Compound having AKT kinase-degrading activity, preparation method therefor, and pharmaceutical use thereof

Abstract

The present invention belongs to the field of pharmaceutical chemistry. Disclosed are a compound having AKT kinase-degrading activity, a preparation method therefor, and pharmaceutical use thereof. The compound has a B-L-D structure as shown in formula (I).

Description

A compound with AKT kinase degradation activity and its preparation method and pharmaceutical application Technical Field

[0001] The present invention relates to bivalent compounds (e.g., bifunctional small molecule compounds) that degrade and / or destroy the serine threonine kinase AKT (also known as protein kinase B or PKB), compositions comprising one or more of the bivalent compounds, and methods of use thereof for treating AKT-mediated diseases in subjects in need thereof. Background Art

[0002] The PI3K / AKT / mTOR pathway, composed of phosphatidylinositol 3-kinase (PI3K), its downstream protein AKT (also known as protein kinase B, PKB), and mammalian target of rapamycin (mTOR), is a crucial intracellular signal transduction pathway that plays a crucial role in cell growth, survival, proliferation, apoptosis, angiogenesis, autophagy, and other processes. Abnormal activation of this pathway can cause a range of diseases, including cancer, neuropathies, autoimmune diseases, and hematolymphatic system disorders.

[0003] AKT is a serine / threonine kinase that influences cell survival, growth, metabolism, proliferation, migration, and differentiation through numerous downstream effectors. Over 50% of human tumors exhibit AKT overactivation, particularly in prostate, pancreatic, bladder, ovarian, and breast cancers. AKT overactivation can lead to tumorigenesis, metastasis, and drug resistance.

[0004] AKT has three isoforms: AKT1, AKT2, and AKT3. As typical protein kinases, each isoform consists of an amino-terminal PH domain (Pleckstrin homology domain), a central ATP-binding kinase domain, and a carboxyl-terminal regulatory domain. The three isoforms share approximately 80% amino acid sequence homology, with significant variations only in the linker region between the PH domain and the kinase domain.

[0005] At present, the targeted drugs for the PI3K / AKT / mTOR signaling pathway are mainly PI3K inhibitors and mTOR inhibitors, and AKT is at the core of this signal transduction pathway. Inhibiting AKT activity can avoid the serious side effects caused by inhibiting upstream PI3K, and can also avoid the negative feedback mechanism caused by inhibiting downstream mTOR that affects the efficacy of the drug. Therefore, finding effective and selective AKT inhibitors is an important direction for the current research and development of tumor targeted drugs. CN101631778A discloses a class of cyclopentadien[D]pyrimidine derivatives, CN101578273A discloses a class of hydroxylated and methoxylated cyclopentadien[D]pyrimidine derivatives, CN101511842A discloses a class of dihydrofuranpyrimidine derivatives, and CN101970415A discloses a class of 5H-cyclopentadien[d]pyrimidine derivatives. These compounds have an IC2 of less than 10 μM for inhibiting AKT1. 50 .

[0006] Unlike conventional enzyme inhibitors that only inhibit the catalytic activity of the target enzyme, the AKT degradation / destruction compounds disclosed herein ("AKT degraders") bind to and induce the degradation of AKT, thereby eliminating any scaffolding function of AKT in addition to its enzymatic activity. The AKT degraders disclosed herein are bivalent compounds that include an AKT ligand conjugated to a degradation / destruction tag via a linker.

[0007] The AKT degraders disclosed herein provide a novel mechanism for treating AKT-mediated diseases. Specifically, as opposed to merely inhibiting AKT catalytic activity, the ability of AKT degraders to target AKT for degradation is expected to overcome resistance, regardless of whether a specific drug has been used in prior treatment and regardless of whether resistance is caused by gene mutation, amplification, or otherwise. Summary of the Invention

[0008] The present invention generally relates to bivalent compounds (e.g., bifunctional compounds) that degrade and / or destroy AKT, and methods for treating AKT-mediated cancers (i.e., cancers that depend on AKT proteins; or cancers that have elevated AKT levels or AKT activity relative to wild-type tissues of the same species and tissue type). Because AKT degraders / destructors have dual functions (enzyme inhibition plus protein degradation / destruction), the bivalent compounds disclosed herein can be significantly more effective therapeutic agents than existing AKT inhibitors that inhibit the enzymatic activity of AKT but do not affect AKT protein levels. The present invention further provides methods for identifying AKT degraders / destructors as described herein.

[0009] More specifically, the present invention provides a bivalent compound comprising an AKT ligand conjugated to a degradation / destruction tag via a linker, having the structure described in Formula I:

[0010] B-L-D(I)

[0011] L is selected from —Ak1—C1—Ak2—C2—Ak3— or —Ak4—Cy1—Ak5—Cy2—Ak6—;

[0012] wherein Ak1, Ak2, and Ak3 are independently selected from or key;

[0013] C1 and C2 are independently selected from C 1-12 Alkyl, C 2-12 Alkenyl or C 2-12 Alkynyl or bond, and C1 and C2 are not bonds at the same time, the C 1-12 Alkyl, C 2-12 Alkenyl or C 2-12 The alkynyl group is optionally replaced by one or more C 1-4 alkyl or halogen substituted;

[0014] wherein Ak4, Ak5, and Ak6 are independently selected from optionally substituted by one or more oxygen, C 1-4 Alkyl or halogen substituted C 1-12 an alkyl group or a bond;

[0015] Cy1 and Cy2 are independently selected from 3-12 membered heterocyclic rings, 3-12 membered cycloalkyl groups, 6-10 membered aryl groups or bonds, and Cy1 and Cy2 are not bonds at the same time, and the 3-12 membered heterocyclic rings, 3-12 membered cycloalkyl groups, 6-10 membered aryl groups are optionally substituted by one or more halogens or C 1-4 Alkyl substitution;

[0016] B is

[0017] wherein X is selected from C or N;

[0018] R 1 is halogen or hydrogen;

[0019] R 2 Selected from H, CN, C 1-6 Alkyl or C 1-6 Alkoxy, wherein the C 1-6 Alkyl or C 1-6 Alkoxy is optionally substituted by halogen, OH, CN;

[0020] G is optional and C 1-4 a 5-12 membered saturated heterocyclic ring containing 1-2 nitrogen atoms substituted by an alkyl group;

[0021] R 3 For NH, or does not exist;

[0022] D is selected from the following structures:

[0023] When B is When , L is not —Ak1—C1—Ak2—C2—Ak3—.

[0024] In some specific embodiments,

[0025] L is selected from C 1-12 Alkyl, C 2-12 Alkenyl or C 2-12 Alkynyl, wherein the C 1-12 Alkyl, C 2-12 Alkenyl or C 2-12 The alkynyl group is optionally replaced by one or more C 1-4 Alkyl or halogen substituted,

[0026] or—Ak4—Cy1—Ak5—Cy2—Ak6;

[0027] wherein Ak4, Ak5, and Ak6 are independently selected from C optionally substituted by one or more oxygens. 1-12 an alkyl group or a bond;

[0028] Cy1 and Cy2 are independently selected from the group consisting of one or more halogens, C 1-4 It is a 3-12 membered heterocycle substituted by an alkyl group or a bond, and Cy1 and Cy2 are not bonds at the same time.

[0029] In some more specific embodiments,

[0030] L is optionally selected from one or more C 1-4 Alkyl or halogen substituted C 1-12 Alkyl or C 2-12 Alkynyl,

[0031] or—Ak4—Cy1—Ak5—Cy2—Ak6;

[0032] wherein Ak4, Ak5, and Ak6 are independently selected from C 1-10 further Ak4, Ak5, Ak6 are independently selected from C 1-10 an alkyl group or a bond;

[0033] Cy1 and Cy2 are independently selected from a 4-9 membered heterocycle or a bond, and Cy1 and Cy2 are not bonds at the same time.

[0034] Furthermore, Cy1 and Cy2 are independently selected from a 4-9 membered heterocycle containing 1-2 N atoms or a bond, and Cy1 and Cy2 are not bonds at the same time.

[0035] Further, Cy1 and Cy2 are independently selected from azetidinyl, azetyl, piperidine, piperazine, cyclopropyl azetidinyl, cyclopropyl azetyl, cyclopropyl azetyl, cyclopropyl azetyl, cyclopropyl piperidine, cyclobutyl azetidinyl, cyclobutyl azetyl, cyclobutyl azetyl, cyclobutyl azetyl, cyclobutyl azetyl, cyclobutyl piperidine, cyclopentyl azetidinyl, cyclopentyl azetyl, cyclopentyl azetyl, cyclopentyl piperidine, cyclohexyl azetidinyl, cyclohexyl azetyl, azetidinyl azetyl, azetidinyl azetyl, azetidinyl azetyl, azetidinyl azetyl, azetidinyl piperidine , azetidinyl and azetidinyl, azetidinyl and azetidinyl, azetidinyl and azetidinyl, azetidinyl and piperidine, cyclobutyl spiroazetidinyl, cyclobutyl spiroazetidinyl, cyclobutyl spiroazetidinyl, cyclobutyl spiroazetidinyl, cyclopentyl spiroazetidinyl, cyclopentyl spiroazetidinyl, cyclohexyl spiroazetidinyl, azetidinyl spiroazetidinyl, azetidinyl spiroazetidinyl, azetidinyl spiroazetidinyl, azetidinyl spiroazetidinyl, azetidinyl spiroazetidinyl, azetidinyl spiroazetidinyl, azetidinyl spiroazetidinyl, azetidinyl spiroazetidinyl, azetidinyl spiroazetidinyl, azetidinyl spiroazetidinyl, azetidinyl spiroazetidinyl, azetidinyl spiroazetidinyl, cyclobutyl spiropiperidine, azetidinyl spiropiperidine or a bond, Cy1 and Cy2 are not bonds at the same time.

[0036] Furthermore, Cy1 and Cy2 are independently selected from piperidine, piperazine or cyclobutyl spiroazaheterocyclohexyl or a bond, and Cy1 and Cy2 are not bonds at the same time.

[0037] Furthermore, in some more typical embodiments,

[0038] L is selected from C optionally substituted by one or more methyl groups 1-12 Alkyl or C 2-12 Alkynyl, further preferably optionally substituted by one or more methyl groups C 8-12 Alkyl or C 8-12 Alkynyl, further, preferably C 8-12 Alkyl or C 8-12 of alkynyl.

[0039] Furthermore, in some more typical embodiments,

[0040] L is selected from the following structures: The left side of L is connected to B, and the right side is connected to D.

[0041] Furthermore, L is selected from the following structures: The left side of L is connected to B, and the right side is connected to D.

[0042] Furthermore, L is

[0043] In some specific embodiments,

[0044] B is

[0045] wherein X is selected from C or N;

[0046] R 1 is chlorine or hydrogen; R 2 is a C1-C6 alkyl group, wherein the C1-C6 alkyl group is optionally substituted with OH;

[0047] G is a 5-12 membered saturated heterocyclic ring containing 1-2 nitrogen atoms, which is optionally substituted by methyl;

[0048] R 3 For NH, Or does not exist.

[0049] Furthermore, R 2 It is methyl, ethyl or -(CH2)2OH.

[0050] Furthermore, R 2 It is methyl or ethyl.

[0051] Further R 1 For chlorine.

[0052] Furthermore, G is the following group optionally substituted by methyl:

[0053] The single wavy line is where G is attached to the carbonyl group, and the double wavy line is where G is attached to the pyrimidine.

[0054] Furthermore, G is selected from the following groups:

[0055] Furthermore, G is selected from the following groups:

[0056] Further, in some more typical embodiments, B is selected from the following structures:

[0057] Further, in some more typical embodiments, B is selected from the following structures:

[0058] Further, in some more typical embodiments, B is selected from the following structures:

[0059] Further, in some more typical embodiments, B is selected from the following structures:

[0060] In some embodiments, D is selected from the following structures:

[0061] Further, in some specific embodiments, D is selected from the following structures:

[0062] Further, in some specific embodiments, D is the following structure

[0063] In some more typical embodiments, the present invention provides a compound having the structure shown in the following II or a pharmaceutically acceptable salt thereof:

[0064] L1 is selected from —Ak1—C1—Ak2—C2—Ak3— or —Ak4—Cy1—Ak5—Cy2—Ak6—;

[0065] wherein Ak1, Ak2, and Ak3 are independently selected from or key;

[0066] C1 and C2 are independently selected from C 1-12 Alkyl, C 2-12 Alkenyl or C 2-12 Alkynyl or bond, and C1 and C2 are not bonds at the same time, the C 1-12 Alkyl, C 2-12 Alkenyl or C 2-12 The alkynyl group is optionally replaced by one or more C 1-4 alkyl or halogen substituted;

[0067] wherein Ak4, Ak5, and Ak6 are independently selected from optionally substituted by one or more oxygen, C 1-4 Alkyl or halogen substituted C 1-12 an alkyl group or a bond;

[0068] Cy1 and Cy2 are independently selected from 3-12 membered heterocyclic rings, 3-12 membered cycloalkyl groups, 6-10 membered aryl groups or bonds, and Cy1 and Cy2 are not bonds at the same time, and the 3-12 membered heterocyclic rings, 3-12 membered cycloalkyl groups, 6-10 membered aryl groups are optionally substituted by one or more halogens or C 1-4 Alkyl substitution;

[0069] D1 is selected from the following structure:

[0070] Further,

[0071] L1 is -Ak1-C1-Ak2-C2-Ak3-, wherein Ak1, Ak2, and Ak3 are independently selected from or key;

[0072] C1 and C2 are independently selected from C 1-12 Alkyl, C 2-12 Alkenyl or C 2-12 Alkynyl or bond, and C1 and C2 are not bonds at the same time, wherein the C 1-12 Alkyl, C 2-12 Alkenyl or C 2-12 The alkynyl group is optionally replaced by one or more C 1-4 alkyl or halogen substituted.

[0073] Further,

[0074] L1 is optionally selected from one or more C 1-4 Alkyl or halogen substituted C 1-12 Alkyl, C 2-12 Alkenyl or C 2-12 Alkynyl, further, preferably C optionally substituted by one or more methyl groups 1-12 Alkyl, C 2-12 Alkenyl or C 2-12 Alkynyl, further preferably C optionally substituted by one or more methyl groups 8-12 Alkyl or C 8-12 Alkynyl, further preferably C 8-12 Alkyl or C 8-12 of alkynyl.

[0075] Furthermore, L1 is selected from the following structures:

[0076] Furthermore, L1 is selected from the following structures:

[0077] Furthermore, D1 is selected from the following structures:

[0078] Furthermore, D1 is selected from the following structures:

[0079] Further, in some specific embodiments, D1 is selected from the following structures:

[0080] Further, in some specific embodiments, D1 is the following structure

[0081] In some more typical embodiments, the present invention provides a compound having the structure shown in the following III or a pharmaceutically acceptable salt thereof:

[0082] L2 is selected from —Ak1—C1—Ak2—C2—Ak3— or —Ak4—Cy1—Ak5—Cy2—Ak6—;

[0083] wherein Ak1, Ak2, and Ak3 are independently selected from or key;

[0084] C1 and C2 are independently selected from C 1-12 Alkyl, C 2-12 Alkenyl or C 2-12 Alkynyl or bond, and C1 and C2 are not bonds at the same time, wherein the C 1-12 Alkyl, C 2-12 Alkenyl or C 2-12 The alkynyl group is optionally replaced by one or more C 1-4 alkyl or halogen substituted;

[0085] wherein Ak4, Ak5, and Ak6 are independently selected from optionally substituted by one or more oxygen, C 1-4 Alkyl or halogen substituted C 1-12 an alkyl group or a bond;

[0086] Cy1 and Cy2 are independently selected from 3-12 membered heterocyclic rings, 3-12 membered cycloalkyl groups, 6-10 membered aryl groups or bonds, and Cy1 and Cy2 are not bonds at the same time, wherein the 3-12 membered heterocyclic rings, 3-12 membered cycloalkyl groups, 6-10 membered aryl groups are optionally substituted by one or more halogens or C 1-4 Alkyl substitution;

[0087] D2 is selected from the following structure:

[0088] Further,

[0089] L2 is -Ak1-C1-Ak2-C2-Ak3-, wherein Ak1, Ak2, and Ak3 are independently selected from or key;

[0090] C1 and C2 are independently selected from C 1-12 Alkyl, C 2-12 Alkenyl or C 2-12 Alkynyl or bond, and C1 and C2 are not bonds at the same time, wherein the C 1-12 Alkyl, C 2-12 Alkenyl or C 2-12 The alkynyl group is optionally replaced by one or more C 1-4 alkyl or halogen substituted.

[0091] Further,

[0092] L2 is selected from one or more C 1-4 Alkyl or halogen substituted C 1-12 Alkyl, C 2-12 Alkenyl or C2-12 Alkynyl, further, preferably C optionally substituted by one or more methyl groups 1-12 Alkyl, C 2-12 Alkenyl or C 2-12 Alkynyl, further preferably C optionally substituted by one or more methyl groups 8-12 Alkyl or C 8-12 Alkynyl, further preferably C 8-12 Alkyl or C 8-12 of alkynyl.

[0093] Further, L2 is selected from the following structures:

[0094] Further, L2 is selected from the following structures:

[0095] Further, D2 is selected from the following structures:

[0096] Further, D2 is selected from the following structures:

[0097] Further, in some specific embodiments, D2 is selected from the following structures:

[0098] Further, in some specific embodiments, D2 is the following structure

[0099] In some more typical embodiments, the present invention provides a compound having a structure shown in IV below or a pharmaceutically acceptable salt thereof:

[0100] Among them, L3 is—Ak4—Cy1—Ak5—Cy2—Ak6—;

[0101] wherein Ak4, Ak5, and Ak6 are independently selected from optionally substituted by one or more oxygen, C 1-4 Alkyl or halogen substituted C 1-12 an alkyl group or a bond;

[0102] Cy1 and Cy2 are independently selected from 3-12 membered heterocyclic rings, 3-12 membered cycloalkyl groups, 6-10 membered aryl groups or bonds, and Cy1 and Cy2 are not bonds at the same time, wherein the 3-12 membered heterocyclic rings, 3-12 membered cycloalkyl groups, 6-10 membered aryl groups are optionally substituted by one or more halogens or C 1-4 Alkyl substitution;

[0103] D3 is selected from the following structure:

[0104] Further, L3 is —Cy1—Ak6—;

[0105] Ak6 is C substituted by one or more oxygen 1-10 Alkyl; further preferably C 3-10 Alkyl;

[0106] Cy1 is a 4-9 membered heterocycle, more preferably a 4-9 membered heterocycle containing 1-2 N atoms, more preferably piperidine, piperazine or cyclobutyl spiroazaheterocyclohexyl, more preferably piperazine.

[0107] Further, L3 is selected from the following structures:

[0108] Furthermore, D3 has the following structure:

[0109] Furthermore, D3 has the following structure:

[0110] In some more typical embodiments, the present invention provides a compound having the structure shown in V below or a pharmaceutically acceptable salt thereof:

[0111] Among them, L4 is—Ak4—Cy1—Ak5—Cy2—Ak6—;

[0112] wherein Ak4, Ak5, and Ak6 are independently selected from optionally substituted by one or more oxygen, C 1-4 Alkyl or halogen substituted C 1-12 an alkyl group or a bond;

[0113] Cy1 and Cy2 are independently selected from 3-12 membered heterocyclic rings, 3-12 membered cycloalkyl groups, 6-10 membered aryl groups or bonds, and Cy1 and Cy2 are not bonds at the same time, wherein the 3-12 membered heterocyclic rings, 3-12 membered cycloalkyl groups, 6-10 membered aryl groups are optionally substituted by one or more halogens or C 1-4 Alkyl substitution;

[0114] D4 is selected from the following structures:

[0115] Furthermore, L4 is

[0116] —Ak4—Cy1—Ak5—Cy2—Ak6—;

[0117] wherein Ak4, Ak5, and Ak6 are independently selected from C 1-10 an alkyl group or a bond;

[0118] Cy1 and Cy2 are independently selected from a 4-9 membered heterocycle or a bond, and Cy1 and Cy2 are not bonds at the same time.

[0119] Furthermore, Cy1 and Cy2 are independently selected from a 4-9 membered heterocycle containing 1-2 N atoms or a bond, and Cy1 and Cy2 are not bonds at the same time.

[0120] Further, Cy1 and Cy2 are independently selected from azetidinyl, azepentyl, piperidine, piperazine, cyclopropyl azetidinyl, cyclopropyl azepentyl, cyclopropyl azehexyl, cyclopropyl piperidine, cyclobutyl azetidinyl, cyclobutyl azepentyl, cyclobutyl azehexyl, cyclobutyl piperidine, cyclopentyl azetidinyl, cyclopentyl azepentyl, cyclopentyl azehexyl, cyclopentyl piperidine, cyclohexyl azetidinyl, cyclohexyl azepentyl, azetidinyl azetidinyl, azetidinyl azepentyl, azetidinyl azehexyl, azetidinyl piperidine , azetidinyl and azetidinyl, azetidinyl and azetidinyl, azetidinyl and azetidinyl, azetidinyl and piperidine, cyclobutyl spiroazetidinyl, cyclobutyl spiroazetidinyl, cyclobutyl spiroazetidinyl, cyclobutyl spiroazetidinyl, cyclopentyl spiroazetidinyl, cyclopentyl spiroazetidinyl, cyclohexyl spiroazetidinyl, azetidinyl spiroazetidinyl, azetidinyl spiroazetidinyl, azetidinyl spiroazetidinyl, azetidinyl spiroazetidinyl, azetidinyl spiroazetidinyl, azetidinyl spiroazetidinyl, azetidinyl spiroazetidinyl, azetidinyl spiroazetidinyl, azetidinyl spiroazetidinyl, azetidinyl spiroazetidinyl, azetidinyl spiroazetidinyl, azetidinyl spiroazetidinyl, cyclobutyl spiropiperidine, azetidinyl spiropiperidine or a bond, Cy1 and Cy2 are not bonds at the same time.

[0121] Furthermore, Cy1 and Cy2 are independently selected from piperidine, piperazine or cyclobutyl spiroazaheterocyclohexyl or a bond, and Cy1 and Cy2 are not bonds at the same time.

[0122] Furthermore, in some more typical embodiments,

[0123] L4 is selected from the following structures:

[0124] The left side of L is connected to B, and the right side is connected to D4.

[0125] Furthermore, in some more typical embodiments,

[0126] L4 is selected from the following structures:

[0127] The left side of L is connected to B, and the right side is connected to D4.

[0128] Furthermore, D4 ​​is selected from the following structure:

[0129] Furthermore, D4 ​​is selected from the following structure:

[0130] In some more typical embodiments, the present invention provides a compound having the structure shown in the following VI or a pharmaceutically acceptable salt thereof:

[0131] Among them, L5 is—Ak4—Cy1—Ak5—Cy2—Ak6—;

[0132] wherein Ak4, Ak5, and Ak6 are independently selected from optionally substituted by one or more oxygen, C 1-4 Alkyl or halogen substituted C 1-12 an alkyl group or a bond;

[0133] Cy1 and Cy2 are independently selected from 3-12 membered heterocyclic rings, 3-12 membered cycloalkyl groups, 6-10 membered aryl groups or bonds, and Cy1 and Cy2 are not bonds at the same time, wherein the 3-12 membered heterocyclic rings, 3-12 membered cycloalkyl groups, 6-10 membered aryl groups are optionally substituted by one or more halogens or C 1-4 Alkyl substituted; D5 is selected from the following structure:

[0134] Further, L5 is —Cy1—Ak6—;

[0135] Ak6 is C substituted by one or more oxygen 1-10 Alkyl; further preferably C 3-10 Alkyl;

[0136] Cy1 is a 4-9 membered heterocycle, more preferably a 4-9 membered heterocycle containing 1-2 N atoms, more preferably piperidine, piperazine or cyclobutyl spiroazaheterocyclohexyl, more preferably piperazine.

[0137] Further, L6 is selected from the following structures:

[0138] In some more specific embodiments, the structure of the compound of Formula I is as follows:

[0139] The bifunctional compound of Formula I may be in the form of a free acid or free base, or a pharmaceutically acceptable salt. As used herein, the term "pharmaceutically acceptable salt" in the context of a compound refers to a salt of the compound that does not destroy the biological activity or properties of the compound and is relatively non-toxic, that is, the compound in salt form can be administered to a subject without causing undesirable biological effects (e.g., dizziness or stomach upset) or interacting in a harmful manner with any other ingredients contained in the composition. The term "pharmaceutically acceptable salt" means the product obtained by reacting a compound of the present invention with a formulated acid or base. Examples of pharmaceutically acceptable salts of the present invention include those derived from formulated inorganic bases such as Li, Na, K, Ca, Mg, Fe, Cu, Al, Zn, and Mn salts. Examples of inorganic acid addition salts include hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, isonicotinate, acetate, lactate, salicylate, citrate, tartrate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisate, fumarate, gluconate, glucuronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, etc. Certain compounds of the present invention can form pharmaceutically acceptable salts with various organic bases such as arginine, guanidine, diethanolamine or metformin.

[0140] In some embodiments, the compounds of the invention are isotopically derivatives because they have at least one atom substituted with a desired isotope in an amount greater than the natural abundance of the isotope, i.e., enriched. In some embodiments, the compounds include deuterium. 2 H, substitution may offer certain therapeutic advantages due to greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements, and thus may be advantageous in certain circumstances.

[0141] The bifunctional compounds of Formula I may have at least one chiral center and may therefore be in the form of stereoisomers, which, as used herein, encompass all isomers of a particular compound that differ only in the orientation of their atoms in space. The term "stereoisomer" includes mirror image isomers (including enantiomers in the (R-) or (S-) configuration of a compound), mixtures of mirror image isomers (physical mixtures, racemates, or racemic mixtures of enantiomers), geometric (cis / trans or E / Z) isomers of compounds, and isomers of compounds with more than one chiral center that are not mirror images of each other (diastereomers). The chiral centers of a compound may undergo epimerization in vivo; therefore, for these compounds, administration of the compound in the (R-) form is considered equivalent to administration of the compound in the (S-) form. Thus, the bifunctional compounds of Formula I can be prepared and used as individual isomers substantially free of other isomers, or as mixtures of various isomers, such as racemic mixtures of stereoisomers.

[0142] In some embodiments, the bifunctional compound of Formula I is an isotopic derivative because it has at least one atom substituted with a desired isotope in an amount above the natural abundance of the isotope, i.e., it is enriched. In some embodiments, the compound includes deuterium. Substitution with heavier isotopes, i.e., 2H, can provide certain therapeutic advantages due to greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements, and thus may be advantageous in some circumstances.

[0143] Synthesis method

[0144] In some embodiments, the present invention relates to methods for making bifunctional compounds of Formula I or pharmaceutically acceptable salts or stereoisomers thereof. In general, bifunctional compounds or pharmaceutically acceptable salts or stereoisomers thereof can be prepared by any method known to be suitable for preparing chemically related compounds. The compounds of the present invention will be better understood in conjunction with the synthetic schemes described in the various working examples, which illustrate non-limiting methods by which the compounds of the present invention can be prepared.

[0145] The present invention discloses a method for preparing a compound of formula I, which comprises:

[0146] Method 1:

[0147] Among them, R 1 、R 2 , G, L, D are as defined in Formula I, R 1a is selected from halogen, preferably bromine, R 1b is methyl or hydrogen.

[0148] The compound of general formula (I-1A) and the compound of general formula (I-1B) are coupled or nucleophilically substituted under palladium catalysis to obtain the compound of general formula (I-1C). The compound of general formula (I-1C) is oxidized to obtain the compound of general formula (I-1D). The compound of general formula (I-2D) is combined with the compound of general formula (I-1E) to undergo reductive amination to obtain the compound of general formula (I-1). Before the oxidation reaction, the compound of general formula (I-2C) can be reduced to reduce the alkynyl group on the linker to an alkenyl or alkyl group.

[0149] Method 2:

[0150] Among them, R 1 、R 2 , G, L, D are as defined in Formula I, R 2a is selected from halogen, preferably bromine.

[0151] The compound of general formula (I-2A) and the compound of general formula (I-2B) are coupled or nucleophilically substituted under palladium catalysis to obtain the compound of general formula (I-2C). The compound of general formula (I-2C) is oxidized to obtain the compound of general formula (I-2D). The compound of general formula (I-2D) is combined with the compound of general formula (I-2E) to undergo reductive amination to obtain the compound of general formula (I-2). Before the oxidation reaction, the compound of general formula (I-2C) can be reduced to reduce the alkynyl group on the linker to an alkenyl or alkyl group.

[0152] Method 3

[0153] Among them, R 1 、R 2 , G, L, and D are as defined in Formula I,

[0154] The compound of general formula (I-2D) and the compound of general formula (I-2E) undergo reductive amination to obtain the compound of general formula (I).

[0155] Pharmaceutical composition

[0156] Another aspect of the present invention relates to a pharmaceutical composition comprising a therapeutically effective amount of a bifunctional compound of formula I or a pharmaceutically acceptable salt or stereoisomer thereof, and a pharmaceutically acceptable carrier. The term "pharmaceutically acceptable carrier" as known in the art refers to a pharmaceutically acceptable material, composition or carrier suitable for administering the compound of the present invention to a mammal. Suitable carriers may include, for example, liquids (aqueous and non-aqueous analogs, and combinations thereof), solids, encapsulating materials, gases, and combinations thereof (e.g., semisolids), and compounds that carry or transport gases from one organ or part of the body to another organ or part of the body. A carrier is "acceptable" in the sense that it is physiologically inert to the other ingredients of the formulation and is compatible with the other ingredients of the formulation and harmless to the subject or patient. Depending on the type of formulation, the composition may include one or more pharmaceutically acceptable excipients.

[0157] How to use

[0158] The present invention relates to a method for treating diseases or conditions involving AKT dysfunction or disorder, which requires administering to a subject in need thereof a therapeutically effective amount of a bifunctional compound of Formula I or a pharmaceutically acceptable salt or stereoisomer thereof.

[0159] Disease or illness can be said to be characterized or mediated by dysfunctional AKT activity (e.g., elevated AKT levels or other dysfunctional AKT relative to a non-pathological state). "Disease" is generally considered to be a state of health in a subject in which the subject is unable to maintain homeostasis, and in which the subject's health continues to deteriorate if the disease does not improve. In contrast, a "disease" in a subject is a state of health in which the subject is able to maintain homeostasis, but the subject's health is not as good as it would be in the absence of the disease. If left untreated, the disease does not necessarily lead to a further decline in the animal's health.

[0160] The terms subject or patient, as used herein, include all members of the animal kingdom that are susceptible to or suffer from a specified disease or illness. In some embodiments, the subject is a mammal, such as a human or non-human mammal. The method is also applicable to companion animals such as dogs and cats, as well as domestic animals and other domesticated and wild animals such as cattle, horses, sheep, goats, and pigs. A subject who "needs" treatment according to the present invention may "suffer from or be suspected of having" a specific disease or illness, may have been positively diagnosed or otherwise present a sufficient number of risk factors or a sufficient number or combination of signs or symptoms so that a medical professional can diagnose or suspect that the subject has a disease or illness. Therefore, subjects suffering from and suspected of having a specific disease or illness are not necessarily two different groups.

[0161] In some embodiments, the compounds of Formula I can be used to treat cell proliferative diseases and disorders (e.g., cancer or benign tumors). As used herein, the term "cell proliferative disease or disorder" refers to a condition characterized by dysregulated or abnormal cell growth, or both, including non-cancerous conditions such as tumors, precancerous conditions, and benign tumors.

[0162] Medical test kits

[0163] The bifunctional compounds of the present invention and / or compositions containing these compounds can be assembled into a kit or pharmaceutical system. The kit or pharmaceutical system according to this aspect of the present invention includes a carrier or packaging, such as a box, carton, tube, etc., which has one or more containers, such as vials, tubes, ampoules or bottles, which are tightly confined to contain the compound of Formula I or its pharmaceutical composition. The kit or pharmaceutical system of the present invention can also include printed instructions for using the compounds and compositions.

[0164] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the subject matter of this invention belongs. As used in the specification and appended claims, unless otherwise indicated, the following terms have the indicated meanings to facilitate understanding of the present invention.

[0165] The "compounds" described in the present invention include all stereoisomers and tautomers.

[0166] The compounds of the present invention may be asymmetric, for example, having one or more stereoisomers. Unless otherwise indicated, all stereoisomers are included, such as enantiomers and diastereomers. Compounds of the present invention containing asymmetric carbon atoms can be isolated in optically pure forms or racemic forms. Optically pure forms can be resolved from racemic mixtures or synthesized using chiral starting materials or chiral reagents. Racemates, diastereomers, and enantiomers are all included within the scope of the present invention.

[0167] The compounds of the present invention also include tautomeric forms, which result from the exchange of a single bond with an adjacent double bond accompanied by the migration of a proton.

[0168] In the present invention, Ak1, Ak2, and Ak3 in L may all be bonds. When they are all bonds, L is "—C1—C2—." If C1 is also a bond, L is "—C2—." Similarly, Ak4, Ak5, and Ak6 may all be bonds. In this case, L is "—Cy1—Cy2—." If Cy1 is also a bond, L is "—Cy2—." If Ak1 and C1 are all bonds, L is "—Ak2—C2—Ak3—." If Ak4, Cy1, and Ak5 are all bonds, L is "—Cy2—Ak6—." This means that if all adjacent bonds are bonds, there is only one link.

[0169] The structure of B of the present invention is as follows:

[0170] When R 3 When absent, it refers to the following structure: This structure is directly connected to L.

[0171] The term "optional" or "optionally" means that the subsequently described event or circumstance may or may not occur, and that the description includes both occurring and not occurring.

[0172] Examples of the term "halogen" include a fluorine atom, a chlorine atom, a bromine atom, an iodine atom.

[0173] The term "alkyl" refers to a saturated aliphatic hydrocarbon group, including straight-chain or branched saturated hydrocarbon groups, having the indicated number of carbon atoms. 1-12The "alkyl" includes C1 alkyl, C2 alkyl, C3 alkyl, C4 alkyl, C5 alkyl, C6 alkyl, C7 alkyl, C8 alkyl, C9 alkyl, C10 alkyl, C11 alkyl, C12 alkyl, examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, 2-pentyl, 3-pentyl, n-hexyl, 2-hexyl, 3-hexyl and the like. It may be divalent, such as methylene, ethylene.

[0174] The term "alkenyl" refers to a straight or branched chain hydrocarbon group containing at least one carbon-carbon double bond. Alkenyl groups include groups having "cis" and "trans" orientations, or alternatively, "E" and "Z" orientations. As the term "C 8-12 The “alkenyl group” includes C8 alkenyl, C9 alkenyl, C10 alkenyl, C11 alkenyl, C12 alkenyl, and examples include, but are not limited to, octene, (E)-non-2-ene, (E)-dec-2-ene, (E)-undec-2-ene, and the like.

[0175] The term "alkynyl" refers to a straight or branched chain hydrocarbon group containing at least one carbon-carbon triple bond. 8-12 The term "alkynyl" refers to a hydrocarbon group having 8 to 12 carbon atoms and containing at least one triple bond, and may be, but is not limited to, octyne, (E)-non-2-yne, (E)-dec-2-yne, (E)-undec-2-yne, and the like.

[0176] The term "alkoxy" refers to a group having an alkyl-O-structure, wherein the alkyl group is a saturated monovalent hydrocarbon group including a straight or branched chain. Non-limiting examples include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentoxy, and n-hexoxy.

[0177] The term "heterocyclyl" or "heterocycle" refers to a saturated or unsaturated non-aromatic ring system. The non-aromatic ring can be a 3-8 membered monocyclic ring, a 4-12 membered bicyclic ring or a 10-15 membered tricyclic ring system, and contains 1 to 3 heteroatoms selected from N, O or S. It is preferably a 4-9 membered heterocyclyl. The optionally substituted N in the heterocyclyl ring can be oxidized to various oxidation states. The heterocyclic group may be attached to a heteroatom or a carbon atom, and may be connected to a bridged ring or a spirocyclic ring. Examples of monocyclic saturated heterocyclic groups are oxetanyl, azetidinyl, pyrrolidinyl, 2-oxo-pyrrolidin-3-yl, tetrahydrofuranyl, tetrahydro-thienyl, pyrazolidinyl, imidazolidinyl, thiazolidinyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperazinyl, morpholinyl, thiomorpholinyl, 1,1-dioxo-thiomorpholin-4-yl, azepanyl, diazepanyl, homopiperazinyl or oxazepanyl. Examples of bicyclic saturated heterocyclyl are 8-aza-bicyclo[3.2.1]octyl, quinuclidinyl, 8-oxa-3-aza-bicyclo[3.2.1]octyl, 9-aza-bicyclo[3.3.1]nonyl, examples of partially unsaturated heterocyclyl are dihydrofuranyl, imidazolinyl, tetrahydro-pyridinyl or dihydropyranyl.

[0178] The term "cycloalkyl" refers to a monocyclic saturated hydrocarbon system with no heteroatoms and no double bonds. Examples of the term "3-12 membered cycloalkyl" include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0179] The term "aryl" refers to a substituted or unsubstituted aromatic hydrocarbon group having a single ring or fused rings, wherein the number of ring atoms in the aromatic ring includes, but is not limited to, 6 to 18, 6 to 12, or 6 to 10 carbon atoms. The aryl ring may be fused to a saturated or unsaturated carbocyclic or heterocyclic ring, wherein the ring attached to the parent structure is the aryl ring, non-limiting examples of which include a benzene ring and a naphthalene ring.

[0180] The term "bond" refers to a direct connection via a single chemical bond.

[0181] Single wave line Refers to the chemical bond connection.

[0182] The term "pharmaceutically acceptable salt" refers to a salt that retains the biological effectiveness of the free acids and bases of the specified compound without adverse biological effects, such as acid addition salts (including organic acids and inorganic acids) or base addition salts (including organic bases and inorganic bases).

[0183] Pharmaceutically acceptable salts of the present invention can be synthesized by conventional chemical methods from parent compounds containing acid radicals or bases. Generally, such salts are prepared by reacting these compounds in free acid or base form with a stoichiometric amount of a suitable base or acid in water or an organic solvent or a mixture of the two.

[0184] The term "effective amount" or "therapeutically effective amount" refers to a non-toxic but sufficient amount of a drug or pharmaceutical agent to achieve the desired effect.

[0185] The present invention will be further understood by considering the following examples, which are intended to illustrate certain specific embodiments of the present invention but are not intended to limit the scope of protection thereof.

[0186] Synthesis part

[0187] Preparation of Intermediate 1(R)-4-((1S,6R)-5-((S)-2-(4-chlorophenyl)-3-(piperazin-1-yl)propanoyl)-2,5-diazabicyclo[4.1.0]hept-2-yl)-5-methyl-5,8-dihydropyrido[2,3-d]pyrimidin-7(6H)-one

[0188] a) Preparation of (R)-4-((1S,6R)-5-((S)-3-(4-benzylpiperazin-1-yl)-2-(4-chlorophenyl)propionyl)-2,5-diazabicyclo[4.1.0]hept-2-yl)-5-methyl-5,8-dihydropyrido[2,3-d]pyrimidin-7(6H)-one

[0189] (R)-4-((1S,6R)-5-((S)-3-amino-2-(4-chlorophenyl)propanoyl)-2,5-diazabicyclo[4.1.0]hept-2-yl)-5-methyl-5,8-dihydropyrido[2,3-d]pyrimidin-7(6H)-one (500 mg), N-benzyl-2-bromo-N-(2-bromoethyl)ethan-1-amine (437 mg), N,N-diisopropylethylamine (293 mg), and ethanol (5 mL) were added to a reaction flask, and the mixture was stirred at room temperature overnight. After completion of the reaction, the resulting mixture was concentrated under reduced pressure, and the crude product was purified by column chromatography (mobile phase: ethyl acetate / petroleum ether) to obtain 210 mg of the title compound.

[0190] b) Preparation of (R)-5-methyl-4-((1S,6R)-5-((S)-2-phenyl-3-(piperazin-1-yl)propanoyl)-2,5-diazabicyclo[4.1.0]heptane-2-yl)-5,8-dihydropyrido[2,3-d]pyrimidin-7(6H)-one

[0191] (R)-4-((1S,6R)-5-((S)-3-(4-benzylpiperazin-1-yl)-2-(4-chlorophenyl)propanoyl)-2,5-diazabicyclo[4.1.0]hept-2-yl)-5-methyl-5,8-dihydropyrido[2,3-d]pyrimidin-7(6H)-one (210 mg), palladium / carbon (210 mg), palladium hydroxide / carbon (210 mg), 1,4-dioxane hydrochloric acid solution (4M, 0.01 mL), and methanol (5 mL) were added to a reaction flask, and the mixture was stirred at 50°C under a hydrogen atmosphere overnight. After the reaction was completed, the mixture was filtered, the filter cake was washed with methanol, and the organic phase was collected and concentrated to obtain the crude product for the next step.

[0192] Example 1 Preparation of 3-(4-(10-(((S)-2-(4-chlorophenyl))-3-((1R,5S)-3-(5-ethyl-7-oxo-5,6,7,8-tetrahydropteridin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-3-oxopropyl)amino)decyl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione

[0193] a) Preparation of 3-(4-bromo-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione

[0194] To 7-bromo-1-methyl-1,3-dihydro-2H-benzo[d]imidazol-2-one (5.0 g) and 3-bromopiperidine-2,6-dione (6.3 g) was added N,N-dimethylformamide (50 mL) and then sodium hydride (1.6 g). The mixture was stirred at room temperature under a nitrogen atmosphere for 4 hours. After the reaction was completed, the resulting mixture was extracted with ethyl acetate (200 mL × 3). The combined organic layer was washed with brine (300 mL × 3) and dried over anhydrous sodium sulfate. After filtering out the solid, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with ethyl acetate / petroleum ether to obtain 6.0 g of the title compound.

[0195] b) Preparation of 3-(4-(10-hydroxydec-1-yn-1-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione

[0196] 3-(4-Bromo-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (1.0 g), 9-decyn-1-ol (912 mg), triethylamine (897 mg), cuprous iodide (112 mg), bis(triphenylphosphine)palladium chloride (207 mg) and N,N-dimethylformamide (10 mL) were added to a reaction flask. The mixture was stirred at 70°C under a nitrogen atmosphere for 3 hours. After the reaction was completed, the resulting mixture was extracted with ethyl acetate (70 mL × 3). The combined organic layers were washed with brine (70 mL × 3) and dried over anhydrous sodium sulfate. After filtering out the solid, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with methanol / dichloromethane to obtain 600 mg of the title compound.

[0197] c) Preparation of 3-(4-(10-hydroxydecyl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione

[0198] To 3-(4-(10-hydroxydec-1-yn-1-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (300 mg) and palladium / carbon (60 mg) was added ethyl acetate (5 mL), and the mixture was stirred at 50°C under a hydrogen atmosphere for 15 hours. The resulting mixture was filtered, the filter cake was washed with methanol (10 mL x 3), and the filtrate was concentrated under reduced pressure to obtain 200 mg of the title compound.

[0199] d) Preparation of 10-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)decanal

[0200] To 3-(4-(10-hydroxydecyl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (100 mg) in dichloromethane (1 mL) was added (1,1,1-triacetoxy)-1,1-dihydro-1,2-benzoiodine-3(1H)-one (206 mg). The mixture was stirred at room temperature for 2 hours under a nitrogen atmosphere. After the reaction was completed, the mixture was diluted with saturated sodium bicarbonate (20 mL), the resulting mixture was extracted with dichloromethane (30 mL×3), and the combined organic layers were dried over anhydrous sodium sulfate. After filtering out the solid, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with ethyl acetate / petroleum ether to give 80 mg of the title compound.

[0201] e) Preparation of 3-[4-(10-{[(2S)-2-(4-chlorophenyl)-3-[3-(5-ethyl-7-oxo-6,8-dihydropteridin-4-yl)-3,8-diazabicyclo[3.2.1]oct-8-yl]-3-oxopropyl]amino}dec-1-yn-1-yl)-3-methyl-2-oxo-1,3-benzodiazol-1-yl]piperidine-2,6-dione

[0202] 10-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)decanal (80 mg) and 4-{8-[(2S)-3-amino-2-(4-chlorophenyl)propionyl]-3,8-diazabicyclo[3.2.1]octan-3-yl}-5-ethyl-6,8-dihydropteridin-7-one (110 mg) were dissolved in 1,2-dichloroethane (2 mL) and stirred at room temperature for 30 minutes. Sodium triacetoxyborohydride (103 mg) was then added to the mixture, and the mixture was stirred at room temperature under a nitrogen atmosphere for 1 hour. After the reaction was completed, the resulting mixture was concentrated under reduced pressure. The crude product was separated by preparative liquid phase to obtain 37.8 mg of the title compound.

[0203] 1H NMR (400MHz, DMSO-d6) δ11.09(s,1H),10.82(d,J=19.3Hz,1H),8.09(d,J=23.4Hz,1H) ,7.39(d,J=2.1Hz,2H),7.36(s,2H),7.03-6.90(m,2H),6.85(d,J=3.5Hz,1H),5.36(d d,J=12.5,5.3Hz,1H),5.33(dd,J=12.5,5.3Hz,2H),4.59(t,J=8.0Hz,1H)4.57(t,J=8 .0Hz,1H),4.52(s,1H),4.32-4.03(m,1H),3.61(d,J=4.7Hz,3H),3.55(dd,J=7.6,2.4 Hz,3H),3.15(dd,J=20.9,11.3Hz,3H),2.87(m,1H),2.85(m,1H),2.84(m,1H),2.82(m ,2H),2.80(m,1H),2.71(m,1H),2.70(s,1H),2.68-2.62(m,3H),2.33(p,J=1.8Hz,1H) ,2.17-1.82(m,1H),1.73(d,J=7.8Hz,1H),1.65(t,J=8.8Hz,1H),1.57(d,J=7.9Hz,2H ),1.33(s,5H),1.23(s,6H),1.18(s,3H),0.92(t,J=7.0Hz,1H),0.85(t,J=7.0Hz,1H).

[0204] LCMS m / z=867[M+1] +

[0205] Example 2 Preparation of 3-[4-(10-{[(2S)-2-(4-chlorophenyl)-3-[3-(5-ethyl-7-oxo-6,8-dihydropteridin-4-yl)-3,8-diazabicyclo[3.2.1]oct-8-yl]-3-oxopropyl]amino}dec-1-yn-1-yl)-3-methyl-2-oxo-1,3-benzodiazol-1-yl]piperidine-2,6-dione

[0206] a) Preparation of 10-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)dec-9-ynal

[0207] To 3-(4-(10-hydroxydec-1-yn-1-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (100 mg) in dichloromethane (1 mL) was added (1,1,1-triacetoxy)-1,1-dihydro-1,2-benzoiodine-3(1H)-one (206 mg). The mixture was stirred at room temperature for 2 hours under a nitrogen atmosphere. After the reaction was completed, the mixture was diluted with saturated sodium bicarbonate (20 mL), and the resulting mixture was extracted with dichloromethane (30 mL×3), and the combined organic layers were dried over anhydrous sodium sulfate. After filtering out the solid, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with ethyl acetate / petroleum ether to give 80 mg of the title compound.

[0208] b) Preparation of 3-[4-(10-{[(2S)-2-(4-chlorophenyl)-3-[3-(5-ethyl-7-oxo-6,8-dihydropteridin-4-yl)-3,8-diazabicyclo[3.2.1]oct-8-yl]-3-oxopropyl]amino}dec-1-yn-1-yl)-3-methyl-2-oxo-1,3-benzodiazol-1-yl]piperidine-2,6-dione

[0209] 10-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)dec-9-ynal (80 mg) and 4-{8-[(2S)-3-amino-2-(4-chlorophenyl)propionyl]-3,8-diazabicyclo[3.2.1]octan-3-yl}-5-ethyl-6,8-dihydropteridin-7-one (110 mg) were dissolved in 1,2-dichloroethane (2 mL) and stirred at room temperature for 30 minutes. Sodium triacetoxyborohydride (103 mg) was then added to the mixture, and the mixture was stirred at room temperature under a nitrogen atmosphere for 1 hour. After the reaction was completed, the resulting mixture was concentrated under reduced pressure. The crude product was separated by preparative liquid phase to obtain 19.8 mg of the title compound.

[0210] 1H NMR (400MHz, DMSO-d6) δ11.10(s,1H),10.82(d,J=18.4Hz,1H),8.09(d,J=25.9Hz,1H),7.51-7.24(m,4H),7.11(d,J=7. 7Hz,1H),7.06-7.01(m,1H),6.98(t,J=7.8Hz,1H),5.38(dd,J=12.7,5.4Hz,1H),4.72-4.36(m,4H),4.23-4.13(m,1H),3 .62(dd,J=9.0,3.5Hz,3H),3.55(d,J=3.7Hz,2H),3.17(d,J=12.4Hz,1H),3.04-2.77(m,3H),2.76-2.52(m,5H),2.45(d ,J=7.0Hz,4H),2.09-1.97(m,2H),1.76-1.50(m,5H),1.38(s,4H),1.25(d,J=13.1Hz,7H),0.88(dt,J=28.4,7.0Hz,3H).

[0211] LCMS m / z=863[M+1] +

[0212] Example 3 Preparation of 3-[4-(11-{[(2S)-2-(4-chlorophenyl)-3-[3-(5-ethyl-7-oxo-6,8-dihydropteridin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl]-3-oxopropyl]amino}undecyl)-3-methyl-2-oxo-1,3-benzodiazol-1-yl]piperidine-2,6-dione

[0213] a) Preparation of (4,6-dichloropyrimidin-5-yl)glycine ethyl ester

[0214] A solution of 4,6-dichloropyrimidin-5-amine (11 g) in tetrahydrofuran (120 mL) was cooled to 0°C, maintained under a nitrogen atmosphere, and then sodium hydride (3.22 g) was slowly added over 30 minutes. Ethyl bromoacetate (16.80 g) was subsequently added dropwise at 0°C. Finally, tetrabutylammonium iodide (49.55 g) was added to the above mixture in batches. The resulting mixture was stirred at room temperature overnight. After the reaction was completed, the reaction was quenched with water at 0°C. The resulting mixture was extracted with ethyl acetate (200 mL × 3), and the combined organic layers were washed with brine (100 mL × 3) and dried over anhydrous sodium sulfate. After filtering out the solid, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with ethyl acetate / petroleum ether to obtain 8.9 g of the title compound.

[0215] b) Preparation of 4-chloro-8-[(3,4-dimethoxyphenyl)methyl]-5,6-dihydropteridin-7-one

[0216] Ethyl (4,6-dichloropyrimidin-5-yl)glycine (8.9 g), 3,4-dimethoxybenzylamine (6.55 g), triethylamine (7.92 g), and isopropanol (150 mL) were added to a reaction flask and stirred at 80°C overnight. After the reaction, the mixture was cooled to room temperature. Filtered, and the filter cake was washed with ethanol (20 mL x 3) to obtain 8.5 g of the title compound.

[0217] c) Preparation of 4-chloro-8-[(3,4-dimethoxyphenyl)methyl]-5-ethyl-6H-pteridin-7-one

[0218] A solution of 4-chloro-8-[(3,4-dimethoxyphenyl)methyl]-5,6-dihydropteridin-7-one (7.3 g) in N,N-dimethylformamide (100 mL) was cooled to -10°C and maintained under a nitrogen atmosphere. Ethyl iodide (5.1 g) was then added, followed by the slow addition of sodium hydride (1.05 g). The reaction was continued at -10°C for 3 hours. After completion of the reaction, the mixture was quenched with aqueous ammonium chloride. The resulting mixture was extracted with ethyl acetate (100 mL × 3), and the combined organic layers were washed with brine (50 mL × 3) and dried over anhydrous sodium sulfate. After filtering out the solid, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with ethyl acetate / petroleum ether (0-50%) to obtain 3.4 g of the title compound.

[0219] d) Preparation of 4-chloro-5-ethyl-5,8-dihydropteridin-7(6H)-one

[0220] A solution of 4-chloro-8-[(3,4-dimethoxyphenyl)methyl]-5-ethyl-6H-pteridin-7-one (3.3 g) in trifluoroacetic acid (30 mL) and n-butanol (10 mL) was stirred at 80°C for 2 hours. After the reaction was completed, the resulting mixture was concentrated under reduced pressure. The pH of the mixture was adjusted to 9 with saturated sodium bicarbonate solution. The resulting mixture was extracted with ethyl acetate (50 mL x 3), and the combined organic layers were dried over anhydrous sodium sulfate. After filtering out the solid, the filtrate was concentrated under reduced pressure. 1.8 g of the target compound was obtained.

[0221] e) Preparation of tert-butyl 3-(5-ethyl-7-oxo-6,8-dihydropteridin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0222] A solution of 4-chloro-5-ethyl-5,8-dihydropteridin-7(6H)-one (1.8 g), N,N-diisopropylethylamine (3.28 g) and tert-butyl 3,8-diazabicyclo[3.2.1]octane-8-carboxylate (2.70 g) in acetonitrile (20 mL) was stirred at 100°C for 8 hours. After the reaction was completed, the resulting mixture was concentrated under reduced pressure. The pH of the residue was adjusted to 5 with dilute hydrochloric acid. The resulting mixture was extracted with ethyl acetate (50 mL × 3), and the combined organic layers were dried over anhydrous sodium sulfate. After filtering out the solid, the filtrate was concentrated under reduced pressure. 2.8 g of the target compound was obtained.

[0223] f) Preparation of 4-{3,8-diazabicyclo[3.2.1]octan-3-yl}-5-ethyl-6,8-dihydropteridin-7-one

[0224] Add tert-butyl 3-(5-ethyl-7-oxo-6,8-dihydropteridin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (2.8 g) to a 4M 1,4-dioxane hydrochloride solution (30 mL) and stir at room temperature for 3 hours. After the reaction is complete, concentrate under reduced pressure to obtain 3 g of the title compound.

[0225] g) Preparation of tert-butyl N-[(2S)-2-(4-chlorophenyl)-3-[3-(5-ethyl-7-oxo-6,8-dihydropteridin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl]-3-oxopropyl]carbamate

[0226] A solution of 4-{3,8-diazabicyclo[3.2.1]octan-3-yl}-5-ethyl-6,8-dihydropteridin-7-one (3 g), O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (5.93 g), N,N-diisopropylethylamine (4.03 g), and (S)-3-((tert-butoxycarbonyl)amino)-2-(4-chlorophenyl)propanoic acid (3.74 g) in N,N-dimethylformamide (40 mL) was stirred at room temperature for 3 hours. After the reaction, the resulting mixture was extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with brine (30 mL x 3) and dried over anhydrous sodium sulfate. After filtering out the solid, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with methanol / dichloromethane (0% to 10%) to give 4.2 g of the title compound.

[0227] h) Preparation of 4-{8-[(2S)-3-amino-2-(4-chlorophenyl)propionyl]-3,8-diazabicyclo[3.2.1]octan-3-yl}-5-ethyl-6,8-dihydropteridin-7-one

[0228] Tert-butyl N-[(2S)-2-(4-chlorophenyl)-3-[3-(5-ethyl-7-oxo-6,8-dihydropteridin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl]-3-oxopropyl]carbamate (4.2 g) was added to a 1,4-dioxane hydrochloric acid solution (4 M, 40 mL), followed by stirring at room temperature for 2 hours. After completion of the reaction, the mixture was concentrated under reduced pressure, and the pH of the residue was adjusted to 9 with saturated sodium bicarbonate solution. The resulting mixture was extracted with ethyl acetate (100 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate. After filtering out the solid, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with methanol / dichloromethane (0% to 10%) to obtain 3.4 g of the title compound.

[0229] i) Preparation of 3-[4-(11-{[(2S)-2-(4-chlorophenyl)-3-[3-(5-ethyl-7-oxo-6,8-dihydropteridin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl]-3-oxopropyl]amino}undecyl)-3-methyl-2-oxo-1,3-benzodiazol-1-yl]piperidine-2,6-dione

[0230] 11-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)undecanal (50 mg) and 4-{8-[(2S)-3-amino-2-(4-chlorophenyl)propionyl]-3,8-diazabicyclo[3.2.1]octan-3-yl}-5-ethyl-6,8-dihydropteridin-7-one (55 mg) were dissolved in 1,2-dichloroethane (2 mL) and stirred at room temperature for 30 minutes. Sodium triacetoxyborohydride (49.5 mg) was then added to the mixture, and the mixture was stirred at room temperature under a nitrogen atmosphere for 1 hour. After the reaction was completed, the resulting mixture was concentrated under reduced pressure. The crude product was separated by preparative liquid phase to obtain 8.4 mg of the title compound.

[0231] 1H NMR (400MHz, DMSO-d6) δ11.08(s,1H),10.81(d,J=18.9Hz,1H),8.08(d,J=23.1Hz,1H),7.47-7.28(m,4H),7.03-6.86(m,2H),6.85( dd,J=5.4,3.5Hz,1H),5.36(dd,J=12.6,5.4Hz,1H),4.54(dt,J=29.8,8.3Hz,3H),4.20-4.05(m,1H),3.61(d,J=4.5Hz,1H),3.56(d ,J=3.5Hz,1H),3.54(s,3H),3.30-3.23(m,2H),3.13(dt,J=21.0,10.7Hz,2H),3.02-2.70(m,5H),2.76-2.54(m,4H),2.05-1.84(m, 2H),1.75(dd,J=11.3,7.2Hz,2H),1.62(dd,J=35.2,7.7Hz,3H),1.33(s,6H),1.20(d,J=19.5Hz,11H),0.88(dt,J=29.3,7.0Hz,3H).

[0232] LCMS m / z=881[M+1] +

[0233] Example 4 Preparation of 3-(4-(11-(((S)-2-(4-chlorophenyl))-3-((1R,5S)-3-(5-ethyl-7-oxo-5,6,7,8-tetrahydropteridin-4-yl)-3,8-diazabicyclo[3.2.1]oct-8-yl)-3-oxopropyl)amino)undec-1-yn-1-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione

[0234] a) Preparation of 3-(4-(11-hydroxyundec-1-yn-1-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione

[0235] 3-(4-Bromo-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (1.0 g), undec-10-yn-1-ol (950 mg), triethylamine (897 mg), cuprous iodide (112 mg), bis(triphenylphosphine)palladium chloride (207 mg), and N,N-dimethylformamide (10 mL) were added to a reaction flask. The mixture was stirred at 70°C under a nitrogen atmosphere for 3 hours. After the reaction was completed, the resulting mixture was extracted with ethyl acetate (70 mL x 3). The combined organic layers were washed with brine (70 mL x 3) and dried over anhydrous sodium sulfate. After filtering out the solid, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with methanol / dichloromethane (0% to 10%) to obtain 500 mg of the title compound.

[0236] b) Preparation of 11-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)undec-10-ynal

[0237] To 3-(4-(11-hydroxyundec-1-yn-1-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (100 mg) in dichloromethane (1 mL) was added (1,1,1-triacetoxy)-1,1-dihydro-1,2-benzoiodine-3(1H)-one (199 mg). The mixture was stirred at room temperature for 2 hours under a nitrogen atmosphere. After the reaction was completed, the mixture was diluted with saturated sodium bicarbonate (20 mL), and the resulting mixture was extracted with dichloromethane (30 mL×3), and the combined organic layers were dried over anhydrous sodium sulfate. After filtering out the solid, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with ethyl acetate / petroleum ether (10%-70%) to give 50 mg of the title compound.

[0238] c) Preparation of 3-[4-(11-([(2S)-2-(4-chlorophenyl)-3-[3-(5-ethyl-7-oxo-6,8-dihydropteridin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl]-3-oxopropyl]aminoundec-1-yn-1-yl)-3-methyl-2-oxo-1,3-benzodiazol-1-yl]piperidine-2,6-dione

[0239] 11-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)undec-10-ynal (50 mg) and 4-{8-[(2S)-3-amino-2-(4-chlorophenyl)propionyl]-3,8-diazabicyclo[3.2.1]octan-3-yl}-5-ethyl-6,8-dihydropteridin-7-one (61 mg) were dissolved in 1,2-dichloroethane (2 mL) and stirred at room temperature for 30 minutes. Sodium triacetoxyborohydride (62.5 mg) was then added to the mixture, and the mixture was stirred at room temperature under a nitrogen atmosphere for 1 hour. After the reaction was completed, the resulting mixture was concentrated under reduced pressure. The crude product was separated by preparative liquid phase separation to obtain 10.4 mg of the title compound.

[0240] 1 H NMR(400MHz,DMSO-d6)δ11.10(s,1H),10.84 -10.79(d,1H),8.12(s,1H),8.05-7.10(m,4H),7.04(d,J=7.5Hz,1H),6.98(t,J=7.8Hz,2H),5.41-5.33(m,1H),4.58-4.4 7(m,4H),4.22(d,J=12.4Hz,1H),4.16(s,3H),3.65-3.60(m,1H),3.60-3.58(m,1H),3.56(m,1H),2.89-2.86(m,3H),2.86 -2.70(m,5H),2.37-2.31(s,2H),2.11 -2.05(m,1H),2.02(s,2H),1.73(s,3H),1.66(d,J=7.0Hz,3H),1.56-1.37(m,4H),1.22(d,J=14.7Hz,9H),0.92 -0.85(m,3H).

[0241] LCMS m / z=877[M+1] +

[0242] Example 5 Preparation of 5-(11-(((S)-2-(4-chlorophenyl)-3-((1R,5S)-3-(5-ethyl-7-oxo-5,6,7,8-tetrahydropteridin-4)-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl-3-oxopropyl)amino)undecyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

[0243] a) Preparation of 2-(2,6-dioxopiperidin-3-yl)-5-(11-hydroxyundecan-1-yn-1-yl)isoindole-1,3-dione

[0244] 5-Bromo-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione (1 g), undec-10-yn-1-ol (1 g), bis(triphenylphosphine)palladium dichloride (0.21 g), and cuprous iodide (0.11 g) were added to triethylamine (5 mL) and N,N-dimethylformamide (5 mL) and reacted at 70°C under a nitrogen atmosphere for 3 hours. After completion of the reaction, water (100 mL) was added to quench the reaction, followed by extraction with ethyl acetate (50 mL x 3). The combined organic phases were washed with brine (100 mL x 2) and dried over anhydrous sodium sulfate. After filtering the solid, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with methanol / dichloromethane (0%-10%) to obtain 900 mg of the title compound.

[0245] b) Preparation of 2-(2,6-dioxopiperidin-3-yl)-5-(11-hydroxyundecyl)isoindole-1,3-dione

[0246] Methanol (3 mL) was added to 2-(2,6-dioxopiperidin-3-yl)-5-(11-hydroxyundecan-1-yn-1-yl)isoindole-1,3-dione (300 mg) and palladium / carbon (60 mg), and the mixture was stirred at 50°C under a hydrogen atmosphere for 24 hours. The resulting mixture was filtered, and the filter cake was washed with methanol (10 mL x 3). The filtrate was concentrated under reduced pressure to obtain 200 mg of the title compound.

[0247] c) Preparation of 11-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindole-5-yl]undecanal

[0248] To 2-(2,6-dioxopiperidin-3-yl)-5-(11-hydroxyundecyl)isoindole-1,3-dione (200 mg) in dichloromethane (5 mL) was added (1,1,1-triacetoxy)-1,1-dihydro-1,2-benzoiodine-3(1H)-one (398 mg). The mixture was stirred at room temperature for 2 hours under a nitrogen atmosphere. After the reaction was completed, the mixture was quenched with water (100 mL), then extracted with ethyl acetate (50 mL×3), and the combined organic layers were dried over anhydrous sodium sulfate. After filtering out the solid, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with methanol / dichloromethane (0%-10%) to give 70 mg of the title compound.

[0249] d) Preparation of 5-(11-(((S)-2-(4-chlorophenyl)-3-((1R,5S)-3-(5-ethyl-7-oxo-5,6,7,8-tetrahydropteridin-4)-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl-3-oxopropyl)amino)undecyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

[0250] 11-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindole-5-yl]undecanal (100 mg) and 4-{8-[(2S)-3-amino-2-(4-chlorophenyl)propionyl]-3,8-diazabicyclo[3.2.1]octan-3-yl}-5-ethyl-6,8-dihydropteridin-7-one (110 mg) were dissolved in 1,2-dichloroethane (1 mL) and stirred at room temperature for 30 minutes. Sodium triacetoxyborohydride (159.5 mg) was then added to the mixture, and the mixture was stirred at room temperature under a nitrogen atmosphere for 1 hour. After the reaction was completed, the resulting mixture was concentrated under reduced pressure. The crude product was separated by preparative liquid phase separation to obtain 13.2 mg of the title compound.

[0251] 1 H NMR (400MHz, DMSO-d6) δ10.83(d,J=19.4Hz,1H),8.19(s,1H).8.08(d,J=23.8Hz,1H),7.83(d,J=7.7Hz,1H),7.76(s,1H),7.70(d,J= 7.7Hz,1H),7.38(d,J=13.0Hz,4H),5.13(dd,J=13.0,5.4Hz,1H),4.60(d,J=14.2Hz,2H),4.51(s,2H),4.22-4.12(m,2H),3.61(d,J=4 .5Hz,1H),3.56(d,J=3.7Hz,1H),3.21-3.11(m,2H),3.01-2.95(m,1H),2.97-2.84(m,4H),2.84-2.78(m,1H),2.81-2.73(m,1H),2.7 7-2.68(m,2H),2.10-1.99(m,2H),1.95-1.82(m,1H),1.79-1.70(m,2H),1.70-1.54(m,3H),1.37-1.13(m,16H),0.863-0.828(m,3H).

[0252] LCMS m / z=881[M+1] +

[0253] Example 6 Preparation of 3-(4-(11-(((S)-2-(4-chlorophenyl))-3-((1R,5S)-3-(5-ethyl-7-oxo-5,6,7,8-tetrahydropteridin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-3-oxopropyl)amino)undecyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[0254] 11-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)undecanal (70 mg) and 4-{8-[(2S)-3-amino-2-(4-chlorophenyl)propionyl]-3,8-diazabicyclo[3.2.1]octan-3-yl}-5-ethyl-6,8-dihydropteridin-7-one (80.5 mg) were dissolved in 1,2-dichloroethane (2 mL) and stirred at room temperature for 30 minutes. Sodium triacetoxyborohydride (72 mg) was then added to the mixture, and the mixture was stirred at room temperature under a nitrogen atmosphere for 1 hour. After the reaction was completed, the resulting mixture was concentrated under reduced pressure. The crude product was separated by preparative liquid phase to obtain 9.1 mg of the title compound.

[0255] 1H NMR (400MHz, DMSO-d6) δ10.83(d,J=18.9Hz,1H),8.08(d,J=22.9Hz,1H),7.56(dd,J =4.9,3.7Hz,1H),7.48-7.42(m,2H),7.41-7.31(m,4H),5.13(dd,J=13.2,5.1Hz,1H) ,4.70-4.46(m,3H),4.43(s,1H),4.29(d,J=17.1Hz,1H),4.17(ddd,J=21.8,19.0,9. 8Hz,1H),3.61(d,J=4.4Hz,1H),3.56(d,J=3.6Hz,1H),3.15(p,J=10.0,9.1Hz,1H),2 .96(dd,J=11.9,5.9Hz,1H),2.93-2.86(m,1H),2.81(q,J=7.0Hz,1H),2.73-2.65(m, 1H),2.62(d,J=5.2Hz,3H),2.57(d,J=2.3Hz,3H),2.41(dd,J=13.2,9.0Hz,1H),2.33 (p,J=1.9Hz,1H),2.11-1.94(m,1H),1.90(d,J=7.1Hz,3H),1.80(m,2H),1.72-1.57( m,3H),1.29(d,J=4.8Hz,6H),1.19(d,J=19.3Hz,10H),0.88(dt,J=28.7,7.0Hz,3H).

[0256] LCMS m / z=866[M+1] +

[0257] Example 7 Preparation of 3-(5-(11-(((S)-2-(4-chlorophenyl))-3-((1R,5S)-3-(5-ethyl-7-oxo-5,6,7,8-tetrahydropteridin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-3-oxopropyl)amino)undecyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[0258] a) Preparation of 3-(5-(11-hydroxyundec-1-yn-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[0259] 3-(5-Bromo-1-oxoisoindolin-2-yl)piperidine-2,6-dione (1 g), undec-10-yn-1-ol (780 mg), cuprous iodide (120 mg), triethylamine (940 mg), and bis(triphenylphosphine)palladium chloride (250 mg) were added to N,N-dimethylformamide (10 mL). The atmosphere was purged with nitrogen and the mixture was reacted at 70°C for 3 hours. After completion of the reaction, the mixture was extracted with ethyl acetate (70 mL x 3). The combined organic phases were washed with saturated brine (200 mL x 3) and dried over anhydrous sodium sulfate. After filtering out the solid, the filtrate was concentrated under reduced pressure, and the crude product was purified by column chromatography (mobile phase: methanol / dichloromethane) to obtain 1.1 g of the title compound.

[0260] b) Preparation of 3-(5-(11-hydroxyundecyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[0261] 3-(5-(11-hydroxyundecan-1-yn-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (300 mg) and palladium / carbon (60 mg) were added to methanol (3 mL) and stirred at 50°C under a hydrogen atmosphere for 15 hours. The resulting mixture was filtered, and the filter cake was washed with methanol (10 mL x 3). The filtrate was concentrated under reduced pressure to obtain 270 mg of the title compound.

[0262] c) Preparation of 11-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)undecanal

[0263] 3-(5-(11-Hydroxyundecyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (100 mg) and (1,1,1-triacetoxy)-1,1-dihydro-1,2-benzoiodooxolan-3(1H)-one (204 mg) were added to dichloromethane (2 mL). After nitrogen substitution, the mixture was stirred at room temperature for 2 hours. After the reaction, dichloromethane (30 mL) was added, and the organic phase was washed with saturated brine (50 mL × 3) and dried over anhydrous sodium sulfate. After filtering out the solid, the filtrate was concentrated under reduced pressure, and the crude product was purified by column chromatography (mobile phase: ethyl acetate / petroleum ether) to obtain 35 mg of the title compound.

[0264] d) Preparation of 3-(5-(11-(((S)-2-(4-chlorophenyl))-3-((1R,5S)-3-(5-ethyl-7-oxo-5,6,7,8-tetrahydropteridin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-3-oxopropyl)amino)undecyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[0265] 11-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)undecanal (50 mg) and 4-{8-[(2S)-3-amino-2-(4-chlorophenyl)propionyl]-3,8-diazabicyclo[3.2.1]octan-3-yl}-5-ethyl-6,8-dihydropteridin-7-one (68 mg) were dissolved in 1,2-dichloroethane (2 mL) and stirred at room temperature for 30 minutes. Sodium triacetoxyborohydride (64 mg) was then added to the mixture, and the mixture was stirred at room temperature under a nitrogen atmosphere for 1 hour. After the reaction was completed, the resulting mixture was concentrated under reduced pressure. The crude product was separated by preparative liquid phase to obtain 2.1 mg of the title compound.

[0266] 1 H NMR (400MHz, DMSO-d6) δ11.05-10.74(m,2H),8.08(m,1H),7.62(d,J=7.7Hz,1H),7.46-7.28(m,6H),5.09(dd ,J=13.3,5.1Hz,1H),4.64-4.46(m,4H),4.41(d,J=17.2Hz,1H),4.31-4.24(m,1H),4.23-4.10(m,2H),3.58( m,2H),3.01-2.86(m,1H),2.86-2.76(m,2H),2.72-2.65(m,1H),2.62-2.57(m,3H),2.56-2.53(m,1H),2.43- 2.28(m,3H),2.12-1.86(m,1H),1.77-1.71(m,1H),1.67-1.52(m,4H),1.41-1.06(m,18H),0.80-0.96(m,3H).

[0267] LCMS m / z=866[M+1] +

[0268] Example 8 Preparation of 3-(5-(11-(((S)-2-(4-chlorophenyl))-3-((1R,5S)-3-(5-ethyl-7-oxo-5,6,7,8-tetrahydropteridin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-3-oxopropyl)amino)undecyl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione

[0269] a) Preparation of 3-(5-(11-hydroxyundec-1-yn-1-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione

[0270] 3-(5-Bromo-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (700 mg), undec-10-yn-1-ol (418 mg), cuprous iodide (79 mg), triethylamine (419 mg), and bis(triphenylphosphine)palladium chloride (145 mg) were added to N,N-dimethylformamide (7 mL). After nitrogen substitution, the mixture was reacted at 70°C for 3 hours. After completion of the reaction, the mixture was extracted with ethyl acetate (70 mL x 3). The combined organic phases were washed with saturated brine (200 mL x 3) and dried over anhydrous sodium sulfate. After filtering out the solid, the filtrate was concentrated under reduced pressure, and the crude product was purified by column chromatography (mobile phase: methanol / dichloromethane) to obtain 600 mg of the title compound.

[0271] b) Preparation of 3-(5-(11-hydroxyundecyl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione

[0272] 3-(5-(11-hydroxyundecan-1-yn-1-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (300 mg) and palladium / carbon (60 mg) were added to methanol (10 mL) and stirred at 50°C overnight under a hydrogen atmosphere. The resulting mixture was filtered, and the filter cake was washed with methanol (10 mL x 3). The filtrate was concentrated under reduced pressure to obtain 250 mg of the title compound.

[0273] c) Preparation of 11-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)undecanal

[0274] 3-(5-(11-Hydroxyundecyl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (100 mg) and (1,1,1-triacetoxy)-1,1-dihydro-1,2-benzoiodooxolan-3(1H)-one (197.5 mg) were added to dichloromethane (1 mL). After nitrogen substitution, the mixture was stirred at room temperature for 2 hours. After the reaction, dichloromethane (30 mL) was added, and the organic phase was washed with saturated brine (50 mL x 3) and dried over anhydrous sodium sulfate. After filtering out the solid, the filtrate was concentrated under reduced pressure, and the crude product was purified by column chromatography (mobile phase: ethyl acetate / petroleum ether) to obtain 60 mg of the title compound.

[0275] d) Preparation of 3-(5-(11-(((S)-2-(4-chlorophenyl))-3-((1R,5S)-3-(5-ethyl-7-oxo-5,6,7,8-tetrahydropteridin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-3-oxopropyl)amino)undecyl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione

[0276] 11-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)undecanal (50 mg) and 4-{8-[(2S)-3-amino-2-(4-chlorophenyl)propionyl]-3,8-diazabicyclo[3.2.1]octan-3-yl}-5-ethyl-6,8-dihydropteridin-7-one (82.5 mg) were dissolved in 1,2-dichloroethane (1 mL) and stirred at room temperature for 30 minutes. Sodium triacetoxyborohydride (50 mg) was then added to the mixture, and the mixture was stirred at room temperature under a nitrogen atmosphere for 1 hour. After the reaction was completed, the resulting mixture was concentrated under reduced pressure. The crude product was separated by preparative liquid phase to obtain 5.4 mg of the title compound.

[0277] 1 H NMR (400MHz, DMSO-d6) δ10.81(d,J=19.2Hz,2H),8.08(m,1H),7.39(d,J=3.1Hz,2H),7.36(s,2H),7.06-6.9 2(m,2H),6.85(d,J=8.0Hz,1H),5.33(dd,J=12.7,5.4Hz,1H),4.62-4.46(m,3H),4.27-4.01(m,2H),3.58(m ,2H),3.26-3.04(m,2H),3.00-2.84(m,2H),2.80(t,J=7.1Hz,1H),2.72(d,J=13.0Hz,2H),2.67(p,J=1.9Hz ,2H),2.61(d,J=18.6Hz,3H),2.14-1.94(m,2H),1.94-1.62(m,4H),1.57(s,3H),1.23(m,18H),0.88(m,3H).

[0278] LCMS m / z=881[M+1] +

[0279] Example 9 Preparation of 5-(11-(((S)-2-(4-chlorophenyl)-3-((1R,5S)-3-(5-ethyl-7-oxo-5,6,7,8-tetrahydropteridin-4)-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-3-oxopropyl)amino)undec-1-yn-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

[0280] a) Preparation of 11-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl)undecynal

[0281] 2-(2,6-dioxopiperidin-3-yl)-5-(11-hydroxyundecan-1-yn-1-yl)isoindoline-1,3-dione (170 mg) and (1,1,1-triacetoxy)-1,1-dihydro-1,2-benzoiodooxolan-3(1H)-one (340 mg) were added to dichloromethane (2 mL). After nitrogen substitution, the mixture was stirred at room temperature for 2 hours. After the reaction, dichloromethane (30 mL) was added, and the organic phase was washed with saturated brine (50 mL x 3) and dried over anhydrous sodium sulfate. After filtering out the solid, the filtrate was concentrated under reduced pressure, and the crude product was purified by column chromatography (mobile phase: ethyl acetate / petroleum ether) to obtain 106 mg of the title compound.

[0282] b) Preparation of 5-(11-(((S)-2-(4-chlorophenyl)-3-((1R,5S)-3-(5-ethyl-7-oxo-5,6,7,8-tetrahydropteridin-4)-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-3-oxopropyl)amino)undecan-1-yn-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

[0283] 11-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl)undecynal (106 mg) and 4-{8-[(2S)-3-amino-2-(4-chlorophenyl)propionyl]-3,8-diazabicyclo[3.2.1]octan-3-yl}-5-ethyl-6,8-dihydropteridin-7-one (118 mg) were dissolved in 1,2-dichloroethane (2 mL) and stirred at room temperature for 30 minutes. Sodium triacetoxyborohydride (160 mg) was then added to the mixture, and the mixture was stirred at room temperature under a nitrogen atmosphere for 1 hour. After the reaction was completed, the resulting mixture was concentrated under reduced pressure. The crude product was separated by preparative liquid phase to obtain 11.6 mg of the title compound.

[0284] 1H NMR (400MHz, DMSO-d6) δ11.12(s,1H),10.83(d,J=20.4Hz,1H),8.09(d,J=26.9Hz,1H),7.89(d,J=8.1Hz,1H),7.84(dd,J=5.5 ,1.6Hz,2H),7.48-7.30(m,4H),5.15(dd,J=12.8,5.4Hz,1H),4.53(m,4H),4.28-4.10(m,2H),3.61(d,J=5.2Hz,1H),3.56(d,J =4.0Hz,1H),2.92(m,4H),2.81(d,J=7.0Hz,3H),2.67(dt,J=3.7,1.9Hz,3H),2.62(s,2H),2.56(d,J=13.0Hz,3H),2.12-1.91 (m,2H),1.73(s,1H),1.56(d,J=7.7Hz,3H),1.37(s,3H),1.23(d,J=14.7Hz,8H),0.92(t,J=7.0Hz,1H),0.84(t,J=7.0Hz,1H).

[0285] LCMS m / z=876[M+1] +

[0286] Example 10 Preparation of 3-(4-(11-(((S)-2-(4-chlorophenyl))-3-((1R,5S)-3-(5-ethyl-7-oxo-5,6,7,8-tetrahydropteridin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-3-oxopropyl)amino)undecan-1-yn-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[0287] 11-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindol-4-yl)undec-10-ynal (70 mg) and 4-{8-[(2S)-3-amino-2-(4-chlorophenyl)propionyl]-3,8-diazabicyclo[3.2.1]octan-3-yl}-5-ethyl-6,8-dihydropteridin-7-one (80 mg) were dissolved in 1,2-dichloroethane (2 mL) and stirred at room temperature for 30 minutes. Sodium triacetoxyborohydride (72 mg) was then added to the mixture, and the mixture was stirred at room temperature under a nitrogen atmosphere for 1 hour. After the reaction was completed, the resulting mixture was concentrated under reduced pressure. The crude product was separated by preparative liquid phase separation to obtain 6.5 mg of the title compound.

[0288] 1H NMR (400MHz, DMSO-d6) δ10.83(d,J=19.2Hz,1H),8.09(d,J=24.7Hz,1H),7.70(d,J=7.5Hz,1H ),7.62(d,J=7.5Hz,1H),7.51(t,J=7.6Hz,1H),7.38(d,J=12.4Hz,4H),5.15(dd,J=13.4,5.1 Hz,1H),4.64-4.43(m,3H),4.42(s,1H),4.31(s,1H),4.29-4.20(m,1H),4.19-4.08(m,1H),3 .61(d,J=4.5Hz,1H),3.56(d,J=3.7Hz,1H),3.13(dt,J=20.8,10.8Hz,1H),2.93(ddd,J=22.7 ,12.5,5.7Hz,1H),2.81(q,J=7.1Hz,1H),2.73-2.63(m,1H),2.57(d,J=3.6Hz,3H),2.44(d,J =7.2Hz,2H),2.43-2.37(m,1H),2.33(p,J=1.9Hz,2H),2.17(d,J=12.5Hz,1H),2.12-1.96(m, 1H), 1.90 (d, J = 7.2Hz, 1H), 1.73 (d, J = 7.9Hz, 1H), 1.66 (d, J = 8.6Hz, 2H), 1.54 (dq, J = 14.0, 7. 0Hz,1H),1.32(s,2H),1.23(s,3H),1.19(s,3H),0.92(t,J=7.1Hz,6H),0.84(t,J=7.0Hz,3H).

[0289] LCMS m / z=862[M+1] +

[0290] Example 11 Preparation of 3-(5-(11-(((S)-2-(4-chlorophenyl))-3-((1R,5S)-3-(5-ethyl-7-oxo-5,6,7,8-tetrahydropteridin-4-yl)-3,8-diazabicyclo[3.2.1]oct-8-yl)-3-oxopropyl)amino)undecan-1-yn-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[0291] a) Preparation of 11-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)undec-10-ynal

[0292] 3-(5-(11-hydroxyundecan-1-yn-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (100 mg) and (1,1,1-triacetoxy)-1,1-dihydro-1,2-benzoiodooxolan-3(1H)-one (206 mg) were added to dichloromethane (2 mL). After nitrogen substitution, the mixture was stirred at room temperature for 2 hours. After the reaction, dichloromethane (30 mL) was added, and the organic phase was washed with saturated brine (50 mL × 3) and dried over anhydrous sodium sulfate. After filtering out the solid, the filtrate was concentrated under reduced pressure, and the crude product was purified by column chromatography (mobile phase: ethyl acetate / petroleum ether) to obtain 80 mg of the title compound.

[0293] b) Preparation of 3-(5-(11-(((S)-2-(4-chlorophenyl))-3-((1R,5S)-3-(5-ethyl-7-oxo-5,6,7,8-tetrahydropteridin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-3-oxopropyl)amino)undecan-1-yn-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[0294] 11-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)undec-10-ynal (80 mg) and 4-{8-[(2S)-3-amino-2-(4-chlorophenyl)propionyl]-3,8-diazabicyclo[3.2.1]octan-3-yl}-5-ethyl-6,8-dihydropteridin-7-one (138 mg) were dissolved in 1,2-dichloroethane (2 mL) and stirred at room temperature for 30 minutes. Sodium triacetoxyborohydride (124 mg) was then added to the mixture, and the mixture was stirred at room temperature under a nitrogen atmosphere for 1 hour. After the reaction was completed, the resulting mixture was concentrated under reduced pressure. The crude product was separated by preparative liquid phase to obtain 5.1 mg of the title compound. 1H NMR (400MHz, DMSO-d6) δ10.85(s,1H),8.09(d,J=25.7Hz,1H),7.68(d,J=7.9Hz,1H),7. 61(s,1H),7.49(d,J=8.0Hz,1H),7.42-7.33(d,J=11.1Hz,4H),5.11(dd,J=13.3,5.0Hz ,1H),4.64-4.55(m,2H),4.54-4.88(m,2H),4.44(d,J=17.5Hz,1H),4.31(d,J=17.4Hz, 1H),4.27-4.16(m,1H),4.18-4.07(m,1H),3.61(d,J=5.1Hz,1H),3.56(d,J=3.9Hz,1H), 3.20-3.03(m,1H),3.00-2.89(m,1H),2.88-2.77(m,1H),2.72-2.66(m,2H),2.64-2.58 (m,2H),2.47-2.43(m,1H),2.42-2.39(m,1H),2.38-2.31(m,1H),2.12-2.06(m,1H),2.0 4-1.95(m,1H),1.93-1.85(m,1H),1.79-1.71(m,1H),1.68-1.63(m,1H),1.60-1.49(m, 2H),1.45-1.32(m,5H),1.29-1.15(m,9H),0.92(t,J=7.0Hz,2H),0.85(t,J=6.9Hz,2H).

[0295] LCMS m / z=862[M+1] +

[0296] Example 12 Preparation of 4-(11-(((S)-2-(4-chlorophenyl)-3-((1R,5S)-3-(5-ethyl-7-oxo-5,6,7,8-tetrahydropteridin-4)-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-3-oxopropyl)amino)undecyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

[0297] a) Preparation of 2-(2,6-dioxopiperidin-3-yl)-4-(11-hydroxyundecan-1-yn-1-yl)isoindole-1,3-dione

[0298] 4-Bromo-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione (1 g), undec-10-yn-1-ol (1 g), bis(triphenylphosphine)palladium dichloride (0.21 g), and cuprous iodide (0.11 g) were added to triethylamine (5 mL) and N,N-dimethylformamide (5 mL) and reacted at 70°C for 3 hours under a nitrogen atmosphere. After completion of the reaction, water (100 mL) was added to quench the reaction, followed by extraction with ethyl acetate (50 mL x 3). The combined organic phases were washed with brine (100 mL x 2) and dried over anhydrous sodium sulfate. After filtering the solid, the filtrate was concentrated under reduced pressure. The crude product was purified by column chromatography (mobile phase: methanol / dichloromethane) to obtain 900 mg of the title compound.

[0299] b) Preparation of 2-(2,6-dioxopiperidin-3-yl)-4-(11-hydroxyundecyl)isoindole-1,3-dione

[0300] Methanol (7 mL) was added to 2-(2,6-dioxopiperidin-3-yl)-4-(11-hydroxyundecan-1-yn-1-yl)isoindole-1,3-dione (400 mg) and palladium / carbon (200 mg), and the mixture was stirred at 50°C under a hydrogen atmosphere overnight. The resulting mixture was filtered, and the filter cake was washed with methanol (10 mL x 3). The filtrate was concentrated under reduced pressure to obtain 300 mg of the title compound.

[0301] c) Preparation of 11-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoindole-4-yl]undecanal

[0302] To 2-(2,6-dioxopiperidin-3-yl)-4-(11-hydroxyundecyl)isoindole-1,3-dione (200 mg) in dichloromethane (2 mL) was added (1,1,1-triacetoxy)-1,1-dihydro-1,2-benzoiodoxolane-3(1H)-one (200 mg). The mixture was stirred at room temperature for 2 hours under a nitrogen atmosphere. After the reaction was completed, the mixture was quenched with water (100 mL), then extracted with ethyl acetate (50 mL × 3), and the combined organic layers were dried over anhydrous sodium sulfate. After filtering out the solid, the filtrate was concentrated under reduced pressure. The crude product was purified by column chromatography (mobile phase: ethyl acetate / petroleum ether = 0%-70%) to obtain 80 mg of the title compound.

[0303] d) Preparation of 4-(11-(((S)-2-(4-chlorophenyl)-3-((1R,5S)-3-(5-ethyl-7-oxo-5,6,7,8-tetrahydropteridin-4)-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-3-oxopropyl)amino)undecyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

[0304] 11-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindole-4-yl]undecanal (80 mg) and 4-{8-[(2S)-3-amino-2-(4-chlorophenyl)propionyl]-3,8-diazabicyclo[3.2.1]octan-3-yl}-5-ethyl-6,8-dihydropteridin-7-one (106 mg) were dissolved in 1,2-dichloroethane (1 mL) and stirred at room temperature for 30 minutes. Sodium triacetoxyborohydride (79.5 mg) was then added to the mixture, and the mixture was stirred at room temperature under a nitrogen atmosphere for 1 hour. After the reaction was completed, the resulting mixture was concentrated under reduced pressure. The crude product was separated by preparative liquid phase separation to obtain 25.7 mg of the title compound.

[0305] 1 H NMR (400MHz, DMSO-d6) δ10.81(d,J=17.3Hz,1H),8.28(s,1H),8.08(d,J=22.6Hz,1H),7.81-7.72(m,2H),7.69(dd,J=6.9,1.9Hz,1H),7.49-7.31(m ,4H),5.12(dd,J=12.9,5.4Hz,1H),4.67-4.43(m,4H),4.28-4.12(m,2H) ,3.61(d,J=4.3Hz,1H),3.56(d,J=3.6Hz,1H),3.17(d,J=11.5Hz,2H),3.1 4-3.06(m,2H),3.05-2.99(m,2H),2.89(dd,J=5.5,3.3Hz,1H),2.83(dd, J=14.8,6.7Hz,2H),2.75-2.66(m,2H)2.62(d,J=4.5Hz,2H),2.13-1.99(m ,2H),1.90(d,J=7.1Hz,1H),1.73(d,J=8.0Hz,2H),1.63(dd,J=29.2,8.3H z,4H),1.30(s,6H),1.19(d,J=18.2Hz,8H),0.88(dt,J=28.5,7.0Hz,3H).

[0306] LCMS m / z=880[M+1] +

[0307] Example 13 Preparation of 1-(6-(11-(((S)-2-(4-chlorophenyl))-3-((1R,5S)-3-(5-ethyl-7-oxo-5,6,7,8-tetrahydropteridin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-3-oxopropyl)amino)undecyl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

[0308] a) Preparation of 1-(6-(11-hydroxyundec-1-yn-1-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

[0309] 1-(6-Bromo-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (1 g), undec-10-yn-1-ol (1.04 g), cuprous iodide (118 mg), triethylamine (939 mg), and bis(triphenylphosphine)palladium chloride (217 mg) were added to N,N-dimethylformamide (10 mL). After nitrogen substitution, the mixture was reacted at 70°C for 3 hours. After completion of the reaction, the mixture was extracted with ethyl acetate (200 mL x 3). The combined organic phases were washed with saturated brine (200 mL x 3) and dried over anhydrous sodium sulfate. After filtering out the solid, the filtrate was concentrated under reduced pressure, and the crude product was purified by column chromatography (mobile phase: methanol / dichloromethane) to obtain 400 mg of the title compound.

[0310] b) Preparation of 1-(6-(11-hydroxyundecyl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

[0311] 1-(6-(11-hydroxyundecan-1-yn-1-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (200 mg) and palladium / carbon (15.5 mg) were added to methanol (2 mL) and stirred at 50°C overnight under a hydrogen atmosphere. The resulting mixture was filtered, and the filter cake was washed with methanol (10 mL x 3). The filtrate was concentrated under reduced pressure to obtain 150 mg of the title compound.

[0312] c) Preparation of 11-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)undecanal

[0313] 1-(6-(11-Hydroxyundecyl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (150 mg) and (1,1,1-triacetoxy)-1,1-dihydro-1,2-benzoiodooxolan-3(1H)-one (308 mg) were added to dichloromethane (2 mL). After nitrogen substitution, the mixture was stirred at room temperature for 2 hours. After the reaction, the pH was adjusted to 8 with saturated aqueous sodium bicarbonate solution and extracted with dichloromethane (20 mL × 3). The organic phase was washed with saturated brine (10 mL × 3) and dried over anhydrous sodium sulfate. After filtering out the solid, the filtrate was concentrated under reduced pressure, and the crude product was purified by column chromatography (mobile phase: ethyl acetate / petroleum ether) to obtain 90 mg of the title compound.

[0314] d) Preparation of 1-(6-(11-(((S)-2-(4-chlorophenyl))-3-((1R,5S)-3-(5-ethyl-7-oxo-5,6,7,8-tetrahydropteridin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-3-oxopropyl)amino)undecyl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

[0315] 11-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)undecanal (100 mg) and 4-{8-[(2S)-3-amino-2-(4-chlorophenyl)propionyl]-3,8-diazabicyclo[3.2.1]octan-3-yl}-5-ethyl-6,8-dihydropteridin-7-one (114 mg) were dissolved in 1,2-dichloroethane (1 mL) and stirred at room temperature for 30 minutes. Sodium triacetoxyborohydride (103 mg) was then added to the mixture, and the mixture was stirred at room temperature under a nitrogen atmosphere for 1 hour. After completion of the reaction, the resulting mixture was concentrated under reduced pressure. The crude product was separated by preparative liquid phase to obtain 20.7 mg of the title compound.

[0316] 1H NMR (400MHz, DMSO-d6) δ10.81(d,J=19.8Hz,1H),10.52(s,1H),8.31(s,2H),8.08(d,J=23.7Hz,1H),7.53(d,J=8.4Hz,1H ),7.44-7.34(m,5H),6.96(dd,J=8.5,1.3Hz,1H),4.58(q,J=9.6,8.4Hz,2H),4.51(s,2H),4.19(dd,J=19.3,16.1,10.1H z,2H),3.95(s,3H),3.91(t,J=6.7Hz,2H),3.61(d,J=4.3Hz,2H),3.56(d,J=3.7Hz,2H),3.21-3.14(m,2H),3.13-3.07(m ,1H),2.97(d,J=12.4Hz,1H),2.81(q,J=6.9Hz,1H),2.75(s,2H),2.72-2.60(m,4H),2.12-2.04(m,2H),1.64(m,4H),1.40 -1.24(m,4H),1.24 -1.19(m,9H),0.92-0.85(m,3H).

[0317] LCMS m / z=866[M+1] +

[0318] Example 14 Preparation of 4-(11-(((S)-2-(4-chlorophenyl)-3-((1R,5S)-3-(5-ethyl-7-oxo-5,6,7,8-tetrahydropteridin-4)-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-3-oxopropyl)amino)undec-1-yn-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

[0319] a) Preparation of 11-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)undec-10-ynal

[0320] 2-(2,6-dioxopiperidin-3-yl)-4-(11-hydroxyundecan-1-yn-1-yl)isoindoline-1,3-dione (100 mg) and (1,1,1-triacetoxy)-1,1-dihydro-1,2-benzoiodooxolan-3(1H)-one (210 mg) were added to dichloromethane (2 mL). After nitrogen substitution, the mixture was stirred at room temperature for 2 hours. After the reaction, dichloromethane (30 mL) was added, and the organic phase was washed with saturated brine (50 mL x 3) and dried over anhydrous sodium sulfate. After filtering out the solid, the filtrate was concentrated under reduced pressure, and the crude product was purified by column chromatography (mobile phase: ethyl acetate / petroleum ether) to obtain 40 mg of the title compound.

[0321] b) Preparation of 4-(11-(((S)-2-(4-chlorophenyl)-3-((1R,5S)-3-(5-ethyl-7-oxo-5,6,7,8-tetrahydropteridin-4)-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-3-oxopropyl)amino)undecan-1-yn-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

[0322] 11-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)undec-10-ynal (30 mg) and 4-{8-[(2S)-3-amino-2-(4-chlorophenyl)propionyl]-3,8-diazabicyclo[3.2.1]octan-3-yl}-5-ethyl-6,8-dihydropteridin-7-one (40 mg) were dissolved in 1,2-dichloroethane (0.5 mL) and stirred at room temperature for 30 minutes. Sodium triacetoxyborohydride (30 mg) was then added to the mixture, and the mixture was stirred at room temperature under a nitrogen atmosphere for 1 hour. After the reaction was completed, the resulting mixture was concentrated under reduced pressure. The crude product was separated by preparative liquid phase separation to obtain 37.1 mg of the title compound.

[0323] 1H NMR (400MHz, DMSO-d6) δ10.81(d,J=18.3Hz,1H),8.25(s,1H),8.08(d,J=25.7 Hz,1H),7.85(dt,J=6.8,3.4Hz,1H),7.83-7.76(m,2H),7.38(d,J=12.8Hz,4H ),5.13(dd,J=12.8,5.4Hz,1H),4.60(d,J=14.1Hz,2H),4.50(t,J=8.2Hz,2H) ,4.28-4.10(m,2H),3.61(d,J=4.7Hz,1H),3.56(d,J=3.8Hz,1H),3.14(dd,J= 21.1,11.0Hz,4H),2.97(d,J=12.4Hz,1H),2.94-2.87(m,1H),2.83(dd,J=15. 3,6.8Hz,2H),2.66(d,J=11.6Hz,2H),2.12-1.99(m,2H),1.96-1.85(m,1H),1 .73(d,J=7.8Hz,2H),1.69(dd,J=27.8,8.2Hz,2H),1.60-1.53(m,2H),1.49-1 .40(m,2H),1.34(s,2H),1.22(d,J=13.7Hz,8H),0.88(dt,J=28.2,7.1Hz,3H).

[0324] LCMS m / z=876[M+1] +

[0325] Example 15 Preparation of 3-(5-(11-(((S)-2-(4-chlorophenyl))-3-((1R,5S)-3-(5-ethyl-7-oxo-5,6,7,8-tetrahydropteridin-4-yl)-3,8-diazabicyclo[3.2.1]oct-8-yl)-3-oxopropyl)amino)undecan-1-yn-1-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione

[0326] a) Preparation of 11-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)undec-10-ynal

[0327] 3-(5-(11-hydroxyundecan-1-yn-1-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (100 mg) and (1,1,1-triacetoxy)-1,1-dihydro-1,2-benzoiodooxolan-3(1H)-one (199 mg) were added to dichloromethane (2 mL). After nitrogen substitution, the mixture was stirred at room temperature for 2 hours. After the reaction, dichloromethane (30 mL) was added, and the organic phase was washed with saturated brine (50 mL × 3) and dried over anhydrous sodium sulfate. After filtering out the solid, the filtrate was concentrated under reduced pressure, and the crude product was purified by column chromatography (mobile phase: ethyl acetate / petroleum ether) to obtain 50 mg of the title compound.

[0328] b) Preparation of 3-(5-(11-(((S)-2-(4-chlorophenyl))-3-((1R,5S)-3-(5-ethyl-7-oxo-5,6,7,8-tetrahydropteridin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-3-oxopropyl)amino)undecan-1-yn-1-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione

[0329] 11-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)undec-10-ynal (50 mg) and 4-{8-[(2S)-3-amino-2-(4-chlorophenyl)propionyl]-3,8-diazabicyclo[3.2.1]octan-3-yl}-5-ethyl-6,8-dihydropteridin-7-one (83 mg) were dissolved in 1,2-dichloroethane (1 mL) and stirred at room temperature for 30 minutes. Sodium triacetoxyborohydride (50 mg) was then added to the mixture, and the mixture was stirred at room temperature under a nitrogen atmosphere for 1 hour. After the reaction was completed, the resulting mixture was concentrated under reduced pressure. The crude product was separated by preparative liquid phase separation to obtain 6.2 mg of the title compound.

[0330] 1H NMR (400MHz, DMSO-d6) δ10.82(d,J=21.1Hz,2H),8.11-8.05(m,1H),7.45-7.28(m,4H),7.22(d,J=1.2Hz,1H),7.14-6.97(m,2H),5 .37(dd,J=12.8,5.3Hz,1H),4.71-4.00(m,5H),3.61(d,J=5.1Hz,1H),3.56(d,J=4.0Hz,1H),3.25(s,3H),3.16(t,J=11.5Hz,1H),3 .09(d,J=8.3Hz,1H),3.00-2.87(m,1H),2.81(q,J=7.6,7.0Hz,2H),2.73-2.57(m,5H),2.39(q,J=7.3Hz,2H),2.13-1.97(m,2H),1 .73(d,J=8.0Hz,1H),1.65(t,J=8.8Hz,1H),1.52(dp,J=13.9,6.9Hz,2H),1.34(s,4H),1.22(d,J=16.4Hz,10H),0.93-0.83(m,3H).

[0331] LCMS m / z=877[M+1] +

[0332] Example 16 Preparation of 1-(6-(11-(((S)-2-(4-chlorophenyl))-3-((1R,5S)-3-(5-ethyl-7-oxo-5,6,7,8-tetrahydropteridin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-3-oxopropyl)amino)undecan-1-yn-1-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

[0333] a) Preparation of 11-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)undec-10-ynal

[0334] 1-(6-(11-hydroxyundecan-1-yn-1-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (200 mg) and (1,1,1-triacetoxy)-1,1-dihydro-1,2-benzoiodooxolan-3(1H)-one (413 mg) were added to dichloromethane (2 mL). After nitrogen substitution, the mixture was stirred at room temperature for 2 hours. After the reaction, dichloromethane (30 mL) was added, and the organic phase was washed with saturated brine (50 mL × 3) and dried over anhydrous sodium sulfate. After filtering out the solid, the filtrate was concentrated under reduced pressure, and the crude product was purified by column chromatography (mobile phase: ethyl acetate / petroleum ether) to obtain 40 mg of the title compound.

[0335] b) Preparation of 1-(6-(11-(((S)-2-(4-chlorophenyl))-3-((1R,5S)-3-(5-ethyl-7-oxo-5,6,7,8-tetrahydropteridin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-3-oxopropyl)amino)undecan-1-yn-1-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

[0336] 11-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)undec-10-ynal (40 mg) and 4-{8-[(2S)-3-amino-2-(4-chlorophenyl)propionyl]-3,8-diazabicyclo[3.2.1]octan-3-yl}-5-ethyl-6,8-dihydropteridin-7-one (46 mg) were dissolved in 1,2-dichloroethane (1 mL) and stirred at room temperature for 30 minutes. Sodium triacetoxyborohydride (41.5 mg) was then added to the mixture, and stirred at room temperature under a nitrogen atmosphere for 1 hour. After completion of the reaction, the resulting mixture was concentrated under reduced pressure. The crude product was separated by preparative liquid phase to obtain 9 mg of the title compound.

[0337] 1H NMR(400MHz,DMSO-d6)δ10.83(d,J=21.5Hz,1H),10.57(s,1H),8.21(s,1H ),8.09(d,J=27.5Hz,1H),7.69(s,1H),7.60(d,J=8.5Hz,1H),7.42-7.34(m ,4H),7.06(dd,J=8.5,1.3Hz,1H),4.58(s,2H),4.50(s,2H),4.19(m,1H), 3.97(s,3H),3.92(t,J=6.6Hz,2H),3.61(d,J=5.1Hz,1H),3.55(d,J=4.1Hz ,1H),3.32(s,3H),3.16(t,J=10.6Hz,1H),2.97(d,J=12.5Hz,1H),2.81(d ,J=7.0Hz,2H),2.75(t,J=6.6Hz,3H),2.67(dt,J=3.7,1.9Hz,3H),2.33(p, J=1.8Hz,1H),2.11-2.01(m,1H),1.72(s,1H),1.66(d,J=8.1Hz,1H),1.54 (dd,J=14.0,7.3Hz,2H),1.34(s,4H),1.23(d,J=15.6Hz,7H),0.88(m,3H).

[0338] LCMS m / z=862[M+1] +

[0339] Example 17 Preparation of 3-(6-(11-(((S)-2-(4-chlorophenyl))-3-((1R,5S)-3-(5-ethyl-7-oxo-5,6,7,8-tetrahydropteridin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-3-oxopropyl)amino)undecyl)-1-oxophthalazin-2(1H)-yl)piperidine-2,6-dione

[0340] a) Preparation of 3-(6-bromo-1-oxophthalazin-2(1H)-yl)piperidine-2,6-dione

[0341] 6-Bromo-2H-phthalazin-1-one (1 g), 3-bromopiperidine-2,6-dione (1.02 g), cesium carbonate (2.9 g), and tetrahydrofuran (20 mL) were added to a reaction flask, and the mixture was stirred at 100°C under a nitrogen atmosphere for 15 hours. After the reaction was completed, the solid was filtered off, and the filter cake was washed with ethyl acetate (80 mL x 3). The organic phases were combined and dried over anhydrous sodium sulfate. After filtering out the solid, the filtrate was concentrated under reduced pressure, and the crude product was separated using a reverse-phase column (column: C18, mobile phase: acetonitrile / water (0.1% NH3.H2O)) to obtain 750 mg of the title compound.

[0342] b) Preparation of 3-(6-(11-hydroxyundec-1-yn-1-yl)-1-oxophthalazin-2(1H)-yl)piperidine-2,6-dione

[0343] 3-(6-Bromo-1-oxophthalazin-2(1H)-yl)piperidine-2,6-dione (750 mg), undec-10-yn-1-ol (563 mg), cuprous iodide (85 mg), triethylamine (677 mg), and bis(triphenylphosphine)palladium chloride (157 mg) were added to N,N-dimethylformamide (10 mL). After nitrogen substitution, the mixture was reacted at 70°C for 3 hours. After completion of the reaction, the mixture was extracted with ethyl acetate (70 mL x 3). The combined organic phases were washed with saturated brine (70 mL x 3) and dried over anhydrous sodium sulfate. After filtering out the solid, the filtrate was concentrated under reduced pressure, and the crude product was purified by column chromatography (mobile phase: methanol / dichloromethane = 0%-10%) to yield 360 mg of the title compound.

[0344] c) Preparation of 3-(6-(11-hydroxyundecyl)-1-oxophthalazin-2(1H)-yl)piperidine-2,6-dione

[0345] 3-(6-(11-hydroxyundec-1-yn-1-yl)-1-oxophthalazin-2(1H)-yl)piperidine-2,6-dione (150 mg) and palladium / carbon (45 mg) were added to methanol (5 mL) and stirred at 50°C under a hydrogen atmosphere for 15 hours. The resulting mixture was filtered, and the filter cake was washed with methanol (10 mL x 3). The filtrate was concentrated under reduced pressure to obtain 90 mg of the title compound.

[0346] d) Preparation of 11-(2-(2,6-dioxopiperidin-3-yl)-1-oxo-1,2-dihydrophthalazin-6-yl)undecanal

[0347] 3-(6-(11-Hydroxyundecyl)-1-oxophthalazin-2(1H)-yl)piperidine-2,6-dione (90 mg) and (1,1,1-triacetoxy)-1,1-dihydro-1,2-benzoiodooxolan-3(1H)-one (178.5 mg) were added to dichloromethane (2 mL). After nitrogen substitution, the mixture was stirred at room temperature for 2 hours. After the reaction, the pH was adjusted to 8 with saturated aqueous sodium bicarbonate solution, and the mixture was extracted with dichloromethane (20 mL × 3). The organic phase was washed with saturated brine (10 mL × 3) and dried over anhydrous sodium sulfate. After filtering out the solid, the filtrate was concentrated under reduced pressure, and the crude product was purified by column chromatography (mobile phase: ethyl acetate / petroleum ether) to obtain 80 mg of the title compound.

[0348] e) Preparation of 3-(6-(11-(((S)-2-(4-chlorophenyl))-3-((1R,5S)-3-(5-ethyl-7-oxo-5,6,7,8-tetrahydropteridin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-3-oxopropyl)amino)undecyl)-1-oxophthalazin-2(1H)-yl)piperidine-2,6-dione

[0349] 11-(2-(2,6-dioxopiperidin-3-yl)-1-oxo-1,2-dihydrophthalazin-6-yl)undecanal (80 mg) and 4-{8-[(2S)-3-amino-2-(4-chlorophenyl)propionyl]-3,8-diazabicyclo[3.2.1]octan-3-yl}-5-ethyl-6,8-dihydropteridin-7-one (132.5 mg) were dissolved in 1,2-dichloroethane (2 mL) and stirred at room temperature for 30 minutes. Sodium triacetoxyborohydride (119.5 mg) was then added to the mixture, and the mixture was stirred at room temperature under a nitrogen atmosphere for 1 hour. After completion of the reaction, the resulting mixture was concentrated under reduced pressure. The crude product was separated by preparative liquid phase separation to obtain 26.5 mg of the title compound.

[0350] 1H NMR (400MHz, DMSO-d6) δ11.03(s,1H),10.83(m,1H),8.42(s,1H),8.25(s,1H),8.18(d,J=8.1Hz,1H),8.08(m,1H),7 .77(s,1H),7.76-7.71(m,1H),7.43-7.38(m,2H),7.36(m,2H),5.80(dd,J=12.4,5.4Hz,1H),4.64-4.54(m,2H),4.54 -4.43(m,1H),4.32-4.02(m,2H),3.58(m,2H),3.21-3.06(m,2H),3.00-2.87(m,2H),2.84-2.74(m,3H),2.73-2.62( m,3H),2.62-2.54(m,2H),2.19-2.04(m,1H),1.96-1.85(m,1H),1.80-1.53(m,4H),1.41-1.09(m,18H),0.88(m,3H).

[0351] LCMS m / z=879[M+1]+

[0352] Example 18 Preparation of 3-(6-(11-(((S)-2-(4-chlorophenyl))-3-((1R,5S)-3-(5-ethyl-7-oxo-5,6,7,8-tetrahydropteridin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-3-oxopropyl)amino)undecan-1-yn-1-yl)-1-oxophthalazin-2(1H)-yl)piperidine-2,6-dione

[0353] a) Preparation of 11-(2-(2,6-dioxopiperidin-3-yl)-1-oxo-1,2-dihydrophthalazin-6-yl)undec-10-ynal

[0354] 3-(6-(11-hydroxyundecan-1-yn-1-yl)-1-oxophthalazin-2(1H)-yl)piperidine-2,6-dione (100 mg) and (1,1,1-triacetoxy)-1,1-dihydro-1,2-benzoiodooxolan-3(1H)-one (200 mg) were added to dichloromethane (2 mL). After nitrogen displacement, the mixture was stirred at room temperature for 2 hours. After the reaction, the pH was adjusted to 8 with saturated aqueous sodium bicarbonate solution, and the mixture was extracted with dichloromethane (30 mL × 3). The organic phase was washed with saturated brine (15 mL × 3) and dried over anhydrous sodium sulfate. After filtering out the solid, the filtrate was concentrated under reduced pressure, and the crude product was purified by column chromatography (mobile phase: ethyl acetate / petroleum ether) to obtain 85 mg of the title compound.

[0355] b) Preparation of 3-(6-(11-(((S)-2-(4-chlorophenyl))-3-((1R,5S)-3-(5-ethyl-7-oxo-5,6,7,8-tetrahydropteridin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-3-oxopropyl)amino)undecan-1-yn-1-yl)-1-oxophthalazin-2(1H)-yl)piperidine-2,6-dione

[0356] 11-(2-(2,6-dioxopiperidin-3-yl)-1-oxo-1,2-dihydrophthalazin-6-yl)undec-10-ynal (80 mg) and 4-{8-[(2S)-3-amino-2-(4-chlorophenyl)propionyl]-3,8-diazabicyclo[3.2.1]octan-3-yl}-5-ethyl-6,8-dihydropteridin-7-one (132.5 mg) were dissolved in 1,2-dichloroethane (2 mL) and stirred at room temperature for 30 minutes. Sodium triacetoxyborohydride (119.5 mg) was then added to the mixture, and the mixture was stirred at room temperature under a nitrogen atmosphere for 1 hour. After the reaction was completed, the resulting mixture was concentrated under reduced pressure. The crude product was separated by preparative liquid phase separation to obtain 10.1 mg of the title compound.

[0357] 1 H NMR (400MHz, DMSO-d6) δ11.06(s,1H),10.83(d,J=21.6Hz,1H),8.44(s,1H),8.21(d,J=8.3Hz,1H),8.09(m,1H),8 .00(s,1H),7.82(d,J=8.4Hz,1H),7.38(d,J=12.8Hz,4H),5.80(dd,J=12.7,5.3Hz,1H),4.71-4.39(m,4H),4.30- 4.09(m,2H),3.58(dd,J=22.2,4.6Hz,2H),3.22-3.07(m,3H),3.02-2.87(m,2H),2.81(d,J=7.3Hz,1H),2.67(t,J =9.2Hz,2H),2.20-2.01(m,2H),1.90(s,1H),1.80-1.50(m,6H),1.49-1.10(m,14H),0.88(dt,J=29.3,7.1Hz,3H).

[0358] LCMS m / z=875[M+1] +

[0359] Example 19 Preparation of 4-((1R,5S)-8-((S)-2-(4-chlorophenyl)-3-((11-(4-(6-oxo-1,6-dihydropyridazin-3-yl))-2-(trifluoromethyl)phenyl)undecyl)amino)propanoyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-5-ethyl-5,8-dihydropteridin-7(6H)-one

[0360] a) Preparation of methyl 4-(4-bromo-3-(trifluoromethyl)phenyl)-4-oxobutanoate

[0361] To a solution of sodium cyanide (60 mg) in N,N-dimethylformamide (30 mL) was added 4-bromo-3-(trifluoromethyl)benzaldehyde (3 g), and the mixture was stirred at 35°C under a nitrogen atmosphere for 30 minutes. Methyl acrylate (1.22 g) was then added portionwise. The resulting mixture was used directly in the next step without further purification.

[0362] b) Preparation of 6-(4-bromo-3-(trifluoromethyl)phenyl)-4,5-dihydropyridazin-3(2H)-one

[0363] To the mixture obtained in the previous step, add hydrazine hydrate (1.48 g, 98%) and stir at 60°C under a nitrogen atmosphere for 8 hours. After the reaction is completed, quench with sodium hypochlorite at room temperature. Filter out the solids, and add ethyl acetate (300 mL) to the organic phase. The combined organic layers are washed with brine (100 mL x 3) and dried over anhydrous sodium sulfate. After filtering out the solids, the filtrate is concentrated under reduced pressure, and the crude product is purified by column chromatography (mobile phase: ethyl acetate / petroleum ether) to obtain 1.4 g of the title compound.

[0364] c) Preparation of 6-(4-bromo-3-(trifluoromethyl)phenyl)pyridazin-3(2H)-one

[0365] 6-(4-Bromo-3-(trifluoromethyl)phenyl)-4,5-dihydropyridazin-3(2H)-one (1.4 g), cupric chloride (1.17 g), and acetonitrile (14 mL) were added to a reaction flask and stirred at 80°C for 1 hour. After the reaction, the precipitated solid was collected by filtration, and the filter cake was washed with acetonitrile (30 mL x 3) and dried to obtain 500 mg of the desired product.

[0366] d) Preparation of 6-(4-(11-hydroxyundec-1-yn-1-yl)-3-(trifluoromethyl)phenyl)pyridazin-3(2H)-one

[0367] 6-(4-bromo-3-(trifluoromethyl)phenyl)pyridazin-3(2H)-one (500 mg), undec-10-yn-1-ol (527 mg), cuprous iodide (60 mg), triethylamine (476 mg), and bis(triphenylphosphine)palladium chloride (110 mg) were added to N,N-dimethylformamide (5 mL). After nitrogen substitution, the mixture was reacted at 70°C for 3 hours. After completion of the reaction, the mixture was extracted with ethyl acetate (70 mL x 3). The combined organic phases were washed with saturated brine (70 mL x 3) and dried over anhydrous sodium sulfate. After filtering out the solid, the filtrate was concentrated under reduced pressure, and the crude product was purified by column chromatography (mobile phase: methanol / dichloromethane) to obtain 570 mg of the title compound.

[0368] e) Preparation of 6-(4-(11-hydroxyundecyl)-3-(trifluoromethyl)phenyl)pyridazin-3(2H)-one

[0369] 6-(4-(11-hydroxyundec-1-yn-1-yl)-3-(trifluoromethyl)phenyl)pyridazin-3(2H)-one (100 mg) and palladium / carbon (60 mg) were added to methanol (5 mL) and stirred at 50°C overnight under a hydrogen atmosphere. The resulting mixture was filtered, and the filter cake was washed with methanol (10 mL x 3). The filtrate was concentrated under reduced pressure to obtain 50 mg of the title compound.

[0370] f) Preparation of 11-(4-(6-oxo-1,6-dihydropyridazin-3-yl)-2-(trifluoromethyl)phenyl)undecanal

[0371] 6-(4-(11-hydroxyundecyl)-3-(trifluoromethyl)phenyl)pyridazin-3(2H)-one (50 mg) and (1,1,1-triacetoxy)-1,1-dihydro-1,2-benzoiodooxolan-3(1H)-one (103 mg) were added to dichloromethane (1 mL). After nitrogen displacement, the mixture was stirred at room temperature for 2 hours. After the reaction, the pH was adjusted to 8 with saturated aqueous sodium bicarbonate solution, and the mixture was extracted with dichloromethane (20 mL × 3). The organic phase was washed with saturated brine (10 mL × 3) and dried over anhydrous sodium sulfate. After filtering out the solid, the filtrate was concentrated under reduced pressure, and the crude product was purified by column chromatography (mobile phase: ethyl acetate / petroleum ether) to obtain 20 mg of the title compound.

[0372] g) Preparation of 4-((1R,5S)-8-((S)-2-(4-chlorophenyl)-3-((11-(4-(6-oxo-1,6-dihydropyridazin-3-yl))-2-(trifluoromethyl)phenyl)undecyl)amino)propanoyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-5-ethyl-5,8-dihydropteridin-7(6H)-one

[0373] 11-(4-(6-oxo-1,6-dihydropyridazin-3-yl)-2-(trifluoromethyl)phenyl)undecanal (20 mg) and 4-{8-[(2S)-3-amino-2-(4-chlorophenyl)propionyl]-3,8-diazabicyclo[3.2.1]octan-3-yl}-5-ethyl-6,8-dihydropteridin-7-one (23 mg) were dissolved in 1,2-dichloroethane (1 mL) and stirred at room temperature for 30 minutes. Sodium triacetoxyborohydride (21 mg) was then added to the mixture, and stirred at room temperature under a nitrogen atmosphere for 1 hour. After the reaction was completed, the resulting mixture was concentrated under reduced pressure. The crude product was separated by preparative liquid phase to obtain 4.2 mg of the title compound.

[0374] 1 H NMR (400MHz, DMSO-d6) δ10.84(d,J=18.5Hz,1H),8.17-8.03(m,4H),7.60(d,J=8.0Hz,1H),7.38(d,J=12.8Hz,4H),7.02( d,J=9.9Hz,1H),4.59(s,2H),4.51(s,2H),4.21(s,1H),4.15(s,1H).3.61(d,J=4.5Hz,2H),3.56(d,J=3.7Hz,2H),3.17(d ,J=12.4Hz,2H),2.97(d,J=12.5Hz,1H),2.81(d,J=7.2Hz,1H),2.76(s,2H),2.67(dt,J=3.8,1.8Hz,1H),2.33(q,J=1.8Hz ,1H),2.06(d,J=12.5Hz,1H),1.91(s,1H),1.82-1.63(m,2H),1.58(s,2H),1.33(s,4H),1.25-1.14(m,12H),0.89(m,3H).

[0375] LCMS m / z=862[M+1] +

[0376] Example 20 Preparation of 4-((1R,5S)-8-((S)-2-(4-chlorophenyl)-3-((11-(4-(6-oxo-1,6-dihydropyridazin-3-yl))-2-(trifluoromethyl)phenyl)undec-10-yn-1-yl)amino)propanoyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-5-ethyl-5,8-dihydropteridin-7(6H)-one

[0377] a) Preparation of 11-(4-(6-oxo-1,6-dihydropyridazin-3-yl)-2-(trifluoromethyl)phenyl)undec-10-ynal

[0378] 6-(4-(11-hydroxyundecan-1-yn-1-yl)-3-(trifluoromethyl)phenyl)pyridazin-3(2H)-one (100 mg) and (1,1,1-triacetoxy)-1,1-dihydro-1,2-benzoiodooxolan-3(1H)-one (209 mg) were added to dichloromethane (1 mL). After nitrogen substitution, the mixture was stirred at room temperature for 2 hours. After the reaction, the pH was adjusted to 8 with saturated aqueous sodium bicarbonate solution, and the mixture was extracted with dichloromethane (20 mL × 3). The organic phase was washed with saturated brine (10 mL × 3) and dried over anhydrous sodium sulfate. After filtering out the solid, the filtrate was concentrated under reduced pressure, and the crude product was purified by column chromatography (mobile phase: ethyl acetate / petroleum ether) to obtain 40 mg of the title compound.

[0379] b) Preparation of 4-((1R,5S)-8-((S)-2-(4-chlorophenyl)-3-((11-(4-(6-oxo-1,6-dihydropyridazin-3-yl))-2-(trifluoromethyl)phenyl)undecan-10-yn-1-yl)amino)propanoyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-5-ethyl-5,8-dihydropteridin-7(6H)-one

[0380] 11-(4-(6-oxo-1,6-dihydropyridazin-3-yl)-2-(trifluoromethyl)phenyl)undec-10-ynal (38 mg) and 4-{8-[(2S)-3-amino-2-(4-chlorophenyl)propionyl]-3,8-diazabicyclo[3.2.1]octan-3-yl}-5-ethyl-6,8-dihydropteridin-7-one (45 mg) were dissolved in 1,2-dichloroethane (1 mL) and stirred at room temperature for 30 minutes. Sodium triacetoxyborohydride (40 mg) was then added to the mixture, and the mixture was stirred at room temperature under a nitrogen atmosphere for 1 hour. After the reaction was completed, the resulting mixture was concentrated under reduced pressure. The crude product was separated by preparative liquid phase separation to yield 15.8 mg of the title compound.

[0381] 1H NMR (400MHz, DMSO-d6) δ13.71-13.03(s,1H)10.82(d,J=18.3Hz,1H),8.16(d,J=10.3Hz,2H),8.08(m,2H),7.72(d, J=8.1Hz,1H),7.42-7.34(m,4H),7.02(d,J=9.9Hz,1H),4.58(s,2H),4.50(t,J=10.6Hz,2H),4.12(m,1H),3.58(m,2 H),3.23-3.01(m,1H),2.96(d,J=12.4Hz,1H),2.81(d,J=7.1Hz,1H),2.67(t,J=2.0Hz,1H),2.37-2.25(m,2H),2.08 (d,J=12.6Hz,1H),1.95-1.86(m,1H),1.77-1.63(m,3H),1.59-1.49(m,3H),1.36(m,5H),1.22(m,9H),0.88(m,3H).

[0382] LCMS m / z=858[M+1] +

[0383] Example 21 3-(4-(11-(((S)-2-(4-chlorophenyl))-3-((1R,5S)-3-(5-ethyl-7-oxo-5,6,7,8-tetrahydropteridin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-3-oxopropyl)(methyl)amino)undecyl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione

[0384] a) Preparation of (S)-3-((tert-butoxycarbonyl)(methyl)amino)-2-(4-chlorophenyl)propionic acid

[0385] A solution of (2S)-3-[(tert-butoxycarbonyl)amino]-2-(4-chlorophenyl)propanoic acid (500 mg) in tetrahydrofuran (5 mL) was cooled to 0°C, and then sodium hydride (100 mg) was added in batches under nitrogen protection over 30 minutes. Maintaining 0°C and a nitrogen atmosphere, iodomethane (710 mg) was added in batches. Stirring was then continued at room temperature for 3 hours. After the reaction was completed, the temperature was lowered to 0°C and the reaction was quenched with water. The resulting mixture was extracted with ethyl acetate (50 mL × 3), and the combined organic layers were washed with saturated brine (10 mL) and dried over anhydrous sodium sulfate. After filtering out the solid, the filtrate was concentrated under reduced pressure, and the crude product was purified by column chromatography (mobile phase: ethyl acetate / petroleum ether) to obtain 400 mg of the title compound.

[0386] b) Preparation of tert-butyl ((S)-2-(4-chlorophenyl)-3-((1R,5S)-3-(5-ethyl-7-oxo-5,6,7,8-tetrahydropteridin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-3-oxopropyl)(methyl)carbamate

[0387] 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-5-ethyl-5,8-dihydropteridin-7(6H)-one hydrochloride (200 mg), (S)-3-((tert-butoxycarbonyl)(methyl)amino)-2-(4-chlorophenyl)propanoic acid (232 mg), O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (468 mg), N,N-diisopropylethylamine (796 mg), and N,N-dimethylformamide (2 mL) were added to a reaction flask, and the mixture was stirred at room temperature under a nitrogen atmosphere for 3 hours. After the reaction, ethyl acetate (30 mL) was added, and the organic layer was washed with brine (10 mL x 3) and dried over anhydrous sodium sulfate. After filtering off the solid, the filtrate was concentrated under reduced pressure and the crude product was purified by column chromatography (mobile phase: ethyl acetate / petroleum ether) to obtain 100 mg of the title compound.

[0388] c) Preparation of 4-((1R,5S)-8-((S)-2-(4-chlorophenyl)-3-(methylamino)propionyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-5-ethyl-5,8-dihydropteridin-7(6H)-one

[0389] Tert-butyl ((S)-2-(4-chlorophenyl)-3-((1R,5S)-3-(5-ethyl-7-oxo-5,6,7,8-tetrahydropteridin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-3-oxopropyl)(methyl)carbamate (100 mg) was added to a 1,4-dioxane hydrochloric acid solution (4 M, 5 mL). The reaction mixture was stirred at room temperature for 2 hours. After completion of the reaction, the resulting mixture was concentrated under reduced pressure to obtain 80 mg of the title compound.

[0390] d) Preparation of 3-(4-(11-(((S)-2-(4-chlorophenyl))-3-((1R,5S)-3-(5-ethyl-7-oxo-5,6,7,8-tetrahydropteridin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-3-oxopropyl)(methyl)amino)undecyl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione

[0391] 11-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)undecanal (50 mg) and 4-((1R,5S)-8-((S)-2-(4-chlorophenyl)-3-(methylamino)propanoyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-5-ethyl-5,8-dihydropteridin-7(6H)-one (45 mg) were dissolved in 1,2-dichloroethane (2 mL) and stirred at room temperature for 30 minutes. Sodium triacetoxyborohydride (39.5 mg) was then added to the mixture, and the mixture was stirred at room temperature under a nitrogen atmosphere for 1 hour. After the reaction was completed, the resulting mixture was concentrated under reduced pressure. The crude product was separated by preparative liquid phase to obtain 29.5 mg of the title compound.

[0392] 1 H NMR (400MHz, DMSO-d6) δ11.08(s,1H),10.82(d,J=18.6Hz,1H),8.08(d,J= 21.7Hz,1H),7.52-7.20(m,4H),6.95(d,J=4.8Hz,2H),6.88-6.79(m,1H),5 .36(dd,J=12.5,5.4Hz,1H),4.70(d,J=9.1Hz,1H),4.52(dd,J=39.0,15.5H z,3H),4.30(d,J=12.6Hz,1H),4.18(dd,J=15.8,9.9Hz,2H),3.64-3.50(m, 3H),3.12(m,3H),2.95(d,J=12.0Hz,2H),2.86-2.79(m,1H),2.71(dd,J=1 2.6,8.1Hz,2H),2.62(d,J=18.3Hz,2H),2.42(s,1H),2.35(s,1H),2.26(d, J=13.9Hz,2H),2.17(d,J=12.9Hz,3H),2.04-1.90(m,2H),1.72(q,J=11.2, 10.2Hz,2H),1.58(d,J=8.1Hz,2H),1.31(m,8H),1.15(m,8H),0.89(m,3H).

[0393] LCMS m / z=895[M+1] +

[0394] Example 22 Preparation of 3-(4-(11-(((S)-2-(4-chlorophenyl)-3-((R)-3-methyl-4-((R)-5-methyl-7-oxo-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-4-yl)piperazin-1-yl)-3-oxopropyl)amino)undecyl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione

[0395] a) Preparation of tert-butyl (R)-3-methyl-4-((R)-5-methyl-7-oxo-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-4-yl)piperazine-1-carboxylate

[0396] (R)-4-chloro-5-methyl-5,8-dihydropyrido[2,3-d]pyrimidin-7(6H)-one (1 g), (R)-tert-butyl 3-methylpiperazine-1-carboxylate (10 g), N,N-diisopropylethylamine (6.5 g), and acetonitrile (30 mL) were added to a reaction flask, and the mixture was stirred at 100°C under a nitrogen atmosphere for 48 hours. The resulting mixture was concentrated under reduced pressure, and the crude product was purified by column chromatography (mobile phase: ethyl acetate / petroleum ether) to obtain 1.1 g of the title compound.

[0397] b) Preparation of (R)-5-methyl-4-((R)-2-methylpiperazin-1-yl)-5,8-dihydropyrido[2,3-d]pyrimidin-7(6H)-one

[0398] Tert-butyl (R)-3-methyl-4-((R)-5-methyl-7-oxo-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-4-yl)piperazine-1-carboxylate (200 mg) was added to a 1,4-dioxane hydrochloride solution (4 M, 5 mL). The reaction mixture was stirred at room temperature for 1 hour. After the reaction, the resulting mixture was concentrated under reduced pressure to obtain 120 mg of the title compound.

[0399] c) Preparation of tert-butyl ((S)-2-(4-chlorophenyl)-3-((R)-3-methyl-4-((R)-5-methyl-7-oxo-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-4-yl)piperazin-1-yl)-3-oxopropyl)carbamate

[0400] (S)-3-((tert-Butoxycarbonyl)amino)-2-(4-chlorophenyl)propanoic acid (138 mg), O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (58 mg), N,N-diisopropylethylamine (20 mg), and N,N-dimethylformamide (2 mL) were added to a reaction flask. The mixture was stirred at room temperature under a nitrogen atmosphere for 10 minutes. Then, (R)-5-methyl-4-((R)-2-methylpiperazin-1-yl)-5,8-dihydropyrido[2,3-d]pyrimidin-7(6H)-one (100 mg) was added, and stirring was continued at room temperature for 3 hours. After completion of the reaction, ethyl acetate (30 mL) was added, and the organic layer was washed with brine (10 mL x 3) and dried over anhydrous sodium sulfate. After filtering off the solid, the filtrate was concentrated under reduced pressure and the crude product was purified by column chromatography (mobile phase: ethyl acetate / petroleum ether) to obtain 120 mg of the title compound.

[0401] d) Preparation of (R)-4-((R)-4-((S)-3-amino-2-(4-chlorophenyl)propionyl)-2-methylpiperazin-1-yl)-5-methyl-5,8-dihydropyridinyl[2,3-d]pyrimidin-7(6H)-one

[0402] (R)-4-((R)-4-((S)-3-amino-2-(4-chlorophenyl)propanoyl)-2-methylpiperazin-1-yl)-5-methyl-5,8-dihydropyridinyl[2,3-d]pyrimidin-7(6H)-one (120 mg) was added to a 1,4-dioxane hydrochloride solution (4 M, 5 mL). The reaction mixture was stirred at room temperature for 2 hours. After completion of the reaction, the resulting mixture was concentrated under reduced pressure to obtain 80 mg of the title compound.

[0403] e) Preparation of 3-(4-(11-(((S)-2-(4-chlorophenyl)-3-((R)-3-methyl-4-((R)-5-methyl-7-oxo-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-4-yl)piperazin-1-yl)-3-oxopropyl)amino)undecyl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione

[0404] 11-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)undecanal (50 mg) and (R)-4-((R)-4-((S)-3-amino-2-(4-chlorophenyl)propanoyl)-2-methylpiperazin-1-yl)-5-methyl-5,8-dihydropyridinyl[2,3-d]pyrimidin-7(6H)-one (39 mg) were dissolved in 1,2-dichloroethane (2 mL) and stirred at room temperature for 30 minutes. Sodium triacetoxyborohydride (72 mg) was then added to the mixture, and the mixture was stirred at room temperature for 1 hour under a nitrogen atmosphere. After the reaction was completed, the resulting mixture was concentrated under reduced pressure. The crude product was separated by preparative liquid phase to obtain 5.7 mg of the title compound.

[0405] 1 H NMR (400MHz, DMSO-d6) δ11.07 (s, 1H), 10.66 (d, J = 7.3Hz, 1H), 8.41-8.23 (m, 1H), 7.48-7.23 (m, 4H), 7.04-6.89 (m, 2H), 6 .88-6.82(m,1H),5.35(dd,J=12.5,5.4Hz,1H),4.31-4.14(m,1H),3.94-3.64(m,2H),3.54(s,3H),3.49-3.39(m,1H),3. 23-3.15(m,2H),3.13-3.06(m,2H),2.94-2.83(m,4H),2.81-2.68(m,1H),2.68-2.58(m,4H),2.36-2.21(m,1H),2.05-1. 94(m,1H),1.66-1.49(m,2H),1.42-1.15(m,18H),1.07-0.93(m,4H),0.85(t,J=6.7Hz,1H),0.71(dd,J=63.4,6.3Hz,2H).

[0406] LCMS m / z=854[M+1] +

[0407] Example 23 Preparation of 3-(4-(11-(((S)-2-(4-chlorophenyl))-3-((1R,5S)-3-(5-ethyl-7-oxo-5,6,7,8-tetrahydropteridin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-3-oxopropyl)amino)dodecyl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione

[0408] a) Preparation of 2-(dec-9-yn-1-yl)-2-methyl-1,3-dioxolane

[0409] A solution of dodec-11-yn-2-one (1.2 g) and ethylene glycol (825 mg) in toluene (10 mL) was stirred at 110°C for 12 h. After completion of the reaction, the reaction was quenched with water (200 mL) and extracted with ethyl acetate (60 mL × 3). The combined organic phases were washed with brine (30 mL × 3) and dried over anhydrous sodium sulfate. The solid was filtered off and the filter cake was washed with ethyl acetate. The filtrate was concentrated under reduced pressure, and the crude product was purified by column chromatography (mobile phase: ethyl acetate / petroleum ether) to obtain 600 mg of the title compound.

[0410] b) Preparation of 3-(3-methyl-4-(10-(2-methyl-1,3-dioxolan-2-yl)dec-1-yn-1-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione

[0411] 3-(4-Bromo-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (1.085 g), 2-(dec-9-yn-1-yl)-2-methyl-1,3-dioxolane (600 mg), cuprous iodide (102 mg), triethylamine (5 mL), and bis(triphenylphosphine)palladium chloride (188 mg) were added to N,N-dimethylformamide (5 mL). After replacing the atmosphere with nitrogen, the mixture was reacted at 70°C for 3 hours. After completion of the reaction, water (200 mL) was added to quench the reaction. The mixture was extracted with ethyl acetate (70 mL x 3). The combined organic phases were washed with saturated brine (70 mL x 3) and dried over anhydrous sodium sulfate. After filtering out the solid, the filtrate was concentrated under reduced pressure, and the crude product was purified by column chromatography (mobile phase: ethyl acetate / petroleum ether) to obtain 110 mg of the title compound.

[0412] c) Preparation of 3-(3-methyl-4-(10-(2-methyl-1,3-dioxolan-2-yl)decyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione

[0413] 3-(3-methyl-4-(10-(2-methyl-1,3-dioxolan-2-yl)dec-1-yn-1-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (100 mg) and palladium / carbon (22 mg) were added to methanol (10 mL) and stirred at 50°C under a hydrogen atmosphere for 15 hours. The resulting mixture was filtered, and the filter cake was washed with methanol (10 mL x 3). The filtrate was concentrated under reduced pressure to obtain 95 mg of the title compound.

[0414] d) Preparation of 3-(3-methyl-2-oxo-4-(11-oxododecyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione

[0415] 3-(3-methyl-4-(10-(2-methyl-1,3-dioxolan-2-yl)decyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (95 mg) was added to a 4M 1,4-dioxane hydrochloric acid solution (1 mL). The reaction mixture was stirred at room temperature for 2 hours. After the reaction, the resulting mixture was concentrated under reduced pressure to obtain 77 mg of the title compound.

[0416] e) Preparation of 3-(4-(11-(((S)-2-(4-chlorophenyl))-3-((1R,5S)-3-(5-ethyl-7-oxo-5,6,7,8-tetrahydropteridin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-3-oxopropyl)amino)dodecyl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione

[0417] 3-(3-methyl-2-oxo-4-(11-oxododecyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (40 mg) and 4-{8-[(2S)-3-amino-2-(4-chlorophenyl)propionyl]-3,8-diazabicyclo[3.2.1]octan-3-yl}-5-ethyl-6,8-dihydropteridin-7-one (51 mg) were dissolved in 1,2-dichloroethane (2 mL) and stirred at room temperature for 30 minutes. Sodium triacetoxyborohydride (58 mg) was then added to the mixture, and the mixture was stirred at room temperature under a nitrogen atmosphere for 1 hour. After the reaction was completed, the resulting mixture was concentrated under reduced pressure. The crude product was separated by preparative liquid phase separation to obtain 4.2 mg of the title compound.

[0418] 1H NMR (400MHz, DMSO-d6) δ11.09(s,1H),10.83(d,J=20.2Hz,1H),8.08(d,J=23.4Hz,1H),7.38(d,J=13.3Hz,4H),6.95(d,J=5.2Hz, 2H),6.89-6.75(m,1H),5.36(dd,J=12.6,5.5Hz,1H),4.56(d,J=16.1Hz,1H),4.49(s,2H),4.20(s,1H),4.09(s,1H),3.61(d,J=4. 3Hz,1H),3.54(s,4H),3.19(dd,J=9.8,8.1Hz,4H),2.95(s,4H),2.87(s,1H),2.80-2.72(m,2H),2.70-2.64(m,1H),2.60(s,1H),2 .07-1.91(m,2H),1.73(s,2H),1.57(s,3H),1.42-1.29(m,3H),1.35-1.07(m,13H),0.98-0.87(m,3H),0.84(t,J=7.1Hz,2H).LCMS m / z=895[M+1] +

[0419] Example 24 Preparation of 1-(6-(7-(4-((S)-2-(4-chlorophenyl))-3-((1R,6S)-5-((R)-5-methyl-7-oxo-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-4-yl)-2,5-diazabicyclo[4.1.0]hept-2-yl)-3-oxopropyl)piperazin-1-yl)heptyl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

[0420] a) Preparation of 1-(6-(7-hydroxyhept-1-yn-1-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

[0421] 1-(6-Bromo-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (300 mg), hept-6-yn-1-ol (125 mg), cuprous iodide (35.5 mg), triethylamine (471 mg), and bis(triphenylphosphine)palladium chloride (65 mg) were added to N,N-dimethylformamide (9 mL). After nitrogen substitution, the mixture was reacted at 70°C for 3 hours. After completion of the reaction, the mixture was extracted with ethyl acetate (200 mL × 3). The combined organic phases were washed with saturated brine (200 mL × 3) and dried over anhydrous sodium sulfate. After filtering out the solid, the filtrate was concentrated under reduced pressure, and the crude product was purified by column chromatography (mobile phase: ethyl acetate / petroleum ether) to obtain 285 mg of the title compound.

[0422] b) Preparation of 1-(6-(7-hydroxyheptyl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

[0423] 1-(6-(7-hydroxyhept-1-yn-1-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (285 mg) and palladium / carbon (284.5 mg) were added to ethyl acetate (5 mL) and stirred at 50°C overnight under a hydrogen atmosphere. The resulting mixture was filtered, and the filter cake was washed with ethyl acetate (10 mL x 3). The filtrate was concentrated under reduced pressure to obtain 170 mg of the title compound.

[0424] c) Preparation of 7-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)heptanal

[0425] 1-(6-(7-hydroxyhept-1-yn-1-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (170 mg) and (1,1,1-triacetoxy)-1,1-dihydro-1,2-benzoiodooxolan-3(1H)-one (121 mg) were added to dichloromethane (2 mL). After nitrogen substitution, the mixture was stirred at room temperature for 2 hours. After the reaction, the pH was adjusted to 8 with saturated aqueous sodium bicarbonate solution, and the mixture was extracted with dichloromethane (30 mL × 3). The organic phase was washed with saturated brine (10 mL × 3) and dried over anhydrous sodium sulfate. After filtering out the solid, the filtrate was concentrated under reduced pressure, and the crude product was purified by column chromatography (mobile phase: ethyl acetate / petroleum ether) to obtain 100 mg of the title compound.

[0426] d) Preparation of 1-(6-(7-(4-((S)-2-(4-chlorophenyl))-3-((1R,6S)-5-((R)-5-methyl-7-oxo-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-4-yl)-2,5-diazabicyclo[4.1.0]hept-2-yl)-3-oxopropyl)piperazin-1-yl)heptyl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

[0427] 7-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)heptanal (80 mg), (R)-4-((1S,6R)-5-((S)-2-(4-chlorophenyl)-3-(piperazin-1-yl)propanoyl)-2,5-diazabicyclo[4.1.0]hept-2-yl)-5-methyl-5,8-dihydropyrido[2,3-d]pyrimidin-7(6H)-one (38 mg), tetraisopropoxytitanium (106 mg), triethylamine (23 mg), and N,N-dimethylformamide (1 mL) were added to a reaction flask, and the mixture was stirred at 50°C under a nitrogen atmosphere for 1 hour. Sodium triacetoxyborohydride (32 mg) was then added to the mixture, and the mixture was stirred at room temperature under a nitrogen atmosphere for 1 hour. After the reaction was completed, the resulting mixture was concentrated under reduced pressure. The crude product was separated by preparative liquid phase to obtain 11.3 mg of the title compound.

[0428] 1 H NMR (400MHz, DMSO-d6) δ10.62-10.39(m,2H),8.26-8.15(m,1H),7.53(d,J=8.4Hz,1H),7.45-7.38(m,1H),7.36(d,J=9.5Hz,2H),7 .34-7.07(m,2H),6.96(dt,J=8.5,1.6Hz,1H),4.49(t,J=7.1Hz,2H),4.26-3.95(m,3H),3.90(t,J=6.7Hz,2H),3.82-3.69(m,1H),3 .59(d,J=11.9Hz,1H),3.51(s,1H),3.17(d,J=9.5Hz,2H),3.02(dd,J=21.9,13.9Hz,2H),2.76(q,J=6.8Hz,3H),2.70(s,2H),2.45 (s,4H),2.32-2.03(m,6H),2.01-1.94(m,1H),1.62(s,2H),1.29(s,5H),1.24(s,5H),1.08(t,J=7.7Hz,2H),0.95(d,J=6.9Hz,2H).

[0429] LCMS m / z=850[M+1] +

[0430] Example 25 Preparation of 1-(6-(5-(4-((S)-2-(4-chlorophenyl))-3-((1R,6S)-5-((R)-5-methyl-7-oxo-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-4-yl)-2,5-diazabicyclo[4.1.0]hept-2-yl)-3-oxopropyl)piperazin-1-yl)pentyl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

[0431] a) Preparation of 1-(6-(5-hydroxypent-1-yn-1-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

[0432] 1-(6-Bromo-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (130 mg), pent-4-yn-1-ol (20 mg), cuprous iodide (8 mg), triethylamine (102 mg), and bis(triphenylphosphine)palladium chloride (14 mg) were added to N,N-dimethylformamide (2 mL). After nitrogen substitution, the mixture was reacted at 70°C for 3 hours. After completion of the reaction, the mixture was extracted with ethyl acetate (200 mL x 3). The combined organic phases were washed with saturated brine (200 mL x 3) and dried over anhydrous sodium sulfate. After filtering out the solid, the filtrate was concentrated under reduced pressure, and the crude product was purified by column chromatography (mobile phase: ethyl acetate / petroleum ether) to obtain 110 mg of the title compound.

[0433] b) Preparation of 1-(6-(5-hydroxypentyl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

[0434] 1-(6-(5-hydroxypent-1-yn-1-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (110 mg) and palladium / carbon (110 mg) were added to ethyl acetate (5 mL) and stirred at 50°C overnight under a hydrogen atmosphere. The resulting mixture was filtered, and the filter cake was washed with ethyl acetate (10 mL x 3). The filtrate was concentrated under reduced pressure to obtain 100 mg of the title compound.

[0435] c) Preparation of 5-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)pentanal

[0436] 1-(6-(5-hydroxypentyl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (100 mg) and (1,1,1-triacetoxy)-1,1-dihydro-1,2-benzoiodooxolan-3(1H)-one (257 mg) were added to dichloromethane (2 mL). After nitrogen substitution, the mixture was stirred at room temperature for 2 hours. After the reaction, the pH was adjusted to 8 with saturated aqueous sodium bicarbonate solution, and the mixture was extracted with dichloromethane (30 mL × 3). The organic phase was washed with saturated brine (10 mL × 3) and dried over anhydrous sodium sulfate. After filtering out the solid, the filtrate was concentrated under reduced pressure, and the crude product was purified by column chromatography (mobile phase: ethyl acetate / petroleum ether) to obtain 70 mg of the title compound.

[0437] d) Preparation of 1-(6-(5-(4-((S)-2-(4-chlorophenyl))-3-((1R,6S)-5-((R)-5-methyl-7-oxo-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-4-yl)-2,5-diazabicyclo[4.1.0]hept-2-yl)-3-oxopropyl)piperazin-1-yl)pentyl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

[0438] 5-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)pentanal (51.5 mg) and (R)-4-((1S,6R)-5-((S)-2-(4-chlorophenyl)-3-(piperazin-1-yl)propanoyl)-2,5-diazabicyclo[4.1.0]hept-2-yl)-5-methyl-5,8-dihydropyrido[2,3-d]pyrimidin-7(6H)-one (80 mg) were dissolved in 1,2-dichloroethane (1 mL) and stirred at 50°C for 30 minutes. Sodium triacetoxyborohydride (99 mg) was then added to the mixture, and the mixture was stirred at room temperature under a nitrogen atmosphere for 1 hour. After completion of the reaction, the resulting mixture was concentrated under reduced pressure. The crude product was separated by preparative liquid phase to obtain 11.2 mg of the title compound.

[0439] 1H NMR (400MHz, DMSO-d6) δ10.60-10.40(m,2H),8.24-8.13(m,1H),7.68-7.49(m,2H),7.46-7.39(m,1H),7.37(d,J=3.7Hz,1H),7.35(s,2 H),7.00-6.92(m,1H),4.49(t,J=7.0Hz,1H),4.15-4.03(m,1H),4.01-3.91(m,3H),3.90-3.74(m,2H),3.59(d,J=11.8Hz,1H),3.50(d, J=6.2Hz,1H),3.41-3.36(m,1H),3.17(d,J=9.4Hz,3H),3.09-2.90(m,2H),2.75(t,J=6.7Hz,3H),2.70(d,J=7.3Hz,2H),2.56-2.5(m,5 H),2.27(t,J=15.8Hz,6H),1.71-1.57(m,2H),1.47(d,J=34.9Hz,2H),1.33-1.20(m,3H),1.08(t,J=8.1Hz,2H),0.95(d,J=6.9Hz,2H).

[0440] LCMS m / z=822[M+1] +

[0441] Example 26 Preparation of 1-(6-(3-(4-((S)-2-(4-chlorophenyl)-3-((1R,6S)-5-((R)-5-methyl-7-oxo-5),6,7,8-tetrahydropyrido[2,3-d]pyrimidin-4-yl)-2,5-diazabicyclo[4.1.0]hept-2-yl)-3-oxopropyl)piperazin-1-yl)propyl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

[0442] a) Preparation of tert-butyldiphenyl(prop-2-yn-1-yloxy)silane

[0443] Propargyl alcohol (2 g), imidazole (4.86 g), tert-butyldiphenylsilyl chloride (14.7 g), and dichloromethane (20 mL) were added to a reaction flask and the mixture was stirred at room temperature under a nitrogen atmosphere for 12 hours. After the reaction was completed, dichloromethane (180 mL) was added. The organic layer was washed with brine (150 mL x 3) and dried over anhydrous sodium sulfate. After filtering out the solid, the filtrate was concentrated under reduced pressure to obtain the title compound (8 g).

[0444] b) Preparation of 1-(6-(3-((tert-butyldiphenylsilyl)oxy)prop-1-yn-1-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

[0445] 1-(6-Bromo-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (500 mg), tert-butyldiphenyl(prop-2-yn-1-yloxy)silane (911 mg), cuprous iodide (58 mg), 1,8-diazabicyclo(5.4.0)undec-7-ene (471 mg), and tetrakis(triphenylphosphine)palladium (178 mg) were added to tetrahydrofuran (5 mL). After nitrogen substitution, the reaction was carried out at 80°C for 3 hours. After completion of the reaction, the solid was filtered off, the filtrate was concentrated under reduced pressure, and the crude product was purified by column chromatography (mobile phase: methanol / dichloromethane) to obtain 280 mg of the title compound.

[0446] c) Preparation of 1-(6-(3-hydroxyprop-1-yn-1-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

[0447] 1-(6-(3-((tert-butyldiphenylsilyl)oxy)prop-1-yn-1-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (280 mg), tetrabutylammonium fluoride (272 mg), and tetrahydrofuran (3 mL) were added to a reaction flask, and the mixture was stirred at room temperature under a nitrogen atmosphere for 2 hours. After the reaction was completed, the resulting mixture was concentrated under reduced pressure. The crude product was purified by column chromatography (mobile phase: methanol / dichloromethane) to obtain 120 mg of the title compound.

[0448] d) Preparation of 1-(6-(3-hydroxypropyl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

[0449] 1-(6-(3-hydroxyprop-1-yn-1-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (120 mg), palladium / carbon (60 mg), and palladium hydroxide (60 mg) were added to methanol (5 mL) and stirred at 50°C overnight under a hydrogen atmosphere. The resulting mixture was filtered, and the filter cake was washed with methanol (10 mL x 3). The filtrate was concentrated under reduced pressure to obtain 90 mg of the title compound.

[0450] e) Preparation of 3-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)propanal

[0451] 1-(6-(3-Hydroxypropyl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (90 mg) and (1,1,1-triacetoxy)-1,1-dihydro-1,2-benzoiodooxolan-3(1H)-one (252 mg) were added to dichloromethane (2 mL). After nitrogen displacement, the mixture was stirred at room temperature for 2 hours. After the reaction, the pH was adjusted to 8 with saturated aqueous sodium bicarbonate solution, and the mixture was extracted with dichloromethane (30 mL × 3). The organic phase was washed with saturated brine (10 mL × 3) and dried over anhydrous sodium sulfate. After filtering out the solid, the filtrate was concentrated under reduced pressure, and the crude product was purified by column chromatography (mobile phase: ethyl acetate / petroleum ether) to obtain 45 mg of the title compound.

[0452] f) Preparation of 1-(6-(3-(4-((S)-2-(4-chlorophenyl)-3-((1R,6S)-5-((R)-5-methyl-7-oxo-5),6,7,8-tetrahydropyrido[2,3-d]pyrimidin-4-yl)-2,5-diazabicyclo[4.1.0]hept-2-yl)-3-oxopropyl)piperazin-1-yl)propyl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

[0453] 3-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)propanal (17 mg) and (R)-4-((1S,6R)-5-((S)-2-(4-chlorophenyl)-3-(piperazin-1-yl)propanoyl)-2,5-diazabicyclo[4.1.0]hept-2-yl)-5-methyl-5,8-dihydropyrido[2,3-d]pyrimidin-7(6H)-one (30 mg, Intermediate 1) in 1,2-dichloroethane (1 mL) were dissolved and stirred at 50°C for 30 minutes. Sodium triacetoxyborohydride (37 mg) was then added to the mixture, and the mixture was stirred at room temperature under a nitrogen atmosphere for 1 hour. After completion of the reaction, the resulting mixture was concentrated under reduced pressure. The crude product was separated by preparative liquid phase to obtain 1.4 mg of the title compound.

[0454] LCMS m / z=794[M+1] +

[0455] Example 27 Preparation of 1-(6-(9-(4-((S)-2-(4-chlorophenyl))-3-((1R,6S)-5-((R)-5-methyl-7-oxo-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-4-yl)-2,5-diazabicyclo[4.1.0]hept-2-yl)-3-oxopropyl)piperazin-1-yl)nonyl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

[0456] a) Preparation of 1-(6-(9-hydroxynon-1-yn-1-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

[0457] 1-(6-Bromo-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (150 mg), non-8-yn-1-ol (130 mg), cuprous iodide (17 mg), triethylamine (140 mg), and bis(triphenylphosphine)palladium chloride (32 mg) were added to N,N-dimethylformamide (2 mL). After nitrogen substitution, the reaction was allowed to proceed at 70°C for 3 hours. After completion of the reaction, the mixture was extracted with ethyl acetate (50 mL x 3). The combined organic phases were washed with saturated brine (50 mL x 3) and dried over anhydrous sodium sulfate. After filtering out the solid, the filtrate was concentrated under reduced pressure, and the crude product was purified by column chromatography (mobile phase: methanol / dichloromethane) to obtain 130 mg of the title compound.

[0458] b) Preparation of 1-(6-(9-hydroxynonyl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

[0459] 1-(6-(9-Hydroxynon-1-yn-1-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (130 mg) and palladium / carbon (40 mg) were added to ethyl acetate (5 mL) and stirred at 50°C overnight under a hydrogen atmosphere. The resulting mixture was filtered, and the filter cake was washed with ethyl acetate (10 mL x 3). The filtrate was concentrated under reduced pressure to obtain 98 mg of the title compound.

[0460] c) Preparation of 9-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)nonanal

[0461] 1-(6-(9-Hydroxynonyl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (98 mg) and (1,1,1-triacetoxy)-1,1-dihydro-1,2-benzoiodooxolan-3(1H)-one (215 mg) were added to dichloromethane (2 mL). After nitrogen substitution, the mixture was stirred at room temperature for 2 hours. After the reaction, the pH was adjusted to 8 with saturated aqueous sodium bicarbonate solution, and the mixture was extracted with dichloromethane (30 mL × 3). The organic phase was washed with saturated brine (10 mL × 3) and dried over anhydrous sodium sulfate. After filtering out the solid, the filtrate was concentrated under reduced pressure, and the crude product was purified by column chromatography (mobile phase: ethyl acetate / petroleum ether) to obtain 54 mg of the title compound.

[0462] d) Preparation of 1-(6-(9-(4-((S)-2-(4-chlorophenyl))-3-((1R,6S)-5-((R)-5-methyl-7-oxo-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-4-yl)-2,5-diazabicyclo[4.1.0]hept-2-yl)-3-oxopropyl)piperazin-1-yl)nonyl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

[0463] 9-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)nonanal (30 mg) and (R)-4-((1S,6R)-5-((S)-2-(4-chlorophenyl)-3-(piperazin-1-yl)propanoyl)-2,5-diazabicyclo[4.1.0]hept-2-yl)-5-methyl-5,8-dihydropyrido[2,3-d]pyrimidin-7(6H)-one (47 mg, Intermediate 1) were dissolved in 1,2-dichloroethane (1 mL) and stirred at room temperature for 30 minutes. Sodium triacetoxyborohydride (49 mg) was then added to the mixture, and the mixture was stirred at room temperature for 1 hour under a nitrogen atmosphere. After completion of the reaction, the resulting mixture was concentrated under reduced pressure. The crude product was separated by preparative liquid phase to obtain 3.2 mg of the title compound.

[0464] LCMS m / z=878[M+1] +

[0465] Example 28 Preparation of 1-(6-(4-(8-(((S)-2-(4-chlorophenyl))-3-((1R,6S)-5-((R)-5-methyl-7-oxo-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-4-yl)-2,5-diazabicyclo[4.1.0]hept-2-yl)-3-oxopropyl)amino)octyl)piperazin-1-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

[0466] a) Preparation of tert-butyl 4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperazine-1-carboxylate

[0467] 1-(6-Bromo-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (1.5 g), tert-butyl piperazine 1-carboxylate (2 g), N,N-diisopropylethylamine (3 g), and N-methylpyrrolidone (20 mL) were added to a reaction flask. After nitrogen replacement, the reaction was carried out at 90°C for 16 hours. After completion of the reaction, the mixture was filtered and the filtrate was concentrated. The crude product was purified by column chromatography (mobile phase: methanol / dichloromethane) to obtain 500 mg of the title compound.

[0468] b) Preparation of 1-(1-methyl-6-(piperazin-1-yl)-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

[0469] Dissolve tert-butyl 4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperazine-1-carboxylate (303 mg) in 5 mL of methanolic hydrochloric acid solution and stir at room temperature for 2 hours. After completion of the reaction, concentrate under reduced pressure to obtain the title compound (260 mg).

[0470] c) Preparation of 1-(6-(4-(8-hydroxyoctyl)piperazin-1-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

[0471] Dissolve 1-(1-methyl-6-(piperazin-1-yl)-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (50 mg), 8-bromooctanol (28.5 mg), triethylamine (28 mg), and potassium iodide (25 mg) in N,N-dimethylformamide (5 mL). After nitrogen substitution, react at room temperature for 2 hours. After completion of the reaction, extract with ethyl acetate and water, dry the organic phase over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain 50 mg of the title compound.

[0472] d) Preparation of 8-(4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperazin-1-yl)octanal

[0473] The compound 1-(6-(4-(8-hydroxyoctyl)piperazin-1-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (19 mg) and (1,1,1-triacetoxy)-1,1-dihydro-1,2-benzoiodoxolane-3(1H)-one (21 mg) were dissolved in dichloromethane (1 mL). After nitrogen substitution, the mixture was reacted at room temperature for 2 hours. After completion of the reaction, 11 mg of the product was isolated using a silica gel preparation plate (developing solvent: methanol / dichloromethane).

[0474] e) Preparation of 1-(6-(4-(8-(((S)-2-(4-chlorophenyl))-3-((1R,6S)-5-((R)-5-methyl-7-oxo-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-4-yl)-2,5-diazabicyclo[4.1.0]hept-2-yl)-3-oxopropyl)amino)octyl)piperazin-1-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

[0475] 8-(4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperazin-1-yl)octanal (11 mg) and (R)-4-((1S,6R)-5-((S)-3-amino-2-(4-chlorophenyl)propanoyl)-2,5-diazabicyclo[4.1.0]hept-2-yl)-5-methyl-5,8-dihydropyrido[2,3-d]pyrimidin-7(6H)-one (11 mg) were dissolved in N,N-dimethylformamide (1 mL). Sodium triacetoxyborohydride (8 mg) was added, and the mixture was reacted at room temperature for 2 hours after nitrogen substitution. After completion of the reaction, the resulting mixture was concentrated under reduced pressure. The crude product was separated by preparative liquid chromatography to obtain 4.5 mg of the title compound.

[0476] 1 H NMR(400MHz,DMSO-d6)δ10.49(s,1H),10.46(s,1H),8.36(s,1H),8.20(s,1H),7.46-7.43(m,1H),7 .38(s,1H),7.35(m,2H),6.91(d,J=8.9Hz,1H),6.80(d,J=7.3Hz,1H),4.45-4.42(m,1H),4.11(s,2 H),3.89(m,5H),3.20(m,6H),3.15(s,4H),2.76-2.69(m,3H),2.67(s,1H),2.35-2.20(m,4H),2.03 -1.99(m,1H),1.45(s,3H),1.39-1.13(m,14H),1.10-1.06(m,1H),0.96(m,3H),0.87-0.84(m,1H).

[0477] LCMS m / z=879[M+1] +

[0478] Example 29 Preparation of 5-(4-(8-(((S)-2-(4-chlorophenyl))-3-((1R,6S)-5-((R)-5-methyl-7-oxo-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-4-yl)-2,5-diazabicyclo[4.1.0]hept-2-yl)-3-oxopropyl)amino)octyl)piperazin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

[0479] a) Preparation of tert-butyl 4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazine-1-carboxylate

[0480] 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (2g), tert-butyl piperazine 1-carboxylate (2.7g), N,N-diisopropylethylamine (3.74g), and N-methylpyrrolidone (25mL) were added to a reaction flask. After nitrogen substitution, the reaction was carried out at 90°C for 16 hours. After completion of the reaction, the mixture was filtered and the filtrate was concentrated. The crude product was purified by column chromatography (mobile phase: methanol / dichloromethane) to obtain 1.3g of the title compound.

[0481] b) Preparation of 2-(2,6-dioxopiperidin-3-yl)-5-(piperazin-1-yl)isoindoline-1,3-dione

[0482] tert-Butyl 4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazine-1-carboxylate (1.3 g), trifluoroacetic acid (2.5 mL), and dichloromethane (5 mL) were added to a reaction flask and allowed to react at room temperature for 1 hour. After completion of the reaction, the mixture was filtered and the filtrate was concentrated. The crude product was purified by column chromatography (mobile phase: methanol / dichloromethane) to obtain 900 mg of the title compound.

[0483] c) Preparation of 2-(2,6-dioxopiperidin-3-yl)-5-(4-(8-hydroxyoctyl)piperazin-1-yl)isoindoline-1,3-dione

[0484] Dissolve 2-(2,6-dioxopiperidin-3-yl)-5-(piperazin-1-yl)isoindoline-1,3-dione (150 mg), 8-bromooctan-1-ol (68 mg), potassium iodide (55 mg), and triethylamine (133 mg) in N,N-dimethylformamide (4 mL). After nitrogen substitution, react at room temperature for 20 hours. After completion of the reaction, filter and concentrate the filtrate. The crude product is purified by column chromatography (mobile phase: methanol / dichloromethane) to obtain 118 mg of the title compound.

[0485] d) Preparation of 8-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)octanal

[0486] 2-(2,6-dioxopiperidin-3-yl)-5-(4-(8-hydroxyoctyl)piperazin-1-yl)isoindoline-1,3-dione (118 mg) and (1,1,1-triacetoxy)-1,1-dihydro-1,2-benzoiodooxolan-3(1H)-one (128 mg) were dissolved in dichloromethane (4 mL). After nitrogen substitution, the mixture was reacted at room temperature for 2 hours. After completion of the reaction, the mixture was filtered and the filtrate was concentrated. The crude product was purified by column chromatography (mobile phase: methanol / dichloromethane = 0%-10%) to obtain 87 mg of the title compound.

[0487] e) Preparation of 5-(4-(8-(((S)-2-(4-chlorophenyl))-3-((1R,6S)-5-((R)-5-methyl-7-oxo-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-4-yl)-2,5-diazabicyclo[4.1.0]hept-2-yl)-3-oxopropyl)amino)octyl)piperazin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

[0488] 8-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)octanal (20 mg) and (R)-4-((1S,6R)-5-((S)-3-amino-2-(4-chlorophenyl)propanoyl)-2,5-diazabicyclo[4.1.0]hept-2-yl)-5-methyl-5,8-dihydropyrido[2,3-d]pyrimidin-7(6H)-one (10 mg) were dissolved in N,N-dimethylformamide (3 mL). Sodium triacetoxyborohydride (14 mg) was added, and the mixture was reacted at room temperature for 2 hours after nitrogen substitution. After completion of the reaction, the resulting mixture was concentrated under reduced pressure. The crude product was separated by preparative liquid chromatography to obtain 1.04 mg of the title compound.

[0489] 1 H NMR (400MHz, DMSO-d6) δ11.07(s,2H),10.49(d,J=11.3Hz,1H),8.19(s,1H),7.67(d,J=8.5Hz,1H),7.44-7.29(m,4H),7.25 (dd,J=8.7,2.3Hz,1H),5.07(dd,J=12.9,5.4Hz,1H),4.46(t,J=7.0Hz,1H),4.11(d,J=9.3Hz,1H),3.97-3.83(m,1H),3.83- 3.73(m,1H),3.65(d,J=10.9Hz,1H),3.56-3.38(m,6H),3.23-3.05(m,4H),2.95-2.64(m,4H),2.64-2.52(m,2H),2.48-2.3 7(m,4H),2.34-2.20(m,3H),2.01(ddd,J=8.0,6.1,2.2Hz,2H),1.51-1.32(m,5H),1.27-1.20(m,9H),0.94(d,J=6.9Hz,2H).

[0490] LCMS m / z=893[M+1] +

[0491] Example 30 Preparation of 5-(4-(6-(((S)-2-(4-chlorophenyl))-3-((1R,6S)-5-((R)-5-methyl-7-oxo-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-4-yl)-2,5-diazabicyclo[4.1.0]hept-2-yl)-3-oxopropyl)amino)hexyl)piperazin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

[0492] a) Preparation of 2-(2,6-dioxopiperidin-3-yl)-5-(4-(6-hydroxyhexyl)piperazin-1-yl)isoindoline-1,3-dione

[0493] Dissolve 2-(2,6-dioxopiperidin-3-yl)-5-(piperazin-1-yl)isoindoline-1,3-dione (150 mg), 6-bromohexan-1-ol (59 mg), potassium iodide (55 mg), and triethylamine (133 mg) in N,N-dimethylformamide (4 mL). After nitrogen substitution, react at room temperature for 20 hours. After completion of the reaction, filter and concentrate the filtrate. The crude product is purified by column chromatography (mobile phase: methanol / dichloromethane) to obtain 86 mg of the title compound.

[0494] b) Preparation of 6-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)hexanal

[0495] 2-(2,6-dioxopiperidin-3-yl)-5-(4-(6-hydroxyhexyl)piperazin-1-yl)isoindoline-1,3-dione (86 mg) and (1,1,1-triacetoxy)-1,1-dihydro-1,2-benzoiodooxolan-3(1H)-one (99 mg) were dissolved in dichloromethane (4 mL). After nitrogen substitution, the mixture was reacted at room temperature for 2 hours. After completion of the reaction, the mixture was filtered and the filtrate was concentrated. The crude product was purified by column chromatography (mobile phase: methanol / dichloromethane) to obtain 57 mg of the title compound.

[0496] c) Preparation of 5-(4-(6-(((S)-2-(4-chlorophenyl))-3-((1R,6S)-5-((R)-5-methyl-7-oxo-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-4-yl)-2,5-diazabicyclo[4.1.0]hept-2-yl)-3-oxopropyl)amino)hexyl)piperazin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

[0497] 6-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)hexanal (45 mg) and (R)-4-((1S,6R)-5-((S)-3-amino-2-(4-chlorophenyl)propanoyl)-2,5-diazabicyclo[4.1.0]hept-2-yl)-5-methyl-5,8-dihydropyrido[2,3-d]pyrimidin-7(6H)-one (15 mg) were dissolved in N,N-dimethylformamide (3 mL). Sodium triacetoxyborohydride (22 mg) was added, and the mixture was reacted at room temperature for 2 hours after nitrogen substitution. After completion of the reaction, the resulting mixture was concentrated under reduced pressure. The crude product was separated by preparative liquid phase to obtain 2.45 mg of the title compound.

[0498] 1 H NMR (400MHz, DMSO-d6) δ11.07(s,2H),10.48(d,J=10.8Hz,1H),8.20(d,J=8.4Hz,1H),7.66(t,J=7.9Hz,1H), 7.36(dd,J=16.4,11.8Hz,3H),7.24(d,J=9.5Hz,1H),5.07(dd,J=13.2,5.4Hz,1H),4.43(d,J=23.1Hz,1H),4 .12(s,1H),4.05-3.8(m,3H),3.75-3.49(m,10H),3.25-3.03(m,J=12.4Hz,5H),2.96-2.55(m,7H),2.28(q,J =16.3,14.9Hz,4H),2.01(d,J=11.9Hz,1H),1.47-1.13(m,7H),1.08(t,J=8.4Hz,1H),0.95(t,J=7.4Hz,2H).

[0499] LCMS m / z=865[M+1] +

[0500] Example 31 Preparation of 5-(4-(4-(((S)-2-(4-chlorophenyl))-3-((1R,6S)-5-((R)-5-methyl-7-oxo-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-4-yl)-2,5-diazabicyclo[4.1.0]hept-2-yl)-3-oxopropyl)amino)butyl)piperazin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

[0501] a) Preparation of 4-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)butyraldehyde

[0502] Dissolve 2-(2,6-dioxopiperidin-3-yl)-5-(piperazin-1-yl)isoindoline-1,3-dione (236 mg), succinaldehyde (148 mg), sodium triacetoxyborohydride (147 mg), and triethylamine (93 mg) in acetonitrile (4 mL). After nitrogen substitution, react at room temperature for 2 hours. After completion of the reaction, filter and concentrate the filtrate. The crude product is purified by column chromatography (mobile phase: methanol / dichloromethane) to obtain 116 mg of the title compound.

[0503] b) Preparation of 5-(4-(4-(((S)-2-(4-chlorophenyl))-3-((1R,6S)-5-((R)-5-methyl-7-oxo-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-4-yl)-2,5-diazabicyclo[4.1.0]hept-2-yl)-3-oxopropyl)amino)butyl)piperazin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

[0504] 4-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)butanal (32 mg) and (R)-4-((1S,6R)-5-((S)-3-amino-2-(4-chlorophenyl)propanoyl)-2,5-diazabicyclo[4.1.0]hept-2-yl)-5-methyl-5,8-dihydropyrido[2,3-d]pyrimidin-7(6H)-one (11 mg) were dissolved in N,N-dimethylformamide (3 mL). Sodium triacetoxyborohydride (25 mg) was added, and the atmosphere was replaced with nitrogen, followed by reaction at room temperature for 2 hours. After completion of the reaction, the resulting mixture was concentrated under reduced pressure. The crude product was separated by preparative liquid chromatography to afford 6.64 mg of the title compound.

[0505] LCMS m / z=837[M+1] +

[0506] Example 32 Preparation of 5-(4-(((S)-2-(4-chlorophenyl)-3-((1R,6S)-5-((R)-5-methyl-7-oxo-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-4-yl)-2,5-diazabicyclo[4.1.0]heptane-2-yl)-3-oxopropyl)amino)-[1,4'-bipiperidinyl]-1'-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

[0507] a) Preparation of tert-butyl 4-(((S)-2-(4-chlorophenyl)-3-((1R,6S)-5-((R)-5-methyl-7-oxo-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-4-yl)-2,5-diazabicyclo[4.1.0]hept-2-yl)-3-oxopropyl)amino)piperidine-1-carboxylate

[0508] (R)-4-((1S,6R)-5-((S)-3-amino-2-(4-chlorophenyl)propanoyl)-2,5-diazabicyclo[4.1.0]hept-2-yl)-5-methyl-5,8-dihydropyrido[2,3-d]pyrimidin-7(6H)-one (200 mg), tert-butyl 4-oxopiperidine-1-carboxylate (90 mg), and 1,2-dichloroethane (2 mL) were added to a reaction flask and the mixture was stirred at room temperature for 1 hour. Sodium triacetoxyborohydride (288 mg) was then added to the above mixture, and the resulting mixture was stirred at room temperature for an additional 2 hours. After the reaction was complete, the mixture was concentrated and used directly in the next step.

[0509] b) Preparation of (R)-4-((1S,6R)-5-((S)-2-(4-chlorophenyl)-3-(piperidin-4-ylamino)propanoyl)-2,5-diazabicyclo[4.1.0]hept-2-yl)-5-methyl-5,8-dihydropyrido[2,3-d]pyrimidin-7(6H)-one

[0510] Tert-butyl 4-(((S)-2-(4-chlorophenyl)-3-((1R,6S)-5-((R)-5-methyl-7-oxo-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-4-yl)-2,5-diazabicyclo[4.1.0]hept-2-yl)-3-oxopropyl)amino)piperidine-1-carboxylate (100 mg) was added to a 1,4-dioxane hydrochloric acid solution (4 M, 2 mL) and stirred at room temperature for 1 hour. After the reaction, the mixture was concentrated and used directly in the next step.

[0511] c) Preparation of 5-(4-(((S)-2-(4-chlorophenyl)-3-((1R,6S)-5-((R)-5-methyl-7-oxo-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-4-yl)-2,5-diazabicyclo[4.1.0]heptane-2-yl)-3-oxopropyl)amino)-[1,4'-bipiperidinyl]-1'-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

[0512] (R)-4-((1S,6R)-5-((S)-2-(4-chlorophenyl)-3-(piperidin-4-ylamino)propanoyl)-2,5-diazabicyclo[4.1.0]hept-2-yl)-5-methyl-5,8-dihydropyrido[2,3-d]pyrimidin-7(6H)-one (60 mg), 2-(2,6-dioxopiperidin-3-yl)-5-(4-oxopiperidin-1-yl)isoindoline-1,3-dione (40 mg), tetraisopropoxytitanium (98 mg), and dichloromethane (1 mL) were added to a reaction flask, and the mixture was stirred at room temperature under a nitrogen atmosphere for 1 hour. Sodium triacetoxyborohydride (73 mg) was then added to the mixture, and the mixture was stirred at room temperature under a nitrogen atmosphere for 2 hours. After the reaction was completed, the resulting mixture was concentrated under reduced pressure. The crude product was separated by preparative liquid phase to obtain 19.8 mg of the title compound.

[0513] 1 H NMR (400MHz, DMSO-d6) δ11.07 (s, 1H), 10.49 (d, J = 9.7Hz, 1H), 8.30-8.12 (m ,2H),7.65(d,J=8.5Hz,1H),7.45-7.36(m,3H),7.34-7.26(m,1H),7.26-7. 19(m,1H),5.06(dd,J=12.9,5.4Hz,1H),4.39(m,1H),4.20-4.10(m,4H),4. 07(d,J=14.3Hz,1H),3.93-3.81(m,1H),3.77(t,J=6.5Hz,1H),3.64(d,J=1 2.6Hz,2H),3.49(s,2H),3.35(s,2H),3.20-3.08(m,2H),2.98-2.85(m,3H) ,2.77(dt,J=16.5,6.1Hz,4H),2.58-2.52(m,1H),2.35-2.20(m,1H),2.11( m,2H),2.01(dd,J=9.3,4.1Hz,1H),1.79(s,4H),1.45(dd,J=15.3,8.3Hz,2 H),1.22(d,J=13.4Hz,2H),1.07(dd,J=10.2,6.8Hz,1H),1.00-0.88(m,2H).

[0514] LCMS m / z=863[M+1] +

[0515] Example 33 Preparation of 5-(4-((4-(((S)-2-(4-chlorophenyl))-3-((1R,6S)-5-((R)-5-methyl-7-oxo-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-4-yl)-2,5-diazabicyclo[4.1.0]hept-2-yl)-3-oxopropyl)amino)piperidin-1-yl)methyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

[0516] a) Preparation of 4-piperidinecarboxaldehyde

[0517] tert-Butyl 4-formylpiperidine-1-carboxylate (500 mg) was added to a 1,4-dioxane hydrochloric acid solution (4 M, 5 mL), and the mixture was stirred at room temperature for 1 hour. After the reaction was complete, the mixture was concentrated and used directly in the next step.

[0518] b) Preparation of 1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidine-4-carboxaldehyde

[0519] 4-Piperidinecarboxaldehyde (255 mg), 2-(2,4-dioxocyclohexyl)-5-fluoroisoindoline-1,3-dione (391 mg), N,N-diisopropylethylamine (1101 mg), and dimethyl sulfoxide (3 mL) were added to a reaction flask and stirred at 50°C for 12 hours. After the reaction, the mixture was concentrated, and the crude product was purified by column chromatography (mobile phase: ethyl acetate / petroleum ether) to obtain 130 mg of the title compound.

[0520] c) Preparation of 5-(4-((4-(((S)-2-(4-chlorophenyl))-3-((1R,6S)-5-((R)-5-methyl-7-oxo-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-4-yl)-2,5-diazabicyclo[4.1.0]hept-2-yl)-3-oxopropyl)amino)piperidin-1-yl)methyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

[0521] (R)-4-((1S,6R)-5-((S)-2-(4-chlorophenyl)-3-(piperidin-4-ylamino)propanoyl)-2,5-diazabicyclo[4.1.0]hept-2-yl)-5-methyl-5,8-dihydropyrido[2,3-d]pyrimidin-7(6H)-one (69 mg), 1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidine-4-carbaldehyde (30 mg), tetraisopropoxytitanium (23 mg), and 1,2-dichloroethane (1 mL) were added to a reaction flask, and the mixture was stirred at room temperature under a nitrogen atmosphere for 1 hour. Sodium triacetoxyborohydride (52 mg) was then added to the mixture, and the mixture was stirred at room temperature under a nitrogen atmosphere for 2 hours. After the reaction was completed, the resulting mixture was concentrated under reduced pressure. The crude product was separated by preparative liquid phase to obtain 8.8 mg of the title compound.

[0522] 1 H NMR(400MHz,DMSO-d6)δ11.06(s,1H),10.47(d,J=9.5Hz,1H),8.24-8.18(m,1H),7.64(dd,J=8.5,1.4Hz,1 H),7.40(d,J=2.4Hz,4H),7.37-7.25(m,1H),7.21(d,J=9.3Hz,1H),5.05(dd,J=12.9,5.4Hz,1H),4.36(m,1 H),4.22-3.98(m,1H),3.93-3.73(m,2H),3.51(d,J=6.0Hz,3H),2.91(m,4H),2.79-2.66(m,4H),2.65-2.5 4(m,4H),2.35-2.18(m,1H),2.08(d,J=8.3Hz,4H),2.02(s,2H),1.82(d,J=56.7Hz,6H),1.26-0.90(m,9H).

[0523] LCMS m / z=877[M+1] +

[0524] Example 34 Preparation of 5-(4-((4-((((S)-2-(4-chlorophenyl))-3-((1R,6S)-5-((R)-5-methyl-7-oxo-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-4-yl)-2,5-diazabicyclo[4.1.0]hept-2-yl)-3-oxopropyl)amino)methyl)piperidin-1-yl)methyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

[0525] a) Preparation of 5-(4-((4-(dimethoxymethyl)piperidin-1-yl)methyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

[0526] 4-(Dimethoxymethyl)piperidine (215.5 mg), 1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidine-4-carbaldehyde (500 mg), tetraisopropoxytitanium (1.15 g), and 1,2-dichloroethane (5 mL) were added to a reaction flask, and the mixture was stirred at room temperature under a nitrogen atmosphere for half an hour. Sodium triacetoxyborohydride (861 mg) was then added to the mixture, and the mixture was stirred at room temperature under a nitrogen atmosphere for 2 hours. After the reaction was completed, the mixture was concentrated, and the crude product was purified by column chromatography (mobile phase: ethyl acetate / petroleum ether) to obtain 220 mg of the title compound.

[0527] b) Preparation of 1-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)methyl)piperidine-4-carboxaldehyde

[0528] 5-(4-((4-(dimethoxymethyl)piperidin-1-yl)methyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (120 mg) was added to a 4M 1,4-dioxane hydrochloride solution (2 mL), and the mixture was stirred at room temperature for 1 hour. After the reaction was complete, the mixture was concentrated and used directly in the next step.

[0529] c) Preparation of 5-(4-((4-((((S)-2-(4-chlorophenyl))-3-((1R,6S)-5-((R)-5-methyl-7-oxo-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-4-yl)-2,5-diazabicyclo[4.1.0]hept-2-yl)-3-oxopropyl)amino)methyl)piperidin-1-yl)methyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

[0530] (R)-4-((1S,6R)-5-((S)-3-amino-2-(4-chlorophenyl)propanoyl)-2,5-diazabicyclo[4.1.0]hept-2-yl)-5-methyl-5,8-dihydropyrido[2,3-d]pyrimidin-7(6H)-one (24 mg), 1-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)methyl)piperidine-4-carbaldehyde (25 mg), and tetrahydrofuran (1 mL) were added to a reaction flask, and the mixture was stirred at room temperature under a nitrogen atmosphere for 1 hour. Sodium triacetoxyborohydride (159.5 mg) was then added to the mixture, and the mixture was stirred at room temperature under a nitrogen atmosphere for 2 hours. After completion of the reaction, the resulting mixture was concentrated under reduced pressure. The crude product was separated by preparative liquid phase to obtain 16.2 mg of the title compound.

[0531] 1 H NMR (400MHz, DMSO-d6) δ11.03 (s, 1H), 10.48 (d, J = 10.2Hz, 1H), 8.42 (s, 1H), 7. 64(d,J=8.5Hz,1H),7.39(d,J=4.6Hz,2H),7.35(d,J=4.4Hz,2H),7.29(s,1H),7 .21(d,J=8.7Hz,1H),5.06(dd,J=12.8,5.5Hz,1H),4.42(t,J=10.0Hz,1H),4.2 0-4.06(m,1H),4.06-3.96(m,2H),3.86-3.73(m,1H),3.64(d,J=7.4Hz,1H),3.5 1(d,J=6.6Hz,2H),3.21-3.05(m,3H),2.96(d,J=12.3Hz,3H),2.90(d,J=13.5H z,4H),2.83-2.76(m,2H),2.74(d,J=8.1Hz,3H),2.70-2.57(m,3H),2.43-2.34( m,2H),2.27(t,J=16.4Hz,1H),2.14-1.94(m,1H),1.87-1.65(m,3H),1.59(d,J= 16.7Hz,2H),1.28(s,1H),1.07(d,J=13.7Hz,3H),0.96(dd,J=15.3,6.7Hz,3H).

[0532] LCMS m / z=891[M+1] +

[0533] Example 35 Preparation of 5-(2-(4-(((S)-2-(4-chlorophenyl))-3-((1R,6S)-5-((R)-5-methyl-7-oxo-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-4-yl)-2,5-diazabicyclo[4.1.0]hept-2-yl)-3-oxopropyl)amino)piperidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

[0534] a) Preparation of 7-azaspiro[3.5]nonan-2-one

[0535] tert-Butyl 2-oxo-7-azaspiro[3.5]nonane-7-carboxylate (1 g) was added to a 1,4-dioxane hydrochloric acid solution (4 M, 10 mL), and the mixture was stirred at room temperature for 1 hour. After the reaction was complete, the mixture was concentrated and used directly in the next step.

[0536] b) Preparation of 2-(2,6-dioxopiperidin-3-yl)-5-(2-oxo-7-azaspiro[3.5]nonan-7-yl)isoindoline-1,3-dione: 7-Azaspiro[3.5]nonan-2-one (300 mg), 2-(2,4-dioxocyclohexyl)-5-fluoroisoindoline-1,3-dione (472 mg), N,N-diisopropylethylamine (1324 mg), and dimethyl sulfoxide (5 mL) were added to a reaction flask and stirred at 100°C for 12 hours. After completion of the reaction, the mixture was concentrated, and the crude product was purified by column chromatography (mobile phase: ethyl acetate / petroleum ether) to obtain 250 mg of the title compound.

[0537] c) Preparation of 5-(2-(4-(((S)-2-(4-chlorophenyl))-3-((1R,6S)-5-((R)-5-methyl-7-oxo-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-4-yl)-2,5-diazabicyclo[4.1.0]hept-2-yl)-3-oxopropyl)amino)piperidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

[0538] (R)-4-((1S,6R)-5-((S)-2-(4-chlorophenyl)-3-(piperidin-4-ylamino)propanoyl)-2,5-diazabicyclo[4.1.0]hept-2-yl)-5-methyl-5,8-dihydropyrido[2,3-d]pyrimidin-7(6H)-one (93 mg), 2-(2,6-dioxopiperidin-3-yl)-5-(2-oxo-7-azaspiro[3.5]nonan-7-yl)isoindoline-1,3-dione (70 mg), and 1,2-dichloroethane (7 mL) were added to a reaction flask, and the mixture was stirred at room temperature under a nitrogen atmosphere for 1 hour. Sodium triacetoxyborohydride (112.5 mg) was then added to the mixture, and the mixture was stirred at room temperature under a nitrogen atmosphere for 2 hours. After the reaction was completed, the resulting mixture was concentrated under reduced pressure. The crude product was separated by preparative liquid phase to obtain 7.1 mg of the title compound.

[0539] 1 H NMR (400MHz, DMSO-d6) δ11.07(s,1H),10.50(s,1H),8.20(s,1H),7.65(d,J=8.4Hz,1H),7.44(s,2H),7.34(d,J=8.2Hz,3H ),7.25(s,1H),5.06(d,J=12.0Hz,1H),4.75-4.43(m,1H),4.21-4.04(m,1H),3.87-3.66(m,3H),3.52-3.43(m,5H),3.20(s ,5H),2.88(s,2H),2.76(d,J=14.6Hz,2H),2.67(s,1H),2.60(s,1H),2.36-2.15(m,1H),2.17-2.08(m,1H),2.09-1.94(m, 1H),1.82-1.71(m,6H),1.69-1.48(m,2H),1.35-1.18(m,5H),1.07(d,J=7.3Hz,1H),0.99-0.85(m,1H),0.87-0.76(m,4H).

[0540] LCMS m / z=903[M+1] +

[0541] Example 36 Preparation of 5-(4-(2-(4-(((S)-2-(4-chlorophenyl))-3-((1R,6S)-5-((R)-5-methyl-7-oxo-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-4-yl)-2,5-diazabicyclo[4.1.0]hept-2-yl)-3-oxopropyl)amino)piperidin-1-yl)ethyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

[0542] a) Preparation of 2-(2,6-dioxopiperidin-3-yl)-5-(4-(2-hydroxyethyl)piperidin-1-yl)isoindoline-1,3-dione

[0543] 2-(Piperidin-4-yl)ethan-1-ol (300 mg), 2-(2,4-dioxocyclohexyl)-5-fluoroisoindoline-1,3-dione (641 mg), N,N-diisopropylethylamine (1.8 g), and N-methylpyrrolidone (3 mL) were added to a reaction flask and stirred at 90°C for 16 hours. After the reaction, water (10 mL) was added and the mixture was extracted with ethyl acetate (15 mL x 3). The organic phases were combined and dried over anhydrous sodium sulfate. The solid was filtered, the organic phase was concentrated, and the crude product was purified by column chromatography (mobile phase: ethyl acetate / petroleum ether) to obtain 450 mg of the title compound.

[0544] b) Preparation of 2-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)acetaldehyde

[0545] 2-(2,6-dioxopiperidin-3-yl)-5-(4-(2-hydroxyethyl)piperidin-1-yl)isoindoline-1,3-dione (450 mg), (1,1,1-triacetoxy)-1,1-dihydro-1,2-benzoiodooxolane-3(1H)-one (2.47 g), and dichloromethane (10 mL) were added to a reaction flask and stirred at room temperature for 1 hour. After the reaction was completed, water (15 mL) was added and the mixture was extracted with ethyl acetate (20 mL × 3). The organic phases were combined and dried over anhydrous sodium sulfate. The solid was filtered off, the organic phase was concentrated, and the crude product was purified by column chromatography (mobile phase: ethyl acetate / petroleum ether) to obtain 350 mg of the title compound.

[0546] c) Preparation of 5-(4-(2-(4-(((S)-2-(4-chlorophenyl))-3-((1R,6S)-5-((R)-5-methyl-7-oxo-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-4-yl)-2,5-diazabicyclo[4.1.0]hept-2-yl)-3-oxopropyl)amino)piperidin-1-yl)ethyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

[0547] (R)-4-((1S,6R)-5-((S)-2-(4-chlorophenyl)-3-(piperidin-4-ylamino)propanoyl)-2,5-diazabicyclo[4.1.0]hept-2-yl)-5-methyl-5,8-dihydropyrido[2,3-d]pyrimidin-7(6H)-one (68 mg), 2-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)acetaldehyde (50 mg), tetraisopropoxytitanium (56 mg), and tetrahydrofuran (2 mL) were added to a reaction flask, and the mixture was stirred at room temperature under a nitrogen atmosphere for half an hour. Sodium triacetoxyborohydride (55 mg) was then added to the mixture, and the mixture was stirred at room temperature under a nitrogen atmosphere for 2 hours. After completion of the reaction, the resulting mixture was concentrated under reduced pressure. The crude product was separated by preparative liquid phase to obtain 20.8 mg of the title compound.

[0548] 1 H NMR (400MHz, DMSO-d6) δ11.01(s,1H),10.43(d,J=8.0Hz,1H),8.13-8.10(m,1H),7.58(d,J= 8.5Hz,1H),7.31(m,4H),7.23(d,J=2.3Hz,1H),7.15(dd,J=8.7,2.2Hz,1H),4.99(dd,J=12.9 ,5.4Hz,1H),4.41-4.30(m,1H),4.41-4.24(m,1H),4.09-4.01(m,1H),4.00-3.96(m,1H),3.9 6-3.93(m,1H),3.76-3.70(m,1H),3.70-3.66(m,1H),3.63-3.58(m,1H),3.21-3.17(m,1H),3 .16-3.13(m,1H),3.12-3.09(m,1H),3.09-3.03(m,1H),2.92-2.85(m,2H),2.84-2.79(m,1H ),2.79-2.66(m,4H),2.58-2.48(m,2H),2.33-2.21(m,2H),2.18(d,J=15.9Hz,2H),1.96(dd, J=6.7,3.9Hz,1H),1.92(d,J=3.8Hz,3H),1.75-1.61(m,4H),1.58-1.42(m,1H),1.31(q,J=7. 7Hz,2H),1.21-1.08(m,2H),1.03-0.90(m,1H),0.88(t,J=6.5Hz,3H),0.09(q,J=5.2Hz,1H).

[0549] LCMS m / z=892[M+1] +

[0550] Example 37 Preparation of 5-(4-(2-(4-(2-(((S)-2-(4-chlorophenyl))-3-((1R,6S)-5-((R)-5-methyl-7-oxo-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-4-yl)-2,5-diazabicyclo[4.1.0]hept-2-yl)-3-oxopropyl)amino)ethyl)piperidin-1-yl)ethyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

[0551] a) Preparation of 5-(4-(2-(4-(2,2-dimethoxyethyl)piperidin-1-yl)ethyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

[0552] A solution of 2-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)acetaldehyde (100 mg) and 4-(2,2-dimethoxyethyl)piperidine (45 mg) in 1,2-dichloroethane (2 mL) was stirred at room temperature for half an hour. Sodium triacetoxyborohydride (110.5 mg) was then added to the mixture and stirring continued at room temperature for 1.5 hours. After the reaction was complete, the resulting mixture was diluted with water (5 mL) and extracted with ethyl acetate (5 mL x 3). The combined organic layers were washed with brine (5 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and used directly in the next step.

[0553] b) Preparation of 2-(1-(2-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)ethyl)piperidin-4-yl)acetaldehyde

[0554] 5-(4-(2-(4-(2,2-dimethoxyethyl)piperidin-1-yl)ethyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (90 mg) was added to a 1,4-dioxane hydrochloric acid solution (4 M, 1 mL) and stirred at room temperature for 1 hour. After the reaction, the pH was adjusted to 8-9 with aqueous sodium bicarbonate solution, and then extracted with ethyl acetate (10 mL x 3). The organic phases were combined and dried over anhydrous sodium sulfate. The solid was filtered, and the organic phase was concentrated. The crude product was separated by preparative liquid phase separation to obtain 60 mg of the title compound.

[0555] c) Preparation of 5-(4-(2-(4-(2-(((S)-2-(4-chlorophenyl))-3-((1R,6S)-5-((R)-5-methyl-7-oxo-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-4-yl)-2,5-diazabicyclo[4.1.0]hept-2-yl)-3-oxopropyl)amino)ethyl)piperidin-1-yl)ethyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

[0556] (R)-4-((1S,6R)-5-((S)-3-amino-2-(4-chlorophenyl)propanoyl)-2,5-diazabicyclo[4.1.0]hept-2-yl)-5-methyl-5,8-dihydropyrido[2,3-d]pyrimidin-7(6H)-one (44.5 mg), 2-(1-(2-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)ethyl)piperidin-4-yl)acetaldehyde (50 mg), and 1,2-dichloroethane (2 mL) were added to a reaction flask, and the mixture was stirred at room temperature under a nitrogen atmosphere for half an hour. Sodium triacetoxyborohydride (43 mg) was then added to the mixture, and the mixture was stirred at room temperature under a nitrogen atmosphere for 2 hours. After completion of the reaction, the resulting mixture was concentrated under reduced pressure. The crude product was separated by preparative liquid phase to obtain 2.5 mg of the title compound.

[0557] 1H NMR (400MHz, DMSO-d6) δ11.08 (s, 1H), 10.50 (d, J = 9.0Hz, 1H), 8.22-8.18 ( m,1H),7.64(d,J=8.6Hz,1H),7.43-7.37(m,2H),7.37-7.32(m,2H),7.29( d,J=2.3Hz,1H),7.22(dd,J=8.8,2.3Hz,1H),5.06(dd,J=12.9,5.4Hz,1H) ,4.44-4.38(m,1H),4.11(d,J=10.0Hz,1H),4.02(d,J=13.1Hz,2H),3.79-3 .76(m,1H),3.64-3.61(m,1H),3.55-3.48(m,1H),3.15-3.13(m,6H),3.00 -2.87(m,3H),2.86-2.72(m,4H),2.71-2.64(m,2H),2.35-2.21(m,3H),2. 01(dd,J=9.4,4.2Hz,1H),1.77(dd,J=31.9,12.1Hz,4H),1.54(t,J=15.3H z,3H),1.43-1.08(m,9H),1.12-1.03(m,2H),0.96(dd,J=14.7,6.7Hz,3H).

[0558] LCMS m / z=919[M+1] +

[0559] Example 38 Preparation of 5-(4-(2-(4-(2-(((S)-2-(4-chlorophenyl))-3-((1R,6S)-5-((R)-5-methyl-7-oxo-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-4-yl)-2,5-diazabicyclo[4.1.0]hept-2-yl)-3-oxopropyl)amino)ethyl)piperidin-1-yl)ethyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

[0560] a) Preparation of tert-butyl 4-((1,3-dioxolan-2-yl)methyl)piperidine-1-carboxylate

[0561] tert-Butyl 4-(2-oxoethyl)piperidine-1-carboxylate (1 g), ethylene glycol (0.27 g), p-toluenesulfonic acid (0.04 g), and toluene (10 mL) were added to a reaction flask and stirred overnight at 100°C under air. After the reaction, the resulting mixture was concentrated under reduced pressure, and ethyl acetate (60 mL) was added. The organic layer was washed with water (20 mL x 3) and dried over anhydrous sodium sulfate. The solid was filtered off, and the filtrate was concentrated to obtain 980 mg of the title compound.

[0562] b) Preparation of 4-((1,3-dioxolan-2-yl)methyl)piperidine

[0563] tert-Butyl 4-((1,3-dioxolan-2-yl)methyl)piperidine-1-carboxylate (900 mg), zinc bromide (747 mg), and hexafluoroisopropanol (10 mL) were added to a reaction flask and stirred overnight at room temperature. After the reaction, the solid was filtered off and the reaction mixture was concentrated to obtain 500 mg of crude product, which was used directly in the next step.

[0564] c) Preparation of 5-(4-((4-((1,3-dioxolan-2-yl)methyl)piperidin-1-yl)methyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

[0565] A solution of 1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidine-4-carbaldehyde (431 mg), 4-((1,3-dioxolan-2-yl)methyl)piperidine (200 mg), and tetraisopropoxytitanium (664 mg) in 1,2-dichloroethane (5 mL) was stirred at room temperature for half an hour. Sodium triacetoxyborohydride (495 mg) was then added to the mixture, and stirring was continued at room temperature for 1.5 hours. After the reaction was completed, the resulting mixture was quenched with water (2 mL), and the crude product was separated using a reverse-phase column (C18 column, mobile phase: acetonitrile / water (0.1% NH3.H2O)) to yield 150 mg of the title compound.

[0566] d) Preparation of 2-(1-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)methyl)piperidin-4-yl)acetaldehyde

[0567] 5-(4-((4-((1,3-dioxolane-2-yl)methyl)piperidin-1-yl)methyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (50 mg) was added to trifluoroacetic acid (1 mL) and stirred at room temperature for 1 hour. After the reaction, the reaction mixture was concentrated to obtain the crude product, which was used directly in the next step.

[0568] e) Preparation of 5-(4-(2-(4-(2-(((S)-2-(4-chlorophenyl))-3-((1R,6S)-5-((R)-5-methyl-7-oxo-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-4-yl)-2,5-diazabicyclo[4.1.0]hept-2-yl)-3-oxopropyl)amino)ethyl)piperidin-1-yl)ethyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

[0569] (R)-4-((1S,6R)-5-((S)-3-amino-2-(4-chlorophenyl)propanoyl)-2,5-diazabicyclo[4.1.0]hept-2-yl)-5-methyl-5,8-dihydropyrido[2,3-d]pyrimidin-7(6H)-one (46 mg), 2-(1-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)methyl)piperidin-4-yl)acetaldehyde (40 mg), tetraisopropoxytitanium (47 mg), and 1,2-dichloroethane (2 mL) were added to a reaction flask, and the mixture was stirred at room temperature under a nitrogen atmosphere for half an hour. Sodium triacetoxyborohydride (35 mg) was then added to the mixture, and the mixture was stirred at room temperature under a nitrogen atmosphere for 2 hours. After completion of the reaction, the resulting mixture was concentrated under reduced pressure. The crude product was separated by preparative liquid phase to obtain 5 mg of the title compound.

[0570] 1H NMR (400MHz, DMSO-d6) δ11.06(s,1H),10.48(d,J=10.2Hz,1H),8.20(d,J=7.8Hz,1H),7.64(d,J=8.5Hz,1H),7.39(s,2H),7.35(d,J=4. 0Hz,1H),7.29(d,J=2.4Hz,2H),7.25-7.18(m,1H),5.06(dd,J=12.8,5.4Hz,1H),4.40(dd,J=15.6,7.8Hz,1H),4.26-4.06(m,1H),4.05 -3.94(m,3H),3.90-3.82(m,1H),3.79 -3.54(m,2H),3.22 -3.18(m,1H),3.18 -3.11(m,2H),2.93(q,J=12.4Hz,4H),2.83-2.65(m,4H),2.63-2.56(m,2H),2.55-2.53(m,1H),2.26(t,J=15.7Hz,2H),2.14- 1.92(m,4H),1.88-1.65(m,6H),1.62-1.44(m,4H),1.43-1.35(m,1H),1.24(s,3H),1.11(d,J=4.2Hz,2H),1.09-0.98(m,2H).

[0571] LCMS m / z=905[M+1]+

[0572] 2. Active Part

[0573] The specific structure of the positive reference compound used in the activity experiment is as follows:

[0574] (Yangshen MS170, J. Med. Chem. 2021, 64, 24, 18054-18081)

[0575] Experiment 1 In vitro enzyme activity test

[0576] 1. Materials and Reagents

[0577] Envision plate reader (Molecular Devices)

[0578] White 384-well plate (Cat. #264706, Thermo)

[0579] Key Reagents Included in the HTRK KinEASE STK Kit (Cat. #62TKOPEC, Cisbio)

[0580] STK-biotin substrate

[0581] Streptavidin-XL665

[0582] Europium-labeled tyrosine kinase substrate antibodies

[0583] 5× enzyme reaction buffer

[0584] HTRF detection buffer

[0585] AKT1 (Cat. No. 01-101, Carna)

[0586] AKT2 (Cat. #01-102, Carna)

[0587] AKT3 (Cat. #PV3185, Invitrogen)

[0588] ATP 10 mM (Cat. #PV3227, Invitrogen)

[0589] DTT 1M (Cat. #D5545, Sigma)

[0590] MgCl2 1M (Cat. #M8266, Sigma)

[0591] 2. Experimental Procedure

[0592] 2.1 Reagent preparation

[0593] Table 1 Components and concentrations of kinase reaction system

[0594] (1) 1× kinase reaction buffer

[0595] 1 mL of 1× kinase reaction buffer for AKT1 / 2 / 3 contains 200 μL of 5× kinase reaction buffer, 5 μL of 1M MgCl2, 1 μL of 1M DTT, and 794 μL of ultrapure water.

[0596] (2) 5×STK-biotin substrate and ATP working solution

[0597] The specific concentrations of STK-biotin substrate and ATP are shown in Table 1.

[0598] Dilute substrate and ATP to 5 times the reaction concentration in 1× kinase reaction buffer.

[0599] (3) 5× kinase working solution

[0600] The concentrations used in enzyme screening are shown in Table 1. 5× enzyme working solution was prepared using 1× kinase reaction buffer.

[0601] (4) 4× Streptavidin-XL665 working solution

[0602] The concentration of streptavidin-XL665 in the reaction is shown in Table 1. Prepare 4× streptavidin-XL665 working solution in assay buffer.

[0603] (5) 4× Europium-labeled tyrosine kinase substrate antibody working solution

[0604] The europium-labeled tyrosine kinase substrate antibody was diluted 100-fold with detection reaction buffer to prepare the working solution.

[0605] 2.2 Experimental Procedure

[0606] After all reagents except the enzyme are prepared according to the above method and equilibrated to room temperature, start adding samples.

[0607] a) First, dilute the compound stock solution (10 mM in DMSO) to a 100 μM compound solution with DMSO. Then, dilute the compound to a 2.5 μM working solution (containing 2.5% DMSO) using 1x kinase reaction buffer. Prepare a 2.5% DMSO solution in 1x kinase reaction buffer, then dilute the 2.5 μM compound working solution with the 2.5% DMSO solution. Perform a 4-fold serial dilution sequence seven times, for a total of eight working concentrations (2500 nM, 625 nM, 156 nM, 39 nM, 9.8 nM, 2.4 nM, 0.6 nM, and 0.15 nM). Add 4 μL of the diluted compound working solution to all reaction wells, except for the control wells, to which 4 μL of the previously prepared 2.5% DMSO / kinase buffer solution was added.

[0608] b) Add 2 μL of the previously prepared STK-biotin substrate solution to all reaction wells (see Table 1 for the amount of substrate used in enzyme screening).

[0609] c) Add 2 μL of the previously prepared enzyme solution (see Table 1 for enzyme dosage) to all reaction wells except the negative wells. For the negative wells, add 2 μL of enzyme to the corresponding volume of 1× kinase reaction buffer. Seal the plate with sealing film, mix thoroughly, and incubate at room temperature for 10 minutes to allow the compound and enzyme to fully interact and bind.

[0610] d) Add 2 μL of ATP solution to all reaction wells to start the kinase reaction (see Table 1 for ATP concentration and reaction time for enzyme screening).

[0611] e) Prepare the detection solution 5 minutes before the end of the kinase reaction. Prepare the detection solution containing streptavidin-XL665 and europium-labeled tyrosine kinase substrate antibody (1:100) using the detection buffer provided in the kit (see Table 1 for detection reagent concentrations for enzyme screening).

[0612] f) After the kinase reaction is complete, add 5 μL of diluted streptavidin-XL665 to all reaction wells, mix thoroughly, and immediately add diluted europium-labeled tyrosine kinase substrate antibody detection solution.

[0613] g) Seal the plate and mix thoroughly. After incubation at room temperature for 1 hour, use ENVISION (PerkinElmer) to detect the fluorescence signal (320 nm excitation, 665 nm, 615 nm emission). Calculate the inhibition rate of each well based on the total activity wells and background signal wells, and take the average value of the duplicate wells. At the same time, use the professional drawing and analysis software PRISM 5.0 to calculate the half inhibition activity (IC) of each test compound. 50 ) of the fitting.

[0614] Table 2: Experimental sample addition process

[0615] 2.3 Data Analysis

[0616] ER = fluorescence value at 665 nm / fluorescence value at 615 nm

[0617] Inhibition rate = (ER 阳性对照 -ER 样品 ) / (ER 阳性对照 -ER 阴性对照 )*100%

[0618] 3. Experimental Results

[0619] The experimental results are shown in Table 3:

[0620] Table 3: AKT inhibitory activity

[0621] Experiment 2: NanoLuc assay to detect the degradation activity of compounds on target proteins in cells

[0622] 1. Materials and Reagents

[0623] HEK293 cells

[0624] DMEM medium (catalog number #SH30243.01, Hyclone)

[0625] Opti-MEM I medium (catalog #31985-070, Gibco)

[0626] Fetal bovine serum (catalog number #10099-141C, Gibco)

[0627] FuGENE HD Transfection Reagent (Cat. No. E2312, Promega)

[0628] DMSO (catalog number D2650-100 ml, Sigma)

[0629] pNLF1-N[CMV / Hygro] Vector (Cat. #N1351, Promega)

[0630] Nano-Glo Luciferase Assay System (Cat. #N1110, Promega)

[0631] Trans5α Chemically Competent Cell (Cat. #CD201-01, TransGen)

[0632] LB sterile liquid medium (catalog number #B540111, Sangon)

[0633] UNIQ-500 Endotoxin-Free Plasmid Mass Extraction Kit (Cat. No. B11249, Sangon)

[0634] Ultra-micro digital pipette (Model #D300e, Tecan)

[0635] Cell counter (model #RigelS2, Countstar )

[0636] Multifunctional microplate reader (Model #SPARK, Tecan)

[0637] Nucleic acid quantitative analyzer (model #NanoDrop One, Thermo)

[0638] 2. Experimental Procedure

[0639] 2.1 Construction and amplification of target plasmids

[0640] Using molecular biology techniques, the complete nucleic acid sequences of the protein coding regions of AKT1 (NM_005163.2), AKT2 (NM_001626.6), and AKT3 (NM_005465.7) were cloned into the pNLF1-N[CMV / Hygro] plasmid, using restriction enzyme sites: EcoRI at the 5' end and XbalI at the 3' end. After sequencing confirmed the correct insertion of the target sequences into the pNLF1-N[CMV / Hygro] plasmid (target plasmid), the target plasmids were transformed into Trans5α chemically competent cells and amplified in sterile LB liquid medium (220 rpm for 16–18 hours). Following amplification, the target plasmids were purified using the UNIQ-500 Endotoxin-Free Plasmid Maxi-Purification Kit, and the concentration and purity of the target plasmids were determined using the NanoDrop One assay.

[0641] 2.2 Transfection of target plasmid

[0642] a) Dilute the target plasmid (AKT1, AKT2, AKT3) to 10 ng / μL using TE Buffer.

[0643] b) HEK293 cell density was adjusted to 2E5 / mL using DMEM medium.

[0644] c) 2 μg of plasmid complex (10 ng target plasmid and 1990 ng pcDNA3.1(+) empty plasmid) was diluted in 200 μL Opti-MEM I medium and mixed thoroughly.

[0645] d) Add 6 μL of FuGENE HD Transfection Reagent to the Opti-MEM I medium containing the plasmid, mix thoroughly by inverting the tube 5-10 times, and incubate at room temperature for 20 minutes.

[0646] e) Add the incubated plasmid / transfection reagent mixture to 5 mL of HEK-293 cells, mix thoroughly by inverting five times, and transfer the cells to a culture flask. Incubate the cells in a 37° C., 5% CO 2 incubator for 12 hours.

[0647] 2.3 Compound treatment

[0648] The cells in the culture flask were routinely digested, centrifuged, and counted. HEK-293 cells transfected with the target plasmid were seeded into a 96-well plate with a white bottom opaque base at a density of 10,000 cells per well (100 μL culture medium per well). After 24 hours, the cells were treated with different concentrations of the compound for the corresponding time (4 hours to 24 hours) using an ultra-micro digital pipette.

[0649] 2.4 Signal detection and data analysis

[0650] a) Thaw the substrate and buffer in the Nano-Glo Luciferase Assay System kit overnight at 4°C. Mix 25 μL of substrate with 1.25 mL of buffer in the appropriate proportions for the assay volume. (This mixture forms the assay working solution. After thawing, pipette to mix thoroughly, then add to the buffer and mix thoroughly.) Store the prepared reagents at 4°C until use.

[0651] b) Before testing, equilibrate the test solution to room temperature and leave the cells at room temperature for 10 minutes.

[0652] c) Add an equal volume of assay working solution to the cell culture medium into a 96-well plate and mix on a microplate shaker for 3 minutes.

[0653] d) Detect the chemiluminescent signal in each well using a multifunctional microplate reader.

[0654] e) DC was calculated using Graphpad Prism software 50 (50% degradation concentration of compound) and D MAX (The maximum degradation degree of the target protein).

[0655] 3. Experimental Results

[0656] The experimental results are shown in Table 4.

[0657] Table 4 NanoLuc assay for the degradation activity of compounds on target proteins in cells

[0658] Experiment 3: ICW (In-Cell Western) assay of AKT1 / 2 / 3 protein degradation in PC-3 cells

[0659] On the first day, PC-3 cells (human prostate cancer cells, culture medium: F12K + 10% FBS + 1% P / S), purchased from ATCC (Cat. No. CRL-1435), were seeded. These cells, in the logarithmic growth phase, were plated at a density of 3,000 cells / well in a 384-well plate and cultured overnight in a 37°C, 5% CO2 incubator.

[0660] On the second day, the compounds were incubated using an Echo 665 Liquid Handler, with 40 ml / well of serially diluted compounds (starting concentration 10 μM, 3-fold serial dilutions, 10 doses in total, 0.1% DMSO) added, and the cells were incubated in a 37°C, 5% CO2 incubator for 24 h.

[0661] On the third day, centrifuge the plate for 1 minute and add 40 ml / well of 8% PFA (paraformaldehyde) fixative using an Apricot Personal Pipettor 384-channel pipetting station. Incubate at room temperature for 20 minutes. Remove the supernatant, wash twice with 40 ml / well of DPBS, and permeabilize the cells with 100% cold methanol and incubate at room temperature for 10 minutes. Remove the supernatant, wash once with 40 ml / well of DPBS, add 40 ml / well of Li-Cor blocking buffer, and incubate at room temperature for 1 hour. Remove the supernatant, and add 20 ml / well of primary antibody solution (antibodies diluted in blocking buffer: AKT1 Rabbit mAb (CST, Cat. No. 75692S) at a dilution of 1:500; AKT2 Rabbit mAb (CST, Cat. No. 3063S) at a dilution of 1:1000; AKT3 Rabbit mAb (CST, Cat. No. 14982S) at a dilution of 1:200). Incubate overnight at 4°C.

[0662] On the fourth day, the supernatant solution was discarded and the cells were washed three times with 40 ml / well TBST (0.05% Tween-20 in TBS) and soaked for 5 min / time. Then, 20 ml / well secondary antibody solution (Alexa Fluor 488 goat anti-rabbit 1:1000 and Hoechst 1:5000 diluted with blocking buffer) was added and incubated at room temperature for 1 hour. The supernatant solution was discarded and the cells were washed three times with 40 ml / well PBST (0.05% Tween-20 in PBS) and soaked for 5 min / time. The plate was centrifuged at 1000 rpm for 1 minute and then detected using an Operetta high-content cell analyzer. The dose-effect curve was fitted using GraphPad Prism 5 software log (inhibitor) vs. response-Variable slope to obtain the DC effect of the compound on the degradation of AKT1 / 2 / 3 protein in cells. 50 value.

[0663] The compounds of the relevant examples had an activity of <100 uM.

[0664] Experiment 4: MDA-MB-468 cell proliferation inhibition experiment

[0665] MDA-MB-468 (purchased from Kebai, Cat: CBP60387) human breast cancer cell line was cultured in DMEM supplemented with 10% FBS (fetal bovine serum). Cells in the logarithmic growth phase were plated at a density of 3,000 cells / well in a 96-well plate (purchased from PerkinElmer, Cat: 6005181). A G0 control plate was also prepared for testing the following day. The seeded cell plates were incubated in a 37°C, 5% CO2 incubator for 24 hours.

[0666] On the first day of the experiment, the cell plates were removed and the compounds were added using an automated dosing device (Tecan, D300e). The starting concentration of the compounds was 30 mM, and a 3-fold gradient dilution was performed for a total of 9 gradients. The final DMSO concentration in each well was 0.3%. After the addition of the compounds, the cell plates were placed in a 37°C, 5% CO2 incubator for 120 h. At the same time, the G0 control plate was removed from the incubator and 50 μl of Cell Counting-Lite was added to each well. TM 2.0 Solution (purchased from Vazyme), and the fluorescence signal was measured on Envision (PerkinElmer) according to the operating procedures in the instruction manual.

[0667] On the 6th day of the experiment, the cell plate was removed and 50 μl Cell Counting-Lite was added to each well. TM 2.0 The fluorescence signal was measured on Envision (PerkinElmer) according to the instructions of the manufacturer's instructions. The dose-effect curve was fitted using GraphPad Prism 5 software: log (inhibitor) vs. response-Variable slope, and the absolute GI of the compound's inhibitory activity on cell proliferation was obtained. 50 Value. The formula for calculating activity rate is:

[0668] in:

[0669] Test substance signal value: mean fluorescence signal of cell+medium+compound group;

[0670] Signal value of G0 group: mean fluorescence signal of cells + culture medium group detected on day 1;

[0671] Signal value of negative control group: mean fluorescence signal of cells + culture medium group detected on day 6.

[0672] For detailed results, see Table 5

[0673] Table 5 Results of MDA-MB-468 cell proliferation inhibition experiment

[0674] Experiment 5: Pharmacokinetics in mice

[0675] (1) Prescription preparation of the compound:

[0676] Mixed solvent: DMSO: Solutol HS: normal saline = 5:10:85 (V / V / V)

[0677] Drug preparation process:

[0678] Weigh the required amount of test material into a brown glass bottle, add DMSO (5% by volume of the total solvent), mix thoroughly, then add Solutol HS (10% by volume of the total solvent), mix thoroughly, and finally add physiological saline (85% by volume of the total solvent). Ultrasonicate until the solution is clear to obtain a clear, transparent solution of the desired concentration.

[0679] (2) Experimental animals: Mice, strain ICR, source: Hunan Slake Jingda Experimental Animal Co., Ltd., age: 6-8 weeks, male.

[0680] (3) Experimental plan:

[0681] Experimental animals were housed in the animal room of the Experimental Animal Center of Hunan University of Chinese Medicine. The animals were housed in rat cages in a well-ventilated, air-conditioned room with a temperature maintained between 20 and 26°C and a humidity maintained between 40% and 70%. A time-controlled lighting system provided a 12-hour light / 12-hour dark cycle. Animal cages and water bottles were changed regularly throughout the study. Mice were selected for this study if they were fed normally for at least 3 days and were in good physical condition after veterinary examination. Each mouse was identified by a tail number. The animal experimental protocol is detailed in Table 1.

[0682] Table 1 Animal experiment plan

[0683] After weighing the body weight, the theoretical administration volume for each mouse was calculated according to the following formula.

[0684] The day before the experiment, mice were fasted overnight (>12 h) and had free access to water. They were fed 4 h after drug administration.

[0685] On the day of the experiment, mice in the treatment group were gavage-administered a 10 mg / kg dose solution. At various time points after dosing, approximately 0.1 mL of blood was collected from the mouse's orbital cavity and placed in an EDTA-K2 anticoagulant tube. The tubes were gently inverted to thoroughly mix the anticoagulant (EDTA-2K) and blood, then immediately placed on wet ice. Plasma was rapidly centrifuged within 1 hour of blood collection at 4°C, 6800 g, and 6 minutes. After centrifugation, plasma was transferred to labeled EP tubes and stored in a -20°C freezer within 1 hour for biological sample analysis. An LC-MS / MS analytical method was developed to determine compound concentrations in mouse plasma and used to determine compound concentrations in the biological samples obtained in this experiment. Pharmacokinetic parameters were calculated using a non-compartmental model in Phoenix WinNonlin 8.3.

Claims

1. A compound of formula I or a pharmaceutically acceptable salt thereof, the specific structure of which is as follows: B—L—D (I) in, L is selected from —Ak1—C1—Ak2—C2—Ak3—or —Ak4—Cy1—Ak5—Cy2—Ak6—; Wherein Ak1, Ak2, and Ak3 are independently selected from or key; C1 and C2 are independently selected from C 1-12 Alkyl, C 2-12 Alkenyl or C 2-12 alkynyl or bond, and C1 and C2 are not bonds at the same time, the C 1-12 Alkyl, C 2-12 Alkenyl or C 2-12 The alkynyl group is optionally substituted with one or more C 1-4 Alkyl or halogen substitution; wherein Ak4, Ak5, and Ak6 are independently selected from optionally substituted with one or more oxygen, C 1-4 Alkyl or halogen substituted C 1-12 An alkyl group or bond; Cy1 and Cy2 are independently selected from a 3-12 membered heterocyclic ring, a 3-12 membered cycloalkyl group, a 6-10 membered aryl group or a bond, and Cy1 and Cy2 are not simultaneously a bond, and the 3-12 membered heterocyclic ring, the 3-12 membered cycloalkyl group, the 6-10 membered aryl group is optionally substituted by one or more halogens or C 1-4 Alkyl substitution; B is wherein X is selected from C or N; R 1 is halogen or hydrogen; R 2 Selected from H, CN, C 1-6 Alkyl or C 1-6 Alkoxy, wherein the C 1-6 Alkyl or C 1-6 Alkoxy is optionally substituted by halogen, OH, CN; G is optionally substituted by C 1-4 A 5-12 membered saturated heterocyclic ring containing 1-2 nitrogen atoms which is substituted by an alkyl group; R 3 For NH, or does not exist; D is selected from the following structure: When B is When , L is not —Ak1—C1—Ak2—C2—Ak3—.

2. The compound of formula (I) according to claim 1, wherein L is selected from C 1-12 Alkyl, C 2-12 Alkenyl or C 2-12 The alkynyl group, wherein the C 1-12 Alkyl, C 2-12 Alkenyl or C 2-12 The alkynyl group is optionally substituted with one or more C 1-4 Alkyl or halogen substituted, or—Ak4—Cy1—Ak5—Cy2—Ak6, wherein Ak4, Ak5, and Ak6 are independently selected from C optionally substituted by one or more oxygen radicals. 1-12 An alkyl group or bond, Cy1 and Cy2 are independently selected from the group consisting of 1-4 A 3-12 membered heterocyclic ring or a bond substituted by an alkyl group, and Cy1 and Cy2 are not bonds at the same time; Preferably, L is selected from optionally one or more C 1-4 Alkyl or halogen substituted C 1-12 Alkyl or C 2-12 The alkynyl group, or—Ak4—Cy1—Ak5—Cy2—Ak6; wherein Ak4, Ak5, and Ak6 are independently selected from C substituted by one or more oxygen 1-10 alkyl or bond; further Ak4, Ak5, Ak6 are independently selected from C 1-10 An alkyl group or bond; Cy1 and Cy2 are independently selected from a 4-9 membered heterocycle or a bond, and Cy1 and Cy2 are not bonds at the same time; Preferably, L is selected from C optionally substituted by one or more methyl groups. 1-12 Alkyl or C 2-12 The alkynyl group is further preferably optionally substituted by one or more methyl groups. 8-12 Alkyl or C 8-12 The alkynyl group is preferably C 8-12 Alkyl or C 8-12 The alkynyl group.

3. The compound of formula (I) as claimed in claim 2, wherein Cy1 and Cy2 are independently selected from a 4-9 membered heterocycle or a bond, and Cy1 and Cy2 are not bonds at the same time; Preferably, Cy1 and Cy2 are independently selected from a 4-9 membered heterocycle or a bond containing 1-2 N, and Cy1 and Cy2 are not bonds at the same time; Preferably, Cy1 and Cy2 are independently selected from azetidinyl, azetyl, piperidine, piperazine, cyclopropyl azetidinyl, cyclopropyl azetyl, cyclopropyl azetyl, cyclopropyl azetyl, cyclopropyl piperidine, cyclobutyl azetidinyl, cyclobutyl azetyl, cyclobutyl azetyl, cyclobutyl azetyl, cyclobutyl azetyl, cyclobutyl piperidine, cyclopentyl azetidinyl, cyclopentyl azetyl, cyclopentyl azetyl, cyclopentyl piperidine, cyclohexyl azetidinyl, cyclohexyl azetyl, azetidin azetidinyl, azetidin azetyl, azetidin azetyl, azetidin azetyl, azetidin piperidine , azetidinyl, azetidinyl, azetidinyl, azetidinyl, azetidinyl, azetidinyl piperidine, cyclobutyl spiroazetidinyl, cyclobutyl spiroazetidinyl, cyclobutyl spiroazetidinyl, cyclopentyl spiroazetidinyl, cyclopentyl spiroazetidinyl, cyclohexyl spiroazetidinyl, azetidinyl spiroazetidinyl, azetidinyl spiroazetidinyl, azetidinyl spiroazetidinyl, azetidinyl spiroazetidinyl, azetidinyl spiroazetidinyl, azetidinyl spiroazetidinyl, azetidinyl spiroazetidinyl, azetidinyl spiroazetidinyl, azetidinyl spiroazetidinyl, azetidinyl spiroazetidinyl, azetidinyl spiroazetidinyl, cyclobutyl spiro piperidine, azetidinyl spiro piperidine or a bond, Cy1 and Cy2 are not bonds at the same time; Preferably, Cy1 and Cy2 are independently selected from piperidine, piperazine or cyclobutyl spiroazaheterocyclohexyl or a bond, and Cy1 and Cy2 are not bonds at the same time.

4. The compound of formula (I) as claimed in claim 1, wherein L is selected from the following structures: The left side of L is connected to B, and the right side is connected to D; Preferably, L is selected from the following structures: Preferably, L is 5. The compound of formula (I) according to claim 1, characterized in that B is wherein X is selected from C or N; R 1 is chlorine or hydrogen; R 2 is a C1-C6 alkyl group, wherein the C1-C6 alkyl group is optionally substituted by OH; G is a 5-12 membered saturated heterocyclic ring containing 1-2 nitrogen atoms which is optionally substituted by methyl; R 3 For NH, Or does not exist.

6. The compound of formula (I) according to claim 5, wherein R 2 is methyl, ethyl or -(CH2)2OH, preferably, R 2 is methyl or ethyl; R 1 is chlorine, and G is the following group optionally substituted by methyl: Preferably, G is selected from the following groups: Preferably G is selected from the following groups:

7. The compound as claimed in claim 1, wherein B is selected from the following structures: Preferably, B is selected from the following structures: Preferably, B is selected from the following structures: Preferably, B is selected from the following structures:

8. The compound of formula (I) as claimed in claim 1, wherein D is selected from the following structures: Preferably, D is selected from the following structures: Preferably, D is the following structure 9. A compound of formula (II), formula (III), formula (IV), formula (V) or formula (VI) or a pharmaceutically acceptable salt thereof, the specific structure of which is as follows: L1 is selected from —Ak1—C1—Ak2—C2—Ak3—or —Ak4—Cy1—Ak5—Cy2—Ak6—; Wherein Ak1, Ak2, and Ak3 are independently selected from or key; C1 and C2 are independently selected from C 1-12 Alkyl, C 2-12 Alkenyl or C 2-12 alkynyl or bond, and C1 and C2 are not bonds at the same time, the C 1-12 Alkyl, C 2-12 Alkenyl or C 2-12 The alkynyl group is optionally substituted with one or more C 1-4 Alkyl or halogen substitution; wherein Ak4, Ak5, and Ak6 are independently selected from optionally substituted with one or more oxygen, C 1-4 Alkyl or halogen substituted C 1-12 An alkyl group or bond; Cy1 and Cy2 are independently selected from a 3-12 membered heterocyclic ring, a 3-12 membered cycloalkyl group, a 6-10 membered aryl group or a bond, and Cy1 and Cy2 are not simultaneously a bond, and the 3-12 membered heterocyclic ring, the 3-12 membered cycloalkyl group, the 6-10 membered aryl group is optionally substituted by one or more halogens or C 1-4 Alkyl substitution; D1 is selected from the following structure: L2 is selected from —Ak1—C1—Ak2—C2—Ak3—or —Ak4—Cy1—Ak5—Cy2—Ak6—; Wherein Ak1, Ak2, and Ak3 are independently selected from or key; C1 and C2 are independently selected from C 1-12 Alkyl, C 2-12 Alkenyl or C 2-12 alkynyl or bond, and C1 and C2 are not bonds at the same time, wherein the C 1-12 Alkyl, C 2-12 Alkenyl or C 2-12 The alkynyl group is optionally substituted with one or more C 1-4 Alkyl or halogen substitution; wherein Ak4, Ak5, and Ak6 are independently selected from optionally substituted with one or more oxygen, C 1-4 Alkyl or halogen substituted C 1-12 An alkyl group or bond; Cy1 and Cy2 are independently selected from a 3-12 membered heterocyclic ring, a 3-12 membered cycloalkyl group, a 6-10 membered aryl group or a bond, and Cy1 and Cy2 are not simultaneously a bond, wherein the 3-12 membered heterocyclic ring, the 3-12 membered cycloalkyl group, the 6-10 membered aryl group is optionally substituted by one or more halogens or C 1-4 Alkyl substitution; D2 is selected from the following structure: in, L3 is—Ak4—Cy1—Ak5—Cy2—Ak6—; wherein Ak4, Ak5, and Ak6 are independently selected from optionally substituted with one or more oxygen, C 1-4 Alkyl or halogen substituted C 1-12 An alkyl group or bond; Cy1 and Cy2 are independently selected from a 3-12 membered heterocyclic ring, a 3-12 membered cycloalkyl group, a 6-10 membered aryl group or a bond, and Cy1 and Cy2 are not simultaneously a bond, wherein the 3-12 membered heterocyclic ring, the 3-12 membered cycloalkyl group, the 6-10 membered aryl group is optionally substituted by one or more halogens or C 1-4 Alkyl substitution; D3 is selected from the following structure: Among them, L4 is —Ak4—Cy1—Ak5—Cy2—Ak6—; wherein Ak4, Ak5, and Ak6 are independently selected from optionally substituted with one or more oxygen, C 1-4 Alkyl or halogen substituted C 1-12 An alkyl group or bond; Cy1 and Cy2 are independently selected from a 3-12 membered heterocyclic ring, a 3-12 membered cycloalkyl group, a 6-10 membered aryl group or a bond, and Cy1 and Cy2 are not simultaneously a bond, wherein the 3-12 membered heterocyclic ring, the 3-12 membered cycloalkyl group, the 6-10 membered aryl group is optionally substituted by one or more halogens or C 1-4 Alkyl substitution; D4 is selected from the following structure: Among them, L5 is —Ak4—Cy1—Ak5—Cy2—Ak6—; wherein Ak4, Ak5, and Ak6 are independently selected from optionally substituted with one or more oxygen, C 1-4 Alkyl or halogen substituted C 1-12 An alkyl group or bond; Cy1 and Cy2 are independently selected from a 3-12 membered heterocyclic ring, a 3-12 membered cycloalkyl group, a 6-10 membered aryl group or a bond, and Cy1 and Cy2 are not simultaneously a bond, wherein the 3-12 membered heterocyclic ring, the 3-12 membered cycloalkyl group, the 6-10 membered aryl group is optionally substituted by one or more halogens or C 1-4 Alkyl substitution; D5 is selected from the following structure:

10. A compound having the following structure or a pharmaceutically acceptable salt thereof,

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