Cyclopropyl and 1,3,4-oxodiazole 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

CYCLOPROPYL AND 1 ,3,4-OXODIAZOLE COMPOUNDS THAT MEDIATE PROTEIN DEGRADATION AND METHODS OF USE THEREOFBACKGROUND

[0001] The ubiquitin proteasome system can be manipulated with different small molecules to trigger targeted degradation of specific proteins of interest. Promoting the targeted degradation of pathogenic proteins using small molecule degraders is emerging as a new modality in the treatment of diseases. One such modality relies on redirecting the activity of E3 ligases such as cereblon (a phenomenon known as E3 reprogramming) using low molecular weight compounds, which have been termed molecular glues to promote the poly-ubiquitination and ultimately proteasomal degradation of new protein substrates involved in the development of diseases. The molecular glues bind to both the E3 ligase and the target protein, thereby mediating an alteration of the ligase surface and enabling an interaction with the target protein.

[0002] WO 2023 / 069700 and WO 2023 / 069720 provide compounds that mediate the degradation of the protein cyclin-dependent kinase 2 (CDK2) and are therefore useful in the treatment of various disorders, such as cancer.

[0003] There exists a need for further therapeutics that effectively mediate the degradation of CDK2 and that have favourable properties.SUMMARY

[0004] Provided herein are compounds useful as modulators of cereblon for mediating the targeted degradation of CDK2, and are therefore are useful in the treatment of various disorders, such as cancer.

[0005] In an aspect, provided herein is a compound of Formula (I):Formula (I), or a pharmaceutically acceptable salt thereof, wherein: X is hydrogen or deuterium; each of R1, R2, and R3is independently hydrogen, halogen, hydroxy, cyano, NO2, oxo, -N(RZa)(Rzb), C1-6 alkoxy, or C1-6 alkyl, wherein Ci-6 alkyl is optionally substituted with one or more halogens; ring A is aryl, heteroaryl, or bicyclo [1.1.1 ]pentyl, and ring A is optionally substituted with one or more R4; each R4is independently halogen, cyano, -NO2, hydroxy, -S(O)2N(RZa)(Rzb), C1-6 alkyl, C2-6 alkynyl, C1-6 alkoxy, C1-6 thioalkoxy, C3io cycloalkyl, 3-10 membered heterocyclyl, aryl, or heteroaryl, wherein each of Ci-6 alkyl, C2-6 alkynyl, C1-6 alkoxy, C1-6 thioalkoxy, C3-10 cycloalkyl, 3-10 membered heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more R5; or two R4attached to the same ring A atom or adjacent ring A atoms, together with the atoms to which they are attached, form a 3-10 membered heterocyclic ring or C3-10 cycloalkyl ring, wherein the 3-10 membered heterocyclic ring or C3-10 cycloalkyl ring is optionally substituted with one or more R5; each R5is independently halogen, oxo, hydroxy, C2-6 alkynyl, C1-6 alkyl, Ci- 6 alkoxy, C1-6 thioalkoxy, C3-10 cycloalkyl, 3-10 membered heterocyclyl, aryl, or heteroaryl, wherein C1-6 alkyl is optionally substituted by one or more halogens; and each of RZaand Rzbis independently hydrogen or C1-6 alkyl; or RZaand Rzb, together with the nitrogen to which they are attached, form a 3-10 membered heterocyclic ring.

[0006] In an aspect, described herein is a pharmaceutical composition comprising a compound described herein, or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0007] In an aspect, described herein is a method of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound described herein, or pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein.BRIEF DESCRIPTION OF FIGURES

[0008] FIG. 1 shows the results of an in vivo experiment to test the antitumor activity of compound1.DETAILED DESCRIPTION

[0009] The features and other details of the disclosure will now be more particularly described.Certain terms employed in the specification, examples and appended claims are collected here. These definitions should be read in light of the remainder of the disclosure and as understood by a person of skill in the art. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by a person of ordinary skill in the art.Compounds

[0010] In one aspect, described herein is a compound of Formula (I):Formula (I), or a pharmaceutically acceptable salt thereof, wherein: X is hydrogen or deuterium; each of R1, R2, and R3is independently hydrogen, halogen, hydroxy, cyano, NO2, oxo, -N(RZa)(Rzb), C1-6 alkoxy, or C1-6 alkyl, wherein C1-6 alkyl is optionally substituted with one or more halogens; ring A is aryl, heteroaryl, or bicyclo [1.1.1 ]pentyl, and ring A is optionally substituted with one or more R4; each R4is independently halogen, cyano, -NO2, hydroxyl, -S(0)2N(RZa)(Rzb), C1-6 alkyl, C2-6 alkynyl, C1-6 alkoxy, C1-6 thioalkoxy, C3 10 cycloalkyl, 3-10 membered heterocyclyl, aryl, or heteroaryl, wherein each of C1-6 alkyl, C2-6 alkynyl, C1-6 alkoxy, C1-6 thioalkoxy, C3-10 cycloalkyl, 3-10 membered heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more R5; or two R4attached to the same ring A atom or adjacent ring A atoms, together with the atoms to which they are attached, form a 3-10 membered heterocyclic ring or C3-10 cycloalkyl ring, wherein the 3-10 membered heterocyclic ring or C3-10 cycloalkyl ring is optionally substituted with one or more R5; each R5is independently halogen, oxo, hydroxy, C2-6 alkynyl, C1-6 alkyl, Ci- 6 alkoxy, C1-6 thioalkoxy, C3-10 cycloalkyl, 3-10 membered heterocyclyl, aryl, or heteroaryl, wherein C1-6 alkyl is optionally substituted by one or more halogens; and each of RZaand Rzbis independently hydrogen or C1-6 alkyl; or RZaand Rzb, together with the nitrogen to which they are attached, form a 3-10 membered heterocyclic ring.

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

[0012] In some embodiments, each of R1, R2, and R3is independently hydrogen, halogen, hydroxy, cyano, NO2, oxo, -N(RZa)(Rzb), C1-6 alkoxy, or C1-6 alkyl, wherein C1-6 alkyl is optionally substituted with one or more halogens. In some embodiments, each of R1, R2, and R3is independently hydrogen, halogen, hydroxy, cyano, -N(RZa)(Rzb), C1-6 alkoxy, or C1-6 alkyl, wherein C1-6 alkyl is optionally substituted with one or more halogens. In some embodiments, each of R1, R2, and R3is independently hydrogen, flouro, chloro, bromo, hydroxy, cyano, NH2, OCH3, CH3, CHF2, or CF3.

[0013] In some embodiments, R1is hydrogen.

[0014] In some embodiments, R2is hydrogen, halogen, or C1-6 alkyl, wherein C1-6 alkyl is optionally substituted with one or more halogens. In some embodiments R2is hydrogen, flouro, chloro, CH3, or CHF2. In some embodiments R2is chloro.

[0015] In some embodiments, R3is hydrogen.

[0016] In some embodiments, R1and R3are hydrogen. In some embodiments, R1and R3are hydrogen and R2is chloro.

[0017] In some embodiments, each of RZaand Rzbis independently hydrogen or Ci-6 alkyl; or RZaand Rzb, together with the nitrogen to which they are attached, form a 3-10 membered heterocyclic ring. In some embodiments, each of RZaand Rzbis independently Ci-6 alkyl; or RZaand Rzb, together with the nitrogen to which they are attached, form a 3-6 membered heterocyclic ring. In some embodiments, the Ci-6 alkyl is CH3. In some embodiments, the 3-6 membered heterocyclic ring comprises 1 ring heteroatom that is nitrogen. In some embodiments, the 3-6 membered heterocyclic ring is an azetidine or a pyrrolidine ring.

[0018] In some embodiments, the compound comprises up to 2 R4. In some embodiments, the compound comprises up to 1 R4. In some embodiments, the compound is not substituted with R4.

[0019] In some embodiments, each R4is independently halogen, cyano, -NO2, hydroxyl, - S(O)2N(RZa)(Rzb), C1-6 alkyl, C2-6 alkynyl, C1-6 alkoxy, C1-6 thioalkoxy, C3-10 cycloalkyl, 3-10 membered heterocyclyl, aryl, or heteroaryl, wherein each of C1-6 alkyl, C2-6 alkynyl, C1-6 alkoxy, C1-6 thioalkoxy, C3-10 cycloalkyl, 3-10 membered heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more R5; or two R4attached to the same ring A atom or adjacent ring A atoms, together with the atoms to which they are attached, form a 3-10 membered heterocyclic ring or C3-10 cycloalkyl ring, wherein the 3-10 membered heterocyclic ring or C3-10 cycloalkyl ring is optionally substituted with one or more R5. In some embodiments, each R4is independently halogen, -S(O)2N(RZa)(Rzb), C1-6 alkyl, C1-6 alkoxy, or C3-10 cycloalkyl, wherein each of C1-6 alkyl, C1-6 alkoxy, and C3-10 cycloalkyl is optionally substituted with one or more R5; or two R4attached to adjacent ring A atoms, together with the atoms to which they are attached, form a 5-6 membered heterocyclic ring that is optionally substituted with one or more R5. In some embodiments, each R4is independently fluoro, chloro, -S(O)2N(RZa)(Rzb), C1-3 alkyl, C1-3 alkoxy, or C3-4 cycloalkyl, wherein each of C1-3 alkyl, C1-3 alkoxy, and C3-4 cycloalkyl is optionally substituted with one or more R5; or two R4attached to adjacent ring A atoms, together with the atoms to which they are attached, form a 5-6 membered heterocyclic ring that is optionally substituted with one or more R5. In some embodiments, the 5-6 membered heterocyclic ring comprises 1-2 ring heteroatoms chosen from N and O. In some embodiments, the 5-6 membered heterocyclic ring comprises 1-2 ring heteroatoms that are O, or the 5-6 membered heterocyclic ring comprises 1 ring heteroatom that is N.

[0020] In some embodiments, each R4is independently selected from the group consisting of:,or two R4attached to adjacent ring A atoms, together with the atoms to which they are attached, form a heterocyclic ring selected from the group consisting of:

[0021] In some embodiments, each R4is independently selected from the group consisting of:, or two R4attached to adjacent ring A atoms, together with the atoms to which they are attached, form a heterocyclic ring selected from the group consisting of:

[0022] In some embodiments, each R4is independently halogen, cyano, -NO2, hydroxyl, - S(O)2N(RZa)(Rzb), C1-6 alkyl, C2-6 alkynyl, C1-6 alkoxy, C1-6 thioalkoxy, C3-10 cycloalkyl, 3-10 membered heterocyclyl, aryl, or heteroaryl, wherein each of Ci-6 alkyl, C2-6 alkynyl, C1-6 alkoxy, C1-6 thioalkoxy, C3-10 cycloalkyl, 3-10 membered heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more R5. In some embodiments, each R4is independently halogen, -S(O)2N(RZa)(Rzb), C1-6 alkyl, C1-6 alkoxy, or C3-10 cycloalkyl, wherein each of C1-6 alkyl, C1-6 alkoxy, and C3-10 cycloalkyl is optionally substituted with one or more R5. In some embodiments, each R4is independently fluoro, chloro, -S(O)2N(RZa)(Rzb), C1-3 alkyl, C1-3 alkoxy, or C3-4 cycloalkyl, wherein each of C1-3 alkyl, C1-3 alkoxy, and C3-4 cycloalkyl is optionallysubstituted with one or more R5. In some embodiments, each R4is independently selected from the group

[0023] In some embodiments, each R4is independently selected from the group consisting of:

[0024] In some embodiments, two R4attached to the same ring A atom or adjacent ring A atoms, together with the atoms to which they are attached, form a 3-10 membered heterocyclic ring or C3-10 cycloalkyl ring, wherein the 3-10 membered heterocyclic ring or C3-10 cycloalkyl ring is optionally substituted with one or more R5. In some embodiments, two R4attached to adjacent ring A atoms, together with the atoms to which they are attached, form a 5-6 membered heterocyclic ring that is optionally substituted with one or more R5. In some embodiments, the 5-6 membered heterocyclic ring comprises 1-2 ring heteroatoms chosen from N and O. In some embodiments, the 5-6 membered heterocyclic ring comprises 1-2 ring heteroatoms that are O, or the 5-6 membered heterocyclic ring comprises 1 ring heteroatom that is N.

[0025] In some embodiments, two R4attached to adjacent ring A atoms, together with the atoms to which they are attached, form a heterocyclic ring selected from the group consisting of:

[0026] In some embodiments, two R4attached to adjacent ring A atoms, together with the atoms to which they are attached, form a heterocyclic ring selected from the group consisting of:

[0027] In some embodiments, the compound comprises up to 3 R5. In some embodiments, the compound comprises up to 2 R5. In some embodiments, the compound comprises up to 1 R5. In some embodiments, the compound is not substituted with R5.

[0028] In some embodiments, each R5is independently halogen, oxo, hydroxy, C2-6 alkynyl, C1-6 alkyl, C1-6 alkoxy, C1-6 thioalkoxy, C3-10 cycloalkyl, 3-10 membered heterocyclyl, aryl, or heteroaryl, wherein C1-6 alkyl is optionally substituted by one or more halogens. In some embodiments, each R5is independently halogen, C1-6 alkyl, C1-6 alkoxy, or C3-10 cycloalkyl. In some embodiments, each R5is independently halogen, C1-3 alkyl, C1-3 alkoxy, or C3-6 cycloalkyl. In some embodiments, each R5is independently fluoro, CH3, OCH3, or cyclopropyl.

[0029] In some embodiments, ring A is aryl, heteroaryl, or bicyclo [l.l.l]pentyl, and ring A is optionally substituted with one or more R4.

[0030] In some embodiments, ring A is aryl or heteroaryl, and ring A is optionally substituted with one or more R4. In some embodiments, ring A is phenyl or 5-6 membered heteroaryl, and ring A is optionally substituted with one or more R4. In some embodiments, 5-6 membered heteroaryl is 5-6 membered nitrogencontaining heteroaryl. In some embodiments, 5-6 membered nitrogen-containing heteroaryl is pyridine, pyrimidine, pyrazine, pyridazine, pyrazole, oxazole, or isoxazole.

[0034] In some embodiments, ring A is aryl that is optionally substituted with one or more R4. In some embodiments, ring A is phenyl that is optionally substituted with one or more R4.

[0035] In some embodiments, ring A is selected from the group consisting of:X2, X3, and X4are oxygen and the rest are carbon.

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

[0038] In some embodiments, ring A is heteroaryl that is optionally substituted with one or more R4. In some embodiments, ring A is 5-6 membered heteroaryl that is optionally substituted with one or more R4. In some embodiments, 5-6 membered heteroaryl is 5-6 membered nitrogen-containing heteroaryl. In some embodiments, 5-6 membered nitrogen-containing heteroaryl is pyridine, pyrimidine, pyrazine, pyridazine, pyrazole, oxazole, or isoxazole.

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

[0041] In some embodiments, ring A is selected from the group consisting of:Formula (I-A).

[0043] In one aspect, described herein is a compound of Formula (I-A):Formula (I-A), or a pharmaceutically acceptable salt thereof, wherein: R2is hydrogen, halogen, or Ci-6 alkyl, wherein Ci-6 alkyl is optionally substituted with one or more halogens; ring A is phenyl that is optionally substituted with one or more R4; each R4is independently halogen, -S(O)2N(RZa)(Rzb), Ci-6 alkyl, Ci-6 alkoxy, wherein each of Ci-6 alkyl and Ci-6 alkoxy is optionally substituted with one or more R5; or two R4attached to adjacent ring A atoms, together with the atoms to which they are attached, form a 5-6 membered heterocyclic ring; each R5is independently halogen or Ci-6 alkoxy; and each of RZaand Rzbis independently Ci-6 alkyl; or RZaand Rzb, together with the nitrogen to which they are attached, form a 3-6 membered heterocyclic ring.

[0044] In one aspect, described herein is a compound of Formula (I-A):Formula (I-A), or a pharmaceutically acceptable salt thereof, wherein: R2is hydrogen, halogen, or C1-3 alkyl, wherein C1-3 alkyl is optionally substituted with one or more fluoro groups; ring A is phenyl that is optionally substituted with one or more R4; each R4is independently halogen, -S(O)2N(RZa)(Rzb), C1-3 alkyl, C1-3 alkoxy, wherein each of C1-3 alkyl and C1-3 alkoxy is optionally substituted with one or more R5; or two R4attached to adjacent ring A atoms, together with the atoms to which they are attached, form a 6 membered heterocyclic ring that comprises 1-2 ring heteroatoms; each R5is independently halogen or C1-3 alkoxy; and each of RZaand Rzbis independently C1-3 alkyl; or RZaand Rzb, together with the nitrogen to which they are attached, form a 3-6 membered heterocyclic ring that comprises 1 ring heteroatoms that is N.

[0045] In one aspect, described herein is a compound of Formula (I-A):Formula (I-A), or a pharmaceutically acceptable salt thereof, wherein: R2is hydrogen, flouro, chloro, CH3, or CHF2; ring A is phenyl that is optionally substituted with one or more R4; each R4is independently fluoro, chloro, - S(O)2N(RZa)(Rzb), Ci-2 alkyl, C1-3 alkoxy, wherein each of C1-2 alkyl and C1-3 alkoxy is optionally substituted with one or more R5; or two R4attached to adjacent ring A atoms, together with the atoms to which they are attached, form a 6 membered heterocyclic ring that comprises 1-2 ring heteroatoms that are 0; each R5is independently fluoro or OCH3; and each of RZaand Rzbis CH;,: or RZaand Rzb, together with the nitrogen to which they are attached, form an azetidine or a pyrrolidine ring.

[0046] In some embodiments, the compound is a compound of Formula (I-B):Formula (I-B).

[0047] In one aspect, described herein is a compound of Formula (I-B):Formula (I-B), or a pharmaceutically acceptable salt thereof, wherein: ring A is phenyl that is optionally substituted with one or more R4; each R4is independently halogen, -S(O)2N(RZa)(Rzb), C1-6 alkyl, C1-6 alkoxy, wherein each of Ci- 6 alkyl and C1-6 alkoxy is optionally substituted with one or more R5; or two R4attached to adjacent ring A atoms, together with the atoms to which they are attached, form a 5-6 membered heterocyclic ring; each R5isindependently halogen or Ci-6 alkoxy; and each of RZaand Rzbis independently Ci-6 alkyl; or RZaand Rzb, together with the nitrogen to which they are attached, form a 3-6 membered heterocyclic ring.

[0048] In one aspect, described herein is a compound of Formula (I-B):Formula (I-B), or a pharmaceutically acceptable salt thereof, wherein: ring A is phenyl that is optionally substituted with one or more R4; each R4is independently halogen, -S(O)2N(RZa)(Rzb), C1-3 alkyl, C1-3 alkoxy, wherein each of Ci- 3 alkyl and C1-3 alkoxy is optionally substituted with one or more R5; or two R4attached to adjacent ring A atoms, together with the atoms to which they are attached, form a 6 membered heterocyclic ring that comprises 1-2 ring heteroatoms; each R5is independently halogen or C1-3 alkoxy; and each of RZaand Rzbis independently C1-3 alkyl; or RZaand Rzb, together with the nitrogen to which they are attached, form a 3-6 membered heterocyclic ring that comprises 1 ring heteroatoms that is N.

[0049] In one aspect, described herein is a compound of Formula (I-B):Formula (I-B), or a pharmaceutically acceptable salt thereof, wherein: ring A is phenyl that is optionally substituted with one or more R4; each R4is independently fluoro, chloro, -S(O)2N(RZa)(Rzb), C1-2 alkyl, C1-3 alkoxy, wherein each of C1-2 alkyl and C1-3 alkoxy is optionally substituted with one or more R5; or two R4attached to adjacent ring A atoms, together with the atoms to which they are attached, form a 6 membered heterocyclic ring that comprises 1-2 ring heteroatoms that are 0; each R5is independently fluoro or OCH3; and each of RZaand Rzbis CH3; or RZaand Rzb, together with the nitrogen to which they are attached, form an azetidine or a pyrrolidine ring.

[0050] In some embodiments, ring A is bicyclo [l.l.l]pentyl that is optionally substituted with one or more R4. In some embodiments, the compound comprises up to 1 R4. In some embodiments, the compound comprises up to 3 R5. In some embodiments, the compound comprises up to 2 R5. In some embodiments, the compound comprises up to 1 R5. In some embodiments the compound is not substituted with R5. In someembodiments, each R5is halogen. In some embodiments, each R5is fluoro. In some embodiments, ring A is

[0051] In some embodiments, each R4is independently Ci-6 alkyl (for example C1-4 alkyl), aryl (for example phenyl), or cyano, and R4is optionally substituted with one or more R5. In some embodiments, each R4is independently selected from the group consisting of:In some embodiments, each R4is independently selected from the group consisting of:In some embodiments, ring A is selected from the

[0052] In some embodiments, each R4is C1-6 alkyl that is optionally substituted with one or moreR5. In some embodiments, each R4is CH3 that is optionally substituted with one or more R5. In someR5R5embodiments, each R4is independently selected from the group consisting of:, , andIn some embodiments, each R4is independently selected from the group consisting of:F, and F In some embodiments, ring A is selected from the group consisting of:

[0053] In some embodiments, the compound is a compound of Formula (I-C):Formula (I-C).

[0054] In some embodiments, the compound is a compound of Formula (I-D):Formula (I-D).

[0055] In some embodiments, X is hydrogen; each of R1, R2, and R3is independently hydrogen, halogen, hydroxy, cyano, -N(RZa)(Rzb), Ci-6 alkoxy, or Ci-6 alkyl, wherein Ci-6 alkyl is optionally substituted with one or more halogens; ring A is aryl, heteroaryl, or bicyclo [l.l.l]pentyl, and ring A is optionally substituted with one or more R4; each R4is independently halogen, -NO2, -S(O)2N(RZa)(Rzb), C1-6 alkyl, C2-6 alkynyl, C1-6 alkoxy, C1-6 thioalkoxy, C3-10 cycloalkyl, 3-10 membered heterocyclyl, aryl, or heteroaryl, wherein each of C1-6 alkyl, C2-6 alkynyl, C1-6 alkoxy, C1-6 thioalkoxy, C3-10 cycloalkyl, 3-10 membered heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more R5; or two R4attached to adjacent ring A atoms, together with the atoms to which they are attached, form a 3-10 membered heterocyclic ring, wherein the 3-10 membered heterocyclic ring is optionally substituted with one or more R5; each R5is independently halogen, oxo, hydroxy, C1-6 alkyl, C1-6 alkoxy, C3-10 cycloalkyl, wherein C1-6 alkyl is optionally substituted by one or more halogens; and each of RZaand Rzbis independently hydrogen or C1-6 alkyl; or RZaand Rzb, together with the nitrogen to which they are attached, form a 3-10 membered heterocyclic ring.

[0056] In some embodiments, X is hydrogen; R1and R3are hydrogen; R2is hydrogen, halogen, or C1-6 alkyl, wherein C1-6 alkyl is optionally substituted with one or more halogens; ring A is phenyl, 5-6 membered heteroaryl, or bicyclo [l.l.l]pentyl, and ring A is optionally substituted with one or more R4; each R4is independently halogen, -S(O)2N(RZa)(Rzb), C1-6 alkyl, C1-6 alkoxy, or C3-10 cycloalkyl, wherein each of C1-6 alkyl, C1-6 alkoxy, and C3-10 cycloalkyl is optionally substituted with one or more R5; or two R4attached to adjacent ring A atoms, together with the atoms to which they are attached, form a 5-6 membered heterocyclic ring that is optionally substituted with one or more R5; each R5is independently halogen, C1-6alkyl, Ci-6 alkoxy, or C3-10 cycloalkyl; and each of RZaand Rzbis independently C1-6 alkyl; or RZaand Rzb, together with the nitrogen to which they are attached, form a 3-6 membered heterocyclic ring.

[0057] In some embodiments, X is hydrogen; R1and R3are hydrogen; R2is hydrogen, flouro, chloro, CH3, or CHF2; ring A is phenyl, 5-6 membered nitrogen-containing heteroaryl, or bicyclo [l.l.l]pentyl, and ring A is optionally substituted with one or more R4; each R4is independently fluoro, chloro, -S(O)2N(RZa)(Rzb), C1-3 alkyl, C1-3 alkoxy, or C3-4 cycloalkyl, wherein each of C1-3 alkyl, C1-3 alkoxy, and C3-4 cycloalkyl is optionally substituted with one or more R5; or two R4attached to adjacent ring A atoms, together with the atoms to which they are attached, form a 5-6 membered heterocyclic ring that is optionally substituted with one or more R5, wherein the 5-6 membered heterocyclic ring comprises 1-2 ring heteroatoms that are 0, or the 5-6 membered heterocyclic ring comprises 1 ring heteroatom that is N; each R5is independently halogen, C1-3 alkyl, C1-3 alkoxy, or C3-6 cycloalkyl; and each of RZaand Rzbis CH3; or RZaand Rzb, together with the nitrogen to which they are attached, form an azetidine or a pyrrolidine ring.

[0058] In some embodiments, the compound is a compound described in Table 1 below. Table 1 also includes the compound number of each compound in accordance with the contents of the present specification.Table 1. Exemplary CompoundsPharmaceutical Compositions

[0059] In another embodiment, the present disclosure provides a pharmaceutical composition comprising a compound described herein, or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. In certain embodiments, the pharmaceutical composition comprises an effective amount of the compound. In certain embodiments, the pharmaceutical composition comprises a therapeutically effective amount of the compound.

[0060] The pharmaceutical compositions provided herein can be administered by a variety of routes including, but not limited to, parenteral (by injection) administration, rectal administration, transdermal administration, intradermal administration, intrathecal administration, subcutaneous (SC) administration, intravenous (IV) administration, intramuscular (IM) administration, and intranasal administration.

[0061] Compositions can take the form of bulk liquid solutions or suspensions, or bulk powders. In some embodiments, the compositions are presented in unit dosage forms to facilitate accurate dosing. The term “unit dosage forms” refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient. Typical unit dosage forms include prefilled, premeasured ampules or syringes of the liquid compositions or pills, tablets, capsules or the like in the case of solid compositions. In such compositions, the compound is usually a minor component with the remainder being various vehicles or excipients and processing aids helpful for forming the desired dosing form.

[0062] Liquid forms may include a suitable aqueous or nonaqueous vehicle with buffers, suspending and dispensing agents, colorants, and the like. Solid forms may include, for example, any of the following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, or com starch; a lubricant such as magnesium stearate; or a glidant such as colloidal silicon dioxide.

[0063] Injectable compositions are typically based upon injectable sterile saline or phosphate- buffered saline or other injectable excipients known in the art. As before, the active compound in such compositions is typically a minor component with the remainder being the injectable excipient and the like.

[0064] Transdermal compositions are typically formulated as a topical ointment or cream containing the active ingredient(s). When formulated as an ointment, the active ingredients will typically be combined with either a paraffinic or a water-miscible ointment base. Alternatively, the active ingredients may be formulated in a cream with, for example, an oil-in-water cream base. Such transdermal formulations are well-known in the art and generally include additional ingredients to enhance the dermal penetration or stability of the active ingredients or formulation. All such known transdermal formulations and ingredients are included within the scope of the disclosure provided herein.

[0065] The compounds provided herein can also be administered by a transdermal device. Accordingly, transdermal administration can be accomplished using a patch either of the reservoir or porous membrane type, or of a solid matrix variety.

[0066] The above-described components for injectable or topically administrable compositions are merely representative. Other materials as well as processing techniques and the like are set forth in Part 8 of Remington ’s Pharmaceutical Sciences, 17th edition, 1985, Mack Publishing Company, Easton, Pennsylvania, which is incorporated herein by reference.Methods of Treatment and Uses

[0067] The compounds described herein can be used to degrade CDK2. In some embodiments, a compound or pharmaceutical composition described herein is used to degrade CDK2 in a subject.

[0068] In some embodiments of the disclosure, a compound described herein is used to degrade CDK2 in an ex vivo system or in an in vitro system. In some embodiments, a compound described herein is used to degrade CDK2 in an ex vivo system. In some embodiments, a compound described herein is used to degrade CDK2 in an in vitro system.

[0069] Described herein is a method of degrading CDK2 comprising combining CDK2 and cereblon with a compound described herein in an ex vivo system or in an vitro system. In some embodiments, the method comprises combining CDK2 and cereblon with a compound described herein in an ex vivo system. In some embodiments, the method comprises combining CDK2 and cereblon with a compound described herein in vitro system.

[0070] The compounds and pharmaceutical compositions described herein are contemplated as useful in the treatment or prevention of disorders in subjects in need thereof. Compounds described herein, in one embodiment, are used to degrade CDK2 for the treatment or prevention of a disorder.

[0071] Cyclin dependent kinases, or CDKs, are a family of closely related kinases that regulate progression through the cell cycle. CDK activity is further modulated by levels of specific cyclins, for example, cyclin El activates cyclin dependent kinase 2, or CDK2. Tumors with CDK2 are activated by (i) the amplification of Cyclin El or E2 or (ii) the loss of the AMBRA1 gene. Elimination of CDK2 is contemplated to treat such disorders in patients in need thereof.

[0072] Accordingly, in one embodiment of the disclosure, a compound, or pharmaceutically acceptable salt thereof, or pharmaceutical composition described herein is administered to a subject to degrade CDK2 in the subject.

[0073] In one aspect of the disclosure, described herein is a method of treating or preventing a disorder in a subject in need thereof, comprising administering to the subject an effective amount of a compound, or pharmaceutically acceptable salt thereof, or pharmaceutical composition described herein.

[0074] In another aspect, described herein is a method of degrading CDK2 in a subject suffering from a disorder, comprising administering to the subject a therapeutically effective amount of a compound described herein, or pharmaceutically acceptable salt thereof, or pharmaceutical composition described herein. For example, described herein is a method of degrading CDK2 in a subject suffering from cancer, comprising administering to the subject an effective amount of a compound described herein, or pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein. In some embodiments, the compound binds to cereblon and a CDK2 protein to induce ubiquitination and subsequent proteasomal degradation of the CDK2.31

[0075] Exemplary disorders that can be treated or prevented by the methods of the present disclosure include but are not limited to, cancer of the bladder, bone, brain, breast, cervix, chest, colon, endometrium, esophagus, eye, head, kidney, liver, lymph nodes, lung, upper aerodigestive tract (including nasal cavity and paranasal sinuses, nasopharynx or cavum, oral cavity, oropharynx, larynx, hypopharynx and salivary glands, neck, ovaries, pancreas, prostate, rectum, skin, stomach, testis, throat, or uterus. Other exemplary disorders include, but are not limited to, amyloidosis, neuroblastoma, meningioma, hemangiopericytoma, multiple brain metastase, glioblastoma multiforms, glioblastoma, brain stem glioma, poor prognosis malignant brain tumor, malignant glioma, recurrent malignant glioma, anaplastic astrocytoma, anaplastic oligodendroglioma, neuroendocrine tumor, e.g., neuroendocrine prostate cancer such as castration-resistant neuroendocrine prostate cancer (NEPC) and lung neuroendocrine tumors (Lu-NETs), rectal adenocarcinoma, colorectal cancer, including stage 3 and stage 4 colorectal cancer, unresectable colorectal carcinoma, metastatic hepatocellular carcinoma, Kaposi's sarcoma, malignant melanoma, malignant mesothelioma, malignant pleural effusion mesothelioma syndrome, peritoneal carcinoma, papillary serous carcinoma, gynecologic sarcoma, soft tissue sarcoma, scleroderma, cutaneous vasculitis, Langerhans cell histiocytosis, leiomyosarcoma, fibrodysplasia ossificans progressive, hormone refractory prostate cancer, resected high-risk soft tissue sarcoma, unrescectable 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 bourne (liquid) or hematological cancers, including but not limited to leukemias, lymphomas, and myelomas, 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’s lymphoma (HL), non-Hodgkin’s lymphoma (NHL), AIDS-related lymphoma, follicular lymphoma, small lymphocytic lymphoma, T- cell / histiocyte rich large B-cell lymphoma, transformed lymphoma, primary mediastinal (thymic) large B-cell lymphoma, splenic marginal zone lymphoma, Richter's transformation, nodal marginal zone lymphoma, ALK-positive large B-cell lymphoma, indolent lymphoma (for example, DLBCL, follicular lymphoma, or marginal zone lymphoma), acute myelogenous leukemia (AML), acute lymphocytic leukemia (ALL), adult T-cell leukemia, chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), hairy cell leukemia, myelodysplasia, myeloproliferative disorders, chronic myelogenous 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's Lymphoma, Hodgkin's Lymphoma, and multiple myeloma (MM).

[0076] In some embodiments, the disorder is cancer.

[0077] In some embodiments, the disorder is breast cancer. In some embodiments, the breast cancer is HR+ (hormone receptor positive) breast cancer. In some embodiments, the breast cancer is ER+ (estrogen receptor positive) breast cancer. In some embodiments, the breast cancer is HR+ HER2- (human epidermal growth factor 2 negative) breast cancer. In some embodiments, the breast cancer is ER+ HER2- breast cancer.

[0078] In some embodiments, the disorder is cancer selected from the group consisting of: ovarian cancer, endometrial cancer, gastric cancer, esophaegeal cancer, triple negative breast cancer, and lung adenosarcoma. In some embodiments, the cancer is triple negative breast cancer.

[0079] In some embodiments, the disorder is cancer that comprises a solid tumor. In some embodiments, the solid tumor is at least one of the group consisting of: uterine cancer (such as uterine carcinosarcoma and uterine corpus endometrial carcinoma), endometrial cancer, breast cancer, (such as breast invasive carcinoma and triple negative breast cancer, ER+ HER2- breast cancer, and HER2+ breast cancer), ovarian cancer (such as ovarian serous cystadenocarcinoma), stomach cancer (such as stomach adenocarcinoma), gastric cancer (such as gastrointestinal stromal cancer), 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 lung squamous 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 embodiments, the solid tumor is at least one of the group consisting of: prostate cancer, colon cancer, esophageal cancer, endometrial cancer, ovarian cancer, uterine cancer, renal cancer, hepatic cancer, pancreatic cancer, gastric cancer, breast cancer, lung cancer, cancers of the head and neck, thyroid cancer, glioblastoma, sarcoma, bladder cancer, and melanoma.

[0080] In some embodiments, the disorder is cancer that comprises a liquid tumor. In some embodiments, the liquid tumor is at least one of the group consisting of: diffuse large B-cell lymphoma (DLBCL), B-cell immunoblastic lymphoma, small non-cleaved cell lymphoma, human lymphotropic virustype 1 (HTLV-1) leukemia / lymphoma, adult T-cell lymphoma, peripheral T-cell lymphoma (PTCL), cutaneous T-cell lymphoma (CTCL), mantle cell lymphoma (MCL), Hodgkin’s lymphoma (HL), nonHodgkin’s lymphoma (NHL), AIDS-related lymphoma, follicular lymphoma, small lymphocytic lymphoma, T-cell / histiocyte rich large B-cell lymphoma, transformed lymphoma, primary mediastinal (thymic) large B- cell lymphoma, splenic marginal zone lymphoma, Richter's transformation, nodal marginal zone lymphoma, ALK-positive large B-cell lymphoma, indolent lymphoma (for example, DLBCL, follicular lymphoma, or marginal zone lymphoma), acute myelogenous leukemia (AML), acute lymphocytic leukemia (ALL), adult T-cell leukemia, chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), hairy cell leukemia, myelodysplasia, myeloproliferative disorders, chronic myelogenous leukemia (CML), acutemonocytic leukemia (AMoL), myelodysplastic syndrome (MDS), human lymphotropic virus- type 1 (HTLV- 1) leukemia, mastocytosis, B-cell acute lymphoblastic leukemia, Non-Hodgkin's Lymphoma, Hodgkin's Lymphoma, and multiple myeloma (MM). In some embodiments, the liquid tumor is at least one of the group consisting of: acute lymphoblastic leukemia (ALL), acute myelogenous leukemia (AML), chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), DLBCL, mantle cell lymphoma, NonHodgkin lymphoma (such as follicular lymphoma, including relapsed or refractory NHL and recurrent follicular), Hodgkin lymphoma, and multiple myeloma.

[0081] In some embodiments, the disorder is ovarian cancer.

[0082] In some embodiments, a compound, or pharmaceutically acceptable salt thereof, or pharmaceutical composition described herein is administered as a first-line therapy. In some embodiments, a compound, or pharmaceutically acceptable salt thereof, or pharmaceutical composition described herein is administered to a treatment-naive subject, i.e. a subject that has not yet been treated with the standard of care.

[0083] In another aspect of the disclosure, described herein is a method of treating cancer (e.g., a cancer described herein) in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound described herein, or phamaceutically acceptable salt thereof, or pharmaceutical composition described herein.

[0084] In another aspect, described herein is a method of degrading CDK2 in a subject suffering from cancer (e.g., a cancer described herein), comprising administering to the subject a therapeutically effective amount of a compound described herein, or phamaceutically acceptable salt thereof, or pharmaceutical composition described herein.

[0085] In another aspect, described herein is a method of treating a solid tumor (e.g., a solid tumor described herein) in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound described herein, or phamaceutically acceptable salt thereof, or pharmaceutical composition described herein.

[0086] In another aspect, described herein is a method of treating a liquid tumor (e.g., a liquid tumor described herein) in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound described herein, or phamaceutically acceptable salt thereof, or pharmaceutical composition described herein. In some embodiments, the liquid tumor is that of a haematological cancer (e.g., a haematological cancer described herein).Combinations

[0087] The compounds and pharmaceutical compositions described herein can be administered as single agents or in combination with one or more additional therapeutic agents such as additional anticancer agents. Therefore, in some embodiments, a compound, or pharmaceutically acceptable salt thereof, orpharmaceutical composition described herein is administered in combination with an additional therapeutic agent.

[0088] The additional therapeutic agent may be administered at the same time, or at a different time to the compounds and pharmaceutical compositions described herein.

[0089] Additional anticancer agents that can be administered in the methods of the present disclosure include anticancer agents of the following classes: mitotic inhibitors, alkylating agents, antimetabolites, antitumor antibiotics, anti-angiogenesis agents, topoisomerase I and II inhibitors, plant alkaloids, hormonal agents and antagonists, growth factor inhibitors, radiation, signal transduction inhibitors, such as inhibitors of protein tyrosine kinases, biological response modifiers, enzyme inhibitors, antisense oligonucleotides or oligonucleotide derivatives, cytotoxics, immuno -oncology agents, and the like.

[0090] Alternatively, the additional anticancer agent may be an anticancer agent of one of the following classes: endocrine agents, PIK3CA inhibitors, antibody-drug conjugates, PLK1 inhibitors, Estrogen PROTAC, anti-angiogenesis agents, signal transduction inhibitors such as kinase inhibitors, classical antineoplastic agents such as hormonal modulators, epigenetic modulators, immunomodulatory agents, and EGFR inhibitors.

[0091] In some embodiments, the additional anticancer agent is an endocrine agent such as an aromatase inhibitor, a SERD (Selective Estrogen-Receptor Downregulators), or a 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, afimoxifene, arzoxifene, bazedoxifene, fispemifene, ormeloxifene, ospemifene, tesmilifene, toremifene, trilostane, and CHF 4227 (Cheisi).

[0092] In some embodiments, the additional anticancer agent is a PIK3CA inhibitor such as alpelisib (PIQRAY), BEBT-908, BPI-21668, bupalisib, inavolisib, TQB-3525, RLY-2608, miransertib, MEN-1611, LOXO-783, HS-10352, HH-CYH33, gedatolisib, or fimepinostat.

[0093] In some embodiments, the additional anticancer agent is an antibody-drug conjugate such as Trastuzumab deruxtecan (Enhertu), Trastuzumab duocarmazine, Trastuzumab emtansine (Kadcyla), Upifitamab rilsodotin, mirvetuximab soravtansine, Tisotumab vedotin (Tivdak), Praluzatamab ravtansine, Sacituzumab govitecan or Sacituzumab Govitecan-hziy (Trodelvy), Datopotamab deruxtecan, Ladiratuzumab vedotin, Patritumab deruxtecan, STRO-002, MORab-202, DS-6000, Anetumab, avtansine, XMT-2056, Disitamab Vedotin (RC48-ADC, Aidexi).

[0094] In some embodiments, the additional anticancer agent is a PLK1 inhibitor such as onvansertib, B12536, BI6727, GSK461364A, TAK960, rigosertib.

[0095] In some embodiments, the additional anticancer agent is Estrogen PROTAC (ARV-471, H3B-5942).

[0096] In some embodiments, a compound, or pharmaceutically acceptable salt thereof, or pharmaceutical composition described herein is administered in combination with endocrine therapy, for example, an agent such as letrozole, fulvestrant, tamoxifen, exemestane, or anastrozole. In some embodiments, a compound, or pharmaceutically acceptable salt thereof, or pharmaceutical composition described herein is administered in combination with a chemotherapeutic agent, for example, docetaxel, paclitaxel, cisplatin, carboplatin, capecitabine, gemcitabine, vinorelbine, or liposomal doxorubicin. In other embodiments, a compound, or pharmaceutically acceptable salt thereof, or pharmaceutical composition described herein is administered in combination with an anti-HER2 agent, for example, trastuzumab or pertuzumab.

[0097] In some embodiments, the additional therapeutic agent is carboplatin, fulvestrant, or a combination thereof.

[0098] In some embodiments, the additional anticancer agent is an anti-angiogenesis agent such as an anti-angiogenesis agent selected from the group consisting of: VEGF inhibitors, VEGFR inhibitors, TIE-2 inhibitors, PDGFR inhibitors, angiopoetin inhibitors, PKCb inhibitors, COX-2 (cyclooxygenase II) inhibitors, integrins (alpha-v / beta-3), MMP-2 (matrix-metalloproteinase 2) inhibitors, and MMP-9 (matrixmetalloproteinase 9) inhibitors. Preferred anti-angiogenesis agents include sunitinib (Sutent™), bevacizumab (Avastin™), axitinib (AG 13736), SU 14813 (Pfizer), and AG 13958 (Pfizer). Additional anti-angiogenesis 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-angiogenesis agents include enzastaurin (LY 317615), midostaurin (CGP 41251), perifosine (KRX 0401), teprenone (Selbex™), and UCN 01 (Kyowa Hakko). Other examples of antiangiogenesis 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™). Yet further anti-angiogenesis 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™), ketorolac (Toradol™), and oxaprozin (Daypro™). Yet further anti-angiogenesis agents include ABT 510 (Abbott), apratastat (TMI 005), AZD 8955 (AstraZeneca), incyclinide (Metastat™), and PCK 3145 (Procyon). Yet further anti-angiogenesis agents (including VEGFR / PDGFR inhibitors) include ponatinib(Iclusig), BT1718, anlotinib, lenvatinib (Lenvima), tivozanib (Fotivda), dovitinib, brolucizumab (Beovu), aflibercept (Eylea), and faricimab. Yet further anti-angiogenesis agents include acitretin (Neotigason™), plitidepsin (aplidine™), cilengtide (EMD 121974), combretastatin A4 (CA4P), fenretinide (4 HPR), halofuginone (Tempostatin™), Panzem™ (2~methoxyestradiol), PF-03446962 (Pfizer), rebimastat (BMS 275291), catumaxomab (Removab™), lenalidomide (Revlimid™), squalamine (EVIZON™), thalidomide (Thalomid™), Ukrain™ (NSC 631570), Vitaxin™ (MED1522), and zoledronic acid (Zometa™).

[0099] In other embodiments, the additional anticancer agent is a signal transduction inhibitor (an agent that inhibits how regulatory molecules that govern the 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 famesyl protein transferase inhibitors, EGF inhibitors, ErbB-1 (EGER), ErbB-2, pan erb, IGF 1R 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, inhibitors of the WNT pathway, and multi-targeted kinase inhibitors. Additional examples of signal transduction inhibitors include BMS 214662 (Bristol-Myers Squibb), lonafamib (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), gedatolisib (Pfizer), canertinib (Cl 1033), pertuzumab (Omnitarg™), lapatinib (Tycerb™), pelitinib (EKB 569), miltefosine (Miltefosin™), 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 (Array Biopharm), everolimus (Certican™), zotarolimus (Endeavor™), temsirolimus (Torisel™), AP 23573 (ARIAD), and VX 680 (Vertex), XL 647 (Exelixis), sorafenib (Nexavar™), LE-AON (Georgetown University), and GI-4000 (Globelmmune). Other signal transduction inhibitors include ABT 751 (Abbott), alvocidib (flavopiridol), BMS 387032 (Bristol Myers), EM 1421 (Erimos), indisulam (E 7070), seliciclib (CYC 200), BIO 112 (One Bio), BMS 387032 (Bristol-Myers Squibb), and AG 024322 (Pfizer).

[0100] In other embodiments, the additional anticancer agent is a classical antineoplastic agent. Classical antineoplastic agents include hormonal modulators such as hormonal, anti-hormonal, androgen agonist, androgen antagonist and anti-estrogen therapeutic agents, histone deacetylase (HDAC) inhibitors, DNA methyltransferase inhibitors, silencing agents or gene activating agents, ribonucleases, proteosomics, Topoisomerase I inhibitors, Camptothecin derivatives, Topoisomerase II inhibitors, alkylating agents,antimetabolites, poly(ADP-ribose) polymerase-1 (PARP-1) inhibitors (such as talazoparib, olapariv, rucaparib, niraparib, iniparib, veliparib), microtubulin inhibitors, antibiotics, plant derived spindle inhibitors, platinum -coordinated compounds, gene therapeutic agents, antisense oligonucleotides, vascular targeting agents (VTAs), and statins. Examples of classical antineoplastic agents include glucocorticoids such as dexamethasone, prednisone, prednisolone, methyl prednisolone, hydrocortisone, and progestins such as medroxyprogesterone, megestrol acetate (Megace), mifepristone (RU-486), Selective Estrogen Receptor Modulators (SERMs, such as tamoxifen, raloxifene, lasofoxifene, afimoxifene, arzoxifene, bazedoxifene, fispemifene, ormeloxifene, ospemifene, tesmilifene, toremifene, trilostane, and CHF 4227 (Cheisi)), Selective Estrogen-Receptor Downregulators (SERDs, such as fulvestrant, SZ102, G1T48, RADI 901, elacestrant, GDC-9545, giredestrant, SAR439859, amcenestrant, AZD9833, camizestrant, LY3484356, Zn-c5, D-0502), exemestane (Aromasin), anastrozole (Arimidex), atamestane, fadrozole, letrozole (Femara), formestane; gonadotropin-releasing hormone (GnRH, also commonly referred to as luteinizing hormone-releasing hormone [LHRH]) agonists such as buserelin (Suprefact), goserelin (Zoladex), leuprorelin (Lupron), and triptorelin (Trelstar), abarelix (Plenaxis), cyproterone, flutamide (Eulexin), megestrol, nilutamide (Nilandron), and osaterone, dutasteride, epristeride, finasteride, Serenoa repens, PHL 00801, abarelix, goserelin, leuprorelin, triptorelin, bicalutamide; antiandrogen agents, such as enzalutamide, abiraterone acetate, bicalutamide (Casodex); and combinations thereof. Other examples of classical antineoplastic agents include suberolanilide hydroxamic acid (SAHA, Merck Inc. / Aton Pharmaceuticals), depsipeptide (FR901228 or FK228), G2M-777, MS-275, pivaloyloxymethyl butyrate and PXD-101; Onconase (ranpimase), PS-341 (MLN-341), Velcade (bortezomib), 9-aminocamptothecin, belotecan, BN-80915 (Roche), camptothecin, diflomotecan, edotecarin, exatecan (Daiichi), gimatecan, 10-hydroxycamptothecin, irinotecan HC1 (Camptosar), lurtotecan, Orathecin (rubitecan, Supergen), SN-38, topotecan, camptothecin, 10-hydroxy camptothecin, 9-aminoearaptothecin, irinotecan, SN-38, edotecarin, topotecan, aclarubicin, adriamycin, amonafide, amrubicin, annamycin, daunorubicin, doxorubicin, elsamitrucin, epirubicin, etoposide, idarubicin, galarubicin, hydroxycarbamide, nemorubicin, novantrone (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, fotemustine, glufosfamide, ifosfamide, KW-2170, lomustine, mafosfamide, mechlorethamine, melphalan, mitobronitol, mitolactol, mitomycin C, mitoxatrone, nimustine, ranimustine, temozolomide, thiotepa, and platinum -coordinated alkylating compounds such as cisplatin, Paraplatin (carboplatin), eptaplatin, lobaplatin, nedaplatin, Eloxatin (oxaliplatin, Sanofi), streptozocin, satrplatin, and combinations thereof. Other examples of classical antineoplastic cytotoxic agents include Abraxane (Abraxis BioScience, Inc.), Batabulin (Amgen), EPO 906 (Novartis), Vinflunine (Bristol-Myers Squibb Company), actinomycin D, bleomycin, mitomycin C, neocarzinostatin (Zinostatin), vinblastine, vincristine, vindesine, vinorelbine (Navelbine), docetaxei(Taxotere), Ortataxel, paclitaxel (including Taxoprexin, a DHA / paciltaxel conjugate), cisplatin, carboplatin, Nedaplatin, oxaliplatin (Eloxatin), Satraplatin, Camptosar, capecitabine (Xeloda), oxaliplatin (Eloxatin), Taxotere alitretinoin, Canfosfamide (Telcyta™), DMXAA (Antisoma), ibandronic acid, L-asparaginase, pegaspargase (Oncaspar™), Efaproxiral (Efaproxyn™ - radiation therapy), bexarotene (Targretin™), Tesmilifene (DPPE - enhances efficacy of cytotoxics), Theratope™ (Biomira), Tretinoin (Vesanoid™), tirapazamine (Trizaone™), motexafin gadolinium (Xcytrin™), Cotara™ (mAb), NBI-3001 (Protox Therapeutics), polyglutamate-paclitaxel (Xyotax™), and combinations thereof. Further examples of classical antineoplastic agents include Advexin (ING 201), TNFerade (GeneVec, a compound which expresses TNF alpha in response to radiotherapy), RB94 (Baylor College of Medicine), Genasense (Oblimersen, Genta), Combretastatin 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 (Bay col, Bayer), Rosuvastatin (Crestor, AstraZeneca), Lovostatin, Niacin (Advicor, Kos Pharmaceuticals), Caduet, Lipitor, torcetrapib, and combinations thereof.

[0101] In some embodiments, the additional anticancer agent is an epigenetic modulator 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.

[0102] In some embodiments, the additional anticancer agent is an immunomodulatory agent such as an inhibitor of CTLA-4 (for example, ipilimumab), PD-1 or PD-L1 (for example, pembrolizumab, nivolumab, avelumab, atezolizumab, durvalumab, cemiplimab, or dosterlimab), LAG-3 (for example, relatlimab), TIM-3, TIGIT, 4-1BB, 0X40, GITR, or CD40, or a CAR-T-cell therapy.

[0103] In some embodiments, 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.

[0104] Alternatively, the additional anticancer agent is an anticancer agent that is not an EGFR inhibitor, for example selected from MEK, including mutant MEK inhibitors (trametinib, cobimetinib, binimetinib, selumetinib, refametinib); c-MET, including mutant c-Met inhibitors (savolitinib, cabozantinib, foretinib) and MET antibodies (emibetuzumab); anti-angiogenic agents such as bevacizumab, nintedanib; apoptosis inducers such as Bcl-2 inhibitors e.g., venetoclax, obatoclax, navitoclax, and Mcl-1 inhibitors e.g., AZD-5991, AMG-176, S-64315; and mTOR inhibitors such as rapamycin, temsirolimus, everolimus, ridoforo limns.

[0105] In some embodiments, the additional anticancer agent is 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®), an EGFR inhibitor, pralsetinib, ABT-263 (navitoclax), MK-1775 (adavosertib), BAY-1895344, berzosertib, ceralasertib, SRA-737, LY2603618 (rabusertib), and trastuzumab (e.g., herceptin®), or combinations thereof. The EGFR inhibitor may be afatinib, osimertinib, lapatinib, erlotinib, dacomitinib, poziotinib, neratinib, gefitinib JBJ-04-125-02, alflutinib (AST 2818), aumolertinib (formerly almonertinib) (HS10296), BBT-176, BI-4020, BPI-361175, BPI-D0316, CH7233163, gilitertinib, icotinib, JND-3229, lazertinib, nazartinib (EGF 816), avitinib, PCC-0208027, rezivertinib (BRI-77G1), TQB3804, zorifertinib (AZ-3759), or DZD9008; an EGFR antibody such as cetuximab, panitumumab, necitumumab, HLX07, or JMT101; or a bispecific EGFR and MET antibody (e.g., amivantamab (JNJ-61186372, JNJ-372)).Definitions

[0106] Definitions of specific functional groups and chemical terms are described in more detail below. The chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75thEd., inside cover, and specific functional groups are generally defined as described therein. Additionally, general principles of organic chemistry, as well as specific functional moieties and reactivity, are described in Thomas Sorrell, Organic Chemistry, University Science Books, Sausalito, 1999; Smith and March, March ’s Advanced Organic Chemistry, 5thEdition, 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, 3rdEdition, Cambridge University Press, Cambridge, 1987.

[0107] When a range of values is listed, it is intended to encompass each value and sub-range within the range. For example “Ci-6 alkyl” is intended to encompass, Ci, C2, C3, C4, C5, Ce, C1-6, C1-5, C1-4, C1-3, Ci 2, C2-6, C2-5, C2-4, C2-3, C3-6, C3-5, C3-4, C4-6, C4-5, and C5-6 alkyl.

[0108] Compounds that are described as being “optionally substituted” may be substituted with one or more specifically described groups, or may be unsubstituted. In some embodiments, compounds that are described as being “optionally substituted” are unsubstituted.

[0109] The term “alkyl” as used herein refers to a radical of a straight-chain or branched saturated hydrocarbon group. In some embodiments, an alkyl group has 1 to 12 carbon atoms (“C1-12 alkyl”). In some embodiments, an alkyl group has 1 to 10 carbon atoms (“CMO alkyl”). In some embodiments, an alkyl group has 1 to 9 carbon atoms (“C1-9 alkyl”). In some embodiments, an alkyl group has 1 to 8 carbon atoms (“C1-8 alkyl”). In some embodiments, an alkyl group has 1 to 7 carbon atoms (“C1-7 alkyl”). In some embodiments, an alkyl group has 1 to 6 carbon atoms (“C1-6 alkyl”, also referred to herein as “lower alkyl”). In some embodiments, an alkyl group has 1 to 5 carbon atoms (“C1-5 alkyl”). In some embodiments, an alkyl group has 1 to 4 carbon atoms (“C1-4 alkyl”). In some embodiments, an alkyl group has 1 to 3 carbon atoms (“C1-3 alkyl”). In some embodiments, an alkyl group has 1 to 2 carbon atoms (“C1-2 alkyl”). In some embodiments,an alkyl group has 1 carbon atom (“Ci alkyl”). In some embodiments, an alkyl group has 2 to 6 carbon atoms (“C2-6 alkyl”). Examples of C1-6 alkyl groups include methyl (Ci), ethyl (C2), n-propyl (C3), isopropyl (C3), n-butyl (C4), tert-butyl (C4), sec-butyl (C4), iso-butyl (C4), n-pentyl (C5), 3-pentanyl (C5), amyl (C5), neopentyl (C5), 3-methyl-2-butanyl (C5), tertiary amyl (C5), and n-hexyl (Ce). Additional examples of alkyl groups include n-heptyl (C7), n-octyl (Cs) and the like. Common alkyl abbreviations include Me (-CH3), Et (-CH2CH3), iPr (-CH(CH3)2), nPr (-CH2CH2CH3), n-Bu (-CH2CH2CH2CH3), or i-Bu (-CH2CH(CH3)2).

[0110] The term “alkenyl” as used herein refers to a radical of a straight-chain or branched hydrocarbon group having one or more carbon-carbon double bonds. In some embodiments, an alkenyl group has 2 to 10 carbon atoms (“C2-10 alkenyl”). In some embodiments, an alkenyl group has 2 to 9 carbon atoms (“C2-9 alkenyl”). In some embodiments, an alkenyl group has 2 to 8 carbon atoms (“C2-8 alkenyl”). In some embodiments, an alkenyl group has 2 to 7 carbon atoms (“C2-7 alkenyl”). In some embodiments, an alkenyl group has 2 to 6 carbon atoms (“C2-6 alkenyl”). In some embodiments, an alkenyl group has 2 to 5 carbon atoms (“C2-5 alkenyl”). In some embodiments, an alkenyl group has 2 to 4 carbon atoms (“C2-4 alkenyl”). In some embodiments, an alkenyl group has 2 to 3 carbon atoms (“C2-3 alkenyl”). In some embodiments, an alkenyl group has 2 carbon atoms (“C2 alkenyl”). The one or more carbon-carbon double bonds can be internal (such as in 2-butenyl) or terminal (such as in 1-butenyl). Examples of C2-4 alkenyl groups include ethenyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), and the like. Examples of C2-6 alkenyl groups include the aforementioned C2-4 alkenyl groups as well as pentenyl (C5), pentadienyl (C5), hexenyl (Ce), and the like. Additional examples of alkenyl include heptenyl (C7), octenyl (Cs), octatrienyl (Cs), and the like.

[0111] The term “alkynyl” as used herein refers to a radical of 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, an alkynyl group has 2 to 10 carbon atoms (“C2-10 alkynyl”). In some embodiments, an alkynyl group has 2 to 9 carbon atoms (“C2-9 alkynyl”). In some embodiments, an alkynyl group has 2 to 8 carbon atoms (“C2-8 alkynyl”). In some embodiments, an alkynyl group has 2 to 7 carbon atoms (“C2-7 alkynyl”). In some embodiments, an alkynyl group has 2 to 6 carbon atoms (“C2-6 alkynyl”). In some embodiments, an alkynyl group has 2 to 5 carbon atoms (“C2-5 alkynyl”). In some embodiments, an alkynyl group has 2 to 4 carbon atoms (“C2-4 alkynyl”). In some embodiments, an alkynyl group has 2 to 3 carbon atoms (“C2-3 alkynyl”). In some embodiments, an alkynyl group has 2 carbon atoms (“C2 alkynyl”). The one or more carbon-carbon triple bonds can be internal (such as in 2-butynyl) or terminal (such as in 1- butynyl). Examples of C2-4 alkynyl groups include, without limitation, ethynyl (C2), 1-propynyl (C3), 2- propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), and the like. Examples of C2-6 alkenyl groups include the aforementioned C2-4 alkynyl groups as well as pentynyl (C5), hexynyl (Ce), and the like. Additional examples of alkynyl include heptynyl (C7), octynyl (Cs), and the like.

[0112] The term “cycloalkyl” as used herein refers to a radical of a saturated or partially unsaturated cyclic hydrocarbon group having from 3 to 12 ring carbon atoms (“C3-12 cycloalkyl”) and zero heteroatoms in the ring system. In some embodiments, a cycloalkyl group has 3 to 10 ring carbon atoms (“C3-10 cycloalkyl”). In some embodiments, a cycloalkyl group has 3 to 8 ring carbon atoms (“C3-8 cycloalkyl”). In some embodiments, a cycloalkyl group has 3 to 6 ring carbon atoms (“C3-6 cycloalkyl”). In some embodiments, a cycloalkyl group has 3 to 6 ring carbon atoms (“C3-6 cycloalkyl”). In some embodiments, a cycloalkyl group has 5 to 10 ring carbon atoms (“C5-10 cycloalkyl”). Exemplary C3-6 cycloalkyl groups include, without limitation, cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (Ce), cyclohexenyl (Ce), cyclohexadienyl (Ce), and the like. Exemplary C3-8 cycloalkyl groups include, without limitation, the aforementioned C3-6 cycloalkyl groups as well as cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (Cs), cyclooctenyl (Cs), bicyclo[2.2.1]heptanyl (C7), bicyclo[2.2.2]octanyl (Cs), and the like. Exemplary C3-10 cycloalkyl groups include, without limitation, the aforementioned C3-8 cycloalkyl groups as well as cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C10), cyclodecenyl (C10), octahydro-1 H-indenyl (C9), decahydronaphthalenyl (C10), spiro[4.5]decanyl (C10), and the like. In certain embodiments, the cycloalkyl group is either monocyclic (“monocyclic cycloalkyl”) or contain a fused, bridged or spiro ring system such as a bicyclic system (“bicyclic cycloalkyl”) or tricyclic system (“tricyclic cycloalkyl”). “Cycloalkyl” also includes ring systems wherein the cycloalkyl ring, as defined above, is fused with one or more aryl or heteroaryl groups wherein the point of attachment is on the cycloalkyl ring or the one or more aryl or heteroaryl groups, and in such instances, the number of carbons continue to designate the number of carbons in the cycloalkyl ring system.

[0113] The term “heterocyclyl” as used herein refers to a radical of a saturated or partially unsaturated 3 to 10-membered ring system having ring carbon atoms and 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon (“3 to 10 membered heterocyclyl”). In heterocyclyl groups that contain one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valency permits. A heterocyclyl group can either be monocyclic (“monocyclic heterocyclyl”) or a fused, bridged or spiro ring system such as a bicyclic system (“bicyclic heterocyclyl”). Heterocyclyl bicyclic ring systems can include one or more heteroatoms in one or both rings. “Heterocyclyl” also includes ring systems wherein the heterocyclyl ring, as defined above, is fused with one or more cycloalkyl groups wherein the point of attachment is either on the cycloalkyl or heterocyclyl ring, or ring systems wherein the heterocyclyl ring, as defined above, is fused with one or more aryl or heteroaryl groups, wherein the point of attachment is on the heterocyclyl ring or the one or more aryl or heteroaryl groups, and in such instances, the number of ring members continue to designate the number of ring members in the heterocyclyl ring system.

[0114] In some embodiments, a heterocyclyl group is a 5 to 10 membered saturated or partially unsaturated ring system having ring carbon atoms and 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon (“5 to 10 membered heterocyclyl”). In some embodiments, a heterocyclyl group is a 5 to 8 membered saturated or partially unsaturated ring system having ring carbon atoms and 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5 to 8 membered heterocyclyl”). In some embodiments, a heterocyclyl group is a 5 to 6 membered saturated or partially unsaturated ring system having ring carbon atoms and 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5 to 6 membered heterocyclyl”). In some embodiments, the 5 to 6 membered heterocyclyl has 1 to 3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5 to 6 membered heterocyclyl has 1 to 2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5 to 6 membered heterocyclyl has one ring heteroatom selected from nitrogen, oxygen, and sulfur.

[0115] Exemplary 3-membered heterocyclyl groups containing one heteroatom include, without limitation, azirdinyl, oxiranyl, thiorenyl. Exemplary 4-membered heterocyclyl groups containing one heteroatom include, without limitation, azetidinyl, oxetanyl and thietanyl. Exemplary 5-membered heterocyclyl groups containing one heteroatom include, without limitation, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl and pyrrolyl-2, 5-dione. Exemplary 5-membered heterocyclyl groups containing two heteroatoms include, without limitation, dioxolanyl, oxasulfuranyl, disulfuranyl, and oxazolidin-2-one. Exemplary 5-membered heterocyclyl groups containing three heteroatoms include, without limitation, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6- membered heterocyclyl groups containing one heteroatom include, without limitation, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl. Exemplary 6-membered heterocyclyl groups containing two heteroatoms include, without limitation, piperazinyl, morpholinyl, dithianyl, dioxanyl. Exemplary 6- membered heterocyclyl groups containing two heteroatoms include, without limitation, triazinanyl. Exemplary 7-membered heterocyclyl groups containing one heteroatom include, without limitation, azepanyl, oxepanyl and thiepanyl. Exemplary 8-membered heterocyclyl groups containing one heteroatom include, without limitation, azocanyl, oxecanyl and thiocanyl. Exemplary 5-membered heterocyclyl groups fused to a Ce aryl ring (also referred to herein as a 5,6-bicyclic heterocyclic ring) include, without limitation, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, benzoxazolinonyl, and the like. Exemplary 6-membered heterocyclyl groups fused to an aryl ring (also referred to herein as a 6,6-bicyclic heterocyclic ring) include, without limitation, tetrahydroquinolinyl, tetrahydroiso quinolinyl, and the like.

[0116] The term “aryl” as used herein refers to a radical of a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 it electrons shared in a cyclic array) having 6to 14 ring carbon atoms and zero heteroatoms provided in the aromatic ring system (“Ce i4 aryl”). In some embodiments, an aryl group has six ring carbon atoms (“Ce aryl”; e.g., phenyl). In some embodiments, an aryl group has ten ring carbon atoms (“Cio aryl”; e.g., naphthyl such as 1-naphthyl and 2-naphthyl). In some embodiments, an aryl group has fourteen ring carbon atoms (“C14 aryl”; e.g., anthracyl). Typical aryl groups include, but are not limited to, groups derived from aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene, coronene, fluoranthene, fluorene, hexacene, hexaphene, hexalene, as-indacene, s-indacene, indane, indene, naphthalene, octacene, octaphene, octalene, ovalene, penta-2,4-diene, pentacene, pentalene, pentaphene, perylene, phenalene, phenanthrene, picene, pleiadene, pyrene, pyranthrene, rubicene, triphenylene, and trinaphthalene. Particularly aryl groups include phenyl, naphthyl, indenyl, and tetrahydronaphthyl.

[0117] The term “heteroaryl” as used herein refers to a radical of a 5 to 10 membered monocyclic or bicyclic 4n+2 aromatic ring system (e.g., having 6 or 10 it electrons shared in a cyclic array) having ring carbon atoms and 1 to 4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen and sulfur (“5 to 10 membered heteroaryl”). In heteroaryl groups that contain one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valency permits. Heteroaryl bicyclic ring systems can include one or more heteroatoms in one or both rings. “Heteroaryl” also includes ring systems wherein the heteroaryl ring, as defined above, is fused with one or more aryl groups wherein the point of attachment is either on the aryl or heteroaryl ring, and in such instances, the number of ring members designates the number of ring members in the fused (ary 1 / hetero aryl) ring system. Bicyclic heteroaryl groups wherein one ring does not contain a heteroatom (e.g., indolyl, quinolinyl, carbazolyl, and the like) the point of attachment can be on either ring, i.e., either the ring bearing a heteroatom (e.g., 2-indolyl) or the ring that does not contain a heteroatom (e.g., 5-indolyl).

[0118] In some embodiments, a heteroaryl group is a 5 to 10 membered aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms provided 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 having ring carbon atoms and 1 to 4 ring heteroatoms provided 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 having ring carbon atoms and 1 to 4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5 to 6 membered heteroaryl”). In some embodiments, the 5 to 6 membered heteroaryl has 1 to 3 ring heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5 to 6 membered heteroaryl has 1 to 2 ring heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5 to 6 membered heteroaryl has 1 ringheteroatom selected from nitrogen, oxygen, and sulfur. In some embodiments, a heteroaryl group is a monocyclic 5 membered aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-membered heteroaryl”). In some embodiments, a heteroaryl group is a monocyclic 6 membered aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“6-membered heteroaryl”).

[0119] In some embodiments, a heteroaryl group is a 5 to 10 membered aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms provided 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 having ring carbon atoms and 1 to 4 ring heteroatoms provided 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 having ring carbon atoms and 1 to 4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently nitrogen or oxygen (“5 to 6 membered heteroaryl”). In some embodiments, the 5 to 6 membered heteroaryl has 1 to 3 ring heteroatoms that are independently nitrogen or oxygen. In some embodiments, the 5 to 6 membered heteroaryl has 1 to 2 ring heteroatoms that are independently nitrogen or oxygen. In some embodiments, the 5 to 6 membered heteroaryl has 1 ring heteroatom that is independently nitrogen or oxygen. In some embodiments, a heteroaryl group is a monocyclic 5 membered aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently nitrogen or oxygen (“5 -membered heteroaryl”). In some embodiments, a heteroaryl group is a monocyclic 6 membered aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently nitrogen or oxygen (“6-membered heteroaryl”).

[0120] Exemplary 5-membered heteroaryl groups containing one heteroatom include, without limitation, pyrrolyl, furanyl and thiophenyl. Exemplary 5 -membered heteroaryl groups containing two heteroatoms include, without limitation, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5 -membered heteroaryl groups containing three heteroatoms include, without limitation, triazolyl, oxadiazolyl, and thiadiazolyl. Exemplary 5-membered heteroaryl groups containing four heteroatoms include, without limitation, tetrazolyl. Exemplary 6-membered heteroaryl groups containing one heteroatom include, without limitation, pyridinyl. Exemplary 6-membered heteroaryl groups containing two heteroatoms include, without limitation, pyridazinyl, pyrimidinyl, and pyrazinyl. Exemplary 6-membered heteroaryl groups containing three or four heteroatoms include, without limitation, triazinyl and tetrazinyl, respectively. Exemplary 7-membered heteroaryl groups containing one heteroatom include,without limitation, azepinyl, oxepinyl, and thiepinyl. Exemplary 5,6-bicyclic heteroaryl groups include, without limitation, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzoisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzthiazolyl, benzisothiazolyl, benzthiadiazolyl, indolizinyl, and purinyl. Exemplary 6,6-bicyclic heteroaryl groups include, without limitation, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl.

[0121] The term “alkoxy” as used herein refers to the group -OR100where R100is alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl. Exemplary alkoxy groups include methoxy, ethoxy, n- propoxy, isopropoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, and 1,2-dimethylbutoxy. Other exemplary alkoxy groups are lower alkoxy, i.e. with between 1 and 6 carbon atoms. In other examples, alkoxy groups have between 1 and 4 carbon atoms.

[0122] The term “thioalkoxy” as used herein refers to the group -SR101where R101is alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl. Exemplary thioalkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, and 1 ,2-dimethylbutoxy. Other exemplary thioalkoxy groups are lower thioalkoxy, i.e. with between 1 and 6 carbon atoms. In other examples, thioalkoxy groups have between 1 and 4 carbon atoms.

[0123] The term “hydroxy” as used herein refers to the radical -OH.

[0124] The term “cyano” as used herein refers to the radical -CN.

[0125] The term “halogen” as used herein refers to F, Cl, Br, or I.

[0126] The term “oxo” as used herein refers to =0.

[0127] As used herein, the term “pharmaceutically acceptable salt” refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, Berge et al., describes pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences (1977) 66:1-19. Pharmaceutically acceptable salts of the compounds of the present disclosure include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate,lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2- naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3- phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and the like. Pharmaceutically acceptable salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N+(Ci-4alkyl)4 salts. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate, and aryl sulfonate.

[0128] A “subject” to which administration is contemplated includes, but is not limited to, humans (i.e., a male or female of any age group, e.g., a pediatric subject (e.g, infant, child, adolescent) or adult subject (e.g., young adult, middle-aged adult or senior adult)) and / or a non-human animal, e.g., a mammal such as primates (e.g., cynomolgus monkeys, rhesus monkeys), cattle, pigs, horses, sheep, goats, rodents, cats, and / or dogs. In certain embodiments, the subject is a human. In certain embodiments, the subject is a non-human animal. The terms “human,” “patient,” and “subject” are used interchangeably herein.

[0129] The terms “disease,” “disorder,” and “condition” are used interchangeably herein.

[0130] As used herein, and unless otherwise specified, the terms “treat,” “treating” and “treatment” contemplate an action that occurs while a subject is suffering from the specified disease, disorder or condition, which reduces the severity of the disease, disorder or condition, or retards or slows the progression of the disease, disorder or condition. In an alternative embodiment, the present disclosure contemplates administration of the compounds described herein as a prophylactic before a subject begins to suffer from the specified disease, disorder or condition.

[0131] In general, the “effective amount” of a compound as used herein refers to an amount sufficient to elicit the desired biological response. As will be appreciated by those of ordinary skill in this art, the effective amount of a compound of the present disclosure may vary depending on such factors as the desired biological endpoint, the pharmacokinetics of the compound, the disease being treated, the mode of administration, and the age, health, and condition of the subject.

[0132] As used herein, and unless otherwise specified, a “therapeutically effective amount” of a compound is an amount sufficient to provide a therapeutic benefit in the treatment of a disease, disorder or condition, or to delay or minimize one or more symptoms associated with the disease, disorder or condition. A therapeutically effective amount of a compound means an amount of therapeutic agent, alone or in combination with other therapies, which provides a therapeutic benefit in the treatment of the disease, disorder or condition. The term “therapeutically effective amount” can encompass an amount that improvesoverall therapy, reduces or avoids symptoms or causes of disease or condition, or enhances the therapeutic efficacy of another therapeutic agent.

[0133] It is also to be understood that compounds that have the same molecular formula but differ in the nature or sequence of bonding of their atoms or the arrangement of their atoms in space are termed “isomers.” Isomers that differ in the arrangement of their atoms in space are termed “stereoisomers.” Stereoisomers that are not mirror images of one another are termed “diastereomers” and those that are non-superimposable mirror images of each other are termed “enantiomers.” When a compound has an asymmetric center, for example, it is bonded to four different groups, a pair of enantiomers is possible. An enantiomer can be characterized by the absolute configuration of its asymmetric center and is described by the R- and S- sequencing rules of Cahn and Prelog, or by the manner in which the molecule rotates the plane of polarized light and designated as dextrorotatory or levorotatory (i.e., as (+) or (-)-isomers respectively). A chiral compound can exist as either individual enantiomer or as a mixture thereof. A mixture containing equal proportions of the enantiomers is called a “racemic mixture”.

[0134] Isomers, e.g., stereoisomers, can be isolated from mixtures by methods known to those skilled in the art, including chiral high pressure liquid chromatography (HPLC) and the formation of chiral salts; or preferred isomers can be prepared by asymmetric syntheses. 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 p. 268 (E.L. Eliel, Ed., Univ, of Notre Dame Press, Notre Dame, IN 1972). The present disclosure additionally encompasses compounds described herein as individual isomers substantially free of other isomers, and alternatively, as mixtures of various isomers.

[0135] The compounds provided herein can be administered as the sole active agent, or they can be administered in combination with other active agents. In some embodiments, the present invention provides a combination of a compound of the present invention and another pharmacologically active agent.Administration in combination can proceed by any technique apparent to those of skill in the art including, for example, separate, sequential, concurrent, and alternating administration.

[0136] The present disclosure, in an alternative embodiment, also embraces isotopically labeled compounds which are identical to those recited herein, except that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into compounds described herein include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine, such as2H,3H,13C,14C,15N,18O,170,31P,32P,35S,18F, and36C1, respectively. For example, a compound of the disclosure may have one or more H atom replaced with deuterium.Preparation of compounds

[0137] The compounds of the present invention, including salts, stereoisomers and isotopomers, can be prepared in a number of ways well known to those skilled in the art of synthetic organic chemistry. The compounds of formula I may for example be prepared using the reactions and techniques outlined below together with methods known in the art of synthetic organic chemistry, or variations thereof, as appreciated by those skilled in the art. Preferred methods include, but are not limited to, those described below.

[0138] The reactions are carried out in solvents appropriate to the reagents and materials employed and suitable for the transformations being effected. Also, in the synthetic methods described below, it is to be understood that all proposed reaction conditions, including choice of solvent, reaction atmosphere, reaction temperature, reaction time and work-up procedures, are chosen to be conditions of standard for that reaction, which should be readily recognized by one skilled in the art of synthetic organic chemistry.

[0139] The schemes below provide general guidance in connection with preparing the compounds of the invention. One skilled in the art would understand that the preparations shown in the schemes can be modified or optimized using general knowledge of organic chemistry to prepare various compounds of the invention. Not all compounds falling into a given class may be compatible with some reaction conditions required in some of the methods described. Such restrictions to the substituents which are compatible with the reaction conditions will be readily apparent to one skilled in the art and alternative methods can then be used.

[0140] All starting materials are either commercially available or can be prepared by routine synthetic methods well known to a person skilled in the art.General Scheme 1

[0141] Reagents and conditions: (a) NIS, H2SO4, 0-25 °C, 12 h; (b) SOCI2, MeOH, 80 °C, 12 h; (c)NBS, AIBN or BPO, CHC13, 80 °C, 12 h; (d) DIPEA, MeCN, 80 °C, 12 h; (e) [(bipy^ g-Cl^Ch lWHZn, TMSC1, DMA, 0-25 °C, 12 h; (f) HC1, dioxane, 20-25 °C, 0.5-2 h; (g) Trimethylboroxine, XPhos Pd G2, XPhos, K2CO3, DMF, 100 °C, 12 h; or trimethylboroxine, PEPPSI™-IPr catalyst, K2CO3, dioxane, 100 °C, 12 h; (h) CHCIF2, MgCl2, MS 3 A, NiCl2, 4,4’-diamino-2,2’-bipyridyl, DMAP, Zn, DMA, 60 °C, 12 h; (i) SEMC1, DBU, DMF or THF, 0-25 °C, 1-6 h; (j) 4 M HC1 in dioxane, 20 °C, 1 h, then TFA, CH2C12, 20 °C, 1 h, then NH3(aq), MeCN, 20 °C, 1 h; (k) Pd(CBu3P)2, THF, 70 °C, 12 h; (1) TFA, CH2C12, 20 °C, 1 h, then NH3(aq), MeCN, 20 °C, 1 h; (m) LiCl, DMF, 160 °C, 1 h (microwave heating); (n) DPPA, TEA, MS 4 A, dioxane, 20 °C, 1 h, then 1 N HC1, 80 °C, 4 h.

[0142] Compounds of formula Intermediate A can be synthesized using the processes shown in General Scheme 1. Iodination of benzoic acids 1-1 under appropriate conditions, e.g., treatment of a suspension or solution of 1-1 in sulfuric acid with A-iodosuccinimide at 0-25 °C for 12 h, affords iodides 1-2. Esterification of acids 1-2 under appropriate conditions, e.g., treatment of a suspension or solution of 1-2 in methanol with thionyl chloride at 80 °C for 12 h, yields methyl esters 1-3. Bromination of esters 1-3 with an appropriate reagent, e.g., A-bromo succinimide together with azobisisobutyronitrile or benzoyl peroxide, in an appropriate solvent, e.g., chloroform, under appropriate conditions, e.g., at 80 °C for 12 h, affords bromides1-4. Treatment of bromides 1-4 with amine hydrochloride 1-5 and a suitable base, e.g., N.N- diisopropylethylamine, in a suitable solvent, e.g., acetonitrile, under appropriate conditions, e.g., at 80 °C for 12 h, yields isoindolinones 1-6. Reacting isoindolinones 1-6 with cyclopropane 1-7 under appropriate conditions, e.g., [(bipy)2Ni2(p-Cl)2C12(H2O)2], zinc, and trimethylchorosilane in dimethylacetamide at 0-25 °C for 12 h, affords cyclopropanes 1-8.

[0143] A person skilled in the art would understand that Intermediate A can be prepared with various R2groups by starting from 1-1 with the desired R2group already present. For example, to make Intermediate A with R2= hydrogen or halogen, the synthesis might start from 1-1 with the desired R2already in place. Alternatively, the desired R2group could be introduced at a later step of the process. For example, from 1-8 with R2= Cl, other R2groups could be introduced by e.g., coupling reactions with the R2= Cl substituent, as illustrated in optional steps g and h which can be used to prepare Intermediate A with R2= alkyl. Optional step g illustrates how 1-8 with R2= methyl can be synthesised from 1-8 with R2= Cl under appropriate conditions, e.g., using trimethylboroxine, XPhos Pd G2, XPhos, and K2CO3 in dimethylformamide at 100 °C for 12 h, or using trimethylboroxine, PEPPSI™-IPr catalyst, and K2CO3 in dioxane at 100 °C for 12 h, whereas optional step h illustrates how 1-8 with R2= difluoromethyl can be synthesised from 1-8 with R2= Cl under appropriate conditions, e.g., using CHCIF2, MgCF. MS 3 A, NiCF, 4,4’-diamino-2,2’-bipyridyl, 4-(A'.A'-dimcthylamino)pyridinc. and zinc in dimethylacetamide at 60 °C for 12 h.

[0144] Deprotection of cyclopropanes 1-8 under appropriate conditions, e.g., treatment of a suspension or solution of 1-8 in dioxane with anhydrous hydrogen chloride at 20-25 °C for 0.5-2 h, yields compounds of formula Intermediate A.

[0145] Alternatively, isoindolinones 1-6 may be SEM-protected under appropriate conditions, e.g., treatment of a suspension or solution of 1-6 in dimethylformamide or tetrahydrofuran with (2- chloromethoxyethyl)trimethylsilane (SEMC1) and l,8-diazabicyclo[5.4.0]undec-7-ene (DBU) at 0-25 °C for 1-6 h, to yield isoindolinones 1-9. Similar to the preparation of cyclopropane 1-8, reacting isoindolinones 1-9 with cyclopropane 1-7 under appropriate conditions, e.g., [(bipy)2Ni2(p-Cl)2C12(H2O)2], zinc, and trimethylchorosilane in dimethylacetamide at 0-25 °C for 12 h, affords cyclopropanes 1-10. Deprotection of cyclopropanes 1-10 under appropriate conditions, e.g., sequential treatment with 4 M HC1 in dioxane at 20 °C for 1 h, then trifluoro acetic acid in dichloromethane at 20 °C for 1 h, and finally aqueous ammonia in acetonitrile at 20 °C for 1 h, yields compounds of formula Intermediate A.

[0146] Alternatively, isoindolinones 1-9 may be coupled with cyclopropane 1-11 under appropriate conditions, e.g., using a suitable catalyst such as Pd(ABu3?)2 in tetrahydrofuran at 70 °C for 12 h, to yield cyclopropanes 1-12. Deprotection of cyclopropanes 1-12 under appropriate conditions, e.g., treatment of a suspension or solution of 1-12 in dichloromethane with trifluoro acetic acid at 20 °C for 1 h followed byaqueous ammonia in acetonitrile at 20 °C for 1 h, yields methyl esters 1-13. Hydrolysis of methyl esters 1-13 under appropriate conditions, e.g., microwave heating of a suspension or solution of 1-13 and lithium chloride in dimethylformamide at 160 °C for 1 h, affords carboxylic acids 1-14. Reacting carboxylic acids 1- 14 under appropriate conditions, e.g., diphenylphosphoryl azide, triethylamine, and 4 A molecular sieves in dioxane at 20 °C for 1 h followed by 1 M hydrochloric acid at 80 °C for 4 h, yields compounds of formula Intermediate A.General Scheme 2

[0147] Reagents and conditions: (a) Mel, K2CO3, DMF, 20-30 °C, 2-12 h; or SOCI2 (added at 0 °C), MeOH, 25-75 °C, 2-12 h; or MeOH, DMAP, DCC, CH2C12, 25 °C, 12 h; (b) H2NNH2H2O, MeOH or EtOH, 50-80 °C, 1-12 h; (c) CDI, THF, 60 °C, 3 h, then H2NNH2H2O, THF, 25 °C, 1 h; (d) H2NNHBoc, EDCI, CH2CI2, 20-25 °C, 2-12 h; or H2NNHBoc, EDCI, HOBt, TEA, CH2C12, 25 °C, 12 h; (e) TFA, CH2C12, 20-25 °C, 1-4 h; or HC1, EtOAc, 25 °C, 2 h; (f) BrCN, NaHCO3, dioxane, water, 25 °C, 2-12 h; or BrCN, MeOH, 60-80 °C, 1-12 h; or diimidazole imine, THF, 60-80 °C, 2-12 h; (g) FBuONO, CuBr, MeCN, 60-80 °C, 1-3 h; or 1-BuONO, CuBr2, MeCN, 60-65 °C, 0.5-5 h; or 1-BuONO, KBr, MeCN, 20 °C, 12 h; (h) DIPEA or TEA, DMSO or DMA, 80-130 °C, 1-12 h; (i) H2NNHBoc, HOAc, MeOH, 60 °C, 5 h; (j) [Z> / s(acetoxy)iodo]benzene, MeOH, 60 °C, 12-18 h; (k) CDI, DIPEA, CH2C12, 25 °C, 6 h; (1) PyCloP, DIPEA, DMA, 25-60 °C, 12-18 h.

[0148] Compounds of Formula I can be synthesized using the processes shown in General Scheme 2. Esterification of carboxylic acids 2-1 under appropriate conditions, e.g., treatment of a suspension or solution of 2-1 in dimethylformamide with methyl iodide in the presence of potassium carbonate at 20-30 °C for 2-12 h; or treatment of a suspension or solution of 2-1 in methanol with SOCI2 (added at 0 °C) followed by stirring at 25-75 °C for 2-12 h; or treatment of a suspension or solution of 2-1 in dichloromethane withmethanol, 4-(A'.A'-dimcthylamino)pyridinc. and A'.A' -dicyclohcxylcarbodiimidc at 25 °C for 12 h, affords esters 2-2. Alternatively, esters 2-2 can be purchased from commercial suppliers. Treatment of a suspension or solution of esters 2-2 in a suitable solvent, e.g., methanol or ethanol, with hydroxylamine hydrate at 50-80 °C for 1-12 h yields hydrazides 2-3. Alternatively, hydrazides 2-3 can be prepared from carboxylic acids 2-1 under appropriate conditions, e.g., sequential treatment of 2-1 with carbonyldiimidazole in tetrahydrofuran at 60 °C for 3 h followed by hydroxylamine hydrate in tetrahydrofuran at 25 °C for 1 h. Alternatively, protected hydrazides 2-6 can be prepared from carboxylic acids 2-1 under appropriate conditions, e.g., treatment of 2-1 with H2NNHB0C and EDCI in dichloromethane at 20-25 °C for 2-12 h; or treatment of 2-1 with H2NNHB0C, EDCI, HOBt, and triethylamine in dichloromethane at 25 °C for 12 h. Deprotection of protected hydrazides 2-6 under appropriate conditions, e.g., treatment of a suspension or solution of 2-6 in dichloromethane with trifluoroacetic acid at 20-25 °C for 1-4 h; or of a suspension or solution of 2-6 in ethyl acetate with hydrogen chloride at 25 °C for 2 h, yields hydrazides 2-3.

[0149] Cyclization of hydrazides 2-3 under appropriate conditions, e.g., cyanogen bromide and sodium hydrogen carbonate in dioxane and water at 25 °C for 2-12 h; or cyanogen bromide in methanol at 60-80 °C for 1-12 h; or diimidazole imine in tetrahydrofuran at 60-80 °C for 2-12 h, yields aminooxadiazoles 2-4. Treatment of aminooxadiazoles 2-4 under appropriate conditions, e.g., with ZcrZ-butylnitritc and copper(I) bromide in acetonitrile at 60-80 °C for 1-3 h; or with ZcrZ-but lnitritc and copper(II) bromide in acetonitrile at 60-65 °C for 0.5-5 h; or with with ZcrZ-butylnitritc and potassium bromide in acetonitrile at 20 °C for 12 h, affords bromooxadiazoles 2-5. Coupling of bromooxadiazoles 2-5 with Intermediate B under appropriate conditions, e.g., treatment of a suspension or solution of these two reactants with a suitable base such as A'.A'-diisopropylcthylaminc or triethylamine in a suitable solvent such as dimethyl sulfoxide or dimethyl acetamide at 80-130 °C for 1-12 h yields compounds of Formula I.

[0150] Alternatively, aldehydes 2-7 may be converted to hydroxyoxadiazoles 2-9 via intermediate hydrazones 2-8, which are not isolated. For example, condensation of 2-7 with EENNHBoc in the presence of acetic acid in an appropriate solvent, e.g., methanol, at 60 °C for 5 h affords intermediate hydrazones 2-8, which are reacted without isolation with [ ?A(acetoxy)iodo]benzene in methanol at 60 °C for 12-18 h to yield hydroxyoxadiazoles 2-9. Alternatively, hydroxyoxadiazoles 2-9 may be obtained from hydrazides 2-3 under appropriate conditions, e.g., treating a solution or suspension of 2-3 in dichloromethane with carbonyldiimidazole and A'.A'-diisopropylcthylaminc at 25 °C for 6 h. Coupling of hydroxyoxadiazoles 2-9 with Intermediate B under appropriate conditions, e.g., treatment of a suspension or solution of these two reactants in a suitable solvent, e.g., dimethylacetamide, with an appropriate coupling reagent, e.g., chlorotripyrrolidinophosphonium hexafluorophosphate (PyCloP), in the presence of a suitable base, e.g., N,N- diisopropylethylamine, at 25-60 °C for 12-18 h yields compounds of Formula I.EXEMPLARY EMBODIMENTS1. A compound of Formula (I):Formula (I), or a pharmaceutically acceptable salt thereof, wherein:X is hydrogen or deuterium; each of R1, R2, and R3is independently hydrogen, halogen, hydroxy, cyano, -NO2, oxo, -N(RZa)(Rzb), C1-6 alkoxy, or C1-6 alkyl, wherein C1-6 alkyl is optionally substituted with one or more halogens; ring A is aryl, heteroaryl, or bicyclo[l . 1. l]pentyl, and ring A is optionally substituted with one or more R4; each R4is independently halogen, cyano, -NO2, hydroxy, oxo, -S(O)2N(RZa)(Rzb), C1-6 alkyl, C2-6 alkynyl, C1-6 alkoxy, C1-6 thioalkoxy, C3-10 cycloalkyl, 3-10 membered heterocyclyl, aryl, or heteroaryl, wherein each of C1-6 alkyl, C2-6 alkynyl, C1-6 alkoxy, C1-6 thioalkoxy, C3-10 cycloalkyl, 3-10 membered heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more R5; or two R4attached to the same ring A atom or adjacent ring A atoms, together with the atoms to which they are attached, form a 3-10 membered heterocyclic ring or C3-10 cycloalkyl ring, wherein the 3-10 membered heterocyclic ring or C3-10 cycloalkyl ring is optionally substituted with one or more R5; each R5is independently halogen, oxo, hydroxy, C2-6 alkynyl, C1-6 alkyl, C1-6 alkoxy, C1-6 thioalkoxy, C3-10 cycloalkyl, 3-10 membered heterocyclyl, aryl, or hetero aryl, wherein C1-6 alkyl is optionally substituted by one or more halogens; and each of RZaand Rzbis independently hydrogen or C1-6 alkyl; or RZaand Rzb, together with the nitrogen to which they are attached, form a 3-10 membered heterocyclic ring.2. The compound of embodiment 1, wherein X is hydrogen.3. The compound of embodiment 1 or embodiment 2, wherein R1and R3are hydrogen.4. The compound of any one of embodiments 1-3, wherein the compound is a compound of Formula (I- A):Formula (I-A). The compound of any one of embodiments 1-4, wherein R2is hydrogen, halogen, or Ci-6 alkyl, wherein Ci-6 alkyl is optionally substituted with one or more halogens. The compound of embodiment 5, wherein R2is hydrogen, flouro, chloro, CH3, or CHF2. The compound of embodiment 6, wherein R2is chloro. The compound of any one of embodiments 1-7, wherein the compound is a compound of Formula (I- B):Formula (I-B). The compound of any one of embodiments 1-8, wherein each of RZaand Rzbis independently C1-6 alkyl (for example CH3); or RZaand Rzb, together with the nitrogen to which they are attached, form a 3-6 membered heterocyclic ring. The compound of embodiment 9, wherein the 3-6 membered heterocyclic ring comprises 1 ring heteroatom that is nitrogen. The compound of embodiment 10, wherein the 3-6 membered heterocyclic ring is an azetidine or a pyrrolidine ring. The compound of any one of embodiments 1-11, wherein the compound comprises up to 2 R4, for example up to 1 R4, for example wherein the compound is not substituted with R4. The compound of any one of embodiments 1-12, wherein each R4is independently halogen (for example fluoro or chloro), -S(O)2N(RZa)(Rzb), C1-6 alkyl (for example C1-3 alkyl), C1-6 alkoxy (for example C1-3 alkoxy), or C3-10 cycloalkyl (for example C3-4 cycloalkyl), wherein each of C1-6 alkyl (or C1-3 alkyl), C1-6 alkoxy (or C1-3 alkoxy), and C3-10 cycloalkyl (or C3-4 cycloalkyl) is optionally substituted with one or more R5; or two R4attached to adjacent ring A atoms, together with the atoms to which they are attached, form a 5-6 membered heterocyclic ring that is optionally substituted with one or more R5.The compound of embodiment 13, wherein the 5-6 membered heterocyclic ring comprises 1-2 ring heteroatoms chosen from N and 0. The compound of embodiment 14, wherein the 5-6 membered heterocyclic ring comprises 1-2 ring heteroatoms that are 0, or the 5-6 membered heterocyclic ring comprises 1 ring heteroatom that is N. The compound of embodiment 15, wherein each R4is independently selected from the groupthe atoms to which they are attached, form a heterocyclic ring selected from the group consisting of:The compound of embodiment 16, wherein each R4is independently selected from the groupto adjacent ring A atoms, together with the atoms to which they are attached, form a heterocyclic ringselected from the group consisting of:The compound of any one of embodiments 1-17 wherein the compound comprises up to 3 R5, for example up to 2 R5, for example up to 1 R5, for example wherein the compound is not substituted with R5. The compound of any one of embodiments 1-18, wherein each R5is independently halogen, Ci-6 alkyl (for example C1-3 alkyl), C1-6 alkoxy (for example C1-3 alkoxy), or C3-10 cycloalkyl (for example C3-6 cycloalkyl). The compound of embodiment 19, wherein each R5is independently fluoro, CH3, OCH3, or cyclopropyl. The compound of any one of embodiments 1-20, wherein ring A is aryl or heteroaryl, and ring A is optionally substituted with one or more R4. The compound of embodiment 21, wherein ring A is phenyl or 5-6 membered heteroaryl, and ring A is optionally substituted with one or more R4. The compound of embodiment 22, wherein 5-6 membered heteroaryl is 5-6 membered nitrogencontaining heteroaryl. The compound of embodiment 23, wherein 5-6 membered nitrogen-containing heteroaryl is pyridine, pyrimidine, pyrazine, pyridazine, pyrazole, oxazole, or isoxazole. The compound of embodiment 24, wherein ring A is selected from the group consisting of:X2, X3, and X4are oxygen and the rest are carbon.26. The compound of embodiment 25, wherein ring A is selected from the group consisting of:The compound of any one of embodiments 1-20, wherein ring A is bicyclo [1.1. l]pentyl that is optionally substituted with one or more R4. The compound of embodiment 28, wherein the compound comprises up to 1 R4. The compound of embodiment 28 or embodiment 29, wherein each R4is independently Ci-6 alkyl (for example Ci-4 alkyl), aryl (for example phenyl), or cyano, and R4is optionally substituted with one or more R5. The compound of embodiment 30, wherein each R4is independently selected from the groupThe compound of embodiment 31, wherein each R4is independently selected from the groupThe compound of embodiment 28 or embodiment 29, wherein each R4is Ci-6 alkyl that is optionally substituted with one or more R5. The compound of embodiment 33, wherein each R4is CH3that is optionally substituted with one or more R5. The compound of embodiment 34, wherein each R4is independently selected from the group consisting of:The compound of embodiment 35, wherein each R4is independently selected from the group consisting of:The compound of any one of embodiments 28-36, wherein the compound comprises up to 3 R5, for example up to 2 R5, for example up to 1 R5, for example wherein the compound is not substituted with R5. The compound of any one of embodiments 28-37, wherein each R5is halogen. The compound of embodiment 38, wherein each R5is fluoro. The compound of any one of embodiments 28-39, wherein ring A isThe compound of embodiment 40, wherein ring A is selected from the group consisting of:The compound of embodiment 41, wherein ring A is selected from the group consisting of:The compound of embodiment 40, wherein ring A is selected from the group consisting of:The compound of embodiment 43, wherein ring A is selected from the group consisting of:A compound of embodiment 1 selected from Table 1 or a pharmaceutically acceptable salt thereof. A pharmaceutical composition comprising the compound of any one of embodiments 1-45, or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. A method of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the compound of any one of embodiments 1-45, or pharmaceutically acceptable salt thereof, or the pharmaceutical composition of embodiment 46. The method of embodiment 47, wherein the cancer is breast cancer. The method of embodiment 48, wherein the breast cancer is HR+ (hormone receptor positive) breast cancer. The method of embodiment 49, wherein the breast cancer is ER+ (estrogen receptor positive) breast cancer. The method of embodiment 49, wherein the breast cancer is HR+ HER2- (human epidermal growth factor 2 negative) breast cancer. The method of embodiment 50, wherein the breast cancer is ER+ HER2- (human epidermal growth factor 2 negative) breast cancer.The method of embodiment 47, wherein the cancer is selected from the group consisting of: ovarian cancer, endometrial cancer, gastric cancer, esophaegeal cancer, triple negative breast cancer, and lung adenosarcoma. The method of embodiment 53, wherein the cancer is triple negative breast cancer. The method of embodiment 47, wherein the cancer comprises a solid tumor. The method of embodiment 55, wherein the solid tumor is at least one of the group consisting of: uterine cancer (such as uterine carcinosarcoma and uterine corpus endometrial carcinoma), endometrial cancer, breast cancer, (such as breast invasive carcinoma and triple negative breast cancer, ER+ HER2- breast cancer, and HER2+ breast cancer), ovarian cancer (such as ovarian serous cystadenocarcinoma), stomach cancer (such as stomach adenocarcinoma), gastric cancer (such as gastrointestinal stromal cancer), 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 lung squamous 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. The method of embodiment 47, wherein the cancer comprises a liquid tumor. The method of embodiment 55, wherein the liquid tumor is at least one of the group consisting of: 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’s lymphoma (HL), non-Hodgkin’s lymphoma (NHL), AIDS-related lymphoma, follicular lymphoma, small lymphocytic lymphoma, T-cell / histiocyte rich large B-cell lymphoma, transformed lymphoma, primary mediastinal (thymic) large B-cell lymphoma, splenic marginal zone lymphoma, Richter's transformation, nodal marginal zone lymphoma, ALK-positive large B-cell lymphoma, indolent lymphoma (for example, DLBCL, follicular lymphoma, or marginal zone lymphoma), acute myelogenous leukemia (AML), acute lymphocytic leukemia (ALL), adult T - cell leukemia, chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), hairy cell leukemia, myelodysplasia, myeloproliferative disorders, chronic myelogenous leukemia (CML), acute monocytic leukemia (AMoL), myelodysplastic syndrome (MDS), human lymphotropic virustype 1 (HTLV-1) leukemia, mastocytosis, B-cell acute lymphoblastic leukemia, Non-Hodgkin's Lymphoma, Hodgkin's Lymphoma, and multiple myeloma (MM). The method of any one of embodiments 47-58, further comprising administering to the subject an additional therapeutic agent.60. The method of embodiment 59, wherein the additional therapeutic agent is carboplatin, fulvestrant, or a combination thereof.61. The method of any one of embodiments 47-60, wherein the subject is treatment-naive.EXAMPLES

[0151] The compounds provided herein can be prepared from readily available starting materials using the following general methods and procedures. It will be appreciated that where typical or preferred process conditions (z.e., reaction temperatures, times, mole ratios of reactants, solvents, pressures, etc.) are given, other process conditions can also be used unless otherwise stated. Optimum reaction conditions may vary with the particular reactants or solvent used, but such conditions can be determined by one skilled in the art by routine optimization.

[0152] The labeling of compounds as ‘Intermediate X’ or ‘Compound Y’ is consistent throughout this description. However, in the preparations below the numbering of compounds used as a starting material or prepared in an intermediate step, i.e. those compounds labelled with just a number, i.e. as ‘Z’, is standalone. In other words, a compound labeled ‘ 1 ’ in one preparation will not necessarily be the same as a compound labeled ‘1’ in another preparation.

[0153] Abbreviations'. ACN: acetonitrile; AIBN: 2, 2-azobis(2 -methylpropionitrile); BH;,-Mc?S: borane dimethyl sulfide complex; BrCN: bromine cyanide; brd. broad doublet; brdd. broad doublet of doublet; BPO: benzoyl benzenecarboperoxoate; brs'. broad singlet; br . broad triplet; eq: equivalents; CHCI3: trichloromethane; CDCI3: deuterated chloroform; CDI: l,T-carbonyldiimidazole; CS2CO3: cesium carbonate; CuBr: copper bromide; CuBr2: copper(II) bromide; Cu(OAc)2: copper acetate; d. doublet; dd. doublet of doublet; ddd. doublet of doublet of doublet; DAST: (diethylamino)sulfur trifluoride; DBU: 2,3,4,6,7,8,9,10- octahydropyrimido[l,2-a]azepine ; DCC: A'.A'-mcthancdiylidcncdicyclohcxan amine; DCM: dichloromethane; DIEA: diisopropyethylamine; DMA: A'.A'-dimcthylacctamidc: DMAP: 4- dimethylaminopyridine;DMF: dimethylformamide; DMSO: dimethyl sulfoxide; DPPA: diphenylphosphoryl azide; DPPP: 3-(6-(l-((5-(2-(methoxymethyl)-4-methylphenyl)-l,3,4-oxadiazol-2-yl)amino)cyclopropyl)-4- methyl- l-oxoisoindolin-2-yl)piperidine-2, 6-dione; EDO: 1 -(3 -dim ethylaminopropyl)-3 -ethylcarbodiimide hydrochloride ; ESI: electrospray ionization; EtOH: ethanol; h: hours; HC1: hydrochloric acid; H2SO4: sulfuric acid; HOBt: benzotriazol- l-ol; HPLC: high-performance liquid chromatography; KBr: potassium bromide; K2CO3: potassium carbonate; K3PO4: potassium phosphate; LiCl: lithium chloride; nr. multiplet; MeCN: acetonitrile; Mel: iodomethane; MeOH: methanol; MeONa: sodium methanol; MgCE: magnesium chloride; MS: mass spectrometry; 3 or 4A MS: 3 or 4 amstrong molecular sieves; M.W.: microwave; NaH: sodium hydride; NaHCCh: sodium bicarbonate; NBS: A'-bromosuccinimidc: NH2-NH2 • H2O: hydrazinemonohydrate; NH2NHB0C: ZcrZ-butyl A'-aminocarbamatc: NH3 • H2O: ammonium hydroxide; NiCL: nickel(II) chloride; NiCL • 6H2O: nickel chloride hexahydrate; NIS: A'-iodosuccinimidc: NMP: A'-mcthyl pyrrolidone; NMR: nuclear magnetic resonance; q: quartet; singlet; O-phen: 1,10-phenanthroline;Pd(TFA)2: bis[(2,2,2-trifluoroacetyl)oxy]palladium; PdlZ-BmPL: bis(tri-tert-butylphosphine)palladium(0); PEPPSI-IPr: [l,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene](3-chloropyridyl)palladium(II) dichloride; PyCLOP: chloro(tripyrrolidin-l-yl)phosphonium;hexafluorophosphate: quin', quintet; SEM-C1: (2- (chloromethoxy)ethyl)trimethylsilane; SOCI2: thionyl chloride; Z: triplet; Z-BuONO: ZcrZ-butyl nitrite; id triplet of doublet; TEA: triethylamine; TFA: trifluoroacetic acid; THF: tetrahydrofuran; TMSC1: chlorotrimethylsilane; tt: triplet of triplet; Zn: zincPREPARATION OF INTERMEDIATESPreparation of Intermediate 1

[0154] Preparation of 2: To a solution of methyl 3 -chloro-2-m ethylbenzoate (20.0 g, 108 mmol,1.00 eq) in sulfuric acid (160 mL) was added A'-iodosuccinimidc (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 in water (200 mL) at 0 °C and extracted with ethyl acetate (3 * 100 mL). The combined organic layers were with dried over sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiCL, petroleum ether / ethyl acetate=10 / l to 5 / 1) to afford 3-chloro-5-iodo-2- methylbenzoic acid (24.7 g, 83.3 mmol, 77% yield) as a white solid. 'H NMR (400 MHz, CDCh) 8 = 8.20 ( , J= 1.8 Hz, 1H), 7.91 ( , J= 1.6 Hz, 1H), 2.63 (s, 3H).

[0155] Preparation of 3: To a solution of 3 -chloro-5-iodo-2-m ethylbenzoic acid (24.7 g, 83.3 mmol,1.00 eq) in methanol (250 mL) was added thionyl chloride (19.8 g, 167 mmol, 12.1 mL, 2.00 eq). Thereaction mixture was stirred at 80 °C for 12 h. The reaction mixture was concentrated under reduced pressure to afford methyl 3 -chloro-5-iodo-2-m ethylbenzoate (17.0 g, 54.8 mmol, 66% yield) as a yellow oil. 'H NMR (400MHz, CDCh) 8 = 7.99 - 7.89 (m, 1H), 7.82 - 7.70 (m, 1H), 3.83 (s, 3H), 2.48 - 2.44 (m, 3H).

[0156] Preparation of 4: To a solution of methyl 3-chloro-5-iodo-2-methyl-benzoate (17.0 g, 54.8 mmol, 1.00 eq) in trichloromethane (200 mL) was added 2, 2-azobis(2 -methylpropionitrile) (8.99 g, 54.8 mmol, 1.00 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 a residue. The residue was purified by column chromatography (SiCL, petroleum ether / ethyl acetate=l / 0 to 10 / 1) to afford methyl 2- (bromomethyl)-3-chloro-5-iodo-benzoate (18.0 g, 46.2 mmol, 84% yield) as a colorless oil. 'H NMR (400MHz, CDCh) 8 = 8.18 (d, J= 1.8 Hz, 1H), 7.93 (d, J= 1.6 Hz, 1H), 5.05 (s, 2H), 3.96 (s, 3H).

[0157] Preparation of Intermediate 1: To a solution of methyl 2-(bromomethyl)-3-chloro-5- iodobenzoate (17.0 g, 43.7 mmol, 1.00 eq) in acetonitrile (200 mL) was added A' A'-diisopropylcthylaminc (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 triturated 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 afford 3-(4-chloro-6-iodo-l-oxoisoindolin-2-yl)piperidine-2, 6-dione (11.0 g, 27.2 mmol, 62% yield) as a black solid.1H NMR (400MHz, DMSO-O 8 = 11.02 (s, 1H), 8.13 (d, J= 1.2 Hz, 1H), 8.03 (d, J = 1.2 Hz, 1H), 5.13 (dd, 7= 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).Preparation of Intermediate 211 6A

[0158] Preparation of 6A: To a solution of zinc powder (21.9 g, 335 mmol, 12.0 eq) in tetrahydrofuran (30.0 mL) was added chlorotrimethylsilane (303 mg, 2.79 mmol, 355 pL. 0.100 eq) at 70 °C. The reaction mixture was stirred at 70 °C for 1 h. Then methyl 1 -bromocyclopropanecarboxylate (5.00 g, 27.9 mmol, 1.00 eq) was added at 40 °C. The reaction mixture was sitrred at 40 °C for 0.5 h. The reaction mixture was to afford (l-(methoxycarbonyl)cyclopropyl)zinc(II) bromide (6.80 g, 27.8 mmol, 99% yield) as a black oil, which was used for the next step directly.

[0159] Preparation of 6: To a solution of 3-(4-chloro-6-iodo-l-oxo-isoindolin-2-yl)piperidine-2,6- dione (11.0 g, 27.2 mmol, 1.00 eq) in tetrahydrofuran (110 mL) was added 2,3,4,6,7,8,9,10- octahydropyrimido[l,2-a]azepine (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) at 0 °C. 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 (SiCL, petroleum ether / ethyl acetate=l / O to 1 / 1) to afford 3-(4-chloro-6-iodo-l-oxoisoindolin-2-yl)-l-((2-(trimethylsilyl)ethoxy)methyl)piperidine-2, 6-dione (6.00 g, 11.2 mmol, 41% yield) as a blue oil.1H NMR (400MHz, CDC13) S = 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).

[0160] Preparation of 7: To a solution of 3-(4-chloro-6-iodo-l-oxoisoindolin-2-yl)-l-((2- (trimethylsilyl)ethoxy)methyl)piperidine-2, 6-dione (3.80 g, 7.10 mmol, 1.00 eq) in tetrahydrofuran (40.0 mL) was added bis(tri-tert-butylphosphine)palladium(0) (363 mg, 710 umol, 0.100 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 (SiCL, petroleum ether / ethyl acetate=l / 0 to 10 / 1) to afford methyl- 1 -(7-chloro-2-(2,6-dioxo- 1 -((2-(trimethylsilyl)ethoxy)methyl)piperidin-3 -yl)-3 -oxoisoindolin-5 - yl)cyclopropanecarboxylate (3.00 g, 5.92 mmol, 83% yield) as a white solid.1H NMR (400MHz, CDCh) 8 = 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).

[0161] Preparation of 8: To a solution of methyl l-(7-chloro-2-(2,6-dioxo-l-((2- (trimethylsilyl)ethoxy)methyl)piperidin-3-yl)-3 -oxoisoindolin-5 -yl)cyclopropanecarboxylate (3.00 g, 5.92 mmol, 1.00 eq) in dichloromethane (30.0 mL) was added trifluoro acetic acid (3.00 mL). The reaction mixture was stirred at 20 °C for 1 h. The reaction mixture was concentrated under reduced pressure to afford methyl l-(7-chloro-2-(l-(hydroxymethyl)-2,6-dioxopiperidin-3-yl)-3 -oxoisoindolin-5 - yl)cyclopropanecarboxylate (2.41 g, 5.92 mmol, 100% yield) as a white solid.

[0162] Preparation of 9: To a solution of methyl l-(7-chloro-2-(l-(hydroxymethyl)-2,6- dioxopiperidin-3-yl)-3 -oxoisoindolin-5 -yl)cyclopropanecarboxylate (2.41 g, 5.92 mmol, 1.00 eq) in acetonitrile (20.0 mL) was added ammonium hydroxide (1.00 mL). The reaction mixture was stirred at 20 °C for 1 h. The reaction mixture was filtered and concentrated under reduced pressure to afford methyl l-(7- chloro-2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)cyclopropanecarboxylate (2.20 g, 5.84 mmol, 99% yield) as a white solid.1H NMR (400MHz, DMSO-O 8 = 10.92 (s, 1H), 7.67 - 7.55 (m, 2H), 5.02 (dd, 7 = 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).

[0163] Preparation of 10: To a solution of methyl l-(7-chloro-2-(2,6-dioxopiperidin-3-yl)-3- oxoisoindolin-5-yl)cyclopropanecarboxylate (200 mg, 531 pmol, 1.00 eq) in dimethyformamide (2.00 mL) was added lithium chloride (113 mg, 2.65 mmol, 54.4 pL, 5.00 eq). The reaction mixture was stirred at 160 °C for 1 h under M. W.. The reaction mixture was concentrated under reduced pressure. The reaction mixture was lyophilized to afford l-(7-chloro-2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5- yl)cyclopropanecarboxylic acid (900 mg, 2.48 mmol, 42% yield) was obtained as a red solid.1H NMR (400MHz, DMS0-<7) 8 = 11.01 (br s, 1H), 7.69 - 7.60 (m, 2H), 5.13 (dd, 7= 5.1, 13.3 Hz, 1H), 4.50 - 4.41 (m, 1H), 4.34 - 4.26 (m, 1H), 2.93 - 2.85 (m, 1H), 2.65 - 2.57 (m, 2H), 2.06 - 1.96 (m, 1H), 1.49 (br d, 7= 2.8 Hz, 2H), 1.24 (br s, 2H).

[0164] Preparation of Intermediate 2: To a solution of l-(7-chloro-2-(2,6-dioxopiperidin-3-yl)-3- oxoisoindolin-5-yl)cyclopropanecarboxylic acid (100 mg, 276 pmol, 1.00 eq) in dioxane (2.00 mL) was added triethylamine (83.7 mg, 827 pmol, 115 pL, 3.00 eq), 4A MS (100 mg) and diphenylphosphoryl azide(114 mg, 413 pmol, 89.3 pL, 1.50 eq). The reaction mixture was stirred at 20 °C for 1 h. hydrochloric acid (1 M, 1.38 mL, 5.00 eq) was added. The reaction mixture was stirred at 80 °C for 4 h. The reaction mixture was concentrated under reduced pressure and lyophilized. The residue was added water (3.00 mL) and filtered. The filter cake was lyophilized to afford 3-(6-(l-aminocyclopropyl)-4-chloro-l-oxoisoindolin-2- yl)piperidine-2, 6-dione (200 mg, crude) as a yellow solid.1H NMR (400MHz, DMS0-< ) S = 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 (br s, 2H).Preparation of Intermediate 3

[0165] Preparation of 2: To a solution of 4-(azetidin-l-ylsulfonyl)benzohydrazide (986 mg, 3.86 mmol, 1.00 eq) in dioxane (5.00 mL) and water (5.00 mL) were added saturated sodium bicarbonate (324 mg, 3.86 mmol, 150 pL, 1.00 eq) and bromine cyanide (409 mg, 3.86 mmol, 283 pL, 1.00 eq). The 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, dried in vacuum to afford 5-(4-(azetidin-l-ylsulfonyl)phenyl)-l,3,4-oxadiazol-2- amine (908 mg, 3.24 mmol, 83% yield) as a white solid.

[0166] Preparation of Intermediate 3: To a solution of 5-(4-(azetidin-l-ylsulfonyl)phenyl)-l,3,4- oxadiazol-2-amine (454 mg, 1.62 mmol, 1.00 eq) in acetonitrile (5.00 mL) were added copper bromide (464 mg, 3.24 mmol, 98.6 pL, 2.00 eq) and tert-butyl nitrite (334 mg, 3.24 mmol, 385 pL, 2.00 eq). The reaction mixture was stirred at 65 °C for 2 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiCL, petroleum ether / ethyl acetate=l / O to 0 / 1) to afford 2-(4-(azetidin-l-ylsulfonyl)phenyl)-5-bromo-l,3,4-oxadiazole (215 mg, 624 pmol, 38% yield) as a white solid. ’H NMR (400 MHz, DMSO-O 8 = 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).Preparation of Intermediate 4

[0167] Preparation of 2: The preparation was carried out according to the method described for structure 2 of the scheme for preparing 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.

[0168] Preparation of 3: The preparation was carried out according to the method described for structure 3 of the scheme for preparing intermediate 1 except that (i) 5.00 eq of thionyl chloride were used and (ii) the crude product was purified by reversed-phase column (0.1% FA condition), and the desired fraction was collected and lyophilized to give methyl 3-fluoro-5-iodo-2-methylbenzoate as colorless liquid.

[0169] Preparation of 4: A mixture of methyl 3-fluoro-5-iodo-2-methyl-benzoate (2.80 g, 9.52 mmol, 1.00 eq). A'-Bromosuccinimidc (1.69 g, 9.52 mmol, 1.00 eq) and benzoyl benzenecarboperoxoate (461 mg, 1.90 mmol, 0.200 eq) in trichloromethane (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 layer was washed with brine (50.0 mL), dried over sodium sulfate, filtered and concentrated in vacuum. The residue was purified by silica gel chromatography (petroleum ether / ethyl acetate = 3 / 1) to give methyl 2- (bromomethyl)-3-fluoro-5- iodobenzoate (1.70 g, 4.42 mmol, 46% yield, 97% purity) as a brown solid.

[0170] Preparation of 5: The preparation was carried out according to the method described for intermediate 1 except that (i) 4.00 eq of A' A'-diisopropylcthylaminc were used and (ii) the crude product was triturated with ethyl acetate / water = 2 / 1 and filtered, and the filter cake was dried in vacuum to give 3-(4- fluoro-6-iodo-l-oxoisoindolin-2-yl) piperidine-2, 6-dione (65 % yield) as a blue solid.

[0171] Preparation of Intermediate 4: The preparation was carried out according to the method described for structure 6 of the scheme for preparing intermediate 2 except that (i) dimethyl formamide (0.5M) 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-l -oxoisoindo lin- 2-yl)-l-((2-(trimethylsilyl)ethoxy)methyl)piperidine-2, 6-dione (61% yield) as a black blue liquid. 'H NMR (400 MHz, DMSO-O 8 =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).Preparation of Intermediate 5

[0172] Preparation of 1A: To a solution of l-((tert-butoxycarbonyl)amino)cyclopropanecarboxylic acid (10.0 g, 49.7 mmol, 1.00 eq) in dichloromethane (200 mL) was added 2 -hydroxyisoindoline- 1,3 -dione (8.92 g, 54.7 mmol, 1.10 eq , 4-dimethylaminopyridine (607 mg, 4.97 mmol, 0.100 eq) and l-(3- dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (10.5 g, 54.7 mmol, 1.10 eq) at 0 °C. 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 x 500 mL), washed with brine (2 x 500 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate=l / 0 to 1 / 1) to afford l,3-dioxoisoindolin-2-yl l-((tert- butoxycarbonyl)amino)cyclopropanecarboxylate (14.0 g, 40.4 mmol, 81% yield) as a white solid.

[0173] Preparation of IB: To a solution of nickel chloride hexahydrate (20.0 g, 84.1 mmol, 1.00 eq) in ethanol (300 mL) was added 2,2'-bipyridine (13.1 g, 84.1 mmol, 1.00 eq). The reaction mixture was stirred at 20 °C for 2 h. The reaction mixture was filtered. The filter cake was concentrated under reduced pressure to afford (bipy)2Ni2(p-Cl)2C12(H2O)2 (11.0 g, 18.0 mmol, 21% yield) as a green solid

[0174] Preparation of 2: To a solution of 3-(4-fluoro-6-iodo-l-oxoisoindolin-2-yl)-l-((2- (trimethylsilyl)ethoxy)methyl)piperidine- 2,6-dione (2.00 g, 3.86 mmol, 1.00 eq) (see ‘Preparation of Intermediate 4’ for preparation steps) in A'jV-dimcthylacctamidc (20.0 mL) were added 1,3 -dioxoisoindo lin-2-yl l-((terLbutoxycarbonyl)amino)cyclopropane-l -carboxylate (2.67 g, 7.72 mmol, 2.00 eq), chlorotrimethylsilane (1.26 g, 11.5 mmol, 1.47 mL, 3.00 eq), (bipy)2Ni2(p-Cl)2C12(H2O)2 (117 mg, 192 pmol, 0.0500 eq) and zinc powder (2.02 g, 30.8 mmol, 8.00 eq) at 0 °C. The reaction mixture was stirred at 20 °C for 12 h under nitrogen atmosphere. The reaction mixture was filtered. The filtrate was extracted with ethyl acetate (3 x 100 mL). The organic layer was washed with water (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiCL, petroleum ether / ethyl acetate=l / O to 0 / 1) to afford ZcrZ-butyl (l-(2-(2,6-dioxo- l-((2-(trimethylsilyl)ethoxy)methyl)piperidin-3-yl)-7-fluoro-3-oxoisoindolin-5-yl)cyclopropyl)carbamate (1.50 g, 2.74 mmol, 70% yield) as yellow oil.

[0175] Preparation of Intermediate 5: A solution of tert-butyl (l-(2-(2,6-dioxo-l-((2- (trimethylsilyl)ethoxy)methyl)piperidin-3-yl)-7-fluoro-3- oxoisoindolin-5-yl)cyclopropyl)carbamate (1.50 g, 2.74 mmol, 1.00 eq) in hydrochloric acid / dioxane (4.00 M, 15.0 mL, 21.9 eq) was stirred at 20 °C for 1 h. The reaction mixture was concentrated under reduced pressure to give a residue. The solid was added trifluoroacetic acid (2.30 g, 20.1 mmol, 1.50 mL, 7.37 eq) and dichloromethane (10.0 mL). The reaction mixture was stirred at 20 °C for 1 h. The reaction mixture was concentrated under reduced pressure to give yellow oil (951 mg, 2.74 mmol, 99% yield). The obtained yellow oil (951 mg, 2.74 mmol, 1.00 eq) in acetonitrile (15.0 mL) were added ammonium hydroxide (340 mg, 2.43 mmol, 374 L. 25% purity, 8.88e-l 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 rep-HPLC (column: UniSil 10-120 C18 70 x 250 mm; mobile phase: [water (formic acid) - acetonitrile]; gradient: 0%-20% B over 15 min) and lyophilized to afford 3 -(6-(l-aminocyclopropyl)-4-fluoro-l -oxoisoindo lin-2-yl)piperidine-2, 6-dione (518 mg, 1.43 mmol, 52% yield, formate) as a white solid. ’H NMR (400 MHz, DMSO-O 8 = 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).Preparation of Intermediate 6

[0176] Preparation of 2: To a solution of 4-(trifluoromethoxy)benzoic acid (3.00 g, 14.6 mmol, 1.00 eq) in methanol (30.0 mL) was added thionyl chloride (2.60 g, 21.8 mmol, 1.58 mL, 1.50 eq) at 0 °C. 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) as a white solid.

[0177] Preparation of 3: To a solution of methyl methyl 4-(trifluoromethoxy)benzoate (2.60 g, 11.8 mmol, 1.00 eq) in ethanol (30.0 mL) was added hydrazine hydrate (1.39 g, 23.6 mmol, 1.35 mL, 85% purity, 2.00 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 (SiCL, petroleum ether / ethyl acetate = 0 / 1) to afford 4-(trifluoromethoxy)benzohydrazide (1.95 g, 8.24 mmol, 69% yield, 93% purity) as a white solid.

[0178] Preparation of 4: To a solution of 4-(trifluoromethoxy)benzohydrazide (1.20 g, 5.45 mmol, 1.00 eq) in methanol (7.00 mL) was added cyanic bromide (693 mg, 6.54 mmol, 481 uL, 1.20 eq). The mixture was stirred at 65 °C for 4 h. The reaction mixture was cooled to 25 °C. The mixture was added water (60.0 mL) and extracted with ethyl acetate (2 x 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 triturated 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 filtration to give 5-(4- (trifluorom ethoxy )phenyl)-l, 3, 4-oxadiazol-2-amine (800 mg, 3.23 mmol, 59% yield, 99% purity) as a white solid.

[0179] Preparation of Intermediate 6: The preparation was carried out according to the method described 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 (SiCh, petroleum ether / ethyl acetate = 9 / 1) to give 2- bromo-5-(4-(trifluorom ethoxy )phenyl)-l, 3, 4-oxadiazole (37% yield) as a white solid. 'H NMR (400 MHz, DMSO-O 8 = 8.12 (d, J= 8.8 Hz, 2H), 7.61 (d, J= 8.0 Hz, 2H).Preparation of Intermediate 7n erme a e 7

[0180] Preparation of 2: The preparation was carried out according to the method described for structure 3 of the scheme for preparing intermediate 6 except that (i) methanol was used instead of ethanol and (ii) the mixture was stirred at 60 °C for 12 h. 4-methylbenzohydrazide (98% yield) was obtained as a white solid.

[0181] Preparation of 3: The preparation was carried out according to the method described for structure 2 of the scheme for preparing intermediate 3. 5-i / i-tol l)- 1 ,3.4-oxadiazol-2-aminc (88% yield) was obtained as a white solid.

[0182] Preparation of Intermediate 7: The preparation was carried out according to the method described for intermediate 3. 2-bromo-5-(p-tol l)- 1 ,3.4-oxadiazolc (28 % yield) was obtained as a white solid. ’H NMR (400 MHz, DMSO-< / 6) 8 = 7.87 (d, J= 8.2 Hz, 2H), 7.42 (d, J= 8.0 Hz, 2H), 2.41 (s, 3H).Preparation of Intermediate 84 Intermediate 8

[0183] Preparation of 2: To a solution of 4-cyclopropoxybenzoic acid (1.00 g, 5.61 mmol, 1.00 eq) in A' A'-dimcthylform amide (10.0 mL) was added potassium carbonate (2.33 g, 16.8 mmol, 3.00 eq) and iodomethane (956 mg, 6.73 mmol, 419 pL, 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 x 50 mL). The combined organic layer was washed with brine (50 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to give residue. The residue was purified by column chromatography (Si O2, Petroleum ether / Ethyl acetate = 1 / 0 to 10 / 1) to afford methyl 4-cyclopropoxybenzoate (1.08 g, 5.62 mmol, 100% yield) as yellow oil.

[0184] Preparation of 3: The preparation was carried out according to the method described for structure 3 of the scheme for preparing intermediate 6 except that (i) methanol (10.0 mL) was used instead of ethanol, (ii) 15.0 eq of hydrazine hydrate were used, (Hi) the mixture was stirred at 60 °C for 12 h, and (iv) the reaction mixture was concentrated under reduced pressure to afford 4-cyclopropoxybenzohydrazide (93% yield) as a yellow solid.

[0185] 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 triturated with ethyl acetate to afford 5-(4-cyclopropoxyphenyl)-l,3,4-oxadiazol-2-amine (98% yield) as a yellow solid.

[0186] Preparation of Intermediate 8: The preparation was carried out according to the method described for intermediate 3 except that (i) 1.50 eq of copper(I) bromide and 1.50 eq of tert-butyl nitrite were used and (ii) the residue was purified by column chromatography (SiCL, Petroleum ether / Ethyl acetate = 1 / 0 to 1 / 1) to afford 2-bromo-5-(4-cyclopropoxyphenyl)-l,3,4-oxadiazole (42% yield) as a white solid. 'H NMR(400 MHz, DMSO-O 8 = 7.93 (d, J= 8.8 Hz, 2H), 7.26 (d, J= 8.8 Hz, 2H), 3.99 - 3.95 (m, 1H), 0.87 - 0.82 (m, 2H), 0.73 - 0.69 (m, 2H).PREPARATION OF COMPOUNDSExample 1. Preparation of Compound 1

[0187] Preparation of 2 Intermediate 1 was used as the starting material. The preparation was carried out according to the method described for structure 2 of the scheme for preparing intermediate 5 except that the residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate=l / O to 1 / 1) to afford crude product and the crude product was triturated with ethyl acetate at 20 °C for 12 h to afford tert-butyl (l-(7-chloro-2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)cyclopropyl)carbamate (34% yield) as a yellow solid. ’H NMR (400 MHz, DMSO-O 8 = 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).

[0188] Preparation of 3: A mixture of tert-butyl-(l-(7-chloro-2-(2,6-dioxopiperidin-3-yl)-3- oxoisoindolin-5-yl)cyclopropyl) carbamate (140 mg, 323 pmol, 1.00 eq) in hydrochloric acid (4 M in dioxane, 1 mL) and dioxane (1.00 mL) was stirred at 20 °C for 1.5 h. Two batches were combined. The reaction mixture was concentrated under reduced pressure to give a residue to afford 3-(6-(l- aminocyclopropyl)-4-chloro-l-oxoisoindolin-2-yl)piperidine-2, 6-dione (238 mg, 643 pmol, 99% yield, hydrochloric acid) as a white solid. 'H NMR (400 MHz, DMSO-t / s) 8 = 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).

[0189] Preparation of Compound 1: To a solution of 3-(6-(l-aminocyclopropyl)-4-chloro-l- oxoisoindolin-2-yl)piperidine-2, 6-dione (200 mg, 540 pmol, 1.00 eq, hydrochloric acid) in dimethylsulfoxide (2.00 mL) was added 2-bromo-5-(4-(trifluoromethoxy)phenyl)-l,3,4-oxadiazole (167 mg, 540 pmol, 1.00 eq(see ‘Preparation of Intermediate 6’ for preparation steps) and A' A'-diisopropylcthylaminc (140 mg, 1.08 mmol, 188 pL. 2.00 eq). The reaction mixture was stirred at 80 °C for 12 h. The reaction mixture was filtered. Purification / M'c -HPLC (column: Cl 8 150x30mm;mobile phase: [water(formic acid)- acetonitrile];gradient:42%-72% B over 7 min) afforded 3-(4-chloro-l-oxo-6-(l-((5-(4- (trifluoromethoxy)phenyl)-l, 3, 4-oxadiazol-2-yl)amino)cyclopropyl)isoindolin-2-yl)piperidine-2, 6-dione (158.01 mg, 278.40 pmol, 52% yield, 99% purity) as a off-white solid. 'H NMR (400 MHz, DMS0-< ) d = 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).Example 2. Preparation of Compound 2

[0190] Preparation of 2: The preparation was carried out according to the method described for structure 4 of the scheme for preparing intermediate 1 except that (i) 0.100 eq of 2,2-azobis(2- methylpropionitrile) were used and (ii) the reaction mixture was poured into water and extracted with ethyl acetate, then the combined organic layers were washed with brine, dried over anhydrous sodium sulfate, andconcentrated under reduced pressure to afford methyl 2-(bromomethyl)-5 -iodobenzoate (91 % yield) as a white solid.

[0191] Preparation of 3: The preparation was carried out according to the method described for intermediate 1 except that the residue was triturated with a mixture of ethyl acetate / water = 2 / 1 at 20 °C for 1 h and then filtered, then the filter cake was concentrated under reduced pressure to afford 3-(6-iodo-l- oxoisoindolin-2-yl)piperidine-2, 6-dione (78% yield) as a black solid.

[0192] Preparation of 4: The preparation was carried out according to the method described for structure 6 of the scheme for preparing intermediate 2 except that the residue was purified by column chromatography (SiCh, petroleum ether / ethyl acetate=l / 0 to 0 / 1) to afford 3 -(6-iodo-l -oxoisoindo lin -2 -yl)-l - ((2-(trimethylsilyl)ethoxy)methyl)piperidine-2, 6-dione (28 % yield) as a blue solid.

[0193] Preparation of 5: The preparation was carried out according to the method described for structure 7 of the scheme for preparing intermediate 2 except that the residue was purified by column chromatography (SiCh, petroleum ether / ethyl acetate=l / 0 to 0 / 1) to afford methyl l-(2-(2,6-dioxo-l-((2- (trimethylsilyl)ethoxy)methyl)piperidin-3-yl)-3-oxoisoindolin-5-yl)cyclopropane-l-carboxylate (79% yield) as a white solid.

[0194] Preparation of 6: The preparation was carried out according to the method described for structure 8 of the scheme for preparing intermediate 2. Methyl l-(2-(l-(hydroxymethyl)-2,6-dioxopiperidin- 3-yl)-3-oxoisoindolin-5-yl)cyclopropane-l-carboxylate ( 95% yield) was obtained as a yellow solid.

[0195] Preparation of 7: The preparation was carried out according to the method described for structure 9 of the scheme for preparing intermediate 2. Methyl l-(2-(2,6-dioxopiperidin-3-yl)-3- oxoisoindolin-5-yl)cyclopropane-l -carboxylate (93% yield) was obtained as a white solid.

[0196] Preparation of 8: The preparation was carried out according to the method described for structure 10 of the scheme for preparing intermediate 2. The reaction mixture was lyophilized to afford l-(7- chloro-2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)cyclopropane-l-carboxylic acid ( 19% yield) as a red solid.

[0197] Preparation of 9: The preparation was carried out according to the method described for intermediate 2. 3 -(6-(l -aminocyclopropyl)- l-oxoisoindolin-2-yl)piperidine-2, 6-dione (89% yield, hydrochloric acid) was obtained as a yellow solid. 'H NMR (400 MHz, DMSO-t / e) d = 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).

[0198] Preparation of Compound 2: Prepared and purified according to compound 1 ( rep-HPLC gradient:40%-70% B). 3-(l-oxo-6-(l-((5-(4-(trifluoromethoxy)phenyl)-l,3,4-oxadiazol-2-yl)amino)cyclopro- pyl)isoindolin-2-yl)piperidine-2, 6-dione (99% purity) was obtained as an off-white solid. 'H NMR (400 MHz,DMSO-O 8 = 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, .7= 4.3, 13.2 Hz, 1H), 2.03 - 1.93 (m, 1H), 1.37 (s, 4H).Example 3. Preparation of Compound 3

[0199] The preparation was carried out according to the method described for compound 1 except that (i) 4.00 eq of A' A'-diisopropylcthylaminc were used and (ii) purification was carried out by rep-HPLC (column: YMC-Actus Triart Cl 8 150*30 mm*7 um; mobile phase: [water (formic acid) - acetonitrile]; gradient: 35%-65% B over 10 min) which afforded 3-(4-chloro-l-oxo-6-(l-((5-(p-tolyl)-l,3,4-oxadiazol-2- yl)amino)cyclopropyl)isoindolin-2-yl)piperidine-2, 6-dione (27% yield) as an off-white solid. 'H NMR (400 MHz, DMSO-< / 6) 8 = 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 = 8.0 Hz, 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).Example 4. Preparation of Compound 4

[0200] Preparation of 2: The preparation was carried out according to the method described for structure 3 of the scheme for preparing intermediate 6 except that (i) the reaction was carried out in methanol instead of ethanol, (ii) 10.0 eq of hydrazine monohydrate were used as the hydrazine hydrate, (Hi) the mixture was stirred at 60 °C for 1 h, and (iv) the reaction mixture was concentrated under reduced pressure to afford 4-(difluoromethoxy)benzohydrazide (99% yield) as a white solid.

[0201] 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) the bromine cyanide was added in three portions over 15 min and (ii) the reaction was diluted with water (20.0 mb), filtered, and the resultant solid rinsed with water to afford 5-(4-(difluoromethoxy)phenyl)-l,3,4-oxadiazol-2-amine (38% yield) as an off- white solid.

[0202] Preparation of 4: The preparation was carried out according to the method described 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=l / 0 to 3 / 1) to afford 2-bromo-5-(4- (difluorom ethoxy )phenyl)-l, 3 ,4-oxadiazole ( 22% yield) as a yellow oil. 'H NMR (400 MHz, CDCh) 8 = 8.04 (d, J= 8.8 Hz, 2H), 7.25 (d, J= 1.6 Hz, 2H), 6.60 (t, J= 72.8 Hz, 1H).

[0203] Preparation of Compound 4: The preparation was carried out according to the method described for compound 1 except that (i) triethylamine (2.50 eq) was used instead of N,N- diisopropylethylamine and (ii) purification was carried out by prep-HPLC (formic acid condition; column: YMC-Actus Triart C18 150*30mm*7um;mobile phase: [water(formic acid)- acetonitrile];gradient:35%-65% B over 10 min ) which afforded 3-(4-chloro-6-(l-((5-(4-(difluoromethoxy)phenyl)-l,3,4-oxadiazol-2- yl)amino)cyclopropyl)-l-oxoisoindolin-2-yl)piperidine-2, 6-dione (96% purity) as a yellow solid. 'H NMR (400 MHz, DMSO-O 8 = 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).Example 5. Preparation of Compound 5

[0204] Preparation of 2: The preparation was carried out according to the method described for structure 3 of the scheme for preparing intermediate 6 except that (i) 10.0 eq of hydrazine hydrate were used and (ii) the mixture was diluted with water and extracted with ethyl acetate, then the combined organic layer was washed with brine and dried over sodium sulfate, filtered and concentrated to afford 4- methoxybenzohydrazide as a white solid which was taken to the next step without purification.

[0205] 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) the bromine cyanide was added in three portions over 15 min, (ii) the reaction mixture was stirred at 25 °C for 12 h and (Hi) the reaction was diluted with water, filtered, and the resultant solid rinsed with water, then the reaction mixture was filtered and concentrated under reduced pressure to afford 5-(4-methoxyphenyl)-l,3,4-oxadiazol-2-amine (75% yield) as a white solid.

[0206] 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 / l) to afford 2-bromo-5-(4-methoxyphenyl)-l,3,4-oxadiazole ( 26 % yield) as a yellow oil. 'H NMR (400 MHz, DMSO-O 8 = 7.96 - 7.88 (m, 2H), 7.20 - 7.11 (m, 2H), 3.86 (s, 3H)

[0207] Preparation of Compound 5: The preparation was carried out according to the method described for compound 1 except that (i) triethylamine (2.50 eq) was used instead of N,N- diisopropylethylamine and (ii) purification was carried out by prep-HPLC( column: Phenom enex luna Cl 8 150*25mm* 10um;mobile phase: [water(formic acid)- acetonitrile];gradient:32%-62% B over 9 min) which afforded 3-(4-chloro-6-(l-((5-(4-methoxyphenyl)-l,3,4-oxadiazol-2-yl)amino)cyclopropyl)-l-oxoisoindolin- 2-yl)piperidine-2, 6-dione (28% yield) as an orange solid. 'H NMR (400 MHz, DMSO-t / e) 8 = 11.01 (s, 1H), 8.85 (s, 1H), 7.72 (d, J= 8.8 Hz, 2H), 7.63 (dd, J= 1.4, 14.4 Hz, 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).Example 6. Preparation of Compound 6

[0208] Preparation of 2: The preparation was carried out according to the method described for structure 3 of the scheme for preparing intermediate 6 except that (i) 10.0 eq of hydrazine monohydrate were used, (ii) the mixture was stirred at 60 °C for 1 h, and (iii) the reaction mixture was concentrated under reduced pressure to afford 3 -methylbenzohydrazide (99% yield) as a white solid.

[0209] Preparation of 3: To a solution of 3 -methylbenzohydrazide (1.00 g, 6.66 mmol, 1.00 eq) in dioxane (5.00 mL) and water (5.00 mL) was added sodium bicarbonate (559 mg, 6.66 mmol, 259 pL, 1.00 eq) and the resulting suspension stirred for 10 min at 25 °C. The mixture was added cyanogen bromide (705 mg, 6.66 mmol, 489 pL, 1.00 eq) in three portions over 15 min and stirred at 25 °C for 12 h. The reaction was diluted with water (20.0 mL), filtered, and the resultant solid rinsed with water to afford 5-(m-tolyl)- l,3,4-oxadiazol-2-amine (840 mg, 4.79 mmol, 72% yield) as an off-white solid.

[0210] Preparation of 4: The preparation was carried out according to the method described for intermediate 3 except that purification was carried out by column chromatography (SiO2, Petroleum ether / Ethyl acetate=l / 0 to 3 / 1) which afforded 2-bromo-5-(m-tolyl)-l,3,4-oxadiazole (32% yield) as a yellow solid. ’H NMR (400 MHz, CDCh) 8 = 7.87 (s, 1H), 7.83 (br d, J= 7.2 Hz, 1H), 7.45 - 7.36 (m, 2H), 2.45 (s, 3H)

[0211] Preparation of Compound 6: The preparation was carried out according to the method described for compound 1 except that (i) triethylamine (2.50 eq) was used instead of N,N- diisopropylethylamine and (ii) purification was carried out by prep-HPLC (formic acid condition; column: YMC-Actus Triart Cl 8 150*30mm*7um; mobile phase: [water(formic acid)- acetonitrile]; gradient:35%- 65% B over 10 min) which afforded 3-(4-chloro-l-oxo-6-(l-((5-(m-tolyl)-l,3,4-oxadiazol-2- yl)amino)cyclopropyl)isoindolin-2-yl)piperidine-2, 6-dione (22.6 mg, 43.1 pmol, 16% yield, 94% purity) as a yellow solid. 'H NMR (400 MHz, DMSO-< / 6) 8 = 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, 13.2 Hz, 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

[0212] Preparation of 2: The preparation was carried out according to the method described for structure 3 of the scheme for preparing intermediate 6 except that (i) 10.0 eq of hydrazine hydrate were used, (ii) the mixture was stirred at 60 °C for 1 h, and (iii) the mixture was concentrated under reduced pressure to afford 5-(difluoromethoxy)picolinohydrazide ( 96% yield) as a yellow solid.

[0213] 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 give a crude product and (iii) the crude product was purified by rep-HPLC (column: YMC-Actus Triart C18 150 * 30 mm * 7 um; mobile phase: [water(formic acid)- acetonitrile] gradient: 13 %-45 % B over 10 min) and lyophilized to afford 5-(5- (difluoromethoxy)pyridin-2-yl)-l,3,4-oxadiazol-2-amine ( 49% yield) as a white solid.

[0214] Preparation of 4: The preparation was carried out according to the method described for intermediate 3 except that (i) 1.00 eq of copper bromide were used and (ii) purification was carried out by Prep- HPLC (column: YMC-Actus Triart C18 150 * 30mm * 7um;mobile phase: [water(formic acid)- acetonitrile];gradient:30%-60% B over 10 min) which afforded 2-bromo-5 -(5 -(difluorom ethoxy )pyridin-2-yl)- 1,3,4-oxadiazole ( 14% yield) as a pink solid. ’H NMR (400 MHz, DMSO-O 8 = 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).

[0215] 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) purification was carried out by / Vc -HPLC (column: Waters Xbridge 150 * 25 mm * 5 um; mobile phase: [water( ammonium bicarbonate)- acetonitrile]; gradient:22 %-52 % B over 9 min) which afforded 3-(4-chloro-6-(l-((5-(5- (difluoromethoxy)pyridin-2-yl)-l,3,4-oxadiazol-2-yl)amino)cyclopropyl)-l-oxoisoindolin-2-yl)piperidine- 2,6-dione (6.45 mg, 11.72 pmol, 34% yield, 99% purity) as a yellow solid. 'H NMR (400 MHz, DMSO-t / e) 8 = 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), 4.5O - 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).Example 8. Preparation of Compound 8

[0216] Preparation of 2: To a solution of methyl 5 -fluoropicolinate (3.00 g, 19.3 mmol, 1.00 eq), cyclopropanol (1.68 g, 29.0 mmol, 1.50 eq) in dimethylformamide (25.0 mL) was added cesium carbonate (9.45 g, 29.0 mmol, 1.50 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 x 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 a residue. The residue was purified by column chromatography (SiCL, petroleum ether / ethyl acetate = 1 / 0 to 5 / 1) and concentrated to afford methyl 5 -cyclopropoxypicolinate (850 mg, 4.05 mmol, 21% yield, 92% purity) as a white solid.

[0217] Preparation of 3: The preparation was carried out according to the method described for structure 3 of the scheme for preparing intermediate 6 except that (i) 11.1 eq of hydrazine hydrate were used, (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 afford 5-cyclopropoxypicolinohydrazide (99% yield) as a pink solid.

[0218] 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 give a residue and the residue was triturated with ethyl acetate at 25 °C for 10 min to afford 5-(5-cyclopropoxypyridin-2-yl)-l,3,4-oxadiazol-2-amine (74% yield) as a white solid.

[0219] Preparation of 5: A mixture of 5-(5-cyclopropoxypyridin-2-yl)-l,3,4-oxadiazol-2-amine(210 mg, 770 pmol, 1.00 eq), cupric bromide (172 mg, 770 pmol, 1.00 eq), tert-butyl nitrite (159 mg, 1.54 mmol, 183 pL, 2.00 eq) in acetonitrile (4.00 mL) was degassed and purged with nitrogen for 3 times, and then the mixture was stirred at 65 °C for 0.5 hour under nitrogen atmosphere. The reaction mixture was diluted with water (20.0 mL) and extracted with ethyl acetate (3 x 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 residue. The residue was purified by column chromatography (SiCL, petroleum ether / ethyl acetate = 1 / 0 to 10 / 1) to 2-bromo-5-(5-cyclopropoxypyridin-2-yl)-l,3,4-oxadiazole (100 mg, 340 pmol, 44% yield, 96% purity) as a white solid. 'H NMR (400 MHz, DMSO-t / e) 8 = 8.52 (d, J= 2.4 Hz, 1H), 8.14 (d, J= 8.8 Hz, 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).

[0220] Preparation of Compound 8: A mixture of 2-bromo-5-(5-cyclopropoxypyridin-2-yl)-l,3,4- oxadiazole (50.0 mg, 177 pmol, 1.00 eq), 3-(6-(l-aminocyclopropyl)-4-chloro-l-oxoisoindolin-2- yl)piperidine-2, 6-dione (65.6 mg, 177 pmol, 1.00 eq, hydrochloric acid) (see ‘Preparation of Compound 1 ’ for preparation steps), AA'-diisopropylcthylaminc (115 mg, 886 pmol, 154 pL, 5.00 eq) in dimethylsulfoxide (1.00 mL) was degassed and purged with nitrogen for 3 times, and then the mixture was stirred at 110 °C for 5 h under nitrogen atmosphere. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give a residue. Purification by rep-HPLC (column: Phenomenex luna C18 150 x 25 mm x 10 / / m; mobile phase: [water(formic acid)- acetonitrile]; B%: 24%-54%, 11 min) afforded 3-(4-chloro- 6-(l -((5 -(5 -cyclopropoxypyridin-2-yl)- 1 ,3,4-oxadiazol-2-yl)amino)cyclopropyl)- 1 -oxoisoindolin-2- yl)piperidine-2, 6-dione (16.53 mg, 30.16 pmol, 17.01% yield, 97.6% purity) as a white solid. 'H NMR (400 MHz, DMSO-O 8 = 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= 3.6 Hz, 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).Example 9. Preparation of Compound 9

[0221] Preparation of 2: To a solution of methyl 6-bromopicolinate (1.00 g, 4.63 mmol, 1.00 eq) and cyclopropylboronic acid (994 mg, 11.6 mmol, 2.50 eq) in toluene (15.0 mL) was added potassium phosphate (1.97 g, 9.26 mmol, 2.00 eq) and [l,l-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (169 mg, 232 pmol, 0.05 eq) under nitrogen atmosphere. The mixture was stirred at 100 °C for 12 h. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiCh, petroleum ether / ethyl acetate=10 / l) and concentrated under reduced pressure to afford methyl 6-cyclopropylpicolinate (505 mg, 2.85 mmol, 62% yield) as brown oil.

[0222] Preparation of 3: The preparation was carried out according to the method described for structure 3 of the scheme for preparing intermediate 6 except that (i) the reaction was carried out in methanol instead of ethanol, (ii) 10.0 eq of hydrazine hydrate were used, (Hi) the reaction mixture was stirred at 60 °C for 1 h, and (iv) the reaction mixture was concentrated under reduced pressure to afford 6- cyclopropylpicolinohydrazide (100% yield) as a white solid.

[0223] 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 3.00 eq of cyanic bromide was used. 5-(6- cyclopropylpyridin-2-yl)-l,3,4-oxadiazol-2-amine (71% yield) was afforded as a brown solid.

[0224] Preparation of 5: The preparation was carried out according to the method described for intermediate 3 except that (i) 1.00 eq of copper bromide were used and (ii) purification was carried out by column chromatography (SiCh, petroleum ether / ethyl acetate = 10: 1) which afforded 2-bromo-5-(6- cyclopropylpyridin-2-yl)-l,3,4-oxadiazole (29% yield) as brown oil. 'H NMR (400 MHz, DMSO-t / s) d = 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).

[0225] Preparation of Compound 9: The preparation was carried out according to the method described for compound 1 except that (i) 4.00 eq of A'A'-diisopropylcthylaminc were used, (ii) the reaction mixture was stirred at 100 °C for 8 h, and (iii) purification was carried out by rep-HPLC (column: Ph enomen ex luna Cl 8 150*25mm* 10um;mobile phase: [water(formic acid)- acetonitrile] ;gradient:26%-56% B over 15 min) which afforded 3-(4-chloro-6-(l-((5-(6-cyclopropylpyridin-2-yl)-l,3,4-oxadiazol-2- yl)amino)cyclopropyl)-l-oxoisoindolin-2-yl)piperidine-2, 6-dione ( 5.95% yield) as a white solid. 'H NMR (400 MHz, DMSO-O d = 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).Example 10. Preparation of Compound 10

[0226] Preparation of 2: To a solution of sodium carbonate (907 mg, 8.56 mmol, 0.600 eq) in water(5.00 mL) was added hydroxylamine hydrochloride (1.49 g, 21.4 mmol, 1.50 eq) at 0 °C for 0.5 h. The cyclopropanecarbaldehyde (1.00 g, 14.3 mmol, 1.07 mL, 1.00 eq) in ethanol (5.00 mL) was added to the aqueous solution and stirred at 20 °C for 2 h. The reaction mixture was extracted with ethyl acetate (2 x 10.0 mL). The combined organic layers were washed with brine (10.0 mL), dried over anhydrous sodiumsulfate, filtered and concentrated under reduced pressure to afford (E)-cyclopropanecarbaldehyde oxime (895 mg, 10.5 mmol, 74% yield) as colorless oil.

[0227] Preparation of 3: To a solution of (E)-cyclopropanecarbaldehyde oxime (790 mg, 9.28 mmol, 1.00 eq) in 2-butanone (10.0 mL) was added ethyl propiolate (1.00 g, 10.2 mmol, 1.00 mL, 1.10 eq) and isopentyl nitrite (1.20 g, 10.2 mmol, 1.37 mL, 1.10 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 x 100 mL). The combined organic layers were washed with hydrochloric acid (30.0 mL, 0.1 M), dried over anhydrous sodiumsulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiCL, petroleum ether / ethyl acetate=20 / l to 5 / 1) to afford ethyl 3- cyclopropylisoxazole-5-carboxylate (330 mg, 1.82 mmol, 20% yield).

[0228] Preparation of 4: The preparation was carried out according to the method described for structure 3 of the scheme for preparing intermediate 6 except that 10.0 eq of hydrazine hydrate were used. 3- cyclopropylisoxazole-5-carbohydrazide (96% yield) afforded as a yellow solid.

[0229] 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 carried out by reversed phase chromatography (0.1% formic acid condition) which afforded 5-(3-cyclopropylisoxazol-5-yl)-l,3,4- oxadiazol-2-amine (59.8% yield) was a yellow solid.

[0230] Preparation of 6: The preparation was carried out according to the method described for intermediate 3 except that (i) 1.00 eq of copper bromide were used, (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 (Hi) the residue was purified by column chromatography (SiCh, petroleum ether / ethyl acetate=l / 0 to 10 / 1) to afford 2-bromo-5-(3-cyclopropylisoxazol-5-yl)-l,3,4-oxadiazole (38.2% yield, ) as yellow oil. 'H NMR (400 MHz, CDCh) 8 =6.75 (s, 1H), 2.17 - 2.08 (m, 1H), 1.17 - 1.14 (m, 2H), 0.96 - 0.91 (m, 2H).

[0231] Preparation of Compound 10: The preparation was carried out according to the method described for compound 1 except that (i) 5.00 eq of A'jV-diisopropylcthylaminc were used, (ii) the reaction mixture was stirred at 110 °C for 4 h, and (iii) purification was carried out by rep-HPLC(column:Ph enomen ex luna Cl 8 150*25mm* 10um;mobile phase: [water(formic acid)- acetonitrile] ;gradient:22%- 52% B over 10 min) which afforded 3-(4-chloro-6-(l-((5-(3-cyclopropylisoxazol-5-yl)-l,3,4-oxadiazol-2- yl)amino)cyclopropyl)-l-oxoisoindolin-2-yl)piperidine-2, 6-dione (16.11% yield) as a white solid. ' H NMR (400 MHz, DMSO-O 8 = 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.O3 - 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).Example 11. Preparation of Compound 11

[0232] Preparation of 2: To a solution of methyl 6-bromonicotinate (2.00 g, 9.26 mmol, 1.00 eq) and cyclopropylboronic acid (994 mg, 11.6 mmol, 1.25 eq) in toluene (40.0 mL) and water (4.00 mL) were added tricyclohexylphosphane (779 mg, 2.78 mmol, 0.300 eq), potassium carbonate (3.84 g, 27.8 mmol, 3.00 eq) and tris(dibenzylideneacetone) dipalladium(O) (848 mg, 926 pmol, 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 x 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 a residue. The residue was purified by reversed phase chromatography (C18, 240 g, condition:water / acetonitrile=100:0 to 50:50, 0.1% formic acid) to afford methyl 6-cyclopropylnicotinate (1.30 g, 6.97 mmol, 75% yield) as a white solid.

[0233] Preparation of 3: The preparation was carried out according to the method described for structure 3 of the scheme for preparing intermediate 6 except that 13.2 eq of hydrazine hydrate were used. 6- cyclopropylnicotinohydrazide (92% yield) afforded as a white solid.

[0234] 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 triturated with acetonitrile to afford 5-(6-cyclopropylpyridin-3-yl)-l,3,4-oxadiazol-2-amine (87% yield) as a yellow solid.

[0235] Preparation of 5: The preparation was carried out according to the method described for intermediate 3 except that (i) 1.00 eq of copper bromide were used and (ii) purification was carried out by column chromatography (SiCL, petroleum ether / ethyl acetate=l / 0 to 3 / 1) which afforded 2-bromo-5-(6- cyclopropylpyridin-3-yl)-l,3,4-oxadiazole (22% yield) as a yellow solid. MS (ESI) m / z 267.9 [M+H]+

[0236] Preparation of Compound 11. The preparation was carried out according to the method described for compound 1 except that (i) 5.00 eq of A'jV-diisopropylcthylaminc were used, (ii) the reaction mixture was stirred at 100 °C for 1.5 h, and (Hi) purification was carried out by rep-HPLC (column: Ph enomen ex luna Cl 8 150*25mm* 10um;mobile phase: [water(formic acid)-acetonitrile];gradient:23%-53% B over 10 min) which afforded 3-(4-chloro-6-(l-((5-(6-cyclopropylpyridin-3-yl)-l,3,4-oxadiazol-2-yl)amino)cyclopropyl)-l-oxoisoindolin-2-yl)piperidine-2, 6-dione (11.4% yield) as a white solid. 'H NMR (400 MHz, DMSO-O d = 10.99 (s, 1H), 9.00 (s, 1H), 8.77 (d, J= 2.0 Hz, 1H), 7.98 (dd, J= 2.0, 8.4 Hz, 1H), 7.65 (d, J= 1.6 Hz, 1H), 7.61 (d, J= 1.6 Hz, 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).Example 12. Preparation of Compound 12

[0237] Preparation of 2: A mixture of 3-(4-chloro-6-iodo-l-oxoisoindolin-2-yl)piperidine-2, 6-dione(1.66 g, 4.10 mmol, 1.00 eq) (see ‘Preparation of Compound 1’ for preparation steps), l,3-dioxoisoindolin-2- yl l-((terLbutoxycarbonyl)amino)cyclopropane-l -carboxylate (1.42 g, 4.10 mmol, 1.00 eq) (see ‘Preparation of Compound 1’ for preparation steps), [(bipy)2Ni2(p-Cl)2C12(H2O)2] (249 mg, 410 pmol, 0.100 eq), zinc powder (2.15 g, 32.8 mmol, 8.00 eq) and trimethylchlorosilane (1.34 g, 12.3 mmol, 1.56 mL, 3.00 eq) in Nf - dimethylacetamide (10.0 mL) was degassed and purged with nitrogen for 3 times at 0 °C, and then the mixture was stirred at 25 °C for 12 h under nitrogen atmosphere. 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 x 3). The organic layer was washed with water (40 mL), dried over anhydrous sodium sulfate, filtered andconcentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiCL, petroleum ether / ethyl acetate=l / O to 0 / 1) to afford Zcrt-but l (l-(7-chloro-2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)cyclopropyl)carbamate (2.72 g, 6.27 mmol, 50% yield) as a yellow solid.

[0238] Preparation of 3: A mixture of tert-butyl (l-(7-chloro-2-(2,6-dioxopiperidin-3-yl)-3- oxoisoindolin-5-yl)cyclopropyl)carbamate (800 mg, 1.84 mmol, 1.00 eq), 2,4,6-trimethyl-l,3,5,2,4,6- trioxatriborinane (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-ylidene](3-chloropyridyl)palladium(II) dichloride (62.8 mg, 92.2 pmol, 0.0500 eq) and potassium carbonate (764 mg, 5.53 mmol, 3.00 eq) in dioxane (10.0 mL) was degassed and purged with nitrogen for 3 times, and then the mixture was stirred at 100 °C for 12 h under nitrogen atmosphere. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by rep-HPLC(column: Phenomenex luna C18 150*40 mm* 15 um; mobile phase: [water(formic acid)- acetonitrile]; gradient: 25%-55% B over 15 min) and lyophilized to afford tert-butyl (l-(2-(2,6- dioxopiperidin-3-yl)-7-methyl-3-oxoisoindolin-5-yl)cyclopropyl)carbamate (470 mg, 1.14 mmol, 20% yield) as a white solid.

[0239] Preparation of 4: To a solution of tert-butyl (l-(2-(2,6-dioxopiperidin-3-yl)-7-methyl-3- oxoisoindolin-5-yl)cyclopropyl)carbamate (470 mg, 1.14 mmol, 1.00 eq) was added hydrochloric acid / dioxane (2 M, 5.00 mL, 8.80 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 (60mLx 3), and freeze-dried in water layer. The yellow solid was triturated with ethyl acetate at 25 °C for 30 min to afford 3-(6-(l-aminocyclopropyl)-4-methyl-l- oxoisoindolin-2-yl)piperidine-2, 6-dione (360 mg, 1.03 mmol, 90% yield, hydrochloride) as a yellow solid. 'H NMR (400 MHz, DMSO-O 8 = 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).

[0240] Preparation of Compound 12: The preparation was carried out according to the method described for compound 1 except that (i) 3.00 eq of A'jV-diisopropylcthylaminc were used, (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, then the organic layer was washed with water, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue, (iv) the residue was purified by column chromatography (SiCL, petroleum ether / ethyl acetate=5 / l to 1 / 5), and (v) the yellow solid was triturated with ethyl acetate at 25 °C for 4 h, then the yellow solid was triturated with ethyl alcohol at 25 °C for 6 h to afford 3-(4-m ethyl- l-oxo-6-(l -((5-(4-(trifluorom ethoxy )phenyl)-l, 3, 4-oxadiazol-2- yl)amino)cyclopropyl)isoindolin-2-yl)piperidine-2, 6-dione (46.2% yield) as a white solid. 'H NMR (400 MHz, DMSO-O 8 = 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).Example 13. Preparation of Compound 13

[0241] Preparation of 2: To a solution of dimethylamine (695 mg, 8.52 mmol, 1.00 eq, hydron chloride) and methyl 4-(chlorosulfonyl)benzoate (2.00 g, 8.52 mmol, 1.00 eq) in dichloromethane (20.0 mL) was added triethylamine (862 mg, 8.52 mmol, 1.19 mL, 1.00 eq). The mixture was stirred at 25 °C for 12 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiCL, Petroleum ether / Ethyl acetate = 1 / 0 to 3 / 1) to methyl methyl )-(N,N- dimethylsulfamoyl)benzoate (954 mg, 3.92 mmol, 46% yield) as a white solid.

[0242] Preparation of 3: The preparation was carried out according to the method described for structure 3 of the scheme for preparing intermediate 6 except that (i) 15.0 eq of hydrazine hydrate were used, (ii) the reaction mixture was stirred at 60 °C for 2 h, and (Hi) the reaction mixture was filtered and concentrated under reduced pressure to afford 4-(hydrazinecarbonyl)- / V, / V-dimethylbenzenesulfonamide (97% yield) as a yellow solid.

[0243] 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 give a residue, then the residue was triturated with a mixture of ethyl acetate (10.0 mL) at 20 °C for 1 h to afford 4-(5-amino-l,3,4-oxadiazol-2-yl)- / V, / V-dimethylbenzenesulfonamide (97% yield) as a yellow solid.

[0244] Preparation of 5: The preparation was carried out according to the method described for intermediate 3 except that purification was carried out by column chromatography (SiCL, Petroleum ether / Ethyl acetate = 0 / 1 to 3 / 1) which afforded 4-(5 -bromo- 1,3, 4-oxadiazol-2-yl)- / V, / V- dimethylbenzenesulfonamide (38% yield) as a white solid. 'H NMR (400 MHz, DMS0-< ) S = 8.26 - 8.19 (m, 2H), 8.00 - 7.93 (m, 2H), 2.66 (s, 6H).

[0245] Preparation of Compound 13: The preparation was carried out according to the method described for compound 1 except that purification was carried out by / Vc -HPLC (column: YMC-ActusTriart C18 150*30mm*7um; mobile phase: [water(formic acid) - acetonitrile]; gradient: 35% - 65% B over 10 min) which afforded 4-(5-((l-(7-chloro-2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5- yl)cyclopropyl)amino)-l, 3, 4-oxadiazol-2-yl)-2V,2V-dim ethylbenzenesulfonamide (20% yield) as yellow solid. ’H NMR (400 MHz, DMSO-O 8 = 11.16 - 10.74 (m, lH), 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).Example 14. Preparation of Compound 14

[0246] The preparation was carried out according to the method described for compound 1 except that purification was carried out by rep-HPLC (column: Phenomenex luna C18 150*25 mm* 10 um; mobile phase: [water (formic acid)- acetonitrile]; gradient: 32%-62% B over min) which afforded 3-(6-(l-((5-(4- (azetidin- 1 -ylsulfonyl)phenyl)- 1 ,3 ,4-oxadiazol-2-yl)amino)cyclopropyl)-4-chloro- 1 -oxoisoindo lin-2- yl)piperidine-2, 6-dione (25% yield, 92%) as a white solid. 'H NMR (400 MHz, DMS0-< ) 8 = 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).Example 15. Preparation of Compound 15

[0247] Preparation of 2: To a solution of cyclopropanol (1.12 g, 19.3 mmol, 1.50 eq) in tetrahydrofuran (10.0 mL) was added sodium hydride (1.03 g, 25.8 mmol, 60% purity, 2.00 eq) at 0 °C under nitrogen atmosphere. The reaction mixture was stirred at 0 °C for 0.5 h under nitrogen atmosphere. Then methyl 6-fluoronicotinate (2.00 g, 12.9 mmol, 1.00 eq) in the tetrahydrofuran (10.0 mL) was added to the reaction mixture at 0 °C. 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 x 100 mL) and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiCL, petroleum ether / ethyl acetate= 50 / 0 to 30 / 1) to afford methyl 6-cyclopropoxynicotinate (800 mg, 4.14 mmol, 32.1% yield) as a white solid.

[0248] Preparation of 3: The preparation was carried out according to the method described for structure 3 of the scheme for preparing intermediate 6 except that (i) 10.0 eq of hydrazine hydrate were used and (ii) the mixture was concentrated under reduced pressure to afford 6-cyclopropoxynicotinohydrazide (81% yield) as a white solid.

[0249] 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 give a crude product, then the crude product was triturated with ethyl acetate at 25 °C for 30 minutes to afford 5-(6-cyclopropoxypyridin-3-yl)-l,3,4-oxadiazol-2-amine (94.4% yield) as a white solid.

[0250] Preparation of 5: The preparation was carried out according to the method described for intermediate 3 except that (i) 1.00 eq of copper bromide were used, (ii) the residue was diluted with water and extracted with ethyl acetate, then the combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue, and (Hi) the residue was purified by column chromatography (SiCL, petroleum ether / ethyl acetate= 10 / 1 to 5 / 1) to afford 2-bromo-5-(6-cyclopropoxypyridin-3-yl)-l,3,4-oxadiazole (38.7% yield) as a yellow solid. 'H NMR (400 MHz, DMSO-ds) 8 = 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).

[0251] Preparation of Compound 15: The preparation was carried out according to the method described for compound 1 except that (i) 5.00 eq of A'A'-diisopropylcthylaminc were used, (ii) the reaction mixture was stirred at 110 °C for 12 h, and (iii) purification was carried out by rep-HPLC (column: Phenomenex Luna Cl 8 150*25mm* 10um; mobile phase: [water (formic acid)- acetonitrile]; gradient:23%- 53% B over 10 min), which afforded 3-(4-chloro-6-(l-((5-(6-cyclopropoxypyridin-3-yl)-l,3,4-oxadiazol-2- yl)amino)cyclopropyl)-l-oxoisoindolin-2-yl)piperidine-2, 6-dione (25.62 mg, 47.4 pmol, 16.7% yield, 99% purity) as a white solid. ’H NMR (400 MHz, DMSO-O 8 = 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).Example 16. Preparation of Compound 16

[0252] Preparation of 2: The preparation was carried out according to the method described for structure 3 of the scheme for preparing intermediate 6 except that (i) 10.0 eq of hydrazine hydrate were used and (ii) the mixture was concentrated under reduced pressure to afford 6-methoxypyridazine-3- carbohydrazide as a white solid.

[0253] 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 give a crude product and the crude product was triturated with ethyl acetate at 25°C for 30 minutes to afford 5-(6-methoxypyridazin-3-yl)-l,3,4-oxadiazol-2-amine (99% yield) as a white solid.

[0254] Preparation of 4: The preparation was carried out according to the method described for intermediate 3 except that (i) 1.00 eq of copper bromide were used, (ii) the mixture was diluted with water and extracted with ethyl acetate, then the combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue, and (iii) the residue was purified by column chromatography (SiCL, petroleum ether / ethyl acetate= 10 / 1 to 2 / 1) to afford 2-bromo-5-(6- methoxypyridazin-3-yl)-l,3,4-oxadiazole (31% yield) as a white solid. 'H NMR (400 MHz, DMS0-< ) d = 8.27 (d, J= 9.2 Hz, 1H), 7.48 (d, J= 9.2Hz, 1H), 4.14 (s, 3H).

[0255] Preparation of Compound 16: The preparation was carried out according to the method described for compound 1 except that (i) 5.00 eq of A'jV-diisopropylcthylaminc were used, (ii) the reaction mixture was stirred at 110 °C for 2 h, and (iii) purification was carried out by rep-HPLC (column: Ph enomen ex luna Cl 8 150*25mm* 10um;mobile phase: [water(formic acid)- acetonitrile] ;gradient:14%- 44% B over 10 min) which afforded 3-(4-chloro-6-(l-((5-(6-methoxypyridazin-3-yl)-l,3,4-oxadiazol-2- yl)amino)cyclopropyl)-l-oxoisoindolin-2-yl)piperidine-2, 6-dione ( 11.5% yield) as a white solid. 'H NMR (400 MHz, DMSO-O 8 = 10.99 (s, 1H), 9.19 (s, 1H), 8.10 (d, J = 9.2 Hz, 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).Example 17. Preparation of Compound 17

[0256] Preparation of 2: To a solution of 6-fluoro-2-methylnicotinic acid (1.80 g, 11.6 mmol, 1.00 eq) in dimethylformamide (30.0 mL) was added potassium carbonate (4.01 g, 29.0 mmol, 2.50 eq) and iodomethane (2.47 g, 17.4 mmol, 1.08 mL, 1.50 eq). The mixture was stirred at 20 °C for 2 h. The mixturewas diluted with water(30.0 mL), extracted with ethyl acetate (3 x 50.0 mL). The combined organic layers were washed with brine (3 x 20.0 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford methyl 6-fluoro-2-methylnicotinate(1.90 g, 11.2 mmol, 96% yield) as yellow oil.

[0257] Preparation of 3: To a solution of cyclopropanol (515 mg, 8.87 mmol, 1.50 eq) in tetrahydrofuran (10.0 mL) was added sodium hydride (472 mg, 11.8 mmol, 60% purity, 2.00 eq) at 0 °C under nitrogen atmosphere. The reaction mixture was stirred at 0 °C for 0.5 h under nitrogen atmosphere. Then methyl 6-fluoro-2-methylnicotinate (1.00 g, 5.91 mmol, 1.00 eq) in the tetrahydrofuran (10.0 mL) was added to the reaction mixture at 0 °C. 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 x 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 a residue. The residue was purified by column chromatography (SiCL, petroleum ether / ethyl acetate= 1 / 0 to 100 / 1) to afford methyl 6-cyclopropoxy-2- methylnicotinate (812 mg, 3.92 mmol, 66% yield) as colorless oil.

[0258] Preparation of 4: The preparation was carried out according to the method described for structure 3 of the scheme for preparing intermediate 6 except that (i) 20.0 eq of hydrazine hydrate were used and (ii) the mixture was concentrated under reduced pressure to afford 6-cyclopropoxy-2- methylnicotinohydrazide (98% yield) as a white solid.

[0259] 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 triturated with ethyl acetate to afford 5-(6-cyclopropoxy-2-methylpyridin-3-yl)-l,3,4-oxadiazol-2-amine (99% yield) as a white solid.

[0260] Preparation of 6: The preparation was carried out according to the method described for intermediate 3 except that (i) 1.00 eq of copper bromide were used and (ii) purification was carried out by column chromatography (SiCL, petroleum ether / ethyl acetate= 20 / 1 to 10 / 1) which afforded 2-bromo-5-(6- cyclopropoxy-2-methylpyridin-3-yl)-l,3,4-oxadiazole (15% yield) as a yellow solid. 'H NMR (400 MHz, DMSO-O d = 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).

[0261] Preparation of Compound 17: The preparation was carried out according to the method described for compound 1 except that (i) 3.00 eq of A jV-diisopropylcthylaminc were used, (ii) the reaction mixture was stirred at 110 °C for 1 h, (iii) the mixture was diluted with water and extracted with ethyl acetate, then the combined organic layers were washed with brine, and dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue, and (iv) purification was carried out by column chromatography (SiCL, petroleum ether / ethyl acetate= 1 / 5 to 0 / 1) which afforded 3-(4-chloro-6-(l-((5-(6- cyclopropoxy-2-methylpyridin-3-yl)-l,3,4-oxadiazol-2-yl)amino)cyclopropyl)-l-oxoisoindolin-2-yl)piperidine-2, 6-dione (50% yield) as a white solid. 'H NMR (400 MHz, DMSO-t<L) 8 = 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).Example 18. Preparation of Compound 18

[0262] Preparation of 2: To a solution of 6-(difluoromethoxy)nicotinic acid (500 mg, 2.64 mmol, 1.00 eq) in dimethylformamide (10.0 mL) was added potassium carbonate (914 mg, 6.61 mmol, 2.50 eq) and iodomethane (563 mg, 3.97 mmol, 247 L. 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 x 10.0 mL). The combined organic layers were washed with brine (3 x 10.0 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford methyl 6-(difluoromethoxy)nicotinate (530 mg, 2.61 mmol, 98% yield) as yellow oil.

[0263] Preparation of 3: The preparation was carried out according to the method described for structure 3 of the scheme for preparing intermediate 6 except that (i) 20.0 eq of hydrazine hydrate were used and (ii) the reaction mixture was concentrated under reduced pressure to afford 6- (difluoromethoxy)nicotinohydrazide (98% yield) as a white solid.

[0264] 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 (i) 2.00 eq of cyanic bromide were used and (ii) the mixture was diluted with ethanol (10.0 mL) and concentrated under reduced pressure to afford 5- (6-(difluoromethoxy)pyridin-3-yl)-l,3,4-oxadiazol-2-amine (94% yield) as a yellow solid.

[0265] 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 (Si O2, petroleum ether / ethyl acetate=9 / l) to afford 2-bromo-5-(6-(difluoromethoxy)pyridin-3-yl)-l,3,4-oxadiazole (100 mg, 342 pmol, 16% yield) as a yellow solid. ’H NMR (400 MHz, DMSO-76) 8 = 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).

[0266] Preparation of Compound 18: The preparation was carried out according to the method described for compound 1 except that (i) 3.00 eq of A'jV-diisopropylcthylaminc. (ii) the reaction mixture was stirred at 130 °C for 5 h and (iii) the residue was purified by column chromatography (SiCh, petroleum ether / ethyl acetate = 1 / 5) and concentrated under reduced pressure to give a solid, then purification by reverse phase chromatography (C18, 80 g; condition: water / acetonitrile = 100:0 to 0: 100, 0.1% formic acid) afforded 3-(4-chloro-6-(l-((5-(6-(difluoromethoxy)pyridin-3-yl)-l,3,4-oxadiazol-2-yl)amino)cyclopropyl)-l- oxoisoindolin-2-yl)piperidine-2, 6-dione (20.35% yield) as a white solid. 'H NMR (400 MHz, DMSO-<7s) 8 = 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).Example 19. Preparation of Compound 19

[0267] The preparation was carried out according to the method described for compound 1 except that (i) 5.00 eq of A'.A'-diisopropylcthylaminc were used), (ii) the reaction mixture was stirred at 120 °C for 1 h, and (iii) purification was carried out by rep-HPLC(column: YMC-Actus Triart C18 150*30 mm*7 um; mobile phase: [water(formic acid)-acetonitrile]; gradient: 40%-70% B over 10 min) which afforded 3-(4- fluoro-l-oxo-6-(l-((5-(4-(trifluoromethoxy)phenyl)-l,3,4-oxadiazol-2-yl)amino)cyclopropyl)isoindolin-2- yl)piperidine-2, 6-dione (18.3% yield) as an off-white solid. 'H NMR (400 MHz, DMSO-t / y) 8 = 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 (br d, J= 18.4 Hz, 1H), 2.41 (br dd, 7= 4.6, 13.0 Hz, 1H), 2.03 - 1.94 (m, 1H), 1.42 (br d, J= 10.4 Hz, 4H).Example 20. Preparation of Compound 20

[0268] Preparation of 2: To a solution of pyrrolidine (606 mg, 8.52 mmol, 711 pL. 1.00 eq) and methyl 4-(chlorosulfonyl)benzoate (2.00 g, 8.52 mmol, 1.00 eq) in dichloromethane (20.0 mL) was added triethylamine (862 mg, 8.52 mmol, 1.19 mL, 1.00 eq). The mixture was stirred at 25 °C for 12 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiCL, Petroleum ether / Ethyl acetate = 1 / 0 to 3 / 1) to afford methyl 4-(pyrrolidin-l- ylsulfonyl)benzoate (1.88 g, 6.98 mmol, 82% yield) as a white solid.

[0269] Preparation of 3: The preparation was carried out according to the method described for structure 3 of the scheme for preparing intermediate 6 except that (i) 15.0 eq of MA'-hydrazinc hydrate were used as the hydrazine hydrate and (ii) the reaction mixture was stirred at 60 °C for 2 h. 4-(pyrrolidin-l- ylsulfonyl)benzohydrazide (99% yield) afforded as a yellow solid.

[0270] Preparation of 4: The preparation was carried out according to the method described for structure 4 of the scheme for preparing intermediate 6. 5-(4-(pyrrolidin-l-ylsulfonyl)phenyl)-l,3,4-oxadiazol- 2-amine (80% purity) was afforded as a yellow solid.

[0271] Preparation of 5: The preparation was carried out according to the method described for intermediate 3 except that (i) 1.00 eq of copper bromide were used and (ii) the residue was purified by column chromatography (SiCL, Petroleum ether / Ethyl acetate = 0 / 1 to 3 / 1) to afford 2-bromo-5-(4- (pyrrolidin-l-ylsulfonyl)phenyl)-l,3,4-oxadiazole ( 23% yield) as a yellow solid. 'H NMR (400 MHz, DMSO-O 8 = 8.24 - 8.11 (m, 2H), 8.05 - 7.94 (m, 2H), 3.23 - 3.13 (m, 4H), 1.70 - 1.62 (m, 4H).

[0272] Preparation of Compound 20: The preparation was carried out according to the method described for compound 1 except that purification was carried out by / Vc -HPLC (column: Cl 8 150 x 30 mm; mobile phase: [water(formic acid)- acetonitrile]; gradient: 35% - 65% B over 12 min) which afforded 3- (4-chloro- 1 -oxo-6-( 1 -((5 -(4-(pyrrolidin- 1 -ylsulfonyl)phenyl)- 1 ,3 ,4-oxadiazol-2-yl)amino)cyclopropyl) isoindolin-2-yl)piperidine-2, 6-dione (20% yield, ) as a off-white solid. 'H NMR (400 MHz, DMSO-tsL) 8 =10.99 (s, lH), 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).Example 21. Preparation of Compound 21

[0273] The preparation was carried out according to the method described for compound 1 except that purification was carried out by rep-HPLC (column: C18 150 x 30 mm; mobile phase: [water(formic acid)- acetonitrile]; gradient: 30% - 60% B over 12 min) which afforded 3-(4-chloro-6-(l-((5-(4- cyclopropoxyphenyl)-!, 3 ,4-oxadiazol-2-yl)amino)cyclopropyl)-l-oxoisoindolin-2-yl)piperidine-2, 6-dione (39% yield) as a white solid. ’H NMR (400 MHz, DMSO-O d = 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).Example 22. Preparation of Compound 22

[0274] 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 3.00 eq of thionyl chloride were used. 3- (difluoromethyl)benzoate ( 92% yield) afforded as colorless oil.

[0275] Preparation of 3: The preparation was carried out according to the method described for structure 3 of the scheme for preparing intermediate 6 except that 16.8 eq of hydrazine hydrate were used. 3- (difluoromethyl)benzohydrazide (1.00 g, crude) afforded as an white solid.

[0276] 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 (i) 4.5 eq of cyanic bromide were used and (ii) the crude product was triturated with ethyl acetateand concentrated under reduced pressure to afford 5-(3- (difluoromethyl)phenyl)-l,3,4-oxadiazol-2-amine (57% yield) as an white solid.

[0277] Preparation of 5: The preparation was carried out according to the method described for intermediate 3 except that (i) 2.00 eq of copper bromide were used and (ii) the residue was purified by column chromatography (SiCh, petroleum ether / ethyl acetate=10 / l to 3 / 1) to afford 2-bromo-5-(3- (difluoromethyl)phenyl)-l,3,4-oxadiazole (25% yield) as an orange solid. 'H NMR (400 MHz, DMSO-t / e) d = 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).

[0278] Preparation of Compound 22: The preparation was carried out according to the method described for compound 1 except that (i) 3.00 eq of A'jV-diisopropylcthylaminc were used, (ii) the reaction mixture was stirred at 100 °C for 2 h, and (Hi) purification was carried out by rep-HPLC (column: Ph enomen ex luna Cl 8 150*25mm* 10um;mobile phase: [water(formic acid)- acetonitrile];gradient:31%- 51% B over 10 min) which afforded 3-(4-chloro-6-(l-((5-(3-(difluoromethyl)phenyl)-l,3,4-oxadiazol-2- yl)amino)cyclopropyl)-l-oxoisoindolin-2-yl)piperidine-2, 6-dione ( 33.06% yield) as an off-white solid. 'H NMR (400 MHz, DMSO-< / 6) 8 = 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).Example 23. Preparation of Compound 23

[0279] 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 3.00 eq of thionyl chloride were used. Methyl chromane-6-carboxylate (98% yield) afforded as a yellow liquid.

[0280] Preparation of 3: The preparation was carried out according to the method described for structure 3 of the scheme for preparing intermediate 6 except that 11.9 eq of hydrazine hydrate were used. Chromane-6-carbohydrazide (97% yield) afforded as a yellow solid.

[0281] 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 triturated with acetonitrile (5.00 mL) to afford 5-(chroman-6-yl)-l,3,4-oxadiazol-2-amine (64% yield) as a yellow solid.

[0282] Preparation of 5: The preparation was carried out according to the method described for intermediate 3 except that (i) 1.00 eq of copper bromide were used and (ii) he residue was purified by column chromatography (SiCh, petroleum ether / ethyl acetate = 1 / 0 to 10 / 1) to afford 2-bromo-5-(chroman-6-yl)- 1,3,4-oxadiazole (26% yield) as a yellow solid. ’H NMR (400 MHz, CDCh) 8 = 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).

[0283] Preparation of Compound 23: The preparation was carried out according to the method described for compound 1 except that (i) 4.00 eq of A'jV-diisopropylcthylaminc were used, (ii) the reaction mixture was stirred at 100 °C for 2 h and (Hi) purification was carried out by rep-HPLC (column:Ph enomen ex luna Cl 8 150*25mm* lOum; mobile phase: [water(formic acid)-acetonitrile];gradient:26%- 56% B over 11 min) which afforded 3-(4-chloro-6-(l-((5-(chroman-6-yl)-l,3,4-oxadiazol-2- yl)amino)cyclopropyl)-l-oxoisoindolin-2-yl)piperidine-2, 6-dione ( 23% yield) as a yellow solid. *H NMR (400 MHz, DMSO-O 8 = 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).I l lExample 24. Preparation of Compound 24

[0284] 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) 4.00 eq of thionyl chloride were used and (ii) the reaction mixture was stirred at 25 °C for 2 h. Chromane-8-carboxylate (900 mg, crude) as yellow oil.

[0285] Preparation of 3: The preparation was carried out according to the method described for structure 3 of the scheme for preparing intermediate 6 except that (i) 15.0 eq of hydrazine hydrate were used and (ii) the reaction mixture was concentrated under reduced pressure to afford chromane-8-carbohydrazide as a yellow solid.

[0286] 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 triturated with ethyl acetate (10.0 mL) to afford 5-(chroman-8-yl)-l,3,4-oxadiazol-2-amine (62% yield) as a yellow solid.

[0287] 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 (Si O2, petroleum ether / ethyl acetate=8 / l to 6 / 1) to afford 2-bromo-5-(chroman-8-yl)-l,3,4-oxadiazole (24% yield) as a white solid. 'H NMR (400 MHz, DMSO-< / 6) 8 = 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).

[0288] Preparation of Compound 24: The preparation was carried out according to the method described for compound 1 except that (i) 4.00 eq of A'A'-diisopropylcthylaminc were used, (ii) the reaction mixture was stirred at 100 °C for 6 h, and (Hi) purification was carried out by reverse phase chromatography (Cl 8, 40 g; condition: water / acetonitrile = 100:0 to 0: 100, 0.1% formic acid) which afforded 3-(4-chloro-6- (l-((5-(chroman-8-yl)-l,3,4-oxadiazol-2-yl)amino)cyclopropyl)-l-oxoisoindolin-2-yl)piperidine-2, 6-dione (33.2% yield) as a yellow solid. 'H NMR (400 MHz, DMSO-O S = 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).Example 25. Preparation of Compound 25

[0289] Preparation of 2: To a solution of 3 -(difluoromethoxy )benzoic acid (2.00 g, 10.6 mmol, 1.00 eq) in dichloromethane (15.0 mL) was added ZcrZ-butyl A'-aminocarbamatc (1.45 g, 10.9 mmol, 1.03 eq) and 1 -(3 -dim ethylaminopropyl)-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 (SiCL, petroleum ether / ethyl acetate = 50 / 1 to 1 / 1) to afford tert-butyl 2-(3-(difluorom ethoxy )benzoyl)hydrazine-l -carboxylate (2.90 g, 9.59 mmol, 90% yield) as a white solid.

[0290] Preparation of 3: To a solution of ZcrZ-butyl 2-(3-(difluoromethoxy)benzoyl)hydrazine-l- carboxylate (1.00 g, 3.31 mmol, 1.00 eq) in dichloromethane (10.0 mL) was added trifluoro acetic acid (3.07 g, 26.9 mmol, 2.00 mL, 8.14 eq). The two batch of mixture was stirred at 20 °C for 1 h. The reaction mixture was concentrated under reduced pressure to give 3-(difluoromethoxy)benzohydrazide (660 mg, 3.26 mmol, 98% yield) as a white solid.

[0291] Preparation of 4: To a solution of 3-(difluoromethoxy)benzohydrazide (660 mg, 3.26 mmol, 1.00 eq) in tetrahydrofuran (10.0 mL) was added di(lZ7-imidazol-l-yl)methanimine (526 mg, 3.26 mmol, 1.00 eq). The mixture was stirred at 60 °C for 2 h. The two batch of reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiCL,petroleum ether / ethyl acetate = 10 / 1 to 0 / 1) to afford 5-(3-(difluoromethoxy)phenyl)-l,3,4-oxadiazol-2-amine (650 mg, 2.86 mmol, 87% yield) as a white solid.

[0292] Preparation of 5: The preparation was carried out according to the method described for intermediate 3 except that (i) 1.10 eq of copper bromide were used and (ii) the residue was purified by column chromatography (SiCh, petroleum ether / ethyl acetate = 10 / 1 to 1 / 1) to afford 2-bromo-5-(3- (difluorom ethoxy )phenyl)-l, 3 ,4-oxadiazole (54% yield) as a white solid. 'H NMR (400 MHz, DMSO-t / y) 8 = 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).

[0293] Preparation of Compound 25: The preparation was carried out according to the method described for compound 1 except that (i) 5.00 eq of A'jV-diisopropylcthylaminc. (ii) the reaction mixture was stirred at 110 °C for 4 h, and (Hi) purification was carried out by column chromatography (SiCh, petroleum ether / ethyl acetate = 5 / 1 to 0 / 1) which afforded 3-(4-chloro-6-(l-((5-(3-(difluoromethoxy)phenyl)-l,3,4- oxadiazol-2-yl)amino)cyclopropyl)-l-oxoisoindolin-2-yl)piperidine-2, 6-dione (40.25% yield) as a white solid. ’H NMR (400 MHz, DMSO-< / 6) 8 = 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).Example 26. Preparation of Compound 26

[0294] Preparation of 2: To a solution of 2,3 -dihydrobenzo [Z> ][ 1 ,4]dioxine-6-carboxylic acid (2.00 g, 11.1 mmol, 1.00 eq) in dimethylformamide (20.0 mL) was added potassium carbonate (3.84 g, 27.8 mmol, 2.50 eq and iodomethane (1.65 g, 11.7 mmol, 726 pL, 1.05 eq). The mixture was stirred at 25 °C for 2 h.The mixture was diluted with water (30.0 mL) and extracted with ethyl acetate (3 x 60.0 mL). The combined organic layers were washed with brine (3 x 60.0 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford methyl 2,3-dihydrobenzo[Z>][l,4]dioxine-6-carboxylate (2.05 g, 10.6 mmol, 95% yield) as yellow oil.

[0295] Preparation of 3: The preparation was carried out according to the method described for structure 3 of the scheme for preparing intermediate 6 except that (i) 15.0 eq of hydrazine hydrate were used and (ii) the mixture was concentrated under reduced pressure to afford 2, 3 -dihydrobenzo [Z>][l,4]dioxine-6- carbohydrazide (100% yield) as a yellow solid.

[0296] 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 (i) 2.00 eq of cyanic bromide were used and (ii) the residue was triturated with ethyl acetate / methanol = 10 / 1 to afford 5-(2,3- dihydrobenzo[Z>][l,4]dioxin-6-yl)-l,3,4-oxadiazol-2-amine (79% yield) as a white solid.

[0297] Preparation of 5: The preparation was carried out according to the method described for intermediate 3 except that (i) 1.00 eq of copper bromide were used and (ii) the residue was purified by column chromatography (SiCL, petroleum ether / ethyl acetate= 5 / 1 to 0 / 1) to afford 2-bromo-5-(2,3- dihydrobenzo[Z>][l,4]dioxin-6-yl)-l,3,4-oxadiazole (31% yield) as a yellow solid. *H NMR (400 MHz, DMSO-O 8 = 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).

[0298] Preparation of Compound 26: The preparation was carried out according to the method described for compound 1 except that (i) 3.00 eq of A'jV-diisopropylcthylaminc were used and (ii) purification was carried out by column chromatography (SiCL, petroleum ether / ethyl acetate = 5 / 1 to 0 / 1) which afforded 3-(4-chloro-6-(l -((5-(2, 3 -dihydrobenzo [ / >][!, 4]dioxin-6-yl)-l, 3, 4-oxadiazol-2- yl)amino)cyclopropyl)-l-oxoisoindolin-2-yl)piperidine-2, 6-dione (41.32% yield) as a white solid. *H NMR (400 MHz, DMSO-O 8 = 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 (br s, 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).Example 27. Preparation of Compound 27

[0299] 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) 2.50 eq of thionyl chloride were used (ii) the reaction mixture was stirred at 50°C for 3 h, and (Hi) purification was carried out by column chromatography (SiCh, petroleum ether / ethyl acetate=20 / l to 3 / 1) which afforded methyl 3-fluoro-4- methoxybenzoate (92% yield) as a brown oil.

[0300] Preparation of 3: The preparation was carried out according to the method described for structure 3 of the scheme for preparing intermediate 6 except that (i) 15.0 eq of N, A'-h drazinc hydrate were used and (ii) the reaction mixture was concentrated under reduced pressure to afford 3-fluoro-4- methoxybenzohydrazide (99% yield) as a white solid.

[0301] Preparation of 4: The preparation was carried out according to the method described for structure 4 of the scheme for preparing intermediate 6. 5 -(3 -fluoro-4-m ethoxyphenyl)- 1,3, 4-oxadiazol-2- amine (80% yield) afforded as white solid.

[0302] Preparation of 5: The preparation was carried out according to the method described for intermediate 3 except that (i) 2.00 eq of copper bromide were used and (ii) purification was caried out by column chromatography (SiCh, petroleum ether / ethyl acetate=80 / l to 10 / 1) which afforded 2-bromo-5-(3- fluoro-4-methoxyphenyl)-l,3,4-oxadiazole (55% yield) as a white solid. 'H NMR (400 MHz, DMSO-i / g) 8 = 7.85 - 7.75 (m, 2H), 7.40 (t, J= 8.5 Hz, 1H), 3.94 (s, 3H).

[0303] Preparation of Compound 27: The preparation was carried out according to the method described for compound 1 except that (i) 4.00 eq of / V, / V-diisopropylethylamine were used, (ii) the reaction mixture was stirred at 100 °C for 5 h, and (iii) purification was carried out by rep-HPLC (C18, 40 g; column: phenomenex luna C18 150*25mm* 10um;mobile phase: [water(formic acid)-acetonitrile] ;gradient:26%-56% B over 10 min ) which afforded 3-(4-chloro-6-(l-((5-(3-fluoro-4- methoxyphenyl)-!, 3 ,4-oxadiazol-2-yl)amino)cyclopropyl)-l-oxoisoindolin-2-yl)piperidine-2, 6-dione (14.94% yield) as a yellow solid. ‘H NMR (400 MHz, DMSO-O 8 = 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).Example 28. Preparation of Compound 28

[0304] 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 5.00 eq of thionyl chloride were used. 4- fluoro-3 -methoxybenzoate (100% yield) afforded as a white solid.

[0305] Preparation of 3: The preparation was carried out according to the method described for structure 3 of the scheme for preparing intermediate 6 except that 10.0 eq of A'-hydrazinc hydrate were used. 4-fluoro-3 -methoxybenzohydrazide (100% yield) afforded as a white solid.

[0306] 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 (i) 3.50 eq of cyanic bromide were used and (ii) the reaction mixture was stirred at 75 °C for 0.5 h. 5-(4-fluoro-3-methoxyphenyl)-l,3,4-oxadiazol-2- amine (81% yield) afforded as a white solid.

[0307] Preparation of 5: The preparation was carried out according to the method described for intermediate 3 except that (i) 1.00 eq of copper bromide were used and (ii) purification was carried out by column chromatography (SiCh, petroleum ether / ethyl acetate=50 / l to 1 / 1) which afforded 2-bromo-5-(4- fluoro-3-methoxyphenyl)-l,3,4-oxadiazole (18% yield) as a white solid. 'H NMR (400 MHz, DMS0-< ) 8 =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).

[0308] Preparation of Compound 28: The preparation was carried out according to the method described for compound 1 except that (i) 4.00 eq of A'jV-diisopropylcthylaminc were used, (ii) the reaction mixture was stirred at 100 °C for 3 h, and (iii) purification was carried out by rep-HPLC (C18, 40 g; column: Phenomenex luna C18 150*25mm* 10um;mobile phase: [water(formic acid)- acetonitrile];gradient:25%-55% B over 11 min ) which afforded 3-(4-chloro-6-(l-((5-(4-fluoro-3- methoxyphenyl)-!, 3 ,4-oxadiazol-2-yl)amino)cyclopropyl)-l-oxoisoindolin-2-yl)piperidine-2, 6-dione (30.26% yield) as a yellow solid. ‘H NMR (400 MHz, DMSO-O d = 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).Example 29. Preparation of Compound 29

[0309] 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 4.00 eq of thionyl chloride were used. Methyl 4-(difluoromethyl)benzoate (92% yield) afforded as colorless oil.

[0310] Preparation of 3: The preparation was carried out according to the method described for structure 3 of the scheme for preparing intermediate 6 except that (i) the reaction was carried out in methanol instead of ethanol and (ii) 15.0 eq of A' A-hydrazinc hydrate were used. 4-(difluoromethyl)benzohydrazide afforded as a white solid.

[0311] Preparation of 4: The preparation was carried out according to the method described for structure 4 of the scheme for preparing intermediate 6. 5-(4-(difluoromethyl)phenyl)-l,3,4-oxadiazol-2-amine (68% yield) afforded as a white solid.

[0312] Preparation of 5: The preparation was carried out according to the method described for intermediate 3 except that (i) 1.00 eq of copper bromide were used and (ii) purification was carried out by column chromatography (SiCh, petroleum ether: ethyl acetate=10: l) which afforded 2-bromo-5-(4- (difluoromethyl)phenyl)-l,3,4-oxadiazole ( 57% yield) as a white solid. 'H NMR (400 MHz, DMSO-t / e) d = 8.13 (d, J= 8.1 Hz, 2H), 7.81 (br d, J= 8.1 Hz, 2H), 7.16 (t, J= 55.5 Hz, 1H).

[0313] Preparation of Compound 29: The preparation was carried out according to the method described for compound 1 except that (i) 4.00 eq of A'jV-diisopropylcthylaminc were used, (ii) the reaction mixture was stirred at 100 °C for 6 h and (iii) purification was carried out by rep-HPLC (column: Welch Ultimate Cl 8 150*25mm*5um;mobile phase: [water(formic acid)- acetonitrile];gradient:24%-54% B over 10 min) which afforded 3-(4-chloro-6-(l-((5-(4-(difluoromethyl)phenyl)-l,3,4-oxadiazol-2- yl)amino)cyclopropyl)-l-oxoisoindolin-2-yl)piperidine-2, 6-dione (16.67% yield) as an off-white solid. 'H NMR (400 MHz, DMSO-O 8 = 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).Example 30. Preparation of Compound 30

[0314] Preparation of 2: To a solution of 4-fluorobenzoic acid (2.00 g, 14.2 mmol, 1.00 eq) in dimethylformamide (20.0 mL) was added iodomethane (2.13 g, 14.9 mmol, 933 pL. 1.05 eq) and potassiumcarbonate (3.95 g, 28.5 mmol, 2.00 eq). The 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 afford methyl 4- fluorobenzoate (700 mg, 4.54 mmol, 31% yield) as brown oil.

[0315] Preparation of 3: The preparation was carried out according to the method described for structure 3 of the scheme for preparing intermediate 6 except that 20.0 eq of A'-hydrazinc hydrate were used. 4-fluorobenzohydrazide afforded as a white solid.

[0316] 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 2.50 eq of cyanic bromide were used. 5-(4- fluorophenyl)-l,3,4-oxadiazol-2-amine (49% yield) afforded as a white solid.

[0317] Preparation of 5: The preparation was carried out according to the method described for intermediate 3 except that (i) 2.00 eq of copper bromide were used and (ii) purification was carried out by column chromatography (SiCL, petroleum ether / ethyl acetate = 30 / 1 to 1 / 1) which afforded 2-bromo-5-(4- fluorophenyl)-l,3,4-oxadiazole (73% yield) as a white solid. 'H NMR (400 MHz, DMS0-< ) 8 = 8.10 - 7.99 (m, 2H), 7.51 - 7.41 (m, 2H).

[0318] Preparation of Compound 30: The preparation was carried out according to the method described for compound 1 except that (i) 5.00 eq of A'jV-diisopropylcthylaminc were used, (ii) the reaction mixture was stirred at 110 °C for 3 h, and (Hi) purification was carried out by reverse phase chromatography (C18, 25 g; condition: water / acetonitrile = 100:0 to 0:100, 0.1% formic) which afforded 3-(4-chloro-6-(l-((5- (4-fluorophenyl)- 1 ,3 ,4-oxadiazol-2-yl)amino)cyclopropyl)- 1 -oxoisoindolin-2-yl)piperidine-2, 6-dione (33.30% yield as a white solid. ’H NMR (400 MHz, DMSO-O 8 = 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).Example 31. Preparation of Compound 31

[0319] 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) purification was carried out by column chromatography (SiO2, petroleum ether / ethyl acetate=10 / l) which afforded methyl chromane-7-carboxylate (1.08 g, 100% yield) as colorless oil.

[0320] Preparation of 3: The preparation was carried out according to the method described for structure 3 of the scheme for preparing intermediate 6 except that 10.0 eq of hydrazine hydrate were used. Chromane-7-carbohydrazide afforded as yellow oil.

[0321] Preparation of 4: The preparation was carried out according to the method described for structure 4 of the scheme for preparing intermediate 6. 5-(chroman-7-yl)-l,3,4-oxadiazol-2-amine (98% yield) afforded as a yellow solid.

[0322] Preparation of 5: The preparation was carried out according to the method described for intermediate 3 except that (i) 1.00 eq of copper bromide were used and (ii) purification was carried out by column chromatography (SiCh, petroleum ether / ethyl acetate=20 / l to 10 / 1) to afford 2-bromo-5-(chroman-7- yl)-l,3,4-oxadiazole (26 % yield) as a yellow solid. 'H NMR (400 MHz, DMS0-< ) 8 = 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).

[0323] Preparation of Compound 31: The preparation was carried out according to the method described for compound 1 except that (i) 4.00 eq of / V, / V-diisopropylethylamine were used, (ii) the reaction mixture was stirred at 110 °C for 4 h, and (Hi) purification was carried out by rep-HPLC(column:Ph enomen ex luna Cl 8 150*25mm* 10um;mobile phase: [water(formic acid)-acetonitrile];gradient:26%-56% B over 10 min ) which afforded 3-(4-chloro-6-(l-((5-(chroman-7-yl)-l,3,4-oxadiazol-2- yl)amino)cyclopropyl)-l-oxoisoindolin-2-yl)piperidine-2, 6-dione ( 8.52% yield) as a white solid. 'H NMR (400 MHz, DMSO-O 8 = 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).Example 32. Preparation of Compound 32

[0324] Preparation of 2: To a solution of methyl 3 -hydroxybenzoate (2.00 g, 13.1 mmol, 1.00 eq), cyclopropyl(trifluoro)boron;potassium salt (5.84 g, 39.4 mmol, 3.00 eq) in toluene (21.0 mL) and water (7.00 mL) were added copper acetate (239 mg, 1.31 mmol, 0.100 eq) and 1,10-phenanthroline (237 mg, 1.31 mmol, 0.100 eq), potassium carbonate (3.63 g, 26.3 mmol, 2.00 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 x 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 a residue. The residue was purified by column chromatography (SiCL, petroleum ether / ethyl acetate = 1 / 0 to 50 / 1) and concentrated under reduced pressure to afford methyl 3 -cyclopropoxybenzoate (1.32 g, 5.84 mmol, 44% yield) as yellow oil.

[0325] Preparation of 3: The preparation was carried out according to the method described for structure 3 of the scheme for preparing intermediate 6 except that 10.0 eq of hydrazine hydrate were used. 3- cyclopropoxybenzohydrazide (81% yield) afforded as yellow oil.

[0326] 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 purification was carried out by reversed phase chromatography (Cl 8, 220 g; condition: water / acetonitrile = 3 / 7 to 1 / 1, 0.1% formic acid) which afforded 5-(3-cyclopropoxyphenyl)-l,3,4-oxadiazol-2-amine (28% yield) as a white solid.

[0327] Preparation of 5: A mixture of 5 -(3 -cyclopropoxyphenyl)-!, 3, 4-oxadiazol-2-amine (500 mg, 2.07 mmol, 1.00 eq), copper(II) bromide (463 mg, 2.07 mmol, 97.0 L. 1.00 eq), Zc / 7-butyl nitrite (427 mg,4.14 mmol, 493 pL. 2.00 eq in acetonitrile (6.00 mL) was degassed and purged with nitrogen for 3 times, and then the mixture was stirred at 65 °C for 1 h under nitrogen atmosphere. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiCh, petroleum ether / ethyl acetate = 1 / 0 to 20 / 1) and concentrated under reduced pressure to afford 2-bromo-5-(3-cyclopropoxyphenyl)-l,3,4-oxadiazole (140 mg, 468 pmol, 23% yield) as yellow oil. ’H NMR (400 MHz, DMSO-O 8 = 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,

[0328] Preparation of Compound 32: The preparation was carried out according to the method described for compound 1 except that (i) 5.00 eq of A jV-diisopropylcthylaminc were used, (ii) the reaction mixture was stirred at 110 °C for 3 h, and (iii) purification was carried out by rep-HPLC (column: Phenomenex luna C18 150 x 25 mm x 10 / zm; mobile phase: [water (formic acid) - acetonitrile]; B%: 30%- 60%, 10 min) which afforded 3-(4-chloro-6-(l-((5-(3-cyclopropoxyphenyl)-l,3,4-oxadiazol-2- yl)amino)cyclopropyl)-l-oxoisoindolin-2-yl)piperidine-2, 6-dione (26.52% yield) as a white solid. ’H NMR (400 MHz, DMSO-O 8 = 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).Example 33. Preparation of Compound 33

[0329] Preparation of 2: The preparation was carried out according to the method described for intermediate 3 except that (i) 1.00 eq of copper bromide were used and (ii) purification was carried out by column chromatography (SiCh, petroleum ether / ethyl acetate = 20 / 1 to 10 / 1) which afforded 2-bromo-5-(6- cyclopropoxy-2-methylpyridin-3-yl)-l,3,4-oxadiazole (15% yield) as a yellow solid. 'H NMR (400 MHz, DMSO-O 8 = 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).

[0330] Preparation of Compound 33: The preparation was carried out according to the method described for compound 1 except that (i) 5.00 eq of A'jV-diisopropylcthylaminc were used, (ii) the reaction mixture was stirred at 110 °C for 1 h, and (iii) purification was carried out by rep-HPLC (column: Phenomenex luna C18 150 x 25mm x 10 / / m; mobile phase: [water(formic acid)- acetonitrile]; B%: 24%- 54%, 10 min) which afforded 3-(6-(l-((5-(6-cyclopropoxy-2-methylpyridin-3-yl)-l,3,4-oxadiazol-2- yl)amino)cyclopropyl)-4-methyl-l-oxoisoindolin-2-yl)piperidine-2, 6-dione (25.96% yield) as a pink solid. 'H NMR (400 MHz, DMSO-O 8 = 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).Example 34. Preparation of Compound 34

[0331] The preparation was carried out according to the method described for compound 1 except that (i) 5.00 eq of A'jV-diisopropylcthylaminc were used, (ii) the reaction mixture was stirred at 110 °C for 3 h, and (iii) purification was carried out by column chromatography (SiCh, petroleum ether / ethyl acetate = 1 / 1 to 0 / 1) which afforded 3-(4-methyl-l-oxo-6-(l-((5-(p-tolyl)-l,3,4-oxadiazol-2- yl)amino)cyclopropyl)isoindolin-2-yl)piperidine-2, 6-dione (28.56% yield) as an off-white solid. ' H NMR (400 MHz, DMSO-O 8 = 10.98 (s, 1H), 8.84 (s, 1H), 7.66 (d, J= 8.0 Hz, 2H), 7.50 (s, 1H), 7.34 (br s, 2H), 7.31 (s, 1H), 5.11 (dd, .7= 4.9, 13.2 Hz, 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).Example 35. Preparation of Compound 35

[0332] Preparation of 2: The preparation was carried out according to the method described for intermediate 3 except that (i) 1.00 eq of copper bromide were used and (ii) purification was carried out by column chromatography (SiCh, petroleum ether / ethyl acetate= 1 / 0 to 5 / 1) which afforded 2-bromo-5-(6- cyclopropylpyridin-3-yl)-l,3,4-oxadiazole (19% yield) as a brown solid. 'H NMR (400 MHz, DMS0-< ) d = 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).

[0333] Preparation of Compound 35: The preparation was carried out according to the method described for compound 1 except that (i) 63.00 eq of A'jV-diisopropylcthylaminc were used, (ii) the reaction mixture was stirred at 110 °C for 12 h, and (Hi) purification was carried out by column chromatography (SiCh, petroleum ether / ethyl acetate = 1 / 1 to 0 / 1) which afforded 3-(6-(l-((5-(6-cyclopropylpyridin-3-yl)- 1, 3 ,4-oxadiazol-2-yl)amino)cyclopropyl)-4-methyl-l-oxoisoindolin-2-yl)piperidine-2, 6-dione (41.19% yield) as an off-white solid. ’H NMR (400 MHz, DMSO-O d = 10.98 (br s, 1H), 8.95 (s, 1H), 8.76 (d, J= 2.1 Hz, 1H), 7.97 (dd, .7= 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, 15.3 Hz, 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).Example 36. Preparation of Compound 36

[0334] 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 afford methyl isochromane-7-carboxylate as yellow oil.

[0335] Preparation of 3: The preparation was carried out according to the method described for structure 3 of the scheme for preparing intermediate 6 except that (i) 15.0 eq of hydrazine hydrate were used and (ii) the reaction mixture was stirred at 60 °C for 2 h. Isochromane-7-carbohydrazide (95% yield) afforded as a white solid.

[0336] Preparation of 4: The preparation was carried out according to the method described for structure 2 of the scheme for preparing intermediate 6. 5-(isochroman-7-yl)-l,3,4-oxadiazol-2-amine (99% yield) afforded as a grey solid.

[0337] Preparation of 5: The preparation was carried out according to the method described for intermediate 3, except that purification was carried out by column chromatography (SiCE, Petroleum ether / Ethyl acetate = 1 / 0 to 3 / 1) which afforded 2-bromo-5-(isochroman-7-yl)-l,3,4-oxadiazole (20% yield) as a yellow solid. ’H NMR (400 MHz, DMSO-< / 6) 8 = 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).

[0338] 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) purification was carried out by Pre -HPLC (column: C18 150 x 30 mm; mobile phase: [water(formic acid)- acetonitrile]; gradient: 32% - 62% B over 7 min) which afforded 3-(4-chloro-6-(l-((5-(isochroman-7-yl)- 1, 3, 4-oxadiazol-2-yl)amino)cyclopropyl)-l-oxoisoindolin-2-yl)piperidine-2, 6-dione (23% yield) as an off- white solid. ’H NMR (400 MHz, DMSO-< / 6) 8 = 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, 7= 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).Example 37. Preparation of Compound 37

[0339] Preparation of 2: The preparation was carried out according to the method described for structure 3 of the scheme for preparing intermediate 6 except that (i) 8.50 eq of hydrazine hydrate were used, (ii) the reaction was carried out 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 afford 4- (hydroxymethyl)benzohydrazide (98% yield) as a yellow solid.

[0340] Preparation of 3: The preparation was carried out according to the method described for structure 4 of the scheme for preparing intermediate 6. (4-(5-amino-l,3,4-oxadiazol-2-yl)phenyl)methanol (2.00 g, 10.5 mmol, 93% yield) afforded as a yellow solid.

[0341] Preparation of 4: The preparation was carried out according to the method described for intermediate 3 except that (i) 1.00 eq of copper bromide were used and (ii) purification was carried out by column chromatography (SiCL, Petroleum ether / Ethyl acetate = 1 / 0 to 1 / 1) which afforded (4-(5 -bromo- 1,3,4- oxadiazol-2-yl)phenyl)methanol (24% yield) as a yellow solid.

[0342] Preparation of 5: To a solution of (4-(5 -bromo- 1, 3 ,4-oxadiazol-2-yl)phenyl)m ethanol (326 mg, 1.28 mmol, 1.00 eq) in dichloromethane (5.00 mL) was added (diethylamino)sulfur trifluoride (538 mg, 3.34 mmol, 441 pL. 2.61 eq) at 0 °C. The mixture was stirred at 25 °C for 12 h. The reaction mixture was quenched by addition of 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 a residue. The residue was purified by column chromatography (SiCL, Petroleum ether / Ethyl acetate = 1 / 0 to3 / 1) to afford 2-bromo-5-(4-(fluoromethyl)phenyl)-l,3,4-oxadiazole (110 mg, 428 pmol, 33% yield) as a yellow solid. ’H NMR (400 MHz, DMSO-O 8 = 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).

[0343] Preparation of Compound 37: The preparation was carried out according to the method described for compound 1 except that purification was carried out by rep-HPLC (column: Cl 8 150 x 30 mm; mobile phase: [water(formic acid)- acetonitrile]; gradient: 25% - 55% B over 12 min) which afforded 3- (4-chloro-6-(l-((5-(4-(fluoromethyl)phenyl)-l,3,4-oxadiazol-2-yl)amino)cyclopropyl)-l-oxoisoindolin-2- yl)piperidine-2, 6-dione ( 16% yield) as an off-white solid. 'H NMR (400 MHz, DMS0-< ) 8 = 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= 47.2 Hz, 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).Example 38. Preparation of Compound 38

[0344] Preparation of 2: To a solution of cyclopropanol (1.12 g, 19.3 mmol, 1.50 eq) in tetrahydrofuran (10.0 mL) was added sodium hydride (1.03 g, 25.8 mmol, 60% purity, 2.00 eq at 0 °C. The mixture was stirred at 0 °C for 0.5 h. Then methyl 6 -fluoronicotinate (2.00 g, 12.9 mmol, 1.00 eq) was added. 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 x 100 mL) and concentrated under reduced pressure to give a residue. The residue was purified by reversed phase chromatography (C18, 120 g, condition: water / acetonitrile=l / 0 to 0 / 1, 0.1% formic acid) and lyophilized to afford methyl 6-cyclopropoxynicotinate (800 mg, 4.14 mmol, 32% yield) as a yellow solid.

[0345] Preparation of 3: The preparation was carried out according to the method described for structure 2 of the scheme for preparing intermediate 6 except that 10.0 eq of hydrazine hydrate were used. 6- cyclopropoxynicotinohydrazide (100% yield) afforded as a yellow solid.

[0346] 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 filtered and concentrated under reduced pressure to afford 5-(6-cyclopropoxypyridin-3-yl)-l,3,4-oxadiazol-2-amine (68% purity) as a white solid.

[0347] Preparation of 5: The preparation was carried out according to the method described for intermediate 3 except that (i) 1.00 eq of copper bromide were used, (ii) the reaction was carried out under a nitrogen atmosphere, and (iii) purification was carried out by reversed phase chromatography (C18, 40 g, condition: water / acetonitrile=l / 0 to 0 / 1, 0.1% formic acid) which afforded 2-bromo-5-(6- cyclopropoxypyridin-3-yl)-l,3,4-oxadiazole (25% yield) as a yellow solid. 'H NMR (400 MHz, DMS0-< ) d = 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, 6.1 Hz, 1H), 0.84 - 0.78 (m, 2H), 0.76 - 0.70 (m, 2H).

[0348] Preparation of Compound 38: The preparation was carried out according to the method described for compound 1 except that (i) 4.00 eq of A jV-diisopropylcthylaminc were used, (ii) the reaction mixture was stirred at 110 °C for 4 h, and (iii) purification was carried out by rep-HPLC(column:Ph enomen ex luna Cl 8 150*25mm* 10um;mobile phase: [water(formic acid)- acetonitrile];gradient:23%- 53% B over 10 min) which afforded 3-(6-(l-((5-(6-cyclopropoxypyridin-3-yl)-l,3,4-oxadiazol-2- yl)amino)cyclopropyl)-4-methyl-l-oxoisoindolin-2-yl)piperidine-2, 6-dione (24.69 mg, 47.03 pmol, 22.11% yield, 98% purity) as a white solid. ’H NMR (400 MHz, DMSO-< / 6) d = 10.97 (br s, 1H), 8.91 (s, 1H), 8.58 (d, 7= 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, 7= 5.0, 13.3 Hz, 1H), 4.40 - 4.33 (m, 1H), 4.26 (dt, 7= 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).Example 39. Preparation of Compound 39

[0349] The preparation was carried out according to the method described for compound 1 except that (i) 4.00 eq of MA'-diisopropylcthylaminc were used, (ii) the reaction mixture was stirred at 110 °C for 5 h, and (iii) purification was carried out by rep-HPLC(0.1% formic acid condition, column: Phenom enex luna C18 150*25mm* 10um;mobile phase: [water(formic acid)- acetonitrile] ;gradient:29%-59% B over 10 min )give a crude product, then the crude product was purified by rep-TLC (SiCL, petroleum ether : ethyl acetate = 0: 1) to afford 3-(6-(l-((5-(6-(difluoromethoxy)pyridin-3-yl)-l,3,4-oxadiazol-2-yl)amino)cyclopropyl)-4- methyl- l-oxoisoindolin-2-yl)piperidine-2, 6-dione ( 6.96% yield) as a white solid. *H NMR (400 MHz, DMSO-O 8 = 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, 17.5 Hz, 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).Example 40. Preparation of Compound 40

[0350] Preparation of 2: The preparation was carried out according to the method described for structure 2 of the scheme for preparing compound 25, except that the mixture was concentrated under reduced pressure to afford ZcrZ-butyl 2-(2,4-dimethylbenzoyl) hydrazine- 1 -carboxylate (97% yield) as a white solid.

[0351] Preparation of 3: To a solution of ZcrZ-butyl 2-(2,4-dimethylbenzoyl)hydrazine-l -carboxylate (1.70 g, 6.43 mmol, 1.00 eq) in dichloromethane (20.0 mL) was added trifluoroacetic acid (6.14 g, 53.9 mmol, 4.00 mL, 8.37 eq). The reaction mixture was stirred at 20 °C for 1 h. The mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiCL, petroleum ether / ethyl acetate=2 / 3) and concentrated under reduced pressure to afford 2,4- dimethylbenzohydrazide (1.17 g, 4.21 mmol, 65% yield, trifluoroacetate) as a yellow solid.

[0352] Preparation of 4: The preparation was carried out according to the method described for structure 4 of the scheme for preparing compound 25. 5-(2,4-dimethylphenyl)-l,3,4-oxadiazol-2-amine afforded as a white solid.

[0353] Preparation of 5: The preparation was carried out according to the method described for intermediate 3 except that (i) 1.00 eq of copper bromide were used and (ii) purification was carried out bycolumn chromatography (SiCh, petroleum ether / ethyl acetate = 20 / 1) 2-bromo-5-(2,4-dimethylphenyl)-l,3,4- oxadiazole (78% yield) which afforded as a yellow solid. 'H NMR (400 MHz, DMSO-t / e) d = 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).

[0354] Preparation of Compound 40: The preparation was carried out according to the method described for compound 1 except that (i) 3.00 eq of A'jV-diisopropylcthylaminc were used, (ii) the reaction mixture was stirred at 130 °C for 1 h, and (iii) he residue was purified by column chromatography (SiCh, petroleum ether / ethyl acetate = 1 / 1 to 1 / 4) and concentrated under reduced pressure to give a solid, then the solid was triturated with petroleum ether / ethyl acetate=20 / l (20.0 mL) and petroleum ether (20.0 mL) to afford 3-(4-chloro-6-(l-((5-(2,4-dimethylphenyl)-l,3,4-oxadiazol-2-yl)amino)cyclopropyl)-l-oxoisoindolin- 2-yl)piperidine-2, 6-dione (35.93% yield) as a white solid. 'H NMR (400 MHz, DMSO-t / e) 8 = 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).Example 41. Preparation of Compound 41

[0355] Preparation of 2: The preparation was carried out according to the method described for structure 2 of the scheme for preparing intermediate 6. Methyl isochromane-5-carboxylate (99% yield) afforded as yellow oil.

[0356] Preparation of 3: The preparation was carried out according to the method described for structure 3 of the scheme for preparing intermediate 6 except that (i) 35.0 eq of hydrazine hydrate were used and (ii) the mixture was concentrated under reduced pressure to afford isochromane-5 -carbohydrazide as a white solid.

[0357] 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 purification was carried out by rep-HPLC(column: Phenomenex luna C18 150 * 25 mm * 10 um;mobile phase: [water(formic acid)- acetonitrile];gradient:18 %-48 % B over 9 min) which afforded 5-(isochroman-5-yl)-l,3,4-oxadiazol-2-amine (37 % yield) as a white solid.

[0358] Preparation of 5: The preparation was carried out according to the method described for intermediate 3, except that purification was carried out by column chromatography (SiCE, Petroleum ether / Ethyl acetate=l / l to 0 / 1) which afforded 2-bromo-5-(isochroman-5-yl)-l,3,4-oxadiazole (62% yield) as a white solid. 'HNMR (400 MHz, DMSO-< / 6) 8 = 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).

[0359] Preparation of Compound 41: The preparation was carried out according to the method described for compound 1 except that (i) 3.00 eq of A' A'-diisopropylcthylaminc were used, (ii) the reaction mixture was stirred at 120 °C for 2 h, and (iii) purification was carried out by rep-HPLC (column: YMC- Actus Triart C18 150 * 30 mm*7 um;mobile phase: [water(formic acid)- acetonitrile];gradient:33 %-63 % B over 10 min) which afforded 3-(4-chloro-6-(l-((5-(isochroman-5-yl)-l,3,4-oxadiazol-2- yl)amino)cyclopropyl)-l-oxoisoindolin-2-yl)piperidine-2, 6-dione (36% yield) as an off-white solid. 'H NMR (400 MHz, DMSO-t / e) 8 = 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= 7.6 Hz, 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, .7= 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).Example 42. Preparation of Compound 42

[0360] Preparation of 2: The preparation was carried out according to the method described for structure 2 of the scheme for preparing intermediate 6. Methyl isochromane-6-carboxylate (98% yield) afforded as an off-white solid.

[0361] Preparation of 3: The preparation was carried out according to the method described for structure 3 of the scheme for preparing intermediate 6 except that 34.0 eq of hydrazine hydrate were used. Isochromane-6-carbohydrazide (99% purity) afforded as a white solid.

[0362] 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 give a crude product, then the crude product was triturated with ethyl acetate to afford 5- (isochroman-6-yl)-l,3,4-oxadiazol-2-amine (92% yield) as an off-white solid.

[0363] Preparation of 5: The preparation was carried out according to the method described for intermediate 3, except that purification was carried out by column chromatography (SiCE, Petroleum ether / Ethyl acetate=l / l to 0 / 1) which afforded 2-bromo-5-(isochroman-6-yl)-l,3,4-oxadiazole (20% yield) as a white solid. ’H NMR (400 MHz, DMSO-< / 6) 8 = 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)

[0364] Preparation of Compound 42: The preparation was carried out according to the method described for compound 1 except that (i) 4.00 eq of A' A'-diisopropylcthylaminc were used, (ii) the reaction mixture was stirred at 120 °C for 4 h, and (Hi) purification was carried out by rep-HPLC (column: YMC- Actus Triart Cl 8 150 * 30 mm * 7 um;mobile phase: [water(formic acid)- acetonitrile] gradient :33 %-63 % B over 10 min) which afforded 3-(4-chloro-6-(l-((5-(isochroman-6-yl)-l,3,4-oxadiazol-2- yl)amino)cyclopropyl)-l-oxoisoindolin-2-yl)piperidine-2, 6-dione (28% yield). 'H NMR (400 MHz, DMSO- d6) 8 = 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).Example 43. Preparation of Compound 43

[0365] Preparation of 2: To a solution of 2-bromo-5 -methylbenzoic acid (10.0 g, 46.5 mmol, 1.00 eq) in tetrahydrofuran (100 mL) was added borane dimethyl sulfide complex (10.0 M, 9.30 mL, 2.00 eq) at 0°C. The mixture was stirred at 25 °C for 12 h under nitrogen atmosphere. The reaction mixture was quenched with methanol (100 mL) at 0 °C and hydrochloric acid (6 M, 20 mL). The mixture was concentrated under reduced pressure to afford (2-bromo-5-methylphenyl)methanol (9.30 g, 46.2 mmol, 99% yield) as a yellow solid.

[0366] Preparation of 3: To a solution of (2-bromo-5-methylphenyl)methanol (9.30 g, 46.2 mmol, 1.00 eq) in dimethylformamide (10.0 mL) was added sodium hydride (2.78 g, 69.3 mmol, 60% purity, 1.50 eq) and iodomethane (13.1 g, 92.5 mmol, 5.76 mL, 2.00 eq) at 0 °C. The 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 x 50.0 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford l-bromo-2-(methoxymethyl)-4-methylbenzene (9.90 g, 46.0 mmol, 99% yield) as yellow oil.

[0367] Preparation of 4: A mixture of potassium 2-ethoxy-2-oxoacetate (545 mg, 3.49 mmol, 1.50 eq), 3 -(6-(l -((5 -(2-(methoxymethyl)-4-methylphenyl)- 1 ,3 ,4-oxadiazol-2-yl)amino)cyclopropyl)-4-m ethyl- 1 - oxoisoindolin-2-yl)piperidine-2, 6-dione (28.7 mg, 69.7 pmol, 0.0300 eq) and bis[(2,2,2- trifluoroacetyl)oxy]palladium (7.73 mg, 23.2 pmol, 0.0100 eq) and l-bromo-2-(methoxymethyl)-4- methylbenzene (500 mg, 2.32 mmol, 1.00 eq) in A-methyl pyrrolidone (5.00 mL) was degassed and purged with nitrogen atmosphere for 3 times. The mixture was stirred at 150 °C for 12 h under nitrogen atmosphere. The mixture was diluted with water (10.0 mL) and extracted with ethyl acetate (3 x 20.0 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiCL, petroleum ether / ethyl acetate = 50 / 1 to 1 / 1) and concentrated under reduced pressure to afford ethyl 2-(methoxymethyl)-4-methylbenzoate (220 mg, 1.06 mmol, 45% yield) as a white solid.

[0368] Preparation of 5: The preparation was carried out according to the method described for structure 3 of the scheme for preparing intermediate 6 except that 20.0 eq of hydrazine hydrate were used. 2- (methoxymethyl)-4-methylbenzohydrazide (97% yield) afforded as a white solid.

[0369] Preparation of 6: The preparation was carried out according to the method described for structure 4 of the scheme for preparing compound 25. 5 -(2-(methoxymethyl)-4-m ethylphenyl)- 1,3,4- oxadiazol-2-amine afforded as a white solid.

[0370] Preparation of 7: The preparation was carried out according to the method described for intermediate 3 except that (i) 1.10 eq of copper bromide were used and (ii) purification was carried out by column chromatography (SiCL, petroleum ether / ethyl acetate = 100 / 1 to 50 / 1) which afforded 2-bromo-5-(2- (methoxymethyl)-4-m ethylphenyl)-!, 3 ,4-oxadiazole (31% yield) as a white solid. 'H NMR (400 MHz, DMSO-O d = 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).

[0371] Preparation of Compound 43: The preparation was carried out according to the method described for compound 1 except that (i) 5.00 eq of A'jV-diisopropylcthylaminc were used, (ii) the reaction mixture was stirred at 130 °C for 1 h, and (Hi) purification was carried out by reverse phase chromatography (Cl 8, 80 g; condition: water / acetonitrile = 100:0 to 0: 100, 0.1% formic) which afforded 3-(6-(l-((5-(2- (methoxymethyl)-4-m ethylphenyl)- 1 ,3 ,4-oxadiazol-2-yl)amino)cyclopropyl)-4-m ethyl- 1 -oxoisoindolin-2- yl)piperidine-2, 6-dione (30.53 mg, 56.26 pmol, 49.20% yield, 95% purity) as an off-white solid. 'H NMR (400 MHz, DMSO-O 8 = 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, 7= 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).Example 44. Preparation of Compound 44

[0372] Preparation of 2: The preparation was carried out according to the method described for structure 3 of the scheme for preparing intermediate 6 except that (i) 15.0 eq of hydrazine hydrate were used and (ii) the mixture was concentrated under reduced pressure to afford 2-fluoro-4-methylbenzohydrazide as an off-white solid.

[0373] Preparation of 3: The preparation was carried out according to the method described for structure 4 of the scheme for preparing intermediate 6. 5 -(2 -fluoro-4-m ethylphenyl)-!, 3 ,4-oxadiazol-2-amine (310 mg, crude) afforded as a yellow solid.

[0374] Preparation of 4: The preparation was carried out according to the method described forintermediate 3, except that purification was carried out by column chromatography (SiCL, petroleum ether / ethyl acetate=l / l to 0 / 1) which afforded 2-bromo-5-(2-fluoro-4-methylphenyl)-l,3,4-oxadiazole (65% yield) as a white solid. ’H NMR (400 MHz, DMSO-< / 6) 8 = 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).

[0375] Preparation of Compound 44: The preparation was carried out according to the method described for compound 1 except that (i) 4.00 eq of / V, / V-diisopropylethylamine were used, (ii) the reaction mixture was stirred at 120 °C for 2 h, and (iii) purification was carried out by rep-HPLC (column: YMC- Actus Triart Cl 8 150 * 30 mm * 7 um; mobile phase: [water(formic acid)- acetonitrile] gradient :35 %-65 % B over 10 min) and lyophilization afforded 3-(4-chloro-6-(l-((5-(2-fluoro-4-methylphenyl)-l,3,4-oxadiazol-2- yl)amino)cyclopropyl)-l-oxoisoindolin-2-yl)piperidine-2, 6-dione (38% yield) as an off-white solid. 'H NMR (400 MHz, DMSO-O 8 = 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 = 12.0 Hz, 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).Example 45. Preparation of Compound 45

[0376] Preparation of 2: To a solution of 5 -methylisobenzofuran- l(3Z / )-one (1.00 g, 6.75 mmol, 1.00 eq) in methanol (10.0 mL) was added thionyl chloride (8.03 g, 67.5 mmol, 4.90 mL, 10.0 eq). The mixture was stirred at 80 °C for 12 hr. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate=l / O to 10 / 1) to afford methyl 2-(chloromethyl)-4-methylbenzoate (440 mg, 2.21 mmol, 33% yield) as white oil.

[0377] Preparation of 3: To a solution of methyl 2-(chloromethyl)-4-methylbenzoate (540 mg, 2.72 mmol, 1.00 eq) in methanol (6.00 mL) was added sodium methanol (294 mg, 5.44 mmol, 2.00 eq). The mixture was stirred at 40 °C for 12 hr. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate=l / O to10 / 1) to afford methyl 2-(methoxymethyl)-4-methylbenzoate (180 mg, 927 pmol, 34% yield) as colourless oil.

[0378] Preparation of 4: The preparation was carried out according to the method described for structure 3 of the scheme for preparing intermediate 6 except that (i) 20.0 eq of hydrazine monohydrate were used, (ii) the reaction mixture was stirred at 60 °C for 2 hr, and (iii) the reaction mixture was concentrated under reduced pressure to give a residue to afford 2-(methoxymethyl)-4-methylbenzohydrazide (91% purity) as a white solid.

[0379] 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 hr and (ii) the crude product was triturated with ethyl acetate at 25 °C for 30 min to afford 5-(2- (methoxymethyl)-4-m ethylphenyl)-!, 3 ,4-oxadiazol-2-amine (92% purity) as an off-white solid.

[0380] Preparation of 6: The preparation was carried out according to the method described for intermediate 3 except that purification was carried out by prep-TLC (SiO2, Petroleum ether: Ethyl acetate=5:l) which afforded 2-bromo-5-(2-(methoxymethyl)-4-methylphenyl)-l,3,4-oxadiazole (40% yield) as a white solid. MS (ESI) m / z 250.9 [M+H]+

[0381] 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 hr and (ii) purification was carried out by prep-HPLC (formic acid condition; column: YMC-Actus Triart Cl 8 150*30mm*7um; mobile phase: [water(formic acid)- acetonitrile];gradient:40%-70% B over 10 min ) which afforded 3-(4-chloro-6-(l-((5-(2-(methoxymethyl)-4-methylphenyl)-l,3,4-oxadiazol-2- yl)amino)cyclopropyl)-l-oxoisoindolin-2yl)piperidine-2, 6-dione ( 28% yield) as a yellow solid. 'H NMR (400 MHz, DMSO-O 8 = 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

[0382] Preparation of 2: The preparation was carried out according to the method described for structure 2 of the scheme for preparing compound 25, except that purification was carried out by column chromatography (SiCL, petroleum ether / ethyl acetate= 1 / 0 to 3 / 1) which afforded tert -butyl 2-(2-methoxy-4- methylbenzoyl)hydrazine-l -carboxylate (98% yield) as a white solid.

[0383] Preparation of 3: To a solution of tert-butyl 2-(2-methoxy-4-methylbenzoyl)hydrazine-l- carboxylate (3.31 g, 11.8 mmol, 1.00 eq) in dichloromethane (20.0 mL) was added trifluoro acetic acid (7.68 g, 67.3 mmol, 5.00 mL, 5.70 eq). The mixture was stirred at 20 °C for 4 h. The mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiCL, petroleum ether / ethyl acetate= 1 / 1 to 0 / 1) to afford 2-methoxy-4-methylbenzohydrazide (1.90 g, 6.46 mmol, 54% yield, trifluoroacetate) as a white solid.

[0384] 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 mixture was concentrated under reduced pressure to afford 5 -(2 -methoxy-4-m ethylphenyl)-!, 3 ,4-oxadiazol-2-amine (90% yield) as a white solid.

[0385] Preparation of 5: The preparation was carried out according to the method described for intermediate 3 except that (i) 1.00 eq of copper bromide were used and (ii) purification was carried out by column chromatography (SiCL, petroleum ether / ethyl acetate= 1 / 0 to 5 / 1) which afforded 2-bromo-5-(2- methoxy-4-methylphenyl)-l,3,4-oxadiazole (10% yield) as a brown solid. 'H NMR (400 MHz, DMS0-< ) 8 = 7.70 (br d, J= 7.9 Hz, 1H), 7.11 (s, 1H), 6.95 (br d, J= 7.8 Hz, 1H), 3.89 (s, 3H), 2.40 (s, 3H).

[0386] Preparation of Compound 46: The preparation was carried out according to the method described for compound 1 except that (i) 3.00 eq of A'jV-diisopropylcthylaminc were used, (ii) the reaction mixture was stirred at 110 °C for 2 h, and (Hi) purification was carried out by reverse phase chromatography(Cl 8, 40 g; condition: water / acetonitrile = 100:0 to 0: 100, 0.1% formic acid condition) which afforded 3-(4- chloro-6-(l -((5-(2 -methoxy-4-methylphenyl)-l, 3 ,4-oxadiazol-2-yl)amino)cyclopropyl)-l -oxoisoindo lin-2- yl)piperidine-2, 6-dione ( 21.24% yield) as a off-white solid. 'H NMR (400 MHz, DMSO-tsL) 8 = 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 (br d, J= 6.9 Hz, 1H), 1.40 (br s, 2H), 1.34 (br s, 2H).Example 47. Preparation of Compound 475

[0387] Preparation of 2 The preparation was carried out according to the method described for structure 2 of the scheme for preparing compound 25, except that purification was carried out by column chromatography (SiCL, petroleum ether / ethyl acetate=10 / l to 1 / 1) afforded ZcrZ-butyl 2-(4-methoxy-2- methylbenzoyl)hydrazine-l -carboxylate (96% yield) as a white solid.

[0388] Preparation of 3: To a solution of ZcrZ-butyl 2-(4-methoxy-2-methylbenzoyl)hydrazine-l- carboxylate (1.85 g, 6.60 mmol, 1.00 eq) in dichloromethane (10.0 mL) was added trifluoro acetic acid (3.07 g, 26.9 mmol, 2.00 mL, 4.08 eq). The mixture was stirred at 25 °C for 1 h. The mixture was concentrated under reduced pressure to afford 4-methoxy-2-methylbenzohydrazide (1.15 g, 6.38 mmol, 96% yield) as an white solid.

[0389] 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 mixture was concentrated under reduced pressure to give 5 -(4-methoxy-2-m ethylphenyl)-!, 3 ,4-oxadiazol-2-amine as colorless oil.

[0390] Preparation of 5: The preparation was carried out according to the method described for intermediate 3 except that (i) 2.00 eq of copper bromide were used and (ii) purification was carried out by column chromatography (SiCh, petroleum ether / ethyl acetate=10 / l to 3 / 1) which afforded 2-bromo-5-(4- methoxy-2-m ethylphenyl)-!, 3 ,4-oxadiazole (97% purity) as an orange solid. 'H NMR (400 MHz, DMSO-t / e) 8 = 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).

[0391] Preparation of Compound 47: The preparation was carried out according to the method described for compound 1 except that (i) 3.00 eq of A'jV-diisopropylcthylaminc were used, (ii) the reaction mixture was stirred at 100 °C for 3 h, and (Hi) purification was carried out by rep-HPLC (column: Ph enomen ex luna Cl 8 150*25mm* 10um;mobile phase: [water(formic acid)- acetonitrile];gradient:32%- 52% B over 10 min) which afforded 3 -(4-chloro-6-(l -((5 -(4-methoxy-2-m ethylphenyl)- 1,3, 4-oxadiazol-2- yl)amino)cyclopropyl)-l-oxoisoindolin-2-yl)piperidine-2, 6-dione (45.46% yield) as an off-white solid. 'H NMR (400 MHz, DMSO-< / 6) 8 = 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).Example 48. Preparation of Compound 485

[0392] Preparation of 2: The preparation was carried out according to the method described for structure 2 of the scheme for preparing compound 25, except that purification was carried out by column chromatography (SiCh, petroleum ether / ethyl acetate = 6 / 1 to 3 / 1) which afforded tert-butyl 2 -(4 -fluoro -2- methoxybenzoyl)hydrazine-l -carboxylate (88.9% yield) as a yellow solid.

[0393] Preparation of 3: To a solution of tert-butyl 2-(4-fluoro-2-methoxybenzoyl)hydrazine-l- carboxylate (1.40 g, 4.92 mmol, 1.00 eq) in dichloromethane (15.0 mL) was added trifluoro acetic acid (4.61g, 40.4 mmol, 3.00 mL, 8.20 eq). The two batch of mixture was stirred at 20 °C for 1 h. The reaction mixture was concentrated under reduced pressure to give 4-fluoro-2-methoxybenzohydrazide (900 mg, 4.89 mmol, 99.2% yield) as a yellow oil.

[0394] 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)-l,3,4-oxadiazol-2-amine (97.8% yield) as a yellow solid.

[0395] Preparation of 5: The preparation was carried out according to the method described for intermediate 3 except that (i) 1.10 eq of copper bromide were used and (ii) purification was carried out by column chromatography (SiCh, petroleum ether / ethyl acetate = 8 / 1 to 6 / 1) which afforded 2-bromo-5-(4- fluoro-2-methoxyphenyl)-l,3,4-oxadiazole (7.66% yield) as a white solid. 'H NMR (400 MHz, DMS0-< ) 8 = 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).

[0396] Preparation of Compound 48: The preparation was carried out according to the method described for compound 1 expect that (i) the reaction mixture was stirred at 100 °C for 2 h and (ii) purification was carried out by rep-HPLC (column: Phenomenex luna C18 150*25mm* 10um;mobile phase: [water(formic acid)- acetonitrile] ;gradient:22%-52% B over 10 min) which afforded 3-(4-chloro-6-(l- ((5-(4-fluoro-2-methoxyphenyl)-l,3,4-oxadiazol-2-yl)amino)cyclopropyl)-l-oxoisoindolin-2-yl)piperidine- 2,6-dione (47.6% yield) as an off-white solid. ’H NMR (400 MHz, DMSO-< / 6) 8 = 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).Example 49. Preparation of Compound 49

[0397] Preparation of 2: The preparation was carried out according to the method described for structure 2 of the scheme for preparing compound 25, except that purification was carried out by column chromatography (SiCL, petroleum ether / ethyl acetate=10 / l to 1 / 1) which afforded tert-butyl 2-(2-fluoro-4- methoxybenzoyl)hydrazine-l -carboxylate ( 90% yield) as a white solid.

[0398] Preparation of 3: To a solution of tert-butyl 2-(2-fluoro-4-methoxybenzoyl)hydrazine-l- carboxylate (3.00 g, 10.6 mmol, 1.00 eq) in dichloromethane (30.0 mL) was added trifluoro acetic acid (9.21 g, 80.8 mmol, 6.00 mL, 7.65 eq) at 25 °C. The mixture was stirred at 25 °C for 1 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was diluted with water (20 mL) and lyophilized to afford 2-fluoro-4-methoxybenzohydrazide (3.10 g, 10.4 mol, 98% yield, trifluoroacetate) as a white solid.

[0399] 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 triturated with acetonitrile, and the precipitate was dried under reduced pressure to afford 5-(2-fluoro-4-methoxyphenyl)-l,3,4- oxadiazol-2-amine (78% yield) as a white solid.

[0400] Preparation of 5: The preparation was carried out according to the method described for intermediate 3 except that (i) 1.00 eq of copper bromide were used and (ii) purification was carried out by column chromatography (SiCL, petroleum ether / ethyl acetate = 1:0 to 5:1) which afforded2-bromo-5-(2- fluoro-4-methoxyphenyl)-l,3,4-oxadiazole (40% yield) as a yellow solid. 'H NMR (400 MHz, DMS0-<7) 8 = 7.91 (t, 7= 8.8 Hz, 1H), 7.12 (dd, 7= 2.4, 12.8 Hz, 1H), 7.01 (dd, 7= 2.4, 8.8 Hz, lH), 3.87 (s, 3H).

[0401] Preparation of Compound 49: The preparation was carried out according to the method described for compound 1 except that (i) 4.00 eq of A'jV-diisopropylcthylaminc were used, (ii) the reaction mixture was stirred at 100 °C for 1 h, and (Hi) purification was carried out by rep-HPLC (column: Phenomenex luna C18 150 x 25 mm x lOum; mobile phase: [water(formic acid)- acetonitrile]; gradient: 24%- 54% B over 11 min) which afforded 3-(4-chloro-6-(l-((5-(2-fluoro-4-methoxyphenyl)-l,3,4-oxadiazol-2- yl)amino)cyclopropyl)-l-oxoisoindolin-2-yl)piperidine-2, 6-dione (19% yield) as a yellow solid. *H NMR (400 MHz, DMS0-O <5 = 10.99 (br s, 1H), 8.91 (s, 1H), 7.72 (t, 7= 8.8 Hz, 1H), 7.64 (d, 7= 0.8 Hz, 1H), 7.60 (d, 7= 0.8 Hz, 1H), 7.03 (dd, 7= 2.4, 12.8 Hz, 1H), 6.93 (dd, 7= 2.4, 8.8 Hz, 1H), 5.12 (dd, 7= 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).Example 50. Preparation of Compound 50

[0402] Preparation of 2: The preparation was carried out according to the method described for structure 2 of the scheme for preparing intermediate 6. Methyl isochromane-8-carboxylate (99% yield) afforded as a yellow solid.

[0403] Preparation of 3: The preparation was carried out according to the method described for structure 3 of the scheme for preparing intermediate 6 except that (i) 15.0 eq of hydrazine hydrate were used, (ii) the reaction was carried out in methanol instead of ethanol, (Hi) the reaction mixture was stirred at 60 °C for 2 h, and (iv) the reaction mixture was concentrated under reduced pressure to afford isochromane-8- carbohydrazide (96% yield) as a brown solid.

[0404] 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 over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a crude product, followed by trituration with ethyl acetate at 25 °C for 0.5 h afforded 5-(isochroman-8-yl)-l,3,4-oxadiazol-2-amine (51% yield) as a gray solid.

[0405] Preparation of 5: The preparation was carried out according to the method described for intermediate 3, except that purification was carried out by column chromatography (SiCh, Petroleum ether / Ethyl acetate = 1 / 0 to 3 / 1) which afforded 2-bromo-5-(isochroman-8-yl)-l,3,4-oxadiazole (30% yield) as a yellow solid. ’H NMR (400 MHz, DMSO-t^ 8 = 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).

[0406] Preparation of Compound 50: The preparation was carried out according to the method described for compound 1 except that (i) 4.00 eq of A'A'-diisopropylcthylaminc were used, (ii) the reaction mixture was stirred at 120 °C for 2 h, and (iii) purification was carried out by rep-HPLC (column: C18 150x30 mm; mobile phase: [water(formic acid)- acetonitrile]; gradient: 32%-62% B over 7 min) which afforded 3-(4-chloro-6-(l-((5-(isochroman-8-yl)-l,3,4-oxadiazol-2-yl)amino)cyclopropyl)-l-oxoisoindolin-2- yl)piperidine-2, 6-dione (23% yield) as an off-white solid. 'H NMR (400 MHz, DMS0-< ) 8 = 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).Example 51. Preparation of Compound 51

[0407] Preparation of 2: To a solution of methyl 5 -fluoro-3 -methylpicolinate (3.90 g, 23.5 mmol, 1.00 eq) in A'.A'-dimcthylform amide (40.0 mL) was added cyclopropanol (2.68 g, 46.1 mmol, 2.00 eq) and cesium carbonate (22.5 g, 69.2 mmol, 3.00 eq). The mixture was stirred at 80 °C for 12 h. The reaction mixture was quenched by addition water (100 mL), and extracted with ethyl acetate (2 x 50 mL). The combined organic layers were washed with brine (2 x 50 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiCL, Petroleum ether / Ethyl acetate = 1 / 0 to 3 / 1) to afford methyl 5 -cyclopropoxy -3 -methylpicolinate (1.06 g, 5.12 mmol, 22% yield) as yellow oil.

[0408] Preparation of 3: The preparation was carried out according to the method described for structure 3 of the scheme for preparing intermediate 6 except that (i) 10.0 eq of hydrazine hydrate were used, (ii) the reaction was carried out in methanol instead of ethanol, (Hi) the reaction mixture was stirred at 60 °C for 2 h, and (iv) the reaction mixture was concentrated under reduced pressure to afford 5 -cyclopropoxy -3- methylpicolinohydrazide (98% yield) as a yellow solid.

[0409] 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 purification was carried out by columnchromatography (SiCE, dichloromethane methanol = 1 / 0 to 10 / 1) which afforded 5 -(5 -cyclopropoxy -3- methylpyridin-2-yl)-l,3,4-oxadiazol-2-amine (89% yield) as a yellow solid.

[0410] Preparation of 5: The preparation was carried out according to the method described for intermediate 3, except that purification was carried out by column chromatography (SiCE, Petroleum ether / Ethyl acetate = 1 / 0 to 1 / 1) which afforded 2-bromo-5-(5-cyclopropoxy-3-methylpyridin-2-yl)-l,3,4- oxadiazole (13% yield) as a yellow solid. ’H NMR (400 MHz, DMSO-< / 6) 8 = 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).

[0411] Preparation of Compound 51: The preparation was carried out according to the method described for compound 1 except that (i) 4.00 eq of MA-diisopropylcthylaminc were used, (ii) the reaction mixture was stirred at 120 °C for 2 h, and (iii) purification was carried out by rep-HPLC (column: C18 150x30 mm; mobile phase: [water(formic acid)- acetonitrile]; gradient: 38%-68% B over 7 min) which afforded 3 -(4-chloro-6-( 1 -((5 -(5 -cyclopropoxy-3 -methylpyridin-2-yl)- 1 ,3 ,4-oxadiazol-2- yl)amino)cyclopropyl)-l-oxoisoindolin-2-yl)piperidine-2, 6-dione (29% yield) as a brown solid. 'H NMR (400 MHz, DMSO-O 8 = 10.99 (s, 1H), 8.95 (s, 1H), 8.28 (br s, 1H), 7.64 (d, J= 1.2 Hz, 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, 6.0 Hz, 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).Example 52. Preparation of Compounds 52-91 and 98-121

[0412] Compounds 52-91 and 98-121 were prepared by parallel synthesis.1 (

[0413] Step A (A = H): Aldehyde 1 (1 eq), tert-butyl hydrazinecarboxylate (1 eq) and a few drops of acetic acid were dissolved in dry methanol and the reaction mixture was stirred at 60 °C for 5 h. The completion of the reaction was monitored by LCMS. Upon completion, the reaction mixture was cooled down to room temperature and resulting methanol solution of intermediate 2 was used directly in the next step without work up.

[0414] Step A (A = OH): Acid 1 (1 eq) was dissolved in dry THF followed by portion wise addition of l-(lH-imidazole-l -carbonyl)- IH-imidazole (1.2 eq). Reaction mixture was stirred at 60 °C for 3 h, cooled down to room temperature and added dropwise to hydrazine hydrate (15 eq) with vigorous stirring. After 1 h, the reaction mixture was concentrated in vacuo. The residue was dissolved in DCM, dried over anhydroussodium sulphate and concentrated under reduced pressure. The resulting crude hydrazide 2 was used in the next step without purification.

[0415] Step B (A = H): [Bis(acetoxy)iodo]benzene (1.2 eq) was added portion wise to a stirred methanol solution of intermediate 2 (1 eq) at room temperature. Resulting clear reaction mixture was stirred at 60 °C overnight and then concentrated under reduced pressure. The residue was purified by recrystallization from CC14 or submitted to chromatography to afford pure oxadiazalone 3.

[0416] Step B (A = OH): l-(lH-imidazole-l -carbonyl)- IH-imidazole (1.4 eq) was added portion wise to the mixture of crude hydrazide 2 (1 eq) and DIPEA (5 eq) in dry DCM and stirred for 6 h. The progress of the reaction was monitored using LCMS and, if necessary, up to 0.5 eq of CDI was added additionally. Upon completion, the reaction mixture was concentrated and subjected to flash chromatography to obtain oxadiazalone 3.

[0417] Step C: Amine 4 (1 eq HC1) (see e.g. Example 1 for preparation steps), oxadiazolone 3 (1.2 eq), PyClOP (1.5 eq) and DIPEA (5 eq) were placed in vial followed by addition of DMA (0.5 ml). Reaction mixture was stirred at room temperature for 10 min and then at 60 °C overnight. Upon completion, a clear solution was observed. LCMS of reaction mixture showed complete amine consumption. Reaction mixture was submitted to reverse phase HPLC to afford desired TM.Table 2. Yields and QC Data for Compounds 52-91 and 98-121Example 53. Preparation of Compound 92Compound 92

[0418] Prepared according compound 1 except that (i) 4.00 eq of A'A'-diisopropylcthylaminc were used, (ii) the reaction mixture was stirred at 120 °C for 2 h, and (Hi) double purification was carried out by rep-HPLC (column: C18 150x30mm; mobile phase: [water(formic acid)-acetonitrile]; gradient: 38%-68% B over 7 min followed by column: Waters Xbridge 150*25mm* 5um; mobile phase: [water( ammonium bicarbonate)- acetonitrile]; gradient: 30%-60% B over 9 min) which afforded 3-(6-(l-((5-(4- cyclopropoxyphenyl)- 1 ,3,4-oxadiazol-2-yl)amino)cyclopropyl)-4-(difluoromethyl)- 1 -oxoisoindolin-2- yl)piperidine-2, 6-dione ( 17% yield) as a white solid. 'H NMR (400 MHz, DMS0-< ) 8 = 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).Example 54. Preparation of Compound 93

[0419] Preparation of 2'. To a solution of tert-butyl (l-(7-chloro-2-(2,6-dioxopiperidin-3-yl)-3- oxoisoindolin-5-yl)cyclopropyl)carbamate (500 mg, 1.15 mmol, 1.00 eq) (see ‘Preparation of Intermediate 2’ for preparation steps) in A'A'-dimcthylacctamidc (10.0 mL) was added nickel(II) chloride (50.6 mg, 230 pmol, 0.200 eq), 2-(4-amino-2-pyridyl)pyridin-4-amine (21.5 mg, 115 pmol, 0.100 eq), zinc powder (452 mg,6.91 mmol, 6.00 eq), magnesium chloride (878 mg, 9.22 mmol, 378 pL, 8.00 eq), molecularsieves 3A (1.00 g, 2.30 mmol, 2.00 eq), [2,2'-bipyridine]-4,4'-diamine (56.3 mg, 461 pmol, 0.400 eq) under nitrogen atmosphere. Then chlorodifluoromethane (5.20 M, 5.76 mL, 26.0 eq) was added. The reaction mixture was stirred at 60 °C for 12 h. Then the reaction mixture was filtered. The filtrate was washed with brine (50 mL), extracted with ethyl acetate (3 x 50 mL). Then the organic layer was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by / Vc -HPLC (column: C18 150x30mm;mobile phase: [water(formic acid)- acetonitrile];gradient:35%-65% B over 7 min) and lyophilized to afford tert-butyl (l-(7-(difluoromethyl)-2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5- yl)cyclopropyl)carbamate (50.0 mg, 111 pmol, 10% yield) as a white solid.

[0420] Preparation of 3: To a solution of tert-butyl (l-(7-(difluoromethyl)-2-(2,6-dioxopiperidin-3- yl)-3-oxoisoindolin-5-yl)cyclopropyl)carbamate (50.0 mg, 111 pmol, 1.00 eq) in dioxane (0.500 mL) was added hydrochloric acid (2.00 N in dioxane, 0.50 mL). The reaction mixture was stirred at 20 °C for 0.5 h. Then the reaction mixture was concentrated under reduced pressure and lyophilized to afford 3-(6-(l - aminocyclopropyl)-4-(difluoromethyl)-l-oxoisoindolin-2-yl)piperidine-2, 6-dione (42.0 mg, 109 pmol, 98% yield, hydrochloric acid) as a white solid. 'H NMR (400 MHz, DMS0-< ) 8 = 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).

[0421] 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) purification was carried out by / Vc -HPLC (column: C18 150x30mm;mobile phase: [water(formic acid)- acetonitrile];gradient:35%-65% B over 7 min) followed by pre-TLC (Petroleum ether / Ethyl acetate = 1 / 1) which afforded 3-(4-(difluoromethyl)-l-oxo-6-(l-((5-(p-tolyl)-l,3,4-oxadiazol-2- yl)amino)cyclopropyl)isoindolin-2-yl)piperidine-2, 6-dione (33% yield) as a white solid. 'H NMR (400 MHz, DMSO-rig) d = 11.01 (s, 1H), 9.O2 (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).Example 55. Preparation of Compound 94Compound 94

[0422] The preparation was carried out according to the method described for compound 1 except that (i) 5.00 eq of A'jV-diisopropylcthylaminc were used, (ii) the reaction mixture was stirred at 130 °C for 1 h, and (iii) purification was carried out by column chromatography (SiCL, petroleum ether / ethyl acetate = 2 / 1 to 0 / 1) which afforded 3-(4-(difluoromethyl)-6-(l-((5-(2-(methoxymethyl)-4-methylphenyl)-l,3,4- oxadiazol-2-yl)amino)cyclopropyl)-l-oxoisoindolin-2-yl)piperidine-2, 6-dione (41% yield) as a white solid. ’H NMR (400 MHz, DMSO-O d = 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, lH), 2.36 (s, 3H), 2.00 (td, J= 5.0, 10.4 Hz, 1H), 1.41 (br s, 4H).Example 56. Preparation of Compound 95

[0423] Preparation of 2: To a solution of 6-fluoro-2-methyl-pyridine-3-carboxylic acid (1.00 g, 6.45 mmol, 1.00 eq) in dichloromethane (10.0 mL) was added / V, / V-methanediylidenedicyclohexanamine (1.60 g, 7.74 mmol, 1.56 mL, 1.20 eq), / V, / V-dimethylpyridin-4-amine (394 mg, 3.22 mmol, 0.50 eq) and methanol (310 mg, 9.67 mmol, 391 L. 1.50 eq). The mixture was stirred at 25 °C for 12 hr. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by columnchromatography (SiO2, Petroleum ether / Ethyl acetate=l / 0 to 5 / 1) to afford methyl 6-fluoro-2- methylnicotinate (1.80g, 10.5 mmol, 82% yield, 99% purity) as colorless liquid.

[0424] Preparation of 3: To a solution of methyl methyl 6-fluoro-2-methylnicotinate (800 mg, 4.73 mmol, 1.00 eq) in dimethylformamide (8.00 mL) was added cesium carbonate (2.31 g, 7.09 mmol, 1.50 eq and cyclopropanol (824 mg, 14.2 mmol, 3.00 eq). The mixture was stirred at 25 °C for 12 hr. The reaction mixture was quenched by addition water (50 mL) and then extracted with ethyl acetate (3 x 25 mL). The combined organic layers were washed with brine (20 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (formic acid condition; column: Phenomenex luna C18 150*40mm* 15um; mobile phase: [water (formic acid) - acetonitrile];gradient:38%-68% B over 15 min) and lyophilized to afford methyl 6-cyclopropoxy-2- methylnicotinate (382 mg, 1.84 mmol, 39% yield) as yellow liquid.

[0425] Preparation of 4: The preparation was carried out according to the method described for structure 3 of the scheme for preparing intermediate 6 except that (i) 15.0 eq of hydrazine monohydrate were used, (ii) the reaction was carried out in methanol instead of ethanol, (Hi) the reaction mixture was stirred at 60 °C for 2 hr, and (iv) the reaction mixture was concentrated under reduced pressure to give a residue to afford 6-cyclopropoxy-2-methylnicotinohydrazide (99% yield) as a white solid.

[0426] Preparation of 5: The preparation was carried out according to the method described for structure 4 of the scheme for preparing intermediate 6. 5-(6-cyclopropoxy-2-methylpyridin-3-yl)-l,3,4- oxadiazol-2-amine (87% yield) afforded as a yellow solid.

[0427] Preparation of 6: The preparation was carried out according to the method described for intermediate 3, except that purification was carried out by column chromatography (SiO2, Petroleum ether / Ethyl acetate=l / 0 to 5 / 1) which afforded 2-bromo-5-(6-cyclopropoxy-2-methylpyridin-3-yl)- 1,3,4- oxadiazole (23% yield) as a yellow solid. MS (ESI) m / z 297.9 [M+H]+

[0428] 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 hr and (ii) purification was carried out by prep-HPLC (formic acid condition; column: YMC-Actus Triart Cl 8 150*30mm*7um;mobile phase: [water(formic acid)- acetonitrile];gradient:35%-65% B over 10 min) followed by preparative TLC (SiO2, Petroleum ether: Ethyl acetate =1: 1) which afforded 3-(6-(l-((5-(6- cyclopropoxy-2-methylpyridin-3-yl)-l,3,4-oxadiazol-2-yl)amino)cyclopropyl)-4-(difluoromethyl)-l- oxoisoindolin-2-yl)piperidine-2, 6-dione (27% yield) as an off-white solid. 'H NMR (400 MHz, DMSO-t / <) d = 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, 6.0 Hz, 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

[0429] 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) purification was carried out by rep-HPLC (column: C18 150x30mm;mobile phase: [water(formic acid)-acetonitrile];gradient:42%-72% B over 7 min) which afforded 3-(4-(difluoromethyl)- 1 -oxo-6-(l -((5 -(4-(trifluoromethoxy)phenyl)- 1 ,3,4-oxadiazol-2- yl)amino)cyclopropyl) isoindolin-2-yl)piperidine-2, 6-dione (25% yield) as an off-white solid. 'H NMR (400 MHz, DMSO-O d = 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, .7= 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).Example 58. Preparation of Compound 97

[0430] 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) 10.0 eq of thionyl chloride were used, (ii) the reaction mixture was stirred at 75 °C for 12 h and (iii) purification was carried out by re -TLC (SiCh, Petroleum ether / Ethyl acetate = 0 / 1) which afforded methyl 5 -methoxy-3 -methylpicolinate (60% yield) as a white solid.

[0431] Preparation of 3: The preparation was carried out according to the method described for structure 3 of the scheme for preparing intermediate 6 except that (i) 10.0 eq of hydrazine hydrate were used and (ii) the reaction mixture was stirred at 60 °C for 2 h. 5 -m ethoxy-3 -methylpicolinohydrazide (85% yield) afforded as a white solid.

[0432] 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 purification was carried out by column chromatography (SiCh, dichloromethane / m ethanol = 1 / 1 to 0 / 1) which afforded 5 -(5 -methoxy -3- methylpyridin-2-yl)-l,3,4-oxadiazol-2-amine (78% yield) as a yellow solid.

[0433] Preparation of 5: To a solution of 5-(5-methoxy-3-methylpyridin-2-yl)-l,3,4-oxadiazol-2- amine (20.0 mg, 97.0 pmol, 1.00 eq) in acetonitrile (10.0 mL) was added tert-butyl nitrite (15.0 mg, 145 pmol, 17.3 pL, 1.50 eq and potassium bromide (17.3 mg, 145 pmol, 6.30 pL, 1.50 eq) at 0 °C. 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 chromatography on silica gel (Petroleum ether / Ethyl acetate = 1 / 1 to 5 / 1) to afford 2- bromo-5-(5-methoxy-3-methylpyridin-2-yl)-l,3,4-oxadiazole (60.0 mg, 222 pmol, 33% yield) as a yellow oil. ’H NMR (400 MHz, CDCh) 8 = 8.35 (br d, J= 2.8 Hz, 1H), 7. 19 (d, J= 2.4 Hz, 1H), 3.96 (s, 3H), 2.78 (s, 3H).

[0434] 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) purification was carried out by rep-HPLC (column: C18 150x30mm;mobile phase: [water(formic acid)- acetonitrile];gradient:20%-50% B over 7 min) which afforded 3-(4-chloro-6-(l-((5-(5-methoxy-3- methylpyridin-2-yl)-l, 3 ,4-oxadiazol-2-yl)amino)cyclopropyl)-l-oxoisoindolin-2-yl)piperidine-2, 6-dione (20% yield) as a yellow solid. ’H NMR (400 MHz, DMSO-< / 6) 8 = 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 = 2.8 Hz, 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).Example 59. Preparation of Compound 122

[0435] The preparation was carried out according to the method described for compound 1 except that (i) MA'-dimcthylacctamidc was used instead of DMSO, (ii) the reaction mixture was stirred at 110 °C for 1 hr, and (iii) purification was carried out by re -HPLC (formic acid condition;column: Phenomenex luna C18 150*40mm* 15um;mobile phase: [water(formic acid)- acetonitrile];gradient:35%-65% B over 15 min ) which afforded 3 -(4-chloro- 1 -oxo-6-( 1 -((5 -(4-(trifluoromethyl)phenyl)- 1 ,3 ,4-oxadiazol-2- yl)amino)cyclopropyl)isoindolin-2-yl)piperidine-2, 6-dione (43% yield) as an off-white solid. 'H NMR (400 MHz, DMSO-O d = 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 - 1.32 (m, 4H)Example 60. Preparation of Compound 123

[0436] Preparation of 2: The preparation was carried out according to the method described for structure 3 of the scheme for preparing intermediate 6 except that (i) 10.0 eq of hydrazine monohydrate were used, (ii) the reaction mixture was stirred at 60 °C for 2 h, and (iii) the filtrate was concentrated under reduced pressure to afford 6-methoxynico tinohydrazide (91% yield) as a white solid.

[0437] Preparation of 2: The preparation was carried out according to the method described for structure 4 of the scheme for preparing intermediate 6. 5-(6-methoxypyridin-3-yl)-l,3,4-oxadiazol-2-amine afforded as a white solid.

[0438] Preparation of 4: The preparation was carried out according to the method described for intermediate 3, except that purification was carried out by flash silica gel chromatography (ISCO®; 20 g SepaFlash® Silica Flash Column, eluent of 0%— 15% ethyl acetate / petroleum ether gradient at 50 mL / min) which afforded 2-bromo-5-(6-methoxypyridin-3-yl)-l,3,4-oxadiazole (9% yield) as a white solid. 'H NMR(400 MHz, DMSO-O 8 = 8.78 (d, J= 2.4 Hz, 1H), 8.24 (dd, J= 2.4, 8.8 Hz, 1H), 7.05 (d, J= 8.8 Hz, 1H),3.95 (s, 3H)

[0439] Preparation of Compound 123: The preparation was carried out according to the method described for compound 1 except that (i) 5.06 eq of A'A'-diisopropylcthylaminc were used, (ii) the reaction mixture was stirred at 100 °C for 1 h, and (Hi) purification was carried out by rep-HPLC (column: Phenomenex luna C18 150 mm x 25 mm x 10 z / m: mobile phase: [water (formic acid) - acetonitrile]; gradient: 24%-54% B over 10 min) and rep-HPLC (column: Waters Xbridge 150 mm x 25 mm x 5 ^m; mobile phase: [water (ammonium bicarbonate) - acetonitrile]; gradient: 10%-30% B over 53 min) which afforded 3-(4-chloro-6-(l-((5-(6-methoxypyridin-3-yl)-l,3,4-oxadiazol-2-yl)amino)cyclopropyl)-l- oxoisoindolin-2-yl)-piperidine-2, 6-dione (18% yield) as a white solid. 'H NMR (400 MHz, DMS0-< ) 8 = 10.98 (s, 1H), 8.95 (s, 1H), 8.56 (d, J= 2.4 Hz, 1H), 8.06 (dd, J= 2.4, 8.8 Hz, 1H), 7.63 (dd, J= 1.2, 15.2 Hz, 2H), 6.97 (d, J= 8.8 Hz, 1H), 5.11 (dd, J= 5.2, 13.2 Hz, 1H), 4.48 - 4.40 (m, 1H), 4.33 - 4.23 (m, 1H), 3.91 (s, 3H), 2.93 - 2.84 (m, 1H), 2.61 - 2.55 (m, 1H), 2.46 - 2.37 (m, 1H), 2.04 - 1.93 (m, 1H), 1.49 - 1.32 (m, 4H)Example 61. Preparation of Compound 124

[0440] Preparation of 2: The preparation was carried out according to the method described for structure 4 of the scheme for preparing intermediate 6. 5 -(3 -(trifluoromethyl)bicyclo [1.1.1 ]pentan- 1 -yl)- l,3,4-oxadiazol-2-amine (30 % yield) afforded as a white solid.

[0441] Preparation of 3: The preparation was carried out according to the method described for intermediate 3, except that purification was carried out by column chromatography (Petroleum ether / Ethyl acetate=5 / l) which afforded 2-bromo-5-(3-(trifluoromethyl)bicyclo[l.l.l]pentan-l-yl)-l,3,4-oxadiazole (39% yield) as a white solid. ’H NMR (400 MHz, DMSO-O 8 = 2.54 - 2.48 (m, 6H)

[0442] Preparation of Compound 124: 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) purification was carried out by prep-HPLC( column: Phenomenex luna C18 150*40mm* 15um;mobile phase: [water(formic acid)- acetonitrile] ;B%:%, isocratic elution mode) which afforded 3-(4-chloro-l-oxo-6- (1 -((5 -(3 -(trifluoromethyl)bicyclo [1.1.1 ]pentan- 1 -yl)- 1 ,3 ,4-oxadiazol-2-yl)amino)cyclopropyl)isoindolin-2- yl)piperidine-2, 6-dione (47.% yield) as a yellow solid. 'H NMR (400 MHz, DMSO-<7y) 8 = 11.02 (s, 1H),8.78 (s, 1H), 7.61 (d, J= 1.2 Hz, 1H), 7.56 (d, J= 1.4 Hz, 1H), 5.13 (dd, J= 5.2, 13.2 Hz, 1H), 4.49 - 4.43 (m, 1H), 4.32 - 4.26 (m, 1H), 2.95 - 2.88 (m, 1H), 2.56 (br d, J= 8.2 Hz, 1H), 2.44 (br d, J= 4.2 Hz, 1H), 2.39 (s, 6H), 2.04 - 1.98 (m, 1H), 1.38 (br d, J= 2.8 Hz, 2H), 1.30 (br s, 2H).Example 62. Preparation of Compound 1251 2

[0443] Preparation of 2: The preparation was carried out according to the method described for structure 4 of the scheme for preparing compound 25, except that the mixture was concentrated under reduced pressure to afford 5-(5-methylisoxazol-3-yl)-l,3,4-oxadiazol-2-amine as a white solid.

[0444] Preparation of 3: The preparation was carried out according to the method described for intermediate 3, except that purification was carried out by column chromatography (SiCh, petroleum ether / ethyl acetate = 3 / 1) which afforded 2-bromo-5-(5-methylisoxazol-3-yl)-l,3,4-oxadiazole (23% yield) as a white solid. ’H NMR (400 MHz, DMSO-O 8 = 6.93 (s, 1H), 2.54 (s, 3H).

[0445] Preparation of Compound 125: The preparation was carried out according to the method described for compound 1 except that (i) 3.00 eq of A'jV-diisopropylcthylaminc were used, (ii) the reaction mixture was stirred at 130 °C for 1 h, and (Hi) purification was carried out by column chromatography (SiCh, petroleum ether / ethyl acetate = 1 / 10) which afforded 3-(4-chloro-6-(l-((5-(5-methylisoxazol-3-yl)-l,3,4- oxadiazol-2-yl)amino)cyclopropyl)-l-oxoisoindolin-2-yl)piperidine-2, 6-dione ( 24.11% yield) as an off-white solid. ’H NMR (400 MHz, DMSO-< / 6) 8 = 10.98 (br s, 1H), 9.19 (s, 1H), 7.61 (dd, J= 1.3, 9.4 Hz, 2H), 6.72 (s, 1H), 5.12 (dd, J= 5.1, 13.3 Hz, 1H), 4.49 - 4.40 (m, 1H), 4.33 - 4.25 (m, 1H), 2.96 - 2.84 (m, 1H), 2.58 (td, J= 2.0, 15.2 Hz, 1H), 2.48 (s, 3H), 2.46 - 2.39 (m, 1H), 2.04 - 1.94 (m, 1H), 1.48 - 1.42 (m, 2H), 1.41 - 1.35 (m, 2H).Example 63. Preparation of Compound 126

[0446] Preparation of 2: To a solution of 3-methylbicyclo[l.l.l]pentane-l-carboxylic acid (100 mg,793 pmol, 1.00 eq) in dichloromethane (1.00 mL) were added tert-butyl hydrazinecarboxylate (108 mg, 816 pmol, 1.03 eq , benzotriazol- l-ol (53.6 mg, 396 pmol, 0.500 eq), triethylamine (160 mg, 1.59 mmol, 221 pL, 2.00 eq) and 1 -(3 -dim ethylaminopropyl)-3 -ethylcarbodiimide hydrochloride (155 mg, 809 pmol, 1.02 eq). The mixture was stirred at 25 °C for 12 h. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: YMC-Actus Triart Cl 8 150*30mm*7um;mobile phase: [water(formic acid)- acetonitrile];gradient:30%-60% B over 10 min) to afford tert-butyl 2V-[(3-methylbicyclo[l.l.l]pentane-l-carbonyl)amino]carbamate (93.0 mg, 387 pmol, 49% yield) as a white solid.

[0447] Preparation of 3: To a solution of tert-butyl 2V-[(3-methylbicyclo[l.l.l]pentane-l- carbonyl)amino]carbamate (93 mg, 387 pmol, 1.00 eq) in hydrochloric acid / ethyl acetate (5.00 mL). The mixture was stirred at 25 °C for 2 h. The mixture was concentrated to afford 3-methylbicyclo[l.l.l]pentane- 1 -carbohydrazide (54.0 mg, 385 pmol, 99 % yield) as a white solid.

[0448] Preparation of 4: To a solution of l,T-carbonyldiimidazole (75.0 mg, 462 pmol, 1.20 eq) in dichloromethane (1.00 mL) were added triethylamine (117 mg, 1.16 mmol, 161 pL, 3.00 eq) and 3- m ethylbicyclo [l.l.l]pentane-l -carbohydrazide (54.0 mg, 385 pmol, 1.00 eq) at 0°C. The mixture was stirred at 25 °C for 1 h. The mixture was diluted with water (30 mL) and extracted with ethyl acetate (3 x 30 mL). The combined organic layer was washed with brine (10 mL) and dried over sodium sulfate, filtered and concentrated to give crude product. The reaction mixture was filtered and concentrated under reduced pressure to afford 5-(3-methylbicyclo[l.l.l]pentan-l-yl)-l,3,4-oxadiazol-2-ol (64.0 mg, 385 pmol, 99% yield) as a white solid. ’H NMR (400 MHz, DMSO-O d = 1.98 (s, 6H), 1.20 (s, 3H).

[0449] Preparation of Compound 126: To a solution of 3-(6-(l-aminocyclopropyl)-4-chloro-l- oxoisoindolin-2-yl)piperidine-2, 6-dione (143 mg, 428 pmol, 1.00 eq) (see ‘Preparation of Compound 1’ forpreparation steps) and 5 -(3 -m ethylbicyclo [l. l.l]pentan-l-yl)-l, 3, 4-oxadiazol-2-ol (64.1 mg, 386 pmol, 0.900 eq) in A' jV-dim eth l acetamide (1.50 mL) was added chloro(tripyrrolidin-l- yl)phosphonium;hexafluorophosphate (271 mg, 643 pmol, 1.50 eq) and A'.A'-diisopropylcthylaminc (277 mg, 2.14 mmol, 373 pL, 5.00 eq) at 25 °C. After Ih, the mixture was stirred at 60 °C for 11 h. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by j>rep-HPLC( column: Waters Xbridge 150*25mm* 5um;mobile phase: [water (ammonium bicarbonate) - acetonitrile];gradient:25%-55% B over 9 min) to afford 3-(4-chloro-6-(l-((5-(3-methylbicyclo[l.l.l]pentan- 1 -yl)- 1 ,3 ,4-oxadiazol-2-yl)amino)cyclopropyl)- 1 -oxoisoindolin-2-yl)piperidine-2, 6-dione (6.44 mg, 12.83 pmol, 2.99% yield, 96% purity) as an off-white solid. 'H NMR (400 MHz, DMSO-t / s) 8 = 10.99 (br s, IH), 8.61 (s, IH), 7.62 - 7.53 (m, 2H), 5.16 - 5.08 (m, IH), 4.49 - 4.41 (m, IH), 4.34 - 4.25 (m, IH), 3.05 - 3.00 (m, IH), 2.92 - 2.86 (m, lH), 2.57 (br s, IH), 2.43 (br d, J= 4.0 Hz, IH), 1.99 (s, 6H), 1.39 - 1.32 (m, 2H), 1.31 - 1.26 (m, 2H), 1.20 (s, 3H)Example 64. Preparation of Compound 127

[0450] The preparation was carried out according to the method described for compound 1 except that (i) 2V-ethyl-A-isopropylpropan-2-amine (3.00 eq) was used, (ii) the reaction mixture was stirred at 120 °C for 2 h, and (iii) purification was carried out by rep-HPLC(column: Waters Xbridge 150*25 mm* 5 um; mobile phase: [water(ammonium bicarbonate)-acetonitrile]; gradient: 25%-55% B over 9 min) which afforded 3 -(4-chloro-6-( 1 -((5 -(3 -(difluoromethyl)bicyclo [1.1.1 ]pentan- 1 -yl)- 1 ,3 ,4-oxadiazol-2- yl)amino)cyclopropyl)-l-oxoisoindolin-2-yl)piperidine-2, 6-dione (11.5% yield) as a yellow solid. 'H NMR (400 MHz, DMSO-O 8 = 10.98 (s, 1H), 8.69 (s, 1H), 7.61 (d, J= 1.4 Hz, 1H), 7.55 (d, J= 1.4 Hz, 1H), 6.28 - 5.96 (m, 1H), 5.12 (dd, J= 5.0, 13.2 Hz, 1H), 4.48 - 4.41 (m, 1H), 4.33 - 4.23 (m, 1H), 2.95 - 2.86 (m, 1H), 2.63 - 2.58 (m, 1H), 2.46 - 2.39 (m, 1H), 2.20 (s, 6H), 2.02 - 1.96 (m, 1H), 1.39 - 1.25 (m, 4H).Example 65. Preparation of Compound 128

[0451] Preparation of 2: To a solution of 3 -methoxyisoxazole-5 -carboxylic acid (700 mg, 4.89 mmol, 1.00 eq) in dimethylformamide (7.00 mL) was added potassium carbonate (1.35 g, 9.78 mmol, 2.00 eq and iodomethane (764 mg, 5.38 mmol, 335 pL. 1.10 eq). The mixture was stirred at 25 °C for 12 hr. The reaction mixture was quenched by addition water 30 mL, and then extracted with ethyl acetate 50 mL (2 x 50 mL). The combined organic layers were washed with brine 20 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=l / O to 5 / 1) to afford methyl 3 -methoxyisoxazole-5 - carboxylate (630 mg, 4.01 mmol, 82% yield) as a white solid.

[0452] Preparation of 3: The preparation was carried out according to the method described for structure 3 of the scheme for preparing intermediate 6 except that (i) the reaction was carried out in methanol instead of ethanol, (ii) the reaction mixture was stirred at 60 °C for 2hr, and (Hi) the reaction mixture was concentrated under reduced pressure to afford 3 -methoxyisoxazole-5 -carbohydrazide as a white solid.

[0453] 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 trituration with ethyl acetate was carried out at 25 °C for 30 min to afford 5-(3-methoxyisoxazol-5-yl)-l,3,4-oxadiazol-2-amine (47.2% yield) as a yellow solid.

[0454] Preparation of 5: The preparation was carried out according to the method described for intermediate 3, except that purification was carried out by column chromatography (SiO2, Petroleum ether / Ethyl acetate=l / 0 to 5 / 1) which afforded 2-bromo-5-(3-methoxyisoxazol-5-yl)-l,3,4-oxadiazole (43% yield) as a yellow solid. ’H NMR (400 MHz, DMSO-< / 6) d = 7.30 (s, 1H), 4.00 (s, 3H).

[0455] Preparation of Compound 128: The preparation was carried out according to the method described for compound 1 except that (i) 2.00 eq of A'jV-diisopropylcthylaminc were used, (ii) the reaction mixture was stirred at 120 °C for 2 hr, and (iii) purification was carried out by re -HPLC (formic acidcondition ;column: YMC-Actus Triart C18 150*30mm*7um;mobile phase: [water(formic acid)- acetonitrile];gradient:28%-58% B over 10 min) which afforded 3-(4-chloro-6-(l-((5-(3-methoxyisoxazol-5- yl)-l, 3 ,4-oxadiazol-2-yl)amino)cyclopropyl)-l-oxoisoindolin-2-yl)piperidine-2, 6-dione (41% yield) as a yellow solid. ’H NMR (400 MHz, DMSO-O 8 = 11.00 (s, 1H), 9.28 (s, 1H), 7.63 - 7.58 (m, 2H), 6.89 (s, 1H), 5.12 (dd, J= 5.2, 13.4 Hz, 1H), 4.49 - 4.41 (m, 1H), 4.33 - 4.24 (m, 1H), 3.96 (s, 3H), 2.96 - 2.85 (m, 1H), 2.58 (br d, J= 17.6 Hz, 1H), 2.47 - 2.37 (m, 1H), 2.03 - 1.95 (m, 1H), 1.48 - 1.36 (m, 4H)Example 66. Preparation of Compound 129

[0456] Preparation of 2: The preparation was carried out according to the method described for structure 3 of the scheme for preparing intermediate 6 except that (i) 15.0 eq of hydrazine monohydrate were used, (ii) the reaction was carried out in methanol instead of ethanol, (iii) the reaction mixture was stirred at 60 °C for 12 hr, and (iv) he reaction mixture was concentrated under reduced pressure to afford 3- methylisoxazole-5 -carbohydrazide as a white solid.

[0457] Preparation of 3: The preparation was carried out according to the method described for structure 4 of the scheme for preparing intermediate 6. 5-(3-methylisoxazol-5-yl)-l,3,4-oxadiazol-2-amine (56% yield) afforded as a yellow solid.

[0458] Preparation of 4: The preparation was carried out according to the method described...

Claims

CLAIMSWhat is claimed is:

1. A compound of Formula (I):Formula (I), or a pharmaceutically acceptable salt thereof, wherein:X is hydrogen or deuterium; each of R1, R2, and R3is independently hydrogen, halogen, hydroxy, cyano, -NO2, oxo, -N(RZa)(Rzb), C1-6 alkoxy, or C1-6 alkyl, wherein C1-6 alkyl is optionally substituted with one or more halogens; ring A is aryl, heteroaryl, or bicyclo[l .

1. l]pentyl, and ring A is optionally substituted with one or more R4; each R4is independently halogen, cyano, -NO2, hydroxy, oxo, -S(O)2N(RZa)(Rzb), C1-6 alkyl, C2-6 alkynyl, C1-6 alkoxy, C1-6 thioalkoxy, C3-10 cycloalkyl, 3-10 membered heterocyclyl, aryl, or heteroaryl, wherein each of C1-6 alkyl, C2-6 alkynyl, C1-6 alkoxy, C1-6 thioalkoxy, C3-10 cycloalkyl, 3-10 membered heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more R5; or two R4attached to the same ring A atom or adjacent ring A atoms, together with the atoms to which they are attached, form a 3-10 membered heterocyclic ring or C3-10 cycloalkyl ring, wherein the 3-10 membered heterocyclic ring or C3-10 cycloalkyl ring is optionally substituted with one or more R5; each R5is independently halogen, oxo, hydroxy, C2-6 alkynyl, C1-6 alkyl, C1-6 alkoxy, C1-6 thioalkoxy, C3-10 cycloalkyl, 3-10 membered heterocyclyl, aryl, or hetero aryl, wherein C1-6 alkyl is optionally substituted by one or more halogens; and each of RZaand Rzbis independently hydrogen or C1-6 alkyl; or RZaand Rzb, together with the nitrogen to which they are attached, form a 3-10 membered heterocyclic ring.

2. The compound of claim 1, wherein the compound is a compound of Formula (I -A):Formula (I-A); for example, wherein the compound is a compound of Formula (I-B):Formula (I-B).

3. The compound of claim 1 or claim 2, wherein each of RZaand Rzbis independently Ci-6 alkyl (for example CH3); or RZaand Rzb, together with the nitrogen to which they are attached, form a 3-6 membered heterocyclic ring.

4. The compound of any one of claims 1-3, wherein each R4is independently halogen (for example fluoro or chloro), -S(0)2N(RZa)(Rzb), C1-6 alkyl (for example C1-3 alkyl), C1-6 alkoxy (for example C1-3 alkoxy), or C3-10 cycloalkyl (for example C3-4 cycloalkyl), wherein each of C1-6 alkyl (or C1-3 alkyl), C1-6 alkoxy (or C1-3 alkoxy), and C3-10 cycloalkyl (or C3-4 cycloalkyl) is optionally substituted with one or more R5; or two R4attached to adjacent ring A atoms, together with the atoms to which they are attached, form a 5-6 membered heterocyclic ring that is optionally substituted with one or more R5.

5. The compound of any one of claims 1-4, wherein each R5is independently halogen, C1-6 alkyl (for example C1-3 alkyl), C1-6 alkoxy (for example C1-3 alkoxy), or C3-10 cycloalkyl (for example C3-6 cyclo alkyl).

6. The compound of any one of claims 1-5, wherein ring A is aryl or heteroaryl, and ring A is optionally substituted with one or more R4; for example, wherein ring A is phenyl or 5-6 membered heteroaryl, and ring A is optionally substituted with one or more R4.

7. The compound of any one of claims 1-5, wherein ring A is bicyclo [1.

1. l]pentyl that is optionally substituted with one or more R4; for example, wherein ring A is8. The compound of claim 7,(a) wherein each R4is independently Ci-6 alkyl (for example C1-4 alkyl), aryl (for example phenyl), or cyano, and R4is optionally substituted with one or more R5; or(b) wherein each R4is C1-6 alkyl that is optionally substituted with one or more R5; for example, wherein each R4is CH3 that is optionally substituted with one or more R5.

9. The compound of claim 7 or claim 8, wherein each R5is halogen; for example, wherein each R5is fluoro.

10. A compound of claim 1 selected from the group consisting of:or a pharmaceutically acceptable salt thereof.

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

12. The compound of any one of claims 1-10, or pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 11, for use in a method of treating cancer in a subject in need thereof, wherein the method comprises administering to the subject a therapeutically effective amount of the compound, pharmaceutically acceptable salt, or pharmaceutical composition.

13. The compound, pharmaceutically acceptable salt, or pharmaceutical composition for use according to claim 12,(a) wherein the cancer is breast cancer; for example wherein the breast cancer is HR+ (hormone receptor positive) breast cancer, ER+ (estrogen receptor positive) breast cancer, HR+ HER2- (human epidermal growth factor 2 negative) breast cancer, or ER+ HER2- (human epidermal growth factor 2 negative) breast cancer;(b) wherein the cancer is selected from the group consisting of: ovarian cancer, endometrial cancer, gastric cancer, esophaegeal cancer, triple negative breast cancer, and lung adenosarcoma; for example wherein the cancer is triple negative breast cancer;(c) wherein the cancer comprises a solid tumor; for example, wherein the solid tumor is at least one of the group consisting of: uterine cancer (such as uterine carcinosarcoma and uterine corpus endometrial carcinoma), endometrial cancer, breast cancer, (such as breast invasive carcinoma and triple negative breast cancer, ER+ HER2- breast cancer, and HER2+ breast cancer), ovarian cancer (such as ovarian serous cystadenocarcinoma), stomach cancer (such as stomach adenocarcinoma), gastric cancer (such as gastrointestinal stromal cancer), 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 lung squamous 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) wherein the cancer comprises a liquid tumor; for example, wherein the liquid tumor is at least one of the group consisting of: 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’s lymphoma (HL), non-Hodgkin’s lymphoma (NHL), AIDS- related lymphoma, follicular lymphoma, small lymphocytic lymphoma, T-cell / histiocyte rich large B- cell lymphoma, transformed lymphoma, primary mediastinal (thymic) large B-cell lymphoma, splenic marginal zone lymphoma, Richter's transformation, nodal marginal zone lymphoma, ALK- positive large B-cell lymphoma, indolent lymphoma (for example, DLBCL, follicular lymphoma, or marginal zone lymphoma), acute myelogenous leukemia (AML), acute lymphocytic leukemia (ALL), adult T-cell leukemia, chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), hairy cell leukemia, myelodysplasia, myeloproliferative disorders, chronic myelogenous leukemia (CML), acute monocytic leukemia (AMoL), myelodysplastic syndrome (MDS), human lymphotropic virus- type 1 (HTLV-1) leukemia, mastocytosis, B-cell acute lymphoblastic leukemia, NonHodgkin's Lymphoma, Hodgkin's Lymphoma, and multiple myeloma (MM).

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

15. The compound, pharmaceutically acceptable salt, or pharmaceutical composition for use according to any one of claims 12-14, wherein the subject is treatment-naive.