Bifunctional chimeric heterocyclic compounds targeting degradation of androgen receptor and uses thereof

Abstract

The present application relates to a kind of targeted degradation androgen receptor bifunctional chimeric heterocyclic compound and its purposes, specifically provides the compound shown in formula (I), or its isotopic compound, or its optical isomer, or its tautomer, or its pharmaceutically acceptable salt, or its prodrug, or its solvate, wherein, ARB is androgen receptor recognition / binding portion, L is linking portion, U is ubiquitin protease recognition / binding portion;Three parts are connected by chemical bond.The above-mentioned compound provided by the present application can target degradation androgen receptor in prostate cancer cell, and inhibit the proliferation of prostate cancer cell, also show good metabolic stability and pharmacokinetic property.The compound of the present application has good application prospect in the preparation of androgen receptor protein degradation targeting chimera, and the preparation of the drug for treating related diseases (including prostate cancer, breast cancer, Kennedy disease) regulated by androgen receptor.

Description

Technical Field

[0001] This invention belongs to the field of medicine. Specifically, this invention relates to a class of bifunctional chimeric heterocyclic compounds that target and degrade androgen receptors and their uses. Background Technology

[0002] With a continuously growing and aging global population, the incidence of prostate cancer continues to rise, and the main treatment currently is androgen deprivation therapy. The androgen receptor (AR) belongs to the nuclear receptor family and is a class of ligand-dependent transcription factors. Aberrant regulation of the AR signaling pathway plays a crucial role in the occurrence and development of prostate cancer; studies have shown that castration-resistant prostate cancer (CRPC) still depends on the action of AR. The androgen receptor contains 918 amino acids and has a similar structure and function to other nuclear receptors. It consists of three important domains: the DNA-binding domain (DBD), the ligand-binding domain (LBD), and the N-terminal domain (NTD). The DBD and LBD are connected by a hinge region. The LBD, located at the C-terminus of AR, is the site where AR binds to ligands, determining the specificity of ligand binding to AR. Ligand binding to the LBD activates AR. Two transcriptional activation regions have been identified in AR: activation function 1 (AF1) in the NTD domain and the highly conserved hydrophobic pocket activation function 2 (AF2) in the LBD domain. Prior to 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 comprising a small molecule compound that binds to the target protein (POI), with a linker group introduced at an appropriate position, and then linked to a small molecule compound that binds to a ubiquitin protease. The resulting small probe can simultaneously bind to both the target protein and the ubiquitin protease, thereby promoting the ubiquitination of the target protein. The multiubiquitinated protein can then be recognized and degraded by the proteasome.

[0004] Using the PROTACs strategy, a protein degradation-targeting chimera capable of targeting and recognizing / binding to androgen receptors was prepared. This chimera can regulate androgen receptor levels through the intracellular ubiquitin-proteasome degradation system, inducing androgen receptor degradation, thereby achieving therapeutic effects on androgen receptor-regulated diseases such as prostate cancer.

[0005] Therefore, developing a bifunctional chimeric molecule that can target and bind to androgen receptors and effectively degrade androgen receptors has promising applications in treating diseases regulated by androgen receptors. Summary of the Invention

[0006] The purpose of this invention is to provide a protein degradation targeting chimera with stronger binding ability to androgen receptors and higher activity in degrading androgen receptors.

[0007] This invention provides compounds of formula (I), or isotopic compounds thereof, or optical isomers thereof, or tautomers thereof, or pharmaceutically acceptable salts thereof, or prodrugs thereof, or solvates thereof:

[0008]

[0009] ARB is the androgen receptor recognition / binding part, L is the linking part, and U is the ubiquitin protease recognition / binding part; these three parts are linked by chemical bonds.

[0010] Wherein, the aforementioned ARB is selected from the structure shown in formula (IA):

[0011]

[0012] Among them, W 1 The W is selected from substituted or unsubstituted aryl or heteroaryl groups. 1 The substituents on the group are each independently selected from halogen, hydroxyl, amino, mercapto, sulfone, sulfoxide, nitro, cyano, CF3, heterocyclic, C 1-6 Alkyl groups or their halogenated or deuterated forms, C 3-6 cycloalkyl, C 1-6 Alkoxy or its halogenated or its deuterated derivative, C 1-6 Alkylamine group, C 2-6 alkenyl or C 2-6 alkynyl group;

[0013] Y 1 Y 2 Y 3 Y 4 Each is independently selected from a single bond, O, S, NR. 1 CR 2 R 3C=O, C=S, SO or SO2; the above R 1 R 2 R 3 Selected independently from H and C respectively 1-6 Alkyl groups or their halogenated or deuterated derivatives, 3-8 membered cycloalkyl or heterocyclic groups containing 0-2 heteroatoms, or R 2 With R 3 These can be linked together to form 3-8 membered rings containing 0-2 heteroatoms;

[0014] Q is selected from 0 to 6 R's. q The R is a substituted saturated cycloalkyl group, a saturated heterocyclic group, or an aryl or heteroaryl group containing 0-4 heteroatoms. q Each is independently selected from H, D, OH, halogens, and C. 1-6 Alkyl groups or their halogenated derivatives, C 1-6 Alkoxy groups or their halogenated derivatives, or two substituents linked together to form a 3-8 membered ring containing 0-2 heteroatoms;

[0015] W 2 Selected from a key, or by 0 to 4 Rs 4 The following groups are substituted: alkenyl, ynyl, C 1-6 Alkyl, C 1-6 Alkoxy, monocycloalkyl, monoheterocyclic, aryl, heteroaryl, bridged cycloalkyl, heterobridged cycloalkyl, spirocycloalkyl, heterospirocycloalkyl, fused cycloalkyl, heterofused cycloalkyl;

[0016] The above R 4 Each group is independently selected from H, halogen, hydroxyl, amino, mercapto, sulfone, sulfoxide, nitro, cyano, CF3, C 1-6 Alkyl groups or their halogenated or deuterated forms, C 3-6 cycloalkyl, C 1-6 Alkoxy or its halogenated or its deuterated derivative, C 1-6 Alkylamine group, C 2-6 alkynyl group, C 2-6 alkenyl, or R 4 Selected from R 1c Selected from O or S;

[0017] or,

[0018] ARB is selected from the structure shown in formula (IB):

[0019]

[0020] Among them, W 1 The W is selected from substituted or unsubstituted aryl or heteroaryl groups. 1The substituents on the group are each independently selected from halogen, hydroxyl, amino, mercapto, sulfone, sulfoxide, nitro, cyano, CF3, heterocyclic, C 1-6 Alkyl groups or their halogenated or deuterated forms, C 3-6 cycloalkyl, C 1-6 Alkoxy or its halogenated or its deuterated derivative, C 1-6 Alkylamine group, C 2-6 alkenyl or C 2-6 alkynyl group;

[0021] Y 1 Y 5 Y 6 Each is independently selected from a single bond, O, S, NR. 1 CR 2 R 3 C=O, C=S, SO, SO2; the above R 1 R 2 R 3 Selected independently from H and C respectively 1-6 Alkyl groups or their halogenated or deuterated derivatives, 3-8 membered cycloalkyl or heterocyclic groups containing 0-2 heteroatoms, or R 2 With R 3 These can be linked together to form 3-8 membered rings containing 0-2 heteroatoms;

[0022] Q is selected from 0 to 6 R's. q The R is a substituted saturated cycloalkyl group, a saturated heterocyclic group, or an aryl or heteroaryl group containing 0-4 heteroatoms. q Each is independently selected from H, D, OH, halogens, and C. 1-6 Alkyl groups or their halogenated derivatives, C 1-6 Alkoxy groups or their halogenated derivatives, or two substituents linked together to form a 3-8 membered ring containing 0-2 heteroatoms;

[0023] W 2 Selected from a key, or by 0 to 3 Rs 4 Substituted alkenyl, alkynyl, C 1-6 Alkyl, C 1-6 Alkoxy, monocycloalkyl, monoheterocyclic, aryl, heteroaryl, bridged cycloalkyl, heterobridged cycloalkyl, spirocycloalkyl, heterospirocycloalkyl, fused cycloalkyl, heterofused cycloalkyl;

[0024] Where R 4 Each group is independently selected from H, halogen, hydroxyl, amino, mercapto, sulfone, sulfoxide, nitro, cyano, CF3, C 1-6 Alkyl groups or their halogenated or deuterated forms, C 3-6 cycloalkyl, C 1-6 Alkoxy or its halogenated or its deuterated derivative, C 1-6 Alkylamine group, C 2-6alkynyl group, C 2-6 alkenyl;

[0025] or,

[0026] ARB is selected from the structure shown in formula (IC):

[0027]

[0028] Among them, W 1 The W is selected from substituted or unsubstituted aryl or heteroaryl groups. 1 The substituents on the group are each independently selected from halogen, hydroxyl, amino, mercapto, sulfone, sulfoxide, nitro, cyano, CF3, heterocyclic, C 1-6 Alkyl groups or their halogenated or deuterated forms, C 3-6 cycloalkyl, C 1-6 Alkoxy or its halogenated or its deuterated derivative, C 1-6 Alkylamine group, C 2-6 alkenyl or C 2-6 alkynyl group;

[0029] Y 1 Selected from a single bond, O, S, NR 1 CR 2 R 3 , C=O, C=S, SO, SO2;

[0030] Y 7 Selected from N, CR 2 ;Y 8 Selected from a single bond, O, S, NR 1 CR 2 R 3 , C=O, C=S, SO, SO2;

[0031] Y 7 and W 2 Connected to Y 8 Together they form a 4-7 membered ring, which is replaced by 0 to 4 deuterium or halogens;

[0032] The above R 1 R 2 R 3 Selected independently from H and C respectively 1-6 Alkyl groups or their halogenated or deuterated derivatives, 3-8 membered cycloalkyl or heterocyclic groups containing 0-2 heteroatoms, or R 2 With R 3 These can be linked together to form 3-8 membered rings containing 0-2 heteroatoms;

[0033] Q is selected from 0 to 6 R's. q The R is a substituted saturated cycloalkyl group, a saturated heterocyclic group, or an aryl or heteroaryl group containing 0-4 heteroatoms.q Each is independently selected from H, D, OH, halogens, and C. 1-6 Alkyl groups or their halogenated derivatives, C 1-6 Alkoxy groups or their halogenated derivatives, or two substituents linked together to form a 3-8 membered ring containing 0-2 heteroatoms;

[0034] W 2 Selected from a key, or by 0 to 3 Rs 4 Substituted alkenyl, alkynyl, C 1-6 Alkyl, C 1-6 Alkoxy, monocycloalkyl, monoheterocyclic, aryl, heteroaryl, bridged cycloalkyl, heterobridged cycloalkyl, spirocycloalkyl, heterospirocycloalkyl, fused cycloalkyl, heterofused cycloalkyl;

[0035] Where R 4 Each group is independently selected from H, halogen, hydroxyl, amino, mercapto, sulfone, sulfoxide, nitro, cyano, CF3, C 1-6 Alkyl groups or their halogenated or deuterated forms, C 3-6 cycloalkyl, C 1-6 Alkoxy or its halogenated or its deuterated derivative, C 1-6 Alkylamine group, C 2-6 alkynyl group, C 2-6 alkenyl;

[0036] or,

[0037] ARB is selected from the structure shown in formula (ID):

[0038]

[0039] Among them, W 1 The W is selected from substituted or unsubstituted aryl or heteroaryl groups. 1 The substituents on the group are each independently selected from halogen, hydroxyl, amino, mercapto, sulfone, sulfoxide, nitro, cyano, CF3, heterocyclic, C 1-6 Alkyl groups or their halogenated or deuterated forms, C 3-6 cycloalkyl, C 1-6 Alkoxy or its halogenated or its deuterated derivative, C 1-6 Alkylamine group, C 2-6 alkenyl or C 2-6 alkynyl group;

[0040] Y 9 Y 10 Y 11 Each is independently selected from CH, O, and S;

[0041] Y 12 Selected from one bond, or CO, CO2, O, S, NR 1e NR 1e CO, NR1e SO2; the R 1e Selected from H, C 1-6 Alkyl groups or their halogenated or deuterated derivatives, 3-8 membered cycloalkyl or heterocyclic groups containing 0-2 heteroatoms;

[0042] R q Each is independently selected from H, D, OH, halogens, and C. 1-6 Alkyl groups or their halogenated derivatives, C 1-6 Alkoxy or its halogenated derivative, or two R groups q They connect to form 3-8 membered rings containing 0-2 heteroatoms;

[0043] W 2 Selected from a key, or by 0 to 3 Rs 4 Substituted alkenyl, alkynyl, C 1-6 Alkyl, C 1-6 Alkoxy, monocycloalkyl, monoheterocyclic, aryl, heteroaryl, bridged cycloalkyl, heterobridged cycloalkyl, spirocycloalkyl, heterospirocyclic, fused cycloalkyl, heterofused cycloalkyl; R 4 Each group is independently selected from H, halogen, hydroxyl, amino, mercapto, sulfone, sulfoxide, nitro, cyano, CF3, C 1-6 Alkyl groups or their halogenated or deuterated forms, C 3-6 cycloalkyl, C 1-6 Alkoxy or its halogenated or its deuterated derivative, C 1-6 Alkylamine group, C 2-6 alkynyl group, C 2-6 Alkenyl group.

[0044] Furthermore,

[0045] The formula (IA), formula (IB) or formula (IC) The structure is shown in the following formulas (II-A), (IV-B), (IV-C), (IV-D), (IV-E), (IV-F), (IV-G), or (IV-H):

[0046]

[0047]

[0048] Among them, R q Each is independently selected from H, OH, halogens, and C. 1-6 Alkyl groups or their halogenated derivatives, C 1-6 Alkoxy or its halogenated derivative, or two R groups q They connect to form 3-8 membered rings containing 0-2 heteroatoms;

[0049] a, b, c, and d are each independently selected from integers between 0 and 3.

[0050] Furthermore, in the formula (IA), formula (IB), or formula (IC) The structure is shown in equation (III-A), (III-B), (III-C), or (III-D) below:

[0051]

[0052] Alternatively, in formula (IA), formula (IB), or formula (IC) The structure is shown in the following formulas (III-E), (III-F), (III-G), (III-H), (III-I), (III-J), (III-K), (III-L), (III-M), or (III-N):

[0053]

[0054] Among them, R w1 R w2 R w3 R w4 R w5 Each group is independently selected from halogen, hydroxyl, amino, mercapto, sulfone, sulfoxide, nitro, cyano, CF3, heterocyclic, and C. 1-6 Alkyl groups or their halogenated or deuterated forms, C 3-6 cycloalkyl, C 1-6 Alkoxy or its halogenated or its deuterated derivative, C 1-6 Alkylamine group, C 2-6 alkenyl or C 2-6 Alkyne group; the halogen is preferably chlorine or bromine, and the C 1-6 The alkyl group is preferably methyl, wherein the C 1-6 The alkoxy group is preferably methoxy or ethoxy;

[0055] R q Each is independently selected from H, OH, halogens, and C. 1-6 Alkyl groups or their halogenated derivatives, C 1-6 Alkoxy or its halogenated derivative, or any two R groups q They connect to form 3-8 membered rings containing 0-2 heteroatoms.

[0056] Furthermore,

[0057] In the formula (IC) Selected from the following structures:

[0058]

[0059] Furthermore, the structure of the formula (ID) is as shown in the following formula (VD):

[0060]

[0061] Among them, W 1 W 2 Y 12 R q As described in the above formula (ID).

[0062] Furthermore, the ARB is selected from the structure of the following formula:

[0063]

[0064]

[0065]

[0066]

[0067]

[0068] Among them, R w1 R w2 R w3 R w4 R w5 Each group is independently selected from halogen, hydroxyl, amino, mercapto, sulfone, sulfoxide, nitro, cyano, heterocyclic, CF3, C 1-6 Alkyl groups or their halogenated or deuterated forms, C 3-6 cycloalkyl, C 1-6 Alkoxy or its halogenated or its deuterated derivative, C 1-6 Alkylamine group, C 2-6 alkenyl or C 2-6 Alkyne group; the halogen is preferably chlorine or bromine, and the C 1-6 The alkyl group is preferably methyl, wherein the C 1-6 The alkoxy group is preferably methoxy or ethoxy;

[0069] R w6 Selected from H, halogen, hydroxyl, amino, mercapto, sulfone, sulfoxide, nitro, cyano, CF3, C 1-6 Alkyl groups or their halogenated or deuterated forms, C 3-6 cycloalkyl, C 1-6 Alkoxy or its halogenated or its deuterated derivative, C 1-6 Alkylamine group, C 2-6 alkynyl group, C 2-6 alkenyl;

[0070] R q Each is independently selected from H, OH, halogens, and C. 1-6 Alkyl groups or their halogenated derivatives, C 1-6Alkoxy or its halogenated derivative, or any two R groups q They connect to form 3-8 membered rings containing 0-2 heteroatoms;

[0071] Y 12 Selected from one bond, or CO, CO2, O, S, NR 1e NR 1e CO, NR 1e SO2; the R 1e Selected from H, C 1-6 Alkyl groups or their halogenated or deuterated derivatives.

[0072] Furthermore, the ARB is selected from the structure of the following formula:

[0073]

[0074]

[0075]

[0076]

[0077]

[0078]

[0079]

[0080] Alternatively, the ARB may be selected from the following structure:

[0081]

[0082]

[0083]

[0084]

[0085]

[0086]

[0087]

[0088]

[0089]

[0090]

[0091]

[0092]

[0093] Furthermore, the L is selected from the structure of the following formula (VIII-A):

[0094]

[0095] Where: L 1 L 2 L 3 L 4 L 5 L 6 Each is independently selected from none, a single bond, O, S, NR. L1 CR L2 R L3 , C=O, C=S, SO, SO2, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted monocycloalkyl, substituted or unsubstituted monoheterocyclic, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted bridged cycloalkyl, substituted or unsubstituted heterobridged cycloalkyl, substituted or unsubstituted spirocycloalkyl, substituted or unsubstituted heterospirocycloalkyl, substituted or unsubstituted fused cycloalkyl, substituted or unsubstituted heterofused cycloalkyl;

[0096] The above substituents are selected from C 1-6 Alkyl, -L 7 -OH, halogen, L 7 Selected from 0 to 6 methylene groups;

[0097] R L1 R L2 R L3 Selected independently from H and C respectively 1-6 Alkyl groups or their halogenated or deuterated derivatives, 3-8 membered cycloalkyl or heterocyclic groups containing 0-2 heteroatoms, or R L2 R L3 These can be linked together to form 3-8 membered rings containing 0-2 heteroatoms;

[0098] a, b, c, d, e, f are each independently selected from integers between 0 and 5;

[0099] L 1 and L 6 It can be freely connected to either ARB or U;

[0100] Alternatively, the L may be selected from the structure shown in formula (VIII-B):

[0101]

[0102] Ring A and ring B are each independently selected from halogenated or non-halogenated structures of the following:

[0103]

[0104] X 0 Selected from: None, O,S,SO,SO 2, NR X1 ,CR X1 R X2 ;R X1 R X2 Each group is independently selected from H, halogen, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkyl substituted with halogen, hydroxyl, or amino, groups obtained by replacing carbon atoms in the C1-C6 alkyl backbone with oxygen or nitrogen atoms, heterocyclic, aryl, hydroxyl, amino, or R. X1 and R X2 They connect to form 3-7 elemental rings;

[0105] Ring A and Ring B can be freely connected to ARB or U, respectively.

[0106] Furthermore, the formula (VIII-A) is selected from the following structures:

[0107]

[0108]

[0109]

[0110]

[0111]

[0112]

[0113]

[0114]

[0115]

[0116]

[0117]

[0118]

[0119]

[0120] Where X is selected from H or halogen, and m and n are each independently selected from integers from 0 to 5.

[0121] Furthermore, the L is selected from the structure shown below:

[0122]

[0123]

[0124]

[0125]

[0126]

[0127] Preferably, the L is selected from the following structures:

[0128]

[0129]

[0130] Furthermore, the U is selected from the structure of the following formula (XA):

[0131]

[0132] Where T and Y are each independently selected from a bond, O, S, NR T1 or CR T2 R T3 ;

[0133] V and J are each independently selected from a bond, C = O, -SO-, -SO2-, or CR. 2 R 3 ;

[0134] R T1 R T2 R T3 Selected independently from H and C respectively 1-6 Alkyl groups or their halogenated or deuterated derivatives, 3-8 membered cycloalkyl or heterocyclic groups containing 0-2 heteroatoms, or R T2 With R T3 These can be linked together to form 3-8 membered rings containing 0-2 heteroatoms;

[0135] R v Selected from H, C 1-6 Alkyl groups or their halogenated or deuterated derivatives, cycloalkyl or heterocyclic groups containing 0-3 heteroatoms or their halogenated derivatives, or R x With R y These can be linked together to form 3-8 membered rings containing 0-2 heteroatoms;

[0136] g and h are each independently selected from integers from 0 to 3, and g and h are not both 0 at the same time;

[0137] Z is selected from H, hydroxyl, amino, C. 1-6 Alkyl, C 3-6 Cycloalkyl, oxygen- or halogen-substituted C 1-6 Alkyl, -OR Z1 ,-NR Z1 R Z2 -COR Z3 -CO2R Z3 -OCOR Z3 -NHCOR Z3 -CONHR Z3 -SO2R Z3 ;R Z1 R Z2 Selected independently from H and C respectively 1-6 Alkyl groups or their halogenated or deuterated derivatives, 3-8 membered cycloalkyl or heterocyclic groups containing 0-2 heteroatoms;

[0138] The above R Z3 Selected from substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 3-6 Cycloalkyl, substituted or unsubstituted C 3-6 Heterocyclic group, substituted or unsubstituted aryl group, substituted or unsubstituted heteroaryl group; said R Z3 The substituents on it are selected from halogens, C 1-3 alkyl;

[0139] R x R y Selected independently from H and C respectively 1-6 Alkyl, Halogenated C 1-6 Alkyl groups, C substituted with heteroatoms 1-6 Alkyl, -L y -OH, a cycloalkyl or heterocyclic group containing 0-3 heteroatoms, or its halogenated derivative, or R x With R y Linked together, they form 3-8 membered rings containing 0-2 heteroatoms; among which, L y Selected from 0 to 5 methylene groups;

[0140] W 4 W 5 Each substituent is independently selected from aryl and heteroaryl groups substituted with 0 to 3 substituents, wherein each substituent is independently selected from H, halogen, hydroxyl, amino, mercapto, sulfone, sulfoxide, nitro, cyano, CF3, heterocyclic, C 1-6 Alkyl, C 3-6 cycloalkyl, C 1-6 Alkoxy, C 1-6 Alkylamine group, C 2-6 alkenyl, C 2-6 alkynyl group;

[0141] or,

[0142] The U is selected from the structure of the following formula (XB):

[0143]

[0144] Where M is selected from O, S, NR m ;where R m Selected from H, C 1-6 Alkyl, C 3-6 cycloalkyl, C 3-6 Heterocyclic group,

[0145] The above R m1 Selected from H, C 1-6 Alkyl, C 3-6 cycloalkyl; X m Selected from none, O, S, NR m3 ;

[0146] R m2 ,R m3 Selected independently from H and C respectively 1-6 Alkyl, C 3-6 cycloalkyl, C 3-6 Heterocyclic group, The i above is selected from integers from 0 to 12, R m4 Selected from H, C 1-6 Alkyl, L m Selected from 0 to 5 methylene groups, M a Selected from N, CH, M b Selected from O, S, CH2, NH;

[0147] E and F are each independently selected from CO, CS, NR e1 O, S, SO2, CH2, CD2, CR e2 R e3 , R e1 R e2 R e3 Selected independently from C 1-6 Alkyl, H, halogen, hydroxyl, amino;

[0148] Y 15 Y 13 Y 14 Selected independently from H, O, S, C 1-3 alkyl;

[0149] j and k are each independently selected from integers between 0 and 3, and j and k are not both 0 at the same time;

[0150] G1 G 2 G 3 G 4 Selected independently from O, S, N, CR g1 CR g2 CR g3 CR g4 , where R g1 R g2 R g3 R g4 Each group is independently selected from H, halogen, hydroxyl, amino, mercapto, sulfone, sulfoxide, nitro, cyano, CF3, heterocyclic, and C. 1-6 Alkyl, C 3-6 cycloalkyl, C 1-6 Alkoxy, C 1-6 Alkylamine group, C 2-6 alkenyl, C 2-6 alkynyl group;

[0151] R u1 Selected from H, C1-C6 alkyl;

[0152] or,

[0153] The U is selected from the structure of the following formula (XC):

[0154]

[0155] Furthermore, the formula (XA) is selected from the structure shown in the following formula (XI-A):

[0156]

[0157] Among them, R v Z, g, h, R x R y W 4 W 5 The selection range is the same as in equation (II-A) above;

[0158] or,

[0159] In the formula (XB) Select from the structures shown in (XI-B), (XI-C), (XI-D), (XI-E), or (XI-F):

[0160]

[0161] Among them, G 1 G 2 G 3 G 4 The selection range is the same as in the above formula (XB).

[0162] Furthermore, the formula (XI-A) is selected from the structure shown in the following formula (XII-A):

[0163]

[0164] Among them, R w7 Selected from H, halogen, hydroxyl, amino, mercapto, sulfone, sulfoxide, nitro, cyano, CF3, heterocyclic, C 1-6 Alkyl, C 3-6 cycloalkyl, C 1-6 Alkoxy, C 1-6 Alkylamine group, C 2-6 alkenyl, C 2-6 alkynyl group;

[0165] M 1 M 2 M 3 M 4 Selected independently from O, S, NR 12 ,C(R 12 )2, where R 12 Selected from H, halogen, hydroxyl, amino, mercapto, sulfone, sulfoxide, nitro, cyano, CF3, heterocyclic, C 1-6 Alkyl, C 3-6 cycloalkyl, C 1-6 Alkoxy, C 1-6 Alkylamine group, C 2-6 alkenyl, C 2-6 alkynyl group,

[0166] R v Z, R x R y The selection range is the same as in the above formula (XI-A).

[0167] Furthermore, in the formula (XI-A), W 5 Selected from the following structures:

[0168]

[0169] Furthermore, the U is selected from the following structures:

[0170]

[0171]

[0172]

[0173]

[0174] Furthermore, the compound is selected from one of the following compounds:

[0175]

[0176]

[0177]

[0178]

[0179]

[0180]

[0181]

[0182]

[0183]

[0184]

[0185]

[0186]

[0187]

[0188]

[0189]

[0190]

[0191]

[0192]

[0193]

[0194]

[0195]

[0196]

[0197]

[0198]

[0199]

[0200] The present invention also provides the use of the above-described compounds, or isotopic compounds thereof, or optical isomers thereof, or tautomers thereof, or pharmaceutically acceptable salts thereof, or prodrugs thereof, or solvates thereof, in the preparation of protein degradation-targeting chimeras of androgen receptors.

[0201] Furthermore, the protein degradation targeting chimera is capable of targeting and / or binding to androgen receptors.

[0202] Furthermore, the protein degradation targeting chimera can degrade and / or downregulate androgen receptors.

[0203] Furthermore, the protein degradation-targeting chimera is an active ingredient in drugs for treating diseases regulated by androgen receptors.

[0204] Furthermore, the diseases mentioned are selected from prostate cancer, breast cancer, and Kennedy's disease.

[0205] The present invention also provides a medicament for treating diseases regulated by androgen receptors, wherein the medicament is a formulation prepared by adding pharmaceutically acceptable excipients to the above-mentioned compound, or its isotopic compound, or its optical isomer, or its tautomer, or its pharmaceutically acceptable salt, or its prodrug, or its solvate as the active ingredient.

[0206] Experiments have demonstrated that the compound represented by formula (I) provided by this invention can target and degrade androgen receptors in prostate cancer cells and inhibit their proliferation, while also exhibiting good metabolic stability and pharmacokinetic properties. The compound of this invention shows promising application potential in the preparation of androgen receptor protein degradation-targeting chimeras and in the development of drugs for treating androgen receptor-regulated diseases (including prostate cancer, breast cancer, and Kennedy's disease).

[0207] Regarding the definition of terms used in this invention: Unless otherwise stated, the initial definitions provided for groups or terms herein apply to the groups or terms used throughout this specification; for terms not specifically defined herein, the meanings that a person skilled in the art would give them should be given based on the disclosure and context.

[0208] The minimum and maximum carbon atom content in hydrocarbon groups are indicated by a prefix, for example, the prefix C. a～b Alkyl groups refer to any alkyl group containing one to two carbon atoms ("a" to "b"). For example, C 1～6 Alkyl groups are straight-chain or branched alkyl groups containing 1 to 6 carbon atoms.

[0209] In this article, "substitution" refers to the replacement of one, two, or more hydrogen atoms in a molecule by other different atoms or molecules, including one, two, or more substitutions on isotopes or ectopic atoms in the molecule.

[0210] The minimum and maximum carbon atom content in hydrocarbon groups in this article are indicated by prefixes, for example, C 1-6 Alkyl groups refer to any straight-chain or branched alkyl group containing 1-6 carbon atoms; C 1-6 Alkoxy refers to any straight-chain or branched alkoxy group containing 1 to 6 carbon atoms.

[0211] In this invention, "aryl" refers to an all-carbon monocyclic or fused polycyclic (i.e., a ring sharing adjacent carbon atom pairs) group with a conjugated π-electron system, such as phenyl and naphthyl. The aryl ring may 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 group must be on a carbon atom of a ring with a conjugated π-electron system. The aryl group may be substituted or unsubstituted.

[0212] "Heteroaryl" refers to a heteroaryl group containing one or more heteroatoms. Heteratoms include oxygen, sulfur, and nitrogen. Examples include furanyl, thiophene, pyridinyl, pyrazolyl, pyrroleyl, N-alkylpyrroleyl, pyrimidinyl, pyrazinyl, imidazolyl, tetrazolyl, etc. The heteroaryl ring may be fused to an aryl, heterocyclic, or cycloalkyl ring, wherein the ring attached to the parent structure is the heteroaryl ring. The heteroaryl group may be optionally substituted or unsubstituted.

[0213] "Alkyl" is a hydrocarbon group formed by removing one hydrogen atom from an alkane molecule, such as methyl-CH3, ethyl-CH3CH2, etc.

[0214] "Alkylamine" is a group obtained by replacing one or more hydrogen atoms in an alkyl group with an amino group.

[0215] "Alynyl" refers to an aliphatic hydrocarbon group having at least one carbon-carbon triple bond. The alkynyl group can be straight-chain or branched. When the alkynyl group is preceded by a carbon number qualifier, for example, "C..." 2-6 "Alkyne group" refers to a straight-chain or branched alkynyl group with 2-6 carbon atoms.

[0216] "Alkenyl" refers to an aliphatic hydrocarbon group having at least one carbon-carbon double bond. The alkenyl group can be straight-chain or branched. When the alkenyl group is preceded by a number of carbon atoms, for example, "C2-6 alkenyl" refers to a straight-chain or branched alkenyl group having 2-6 carbon atoms.

[0217] "Substituted or unsubstituted alkenyl" means that the alkenyl group can be substituted or unsubstituted.

[0218] "Cycloalkyl" refers to a substituent in a saturated or unsaturated cyclic hydrocarbon; the cyclic hydrocarbon can be monocyclic or polycyclic. For example, "3-8 membered cycloalkyl" refers to a cycloalkyl group having 3 to 8 carbon atoms.

[0219] "Saturated cycloalkyl" refers to saturated cycloalkyl groups.

[0220] "Monocylalkyl" means that the cycloalkyl group is monocyclic.

[0221] "Bridged cycloalkyl" refers to a polycyclic cycloalkyl group in which two rings share two non-adjacent carbon atoms.

[0222] "Spirocycloalkyl" refers to a polycyclic cycloalkyl group in which two rings share a single carbon atom.

[0223] "Fused cycloalkyl" refers to a polycyclic cycloalkyl group in which two rings share two adjacent carbon atoms.

[0224] "Heterocyclic group" refers to a substituent in a saturated or unsaturated cyclic hydrocarbon; the cyclic hydrocarbon can be monocyclic or polycyclic and carries at least one cyclic heteroatom (including but not limited to O, S, or N). For example, "3- to 8-membered heterocyclic group" refers to a heterocyclic group with 3 to 8 carbon atoms.

[0225] "Saturated heterocyclic group" refers to a saturated heterocyclic group.

[0226] "Monocyclic heterocyclic group" means that the heterocyclic group is monocyclic.

[0227] "Hybrid cyclic group" is a multi-ring heterocyclic group in which two rings share two non-adjacent carbon atoms or heteroatoms.

[0228] "Heterospirocyclic group" is a polycyclic heterocyclic group in which two rings share a single carbon atom or heteroatom.

[0229] "Heterocyclic fused ring group" is a polycyclic heterocyclic group in which two rings share two adjacent carbon atoms or heteroatoms.

[0230] Halogens are fluorine, chlorine, bromine or iodine.

[0231] "Isotopic compounds" refer to compounds obtained by replacing one or more atoms of a compound with their corresponding isotopes. For example, compounds obtained by replacing one or more hydrogen atoms (H) with deuterium (D) or tritium (T); or compounds obtained by replacing one or more carbon atoms with deuterium (D) or tritium (T). 12 Carbon 11 or carbon 13 The compound obtained after substitution.

[0232] "Pharmaceutical acceptable" means that a carrier, delivery substance, diluent, excipient, and / or the salt formed therefrom is generally chemically or physically compatible with other components constituting a drug dosage form and physiologically compatible with receptors.

[0233] "Salt" is an acidic and / or basic salt formed by a compound or its stereoisomer with an inorganic and / or organic acid and / or base, including zwitterionic salts (internal salts) and quaternary ammonium salts, such as alkylammonium salts. These salts can be obtained directly during the final separation and purification of the compound. Alternatively, they can be obtained by mixing the compound, or its stereoisomer, with an appropriate amount (e.g., equimolar amounts) of an acid or base. These salts may form a precipitate in solution and be collected by filtration, or be recovered after solvent evaporation, or be prepared by freeze-drying after reaction in an aqueous medium. The salts described in this invention can be hydrochlorides, sulfates, citrates, benzenesulfonates, hydrobromides, hydrofluoric acids, phosphates, acetates, propionates, succinates, oxalates, malates, succinates, fumarates, maleates, tartrates, or trifluoroacetates of the compound.

[0234] "Solvate" refers to the solvate formed by the compound of the present invention and a solvent, wherein the solvent includes (but is not limited to): water, ethanol, methanol, isopropanol, propylene glycol, tetrahydrofuran, and dichloromethane.

[0235] In the compounds of this invention, ARB is the androgen receptor recognition / binding moiety, which acts as a ligand for the androgen receptor in the compound.

[0236] In this invention, "selected from one bond" means that the group or atom is absent, and the two ends of its bonding sites are directly connected, such as formula (IA). Middle, Y 3 When selected from a single key, the structure is as follows:

[0237] In the structure of the present invention (XII-A) Indicates CH, M 1 M 2 M 3 M 4 It is composed of a pentagonal ring with a conjugate structure.

[0238] In the present invention formula (VIII-A), "L" 1 and L 6 "Can be freely connected to ARB or U" indicates L 1 Connected to ARB, and simultaneously L 6 Connect to U, or L 1 Connected to U, and simultaneously L 6 Connect to ARB.

[0239] Similarly, in the present invention formula (VIII-B), "ring A and ring B can be freely connected to ARB or U respectively" means that ring A is connected to ARB and ring B is connected to U, or ring A is connected to U and ring B is connected to ARB.

[0240] In this invention, "D" represents deuterium.

[0241] There are several ways to name the specific compounds of this invention: (1) numerical designation, such as compounds "315" and "3"; (2) compound naming, such as (3R,5S)-1-((S)-2-(2-((5-((4-(3-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)ureo)phenyl)amino)pentyl)oxy)acetamido)-3,3-dimethylbutyryl)-5-(((S)-1-(4-(4-methylthiazol-5-yl))phenyl)ethyl)carbamoyl)pyrrolidine-3-ylacetate. Although the naming methods are different, each specific compound of this invention can be uniquely identified based on its structure.

[0242] Obviously, based on the above description of the present invention, and according to common technical knowledge and conventional methods in the field, various other modifications, substitutions or alterations can be made without departing from the basic technical concept of the present invention.

[0243] The following detailed embodiments further illustrate the above-described content of the present invention. However, this should not be construed as limiting the scope of the present invention to the following examples. All technologies implemented based on the above-described content of the present invention fall within the scope of the present invention. Attached Figure Description

[0244] Figure 1 The results of Western blot experiments on the protein immunoblotting of compound 99 of the present invention at different concentrations are shown. Detailed Implementation

[0245] The raw materials and equipment used in the specific embodiments of the present invention are all known products, obtained by purchasing commercially available products.

[0246] First, synthesize the intermediate:

[0247]

[0248] SM-A-1:4-((1r,3r)-3-(2-bromo-5-oxo-5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl)-2,2,4,4-tetramethylcyclobutoxy)-2-chlorobenzonitrile

[0249]

[0250] 1. Compound 3-(methoxycarbonyl)-2-methylpyridine-1-oxo derivative

[0251] 2-Methylnicotinate (30.0 g, 199.0 mmol) was dissolved in dichloromethane (500 mL), followed by the addition of m-chloroperoxybenzoic acid (68.7 g, 398.0 mmol) in portions. The mixture was stirred overnight at room temperature, filtered, and the filter cake was washed with dichloromethane. The filtrate was added to 5% sodium sulfite solution (200 mL) and stirred for 30 minutes. The mixture was separated and extracted with dichloromethane (100 mL × 3). The filtrates were combined, dried over anhydrous sodium sulfate, and purified by silica gel column chromatography (dichloromethane:methanol = 100:1 to 20:1) to give a white solid compound 3-(methoxycarbonyl)-2-methylpyridine-1-oxocyanate (18 g, 107.8 mmol), yield: 54%. MS: calcd for C8H9NO3[M+H] + :168.0; found:168.1.

[0252] 2. Compound 6-chloro-2-methylnicotinic acid methyl ester

[0253] Compound 3-(methoxycarbonyl)-2-methylpyridine-1-oxoform (36.5 g, 218.6 mmol) was added in portions to phosphorus oxychloride (300 mL) under ice bath conditions. The mixture was then slowly refluxed for 3 hours. Most of the solvent was removed from the reaction mixture under reduced pressure. The solution was diluted with ethyl acetate (500 mL), washed with 10% Na₂CO₃ aqueous solution (100 mL × 3), and then washed with saturated brine (100 mL × 3). The organic layer was dried over anhydrous sodium sulfate, evaporated to dryness, and purified by silica gel column chromatography (petroleum ether:ethyl acetate = 10:1 to 5:1) to give a white solid, methyl 6-chloro-2-methylnicotinate (8 g, 43.2 mmol). Yield: 20%. MS: calcd. for C₈H₈ClNO₂[M+H] + :186.0; found:186.1.

[0254] 3. Compound 6-bromo-2-methylnicotinic acid methyl ester

[0255] 6-Chloro-2-methylnicotinic acid methyl ester (8.0 g, 43.2 mmol) was dissolved in acetonitrile (80 mL), followed by the addition of trimethylbromosilane (19.8 g, 129.7 mmol). The reaction mixture was heated under reflux overnight. The solvent was removed from the reaction mixture under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 30:1 to 10:1) to give a yellow solid of 6-bromo-2-methylnicotinic acid methyl ester (7.0 g, 30.6 mmol). Yield: 71%. MS: calcd for C8H8BrNO2[M+H] + :230.0; found:230.1.

[0256] 4. Compound 2-(bromomethyl)-6-bromonicotinic acid methyl ester

[0257] 6-Bromo-2-methylnicotinic acid methyl ester (7.0 g, 30.6 mmol) and N-bromosuccinimide (8.16 g, 45.9 mmol) were added to carbon tetrachloride (100 mL), followed by the addition of azobisisobutyronitrile (566 mg, 3.06 mmol). The reaction mixture was refluxed overnight. The solvent was removed from the reaction mixture under reduced pressure, and the residue was subjected to silica gel column chromatography (petroleum ether:ethyl acetate = 30:1 to 10:1) to give crude 2-(bromomethyl)-6-bromonicotinic acid methyl ester (A-1-5).

[0258] The crude product was dissolved in dichloromethane (60 mL), and N,N-diisopropylethylamine (2.36 g, 18.3 mmol) was added. Diethyl phosphite (1.21 g, 8.76 mmol) was added dropwise in an ice bath, and the mixture was stirred overnight at room temperature. The reaction solution was diluted with water (100 mL), extracted with dichloromethane (40 mL × 3), washed with saturated brine (50 mL × 3), and the combined organic phases were dried over anhydrous sodium sulfate. The solutions were then evaporated to dryness and purified by silica gel column chromatography (petroleum ether:ethyl acetate = 30:1 to 10:1) to give a white solid methyl 2-(bromomethyl)-6-bromonicotinic acid (6.0 g, 19.5 mmol), yield: 64%. MS: calcd. for C8H7Br2NO2[M+H] + :307.9; found:308.1.

[0259] 5. Compound 3-carbonyl-2,2,4,4-tetramethylcyclobutanone oxime

[0260] Hydroxylamine hydrochloride (26.0 g, 374.5 mmol) was dissolved in water (40 mL) and ethanol (250 mL), followed by the addition of 1,3-tetramethylcyclobutanedione (50 g, 356.7 mmol) and sodium acetate (29.3 g, 356.7 mmol). The reaction mixture was heated under reflux for 2 hours. Ethanol and water were removed by rotary evaporation. The residue was added to toluene (300 mL) and refluxed for 3 hours, followed by hot filtration. The filter cake was washed with toluene (100 mL). The filtrate was evaporated to dryness to give a white solid, 3-carbonyl-2,2,4,4-tetramethylcyclobutane oxime (32.0 g, 206.5 mmol), yield: 59%.

[0261] MS:calcd.for C8H 13 NO2[M+H] + :156.1; found:156.1.

[0262] 6. Compound 3-hydroxy-2,2,4,4-tetramethylcyclobutanone oxime

[0263] 3-Carbonyl-2,2,4,4-Tetramethylcyclobutanone oxime (110.9 g, 714.6 mmol) was dissolved in isopropanol (715 mL), followed by the addition of sodium borohydride (18.9 g, 500.2 mmol) in portions. The reaction mixture was stirred overnight at room temperature. The reaction mixture was quenched at 5 °C with sodium hydroxide (2000 mL). The mixture was then extracted with ethyl acetate (700 mL × 3), and the combined organic phases were dried over sodium sulfate and evaporated to dryness to give a white solid, 3-hydroxy-2,2,4,4-tetramethylcyclobutanone oxime (100.8 g, 642.0 mmol), yield: 90%.

[0264] MS:calcd.for C8H 15 NO2[M+H] + :158.1; found:158.1.

[0265] 7. Compound 3-aminotetramethylcyclobutanone

[0266] 3-Hydroxy-2,2,4,4-Tetramethylcyclobutanone oxime (A-1-7) (35.1 g, 223.3 mmol) was dissolved in tetrahydrofuran (300 mL), and then nickel-aluminum alloy (76.5 g, 893.3 mmol) was added under nitrogen protection. The reaction mixture was refluxed for 30 minutes, and then 15% sodium hydroxide (300 mL) was added while maintaining reflux. After the addition was complete, reflux was continued for 2 hours. After the reaction was complete, the mixture was filtered, and the filter cake was washed with tetrahydrofuran (100 mL × 3). The filtrate was extracted with ethyl acetate (200 mL × 3), and the combined organic phases were washed with saturated brine (200 mL × 3), dried over sodium sulfate, and evaporated to dryness to give a pale yellow solid, 3-aminotetramethylcyclobutanone (24.5 g, 171.3 mmol), yield: 77%.

[0267] MS:calcd.for C8H 17 NO[M+H] + :144.1; found:144.1.

[0268] 8. Compound 3-hydroxy-2,2,4,4-tetramethylcyclobutylcarbamate tert-butyl ester

[0269] 3-Aminotetramethylcyclobutanone (26.9 g, 188.1 mmol) was dissolved in dichloromethane (500 mL), followed by the addition of di-tert-butyl dicarbonate (41.4 g, 190.0 mmol) and triethylamine (38.0 g, 376.2 mmol). The reaction mixture was stirred overnight at room temperature. The reaction mixture was diluted with water (300 mL) and extracted with dichloromethane (100 mL × 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 = 10:1 to 1:1) to give a pale yellow solid, 3-hydroxy-2,2,4,4-tetramethylcyclobutylcarbamate (30.1 g, 123.9 mmol), yield: 66%.

[0270] MS:calcd.for C8H 17 NO[M+H] + :244.2; found:244.2.

[0271] 9. Compound (1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutylcarbamate tert-butyl ester

[0272] 25.0 g (102.9 mmol) of 3-hydroxy-2,2,4,4-tetramethylcyclobutylcarbamate tert-butyl ester was dissolved in tetrahydrofuran (250 mL). Sodium hydride (60% in mineral oil) (8.23 g, 205.8 mmol) was added in portions under ice bath conditions, and the mixture was stirred for 30 minutes under ice bath conditions. Then, 17.6 g (113.2 mmol) of 2-chloro-4-fluorobenzonitrile (50 mL) was dissolved in tetrahydrofuran 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 × 3). The 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 (1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutylcarbamate tert-butyl ester (15.0 g, 39.7 mmol), yield: 39%. MS: calcd. for C 20 H 27 ClN2O3[M+H] + :379.2; found:279.2.

[0273] 10. Compound 4-((1r,3r)-3-amino-2,2,4,4-tetramethylcyclobutoxy)-2-chlorobenzonitrile trifluoroacetate

[0274] (1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutylcarbamate tert-butyl ester (5.0 g, 13.2 mmol) was dissolved in dichloromethane (50 mL), and trifluoroacetic acid (50 mL) was added under ice bath conditions. The reaction mixture was stirred at room temperature for 1 hour, and then evaporated to dryness to obtain crude 4-((1r,3r)-3-amino-2,2,4,4-tetramethylcyclobutoxy)-2-chlorobenzonitrile trifluoroacetate, which was used directly in the next step of the reaction. MS: calcd.for C 17 H 19 ClF3N2O2[M+H] + :376.1; found:279.1.

[0275] 11. Compound 4-((1r,3r)-3-(2-bromo-5-oxo-5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl)-2,2,4,4-tetramethylcyclobutoxy)-2-chlorobenzonitrile

[0276] 4-((1r,3r)-3-amino-2,2,4,4-tetramethylcyclobutoxy)-2-chlorobenzonitrile trifluoroacetate (13.2 mmol, crude product derived from the previous step) was dissolved in acetonitrile (240 mL), followed by the addition of N,N-diisopropylethylamine (8.51 g, 66.0 mmol) and methyl 2-(bromomethyl)-6-bromonicotinic acid (4.0 g, 13.2 mmol). The reaction was also heated under reflux overnight. After the reaction mixture was evaporated to dryness, toluene (50 mL) was added and refluxed overnight. The reaction mixture 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). Two-step yield: 63%. MS: calcd.for C 22 H 21 BrClN3O2[M+H] + :474.0; found:474.0.

[0277] SM-A-2, SM-A-3, SM-A-4, and SM-A-5 were prepared using a method similar to that used for SM-A-1.

[0278] SM-A-2:2-Chloro-4-((1r,3r)-3-(2-chloro-5-oxo-5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl)-2,2,4,4-tetramethylcyclobutoxy)benzonitrile

[0279]

[0280] Compound 4-((1r,3r)-3-amino-2,2,4,4-tetramethylcyclobutoxy)-2-chlorobenzonitrile (527 mg, 1.89 mmol), potassium carbonate (392 mg, 2.84 mmol), and 10 mL of DMF were added sequentially under nitrogen protection. After stirring until homogeneous, a DMF solution of methyl 2-(bromomethyl)-6-chloronicotinate (500 mg, 1.89 mmol) was added dropwise, and the mixture was stirred at room temperature for 2 h. The reaction endpoint was determined by TLC. The reaction solution was extracted three times with ethyl acetate, dried over anhydrous sodium sulfate, washed three times with saturated brine, dried over anhydrous sodium sulfate, and evaporated to dryness to obtain the crude product. The intermediate was obtained by silica gel column chromatography. The intermediate was added to DIEA (734 mg, 1.48 mmol) and 5 mL of 1,4-dioxane, and reacted at 100 °C for 2 days. The reaction endpoint was determined by TLC, and silica gel column chromatography yielded the intermediate 2-chloro-4-((1r,3r)-3-(2-chloro-5-oxo-5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl)-2,2,4,4-tetramethylcyclobutoxy)benzonitrile (536 mg, 1.25 mmol). Yield: 66%. LC / MS (ESI+) calcd for C 22 H 21 C l2 N3O2(M+H + )m / z,430.1;found,430.1.

[0281] Synthesis of SM-A-3:4-((1r,3r)-3-(5-bromo-1-isoindoline-2-yl)-2,2,4,4-tetramethylcyclobutyl ether)-2-chlorobenzonitrile

[0282]

[0283] Compound 4-((1r,3r)-3-amino-2,2,4,4-tetramethylcyclobutyl ether)-2-chlorobenzonitrile (1.0 g, 3.59 mmol) and K₂CO₃ (743.0 mg, 5.38 mmol) were added to 20 mL of DMF. Methyl 4-bromo-2-(bromomethyl)benzoate (1.10 g, 3.59 mmol) was added in portions to the reaction mixture. The mixture was stirred at room temperature for 1 hour, and the reaction was monitored by TLC until complete, with the formation of a new spot. The mixture was extracted with ethyl acetate and saturated brine, and the organic layer was washed twice with saturated brine, dried over anhydrous sodium sulfate, evaporated to dryness, and purified by silica gel column chromatography to obtain 1.2 g of an oily liquid. 10 mL of toluene and 1 mL of triethylamine were added, and the mixture was heated to reflux and stirred for 16 h. The solvent was evaporated to dryness, and a small amount of petroleum ether and ethyl acetate (4:1) were added. The solid was filtered and dried to give a white solid 4-((1r,3r)-3-(5-bromo-1-isoindoline-2-yl)-2,2,4,4-tetramethylcyclobutyl ether)-2-chlorobenzonitrile (900.0 mg, 1.9 mmol). Yield: 52.9%.

[0284] SM-A-4:4-(((1r,4r)-4-(5-bromo-1-oxoisoindoline-2-yl)cyclohexyl)oxy)-2-chlorobenzonitrile

[0285]

[0286] Step 1: Synthesis of 4-(((1r,4r)-4-aminocyclohexyl)oxy)-2-chlorobenzonitrile

[0287] The compound trans-para-aminocyclohexanol hydrochloride (26.8 g, 177 mmol) was dissolved in 0.8 L DMF. Under ice bath and N2 protection, NaH (22.3 g, 531 mmol) was added in portions, and the reaction was carried out at 0 °C for 1 h. The compound 2-chloro-4-fluorobenzonitrile was dissolved in 200 mL DMF and slowly added dropwise to the reaction mixture. The mixture was kept at 0 °C for 0.5 h, then cooled to room temperature and stirred for 3 h. The reaction was then observed on a TLC plate until complete. The mixture was extracted with EA and water. The EA was washed twice with saturated brine. The mixture was dried over anhydrous sodium sulfate, evaporated to dryness, and purified by silica gel column chromatography to give a white solid product, 4-(((1r,4r)-4-aminocyclohexyl)oxy)-2-chlorobenzonitrile (27.7 g).

[0288] Step Two:

[0289] Compound 4-(((1r,4r)-4-aminocyclohexyl)oxy)-2-chlorobenzonitrile (1 g, 4 mmol) was dissolved in 20 mL of LMF, and K₂CO₃ (0.82 g, 6 mmol) was added. Methyl 4-bromo-2-(bromomethyll)benzoate (1.2 g, 4 mmol) was added in portions. The mixture was stirred overnight at room temperature. Water was added, and a white solid precipitated. The solid was filtered and dried to give compound SM-A-3 (1.3 g, 2.9 mmol).

[0290] SM-A-5: 2-chloro-4-((1r,4r)-4-(2-chloro-5-oxo-5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl)cyclohexyl)oxy)benzonitrile

[0291]

[0292] Compound 4-((1r,4r)-4-aminocyclohexyl)oxy)-2-chlorobenzonitrile (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. After stirring until homogeneous, a DMF solution of methyl 2-(bromomethyl)-6-chloronicotinate (2.5 g, 9.45 mmol) was added dropwise, and the mixture was stirred at room temperature for 2 h. The reaction endpoint was determined by TLC. The reaction solution was extracted three times with ethyl acetate, washed three times with saturated brine, dried over anhydrous sodium sulfate, and evaporated to dryness to obtain the crude product. The intermediate was obtained by silica gel column chromatography. The intermediate was added to DIEA (4.73 mg, 36.61 mmol) and 20 mL of 1,4-dioxane, and reacted at 100 °C for 2 days. The reaction endpoint was determined by TLC, and silica gel column chromatography was used to separate the intermediate 2-chloro-4-((1r,4r)-4-(2-chloro-5-oxo-5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl)cyclohexyl)oxy)benzonitrile (1.85 g, 4.60 mmol). Yield: 49%.

[0293] LC / MS(ESI+)calcd for C 20 H 17 Cl2N3O2(M+H + )m / z,402.1;found,402.1.

[0294] SM-A-6: 2-chloro-4-((1r,3r)-2,2,4,4-tetramethyl-3-(2-(methylthio)-5-oxo-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidin-6-yl)cyclobutoxy)benzonitrile

[0295]

[0296] 1,4-(bromomethyl)-2-(methylthio)pyrimidine-5-carboxylic acid ethyl ester

[0297] Ethyl 4-methyl-2-(methylthio)pyrimidine-5-carboxylate (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 solution in an ice bath. The reaction solution was heated to 60 °C and reacted for 3 hours. The reaction solution was poured into ice water (100 mL) and then extracted with ethyl acetate (50 mL × 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 oily substance, ethyl 4-(bromomethyl)-2-(methylthio)pyrimidine-5-carboxylate (8.3 g, 28.6 mmol), yield: 57%. MS: calcd. for C9H 11 BrN2O2S[M+H] + :291.0; found:291.0.

[0298] 2,4-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutylamino)methyl)-2-(methylthio)pyrimidine-5-carboxylic acid ethyl ester

[0299] 4-((1r,3r)-3-amino-2,2,4,4-tetramethylcyclobutoxy)-2-chlorobenzonitrile trifluoroacetate (11.4 mmol, crude product from a previous route) was dissolved in acetonitrile (120 mL), followed by the addition of N,N-diisopropylethylamine (7.35 g, 11.4 mmol) and ethyl 4-(bromomethyl)-2-(methylthio)pyrimidine-5-carboxylate (4.3 g, 11.4 mmol). The reaction mixture was stirred overnight at room temperature. The reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (50 mL × 3). The 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 10:1) to give an off-white solid, ethyl 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, 7.0 mmol), yield: 61%. MS: calcd.for C 24 H 29 ClN4O3S[M+H] + :489.2; found:489.2.

[0300] 3,2-Chloro-4-((1r,3r)-2,2,4,4-Tetramethyl-3-(2-(methylthio)-5-oxo-5H-pyrrolo[3,4-d]pyrimidin-6(7H)-yl)cyclobutoxy)benzonitrile (SM-A-6)

[0301] Ethyl 4-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutylamino)methyl)-2-(methylthio)pyrimidine-5-carboxylic acid (2.0 g, 4.1 mmol) was dissolved in toluene (100 mL), then the atmosphere was purged with nitrogen, and a 2.0 M solution of trimethylaluminum in n-hexane (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 × 3). The 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-pyrrolo[3,4-d]pyrimidin-6(7H)-yl)cyclobutoxy)benzonitrile (0.8 g, 1.8 mmol), yield: 49%. MS: calcd. for C 22 H 23 ClN4O2S[M+H] + :443.1; found:443.1.

[0302] Other lactam intermediates were synthesized using a method similar to the route described above.

[0303] The following amide intermediates were synthesized using methods described in the literature (US20180099940, US20170327469) or similar methods.

[0304]

[0305] The following SM-E intermediate compounds were synthesized using methods described in the literature (US20180099940, US20170327469) or similar methods.

[0306]

[0307] Intermediate SM-L-1: 4-ethynyl-1,4'-dipiperidine-1'-carboxylic acid tert-butyl ester

[0308]

[0309] 1. Compound 4-(p-Toluenesulfonyloxy)piperidine-1-carboxylic acid tert-butyl ester

[0310] 4-Hydroxypiperidine-1-carboxylic acid tert-butyl ester (10.0 g, 49.7 mmol) was dissolved in dichloromethane, followed by the addition of p-toluenesulfonyl chloride (10.8 g, 56.6 mmol), triethylamine (7.5 g, 74.5 mmol), and 4-dimethylaminopyridine (183 mg, 1.5 mmol). The reaction mixture was stirred overnight at room temperature. The reaction mixture was diluted with water (100 mL) and extracted with dichloromethane (50 mL × 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 = 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), yield: 83%. MS: calcd.for C 17 H 25 NO5S[M+H] + :356.1; found:356.1.

[0311] 2. Synthesis of compound 4-ethynyl-1,4'-dipiperidine-1'-carboxylic acid tert-butyl ester (SM-L-1)

[0312] 4-(p-Toluenesulfonyloxy)piperidine-1-carboxylic acid tert-butyl ester (1.2 g, 3.4 mmol) was dissolved in acetonitrile, followed by the addition of 4-acetylenide piperidine hydrochloride (490 mg, 3.4 mmol), potassium carbonate (1.0 g, 7.5 mmol), and potassium iodide (113 mg, 0.68 mmol). 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 × 3). The combined organic phases were washed with saturated brine (20 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 white solid 4-acetylenyl-1,4'-dipiperidine-1'-carboxylic acid tert-butyl ester (0.6 g, 2.1 mmol), yield: 60%. MS: calcd.for C 17 H 28 N₂O₂[M+H] + :293.1; found:293.1.

[0313] SM-L-3 was prepared using a method similar to that used to synthesize SM-L-1.

[0314] Intermediate SM-L-2: 3-(4-ethynylpiperidin-1-yl)azacyclobutane-1-carboxylic acid tert-butyl ester

[0315]

[0316] 4-Ethynylpiperidin hydrochloride (2.0 g, 13.8 mmol) and 3-azacyclobutanone tert-butyl carboxylate (2.35 g, 13.8 mmol) were dissolved in 1,2-dichloroethane (40 mL), followed by the addition of acetic acid (1 mL), and finally sodium triacetoxyborohydride (5.85 g, 27.6 mmol). The reaction mixture was stirred overnight at room temperature. The reaction mixture was diluted with water (50 mL) and extracted with dichloromethane (30 mL × 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 oily substance 3-(4-ethynylpiperidin-1-yl)azacyclobutanone-1-carboxylate tert-butyl ester (1.0 g, 3.8 mmol), yield: 27%. MS: calcd.for C 15 H 24 N₂O₂[M+H] + :265.2; found:265.2.

[0317] The synthesis of intermediates SM-L-4, SM-L-8, SM-L-9 and SM-L-10 is similar to that of SM-L-2.

[0318]

[0319] Intermediate SM-L-11: 4-(2-methyl-3-yn-2-yl)piperazine-1-carboxylic acid tert-butyl ester

[0320]

[0321] 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), followed by the addition of cuprous chloride (179 mg, 1.8 mmol). 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 × 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 = 10:1 to 2:1) to give a colorless oily substance, 4-(2-methyl-3-yn-2-yl)piperazine-1-carboxylic acid tert-butyl ester (3.0 g, 11.9 mmol), yield: 67%. MS: calcd.for C 14 H 24 N₂O₂[M+H] + :253.2; found:253.2.

[0322] Intermediate SM-L-13: 4-(2-methyl-3-yn-2-ylamino)piperidine-1-carboxylic acid tert-butyl ester (

[0323]

[0324] 4-Aminopiperidin-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), followed by dropwise addition of a 10 mL solution of 3-chloro-3-methylbutyne (1.0 g, 10.0 mmol) in acetonitrile. 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 × 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 = 10:1 to 2:1) to give a colorless oily substance 4-(2-methyl-3-yn-2-ylamino)piperidin-1-carboxylic acid tert-butyl ester (0.6 g, 2.3 mmol), yield: 22%. MS: calcd.for C 15 H 26 N₂O₂[M+H] + :267.2; found:267.2.

[0325] Intermediate SM-L-14: 4-(4-ethynylphenyl)piperazine-1-carboxylic acid tert-butyl ester

[0326]

[0327] 1. Compound 4-(4-formylphenyl)piperazine-1-carboxylic acid tert-butyl ester

[0328] 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), followed by the addition of potassium carbonate (11.2 g, 80.6 mmol). The reaction mixture was stirred at 110 °C for 2 days. The reaction mixture was diluted with water (150 mL) and extracted with ethyl acetate (100 mL × 3). The combined organic phases were washed with saturated brine (100 mL × 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), yield: 61%.

[0329] MS:calcd.for C 16 H 23 O2N3[M+H] + :290.2; found:290.0.

[0330] 2. Compound 4-(4-ethynylphenyl)piperazine-1-carboxylic acid tert-butyl ester

[0331] 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 slowly heated to room temperature overnight. The reaction mixture was evaporated to dryness and 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), yield: 54%. MS: calcd.for C 17 H 23 O2N2[M+H] + :287.2; found:287.2.

[0332] Intermediates 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)

[0333]

[0334] 1. Compound 4-(3-(methoxycarbonyl)cyclobutyl)piperazine-1-carboxylic acid tert-butyl ester

[0335] Methyl 3-oxocyclobutane carboxylate (5.12 g, 40.0 mmol) and piperazine-1-carboxylate tert-butyl ester (8.9 g, 48.0 mmol) were dissolved in 1,2-dichloroethane (100 mL), followed by the addition of acetic acid (4.8 g, 80.0 mmol), and finally sodium triacetoxyborohydride (21.2 g, 100 mmol). The reaction mixture was stirred overnight at room temperature. The reaction mixture was diluted with water (100 mL) and extracted with dichloromethane (50 mL × 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 = 10:1 to pure ethyl acetate) to give a white solid 4-(3-(methoxycarbonyl)cyclobutyl)piperazine-1-carboxylate tert-butyl ester (6.0 g, 20.8 mmol), yield: 52%. MS: calcd.for C 15 H 26 N₂O₄[M+H] + :299.2; found:299.4.

[0336] 2. Compound 4-(3-(hydroxymethyl)cyclobutyl)piperazine-1-carboxylic acid tert-butyl ester

[0337] 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 tetrahydrogenate (4.8 g, 80.0 mmol) was added in portions while in an ice bath. The reaction mixture was stirred in an ice bath for 1 hour. The reaction mixture was diluted with tetrahydrofuran (100 mL), kept in an ice bath, and then water (4.8 mL) was added dropwise with stirring for 10 minutes. Then, 15% sodium hydroxide solution (4.8 mL) was added with stirring for another 10 minutes, followed by the addition of water (14.4 mL) with stirring for another 20 minutes. Finally, anhydrous magnesium sulfate was added with stirring for another 20 minutes. The reaction mixture was filtered, and the filtrate was evaporated to dryness to give a colorless oily product, 4-(3-(hydroxymethyl)cyclobutyl)piperazine-1-carboxylic acid tert-butyl ester (4.4 g, 14.8 mmol), yield: 78%. MS: calcd.for C 14 H 26 N₂O₃[M+H] + :271.2; found:271.4.

[0338] 3. Compound 4-(3-formylcyclobutyl)piperazine-1-carboxylic acid tert-butyl ester

[0339] 4-(3-(hydroxymethyl)cyclobutyl)piperazine-1-carboxylic acid tert-butyl ester (4.0 g, 14.8 mmol) was dissolved in dichloromethane (80 mL), followed by the addition of 1,1',1'-(3-oxo-1λ5-1,2-phenyliodo-1(3H)-yelone) acetoacetate (9.4 g, 22.2 mmol). The reaction mixture was stirred at room temperature for 24 hours. The mixture was then filtered, and the filtrate was evaporated to dryness to obtain 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.

[0340] 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)

[0341] 4-(3-formylcyclobutyl)piperazine-1-carboxylic acid tert-butyl ester (14.8 mmol, crude product 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 slowly heated to room temperature overnight. The reaction 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 × 3), dried over sodium sulfate, and purified by silica gel column chromatography (petroleum ether:ethyl acetate = 20:1 to 12:1) to give a white solid 4-((1s,3s)-3-ethynylcyclobutyl)piperazine-1-carboxylic acid tert-butyl ester (SM-L-18Q) (0.84 g, 3.2 mmol), two-step yield: 16%. MS: calcd.for C 15 H 24 N₂O₂[M+H] + Found: 265.2; found: 265.4. A white solid 4-((1r,3r)-3-ethynylcyclobutyl)piperazine-1-carboxylic acid tert-butyl ester (SM-L-18H) (0.36 g, 1.4 mmol) was also obtained. Two-step yield: 7%. MS: calcd. for C 15 H 24 N₂O₂[M+H] + :265.2; found:265.4.

[0342] Synthesis of intermediate SM-L-5

[0343]

[0344] 1. Synthesis of compound 4-(4-(methoxycarbonyl)cyclohexyl)piperazine-1-carboxylic acid tert-butyl ester

[0345] Methyl 4-oxocyclohexylcarboxylate (10.0 g, 64.0 mmol) and piperazine-1-carboxylate tert-butyl ester (13.0 g, 70.0 mmol) were dissolved in 1,2-dichloroethane (200 mL), followed by the addition of acetic acid (7.6 g, 128.0 mmol), and finally sodium triacetoxyborohydride (34.0 g, 160 mmol). The reaction mixture was stirred overnight at room temperature. The reaction mixture was diluted with water (200 mL) and extracted with dichloromethane (100 mL × 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 = 1:1) to give a white solid 4-(4-(methoxycarbonyl)cyclohexyl)piperazine-1-carboxylate tert-butyl ester (9.6 g, 29.4 mmol), yield: 46%. MS: calcd.for C 17 H 30 N₂O₄[M+H]+ :327.2; found:327.4.

[0346] 2. Synthesis of compound 4-((1r,4r)-4-(hydroxymethyl)cyclohexyl)piperazine-1-carboxylic acid tert-butyl ester

[0347] 9.6 g (29.4 mmol) of 4-(4-(methoxycarbonyl)cyclohexyl)piperazine-1-carboxylic acid tert-butyl ester was dissolved in 200 mL of tetrahydrofuran. Lithium aluminum tetrahydrofuran (2.23 g, 58.8 mmol) was added in portions while the mixture was in an ice bath. The reaction mixture was stirred for 1 hour while still in an ice bath. The reaction mixture was then diluted with 100 mL of tetrahydrofuran and kept in an ice bath. Water (2.3 mL) was added dropwise and stirred for 10 minutes. Then, 2.3 mL of 15% sodium hydroxide solution was added and the mixture was stirred for another 10 minutes. Water (6.9 mL) was added and the mixture was stirred for another 20 minutes. Finally, anhydrous magnesium sulfate was added and the mixture was stirred for another 20 minutes. The reaction mixture was filtered, and the filtrate was evaporated to dryness and purified by silica gel column chromatography (petroleum ether:ethyl acetate = 1:1 to ethyl acetate) to give a pale yellow oil, 4-((1r,4r)-4-(hydroxymethyl)cyclohexyl)piperazine-1-carboxylic acid tert-butyl ester (1.2 g, 4.0 mmol), yield: 14%. The configuration was determined with reference to patent WO2012145361. MS: calcd for C 14 H 26 N₂O₃[M+H] + :299.2; found:299.4. 1 H NMR (400MHz, CDCl3): δ3.46–3.33(m,6H),2.51–2.38(m,4H),2.28–2.17(m,1H),1.91 –1.84(m,4H),1.62–1.48(m,1H),1.42(s,9H),1.27–1.13(m,3H),1.02–0.88(m,2H).

[0348] A pale yellow oil, 4-((1S,4S)-4-(hydroxymethyl)cyclohexyl)piperazine-1-carboxylic acid tert-butyl ester (3.0 g, 10.0 mmol), was also obtained, in a yield of 34%. MS: calcd.for C 14 H 26 N₂O₃[M+H] + :299.2; found:299.4.

[0349] 3. Synthesis of compound 4-((1r,4r)-4-(formyl)cyclohexyl)piperazine-1-carboxylic acid tert-butyl ester

[0350] 1.2 g (4.0 mmol) of 4-((1r,4r)-4-(hydroxymethyl)cyclohexyl)piperazine-1-carboxylic acid tert-butyl ester was dissolved in dichloromethane (50 mL), followed by the addition of 2.0 g (4.8 mmol) of 1,1',1'-(3-oxo-1λ5-1,2-phenyliodo-1(3H)-yelone)acetoacetate. The reaction mixture was stirred at room temperature for 24 hours. The mixture was then filtered, and the filtrate was evaporated to dryness to obtain 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.forC 16 H 28 N₂O₃[M+H] + :297.2; found:297.4.

[0351] 4. Synthesis of compound 4-((1r,3r)-4-ethynylcyclohexyl)piperazine-1-carboxylic acid tert-butyl ester

[0352] 4-((1r,4r)-4-(formyl)cyclohexyl)piperazine-1-carboxylic acid tert-butyl ester (4.0 mmol, crude product derived from Method 1 in the previous step) and 1-diazo-2-oxopropylphosphonate dimethyl ester (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 slowly heated to room temperature overnight. The reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (50 mL × 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 = 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), two-step yield: 57%. MS: calcd.for C 17 H 28 N₂O₂[M+H] + :293.2; found:293.2. 1 H NMR (400MHz, CDCl3): δ3.46–3.36(m,4H),2.53–2.44(m,4H),2.35–2.23(m,1H),2.22–2.11(m, 1H),2.09–2.00(m,3H),1.93–1.83(m,2H),1.45(s,9H),1.43–1.34(m,2H),1.28–1.20(m,2H).

[0353] The synthesis of 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 is similar to that of SM-L-18.

[0354]

[0355] The following are specific examples of the preparation of compounds provided by this invention:

[0356] 1:(3R,5S)-1-((S)-2-(2-((5-((4-(3-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)ureo)phenyl)amino)pentyl)oxy)acetamido)-3,3-dimethylbutyryl)-5-(((S)-1-(4-(4-methylthiazolyl-5-yl))phenyl)ethyl)carbamoyl)pyrrolidine-3-ylacetate

[0357]

[0358] 1. Synthesis of 2-((5-((4-(3-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)ureo)phenyl)ethyl)pentyl)oxy)aminotert-butyl ester

[0359] 1-(4-aminophenyl)-3-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)urea (100.0 mg, 0.24 mmol) and 2-((5-oxopentyl)oxy)acetic acid tert-butyl ester (52.4 mg, 0.24 mmol) were dissolved in 5 mL of DCM, cooled to 0 °C, and one drop of acetic acid was added. Then, sodium cyanoborohydride (45.6 mg, 0.73 mmol) was added in portions, and the mixture was brought to room temperature and stirred overnight. Water was added, and the mixture was extracted with DCM, dried, and evaporated to dryness. Pre-TLC purification yielded 73.4 mg of compound 2-((5-((4-(3-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)ureo)phenyl)ethyl)pentyl)oxy)aminotert-butyl ester. Yield: 54.6%. LC / MS (ESI+) Calculated for C 33 H 45 ClN4O5(M-56+H + )m / z,612.3;Found,557.3.

[0360] 2,2-((5-((4-(3-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)ureo)phenyl)amino)pentyl)oxy)acetic acid

[0361] 2-((5-((4-(3-(((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)ureo)phenyl)ethyl)pentyl)oxy)amino tert-butyl ester (70.0 mg, 0.09 mmol) was dissolved in 2 mL of DCM, and 5 mL of TFA was added. The mixture was stirred at room temperature for 1 h, and the reaction was confirmed to be complete by TLC. The mixture was then evaporated to dryness, dissolved in DCM, and washed with saturated sodium bicarbonate solution until the pH was 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)ureo)phenyl)amino)pentyl)oxy)acetic acid was obtained. Yield: 32.6%.

[0362] 3. Synthesis of (3R,5S)-1-((S)-2-(2-((5-((4-(3-(((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)ureo)phenyl)amino)pentyl)oxy)acetamido)-3,3-dimethylbutyryl)-5-(((S)-1-(4-(4-methylthiazolyl-5-yl))phenyl)ethyl)carbamoyl)pyrrolidine-3-ylacetate

[0363] 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, cooled to about 0 °C, and 0.5 ml of DIEA and HATU (29.1 mg, 0.13 mmol) were added. The mixture was stirred for 5 min. Then (3R,5S)-1-((S)-2-amino-3,3-dimethylbutyryl)-5-(((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)amido)pyrrolidine-3-acetic acid ester (26.0 mg, 0.10 mmol) was added, and the mixture was brought back to room temperature and stirred for 1 h. Extracted with ethyl acetate and 1N hydrochloric acid, the organic layer was washed twice with brine, dried, and evaporated to dryness. Purified by silica gel column chromatography, the compound (3R,5S)-1-((S)-2-(2-((5-((4-(3-(((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)ureo)phenyl)amino)pentyl)oxy)acetamido)-3,3-dimethylbutyryl)-5-(((S)-1-(4-(4-methylthiazol-5-yl))phenyl)ethyl)carbamoyl)pyrrolidine-3-ylacetate 8.2

[0364] mg. Yield: 37.2%. LC / MS (ESI+) Calcd for C 54 H 69 ClN8O8S(M+H + )m / z,1024.5;Found,1024.4. 1H NMR(400MHz,DMSO-d6)δ9.21(m,1H),9.11(m,1H),8.87-8.82(d,J=7.6Hz,1H ),8.13(m,1H),7.90(d,J=8.8Hz,1H),7.38(dt,J=8.7,7.5Hz,6H),7.28(d,J= 2.4Hz,1H),7.06(dd,J=8.8,2.4Hz,1H),6.85(d,J=8.3Hz,1H),6.77(s,1H), 5.87(s,1H),5.20(s,1H),4.93–4.88(m,1H),4.60(s,2H),4.53(s,1H),4.45( dd,J=14.4,8.7Hz,2H),4.29(s,1H),3.90(dd,J=16.2,6.4Hz,3H),3.77(dd, J=11.8,3.9Hz,1H),3.49(t,J=6.4Hz,2H),3.05(s,2H),2.45(s,3H),2.29–2. 23(m,1H),2.09(s,1H),1.99(s,3H),1.98(d,J=3.1Hz,1H),1.62–1.56(m,4H ),1.45(d,J=4.9Hz,3H),1.39(s,6H),1.31(s,1H),1.21(s,6H),0.93(s,9H).

[0365] 2: (3R,5S)-1-((S)-2-(2-(2-(4-(2-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-1-oxoisoindoline-5-yl)piperazin-1-yl)ethoxy)acetamido)-3,3-dimethylbutyryl)-5-(((S)-1-(4-(4-methylthiazolyl-5-yl)phenyl)ethyl)carbamoyl)pyrrolidine-3-ylacetate

[0366]

[0367] 1. 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

[0368] 4-((1r,3r)-3-(5-bromo-1-oxoisoindoline-2-yl)-2,2,4,4-tetramethylcyclobutoxy)-2-chlorobenzonitrile (100.0 mg, 0.21 mmol), 2-(2-(piperazin-1-yl)ethoxy)tert-butyl acetate (154.5 mg, 0.63 mmol), BINAP (39.0 mg, 0.633 mmol), Pb2(dba)3 (19.1 mg, 0.02 mmol), and Cs2CO3 (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 solution was filtered through diatomaceous earth, the filtrate was concentrated, water was added, and the solution was extracted with dichloromethane. The organic phase was dried, filtered, concentrated, and purified by Pre-TLC to give 94.7 mg 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-acetate tert-butyl ester. Yield: 49.3%. LC / MS (ESI+) Calcd for C 35 H 45 ClN4O5(M-56+H + )m / z,636.3;Found,581.2.

[0369] 2. Synthesis of compound 2-(2-(4-(2-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutane)-1-dioxoisoindoline-5-yl)piperazin-1-yl)ethoxy)acetic acid

[0370] 90.0 mg (0.19 mmol) of tert-butyl 2-(2-(4-(2–((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutane)-1-oxoisoindoline)piperazin-1-yl)ethoxy)-5-acetic acid was dissolved in 1 mL of dichloromethane, and then 5 mL of trifluoroacetic acid was added and stirred at room temperature for 30 min. After the reaction was completed by TLC, the solution was directly evaporated to dryness, dissolved in dichloromethane, and the pH was adjusted to 6 with saturated sodium bicarbonate. The mixture was separated, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to give 63.3 mg of compound 2-(2-(4-(2-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutane)-1-dioxoisoindoline-5-yl)piperazin-1-yl)ethoxy)acetic acid. Yield: 89.3%.

[0371] 3. Synthesis of (3R,5S)-1-((S)-2-(2-(2-(4-(2-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-1-oxoisoindoline-5-yl)piperazin-1-yl)ethoxy)acetamido)-3,3-dimethylbutyryl)-5-(((S)-1-(4-(4-methylthiazolyl-5-yl)phenyl)ethyl)carbamoyl)pyrrolidine-3-ylacetate

[0372] 2-(2-(4-(2-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutane)-1-dioxoisoindoline-5-yl)piperazin-1-yl)ethoxy)acetic acid (30.0 mg, 0.09 mmol) was dissolved in 2 ml DMF, cooled to approximately 0 °C, and 0.5 ml DIEA and HATU (29.1 mg, 0.13 mmol) were added. The mixture was stirred for 5 min. Then, (3R,5S)-1-((S)-2-amino-3,3-dimethylbutyryl)-5-(((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)amido)pyrrolidine-3-acetic acid ester (26.0 mg, 0.10 mmol) was added, and the mixture was brought back to room temperature and stirred for 1 h. Extracted with ethyl acetate and 1N hydrochloric acid, the organic layer was washed twice with brine, dried, and evaporated to dryness. Purified by silica gel column chromatography, the compound (3R,5S)-1-((S)-2-(2-(2-(4-(2-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-1-oxoisoindoline-5-yl)piperazin-1-yl)ethoxy)acetamido)-3,3-dimethylbutyryl)-5-(((S)-1-(4-(4-methylthiazolyl-5-yl)phenyl)ethyl)carbamoyl)pyrrolidine-3-ylacetate 11.6 mg was obtained. Yield: 33.5%. LC / MS (ESI+) Calcd for C 56 H 69 ClN8O8S(M+H + )m / z,1048.5;Found,1048.5. 1H NMR (400MHz, DMSO-d6) δ9.02 (m, 1H), 8.98–8.93 (m, 1H), 8.47 (d, = 7.6Hz, 1H), 7.97 (d, J = 8.8Hz, 1H), 7.38 (dt, J = 8.7, 7.5Hz, 6H), 7.28 (d, J = 2.4Hz, 1H),7.06(dd,J=8.8,2.4Hz,1H),6.85(d,J=8.3Hz,1H),6.77(s,1H),5.8 7(s,1H),5.20(s,1H),4.93–4.88(m,1H),4.60(s,2H),4.53(s,1H),4.45( dd,J=14.4,8.7Hz,2H),4.29(s,1H),4.22–4.05(m,4H),3.90(dd,J=16.2 ,6.4Hz,3H),3.77(dd,J=11.8,3.9Hz,1H),3.49(t,J=6.4Hz,2H),3.05(s, 2H),2.29–2.23(m,1H),2.09(s,1H),1.99(s,3H),1.98(d,J=3.1Hz,1H),1 .45(d,J=4.9Hz,3H),1.37(s,6H),1.35(s,1H),1.14(s,6H),0.95(s,9H).

[0373] 3: Compound (2S,4R)-1-((S)-2-(2-(2-(4-(2-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-1-oxoisoindoline-5-yl)piperazin-1-yl)ethoxy)acetamido)-3,3-dimethylbutyryl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazolyl-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide

[0374]

[0375] 2-(2-(4-(2-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutane)-1-dioxoisoindoline-5-yl)piperazin-1-yl)ethoxy)acetic acid (30.0 mg, 0.09 mmol) was dissolved in 2 ml of DMF, cooled to approximately 0 °C, and 0.5 ml of DIEA and HATU (29.1 mg, 0.13 mmol) were added. The mixture was stirred for 5 min. Then, (2S,4R)-1-((S)-2-amino-3,3-dimethylbutyryl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazolyl-5-yl)phenyl)ethyl)amido)pyrrolidine-2-carboxamide (24.0 mg, 0.10 mmol) was added, and the mixture was brought to room temperature and stirred for 1 h. Extracted with ethyl acetate and 1N hydrochloric acid, the organic layer was washed twice with brine, dried, and evaporated to dryness. Purified by silica gel column chromatography, the compound (3R,5S)-1-((S)-2-(2-(2-(4-(2-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-1-oxoisoindoline-5-yl)piperazin-1-yl)ethoxy)acetamido)-3,3-dimethylbutyryl)-5-(((S)-1-(4-(4-methylthiazolyl-5-yl)phenyl)ethyl)carbamoyl)pyrrolidine-3-ylacetate 8.2 mg was obtained. Yield: 31.7%. LC / MS (ESI+) Calcd for C 54 H 67 ClN8O7S(M+H + )m / z,1007.5;Found,1007.5. 1H NMR (400MHz, DMSO-d6) δ9.14(m,1H),9.02(m,1H),8.47(d,J=7.6Hz,1H),7.97(d,J=8.8Hz,1H),7.38(dt,J=8.7,7.5Hz,6H),7.28(d,J=2.4Hz,1H),7. 06(dd,J=8.8,2.4Hz,1H),6.85(d,J=8.3Hz,1H),6.77(s,1H),5.87(s,1H) ,5.20(s,1H),4.93–4.88(m,1H),4.60(s,2H),4.53(s,1H),4.45(dd,J=14. 4,8.7Hz,2H),4.29(s,1H),4.22–4.05(m,4H),3.90(dd,J=16.2,6.4Hz,3H ),3.77(dd,J=11.8,3.9Hz,1H),3.49(t,J=6.4Hz,2H),3.05(s,2H),2.45(s ,3H),2.29–2.23(m,1H),2.09(s,1H),1.99(s,3H),1.98(d,J=3.1Hz,1H), 1.45(d,J=4.9Hz,3H),1.37(s,6H),1.35(s,1H),1.14(s,6H),0.95(s,9H).

[0376] 4: (3R,5R)-1-((S)-2-(2-((6-(2-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-3-oxoisoindoline-5-yl)hex-5-yn-1-yl)oxy)acetamido)-3,3-dimethylbutyryl)-5-(((S)-1-(4-(4-methylthiazolyl-5-yl)phenyl)ethyl)carbamoyl)pyrrolidine-3-ylacetate

[0377]

[0378] 1. 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)tert-butyl acetate

[0379] 4-((1r,3r)-3-)-6-bromo-1-oxoisoindoline-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 tert-butyl 2-(hexane-5-yn-1-yloxy)acetate (38.5 mg, 0.18 mmol) were added sequentially to the reaction flask. The mixture was purged with nitrogen, and 1.2 mL of toluene and 0.4 mL of triethylamine were added using a syringe, followed by another nitrogen purging. The reaction was carried out overnight at 110 °C, and TLC was used to confirm complete reaction. The system was cooled to room temperature, filtered through a diatomaceous earth liner, and the filtrate was concentrated. The filtrate was dissolved in dichloromethane, washed with 0.5 M HCl and saturated brine, dried, filtered, and concentrated under vacuum. Pre-TLC purification yielded 97.3 mg of tert-butyl 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)acetate. Yield: 78.8%. LC / MS (ESI+) Calcd for C 35 H 41 ClN2O5(M-56+H + )m / z,604.3;Found,549.2.

[0380] Synthesis of 2,2-((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

[0381] 95.0 mg (0.15 mmol) of tert-butyl 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 dissolved in 1 mL of DCM, and 5 mL of TFA was added. The reaction was carried out at room temperature for 1 h, and the reaction was confirmed by TLC to be complete. The mixture was evaporated to dryness, dissolved in DCM, and washed with saturated sodium bicarbonate aqueous 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. Yield: 92.6%.

[0382] 3.(3R,5R)-1-((S)-2-(2-((6-(2-(((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-3-oxoisoindoline-5-yl)hex-5-yn-1-yl)oxy)acetamido)-3,3-dimethylbutyryl)-5-(((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidine-3-ylacetate (4)

[0383] 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, and DIEA (98.5 mg, 0.76 mmol) was added. The mixture was cooled to approximately 0 °C, and HATU (96.0 mg, 0.18 mmol) was added. After stirring for 10 min, (2S,4R)-1-((S)-2-amino-3,3-dimethylbutyryl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazolyl-5-yl)phenyl)ethyl)amido)pyrrolidine-2-carboxamide (130.1 mg, 0.22 mmol) was added. The mixture was then allowed to return to room temperature and reacted for 2 h. The reaction was detected by TLC upon completion. The system was slowly added to 5 mL of H₂O, extracted with ethyl acetate, and the organic phase was washed five times with water, followed by washing with 0.5 M HCl and saturated brine, respectively. The mixture was dried, filtered, and concentrated under vacuum. Pre-TLC purification yielded 38.0 mg of (3R,5R)-1-((S)-2-(2-((6-(2-(((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-3-oxoisoindoline-5-yl)hex-5-yn-1-yl)oxy)acetamido)-3,3-dimethylbutyryl)-5-(((S)-1-(4-(4-methylthiazolyl-5-yl)phenyl)ethyl)carbamoyl)pyrrolidine-3-ylacetate. Yield: 53.8%. 1H NMR (400MHz, CDCl3) δ8.69(s,1H),7.88(s,1H),7.59-7.54(m,2H),7.38(dd,J=16.0,8.3Hz,6H),7.19(d,J=9.2Hz,1H),6.99(d,J=2.4Hz,1H),6.83(d d,J=8.7,2.4Hz,1H),5.35(s,1H),5.10-5.05(m,1H),4.75(dd,J=8.3,6.5H z,1H),4.65(s,2H),4.59(d,J=9.3Hz,1H),4.39(s,1H),4.31(s,1H),4.05( d,J=13.0Hz,1H),3.96(d,J=6.2Hz,2H),3.83(dd,J=11.6,4.9Hz,1H),3.59 (t,J=6.2Hz,2H),2.74-2.68(m,1H),2.53(s,3H),2.50(s,1H),2.16-2.10( m,1H),2.03(d,J=8.6Hz,4H),1.86-1.80(m,2H),1.73(dd,J=11.5,4.6Hz,2 H), 1.47 (d, J = 6.9 Hz, 3H), 1.44 (t, J = 3.1 Hz, 6H), 1.25 (s, 6H), 1.05 (s, 9H). LC / MS(ESI+)Calcd forC 56 H 65 ClN6O8S(M / 2+H + )m / z,1016.5;Found,509.3.

[0384] 5:(2R,4R)-1-((S)-2-(2-((6-(2-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-3-oxoisoindoline-5-yl)hex-5-yn-1-yl)oxy)acetamido)-3,3-dimethylbutyryl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide(5)

[0385]

[0386] Dissolve (3R,5R)-1-((S)-2-(2-((6-(2-(((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-3-oxoisoindoline-5-yl)hex-5-yn-1-yl)oxy)acetamido)-3,3-dimethylbutyryl)-5-(((S)-1-(4-(4-methylthiazolyl-5-yl)phenyl)ethyl)carbamoyl)pyrrolidine-3-ylacetate (5.0 mg, 4.54 μmol) in 1 mL of methanol, and slowly add a mixture of LiOH·H₂O (0.9 mg, 0.02 mmol) and 0.5 mL of H₂O. The reaction was complete by TLC monitoring after approximately 30 min. Water was added, and the mixture was extracted with DCM. Pre-TLC purification yielded 3.0 mg of compound (2R,4R)-1-((S)-2-(2-((6-(2-(((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-3-oxoisoindoline-5-yl)hex-5-yn-1-yl)oxy)acetamido)-3,3-dimethylbutyryl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide. Yield: 84.3%. 1 H NMR (400MHz, CDCl3) δ8.71(s,1H),7.86(s,1H),7.57(dd,J=7.6,4.6,2H),7.53-7.46(m,1H),7.38(q,J=8.5,5H),7.23(d,J =9.0,1H),6.99(d,J=2.3,1H),6.83(dd,J=8.7,2.3,1H),5.11-5.03(m,1H),4.78(t,J=7.9,1H),4.65(s,2H),4.54(d,J=8.4 ,2H),4.40(s,1H),4.31(s,1H),4.15(d,J=11.3,1H),3.95(t,J=11.5,2H),3.60(t,J=6.1,3H),2.54(s,4H),2.50(t,J=6.7 ,2H),2.13-1.98(m,2H),1.82(d,J=6.6,2H),1.78-1.73(m,2H),1.47(d,J=6.9,3H),1.44(s,6H),1.25(s,6H),1.07(s,9H). LC / MS(ESI+)Calcd for C 54 H 63 ClN6O7S(M+H + )m / z,975.4;Found,975.5.

[0387] 6: (3R,5S)-1-((S)-2-(2-((5-((2-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-3-oxoisoindoline-5-yl)amino)pentyl)oxy)acetamido)-3,3-dimethylbutyryl)-5-(((S)-1-(4-(4-methylthiazol-5)-yl)phenyl)ethyl)carbamoyl)pyrrolidine-3-ylacetate (6)

[0388]

[0389] Synthesis of 1,2-((2-((2-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-3-oxoisoindol-5-yl)amino)pentyl)oxy)tert-butyl acetate

[0390] 4-((1r,3r)-3-(6-amino-1-oxoisoindoline-2-yl)-2,2,4,4-tetramethylcyclobutoxy)-2-chlorobenzonitrile (150.0 mg, 0.37 mmol) and 2-((5-oxopentyl)oxy)tert-butyl acetate (79.1 mg, 0.35 mmol) were dissolved in 5 mL of DCM, cooled to 0 °C, and one drop of acetic acid was added. Then, sodium cyanoborohydride (58.6 mg, 0.92 mmol) was added in portions, and the mixture was brought to room temperature and stirred overnight. Water was added, and the mixture was extracted with DCM, dried, and evaporated to dryness. Pre-TLC purification yielded 74.4 mg of compound 2-((2-((2-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-3-oxoisoindoline-5-yl)amino)pentyl)oxy)tert-butyl acetate. Yield: 67.5%. LC / MS (ESI+) Calculated for C 34 H 44 ClN3O5(M-56+H + )m / z,609.3;Found,554.2.

[0391] Synthesis of 2,2-((2-((2-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-3-oxoisoindol-5-yl)amino)pentyl)oxy)acetic acid

[0392] 74.0 mg (0.12 mmol) of tert-butyl 2-((2-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-3-oxoisoindol-5-yl)amino)pentyl)oxy)acetic acid was dissolved in 1 mL of DCM, and 5 mL of TFA was added. The mixture was stirred at room temperature for 1 h. TLC was used to confirm the reaction was complete. The mixture was evaporated to dryness, dissolved in DCM, and washed with saturated sodium bicarbonate solution until the pH was 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. Yield: 96.3%.

[0393] 3. Synthesis of (3R,5S)-1-((S)-2-(2-((5-((2-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-3-oxoisoindoline-5-yl)amino)pentyl)oxy)acetamido)-3,3-dimethylbutyryl)-5-(((S)-1-(4-(4-methylthiazolyl-5)-yl)phenyl)ethyl)carbamoyl)pyrrolidine-3-ylacetate

[0394] 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, and DIEA (81.5 mg, 0.63 mmol) was added. The mixture was cooled to approximately 0 °C, and HATU (72.0 mg, 0.19 mmol) was added. After stirring for 10 min, (2S,4R)-1-((S)-2-amino-3,3-dimethylbutyryl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazolyl-5-yl)phenyl)ethyl)amido)pyrrolidine-2-carboxamide (92.1 mg, 0.19 mmol) was added. The mixture was then allowed to return to room temperature and reacted for 2 h. The reaction was detected by TLC upon completion. The system was slowly added to 5 ml of H₂O, extracted with ethyl acetate, and the organic phase was washed five times with water, followed by washing with 0.5 M HCl and saturated brine. The mixture was dried, filtered, and concentrated under vacuum. Pre-TLC purification yielded 31.3 mg of (3R,5S)-1-((S)-2-(2-((5-((2-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-3-oxoisoindoline-5-yl)amino)pentyl)oxy)acetamido)-3,3-dimethylbutyryl)-5-(((S)-1-(4-(4-methylthiazolyl-5)-yl)phenyl)ethyl)carbamoyl)pyrrolidine-3-ylacetate. Yield: 38.8%. 1H NMR (400MHz, DMSO-d6) δ8.98(m,1H),8.47(d,J=7.6Hz,1H),7.90(d,J=8.8Hz,1H),7.38(dt,J=8.7,7.5Hz,6H),7.28(d,J=2.4Hz,1H),7.06(dd,J= 8.8,2.4Hz,1H),6.85(d,J=8.3Hz,1H),6.77(s,1H),5.87(s,1H),5.20(s ,1H),4.93-4.88(m,1H),4.60(s,2H),4.53(s,1H),4.45(dd,J=14.4,8.7 Hz,2H),4.29(s,1H),3.90(dd,J=16.2,6.4Hz,3H),3.77(dd,J=11.8,3.9 Hz,1H),3.49(t,J=6.4Hz,2H),3.05(s,2H),2.45(s,3H),2.29-2.23(m,1 H),2.09(s,1H),1.99(s,3H),1.98(d,J=3.1Hz,1H),1.62-1.56(m,4H),1 .45(d,J=4.9Hz,3H),1.37(s,6H),1.35(s,1H),1.14(s,6H),0.95(s,9H). LC / MS(ESI+)Calcd for C 55 H 68 ClN7O8S(M+H + )m / z,1021.5;Found,1022.5.

[0395] 7:(2S,4R)-1-((S)-2-(2-((5-((2-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-3-oxoisoindoline-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)

[0396]

[0397] Dissolve (3R,5S)-1-((S)-2-(2-((5-((2-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-3-oxoisoindoline-5-yl)amino)pentyl)oxy)acetamido)-3,3-dimethylbutyryl)-5-(((S)-1-(4-(4-methylthiazolyl-5)-yl)phenyl)ethyl)carbamoyl)pyrrolidine-3-ylacetate (5.0 mg, 4.30 μmol) in 1 mL of methanol, and slowly add a mixture of LiOH·H₂O (0.9 mg, 0.02 mmol) and 0.5 mL of H₂O. The reaction was monitored by TLC for approximately 30 min until completion. Water was added, and the mixture was extracted with DCM. Prep-TLC purification yielded 3.3 mg of compound (2S,4R)-1-((S)-2-(2-((5-((2-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-3-oxoisoindoline-5-yl)amino)pentyl)oxy)acetamido)-3,3-dimethylbutyryl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazolyl-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide. Yield: 87.4%. 1 H NMR (400MHz, DMSO-d6) δ8.97(m,1H),8.46(d,J=7.6Hz,1H),7.89(d,J=8.8Hz,1H),7.38(dt,J=8.7,7.5Hz,6H),7.28(d,J=2.4Hz,1H),7.06(dd ,J=8.8,2.4Hz,1H),6.85(d,J=8.3Hz,1H),6.77(s,1H),5.87(s,1H),5. 20(s,1H),4.93-4.88(m,1H),4.60(s,2H),4.53(s,1H),4.45(dd,J=14. 4,8.7Hz,2H),4.29(s,1H),3.90(dd,J=16.2,6.4Hz,3H),3.77(dd,J=11.8,3.9Hz,1H),3.49(t,J=6.4Hz,2H),3.05(s,2H),2.45(s,3H),2.28- 2.22(m,1H),2.08(s,1H),1.98(d,J=3.1Hz,1H),1.62-1.54(m,4H),1.4 3(d,J=4.9Hz,3H),1.36(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.

[0398] 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)pyrrolidine-3-ylacetate (8)

[0399]

[0400] 1. Synthesis of N-((1R,3R)-3-(3-bromo-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-iodobenzamide

[0401] 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. The mixture was stirred at low temperature for 10 min, and then 4–((1R,3R)-3-amino-2,2,4,4-tetramethylcyclobutyl)-2-chlorobenzyl nitrile 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. The reaction was confirmed by TLC. The reaction mixture was washed with 0.5 M HCl aqueous solution and saturated brine, dried, and concentrated under vacuum until no dripping occurred. Column purification yielded 221.0 mg of N-((1R,3R)-3-(3-bromo-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-iodobenzoamide. Yield: 73.7%. LC / MS (ESI+) Calculated for C 22 H 22 BrIN2O2(M+H + )m / z,554.0;Found,555.1.

[0402] Synthesis of 2,2-(6-(4-((1r,3r)-3-(3-bromo-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)carbamoyl-phenyl)hex-5-yn-1-yloxy)tert-butyl acetate

[0403] 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 tert-butyl 2-(hexane-5-yn-1-yloxy)acetate (38.5 mg, 0.18 mmol) were added sequentially to the reaction flask. The mixture was purged with nitrogen, and 1.2 ml of toluene and 0.4 ml of triethylamine were added using a syringe, followed by another nitrogen purging. The reaction was incubated at 90 °C for 3 h, and TLC was used to confirm complete reaction. The system was cooled to room temperature, filtered through a diatomaceous earth liner, and the filtrate was concentrated. The filtrate was dissolved in dichloromethane, washed with 0.5 M HCl and saturated brine, dried, filtered, and concentrated under vacuum. Pre-TLC purification yielded 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)tert-butyl acetate. Yield: 91.6%. LC / MS (ESI+) Calcd for C 34 H 41 BrN2O5(M-56+H + )m / z,638.2;Found,583.2.

[0404] Synthesis of 3,2-(6-(4-((1r,3r)-3-(3-bromo-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)carbamoyl-phenyl)hex-5-yn-1-yloxy)acetic acid

[0405] 120.0 mg (0.19 mmol) of tert-butyl 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 dissolved in 1 mL of DCM, and 5 mL of TFA was added. The reaction was carried out at room temperature for 1 h, and the reaction was confirmed by TLC to be complete. The mixture was evaporated to dryness, dissolved in DCM, and washed with saturated sodium bicarbonate solution until the pH was 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. Yield: 92.4%.

[0406] 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)pyrrolidine-3-ylacetate

[0407] 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, and DIEA (113.5 mg, 0.89 mmol) was added. The mixture was cooled to approximately 0 °C, and HATU (101.0 mg, 0.24 mmol) was added. After stirring for 10 min, (2S,4R)-1-((S)-2-amino-3,3-dimethylbutyryl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazolyl-5-yl)phenyl)ethyl)amido)pyrrolidine-2-cyclopropionamide (130.1 mg, 0.22 mmol) was added. The mixture was then allowed to return to room temperature and reacted for 2 h. The reaction was detected by TLC upon completion. The system was slowly added to 5 ml of H2O, extracted with ethyl acetate, and the organic phase was washed five times with water, followed by washing with 0.5 M HCl and saturated brine. The mixture was dried, filtered, and concentrated under vacuum. Pre-TLC purification yielded 40.0 mg 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)pyrrolidine-3-yl acetate. Yield: 46.7%. 1H NMR (400MHz, CDCl3) δ8.81(s,1H),7.70(d,J=8.1Hz,2H),7.56(d,J=8.7Hz,1H),7.45(d,J=8.4Hz,3H),7.33(d,J=3.6Hz,4H),7.15(d,J=2.3 Hz,2H),6.85(dd,J=8.7,2.3Hz,1H),6.27(d,J=8.3Hz,1H),5.37(s,1H),4.64(t,J=7.4Hz,1H),4.54(d,J=9.3Hz,1H),4.15(d,J=8.2Hz,1H), 4.06(s,1H),4.01-3.92(m,2H),3.80(dd,J=11.6,4.5Hz,1H),3.60(t,J=6.1Hz,3H),2.68-2.61(m,1H),2.52(d,J=3.4Hz,3H),2.50(s,1H),2 .18(d,J=11.2Hz,1H),2.05(s,3H),1.83(d,J=7.3Hz,2H),1.75(dd,J=13.6,6.7Hz,4H),1.27(s,6H),1.25(s,4H),1.23(s,6H),0.97(s,9H). LC / MS(ESI+)Calcd for C 56 H 65 BrN6O8S(M+H+)m / z,1062.4; Found,1063.4.

[0408] 9: Compound (2R,4R)-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)-4-hydroxy-N-(1-(4-(4-methyl-5-yl)phenyl)cyclopropyl)pyrrolidine-2-carboxamide (9).

[0409]

[0410] Dissolve (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)pyrrolidine-3-yl acetate (5.0 mg, 4.70 μmol) in 1 mL of methanol, and slowly add a mixture of LiOH·H₂O (0.9 mg, 0.02 mmol) and 0.5 mL of H₂O. The reaction was monitored by TLC for approximately 30 min until completion. Water was added, and the mixture was extracted with DCM. Pre-TLC purification yielded 3.0 mg of compound (2R,4R)-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)-4-hydroxy-N-(1-(4-(4-methyl-5-yl)phenyl)cyclopropyl)pyrrolidine-2-carboxamide. Yield: 84.3%. LC / MS (ESI+) Calcd for C 56 H 65 BrN6O8S(M+H + )m / z,1020.4;Found,1021.4. 1 H NMR(400MHz, CDCl3)δ8.96(s,1H),7.70(s,1H),7.59–7.49(m,2H),7.43(s,1H),7.35(s,2H),7.31(s,1H),7.21(d,J =8.5Hz,1H),7.15(s,1H),6.85(d,J=8.0Hz,1H),6.44–6.34(m,1H),4.66(s,1H),4.58–4.43(m,2H),4.23–4.06(m,3H ),4.03–3.89(m,2H),3.62(d,J=16.3Hz,3H),2.53(d,J=13.9Hz,3H),2.47–2.39(m,1H),2.38–2.29(m,1H),2.14(s, 2H),2.04(s,1H),1.82(s,4H),1.75(s,10H),1.29(s,6H),1.25(s,9H),1.23(s,6H),1.01(s,7H),0.93–0.78(m,5H).

[0411] 10:(3R,5S)-1-((S)-2-(2-(4-((2-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-1-oxoisoindoline-5-ylethynyl)-1H-pyrazole-1-yl)acetamido)-3,3-dimethylbutyryl)-5-((((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidine-3-ylacetate (10)

[0412]

[0413] LC / MS (ESI+) Calculated for C 55 H 59 ClN8O7S(M+H + )m / z,1011.4;found 1011.4. 1 H NMR (400MHz, DMSO-d6) δ8.99(s,1H),8.47(d,J=7.6Hz,1H),8.32(d,J=8.5Hz,1H),8.13(d,J=6.3Hz,1H),7.91(d,J=8.8Hz,1H),7.76 (s,1H),7.70(d,J=7.1Hz,2H),7.59(d,J=8.1Hz,1H),7.41(dd,J=25.1,8.2Hz,4H),7.30(d,J=2.4Hz,1H),7.08(dd,J=8.8,2.4Hz,1H ),5.76(s,1H),5.17(s,1H),5.02–4.90(m,3H),4.79(d,J=15.3Hz,2H),4.55(s,1H),4.48(t,J=8.3Hz,1H),4.41–4.31(m,2H),3.90( d,J=11.8Hz,1H),3.74(dd,J=11.6,3.9Hz,1H),3.32(s,1H),2.46(s,3H),1.93(s,3H),1.43–1.34(m,9H),1.16(s,6H),0.98(s,9H).

[0414] 11:(2S,4R)-1-((S)-2-(2-(4-((2-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-1-oxoisoindoline-5-ylethynyl)-1H-pyrazole-1-yl)acetamido)-3,3-dimethylbutyryl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide(11)

[0415] LC / MS (ESI+) Calculated for C 53 H 57 ClN8O6S(M+H + )m / z,969.4; found 969.4. 1 H NMR (400MHz, DMSO-d6) δ8.99(d,J=3.0Hz,1H),8.45(d,J=7.6Hz,1H),8.27(d,J=8.8Hz,1H),8.14(d,J=2.8Hz,1H),7.91(dd,J=8.7,3.1Hz,1H ),7.77(d,J=2.9Hz,1H),7.73–7.67(m,2H),7.59(d,J=7.9Hz,1H),7.46–7.35(m,4H),7.30(d,J=2.5Hz,1H),7.08(dd,J=8.8,2.5Hz,1H),5.76 (d,J=3.1Hz,0H),5.14(d,J=3.3Hz,1H),4.96(dd,J=21.1,4.4Hz,3H),4.81(s,2H),4.58–4.49(m,2H),4.44(d,J=7.9Hz,1H),4.33(s,1H),4.2 8(s,1H),3.66–3.51(m,2H),2.45(d,J=3.1Hz,3H),2.03(s,1H),1.77( d,J=8.8Hz,1H),1.44–1.36(m,9H),1.16(d,J=2.7Hz,6H),0.96(s,9H).

[0416] 12:(3R,5S)-1-((S)-2-(2-((3-(2-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-1-oxoisoindoline-5-yl)prop-2-yn-1-yl)oxy)propoxy)acetamido)-3,3-dimethylbutyryl)-5-((((S)-1-acetic acid (4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidine-3-ylacetate (12)

[0417]

[0418] LC / MS (ESI+) Calculated for C 55 H 63 ClN6O9S(M+H + )m / z,1019.4;found 1019.4. 1H NMR (400MHz, DMSO-d6) δ8.99(s,1H),8.47(d,J=7.6Hz,1H),7.91(d,J=8.8Hz,1H),7.69(d,J=2.9Hz,2H),7.57(d, J=7.9Hz,1H),7.43(d,J=8.3Hz,3H),7.37(s,2H),7.29(d,J=2.3Hz,1H),7.07(dd,J=8.7,2.4Hz,1H),5.20(s,1H), 4.90(s,1H),4.79(s,2H),4.54(s,1H),4.49(s,5H),4.32(s,1H),3.99(s,3H),3.75–3.67(m,4H),3.38(s,1H),3.3 2(s,2H),2.45(s,3H),2.00(s,5H),1.37(dd,J=19.0,4.4Hz,9H),1.23(s,1H),1.15(s,6H),0.95(d,J=7.4Hz,9H).

[0419] 13:(2S,4R)-1-((S)-2-(2-((3-(2-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-1-oxoisoindoline-5-yl)prop-2-yn-1-yl)oxy)propoxy)acetamido)-3,3-dimethylbutyryl)-4-hydroxy-N-((S)-1-(4-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide(13)

[0420] LC / MS (ESI+) Calculated for C 53 H 61 ClN6O8S(M+H + )m / z,977.4; found 977.4. 1H NMR (400MHz, DMSO-d6) δ8.99(s,1H),8.47(d,J=7.6Hz,1H),8.32(d,J=8.5Hz,1H),8.13(d,J=6.3Hz,1H),7.91(d,J=8.8Hz,1H),7.76 (s,1H),7.70(d,J=7.1Hz,2H),7.59(d,J=8.1Hz,1H),7.41(dd,J=25.1,8.2Hz,4H),7.30(d,J=2.4Hz,1H),7.08(dd,J=8.8,2.4Hz,1H ),5.76(s,1H),5.17(s,1H),5.02–4.90(m,3H),4.79(d,J=15.3Hz,2H),4.55(s,1H),4.48(t,J=8.3Hz,1H),4.41–4.31(m,2H),3.90( d,J=11.8Hz,1H),3.74(dd,J=11.6,3.9Hz,1H),3.32(s,1H),2.46(s,3H),1.93(s,3H),1.43–1.34(m,9H),1.16(s,6H),0.98(s,9H).

[0421] 14:(3R,5S)-1-((2S)-2-(2-((3-(2-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-1-oxoisoindol-5-yl)prop-2-yn-1-yl)oxy)propoxy)acetamido)-3,3-dimethylbutyryl)-5-((((S)-1-acetic acid (4-(4-methylthiazolyl-5-yl)phenyl)ethyl)carbamoyl)pyrrolidine-3-ylacetate (14);

[0422]

[0423] LC / MS (ESI+) Calculated for C 56 H 65 ClN6O9S(M+H + )m / z,1033.4;found 1033.4. 1H NMR (400MHz, DMSO-d6) δ8.98(s,1H),8.48(d,J=6.7Hz,1H),7.91(d,J=8.8Hz,1H),7.70(d,J=7.6Hz,2H),7.58(t,J=6.0Hz,1H),7.40(dd,J=2 7.2,7.6Hz,4H),7.29(d,J=2.3Hz,1H),7.07(dd,J=8.8,2.3Hz,1H),5.20(s,1H),4.89(s,1H),4.79(s,2H),4.56–4.42(m,5H),4.32(s,1H),4 .00(d,J=6.7Hz,2H),3.93–3.85(m,1H),3.81–3.70(m,2H),3.57(s,3H ),3.41–3.37(m,1H),3.20–3.10(m,1H),2.69(s,9H),2.45(s,3H),2.3 1–2.21(m,1H),2.00(s,3H),1.98(s,1H),1.39(s,5H),1.36(dd,J=6.9,3.2Hz,3H),1.26(t,J=6.4Hz,6H),1.14(d,J=6.0Hz,7H),0.97(s,9H).

[0424] 15:(2S,4R)-1-((2S)-2-(2-((3-(2-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-1-oxoisoindol-5-yl)prop-2-yn-1-yl)oxy)propoxy)acetamido)-3,3-dimethylbutyryl)-4-hydroxy-N-((S)-1-(4-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide(15)

[0425] LC / MS (ESI+) Calculated for C 54 H 63 ClN6O8S(M+H + )m / z,991.4;found 991.4. 1H NMR (400MHz, DMSO-d6) δ8.98(s,1H),8.46(d,J=6.7Hz,1H),7.90(d,J=8.8Hz,1H),7.71(d,J=7.6Hz,2H),7.58(t,J=6.0Hz,1H),7.42(dd, J=27.2,7.6Hz,4H),7.31(d,J=2.3Hz,1H),7.07(dd,J=8.8,2.3Hz,1H),5.21(s,1H),4.89(s,1H),4.79(s,2H),4.57–4.43(m,5H),4.32(s, 1H),4.00(d,J=6.7Hz,2H),3.92–3.84(m,1H),3.81–3.70(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(m,1H),2.00(s,3H),1.98(s,1H),1.39(s,5H),1.38(dd,J=6.9,3.2Hz,3H),1.26(t,J=6.4Hz,6H),1.11(d,J=6.0Hz,7H),0.97(s,9H).

[0426] Synthesis of (2R,4R)-1-((S)-2-(2-((5-((2-((1r,3r)-3-(4-cyano-3-(trifluoromethyl)phenoxy)-2,2,4,4-tetramethylcyclobutyl)-1-oxoisoindoline-5-yl)amino)phenyl)oxy)acetamido)-3,3-dimethylbutyryl)-4-hydroxy-N-((R)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrole-2-carbamoyl (16)

[0427]

[0428] 1. Synthesis of tert-butyl ((1r,3r)-3-(4-cyano-3-(trifluoromethyl)phenoxy)-2,2,4,4-tetramethylcyclobutyl)carbamate

[0429] (3-Hydroxy-2,2,4,4-Tetramethylcyclobutyl)carbamate tert-butyl ester (4700 mg, 19.31 mmol) was dissolved in 100 mL of DMF, and then the system was purged with argon gas eight times to ensure an inert atmosphere. The system was then transferred to an ice-water bath for cooling and stirring. When the system temperature reached approximately 0 °C, NaH (60%) (1600 mg, 40.55 mmol) was slowly added. After this, the system was kept at 0 °C with stirring for 1 h. Subsequently, 50 mL of DMF solution containing 2-trifluoromethyl-4-fluorobenzonitrile (1700 mg, 11.00 mmol) was added dropwise, controlling the dropping rate to ensure the system temperature did not exceed 5 °C. After the addition was complete, the system continued to react at 0 °C. After 2 h, a sample was taken and spotted onto a TLC plate; the reaction was complete. The system was slowly poured into ice water with stirring, resulting in the precipitation of a large amount of viscous solid. The filter cake was dissolved in ethyl acetate, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product. This crude product was then purified by column chromatography to obtain a white solid ((1r,3r)-3-(4-cyano-3-(trifluoromethyl)phenoxy)-2,2,4,4-tetramethylcyclobutyl)carbamate (3700 mg). Yield: 46%. LC / MS (ESI) + )Calcd forC 21 H 27 F3N2O3(M+H) + m / z, 412.2; Found: 357.1.

[0430] Synthesis of 2,4-((1r,3r)-3-amino-2,2,4,4-tetramethylcyclobutoxy)-2-(trifluoromethyl)benzonitrile

[0431] Weigh 650 mg (1.58 mmol) of tert-butyl ((1r,3r)-3-(4-cyano-3-(trifluoromethyl)phenoxy)-2,2,4,4-tetramethylcyclobutyl)carbamate into a 25 mL single-necked round-bottom flask, and simultaneously add 15 mL of dichloromethane. Stir at room temperature. Then add 3 mL of trifluoroacetic acid to the system. After completion, stir the system at room temperature. After 3 h, take a sample and spot it on a TLC plate. The TLC showed that the starting material had been completely consumed. Remove the solvent and excess trifluoroacetic acid by rotary evaporation, and repeatedly remove the residual trifluoroacetic acid by rotary evaporation with dichloromethane to obtain a white solid 4-((1r,3r)-3-amino-2,2,4,4-tetramethylcyclobutoxy)-2-(trifluoromethyl)benzonitrile trifluoroacetate. Without further purification, use it directly in the next reaction.

[0432] Synthesis of methyl 3,2-((((1r,3r)-3-(4-cyano-3-(trifluoromethyl)phenoxy)-2,2,4,4-tetramethylcyclobutyl)amino)methyl)-4-nitrobenzene

[0433] 10 mL of DMF was added to a 25 mL single-necked round-bottom flask containing 4-((1r,3r)-3-amino-2,2,4,4-tetramethylcyclobutoxy)-2-(trifluoromethyl)benzonitrile trifluoroacetate, and the mixture was stirred at room temperature until dissolved and clear. Subsequently, potassium carbonate (437 mg, 3.16 mmol) and methyl 2-(bromomethyl)-4-nitrobenzene (433 mg, 1.58 mmol) were added sequentially to the system. After completion, the system was stirred in an oil bath at 100 °C. After 1 hour, a sample was taken and spotted onto a TLC plate; the TLC showed that the starting material had been completely consumed. Ethyl acetate (15 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 separate into layers. The aqueous layer was back-extracted with ethyl acetate (10 mL * 3). The organic phases were combined and washed successively with water (10 mL * 3) and saturated brine (15 mL). The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum to obtain a crude product. This crude product was then purified by column chromatography to obtain methyl 2-((((1r,3r)-3-(4-cyano-3-(trifluoromethyl)phenoxy)-2,2,4,4-tetramethylcyclobutyl)amino)methyl)-4-nitrobenzene (532 mg). Yield (two steps): 67%.

[0434] LC / MS (ESI) + )Calcd for C 25 H 26 F3N3O5(M+H) + m / z, 505.1; Found: 506.3.

[0435] 4,4-((1r,3r)-2,2,4,4-tetramethyl-3-(5-nitro-1-oxoisoindoline-2-yl)epoxybutoxy)-2-(trifluoromethyl)benzonitrile

[0436] Methyl 2-((((1r,3r)-3-(4-cyano-3-(trifluoromethyl)phenoxy)-2,2,4,4-tetramethylcyclobutyl)amino)methyl)-4-nitrobenzene (532 mg, 1.05 mmol) was weighed into a 25 mL single-necked round-bottom flask, and toluene (10 mL) was added. The mixture was stirred at room temperature. Subsequently, triethylamine (319 mg, 3.15 mmol) was added to the system. After completion, the system was transferred to an oil bath at 110 °C and heated under reflux with stirring overnight. The next day, a sample was taken and spotted onto a TLC plate, which showed that the reaction was complete. After the system cooled to room temperature, the solvent was removed by rotary evaporation to obtain the crude product. The crude product was then slurried using n-hexane (20 mL) and ethyl acetate (1 mL) at room temperature. After 30 min, the system was filtered. The filter cake was washed with n-hexane (30 mL) and dried to give a white solid 4-((1r,3r)-2,2,4,4-tetramethyl-3-(5-nitro-1-oxoisoindoline-2-yl)epoxybutoxy)-2-(trifluoromethyl)benzonitrile (395 mg). Yield: 79%.

[0437] LC / MS (ESI) + )Calcd for C 24 H 22 F3N3O4(M+H) + m / z, 473.1; Found: 474.3.

[0438] 5,4-((1r,3r)-3-(5-amino-1-oxoisoindoline-2-yl)-2,2,4,4-tetramethylepoxybutoxy)-2-(trifluoromethyl)benzonitrile

[0439] Weigh 395 mg (0.83 mmol) of 4-((1r,3r)-2,2,4,4-tetramethyl-3-(5-nitro-1-oxoisoindoline-2-yl)epoxybutoxy)-2-(trifluoromethyl)benzonitrile (12 mL) into a 25 mL single-necked round-bottom flask and add glacial acetic acid (12 mL). Stir at room temperature. Then add reduced iron powder (1400 mg, 24.90 mmol) to the system. After completion, transfer the system to an oil bath at 65 °C and continue heating and stirring. After 30 min, take a sample and spot it on a TLC plate. The TLC showed that the starting material had been consumed, and heating was stopped. Filter the system while it is still hot, and wash the filter cake with glacial acetic acid (36 mL). Collect the filtrate, remove the acetic acid by rotary evaporation, and obtain the crude product. Slurry the crude product with n-hexane (5 mL) and ethyl acetate (2 mL) at room temperature. After 20 min, the system was filtered, and the filter cake was washed with n-hexane (5 mL), dried, and a white solid 4-((1r,3r)-3-(5-amino-1-oxoisoindoline-2-yl)-2,2,4,4-tetramethylepoxybutoxy)-2-(trifluoromethyl)benzonitrile (324 mg) was obtained. Yield: 88%.

[0440] LC / MS (ESI) + )Calcd for C 24 H 24 F3N3O2(M+H) + m / z, 443.1; Found: 444.2.

[0441] Synthesis of 6.2-((5-((2-((1r,3r)-3-(4-cyano-3-(trifluoromethyl)phenoxy)-2,2,4,4-tetramethylepoxybutyl)-1-oxoisoindoline-5-yl)amino)pentyl)oxy)tert-butyl acetate

[0442] Weigh 150 mg (0.34 mmol) of 4-((1r,3r)-3-(5-amino-1-oxoisoindoline-2-yl)-2,2,4,4-tetramethylepoxybutoxy)-2-(trifluoromethyl)benzonitrile into a 50 mL single-necked round-bottom flask. Add 73 mg (0.34 mmol) of 2-((5-oxopentyl)oxy)tert-butyl acetate, 15 mL of methanol, and 61 mg (1.02 mmol) sequentially. Stir at room temperature until dissolved and clear. After 15 min, add 86 mg (1.36 mmol) of NaBH3CN to the system. The reaction mixture is then stirred overnight at room temperature. The following day, a TLC sample was taken; the reactants were almost completely consumed. After removing the solvent by rotary evaporation, ethyl acetate (20 mL) and water (10 mL) were added to the system. The mixture was stirred vigorously and allowed to stand for 3 minutes to separate into layers. The aqueous layer was back-extracted with ethyl acetate (10 mL * 3). The organic phases were combined and washed successively with water (10 mL * 3) and saturated brine (15 mL). The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum to obtain a crude product. The crude product was then purified by Pre-TLC to obtain a white solid 2-((5-((2-((1r,3r)-3-(4-cyano-3-(trifluoromethyl)phenoxy)-2,2,4,4-tetramethylepoxybutyl)-1-oxoisoindoline-5-yl)amino)pentyl)oxy)tert-butyl acetate (80 mg). Yield: 37%.

[0443] LC / MS (ESI) + )Calcd for C 35 H 44 F3N3O5(M+H) + m / z, 643.3; Found: 644.3.

[0444] Synthesis of 7.2-((5-((2-((1r,3r)-3-(4-cyano-3-(trifluoromethyl)phenoxy)-2,2,4,4-tetramethylcyclobutyl)-1-oxoisoindoline-5-yl)amino)pentyl)oxy)acetic acid

[0445] Weigh 38 mg (0.06 mmol) of 2-((5-((2-((1r,3r)-3-(4-cyano-3-(trifluoromethyl)phenoxy)-2,2,4,4-tetramethylepoxybutyl)-1-oxoisoindoline-5-yl)amino)pentyl)oxy)tert-butyl acetate into a 25 mL single-necked round-bottom flask, and simultaneously add 10 mL of dichloromethane. Stir at room temperature. Then add 1 mL of trifluoroacetic acid to the system. After completion, stir the system at room temperature. After 3 hours, take a sample and spot it on a TLC plate. The TLC showed that the starting material had been completely consumed. The solvent and excess trifluoroacetic acid were removed by rotary evaporation, and residual trifluoroacetic acid was removed by repeated rotary evaporation with dichloromethane to obtain a white solid 2-((5-((2-((1r,3r)-3-(4-cyano-3-(trifluoromethyl)phenoxy)-2,2,4,4-tetramethylcyclobutyl)-1-oxoisoindoline-5-yl)amino)pentyl)oxy)acetic acid. This solid was used directly in the next reaction without further purification.

[0446] 8. Synthesis of (2R,4R)-1-((S)-2-(2-((5-((2-((1r,3r)-3-(4-cyano-3-(trifluoromethyl)phenoxy)-2,2,4,4-tetramethylcyclobutyl)-1-oxoisoindoline-5-yl)amino)phenyl)oxy)acetamido)-3,3-dimethylbutyryl)-4-hydroxy-N-((R)-1-(4-(4-methylthiazolyl-5-yl)phenyl)ethyl)pyrrole-2-carbamoyl

[0447] To a 25 mL single-necked round-bottom flask containing 2-((5-((2-((1r,3r)-3-(4-cyano-3-(trifluoromethyl)phenoxy)-2,2,4,4-tetramethylcyclobutyl)-1-oxoisoindoline-5-yl)amino)pentyl)oxy)acetic acid, HATU (34 mg, 0.09 mmol), DMF (5 mL), VHL(OAc) (39 mg, 0.07 mmol), and diisopropylethylamine (23 mg, 0.18 mmol) were added sequentially. The system was then stirred and reacted overnight at room temperature. The following day, a sample was taken and spotted onto a TLC plate; the TLC showed that the starting materials had been completely consumed. Add ethyl acetate (15 mL) and water (10 mL) to the system, stir vigorously, and allow to stand for 3 min to separate into layers. The aqueous layer is back-extracted with ethyl acetate (10 mL * 3). Combine the organic phases and wash successively with water (10 mL * 3) and saturated brine (15 mL). Dry with anhydrous sodium sulfate and remove the solvent by rotary evaporation to obtain the crude product. Then, the crude product is purified by Pre-TLC to obtain a white solid (2R,4R)-1-((S)-2-(2-((5-((2-((1r,3r)-3-(4-cyano-3-(trifluoromethyl)phenoxy)-2,2,4,4-tetramethylcyclobutyl)-1-oxoisoindoline-5-yl)amino)phenyl)oxy)acetamido)-3,3-dimethylbutyryl)-4-hydroxy-N-((R)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrole-2-carbamoyl (31 mg). Yield (two steps): 52%.

[0448] LC / MS (ESI) + )Calcd for C 54 H 66 F3N7O7S(M+H) + m / z, 1013.4; Found: 1014.2.

[0449] 1H NMR(400MHz, DMSO-d6)δ8.98(s,1H),8.44(d,J=7.8Hz,1H),8.10(d,J=8.7Hz,1H),7.46–7.31(m,10H),6.69–6.57(m,2H),6 .39–6.27(m,1H),5.14(s,1H),4.92–4.84(m,1H),4.62(s,2H),4.58(s,1H),4.55(d,J=9.8Hz,1H),4.45(t,J=8.3Hz,1H),3. 92(d,J=2.2Hz,2H),3.60–3.56(dd,J=4.8,1.8Hz,2H),3.50(t,J=6.3Hz,3H),3.13–3.05(m,2H),2.45(s,3H),2.11–2.01(m ,1H),1.80–1.73(m,1H),1.66–1.54(m,4H),1.50–1.41(m,2H),1.38(s,6H),1.34(d,J=6.9Hz,2H)1.13(s,6H),0.94(s,9H).

[0450] 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-epoxyisoindoline-5-yl)carbamoyl)pyridin-2-yl)piperazin-1-yl)methyl)piperidin-1-yl)acetamido)-3,3-dimethylbutyryl)-5-(((S)-1-(4-(4-methylthiazolyl-5-yl)phenyl)ethyl)carbamoyl)pyrrolidine-3-ylacetate

[0451]

[0452] 1. Synthetic intermediate: 1,4-(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

[0453] Weigh 130 mg (0.42 mmol) of 6-[4-(tert-butyloxycarbonyl)piperazin-1-yl]nicotinic acid into a 25 mL single-necked round-bottom flask, and simultaneously add 8 mL of DMF. Stir at room temperature until dissolved and clear. Then, add 200 mg (1.05 mmol) of EDCI, 85 mg (0.63 mmol) of HOBt, 5 mg (0.04 mmol) of DMAP, and 106 mg (1.05 mmol) of triethylamine to the system in sequence. After completion, stir the system at room temperature for 5 min. Then, add 145 mg (0.42 mmol) of 4-((3aR,4R,7R,7aS)-5-amino-4,7-dimethyl-1,3-dioxahexahydro-1-hydro-4,7-epoxyisoindole-2(3-hydro)-yl)-2-chlorobenzonitrile (prepared according to literature method) to the system, and stir the system at room temperature overnight. The following day, TLC analysis showed the reaction was complete. Ethyl acetate (20 mL) and water (15 mL) were added to the system, and the mixture was stirred vigorously. After 5 minutes, the layers were allowed to separate. The aqueous layer was back-extracted with ethyl acetate (10 mL x 3). The organic phases were combined and washed successively with water (10 mL x 3) and saturated brine (15 mL). The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum to obtain the crude product. Pre-TLC purification yielded 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). Yield: 71%. LC / MS (ESI) + )Calcd for C 32 H 35 ClN6O6(M+H) + m / z, 635.1; Found: 634.7.

[0454] 2. Synthesis of N-((3aR,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

[0455] Weigh 175 mg (0.28 mmol) of 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 into a 25 mL single-necked round-bottom flask, and simultaneously add 10 mL of dichloromethane. Stir at room temperature. Then add 1 mL of trifluoroacetic acid to the system. After completion, stir the system at room temperature. After 3.5 h, take a sample and spot it on a TLC plate. The TLC showed that the starting material had been completely consumed. The solvent and excess trifluoroacetic acid were removed by rotary evaporation, and residual trifluoroacetic acid was removed by repeated rotary evaporation with dichloromethane to obtain a white solid N-((3aR,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. It was used directly in the next reaction without further purification.

[0456] Synthesis of 3,4-((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

[0457] To a 25 mL single-necked round-bottom flask containing N-((3aR,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, add 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), and stir to dissolve at room temperature. Then, evacuate the system and purge with argon five times to ensure an inert gas atmosphere. After completion, transfer the system to an oil bath and heat under reflux overnight. After 15 hours, take a sample and spot it on a TLC plate; the reaction was complete. The solvent was removed by rotary evaporation. Ethyl acetate (15 mL) and water (10 mL) were then added to the system. The mixture was stirred vigorously and allowed to stand for 3 minutes to separate into layers. The aqueous layer was back-extracted with ethyl acetate (10 mL x 3). The organic phases were combined and washed successively with water (10 mL x 3) and saturated brine (15 mL). The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum to obtain the crude product. Pre-TLC purification yielded tert-butyl 4-((4-(5-(((3aR,4R,7R,7aS)-2-(3-chloro-4-benzonitrile)-4,7-dimethyl-1,3-dioxooctahydro-1-hydro-4,7-epoxyisoindole-5-yl)carbamoyl)pyridin-2-yl)piperazin-1-yl)methyl)piperidine-1-carboxylic acid (124 mg). Yield (two steps): 61%. LC / MS (ESI) + )Calcd for C 38 H 46 ClN7O6(M+H) + m / z, 732.3; Found: 732.2.

[0458] 4. Synthesis of N-((3aR,4R,7R,7aS)-2-(3-chloro-4-benzonitrile)-4,7-dimethyl-1,3-dioxooctahydro-1-hydro-4,7-epoxyisoindol-5-yl)-6-(4-(piperidin-4-ylmethyl)piperazin-1-yl)nicotinamide trifluoroacetate

[0459] Weigh 124 mg (0.16 mmol) of 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 into a 25 mL single-necked round-bottom flask, and simultaneously add 8 mL of dichloromethane. Stir at room temperature. Then add 1 mL of trifluoroacetic acid to the system. After completion, stir the system at room temperature. After 3 h, take a sample and spot it on a TLC plate. The TLC showed that the reaction was complete. The solvent and excess trifluoroacetic acid were removed by rotary evaporation, and residual trifluoroacetic acid was removed by repeated rotary evaporation with dichloromethane to obtain a white solid N-((3aR,4R,7R,7aS)-2-(3-chloro-4-benzonitrile)-4,7-dimethyl-1,3-dioxooctahydro-1-hydro-4,7-epoxyisoindol-5-yl)-6-(4-(piperidin-4-ylmethyl)piperazin-1-yl)nicotinamide trifluoroacetate. This solid was used directly in the next reaction without further purification.

[0460] Synthesis of 5.2-(4-((4-(5-(((3aR,4R,7R,7aS)-2-(3-chloro-4-benzonitrile)-4,7-dimethyl-1,3-dioxooctahydro-1-hydro-4,7-epoxyisoindoline-5-yl)carbamoyl)pyridin-2-yl)piperazin-1-yl)methyl)piperidin-1-yl)tert-butyl acetate

[0461] To a 25 mL single-necked round-bottom flask containing N-((3aR,4R,7R,7aS)-2-(3-chloro-4-benzonitrile)-4,7-dimethyl-1,3-dioxooctahydro-1-hydro-4,7-epoxyisoindoline-5-yl)-6-(4-(piperidin-4-ylmethyl)piperazin-1-yl)nicotinamide trifluoroacetate, tert-butyl bromoacetate (62 mg, 0.32 mmol), dichloromethane (10 mL), and diisopropylethylamine (83 mg, 0.64 mmol) were added sequentially. The mixture was then stirred overnight at room temperature. The following day, a sample was spotted onto a TLC plate, and the reaction was confirmed to be complete. Dichloromethane (10 mL) and water (10 mL) were added to the system, and the mixture was stirred vigorously. After 3 min, the mixture was allowed to stand and separate into layers. The aqueous layer was back-extracted with dichloromethane (5 mL * 3). The organic phases were combined and washed successively with water (5 mL * 3) and saturated brine (10 mL). The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum to obtain a crude product. The crude product was then purified by Pre-TLC to obtain 2-(4-((4-(5-(((3aR,4R,7R,7aS)-2-(3-chloro-4-benzonitrile)-4,7-dimethyl-1,3-dioxooctahydro-1-hydro-4,7-epoxyisoindoline-5-yl)carbamoyl)pyridin-2-yl)piperazin-1-yl)methyl)piperidin-1-yl)tert-butyl acetate (74 mg). Yield (two steps): 59%.

[0462] LC / MS (ESI) + )Calcd for C 39 H 48 ClN7O6(M+H) + m / z, 746.3; Found: 745.2.

[0463] Synthesis of 6.2-(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

[0464] Weigh 40 mg (0.05 mmol) of 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)tert-butyl acetate into a 25 mL single-necked round-bottom flask, and simultaneously add 5 mL of dichloromethane. Stir at room temperature. Then add 1 mL of trifluoroacetic acid to the system. After completion, stir the system at room temperature. After 3 h, take a sample and spot it on a TLC plate. The TLC showed that the reaction was complete. The solvent and excess trifluoroacetic acid were removed by rotary evaporation, and residual trifluoroacetic acid was removed by repeated rotary evaporation with dichloromethane to give a white solid 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. This solid was used directly in the next reaction without further purification.

[0465] 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-epoxyisoindoline-5-yl)carbamoyl)pyridin-2-yl)piperazin-1-yl)methyl)piperidin-1-yl)acetamido)-3,3-dimethylbutyryl)-5-(((S)-1-(4-(4-methylthiazolyl-5-yl)phenyl)ethyl)carbamoyl)pyrrolidine-3-ylacetate

[0466] To a 25 mL single-necked round-bottom flask containing 2-(4-((4-(5-((((3aR,4R,7R,7aS)-2-(3-chloro-4-benzonitrile)-4,7-dimethyl-1,3-dioxooctahydro-1-hydro-4,7-epoxyisoindoline-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. The system was then stirred and reacted overnight at room temperature. The following day, a sample was taken and spotted onto a TLC plate; TLC showed that the starting materials had been completely consumed. Ethyl acetate (15 mL) and water (10 mL) were added to the system, and the mixture was stirred vigorously. After standing and separating into layers, the aqueous layer was back-extracted with ethyl acetate (10 mL x 3). The organic phases were combined and washed successively with water (10 mL x 3) and saturated brine (15 mL). The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum to obtain the crude product. Pre-TLC separation and purification yielded (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-epoxyisoindoline-5-yl)carbamoyl)pyridin-2-yl)piperazin-1-yl)methyl)piperidin-1-yl)acetamido)-3,3-dimethylbutyryl)-5-(((S)-1-(4-(4-methylthiazolyl-5-yl)phenyl)ethyl)carbamoyl)pyrrolidine-3-ylacetate (34 mg). Yield (two steps): 55%. LC / MS (ESI) + )Calcd for C 60 H 72 ClN 11 O9S(M+H) + m / z, 1158.8; Found: 1157.6.

[0467] 1H NMR (400MHz, DMSO-d6) δ8.98(s,1H),8.46(d,J=7.7Hz,1H),8.30(d,J=7.7Hz,1H),8.13(d,J=8.4Hz,1H),7.77(dd,J=8.4,5.3Hz,3H),7.70(d,J=9.4H z,1H),7.53(dd,J=8.4,1.8Hz,1H),7.40(dd,J=28.8,8.2Hz,4H),6.98(d,J =8.5Hz,2H),5.20(s,1H),4.94–4.86(m,1H),4.49–4.43(m,1H),4.41–4.30 (m,2H),3.88(d,J=12.2Hz,1H),3.76(dd,J=11.1,4.0Hz,1H),3.47(d,J=7. 2Hz,1H),3.29–3.25(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(m,2H),1.79–1.70(m,2H),1.49(s,3H),1.42( s,3H),1.38(d,J=7.0Hz,3H),1.24(s,2H),1.17–1.10(m,3H),0.95(s,9H).

[0468] 18. Synthesis of N-((3aR,4R,7R,7aS)-2-(3-chloro-4-benzonitrile)-4,7-dimethyl-1,3-dioxooctahydro-1H-4,7-epoxyisoindoline-5-yl)-6-(4-((1-(2-(((S)-1-((2S,4R)-4-hydroxy-2-(((S)-1-(4-(4-methylthiazolyl-5-yl)phenyl)ethyl)carbamoyl)pyrrolidine-1-yl)-3,3-dimethyl-1-oxobutane-2-yl)amino)-2-oxoethyl)piperidin-4-yl)methyl)piperazin-1-yl)nicotinamide

[0469]

[0470] LC / MS (ESI) + )Calcd for C 58 H 70 ClN 11 O8S(M+H) + m / z, 1116.8; Found: 1116.6.

[0471] 1H NMR(400MHz,DMSO-d6)δ8.99(s,1H),8.66(d,J=2.2Hz,1H),8.45(d,J=7.7Hz ,1H),8.37(d,J=7.2Hz,1H),8.13(d,J=8.4Hz,1H),7.99(dd,J=9.2,2.2Hz,1H ),7.76(d,J=1.8Hz,1H),7.53(dd,J=8.4,1.9Hz,1H),7.40(dd,J=28.7,8.2Hz ,4H),6.88(d,J=9.0Hz,1H),5.13(d,J=3.1Hz,1H),4.92–4.86(m,1H),4.50(d ,J=9.8Hz,1H),4.44(t,J=8.1Hz,1H),4.38–4.31(m,1H),4.28(dt,J=9.2,5. 6Hz,1H),3.61–3.52(m,7H),3.48(d,J=7.2Hz,1H),2.84–2.75(m,3H),2.46(s ,3H),2.11–1.94(m,9H),1.89(dd,J=12.8,5.2Hz,2H),1.79–1.69(m,3H),1.4 9(s,3H),1.43(s,3H),1.38(d,J=7.0Hz,3H),1.18–0.97(m,5H),0.94(s,9H).

[0472] 19: (3S,5R)-1-((2R)-2-(2-((5-((4-(((3aS,4S,7S,7aR)-2-(3-chloro-4-benzonitrile)-4,7-dimethyl-1,3-dioxooctahydro-1-hydro-4,7-epoxyisoindoline-5-yl)carbamoyl)-3-fluorophenyl)amino)pentyl)oxy)acetamido)-3,3-dimethylbutyryl)-5-(((R)-1-(4-(4-methylthiazolyl-5-yl)phenyl)ethyl)carbamoyl)pyrrolidine-3-ylacetate

[0473]

[0474] LC / MS (ESI) + )Calcd for C 56 H 64 ClFN8O 10 S(M+H) + m / z, 1095.7; Found: 1095.2.

[0475] 1H NMR(400MHz, DMSO-d6)δ8.98(s,1H),8.44(dd,J=11.8,7.4Hz,2H),8.13(d,J=8.5Hz ,1H),7.92(s,1H),7.76(d,J=1.7Hz,1H),7.69(dd,J=8.7,6.6Hz,1H),7.53(dd,J=8 .4,1.5Hz,1H),7.39(dt,J=14.0,7.0Hz,5H),6.47(dd,J=12.9,2.3Hz,1H),6.40(td ,J=8.2,2.4Hz,1H),5.20(dd,J=4.0,3.1Hz,1H),4.94–4.85(m,1H),4.44(dd,J=16. 0,8.7Hz,2H),4.31(td,J=12.6,5.8Hz,1H),3.95–3.84(m,3H),3.76(dd,J=11.5,3. 5Hz,1H),3.48(m,3H),3.11(dd,J=11.6,6.0Hz,2H),2.69(s,3H),2.45(s,3H),2.30 –2.21(m,1H),2.11(t,J=12.0Hz,1H),1.90(dd,J=13.4,4.6Hz,1H),1.65–1.55(m,4 H),1.49(s,3H),1.46–1.39(m,5H),1.36(d,J=7.1Hz,3H),1.23(s,2H),0.94(s,9H).

[0476] 20:(2R,4S)-1-((2R)-2-(2-((5-((4-(((3aS,4S,7S,7aR)-2-(3-chloro-4-benzonitrile)-4,7-dimethyl-1,3-dioxooctahydro-1-hydro-4,7-epoxyisoindoline-5-yl)carbamoyl)-3-fluorophenyl)amino)pentyl)oxy)acetamido)-3,3-dimethylbutyryl)-4-hydroxy-N-((R)-1-(4-(4-methylthiazolyl-5-yl)phenyl)ethyl)pyrrolidine-2-carbamoyl)

[0477]

[0478] LC / MS (ESI) + )Calcd for C 54 H 62 ClFN8O9S(M+H) + m / z, 1053.6; Found: 1053.5.

[0479] 1H NMR (400MHz, DMSO-d6) δ8.98(s,1H),8.43(t,J=6.6Hz,2H),8.13(d,J=8.4Hz,1H),7.92(s,1H),7.76(d,J=1.7Hz,1H),7.69(dd,J=8.2,6.9Hz ,1H),7.53(dd,J=8.5,1.7Hz,1H),7.48–7.25(m,6H),6.52–6.36(m,2H),5.13(d,J=3.5Hz,1H),4.89(m,1H),4.54(d,J=9.6Hz,1H),4.45(t,J =7.9Hz,1H),4.28(m,1H),3.92(s,2H),3.60–3.55(m,2H),3.49(dd,J=12.5,7.0Hz,3H),3.30(s,3H),3.11(qd,J=7.3,1.4Hz,2H),2.45(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(s,3H),1.43(s,3H),1.36(d,J=6.8Hz,3H),0.93(s,9H).

[0480] 21: (2S,4R)-1-((S)-2-(2-((6-(4-(((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-1-oxoisoindoline-5-yl)pent-4-yn-1-yl)oxy)acetamyl)-3,3-dimethylbutyryl)-4-hydro-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide(21)

[0481]

[0482] 1. Synthesis of tert-butyl 2-((5-(2-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-1-oxoisoindoline-5-yl)pent-4-yn-1-yl)oxy)acetate

[0483] Compounds 4-((1R,3R)-3-(5-bromo-1-oxoisoindoline-2-yl)-2,2,4,4-tetramethylcyclobutoxy)-2-chlorobenzonitrile (1-1) (189 mg, 0.4 mmol) and 2-(pentyl-4-yn-1-oxy)tert-butyl acetate (119 mg, 0.6 mmol) were dissolved in 3 mL of toluene. 1 mL of triethylamine, 30 mg of Pd(dppf)₂Cl₂, and 150 mg of CuI were added. Under N₂ protection, the reaction mixture was heated to 90-100 °C and stirred for 12 h. After the reaction was complete, the solvent was removed by vacuum distillation. The crude product was purified by plate chromatography (PE:EA = 3:1) to give 177 mg of intermediate 1-2, yield: 75%. Mass spectrometry (ES): m / z = 591 [M+H] + .

[0484] 2. Synthetic intermediate: 2-((5-(2-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-1-oxoisoindoline-5-yl)pent-4-yn-1-yl)oxy)acetic acid

[0485] Compound 2-((5-(2-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-1-oxoisoindoline-5-yl)pent-4-yn-1-yl)oxy)tert-butyl acetate (intermediate 1-2) (118 mg, 0.2 mmol) was dissolved in 2 mL of dichloromethane, and 1 mL of trifluoroacetic acid was added. The reaction was stirred at room temperature for 2 h until the solvent was removed under reduced pressure. The product was used directly in the next reaction without further purification.

[0486] 3. Synthesize the final product: (2S,4R)-1-((S)-2-(2-((6-(4-(((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-1-oxoisoindoline-5-yl)pent-4-yn-1-yl)oxy)acetamyl)-3,3-dimethylbutyryl)-4-hydro-N-((S)-1-(4-(4-methylthiazolyl-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide

[0487] The compounds 2-((5-(2-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-1-oxoisoindoline-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-methylthiazolyl-5-yl)phenyl)ethyl)pyrrolidine- 2-Formamide (44.5 mg, 0.1 mmol) was dissolved in 2 mL of dichloromethane, followed by DIPEA (38.7 mg, 0.3 mmol) and HATU (76.05 mg, 0.2 mmol). 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 subjected to vacuum distillation to remove the solvent. The crude product was purified by plate chromatography (MeOH:DCM = 10:1) to give 52 mg of the final product, yield: 54%. Mass spectrometry (ES): m / z = 961 [M+H] + . 1 H 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,3H),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).

[0488] 22: (2S,4R)-1-((S)-2-(2-((5-(4-(((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)(trideuterated methyl)benzamide)-4-ynylpentyl-oxyacetamido-3,3-dimethylbutane)-4-hydroxy-N-((s)-1-(4-methylthiazolyl-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide

[0489]

[0490] Synthetic intermediate: ((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)(deuterated methyl)carbamate tert-butyl

[0491] Compound ((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)carbamate tert-butyl ester (1.89 g, 5 mmol) was dissolved in 5 mL of DMF. Sodium hydride (0.4 g, 10 mmol) was added under ice bath conditions, and the mixture was stirred at room temperature for 0.5 h. Deuterated iodomethane (1.09 g, 7.5 mmol) was then added, and the reaction was continued with stirring for another 3 h. After the reaction was complete, water was added, and the mixture was extracted with ethyl acetate. The organic phase was removed by vacuum distillation. The crude product was purified by column chromatography to give 1.74 g of intermediate 2-2, with a yield of 88%. Mass spectrometry (ES): m / z = 397 [M+H] + .

[0492] Synthetic intermediate: ((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)(deuterated methyl)carbamic acid

[0493] The compound ((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)(deuterated methyl)carbamate tert-butyl ester (intermediate 2-2) (396 mg, 0.1 mmol) was dissolved in 2 mL of dichloromethane, and 1 mL of trifluoroacetic acid was added. The reaction was carried out by stirring at room temperature for 2 h. The solvent was removed under reduced pressure, and the product was used directly in the next step of the reaction without further purification.

[0494] Synthetic intermediate: N-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-iodo-N-deuterated methylbenzamide

[0495] Compound ((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)(deuterated methyl)carbamic acid (intermediate 2-3) (296 mg, 1 mmol) and p-iodobenzoic acid (248 mg, 1 mmol) were dissolved in 2 mL of DMF, DIPEA (258 mg, 2 mmol), and HATU (570 mg, 1.5 mmol). The mixture was stirred at room temperature for 3 h. After the reaction was complete, water was added and the mixture was extracted with ethyl acetate. The resulting organic phase was subjected to vacuum distillation to remove the solvent. The crude product was purified by plate chromatography (PE:EA = 3:1) to give 395 mg of intermediate 2-4, yield: 75%. Mass spectrometry (ES): m / z = 526 [M+H] + .

[0496] Synthetic intermediate: 2-((5-(4-(((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)(deuterated methyl)carbamoyl)phenyl)pentyl-5-yn-1-yl)oxy)tert-butyl acetate

[0497] Compounds 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-(pentyl-4-ynyl-1-oxy)tert-butyl acetate (119 mg, 0.6 mmol) were dissolved in 3 mL of toluene. 1 mL of triethylamine, 30 mg of Pd(dppf)₂Cl₂, and 150 mg of CuI were added. Under N₂ protection, the reaction solution temperature was raised to 90-100 °C, and the reaction was continued with stirring for 12 h. After the reaction was complete, the solvent was removed by vacuum distillation. The crude product was purified by plate chromatography (PE:EA = 3:1) to give 203 mg of intermediate 2-5, yield: 85%. Mass spectrometry (ES): m / z = 596 [M+H] + Synthetic intermediate: 2-((5-(4-(((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)(deuterated methyl)carbamoyl)phenyl)pentyl-5-yn-1-yl)oxy)acetic acid

[0498] Compound 2-((5-(4-(((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)(deuterated methyl)carbamoyl)phenyl)pentyl-5-yn-1-yl)oxy)tert-butyl acetate (intermediate 2-5) (59.6 mg, 0.1 mmol) was dissolved in 2 mL of dichloromethane, and 1 mL of trifluoroacetic acid was added. The reaction was stirred at room temperature for 2 h until the solvent was removed under reduced pressure. The product was used directly in the next reaction without further purification.

[0499] The compounds 2-((5-(4-(((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)(deuterated methyl)carbamoyl)phenyl)pentyl-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-methylthiazolyl-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide) were prepared. (44.5 mg, 0.1 mmol) was dissolved in 2 mL of dichloromethane, followed by DIPEA (38.7 mg, 0.3 mmol) and HATU (76.05 mg, 0.2 mmol). 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 subjected to vacuum distillation to remove the solvent. The crude product was purified by plate chromatography (MeOH:DCM = 10:1) to give 49 mg of the final product HC-2797-01, yield: 51%. Mass spectrometry (ES): m / z = 966 [M+H] + .1 H NMR (400MHz, DMSO-d6) δ8.98(s,1H),8.46(d,J=7.6Hz,1H),7.87(d,J=8.7Hz,1H),7.45(dd,J=12.0,8.1Hz,5H),7. 41-7.34(m,4H),7.25(s,1H),7.03(d,J=8.4Hz,1H),5.16(d,J=3.3Hz,1H),4.96-4.87(m,1H),4.67(d,J=7.9Hz,1H ),4.56(d,J=9.5Hz,1H),4.46(t,J=8.1Hz,1H),4.29(s,1H),3.98(s,2H),3.62(dd,J=13.7,7.8Hz,4H),2.58-2.49 (m,8H),2.12-2.02(m,1H),1.90-1.74(m,3H),1.48(d,J=6.9Hz,1H),1.40-1.32(m,9H),1.23(s,3H),0.94(s,9H).

[0500] 23: (2S,4R)-1-((S)-2-(2-((6-(4-(((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)(deuterated methyl)benzamide)-5-ynylhexyl-oxyacetamido-3,3-dimethylbutane)-4-hydroxy-N-((S)-1-(4-methylthiazolyl-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide

[0501]

[0502] 1. Synthetic intermediate: 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)tert-butyl acetate

[0503] 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 tert-butyl 2-(hexyl-5-ynyl-1-oxy)acetate (127 mg, 0.6 mmol) were dissolved in 3 mL of toluene. 1 mL of triethylamine, 30 mg of Pd(dppf)₂Cl₂, and 150 mg of CuI were added. Under N₂ protection, the reaction mixture was heated to 90-100 °C and stirred for 12 h. After the reaction was complete, the solvent was removed by vacuum distillation. The crude product was purified by plate chromatography (PE:EA = 3:1) to give 205 mg of intermediate 4-1, yield: 84%. Mass spectrometry (ES): m / z = 610 [M+H] + .

[0504] 2. Synthetic intermediate: 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

[0505] 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)tert-butyl acetate (intermediate 4-1) (61 mg, 0.1 mmol) was dissolved in 2 mL of dichloromethane, and 1 mL of trifluoroacetic acid was added. The reaction was stirred at room temperature for 2 h until the solvent was removed under reduced pressure. The product was used directly in the next reaction without further purification.

[0506] 3. Synthesize the 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)benzamide)-5-ynylhexyl-oxyacetamido-3,3-dimethylbutane)-4-hydroxy-N-((S)-1-(4-methylthiazolyl-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide

[0507] The compounds 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-methylthiazolyl-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide) were prepared. (44.5 mg, 0.1 mmol) was dissolved in 2 mL of dichloromethane, followed by DIPEA (38.7 mg, 0.3 mmol) and HATU (76.1 mg, 0.2 mmol). 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 subjected to vacuum distillation to remove the solvent. The crude product was purified by plate chromatography (MeOH:DCM = 10:1) to give 53 mg of the final product HC-2799-01, yield: 54%. Mass spectrometry (ES): m / z = 980 [M+H] + . 1 H 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=9.6Hz,1H),4.46(t,J=8.2Hz,1H),4.29(s,1H),3.92(d,J=16.9Hz,2H),3.56(dd,J=14.7,9.1H z,4H),2.48(d,J=21.7Hz,11H),2.05(d,J=8.4Hz,1H),1.82-1.59(m,4H),1.42-1.17(m,11H),0.94(s,9H).

[0508] 24: (2S,4R)-1-((S)-2-(2-((7-(4-(((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)(deuterated methyl)benzamide)-6-ynylheptyl-oxyacetamido-3,3-dimethylbutane)-4-hydroxy-N-((S)-1-(4-methylthiazolyl-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide

[0509]

[0510] 1. Synthetic intermediate: 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)tert-butyl acetate

[0511] Compounds 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)tert-butyl acetate (136 mg, 0.6 mmol) were dissolved in 3 mL of toluene. 1 mL of triethylamine, 30 mg of Pd(dppf)₂Cl₂, and 150 mg of CuI were added. Under N₂ protection, the reaction mixture was heated to 90-100 °C and stirred for 12 h. After the reaction was complete, the solvent was removed by vacuum distillation. The crude product was purified by plate chromatography (PE:EA = 3:1) to give 212 mg of intermediate 6-1, yield: 85%. Mass spectrometry (ES): m / z = 624 [M+H] + .

[0512] 2. Synthetic intermediate: 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

[0513] 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)tert-butyl acetate (intermediate 6-1) (62 mg, 0.1 mmol) was dissolved in 2 mL of dichloromethane, and 1 mL of trifluoroacetic acid was added. The reaction was stirred at room temperature for 2 h until the solvent was removed under reduced pressure. The product was used directly in the next reaction without further purification.

[0514] 3. Synthesis of the 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)benzamide)-6-ynylheptyl-oxyacetamido-3,3-dimethylbutane)-4-hydroxy-N-((s)-1-(4-methylthiazolyl-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide

[0515] The compounds 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-methylthiazolyl-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide) were prepared. (44.5 mg, 0.1 mmol) was dissolved in 2 mL of dichloromethane, followed by DIPEA (38.7 mg, 0.3 mmol) and HATU (76.1 mg, 0.2 mmol). 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 subjected to vacuum distillation to remove the solvent. The crude product was purified by plate chromatography (MeOH:DCM = 10:1) to give 50 mg of the final product HC-2801-01, yield: 50%. Mass spectrometry (ES): m / z = 994 [M+H] + . 1 H 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=9.6Hz,1H),4.46(t,J=8.2Hz,1H),4.29(s,1H),3.92(d,J=16.9Hz,2H),3.56(dd,J=14.7,9.1H z,4H),2.48(d,J=21.7Hz,11H),2.05(d,J=8.4Hz,1H),1.82-1.59(m,4H),1.42-1.17(m,13H),0.94(s,9H).

[0516] 25: N-(5-(2-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-1-oxoisoindoline-5-yl)pentyl-4-yn-1-yl)-N-((S)-1-((2S,4R)-4-hydroxy-2-((S)-1-(4-(4-methylthiazolyl-5-yl)phenyl)ethyl)carbamoyl)pyrrolidine-1-yl)-3,3-dimethyl-1-oxobutane-2-yl)cyclopropane-1,1-dicarboxamide

[0517]

[0518] 1. Synthetic intermediate: 2-(pent-4-en-1-yl)isoindoline-1,3-dione

[0519] 4.2 g (0.05 mol) of pentyryn-1-ol was dissolved in 30 mL of DCM, and 7.6 g (0.075 mol) of TEA was added. Methylsulfonyl chloride (6.9 g (0.06 mol) was added dropwise under ice bath conditions, and the reaction was stirred for 5 h. After the reaction was complete, 25 mL of water and 30 mL of dichloromethane were added for extraction. The resulting organic phase was subjected to vacuum distillation to remove the solvent. The crude product was used directly in the next reaction without further purification.

[0520] The above product (3.2 g, 0.02 mol) was dissolved in 20 mL of DMF, and potassium phthalimide salt (5.6 g, 0.03 mol) was added. The reaction solution temperature was raised to 80 °C, and the reaction was stirred for 6 h. After the reaction was complete, 30 mL of water and 90 mL of ethyl acetate were added for extraction. The obtained organic phase was subjected to vacuum distillation to remove the solvent, and the crude product was purified by column chromatography (PE:EA = 3:1) to give 3.9 g of intermediate 8-3, yield: 91%. Mass spectrometry (ES): m / z = 214 [M+H] + .

[0521] 2. Synthetic intermediate: Pentyl-4-yne-1-amine

[0522] The above product (2.1 g, 0.01 mol) was dissolved in 30 mL of anhydrous ethanol, and hydrazine hydrate (0.75 g, 0.015 mol) was added. The reaction solution temperature was raised to 80 °C, and the reaction was stirred for 5 h. After the reaction was completed, the reaction solution was cooled, and insoluble matter was removed by filtration. 30 mL of water and 90 mL of ethyl acetate were added to the filtrate for extraction. The obtained organic phase was subjected to vacuum distillation to remove the solvent. The crude product was used directly in the next reaction without further purification.

[0523] 3. Synthetic intermediate: Methyl 1-(4-pentyne-1-carbamoyl)cyclopropane-1-carboxylic acid ester

[0524] The above-mentioned products, pentyneamine (830 mg, 10 mmol) and 1-methoxycarbonylcyclopropane-1-carboxylic acid (1.44 g, 10 mmol), were dissolved in 2 mL of dichloromethane, followed by DIPEA (3.9 g, 30 mmol) and HATU (7.6 g, 20 mmol). 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 subjected to vacuum distillation to remove the solvent. The crude product was purified by plate chromatography (PE:EA = 3:1) to give 1.79 g of intermediate 8-5, yield: 85%. Mass spectrometry (ES): m / z = 210 [M+H] + .

[0525] 4. Synthetic intermediate: methyl 1-((5-(2-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-1-oxoisoindoline-5-yl)pent-4-cyclo-1-yl)carbamoyl)cyclopropane-1-carboxylic acid ester

[0526] Compounds 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-pentyn-1-carbamoyl)cyclopropane-1-carboxylic acid (126 mg, 0.6 mmol) were dissolved in 3 mL of toluene. 1 mL of triethylamine, 30 mg of Pd(dppf)₂Cl₂, and 150 mg of CuI were added. Under N₂ protection, the reaction mixture was heated to 90-100 °C and stirred for 12 h. After the reaction was complete, the solvent was removed by vacuum distillation. The crude product was purified by plate chromatography (PE:EA = 2:1) to give 188 mg of intermediate 8-6, yield: 78%. Mass spectrometry (ES): m / z = 602 [M+H] + .

[0527] 5. Synthetic intermediate: 1-((5-(2-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-1-oxoisoindoline-5-yl)pent-4-cyclo-1-yl)carbamoyl)cyclopropane-1-carboxylic acid

[0528] Compound methyl 1-((5-(2-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-1-oxoisoindoline-5-yl)pent-4-cyclo-1-yl)carbamoyl)cyclopropane-1-carboxylic acid (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. The mixture was stirred at room temperature for 5 h. After the reaction was complete, 10 mL of water and 20 mL of ethyl acetate were added to the filtrate for extraction. The obtained organic phase was subjected to vacuum distillation to remove the solvent. The crude product was used directly in the next reaction without further purification.

[0529] 6. Synthesis of final product 25: N-(5-(2-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-1-oxoisoindoline-5-yl)pentyl-4-yn-1-yl)-N-((S)-1-((2S,4R)-4-hydroxy-2-((S)-1-(4-(4-methylthiazolyl-5-yl)phenyl)ethyl)carbamoyl)pyrrolidine-1-yl)-3,3-dimethyl-1-oxobutane-2-yl)cyclopropane-1,1-dicarboxamide

[0530] The compounds 1-((5-(2-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-1-oxoisoindoline-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-methylthiazolyl-5-yl)phenyl)ethyl)pyrrolidine-2-methyl Amide (44.5 mg, 0.1 mmol) was dissolved in 2 mL of dichloromethane, followed by DIPEA (38.7 mg, 0.3 mmol) and HATU (76.1 mg, 0.2 mmol). 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 subjected to vacuum distillation to remove the solvent. The crude product was purified by plate chromatography (MeOH:DCM = 10:1) to give 55 mg of the final product HC-2803-01, yield: 54%. Mass spectrometry (ES): m / z = 1014 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ9.40(d,J=8.7Hz,1H),8.98(s,1H),8.42(d,J=7.7Hz,1H),7.90(d,J=8.8Hz,1H),7.82(s,1H),7.66(d,J=7.9 Hz,1H),7.61(s,1H),7.51(d,J=7.8Hz,1H),7.43(d,J=8.3Hz,2H),7.37(d,J=8.2Hz,2H),7.28(d,J=2.3Hz,1H),7.07(dd,J=8.8,2.4H z,1H),5.13(d,J=3.5Hz,1H),4.90(s,1H),4.77(s,2H),4.59-4.38(m,3H),4.30(d,J=10.6Hz,2H),3.59(s,2H),3.23(d,J=6.2Hz,2H) ,2.49–2.43(m,4H),2.08-1.97(m,1H),1.83-1.68(m,3H),1.42-1.34(m,8H),1.32-1.21(m,8H),1.15(s,4H),0.94(d,J=11.9Hz,9H).

[0531] 26: (2S,4R)-1-((S)-2-(2-((4-(4-(((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)(deuterated methyl)benzamide)-3-ynylbutyl-oxyacetamido-3,3-dimethylbutane)-4-hydroxy-N-((S)-1-(4-methylthiazolyl-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide

[0532]

[0533] 1. Synthetic intermediate: 2-((4-(4-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)(methyl-d3)carbamoyl)phenyl)-3-yne-1-butyl)oxy)tert-butyl acetate

[0534] Compounds 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-ynyl-1-oxy)tert-butyl acetate (111 mg, 0.6 mmol) were dissolved in 3 mL of toluene. 1 mL of triethylamine, 30 mg of Pd(dppf)₂Cl₂, and 150 mg of CuI were added. Under N₂ protection, the reaction mixture was heated to 90-100 °C and stirred for 12 h. After the reaction was complete, the solvent was removed by vacuum distillation. The crude product was purified by plate chromatography (PE:EA = 3:1) to give 203 mg of product, yield: 87%. Mass spectrometry (ES): m / z = 582 [M+H] + .

[0535] 2. Synthetic intermediate: 2-((4-(4-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)(methyl-d3)carbamoyl)phenyl)-3-yne-1-butyl)oxy)acetic acid

[0536] Compound 2-((4-(4-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)(methyl-d3)carbamoyl)phenyl)-3-yne-1-butyl)oxy)tert-butyl acetate (58 mg, 0.1 mmol) was dissolved in 2 mL of dichloromethane, and 1 mL of trifluoroacetic acid was added. The reaction was stirred at room temperature for 2 h until the solvent was removed under reduced pressure. The product was used directly in the next reaction without further purification.

[0537] 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)benzamide)-3-ynylbutyl-oxyacetamido-3,3-dimethylbutane)-4-hydroxy-N-((S)-1-(4-methylthiazolyl-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide

[0538] Compound 2-((4-(4-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)(methyl-d3)carbamoyl)phenyl)-3-ynyne-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-methylthiazolyl-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide) 44.5 mg (0.1 mmol) was dissolved in 2 mL of dichloromethane, followed by DIPEA (38.7 mg, 0.3 mmol) and HATU (76.1 mg, 0.2 mmol). 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 subjected to vacuum distillation 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, yield: 52%. Mass spectrometry (ES): m / z = 952 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ8.99(s,1H),8.46(d,J=7.8Hz,1H),7.88(d,J=8.5Hz,1H),7.55 -7.35(m,9H),7.26(s,1H),7.08-7.00(m,1H),5.38(s,1H),5.15(s,1H),4.92(s,1H),4 .56(d,J=9.3Hz,2H),4.46(s,2H),4.29(s,1H),4.04(s,3H),3.65(d,J=40.9Hz,6H),2. 77(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).

[0539] 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)acetamyl)-3,3-dimethylbutyryl)-4-hydroxy-N-((S)-1-(4-methylthiazolyl-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide

[0540]

[0541] 1. Synthetic intermediate: 2-((4-(2-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-1-oxoisoindoline-5-yl)-3-butyn-1-yl)oxy)tert-butyl acetate

[0542] Compounds 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-ynyl-1-oxy)acetic acid tert-butyl ester (119 mg, 0.6 mmol) were dissolved in 3 mL of toluene. 1 mL of triethylamine, 30 mg of Pd(dppf)₂Cl₂, and 150 mg of CuI were added. Under N₂ protection, the reaction mixture was heated to 90-100 °C and stirred for 12 h. After the reaction was complete, the solvent was removed by vacuum distillation. The crude product was purified by plate chromatography (PE:EA = 3:1) to give 180 mg of intermediate 12-1, yield: 78%. Mass spectrometry (ES): m / z = 577 [M+H] + .

[0543] 2. Synthetic intermediate: 2-((4-(2-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-1-oxoisoindoline-5-yl)-3-butyn-1-yl)oxy)acetic acid

[0544] Compound 2-((4-(2-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-1-oxoisoindoline-5-yl)-3-butyn-1-yl)oxy)tert-butyl acetate (intermediate 12-1) (58 mg, 0.1 mmol) was dissolved in 2 mL of dichloromethane, and 1 mL of trifluoroacetic acid was added. The reaction was stirred at room temperature for 2 h until the solvent was removed under reduced pressure. The product was used directly in the next reaction without further purification.

[0545] 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)acetamyl)-3,3-dimethylbutyryl)-4-hydroxy-N-((S)-1-(4-methylthiazolyl-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide

[0546] The compounds 2-((4-(4-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)(methyl-d3)carbamoyl)phenyl)-3-ynyne-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-methylthiazolyl-5-yl)phenyl)ethyl)pyrrolidine-2 α-Formamide (44.5 mg, 0.1 mmol) was dissolved in 2 mL of dichloromethane, followed by DIPEA (38.7 mg, 0.3 mmol) and HATU (76.1 mg, 0.2 mmol). 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 subjected to vacuum distillation to remove the solvent. The crude product was purified by plate chromatography (MeOH:DCM = 10:1) to give 53 mg of the final product 27, yield: 56%. Mass spectrometry (ES): m / z = 947 [M+H] + . 1 H 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,3H),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).

[0547] 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-methylthiazolyl-5-yl)phenyl)ethyl)carbamoyl)pyrrolidine-1-yl)-3,3-dimethyl-1-oxobutane-2-yl)cyclopropane-1,1-dicarboxamide

[0548]

[0549] 51 mg of final product 28 was obtained, yield: 50%. Mass spectrometry (ES): m / z = 1019 [M+H] + . 1 H 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).

[0550] 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)acetamyl)-3,3-dimethylbutyryl)-N-((S)-1-(4-(3,5-dimethylthiazolyl-4-yl)phenyl)ethyl)-4-hydroxypyrrolidine-2-carboxamide

[0551]

[0552] 51 mg of the final product HC-2820-01 was obtained, yield: 52%. Mass spectrometry (ES): m / z = 975 [M+H] + .1 H 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,3H),3.82-3.73(m,1H),3.63(s,2H),2.46(s,3H),2.3 2-2.21(m,2H),1.76(m,2H),1.52(m,2H),1.39(s,8H),1.24(s,3H),1.15(s,6H),0.96(s,9H).

[0553] 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)acetamyl)-3,3-dimethylbutyryl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazolyl-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide

[0554]

[0555] 1. Synthetic intermediate: 2-chloro-4-((1R,3R)-3-(5-ethynyl-1-oxoisobutanol-2-yl)-2,2,4,4-tetramethylcyclobutoxy)benzonitrile

[0556] Compounds 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. 1 mL of triethylamine, 30 mg of Pd(dppf)₂Cl₂, and 150 mg of CuI were added. Under N₂ protection, the reaction mixture was heated to 90-100 °C and stirred for 12 h. After the reaction was complete, the solvent was removed by vacuum distillation. The crude product was purified by plate chromatography (PE:EA = 3:1) to give 147 mg of intermediate 17-1, yield: 88%. Mass spectrometry (ES): m / z = 419 [M+H] + .

[0557] 2. Synthetic intermediate: 2-(4-(4-(2-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-1-oxoisoindoline-5-yl)-1H-1,2,3-triazol-1-yl)butoxy)tert-butyl acetate

[0558] Compounds 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 complete, water was added and the mixture was extracted with ethyl acetate. The resulting organic phase was subjected to vacuum distillation to remove the solvent. The crude product was purified by plate chromatography (PE:EA = 3:1) to give 558 mg of intermediate 17-2, yield: 86%. Mass spectrometry (ES): m / z = 648 [M+H] + .

[0559] 3. Synthetic intermediate: 2-(4-(4-(2-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-1-oxoisoindoline-5-yl)-1H-1,2,3-triazol-1-yl)butoxy)acetic acid

[0560] Compound 2-(4-(4-(2-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-1-oxoisoindoline-5-yl)-1H-1,2,3-triazol-1-yl)butoxy)tert-butyl acetate (intermediate 17-2) (65 mg, 0.1 mmol) was dissolved in 2 mL of dichloromethane, and 1 mL of trifluoroacetic acid was added. The reaction was stirred at room temperature for 2 h until the solvent was removed under reduced pressure. The product was used directly in the next reaction without further purification.

[0561] 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)acetamyl)-3,3-dimethylbutyryl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazolyl-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide

[0562] The compound 2-(4-(4-(2-((1R,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-1-oxoisoindoline-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-Formamide (44.5 mg, 0.1 mmol) was dissolved in 2 mL of dichloromethane, followed by DIPEA (38.7 mg, 0.3 mmol) and HATU (76.1 mg, 0.2 mmol). 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 subjected to vacuum distillation to remove the solvent. The crude product was purified by plate chromatography (MeOH:DCM = 10:1) to obtain 56 mg of the target product, yield: 55%. Mass spectrometry (ES): m / z = 1018 [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=8.0Hz,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).

[0563] 31: (2s,4r)-1-((s)-2-(2-(3-(2-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-1-oxoisoindoline-5-yl)piperazin-1-yl)propoxy)acetamyl)-3,3-dimethylbutyryl)-4-hydroxy-N-((s)-1-(4-methylthiazolyl-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide

[0564]

[0565] 59 mg of final product 31 was obtained, yield: 58%. Mass spectrometry (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=8.0Hz,1H),7.47-7.28(m,5H),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,4H),3.98-3.72(m,4H),3.52(t,J=6.1Hz,2H),3.48(m,8H),2.30-2.22(m,1H),1.9 9(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).

[0566] 32: (2s,4r)-1-((s)-2-(2-((1-(4-(2-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-1-oxoisoazon-5-yl)-3-butyn-1-yl)azacyclobutane-3-yl)oxy)acetamyl)-3,3-dimethylbutyryl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazolyl-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide

[0567]

[0568] 51 mg of final product 32 was obtained, yield: 50%. Mass spectrometry (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),5.25-5.17(m,2H),4.95-4.86(m,1H),4.77(s ,2H),4.54(s,3H),4.31(s,1H),3.98(s,3H),3.82-3.73(m,1H),3.65(m,2H),3.45(m,2H),2.5 8(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).

[0569] 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-methylthiazolyl-5-yl)phenyl)ethyl)carbamoyl)pyrrolidine-1-yl)-3,3-dimethyl-1-oxobutane-2-yl)amino)-2-oxoethoxy)-1-hexyn-1-yl)-N-(methyl-d3)nicotinamide

[0570]

[0571] 59 mg of final product 33 was obtained, yield: 60%. Mass spectrometry (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. 4Hz,2H),7.56-6.89(m,12H),5.29(s,1H),5.20(s,1H),4.90(d,J=7.3Hz,1H),4 .45(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).

[0572] 34: (2S,4R)-1-((S)-2-(3-((4-(2-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-1-oxoisoindoline-5-yl)-3-butynoxy)propylamino)-3,3-dimethylbutanol)-4-hydroxy-N-(S)-1-(4-(4-methylthiazole)phenyl)ethyl)formamide

[0573]

[0574] 1. Synthesis of ethyl 3-(3-butynoxy)propionate

[0575] 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 added sequentially to a reaction flask under nitrogen protection and reacted overnight at 70 °C. The reaction endpoint was determined by TCL. The mixture was extracted three times with water and ethyl acetate. The combined organic layers were washed once with 10% citric acid aqueous solution, three times with saturated brine, dried over anhydrous sodium sulfate, evaporated to dryness, and purified by silica gel column chromatography to give a colorless oily compound, ethyl 3-(3-butynoxy)propionate (826 mg, 4.85 mmol), yield: 34%. LC / MS (ESI+) calcd for C9H 14 O3(M+H + )m / z,171.1;found,171.2.

[0576] 2. Synthesis of ethyl propionate of compound 3-((4-(2-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-1-oxoisoindol-5-yl)-3-butynoxy)oxy)propionate

[0577] Ethyl 3-(3-butynoxy)propionate (150 mg, 0.32 mmol), 4-((1r,3r)-3-(5-bromo-1-oxoisoindol-2-yl)-2,2,4,4-tetramethylcyclobutoxy)-2-chlorobenzyl nitrile (108 mg, 0.64 mmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (46 mg, 0.06 mmol), cuprous iodide (30 mg, 0.16 mmol), 0.5 mL of triethylamine, and 1.5 mL of toluene were added sequentially to the reactor. Under nitrogen protection, the reaction was carried out overnight at 110 °C. The reaction was confirmed to be complete by TLC. The mixture was filtered, the filter cake was washed with dichloromethane, evaporated to dryness, and purified by silica gel column chromatography to give ethyl 3-((4-(2-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-1-oxoisoindol-5-yl)-3-butynoxy)oxy)propionate (56 mg, 0.10 mmol), yield: 31%.

[0578] LC / MS(ESI+)calcd for C 32 H 35 ClN2O5(M+H + )m / z,563.2;found,563.2.

[0579] 3. Synthesis of compound (3R,5S)-1-((S)-2-(3-((4-(2-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-1-oxoisoindol-5-yl)-3-butynoxy)oxy)propylamino)-3,3-dimethylbutanol)-5-((S)-1-(4-methylthiazolyl-5-yl)phenyl)ethyl)carbamoyl)pyrrolidine-3-ylacetic acid

[0580] Ethyl 3-((4-(2-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-1-oxoisoindol-5-yl)-3-butynoxy)oxy)propionate (50 mg, 0.09 mmol) was dissolved in 2 mL of methanol. Lithium hydroxide monohydrate (15 mg, 0.36 mmol) was dissolved in 0.5 mL of water and added to the reactor. The mixture was stirred at room temperature for 3 h. The reaction endpoint was determined by TLC. Water was added to the reaction solution, and the pH was adjusted to 2-3 with 1 N hydrochloric acid. The mixture was extracted three times with ethyl acetate, dried over anhydrous sodium sulfate, and evaporated to dryness to obtain the crude product. 2 mL of the crude product was added to... DMF and DIPEA (54 mg, 0.42 mmol) were added to HATU (64 mg, 0.17 mmol) in an ice bath and stirred for 0.5 h. Then (3R,5S)-1-((S)-2-amino-3,3-dimethylbutyryl)-5-((((S)-1-(4-(4-methylthiazolyl-5-yl)phenyl)ethyl))carbamoyl)pyrrolidine-3-acetate (45 mg, 0.09 mmol) was added and the mixture was stirred at room temperature for 2 h. The reaction endpoint was determined by TLC. The mixture was extracted three times with water and ethyl acetate and washed three times with saturated brine. The solution was dried over anhydrous sodium sulfate, and then evaporated by pre-TLC to obtain a white solid compound (3R,5S)-1-((S)-2-(3-((4-(2-(((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-1-oxoisoindoline-5-yl)-3-butynoxy)oxy)propylamino)-3,3-dimethylbutanol)-5-((S)-1-(4-methylthiazolyl-5-yl)phenyl)ethyl)carbamoyl)pyrrolidine-3-ylacetic acid (59 mg, 0.06 mmol). Yield: 70%.

[0581] LC / MS(ESI+)calcd for C 55 H 63 ClN6O8S(M+H + )m / z,1003.4;found,1003.5.

[0582] 1H NMR (400MHz, CDCl3) δ8.78(s,1H),7.76(d,J=7.8Hz,1H),7.57(d,J=8.7Hz,1H),7.48(d,J=8.0Hz,1H),7.45(s,1H),7.43–7.31(m,5H) ,7.00(d,J=2.4Hz,1H),6.87–6.78(m,2H),5.35(s,1H),5.08(p,J=7.1Hz,1H),4.73(dd,J=8.2,6.3Hz,1H),4.63(s,2H),4.56(d,J=8.9 Hz,1H),4.39(s,1H),4.32(s,1H),4.07(d,J=11.4Hz,1H),3.82–3.77(m,2H),3.72(t,J=7.1Hz,2H),2.79–2.70(m,3H),2.56(s,3H),2. 53(t,J=6.1Hz,2H),2.16–2.07(m,2H),2.06(s,3H),1.48(d,J=6.9Hz,3H),1.43(d,J=12.3Hz,6H),1.26(s,6H),1.05(d,J=8.6Hz,9H).

[0583] 4. Synthesis of compound (2S,4R)-1-((S)-2-(3-((4-(2-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-1-oxoisoindoline-5-yl)-3-butynoxy)propylamino)-3,3-dimethylbutanol)-4-hydroxy-N-(S)-1-(4-(4-methylthiazole)phenyl)ethyl)formamide

[0584] Compound (3R,5S)-1-((S)-2-(3-((4-(2-(((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-1-oxoisoindoline-5-yl)-3-butynoxy)oxy)propylamino)-3,3-dimethylbutanol)-5-((S)-1-(4-methylthiazolyl-5-yl)phenyl)ethyl)carbamoyl)pyrrolidine-3-ylacetic acid (24 mg, 0.02 mmol) was dissolved in 2 mL of methanol, and lithium hydroxide monohydrate (4 mg, 0.10 mmol) was dissolved in 0.5 mL of water and added to the reactor. The mixture was stirred at room temperature for 3 h. The reaction endpoint was determined by TLC. The reaction solution was extracted three times with ethyl acetate, dried over anhydrous sodium sulfate, and evaporated to dryness to obtain the crude product. Pre-TLC separation yielded a pale yellow solid compound (2S,4R)-1-((S)-2-(3-((4-(2-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-1-oxoisoindol-5-yl)-3-butynoxy)propylamino)-3,3-dimethylbutanol)-4-hydroxy-N-(S)-1-(4-(4-methylthiazolyl)phenyl)ethyl)formamide (21 mg, 0.02 mmol). Yield: 91%. LC / MS (ESI+) calcd for C 53 H 61 ClN6O7S(M+H + )m / z,961.4;found,961.4. 1 H NMR (400MHz, CDCl3) δ8.69(s,1H),7.76(d,J=7.9Hz,1H),7.58(d,J=8.7Hz,1H),7.52–7.43(m,3H),7.39(q,J=8.4Hz,4H),6.99 (t,J=6.3Hz,2H),6.84(dd,J=8.7,2.4Hz,1H),5.12–5.02(m,1H),4.75(t,J=7.9Hz,1H),4.63(s,2H),4.51(d,J=8.1Hz,2H),4. 40(s,1H),4.32(s,1H),4.15(d,J=11.6Hz,1H),3.78(d,J=2.6Hz,2H),3.72(t,J=7.0Hz,2H),3.57(dd,J=11.4,3.3Hz,1H),2.7 6(t,J=7.0Hz,2H),2.53(d,J=7.3Hz,5H),2.12–2.02(m,1H),1.46(dd,J=10.7,3.9Hz,9H),1.25(s,9H),1.02(d,J=30.5Hz,9H).

[0585] 35: Synthesis of (2S,4R)-1-((S)-2-(4-(4-((2-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-1-oxoisoindoline-5-yl)ethynyl)-1H-pyrazole-1-yl)butanyl)-3,3-dimethylbutanol)-4-hydroxy-N-((S)-1-(4-methylthiazolyl-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide

[0586]

[0587] 1. Synthesis of methyl 4-(4-iodo-1H-pyrazol-1-yl)butyrate

[0588] Compound 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 added sequentially to a reaction flask. Under nitrogen protection, the mixture was stirred overnight at room temperature. The reaction endpoint was determined by TCL. The mixture was extracted three times with water and ethyl acetate. The combined organic layers were washed once with 10% citric acid aqueous solution, three times with saturated brine, dried over anhydrous sodium sulfate, evaporated to dryness, and purified by silica gel column chromatography to give a colorless oily compound methyl 4-(4-iodo-1H-pyrazole-1-yl)butyrate (1.23 mg, 4.18 mmol), yield: 81%.

[0589] LC / MS(ESI+)calcd for C8H 11 IN2O2(M+H + )m / z,295.0;found,295.0.

[0590] 2. Synthesis of methyl 4-(4-((trimethylsilyl)ethynyl)-1H-pyrazole-1-yl)butyrate

[0591] 4-(4-iodo-1H-pyrazole-1-yl)butyrate methyl ester (1.00 g, 3.40 mmol), trimethylsilyne (510 mg, 5.10 mmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (249 mg, 0.34 mmol), cuprous iodide (259 mg, 1.36 mmol), 6 mL of triethylamine, and 17 mL of toluene were added sequentially to the reactor. Under nitrogen protection, the reaction was carried out overnight at 80 °C. The reaction was confirmed to be complete by TLC. The mixture was filtered, the filter cake was washed with dichloromethane, evaporated to dryness, and purified by silica gel column chromatography to give a brownish-yellow oily compound, 4-(4-((trimethylsilyl)ethynyl)-1H-pyrazole-1-yl)butyrate methyl ester (806 mg, 3.05 mmol), yield: 90%.

[0592] LC / MS(ESI+)calcd for C 13 H 20 N2O2Si(M+H + )m / z,265.1;found,265.1.

[0593] 3. Synthesis of methyl 4-(4-ethynyl-1H-pyrazol-1-yl)butyrate

[0594] 4-(4-((trimethylsilyl)ethynyl)-1H-pyrazole-1-yl)methyl butyrate (800 mg, 3.03 mmol), TBAF (1.91 g, 7.30 mmol), and 20 mL THF were sequentially added to a reactor under nitrogen protection and stirred at room temperature for 1 h. The reaction was confirmed to be complete by TLC. Water was added to the reaction mixture, and the extract was extracted three times with EA. The extracts were combined, washed twice with saturated brine, dried, and evaporated to dryness to obtain a brownish-yellow oily crude product of 4-(4-ethynyl-1H-pyrazole-1-yl)methyl butyrate (580 mg, 3.02 mmol), with a crude yield of 100%. LC / MS (ESI+) calcd for C 10 H 12 N2O2(M+H + )m / z,193.1;found,193.1.

[0595] 3. Synthesis of methyl 4-(4-((2-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-1-oxoisoindoline-5-yl)ethynyl)-1H-pyrazole-1-yl)butyrate

[0596] Crude methyl 4-(4-ethynyl-1H-pyrazol-1-yl)butyrate (151 mg, 0.78 mmol), 4-((1r,3r)-3-(5-bromo-1-oxoisoindoline-2-yl)-2,2,4,4-tetramethylcyclobutoxy)-2-chlorobenzyl nitrile (200 mg, 0.42 mmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (59 mg, 0.081 mmol), cuprous iodide (55 mg, 0.29 mmol), 1 mL of triethylamine, and 3 mL of toluene were added sequentially to the reactor. Under nitrogen protection, the reaction was carried out overnight at 110 °C. The reaction was confirmed to be complete by TLC. The mixture was filtered, the filter cake was washed with dichloromethane, evaporated to dryness, and purified by silica gel column chromatography to give a pale yellow solid, methyl 4-(4-((2-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-1-oxoisoindol-5-yl)ethynyl)-1H-pyrazol-1-yl)butyrate (228 mg, 0.10 mmol), yield: 92%. LC / MS (ESI+) calcd for C33 H 33 ClN4O4(M+H + )m / z,545.2;found,545.2.

[0597] 4. Synthesis of compound (3R,5S)-1-((S)-2-(4-(4-((2-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-1-oxoisoindoline-5-yl)ethynyl)-1H-pyrazole-1-yl)butamido)-3,3-dimethylbutanol)-5-((S)-1-(4-methylthiazolyl-5-yl)phenyl)ethyl)carbamoyl)-3-pyrrolidinyl acetate

[0598] methyl 4-(4-((2-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-1-oxoisoindoline-5-yl)ethynyl)-1H-pyrazole-1-yl)butyrate (130 mg, 0.22 mmol) was dissolved in 2 mL of methanol, and lithium hydroxide monohydrate (37 mg, 0.89 mmol) was dissolved in 0.5 mL of water and added to the reactor. The mixture was stirred at room temperature for 3 h. The reaction endpoint was determined by TLC. Water was added to the reaction solution, and the pH was adjusted to 2-3 with 1N hydrochloric acid. The mixture was extracted three times with ethyl acetate, dried over anhydrous sodium sulfate, and evaporated to dryness to obtain the crude product. 3 mL of the crude product was added to... DCM and DIPEA (135 mg, 1.04 mmol) were added to HATU (127 mg, 0.33 mmol) in an ice bath and stirred for 0.5 h. Then (3R,5S)-1-((S)-2-amino-3,3-dimethylbutyryl)-5-((((S)-1-(4-(4-methylthiazolyl-5-yl)phenyl)ethyl))carbamoyl)pyrrolidine-3-acetate (151 mg, 0.29 mmol) was added and the mixture was stirred at room temperature for 2 h. The reaction endpoint was determined by TLC. The mixture was extracted three times with water and ethyl acetate and dried over anhydrous sodium sulfate. The solution was dried and evaporated to dryness. Pre-TLC separation yielded a white solid compound (3R,5S)-1-((S)-2-(4-(4-((2-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-1-oxoisoindoline-5-yl)ethynyl)-1H-pyrazole-1-yl)butamido)-3,3-dimethylbutanolyl)-5-((S)-1-(4-methylthiazolyl-5-yl)phenyl)ethyl)carbamoyl)-3-pyrrolidinyl acetate (123 mg, 0.12 mmol). Yield: 53%. LC / MS (ESI+) calcd for C 57 H 63 ClN8O7S(M+H + )m / z,1039.4;found,1039.5.1 H NMR (400MHz, CDCl3) δ8.77(s,1H),7.80(d,J=7.8Hz,1H),7.67(t,J=8.6Hz,2H),7.56(t,J=7.7Hz,2H),7.52(s,1H),7.42–7.35(m,4H),7.33 (d,J=7.8Hz,1H),6.99(d,J=2.4Hz,1H),6.84(dd,J=8.7,2.4Hz,1H),6.56(d,J=8.6Hz,1H),5.07(p,J=7.0Hz,1H),4.74(dd,J=8.2,6.5Hz,1 H),4.66(s,2H),4.54–4.49(m,1H),4.40(s,1H),4.33(s,1H),4.21(dt,J=14.3,7.1Hz,2H),4.10(d,J=11.6Hz,1H),3.81(dd,J=11.6,4.7Hz ,1H),2.74(dt,J=13.7,6.0Hz,1H),2.55(s,3H),2.25–2.10(m,6H),2.06(s,3H),1.47(d,J=9.3Hz,9H),1.26(s,6H),1.06(d,J=6.0Hz,9H).

[0599] 5. Synthesis of compound (2S,4R)-1-((S)-2-(4-(4-((2-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-1-oxoisoindoline-5-yl)ethynyl)-1H-pyrazol-1-yl)butanyl)-3,3-dimethylbutanol)-4-hydroxy-N-((S)-1-(4-methylthiazolyl-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide

[0600] Compound (3R,5S)-1-((S)-2-(4-(4-((2-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-1-oxoisoindoline-5-yl)ethynyl)-1H-pyrazole-1-yl)butamido)-3,3-dimethylbutanolyl)-5-((S)-1-(4-methylthiazolyl-5-yl)phenyl)ethyl)carbamoyl)-3-pyrrolidinyl acetate (60 mg, 0.058 mmol) was dissolved in 2 mL of methanol, and lithium hydroxide monohydrate (24 mg, 0.58 mmol) was dissolved in 0.5 mL of water and added to the reactor. The mixture was stirred at room temperature for 3 h. The reaction endpoint was determined by TLC. The reaction solution was extracted three times with ethyl acetate, dried over anhydrous sodium sulfate, and evaporated to dryness to obtain the crude product. Prep-TLC yielded a white solid compound (2S,4R)-1-((S)-2-(4-(4-((2-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-1-oxoisoindol-5-yl)ethynyl)-1H-pyrazole-1-yl)butanyl)-3,3-dimethylbutanol)-4-hydroxy-N-((S)-1-(4-methylthiazolyl-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (50 mg, 0.050 mmol). Yield: 87%.

[0601] LC / MS(ESI+)calcd for C 55 H 61 ClN8O6S(M+H + )m / z,997.4; found,997.5. 1H NMR (400MHz, CDCl3) δ8.73(s,1H),7.73(d,J=7.9Hz,1H),7.61(d,J=3.2Hz,2H),7.50(t,J=8.4Hz,2H),7.45(s,1H),7.41(d, J=7.7Hz,1H),7.36–7.28(m,4H),6.92(dd,J=8.2,5.2Hz,2H),6.77(dd,J=8.7,2.4Hz,1H),5.01(p,J=6.8Hz,1H),4.72(t,J= 7.9Hz,1H),4.59(s,2H),4.44(dd,J=11.8,6.1Hz,2H),4.34(s,1H),4.26(s,1H),4.21–4.08(m,3H),3.52(dd,J=11.4,3.2Hz ,1H),2.49(s,4H),2.11(ddd,J=24.9,14.0,5.4Hz,6H),1.40(d,J=7.9Hz,9H),1.18(d,J=7.8Hz,6H),0.99(d,J=20.9Hz,9H).

[0602] 36: Synthesis of (2S,4R)-1-((S)-2-(2-((6-(6-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-5-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyridinyl-2-yl)hexyl-5-yn-1-yl)oxy)acetamido)-3,3-dimethylbutyryl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazolyl-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide

[0603]

[0604] LC / MS(ESI+)calcd for C 53 H 62 ClN7O7S(M+H + )m / z,108.4;found,996.4.

[0605] 1H NMR (400MHz, CDCl3) δ8.77(s,1H),7.98(d,J=7.9Hz,1H),7.51(d,J=8.7Hz,1H),7.40(t,J=7.6Hz,2H),7.36–7.29(m,4H ),7.13(d,J=8.6Hz,1H),6.93(t,J=2.7Hz,1H),6.76(dd,J=8.7,2.4Hz,1H),5.01(p,J=6.9Hz,1H),4.69(t,J=7.7Hz,1H) ,4.62(s,2H),4.47(d,J=8.7Hz,2H),4.38(s,1H),4.23(s,1H),3.89(q,J=15.4Hz,2H),3.57–3.48(m,3H),2.51(s,6H),1 .98(s,3H),1.73(ddd,J=19.9,13.9,7.2Hz,4H),1.41(d,J=6.9Hz,3H),1.38(s,6H),1.19(d,J=1.3Hz,6H),1.00(s,9H).

[0606] 37: Synthesis of (2S,4R)-1-((2S)-2-(2-((4-(2-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-1-oxoisoindoline-5-yl)but-3-yn-2-yl)oxy)ethoxy)acetamide)-3,3-dimethylbutyryl)-4-hydroxy-N-((S)-1-(4-methylthiazolyl-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide

[0607]

[0608] A white solid compound 37 (14 mg, 0.014 mmol) was obtained. LC / MS (ESI+) calcd for C 54 H 63 ClN6O8S(M+H + )m / z,991.4; found,991.5. 1H NMR(400MHz, CDCl3)δ8.78(s,1H),7.83–7.74(m,1H),7.57(d,J=8.6Hz,1H),7.52(d,J=8.1Hz,3H),7 .38(s,5H),6.99(s,1H),6.83(d,J=7.4Hz,1H),5.07(s,1H),4.75(s,1H),4.64(s,2H),4.58–4.44(m, 3H),4.40(s,1H),4.31(s,1H),4.10(s,1H),4.05(s,2H),3.99(s,1H),3.72(t,J=14.8Hz,5H),3.60(d ,J=9.5Hz,1H),2.08(s,1H),1.56(d,J=3.7Hz,3H),1.46(d,J=12.9Hz,9H),1.25(s,9H),1.07(s,9H).

[0609] 38: Synthesis of (2R,4R)-1-((S)-2-(2-((6-(2-((1r,3r)-3-)3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-3-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridinyl-6-yl)hex-5-yl-yn-1-yl)oxy)acetamido)-3,3-dimethylbutyryl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazolyl-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide

[0610]

[0611] LC / MS(ESI+)calcd for C 53 H 62 ClN7O7S(M+H + m / z, 996.4; found, 996.7

[0612] 1H NMR(400MHz, CDCl3)δ9.01(s,1H),8.70(s,1H),8.02(s,1H),7.58(d,J=8.7Hz,1H),7.48(s,2H),7.44–7.31 (m,4H),7.23(s,2H),6.99(d,J=2.0Hz,1H),6.90–6.77(m,1H),5.16–5.00(m,1H),4.75(s,1H),4.68(s,2H) ,4.62–4.47(m,2H),4.41(s,1H),4.30(s,1H),4.10(d,J=11.2Hz,1H),3.96(q,J=15.2Hz,2H),3.61(d,J=14 .3Hz,3H),2.54(d,J=8.4Hz,5H),1.79(dd,J=23.9,6.3Hz,4H),1.53–1.38(m,8H),1.25(s,6H),1.06(s,9H).

[0613] 39: (2S,4R)-1-((S)-2-(2-(4-(3-(2((1s,3s)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-1-oxoisoindoline-5-yl)prop-2-yn-1-yl)piperidin-1-yl)acetamido)-3,3-dimethylbutyryl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazolyl-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide

[0614]

[0615] LC / MS(ESI+)calcd for C 56 H 66 ClN7O6S(M+H + )m / z,1000.5;found,1000.5.

[0616] 1H NMR (400MHz, DMSO-d6) δ8.98(s,1H),8.44(d,J=7.6Hz,1H),7.90(d,J=8.8Hz,1H),7.85(d,J=9.7Hz,1H),7.65(d,J=8.3Hz,3H),7.54(dd ,J=7.9,1.4Hz,1H),7.43(d,J=8.2Hz,3H),7.29(d,J=2.4Hz,1H),7.06(dd,J=8.8,2.4Hz,1H),5.32(t,J=4.8Hz,1H),5.14(d,J=3.4Hz,1 H),4.77(s,3H),4.53(d,J=5.0Hz,2H),4.47-4.43(m,2H),3.59(d,J=14.9Hz,4H),3.41-3.36(m,2H),3.02(d,J=16.4Hz,2H),2.89(t,J= 17.4Hz,6H),2.70-2.62(m,1H),2.04(d,J=11.3Hz,2H),2.02-1.96(m,1H),1.76(d,J=12.7Hz,5H),1.15(s,9H),0.94(d,J=6.1Hz,12H).

[0617] 40: (2R,4R)-1-((S)-2-(2-((1-(3-(2-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-1-oxoisoindoline-5-yl)prop-2-yn-1-yl)azacyclobutane-3-yl)oxy)acetamido)-3,3-dimethylbutyryl)-4-hydroxy-N-((S)-1-(4-(4-(4-methylthiazolyl-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide

[0618]

[0619] 41:(2S,4R)-1-((S)-2-(1-((6-(2-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-1-oxoisoindoline-5-yl)hexa-5-yn-1-yl)oxy)cyclopropanecarboxamide)-3,3-dimethylbutyryl)-4-hydroxy-N-((S)-1-(4-methylthiazolyl-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide

[0620]

[0621] 1. Synthesis of ethyl 1-(5-pentynyl-1-oxo)cyclopropionate

[0622] Under nitrogen protection, methyl 1-hydroxycyclopropanecarboxylate (100.0 mg, 0.86 mmol) was dissolved in 2 mL of THF. The solution was placed in an ice bath, and NaH (41.0 mg, 1.03 mmol) was added. The mixture was stirred for 30 minutes, followed by the addition of 6-iodo-1-yne (179.0 mg, 0.86 mmol). The mixture was stirred overnight at room temperature. Extraction was performed with ethyl acetate and water. The organic layer was washed with saturated brine, dried, and evaporated to dryness. Purification was then achieved by silica gel column chromatography. Ethyl 1-(5-pentynyl-1-oxo)cyclopropionate (110.0 mg, 0.56 mmol) was obtained. The yield was 65.1%.

[0623] LC / MS(ESI+)calcd for C 11 H 17 O3 + ([M+H)) + )m / z:197.1; found 197.1.

[0624] 2. Synthesis of methyl 1-((6-(2-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-1-oxoisoindol-5-yl)hexa-5-yn-1-yl)oxy)cyclopropanecarboxylate

[0625] Under nitrogen protection, ethyl 1-(5-pentynyl-1-oxo)cyclopropionate (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. It was then cooled to room temperature. The mixture was filtered, washed with ethyl acetate, dried, evaporated to dryness, and purified by silica gel column chromatography. The compound methyl 1-((6-(2-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-1-oxoisoindol-5-yl)hexa-5-yn-1-yl)oxy)cyclopropanecarboxylate (65.0 mg, 0.13 mmol) was obtained. The yield was 52.3%.

[0626] LC / MS(ESI+)calcd for C 34 H 38 ClN2O5 + ([M+H)) + )m / z:589.2; found 589.1.

[0627] 3. Synthesis of compound 1-((6-(2-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-1-oxoisoindoline-5-yl)hexadecyl-5-yn-1-yl)oxy)cyclopropanecarboxylic acid

[0628] Methyl 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 dissolved in 2 mL of methanol and 2 mL of 2N NaOH was added. The mixture was stirred at room temperature for 2 h. The pH was adjusted to 4-5 with 1N HCl, and the mixture was extracted with dichloromethane. The organic layer was washed with saturated brine, dried, and evaporated to dryness to give 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). Yield: 100.0%.

[0629] 4. Synthesis of compound (2S,4R)-1-((S)-2-(1-((6-(2-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-1-oxoisoindoline-5-yl)hexa-5-yn-1-yl)oxy)cyclopropanecarboxamide)-3,3-dimethylbutyryl)-4-hydroxy-N-((S)-1-(4-methylthiazolyl-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide

[0630] 1-((6-(2-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-1-oxoisoindol-5-yl)hexadecyl-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-methylthiazolyl-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, the organic layer was washed with saturated brine, dried, evaporated to dryness, and purified by silica gel column chromatography. (2S,4R)-1-((S)-2-(1-((6-(2-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-1-oxoisoindoline-5-yl)hexa-5-yn-1-yl)oxy)cyclopropanecarboxamide)-3,3-dimethylbutyryl)-4-hydroxy-N-((S)-1-(4-methylthiazolyl-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (40.0 mg, 0.04 mmol). Yield 44.9%. LC / MS (ESI+) calcd for C 56 H 66 ClN6O7S + ([M+H)) + m / z:1001.4; found1001.5. 1H NMR (400MHz, CDCl3) δ8.75(s,1H),7.76(d,J=7.8Hz,1H),7.57(d,J=8.7Hz,1H),7.47(d,J=7.9Hz,2H),7.44(s,1H),7.39(q,J=8.3Hz,4H) ,7.31(d,J=8.4Hz,1H),6.99(d,J=2.3Hz,1H),6.84(dd,J=8.7,2.4Hz,1H),5.14–5.02(m,1H),4.81–4.73(m,1H),4.66–4.57(m,2H),4.54– 4.45(m,2H),4.42–4.36(m,1H),4.35–4.28(m,1H),4.21–4.12(m,1H),3.63–3.52(m,3H),2.65(d,J=9.4Hz,1H),2.59–2.46(m,6H),2.14– 2.04(m,2H),1.82–1.71(m,4H),1.47(d,J=6.9Hz,3H),1.43(d,J=5.8Hz,6H),1.25(s,6H),1.07(d,J=17.6Hz,11H),0.88(t,J=6.7Hz,2H).

[0631] 42:((2S,4R)-1-((S)-2-(3-((2-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-1-oxoisoindoline-5-yl)ethynyl)-1H-pyrazole-1-yl)propamido)-3,3-dimethylbutanol)-4-hydroxy-N-((S)-1-(4-methylthiazolyl-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide

[0632]

[0633] Compound 42 (45.0 mg, 0.04 mmol) was obtained. LC / MS (ESI+) calcd for C 54 H 60 ClN8O6S + ([M+H)) + )m / z:983.4; found 983.4. 1H NMR (400MHz, CDCl3) δ9.02(s,1H),7.79(d,J=7.8Hz,1H),7.67(d,J=15.9Hz,2H),7.58(d,J=8.7Hz,1H),7.53(d,J=8 .6Hz,1H),7.50(s,1H),7.45(s,1H),7.37(d,J=10.7Hz,4H),7.00(d,J=2.2Hz,1H),6.88–6.81(m,1H),6.62(s,1H), 5.06(d,J=6.1Hz,1H),4.78(s,1H),4.64(s,2H),4.39(s,1H),4.33(s,1H),4.10(d,J=12.7Hz,1H),3.75–3.57(m,4H ),2.84(d,J=25.6Hz,2H),2.62(s,4H),2.03(d,J=7.1Hz,2H),1.47–1.40(m,9H),1.28(d,J=3.0Hz,6H),1.00(s,9H).

[0634] 43: (2S, 4R)-1-((S)-2-(3-(3-(2-((1r, 3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-1-oxoisoindoline-5-yl)propyl-2-yn-1-yl)nonan-1-yl)acetamide)-3,3-dimethylbutyryl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazolyl-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide

[0635]

[0636] 43 (18.0 mg, 0.02 mmol) was obtained. LC / MS (ESI+) calcd for C 54 H 63 ClN7O6S + ([M+H)) + m / z:972.4; found 972.5. 1H NMR (400MHz, CDCl3) δ8.67(s,1H),7.90(s,1H),7.78(d,J=8.2Hz,1H),7.57(d,J=8.7Hz,1H),7.50(d,J=7.0Hz,2H),7.43–7. 31(m,4H),6.99(d,J=2.3Hz,1H),6.84(dd,J=8.7,2.3Hz,1H),5.11–5.02(m,1H),4.77(t,J=7.9Hz,1H),4.65(s,2H),4.51(d, J=8.8Hz,2H),4.40(s,1H),4.32(s,1H),4.12(d,J=11.9Hz,1H),3.85(s,2H),3.59(d,J=8.5Hz,1H),3.47(s,2H),2.95(s,1H) ,2.73(s,2H),2.53(d,J=3.7Hz,4H),2.13(s,1H),1.74(s,3H),1.47(d,J=8.3Hz,3H),1.45(s,6H),1.26(s,6H),1.07(s,9H).

[0637] 44:((2S, 4R)-1-((S)-2-(3-(3-(3-(2-((1r, 3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-1-oxoisoindoline-5-yl)prop-2-yn-1-yl)azetidin-1-yl)propylamino)-3,3-dimethylbutanol)-4-hydroxy-N-((S)-1-(4-(4-methylthiazolyl-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide

[0638]

[0639] Compound 44 (20 mg, 0.02 mmol) was obtained. LC / MS (ESI+) calcd for C 55 H 65 ClN7O6S + ([M+H)) + )m / z:986.4; found 986.5. 1H NMR (400MHz, CDCl3) δ8.67(s,1H),8.20(s,1H),7.80(d,J=7.8Hz,1H),7.74(d,J=7.8Hz,1H),7.58(d,J=8.7Hz,1H),7.54–7.46(m,2H),7. 38(s,4H),6.99(d,J=2.3Hz,1H),6.84(dd,J=8.7,2.3Hz,1H),5.12–5.05(m,1H),4.81(d,J=8.2Hz,1H),4.65(s,2H),4.58(d,J=8.3Hz,1H) ,4.47(s,1H),4.40(s,1H),4.31(s,1H),4.19(s,2H),4.10(d,J=11.5Hz,1H),3.78(d,J=31.2Hz,2H),3.61(d,J=8.9Hz,1H),3.38(s,1H), 3.21(d,J=42.9Hz,2H),2.76(s,2H),2.64(s,2H),2.52(s,3H),2.34(s,2H),1.48(d,J=6.9Hz,3H),1.45(s,6H),1.25(s,6H),1.08(s,9H).

[0640] 45:2-Chloro-4-((1r,3r)-3-(5-((1-(1-(2-(2,6-dioxopiridin-3-yl)-6-fluoro-1,3-dioxoisoindol-5-yl)azelanoic acid-3-yl)-1H-pyrazol-4-yl)ethynyl)-1-oxoisoindololin-2-yl)-2,2,4,4-tetramethylcyclobutoxy)benzonitrile

[0641]

[0642] 1. Synthesis of compound (2-chloro-4-((1r,3r)-2,2,4,4-tetramethyl-3-(1-oxo-5-((trimethylsilyl)ethynyl)isoindoline-2-yl)cyclobutoxy)benzonitrile

[0643] Under nitrogen protection, 4-((1r,3r)-3-(5-bromo-1-oxoisoindoline-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. It was then cooled to room temperature. The mixture was filtered, washed with ethyl acetate, dried, evaporated to dryness, and purified by silica gel column chromatography. The compound (2-chloro-4-((1r,3r)-2,2,4,4-tetramethyl-3-(1-oxo-5-((trimethylsilyl)ethynyl)isoindol-2-yl)cyclobutoxy)benzonitrile (400 mg, 0.80 mmol) was obtained. Yield 77.2%. LC / MS (ESI+) calcd for C 28 H 32 ClN2O2Si + ([M+H)) + )m / z:491.2; found 491.1.

[0644] 2. Synthesis of compound 2-chloro-4-((1r,3r)-3-(5-ethynyl-1-oxoisoindoline-2-yl)-2,2,4,4-tetramethylcyclobutoxy)benzonitrile

[0645] 2-Chloro-4-((1r,3r)-2,2,4,4-tetramethyl-3-(1-oxo-5-((trimethylsilyl)ethynyl)isoindol-2-yl)cyclobutoxy)benzonitrile (400.0 mg, 0.80 mmol) and TBAF (1.0 g, 1.60 mmol) were dissolved in 10 mL THF. The mixture was stirred overnight at room temperature. The mixture was extracted with water and ethyl acetate, and the organic layer was washed with saturated brine, dried, evaporated to dryness, and purified by silica gel column chromatography. The result was 2-chloro-4-((1r,3r)-3-(5-ethynyl-1-oxoisoindol-2-yl)-2,2,4,4-tetramethylcyclobutoxy)benzonitrile (150 mg, 0.35 mmol). Yield: 43.9%.

[0646] LC / MS(ESI+)calcd for C 25 H 24 ClN2O2 + ([M+H)) + )m / z:419.2; found 419.1.

[0647] 3. Synthesis of tert-butyl 3-(4-iodo-1H-pyrazol-1-yl)azelate

[0648] 4-Iodo-1H-pyrazole (400.0 mg, 1.40 mmol), tert-butyl-3-iodozazidane-1-carboxylic acid ester (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. It was then cooled to room temperature. The mixture was extracted with water and ethyl acetate, and the organic layer was washed with saturated brine, dried, and evaporated to dryness. The solution was purified by silica gel column chromatography. The result was tert-butyl 3-(4-iodo-1H-pyrazole-1-yl)azelate (380 mg, 1.08 mmol). Yield: 77.0%.

[0649] 4. Synthesis of compound 1-(azelanoic-3-yl)-4-iodo-1H-pyrazole

[0650] 3-(4-iodo-1H-pyrazol-1-yl)tert-butyl azelate (380.0 mg, 1.08 mmol) was dissolved in 2 mL of dichloromethane and 2 mL of trifluoroacetic acid. The solution was stirred at room temperature for 2 h. The solution was concentrated and evaporated to dryness to give compound 1-(azelanoic-3-yl)-4-iodo-1H-pyrazol (180 mg, 1.08 mmol). Yield: 100.0%.

[0651] 5. Synthesis of compound 2-(2,6-dioxadiazin-3-yl)-5-fluoro-6-(3-(4-iodo-1H-pyrazol-1-yl)azelanoic-1-yl)isoindoline-1,3-dione

[0652] 1-(azelanoic-3-yl)-4-iodo-1H-pyrazole (180.0 mg, 1.08 mmol), 2-(2,6-dioxadiazin-3-yl)-5,6-difluoroisoindoline-1,3-dione (100.0 mg, 0.339 mmol), and DIEA (219.0 mg, 1.70 mmol) were dissolved in 3 mL DMSO. The mixture was heated to 130 °C and stirred for 3 h. It was then cooled to room temperature. The mixture was extracted with water and ethyl acetate, and the organic layer was washed with saturated brine, dried, evaporated to dryness, and purified by silica gel column chromatography. The result was 2-(2,6-dioxadiazin-3-yl)-5-fluoro-6-(3-(4-iodo-1H-pyrazole-1-yl)azelanoic-1-yl)isoindoline-1,3-dione (150 mg, 0.26 mmol). Yield: 84.0%.

[0653] LC / MS(ESI+)calcd for C 19 H 16 FIN5O4 + ([M+H)) + )m / z:524.0; found 524.0.

[0654] 6. Synthesis of compound 2-chloro-4-((1r,3r)-3-(5-((1-(1-(2-(2,6-dioxopiridin-3-yl)-6-fluoro-1,3-dioxoisoindoline-5-yl)azelanoic acid-3-yl)-1H-pyrazol-4-yl)ethynyl)-1-oxoisoindoline-2-yl)-2,2,4,4-tetramethylcyclobutoxy)benzonitrile

[0655] Under nitrogen protection, 2-(2,6-dioxadiazin-3-yl)-5-fluoro-6-(3-(4-iodo-1H-pyrazol-1-yl)azelanoic-1-yl)isoindoline-1,3-dione (50.0 mg, 0.10 mmol), 2-chloro-4-((1r,3r)-3-(5-ethynyl-1-oxoisoindoline-2-yl)-2,2,4,4-tetramethylcyclobutoxy)benzonitrile (40.0 mg, 0.10 mmol), Pd(PPh3)2Cl2 (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. It was then cooled to room temperature. The mixture was filtered, washed with ethyl acetate, dried, evaporated to dryness, and purified by silica gel column chromatography. The compound (2-chloro-4-((1r,3r)-3-(5-((1-(1-(2-(2,6-dioxopiridin-3-yl)-6-fluoro-1,3-dioxoisoindol-5-yl)azelanoic acid-3-yl)-1H-pyrazol-4-yl)ethynyl)-1-oxoisoindololin-2-yl)-2,2,4,4-tetramethylcyclobutoxy)benzonitrile (15 mg, 0.80 mmol) was obtained. The yield was 19.2%.

[0656] LC / MS(ESI+)calcd for C 44 H 38 ClFN7O6 + ([M+H)) + )m / z:814.3; found 814.2.

[0657] 1H NMR(400MHz, CDCl3)δ8.05–7.98(m,1H),7.81(d,J=7.9Hz,1H),7.74(s,1H),7.64(s,1H),7.60–7 .49(m,3H),7.41(d,J=12.2Hz,1H),7.09(d,J=7.2Hz,1H),7.00(d,J=2.4Hz,1H),6.85(dd,J=8.7, 2.4Hz,1H),5.11–4.98(m,1H),4.97–4.88(m,1H),4.66(s,2H),3.81–3.69(m,3H),3.23(td,J=9. 8,5.1Hz,1H),2.99–2.85(m,5H),2.85–2.70(m,2H),2.16–2.08(m,1H).1.46(s,6H),1.27(s,6H).

[0658] 46: (3R,5S)-1-((S)-2-(2-((5-((4-(((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)carbamoyl)phenyl)amino)pentyl)oxy)acetamyl)-3,3-dimethylbutanol)-5-((1-(4-methylthiazolyl-5-yl)phenyl)cyclopropyl)carbamoyl)pyrrolidine-3-ylacetate

[0659]

[0660] 1H NMR (400MHz, DMSO-d6) δ8.95(s,1H),8.87(s,1H),7.90(d,J=8.8Hz,1H),7.63(d,J=8.7Hz,2H),7.47(d,J=9.1Hz,1H),7.32(d,J= 9.4Hz,1H),7.21(d,J=2.3Hz,1H),7.00(dd,J=8.8,2.3Hz,1H),6.59-6.51(m,2H),6.17(s,1H),5.28(s,1H),4.31(s,1H),4.06-4 .03(m,1H),3.94(s,2H),3.49(t,J=6.3Hz,2H),3.05(d,J=5.5Hz,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=6.4Hz,2H),1.20(d,J=4.6Hz,6H),1.17(d,J=7.1Hz,2H),1.11(s,9H),1.02-0.80(m,12H).LC / MS(ESI+)calcdfor C 55 H 68 ClN7O8S([M+H)) + )m / z:1022.70; found 511.8.

[0661] 47:(2S,4R)-1-((S)-2-(2-((5-((4-(((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)carbamoyl)phenyl)amino)pentyl)oxy)acetamide)-3,3-dimethylbutyryl)-4-hydroxy-N-(1-(4-methylthiazolyl-5-yl)phenyl)cyclopropyl)pyrrolidine-2-carboxamide

[0662]

[0663] 1H NMR (400MHz, DMSO-d6) δ8.94(s,1H),8.84(s,1H),7.90(d,J=8.8Hz,1H),7.66-7.60(m,2H),7.45(d,J=9.5Hz,1H),7.33(s,2H),7.20( d,J=2.3Hz,1H),7.00(dd,J=8.8,2.4Hz,1H),6.54(d,J=8.7Hz,2H),6.16(s,1H),5.17(s,1H),4.56(d,J=9.7Hz,1H),4.42(t,J=8.3Hz ,1H),4.35(s,1H),4.31(s,1H),4.03(d,J=7.1Hz,2H),3.94(s,1H),3.63(d,J=11.2Hz,1H),3.50(t,J=6.6Hz,3H),3.17(s,2H),3.05( d,J=5.9Hz,2H),2.43(d,J=6.4Hz,3H),1.99(s,3H),1.59(d,J=6.1Hz,4H),1.44(s,2H),1.11(s,9H),0.94(s,12H).LC / MS(ESI+)calcd for C 53 H 66 ClN7O7S([M+H)) + m / z:980.66; found 980.3

[0664] 48:(2S,4R)-1-((S)-2-(2-((6-(2-(((1r,3r)-3-(3-chloro-4-cyanophenoxy))-2,2,4,4-tetramethylcyclobutyl)-1-oxoisoindoline-5-yl)hexyl-5-yn-1-yl)oxy)acetamyl)-3,3-dimethylbutyryl)-4-hydroxy-N-((R)-2-hydroxy-1-(4-(4-methylthiazolyl-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide

[0665] 49:(3R,5S)-1-((S)-2-(2-((6-(2-((((1r,3r)-3-(3-chloro-4-cyanophenoxy))-2,2,4,4-tetramethylcyclobutyl)-1-oxoisoindoline-5-yl)hexyl-5-yn-1-yl)oxy)acetamyl)-3,3-dimethylbutyryl)-5-(((R)-2-hydroxy-1-(4-(4-methylthiazolyl-5-yl)phenyl)ethyl)carbamoyl)pyrrolidine-3-ylacetate

[0666]

[0667] 1. Synthesis of tert-butyl 2-((6-(2-(((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-1-oxoisoindol-5-yl)hexyl(5-yn-1-yl)oxy)acetate

[0668] The sample was synthesized according to the aforementioned examples, with a yield of 42%. LC / MS (ESI+) calcd for: C 35 H 41 ClN2O5(M+H + )m / z,605.2;found,605.2.

[0669] 2. Synthesis of 2-((6-(2-(((1r,3r-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-1-oxoisoindol-5-yl)hexyl-5-yn-1-yl)oxy)acetic acid

[0670] The sample was synthesized according to the aforementioned examples, with a yield of 80%. LC / MS (ESI+) calcd for: C 31 H 33 ClN2O5(M+H + )m / z,549.2;found,549.2.

[0671] 3. Synthesis of (2S,4R)-1-((S)-2-(2-((6-(2-(((1r,3r)-3-(3-chloro-4-cyanophenoxy))-2,2,4,4-tetramethylcyclobutyl)-1-oxoisoindol-5-yl)hexyl-5-yn-1-yl)oxy)acetamyl)-3,3-dimethylbutyryl)-4-hydroxy-N-((R)-2-hydroxy-1-(4-(4-methylthiazolyl-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide

[0672] The sample was synthesized according to the aforementioned examples, with a yield of 43%. LC / MS (ESI+) calcd for: C 54 H 63 ClN6O8S(M+H + )m / z,991.4;found,991.4. 1H NMR (400MHz, CDCl3) δ7.77(d,J=7.6Hz,1H),7.57(d,J=8.7Hz,1H),7.54-7.37(m,6H ),7.20(m,2H),6.99(d,J=2.9Hz,1H),6.84(d,J=8.8Hz,1H),5.17(s,1H),4.64(s,2 H),4.54(s,3H),4.39(s,1H),4.31(s,1H),3.97(s,3H),3.83(m,1H),3.73(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).

[0673] 4. Synthesis of (3R,5S)-1-((S)-2-(2-((6-(2-((((1r,3r)-3-(3-chloro-4-cyanophenoxy))-2,2,4,4-tetramethylcyclobutyl)-1-oxoisoindol-5-yl)hexyl-5-yn-1-yl)oxy)acetamyl)-3,3-dimethylbutyryl)-5-(((R)-2-hydroxy-1-(4-(4-methylthiazolyl-5-yl)phenyl)ethyl)carbamoyl)pyrrolidine-3-ylacetate

[0674] The sample was synthesized according to the aforementioned examples, with a yield of 40%. LC / MS (ESI+) calcd for: C 56 H 65 ClN6O9S(M+H + )m / z,1033.4;found,1033.4. 1 H NMR (400MHz, CDCl3) δ9.23(s,1H),7.78(d,J=7.9Hz,1H),7.57(d,J=8.6Hz,1H),7.54-7.38(m,6H),7.16(d ,J=9.1Hz,1H),6.99(d,J=2.5Hz,1H),6.84(d,J=8.6Hz,1H),5.15(s,1H),4.68-4.51(m,4H),4.40(s,1H), 4.31(s,1H),4.13(d,J=11.9Hz,1H),4.07-3.94(m,3H),3.89(dd,J=11.7,4.4Hz,1H),3.60(s,2H),2.69(s ,3H),2.52(t,J=6.7Hz,3H),2.31-2.18(m,2H),2.05(d,J=2.3Hz,2H),1.25(d,J=2.4Hz,19H),1.05(s,9H).

[0675] 51:2-Chloro-4-((1R,3R)-3-(5-((1'-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindoline-5-yl)-[1,4'-bispiperidin]-4-yl)ethynyl)-1-oxoisoindoline-2-yl)-2,2,4,4-tetramethylcyclobutoxy)benzonitrile

[0676]

[0677] LC / MS (ESI+) Calculated for C 48 H 48 ClFN6O6(M+H + )m / z,859.3;found 859.3. 1 H NMR (400MHz, CDCl3) δ7.78(d,J=7.9Hz,1H),7.58(d,J=8.7Hz,1H),7.48(dd,J=12.8,6.1Hz,3H),7.39( d,J=7.3Hz,1H),7.00(d,J=2.4Hz,1H),6.84(dd,J=8.7,2.4Hz,1H),4.93(dd,J=12.3,5.3Hz,1H),4.64 (s,2H),4.40(s,1H),4.32(s,1H),3.74(d,J=11.6Hz,2H),3.01(s,2H),2.88(dd,J=23.1,12.0Hz,4H), 2.81–2.69(m,4H),2.62(s,1H),2.13(d,J=5.0Hz,3H),2.05(d,J=8.0Hz,4H),1.45(s,6H),1.26(s,6H).

[0678] 52:2-Chloro-4-((1R,3R)-3-(5-((1'-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)-[1,4'-bispiperidin]-4-yl)ethynyl)-1-oxoisoindoline-2-yl)-2,2,4,4-tetramethylcyclobutoxy)benzonitrile

[0679]

[0680] LC / MS (ESI+) Calculated for C 48 H 49 ClN6O6(M+H + )m / z,841.3;found 841.3. 1H NMR (400MHz, CDCl3) δ8.20–7.96(m,1H),7.78(d,J=7.8Hz,1H),7.70(d,J=8.4Hz,1H),7.58(d,J=8.7Hz,1H ),7.53–7.44(m,2H),7.28(s,1H),7.07(d,J=6.7Hz,1H),7.00(d,J=2.3Hz,1H),6.84(dd,J=8.7,2.2Hz,1H ),4.94(dd,J=12.0,5.3Hz,1H),4.64(s,2H),4.40(s,1H),4.33(s,1H),4.05(d,J=12.1Hz,2H),3.75(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).

[0681] Synthesis of 53:2-Chloro-4-((1r,3r)-3-(5-((1-(1-(2-(2,6-dioxadiazin-3-yl)-1,3-dioxoisoindoline-5-yl)azelanoic acid-3-yl)piperidin-4-yl)ethynyl)-1-oxoisoindoline-2-yl)-2,2,4,4-tetramethylcyclobutoxy)benzonitrile

[0682]

[0683] LC / MS (ESI+) Calculated for C 46 H 45 ClFN6O6(M+H + )m / z,813.3;found 813.3. 1H NMR (400MHz, CDCl3) δ8.18(s,1H),7.78(d,J=7.9Hz,1H),7.65(d,J=8.3Hz,1H),7.57(d,J=8.7Hz,1H),7.54–7. 45(m,2H),7.00(d,J=2.4Hz,1H),6.89–6.76(m,2H),6.54(dd,J=8.3,2.0Hz,1H),4.93(dd,J=12.3,5.3Hz,1H),4 .64(s,2H),4.40(s,1H),4.32(s,1H),4.12(t,J=7.5Hz,2H),3.94(s,2H),3.42(s,1H),3.01(d,J=16.1Hz,1H),2 .92–2.81(m,2H),2.80–2.71(m,4H),2.29(s,2H),2.02(s,2H),1.84(d,J=9.1Hz,2H),1.45(s,6H),1.26(s,7H).

[0684] 54:2-Chloro-4-((1S,4r)-4-(2-((3S)-3-((4-(2-(2,6-dioxopiridine-3-yl)-6-fluoro-3-oxoisoindoline-5-yl)piperazin-1-yl)methyl)pyrrolidine-1-yl)-5-oxo-5H-pyrrolo[3,4-b]pyridine-6(7H)-yl)cyclohexyl)oxy)benzonitrile

[0685]

[0686] LC / MS (ESI+) Calculated for C 42 H 44 ClFN8O5(M+H + )m / z,795.3;found 795.3. 1H NMR (400MHz, DMSO-d6) δ7.88(d,J=8.7Hz,1H),7.69(d,J=8.7Hz,1H),7.45(d,J=11.5Hz,1H),7.40(d,J=2.4Hz,1H),7.31(d,J=7.8Hz ,1H),7.18–7.11(m,1H),6.49(d,J=8.7Hz,1H),5.33(s,1H),5.09(d,J=12.9Hz,1H),4.57(s,2H),4.45(s,1H),4.38(d,J=17.6Hz,1H) ,4.26(d,J=8.8Hz,2H),4.07(s,2H),3.68(s,1H),3.58(s,1H),3.49–3.37(m,3H),3.21(s,1H),3.09(s,3H),2.91(s,2H),2.68(s,4H ),2.60(d,J=17.0Hz,3H),2.46–2.38(m,2H),2.34(s,1H),2.14(s,2H),2.00(d,J=7.5Hz,2H),1.80(s,3H),1.57(s,2H),1.24(s,2H).

[0687] 55:2-Chloro-4-((1S,4r)-4-(2-((3S)-3-((4-(2-(2,6-dioxopiridine-3-yl)-6-fluoro-1-oxoisoindoline-5-yl)piperazin-1-yl)methyl)pyrrolidine-1-yl)-5-oxo-5H-pyrrolo[3,4-b]pyridine-6(7H)-yl)cyclohexyl)oxy)benzonitrile

[0688] LC / MS (ESI+) Calculated for C 42 H 44 ClFN8O5(M+H + )m / z,795.3;found 795.3. 1H NMR (400MHz, DMSO-d6) δ10.99(s,1H),7.88(d,J=8.7Hz,1H),7.69(d,J=8.7Hz,1H),7.45(d,J=11.5Hz,1H),7.40(d,J=2.4Hz,1H),7. 31(d,J=7.8Hz,1H),7.18–7.11(m,1H),6.49(d,J=8.7Hz,1H),5.33(s,1H),5.09(d,J=12.9Hz,1H),4.57(s,2H),4.45(s,1H),4.38(d, J=17.6Hz,1H),4.26(d,J=8.8Hz,2H),4.07(s,2H),3.60(s,1H),3.49–3.37(m,3H),3.21(s,1H),3.15(s,2H),2.91(s,2H),2.68(s,4H) ),2.60(d,J=17.0Hz,3H),2.46–2.38(m,2H),2.34(s,1H),2.14(s,2H),2.00(d,J=7.5Hz,2H),1.80(s,3H),1.57(s,2H),1.24(s,2H).

[0689] Synthesis of 56:2-Chloro-4-((1r,4r)-4-(2-(4-((4-(2,6-dioxopiridine-3-yl)-1-oxoisoindoline-5-yl)piperazin-1-yl)methyl)piperidine-1-yl)-5-oxo-5H-pyrrole[3,4-b]pyridin-6(7H)-yl)cyclohexyl)oxy)benzonitrile

[0690]

[0691] LC / MS (ESI+) Calculated for C 43 H 47 ClN8O5(M+H + )m / z,791.3;found 791.3.

[0692] Synthesis of 57:2-Chloro-4-((1r,4r)-4-(2-(4-((4-(2,6-dioxopiridine-3-yl)-1,3-dioxoisoindoline-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)-5-oxo-5H-pyrrole[3,4-b]pyridin-6(7H)-yl)cyclohexyl)oxy)benzonitrile

[0693]

[0694] LC / MS (ESI+) Calculated for C 43 H45 ClN8O6(M+H + )m / z,805.3;found 805.3.

[0695] 1 H NMR (400MHz, CDCl3) δ8.07(s,1H),7.84(d,J=8.7Hz,1H),7.74(s,1H),7.58(d,J=8.7Hz,1H),7.33(s,1H),7.11(s,1H),7.03(d ,J=2.3Hz,1H),6.88(dd,J=8.7,2.4Hz,1H),6.68(d,J=8.9Hz,1H),4.97(dd,J=12.0,5.1Hz,1H),4.51(s,2H),4.32(d,J=7.4Hz ,2H),4.22(s,2H),3.91(s,1H),3.75(s,1H),3.56(s,1H),3.46(s,2H),2.97(d,J=17.2Hz,4H),2.91(s,1H),2.88–2.82(m,1H) ,2.78(d,J=16.0Hz,1H),2.61(s,3H),2.26(s,4H),2.16(d,J=7.2Hz,2H),1.98(d,J=43.1Hz,5H),1.72(dd,J=16.4,8.0Hz,4H).

[0696] 58: Synthesis of N-((1R,4R)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-4-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)-1,4-diazacycloheptane-1-yl)methyl)piperidin-1-yl)benzamide

[0697]

[0698] 1. Synthesis of methyl 4-(4-(hydroxymethyl)piperidin-1-yl)benzoate

[0699] 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 reacted overnight. The next day, after the methyl p-fluorobenzoate was completely consumed, the mixture was cooled to room temperature and extracted with water and ethyl acetate. The organic phase was washed with 0.05 M HCl solution and saturated brine. The solution was dried over anhydrous sodium sulfate and concentrated to give 1.1 g of methyl 4-(4-(hydroxymethyl)piperidin-1-yl)benzoate. Yield: 68.1%. MS (ESI) m / e 249.1 (M+H)+ .

[0700] 2. Synthesis of compound 4-(4-(hydroxymethyl)piperidin-1-yl)benzoic acid

[0701] 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. The aqueous phase was then slowly adjusted to pH 4-5 with 1N HCl, resulting in the precipitation of a large amount of white solid. The solid was filtered, and the filter cake was dried to give 510.0 mg of 4-(4-(hydroxymethyl)piperidin-1-yl)benzoic acid. Yield: 54.1%. MS (ESI) m / e 235.1 (M+H) + .

[0702] 3. Compound N-((1R,4R)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-4-(4-(hydroxymethyl)piperidin-1-yl)benzamide

[0703] 4-((1R,4R)-4-aminocyclohexyl)oxy)-2-chlorobenzonitrile (328.0 mg, 1.3 mmol) was dissolved in DCM, cooled to 0 °C, and 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 reaction was brought to room temperature for 2 h. The mixture was extracted with CH2Cl2 and water, the organic layer was washed with brine, dried over anhydrous sodium sulfate, evaporated to dryness, and purified by silica gel column chromatography. The result was 370.0 mg of N-((1R,4R)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-4-(4-(hydroxymethyl)piperidin-1-yl)benzamide, yield: 66.4%. MS (ESI) m / e 467.2 (M+H) + .

[0704] 4. Compound N-((1R,4R)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-4-formylpiperidin-1-yl)benzamide

[0705] N-((1R,4R)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-4-(4-(hydroxymethyl)piperidin-1-yl)benzamide (370 mg, 0.8 mmol) was dissolved in 10 mL of a mixture of DCM and 1 mL of tetrahydrofuran. Dess-Martin (373.2 mg, 0.9 mmol) was added, and the reaction was carried out at room temperature for 1 h. The mixture was filtered through diatomaceous earth, and the filtrate was washed with sodium bisulfite aqueous solution and saturated brine. 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. Yield: 81.4%. MS (ESI) m / e: 465.2 (M+H) + .

[0706] 5,4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl)-1,4-diazacycloheptane-1-carboxylic acid tert-butyl ester

[0707] 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (200.0 mg, 0.7 mmol) and tert-butyl 1,4-diazacycloheptane-1-carboxylate (174.1 mg, 0.9 mmol) were dissolved in 6 mL DMSO, and 0.5 mL DIEA was added. The mixture was reacted at 100 °C for 1.5 h. After cooling to room temperature, the mixture was extracted with water and ethyl acetate, washed with saturated brine, dried, concentrated, and column chromatography was performed to give 185.3 mg of tert-butyl 4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)-1,4-diazacycloheptane-1-carboxylate. Yield: 56.2%. MS (ESI) m / e 401.2 (M-56+H) + .

[0708] 6,5-(1,4-diazacyclohepta-1-yl)-2-(2,6-dioxopiperidin-3-yl)isodihydroindole-1,3-dione trifluoroacetate

[0709] 4-(2-(2,6-dioxadiazin-3-yl)-1,3-dioxadiazindol-5-yl)-1,4-diazacycloheptane-1-carboxylic acid tert-butyl ester (185.0 mg, 0.4 mmol) was dissolved in 2 mL of DCM, and 6 mL of TFA was added. The reaction was carried out at room temperature for 1 h. The product was concentrated directly to dryness for later use. 191 mg of the product was 5-(1,4-diazacycloheptane-1-yl)-2-(2,6-dioxadiazin-3-yl)isodihydroindol-1,3-dione trifluoroacetate. Yield: 99.0%. MS (ESI) m / e 356.2 (M+H) + .

[0710] 7. Preparation of compound N-((1R,4R)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-4-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)-1,4-diazacycloheptane-1-yl)methyl)piperidin-1-yl)benzamide

[0711] 5-(1,4-diazacyclohepten-1-yl)-2-(2,6-dioxopiperidin-3-yl)isodihydroindole-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 carried out at room temperature for 4 h. The reaction was quenched with water, and the mixture was extracted with DCM. After drying and concentration, column chromatography yielded 101.5 mg of N-((1R,4R)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-4-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)-1,4-diazacycloheptane-1-yl)methyl)piperidin-1-yl)benzamide. Yield: 58.8%. MS (ESI) m / e 805.3 (M+H) + . 1 H NMR (400MHz, CDCl3) δ8.20(s,1H),7.67(dd,J=8.6,3.4Hz,3H),7.57(d,J=8.7Hz,1H),7.12(d,J=2.1Hz,1H),7. 01(d,J=2.3Hz,1H),6.94–6.83(m,4H),5.91(d,J=7.8Hz,1H),4.96(dd,J=12.2,5.3Hz,1H),4.29(dd,J=12.2,8 .4Hz,1H),4.05(dd,J=11.0,7.3Hz,1H),3.82(d,J=12.7Hz,2H),3.64(t,J=6.0Hz,4H),2.97–2.73(m,7H),2.65 (s,2H),2.38(s,2H),2.18(dd,J=28.4,13.7Hz,6H),1.99(s,2H),1.83(s,2H),1.69(s,4H),1.46–1.37(m,2H).

[0712] Synthesis of 59:2-Chloro-4-(((1r,4r)-4-(2-(4-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-4-yl)piperidin-4-yl)oxy)piperidin-1-yl)-5-oxo-5H-pyrrolo[3,4-b]pyridin-6(7H)-yl)cyclohexyl)oxy)benzonitrile

[0713]

[0714] LC / MS (ESI+) Calculated for C 43 H 44 ClN7O7(M+H + )m / z,806.3;found 806.3.

[0715] 1 H NMR (400MHz, CDCl3) δ8.08(s,1H),7.84(d,J=8.8Hz,1H),7.59(t,J=8.1Hz,2H),7.40(d,J=7.0Hz,1H),7.20(d,J=8.4 Hz,1H),7.03(d,J=2.3Hz,1H),6.88(dd,J=8.8,2.3Hz,1H),6.70(d,J=8.8Hz,1H),4.99(dd,J=12.1,5.3Hz,1H),4.31( s,2H),4.22(s,2H),4.07(d,J=15.7Hz,2H),3.76(s,2H),3.66–3.56(m,2H),3.52–3.42(m,2H),3.20(d,J=8.3Hz,2H) ,2.94–2.71(m,3H),2.26(s,2H),2.14(d,J=7.8Hz,1H),2.04(s,4H),1.94(s,2H),1.88(s,2H),1.71(d,J=8.4Hz,5H).

[0716] Synthesis of 60:2-Chloro-4-(((1r,4r)-4-(2-(4-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)piperidin-4-yl)oxy)piperidin-1-yl)-5-oxo-5H-pyrrolo[3,4-b]pyridin-6(7H)-yl)cyclohexyl)oxy)benzyl nitrile

[0717]

[0718] 1,4-((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)piperidin-1-carboxylic acid tert-butyl ester

[0719] 2-Chloro-4-(((1R,4R)-4-(2-chloro-5-oxo-5H-pyrrolo[3,4-b]pyridin-6(7H)-yl)cyclohexyl)oxy)benzyl nitrile (100.0 mg, 0.3 mmol) and 4-(piperidin-4-yloxy)piperidin-1-carboxylic acid tert-butyl ester (212.1 mg, 0.8 mmol) were dissolved in 3 mL of NMP, and 0.5 mL of DIEA was added. The mixture was heated to 100 °C overnight. After cooling to room temperature, water and EA were added for extraction. The organic phase was then washed with water, 0.5 M HCl aqueous solution, and saturated brine. The solution 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)piperidin-1-carboxylic acid was obtained. Yield: 88.2%. MS (ESI) m / e 594.3 (M-56+H) + .

[0720] 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)benzyl nitrile trifluoroacetate

[0721] 140.0 mg (0.2 mmol) of compound 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)piperidin-1-carboxylic acid tert-butyl ester was dissolved in 1 mL DCM, and then 3 mL TFA was added. The mixture was stirred at room temperature for 1 h, and the reaction was monitored until completion. The solution was directly concentrated under reduced pressure until viscous, and then carried to solidification 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)benzyl nitrile trifluoroacetate was obtained. Yield: 99.2%. MS (ESI) m / e 549.1 (M+H) + .

[0722] 3,2-Chloro-4-(((1r,4r)-4-(2-(4-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)piperidin-4-yl)oxy)piperidin-1-yl)-5-oxo-5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl)cyclohexyl)oxy)benzylnitrile

[0723] 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)benzylnitrile trifluoroacetate (100.0 mg, 0.2 mmol) was dissolved in 2 mL DMSO, and DIEA (97.3 mg, 0.8 mmol) was added. After stirring until homogeneous, 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (49.9 mg, 0.2 mmol) was added. The reaction was heated to 120 °C and reacted for 2 h, monitoring for completion. After cooling to room temperature, water and ethyl acetate were added for extraction. The organic phase was washed with 0.5M hydrochloric acid aqueous solution and saturated brine, dried over anhydrous sodium sulfate, concentrated, and then 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-dioxoisoindoline-5-yl)piperidin-4-yl)oxy)piperidin-1-yl)-5-oxo-5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl)cyclohexyl)oxy)benzyl nitrile. Yield: 41.6%. MS (ESI) m / e 805.3 (M+H) + . 1 H NMR (400MHz, CDCl3) δ8.11(s,1H),7.84(d,J=8.8Hz,1H),7.70(d,J=8.5Hz,1H),7.58(d,J=8.7Hz,1H),7.31(d,J=2. 1Hz,1H),7.08(dd,J=8.6,2.1Hz,1H),7.03(d,J=2.3Hz,1H),6.88(dd,J=8.7,2.2Hz,1H),6.70(d,J=8.9Hz,1H),4.9 6(dd,J=12.1,5.2Hz,1H),4.32(d,J=8.0Hz,2H),4.22(s,2H),4.12–4.02(m,2H),3.86–3.68(m,4H),3.52–3.40(m,2 H),3.37–3.28(m,2H),2.96–2.71(m,3H),2.26(s,2H),2.20–2.10(m,1H),2.06–1.89(m,6H),1.72(d,J=8.3Hz,8H).

[0724] 61: Synthesis of N-((1R,4R)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-6-(4-(7-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindoline-5-yl)-2,7-diazaspiro[3.5]nonyl-2-yl)piperidin-1-yl)pyridazine-3-carboxamide

[0725]

[0726] 1. Synthesis of compound N-((1R,4R)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-6-(4-oxopiperidin-1-yl)pyridazine-3-carboxamide:

[0727] 6-Chloro-N-((1R,4R)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)pyridazin-3-carboxamide (200.0 mg, 0.51 mmol) and 4-piperidinone trifluoroacetate (217.9 mg, 1.02 mmol) were dissolved in 5 mL of NMP, and 0.5 mL of DIEA was added. 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 citric acid solution, and saturated brine. The solution was then dried over anhydrous sodium sulfate and concentrated. Column purification yielded 120.1 mg of N-((1R,4R)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-6-(4-oxopiperidin-1-yl)pyridazin-3-carboxamide. Yield: 51.7%. MS (ESI) m / e 453.9 (M+H) + .

[0728] 2,7-(2-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindoline-5-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester

[0729] 2-(2,6-dioxadiazin-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, and 0.5 mL of DIEA was added. The mixture was heated to 130 °C and reacted for 2 h. The reaction was monitored until completion. After cooling to room temperature, 10 mL of water and 10 mL of ethyl acetate were added for extraction. The mixture was washed with saturated citric acid solution and saturated brine. The solution was then dried over anhydrous sodium sulfate and concentrated. Column purification yielded 750.6 mg of tert-butyl 7-(2-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindoline-5-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylic acid. Yield: 88.2%. MS (ESI) m / e 445.2 (M-56+H) +

[0730] 3,2-(2,6-dioxadiepidin-3-yl)-5-fluoro-6-(2,7-diazaspiro[3.5]nonyl-7-yl)isoindoline-1,3-dione trifluoroacetate

[0731] 7-(2-(2-(2,6-dioxadipinidin-3-yl)-6-fluoro-1,3-dioxadiospiro[3.5]nonane-2-carboxylic acid tert-butyl ester (750 mg, 1.51 mmol) was dissolved in a mixed solvent of 4 mL DCM and 8 mL trifluoroacetic acid and stirred at room temperature for 1 h. The solution was directly concentrated by vacuum distillation and carried to the system with dichloromethane to form a yellow solid. 822.6 mg of 2-(2,6-dioxadipinidin-3-yl)-5-fluoro-6-(2,7-dioxadiospiro[3.5]nonyl-7-yl)isoindoline-1,3-dione trifluoroacetate was obtained. Yield: 99.5%. MS (ESI) m / e 400.1 (M+H) +

[0732] 4. Compound N-((1R,4R)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-6-(4-(7-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindoline-5-yl)-2,7-diazaspiro[3.5]nonyl-2-yl)piperidin-1-yl)pyridazine-3-carboxamide

[0733] The 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-dioxadipiperidin-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 dichloromethane and 1 mL methanol, and sodium triacetoxyborohydride (93.4 mg, 0.44 mmol) was added. The reaction was carried out overnight at room temperature. Quenching with water, extraction with dichloromethane, washing with saturated brine, drying the organic phase, filtering, concentrating, and purifying yielded 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-dioxoisoindoline-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(d,J=8.1Hz,1H),7.85(d,J=8.8Hz,1H),7.80(d,J=9.5Hz,1H),7.71(d,J=11.4Hz,1H),7.44(d,J=7.4Hz ,1H),7.39(d,J=2.3Hz,1H),7.34(d,J=9.6Hz,1H),7.13(dd,J=8.8,2.4H z,1H),5.10(dd,J=12.8,5.4Hz,1H),4.53(s,1H),4.21(d,J=13.0Hz,2H), 3.85(d,J=8.3Hz,1H),3.24(s,1H),3.17(s,4H),2.99(s,4H),2.91–2.80 (m,1H),2.59(d,J=18.4Hz,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=11.0H z,2H),1.64(d,J=12.8Hz,2H),1.51(d,J=12.3Hz,2H),1.28–1.11(m,3H).

[0734] 62: Synthesis of N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-6-(4-(5-(2-(2,6-dioxoperidin-3-yl)-1,3-dioxoisoindoline-5-yl)hexahydropyrrole[3,4-c]pyrrole-2(1H)-yl)piperidin-1-yl)pyridazine-3-carboxamide

[0735]

[0736] LC / MS (ESI+) Calculated for C 42 H 44 ClN9O6(M+H + )m / z,806.3;found 806.3.

[0737] 1 H NMR (400MHz, CDCl3) δ8.16(s,1H),8.00(d,J=9.5Hz,1H),7.86(d,J=8.1Hz,1H),7.68(d,J=8.3Hz,1H) ,7.56(d,J=8.7Hz,1H),7.00(d,J=2.2Hz,3H),6.85(dd,J=8.8,2.2Hz,1H),6.76(d,J=7.1Hz,1H).4.9 4(dd,J=12.1,5.3Hz,1H),4.52(s,2H),4.31(s,2H),4.02(s,2H),3.59(s,2H),3.51(s,2H),3.40(s,2 H),3.02(s,3H),2.93–2.66(m,6H),2.17(d,J=4.1Hz,6H),2.02(d,J=14.6Hz,2H),1.54–1.42(m,4H).

[0738] 63: Synthesis of N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-5-(4-(5-(2-(2,6-dioxoperidin-3-yl)-1,3-dioxoisoindoline-5-yl)hexahydropyrrole[3,4-c]pyrrole-2(1H)-yl)piperidin-1-yl)pyrazine-2-carboxamide

[0739]

[0740] LC / MS (ESI+) Calculated for C 42 H 44 ClN9O6(M+H + )m / z,806.3;found 806.3.

[0741] 1H NMR (400MHz, CDCl3) δ8.83(s,1H),8.19(s,1H),7.98(s,1H),7.70(d,J=8.3Hz,1H),7.56(d,J=8.7Hz, 1H),7.40(d,J=8.1Hz,1H),7.05–6.97(m,2H),6.85(dd,J=8.8,2.3Hz,1H),6.78(d,J=7.4Hz,1H),4.9 4(dd,J=12.1,5.3Hz,1H),4.52(s,2H),4.31(s,2H),4.02(s,2H),3.59(s,2H),3.51(s,2H),3.40(s,2 H),3.02(s,3H),2.93–2.66(m,6H),2.17(d,J=4.1Hz,6H),2.02(d,J=14.6Hz,2H),1.53–1.41(m,4H).

[0742] 64: Synthesis of N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-5-(4-(5-(2-(2,6-dioxoperidin-3-yl)-6-fluoro-1,3-dioxoisoindoline-5-yl)hexahydropyrrole[3,4-c]pyrrole-2(1H)-yl)piperidin-1-yl)pyrazine-2-carboxamide

[0743]

[0744] LC / MS (ESI+) Calculated for C 42 H 43 ClFN9O6(M+H + )m / z,826.3;found 826.3.

[0745] 1 H NMR (400MHz, CDCl3) δ8.80(s,1H),8.21(d,J=9.5Hz,1H),7.86(d,J=8.2Hz,1H),7.56(d, J=8.7Hz,1H),7.17(d,J=6.7Hz,1H),7.00(dd,J=5.9,3.6Hz,2H),6.85(dd,J=8.7,2.4Hz, 1H),4.92(dd,J=12.3,5.3Hz,1H),4.49(s,2H),4.32(t,J=10.1Hz,2H),4.05(d,J=8.2Hz ,2H),3.53(s,4H),3.12(s,4H),2.91–2.66(m,6H),2.20–2.10(m,7H),1.51–1.35(m,4H).

[0746] 65: Synthesis of N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-6-(4-(5-(2-(2,6-dioxoperidin-3-yl)-6-fluoro-1,3-dioxoisoindoline-5-yl)hexahydropyrrole[3,4-c]pyrrole-2(1H)-yl)piperidin-1-yl)pyridazine-3-carboxamide

[0747]

[0748] LC / MS (ESI+) Calculated for C 42 H 43 ClFN9O6(M+H + )m / z, 826.3; found 826.3.

[0749] 1 H NMR (400MHz, CDCl3) δ8.10(s,1H),8.00(d,J=9.5Hz,1H),7.86(d,J=8.2Hz,1H),7.56(d,J=8.7 Hz,1H),7.45(d,J=11.8Hz,1H),7.17(d,J=6.7Hz,1H),7.00(dd,J=5.9,3.6Hz,2H),6.85(dd,J= 8.7,2.4Hz,1H),4.92(dd,J=12.3,5.3Hz,1H),4.49(s,2H),4.32(t,J=10.1Hz,2H),4.05(d,J= 8.2Hz,2H),3.53(s,4H),3.14(s,4H),2.91–2.66(m,6H),2.20–2.10(m,7H),1.54–1.38(m,4H).

[0750] 66: Synthesis of N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-2-(4-(5-(2-(2,6-dioxoperidin-3-yl)-6-fluoro-1,3-dioxoisoamyl-5-yl)hexahydropyrrole[3,4-c]pyrrole-2(1H)-yl)piperidin-1-yl)pyrimidine-5-carboxamide

[0751]

[0752] LC / MS (ESI+) Calculated for C 42 H 44 ClN9O6(M+H + )m / z,806.3;found 806.3.

[0753] 1H NMR (400MHz, CDCl3) δ8.81(s,1H),8.18(d,J=9.5Hz,1H),7.86(d,J=8.2Hz,1H),7.56(d, J=8.7Hz,1H),7.17(d,J=6.7Hz,1H),7.00(dd,J=5.9,3.6Hz,2H),6.85(dd,J=8.7,2.4Hz, 1H),4.82(dd,J=12.3,5.3Hz,1H),4.56(s,2H),4.32(t,J=10.1Hz,2H),4.05(d,J=8.2Hz ,2H),3.51(s,4H),3.12(s,4H),2.91–2.66(m,6H),2.20–2.10(m,7H),1.55–1.38(m,4H).

[0754] 67: Synthesis of N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-6-(5-(1-(2-(2,6-dioxopiridine-3-yl)-6-fluoro-1,3-dioxoisoindoline-5-yl)hexahydropyrrole[3,4-c]pyrrole-2(1H)-yl)pyridazine-3-carboxamide

[0755]

[0756] LC / MS (ESI+) Calculated for C 42 H 43 ClFN9O6(M+H + )m / z,824.3;found 824.3.

[0757] 1H NMR (400MHz, CDCl3) δ7.99(d,J=9.4Hz,1H),7.91(d,J=8.2Hz,1H),7.56(d,J=8.7Hz,1H),7.45(d,J=11.0Hz,1H),7.37(d,J=7.3 Hz,1H),7.00(d,J=2.4Hz,1H),6.86(dd,J=8.8,2.4Hz,1H),6.74(d,J=9.4Hz,1H),4.92(dd,J=12.3,5.3Hz,3H),4.32(t,J=9.9Hz ,1H),4.11–3.99(m,2H),3.84(s,2H),3.59(dd,J=24.3,11.8Hz,5H),3.08(s,2H),2.95–2.86(m,5H),2.83–2.62(m,6H),2.32(d, J=10.1Hz,4H),2.16(dd,J=22.5,11.8Hz,7H),2.05–1.95(m,4H),1.89(s,2H),1.71(dt,J=22.4,10.2Hz,5H),1.54–1.40(m,3H).

[0758] 68: Synthesis of N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-2-(4-(5-(2-(2,6-dioxoperidin-3-yl)-1,3-dioxoisoindoline-5-yl)hexahydropyrrole[3,4-c]pyrrole-2(1H)-yl)piperidin-1-yl)pyrimidine-5-carboxamide

[0759]

[0760] LC / MS (ESI+) Calculated for C 42 H 44 ClN9O6(M+H + )m / z,806.3;found 806.3. 1H NMR (400MHz, CDCl3) δ8.67(s,2H),8.45(s,1H),7.66(d,J=8.4Hz,1H),7.55(d,J=8.7Hz,1H) ,7.02–6.95(m,2H),6.84(dd,J=8.8,2.4Hz,1H),6.75(s,1H),5.91(s,1H),4.94(s,1H),4.66 (d,J=9.8Hz,2H),4.26(d,J=10.3Hz,1H),4.00(s,1H),3.64(d,J=7.5Hz,2H),3.37(d,J=7.2 Hz,2H),3.08(s,3H),2.92–2.62(m,6H),2.14(s,5H),1.87(s,2H),1.46(s,5H),1.25(s,2H).

[0761] 69: Synthesis of N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-5-(5-(1-(2-(2,6-dioxoperidin-3-yl)-1,3-dioxoisoindoline-5-yl)piperidin-4-yl)hexahydropyrrole[3,4-c]pyrrole-2(1H)-yl)pyrazine-2-carboxamide

[0762]

[0763] LC / MS (ESI+) Calculated for C 42 H 44 ClN9O6(M+H + )m / z,806.3;found 806.3.

[0764] 1H NMR (400MHz, CDCl3) δ8.81(d,J=1.3Hz,1H),7.72(d,J=1.3Hz,1H),7.56(d,J=8.7Hz,1H),7.45(d,J=11.1Hz,1H),7.38(dd,J=10.5,7 .8Hz,2H),7.16(d,J=5.6Hz,1H),6.99(d,J=2.4Hz,1H),6.85(dd,J=8.8,2.4Hz,1H),4.92(dd,J=12.3,5.3Hz,1H),4.35–4.26(m,1H), 4.08–3.98(m,1H),3.82(dd,J=11.0,8.1Hz,2H),3.62(d,J=12.3Hz,2H),3.50(d,J=11.0Hz,2H),3.05(s,2H),2.98–2.83(m,6H),2.8 0–2.71(m,2H),2.71–2.65(m,2H),2.33(d,J=10.3Hz,2H),2.21–2.11(m,6H),2.05(s,3H),1.77–1.61(m,5H),1.42(d,J=12.0Hz,3H).

[0765] 70: Synthesis of N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-5-(5-(1-(2-(2,6-dioxoperidin-3-yl)-6-fluoro-1,3-dioxoisoindoline-5-yl)piperidin-4-yl)hexahydropyrrole[3,4-c]pyrrole-2(1H)-yl)pyrazine-2-carboxamide

[0766]

[0767] LC / MS (ESI+) Calculated for C 42 H 43 ClFN9O6(M+H + )m / z,824.3;found 824.3.

[0768] 1H NMR (400MHz, CDCl3) δ8.85(d,J=1.3Hz,1H),7.72(d,J=1.3Hz,1H),7.56(d,J=8.7Hz,1H),7.45(d,J=11.1Hz,1H),7.38(dd,J=1 0.5,7.8Hz,2H),6.99(d,J=2.4Hz,1H),6.85(dd,J=8.8,2.4Hz,1H),4.92(dd,J=12.3,5.3Hz,1H),4.35–4.26(m,1H),4.08–3.98 (m,1H),3.82(dd,J=11.0,8.1Hz,2H),3.62(d,J=12.3Hz,2H),3.50(d,J=11.0Hz,2H),3.05(s,2H),2.98–2.83(m,6H),2.80–2.7 1(m,2H),2.71–2.65(m,2H),2.31(d,J=10.3Hz,2H),2.21–2.11(m,6H),2.05(s,3H),1.78–1.62(m,5H),1.46(d,J=12.0Hz,3H).

[0769] 71: Synthesis of N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-6-(2-(2,6-dioxopiridine-3-yl)-6-fluoro-1,3-dioxoisoindoline-5-yl)piperidin-4-yl)-2,7-diazaspirocyclic[3.5]non-7-yl)pyridazine-3-carboxamide

[0770]

[0771] LC / MS (ESI+) Calculated for C 43 H 45 ClFN9O6(M+H + )m / z,838.3;found 838.3.

[0772] 1H NMR (400MHz, DMSO-d6) δ11.01(s,1H),8.60(d,J=8.1Hz,1H),7.87(d,J=8.8Hz,1H),7.82(d,J=9.5Hz,1H),7.70(d,J=11.4Hz,1H),7.41(d,J=7.4H z,1H),7.36(d,J=2.3Hz,1H),7.32(d,J=9.6Hz,1H),7.13(dd,J=8.8,2.4Hz,1H),5.09(dd,J=12.8,5.4Hz,1H),4.53(s,1H),4.21(d,J=13.0Hz,2H) ,3.85(d,J=8.3Hz,1H),3.24(s,1H),3.17(s,4H),2.99(s,4H),2.91–2.8 0(m,1H),2.59(d,J=18.4Hz,1H),2.35(d,J=18.7Hz,2H),2.10(d,J=10.0H z,2H),2.03(s,1H),1.89(d,J=10.2Hz,2H),1.81(s,4H),1.73(d,J=11.0 Hz,2H),1.64(d,J=12.8Hz,2H),1.51(d,J=12.3Hz,2H),1.2–1.10(m,3H).

[0773] 72: N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-6-(5-(1-(2-(2,6-dioxoperidin-3-yl)-6-fluoro-1,3-dioxoisoindoline-5-yl)piperidin-4-yl)hexahydropyrrole[3,4-c]pyrrole-2(1H)-yl)pyridazine-3-carboxamide

[0774]

[0775] LC / MS (ESI+) Calculated for C 44 H 47 ClFN9O6(M+H + )m / z,852.3;found 852.3.

[0776] 1H NMR (400MHz, CDCl3) δ8.19(d,J=9.1Hz,1H),7.99(d,J=9.4Hz,1H),7.57(d,J=8.7Hz,1H),7.45(d,J=11.0Hz,1H),7.37(d,J =7.3Hz,1H),6.97(d,J=2.4Hz,1H),6.81(dd,J=8.7,2.4Hz,1H),6.76(d,J=9.4Hz,1H),4.92(dd,J=12.3,5.3Hz,1H),4.55( s,1H),4.19(d,J=9.1Hz,1H),4.07(s,1H),3.85(s,2H),3.61(t,J=13.4Hz,4H),3.10(s,2H),2.91(dd,J=22.3,8.6Hz,5H), 2.85–2.65(m,4H),2.13(dd,J=11.3,6.2Hz,2H),2.07–1.95(m,4H),1.74(dd,J=20.5,9.9Hz,2H),1.28(s,5H),1.21(s,6H).

[0777] 73: Synthesis of N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-5-(4-((1-(2,6-dioxopiridine-3-yl-6-fluoro-1,3-dioxoisoindoline-5-yl)piperidin-4-yl)amino)piperidin-1-yl)pyrazin-2-carboxamide

[0778]

[0779] 1. Synthesis of tert-butyl(1-(5-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)carbamoyl)pyrazin-2-yl)piperidin-4-yl)carbamate

[0780] 5-Chloro-N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)pyrazin-2-carboxamide (400 mg, 1.02 mmol) was dissolved in 10 mL of NMP, and tert-butylpiperidin-4-ylcarbamate (246 mg, 1.23 mmol) and DIEA (661 mg, 5.11 mmol) were added. The reaction was heated to 100 °C. The reaction was quenched with water, extracted with EA, and washed with saturated citric acid solution. After purification, 450 mg of tert-butyl(1-(5-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)pyrazin-2-yl)piperidin-4-yl)carbamate was obtained. Yield: 79.3%. LC / MS (ESI+) Calcd for C 28 H 35 ClN6O4(M-56+H+ )m / z,500.2;found 500.2.

[0781] 2,5-(4-aminopiperidin-1-yl)-N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)hexyl)azine-2-carboxamide trifluoroacetate

[0782] 300 mg (0.54 mmol) of tert-butyl(1-(5-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)carbamoyl)pyrazin-2-yl)piperidin-4-yl)carbamate was dissolved in 2 mL of DCM, and 4 mL of trifluoroacetic acid was added. The mixture was stirred for 2 h. The solution was then concentrated directly 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)azin-2-carboxamide trifluoroacetate was obtained.

[0783] 3. Synthesis of N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-5-(4-((1-(2,6-dioxopiridine-3-yl-6-fluoro-1,3-dioxoisoindoline-5-yl)piperidin-4-yl)amino)piperidin-1-yl)pyrazin-2-carboxamide

[0784] 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-dioxadipinidin-3-yl)-5-fluoro-6-(4-oxoperidinidin-1-yl)isoindoline-1,3-dione (83 mg, 0.22 mmol) were dissolved in a mixture of 2 mL DCM and 2 mL methanol. Sodium triacetoxyborohydride (186 mg, 0.88 mmol) was slowly added, and the reaction was allowed to proceed for 5 h. N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-5-(4-((1-(2,6-dioxopiridin-3-yl-6-fluoro-1,3-dioxoisoindololin-5-yl)piperidin-4-yl)amino)piperidin-1-yl)pyrazin-2-carboxamide 12 mg was purified by silica gel plate, yield: 7.3%. LC / MS (ESI+) Calcd for C 28 H 35 ClN6O4(M+H + )m / z,812.3;found 812.3. 1H NMR (400MHz, CDCl3) δ8.84(s,1H),7.99(s,1H),7.56(d,J=8.7Hz,1H),7.47(dd,J=11.0,2.7Hz,1H),7.40 (dd,J=13.9,7.5Hz,2H),7.00(d,J=2.3Hz,1H),6.85(dd,J=8.8,2.4Hz,1H),4.99–4.88(m,2H),4.48(s,2H ),4.31(s,2H),4.05(s,2H),3.71(d,J=7.5Hz,2H),3.61–3.51(m,1H),3.16(s,1H),3.08(d,J=10.3Hz,3H ),2.93(t,J=12.9Hz,4H),2.79(dd,J=25.3,13.3Hz,3H),2.18(d,J=4.6Hz,8H),2.07(s,1H),1.25(s,3H).

[0785] 74: Synthesis of N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-6-(2-(2,6-dioxoperidin-3-yl)-1,3-dioxoisoindoline-5-yl)piperidin-4-yl)-2,7-diazaspirocyclic[3.5]non-7-yl)pyridazine-3-carboxamide

[0786]

[0787] LC / MS (ESI+) Calculated for C 43 H 46 ClN9O6(M+H + )m / z,820.3;found 820.3.

[0788] 1H NMR (400MHz, CDCl3) δ8.21(s,1H),7.94(d,J=9.5Hz,1H),7.87(d,J=8.2Hz,1H),7.66(d,J=8.5Hz,1H),7.56(d,J= 8.7Hz,1H),7.28(d,J=2.2Hz,1H),7.06(dd,J=8.6,2.2Hz,1H),7.00(t,J=5.7Hz,2H),6.86(dd,J=8.8,2.4Hz,1H), 4.97(dd,J=12.3,5.3Hz,1H),4.55(s,2H),4.32(t,J=10.0Hz,1H),4.05(dd,J=11.4,7.2Hz,1H),3.43–3.37(m,4H) ,3.22(d,J=10.9Hz,3H),2.94–2.67(m,4H),2.24–2.10(m,6H),1.94(s,6H),1.78–1.63(m,8H),1.52–1.40(m,3H).

[0789] 75: Synthetic route of N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-6-(2-((1-(2,6-dioxopiridine-3-yl)-6-fluoro-1,3-dioxoisoindoline-5-yl)piperidin-4-yl)methyl)-2,7-diazaspiro[3.5]non-7-yl)pyridazine-3-carboxamide:

[0790]

[0791] LC / MS (ESI+) Calculated for C 44 H 47 ClFN9O6(M+H + )m / z,852.3;found 852.3. 1H NMR (400MHz, CDCl3) δ8.46(d,J=2.3Hz,1H),7.58(dd,J=9.0,2.4Hz,1H),7.55(d,J=8.7Hz,1H),7.47(d,J=10.9Hz,1H),7.38(d ,J=7.3Hz,1H),6.99(d,J=2.4Hz,1H),6.85(dd,J=8.7,2.4Hz,1H),6.64(d,J=9.0Hz,1H),5.90(d,J=7.7Hz,1H),4.93(dd,J=12 .3,5.3Hz,1H),4.52–4.25(m,4H),4.04(d,J=7.7Hz,1H),3.33(s,3H),3.18(s,3H),3.04–2.65(m,6H),2.57(s,1H),2.27(s,4H ),2.17(dd,J=25.9,12.6Hz,9H),2.05(s,3H),1.98(s,4H),1.86(d,J=11.4Hz,2H),1.76(d,J=12.9Hz,2H),1.48–1.36(m,4H).

[0792] 76: N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-5-(2-((1-(2,6-dioxadiazin-3-yl)-6-fluoro-1,3-dioxoisoindoline-5-yl)piperidin-4-yl)methyl)-2,7-diazaspiro[3.5]non-7-yl)pyridazine-2-carboxamide

[0793]

[0794] LC / MS (ESI+) Calculated for C 44 H 47 ClFN9O6(M+H + )m / z,852.3;found 852.3. 1H NMR (400MHz, CDCl3) δ8.84(d,J=2.3Hz,1H),8.25(dd,J=9.0,2.4Hz,1H),7.56(d,J=8.7Hz,1H),7.47(d,J=10.9Hz,1H),7.38(d ,J=7.3Hz,1H),6.99(d,J=2.4Hz,1H),6.85(dd,J=8.7,2.4Hz,1H),6.77(d,J=9.0Hz,1H),5.93(d,J=7.7Hz,1H),4.93(dd,J=12 .3,5.3Hz,1H),4.52–4.25(m,4H),4.04(d,J=7.7Hz,1H),3.33(s,3H),3.18(s,3H),3.04–2.65(m,6H),2.57(s,1H),2.27(s,4H ),2.17(dd,J=25.9,12.6Hz,9H),2.05(s,3H),1.97(s,4H),1.85(d,J=11.4Hz,2H),1.67(d,J=12.9Hz,2H),1.45–1.33(m,4H).

[0795] 77: N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-6-(4-(7-(2-(2,6-dioxoperidin-3-yl)-6-fluoro-1,3-dioxoisoindoline-5-yl)-2,7-diazaspirocyclic[3.5]non-2-yl)piperidin-1-yl)nicotinamide

[0796]

[0797] LC / MS (ESI+) Calculated for C 44 H 46 ClFN8O6(M+H + )m / z,837.3;found 837.3. 1H NMR (400MHz, CDCl3) δ8.84(d,J=2.3Hz,1H),8.25(dd,J=9.0,2.4Hz,1H),7.56(d,J=8.7Hz,1H),7.47(d,J=10.9Hz,1H),7.38(d ,J=7.3Hz,1H),6.99(d,J=2.4Hz,1H),6.85(dd,J=8.7,2.4Hz,1H),6.77(d,J=9.0Hz,1H),5.93(d,J=7.7Hz,1H),4.93(dd,J=12 .3,5.3Hz,1H),4.52–4.25(m,4H),4.04(d,J=7.7Hz,1H),3.33(s,3H),3.18(s,3H),3.04–2.65(m,6H),2.57(s,1H),2.27(s,4H ),2.17(dd,J=25.9,12.6Hz,9H),2.05(s,3H),1.97(s,4H),1.85(d,J=11.4Hz,2H),1.67(d,J=12.9Hz,2H),1.45–1.33(m,4H).

[0798] 78: HC-4304-01: N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-6-(4-(7-(2-(2,6-dioxopiridine-3-yl)-1,3-dioxoisoindoline-5-yl)-2,7-diazospiro[3.5]non-2-yl)pyridin-1-yl)azine-3-carboxamide

[0799]

[0800] LC / MS (ESI+) Calcd for C 43 H 46 ClN9O6(M+H + )m / z,820.3;found 820.3. 1H NMR (400MHz, CDCl3) δ8.21(s,1H),7.99(d,J=9.5Hz,1H),7.87(d,J=8.2Hz,1H),7.69(d,J=8.5Hz,1H),7.56(d,J= 8.7Hz,1H),7.28(d,J=2.2Hz,1H),7.06(dd,J=8.6,2.2Hz,1H),7.00(t,J=5.7Hz,2H),6.86(dd,J=8.8,2.4Hz,1H), 4.94(dd,J=12.3,5.3Hz,1H),4.39(s,2H),4.32(t,J=10.0Hz,1H),4.05(dd,J=11.4,7.2Hz,1H),3.43–3.37(m,4H) ,3.22(d,J=10.9Hz,3H),2.94–2.67(m,4H),2.24–2.10(m,6H),1.94(s,6H),1.78–1.63(m,8H),1.52–1.40(m,3H).

[0801] 79: N-((1r,4r)-4-(4-cyano-3-(trifluoromethyl)phenoxy)cyclohexyl)-6-(4-(7-(2-(2,6-dioxopiridin-3-yl)-6-fluoro-1,3-dioxoisoindoline-5-yl)-2,7-diazaspiro[3.5]non-2-yl)piperidin-1-yl)pyridazine-3-carboxamide

[0802]

[0803] LC / MS (ESI+) Calculated for C 44 H 45 F4N9O6(M+H + )m / z,872.3; found 872.3. 1H NMR (400MHz, CDCl3) δ8.45(s,1H),8.00(d,J=9.5Hz,1H),7.89(d,J=8.2Hz,1H),7.75(d,J=8.6Hz,1H),7.47(d,J=10.8 Hz,1H),7.38(d,J=7.2Hz,1H),7.26(s,1H),7.11(dd,J=8.7,2.4Hz,1H),7.00(d,J=9.6Hz,1H),4.93(dd,J=12.3,5.3H z,1H),4.48(d,J=13.3Hz,2H),4.40(dd,J=11.8,8.1Hz,2H),4.13–4.01(m,2H),3.49(s,4H),3.16(d,J=14.6Hz,7H),2 .96–2.68(m,6H),2.24–2.16(m,7H),2.05(s,2H),2.02(s,6H),1.95(s,2H),1.77–1.67(m,3H),1.49(d,J=12.2Hz,3H).

[0804] 80: N-((1s,3s)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-6-(4-(7-(2-(2,6-dioxopiridine-3-yl)-6-fluoro-1,3-dioxoisoindoline-5-yl)-2,7-diazaspiro[3.5]non-2-yl)piperidin-1-yl)pyridazine-3-carboxamide

[0805]

[0806] LC / MS (ESI+) Calculated for C 45 H 49 ClF4N9O6(M+H + )m / z,866.3;found 866.3. 1H NMR (400MHz, CDCl3) δ8.55–8.41(m,1H),8.16(d,J=9.1Hz,1H),7.99(d,J=9.5Hz,1H),7.57(d,J=8.7Hz,1H),7.47(d,J =10.9Hz,1H),7.38(d,J=7.2Hz,1H),6.99(dd,J=12.0,6.0Hz,2H),6.81(dd,J=8.7,2.4Hz,1H),4.93(dd,J=12.3,5.3H z,2H),4.44(d,J=13.4Hz,3H),4.19(d,J=9.0Hz,1H),4.07(s,1H),3.30(s,4H),3.18(d,J=6.2Hz,6H),2.96–2.72(m,6 H),2.17–2.10(m,2H),2.05(s,4H),2.00–1.85(m,9H),1.51(d,J=10.6Hz,3H),1.28(s,6H),1.25(s,1H),1.21(s,6H).

[0807] 81: N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-6-(6-(1-(2-(2,6-dioxopiridine-3-yl)-6-fluoro-1,3-dioxoisoindoline-5-yl)piperidine-4-yl)-2,6-diazaspirocyclo[3,4]octane-2-yl)pyridazine-3-carboxamide

[0808]

[0809] LC / MS (ESI+) Calculated for C 41 H 43 ClFN9O6s(M+H + )m / z,824.3;found 824.3. 1H NMR (400MHz, CDCl3) δ8.20(s,1H),7.99(d,J=9.2Hz,1H),7.88(d,J=8.2Hz,1H),7.56(d,J=8.7Hz,1H),7.47(d,J=10.9Hz,1H),7.39( d,J=7.3Hz,1H),7.00(d,J=2.3Hz,1H),6.86(dd,J=8.7,2.3Hz,1H),6.61(d,J=9.2Hz,1H),4.94(dd,J=12.3,5.3Hz,1H),4.32(t,J=9. 8Hz,1H),4.19(dd,J=24.2,8.6Hz,4H),4.05(d,J=7.9Hz,1H),3.67(d,J=11.9Hz,2H),3.06(s,2H),2.98–2.70(m,8H),2.54–2.36(m, 1H), 2.27 (s, 2H), 2.16 (d, J = 10.3Hz, 6H), 2.05 (d, J = 11.8Hz, 3H), 1.83 (s, 3H), 1.69 (d, J = 11.8Hz, 9H), 1.47 (dd, J = 22.4, 10.4Hz, 3H).

[0810] 82: N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-5-(6-(1-(2-(2,6-dioxadiazin-3-yl)-6-fluoro-1,3-dioxoisoindoline-5-yl)piperidin-4-yl)-2,6-diazaspiro[3.4]octane-2-yl)pyrazine-2-carboxamide

[0811]

[0812] LC / MS (ESI+) Calculated for C 41 H 43 ClFN9O6s(M+H + )m / z,824.3;found 824.3. 1H NMR (400MHz, CDCl3) δ8.83(d,J=1.3Hz,1H),8.16(s,1H),7.62–7.53(m,2H),7.47(d,J=10.9Hz,1H),7.40(dd,J=12.6,7.8 Hz,2H),6.99(d,J=2.4Hz,1H),6.85(dd,J=8.8,2.4Hz,1H),4.94(dd,J=12.3,5.3Hz,1H),4.31(s,1H),4.20(s,2H),4.14(d ,J=8.6Hz,2H),4.03(d,J=7.8Hz,1H),3.68(d,J=12.7Hz,2H),3.07(s,2H),2.91(dd,J=21.2,10.1Hz,4H),2.86–2.71(m,3H ),2.62(s,2H),2.29(s,2H),2.24–2.11(m,6H),2.05(s,2H),1.88(s,2H),1.69(dd,J=22.2,9.9Hz,8H),1.53–1.39(m,3H).

[0813] 83: N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-5-(4-(2-(2,6-dioxadiazin-3-yl)-6-fluoro-1,3-dioxoisoindoline-5-yl)-2,7-diazaspirocyclic[3.5]non-7-yl)piperidin-1-yl)-1,3,4-thiadiazole-2-carboxamide

[0814]

[0815] LC / MS (ESI+) Calculated for C 41 H 43 ClFN9O6s(M+H + )m / z,844.3;found 844.3. 1H NMR(400MHz, CDCl3)δ8.00(s,1H),7.56(d,J=8.7Hz,1H),7.38(dd,J=11.6,5.3Hz,1H),7.05–6 .97(m,2H),6.88–6.78(m,2H),4.91(dd,J=12.0,5.4Hz,1H),4.31(s,1H),4.13(s,2H),3.98(s, 1H),3.95–3.85(m,4H),3.59(d,J=7.0Hz,2H),3.23(t,J=12.3Hz,2H),2.80(ddd,J=30.6,27.4 ,9.4Hz,6H),2.16(d,J=10.4Hz,6H),1.68(s,2H),1.62(s,4H),1.53–1.46(m,2H),1.25(s,6H).

[0816] 84: Synthesis of N-((1r,4R)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-1-(1r,4R)-4-((2-(2-(2,6-dioxoperidin-3-yl)-1,3-dioxoisoindoline-5-yl)-2,7-diazaspiro[3.5]non-7-yl)methyl)cyclohexyl)-1H-1,2,4-triazol-3-carboxamide

[0817]

[0818] 1. Synthesis of N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-1H-1,2,4-triazole-3-carboxamide

[0819] 1H-1,2,4-triazole-3-carboxylic acid (500 mg, 1.99 mmol) was mixed with 10 mL of DMF and was sparingly soluble. DIEA (309 mg, 2.39 mmol) was added, and the solution was dissolved completely. The mixture was cooled to -5 °C, and HATU (796 mg, 2.09 mmol) was added. The mixture was stirred for at least 1 h, and then 4-(((1r,4r)-4-aminocyclohexyl)oxy)-2-chlorobenzyl nitrile (237 mg, 2.09 mmol) was added. The mixture was stirred at low temperature for 30 min, the ice-salt bath was removed, and the mixture was allowed to warm naturally to room temperature for 2 h. Water was added to the reaction system with stirring, resulting in the precipitation of a large amount of solid. The mixture was filtered, and the filter cake was dried to give 660 mg of N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-1H-1,2,4-triazole-3-carboxamide. Yield: 95.7%. LC / MS (ESI+) Calculated for C 16 H 16 ClN5O2(M+H + )m / z,346.1;found 346.1.

[0820] 2. Synthesis of (1R,4r)-methyl 4-(3-((1R,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)carbamoyl)-1H-1,2,4-triazol-1-yl)cyclohexanoate

[0821] N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-1H-1,2,4-triazol-3-carboxamide (500 mg, 1.45 mmol) was dissolved in DMF, followed by the addition of (1S,4S)-methyl-4-((methanesulfonyl)oxy)cyclohexylcarboxylate (1.02 g, 4.34 mmol) and cesium carbonate (1.41 g, 4.34 mmol). The reaction was carried out overnight at 95 °C. The mixture was quenched with water, extracted with EA, dried, and concentrated to obtain 210 mg of (1R,4r)-methyl-4-(3-((1R,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)carbamoyl)-1H-1,2,4-triazol-1-yl)cyclohexanoate. Yield: 31.65%. LC / MS (ESI+) Calcd for C 24 H 28 ClN5O4(M+H + )m / z,486.2;found 486.2.

[0822] 3.N-((1r,4R)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-1-((1r,4R)-4-(hydroxymethyl)cyclohexyl)-1H-1,2,4-triazol-3-carboxamide

[0823] (1R,4r)-methyl 4-(3-((1R,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)carbamoyl)-1H-1,2,4-triazol-1-yl)cyclohexanoate (200 mg, 0.41 mmol) was dissolved in a 1:1 mixture of THF and methanol. Sodium borohydride (62 mg, 1.65 mmol) was slowly added, and the mixture was refluxed at 65 °C for 2 h until complete. The mixture was cooled to room temperature, quenched with water, extracted with EA, dried, and purified by silica gel plate to obtain 140 mg of N-((1r,4R)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-1-((1r,4R)-4-(hydroxymethyl)cyclohexyl)-1H-1,2,4-triazol-3-carboxamide. Yield: 61.87%. LC / MS (ESI+) Calcd for C 23 H 28 ClN5O3(M+H + )m / z,458.2;found 458.2.

[0824] 4. Synthesis of compound N-((1r,4R)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-1-((1r,4R)-4-formylcyclohexyl)-1H-1,2,4-triazole-3-carboxamide

[0825] N-((1r,4R)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-1-((1r,4R)-4-(hydroxymethyl)cyclohexyl)-1H-1,2,4-triazol-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. The reaction was allowed to proceed for 1 h. The mixture was filtered, and the filtrate was washed with sodium bisulfite, then with saturated sodium bicarbonate solution, dried, and filtered again. The solution was concentrated and purified to obtain 80 mg of N-((1r,4R)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-1-((1r,4R)-4-formylcyclohexyl)-1H-1,2,4-triazol-3-carboxamide. Yield: 61.84% 5.N-((1r,4R)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-1-(1r,4R)-4-((2-(2-(2,6-dioxopiridine-3-yl)-1,3-dioxoisoindoline-5-yl)-2,7-diazaspiro[3.5]non-7-yl)methyl)cyclohexyl)-1H-1,2,4-triazol-3-carboxamide

[0826] N-((1r,4R)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-1-((1r,4R)-4-formylcyclohexyl)-1H-1,2,4-triazol-3-carboxamide (40 mg, 0.09 mmol) and 2-(2,6-dioxadiazin-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 mixture of DCM and MeOH. Sodium triacetoxyborohydride (75 mg, 0.35 mmol) was slowly added. The reaction was monitored for completion over 2 hours. The reaction was quenched with water and extracted with DCM. Dry purification yielded 35 mg of N-((1r,4R)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-1-(1r,4R)-4-((2-(2-(2,6-dioxoperidin-3-yl)-1,3-dioxoisoindoline-5-yl)-2,7-diazaspiro[3.5]non-7-yl)methyl)cyclohexyl)-1H-1,2,4-triazol-3-carboxamide. Yield: 48.57%. LC / MS (ESI+) Calcd for C 43 H 48 ClN9O6(M+H + )m / z,822.3;found 822.3. 1H NMR (400MHz, CDCl3) δ8.11(s,1H),7.64(d,J=8.3Hz,1H),7.55(d,J=8.7Hz,1H),7.15(d,J=8.2Hz,1H),6.98(d,J=2.3Hz, 1H),6.84(dd,J=8.7,2.3Hz,1H),6.77(d,J=1.7Hz,1H),6.50(dd,J=8.3,1.9Hz,1H),4.94(dd,J=12.3,5.3Hz,2H),4.72(d ,J=25.2Hz,6H),4.25(dt,J=15.4,11.1Hz,3H),4.09(d,J=8.1Hz,1H),3.73(s,4H),2.81(ddd,J=33.0,24.0,10.4Hz,3H) ,2.40(s,3H),2.23–2.16(m,6H),1.87(s,6H),1.67(dd,J=23.0,10.0Hz,4H),1.47(dd,J=23.1,10.5Hz,2H),1.25(s,1H).

[0827] 85: N-((1r,4R)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-1-((1r,4R)-4-((2-(2,6-dioxopiridine-3-yl)-6-fluoro-1,3-dioxoisoindoline-5-yl)-2,7-diazaspirocyclo[3.5]non-7-yl)methyl)cyclohexyl)-1H-1,2,4-triazol-3-carboxamide:

[0828] LC / MS (ESI+) Calculated for C 41 H 43 ClFN9O6s(M+H + )m / z,844.3;found 844.3. 1H NMR (400MHz, CDCl3) δ8.63(s,1H),8.12(s,1H),7.56(d,J=8.7Hz,1H),7.36(d,J=10.8Hz,1H),7.18(d,J =8.3Hz,1H),6.99(d,J=2.4Hz,1H),6.87–6.77(m,2H),4.92(dd,J=12.2,5.3Hz,1H),4.63(s,2H),4.32– 4.18(m,2H),4.15–4.05(m,1H),3.89(s,4H),2.97–2.65(m,4H),2.41(s,5H),2.27(d,J=6.9Hz,4H),2.1 5(dd,J=8.9,6.4Hz,5H),2.08(s,4H),1.92(s,4H),1.67(dd,J=22.6,9.8Hz,4H),1.47(d,J=12.7Hz,2H).

[0829] 86: N-((1r,4R)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-1-((1r,4R)-4-((2-(2-(2,6-dioxopiridine-3-yl)-1,3-dioxoisoindoline-5-yl)-2,7-diazaspiro[3.5]non-7-yl)methyl)cyclohexyl)-1H-1,2,4-triazol-5-carboxamide:

[0830] LC / MS (ESI+) Calculated for C 43 H 48 ClN9O6(M+H + )m / z,822.3;found 822.3. 1H NMR (400MHz, CDCl3) δ8.35(s,1H),7.86(s,1H),7.64(d,J=8.3Hz,1H),7.56(d,J=8.7Hz,1H),7.48(d,J=8.2Hz,1H),6 .99(d,J=2.4Hz,1H),6.84(dd,J=8.7,2.4Hz,1H),6.77(d,J=2.0Hz,1H),6.50(dd,J=8.4,2.0Hz,1H),5.39(s,1H),4.9 3(dd,J=12.3,5.3Hz,2H),4.79(s,4H),4.30(t,J=10.2Hz,1H),3.99(d,J=8.3Hz,1H),3.73(s,4H),2.93–2.69(m,3H), 2.28(s,4H),2.07(d,J=13.4Hz,4H),1.98(d,J=11.0Hz,4H),1.91–1.82(m,6H),1.70–1.60(m,3H),1.57–1.47(m,2H).

[0831] 87: N-((1r,4R)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-1-((1r,4R)-4-((2-(2,6-dioxoperidin-3-yl)-6-fluoro-1,3-dioxoisoindoline-5-yl)-2,7-diazaspirocyclo[3.5]non-7-yl)methyl)cyclohexyl)-1H-1,2,4-triazol-5-carboxamide: LC / MS (ESI+) Calcd for C 41 H 43 ClFN9O6s(M+H + )m / z,844.3;found 844.3. 1H NMR (400MHz, CDCl3) δ8.36(s,1H),7.86(s,1H),7.56(d,J=8.7Hz,1H),7.48(d,J=8.2Hz,1H),7.36(d,J=10.9Hz,1H),6.99(d ,J=2.4Hz,1H),6.84(dd,J=8.8,2.4Hz,1H),6.80(d,J=7.5Hz,1H),5.39(t,J=11.5Hz,1H),4.91(dd,J=12.2,5.3Hz,1H),4.58 (s,4H),4.30(t,J=10.1Hz,1H),3.99(dd,J=11.6,7.4Hz,1H),3.89(d,J=1.7Hz,4H),2.95–2.65(m,4H),2.20(d,J=5.1Hz,4H ),2.08(s,3H),2.04(d,J=4.3Hz,1H),1.97(t,J=11.2Hz,4H),1.89(s,4H),1.72–1.59(m,4H),1.51(dd,J=21.8,11.3Hz,3H).

[0832] Synthesis of N-((1r, 4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-6-(7-(1-(2-(2,6-dioxopiridine-3-yl)-1,3-dioxoisoindoline-5-yl)piperidine-4-yl)-2,7-diazaspiro[3.5]nonyl-2-yl)pyridazine-3-carboxamide

[0833]

[0834] 1. Synthesis of tert-butyl 4-(2-{6-[4-(3-chloro-4-cyano-phenoxy)-cyclohexylcarbamoyl]-pyridazin-3-yl}-2,7-diaza-spirocyclic[3.5]non-7-yl)piperidine-1-carboxylic acid

[0835] Add 5 mL of N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-6-(2,7-diazaspiro[3.5]non-2-yl)pyridazine-3-carboxamide (100 mg, 0.208 mmol) to dichloromethane, add 4-Boc piperidinone (414 mg, 2.1 mmol), add 0.5 drops of acetic acid, reflux at 40 °C for 1 h, cool to room temperature, and add sodium triacetylborohydride (441 mg). 2.08 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 obtain 120 mg of 4-(2-{6-[4-(3-chloro-4-cyano-phenoxy)-cyclohexylcarbamoyl]-pyridazin-3-yl}-2,7-diaza-spirocyclic[3.5]non-7-yl)-piperidine-1-carboxylic acid tert-butyl ester, yield: 86.8%, LC / MS (ESI+) calcd for C 35 H 46 ClN7O4([M+H]+)m / e663.8.

[0836] 2. Synthesis of N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-6-(7-(1-(2-(2,6-dioxadiazin-3-yl)-1,3-dioxadiazine-5-yl)piperidin-4-yl)-2,7-diazospiro[3.5]non-2-yl)pyridazine-3-carboxamide

[0837] 4-(2-{6-[4-(3-chloro-4-cyano-phenoxy)-cyclohexylcarbamoyl]-pyridazin-3-yl}-2,7-diaza-spirocyclo[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 h, concentrated to dryness under reduced pressure, and then concentrated twice more under reduced pressure with the addition of dichloromethane. 3 mL of trifluoroacetic acid was added... DMSO was added, followed by 0.5 mL of DIEA and 2-(2,6-dioxadiazin-3-yl)-5-fluoroisoindole-1,3-dione. The mixture was refluxed at 135 °C for 1.5 h, cooled to room temperature, and then 10 mL of dichloromethane was added. The mixture was washed twice with 10 mL of water, then once with saturated brine. The mixture was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by thin-layer chromatography to obtain a yellow solid product, N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-6-(7-(1-(2-(2,6-dioxadiazin-3-yl)-1,3-dioxadiazindole-5-yl)piperidin-4-yl)-2,7-diazaspiro[3.5]non-2-yl)pyridazine-3-carboxamide 35 mg. Yield: 62.7%. LC / MS (ESI+) calcd for C 43 H 46 ClN9O6([M+H]+)m / e 820.3,1 H NMR (400MHz, CDCl3) δ8.20(s,1H),7.98(d,J=9.2Hz,1H),7.88(d,J=8.3Hz,1H),7.69(d,J=8.5Hz,1H),7.56(d,J=8.7Hz, 1H),7.29(d,J=2.2Hz,1H),7.06(dd,J=8.6,2.2Hz,1H),7.00(d,J=2.3Hz,1H),6.85(dd,J=8.8,2.4Hz,1H),6.58(d,J=9.3 Hz,1H),4.95(dd,J=12.3,5.3Hz,1H),4.32(dd,J=11.7,8.1Hz,1H),4.03(t,J=11.6Hz,3H),3.91(s,4H),3.00(t,J=11.8 Hz,2H),2.94–2.70(m,4H),2.62(s,4H),2.15(dt,J=10.4,7.8Hz,6H),1.97(s,4H),1.72–1.65(m,5H),1.53–1.43(m,2H).

[0838] 89: Synthesis of N-((1r, 4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-5-(7-(1-(2-(2,6-dioxopiridine-3-yl)-1,3-dioxoisoindoline-5-yl)piperidine-4-yl)-2,7-diazaspiro[3.5]nonyl-2-yl)pyrazine-2-carboxamide

[0839]

[0840] The synthesis steps are as described in 88.

[0841] LC / MS(ESI+)calcd for C 43 H 46 ClN9O6([M+H]+)m / e 820.3, 1H NMR (400MHz, CDCl3) δ8.83(d,J=1.2Hz,1H),8.09(s,1H),7.70(d,J=8.5Hz,1H),7.63–7.51(m,2H),7.39(d,J=8.2Hz, 1H),7.29(d,J=2.0Hz,1H),7.07(dd,J=8.5,2.0Hz,1H),6.99(d,J=2.3Hz,1H),6.84(dd,J=8.7,2.4Hz,1H),4.99–4.9 0(m,1H),4.30(td,J=10.1,5.2Hz,1H),4.03(d,J=9.1Hz,3H),3.91(s,4H),3.00(t,J=12.1Hz,2H),2.94–2.72(m,4H) ,2.66(d,J=33.9Hz,4H),2.29–2.09(m,6H),1.99(s,4H),1.71(dd,J=18.7,8.9Hz,5H),1.48(dd,J=18.3,6.9Hz,2H).

[0842] 90:2-Chloro-4-((1r,3r)-3-(2-(4-((2-(2,6-dioxopiridine-3-yl)-6-fluoro-1,3-dioxoisoindoline-5-yl)-2,7-diazaspiro[3.5]nonane-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

[0843]

[0844] 2-Chloro-4-(3-(2-(4-formylpiperidin-1-yl)-5-oxoisoindoline-5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl)-2,2,4,4-tetramethylcyclobutoxy)benzonitrile (66 mg, 0.13 mmol) was dissolved in 5 mL of dichloromethane, and 2-(2,6-dioxoisoindoline-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 were added, and the mixture was reacted at room temperature for 15 min. Then, sodium triacetylborohydride (200 mg) was added. mg, 0.94 mmol), reacted at room temperature for 1 h, washed with water, concentrated under reduced pressure to dryness, separated by thin-layer chromatography to give a yellow solid product 2-chloro-4-(3-(2-(4-((2-(2,6-dioxadiazin-3-yl)-6-fluoro-1,3-dioxoisoindoline-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 55 mg, yield: 56.1%, LC / MS (ESI+) calcd for C 48 H 52 ClFN8O6([M+H]+)m / e 891.3, 1 H NMR (400MHz, CDCl3) δ8.03(s,1H),7.80(d,J=8.8Hz,1H),7.57(d,J=8.7Hz,1H),7.36(d,J=10.5Hz,1H) ,6.98(d,J=2.4Hz,1H),6.87–6.76(m,2H),6.67(d,J=8.9Hz,1H),4.91(dd,J=12.2,5.3Hz,1H),4.54(s, 2H),4.45(d,J=10.1Hz,3H),4.25(s,1H),3.98(s,1H),3.89(s,2H),3.63(t,J=34.0Hz,1H),3.18–2.59 (m,7H),2.37(s,3H),2.14(dd,J=15.6,7.6Hz,4H),1.86(s,5H),1.61(s,2H),1.45(s,6H),1.23(s,6H).

[0845] 91: N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-6-(2-((1-(2,6-dioxopiridine-3-yl)-6-fluoro-1,3-dioxoisoindoline-5-yl)piperidin-4-yl)methyl)-2,7-diazaspirocyclic[3.5]non-7-yl)-N-(methyl-d3)pyridazine-3-carboxamide

[0846]

[0847] 1. Synthesis of 7-{6-[4-(3-chloro-4-cyano-phenoxy)-cyclohexylcarbamoyl]-pyridazin-3-yl}-2,7-diaza-spirocyclic[3.5]nonane-2-carboxylic acid tert-butyl ester

[0848] 113 mg (0.5 mmol) of 2,7-diazaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester was dissolved in 6 mL of DMF, and anhydrous potassium carbonate (207 mg, 1.5 mmol) was added. Then, 196 mg (0.5 mmol) of 6-chloro-pyridazine-3-carboxylic acid [4-(3-chloro-4-cyano-phenoxy)-cyclohexyl]-amide (196 mg, 0.5 mmol) was added. The mixture was reacted overnight at 80 °C, cooled to room temperature, and 15 mL of ethyl acetate was added. The mixture was washed three times with 10 mL of water, once with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and separated by thin-layer chromatography to obtain 190 mg of the product 7-{6-[4-(3-chloro-4-cyano-phenoxy)-cyclohexylcarbamoyl]-pyridazine-3-yl}-2,7-diazaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester. Yield: 65.4%. LC / MS (ESI+) was performed for C 30 H 37 ClN6O4([M+H]+)m / e581.2.

[0849] 2. Synthesis of tert-butyl 7-(6-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)(methyl-d3)carbamoyl)pyridazin-3-yl)-2,7-diazaspiro[3.5]non-2-carboxylic acid ester

[0850] 7-{6-[4-(3-chloro-4-cyano-phenoxy)-cyclohexylcarbamoyl]-pyridazin-3-yl}-2,7-diaza-spirocyclo[3,5]nonane-2-carboxylic acid tert-butyl ester (58 mg, 0.1 mmol) was dissolved in 5 mL of LDM, sodium hydride (8 mg, 0.2 mmol) was added, and the mixture was stirred at rt for 10 min. Deuterated iodomethane (17 mg, 0.12 mmol) was added, and the reaction was carried out at room temperature for 2 h. The reaction was quenched with water, and 15 mL of the solution was added. Extracted with ethyl acetate, the organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and separated by thin-layer chromatography to obtain 58 mg of tert-butyl 7-(6-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)(methyl-d3)carbamoyl)pyridazin-3-yl)-2,7-diazaspiro[3.5]non-2-carboxylic acid ester, yield: 97.15%, LC / MS (ESI+) calcd for C 31 H 36D3ClN6O4([M+H]+)m / e 598.3.

[0851] 3. Synthesis of N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-6-(2-((1-(2,6-dioxopiridine-3-yl)-6-fluoro-1,3-dioxoisoindoline-5-yl)piperidin-4-yl)methyl)-2,7-diazaspirocyclic[3.5]non-7-yl)-N-(methyl-d3)pyridazine-3-carboxamide

[0852] 57 mg (0.095 mmol) of tert-butyl 7-(6-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)(methyl-d3)carbamoyl)pyridazin-3-yl)-2,7-diazaspiro[3.5]non-2-carboxylic acid ester was dissolved in 3 mL of dichloromethane, and 3 mL of trifluoroacetic acid was added. The mixture was stirred at room temperature for 2 h, concentrated under reduced pressure, and the pH was adjusted to alkaline with saturated Na2CO3 aqueous solution. The mixture was extracted twice with DCM, and the organic layers were combined. The mixture was washed once with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to obtain 30 mg of white solid. The product was dissolved in 5 mL of dichloromethane, and 1-[2-(2,6-dioxadiazin-3-yl)-6-fluoro-1,3-dioxo-2,3-dihydro-1H-isoindole] was added. -5-yl]-piperidin-4-carboxaldehyde (30 mg, 0.078 mmol), 0.5 drops of acetic acid were added, and the mixture was reacted at room temperature for 15 min. Triacetylborohydride sodium (106 mg, 0.5 mmol) was added, and the mixture was reacted overnight at room temperature. The mixture was washed with water, concentrated under reduced pressure to dryness, and separated by thin-layer chromatography to obtain a yellow solid product N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-6-(2-((1-(2,6-dioxadiazin-3-yl)-6-fluoro-1,3-dioxoisoindoline-5-yl)piperidin-4-yl)methyl)-2,7-diazaspirocyclo[3.5]non-7-yl)-N-(methyl-d3)pyridazine-3-carboxamide 40 mg, yield: 48.4%, LC / MS (ESI+) calcd for C 45 H 46 D3ClFN9O6([M+H) + )m / e 869.3, 1H NMR (400MHz, CDCl3) δ8.53(s,1H),7.64(t,J=10.8Hz,1H),7.55(dd,J=8.7,5.2Hz,1H),7.46(d,J=11.0Hz,1H),7.38(d,J =7.3Hz,1H),7.03–6.92(m,2H),6.83(ddd,J=18.8,8.8,2.1Hz,1H),4.93(dd,J=12.3,5.3Hz,1H),4.24(s,1H),3.77–3.58 (m,6H),3.28(s,3H),2.94–2.68(m,5H),2.57(d,J=5.2Hz,2H),2.25(d,J=8.6Hz,1H),2.15(dd,J=16.3,8.4Hz,2H),2.07( d,J=7.6Hz,1H),1.98(d,J=10.1Hz,1H),1.88(d,J=13.0Hz,6H),1.82–1.64(m,5H),1.58–1.39(m,3H),1.28–1.23(m,1H).

[0853] 92: N-((1r, 4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-6-(6-((1R, 5S, 6S)-3-(2-(2,6-dioxopiridine-3-yl)-6-fluoro-1,3-dioxoisoindoline-5-yl)-3-azabicyclo[3.1.0]n-hexane-6-yl)methyl)-2,6-diazaspiro[3.3]heptane-2-yl)pyridazine-3-carboxamide

[0854]

[0855] 1. Synthesis of tert-butyl 6-(6-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)carbamoyl)pyridazin-3-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylic acid

[0856] 2,6-diazaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester (182 mg, 0.75 mmol) was dissolved in 5 mL of LMF, and 6-chloro-N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)pyridazin-3-carboxamide (196 mg, 0.5 mmol) was added. The mixture was reacted at 80 °C for 3 h, cooled to room temperature, and 15 mL of ethyl acetate was added. The mixture was washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and separated by thin-layer chromatography to obtain 220 mg of 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. Yield: 79.6%. LC / MS (ESI+) calcd for C 28 H 33 ClN6O4([M+H) + )m / e 553.2.

[0857] 2. Synthesis of N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-6-(6-((1R,5S,6S)-3-(2-(2,6-dioxoperidin-3-yl)-6-fluoro-1,3-dioxoisoindoline-5-yl)-3-azabicyclo[3.1.0]n-hexane-6-yl)methyl)-2,6-diazaspiro[3.3]heptane-2-yl)pyridazine-3-carboxamide

[0858] 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, and 3 mL of trifluoroacetic acid was added. The mixture was stirred at room temperature for 2 h, concentrated to dryness under reduced pressure, and the pH was adjusted to alkaline with saturated Na2CO3 aqueous solution. The mixture was extracted twice with DCM, and the organic layers were combined. The mixture was washed once with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated to dryness under reduced pressure to obtain 210 mg of white solid. The obtained product (45 mg, 0.1 mmol) was dissolved in 5 mL of dichloromethane, and 3-[2-(2,6-dioxypiperidin-3-yl)-6-fluoro-1,3-dioxy-2,3-dihydro-1H-isoindoline-5-yl]-3-aza- Bicyclo[3.1.0]hexane-6-carboxaldehyde (37 mg, 0.096 mmol) was mixed with 0.5 drops of acetic acid and stirred at room temperature for 5 min. Triacetylborohydride sodium (212 mg, 1.0 mmol) was added and stirred overnight at room temperature. The mixture was washed with water, concentrated under reduced pressure, and separated by thin-layer chromatography to obtain a yellow solid product N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-6-(6-((1R,5S,6S)-3-(2-(2,6-dioxadiazin-3-yl)-6-fluoro-1,3-dioxoisoindoline-5-yl)-3-azabicyclo[3.1.0]n-hexane-6-yl)methyl)-2,6-diazaspiro[3.3]heptane-2-yl)pyridazine-3-carboxamide 50 mg, yield: 60.8%, LC / MS (ESI+) calcd for C 42 H 41 ClFN9O6([M+H)) + )m / e 822.3, 1H NMR (400MHz, CDCl3) δ8.39(s,1H),8.01(d,J=9.2Hz,1H),7.86(d,J=8.1Hz,1H),7.56(d,J=8.7Hz,1H),7.39(d,J=1 2.5Hz,1H),7.03(d,J=7.4Hz,1H),7.00(d,J=2.3Hz,1H),6.85(dd,J=8.8,2.4Hz,1H),6.63(d,J=9.2Hz,1H),4.91(d d,J=12.2,5.3Hz,1H),4.42–4.28(m,4H),4.05(d,J=8.0Hz,1H),3.87(d,J=7.9Hz,2H),3.77(s,3H),3.57(d,J=9.9 Hz,2H),2.96–2.70(m,3H),2.70–2.52(m,2H),2.25–2.07(m,5H),1.72–1.67(m,6H),1.46(dd,J=22.5,10.3Hz,3H).

[0859] 93: N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-6-(4-((1R,5S,6S)-3-(2-(2,6-dioxopiridin-3-yl)-6-fluoro-1,3-dioxoisoindoline-5-yl)-3-azabicyclo[3.1.0]n-hexane-6-yl)methyl)-1,4-diaza-1-yl)pyridazine-3-carboxamide

[0860]

[0861] The synthesis steps are as described in 92.

[0862] LC / MS(ESI+)calcd for C 42 H 43 ClFN9O6([M+H)) + )m / e 824.3, 1H NMR (400MHz, CDCl3) δ8.27(s,1H),8.01(d,J=9.5Hz,1H),7.88(d,J=8.2Hz,1H),7.56(d,J=8.7Hz,1H),7.4 0(s,1H),7.01(dd,J=7.5,4.9Hz,2H),6.91–6.82(m,2H),4.91(dd,J=12.2,5.3Hz,1H),4.37–4.25(m,1H), 4.05(dd,J=11.5,7.4Hz,2H),3.86(dd,J=9.9,2.3Hz,2H),3.74(d,J=5.0Hz,2H),3.57(d,J=9.2Hz,2H),2. 81(qdd,J=17.5,15.9,10.0Hz,7H),2.59(s,2H),2.22–2.05(m,6H),1.75–1.64(m,6H),1.54–1.36(m,3H).

[0863] 94: N-((1r,4r)-4-(4-cyano-3-(trifluoromethyl)phenoxy)cyclohexyl)-5-(4-((1R,5S,6S)-3-(2-(2,6-dioxopiridine-3-yl)-6-fluoro-1,3-dioxoisoindoline-5-yl)-3-azabicyclo[3.1.0]n-hexane-6-yl)methyl)piperazin-1-yl)pyrazin-2-carboxamide

[0864]

[0865] 1. Synthesis of 5'-[4-(4-cyano-3-trifluoromethylphenoxy)-cyclohexylcarbamoyl]-2,3,5,6-tetrahydro-[1,2']bipyrazinyl-4-carboxylic acid tert-butyl ester

[0866] N-Boc piperazine (93 mg, 0.5 mmol) was dissolved in 5 mL DMF, and potassium carbonate (138 mg, 1.0 mmol) and 5-chloro-pyrazine-2-carboxylic acid [4-(4-cyano-3-trifluoromethylphenoxy)-cyclohexyl]-amide (142 mg, 0.33 mmol) were added. The mixture was reacted at 80 °C for 3 h, and 15 mL ethyl acetate was added. The mixture was washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and separated by thin-layer chromatography to give 120 mg of 5'-[4-(4-cyano-3-trifluoromethylphenoxy)-cyclohexylcarbamoyl]-2,3,5,6-tetrahydro-[1,2']bipyrazinyl-4-carboxylic acid tert-butyl ester, yield: 63.3%. LC / MS (ESI+) C 28 H 33 F3ClN6O4([M+H) + )m / e 574.9.

[0867] 2. Synthesis of N-((1r,4r)-4-(4-cyano-3-(trifluoromethyl)phenoxy)cyclohexyl)-5-(4-((1R,5S,6S)-3-(2-(2,6-dioxoperidin-3-yl)-6-fluoro-1,3-dioxoisoindoline-5-yl)-3-azabicyclo[3.1.0]n-hexane-6-yl)methyl)piperazin-1-yl)pyrazin-2-carboxamide

[0868] 120 mg (0.21 mmol) of 5'-[4-(4-cyano-3-trifluoromethylphenoxy)-cyclohexylcarbamoyl]-2,3,5,6-tetrahydro-[1,2']bipyrazinyl-4-carboxylic acid tert-butyl ester 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 alkaline with saturated Na2CO3 aqueous solution, 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 obtain 100 mg of white solid. The obtained product (49 mg, 0.103 mmol) was dissolved in 5 mL of dichloromethane, and 3-[2-(2,6-dioxypiperidin-3-yl)-6-fluoro-1,3-dioxy-2,3-dihydro-1H-isoindol-5-yl]-3-aza-bicyclo[3.1.0]hexane-6-carboxaldehyde (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 min. Then, sodium triacetylborohydride (212 mg, 1.0 mmol) was added, and the mixture was reacted overnight at room temperature. The mixture was washed with water and concentrated under reduced pressure. The product was condensed and separated by thin-layer chromatography to obtain a yellow solid product N-((1r,4r)-4-(4-cyano-3-(trifluoromethyl)phenoxy)cyclohexyl)-5-(4-((1R,5S,6S)-3-(2-(2,6-dioxopiridine-3-yl)-6-fluoro-1,3-dioxoisoindoline-5-yl)-3-azabicyclo[3.1.0]n-hexane-6-yl)methyl)piperazin-1-yl)pyrazin-2-carboxamide 45 mg, yield: 50%, LC / MS (ESI+) calcd for C 42 H 41 F4ClN9O6([M+H) + )m / e 844.3, 1H NMR (400MHz, CDCl3) δ8.86(s,1H),8.24(s,1H),7.97(s,1H),7.74(d,J=8.6Hz,1H),7.45–7.35(m,2H),7.25(d,J=2 .1Hz,1H),7.10(dd,J=8.7,2.2Hz,1H),7.04(d,J=7.3Hz,1H),4.92(dd,J=12.0,5.3Hz,1H),4.38(t,J=10.0Hz,1H), 4.05(dd,J=18.5,11.1Hz,1H),3.87(dd,J=23.6,6.9Hz,4H),3.60(d,J=9.5Hz,2H),2.95–2.66(m,6H),2.56(d,J=14 .1Hz,2H),2.28–2.09(m,5H),1.73–1.64(m,5H),1.56–1.45(m,3H),1.25(dd,J=8.4,5.6Hz,1H),1.10–0.99(m,1H).

[0869] 95: N-((1r,4r)-4-(4-cyano-3-(trifluoromethyl)phenoxy)cyclohexyl)-6-(4-((1R,5S,6S)-3-(2-(2,6-dioxopiridine-3-yl)-6-fluoro-1,3-dioxoisoindoline-5-yl)-3-azabicyclo[3.1.0]n-hexane-6-yl)methyl)piperazin-1-yl)pyridazin-3-carboxamide

[0870]

[0871] The synthesis steps are as described in 94.

[0872] LC / MS(ESI+)calcd for C 42 H 41 F4ClFN9O6([M+H) + )m / e 844.3, 1H NMR (400MHz, CDCl3) δ8.27(s,1H),8.05(d,J=9.4Hz,1H),7.88(d,J=8.2Hz,1H),7.75(d,J=8.6Hz,1H),7.40(d,J=12.4Hz,1H) ,7.26(d,J=2.5Hz,1H),7.11(dd,J=8.6,2.4Hz,1H),7.03(dd,J=11.8,8.6Hz,2H),4.92(dd,J=12.2,5.3Hz,1H),4.39(dd,J=1 1.9,8.3Hz,1H),4.07(dd,J=11.4,7.5Hz,1H),3.91(d,J=7.7Hz,4H),3.60(d,J=9.0Hz,2H),2.96–2.67(m,6H),2.67–2.44(m, 2H),2.28–2.09(m,5H),1.74(dd,J=18.1,8.7Hz,5H),1.55–1.40(m,3H),1.25(dd,J=8.5,5.5Hz,1H),1.06(d,J=11.1Hz,1H).

[0873] 96: N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-5-(6-((1-(2,6-dioxadipinidin-3-yl)-6-fluoro-1,3-dioxoisoindoline-5-yl)piperidin-4-yl)methyl)-2,6-diazaspirocyclic[3,4]octane-2-yl)pyrazine-2-carboxamide

[0874]

[0875] N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-5-(2,6-diazaspiro[3,4]octane-2-yl)pyrazin-2-carboxamide (50 mg, 0.11 mmol) was dissolved in 5 mL of dichloromethane, and 1-[2-(2,6-dioxopiridin-3-yl)-6-fluoro-1,3-dioxo-2,3-dihydro-1H-isoindol-5-yl]-piperidin-4-carboxaldehyde (45 mg, 0.12 mmol) was added. 0.5 drops of acetic acid were added, and the mixture was reacted at room temperature for 15 min. Triacetylboronic acid was then added. Sodium hydroxide (NaOH) was reacted overnight at room temperature, cooled to room temperature, washed with water, concentrated under reduced pressure to dryness, and separated by thin-layer chromatography to give a yellow solid product N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-5-(6-((1-(2,6-dioxadiazin-3-yl)-6-fluoro-1,3-dioxoisoindoline-5-yl)piperidin-4-yl)methyl)-2,6-diazaspirocyclo[3,4]octane-2-yl)pyrazine-2-carboxamide 35 mg, yield: 39.0%, LC / MS (ESI+) calcd for C 43 H 45 ClFN9O6([M+H)) + )m / e 837.7.

[0876] 97: N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-6-(7-(1-(2-(2,6-dioxadiazin-3-yl)-6-fluoro-1,3-dioxoisoindoline-5-yl)piperidin-4-yl)-2,7-diazaspiro[3.5]non-2-yl)pyridazine-3-carboxamide

[0877]

[0878] The synthesis steps are as described in 88.

[0879] Characterization data LC / MS(ESI+)calcd for C 43 H 45 ClFN9O6([M+H)) + )m / e 837.7, 1H NMR (400MHz, CDCl3) δ8.42–8.26(m,1H),7.99(d,J=9.2Hz,1H),7.88(d,J=8.1Hz,1H),7.56(d,J=8.7Hz,1H),7.48(d,J= 10.9Hz,1H),7.39(d,J=7.3Hz,1H),7.00(d,J=2.3Hz,1H),6.86(dd,J=8.8,2.4Hz,1H),6.60(d,J=9.3Hz,1H),5.00–4.9 0(m,1H),4.77–4.59(m,2H),4.38–4.26(m,1H),4.12–4.00(m,1H),3.93(s,4H),3.74(d,J=12.0Hz,2H),2.91(d,J=12.2 Hz,3H),2.82–2.69(m,4H),2.22–2.13(m,5H),2.04(s,5H),1.82(s,3H),1.69(d,J=12.2Hz,3H),1.47(d,J=12.1Hz,2H).

[0880] 98: N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-6-(6-((1-(2,6-dioxadipinidin-3-yl)-6-fluoro-1,3-dioxoisoindol-5-yl)piperidin-4-yl)methyl)-2,6-diazaspiro[3,4]octane-2-yl)pyridazine-3-carboxamide

[0881]

[0882] The synthesis steps are as described in 96.

[0883] Characterization data: LC / MS (ESI+)C 43 H 45 ClFN9O6([M+H)) + )m / e 838.

[0884] 99:N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-5-(4-((1R,5S,6S)-3-(2-(2,6-dioxopiridine-3-yl)-6-fluoro-1,3-dioxoisoindoline-5-yl)-3-azabicyclo[3.1.0]n-hexane-6-yl)methyl)piperazin-1-yl)pyrazine-2-carboxamide

[0885]

[0886] 1. 5'-[4-(3-chloro-4-cyano-phenoxy)-cyclohexylcarbamoyl]-2,3,5,6-tetrahydro-[1,2']bipyrazinyl-4-carboxylic acid tert-butyl ester

[0887] N-Boc piperazine (140 mg, 0.75 mmol) was dissolved in 5 mL of LDM, anhydrous potassium carbonate (207 mg, 1.5 mmol) was added, followed by 5-chloro-pyrazin-2-carboxylic acid [4-(4-cyano-3-chloro-phenoxy)-cyclohexyl]-amide (196 mg, 0.5 mmol). 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, concentrated under reduced pressure, and separated by thin-layer chromatography to obtain 130 mg of the product 5'-[4-(3-chloro-4-cyano-phenoxy)-cyclohexylcarbamoyl]-2,3,5,6-tetrahydro-[1,2']bipyrazinyl-4-carboxylic acid tert-butyl ester, yield: 46%. LC / MS (ESI+) showed a positive result for C. 27 H 33 ClN6O4([M+H) + )m / e 540.8.

[0888] 2. Synthesis of N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-5-(4-((1R,5S,6S)-3-(2-(2,6-dioxoperidin-3-yl)-6-fluoro-1,3-dioxoisoindoline-5-yl)-3-azabicyclo[3.1.0]n-hexane-6-yl)methyl)piperazin-1-yl)pyrazin-2-carboxamide

[0889] 5'-[4-(3-chloro-4-cyano-phenoxy)-cyclohexylcarbamoyl]-2,3,5,6-tetrahydro-[1,2']bipyrazinyl-4-carboxylic acid tert-butyl ester (130 mg, 0.23 mmol) was dissolved in 3 mL of dichloromethane, and 3 mL of trifluoroacetic acid was added. The mixture was stirred at room temperature for 2 h, concentrated to dryness under reduced pressure, and the pH was adjusted to alkaline with saturated Na2CO3 aqueous solution. The mixture was extracted twice with DCM, and the organic layers were combined. The mixture was washed once with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated to dryness under reduced pressure to obtain 100 mg of white solid. The obtained product (45 mg, 0.1 mmol) was dissolved in 5 mL of dichloromethane, and 3-[2-(2,6-dioxypiperidin-3-yl)-6-fluoro-1,3-dioxy-2,3-dihydro-1H-isoindol-5-yl]-3- Azabicyclo[3.1.0]hexane-6-carboxaldehyde (37 mg, 0.1 mmol) was reacted with 0.5 drops of acetic acid at room temperature for 15 min, followed by the addition of sodium cyanoborohydride (80 mg, 1.3 mmol) and the reaction proceeding overnight at room temperature. The mixture was cooled to room temperature, washed with water, concentrated under reduced pressure to dryness, and separated by thin-layer chromatography to yield a yellow solid product: N-((1r, 4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-5-(4-((1R, 5S, 6S)-3-(2-(2,6-dioxopiridine-3-yl)-6-fluoro-1,3-dioxoisoindol-5-yl)-3-azabicyclo[3.1.0]n-hexane-6-yl)methyl)piperazin-1-yl)pyrazin-2-carboxamide 20 mg, yield: 24.7%. LC / MS (ESI+) for C 41 H 41 ClFN9O6([M+H)) + )m / e 809.8, 1 H NMR (400MHz, CDCl3) δ8.86(d,J=1.0Hz,1H),8.26(s,1H),7.97(s,1H),7.56(d,J=8.7Hz,1H),7. 44–7.36(m,2H),7.04(d,J=7.4Hz,1H),6.99(d,J=2.3Hz,1H),6.85(dd,J=8.8,2.4Hz,1H),4.96 –4.86(m,1H),4.34–4.26(m,1H),4.08–3.97(m,1H),3.88(s,2H),3.82(s,3H),3.65–3.53(m,2H ),2.73(s,6H),2.58–2.42(m,2H),2.17(d,J=11.9Hz,4H),1.74–1.68(m,6H),1.56–1.38(m,3H).

[0890] 100:N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-6-(5-((1R,5S,6S)-3-(2-(2,6-dioxopiridine-3-yl)-1,3-dioxoisoindoline-5-yl)-3-azabicyclo[3.1.0]n-hexane-6-yl)methyl)hexahydropyrrole[3,4-c]pyrrole-2(1H)-yl)pyridazine-3-carboxamide

[0891]

[0892] LC / MS(ESI+)calcd for C 43 H 44 ClN9O6([M+H)) + )m / e 817.8, 1 H NMR (400MHz, CDCl3) δ8.34(s,1H),8.05(d,J=9.5Hz,1H),7.93(d,J=8.2Hz,1H),7.67(d,J=8.4Hz,1H),7.58(d,J=8.7Hz,1H),7.02(d,J=2 .3Hz,1H),6.94(d,J=1.8Hz,1H),6.87(dd,J=8.8,2.4Hz,1H),6.81(d,J=9.0Hz,1H),6.68(d,J=6.9Hz,1H),4.94(dd,J=12.2,5.4Hz,1H),4 .35(d,J=4.1Hz,1H),4.09(s,1H),3.78(s,2H),3.68(d,J=10.0Hz,2H),3.48(d,J=8.6Hz,2H),3.36–3.25(m,1H),2.95–2.65(m,6H),2.44 (d,J=5.0Hz,1H),2.30(d,J=5.4Hz,1H),2.23–2.10(m,5H),1.87(s,2H),1.71(d,J=12.7Hz,4H),1.55–1.43(m,3H),1.28(d,J=7.8Hz,2H).

[0893] 101:N-((1r,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-6-(4-((1R,5S,6S)-3-(2-(2,6-dioxopiridine-3-yl)-6-fluoro-1,3-dioxoisoindoline-5-yl)-3-azabicyclo[3.1.0]n-hexane-6-yl)methyl)piperazin-1-yl)pyridazin-3-carboxamide

[0894]

[0895] 1. Synthesis of 4-(6-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)carbamoyl)pyridazine-3-yl)piperazine-1-carboxylic acid tert-butyl ester

[0896] N-Boc piperidinone (60 mg, 0.38 mmol) was dissolved in 5 mL DMF, anhydrous potassium carbonate (100 mg, 0.75 mmol) was added, followed by 6-chloro-pyridazine-3-carboxylic acid [3-(3-chloro-4-cyano-phenoxy)-2,2,4,4-tetramethyl-cyclobutyl]-amide (105 mg, 0.25 mmol). The mixture was reacted at 80 °C for 3 h, and 15 mL ethyl acetate was added. The mixture was washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and separated by thin-layer chromatography to obtain 85 mg of the product 4-(6-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)carbamoyl)pyridazine-3-yl)piperazine-1-carboxylic acid tert-butyl ester. Yield: 59.7%. LC / MS (ESI+) calcd for C 29 H 37 ClN6O4([M+H) + )m / e 568.9.

[0897] 2. N-((1r,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-6-(4-((1R,5S,6S)-3-(2-(2,6-dioxopiridine-3-yl)-6-fluoro-1,3-dioxoisoindoline-5-yl)-3-azabicyclo[3.1.0]n-hexane-6-yl)methyl)piperazin-1-yl)pyridazin-3-carboxamide

[0898] 4-(6-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)carbamoyl)pyridazine-3-yl)piperazine-1-carboxylic acid tert-butyl ester (85 mg, 0.15 mmol) was dissolved in 3 mL of dichloromethane, and 3 mL of trifluoroacetic acid was added. The mixture was stirred at room temperature for 2 h, concentrated to dryness under reduced pressure, and the pH was adjusted to alkaline with saturated Na2CO3 aqueous solution. The mixture was extracted twice with DCM, and the organic layers were combined. The mixture was washed once with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated to dryness under reduced pressure to obtain 70 mg of white solid. The obtained product (35 mg, 0.07 mmol) was dissolved in 5 mL of dichloromethane, and 3-[2-(2,6-dioxypiperidin-3-yl)-6-fluoro-1,3-dioxy-2,3-dihydro-1H-isoindol-5-yl]-3-aza-bicyclo[ [3.1.0] Hexane-6-carboxaldehyde (30 mg, 0.077 mmol) was added with 0.5 drops of acetic acid and reacted at room temperature for 15 min. Triacetylborohydride sodium (224 mmol, 1.0 mmol) was added and reacted overnight at room temperature. 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 product: N-((1r,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-6-(4-((1R,5S,6S)-3-(2-(2,6-dioxopiridine-3-yl)-6-fluoro-1,3-dioxoisoindoline-5-yl)-3-azabicyclo[3.1.0]n-hexane-6-yl)methyl)piperazin-1-yl)pyridazin-3-carboxamide 20 mg, yield: 34%. LC / MS (ESI+) for C 43 H 45 ClFN9O6([M+H)) + )m / e 837.7, 1H NMR (400MHz, CDCl3) δ8.25–8.12(m,2H),8.06(d,J=9.5Hz,1H),7.59(d,J=8.7Hz,1H),7.42(d,J=12.5Hz,1 H),7.06(t,J=8.8Hz,2H),6.99(d,J=2.3Hz,1H),6.83(dd,J=8.7,2.4Hz,1H),4.97–4.88(m,1H),4.21(d,J= 9.0Hz,1H),4.09(s,1H),3.93(d,J=7.4Hz,2H),3.62(d,J=9.1Hz,2H),3.08–2.70(m,6H),2.70–2.52(m,2H) ,2.20–2.11(m,1H),1.76(s,6H),1.29(d,J=12.5Hz,6H),1.23(s,6H),1.07(s,1H),0.88(d,J=20.0Hz,1H).

[0899] 102:N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-6-(4-((1R,5S,6S)-3-(2-(2,6-dioxopiridine-3-yl)-1,3-dioxoisoindoline-5-yl)-3-azabicyclo[3.1.0]n-hexane-6-yl)methyl)piperazin-1-yl)pyridazin-3-carboxamide

[0900]

[0901] LC / MS(ESI+) for C 41 H 42 ClN9O6([M+H)) + )m / e 791.7, 1H NMR (400MHz, CDCl3) δ8.26(s,1H),8.07(d,J=9.1Hz,1H),7.90(d,J=8.1Hz,1H),7.67(d,J=8.4Hz,1H),7.58(d,J =8.7Hz,1H),7.06–7.00(m,2H),6.96(d,J=2.0Hz,1H),6.87(dd,J=8.7,2.4Hz,1H),6.70(dd,J=8.4,2.1Hz,1H), 4.96(dd,J=12.2,5.3Hz,1H),4.34(t,J=10.0Hz,1H),4.08(d,J=8.0Hz,1H),3.93(s,2H),3.71(d,J=9.9Hz,2H), 3.52(d,J=9.7Hz,2H),2.83(ddd,J=33.3,23.9,10.4Hz,5H),2.20(s,4H),1.73–1.59(m,11H),1.55–1.42(m,3H).

[0902] 103:N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-6-(4-(6-(2-(2,6-dioxadiazin-3-yl)-6-fluoro-1,3-dioxoisoindoline-5-yl)-2,6-diazaspirocyclic[3.4]octyl-2-yl)piperidin-1-yl)pyridazine-3-carboxamide

[0903]

[0904] 1. Synthesis of 6-(4-hydroxypiperidin-1-yl)-pyridazine-3-carboxylic acid [4-(3-chloro-4-cyano-phenoxy)-cyclohexyl]-amide

[0905] Piperidine-4-ol (100 mg, 1.0 mmol) was dissolved in 5 mL of DMF, anhydrous potassium carbonate (415 mg, 3.0 mmol) was added, followed by 5-chloro-pyridazine-2-carboxylic acid [4-(4-cyano-3-chloro-phenoxy)-cyclohexyl]-amide (390 mg, 1.0 mmol). The mixture was reacted at 80 °C for 3 h, and then 15 mL of ethyl acetate was added. The mixture was washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and separated by thin-layer chromatography to obtain 310 mg of the product 6-(4-hydroxypiperidine-1-yl)-pyridazine-3-carboxylic acid [4-(3-chloro-4-cyano-phenoxy)-cyclohexyl]-amide. Yield: 68.3%. LC / MS (ESI+) calcd for C 23 H 26 ClN5O3([M+H) + )m / e 455.9.

[0906] 2. 6-(4-Oxopiridin-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 h, filtered, and the filtrate was concentrated to dryness under reduced pressure. Thin-layer chromatography was used to separate the product, yielding 180 mg of 6-(4-oxopiridin-1-yl)-pyridazine-3-carboxylic acid [4-(3-chloro-4-cyano-phenoxy)-cyclohexyl]-amide, yield: 72%. LC / MS (ESI+) calcd for C 23 H 24 ClN5O3([M+H) + )m / e453.9.

[0907] 3,N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-6-(4-(6-(2-(2,6-dioxoperidin-3-yl)-6-fluoro-1,3-dioxoisoindoline-5-yl)-2,6-diazaspirocyclic[3.4]octyl-2-yl)piperidin-1-yl)pyridazine-3-carboxamide

[0908] 6-(4-oxopiperidin-1-yl)-pyridazine-3-carboxylic acid [4-(3-chloro-4-cyano-phenoxy)-cyclohexyl]-amide (46 mg, 0.1 mmol) and 5-(2,6-diazaspiro[3,4]oct-6-yl)-2-(2,6-dioxadiazin-3-yl)-6-fluoroisoindoline-1,3-dione were dissolved in 5 mL of dichloromethane. One drop of acetic acid was added, and the mixture was reacted at room temperature for 15 min. Then, sodium cyanoborohydride (80 mg, 1.3 mmol) was added, and 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 a yellow solid product N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-6-(4-(6-(2-(2,6-dioxoperidin-3-yl)-6-fluoro-1,3-dioxoisoindoline-5-yl)-2,6-diazaspirocyclo[3.4]octyl-2-yl)piperidin-1-yl)pyridazine-3-carboxamide 16 mg, yield: 19.5%, LC / MS (ESI+) for C 42 H 43 ClFN9O6([M+H)) + )m / e 823.8, 1H NMR(400MHz, CDCl3)δ8.14–8.06(m,1H),8.06–8.01(m,1H),7.91–7.85(m,1H),7.61–7.56(m,1H),7 .47–7.41(m,1H),7.03(s,3H),6.90–6.85(m,1H),4.94(dd,J=12.2,5.3Hz,1H),4.53(s,1H),4.34(s ,1H),4.07(s,1H),3.81(d,J=4.5Hz,2H),3.65(s,2H),3.20(s,2H),2.93–2.75(m,3H),2.19(d,J=11 .1Hz,5H),1.99(d,J=6.6Hz,2H),1.71(d,J=12.4Hz,2H),1.61(s,9H),1.52(dd,J=18.4,7.6Hz,3H).

[0909] 104:N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-5-(4-((1R,5S,6S)-3-(2-(2,6-dioxopiridine-3-yl)-1,3-dioxoisoindoline-5-yl)-3-azabicyclo[3.1.0]n-hexane-6-yl)methyl)piperazin-1-yl)pyrazine-2-carboxamide

[0910]

[0911] LC / MS(ESI+)m / e 791.8 for C 42 H 43 ClN9O6([M+H)) + ). 1H 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),6.74–6.66(m,1H),4.95(dd,J=12.1,5. 2Hz,1H),4.32(dd,J=12.9,6.8Hz,1H),4.06(d,J=10.0Hz,2H),3.88(s,3H),3.70(d,J=9.9Hz,2H),3.53(d,J=8 .5Hz,2H),2.98–2.69(m,6H),2.58(s,2H),2.29–2.09(m,5H),1.73(dd,J=19.2,9.9Hz,5H),1.55–1.45(m,3H).

[0912] 105:N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-5-(7-((1-(2-(2,6-dioxadiazin-3-yl)-1,3-dioxoisoindoline-5-yl)piperidin-4-yl)methyl)-2,7-diazaspiro[3.5]non-2-yl)-1,3,4-thiadiazole-2-carboxamide

[0913]

[0914] 1. Synthesis of ethyl 5-(7-(tert-butoxycarbonyl)-2,7-diazaspiro[3.5]non-2-yl)-1,3,4-thiadiazole-2-carboxylic acid ester

[0915] 2,7-diazaspiro[3.5]nonane-7-carboxylic acid tert-butyl ester (249 mg, 1.1 mmol) was dissolved in 6 mL DMF, anhydrous potassium carbonate (416 mg, 3.0 mmol) was added, followed by ethyl 5-chloro-1,3,4-thiadiazole-2-carboxylic acid (193 mg, 1.0 mmol). The mixture was reacted at 80 °C for 1.5 h, cooled to room temperature, and 20 mL ethyl acetate was added. The mixture was washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and 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, yield: 79.9%. LC / MS (ESI+) showed a positive result for C. 17 H 26 N₂O₂S([M+H)) + )m / e 369.1.

[0916] 2. Synthesis of 5-(2,7-diazaspiro[3.5]non-2-yl)-[1,3,4]thiadiazole-2-carboxylic acid [4-(3-chloro-4-cyano-phenoxy)-cyclohexyl]-amide

[0917] 4-(4-aminocyclohexyloxy)-2-chlorobenzonitrile (210 mg, 0.84 mmol) was dissolved in 5 mL of methanol, and 2-(5-ethoxycarbonyl-[1,3,4]thiadiazol-2-yl)-2,7-diazaspirocyclo[3,5]non-7-carboxylic acid tributyl ester (268 mg, 0.7 mmol) was added. The mixture was refluxed overnight at 85 °C, and separated by thin-layer chromatography to obtain 360 mg of a white solid product. This solid was dissolved in 5 mL of dichloromethane, and 3 mL of trifluoroacetic acid was added. The mixture was stirred at room temperature. 2.5 h, concentrated to dryness under reduced pressure, pH adjusted to alkaline with saturated Na2CO3 aqueous solution, extracted twice with DCM, combined organic layers, washed once with saturated brine, dried over anhydrous magnesium sulfate, filtered, concentrated to dryness under reduced pressure, yielding 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, yield: 85%, LC / MS (ESI+) called for C 23 H 27 ClN6O2S([M+H)) + )m / e 487.1.

[0918] 3. Synthesis of N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-5-(7-((1-(2-(2,6-dioxadiazin-3-yl)-1,3-dioxoisoindoline-5-yl)piperidin-4-yl)methyl)-2,7-diazaspiro[3.5]non-2-yl)-1,3,4-thiadiazole-2-carboxamide

[0919] 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) and 1-[2-(2,6-dioxypiperidin-3-yl)-1,3-dioxy-2,3-dihydro-1H-isoindol-5-yl]-piperidin-4-acetaldehyde (37 mg, 0.1 mmol) were added to a round-bottom flask, followed by 5 mL of dichloromethane and 1 drop of acetic acid to catalyze the reaction. The mixture was stirred at room temperature for 10 min under argon protection. Then, 212 mg of sodium triacetylborohydride (1...) was added. 0 mmol), reacted at room temperature for 3 h, washed twice with water, the organic layer was washed once with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by thin-layer chromatography to obtain a yellow solid product N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-5-(7-((1-(2-(2,6-dioxadiazin-3-yl)-1,3-dioxoisoindoline-5-yl)piperidin-4-yl)methyl)-2,7-diazaspiro[3.5]non-2-yl)-1,3,4-thiadiazole-2-carboxamide 45 mg, yield: 53.6%, LC / MS (ESI+) C 42 H 46 ClN9O6S([M+H)) + )m / e 840.3. 1 H NMR (400MHz, CDCl3) δ8.14(s,1H),7.67(d,J=8.5Hz,1H),7.56(d,J=8.7Hz,1H),7.27(s, 1H),7.08–6.95(m,3H),6.84(dd,J=8.8,2.4Hz,1H),4.94(dd,J=12.3,5.3Hz,1H),4.30(t ,J=10.0Hz,1H),3.96(dd,J=26.6,12.1Hz,6H),3.07–2.66(m,6H),2.35(s,2H),2.18(s, 6H),1.88(s,4H),1.65(d,J=17.7Hz,7H),1.53–1.44(m,2H),1.25(dd,J=8.5,5.5Hz,3H).

[0920] 106:N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-5-(7-(1-(2-(2,6-dioxopiridine-3-yl)-1,3-dioxoisoindoline-5-yl)piperidine-4-yl)-2,7-diazaspiro[3.5]nonyl-2-yl)pyrimidine-2-carboxamide

[0921]

[0922] 1. Synthesis of 2-{2-[4-(3-chloro-4-cyano-phenoxy)-cyclohexylcarbamoyl]pyrimidin-5-yl}-2,7-diaza-spirocyclic[3,5]nonane-7-carboxylic acid tert-butyl ester

[0923] 5-Bromopyrimidine-2-carboxylic acid [4-(3-chloro-4-cyano-phenoxy)-cyclohexyl]-amide (109 mg, 0.25 mmol) was dissolved in 5 mL 1,4-Dioxane was added to 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, 12.5 μmol). The mixture was refluxed overnight at 110 °C under argon protection. 15 mL of ethyl acetate was added, followed by washing three times with 10 mL of water and once with saturated brine. The mixture was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by wave chromatography to obtain 100 mg of the product 2-{2-[4-(3-chloro-4-cyano-phenoxy)-cyclohexylcarbamoyl]pyrimidin-5-yl}-2,7-diazaspiro[3.5]nonane-7-carboxylic acid tert-butyl ester, yield: 68.9%. LC / MS (ESI+) was performed for C... 30 H 37 ClN6O4([M+H) + )m / e 580.9.

[0924] 2. Synthesis of tert-butyl 4-(2-{2-[4-(3-chloro-4-cyano-phenoxy)-cyclohexylcarbamoyl]pyrimidin-5-yl}-2,7-diaza-spirocyclic[3.5]non-7-yl)piperidine-1-carboxylic acid

[0925] 100 mg (0.17 mmol) 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 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 under pressure to dryness, the pH was adjusted to alkaline with saturated Na2CO3 aqueous solution, 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 obtain 80 mg of white solid. The obtained product (78 mg, 0.16 mmol) was dissolved in 5 mL of dichloromethane, 4-Boc piperidinone (199 mg, 0.98 mmol) was added, 0.5 drops of acetic acid were added, and the mixture was refluxed at 40 °C for 1 h. After cooling to room temperature, sodium triacetylborohydride (424 mg, 2.0 mmol) was added, and the mixture was refluxed at 40 °C for 5 h. After cooling to room temperature, the mixture was washed with water, concentrated under reduced pressure to dryness, and separated by thin-layer chromatography to obtain 50 mg of 4-(2-{2-[4-(3-chloro-4-cyano-phenoxy)-cyclohexylcarbamoyl]pyrimidin-5-yl}-2,7-diaza-spirocyclic[3.5]non-7-yl)-piperidin-1-carboxylic acid tert-butyl ester, yield: 47.0%, LC / MS (ESI+) called for C 35 H 46 ClN7O4([M+H) + )m / e 664.3.

[0926] 3. Synthesis of N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-5-(7-(1-(2-(2,6-dioxadiazin-3-yl)-1,3-dioxadiazin-4-yl)-2,7-diazospiro[3.5]non-2-yl)pyrimidine-2-carboxamide

[0927] 4-(2-{2-[4-(3-chloro-4-cyano-phenoxy)-cyclohexylcarbamoyl]pyrimidin-5-yl}-2,7-diaza-spirocyclo[3,5]non-7-yl)piperidin-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, concentrated to dryness under reduced pressure, and then concentrated twice more under reduced pressure with the addition of dichloromethane. 3 mL of DMSO was added, followed by the addition of DIEA. 0.5 mL of 2-(2,6-dioxadiazin-3-yl)-5-fluoroisoindole-1,3-dione (30 mg, 0.11 mmol) was added, refluxed at 135 °C for 1.5 h, cooled to room temperature, 10 mL of dichloromethane was added, washed twice with 10 mL of water, and then washed once with saturated brine. The mixture was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by thin-layer chromatography to obtain a yellow solid product, N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-5-(7-(1-(2-(2,6-dioxadiazin-3-yl)-1,3-dioxadiazindole-5-yl)piperidin-4-yl)-2,7-diazaspiro[3.5]non-2-yl)pyrimidine-2-carboxamide 26 mg, yield: 42.3%, LC / MS (ESI+) m / e 820.3 for C 43 H 46 ClN9O6([M+H)) + ). 1 H NMR (400MHz, CDCl3) δ8.16(s,1H),7.95(s,2H),7.69(d,J=8.5Hz,2H),7.56(d,J=8.7Hz,1H),7.28(d,J=2 .1Hz,1H),7.06(dd,J=8.6,2.1Hz,1H),6.99(d,J=2.3Hz,1H),6.85(dd,J=8.8,2.4Hz,1H),4.99–4.90(m, 1H),4.34–4.25(m,1H),4.15–4.07(m,1H),4.02(d,J=13.3Hz,2H),3.80(s,4H),3.00(t,J=12.0Hz,2H),2 .95–2.71(m,4H),2.25–2.13(m,7H),2.01(s,4H),1.69(d,J=12.3Hz,8H),1.46(dd,J=24.4,11.7Hz,2H).

[0928] 107:N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-5-(7-((1-(2-(2,6-dioxadiazin-3-yl)-6-fluoro-1,3-dioxoisoindoline-5-yl)piperidin-4-yl)methyl)-2,7-diazaspiro[3.5]nonane-2-yl)-1,3,4-thiadiazole-2-carboxamide

[0929]

[0930] The synthesis steps are as described in 105.

[0931] Characterization data: LC / MS (ESI+) m / e 858.3 for C 42 H 45 ClFN9O6S([M+H) + ), 1 H NMR (400MHz, CDCl3) δ8.14–8.08(m,1H),7.56(d,J=8.7Hz,1H),7.46(d,J=11.0Hz,1H),7.39(d,J=7.3Hz,1H),7. 03(d,J=8.2Hz,1H),6.99(d,J=2.3Hz,1H),6.84(dd,J=8.8,2.4Hz,1H),4.97–4.90(m,1H),4.36–4.26(m,1H),4.0 5–3.95(m,1H),3.90(s,4H),3.73(q,J=7.0Hz,3H),3.65(d,J=12.1Hz,2H),2.95–2.70(m,5H),2.40–2.34(m,2H), 2.22(d,J=7.6Hz,2H),1.92–1.86(m,6H),1.69–1.61(m,4H),1.50(dd,J=18.4,7.7Hz,2H),1.25(t,J=7.0Hz,5H).

[0932] 108: N-(1-(3-chloro-4-cyanophenyl)piperidin-4-yl)-6-(4-((4-(2-(2,6-dioxopiridin-3-yl)-1,3-dioxoisoindoline-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)pyridazin-3-carboxamide

[0933]

[0934] 1) 2-Chloro-4-carboxybenzonitrile

[0935] 4-Bromo-2-chlorobenzonitrile (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 isopropyl magnesium bromide / THF solution was added dropwise. After the addition was complete, the mixture was stirred for 1 h. Piperidine-1-acetaldehyde (7.75 g, 68.5 mmol) was added, and the reaction was maintained for 2 h. The reaction was quenched with 15 mL of saturated ammonium chloride aqueous solution. The mixture was extracted with 20 mL of ethyl acetate, and 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 to dryness under reduced pressure. The product, 2-chloro-4-carboxybenzonitrile, was purified by column chromatography to obtain 2.22 g of 2-chloro-4-carboxybenzonitrile (yield: 58%). 2)(1-(3-chloro-4-cyanophenyl)piperidin-4-yl)tert-butyl carbamate

[0936] 2-Chloro-4-carboxybenzonitrile (820 mg, 5.0 mmol) and piperin-4-ylcarbamate tert-butyl ester (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. After cooling to room temperature, sodium cyanoborohydride (942 mg, 15 mmol) was added, and the reaction was continued overnight. 20 mL of acetone was added, and the mixture was stirred for 20 min. The mixture was concentrated to dryness under reduced pressure, and 20 mL of ethyl acetate was added. The mixture was washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure. The product (1-(3-chloro-4-cyanobenzene)piperidin-4-yl)carbamate tert-butyl ester) was purified by column chromatography to obtain 680 mg of the product, yield: 38.9%. LC / MS (ESI+) was positive for C 18 H 24 ClN3O2([M+H) + )m / e 350.2.

[0937] 3) 6-Chloro-N-(1-(3-chloro-4-cyanophenyl)piperidin-4-yl)pyridazine-3-carboxamide

[0938] 370 mg (0.95 mmol) of tert-butyl (1-(3-chloro-4-cyanophenyl)piperidin-4-yl)carbamate 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 to dryness under reduced pressure, the pH was adjusted to alkaline with saturated Na2CO3 aqueous solution, extracted with ethyl acetate, the organic layer was dried over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure to obtain 230 mg of product. 6-Chloropyridine-3-carboxylic acid (145 mg, 0.91 mmol) was dissolved in 5 mL of dichloromethane, and N,N-diisopropylethylamine (235 mg, 1.82 mmol) was added. HATU (533 mg, 1.38 mmol) was added under ice-water bath conditions. The compound from the previous step was dissolved in 5 mL of dichloromethane and added dropwise to the reaction system. After the addition was complete, the temperature was slowly raised to room temperature, and the reaction was allowed to proceed for 2 h. The mixture was washed with saturated ammonium chloride aqueous solution and saturated brine, dried over anhydrous magnesium sulfate, filtered, concentrated under reduced pressure, and purified by thin-layer chromatography to obtain 200 mg of the product 6-chloro-N-(1-(3-chloro-4-cyanophenyl)piperidin-4-yl)pyridazine-3-carboxamide, yield: 53.7%. LC / MS (ESI+) was called for C 18 H 17 Cl2N5O([M+H)) + )m / e 390.

[0939] 4) 4-((1-(6-((1-(3-chloro-4-cyanophenyl)piperidin-4-yl)carbamoyl)pyridazine-3-yl)piperidin-4-yl)methyl)piperazine-1-carboxylic acid tert-butyl ester

[0940] 4-(piperidin-4-ylmethyl)piperazine-1-carboxylic acid tert-butyl ester (71 mg, 0.25 mmol) was dissolved in 5 mL of DMF, anhydrous potassium carbonate (102 mg, 0.75 mmol) was added, followed by 6-chloro-N-(1-(3-chloro-4-cyanophenyl)piperidin-4-yl)pyridazine-3-carboxamide (100 mg, 0.25 mmol). The mixture was reacted at 80 °C for 3 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, concentrated under reduced pressure, and separated by thin-layer chromatography to obtain 140 mg of the product 4-((1-(6-((1-(3-chloro-4-cyanophenyl)piperidin-4-yl)carbamoyl)pyridazine-3-yl)piperidin-4-yl)methyl)piperazine-1-carboxylic acid tert-butyl ester, yield: 87.9%. LC / MS (ESI+) was called for C 33 H 45 ClN8O3([M+H) + )m / e 637.3.

[0941] 5)N-(1-(3-chloro-4-cyanophenyl)piperidin-4-yl)-6-(4-((4-(2-(2,6-dioxopiridin-3-yl)-1,3-dioxoisoindoline-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)pyridazin-3-carboxamide

[0942] 4-((1-(6-((1-(3-chloro-4-cyanophenyl)piperidin-4-yl)carbamoyl)pyridazine-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 h, concentrated to dryness under reduced pressure, 5 mL of DMSO was added, and 0.8 mL of... DIEA was added to 2-(2,6-dioxadiazin-3-yl)-5-fluoroisoindoline-1,3-dione (60 mg, 0.22 mmol), and the mixture was reacted at 140 °C for 3 h. After cooling to room temperature, 15 mL of dichloromethane was added, and the mixture was washed twice with saturated ammonium chloride and once with saturated brine. The mixture was dried over anhydrous magnesium sulfate, filtered, concentrated under reduced pressure, and purified by thin-layer chromatography to obtain 42 mg of the product N-(1-(3-chloro-4-cyanophenyl)piperidin-4-yl)-6-(4-((4-(2-(2,6-dioxadiazin-3-yl)-1,3-dioxadiazindoline-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)pyridazin-3-carboxamide, yield: 44.1%. LC / MS (ESI+) for C 41 H 45 ClN 10 O5([M+H] + )m / e 793.3, 1H NMR (400MHz, CDCl3) δ8.12(s,1H),7.97(d,J=9.5Hz,1H),7.90(d,J=8.0Hz,1H),7.70(d,J=8.5Hz,1H),7.63(d,J=7.9Hz,1H ),7.54(s,1H),7.37(d,J=8.5Hz,1H),7.29(d,J=2.0Hz,1H),7.06(dd,J=8.6,2.0Hz,1H),6.98(d,J=9.6Hz,1H),4.95(dd,J =12.2,5.2Hz,1H),4.52(d,J=13.0Hz,2H),4.08–3.95(m,1H),3.55(s,2H),3.44(s,4H),3.05(t,J=12.0Hz,2H),2.95–2.72 (m,5H),2.60(s,3H),2.28(d,J=11.0Hz,4H),2.14(dd,J=7.6,5.3Hz,1H),1.99(dd,J=24.5,13.5Hz,5H),1.36–1.16(m,5H).

[0943] 109: N-(6-(3-chloro-4-cyanophenoxy)spirocyclic[3.3]heptane-2-yl)-6-(4-((4-(2,6-dioxopiridine-3-yl)-1,3-dioxoisoindoline-5-yl)piperazin-1-yl)piperazin-1-yl)pyridazin-3-carboxamide

[0944]

[0945] LC / MS(ESI+) for C 42 H 44 ClN9O6([M+H)) + )m / e 806.2, 1H NMR (400MHz, CDCl3) δ8.09(s,1H),8.05(d,J=8.1Hz,1H),7.95(d,J=9.6Hz,1H),7.71(d,J=8.5Hz,1H),7.55(d,J=8.7Hz,1H),7.30(d,J=2.1 Hz,1H),7.07(dd,J=8.6,2.1Hz,1H),6.97(d,J=9.7Hz,1H),6.88(d,J=2.3Hz,1H),6.75(dd,J=8.7,2.4Hz,1H),4.95(dd,J=12.3,5.3Hz,1H), 4.66–4.59(m,1H),4.56–4.51(m,2H),3.49(s,3H),3.06(t,J=12.1Hz, 2H),2.98–2.74(m,4H),2.75–2.67(m,2H),2.65–2.57(m,2H),2.56–2. 49(m,2H),2.26(ddd,J=24.1,11.9,6.9Hz,4H),2.18–2.08(m,3H),1.99(d,J=12.8Hz,3H),1.50–1.40(m,1H),1.29(dd,J=20.4,11.2Hz,4H).

[0946] 110: N-((1r,4S)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-6-(4-((3S)-1-(2-(2,6-dioxopiridine-3-yl)-6-fluoro-1,3-dioxoisoindoline-5-yl)pyrrolidine-3-yl)oxy)piperidine-1-yl)pyridazine-3-carboxamide

[0947]

[0948] LC / MS(ESI+)calcd for C 40 H 40 ClFN8O7([M+H) + )m / e 799.2, 1H NMR (400MHz, CDCl3) δ8.06(d,J=6.8Hz,2H),7.92(d,J=7.8Hz,1H),7.56(d,J=8.7Hz,1H),7.41(d,J=12.3Hz,1H ),7.13(d,J=9.7Hz,1H),7.04(d,J=7.5Hz,1H),7.00(d,J=2.3Hz,1H),6.86(dd,J=8.7,2.3Hz,1H),4.92(dd,J= 12.2,5.3Hz,1H),4.33(dd,J=21.3,12.3Hz,2H),4.05(d,J=3.7Hz,2H),3.84–3.58(m,6H),2.96–2.69(m,3H),2 .15(t,J=13.5Hz,6H),1.98(s,2H),1.78(s,2H),1.67(dd,J=21.9,10.8Hz,4H),1.48(dd,J=22.3,11.5Hz,3H).

[0949] 111: N-((1r,4R)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-4-(4-((3R)-1-(2-(2,6-dioxoperidin-3-yl)-1,3-dioxoisoindoline-5-yl)pyrrolidine-3-yl)oxy)piperidin-1-yl)benzamide

[0950]

[0951] 1)(S)-3-((1-(4-(methoxycarbonyl)phenyl)piperidin-4-yl)oxy)pyrrolidine-1-carboxylic acid tert-butyl ester: 260 mg (0.96 mmol) of (S)-3-(piperidin-4-yl)pyrrolidine-1-carboxylic acid tert-butyl ester was dissolved in 5 mL DMSO, potassium carbonate (420 mg, 3.0 mmol) was added, and methyl p-fluorobenzoate (308 mg, 2.0 mmol) was added. The mixture was reacted at 100 °C for 3 h, cooled to room temperature, and 15 mL of ethyl acetate was added. The mixture was washed with water and brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by thin-layer chromatography to obtain 130 mg of (S)-3-((1-(4-(methoxycarbonyl)phenyl)piperidin-4-yl)oxy)pyrrolidine-1-carboxylic acid tert-butyl ester, yield: 33.5%. LC / MS (ESI+) called for C 22 H 32 N₂O₅([M+H)) + )m / e 405.3.

[0952] 2)(R)-3-((1-(4-((1r,4R)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)carbamoyl)phenyl)piperidin-4-yl)oxy)pyrrolidine-1-carboxylic acid tert-butyl ester

[0953] (S)-3-((1-(4-(methoxycarbonyl)phenyl)piperidin-4-yl)oxy)pyrrolidine-1-carboxylic acid tert-butyl ester (130 mg, 0.32 mmol) was dissolved in 5 mL of tetrahydrofuran, and 5 mL of 2N NaOH aqueous solution was added. The mixture was stirred overnight at room temperature, and 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 under reduced pressure to obtain the product. Dissolve it in 5 mL of dichloromethane, add DIEA (101 mg, 1.0 mmol), add HATU (141 mg, 0.37 mmol), stir at room temperature for 10 min, add 4-(((1r,4r)-4-aminocyclohexyl)oxy)-2-chlorobenzonitrile (80 mg, 0.32 mmol), react at room temperature overnight, wash with saturated ammonium chloride aqueous solution, water, a...

Claims

1. The compound represented by formula (I), or its isotopes, tautomers, or pharmaceutically acceptable salts thereof: （I） in, ARB is the androgen receptor recognition / binding part, L is the linking part, and U is the ubiquitin protease recognition / binding part; these three parts are linked by chemical bonds. The ARB is selected from the following structure: The L is selected from the following structure: ; The U is selected from the structure of the following formula (XB-1): XB-1 Among them, R g3 Selected from H, halogen.

2. The compound, or its isotope, its tautomer, or its pharmaceutically acceptable salt according to claim 1, characterized in that: The halogen is chlorine or bromine.

3. The compound, or its isotope, its tautomer, or its pharmaceutically acceptable salt according to claim 1, characterized in that: The U is selected from the following structures: 。 4. Use of the compound of any one of claims 1-3, or its isotopic compound, its tautomer, or its pharmaceutically acceptable salt in the preparation of a protein degradation-targeting chimera of the androgen receptor.

5. The use according to claim 4, characterized in that: The protein degradation targeting chimera can target and / or bind to androgen receptors.

6. The use according to claim 4, characterized in that: The protein degradation-targeting chimera can degrade and / or downregulate androgen receptors.

7. The use according to any one of claims 4-6, characterized in that: The protein degradation-targeting chimera is the active ingredient in drugs for treating diseases regulated by androgen receptors.

8. The use according to claim 7, characterized in that: The diseases mentioned are selected from prostate cancer, breast cancer, and Kennedy's disease.

9. A drug for treating diseases regulated by androgen receptors, characterized in that: The drug is a formulation made from the compound of any one of claims 1-3, or its isotope, tautomer, or pharmaceutically acceptable salt thereof as the active ingredient, plus pharmaceutically acceptable excipients.

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