried with anhydrous sodium sulfate. The solvent was removed by rotary evaporation, and the mixture was purified by silica gel column chromatography to obtain the white solid product 4-(((1r,4r)-4-aminocyclohexyl)oxy)-2-chlorobenzonitrile (27.7 g). Step 2, The compound 4-(((1r,4r)-4-aminocyclohexyl)oxy)-2-chlorobenzonitrile (1 g, 4 mmol) was dissolved in 20 mL of DMF, and K2CO3 (0.82 g, 6 mmol) was added. The compound 4-bromo-2-(bromomethyl-1)methylbenzoate (1.2 g, 4 mmol) was added in batches. The mixture was stirred at room temperature overnight. Water was added to precipitate a white solid, which was then suction filtered and dried to obtain compound SM-A-3 (1.3 g, 2.9 mmol).

[0074] TIFF0007603609000115.tif15151)benzonitrile Nitrile (2.37 g, 9.45 mmol), potassium carbonate (1.96 g, 14.18 mmol), and 40 mL of DMF were added sequentially. Under nitrogen protection, the mixture was stirred uniformly. A DMF solution of methyl 2-(bromomethyl)-6-chloronicotinate (2.5 g, 9.45 mmol) was then added dropwise and stirred at room temperature for 2 hours. The end point of the reaction was determined by TLC. The reaction mixture was then added with water, extracted three times with ethyl acetate, washed three times with saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed by rotary evaporation to obtain the crude product. The intermediate was isolated by silica gel column chromatography. DIEA (4.73 mg, 36.61 mmol) and 20 ml of 1,4-dioxane were added to the intermediate, and the mixture was reacted at 100°C for 2 days. The end point of the reaction was determined by TLC, and the intermediate 2-chloro- TIFF0007603609000117.tif8150)(3,4-b)pyridin-6-yl)cyclohexyl)oxy)benzonitrile (1.85 g, 4.60 mmol) was obtained in 49% yield. LC / MS(ESI+)calcd for C 20 H 17 Cl2N3O2(M+H + ) m / z, 402.1; found, 402.1.

[0075] SM-A-6: 2-chloro-4-((1r,3r)-2,2,4,4-tetramethyl-3-(2-(methylthio)-5-oxy-5,7-dihydro-6H-pyrrole[3,4-d]pyrimidin-6-yl)cyclobutoxy)benzonitrile TIFF0007603609000118.tif331571. 4-(Bromomethyl)-2-(methylthio)pyrimidine-5-carboxylic acid ethyl ester 4-Methyl-2-(methylthio)pyrimidine-5-carboxylic acid ethyl ester (10.6 g, 50.0 mmol) was dissolved in acetic acid (30 mL), and bromine (9.6 g, 60.0 mmol) was added dropwise to the reaction mixture in an ice bath. The reaction mixture was heated to 60 °C and reacted for 3 hours. The reaction mixture was poured into ice water (100 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic phases were washed with saturated brine (50 mL x 3), dried over sodium sulfate, and purified by silica gel column chromatography (petroleum ether:ethyl acetate = 50:1 to 30:1) to give a yellow oily substance, 4-(bromomethyl)-2-(methylthio)pyrimidine-5-carboxylic acid ethyl ester (8.3 g, 28.6 mmol), in 57% yield. MS: Calcd. for CH 11 BrN2O2S[M+H] + :291.0;found:291.0. 2,4-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutylamino)methyl)-2-(methylthio)pyrimidine-5-carboxylic acid ethyl ester 4-((1r,3r)-3-amino-2,2,4,4-tetramethylcyclobutoxy)-2-chlorobenzonitrile trifluoroacetate (11.4 mmol, crude product obtained from the previous step) was dissolved in acetonitrile (120 mL), and N,N-diisopropylethylamine (7.35 g, 11.4 mmol) and 4-(bromomethyl)-2-(methylthio)pyrimidine-5-carboxylic acid ethyl ester (4.3 g, 11.4 mmol) were added. The reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (50 mL x 3). The organic phases were combined, washed with saturated brine (50 mL × 3), dried over sodium sulfate, and purified by silica gel column chromatography (petroleum ether: ethyl acetate = 50:1 to 10:1) to give an off-white solid, 4-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutylamino)methyl)-2-(methylthio)pyrimidine-5-carboxylic acid ethyl ester (3.4 g, 7. TIFF0007603609000119.tif8152[M+H]+ :489.2;found:489.2. 3. 2-Chloro-4-((1r,3r)-2,2,4,4-tetramethyl-3-(2-(methylthio)-5-oxo-5H-pyrrole[3,4-d]pyrimidin-6(7H)-yl)cyclobutoxy)benzonitrile (SM-A-6) 4-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutylamino)methyl)-2-(methylthio)pyrimidine-5-carboxylic acid ethyl ester (2.0 g, 4.1 mmol) was dissolved in toluene (100 mL), the atmosphere was purged with nitrogen, and a 2.0 M n-hexane solution of trimethylaluminum (4.1 mL, 8.2 mmol) was added dropwise in an ice bath. The reaction mixture was heated to 110°C and reacted for 20 hours. The reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic phases were washed with saturated brine (50 mL × 3), dried over sodium sulfate, and purified by silica gel column chromatography (petroleum ether:ethyl acetate = 50:1 to 30:1) to give a yellow solid, 2-chloro-4-((1r,3r)-2,2,4,4-tetramethyl-3-(2-(methylthio)-5-oxo-5H-pyrrole[3,4-d]pyrimidin-6(7H)-yl)cyclobutoxy)benzonitrile (0.8 g, 1.8 mmol) in 49% yield. MS: calcd. for C 22 H 23 ClN4O2S[M+H] + :443.1;found:443.1.

[0076] Other lactam intermediates were synthesized in a similar manner to the above steps.

[0077] The following amide intermediate compounds were synthesized by methods described in the literature (US20180099940, US20170327469) or methods similar thereto. TIFF0007603609000120.tif55158

[0078] The following SM-E intermediate compounds were synthesized by methods described in the literature (US20180099940, US20170327469) or methods similar thereto. TIFF0007603609000121.tif36145

[0079] TIFF0007603609000122.tif8146rt-butyl ester TIFF0007603609000123.tif351321.Compound 4-(p-toluenesulfonyloxy)piperidine-1-carboxylic acid tert-butyl ester 4-Hydroxypiperidine-1-carboxylic acid tert-butyl ester (10.0 g, 49.7 mmol) was dissolved in dichloromethane, and p-toluenesulfonyl chloride (10.8 g, 56.6 mmol), triethylamine (7.5 g, 74.5 mmol), and 4-dimethylaminopyridine (183 mg, 1.5 mmol) were added. The reaction mixture was stirred overnight at room temperature. The mixture was diluted with water (100 mL) and extracted with dichloromethane (50 mL x 3). The combined organic phases were washed with saturated brine (50 mL x 3), dried over sodium sulfate, and purified by silica gel column chromatography (petroleum ether:ethyl acetate = 10:1 to 3:1) to give a white solid, 4-(p-toluenesulfonyloxy)piperidine-1-carboxylic acid tert-butyl ester (13.2 g, 37.2 mmol), in 83% yield. MS: calcd. for C 17 H 25 NO5S[M+H] + :356.1;found:356.1. TIFF0007603609000124.tif9149Synthesis of SM-L-1 4-(p-Toluenesulfonyloxy)piperidine-1-carboxylic acid tert-butyl ester (1.2 g, 3.4 mmol) was dissolved in acetonitrile, and 4-ethynylpiperidine hydrochloride (490 mg, 3.4 mmol), potassium carbonate (1.0 g, 7.5 mmol), and potassium iodide (113 mg, 0.68 mmol) were added. The reaction mixture was heated under reflux for 36 hours. The reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic phases were washed with saturated brine (20 mL x 3), dried over sodium sulfate, and purified by silica gel column chromatography (petroleum ether:ethyl acetate = 10:1 to pure ethyl acetate). TIFF0007603609000125.tif10151 tert-butyl carboxylic acid ester (0.6 g, 2.1 mmol) was obtained in 60% yield. MS: calcd. for C 17 H 28 N2O2[M+H] + :293.1;found:293.1.

[0080] TIFF0007603609000126.tif28153

[0081] Intermediate SM-L-2: 3-(4-ethynylpiperidin-1-yl)azetidine-1-carboxylic acid tert-butyl ester 4-Ethynylpiperidine hydrochloride (2.0 g, 13.8 mmol) and 3-azetidinone-3-carboxylic acid tert-butyl ester (2.35 g, 13.8 mmol) were dissolved in 1,2-dichloroethane (40 mL), acetic acid (1 mL) was added, and finally sodium triacetoxyborohydride (5.85 g, 27.6 mmol) was added. The reaction mixture was stirred overnight at room temperature. The mixture was diluted with water (50 mL) and extracted with dichloromethane (30 mL x 3). The combined organic phases were washed with saturated brine (30 mL × 3), dried over sodium sulfate, and purified by silica gel column chromatography (petroleum ether:ethyl acetate = 10:1 to pure ethyl acetate) to give a colorless oil, 3-(4-ethynylpiperidin-1-yl)azetidine-1-carboxylic acid tert-butyl ester (1.0 g, 3.8 mmol), in 27% yield. MS: calcd. for C 15 H 24 N2O2[M+H] + :265.2;found:265.2.

[0082] Intermediates SM-L-4, SM-L-8, SM-L-9, and SM-L-10 were synthesized similarly to SM-L-2. TIFF0007603609000128.tif32157

[0083] Intermediate SM-L-11: 4-(2-methyl-3-yn-2-yl)piperazine-1-carboxylic acid tert-butyl ester TIFF0007603609000129.tif3479 Piperazine-1-carboxylic acid tert-butyl ester (3.3 g, 17.7 mmol), triethylamine (3.57 g, 35.4 mmol), and 3-chloro-3-methylbutyne (1.8 g, 17.7 mmol) were dissolved in tetrahydrofuran (30 mL), and cuprous chloride (179 mg, 1.8 mmol) was added. The reaction mixture was stirred at room temperature for 10 minutes. The reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic phases were washed with saturated brine (50 mL x 3), dried over sodium sulfate, and purified by silica gel column chromatography (petroleum ether:ethyl acetate = 10:1 to 2:1) to give a colorless oil, 4-(2-methyl-3-yn-2-yl)piperazine-1-carboxylic acid tert-butyl ester (3.0 g, 11.9 mmol), in 67% yield. MS: calcd. for C 14 H 24 N2O2[M+H] + :253.2;found:253.2.

[0084] Intermediate SM-L-13: 4-(2-methyl-3-yn-2-ylamino)piperidine-1-carboxylic acid tert-butyl ester TIFF0007603609000130.tif32864-Aminopiperidine-1-carboxylic acid tert-butyl ester (2.6 g, 13.0 mmol), triethylamine (1.51 g, 15.0 mmol), and cuprous bromide (144 mg, 1.0 mmol) were added to acetonitrile (30 mL), and a solution of 3-chloro-3-methylbutyne (1.0 g, 10.0 mmol) in acetonitrile (10 mL) was added dropwise to the reaction mixture. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic phase was washed with saturated brine (50 mL x 3), dried over sodium sulfate, and purified by silica gel column chromatography (petroleum ether:ethyl acetate = 10:1 to 2:1) to give a colorless oil, 4-(2-methyl-3-yn-2-ylamino)piperidine-1-carboxylic acid tert-butyl ester (0.6 g, 2.3 mmol), in 22% yield. MS: calcd. for C15 H 26 N2O2[M+H] + :267.2;found:267.2.

[0085] Intermediate SM-L-14: 4-(4-ethynylphenyl)piperazine-1-carboxylic acid tert-butyl ester TIFF0007603609000131.tif311161.Compound 4-(4-formylphenyl)piperazine-1-carboxylic acid tert-butyl ester 4-Fluorobenzaldehyde (5.0 g, 40.3 mmol) and piperazine-1-carboxylic acid tert-butyl ester (7.5 g, 40.3 mmol) were dissolved in N,N-dimethylformamide (100 mL), and potassium carbonate (11.2 g, 80.6 mmol) was added. The reaction mixture was stirred at 110 °C for 2 days. The mixture was diluted with water (150 mL) and extracted with ethyl acetate (100 mL x 3). The combined organic phases were washed with saturated brine (100 mL x 3), dried over sodium sulfate, and purified by silica gel column chromatography (petroleum ether:ethyl acetate = 20:1 to 5:1) to give a white solid, 4-(4-formylphenyl)piperazine-1-carboxylic acid tert-butyl ester (7.1 g, 24.5 mmol), in 61% yield. MS:calcd.for C 16 H 23 O2N3[M+H] + :290.2;found:290.0. 2. Compound 4-(4-ethynylphenyl)piperazine-1-carboxylic acid tert-butyl ester 4-(4-Formylphenyl)piperazine-1-carboxylic acid tert-butyl ester (B-14-1) (2.9 g, 10.0 mmol) and dimethyl 1-diazo-2-oxopropylphosphonate (3.8 g, 20.0 mmol) were dissolved in methanol (50 mL), and potassium carbonate (5.5 g, 40 mmol) was added in an ice bath. The reaction mixture was allowed to warm slowly to room temperature overnight. The solvent was removed from the reaction mixture by rotary evaporation, and the mixture was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 50:1 to 15:1) to give a white solid, 4-(4-ethynylphenyl)piperazine-1-carboxylic acid tert-butyl ester (1.5 g, 5.2 mmol), in 54% yield. MS: calcd. for C 17 H 23 O2N2[M+H] + :287.2;found:287.2.

[0086] Intermediate SM-L-18: 4-((1s,3s)-3-ethynylcyclobutyl)piperazine-1-carboxylic acid tert-butyl ester (SM-L-18Q) and 4-((1r,3r)-3-ethynylcyclobutyl)piperazine-1-carboxylic acid tert-butyl ester (SM-L-18H) TIFF0007603609000132.tif601551.Compound 4-(3-(methoxycarbonyl)cyclobutyl)piperazine-1-carboxylic acid tert-butyl ester Methyl 3-oxocyclobutanecarboxylate (5.12 g, 40.0 mmol) and piperazine-1-carboxylic acid tert-butyl ester (8.9 g, 48.0 mmol) were dissolved in 1,2-dichloroethane (100 mL). Acetic acid (4.8 g, 80.0 mmol) was then added, followed by sodium triacetoxyborohydride (21.2 g, 100 mmol). The reaction mixture was stirred overnight at room temperature. The mixture was diluted with water (100 mL) and extracted with dichloromethane (50 mL x 3). The combined organic phases were washed with saturated brine (50 mL x 3), dried over sodium sulfate, and purified by silica gel column chromatography (petroleum ether:ethyl acetate = 10:1 to pure ethyl acetate) to give a white solid, 4-(3-(methoxycarbonyl)cyclobutyl)piperazine-1-carboxylic acid tert-butyl ester (6.0 g, 20.8 mmol), in 52% yield. MS:calcd.for C 15 H 26 N2O4[M+H] + :299.2;found:299.4. 2. Compound 4-(3-(hydroxymethyl)cyclobutyl)piperazine-1-carboxylic acid tert-butyl ester 4-(3-(Methoxycarbonyl)cyclobutyl)piperazine-1-carboxylic acid tert-butyl ester (6.0 g, 20.8 mmol) was dissolved in tetrahydrofuran (120 mL) and lithium aluminum hydride (4.8 g, 80.0 mmol) was added batchwise in an ice bath. The reaction was stirred in the ice bath for 1 hour. The reaction was diluted with tetrahydrofuran (100 mL), kept in the ice bath, and water (4.8 mL) was added dropwise and stirred for 10 minutes. Then, 15% sodium hydroxide solution (4.8 mL) was added and stirred for 10 minutes. Water (14.4 mL) was added again and stirred for 20 minutes. Finally, anhydrous magnesium sulfate was added and stirred for 20 minutes. The reaction mixture was filtered, and the solvent was removed from the filtrate by rotary evaporation to give 4-(3-(hydroxymethyl)cyclobutyl)piperazine-1-carboxylic acid tert-butyl ester (4.4 g, 14.8 mmol) as a colorless oil in 78% yield. MS:calcd.for C 14 H 26 N2O3[M+H] +:271.2;found:271.4. 3. Compound 4-(3-formylcyclobutyl)piperazine-1-carboxylic acid tert-butyl ester 4-(3-(hydroxymethyl)cyclobutyl)piperazine-1-carboxylic acid tert-butyl ester (4.0 g, 14.8 mmol) was dissolved in dichloromethane (80 mL). TIFF0007603609000133.tif9152) acetoacetate (9.4 g, 22.2 mmol) was added. The reaction was stirred at room temperature for 24 hours. It was then filtered, and the solvent was removed from the filtrate by rotary evaporation to give crude 4-(3-formylcyclobutyl)piperazine-1-carboxylic acid tert-butyl ester (5.3 g), which was used directly in the next reaction. MS: calcd. for C 14 H 24 N2O3[M+H] + :269.2;found:269.4. 4. Synthesis of compounds 4-((1s,3s)-3-ethynylcyclobutyl)piperazine-1-carboxylic acid tert-butyl ester (SM-L-18Q) and 4-((1r,3r)-3-ethynylcyclobutyl)piperazine-1-carboxylic acid tert-butyl ester (SM-L-18H) 4-(3-Formylcyclobutyl)piperazine-1-carboxylic acid tert-butyl ester (14.8 mmol, crude product obtained from the previous step) and dimethyl 1-diazo-2-oxopropylphosphonate (5.68 g, 29.6 mmol) were dissolved in methanol (100 mL) and potassium carbonate (10.2 g, 74.0 mmol) was added in an ice bath. The reaction mixture was allowed to warm slowly to room temperature overnight. The mixture was diluted with water (200 mL) and extracted with ethyl acetate (80 mL × 3). The combined organic phases were washed with saturated brine (80 mL x 3), dried over sodium sulfate, and purified by silica gel column chromatography (petroleum ether:ethyl acetate = 20:1 to 12:1) to give an off-white solid, 4-((1s,3s)-3-ethynylcyclobutyl)piperazine-1-carboxylic acid tert-butyl ester (SM-L-18Q) (0.84 g, 3.2 mmol), in a two-step yield of 16%. MS: calculated for C15 H 24 N2O2[M+H] + : 265.2; found: 265.4. At the same time, off-white solid 4-((1r,3r)-3-ethynylcyclobutyl)piperazine-1-carboxylic acid tert-butyl ester (SM-L-18H) (0.36 g, 1.4 mmol) was obtained in a two-step yield of 7%. MS: calculated for C 15 H 24 N2O2[M+H] + :265.2;found:265.4.

[0087] Synthesis of intermediate SM-L-5 TIFF0007603609000134.tif571461.Synthesis of compound 4-(4-(methoxycarbonyl)cyclohexyl)piperazine-1-carboxylic acid tert-butyl ester Methyl 4-oxocyclohexylcarboxylate (10.0 g, 64.0 mmol) and piperazine-1-carboxylic acid tert-butyl ester (13.0 g, 70.0 mmol) were dissolved in 1,2-dichloroethane (200 mL). Acetic acid (7.6 g, 128.0 mmol) was then added, followed by sodium triacetoxyborohydride (34.0 g, 160 mmol). The reaction mixture was stirred overnight at room temperature. The mixture was diluted with water (200 mL) and extracted with dichloromethane (100 mL x 3). The combined organic phases were washed with saturated brine (50 mL x 3), dried over sodium sulfate, and purified by silica gel column chromatography (petroleum ether:ethyl acetate = 1:1) to give a white solid, 4-(4-(methoxycarbonyl)cyclohexyl)piperazine-1-carboxylic acid tert-butyl ester (9.6 g, 29.4 mmol), in 46% yield. MS:calcd.for C 17 H 30 N2O4[M+H] + :327.2;found:327.4. 2. Synthesis of compound 4-((1r,4r)-4-(hydroxymethyl)cyclohexyl)piperazine-1-carboxylic acid tert-butyl ester 4-(4-(Methoxycarbonyl)cyclohexyl)piperazine-1-carboxylic acid tert-butyl ester (9.6 g, 29.4 mmol) was dissolved in tetrahydrofuran (200 mL) and lithium aluminum hydride (2.23 g, 58.8 mmol) was added in batches in an ice bath. The reaction mixture was stirred for 1 hour in an ice bath. The reaction mixture was diluted with tetrahydrofuran (100 mL), kept in an ice bath, and water (2.3 mL) was added dropwise and stirred for 10 minutes. Then, 15% sodium hydroxide solution (2.3 mL) was added and stirred for 10 minutes. Water (6.9 mL) was added again and stirred for 20 minutes. Finally, anhydrous magnesium sulfate was added and stirred for 20 minutes. The reaction mixture was filtered, and the solvent was removed from the filtrate by rotary evaporation. The filtrate was then purified by silica gel column chromatography (petroleum ether:ethyl acetate=1:1 to ethyl acetate) to obtain a pale yellow oil, 4-((1r,4r)-4-(hydroxymethyl)cyclohexyl)piperazine-1-carboxylic acid tert-butyl ester (1.2 g, 4.0 mmol), in a 14% yield. The composition was identified by reference to Patent WO2012145361. MS: calcd. for C 14 H 26 N2O3[M+H] + :299.2;found:299.4. 1 H NMR (400 mHz, CDCl): δ 3.46- TIFF0007603609000135.tif10153(m,1H),1.42(s,9H),1.27-1.13(m,3H),1.02-0.88(m,2H). At the same time, a pale yellow oily substance, 4-((1s,4s)-4-(hydroxymethyl)cyclohexyl)piperazine-1-carboxylic acid tert-butyl ester (3.0 g, 10.0 mmol), was obtained in a yield of 34%. MS: calculated for C 14 H 26 N2O3[M+H] + :299.2;found:299.4. 3. Synthesis of compound 4-((1r,4r)-4-(formyl)cyclohexyl)piperazine-1-carboxylic acid tert-butyl ester 4-((1r,4r)-4-(hydroxymethyl)cyclohexyl)piperazine-1-carboxylic acid tert-butyl ester (1.2 g, 4.0 mmol) was dissolved in dichloromethane (5 TIFF0007603609000136.tif9152(3H)-Pyridonyl)acetoacetate (2.0 g, 4.8 mmol) was added. The reaction was stirred at room temperature for 24 hours. It was then filtered, and the solvent was removed from the filtrate by rotary evaporation to give crude 4-((1r,4r)-4-(formyl)cyclohexyl)piperazine-1-carboxylic acid tert-butyl ester (1.4 g), which was used directly in the next reaction. MS: calcd. for C 16 H 28 N2O3[M+H] + :297.2;found:297.4. 4. Synthesis of compound 4-((1r,3r)-4-ethynylcyclohexyl)piperazine-1-carboxylic acid tert-butyl ester 4-((1r,4r)-4-(formyl)cyclohexyl)piperazine-1-carboxylic acid tert-butyl ester (4.0 mmol, crude product obtained from Method 1 in the previous step) and dimethyl 1-diazo-2-oxopropylphosphonate (7.2 g, 6.0 mmol) were dissolved in methanol (50 mL), and potassium carbonate (1.1 g, 8.0 mmol) was added in an ice bath. The reaction mixture was allowed to warm slowly to room temperature overnight. The reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic phases were washed with saturated brine (50 mL x 3), dried over sodium sulfate, and purified by silica gel column chromatography (petroleum ether:ethyl acetate = 3:1 to 2:1) to give a pale yellow solid, 4-((1r,3r)-3-ethynylcyclohexyl)piperazine-1-carboxylic acid tert-butyl ester (0.67 g, 2.3 mmol), in a two-step yield of 57%. MS: calcd. for C 17 H 28 N2O2 TIFF0007603609000137.tif181531.83(m,2H),1.45(s,9H),1.43-1.34(m,2H),1.28-1.20(m,2H).

[0088] Intermediates SM-L-6, SM-L-7, SM-L-15, SM-L-16, SM-L-17, SM-L-18, SM-L-19, SM-L-20, SM-L-21, SM-L-22, SM-L-23, and SM-L-24 were synthesized similarly to SM-L-18. TIFF0007603609000138.tif170154

[0089] Below were examples of the preparation of specific compounds according to the invention.

[0090] TIFF0007603609000139.tif91513-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)ureido)phenyl)amino)pentyl)oxy)acetamido)-3,3-dimethylbutane TIFF0007603609000140.tif8153Ethyl)carbamoyl)pyrrolidin-3-yl acetate TIFF0007603609000141.tif591551. Synthesis of 2-((5-((4-(3-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)ureido)phenyl)ethyl)pentyl)oxy)amino tert-butyl ester 1-(4-aminophenyl)-3-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)urea (100.0 mg, 0.24 mmol) and tert-butyl 2-((5-oxopentyl)oxy)acetate (52.4 mg, 0.24 mmol) were dissolved in 5 ml of DCM, the temperature was lowered to 0°C, one drop of acetic acid was added, and sodium cyanoborohydride (45.6 mg, 0.73 mmol) was added in batches. The temperature was returned to room temperature and the mixture was stirred overnight. Water was added, extracted with DCM, dried and the solvent removed by rotary evaporation, and purified by Pre-TLC to give compound 2-((5-((4-(3-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)ureido)phenyl)ethyl)pentyl)oxy)amino tert-butyl ester TIFF0007603609000142.tif915156+H + ) m / z, 612.3; Found, 557.3. 2.2-((5-((4-(3-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)ureido)phenyl)amino)pentyl)oxy)acetic acid 2-((5-((4-(3-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)ureido)phenyl)ethyl)pentyl)oxy)amino tert-butyl ester (70.0 mg, 0.09 mmol) was dissolved in 2 mL of DCM, 5 mL of TFA was added, and the mixture was stirred at room temperature for 1 h. Complete reaction of the raw material was confirmed by TLC. The solvent was removed from the system by rotary evaporation, and DCM was added to dissolve the mixture. The mixture was washed with saturated aqueous sodium bicarbonate solution to a pH of approximately 6. The organic phase was dried, filtered, and concentrated. 21.3 mg of 2-((5-((4-(3-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)ureido)phenyl)amino)pentyl)oxy)acetic acid was obtained in a yield of 32.6%. TIFF0007603609000143.tif91503-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)ureido)phenyl)amino)pentyl)oxy)acetamido)-3,3-dimethylbutane TIFF0007603609000144.tif10152Synthesis of ethyl)carbamoyl)pyrrolidin-3-yl acetate 2-((5-((4-(3-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)ureido)phenyl)amino)pentyl)oxy)acetic acid (20.0 mg, 0.09 mmol) was dissolved in 2 ml of DMF, the temperature was lowered to about 0°C, and 0.5 ml of DIEA and HATU (29.1 mg, 0.13 mmol) were added. TIFF0007603609000145.tif17153) (ethyl) amide) pyrrolidine-3-acetate (26.0 mg, 0.10 mmol) was added, and the mixture was allowed to warm to room temperature and stirred for 1 h. Ethyl acetate and 1N hydrochloric acid were added for extraction, and the organic layer was washed twice with brine, dried, and the solvent was removed by rotary evaporation. The mixture was then purified by silica gel column chromatography. TIFF0007603609000146.tif171534-Tetramethylcyclobutyl)ureido)phenyl)amino)pentyl)oxy)acetate TIFF0007603609000147.tif9152 8.2 mg of phenyl-5-ol-ethyl-carbamoyl-pyrrolidin-3-yl acetate was obtained in a yield of 37.2%. LC / MS (ESI+) Calcd for C 54 H 69 ClN8O8S(M TIFF0007603609000148.tif70154(s,6H),0.93(s,9H).

[0091] TIFF0007603609000149.tif8150-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-1-oxoisoindolin-5-yl)piperazin-1-yl)ethoxy)acetami TIFF0007603609000150.tif10154-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-3-yl acetate TIFF0007603609000151.tif691501.Synthesis of compound 2-(2-(4-(2-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-1-oxoisoindoline)piperazin-1-yl)ethoxy)-5-acetic acid tert-butyl ester 4-((1r,3r)-3-(5-bromo-1-oxoisoindolin-2-yl)-2,2,4,4-tetramethylcyclobutoxy)-2-chlorobenzonitrile (100.0 mg, 0.21 mmol), 2-(2-(piperazin-1-yl)ethoxy)acetic acid tert-butyl ester (154.5 mg, 0.63 mmol), BINAP (39.0 mg, 0.633 mmol), Pb(dba) (19.1 mg, 0.02 mmol), and CsCO (137.5 mg, 0.42 mmol) were dissolved in 10 mL of toluene. After purging with nitrogen, the mixture was heated to 100 °C and reacted overnight. The mixture was filtered through diatomaceous earth, and the filtrate was concentrated, water was added, and the mixture was extracted with dichloromethane. The organic phase was dried, filtered, concentrated, and purified by Pre-TLC to give 94.7 mg of the compound 2-(2-(4-(2-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-1-oxoisoindoline)piperazin-1-yl)ethoxy)-5-acetic acid tert-butyl ester in a yield of 49.3%. LC / MS (ESI+) Calcd for C 35 H 45 ClN4O5(M-56+H + ) m / z, 636.3; Found, 581.2. 2. Synthesis of compound 2-(2-(4-(2-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutane)-1-dioxoisoindolin-5-yl)piperazin-1-yl)ethoxy)acetic acid 2-(2-(4-(2-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-1-oxoisoindoline)piperazin-1-yl)ethoxy)-5-acetic acid tert-butyl ester (90.0 mg, 0.19 mmol) was dissolved in 1 ml of dichloromethane, and 5 ml of trifluoroacetic acid was added, followed by stirring at room temperature for 30 minutes. When the completion of the reaction was detected by TLC, the solvent was directly removed by rotary evaporation, dichloromethane was added to dissolve, and the pH was adjusted to 6 with saturated sodium bicarbonate, separated, the organic phase was dried with anhydrous sodium sulfate, filtered, and the solvent was removed by rotary evaporation to obtain 63.3 mg of the compound 2-(2-(4-(2-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutane)-1-dioxoisoindolin-5-yl)piperazin-1-yl)ethoxy)acetic acid in a yield of 89.3%. TIFF0007603609000152.tif8147-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-1-oxoisoindolin-5-yl)piperazin-1-yl)ethoxy)acetami TIFF0007603609000153.tif10152-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-3-yl acetate synthesis 2-(2-(4-(2-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutane)-1-dioxoisoindolin-5-yl)piperazin-1-yl)ethoxy)acetic acid (30.0 mg, 0.09 mmol) was dissolved in 2 ml of DMF, the temperature was lowered to about 0°C, and 0.5 ml of DIEA and HATU (29.1 mg, TIFF0007603609000154.tif17150) (5-(2-phenyl-5-yl)phenyl)ethyl)amido)pyrrolidine-3-acetate (26.0 mg, 0.10 mmol) was added, and the mixture was allowed to warm to room temperature and stirred for 1 h. Ethyl acetate and 1N hydrochloric acid were added for extraction, and the organic layer was washed twice with brine, dried, and the solvent was removed by rotary evaporation. TIFF0007603609000155.tif17155Oxy)-2,2,4,4-tetramethylcyclobutyl)-1-oxoisoindolin-5-yl)piperazin-1-yl)ethoxy)acetamido)-3,3-dimethylbutyryl) TIFF0007603609000156.tif8152 11.6 mg of (rubamoyl)pyrrolidin-3-yl acetate was obtained in 33.5% yield. LC / MS (ESI+) Calcd for C 56 H 69 ClN8O8S(M+H + ) m / z, 1048.5; Found, 1048.5. 1 H NMR TIFF0007603609000157.tif60153(s,1H),1.14(s,6H),0.95(s,9H).

[0092] TIFF0007603609000158.tif7146-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-1-oxoisoindolin-5-yl)piperazin-1-yl)ethoxy)acetoacetate TIFF0007603609000159.tif10153-Methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide TIFF0007603609000160.tif431532-(2-(4-(2-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutane)-1-dioxoisoindolin-5-yl)piperazin-1-yl)ethoxy)acetic acid (30.0 mg, 0.09 mmol) was dissolved in 2 ml of DMF, the temperature was lowered to about 0°C, and 0.5 ml of DIEA and HATU (29.1 mg, TIFF0007603609000161.tif17155-Methylthiazol-5-yl)phenyl)ethyl)amido)pyrrolidine-2-carboxamide (24.0 mg, 0.10 mmol) was added, and the mixture was allowed to warm to room temperature and stirred for 1 h. Ethyl acetate and 1N hydrochloric acid were added for extraction, and the organic layer was washed twice with brine, dried, and evaporated by rotary evaporation. TIFF0007603609000162.tif17151 (4-Cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-1-oxoisoindolin-5-yl)piperazin-1-yl)ethoxy)acetamido)-3,3 TIFF0007603609000163.tif10152 8.2 mg of phenyl)ethyl)carbamoyl)pyrrolidin-3-yl acetate was obtained in a yield of 31.7%. LC / MS (ESI+) Calcd for C 54 H 67 ClN8O7S(M+H + ) m / z, 1007.5; Found, 1007.5. TIFF0007603609000164.tif61155(s,6H),1.35(s,1H),1.14(s,6H),0.95(s,9H).

[0093] TIFF0007603609000165.tif8149-Chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-3-oxoisoindolin-5-yl)hex-5-yn-1-yl)oxy)acetamide TIFF0007603609000166.tif8151-yl)phenyl)ethyl)carbamoyl)pyrrolidin-3-yl acetate TIFF0007603609000167.tif461481. Synthesis of compound 2-((6-(2-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-3-oxoisoindol-5-yl)hex-5-yn-1-yl)oxy)acetic acid tert-butyl ester 4-((1r,3r)-3-)-6-bromo-1-oxoisoindolin-2-yl)-2,2,4,4-tetramethylcyclobutoxy)-2-chlorobenzonitrile (85.0 mg, 0.18 mmol), PbdppfCl2 (26.5 mg, 0.04 mmol), CuI (17.5 mg, 0.09 mmol), and 2-(hex-5-yn-1-yloxy)acetic acid tert-butyl ester (38.5 mg, 0.18 mmol) were sequentially added to a reaction flask. The atmosphere was purged with nitrogen, and 1.2 mL of toluene and 0.4 mL of triethylamine were added via syringe. The atmosphere was then purged with nitrogen again. The reaction was carried out overnight at 110 °C, and complete reaction was confirmed by TLC. The system was cooled to room temperature, filtered through a layer of diatomaceous earth, and the filtrate was concentrated. The organic phase was dissolved in dichloromethane, washed with 0.5 M HCl and saturated brine, dried, filtered, and concentrated in vacuo. Purification by pre-TLC gave 97.3 mg of 2-((6-(2-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-3-oxoisoindol-5-yl)hex-5-yn-1-yl)oxy)acetic acid tert-butyl ester in a 78.8% yield. LC / MS (ESI+) Calcd for C 35 H 41 ClN2O5(M-56+H + ) m / z, 604.3; Found, 549.2. 2. Synthesis of 2-((6-(2-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-3-oxoisoindol-5-yl)hex-5-yn-1-yl)oxy)acetic acid 2-((6-(2-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-3-oxoisoindol-5-yl)hex-5-yn-1-yl)oxy)acetic acid tert-butyl ester (95.0 mg, 0.15 mmol) was dissolved in 1 mL of DCM, 5 mL of TFA was added, and the mixture was reacted at room temperature for 1 h. Complete reaction of the raw material was confirmed by TLC. The solvent was removed from the system by rotary evaporation, and the mixture was dissolved in DCM and washed with saturated aqueous sodium bicarbonate solution until the pH was approximately 6. The organic phase was dried, filtered, and concentrated. 81.2 mg of 2-((6-(2-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-3-oxoisoindol-5-yl)hex-5-yn-1-yl)oxy)acetic acid was obtained in a yield of 92.6%. TIFF0007603609000168.tif8148-Chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-3-oxoisoindolin-5-yl)hex-5-yn-1-yl)oxy)acetamide TIFF0007603609000169.tif7151-yl)phenyl)ethyl)carbamoyl)pyrrolidin-3-yl acetate (4) 2-((6-(2-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-3-oxoisoindol-5-yl)hex-5-yn-1-yl)oxy)acetic acid (80.0 mg, 0.12 mmol) was dissolved in 2 ml of DMF, DIEA (98.5 mg, 0.76 mmol) was added, the temperature was lowered to about 0°C, and HATU( After stirring for 10 minutes, (2S,4R)-1-((S)-2-amino-3,3-dimethylbutyryl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)amido)pyrrolidine-2-carboxamide (130.1 mg, 0.22 mmol) was added, the mixture was allowed to warm to room temperature, and the reaction was continued for 2 hours. Completion of the reaction was detected by TLC. The mixture was slowly added to 5 ml of H2O, extracted with ethyl acetate, and the organic phase was washed five times with water, diluted with 0.5 M HCl, saturated sodium chloride, and then diluted with 0.5 M HCl. TIFF0007603609000170.tif19153-Cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-3-oxoisoindolin-5-yl)hex-5-yn-1-yl)oxy)acetamido)-3,3- TIFF0007603609000171.tif9156 38.0 mg of (phenylethyl)carbamoyl)pyrrolidin-3-yl acetate was obtained in a yield of 53.8%. 1 H NMR(400mHz,CDCl3)δ8.69(s,1H),7.88(s,1H),7.59-7.54(m, TIFF0007603609000172.tif59154(ESI+)Calcd for C 56 H 65 ClN6O8S(M / 2+H + ) m / z, 1016.5; Found, 509.3.

[0094] TIFF0007603609000173.tif10151-Chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-3-oxoisoindolin-5-yl)hex-5-yn-1-yl)oxy)acetamide TIFF0007603609000174.tif8153Thiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide(5) TIFF0007603609000175.tif33153Chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-3-oxoisoindolin-5-yl)hex-5-yn-1-yl)oxy)acetamide TIFF0007603609000176.tif9153-yl)phenyl)ethyl)carbamoyl)pyrrolidin-3-yl acetate (5.0 mg, 4.54 μmol) was dissolved in 1 ml of methanol, and a mixture of LiOH.HO (0.9 mg, 0.02 mmol) and 0.5 ml of HO was slowly added. The reaction was monitored for completion by TLC in about 30 min. Water was added, and the mixture was extracted with DCM. Pre-TLC showed a clear chromatographic result. TIFF0007603609000177.tif9152-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-3-oxoisoindolin-5-yl)hex-5-yn-1-yl)oxy)a TIFF0007603609000178.tif9154 3.0 mg of (4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide was obtained in a yield of 84.3%. 1 H NMR(400mHz,CDCl3)δ8.71(s,1H),7.86 TIFF0007603609000179.tif51153(ESI+)Calcd for C 54 H 63 ClN6O7S(M+H + ) m / z, 975.4; Found, 975.5.

[0095] TIFF0007603609000180.tif8149-Chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-3-oxoisoindolin-5-yl)amino)pentyl)oxy)acetamido)-3,3 TIFF0007603609000181.tif8149Phenyl)ethyl)carbamoyl)pyrrolidin-3-yl acetate (6) TIFF0007603609000182.tif451501. Synthesis of 2-((2-((2-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-3-oxoisoindol-5-yl)amino)pentyl)oxy)acetic acid tert-butyl ester 4-((1r,3r)-3-(6-amino-1-oxoisoindolin-2-yl)-2,2,4,4-tetramethylcyclobutoxy)-2-chlorobenzonitrile (150.0 mg, 0.37 mmol) and tert-butyl 2-((5-oxopentyl)oxy)acetate (79.1 mg, 0.35 mmol) were dissolved in 5 ml of DCM, the temperature was lowered to 0°C, one drop of acetic acid was added, and sodium cyanoborohydride (58.6 mg, 0.92 mmol) was added in batches. The temperature was returned to room temperature and the mixture was stirred overnight. Water was added, extracted with DCM, dried and the solvent removed by rotary evaporation, and purified by Pre-TLC to give 74.4 mg of compound 2-((2-((2-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-3-oxoisoindol-5-yl)amino)pentyl)oxy)acetic acid tert-butyl ester in 67.5% yield. LC / MS (ESI+) Calcd for C 34 H 44 ClN3O5(M-56+H + ) m / z, 609.3; Found, 554.2. 2. Synthesis of 2-((2-((2-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-3-oxoisoindol-5-yl)amino)pentyl)oxy)acetic acid 2-((2-((2-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-3-oxoisoindol-5-yl)amino)pentyl)oxy)acetic acid tert-butyl ester (74.0 mg, 0.12 mmol) was dissolved in 1 ml of DCM, 5 ml of TFA was added, and the mixture was stirred at room temperature for 1 h. Complete reaction of the raw materials was detected by TLC. The solvent was removed from the system by rotary evaporation, and DCM was added to dissolve the residue. The mixture was washed with saturated aqueous sodium bicarbonate solution to a pH of approximately 6. The organic phase was dried, filtered, and concentrated. 70.3 mg of 2-((2-((2-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-3-oxoisoindol-5-yl)amino)pentyl)oxy)acetic acid was obtained in a yield of 96.3%. TIFF0007603609000183.tif9149-Chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-3-oxoisoindolin-5-yl)amino)pentyl)oxy)acetamido)-3,3 TIFF0007603609000184.tif8150Synthesis of (phenyl)ethyl)carbamoyl)pyrrolidin-3-yl acetate 2-((2-((2-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-3-oxoisoindol-5-yl)amino)pentyl)oxy)acetic acid (70.0 mg, 0.13 mmol) was dissolved in 4 mL of DMF, DIEA (81.5 mg, 0.63 mmol) was added, and the temperature was lowered to about 0°C. HATU (72. TIFF0007603609000185.tif19153 (4-Methylthiazol-5-yl)phenyl)ethyl)amido)pyrrolidine-2-carboxamide (92.1 mg, 0.19 mmol) was added, and the mixture was allowed to warm to room temperature and react for 2 hours. Completion of the reaction was detected by TLC. The mixture was slowly added to 5 ml of H2O, extracted with ethyl acetate, and the organic phase was washed five times with water, 0.5 M HCl, and saturated brine. The mixture was then dried. TIFF0007603609000186.tif17152-2,2,4,4-tetramethylcyclobutyl)-3-oxoisoindolin-5-yl TIFF0007603609000187.tif9151-1-(4-(4-methylthiazol-5)-yl)phenyl)ethyl)carbamoyl)pyrrolidin-3-yl acetate 31.3 mg was obtained in a yield of 38.8%. 1 H NMR TIFF0007603609000188.tif27152TIFF0007603609000189.tif44157(M+H + ) m / z, 1021.5; Found, 1022.5.

[0096] TIFF0007603609000190.tif10150-Chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-3-oxoisoindolin-5-yl)amino)pentyl)oxy)acetamido)-3,3-dimethylbutyryl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (7) TIFF0007603609000191.tif32152Chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-3-oxoisoindolin-5-yl)amino)pentyl)oxy)acetamido)-3,3- TIFF0007603609000192.tif8153 Phenyl)ethyl)carbamoyl)pyrrolidin-3-yl acetate (5.0 mg, 4.30 μmol) was dissolved in 1 ml of methanol, and a mixture of LiOH.HO (0.9 mg, 0.02 mmol) and 0.5 ml of HO was slowly added. The reaction was monitored for completion by TLC in approximately 30 min. Water was added, and the mixture was extracted with DCM. The product was purified by prep-TLC. TIFF0007603609000193.tif7151-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-3-oxoisoindolin-5-yl)amino)pentyl)oxy)acetamido)- TIFF0007603609000194.tif10155 Azol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide 3.3 mg TIFF0007603609000195.tif19155TIFF0007603609000196.tif41152(s,6H),1.35(s,1H),1.13(s,6H),0.95(s,9H). LC / MS(ESI+)Calcd for C 53 H 66 ClN7O7S(M+H + ) m / z, 979.4; Found, 980.3.

[0097] 8: (3R,5R)-1-((S)-2-(2-((6-(4-(((1R,3R)-3-(3-bromo-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)carbamoyl)phenyl)hex-5-yn-1-yl)oxy)acetamido)-3,3-dimethylbutyryl)-5-((1-(4-(4-methylthiazol-5-yl)phenyl)cyclopropyl)carbamoyl)pyrrolidin-3-yl acetate (8) TIFF0007603609000197.tif921531.Synthesis of N-((1R,3R)-3-(3-bromo-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-iodobenzamide p-Iodobenzoic acid (103.0 mg, 0.42 mmol) was dissolved in 2 mL of DCM and cooled to approximately 0 °C. DIEA (266.6 mg, 2.08 mmol) and HATU (237.2 mg, 0.62 mmol) were added sequentially. After stirring at low temperature for 10 min, 4-((1R,3R)-3-amino-2,2,4,4-tetramethylcyclobutyl)-2-chlorobenzonitrile trifluoroacetate (200.0 mg, 0.46 mmol) was added. The ice bath was removed and the reaction was allowed to proceed at room temperature for 2 h. Completion of the reaction was monitored by TLC. The reaction mixture was washed with 0.5M aqueous HCl, washed with saturated brine, dried, concentrated under vacuum without dripping, and purified by column chromatography to give 221.0 mg of N-((1R,3R)-3-(3-bromo-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-iodobenzamide in a yield of 73.7%. LC / MS (ESI+) Calcd for C 22 H 22 BrIN2O2(M+H + ) m / z, 554.0; Found, 555.1. 2. Synthesis of 2-(6-(4-((1r,3r)-3-(3-bromo-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)carbamoyl-phenyl)hex-5-yn-1-yloxy)acetic acid tert-butyl ester N-((1R,3R)-3-(3-bromo-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-iodobenzamide (100.0 mg, 0.18 mmol), PbdppfCl2 (26.5 mg, 0.04 mmol), CuI (17.5 mg, 0.09 mmol), and 2-(hex-5-yn-1-yloxy)acetic acid tert-butyl ester (38.5 mg, 0.18 mmol) were sequentially added to a reaction flask. The atmosphere was purged with nitrogen, and 1.2 mL of toluene and 0.4 mL of triethylamine were added via syringe. The atmosphere was then purged with nitrogen again. The reaction was carried out at 90 °C for 3 h, and complete reaction was confirmed by TLC. The system was cooled to room temperature, filtered through a layer of diatomaceous earth, and the filtrate was concentrated. The organic phase was dissolved in dichloromethane, washed with 0.5 M HCl and saturated brine, dried, filtered, and concentrated in vacuo. Purification by pre-TLC afforded 121.3 mg of 2-(6-(4-((1r,3r)-3-(3-bromo-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)carbamoyl-phenyl)hex-5-yn-1-yloxy)acetic acid tert-butyl ester in a 91.6% yield. LC / MS (ESI+) Calcd for C 34 H 41 BrN2O5(M-56+H + ) m / z, 638.2; Found, 583.2. 3. Synthesis of 2-(6-(4-((1r,3r)-3-(3-bromo-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)carbamoyl-phenyl)hex-5-yn-1-yloxy)acetic acid 2-(6-(4-((1r,3r)-3-(3-bromo-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)carbamoyl-phenyl)hex-5-yn-1-yloxy)acetic acid tert-butyl ester (120.0 mg, 0.19 mmol) was dissolved in 1 mL of DCM, 5 mL of TFA was added, and the mixture was allowed to react at room temperature for 1 h. Complete reaction of the raw material was confirmed by TLC. The solvent was removed from the system by rotary evaporation, and the mixture was dissolved in DCM and washed with saturated aqueous sodium bicarbonate solution to a pH of approximately 6. The organic phase was dried, filtered, and concentrated. 95.2 mg of 2-(6-(4-((1r,3r)-3-(3-bromo-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)carbamoyl-phenyl)hex-5-yn-1-yloxy)acetic acid was obtained in a yield of 92.4%. 4. Synthesis of (3R,5R)-1-((S)-2-(2-((6-(4-(((1R,3R)-3-(3-bromo-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)carbamoyl)phenyl)hex-5-yn-1-yl)oxy)acetamido)-3,3-dimethylbutyryl)-5-((1-(4-(4-methylthiazol-5-yl)phenyl)cyclopropyl)carbamoyl)pyrrolidin-3-yl acetate 2-(6-(4-((1r,3r)-3-(3-bromo-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)carbamoyl-phenyl)hex-5-yn-1-yloxy)acetic acid (95.0 mg, 0.16 mmol) was dissolved in 2 mL of DMF, DIEA (113.5 mg, 0.89 mmol) was added, the temperature was lowered to approximately 0°C, HATU (101.0 mg, 0.24 mmol) was added, and after stirring for 10 minutes, (2S,4R)-1-((S)-2-amino-3,3-dimethylbutyryl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)amido)pyrrolidine-2-cyclopropanamide (130.1 mg, 0.22 mmol) was added, the mixture was returned to room temperature, and the reaction was carried out for 2 hours. The completion of the reaction was detected by TLC. The system was slowly added to 5 ml of H2O and extracted with ethyl acetate. The organic phase was washed five times with water, 0.5 M HCl, and saturated brine. It was dried, filtered, and concentrated in vacuo. Purification by pre-TLC gave (3R,5R)-1-((S)-2-(2-((6-(4-(((1R,3R)-3-(3-bromo-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)carbamoyl)phenyl)hex-5-yn-1-yl)oxy)acetamido)-3,3-dimethylbutyryl)-5-((1-(4-(4-methylthiazol-5-yl)phenyl)cyclopropyl)carbamoyl)pyrrolidin-3-yl acetate 40.0 mg in 46.7% yield. TIFF0007603609000198.tif9151(d,J=8.7Hz,1H),7.45(d,J=8.4Hz,3H),7.33(d,J=3.6Hz,4H),7.15(d,J=2.3Hz,2H),6.85 TIFF0007603609000199.tif35153TIFF0007603609000200.tif17152Found,1063.4.

[0098] TIFF0007603609000201.tif91503-(3-Bromo-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)carbamoyl)phenyl)hex-5-yn-1-yl)oxy)acetamido)-3,3-dimethylbutyryl)-4-hydroxy-N-(1-(4-(4-methyl-5-yl)phenyl)cyclopropyl)pyrrolidine-2-carboxamide (9) TIFF0007603609000202.tif34152 Bromo-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)carbamoyl)phenyl)hex-5-yn-1-yl)oxy)acetamido)-3,3-dimethylbutyryl)-5-((1-(4-(4-methylthiazol-5-yl)phenyl)cyclopropyl)carbamoyl)pyrrolidin-3-yl acetate (5.0 mg, 4.70 μmol) was dissolved in 1 ml of methanol, and a mixture of LiOH.HO (0.9 mg, 0.02 mmol) and 0.5 ml of HO was slowly added. The reaction was monitored for completion by TLC in about 30 min. Water was added and extracted with DCM. Purification by pre-TLC gave the compound. TIFF0007603609000203.tif10150-Bromo-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)carbamoyl)phenyl)hex-5-yn-1-yl)oxy)acetamido)-3,3-di TIFF0007603609000204.tif8151 3.0 mg of (cyclopropyl)pyrrolidine-2-carboxamide was obtained in 84.3% yield. LC / MS (ESI+) Calcd for C 56 H 65 BrNOS(M+H + ) m / z, 1020.4; Found, 1021.4. 1 H NMR TIFF0007603609000205.tif34152TIFF0007603609000206.tif10152(s,6H),1.01(s,7H),0.93-0.78(m,5H).

[0099] 10: (3R,5S)-1-((S)-2-(2-(4-((2-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-1-oxoisoindolin-5-ylethynyl)-1H-pyrazol-1-yl)acetamido)-3,3-dimethylbutyryl)-5-((((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-3-yl acetate (10) TIFF0007603609000207.tif53150LC / MS(ESI+)Calcd for C 55 H 59 ClN8O7S(M+H + ) m / z, 1011.4; found 1011.4. 1 H NMR TIFF0007603609000208.tif48152(s,3H),1.43-1.34(m,9H),1.16(s,6H),0.98(s,9H).

[0100] 11: (2S,4R)-1-((S)-2-(2-(4-((2-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-1-oxoisoindolin-5-ylethynyl)-1H-pyrazol-1-yl)acetamido)-3,3-dimethylbutyryl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (11) LC / MS(ESI+)Calcd for C 53 H 57 ClN8O6S(M+H + ) m / z, 969.4; found 969.4. 1 H NMR TIFF0007603609000209.tif9151TIFF0007603609000210.tif50154

[0101] TIFF0007603609000211.tif81473-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-1-oxoisoindolin-5-yl)prop-2-yn-1-yl)oxy)propion TIFF0007603609000212.tif10152-Methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-3-yl acetate (12) TIFF0007603609000213.tif49148LC / MS(ESI+)Calcd for C 55 H 63 ClN6O9S(M+H + ) m / z, 1019.4; found 1019.4. 1 H NMR TIFF0007603609000214.tif51153

[0102] TIFF0007603609000215.tif81503-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-1-oxoisoindolin-5-yl)prop-2-yn-1-yl)oxy)propion TIFF0007603609000216.tif10154-(4-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (13) LC / MS(ESI+)Calcd for C 53 H 61 ClN6O8S(M+H + ) m / z, 977.4; found 977.4. 1 H NMR TIFF0007603609000217.tif50154(s,3H),1.43-1.34(m,9H),1.16(s,6H),0.98(s,9H).

[0103] TIFF0007603609000218.tif7145-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-1-oxoisoindol-5-yl)prop-2-yn-1-yl)oxy)prop TIFF0007603609000219.tif9152-(4-Methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-3-yl acetate (14) TIFF0007603609000220.tif49146LC / MS(ESI+)Calcd for C 56 H 65 ClN6O9S(M+H + ) m / z, 1033.4; found 1033.4. 1 H NMR TIFF0007603609000221.tif331523.70(m,2H),3.57(s,3H),3.41-3.37(m,1H),3.20-3.10(m,1H),2.69(s,9H),2.45 TIFF0007603609000222.tif16154

[0104] TIFF0007603609000223.tif9145-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-1-oxoisoindol-5-yl)prop-2-yn-1-yl)oxy)prop TIFF0007603609000224.tif9153-1-(4-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (15) LC / MS(ESI+)Calcd for C 54 H 63 ClN6O8S(M+H + ) m / z, 991.4; found 991.4. 1 H NMR TIFF0007603609000225.tif331523.70(m,2H),3.41-3.37(m,1H),3.20-3.10(m,1H),2.69(s,9H),2.45(s,3H),2.31-2.21 TIFF0007603609000226.tif17155

[0105] 16: (2R,4R)-1-((S)-2-(2-((5-((2-((1r,3r)-3-(4-cyano-3-(trifluoromethyl)phenoxy)-2,2,4,4-tetramethylcyclobutyl)-1-oxoisoindolin-5-yl)amino)phenyl)oxy)a TIFF0007603609000227.tif8152Synthesis of (4-methylthiazol-5-yl)phenyl)ethyl)pyrrole-2-carbamoyl (16) TIFF0007603609000228.tif651511.Synthesis of tert-butyl ((1r,3r)-3-(4-cyano-3-(trifluoromethyl)phenoxy)-2,2,4,4-tetramethylcyclobutyl)carbamate tert-Butyl (3-hydroxy-2,2,4,4-tetramethylcyclobutyl)carbamate (4700 mg, 19.31 mmol) was dissolved in 100 mL of DMF. The system was then purged with argon, and this process was repeated eight times to ensure an inert gas atmosphere. The system was then transferred to an ice-water bath and cooled while stirring. When the internal temperature of the system dropped to approximately 0 °C, NaH (60%) (1600 mg, 40.55 mmol) was slowly added to the system. After completion, the system was kept at 0 °C with stirring for 1 h. Then, 2-trifluoromethyl-4-fluorobenzonitrile (1700 mg, 11.00 mmol) in 50 mL of DMF was added dropwise to the system, controlling the addition rate so that the internal temperature did not exceed 5 °C. After the addition was completed, the system was allowed to react at 0 °C. After 2 h, a sample was sampled and analyzed by thin-layer chromatography, and TLC showed the reaction was complete. While stirring, the system was slowly poured into ice water, causing a large amount of solid (sticky) to precipitate. The filter cake was dissolved in ethyl acetate, dried over anhydrous sodium sulfate, filtered and concentrated to obtain a crude product, which was then separated and purified by column chromatography to obtain an off-white solid tert-butyl ((1r,3r)-3-(4-cyano-3-(trifluoromethyl)phenoxy)-2,2,4,4-tetramethylcyclobutyl)carbamate (3700 mg) in a yield of 46%. LC / MS (ESI + )Calcd for C 21 H 27 F3N2O3(M+H) + m / z, 412.2; Found: 357.1. Synthesis of 2,4-((1r,3r)-3-amino-2,2,4,4-tetramethylcyclobutoxy)-2-(trifluoromethyl)benzonitrile tert-Butyl ((1r,3r)-3-(4-cyano-3-(trifluoromethyl)phenoxy)-2,2,4,4-tetramethylcyclobutyl)carbamate (650 mg, 1.58 mmol) was placed in a 25 mL single-neck round-bottom flask, and dichloromethane (15 mL) was added and stirred at room temperature. Trifluoroacetic acid (3 mL) was then added to the system, and upon completion, the system was stirred and reacted at room temperature. After 3 h, a sample was taken and thin-layer chromatography was performed. TLC showed that the starting material had been completely consumed. The solvent and excess trifluoroacetic acid were removed by rotary evaporation, and the remaining trifluoroacetic acid was removed by repeated rotation with dichloromethane to obtain an off-white solid, 4-((1r,3r)-3-amino-2,2,4,4-tetramethylcyclobutoxy)-2-(trifluoromethyl)benzonitrile trifluoroacetate. This was used directly in the next reaction without further purification. 3. Synthesis of methyl 2-((((1r,3r)-3-(4-cyano-3-(trifluoromethyl)phenoxy)-2,2,4,4-tetramethylcyclobutyl)amino)methyl)-4-nitrobenzoate DMF (10 mL) was added to a 25 mL single-necked round-bottom flask charged with 4-((1r,3r)-3-amino-2,2,4,4-tetramethylcyclobutoxy)-2-(trifluoromethyl)benzonitrile trifluoroacetate, and the mixture was stirred at room temperature to dissolve and clarify the reaction. Potassium carbonate (437 mg, 3.16 mmol) and methyl 2-(bromomethyl)-4-nitrobenzoate (433 mg, 1.58 mmol) were then added to the mixture. After completion, the mixture was stirred in an oil bath at 100°C. After 1 h, a sample was taken and analyzed by thin-layer chromatography. TLC showed that the starting material had been completely consumed. Ethyl acetate (15 mL) and water (10 mL) were added to the mixture, and the mixture was stirred vigorously. After 3 min, the mixture was allowed to stand and separated. The aqueous layer was separated into ethyl acetate (10 mL) and ethyl acetate (10 mL). * 3), and the organic phases were combined and diluted with water (10 mL * 3), washed successively with saturated brine (15 mL), dried over anhydrous sodium sulfate, and concentrated in vacuo to obtain a crude product, which was separated and purified by column chromatography to obtain methyl 2-((((1r,3r)-3-(4-cyano-3-(trifluoromethyl)phenoxy)-2,2,4,4-tetramethylcyclobutyl)amino)methyl)-4-nitrobenzoate (532 mg) in a 67% yield (two steps). LC / MS (ESI + )Calcd for C 25 H 26 F3N3O5(M+H) + m / z, 505.1; Found: 506.3. 4.4-((1r,3r)-2,2,4,4-tetramethyl-3-(5-nitro-1-oxoisoindolin-2-yl)epoxybutoxy)-2-(trifluoromethyl)benzonitrile Methyl 2-((((1r,3r)-3-(4-cyano-3-(trifluoromethyl)phenoxy)-2,2,4,4-tetramethylcyclobutyl)amino)methyl)-4-nitrobenzoate (532 mg, 1.05 mmol) was placed in a 25 mL single-neck round-bottom flask, toluene (10 mL) was added, and the mixture was stirred at room temperature. Then, triethylamine (319 mg, 3.15 mmol) was added to the mixture. After completion, the mixture was placed in a 110 °C oil bath and heated to reflux, and the mixture was stirred overnight. The next day, a sample was taken and analyzed by thin-layer chromatography. TLC showed the completion of the reaction. After cooling to room temperature, the mixture was rotary evaporated to remove the solvent, yielding the crude product. The mixture was triturated with n-hexane (20 mL) and ethyl acetate (1 mL) at room temperature. After 30 min, the system was suction filtered, and the filter cake was washed with n-hexane (30 mL) and dried to obtain a white solid, 4-((1r,3r)-2,2,4,4-tetramethyl-3-(5-nitro-1-oxoisoindolin-2-yl)epoxybutoxy)-2-(trifluoromethyl)benzonitrile (395 mg), in a yield of 79%. LC / MS (ESI + )Calcd for C 24 H 22 F3N3O4(M+H) + m / z, 473.1; Found: 474.3. 5. 4-((1r,3r)-3-(5-amino-1-oxoisoindolin-2-yl)-2,2,4,4-tetramethylepoxybutoxy)-2-(trifluoromethyl)benzonitrile 4-((1r,3r)-2,2,4,4-tetramethyl-3-(5-nitro-1-oxoisoindolin-2-yl)epoxybutoxy)-2-(trifluoromethyl)benzonitrile (395 mg, 0.83 mmol) was placed in a 25 mL single-neck round-bottom flask, and glacial acetic acid (12 mL) was added. The mixture was stirred at room temperature. Reduced iron powder (1400 mg, 24.90 mmol) was then added to the mixture. After completion, the mixture was placed in a 65 °C oil bath and heated with stirring. After 30 min, a sample was sampled and analyzed by thin-layer chromatography. TLC showed that the starting material was completely consumed, and heating was stopped. The mixture was filtered while still hot, and the filter cake was washed with glacial acetic acid (36 mL). The filtrate was collected and rotary evaporated to remove acetic acid, yielding a crude product. The mixture was then triturated with n-hexane (5 mL) and ethyl acetate (2 mL) at room temperature. After 20 min, the system was suction filtered, and the filter cake was washed with n-hexane (5 mL) and dried to obtain an off-white solid, 4-((1r,3r)-3-(5-amino-1-oxoisoindolin-2-yl)-2,2,4,4-tetramethylepoxybutoxy)-2-(trifluoromethyl)benzonitrile (324 mg), in a yield of 88%. LC / MS (ESI + )Calcd for C 24 H 24 F3N3O2(M+H) + m / z, 443.1; Found: 444.2. 6. Synthesis of 2-((5-((2-((1r,3r)-3-(4-cyano-3-(trifluoromethyl)phenoxy)-2,2,4,4-tetramethylepoxybutyl)-1-oxoisoindolin-5-yl)amino)pentyl)oxy)acetic acid tert-butyl ester 4-((1r,3r)-3-(5-amino-1-oxoisoindolin-2-yl)-2,2,4,4-tetramethylepoxybutoxy)-2-(trifluoromethyl)benzonitrile (150 mg, 0.34 mmol) was placed in a 50 mL single-neck round-bottom flask, and 2-((5-oxopentyl)oxy)acetic acid tert-butyl ester (73 mg, 0.34 mmol), methanol (15 mL), and acetic acid (61 mg, 1.02 mmol) were added sequentially. The mixture was stirred at room temperature to dissolve and clarify the reaction. After 15 min, NaBHCN (86 mg, 1.36 mmol) was added to the mixture. After completion, the mixture was stirred overnight at room temperature. The next day, a sample was taken and analyzed by thin-layer chromatography, and the starting material was almost consumed. After removing the solvent by rotary evaporation, ethyl acetate (20 mL) and water (10 mL) were added to the system, and the mixture was stirred vigorously. After 3 minutes, the mixture was allowed to stand and the layers were separated. The aqueous layer was separated into ethyl acetate (10 mL) and water (10 mL). * 3), and the organic phases were combined and diluted with water (10 mL * 3), washed successively with saturated brine (15 mL), dried over anhydrous sodium sulfate, and concentrated in vacuo to obtain a crude product, which was separated and purified by pre-TLC to obtain an off-white solid, 2-((5-((2-((1r,3r)-3-(4-cyano-3-(trifluoromethyl)phenoxy)-2,2,4,4-tetramethylepoxybutyl)-1-oxoisoindolin-5-yl)amino)pentyl)oxy)acetic acid tert-butyl ester (80 mg) in a 37% yield. LC / MS (ESI + )Calcd for C 35 H 44 F3N3O5(M+H) + m / z, 643.3; Found: 644.3. 7. Synthesis of 2-((5-((2-((1r,3r)-3-(4-cyano-3-(trifluoromethyl)phenoxy)-2,2,4,4-tetramethylcyclobutyl)-1-oxoisoindolin-5-yl)amino)pentyl)oxy)acetic acid 2-((5-((2-((1r,3r)-3-(4-cyano-3-(trifluoromethyl)phenoxy)-2,2,4,4-tetramethylepoxybutyl)-1-oxoisoindolin-5-yl)amino)pentyl)oxy)acetic acid tert-butyl ester (38 mg, 0.06 mmol) was placed in a 25 mL single-necked round-bottom flask, and dichloromethane (10 mL) was added and stirred at room temperature. Then, trifluoroacetic acid (1 mL) was added to the system, and after completion, the system was stirred and reacted at room temperature. After 3 h, a sample was taken and thin-layer chromatography was performed, and TLC showed that the starting material was completely consumed. The solvent and excess trifluoroacetic acid were removed by rotary evaporation, followed by repeated rotation with dichloromethane to remove residual trifluoroacetic acid, to give an off-white solid, 2-((5-((2-((1r,3r)-3-(4-cyano-3-(trifluoromethyl)phenoxy)-2,2,4,4-tetramethylcyclobutyl)-1-oxoisoindolin-5-yl)amino)pentyl)oxy)acetic acid, which was used directly in the next reaction without further purification. 8. (2R,4R)-1-((S)-2-(2-((5-((2-((1r,3r)-3-(4-cyano-3-(trifluoromethyl)phenoxy)-2,2,4,4-tetramethylcyclobutyl)-1-oxoisoindolin-5-yl)amino)phenyl)oxy)aceto Synthesis of TIFF0007603609000229.tif8153-Methylthiazol-5-yl)phenyl)ethyl)pyrrole-2-carbamoyl. To a 25 mL single-neck round-bottom flask charged with 2-((5-((2-((1r,3r)-3-(4-cyano-3-(trifluoromethyl)phenoxy)-2,2,4,4-tetramethylcyclobutyl)-1-oxoisoindolin-5-yl)amino)pentyl)oxy)acetic acid were added HATU (34 mg, 0.09 mmol), DMF (5 mL), VHL(OAc) (39 mg, 0.07 mmol), and diisopropylethylamine (23 mg, 0.18 mmol) sequentially. The mixture was then stirred overnight at room temperature. The next day, a sample was taken and analyzed by thin-layer chromatography. TLC showed that the starting material had been completely consumed. Ethyl acetate (15 mL) and water (10 mL) were added to the system, which was then vigorously stirred. After 3 minutes, the system was allowed to stand to separate the layers, and the aqueous layer was separated into ethyl acetate (10 mL * 3), and the organic phases were combined and diluted with water (10 mL * 3), washed successively with saturated brine (15 mL), dried over anhydrous sodium sulfate, and rotary evaporated to remove the solvent to obtain a crude product, which was then separated and purified by pre-TLC to obtain an off-white solid (2R,4R)-1-((S)-2-(2-((5-((2-((1r,3r)-3-(4-cyano-3-(trifluoromethyl)phenoxy)-2,2,4,4-tetramethylcyclobutyl)-1-oxoisoindolin-5-yl)amino)phenyl)oxa TIFF0007603609000230.tif7152 (4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrole-2-carbamoyl (31 mg) was obtained in a yield (two steps) of 52%. LC / MS (ESI + )Calcd for C 54 H 66 F3N7O7S(M+H) +m / z,1013.4;Found:1014.2. TIFF0007603609000231.tif27153TIFF0007603609000232.tif27154(s,6H),0.94(s,9H).

[0106] 17. (3R,5S)-1-((2S)-2-(2-(4-((4-(5-(((3aR,4R,7R,7aS)-2-(3-chloro-4-benzonitrile)-4,7-dimethyl-1,3-dioxooctahydro-1-hydro-4,7-epoxyisoindolin-5-yl)carbamoyl)pyridin-2-yl)piperazin-1-yl)methyl)piperidin-1-yl)acetamido)-3,3-dimethylbutyryl)-5-(((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-3-yl acetate TIFF0007603609000233.tif611501.Synthesis of intermediate: 1. 4-(5-(((3aR,4R,7R,7aS)-2-(3-chloro-4-benzonitrile)-4,7-dimethyl-1,3-dioxooctahydro-1hydro-4,7-epoxyisoindol-5-yl)carbamoyl)pyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester 6-[4-(tert-butoxycarbonyl)piperazin-1-yl]nicotinic acid (130 mg, 0.42 mmol) was placed in a 25 mL single-necked round-bottom flask and DMF (8 mL) was added. The mixture was stirred at room temperature to dissolve and clarify the reaction. EDCI (200 mg, 1.05 mmol), HOBt (85 mg, 0.63 mmol), DMAP (5 mg, 0.04 mmol), and triethylamine (106 mg, 1.05 mmol) were then added sequentially. The mixture was stirred at room temperature for 5 min. Then, 4-((3aR,4R,7R,7aS)-5-amino-4,7-dimethyl-1,3-dioxahydro-1-hydro-4,7-epoxyisoindol-2(3-hydro)yl)-2-chlorobenzonitrile (145 mg, 0.42 mmol) prepared by a literature method was added to the system, and the system was stirred overnight at room temperature. The next day, the completion of the reaction was detected by TLC. Ethyl acetate (20 mL) and water (15 mL) were added to the system, and the system was stirred vigorously. After 5 minutes, the system was allowed to stand and the layers were separated. The aqueous layer was separated with ethyl acetate (10 mL). * 3), and the organic phases were combined and diluted with water (10 mL *3), washed successively with saturated brine (15 mL), dried over anhydrous sodium sulfate, and concentrated in vacuo to obtain the crude product, which was separated and purified by pre-TLC to give 4-(5-(((3aR,4R,7R,7aS)-2-(3-chloro-4-benzonitrile)-4,7-dimethyl-1,3-dioxooctahydro-1-hydro-4,7-epoxyisoindol-5-yl)carbamoyl)pyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (191 mg) in 71% yield. LC / MS (ESI) + )Calcd for C 32 H 35 ClN6O6(M+H) + m / z, 635.1; Found: 634.7. TIFF0007603609000234.tif9153Synthesis of 4,7-dimethyl-1,3-dioxooctahydro-1hydro-4,7-epoxyisoindol-5-yl)-6-(piperazin-1-yl)nicotinamide trifluoroacetate 4-(5-(((3aR,4R,7R,7aS)-2-(3-chloro-4-benzonitrile)-4,7-dimethyl-1,3-dioxooctahydro-1-hydro-4,7-epoxyisoindol-5-yl)carbamoyl)pyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (175 mg, 0.28 mmol) was placed in a 25 mL single-necked round-bottom flask, and dichloromethane (10 mL) was added and stirred at room temperature. Then, trifluoroacetic acid (1 mL) was added to the system, and after completion, the system was stirred and reacted at room temperature. After 3.5 h, a sample was taken and thin-layer chromatography was performed, and TLC showed that the raw material was completely consumed. The solvent and excess trifluoroacetic acid were removed by rotary evaporation, and the dichloromethane was added. TIFF0007603609000235.tif9155aR,4R,7R,7aS)-2-(3-chloro-4-benzonitrile)-4,7-dimethyl-1,3-dioxooctahydro-1-hydro-4,7-epoxyisoindol-5-yl)-6-(piperazin-1-yl)nicotinamide trifluoroacetate was obtained, which was used directly in the next reaction without further purification. 3. Synthesis of 4-((4-(5-(((3aR,4R,7R,7aS)-2-(3-chloro-4-benzonitrile)-4,7-dimethyl-1,3-dioxooctahydro-1hydro-4,7-epoxyisoindol-5-yl)carbamoyl)pyridin-2-yl)piperazin-1-yl)methyl)piperidine-1-carboxylic acid tert-butyl ester TIFF0007603609000236.tif81507-Dimethyl-1,3-dioxooctahydro-1-hydro-4,7-epoxyisoindol-5-yl)-6-(piperazin-1-yl)nicotinamide trifluoroacetate was added to a 25 mL single-neck round-bottom flask and dissolved in 1-Boc-4 bromomethylpiperidine (86 mg, 0.31 mmol), potassium carbonate (155 mg, 1.12 mmol), sodium iodide (42 mg, 0.28 mmol), and acetonitrile (10 mL). The mixture was then evacuated and argon was introduced five times to ensure an inert atmosphere. After completion of the reaction, the mixture was placed in an oil bath and heated to reflux overnight. After 15 h, a sample was taken and analyzed by thin-layer chromatography (TLC) to confirm completion of the reaction. The solvent was removed by rotary evaporation, and ethyl acetate (15 mL) and water (10 mL) were added to the system. The system was stirred vigorously and allowed to stand for 3 minutes to separate the layers. The aqueous layer was separated into ethyl acetate (10 mL) * 3), and the organic phases were combined and diluted with water (10 mL * 3), washed successively with saturated brine (15 mL), dried over anhydrous sodium sulfate, and concentrated in vacuo to give the crude product, which was separated and purified by pre-TLC to give 4-((4-(5-(((3aR,4R,7R,7aS)-2-(3-chloro-4-benzonitrile)-4,7-dimethyl-1,3-dioxooctahydro-1-hydro-4,7-epoxyisoindol-5-yl)carbamoyl)pyridin-2-yl)piperazin-1-yl)methyl)piperidine-1-carboxylic acid tert-butyl ester (124 mg) in 61% yield (two steps). LC / MS (ESI + )Calcd for C 38 H 46 ClN7O6(M+H) +m / z, 732.3; Found: 732.2. 4. Synthesis of N-((3aR,4R,7R,7aS)-2-(3-chloro-4-benzonitrile)-4,7-dimethyl-1,3-dioxooctahydro-1hydro-4,7-epoxyisoindol-5-yl)-6-(4-(piperidin-4-ylmethyl)piperazin-1-yl)nicotinamide trifluoroacetate 4-((4-(5-(((3aR,4R,7R,7aS)-2-(3-chloro-4-benzonitrile)-4,7-dimethyl-1,3-dioxooctahydro-1-hydro-4,7-epoxyisoindol-5-yl)carbamoyl)pyridin-2-yl)piperazin-1-yl)methyl)piperidine-1-carboxylic acid tert-butyl ester (124 mg, 0.16 mmol) was placed in a 25 mL single-necked round-bottom flask, and dichloromethane (8 mL) was added and stirred at room temperature. Trifluoroacetic acid (1 mL) was then added to the system, and upon completion, the system was stirred and reacted at room temperature. After 3 h, a sample was taken and analyzed by thin layer chromatography, and TLC showed the completion of the reaction. The solvent and excess trifluoroacetic acid were removed by rotary evaporation, and the remaining trifluoroacetic acid was removed by repeated rotation with dichloromethane, and the resulting solution was then purified by white elution. TIFF0007603609000237.tif8153-4,7-Dimethyl-1,3-dioxooctahydro-1hydro-4,7-epoxyisoindol-5-yl)-6-(4-(piperidin-4-ylmethyl)piperazin-1-yl)nicotinamide trifluoroacetate was obtained, which was used directly in the next reaction without further purification. 5. Synthesis of 2-(4-((4-(5-(((3aR,4R,7R,7aS)-2-(3-chloro-4-benzonitrile)-4,7-dimethyl-1,3-dioxooctahydro-1hydro-4,7-epoxyisoindolin-5-yl)carbamoyl)pyridin-2-yl)piperazin-1-yl)methyl)piperidin-1-yl)acetic acid tert-butyl ester TIFF0007603609000238.tif91517-Dimethyl-1,3-dioxooctahydro-1-hydro-4,7-epoxyisoindolin-5-yl)-6-(4-(piperidin-4-ylmethyl)piperazin-1-yl)nicotinamide trifluoroacetate was added to a 25 mL single-neck round-bottom flask in succession, followed by the addition of tert-butyl bromoacetate (62 mg, 0.32 mmol), dichloromethane (10 mL), and diisopropylethylamine (83 mg, 0.64 mmol). After completion, the reaction mixture was stirred overnight at room temperature. The next day, a sample was taken and analyzed by thin-layer chromatography. TLC showed the completion of the reaction. Dichloromethane (10 mL) and water (10 mL) were added to the mixture, which was stirred vigorously for 3 minutes. The mixture was then allowed to stand for 3 minutes, allowing the layers to separate. The aqueous layer was separated into 10 mL of dichloromethane and 10 mL of water. * 3), back-extract with water (5 mL) and combine the organic phases. * 3), washed successively with saturated brine (10 mL), dried over anhydrous sodium sulfate, and concentrated in vacuo to obtain the crude product, which was separated and purified by pre-TLC to give 2-(4-((4-(5-(((3aR,4R,7R,7aS)-2-(3-chloro-4-benzonitrile)-4,7-dimethyl-1,3-dioxooctahydro-1hydro-4,7-epoxyisoindolin-5-yl)carbamoyl)pyridin-2-yl)piperazin-1-yl)methyl)piperidin-1-yl)acetic acid tert-butyl ester (74 mg) in a 59% yield (two steps). LC / MS (ESI + )Calcd for C 39 H 48 ClN7O6(M+H) + m / z, 746.3; Found: 745.2. 6. Synthesis of 2-(4-((4-(5-(((3aR,4R,7R,7aS)-2-(3-chloro-4-benzonitrile)-4,7-dimethyl-1,3-dioxooctahydro-1hydro-4,7-epoxyisoindol-5-yl)carbamoyl)pyridin-2-yl)piperazin-1-yl)methyl)piperidin-1-yl)acetic acid 2-(4-((4-(5-(((3aR,4R,7R,7aS)-2-(3-chloro-4-benzonitrile)-4,7-dimethyl-1,3-dioxooctahydro-1-hydro-4,7-epoxyisoindol-5-yl)carbamoyl)pyridin-2-yl)piperazin-1-yl)methyl)piperidin-1-yl)acetic acid tert-butyl ester (40 mg, 0.05 mmol) was placed in a 25 mL single-necked round-bottom flask, and dichloromethane (5 mL) was added and stirred at room temperature. Then, trifluoroacetic acid (1 mL) was added to the system, and after completion, the system was stirred and reacted at room temperature. After 3 h, a sample was sampled and analyzed by thin layer chromatography, and TLC showed that the reaction was complete. The solvent and excess trifluoroacetic acid were removed by rotary evaporation, followed by repeated rotation with dichloromethane to remove residual trifluoroacetic acid, to give an off-white solid, 2-(4-((4-(5-(((3aR,4R,7R,7aS)-2-(3-chloro-4-benzonitrile)-4,7-dimethyl-1,3-dioxooctahydro-1hydro-4,7-epoxyisoindol-5-yl)carbamoyl)pyridin-2-yl)piperazin-1-yl)methyl)piperidin-1-yl)acetic acid, which was used directly in the next reaction without further purification. 7. (3R,5S)-1-((2S)-2-(2-(4-((4-(5-(((3aR,4R,7R,7aS)-2-(3-chloro-4-benzonitrile)-4,7-dimethyl-1,3-dioxooctahydro-1-hydro-4,7-epoxyisoindolin-5-yl)carbamoyl)pyridin-2-yl)piperazin-1-yl)methyl)piperidin-1-yl)acetamido)-3,3-dimethylbutyryl)-5-(((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-3-yl acetate To a 25 mL single-necked round-bottom flask charged with 2-(4-((4-(5-(((3aR,4R,7R,7aS)-2-(3-chloro-4-benzonitrile)-4,7-dimethyl-1,3-dioxooctahydro-1-hydro-4,7-epoxyisoindolin-5-yl)carbamoyl)pyridin-2-yl)piperazin-1-yl)methyl)piperidin-1-yl)acetic acid, HATU (29 mg, 0.08 mmol), DMF (5 mL), VHL(OAc) (36 mg, 0.06 mmol), and diisopropylethylamine (19 mg, 0.15 mmol) were added sequentially, and the mixture was stirred overnight at room temperature. The next day, a sample was taken and analyzed by thin layer chromatography. TLC showed that the starting material was completely consumed. Ethyl acetate (15 mL) and water (10 mL) were added to the system, vigorously stirred, and the system was allowed to stand to separate the layers. The aqueous layer was separated into ethyl acetate (10 mL * 3), and the organic phases were combined and diluted with water (10 mL * 3), washed successively with saturated brine (15 mL), dried over anhydrous sodium sulfate, and concentrated in vacuo to give the crude product, which was separated and purified by pre-TLC to give (3R,5S)-1-((2S)-2-(2-(4-((4-(5-(((3aR,4R,7R,7aS)-2-(3-chloro-4-benzonitrile)-4,7-dimethyl-1,3-dioxooctahydro-1-hydro-4,7-epoxyisoindolin-5-yl)carbamoyl)pyridin-2-yl)piperazin-1-yl)methyl)piperidin-1-yl)acetamido)-3,3-dimethylbutyryl)-5-(((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-3-yl acetate (34 mg) in 55% yield (two steps). LC / MS (ESI + )Calcd for C 60 H 72 ClN 11 O9S(M+H) + m / z, 1158.8; Found: 1157.6. TIFF0007603609000239.tif421533.25(m,7H),2.86-2.76(m,2H),2.46(s,3H),2.35-2.05(m,7H),2.00(s,3H),1.94-1.85 TIFF0007603609000240.tif10155(s,2H),1.17-1.10(m,3H),0.95(s,9H).

[0107] Synthesis of TIFF0007603609000241.tif10148-4,7-dimethyl-1,3-dioxooctahydro-1H-4,7-epoxyisoindolin-5-yl)-6-(4-((1-(2-(((S)-1-((2S,4R)-4-hydroxy-2-(((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-2-oxyethyl)piperidin-4-yl)methyl)piperazin-1-yl)nicotinamide TIFF0007603609000242.tif2980LC / MS(ESI + )Calcd for C 58 H 70 ClN 11 O8S(M+H) + m / z, 1116.8; Found: 1116.6. TIFF0007603609000243.tif68153

[0108] 19: (3S,5R)-1-((2R)-2-(2-((5-((4-(((3aS,4S,7S,7aR)-2-(3-chloro-4-benzonitrile)-4,7-dimethyl-1,3-dioxooctahydro-1hydro-4,7-epoxyisoindolin-5-yl)carbamoyl)-3-fluorophenyl)amino)pentyl)oxy)acetamido)-3,3-dimethylbutyryl)-5-(((R)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-3-yl acetate TIFF0007603609000244.tif3887LC / MS(ESI + )Calcd for C 56 H 64 ClFN8O 10 S(M+H) +m / z, 1095.7; Found: 1095.2. TIFF0007603609000245.tif34154TIFF0007603609000246.tif34153(s,9H).

[0109] 20: (2R,4S)-1-((2R)-2-(2-((5-((4-(((3aS,4S,7S,7aR)-2-(3-chloro-4-benzonitrile)-4,7-dimethyl-1,3-dioxooctahydro-1hydro-4,7-epoxyisoindolin-5-yl)carbamoyl)-3-fluorophenyl)amino)pentyl)oxy)acetamide)-3,3- TIFF0007603609000247.tif9152(5-yl)phenyl)ethyl)pyrrolidine-2-carbamoyl TIFF0007603609000248.tif3485LC / MS(ESI + )Calcd for C 54 H 62 ClFN8O9S(M+H) + m / z, 1053.6; Found: 1053.5. TIFF0007603609000249.tif42155(s,3H),2.16-2.01(m,2H),1.93-1.86(m,1H),1.81-1.72(m,1H),1.67-1.54(m,4H),1.49 TIFF0007603609000250.tif9100

[0110] 21: (2S,4R)-1-((S)-2-(2-((6-(4-(((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-1-oxoisoindolin-5-yl)pent-4-yn-1-yl)oxy)acetamido)-3,3-dimethylbutyryl)-4-hydro-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (21) TIFF0007603609000251.tif511501. Synthesis of 2-((5-(2-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-1-oxoisoindolin-5-yl)pent-4-yn-1-yl)oxy)acetic acid tert-butyl ester Compound 4-((1R,3R)-3-(5-bromo-1-oxoisoindolin-2-yl)-2,2,4,4-tetramethylcyclobutoxy)-2-chlorobenzonitrile (1-1) (189 mg, 0.4 mmol) and 2-(pent-4-yn-1-oxy)acetic acid tert-butyl ester (119 mg, 0.6 mmol) were dissolved in 3 mL of toluene, and 1 mL of triethylamine, 30 mg of Pd(dppf)2Cl2, and 150 mg of CuI were added. The reaction mixture was heated to 90-100 °C under N2 protection and stirred for 12 h. After completion of the reaction, the solvent was removed by vacuum distillation. The crude product was purified by plate chromatography (PE:EA = 3:1) to obtain 177 mg of intermediate 1-2 in 75% yield. Mass spectrum (ES): m / z = 591 [M+H]. + . 2. Intermediate: Synthesis of 2-((5-(2-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-1-oxoisoindolin-5-yl)pent-4-yn-1-yl)oxy)acetic acid Compound 2-((5-(2-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-1-oxoisoindolin-5-yl)pent-4-yn-1-yl)oxy)acetic acid tert-butyl ester (Intermediate 1-2) (118 mg, 0.2 mmol) was dissolved in 2 mL of dichloromethane, 1 mL of trifluoroacetic acid was added, and the mixture was stirred at room temperature for 2 h. The reaction was completed, and the solvent was removed under reduced pressure. The mixture was used directly in the next reaction without further purification. 3. Synthesis of the final product: (2S,4R)-1-((S)-2-(2-((6-(4-(((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-1-oxoisoindolin-5-yl)pent-4-yn-1-yl)oxy)acetamido)-3,3-dimethylbutyryl)-4-hydro-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide The compound 2-((5-(2-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-1-oxoisoindolin-5-yl)pent-4-yn-1-yl)oxy)acetic acid (Intermediate 1-3) (53.5 mg, 0.1 mmol) and ((2s,4r)-1-((s)-2-amino-3,3-dimethylbutyryl)-4-hydroxy-N-((s)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide The amide (44.5 mg, 0.1 mmol) was dissolved in 2 mL of dichloromethane, DIPEA (38.7 mg, 0.3 mmol) and HATU (76.05 mg, 0.2 mmol) were added, and the mixture was stirred at room temperature for 2 h. After the reaction was complete, water was added and the mixture was extracted with dichloromethane. The resulting organic phase was distilled under reduced pressure to remove the solvent, and the crude product was purified by plate chromatography (MeOH:DCM = 10:1) to give 52 mg of the final product in 54% yield. Mass spectrum (ES): m / z = 961 [M+H] + . 1 H NMR TIFF0007603609000252.tif17153(m,2H),4.95-4.86(m,1H),4.77(s,2H),4.54(s,3H),4.31(s,1H),3.98(s,3H),3.82- TIFF0007603609000253.tif10155(s,8H),1.24(s,3H),1.15(s,6H),0.96(s,9H).

[0111] 22: (2S,4R)-1-((S)-2-(2-((5-(4-(((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)(tritiated methyl)benzamido)-4-alkynylpentyl-oxyacetamido-3,3-dimethylbutane)-4-hydroxy-N-((s)-1-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide TIFF0007603609000254.tif58147 Intermediate: Synthesis of ((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)(deuterated methyl) tert-butylcarbamate The compound ((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl) tert-butylcarbamate (1.89 g, 5 mmol) was dissolved in 5 mL of DMF, and sodium bicarbonate (0.4 g, 10 mmol) was added under ice bath conditions. The mixture was stirred at room temperature for 0.5 h. Deuterated methyl iodide (1.09 g, 7.5 mmol) was added and the mixture was stirred for 3 h. After the reaction was completed, water was added, and the mixture was extracted with ethyl acetate. The organic phase was distilled under reduced pressure to remove the solvent. The crude product was purified by column chromatography to obtain 1.74 g of intermediate 2-2 in an 88% yield. Mass spectrum (ES): m / z = 397 [M+H] + . Intermediate: Synthesis of ((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)(deuterated methyl)carbamate The compound ((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl) (deuterated methyl) tert-butylcarbamate (Intermediate 2-2) (396 mg, 0.1 mmol) was dissolved in 2 mL of dichloromethane, 1 mL of trifluoroacetic acid was added, and the mixture was stirred at room temperature for 2 h. The reaction was completed, and the solvent was removed under reduced pressure. The product was used directly in the next reaction without further purification. Intermediate: Synthesis of N-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-iodo-N-deuterated methylbenzamide The compound (1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl) (deuterated methyl)carbamate (Intermediate 2-3) (296 mg, 1 mmol) and p-iodobenzoic acid (248 mg, 1 mmol) were dissolved in 2 mL of DMF, and DIPEA (258 mg, 2 mmol) and HATU (570 mg, 1.5 mmol) were added. The mixture was stirred at room temperature for 3 hours. After the reaction was complete, water was added and the mixture was extracted with ethyl acetate. The resulting organic phase was distilled under reduced pressure to remove the solvent, and the crude product was purified by plate chromatography (PE:EA = 3:1) to obtain 395 mg of Intermediate 2-4 in a 75% yield. Mass spectrum (ES): m / z = 526 [M+H] + . Intermediate: Synthesis of 2-((5-(4-(((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)(deuterated methyl)carbamoyl)phenyl)pent-5-yn-1-yl)oxy)acetic acid tert-butyl ester The compound N-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-iodo-N-deuterated methylbenzamide (intermediate 2-4) (210 mg, 0.4 mmol) and 2-(pent-4-yn-1-oxy)acetic acid tert-butyl ester (119 mg, 0.6 mmol) were dissolved in 3 mL of toluene, and 1 mL of triethylamine, 30 mg of Pd(dppf)2Cl2, and 150 mg of CuI were added. The reaction mixture was heated to 90-100 °C under N2 protection and stirred for 12 h. After completion of the reaction, the solvent was removed by vacuum distillation. The crude product was purified by plate chromatography (PE:EA = 3:1) to obtain 203 mg of intermediate 2-5 in 85% yield. Mass spectrum (ES): m / z = 596 [M+H]. + . Intermediate: Synthesis of 2-((5-(4-(((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)(deuterated methyl)carbamoyl)phenyl)pent-5-yn-1-yl)oxy)acetic acid Compound 2-((5-(4-(((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)(deuterated methyl)carbamoyl)phenyl)pent-5-yn-1-yl)oxy)acetic acid tert-butyl ester (Intermediate 2-5) (59.6 mg, 0.1 mmol) was dissolved in 2 mL of dichloromethane, 1 mL of trifluoroacetic acid was added, and the mixture was stirred at room temperature for 2 h. The reaction was completed, and the solvent was removed under reduced pressure. The mixture was used directly in the next reaction without further purification. The compound 2-((5-(4-(((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)(deuterated methyl)carbamoyl)phenyl)pent-5-yn-1-yl)oxy)acetic acid (Intermediate 2-6) (54 mg, 0.1 mmol) and ((2s,4r)-1-((s)-2-amino-3,3-dimethylbutyryl)-4-hydroxy-N-((s)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide The amide (44.5 mg, 0.1 mmol) was dissolved in 2 mL of dichloromethane, DIPEA (38.7 mg, 0.3 mmol) and HATU (76.05 mg, 0.2 mmol) were added, and the mixture was stirred at room temperature for 2 hours. After the reaction was completed, water was added and the mixture was extracted with dichloromethane. The organic phase was distilled under reduced pressure to remove the solvent, and the crude product was purified by plate chromatography (MeOH:DCM=10:1) to obtain 49 mg of the final product HC-2797-01 in a 51% yield. Mass spectrum (ES): TIFF0007603609000255.tif50153

[0112] 23: (2S,4R)-1-((S)-2-(2-((6-(4-(((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)(deuterated methyl)benzamido)-5-alkynylhexyl-oxyacetamido-3,3-dimethylbutane)-4-hydroxy-N-((S)-1-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide TIFF0007603609000256.tif421441. Intermediate: Synthesis of 2-((6-(4-(((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)(deuterated methyl)carbamoyl)phenyl)hexyl-5-yn-1-yl)oxy)acetic acid tert-butyl ester The compound N-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-iodo-N-deuterated methylbenzamide (intermediate 2-4) (210 mg, 0.4 mmol) and 2-(hexyl-5-yn-1-oxy)acetic acid tert-butyl ester (127 mg, 0.6 mmol) were dissolved in 3 mL of toluene, and 1 mL of triethylamine, Pd(dppf)2Cl2 (30 mg), and CuI (150 mg) were added. The reaction mixture was heated to 90-100 °C under N2 protection and stirred for 12 h. After completion of the reaction, the solvent was removed by vacuum distillation. The crude product was purified by plate chromatography (PE:EA = 3:1) to obtain 205 mg of intermediate 4-1 in 84% yield. Mass spectrum (ES): m / z = 610 [M+H] + . 2. Intermediate: Synthesis of 2-((6-(4-(((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)(deuterated methyl)carbamoyl)phenyl)hexyl-5-yn-1-yl)oxy)acetic acid Compound 2-((6-(4-(((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)(deuterated methyl)carbamoyl)phenyl)hexyl-5-yn-1-yl)oxy)acetic acid tert-butyl ester (Intermediate 4-1) (61 mg, 0.1 mmol) was dissolved in 2 mL of dichloromethane, 1 mL of trifluoroacetic acid was added, and the mixture was stirred at room temperature for 2 h. The reaction was completed, and the solvent was removed under reduced pressure. The mixture was used directly in the next reaction without further purification. 3. Synthesis of final product HC-2799-01: (2S,4R)-1-((S)-2-(2-((6-(4-(((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)(deuterated methyl)benzamido)-5-alkynylhexyl-oxyacetamido-3,3-dimethylbutane)-4-hydroxy-N-((S)-1-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide The compound 2-((6-(4-(((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)(deuterated methyl)carbamoyl)phenyl)hexyl-5-yn-1-yl)oxy)acetic acid (Intermediate 4-2) (55 mg, 0.1 mmol) and ((2s,4r)-1-((s)-2-amino-3,3-dimethylbutyryl)-4-hydroxy-N-((s)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carbohydrate were synthesized. The oxamide (44.5 mg, 0.1 mmol) was dissolved in 2 mL of dichloromethane, and DIPEA (38.7 mg, 0.3 mmol) and HATU (76.1 mg, 0.2 mmol) were added. The mixture was stirred at room temperature for 2 hours. After the reaction was complete, water was added and the mixture was extracted with dichloromethane. The resulting organic phase was distilled under reduced pressure to remove the solvent. The crude product was purified by plate chromatography (MeOH:DCM=10:1) to obtain 53 mg of the final product HC-2799-01 in a 54% yield. Mass spectrum (ES): TIFF0007603609000257.tif42154(m,4H),1.42-1.17(m,11H),0.94(s,9H).

[0113] 24: (2S,4R)-1-((S)-2-(2-((7-(4-(((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)(deuterated methyl)benzamido)-6-alkynylheptyl-oxyacetamido-3,3-dimethylbutane)-4-hydroxy-N-((S)-1-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide TIFF0007603609000258.tif511521. Intermediate: Synthesis of 2-((7-(4-(((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)(deuterated methyl)carbamoyl)phenyl)heptyl-6-yn-1-yl)oxy)acetic acid tert-butyl ester N-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-iodo-N-deuterated methylbenzamide (intermediate 2-4) (210 mg, 0.4 mmol) and 2-(heptyl-6-yn-1-oxy)acetic acid tert-butyl ester (136 mg, 0.6 mmol) were dissolved in 3 mL of toluene, and 1 mL of triethylamine, Pd(dppf)2Cl2 (30 mg), and CuI (150 mg) were added. The reaction mixture was heated to 90-100 °C under N2 protection and stirred for 12 h. After completion of the reaction, the solvent was removed by vacuum distillation. The crude product was purified by plate chromatography (PE:EA = 3:1) to obtain 212 mg of intermediate 6-1 in 85% yield. Mass spectrum (ES): m / z = 624 [M+H] + . 2. Intermediate: Synthesis of 2-((7-(4-(((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)(deuterated methyl)carbamoyl)phenyl)heptyl-6-yn-1-yl)oxy)acetic acid Compound 2-((7-(4-(((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)(deuterated methyl)carbamoyl)phenyl)heptyl-6-yn-1-yl)oxy)acetic acid tert-butyl ester (Intermediate 6-1) (62 mg, 0.1 mmol) was dissolved in 2 mL of dichloromethane, 1 mL of trifluoroacetic acid was added, and the mixture was stirred at room temperature for 2 h. The reaction was completed, and the solvent was removed under reduced pressure. The mixture was used directly in the next reaction without further purification. 3. Synthesis of final product 24: (2S,4S)-1-((S)-2-(2-((7-(4-(((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)(deuterated methyl)benzamido)-6-alkynylheptyl-oxyacetamido-3,3-dimethylbutane)-4-hydroxy-N-((s)-1-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide The compound 2-((7-(4-(((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)(deuterated methyl)carbamoyl)phenyl)heptyl-6-yn-1-yl)oxy)acetic acid (Intermediate 6-2) (57 mg, 0.1 mmol) and ((2s,4r)-1-((s)-2-amino-3,3-dimethylbutyryl)-4-hydroxy-N-((s)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (4 The resulting mixture (4.5 mg, 0.1 mmol) was dissolved in 2 mL of dichloromethane, and DIPEA (38.7 mg, 0.3 mmol) and HATU (76.1 mg, 0.2 mmol) were added. The mixture was stirred at room temperature for 2 h. After the reaction was complete, water was added and the mixture was extracted with dichloromethane. The resulting organic phase was distilled under reduced pressure to remove the solvent. The crude product was purified by plate chromatography (MeOH:DCM = 10:1) to obtain 50 mg of the final product HC-2801-01 in 50% yield. Mass spectrum (ES): m / z = 994 [M+H] + . 1H NMR(400mHz,DMSO-d6)δ8.98(s,1H),8.45(d,J=7.7Hz,1H),7.87(d,J=8.6Hz,1H),7.38(ddd,J=48.2,28.5,19.8Hz, 9H),7.25(s,1H),7.03(d,J=9.0Hz,1H),5.15(d,J=3.4Hz,1H),4.95-4.85(m,1H),4.77-4.61(m,1H),4.55(d,J=9.6 TIFF0007603609000259.tif10155(dd,J=14.7,9.1Hz,4H),2.48(d,J=21.7Hz,1 1H),2.05(d,J=8.4Hz,1H),1.82-1.59(m,4H),1.42-1.17(m,13H),0.94(s,9H).

[0114] 25: N-(5-(2-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-1-oxoisoindolin-5-yl)pent-4-yn-1-yl)-N-((S)-1-((2S,4R)-4-hydroxy-2-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)cyclopropane-1,1-dicarboxamide TIFF0007603609000260.tif631511. Intermediate: Synthesis of 2-(pent-4-en-1-yl)isoindoline-1,3-dione Pent-4-yn-1-ol (4.2 g, 0.05 mol) was dissolved in 30 mL of DCM, and TEA (7.6 g, 0.075 mol) was added. Methanesulfonyl chloride (6.9 g, 0.06 mol) was added dropwise in an ice bath, and the mixture was stirred for 5 h. After the reaction was completed, 25 mL of water and 30 mL of dichloromethane were added and extracted. The resulting organic phase was distilled under reduced pressure to remove the solvent, and the crude product was used directly in the next reaction without further purification. The above product (3.2 g, 0.02 mol) was dissolved in 20 mL of DMF, and phthalimide potassium salt (5.6 g, 0.03 mol) was added. The temperature of the reaction mixture was raised to 80 °C and the mixture was stirred for 6 h. After the reaction was completed, 30 mL of water and 90 mL of ethyl acetate were added for extraction. The resulting organic phase was distilled under reduced pressure to remove the solvent. The crude product was purified by column chromatography (PE:EA = 3:1) to obtain 3.9 g of intermediate 8-3 in a 91% yield. Mass spectrum (ES): m / z = 214 [M+H] + . 2. Intermediate: Synthesis of pent-4-yn-1-amine The above product (2.1 g, 0.01 mol) was dissolved in 30 mL of absolute ethanol, and hydrazine hydrate (0.75 g, 0.015 mol) was added. The temperature of the reaction mixture was raised to 80°C and the mixture was stirred for 5 hours. After the reaction was completed, the reaction mixture was cooled and filtered to remove insoluble materials. 30 mL of water and 90 mL of ethyl acetate were added to the filtrate for extraction. The resulting organic phase was distilled under reduced pressure to remove the solvent. The crude product was used directly in the next reaction without further purification. 3. Intermediate: Synthesis of methyl 1-(4-pentyne-1-carbamoyl)cyclopropane-1-carboxylate The above product, pentynamine (830 mg, 10 mmol) and 1-methoxycarbonylcyclopropane-1-formic acid (1.44 g, 10 mmol) were dissolved in 2 mL of dichloromethane, DIPEA (3.9 g, 30 mmol) and HATU (7.6 g, 20 mmol) were added, and the mixture was stirred at room temperature for 4 h. After the reaction was complete, water was added and the mixture was extracted with dichloromethane. The resulting organic phase was distilled under reduced pressure to remove the solvent, and the crude product was purified by plate chromatography (PE:EA = 3:1) to obtain 1.79 g of intermediate 8-5 in an 85% yield. Mass spectrum (ES): m / z = 210 [M+H] + . 4. Intermediate: Synthesis of methyl 1-((5-(2-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-1-oxoisoindolin-5-yl)pent-4-cyclo-1-yl)carbamoyl)cyclopropane-1-carboxylate Compound 4-((1R,3R)-3-(5-bromo-1-oxoisobutanol-2-yl)-2,2,4,4-tetramethylcyclobutoxy)-2-chlorobenzonitrile (1-1) (189 mg, 0.4 mmol) and methyl 1-(4-pentyne-1-carbamoyl)cyclopropane-1-carboxylate (126 mg, 0.6 mmol) were dissolved in 3 mL of toluene, and 1 mL of triethylamine, 30 mg of Pd(dppf)2Cl2, and 150 mg of CuI were added. The reaction mixture was heated to 90-100 °C under N2 protection and stirred for 12 h. After completion of the reaction, the solvent was removed by vacuum distillation. The crude product was purified by plate chromatography (PE:EA = 2:1) to obtain 188 mg of intermediate 8-6 in 78% yield. Mass spectrum (ES): m / z = 602 [M+H]. + . 5. Intermediate: Synthesis of 1-((5-(2-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-1-oxoisoindolin-5-yl)pent-4-cyclo-1-yl)carbamoyl)cyclopropane-1-carboxylic acid The compound 1-((5-(2-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-1-oxoisoindolin-5-yl)pent-4-cyclo-1-yl)carbamoyl)cyclopropane-1-carboxylate (Intermediate 8-6) (60 mg, 0.1 mmol) was dissolved in 2 mL of anhydrous methanol, and lithium hydroxide (9.6 mg, 0.4 mmol) was added and stirred at room temperature for 5 h. After the reaction was completed, 10 mL of water and 20 mL of ethyl acetate were added to the filtrate for extraction. The resulting organic phase was distilled under reduced pressure to remove the solvent, and the crude product was used directly in the next reaction without purification. 6. Synthesis of final product 25: N-(5-(2-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-1-oxoisoindolin-5-yl)pent-4-yn-1-yl)-N-((S)-1-((2S,4R)-4-hydroxy-2-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)cyclopropane-1,1-dicarboxamide The compound 1-((5-(2-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-1-oxoisoindolin-5-yl)pent-4-cyclo-1-yl)carbamoyl)cyclopropane-1-carboxylic acid (Intermediate 8-7) (59 mg, 0.1 mmol) and ((2s,4r)-1-((s)-2-amino-3,3-dimethylbutyryl)-4-hydroxy-N-((s)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)- (I)pyrrolidine-2-carboxamide (44.5 mg, 0.1 mmol) was dissolved in 2 mL of dichloromethane, DIPEA (38.7 mg, 0.3 mmol) and HATU (76.1 mg, 0.2 mmol) were added, and the mixture was stirred at room temperature for 2 h. After the reaction was completed, water was added and the mixture was extracted with dichloromethane. The resulting organic phase was distilled under reduced pressure to remove the solvent, and the crude product was purified by plate chromatography (MeOH:DCM=10:1) to obtain 55 mg of the final product HC-2803-01 in a 54% yield. TIFF0007603609000261.tif28156TIFF0007603609000262.tif35154

[0115] 26: (2S,4R)-1-((S)-2-(2-((4-(4-(((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)(deuterated methyl)benzamido)-3-alkynylbutyl-oxyacetamido-3,3-dimethylbutane)-4-hydroxy-N-((S)-1-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide TIFF0007603609000263.tif521501. Intermediate: Synthesis of 2-((4-(4-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)(methyl-d3)carbamoyl)phenyl)-3-yn-1-butyl)oxy)acetic acid tert-butyl ester The compound N-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-iodo-N-deuterated methylbenzamide (210 mg, 0.4 mmol) and 2-(butyl-3-yn-1-oxy)acetic acid tert-butyl ester (111 mg, 0.6 mmol) were dissolved in 3 mL of toluene, and 1 mL of triethylamine, 30 mg of Pd(dppf)2Cl2, and 150 mg of CuI were added. The reaction mixture was heated to 90-100 °C under N2 protection and stirred for 12 h. After completion of the reaction, the solvent was removed by vacuum distillation. The crude product was purified by plate chromatography (PE:EA = 3:1) to obtain 203 mg of product in 87% yield. Mass spectrum (ES): m / z = 582 [M+H]. + . 2. Intermediate: Synthesis of 2-((4-(4-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)(methyl-d3)carbamoyl)phenyl)-3-yn-1-butyl)oxy)acetic acid The compound 2-((4-(4-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)(methyl-d3)carbamoyl)phenyl)-3-yn-1-butyl)oxy)acetic acid tert-butyl ester (58 mg, 0.1 mmol) was dissolved in 2 mL of dichloromethane, 1 mL of trifluoroacetic acid was added, and the mixture was stirred at room temperature for 2 h until the reaction was complete. The solvent was removed under reduced pressure, and the mixture was used directly in the next reaction without further purification. 3. Synthesis of final product 26: (2S,4R)-1-((S)-2-(2-((4-(4-(((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)(deuterated methyl)benzamido)-3-alkynylbutyl-oxyacetamido-3,3-dimethylbutane)-4-hydroxy-N-((S)-1-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide The compounds 2-((4-(4-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)(methyl-d3)carbamoyl)phenyl)-3-yn-1-butyl)oxy)acetic acid (53 mg, 0.1 mmol) and ((2s,4r)-1-((s)-2-amino-3,3-dimethylbutyryl)-4-hydroxy-N-((s)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (44. 26 (5 mg, 0.1 mmol) was dissolved in 2 mL of dichloromethane, and DIPEA (38.7 mg, 0.3 mmol) and HATU (76.1 mg, 0.2 mmol) were added. The mixture was stirred at room temperature for 2 h. After the reaction was complete, water was added and the mixture was extracted with dichloromethane. The resulting organic phase was distilled under reduced pressure to remove the solvent. The crude product was purified by plate chromatography (MeOH:DCM = 10:1) to give 50 mg of the final product 26 in 52% yield. Mass spectrum (ES): m / z = 952 [M+H] + . 1 H NMR (400 mHz, DMSO-d) δ 8.99 TIFF0007603609000264.tif25154(s,2H),2.12-1.93(m,2H),1.83-1.67(m,2H),1.36(d,J=12.4Hz,9H),0.92(s,12H).

[0116] 27: (2R,4R)-1-((R)-2-(2-((4-(2-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-1-oxoisobutanol-5-yl)-3-butyn-1-yl)oxy)acetamido)-3,3-dimethylbutyryl)-4-hydroxy-N-((S)-1-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide TIFF0007603609000265.tif461551. Intermediate: Synthesis of 2-((4-(2-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-1-oxoisoindolin-5-yl)-3-butyn-1-yl)oxy)acetic acid tert-butyl ester Compound 4-((1R,3R)-3-(5-bromo-1-oxoisobutanol-2-yl)-2,2,4,4-tetramethylcyclobutoxy)-2-chlorobenzonitrile (1-1) (189 mg, 0.4 mmol) and 2-(butyl-3-yn-1-oxy)acetic acid tert-butyl ester (119 mg, 0.6 mmol) were dissolved in 3 mL of toluene, and 1 mL of triethylamine, 30 mg of Pd(dppf)2Cl2, and 150 mg of CuI were added. The reaction mixture was heated to 90-100 °C under N2 protection and stirred for 12 h. After completion of the reaction, the solvent was removed by vacuum distillation. The crude product was purified by plate chromatography (PE:EA = 3:1) to obtain 180 mg of intermediate 12-1 in 78% yield. Mass spectrum (ES): m / z = 577 [M+H]. + . 2. Intermediate: Synthesis of 2-((4-(2-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-1-oxoisoindolin-5-yl)-3-butyn-1-yl)oxy)acetic acid Compound 2-((4-(2-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-1-oxoisoindolin-5-yl)-3-butyn-1-yl)oxy)acetic acid tert-butyl ester (Intermediate 12-1) (58 mg, 0.1 mmol) was dissolved in 2 mL of dichloromethane, 1 mL of trifluoroacetic acid was added, and the mixture was stirred at room temperature for 2 h. The reaction was completed, and the solvent was removed under reduced pressure. The mixture was used directly in the next reaction without further purification. 3. Synthesis of final product 27: (2R,4R)-1-((R)-2-(2-((4-(2-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-1-oxoisobutanol-5-yl)-3-butyn-1-yl)oxy)acetamido)-3,3-dimethylbutyryl)-4-hydroxy-N-((S)-1-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide The compound 2-((4-(4-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)(methyl-d3)carbamoyl)phenyl)-3-yn-1-butyl)oxy)acetic acid (Intermediate 10-2) (52 mg, 0.1 mmol) and ((2s,4r)-1-((s)-2-amino-3,3-dimethylbutyryl)-4-hydroxy-N-((s)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (44.5 mg, 0.1 mmol) was dissolved in 2 mL of dichloromethane, DIPEA (38.7 mg, 0.3 mmol) and HATU (76.1 mg, 0.2 mmol) were added, and the mixture was stirred at room temperature for 2 h. After the reaction was complete, water was added and the mixture was extracted with dichloromethane. The resulting organic phase was distilled under reduced pressure to remove the solvent, and the crude product was purified by plate chromatography (MeOH:DCM = 10:1) to give 53 mg of the final product 27 in 56% yield. Mass spectrum (ES): m / z = 947 [M+H] + . 1H NMR(400mHz,DMSO-d6)δ8.98(s,1H),8.51-8.44(m,1H),7.91(s,1H),7.63(d,J=9.9Hz,2H),7.54 ~ 7.33(m,6H),7.29(s,1H),7.11-7.03(m,1H),5.25-5.17(m,2H),4.95-4.86(m,1H),4.77(s,2H),4.54(s,3H),4.31(s,1H),3.98(s,3 H),3.82-3.73(m,1H),3.63(s,2H),2.46(s,3H),2.32-2.21(m,2H),1.86(s,2H),1.39(s,8H),1.24(s,3H),1.15(s,6H),0.96(s,9H).

[0117] 28: N-(5-(4-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)(methyl-d3)carbamoyl)phenyl)-4-pentyn-1-yl)-N-((S)-1-((2S,4R)-4-hydroxy-2-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)cyclopropane-1,1-dicarboxamide TIFF0007603609000266.tif5915651 mg of the final product 28 was obtained in 50% yield. Mass spectrum (ES): m / z = 1019 [M+H] + . 1H NMR(400mHz,DMSO-d6)δ9.39(d,J=8.8Hz,1H),8.99(s,1H),8.42(d,J=7.7Hz,1H),7.89-7.80(m,2H),7.49-7. 41(m,4H),7.37(d,J=8.0Hz,2H),7.26(s,1H),7.04(s,1H),5.12(s,1H),4.92(d,J=7.0Hz,1H),4.78-4.60(m,2) H),4.46(dd,J=21.3,8.4Hz,3H),4.29(s,1H),3.55(d,J=29.2Hz,5H),3.22(s,2H),3.00-2.83(m,1H),2.46(s ,5H),2.07-1.95(m,1H),1.84-1.64(m,3H),1.41-1.31(m,9H),1.28(d,J=9.5Hz,4H),0.94(d,J=10.6Hz,12H).

[0118] 29: (2S,4R)-1-((S)-2-(2-((6-(2-(((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-1-oxoisobutanol-5-yl)hept-5-yn-1-yl)oxy)acetamido)-3,3-dimethylbutyryl)-N-((S)-1-(4-(3,5-dimethylthiazol-4-yl)phenyl)ethyl)-4-hydroxypyrrolidine-2-carboxamide TIFF0007603609000267.tif4715251 mg of the final product HC-2820-01 was obtained in a 52% yield. Mass Spectrum (ES): m / z = 975 [M+H] + . TIFF0007603609000268.tif18154(m,2H),4.95-4.86(m,1H),4.77(s,2H),4.54(s,3H),4.31(s,1H),3.98(s,3H),3.82- TIFF0007603609000269.tif9153(m,2H),1.39(s,8H),1.24(s,3H),1.15(s,6H),0.96(s,9H).

[0119] 30: (2s,4r)-1-((s)-2-(2-(4-(4-(2-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-1-oxoisobutanol-5-yl)-1H-1,2,3-triazol-1-yl)butoxy)acetamido)-3,3-dimethylbutyryl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide TIFF0007603609000270.tif581521. Intermediate: Synthesis of 2-chloro-4-((1R,3R)-3-(5-ethynyl-1-oxoisobutanol-2-yl)-2,2,4,4-tetramethylcyclobutoxy)benzonitrile Compound 4-((1R,3R)-3-(5-bromo-1-oxoisobutanol-2-yl)-2,2,4,4-tetramethylcyclobutoxy)-2-chlorobenzonitrile (189 mg, 0.4 mmol) and trimethylsilylacetylene (59 mg, 0.6 mmol) were dissolved in 3 mL of toluene, and 1 mL of triethylamine, Pd(dppf)2Cl2 (30 mg), and CuI (150 mg) were added. The reaction mixture was heated to 90-100 °C under N2 protection and stirred for 12 h. After completion of the reaction, the solvent was removed by vacuum distillation. The crude product was purified by plate chromatography (PE:EA = 3:1) to obtain 147 mg of intermediate 17-1 in 88% yield. Mass spectrum (ES): m / z = 419 [M+H]. + . 2. Intermediate: Synthesis of 2-(4-(4-(2-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-1-oxoisoindolin-5-yl)-1H-1,2,3-triazol-1-yl)butoxy)acetic acid tert-butyl ester Compound 2-chloro-4-((1R,3R)-3-(5-ethynyl-1-oxoisobutanol-2-yl)-2,2,4,4-tetramethylcyclobutoxy)benzonitrile (17-1) (419 mg, 1 mmol) and 2-(4-azidobutoxy)acetic acid tert-butyl ester (229 mg, 1 mmol) were dissolved in 5 mL of DMF, CuI (38 mg, 0.2 mmol) and triethylamine (0.1 mL) were added, and the mixture was stirred at room temperature for 4 h. After the reaction was completed, water was added, and the mixture was extracted with ethyl acetate. The resulting organic phase was distilled under reduced pressure to remove the solvent, and the crude product was purified by plate chromatography (PE:EA = 3:1) to obtain 558 mg of intermediate 17-2 in 86% yield. Mass spectrum (ES): m / z = 648 [M+H] + . 3. Intermediate: Synthesis of 2-(4-(4-(2-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-1-oxoisoindolin-5-yl)-1H-1,2,3-triazol-1-yl)butoxy)acetic acid Compound 2-(4-(4-(2-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-1-oxoisoindolin-5-yl)-1H-1,2,3-triazol-1-yl)butoxy)acetic acid tert-butyl ester (Intermediate 17-2) (65 mg, 0.1 mmol) was dissolved in 2 mL of dichloromethane, 1 mL of trifluoroacetic acid was added, and the mixture was stirred at room temperature for 2 h. The reaction was completed, and the solvent was removed under reduced pressure. The mixture was used directly in the next reaction without further purification. 4. Synthesis of Final Product 30: (2s,4r)-1-((s)-2-(2-(4-(4-(2-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-1-oxoisobutanol-5-yl)-1H-1,2,3-triazol-1-yl)butoxy)acetamido)-3,3-dimethylbutyryl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide The compound 2-(4-(4-(2-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-1-oxoisoindolin-5-yl)-1H-1,2,3-triazol-1-yl)butoxy)acetic acid (59 mg, 0.1 mmol) and ((2s,4r)-1-((s)-2-amino-3,3-dimethylbutyryl)-4-hydroxy-N-((s)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide The amide (44.5 mg, 0.1 mmol) was dissolved in 2 mL of dichloromethane, DIPEA (38.7 mg, 0.3 mmol) and HATU (76.1 mg, 0.2 mmol) were added, and the mixture was stirred at room temperature for 2 h. After the reaction was complete, water was added and the mixture was extracted with dichloromethane. The resulting organic phase was distilled under reduced pressure to remove the solvent, and the crude product was purified by plate chromatography (MeOH:DCM = 10:1) to give 56 mg of the target product in 55% yield. Mass spectrum (ES): m / z = 1018 [M+H] + . 1 H NMR TIFF0007603609000271.tif10153(s,1H),7.97(d,J=7.8Hz,1H),7.91(d,J=8.7Hz,1H),7.77(d,J=8.0Hz, 1H),7.47-7.28(m,6H),7.08(d,J=8.7Hz,1H),5.35(s,1H),5.21(s,1H),4.81(d,J=36.8Hz,3H),4.44(ddd, J=61.5,38.1,19.5Hz,6H),3.98-3.72(m,4H),3.52(t,J=6.1Hz,2H),2.30-2.22(m,1H),1.99(d,J=5.2Hz, 5H),1.59(d,J=7.3Hz,2H),1.39(d,J=20.9Hz,6H),1.34-1.21(m,4H),1.15(d,J=12.8Hz,6H),0.95(s,9H).

[0120] 31: (2s,4r)-1-((s)-2-(2-(3-(2-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-1-oxoisoindolin-5-yl)piperazin-1-yl)propoxy)acetamido)-3,3-dimethylbutyryl)-4-hydroxy-N-((s)-1-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide TIFF0007603609000272.tif5415359 mg of the final product 31 was obtained in 58% yield. Mass spectrum (ES): m / z = 1021 [M+H] + . 1 H NMR(400mHz,DMSO-d6)δ8.98(s,1H),8.75(s,1H),8.45(d,J=7.7Hz,1H),8.09(s,1H),7.97(d,J=7.8Hz,1H),7.91(d,J=8.7Hz,1H),7.77(d,J=8.0 TIFF0007603609000273.tif17153(t,J=6.1Hz,2H),3.48(m,8H),2.30-2.22(m,1H),1.99(d,J=5.2Hz,5H ),1.59(d,J=7.3Hz,2H),1.39(d,J=20.9Hz,6H),1.34-1.21(m,4H),1.15(d,J=12.8Hz,6H),0.95(s,9H).

[0121] 32: (2s,4r)-1-((s)-2-(2-((1-(4-(2-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-1-oxoisocyanato-5-yl)-3-butyn-1-yl)azetidin-3-yl)oxy)acetamido)-3,3-dimethylbutyryl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide TIFF0007603609000274.tif5315151 mg of the final product 32 was obtained in 50% yield. Mass spectrum (ES): m / z = 1002 [M+H] + . 1H NMR(400mHz,DMSO-d6)δ8.98(s,1H),8.51-8.44(m,1H),7.91(s,1H),7.63(d,J=9.9Hz,2H),7.54 ~ 7.33(m,6H),7.29(s,1H),7.11-7.03(m,1H),5.25- TIFF0007603609000275.tif10154(s,3H),3.82-3.73(m,1H),3.65(m,2H)3.45(m,2H),2.58 (m,2H),2.46(m,4H),2.32-2.21(m,2H),1.39(s,8H),1.24(s,3H),1.15(s,6H),0.96(s,9H).

[0122] 33: N-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-6-(6-(2-((S)-1-((2R,4R)-4-hydroxy-2-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-2-oxoethoxy)-1-hexyn-1-yl)-N-(methyl-d3)nicotinamide TIFF0007603609000276.tif4315459 mg of the final product 33 was obtained in 60% yield. Mass spectrum (ES): m / z = 981 [M+H] + . 1 H NMR(400mHz,DMSO-d6)δ8.99(s,1H),8.47(d,J=7.3Hz,2H),7.82(dd,J=50.3,8.4 TIFF0007603609000277.tif9154(dd,J=15.1,8.9Hz,2H),3.98-3.71(m,5H),3.57(t,J=26.1Hz ,4H),2.46(m,1H),2.35-2.22(m,2H),1.68(dd,J=12.9,6.1Hz,6H),1.36(s,9H),0.95(s,12H).

[0123] TIFF0007603609000278.tif9150-Chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-1-oxoisoindolin-5-yl)-3-butynyloxy)propylamino)-3,3- TIFF0007603609000279.tif11151(phenyl)ethyl)carboxamide TIFF0007603609000280.tif491511.Synthesis of compound ethyl 3-(3-butynyloxy)propanoate The compound 3-butyn-1-ol (1.00 g, 14.27 mmol), ethyl acrylate (1.71 g, 17.12 mmol), 10 mL of acetonitrile, and DBU (1.09 g, 7.13 mmol) were sequentially added to a reaction flask and reacted overnight at 70 °C under nitrogen protection. The end point of the reaction was determined by TLC, and the mixture was extracted three times with water and ethyl acetate. The combined organic layers were washed once with 10% aqueous citric acid solution, three times with saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed by rotary evaporation. The product was purified by silica gel column chromatography to obtain the colorless oily compound ethyl 3-(3-butynyloxy)propanoate (826 mg, 4.85 mmol) in 34% yield. LC / MS (ESI+) calculation for CH 14 O3(M+H + ) m / z, 171.1; found, 171.2. 2. Synthesis of compound ethyl 3-((4-(2-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-1-oxoisoindol-5-yl)-3-butynyloxy)oxy)propanoate The compounds ethyl 3-(3-butynyloxy)propanoate (150 mg, 0.32 mmol), 4-((1r,3r)-3-(5-bromo-1-oxoisoindol-2-yl)-2,2,4,4-tetramethylcyclobutoxy)-2-chlorobenzonitrile (108 mg, 0. A solution of 46 mg (0.06 mmol), copper(I) iodide (30 mg, 0.16 mmol), 0.5 mL of triethylamine, and 1.5 mL of toluene was added to the reactor, and the mixture was reacted overnight at 110°C under nitrogen protection. The completion of the reaction was confirmed by TLC, and the mixture was filtered. The filter cake was washed with dichloromethane, and the solvent was removed by rotary evaporation. The resulting mixture was purified by silica gel column chromatography to give an off-white solid, ethyl 3-((4-(2-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-1-oxoisoindol-5-yl)-3-butynyloxy)oxy)propanoate (56 mg, 0.10 mmol), in a 31% yield. LC / MS(ESI+)calcd for C 32 H 35 ClN2O5(M+H + ) m / z, 563.2; found, 563.2. TIFF0007603609000282.tif121503-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-1-oxoisoindol-5-yl)-3-butynyloxy)oxy)propylamine TIFF0007603609000283.tif11152Synthesis of (phenyl)ethyl)carbamoyl)pyrrolidin-3-ylacetic acid Ethyl 2,2,4,4-tetramethylcyclobutyl-1-oxoisoindol-5-yl-3-butynyloxy)oxypropanoate (50 mg, 0.09 mmol) was dissolved and clarified by adding 2 mL of methanol. Lithium hydroxide monohydrate (15 mg, 0.36 mmol) was dissolved and clarified in 0.5 mL of water and added to the reactor and stirred at room temperature for 3 h. The end point of the reaction was determined by TLC. Water was added to the reaction mixture, the pH was adjusted to 2-3 with 1N hydrochloric acid, extracted three times with ethyl acetate, dried over anhydrous sodium sulfate, and the solvent was removed by rotary evaporation to obtain the crude product. 2 mL of DMF and DIPEA (54 mg, 0.42 mmol) were added to the crude product, and HATU (64 mg, 0.17 mmol) was added in an ice bath. TIFF0007603609000285.tif18155))carbamoyl)pyrrolidine-3-acetate (45 mg, 0.09 mmol) was added, and the mixture was stirred at room temperature for 2 hours. The end point of the reaction was determined by TLC, and the mixture was extracted three times with water and ethyl acetate, washed three times with saturated brine, dried over anhydrous sodium sulfate, and evaporated by rotary evaporation. TIFF0007603609000286.tif17153)-2,2,4,4-tetramethylcyclobutyl)-1-oxoisoindolin-5-yl)-3-butynyloxy)oxy)propylamino)-3,3-dimethylbutano TIFF0007603609000287.tif9155)Rubamoylpyrrolidin-3-ylacetic acid (59 mg, 0.06 mmol) was obtained in 70% yield. LC / MS(ESI+)calcd for C 55 H 63 ClN6O8S(M+H + ) m / z, 1003.4; found, 1003.5. TIFF0007603609000288.tif671563-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-1-oxoisoindolin-5-yl)-3-butynyloxy)propylamino)-3, TIFF0007603609000289.tif8152Synthesis of (phenyl)ethyl)carboxamide TIFF0007603609000290.tif8151(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-1-oxoisoindolin-5-yl)-3-butynyloxy)oxy)propylamino) TIFF0007603609000291.tif8151) (phenyl)ethyl)carbamoyl)pyrrolidin-3-ylacetic acid (24 mg, 0.02 mmol) was dissolved and clarified by adding 2 mL of methanol, and lithium hydroxide monohydrate (4 mg, 0.10 mmol) was dissolved and clarified in 0.5 mL of water and added to the reactor and stirred at room temperature for 3 h. The end of the reaction was determined by TLC, and the reaction mixture was added with water, extracted three times with ethyl acetate, dried over anhydrous sodium sulfate, and the solvent was removed by rotary evaporation to obtain the crude product. TIFF0007603609000292.tif18152-2,2,4,4-Tetramethylcyclobutyl)-1-oxoisoindol-5-yl)-3-butynyloxy)propylamino)-3,3-dimethylbutanol)-4-hydro TIFF0007603609000293.tif8152 The amide (21 mg, 0.02 mmol) was obtained in 91% yield. LC / MS (ES1+) calculations TIFF0007603609000294.tif59154

[0124] TIFF0007603609000295.tif9150-Chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-1- TIFF0007603609000296.tif18154Synthesis of 5-(luthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide TIFF0007603609000297.tif691571.Synthesis of compound 4-(4-iodo-1H-pyrazol-1-yl)butyric acid methyl ester 4-Iodopyrazole (1.00 g, 5.16 mmol), methyl 4-bromobutyrate (1.03 g, 5.68 mmol), 50 mL of acetonitrile, and potassium carbonate (1.07 g, 7.73 mmol) were sequentially added to a reaction flask and stirred overnight at room temperature under nitrogen protection. The end point of the reaction was determined by TLC, and the mixture was extracted three times with water and ethyl acetate. The combined organic layers were washed once with 10% aqueous citric acid and three times with saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed by rotary evaporation. The product was purified by silica gel column chromatography to give methyl 4-(4-iodo-1H-pyrazol-1-yl)butyrate (1.23 mg, 4.18 mmol) as a colorless oil in 81% yield. LC / MS(ESI+)calcd for C8H 11 IN2O2(M+H + ) m / z, 295.0; found, 295.0. TIFF0007603609000298.tif9150 Synthesis of methyl butyrate TIFF0007603609000299.tif17153 (phenylphosphino)ferrocene]dichloropalladium (249 mg, 0.34 mmol), cuprous iodide (259 mg, 1.36 mmol), 6 mL of triethylamine, and 17 mL of toluene were added to the reactor in this order, and the reaction was carried out overnight at 80 °C under nitrogen protection. The completion of the reaction was confirmed by TLC, and the mixture was filtered. The filter cake was washed with dichloromethane, and the solvent was removed by rotary evaporation. The mixture was purified by silica gel column chromatography to give a yellow-brown oily product, 4- TIFF0007603609000300.tif1015206 mg, 3.05 mmol) was obtained in a 90% yield. LC / MS(ESI+)calcd for C 13 H 20 N2O2Si(M+H + ) m / z, 265.1; found, 265.1. TIFF0007603609000301.tif18148 Methyl butyrate (800 mg, 3.03 mmol), TBAF (1.91 g, 7.30 mmol), and 20 mL of THF were added to the reactor in this order, and the reaction was stirred at room temperature for 1 h under nitrogen protection. The completion of the reaction was confirmed by TLC, and the reaction mixture was added with water, extracted three times with EA, combined, washed twice with saturated brine, combined, dried, and the solvent was removed by rotary evaporation to give a yellow-brown oil. The crude product was obtained in 100% yield. LC / MS (ESI+) calculation for C 10 H 12 N2O2(M+H + ) m / z, 193.1; found, 193.1. 4. Compound 4-(4-((2-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-1-oxoisoindoline-5- TIFF0007603609000303.tif161540.78mmol) Crude product, 4-((1r,3r)-3-(5-bromo-1-oxoisoindolin-2-yl)-2,2,4,4-tetramethylcyclobutoxy)-2-chlorobenzyl TIFF0007603609000304.tif8154) Ferrocene] dichloropalladium (59 mg, 0.081 mmol), cuprous iodide (55 mg, 0.29 mmol), 1 mL of triethylamine, and 3 mL of toluene were added to the reactor in this order, and the reaction was carried out overnight at 110 °C under nitrogen protection. The completion of the reaction was confirmed by TLC, and the filter cake was filtered, washed with dichloromethane, and the solvent was removed by rotary evaporation. The product was purified by silica gel column chromatography to give a pale yellow solid, 4-(4-((2-((1 TIFF0007603609000305.tif171521-yl)methyl butyrate (228 mg, 0.10 mmol) was obtained in 92% yield. LC / MS (ESI+) calculation for C 33 H 33 ClN4O4(M+H + ) m / z, 545.2; found, 545.2. TIFF0007603609000306.tif91483-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl) TIFF0007603609000307.tif18154 Synthesis of (5-yl)phenyl)ethyl)carbamoyl)-3-pyrrolylalkylyl acetate TIFF0007603609000308.tif9153-2,2,4,4-tetramethylcyclobutyl)-1-oxoisoindolin-5-yl TIFF0007603609000309.tif9152 was dissolved and clarified by adding 2 mL of methanol. Lithium hydroxide monohydrate (37 mg, 0.89 mmol) was dissolved and clarified in 0.5 mL of water and added to the reactor and stirred at room temperature for 3 h. The end point of the reaction was determined by TLC. Water was added to the reaction solution, the pH was adjusted to 2-3 with 1N hydrochloric acid, extracted three times with ethyl acetate, dried over anhydrous sodium sulfate, and the solvent was removed by rotary evaporation to obtain the crude product. 3 mL of DCM and DIPEA (135 mg, 1.04 mmol) were added to the crude product, and HATU (127 mg, 0.33 mmol) was added in an ice bath. TIFF0007603609000310.tif17155) Ethyl) carbamoyl) pyrrolidine-3-acetate (151 mg, 0.29 mmol) was added, and the mixture was stirred at room temperature for 2 hours. The end point of the reaction was determined by TLC, and the mixture was extracted three times with water and ethyl acetate, dried over anhydrous sodium sulfate, and the solvent was removed by rotary evaporation. TIFF0007603609000311.tif161542,4,4-Tetramethylcyclobutyl)-1-oxoisoindolin-5-yl)ethynyl TIFF0007603609000312.tif17151)-3-pyrrolylalkylyl acetate (123 mg, 0.12 mmol) was obtained in 53% yield. LC / MS (ESI+) calculation for C 57 H 63 ClN8O7S(M+H + ) m / z, 1039.4; found, 1039.5. 1 H TIFF0007603609000313.tif59156TIFF0007603609000314.tif81533-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl) TIFF0007603609000315.tif1615Synthesis of 3-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide TIFF0007603609000316.tif9151(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)- TIFF0007603609000317.tif17154-5-yl)phenyl)ethyl)carbamoyl)-3-pyrrolylalkylyl acetate (60 mg, 0.058 mmol) was dissolved and clarified by adding 2 mL of methanol, and lithium hydroxide monohydrate (24 mg, 0.58 mmol) was dissolved and clarified in 0.5 mL of water and added to the reactor, followed by stirring at room temperature for 3 h. The end of the reaction was determined by TLC, and the reaction mixture was added with water, extracted three times with ethyl acetate, dried over anhydrous sodium sulfate, and the solvent was removed by rotary evaporation to obtain the crude product. Separation by prep-TLC yielded an off-white solid. TIFF0007603609000318.tif9156-Chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-1- TIFF0007603609000319.tif16152 Luthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (50 mg, 0.050 mmol) was obtained in 87% yield. LC / MS(ESI+)calcd for C 55 H 61 ClN8O6S(M+H + ) m / z, 997.4; found, 997.5. 1 H NMR TIFF0007603609000320.tif59153

[0125] TIFF0007603609000321.tif9151-Chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-5- TIFF0007603609000322.tif101545-yn-1-yl)oxy)acetamido)-3,3-dimethylbutyryl)-4-hydroxy TIFF0007603609000323.tif8152 Synthesis of pyrrolidine-2-carboxamide TIFF0007603609000324.tif45152LC / MS(ESI+)calcd for C 53 H 62 ClN7O7S(M+H + ) m / z, 108.4; found, 996.4. TIFF0007603609000325.tif52157

[0126] TIFF0007603609000326.tif9150(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-1-oxoisoindolin-5-yl)but-3-yn-2-yl)oxy)ethoxy) TIFF0007603609000327.tif915Synthesis of 4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide TIFF0007603609000328.tif72155 Obtained white solid compound 37 (14 mg, 0.014 mmol). LC / MS (ESI+) calculation TIFF0007603609000329.tif50155

[0127] TIFF0007603609000330.tif91473-Chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-3 TIFF0007603609000331.tif91535-yl-yn-1-yl)oxy)acetamido)-3,3-dimethylbutyryl)-4 TIFF0007603609000332.tif9150Synthesis of (ethyl)pyrrolidine-2-carboxamide TIFF0007603609000333.tif53152LC / MS(ESI+)calcd for C 53 H 62 ClN7O7S(M+H + ) m / z, 996.4; found, 996.7 TIFF0007603609000334.tif10151TIFF0007603609000335.tif36160(s,6H),1.06(s,9H).

[0128] TIFF0007603609000336.tif10151-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-1-oxoisoindolin-5-yl)prop-2-yn-1-yl)piperidine-1 TIFF0007603609000337.tif91531-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide TIFF0007603609000338.tif87156LC / MS(ESI+)calcd for C 56 H 66 ClN7O6S(M+H + ) m / z, 1000.5; found, 1000.5. TIFF0007603609000339.tif60156

[0129] TIFF0007603609000340.tif91523-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-1-oxoisoindolin-5-yl)prop-2-yn-1-yl)azetidine-3 TIFF0007603609000341.tif18153 Roridin-2-carboxamide TIFF0007603609000342.tif79156

[0130] 41: (2S,4R)-1-((S)-2-(1-((6-(2-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-1-oxoisoindolin-5-yl)hex-5-yn-1-yl)oxy)cyclopropanecarboxamide)-3,3-dimethylbutyryl)-4-hydroxy-N-((S)-1-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide TIFF0007603609000343.tif541581.Synthesis of compound ethyl 1-(5-pentynyl-1-oxy)cyclopropanoate Under nitrogen protection, methyl 1-hydroxycyclopropanecarboxylate (100.0 mg, 0.86 mmol) was dissolved in 2 mL of THF. Under ice bath conditions, NaH (41.0 mg, 1.03 mmol) was added and stirred for 30 minutes. 6-iodo-1-yne (179.0 mg, 0.86 mmol) was added. The mixture was stirred overnight at room temperature. Ethyl acetate and water were added for extraction. The organic layer was washed with saturated brine, dried, and the solvent was removed by rotary evaporation. The mixture was purified using a silica gel column. The compound, ethyl 1-(5-pentynyl-1-oxy)cyclopropanoate (110.0 mg, 0.56 mmol), was obtained in a 65.1% yield. LC / MS(ESI+)calcd for C 11 H 17 O3 + ([M+H] + ) m / z: 197.1; found 197.1. 2. Synthesis of compound methyl 1-((6-(2-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-1-oxoisoindol-5-yl)hex-5-yn-1-yl)oxy)cyclopropanecarboxylate Under the protection of nitrogen, ethyl 1-(5-pentynyl-1-oxy)cyclopropanoate (110.0 mg, 0.56 mmol), 4-((1r,3r)-3-(5-bromo-1-oxoisoindol-2-yl)-2,2,4,4-tetramethylcyclobutoxy)-2-chlorobenzonitrile (100.0 mg, 0.21 mmol), Pd(PPh3)2Cl2 (50.0 mg, 0.05 mmol), CuI (4.0 mg, 0.1 mmol), and 0.5 mL of triethylamine were added to 2 mL of toluene. The mixture was heated to 110 °C and stirred overnight. The mixture was cooled to room temperature. The mixture was suction filtered, washed with ethyl acetate, dried, and the solvent was removed by rotary evaporation. The mixture was then purified using a silica gel column. The compound methyl 1-((6-(2-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-1-oxoisoindol-5-yl)hex-5-yn-1-yl)oxy)cyclopropanecarboxylate (65.0 mg, 0.13 mmol) was obtained in a yield of 52.3%. LC / MS(ESI+)calcd for C 34 H 38 ClN2O5 + ([M+H] + ) m / z: 589.2; found 589.1. 3. Synthesis of compound 1-((6-(2-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-1-oxoisoindolin-5-yl)hexadec-5-yn-1-yl)oxy)cyclopropanecarboxylic acid Methyl 1-((6-(2-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-1-oxoisoindol-5-yl)hex-5-yn-1-yl)oxy)cyclopropanecarboxylate (65.0 mg, 0.13 mmol) was dissolved in 2 mL of methanol, and 2 mL of 2 N NaOH was added. The mixture was stirred at room temperature for 2 h. The pH was adjusted to 4-5 with 1 N HCl, and dichloromethane was added for extraction. The organic layer was washed with saturated brine, dried, and the solvent was removed by rotary evaporation. The compound 1-((6-(2-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-1-oxoisoindol-5-yl)hexadec-5-yn-1-yl)oxy)cyclopropanecarboxylic acid (65.0 mg, 0.13 mmol) was obtained in a yield of 100.0%. 4. Synthesis of the compound (2S,4R)-1-((S)-2-(1-((6-(2-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-1-oxoisoindolin-5-yl)hex-5-yn-1-yl)oxy)cyclopropanecarboxamide)-3,3-dimethylbutyryl)-4-hydroxy-N-((S)-1-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide 1-((6-(2-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-1-oxoisoindol-5-yl)hexadec-5-yn-1-yl)oxy)cyclopropanecarboxylic acid (50.0 mg, 0.08 mmol), HATU (37.0 mg, 0.08 mmol), and DIEA (35.0 mg, 0.24 mmol) were dissolved in 2 mL of DMF, and (2R,4R)-1-((S)-2-amino-3,3-dimethylbutanol)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (46.0 mg, 0.08 mmol) was added. The mixture was stirred at room temperature for 2 h. The mixture was extracted with water and ethyl acetate, and the organic layer was washed with saturated brine, dried, and the solvent removed by rotary evaporation. The mixture was then purified using a silica gel column. (2S,4R)-1-((S)-2-(1-((6-(2-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-1-oxoisoindolin-5-yl)hex-5-yn-1-yl)oxy)cyclopropanecarboxamide)-3,3-dimethylbutyryl)-4-hydroxy-N-((S)-1-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (40.0 mg, 0.04 mmol) was obtained in a yield of 44.9%. LC / MS (ESI+) calculation for C 56 H 66 ClN6O7S + ([M+H] + ) m / z: 1001.4; found 1001.5. 1 H NMR TIFF0007603609000344.tif10153TIFF0007603609000345.tif51157

[0131] 42: ((2S,4R)-1-((S)-2-(3-((2-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-1-oxoisoindolin-5-yl)ethynyl)-1H-pyrazol-1-yl)propionamido)-3,3-dimethylbutanol)-4-hydroxy-N-((S)-1-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide TIFF0007603609000346.tif48152 Compound 42 (45.0 mg, 0.04 mmol) was obtained. LC / MS (ESI+) calculation for TIFF0007603609000347.tif60158

[0132] 43: (2S,4R)-1-((S)-2-(3-(3-(2-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-1-oxoisoindolin-5-yl)prop-2-yn-1-yl)nonanoside-1-yl)acetamido)-3,3-dimethylbutyryl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide TIFF0007603609000348.tif4115143 (18.0 mg, 0.02 mmol) was obtained. LC / MS (ESI+) calculation for TIFF0007603609000349.tif59155

[0133] 44: ((2S,4R)-1-((S)-2-(3-(3-(3-(2-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-1-oxoisoindolin-5-yl)prop-2-yn-1-yl)azetidin-1-yl)propylamino)-3,3-dimethylbutanol)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide TIFF0007603609000350.tif64152 Compound 44 (20 mg, 0.02 mmol) was obtained. LC / MS (ESI+) calculation for C 55 H 65 ClN7O6S + TIFF0007603609000351.tif59154(s,9H).

[0134] 45: 2-chloro-4-((1r,3r)-3-(5-((1-(1-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindol-5-yl)azelaic acid-3-yl)-1H-pyrazol-4-yl)ethynyl)-1-oxoisoindolin-2-yl)-2,2,4,4-tetramethylcyclobutoxy)benzonitrile TIFF0007603609000352.tif721491. Synthesis of the compound (2-chloro-4-((1r,3r)-2,2,4,4-tetramethyl-3-(1-oxy-5-((trimethylsilyl)ethynyl)isoindolin-2-yl)cyclobutoxy)benzonitrile Under the protection of nitrogen, 4-((1r,3r)-3-(5-bromo-1-oxoisoindolin-2-yl)-2,2,4,4-tetramethylcyclobutoxy)-2-chlorobenzonitrile (500.0 mg, 1.06 mmol), ethynyltrimethylsilane (518.0 mg, 5.28 mmol), Pd(PPh3)2Cl2 (100.0 mg, 0.1 mmol), CuI (60.0 mg, 0.2 mmol), and 2 mL of triethylamine were added to 6 mL of toluene. The mixture was heated to 100 °C and stirred overnight. The mixture was cooled to room temperature. The mixture was suction filtered, washed with ethyl acetate, dried, and the solvent was removed by rotary evaporation. The mixture was then purified using a silica gel column. TIFF0007603609000353.tif7152-5-((trimethylsilyl)ethynyl)isoindolin-2-yl)cyclobutoxy)benzonitrile (400 mg, 0.80 mmol) was obtained in 77.2% yield. LC / MS (ESI+) calculation for C 28 H 32 ClN2O2Si + ([M+H]+ ) m / z: 491.2; found 491.1. 2. Synthesis of the compound 2-chloro-4-((1r,3r)-3-(5-ethynyl-1-oxoisoindolin-2-yl)-2,2,4,4-tetramethylcyclobutoxy)benzonitrile TIFF0007603609000354.tif81515-((trimethylsilyl)ethynyl)isoindolin-2-yl)cyclobutoxy)benzonitrile (400.0 mg, 0.80 mmol) and TBAF (1.0 g, 1.60 mmol) were dissolved in 10 mL of THF. The mixture was stirred overnight at room temperature. Water and ethyl acetate were added for extraction. The organic layer was washed with saturated brine, dried, and the solvent was removed by rotary evaporation. The mixture was then purified using a silica gel column. The compound 2-chloro-4-((1r,3r)-3-(5-ethynyl-1-oxoisoindol-2-yl)-2,2,4,4-tetramethylcyclobutoxy)benzonitrile (150 mg, 0.35 mmol) was obtained in a 43.9% yield. LC / MS(ESI+)calcd for C 25 H 24 ClN2O2 + ([M+H] + ) m / z: 419.2; found 419.1. 3. Synthesis of compound tert-butyl 3-(4-iodo-1H-pyrazol-1-yl)azelaate 4-Iodo-1H-pyrazole (400.0 mg, 1.40 mmol), tert-butyl 3-iodoazetidine-1-carboxylate (274.0 mg, 1.41 mmol), and K2CO3 (292.0 mg, 2.12 mmol) were dissolved in 5 mL of DMF. The mixture was heated to 85 °C and stirred overnight. The mixture was cooled to room temperature. Water and ethyl acetate were added for extraction. The organic layer was washed with saturated brine, dried, and the solvent was removed by rotary evaporation. The mixture was then purified using a silica gel column. The compound tert-butyl 3-(4-iodo-1H-pyrazol-1-yl)azelate (380 mg, 1.08 mmol) was obtained in a 77.0% yield. 4. Synthesis of compound 1-(azelaic acid-3-yl)-4-iodo-1H-pyrazole Tert-butyl 3-(4-iodo-1H-pyrazol-1-yl)azelate (380.0 mg, 1.08 mmol) was dissolved in 2 mL of dichloromethane and 2 mL of trifluoroacetic acid. The mixture was stirred at room temperature for 2 h. The mixture was concentrated and the solvent was removed by rotary evaporation to give the compound 1-(azelaic acid-3-yl)-4-iodo-1H-pyrazole (180 mg, 1.08 mmol) in 100.0% yield. 5. Synthesis of compound 2-(2,6-dioxopiperidin-3-yl)-5-fluoro-6-(3-(4-iodo-1H-pyrazol-1-yl)azelaic acid-1-yl)isoindoline-1,3-dione 1-(Azelaic acid-3-yl)-4-iodo-1H-pyrazole (180.0 mg, 1.08 mmol), 2-(2,6-dioxopiperidin-3-yl)-5,6-difluoroisoindole-1,3-dione (100.0 mg, 0.339 mmol), and DIEA (219.0 mg, 1.70 mmol) were dissolved in 3 mL of DMSO. The mixture was heated to 130 °C and stirred for 3 h. The mixture was cooled to room temperature. Water and ethyl acetate were added for extraction. The organic layer was washed with saturated brine, dried, and the solvent was removed by rotary evaporation. The mixture was then purified using a silica gel column. The compound 2-(2,6-dioxopiperidin-3-yl)-5-fluoro-6-(3-(4-iodo-1H-pyrazol-1-yl)azelaic acid-1-yl)isoindoline-1,3-dione (150 mg, 0.26 mmol) was obtained in a yield of 84.0%. LC / MS(ESI+)calcd for C 19 H 16 FIN5O4 + ([M+H] + ) m / z: 524.0; found 524.0. 6. Synthesis of compound 2-chloro-4-((1r,3r)-3-(5-((1-(1-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)azelaic acid-3-yl)-1H-pyrazol-4-yl)ethynyl)-1-oxoisoindol-2-yl)-2,2,4,4-tetramethylcyclobutoxy)benzonitrile Under nitrogen protection, 2-(2,6-dioxopiperidin-3-yl)-5-fluoro-6-(3-(4-iodo-1H-pyrazol-1-yl)azelaic acid-1-yl)isoindoline-1,3-dione (50.0 mg, 0.10 mmol), 2-chloro-4-((1r,3r)-3-(5-ethynyl-1-oxoisoindolin-2-yl)-2,2,4,4-tetramethylcyclobutoxy)benzonitrile (40.0 mg, 0.10 mmol), Pd(PPh)Cl (8.0 mg, 0.01 mmol), CuI (10.0 mg, 0.02 mmol), and 0.3 mL of triethylamine were added to 1 mL of toluene. The mixture was heated to 100 °C and stirred overnight. The mixture was then cooled to room temperature. The mixture was filtered with suction, washed with ethyl acetate, dried, and the solvent was removed by rotary evaporation. The resulting mixture was purified on a silica gel column to give the compound (2-chloro-4-((1r,3r)-3-(5-((1-(1-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindol-5-yl)azelate-3-yl)-1H-pyrazol-4-yl)ethynyl)-1-oxoisoindolin-2-yl)-2,2,4,4-tetramethylcyclobutoxy)benzonitrile (15 mg, 0.80 mmol) in a yield of 19.2%. LC / MS(ESI+)calcd for C 44 H 38 ClFN7O6 + ([M+H] +) m / z: 814.3; found 814.2. TIFF0007603609000355.tif33154(m,5H),2.85-2.70(m,2H),2.16-2.08(m,1H).1.46(s,6H),1.27(s,6H).

[0135] TIFF0007603609000356.tif10149-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)carbamoyl)phenyl)amino)pentyl)oxy)acetamido)-3,3-dimethylbutanol)-5-((1-(4-methylthiazol-5-yl)phenyl)cyclopropyl)carbamoyl)pyrrolidin-3-yl acetate TIFF0007603609000357.tif86154Hz,2H),2.69(s,6H),2.43(s,2H),2.04-1.96(m,4H),1.65-1.50(m,4H),1.44(d,J=6.4 TIFF0007603609000358.tif10153LC / MS(ESI+)calcd for C 55 H 68 ClNOS([M+H] + ) m / z: 1022.70; found 511.8.

[0136] TIFF0007603609000359.tif8146-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)carbamoyl)phenyl)amino)pentyl)oxy)acetamido)-3,3-dimethylbutyryl)-4-hydroxy-N-(1-(4-methylthiazol-5-yl)phenyl)cyclopropyl)pyrrolidine-2-carboxamide TIFF0007603609000360.tif73157(s,9H),0.94(s,12H).LC / MS(ESI+)calcd for C 53 H 66 ClNOS([M+H] + ) m / z: 980.66; found 980.3

[0137] TIFF0007603609000361.tif8149(3-chloro-4-cyanophenoxy))-2,2,4,4-tetramethylcyclobutyl)-1-oxoisoindolin-5-yl)hexyl-5-yn-1-yl)oxy)acetoacetate TIFF0007603609000362.tif8154-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide

[0138] TIFF0007603609000363.tif9152(3-chloro-4-cyanophenoxy))-2,2,4,4-tetramethylcyclobutyl)-1-oxoisoindolin-5-yl)hexyl-5-yn-1-yl)oxy)acetoacetate TIFF0007603609000364.tif9152-Methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-3-yl acetate TIFF0007603609000365.tif70157 Synthesis of (annophenoxy)-2,2,4,4-tetramethylcyclobutyl)-1-oxoisoindol-5-yl)hexyl (5-yn-1-yl)oxy)acetate In the above example, it was synthesized with a yield of 42%. LC / MS (ESI+) calculation: 35 H 41 ClN2O5(M+H + ) m / z, 605.2; found, 605.2. TIFF0007603609000366.tif10151Synthesis of 2,2,4,4-tetramethylcyclobutyl)-1-oxoisoindol-5-yl)hexyl-5-yn-1-yl)oxy)acetic acid In the above example, it was synthesized with a yield of 80%. LC / MS (ESI+) calculation: 31 H 33 ClN2O5(M+H + ) m / z, 549.2; found, 549.2. TIFF0007603609000367.tif9150-Chloro-4-cyanophenoxy))-2,2,4,4-tetramethylcyclobutyl)-1-oxoisoindol-5-yl)hexyl-5-yn-1-yl)oxy)acetami TIFF0007603609000368.tif8149-Synthesis of (4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide In the above example, it was synthesized with a yield of 43%. LC / MS (ESI+) calculation: 54 H 63 ClN6O8S TIFF0007603609000369.tif18153TIFF0007603609000370.tif10154(s,3H),3.83(m,1H),3.7 3(m,2H),3.59(s,2H),2.65(s,2H),2.51(m,2H),2.25-2.15(m,2H),1.25(s,19H),1.07(s,9H). TIFF0007603609000371.tif8148-Chloro-4-cyanophenoxy))-2,2,4,4-tetramethylcyclobutyl)-1-oxoisoindol-5-yl)hexyl-5-yn-1-yl)oxy)acetami TIFF0007603609000372.tif9153Synthesis of methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-3-yl acetate In the above example, it was synthesized with a yield of 40%. LC / MS (ESI+) calculation: 56 H 65 ClN6O9S TIFF0007603609000373.tif52153

[0139] TIFF0007603609000374.tif10151isopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl) TIFF0007603609000375.tif13156-yl)-2,2,4,4-tetramethylcyclobutoxy)benzonitrile TIFF0007603609000376.tif56151LC / MS(ESI+)Calcd for C 48 H 48 ClFN6O6(M+H + ) m / z, 859.3; found 859.3. 1 H NMR TIFF0007603609000377.tif10151TIFF0007603609000378.tif34154

[0140] TIFF0007603609000379.tif21154Dipiperidin-4-yl)ethynyl)-1-oxoisoindolin-2-yl)-2,2,4,4-tetramethylcyclobutoxy)benzonitrile TIFF0007603609000380.tif64159LC / MS(ESI+)Calcd for C 48 H 49 ClN6O6(M+H + ) m / z, 841.3; found 841.3. 1 H NMR TIFF0007603609000381.tif35155(s,1H),3.10-2.98(m,5H),2.95-2.69 (m,6H),2.26(s,2H),2.16(s,2H),1.98(s,3H),1.45(s,6H),1.26(s,6H).

[0141] 53: Synthesis of 2-chloro-4-((1r,3r)-3-(5-((1-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)azelaic acid-3-yl)piperidin-4-yl)ethynyl)-1-oxoisoindolin-2-yl)-2,2,4,4-tetramethylcyclobutoxy)benzonitrile TIFF0007603609000382.tif59151LC / MS(ESI+)Calcd for C 46 H 45 ClFN6O6(M+H + ) m / z, 813.3; found 813.3. 1 H NMR TIFF0007603609000383.tif43154(s,6H),1.26(s,7H).

[0142] 54: 2-chloro-4-((1S,4r)-4-(2-((3S)-3-((4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-3-oxoisoindolin-5-yl)piperazin-1-yl)methyl)pyrrolidin-1-yl)-5-oxy-5H-pyrrole[3,4-b]pyridin-6(7H)-yl)cyclohexyl)oxy)benzonitrile TIFF0007603609000384.tif52151LC / MS(ESI+)Calcd for C 42 H 44 ClFN8O5(M+H + ) m / z, 795.3; found 795.3. 1 H NMR TIFF0007603609000385.tif27153TIFF0007603609000386.tif25155(s,3H),1.57(s,2H),1.24(s,2H).

[0143] 55: 2-chloro-4-((1S,4r)-4-(2-((3S)-3-((4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1-oxoisoindolin-5-yl)piperazin-1-yl)methyl)pyrrolidin-1-yl)-5-oxy-5H-pyrrole[3,4-b]pyridin-6(7H)-yl)cyclohexyl)oxy)benzonitrile LC / MS(ESI+)Calcd for C 42 H 44 ClFN8O5(M+H + ) m / z, 795.3; found 795.3. 1 H NMR TIFF0007603609000387.tif51153(s,3H),1.57(s,2H),1.24(s,2H).

[0144] 56: Synthesis of 2-chloro-4-((1r,4r)-4-(2-(4-((4-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)-5-oxo-5H-pyrrole[3,4-b]pyridin-6(7H)-yl)cyclohexyl)oxy)benzonitrile TIFF0007603609000388.tif68151LC / MS(ESI+)Calcd for C 43 H 47 ClN8O5(M+H + ) m / z, 791.3; found 791.3.

[0145] 57: Synthesis of 2-chloro-4-((1r,4r)-4-(2-(4-((4-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)-5-oxo-5H-pyrrole[3,4-b]pyridin-6(7H)-yl)cyclohexyl)oxy)benzonitrile TIFF0007603609000389.tif67152LC / MS(ESI+)Calcd for C 43 H 45 ClNO(M+H + ) m / z, 805.3; found 805.3. TIFF0007603609000390.tif52155

[0146] 58: Synthesis of N-((1R,4R)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-4-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)-1,4-diazepan-1-yl)methyl)piperidin-1-yl)benzamide TIFF0007603609000391.tif891391.Synthesis of compound methyl 4-(4-(hydroxymethyl)piperidin-1-yl)benzoate Methyl p-fluorobenzoate (1.0 g, 6.5 mmol) was dissolved in 30 mL of DMSO, and 4-hydroxymethylpiperidine (2.2 g, 19.5 mmol) and potassium carbonate (2.7 g, 19.5 mmol) were added. The mixture was heated to 100°C and allowed to react overnight. The next day, the methyl p-fluorobenzoate was monitored for consumption. After cooling to room temperature, the mixture was extracted with water and ethyl acetate. The organic phase was washed with 0.05 M HCl solution and saturated brine. The mixture was dried over anhydrous sodium sulfate and concentrated to give 1.1 g of methyl 4-(4-(hydroxymethyl)piperidin-1-yl)benzoate in 68.1% yield. MS (ESI) m / e 249.1 (M+H). + . 2. Synthesis of compound 4-(4-(hydroxymethyl)piperidin-1-yl)benzoic acid Methyl 4-(4-(hydroxymethyl)piperidin-1-yl)benzoate (1.0 g, 4.0 mmol) was dissolved in 8 mL of MeOH / THF (1:1) and 3 mL of 5N NaOH was added. The mixture was stirred at room temperature for 16 h. Water and DCM were added to extract organic impurities, and the pH of the aqueous phase was slowly adjusted to 4-5 with 1N HCl, resulting in the precipitation of a large amount of white solid. Filtration and drying of the filter cake afforded 510.0 mg of 4-(4-(hydroxymethyl)piperidin-1-yl)benzoic acid in a 54.1% yield. MS (ESI) m / e 235.1 (M+H). + . 3. The compound N-((1R,4R)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-4-(4-(hydroxymethyl)piperidin-1-yl)benzamide 4-((1R,4R)-4-aminocyclohexyl)oxy)-2-chlorobenzonitrile (328.0 mg, 1.3 mmol) was dissolved in DCM and cooled to 0 °C. HATU (475.1 mg, 1.3 mmol) and DIEA (461.4 mg, 3.6 mmol) were added, followed by 4-(4-(hydroxymethyl)piperidin-1-yl)benzoic acid (280.0 mg, 1.2 mmol). The mixture was then cooled to room temperature and reacted for 2 h. CHCl and water were added for extraction. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and the solvent was removed by rotary evaporation. The mixture was then purified by silica gel column chromatography. 370.0 mg of the compound N-((1R,4R)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-4-(4-(hydroxymethyl)piperidin-1-yl)benzamide was obtained in a 66.4% yield. MS(ESI) m / e 467.2(M+H) + . 4. Compound N-((1R,4R)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-4-formylpiperidin-1-yl)benzamide N-((1R,4R)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-4-(4-(hydroxymethyl)piperidin-1-yl)benzamide (370 mg, 0.8 mmol) was dissolved in a mixture of 10 mL of DCM and 1 mL of tetrahydrofuran, and Dess-Martin (373.2 mg, 0.9 mmol) was added. The mixture was allowed to react at room temperature for 1 hour. The mixture was filtered through diatomaceous earth, washed with aqueous sodium bisulfite and saturated brine, and the DCM phase was dried over anhydrous sodium sulfate, filtered, and concentrated. 310.2 mg of N-((1R,4R)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-4-formylpiperidin-1-yl)benzamide was obtained in an 81.4% yield. MS (ESI) m / e 465.2 (M+H). + . 5. tert-Butyl 4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl)-1,4-diazepane-1-carboxylate 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (200.0 mg, 0.7 mmol) and tert-butyl 1,4-diazepane-1-carboxylate (174.1 mg, 0.9 mmol) were dissolved in 6 mL of DMSO, 0.5 mL of DIEA was added, and the mixture was reacted at 100 °C for 1.5 hours. The mixture was cooled to room temperature, extracted with water and ethyl acetate, washed with saturated brine, dried, concentrated, and subjected to column chromatography to obtain 185.3 mg of tert-butyl 4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl)-1,4-diazepane-1-carboxylate in 56.2% yield. MS (ESI) m / e 401.2 (M-56+H). + . 6.5-(1,4-Diazepam-1-yl)-2-(2,6-dioxopiperidin-3-yl)dihydroisoindole-1,3-dione trifluoroacetate tert-Butyl 4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl)-1,4-diazepane-1-carboxylate (185.0 mg, 0.4 mmol) was dissolved in 2 mL of DCM, 6 mL of TFA was added, and the mixture was allowed to react at room temperature for 1 h. The mixture was then directly concentrated to dryness for further use. The product (191 mg) was 5-(1,4-diazepam-1-yl)-2-(2,6-dioxopiperidin-3-yl)dihydroisoindole-1,3-dione trifluoroacetate. The yield was 99.0%. MS (ESI) m / e 356.2 (M+H). + . 7. Preparation of compound N-((1R,4R)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-4-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)-1,4-diazepan-1-yl)methyl)piperidin-1-yl)benzamide 5-(1,4-Diazepam-1-yl)-2-(2,6-dioxopiperidin-3-yl)dihydroisoindole-1,3-dione trifluoroacetate (121.2 mg, 0.3 mmol) and N-((1R,4R)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-4-formylpiperidin-1-yl)benzamide (100.0 mg, 0.2 mmol) were dissolved in 8 mL of a mixed solvent (DCM / MeOH = 5 / 1). Sodium triacetoxyborohydride (170.0 mg, 0.8 mmol) was added and the reaction was allowed to proceed at room temperature for 4 hours. The reaction was quenched with water and extracted with DCM. After drying, concentration and column chromatography, 101.5 mg of N-((1R,4R)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-4-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)-1,4-diazepan-1-yl)methyl)piperidin-1-yl)benzamide was obtained in a yield of 58.8%. MS TIFF0007603609000392.tif17155TIFF0007603609000393.tif26153Hz,6H),1.99(s,2H),1.83(s,2H),1.69(s,4H),1.46-1.37(m,2H).

[0147] 59: Synthesis of 2-chloro-4-(((1r,4r)-4-(2-(4-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)piperidin-4-yl)oxy)piperidin-1-yl)-5-oxo-5H-pyrrolo[3,4-b]pyridin-6(7H)-yl)cyclohexyl)oxy)benzonitrile TIFF0007603609000394.tif45144LC / MS(ESI+)Calcd for C 43 H 44 ClN7O7(M+H + ) m / z, 806.3; found 806.3. TIFF0007603609000395.tif52155

[0148] 60: Synthesis of 2-chloro-4-(((1r,4r)-4-(2-(4-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)oxy)piperidin-1-yl)-5-oxo-5H-pyrrolo[3,4-b]pyridin-6(7H)-yl)cyclohexyl)oxy)benzonitrile TIFF0007603609000396.tif451501. tert-Butyl 4-((1-(6-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-5-oxo-6,7-dihydro-5H-pyrrolo[3,4]-b]pyridin-2-yl)piperidin-4-yl)oxy)piperidine-1-carboxylate 2-Chloro-4-(((1R,4R)-4-(2-chloro-5-oxo-5H-pyrrolo[3,4-b]pyridin-6(7H)-yl)cyclohexyl)oxy)benzonitrile (100.0 mg, 0.3 mmol) and 4-(piperidin-4-yloxy)piperidine-1-carboxylic acid tert-butyl ester (212.1 mg, 0.8 mmol) were dissolved in 3 mL of NMP, 0.5 mL of DIEA was added, and the mixture was heated to 100°C overnight. After cooling to room temperature, water and EA were added for extraction, and the organic phase was washed with water, 0.5 M aqueous HCl solution, and saturated brine. The mixture was then dried over anhydrous sodium sulfate and concentrated. 142.1 mg of tert-butyl 4-((1-(6-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-5-oxo-6,7-dihydro-5H-pyrrolo[3,4]-b]pyridin-2-yl)piperidin-4-yl)oxy)piperidine-1-carboxylate was obtained in 88.2% yield. MS (ESI) m / e 594.3 (M-56+H). + . 2,2-Chloro-4-(((1R,4R)-4-(5-oxo-2-(4-(piperidin-4-yloxy)piperidin-1-yl)-5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl)cyclohexyl)oxy)benzonitrile trifluoroacetate The compound tert-butyl 4-((1-(6-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-5-oxo-6,7-dihydro-5H-pyrrolo[3,4]-b]pyridin-2-yl)piperidin-4-yl)oxy)piperidine-1-carboxylate (140.0 mg, 0.2 mmol) was dissolved in 1 mL of DCM, 3 mL of TFA was added, and the mixture was stirred at room temperature for 1 h to monitor the reaction completion. The mixture was concentrated under reduced pressure and the resulting viscous solid was directly removed by evaporation with DCM. 142.1 mg of 2-chloro-4-(((1R,4R)-4-(5-oxo-2-(4-(piperidin-4-yloxy)piperidin-1-yl)-5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl)cyclohexyl)oxy)benzonitrile trifluoroacetate was obtained in 99.2% yield. MS (ESI) m / e 549.1 (M+H). + . 3. 2-Chloro-4-(((1r,4r)-4-(2-(4-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)oxy)piperidin-1-yl)-5-oxo-5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl)cyclohexyl)oxy)benzonitrile The intermediate 2-chloro-4-(((1R,4R)-4-(5-oxo-2-(4-(piperidin-4-yloxy)piperidin-1-yl)-5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl)cyclohexyl)oxy)benzonitrile trifluoroacetate (100.0 mg, 0.2 mmol) was dissolved in 2 mL of DMSO, DIEA (97.3 mg, 0.8 mmol) was added, and after uniform stirring, 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (49.9 mg, 0.2 mmol) was added. The temperature was raised to 120 °C and the reaction was carried out for 2 h, and the reaction completion was monitored. After cooling to room temperature, water and ethyl acetate were added and the mixture was extracted. The organic phase was washed with 0.5 M aqueous hydrochloric acid and saturated brine, dried over anhydrous sodium sulfate, concentrated, and subjected to column chromatography to obtain 61.2 mg of 2-chloro-4-(((1r,4r)-4-(2-(4-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)oxy)piperidin-1-yl)-5-oxo-5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl)cyclohexyl)oxy)benzonitrile in a yield of 41.6%. MS (ESI) m / e 805.3 (M+H) + . 1 H NMR (400 mHz, CDCl3) δ 8.11 TIFF0007603609000397.tif51151

[0149] Synthesis of TIFF0007603609000398.tif9150(yl)-6-(4-(7-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)-2,7-diazaspiro[3.5]nonyl-2-yl)piperidin-1-yl)pyridazine-3-carboxamide TIFF0007603609000399.tif77156Synthesis of (4-oxopiperidin-1-yl)-6-(4-oxopiperidin-1-yl)pyridazine-3-carboxamide 6-Chloro-N-((1R,4R)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)pyridazine-3-carboxamide (200.0 mg, 0.51 mmol) and 4-piperidone trifluoroacetate (217.9 mg, 1.02 mmol) were dissolved in 5 mL of NMP, 0.5 mL of DIE was added, and the mixture was heated to 100 °C overnight. After cooling to room temperature, water and EA were added for extraction. The organic phase was washed with water, saturated aqueous citric acid, and saturated brine. It was then dried over anhydrous sodium sulfate and concentrated. Purification using a column chromatography afforded 120.1 mg of N-((1R,4R)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-6-(4-oxopiperidin-1-yl)pyridazine-3-carboxamide in a 51.7% yield. MS(ESI) m / e 453.9(M+H) + . 2,7-(2-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester 2-(2,6-Dioxapiperidin-3-yl)-5,6-difluoroisoindoline-1,3-dione (500 mg, 1.7 mmol) and 2-tert-butoxycarbonyl-2,7-diazaspiro[3.5]nonane (461.54 mg, 2.04 mmol) were dissolved in 8 mL of DMSO, 0.5 mL of DIEA was added, and the mixture was heated to 130 °C and reacted for 2 h. The reaction was monitored for completion. After cooling to room temperature, 10 mL of water was added, and the mixture was extracted with 10 mL of ethyl acetate, washed with saturated aqueous citric acid, and then washed with saturated brine. The mixture was then dried over anhydrous sodium sulfate and concentrated. Purification by column chromatography gave 750.6 mg of 7-(2-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester in 88.2% yield. MS (ESI) m / e 445.2 (M-56+H). + 3.2-(2,6-Dioxapiperidin-3-yl)-5-fluoro-6-(2,7-diazaspiro[3.5]nonyl-7-yl)isoindoline-1,3-dione trifluoroacetate 7-(2-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester (750 mg, 1.51 mmol) was dissolved in a mixture of 4 mL of DCM and 8 mL of trifluoroacetic acid and stirred at room temperature for 1 h. The mixture was concentrated by direct evaporation and the solution was washed with dichloromethane to give a yellow solid, which was weighed to give 822.6 mg of 2-(2,6-dioxapiperidin-3-yl)-5-fluoro-6-(2,7-diazaspiro[3.5]nonyl-7-yl)isoindoline-1,3-dione trifluoroacetate in 99.5% yield. MS (ESI) m / e 400.1 (M+H). + TIFF0007603609000400.tif9149)-6-(4-(7-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)-2,7-diazaspiro[3.5]nonyl-2-yl)piperidin-1-yl)pyridazine-3-carboxamide Compound N-((1R,4R)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-6-(4-oxopiperidin-1-yl)pyridazine-3-carboxamide (50.0 mg, 0.11 mmol), and 2-(2,6-dioxapiperidin-3-yl)-5-fluoro-6-(2,7-diazaspiro[3.5]nonyl-7-yl)isoindoline-1,3-dione trifluoroacetate (62.3 mg, 0.12 mmol) were dissolved in a mixed solvent of 2 mL of dichloromethane and 1 mL of methanol, and sodium triacetoxyborohydride (93.4 mg, 0.44 mmol) was added and the mixture was allowed to react at room temperature overnight. The mixture was quenched with water, extracted with dichloromethane, washed with saturated brine, and the organic phase was dried, filtered, concentrated, and purified to give 23.3 mg of N-((1R,4R)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-6-(4-(7-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)-2,7-diazaspiro[3.5]nonyl-2-yl)piperidin-1-yl)pyridazine-3-carboxamide. MS (ESI) m / e 837.3 (M+H) + . 1 H NMR(400mHz,DMSO-d6)δ11.11(s,1H),8.60 TIFF0007603609000401.tif59153

[0150] Synthesis of TIFF0007603609000402.tif9149-1H-yl)-6-(4-(5-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)hexahydropyrrole[3,4-c]pyrrol-2(1H)-yl)piperidin-1-yl)pyridazine-3-carboxamide TIFF0007603609000403.tif51150LC / MS(ESI+)Calcd for C 42 H 44 ClNO6(M+H + ) m / z, 806.3; found 806.3. TIFF0007603609000404.tif43152(m,4H).

[0151] Synthesis of TIFF0007603609000405.tif10150-5-(4-(5-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)hexahydropyrrole[3,4-c]pyrrol-2(1H)-yl)piperidin-1-yl)pyrazine-2-carboxamide TIFF0007603609000406.tif46147LC / MS(ESI+)Calcd for C 42 H 44 ClNO6(M+H + ) m / z, 806.3; found 806.3. TIFF0007603609000407.tif43154(m,4H).

[0152] Synthesis of TIFF0007603609000408.tif9149-1H-yl)-5-(4-(5-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)hexahydropyrrole[3,4-c]pyrrol-2(1H)-yl)piperidin-1-yl)pyrazine-2-carboxamide TIFF0007603609000409.tif44149LC / MS(ESI+)Calcd for C 42 H 43 ClFN9O6(M+H + ) m / z, 826.3; found 826.3. TIFF0007603609000410.tif18154TIFF0007603609000411.tif26154

[0153] Synthesis of TIFF0007603609000412.tif8148 hexahydropyrrole[3,4-c]pyrrol-2(1H)-yl)piperidin-1-yl)pyridazine-3-carboxamide TIFF0007603609000413.tif46150LC / MS(ESI+)Calcd for C 42 H 43 ClFN9O6(M+H + ) m / z, 826.3; found 826.3. TIFF0007603609000414.tif44152

[0154] Synthesis of TIFF0007603609000415.tif10148 hexahydropyrrole[3,4-c]pyrrol-2(1H)-yl)piperidin-1-yl)pyrimidine-5-carboxamide TIFF0007603609000416.tif43149LC / MS(ESI+)Calcd for C 42 H 44 ClNO6(M+H + ) m / z, 806.3; found 806.3. TIFF0007603609000417.tif43152

[0155] Synthesis of TIFF0007603609000418.tif8148yl)-6-(5-(1-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)hexahydropyrrole[3,4-c]pyrrol-2(1H)-yl)pyridazine-3-carboxamide TIFF0007603609000419.tif56151LC / MS(ESI+)Calcd for C 42 H 43 ClFN9O6(M+H + ) m / z, 824.3; found 824.3. TIFF0007603609000420.tif43152TIFF0007603609000421.tif17151

[0156] Synthesis of TIFF0007603609000422.tif8148 hexahydropyrrole[3,4-c]pyrrol-2(1H)-yl)piperidin-1-yl)pyrimidine-5-carboxamide TIFF0007603609000423.tif44149LC / MS(ESI+)Calcd for C 42 H 44 ClNO6(M+H + ) m / z, 806.3; found 806.3. 1 H NMR TIFF0007603609000424.tif33153(s,2H),1.46(s,5H),1.25(s,2H).

[0157] Synthesis of 5-(5-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)hexahydropyrrole[3,4-c]pyrrol-2(1H)-yl)pyrazine-2-carboxamide TIFF0007603609000426.tif47150LC / MS(ESI+)Calcd for C 42 H 44 ClNO6(M+H + ) m / z, 806.3; found 806.3. TIFF0007603609000427.tif60154

[0158] Synthesis of TIFF0007603609000428.tif8149-1H-yl)-5-(5-(1-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)hexahydropyrrole[3,4-c]pyrrol-2(1H)-yl)pyrazine-2-carboxamide TIFF0007603609000429.tif47152LC / MS(ESI+)Calcd for C 42 H43 ClFN9O6(M+H + ) m / z, 824.3; found 824.3. TIFF0007603609000430.tif59153

[0159] Synthesis of TIFF0007603609000431.tif9149yl)-6-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)-2,7-diazaspiro[3.5]non-7-yl)pyridazine-3-carboxamide TIFF0007603609000432.tif49154LC / MS(ESI+)Calcd for C 43 H 45 ClFN9O6(M+H + ) m / z, 838.3; found 838.3. TIFF0007603609000433.tif42155Hz,1H),2.35(d,J=18.7Hz,2H),2.10(d,J=10.0Hz,2H),2.03(s,1H),1.89(d,J= 10.2Hz,2H),1.81(s,4H),1.73(d,J=11.0Hz,2H),1.64(d,J=12.8Hz,2H),1.51(d,J=12.3Hz,2H),1.2-1.10(m,3H).

[0160] TIFF0007603609000434.tif91454-Tetramethylcyclobutyl)-6-(5-(1-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)hexahydropyrrole[3,4-c]pyrrol-2(1H)-yl)pyridazine-3-carboxamide TIFF0007603609000435.tif43153LC / MS(ESI+)Calcd for C 44 H 47 ClFN9O6(M+H + ) m / z, 852.3; found 852.3. TIFF0007603609000436.tif17153TIFF0007603609000437.tif35155(s,5H),1.21(s,6H).

[0161] TIFF0007603609000438.tif17154Synthesis of 3-dioxoisoindolin-5-yl)piperidin-4-yl)amino)piperidin-1-yl)pyrazine-2-carboxamide TIFF0007603609000439.tif471511.Synthesis of tert-butyl (1-(5-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)carbamoyl)pyrazin-2-yl)piperidin-4-yl)carbamate 5-Chloro-N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)pyrazine-2-carboxamide (400 mg, 1.02 mmol) was dissolved in 10 mL of NMP, and tert-butyl piperidin-4-ylcarbamate (246 mg, 1.23 mmol) and DIEA (661 mg, 5.11 mmol) were added. The temperature was raised to 100°C and the reaction was carried out. The mixture was quenched by adding water, extracted with EA, and washed with saturated aqueous citric acid. Purification gave 450 mg of tert-butyl (1-(5-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)carbamoyl)pyrazin-2-yl)piperidin-4-yl)carbamate in a 79.3% yield. LC / MS (ESI+) Calcd for C 28 H 35 ClN6O4(M-56+H + ) m / z, 500.2; found 500.2. TIFF0007603609000440.tif8149(4-Cyanophenoxy)hexyl)azine-2-carboxamide trifluoroacetate tert-Butyl (1-(5-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)carbamoyl)pyrazin-2-yl)piperidin-4-yl)carbamate (300 mg, 0.54 mmol) was dissolved in 2 mL of DCM, 4 mL of trifluoroacetic acid was added, and the mixture was stirred for 2 h. The mixture was directly concentrated to dryness, and most of the TFA was removed with DCM. 325 mg of 5-(4-aminopiperidin-1-yl)-N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)hexyl)azine-2-carboxamide trifluoroacetate was obtained. 3. Synthesis of N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-5-(4-((1-(2,6-dioxopiperidin-3-yl-6-fluoro-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)amino)piperidin-1-yl)pyrazine-2-carboxamide 5-(4-aminopiperidin-1-yl)-N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)hexyl)azine-2-carboxamide trifluoroacetate (100 mg, 0.22 mmol) and 2-(2,6-dioxopiperidin-3-yl)-5-fluoro-6-(4-oxypiperidin-1-yl)isoindoline-1,3-dione (83 mg, 0.22 mmol) were dissolved in a mixture of 2 mL of DCM and 2 mL of methanol. Sodium triacetoxyborohydride (186 mg, 0.88 mmol) was added slowly. TIFF0007603609000441.tif8152 chloro-4-cyanophenoxy)cyclohexyl)-5-(4-((1-(2,6-dioxopiperidin-3-yl-6-fluoro-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)amino)piperidin-1-yl)pyrazine-2-carboxamide 12 mg was obtained in 7.3% yield. LC / MS (ESI+) Calcd for C 28 H 35 ClNO4(M+H + ) m / z, 812.3; found 812.3. 1 H NMR(400mHz,CDCl3)δ8.84(s,1H),7.99(s,1H),7.56 TIFF0007603609000442.tif34154Hz,8H),2.07(s,1H),1.25(s,3H).

[0162] Synthesis of (2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)-2,7-diazaspiro[3.5]non-7-yl)pyridazine-3-carboxamide TIFF0007603609000444.tif58155LC / MS(ESI+)Calcd for C 43 H 46 ClNO6(M+H + ) m / z, 820.3; found 820.3. TIFF0007603609000445.tif50155

[0163] TIFF0007603609000446.tif8151 Method for the synthesis of)-6-(2-((1-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)methyl)-2,7-diazaspiro[3.5]non-7-yl)pyridazine-3-carboxamide TIFF0007603609000447.tif48156LC / MS(ESI+)Calcd for C 44 H 47 ClFN9O6(M+H + ) m / z, 852.3; found 852.3. 1 H NMR TIFF0007603609000448.tif9154TIFF0007603609000449.tif49155

[0164] TIFF0007603609000450.tif9149)-5-(2-((1-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)methyl)-2,7-diazaspiro[3.5]non-7-yl)pyridazine-2-carboxamide TIFF0007603609000451.tif48154LC / MS(ESI+)Calcd for C 44 H 47 ClFN9O6(M+H + ) m / z, 852.3; found 852.3. 1 H NMR TIFF0007603609000452.tif57154

[0165] TIFF0007603609000453.tif9151sil)-6-(4-(7-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)-2,7-diazaspiro[3.5]non-2-yl)piperidin-1-yl)nicotinamide TIFF0007603609000454.tif53151LC / MS(ESI+)Calcd for C 44 H 46 ClFN8O6(M+H + ) m / z, 837.3; found 837.3. 1 H NMR TIFF0007603609000455.tif58156

[0166] TIFF0007603609000456.tif9150)phenoxy)cyclohexyl)-6-(4-(7-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)-2,7-diazaspiro[3.5]non-2-yl)pyridin-1-yl)azine-3-carboxamide TIFF0007603609000457.tif51153LC / MS(ESI+)Calcd for C 43 H 46 ClNO6(M+H+ ) m / z, 820.3; found 820.3. 1 H NMR TIFF0007603609000458.tif34154TIFF0007603609000459.tif18154

[0167] TIFF0007603609000460.tif9150)Cyclohexyl)-6-(4-(7-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)-2,7-diazaspiro[3.5]non-2-yl)piperidin-1-yl)pyridazine-3-carboxamide TIFF0007603609000461.tif47153LC / MS(ESI+)Calcd for C 44 H 45 F4N9O6(M+H + ) m / z, 872.3; found 872.3. 1 H NMR TIFF0007603609000462.tif51157

[0168] TIFF0007603609000463.tif81514-Tetramethylcyclobutyl)-6-(4-(7-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)-2,7-diazaspiro[3.5]non-2-yl)piperidin-1-yl)pyridazine-3-carboxamide TIFF0007603609000464.tif54155LC / MS(ESI+)Calcd for C 45 H 49 ClF4N9O6(M+H + ) m / z, 866.3; found 866.3. 1 H NMR TIFF0007603609000465.tif50156

[0169] TIFF0007603609000466.tif7149)-6-(6-(1-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)-2,6-diazaspiro[3.4]octan-2-yl)pyridazine-3-carboxamide TIFF0007603609000467.tif48155LC / MS(ESI+)Calcd for C 41 H 43 ClFN9O6s(M+H + ) m / z, 824.3; found 824.3. 1 H NMR TIFF0007603609000468.tif41153TIFF0007603609000469.tif18156

[0170] TIFF0007603609000470.tif8149)-5-(6-(1-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)-2,6-diazaspiro[3.4]octan-2-yl)pyrazine-2-carboxamide TIFF0007603609000471.tif48154LC / MS(ESI+)Calcd for C 41 H 43 ClFN9O6s(M+H + ) m / z, 824.3; found 824.3. 1 H NMR TIFF0007603609000472.tif52156

[0171] TIFF0007603609000473.tif9148 yl)-5-(4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)-2,7-diazaspiro[3.5]non-7-yl)piperidin-1-yl)-1,3,4-thiadiazole-2-carboxamide TIFF0007603609000474.tif47151LC / MS(ESI+)Calcd for C41 H 43 ClFN9O6s(M+H + ) m / z, 844.3; found 844.3. 1 H NMR TIFF0007603609000475.tif43154

[0172] Synthesis of TIFF0007603609000476.tif8150(1r,4R)-4-((2-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)-2,7-diazaspiro[3.5]non-7-yl)methyl)cyclohexyl)-1H-1,2,4-triazole-3-carboxamide TIFF0007603609000477.tif89153-Synthesis of 1H-1,2,4-triazole-3-carboxamide 1H-1,2,4-Triazole-3-carboxylic acid (500 mg, 1.99 mmol) was mixed with 10 mL of DMF, but dissolution became difficult. DIEA (309 mg, 2.39 mmol) was added, and the mixture was dissolved and clarified. The temperature was lowered to -5°C, HATU (796 mg, 2.09 mmol) was added, and the mixture was stirred for more than 1 hour. 4-(((1r,4r)-4-aminocyclohexyl)oxy)-2-chlorobenzonitrile (237 mg, 2.09 mmol) was added, and the mixture was stirred at low temperature for 30 minutes. The ice-salt bath was removed, and the mixture was allowed to warm to room temperature naturally and react for 2 hours. TIFF0007603609000478.tif8156 ((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-1H-1,2,4-triazole-3-carboxamide 660 mg was obtained in 95.7% yield. LC / MS (ESI+) Calcd for C 16 H 16 ClNO2(M+H + ) m / z, 346.1; found 346.1. TIFF0007603609000479.tif9150Synthesis of (phenoxy)cyclohexyl)carbamoyl)-1H-1,2,4-triazol-1-yl)cyclohexanoate TIFF0007603609000480.tif91501H-1,2,4-triazole-3-carboxamide (500 mg, 1.45 mmol) was dissolved in DMF, and (1s,4s)-methyl 4-((methylsulfonyl)oxy)cyclohexanecarboxylic acid ester (1.02 g, 4.34 mmol) and cesium carbonate (1.41 g, 4.34 mmol) were added. The temperature was raised to 95°C and the reaction was carried out overnight. Water was added to the system. TIFF0007603609000481.tif81513-((1R,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)carbamoyl)-1H-1,2,4-triazol-1-yl)cyclohexanoate 210m TIFF0007603609000482.tif9156C 24 H 28 ClNO4(M+H + ) m / z, 486.2; found 486.2. TIFF0007603609000483.tif8149-1-((1r,4R)-4-(hydroxymethyl)cyclohexyl)-1H-1,2,4-triazole-3-carboxamide N-((1r,4R)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-1-((1r,4R)-4-(hydroxymethyl)cyclohexyl)-1H-1,2,4-triazole-3-carboxamide (140 mg, 61.87%) was obtained by dissolving N-((1r,4R)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-1-((1r,4R)-4-(hydroxymethyl)cyclohexyl)-1H-1,2,4-triazole-3-carboxamide (140 mg, 61.87%) in a 61.87% yield. LC / MS(ESI+)Calcd for C 23 H 28 ClNO3(M+H + ) m / z, 458.2; found 458.2. TIFF0007603609000485.tif9151Synthesis of (1r,4R)-4-formylcyclohexyl)-1H-1,2,4-triazole-3-carboxamide N-((1r,4R)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-1-((1r,4R)-4-(hydroxymethyl)cyclohexyl)-1H-1,2,4-triazole-3-carboxamide (130 mg, 0.28 mmol) was dissolved in 3 mL of DCM, and Dess-Martin reagent (181 mg, 0.43 mmol) was added at room temperature and reacted for 1 h. The mixture was filtered, and the filtrate was washed with sodium bisulfite and saturated sodium bicarbonate. TIFF0007603609000486.tif10153 80 mg of (1r,4R)-4-cyanophenoxy)cyclohexyl)-1-((1r,4R)-4-formylcyclohexyl)-1H-1,2,4-triazole-3-carboxamide was obtained in a yield of 61.84%. 5. N-((1r,4R)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-1-(1r,4R)-4-((2-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)-2,7-diazaspiro[3.5]non-7-yl)methyl)cyclohexyl)-1H-1,2,4-triazole-3-carboxamide TIFF0007603609000487.tif81511-((1r,4R)-4-Formylcyclohexyl)-1H-1,2,4-triazole-3-carboxamide (40 mg, 0.09 mmol) and 2-(2,6-dioxopiperidin-3-yl)-5-(2,7-diazaspiro[3.5]non-2-yl)isoindoline-1,3-dione (37 mg, 0.10 mmol) were dissolved in 2 mL of a 1:1 DCM:MeOH mixture, and sodium triacetoxyborohydride (75 mg, 0.35 mmol) was slowly added. The reaction was monitored for completion over 2 h. The mixture was quenched with water and diluted with DCM. TIFF0007603609000488.tif9153 35 mg of ((2-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)-2,7-diazaspiro[3.5]non-7-yl)methyl)cyclohexyl)-1H-1,2,4-triazole-3-carboxamide was obtained in 48.57% yield. LC / MS (ESI+) Calcd for C 43 H 48 ClNO6(M+H + ) m / z, 822.3; found 822.3. 1 H NMR (400 mHz, CDCl3) δ 8.11 TIFF0007603609000489.tif50154

[0173] TIFF0007603609000490.tif10149)-1-((1r,4R)-4-((2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)-2,7-diazaspiro[3.5]non-7-yl)methyl)cyclohexyl)-1H-1,2,4-triazole-3-carboxamide LC / MS(ESI+)Calcd for C 41 H 43 ClFN9O6s(M+H + ) m / z, 844.3; found 844.3. 1 H NMR TIFF0007603609000491.tif43154

[0174] TIFF0007603609000492.tif17155)-1,3-dioxoisoindolin-5-yl)-2,7-diazaspiro[3.5]non-7-yl)methyl)cyclohexyl)-1H-1,2,4-triazole-5-carboxamide LC / MS(ESI+)Calcd for C 43 H 48 ClNO6(M+H + ) m / z, 822.3; found 822.3. 1H NMR TIFF0007603609000493.tif42153TIFF0007603609000494.tif1099

[0175] TIFF0007603609000495.tif18152-6-Fluoro-1,3-dioxoisoindolin-5-yl)-2,7-diazaspiro[3.5]non-7-yl)methyl)cyclohexyl)-1H-1,2,4-triazole-5-carboxamide LC / MS(ESI+)Calcd for C 41 H 43 ClFN9O6s(M+H + ) m / z, 844.3; found 844.3. 1 H NMR TIFF0007603609000496.tif49152Hz,3H).

[0176] Synthesis of TIFF0007603609000497.tif10149yl)-6-(7-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)-2,7-diazaspiro[3.5]non-2-yl)pyridazine-3-carboxamide TIFF0007603609000498.tif531441. Synthesis of 4-(2-{6-[4-(3-chloro-4-cyano-phenoxy)-cyclohexylcarbamoyl]-pyridazin-3-yl}-2,7-diaza-spiro[3.5]non-7-yl)-piperidine-1-carboxylic acid tert-butyl ester TIFF0007603609000499.tif91516-(2,7-diazaspiro[3.5]non-2-yl)pyridazine-3-carboxamide (100 mg, 0.208 mmol) was dissolved in 5 mL of dichloromethane, 4-Boc piperidone (414 mg, 2.1 mmol) was added, 0.5 drops of acetic acid was added dropwise, and the mixture was refluxed at 40 °C for 1 h, cooled to room temperature, and sodium triacetylborohydride (441 mg, 2.08 mmol) was added. The mixture was added with 1 mmol), refluxed at 40°C overnight, cooled to room temperature, washed with water, concentrated under reduced pressure to dryness, and separated by thin layer chromatography to give the product 4-(2-{6-[4-(3-chloro-4-cyano-phenoxy)-cyclohexylcarbamoyl]-pyridazin-3-yl}-2,7-diaza-spiro[3.5]non-7-yl)-piperidine-1-carboxylic acid tert-butyl ester 120 mg in 86.8% yield. LC / MS (ESI+) calculation for C 35 H 46 ClN7O4([M+H]+) m / e 663.8. TIFF0007603609000500.tif8150-Synthesis of 6-(7-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoamylalcohol-5-yl)piperidin-4-yl)-2,7-diazaspiro[3.5]non-2-yl)pyridazine-3-carboxamide 4-(2-{6-[4-(3-chloro-4-cyano-phenoxy)-cyclohexylcarbamoyl]-pyridazin-3-yl}-2,7-diaza-spiro[3.5]non-7-yl)-piperidine-1-carboxylic acid tert-butyl ester (45 mg, 0.068 mmol) was dissolved in 3 mL of dichloromethane, 3 mL of trifluoroacetic acid was added, the mixture was stirred at room temperature for 2 hours, and concentrated under reduced pressure to dryness. Dichloromethane was added and concentrated under reduced pressure twice, 3 mL of DMSO was added, 0.5 mL of DIEA was added, and 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindole-1,3-dione was added, the mixture was refluxed at 135 °C for 1.5 hours, cooled to room temperature, 10 mL of dichloromethane was added, the mixture was washed with 10 mL of water twice, washed with saturated brine once, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to dryness. TIFF0007603609000501.tif9153 chloro-4-cyanophenoxy)cyclohexyl)-6-(7-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)-2,7-diazaspiro[3.5]non-2-yl)pyridazine-3-carboxamide 35 mg was obtained in 62.7% yield. LC / MS (ESI+) calculation for C 43 H 46 ClN9O6 TIFF0007603609000502.tif18152TIFF0007603609000503.tif41154

[0177] Synthesis of TIFF0007603609000504.tif9149yl)-5-(7-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)-2,7-diazaspiro[3.5]non-2-yl)pyrazine-2-carboxamide TIFF0007603609000505.tif53152 For synthesis steps, see 88. LC / MS(ESI+)calcd for C 43 H 46 ClN9O6([M+H]+) m / e 820.3, 1 H NMR (400 mHz, CDCl3) δ TIFF0007603609000506.tif51157

[0178] 90: 2-chloro-4-((1r,3r)-3-(2-(4-((2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)-2,7-diazaspiro[3.5]nonan-7-yl)methyl)piperidin-1-yl)-5-oxo-5,7-dihydro-6H-pyrrole[3,4-b]pyridin-6-yl)-2,2,4,4-tetramethylcyclobutoxy)benzonitrile TIFF0007603609000507.tif261532-Chloro-4-(3-(2-(4-formylpiperidin-1-yl)-5-oxoisoindoline-5,7-dihydro-6H-pyrrole[3,4-b]pyridin-6-yl)-2,2,4,4-tetramethylcyclobutoxy)benzonitrile (66 mg, 0.13 mmol) was dissolved in 5 mL of dichloromethane, 2-(2,6-dioxoisoindolin-3-yl)-5-fluoro-6-(2,7-diazaspiro[3.5]non-2-yl)isobenzyl-1,3-dione (45 mg, 0.11 mmol) was added, 0.3 drops of acetic acid was added, and the mixture was allowed to react at room temperature for 15 minutes. Sodium triacetylborohydride (200 mg, 0.94 mmol) was added, and the mixture was reacted at room temperature for 1 hour. The mixture was washed with water, concentrated under reduced pressure to dryness, and separated by thin layer chromatography to obtain 55 mg of yellow solid product, 2-chloro-4-(3-(2-(4-((2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)-2,7-diazaspiro[3.5]non-7-yl)methyl)piperidin-1-yl)-5-oxo-5,7-dihydro-6H-pyrrole[3,4-b]pyridin-6-yl)-2,2,4,4-tetramethylcyclobutoxy)benzonitrile in a yield of 56.1%. LC / MS (ESI+) calculation for C 48 H 52 ClFN8O6([M+H]+)m / e TIFF0007603609000508.tif42154(s,6H),1.23(s,6H).

[0179] TIFF0007603609000509.tif9150)-6-(2-((1-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)methyl)-2,7-di TIFF0007603609000510.tif9155oxamide TIFF0007603609000511.tif471561.Synthesis of 7-{6-[4-(3-chloro-4-cyano-phenoxy)-cyclohexylcarbamoyl]-pyridazin-3-yl}-2,7-diaza-spiro[3.5]nonane-2-carboxylic acid tert-butyl ester 2,7-Diazaspiro[3.5]non-2-carboxylic acid tert-butyl ester (113 mg, 0.5 mmol) was dissolved in 6 mL of DMF, anhydrous potassium carbonate (207 mg, 1.5 mmol) was added, and 6-chloro-pyridazine-3-carboxylic acid [4-(3-chloro-4-cyano-phenoxy)-cyclohexyl]-amide (196 mg, 0.5 mmol) was added, and the mixture was reacted at 80°C overnight, cooled to room temperature, and 15 mL of ethyl acetate was added. The mixture was added with ethanol, washed three times with 10 mL of water, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated to dryness under reduced pressure, and separated by thin layer chromatography to obtain the product 7-{6-[4-(3-chloro-4-cyano-phenoxy)-cyclohexylcarbamoyl]-pyridazin-3-yl}-2,7-diaza-spiro[3.5]nonane-2-carboxylic acid tert-butyl ester (190 mg) in 65.4% yield. LC / MS (ESI+) analysis called for C 30 H 37 ClN6O4([M+H]+) m / e 581.2. 2. tert-Butyl 7-(6-((1r,4r)-4-(3-chloro-4-cyanophenoxy)methyl) TIFF0007603609000512.tif91547-Synthesis of diazaspiro[3.5]non-2-carboxylic acid esters 7-{6-[4-(3-chloro-4-cyano-phenoxy)-cyclohexylcarbamoyl]-pyridazin-3-yl}-2,7-diaza-spiro[3.5]nonane-2-carboxylic acid tert-butyl ester (58 mg, 0.1 mmol) was dissolved in 5 mL of DMF, sodium hydride (8 mg, 0.2 mmol) was added, and the mixture was stirred at room temperature for 10 min. Deuterated methyl iodide (17 mg, 0.12 mmol) was added, and the mixture was reacted at room temperature for 2 h. Water was added to quench the reaction. The mixture was extracted with 15 mL of ethyl acetate, and the organic layer was washed with water and saturated brine, respectively, dried over anhydrous sodium sulfate, filtered, concentrated to dryness under reduced pressure, and separated by thin layer chromatography to obtain the product tert-butyl 7-(6-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)(methyl-d3)carbamoyl)pyridazin-3-yl)-2,7-diazaspiro[3.5]one-2-carboxylate 58 mg in 97.15% yield. LC / MS (ESI+) calculation for C 31 H 36 D3ClN6O4([M+H]+) m / e 598.3. TIFF0007603609000513.tif8151-6-(2-((1-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)methyl)-2,7-diazo TIFF0007603609000514.tif8155Synthesis of thiamid tert-Butyl 7-(6-((1r,4r)-4-(3-chloro-4-cyanophenoxy) TIFF0007603609000515.tif9153 Diazaspiro[3.5]non-2-carboxylic acid ester (57 mg, 0.095 mmol) was dissolved in 3 mL of dichloromethane, 3 mL of trifluoroacetic acid was added, the mixture was stirred at room temperature for 2 h, concentrated to dryness under reduced pressure, the pH was adjusted to basic with saturated aqueous Na2CO3, extracted twice with DCM, the organic layers were combined, washed once with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated to dryness under reduced pressure to give a white solid, 30 The resulting product was dissolved in 5 mL of dichloromethane, and 1-[2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxy-2,3-dihydro-1H-isoindol-5-yl]-piperidine-4-carboxaldehyde (30 mg, 0.078 mmol) was added. 0.5 drops of acetic acid were added, and the mixture was reacted at room temperature for 15 minutes. Sodium triacetylborohydride (106 mg, 0.5 mmol) was added, and the mixture was reacted at room temperature overnight. The mixture was washed with water and reduced to dryness. TIFF0007603609000516.tif9153-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-6-(2-((1-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)methyl)-2,7-diazaspiro[3.5]non- TIFF0007603609000517.tif91514%. LC / MS(ESI+)calcd for C 45 H 46 D3ClFN9O6([M+H] + )m / e 869.3, 1 H NMR TIFF0007603609000518.tif18157TIFF0007603609000519.tif35158(m,1H).

[0180] TIFF0007603609000520.tif9152)-6-(6-((1R,5S,6s)-3-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)-3-azabicyclo[3.1.0]n-hexan-6-yl)methyl)-2,6-diazaspiro[3.3]heptan-2-yl)pyridazine-3-carboxamide TIFF0007603609000521.tif581261. Synthesis of 6-(6-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)carbamoyl)pyridazin-3-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester 2,6-Diazaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester TIFF0007603609000522.tif10153r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)pyridazine-3-carboxamide (196 mg, 0.5 mmol) was added and the mixture was reacted at 80 °C for 3 h. The mixture was cooled to room temperature, 15 mL of ethyl acetate was added, and the mixture was washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure. The mixture was separated by thin layer chromatography to obtain the product 6-(6-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)carbamoyl)pyridazin-3-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester (220 mg) in a 79.6% yield. LC / MS (ESI+) calculation for C 28 H 33 ClNO([M+H] + )m / e 553.2. TIFF0007603609000523.tif9149 Synthesis of 6-(6-((1R,5S,6s)-3-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)-3-azabicyclo[3.1.0]n-hexan-6-yl)methyl)-2,6-diazaspiro[3.3]heptan-2-yl)pyridazine-3-carboxamide 6-(6-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)carbamoyl)pyridazin-3-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester (220 mg, 0.4 mmol) was dissolved in 3 mL of dichloromethane, 3 mL of trifluoroacetic acid was added, the mixture was stirred at room temperature for 2 h, concentrated to dryness under reduced pressure, the pH was adjusted to basic with saturated aqueous Na2CO3, extracted twice with DCM, the organic layers were combined, washed once with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated to dryness under reduced pressure to give a white solid. The resulting product (45 mg, 0.1 mmol) was dissolved in 5 mL of dichloromethane, 3-[2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxy-2,3-dihydro-1H-isoindolin-5-yl]-3-aza-bicyclo[3.1.0]hexane-6-formaldehyde (37 mg, 0.096 mmol) was added, 0.5 drops of acetic acid was added, and the mixture was stirred at room temperature for 5 minutes. Sodium triacetylborohydride (212 mg, 1.0 mmol) was added, and the mixture was stirred at room temperature overnight. The mixture was washed with water, concentrated under reduced pressure to dryness, and then analyzed by thin layer chromatography. TIFF0007603609000524.tif9152 (1R,5S,6s)-3-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)-3-azabicyclo[3.1.0]n-hexan-6-yl)methyl)-2,6-diazaspiro[3.3]heptan-2-yl)pyridazine-3-carboxamide (50 mg) was obtained in 60.8% yield. LC / MS (ESI+) calculation for C 42 H 41 ClFN9O6([M+H] + )m / e 822.3, 1 H NMR TIFF0007603609000525.tif42155TIFF0007603609000526.tif10105

[0181] TIFF0007603609000527.tif9151 yl)-6-(4-((1R,5S,6s)-3-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)-3-azabicyclo[3.1.0]n-hexan-6-yl)methyl)-1,4-diaz-1-yl)pyridazine-3-carboxamide TIFF0007603609000528.tif35152For synthesis steps, please refer to 92 LC / MS(ESI+)calcd for C 42 H 43 ClFN9O6([M+H] + )m / e 824.3, 1 H NMR (400 mHz, CDCl3) δ TIFF0007603609000529.tif41152

[0182] TIFF0007603609000530.tif10150)cyclohexyl)-5-(4-((1R,5S,6s)-3-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)-3-azabicyclo[3.1.0]n-hexan-6-yl)methyl)piperazin-1-yl)pyrazine-2-carboxamide TIFF0007603609000531.tif53152TIFF0007603609000532.tif17153Synthesis of acid tert-butyl ester N-Boc piperazine (93 mg, 0.5 mmol) was dissolved in 5 mL of DMF, potassium carbonate (138 mg, 1.0 mmol) and 5-chloro-pyrazine-2-carboxylic acid [4-(4-cyano-3-trifluoromethyl-phenoxy)-cyclohexyl]-amide (142 mg, 0.33 mmol) were added, and the mixture was reacted at 80°C for 3 hours. 15 mL of ethyl acetate was added, and the mixture was washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. TIFF0007603609000533.tif10154-3-Trifluoromethylphenoxy)-cyclohexylcarbamoyl]-2,3,5,6 TIFF0007603609000534.tif915220mg was obtained in a yield of 63.3%. LC / MS(ESI+)C 28 H 33 F3ClN6O4([M+H] + )m / e 574.9. TIFF0007603609000535.tif9149Synthesis of)-5-(4-((1R,5S,6s)-3-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)-3-azabicyclo[3.1.0]n-hexan-6-yl)methyl)piperazin-1-yl)pyrazine-2-carboxamide TIFF0007603609000536.tif17153 ert-butyl ester (120 mg, 0.21 mmol) was dissolved in 3 mL of dichloromethane, 3 mL of trifluoroacetic acid was added, the mixture was stirred at room temperature for 2 h, concentrated to dryness under reduced pressure, the pH was adjusted to basic with saturated aqueous Na2CO3, extracted twice with DCM, the organic layers were combined, washed once with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated to dryness under reduced pressure to give 100 mg of a white solid. The obtained product (49 mg, 0.103 mmol) was dissolved in 5 mL of dichloromethane, and 3-[2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxy-2,3-dihydro-1H-isoindol-5-yl]-3-aza-bicyclo[3.1.0]hexane-6-formaldehyde (39 mg, 0.1 mmol) was added. 0.5 drops of acetic acid were added, and the mixture was stirred at room temperature for 15 minutes. Sodium triacetylborohydride (212 mg, 1.0 mmol) was added, and the mixture was reacted at room temperature overnight. The mixture was washed with water, concentrated under reduced pressure to dryness, and separated by thin-layer chromatography. The yellow solid was obtained. TIFF0007603609000537.tif11155 45 mg of (hydroxy)cyclohexyl)-5-(4-((1R,5S,6s)-3-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)-3-azabicyclo[3.1.0]n-hexan-6-yl)methyl)piperazin-1-yl)pyrazine-2-carboxamide was obtained in 50% yield. LC / MS (ESI+) calculation for C 42 H 41 F4ClNO6([M+H] + )m / e 844.3, 1 H NMR(400mHz,CDCl3)δ8.86(s,1H),8.24 TIFF0007603609000538.tif411530.99(m,1H).

[0183] TIFF0007603609000539.tif9149)cyclohexyl)-6-(4-((1R,5S,6s)-3-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)-3-azabicyclo[3.1.0]n-hexan-6-yl)methyl)piperazin-1-yl)pyridazine-3-carboxamide TIFF0007603609000540.tif53153For synthesis steps, see 94 LC / MS(ESI+)calcd for C 42 H 41 F4ClFN9O6([M+H] + )m / e 844.3, 1 H NMR (400 mHz, CDCl3) δ TIFF0007603609000541.tif37153TIFF0007603609000542.tif18154

[0184] TIFF0007603609000543.tif8150)-5-(6-((1-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)methyl)-2,6-diazaspiro[3.4]octan-2-yl)pyrazine-2-carboxamide TIFF0007603609000544.tif25148N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-5-(2,6-diazaspiro[3.4]octan-2-yl)pyrazine-2-carboxamide (50 mg, 0.11 mmol) was dissolved in 5 mL of dichloromethane, and 1-[2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxy-2,3-dihydro-1H-isoindol-5-yl]-piperidine-4-carboxaldehyde (45 mg, 0.12 mmol) was added. 0.5 drops of acetic acid were added, and the mixture was heated at room temperature. The mixture was reacted at rt for 15 min, sodium triacetylborohydride was added, the mixture was reacted at room temperature overnight, cooled to room temperature, washed with water, concentrated under reduced pressure to dryness, and separated by thin layer chromatography to obtain 35 mg of yellow solid product N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-5-(6-((1-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)methyl)-2,6-diazaspiro[3.4]octan-2-yl)pyrazine-2-carboxamide in a yield of 39.0%. LC / MS (ESI+) calculation for C 43 H 45 ClFN9O6([M+H] + )m / e 837.7.

[0185] TIFF0007603609000545.tif9147yl)-6-(7-(1-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)-2,7-diazaspiro[3.5]non-2-yl)pyridazine-3-carboxamide TIFF0007603609000546.tif62152 For synthesis steps, see 88 Characterization data: LC / MS (ESI+) calculated for C 43 H 45 ClFN9O6([M+H] + )m / e 837.7, 1 H NMR TIFF0007603609000547.tif51155

[0186] TIFF0007603609000548.tif9148 6-(6-((1-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindol-5-yl)piperidin-4-yl)methyl)-2,6-diazaspiro[3.4]octan-2-yl)pyridazine-3-carboxamide TIFF0007603609000549.tif25152 For synthesis steps, see 96. Characterization data: LC / MS (ESI+) C 43 H 45 ClFN9O6([M+H] + )m / e 838.

[0187] TIFF0007603609000550.tif10149)-5-(4-((1R,5S,6s)-3-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)-3-azabicyclo[3.1.0]n-hexan-6-yl)methyl)piperazin-1-yl)pyrazine-2-carboxamide TIFF0007603609000551.tif69154-Butyl ester N-Boc piperazine (140 mg, 0.75 mmol) was dissolved in 5 mL of DMF, anhydrous potassium carbonate (207 mg, 1.5 mmol) was added, and 5-chloro-pyrazine-2-carboxylic acid [4-(4-cyano-3-chloro-phenoxy)-cyclohexyl]-amide (196 mg, 0.5 mmol) was added. The mixture was reacted at 80°C for 3 hours, and 15 mL of ethyl acetate was added. The mixture was washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. TIFF0007603609000552.tif10155-Chloro-4-cyano-phenoxy)-cyclohexylcarbamoyl]-2,3,5,6- TIFF0007603609000553.tif101530mg was obtained in a yield of 46%. LC / MS (ESI+) called for C 27 H 33 ClNO([M+H] + )m / e 540.8. TIFF0007603609000554.tif915Synthesis of 1-5-(4-((1R,5S,6s)-3-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)-3-azabicyclo[3.1.0]n-hexan-6-yl)methyl)piperazin-1-yl)pyrazine-2-carboxamide The methyl ester (130 mg, 0.23 mmol) was dissolved in 3 mL of dichloromethane, 3 mL of trifluoroacetic acid was added, the mixture was stirred at room temperature for 2 h, concentrated to dryness under reduced pressure, the pH was adjusted to basic with saturated aqueous Na2CO3, extracted twice with DCM, the organic layers were combined, washed once with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated to dryness under reduced pressure to give 100 mg of a white solid. The resulting product (45 mg, 0.1 mmol) was dissolved in 5 mL of dichloromethane. The mixture was dissolved in ethanol, and 3-[2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxy-2,3-dihydro-1H-isoindol-5-yl]-3-aza-bicyclo[3.1.0]hexane-6-formaldehyde (37 mg, 0.1 mmol) was added. 0.5 drops of acetic acid were added and the mixture was reacted at room temperature for 15 minutes. Sodium cyanoborohydride (80 mg, 1.3 mmol) was added and the mixture was reacted at room temperature overnight. The mixture was cooled to room temperature, washed with water, concentrated under reduced pressure to dryness, and separated by thin layer chromatography to give a yellow solid. TIFF0007603609000556.tif8153-5-(4-((1R,5S,6s)-3-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindol-5-yl)-3-azabicyclo[3.1.0]n-hexan-6-yl)methyl)piperazin-1-yl)pyrazine-2-carboxamide (20 mg) was obtained in 24.7% yield. LC / MS (ESI+) for C 41 H 41 ClFN9O6([M+H] + )m / e TIFF0007603609000557.tif251543.97(m,1H),3.88(s,2H),3.82(s,3H),3.65-3.53(m,2H),2.73(s,6H),2.58-2.42 TIFF0007603609000558.tif9129

[0188] TIFF0007603609000559.tif9150silyl)-6-(5-((1R,5S,6s)-3-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)-3-azabicyclo[3.1.0]n-hexan-6-yl)methyl)hexahydropyrrole[3,4-c]pyrrol-2(1H)-yl)pyridazine-3-carboxamide TIFF0007603609000560.tif46136LC / MS(ESI+)calcd for C 43 H 44 ClNO([M+H] + )m / e 817.8, 1 H NMR (400 mHz, CDCl3) δ TIFF0007603609000561.tif59154

[0189] TIFF0007603609000562.tif16153-Dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)-3-azabicyclo[3.1.0]n-hexan-6-yl)methyl)piperazin-1-yl)pyridazine-3-carboxamide TIFF0007603609000563.tif581371. Synthesis of 4-(6-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)carbamoyl)pyridazin-3-yl)piperazine-1-carboxylic acid tert-butyl ester N-Boc piperidone (60 mg, 0.38 mmol) was dissolved in 5 mL of DMF, anhydrous potassium carbonate (100 mg, 0.75 mmol) was added, and 6-chloro-pyridazine-3-carboxylic acid [3-(3-chloro-4-cyano-phenoxy)-2,2,4,4-tetramethyl-cyclobutyl]-amide (105 mg, 0.25 mmol) was added. The mixture was reacted at 80 ° C for 3 h, and 15 mL of ethyl acetate was added. The mixture was washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to dryness. The mixture was separated by thin layer chromatography to obtain the product 4-(6-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)carbamoyl)pyridazin-3-yl)piperazine-1-carboxylic acid tert-butyl ester 85 mg in a yield of 59.7%. LC / MS(ESI+)calcd for C 29 H 37 ClNO([M+H] + )m / e 568.9. 2. N-((1r,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-6-(4-((1R,5S,6s)-3-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)-3-azabicyclo[3.1.0]n-hexan-6-yl)methyl)piperazin-1-yl)pyridazine-3-carboxamide 4-(6-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)carbamoyl)pyridazin-3-yl)piperazine-1-carboxylic acid tert-butyl ester (85 mg, 0.15 mmol) was dissolved in 3 mL of dichloromethane, 3 mL of trifluoroacetic acid was added, the mixture was stirred at room temperature for 2 h, concentrated to dryness under reduced pressure, the pH was adjusted to basic with saturated aqueous Na2CO3, extracted twice with DCM, the organic layers were combined, washed once with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated to dryness under reduced pressure to give a white solid, 70 The resulting product (35 mg, 0.07 mmol) was dissolved in 5 mL of dichloromethane, 3-[2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxy-2,3-dihydro-1H-isoindol-5-yl]-3-aza-bicyclo[3.1.0]hexane-6-formaldehyde (30 mg, 0.077 mmol) was added, 0.5 drops of acetic acid were added, and the mixture was reacted at room temperature for 15 minutes. Sodium triacetylborohydride (224 mmol, 1.0 mmol) was added, and the mixture was reacted at room temperature overnight. The mixture was cooled to room temperature, washed with water, and concentrated under reduced pressure to dryness. TIFF0007603609000564.tif9152 20 mg of (1R,5S,6s)-3-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)-3-azabicyclo[3.1.0]n-hexan-6-yl)methyl)piperazin-1-yl)pyridazine-3-carboxamide was obtained in 34% yield. LC / MS (ESI+) for C 43 H 45 ClFN9O6([M+H] + )m / e 837.7, 1 H TIFF0007603609000565.tif26153TIFF0007603609000566.tif25152

[0190] TIFF0007603609000567.tif9148sil)-6-(4-((1R,5S,6s)-3-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)-3-azabicyclo[3.1.0]n-hexan-6-yl)methyl)piperazin-1-yl)pyridazine-3-carboxamide TIFF0007603609000568.tif47128LC / MS(ESI+)for C 41 H 42 ClNO([M+H] + )m / e 791.7, 1 H NMR (400 mHz, CDCl3) δ 8.26 TIFF0007603609000569.tif411531.42(m,3H).

[0191] TIFF0007603609000570.tif9146sil)-6-(4-(6-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)-2,6-diazaspiro[3.4]octyl-2-yl)piperidin-1-yl)pyridazine-3-carboxamide TIFF0007603609000571.tif461501.Synthesis of 6-(4-hydroxypiperidin-1-yl)-pyridazine-3-carboxylic acid [4-(3-chloro-4-cyano-phenoxy)-cyclohexyl]-amide Piperidin-4-ol (100 mg, 1.0 mmol) was dissolved in 5 mL of DMF, anhydrous potassium carbonate (415 mg, 3.0 mmol) was added, and 5-chloro-pyridazine-2-carboxylic acid [4-(4-cyano-3-chloro-phenoxy)-cyclohexyl]amide (390 mg, 1.0 mmol) was added. The mixture was reacted at 80 °C for 3 hours, and 15 mL of ethyl acetate was added. The mixture was washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure. The product was separated by thin layer chromatography to obtain 310 mg of the product 6-(4-hydroxypiperidin-1-yl)-pyridazine-3-carboxylic acid [4-(3-chloro-4-cyano-phenoxy)-cyclohexyl]amide in 68.3% yield. LC / MS (ESI+) calculation for C 23 H 26 ClNO3([M+H] + )m / e 455.9. 2.6-(4-oxopiperidin-1-yl)-pyridazine-3-carboxylic acid [4-(3-chloro-4-cyano-phenoxy)-cyclohexyl]-amide 6-(4-Hydroxypiperidin-1-yl)-pyridazine-3-carboxylic acid [4-(3-chloro-4-cyano-phenoxy)-cyclohexyl]amide (250 mg, 0.55 mmol) was dissolved in 10 mL of dichloromethane, and Dess-Martin oxidant (280 mg, 0.66 mmol) was added. The mixture was stirred at room temperature for 3 hours, filtered, and the filtrate was concentrated under reduced pressure to dryness. The product was separated by thin layer chromatography to obtain 180 mg of the product 6-(4-oxopiperidin-1-yl)-pyridazine-3-carboxylic acid [4-(3-chloro-4-cyano-phenoxy)-cyclohexyl]amide in 72% yield. LC / MS (ESI+) calculation for C 23 H 24 ClNO3([M+H] + )m / e 453.9. TIFF0007603609000572.tif8148-6-(4-(6-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)-2,6-diazaspiro[3.4]octyl-2-yl)piperidin-1-yl)pyridazine-3-carboxamide 6-(4-oxopiperidin-1-yl)-pyridazine-3-carboxylic acid [4-(3-chloro-4-cyano-phenoxy)-cyclohexyl]-amide (46 mg, 0.1 mmol), 5-(2,6-diazaspiro[3.4]oct-6-yl)-2-(2,6-dioxopiperidin-3-yl)-6-fluoroisoindoline-1,3-dione were dissolved in 5 mL of dichloromethane, and one drop of acetic acid was added. The mixture was reacted at room temperature for 15 minutes. Sodium cyanoborohydride (80 mg, 1.3 mmol) was added and the mixture was reacted at room temperature overnight. The mixture was cooled to room temperature, washed with water, concentrated under reduced pressure to dryness, and separated by thin layer chromatography. The yellow solid was obtained. TIFF0007603609000573.tif8154)-6-(4-(6-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)-2,6-diazaspiro[3.4]octyl-2-yl)piperidin-1-yl)pyridazine-3-carboxamide 16 mg was obtained in 19.5% yield. LC / MS (ESI+) for C 42 H 43 ClFN9O6([M+H] + )m / e 823.8, 1 H NMR(400mHz,CDCl3)δ8.14-8.06(m,1H),8.06-8.01(m,1H),7.91-7.85(m,1H),7.61 TIFF0007603609000574.tif35154

[0192] TIFF0007603609000575.tif9150silyl)-5-(4-((1R,5S,6s)-3-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)-3-azabicyclo[3.1.0]n-hexan-6-yl)methyl)piperazin-1-yl)pyrazine-2-carboxamide TIFF0007603609000576.tif48142LC / MS(ESI+)m / e 791.8 for C 42 H 43 ClNO([M+H] + ). 1 H NMR(400mHz,CDCl3)δ8.88(s,1H),8.34-8.24(m,1H),8.04-7.96(m,1H),7.72-7.64(m,1H),7 .62-7.55(m,1H),7.47-7.38(m,1H),7.02(s,1H),6.99-6.93(m,1H),6.90-6.83(m,1H),6.74 TIFF0007603609000577.tif251521.45(m,3H).

[0193] TIFF0007603609000578.tif8149sil)-5-(7-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)methyl)-2,7-diazaspiro[3.5]non-2-yl)-1,3,4-thiadiazole-2-carboxamide TIFF0007603609000579.tif401501.Synthesis of ethyl 5-(7-(tert-butoxycarbonyl)-2,7-diazaspiro[3.5]non-2-yl)-1,3,4-thiadiazole-2-carboxylate 2,7-Diazaspiro[3.5]nonane-7-carboxylic acid tert-butyl ester (249 mg, 1.1 mmol) was dissolved in 6 mL of DMF, and anhydrous potassium carbonate (416 mg, 3.0 mmol) and 5-chloro-1,3,4-thiadiazole-2-carboxylic acid ethyl ester (193 mg, 1.0 mmol) were added. The mixture was reacted at 80 °C for 1.5 h, cooled to room temperature, and 20 mL of ethyl acetate was added. The mixture was washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure. The product was separated by thin-layer chromatography to obtain 295 mg of the product, ethyl 5-(7-(tert-butoxycarbonyl)-2,7-diazaspiro[3.5]non-2-yl)-1,3,4-thiadiazole-2-carboxylic acid ester, in a 79.9% yield. LC / MS (ESI+) analysis called for C 17 H 26 N2O2S([M+H] + )m / e 369.1. Synthesis of 2,5-(2,7-diazaspiro[3.5]non-2-yl)-[1,3,4]thiadiazole-2-carboxylic acid [4-(3-chloro-4-cyano-phenoxy)-cyclohexyl]-amide 4-(4-aminocyclohexyloxy)-2-chloro-benzonitrile (210 mg, 0.84 mmol) was dissolved in 5 mL of methanol, and tert-butyl 2-(5-ethoxycarbonyl-[1,3,4]thiadiazol-2-yl)-2,7-diazaspiro[3.5]one-7-carboxylate (268 mg, 0.7 mmol) was added. The mixture was refluxed at 85° C. overnight, and separated by thin layer chromatography to obtain 360 mg of a white solid product. This product was dissolved in 5 mL of dichloromethane and added with 3 mL of trifluoromethane. Acetic acid was added, and the mixture was stirred at room temperature for 2.5 h. The mixture was concentrated under reduced pressure to dryness, the pH was adjusted to basic with saturated aqueous Na2CO3, and extracted twice with DCM. The organic layers were combined, washed once with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to dryness to give 290 mg of white solid product, 5-(2,7-diazaspiro[3.5]non-2-yl)-[1,3,4]thiadiazole-2-carboxylic acid [4-(3-chloro-4-cyano-phenoxy)-cyclohexyl]-amide, in 85% yield. LC / MS (ESI+) analysis of C 23 H 27 ClNOS([M+H] + )m / e 487.1. TIFF0007603609000580.tif9147-Synthesis of 5-(7-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)methyl)-2,7-diazaspiro[3.5]non-2-yl)-1,3,4-thiadiazole-2-carboxamide 5-(2,7-diazaspiro[3.5]non-2-yl)-[1,3,4]thiadiazole-2-carboxylic acid [4-(3-chloro-4-cyano-phenoxy)-cyclohexyl]-amide (49 mg, 0.1 mmol), 1-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxy-2,3-dihydro-1H-isoindol-5-yl]-piperidine-4-acetaldehyde (37 mg, 0.1 mmol) were added to a round-bottom flask, 5 mL of dichloromethane was added, and one drop of acetic acid was added to catalyze the reaction. Under argon protection, the mixture was stirred at room temperature for 10 min, sodium triacetylborohydride (212 mg, 1.0 mmol) was added, and the mixture was reacted at room temperature for 3 h. The organic layer was washed twice with water, washed once with saturated brine, dried over anhydrous sodium sulfate, concentrated to dryness under reduced pressure, and analyzed by thin-layer chromatography. TIFF0007603609000581.tif9152 45 mg of (cyclohexyl)-5-(7-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)methyl)-2,7-diazaspiro[3.5]non-2-yl)-1,3,4-thiadiazole-2-carboxamide was obtained in 53.6% yield. LC / MS (ESI+) C 42 H 46 ClNOS([M+H] + )m / e 840.3. TIFF0007603609000582.tif42153

[0194] TIFF0007603609000583.tif7149sil)-5-(7-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)-2,7-diazaspiro[3.5]non-2-yl)pyrimidine-2-carboxamide TIFF0007603609000584.tif461521.Synthesis of 2-{2-[4-(3-chloro-4-cyano-phenoxy)-cyclohexylcarbamoyl]-pyrimidin-5-yl}-2,7-diaza-spiro[3.5]nonane-7-carboxylic acid tert-butyl ester 5-Bromo-pyrimidine-2-carboxylic acid [4-(3-chloro-4-cyano-phenoxy)-cyclohexyl]-amide (109 mg, 0.25 mmol) was dissolved in 5 mL of 1,4-dioxane, and 2,7-diazaspiro[3.5]nonane-7-carboxylic acid tert-butyl ester (57 mg, 0.25 mmol), BINAP (8 mg, 12.5 μmol), Cs2CO3 (163 mg, 0.5 mmol), and Pd(OAc)2 (3 mg, 125 μmol) were added. The mixture was refluxed at 110 °C overnight under the protection of methylpropanol, 15 mL of ethyl acetate was added, washed three times with 10 mL of water, washed once with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure to dryness, and separated by thin layer chromatography to obtain the product 2-{2-[4-(3-chloro-4-cyano-phenoxy)-cyclohexylcarbamoyl]-pyrimidin-5-yl}-2,7-diaza-spiro[3.5]nonane-7-carboxylic acid tert-butyl ester (100 mg) in 68.9% yield. LC / MS (ESI+) calculated for C 30 H 37 ClNO([M+H] + )m / e 580.9. Synthesis of 2,4-(2-{2-[4-(3-chloro-4-cyano-phenoxy)-cyclohexylcarbamoyl]-pyrimidin-5-yl}-2,7-diaza-spiro[3.5]non-7-yl)-piperidine-1-carboxylic acid tert-butyl ester 2-{2-[4-(3-chloro-4-cyano-phenoxy)-cyclohexylcarbamoyl]-pyrimidin-5-yl}-2,7-diaza-spiro[3.5]nonane-7-carboxylic acid tert-butyl ester (100 mg, 0.17 mmol) was dissolved in 5 mL of dichloromethane, 3 mL of trifluoroacetic acid was added, the mixture was stirred at room temperature for 3 h, concentrated to dryness under pressure, the pH was adjusted to basic with saturated aqueous Na2CO3, extracted twice with DCM, the organic layers were combined, washed once with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated to dryness under reduced pressure to give 80 mg of a white solid. The resulting product (78 mg, 0.16 mmol) was dissolved in 5 mL of dichloromethane, 4-Boc piperidone (199 mg, 0.98 mmol) was added, 0.5 drops of acetic acid was added, the mixture was refluxed at 40 ° C for 1 h, cooled to room temperature, sodium triacetylborohydride (424 mg, 2.0 mmol) was added, the mixture was refluxed at 40 ° C for 5 h, cooled to room temperature, washed with water, concentrated under reduced pressure to dryness, and separated by thin layer chromatography to obtain the product 4-(2-{2-[4-(3-chloro-4-cyano-phenoxy)-cyclohexylcarbamoyl]-pyrimidin-5-yl}-2,7-diaza-spiro[3.5]non-7-yl)-piperidine-1-carboxylic acid tert-butyl ester (50 mg) in a yield of 47.0%. LC / MS (ESI+) called for C 35 H 46 ClNO([M+H] + )m / e 664.3. TIFF0007603609000585.tif8149-Synthesis of 5-(7-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoamylalcohol-5-yl)piperidin-4-yl)-2,7-diazaspiro[3.5]non-2-yl)pyrimidine-2-carboxamide 4-(2-{2-[4-(3-chloro-4-cyano-phenoxy)-cyclohexylcarbamoyl]-pyrimidin-5-yl}-2,7-diaza-spiro[3.5]non-7-yl)-piperidine-1-carboxylic acid tert-butyl ester (50 mg, 0.075 mmol) was dissolved in 3 mL of dichloromethane, 3 mL of trifluoroacetic acid was added, the mixture was stirred at room temperature for 2 h, and the mixture was concentrated under reduced pressure to dryness. Dichloromethane was added, and the mixture was concentrated under reduced pressure twice. 3 mL of DMSO, 0.5 mL of DIEA, and 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindole-1,3-dione (30 mg, 0.11 mmol) were added, and the mixture was refluxed at 135°C for 1.5 hours. The mixture was cooled to room temperature, and 10 mL of dichloromethane was added. The mixture was washed twice with 10 mL of water and once with saturated brine, dried over anhydrous sodium sulfate, and evaporated to dryness. TIFF0007603609000586.tif71504r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-5-(7-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)-2,7-diazaspiro[3.5]non-2-yl)pyrimidine-2-carboxamide (26 mg) was obtained in 42.3% yield. LC / MS (ESI+) m / e TIFF0007603609000587.tif49152

[0195] 107: N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-5-(7-((1-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)-1,3,4-thiadiazole-2-carboxamide TIFF0007603609000588.tif23153 For synthesis steps, see 105. Characterization data: LC / MS(ESI+) m / e 858.3 for C 42 H 45 ClFN9O6S([M+H] + ), 1 H NMR TIFF0007603609000589.tif41155TIFF0007603609000590.tif8104

[0196] TIFF0007603609000591.tif7149-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)pyridazine-3-carboxamide TIFF0007603609000592.tif411521)2-Chloro-4-formylbenzonitrile 4-Bromo-2-chloro-benzonitrile (5.0 g, 23.1 mmol) was dissolved in 10 mL of anhydrous tetrahydrofuran. Under argon protection, in an ice-water bath, 15 mL of 2N isopropylmagnesium bromide / THF solution was added dropwise. After the addition was completed, the mixture was stirred for 1 hour and kept warm. Piperidine-1-acetaldehyde (7.75 g, 68.5 mmol) was added and the mixture was kept warm for 2 hours. 15 mL of saturated aqueous ammonium chloride was added to the mixture to quench the reaction. The mixture was extracted with 20 mL of ethyl acetate. The aqueous layer was back-extracted once with 20 mL of ethyl acetate. The organic layers were combined, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to dryness. The mixture was purified by column chromatography to obtain 2.22 g of the product, 2-chloro-4-formylbenzonitrile, in a 58% yield. 2) (1-(3-chloro-4-cyanobenzene)piperidin-4-yl) tert-butylcarbamate 2-Chloro-4-formylbenzonitrile (820 mg, 5.0 mmol) and piperidine-4-tert-butylylcarbamate (1.0 g, 5.0 mmol) were dissolved in 15 mL of anhydrous methanol, two drops of acetic acid were added, and the mixture was reacted at 60 °C for 1 h. The mixture was cooled to room temperature, sodium cyanoborohydride (942 mg, 15 mmol) was added, and the mixture was reacted overnight. 20 mL of acetone was added, and the mixture was stirred for 20 min. The mixture was concentrated under reduced pressure to dryness. 20 mL of ethyl acetate was added, and the mixture was washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to dryness. The mixture was purified by column chromatography to obtain 680 mg of the product (1-(3-chloro-4-cyanobenzene)piperidin-4-yl) tert-butylcarbamate in a 38.9% yield. LC / MS (ESI+) analysis of the product (C) was performed. 18 H 24 ClN3O2([M+H] + )m / e 350.2. TIFF0007603609000593.tif7151)pyridazine-3-carboxamide (1-(3-chloro-4-cyanobenzene)piperidin-4-yl) tert-butylcarbamate (370 mg, 0.95 mmol) was dissolved in 10 mL of dichloromethane, 8 mL of trifluoroacetic acid was added, the mixture was stirred at room temperature for 2 h, concentrated under reduced pressure to dryness, the pH was adjusted to basic with saturated aqueous Na2CO3, extracted with ethyl acetate, the organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to dryness to give 230 mg of product. 6-Chloropyridine-3-carboxylic acid (145 mg, 0.91 mmol) was dissolved in 5 mL of dichloromethane. TIFF0007603609000594.tif8151Add HATU (533 mg, 1.38 mmol) in an ice-water bath, dissolve the compound from the previous step in 5 mL of dichloromethane, add dropwise to the reaction system, and after the addition is complete, slowly warm to room temperature and react for 2 hours. Then, wash with saturated aqueous ammonium chloride and saturated brine, dry over anhydrous magnesium sulfate, filter, and concentrate under reduced pressure to dryness. TIFF0007603609000595.tif8150 200 mg of phenyl)piperidin-4-yl)pyridazine-3-carboxamide was obtained in a yield of 53.7%. LC / MS (ESI+) called for C 18 H 17 Cl2NO([M+H] + )m / e 390. 4) 4-((1-(6-((1-(3-chloro-4-cyanobenzene)piperidin-4-yl)carbamoyl)pyridazin-3-yl)piperidin-4-yl)methyl)piperazine-1-carboxylic acid tert-butyl ester 4-(Piperidin-4-ylmethyl)piperazine-1-carboxylic acid tert-butyl ester (71 mg, 0.25 mmol) was dissolved in 5 mL of DMF, and anhydrous potassium carbonate (102 mg, 0.75 mmol) and 6-chloro-N-(1-(3-chloro-4-cyanobenzene)piperidin-4-yl)pyridazine-3-carboxamide (100 mg, 0.25 mmol) were added, and the mixture was reacted at 80° C. for 3 hours. The mixture was cooled to room temperature and added to 20 mL of DMF. Ethyl acetate was added, and the mixture was washed with water and saturated brine, respectively, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to dryness, and separated by thin layer chromatography to obtain the product 4-((1-(6-((1-(3-chloro-4-cyanobenzene)piperidin-4-yl)carbamoyl)pyridazin-3-yl)piperidin-4-yl)methyl)piperazine-1-carboxylic acid tert-butyl ester 140 mg in 87.9% yield. LC / MS (ESI+) called for C 33 H 45 ClNO3([M+H] + )m / e 637.3. TIFF0007603609000596.tif8149-((4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)pyridazine-3-carboxamide 4-((1-(6-((1-(3-chloro-4-cyanobenzene)piperidin-4-yl)carbamoyl)pyridazin-3-yl)piperidin-4-yl)methyl)piperazine-1-carboxylic acid tert-butyl ester (75 mg, 0.12 mmol) was dissolved in 3 mL of dichloromethane, 2 mL of trifluoroacetic acid was added, the mixture was stirred at room temperature for 2 hours, and the mixture was concentrated under reduced pressure until dryness. 5 mL of DMSO, 0.8 mL of DIEA, and 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (60 mg, 0.22 mmol) were added, and the mixture was reacted at 140°C for 3 hours. The mixture was cooled to room temperature, 15 mL of dichloromethane was added, the mixture was washed twice with saturated ammonium chloride, washed once with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure until dryness. The resulting mixture was purified by thin layer chromatography. TIFF0007603609000597.tif81504-yl)-6-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)pyridazine-3-carboxamide 42 mg was obtained in 44.1% yield. LC / MS (ESI+) for C 41 H 45 ClN 10 O5([M+H] + )m / e 793.3, 1 H NMR(400mHz,CDCl3)δ8.12(s,1H),7.97 TIFF0007603609000598.tif48152

[0197] TIFF0007603609000599.tif7150-2-yl)-6-(4-((4-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)piperidin-1-yl)pyridazine-3-carboxamide TIFF0007603609000600.tif52155LC / MS(ESI+)for C 42 H 44 ClNO([M+H] + )m / e 806.2, 1H NMR (400 mHz, CDCl3) δ 8.09 TIFF0007603609000601.tif60157

[0198] TIFF0007603609000602.tif9152oxyl)-6-(4-((3S)-1-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)pyrrolidin-3-yl)oxy)piperidin-1-yl)pyridazine-3-carboxamide TIFF0007603609000603.tif51150LC / MS(ESI+)calcd for C 40 H 40 ClFN8O7([M+H] + )m / e 799.2, 1 H NMR (400 mHz, CDCl3) δ TIFF0007603609000604.tif16153TIFF0007603609000605.tif26154

[0199] TIFF0007603609000606.tif181521,3-Dioxoisoindolin-5-yl)pyrrolidin-3-yl)oxy)piperidin-1-yl)benzamide TIFF0007603609000607.tif50148(R)oxy)pyrrolidine-1-carboxylic acid tert-butyl ester TIFF0007603609000608.tif9151 The diol ester (260 mg, 0.96 mmol) was dissolved in 5 mL of DMSO, potassium carbonate (420 mg, 3.0 mmol) and methyl p-fluorobenzoate (308 mg, 2.0 mmol) were added, and the mixture was reacted at 100°C for 3 hours. After cooling to room temperature, 15 mL of ethyl acetate was added, and the mixture was washed with water and brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to dryness. TIFF0007603609000609.tif9152-(Methoxycarbonyl)phenyl)piperidin-4-yl)oxy)pyrrolidine-1-carboxylic acid tert-butyl ester 130 mg was obtained in a yield of 33.5%. LC / MS (ESI+) called for C 22 H 32 N2O5([M+H] + )m / e 405.3. TIFF0007603609000610.tif9150Oxy)cyclohexyl)carbamoyl)phenyl)piperidin-4-yl)oxy)pyrrolidine-1-carboxylic acid tert-butyl ester TIFF0007603609000611.tif8149 (oxy)pyrrolidine-1-carboxylic acid tert-butyl ester (130 mg, 0.32 mmol) was dissolved in 5 mL of tetrahydrofuran, 5 mL of 2N aqueous NaOH was added, and the mixture was stirred at room temperature overnight. The pH was adjusted to 5 with 0.5N HCl, 15 mL of ethyl acetate was added, and the mixture was washed with water and brine, dried over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure to obtain the product. The mixture was dissolved in 5 mL of dichloromethane, DIEA (101 mg, 1.0 mmol) and HATU (141 mg, 0.37 mmol) were added, and the mixture was stirred at room temperature for 10 min. 4-(((1r,4r)-4-aminocyclohexyl)oxy)-2-chlorobenzonitrile (80 mg, 0.32 mmol) was added, and the mixture was reacted at room temperature overnight. The mixture was washed with saturated aqueous ammonium chloride, water, and saturated brine, dried over anhydrous sodium sulfate, and concentrated to dryness. TIFF0007603609000612.tif21157 160 mg of (xyl)carbamoyl)phenyl)piperidin-4-yl)oxy)pyrrolidine-1-carboxylic acid tert-butyl ester was obtained in a yield of 80.26%. LC / MS (ESI+) called for C 34 H 43 ClN4O5([M+H] + )m / e 623.2. TIFF0007603609000613.tif17152-Dioxoisoindolin-5-yl)pyrrolidin-3-yl)oxy)piperidin-1-yl)benzamide TIFF0007603609000614.tif10152 Cyanophenoxy)cyclohexyl)carbamoyl)phenyl)piperidin-4-yl)oxy)pyrrolidine-1-carboxylate (50 mg, 0.080 mmol) was dissolved in 3 mL of dichloromethane, 2 mL of trifluoroacetic acid was added, the mixture was stirred at room temperature for 2 hours, and concentrated under reduced pressure until dry. 5 mL of DMSO, 0.8 mL of DIEA, and 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindole-1,3-dione (23 mg, 0.080 mmol) were added, and the mixture was reacted at 140°C for 3 hours. The mixture was cooled to room temperature, 15 mL of dichloromethane was added, and the mixture was washed twice with saturated ammonium chloride and once with saturated brine, dried over anhydrous magnesium sulfate, filtered, concentrated under reduced pressure until dry, and purified by thin layer chromatography. TIFF0007603609000615.tif18153 36 mg of (1,3-dioxoisoindolin-5-yl)pyrrolidin-3-yl)oxy)piperidin-1-yl)benzamide was obtained in 57.8% yield. LC / MS (ESI+) for C 42 H 43 ClN6O7([M+H] + )m / e 779.2, 1 H NMR(400mHz,CDCl3)δ8.13(s,1H),7.67 TIFF0007603609000616.tif53155(m,3H).

[0200] TIFF0007603609000617.tif171546-Fluoro-1,3-dioxoisoindolin-5-yl)-2,7-diazaspiro[3.5]non-7-yl)methyl)cyclohexyl)-1H-imidazole-4-carboxamide TIFF0007603609000618.tif61150-1H-imidazole-4-carboxamide 1H-Imidazole-4-carboxylic acid (448 mg, 4.0 mmol) was dissolved in 10 mL of DMF, DIEA (1.03 g, 8.0 mmol) and HATU (1.52 g, 4.0 mmol) were added, and the mixture was stirred at room temperature for 30 min. 4-((1r,4r)-4-aminocyclohexyl)oxy)-2-chlorobenzonitrile (1.0 g, 4.0 mmol) was added, and the mixture was stirred at room temperature overnight. 25 mL of ethyl acetate was added, and the mixture was washed with 20 mL of water. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness under reduced pressure. TIFF0007603609000619.tif9152-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-1H-imidazole-4-carboxamide (610 mg) was obtained in a yield of 44.2%. LC / MS (ESI+) called for C 17 H 17 ClNO2([M+H] + )m / e 345.1. TIFF0007603609000620.tif8151)Cyclohexyl)carbamoyl)-1H-imidazol-1-yl)cyclohexane-1-carboxylic acid methyl ester TIFF0007603609000621.tif81511H-Imidazole-4-carboxamide (345 mg, 1.0 mmol) was dissolved in 6 mL of DMF, cesium carbonate (975 mg, 3.0 mmol) was added, and the mixture was stirred at room temperature for 5 minutes. Methyl (1r,4r)-4-((methylsulfonyl)oxy)cyclohexane-1-carboxylate (354 mg, 4.5 mmol) was added, and the mixture was reacted at 95°C overnight. 25 mL of ethyl acetate was added, and the mixture was washed with 20 mL of water. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to dryness. The resulting mixture was analyzed by thin-layer chromatography. TIFF0007603609000622.tif9152-4-(3-chloro-4-cyanophenoxy)cyclohexyl)carbamoyl)-1H-imidazol-1-yl)cyclohexane-1-carboxylic acid methyl ester 130 mg was obtained in a yield of 26.8%. LC / MS (ESI+) called for C 25 H 29ClN4O4([M+H] + )m / e 485.3. TIFF0007603609000623.tif18151 4-carboxamide TIFF0007603609000624.tif10149)Cyclohexyl)carbamoyl)-1H-imidazol-1-yl)cyclohexane-1-carboxylic acid methyl ester (130 mg, 0.27 mmol) was dissolved in 5 mL of tetrahydrofuran, 4 mL of methanol and sodium borohydride (76 mg, 2.0 mmol) were added, and the mixture was reacted at 70°C overnight. The mixture was concentrated under reduced pressure until dryness was achieved, 10 mL of ethyl acetate was added, the mixture was washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, and then evaporated to dryness. TIFF0007603609000625.tif18153-4-(hydroxymethyl)cyclohexyl)-1H-imidazole-4-carboxamide (54 mg) was obtained in a yield of 43.8%. LC / MS (ESI+) calculation for C 24 H 29 ClNO 43 ([M+H] + )m / e 457.3. TIFF0007603609000626.tif11150TIFF0007603609000627.tif9153Voxamide TIFF0007603609000628.tif17154-4-carboxamide (54 mg, 0.12 mmol) was dissolved in 5 mL of dichloromethane, and Dess-Martin oxidant (102 mg, 0.24 mmol) was added. The mixture was stirred at room temperature for 1 TIFF0007603609000629.tif17154 45 mg of (Irurylcyclohexyl)-1H-imidazole-4-carboxamide was obtained in 84.5% yield. LC / MS (ESI+) called for C 24 H 27 ClN4O3([M+H] + )m / e 455.2. TIFF0007603609000630.tif17154)fluoro-1,3-dioxoisoindol-5-yl-2,7-diazaspiro[3.5]non-7-yl)methyl)cyclohexyl)-1H-imidazole-4-carboxamide TIFF0007603609000631.tif18154 Dioxamide (30 mg, 0.066 mmol) and 2-(2,6-dioxopiperidin-3-yl)-5-fluoro-6-(2,7-diazaspiro[3.5]non-2-yl)isoindoline-1,3-dione (26 mg, 0.066 mmol) were dissolved in 5 mL of dichloromethane, 0.5 drops of acetic acid were added, and the mixture was stirred at room temperature for 10 min. Sodium triacetylborohydride (212 mg, 1.0 mmol) was added, and the mixture was stirred at room temperature for 3 h. The mixture was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to dryness. Thin-layer chromatography (TLC) was performed. TIFF0007603609000632.tif18153 16 mg of (isopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)-2,7-diazaspiro[3.5]non-7-yl)methyl)cyclohexyl)-1H-imidazole-4-carboxamide was obtained in 28.9% yield. LC / MS (ESI+) for TIFF0007603609000633.tif26154TIFF0007603609000634.tif17155(m,3H),1.29(s,2H),1.17(s,2H).

[0201] TIFF0007603609000635.tif17153)-1,3-dioxoisoindolin-5-yl)-2,7-diazaspiro[3.5]non-7-yl)methyl)cyclohexyl)-1H-imidazole-4-carboxamide TIFF0007603609000636.tif17153 Dioxamide (15 mg, 0.033 mmol) and 2-(2,6-dioxopiperidin-3-yl)-5-fluoro-6-(2,7-diazaspiro[3.5]non-2-yl)isoindole-1,3-dione (13 mg, 0.033 mmol) were dissolved in 5 mL of dichloromethane, 0.3 drops of acetic acid were added, and the mixture was stirred at room temperature for 10 min. Sodium triacetylborohydride (106 mg, 0.5 mmol) was added, and the mixture was stirred at room temperature for 3 h. The mixture was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated to dryness under reduced pressure. Thin-layer chromatography (TLC) was performed. TIFF0007603609000637.tif26153-Diazaspiro[3.5]non-7-yl)methyl)cyclohexyl)-1H-imidazole-4-carboxamide (13 mg) was obtained in 47.0% yield. LC / MS (ESI+) for TIFF0007603609000638.tif50154

[0202] TIFF0007603609000639.tif16153)-1,3-dioxoisoindolin-5-yl)-2,7-diazaspiro[3.5]non-7-yl)methyl)cyclohexyl)-1H-1,2,3-triazole-4-carboxamide TIFF0007603609000640.tif103156 For synthesis steps, please refer to 112 Characterization data: LC / MS (ESI+) for C 43 H 48 ClNO([M+H] + )m / e 822.3, 1 H NMR TIFF0007603609000641.tif42154

[0203] TIFF0007603609000642.tif181536-Fluoro-1,3-dioxoisoindolin-5-yl)-2,7-diazaspiro[3.5]non-7-yl)methyl)cyclohexyl)-1H-1,2,3-triazole-4-carboxamide LC / MS(ESI+) for C43 H 47 ClFN9O6([M+H] + )m / e 840.3, 1 H NMR (400 mHz, CDCl3) δ 8.10 TIFF0007603609000643.tif7152TIFF0007603609000644.tif35154

[0204] TIFF0007603609000645.tif17154)-1,3-dioxoisoindolin-5-yl)-2,7-diazaspiro[3.5]non-7-yl)methyl)cyclohexyl)-2H-1,2,3-triazole-4-carboxamide LC / MS(ESI+) for C 43 H 48 ClNO([M+H] + )m / e 822.3, 1 H NMR (400 mHz, CDCl3) δ 8.09- TIFF0007603609000646.tif431561.43(m,2H),1.25(s,3H).

[0205] TIFF0007603609000647.tif171556-Fluoro-1,3-dioxoisoindolin-5-yl)-2,7-diazaspiro[3.5]non-7-yl)methyl)cyclohexyl)-2H-1,2,3-triazole-4-carboxamide LC / MS(ESI+) for C 43 H 47 ClFN9O6([M+H] + )m / e 840.3, 1 H NMR (400 mHz, CDCl3) δ 8.03 TIFF0007603609000648.tif42153

[0206] TIFF0007603609000649.tif10153Synthesis of)-6-(4-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)amino)piperidin-1-yl)pyridazin-3-amide TIFF0007603609000650.tif71147-6-(4-(tert-butoxyamido-piperidin-1-yl)pyridazin-3-amide TIFF0007603609000651.tif8151)-6-chloropyridazine-3-carboxamide (500 mg, 1.28 mmol), 4-tert-butoxycarbonylaminopiperidine (384 mg, 1.92 mmol), The mixture was added to DOX (TIFF0007603609000652.tif10152), heated to 110°C, and stirred overnight. After cooling to room temperature, water and ethyl acetate were added for extraction. The organic layer was washed three times with saturated ammonium chloride solution and saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed by rotary evaporation. The mixture was then loaded onto a silica gel column. TIFF0007603609000653.tif10153-Chloro-4-cyanophenoxy)cyclohexyl)-6-(4-(tert-butoxyamido)piperidin-4-yl)amino)piperidin-1-yl)pyridazin-3-amide (493 mg, 0.87 mmol) was obtained in 68% yield. LC / MS(ESI+)calcd for C 28 H 35 ClN6O4 + (M+H + ) m / z, 555.2; found555.2. TIFF0007603609000654.tif8149-6-(4-aminopiperidin-4-yl)amino)piperidin-1-yl)pyridazin-3-amide TIFF0007603609000655.tif9151)-6-(4-(tert-butoxyamido)piperidin-4-yl)amino)piperidin-1-yl)pyridazine-3-carboxamide (200 mg, 0.36 mmol) was dissolved in 3 mL of dichloromethane, 6 mL of trifluoroacetic acid was added, the mixture was stirred at room temperature for 2 h, concentrated by distillation under reduced pressure, the pH was adjusted to 10 by adding saturated sodium carbonate solution, and extracted with dichloromethane. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and evaporated by rotary evaporation. TIFF0007603609000656.tif10153)Cyanophenoxy)cyclohexyl)-6-(4-aminopiperidin-4-yl)amino)piperidin-1-yl)pyridazin-3-amide (159 mg, 0.35 mmol) was obtained in 97% yield. LC / MS (ESI+) calculation for C 23 H 27 ClN6O2 + (M+H + ) m / z, 455.2; found 455.2. TIFF0007603609000657.tif9147-6-(4-(4-tert-butyloxyoxoamino-piperidin-1-yl)-(4-aminopiperidin-1-yl)pyridazin-3-amide TIFF0007603609000658.tif8151)-6-(4-aminopiperidin-4-yl)amino)piperidin-1-yl)pyridin TIFF0007603609000659.tif9154 Nyl-4-piperidone (131 mg, 0.66 mmol) was dissolved in a mixed solvent of 1 mL of methanol and 2 mL of dichloromethane, and stirred at room temperature for 30 minutes under the catalysis of two drops of glacial acetic acid. Sodium triacetoxyborohydride (91 mg, 0.43 mmol) was added and stirred at room temperature overnight. The reaction mixture was concentrated, water was added, and the mixture was extracted with dichloromethane. The organic layer was washed with saturated ammonium chloride and brine, dried over anhydrous sodium sulfate, and the solvent was removed by rotary evaporation. TIFF0007603609000660.tif9154 ((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-6-(4-(4-tert-butyloxyoxoamino-piperidin-1-yl)-(4-aminopiperidin-1-yl)pyridazin-3-amide (60 mg, 0.094 mmol) was obtained in 28% yield. LC / MS (ESI+) calculation for C 33 H 44 ClN7O4 + (M+H + ) m / z, 638.3; found 638.3. TIFF0007603609000661.tif8145-6-(4-(4-amino-piperidin-1-yl)-(4-aminopiperidin-1-yl)pyridazine-3-amide TIFF0007603609000662.tif8149 yl)-6-(4-(4-tert-butyloxyoxoamino-piperidin-1-yl)-(4-aminopiperidin-1-yl)pyridazin-3-amide (60 mg, 0.094 mmol) was dissolved in 3 mL of dichloromethane, 6 mL of trifluoroacetic acid was added, and the mixture was heated at room temperature. TIFF0007603609000663.tif10154 (Chloro-4-cyanophenoxy)cyclohexyl)-6-(4-aminopiperidin-4-yl)amino)piperidin-1-yl)pyridazine-3-amide trifluoroacetate (55 mg, 0.084 mmol) was obtained in 90% yield. LC / MS (ESI+) calculation for C 28 H 36 ClN7O2 + (M+H + ) m / z, 538.3; found 538.3. TIFF0007603609000664.tif9147-Synthesis of 6-(4-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)amino)piperidin-1-yl)pyridazin-3-amide TIFF0007603609000665.tif10149)-6-(4-aminopiperidin-4-yl)amino)piperidin-1-yl)pyridazine-3-amide trifluoroacetate (55 mg, 0.084 mmol), 2-(2,6-dioxopiperidin-3-yl)-5-fluoro-1,3-dioxoisoindoline (23 mg, 0.084 mmol), and DIPEA (54 mg, 0.42 mmol) were added to 1 mL of DMSO. The mixture was heated to 130 °C and stirred for 3 h. After cooling to room temperature, the mixture was extracted with water and ethyl acetate. The organic layer was washed with saturated ammonium chloride solution and brine, dried over anhydrous sodium sulfate, and the solvent was removed by rotary evaporation. The mixture was purified by silica gel column chromatography. TIFF0007603609000666.tif10153)-6-(4-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)amino)piperidin-1-yl)pyridazin-3-amide (15 mg, 0.019 mmol) was obtained in 23% yield. LC / MS (ESI+) calculation for C 41 H 44 ClN9O6 + (M+H + ) m / z , 794.3; TIFF0007603609000667.tif44155TIFF0007603609000668.tif18155

[0207] Synthesis of TIFF0007603609000669.tif9150silyl)-6-(4-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)methylamino)piperidin-1-yl)pyridazin-3-amide TIFF0007603609000670.tif69159LC / MS(ESI+)calcd for C 42 H 45 ClFN9O6 + (M+H + ) m / z, 826.3; found 826.3 TIFF0007603609000671.tif60157

[0208] 120: Synthesis of 2-chloro-4-((2-(6-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)pyridazine-3-carbonyl)-2-azaspiro[3.3]heptan-6-yl)oxy)benzonitrile TIFF0007603609000672.tif641571.Synthesis of compound 6-(3-chloro-4-cyanophenoxy)-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester The compound sodium hydride (60%) (514 mg, 12.86 mmol) was dissolved in 20 mL of DMF and stirred at -10 to 0 °C for 10 min. 6-hydroxy-2-azaspiro[3.3]heptane-2-carboxylate tert-butyl (2.05 g, 9.64 mmol) was added and stirred at -10 to 0 °C for 30 min. A DMF solution of 2-chloro-4-fluorobenzonitrile (1.00 g, 6.43 mmol) was slowly added dropwise. The mixture was stirred at -10 to 0 °C for 1 h, then allowed to warm to room temperature and stirred for 2 h. The reaction mixture was extracted with water and ethyl acetate, and the organic layer was washed three times with saturated ammonium chloride solution and saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed by rotary evaporation. The residue was purified by silica gel column chromatography to obtain a yellow oily compound, tert-butyl 6-(3-chloro-4-cyanophenoxy)-2-azaspiro[3.3]heptane-2-carboxylate (1.12 g, 3.21 mmol), in a 50% yield. LC / MS(ESI+)calcd for C 18 H 21 ClN2O3 + (M+H + ) m / z, 349.1; found 349.1. 2. Synthesis of the compound 4-(2-azaspiro[3.3]hept-6-yloxy)-2-chlorobenzonitrile The compound 6-(3-chloro-4-cyanophenoxy)-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester (348 mg, 1.00 mmol) and 2 mL of trifluoroacetic acid were dissolved in 1 mL of dichloromethane and stirred at room temperature for 1 h. After complete reaction was confirmed by TLC, the reaction mixture was concentrated to give the white solid compound 4-(2-azaspiro[3.3]hept-6-yloxy)-2-chlorobenzonitrile trifluoroacetate in 100% yield, which was used directly as the starting material for the next reaction. LC / MS (ESI+) calculation for C 13 H 13 ClNO + (M+H + ) m / z, 249.1; found 249.1 3. Synthesis of the compound 2-chloro-4-((2-(6-chloropyridazine-3-carbonyl)-2-azaspiro[3.3]hept-6-yl)oxy)benzonitrile The compound 4-(2-azaspiro[3.3]hept-6-yloxy)-2-chlorobenzonitrile trifluoroacetate (363 mg, 1.00 mmol), 6-chloropyridazine-3-carboxylic acid (316 mg, 2.00 mmol), and HATU (570 mg, 1.50 mmol) were added to 10 mL of dichloromethane, and DIPEA (645 mg, 5.00 mmol) was added under ice-water bath conditions. The ice bath was removed and the mixture was stirred at room temperature overnight. The organic layer was extracted with dichloromethane and water, washed with saturated ammonium chloride solution and saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed by rotary evaporation. The product was purified by silica gel column chromatography. The compound 2-chloro-4-((2-(6-chloropyridazine-3-carbonyl)-2-azaspiro[3.3]hept-6-yl)oxy)benzonitrile (222 mg, 0.57 mmol) was obtained in 57% yield. LC / MS(ESI+)calcd for C 18 H 14 Cl2N4O2 + (M+H + ) m / z, 389.0; found 389.0 4. Synthesis of compound tert-butyl 4-((1-(6-(6-(3-chloro-4-cyanophenoxy)-2-azaspiro[3.3]heptane-2-carbonyl)pyridazin-3-yl)piperidin-4-yl)methylpiperazin-1-amide The compound 2-chloro-4-((2-(6-chloropyridazine-3-carbonyl)-2-azaspiro[3.3]hept-6-yl)oxy)benzonitrile (222 mg, 0.57 mmol), 4-(piperidin-4-ylmethyl)piperazine-1-carboxylic acid tert-butyl ester (323 mg, 1.14 mmol), and DIPEA (221 mg, 1.71 mmol) were dissolved in 2 mL of DOX and stirred at 110° C. overnight. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic phase was washed three times with saturated ammonium chloride solution and saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography. The compound tert-butyl 4-((1-(6-(6-(3-chloro-4-cyanophenoxy)-2-azaspiro[3.3]heptane-2-carbonyl)pyridazin-3-yl)piperidin-4-yl)methylpiperazin-1-amide (150 mg, 0.23 mmol) was obtained in 40% yield. LC / MS(ESI+)calcd for C 33 H 42 ClN7O4 + (M+H + ) m / z, 636.3; found 636.3. 5. Synthesis of compound 2-chloro-4-((2-(6-(4-(4-piperazin-1-ylmethyl)piperidin-1-yl)pyridazine-3-carbonyl)-2-azaspiro[3.3]hept-6-yl)oxy)benzonitrile The compound tert-butyl 4-((1-(6-(6-(3-chloro-4-cyanophenoxy)-2-azaspiro[3.3]heptane-2-carbonyl)pyridazin-3-yl)piperidin-4-yl)methylpiperazine-1-amide (150 mg, 0.23 mmol) and 2 mL of trifluoroacetic acid were dissolved in 1 mL of dichloromethane and stirred at room temperature for 1 h. Complete reaction was detected by TLC, and the reaction solution was concentrated to obtain the white solid compound 2-chloro-4-((2-(6-(4-(4-piperazin-1-ylmethyl)piperidin-1-yl)pyridazine-3-carbonyl)-2-azaspiro[3.3]hept-6-yl)oxy)benzonitrile trifluoroacetate in 100% yield, which was used directly as the starting material for the next reaction. LC / MS(ESI+)calcd for C 28 H 34 ClN7O2 + (M+H + ) m / z, 536.2; found 536.2. 6. Synthesis of compound 2-chloro-4-((2-(6-(4-((4-(2-(2,6-dioxopiperidin-3-yl))-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)pyridazine-3-carbonyl)-2-azaspiro[3.3]hept-6-yl)oxy)benzonitrile The compound 2-chloro-4-((2-(6-(4-(4-piperazin-1-ylmethyl)piperidin-1-yl)pyridazine-3-carbonyl)-2-azaspiro[3.3]hept-6-yl)oxy)benzonitrile trifluoroacetate (153 mg, 0.23 mmol), 2-(2,6-dioxopiperidin-3-yl)-5-fluoro-1,3-dioxoisoindoline (64 mg, 0.23 mmol), and DIPEA (149 mg, 1.15 mmol) were added to 2 mL of DMSO. The mixture was heated to 130 °C and stirred for 3 h. After cooling to room temperature, water and ethyl acetate were added for extraction. The organic layer was washed with saturated ammonium chloride solution and brine, dried over anhydrous sodium sulfate, and the solvent was removed by rotary evaporation. The mixture was purified by silica gel column chromatography. The yellow solid compound 2-chloro-4-((2-(6-(4-((4-((2-(2,6-dioxopiperidin-3-yl))-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)pyridazine-3-carbonyl)-2-azaspiro[3.3]hept-6-yl)oxy)benzonitrile (40 mg, 0.50 mmol) was obtained in 22% yield. LC / MS (ESI+) calculation TIFF0007603609000673.tif17152TIFF0007603609000674.tif53157

[0209] Synthesis of TIFF0007603609000675.tif8153sil)-6-(4-((6-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)-2,6-diazaspiro[3.3]hept-2-yl)methyl)piperidin-1-yl)pyridazin-3-amide TIFF0007603609000676.tif66156-Synthesis of 6-(4-(hydroxymethyl)piperidin-1-yl)pyridazin-3-amide The compound 6-chloro-N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)pyridazin-3-amide (300 mg, 0.77 mmol), 4-hydroxymethylpiperidine (177 mg, 1.54 mmol), and DIPEA (298 mg, 2.31 mmol) were dissolved in 5 mL of DOX and stirred. The temperature was raised to 110 °C and stirred overnight. Water was added to the reaction solution, which was then extracted with ethyl acetate. The organic phase was washed three times with saturated ammonium chloride solution and saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography. TIFF0007603609000677.tif9153)-6-(4-(hydroxymethyl)piperidin-1-yl)pyridazin-3-amide (320 mg, 0.68 mmol) was obtained in 88% yield. LC / MS(ESI+)calcd for C 23 H 24 ClN5O3 + (M+H + ) m / z, 470.2; found 407.2. TIFF0007603609000678.tif11147-Synthesis of 6-(4-formylpiperidin-1-yl)pyridazin-3-amide TIFF0007603609000679.tif10151)-6-(4-(hydroxymethyl)piperidin-1-yl)pyridazin-3-amide (320 mg, 0.68 mmol) and Dess-Martin oxidant (377 mg, 0.89 mmol) were dissolved in 5 mL of dichloromethane and stirred at room temperature for 1.5 h. Complete reaction was confirmed by TLC. The reaction mixture was filtered, and the filtrate was washed twice with saturated sodium bisulfite solution, once with saturated sodium carbonate solution, once with saturated brine, and then with anhydrous sodium sulfate. TIFF0007603609000680.tif10156)-6-(4-formylpiperidin-1-yl)pyridazin-3-amide (300 mg, 0.64 mmol) was obtained in 94% yield. LC / MS(ESI+)calcd for C 24 H 36 ClN5O3 + (M+H+ ) m / z, 468.2; found 468.2. 3. Synthesis of compound tert-butyl-6-((1-(6-(((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)carbamoyl)pyridazin-3-yl)piperidin-4-yl)methyl)-2,6-diazaspiro[3.3]heptan-2-amide (TIFF0007603609000681.tif8149)-6-(4-formylpiperidin-1-yl)pyridazine-3-amide (300 mg, 0.64 mmol) and 2,6-diazaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester (255 mg, 1.28 mmol) were dissolved in 5 mL of 1,2-dichloroethane and stirred at room temperature for 30 minutes with two drops of glacial acetic acid as catalyst. Sodium triacetoxyborohydride (206 mg, 0.96 mmol) was added and stirred overnight at room temperature. The reaction mixture was concentrated, water was added, and the mixture was extracted with dichloromethane. The organic layer was washed with saturated ammonium chloride and brine, dried over anhydrous sodium sulfate, and the solvent was removed by rotary evaporation. The product was purified by silica gel column chromatography. The white solid compound tert-butyl 6-((1-(6-(((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)carbamoyl)pyridazin-3-yl)piperidin-4-yl)methyl)-2,6-diazaspiro[3.3]heptan-2-amide (150 mg, 0.23 mmol) was obtained in 36% yield. LC / MS(ESI+)calcd for C 34 H 44 ClN4O5 + (M+H + ) m / z, 650.3; found 650.3. 4. Synthesis of compound 6-((1-(6-(((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)carbamoyl)pyridazin-3-yl)piperidin-4-yl)methyl)-2,6-diazaspiro[3.3]heptan-2-amide The compound tert-butyl-6-((1-(6-(((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)carbamoyl)pyridazin-3-yl)piperidin-4-yl)methyl)-2,6-diazaspiro[3.3]heptan-2-amide (50 mg, 0.77 mmol) and 2 mL of trifluoroacetic acid were dissolved in 1 mL of dichloromethane and stirred at room temperature for 1 h. Complete reaction was detected by TLC, and the reaction solution was concentrated to give the white solid compound 6-((1-(6-(((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)carbamoyl)pyridazin-3-yl)piperidin-4-yl)methyl)-2,6-diazaspiro[3.3]heptan-2-amide trifluoroacetate in 100% yield, which was used directly as the starting material for the next reaction. LC / MS(ESI+)calcd for C 29 H 36 ClN7O2 + (M+H + ) m / z, 550.3; found 550.3. Synthesis of TIFF0007603609000682.tif9150(4-((6-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)-2,6-diazaspiro[3.3]hept-2-yl)methyl)piperidin-1-yl)pyridazin-3-amide The compound 6-((1-(6-(((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)carbamoyl)pyridazin-3-yl)piperidin-4-yl)methyl)-2,6-diazaspiro[3.3]heptan-2-amide trifluoroacetic acid salt (51 mg, 0.077 mmol), 2-(2,6-dioxopiperidin-3-yl)-5-fluoro-1,3-dioxoisoindoline (22 mg, 0.077 mmol), and DIPEA (50 mg, 0.39 mmol) were added to 1 mL of DMSO. The mixture was heated to 130° C. and stirred for 4 h. The mixture was cooled to room temperature and extracted with water and ethyl acetate. The organic layer was washed with saturated ammonium chloride solution and brine, dried over anhydrous sodium sulfate, and the solvent was removed by rotary evaporation. TIFF0007603609000683.tif10152r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-6-(4-((6-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)-2,6-diazaspiro[3.3]hept-2-yl)methyl)piperidin-1-yl)pyridazin-3-amide (20 mg, 0.025 mmol) was obtained in 32% yield. LC / MS(ESI+)calcd for C 42 H 44 ClN9O6 + (M+H + ) m / z, 806.2; found 805.8. TIFF0007603609000684.tif59155

[0210] Synthesis of TIFF0007603609000685.tif8152sil)-6-(4-((6-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)-2,6-diazaspiro[3.3]hept-2-yl)methyl)piperidin-1-yl)pyridazin-3-amide TIFF0007603609000686.tif58153LC / MS(ESI+)calcd for C 42 H 43 ClFN9O6 + (M+H + ) m / z, 824.3; found 823.8. TIFF0007603609000687.tif61157

[0211] Synthesis of TIFF0007603609000688.tif10150silyl)-6-(4-((6-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)-2,6-diazaspiro[3.3]hept-2-yl)methyl)piperidin-1-yl)pyrazin-2-amide TIFF0007603609000689.tif63153LC / MS(ESI+)calcd for C 42 H43 ClFN9O6 + (M+H + ) m / z, 824.3; found 824.2. TIFF0007603609000690.tif60154

[0212] TIFF0007603609000691.tif8149Synthesis of (6-(6-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)methyl)-2,6-diazaspiro[3.3]heptan-2-yl)pyridazin-3-amide TIFF0007603609000692.tif721541.Synthesis of tert-butyl 6-(6-(((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)carbamoyl)pyridazin-3-yl)-2,6-diazaspiro[3.3]heptan-2-amide TIFF0007603609000693.tif9153)Cyclohexylpyridazine-3-amide (200 mg, 0.51 mmol), 2,6-diazaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester (202 mg, 1.02 mmol), and DIPEA (198 mg, 1.53 mmol) were added to 5 mL of DOX, heated to 110 °C, and stirred overnight. The mixture was cooled to room temperature, extracted with water and ethyl acetate, and the organic layer was washed three times with saturated ammonium chloride solution and saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed by rotary evaporation. The mixture was purified by silica gel column chromatography to obtain a white solid compound, tert-butyl 6-(6-(((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)carbamoyl)pyridazin-3-yl)-2,6-diazaspiro[3.3]heptan-2-amide (200 mg, 0.36 mmol), in a 71% yield. LC / MS(ESI+)calcd for C 23 H 35 N2O5 + (M+H + ) m / z, 553.2; found 553.2. TIFF0007603609000694.tif8151-6-(2,6-diazaspiro[3.3]heptan-2-yl)pyridazin-3-amide The compound tert-butyl 6-(6-(((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)carbamoyl)pyridazin-3-yl)-2,6-diazaspiro[3.3]heptan-2-amide (200 mg, 0.36 mmol) and 2 mL of trifluoroacetic acid were dissolved in 1 mL of dichloromethane, stirred at room temperature for 1 hour, and the complete reaction was detected by TLC. The mixture was concentrated, the pH was adjusted to 10 by adding saturated sodium carbonate solution, and extracted with dichloromethane. The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. TIFF0007603609000695.tif9152)-6-(2,6-diazaspiro[3.3]heptan-2-yl)pyridazin-3-amide (150 mg, 0.33 mmol) was obtained in 92% yield. LC / MS (ESI+) calculation for C 22 H 33 N2O5 + (M+H + ) m / z, 453.2; found 453.2. 3. Synthesis of tert-butyl 4-((6-(6-(((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)carbamoyl)pyridazin-3-yl)-2,6-diazaspiro[3.3]heptan-2-yl)piperidine-1-formate TIFF0007603609000696.tif8149)-6-(2,6-diazaspiro[3.3]heptan-2-yl)pyridazine-3-amide (150 mg, 0.33 mmol), 4-formylpiperidine-1-carboxylic acid tert-butyl ester (141 mg, 0.66 mmol) were dissolved in 3 mL of 1,2-dichloroethane and stirred at room temperature for 30 minutes under the catalysis of 2 drops of glacial acetic acid. Sodium triacetoxyborohydride (186 mg, 0.49 mmol) was added and stirred at room temperature overnight. The reaction mixture was concentrated, and extracted with water and dichloromethane. The organic phase was washed with saturated ammonium chloride solution and saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography to obtain the compound 4-tert-butyl 4-((6-(6-(((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)carbamoyl)pyridazin-3-yl)-2,6-diazaspiro[3.3]heptan-2-yl)piperidine-1-methyl formate (100 mg, 0.15 mmol) in a 46% yield. LC / MS(ESI+)calcd for C 35 H 46 ClN4O5 + (M+H + ) m / z, 637.3; found 637.2. Synthesis of TIFF0007603609000697.tif9150(6-(piperidin-4-yl-methyl)-2,6-diazaspiro[3.3]heptan-2-yl)pyridazin-3-amide The compound 4-tert-butyl 4-((6-(6-(((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)carbamoyl)pyridazin-3-yl)-2,6-diazaspiro[3.3]heptan-2-yl)piperidine-1-formate methyl ester (100 mg, 0.15 mmol) and 2 mL of trifluoroacetic acid were dissolved in 1 mL of dichloromethane and stirred at room temperature for 1 h. Complete reaction was detected by TLC. The reaction mixture was concentrated to give a white solid. TIFF0007603609000698.tif10153-6-(6-(piperidin-4-yl-methyl)-2,6-diazaspiro[3.3]heptan-2-yl)pyridazine-3-amide trifluoroacetate was obtained in 100% yield and used directly as starting material for the next reaction. LC / MS(ESI+)calcd for C 30 H 38 ClN4O3 + (M+H + ) m / z, 537.3; found 537.3. Synthesis of TIFF0007603609000699.tif9151oxyl)-4-(4-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)oxy)piperidin-1-yl)benzamide TIFF0007603609000700.tif9150)-6-(6-(piperidin-4-yl-methyl)-2,6-diazaspiro[3.3]heptan-2-yl)pyridazine-3-amide trifluoroacetate (97 mg, 0.15 mmol), 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindole-1,3-dione (44 mg, 0.15 mmol), and DIPEA (97 mg, 0.75 mmol) were added to 3 mL of DMSO. The mixture was heated to 130 °C and stirred for 3 h. After cooling to room temperature, water and ethyl acetate were added for extraction. The organic phase was washed with saturated ammonium chloride solution and saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed by rotary evaporation. The mixture was then eluted with silica gel. TIFF0007603609000701.tif8152)-4-(4-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)oxy)piperidin-1-yl)benzamide (18 mg, 0.022 mmol) was obtained in 15% yield. LC / MS (ESI+) calculation for C 42 H 43 ClN9O6 + (M+H + ) m / z , 824.3; TIFF0007603609000702.tif60152

[0213] TIFF0007603609000703.tif10150Synthesis of (6-(6-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)methyl)-2,6-diazaspiro[3.3]heptan-2-yl)pyrazin-2-amide TIFF0007603609000704.tif66151LC / MS(ESI+)calcd for C 42 H 43 ClN9O6 + (M+H + ) m / z, 824.3; found 824.2. TIFF0007603609000705.tif52154

[0214] Synthesis of TIFF0007603609000706.tif8149sil)-6-(4-(((1R,5S,6s)-3-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)-3-azabicyclo[3.1.0]hexan-6-yl)methyl)piperazin-1-yl)pyridazin-3-amide TIFF0007603609000707.tif661581.Synthesis of compound 4-(((1r,4r)-4-aminocyclohexyl)oxy)-2-bromobenzonitrile Sodium hydride (60%, 3.50 g, 87.50 mmol) was dissolved in 400 mL of DMF and stirred at -10 to 0°C for 10 min. (1r,4r)-4-hydroxycyclohexylamine hydrochloride (4.17 g, 27.5 mmol) was added and stirred at -10 to 0°C for 30 min. A DMF solution of 2-bromo-4-fluorobenzonitrile (5.00 g, 25.00 mmol) was slowly added dropwise and stirred at -10 to 0°C for 1 h. The mixture was then allowed to warm to room temperature and stirred for 4 h. The reaction mixture was extracted with an ice-water mixture and ethyl acetate, and the organic layer was washed three times with saturated brine. The pH of the organic phase was adjusted to 1 with 1 mol / L dilute hydrochloric acid, back-extracted three times with ethyl acetate, adjusted to pH 12 by adding saturated sodium hydroxide solution, extracted with ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated to obtain the compound 4-(((1r,4r)-4-aminocyclohexyl)oxy)-2-bromobenzonitrile (5.20 g, 17.63 mmol) in a yield of 71%. LC / MS(ESI+)calcd for C 13 H 15 BrNO + (M+H + ) m / z, 295.0; found 295.0. TIFF0007603609000708.tif10149Synthesis of (silyl)-6-chloropyridazine-3-amide The compound 4-(((1r,4r)-4-aminocyclohexyl)oxy)-2-bromobenzonitrile (1.00 g, 3.39 mmol), 5-chloropyrazine-2-carboxylic acid (805 mg, 5.08 mmol), and HATU (1.67 g, 4.41 mmol) were added to 30 mL of dichloromethane, and DIPEA (1.13 g, 10.17 mmol) was added under an ice-water bath. The ice bath was removed, and the mixture was stirred at room temperature overnight. Water and ethyl acetate were added for extraction, and the organic layer was washed with saturated ammonium chloride solution and saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed by rotary evaporation. The mixture was purified by silica gel column chromatography. TIFF0007603609000709.tif9153-6-Chloropyridazine-3-amide (1.30 g, 2.98 mmol) was obtained in 88% yield. LC / MS(ESI+)calcd for C 18 H 16 BrClN4O2 + (M+H + ) m / z, 435.0; found 435.0. 3. tert-Butyl 4-(6-(((1r,4r)-4-(3-bromo-4-cyanophenoxy)cyclohexyl)carbamoyl)pyridazin-3-yl)piperazin-1-amide TIFF0007603609000710.tif10150-6-chloropyridazine-3-amide (200 mg, 0.46 mmol), piperazine-1-carboxylic acid tert-butyl ester (172 mg, 0.92 mmol), and DIPEA (178 mg, 1.38 mmol) were dissolved in 3 mL of DOX and stirred. The mixture was heated to 110 °C and stirred overnight. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic phase was washed three times with saturated ammonium chloride solution and saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography to give the compound tert-butyl 4-(6-(((1r,4r)-4-(3-bromo-4-cyanophenoxy)cyclohexyl)carbamoyl)pyridazin-3-yl)piperazine-1-amide (150 mg, 0.26 mmol) in 57% yield. LC / MS(ESI+)calcd for C 27 H 33 BrN6O4 + (M+H + ) m / z, 585.2; found 585.2. TIFF0007603609000711.tif9148Synthesis of (xyl)-6-(piperazin-1-yl)pyridazin-3-amide The compound tert-butyl 4-(6-(((1r,4r)-4-(3-bromo-4-cyanophenoxy)cyclohexyl)carbamoyl)pyridazin-3-yl)piperazin-1-amide (150 mg, 0.26 mmol) was dissolved in 1 mL of dichloromethane and 2 mL of trifluoroacetic acid and stirred at room temperature for 2 h. The solvent was removed by rotary evaporation, the pH was adjusted to 12 by adding saturated sodium carbonate, extracted with dichloromethane, and the organic phase was washed with saturated brine, anhydrous TIFF0007603609000712.tif8153 Cyanophenoxy)cyclohexyl)-4-(4-(piperidine-4-acyloxy)piperidin-1-yl)benzamide (60 mg, 0.12 mmol) was obtained in 46% yield. LC / MS(ESI+)calcd for C 22 H 25 BrN6O2 + (M+H + ) m / z, 485.1; found 485.1 . TIFF0007603609000713.tif9147-6-(4-(((1R,5S,6s)-3-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)-3-azabicyclo[3.1.0]hexan-6-yl)methyl)piperazin-1-yl)pyridazin-3-amide (1R,5S,6R)-6-(piperazin-1-yl)pyridazine-3-amide (60 mg, 0.12 mmol) and (1R,5S,6R)-3-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindol-5-yl)-3-azabicyclo[3.1.0]hexane-6-formaldehyde (48 mg, 0.12 mmol) were dissolved in 1 mL of 1,2-dichloroethane and stirred at room temperature for 30 minutes under the catalysis of two drops of glacial acetic acid. Sodium triacetoxyborohydride (27 mg, 0.12 mmol) was added and stirred at room temperature overnight. The reaction mixture was concentrated, water was added, and the mixture was extracted with dichloromethane. The organic layer was washed with saturated ammonium chloride and brine, dried over anhydrous sodium sulfate, and the solvent was removed by rotary evaporation. TIFF0007603609000715.tif9153r)-4-(3-bromo-4-cyanophenoxy)cyclohexyl)6-(4-(((1R,5S,6s)-3-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)-3-azabicyclo[3.1.0]hexan-6-yl)methyl)piperazin-1-yl)pyridazin-3-amide (16 mg, 0.019 mmol) was obtained in 16% yield. LC / MS(ESI+)calcd for C 41 H 41 BrFN9O6 + (M+H + ) m / z, 854.2; found 854.2. TIFF0007603609000716.tif50151

[0215] Synthesis of TIFF0007603609000717.tif9147sil)-6-(4-(((1R,5S,6s)-3-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)-3-azabicyclo[3.1.0]hexan-6-yl)methyl)piperazin-1-yl)pyrazin-2-amide TIFF0007603609000718.tif69141LC / MS(ESI+)calcd for C 41 H 41 BrFN9O6 + (M+H + ) m / z, 854.2; found 854.3. TIFF0007603609000719.tif51152

[0216] TIFF0007603609000720.tif10150silyl)-2-(4-(((((1R,5S,6s)-3-(2-(2,6-dioxapiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)-3-azabicyclo[3.1.0]hexan-6-yl)methyl)piperazin-1-yl)pyrimidin-5-amide TIFF0007603609000721.tif42151LC / MS(ESI+)calcd for C 41 H 41 BrFN9O6 + (M+H + ) m / z, 810 found, 810.3. TIFF0007603609000722.tif52152

[0217] Synthesis of TIFF0007603609000723.tif8150silyl)-6-(6-(4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)-2-azaspiro[3.3]heptan-2-yl)pyridazin-3-amide TIFF0007603609000724.tif56146-6-(6-hydroxy-2-azaspiro[3.3]heptan-2-yl)pyridazin-3-amide The compound 6-hydroxy-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester (300 mg, 1.40 mmol) and 30 mL of trifluoroacetic acid were dissolved in 15 mL of dichloromethane, stirred at room temperature for 2 h, and the complete reaction was detected by TLC. TIFF0007603609000725.tif10150) Cyclohexylpyridazine-3-carboxamide (200 mg, 0.51 mmol) and DIPEA (330 mg, 2.55 mmol) were added and dissolved in 5 mL of DOX, heated to 110 °C, and stirred overnight. After cooling to room temperature, water and ethyl acetate were added for extraction. The organic layer was washed three times with saturated ammonium chloride solution and saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed by rotary evaporation. The mixture was then purified by silica gel column chromatography. TIFF0007603609000726.tif11149)-6-(6-hydroxy-2-azaspiro[3.3]heptan-2-yl)pyridazin-3-amide (220 mg, 0.47 mmol) was obtained in 92% yield. LC / MS(ESI+)calcd for C 23 H 35 N2O5 + (M+H + ) m / z, 468.2; found 468.2. TIFF0007603609000727.tif9149-6-(6-oxo-2-azaspiro[3.3]hept-2-yl)pyridazine-3-amide TIFF0007603609000728.tif11149)-6-(6-hydroxy-2-azaspiro[3.3]heptan-2-yl)pyridazin-3-amide (220 mg, 0.41 mmol) and Dess-Martin oxidant (225 g, 0.53 mmol) were dissolved in 4 mL of dichloromethane and stirred at room temperature for 1 h. Complete reaction was confirmed by TLC. The reaction mixture was filtered, and the filtrate was washed twice with saturated sodium bisulfite solution, once with saturated sodium carbonate, once with saturated brine, and then with anhydrous sodium sulfate. TIFF0007603609000729.tif11153)cyclohexyl)-6-(6-oxo-2-azaspiro[3.3]hept-2-yl)pyridazin-3-amide (210 mg, 0.45 mmol) was obtained in 96% yield. LC / MS(ESI+)calcd for C 22 H 33 N2O5 + (M+H + ) m / z, 466.2; found 466.2. Synthesis of TIFF0007603609000730.tif10150(6-(4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)-2-azaspiro[3.3]hept-2-yl)pyridazin-3-amide TIFF0007603609000731.tif10148)-6-(6-oxo-2-azaspiro[3.3]hept-2-yl)pyridazine-3-amide (50 mg, 0.11 mmol) and 2-(2,6-dioxapiperidin-3-yl)-5-fluoro-6-(piperazin-1-yl)isoindoline-1,3-dione (40 mg, 0.11 mmol) were dissolved in 1 mL of 1,2-dichloroethane, two drops of glacial acetic acid were added, and the mixture was stirred at room temperature for 30 minutes. Sodium triacetoxyborohydride (23 mg, 0.11 mmol) was added and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated, water was added, and the mixture was extracted with dichloromethane. The organic layer was washed with saturated ammonium chloride and brine, dried over anhydrous sodium sulfate, and the solvent was removed by rotary evaporation. The resulting product was purified by silica gel column chromatography. TIFF0007603609000732.tif9152)cyclohexyl)-6-(6-(4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)-2-azaspiro[3.3]heptan-2-yl)pyridazin-3-amide (22 mg, 0.027 mmol) was obtained in 25% yield. LC / MS (ESI+) calculation for C 41 H 41 ClN9O6 ...

Claims

1. A compound selected from any one of the following compounds, or an isotopic compound thereof, or an optical isomer thereof, or a tautomer thereof, or a pharma- ceutically acceptable salt thereof, or a solvate thereof:

2. Use of the compound according to claim 1, or an isotopic compound thereof, or an optical isomer thereof, or a tautomer thereof, or a pharma- ceutically acceptable salt thereof, or a solvate thereof, in the manufacture of an androgen receptor proteolytic targeting chimera.

3. The use according to claim 2, characterized in that the proteolytic targeting chimera is capable of recognizing and / or binding to the androgen receptor as a target.

4. The use according to claim 2, characterized in that the proteolysis targeting chimera is capable of degrading and / or downregulating the androgen receptor.

5. The use according to any one of claims 2 to 4, characterized in that the proteolytic targeting chimera is an active ingredient of a medicinal product for treating a related disease regulated by the androgen receptor.

6. The use according to claim 5, characterized in that the disease is selected from prostate cancer, breast cancer and Kennedy's disease.

7. A pharmaceutical for treating a disease regulated by the androgen receptor, characterized in that it is a formulation produced by adding pharma- ceutical acceptable auxiliary materials to the compound according to claim 1, or an isotope thereof, or an optical isomer thereof, or a tautomer thereof, or a pharma- ceutical acceptable salt thereof, or a solvate thereof, as an active ingredient.

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