Cyclopropyl and 1,3,4-oxadiazole compounds that mediate protein degradation and methods of use thereof

Abstract

Described herein, in part, are compounds that mediate the degradation of cyclin-dependent kinase 2 (CDK2) and are therefore useful in the treatment of various disorders, such as cancer.

Description

Background Technology

[0001] Different small molecules can be used to manipulate the ubiquitin-proteasome system to trigger targeted degradation of specific proteins of interest. Utilizing small-molecule degradative agents to promote the targeted degradation of pathogenic proteins is emerging as a novel approach to disease treatment. One such approach relies on reorienting the activity of E3 ligases such as cereblon using low-molecular-weight compounds (a phenomenon known as E3 reprogramming). These low-molecular-weight compounds, called molecular glues, promote polyubiquitination and ultimately facilitate the proteasome degradation of novel protein substrates associated with disease development. The molecular glue binds to both the E3 ligase and the target protein, thereby mediating changes on the ligase surface and enabling interaction with the target protein.

[0002] WO 2023 / 069700 and WO 2023 / 069720 provide compounds that mediate the degradation of protein cyclin-dependent kinase 2 (CDK2) and are therefore used to treat various conditions such as cancer.

[0003] Further therapeutic agents that effectively mediate the degradation of CDK2 and possess favorable properties are needed. Summary of the Invention

[0004] This article provides compounds that can be used as hydroxycerebroside modulators to mediate the targeted degradation of CDK2, and thus could be used to treat various conditions, such as cancer.

[0005] In one respect, this paper provides a compound of formula (I): Formula (I), Or a pharmaceutically acceptable salt thereof, wherein: X is hydrogen or deuterium; R 1 R 2 and R 3 Each of these elements is independently hydrogen, halogen, hydroxyl, cyano, NO2, oxo, -N(R) Za (R) Zb C 1–6 Alkoxy or C 1–6 Alkyl, wherein C 1–6 The alkyl group is optionally substituted with one or more halogens; ring A is aryl, heteroaryl, or bicyclic [1.1.1]pentyl, and ring A is optionally substituted with one or more R... 4 Replace; each R 4 Independently halogen, cyano, -NO2, hydroxyl, -S(O)2N(R) Za (R) Zb C 1–6 Alkyl, C 2–6 alkynyl group, C 1–6 Alkoxy, C 1–6Thioalkoxy, C 3–10 Cycloalkyl, 3-10 membered heterocyclic, aryl or heteroaryl, wherein C 1–6 Alkyl, C 2–6 alkynyl group, C 1–6 Alkoxy, C 1–6 Thioalkoxy, C 3–10 Each of cycloalkyl, 3-10 membered heterocyclic, aryl, and heteroaryl groups is optionally bounded by one or more R groups. 5 Substitution; or attachment of two R atoms to the same ring A atom or adjacent ring A atom 4 Together with the atoms to which they are attached, they form 3-10 membered heterocycles or C rings. 3–10 Cycloalkyl rings, wherein the 3-10 membered heterocycles or C 3–10 The cycloalkyl ring is optionally surrounded by one or more R 5 Replace; each R 5 Independently halogen, oxo, hydroxyl, C 2-6 alkynyl group, C 1–6 Alkyl, C 1–6 Alkoxy, C 1–6 Thioalkoxy, C 3–10 Cycloalkyl, 3-10 membered heterocyclic, aryl or heteroaryl, wherein C 1–6 The alkyl group is optionally substituted with one or more halogens; and R Za and R Zb Each of them is independently hydrogen or C. 1–6 Alkyl; or R Za and R Zb Together with the nitrogen attached to them, they form 3-10 membered heterocycles.

[0006] In one aspect, this article describes a pharmaceutical composition comprising the compound described herein or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0007] In one aspect, this article describes a method for treating cancer in a subject in need, comprising administering to the subject a therapeutically effective amount of the compound described herein or a pharmaceutically acceptable salt thereof or a pharmaceutical composition described herein. Attached Figure Description

[0008] Figure 1 The results of in vivo experiments testing the antitumor activity of compound 1 are shown. Detailed Implementation

[0009] The features and other details of this disclosure will now be described in more detail. Certain terms used in this specification, embodiments, and appended claims are collected herein. These definitions should be read in light of the remainder of this disclosure and as understood by one of ordinary skill in the art. 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.

[0010] compound In one respect, this paper describes a compound of formula (I): Formula (I), Or a pharmaceutically acceptable salt thereof, wherein: X is hydrogen or deuterium; R 1 R 2 and R 3 Each of these elements is independently hydrogen, halogen, hydroxyl, cyano, NO2, oxo, -N(R) Za (R) Zb C 1–6 Alkoxy or C 1–6 Alkyl, wherein C 1–6 The alkyl group is optionally substituted with one or more halogens; ring A is aryl, heteroaryl, or bicyclic [1.1.1]pentyl, and ring A is optionally substituted with one or more R... 4 Replace; each R 4 Independently halogen, cyano, -NO2, hydroxyl, -S(O)2N(R) Za (R) Zb C 1–6 Alkyl, C 2–6 alkynyl group, C 1–6 Alkoxy, C 1–6 Thioalkoxy, C 3–10 Cycloalkyl, 3-10 membered heterocyclic, aryl or heteroaryl, wherein C 1–6 Alkyl, C 2–6 alkynyl group, C 1–6 Alkoxy, C 1–6 Thioalkoxy, C 3–10 Each of cycloalkyl, 3-10 membered heterocyclic, aryl, and heteroaryl groups is optionally bounded by one or more R groups. 5 Substitution; or attachment of two R atoms to the same ring A atom or adjacent ring A atom 4 Together with the atoms to which they are attached, they form 3-10 membered heterocycles or C rings. 3–10 Cycloalkyl rings, wherein the 3-10 membered heterocycles or C 3–10 The cycloalkyl ring is optionally surrounded by one or more R 5 Replace; each R 5 Independently halogen, oxo, hydroxyl, C 2-6alkynyl group, C 1–6 Alkyl, C 1–6 Alkoxy, C 1–6 Thioalkoxy, C 3–10 Cycloalkyl, 3-10 membered heterocyclic, aryl or heteroaryl, wherein C 1–6 The alkyl group is optionally substituted with one or more halogens; and R Za and R Zb Each of them is independently hydrogen or C. 1–6 Alkyl; or R Za and R Zb Together with the nitrogen attached to them, they form 3-10 membered heterocycles.

[0011] In some embodiments, X is hydrogen or deuterium. In some embodiments, X is hydrogen. In some embodiments, X is deuterium.

[0012] In some implementation schemes, R 1 R 2 and R 3 Each of these elements is independently hydrogen, halogen, hydroxyl, cyano, NO2, oxo, -N(R) Za (R) Zb C 1–6 Alkoxy or C 1–6 Alkyl, wherein C 1–6 The alkyl group is optionally substituted with one or more halogens. In some embodiments, R 1 R 2 and R 3 Each of these is independently hydrogen, halogen, hydroxyl, cyano, -N(R) Za (R) Zb C 1–6 Alkoxy or C 1–6 Alkyl, wherein C 1–6 The alkyl group is optionally substituted with one or more halogens. In some embodiments, R 1 R 2 and R 3 Each of these can be independently hydrogen, fluorine, chlorine, bromine, hydroxyl, cyano, NH2, OCH3, CH3, CHF2, or CF3.

[0013] In some implementation schemes, R 1 It is hydrogen.

[0014] In some implementation schemes, R 2 It is hydrogen, halogen or C 1–6 Alkyl, wherein C 1–6 The alkyl group is optionally substituted with one or more halogens. In some embodiments, R 2 It can be hydrogen, fluorine, chlorine, CH3, or CHF2. In some embodiments, R 2It is chlorine.

[0015] In some implementation schemes, R 3 It is hydrogen.

[0016] In some implementation schemes, R 1 and R 3 It is hydrogen. In some implementations, R 1 and R 3 It is hydrogen and R 2 It is chlorine.

[0017] In some implementation schemes, R Za and R Zb Each of them is independently hydrogen or C. 1–6 Alkyl; or R Za and R Zb Together with the nitrogen atoms attached to them, they form 3-10 membered heterocycles. In some embodiments, R Za and R Zb Each of them is independently C 1–6 Alkyl; or R Za and R Zb Together with the nitrogen atoms attached to them, they form 3-6 membered heterocycles. In some embodiments, C 1–6 The alkyl group is CH3. In some embodiments, the 3-6 membered heterocycle contains one nitrogen-containing cyclic heteroatom. In some embodiments, the 3-6 membered heterocycle is an azide-containing butane or pyrrolidine ring.

[0018] In some implementations, the compound contains up to two R atoms. 4 In some embodiments, the compound contains at most one R. 4 In some embodiments, the compound is not R 4 replace.

[0019] In some implementations, each R 4 Independently halogen, cyano, -NO2, hydroxyl, -S(O)2N(R) Za (R) Zb C 1–6 Alkyl, C 2–6 alkynyl group, C 1–6 Alkoxy, C 1–6 Thioalkoxy, C 3–10 Cycloalkyl, 3-10 membered heterocyclic, aryl or heteroaryl, wherein C 1–6 Alkyl, C 2–6 alkynyl group, C 1–6 Alkoxy, C 1–6 Thioalkoxy, C 3–10 Each of cycloalkyl, 3-10 membered heterocyclic, aryl, and heteroaryl groups is optionally bounded by one or more R groups. 5Substitution; or attachment of two R atoms to the same ring A atom or adjacent ring A atom 4 Together with the atoms to which they are attached, they form 3-10 membered heterocycles or C rings. 3–10 Cycloalkyl rings, wherein the 3-10 membered heterocycles or C 3–10 The cycloalkyl ring is optionally surrounded by one or more R 5 Replacement. In some implementations, each R 4 Independently halogen, -S(O)2N(R) Za (R) Zb C 1–6 Alkyl, C 1–6 Alkoxy or C 3–10 cycloalkyl, wherein C 1–6 Alkyl, C 1–6 Alkoxy and C 3–10 Each of the cycloalkyl groups is optionally divided by one or more R 5 Substitution; or attachment of two R atoms to adjacent ring A atoms. 4 Together with the atoms to which they are attached, they form a group optionally bounded by one or more R 5 Replaced 5-6 membered heterocyclic rings. In some implementations, each R 4 Independently fluorine, chlorine, -S(O)2N(R) Za (R) Zb C 1–3 Alkyl, C 1–3 Alkoxy or C 3–4 cycloalkyl, wherein C 1–3 Alkyl, C 1–3 Alkoxy and C 3–4 Each of the cycloalkyl groups is optionally divided by one or more R 5 Substitution; or attachment of two R atoms to adjacent ring A atoms. 4 Together with the atoms to which they are attached, they form a group optionally bounded by one or more R 5 The substituted 5-6 membered heterocycle. In some embodiments, the 5-6 membered heterocycle comprises 1-2 cyclic heteroatoms selected from N and O. In some embodiments, the 5-6 membered heterocycle comprises 1-2 cyclic heteroatoms of O, or the 5-6 membered heterocycle comprises 1 cyclic heteroatom of N.

[0020] In some implementations, each R 4 Choose independently from the following groups: , , , , , , , , , , , , , , , , , , , and Or two R atoms attached to the adjacent ring A atom 4 Together with the atoms to which they are attached, they form heterocycles selected from the following groups: , , , , , and .

[0021] In some implementations, each R 4 Choose independently from the following groups: , , , , , , , , , , , , , , , , , , , , , , , and Or two R atoms attached to the adjacent ring A atom 4 Together with the atoms to which they are attached, they form heterocycles selected from the following groups: , , , , , and .

[0022] In some implementations, each R 4 Independently halogen, cyano, -NO2, hydroxyl, -S(O)2N(R) Za (R) Zb C 1–6 Alkyl, C2–6 alkynyl group, C 1–6 Alkoxy, C 1–6 Thioalkoxy, C 3–10 Cycloalkyl, 3-10 membered heterocyclic, aryl or heteroaryl, wherein C 1–6 Alkyl, C 2–6 alkynyl group, C 1–6 Alkoxy, C 1–6 Thioalkoxy, C 3–10 Each of cycloalkyl, 3-10 membered heterocyclic, aryl, and heteroaryl groups is optionally bounded by one or more R groups. 5 Replacement. In some implementations, each R 4 Independently halogen, -S(O)2N(R) Za (R) Zb C 1–6 Alkyl, C 1–6 Alkoxy or C 3–10 cycloalkyl, wherein C 1–6 Alkyl, C 1–6 Alkoxy and C 3–10 Each of the cycloalkyl groups is optionally divided by one or more R 5 Replacement. In some implementations, each R 4 Independently fluorine, chlorine, -S(O)2N(R) Za (R) Zb C 1–3 Alkyl, C 1–3 Alkoxy or C 3–4 cycloalkyl, wherein C 1–3 Alkyl, C 1–3 Alkoxy and C 3–4 Each of the cycloalkyl groups is optionally divided by one or more R 5 Replacement. In some implementations, each R 4 Choose independently from the following groups: , , , , , , , , , , , , , , , , , , , and .

[0023] In some implementations, each R 4 Choose independently from the following groups: , , , , , , , , , , , , , , , , , , , , , , , and .

[0024] In some implementations, two R atoms attached to the same ring A atom or adjacent ring A atoms 4 Together with the atoms to which they are attached, they form 3-10 membered heterocycles or C rings. 3-10 Cycloalkyl rings, wherein the 3-10 membered heterocycles or C 3-10 The cycloalkyl ring is optionally surrounded by one or more R 5 Replacement. In some embodiments, the two R atoms attached to the adjacent ring A atom... 4 Together with the atoms to which they are attached, they form a group optionally bounded by one or more R 5 The substituted 5-6 membered heterocycle. In some embodiments, the 5-6 membered heterocycle comprises 1-2 cyclic heteroatoms selected from N and O. In some embodiments, the 5-6 membered heterocycle comprises 1-2 cyclic heteroatoms of O, or the 5-6 membered heterocycle comprises 1 cyclic heteroatom of N.

[0025] In some implementations, two R atoms attached to adjacent ring A atoms 4 Together with the atoms to which they are attached, they form heterocycles selected from the following groups: , , , , , and .

[0026] In some implementations, two R atoms attached to adjacent ring A atoms 4 Together with the atoms to which they are attached, they form heterocycles selected from the following groups: , , , , , and .

[0027] In some implementations, the compound contains up to 3 Rs. 5 In some implementations, the compound contains up to two R atoms. 5 In some embodiments, the compound contains at most one R. 5 In some embodiments, the compound is not R 5 replace.

[0028] In some implementations, each R 5 Independently halogen, oxo, hydroxyl, C 2-6 alkynyl group, C 1–6 Alkyl, C 1–6 Alkoxy, C 1–6 Thioalkoxy, C 3–10 Cycloalkyl, 3-10 membered heterocyclic, aryl or heteroaryl, wherein C 1–6 The alkyl group is optionally replaced by one or more halogens. In some embodiments, each R... 5 Independent of halogen, C 1–6 Alkyl, C 1–6 Alkoxy or C 3–10 Cycloalkyl. In some embodiments, each R 5 Independent of halogen, C 1–3 Alkyl, C 1–3 Alkoxy or C 3–6 Cycloalkyl. In some embodiments, each R 5 It can be fluorine, CH3, OCH3 or cyclopropyl independently.

[0029] In some embodiments, ring A is aryl, heteroaryl, or bicyclic [1.1.1]pentyl, and ring A is optionally surrounded by one or more R 4 replace.

[0030] In some embodiments, ring A is aryl or heteroaryl, and ring A is optionally surrounded by one or more R 4 Substitution. In some embodiments, ring A is a phenyl or a 5-6-membered heteroaryl group, and ring A is optionally replaced by one or more R groups. 4 Substitution. In some embodiments, the 5-6-membered heteroaryl group is a 5-6-membered nitrogen-containing heteroaryl group. In some embodiments, the 5-6-membered nitrogen-containing heteroaryl group is pyridine, pyrimidine, pyrazine, pyridazine, pyrazole, oxazole, or isoxazole.

[0031] In some implementations, ring A is selected from the group consisting of: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , and , where X 1 X 2 X 3 and X 4 One or both of them are oxygen and the rest are carbon.

[0032] In some implementations, ring A is selected from the group consisting of: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 , , , , , , , , , , , and .

[0033] In some implementations, ring A is selected from the group consisting of: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , and .

[0034] In some implementations, ring A is optionally bounded by one or more R 4 Substituted aryl group. In some embodiments, ring A is optionally replaced by one or more R groups. 4 Substituted phenyl groups.

[0035] In some implementations, ring A is selected from the group consisting of: , , , , and , where X 1 X 2 X 3 and X 4 One or both of them are oxygen and the rest are carbon.

[0036] In some implementations, ring A is selected from the group consisting of: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , and .

[0037] In some implementations, ring A is selected from the group consisting of: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , and .

[0038] In some implementations, ring A is optionally bounded by one or more R 4 Substituted heteroaryl groups. In some embodiments, ring A is optionally replaced by one or more R groups. 4 The substituted 5-6-membered heteroaryl group. In some embodiments, the 5-6-membered heteroaryl group is a 5-6-membered nitrogen-containing heteroaryl group. In some embodiments, the 5-6-membered nitrogen-containing heteroaryl group is pyridine, pyrimidine, pyrazine, pyridazine, pyrazole, oxazole, or isoxazole.

[0039] In some implementations, ring A is selected from the group consisting of: , , , , , , , , , , , , , , , , , , , , , , , , , and .

[0040] In some implementations, ring A is selected from the group consisting of: , , , , , , , 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 , and .

[0041] In some implementations, ring A is selected from the group consisting of: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , and .

[0042] In some embodiments, the compound is a compound of formula (IA): Formula (IA).

[0043] In one respect, this paper describes a compound of formula (IA): Formula (IA), Or a pharmaceutically acceptable salt thereof, wherein: R 2 It is hydrogen, halogen or C 1–6 Alkyl, wherein C 1–6 Alkyl groups are optionally substituted with one or more halogens; ring A is optionally substituted with one or more R groups. 4 Substituted phenyl; each R 4 Independently halogen, -S(O)2N(R) Za (R) Zb C 1–6 Alkyl, C 1–6 Alkoxy, where C 1–6 Alkyl and C 1–6 Each of the alkoxy groups is optionally surrounded by one or more R groups. 5 Substitution; or attachment of two R atoms to adjacent ring A atoms. 4 Together with the atoms to which they are attached, they form 5-6 membered heterocycles; each R 5 Independently halogen or C 1–6 alkoxy groups; and R Za and R Zb Each of them is independently C 1–6 Alkyl; or R Za and R Zb Together with the nitrogen attached to them, they form 3-6 membered heterocycles.

[0044] In one respect, this paper describes a compound of formula (IA): Formula (IA), Or a pharmaceutically acceptable salt thereof, wherein: R 2 It is hydrogen, halogen or C 1–3 Alkyl, wherein C 1–3 The alkyl group is optionally substituted with one or more fluorine groups; ring A is optionally substituted with one or more R groups. 4 Substituted phenyl; each R 4 Independently halogen, -S(O)2N(R) Za (R) Zb C 1–3 Alkyl, C 1–3 Alkoxy, where C 1–3 Alkyl and C 1–3 Each of the alkoxy groups is optionally surrounded by one or more R groups. 5 Substitution; or attachment of two R atoms to adjacent ring A atoms. 4 Together with the atoms to which they are attached, they form a 6-membered heterocycle containing 1-2 cyclic heteroatoms; each R 5 Independently halogen or C 1–3 alkoxy groups; and R Za and R Zb Each of them is independently C 1–3 Alkyl; or R Za and R Zb Together with the nitrogen atoms attached to them, they form 3-6 membered heterocycles containing one N-type cyclic heteroatom.

[0045] In one respect, this paper describes a compound of formula (IA): Formula (IA), Or a pharmaceutically acceptable salt thereof, wherein: R 2 It is hydrogen, fluorine, chlorine, CH3 or CHF2; ring A is optionally surrounded by one or more R 4 Substituted phenyl; each R 4 Independently fluorine, chlorine, -S(O)2N(R) Za (R) Zb C 1–2 Alkyl, C 1–3 Alkoxy, where C 1–2 Alkyl and C 1–3 Each of the alkoxy groups is optionally surrounded by one or more R groups. 5 Substitution; or attachment of two R atoms to adjacent ring A atoms. 4 Together with the atoms to which they are attached, they form a 6-membered heterocycle containing 1-2 O atoms; each R 5 Independently fluorine or OCH3; and R Za and R Zb Each of them is CH3; or RZa and R Zb Together with the nitrogen attached to them, they form nitrogen heterocyclic butane or pyrrolidine rings.

[0046] In some implementations, the compound is a compound of formula (IB): Formula (IB).

[0047] In one respect, this paper describes a compound of formula (IB): Formula (IB), Or a pharmaceutically acceptable salt thereof, wherein: ring A is optionally surrounded by one or more R 4 Substituted phenyl; each R 4 Independently halogen, -S(O)2N(R) Za (R) Zb C 1–6 Alkyl, C 1–6 Alkoxy, where C 1–6 Alkyl and C 1–6 Each of the alkoxy groups is optionally surrounded by one or more R groups. 5 Substitution; or attachment of two R atoms to adjacent ring A atoms. 4 Together with the atoms to which they are attached, they form 5-6 membered heterocycles; each R 5 Independently halogen or C 1–6 alkoxy groups; and R Za and R Zb Each of them is independently C 1–6 Alkyl; or R Za and R Zb Together with the nitrogen attached to them, they form 3-6 membered heterocycles.

[0048] In one respect, this paper describes a compound of formula (IB): Formula (IB), Or a pharmaceutically acceptable salt thereof, wherein: ring A is optionally surrounded by one or more R 4 Substituted phenyl; each R 4 Independently halogen, -S(O)2N(R) Za (R) Zb C 1–3 Alkyl, C 1–3 Alkoxy, where C 1–3 Alkyl and C 1–3 Each of the alkoxy groups is optionally surrounded by one or more R groups. 5 Substitution; or attachment of two R atoms to adjacent ring A atoms.4 Together with the atoms to which they are attached, they form a 6-membered heterocycle containing 1-2 cyclic heteroatoms; each R 5 Independently halogen or C 1–3 alkoxy groups; and R Za and R Zb Each of them is independently C 1–3 Alkyl; or R Za and R Zb Together with the nitrogen atoms attached to them, they form 3-6 membered heterocycles containing one N-type cyclic heteroatom.

[0049] In one respect, this paper describes a compound of formula (IB): Formula (IB), Or a pharmaceutically acceptable salt thereof, wherein: ring A is optionally surrounded by one or more R 4 Substituted phenyl; each R 4 Independently fluorine, chlorine, -S(O)2N(R) Za (R) Zb C 1–2 Alkyl, C 1–3 Alkoxy, where C 1–2 Alkyl and C 1–3 Each of the alkoxy groups is optionally surrounded by one or more R groups. 5 Substitution; or attachment of two R atoms to adjacent ring A atoms. 4 Together with the atoms to which they are attached, they form a 6-membered heterocycle containing 1-2 O-type ring heteroatoms; each R 5 Independently fluorine or OCH3; and Za and R Zb Each of them is CH3; or R Za and R Zb Together with the nitrogen attached to them, they form nitrogen heterocyclic butane or pyrrolidine rings.

[0050] In some implementations, ring A is optionally bounded by one or more R 4 Substituted bicyclic [1.1.1]pentyl. In some embodiments, the compound contains at most one R 4 In some implementations, the compound contains up to three R... 5 In some implementations, the compound contains up to two R atoms. 5 In some embodiments, the compound contains at most one R. 5 In some embodiments, the compound is not R 5 Replacement. In some implementations, each R 5 It is a halogen. In some implementations, each R 5It is fluorine. In some embodiments, ring A is... .

[0051] In some implementations, each R 4 Independently for C 1–6 Alkyl (e.g., C10) 1–4 Alkyl), aryl (e.g., phenyl), or cyano, and R 4 Optionally by one or more R 5 Replacement. In some implementations, each R 4 Choose independently from the following groups: , , , , and In some implementations, each R 4 Choose independently from the following groups: , , , , , and In some implementations, ring A is selected from the group consisting of: , , , , and In some implementations, ring A is selected from the group consisting of: , , , , and .

[0052] In some implementations, each R 4 To be optionally used by one or more R 5 Replacement C 1–6 Alkyl group. In some embodiments, each R 4 To be optionally used by one or more R 5 Replaced CH3. In some implementations, each R 4 Choose independently from the following groups: , and In some implementations, each R 4 Choose independently from the following groups: , and In some implementations, ring A is selected from the group consisting of: , and In some implementations, ring A is selected from the group consisting of: , and .

[0053] In some embodiments, the compound is a compound of formula (IC): Formula (IC).

[0054] In some implementations, the compound is a compound of formula (ID): Formula (ID).

[0055] In some implementations, X is hydrogen; R 1 R 2 and R 3 Each of these is independently hydrogen, halogen, hydroxyl, cyano, -N(R) Za (R) Zb C 1–6 Alkoxy or C 1–6 Alkyl, wherein C 1–6 The alkyl group is optionally substituted with one or more halogens; ring A is aryl, heteroaryl, or bicyclic [1.1.1]pentyl, and ring A is optionally substituted with one or more R... 4 Replace; each R 4 Independently halogen, -NO2, -S(O)2N(R) Za (R) Zb C 1–6 Alkyl, C 2–6 alkynyl group, C 1–6 Alkoxy, C 1–6 Thioalkoxy, C 3–10 Cycloalkyl, 3-10 membered heterocyclic, aryl or heteroaryl, wherein C 1–6 Alkyl, C 2–6 alkynyl group, C 1–6 Alkoxy, C 1–6 Thioalkoxy, C 3–10 Each of cycloalkyl, 3-10 membered heterocyclic, aryl, and heteroaryl groups is optionally bounded by one or more R groups. 5 Substitution; or attachment of two R atoms to adjacent ring A atoms. 4 Together with the atoms to which they are attached, they form 3-10 membered heterocycles, wherein the 3-10 membered heterocycles are optionally separated by one or more R atoms. 5 Replace; each R 5 Independently halogen, oxo, hydroxyl, C 1–6 Alkyl, C 1–6 Alkoxy, C 3–10cycloalkyl, wherein C 1–6 The alkyl group is optionally substituted with one or more halogens; and R Za and R Zb Each of them is independently hydrogen or C. 1–6 Alkyl; or R Za and R Zb Together with the nitrogen attached to them, they form 3-10 membered heterocycles.

[0056] In some implementations, X is hydrogen; R 1 and R 3 It is hydrogen; R 2 It is hydrogen, halogen or C 1–6 Alkyl, wherein C 1–6 The alkyl group is optionally substituted with one or more halogens; ring A is phenyl, 5-6-membered heteroaryl, or bicyclic [1.1.1]pentyl, and ring A is optionally substituted with one or more R 4 Replace; each R 4 Independently halogen, -S(O)2N(R) Za (R) Zb C 1–6 Alkyl, C 1–6 Alkoxy or C 3–10 cycloalkyl, wherein C 1–6 Alkyl, C 1–6 Alkoxy and C 3–10 Each of the cycloalkyl groups is optionally divided by one or more R 5 Substitution; or attachment of two R atoms to adjacent ring A atoms. 4 Together with the atoms to which they are attached, they form a group optionally bounded by one or more R 5 Substituted 5-6 member heterocycles; each R 5 Independent of halogen, C 1–6 Alkyl, C 1–6 Alkoxy or C 3–10 cycloalkyl; and R Za and R Zb Each of them is independently C 1–6 Alkyl; or R Za and R Zb Together with the nitrogen attached to them, they form 3-6 membered heterocycles.

[0057] In some implementations, X is hydrogen; R 1 and R 3 It is hydrogen; R 2 It is hydrogen, fluorine, chlorine, CH3 or CHF2; ring A is phenyl, 5-6 nitrogen-containing heteroaryl or bicyclic [1.1.1]pentyl, and ring A is optionally separated by one or more R 4 Replace; each R 4 Independently fluorine, chlorine, -S(O)2N(R)Za (R) Zb C 1–3 Alkyl, C 1–3 Alkoxy or C 3–4 cycloalkyl, wherein C 1–3 Alkyl, C 1–3 Alkoxy and C 3–4 Each of the cycloalkyl groups is optionally divided by one or more R 5 Substitution; or attachment of two R atoms to adjacent ring A atoms. 4 Together with the atoms to which they are attached, they form a group optionally bounded by one or more R 5 A substituted 5-6 membered heterocycle, wherein the 5-6 membered heterocycle comprises 1-2 O-type cyclic heteroatoms, or the 5-6 membered heterocycle comprises 1 N-type cyclic heteroatom; each R 5 Independent of halogen, C 1–3 Alkyl, C 1–3 Alkoxy or C 3–6 cycloalkyl; and R Za and R Zb Each of them is CH3; or R Za and R Zb Together with the nitrogen attached to them, they form nitrogen heterocyclic butane or pyrrolidine rings.

[0058] In some embodiments, the compounds are those described in Table 1 below. Table 1 also includes compound numbers for each compound in accordance with the contents of this specification.

[0059] Table 1. Exemplary Compounds

[0060] Pharmaceutical Composition In another embodiment, this disclosure provides a pharmaceutical composition comprising the compound described herein or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. In some embodiments, the pharmaceutical composition comprises an effective amount of the compound. In some embodiments, the pharmaceutical composition comprises a therapeutically effective amount of the compound.

[0061] The pharmaceutical compositions described herein can be administered via a variety of routes, including but not limited to parenteral (by injection), rectal, transdermal, intradermal, intrathecal, subcutaneous (SC), intravenous (IV), intramuscular (IM), and intranasal administration.

[0062] The composition may be in the form of a large volume liquid solution or suspension or a large volume powder. In some embodiments, the composition is presented in unit dose form to facilitate accurate administration. The term "unit dose form" refers to a physically discrete unit suitable as a unit dose for use in a human subject or other mammal, each unit containing a predetermined amount of active substance, calculated to produce the desired therapeutic effect, associated with a suitable pharmaceutical excipient. Typical unit dose forms include pre-filled liquid compositions, ampoules or syringes of predicted quantities, or, in the case of solid compositions, pills, tablets, capsules, etc. In such compositions, the compound is typically a minor component, with the remaining components being various mediators or excipients and processing aids that facilitate the formation of the desired dosage form.

[0063] Liquid forms may include suitable aqueous or non-aqueous media, as well as buffers, suspending and dispersing agents, colorants, etc. Solid forms may include, for example, any of the following components or compounds with similar properties: binders, such as microcrystalline cellulose, tragacanth gum, or gelatin; excipients, such as starch or lactose; disintegrants, such as alginate, Primogel, or corn starch; lubricants, such as magnesium stearate; or flow aids, such as colloidal silica.

[0064] Injectable compositions are typically based on injectable sterile saline or phosphate-buffered saline or other injectable excipients known in the art. As described above, the active compound in such compositions is typically a minor component, with the remainder being injectable excipients, etc.

[0065] Transdermal compositions are typically formulated as topical ointments or creams containing one or more active ingredients. When formulated as an ointment, the active ingredient is usually combined with a paraffin or water-miscible ointment base. Alternatively, the active ingredient may be formulated as a cream with, for example, an oil-in-water emulsion base. Such transdermal formulations are well known in the art and typically include additional ingredients that enhance the skin permeability or stability of the active ingredient or formulation. All such known transdermal formulations and ingredients are included within the scope of the disclosure provided herein.

[0066] The compounds described herein can also be administered via transdermal devices. Therefore, transdermal administration can be achieved using reservoirs and porous membrane-type patches or solid matrix-type patches.

[0067] The components of the injectable or topical compositions described above are merely representative. Other materials and processing techniques, etc., may vary. Remington's Pharmaceutical Sciences The references are described in Part 8 of the 17th edition, 1985, Mack Publishing Company, Easton, Pennsylvania, and are incorporated herein by reference.

[0068] Treatment methods and uses The compounds described herein can be used to degrade CDK2. In some embodiments, the compounds or pharmaceutical compositions described herein are used to degrade CDK2 in a subject.

[0069] In some embodiments of this disclosure, the compounds described herein are used to degrade CDK2 in in vitro or ex vivo systems. In some embodiments, the compounds described herein are used to degrade CDK2 in in vitro systems. In some embodiments, the compounds described herein are used to degrade CDK2 in ex vivo systems.

[0070] This document describes a method for degrading CDK2, comprising combining CDK2 and hydroxycerebroside with the compounds described herein in an in vitro or ex vivo system. In some embodiments, the method comprises combining CDK2 and hydroxycerebroside with the compounds described herein in an in vitro system. In some embodiments, the method comprises combining CDK2 and hydroxycerebroside with the compounds described herein in an ex vivo system.

[0071] The compounds and pharmaceutical compositions described herein are considered useful for treating or preventing conditions in subjects of need. In one embodiment, the compounds described herein are used to degrade CDK2 for the treatment or prevention of conditions.

[0072] Cyclin-dependent kinases, or CDKs, are a closely related family of kinases that regulate processes throughout the cell cycle. CDK activity is further regulated by specific cyclin levels; for example, cyclin E1 activates cyclin-dependent kinase 2, or CDK2. Tumors with CDK2 are activated by (i) amplification of cyclin E1 or E2 or (ii) loss of the AMBRA1 gene. CDK2 elimination is being considered for the treatment of such conditions in patients of need.

[0073] Therefore, in one embodiment of this disclosure, the subject is administered the compound described herein or a pharmaceutically acceptable salt or pharmaceutical composition thereof to degrade CDK2 in the subject.

[0074] In one aspect of this disclosure, a method for treating or preventing a condition in a subject in need is described herein, comprising administering to the subject an effective amount of the compound described herein or a pharmaceutically acceptable salt or pharmaceutical composition thereof.

[0075] On the other hand, this document describes a method for degrading CDK2 in a subject suffering from a disease, comprising administering to the subject a therapeutically effective amount of the compound described herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein. For example, this document describes a method for degrading CDK2 in a subject suffering from cancer, comprising administering to the subject an effective amount of the compound described herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein. In some embodiments, the compound binds to cerebroside and the CDK2 protein to induce ubiquitination of CDK2 and subsequent proteasomal degradation.

[0076] Exemplary conditions that can be treated or prevented by the methods disclosed herein include, but are not limited to, bladder cancer, bone cancer, brain cancer, breast cancer, cervical cancer, chest cancer, colon cancer, endometrial cancer, esophageal cancer, eye cancer, head cancer, kidney cancer, liver cancer, lymph node cancer, lung cancer, cancer of the upper respiratory and digestive tract (including the nasal cavity and paranasal sinuses, nasopharynx or nasal cavity, oral cavity, oropharynx, larynx, hypopharynx and salivary glands), cervical cancer, ovarian cancer, pancreatic cancer, prostate cancer, rectal cancer, skin cancer, stomach cancer, testicular cancer, laryngeal cancer or uterine cancer. Other exemplary conditions include, but are not limited to, amyloidosis, neuroblastoma, meningioma, hemangiopericytoma, multiple brain metastases, glioblastoma multiforme, glioblastoma, brainstem glioma, malignant brain tumors with poor prognosis, malignant glioma, recurrent malignant glioma, anaplastic astrocytoma, anaplastic oligodendroglioma, neuroendocrine tumors (e.g., neuroendocrine prostate cancer (such as castration-resistant neuroendocrine prostate cancer (NEPC)) and pulmonary neuroendocrine tumors (Lu-NET)), rectal adenocarcinoma, colorectal cancer (including stage 3 and 4 colorectal cancer), unresectable colorectal cancer, metastatic hepatocellular carcinoma, and Kaposi's sarcoma. Sarcoma), malignant melanoma, malignant mesothelioma, malignant pleural effusion mesothelioma syndrome, peritoneal cancer, papillary serous carcinoma, gynecologic sarcoma, soft tissue sarcoma, scleroderma, cutaneous vasculitis, Langerhans cell histiocytosis, leiomyosarcoma, progressive ossifying fibrous dysplasia, hormone-refractory prostate cancer, resected high-risk soft tissue sarcoma, unresectable hepatocellular carcinoma, fallopian tube cancer, androgen-independent prostate cancer, androgen-dependent stage IV non-metastatic prostate cancer, hormone-insensitive prostate cancer, chemotherapy-insensitive prostate cancer, papillary thyroid carcinoma, follicular thyroid carcinoma, medullary thyroid carcinoma, and leiomyoma;And blood-borne (liquid) or blood cancers, including but not limited to leukemia, lymphoma, and myeloma, such as diffuse large B-cell lymphoma (DLBCL), B-cell immunoblastic lymphoma, small non-cleaved cell lymphoma, human lymphotropic virus type 1 (HTLV-1) leukemia / lymphoma, adult T-cell lymphoma, peripheral T-cell lymphoma (PTCL), cutaneous T-cell lymphoma (CTCL), mantle cell lymphoma (MCL), Hodgkin lymphoma (HL), non-Hodgkin lymphoma (NHL), AIDS-related lymphoma, follicular lymphoma, small lymphocytic lymphoma, large B-cell lymphoma rich in T cells / histocytes, transformed lymphoma, primary mediastinal (thymic) large B-cell lymphoma, splenic marginal zone lymphoma, Richter's transformation (Richter's transformation) The following are listed: lymph node marginal zone lymphoma, ALK-positive large B-cell lymphoma, indolent lymphoma (e.g., DLBCL, follicular lymphoma, or marginal zone lymphoma), acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), adult T-cell leukemia, chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), hairy cell leukemia, myelodyplasia, myeloproliferative disorders, chronic myeloid leukemia (CML), acute monocytic leukemia (AMoL), myelodysplastic syndrome (MDS), human lymphotropic virus type 1 (HTLV-1) leukemia, mastocytosis, B-cell acute lymphoblastic leukemia, non-Hodgkin lymphoma, Hodgkin lymphoma, and multiple myeloma (MM).

[0077] In some implementation schemes, the condition is cancer.

[0078] In some implementations, the disease is breast cancer. In some implementations, the breast cancer is HR+ (hormone receptor positive) breast cancer. In some implementations, the breast cancer is ER+ (estrogen receptor positive) breast cancer. In some implementations, the breast cancer is HR+ HER2- (human epidermal growth factor receptor 2 negative) breast cancer. In some implementations, the breast cancer is ER+ HER2- breast cancer.

[0079] In some implementations, the disease is selected from the group consisting of: ovarian cancer, endometrial cancer, gastric cancer, esophageal cancer, triple-negative breast cancer, and lung adenosarcoma. In some implementations, the cancer is triple-negative breast cancer.

[0080] In some implementations, the disease is cancer including solid tumors. In some implementations, solid tumors are at least one of the following: uterine cancer (such as uterine carcinoma and endometrial cancer of the uterine corpus), endometrial cancer, breast cancer (such as invasive breast cancer and triple-negative breast cancer, ER+ HER2- breast cancer and HER2+ breast cancer), ovarian cancer (such as ovarian serous cystadenocarcinoma), stomach cancer (such as gastric adenocarcinoma), gastric cancer (such as gastrointestinal stromal carcinoma), colorectal cancer, pancreatic cancer, kidney cancer, head and neck cancer, liver cancer, prostate cancer, skin cancer, lymphoma (such as B-cell lymphoma), sarcoma, esophageal cancer (such as esophageal carcinoma), bladder cancer (such as bladder urothelial carcinoma), lung cancer (such as squamous cell carcinoma and non-small cell lung cancer, including EGFRm+ (epidermal growth factor receptor mutant positive) non-small cell lung cancer), cholangiocarcinoma, adrenocortical carcinoma, mesothelioma, and malignant melanoma. In some implementations, a solid tumor is at least one of the following: prostate cancer, colon cancer, esophageal cancer, endometrial cancer, ovarian cancer, uterine cancer, kidney cancer, liver cancer, pancreatic cancer, gastric cancer, breast cancer, lung cancer, head and neck cancer, thyroid cancer, glioblastoma, sarcoma, bladder cancer, and melanoma.

[0081] In some implementations, the condition is a cancer including a liquid tumor. In some implementations, the liquid tumor is at least one of the following: diffuse large B-cell lymphoma (DLBCL), B-cell immunoblastic lymphoma, small non-cleaved cell lymphoma, human lymphotropic virus type 1 (HTLV-1) leukemia / lymphoma, adult T-cell lymphoma, peripheral T-cell lymphoma (PTCL), cutaneous T-cell lymphoma (CTCL), mantle cell lymphoma (MCL), Hodgkin lymphoma (HL), non-Hodgkin lymphoma (NHL), AIDS-related lymphoma, follicular lymphoma, small lymphocytic lymphoma, large B-cell lymphoma rich in T cells / histocytes, transformed lymphoma, primary mediastinal (thymic) large B-cell lymphoma, splenic marginal zone lymphoma, Richter transformation, lymphoma. Nodal marginal zone lymphoma, ALK-positive large B-cell lymphoma, indolent lymphoma (e.g., DLBCL, follicular lymphoma, or marginal zone lymphoma), acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), adult T-cell leukemia, chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), hairy cell leukemia, myelodysplastic syndrome, myeloproliferative disorders, chronic myeloid leukemia (CML), acute monocytic leukemia (AMoL), myelodysplastic syndrome (MDS), human lymphotropic virus type 1 (HTLV-1) leukemia, mastocytosis, B-cell acute lymphoblastic leukemia, non-Hodgkin lymphoma, Hodgkin lymphoma, and multiple myeloma (MM). In some implementations, the liquid tumor is at least one of the following: acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), DLBCL, mantle cell lymphoma, non-Hodgkin lymphoma (such as follicular lymphoma, including relapsed or refractory NHL and relapsed follicular lymphoma), Hodgkin lymphoma, and multiple myeloma.

[0082] In some implementation schemes, the condition is ovarian cancer.

[0083] In some embodiments, the compounds described herein, or pharmaceutically acceptable salts or pharmaceutical compositions thereof, are administered as first-line therapy. In some embodiments, the compounds described herein, or pharmaceutically acceptable salts or pharmaceutical compositions thereof, are administered to untreated subjects, i.e., subjects who have not yet been treated with standard care.

[0084] In another aspect of this disclosure, a method for treating a subject with cancer (e.g., the cancer described herein) is described herein, comprising administering to the subject a therapeutically effective amount of the compound described herein or a pharmaceutically acceptable salt thereof or a pharmaceutical composition described herein.

[0085] On the other hand, this article describes a method for degrading CDK2 in a subject suffering from cancer (e.g., the cancer described herein), comprising administering to the subject a therapeutically effective amount of the compound described herein or a pharmaceutically acceptable salt thereof or a pharmaceutical composition described herein.

[0086] On the other hand, this article describes a method for treating a subject with a solid tumor (e.g., the solid tumor described herein) comprising administering to the subject a therapeutically effective amount of the compound described herein or a pharmaceutically acceptable salt thereof or a pharmaceutical composition described herein.

[0087] On the other hand, this document describes a method for treating a liquid tumor (e.g., the liquid tumor described herein) in a subject in need, comprising administering to the subject a therapeutically effective amount of the compound described herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein. In some embodiments, the liquid tumor is a liquid tumor of a blood cancer (e.g., the blood cancer described herein).

[0088] combination The compounds and pharmaceutical compositions described herein may be administered as a single agent or in combination with one or more additional therapeutic agents, such as anticancer agents. Therefore, in some embodiments, the compounds described herein, or pharmaceutically acceptable salts or compositions thereof, are administered in combination with additional therapeutic agents.

[0089] Additional therapeutic agents may be administered at the same time as or at different times with the compounds and pharmaceutical compositions described herein.

[0090] Additional anticancer agents that can be applied in the methods disclosed herein include the following classes of anticancer agents: mitotic inhibitors, alkylating agents, antimetabolites, antitumor antibiotics, antiangiogenic agents, topoisomerase I and II inhibitors, plant alkaloids, hormonal agents and antagonists, growth factor inhibitors, radiation, signal transduction inhibitors (such as protein tyrosine kinase inhibitors), biological response modifiers, enzyme inhibitors, antisense oligonucleotides or oligonucleotide derivatives, cytotoxic agents, immunotumor agents, etc.

[0091] Alternatively, additional anticancer agents can be anticancer agents from one of the following categories: endocrine agents, PIK3CA inhibitors, antibody-drug conjugates, PLK1 inhibitors, estrogen PROTACs, anti-angiogenic agents, signal transduction inhibitors (such as kinase inhibitors), and classical antitumor agents (such as hormone modulators, epigenetic modulators, immunomodulators, and EGFR inhibitors).

[0092] In some implementations, the additional anticancer agent is an endocrine agent, such as an aromatase inhibitor, SERD (selective estrogen receptor downregulator), or SERM (selective estrogen receptor modulator). Examples of aromatase inhibitors include exemestane (Aromasin), anastrozole (Arimidex), atamestane, fadrozole, letrozole (Femara), and formestane. Examples of SERDs include fulvestrant, SZ102, G1T48, RADI 901, elacestrant, GDC-9545, giredestrant, SAR439859, amcenestrant, AZD9833, camizestrant, LY3484356, Zn-c5, and D-0502. Examples of SERMs include tamoxifen, raloxifene, lasofoxifene, afimoxifen, azoxifene, bazedoxifene, fispemifene, ormeloxifene, ospemifene, tesmilifene, toremifene, trilostane, and CHF 4227 (Cheisi).

[0093] In some implementations, the additional anticancer agent is a PIK3CA inhibitor, such as alpelisib (PIQRAY), BEBT-908, BPI-21668, buparlisib, inavolisib, TQB-3525, RLY-2608, miransertib, MEN-1611, LOXO-783, HS-10352, HH-CYH33, gedatolisib, or fimepinostat.

[0094] In some implementations, the additional anticancer agent is an antibody-drug conjugate, such as trastuzumab deruxtecan (Enhertu), trastuzumab duocarmazine, trastuzumab emtansine (Kadcyla), upifitamabrilsodotin, mirvetuximab soravtansine, tisotumab vedotin (Tivdak), praluzatamab ravtansine, sacituzumab govitecan, or sacituzumab-hziy (Trodelvy), datopotamab deruxtecan, or latiratuzumab vedotin. Vedotin), Patritumab deruxtecan, STRO-002, MORab-202, DS-6000, Anetumab, Avitansine, XMT-2056, Disitamab Vedotin (RC48-ADC, Aidexi).

[0095] In some implementations, the additional anticancer agent is a PLK1 inhibitor, such as onvansertib, B12536, BI6727, GSK461364A, TAK960, and rigosertib.

[0096] In some implementations, the additional anticancer agent is the estrogen PROTAC (ARV-471, H3B-5942).

[0097] In some embodiments, the compounds described herein, or pharmaceutically acceptable salts or compositions thereof, are administered in combination with endocrine therapies, such as agents of letrozole, fulvestrant, tamoxifen, exemestane, or anastrozole. In some embodiments, the compounds described herein, or pharmaceutically acceptable salts or compositions thereof, are administered in combination with chemotherapeutic agents, such as docetaxel, paclitaxel, cisplatin, carboplatin, capecitabine, gemcitabine, vinorelbine, or liposomal doxorubicin. In other embodiments, the compounds described herein, or pharmaceutically acceptable salts or compositions thereof, are administered in combination with anti-HER2 agents, such as trastuzumab or pertuzumab.

[0098] In some implementations, the additional treatment agent is carboplatin, fulvestrant, or a combination thereof.

[0099] In some implementations, the additional anticancer agent is an anti-angiogenic agent, such as an anti-angiogenic agent selected from the group consisting of: VEGF inhibitors, VEGFR inhibitors, TIE-2 inhibitors, PDGFR inhibitors, angiopoietin inhibitors, PKCb inhibitors, COX-2 (cyclooxygenase II) inhibitors, integrin (α-v / β-3), MMP-2 (matrix metalloproteinase 2) inhibitors, and MMP-9 (matrix metalloproteinase 9) inhibitors. Preferred anti-angiogenic agents include sunitinib (Sutent™), bevacizumab (Avastin™), axitinib (AG 13736), SU 14813 (Pfizer), and AG 13958 (Pfizer). Additional anti-angiogenic agents include vatalanib (CGP 79787), sorafenib (Nexavar™), pegaptanib octasodium (Macugen™), vandetanib (Zactima™), PF-0337210 (Pfizer), SU 14843 (Pfizer), AZD 2171 (AstraZeneca), ranibizumab (Lucentis™), Neovastat™ (AE 941), tetrathiomolybdate (Coprexa™), AMG 706 (Amgen), VEGF Trap (AVE 0005), CEP 7055 (Sanofi-Aventis), XL 880 (Exelixis), telatinib (BAY 57-9352), and CP-868,596. (Pfizer). Other anti-angiogenic agents include enzastaurin (LY 317615), midostaurin (CGP 41251), perifosine (KRX 0401), teprenone (Selbex™), and UCN 01 (Kyowa Hakko).Other examples of anti-angiogenic agents include celecoxib (Celebrex™), parecoxib (Dynastat™), deracoxib (SC 59046), lumiracoxib (Preige™), valdecoxib (Bextra™), rofecoxib (Vioxx™), iguratimod (Careram™), IP 751 (Invedus), SC-58125 (Pharmacia), and etoricoxib (Arcoxia™). Other anti-angiogenic agents include exisulind (Aptosyn™), salsalate (Amigesic™), diflunisal (Dolobid™), ibuprofen (Motrin™), ketoprofen (Orudis™), nabumetone (Relafen™), piroxicam (Feldene™), naproxen (Aleve™, Naprosyn™), diclofenac (Voltaren™), indomethacin (Indocin™), sulindac (Clinoril™), tolmetin (Tolectin™), etodolac (Lodine™), and ketorolac. (Toradol™) and oxaprozin (Daypro™). Other anti-angiogenic agents include ABT 510 (Abbott), apratastat (TMI005), AZD 8955 (AstraZeneca), incyclinide (Metastat™), and PCK 3145 (Procyon).Other anti-angiogenic agents (including VEGFR / PDGFR inhibitors) include ponatinib (Iclusig), BT1718, anlotinib, lenvatinib (Lenvima), tivozanib (Fotivda), dovitinib, brolucizumab (Beovu), aflibercept (Eylea), and faricimab. Other anti-angiogenic agents include atratin (Neotigason™), plitidepsin (aplidine™), cilengtide (EMD 121974), compretastatin A4 (CA4P), fenretinide (4HPR), halofuginone (Tempostatin™), Panzem™ (2-methoxyestradiol), PF-03446962 (Pfizer), rebimastat (BMS 275291), catumaxomab (Removab™), lenalidomide (Revlimid™), squalamine (EVIZON™), thalidomide (Thalomid™), and Ukrain™. (NSC631570), Vitaxin™ (MED1522) and zoledronic acid (Zometa™).

[0100] In other implementations, the additional anticancer agent is a signal transduction inhibitor (an agent that inhibits how regulatory molecules controlling fundamental processes of cell growth, differentiation, and survival communicate within the cell). Signal transduction inhibitors include small molecules, antibodies, and antisense molecules. Signal transduction inhibitors include kinase inhibitors, such as tyrosine kinase inhibitors. More specifically, signal transduction inhibitors include farnesyltransferase inhibitors, EGF inhibitors, ErbB-1 (EGFR), ErbB-2, pan-erb, IGF1R inhibitors, MEK, c-Kit inhibitors, FLT-3 inhibitors, K-Ras inhibitors, PI3 kinase inhibitors, JAK inhibitors, STAT inhibitors, Raf kinase inhibitors, Akt inhibitors, mTOR inhibitors, P70S6 kinase inhibitors, WNT pathway inhibitors, and multi-target kinase inhibitors. Additional examples of signal transduction inhibitors include BMS 214662 (Bristol-Myers Squibb), lonafarnib (Sarasar™), pelitrexol (AG 2037), matuzumab (EMD 7200), nimotuzumab (TheraCIM h-R3™), panitumumab (Vectibix™), vandetanib (Zactima™), pazopanib (SB 786034), ALT 110 (Alteris Therapeutics), BIBW 2992 (Boehringer Ingelheim), and Cervene™ (TP 38).Other examples of signal transduction inhibitors include gefitinib (Iressa™), cetuximab (Erbitux™), erlotinib (Tarceva™), trastuzumab (Herceptin™), sunitinib (Sutent™), imatinib (Gleevec™), crizotinib (Pfizer), lorlatinib (Pfizer), dacomitinib (Pfizer), bosutinib (Pfizer), getagliflozinib (Pfizer), canertinib (CI 1033), pertuzumab (Omnitarg™), lapatinib (Tycerb™), pelitinib (EKB 569), miltefosine (Miltefosin™), and BMS 599626. (Bristol-Myers Squibb), Lapuleucel-T (Neuvenge™), NeuVax™ (E75 cancer vaccine), Osidem™ (IDM 1), mubritinib (TAK-165), CP-724,714 (Pfizer), panitumumab (Vectibix™), ARRY 142886 (ArrayBiopharm), everolimus (Certican™), zotarolimus (Endeavor™), temsirolimus (Torisel™), AP 23573 (ARIAD), VX 680 (Vertex), XL647 (Exelixis), sorafenib (Nexavar™), LE-AON (Georgetown University), and GI-4000 (Globelmmune). Other signal transduction inhibitors include ABT 751 (Abbott), avocidib (flavopiridol), BMS 387032 (Bristol Myers), EM 1421 (Erimos), indisulam (E 7070), seliciclib (CYC 200), BIO 112 (Onc Bio), BMS387032 (Bristol-Myers Squibb), and AG 024322 (Pfizer).

[0101] In other implementations, the additional anticancer agent is a classic antitumor agent. Classic antitumor agents include hormone modulators (such as hormones, anti-hormones, androgen agonists, androgen antagonists, and anti-estrogen therapies), histone deacetylase (HDAC) inhibitors, DNA methyltransferase inhibitors, silencing agents or gene activators, ribonucleases, protein bodies, topoisomerase I inhibitors, camptothecin derivatives, topoisomerase II inhibitors, alkylating agents, antimetabolites, poly(ADP-ribose) polymerase-1 (PARP-1) inhibitors (such as talazoparib, olaparib, rucaparib, niraparib, iniparib, veliparib), microtubule inhibitors, antibiotics, plant-derived spindle inhibitors, platinum coordination compounds, gene therapy agents, antisense oligonucleotides, vascular targeting agents (VTAs), and statins. Examples of classic antitumor agents include glucocorticoids such as dexamethasone, prednisone, prednisolone, methylprednisolone, and hydrocortisone; progesterone such as medroxyprogesterone, megace, and mifepristone (RU-486); selective estrogen receptor modulators (SERMs such as tamoxifen, raloxifene, lasoxifene, alfixifene, azoxifen, bardoxifene, fepemifen, olmexifen, opemixifene, telmilifen, toremifene, tralostane, and CHF 4227 (Cheisi); and selective estrogen receptor downregulators (SERDs such as fulvestrant, SZ102, G1T48, and RADI). 901, Irastrant, GDC-9545, Giredestrant, SAR439859, Amcenestrant, AZD9833, Camizestrant, LY3484356, Zn-C5, D-0502, Exemestane (Aromasin), Anastrozole (Arimidex), Atamestane, Fatrazole, Letrozole (Femara), Formestan; Gonadotropin-releasing hormone (GnRH, also commonly known as luteinizing hormone-releasing hormone [LHRH]) agonists, such as Buserelin (Suprefact), Goserelin (Zoladex), Leuprorelin (Lupron), Triptorelin (Trelstar), Abarelix.Plenaxis, cyproterone, flutamide (Eulexin), megestrol acetate, nilutamide (Nilandron), and osaterone, dutasteride, epristeride, finasteride, saw palmetto (Serenoa repens), PHL 00801, abalix, goserelin, leuprorelin, triptorelin, bicalutamide; antiandrogens such as enzalutamide, abiraterone acetate, and Casodex; and combinations thereof. Other examples of classic antitumor agents include suberolanilide hydroxamic acid (SAHA, Merck Inc. / Aton Pharmaceuticals), phenylbutyrate peptides (FR901228 or FK228), G2M-777, MS-275, neopentyloxymethyl butyrate, and PXD-101; onconase (ranpirnase), PS-341 (MLN-341), Velcade (bortezomib), 9-aminocamptothecin, belotecone, BN-80915 (Roche), camptothecin, diflomotecan, edotecarin, exatecan (Daiichi), gimatecan, 10-hydroxycamptothecin, and irinotecan HCl. (Camptosar), lurtotecan, OrathecinRubitecan (Supergen), SN-38, Topotecan, Camptothecin, 10-Hydroxycamptothecin, 9-Aminocamptothecin, Irinotecan, SN-38, Edocarin, Topotecan, Aclarubicin, Adriamycin, Amonafide, Amrubicin, Annamycin, Daunorubicin, Doxorubicin, Elsamitrucin, Epirubicin, Etoposide, Idarubicin, Galarubicin, Hydroxyurea, Nemorubicin, Nodarutrone Mitoxantrone, pirarubicin, pixantrone, procarbazine, rebeccamycin, sobuzoxane, tafluposide, valrubicin, Zinecard (dexrazoxane), nitrogen mustard N-oxide, cyclophosphamide, AMD-473, altretamine, AP-5280, apaziquone, brostallicin, bendamustine, busulfan, carboquone, carmustine, chlorambucil, dacarbazine, estramustine, formustine, glufosfamide, ifosfamide, KW-2170, lomustine, mafosfamide, mechlorethamine, melphalan, mitobronitol, mitolactalol, mitomycin C C) Mitoxatrone, nimustine, ranimustine, temozolomide, thiotepa, and platinum-coordinated alkylating compounds (such as cisplatin and paraplatin).Carboplatin, eptaplatin, lobaplatin, nedaplatin, eloxatin (oxaliplatin, Sanofi), streptozocin, satrplatin, and combinations thereof. Other examples of classic antitumor cytotoxic agents include albumin-bound paclitaxel (Abraxane, Abraxis BioScience, Inc.), batabulin (Amgen), EPO906 (Novartis), vinflunine (Bristol-Myers Squibb), actinomycin D, bleomycin, mitomycin C, and neocarzinostatin. Zinostatin, vinblastine, vincristine, vindesine, navelbine, docetaxel, ortataxel, paclitaxel (including the DHA / paclitaxel conjugate Taxoprexin), cisplatin, carboplatin, nedaplatin, oxaliplatin, Satraplatin, Camptosar, capecitabine (Xeloda), oxaliplatin, taxoterealitretinoin, canfosfamide (Telcyta™), DMXAA (Antisoma), ibandronic acid, L-asparaginase, oncaspar™, efaproxiral (efaproxyn™ - radiotherapy), bexarotene Targretin™, telmilide (DPPE - enhances the efficacy of cytotoxic agents), Theratope™ (Biomira), tretinoin (Vesanoid™), tirapazamine (Trizaone™), motexafin gadolinium (Xcytrin™), Cotara™ (mAb), NBI-3001 (Protox Therapeutics), polyglutamate-paclitaxel (Xyotax™), and combinations thereof. Other examples of classic antitumor agents include Advexin (ING 201), TNFerade...(GeneVec, a compound that expresses TNFα in response to radiotherapy), RB94 (Baylor College of Medicine), Genasense (Oblimersen, Genta), Comparetin A4P (CA4P), Oxi-4503, AVE-8062, ZD-6126, TZT-1027, Atorvastatin (Lipitor, Pfizer Inc.), Provastatin (Pravachol, Bristol-Myers Squibb), Lovastatin (Mevacor, Merck Inc.), Simvastatin (Zocor, Merck Inc.), Fluvastatin (Lescol, Novartis), Cerivastatin (Baycol, Bayer), Rosuvastatin (Crestor, AstraZeneca), Lovostatin, Niacin (Advicor, Kos Pharmaceuticals), Caduet, Lipitor, Torcetrapib, and combinations thereof.

[0102] In some implementations, the additional anticancer agent is an epigenetic regulator, such as an inhibitor of EZH2, SMARCA4, PBRM1, ARID1A, ARID2, ARID IB, DNMT3A, TET2, MLL1 / 2 / 3, NSD1 / 2, SETD2, BRD4, DOTIL, HKMTsanti, PRMT1-9, LSD1, UTX, IDH1 / 2, or BCL6.

[0103] In some implementations, the additional anticancer agent is an immunomodulatory agent, such as a CTLA-4 inhibitor (e.g., ipilimumab), a PD-1 or PD-L1 inhibitor (e.g., pembrolizumab, nivolumab, avelumab, atezolizumab, durvalumab, cemiplimab, or dosterlimab), a LAG-3 inhibitor (e.g., relatlimab), a TIM-3 inhibitor, a TIGIT inhibitor, a 4-1BB inhibitor, an OX40 inhibitor, a GITR inhibitor, or a CD40 inhibitor or CAR-T cell therapy.

[0104] In some implementations, the additional anticancer agent is an EGFR inhibitor, such as afatinib, osimertinib, lapatinib, erlotinib, dacomitinib, poziotinib, neratinib, or gefitinib, or an EGFR antibody, such as cetuximab, panitumumab, or necitumumab.

[0105] Alternatively, additional anticancer agents are those that are not EGFR inhibitors, such as those selected from: MEK, including mutant MEK inhibitors (trametinib, cobimtetinib, binimetinib, selumetinib, refametinib); c-MET, including mutant c-Met inhibitors (savolitinib, cabozantinib, foretinib); and MET antibodies (e.g., EGFR inhibitors). Emibetuzumab; anti-angiogenic agents, such as bevacizumab and nintedanib; apoptosis inducers, such as Bcl-2 inhibitors, such as venetoclax, obatoclax, and navitoclax, and Mcl-1 inhibitors, such as AZD-5991, AMG-176, and S-64315; and mTOR inhibitors, such as rapamycin, tesiromoxetine, everolimus, and ridoforolimus.

[0106] In some implementations, additional anticancer agents include tamoxifen, letrozole, olaparib (e.g., Lynparza®), niraparib, carboplatin, cisplatin, paclitaxel, gemcitabine, megestrol acetate, medroxyprogesterone acetate, capecitabine (e.g., Xeloda®), regorafenib (e.g., Stivarga®), afatinib (e.g., gilotrif®), osimertinib (e.g., Tagrisso®), gefitinib (e.g., Iressa®), erlotinib (e.g., Tarceva®), ramucirumab (e.g., Cyramza®), EGFR inhibitors, prallatinib, ABT-263 (navicola), MK-1775 (adavosertib), BAY-1895344, berzosertib, ceralasertib, SRA-737, and LY2603618. (rabusertib) and trastuzumab (e.g., herceptin®) or a combination thereof. EGFR inhibitors can include afatinib, osimertinib, lapatinib, erlotinib, dacomitinib, poziotinib, neratinib, gefitinib, JBJ-04-125-02, alflutinib (AST 2818), aumoletinib (formerly almonertinib) (HS10296), BBT-176, BI-4020, BPI-361175, BPI-D0316, CH7233163, gilitertinib, icotinib, JND-3229, lazertinib, nazartinib (EGF 816), avitinib, PCC-0208027, and rezivertinib. (BRI-77G1), TQB3804, zorifertinib (AZ-3759) or DZD9008; EGFR antibodies, such as cetuximab, panitumumab, nexituzumab, HLX07 or JMT101; or bispecific EGFR and MET antibodies (e.g. ervantuzumab (JNJ-61186372, JNJ-372)).

[0107] definition The following section describes the definitions of specific functional groups and chemical terms in more detail. Chemical elements are based on the Periodic Table of the Elements, CAS edition. Handbook of Chemistry and PhysicsThe 75th edition (inner cover) is used for identification, and specific functional groups are generally defined as described herein. Furthermore, the general principles of organic chemistry, as well as specific functional groups and reactivity, are described below: Thomas Sorrell, Organic Chemistry , University ScienceBooks, Sausalito, 1999; Smith and March, March's Advanced Organic Chemistry , 5th edition, John Wiley & Sons, Inc., New York, 2001; Larock, Comprehensive Organic Transformations , VCH Publishers, Inc., New York, 1989; and Carruthers, Some Modern Methods of Organic Synthesis , 3rd edition, Cambridge University Press, Cambridge, 1987.

[0108] When listing a range of values, it intends to cover every value within that range and its subranges. For example, "C 1–6 The term "alkyl" is intended to encompass C1, C2, C3, C4, C5, C6, and C6 alkyl groups. 1–6 C 1–5 C 1–4 C 1–3 C 1–2 C 2–6 C 2–5 C 2–4 C 2–3 C 3–6 C 3–5 C 3–4 C 4–6 C 4–5 and C 5–6 alkyl.

[0109] Compounds described as "optionally substituted" may be substituted with one or more of the specifically described groups, or may not be substituted. In some embodiments, compounds described as "optionally substituted" are unsubstituted.

[0110] As used herein, the term "alkyl" refers to a straight-chain or branched saturated hydrocarbon group. In some embodiments, the alkyl group has 1 to 12 carbon atoms ("C12"). 1-12 Alkyl group). In some embodiments, the alkyl group has 1 to 10 carbon atoms (“C10”). 1-10 Alkyl group). In some embodiments, the alkyl group has 1 to 9 carbon atoms (“C1”). 1-9 Alkyl group). In some embodiments, the alkyl group has 1 to 8 carbon atoms (“C1”). 1-8Alkyl group). In some embodiments, the alkyl group has 1 to 7 carbon atoms (“C1”). 1-7 Alkyl group (“C”). In some embodiments, the alkyl group has 1 to 6 carbon atoms (“C”). 1-6 Alkyl group (also referred to herein as "lower alkyl group"). In some embodiments, the alkyl group has 1 to 5 carbon atoms ("C1 to 5 C2"). 1-5 Alkyl group). In some embodiments, the alkyl group has 1 to 4 carbon atoms (“C1”). 1-4 Alkyl group). In some embodiments, the alkyl group has 1 to 3 carbon atoms (“C1”). 1-3 Alkyl group (“alkyl”). In some embodiments, the alkyl group has 1 to 2 carbon atoms (“C”). 1-2 Alkyl group (“C1 alkyl”). In some embodiments, the alkyl group has 1 carbon atom (“C1 alkyl”). In some embodiments, the alkyl group has 2 to 6 carbon atoms (“C1 alkyl”). 2-6 Alkyl group). C 1-6 Examples of alkyl groups include methyl (C1), ethyl (C2), n-propyl (C3), isopropyl (C3), n-butyl (C4), tert-butyl (C4), sec-butyl (C4), isobutyl (C4), n-pentyl (C5), 3-pentyl (C5), pentyl (C5), neopentyl (C5), 3-methyl-2-butyl (C5), tert-pentyl (C5), and n-hexyl (C6). Additional examples of alkyl groups include n-heptyl (C7), n-octyl (C8), etc. Common alkyl abbreviations include Me (-CH3), Et (-CH2CH3), iPr (-CH(CH3)2), nPr (-CH2CH2CH3), n-Bu (-CH2CH2CH2CH3), or i-Bu (-CH2CH(CH3)2).

[0111] As used herein, the term "alkenyl" refers to a straight-chain or branched hydrocarbon group having one or more carbon-carbon double bonds. In some embodiments, the alkenyl group has 2 to 10 carbon atoms ("C2"). 2–10 Alkenyl group (“Alkenyl”). In some embodiments, the alkenyl group has 2 to 9 carbon atoms (“C”). 2–9 Alkenyl group (“Alkenyl”). In some embodiments, the alkenyl group has 2 to 8 carbon atoms (“C”). 2–8 Alkenyl group (“Alkenyl”). In some embodiments, the alkenyl group has 2 to 7 carbon atoms (“C”). 2–7 Alkenyl group (“Alkenyl”). In some embodiments, the alkenyl group has 2 to 6 carbon atoms (“C”). 2–6 Alkenyl group (“Alkenyl”). In some embodiments, the alkenyl group has 2 to 5 carbon atoms (“C”). 2–5 Alkenyl group (“Alkenyl”). In some embodiments, the alkenyl group has 2 to 4 carbon atoms (“C”). 2–4 Alkenyl group (“Alkenyl”). In some embodiments, the alkenyl group has 2 to 3 carbon atoms (“C”). 2–3Alkenyl (“C2-alkenyl”). In some embodiments, the alkenyl group has two carbon atoms (“C2-alkenyl”). One or more carbon-carbon double bonds can be internal (e.g., in 2-butenyl) or terminal (e.g., in 1-butenyl). C 2-4 Examples of alkenyl groups include vinyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), etc. 2-6 Examples of alkenyl groups include the aforementioned C... 2-4 Alkenyl groups include pentenyl (C5), pentadienyl (C5), hexenyl (C6), etc. Additional examples of alkenyl groups include heptenyl (C7), octenyl (C8), octetrinyl (C8), etc.

[0112] As used herein, the term "alkynyl" refers to a straight-chain or branched hydrocarbon group having one or more carbon-carbon triple bonds (e.g., 1, 2, 3, or 4 carbon-carbon triple bonds). In some embodiments, the alkynyl group has 2 to 10 carbon atoms ("C2"). 2–10 The alkynyl group (“C”) is present in some embodiments. In some embodiments, the alkynyl group has 2 to 9 carbon atoms (“C”). 2–9 The alkynyl group (“acetylenic”) has 2 to 8 carbon atoms in some embodiments. 2–8 The alkynyl group (“acetylation”) has 2 to 7 carbon atoms in some embodiments. 2–7 The alkynyl group (“C”) is present in some embodiments. In some embodiments, the alkynyl group has 2 to 6 carbon atoms (“C”). 2–6 The alkynyl group (“H”) has 2 to 5 carbon atoms in some embodiments. 2–5 The alkynyl group (“C”) is present in some embodiments. In some embodiments, the alkynyl group has 2 to 4 carbon atoms (“C”). 2–4 The alkynyl group (“C”) is present in some embodiments. In some embodiments, the alkynyl group has 2 to 3 carbon atoms (“C”). 2–3 The alkynyl group (“C2-alkynyl”) is present in some embodiments. This one or more carbon-carbon triple bonds can be internal (e.g., in 2-butynyl) or terminal (e.g., in 1-butynyl). 2-4 Examples of alkynyl groups include, but are not limited to, ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), and 2-butynyl (C4). 2-6 Examples of alkenyl groups include the aforementioned C... 2-4 Alkynyl groups include pentynyl (C5), hexynyl (C6), etc. Additional examples of alkynyl groups include heptynyl (C7), octynyl (C8), etc.

[0113] As used herein, the term "cycloalkyl" refers to a ring system having 3 to 12 ring carbon atoms ("C12"). 3-12The cycloalkyl group comprises a saturated or partially unsaturated cyclic hydrocarbon group with zero heteroatoms. In some embodiments, the cycloalkyl group has 3 to 10 cyclic carbon atoms (“C”). 3-10 cycloalkyl group (“Cycloalkyl”). In some embodiments, the cycloalkyl group has 3 to 8 cyclic carbon atoms (“C”). 3–8 cycloalkyl group (“Cycloalkyl”). In some embodiments, the cycloalkyl group has 3 to 6 cyclic carbon atoms (“C”). 3-6 cycloalkyl group (“Cycloalkyl”). In some embodiments, the cycloalkyl group has 3 to 6 cyclic carbon atoms (“C”). 3-6 cycloalkyl group (“Cycloalkyl”). In some embodiments, the cycloalkyl group has 5 to 10 cyclic carbon atoms (“C”). 5-10 Cycloalkyl). Exemplary C 3-6 Cycloalkyl groups include, but are not limited to, cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), and cyclohexadienyl (C6). Example C 3-8 Cycloalkyl groups include, but are not limited to, the aforementioned C 3-6 Cycloalkyl groups, including cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cyclohepttrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo[2.2.1]heptyl (C7), bicyclo[2.2.2]octyl (C8), etc. Example C 3-10 Cycloalkyl groups include, but are not limited to, the aforementioned C 3-8 Cycloalkyl groups, including cyclononyl (C9), cyclononenyl (C9), and cyclodecyl (C9). 10 ), cyclodecenyl (C 10 ), octahydro-1H-indenyl (C9), decahydronaphthyl (C9) 10 ), spiro[4.5]decyl (C 10 In some embodiments, the cycloalkyl group is monocyclic (“monocyclic cycloalkyl”) or contains a fused, bridged, or spirocyclic system, such as a bicyclic system (“bicyclic cycloalkyl”) or a tricyclic system (“tricyclic cycloalkyl”). “Cycloalkyl” also includes a cycloalkyl ring fused with one or more aryl or heteroaryl groups as defined above, wherein the attachment point is located on the cycloalkyl ring or one or more aryl or heteroaryl groups, and in such cases, the number of carbons continues to indicate the number of carbons in the cycloalkyl ring system.

[0114] As used herein, the term "heterocyclic group" refers to a group having a saturated or partially unsaturated 3- to 10-membered ring system having a ring carbon atom and 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon ("3- to 10-membered heterocyclic group"). In heterocyclic groups containing one or more nitrogen atoms, the attachment point can be a carbon atom or a nitrogen atom, provided the valence state allows. Heterocyclic groups can be monocyclic ("monocyclic heterocyclic group") or fused, bridged, or spirocyclic systems, such as bicyclic systems ("bicyclic heterocyclic group"). A bicyclic heterocyclic group can contain one or more heteroatoms in one or both rings. "Heterocyclic group" also includes a ring system as defined above where a heterocyclic ring is fused with one or more cycloalkyl groups, wherein the attachment point is located on the cycloalkyl ring or the heterocyclic ring, or a ring system as defined above where a heterocyclic ring is fused with one or more aryl or heteroaryl groups, wherein the attachment point is located on the heterocyclic ring or one or more aryl or heteroaryl groups, and in such cases, the number of ring members continues to indicate the number of ring members in the heterocyclic ring system.

[0115] In some embodiments, the heterocyclic group is a 5- to 10-membered saturated or partially unsaturated ring system having a cyclic carbon atom and 1 to 4 cyclic heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon (“5- to 10-membered heterocyclic group”). In some embodiments, the heterocyclic group is a 5- to 8-membered saturated or partially unsaturated ring system having a cyclic carbon atom and 1 to 4 cyclic heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5- to 8-membered heterocyclic group”). In some embodiments, the heterocyclic group is a 5- to 6-membered saturated or partially unsaturated ring system having a cyclic carbon atom and 1 to 4 cyclic heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5- to 6-membered heterocyclic group”). In some embodiments, the 5- to 6-membered heterocyclic group has 1 to 3 cyclic heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5- to 6-membered heterocyclic group has 1 to 2 cyclic heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5- to 6-membered heterocyclic group has a cyclic heteroatom selected from nitrogen, oxygen, and sulfur.

[0116] Exemplary 3-membered heterocyclic groups containing one heteroatom include, but are not limited to, azirdinyl, ethylene oxide, and thiorenyl. Exemplary 4-membered heterocyclic groups containing one heteroatom include, but are not limited to, azirdinyl, oxadiazolinyl, and thiorenyl. Exemplary 5-membered heterocyclic groups containing one heteroatom include, but are not limited to, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolyl, dihydropyrrolyl, and pyrrolyl-2,5-dione. Exemplary 5-membered heterocyclic groups containing two heteroatoms include, but are not limited to, dioxolaneyl, oxadiazolinyl, dithiophenyl, and oxazolidinyl-2-one. Exemplary 5-membered heterocyclic groups containing three heteroatoms include, but are not limited to, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6-membered heterocyclic groups containing one heteroatom include, but are not limited to, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thiorenyl. Exemplary 6-membered heterocyclic groups containing two heteroatoms include, but are not limited to, piperazinyl, morpholinyl, dithiaalkyl, and dioxalyl. Exemplary 6-membered heterocyclic groups containing two heteroatoms include, but are not limited to, triazinealkyl. Exemplary 7-membered heterocyclic groups containing one heteroatom include, but are not limited to, azirheptanyl, oxeheptanyl, and thioheptanyl. Exemplary 8-membered heterocyclic groups containing one heteroatom include, but are not limited to, azirheptanyl, oxeheptanyl, and thioheptanyl. Exemplary 5-membered heterocyclic groups fused to a C6 aryl ring (also referred to herein as 5,6-bicyclic heterocycles) include, but are not limited to, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothiophenyl, benzoxazolinone, etc. Exemplary 6-membered heterocyclic groups fused to an aryl ring (also referred to herein as 6,6-bicyclic heterocycles) include, but are not limited to, tetrahydroquinolinyl, tetrahydroisoquinolinyl, etc.

[0117] As used herein, the term "aryl" refers to a group in a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., sharing 6, 10, or 14 π electrons in a cyclic array) that provides 6 to 14 ring carbon atoms and zero heteroatoms ("C") in the aromatic ring system. 6-14 Aryl group (“C6 aryl”). In some embodiments, the aryl group has six ring carbon atoms (“C6 aryl”; for example, phenyl). In some embodiments, the aryl group has ten ring carbon atoms (“C6 aryl”). 10 Aryl; for example, naphthyl, such as 1-naphthyl and 2-naphthyl). In some embodiments, the aryl group has fourteen cyclic carbon atoms (“C”). 14"Aryl"; for example, anthracene. Typical aryl groups include, but are not limited to, those derived from the following groups: acepanthene, acenaphthene, phenanthrene, anthracene, azulene, benzene, arbutin, fluorene, benzoxene, hexalene, hexalene, asymmetric indole, symmetric indole, indole, naphthalene, octalene, octalene, oleophane, pentyl-2,4-diene, pentabenzene, pentalene, pentalene, perylene, phenanthracene, phenanthrene, sepium, pyrene, pyrane, rubicene, benzophenanthrene, and trinaphthalene. Specifically, aryl groups include phenyl, naphthyl, indole, and tetrahydronaphthyl.

[0118] As used herein, the term "heteroaryl" refers to a group comprising a 5- to 10-membered monocyclic or bicyclic 4n+2 aromatic ring system (e.g., sharing 6 or 10 π electrons in a cyclic array), wherein the group provides a cyclic carbon atom and 1 to 4 cyclic heteroatoms in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5- to 10-membered heteroaryl"). In heteroaryls containing one or more nitrogen atoms, the attachment site can be a carbon atom or a nitrogen atom, provided the valence state allows. Heteroaryl bicyclic ring systems may include one or more heteroatoms in one or both rings. "Heteroaryl" also includes ring systems fused with one or more aryl rings as defined above, wherein the attachment site is located on the aryl ring or heteroaryl ring, and in such cases, the number of ring members indicates the number of ring members in the fused (aryl / heteroaryl) ring system. Bicyclic heteroaryl groups, in which one ring does not contain heteroatoms (e.g., indole, quinolinyl, carbazolyl, etc.), and the attachment site can be on either ring, i.e., a ring with heteroatoms (e.g., 2-indole) or a ring without heteroatoms (e.g., 5-indole).

[0119] In some embodiments, a heteroaryl group is a 5- to 10-membered aromatic ring system providing a cyclic carbon atom and 1 to 4 cyclic heteroatoms in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5- to 10-membered heteroaryl”). In some embodiments, a heteroaryl group is a 5- to 8-membered aromatic ring system providing a cyclic carbon atom and 1 to 4 cyclic heteroatoms in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5- to 8-membered heteroaryl”). In some embodiments, a heteroaryl group is a monocyclic 5- to 6-membered aromatic ring system providing a cyclic carbon atom and 1 to 4 cyclic heteroatoms in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5- to 6-membered heteroaryl”). In some embodiments, a 5- to 6-membered heteroaryl group has 1 to 3 cyclic heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, a 5- to 6-membered heteroaryl group has 1 to 2 cyclic heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5- to 6-membered heteroaryl group has one cyclic heteroatom selected from nitrogen, oxygen, and sulfur. In some embodiments, the heteroaryl group is a monocyclic 5-membered aromatic ring system providing a cyclic carbon atom and 1 to 4 cyclic heteroatoms in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-membered heteroaryl”). In some embodiments, the heteroaryl group is a monocyclic 6-membered aromatic ring system providing a cyclic carbon atom and 1 to 4 cyclic heteroatoms in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“6-membered heteroaryl”).

[0120] In some embodiments, a heteroaryl group is a 5- to 10-membered aromatic ring system providing a cyclic carbon atom and 1 to 4 cyclic heteroatoms in the aromatic ring system, wherein each heteroatom is independently nitrogen or oxygen (“5- to 10-membered heteroaryl”). In some embodiments, a heteroaryl group is a 5- to 8-membered aromatic ring system providing a cyclic carbon atom and 1 to 4 cyclic heteroatoms in the aromatic ring system, wherein each heteroatom is independently nitrogen or oxygen (“5- to 8-membered heteroaryl”). In some embodiments, a heteroaryl group is a monocyclic 5- to 6-membered aromatic ring system providing a cyclic carbon atom and 1 to 4 cyclic heteroatoms in the aromatic ring system, wherein each heteroatom is independently nitrogen or oxygen (“5- to 6-membered heteroaryl”). In some embodiments, a 5- to 6-membered heteroaryl group has 1 to 3 cyclic heteroatoms that are independently nitrogen or oxygen. In some embodiments, a 5- to 6-membered heteroaryl group has 1 to 2 cyclic heteroatoms that are independently nitrogen or oxygen. In some embodiments, a 5- to 6-membered heteroaryl group has 1 cyclic heteroatom that is independently nitrogen or oxygen. In some embodiments, a heteroaryl is a monocyclic 5-membered aromatic ring system providing a cyclic carbon atom and 1 to 4 cyclic heteroatoms in the aromatic ring system, wherein each heteroatom is independently nitrogen or oxygen (“5-membered heteroaryl”). In some embodiments, a heteroaryl is a monocyclic 6-membered aromatic ring system providing a cyclic carbon atom and 1 to 4 cyclic heteroatoms in the aromatic ring system, wherein each heteroatom is independently nitrogen or oxygen (“6-membered heteroaryl”).

[0121] Exemplary 5-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyrroleyl, furanyl, and thiophenyl. Exemplary 5-membered heteroaryl groups containing two heteroatoms include, but are not limited to, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5-membered heteroaryl groups containing three heteroatoms include, but are not limited to, triazolyl, oxadiazolyl, and thiadiazolyl. Exemplary 5-membered heteroaryl groups containing four heteroatoms include, but are not limited to, tetrazolyl. Exemplary 6-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyridinyl. Exemplary 6-membered heteroaryl groups containing two heteroatoms include, but are not limited to, pyridinyl, pyrimidinyl, and pyrazinyl. Exemplary 6-membered heteroaryl groups containing three or four heteroatoms include, but are not limited to, triazinyl and tetraazinyl, respectively. Exemplary 7-membered heteroaryl groups containing one heteroatom include, but are not limited to, aziryl, oxazinyl, and thioazinyl. Exemplary 5,6-bicyclic heteroaryl groups include, but are not limited to, indolyl, isoindolyl, indazole, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzoisofuranyl, benzoimidazolyl, benzoxazolyl, benzoisoxazolyl, benzoxadiazolyl, benzothiazolyl, benzoisothiazolyl, benzothiadiazolyl, indolazinyl, and purinyl. Exemplary 6,6-bicyclic heteroaryl groups include, but are not limited to, naphthidyl, pteridyl, quinolinyl, isoquinolinyl, cenolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl.

[0122] As used herein, the term "alkoxy" refers to the group -OR 100 , where R 100 The alkoxy group can be alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, or heteroaryl. Exemplary alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexyloxy, and 1,2-dimethylbutoxy. Other exemplary alkoxy groups are lower alkoxy groups, i.e., alkoxy groups having 1 to 6 carbon atoms. In other examples, the alkoxy group has 1 to 4 carbon atoms.

[0123] As used herein, the term "thioalkoxy" refers to the -SR group. 101 , where R 101 The thioalkoxy group is alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, or heteroaryl. Exemplary thioalkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexyloxy, and 1,2-dimethylbutoxy. Other exemplary thioalkoxy groups are lower thioalkoxy groups, i.e., thioalkoxy groups having 1 to 6 carbon atoms. In other examples, the thioalkoxy group has 1 to 4 carbon atoms.

[0124] As used in this article, the term "hydroxyl group" refers to the -OH group.

[0125] As used in this article, the term "cyano" refers to the group -CN.

[0126] As used in this article, the term "halogen" refers to F, Cl, Br, or I.

[0127] As used in this article, the term "oxo" refers to the =O group.

[0128] As used herein, the term "pharmaceutically acceptable salt" refers to salts that, within the bounds of reasonable medical judgment, are suitable for contact with the tissues of humans and lower animals without excessive toxicity, irritation, anaphylactic reactions, etc., and in proportion to a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, Berge et al. in... J. Pharmaceutical Sciences Pharmaceutically acceptable salts are described in detail in (1977) 66:1–19. Pharmaceutically acceptable salts of the compounds disclosed herein include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable, non-toxic acid addition salts are salts formed by amino groups with inorganic acids (e.g., hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid) or with organic acids (e.g., acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid), or salts formed by other methods used in the art (e.g., ion exchange). Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, hydrogen sulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, disglucuronate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucono-heptanoate, glyceryl phosphate, gluconate, hemisulfate, heptaate, hexanoate, hydroiodide, 2-hydroxyethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, dihydroxynaphthalate, pectate, persulfate, 3-phenylpropionate, phosphate, picrate, neopentanoate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, etc. Pharmaceutically acceptable salts derived from suitable bases include alkali metals, alkaline earth metals, ammonium, and nitrogen. + (C 1-4 Alkyl)4 salts. Representative alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, etc. Further pharmaceutically acceptable salts include (where appropriate) non-toxic ammonium, quaternary ammonium, and amine cations formed using counterions (e.g., halide, hydroxide, carboxyl, sulfate, phosphate, nitrate, lower alkyl sulfonate, and aryl sulfonate).

[0129] The term "subject" considered for administration includes, but is not limited to, humans (i.e., men or women of any age group, such as pediatric subjects (e.g., infants, children, adolescents) or adult subjects (e.g., young adults, middle-aged adults, or older adults)) and / or non-human animals, such as mammals, such as primates (e.g., cynomolgus monkeys, rhesus monkeys), cattle, pigs, horses, sheep, goats, rodents, cats, and / or dogs. In some embodiments, the subject is a human. In some embodiments, the subject is a non-human animal. The terms "human," "patient," and "subject" are used interchangeably herein.

[0130] The terms “disease,” “symptom,” and “illness” are used interchangeably in this article.

[0131] As used herein, and unless otherwise stated, the term "treat / treating / treatment" encompasses measures taken when a subject suffers from a particular disease, condition, or disorder that may reduce the severity of the disease, condition, or disorder, or delay or slow its progression. In alternative embodiments, this disclosure contemplates administering the compounds described herein as a preventative agent prior to the subject developing a particular disease, condition, or disorder.

[0132] Generally, as used herein, an "effective amount" of a compound means an amount sufficient to elicit the desired biological response. Those skilled in the art will understand that the effective amount of the compounds disclosed herein can vary depending on factors such as the desired biological endpoint, the pharmacokinetics of the compound, the disease being treated, the route of administration, and the age, health, and condition of the subject.

[0133] As used herein, and unless otherwise stated, a "therapeuticly effective amount" of a compound is an amount sufficient to provide therapeutic benefit in treating a disease, condition, or disorder, or to delay or minimize one or more symptoms associated with a disease, condition, or disorder. A therapeutically effective amount of a compound means the amount of a therapeutic agent that provides therapeutic benefit in treating a disease, condition, or disorder, whether used alone or in combination with other therapies. The term "therapeuticly effective amount" may also encompass amounts that improve overall treatment, reduce or prevent symptoms or causes of a disease or disorder, or enhance the therapeutic efficacy of another therapeutic agent.

[0134] It should also be understood that compounds with the same molecular formula but different atomic bonding properties, sequences, or spatial arrangements are called "isomers." Isomers with different spatial arrangements of atoms are called "stereoisomers." Stereoisomers that are not mirror images of each other are called "diastereomers," and stereoisomers that are non-overlapping mirror images of each other are called "enantiomers." When a compound has an asymmetry center, for example, it is bonded to four different groups, a pair of enantiomers may exist. Enantiomers can be characterized by the absolute configuration of their asymmetry center and described by the R and S ordering rules of Cahn and Prelog, or by rotating the molecular polarization plane and specifying them as dextrorotatory or levorotatory (i.e., (+) or (-)- isomers, respectively). Chiral compounds can exist as individual enantiomers or mixtures thereof. A mixture containing equal proportions of enantiomers is called a "racemic mixture."

[0135] Isomers (e.g., stereoisomers) can be separated from the mixture by methods known to those skilled in the art, including chiral high-performance liquid chromatography (HPLC) and the formation of chiral salts; or preferred isomers can be prepared by asymmetric synthesis. See, for example, Jacques et al. Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen et al., Tetrahedron 33:2725 (1977); Eliel, Stereochemistry of Carbon Compounds (McGraw–Hill, NY, 1962); and Wilen, Tables of Resolving Agents and Optical Resolutions Page 268 (EL Eliel, ed., Univ. of Notre Dame Press, Notre Dame, IN 1972). This disclosure also covers compounds described as individual isomers that do not contain other isomers, and alternatively as mixtures of various isomers.

[0136] The compounds provided herein can be administered as the sole active agent or in combination with other active agents. In some embodiments, the invention provides a combination of the compounds of the invention with another pharmacologically active agent. Combination administration can be performed using any technique readily apparent to those skilled in the art, including, for example, administration alone, sequentially, simultaneously, and alternately.

[0137] This disclosure also includes, in alternative embodiments, isotopically labeled compounds that are identical to those described herein, except that one or more atoms are replaced by atoms having atomic masses or mass numbers different from those normally found in nature. Examples of isotopes that may be incorporated into the compounds described herein include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, respectively, for example... 2 H, 3 H, 13 C 14 C 15 N、 18 O、 17 O、 31 P, 32 P, 35 S, 18 F and 36 Cl. For example, one or more H atoms in the compounds disclosed herein may be replaced by deuterium.

[0138] Preparation of compounds The compounds of the present invention (including salts, stereoisomers, and isotopic isomers) can be prepared by a variety of methods well known to those skilled in the art of synthetic organic chemistry. Compounds of Formula I can be prepared, for example, using the reactions and techniques outlined below, in conjunction with various methods or variations thereof known in the art of synthetic organic chemistry as understood by those skilled in the art. Preferred methods include, but are not limited to, those described below.

[0139] The reaction is carried out in a solvent suitable for the reagents and materials used and for the transformation to be achieved. Furthermore, in the synthetic methods described below, it should be understood that all proposed reaction conditions (including the selection of solvent, reaction atmosphere, reaction temperature, reaction time, and post-treatment procedures) are chosen as standard conditions for the reaction, which should be readily recognized by those skilled in the art of synthetic organic chemistry.

[0140] The following methods provide general guidance for the preparation of the compounds of the present invention. Those skilled in the art will understand that the preparation methods shown in the methods can be modified or optimized using general knowledge of organic chemistry to prepare various compounds of the present invention. Not all compounds belonging to a given category are compatible with some of the reaction conditions required by some of the described methods. Such limitations on substituents compatible with the reaction conditions will be readily apparent to those skilled in the art, and alternative methods can then be used.

[0141] All starting materials are commercially available or can be prepared by conventional synthetic methods known to those skilled in the art.

[0142] General Solution 1 Reagents and conditions: (a) NIS, H2SO4, 0–25 °C, 12 h; (b) SOCl2, MeOH, 80 °C, 12 h; (c) NBS, AIBN or BPO, CHCl3, 80 °C, 12 h; (d) DIPEA, MeCN, 80 °C, 12 h; (e) [(bipy)2Ni2(μ-Cl)2Cl2(H2O)2], Zn, TMSCl, DMA, 0–25 °C, 12 h; (f) HCl, dioxane, 20–25 °C, 0.5–2 h; (g) Trimethylboroxane, XPhos Pd G2, XPhos, K2CO3, DMF, 100 °C, 12 h; or Trimethylboroxane, PEPPSI™-IPr catalyst, K2CO3, dioxane, 100 °C, 12 h; (h) CHClF2, MgCl2, MS 3 Å, NiCl2, 4,4'-diamino-2,2'-bipyridine, DMAP, Zn, DMA, 60 °C, 12 h; (i) SEMCl, DBU, DMF or THF, 0-25 °C, 1-6 h; (j) 4 M HCl in dioxane, 20 °C, 1 h, then TFA, CH2Cl2, 20 °C, 1 h, then NH3 (aqueous solution), MeCN, 20 °C, 1 h; (k) Pd( t (l) TFA, CH2Cl2, 20℃, 1 h, then NH3 (aqueous solution), MeCN, 20℃, 1 h; (m) LiCl, DMF, 160℃, 1 h (microwave heating); (n) DPPA, TEA, MS 4Å, dioxane, 20℃, 1 h, then 1 NHCl, 80℃, 4 h.

[0143] The compound of intermediate A can be synthesized using the process shown in General Scheme 1. Benzoic acid 1-1 is iodinated under suitable conditions (e.g., by iodizing a suspension or solution of 1-1 in sulfuric acid). N - Iodosuccinimide was treated at 0–25 °C for 12 h to give iodide 1-2. Esterification of acid 1-2 under suitable conditions (e.g., treatment of a suspension or solution of 1-2 in methanol with thionyl chloride at 80 °C for 12 h) yielded methyl ester 1-3. Ester 1-3 was then treated with a suitable reagent (e.g., N - Bromosuccinimide, together with azobisisobutyronitrile or benzoyl peroxide, is brominated in a suitable solvent (e.g., chloroform) under suitable conditions (e.g., 80°C) for 12 h to give bromides 1-4. Bromides 1-4 are then reacted with amine hydrochloride 1-5 and a suitable base (e.g., ) N , NDiisopropylethylamine is treated in a suitable solvent (e.g., acetonitrile) under appropriate conditions (e.g., at 80°C) for 12 h to produce isoindolinones 1-6. Isoindolinones 1-6 are then reacted with cyclopropanes 1-7 under appropriate conditions (e.g., [(bipy)2Ni2(μ-Cl)2Cl2(H2O)2] in dimethylacetamide, zinc, and trimethylchlorosilane) at 0-25°C for 12 h to give cyclopropanes 1-8.

[0144] Those skilled in the art will understand that intermediate A can be obtained from the already existing required R. 2 Group 1-1 begins with various R 2 Group preparation. For example, to prepare intermediate A, where R... 2 =Hydrogen or halogen, synthesis can be carried out from the required R that already exists. 2 Begin with step 1-1. Alternatively, the required R can be introduced in subsequent steps of the process. 2 Groups. For example, from those having R 2 =Cl starts with 1-8, which can be obtained by, for example, involving R. 2 =The coupling reaction of Cl substituents introduces other R 2 The optional steps, as shown in steps g and h, can be used to prepare a group having R 2 =alkyl intermediate A. Optional step g illustrates how, under suitable conditions (e.g., using trimethylboroxane, XPhos Pd G2, XPhos and K2CO3 in dimethylformamide at 100°C for 12 h, or using trimethylboroxane, PEPPSI™-IPr catalyst and K2CO3 in dioxane at 100°C for 12 h), intermediate A with R 2 =Cl 1-8 synthesis has R 2 =Methyl 1-8, while optional step h explains how it can be done under appropriate conditions (e.g., using CHClF2, MgCl2, MS 3Å, NiCl2, 4,4'-diamino-2,2'-bipyridine, 4-( N , N (-dimethylamino)pyridine and zinc in dimethylacetamide at 60°C for 12 h) from R 2 =Cl 1-8 synthesis has R 2 =Difluoromethyl 1-8.

[0145] Deprotection of cyclopropanes 1-8 under appropriate conditions (e.g., treating a suspension or solution of 1-8 in dioxane with anhydrous hydrogen chloride at 20-25°C for 0.5-2 h) yields a compound of formula intermediate A.

[0146] Alternatively, isoindolinones 1-6 can be SEM protected under suitable conditions (e.g., treatment of a suspension or solution of 1-6 in dimethylformamide or tetrahydrofuran with (2-chloromethoxyethyl)trimethylsilane (SEMCl) and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) at 0-25 °C for 1-6 h) to produce isoindolinones 1-9. Similar to the preparation of cyclopropanes 1-8, isoindolinones 1-9 are reacted with cyclopropanes 1-7 under suitable conditions (e.g., [(bipy)2Ni2(μ-Cl)2Cl2(H2O)2] in dimethylacetamide, zinc, and trimethylchlorosilane) at 0-25 °C for 12 h to give cyclopropanes 1-10. Deprotection of cyclopropane 1-10 under appropriate conditions (e.g., by the following sequential treatment: treatment with 4 M HCl in dioxane at 20°C for 1 h, treatment with trifluoroacetic acid in dichloromethane at 20°C for 1 h, and finally treatment with ammonia in acetonitrile at 20°C for 1 h) yields a compound of formula intermediate A.

[0147] Alternatively, isoindolinones 1-9 can be used under suitable conditions (e.g., with a suitable catalyst, such as Pd in ​​tetrahydrofuran). t -Bu3P)2, coupled with cyclopropane 1-11 at 70 °C for 12 h, yields cyclopropane 1-12. The cyclopropane 1-12 is deprotected under suitable conditions (e.g., a suspension or solution of 1-12 in dichloromethane is treated with trifluoroacetic acid at 20 °C for 1 h, followed by treatment with ammonia in acetonitrile at 20 °C for 1 h) to yield methyl ester 1-13. Methyl ester 1-13 is hydrolyzed under suitable conditions (e.g., a suspension or solution of 1-13 and lithium chloride in dimethylformamide is microwaved at 160 °C for 1 h) to give formic acid 1-14. Formic acid 1-14 is reacted under suitable conditions (e.g., with diphenyl azidophosphate, triethylamine, and 4 Å molecular sieve in dioxane) at 20 °C for 1 h, followed by reaction with 1 M hydrochloric acid at 80 °C for 4 h to produce a compound of formula intermediate A.

[0148] General Solution 2 Reagents and conditions: (a) MeI, K2CO3, DMF, 20-30℃, 2-12 h; or SOCl2 (added at 0℃), MeOH, 25-75℃, 2-12 h; or MeOH, DMAP, DCC, CH2Cl2, 25℃, 12 h; (b) H2NNH2 . H2O, MeOH or EtOH, 50-80℃, 1-12 h; (c) CDI, THF, 60℃, 3 h, then H2NNH2 .(d) H2O, THF, 25℃, 1 h; or H2NNHBoc, EDCI, CH2Cl2, 20-25℃, 2-12 h; or H2NNHBoc, EDCI, HOBt, TEA, CH2Cl2, 25℃, 12 h; or TFA, CH2Cl2, 20-25℃, 1-4 h; or HCl, EtOAc, 25℃, 2 h; or BrCN, NaHCO3, dioxane, water, 25℃, 2-12 h; or BrCN, MeOH, 60-80℃, 1-12 h; or diimidazolimide, THF, 60-80℃, 2-12 h; or (g) t -BuONO, CuBr, MeCN, 60-80℃, 1-3 h; or t -BuONO, CuBr2, MeCN, 60-65℃, 0.5-5 h; or t (i) BuONO, KBr, MeCN, 20℃, 12 h; (ii) DIPEA or TEA, DMSO or DMA, 80-130℃, 1-12 h; (iii) H2NNHBoc, HOAc, MeOH, 60℃, 5 h; (j) [bis(acetoxy)iodo]benzene, MeOH, 60℃, 12-18 h; (k) CDI, DIPEA, CH2Cl2, 25℃, 6 h; (l) PyCloP, DIPEA, DMA, 25-60℃, 12-18 h.

[0149] Compound I can be synthesized using the process shown in General Scheme 2. Formic acid 2-1 is esterified under suitable conditions (e.g., by treating a suspension or solution of 2-1 in dimethylformamide with iodomethane in the presence of potassium carbonate at 20-30°C for 2-12 h; or by treating a suspension or solution of 2-1 in methanol with SOCl2 (added at 0°C), followed by stirring at 25-75°C for 2-12 h; or by treating a suspension or solution of 2-1 in dichloromethane with methanol, 4-( N , N -dimethylamino)pyridine and N , N'-Dicyclohexylcarbodiimide is treated at 25°C for 12 h to give ester 2-2. Alternatively, ester 2-2 can be purchased from a commercial supplier. A suspension or solution of ester 2-2 in a suitable solvent (e.g., methanol or ethanol) is treated with hydroxylamine hydrate at 50-80°C for 1-12 h to produce acylhydrazine 2-3. Alternatively, acylhydrazine 2-3 can be prepared from formic acid 2-1 under suitable conditions (e.g., by treating 2-1 sequentially with carbonyl diimidazole in tetrahydrofuran at 60°C for 3 h, followed by treatment with hydroxylamine hydrate in tetrahydrofuran at 25°C for 1 h). Alternatively, the protected acylhydrazide 2-6 can be prepared from formic acid 2-1 under suitable conditions (e.g., treating 2-1 with H2NNHBoc and EDCI in dichloromethane at 20-25°C for 2-12 h; or treating 2-1 with H2NNHBoc, EDCI, HOBt, and triethylamine in dichloromethane at 25°C for 12 h). Deprotection of the protected acylhydrazide 2-6 under suitable conditions (e.g., treating a suspension or solution of 2-6 in dichloromethane with trifluoroacetic acid at 20-25°C for 1-4 h; or treating a suspension or solution of 2-6 in ethyl acetate with hydrogen chloride at 25°C for 2 h) yields acylhydrazide 2-3.

[0150] Under suitable conditions (e.g., maintaining cyanogen bromide and sodium bicarbonate in dioxane and water at 25°C for 2-12 h; or maintaining cyanogen bromide in methanol at 60-80°C for 1-12 h; or maintaining diimidazolium imide in tetrahydrofuran at 60-80°C for 2-12 h), cyclization of 2-3 acylhydrazides yields aminooxadiazole 2-4. Under suitable conditions, aminooxadiazole 2-4 is treated, for example, with tert-butyl nitrite in acetonitrile and copper bromide (I) at 60-80°C for 1-3 h; or with tert-butyl nitrite in acetonitrile and copper bromide (II) at 60-65°C for 0.5-5 h; or with tert-butyl nitrite in acetonitrile and potassium bromide at 20°C for 12 h, to obtain brominated oxadiazole 2-5. Under suitable conditions, brominated oxadiazole 2-5 is coupled with intermediate B (e.g., by hydrazine suspension or solution of the two reactants with a suitable base (such as...) N , N (Diisopropylethylamine or triethylamine) is treated in a suitable solvent (such as dimethyl sulfoxide or dimethylacetamide) at 80-130°C for 1-12 h to produce compound I.

[0151] Alternatively, aldehyde 2-7 can be converted to hydroxyoxadiazole 2-9 via intermediate hydrazone 2-8, but the intermediate hydrazone is not isolated. For example, 2-7 is condensed with H2NNHBoc in a suitable solvent (e.g., methanol) at 60°C for 5 h to give intermediate hydrazone 2-8, which is then reacted with [bis(acetoxy)iodo]benzene in methanol at 60°C for 12-18 h without separation to produce hydroxyoxadiazole 2-9. Alternatively, hydroxyoxadiazole 2-9 can be obtained from hydrazide 2-3 under suitable conditions (e.g., by reacting a solution or suspension of 2-3 in dichloromethane with carbonyl diimidazole and... N , N - Diisopropylethylamine was treated at 25°C for 6 h). Hydroxyoxadiazole 2-9 was coupled with intermediate B under appropriate conditions (e.g., by suspending or solubilizing the two reactants in a suitable solvent (e.g., dimethylacetamide) with a suitable coupling agent (e.g., chlorotripyrrolyl phosphonium hexafluorophosphate (PyCloP)) in a suitable base (e.g., ...). N , N Treatment at 25-60°C for 12-18 h in the presence of diisopropylethylamine yields compound I.

[0152] Exemplary Implementation 1. A compound of formula (I): Formula (I), Or its pharmaceutically acceptable salt, wherein: X is hydrogen or deuterium; R 1 R 2 and R 3 Each of these is independently hydrogen, halogen, hydroxyl, cyano, -NO2, oxo, -N(R) Za (R) Zb C 1–6 Alkoxy or C 1–6 Alkyl, wherein C 1–6 The alkyl group may optionally be replaced by one or more halogens; Ring A is aryl, heteroaryl, or bicyclic [1.1.1]pentyl, and ring A is optionally surrounded by one or more R 4 replace; Each R 4 Independently halogen, cyano, -NO2, hydroxyl, oxo, -S(O)2N(R) Za (R) Zb C 1–6 Alkyl, C 2–6 alkynyl group, C 1–6 Alkoxy, C 1–6 Thioalkoxy, C 3–10Cycloalkyl, 3-10 membered heterocyclic, aryl or heteroaryl, wherein C 1–6 Alkyl, C 2–6 alkynyl group, C 1–6 Alkoxy, C 1–6 Thioalkoxy, C 3–10 Each of cycloalkyl, 3-10 membered heterocyclic, aryl, and heteroaryl groups is optionally bounded by one or more R groups. 5 replace; Or two R atoms attached to the same ring A atom or adjacent ring A atoms 4 Together with the atoms to which they are attached, they form 3-10 membered heterocycles or C rings. 3-10 Cycloalkyl rings, wherein the 3-10 membered heterocycles or C 3-10 The cycloalkyl ring is optionally surrounded by one or more R 5 replace; Each R 5 Independently halogen, oxo, hydroxyl, C 2-6 alkynyl group, C 1–6 Alkyl, C 1–6 Alkoxy, C 1–6 Thioalkoxy, C 3–10 Cycloalkyl, 3-10 membered heterocyclic, aryl or heteroaryl, wherein C 1–6 The alkyl group is optionally substituted with one or more halogens; and R Za and R Zb Each of them is independently hydrogen or C. 1–6 alkyl; Or R Za and R Zb Together with the nitrogen attached to them, they form 3-10 membered heterocycles.

[0153] 2. The compound as described in embodiment 1, wherein X is hydrogen.

[0154] 3. The compound as described in embodiment 1 or embodiment 2, wherein R 1 and R 3 It is hydrogen.

[0155] 4. The compound according to any one of embodiments 1-3, wherein the compound is a compound of formula (IA): Formula (IA).

[0156] 5. The compound as described in any one of embodiments 1-4, wherein R 2 It is hydrogen, halogen or C 1–6 Alkyl, wherein C 1–6 The alkyl group may optionally be replaced by one or more halogens.

[0157] 6. The compound as described in embodiment 5, wherein R 2 It can be hydrogen, fluorine, chlorine, CH3 or CHF2.

[0158] 7. The compound as described in embodiment 6, wherein R 2 It is chlorine.

[0159] 8. The compound of any one of embodiments 1-7, wherein the compound is a compound of formula (IB): Formula (IB).

[0160] 9. The compound as described in any one of embodiments 1-8, wherein R Za and R Zb Each of them is independently C 1–6 Alkyl groups (e.g., CH3); or R Za and R Zb Together with the nitrogen attached to them, they form 3-6 membered heterocycles.

[0161] 10. The compound of embodiment 9, wherein the 3-6 membered heterocycle comprises one nitrogen-containing cyclic heteroatom.

[0162] 11. The compound of embodiment 10, wherein the 3-6 membered heterocycle is a nitrogen-containing heterocyclic butane or pyrrolidine ring.

[0163] 12. The compound of any one of embodiments 1-11, wherein the compound comprises at most 2 R... 4 For example, at most one R 4 For example, the compound described is not R 4 replace.

[0164] 13. The compound as described in any one of embodiments 1-12, wherein each R 4 Independently halogenated (e.g., fluorine or chlorine), -S(O)₂N(R) Za (R) Zb C 1–6 Alkyl (e.g., C10) 1–3 Alkyl), C 1–6 Alkoxy groups (e.g., C) 1–3 alkoxy) or C 3–10 cycloalkyl (e.g., C10) 3–4 cycloalkyl), wherein C 1–6 Alkyl (or C) 1–3 Alkyl), C 1–6 Alkoxy (or C) 1–3 alkoxy) and C 3–10 cycloalkyl (or C) 3–4Each of the cycloalkyl groups is optionally construed by one or more R groups. 5 Substitution; or attachment of two R atoms to adjacent ring A atoms. 4 Together with the atoms to which they are attached, they form a group optionally bounded by one or more R 5 Replaced 5-6 membered heterocycles.

[0165] 14. The compound of embodiment 13, wherein the 5-6 membered heterocycle comprises 1-2 cyclic heteroatoms selected from N and O.

[0166] 15. The compound of embodiment 14, wherein the 5-6 membered heterocycle comprises 1-2 cyclic heteroatoms of type O, or the 5-6 membered heterocycle comprises 1 cyclic heteroatom of type N.

[0167] 16. The compound as described in embodiment 15, wherein each R 4 Choose independently from the following groups: , , , , , , , , , , , , , , , , , , , and Or two R atoms attached to the adjacent ring A atom 4 Together with the atoms to which they are attached, they form heterocycles selected from the following groups: , , , , , and .

[0168] 17. The compound as described in embodiment 16, wherein each R 4 Choose independently from the following groups: , , , , , , , , , , , , , , , , , , , , , , , and Or two R atoms attached to the adjacent ring A atom 4 Together with the atoms to which they are attached, they form heterocycles selected from the following groups: , , , , , and .

[0169] 18. The compound of any one of embodiments 1-17, wherein the compound comprises at most 3 R... 5 For example, at most 2 Rs 5 For example, at most one R 5 For example, the compound described is not R 5 replace.

[0170] 19. The compound as described in any one of embodiments 1-18, wherein each R 5 Independent of halogen, C 1–6 Alkyl (e.g., C10) 1–3 Alkyl), C 1–6 Alkoxy groups (e.g., C) 1–3 alkoxy) or C 3–10 cycloalkyl (e.g., C10) 3–6 (cycloalkyl).

[0171] 20. The compound as described in embodiment 19, wherein each R 5 It can be fluorine, CH3, OCH3 or cyclopropyl independently.

[0172] 21. The compound of any one of embodiments 1-20, wherein ring A is aryl or heteroaryl, and ring A is optionally separated by one or more R 4 replace.

[0173] 22. The compound of embodiment 21, wherein ring A is phenyl or a 5-6-membered heteroaryl group, and ring A is optionally separated by one or more R groups. 4 replace.

[0174] 23. The compound as described in embodiment 22, wherein the 5-6 member heteroaryl is a 5-6 member nitrogen-containing heteroaryl.

[0175] 24. The compound as described in embodiment 23, wherein the 5-6 nitrogen-containing heteroaryl group is pyridine, pyrimidine, pyrazine, pyridazine, pyrazole, oxazole or isoxazole.

[0176] 25. The compound of embodiment 24, wherein ring A is selected from the group consisting of: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , and , where X 1 X 2 X 3 and X 4 One or both of them are oxygen and the rest are carbon.

[0177] 26. The compound of embodiment 25, wherein ring A is selected from the group consisting of: , , , , , , , , , , , , , , , , 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 , , , , , , , , , , , , , , , , , , , , , , , , , and .

[0178] 27. The compound of embodiment 26, wherein ring A is selected from the group consisting of: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 , , , and .

[0179] 28. The compound of any one of embodiments 1-20, wherein ring A is optionally surrounded by one or more R 4 Substituted bicyclic [1.1.1]pentyl.

[0180] 29. The compound of embodiment 28, wherein the compound comprises at most one R 4 .

[0181] 30. The compound as described in embodiment 28 or embodiment 29, wherein each R 4 Independently for C 1–6 Alkyl (e.g., C10) 1–4 Alkyl), aryl (e.g., phenyl), or cyano, and R 4 Optionally by one or more R 5 replace.

[0182] 31. The compound as described in embodiment 30, wherein each R 4 Choose independently from the following groups: , , , , and .

[0183] 32. The compound as described in embodiment 31, wherein each R 4 Choose independently from the following groups: , , , , , and .

[0184] 33. The compound as described in embodiment 28 or embodiment 29, wherein each R 4 To be optionally used by one or more R 5 Replacement C 1–6 alkyl.

[0185] 34. The compound as described in embodiment 33, wherein each R 4 To be optionally used by one or more R 5 The CH3 that is replaced.

[0186] 35. The compound as described in embodiment 34, wherein each R 4Choose independently from the following groups: , and .

[0187] 36. The compound as described in embodiment 35, wherein each R 4 Choose independently from the following groups: , and .

[0188] 37. The compound of any one of embodiments 28-36, wherein the compound comprises at most 3 R... 5 For example, at most 2 Rs 5 For example, at most one R 5 For example, the compound described is not R 5 replace.

[0189] 38. The compound as described in any one of embodiments 28-37, wherein each R 5 It is a halogen.

[0190] 39. The compound as described in embodiment 38, wherein each R 5 It is fluorine.

[0191] 40. The compound as described in any one of embodiments 28-39, wherein ring A is .

[0192] 41. The compound of embodiment 40, wherein ring A is selected from the group consisting of: , , , , and .

[0193] 42. The compound of embodiment 41, wherein ring A is selected from the group consisting of: , , , , and .

[0194] 43. The compound of embodiment 40, wherein ring A is selected from the group consisting of: , and .

[0195] 44. The compound of embodiment 43, wherein ring A is selected from the group consisting of: , and .

[0196] 45. A compound selected from the embodiments described in Table 1, or a pharmaceutically acceptable salt thereof.

[0197] 46. ​​A pharmaceutical composition comprising a compound or a pharmaceutically acceptable salt thereof, as described in any one of embodiments 1-45, and a pharmaceutically acceptable excipient.

[0198] 47. A method of treating cancer in a subject in need, comprising administering to the subject a therapeutically effective amount of any one of embodiments 1-45, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of embodiment 46.

[0199] 48. The method as described in embodiment 47, wherein the cancer is breast cancer.

[0200] 49. The method of embodiment 48, wherein the breast cancer is HR+ (hormone receptor positive) breast cancer.

[0201] 50. The method of embodiment 49, wherein the breast cancer is ER+ (estrogen receptor positive) breast cancer.

[0202] 51. The method of embodiment 49, wherein the breast cancer is HR+ HER2- (human epidermal growth factor receptor 2 negative) breast cancer.

[0203] 52. The method of embodiment 50, wherein the breast cancer is ER+ HER2- (human epidermal growth factor receptor 2 negative) breast cancer.

[0204] 53. The method of embodiment 47, wherein the cancer is selected from the group consisting of: ovarian cancer, endometrial cancer, gastric cancer, esophageal cancer, triple-negative breast cancer, and pulmonary adenosarcoma.

[0205] 54. The method as described in embodiment 53, wherein the cancer is triple-negative breast cancer.

[0206] 55. The method as described in embodiment 47, wherein the cancer includes a solid tumor.

[0207] 56. The method of embodiment 55, wherein the solid tumor is at least one of the following: uterine cancer (such as uterine carcinosarcoma and endometrial cancer of the uterine corpus), endometrial cancer, breast cancer (such as invasive breast cancer and triple-negative breast cancer, ER+ HER2- breast cancer and HER2+ breast cancer), ovarian cancer (such as ovarian serous cystadenocarcinoma), gastric cancer (such as gastric adenocarcinoma), gastric cancer (such as gastrointestinal stromal carcinoma), colorectal cancer, pancreatic cancer, kidney cancer, head and neck cancer, liver cancer, prostate cancer, skin cancer, lymphoma (such as B-cell lymphoma), sarcoma, esophageal cancer (such as esophageal cancer), bladder cancer (such as bladder urothelial carcinoma), lung cancer (such as squamous cell carcinoma of the lung and non-small cell lung cancer, including EGFRm+ (epidermal growth factor receptor mutant positive) non-small cell lung cancer), cholangiocarcinoma, adrenocortical carcinoma, mesothelioma, and malignant melanoma.

[0208] 57. The method as described in embodiment 47, wherein the cancer includes a liquid tumor.

[0209] 58. The method of embodiment 55, wherein the liquid tumor is at least one of the following: diffuse large B-cell lymphoma (DLBCL), B-cell immunoblastic lymphoma, small non-cleaved cell lymphoma, human lymphotropic virus type 1 (HTLV-1) leukemia / lymphoma, adult T-cell lymphoma, peripheral T-cell lymphoma (PTCL), cutaneous T-cell lymphoma (CTCL), mantle cell lymphoma (MCL), Hodgkin lymphoma (HL), non-Hodgkin lymphoma (NHL), AIDS-related lymphoma, follicular lymphoma, small lymphocytic lymphoma, large B-cell lymphoma rich in T cells / histocytes, transformed lymphoma, primary mediastinal (thymic) large B-cell lymphoma, splenic marginal zone lymphoma, Richter's transformation lymphoma. The following are considered leukemia types: marginal zone lymphoma, ALK-positive large B-cell lymphoma, indolent lymphoma (e.g., DLBCL, follicular lymphoma, or marginal zone lymphoma), acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), adult T-cell leukemia, chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), hairy cell leukemia, myelodysplastic syndrome, chronic myeloid leukemia (CML), acute monocytic leukemia (AMoL), myelodysplastic syndrome (MDS), human lymphotropic virus type 1 (HTLV-1) leukemia, mastocytosis, B-cell acute lymphoblastic leukemia, non-Hodgkin lymphoma, Hodgkin lymphoma, and multiple myeloma (MM).

[0210] 59. The method as described in any one of embodiments 47-58, further comprising administering an additional therapeutic agent to the subject.

[0211] 60. The method of embodiment 59, wherein the additional therapeutic agent is carboplatin, fulvestrant, or a combination thereof.

[0212] 61. The method as described in any one of embodiments 47-60, wherein the subject is untreated.

[0213] Example The compounds described herein can be prepared from readily available starting materials using the following general methods and procedures. It will be understood that, given typical or preferred process conditions (i.e., reaction temperature, time, molar ratio of reactants, solvent, pressure, etc.), other process conditions may be used unless otherwise stated. Optimal reaction conditions may vary depending on the specific reactants or solvents used, but such conditions can be determined by those skilled in the art through routine optimization.

[0214] The designation of compounds as 'Intermediate X' or 'Compound Y' will be consistent throughout this specification. However, in the preparations described below, the designation of compounds used as starting materials or prepared in intermediate steps, i.e., those compounds designated only by numbers, i.e., 'Z', is independent. In other words, a compound designated as '1' in one preparation is not necessarily the same as a compound designated as '1' in another preparation.

[0215] abbreviation ACN: Acetonitrile; AIBN: 2,2-Azobis(2-methylpropionitrile); BH3-Me2S: Borane-dimethyl sulfide complex; BrCN: Bromine cyanide; brd : Wide double peak; brdd : Broad doublet peaks; BPO: Benzoyl benzoate peroxy acid; brs : Broad single peak; brt : Broad triplet; eq: equivalent; CHCl3: chloroform; CDCl3: deuterated chloroform; CDI: 1,1'-carbonyldiimidazole; Cs2CO3: cesium carbonate; CuBr: copper bromide; CuBr2: copper(II) bromide; Cu(OAc)2: copper acetate; d Double peak; dd Double double peak; ddd : Double doublet; DAST: (diethylamino)sulfur trifluoride; DBU: 2,3,4,6,7,8,9,10-octahydropyrimidino[1,2- a Nitrogen oxides; DCC: N,N '-Methanediethylenedicyclohexylamine; DCM: dichloromethane; DIEA: diisopropylethylamine; DMA: N , N-Dimethylacetamide; DMAP: 4-Dimethylaminopyridine; DMF: Dimethylformamide; DMSO: Dimethyl sulfoxide; DPPA: Diphenyl azidophosphate; DPPP: 3-(6-(1-((5-(2-(methoxymethyl)-4-methylphenyl)-1,3,4-oxadiazol-2-yl)amino)cyclopropyl)-4-methyl-1-oxoisoindololin-2-yl)piperidin-2,6-dione; EDCl: 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride; ESI: Electrospray ionization; EtOH: Ethanol; h: hours; HCl: Hydrochloric acid; H2SO4: Sulfuric acid; HOBt: Benzotriazol-1-ol; HPLC: High performance liquid chromatography; KBr: Potassium bromide; K2CO3: Potassium carbonate; K3PO4: Potassium phosphate; LiCl: Lithium chloride; m Multiplets; MeCN: Acetonitrile; MeI: Iodomethane; MeOH: Methanol; MeONa: Sodium methoxide; MgCl2: Magnesium chloride; MS: Mass spectrometry; 3 or 4 Å MS: 3 or 4 Å molecular sieve; MW: Microwave; NaH: Sodium hydride; NaHCO3: Sodium bicarbonate; NBS: N - Bromosuccinimide; NH2-NH2•H2O: hydrazine monohydrate; NH2NHBoc: N -Aminocarbamic acid Uncle Butyl acetate; NH3•H2O: ammonium hydroxide; NiCl2: nickel(II) chloride; NiCl2•6H2O: nickel chloride hexahydrate; NIS: N -Iodosuccinimide; NMP: N 1-Methylpyrrolidone; NMR: Nuclear Magnetic Resonance; q Four-peaked peak; s : Single peak; O-phen: 1,10-phenanthroline; Pd(TFA)2: bis[(2,2,2-trifluoroacetyl)oxy]palladium; Pd( t -Bu3P)2: Bis(tri-tert-butylphosphine)palladium(0); PEPPSI-IPr: [1,3-bis(2,6-diisopropylphenyl)imidazol-2-yl](3-chloropyridinyl)palladium dichloride(II); PyCLOP: Chloro(tripyrrolidine-1-yl)phosphonium hexafluorophosphate: quin : quintet; SEM-Cl: (2-(chloromethoxy)ethyl)trimethylsilane; SOCl2: thionyl chloride; t Triple peak; t -BuONO: Nitrous acid Uncle Butyl ester; td Double triplet; TEA: triethylamine; TFA: trifluoroacetic acid; THF: tetrahydrofuran; TMSCl: trichlorotrimethylsilane; tt Triple triplet peak; Zn: Zinc Preparation of intermediates Preparation of Intermediate 1 Preparation of 2: Methyl 3-chloro-2-methylbenzoate (20.0 g, 108 mmol, 1.00 g) eq Add to the solution of sulfuric acid (160 mL) N -Iodosuccinimide (24.4 g, 108 mmol, 1.00) eq The reaction mixture was stirred at 20 °C for 12 h. The reaction mixture was added dropwise to water (200 mL) at 0 °C and extracted with ethyl acetate (3 × 100 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure to give the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 10 / 1 to 5 / 1) to give 3-chloro-5-iodo-2-methylbenzoic acid (24.7 g, 83.3 mmol, 77% yield) as a white solid. 1 H NMR (400 MHz, CDCl3) δ = 8.20 ( d , J = 1.8 Hz, 1H), 7.91 ( d , J = 1.6 Hz, 1H), 2.63 (s, 3H).

[0216] Preparation of 3: Add thionyl chloride (19.8 g, 167 mmol, 12.1 mL, 2.00 eq) to a solution of 3-chloro-5-iodo-2-methylbenzoic acid (24.7 g, 83.3 mmol, 1.00 eq) in methanol (250 mL). eq The reaction mixture was stirred at 80 °C for 12 h. The reaction mixture was concentrated under reduced pressure to give methyl 3-chloro-5-iodo-2-methylbenzoate (17.0 g, 54.8 mmol, 66% yield) as a yellow oil. 1 H NMR (400MHz, CDCl3) δ = 7.99 - 7.89 (m, 1H), 7.82 - 7.70 (m, 1H), 3.83 (s, 3H), 2.48 - 2.44 (m, 3H).

[0217] Preparation of 4: Methyl 3-chloro-5-iodo-2-methylbenzoate (17.0 g, 54.8 mmol, 1.00 mmol) eqAdd 2,2-azobis(2-methylpropionitrile) (8.99 g, 54.8 mmol, 1.00 mmol) to a solution of chloroform (200 mL). eq ) and N-bromosuccinimide (9.74 g, 54.8 mmol, 1.00 eq). The reaction mixture was stirred at 80 °C for 12 h. The reaction mixture was concentrated under reduced pressure to give the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0 to 10 / 1) to give methyl 2-(bromomethyl)-3-chloro-5-iodobenzoate (18.0 g, 46.2 mmol, 84% yield) as a colorless oil. 1 H NMR (400MHz, CDCl3) δ = 8.18 (d, J = 1.8 Hz, 1H), 7.93 (d, J = 1.6Hz, 1H), 5.05 (s, 2H), 3.96 (s, 3H).

[0218] Preparation of intermediate 1: Methyl 2-(bromomethyl)-3-chloro-5-iodobenzoate (17.0 g, 43.7 mmol, 1.00 mmol) eq Add to the solution in acetonitrile (200 mL) N,N -Diisopropylethylamine (16.9 g, 131 mmol, 22.8 mL, 3.00) eq ) and 3-aminopiperidine-2,6-dione (7.19 g, 43.7 mmol, 1.00 eq (hydrochloric acid). The reaction mixture was stirred at 80 °C for 12 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was milled with a mixture of ethyl acetate / water = 1 / 1 (10 mL) at 20 °C for 1 h and then filtered. The filter cake was concentrated under reduced pressure to give 3-(4-chloro-6-iodo-1-oxoisoindolin-2-yl)piperidine-2,6-dione (11.0 g, 27.2 mmol, 62% yield) as a black solid. 1 H NMR (400MHz, DMSO- d 6 ) δ = 11.02 (s, 1H), 8.13 (d, J = 1.2 Hz, 1H), 8.03 (d, J =1.2 Hz, 1H), 5.13 (dd, J = 5.1, 13.2 Hz, 1H), 4.46 (d, J= 18.0 Hz, 1H), 4.34 -4.24 (m, 1H), 2.96 - 2.84 (m, 1H), 2.60 (br d, J = 18.0 Hz, 1H), 2.49 - 2.41 (m, 1H), 2.08 - 1.98 (m, 1H).

[0219] Preparation of intermediate 2 Preparation of 6A: At 70°C, zinc powder (21.9 g, 335 mmol, 12.0 g) was added. eq Add chlorotrimethylsilane (303 mg, 2.79 mmol, 355 μL, 0.100 mg) to a solution of tetrahydrofuran (30.0 mL). eq The reaction mixture was stirred at 70°C for 1 h. Then, methyl 1-bromocyclopropanecarboxylate (5.00 g, 27.9 mmol, 1.00 mmol) was added at 40°C. eq The reaction mixture was stirred at 40 °C for 0.5 h. The reaction mixture yielded a black oily substance (1-(methoxycarbonyl)cyclopropyl)zinc(II) bromide (6.80 g, 27.8 mmol, 99% yield), which was used directly in the next step.

[0220] Preparation of 6: At 0°C, 3-(4-chloro-6-iodo-1-oxo-isoindololin-2-yl)piperidine-2,6-dione (11.0 g, 27.2 mmol, 1.00 mmol) was subjected to oxidation. eq Add 2,3,4,6,7,8,9,10-octahydropyrimidine[1,2-] to a solution of tetrahydrofuran (110 mL). a Nitrogen compounds (8.28 g, 54.4 mmol, 8.20 mL, 2.00) eq () and (2-(chloromethoxy)ethyl)trimethylsilane (8.16 g, 48.9 mmol, 8.66 mL, 1.80) eq The reaction mixture was stirred at 20 °C for 1 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0 to 1 / 1) to give a blue oil, 3-(4-chloro-6-iodo-1-oxoisoindoline-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)piperidin-2,6-dione (6.00 g, 11.2 mmol, 41% yield). 1 H NMR (400MHz, CDCl3) δ =8.14 (d,J = 0.8 Hz, 1H), 7.89 (d, J = 1.2 Hz, 1H), 5.29 - 5.24 (m, 1H), 5.23 -5.20 (m, 1H), 5.18 (t, J = 2.4 Hz, 1H), 4.46 - 4.38 (m, 1H), 4.30 - 4.24 (m,1H), 3.69 - 3.58 (m, 2H), 3.11 - 2.99 (m, 1H), 2.96 - 2.83 (m, 1H), 2.36 (dq, J = 4.6, 13.2 Hz, 1H), 2.21 (ttd, J = 2.6, 5.2, 10.2 Hz, 1H), 0.95 (dd, J = 7.3,9.4 Hz, 2H), 0.01 (s, 9H).

[0221] Preparation of 7: To 3-(4-chloro-6-iodo-1-oxoisoindoline-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)piperidin-2,6-dione (3.80 g, 7.10 mmol, 1.00 mmol) eq Add bis(tri-tert-butylphosphine)palladium(0) (363 mg, 710 μmol, 0.100 μL) to a solution of tetrahydrofuran (40.0 mL). eq () and (1-(methoxycarbonyl)cyclopropyl)zinc(II) bromide (5.21 g, 21.3 mmol, 3.00) eq The reaction mixture was stirred at 70 °C for 12 h. The reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0 to 10 / 1) to give methyl 1-(7-chloro-2-(2,6-dioxo-1-((2-(trimethylsilyl)ethoxy)methyl)piperidin-3-yl)-3-oxoisoindoline-5-yl)cyclopropanecarboxylate (3.00 g, 5.92 mmol, 83% yield) as a white solid. 1 H NMR (400MHz, CDCl3) δ = 7.78 - 7.73 (m, 1H), 7.50 (d, J= 1.4 Hz, 1H), 5.22 - 5.10 (m, 3H), 4.43 - 4.36 (m, 1H), 4.32 - 4.21 (m, 1H), 3.60 - 3.54 (m, 5H), 3.03 - 2.93(m, 1H), 2.88 - 2.79 (m, 1H), 2.38 - 2.26 (m, 1H), 2.19 - 2.09 (m, 1H), 1.64- 1.61 (m, 2H), 1.16 (br s, 2H), 0.89 (dd, J = 7.2, 9.2 Hz, 2H), -0.01 - -0.10(s, 9H).

[0222] Preparation of 8: Methyl 1-(7-chloro-2-(2,6-dioxo-1-((2-(trimethylsilyl)ethoxy)methyl)piperidin-3-yl)-3-oxoisoindoline-5-yl)cyclopropanecarboxylate (3.00 g, 5.92 mmol, 1.00 mmol) eq Trifluoroacetic acid (3.00 mL) was added to a solution in dichloromethane (30.0 mL). The reaction mixture was stirred at 20 °C for 1 h. The reaction mixture was concentrated under reduced pressure to give methyl 1-(7-chloro-2-(1-(hydroxymethyl)-2,6-dioxopiperidin-3-yl)-3-oxoisoindoline-5-yl)cyclopropanecarboxylate (2.41 g, 5.92 mmol, 100% yield) as a white solid.

[0223] Preparation of 9: Methyl 1-(7-chloro-2-(1-(hydroxymethyl)-2,6-dioxopiperidin-3-yl)-3-oxoisoindoline-5-yl)cyclopropanecarboxylate (2.41 g, 5.92 mmol, 1.00 mmol) eq Ammonium hydroxide (1.00 mL) was added to a solution of acetonitrile (20.0 mL). The reaction mixture was stirred at 20 °C for 1 h. The reaction mixture was filtered and concentrated under reduced pressure to give methyl 1-(7-chloro-2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindoline-5-yl)cyclopropanecarboxylate (2.20 g, 5.84 mmol, 99% yield) as a white solid. 1 H NMR (400MHz, DMSO- d 6 ) δ = 10.92 (s, 1H), 7.67- 7.55 (m, 2H), 5.02 (dd, J= 5.1, 13.3 Hz, 1H), 4.49 - 4.35 (m, 1H), 4.32 -4.21 (m, 1H), 3.48 (s, 3H), 2.91 - 2.76 (m, 1H), 2.56 (br s, 1H), 2.45 - 2.30(m, 1H), 2.05 - 1.92 (m, 1H), 1.47 (q, J = 3.4 Hz, 2H), 1.30 - 1.17 (m, 2H).

[0224] Preparation of 10: Methyl 1-(7-chloro-2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindoline-5-yl)cyclopropanecarboxylate (200 mg, 531 μmol, 1.00 mg) eq Lithium chloride (113 mg, 2.65 mmol, 54.4 μL, 5.00 mL) was added to a solution of dimethylformamide (2.00 mL). eq The reaction mixture was stirred at 160 °C for 1 h at MW. The reaction mixture was concentrated under reduced pressure. The reaction mixture was lyophilized to give 1-(7-chloro-2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindoline-5-yl)cyclopropanecarboxylic acid (900 mg, 2.48 mmol, 42% yield) as a red solid. 1 H NMR (400MHz, DMSO-) d 6 ) δ = 11.01 (br s, 1H), 7.69 - 7.60 (m, 2H), 5.13 (dd, J 1.49 (br d, J = 2.8 Hz, 2H), 1.24 (brs, 2H).

[0225] Preparation of intermediate 2: To 1-(7-chloro-2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindoline-5-yl)cyclopropanecarboxylic acid (100 mg, 276 μmol, 1.00 eqTriethylamine (83.7 mg, 827 μmol, 115 μL, 3.00 mL) was added to a solution of dioxane (2.00 mL). eq ), 4Å MS (100 mg) and diphenyl azidophosphate (114 mg, 413 μmol, 89.3 μL, 1.50 μmol). eq The reaction mixture was stirred at 20°C for 1 h. Hydrochloric acid (1 M, 1.38 mL, 5.00 mg / L) was added. eq The reaction mixture was stirred at 80 °C for 4 h. The reaction mixture was concentrated under reduced pressure and lyophilized. Water (3.00 mL) was added to the residue and filtered. The filter cake was lyophilized to give 200 mg of crude 3-(6-(1-aminocyclopropyl)-4-chloro-1-oxoisoindoline-2-yl)piperidine-2,6-dione as a yellow solid. 1 H NMR (400MHz, DMSO- d 6 ) δ = 11.10 - 10.95(m, 1H), 9.21 (br s, 3H), 7.81 (br d, J = 13.6 Hz, 2H), 5.24 - 5.08 (m, 1H), 4.51 (br d, J = 17.9 Hz, 1H), 4.39 - 4.26 (m, 1H), 3.22 - 3.18 (m, 1H), 2.89 -2.82 (m, 1H), 2.63 (br s, 1H), 2.08 - 2.00 (m, 1H), 1.50 (br s, 2H), 1.33 (brs, 2H).

[0226] Preparation of intermediate 3 Preparation of 2: To 4-(azacyclobutane-1-ylsulfonyl)benzoylhydrazide (986 mg, 3.86 mmol, 1.00 eq Add saturated sodium bicarbonate (324 mg, 3.86 mmol, 150 μL, 1.00 mL) to a solution of dioxane (5.00 mL) and water (5.00 mL). eq ) and bromine cyanide (409 mg, 3.86 mmol, 283 μL, 1.00 eqThe reaction mixture was stirred at 20 °C for 12 h. The reaction mixture was filtered, and the filter cake was washed with 10 mL of petroleum ether and dried under vacuum to give 5-(4-(azacyclobutane-1-ylsulfonyl)phenyl)-1,3,4-oxadiazol-2-amine (908 mg, 3.24 mmol, 83% yield) as a white solid.

[0227] Preparation of intermediate 3: To 5-(4-(azacyclobutane-1-ylsulfonyl)phenyl)-1,3,4-oxadiazol-2-amine (454 mg, 1.62 mmol, 1.00 eq Add copper bromide (464 mg, 3.24 mmol, 98.6 μL, 2.00 mL) to a solution in acetonitrile (5.00 mL). eq ) and nitrite Uncle Butyl ester (334 mg, 3.24 mmol, 385 μL, 2.00) eq The reaction mixture was stirred at 65 °C for 2 h. The reaction mixture was concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0 to 0 / 1) to give 2-(4-(azacyclobutane-1-ylsulfonyl)phenyl)-5-bromo-1,3,4-oxadiazole (215 mg, 624 μmol, 38% yield) as a white solid. 1 H NMR (400 MHz, DMSO- d 6 )δ = 8.31 - 8.22 (m, 2H), 8.04 - 8.00 (m, 2H), 3.73 (t, J = 7.6 Hz, 4H), 2.05 -2.00 (m, 2H).

[0228] Preparation of intermediate 4 Preparation of 2: The preparation was carried out according to the method described for structure 2 of the scheme used to prepare intermediate 1, except that the residue was purified by silica gel chromatography (petroleum ether / ethyl acetate = 3 / 1) to give 3-fluoro-5-iodo-2-methylbenzoic acid as a white solid.

[0229] Preparation of 3: The preparation was carried out according to the method described for structure 3 of the scheme used to prepare intermediate 1, except that: (i) 5.00 eq(ii) The crude product was purified by reverse-phase column chromatography (0.1% FA conditions), and the desired fraction was collected and lyophilized to give 3-fluoro-5-iodo-2-methylbenzoate as a colorless liquid.

[0230] Preparation of 4: Methyl 3-fluoro-5-iodo-2-methylbenzoate (2.80 g, 9.52 mmol, 1.00 mmol) eq ), N - Bromosuccinimide (1.69 g, 9.52 mmol, 1.00) eq ) and benzoyl benzoate (461 mg, 1.90 mmol, 0.200 mmol) eq The mixture in chloroform (30.0 mL) was stirred at 80 °C for 12 h. The mixture was diluted with water (100 mL) and extracted with ethyl acetate (3 × 100 mL). The combined organic layers were washed with brine (50.0 mL), dried over sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3 / 1) to give methyl 2-(bromomethyl)-3-fluoro-5-iodobenzoate as a brown solid (1.70 g, 4.42 mmol, 46% yield, 97% purity).

[0231] Preparation of 5: The preparation was carried out according to the method described for intermediate 1, except that: (i) 4.00 eqN,N -Diisopropylethylamine and (ii) the crude product was ground with ethyl acetate / water = 2 / 1 and filtered, and the filter cake was dried under vacuum to give 3-(4-fluoro-6-iodo-1-oxoisoindoline-2-yl)piperidine-2,6-dione (65% yield) as a blue solid.

[0232] Preparation of intermediate 4: The preparation was carried out according to the method described for structure 6 of the scheme used to prepare intermediate 2, except that: (i) dimethylformamide (0.5 M) was used instead of tetrahydrofuran and (ii) the residue was purified by silica gel chromatography (petroleum ether / ethyl acetate = 1 / 1) to give 3-(4-fluoro-6-iodo-1-oxoisoindoline-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)piperidine-2,6-dione (61% yield) as a blackish-blue liquid. 1 H NMR (400MHz, DMSO- d 6) δ =7.92 (br d, J= 1.1 Hz, 2H), 5.30 - 5.18 (m, 1H), 5.10 - 5.00(m, 2H), 4.56 (d, J = 17.5 Hz, 1H), 4.32 (d, J = 17.5 Hz, 1H), 3.56 - 3.44 (m,2H), 3.09 - 3.00 (m, 1H), 2.81 - 2.75 (m, 1H), 2.45 - 2.35 (m, 1H), 2.11 -2.02 (m, 1H), 1.17 (t, J = 7.1 Hz, 1H), 0.87 - 0.78 (m, 2H), -0.03 (s, 9H).

[0233] Preparation of intermediate 5 Preparation of 1A: At 0 °C, 1-((tert-butoxycarbonyl)amino)cyclopropanecarboxylic acid (10.0 g, 49.7 mmol, 1.00 mmol) was reacted with 1-((tert-butoxycarbonyl)amino)cyclopropanecarboxylic acid (10.0 g, 49.7 mmol, 1.00 mmol) to form cyclopropanecarboxylic acid. eq Add 2-hydroxyisoindoline-1,3-dione (8.92 g, 54.7 mmol, 1.10 g) to a solution in dichloromethane (200 mL). eq ), 4-Dimethylaminopyridine (607 mg, 4.97 mmol, 0.100 eq ) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (10.5 g, 54.7 mmol, 1.10 eq The mixture was stirred at 20 °C for 2 h. The reaction mixture was diluted with dichloromethane (500 mL) and quenched with hydrochloric acid (0.500 M, 500 mL). The solution was extracted with dichloromethane (2 × 500 mL), washed with brine (2 × 500 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0 to 1 / 1) to give 1,3-dioxoisoindoline-2-yl ester of 1-((tert-butoxycarbonyl)amino)cyclopropanecarboxylic acid as a white solid (14.0 g, 40.4 mmol, 81% yield).

[0234] Preparation of 1B: Nickel chloride hexahydrate (20.0 g, 84.1 mmol, 1.00 mmol) eq Add 2,2'-bipyridine (13.1 g, 84.1 mmol, 1.00 mg) to a solution in ethanol (300 mL). eqThe reaction mixture was stirred at 20°C for 2 h. The reaction mixture was then filtered. The filter cake was concentrated under reduced pressure to give (bipy)₂Ni₂(μ-Cl)₂Cl₂(H₂O)₂ as a green solid (11.0 g, 18.0 mmol, 21% yield). Preparation of 2 : At 0°C, 3-(4-fluoro-6-iodo-1-oxoisoindoline-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)piperidine-2,6-dione (2.00 g, 3.86 mmol, 1.00 mmol) was reacted with 3-(4-fluoro-6-iodo-1-oxoisoindoline-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)piperidine-2,6-dione (2.00 g, 3.86 mmol, 1.00 mmol) eq (For preparation steps, please refer to 'Preparation of Intermediate 4') N , N Add 1-((tert-butoxycarbonyl)amino)cyclopropane-1-carboxylic acid 1,3-dioxoisoindoline-2-yl ester (2.67 g, 7.72 mmol, 2.00 mL) to a solution of dimethylacetamide (20.0 mL). eq ), trichlorotrimethylsilane (1.26 g, 11.5 mmol, 1.47 mL, 3.00 mmol) eq ), (bipy)2Ni2(μ-Cl)2Cl2(H2O)2(117 mg, 192 μmol, 0.0500 eq ) and zinc powder (2.02 g, 30.8 mmol, 8.00 eq The reaction mixture was stirred at 20 °C under a nitrogen atmosphere for 12 h. The reaction mixture was filtered. The filtrate was extracted with ethyl acetate (3 × 100 mL). The organic layer was washed with water (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0 to 0 / 1) to give a yellow oil, tert-butyl 1-(2-(2,6-dioxo-1-((2-(trimethylsilyl)ethoxy)methyl)piperidin-3-yl)-7-fluoro-3-oxoisoindoline-5-yl)cyclopropyl)carbamate (1.50 g, 2.74 mmol, 70% yield).

[0235] Preparation of intermediate 5: (1-(2-(2,6-dioxo-1-((2-(trimethylsilyl)ethoxy)methyl)piperidin-3-yl)-7-fluoro-3-oxoisoindoline-5-yl)cyclopropyl)tert-butyl carbamate (1.50 g, 2.74 mmol, 1.00 mmol) eq ) in hydrochloric acid / dioxane (4.00 M, 15.0 mL, 21.9 eqThe solution in the mixture was stirred at 20°C for 1 h. The reaction mixture was concentrated under reduced pressure to obtain a residue. Trifluoroacetic acid (2.30 g, 20.1 mmol, 1.50 mL, 7.37 mmol) was added to the solid. eq The reaction mixture was stirred at 20 °C for 1 h. The reaction mixture was concentrated under reduced pressure to give a yellow oil (951 mg, 2.74 mmol, 99% yield). The yellow oil (951 mg, 2.74 mmol, 1.00 g) obtained was added to acetonitrile (15.0 mL) and dichloromethane (10.0 mL). eq Ammonium hydroxide (340 mg, 2.43 mmol, 374 μL, 25% purity, 8.88e-1) was added. eq The reaction mixture was stirred at 20°C for 1 h. The reaction mixture was then concentrated under reduced pressure to obtain a residue. Preparative The residue was purified by HPLC (column: UniSil 10-120 C18 70 x 250 mm; mobile phase: [water (formic acid)-acetonitrile]; gradient: 15 min 0%-20% B) and lyophilized to give 3-(6-(1-aminocyclopropyl)-4-fluoro-1-oxoisoindoline-2-yl)piperidine-2,6-dione (518 mg, 1.43 mmol, 52% yield, formate) as a white solid. 1 H NMR (400 MHz, DMSO-) d 6 ) δ = 11.01 (s, 1H), 8.38 - 7.96 (m, 2H), 7.68 (d, J = 1.4 Hz, 1H), 7.48 (dd, J = 1.4, 10.4 Hz, 1H), 5.12 (dd, J = 5.0, 13.2 Hz, 1H), 4.62 -4.55 (m, 1H), 4.45 - 4.36 (m, 1H), 2.97 - 2.86 (m, 1H), 2.61 (br dd, J = 1.8,15.2 Hz, 1H), 2.45 - 2.38 (m, 1H), 2.06 - 1.97 (m, 1H), 1.36 - 1.28 (m, 4H).

[0236] Preparation of intermediate 6 Preparation of 2:At 0°C, 4-(trifluoromethoxy)benzoic acid (3.00 g, 14.6 mmol, 1.00 mmol) was reacted with benzoic acid (3.00 g, 14.6 mmol, 1.00 mmol) to form benzoic acid. eq Add thionyl chloride (2.60 g, 21.8 mmol, 1.58 mL, 1.50 mmol) to a solution in methanol (30.0 mL). eq The mixture was stirred at 60°C for 3 h. The mixture was concentrated under reduced pressure to give methyl 4-(trifluoromethoxy)benzoate (2.6 g, crude product) as a white solid.

[0237] Preparation of 3: Add hydrazine hydrate (1.39 g, 23.6 mmol, 1.35 mL, 85% purity, 2.00 eq) to a solution of methyl 4-(trifluoromethoxy)benzoate (2.60 g, 11.8 mmol, 1.00 eq) in ethanol (30.0 mL). eq The mixture was stirred at 80 °C for 8 h. The reaction mixture was cooled to 25 °C and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 0 / 1) to give 4-(trifluoromethoxy)benzoylhydrazine as a white solid (1.95 g, 8.24 mmol, 69% yield, 93% purity).

[0238] Preparation of 4: To 4-(trifluoromethoxy)benzoylhydrazide (1.20 g, 5.45 mmol, 1.00 g), eq Add cyanogen bromide (693 mg, 6.54 mmol, 481 μL, 1.20 μL) to a methanol (7.00 mL) solution. eq The mixture was stirred at 65°C for 4 h. The reaction mixture was cooled to 25°C. Water (60.0 mL) was added to the mixture and extracted with ethyl acetate (2 × 50.0 mL). The combined layers were washed with brine (50.0 mL), dried over sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give a residue. The residue was ground with ethyl acetate (30.0 mL) at 25°C for 15 min and filtered. The filter cake was washed with saturated sodium bicarbonate solution and filtered to give 5-(4-(trifluoromethoxy)phenyl)-1,3,4-oxadiazol-2-amine (800 mg, 3.23 mmol, 59% yield, 99% purity) as a white solid.

[0239] Preparation of intermediate 6:The preparation was carried out according to the method for intermediate 3, except that: (i) the reaction mixture was stirred at 0°C to 65°C for 3 h and (ii) the residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 9 / 1) to give 2-bromo-5-(4-(trifluoromethoxy)phenyl)-1,3,4-oxadiazole (37% yield) as a white solid. 1 H NMR (400 MHz, DMSO- d 6) δ = 8.12 (d, J = 8.8 Hz, 2H), 7.61 (d, J = 8.0 Hz, 2H).

[0240] Preparation of intermediate 7 Preparation of 2: The preparation was carried out according to the method described for structure 3 of the scheme used to prepare intermediate 6, except that: (i) methanol was used instead of ethanol and (ii) the mixture was stirred at 60°C for 12 h. 4-Methylbenzoylhydrazine (98% yield) was obtained as a white solid.

[0241] Preparation of 3: Preparation was carried out according to the method described for structure 2 of the scheme used to prepare intermediate 3. A white solid 5-( right Tolyl)-1,3,4-oxadiazole-2-amine (88% yield).

[0242] Preparation of intermediate 7: Preparation was carried out according to the method described for intermediate 3. 2-Bromo-5-( right Tolyl)-1,3,4-oxadiazole (28% yield). 1 H NMR (400 MHz, DMSO- d 6 ) δ = 7.87 (d, J =8.2 Hz, 2H), 7.42 (d, J = 8.0 Hz, 2H), 2.41 (s, 3H).

[0243] Preparation of intermediate 8 Preparation of 2: To 4-cyclopropoxybenzoic acid (1.00 g, 5.61 mmol, 1.00 g), eq )At N,NAdd potassium carbonate (2.33 g, 16.8 mmol, 3.00 mL) to a solution of dimethylformamide (10.0 mL). eq ) and methyl iodide (956 mg, 6.73 mmol, 419 μL, 1.20) eq The reaction mixture was stirred at 20 °C for 12 h. The reaction mixture was quenched with water (30 mL) and extracted with ethyl acetate (3 × 50 mL). The combined organic layers were washed with brine (50 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0 to 10 / 1) to give methyl 4-cyclopropoxybenzoate (1.08 g, 5.62 mmol, 100% yield) as a yellow oil.

[0244] Preparation of 3: The preparation was carried out according to the method described for structure 3 of the scheme used to prepare intermediate 6, except that: (i) methanol (10.0 mL) was used instead of ethanol, and (ii) 15.0 mL was used. eq (iii) The mixture was stirred at 60 °C for 12 h, and (iv) the reaction mixture was concentrated under reduced pressure to give 4-cyclopropoxybenzoyl hydrazine as a yellow solid (93% yield).

[0245] Preparation of 4: The preparation was carried out according to the method described for structure 4 of the scheme for preparing intermediate 6, except that the crude product was ground with ethyl acetate to obtain 5-(4-cyclopropoxyphenyl)-1,3,4-oxadiazole-2-amine (98% yield) as a yellow solid.

[0246] Preparation of intermediate 8: The preparation was carried out according to the method described for intermediate 3, except that: (i) 1.50 eq Copper bromide (I) and 1.50 eq (ii) The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0 to 1 / 1) to give 2-bromo-5-(4-cyclopropoxyphenyl)-1,3,4-oxadiazole as a white solid (42% yield). 1 H NMR (400 MHz, DMSO- d 6 ) δ = 7.93 (d, J = 8.8 Hz, 2H), 7.26 (d, J= 8.8Hz, 2H), 3.99 – 3.95 (m, 1H), 0.87 – 0.82 (m, 2H), 0.73 – 0.69 (m, 2H).

[0247] Preparation of compounds Example 1: Preparation of Compound 1 Preparation of 2 Intermediate 1 was used as the starting material. Preparation was carried out according to the method described for structure 2 of the scheme used to prepare intermediate 5, except that the residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0 to 1 / 1) to obtain a crude product, and the crude product was ground with ethyl acetate at 20°C for 12 h to obtain a yellow solid (1-(7-chloro-2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindoline-5-yl)cyclopropyl)carbamate tert-butyl ester (34% yield). 1 H NMR (400 MHz, DMSO- d 6 ) δ = 11.02 (s, 1H), 7.90 (s, 1H), 7.50 (s,1H), 7.43 (s, 1H), 5.13 (dd, J = 5.0, 13.3 Hz, 1H), 4.51 - 4.41 (m, 1H), 4.32 -4.22 (m, 1H), 2.99 - 2.84 (m, 1H), 2.60 (br d, J = 17.5 Hz, 1H), 2.48 - 2.37(m, 1H), 2.06 - 1.99 (m, 1H), 1.39 (s, 9H), 1.27 - 1.21 (m, 2H), 1.21 - 1.15(m, 2H).

[0248] Preparation of 3 : 140 mg, 323 μmol, 1.00 mg of (1-(7-chloro-2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindoline-5-yl)cyclopropyl)tert-butyl carbamate (1.00 mg, 323 μmol, 1.00 μmol). eqThe mixture of dioxane (1 mL, 4 M) in hydrochloric acid and dioxane (1.00 mL) was stirred at 20 °C for 1.5 h. The two batches were combined. The reaction mixture was concentrated under reduced pressure to give a residue as a white solid of 3-(6-(1-aminocyclopropyl)-4-chloro-1-oxoisoindoline-2-yl)piperidine-2,6-dione (238 mg, 643 μmol, 99% yield, hydrochloric acid). 1 H NMR (400 MHz, DMSO- d 6 ) δ = 11.02(s, 1H), 8.94 (br s, 3H), 7.80 (dd, J = 1.4, 11.0 Hz, 2H), 5.15 (dd, J = 5.0,13.3 Hz, 1H), 4.63 - 4.45 (m, 1H), 4.42 - 4.26 (m, 1H), 3.02 - 2.83 (m, 1H), 2.61 (br d, J = 18.3 Hz, 1H), 2.49 - 2.41 (m, 1H), 2.12 - 1.94 (m, 1H), 1.51 -1.41 (m, 2H), 1.39 - 1.27 (m, 2H).

[0249] Preparation of compound 1: To 3-(6-(1-aminocyclopropyl)-4-chloro-1-oxoisoindoline-2-yl)piperidin-2,6-dione (200 mg, 540 μmol, 1.00 eq Add 2-bromo-5-(4-(trifluoromethoxy)phenyl)-1,3,4-oxadiazole (167 mg, 540 μmol, 1.00 mL) to a solution of dimethyl sulfoxide (2.00 mL). eq (See 'Preparation of Intermediate 6' for preparation steps) and N,N -Diisopropylethylamine (140 mg, 1.08 mmol, 188 μL, 2.00) eq The reaction mixture was stirred at 80°C for 12 h. The reaction mixture was then filtered. PreparativePurification was performed by HPLC (column: C18 150×30mm; mobile phase: [water (formic acid)-acetonitrile]; gradient: 42%-72% B, duration: 7 min) to obtain 3-(4-chloro-1-oxo-6-(1-((5-(4-(trifluoromethoxy)phenyl)-1,3,4-oxadiazol-2-yl)amino)cyclopropyl)isoindoline-2-yl)piperidin-2,6-dione as a grayish-white solid (158.01 mg, 278.40 μmol, 52% yield, 99% purity). 1 H NMR (400 MHz, DMSO- d 6 ) δ =11.01 (s, 1H), 9.03 (s, 1H), 7.97 - 7.89 (m, 2H), 7.63 (dd, J = 1.4, 13.1 Hz, 2H), 7.54 (d, J = 8.1 Hz, 2H), 5.13 (dd, J = 4.9, 13.3 Hz, 1H), 4.51 - 4.40 (m,1H), 4.35 - 4.22 (m, 1H), 2.97 - 2.85 (m, 1H), 2.59 (br d, J = 17.5 Hz, 1H), 2.45 (br dd, J = 4.8, 13.1 Hz, 1H), 2.06 - 1.90 (m, 1H), 1.44 (br d, J = 4.0 Hz, 2H), 1.42 - 1.30 (m, 2H).

[0250] Example 2: Preparation of Compound 2 Preparation of 2: Preparation is carried out according to the method described for structure 4 of the scheme used to prepare intermediate 1, except that: (i) 0.100 eq 2,2-Azobis(2-methylpropionitrile) and (ii) the reaction mixture was poured into water and extracted with ethyl acetate, the combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give methyl 2-(bromomethyl)-5-iodobenzoate as a white solid (91% yield).

[0251] Preparation of 3:The preparation was carried out according to the method described for intermediate 1, except that the residue was ground with a mixture of ethyl acetate / water = 2 / 1 at 20°C for 1 h and then filtered, and the filter cake was concentrated under reduced pressure to give 3-(6-iodo-1-oxoisoindoline-2-yl)piperidine-2,6-dione (78% yield) as a black solid.

[0252] Preparation of 4: Preparation was carried out according to the method described for the scheme used to prepare intermediate 2, except that the residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0 to 0 / 1) to give 3-(6-iodo-1-oxoisoindoline-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)piperidine-2,6-dione (28% yield) as a blue solid.

[0253] Preparation of 5: Preparation was carried out according to the method described for structure 7 of the scheme used to prepare intermediate 2, except that the residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0 to 0 / 1) to give methyl 1-(2-(2,6-dioxo-1-((2-(trimethylsilyl)ethoxy)methyl)piperidin-3-yl)-3-oxoisoindoline-5-yl)cyclopropane-1-carboxylate (79% yield) as a white solid.

[0254] Preparation of 6: Preparation was carried out according to the method described for structure 8 of the scheme used to prepare intermediate 2. Methyl 1-(2-(1-(hydroxymethyl)-2,6-dioxopiperidin-3-yl)-3-oxoisoindoline-5-yl)cyclopropane-1-carboxylate (95% yield) was obtained as a yellow solid.

[0255] Preparation of 7: Preparation was carried out according to the method described for structure 9 of the scheme used to prepare intermediate 2. 1-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindoline-5-yl)cyclopropane-1-carboxylate methyl ester (93% yield) was obtained as a white solid.

[0256] Preparation of 8: Preparation was carried out according to the method described for structure 10 of the scheme used to prepare intermediate 2. The reaction mixture was lyophilized to give 1-(7-chloro-2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindoline-5-yl)cyclopropane-1-carboxylic acid (19% yield) as a red solid.

[0257] Preparation of 9:Preparation was carried out according to the method described for intermediate 2. 3-(6-(1-aminocyclopropyl)-1-oxoisoindoline-2-yl)piperidine-2,6-dione (89% yield, hydrochloric acid) was obtained as a yellow solid. 1 H NMR (400 MHz, DMSO- d 6) δ = 11.00 (s, 1H), 9.01 (br s, 3H), 7.81 (s, 1H), 7.69 - 7.62 (m, 2H), 5.17 - 5.07 (m, 1H), 4.51 - 4.43 (m, 1H), 4.37 - 4.30 (m, 1H), 2.92 - 2.86(m, 1H), 2.64 - 2.59 (m, 1H), 2.44 - 2.37 (m, 1H), 2.04 - 1.97 (m, 1H), 1.50- 1.43 (m, 2H), 1.29 - 1.25 (m, 2H).

[0258] Preparation of compound 2: The preparation and purification were carried out according to compound 1. Preparative HPLC, gradient: 40%-70% B). 3-(1-oxo-6-(1-((5-(4-(trifluoromethoxy)phenyl)-1,3,4-oxadiazol-2-yl)amino)cyclopropyl)isoindoline-2-yl)piperidine-2,6-dione (99% purity) was obtained as a grayish-white solid. 1 H NMR (400 MHz, DMSO- d 6) δ =10.98 (s, 1H), 9.01 (s, 1H), 7.89 (d, J = 8.8 Hz, 2H), 7.65 (s, 1H), 7.58 -7.46 (m, 4H), 5.10 (dd, J = 5.1, 13.3 Hz, 1H), 4.45 - 4.37 (m, 1H), 4.32 - 4.24(m, 1H), 2.97 - 2.83 (m, 1H), 2.58 (br d, J = 16.1 Hz, 1H), 2.38 (dq, J = 4.3,13.2 Hz, 1H), 2.03 - 1.93 (m, 1H), 1.37 (s, 4H).

[0259] Example 3: Preparation of Compound 3 The preparation was carried out according to the method described for compound 1, except that: (i) 4.00 eqN,N -Diisopropylethylamine and (ii) via Preparative Purification was performed by HPLC (column: YMC-Actus Triart C18 150*30 mm*7 um; mobile phase: [water (formic acid)-acetonitrile]; gradient: 35%-65% B, duration: 10 min) to obtain 3-(4-chloro-1-oxo-6-(1-((5-(p-tolyl)-1,3,4-oxadiazol-2-yl)amino)cyclopropyl)isoindoline-2-yl)piperidine-2,6-dione (27% yield) as a grayish-white solid. 1 H NMR (400 MHz, DMSO- d 6 ) δ = 10.99 (s, 1H), 8.89 (s,1H), 7.67 (d, J = 8.2 Hz, 2H), 7.63 (dd, J = 1.4, 13.8 Hz, 2H), 7.33 (d, J = 8.0Hz, 2H), 5.12 (dd, J = 4.8, 13.2 Hz, 1H), 4.48 - 4.41 (m, 1H), 4.32 - 4.23 (m,1H), 2.96 - 2.84 (m, 1H), 2.61 - 2.55 (m, 1H), 2.44 (dd, J = 4.4, 13.0 Hz, 1H), 2.35 (s, 3H), 2.03 - 1.94 (m, 1H), 1.46 - 1.34 (m, 4H).

[0260] Example 4: Preparation of Compound 4 Preparation of 2: The preparation was carried out according to the method described for structure 3 of the scheme used to prepare intermediate 6, except that: (i) the reaction was carried out in methanol instead of ethanol, and (ii) 10.0 eq Hydrazine monohydrate was used as hydrazine hydrate, (iii) the mixture was stirred at 60 °C for 1 h, and (iv) the reaction mixture was concentrated under reduced pressure to give 4-(difluoromethoxy)benzoyl hydrazine as a white solid (99% yield).

[0261] Preparation of 3:The preparation was carried out according to the method described for structure 2 of the scheme used to prepare intermediate 3, except that: (i) bromine cyanide was added in three batches over 15 min and (ii) the reaction was diluted with water (20.0 mL), filtered, and the resulting solid was washed with water to give 5-(4-(difluoromethoxy)phenyl)-1,3,4-oxadiazole-2-amine (38% yield) as a grayish-white solid.

[0262] Preparation of 4: The preparation was carried out according to the method for intermediate 3, except that: (i) the reaction mixture was stirred at 70 °C for 1 h and (ii) the residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0 to 3 / 1) to give 2-bromo-5-(4-(difluoromethoxy)phenyl)-1,3,4-oxadiazole (22% yield) as a yellow oil. 1 HNMR (400 MHz, CDCl3) δ = 8.04 (d, J = 8.8 Hz, 2H), 7.25 (d, J = 1.6 Hz, 2H), 6.60(t, J = 72.8 Hz, 1H).

[0263] Preparation of compound 4: The preparation was carried out according to the method described for compound 1, except that: (i) triethylamine (2.50 g / L) was used. eq )replace N,N -Diisopropylethylamine and (ii) purified by preparative HPLC (formic acid conditions; column: YMC-Actus Triart C18 150*30mm*7um; mobile phase: [water (formic acid)-acetonitrile]; gradient: 35%-65% B, duration: 10 min) to obtain 3-(4-chloro-6-(1-((5-(4-(difluoromethoxy)phenyl)-1,3,4-oxadiazol-2-yl)amino)cyclopropyl)-1-oxoisoindoline-2-yl)piperidine-2,6-dione (96% purity) as a yellow solid. 1 H NMR (400MHz, DMSO- d 6 ) δ = 11.00 (s, 1H), 8.96 (s, 1H), 7.83 (d, J = 8.8 Hz, 2H), 7.63(dd, J = 1.4, 13.8 Hz, 2H), 7.53 - 7.16 (m, 3H), 5.12 (dd, J= 5.2, 13.2 Hz, 1H),4.48 - 4.40 (m, 1H), 4.32 - 4.24 (m, 1H), 2.98 - 2.83 (m, 1H), 2.60 - 2.54(m, 1H), 2.47 - 2.39 (m, 1H), 2.04 - 1.94 (m, 1H), 1.46 - 1.35 (m, 4H).

[0264] Example 5: Preparation of Compound 5 Preparation of 2: The preparation was carried out according to the method described for structure 3 of the scheme used to prepare intermediate 6, except that: (i) 10.0 eq (ii) The mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were then washed with brine and dried over sodium sulfate, filtered and concentrated to give 4-methoxybenzoyl hydrazine as a white solid, which was used in the next step without purification.

[0265] Preparation of 3: The preparation was carried out according to the method described for structure 2 of the scheme for preparing intermediate 3, except that: (i) cyanide was added in three batches over 15 min, (ii) the reaction mixture was stirred at 25 °C for 12 h, and (iii) the reaction mixture was diluted with water, filtered, and the resulting solid was washed with water. The reaction mixture was then filtered and concentrated under reduced pressure to give 5-(4-methoxyphenyl)-1,3,4-oxadiazole-2-amine (75% yield) as a white solid.

[0266] Preparation of 4: The preparation was carried out according to the method described for intermediate 3, except that the residue was purified by column chromatography (petroleum ether / ethyl acetate = 5 / 1) to give 2-bromo-5-(4-methoxyphenyl)-1,3,4-oxadiazole (26% yield) as a yellow oil. 1 H NMR (400 MHz, DMSO- d 6) δ = 7.96 - 7.88 (m, 2H), 7.20 -7.11 (m, 2H), 3.86 (s, 3H) Preparation of compound 5: The preparation was carried out according to the method described for compound 1, except that: (i) triethylamine (2.50 g / L) was used. eq )replace N,N-Diisopropylethylamine and (ii) purified by preparative HPLC (column: Phenomenexluna C18 150*25mm* 10um; mobile phase: [water (formic acid)-acetonitrile]; gradient: 32%-62% B, duration: 9 min) to give 3-(4-chloro-6-(1-((5-(4-methoxyphenyl)-1,3,4-oxadiazol-2-yl)amino)cyclopropyl)-1-oxoisoindololin-2-yl)piperidine-2,6-dione (28% yield) as an orange solid. 1 H NMR (400 MHz, DMSO- d 6) δ =11.01 (s, 1H), 8.85 (s, 1H), 7.72 (d, J = 8.8 Hz, 2H), 7.63 (dd, J = 1.4, 14.4Hz, 2H), 7.08 (d, J = 8.8 Hz, 2H), 5.13 (dd, J = 5.2, 13.4 Hz, 1H), 4.48 - 4.42(m, 1H), 4.32 - 4.26 (m, 1H), 3.82 (s, 3H), 2.95 - 2.86 (m, 1H), 2.61 (br s,1H), 2.47 - 2.42 (m, 1H), 2.02 - 1.97 (m, 1H), 1.45 - 1.36 (m, 4H).

[0267] Example 6: Preparation of Compound 6 Preparation of 2: The preparation was carried out according to the method described for structure 3 of the scheme used to prepare intermediate 6, except that: (i) 10.0 eq (ii) The mixture was stirred at 60 °C for 1 h, and (iii) the reaction mixture was concentrated under reduced pressure to give 3-methylbenzoyl hydrazine as a white solid (99% yield).

[0268] Preparation of 3: To 3-methylbenzoylhydrazide (1.00 g, 6.66 mmol, 1.00 eq Sodium bicarbonate (559 mg, 6.66 mmol, 259 μL, 1.00 mmol) was added to a solution of dioxane (5.00 mL) and water (5.00 mL). eqThe resulting suspension was stirred at 25°C for 10 min. Cyanogen bromide (705 mg, 6.66 mmol, 489 μL, 1.00 μL) was added to the mixture in three batches over a period of 15 min. eq The mixture was stirred at 25 °C for 12 h. The reaction mixture was diluted with water (20.0 mL), filtered, and the resulting solid was washed with water to give 5-(m-tolyl)-1,3,4-oxadiazole-2-amine (840 mg, 4.79 mmol, 72% yield) as a grayish-white solid.

[0269] Preparation of 4: The preparation was carried out according to the method described for intermediate 3, except that purification was performed by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0 to 3 / 1) to give 2-bromo-5-(m-tolyl)-1,3,4-oxadiazole as a yellow solid (32% yield). 1 H NMR (400 MHz, CDCl3) δ = 7.87 (s, 1H), 7.83 (br d, J = 7.2Hz, 1H), 7.45 - 7.36 (m, 2H), 2.45 (s, 3H) Preparation of compound 6: The preparation was carried out according to the method described for compound 1, except that: (i) triethylamine (2.50 g / L) was used. eq )replace N,N -Diisopropylethylamine and (ii) purified by preparative HPLC (formic acid conditions; column: YMC-Actus Triart C18 150*30mm*7um; mobile phase: [water (formic acid)-acetonitrile]; gradient: 35%-65% B, duration: 10 min) to obtain 3-(4-chloro-1-oxo-6-(1-((5-(m-tolyl)-1,3,4-oxadiazol-2-yl)amino)cyclopropyl)isoindoline-2-yl)piperidine-2,6-dione (22.6 mg, 43.1 μmol, 16% yield, 94% purity) as a yellow solid. 1 H NMR (400 MHz, DMSO- d 6 ) δ = 11.00 (br s, 1H), 8.93 (s, 1H), 7.67 - 7.55(m, 4H), 7.41 (t, J = 7.8 Hz, 1H), 7.36 - 7.30 (m, 1H), 5.12 (dd, J= 5.2, 13.2Hz, 1H), 4.50 - 4.40 (m, 1H), 4.33 - 4.24 (m, 1H), 2.99 - 2.81 (m, 1H), 2.54(br s, 1H), 2.47 - 2.41 (m, 1H), 2.37 (s, 3H), 2.05 - 1.92 (m, 1H), 1.48 -1.33 (m, 4H) Example 7: Preparation of Compound 7 Preparation of 2: The preparation was carried out according to the method described for structure 3 of the scheme used to prepare intermediate 6, except that: (i) 10.0 eq (ii) The mixture was stirred at 60 °C for 1 h, and (iii) the mixture was concentrated under reduced pressure to give 5-(difluoromethoxy)pyridinecarboxylhydrazine as a yellow solid (96% yield).

[0270] Preparation of 3: The preparation was carried out according to the method described for structure 4 of the scheme for preparing intermediate 6, except that: (i) the mixture was stirred at 60°C for 3 h, (ii) the mixture was concentrated under reduced pressure to obtain a crude product, and (iii) by... Preparative The crude product was purified by HPLC (column: YMC-Actus Triart C18 150 * 30 mm * 7 μm; mobile phase: [water (formic acid)-acetonitrile]; gradient: 10 min 13%-45% B) and lyophilized to give 5-(5-(difluoromethoxy)pyridin-2-yl)-1,3,4-oxadiazol-2-amine as a white solid (49% yield).

[0271] Preparation of 4: The preparation was carried out according to the method described for intermediate 3, except that: (i) 1.00 eq Copper bromide and (ii) through Preparative Purification was performed by HPLC (column: YMC-Actus Triart C18 150 * 30mm * 7um; mobile phase: [water (formic acid)-acetonitrile]; gradient: 30%-60% B, duration: 10 min) to obtain 2-bromo-5-(5-(difluoromethoxy)pyridin-2-yl)-1,3,4-oxadiazole as a pink solid (14% yield). 1 H NMR (400 MHz, DMSO- d 6) δ = 8.70 (d, J= 2.8 Hz, 1H), 8.25 (d, J = 8.8 Hz, 1H), 7.95 - 7.88 (m, 1H),7.68-7.31 (t, J = 72.8 Hz, 1H).

[0272] Preparation of compound 7: The preparation was carried out according to the method described for compound 1, except that: (i) the mixture was stirred for 4 h and (ii) by... Preparative Purification was performed by HPLC (column: Waters Xbridge 150 * 25 mm * 5 μm; mobile phase: [water (ammonium bicarbonate)-acetonitrile]; gradient: 22%-52% B, duration: 9 min) to obtain 3-(4-chloro-6-(1-((5-(5-(difluoromethoxy)pyridin-2-yl)-1,3,4-oxadiazol-2-yl)amino)cyclopropyl)-1-oxoisoindoline-2-yl)piperidin-2,6-dione (6.45 mg, 11.72 μmol, 34% yield, 99% purity) as a yellow solid. 1 H NMR (400MHz, DMSO- d 6) δ = 10.97 (br d, J = 1.6 Hz, 1H), 9.09 (s, 1H), 8.58 (d, J = 2.8 Hz, 1H), 8.04 (d, J = 8.8 Hz, 1H), 7.84 - 7.79 (m, 1H), 7.63 (d, J = 1.6 Hz, 1H), 7.60 (d, J = 1.2 Hz, 1H), 7.60-7.23 (t, J = 72.8 Hz, 1H), 5.16 - 5.07 (m, 1H), 4.50 - 4.40 (m, 1H), 4.32 - 4.25 (m, 1H), 2.95 - 2.85 (m, 1H), 2.60 (br d, J =2.8 Hz, 1H), 2.42 (br d, J = 3.6 Hz, 1H), 2.03 - 1.95 (m, 1H), 1.48 - 1.43 (m, 2H), 1.41 - 1.37 (m, 2H).

[0273] Example 8: Preparation of Compound 8 Preparation of 2: Methyl 5-fluoropyridinecarboxylate (3.00 g, 19.3 mmol, 1.00 mmol) eq ), cyclopropanol (1.68 g, 29.0 mmol, 1.50 mmol) eq Cesium carbonate (9.45 g, 29.0 mmol, 1.50 g) was added to a solution of dimethylformamide (25.0 mL). eq The mixture was stirred at 80 °C for 12 h. The reaction mixture was diluted with water (40.0 mL) and extracted with ethyl acetate (3 × 20.0 mL). The combined organic layers were washed with brine (20.0 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the residue. The residue was purified and concentrated by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0 to 5 / 1) to give methyl 5-cyclopropoxypyridinecarboxylate as a white solid (850 mg, 4.05 mmol, 21% yield, 92% purity).

[0274] Preparation of 3: The preparation is carried out according to the method described for structure 3 of the scheme used to prepare intermediate 6, except that: (i) 11.1 is used. eq (ii) The reaction mixture was stirred at 80 °C for 1.5 h, and (iii) the turbid liquid was filtered and the filtrate was concentrated under reduced pressure to give 5-cyclopropoxypyridinecarboxyhydrazide as a pink solid (99% yield).

[0275] Preparation of 4: The preparation was carried out according to the method described for structure 4 of the scheme for preparing intermediate 6, except that the reaction mixture was concentrated under reduced pressure to obtain a residue, and the residue was ground with ethyl acetate at 25°C for 10 min to give 5-(5-cyclopropoxypyridin-2-yl)-1,3,4-oxadiazole-2-amine (74% yield) as a white solid.

[0276] Preparation of 5: 5-(5-cyclopropoxypyridin-2-yl)-1,3,4-oxadiazole-2-amine (210 mg, 770 μmol, 1.00) eq Copper bromide (172 mg, 770 μmol, 1.00 mg / L) eq ), nitrite Uncle Butyl ester (159 mg, 1.54 mmol, 183 μL, 2.00) eqThe mixture in acetonitrile (4.00 mL) was degassed and purged three times with nitrogen, and then stirred at 65 °C under a nitrogen atmosphere for 0.5 h. The reaction mixture was diluted with water (20.0 mL) and extracted with ethyl acetate (3 × 10.0 mL). The combined organic layers were washed with brine (10.0 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0 to 10 / 1) to give 2-bromo-5-(5-cyclopropoxypyridin-2-yl)-1,3,4-oxadiazole as a white solid (100 mg, 340 μmol, 44% yield, 96% purity). 1 H NMR (400 MHz, DMSO- d 6) δ = 8.52 (d, J = 2.4 Hz, 1H), 8.14 (d, J = 8.8Hz, 1H), 7.76 (dd, J = 2.8, 8.8 Hz, 1H), 4.09 (tt, J = 2.8, 6.0 Hz, 1H), 0.90 -0.85 (m, 2H), 0.78 - 0.73 (m, 2H).

[0277] Preparation of compound 8: 2-Bromo-5-(5-cyclopropoxypyridin-2-yl)-1,3,4-oxadiazole (50.0 mg, 177 μmol, 1.00) eq ), 3-(6-(1-aminocyclopropyl)-4-chloro-1-oxoisoindoline-2-yl)piperidine-2,6-dione (65.6 mg, 177 μmol, 1.00 eq (hydrochloric acid) (For preparation steps, see 'Preparation of Compound 1') N , N -Diisopropylethylamine (115 mg, 886 μmol, 154 μL, 5.00) eq The mixture in dimethyl sulfoxide (1.00 mL) was degassed and purged three times with nitrogen, and then stirred at 110 °C under a nitrogen atmosphere for 5 h. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to obtain the residue. Preparative HPLC (Column: Phenomenex luna C18 150 × 25 mm × 10) μm; mobile phase: [water (formic acid)-acetonitrile]; B%: 24%-54%, 11 min) purification yielded 3-(4-chloro-6-(1-((5-(5-cyclopropoxypyridin-2-yl)-1,3,4-oxadiazol-2-yl)amino)cyclopropyl)-1-oxoisoindoline-2-yl)piperidin-2,6-dione (16.53 mg, 30.16 μmol, 17.01% yield, 97.6% purity) as a white solid. 1 H NMR (400 MHz, DMSO- d 6) δ = 10.99 (s, 1H), 8.98 (s, 1H), 8.42 (d, J = 2.8 Hz, 1H), 7.93 (d, J =8.8 Hz, 1H), 7.66 (dd, J = 2.8, 8.8 Hz, 1H), 7.63 (d, J = 1.6 Hz, 1H), 7.59 (d, J =1.6 Hz, 1H), 5.12 (dd, J = 5.2, 13.2 Hz, 1H), 4.48 - 4.41 (m, 1H), 4.31 - 4.25(m, 1H), 4.03 (tt, J = 2.8, 6.0 Hz, 1H), 2.95 - 2.85 (m, 1H), 2.56 (br d, J = 3.6Hz, 1H), 2.46 (br d, J = 4.4 Hz, 1H), 2.02 - 1.96 (m, 1H), 1.47 - 1.43 (m, 2H), 1.40 - 1.36 (m, 2H), 0.87 - 0.82 (m, 2H), 0.75 - 0.70 (m, 2H).

[0278] Example 9: Preparation of Compound 9 Preparation of 2: Under a nitrogen atmosphere, methyl 6-bromopyridinecarboxylate (1.00 g, 4.63 mmol, 1.00 mmol) was added. eq ) and cyclopropylboronic acid (994 mg, 11.6 mmol, 2.50 mmol) eq Add potassium phosphate (1.97 g, 9.26 mmol, 2.00 mmol) to a solution in toluene (15.0 mL). eq ) and [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (169 mg, 232 μmol, 0.05 eq The mixture was stirred at 100 °C for 12 h. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 10 / 1) and concentrated under reduced pressure to give methyl 6-cyclopropylpyridinecarboxylate (505 mg, 2.85 mmol, 62% yield) as a brown oil.

[0279] Preparation of 3: The preparation was carried out according to the method described for structure 3 of the scheme used to prepare intermediate 6, except that: (i) the reaction was carried out in methanol instead of ethanol, and (ii) 10.0 eq (iii) The reaction mixture was stirred at 60 °C for 1 h, and (iv) the reaction mixture was concentrated under reduced pressure to give 6-cyclopropylpyridinecarboxyhydrazide as a white solid (100% yield).

[0280] Preparation of 4: Preparation was carried out according to the method described for structure 4 of the scheme used to prepare intermediate 6, the difference being the use of 3.00 eq Cyanide bromide. This yields 5-(6-cyclopropylpyridin-2-yl)-1,3,4-oxadiazol-2-amine as a brown solid (71% yield).

[0281] Preparation of 5: The preparation was carried out according to the method described for intermediate 3, except that: (i) 1.00 eq Copper bromide was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 10:1) to give 2-bromo-5-(6-cyclopropylpyridin-2-yl)-1,3,4-oxadiazole as a brown oil (29% yield). 1 H NMR (400 MHz, DMSO- d 6 ) δ = 7.92 - 7.88 (m, 2H), 7.53 (t, J = 4.4 Hz, 1H), 2.25 - 2.21 (m, 1H), 1.06 - 1.03 (m, 2H), 0.99 (dd, J = 2.5, 4.9 Hz, 2H).

[0282] Preparation of compound 9: The preparation was carried out according to the method described for compound 1, except that: (i) 4.00 eqN,N -Diisopropylethylamine, (ii) stirring the reaction mixture at 100°C for 8 h, and (iii) by Preparative Purification was performed by HPLC (column: Phenomenex luna C18 150*25mm* 10um; mobile phase: [water (formic acid)-acetonitrile]; gradient: 26%-56% B, duration: 15 min) to obtain 3-(4-chloro-6-(1-((5-(6-cyclopropylpyridin-2-yl)-1,3,4-oxadiazol-2-yl)amino)cyclopropyl)-1-oxoisoindoline-2-yl)piperidine-2,6-dione as a white solid (5.95% yield). 1 H NMR (400 MHz, DMSO- d 6 ) δ = 11.00 (br s, 1H), 9.07 (s, 1H), 7.83 - 7.76(m, 1H), 7.73 - 7.69 (m, 1H), 7.63 (dd, J = 1.4, 12.0 Hz, 2H), 7.43 - 7.37 (m,1H), 5.13 (dd, J = 5.2, 13.3 Hz, 1H), 4.48 - 4.42 (m, 1H), 4.33 - 4.26 (m, 1H), 2.91 (br d, J = 1.9 Hz, 1H), 2.61 (br d, J = 2.0 Hz, 1H), 2.56 (br d, J = 3.4 Hz,1H), 2.19 - 2.15 (m, 1H), 2.03 - 1.97 (m, 1H), 1.46 - 1.41 (m, 2H), 1.40 -1.35 (m, 2H), 1.02 - 0.98 (m, 2H), 0.96 (td, J = 2.4, 4.8 Hz, 2H).

[0283] Example 10. Preparation of Compound 10 Preparation of 2: Sodium carbonate (907 mg, 8.56 mmol, 0.600 mmol) was added at 0°C. eq Add hydroxylamine hydrochloride (1.49 g, 21.4 mmol, 1.50 mmol) to a solution in water (5.00 mL). eqThe reaction was continued for 0.5 h. Cyclopropane formaldehyde (1.00 g, 14.3 mmol, 1.07 mL, 1.00 mL) was added to ethanol (5.00 mL). eq The mixture was added to an aqueous solution and stirred at 20°C for 2 h. The reaction mixture was extracted with ethyl acetate (2 × 10.0 mL). The combined organic layers were washed with brine (10.0 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a colorless oil. E )-Cyclopropaneformaldehyde oxime (895 mg, 10.5 mmol, 74% yield).

[0284] Preparation of 3: Towards( E Cyclopropane-formaldehyde oxime (790 mg, 9.28 mmol, 1.00 mg) eq Add ethyl propargyl ester (1.00 g, 10.2 mmol, 1.00 mL, 1.10 mL) to a solution of 2-butanone (10.0 mL). eq ) and amyl nitrite (1.20 g, 10.2 mmol, 1.37 mL, 1.10 mmol) eq The mixture was heated at 65 °C for 4 h. The reaction mixture was filtered and diluted with water (50.0 mL), and extracted with ethyl acetate (2 × 100 mL). The combined organic layers were washed with hydrochloric acid (30.0 mL, 0.1 M), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 20 / 1 to 5 / 1) to give ethyl 3-cyclopropylisoxazole-5-carboxylate (330 mg, 1.82 mmol, 20% yield).

[0285] Preparation of 4: Preparation was carried out according to the method described for structure 3 of the scheme used to prepare intermediate 6, the difference being the use of 10.0 eq Hydrazine hydrate. 3-Cyclopropylisoxazole-5-carbonylhydrazine was given as a yellow solid (96% yield).

[0286] Preparation of 5: The preparation was carried out according to the method described for structure 4 of the scheme for preparing intermediate 6, except that purification was performed by reversed-phase chromatography (0.1% formic acid conditions) to give 5-(3-cyclopropylisoxazol-5-yl)-1,3,4-oxadiazole-2-amine as a yellow solid (59.8% yield).

[0287] Preparation of 6: The preparation was carried out according to the method described for intermediate 3, except that: (i) 1.00 eq(ii) The reaction mixture was quenched with water and extracted with ethyl acetate, and the combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue, and (iii) the residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0 to 10 / 1) to give 2-bromo-5-(3-cyclopropylisoxazol-5-yl)-1,3,4-oxadiazole as a yellow oil (38.2% yield). 1 H NMR (400 MHz, CDCl3) δ =6.75 (s, 1H), 2.17 - 2.08 (m, 1H), 1.17 - 1.14 (m, 2H), 0.96 - 0.91 (m, 2H).

[0288] Preparation of compound 10: The preparation was carried out according to the method described for compound 1, except that: (i) 5.00 eqN , N -Diisopropylethylamine, (ii) stirring the reaction mixture at 110°C for 4 h, and (iii) by Preparative Purification was performed by HPLC (column: Phenomenex luna C18 150*25mm* 10um; mobile phase: [water (formic acid)-acetonitrile]; gradient: 22%-52% B, duration: 10 min) to obtain 3-(4-chloro-6-(1-((5-(3-cyclopropylisoxazol-5-yl)-1,3,4-oxadiazol-2-yl)amino)cyclopropyl)-1-oxoisoindololin-2-yl)piperidine-2,6-dione as a white solid (16.11% yield). 1 H NMR (400 MHz, DMSO- d 6) δ = 10.99 (br s, 1H), 9.25 (s, 1H), 7.60 (br d, J =7.0 Hz, 2H), 6.90 (s, 1H), 5.12 (br dd, J = 4.6, 13.3 Hz, 1H), 4.48 - 4.40 (m,1H), 4.32 - 4.24 (m, 1H), 2.95 - 2.85 (m, 1H), 2.56 (br s, 1H), 2.43 (br s,1H), 2.12 - 2.04 (m, 1H), 2.03 - 1.96 (m, 1H), 1.45 (br s, 2H), 1.39 (br s,2H), 1.05 (br d,J = 8.0 Hz, 2H), 0.87 (br d, J = 4.8 Hz, 2H).

[0289] Example 11. Preparation of Compound 11 Preparation of 2: Methyl 6-bromonicotinic acid (2.00 g, 9.26 mmol, 1.00 g) eq ) and cyclopropylboronic acid (994 mg, 11.6 mmol, 1.25 mmol) eq Tricyclohexylphosphine (779 mg, 2.78 mmol, 0.300 mmol) was added to a solution of toluene (40.0 mL) and water (4.00 mL). eq Potassium carbonate (3.84 g, 27.8 mmol, 3.00 mmol) eq ) and tris(dibenzylacetone)dipalladium(0) (848 mg, 926 μmol, 0.100 eq The mixture was stirred at 100 °C for 16 h. The reaction mixture was diluted with water (20.0 mL) and extracted with ethyl acetate (3 × 20.0 mL). The combined organic layers were washed with brine (15.0 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give the residue. The residue was purified by reversed-phase chromatography (C18, 240 g, conditions: water / acetonitrile = 100:0 to 50:50, 0.1% formic acid) to give methyl 6-cyclopropylnicotinic acid as a white solid (1.30 g, 6.97 mmol, 75% yield).

[0290] Preparation of 3: Preparation is carried out according to the method described for structure 3 of the scheme used to prepare intermediate 6, the difference being the use of 13.2. eq Hydrazine hydrate. 6-Cyclopropylnicotinamide was given as a white solid (92% yield).

[0291] Preparation of 4: The preparation was carried out according to the method described for structure 4 of the scheme for preparing intermediate 6, except that the residue was ground with acetonitrile to obtain 5-(6-cyclopropylpyridin-3-yl)-1,3,4-oxadiazol-2-amine (87% yield) as a yellow solid.

[0292] Preparation of 5: The preparation was carried out according to the method described for intermediate 3, except that: (i) 1.00 eq(ii) The copper bromide was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0 to 3 / 1) to give 2-bromo-5-(6-cyclopropylpyridin-3-yl)-1,3,4-oxadiazole as a yellow solid (22% yield). MS (ESI) m / z 267.9 [M+H] + Preparation of compound 11: The preparation was carried out according to the method described for compound 1, except that: (i) 5.00 eqN , N -Diisopropylethylamine, (ii) stirring the reaction mixture at 100°C for 1.5 h, and (iii) by preparation type Purification was performed by HPLC (column: Phenomenex luna C18 150*25mm* 10um; mobile phase: [water (formic acid)-acetonitrile]; gradient: 23%-53% B, duration: 10 min) to obtain 3-(4-chloro-6-(1-((5-(6-cyclopropylpyridin-3-yl)-1,3,4-oxadiazol-2-yl)amino)cyclopropyl)-1-oxoisoindoline-2-yl)piperidine-2,6-dione as a white solid (11.4% yield). 1 H NMR (400 MHz, DMSO- d 6 ) δ = 10.99 (s, 1H), 9.00 (s, 1H), 8.77 (d, J = 2.0Hz, 1H), 7.98 (dd, J = 2.0, 8.4 Hz, 1H), 7.65 (d, J = 1.6 Hz, 1H), 7.61 (d, J = 1.6Hz, 1H), 7.45 (d, J = 8.4 Hz, 1H), 5.12 (dd, J = 5.2, 13.6 Hz, 1H), 4.44 (d, J =17.6 Hz, 1H), 4.28 (d, J= 17.6 Hz, 1H), 2.98 - 2.82 (m, 1H), 2.61 - 2.57 (m,1H), 2.48 - 2.40 (m, 1H), 2.25 - 2.11 (m, 1H), 2.07 - 1.91 (m, 1H), 1.47 -1.34 (m, 4H), 1.05 - 0.96 (m, 4H).

[0293] Example 12. Preparation of Compound 12 Preparation of compound 2: 3-(4-chloro-6-iodo-1-oxoisoindolin-2-yl)piperidine-2,6-dione (1.66 g, 4.10 mmol, 1.00 mmol) eq (See 'Preparation of Compound 1' for preparation steps), 1-((tert-butoxycarbonyl)amino)cyclopropane-1-carboxylic acid 1,3-dioxoisoindoline-2-yl ester (1.42 g, 4.10 mmol, 1.00 mmol) eq (See 'Preparation of Compound 1' for preparation steps), [(bipy)2Ni2(μ-Cl)2Cl2(H2O)2] (249 mg, 410 μmol, 0.100) eq ), zinc powder (2.15g, 32.8 mmol, 8.00) eq ) and trimethylchlorosilane (1.34 g, 12.3 mmol, 1.56 mL, 3.00 eq )At N , N The mixture in dimethylacetamide (10.0 mL) was degassed with nitrogen at 0 °C and purged three times, and then stirred at 25 °C under a nitrogen atmosphere for 12 h. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was diluted with saturated ammonium chloride (50 mL) and extracted with ethyl acetate (30 mL × 3). The organic layer was washed with water (40 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0 to 0 / 1) to give tert-butyl 1-(7-chloro-2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindoline-5-yl)cyclopropyl)carbamate (2.72 g, 6.27 mmol, 50% yield) as a yellow solid.

[0294] Preparation of 3:(1-(7-chloro-2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindoline-5-yl)cyclopropyl)tert-butyl carbamate (800 mg, 1.84 mmol, 1.00 mg) eq ), 2,4,6-trimethyl-1,3,5,2,4,6-trioxaboranecyclohexane (926 mg, 3.69 mmol, 1.03 mL, 2.00 eq (See Example 1 for preparation steps), [1,3-bis(2,6-diisopropylphenyl)imidazol-2-yl](3-chloropyridine)palladium(II) dichloride (62.8 mg, 92.2 μmol, 0.0500 mg / mL) eq ) and potassium carbonate (764 mg, 5.53 mmol, 3.00) eq The mixture in dioxane (10.0 mL) was degassed and purged three times with nitrogen, and then stirred at 100 °C under a nitrogen atmosphere for 12 h. The reaction mixture was concentrated under reduced pressure to obtain the residue. Preparative The residue was purified by HPLC (column: Phenomenex luna C18 150*40 mm* 15 μm; mobile phase: [water (formic acid)-acetonitrile]; gradient: 15 min 25%-55% B) and lyophilized to give tert-butyl 1-(1-(2-(2,6-dioxopiperidin-3-yl)-7-methyl-3-oxoisoindoline-5-yl)cyclopropyl)carbamate (470 mg, 1.14 mmol, 20% yield) as a white solid.

[0295] Preparation of 4: To (1-(2-(2,6-dioxopiperidin-3-yl)-7-methyl-3-oxoisoindoline-5-yl)cyclopropyl)tert-butyl carbamate (470 mg, 1.14 mmol, 1.00 mg) eq Add hydrochloric acid / dioxane (2 M, 5.00 mL, 8.80 mL) to the solution. eq The mixture was stirred at 25 °C for 1 h. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was diluted with water (200 mL) and extracted with ethyl acetate (60 mL × 3), and lyophilized in the aqueous layer. The yellow solid was ground with ethyl acetate at 25 °C for 30 min to give 3-(6-(1-aminocyclopropyl)-4-methyl-1-oxoisoindoline-2-yl)piperidine-2,6-dione (360 mg, 1.03 mmol, 90% yield, hydrochloride) as a yellow solid. 1 H NMR (400 MHz, DMSO-) d 6 ) δ= 11.01 (s, 1H), 7.65 (s, 1H), 7.48 (s, 1H), 5.14 (dd, J =5.0, 13.2 Hz, 1H), 4.50 - 4.40 (m, 1H), 4.34 - 4.23 (m, 1H), 2.99 - 2.87 (m,1H), 2.62 (br d, J = 17.4 Hz, 1H), 2.42 (br dd, J = 4.4, 13.1 Hz, 1H), 2.34 (s, 3H), 2.07 - 1.99 (m, 1H), 1.25 - 1.20 (m, 4H).

[0296] Preparation of compound 12: The preparation was carried out according to the method described for compound 1, except that: (i) 3.00 eqN , N -Diisopropylethylamine, (ii) the reaction mixture was stirred at 130 °C for 1 h, (iii) the reaction mixture was diluted with water and extracted with ethyl acetate, the organic layer was washed with water, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the residue, (iv) the residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 5 / 1 to 1 / 5), and (v) the yellow solid was ground with ethyl acetate at 25 °C for 4 h, and then the yellow solid was ground with ethanol at 25 °C for 6 h to give 3-(4-methyl-1-oxo-6-(1-((5-(4-(trifluoromethoxy)phenyl)-1,3,4-oxadiazol-2-yl)amino)cyclopropyl)isoindoline-2-yl)piperidine-2,6-dione (46.2% yield) as a white solid. 1 H NMR (400 MHz, DMSO- d 6 ) δ = 10.97 (s, 1H), 8.97 (s, 1H), 7.89 (d, J = 8.8 Hz, 2H), 7.58 - 7.47(m, 3H), 7.34 (s, 1H), 5.11 (dd, J = 5.0, 13.2 Hz, 1H), 4.43 - 4.30 (m, 1H), 4.27 - 4.15 (m, 1H), 2.97 - 2.85 (m, 1H), 2.59 (br dd, J = 2.0, 15.4 Hz, 1H),2.39 (br dd,J = 4.6, 13.0 Hz, 1H), 2.30 (s, 3H), 2.03 - 1.93 (m, 1H), 1.35 (s, 4H).

[0297] Example 13. Preparation of Compound 13 Preparation of 2: To dimethylamine (695 mg, 8.52 mmol, 1.00) eq , hydrogen chloride) and methyl 4-(chlorosulfonyl)benzoate (2.00 g, 8.52 mmol, 1.00 eq Triethylamine (862 mg, 8.52 mmol, 1.19 mL, 1.00 mmol) was added to a solution in dichloromethane (20.0 mL). eq The mixture was stirred at 25°C for 12 h. The reaction mixture was concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0 to 3 / 1) to give 4-( N,N Methyl benzoate (dimethylsulfonyl)benzoate (954 mg, 3.92 mmol, 46% yield).

[0298] Preparation of 3: The preparation was carried out according to the method described for structure 3 of the scheme used to prepare intermediate 6, except that: (i) 15.0 eq (ii) The reaction mixture was stirred at 60 °C for 2 h, and (iii) the reaction mixture was filtered and concentrated under reduced pressure to give 4-(hydrazine carbonyl)- hydrazine hydrate as a yellow solid. N,N - Dimethylbenzenesulfonamide (97% yield).

[0299] Preparation of 4: Preparation was carried out according to the method described for structure 4 of the scheme used to prepare intermediate 6, except that the reaction mixture was concentrated under reduced pressure to obtain a residue, which was then ground with a mixture of ethyl acetate (10.0 mL) at 20 °C for 1 h to give a yellow solid of 4-(5-amino-1,3,4-oxadiazol-2-yl)- N,N - Dimethylbenzenesulfonamide (97% yield).

[0300] Preparation of 5: Preparation was carried out according to the method described for intermediate 3, except that purification was performed by column chromatography (SiO2, petroleum ether / ethyl acetate = 0 / 1 to 3 / 1) to give 4-(5-bromo-1,3,4-oxadiazol-2-yl)- as a white solid. N,N- Dimethylbenzenesulfonamide (38% yield). 1 H NMR (400 MHz, DMSO- d 6 ) δ = 8.26 - 8.19 (m,2H), 8.00 - 7.93 (m, 2H), 2.66 (s, 6H).

[0301] Preparation of compound 13: The preparation was carried out according to the method described for compound 1, except that it was performed by... system Spare Purification was performed by HPLC (column: YMC-Actus Triart C18 150*30mm*7um; mobile phase: [water (formic acid)-acetonitrile]; gradient: 35% - 65% B, duration: 10 min) to obtain a yellow solid 4-(5-((1-(7-chloro-2-(2,6-dioxopiridin-3-yl)-3-oxoisoindoline-5-yl)cyclopropyl)amino)-1,3,4-oxadiazol-2-yl)- N,N - Dimethylbenzenesulfonamide (20% yield). 1 H NMR (400 MHz, DMSO- d 6 ) δ = 11.16 - 10.74 (m, 1H), 9.12 (s, 1H), 8.01 (d, J = 8.6 Hz, 2H), 7.88 (d, J = 8.5 Hz, 2H), 7.63 (dd, J = 1.4, 12.3 Hz, 2H), 5.12 (dd, J = 5.1, 13.2 Hz, 1H), 4.49 - 4.39 (m, 1H), 4.28 (d, J = 17.6 Hz,1H), 2.97 - 2.84 (m, 1H), 2.63 (s, 6H), 2.61 - 2.58 (m, 1H), 2.42 (br d, J =4.1 Hz, 1H), 2.03 - 1.96 (m, 1H), 1.49 - 1.38 (m, 4H).

[0302] Example 14. Preparation of Compound 14 The preparation was carried out according to the method described for compound 1, except that it was performed by... Preparative Purification was performed by HPLC (column: Phenomenex luna C18 150*25 mm* 10 μm; mobile phase: [water (formic acid)-acetonitrile]; gradient: 32%-62% B, duration min) to obtain 3-(6-(1-((5-(4-(azacyclobutane-1-ylsulfonyl)phenyl)-1,3,4-oxadiazol-2-yl)amino)cyclopropyl)-4-chloro-1-oxoisoindololin-2-yl)piperidine-2,6-dione (25% yield, 92%) as a white solid. 1 H NMR (400 MHz, DMSO- d 6 ) δ = 11.12 - 10.83 (m, 1H), 9.14 (s, 1H), 8.06 (d, J = 8.4 Hz, 2H), 7.93 (d, J = 8.4 Hz, 2H), 7.63 (dd, J = 1.2, 12.6 Hz, 2H), 5.12(dd, J = 4.8, 13.2 Hz, 1H), 4.50 - 4.40 (m, 1H), 4.35 - 4.24 (m, 1H), 3.69 (t, J = 7.6 Hz, 4H), 3.00 - 2.82 (m, 1H), 2.58 (td, J = 1.8, 15.4 Hz, 1H), 2.47 -2.38 (m, 1H), 1.99 (quin, J = 7.4 Hz, 3H), 1.56 - 1.33 (m, 4H).

[0303] Example 15. Preparation of Compound 15 Preparation of 2: At 0°C under a nitrogen atmosphere, cyclopropanol (1.12 g, 19.3 mmol, 1.50 mmol) was applied to the atmosphere. eq Sodium hydride (1.03 g, 25.8 mmol, 60% purity, 2.00 mL) was added to a solution of tetrahydrofuran (10.0 mL). eq The reaction mixture was stirred at 0°C under a nitrogen atmosphere for 0.5 h. Then, methyl 6-fluoronicotinic acid (2.00 g, 12.9 mmol, 1.00 mL) in tetrahydrofuran (10.0 mL) was added at 0°C. eqThe mixture was added to the reaction mixture. The mixture was stirred at 25 °C for 2 h. The reaction mixture was diluted with saturated ammonium chloride (15.0 mL), extracted with ethyl acetate (3 × 100 mL), and concentrated under reduced pressure to give the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 50 / 0 to 30 / 1) to give methyl 6-cyclopropoxynicotinic acid as a white solid (800 mg, 4.14 mmol, 32.1% yield).

[0304] Preparation of 3: The preparation was carried out according to the method described for structure 3 of the scheme used to prepare intermediate 6, except that: (i) 10.0 eq (ii) The mixture was concentrated under reduced pressure to give 6-cyclopropoxynicotinamide hydrazide as a white solid (81% yield).

[0305] Preparation of 4: The preparation was carried out according to the method described for structure 4 of the scheme for preparing intermediate 6, except that the reaction mixture was concentrated under reduced pressure to obtain a crude product, which was then ground with ethyl acetate at 25°C for 30 minutes to give 5-(6-cyclopropoxypyridin-3-yl)-1,3,4-oxadiazole-2-amine (94.4% yield) as a white solid.

[0306] Preparation of 5: The preparation was carried out according to the method described for intermediate 3, except that: (i) 1.00 eq (ii) The residue was diluted with water and extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the residue. (iii) The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 10 / 1 to 5 / 1) to give 2-bromo-5-(6-cyclopropoxypyridin-3-yl)-1,3,4-oxadiazole as a yellow solid (38.7% yield). 1 H NMR (400 MHz, DMSO-d 6 ) δ = 8.77 (d, J = 2.4 Hz, 1H), 8.23(dd, J = 2.4, 8.8 Hz, 1H), 7.05 (d, J = 8.4 Hz, 1H), 4.29 (tt, J = 3.1, 6.2 Hz,1H), 0.83 - 0.77 (m, 2H), 0.74 - 0.68 (m, 2H).

[0307] Preparation of compound 15: The preparation was carried out according to the method described for compound 1, except that: (i) 5.00 eqN,N -Diisopropylethylamine, (ii) stirring the reaction mixture at 110 °C for 12 h, and (iii) by preparation type Purification was performed by HPLC (column: Phenomenex Luna C18 150*25mm*10um; mobile phase: [water (formic acid)-acetonitrile]; gradient: 23%-53% B, duration: 10 min) to obtain 3-(4-chloro-6-(1-((5-(6-cyclopropoxypyridin-3-yl)-1,3,4-oxadiazol-2-yl)amino)cyclopropyl)-1-oxoisoindoline-2-yl)piperidin-2,6-dione (25.62 mg, 47.4 μmol, 16.7% yield, 99% purity) as a white solid. 1 H NMR (400 MHz, DMSO- d 6 ) δ = 11.04 - 10.90 (m,1H), 8.96 (s, 1H), 8.59 (d, J = 2.4 Hz, 1H), 8.07 (dd, J = 2.4, 8.4 Hz, 1H), 7.64(dd, J = 2.4, 16.4 Hz, 2H), 7.01 (d, J = 8.8 Hz, 1H), 5.12 (dd, J = 5.2, 13.2 Hz,1H), 4.48 - 4.40 (m, 1H), 4.32 - 4.28 (m, 1H), 4.27 - 4.24 (m, 1H), 2.95 -2.85 (m, 1H), 2.61 - 2.55 (m, 1H), 2.42 (br d, J = 8.8 Hz, 1H), 2.02 - 1.95 (m,1H), 1.46 - 1.40 (m, 2H), 1.39 - 1.35 (m, 2H), 0.82 - 0.77 (m, 2H), 0.74 -0.68 (m, 2H).

[0308] Example 16. Preparation of Compound 16 Preparation of 2:The preparation was carried out according to the method described for structure 3 of the scheme used to prepare intermediate 6, except that: (i) 10.0 eq (ii) The mixture was concentrated under reduced pressure to give 6-methoxypyridazine-3-carbonylhydrazine as a white solid.

[0309] Preparation of 3: The preparation was carried out according to the method described for structure 4 of the scheme for preparing intermediate 6, except that the reaction mixture was concentrated under reduced pressure to obtain a crude product, and the crude product was ground with ethyl acetate at 25°C for 30 minutes to give 5-(6-methoxypyridazine-3-yl)-1,3,4-oxadiazole-2-amine (99% yield) as a white solid.

[0310] Preparation of 4: The preparation was carried out according to the method described for intermediate 3, except that: (i) 1.00 eq (ii) The mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. (iii) The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 10 / 1 to 2 / 1) to give 2-bromo-5-(6-methoxypyridazin-3-yl)-1,3,4-oxadiazole as a white solid (31% yield). 1 H NMR (400 MHz, DMSO- d 6 ) δ = 8.27 (d, J = 9.2 Hz, 1H), 7.48 (d, J = 9.2Hz, 1H), 4.14 (s, 3H).

[0311] Preparation of compound 16: The preparation was carried out according to the method described for compound 1, except that: (i) 5.00 eqN , N -Diisopropylethylamine, (ii) stirring the reaction mixture at 110°C for 2 h, and (iii) by Preparative Purification was performed by HPLC (column: Phenomenex luna C18 150*25mm* 10um; mobile phase: [water (formic acid)-acetonitrile]; gradient: 14%-44% B, duration: 10 min) to obtain 3-(4-chloro-6-(1-((5-(6-methoxypyridazin-3-yl)-1,3,4-oxadiazol-2-yl)amino)cyclopropyl)-1-oxoisoindololin-2-yl)piperidine-2,6-dione as a white solid (11.5% yield).1 H NMR (400 MHz, DMSO- d 6 ) δ = 10.99 (s, 1H), 9.19 (s, 1H), 8.10 (d, J = 9.2Hz, 1H), 7.63 (dd, J = 1.2, 14.8 Hz, 2H), 7.36 (d, J = 9.2 Hz, 1H), 5.12 (dd, J =5.2, 13.2 Hz, 1H), 4.48 - 4.42 (m, 1H), 4.32 - 4.25 (m, 1H), 4.09 (s, 3H), 2.95 - 2.85 (m, 1H), 2.62 - 2.55 (m, 1H), 2.44 (br dd, J = 4.4, 13.2 Hz, 1H), 2.02 - 1.96 (m, 1H), 1.48 - 1.44 (m, 2H), 1.42 - 1.38 (m, 2H).

[0312] Example 17. Preparation of Compound 17 Preparation of 2: To 6-fluoro-2-methylnicotinic acid (1.80 g, 11.6 mmol, 1.00 mmol) eq Add potassium carbonate (4.01 g, 29.0 mmol, 2.50 mmol) to a solution of dimethylformamide (30.0 mL). eq ) and iodomethane (2.47 g, 17.4 mmol, 1.08 mL, 1.50 mmol) eq The mixture was stirred at 20 °C for 2 h. The mixture was diluted with water (30.0 mL) and extracted with ethyl acetate (3 × 50.0 mL). The combined organic layers were washed with brine (3 × 20.0 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give methyl 6-fluoro-2-methylnicotinate (1.90 g, 11.2 mmol, 96% yield) as a yellow oil.

[0313] Preparation of 3: At 0°C under a nitrogen atmosphere, cyclopropanol (515 mg, 8.87 mmol, 1.50 mg) was reacted with nitrogen. eq Sodium hydride (472 mg, 11.8 mmol, 60% purity, 2.00 mg) was added to a solution of tetrahydrofuran (10.0 mL). eq The reaction mixture was stirred at 0°C under a nitrogen atmosphere for 0.5 h. Then, methyl 6-fluoro-2-methylnicotinate (1.00 g, 5.91 mmol, 1.00 mL) in tetrahydrofuran (10.0 mL) was added at 0°C. eq The mixture was added to the reaction mixture. The mixture was stirred at 25 °C for 2 h. The reaction mixture was diluted with saturated ammonium chloride (40.0 mL) and extracted with ethyl acetate (3 × 40.0 mL). The combined organic layers were washed with water (20.0 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0 to 100 / 1) to give methyl 6-cyclopropoxy-2-methylnicotinate as a colorless oil (812 mg, 3.92 mmol, 66% yield).

[0314] Preparation of 4: The preparation was carried out according to the method described for structure 3 of the scheme used to prepare intermediate 6, except that: (i) 20.0 eq (ii) The mixture was concentrated under reduced pressure to give 6-cyclopropoxy-2-methylnicotinamide as a white solid (98% yield).

[0315] Preparation of 5: The preparation was carried out according to the method described for structure 4 of the scheme for preparing intermediate 6, except that the reaction mixture was ground with ethyl acetate to give 5-(6-cyclopropoxy-2-methylpyridin-3-yl)-1,3,4-oxadiazole-2-amine (99% yield) as a white solid.

[0316] Preparation of 6: The preparation was carried out according to the method described for intermediate 3, except that: (i) 1.00 eq Copper bromide was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 20 / 1 to 10 / 1) to give 2-bromo-5-(6-cyclopropoxy-2-methylpyridin-3-yl)-1,3,4-oxadiazole as a yellow solid (15% yield). 1 HNMR (400 MHz, DMSO- d 6 ) δ = 8.15 (d, J = 8.8 Hz, 1H), 6.93 (d, J = 8.6 Hz, 1H), 4.31(tt, J= 3.0, 6.2 Hz, 1H), 2.73 (s, 3H), 0.84 - 0.79 (m, 2H), 0.74 - 0.69 (m, 2H).

[0317] Preparation of compound 17: The preparation was carried out according to the method described for compound 1, except that: (i) 3.00 eqN , N -Diisopropylethylamine, (ii) the reaction mixture was stirred at 110 °C for 1 h, (iii) the mixture was diluted with water and extracted with ethyl acetate, the combined organic layers were washed with brine and dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the residue, and (iv) purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 5 to 0 / 1) to give 3-(4-chloro-6-(1-((5-(6-cyclopropoxy-2-methylpyridin-3-yl)-1,3,4-oxadiazol-2-yl)amino)cyclopropyl)-1-oxoisoindoline-2-yl)piperidine-2,6-dione (50% yield) as a white solid. 1 H NMR (400MHz, DMSO- d 6 ) δ = 10.99 (s, 1H), 8.91 (s, 1H), 7.96 (d, J = 8.6 Hz, 1H), 7.66 (d, J = 1.4 Hz, 1H), 7.61 (d, J = 1.4 Hz, 1H), 6.86 (d, J = 8.5 Hz, 1H), 5.12 (dd, J =5.1, 13.3 Hz, 1H), 4.48 - 4.40 (m, 1H), 4.32 - 4.23 (m, 2H), 2.96 - 2.82 (m,1H), 2.65 (s, 3H), 2.61 - 2.55 (m, 1H), 2.42 (br d, J = 4.5 Hz, 1H), 2.03 -1.95 (m, 1H), 1.42 (br d, J = 3.5 Hz, 2H), 1.40 - 1.35 (m, 2H), 0.81 - 0.74 (m, 2H), 0.72 - 0.66 (m, 2H).

[0318] Example 18. Preparation of Compound 18 Preparation of 2: To 6-(difluoromethoxy)nicotinic acid (500 mg, 2.64 mmol, 1.00 mg) eq Add potassium carbonate (914 mg, 6.61 mmol, 2.50 mmol) to a solution of dimethylformamide (10.0 mL). eq ) and methyl iodide (563 mg, 3.97 mmol, 247 μL, 1.50) eq The reaction mixture was stirred at 30 °C for 2 h. The mixture was diluted with water (10.0 mL) and extracted with ethyl acetate (3 × 10.0 mL). The combined organic layers were washed with brine (3 × 10.0 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give methyl 6-(difluoromethoxy)nicotinic acid (530 mg, 2.61 mmol, 98% yield) as a yellow oil.

[0319] Preparation of 3: The preparation was carried out according to the method described for structure 3 of the scheme used to prepare intermediate 6, except that: (i) 20.0 eq (ii) The reaction mixture was concentrated under reduced pressure to give 6-(difluoromethoxy)nicotinic acid hydrazine as a white solid (98% yield).

[0320] Preparation of 4: The preparation was carried out according to the method described for structure 4 of the scheme used to prepare intermediate 6, except that: (i) 2.00 eq (ii) The mixture was diluted with ethanol (10.0 mL) and concentrated under reduced pressure to give 5-(6-(difluoromethoxy)pyridin-3-yl)-1,3,4-oxadiazol-2-amine as a yellow solid (94% yield).

[0321] Preparation of 5: The preparation was carried out according to the method described for intermediate 3, except that the residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 9 / 1) to give 2-bromo-5-(6-(difluoromethoxy)pyridin-3-yl)-1,3,4-oxadiazole (100 mg, 342 μmol, 16% yield) as a yellow solid. 1 H NMR (400 MHz, DMSO- d 6) δ =8.86 (d, J = 2.3 Hz, 1H), 8.46 (dd, J= 2.4, 8.7 Hz, 1H), 7.99 - 7.63 (m, 1H),7.33 (d, J = 8.6 Hz, 1H).

[0322] Preparation of compound 18: The preparation was carried out according to the method described for compound 1, except that: (i) 3.00 eqN , N -Diisopropylethylamine, (ii) the reaction mixture was stirred at 130 °C for 5 h and (iii) the residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 5) and concentrated under reduced pressure to give a solid, which was then purified by reversed-phase chromatography (C18, 80 g; conditions: water / acetonitrile = 100:0 to 0:100, 0.1% formic acid) to give 3-(4-chloro-6-(1-((5-(6-(difluoromethoxy)pyridin-3-yl)-1,3,4-oxadiazol-2-yl)amino)cyclopropyl)-1-oxoisoindololin-2-yl)piperidin-2,6-dione (20.35% yield) as a white solid. 1 H NMR (400 MHz, DMSO- d 6) δ = 11.00 (br s,1H), 9.06 (s, 1H), 8.67 - 8.56 (m, 1H), 8.27 (dd, J = 2.5, 8.6 Hz, 1H), 7.95(s, 0.2H), 7.77 (s, 0.5H), 7.68 - 7.60 (m, 2H), 7.59 (s, 0.2H), 7.26 (d, J =8.6 Hz, 1H), 5.16 - 5.08 (m, 1H), 4.50 - 4.40 (m, 1H), 4.29 (d, J = 17.5 Hz,1H), 2.97 - 2.85 (m, 1H), 2.63 - 2.55 (m, 1H), 2.45 - 2.38 (m, 1H), 2.04 -1.95 (m, 1H), 1.47 - 1.41 (m, 2H), 1.40 - 1.36 (m, 2H).

[0323] Example 19. Preparation of Compound 19 The preparation was carried out according to the method described for compound 1, except that: (i) 5.00 eqN ,N -Diisopropylethylamine, (ii) stirring the reaction mixture at 120°C for 1 h, and (iii) by Preparative Purification was performed by HPLC (column: YMC-Actus Triart C18 150*30 mm*7 um; mobile phase: [water (formic acid)-acetonitrile]; gradient: 40%-70% B, duration: 10 min) to obtain 3-(4-fluoro-1-oxo-6-(1-((5-(4-(trifluoromethoxy)phenyl)-1,3,4-oxadiazol-2-yl)amino)cyclopropyl)isoindoline-2-yl)piperidine-2,6-dione as a grayish-white solid (18.3% yield). 1 H NMR (400 MHz, DMSO-) d 6 ) δ = 10.99 (s, 1H), 9.01 (s, 1H), 7.90 (d, J = 8.8 Hz, 2H),7.61 - 7.46 (m, 3H), 7.37 (d, J = 10.4 Hz, 1H), 5.10 (dd, J = 5.0, 13.4 Hz, 1H),4.57 - 4.48 (m, 1H), 4.35 (d, J = 17.4 Hz, 1H), 2.95 - 2.84 (m, 1H), 2.58 (brd, J = 18.4 Hz, 1H), 2.41 (br dd, J = 4.6, 13.0 Hz, 1H), 2.03 - 1.94 (m, 1H), 1.42 (br d, J = 10.4 Hz, 4H).

[0324] Example 20. Preparation of Compound 20 Preparation of 2: To pyrrolidine (606 mg, 8.52 mmol, 711 μL, 1.00 eq ) and methyl 4-(chlorosulfonyl)benzoate (2.00 g, 8.52 mmol, 1.00 eq Triethylamine (862 mg, 8.52 mmol, 1.19 mL, 1.00 mmol) was added to a solution in dichloromethane (20.0 mL). eqThe mixture was stirred at 25 °C for 12 h. The reaction mixture was concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0 to 3 / 1) to give methyl 4-(pyrrolidine-1-ylsulfonyl)benzoate as a white solid (1.88 g, 6.98 mmol, 82% yield).

[0325] Preparation of 3: The preparation was carried out according to the method described for structure 3 of the scheme used to prepare intermediate 6, except that: (i) 15.0 eqN,N - Hydrazine hydrate was used as hydrazine hydrate and (ii) the reaction mixture was stirred at 60 °C for 2 h. 4-(pyrrolidine-1-ylsulfonyl)benzoyl hydrazine was given as a yellow solid (99% yield).

[0326] Preparation of 4: The preparation was carried out according to the method described for structure 4 of the scheme used to prepare intermediate 6. 5-(4-(pyrrolidine-1-ylsulfonyl)phenyl)-1,3,4-oxadiazole-2-amine (80% purity) was obtained as a yellow solid.

[0327] Preparation of 5: The preparation was carried out according to the method described for intermediate 3, except that: (i) 1.00 eq (ii) The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 0 / 1 to 3 / 1) to give 2-bromo-5-(4-(pyrrolidine-1-ylsulfonyl)phenyl)-1,3,4-oxadiazole as a yellow solid (23% yield). 1 HNMR (400 MHz, DMSO- d 6 ) δ = 8.24 - 8.11 (m, 2H), 8.05 - 7.94 (m, 2H), 3.23 -3.13 (m, 4H), 1.70 - 1.62 (m, 4H).

[0328] Preparation of compound 20: The preparation was carried out according to the method described for compound 1, except that it was performed by... system SparePurification was performed by HPLC (column: C18 150 × 30 mm; mobile phase: [water (formic acid)-acetonitrile]; gradient: 35% - 65% B, duration: 12 min) to obtain 3-(4-chloro-1-oxo-6-(1-((5-(4-(pyrrolidine-1-ylsulfonyl)phenyl)-1,3,4-oxadiazol-2-yl)amino)cyclopropyl)isoindoline-2-yl)piperidine-2,6-dione as a grayish-white solid (20% yield). 1 HNMR (400 MHz, DMSO- d 6 ) δ = 10.99 (s, 1H), 9.12 (s, 1H), 8.02 - 7.97 (m, 2H), 7.96 - 7.91 (m, 2H), 7.62 (dd, J = 1.2, 11.6 Hz, 2H), 5.12 (dd, J = 5.0, 13.0 Hz,1H), 4.48 - 4.41 (m, 1H), 4.32 - 4.25 (m, 1H), 3.16 (br t, J = 6.8 Hz, 4H),2.95 - 2.85 (m, 1H), 2.57 - 2.53 (m, 1H), 2.48 - 2.36 (m, 1H), 2.02 - 1.95(m, 1H), 1.67 - 1.63 (m, 4H), 1.48 - 1.38 (m, 4H).

[0329] Example 21. Preparation of compound 21 The preparation was carried out according to the method described for compound 1, except that it was performed by... Preparative Purification was performed by HPLC (column: C18 150 × 30 mm; mobile phase: [water (formic acid)-acetonitrile]; gradient: 30% - 60% B, duration: 12 min) to give 3-(4-chloro-6-(1-((5-(4-cyclopropoxyphenyl)-1,3,4-oxadiazol-2-yl)amino)cyclopropyl)-1-oxoisoindoline-2-yl)piperidine-2,6-dione as a white solid (39% yield). 1 H NMR (400 MHz, DMSO- d 6 ) δ =10.98 (s, 1H), 8.84 (s, 1H), 7.72 (d, J= 8.8 Hz, 2H), 7.63 (d, J = 14.2 Hz, 2H), 7.18 (d, J = 8.8 Hz, 2H), 5.12 (dd, J = 4.8, 13.2 Hz, 1H), 4.48 - 4.39 (m, 1H), 4.33 - 4.23 (m, 1H), 3.95 - 3.88 (m, 1H), 2.96 - 2.84 (m, 1H), 2.61 - 2.54(m, 1H), 2.46 - 2.38 (m, 1H), 2.03 - 1.94 (m, 1H), 1.46 - 1.34 (m, 4H), 0.85 - 0.78 (m, 2H), 0.71 - 0.64 (m, 2H).

[0330] Example 22. Preparation of Compound 22 Preparation of 2 Preparation is carried out according to the method described for structure 2 of the scheme used to prepare intermediate 6, the difference being the use of 3.00 eq Thionyl chloride. 3-(difluoromethyl)benzoate was obtained as a colorless oil (92% yield).

[0331] Preparation of 3: Preparation was carried out according to the method described for structure 3 of the scheme used to prepare intermediate 6, the difference being the use of 16.8 eq Hydrazine hydrate. 3-(difluoromethyl)benzoyl hydrazine (1.00 g, crude product) was obtained as a white solid.

[0332] Preparation of 4: The preparation is carried out according to the method described for structure 4 of the scheme used to prepare intermediate 6, except that: (i) 4.5 is used. eq (ii) The crude product was ground with ethyl acetate and concentrated under reduced pressure to give 5-(3-(difluoromethyl)phenyl)-1,3,4-oxadiazole-2-amine as a white solid (57% yield).

[0333] Preparation of 5: The preparation was carried out according to the method described for intermediate 3, except that: (i) 2.00 eq (ii) The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 10 / 1 to 3 / 1) to give 2-bromo-5-(3-(difluoromethyl)phenyl)-1,3,4-oxadiazole as an orange solid (25% yield).1 H NMR (400MHz, DMSO- d 6) δ = 8.19 - 8.05 (m, 2H), 7.90 - 7.83 (m, 1H), 7.81 - 7.72 (m,1H), 7.18 (t, J = 55.5 Hz, 1H).

[0334] Preparation of compound 22: The preparation was carried out according to the method described for compound 1, except that: (i) 3.00 eqN , N -Diisopropylethylamine, (ii) stirring the reaction mixture at 100°C for 2 h, and (iii) by Preparative Purification was performed by HPLC (column: Phenomenex luna C18 150*25mm* 10um; mobile phase: [water (formic acid)-acetonitrile]; gradient: 31%-51% B, duration: 10 min) to obtain 3-(4-chloro-6-(1-((5-(3-(difluoromethyl)phenyl)-1,3,4-oxadiazol-2-yl)amino)cyclopropyl)-1-oxoisoindololin-2-yl)piperidine-2,6-dione (33.06% yield) as a grayish-white solid. 1 H NMR (400 MHz, DMSO- d 6) δ = 10.99 (br s, 1H), 9.02 (s, 1H), 7.99 - 7.89(m, 2H), 7.74 - 7.67 (m, 2H), 7.67 - 7.60 (m, 2H), 7.15 (t, J = 55.7 Hz, 1H),5.18 - 5.08 (m, 1H), 4.50 - 4.40 (m, 1H), 4.34 - 4.24 (m, 1H), 2.96 - 2.85(m, 1H), 2.62 - 2.56 (m, 1H), 2.47 - 2.42 (m, 1H), 2.04 - 1.96 (m, 1H), 1.48 - 1.43 (m, 2H), 1.42 - 1.37 (m, 2H).

[0335] Example 23. Preparation of compound 23 Preparation of 2:Preparation was carried out according to the method described for structure 2 of the scheme used to prepare intermediate 6, the difference being the use of 3.00 eq Thionyl chloride. This yields a yellow liquid of methyl chromium-6-carboxylate (98% yield).

[0336] Preparation of 3: Preparation was carried out according to the method described for structure 3 of the scheme used to prepare intermediate 6, the difference being the use of 11.9 eq Hydrazine hydrate. Chromium-6-carbonylhydrazine was obtained as a yellow solid (97% yield).

[0337] Preparation of 4: The preparation was carried out according to the method described for structure 4 of the scheme for preparing intermediate 6, except that the residue was ground with acetonitrile (5.00 mL) to give 5-(chroman-6-yl)-1,3,4-oxadiazol-2-amine (64% yield) as a yellow solid.

[0338] Preparation of 5: The preparation was carried out according to the method described for intermediate 3, except that: (i) 1.00 eq (ii) The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0 to 10 / 1) to give 2-bromo-5-(chroman-6-yl)-1,3,4-oxadiazole as a yellow solid (26% yield). 1 H NMR (400 MHz, CDCl3) δ = 7.76 - 7.71 (m, 2H), 6.90 (d, J = 8.4 Hz, 1H), 4.33 - 4.21 (m, 2H), 2.86 (t, J = 6.4 Hz, 2H), 2.12 - 2.00 (m, 2H).

[0339] Preparation of compound 23: The preparation was carried out according to the method described for compound 1, except that: (i) 4.00 eqN , N -Diisopropylethylamine, (ii) stirring the reaction mixture at 100°C for 2 h and (iii) passing through PreparativePurification was performed by HPLC (column: Phenomenex luna C18 150*25mm* 10um; mobile phase: [water (formic acid)-acetonitrile]; gradient: 26%-56% B, duration: 11 min) to obtain 3-(4-chloro-6-(1-((5-(chroman-6-yl)-1,3,4-oxadiazol-2-yl)amino)cyclopropyl)-1-oxoisoindoline-2-yl)piperidine-2,6-dione (23% yield) as a yellow solid. 1 H NMR (400 MHz, DMSO-) d 6) δ = 10.99 (s, 1H), 8.80 (s, 1H), 7.64 (d, J = 1.2 Hz, 1H), 7.60 (d, J = 1.6 Hz, 1H), 7.51 - 7.44 (m, 2H), 6.85 (d, J = 8.8 Hz, 1H), 5.12(dd, J = 13.2, 4.8 Hz, 1H), 4.49 - 4.39 (m, 1H), 4.33 - 4.23 (m, 1H), 4.18 (t, J = 4.8 Hz, 2H), 2.94 - 2.85 (m, 1H), 2.79 (t, J = 6.4 Hz, 2H), 2.61 - 2.55 (m,1H), 2.46 - 2.39 (m, 1H), 2.03 - 1.97 (m, 1H), 1.96 - 1.88 (m, 2H), 1.46 -1.32 (m, 4H).

[0340] Example 24. Preparation of compound 24 Preparation of 2: The preparation was carried out according to the method described for structure 2 of the scheme used to prepare intermediate 6, except that: (i) 4.00 eq (ii) The reaction mixture was stirred at 25°C for 2 h. The resulting product was a yellow oily chromium-8-carboxylate (900 mg, crude).

[0341] Preparation of 3: The preparation was carried out according to the method described for structure 3 of the scheme used to prepare intermediate 6, except that: (i) 15.0 eq(ii) The reaction mixture was concentrated under reduced pressure to give chromium-8-carbonylhydrazine as a yellow solid.

[0342] Preparation of 4: The preparation was carried out according to the method described for structure 4 of the scheme for preparing intermediate 6, except that the residue was ground with ethyl acetate (10.0 mL) to give 5-(chroman-8-yl)-1,3,4-oxadiazol-2-amine as a yellow solid (62% yield).

[0343] Preparation of 5: The preparation was carried out according to the method described for intermediate 3, except that the residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 8 / 1 to 6 / 1) to give 2-bromo-5-(chroman-8-yl)-1,3,4-oxadiazole as a white solid (24% yield). 1 H NMR (400 MHz, DMSO- d 6 ) δ = 7.61 (d, J = 7.6 Hz, 1H), 7.34 (br d, J = 7.5 Hz, 1H), 6.99 (t, J = 7.6 Hz, 1H), 4.29 - 4.25 (m, 2H), 2.83 (br t, J = 6.4 Hz, 2H), 1.99 - 1.94 (m, 2H).

[0344] Preparation of compound 24: The preparation was carried out according to the method described for compound 1, except that: (i) 4.00 eqN,N -Diisopropylethylamine, (ii) the reaction mixture was stirred at 100 °C for 6 h, and (iii) purified by reversed-phase chromatography (C18, 40 g; conditions: water / acetonitrile = 100:0 to 0:100, 0.1% formic acid) to give 3-(4-chloro-6-(1-((5-(chroman-8-yl)-1,3,4-oxadiazol-2-yl)amino)cyclopropyl)-1-oxoisoindololin-2-yl)piperidine-2,6-dione (33.2% yield) as a yellow solid. 1 H NMR (400 MHz, DMSO- d 6 ) δ = 10.99 (s, 1H), 8.82 (s, 1H), 7.66 (d, J = 1.1 Hz, 1H), 7.61 (d, J= 1.4 Hz, 1H), 7.43 (d, J = 7.9 Hz, 1H), 7.21 (d, J = 7.0 Hz, 1H), 6.90 (t, J = 7.6 Hz, 1H), 5.18 - 5.07 (m, 1H), 4.50 - 4.39 (m, 1H), 4.34 - 4.25 (m, 1H), 4.23 - 4.14 (m, 2H), 2.96 - 2.84(m, 1H), 2.79 (br t, J = 6.4 Hz, 2H), 2.58 (br d, J = 18.0 Hz, 1H), 2.47 - 2.41(m, 1H), 2.04 - 1.97 (m, 1H), 1.96 - 1.90 (m, 2H), 1.44 - 1.37 (m, 2H), 1.37- 1.30 (m, 2H).

[0345] Example 25. Preparation of compound 25 Preparation of 2: To 3-(difluoromethoxy)benzoic acid (2.00 g, 10.6 mmol, 1.00 g), eq Add to a solution of dichloromethane (15.0 mL) N -Aminocarbamic acid Uncle Butyl ester (1.45 g, 10.9 mmol, 1.03 mmol) eq ) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (2.08 g, 10.8 mmol, 1.02 eq The mixture was stirred at 20 °C for 12 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 50 / 1 to 1 / 1) to give tert-butyl 2-(3-(difluoromethoxy)benzoyl)hydrazide-1-carboxylate (2.90 g, 9.59 mmol, 90% yield) as a white solid.

[0346] Preparation of 3: tert-butyl 2-(3-(difluoromethoxy)benzoyl)hydrazide-1-carboxylate (1.00 g, 3.31 mmol, 1.00 g) eq Add trifluoroacetic acid (3.07 g, 26.9 mmol, 2.00 mL, 8.14 mmol) to a solution of dichloromethane (10.0 mL). eq The two batches of the mixture were stirred at 20°C for 1 h. The reaction mixture was concentrated under reduced pressure to give 3-(difluoromethoxy)benzoylhydrazine (660 mg, 3.26 mmol, 98% yield) as a white solid.

[0347] Preparation of 4: To 3-(difluoromethoxy)benzoylhydrazine (660 mg, 3.26 mmol, 1.00) eq Add di(1) to a solution of tetrahydrofuran (10.0 mL). H -imidazol-1-yl)methylimine (526 mg, 3.26 mmol, 1.00) eq The mixture was stirred at 60 °C for 2 h. The two batches of the reaction mixture were concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 10 / 1 to 0 / 1) to give 5-(3-(difluoromethoxy)phenyl)-1,3,4-oxadiazol-2-amine (650 mg, 2.86 mmol, 87% yield) as a white solid.

[0348] Preparation of 5: The preparation was carried out according to the method described for intermediate 3, except that: (i) 1.10 eq (ii) The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 10 / 1 to 1 / 1) to give 2-bromo-5-(3-(difluoromethoxy)phenyl)-1,3,4-oxadiazole as a white solid (54% yield). 1 H NMR (400MHz, DMSO- d 6 ) δ = 7.86 (d, J = 7.9 Hz, 1H), 7.73 (s, 1H), 7.68 (t, J = 8.0 Hz, 1H),7.58 (s, 0.3H), 7.48 (dd, J = 2.0, 8.1 Hz, 1H), 7.39 (s, 0.5H), 7.21 (s, 0.2H).

[0349] Preparation of compound 25: The preparation was carried out according to the method described for compound 1, except that: (i) 5.00 eqN , N-Diisopropylethylamine, (ii) the reaction mixture was stirred at 110 °C for 4 h, and (iii) purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 5 / 1 to 0 / 1) to give 3-(4-chloro-6-(1-((5-(3-(difluoromethoxy)phenyl)-1,3,4-oxadiazol-2-yl)amino)cyclopropyl)-1-oxoisoindololin-2-yl)piperidine-2,6-dione as a white solid (40.25% yield). 1 H NMR (400 MHz, DMSO- d 6 ) δ = 10.99 (s, 1H), 9.03 (s, 1H),7.66 (s, 1H), 7.64 (s, 1H), 7.61 (s, 1H), 7.61 - 7.56 (m, 1H), 7.52 (br s,0.2H), 7.51 (br s, 1H), 7.34 (s, 1H), 7.32 (s, 0.5H), 7.16 (s, 0.2H), 5.12(dd, J = 5.1, 13.2 Hz, 1H), 4.49 - 4.40 (m, 1H), 4.32 - 4.22 (m, 1H), 2.97 -2.84 (m, 1H), 2.58 (br d, J = 17.4 Hz, 1H), 2.46 - 2.38 (m, 1H), 2.02 - 1.95 (m, 1H), 1.48 - 1.42 (m, 2H), 1.41 - 1.35 (m, 2H).

[0350] Example 26. Preparation of compound 26 Preparation of 2: To 2,3-dihydrobenzo[ b [1,4] Dioxane-6-carboxylic acid (2.00 g, 11.1 mmol, 1.00 mmol) eq Add potassium carbonate (3.84 g, 27.8 mmol, 2.50 mmol) to a solution of dimethylformamide (20.0 mL). eq ) and methyl iodide (1.65 g, 11.7 mmol, 726 μL, 1.05 eqThe mixture was stirred at 25°C for 2 h. The mixture was diluted with water (30.0 mL) and extracted with ethyl acetate (3 × 60.0 mL). The combined organic layers were washed with brine (3 × 60.0 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 2,3-dihydrobenzo[…] as a yellow oil. b [1,4] Methyl dioxane-6-carboxylate (2.05 g, 10.6 mmol, 95% yield).

[0351] Preparation of 3: The preparation was carried out according to the method described for structure 3 of the scheme used to prepare intermediate 6, except that: (i) 15.0 eq (ii) The mixture was concentrated under reduced pressure to give 2,3-dihydrobenzo[ ... b [1,4] Dioxane-6-carbonylhydrazine (100% yield).

[0352] Preparation of 4: The preparation was carried out according to the method described for structure 4 of the scheme used to prepare intermediate 6, except that: (i) 2.00 eq (ii) The residue was ground with ethyl acetate / methanol = 10 / 1 to give 5-(2,3-dihydrobenzo[] ] as a white solid. b [1,4]dioxane-6-yl)-1,3,4-oxadiazol-2-amine (79% yield).

[0353] Preparation of 5: The preparation was carried out according to the method described for intermediate 3, except that: (i) 1.00 eq Copper bromide and (ii) the residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 5 / 1 to 0 / 1) to give 2-bromo-5-(2,3-dihydrobenzo[] ) as a yellow solid. b [1,4]dioxane-6-yl)-1,3,4-oxadiazole (31% yield). 1 H NMR (400 MHz, DMSO- d 6 ) δ = 7.46 (dd, J = 2.1, 8.4 Hz, 1H), 7.41 (d, J =2.0 Hz, 1H), 7.07 (d, J = 8.5 Hz, 1H), 4.36 - 4.33 (m, 2H), 4.33 - 4.30 (m, 2H).

[0354] Preparation of compound 26: The preparation was carried out according to the method described for compound 1, except that: (i) 3.00 eqN , N -Diisopropylethylamine and (ii) purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 5 / 1 to 0 / 1) to give 3-(4-chloro-6-(1-((5-(2,3-dihydrobenzo[ b [1,4]dioxacyclohexene-6-yl)-1,3,4-oxadiazol-2-yl)amino)cyclopropyl)-1-oxoisoindoline-2-yl)piperidine-2,6-dione (41.32% yield). 1 H NMR (400 MHz, DMSO- d 6 ) δ = 11.00 (s, 1H), 8.86 (s, 1H), 7.63 (s, 1H),7.60 (s, 1H), 7.26 (dd, J = 1.9, 8.4 Hz, 1H), 7.20 (d, J = 1.8 Hz, 1H), 6.99 (d, J = 8.4 Hz, 1H), 5.12 (dd, J = 5.0, 13.3 Hz, 1H), 4.48 - 4.40 (m, 1H), 4.30 (brs, 4H), 4.25 (s, 1H), 2.95 - 2.85 (m, 1H), 2.58 (br d, J = 17.9 Hz, 1H), 2.45 -2.41 (m, 1H), 2.03 - 1.95 (m, 1H), 1.46 - 1.39 (m, 2H), 1.38 - 1.33 (m, 2H).

[0355] Example 27. Preparation of compound 27 Preparation of 2: The preparation is carried out according to the method described for structure 2 of the scheme used to prepare intermediate 6, except that: (i) 2.50 eq (ii) The reaction mixture was stirred at 50 °C for 3 h and (iii) purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 20 / 1 to 3 / 1) to give methyl 3-fluoro-4-methoxybenzoate as a brown oil (92% yield).

[0356] Preparation of 3: The preparation was carried out according to the method described for structure 3 of the scheme used to prepare intermediate 6, except that: (i) 15.0 eqN,N- (ii) The reaction mixture was concentrated under reduced pressure to give 3-fluoro-4-methoxybenzoyl hydrazine as a white solid (99% yield).

[0357] Preparation of 4: The preparation was carried out according to the method described for structure 4 of the scheme used to prepare intermediate 6. 5-(3-fluoro-4-methoxyphenyl)-1,3,4-oxadiazole-2-amine (80% yield) was obtained as a white solid.

[0358] Preparation of 5: The preparation was carried out according to the method described for intermediate 3, except that: (i) 2.00 eq Copper bromide was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 80 / 1 to 10 / 1) to give 2-bromo-5-(3-fluoro-4-methoxyphenyl)-1,3,4-oxadiazole as a white solid (55% yield). 1 H NMR (400MHz, DMSO- d 6 ) δ = 7.85 - 7.75 (m, 2H), 7.40 (t, J = 8.5 Hz, 1H), 3.94 (s, 3H).

[0359] Preparation of compound 27: The preparation was carried out according to the method described for compound 1, except that: (i) 4.00 eqN,N -Diisopropylethylamine, (ii) stirring the reaction mixture at 100°C for 5 h, and (iii) by Preparative Purification was performed by HPLC (C18, 40 g; column: phenomenex luna C18 150*25mm* 10um; mobile phase: [water (formic acid)-acetonitrile]; gradient: 26%-56% B, duration 10 min) to obtain 3-(4-chloro-6-(1-((5-(3-fluoro-4-methoxyphenyl)-1,3,4-oxadiazol-2-yl)amino)cyclopropyl)-1-oxoisoindololin-2-yl)piperidine-2,6-dione (14.94% yield) as a yellow solid. 1 H NMR (400 MHz, DMSO- d 6 ) δ= 11.00 (br s, 1H), 8.93 (s, 1H), 7.62(d, J = 12.9 Hz, 2H), 7.58 - 7.52 (m, 2H), 7.32 (t, J = 8.8 Hz, 1H), 5.12 (dd, J =5.1, 13.3 Hz, 1H), 4.48 - 4.40 (m, 1H), 4.31 - 4.24 (m, 1H), 3.90 (s, 3H), 2.95 - 2.85 (m, 1H), 2.62 - 2.55 (m, 1H), 2.45 (br d, J = 4.8 Hz, 1H), 2.02 -1.95 (m, 1H), 1.46 - 1.40 (m, 2H), 1.39 - 1.34 (m, 2H).

[0360] Example 28. Preparation of compound 28 Preparation of 2: Preparation was carried out according to the method described for structure 2 of the scheme used to prepare intermediate 6, the difference being the use of 5.00 eq Thionyl chloride. This yields 4-fluoro-3-methoxybenzoate as a white solid (100% yield).

[0361] Preparation of 3: Preparation was carried out according to the method described for structure 3 of the scheme used to prepare intermediate 6, the difference being the use of 10.0 eqN,N- Hydrazine hydrate. 4-Fluoro-3-methoxybenzoylhydrazine was given as a white solid (100% yield).

[0362] Preparation of 4: The preparation is carried out according to the method described for structure 4 of the scheme used to prepare intermediate 6, except that: (i) 3.50 eq (ii) The reaction mixture was stirred at 75 °C for 0.5 h. 5-(4-fluoro-3-methoxyphenyl)-1,3,4-oxadiazole-2-amine (81% yield) was given as a white solid.

[0363] Preparation of 5: The preparation was carried out according to the method described for intermediate 3, except that: (i) 1.00 eqCopper bromide was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 50 / 1 to 1 / 1) to give 2-bromo-5-(4-fluoro-3-methoxyphenyl)-1,3,4-oxadiazole as a white solid (18% yield). 1 H NMR (400 MHz, DMSO- d 6 ) δ = 7.67 (dd, J = 1.8, 8.1 Hz, 1H), 7.58 (ddd, J = 1.9, 4.3, 8.5 Hz, 1H),7.46 (dd, J = 8.4, 11.1 Hz, 1H), 3.95 (s, 3H).

[0364] Preparation of compound 28: The preparation was carried out according to the method described for compound 1, except that: (i) 4.00 eqN , N -Diisopropylethylamine, (ii) stirring the reaction mixture at 100°C for 3 h, and (iii) by Preparative Purification was performed by HPLC (C18, 40 g; column: Phenomenex luna C18 150*25mm* 10um; mobile phase: [water (formic acid)-acetonitrile]; gradient: 25%-55% B, duration 11 min) to obtain 3-(4-chloro-6-(1-((5-(4-fluoro-3-methoxyphenyl)-1,3,4-oxadiazol-2-yl)amino)cyclopropyl)-1-oxoisoindololin-2-yl)piperidine-2,6-dione (30.26% yield) as a yellow solid. 1 H NMR (400 MHz, DMSO- d 6 ) δ = 11.08 - 10.93 (m, 1H), 8.97 (s, 1H), 7.63 (dd, J = 1.3, 15.6 Hz, 2H), 7.48 (dd, J = 1.5, 8.1 Hz, 1H), 7.41 - 7.33 (m,2H), 5.12 (dd, J= 5.1, 13.2 Hz, 1H), 4.50 - 4.40 (m, 1H), 4.32 - 4.24 (m, 1H), 3.91 (s, 3H), 2.94 - 2.86 (m, 1H), 2.59 - 2.56 (m, 1H), 2.44 (br d, J = 8.3 Hz,1H), 2.02 - 1.95 (m, 1H), 1.46 - 1.40 (m, 2H), 1.40 - 1.35 (m, 2H).

[0365] Example 29. Preparation of compound 29 Preparation of 2: Preparation was carried out according to the method described for structure 2 of the scheme used to prepare intermediate 6, the difference being the use of 4.00 eq Thionyl chloride. This yields methyl 4-(difluoromethyl)benzoate as a colorless oil (92% yield).

[0366] Preparation of 3: The preparation was carried out according to the method described for structure 3 of the scheme used to prepare intermediate 6, except that: (i) the reaction was carried out in methanol instead of ethanol and (ii) 15.0 eqN,N- Hydrazine hydrate. This yields 4-(difluoromethyl)benzoyl hydrazide as a white solid.

[0367] Preparation of 4: Preparation was carried out according to the method described for structure 4 of the scheme used to prepare intermediate 6. 5-(4-(difluoromethyl)phenyl)-1,3,4-oxadiazole-2-amine (68% yield) was obtained as a white solid.

[0368] Preparation of 5: The preparation was carried out according to the method described for intermediate 3, except that: (i) 1.00 eq Copper bromide was purified by column chromatography (SiO2, petroleum ether: ethyl acetate = 10:1) to give 2-bromo-5-(4-(difluoromethyl)phenyl)-1,3,4-oxadiazole as a white solid (57% yield). 1 H NMR (400 MHz, DMSO- d 6) δ = 8.13 (d, J = 8.1 Hz, 2H), 7.81 (br d, J = 8.1 Hz, 2H), 7.16 (t, J = 55.5Hz, 1H).

[0369] Preparation of compound 29: The preparation was carried out according to the method described for compound 1, except that: (i) 4.00 eqN , N -Diisopropylethylamine, (ii) stirring the reaction mixture at 100°C for 6 h, and (iii) by Preparative Purification was performed by HPLC (column: Welch Ultimate C18 150*25mm*5um; mobile phase: [water (formic acid)-acetonitrile]; gradient: 24%-54%B, duration: 10 min) to obtain 3-(4-chloro-6-(1-((5-(4-(difluoromethyl)phenyl)-1,3,4-oxadiazol-2-yl)amino)cyclopropyl)-1-oxoisoindololin-2-yl)piperidine-2,6-dione (16.67% yield) as a grayish-white solid. 1 H NMR (400 MHz, DMSO- d 6) δ = 11.00 (s, 1H), 9.04 (s, 1H), 7.92 (d, J = 8.1 Hz, 2H), 7.72 (d, J = 8.3 Hz, 2H), 7.66 - 7.59 (m, 2H), 7.11 (t, J = 55.7 Hz, 1H), 5.12 (dd, J = 5.1, 13.4 Hz, 1H), 4.49 - 4.37 (m, 1H), 4.33 - 4.20 (m, 1H), 2.96- 2.84 (m, 1H), 2.62 - 2.54 (m, 1H), 2.44 - 2.38 (m, 1H), 2.04 - 1.93 (m,1H), 1.50 - 1.42 (m, 2H), 1.41 - 1.33 (m, 2H).

[0370] Example 30. Preparation of compound 30 Preparation of 2: To 4-fluorobenzoic acid (2.00 g, 14.2 mmol, 1.00 mmol) eq Iodimethane (2.13 g, 14.9 mmol, 933 μL, 1.05 mmol) was added to a solution of dimethylformamide (20.0 mL). eq ) and potassium carbonate (3.95 g, 28.5 mmol, 2.00 eqThe mixture was stirred at 20 °C for 2 h. The mixture was diluted with water (60.0 mL) and extracted with ethyl acetate (3 × 100 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give methyl 4-fluorobenzoate (700 mg, 4.54 mmol, 31% yield) as a brown oil.

[0371] Preparation of 3: Preparation was carried out according to the method described for structure 3 of the scheme used to prepare intermediate 6, except that 20.0 g / L was used. eqN,N- Hydrazine hydrate. 4-Fluorobenzoylhydrazine, a white solid, is obtained.

[0372] Preparation of 4: Preparation was carried out according to the method described for structure 4 of the scheme used to prepare intermediate 6, except that 2.50 was used. eq Cyanide bromide. This yields 5-(4-fluorophenyl)-1,3,4-oxadiazole-2-amine as a white solid (49% yield).

[0373] Preparation of 5: The preparation was carried out according to the method described for intermediate 3, except that: (i) 2.00 eq The copper bromide was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 30 / 1 to 1 / 1) to give 2-bromo-5-(4-fluorophenyl)-1,3,4-oxadiazole as a white solid (73% yield). 1 H NMR (400 MHz, DMSO- d 6 ) δ = 8.10 - 7.99 (m, 2H), 7.51 - 7.41 (m, 2H).

[0374] Preparation of compound 30: The preparation was carried out according to the method described for compound 1, except that: (i) 5.00 eqN , N -Diisopropylethylamine, (ii) the reaction mixture was stirred at 110 °C for 3 h, and (iii) purified by reversed-phase chromatography (C18, 25 g; conditions: water / acetonitrile = 100:0 to 0:100, 0.1% formic acid) to give 3-(4-chloro-6-(1-((5-(4-fluorophenyl)-1,3,4-oxadiazol-2-yl)amino)cyclopropyl)-1-oxoisoindololin-2-yl)piperidine-2,6-dione as a white solid (33.30% yield). 1 H NMR (400 MHz, DMSO- d 6 ) δ = 11.00 (br s, 1H), 8.96 (s, 1H), 7.83 (dd, J = 5.5, 8.4 Hz, 2H), 7.62 (d, J = 13.3 Hz, 2H), 7.37 (t, J =8.8 Hz, 2H), 5.12 (dd, J = 4.9, 13.3 Hz, 1H), 4.49 - 4.38 (m, 1H), 4.33 - 4.22(m, 1H), 2.96 - 2.84 (m, 1H), 2.66 - 2.54 (m, 1H), 2.45 - 2.37 (m, 1H), 2.04- 1.92 (m, 1H), 1.48 - 1.40 (m, 2H), 1.40 - 1.34 (m, 2H).

[0375] Example 31. Preparation of compound 31 Preparation of 2: The preparation was carried out according to the method described for structure 2 of the scheme for preparing intermediate 6, except that: (i) the mixture was stirred at 0°C to 50°C for 2 h and (ii) purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 10 / 1) to obtain methyl chroman-7-carboxylate (1.08 g, 100% yield) as a colorless oil.

[0376] Preparation of 3: Preparation was carried out according to the method described for structure 3 of the scheme used to prepare intermediate 6, the difference being the use of 10.0 eq Hydrazine hydrate. A yellow, oily substance, chroman-7-carbonylhydrazine, was obtained.

[0377] Preparation of 4: Preparation was carried out according to the method described for structure 4 of the scheme used to prepare intermediate 6. 5-(chroman-7-yl)-1,3,4-oxadiazol-2-amine was obtained as a yellow solid (98% yield).

[0378] Preparation of 5: The preparation was carried out according to the method described for intermediate 3, except that: (i) 1.00 eq Copper bromide was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 20 / 1 to 10 / 1) to give 2-bromo-5-(chroman-7-yl)-1,3,4-oxadiazole as a yellow solid (26% yield). 1H NMR (400 MHz, DMSO- d 6 ) δ = 7.41 (dd, J = 1.7, 7.8 Hz, 1H), 7.29 (d, J = 8.0 Hz, 1H), 7.27 - 7.23(m, 1H), 4.22 - 4.18 (m, 2H), 2.82 (br t, J = 6.3 Hz, 2H), 1.97 - 1.92 (m, 2H).

[0379] Preparation of compound 31: The preparation was carried out according to the method described for compound 1, except that: (i) 4.00 eqN,N -Diisopropylethylamine, (ii) stirring the reaction mixture at 110 °C for 4 h and (iii) passing through Preparative Purification was performed by HPLC (column: Phenomenex luna C18 150*25mm* 10um; mobile phase: [water (formic acid)-acetonitrile]; gradient: 26%-56% B, duration: 10 min) to obtain 3-(4-chloro-6-(1-((5-(chroman-7-yl)-1,3,4-oxadiazol-2-yl)amino)cyclopropyl)-1-oxoisoindololin-2-yl)piperidine-2,6-dione as a white solid (8.52% yield). 1 H NMR (400 MHz, DMSO-) d 6 ) δ = 11.00 (br s, 1H), 8.91 (s, 1H), 7.65 (s, 1H), 7.61 (s,1H), 7.28 - 7.22 (m, 1H), 7.22 - 7.17 (m, 1H), 7.07 (s, 1H), 5.13 (dd, J = 5.0,13.3 Hz, 1H), 4.49 - 4.40 (m, 1H), 4.33 - 4.25 (m, 1H), 4.20 - 4.14 (m, 2H),2.95 - 2.86 (m, 1H), 2.78 (br t, J= 6.3 Hz, 2H), 2.56 (br s, 1H), 2.42 (br s,1H), 2.03 - 1.97 (m, 1H), 1.96 - 1.90 (m, 2H), 1.46 - 1.40 (m, 2H), 1.40 -1.34 (m, 2H).

[0380] Example 32. Preparation of compound 32 Preparation of 2: Methyl 3-hydroxybenzoate (2.00 g, 13.1 mmol, 1.00 mmol) eq ), cyclopropyl (trifluoro)borate potassium salt (5.84 g, 39.4 mmol, 3.00 mmol) eq Add copper acetate (239 mg, 1.31 mmol, 0.100 mmol) to a solution in toluene (21.0 mL) and water (7.00 mL). eq ) and 1,10-phenanthroline (237 mg, 1.31 mmol, 0.100 eq Potassium carbonate (3.63g, 26.3 mmol, 2.00 mmol) eq The mixture was stirred at 70 °C for 12 h. The reaction mixture was diluted with water (60.0 mL) and extracted with ethyl acetate (3 × 20.0 mL). The combined organic layers were washed with brine (20.0 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0 to 50 / 1) and concentrated under reduced pressure to give methyl 3-cyclopropoxybenzoate (1.32 g, 5.84 mmol, 44% yield) as a yellow oil.

[0381] Preparation of 3: Preparation was carried out according to the method described for structure 3 of the scheme used to prepare intermediate 6, the difference being the use of 10.0 eq Hydrazine hydrate. 3-Cyclopropoxybenzoyl hydrazine, a yellow oil, was obtained (81% yield).

[0382] Preparation of 4: Preparation was carried out according to the method described for structure 4 of the scheme for preparing intermediate 6, except that purification was performed by reversed-phase chromatography (C18, 220 g; conditions: water / acetonitrile = 3 / 7 to 1 / 1, 0.1% formic acid) to give 5-(3-cyclopropoxyphenyl)-1,3,4-oxadiazol-2-amine as a white solid (28% yield).

[0383] Preparation of 5:5-(3-cyclopropoxyphenyl)-1,3,4-oxadiazole-2-amine (500 mg, 2.07 mmol, 1.00 mg) eq Copper(II) bromide (463 mg, 2.07 mmol, 97.0 μL, 1.00 μL) eq ), tert-butyl nitrite (427 mg, 4.14 mmol, 493 μL, 2.00 mg / L). eq The mixture in acetonitrile (6.00 mL) was degassed and purged three times with nitrogen, and then stirred at 65 °C under a nitrogen atmosphere for 1 h. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0 to 20 / 1) and concentrated under reduced pressure to give 2-bromo-5-(3-cyclopropoxyphenyl)-1,3,4-oxadiazole (140 mg, 468 μmol, 23% yield) as a yellow oil. 1 HNMR (400 MHz, DMSO- d 6) δ = 7.64 - 7.60 (m, 1H), 7.60 - 7.56 (m, 1H), 7.56 -7.51 (m, 1H), 7.31 (ddd, J = 1.2, 2.4, 8.0 Hz, 1H), 4.01 - 3.94 (m, 1H), 0.86 -0.81 (m, 2H), 0.72 - 0.68 (m, Preparation of compound 32: The preparation was carried out according to the method described for compound 1, except that: (i) 5.00 eqN , N -Diisopropylethylamine, (ii) stirring the reaction mixture at 110°C for 3 h, and (iii) by Preparative HPLC (Column: Phenomenex luna C18 150 × 25 mm × 10) μ m; mobile phase: [water (formic acid)-acetonitrile]; B%: 30%-60%, 10 min) was purified to give 3-(4-chloro-6-(1-((5-(3-cyclopropoxyphenyl)-1,3,4-oxadiazol-2-yl)amino)cyclopropyl)-1-oxoisoindoline-2-yl)piperidine-2,6-dione (26.52% yield) as a white solid. 1 HNMR (400 MHz, DMSO- d 6) δ= 11.00 (br s, 1H), 8.97 (s, 1H), 7.63 (d, J = 12.4 Hz,2H), 7.49 - 7.40 (m, 2H), 7.40 - 7.35 (m, 1H), 7.16 (dd, J = 1.6, 8.4 Hz, 1H), 5.12 (dd, J = 5.2, 13.2 Hz, 1H), 4.48 - 4.38 (m, 1H), 4.32 - 4.23 (m, 1H), 3.94- 3.88 (m, 1H), 2.97 - 2.83 (m, 1H), 2.61 - 2.54 (m, 1H), 2.44 (br dd, J = 4.8,13.2 Hz, 1H), 2.03 - 1.94 (m, 1H), 1.47 - 1.34 (m, 4H), 0.84 - 0.77 (m, 2H), 0.71 - 0.64 (m, 2H).

[0384] Example 33. Preparation of compound 33 Preparation of 2: The preparation was carried out according to the method described for intermediate 3, except that: (i) 1.00 eq Copper bromide was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 20 / 1 to 10 / 1) to give 2-bromo-5-(6-cyclopropoxy-2-methylpyridin-3-yl)-1,3,4-oxadiazole as a yellow solid (15% yield). 1 HNMR (400 MHz, DMSO- d 6) δ = 8.15 (d, J = 8.8 Hz, 1H), 6.93 (d, J = 8.8 Hz, 1H), 4.32(dt, J = 3.2, 6.0 Hz, 1H), 2.72 (s, 3H), 0.83 - 0.78 (m, 2H), 0.75 - 0.70 (m, 2H).

[0385] Preparation of compound 33: The preparation was carried out according to the method described for compound 1, except that: (i) 5.00 eqN , N-Diisopropylethylamine, (ii) stirring the reaction mixture at 110°C for 1 h, and (iii) by Preparative HPLC (Column: Phenomenex luna C18 150 × 25 mm × 10) μ m; mobile phase: [water (formic acid)-acetonitrile]; B%: 24%-54%, 10 min) was purified to give 3-(6-(1-((5-(6-cyclopropoxy-2-methylpyridin-3-yl)-1,3,4-oxadiazol-2-yl)amino)cyclopropyl)-4-methyl-1-oxoisoindoline-2-yl)piperidine-2,6-dione (25.96% yield) as a pink solid. 1 H NMR (400 MHz, DMSO- d 6) δ = 10.98 (s, 1H), 8.88 (s, 1H), 7.95 (d, J = 8.4 Hz, 1H), 7.52 (s, 1H), 7.34 (s, 1H), 6.86 (d, J = 8.8 Hz, 1H), 5.11 (dd, J = 5.2, 13.2 Hz, 1H), 4.41 - 4.32 (m, 1H), 4.30 - 4.24 (m, 1H), 4.24 - 4.18(m, 1H), 2.97 - 2.84 (m, 1H), 2.64 (s, 3H), 2.61 - 2.55 (m, 1H), 2.45 - 2.35 (m, 1H), 2.30 (s, 3H), 2.03 - 1.92 (m, 1H), 1.34 (s, 4H), 0.81 - 0.75 (m,2H), 0.72 - 0.64 (m, 2H).

[0386] Example 34. Preparation of compound 34 The preparation was carried out according to the method described for compound 1, except that: (i) 5.00 eqN , N -Diisopropylethylamine, (ii) the reaction mixture was stirred at 110 °C for 3 h, and (iii) purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 1 to 0 / 1) to give 3-(4-methyl-1-oxo-6-(1-((5-( rightTolyl)-1,3,4-oxadiazol-2-yl)amino)cyclopropyl)isoindoline-2-yl)piperidine-2,6-dione (28.56% yield). 1 H NMR (400 MHz, DMSO- d 6 ) δ = 10.98 (s, 1H), 8.84 (s, 1H), 7.66 (d, J = 8.0Hz, 2H), 7.50 (s, 1H), 7.34 (br s, 2H), 7.31 (s, 1H), 5.11 (dd, J = 4.9, 13.2Hz, 1H), 4.43 - 4.30 (m, 1H), 4.28 - 4.14 (m, 1H), 2.98 - 2.83 (m, 1H), 2.58(br d, J = 17.8 Hz, 1H), 2.44 - 2.37 (m, 1H), 2.35 (s, 3H), 2.30 (s, 3H), 2.01- 1.93 (m, 1H), 1.34 (s, 4H).

[0387] Example 35. Preparation of compound 35 Preparation of 2: The preparation was carried out according to the method described for intermediate 3, except that: (i) 1.00 eq Copper bromide was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0 to 5 / 1) to give 2-bromo-5-(6-cyclopropylpyridin-3-yl)-1,3,4-oxadiazole as a brown solid (19% yield). 1 H NMR (400 MHz, DMSO- d 6 ) δ = 8.95 (br s, 1H), 8.21 - 8.15 (m, 1H), 7.54 (br d, J = 4.6 Hz, 1H), 2.24 (br s, 1H), 1.07 (br d, J = 2.6 Hz, 2H), 1.02 (br s, 2H).

[0388] Preparation of compound 35: The preparation was carried out according to the method described for compound 1, except that: (i) 63.00 eqN , N -Diisopropylethylamine, (ii) the reaction mixture was stirred at 110 °C for 12 h, and (iii) purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 1 to 0 / 1) to give 3-(6-(1-((5-(6-cyclopropylpyridin-3-yl)-1,3,4-oxadiazol-2-yl)amino)cyclopropyl)-4-methyl-1-oxoisoindoline-2-yl)piperidine-2,6-dione (41.19% yield) as a grayish-white solid. 1 H NMR (400 MHz, DMSO- d 6 ) δ = 10.98 (br s, 1H), 8.95 (s, 1H), 8.76 (d, J = 2.1 Hz, 1H), 7.97 (dd, J = 2.3, 8.1 Hz, 1H), 7.51 (s, 1H), 7.44(d, J = 8.3 Hz, 1H), 7.34 (s, 1H), 5.11 (dd, J = 5.1, 13.3 Hz, 1H), 4.41 - 4.32(m, 1H), 4.26 - 4.16 (m, 1H), 2.97 - 2.84 (m, 1H), 2.58 (br dd, J = 2.1, 15.3Hz, 1H), 2.45 - 2.36 (m, 1H), 2.30 (s, 3H), 2.22 - 2.13 (m, 1H), 2.01 - 1.93(m, 1H), 1.34 (s, 4H), 1.05 - 1.00 (m, 2H), 0.99 - 0.94 (m, 2H).

[0389] Example 36. Preparation of compound 36 Preparation of 2: The preparation was carried out according to the method described for structure 2 of the scheme for preparing intermediate 6, except that the reaction mixture was concentrated under reduced pressure to obtain isochromic methyl 7-carboxylate as a yellow oil.

[0390] Preparation of 3: The preparation was carried out according to the method described for structure 3 of the scheme used to prepare intermediate 6, except that: (i) 15.0 eq(ii) The reaction mixture was stirred at 60 °C for 2 h. This yielded a white solid, heterochromatic 7-carbonyl hydrazine (95% yield).

[0391] Preparation of 4: Preparation was carried out according to the method described for structure 2 of the scheme used to prepare intermediate 6. 5-(isochroman-7-yl)-1,3,4-oxadiazol-2-amine was obtained as a gray solid (99% yield).

[0392] Preparation of 5: The preparation was carried out according to the method described for intermediate 3, except that purification was performed by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0 to 3 / 1) to give 2-bromo-5-(isochroman-7-yl)-1,3,4-oxadiazole as a yellow solid (20% yield). 1 H NMR (400 MHz, DMSO- d 6 ) δ = 7.76 (d, J = 8.0 Hz, 1H), 7.67(s, 1H), 7.37 (d, J = 8.0 Hz, 1H), 4.76 (s, 2H), 3.91 (t, J = 5.6 Hz, 2H), 2.87(t, J = 5.6 Hz, 2H).

[0393] Preparation of compound 36: The preparation was carried out according to the method described for compound 1, except that: (i) the reaction mixture was stirred at 120°C for 2 h and (ii) by... Preparative Purification was performed by HPLC (column: C18 150 × 30 mm; mobile phase: [water (formic acid)-acetonitrile]; gradient: 32%-62% B, duration: 7 min) to obtain 3-(4-chloro-6-(1-((5-(isochroman-7-yl)-1,3,4-oxadiazol-2-yl)amino)cyclopropyl)-1-oxoisoindoline-2-yl)piperidine-2,6-dione as a grayish-white solid (23% yield). 1 H NMR (400 MHz, DMSO- d 6 ) δ = 10.99 (s, 1H), 8.90 (s, 1H), 7.65 (d, J = 1.6 Hz, 1H), 7.61 (d, J = 1.6 Hz, 1H), 7.57 (dd, J= 1.6, 8.0 Hz, 1H),7.46 (s, 1H), 7.28 (d, J = 8.4 Hz, 1H), 5.12 (dd, J = 5.2, 13.2 Hz, 1H), 4.73 (s,2H), 4.48 - 4.40 (m, 1H), 4.32 - 4.24 (m, 1H), 3.89 (t, J = 5.6 Hz, 2H), 2.91 -2.85 (m, 1H), 2.82 (br t, J = 5.6 Hz, 2H), 2.60 (br s, 1H), 2.41 - 2.36 (m,1H), 2.02 - 1.96 (m, 1H), 1.46 - 1.40 (m, 2H), 1.39 - 1.34 (m, 2H).

[0394] Example 37. Preparation of compound 37 Preparation of 2: The preparation is carried out according to the method described for structure 3 of the scheme used to prepare intermediate 6, except that: (i) 8.50 eq Hydrazine hydrate, (ii) reacted in methanol instead of ethanol, (iii) the reaction mixture was stirred at 60 °C for 2 h, and (iv) the reaction mixture was concentrated under reduced pressure to give 4-(hydroxymethyl)benzoyl hydrazine as a yellow solid (98% yield).

[0395] Preparation of 3: Preparation was carried out according to the method described for structure 4 of the scheme used to prepare intermediate 6. A yellow solid (4-(5-amino-1,3,4-oxadiazol-2-yl)phenyl)methanol (2.00 g, 10.5 mmol, 93% yield) was obtained.

[0396] Preparation of 4: The preparation was carried out according to the method described for intermediate 3, except that: (i) 1.00 eq Copper bromide was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0 to 1 / 1) to give (4-(5-bromo-1,3,4-oxadiazol-2-yl)phenyl)methanol as a yellow solid (24% yield).

[0397] Preparation of 5: At 0°C, (326 mg, 1.28 mmol, 1.00 mg) of (4-(5-bromo-1,3,4-oxadiazol-2-yl)phenyl)methanol (326 mg, 1.28 mmol, 1.00 mmol) was reacted with methanol. eq Add (diethylamino)sulfur trifluoride (538 mg, 3.34 mmol, 441 μL, 2.61 mg) to a solution of dichloromethane (5.00 mL). eq The mixture was stirred at 25 °C for 12 h. The reaction mixture was quenched by adding water (50.0 mL) and neutralized with solid saturated sodium bicarbonate at 0 °C. The aqueous layer was extracted with dichloromethane (100 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0 to 3 / 1) to give 2-bromo-5-(4-(fluoromethyl)phenyl)-1,3,4-oxadiazole as a yellow solid (110 mg, 428 μmol, 33% yield). 1 H NMR (400 MHz, DMSO- d 6 ) δ =8.03 (d, J = 8.0 Hz, 2H), 7.63 (d, J = 7.2 Hz, 2H), 5.61 - 5.48 (d, J = 47.2 Hz, 2H).

[0398] Preparation of compound 37: The preparation was carried out according to the method described for compound 1, except that it was performed by... system Spare Purification was performed by HPLC (column: C18 150 × 30 mm; mobile phase: [water (formic acid)-acetonitrile]; gradient: 25% - 55% B, duration: 12 min) to obtain 3-(4-chloro-6-(1-((5-(4-(fluoromethyl)phenyl)-1,3,4-oxadiazol-2-yl)amino)cyclopropyl)-1-oxoisoindoline-2-yl)piperidine-2,6-dione as a grayish-white solid (16% yield). 1 H NMR (400MHz, DMSO- d 6 ) δ = 10.98 (s, 1H), 8.97 (s, 1H), 7.83 (d, J = 8.0 Hz, 2H), 7.64(dd, J = 1.2, 13.6 Hz, 2H), 7.56 (br d, J = 7.2 Hz, 2H), 5.57 - 5.41 (d, J= 47.2Hz, 2H), 5.12 (dd, J = 5.2, 13.2 Hz, 1H), 4.48 - 4.40 (m, 1H), 4.33 - 4.24 (m,1H), 2.96 - 2.84 (m, 1H), 2.60 - 2.55 (m, 1H), 2.43 - 2.38 (m, 1H), 2.02 -1.96 (m, 1H), 1.47 - 1.41 (m, 2H), 1.41 - 1.36 (m, 2H).

[0399] Example 38. Preparation of compound 38 Preparation of 2: At 0°C, cyclopropanol (1.12 g, 19.3 mmol, 1.50 mmol) was applied. eq Sodium hydride (1.03 g, 25.8 mmol, 60% purity, 2.00 mL) was added to a solution of tetrahydrofuran (10.0 mL). eq The mixture was stirred at 0°C for 0.5 h. Then methyl 6-fluoronicotinic acid (2.00 g, 12.9 mmol, 1.00 mmol) was added. eq The mixture was stirred at 20 °C for 2 h. The reaction mixture was diluted with saturated ammonium chloride (20.0 mL), extracted with ethyl acetate (2 × 100 mL), and concentrated under reduced pressure to give a residue. The residue was purified by reversed-phase chromatography (C18, 120 g, conditions: water / acetonitrile = 1 / 0 to 0 / 1, 0.1% formic acid) and lyophilized to give methyl 6-cyclopropoxynicotinic acid as a yellow solid (800 mg, 4.14 mmol, 32% yield).

[0400] Preparation of 3: The preparation was carried out according to the method described for structure 2 of the scheme used to prepare intermediate 6, except that 10.0 was used. eq Hydrazine hydrate. 6-Cyclopropoxynicotinamide hydrazide was given as a yellow solid (100% yield).

[0401] Preparation of 4: The preparation was carried out according to the method described for scheme 4 for preparing compound 25, except that the reaction mixture was filtered and concentrated under reduced pressure to give 5-(6-cyclopropoxypyridin-3-yl)-1,3,4-oxadiazole-2-amine (68% purity) as a white solid.

[0402] Preparation of 5: The preparation was carried out according to the method described for intermediate 3, except that: (i) 1.00 eq Copper bromide, (ii) reacted under a nitrogen atmosphere and (iii) purified by reversed-phase chromatography (C18, 40 g, conditions: water / acetonitrile = 1 / 0 to 0 / 1, 0.1% formic acid) to give 2-bromo-5-(6-cyclopropoxypyridin-3-yl)-1,3,4-oxadiazole as a yellow solid (25% yield). 1 H NMR (400 MHz, DMSO- d 6 ) δ = 8.80 (d, J = 2.3 Hz, 1H), 8.26 (dd, J = 2.4, 8.7 Hz, 1H), 7.08 (d, J = 8.8 Hz, 1H), 4.32 (tt, J = 3.0, 6.1Hz, 1H), 0.84 - 0.78 (m, 2H), 0.76 - 0.70 (m, 2H).

[0403] Preparation of compound 38: The preparation was carried out according to the method described for compound 1, except that: (i) 4.00 eqN , N -Diisopropylethylamine, (ii) stirring the reaction mixture at 110°C for 4 h, and (iii) by Preparative Purification was performed by HPLC (column: Phenomenex luna C18 150*25mm* 10um; mobile phase: [water (formic acid)-acetonitrile]; gradient: 23%-53% B, duration: 10 min) to obtain 3-(6-(1-((5-(6-cyclopropoxypyridin-3-yl)-1,3,4-oxadiazol-2-yl)amino)cyclopropyl)-4-methyl-1-oxoisoindololin-2-yl)piperidine-2,6-dione (24.69 mg, 47.03 μmol, 22.11% yield, 98% purity) as a white solid. 1 H NMR (400 MHz, DMSO- d 6 ) δ = 10.97 (br s,1H), 8.91 (s, 1H), 8.58 (d, J = 2.3 Hz, 1H), 8.06 (dd, J= 2.3, 8.7 Hz, 1H), 7.52(s, 1H), 7.34 (s, 1H), 7.01 (d, J = 8.8 Hz, 1H), 5.11 (dd, J = 5.0, 13.3 Hz,1H), 4.40 - 4.33 (m, 1H), 4.26 (dt, J = 3.1, 6.2 Hz, 1H), 4.24 - 4.18 (m, 1H), 2.94 - 2.87 (m, 1H), 2.61 (br s, 1H), 2.40 - 2.35 (m, 1H), 2.30 (s, 3H), 2.00- 1.95 (m, 1H), 1.34 (s, 4H), 0.81 - 0.77 (m, 2H), 0.73 - 0.68 (m, 2H).

[0404] Example 39. Preparation of compound 39 The preparation was carried out according to the method described for compound 1, except that: (i) 4.00 eqN , N -Diisopropylethylamine, (ii) stirring the reaction mixture at 110°C for 5 h, and (iii) by Preparative Purification was performed by HPLC (0.1% formic acid conditions, column: Phenomenex luna C18 150*25mm* 10um; mobile phase: [water (formic acid)-acetonitrile]; gradient: 10 min duration 29%-59% B) to obtain the crude product, which was then purified by... Preparative The crude product was purified by TLC (SiO2, petroleum ether: ethyl acetate = 0:1) to give 3-(6-(1-((5-(6-(difluoromethoxy)pyridin-3-yl)-1,3,4-oxadiazol-2-yl)amino)cyclopropyl)-4-methyl-1-oxoisoindololin-2-yl)piperidin-2,6-dione (6.96% yield) as a white solid. 1 HNMR (400 MHz, DMSO- d 6) δ = 10.97 (br s, 1H), 9.00 (s, 1H), 8.63 (d, J = 1.9 Hz, 1H), 8.25 (dd, J = 2.4, 8.7 Hz, 1H), 7.76 (t, J= 72.4 Hz, 1H), 7.52 (s, 1H), 7.34 (s, 1H), 7.27 - 7.22 (m, 1H), 5.11 (dd, J = 5.1, 13.1 Hz, 1H), 4.41 - 4.33(m, 1H), 4.25 - 4.17 (m, 1H), 2.96 - 2.85 (m, 1H), 2.59 (br dd, J = 1.8, 17.5Hz, 1H), 2.39 (br dd, J = 4.8, 13.4 Hz, 1H), 2.30 (s, 3H), 2.01 - 1.95 (m, 1H), 1.35 (s, 4H).

[0405] Example 40. Preparation of Compound 40 Preparation of 2: The preparation was carried out according to the method described for scheme 2 for preparing compound 25, except that the mixture was concentrated under reduced pressure to give tert-butyl 2-(2,4-dimethylbenzoyl)hydrazide-1-carboxylate (97% yield) as a white solid.

[0406] Preparation of 3: tert-butyl 2-(2,4-dimethylbenzoyl)hydrazide-1-carboxylate (1.70 g, 6.43 mmol, 1.00 mmol) eq Add trifluoroacetic acid (6.14 g, 53.9 mmol, 4.00 mL, 8.37 mmol) to a solution in dichloromethane (20.0 mL). eq The reaction mixture was stirred at 20 °C for 1 h. The mixture was concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 2 / 3) and concentrated under reduced pressure to give 2,4-dimethylbenzoylhydrazine (1.17 g, 4.21 mmol, 65% yield, trifluoroacetate) as a yellow solid.

[0407] Preparation of 4: The preparation was carried out according to the method described for structure 4 of the scheme used to prepare compound 25. A white solid, 5-(2,4-dimethylphenyl)-1,3,4-oxadiazole-2-amine, was obtained.

[0408] Preparation of 5: The preparation was carried out according to the method described for intermediate 3, except that: (i) 1.00 eqCopper bromide was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 20 / 1) to give 2-bromo-5-(2,4-dimethylphenyl)-1,3,4-oxadiazole as a yellow solid (78% yield). 1 H NMR (400 MHz, DMSO- d 6) δ = 7.75 (d, J = 7.9 Hz, 1H), 7.27 (s, 1H), 7.22 (d, J = 8.0 Hz, 1H), 2.56 (s, 3H), 2.35 (s, 3H).

[0409] Preparation of compound 40: The preparation was carried out according to the method described for compound 1, except that: (i) 3.00 eqN , N -Diisopropylethylamine, (ii) the reaction mixture was stirred at 130 °C for 1 h, and (iii) the residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 1 to 1 / 4) and concentrated under reduced pressure to give a solid, which was then ground with petroleum ether / ethyl acetate = 20 / 1 (20.0 mL) and petroleum ether (20.0 mL) to give 3-(4-chloro-6-(1-((5-(2,4-dimethylphenyl)-1,3,4-oxadiazol-2-yl)amino)cyclopropyl)-1-oxoisoindololin-2-yl)piperidine-2,6-dione (35.93% yield) as a white solid. 1 H NMR (400 MHz, DMSO- d 6) δ = 10.98 (s, 1H), 8.86 (s, 1H), 7.66 (s, 1H), 7.61 (d, J = 1.3 Hz, 1H), 7.57 (d, J = 7.9 Hz, 1H),7.17 (s, 1H), 7.14 (br d, J = 8.1 Hz, 1H), 5.12 (dd, J = 5.1, 13.3 Hz, 1H), 4.48- 4.40 (m, 1H), 4.32 - 4.24 (m, 1H), 2.95 - 2.85 (m, 1H), 2.58 (br dd, J= 2.0,15.4 Hz, 1H), 2.48 (s, 3H), 2.46 - 2.39 (m, 1H), 2.31 (s, 3H), 2.03 - 1.95(m, 1H), 1.46 - 1.40 (m, 2H), 1.39 - 1.34 (m, 2H).

[0410] Example 41. Preparation of compound 41 Preparation of 2: Preparation was carried out according to the method described for structure 2 of the scheme used to prepare intermediate 6. A yellow, oily methyl 5-carboxylate was obtained (99% yield).

[0411] Preparation of 3: The preparation is carried out according to the method described for structure 3 of the scheme used to prepare intermediate 6, except that: (i) 35.0 eq (ii) The mixture was concentrated under reduced pressure to obtain isochromic 5-carbonyl hydrazine as a white solid.

[0412] Preparation of 4: Preparation is carried out according to the method described for structure 4 of the scheme used to prepare intermediate 6, the difference being that... Preparative Purification was performed by HPLC (column: Phenomenex luna C18 150 * 25 mm * 10 μm; mobile phase: [water (formic acid)-acetonitrile]; gradient: 18%-48% B, duration: 9 min) to obtain 5-(isochroman-5-yl)-1,3,4-oxadiazol-2-amine as a white solid (37% yield).

[0413] Preparation of 5: The preparation was carried out according to the method described for intermediate 3, except that purification was performed by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 1 to 0 / 1) to give 2-bromo-5-(isochroman-5-yl)-1,3,4-oxadiazole as a white solid (62% yield). 1 H NMR (400 MHz, DMSO- d 6) δ = 7.77 (d, J = 7.6 Hz, 1H), 7.43- 7.38 (m, 1H), 7.35 - 7.30 (m, 1H), 4.77 (s, 2H), 3.92 (t, J = 5.6 Hz, 2H), 3.09 (t, J = 5.6 Hz, 2H).

[0414] Preparation of compound 41: The preparation was carried out according to the method described for compound 1, except that: (i) 3.00 eqN,N -Diisopropylethylamine, (ii) stirring the reaction mixture at 120°C for 2 h, and (iii) by Preparative Purification was performed by HPLC (column: YMC-Actus Triart C18 150 * 30 mm * 7 μm; mobile phase: [water (formic acid)-acetonitrile]; gradient: 33%-63% B, duration: 10 min) to obtain 3-(4-chloro-6-(1-((5-(isochroman-5-yl)-1,3,4-oxadiazol-2-yl)amino)cyclopropyl)-1-oxoisoindololin-2-yl)piperidine-2,6-dione (36% yield) as a grayish-white solid. 1 H NMR (400 MHz, DMSO- d 6) δ = 10.99 (br s, 1H), 8.94 (s, 1H), 7.66 (s, 1H),7.62 (s, 1H), 7.59 (d, J = 7.6 Hz, 1H), 7.32 (t, J = 7.6 Hz, 1H), 7.18 (d, J = 7.6Hz, 1H), 5.16 - 5.08 (m, 1H), 4.73 (s, 2H), 4.48 - 4.38 (m, 1H), 4.33 - 4.23(m, 1H), 3.87 (t, J = 5.6 Hz, 2H), 2.99 (br t, J = 5.6 Hz, 2H), 2.93 - 2.83 (m,1H), 2.63 - 2.55 (m, 1H), 2.46 (br s, 1H), 2.03 - 1.94 (m, 1H), 1.47 - 1.41(m, 2H), 1.40 - 1.34 (m, 2H).

[0415] Example 42. Preparation of compound 42 Preparation of 2: Preparation was carried out according to the method described for structure 2 of the scheme used to prepare intermediate 6. A discolored methyl 6-carboxylate (98% yield) was obtained as a grayish-white solid.

[0416] Preparation of 3:Preparation is carried out according to the method described for structure 3 of the scheme used to prepare intermediate 6, except that 34.0 is used. eq Hydrazine hydrate. A white solid, heterochromatic 6-carbonyl hydrazine (99% purity) was obtained.

[0417] Preparation of 4: The preparation was carried out according to the method described for structure 4 of the scheme for preparing intermediate 6, except that the mixture was concentrated under reduced pressure to obtain a crude product, which was then ground with ethyl acetate to give 5-(isochroman-6-yl)-1,3,4-oxadiazol-2-amine (92% yield) as a grayish-white solid.

[0418] Preparation of 5: The preparation was carried out according to the method described for intermediate 3, except that it was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 1 to 0 / 1) to give 2-bromo-5-(isochroman-6-yl)-1,3,4-oxadiazole as a white solid (20% yield). 1 H NMR (400 MHz, DMSO- d 6) δ = 7.81 - 7.73 (m, 2H), 7.27(d, J = 8.4 Hz, 1H), 4.76 (s, 2H), 3.94 - 3.89 (m, 2H), 2.89 (t, J = 5.6 Hz, 2H) Preparation of compound 42: The preparation was carried out according to the method described for compound 1, except that: (i) 4.00 eqN,N -Diisopropylethylamine, (ii) stirring the reaction mixture at 120°C for 4 h, and (iii) by Preparative Purification was performed by HPLC (column: YMC-Actus Triart C18 150 * 30 mm * 7 μm; mobile phase: [water (formic acid)-acetonitrile]; gradient: 33%-63% B, duration: 10 min) to give 3-(4-chloro-6-(1-((5-(isochroman-6-yl)-1,3,4-oxadiazol-2-yl)amino)cyclopropyl)-1-oxoisoindoline-2-yl)piperidine-2,6-dione (28% yield). 1 H NMR (400MHz, DMSO- d 6) δ = 10.99 (s, 1H), 8.90 (s, 1H), 7.63 (d, J= 14.0 Hz, 2H), 7.60 -7.52 (m, 2H), 7.18 (d, J = 7.6 Hz, 1H), 5.15 - 5.08 (m, 1H), 4.71 (s, 2H), 4.48- 4.40 (m, 1H), 4.35 - 4.20 (m, 1H), 3.89 (t, J = 5.6 Hz, 2H), 2.96 - 2.87 (m,1H), 2.84 (br t, J = 5.6 Hz, 2H), 2.61 - 2.55 (m, 1H), 2.44 (br d, J = 13.6 Hz,1H), 2.04 - 1.93 (m, 1H), 1.47 - 1.40 (m, 2H), 1.38 (br d, J = 4.4 Hz, 2H).

[0419] Example 43. Preparation of compound 43 Preparation of 2: At 0°C, 2-bromo-5-methylbenzoic acid (10.0 g, 46.5 mmol, 1.00 μL) was reacted with 2-bromo-5-methylbenzoic acid (10.0 g, 46.5 mmol, 1.00 μL) eq Add borane-dimethyl sulfide complex (10.0 M, 9.30 mL, 2.00 mL) to a solution of tetrahydrofuran (100 mL). eq The mixture was stirred at 25 °C under a nitrogen atmosphere for 12 h. The reaction mixture was quenched at 0 °C with methanol (100 mL) and then with hydrochloric acid (6 M, 20 mL). The mixture was concentrated under reduced pressure to give (2-bromo-5-methylphenyl)methanol (9.30 g, 46.2 mmol, 99% yield) as a yellow solid.

[0420] Preparation of 3: At 0°C, (2-bromo-5-methylphenyl)methanol (9.30 g, 46.2 mmol, 1.00 mmol) was reacted with methanol (9.30 g, 46.2 mmol, 1.00 mmol). eq Sodium hydride (2.78 g, 69.3 mmol, 60% purity, 1.50 mL) was added to a solution of dimethylformamide (10.0 mL). eq ) and iodomethane (13.1 g, 92.5 mmol, 5.76 mL, 2.00) eqThe mixture was stirred at 25 °C for 2 h. The mixture was quenched with saturated ammonium chloride (30.0 mL) and extracted with ethyl acetate (3 × 50.0 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 1-bromo-2-(methoxymethyl)-4-methylbenzene (9.90 g, 46.0 mmol, 99% yield) as a yellow oil.

[0421] Preparation of 4: Potassium 2-ethoxy-2-oxoacetate (545 mg, 3.49 mmol, 1.50 mg) eq ), 3-(6-(1-((5-(2-(methoxymethyl)-4-methylphenyl)-1,3,4-oxadiazol-2-yl)amino)cyclopropyl)-4-methyl-1-oxoisoindoline-2-yl)piperidine-2,6-dione (28.7 mg, 69.7 μmol, 0.0300) eq ) and bis[(2,2,2-trifluoroacetyl)oxy]palladium (7.73 mg, 23.2 μmol, 0.0100 eq ) and 1-bromo-2-(methoxymethyl)-4-methylbenzene (500 mg, 2.32 mmol, 1.00 eq )At N The mixture in 2-methylpyrrolidone (5.00 mL) was degassed and purged three times under a nitrogen atmosphere. The mixture was stirred at 150 °C under a nitrogen atmosphere for 12 h. The mixture was diluted with water (10.0 mL) and extracted with ethyl acetate (3 × 20.0 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 50 / 1 to 1 / 1) and concentrated under reduced pressure to give ethyl 2-(methoxymethyl)-4-methylbenzoate as a white solid (220 mg, 1.06 mmol, 45% yield).

[0422] Preparation of 5: Preparation was carried out according to the method described for structure 3 of the scheme used to prepare intermediate 6, except that 20.0 g / L was used. eq Hydrazine hydrate. 2-(methoxymethyl)-4-methylbenzoyl hydrazine was given as a white solid (97% yield).

[0423] Preparation of 6: The preparation was carried out according to the method described for structure 4 of the scheme used to prepare compound 25. 5-(2-(methoxymethyl)-4-methylphenyl)-1,3,4-oxadiazole-2-amine was obtained as a white solid.

[0424] Preparation of 7:The preparation was carried out according to the method described for intermediate 3, except that: (i) 1.10 eq Copper bromide was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 1 to 50 / 1) to give 2-bromo-5-(2-(methoxymethyl)-4-methylphenyl)-1,3,4-oxadiazole as a white solid (31% yield). 1 H NMR (400 MHz, DMSO-) d 6 ) δ = 7.80 (br d, J = 7.9 Hz, 1H), 7.50 (br s, 1H), 7.33 (br d, J = 7.8 Hz, 1H), 4.74 (s, 2H), 3.36 (s, 3H), 2.41 (s, 3H).

[0425] Preparation of compound 43: The preparation was carried out according to the method described for compound 1, except that: (i) 5.00 eqN , N (ii) The reaction mixture was stirred at 130 °C for 1 h and (iii) purified by reversed-phase chromatography (C18, 80 g; conditions: water / acetonitrile = 100:0 to 0:100, 0.1% formic acid) to give 3-(6-(1-((5-(2-(methoxymethyl)-4-methylphenyl)-1,3,4-oxadiazol-2-yl)amino)cyclopropyl)-4-methyl-1-oxoisoindololin-2-yl)piperidine-2,6-dione (30.53 mg, 56.26 μmol, 49.20% yield, 95% purity) as a grayish-white solid. 1 H NMR (400 MHz, DMSO- d 6 ) δ = 10.96 (s, 1H), 8.86 (s, 1H), 7.60 (d, J = 8.0 Hz,1H), 7.52 (s, 1H), 7.42 (s, 1H), 7.35 (s, 1H), 7.23 (d, J = 7.5 Hz, 1H), 5.11(dd, J= 5.0, 13.3 Hz, 1H), 4.67 (s, 2H), 4.40 - 4.32 (m, 1H), 4.26 - 4.16 (m,1H), 3.33 (s, 3H), 2.96 - 2.85 (m, 1H), 2.61 - 2.56 (m, 1H), 2.44 - 2.38 (m,1H), 2.36 (s, 3H), 2.30 (s, 3H), 2.02 - 1.93 (m, 1H), 1.34 (s, 4H).

[0426] Example 44. Preparation of compound 44 Preparation of 2: The preparation was carried out according to the method described for structure 3 of the scheme used to prepare intermediate 6, except that: (i) 15.0 eq (ii) The mixture was concentrated under reduced pressure to give 2-fluoro-4-methylbenzoyl hydrazine as a grayish-white solid.

[0427] Preparation of 3: Preparation was carried out according to the method described for structure 4 of the scheme used to prepare intermediate 6. 5-(2-fluoro-4-methylphenyl)-1,3,4-oxadiazole-2-amine (310 mg, crude product) was obtained as a yellow solid.

[0428] Preparation of 4: The preparation was carried out according to the method described for intermediate 3, except that purification was performed by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 1 to 0 / 1) to give 2-bromo-5-(2-fluoro-4-methylphenyl)-1,3,4-oxadiazole as a white solid (65% yield). 1 H NMR (400 MHz, DMSO- d 6) δ = 7.88 (t, J = 7.6 Hz, 1H), 7.34 (d, J = 12.0 Hz, 1H), 7.26 (d, J = 8.0 Hz, 1H), 2.41 (s, 3H).

[0429] Preparation of compound 44: The preparation was carried out according to the method described for compound 1, except that: (i) 4.00 eqN,N -Diisopropylethylamine, (ii) stirring the reaction mixture at 120°C for 2 h, and (iii) by PreparativePurification was performed by HPLC (column: YMC-Actus Triart C18 150 * 30 mm * 7 μm; mobile phase: [water (formic acid)-acetonitrile]; gradient: 35%-65% B, duration: 10 min) and lyophilized to obtain 3-(4-chloro-6-(1-((5-(2-fluoro-4-methylphenyl)-1,3,4-oxadiazol-2-yl)amino)cyclopropyl)-1-oxoisoindoline-2-yl)piperidine-2,6-dione as a grayish-white solid (38% yield). 1 H NMR (400 MHz, DMSO- d 6) δ = 11.00 (s, 1H), 8.97 (s, 1H), 7.70 (t, J =7.6 Hz, 1H), 7.64 (d, J = 1.2 Hz, 1H), 7.61 (d, J = 1.6 Hz, 1H), 7.24 (d, J = 12.0Hz, 1H), 7.17 (d, J = 8.0 Hz, 1H), 5.16 - 5.07 (m, 1H), 4.51 - 4.39 (m, 1H), 4.35 - 4.22 (m, 1H), 2.96 - 2.84 (m, 1H), 2.62 - 2.54 (m, 1H), 2.47 - 2.40(m, 1H), 2.37 (s, 3H), 2.04 - 1.94 (m, 1H), 1.46 - 1.40 (m, 2H), 1.38 (br d, J = 3.6 Hz, 2H).

[0430] Example 45. Preparation of compound 45 Preparation of 2: To 5-methylisobenzofuran-1(3 H )-Keto (1.00 g, 6.75 mmol, 1.00 eq Add thionyl chloride (8.03 g, 67.5 mmol, 4.90 mL, 10.0 mL) to a solution in methanol (10.0 mL). eqThe mixture was stirred at 80 °C for 12 hours. The reaction mixture was concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0 to 10 / 1) to give methyl 2-(chloromethyl)-4-methylbenzoate (440 mg, 2.21 mmol, 33% yield) as a white oil.

[0431] Preparation of 3: Methyl 2-(chloromethyl)-4-methylbenzoate (540 mg, 2.72 mmol, 1.00 mg) eq Sodium methoxide (294 mg, 5.44 mmol, 2.00 mmol) was added to a methanol (6.00 mL) solution. eq The mixture was stirred at 40 °C for 12 hours. The reaction mixture was concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0 to 10 / 1) to give methyl 2-(methoxymethyl)-4-methylbenzoate (180 mg, 927 μmol, 34% yield) as a colorless oil.

[0432] Preparation of 4: The preparation was carried out according to the method described for structure 3 of the scheme used to prepare intermediate 6, except that: (i) 20.0 eq (ii) The reaction mixture was stirred at 60°C for 2 hours, and (iii) the reaction mixture was concentrated under reduced pressure to obtain a residue, yielding 2-(methoxymethyl)-4-methylbenzoyl hydrazine (91% purity) as a white solid.

[0433] Preparation of 5: The preparation was carried out according to the method described for structure 4 of the scheme for preparing intermediate 6, except that: (i) the reaction mixture was stirred at 80°C for 12 hours and (ii) the crude product was ground with ethyl acetate at 25°C for 30 min to obtain 5-(2-(methoxymethyl)-4-methylphenyl)-1,3,4-oxadiazole-2-amine (92% purity) as a grayish-white solid.

[0434] Preparation of 6: The preparation was carried out according to the method described for intermediate 3, except that purification was performed by preparative TLC (SiO2, petroleum ether:ethyl acetate = 5:1) to give 2-bromo-5-(2-(methoxymethyl)-4-methylphenyl)-1,3,4-oxadiazole as a white solid (40% yield). MS (ESI) m / z 250.9 [M+H] + Preparation of compound 45:The preparation was carried out according to the method described for compound 1, except that: (i) the reaction mixture was stirred at 120 °C for 2 hours and (ii) purified by preparative HPLC (formic acid conditions; column: YMC-ActusTriart C18 150*30mm*7um; mobile phase: [water (formic acid)-acetonitrile]; gradient: 40%-70% B, duration: 10 min) to give 3-(4-chloro-6-(1-((5-(2-(methoxymethyl)-4-methylphenyl)-1,3,4-oxadiazol-2-yl)amino)cyclopropyl)-1-oxoisoindoline-2-yl)piperidine-2,6-dione (28% yield) as a yellow solid. 1 H NMR (400MHz, DMSO- d 6 ) δ = 10.99 (s, 1H), 8.92 (s, 1H), 7.65 (d, J = 1.0 Hz, 1H), 7.64 -7.59 (m, 2H), 7.42 (s, 1H), 7.24 (d, J = 8.2 Hz, 1H), 5.12 (dd, J = 5.2, 13.2 Hz,1H), 4.68 (s, 2H), 4.49 - 4.39 (m, 1H), 4.33 - 4.23 (m, 1H), 3.34 - 3.33 (m,3H), 2.97 - 2.83 (m, 1H), 2.58 (br d, J = 17.8 Hz, 1H), 2.44 (br dd, J = 4.4,13.3 Hz, 1H), 2.36 (s, 3H), 2.05 - 1.93 (m, 1H), 1.48 - 1.41 (m, 2H), 1.41 -1.33 (m, 2H) Example 46. Preparation of compound 46 Preparation of 2: The preparation was carried out according to the method described for structure 2 of the scheme used to prepare compound 25, except that purification was performed by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0 to 3 / 1) to give tert-butyl 2-(2-methoxy-4-methylbenzoyl)hydrazide-1-carboxylate as a white solid (98% yield).

[0435] Preparation of 3:2-(2-methoxy-4-methylbenzoyl)hydrazide-1-carboxylic acid Uncle Butyl ester (3.31 g, 11.8 mmol, 1.00 mmol) eq Add trifluoroacetic acid (7.68 g, 67.3 mmol, 5.00 mL, 5.70 mL) to a solution of dichloromethane (20.0 mL). eq The mixture was stirred at 20 °C for 4 h. The mixture was concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 1 to 0 / 1) to give 2-methoxy-4-methylbenzoylhydrazine (1.90 g, 6.46 mmol, 54% yield, trifluoroacetate) as a white solid.

[0436] Preparation of 4: The preparation was carried out according to the method described for scheme 4 for preparing compound 25, except that the mixture was concentrated under reduced pressure to give 5-(2-methoxy-4-methylphenyl)-1,3,4-oxadiazole-2-amine (90% yield) as a white solid.

[0437] Preparation of 5: The preparation was carried out according to the method described for intermediate 3, except that: (i) 1.00 eq Copper bromide was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0 to 5 / 1) to give 2-bromo-5-(2-methoxy-4-methylphenyl)-1,3,4-oxadiazole as a brown solid (10% yield). 1 H NMR (400MHz, DMSO- d 6 ) δ = 7.70 (br d, J = 7.9 Hz, 1H), 7.11 (s, 1H), 6.95 (br d, J = 7.8Hz, 1H), 3.89 (s, 3H), 2.40 (s, 3H).

[0438] Preparation of compound 46: The preparation was carried out according to the method described for compound 1, except that: (i) 3.00 eqN , N-Diisopropylethylamine, (ii) the reaction mixture was stirred at 110 °C for 2 h, and (iii) purified by reversed-phase chromatography (C18, 40 g; conditions: water / acetonitrile = 100:0 to 0:100, 0.1% formic acid) to give 3-(4-chloro-6-(1-((5-(2-methoxy-4-methylphenyl)-1,3,4-oxadiazol-2-yl)amino)cyclopropyl)-1-oxoisoindololin-2-yl)piperidine-2,6-dione (21.24% yield) as a grayish-white solid. 1 H NMR (400 MHz, DMSO- d 6 ) δ = 10.99(br s, 1H), 8.80 (s, 1H), 7.65 (s, 1H), 7.60 (s, 1H), 7.52 (br d, J = 7.9 Hz,1H), 7.01 (s, 1H), 6.86 (br d, J = 8.0 Hz, 1H), 5.12 (br d, J = 9.4 Hz, 1H), 4.45(br d, J = 17.5 Hz, 1H), 4.32 - 4.25 (m, 1H), 3.81 (s, 3H), 2.95 - 2.86 (m,1H), 2.59 (br d, J = 4.5 Hz, 1H), 2.44 - 2.38 (m, 1H), 2.36 (s, 3H), 2.00 (brd, J = 6.9 Hz, 1H), 1.40 (br s, 2H), 1.34 (br s, 2H).

[0439] Example 47. Preparation of compound 47 Preparation of 2: The preparation was carried out according to the method described for structure 2 of the scheme used to prepare compound 25, except that purification was performed by column chromatography (SiO2, petroleum ether / ethyl acetate = 10 / 1 to 1 / 1) to give tert-butyl 2-(4-methoxy-2-methylbenzoyl)hydrazide-1-carboxylate as a white solid (96% yield).

[0440] Preparation of 3: tert-butyl 2-(4-methoxy-2-methylbenzoyl)hydrazide-1-carboxylate (1.85 g, 6.60 mmol, 1.00 mmol) eqAdd trifluoroacetic acid (3.07 g, 26.9 mmol, 2.00 mL, 4.08 mmol) to a solution of dichloromethane (10.0 mL). eq The mixture was stirred at 25 °C for 1 h. The mixture was concentrated under reduced pressure to give 4-methoxy-2-methylbenzoylhydrazine (1.15 g, 6.38 mmol, 96% yield) as a white solid.

[0441] Preparation of 4: The preparation was carried out according to the method described for structure 4 of the scheme used to prepare compound 25, except that the mixture was concentrated under reduced pressure to obtain 5-(4-methoxy-2-methylphenyl)-1,3,4-oxadiazole-2-amine as a colorless oil.

[0442] Preparation of 5: The preparation was carried out according to the method described for intermediate 3, except that: (i) 2.00 eq Copper bromide was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 10 / 1 to 3 / 1) to give 2-bromo-5-(4-methoxy-2-methylphenyl)-1,3,4-oxadiazole (97% purity) as an orange solid. 1 H NMR (400MHz, DMSO- d 6) δ = 7.81 (d, J = 8.8 Hz, 1H), 7.03 (d, J = 2.4 Hz, 1H), 7.00 - 6.96 (m, 1H), 3.84 (s, 3H), 2.58 (s, 3H).

[0443] Preparation of compound 47: The preparation was carried out according to the method described for compound 1, except that: (i) 3.00 eqN , N -Diisopropylethylamine, (ii) stirring the reaction mixture at 100°C for 3 h, and (iii) by Preparative Purification was performed by HPLC (column: Phenomenex luna C18 150*25mm* 10um; mobile phase: [water (formic acid)-acetonitrile]; gradient: 32%-52% B, duration: 10 min) to obtain 3-(4-chloro-6-(1-((5-(4-methoxy-2-methylphenyl)-1,3,4-oxadiazol-2-yl)amino)cyclopropyl)-1-oxoisoindololin-2-yl)piperidine-2,6-dione (45.46% yield) as a grayish-white solid. 1 H NMR (400 MHz, DMSO-d 6) δ = 10.99 (br s, 1H), 8.83 (s, 1H), 7.68 - 7.56(m, 3H), 6.95 - 6.85 (m, 2H), 5.17 - 5.07 (m, 1H), 4.49 - 4.40 (m, 1H), 4.33- 4.23 (m, 1H), 3.79 (s, 3H), 2.96 - 2.84 (m, 1H), 2.58 (br d, J = 18.3 Hz,1H), 2.51 - 2.51 (m, 3H), 2.46 - 2.42 (m, 1H), 2.03 - 1.95 (m, 1H), 1.45 -1.35 (m, 4H).

[0444] Example 48. Preparation of compound 48 Preparation of 2: The preparation was carried out according to the method described for structure 2 of the scheme used to prepare compound 25, except that purification was performed by column chromatography (SiO2, petroleum ether / ethyl acetate = 6 / 1 to 3 / 1) to give tert-butyl 2-(4-fluoro-2-methoxybenzoyl)hydrazide-1-carboxylate as a yellow solid (88.9% yield).

[0445] Preparation of 3: 2-(4-fluoro-2-methoxybenzoyl)hydrazine-1-carboxylic acid Uncle Butyl ester (1.40 g, 4.92 mmol, 1.00 mmol) eq Add trifluoroacetic acid (4.61 g, 40.4 mmol, 3.00 mL, 8.20 mL) to a solution of dichloromethane (15.0 mL). eq The two batches of the mixture were stirred at 20°C for 1 h. The reaction mixture was concentrated under reduced pressure to give 4-fluoro-2-methoxybenzoylhydrazine (900 mg, 4.89 mmol, 99.2% yield) as a yellow oil.

[0446] Preparation of 4: The preparation was carried out according to the method described for structure 4 of the scheme for preparing compound 25, except that the reaction mixture was concentrated under reduced pressure to give 5-(4-fluoro-2-methoxyphenyl)-1,3,4-oxadiazole-2-amine (97.8% yield) as a yellow solid.

[0447] Preparation of 5:The preparation was carried out according to the method described for intermediate 3, except that: (i) 1.10 eq Copper bromide was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 8 / 1 to 6 / 1) to give 2-bromo-5-(4-fluoro-2-methoxyphenyl)-1,3,4-oxadiazole as a white solid (7.66% yield). 1 H NMR (400MHz, DMSO- d 6 ) δ = 7.88 (br t, J = 7.6 Hz, 1H), 7.22 (br d, J = 11.4 Hz, 1H), 6.99(br t, J = 8.4 Hz, 1H), 3.92 (s, 3H).

[0448] Preparation of compound 48: The preparation was carried out according to the method described for compound 1, except that: (i) the reaction mixture was stirred at 100°C for 2 h and (ii) by... Preparative Purification was performed by HPLC (column: Phenomenex luna C18 150*25mm* 10um; mobile phase: [water (formic acid)-acetonitrile]; gradient: 22%-52% B, duration: 10 min) to obtain 3-(4-chloro-6-(1-((5-(4-fluoro-2-methoxyphenyl)-1,3,4-oxadiazol-2-yl)amino)cyclopropyl)-1-oxoisoindololin-2-yl)piperidine-2,6-dione as a grayish-white solid (47.6% yield). 1 H NMR (400 MHz, DMSO- d 6 ) δ =11.08 - 10.90 (m, 1H), 8.85 (s, 1H), 7.69 (d, J = 8.6 Hz, 1H), 7.65 (s, 1H), 7.60 (s, 1H), 7.12 (dd, J = 2.1, 11.3 Hz, 1H), 6.90 (dt, J = 2.1, 8.5 Hz, 1H), 5.12 (dd, J= 4.9, 13.4 Hz, 1H), 4.49 - 4.41 (m, 1H), 4.32 - 4.24 (m, 1H), 3.84(s, 3H), 2.95 - 2.85 (m, 1H), 2.60 (br s, 1H), 2.40 (br d, J = 3.3 Hz, 1H), 2.03 - 1.95 (m, 1H), 1.43 - 1.38 (m, 2H), 1.37 - 1.32 (m, 2H).

[0449] Example 49. Preparation of compound 49 Preparation of 2: The preparation was carried out according to the method described for structure 2 of the scheme used to prepare compound 25, except that purification was performed by column chromatography (SiO2, petroleum ether / ethyl acetate = 10 / 1 to 1 / 1) to give tert-butyl 2-(2-fluoro-4-methoxybenzoyl)hydrazide-1-carboxylate as a white solid (90% yield).

[0450] Preparation of 3: At 25°C, 2-(2-fluoro-4-methoxybenzoyl)hydrazide-1-carboxylic acid Uncle Butyl ester (3.00 g, 10.6 mmol, 1.00 mmol) eq Add trifluoroacetic acid (9.21 g, 80.8 mmol, 6.00 mL, 7.65 mmol) to a solution in dichloromethane (30.0 mL). eq The mixture was stirred at 25 °C for 1 h. The reaction mixture was concentrated under reduced pressure to obtain a residue. The residue was diluted with water (20 mL) and lyophilized to give 2-fluoro-4-methoxybenzoylhydrazine (3.10 g, 10.4 mol, 98% yield, trifluoroacetate) as a white solid.

[0451] Preparation of 4: The preparation was carried out according to the method described for structure 4 of the scheme for preparing compound 25, except that the residue was ground with acetonitrile and the precipitate was dried under reduced pressure to give 5-(2-fluoro-4-methoxyphenyl)-1,3,4-oxadiazole-2-amine (78% yield) as a white solid.

[0452] Preparation of 5: The preparation was carried out according to the method described for intermediate 3, except that: (i) 1.00 eqCopper bromide was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1:0 to 5:1) to give 2-bromo-5-(2-fluoro-4-methoxyphenyl)-1,3,4-oxadiazole as a yellow solid (40% yield). 1 H NMR (400 MHz, DMSO- d 6 ) δ = 7.91 (t, J = 8.8 Hz, 1H), 7.12 (dd, J = 2.4, 12.8 Hz, 1H), 7.01 (dd, J =2.4, 8.8 Hz, 1H), 3.87 (s, 3H).

[0453] Preparation of compound 49: The preparation was carried out according to the method described for compound 1, except that: (i) 4.00 eqN , N -Diisopropylethylamine, (ii) stirring the reaction mixture at 100°C for 1 h, and (iii) by Preparative Purification was performed by HPLC (column: Phenomenex luna C18 150 × 25 mm × 10 μm; mobile phase: [water (formic acid)-acetonitrile]; gradient: 24%-54% B, duration: 11 min) to obtain 3-(4-chloro-6-(1-((5-(2-fluoro-4-methoxyphenyl)-1,3,4-oxadiazol-2-yl)amino)cyclopropyl)-1-oxoisoindoline-2-yl)piperidine-2,6-dione as a yellow solid (19% yield). 1 H NMR (400 MHz, DMSO- d 6 ) δ = 10.99 (br s, 1H), 8.91 (s, 1H), 7.72 (t, J = 8.8 Hz, 1H), 7.64 (d, J = 0.8 Hz, 1H), 7.60 (d, J = 0.8 Hz, 1H), 7.03 (dd, J =2.4, 12.8 Hz, 1H), 6.93 (dd, J = 2.4, 8.8 Hz, 1H), 5.12 (dd, J= 4.8, 13.2 Hz,1H), 4.49 - 4.38 (m, 1H), 4.33 - 4.23 (m, 1H), 3.83 (s, 3H), 2.97 - 2.83 (m,1H), 2.60 - 2.56 (m, 1H), 2.45 - 2.42 (m, 1H), 2.04 - 1.94 (m, 1H), 1.45 -1.39 (m, 2H), 1.39 - 1.33 (m, 2H).

[0454] Example 50. Preparation of Compound 50 Preparation of 2: Preparation was carried out according to the method described for structure 2 of the scheme used to prepare intermediate 6. A yellow solid of isochromic methyl 8-carboxylate was obtained (99% yield).

[0455] Preparation of 3: The preparation was carried out according to the method described for structure 3 of the scheme used to prepare intermediate 6, except that: (i) 15.0 eq Hydrazine hydrate, (ii) reacted in methanol instead of ethanol, (iii) the reaction mixture was stirred at 60 °C for 2 h, and (iv) the reaction mixture was concentrated under reduced pressure to give isochromic 8-carbonyl hydrazine as a brown solid (96% yield).

[0456] Preparation of 4: The preparation was carried out according to the method described for structure 4 of the scheme for preparing intermediate 6, except that the mixture was quenched with water and extracted with a mixture of dichloromethane:isopropanol = 3:1, dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain a crude product, which was then ground with ethyl acetate at 25°C for 0.5 h to give 5-(isochroman-8-yl)-1,3,4-oxadiazol-2-amine as a gray solid (51% yield).

[0457] Preparation of 5: The preparation was carried out according to the method described for intermediate 3, except that it was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0 to 3 / 1) to give 2-bromo-5-(isochroman-8-yl)-1,3,4-oxadiazole as a yellow solid (30% yield). 1 H NMR (400 MHz, DMSO- d 6 ) δ = 7.81 - 7.69 (m, 2H), 7.32 -7.23 (m, 1H), 4.76 (s, 2H), 3.91 (t,J = 5.6 Hz, 2H), 2.89 (t, J = 5.6 Hz, 2H).

[0458] Preparation of compound 50: The preparation was carried out according to the method described for compound 1, except that: (i) 4.00 eqN,N -Diisopropylethylamine, (ii) stirring the reaction mixture at 120°C for 2 h, and (iii) by Preparative Purification was performed by HPLC (column: C18 150×30 mm; mobile phase: [water (formic acid)-acetonitrile]; gradient: 32%-62% B, duration: 7 min) to obtain 3-(4-chloro-6-(1-((5-(isochroman-8-yl)-1,3,4-oxadiazol-2-yl)amino)cyclopropyl)-1-oxoisoindololin-2-yl)piperidine-2,6-dione as a grayish-white solid (23% yield). 1 H NMR (400 MHz, DMSO- d 6 ) δ =10.99 (s, 1H), 8.89 (s, 1H), 7.65 (d, J = 1.2 Hz, 1H), 7.61 (d, J = 1.2 Hz, 1H),7.59 - 7.54 (m, 2H), 7.18 (d, J = 8.0 Hz, 1H), 5.12 (dd, J = 4.8, 13.2 Hz, 1H), 4.71 (s, 2H), 4.48 - 4.41 (m, 1H), 4.33 - 4.25 (m, 1H), 3.89 (t, J = 5.6 Hz,2H), 2.95 - 2.88 (m, 1H), 2.87 - 2.83 (m, 2H), 2.60 (br d, J = 1.2 Hz, 1H), 2.45 - 2.40 (m, 1H), 2.06 - 1.92 (m, 1H), 1.46 - 1.41 (m, 2H), 1.40 - 1.35 (m, 2H).

[0459] Example 51. Preparation of compound 51 Preparation of 2:Methyl 5-fluoro-3-methylpyridinecarboxylate (3.90 g, 23.5 mmol, 1.00 g) eq )At N,N Add cyclopropanol (2.68 g, 46.1 mmol, 2.00 mL) to a solution of dimethylformamide (40.0 mL). eq ) and cesium carbonate (22.5g, 69.2 mmol, 3.00) eq The mixture was stirred at 80 °C for 12 h. The reaction mixture was quenched by adding water (100 mL) and extracted with ethyl acetate (2 × 50 mL). The combined organic layers were washed with brine (2 × 50 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0 to 3 / 1) to give methyl 5-cyclopropoxy-3-methylpyridinecarboxylate (1.06 g, 5.12 mmol, 22% yield) as a yellow oil.

[0460] Preparation of 3: The preparation was carried out according to the method described for structure 3 of the scheme used to prepare intermediate 6, except that: (i) 10.0 eq Hydrazine hydrate, (ii) reacted in methanol instead of ethanol, (iii) the reaction mixture was stirred at 60 °C for 2 h, and (iv) the reaction mixture was concentrated under reduced pressure to give 5-cyclopropoxy-3-methylpyridinecarboxyhydrazide as a yellow solid (98% yield).

[0461] Preparation of 4: The preparation was carried out according to the method described for structure 4 of the scheme used to prepare intermediate 6, except that purification was performed by column chromatography (SiO2, dichloromethane:methanol = 1 / 0 to 10 / 1) to give 5-(5-cyclopropoxy-3-methylpyridin-2-yl)-1,3,4-oxadiazol-2-amine as a yellow solid (89% yield).

[0462] Preparation of 5: The preparation was carried out according to the method described for intermediate 3, except that it was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0 to 1 / 1) to give 2-bromo-5-(5-cyclopropoxy-3-methylpyridin-2-yl)-1,3,4-oxadiazole as a yellow solid (13% yield). 1 H NMR (400 MHz, DMSO- d 6 ) δ = 8.42 (s, 1H),7.63 (s, 1H), 4.07 (tt, J= 2.8, 5.8 Hz, 1H), 2.64 (s, 3H), 0.90 - 0.85 (m, 2H), 0.77 - 0.71 (m, 2H).

[0463] Preparation of compound 51: The preparation was carried out according to the method described for compound 1, except that: (i) 4.00 eqN,N -Diisopropylethylamine, (ii) stirring the reaction mixture at 120°C for 2 h, and (iii) by Preparative Purification was performed by HPLC (column: C18 150×30 mm; mobile phase: [water (formic acid)-acetonitrile]; gradient: 38%-68% B, duration: 7 min) to give 3-(4-chloro-6-(1-((5-(5-cyclopropoxy-3-methylpyridin-2-yl)-1,3,4-oxadiazol-2-yl)amino)cyclopropyl)-1-oxoisoindoline-2-yl)piperidine-2,6-dione as a brown solid (29% yield). 1 H NMR (400MHz, DMSO- d 6 ) δ = 10.99 (s, 1H), 8.95 (s, 1H), 8.28 (br s, 1H), 7.64 (d, J = 1.2Hz, 1H), 7.60 (d, J = 1.6 Hz, 1H), 7.53 (d, J = 2.0 Hz, 1H), 5.12 (dd, J = 4.8,13.4 Hz, 1H), 4.49 - 4.39 (m, 1H), 4.34 - 4.24 (m, 1H), 4.02 (tt, J = 2.8, 6.0Hz, 1H), 2.95 - 2.85 (m, 1H), 2.60 (br s, 1H), 2.57 (s, 3H), 2.44 - 2.38 (m,1H), 2.02 - 1.96 (m, 1H), 1.46 - 1.40 (m, 2H), 1.39 - 1.33 (m, 2H), 0.87 -0.82 (m, 2H), 0.75 - 0.68 (m, 2H).

[0464] Example 52. Preparation of compounds 52-91 and 98-121 Compounds 52-91 and 98-121 were prepared by parallel synthesis.

[0465] Step A (A=H): Aldehyde 1 (1 eq), tert-butyl hydrazide (1 eq), and a few drops of acetic acid were dissolved in anhydrous methanol, and the reaction mixture was stirred at 60 °C for 5 h. The completion of the reaction was monitored by LCMS. After the reaction was completed, the reaction mixture was cooled to room temperature, and the methanol solution of intermediate 2 was used directly in the next step without post-treatment.

[0466] Step A (A=OH): Acid 1 (1 eq) was dissolved in anhydrous THF, followed by the addition of 1-(1H-imidazol-1-carbonyl)-1H-imidazolium (1.2 eq) fractionally. The reaction mixture was stirred at 60 °C for 3 h, cooled to room temperature, and added dropwise to hydrazine hydrate (15 eq) with vigorous stirring. After 1 h, the reaction mixture was concentrated under vacuum. The residue was dissolved in DCM, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting crude hydrazide 2 was used directly in the next step without purification.

[0467] Step B (A=H): [bis(acetoxy)iodo]benzene (1.2 eq) was added fractionally to a stirred methanol solution of intermediate 2 (1 eq) at room temperature. The resulting clear reaction mixture was stirred overnight at 60 °C and then concentrated under reduced pressure. The residue was purified by recrystallization from CCl4 or by chromatography to give pure oxadiazolone 3.

[0468] Step B (A=OH): 1-(1H-imidazolium-1-carbonyl)-1H-imidazolium (1.4 eq) was added fractionally to a mixture of crude hydrazide 2 (1 eq) and DIPEA (5 eq) in anhydrous DCM and stirred for 6 h. The reaction progress was monitored using LCMS, and up to 0.5 eq of CDI was added as needed. After completion, the reaction mixture was concentrated and subjected to rapid chromatography to obtain oxadiazolone 3.

[0469] Step C: Amine 4 (1 eq HCl) (preparation steps see, for example, Example 1), oxadiazolone 3 (1.2 eq), PyClOP (1.5 eq), and DIPEA (5 eq) were placed in a vial, followed by the addition of DMA (0.5 mL). The reaction mixture was stirred at room temperature for 10 min, and then stirred overnight at 60 °C. A clear solution was observed upon completion. LCMS of the reaction mixture showed complete consumption of the amine. The reaction mixture was subjected to reversed-phase HPLC to obtain the desired TM.

[0470] Table 2. Yields and QC data for compounds 52-91 and 98-121

[0471] Example 53. Preparation of Compound 92 It was prepared according to compound 1, except that: (i) 4.00 eqN,N -Diisopropylethylamine, (ii) stirring the reaction mixture at 120°C for 2 h, and (iii) by Preparative The sample was double-purified by HPLC (column: C18 150×30mm; mobile phase: [water (formic acid)-acetonitrile]; gradient: 38%-68% B, duration 7 min, followed by column: Waters Xbridge 150*25mm* 5um; mobile phase: [water (ammonium bicarbonate)-acetonitrile]; gradient: 30%-60% B, duration 9 min) to obtain 3-(6-(1-((5-(4-cyclopropoxyphenyl)-1,3,4-oxadiazol-2-yl)amino)cyclopropyl)-4-(difluoromethyl)-1-oxoisoindoline-2-yl)piperidine-2,6-dione (17% yield) as a white solid. 1 H NMR (400 MHz, DMSO- d 6 ) δ = 10.98(br s, 1H), 8.87 (s, 1H), 7.80 (s, 1H), 7.74 - 7.69 (m, 3H), 7.35 - 7.08 (m,3H), 5.13 (dd, J = 5.2, 13.2 Hz, 1H), 4.61 - 4.52 (m, 1H), 4.48 - 4.40 (m, 1H), 3.91 (tt, J = 2.8, 6.0 Hz, 1H), 2.95 - 2.84 (m, 1H), 2.61 - 2.55 (m, 1H), 2.45- 2.36 (m, 1H), 2.03 - 1.95 (m, 1H), 1.40 (br d, J = 2.0 Hz, 4H), 0.85 - 0.77 (m, 2H), 0.71 - 0.64 (m, 2H).

[0472] Example 54. Preparation of compound 93 Preparation of 2: Under a nitrogen atmosphere, tert-butyl carbamate (1-(7-chloro-2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindoline-5-yl)cyclopropyl)carbamate (500 mg, 1.15 mmol, 1.00 mmol) was reacted. eq (See 'Preparation of Intermediate 2' for preparation steps) N,N Add nickel(II) chloride (50.6 mg, 230 μmol, 0.200 mL) to a solution of dimethylacetamide (10.0 mL). eq ), 2-(4-amino-2-pyridyl)pyridine-4-amine (21.5 mg, 115 μmol, 0.100 eq ), zinc powder (452mg, 6.91 mmol, 6.00 mmol / L) eq Magnesium chloride (878 mg, 9.22 mmol, 378 μL, 8.00 mg / L) eq ), 3A molecular sieve (1.00 g, 2.30 mmol, 2.00 mmol) eq [2,2'-Bipyridine]-4,4'-diamine (56.3 mg, 461 μmol, 0.400) eq Then add dichlorofluoromethane (5.20 M, 5.76 mL, 26.0 mL). eq The reaction mixture was stirred at 60°C for 12 h. The reaction mixture was then filtered. The filtrate was washed with brine (50 mL) and extracted with ethyl acetate (3 × 50 mL). The organic layer was then dried over sodium sulfate and concentrated under reduced pressure. Preparative HPLC (column: C18 150×30 mm; mobile phase: [water (formic acid)-acetonitrile]; gradient: 7 min 35%-65% B) purification of the residue and lyophilization to give (1-(7-(difluoromethyl)-2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindoline-5-yl)cyclopropyl)carbamic acid as a white solid) Uncle Butyl ester (50.0 mg, 111 μmol, 10% yield).

[0473] Preparation of 3 : To (1-(7-(difluoromethyl)-2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindoline-5-yl)cyclopropyl)carbamic acid Uncle Butyl ester (50.0 mg, 111 μmol, 1.00) eqHydrochloric acid (2.00 N in dioxane, 0.50 mL) was added to a solution of dioxane (0.500 mL). The reaction mixture was stirred at 20 °C for 0.5 h. The reaction mixture was then concentrated under reduced pressure and lyophilized to give 3-(6-(1-aminocyclopropyl)-4-(difluoromethyl)-1-oxoisoindololin-2-yl)piperidine-2,6-dione (42.0 mg, 109 μmol, 98% yield, hydrochloric acid) as a white solid. 1 H NMR (400MHz, DMSO- d 6 ) δ = 11.03 (s, 1H), 8.83 - 8.65 (m, 2H), 8.01 (s, 1H), 7.82 (s,1H), 7.46 - 7.07 (m, 1H), 5.22 - 5.08 (m, 1H), 4.69 - 4.57 (m, 1H), 4.54 -4.46 (m, 1H), 2.91 (br d, J = 3.2 Hz, 1H), 2.60 - 2.57 (m, 1H), 2.47 - 2.44 (m,1H), 2.08 - 1.99 (m, 1H), 1.43 - 1.31 (m, 4H).

[0474] Preparation of compound 93: The preparation was carried out according to the method described for compound 1, except that: (i) the reaction mixture was stirred at 120°C for 1 h and (ii) by... Preparative HPLC (column: C18 150×30mm; mobile phase: [water (formic acid)-acetonitrile]; gradient: 35%-65% B, duration: 7 min) followed by preparative TLC (petroleum ether / ethyl acetate = 1 / 1) to obtain 3-(4-(difluoromethyl)-1-oxo-6-(1-((5-(p-tolyl)-1,3,4-oxadiazol-2-yl)amino)cyclopropyl)isoindoline-2-yl)piperidine-2,6-dione (33% yield) as a white solid. 1 H NMR (400 MHz, DMSO- d 6 ) δ = 11.01 (s, 1H), 9.02 (s, 1H), 7.91 (d, J = 8.8 Hz, 2H), 7.56 - 7.47(m, 3H), 5.14 (dd, J= 5.2, 13.2 Hz, 1H), 4.56 - 4.46 (m, 1H), 4.40 - 4.27 (m,1H), 3.00 - 2.83 (m, 1H), 2.62 - 2.54 (m, 1H), 2.48 (br s, 3H), 2.45 - 2.36(m, 1H), 2.05 - 1.95 (m, 1H), 1.62 (q, J = 3.6 Hz, 2H), 1.42 - 1.32 (m, 2H).

[0475] Example 55. Preparation of Compound 94 The preparation was carried out according to the method described for compound 1, except that: (i) 5.00 eqN , N -Diisopropylethylamine, (ii) the reaction mixture was stirred at 130 °C for 1 h, and (iii) purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 2 / 1 to 0 / 1) to give 3-(4-(difluoromethyl)-6-(1-((5-(2-(methoxymethyl)-4-methylphenyl)-1,3,4-oxadiazol-2-yl)amino)cyclopropyl)-1-oxoisoindoline-2-yl)piperidine-2,6-dione as a white solid (41% yield). 1 H NMR (400 MHz, DMSO- d 6 ) δ = 10.98 (br s, 1H), 8.94 (s,1H), 7.82 (s, 1H), 7.73 (s, 1H), 7.61 (d, J = 8.0 Hz, 1H), 7.42 (s, 1H), 7.35(s, 0.2H), 7.24 (br d, J = 8.4 Hz, 1H), 7.22 (s, 0.5H), 7.08 (s, 0.2H), 5.13(dd, J = 5.1, 13.3 Hz, 1H), 4.67 (s, 2H), 4.59 - 4.41 (m, 2H), 3.32 (s, 3H), 2.95 - 2.84 (m, 1H), 2.58 (br dd, J = 2.6, 15.6 Hz, 1H), 2.46 - 2.40 (m, 1H), 2.36 (s, 3H), 2.00 (td,J = 5.0, 10.4 Hz, 1H), 1.41 (br s, 4H).

[0476] Example 56. Preparation of Compound 95 Preparation of 2: To 6-fluoro-2-methylpyridin-3-carboxylic acid (1.00 g, 6.45 mmol, 1.00 eq Add to a solution of dichloromethane (10.0 mL) N,N '-Methanediethylenedicyclohexylamine (1.60 g, 7.74 mmol, 1.56 mL, 1.20 g) eq ), N,N -Dimethylpyridine-4-amine (394 mg, 3.22 mmol, 0.50) eq ) and methanol (310 mg, 9.67 mmol, 391 μL, 1.50) eq The mixture was stirred at 25°C for 12 hours. The reaction mixture was filtered and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0 to 5 / 1) to give methyl 6-fluoro-2-methylnicotinate as a colorless liquid (1.80 g, 10.5 mmol, 82% yield, 99% purity).

[0477] Preparation of 3: Methyl 6-fluoro-2-methylnicotinic acid ester (800 mg, 4.73 mmol, 1.00 mg) eq Cesium carbonate (2.31 g, 7.09 mmol, 1.50 mmol) was added to a solution of dimethylformamide (8.00 mL). eq ) and cyclopropanol (824 mg, 14.2 mmol, 3.00) eq The mixture was stirred at 25 °C for 12 hours. The reaction mixture was quenched by adding water (50 mL) and then extracted with ethyl acetate (3 × 25 mL). The combined organic layers were washed with brine (20 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give the residue. The residue was purified by preparative HPLC (formic acid conditions; column: Phenomenexluna C18 150*40mm*15um; mobile phase: [water (formic acid)-acetonitrile]; gradient: 15 min 38%-68% B) and lyophilized to give methyl 6-cyclopropoxy-2-methylnicotinate as a yellow liquid (382 mg, 1.84 mmol, 39% yield).

[0478] Preparation of 4:The preparation was carried out according to the method described for structure 3 of the scheme used to prepare intermediate 6, except that: (i) 15.0 eq (ii) hydrazine monohydrate was reacted in methanol instead of ethanol, (iii) the reaction mixture was stirred at 60 °C for 2 hours, and (iv) the reaction mixture was concentrated under reduced pressure to give a residue, yielding 6-cyclopropoxy-2-methylnicotinamide hydrazine as a white solid (99% yield).

[0479] Preparation of 5: Preparation was carried out according to the method described for structure 4 of the scheme used to prepare intermediate 6. 5-(6-cyclopropoxy-2-methylpyridin-3-yl)-1,3,4-oxadiazole-2-amine (87% yield) was obtained as a yellow solid.

[0480] Preparation of 6: The preparation was carried out according to the method described for intermediate 3, except that purification was performed by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0 to 5 / 1) to give 2-bromo-5-(6-cyclopropoxy-2-methylpyridin-3-yl)-1,3,4-oxadiazole as a yellow solid (23% yield). MS (ESI) m / z 297.9 [M+H] + Preparation of compound 95: The preparation was carried out according to the method described for compound 1, except that: (i) the reaction mixture was stirred at 120°C for 2 hours and (ii) purified by preparative HPLC (formic acid conditions; column: YMC-ActusTriart C18 150*30mm*7um; mobile phase: [water (formic acid)-acetonitrile]; gradient: 35%-65% B, duration 10 min), followed by preparative TLC (SiO2, petroleum ether: ethyl acetate = 1:1) to give 3-(6-(1-((5-(6-cyclopropoxy-2-methylpyridin-3-yl)-1,3,4-oxadiazol-2-yl)amino)cyclopropyl)-4-(difluoromethyl)-1-oxoisoindoline-2-yl)piperidine-2,6-dione (27% yield) as a grayish-white solid. 1 H NMR (400 MHz, DMSO- d 6 ) δ = 10.99 (s,1H), 8.95 (s, 1H), 7.95 (d, J = 8.6 Hz, 1H), 7.83 (s, 1H), 7.73 (s, 1H), 7.36(s, 1H), 7.22 (s, 1H), 7.08 (s, 1H), 6.86 (d, J= 8.6 Hz, 1H), 5.13 (dd, J = 5.2,13.2 Hz, 1H), 4.63 - 4.51 (m, 1H), 4.50 - 4.40 (m, 1H), 4.26 (tt, J = 3.0, 6.0Hz, 1H), 2.97 - 2.82 (m, 1H), 2.64 (s, 3H), 2.61 - 2.54 (m, 1H), 2.48 - 2.34(m, 1H), 2.04 - 1.96 (m, 1H), 1.41 (s, 4H), 0.83 - 0.74 (m, 2H), 0.72 - 0.63(m, 2H) Example 57. Preparation of Compound 96 The preparation was carried out according to the method described for compound 1, except that: (i) the reaction mixture was stirred at 120°C for 1 h and (ii) by... Preparative HPLC (column: C18 150×30 mm; mobile phase: [water (formic acid)-acetonitrile]; gradient: 42%-72% B, duration 7 min) yielded 3-(4-(difluoromethyl)-1-oxo-6-(1-((5-(4-(trifluoromethoxy)phenyl)-1,3,4-oxadiazol-2-yl)amino)cyclopropyl)isoindoline-2-yl)piperidine-2,6-dione as a grayish-white solid (25% yield). 1 H NMR (400 MHz, DMSO- d 6 ) δ = 10.99 (s, 1H), 9.05 (s, 1H), 7.94 - 7.86(m, 2H), 7.77 (d, J = 32.4 Hz, 2H), 7.53 (d, J = 8.4 Hz, 2H), 7.21 (t, J = 55.2 Hz, 1H), 5.13 (dd, J = 5.2, 13.4 Hz, 1H), 4.64 - 4.51 (m, 1H), 4.50 - 4.38 (m, 1H), 2.95 - 2.84 (m, 1H), 2.61 - 2.56 (m, 1H), 2.47 - 2.37 (m, 1H), 2.06 - 1.95 (m, 1H), 1.49 - 1.33 (m, 4H).

[0481] Example 58. Preparation of Compound 97 Preparation of 2: The preparation was carried out according to the method described for structure 2 of the scheme used to prepare intermediate 6, except that: (i) 10.0 eq (ii) the reaction mixture was stirred at 75°C for 12 h, and (iii) by... Preparative Purification by TLC (SiO2, petroleum ether / ethyl acetate = 0 / 1) yielded methyl 5-methoxy-3-methylpyridinecarboxylate as a white solid (60% yield).

[0482] Preparation of 3: The preparation was carried out according to the method described for structure 3 of the scheme used to prepare intermediate 6, except that: (i) 10.0 eq (ii) The reaction mixture was stirred at 60 °C for 2 h. 5-Methoxy-3-methylpyridinecarboxyhydrazide was given as a white solid (85% yield).

[0483] Preparation of 4: The preparation was carried out according to the method described for structure 4 of the scheme used to prepare intermediate 6, except that purification was performed by column chromatography (SiO2, dichloromethane / methanol = 1 / 1 to 0 / 1) to give 5-(5-methoxy-3-methylpyridin-2-yl)-1,3,4-oxadiazol-2-amine (78% yield) as a yellow solid.

[0484] Preparation of 5: At 0 °C, 5-(5-methoxy-3-methylpyridin-2-yl)-1,3,4-oxadiazol-2-amine (20.0 mg, 97.0 μmol, 1.00 μmol) was reacted with 5-(5-methoxy-3-methylpyridin-2-yl)-1,3,4-oxadiazol-2-amine (20.0 mg, 97.0 μmol, 1.00 μmol). eq Add tert-butyl nitrite (15.0 mg, 145 μmol, 17.3 μL, 1.50 mL) to a solution in acetonitrile (10.0 mL). eq ) and potassium bromide (17.3 mg, 145 μmol, 6.30 μL, 1.50) eq The reaction mixture was stirred at 20 °C for 12 h. The reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (petroleum ether / ethyl acetate = 1 / 1 to 5 / 1) to give 2-bromo-5-(5-methoxy-3-methylpyridin-2-yl)-1,3,4-oxadiazole (60.0 mg, 222 μmol, 33% yield) as a yellow oil. 1 H NMR (400 MHz, CDCl3) δ = 8.35 (br d,J = 2.8Hz, 1H), 7.19 (d, J = 2.4 Hz, 1H), 3.96 (s, 3H), 2.78 (s, 3H).

[0485] Preparation of compound 97: The preparation was carried out according to the method described for compound 1, except that: (i) the reaction mixture was stirred at 120°C for 1 h and (ii) by... Preparative Purification was performed by HPLC (column: C18 150×30mm; mobile phase: [water (formic acid)-acetonitrile]; gradient: 20%-50% B, duration: 7 min) to obtain 3-(4-chloro-6-(1-((5-(5-methoxy-3-methylpyridin-2-yl)-1,3,4-oxadiazol-2-yl)amino)cyclopropyl)-1-oxoisoindoline-2-yl)piperidine-2,6-dione (20% yield) as a yellow solid. 1 H NMR (400 MHz, DMSO- d 6 ) δ = 10.99 (br s, 1H), 8.94 (s, 1H), 8.23 ​​(d, J = 2.8 Hz, 1H), 7.65 (s, 1H), 7.61 (s, 1H), 7.43 (d, J = 2.8Hz, 1H), 5.13 (dd, J = 5.2, 13.2 Hz, 1H), 4.51 - 4.41 (m, 1H), 4.36 - 4.22 (m,1H), 3.88 (s, 3H), 2.95 - 2.83 (m, 1H), 2.66 - 2.59 (m, 1H), 2.57 (s, 3H),2.45 (br dd, J = 4.8, 13.2 Hz, 1H), 2.04 - 1.95 (m, 1H), 1.47 - 1.41 (m, 2H), 1.39 (br d, J = 4.0 Hz, 2H).

[0486] Example 59. Preparation of Compound 122 The preparation was carried out according to the method described for compound 1, except that: (i) using N , N- Dimethylacetamide instead of DMSO, (ii) stirring the reaction mixture at 110°C for 1 hour, and (iii) by Preparative Purification was performed by HPLC (formic acid conditions; column: Phenomenex luna C18 150*40mm*15um; mobile phase: [water (formic acid)-acetonitrile]; gradient: 35%-65% B, duration: 15 min) to obtain 3-(4-chloro-1-oxo-6-(1-((5-(4-(trifluoromethyl)phenyl)-1,3,4-oxadiazol-2-yl)amino)cyclopropyl)isoindoline-2-yl)piperidine-2,6-dione (43% yield) as a grayish-white solid. 1 H NMR (400 MHz, DMSO- d 6 ) δ = 11.00 (s, 1H), 9.10 (s, 1H), 8.02 - 7.94 (m,2H), 7.93 - 7.86 (m, 2H), 7.63 (dd, J = 1.4, 12.6 Hz, 2H), 5.12 (dd, J = 5.2,13.4 Hz, 1H), 4.50 - 4.38 (m, 1H), 4.34 - 4.22 (m, 1H), 2.97 - 2.83 (m, 1H), 2.58 (br dd, J = 2.2, 15.4 Hz, 1H), 2.48 - 2.36 (m, 1H), 2.05 - 1.93 (m, 1H), 1.52 - 1...

Claims

1. A compound of formula (I): Formula (I), Or its pharmaceutically acceptable salt, wherein: X is hydrogen or deuterium; R 1 R 2 and R 3 Each of these is independently hydrogen, halogen, hydroxyl, cyano, -NO2, oxo, -N(R) Za (R) Zb C 1–6 Alkoxy or C 1–6 Alkyl, wherein C 1–6 The alkyl group may optionally be replaced by one or more halogens; Ring A is aryl, heteroaryl, or bicyclic [1.1.1]pentyl, and ring A is optionally surrounded by one or more R 4 replace; Each R 4 Independently halogen, cyano, -NO2, hydroxyl, oxo, -S(O)2N(R) Za (R) Zb C 1–6 Alkyl, C 2–6 alkynyl group, C 1–6 Alkoxy, C 1–6 Thioalkoxy, C 3–10 Cycloalkyl, 3-10 membered heterocyclic, aryl or heteroaryl, wherein C 1–6 Alkyl, C 2–6 alkynyl group, C 1–6 Alkoxy, C 1–6 Thioalkoxy, C 3–10 Each of cycloalkyl, 3-10 membered heterocyclic, aryl, and heteroaryl groups is optionally bounded by one or more R groups. 5 replace; Or two R atoms attached to the same ring A atom or adjacent ring A atoms 4 Together with the atoms to which they are attached, they form 3-10 membered heterocycles or C rings. 3-10 Cycloalkyl rings, wherein the 3-10 membered heterocycles or C 3-10 The cycloalkyl ring is optionally surrounded by one or more R 5 replace; Each R 5 Independently halogen, oxo, hydroxyl, C 2-6 alkynyl group, C 1–6 Alkyl, C 1–6 Alkoxy, C 1–6 Thioalkoxy, C 3–10 Cycloalkyl, 3-10 membered heterocyclic, aryl or heteroaryl, wherein C 1–6 The alkyl group is optionally substituted with one or more halogens; and R Za and R Zb Each of them is independently hydrogen or C. 1–6 alkyl; Or R Za and R Zb Together with the nitrogen attached to them, they form 3-10 membered heterocycles.

2. The compound of claim 1, wherein the compound is a compound of formula (IA): Formula (IA); For example, the compound described is a compound of formula (IB): Formula (IB).

3. The compound of claim 1 or claim 2, wherein R Za and R Zb Each of them is independently C 1–6 Alkyl groups (e.g., CH3); or R Za and R Zb Together with the nitrogen attached to them, they form 3-6 membered heterocycles.

4. The compound according to any one of claims 1 to 3, wherein each R 4 Independently halogenated (e.g., fluorine or chlorine), -S(O)₂N(R) Za (R) Zb C 1–6 Alkyl (e.g., C10) 1–3 Alkyl), C 1–6 Alkoxy groups (e.g., C) 1–3 alkoxy) or C 3–10 cycloalkyl (e.g., C10) 3–4 cycloalkyl), wherein C 1–6 Alkyl (or C) 1–3 Alkyl), C 1–6 Alkoxy (or C) 1–3 alkoxy) and C 3–10 cycloalkyl (or C) 3–4 Each of the cycloalkyl groups is optionally construed by one or more R groups. 5 Substitution; or attachment of two R atoms to adjacent ring A atoms. 4 Together with the atoms to which they are attached, they form a group optionally bounded by one or more R 5 Replaced 5-6 membered heterocycles.

5. The compound according to any one of claims 1 to 4, wherein each R 5 Independent of halogen, C 1–6 Alkyl (e.g., C10) 1–3 Alkyl), C 1–6 Alkoxy groups (e.g., C) 1–3 alkoxy) or C 3–10 cycloalkyl (e.g., C10) 3–6 (cycloalkyl).

6. The compound according to any one of claims 1 to 5, wherein ring A is aryl or heteroaryl, and ring A is optionally separated by one or more R 4 Substitution; for example, wherein ring A is a phenyl or a 5-6-membered heteroaryl group, and ring A is optionally replaced by one or more R groups. 4 replace.

7. The compound according to any one of claims 1 to 5, wherein ring A is optionally separated by one or more R 4 Substituted bicyclic [1.1.1]pentyl; for example, where ring A is .

8. The compound of claim 7, (a) where each R 4 Independently for C 1–6 Alkyl (e.g., C10) 1–4 Alkyl), aryl (e.g., phenyl), or cyano, and R 4 Optionally by one or more R 5 Replace; or (b) where each R 4 To be optionally used by one or more R 5 Replacement C 1–6 Alkyl; for example, each R 4 To be optionally used by one or more R 5 The CH3 that is replaced.

9. The compound of claim 7 or claim 8, wherein each R 5 For example, each R is a halogen; 5 It is fluorine.

10. The compound of claim 1, wherein the compound is selected from the group consisting of: Or its pharmaceutically acceptable salt.

11. A pharmaceutical composition comprising the compound of any one of claims 1 to 10 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

12. A method of treating a subject with cancer using the compound of any one of claims 1 to 10 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 11, wherein the method comprises administering to the subject a therapeutically effective amount of the compound, the pharmaceutically acceptable salt, or the pharmaceutical composition.

13. The compound, pharmaceutically acceptable salt, or pharmaceutical composition used according to claim 12, (a) The cancer mentioned therein is breast cancer; for example, the breast cancer mentioned therein is HR+ (hormone receptor positive) breast cancer, ER+ (estrogen receptor positive) breast cancer, HR+ HER2- (human epidermal growth factor receptor 2 negative) breast cancer or ER+ HER2- (human epidermal growth factor receptor 2 negative) breast cancer. (b) The cancers described therein are selected from the group consisting of: ovarian cancer, endometrial cancer, gastric cancer, esophageal cancer, triple-negative breast cancer, and lung adenosarcoma; for example, the cancer described therein is triple-negative breast cancer; (c) The cancers described herein include solid tumors; for example, the solid tumors described herein are at least one of the following: uterine cancer (such as uterine carcinosarcoma and endometrial cancer of the uterine corpus), endometrial cancer, breast cancer (such as invasive breast cancer and triple-negative breast cancer, ER+ HER2- breast cancer and HER2+ breast cancer), ovarian cancer (such as ovarian serous cystadenocarcinoma), gastric cancer (such as gastric adenocarcinoma), gastric cancer (such as gastrointestinal stromal carcinoma), colorectal cancer, pancreatic cancer, kidney cancer, head and neck cancer, liver cancer, prostate cancer, skin cancer, lymphoma (such as B-cell lymphoma), sarcoma, esophageal cancer (such as esophageal cancer), bladder cancer (such as bladder urothelial carcinoma), lung cancer (such as squamous cell carcinoma and non-small cell lung cancer, including EGFRm+ (epidermal growth factor receptor mutant positive) non-small cell lung cancer), cholangiocarcinoma, adrenocortical carcinoma, mesothelioma, and malignant melanoma; or (d) The cancer mentioned includes liquid tumors; for example, the liquid tumor is at least one of the following: diffuse large B-cell lymphoma (DLBCL), B-cell immunoblastic lymphoma, small non-cleaved cell lymphoma, human lymphotropic virus type 1 (HTLV-1) leukemia / lymphoma, adult T-cell lymphoma, peripheral T-cell lymphoma (PTCL), cutaneous T-cell lymphoma (CTCL), mantle cell lymphoma (MCL), Hodgkin lymphoma (HL), non-Hodgkin lymphoma (NHL), AIDS-related lymphoma, follicular lymphoma, small lymphocytic lymphoma, large B-cell lymphoma rich in T cells / histocytes, transformed lymphoma, primary mediastinal (thymic) large B-cell lymphoma, splenic marginal zone lymphoma, Richter lymphoma, etc. Transformation, marginal zone lymphoma, ALK-positive large B-cell lymphoma, indolent lymphoma (e.g., DLBCL, follicular lymphoma, or marginal zone lymphoma), acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), adult T-cell leukemia, chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), hairy cell leukemia, myelodysplastic syndrome, myeloproliferative disorders, chronic myeloid leukemia (CML), acute monocytic leukemia (AMoL), myelodysplastic syndrome (MDS), human lymphotropic virus type 1 (HTLV-1) leukemia, mastocytosis, B-cell acute lymphoblastic leukemia, non-Hodgkin lymphoma, Hodgkin lymphoma, and multiple myeloma (MM).

14. The compound, pharmaceutically acceptable salt, or pharmaceutical composition used according to claim 12 or claim 13, wherein the method further comprises administering an additional therapeutic agent to the subject; for example, wherein the additional therapeutic agent is carboplatin, fulvestrant, or a combination thereof.

15. The compound, pharmaceutically acceptable salt, or pharmaceutical composition used in any one of claims 12 to 14, wherein the subject is untreated.

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