Combination therapies comprising a CDK2 degrader and a CDK4 / 6 inhibitor

Abstract

Described herein are combination therapies comprising a CDK2 degrader and a CDK4 / 6 inhibitor. The combination therapies are for use in the treatment of disorders such as cancer.

Description

COMBINATION THERAPIES COMPRISING A CDK2 DEGRADER AND A CDK4 / 6 INHIBITORTECHNICAL FIELD

[0001] Described herein are combination therapies comprising a compound that mediates the degradation of the enzyme cyclin-dependent kinase 2 (CDK2) in combination with an inhibitor of the enzymes cyclin-dependent kinase 4 (CDK4) and cyclin-dependent kinase 6 (CDK6). The combination therapies are for use in the treatment of disorders such as cancer.BACKGROUND

[0002] Cyclin dependent kinases (CDKs) are a family of closely related kinases that regulate progression through the cell cycle. Deregulation of the activity of CDKs is associated with tumor growth in multiple cancer types. Inhibition of CDKs can therefore inhibit cancer cell growth.

[0003] Inhibitors of CDK4 and CDK6 (CDK4 / 6 inhibitors) are known cancer treatments and are considered the standard of care treatment for breast cancer. For example, the CDK4 / 6 inhibitors ribociclib, palbociclib, and abemaciclib have been approved by the FDA and the EMA for the treatment of breast cancer.

[0004] One limitation of using CDK4 / 6 inhibitors to treat cancer is that resistance to the drugs can arise.

[0005] There exists a need for further cancer treatments. There also exists a need for cancer treatments that are effective for a prolonged period of time before the onset of resistance to the treatment or that eradicate the cancer completely.SUMMARY

[0006] CDK2 is another potential target of cancer therapies. Mechanisms that activate CDK2 in tumors are (i) amplification of cyclin El or cyclin E2, and (ii) loss of the AMBRA1 gene. Elimination of CDK2 has the potential to counteract the effects of these anomalies.

[0007] One way to reduce or eliminate CDK2 is to utilise a molecular glue degrader targetingCDK2. Molecular glue degraders are small molecule (low molecular weight) compounds that can be used to manipulate the ubiquitin proteasome system to trigger targeted degradation of specific proteins of interest. In essence, molecular glue degraders redirect the activity of E3 ligases such as cereblon (a phenomenon known as E3 reprogramming) to promote the poly-ubiquitination and ultimately proteasomal degradation of proteinsubstrates 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 the ligase to interact with the target protein. PCT / US2023 / 077781 discloses molecular glue degraders of CDK2 and is hereby incorporated by reference in its entirety.

[0008] The inventors recognised that the compounds disclosed in PCT / US2023 / 077781 could be used to mediate the degradation of CDK2 in combination with a CDK4 / 6 inhibitor. Targeting CDK2 together with CDK4 / 6 has the potential to provide a more durable response in patients (i.e. the onset of resistance may be delayed or the antitumor effect may be greater), because the cancer cells cannot compensate for the loss of activity of CDK4 / 6 by upregulating the activity of CDK2, and vice versa. In addition, the combination therapy may be effective to treat cancers that have previously been treated with a CDK4 / 6 inhibitor and that have developed resistance.

[0009] Therefore, described herein are combination therapies comprising a molecular glue degrader of CDK2 and a CDK4 / 6 inhibitor, including the following.

[0010] In one aspect, described herein is a combination comprising:(i) a compound of F ormula (I) :or a pharmaceutically acceptable salt thereof, wherein: X is selected from H and deuterium; L1is selected from the group consisting of:, and 5-6 membered heteroaryl; L is selected from a bond andeach of R1, R2, R3, and R4is independently selected from the group consisting of hydrogen, halogen, C1-6alkoxy, cyano, hydroxy, C3-6 monocyclic cycloalkyl, and C1-6alkyl; ring A is selected from C3-6 monocyclic cycloalkyl and 3 to 6 membered heterocyclyl, wherein each of C;, .monocyclic cycloalkyl and 3 to 6 membered heterocyclyl is optionally substituted with one or more occurrences of R5; each occurrence of R5is independently selected from the group consisting of hydrogen, C, ,, alkyl, hydroxy, and oxo, wherein C1-6 alkyl is optionally substituted with one or more occurrences of halogen; ring B is selected from the group consisting of C3-12 monocyclic or C3-12 bicyclic cycloalkyl, 3 to 10 membered heterocyclyl, aryl, and heteroaryl, wherein each of C3-12 monocyclic or C3-12 bicyclic cycloalkyl, 3 to 10membered heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more occurrences of R6; each occurrence of R6is independently selected from the group consisting of halogen, cyano, C1-6alkoxy, Ci- ealkyl, -C(O)R7, -C(O)NR7R8, -S(O)2R7, pyridine,, wherein each Ci . alkyl. C1-6alkoxy, and pyridine is optionally substituted with one or more occurrences of a substituent selected from C1-6alkyl and halogen; each occurrence of R7is independently selected from the group consisting of C1-6alkyl, phenyl, cyclopropane, an N-linked C3-9 heterocycloalkyl, an N-linked heteroaryl,optionally substituted with one or more occurrences of a substituent selected from the group consisting of Ci- ealkyl, halogen, cyano, trifluoro(methoxy)methane, and C1-6alkoxy (e.g., methoxy); each occurrence of R8, R9, and R10is independently selected from hydrogen, deuterium, C1-6alkyl, and deuterated C1-6alkyl (e.g., - CD3); and n is an integer selected from the group consisting of 0, 1, 2, and 3; and(ii) a CDK4 / 6 inhibitor.

[0011] In one aspect, described herein is a kit comprising (i) a unit dosage form comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof, and, separately, (ii) a unit dosage form comprising a CDK4 / 6 inhibitor.

[0012] In one aspect, described herein is the combination or kit described above for use in therapy.

[0013] In one aspect, described herein is a compound of Formula (I) or a pharmaceutically acceptable salt thereof, and a CDK4 / 6 inhibitor, as a combined preparation for simultaneous, separate or sequential use in therapy.

[0014] In one aspect, described herein is a compound of Formula (I) or a pharmaceutically acceptable salt thereof for use in therapy, wherein the compound of Formula (I) or pharmaceutically acceptable salt thereof is for use in combination with a CDK4 / 6 inhibitor, and wherein the compound of Formula (I) or pharmaceutically acceptable salt thereof and the CDK4 / 6 inhibitor are administered to a patient simultaneously, separately, or sequentially.

[0015] In one aspect, described herein is a CDK4 / 6 inhibitor for use in therapy, wherein the CDK4 / 6 inhibitor is for use in combination with a compound of Formula (I) or a pharmaceutically acceptable saltthereof, and wherein the CDK4 / 6 inhibitor and the compound of Formula (I) or pharmaceutically acceptable salt thereof are administered to a patient simultaneously, separately, or sequentially.BRIEF DESCRIPTION OF FIGURES

[0016] FIG. 1 shows the results of an in vivo experiment to evaluate antitumor activity in the HR+ / HER2- MCF7 human breast cancer model up to Day 28 (the end of a four-week dosing period).

[0017] FIG. 2 shows the results of the same experiment as FIG. 1 up to Day 49 (the end of a further three-week monitoring period).

[0018] FIG 3. shows the results of an in vivo experiment to evaluate antitumor activity in the HR+ / HER2- xMCF7 human breast cancer model up to Day 28 (the end of a four-week dosing period).

[0019] FIG 4. shows the results of the same experiment as FIG. 3 up to Day 49 (the end of a further three-week monitoring period).

[0020] FIG. 5 shows the results of an in vitro experiment to evaluate the effectiveness of Compound 144, either alone, or in combination with ribociclib, in delaying MCF-7 breast cancer cell growth.

[0021] FIG. 6 shows the results of an in vivo experiment to evaluate the combination potential between Compound 144, ribociclib, and fulvestrant in MCF7 and xxT47D human breast cancer xenograft models.

[0022] FIG. 7 shows results from an in vitro experiment to evaluate the effect of Compound 144 on proliferation of MDA-MB-157 breast, Kuramochi ovarian and MKN1 gastric cancer cells.

[0023] FIG. 8 shows results from an in vitro experiment to evaluate the effect of Compound 144 on the cell cycle of MDA-MB-157 breast, Kuramochi ovarian and MKN1 gastric cancer cells.

[0024] FIG. 9 shows results from an in vivo experiment to evaluate the pharmacokinetic effects of Compound 144 alone and in combination with ribociclib in a human hormone-receptor positive / HER2- negative breast cancer model.

[0025] FIG. 10 shows results from an in vivo experiment to evaluate the pharmacodynamic effects of Compound 144 alone and in combination with ribociclib in a human hormone-receptor positive / HER2- negative breast cancer model.DETAILED DESCRIPTION

[0026] 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 ofordinary 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.Combination therapies

[0027] In one aspect, described herein is a combination comprising:(i) a compound of Formula (I) or a pharmaceutically acceptable salt thereof; and(ii) a CDK4 / 6 inhibitor.

[0028] In one aspect, described herein is a kit comprising (i) a unit dosage form comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof, and, separately, (ii) a unit dosage form comprising a CDK4 / 6 inhibitor. In some embodiments, each unit dosage form is a pharmaceutical composition additionally comprising one or more pharmaceutically acceptable excipients. In some embodiments, the unit dosage forms are present in a single package. In some embodiments, the unit dosage forms are present in separate packages.

[0029] In one aspect, described herein is the combination or kit described in the preceding two paragraphs for use in therapy (e.g., for use in the treatment of cancer). In some embodiments, the combination is for use in therapy (e.g., for use in the treatment of cancer). In some embodiments, the kit is for use in therapy (e.g., for use in the treatment of cancer).

[0030] In one aspect, described herein is a compound of Formula (I) or a pharmaceutically acceptable salt thereof together with instructions to use the compound of Formula (I) or pharmaceutically acceptable salt thereof in combination with a CDK4 / 6 inhibitor. In some embodiments, the instructions specify use of the compound of Formula (I) or pharmaceutically acceptable salt thereof in combination with the CDK4 / 6 inhibitor for the treatment of a disorder (e.g., cancer). In some embodiments, the instructions specify simultaneous, separate, or sequential use of the compound of Formula (I) or pharmaceutically acceptable salt thereof and the CDK4 / 6 inhibitor. In some embodiments, the compound of Formula (I) or pharmaceutically acceptable salt thereof is in a unit dosage form. In some embodiments, the unit dosage form is a pharmaceutical composition additionally comprising one or more pharmaceutically acceptable excipients.

[0031] In one aspect, described herein is a CDK4 / 6 inhibitor together with instructions to use the CDK4 / 6 inhibitor in combination with a compound of Formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the instructions specify use of the CDK4 / 6 inhibitor in combination with the compound of Formula (I) or pharmaceutically acceptable salt thereof for the treatment of a disorder (e.g., cancer). In some embodiments, the instructions specify simultaneous, separate, or sequential use of theCDK4 / 6 inhibitor and the compound of Formula (I) or pharmaceutically acceptable salt thereof. In some embodiments, the CDK4 / 6 inhibitor is in a unit dosage form. In some embodiments, the unit dosage form is a pharmaceutical composition additionally comprising one or more pharmaceutically acceptable excipients.

[0032] In either of the preceding two aspects, the instructions may be of the kind that are provided to a doctor, for example on a drug product label, or they may be of the kind that is provided to a patient, for example by a doctor.

[0033] In one aspect, described herein is a compound of Formula (I) or a pharmaceutically acceptable salt thereof, and a CDK4 / 6 inhibitor, as a combined preparation for simultaneous, separate or sequential use in therapy (e.g., for simultaneous, separate or sequential use in the treatment of cancer).

[0034] In one aspect, described herein is a compound of Formula (I) or a pharmaceutically acceptable salt thereof for use in therapy (e.g., for use in the treatment of cancer), wherein the compound of Formula (I) or pharmaceutically acceptable salt thereof is for use in combination with a CDK4 / 6 inhibitor, and wherein the compound of Formula (I) or pharmaceutically acceptable salt thereof and the CDK4 / 6 inhibitor are administered to a patient simultaneously, separately, or sequentially.

[0035] In one aspect, described herein is a CDK4 / 6 inhibitor for use in therapy (e.g., for use in the treatment of cancer), wherein the CDK4 / 6 inhibitor is for use in combination with a compound of Formula (I) or a pharmaceutically acceptable salt thereof, and wherein the CDK4 / 6 inhibitor and the compound of Formula (I) or pharmaceutically acceptable salt thereof are administered to a patient simultaneously, separately, or sequentially.

[0036] The products set out above are the combination therapies of the present disclosure.

[0037] In one aspect, described herein is a method of treating a subject suffering from a disorder(e.g., cancer), wherein the method comprises administering to the subject a compound of Formula (I) or a pharmaceutically acceptable salt thereof, and a CDK4 / 6 inhibitor. In one aspect, described herein is a method of treating a subject suffering from a disorder (e.g., cancer), wherein the method comprises administering to the subject a compound of Formula (I) or a pharmaceutically acceptable salt thereof, in combination with a CDK4 / 6 inhibitor. In either aspect, the compound of Formula (I) or pharmaceutically acceptable salt thereof and the CDK4 / 6 inhibitor may be administered to the subject simultaneously, separately, or sequentially.

[0038] In one aspect, described herein is the use of a compound of Formula (I) or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for treating a disorder (e.g., cancer) in combination with a CDK4 / 6 inhibitor. In one aspect, described herein is the use of a CDK4 / 6 inhibitor for the manufacture of a medicament for treating a disorder (e.g., cancer) in combination with a compound of Formula (I) or a pharmaceutically acceptable salt thereof. In either aspect, the compound of Formula (I) orpharmaceutically acceptable salt thereof and the CDK4 / 6 inhibitor may be administered to the subject simultaneously, separately, or sequentially.Compounds of Formula (I)

[0039] The combination therapies of the present disclosure comprise a compound of Formula (I) or a pharmaceutically acceptable salt thereof. Formula (I) is defined above.

[0040] In some embodiments, ring A is selected from the group consisting of:

[0041] In some embodiments, ring B is selected from the group consisting of C3-12 monocyclic or C3-12 bicyclic cycloalkyl, 3 to 10 membered heterocyclyl, and aryl, wherein each of C3-12 monocyclic or C3-12 bicyclic cycloalkyl, 3 to 10 membered heterocyclyl, and aryl is substituted with one or more occurrences ofR6. In some embodiments, ring B is selected from the group consisting of:

[0042] In some embodiments, R6is selected from the group consisting of Cl, F, -CN, -CH3, -CF3, - CH(CH3)2, -OCH3, -OC(CH3)3, -OCF3, and -O-Si(CH3)2C(CH3)3. In some embodiments, R6is -C(O)R7, wherein R7is selected from the group consisting of phenyl,is selected from the group consisting of methyl, phenyl,, ,

[0043] In some embodiments, L1is selected from the group consisting of:

[0044] In some embodiments, the compound of Formula (I) is a compound of Formula (1-1-0):

[0045] In some embodiments, the compound of Formula (I) is a compound of Formula (I-I-l-l):

[0046] In some embodiments, the compound of Formula (I) is a compound of Formula (I-I-1-2):

[0047] In some embodiments, the compound of Formula (I) is a compound of Formula (I-I-2):

[0048] In some embodiments, the compound of Formula (I) is a compound of Formula (I-I-2-1):

[0049] In some embodiments, the compound of Formula (I) is a compound of Formula (I-I-2-2):

[0050] In some embodiments, the compound of Formula (I) is a compound of Formula (I-I-3):

[0051] In some embodiments, the compound of Formula (I) is a compound of Formula (I-I-3-1):

[0052] In some embodiments, the compound of Formula (I) is a compound of Formula (I-I-3-2):

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

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

[0055] In some embodiments, X is H.

[0056] In some embodiments, L2is a bond. In some embodiments, L2is a.

[0057] In some embodiments, R1, R2, R3, and R4are H. In some embodiments, R1is fluoro, R2is fluoro, R3is H, and R4is H.

[0058] In some embodiments, n is 0.

[0059] In some embodiments, R7is selected from the group consisting of: methyl, benzene,substituted with one or two occurrences selected from the group consisting of methyl, flourine, chlorine, cyano, and methoxy. In some embodiments, R7is selected from the group consisting of methyl, phenyl,C1-6alkyl (e.g., methyl), halogen, cyano, trifluoro(methoxy)methane, and C1-6alkoxy (e.g., methoxy)

[0060] In some embodiments, each occurrence of R8is independently hydrogen or methyl. In some embodiments, R8is methyl. In some embodiments, R8is -CD3.

[0061] In some embodiments, each occurrence of R8, R9, and R10is independently deuterated Ci- ealkyl. In some embodiments, each occurrence of R8, R9, and R10is independently -CD3.

[0062] In some embodiments, the compound of Formula (I) is a compound described in Table 1 below. Table 1 includes the compound number of each compound in accordance with the contents of the present specification. The compounds described in Table 1 may be present in the form of a pharmaceutically acceptable salt.Table 1. Exemplary Compounds

[0063] In some embodiments, the compound of Formula (I) is Compound 139 (also referred to herein as Compound- 139). Compound 139 may be present in the form of a pharmaceutically acceptable salt.

[0064] In some embodiments, the compound of Formula (I) is Compound 144 (also referred to herein as Compound- 144). Compound 144 may be present in the form of a pharmaceutically acceptable salt.

[0065] In some embodiments, the compound of Formula (I) is Compound 145. Compound 145 may be present in the form of a pharmaceutically acceptable salt.

[0066] In some embodiments, the compound of Formula (I) is Compound 146. Compound 146 may be present in the form of a pharmaceutically acceptable salt.CDK4 / 6 Inhibitors

[0067] All the combination therapies of the present disclosure comprise a CDK4 / 6 inhibitor. Many CDK4 / 6 inhibitors will be known to the person of ordinary skill in the art. The person of ordinary skill in the art will also be aware of the therapeutic indications for which each known CDK4 / 6 inhibitor is generally used or could be used (for example based on the therapeutic indications for which the CDK4 / 6 inhibitor has beenapproved (e.g., by the FDA or the EMA) and any ongoing clinical trials) and will also be aware of suitable ways to administer each known CDK4 / 6 inhibitor.

[0068] The CDK4 / 6 inhibitor may be present in the form of a pharmaceutically acceptable salt. For example, ribociclib, if present, may be in the form of a succinate salt, i.e. as ribociclib succinate. The CDK4 / 6 inhibitor may also be present in the form of a solvate such as a hydrate. Alternatively, the CDK4 / 6 inhibitor may be present in non-solvated form.

[0069] In some embodiments, the CDK4 / 6 inhibitor is palbociclib, ribociclib, abemaciclib, lerociclib, trilaciclib, dalpiciclib, birociclib, BPI-16350, or in each case a pharmaceutically acceptable salt thereof. In some embodiments, the CDK4 / 6 inhibitor is palbociclib, ribociclib, abemaciclib, or in each case a pharmaceutically acceptable salt thereof. In some embodiments, the CDK4 / 6 inhibitor is palbociclib or a pharmaceutically acceptable salt thereof, or ribociclib or a pharmaceutically acceptable salt thereof. In some embodiments, the CDK4 / 6 inhibitor is palbociclib or a pharmaceutically acceptable salt thereof. In some embodiments, the CDK4 / 6 inhibitor is ribociclib or a pharmaceutically acceptable salt thereof. In some embodiments, the CDK4 / 6 inhibitor is abemaciclib or a pharmaceutically acceptable salt thereof.

[0070] In some embodiments, the CDK4 / 6 inhibitor is administered in combination with endocrine therapy, optionally wherein the endocrine therapy is administered in combination with a luteinising hormone- releasing hormone (LHRH) agonist. As used herein, the term “endocrine therapy” has the same meaning as the term “hormone therapy”. In some embodiments, the endocrine therapy is an estrogen receptor antagonist such as fulvestrant, or an aromatase inhibitor such as letrozole. In some embodiments, the endocrine therapy is fulvestrant or an aromatase inhibitor such as letrozole. In some embodiments, the endocrine therapy is an aromatase inhibitor or tamoxifen. In some embodiments, the endocrine therapy is an aromatase inhibitor which is administered in combination with a hormone-releasing hormone (LHRH agonist). In some embodiments, the endocrine therapy is an estrogen receptor antagonist such as fulvestrant. In some embodiments, the endocrine therapy is an aromatase inhibitor such as letrozole. In some embodiments, the endocrine therapy is tamoxifen. In some embodiments, the endocrine therapy is fulvestrant, optionally wherein the CDK4 / 6 inhibitor is ribociclib or a pharmaceutically acceptable salt thereof.Pharmaceutical Compositions

[0071] In some embodiments, the compound of Formula (I) or pharmaceutically acceptable salt thereof is administered in a pharmaceutical composition comprising, in addition to the compound of Formula (I) or pharmaceutically acceptable salt thereof, one or more pharmaceutically acceptable excipients. In some embodiments, the pharmaceutical composition comprises a therapeutically effective amount of the compound of Formula (I) or pharmaceutically acceptable salt thereof.

[0072] In some embodiments, the CDK4 / 6 inhibitor is administered in a pharmaceutical composition comprising, in addition to CDK4 / 6 inhibitor, one or more pharmaceutically acceptable excipients. In some embodiments, the pharmaceutical composition comprises a therapeutically effective amount of the CDK4 / 6 inhibitor.

[0073] In some embodiments, the compound of Formula (I) or pharmaceutically acceptable salt thereof is administered in a pharmaceutical composition additionally comprising one or more pharmaceutically acceptable excipients and the CDK4 / 6 inhibitor is administered in a separate pharmaceutical composition additionally comprising one or more pharmaceutically acceptable excipients.

[0074] The pharmaceutical composition(s) may be administered by any route including, but not limited to, oral (enteral) administration, parenteral (by injection) administration, rectal administration, transdermal administration, intradermal administration, intrathecal administration, subcutaneous (SC) administration, intravenous (IV) administration, intramuscular (IM) administration, and intranasal administration. In some embodiments, the compound of Formula (I) or pharmaceutically acceptable salt thereof is administered orally. In some embodiments, the CDK4 / 6 inhibitor is administered orally. In some embodiments, the compound of Formula (I) or pharmaceutically acceptable salt thereof, and the CDK4 / 6 inhibitor, are administered orally.

[0075] In order to facilitate accurate dosing, the compositions may be presented in unit dosage forms.Therapeutic Indications

[0076] In some embodiments, the combination therapies described herein are for use in therapy. In some embodiments, the combination therapies described herein are for use in the treatment of cancer. In some embodiments, the cancer comprises a solid tumor.

[0077] In some embodiments, the cancer is breast cancer, ovarian cancer, or gastric cancer. In some embodiments, the cancer is ovarian cancer. In some embodiments, the cancer is gastric cancer.

[0078] In some embodiments, the cancer is breast cancer. In some embodiments, the breast cancer is one of the following: HR+ (hormone receptor positive) breast cancer, ER+ (estrogen receptor positive) breast cancer, HER2+ (human epidermal growth factor receptor 2 positive) breast cancer, HER2- (human epidermal growth factor receptor 2 negative) breast cancer, HER2-low breast cancer, HR- breast cancer, PR+ (progesterone receptor positive) breast cancer, HR+ HER2- breast cancer, ER+ HER2- breast cancer, (lymph) node-positive breast cancer, triple negative breast cancer, luminal A breast cancer, luminal B breast cancer, invasive breast cancer (e.g., invasive ductal breast cancer or invasive lobular breast cancer), ductal carcinomain situ (DCIS), or inflammatory breast cancer. In some embodiments, the breast cancer is HR+ HER2- breast cancer.

[0079] In some embodiments, the breast cancer is early breast cancer, such as stage II or III breast cancer. In some embodiments, the breast cancer is advanced breast cancer. In some embodiments, the breast cancer is locally advanced breast cancer. In some embodiments, the breast cancer is metastatic. In some embodiments, the breast cancer is non-metastatic. In some embodiments, the breast cancer is advanced and metastatic. In some embodiments, the breast cancer is recurrent breast cancer. In some embodiments, the breast cancer is at high risk of recurrence (defined as having 4 or more positive axillary lymph nodes, or having 1-3 positive axillary lymph nodes along with a tumor grade of 3 and / or a tumor size of 50 mm or more). In some embodiments, the breast cancer is HR+ HER2- early breast cancer. In other embodiments, the breast cancer is HR+ HER2- advanced breast cancer. In some embodiments, the breast cancer is advanced or metastatic breast cancer. In some embodiments, the breast cancer is locally advanced or metastatic breast cancer. In some embodiments, the breast cancer is node-positive early breast cancer at high risk of recurrence.

[0080] In some embodiments, the combination therapy is administered as a first-line therapy. In some embodiments, the subject to which treatment is administered is a treatment-naive subject. In some embodiments, the subject to which treatment is administered has not yet been treated with the standard of care.

[0081] In some embodiments, the combination therapy is administered as a second (or later) line therapy. In some embodiments, the cancer has acquired resistance to the first line therapy.

[0082] In some embodiments, the breast cancer has progressed after treatment with a CDK4 / 6 inhibitor. In some embodiments, the breast cancer is resistant to treatment with a CDK4 / 6 inhibitor. In some embodiments, the breast cancer is resistant to treatment with palbociclib or a pharmaceutically acceptable salt thereof. In some embodiments, the breast cancer is resistant to treatment with ribociclib or a pharmaceutically acceptable salt thereof. In some embodiments, the breast cancer is resistant to treatment with abemaciclib or a pharmaceutically acceptable salt thereof.

[0083] In some embodiments, the subject to which treatment is administered has received prior endocrine therapy. In some embodiments, the breast cancer is resistant to endocrine therapy.

[0084] In some embodiments, the cancer has amplification or overexpression of cyclin El.Methods of Treatment

[0085] The active agents of the combination therapies described herein can be administered in any order and can be administered by simultaneous (i.e. concurrent), separate, sequential, or alternating modes of administration. In some embodiments, the compound of Formula (I) or pharmaceutically acceptable salt thereof and the CDK4 / 6 inhibitor are administered to a patient simultaneously, separately, or sequentially. The active agents of the combination therapies described herein can be administered by the same or different routes of administration. Each active agent is to be used in a therapeutically effective amount. As used herein, administration in combination has the same meaning as co-administration.

[0086] In some embodiments, the compound of Formula or pharmaceutically acceptable salt thereof is administered prior to administration of the CDK4 / 6 inhibitor. In some embodiments, the CDK4 / 6 inhibitor is administered prior to administration of the compound of Formula or pharmaceutically acceptable salt thereof.

[0087] In some embodiments, the compound of Formula (I) or pharmaceutically acceptable salt thereof and the CDK4 / 6 inhibitor are administered within 24 hours of each other. In some embodiments, the compound of Formula (I) or pharmaceutically acceptable salt thereof and the CDK4 / 6 inhibitor are administered within 24 hours of each other for at least two consecutive days. In some embodiments, the compound of Formula (I) or pharmaceutically acceptable salt thereof and the CDK4 / 6 inhibitor are administered within 24 hours of each other for at least seven consecutive days. In some embodiments, the compound of Formula (I) or pharmaceutically acceptable salt thereof and the CDK4 / 6 inhibitor are administered within 24 hours of each other for at least 21 consecutive days. In some embodiments, the compound of Formula (I) or pharmaceutically acceptable salt thereof and the CDK4 / 6 inhibitor are administered within 24 hours of each other for 21 consecutive days, and the CDK4 / 6 inhibitor is not administered within the following 7 consecutive days. In some embodiments, the compound of Formula (I) or pharmaceutically acceptable salt thereof and the CDK4 / 6 inhibitor are administered within 24 hours of each other for 21 consecutive days, and neither the CDK4 / 6 inhibitor nor the compound of Formula (I) or pharmaceutically acceptable salt thereof is administered within the following 7 consecutive days.

[0088] The combination therapies described herein may be administered in combination with one or more additional therapeutic agents such as additional anticancer agents, in particular where this is in line with the standard of care for the particular disorder (e.g., the particular cancer) to be treated. Therefore, in some embodiments, the compound of Formula (I) or pharmaceutically acceptable salt thereof and the CDK4 / 6 inhibitor are administered in combination with one or more additional therapeutic agents, for example wherein the one or more additional therapeutic agents comprises an additional anticancer agent. In some embodiments, the additional anticancer agent is a standard of care agent.

[0089] Each additional therapeutic agent may be administered at the same time or at a different time to either the compound of Formula (I) or pharmaceutically acceptable salt thereof, or the CDK4 / 6 inhibitor. In some embodiments, the one or more additional therapeutic agents are administered within 24 hours of the compound of Formula (I) or pharmaceutically acceptable salt thereof, and / or the CDK4 / 6 inhibitor.

[0090] In some embodiments, the one or more additional anticancer agents comprises an endocrine agent, for example wherein the endocrine agent is an aromatase inhibitor, a Selective Estrogen-Receptor Downregulator (SERD), or a Selective Estrogen Receptor Modulator (SERM). Examples of aromatase inhibitors that may be used include exemestane (Aromasin), anastrozole (Arimidex), atamestane, fadrozole, letrozole (Femara), and formestane. Examples of SERDs that may be used include fulvestrant, SZ102, G1T48, RADI 901, elacestrant, GDC-9545, giredestrant, SAR439859, amcenestrant, AZD9833, camizestrant, LY3484356, Zn-c5, and D-0502. Examples of SERMs that may be used include tamoxifen, raloxifene, lasofoxifene, afimoxifene, arzoxifene, bazedoxifene, fispemifene, ormeloxifene, ospemifene, tesmilifene, toremifene, trilostane, and CHF 4227 (Cheisi). In some embodiments, the endocrine agent is letrozole, fulvestrant, tamoxifen, exemestane, or anastrozole.

[0091] In some embodiments, the one or more additional anticancer agents comprises an Estrogen PROTAC, for example wherein the Estrogen PROTAC is ARV-471 or H3B-5942.

[0092] In some embodiments, the one or more additional anticancer agents comprises a chemotherapeutic agent, for example wherein the chemotherapeutic agent is docetaxel, paclitaxel, cisplatin, carboplatin, capecitabine, gemcitabine, vinorelbine, or liposomal doxorubicin.

[0093] In some embodiments, the one or more additional anticancer agents comprises an anti-HER2 agent, for example wherein the anti-HER2 agent is trastuzumab or pertuzumab.

[0094] In some embodiments, the one or more additional anticancer agents comprises carboplatin or fulvestrant. In some embodiments, the one or more additional anticancer agents comprises fulvestrant.

[0095] In some embodiments, the cancer to be treated is resistant to treatment with any of the one or more additional anticancer agents recited above.Definitions

[0096] 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, UniversityScience 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.

[0097] 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.

[0098] 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.

[0099] 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 (“C1-10 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), and i-Bu (-CH2CH(CH3)2).

[0100] 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 someembodiments, 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 C? 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.

[0101] 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 C? „ alkynyl 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.

[0102] 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), bicyclo[l. l. l]pentyl (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. l]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 (C$>), cyclononenyl (C$>), cyclodecyl (C10), cyclodecenyl (C10),octahydro- IH-indenyl (C$>), decahydronaphthalenyl (Cio), spiro[4.5]decanyl (Cio), and the like. In some embodiments, the cycloalkyl group is either monocyclic (“monocyclic cycloalkyl”) or contains a fused, bridged or spiro ring system such as a bicyclic system (“bicyclic cycloalkyl”) or tricyclic system (“tricyclic cycloalkyl”). “Cycloalkyl” 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 continues to designate the number of carbons in the cycloalkyl ring system.

[0103] The term “heterocyclyl” or “heterocycloalkyl” 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”). In heterocyclyl bicyclic ring systems, the one or more heteroatoms can be present in one ring or both rings. “Heterocyclyl” or “heterocycloalkyl” 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 heterocyclyl ring or the one or more cycloalkyl groups, and 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 continues to designate the number of ring members in the heterocyclyl ring system.

[0104] 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.

[0105] Exemplary 3-membered heterocyclyl groups containing one heteroatom include, without limitation, azirdinyl, oxiranyl, and 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, oxasulforanyl, 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, and 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 5,6-bicyclic heterocyclic rings) 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 6,6-bicyclic heterocyclic rings) include, without limitation, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and the like.

[0106] 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 K electrons shared in a cyclic array) having 6 to 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.

[0107] 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 K 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 isindependently 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. In heteroaryl bicyclic ring systems, the one or more heteroatoms can be present 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 (aryl / heteroaryl) ring system. In 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).

[0108] As explained above, 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 ring heteroatom 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”).

[0109] 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 aromaticring 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”).

[0110] 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, benzoluranyl, 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.

[0111] 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 groups, i.e. alkoxy groups with between 1 and 6 carbon atoms. In some embodiments, alkoxy groups have between 1 and 4 carbon atoms.

[0112] The term “hydroxy” as used herein refers to the radical -OH.

[0113] The term “cyano” as used herein refers to the radical -CN.

[0114] The term “halogen” as used herein refers to F, Cl, Br, or I.

[0115] The term “oxo” as used herein refers to =0.

[0116] 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 (C’i 4alkyl)4salts.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.

[0117] A “subject” to which administration is contemplated may be a human (z.e., a male or female of any age group, e.g., a pediatric subject (e.g, an infant, child, or adolescent) or adult subject (e.g., a young adult, middle-aged adult or senior adult)) or a non-human animal, e.g., a mammal such as a primate (e.g., a cynomolgus monkey or rhesus monkey). In some embodiments, the subject is a human. The terms “human,” “patient,” and “subject” are used interchangeably herein.

[0118] The terms “disease,” “disorder,” and “condition” are used interchangeably herein.

[0119] As used herein, and unless otherwise specified, the terms “treat,” “treating” and “treatment” refer to 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.

[0120] As used herein, and unless otherwise specified, a “therapeutically effective amount” of a active agent 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. The term “therapeutically effective amount” can encompass an amount that improves overall therapy, reduces or avoids symptoms or causes of a disease, disorder, or condition, or enhances the therapeutic efficacy of another therapeutic agent.

[0121] It is 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, because one of its atoms 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 (z.e., as (+) or (-)-isomers respectively). A chiral compound can exist as either individual enantiomer or as a mixture of enantiomers. A mixture containing equal proportions of the enantiomers is called a “racemic mixture”.

[0122] 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 33'2125 (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 compounds of Formula (I), pharmaceutically acceptable salts thereof, and CDK4 / 6 inhibitors described herein may be present in the combination therapies of the present disclosure as individual stereoisomers (e.g., as individual enantiomers) substantially free of other stereoisomers (or enantiomers), or alternatively, as mixtures of stereoisomers (or enantiomers).

[0123] The compounds of Formula (I), pharmaceutically acceptable salts thereof, and CDK4 / 6 inhibitors described herein may be present in the combination therapies of the present disclosure in solvated (e.g., hydrated) form or in non-solvated form.

[0124] The compounds of Formula (I), pharmaceutically acceptable salts thereof, and CDK4 / 6 inhibitors described herein may be present in the combination therapies of the present disclosure in tautomeric form.

[0125] The present disclosure, in an alternative embodiment, also embraces isotopically labeled therapeutic agents (including compounds of Formula (I), pharmaceutically acceptable salts thereof, and CDK4 / 6 inhibitors) 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.EXEMPLARY EMBODIMENTS

[0126] Various exemplary embodiments are set out below:1. A combination comprising:(i) a compound of F ormula (I) :or a pharmaceutically acceptable salt thereof, wherein:X is selected from H and deuterium;L1is selected from the group consisting of:and 5-6 membered heteroaryl;L2is selected from a bond andeach of R1, R2, R3, and R4is independently selected from the group consisting of hydrogen, halogen, C1-6alkoxy, cyano, hydroxy, C3-6 monocyclic cycloalkyl, and C1-6alkyl; ring A is selected from C3-6 monocyclic cycloalkyl and 3 to 6 membered heterocyclyl, wherein each of C>, . monocyclic cycloalkyl and 3 to 6 membered heterocyclyl is optionally substituted with one or more occurrences of R5; each occurrence of R5is independently selected from the group consisting of hydrogen, C1-6 alkyl, hydroxy, and oxo, wherein C1-6 alkyl is optionally substituted with one or more occurrences of halogen; ring B is selected from the group consisting of C3-12 monocyclic or C3-12 bicyclic cycloalkyl, 3 to 10 membered heterocyclyl, aryl, and heteroaryl, wherein each of C3-12 monocyclic or C3-12 bicyclic cycloalkyl, 3 to 10 membered heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more occurrences of R6; each occurrence of R6is independently selected from the group consisting of halogen, cyano, Cioptionally substituted with one or more occurrences of a substitutent selected from C1-6alkyl and halogen; each occurrence of R7is independently selected from the group consisting of C1-6alkyl, phenyl, cyclopropane, an N-linked C3-9 heterocycloalkyl, an N-linked heteroaryl,,XX JO , wherein R7is optionally substituted with one or more occurrences of a substituent selected from the group consisting of C1-6alkyl, halogen, cyano, frifluoro(methoxy)methane, and C1-6alkoxy (e.g., methoxy); each occurrence of R8, R9, and R10is independently selected from hydrogen, deuterium, Ci- ealkyl, and deuterated C1-6alkyl (e.g., -CD3); and n is an integer selected from the group consisting of 0, 1, 2, and 3; and(ii) a CDK4 / 6 inhibitor.A kit comprising (i) a unit dosage form comprising a compound of Formula (I) as defined in embodiment 1 or a pharmaceutically acceptable salt thereof, and, separately, (ii) a unit dosage form comprising a CDK4 / 6 inhibitor. The kit of embodiment 2, wherein each unit dosage form is a pharmaceutical composition additionally comprising one or more pharmaceutically acceptable excipients. The combination or kit of any one of embodiments 1-3 for use in therapy. A compound of Formula (I) as defined in embodiment 1 or a pharmaceutically acceptable salt thereof, and a CDK4 / 6 inhibitor, as a combined preparation for simultaneous, separate or sequential use in therapy. A compound of Formula (I) as defined in embodiment 1 or a pharmaceutically acceptable salt thereof for use in therapy, wherein the compound of Formula (I) or pharmaceutically acceptable salt thereof is for use in combination with a CDK4 / 6 inhibitor, and wherein the compound of Formula (I) or pharmaceutically acceptable salt thereof and the CDK4 / 6 inhibitor are administered to a patient simultaneously, separately, or sequentially. A CDK4 / 6 inhibitor for use in therapy, wherein the CDK4 / 6 inhibitor is for use in combination with a compound of Formula (I) as defined in embodiment 1 or a pharmaceutically acceptable salt thereof, and wherein the CDK4 / 6 inhibitor and the compound of Formula (I) or pharmaceutically acceptable salt thereof are administered to a patient simultaneously, separately, or sequentially. The (i) combination or kit, (ii) compound of Formula (I) or pharmaceutically acceptable salt thereof, and CDK4 / 6 inhibitor, (iii) compound of Formula (I) or pharmaceutically acceptable salt thereof, or (iv) CDK4 / 6 inhibitor, for use according to any one of embodiments 4-7 in the treatment of cancer. The (i) combination or kit, (ii) compound of Formula (I) or pharmaceutically acceptable salt thereof, and CDK4 / 6 inhibitor, (iii) compound of Formula (I) or pharmaceutically acceptable salt thereof, or (iv) CDK4 / 6 inhibitor, for use according to embodiment 8, wherein the cancer is breast cancer. The (i) combination or kit, (ii) compound of Formula (I) or pharmaceutically acceptable salt thereof, and CDK4 / 6 inhibitor, (iii) compound of Formula (I) or pharmaceutically acceptable salt thereof, or (iv) CDK4 / 6 inhibitor, for use according to embodiment 9, wherein the breast cancer is HR+ (hormone receptor positive) HER2- (human epidermal growth factor receptor 2 negative) breastcancer, for example wherein the breast cancer is HR+ (hormone receptor positive) HER2- (human epidermal growth factor receptor 2 negative) advanced or metastatic breast cancer. The (i) combination or kit, (ii) compound of Formula (I) or pharmaceutically acceptable salt thereof, and CDK4 / 6 inhibitor, (iii) compound of Formula (I) or pharmaceutically acceptable salt thereof, or (iv) CDK4 / 6 inhibitor, for use according to any one of embodiments 8-10, wherein the cancer is resistant to treatment with a CDK4 / 6 inhibitor, for example palbociclib or a pharmaceutically acceptable salt thereof. The (i) combination or kit, (ii) compound of Formula (I) or pharmaceutically acceptable salt thereof, and CDK4 / 6 inhibitor, (iii) compound of Formula (I) or pharmaceutically acceptable salt thereof, or (iv) CDK4 / 6 inhibitor, for use according to any one of embodiments 4-11, wherein the compound of Formula (I) or pharmaceutically acceptable salt thereof and the CDK4 / 6 inhibitor are administered within 24 hours of each other. The (i) combination or kit, (ii) compound of Formula (I) or pharmaceutically acceptable salt thereof, and CDK4 / 6 inhibitor, (iii) compound of Formula (I) or pharmaceutically acceptable salt thereof, or (iv) CDK4 / 6 inhibitor, for use according to any one of embodiments 4-12, wherein the CDK4 / 6 inhibitor is administered in combination with endocrine therapy, optionally wherein the endocrine therapy is administered in combination with a luteinising hormone-releasing hormone (LHRH) agonist. The (i) combination or kit, (ii) compound of Formula (I) or pharmaceutically acceptable salt thereof, and CDK4 / 6 inhibitor, (iii) compound of Formula (I) or pharmaceutically acceptable salt thereof, or (iv) CDK4 / 6 inhibitor, for use according to embodiment 13, wherein the endocrine therapy is an estrogen receptor antagonist such as fulvestrant, or an aromatase inhibitor such as letrozole, for example wherein the endocrine therapy is fulvestrant. The (i) combination or kit, (ii) compound of Formula (I) or pharmaceutically acceptable salt thereof, and CDK4 / 6 inhibitor, (iii) compound of Formula (I) or pharmaceutically acceptable salt thereof, or (iv) CDK4 / 6 inhibitor, for use according to embodiment 14, wherein the endocrine therapy is fulvestrant and the CDK4 / 6 inhibitor is ribociclib or a pharmaceutically acceptable salt thereof, or palbociclib or a pharmaceutically acceptable salt thereof, for example wherein the endocrine therapy is fulvestrant and the CDK4 / 6 inhibitor is ribociclib or a pharmaceutically acceptable salt thereof. The (i) combination or kit, (ii) compound of Formula (I) or pharmaceutically acceptable salt thereof, and CDK4 / 6 inhibitor, (iii) compound of Formula (I) or pharmaceutically acceptable salt thereof, or(iv) CDK4 / 6 inhibitor, for use according to embodiment 14 or embodiment 15, wherein the compound of Formula (I) or pharmaceutically acceptable salt thereof is:pharmaceutically acceptable salt thereof. The (i) combination or kit, (ii) compound of Formula (I) or pharmaceutically acceptable salt thereof, and CDK4 / 6 inhibitor, (iii) compound of Formula (I) or pharmaceutically acceptable salt thereof, or (iv) CDK4 / 6 inhibitor, for use according to embodiment 14 or embodiment 15, wherein the compound of Formula (I) or pharmaceutically acceptable salt thereof is:pharmaceutically acceptable salt thereof. The (i) combination, (ii) kit, (iii) combination or kit for use, (iv) compound of Formula (I) or pharmaceutically acceptable salt thereof, and CDK4 / 6 inhibitor, for use, (v) compound of Formula (I) or pharmaceutically acceptable salt thereof for use, or (vi) CDK4 / 6 inhibitor for use according to any one of embodiments 1-14, wherein the CDK4 / 6 inhibitor is palbociclib, ribociclib, abemaciclib, lerociclib, trilaciclib, dalpiciclib, birociclib, BPI-16350, or in each case a pharmaceutically acceptable salt thereof. The (i) combination, (ii) kit, (iii) combination or kit for use, (iv) compound of Formula (I) or pharmaceutically acceptable salt thereof, and CDK4 / 6 inhibitor, for use, (v) compound of Formula (I) or pharmaceutically acceptable salt thereof for use, or (vi) CDK4 / 6 inhibitor for use according toembodiment 18, wherein the CDK4 / 6 inhibitor is palbociclib, ribociclib, abemaciclib, or in each case a pharmaceutically acceptable salt thereof. The (i) combination, (ii) kit, (iii) combination or kit for use, (iv) compound of Formula (I) or pharmaceutically acceptable salt thereof, and CDK4 / 6 inhibitor, for use, (v) compound of Formula (I) or pharmaceutically acceptable salt thereof for use, or (vi) CDK4 / 6 inhibitor for use according to embodiment 19, wherein the CDK4 / 6 inhibitor is palbociclib or a pharmaceutically acceptable salt thereof, or ribociclib or a pharmaceutically acceptable salt thereof, for example wherein the CDK4 / 6 inhibitor is ribociclib or a pharmaceutically acceptable salt thereof. The (i) combination, (ii) kit, (iii) combination or kit for use, (iv) compound of Formula (I) or pharmaceutically acceptable salt thereof, and CDK4 / 6 inhibitor, for use, (v) compound of Formula (I) or pharmaceutically acceptable salt thereof for use, or (vi) CDK4 / 6 inhibitor for use according to any one of embodiments 1-20, wherein the CDK4 / 6 inhibitor is in the form of a pharmaceutically acceptable salt. The (i) combination, (ii) kit, (iii) combination or kit for use, (iv) compound of Formula (I) or pharmaceutically acceptable salt thereof, and CDK4 / 6 inhibitor, for use, (v) compound of Formula (I) or pharmaceutically acceptable salt thereof for use, or (vi) CDK4 / 6 inhibitor for use according to any one of embodiments 1-21, wherein X is H. The (i) combination, (ii) kit, (iii) combination or kit for use, (iv) compound of Formula (I) or pharmaceutically acceptable salt thereof, and CDK4 / 6 inhibitor, for use, (v) compound of Formula (I) or pharmaceutically acceptable salt thereof for use, or (vi) CDK4 / 6 inhibitor for use according to any one of embodiments 1-22, wherein L1is selected from the group consisting of:The (i) combination, (ii) kit, (iii) combination or kit for use, (iv) compound of Formula (I) or pharmaceutically acceptable salt thereof, and CDK4 / 6 inhibitor, for use, (v) compound of Formula (I) or pharmaceutically acceptable salt thereof for use, or (vi) CDK4 / 6 inhibitor for use according to any one of embodiments 1-23, wherein L2is a bond. The (i) combination, (ii) kit, (iii) combination or kit for use, (iv) compound of Formula (I) or pharmaceutically acceptable salt thereof, and CDK4 / 6 inhibitor, for use, (v) compound of Formula (I)or pharmaceutically acceptable salt thereof for use, or (vi) CDK4 / 6 inhibitor for use according to any one of embodiments 1-24, wherein ring A is selected from the group consisting of:The (i) combination, (ii) kit, (iii) combination or kit for use, (iv) compound of Formula (I) or pharmaceutically acceptable salt thereof, and CDK4 / 6 inhibitor, for use, (v) compound of Formula (I) or pharmaceutically acceptable salt thereof for use, or (vi) CDK4 / 6 inhibitor for use according to any one of embodiments 1-25, wherein n is 0. The (i) combination, (ii) kit, (iii) combination or kit for use, (iv) compound of Formula (I) or pharmaceutically acceptable salt thereof, and CDK4 / 6 inhibitor, for use, (v) compound of Formula (I) or pharmaceutically acceptable salt thereof for use, or (vi) CDK4 / 6 inhibitor for use according to any one of embodiments 1-26, wherein the compound of Formula (I) is a compound of Formula (1-1-0):The (i) combination, (ii) kit, (iii) combination or kit for use, (iv) compound of Formula (I) or pharmaceutically acceptable salt thereof, and CDK4 / 6 inhibitor, for use, (v) compound of Formula (I) or pharmaceutically acceptable salt thereof for use, or (vi) CDK4 / 6 inhibitor for use according to embodiment T1 , wherein the compound of Formula (I) is a compound of Formula (I-I-1-2):The (i) combination, (ii) kit, (iii) combination or kit for use, (iv) compound of Formula (I) or pharmaceutically acceptable salt thereof, and CDK4 / 6 inhibitor, for use, (v) compound of Formula (I) or pharmaceutically acceptable salt thereof for use, or (vi) CDK4 / 6 inhibitor for use according to any one of embodiments 1-28, wherein R1is fluoro, R2is fluoro, R3is H, and R4is H.The (i) combination, (ii) kit, (iii) combination or kit for use, (iv) compound of Formula (I) or pharmaceutically acceptable salt thereof, and CDK4 / 6 inhibitor, for use, (v) compound of Formula (I) or pharmaceutically acceptable salt thereof for use, or (vi) CDK4 / 6 inhibitor for use according to any one of embodiments 1 to 29, wherein ring B is selected from the group consisting of C3-12 monocyclic or C3-i2bicyclic cycloalkyl, 3 to 10 membered heterocyclyl, and aryl, wherein each of C3-12 monocyclic or C3-12 bicyclic cycloalkyl, 3 to 10 membered heterocyclyl, and aryl is substituted with one or more occurrences of R6. The (i) combination, (ii) kit, (iii) combination or kit for use, (iv) compound of Formula (I) or pharmaceutically acceptable salt thereof, and CDK4 / 6 inhibitor, for use, (v) compound of Formula (I) or pharmaceutically acceptable salt thereof for use, or (vi) CDK4 / 6 inhibitor for use according toThe (i) combination, (ii) kit, (iii) combination or kit for use, (iv) compound of Formula (I) or pharmaceutically acceptable salt thereof, and CDK4 / 6 inhibitor, for use, (v) compound of Formula (I) or pharmaceutically acceptable salt thereof for use, or (vi) CDK4 / 6 inhibitor for use according to any one of embodiments 1-31, wherein R6is selected from the group consisting of Cl, F, -CN, -CH3, - CF3, -CH(CH3)2, -OCH3, -OC(CH3)3, -OCF3, -O-Si(CH3)2C(CH3)3, -C(O)R7, -C(O)NR7R8, and - S(O)2R7. The (i) combination, (ii) kit, (iii) combination or kit for use, (iv) compound of Formula (I) or pharmaceutically acceptable salt thereof, and CDK4 / 6 inhibitor, for use, (v) compound of Formula (I) or pharmaceutically acceptable salt thereof for use, or (vi) CDK4 / 6 inhibitor for use according to any one of embodiments 1-32, wherein R7is selected from the group consisting of methyl, benzene,with one or two occurrences selected from the group consisting of methyl, flourine, chlorine, cyano, and methoxy. The (i) combination, (ii) kit, (iii) combination or kit for use, (iv) compound of Formula (I) or pharmaceutically acceptable salt thereof, and CDK4 / 6 inhibitor, for use, (v) compound of Formula (I) or pharmaceutically acceptable salt thereof for use, or (vi) CDK4 / 6 inhibitor for use according to any one of embodiments 1-33, wherein each occurrence of R8is independently hydrogen, CH3, or CD3. The (i) combination, (ii) kit, (iii) combination or kit for use, (iv) compound of Formula (I) or pharmaceutically acceptable salt thereof, and CDK4 / 6 inhibitor, for use, (v) compound of Formula (I) or pharmaceutically acceptable salt thereof for use, or (vi) CDK4 / 6 inhibitor for use according to any one of embodiments 1-34, wherein the compound of Formula (I) or pharmaceutically acceptable salt thereof is a compound selected from Table 1 or a pharmaceutically acceptable salt thereof. The (i) combination, (ii) kit, (iii) combination or kit for use, (iv) compound of Formula (I) or pharmaceutically acceptable salt thereof, and CDK4 / 6 inhibitor, for use, (v) compound of Formula (I) or pharmaceutically acceptable salt thereof for use, or (vi) CDK4 / 6 inhibitor for use according to embodiment 35, wherein the compound of Formula (I) or pharmaceutically acceptable salt thereof is:pharmaceutically acceptable salt thereof optionally wherein the CDK4 / 6 inhibitor is ribociclib or a pharmaceutically acceptable salt thereof, or palbociclib or a pharmaceutically acceptable salt thereof for example wherein the CDK4 / 6 inhibitor is ribociclib or a pharmaceutically acceptable salt thereof37. The (i) combination, (ii) kit, (iii) combination or kit for use, (iv) compound of Formula (I) or pharmaceutically acceptable salt thereof, and CDK4 / 6 inhibitor, for use, (v) compound of Formula (I) or pharmaceutically acceptable salt thereof for use, or (vi) CDK4 / 6 inhibitor for use according to embodiment 35, wherein the compound of Formula (I) or pharmaceutically acceptable salt thereof is:pharmaceutically acceptable salt thereof, optionally wherein the CDK4 / 6 inhibitor is ribociclib or a pharmaceutically acceptable salt thereof, or palbociclib or a pharmaceutically acceptable salt thereof, for example wherein the CDK4 / 6 inhibitor is ribociclib or a pharmaceutically acceptable salt thereofEXAMPLESExample 1. Synthesis of Exemplary Compounds

[0127] The compounds provided herein can be prepared from readily available starting materials using the following 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 varywith the particular reactants or solvent used, but such conditions can be determined by a person of ordinary skill in the art by routine optimization.

[0128] Abbreviations', eq: equivalents; ESI: electrospray ionization; h: hours; HPLC: high- performance liquid chromatography; MS: mass spectrometry; NMR: nuclear magnetic resonance; AcOH or HOAc: acetic acid; Boc: tert -butyloxycarbonyl; BOP: basic oxygen process; BrettPhos: diallylbiaryl phosphine ligand; GDI: carbonyldiimidazole; DBU: 1,8-diazabicyclo [5.4.0]undec-7-ene; DCM: dichloromethane; DIEA: N,N-diisopropylethylamine; DMAP: 4-dimethylaminopyridine; DMF: dimethylformamide; DMSO: dimethyl sulfoxide; EDO: ethylene dichloride; HOBt: hydroxybenzotriazole; LAH: lithium aluminium hydride; MeCN: acetonitrile; MeOH: methanol; Pd PEPPSI-IHetp Cl: dichlorofl, 3- bis(2,6-di-4-heptylphenyl)imidazol-2-ylidene](3-chloropyridyl)palladium(II); Pd(PPh)4: palladium-tetrakis (triphenylphosphine); Py: pyridine; t-BuONa: sodium tert-butoxide; TBuONO: tert-butyl nitrite; TEA: triethylamine; TFA: trifluoroacetic acid; THF: tetrahydrofuran; triphosgene: bis(trichloromethyl) carbonate; ZnEt2: diethylzinc.Synthesis of Compound 1Compound 1Step 1. Procedure for Compound 1 - spiro[3.3]heptan-2-ylmethyl (l-(4-(2,6-dioxopiperidin-3-yl)-3,5- difluorophenyl)azetidin-3-yl)carbamate.

[0129] To a solution of spiro[3.3]heptan-2-ylmethanol (5.98 mg, 47.4 umol, 1.00 eq) in tetrahydrofuran (0.200 mL) was added di( LH-imidazol- l-yl)methanone (15.4 mg, 94.8 umol, 2.00 eq) at 0 °C. The mixture was stirred at 0 °C for 1 h. The resulting solution was added to a mixture of 3-(4-(3-aminoazetidin-l-yl)-2,6-difluorophenyl)piperidine-2, 6-dione (20.0 mg, 47.4 umol, 70% purity, 1.00 eq), 2,3,4,6,7,8,9,10- octahydropyrimido[l,2-a]azepine (7.22 mg, 47.4 umol, 7. 15 uL, 1.00 eq) and ACA'-diisopropylcthylaminc (6. 13 mg, 47.4 umol, 8.26 uL, 1.00 eq) in tetrahydrofuran (0.200 mL) and dimethylformamide (0.200 mL). The reaction mixture was stirred at 20 °C for 12 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was diluted with dimethylformamide (1.00 mL) and then filtered. The filtrate was purified by Pre / ?-HPLC(column: Phenomenex luna C18 150*25mm* 10um;mobile phase: [water(formic acid)- acetonitrile] ;B%: 46%-76%,9 min) and lyophilized to afford spiro[3.3]heptan-2-ylmethyl (l-(4-(2,6- dioxopiperidin-3-yl)-3,5-difluorophenyl)azetidin-3-yl)carbamate (3.93 mg, 8.69 umol, 18 % yield, 99% purity) as an off-white solid.

[0130] 1H NMR (400 MHz, DMSO-d6) δ = 10.86 (s, 1H), 7.82 (br d, J = 7.0 Hz, 1H), 6. 15 (s, 1H), 6.12 (s, 1H), 4.47 - 4.35 (m, 1H), 4.08 (br t, J = 7.9 Hz, 2H), 4.05 - 4.00 (m, 1H), 3.96 - 3.86 (m, 2H), 3.69 - 3.58 (m, 2H), 2.82 - 2.73 (m, 1H), 2.61 (br s, 1H), 2.39 - 2.34 (m, 1H), 2.07 (s, 1H), 2.05 - 2.01 (m, 2H), 2.00 - 1.97 (m, 1H), 1.95 (br d, J = 7.0 Hz, 2H), 1.90 - 1.84 (m, 2H), 1.79 - 1.73 (m, 2H), 1.73 - 1.65 (m, 2H). MS (ESI) m / z 448.2 [M+H]+Synthesis of Compound 2Compound 2 IStep 1. Procedure for Compound 2 - tert-butyl (l-(4-(2,6-dioxopiperidin-3-yl)-3-fluoro-2- methoxyphenyl)- 3- methylazetidin-3-yl)carbamate.

[0131] To a solution of 3-(4-bromo-2-fluoro-3-methoxyphenyl)piperidine-2, 6-dione (100 mg, 316 nmol, 1.00 eq), tert-butyl (3-methylazetidin-3-yl)carbamate (70.5 mg, 316 umol, 1.0 eq, hydrochloric acid) in dioxane (2.00 mL) were added cesium carbonate (309 mg, 949 umol, 3.00 eq) and l,3-bis[2,6-bis(l- propy Ibuty Ijphcny I |-4.5-dichloro-27 / -imidazol- 1 -ium-2-ide;3-chloropyridine;dichloropalladium (30.8 mg, 31.6 umol, 0.100 eg). The mixture was stirred at 100 °C for 12 h under nitrogen atmosphere. The mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiC>2, petroleum ether / ethyl acetate=l / O to 5 / 1) to afford tert-butyl / V-[l-[4-(2,6-dioxo-3-piperidyl)-3-fluoro- 2-methoxy-phenyl]-3-methyl-azetidin-3-yl]carbamate (56.0 mg, 133 umol, 42% yield) as a white solid.Step 2. Procedure for Compound 3 - 3-(4-(3-amino-3-methylazetidin-l-yl)-2-fluoro-3- methoxyphenyl)piperidine-2, 6-dione.

[0132] A solution of tert-butyl (l-(4-(2,6-dioxopiperidin-3-yl)-3-fluoro-2-methoxyphenyl) -3- methylazetidin-3-yl)carbamate (48.0 mg, 114 umol, 1.00 eq) in dichloromethane (2.00 mL) was added methanesulfonic acid (32.8 mg, 341 umol, 24.3 uL, 3.00 eq). The mixture was stirred at 25 °C for 2 h. The mixture was concentrated under reduced pressure to give 3-[4-(3-amino-3-methyl-azetidin-l-yl)-2-fluoro-3- methoxy-phenyl]piperidine-2, 6-dione (40.0 mg, crude) as yellow oil. MS (ESI) m / z.322. 1 [M+H]+Step 3. Procedure for Compound 3A - spiro [3.3 ]heptan-2-ylmethyl carbonochloridate.

[0133] A solution of spiro[3.3]heptan-2-ylmethanol (30.0 mg, 238 umol, 1.00 eq) in dichloromethane (1.00 mL) was added A'A'-diisopropylcthylaminc (61.5 mg, 475 umol, 82.8 uL, 2.00 eq) and triphosgene (106 mg, 357 umol, 1.5 eq) at 0 °C. The mixture was stirred at 20 °C for 1 h. The mixture was concentrated under reduced pressure to give spiro[3.3]heptan-2-ylmethyl carbonochloridate (45 mg, crude) as a white solid.Step 4. Procedure for spiro [3.3]heptan-2-ylmethyl (l-(4-(2,6-dioxopiperidin-3-yl)-3fluoro-2- methoxyphenyl)-3-methylazetidin-3-yl)carbamate.

[0134] To a solution of 3-[4-(3-amino-3-methyl-azetidin-l-yl)-2-fluoro-3-methoxy- phenyl]piperidine-2, 6-dione (40.0 mg, 124 umol, 1.00 eq) in dimethyl formamide (1.00 mL) were added Nf4- diisopropylethylamine (16.1 mg, 124 umol, 21.7 uL, 1.00 eq) and spiro[3.3]heptan-2-ylmethyl carbonochloridate (45.0 mg, 238.54 umol, 1.92 eq). The reaction mixture was stirred at 20 °C for 0.5 h. The reaction mixtur was concentrated under reduced pressure to give a residue. The residue was purified by prep- HPLC (C18, 120 g; condition:water / acetonitrile=100:0 to 60:40, 0.1% formic acid) and lyophilized to afford spiro[3.3]heptan-2-ylmethyl (l-(4-(2,6-dioxopiperidin-3-yl)-3-fluoro-2-methoxyphenyl)-3-methylazetidin -3- yl)carbamate (10.44 mg, 21.8 umol, 17% yield, 99% purity) as a white solid.

[0135] 1H NMR (400 MHz, DMSO-d6 ) δ = 10.80 (br s, 1H), 7.76 - 7.50 (m, 1H), 6.79 (t, J= 8. 1 Hz, 1H), 6.20 (d, J= 8.4 Hz, 1H), 3.88 (br d, J= 6.8 Hz, 5H), 3.75 (d, J = 7.8 Hz, 2H), 3.67 (s, 3H), 2.75 - 2.66 (m, 1H), 2.54 - 2.51 (m, 1H), 2.34 (td, J= 7.5, 14.8 Hz, 1H), 2.20 - 2.10 (m, 1H), 2.04 - 1.93 (m, 5H), 1.89 - 1.84 (m, 2H), 1.79 - 1.67 (m, 4H), 1.51 (s, 3H). MS (ESI) m / z. 474.3 [M+H]+Synthesis of Compound 3Compound 3Step 1. Procedure for preparation of Compound 2 - (1R, 2R, 4S)-bicyclo[2.2.1 ]heptane-2-carboxylic acid.

[0136] To a solution of (lS,2R ,4S)-bicyclo[2.2. l]hept-5-ene-2-carboxylic acid (50.0 mg, 362 umol, 1.00 eq) in methanol (1.00 mL) was added palladium on carbon (50.0 mg, 10% purity) under nitrogen atmosphere. The reaction mixture was stirred at 20 °C for 1 h under hydrogen atmosphere (15 psi). The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to afford ( 1 R,2R,4S)- bicyclo[2.2. l]heptane-2-carboxylic acid (50.0 mg, 357 umol, 99% yield) as colorless oil.Step 2. Procedure for preparation of Compound 3 - (lR,2R,4S)-bicyclo[2.2.1]heptan-2-ylmethanol.

[0137] To a solution of ( l / ?.2 / ?.4.S)-bicyclo|2,2. l]heptane-2 -carboxylic acid (50.0 mg, 357 umol, 1.00 eq) in tetrahydrofuran (1.00 mL) was added borane dimethyl sulfide complex (10.0 M, 71.3 uL, 2.00 eq) at 0 °C. The reaction mixture was stirred at 20 °C for 1 h. The reaction mixture was concentrated under reducedpressure to afford (17?,27?,4lS)-bicyclo[2.2.1]heptan-2-ylmethanol (45.0 mg, 357 umol, 99% yield) as colorless oil.Step 3. Procedure for preparation of Compound 4 - (lR,2R,4S)-bicyclo[2.2.1]heptan-2-ylmethyl carbonochloridate.

[0138] To a solution of (LR,2R,4S)-bicyclo[2.2. l]heptan-2-ylmethanol (45.0 mg, 357 umol, 1.00 eq) in dichloromethane (1.00 mL) were added bis(trichloromethyl) carbonate (106 mg, 357 umol, 1.00 eq) and A'Miisopropylcthylaminc (184 mg, 1.43 mmol, 248 uL, 4.00 eq) at 0 °C. Then the reaction was stirred at 20 °C for 0.5 h. The reaction mixture was concentrated under reduced pressure to afford (17?,27?,4S)- bicyclo[2.2.1]heptan-2-ylmethyl carbonochloridate (65 mg, crude) as a yellow solid.Step 4. Procedure for preparation of (lR,2R,4S)-bicyclo[2.2.1]heptan-2-ylmethyl (l-(4-(2,6-dioxopiperidin- 3-yl)-3,5-difluorophenyl)azetidin-3-yl)carbamate.

[0139] To the solution of 3-(4-(3-aminoazetidin-l-yl)-2,6-difluorophenyl)piperidine-2, 6-dione (111 mg, 284 umol, 1.00 eq, mesylate) in dimethylformamide (1.00 mL) were added A'.A'-diisopropylcth laminc (134 mg, 1.03 mmol, 180 uL, 3.00 eq) and ( l / ?.2 / ?.4S')-bicyclo|2.2. 1 |hcptan-2-ylmcthyl carbonochloridate (65.0 mg, crude). Then the reaction was stirred at 0 °C for 0. 15 h. The reaction mixture was diluted with N,N- dimethylformamide (1.00 mL) and filtered. The filtrate was purified by reverse phase chromatography (C18, 40 g; condition: water / acetonitrile = 100:0 to 0: 100, 0.1% formic) and lyophilized to afford ( 1 R,2R,4S)- bicyclo[2.2.1]heptan-2-ylmethyl (l-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)azetidin-3-yl)carbamate (50.00 mg, 110.62 umol, 32. 11% yield, 99% purity) as a white solid.

[0140] 1H NMR (400 MHz, DMSO-d6) δ = 10.85 (s, 1H), 7.83 (br d, J= 7. 1 Hz, 1H), 6. 14 (d, J= 11. 1 Hz, 2H), 4.50 - 4.30 (m, 1H), 4.08 (br t, J = 7.7 Hz, 2H), 4.03 (br dd, J = 5.1, 12.8 Hz, 1H), 3.77 - 3.66 (m, 2H), 3.63 (br t, J= 6.8 Hz, 2H), 2.85 - 2.70 (m, 1H), 2.48 (br s, 1H), 2.18 (br s, 1H), 2.12 - 2.02 (m, 2H), 1.99 - 1.89 (m, 1H), 1.76 - 1.64 (m, 1H), 1.53 - 1.40 (m, 2H), 1.36 - 1.25 (m, 2H), 1.19 - 0.96 (m, 4H).MS (ESI) m / z 448.2 [M+H]+Synthesis of Compound 4Compound 4Step 1. Procedure for preparation of Compound 2 - 3-hydroxy-N-methoxy-N -methylbicyclo [1.1.1 ] 'pentane- 1- carboxamide.

[0141] To a solution of 3-hydroxybicyclo[l. l. l]pentane-l-carboxylic acid (100 mg, 780 umol, 1.00 eq) in dimethyl formamide (1.00 mL) was added o-(7-azabcnzotriazol- l -yl)-A / '.A / '.A / ' ’.A / ' ’-tctramcthykironium hexafluorophosphate (356. 12 mg, 936.58 umol, 1.2 eq), A'.A''-diisopropylcthylaminc (403 mg, 3. 12 mmol, 544 uL, 4.00 eq) at 25°C to afford mixture A. To a solution of N, O-dimethylhydroxylamine (91.4mg, 937 umol, 1.20 eq, hydrochloride) in dimethyl formamide (1.00 mL) was added ACAMiisopropy lethyl amine (202 mg, 1.56 mmol, 272 uL, 2.00 eq) to give mixture B. The mixture B was added into the mixture A at 25°C. 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=3 / l to 1 / 1) to afford 3-hydroxy-A''-mcthoxy-A''-mcthylbicyclo| 1. 1. 1 |pcntanc- l-carboxamidc (50.0 mg, 292 umol, 37.42% yield) as colorless oil.Step 2. Procedure for preparation of Compound 3 - (3-hydroxybicyclo[l.l.l]pentan-l-yl)(phenyl)methanone.

[0142] A solution of 3-hydroxy-A''-mcthoxy-A''-mcthylbicyclo| 1. 1. 1 |pcntanc- l -carboxamidc (210 mg, 1.23 mmol, 1.00 eq) in tetrahydrofuran (10.0 mL) was degassed and purged with nitrogen atmosphere. The resulting clear solution was cooled to 0 °C. And then a solution of phenylmagnesium bromide (3 M, 1.23 mL, 3.00 eq) was added dropwise to the mixture via syringe. After 20 min, the mixture was allowed to warm to 25 °C for 6 h. The reaction mixture was quenched by addition ammonium chloride (10.0 mL) at 0°C and extracted with ethyl acetate 20 mL (10 mL * 2). The combined organic layers were 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=3 / l) to afford (3 -hydroxy bicyclo [1. 1.1 ]pentan-l- yl)(phenyl)methanone (160 mg, 850 umol, 69.0% yield) as light yellow oil.Step 3. Procedure for preparation of compound 4 - 3-benzoylbicyclo[l.l.l]pentan-l-yl carbonochloridate.

[0143] To a solution of (3 -hydroxy bicyclo [l. l. l]pentan-l-yl)(phenyl)methanone (60.0 mg, 319 umol,1.00 eq) in dichloromethane (2.00 mL) was added triphosgene (151 mg, 510 umol, 1.60 eq) and N.N- diisopropylethylamine (82.4 mg, 638 umol, 111 uL, 2.00 eq) at 0 °C. The mixture was stirred at 25 °C for 1 h. The reaction mixture was filtered and concentrated under reduced pressure to afford 3- bcnzoylbicyclol 1 . 1. l]pentan-l-yl carbonochloridate (70.0 mg, 279 umol, 88% yield) as a yellow solid.Step 4. Procedure for preparation of compound 4 - l-(methyl(p-tolyl)carbamoyl)azetidin-3-yl (l-(4-(2,6- dioxopiperidin-3-yl)-3,5-difluorophenyl)azetidin-3-yl)carbamate.

[0144] To a solution of 3-(4-(3-aminoazetidin-l-yl)-2,6-difluorophenyl)piperidine-2, 6-dione (100 mg, 256 umol, 1.00 eq, methanesulfonic acid) in dichloromethane (3.00 mL) was added NJ4- diisopropylethylamine (33.0 mg, 256 umol, 44.5 uL, 1.00 eq) and 3-benzoylbicyclo[l. l. l]pentan-l-yl carbonochloridate (70 mg, 279 umol, 1.09 eq). The 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 purified by reverse phase chromatography (C18, 40 g; condition: water / acetonitrile = 100:0 to 0: 100, 0. 1% formic) and lyophilized to afford l-(methyl(p-tolyl)carbamoyl)azetidin-3-yl (l-(4-(2,6-dioxopiperidin-3-yl)-3,5- difluorophenyl)azetidin-3-yl)carbamate (11.29 mg, 21.72 umol, 8.50% yield, 98% purity) as a white solid.

[0145] 1H NMR (400 MHz, DMSO-d6 ) δ = 10.86 (s, 1H), 8.03 (d, J = 7.4 Hz, 1H), 7.96 (d, J = 7.4 Hz, 2H), 7.69 - 7.62 (m, 1H), 7.58 - 7.51 (m, 2H), 6.16 (d, J= 11.0 Hz, 2H), 4.50 - 4.36 (m, 1H), 4.11 (t, J = 7.7 Hz, 2H), 4.04 (br dd, J= 5.2, 12.8 Hz, 1H), 3.70 - 3.60 (m, 2H), 2.84 - 2.73 (m, 1H), 2.59 (s, 6H), 2.55 - 2.54 (m, 1H), 2.15 - 2.03 (m, 1H), 2.01 - 1.90 (m, 1H). MS (ESI) m / z 510.3 [M+H]+Synthesis of Compound 5Step 1. Procedure for preparation of Compound 2 - isoindoline-2-carbonyl chloride.

[0146] To a solution of isoindoline (950 mg, 7.97 mmol, 904 uL, 1.00 eq) in dichloromethane (10.0 mL) was added triphosgene (2.84 g, 9.57 mmol, 1 .20 cv / ) and A'.A'-diisopropylcthylaminc (1.55 g, 11.9 mmol, 2.08 mL, 1.50 eq) at 0 °C. The mixture was stirred at 25 °C for 1 h The reaction mixture was concentrated under reduce pressure to afford isoindoline-2 -carbonyl chloride (1.50 g, crude) as a yellow solid.Step 2. Procedure for preparation of Compound 3 - (3-hydroxyazetidin-l-yl)(isoindolin-2-yl)methanone.

[0147] To a solution of isoindoline-2-carbonyl chloride (1.45 g, 7.98 mmol, 1.00 eq) in dimethylformamide (10.0 mL) was added potassium carbonate (8.83 g, 64.0 mmol, 8.00 eq) and azetidin-3-ol (1.75 g, 15.97 mmol, 2.00 eq, hydrochloride). The mixture was stirred at 25 °C for 3 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 / 3 to 0 / 1) to afford (3-hydroxyazetidin-l-yl)(isoindolin- 2-yl)methanone (700 mg, 3.21 mmol, 40% yield) as an off-white solid.Step 3. Procedure for preparation of l-(isoindoline-2-carbonyl)azetidin-3-yl (l-(4-(2,6-dioxopiperidin-3-yl)- 3,5-difluorophenyl)azetidin-3-yl)carbamate.

[0148] To a solution of (3-hydroxyazetidin-l-yl)(isoindolin-2-yl)methanone (100 mg, 275 umol, 60% purity, 1.00 eq) in tetrahydrofuran (2.00 mL) was added l,l'-carbonyldiimidazole (66.9 mg, 412 umol, 1.50 eq). The mixture was stirred at 25 °C for 1 h to give a resulting solution. A solution of 3-(4-(3-aminoazetidin- l-yl)-2,6-difluorophenyl)piperidine-2, 6-dione (107 mg, 273 umol, 1.00 eq, mesylate) and N,N- diisopropylethylamine (53.0 mg, 410 umol, 71.4 uL, 1.50 eq) in dimethylformamide (1.00 mL) was added into the resulting solution. The mixture was stirred at 25 °C for 12 h. The mixture was purified by / Vc / i-HPLC (Phenomenex luna C18 150*25mm* 10um;mobile phase: [water(formic acid)- acetonitrile] ;B%: 31%- 61%,9min) and lyophilized to afford 1 -(isoindoline-2 -carbonyl)azetidin-3-yl (l-(4-(2,6-dioxopiperidin-3-yl)- 3,5-difluorophenyl)azetidin-3-yl)carbamate (17.53 mg, 32. 17 umol, 11% yield, 99% purity) as a white solid.

[0149] 1H NMR (400 MHz, DMSO-d6 ) δ =10.87 - 10.81 (m, 1H), 8. 13 (br d, J= 7.1 Hz, 1H), 7.34 - 7.23 (m, 4H), 6.16 (br d, J= 11.1 Hz, 2H), 5.09 - 5.00 (m, 1H), 4.62 (s, 4H), 4.49 - 4.39 (m, 1H), 4.29 (dd, J = 6.9, 9.3 Hz, 2H), 4.11 (br t, J= 7.6 Hz, 2H), 4.03 (br dd, J = 4.9, 12.4 Hz, 1H), 3.89 (br dd, J = 3.8, 9.3 Hz, 2H), 3.66 (br t, J= 6.6 Hz, 2H), 2.83 - 2.71 (m, 1H), 2.47 - 2.41 (m, 1H), 2.13 - 2.03 (m, 1H), 1.98 - 1.89 (m, 1H). MS (ESI) m / z 539.9 [M+H]+Synthesis of Compound 6Step 1. Procedure for preparation of Compound 2 - l-(4-methylpyridin-2-yl)azetidin-3-ol.

[0150] To a solution of 2-fluoro-4-methylpyridine (500 mg, 4.50 mmol, 1.00 eq) in dimethylsulfoxide (5.00 mL) was added azetidin-3-ol (592 mg, 5.40 mmol, 1.20 eq, hydrochloride) and cesium carbonate (2.93 g, 9.00 mmol, 2.00 eq). The mixture was stirred at 100 °C for 12 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by reverse phase chromatography (Cl 8, 40 g; condition: water / acetonitrile = 100:0 to 0: 100, 0.1% formic acid) and lyophilized to afford l-(4- methylpyridin-2-yl)azetidin-3-ol (730 mg, 4.45 mmol, 98 % yield) as colorless oil. MS (ESI) m / z 165.4 [M+H]+Step 2. Procedure for preparation of l-(4-methylpyridin-2-yl)azetidin-3-yl (l-(4-(2,6-dioxopiperidin-3-yl)-3.5-difluorophenyl)azetidin-3-yl)carbamate.

[0151] To a solution of l-(4-methylpyridin-2-yl)azetidin-3-ol (300 mg, 1.83 mmol, 1.00 eq) in tetrahydrofuran (4.00 mL) was added l,l'-carbonyldiimidazole (311 mg, 1.92 mmol, 1.05 eq). The mixture was stirred at 25 °C for 0.5 h. The resulting solution was added to a mixture of 3-(4-(3-aminoazetidin-l-yl)-2.6-difluorophenyl)piperidine-2, 6-dione (474 mg, 1.21 mmol, 1.00 eq, methanesulfonic acid), triethylamine (123 mg, 1.21 mmol, 168 uL, 1.00 eq) and l,8-diazabicyclo[5.4.0]undec-7-ene (184 mg, 1.21 mmol, 182 uL, 1.00 eq) in dimethylformamide (2.00 mL). 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=5 / l to 0 / 1) to afford a crude product. The crude product was triturated with water (10.0 ml) and filtered. The filter cake was washed with petroleum ether (3x5.00 ml)and lyophilized to afford l-(4-methylpyridin-2-yl)azetidin-3-yl (l-(4-(2,6-dioxopiperidin-3-yl)-3,5- difluorophenyl)azetidin-3-yl)carbamate (19. 18 mg, 39. 1 umol, 3.22% yield, 99.0% purity) as a white solid.

[0152] 1H NMR (400 MHz, DMSO-r / e) 3 = 10.87 (s, 1H), 8.23 (br d, J= 7.3 Hz, 1H), 7.90 (d, J= 6.4 Hz, 1H), 6.87 - 6.65 (m, 2H), 6. 17 (br d, J= 11. 1 Hz, 2H), 5.29 - 5. 15 (m, 1H), 4.59 - 4.50 (m, 2H), 4.49 - 4.40 (m, 1H), 4.20 - 4. 14 (m, 2H), 4. 14 - 4.08 (m, 2H), 4.04 (br dd, J= 4.9, 12.5 Hz, 1H), 3.67 (br t, J= 6.8 Hz, 2H), 2.85 - 2.73 (m, 1H), 2.50 - 2.47 (m, 1H), 2.36 (s, 3H), 2.15 - 2.02 (m, 1H), 2.00 - 1.90 (m, 1H). MS (ESI) m / z 486.4 [M+H]+Synthesis of Compound 7Compound 7Step 1. Procedure for preparation of Compound 2 - 5-(3-(benzyloxy)azetidin-l-yl)-l-methyl-lH-pyrazole.

[0153] To a solution of 5-bromo- 1 -methyl-7 / / -pyrazole (100 mg, 621 umol, 1.00 eq) in toluene (4.00 mL) was added 3-(benzyloxy)azetidine hydrochloride (62.0 mg, 311 umol, 0.500 eq, hydrochloric acid), cesiumcarbonate (809 mg, 2.48 mmol, 4.00 eq) and tris(dibenzylideneacetone)dipalladium(O) (56.9 mg, 62.1 nmol, 0.100 eq) and 2,2'-bis-(diphenylphosphino)-l,r-binaphthyl (77.4 mg, 124 nmol, 0.200 eq). The mixture was stirred at 110 °C for 16 h. The reaction mixture was quenched by addition water (10.0 mL) at 20°C and extracted with ethyl acetate (20.0 mL). The combined organic layers were washed with water (10.0 mL) and dried over sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by reverse phase chromatography (C18, 40 g; condition: water / acetonitrile = 100:0 to 0:100, 0.1% formic acid) to afford 5-(3-(benzyloxy)azetidin-l-yl)-l-methyl-7 / 7-pyrazole (90.0 mg, 370 umol, 60% yield) as a yellow oil.Step 2. Procedure for preparation of Compound 3- l-(l-methyl-lH-pyrazol-5-yl)azetidin-3-ol.

[0154] To a solution of 5-(3-(benzyloxy)azetidin-l-yl)-l-methyl-7 / 7-pyrazole (50.0 mg, 206 umol, 1.00 eq) in dioxane (1.00 mL) was added palladium on activated carbon (50.0 mg, 60% purity, 1.00 eq). The mixture was stirred at 40 °C for 4 h under hydrogen atmosphere. The reaction mixture was concentrated under reduce pressure to afford l-(l-methyl-7 / 7-pyrazol-5-yl)azetidin-3-ol (100 mg, crude) as yellow oil, which was used for next step without further purification.Step 3. Procedure for preparation of l-(l-methyl-lH-pyrazol-5-yl)azetidin-3-yl (l-(4-(2,6-dioxopiperidin-3- yl)-3,5-difluorophenyl)azetidin-3-yl)carbamate.

[0155] To a solution of l-(l-methyl-7 / / -pyrazol-5-yl)azetidin-3-ol (30 mg, 196 umol, 1.00 eq) in tetrahydrofuran (0.50 mL) was added di( l / 7-imidazol- l-yl)methanone (38.1 mg, 235 umol, 1.20 eq). The mixture was stirred at 25 °C for 0.5 h. The resulting solution was added to a mixture of 3-(4-(3-aminoazetidin- l-yl)-2,6-difluorophenyl)piperidine-2, 6-dione (76.7 mg, 196 umol, 1.00 eq, methanesulfonic acid) and A'.A'- diisopropylethylamine (75.9 mg, 588 umol, 102 uL, 3.00 eq) in dimethylformamide (1.00 mL). The reaction 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 reverse phase chromatography (Cl 8, 40 g, condition: water / acetonitrile = 100:0 to 0: 1, 0.1% formic acid) and lyophilized to afford l-(l-methyl-7 / 7-pyrazol-5-yl)azetidin-3-yl (l-(4- (2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)azetidin-3-yl)carbamate (10.29 mg, 21.69 umol, 11.07% yield) as a white solid.

[0156] 1H NMR (400 MHz, DMSO-d6 ) δ = 10.86 (s, 1H), 8. 13 (br d, J= 7. 1 Hz, 1H), 7. 14 (d, J = 1.8 Hz, 1H), 6.15 (d, J= 11.1 Hz, 2H), 5.59 (d, J= 1.3 Hz, 1H), 5.19 - 5.07 (m, 1H), 4.43 (br d, J = 7.3 Hz, 1H), 4. 18 - 4.07 (m, 4H), 4.03 (br dd, J= 5. 1, 12.4 Hz, 1H), 3.75 - 3.68 (m, 2H), 3.65 (br t, J= 6.9 Hz, 2H), 3.52 (s, 3H), 2.83 - 2.72 (m, 1H), 2.62 - 2.57 (m, 1H), 2.13 - 2.01 (m, 1H), 1.99 - 1.88 (m, 1H). MS (ESI) m / z.475.2 [M+H]+Synthesis of Compounds 8, 9, 10, 13, 17, 30, 31 32, 33, 36, 40, 43, 70, 71, 72, 73, 109, 110, 113, 116, 118, 119, 138Step 1. Procedure for Compound 2 - tert-butyl 3-(((4-nitrophenoxy)carbonyl)oxy)azetidine-l-carboxylate.

[0157] To a solution of tert-butyl 3-hydroxyazetidine-l-carboxylate (5.00 g, 28.9 mmol, 1.00 eq) in dichloromethane (50.0 mL) were added 4-nitrophenyl carbonochloridate (20.4 g, 101 mmol, 3.50 eq) and triethylamine (14.6 g, 144 mmol, 20. 1 mL, 5.00 eq) at 0 °C. The reaction mixture was stirred at 20 °C for 1 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by columnchromatography (SiCL, petroleum ether / ethyl acetate=l / O to 10 / 1) to afford tert-butyl 3-(((4- nitrophenoxy)carbonyl)oxy)azetidine-l -carboxylate (9.00 g, 5.32 mmol, 18% yield, 20% purity) as yellow oil.Step 2. Procedure for Compound 3 - tert-butyl 3-(((l-(4-(2,6-dioxopiperidin-3-yl)-3,5- difluorophenyl)azetidin-3-yl)carbamoyl)oxy)azetidine-l-carboxylate.

[0158] To a solution of tert-butyl 3-(((4-nitrophenoxy)carbonyl)oxy)azetidine-l -carboxylate (4.49 g, 2.66 mmol, 20% purity, 1.00 eq) in dimethyformamide (10.0 mL) was added 3-(4-(3-aminoazetidin-l-yl)-2,6- difluorophenyl)piperidine-2, 6-dione (1.00 g, 2.66 mmol, 1.00 eq, methanesulfonic acid) and triethylamine (538 mg, 5.31 mmol, 740 uL, 2.00 eq). The reaction mixture was stirred at 20 °C for 1 h. The reaction mixture was quenched with water (50 mL) and extracted with ethyl acetate (3 x 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=10 / l to 0 / 1) to afford tert-butyl 3-(((l-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)azetidin-3- yl)carbamoyl)oxy)azetidine-l -carboxylate (1.20 g, crude) as a yellow solid.Step 3. Procedure for Compound 4 - azetidin-3-yl (l-(4-(2,6-dioxopiperidin-3-yl)-3,5- difluorophenyl)azetidin-3-yl)carbamate.

[0159] To a solution of tert-butyl-3-(((l-(4-(2,6-dioxopiperidin-3-yl)- 3,5-difluorophenyl)azetidin-3- yl)carbamoyl) oxy)azetidine- 1 -carboxylate (250 mg, 506 umol, 1.00 eq) in dichloromethane (5.00 mL) was added trifluoroacetic acid (1.00 mL). The reaction mixture was stirred at 20 °C for 1 h. The reaction mixture was concentrated under reduced pressure to afford azetidin-3-yl (l-(4-(2,6-dioxopiperidin-3-yl)-3,5- difluorophenyl)azetidin-3-yl)carbamate (199 mg, 505 umol, 99% yield) as yellow oil.Step 4. Procedure for Compound 4A - cyclopropyl(methyl)carbamic chloride.

[0160] To a solution of / V-methylcyclopropanamine (40.0 mg, 562 umol, 1.00 eq) in dichloromethane (3.00 mL) were added bis(trichloromethyl) carbonate (250 mg, 844 umol, 1.50 eq) and N,N- diisopropylethylamine (109 mg, 844 umol, 147 uL, 1.50 eq) at 0 °C. The reaction mixture was stirred at 20 °C for 1 h. The reaction mixture was concentrated under reduced pressure to afford cyclopropyl(methyl)carbamic chloride (75.0 mg, 561 umol, 99% yield) as yellow oil.Step 5. Procedure for l-((3-chlorophenyl)(methyl)carbamoyl)azetidin-3-yl (l-(4-(2,6-dioxopiperidin-3-yl)- 3,5-difluorophenyl)azetidin-3-yl)carbamate.

[0161] To a solution of azetidin-3-yl (l-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)azetidin-3- yl)carbamate (102 mg, 201 umol, 1.00 eq, trifluoroacetic acid) in dichloromethane (3.00 mL) was added 7VJV- diisopropylethylamine (77.8 mg, 602 umol, 105 uL, 3.00 eq) and (3-chlorophenyl)(methyl)carbamic chloride (49. 1 mg, 241 umol, 1.20 eq). The 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 prep-HYLC (column: Phenomenex luna C18 150*25mm* 10um;mobile phase: [water(formid acid)- acetonitrile]; B%: 32%-62%, lOmin) and lyophilized to afford l-((3-chlorophenyl)(methyl)carbamoyl)azetidin-3-yl (l-(4-(2,6-dioxopiperidin-3-yl)-3,5- difluorophenyl)azetidin-3-yl)carbamate (27.53 mg, 51.6 umol, 25.7% yield) as an off-white solid.

[0162] 1H NMR (400 MHz, DMSO-d6 ) δ = 10.85 (s, 1H), 8.06 (br d, J= 7.3 Hz, 1H), 7.45 - 7.36 (m, 2H), 7.26 (br dd, J= 8.3, 15.8 Hz, 2H), 6.13 (br d, J= 11.1 Hz, 2H), 4.89 - 4.82 (m, 1H), 4.43 - 4.31 (m, 1H), 4. 11 - 4.01 (m, 3H), 3.87 - 3.79 (m, 2H), 3.60 (br t, J= 6.7 Hz, 2H), 3.43 (br dd, J = 3.3, 9.3 Hz, 2H), 3. 14 (s, 3H), 2.82 - 2.72 (m, 1H), 2.56 - 2.53 (m, 1H), 2.10 - 2.01 (m, 1H), 1.98 - 1.89 (m, 1H). MS (ESI) m / z 562.4 [M+H]+Compounds 9, 10, 13, 17, 30, 31 32, 33, 36, 40, 43, 70, 71, 72, 73, 109, 110, 113, 116, 118, 119, 138 were synthesized in analogy to Compound 8:Synthesis of Compound 11Compound 11Step 1. Procedure for preparation of Compound 2 - tert-butyl 3-((phenoxycarbonyl)amino)-3- ( trifluoromethyl)azetidine-l -carboxylate.

[0163] To a solution of tert-butyl 3-amino-3-(trifluoromethyl)azetidine-l-carboxylate (500 mg, 2.08 mmol, 1.00 eq) in acetonitrile (3.00 mL) were added pyridine (494 mg, 6.24 mmol, 504 uL, 3.00 eq) and phenyl carbonochloridate (391 mg, 2.50 mmol, 313 uL, 1.20 eq) at 0 °C. The reaction mixture was stirred at 25 °C for 2 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was triturated with petroleum ether (20.0 mL) at 25 °C for 30 min to afford tert-butyl 3-((phenoxycarbonyl)amino)- 3 -(trifluoromethyl)azetidine- 1 -carboxylate (600 mg, crude) as a white solid.Step 2. Procedure for preparation of Compound 3 - tert-butyl 3-((((l-(cyclopropyl(methyl)carbamoyl)azetidin-3-yl)oxy)carbonyl)amino)-3-(trifluoromethyl)azetidine-l- carboxylate.

[0164] To a solution of tert-butyl 3-(phenoxycarbonylamino)-3-(trifluoromethyl)azetidine-l- carboxylate (500 mg, 1.39 mmol, 1.00 eq) in A'A'-dimcthylfonnamidc (5.00 mL) were added A'-cyclopropyl- 3 -hydroxy -JV-methylazetidine-1 -carboxamide (283 mg, 1.67 mmol, 1.20 eq) and sodium hydride (111 mg, 2.78 mmol, 60% purity, 2.00 eq) at 0 °C. The reaction was stirred at 25 °C for 1 h. The reaction mixture was quenched with saturated ammonium chloride (5 mL) and extracted with ethyl acetate (2 x 5 mL). The combined organic layers were washed with brine (10.00 mL), dried over anhydrous sodium sulfate and concentrated under reduce pressure to give a residue. The residue was purified by reverse phase HPLC (Cl 8, 40 g, condition: water / acetonitrile= 7 / 3 to 1 / 1, 0.1% formic) and lyophilized to afford tert-butyl 3-((((l- (cyclopropyl(methyl)carbamoyl)azetidin-3-yl)oxy)carbonyl)amino)-3-(trifluoromethyl)azetidine-l- carboxylate (277 mg, 635 umol, 46% yield) as a white solid.Step 3. Procedure for preparation of Compound 4 - l-(cyclopropyl(methyl)carbamoyl)azetidin-3-yl (3- (trifluoromethyl)azetidin-3-yl)carbamate.

[0165] To a solution of tert-butyl 3 -((((1 -(cyclopropyl (methyl)carbamoyl)azetidin-3- yl)oxy)carbonyl)amino)-3-(trifluoromethyl)azetidine-l-carboxylate (277 mg, 635 umol, 1.00 eq) in dichloromethane (3.00 mL) were added trifluoroacetic acid (924 mg, 8.10 mmol, 0.600 mL, 12.8 eq). The reaction mixture was stirred at 25 °C for 1 h. The reaction mixture was concentrated under reduced pressure to afford l-(cyclopropyl(methyl)carbamoyl)azetidin-3-yl (3-(trifluoromethyl)azetidin-3-yl)carbamate (213 mg, crude) as yellow oil, which was used to next step directly. MS (ESI) m / z.337. 1 [M+H]+Step 4. Procedure for preparation of l-(cyclopropyl(methyl)carbamoyl)azetidin-3-yl (l-(4-(2,6- dioxopiperidin-3-yl)-3,5-difluorophenyl)-3-(trifluoromethyl)azetidin-3-yl)carbamate.

[0166] To a solution of l-(cyclopropyl(methyl)carbamoyl)azetidin-3-yl (3-(trifluoromethyl)azetidin- 3-yl)carbamate (213 mg, 633 umol, 1.00 eq) in dioxane (5.00 mL) was added 3-(4-bromo-2,6-difluoro- phenyl)piperidine-2, 6-dione (289 mg, 950 umol, 1.50 eq), cesium carbonate (619 mg, 1.90 mmol, 3.00 eq) and [ 1 ,3 -bis [2,6-bis( 1 -propylbutyl)phenyl]-4,5-dichloro-imidazol-2-ylidene]-dichloro-(3-chloropyridin- 1 -ium- 1 - yl)palladium (61.6 mg, 63.3 umol, 0. 100 eg). The reaction mixture was stirred at 100 °C for 12 h under nitrogen atmosphere. The reaction mixture was filtered and the filtrate 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) and concentrated under reduced pressure to give a yellow solid. The yellow solid was purified by Prep- HPLC (column: Phenomenex C18 150*25mm* 10um; mobile phase: [water (ammonium bicarbonate) - acetonitrile]; B%: 48%-78%, 8 min) and lyophilized to afford a crude product. The crude product was triturated with acetonitrile (10.0 ml) at 25 °C for 1 h to afford l-(cyclopropyl(methyl)carbamoyl)azetidin-3-yl (l-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)-3-(trifluoromethyl)azetidin-3-yl)carbamate (33.53 mg, 59.33 umol, 9.37% yield, 99% purity) as a white solid.

[0167] 1H NMR (400 MHz, DMSO-O b = 10.87 (s, 1H), 8.77 (br s, 1H), 6.31 (d, J= 10.9 Hz, 2H), 5. 12 - 4.89 (m, 1H), 4.25 - 4. 15 (m, 4H), 4.05 (br d, J= 8.6 Hz, 3H), 3.85 (dd, J= 3.9, 9.9 Hz, 2H), 2.82 - 2.76 (m, 1H), 2.72 (s, 3H), 2.58 - 2.53 (m, 2H), 2.10 - 2.03 (m, 1H), 1.98 - 1.90 (m, 1H), 0.75 - 0.68 (m, 2H), 0.64 - 0.57 (m, 2H). MS (ESI) m / z.559.9 [M+H]+Synthesis of Compound 12Step 1. Procedure for preparation of Compound 2 - phenyl (l-(4-(2,6-dioxopiperidin-3-yl)-3,5- difluorophenyl)-3-methylazetidin-3-yl)carbamate.

[0168] To a solution of 3-(4-(3-amino-3-methylazetidin-l-yl)-2,6-difluorophenyl)piperidine-2,6- dione (400 mg, 1.29 mmol, 1.00 eq) in acetonitrile (2.00 mL) was added 4-dimethylaminopyridine (15.8 mg, 129 nmol, 0.100 eq) and triethylamine (393 mg, 3.88 mmol, 540 uL, 3.00 eq) and phenyl carbonochloridate (243 mg, 1.55 mmol, 194 uL, 1.20 eq). The mixture was stirred at 20 °C for 4 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by reverse phase chromatography (C18, 40 g; condition: water / acetonitrile = 100:0 to 0: 100, 0. 1% formic acid) to afford phenyl (l-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)-3-methylazetidin-3-yl)carbamate (62.0 mg, 144 umol, 11% yield) as a white solid.Step 2. Procedure for preparation of l-(cyclopropyl(methyl)carbamoyl)azetidin-3-yl(l-(4-(2,6- dioxopiperidin-3-yl)-3,5-difluorophenyl)-3-methylazetidin-3-yl)carbamate.

[0169] To a solution of JV-cyclopropyl-3 -hydroxy -A'-mcthylazctidinc- l -carboxamide (28.5 mg, 168. umol, 1.20 eq) in dimethylformamide (1.00 mL) was added sodium hydride (67.1 mg, 279 umol, 60% purity, 2.00 eq) at 0 °C . The mixture was stirred at 25 °C for 0.5 h. To a reasult solution was added phenyl (l-(4- (2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)-3-methylazetidin-3-yl)carbamate (60.0 mg, 140 umol, 1 eq) . The mixture was stirred at 25 °C for 1 h. The reaction mixture was quench with water (1.00 mL) and concentrated under reduce pressure to give a residue. The residue was purified by / Vc / i-HPLC (Phenomenex luna C18 150*25mm* 10um;mobile phase: [water(formic acid)- acetonitrile]; B%: 25%-55%, lOmin) and lyophilized to afford l-(cyclopropyl(methyl)carbamoyl)azetidin-3-yl (l-(4-(2,6-dioxopiperidin-3-yl)-3,5- difluorophenyl)-3-methylazetidin-3-yl)carbamate (13.65 mg, 24.50 umol, 17.54% yield, 96% purity, formic acid) as a white solid.

[0170] 1H NMR (400 MHz, DMSO-d6 ) δ = 10.85 (s, 1H), 8.52 - 8.43 (m, 1H), 8.17 - 7.81 (m, 1H), 6.14 (d, J = 11.1 Hz, 2H), 5.16 - 4.85 (m, 1H), 4.22 (dd, J = 6.8, 9.6 Hz, 2H), 4.03 (br dd, J = 4.9, 12.2 Hz, 1H), 3.88 (br d, J= 7.5 Hz, 2H), 3.81 (dd, J= 3.9, 9.6 Hz, 2H), 3.71 (br d, J= 7.4 Hz, 2H), 2.83 - 2.74 (m, 1H), 2.72 (s, 3H), 2.60 - 2.55 (m, 1H), 2.55 - 2.53 (m, 1H), 2.13 - 2.01 (m, 1H), 1.97 - 1.85 (m, 1H), 1.50 (s, 3H), 0.78 - 0.66 (m, 2H), 0.65 - 0.55 (m, 2H). MS (ESI) m / z.506.3 [M+H]+Synthesis of Compound 14Compound 14Step 1. Procedure for preparation of l-(dimethylcarbamoyl)azetidin-3-yl (l-(4-(2,6-dioxopiperidin-3-yl)-3,5- difluorophenyl)-3-methylazetidin-3-yl)carbamate.

[0171] To a solution of 3-hydro xy -A'. A'-dimcthylazctidinc- 1 -carboxamide (53.0 mg, 368 umol, 1.00 eq) in tetrahydrofuran (1.00 mL) was added di( 1 / 7-imidazol- l-yl)methanone (71.5 mg, 441 umol, 1.20 eq). The mixture was stirred at 25 °C for 1 h. The resulting solution was added to a solution of 3-(4-(3-amino-3- methylazetidin-l-yl)-2,6-difluorophenyl)piperidine-2, 6-dione (148 mg, 366 umol, 1.00 eq, mesylate), triethylamine (56.0 mg, 549 umol, 76.5 uL, 1.50 eq) and 2,3,4,6,7,8,9,10-octahydropyrimido[l,2-a]azepine (83.6 mg, 549 umol, 82.8 uL, 1.50 eq) in tetrahydrofuran (1.00 mL) and dimethylformamide (1.00 mL). The reaction 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 reverse phase chromatography (Cl 8, 40 g; condition: water / acetonitrile = 100:0 to 0: 100, 0.1% formic acid) to afford l-(dimethylcarbamoyl)azetidin-3-yl (l-(4-(2,6- dioxopiperidin-3-yl)-3,5-difluorophenyl)-3-methylazetidin-3-yl)carbamate (6.13 mg, 11.76 umol, 3 % yield, 92% purity) as an off-white solid.

[0172] 1H NMR (400MHz, DMSO-d6 ) δ = 10.85 (s, 1H), 8.41 - 8.36 (m, 1H), 8.04 - 7.96 (m, 1H), 6.19 - 6.10 (m, 2H), 5.04 - 4.92 (m, 1H), 4.20 - 4.10 (m, 2H), 4.06 - 4.00 (m, 1H), 3.88 (br d, J= 7.5 Hz, 2H), 3.78 - 3.69 (m, 4H), 2.85 - 2.77 (m, 1H), 2.74 (s, 6H), 2.59 - 2.56 (m, 1H), 2.09 - 2.05 (m, 1H), 1.96 - 1.91 (m, 1H), 1.50 (s, 3H). MS (ESI) m / z.480.4 [M+H]+Synthesis of Compound 15Step 1. Procedure for preparation of Compound 10- cyclopropyl(methyl)carbamic chloride.

[0173] To a solution of A'-mcthylcyclopropanaminc (3.00 g, 42.2 mmol, 1.00 eq) in dichloromethane (20.0 mL) were added bis(trichloromethyl) carbonate (20.0 g, 67.6 mmol, 1.60 eq) and N,N- diisopropylethylamine (10.9 g, 84.4 mmol, 14.7 mL, 2.00 eq) at 0 °C. The mixture was stirred at 25 °C for 1 h. The reaction mixture was concentrated under reduced pressure to afford cyclopropyl(methyl)carbamic chloride (5.00 g, crude) as a brown solid.Step 2. Procedure for preparation of Compound 8A - N-cyclopropyl-3-hydroxy-N-methylazetidine-l- carboxamide.

[0174] To a solution of azetidin-3-ol (4.51 g, 41.1 mmol, 1.10 eq, hydrochloride) in dichloromethane (50.0 mL) were added A'.A'-diisopropylcthylaminc (9.68 g, 74.8 mmol, 13.0 mL, 2.00 eq), potassium carbonate (5.17 g, 37.4 mmol, 1.00 eq) at 0 °C, then cyclopropyl(methyl)carbamic chloride (5.00 g, 37.4 mmol, 1.00 eq) was added into the mixture. The mixture was stirred at 25 °C for 2 h. The mixture was filtered and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by reverse phase chromatography (C18, 40 g; condition: water / acetonitrile = 100:0 to 0: 100, 0. 1% formic acid) and lyophilized to afford A''-cyclopropyl-3-hydroxy-A''-mcthylazctidinc- 1 -carboxamide (1.00 g, 5.88 mmol, 16% yield) as yellow oil.Step 3. Procedure for preparation of Compound 2 - (4-bromo-2-fluoro-6-methylphenyl)methanol.

[0175] To a solution of 4-bromo-2-fluoro-6-methylbenzoic acid (2.00 g, 8.58 mmol, 1.00 eq) in tetrahydrofuran (20.0 mL) was added borane dimethyl sulfide complex (10.0 M, 1.72 mL, 2.00 eq) at 0 °C. The mixture was stirred at 25 °C for 3 h. The reaction mixture was quenched by addition methanol (20 mL) at 0 °C and concentrated under reduced pressure to afford (4-bromo-2-fluoro-6-methylphenyl)methanol (1.81 g, 8.26 mmol, 96% yield) as a white solid.Step 4. Procedure for preparation of Compound 3 - 5-bromo-2-(chloromethyl)-l-fluoro-3-methylbenzene.

[0176] To a solution of (4-bromo-2-fluoro-6-methylphenyl)methanol (1.80 g, 8.22 mmol, 1.00 eq) in dichloromethane (20.0 mL) was added sulfurous dichloride (1.96 g, 16.4 mmol, 1.19 mL, 2.00 eq) at 0 °C. The mixture was stirred at 25 °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=80 / l) to afford 5-bromo-2-(chloromethyl)-l-fluoro-3-methylbenzene (1.53 g, 6.45 mmol, 78% yield) as light yellow oil.Step 5. Procedure for preparation of Compound 4 - 2-(4-bromo-2fluoro-6-methylphenyl)acetonitrile.13

[0177] To a solution of 5-bromo-2-(chloromethyl)-l-fluoro-3-methylbenzene (1.53 g, 6.45 mmol,I.00 eq) in acetonitrile (15.0 mL) were added tetrabutylammonium fluoride (1.00 M, 19.3 mL, 3.00 eq) and trimethylsilanecarbonitrile (1.92 g, 19.3 mmol, 2.42 mL, 3.00 eq) at 0 °C. The mixture was stirred at 80 °C for 3 h. The reaction mixture was purified by column chromatography (SiCL, petroleum ether / ethyl acetate=80 / l) to afford 2-(4-bromo-2-fluoro-6-methylphenyl) acetonitrile (1.50 g, crude) as colorless oil.Step 6. Procedure for preparation of Compound 5 - methyl 4-(4-bromo-2fluoro-6-methylphenyl)-4- cyanobutanoate.

[0178] To a solution of 2-(4-bromo-2-fluoro-6-methylphenyl) acetonitrile (1.20 g, 5.26 mmol, 1.00 eq) in tetrahydrofuran (10.0 mL) were added sodium methoxide (56.8 mg, 1.05 mmol, 0.200 eq) and methyl acrylate (498 mg, 5.79 mmol, 521 uL, 1.10 eq) at 0 °C. The mixture was stirred at 25 °C for 1 h. The mixture was quenched with saturated ammonium chloride aqueous solution (10 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiCL, petroleum ether / ethyl acetate=10 / l to 1 / 1) to afford methyl 4-(4-bromo-2-fluoro-6-methylphenyl)-4-cyanobutanoate (1.30 g, 4.15 mmol, 87% yield) as colorless oil.Step 7. Procedure for preparation of Compound 6 - 3-(4-bromo-2fluoro-6-methylphenyl)piperidine-2,6- dione.

[0179] To a solution of methyl 4-(4-bromo-2-fluoro-6-methylphenyl)-4-cyanobutanoate (1.30 g, 4.15 mmol, 1.00 eq) in acetic acid (10 mL) was added sulfuric acid (1.84 g, 18.7 mmol, 1.00 mL, 4.52 eq). The mixture was stirred at 90 °C for 2 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was triturated with water and filtered. The filter cake was washed with petroleum ether and concentrated under reduced pressure to afford 3-(4-bromo-2-fluoro-6-methylphenyl)piperidine-2, 6-dione (1.06 g, 3.55 mmol, 85% yield) as a white solid.

[0180] 1H NMR (400 MHz, DMSO-<A) 8 =10.90 (s, 1H), 7.45 - 7.27 (m, 2H), 4.13 (br dd, J = 5.2,I I.9 Hz, 1H), 2.88 - 2.71 (m, 1H), 2.54 (br d, J= 3.1 Hz, 1H), 2.33 (s, 3H), 2.13 - 1.93 (m, 2H).Step 8. Procedure for preparation of Compound 7 - tert-butyl (l-(4-(2,6-dioxopiperidin-3-yl)-3-fluoro-5- methylphenyl)azetidin-3-yl)carbamate.

[0181] A mixture of tert-butyl azetidin-3-ylcarbamate (275 mg, 1.60 mmol, 1.20 eq), 3-(4-bromo-2- fluoro-6-methylphenyl)piperidine-2, 6-dione (400 mg, 1.33 mmol, 1.00 eq), [l,3-bis[2,6-bis(l- propylbutyl)phenyl]-4,5-dichloro-imidazol-2-ylidene]-dichloro-(3-chloropyridin-l-ium-l-yl)palladium (129mg, 133 umol, 0.100 eq), cesium carbonate (1.30 g, 4.00 mmol, 3.00 eq) in dioxane (10.0 mL) was degassed and purged with nitrogen for 3 times. 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 reverse phase chromatography (C18, 40 g; condition: water / acetonitrile = 100:0 to 0: 100, 0.1% formic acid) and lyophilized to afford tert-butyl (l-(4-(2,6-dioxopiperidin-3-yl)-3-fluoro-5-methylphenyl)azetidin-3- yl)carbamate (251 mg, 641 umol, 48% yield) as a white solid.

[0182] 1H NMR (400 MHz, DMSO-d6 ) δ = 10.76 (s, 1H), 7.53 (br d, J= 7.4 Hz, 1H), 6.17 - 6.01 (m,2H), 4.45 - 4.33 (m, 1H), 4.10 - 4.02 (m, 2H), 3.99 - 3.89 (m, 1H), 3.54 (br t, J= 6.8 Hz, 2H), 2.81 - 2.71 (m, 1H), 2.59 - 2.53 (m, 1H), 2.22 (s, 3H), 2.09 - 2.00 (m, 1H), 1.95 - 1.87 (m, 1H), 1.42 - 1.37 (m, 9H).Step 9. Procedure for preparation of Compound 8 - 3-(4-(3-aminoazetidin-l-yl)-2fluoro-6- methylphenyl)piperidine-2, 6-dione.

[0183] To a solution of tert-butyl (l-(4-(2,6-dioxopiperidin-3-yl)-3-fluoro-5-methylphenyl)azetidin- 3-yl)carbamate (130 mg, 332 umol, 1.00 eq) in dichloromethane (2.50 mL) was added trifluoroacetic acid (1.25 g, 10.9 mmol, 812 uL, 33.0 eq). The mixture was stirred at 25 °C for 2 h. The reaction mixture was concentrated under reduced pressure to afford 3-(4-(3-aminoazetidin-l-yl)-2-fluoro-6- methylphenyl)piperidine-2, 6-dione (90.0 mg, crude) as a white solid. MS (ESI) m / z 292.2 [M+H]+Step 10. Procedure for preparation of l-(cyclopropyl(methyl)carbamoyl)azetidin-3-yl (l-(4-(2,6- dioxopiperidin-3-yl)-3fluoro-5-methylphenyl)azetidin-3-yl)carbamate.

[0184] To a solution of A''-cyclopropyl-3-hydroxy-A''-mcthylazctidinc- 1 -carboxamide (100 mg, 587 umol, 1.00 eq) in tetrahydrofuran (5.00 mL) was added di(lH-imidazol-l-yl)methanone (100 mg, 616 umol, 1.05 eq) at 25 °C. The mixture was stirred at 25 °C for 12 h. The resulting solution was added to a mixture of 3 -(4-(3-aminoazetidin-l-yl)-2-fluoro-6-methylphenyl)piperidine-2, 6-dione (89.0 mg, 305 umol, 1.00 eq), triethylamine (30.9 mg, 305 umol, 42.5 uL, 1.00 eq) and 2,3,4,6,7,8,9,10-octahydropyrimido[l,2-a]azepine (46.5 mg, 305 umol, 46.0 uL, 1.00 eq) in dimethylformamide (5.00 mL). The mixture was stirred at 25 °C for 12 h. The mixture was concentrated under reduced pressure to give a residue. The residue was purified by reverse phase chromatography (C18, 40 g; condition: water / acetonitrile = 100:0 to 0: 100, 0.1% formic acid) and lyophilized to afford l-(cyclopropyl(methyl)carbamoyl)azetidin-3-yl (l-(4-(2,6-dioxopiperidin-3-yl)-3- fluoro-5-methylphenyl)azetidin-3-yl)carbamate (24.67 mg, 47.5 umol, 16% yield, 94% purity) as a white solid.

[0185] ’H NMR (400 MHz, DMSO-d6 ) δ = 10.92 - 10.64 (m, 1H), 8.08 (br d, J= 7.4 Hz, 1H), 6.21 -5.97 (m, 2H), 5.01 (br s, 1H), 4.41 (br d, J= 6.9 Hz, 1H), 4.22 (dd, J= 6.8, 9.6 Hz, 2H), 4.11 - 4.03 (m, 2H),3.97 - 3.89 (m, 1H), 3.81 (br dd, J= 3.9, 9.8 Hz, 2H), 3.58 (br t, J= 6.7 Hz, 2H), 2.80 - 2.74 (m, 1H), 2.72 (s,3H), 2.58 (br d, J = 3.9 Hz, 2H), 2.21 (s, 3H), 2.01 (dt, J= 10.0, 12.4 Hz, 1H), 1.90 (br dd, J= 4.4, 6.4 Hz, 1H), 0.72 (br d, J= 5.0 Hz, 2H), 0.66 - 0.56 (m, 2H). MS (ESI) m / z 488.4 [M+H]+Synthesis of Compounds 16, 18, 19, 25, 2716-1 16-216-3Step 1. Procedure for preparation of Compound 2 - cyclopropyl(methyl)carbamic chloride.

[0186] To a solution of A'-mcthylcyclopropanaminc (400 mg, 5.62 mmol, 1.00 eq) in dichloromethane(10.0 mL) were added bis(trichloromethyl) carbonate (2.67 g, 9.00 mmol, 1.60 eq) and Nfl- diisopropylethylamine (1.45 g, 11.25 mmol, 1.96 mL, 2 eq) at 25 °C. The mixture was stirred at 25 °C for 1 h. The mixture was concentrated under reduced pressure to afford cyclopropyl(methyl)carbamic chloride (750 mg, 5.61 mmol, 99% yield) as a red brown solid.Step 2. Procedure for preparation of Compound 3 - (S)-N-cyclopropyl-3-hydroxy-N-methylpyrrolidine-l- carboxamide.

[0187] To a solution of (S)-pyrrolidin-3-ol 1 (300 mg, 3.44 mmol, 278 uL, 1.00 eq) in dichloromethane (9.00 mL) were added A'.A''-diisopropylcthylaminc (890 mg, 6.89 mmol, 1.20 mL, 2.00 eq) and cyclopropyl(methyl)carbamic chloride (736 mg, 5.51 mmol, 1.60 eq) at 0 °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 purified by reverse phase chromatography (C18, 40 g; condition: water / acetonitrile = 100:0 to 0: 100, 0.1% formic acid) to afford (.S')-A''-cyclopropyl-3-hydroxy-A''-mcthylpyrrolidinc- 1 -carboxamide (200 mg, 1.09 mmol, 32% yield) as colorless oil.Step 3. Procedure for preparation of (S)-l-(cyclopropyl(methyl)carbamoyl)pyrrolidin-3-yl (l-(4-(2,6- dioxopiperidin-3-yl)-3,5-difluorophenyl)azetidin-3-yl)carbamate.

[0188] To a solution of CS')-A''-cyclopropyl-3-hydroxy-A''-mcthylpyrrolidinc- 1 -carboxamide (120 mg, 651umol, 1.00 eq) in tetrahydrofuran (5.00 mL) was added di(lH-imidazol-l-yl)methanone (127 mg, 782 umol, 1.20 eq). The mixture was stirred at 25 °C for 1 h. The resulting solution was added to a solution of 3-(4-(3- aminoazetidin-l-yl)-2,6-difluorophenyl)piperidine-2, 6-dione (150 mg, 383 umol, 1.00 eq, mesylate), triethylamine (38.8 mg, 383 umol, 53.3 uL, 1.00 eq) and 2,3,4,6,7,8,9,10-octahydropyrimido[l,2-a]azepine (58.3 mg, 383 umol, 57.8 uL, 1.00 eq) in dimethylformamide (1.00 mL). 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 reverse phase chromatography (C18, 40 g; condition: water / acetonitrile = 100:0 to 0: 100, 0.1% formic acid condition) to afford to (S)-l-(cyclopropyl(methyl)carbamoyl)pyrrolidin-3-yl (l-(4-(2,6-dioxopiperidin-3-yl)-3,5- difluorophenyl)azetidin-3-yl)carbamate (35.54 mg, 68.90 umol, 18% yield, 98% purity) as a white solid.

[0189] 1H NMR (400 MHz, DMSO-d6 ) δ = 10.85 (s, 1H), 7.95 (br d, J= 7.3 Hz, 1H), 6. 13 (d, J= 11.0 Hz, 2H), 5.08 (br s, 1H), 4.47 - 4.38 (m, 1H), 4.08 (br t, J= 7.6 Hz, 2H), 4.05 - 3.98 (m, 1H), 3.67 - 3.60 (m, 3H), 3.47 - 3.38 (m, 2H), 3.29 (br s, 1H), 2.84 - 2.75 (m, 1H), 2.70 (s, 3H), 2.61 (td, J= 3.2, 6.8 Hz, 1H), 2.18 - 1.74 (m, 5H), 0.75 - 0.68 (m, 1H), 0.67 - 0.60 (m, 1H), 0.56 - 0.50 (m, 2H). MS (ESI) m / z 506.1 [M+H]+

[0190] Compounds 18, 19, 25, 27 were synthesized in analogy to Compound 8:Synthesis of Compounds 20, 21, 22, 26Step 1. Procedure for preparation of Compound 2 - 4-(3-hydroxyazetidine-l-carbonyl)benzonitrile.

[0191] To a solution of 4-cyanobenzoic acid (100 mg, 679 umol, 1.00 eq) and azetidin-3-ol (89.3 mg, 815 umol, 1.20 eq, hydrochloride) in dimethylformamide (5.00 mL) was added I / / -bcnzo| c / | 1 1,2,3 ]triazol-l-ol (64.2 mg, 475 umol, 0.700 eq), A'.A'-diisopropylcthylaminc (87.8 mg, 679 umol, 118 uL, 1.00 eq) and l-(3- dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (143 mg, 747 umol, 1.10 eq). The reaction was stirred at 25 °C for 12 h. The reaction was diluted with water (100 mL) and extracted with ethyl acetate (3 x 100 mL). The combined organic layers were washed with brine (100 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=l / l to 0 / 1) to afford 4-(3 -hydroxy azetidine- 1- carbonyl)benzonitrile (110 mg, 543 umol, 80% yield) as a white solid.Step 2. Procedure for preparation of l-(4-cyanobenzoyl)azetidin-3-yl (l-(4-(2,6-dioxopiperidin-3-yl)-3,5- difluorophenyl)azetidin-3-yl)carbamate.

[0192] To a solution of 4-(3-hydroxy azetidine- l-carbonyl)benzonitrile (110 mg, 543.99 umol, 1.00 eq) in tetrahydrofuran (2.00 mL) was added di( 1 / 7-imidazol- l-yl)methanone (88.21 mg, 543.99 umol, 1.00 eq). The mixture was stirred at 25 °C for 1 h. The resulting solution was added to a solution 3-(4-(3-aminoazetidin- l-yl)-2,6-difluorophenyl)piperidine-2, 6-dione (157 mg, 401 umol, 7.43e leq, mesylate), 2,3,4,6,7,8,9,10- octahydropyrimido[l,2-a]azepine (82.2 mg, 540 umol, 81.4 uL, 1.00 eq) and A'.A'-diisopropylcthylaminc (69.7 mg, 540 umol, 94.0 uL, 1.00 eq) in dimethylformamide (1.00 mL). The reaction 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 / Vc / i-HPLC (column: Phenomenex luna C18 150*25mm* 10um; mobile phase: [water (formic acid)- acetonitrile];B%: 26%-56%, 58 min) to afford l-(4-cyanobenzoyl)azetidin-3-yl (l-(4-(2,6-dioxopiperidin-3- yl)-3,5-difluorophenyl)azetidin-3-yl)carbamate (40.57 mg, 75.95 umol, 14% yield, 98% purity) as a white solid.

[0193] 1H NMR (400 MHz, DMSO-d6 ) δ = 10.86 (s, 1H), 8.16 (br d, J= 7.2 Hz, 1H), 7.94 (d, J= 8.0 Hz, 2H), 7.81 (d, .7 = 8.0 Hz. 2H), 6.16 (br d, J= 11.2 Hz, 2H), 5.15 - 5.07 (m, 1H), 4.59 - 4.53 (m, 1H), 4.45 - 4.35 (m, 2H), 4.26 (br d, J= 8.4 Hz, 1H), 4. 10 (br t, J= 7.6 Hz, 2H), 4.06 - 4.01 (m, 1H), 3.97 (br d, J= 10.0 Hz, 1H), 3.66 (br t, J= 6.8 Hz, 2H), 2.76 (br dd, J = 5.2, 12.9 Hz, 1H), 2.48 (br s, 1H), 2.08 (br dd, J = 3.6, 12.9 Hz, 1H), 1.98 - 1.89 (m, 1H). MS (ESI) m / z 524.1 [M+H]+

[0194] Compounds 21, 22, 26 were synthesized in analogy to Compound 20:Synthesis of Compound 23Compound 23Step 1. Procedure for preparation of Compound 2 - (3-hydroxyazetidin-l-yl)(p-tolyl)methanone.

[0195] To a solution of 4-methylbenzoic acid (500 mg, 3.67 mmol, 1.00 eq) in dimethylformamide (5.00 mL) were added 2-(3H-[ l,2,3]triazolo[4,5-A]pyridin-3-yl)-l,l,3,3-tetramethyluronium hexafluorophosphate(V) (1.68 g, 4.41 mmol, 1.20 eq), ACA'-diisopropylcthylaminc (1.42 g, 11.0 mmol, 1.92 mL, 3.00 eq) and azetidin-3-ol (322 mg, 4.41 mmol, 1.20 eq, hydrochloride). The mixture was stirred at 25 °C for 12 h. The reaction was filtered. The filtrate was purified by reverse phase chromatography (Cl 8, 40 g; condition: water / acetonitrile = 100:0 to 0: 100, 0. 1% formic acid) and lyophilized to afford (3 -hydroxy azetidin- l-yl)( / ?-tolyl)methanone (350 mg, 1.76 mmol, 48% yield, 96% purity) as a yellow soild.Step 2. Procedure for preparation of l-(4-methylbenzoyl)azetidin-3-yl (l-(4-(2,6-dioxopiperidin-3-yl)-3,5- difluorophenyl)azetidin-3-yl)carbamate.

[0196] To a solution of (3-hydroxyazetidin-l-yl)( / ?-tolyl)methanone (100 mg, 523 umol, 1.00 eq) in tetrahydrofuran (2.00 mL) was added di( 1 / 7-imidazol- l-yl)methanone (84.8 mg, 523 umol, 1.00 eq) at 0 °C, then the mixture was stirred at 20 °C for 1 h. The resulting solution was added to a mixture of 3-(4-(3- aminoazetidin-l-yl)-2,6-difluorophenyl)piperidine-2, 6-dione (154 mg, 522 umol, 1.00 eq, mesylate), 2,3,4,6,7,8,9,10-octahydropyrimido[l,2-a]azepine (79.5 mg, 522 umol, 78.7 uL, 1.00 eq) and N,N- diisopropylethylamine (67.5 mg, 522 umol, 91.0 uL, 1.00 eq) in dimethylformamide (2.00 mL). The mixturewas stirred at 20 °C for 12 h. The reaction was filtered. The filtrate was purified by / Vc / i-HPLC (column: Phenomenex luna C18 150*25mm* 10um; mobile phase: [water (formic acid) -acetonitrile]; B%: 30%-60%, 10 min) and lyophilized to afford l-(4-methylbenzoyl)azetidin-3-yl (l-(4-(2,6-dioxopiperidin-3-yl)-3,5- difluorophenyl)azetidin-3-yl)carbamate (45.25 mg, 88.34 umol, 17% yield, 97% purity) as a white soild.

[0197] 1H NMR (400 MHz, DMSO-d6 ) δ = 10.86 (s, 1H), 8.14 (br d, J= 7.4 Hz, 1H), 7.54 (d, J= 8.0 Hz, 2H), 7.26 (d, J = 7.9 Hz, 2H), 6.15 (d, J= 11.0 Hz, 2H), 5.20 - 4.99 (m, 1H), 4.56 (br s, 1H), 4.48 - 4.39 (m, 1H), 4.38 - 4.28 (m, 1H), 4.28 - 4. 15 (m, 1H), 4. 10 (br t, J= 7.6 Hz, 2H), 4.03 (br dd, J= 5.0, 12.6 Hz, 1H), 3.92 (br d, J= 7.4 Hz, 1H), 3.65 (br t, J= 6.6 Hz, 2H), 2.85 - 2.70 (m, 1H), 2.47 (br s, 1H), 2.35 (s, 3H), 2.14 - 2.00 (m, 1H), 1.98 - 1.88 (m, 1H). MS (ESI) m / z 513.1 [M+H]+Synthesis of Compound 24Step 1. Procedure for preparation of Compound 2 - azetidin-3-yl (l-(4-(2,6-dioxopiperidin-3-yl)-3,5- difluorophenyl)azetidin-3-yl)carbamate.

[0198] To a solution of tert-butyl 3-(((l-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)azetidin-3- yl)carbamoyl) oxy)azetidine- 1 -carboxylate (100 mg, 202 umol, 1.00 eq) in dichloromethane (1.00 mL) was added methanesulfonic acid (58.3 mg, 607 umol, 43.2 uL, 3.00 eq) at 0 °C. The mixture was stirred at 0 °C for 0.5 h and then warmed to 20 °C. The reaction mixture was stirred at 20 °C for 3.5 h. The reaction mixture was concentrated under reduced pressure to afford azetidin-3-yl (l-(4-(2,6-dioxopiperidin-3-yl)-3,5- difluorophenyl)azetidin-3-yl)carbamate (99.0 mg, crude, mesylate) as yellow oil. MS (ESI) m / z 395. 1 [M+H]+Step 2. Procedure for preparation of l-benzoylazetidin-3-yl (l-(4-(2,6-dioxopiperidin-3-yl)-3,5- difluorophenyl)azetidin-3-yl)carbamate.

[0199] To a solution of azetidin-3-yl (l-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)azetidin-3- yl)carbamate (99.0 mg, 202 umol, 1.00 eq, mesylate) in dimethylformamide (1.00 mL) were added Nff- diisopropylethylamine (78.3 mg, 606 umol, 106 uL, 3.00 eq) and benzoyl chloride (42.6 mg, 303 umol, 35.2 uL, 1.50 eq). The reaction mixture was stirred at 20 °C for 1 h. The reaction mixture was filtered. The filtrate was purified by reverse phase chromatography (C18, 40 g; condition: water / acetonitrile = 100:0 to 52:48, 0. 1% formic acid) and lyophilized to afford l-benzoylazetidin-3-yl (l-(4-(2,6-dioxopiperidin-3-yl)-3,5- difluorophenyl)azetidin-3-yl)carbamate (33.31 mg, 65.49 umol, 32% yield, 98% purity) as a white solid.

[0200] 1H NMR (400MHz, DMSO-d6 ) δ = 10.85 (s, 1H), 8. 15 (br d, J= 7.3 Hz, 1H), 7.64 (br d, J = 7.0 Hz, 2H), 7.56 - 7.50 (m, 1H), 7.49 - 7.41 (m, 2H), 6.16 (s, 1H), 6.14 (s, 1H), 5.18 - 5.06 (m, 1H), 4.65 - 4.51 (m, 1H), 4.48 - 4.32 (m, 2H), 4.30 - 4.17 (m, 1H), 4.1O (br t, J= 7.5 Hz, 2H), 4.03 (br dd, J= 5.0, 12.8 Hz, 1H), 3.98 - 3.89 (m, 1H), 3.65 (br t, J= 6.6 Hz, 2H), 2.82 - 2.73 (m, 1H), 2.48 - 2.46 (m, 1H), 2.12 - 2.03 (m, 1H), 1.99 - 1.89 (m, 1H). MS (ESI) m / z 499.2 [M+H]+Synthesis of Compound 28Step 1. Procedure for preparation of Compound 2 - 5-bromo-2-(bromomethyl)-l,3-dichlorobenzene.

[0201] A solution of 5-bromo-l,3-dichloro-2-methylbenzene (10.0 g, 41.7 mmol, 1.00 eq) and N- bromosuccinimide (7.42 g, 41.7 mmol, 1.00 eq) in carbon tetrachloride (50.0 mL) was added dibenzoyl peroxide (1.01 g, 4.17 mmol, 0.100 eq) under nitrogen atmosphere. The mixture was stirred 80 °C for 3 h under nitrogen atmosphere. The reaction mixture was cooled to 25 °C. Ethyl acetate (40 mL) and water (40 mL) were added and layers were separated. The aqueous phase was extracted with ethyl acetate (2 x 30 mL). Combined extracts were washed with brine (40 mL), dried over sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiC>2, petroleum ether / ethyl acetate = 1 / 0) to afford 5-bromo-2-(bromomethyl)-l,3-dichlorobenzene (16.7 g, crude) as a white solid.Step 2. Procedure for preparation of Compound 3 - 2-(4-bromo-2,6-dichlorophenyl)acetonitrile.

[0202] To a solution of 5-bromo-2-(bromomethyl)-l,3-dichlorobenzene (12.0 g, 37.6 mmol, 1.00 eq) and tetrabutylammonium fluoride (1.00 M, 113 mL, 3.00 eq) in acetonitrile (70.0 mL) was added 2-bromo-5- (bromomethyl)pyridine (11.2 g, 113 mmol, 14. 1 mL, 3.00 eq). The mixture was stirred 20 °C for 15 min. The reaction mixture was diluted with ethyl acetate (200 mL) and water (200 mL). The mixture was extracted with dichloromethane (3 x 200 mL). The combined organic extracts were washed with brine (200 mL), dried over sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiCL, petroleum ether / ethyl acetate = 100 / 1) to afford 2-(4-bromo- 2,6-dichloro-phenyl)acetonitrile (9.00 g, 34.0 mmol, 90% yield) as a white solid.Step 3. Procedure for preparation of Compound 4 - tert-butyl 4-(4-bromo-2,6-dichlorophenyl)-4- cyanobutanoate.

[0203] To mixture of 2-(4-bromo-2,6-dichlorophenyl)acetonitrile (9.00 g, 34.0 mmol, 1.00 eq) and sodium methylate (184 mg, 3.40 mmol, 0.100 eq) in tetrahydrofuran (40.0 mL) was added tert-butyl acrylate (6.53 g, 51.0 mmol, 7.40 mL, 1.50 eq) at 0 °C. The mixture was stirred at 20 °C for 2 h. The mixture was concentrated under reduced pressure to afford tert-butyl 4-(4-bromo-2,6-dichlorophenyl)-4-cyanobutanoate (12.0 g, crude) as a white solid. MS (ESI) m / z 393.8 [M+H+2]+Step 4. Procedure for preparation of Compound 5 - 3-(4-bromo-2,6-dichlorophenyl)piperidine-2, 6-dione.

[0204] To mixture of tert-butyl 4-(4-bromo-2,6-dichlorophenyl)-4-cyanobutanoate (11.8 g, 30.0 mmol, 1.00 eq) in acetic acid (20.0 mL) was added sulfuric acid (4.00 mL). The mixture was stirred at 90 °C for 2 h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure to give crude product. The crude product was triturated with water (150 mL) at 25 °C for 10 min and the filtered. The filter cake was concentrated under reduced pressure to afford 3-(4-bromo-2,6-dichlorophenyl)piperidine-2,6- dione (9.50 g, 28.2 mmol, 93% yield) as a white solid.

[0205] 1H NMR (400 MHz, DMSO-d6 ) δ = 11.01 (s, 1H), 7.89 - 7.83 (m, 1H), 7.80 (d, J = 2.0 Hz, 1H), 4.60 (dd, J= 5.6, 12.6 Hz, 1H), 2.91 - 2.80 (m, 1H), 2.58 - 2.52 (m, 1H), 2.36 (br dd, J= 4.2, 13.4 Hz, 1H), 1.94 - 1.88 (m, 1H).Step 5. Procedure for preparation of Compound 6 - tert-butyl (l-(3,5-dichloro-4-(2,6-dioxopiperidin-3- yl)phenyl)azetidin-3-yl)carbamate.

[0206] To a solution of 3 -(4-bromo-2,6-dichlorophenyl)piperidine-2, 6-dione (300 mg, 890 umol, 1.00 eq) in dioxane (5.00 mL) were added tert-butyl azetidin-3-ylcarbamate (307 mg, 1.78 mmol, 2.00 eq), sodium tert-butoxide (171 mg, 1.78 mmol, 2.00 eq) was added methanesulfonato[2-(di-tert-butylphosphino)-3,6-dimethoxy-2’,4’,6’-tri-i-propyl-l,r-biphenyl](2’-amino-l,r-biphenyl-2-yl)palladium(II) (76.1 mg, 89.0 umol, 0. 100 eq) under nitrogen atmosphere. The reaction mixture was stirred at 90 °C for 16 h under nitrogen atmosphere. The resulting mixture was filtered over celite and the filtrate was added water (50 ml) and extracted with ethyl acetate (3 x 50 mL). Combined extracts were washed with brine (50 mL), dried over sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to give a residue. The residue was purified by reverse phase chromatography (C18, 80 g; condition: water / acetonitrile = 100:0 to 0: 100, 0. 1% formic acid) and lyophilized to afford tert-butyl (l-(3,5-dichloro-4-(2,6-dioxopiperidin-3-yl)phenyl)azetidin- 3-yl)carbamate (87.0 mg, 201 umol, 22% yield, 99% purity) as a white solid.

[0207] 1H NMR (400 MHz, DMSO-d6 ) δ = 10.87 (s, 1H), 7.56 (br d, J= 7.6 Hz, 1H), 6.50 (dd, J = 2.2, 14.2 Hz, 2H), 4.40 (dd, J= 5.6, 12.6 Hz, 2H), 4.10 (t, J= 7.6 Hz, 2H), 3.62 (t, J= 6.8 Hz, 2H), 2.89 - 2.76 (m, 1H), 2.52 (br s, 1H), 2.30 (dq, J= 4.4, 13.3 Hz, 1H), 1.89 - 1.79 (m, 1H), 1.39 (s, 9H).Step 6. Procedure for preparation of Compound 7 - 3-(4-(3-aminoazetidin-l-yl)-2,6- dichlorophenyl)piperidine-2, 6-dione.

[0208] To mixture of tert-butyl (l-(3,5-dichloro-4-(2,6-dioxopiperidin-3-yl)phenyl)azetidin-3- yl)carbamate (87.0 mg, 203 umol, 1.00 eq) in trifluoroacetic acid (1.00 mL) and dichloromethane (5.00 mL). The mixture was stirred at 25 °C for 2 h. The mixture was concentrated under reduced pressure to afford 3-(4- (3-aminoazetidin-l-yl)-2,6-dichlorophenyl)piperidine-2, 6-dione (55.0 mg, crude) as yellow oil. MS (ESI) m / z 328.1 [M+H]+Step 7. Procedure for preparation of Compound 7 A - spiro[3.3]heptan-2-ylmethyl carbonochloridate.

[0209] To mixture of spiro[3.3]heptan-2-ylmethanol (60.0 mg, 475 umol, 1.00 eq) and bis(trichloromethyl) carbonate (212 mg, 713 umol, 1.50 eq) in dichloromethane (2.00 mL) was added A'.A'- diisopropylethylamine (123 mg, 951umol, 166 uL, 2.00 eq) at 0 °C. The mixture was stirred at 25 °C for 1 h. The mixture was concentrated under reduced pressure to afford spiro[3.3]heptan-2-ylmethyl carbonochloridate (60.0 mg, crude) as yellow oil.Step 8. Procedure for preparation of spiro[3.3]heptan-2-ylmethyl (l-(3,5-dichloro-4-(2,6-dioxopiperidin-3- yl)phenyl)azetidin-3-yl)carbamate.

[0210] To mixture of 3-(4-(3-aminoazetidin-l-yl)-2,6-dichlorophenyl)piperidine-2, 6-dione (55.0 mg, 168 umol, 1.00 eq) in dichloromethane (2.00 mL) was added A'.A'-diisopropylcthylaminc (43.3 mg, 335 umol, 58.4 uL, 2.00 eq) at 0 °C for 15 min. Then was added spiro[3.3]heptan-2-ylmethyl carbonochloridate (34.8 mg, 184 umol, 1. 10 eq). The mixture was stirred at 25 °C for 2 h. The mixture was concentrated under reducedpressure to give a residue. The residue was purified by reverse phase chromatography (Cl 8, 80 g; condition: water / acetonitrile = 100:0 to 0: 100, 0.1% formic acid) and lyophilized to afford spiro[3.3]heptan-2-ylmethyl (l-(3,5-dichloro-4-(2,6-dioxopiperidin-3-yl)phenyl)azetidin-3-yl)carbamate (17.57 mg, 36.2 umol, 21% yield, 99% purity) as a white solid.

[0211] 1H NMR (400 MHz, DMSO-d6 ) δ = 10.87 (s, 1H), 7.82 (br d, J= 7.4 Hz, 1H), 6.54 (d, J= 2.0 Hz, 1H), 6.50 (d, J= 2.0 Hz, 1H), 4.45 - 4.36 (m, 2H), 4.12 (t, J= 7.6 Hz, 2H), 3.90 (d, J= 7.0 Hz, 2H), 3.66 (br t, J= 6.6 Hz, 2H), 2.88 - 2.77 (m, 1H), 2.53 - 2.52 (m, 1H), 2.40 - 2.31 (m, 2H), 2.04 - 1.94 (m, 4H), 1.91 - 1.84 (m, 3H), 1.77 - 1.68 (m, 4H). MS (ESI) m / z 480.3 [M+H]+Synthesis of Compound 29Step 1. Procedure for preparation of Compound 2 - l-(3-methylpyridin-2-yl)azetidin-3-ol.

[0212] To the solution of azetidin-3-ol (985 mg, 9.00 mmol, 2.00 eq, hydrochloride), cesium carbonate (4.40 g, 13.5 mmol, 3.00 eq) in dimethylsulfoxide (10.0 mL) was added 2-fhioro-3-methylpyridine (500 mg, 4.50 mmol, 454 uL, 1.00 eq). Then the reaction was stirred at 100 °C for 12 h. The mixture was diluted with water (20 mL), extracted with ethyl acetate (2 x 10 mL). The combined organic layers were washed with brine (10 mL), and dried over anhydrous sodium sulfate, filtered and concentrate under reduced pressure to give a residue. The residue was purified by column chromatography (SiCL, petroleum ether / ethyl acetate = 5 / 1 to 0 / 1) to afford l-(3-methylpyridin-2-yl)azetidin-3-ol (330 mg, 2.01 mmol, 44% yield) as a yellow solid.Step 2. Procedure for preparation of l-(3-methylpyridin-2-yl)azetidin-3-yl (l-(4-(2,6-dioxopiperidin-3-yl)- 3,5-difluorophenyl)azetidin-3-yl)carbamate.

[0213] To the solution of l-(3-methylpyridin-2-yl)azetidin-3-ol (50 mg, 304 umol, 1.00 eq) in tetrahydrofuran (0.50 mL) was added di( IH-imidazol- l-yl)methanone (59.3 mg, 365 umol, 1.20 eq) at 0 °C. Then the reaction was stirred at 25 °C for 0.5 h. Then to the mixture were added dimethylformamide (0.50 mL), 3-(4-(3-aminoazetidin-l-yl)-2,6-difluorophenyl)piperidine-2, 6-dione (119 mg, 304 umol, 1.00 eq, mesylate), A / A'-diisopropylcthylaminc (59.0 mg, 456 umol, 79.6 uL, 1.50 eq). Then the reaction 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 / 2 to 0 / 1) to afford l-(3- methylpyridin-2-yl)azetidin-3-yl (l-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)azetidin-3-yl)carbamate (68.02 mg, 140. 11 umol, 44% yield, 98% purity) as a white solid.

[0214] 1H NMR (400 MHz, DMSO-d6 ) δ = 10.87 - 10.84 (m, 1H), 8.09 (br d, J = 7.4 Hz, 1H), 7.96 (br d, J= 4.0 Hz, 1H), 7.32 (d, J= 7.0 Hz, 1H), 6.68 (dd, J= 4.9, 7.1 Hz, 1H), 6.15 (d, J= 11.0 Hz, 2H), 5.16 - 5.09 (m, 1H), 4.47 - 4.40 (m, 1H), 4.32 (dd, J= 6.6, 9.3 Hz, 2H), 4. 10 (t, J= 7.7 Hz, 2H), 4.03 (br dd, J= 4.8, 12.8 Hz, 1H), 3.91 (br dd, J= 4.2, 9.3 Hz, 2H), 3.65 (br t, J= 6.7 Hz, 2H), 2.82 - 2.73 (m, 1H), 2.48 (br d, J= 3.0 Hz, 1H), 2.12 (s, 3H), 2.10 - 2.02 (m, 1H), 1.97 - 1.90 (m, 1H). MS (ESI) m / z 486.3 [M+H]+Synthesis of Compound 33Compound 33Step 1. Procedure for preparation of Compound 2 - 1 -azaspiro [3.3]heptane-l -carbonyl chloride.

[0215] To a solution of 1 -azaspiro [3.3]heptane (45.0 mg, 337 umol, 50.8 uL, 1.00 eq, hydrochloride) in dichloromethane (3.00 mL) were added bis(trichloromethyl) carbonate (150 mg, 505 umol, 1.50 eq) and A'.A'-diisopropylcthylaminc (65.3 mg, 505 umol, 88.0 uL, 1.50 eq) at 0 °C. The reaction was stirred at 20 °C for 1 h. The reaction mixture was concentrated under reduced pressure to afford l-azaspiro[3.3]heptane-l- carbonyl chloride (53.0 mg, crude) as yellow oil.Step 2. Procedure for preparation of l-(l-azaspiro[3.3]heptane-l-carbonyl)azetidin-3-yl (l-(4-(2,6- dioxopiperidin-3-yl)-3,5-difluorophenyl)azetidin-3-yl)carbamate.

[0216] To a solution of azetidin-3-yl (l-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)azetidin-3- yl)carbamate (153 mg, 301 umol, 1.00 eq, trifluoroacetate) in dimethylformamide (2.00 mL) were added A'.A'- diisopropylethylamine (77.8 mg, 602 umol, 105 uL, 2.00 eq) and l-azaspiro[3.3]heptane-l-carbonyl chloride ((52.8 mg, 331 umol, 1.10 eq) at 0 °C. The reaction mixture was stirred at 0 °C for 1 h. The reaction mixture was filtered. The filtrate was purified by reverse phase chromatography (Cl 8, 80 g; condition: water / acetonitrile = 100:0 to 0: 100, formic acid) and lyophilized to give a crude product. Then the crude product was purified by / Vc / i-HPLC (column: Waters xbridge 150*25mm* 10um; mobile phase: [water (ammonium bicarbonate) - acetonitrile]; B%: 22%-52%, 8 min), added formic acid (20 pL) and lyophilized to afford 1-(1- azaspiro [3.3]heptane- 1 -carbonyl)azetidin-3-yl ( 1 -(4-(2,6-dioxopiperidin-3-yl)-3 ,5 -difluorophenyl)azetidin-3 - yl)carbamate (8.35 mg, 15.33 umol, 5% yield, 95% purity) as a white solid.

[0217] 1H NMR (400 MHz, DMSO-d6 ) δ= 10.86 (s, 1H), 8.11 (br d, J= 1A Hz, 1H), 6.15 (br d, J = 11.3 Hz, 2H), 5.05 - 4.95 (m, 1H), 4.48 - 4.35 (m, 1H), 4. 15 - 4.07 (m, 4H), 4.03 (br dd, J= 4.9, 12.4 Hz, 1H), 3.79 - 3.68 (m, 4H), 3.64 (br t, J= 6.4 Hz, 2H), 2.82 - 2.64 (m, 4H), 2.24 (br t, J= 7.2 Hz, 2H), 2. 11 - 2.02 (m, 1H), 1.99 - 1.87 (m, 3H), 1.69 - 1.59 (m, 1H), 1.57 - 1.49 (m, 1H). MS (ESI) m / z.518.4 [M+H]+Synthesis of Compound 34Step 1. Procedure for preparation of Compound 2- phenethyl carbonochloridate.

[0218] To a solution of 2-phenylethan-l-ol (400 mg, 3.27 mmol, 392 uL, 1.00 eq) in dichloromethane (2.00 mL) were added bis(trichloromethyl) carbonate (1.46 g, 4.91 mmol, 1.50 eq) and N.N- diisopropylethylamine (1.27 g, 9.82 mmol, 1.71 mL, 3.00 eq) at 0 °C. The mixture was stirred at 25 °C for 1 h. The reaction mixture was filtered and concentrated under reduced pressure to afford phenethyl carbonochloridate (300 mg, crude) as a yellow solid.Step 2. Procedure for preparation of phenethyl (l-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)azetidin-3- yl)carbamate.

[0219] To a solution of 3-(4-(3-aminoazetidin-l-yl)-2,6-difluorophenyl)piperidine-2, 6-dione (100 mg, 256 umol, 1.00 eq, mesylate) in dichloromethane (5.00 mL) were added ACA'-diisopropylcthylaminc (99.1 mg, 767 umol, 134 uL, 3.00 eq) and phenethyl carbonochloridate (70.8 mg, 383 umol, 1.50 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 purified by reverse phase chromatography (Cl 8, 40 g; condition: water / acetonitrile = 100:0 to 0: 100, 0.1% formic acid) and lyophilized to afford phenethyl (l-(4-(2,6-dioxopiperidin-3-yl)-3,5- difluorophenyl)azetidin-3-yl)carbamate (18.41 mg, 40.69 umol, 16% yield, 98% purity) as a light yellow solid.

[0220] 1H NMR (400 MHz, DMSO-d6 ) δ = 10.85 (s, 1H), 7.84 (br d, J= 7.1 Hz, 1H), 7.34 - 7.21 (m, 5H), 6.14 (br d, J = 11.3 Hz, 2H), 4.41 (br dd, J= 6.1, 7.2 Hz, 1H), 4.18 (t, J= 6.9 Hz, 2H), 4.12 - 4.05 (m,2H), 4.02 (br d, J= 5.3 Hz, 1H), 3.63 (br t, J= 6.1 Hz, 2H), 2.87 (t, J= 6.8 Hz, 2H), 2.81 - 2.71 (m, 1H), 2.48 (br s, 1H), 2.13 - 2.02 (m, 1H), 1.99 - 1.91 (m, 1H). MS (ESI) m / z 444.3 [M+H]+Synthesis of Compound 35Step 1. Procedure for Compound 1A - 4-(trifluoromethoxy)benzyl carbonochloridate.

[0221] To a solution of (4-(trifluoromethoxy)phenyl)methanol (500 mg, 2.60 mmol, 376 uL, 1.00 eq) in dichloromethane (5.00 mL) were added bis(trichloromethyl) carbonate (1.16 g, 3.90 mmol, 1.50 eq) and MA'-diisopropylcthylaminc (673 mg, 5.20 mmol, 907 uL, 2.00 eq) at 0 °C. The mixture was stirred at 25 °C for 2 h. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give 4- (trifluoromethoxy)benzyl carbonochloridate (600 mg, crude) as colorless oil.Step 2. Procedure for 4-(trifluoromethoxy)benzyl (l-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)azetidin- 3-yl)carbamate.

[0222] To a solution of 4-(trifluoromethoxy)benzyl carbonochloridate (200 mg, 786 umol, 1.00 eq) in dichloromethane (5.00 mL) were added A'.A'-diisopropylcthylaminc (203 mg, 1.57 mmol, 274 uL, 2.00 eq) and 3 -(4-(3-aminoazetidin-l-yl)-2,6-difluorophenyl)piperidine-2, 6-dione (232 mg, 593 umol, 0.754 eq, mesylate). The mixture was stirred at 25 °C for 2 h. The mixture was filtered and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by / Vc / i-HPLC (column: Phenomenex Luna C18 150*25mm* 10um; mobile phase: [water (formic acid) - acetonitrile]; B%: 40%-70%, 8 min) and lyophilizedto afford 4-(trifluoromethoxy)benzyl (l-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)azetidin-3- yl)carbamate (33.91 mg, 65.39 umol, 8% yield, 99% purity) as an off-white solid.

[0223] 1H NMR (400 MHz, DMSO-d6 ) δ = 10.85 (s, 1H), 8.02 (br d, J= 7.6 Hz, 1H), 7.49 (d, J= 8.5 Hz, 2H), 7.37 (d, J= 8.4 Hz, 2H), 6.15 (d, J= 11.1 Hz, 2H), 5.07 (s, 2H), 4.49 - 4.40 (m, 1H), 4.10 (t, J= 7.6 Hz, 2H), 4.06 - 4.00 (m, 1H), 3.64 (br t, J= 6.6 Hz, 2H), 2.83 - 2.72 (m, 1H), 2.57 - 2.52 (m, 1H), 2.12 - 2.02 (m, 1H), 1.97 - 1.90 (m, 1H). MS (ESI) m / z 514.0 | M+H |Synthesis of Compound 37Compound 37Step 1. Procedure for preparation of benzyl (l-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)azetidin-3- yl)carbamate.

[0224] To a solution of 3-(4-(3-aminoazetidin-l-yl)-2,6-difluorophenyl)piperidine-2, 6-dione (300 mg, 767 nmol, 1.00 eq, mesylate) in dimethylformamide (2.00 mL) were added A'.A'-diisopropylcthylaminc (198 mg, 1.53 mmol, 267 uL, 2.00 eq) and benzyl carbonochloridate (131 mg, 767 nmol, 109 uL, l.OOeg). The reaction mixture was stirred at 0 °C for 0. 15 h. The mixture was diluted with water (10 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic layers were washed with brine (2 x 20 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (Si(>. petroleum ether / ethyl acetate=5 / 0 to 1 / 1) and concentrated under reduced pressure to give a solid. The solid was diluted with water (10 mL) and lyophilized to afford benzyl (1- (4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)azetidin-3-yl)carbamate (237.14 mg, 546.72 umol, 71% yield, 99% purity) as a white solid.

[0225] 1H NMR (400 MHz, DMSO-d6 ) δ = 10.87 (s, 1H), 7.99 (br d, J= 7.4 Hz, 1H), 7.40 - 7.29 (m, 5H), 6. 16 (s, 1H), 6. 14 (s, 1H), 5.04 (s, 2H), 4.50 - 4.40 (m, 1H), 4. 10 (t, J= 7.6 Hz, 2H), 4.05 - 4.00 (m, 1H), 3.64 (t, J= 6.8 Hz, 2H), 2.82 - 2.73 (m, 1H), 2.50 - 2.45 (m, 1H), 2.07 (dq, J= 3.7, 12.9 Hz, 1H), 1.98 - 1.89 (m, 1H). MS (ESI) m / z 430.0 [M+H]+Synthesis of Compound 38Step 1.

[0226] Acid 38-1 (0.5 g, 2.4 mmol) was dissolved in a mixture of compound 38-2 / DXN (2 / 10 mL), then triethylamine (0.4 mL, 3 mmol) and DPPA (0.6 mL, 3 mmol) were added, and the reaction mixture was stirred at 40 °C for 1 h and refluxed overnight. The resulting mixture was cooled to rt, and ethyl acetate (40 mL) was added; the organic layer was washed with 10% K2CO3 aq. solution (5 x 30 mL), and brine (1 x 20 mL), dried over sodium sulfate, filtered, and concentrated in vacuo to give crude product 38-3 which was used in the next step without further purification (0.3 g, 29%).Step 2.

[0227] To a mixture of compound 38-3 (0.25 g, 0.75 mmol), compound 38-4 (0.23 g, 0.75 mmol), K2CO3 (0.2 g, 1.5 mmol) in DXN / H2O (5:2, 15 mL), purged with argon, cataCXium A Pd G3 (0.03 g) and cataCXium A (0.015 g,) were added. The reaction mixture was heated at 90 °C overnight. Then the mixture was cooled to rt and filtered. The solution was concentrated under reduced pressure and the residue was diluted with EtOAc and water. The organic layer was washed with water, brine, dried over Na2SC>4 and evaporated in vacuo. The residue was purified by HPLC to afford compound 38 (25.5 mg, 8% yield).

[0228] 1H NMR (400 MHz, DMSO-O 5 10.94 (s, 1H), 9.33 (d, J = 10.1 Hz, 1H), 6.93 (d, J= 10.2 Hz, 2H), 6.59 - 6.37 (m, 1H), 5.25 - 5.00 (m, 1H), 4.19 (dd, J = 12.8, 5.2 Hz, 1H), 3.95 (d, J = 6.9 Hz, 2H),3.28 (d, J= 7.1 Hz, 2H), 2.88 - 2.72 (m, 1H), 2.45 - 2.28 (m, 2H), 2.16 - 1.94 (m, 6H), 1.88 (t, J= 7.4 Hz, 2H), 1.81 - 1.63 (m, 4H). HPLC purity: 100%; Retjime: 1.446 min; HRMS (ESI) calculated for C23H26F2N2O4: 432.19; observed: 431.0 [M-H]’Synthesis of Compound 39Compound 39Step 1. Procedure for Compound 2 - (((ls,3s)-3-isopropoxycyclobutoxy)methyl)benzene.

[0229] To a solution of ( l.s.3.s)-3-(bcnzyloxy)cyclobutanol (200 mg, 1. 12 mmol, 1.00 eq) in toluene (5.00 mL) was added 2-iodopropane (382 mg, 2.24 mmol, 224 uL, 2.00 eq). Then argentiooxysilver (520 mg, 2.24 mmol, 2.00 eq) was added to the mixture and the reaction mixture was stirred at 72 °C for 48 h under nitrogen atmosphere and darkness. The mixture was filtered and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by Prep-lUZ (SiO2, petroleum ether / ethyl acetate=10 / l) to afford (((15,35)-3-isopropoxycyclobutoxy)methyl)benzene (100 mg, crude) as colorless oil.Step 2. Procedure for preparation of Compound 3 - (ls,3s)-3-isopropoxycyclobutanol.

[0230] To a solution of ((( l.s.3.s)-3-isopropoxycyclobiitoxy)mcthyl)bcnzcnc (50.0 mg, 227 umol, 1.00 eq) in methanol (1.00 mL) was added palladium on activated carbon (100 mg, 10% purity). The mixture wasstirred at 25 °C for 12 h under 15 psi of hydrogen atmosphere. The mixture was filtered and the filtrate was concentrated under reduced pressure to afford (ls,3s)-3-isopropoxycyclobutanol (59.0 mg, crude) as colorless oil.Step 3. Procedure for Compound 4 - (ls,3s)-3-isopropoxycyclobutyl carbonochloridate.

[0231] To a solution of ( Is, 3s)-3 -isopropoxycyclobutanol (59.0 mg, 453 umol, 1.00 eq) in dichloromethane (2.00 mL) were added bis(trichloromethyl) carbonate (202 mg, 680 umol, 1.50 eq) and A'.A'- diisopropylethylamine (117 mg, 906 umol, 158 uL, 2.00 eq) at 0 °C. The mixture was stirred at 25 °C for 1 h. The reaction mixture was filtered and concentrated under reduced pressure to afford (ls,3s)-3- isopropoxycyclobutyl carbonochloridate (87.3 mg, crude) as colorless oil.Step 4. Procedure for spiro [3.3]heptan-2-ylmethyl (l-(4-(2,6-dioxopiperidin-3-yl)-3fluorophenyl)azetidin-3- yl)carbamate.

[0232] To a solution of 3-(4-(3-aminoazetidin-l-yl)-2,6-difluorophenyl)piperidine-2, 6-dione (135 mg, 457 umol, 1.00 eq) in dichloromethane (3.00 mL) were added A'.A'-diisopropylcthylaminc (118 mg, 914 umol, 159 uL, 2.00 eq) and (ls,3s)-3-isopropoxycyclobutyl carbonochloridate (87.0 mg, 452 umol, 0.998 eq). The mixture was stirred at 25 °C for 2 h. The mixture was filtered and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by / Vc / i-HPLC (column: Phenomenex luna C18 150*25mm* 10um; mobile phase: [water (formic acid) - acetonitrile]; B%: 34%-64%, min) and lyophilized to afford (ls,3s)-3-isopropoxycyclobutyl (l-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)azetidin-3- yl)carbamate (12.97 mg, 25.55 umol, 6% yield, 98% purity, formate) an white solid.

[0233] 1H NMR (400 MHz, DMSO-d6 ) δ = 10.85 (br s, 1H), 8.44 (s, 1H), 7.87 (br d, J= 7.5 Hz, 1H), 6.14 (d, J= 11.1 Hz, 2H), 4.52 - 4.43 (m, 1H), 4.43 - 4.34 (m, 1H), 4.11 - 4.00 (m, 3H), 3.72 - 3.65 (m, 1H), 3.65 - 3.58 (m, 2H), 3.57 - 3.49 (m, 1H), 2.83 - 2.72 (m, 1H), 2.69 - 2.61 (m, 2H), 2.47 (br s, 1H), 2.14 - 2.00 (m, 1H), 1.99 - 1.89 (m, 1H), 1.87 - 1.76 (m, 2H), 1.05 (d, J= 6.1 Hz, 6H). MS (ESI) m / z 452. 1 [M+H]+Synthesis of Compound 41Compound 41Step 1. Procedure for preparation of Compound 2 - cyclopropyl(3-hydroxyazetidin-l-yl)methanone.

[0234] To the solution of azetidin-3-ol (524 mg, 4.78 mmol, 1.00 eq, hydrochloride), N,N- diisopropylethylamine (1.85 g, 14.4 mmol, 2.50 mL, 3.00 eq) in tetrahydrofuran (5.00 mL) was added cyclopropanecarbonyl chloride (500 mg, 4.78 mmol, 435 uL, 1.00 eq) at 0 °C. Then the reaction 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 (SiO2, petroleum ether / ethyl acetate = 0 / 1) to afford cyclopropyl(3- hydroxyazetidin-l-yl)methanone (550 mg, 3.90 mmol, 81% yield) as a white solid.Step 2. Procedure for preparation of Compound 3 - l-(cyclopropanecarbonyl)azetidin-3-yl (4-nitrophenyl) carbonate.

[0235] To the solution of cyclopropyl(3-hydroxyazetidin-l-yl)methanone (200 mg, 1.42 mmol, 1.00 eq) in dichloromethane (3.00 mL) was added triethylamine (717 mg, 7.08 mmol, 986 uL, 5.00 eq) at 0 °C. After 15 min, to the mixture was added 4-nitrophenyl carbonochloridate (857 mg, 4.25 mmol, 3.00 eq). Then the reaction was stirred at 25 °C for 1 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiCE, petroleum ether / ethyl acetate = 1 / 1) to afford l-(cyclopropanecarbonyl)azetidin-3-yl (4-nitrophenyl) carbonate (240 mg, 392 umol, 27% yield, 50% purity) as a yellow solid.Step 3. Procedure for preparation of l-(cyclopropanecarbonyl)azetidin-3-yl (l-(4-(2,6-dioxopiperidin-3-yl)- 3,5-difluorophenyl)azetidin-3-yl)carbamate.

[0236] To the solution of l-(cyclopropanecarbonyl)azetidin-3-yl (4-nitrophenyl) carbonate (50.0 mg, 163 umol, 1.00 eq), 3 -(4-(3-aminoazetidin-l-yl)-2,6-difluorophenyl)piperidine-2, 6-dione (63.9 mg, 163 umol, 1.00 eq, methanesulfonic acid) in dimethylformamide (0.500 mL) was added triethylamine (33.1 mg, 327 umol, 45.5 uL, 2.00 eq). Then the reaction was stirred at 25 °C for 1 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by / Vc / i-HPLC (column: Phenomenex luna Cl 8 150*25mm* lOum; mobile phase: [column: Waters xbridge 150*25mml0um; mobile phase: [water (ammonium bicarbonate) - acetonitrile]; B%: 13%-43%, 13 min) and lyophilized to afford 1- (cyclopropanecarbonyl)azetidin-3 -yl ( 1 -(4-(2,6-dioxopiperidin-3-yl)-3 ,5 -difluorophenyl)azetidin-3 - yl)carbamate (34.37 mg, 73.58 umol, 90% yield, 99% purity) as a white solid.

[0237] 1H NMR (400 MHz, DMSO-d6 ) δ = 10.85 (br s, 1H), 8. 15 (br d, J= 7.5 Hz, 1H), 6. 17 (s, 1H), 6.14 (s, 1H), 5.12 - 5.07 (m, 1H), 4.56 - 4.50 (m, 1H), 4.45 - 4.39 (m, 1H), 4.11 (br d, J= 7.6 Hz, 4H), 4.06 - 4.01 (m, 1H), 3.73 - 3.69 (m, 1H), 3.65 (br d, J= 6.9 Hz, 2H), 2.82 - 2.73 (m, 1H), 2.48 (br s, 1H), 2. 12 - 2.03 (m, 1H), 1.96 - 1.90 (m, 1H), 1.55 - 1.50 (m, 1H), 0.72 - 0.67 (m, 4H).MS (ESI) m / z 463.1 [M+H]+Synthesis of Compound 42Compound 42Step 1. Procedure for preparation of Compound 2 - l-(cyclopropylsulfonyl)azetidin-3-ol.

[0238] To the solution of azetidin-3-ol (779 mg, 7.11 mmol, 1.00 eq, hydrochloride), Nff- diisopropylethylamine (2.76 g, 21.3 mmol, 3.72 mL, 3.00 eq) in tetrahydrofuran (5.00 mL) was added cyclopropanesulfonyl chloride (1.00 g, 7. 11 mmol, 1.00 eq) at 0 °C. Then the reaction 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 = 0 / 1) to afford 1- (cyclopropylsulfonyl)azetidin-3-ol (1.25 g, 7.05 mmol, 99% yield) as orange oil.Step 2. Procedure for preparation of Compound 3 - l-(cyclopropylsulfonyl)azetidin-3-yl (4-nitrophenyl) carbonate.

[0239] To the solution of l-(cyclopropylsulfonyl)azetidin-3-ol (400 mg, 2.26 mmol, 1.00 eq) in dichloromethane (5.00 mL) was added triethylamine (1.14 g, 11.3 mmol, 1.57 mL, 5.00 eq) at 0 °C. After 15min, to the mixture was added 4-nitrophenyl carbonochloridate (1.36 g, 6.77 mmol, 3.00 eq). Then the reaction was stirred at 25 °C for 1 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiCE, petroleum ether / ethyl acetate = 5 / 1) to afford 1- (cyclopropylsulfonyl)azetidin-3-yl (4-nitrophenyl) carbonate (550 mg, 1.12 mmol, 49% yield, 70% purity) as an off-white solid.Step 3. Procedure for preparation of l-(cyclopropylsulfonyl)azetidin-3-yl (l-(4-(2,6-dioxopiperidin-3-yl)-3,5- difluorophenyl)azetidin-3-yl)carbamate.

[0240] To the solution of l-(cyclopropylsulfonyl)azetidin-3-yl (4-nitrophenyl) carbonate (50.0 mg, 146 umol, 1.00 eq), 3 -(4-(3-aminoazetidin-l-yl)-2,6-difluorophenyl)piperidine-2, 6-dione (57.2 mg, 146 umol, 1.00 eq, methanesulfonic acid) in dimethylformamide (0.500 mL) was added triethylamine (29.6 mg, 292 umol, 40.7 uL, 2.00 eq). Then the reaction was stirred at 25 °C for 1 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by / Vc / i-HPLC (column: Waters xbridge 150*25mml0um; mobile phase: [water (formic acid) - acetonitrile]; B%: 20%-80%, 8 min) and lyophilized to afford 1 -(cyclopropylsulfonyl)azetidin-3-yl ( 1 -(4-(2,6-dioxopiperidin-3-yl)-3 ,5 -difluorophenyl)azetidin-3 - yl)carbamate (13.01 mg, 25.84 umol, 17% yield, 99% purity) as a white solid.

[0241] 1H NMR (400 MHz, DMSO-d6 ) δ = 10.86 (s, 1H), 8. 19 (br d, J = 7.4 Hz, 1H), 6. 17 (s, 1H), 6.15 (s, 1H), 5.12 - 5.06 (m, 1H), 4.47 - 4.38 (m, 1H), 4.18 - 4.09 (m, 4H), 4.04 (br dd, J= 5.1, 12.6 Hz, 1H), 3.86 (br dd, J= 4.9, 9.1 Hz, 2H), 3.66 (br t, J= 6.8 Hz, 2H), 3.30 - 3.19 (m, 1H), 2.82 - 2.73 (m, 2H), 2.11 - 2.03 (m, 1H), 1.98 - 1.92 (m, 1H), 1.05 - 1.02 (m, 2H), 0.97 - 0.93 (m, 2H). MS (ESI) m / z 499.1 [M+H]+Synthesis of Compound 44Compound 44Step 1. Procedure for preparation of Compound 8A- spiro[3.3]heptan-2-ylmethyl carbonochloridate.

[0242] To a solution of spiro[3.3]heptan-2-ylmethanol (60.0 mg, 475 umol, 1.00 eq) in dichloromethane (2.00 mL) were added bis(trichloromethyl) carbonate (226 mg, 761 umol, 1.60 eq)and N.N- diisopropylethylamine (123 mg, 951 umol, 166 uL, 2.00 eq) at 0 °C. The mixture was stirred at 25 °C for 1 h. The reaction mixture was concentrated under reduced pressure to afford spiro[3.3]heptan-2-ylmethyl carbonochloridate (80 mg, crude) as a yellow solid.Step 2. Procedure for preparation of Compound 2- (4-bromo-2-fluoro-3-methoxyphenyl)methanol.

[0243] To a solution of 4-bromo-2-fluoro-3-methoxybenzoic acid (3.70 g, 14.9 mmol, 1.00 eq) in tetrahydrofuran (20.0 mL) was dropwise added borane tetrahydrofuran complex (1.00 M, 59.4 mL, 4.00 eq) under nitrogen atmosphere at 0 °C. After addition, the mixture was stirred at 25 °C for 2 h. The reaction mixture was quenched by addition methanol (20.0 mL) slowly at 25 °C and then diluted with water (10.0 mL). The mixture was extracted with ethyl acetate (3 x 30 mL). The combined organic layers were washed with brine (30 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=5 / l) to afford 4- bromo-2-fluoro-3-methoxyphenyl)methanol (3.00 g, 12.8 mmol, 86% yield) as colorless oil.Step 3. Procedure for preparation of Compound 3 - l-bromo-4-(chloromethyl)-3-fluoro-2-methoxybenzene.

[0244] To a solution of (4-bromo-2-fluoro-3-methoxy-phenyl)methanol (3.00 g, 12.8 mmol, 1.00 eq) in dichloromethane (30.0 mL) was added thionyl chloride (3.04 g, 25.5 mmol, 1.85 mL, 2.00 eq). The mixture was stirred at 25 °C for 3 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 / l) to afford 1- bromo-4-(chloromethyl)-3-fluoro-2 -methoxy-benzene (2.60 g, 10.3 mmol, 80% yield) as colorless oil.Step 4. Procedure for preparation of compound 4 - 2-(4-bromo-2fluoro-3-methoxyphenyl)acetonitrile.

[0245] To a solution of l-bromo-4-(chloromethyl)-3-fluoro-2-methoxybenzene (2.60 g, 103 mmol, 1.00 eq) in acetonitrile (40.0 mL) were added trimethylsilanecarbonitrile (3.05 g, 30.8 mmol, 3.85 mL, 3.00 eq) and tetrabutylammonium fluoride (1.00 M, 30.77 mL, 3.00 eq). The mixture was stirred at 80 °C for 2 h. The reaction mixture was quenched by addition water (10 mL), and then extracted with ethyl acetate (3 x 10 mL). The combined organic layers were filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiCL, petroleum ether / ethyl acetate=50 / l) to afford 2- (4-bromo-2-fluoro-3-methoxyphenyl)acetonitrile (2.00 g, 8. 19 mmol, 80% yield) as a white solid.Step 5. Procedure for preparation of compound 5 - methyl 4-(4-bromo-2-fluoro-3-methoxyphenyl)-4- cyanobutanoate.

[0246] To a solution of 2-(4-bromo-2-fluoro-3-methoxyphenyl)acetonitrile (500 mg, 2.05 mmol, 1.00 eq) in tetrahydrofuran (6.00 mL) was added sodium methylate (16.6 mg, 307 umol, 0. 150 eq) at 0 °C, and then methyl acrylate (194 mg, 2.25 mmol, 203 uL, 1.10 eq) was added into the mixture at 0 °C. The mixture was stirred at 25 °C for 1 h. The reaction mixture was diluted by addition water (10 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic layers were 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=50 / l to 20 / 1) to afford methyl 4-(4-bromo-2-fluoro-3-methoxyphenyl)-4- cyanobutanoate (600 mg, 1.82 mmol, 89% yield) as a white solid.Step 6. Procedure for preparation of compound 6 - 3-(4-bromo-2fluoro-3-methoxyphenyl)piperidine-2,6- dione.

[0247] To a solution of methyl 4-(4-bromo-2-fluoro-3-methoxyphenyl)-4-cyanobutanoate (500 mg, 1.51 mmol, 1.00 eq) in acetic acid (5.00 mL) was added sulfuric acid (920 mg, 9.38 mmol, 0.500 mL, 6.19 eq). The mixture was stirred at 90 °C for 2 h. The reaction mixture was diluted with water (10 mL) and filtered. The filter cake was concentrated under reduced pressure to give a residue. The residue was triturated with petroleum ether (5 mL) and then filtered. The second filter cake was concentrated under reduced pressure to afford 3-(4-bromo-2-fluoro-3-methoxyphenyl)piperidine-2, 6-dione (450 mg, 1.42 mmol, 94% yield) as a gray solid.

[0248] 1H NMR (400 MHz, DMSO-r / fi) 8 = 10.92 (s, 1H), 7.44 (dd, J= 1.6, 8.4 Hz, 1H), 7.09 - 6.95 (m, 1H), 4.10 (br dd, J= 4.9, 12.7 Hz, 1H), 3.86 (s, 3H), 2.78 - 2.70 (m, 1H), 2.56 - 2.52 (m, 1H), 2.28 - 2.17 (m, 1H), 2.10 - 1.96 (m, 1H).Step 7. Procedure for preparation of compound 6 - tert-butyl (l-(4-(2,6-dioxopiperidin-3-yl)-3fluoro-2- methoxyphenyl)azetidin-3-yl)carbamate.

[0249] A mixture of 3-(4-bromo-2-fluoro-3-methoxyphenyl)piperidine-2, 6-dione (100 mg, 316 umol,1.00 eq), tert-butyl azetidin-3-ylcarbamate (81.7 mg, 475 umol, 1.50 eq), cesium carbonate (309 mg, 949 umol, 3.00 eq), and [ 1 , 3 -bi s [2, 6-bi s( 1 -propylbutyl)phenyl]-4,5-dichloro-imidazol-2-ylidene] -dichloro-(3 - chloropyridin-l-ium-l-yl)palladium (30.8 mg, 31.6 umol, 0.100 eq) in dioxane (3.00 mL) was degassed and purged with nitrogen atmosphere for 3 times, and then the mixture was stirred at 100 °C for 12 h under nitrogen atmosphere. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to givea residue. The residue was purified by column chromatography (SiCL, petroleum ether / ethyl acetate=5 / l to 1 / 1) to afford tert-butyl (l-(4-(2,6-dioxopiperidin-3-yl)-3-fluoro-2-methoxyphenyl)azetidin-3-yl)carbamate (50.0 mg, 123 umol, 39% yield) as yellow oil. MS (ESI) m / z 407.9 [M+H]+Step 8. Procedure for preparation of compound 8 - 3-(4-(3-aminoazetidin-l-yl)-2-fluoro-3- methoxyphenyl)piperidine-2, 6-dione.

[0250] To a solution of tert-butyl (l-(4-(2,6-dioxopiperidin-3-yl)-3-fluoro-2- methoxyphenyl)azetidin-3-yl)carbamate (50.0 mg, 123 umol, 1.00 eq) in dichloromethane (4.00 mL) was added trifluoroacetic acid (1.54 g, 13.5 mmol, 1.00 mL, 110 eq). The mixture was stirred at 25 °C for 1 h. The reaction mixture was concentrated under reduced pressure to afford 3-(4-(3-aminoazetidin-l-yl)-2-fluoro-3- methoxyphenyl)piperidine-2, 6-dione (30 mg, 97.6 umol, 80% yield) as a white solid. MS (ESI) m / z 308.0 [M+H]+Step 9. Procedure for preparation of spiro[3.3]heptan-2-ylmethyl (l-(4-(2,6-dioxopiperidin-3-yl)-3-fluoro-2- methoxyphenyl)azetidin-3-yl)carbamate.

[0251] To a solution of 3-(4-(3-aminoazetidin-l-yl)-2-fluoro-3-methoxyphenyl)piperidine-2, 6-dione (30.0 mg, 97.6 umol, 1.00 eq) in dichloromethane (2.00 mL) were added A / A'-diisopropylcthylaminc (37.9 mg, 293 umol, 51.0 uL, 3.00 eq) and spiro[3.3]heptan-2-ylmethyl carbonochloridate (18.4 mg, 97.6 umol, 1.00 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 purified by reverse phase chromatography (Cl 8, 40 g; condition: water / acetonitrile = 100:0 to 0: 100, 0.1% formic acid) and lyophilized to afford spiro[3.3]heptan-2-ylmethyl (l-(4-(2,6-dioxopiperidin-3-yl)-3-fluoro-2-methoxyphenyl)azetidin-3-yl)carbamate (10.84 mg, 23.35 umol, 23.92% yield, 99% purity) as a white solid.

[0252] 1H NMR (400 MHz, DMSO-d6 ) δ = 10.81 (s, 1H), 7.77 (br d, J= 7.4 Hz, 1H), 6.81 (t, J= 8.1 Hz, 1H), 6.22 (d, J= 8.4 Hz, 1H), 4.44 - 4.31 (m, 1H), 4.14 (t, J= 7.6 Hz, 2H), 3.85 (m, 3H), 3.69 (s, 3H), 3.65 (t, J= 7.1 Hz, 2H), 2.72 - 2.68 (m, 1H), 2.38 - 2.33 (m, 1H), 2.21 - 2.04 (m, 2H), 2.03 - 1.84 (m, 7H), 1.80 - 1.69 (m, 4H). MS (ESI) m / z 460.2 [M+H]+Synthesis of Compound 45Compound 45Step 1. Procedure for preparation of l-(dimethylcarbamoyl)azetidin-3-yl (l-(4-(2,6-dioxopiperidin-3-yl)-3,5- difluorophenyl)azetidin-3-yl)carbamate.

[0253] To the solution of l-(dimethylcarbamoyl)azetidin-3-yl (4-nitrophenyl) carbonate (50.0 mg, 113 nmol, 70% purity, 1.00 eq), 3-(4-(3-aminoazetidin-l-yl)-2,6-difluorophenyl)piperidine-2, 6-dione (44.3 mg, 113 umol, 1.00 eq, methanesulfonic acid) in dimethylformamide (0.500 mL) was added triethylamine (22.9 mg, 226 umol, 31.5 uL, 2.00 eq). Then the reaction was stirred at 25 °C for 1 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by Prep --PLC (column: Phenomenex luna C18 150*25mm* lOum; mobile phase: [water (formic acid) - acetonitrile]; B%: 21%-51%, 58 min) and lyophilized to afford l-(dimethylcarbamoyl)azetidin-3-yl (l-(4-(2,6-dioxopiperidin-3-yl)-3,5- difluorophenyl)azetidin-3-yl)carbamate (20.40 mg, 42.51 umol, 37% yield, 97% purity) as a white solid.

[0254] 1H NMR (400 MHz, DMSO-d6 ) δ = 10.85 (br s, 1H), 8.10 (br d, J= 6.4 Hz, 1H), 6. 15 (br d, J = 11.3 Hz, 2H), 5.00 (br s, 1H), 4.42 (br d, J= 6.1 Hz, 1H), 4.20 - 4.07 (m, 4H), 4.07 - 4.01 (m, 1H), 3.76 (br d, J = 5.3 Hz, 2H), 3.65 (br s, 2H), 2.75 (br s, 8H), 2.14 - 2.02 (m, 1H), 1.96 (br s, 1H). MS (ESI) m / z 466.1 [M+H]+Synthesis of Compound 4646-4 46-1 AStep 1. Procedure for preparation of Compound 3 (((ls,3s)-3-(tert-butoxy)cyclobutoxy)methyl)benzene.

[0255] To the solution of ( l.s.3.s)-3-(bcnzyloxy)cyclobiitanol (100 mg, 561 umol, 1.00 eq). perchloric acid (84.6 mg, 841 umol, 50.9 uL, 1.50 eq) in dichloromethane (2.00 mL) was added 2-methylprop-l-ene (2.40M, 2.34 mL, 10.0 eq) at -70 °C. Then the reaction was stirred at -40 °C for 12 h. The reaction was neutralized with saturated aqueous sodium carbonate (5 mL), then extracted by dichloromethane (10 mL). The organic layer was washed with brine (10 mL), and 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 = 20 / 1) to afford (((ls\3s)-3-(tert-butoxy)cyclobutoxy)methyl)benzene (110 mg, 469 umol, 83% yield) as colorless oil.Step 2. Procedure for preparation of Compound 4 - (ls,3s)-3-(tert-butoxy)cyclobutanol.

[0256] To a solution of ((( l.s.3.s)-3- / / m-biitoxy)cyclobiitoxy)mcthyl)bcnzcnc (110 mg, 469 umol, 1.00 eq) in methanol (5.00 mL) was added palladium on activated carbon (220 mg, 10% purity) under nitrogen atmosphere. Then the reaction was stirred under 15 psi of hydrogen atmosphere at 25 °C for 2 h. The suspension was filtered and the filter cake was washed with acetonitrile (10 mL). The combined filtrates were concentrated under reduced pressure to afford ( l.s.3.s)-3- / / m-butoxy)cyclobiitanol (56.0 mg, 388 umol, 82% yield) as colorless oil.Step 3. Procedure for preparation of Compound 1A - ( 1 s, 3 s) -3 -(tert-butoxy) cyclobutyl carbonochloridate.

[0257] To the solution of ( l.s.3.s)-3- / / r77-biitoxy)cyclobiitanol (56.0 mg, 388 umol, 1.00 eq) in dichloromethane (0.500 mL) were added bis(trichloromethyl) carbonate (115 mg, 388 umol, 1.00 eq) and / V, / V-diisopropylethylamine (150 mg, 1. 16 mmol, 203 uL, 3.00 eq) at 0 °C. Then the reaction was stirred at 25 °C for 0.5 h. The reaction mixture was concentrated under reduced pressure to afford (\s,3s)-3-(tert- butoxy)cyclobutyl carbonochloridate (80.2 mg, crude) as an orange solid.Step 4. Procedure for preparation of (ls,3s)-3-(tert-butoxy)cyclobutyl (l-(4-(2,6-dioxopiperidin-3-yl)-3,5- difluorophenyl)azetidin-3-yl)carbamate.

[0258] To the solution of (ls,3s)-3-(tert-butoxy)cyclobutyl carbonochloridate (80.2 mg, 388 umol, 1.00 eq), 3 -(4-(3-aminoazetidin-l-yl)-2,6-difluorophenyl)piperidine-2, 6-dione (152 mg, 388 umol, 1.00 eq, methanesulfonic acid) in dichloromethane (0.50 mL) was added N, A'-diisopropylcthylaminc (201 mg, 1.55 mmol, 270 uL, 4.00 eq). Then the reaction was stirred at 25 °C for 1 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by / Vc / i-HPLC (column: Waters xbridge 150*25mm lOum; mobile phase: [water (formic acid) - acetonitrile]; B%: 32%-62%, 8 min) and lyophilized to afford ( ls,,3s')-3 -(tert-butoxy)cyclobutyl ( 1 -(4-(2,6-dioxopiperidin-3-yl)-3 ,5 -difluorophenyl)azetidin-3 - yl)carbamate (42.44 mg, 82. 14 umol, 21% yield, 99% purity, formate) as a yellow solid.

[0259] 1H NMR (400 MHz, DMSO-cZ) 3 = 10.86 (s, 1H), 8.39 (br s, 1H), 7.86 (br d, J= 7.3 Hz, 1H), 6. 15 (s, 1H), 6. 13 (s, 1H), 4.50 - 4.43 (m, 1H), 4.42 - 4.35 (m, 1H), 4.07 (br t, J= 7.8 Hz, 2H), 4.05 - 4.00 (m, 1H), 3.83 - 3.76 (m, 1H), 3.61 (br t, J= 6.8 Hz, 2H), 2.82 - 2.73 (m, 1H), 2.64 - 2.58 (m, 2H), 2.47 (br s, 1H), 2.12 - 2.02 (m, 1H), 1.98 - 1.91 (m, 1H), 1.85 - 1.77 (m, 2H), 1.10 (s, 9H). MS (ESI) m / z 466.2 [M+H]+Synthesis of Compound 47, 48, 49, 50Compound 47Step 1. Procedure for (lr,3r)-3-((tert-butyldimethylsilyl)oxy)cyclobutyl (l-(4-(2,6-dioxopiperidin-3-yl)-3,5- difluorophenyl)azetidin-3-yl)carbamate.

[0260] To a solution of (lr,3r)-3-((fert-butyldimethylsilyl)oxy)cyclobutanol (50.0 mg, 247 umol, 1.00 eq) in tetrahydroforan (1.00 mL) was added di( 1 / 7-imidazol- l-yl)methanone (40. 1 mg, 247 umol, 1.00 eq) at 0 °C. The reaction mixture was stirred at 20 °C for 1 h. The resulting solution was added to a solution of 3-(4- (3-aminoazetidin-l-yl)-2,6-difluorophenyl)piperidine-2, 6-dione (97.0 mg, 248 umol, 1.00 eq, methanesulfonic acid), triethylamine (25.1 mg, 248 umol, 34.5 uL, 1.00 eq) and 2,3,4,6,7,8,9,10-octahydropyrimido[l,2- «]azepine (37.7 mg, 248 umol, 37.4 uL, 1.00 eq) in tetrahydrofuran (1.00 mL) and dimethylformamide (1.00 mL). The reaction 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 = 2 / 1) to afford (lr,3r)-3-((fert-butyldimethylsilyl)oxy)cyclobutyl(l-(4-(2,6-dioxopiperidin-3-yl)-3,5- difluorophenyl)azetidin-3-yl)carbamate (29.29 mg, 52.58 umol, 21% yield, 94% purity) as a white solid.

[0261] 1H NMR (400 MHz, DMSO-d6 ) δ =10.83 (s, 1H), 7.86 (br d, J= 7.3 Hz, 1H), 6.12 (d, J= 11.1 Hz, 2H), 4.89 (td, J= 3.5, 6.8 Hz, 1H), 4.46 (t, J = 6.2 Hz, 1H), 4.41 - 4.32 (m, 1H), 4.11 - 3.97 (m, 3H), 3.60 (t, J= 6.8 Hz, 2H), 2.82 - 2.70 (m, 1H), 2.45 (br s, 1H), 2.32 - 2.22 (m, 2H), 2.21 - 2.13 (m, 2H), 2.05 (dq, J = 3.5, 13.0 Hz, 1H), 1.96 - 1.84 (m, 1H), 0.83 (s, 9H), 0.00 (s, 6H). MS (ESI) m / z 524.0 [M+H]+

[0262] Compounds 48, 49, 50 were synthesized in analogy to Compound 47:Synthesis of Compound 51Compound 51Step 1. Procedure for preparation of compound 2 - cyclohexylmethyl carbonochloridate.

[0263] To a solution of cyclohexylmethanol (45.0 mg, 394 umol, 48.4 uL, 1.QQeq) in dichloromethane(1.00 mL) were added bis(trichloromethyl) carbonate (187 mg, 631 umol, 1.60 eq) and N.N- diisopropylethylamine (102 mg, 788 umol, 137 uL, 2.00 eq) at 0 °C. The reaction mixture was stirred at 25 °C for 1 h. The reaction mixture was concentrated under reduced pressure to afford cyclohexylmethyl carbonochloridate (69.0 mg, 391 umol, 99 % yield) as yellow oil.Step 2. Procedure for preparation of cyclohexylmethyl (l-(4-(2,6-dioxopiperidin-3-yl)-3,5- difluorophenyl)azetidin-3-yl)carbamate.

[0264] To a solution of 3-(4-(3-aminoazetidin-l-yl)-2,6-difluorophenyl)piperidine-2, 6-dione (100 mg, 256 umol, 1.00 eq, methanesulfonic acid) in tetrahydrofuran (2.00 mL) were added AsA'- diisopropylethylamine (66.0 mg, 511 umol, 89.0 uL, 2.00 eq) and cyclohexylmethyl carbonochloridate (67.7 mg, 383 umol, 1.50 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 purified by P / r / i-HPLC (column: Phenomenex luna C18 150*25mm* 10um; mobile phase: [water (formic acid) - acetonitrile]; B%: 46%-76%,15 min) and lyophilized to afford cyclohexylmethyl (l-(4-(2,6-dioxopiperidin-3-yl)-3,5- difluorophenyl)azetidin-3-yl)carbamate (13.07 mg, 29. 11 umol, 11% yield, 97% purity) as an off-white solid.

[0265] 1H NMR (400 MHz, DMSO-d6 ) δ = 10.85 (s, 1H), 7.94 - 7.66 (m, 1H), 6.14 (d, J= 11.1 Hz, 2H), 4.47 - 4.32 (m, 1H), 4. 13 - 3.97 (m, 3H), 3.78 (d, J= 6.5 Hz, 2H), 3.63 (t, J= 6.8 Hz, 2H), 2.84 - 2.70 (m, 1H), 2.11 - 2.02 (m, 1H), 2.00 - 1.86 (m, 1H), 1.67 (br d, J= 9.8 Hz, 4H), 1.61 (br d, J= 3.6 Hz, 1H), 1.57 - 1.49 (m, 1H), 1.29 - 1.05 (m, 4H), 0.99 - 0.87 (m, 2H). MS (ESI) m / z 457.9 [M+Na]+Synthesis of Compound 52Compound 52Step 1. Procedure for preparation of Compound 2 - ((lr,4r)-4-methylcyclohexyl)methanol.

[0266] To a solution of (lr,4r)-4-methylcyclohexanecarboxylic acid (100 mg, 703 umol, 1.00 eq) in tetrahydrofuran (1.00 mL) was added borane dimethyl sulfide complex (10.0 M, 141 uL, 2.00 eq) at 0 °C. The reaction mixture was stirred at 20 °C for 2 h. The reaction mixture was quenched by methanol (20.0 mL) and concentrated under reduced pressure to afford ((lr,4r)-4-methylcyclohexyl)methanol (80.0 mg, 624 umol, 89% yield) as colorless oil.Step 2. Procedure for preparation of ((lr,4r)-4-methylcyclohexyl)methyl (l-(4-(2,6-dioxopiperidin-3-yl)-3,5- difluorophenyl)azetidin-3-yl)carbamate.

[0267] To a solution of ((lr,4r)-4-methylcyclohexyl)methanol (35.0 mg, 273 umol, 1.00 eq) in tetrahydrofuran (1.00 mL) was added di( 1 / 7-imidazol- l-yl)methanone (44.0 mg, 273 umol, 1.00 eq) at 0 °C, the mixture was stirred at 20 °C for 1 h. The resulting solution was added to a mixture of 3-(4-(3-aminoazetidin- l-yl)-2,6-difluorophenyl)piperidine-2, 6-dione (106 mg, 270 umol, 1.00 eq, methanesulfonic acid),2,3,4,6,7,8,9,10-octahydropyrimido[l,2-a]azepine (41.1 mg, 270 umol, 40.7 uL, 1.00 eq) and N,N- diisopropylethylamine (69.8 mg, 540 umol, 94.0 uL, 2.00 eq) in tetrahydrofuran (1.00 mL) and dimethylformamide (1.00 mL). The reaction mixture was stirred at 20 °C for 12 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was diluted with dimethylformamide (1.00 mL) and then filtered. The filtrate was purified by Pre / ?-HPLC(column: Phenomenex luna C18 150* 25mm* lOum; mobile phase: [water (formic acid) - acetonitrile]; B%: 52%-82%, 9 min) and lyophilized to afford ((lr,4r)-4-methylcyclohexyl)methyl (l-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl) azetidin-3- yl)carbamate (13.95 mg, 28.86 umol, 11% yield, 93% purity) as a white solid.

[0268] 1H NMR (400 MHz, DMSO-d6 ) δ = 10.85 (s, 1H), 7.80 (br d, J = 7.3 Hz, 1H), 6.15 (s, 1H), 6.13 (s, 1H), 4.45 - 4.35 (m, 1H), 4.08 (t, J= 7.6 Hz, 2H), 4.03 (br dd, J= 5.4, 12.8 Hz, 1H), 3.78 (d, J= 6.5 Hz, 2H), 3.62 (t, J= 6.8 Hz, 2H), 2.83 - 2.72 (m, 1H), 2.52 (br s, 1H), 2. 11 - 2.03 (m, 1H), 1.96 - 1.90 (m, 1H), 1.67 (br d, J = 9.4 Hz, 4H), 1.51 - 1.43 (m, 1H), 1.30 - 1.23 (m, 1H), 1.00 - 0.87 (m, 4H), 0.85 (d, .7= 6.5 Hz. 3H). MS (ESI) m / z 450.1 [M+H]+Synthesis of Compound 53Compound 53Step 1. Procedure for Compound 2 - (4,4-dimethylcyclohexyl)methanol.

[0269] To a solution of 4,4-dimethylcyclohexanecarboxylic acid (300 mg, 1.92 mmol, 1.00 eq) in tetrahydrofuran (3.00 mL) was added borane dimethyl sulfide complex (10.0 M, 384 uL, 2.00 eq) at 0 °C. The reaction mixture was stirred at 25 °C for 2 h. The mixture was quenched with methanol (10 mL) and concentrated under reduced pressure to afford (4,4-dimethylcyclohexyl)methanol (265 mg, 1.86 mmol, 97% yield) as colorless oil.Step 2. Procedure for Compound 3 - (4,4-dimethylcyclohexyl)methyl carbonochloridate.

[0270] To a solution of (4,4-dimethylcyclohexyl)methanol (50.0 mg, 351 umol, 1.00 eq) in dichloromethane (0.500 mL) were added triethylamine (71.1 mg, 703 umol, 97.8 uL, 2.00 eq) and triphosgene (104 mg, 351 umol, 1.00 eq) at 0 °C. The reaction mixture was stirred at 25 °C for 1 h. The reaction mixture was concentrated under reduced pressure to afford (4,4-dimethylcyclohexyl)methyl carbonochloridate (71.9 mg, crude) as a white solid.Step 3. Procedure for (4,4-dimethylcyclohexyl)methyl (l-(4-(2,6-dioxopiperidin-3-yl)-3,5- difluorophenyl)azetidin-3-yl)carbamate.

[0271] To a solution of 3-(4-(3-aminoazetidin-l-yl)-2,6-difluorophenyl)piperidine-2, 6-dione (65.0 mg, 166 umol, 1.00 eq, methanesulfonic acid) and (4,4-dimethylcyclohexyl)methyl carbonochloridate (67.9 mg, 332 umol, 2.00 eq) in A'.A'-dimcthyl formamide (1.00 mL) were added triethylamine (50.4 mg, 498 umol, 69.3 uL, 3.00 eq). The reaction mixture was stirred at 25 °C for 2 h. The reaction mixture was dissolved in A'.A'-dimcthyl formamide (0.5 mL) and then filtered. The filtrate was purified by / Vc / i-HPLC (column: Phenomenex luna C18 150*25 mm* 10um; mobile phase: [water (formic acid) - acetonitrile]; B%: 52%-82%, 9 min) and lyophilized to afford (4,4-dimethylcyclohexyl)methyl (l-(4-(2,6-dioxopiperidin-3-yl)-3,5- difluorophenyl)azetidin-3-yl)carbamate (23.55 mg, 50.30 umol, 30% yield, 99% purity) as a white solid.

[0272] 1H NMR (400 MHz, DMSO-d6 ) δ = 10.85 (s, 1H), 7.81 (br d, J= 7. 1 Hz, 1H), 6. 14 (d, J= 11.0 Hz, 2H), 4.46 - 4.35 (m, 1H), 4.08 (t, J= 7.6 Hz, 2H), 4.03 (br dd, J= 5. 1, 12.6 Hz, 1H), 3.82 (br d, J= 5.9 Hz, 2H), 3.63 (t, J= 6.8 Hz, 2H), 2.83 - 2.72 (m, 1H), 2.53 - 2.51 (m, 1H), 2.07 (dq, J= 4.0, 12.9 Hz, 1H), 1.98 - 1.89 (m, 1H), 1.53 - 1.44 (m, 3H), 1.35 (br d, J= 7.4 Hz, 2H), 1.18 - 1.09 (m, 4H), 0.88 (s, 3H), 0.86 (s, 3H). MS (ESI) m / z 464.3 [M+H]+Synthesis of Compound 54 and 55Step 1. Procedure for preparation of Compound 2 - tert-butyl ((3R)-l-(4-(2,6-dioxopiperidin-3-yl)-3,5- difluorophenyl)-2-oxopyrrolidin-3-yl)carbamate.

[0273] To a solution of 3-(4-bromo-2,6-difluorophenyl)piperidine-2, 6-dione (200 mg, 658 nmol, 1.00 eq) in dioxane (3.00 mL) were added Cui (25.1 mg, 132 umol, 0.200 eq), K2CO3 (273 mg, 1.97 mmol, 3.00 eq), (7?)- / er / -biityl (2-oxopyrrolidin-3-yl)carbamate (132 mg, 658 umol, 1.00 eq) and DMEDA (29.0 mg, 329 umol, 35.4 uL, 0.500 eq). The reaction mixture was stirred at 130 °C for 4 h under nitrogen atmosphere by microwave. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by reverse phase chromatography (Cl 8, 40 g; condition: water / acetonitrile = 100:0 to 50:50, 0. 1% formic acid) and lyophilized to afford tert-butyl ((37?)-l-(4-(2,6-dioxopiperidin-3-yl)- 3,5-difluorophenyl)-2-oxopyrrolidin-3-yl)carbamate (120 mg, 283 umol, 43% yield) as an off-white solid.

[0274] 1H NMR (400 MHz, DMSO-O b = 10.96 (s, 1H), 7.52 (s, 1H), 7.49 (s, 1H), 7.30 (br d, J = 8.5 Hz, 1H), 4.43 - 4.31 (m, 1H), 4.21 (dd,J= 5.1, 12.6 Hz, 1H), 3.84 - 3.74 (m, 1H), 3.73 - 3.64 (m, 1H), 2.86 - 2.75 (m, 1H), 2.55 (br d, J= 3.1 Hz, 1H), 2.40 - 2.34 (m, 1H), 2.19 - 2.09 (m, 1H), 2.01 (br d, J = 5.8 Hz, 1H), 1.98 - 1.88 (m, 1H), 1.40 (s, 9H).Step 2. Procedure for preparation of Compound 3 - 3-(4-((R)-3-amino-2-oxopyrrolidin-l-yl)-2,6- difluorophenyl)piperidine-2, 6-dione.

[0275] To a solution of tert-butyl ((3R)-l-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)-2- oxopyrrolidin-3-yl)carbamate (120 mg, 283 umol, 1.00 eq) in dioxane (2.00 mL) was added hydrochloric acid / dioxane (4.00 M, 2.00 mL, 28.2 eq). The reaction mixture was stirred at 20 °C for 2 h. The reaction mixture was concentrated under reduced pressure to afford 3-(4-((R)-3-amino-2-oxopyrrolidin-l-yl)-2,6- difluorophenyl)piperidine-2, 6-dione (110 mg, crude, hydrochloride) as a yellow solid.

[0276] 1H NMR (400 MHz, DMSO-d6 ) δ = 10.98 (s, 1H), 8.62 (br s, 2H), 7.55 (s, 1H), 7.52 (s, 1H), 4.33 - 4.20 (m, 2H), 3.96 - 3.90 (m, 1H), 3.86 - 3.77 (m, 1H), 2.88 - 2.77 (m, 1H), 2.56 (br d, J= 3.4 Hz, 1H), 2.43 - 2.40 (m, 1H), 2.21 - 2.12 (m, 1H), 2.10 (br d, J= 10.9 Hz, 1H), 2.05 - 1.99 (m, 1H).Step 3. Procedure for preparation of Compound 3 A - spiro[3.3]heptan-2-ylmethyl carbonochloridate.

[0277] To a solution of spiro[3.3]heptan-2-ylmethanol (45.0 mg, 357 umol, 1.00 eq) in dichloromethane (1.00 mL) were added bis(trichloromethyl) carbonate (106 mg, 357 umol, 1.00 eq) and A'.A'- diisopropylethylamine (92.2 mg, 713 umol, 124 uL, 2.00 eq) at 0 °C. The reaction mixture was stirred at 20 °C for 1 h. The reaction mixture was concentrated under reduced pressure to afford spiro[3.3]heptan-2- ylmethyl carbonochloridate (67.0 mg, crude) as yellow oil.Step 4. Procedure for preparation of spiro[3.3]heptan-2-ylmethyl ((R)-l-(4-((R)-2,6-dioxopiperidin-3-yl)-3,5- difluorophenyl)-2-oxopyrrolidin-3-yl)carbamate and spiro [3.3 ]heptan-2-ylmethyl ((R)-l-( 4-((S)-2, 6- dioxopiperidin-3-yl)-3,5-difluorophenyl)-2-oxopyrrolidin-3-yl)carbamate.

[0278] To a solution of 3-(4-((R)-3-amino-2-oxopyrrolidin-l-yl)-2,6-difluorophenyl)piperidine-2,6- dione (60.0 mg, 167 umol, 1.00 eq, hydrochloride) in dimethylformamide (0.500 mL) were added Nf4- diisopropylethylamine (64.7 mg, 500 umol, 87.2 uL, 3.00 eq) and spiro[3.3]heptan-2-ylmethyl carbonochloridate (62.9 mg, 334 umol, 2.00 eq). The reaction mixture was stirred at 20 °C for 0.5 h. The reaction mixture was filtered. The filtrate was purified by reverse phase chromatography (Cl 8, 40 g; condition: water / acetonitrile = 100:0 to 40:60, 0.1% formic acid) and lyophilized to give a crude product. The crude product was purified / Vc / i-HPLCTcoliimn: DAICEL CHIRALPAK AD (250mm*30mm, lOum); mobile phase:[isopropanol- acetonitrile]; B%: 60%-60%, A6;44 min) and concentrated under reduced pressure to give two parts. The first part was purified by Pre / ?-HPLC(column: Welch Xtimate C18 150*25mm*5um; mobile phase: [water (formic acid)- acetonitrile]; B%: 43%-73%, 9 min) and lyophilized to afford spiro[3.3]heptan-2- ylmethyl ((R)-l-(4-((R)-2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)-2-oxopyrrolidin-3-yl)carbamate (8.25 mg, 13.88 umol, 8% yield, 80% purity) as a white solid. The another part was purified by Pre / ?-HPLC(column: Welch Xtimate C18 150*25mm*5um; mobile phase: [water (formic acid)- acetonitrile]; B%: 43%-73%,9 min) and lyophilized to afford spiro[3.3]heptan-2-ylmethyl ((R)-l-(4-((S)-2,6-dioxopiperidin-3-yl)-3,5- difluorophenyl)-2-oxopyrrolidin-3-yl)carbamate (7.67 mg, 15.65 umol, 9% yield, 97% purity) as a white solid.

[0279] 1H NMR (400 MHz, DMSO-d6 ) δ = 10.94 (s, 1H), 7.58 (br d, J = 8.5 Hz, 1H), 7.51 (s, 1H), 7.48 (s, 1H), 4.46 - 4.33 (m, 1H), 4.26 - 4. 17 (m, 1H), 3.96 - 3.85 (m, 2H), 3.83 - 3.75 (m, 1H), 3.74 - 3.65 (m, 1H), 2.87 - 2.76 (m, 1H), 2.57 - 2.52 (m, 1H), 2.39 - 2.34 (m, 2H), 2.18 - 2.12 (m, 1H), 2.08 - 1.93 (m, 6H), 1.92 - 1.86 (m, 2H), 1.79 - 1.69 (m, 4H). SFC: RT: 1.258 min. MS (ESI) m / z 475.9 [M+H]+

[0280] 1H NMR (400 MHz, DMSO-d6 ) δ = 10.94 (s, 1H), 7.58 (br d, J = 8.9 Hz, 1H), 7.51 (s, 1H), 7.48 (s, 1H), 4.40 (q, J= 9.3 Hz, 1H), 4.27 - 4.16 (m, 1H), 3.96 - 3.86 (m, 2H), 3.83 - 3.75 (m, 1H), 3.74 - 3.64 (m, 1H), 2.87 - 2.75 (m, 1H), 2.58 - 2.52 (m, 1H), 2.41 - 2.34 (m, 2H), 2.20 - 2.09 (m, 1H), 2.08 - 1.92 (m, 6H), 1.91 - 1.85 (m, 2H), 1.81 - 1.67 (m, 4H). SFC: RT:2.629 min. MS (ESI) m / z 476.0 [M+H]+.Synthesis of Compound 56Step 1. Procedure for preparation of Compound 3 A- spiro[3.3]heptan-2-ylmethyl carbonochloridate.

[0281] To a solution of spiro[3.3]heptan-2-ylmethanol (30.0 mg, 238 umol, 1.00 eq) in dichloromethane (2.00 mL) were added bis(trichloromethyl) carbonate (113 mg, 380 umol, 1.60 eq) and A'.A'- diisopropylethylamine (61.5 mg, 475 umol, 82.8 uL, 2.00 eq) at 0 °C. The mixture was stirred at 25 °C for 1 h. The reaction mixture was filtered and concentrated under reduced pressure to afford spiro[3.3]heptan-2- ylmethyl carbonochloridate (40.0 mg, crude) as a yellow solid.Step 2. Procedure for preparation of Compound 2- tert-butyl (l-(4-(2,6-dioxopiperidin-3-yl)-3,5- difluorophenyl)-3-methylazetidin-3-yl)carbamate.

[0282] A mixture of 3-(4-bromo-2,6-difluorophenyl)piperidine-2, 6-dione (200 mg, 658 umol, 1.00 eq), tert-butyl (3-methylazetidin-3-yl)carbamate (220 mg, 987 umol, 1.50 eq, hydrochloride), cesium carbonate (643 mg, 1.97 mmol, 3.00 eq) and [l,3-bis[2,6-bis(l-propylbutyl)phenyl]-4,5-dichloro-imidazol-2-ylidene]- dichloro-(3-chloropyridin-l-ium-l-yl)palladium (64.0 mg, 65.8 umol, 0.100 eq) in dioxane (3.00 mL) was degassed and purged with nitrogen atmosphere for 3 times. The mixture was stirred at 100 °C for 12 h under nitrogen atmosphere. The reaction mixture was filtered and concentrated under reduced pressure to afford a residue. The residue was purified by reverse phase chromatography (Cl 8, 40 g; condition: water / acetonitrile = 100:0 to 0: 100, 0.1% formic acid) and lyophilized to afford tert-butyl (l-(4-(2,6-dioxopiperidin-3-yl)-3,5- difluorophenyl)-3-methylazetidin-3-yl)carbamate (170 mg, 415 umol, 63% yield) as a white solid.Step 3. Procedure for preparation of Compound 3 - 3-(4-(3-amino-3-methylazetidin-l-yl)-2,6- difluorophenyl)piperidine-2, 6-dione.

[0283] To a solution of tert-butyl (l-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)-3- methylazetidin-3-yl)carbamate (120 mg, 293 umol, 1.00 eq) in dichloromethane (2.50 mL) was added trifluoroacetic acid (1.85 g, 16.2 mmol, 1.20 mL, 55.3 eq) at 25 °C. Then the mixture was stirred at 25°C for 2 h. The reaction mixture was concentrated under reduced pressure to afford 3-(4-(3-amino-3-methylazetidin- l-yl)-2,6-difluorophenyl)piperidine-2, 6-dione (80.0 mg, 259 umol, 88 % yield) as a white solid.

[0284] 1H NMR (400 MHz, DMSO-d6 ) δ = 10.88 (s, 1H), 8.37 (br s, 2H), 6.30 (d, J= 10.9 Hz, 2H), 4.06 (br dd, J= 4.9, 12.3 Hz, 1H), 3.95 - 3.88 (m, 2H), 3.88 - 3.80 (m, 2H), 3.11 (br d, J= 6.3 Hz, 1H), 2.81 - 2.75 (m, 1H), 2.11 - 2.03 (m, 1H), 2.00 - 1.93 (m, 1H), 1.56 (s, 3H).Step 3. Procedure for preparation of spiro[3.3]heptan-2-ylmethyl (l-(4-(2,6-dioxopiperidin-3-yl)-3,5- difluorophenyl)-3-methylazetidin-3-yl)carbamate.

[0285] To a solution of 3-(4-(3-amino-3-methylazetidin-l-yl)-2,6-difluorophenyl)piperidine-2,6- dione (30.0 mg, 97.0 umol, 1.00 eq) in dichloromethane (1.00 mL) were added A'A'-diisopropylcthylaminc (12.5 mg, 97.0 umol, 16.9 uL, 1.00 eq) and spiro[3.3]heptan-2-ylmethyl carbonochloridate (27.45 mg, 145.48 umol, 1.5 eq) at 25 °C. Then 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 purified by reverse phase chromatography (C18, 40 g; condition: water / acetonitrile = 100:0 to 0: 100, 0. 1% formic acid) and lyophilized to afford spiro[3.3]heptan-2-ylmethyl (l-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)-3-methylazetidin-3- yl)carbamate (13.75 mg, 29.8 umol, 31% yield, 96% purity) as a white solid.

[0286] 1H NMR (400 MHz, DMSO-d6 ) δ = 10.86 (s, 1H), 7.72 (br s, 1H), 6. 15 (s, 1H), 6.13 (s, 1H), 4.03 (br dd, J= 5.0, 12.5 Hz, 1H), 3.93 - 3.80 (m, 4H), 3.70 (d, J = 7.6 Hz, 2H), 2.81 - 2.71 (m, 1H), 2.37 -2.31 (m, 1H), 2.14 - 1.90 (m, 7H), 1.89 - 1.82 (m, 2H), 1.74 (br dd, J = 13, 15.0 Hz, 4H), 1.49 (s, 3H). MS (ESI) m / z 462.2 [M+H]+Synthesis of Compound 57Compound 57Step 1. Procedure for preparation of Compound 2 - 3-(4-bromo-2,6-difluorophenyl)-l-((2- ( trimethylsilyl)ethoxy)methyl)piperidine-2, 6-dione.

[0287] To a mixture of 3-(4-bromo-2,6-difluorophenyl)piperidine-2, 6-dione (2.00 g, 6.58 mmol, 1.00 eq) in dimethylformamide (20.0 mL) was added l,8-diazabicyclo[5.4.0]undec-7-ene (2.00 g, 13.2 mmol, 1.98 mL, 2.00 eq), then (2-(chloromethoxy)ethyl)trimethylsilane (1.97 g, 11.8 mmol, 2.10 mL, 1.80 eq) was dropwised at 0 °C. The reaction mixture was stirred at 20 °C for 4 h. The mixture was added water (20 mL) and extracted with ethyl acetate (3 x 30 mL). The combined organic layers were washed with brine (2 x 30 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford 3-(4- bromo-2,6-difluorophenyl)-l-((2-(trimethylsilyl)ethoxy)methyl)piperidine-2, 6-dione (2.80 g, 6.45 mmol, 98% yield) as brown oil.Step 2. Procedure for preparation of Compound 3 - tert-butyl ((3S)-l-(4-(2,6-dioxo-l-((2- (trimethylsilyl)ethoxy)methyl)piperidin-3-yl)-3,5-difluorophenyl)-5-oxopyrrolidin-3-yl)carbamate.

[0288] To a solution of 3-(4-bromo-2,6-difluoro-phenyl)-l-(2-trimethylsilylethoxymethyl)piperidine- 2, 6-dione (195 mg, 449 nmol, 1.00 eq) in dioxane (5.00 mL) were added (S)-tert-butyl (5-oxopyrrolidin-3- yl)carbamate (90.0 mg, 449 nmol, 1.00 eq), copper iodide (85.6 mg, 449 nmol, 1.00 eq), potassium carbonate (186 mg, 1.35 mmol, 3.00 eq) and A'A'’ -dimethylethylenediamine (39.6 mg, 449 umol, 48.4 uL, 1.00 eq). The reaction was stirred at 110 °C for 12 h. The recation mixture was filtered. The filtrate was purified by column chromatography (Si O2- petroleum ether / ethyl acetate=20 / l to 3 / 1) and concentrated under reduced pressure to afford tert-butyl ((3S)- l-(4-(2,6-dioxo- l-((2-(trimethylsilyl)ethoxy)methyl)piperidin-3-yl)-3,5- difluorophenyl)-5-oxopyrrolidin-3-yl)carbamate (130 mg, 235 umol, 52% yield) as a white solid.Step 3. Procedure for preparation of Compound 2 - 3-(4-((S)-4-amino-2-oxopyrrolidin-l-yl)-2,6- difluorophenyl)-! -(hydroxymethyl)piperidine-2, 6-dione.

[0289] A solution of tert-butyl ((3S)-l-(4-(2,6-dioxo-l-((2-(trimethylsilyl)ethoxy)methyl)piperidin- 3-yl)-3,5-difluorophenyl)-5-oxopyrrolidin-3-yl)carbamate (130 mg, 235 umol, 1.00 eq) in dichloromethane (3.00 mL) was added trifluoroacetic acid (924 mg, 8. 10 mmol, 0.600 mL, 34.5 eq). The mixture was stirred at 20 °C for 1 h. The reaction mixture was concentrated under reduced pressure afford 3-(4-((S)-4-amino-2- oxopyrrolidin-l-yl)-2,6-difluorophenyl)-l-(hydroxymethyl)piperidine-2, 6-dione (80.0 mg, 226 umol, 96% yield) as a white solid. MS (ESI) m / z.353.8 [M+H]+Step 4. Procedure for preparation of Compound 3 - 3-(4-((S)-4-amino-2-oxopyrrolidin-l-yl)-2,6- difluorophenyl)piperidine-2, 6-dione.

[0290] A solution of 3-(4-((S)-4-amino-2-oxopyrrolidin-l-yl)-2,6-difhiorophenyl)-l- (hydroxymethyl)piperidine-2, 6-dione (80.0 mg, 226 umol, 1.00 eq) in acetonitrile (3.00 mL) was added ammonium hydroxide (455 mg, 32.5 umol, 0.500 mL, 0.25% purity, 1.43e leq). The mixture was stirred at 20 °C for 1 h. The reaction mixture was concentrated under reduced pressure to afford 3-(4-((S)-4-amino-2- oxopyrrolidin-l-yl)-2,6-difluorophenyl)piperidine-2, 6-dione (70.0 mg, 217 umol, 96% yield) as a white solid. MS (ESI) m / z.323.8 [M+H]+Step 5. Procedure for preparation of spiro[3.3]heptan-2-ylmethyl ((3S)-l-(4-(2,6-dioxopiperidin-3-yl)-3,5- difluorophenyl)-5-oxopyrrolidin-3-yl)carbamate.

[0291] To a solution of 3-(4-((S)-4-amino-2-oxopyrrolidin-l-yl)-2,6-difluorophenyl)piperidine-2,6- dione (70.0 mg, 217 umol, 1.00 eq) in dimethylformamide (1.00 mL) were added A'.A'-diisopropylcthylaminc (56.0 mg, 433 umol, 75.4 uL, 2.00 eq) and spiro[3.3]heptan-2-ylmethyl carbonochloridate (81.7 mg, 433 umol, 2.00 eq). The reaction mixture was stirred at 20 °C for 0.5 h. The reaction mixture was filtered. The filtrate was purified by reverse phase chromatography (C18, 40 g; condition: water / acetonitrile = 100:0 to 0: 100, 0. 1% formic acid) and lyophilized to afford spiro[3.3]heptan-2-ylmethyl ((3S)-l-(4-(2,6-dioxopiperidin-3-yl)- 3,5-difluorophenyl)-5-oxopyrrolidin-3-yl)carbamate (22. 19 mg, 46.20 umol, 21% yield, 99% purity) as a white solid.

[0292] 1H NMR (400 MHz, DMSO-d6 ) δ = 10.95 (s, 1H), 7.77 - 7.65 (m, 1H), 7.47 (s, 1H), 7.44 (s, 1H), 4.25 - 4.17 (m, 2H), 4.07 (dd, J= 7.1, 10.3 Hz, 1H), 3.89 (br d, J= 6.8 Hz, 2H), 3.63 (br dd, J = 2.9, 9.9 Hz, 1H), 2.90 (dd, J= 8.2, 17.3 Hz, 1H), 2.85 - 2.76 (m, 1H), 2.55 (br d, J = 2.5 Hz, 1H), 2.48 - 2.42 (m, 1H), 2.40 - 2.33 (m, 1H), 2.18 - 2.08 (m, 1H), 2.04 (br s, 1H), 2.00 (br d, J= 8.6 Hz, 2H), 1.95 (br t, J= 7.4 Hz, 2H), 1.89 - 1.84 (m, 2H), 1.77 - 1.68 (m, 4H). MS (ESI) m / z.476.1 [M+H]+Synthesis of Compound 58Compound 58Step 1. Procedure for preparation of Compound 2 - tert-butyl ((3R)-l-(4-(2,6-dioxo-l-((2- (trimethylsilyl)ethoxy)methyl)piperidin-3-yl)-3,5-difluorophenyl)-5-oxopyrrolidin-3-yl)carbamate.

[0293] To a solution of 3-(4-bromo-2,6-difluorophenyl)-l-((2-(trimethylsilyl)ethoxy)methyl)piperidine-2, 6-dione (300 mg, 691 nmol, 1.00 eq), and (7?)- / e / 7-butyl (5- oxopyrrolidin-3-yl)carbamate (138 mg, 691 nmol, 1.00 eq) in dioxane (20.0 mL) were added copper iodide (132 mg, 691 nmol, 1.00 eq), potassium carbonate (286 mg, 2.07 mmol, 3.00 eq) and N .A"-dimcthylcthanc- 1,2-diamine (60.9 mg, 691 umol, 74.3 uL, 1.00 eq) under nitrogen atmosphere. The reaction was stirred at 110 °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 (SiO2, petroleum ether / ethyl acetate=10 / l to 2 / 1) and concentrated under reduced pressure to afford tert-butyl ((37?)-l-(4-(2,6-dioxo-l-((2-(trimethylsilyl)ethoxy)methyl)piperidin-3-yl)-3,5-difluorophenyl)-5-oxopyrrolidin-3-yl)carbamate (310 mg, 560 umol, 81% yield) as yellow oil.Step 2. Procedure for preparation of Compound 3 - -(4-((R)-4-amino-2-oxopyrrolidin-l-yl)-2,6- difluorophenyl)-! -(hydroxymethyl)piperidine-2, 6-dione.

[0294] To a solution of tert-butyl ((37?)-l-(4-(2,6-dioxo-l-((2- (trimethylsilyl)ethoxy)methyl)piperidin-3-yl)-3,5-difluorophenyl)-5-oxopyrrolidin-3-yl)carbamate (100 mg, 181 umol, 1.00 eq) in dichloromethane (1.00 mL) was added trifluoroacetic acid (154 mg, 1.35 mmol, 100 uL, 7.48 eq). The reaction was stirred at 25 °C for 1 h. The reaction mixture was concentrated under reduced pressure to afford 3-(4-((7?)-4-amino-2-oxopyrrolidin- l-yl)-2,6-difluorophenyl)- l-(hydroxymethyl)piperidine- 2, 6-dione (63.0 mg, 178 umol, 99% yield) as a white solid. MS (ESI) m / z.375.9 [M+Na]+Step 3. Procedure for preparation of Compound 4 - 3-(4-((R)-4-amino-2-oxopyrrolidin-l-yl)-2,6- difluorophenyl)piperidine-2, 6-dione.

[0295] To a solution of 3-(4-((7?)-4-amino-2-oxopyrrolidin-l-yl)-2,6-difluorophenyl)-l- (hydroxymethyl)piperidine-2, 6-dione (63.0 mg, 178 umol, 1.00 eq) in acetonitrile (1.00 mL) was added ammonium hydroxide (182 mg, 1.30 mmol, 200 uL, 25% purity, 7.28 eq). The reaction was stirred at 25 °C for 1 h. The reaction mixture was concentrated under reduced pressure to afford 3-(4-((7?)-4-amino-2- oxopyrrolidin-l-yl)-2,6-difluorophenyl)piperidine-2, 6-dione (57.0 mg, 176 umol, 99% yield) as a white solid. MS (ESI) m / z.324.0 [M+H]+Step 4. Procedure for preparation of spiro[3.3]heptan-2-ylmethyl ((3R)-l-(4-(2,6-dioxopiperidin-3-yl)-3,5- difluorophenyl)-5-oxopyrrolidin-3-yl)carbamate.

[0296] To a solution of spiro[3.3]heptan-2-ylmethyl carbonochloridate (55.0 mg, 153 umol, 1.00 eq, hydrochloride) in dimethylformamide (1.00 mL) were added spiro[3.3]heptan-2-ylmethyl carbonochloridate (58.0 mg, 306 umol, 2.00 eq) and triethylamine (46.4 mg, 459 umol, 63.8 uL, 3.00 eq). The reaction mixture was stirred at 25 °C for 10 min. The reaction mixture was filtered. The filtrate was purified by / Vc / i-HPLC (column: Phenomenex luna C18 150*25mm* 10um; mobile phase: [water (formic acid) - acetonitrile]; B%: 31%-61%, 10 min) and lyophilized to afford spiro[3.3]heptan-2-ylmethyl (f3R)- l-(4-(2,6-dioxopiperidin-3-yl)- 3,5-difhiorophenyl)-5-oxopyrrolidin-3-yl)carbamate (10.41 mg, 21.67 umol, 14% yield, 99% purity) as a white solid.

[0297] 1H NMR (400 MHz, DMSO-<7„) <5=10.95 (s, 1H), 7.71 (br d, J= 5.9 Hz, 1H), 7.47 (s, 1H), 7.44 (s, 1H), 4.30 - 4.16 (m, 2H), 4.08 (dd, J= 6.9, 10.3 Hz, 1H), 3.89 (br d, J= 6.9 Hz, 2H), 3.63 (dd, J= 3.1, 10.3Hz, 1H), 2.90 (dd, J= 8.2, 17.3 Hz, 1H), 2.85 - 2.75 (m, 1H), 2.55 (br d, J= 3.3 Hz, 1H), 2.48 - 2.42 (m, 1H), 2.35 (td, J = 7.5, 14.7 Hz, 1H), 2.19 - 2.06 (m, 1H), 2.06 - 1.92 (m, 5H), 1.91 - 1.83 (m, 2H), 1.80 - 1.64 (m, 4H). MS (ESI) m / z.476.1 [M+H]+Synthesis of Compound 59Step 1. Procedure for Compound 2 - methyl 4-(4-bromo-2-fluorophenyl)-4-cyanobutanoate.

[0298] To a solution of 2-(4-bromo-2-fluorophenyl)acetonitrile (10.0 g, 46.7 mmol, 1.00 eq) in tetrahydrofuran (100 mL) was added methyl acrylate (4.42 g, 51.3 mmol, 4.63 mL, I. IO cc / ) at 0 °C. The mixture was added sodium methoxide (504 mg, 9.34 mmol, 0.200 eq). The mixture was stirred at 20 °C for 2 h. The mixture was quenched with saturated ammonium chloride aqueous solution (100 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiQ, petroleum ether / ethyl acetate=20 / 0 to 10 / 1) to afford methyl 4-(4-bromo-2-fluorophenyl)-4-cyanobutanoate (8.40 g, 27.9 mmol, 59% yield) as a white solid.Step 2. Procedure for preparation of Compound 3 - 3-(4-bromo-2-fluorophenyl)piperidine-2, 6-dione.

[0299] To a solution of methyl 4-(4-bromo-2-fluorophenyl)-4-cyanobutanoate (7.40 g, 24.6 mmol, 1.00 eq) in acetic acid (70.0 mL) was added sulfuric acid (12.8 g, 131 mmol, 7.00 mL, 5.33 eq). The mixture was stirred at 90 °C for 2 h. The reaction mixture was poured into ice water (200 mL) and filtered. The filter cake was concentrated under reduced pressure to give 3-(4-bromo-2-fluorophenyl)piperidine-2, 6-dione (7.00 g, 24.4 mmol, 99% yield) as an white solid.Step 3. Procedure for Compound 4 - tert-butyl (l-(4-(2,6-dioxopiperidin-3-yl)-3-fluorophenyl)azetidin-3- yl)carbamate.

[0300] To a solution of 3-(4-bromo-2-fluorophenyl)piperidine-2, 6-dione (500 mg, 1.75 mmol, 1.00 eq) in dioxane (10.0 mL) were added tert-butyl azetidin-3-ylcarbamate (300 mg, 1.75 mmol, 1.00 eq), cesium carbonate (1.71 g, 5.24 mmol, 3.00 eq) and [l,3-bis[2,6-bis(l-propylbutyl)phenyl]-4,5-dichloro-imidazol-2- ylidene]-dichloro-(3-chloropyridin-l-ium-l-yl)palladium (85.0 mg, 87.3 umol, 0.0500 eq) under nitrogen atmosphere. The mixture was stirred at 100 °C for 12 h under nitrogen atmosphere. The mixture was filtered and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiCL, petroleum ether / ethyl acetate=10 / l to 1 / 1) to give a crude product. The crude product was purified by / Vc / i-HPLC (column: Phenomenex luna C18 150*25mm* 10um; mobile phase: [water (formic acid) - acetonitrile]; B%: 33%-63%, 10 min) and lyophilized to afford tert-butyl (l-(4-(2,6-dioxopiperidin-3- yl)-3-fluorophenyl)azetidin-3-yl)carbamate (206 mg, 545 umol, 31% yield) as a brown solid.Step 4. Procedure for Compound 5 - 3-(4-(3-aminoazetidin-l-yl)-2-fluorophenyl)piperidine-2, 6-dione.

[0301] To a solution of tert-butyl (l-(4-(2,6-dioxopiperidin-3-yl)-3-fluorophenyl)azetidin-3- yl)carbamate (86.0 mg, 227 umol, 1.00 eq) in dichloromethane (1.00 mL) was added trifluoroacetic acid (308 mg, 2.70 mmol, 0.200 mL, 42.4 eq). The mixture was stirred at 20 °C for 2 h. The mixture was concentrated under reduced pressure to give 3-(4-(3-aminoazetidin-l-yl)-2-fluorophenyl)piperidine-2, 6-dione (89.0 mg, crude, trifluoroacetate) as colorless oil. MS (ESI) m / z 277.9 [M+H]+Step 5. Procedure for spiro [3.3]heptan-2-ylmethyl (l-(4-(2,6-dioxopiperidin-3-yl)-3fluorophenyl)azetidin-3- yl)carbamate.

[0302] To a solution of spiro[3.3]heptan-2-ylmethanol (50.0 mg, 396 umol, 1.00 eq) in tetrahydrofuran (0.500 mL) was added di( 1 / 7-imidazol- l-yl)methanone (64.2 mg, 396 umol, 1.00 eq) at 0 °C. The mixture was stirred at 20 °C for 1 h. The resulting mixture was added to a solution of 3-(4-(3- aminoazetidin-l-yl)-2-fluorophenyl)piperidine-2, 6-dione (88.8 mg, 227 umol, 1.00 eq, trifluoroacetate), 2,3,4,6,7,8,9,10-octahydropyrimido[l,2-a]azepine (34.5 mg, 227 umol, 34.2 uL, 1.00 eq) and triethylamine(22.9 mg, 227 umol, 31.6 uL, 1.00 eq) in tetrahydrofuran (0.250 mL) and dimethylformamide (0.250 mL). The mixture was stirred at 20 °C for 12 h. The mixture was filtered and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by / Vc / i-HPLC (column: Phenomenex luna C18 150*25mm* 10um; mobile phase: [water (formic acid) - acetonitrile]; B%: 46%-76%,10 min) and lyophilized to afford spiro[3.3]heptan-2-ylmethyl (l-(4-(2,6-dioxopiperidin-3-yl)-3-fluorophenyl)azetidin-3-yl)carbamate (12.21 mg, 28. 15 umol, 12% yield, 99% purity) as an off-white solid.

[0303] 1H NMR (400 MHz, DMSO-^) 3 = 10.78 (s, 1H), 7.80 (br d, J= 7.4 Hz, 1H), 7.04 (t, J= 8.6 Hz, 1H), 6.27 - 6. 19 (m, 2H), 4.46 - 4.35 (m, 1H), 4.06 (t, J= 7.5 Hz, 2H), 3.89 (d, J= 7.0 Hz, 2H), 3.88 - 3.82 (m, 1H), 3.58 (t, J= 6.8 Hz, 2H), 2.76 - 2.54 (m, 2H), 2.39 - 2.31 (m, 1H), 2.18 - 2.06 (m, 1H), 2.05 - 1.92 (m, 5H), 1.91 - 1.84 (m, 2H), 1.79 - 1.66 (m, 4H). MS (ESI) m / z 430.1 [M+H]+Synthesis of Compound 60Compound 60Step 1. Procedure for preparation of Compound 2 - 4-bromo-l-(bromomethyl)-2-chlorobenzene.

[0304] To a solution of 4-bromo-2-chloro-l -methylbenzene (10.0 g, 48.7 mmol, 6.49 mL, 1.00 eq) in trichloromethane (100 mL) were added (E)-2,2'-(diazene-l,2-diyl)bis(2-methylpropanenitrile) (799 mg, 4.87 mmol, 0. 100 eq) and A'-Bromosuccinimidc (8.66 g, 48.7 mmol, 1.00 eq). 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 purifiedby column chromatography (SiCL, petroleum ether / ethyl acetate = 10 / 1) to afford 4-bromo-l-(bromomethyl)- 2-chlorobenzene (16.9 g, crude) as yellow oil.Step 2. Procedure for preparation of Compound 3 - 2-(4-bromo-2-chlorophenyl)acetonitrile.

[0305] To a solution of 4-bromo-l-(bromomethyl)-2 -chlorobenzene (16.9 g, 59.4 mmol, 1.00 eq) in acetonitrile (160 mL) were added trimethylsilyl cyanide (17.7 g, 178 mmol, 22.3 mL, 3.00 eq) , tetrabutylammonium fluoride (46.6 g, 178 mmol, 42.0 mL, 3.00 eq). 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 purified column chromatography (SiCL, petroleum ether / ethyl acetate = 20 / 1 to 10 / 1) to afford 2-(4-bromo-2- chlorophenyl)acetonitrile (8.78 g, 38.1 mmol, 64% yield) as a yellow oil.Step 3. Procedure for preparation of Compound 4 - methyl 4-(4-bromo-2-chlorophenyl)-4-cyanobutanoate.

[0306] To solution of 2-(4-bromo-2-chlorophenyl)acetonitrile (8.78 g, 38.1 mmol, 1.00 eq) in tetrahydrofuran (80.0 mL) were added methyl acrylate (3.61 g, 41.9 mmol, 3.77 mL, 1.10 eq) and sodium methoxide (206 mg, 3.81 mmol, 0. 100 eq) at 0 °C. Then the mixture was stirred at 25 °C for 1 h. The mixture was quenched with saturated ammonium chloride aqueous solution (80 mL) and extracted with ethyl acetate (3 x 80 mL). The combined organic layers were washed with brine (2 x 40 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford methyl 4-(4-bromo-2-chlorophenyl)-4- cyanobutanoate (9.78 g, 30.9 mmol, 81% yield) as a yellow oil.Step 4. Procedure for preparation of Compound 5 - 3-(4-bromo-2-chlorophenyl)piperidine-2, 6-dione.

[0307] To a solution of methyl 4-(4-bromo-2-chlorophenyl)-4-cyanobutanoate (9.78 g, 30.9 mmol, 1.00 eq) in acetic acid (100 mL) was added sulfuric acid (18.0 g, 183 mmol, 9.78 mL, 5.94 eq). The mixture was stirred at 90 °C for 2 h. The reaction mixture was quench with (50 mL) water and then filtered. The filter cake was purified by column chromatography (SiCL, petroleum ether / ethyl acetate=l / l to 0 / 1) to afford 3-(4- bromo-2-chlorophenyl)piperidine-2, 6-dione (3.86 g, 12.8 mmol, 41% yield) as a white solid.Step 5. Procedure for preparation of Compound 6 - tert-butyl (l-(3-chloro-4-(2,6-dioxopiperidin-3- yl)phenyl)azetidin-3-yl)carbamate.

[0308] To a solution of 3-(4-bromo-2-chlorophenyl)piperidine-2, 6-dione (50.0 mg, 165 umol, 1.00 eq) in toluene (1.00 mL) were added tert-butyl azetidin-3-ylcarbamate (56.9 mg, 331 umol, 2.00 eq), sodium tert-butoxide (95.3 mg, 992 umol, 6.00 eq), tris(dibenzylideneacetone)dipalladium(0) (15.1 mg, 16.5 umol,0. 100 eq) and dicyclohexyl(2',4',6'-triisopropyl-[l,r-biphenyl]-2-yl)phosphine (15.8 mg, 33. 1 umol, 0.200 eq). The reaction mixture was stirred at 110 °C for 45 min under nitrogen atmosphere by microwave. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was dissolved in dimethylformamide (1 mL) and then filtered. The filtrate was purified by reverse phase chromatography (Cl 8, 40 g; condition: water / acetonitrile = 100:0 to 45:55, 0.1% formic acid) and lyophilized to afford tert-butyl (1- (3-chloro-4-(2,6-dioxopiperidin-3-yl)phenyl)azetidin-3-yl)carbamate (50.0 mg, 127 umol, 77% yield) as a yellow solid.Step 6. Procedure for preparation of Compound 7 - 3-(4-(3-aminoazetidin-l-yl)-2-chlorophenyl)piperidine- 2, 6-dione.

[0309] To a solution of tert-butyl (l-(3-chloro-4-(2,6-dioxopiperidin-3-yl)phenyl)azetidin-3- yl)carbamate (50.0 mg, 127 umol, 1.00 eq) in dichloromethane (0.500 mL) was added trifluoroacetic acid (77.0 mg, 675 umol, 0.0500 mL, 5.32 eq). The reaction mixture was stirred at 20 °C for 1 h. The reaction mixture was concentrated under reduced pressure to afford 3-(4-(3-aminoazetidin-l-yl)-2-chlorophenyl)piperidine-2,6- dione (50.0 mg, crude, trifluoroacetate) as yellow oil. MS (ESI) m / z 293.8 [M+H]+Step 7. Procedure for preparation of spiro[3.3]heptan-2-ylmethyl (l-(3-chloro-4-(2,6-dioxopiperidin-3- yl)phenyl)azetidin-3-yl)carbamate.

[0310] To a solution of spiro[3.3]heptan-2-ylmethanol (20.0 mg, 158 umol, 1.00 eq) in tetrahydrofuran (0.300 mL) was added di(lH-imidazol-l-yl)methanone (25.7 mg, 158 umol, 1.00 eq). The reaction mixture was stirred at 20 °C for 1 h. The resulting solution was added to a mixture of 3-(4-(3- aminoazetidin-l-yl)-2-chlorophenyl)piperidine-2, 6-dione (50.0 mg, 123 umol, 1.00 eq, trifluoroacetate), 2,3,4,6,7,8,9,10-octahydropyrimido [1,2-a] azepine (18.7 mg, 123 umol, 18.5 uL, 1.00 eq) and Nf4- diisopropylethylamine (15.9 mg, 123 umol, 21.4 uL, 1.00 eq) in dimethylformamide (0.500 mL). The reaction mixture was stirred at 20 °C for 12 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was dissolved in dimethylformamide (0.5 mL) and then filtered. The filtrate was purified by reverse phase chromatography (C18, 40 g; condition: water / acetonitrile = 100:0 to 30:70, 0.1% formic acid) and lyophilized to afford spiro[3.3]heptan-2-ylmethyl (l-(3-chloro-4-(2,6-dioxopiperidin-3- yl)phenyl)azetidin-3-yl)carbamate (14. 15 mg, 31.10 umol, 25% yield, 98% purity) as a white solid.

[0311] 1H NMR (400MHz, DMSO-r / 6) S = 10.81 (s, 1H), 7.80 (br d, J= 7.8 Hz, 1H), 7.08 (d, J= 8.5 Hz, 1H), 6.47 (d, J= 2.4 Hz, 1H), 6.38 (dd, J= 2.3, 8.4 Hz, 1H), 4.48 - 4.34 (m, 1H), 4.08 (t, J= 7.6 Hz, 2H), 4.05 - 4.00 (m, 1H), 3.89 (d, J= 6.9 Hz, 2H), 3.59 (t, J= 6.8 Hz, 2H), 2.73 (ddd, J= 5.2, 12.5, 17.4 Hz, 1H),2.48 - 2.44 (m, 1H), 2.41 - 2.33 (m, 1H), 2.27 - 2.15 (m, 1H), 2.05 - 1.99 (m, 2H), 1.99 - 1.90 (m, 3H), 1.90 - 1.85 (m, 2H), 1.79 - 1.67 (m, 4H). MS (ESI) m / z 468.0 [M+Na]+Synthesis of Compound 61Compound 61Step 1. Procedure for preparation of Compound 2 - tert-butyl ((3S)-l-(4-(2,6-dioxopiperidin-3-yl)-3,5- difluorophenyl)pyrrolidin-3-yl)carbamate.

[0312] To a solution of 3-(4-bromo-2,6-difluoro-phenyl)piperidine-2, 6-dione (300 mg, 987 umol, 1.00 eq), (S)-fert-butyl pyrrolidin-3-ylcarbamate (276 mg, 1.48 mmol, 1.50 eq) in dioxane (3.00 ml) were added cesium carbonate (964 mg, 2.96 mmol, 3.00 eq) and [l,3-bis[2,6-bis(l-propylbutyl)phenyl]-4,5- dichloro-imidazol-2-ylidene]-dichloro-(3-chloropyridin-l-ium-l-yl)palladium (96.0 mg, 99.0 umol, 0. lOOeg). The mixture was stirred at 110 °C for 12 h under nitrogen atmosphere. The reaction mixture was filtered. Thefiltrate was concentrated under reduce pressure to give a residue. The residue was purified by reverse phase chromatography (C18, 80 g; condition: water / acetonitrile= 100:0 to 50:50, 0.1% formic acid) and lyophilized to afford tert-butyl ((3S)-l-(4-(2,6-dioxopiperidin-3-yl)-3,5-difhiorophenyl)pyrrolidin-3-yl)carbamate (200 mg, 488 umol, 50% yield) a white solid.Step 2. Procedure for preparation of Compound 3 - 3-(4-((S)-3-aminopyrrolidin-l-yl)-2,6- difluorophenyl)piperidine-2, 6-dione.

[0313] To a solution of tert-butyl ((3lS)-l-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)pyrrolidin- 3-yl)carbamate (200 mg, 489 umol, 1.00 eq) in dioxane (2.00 mL) was added hydrochloric acid / dioxane (4.00 M) (2.00 mL). The mixture was stirred at 25 °C for 1 h. The reaction mixture was concentrated under reduce pressure to afford 3-(4-((S)-3-aminopyrrolidin-l-yl)-2,6-difluorophenyl)piperidine-2, 6-dione (115 mg, 372 umol, 76 % yield, hydrochloride) as a pink solid. MS (ESI) m / z 309.8 [M+H]+Step 3. Procedure for preparation of spiro[3.3]heptan-2-ylmethyl ((3S)-l-(4-(2,6-dioxopiperidin-3-yl)-3,5- difluorophenyl)pyrrolidin-3-yl)carbamate.

[0314] To a solution of spiro[3.4]octan-2-ylmethanol (50.0 mg, 396 umol, 1.00 eq) in tetrahydrofuran (0.300 mL) was added di(lH-imidazol-l-yl)methanone (96.4 mg, 594 umol, 1.50 eq). The reaction mixture was stirred at 20 °C for 1 h. The resulting solution was added to a mixture of 3-(4-((S)-3-aminopyrrolidin-l- yl)-2,6-difluorophenyl)piperidine-2, 6-dione (115 mg, 372 umol, hydrochloride), 2,3,4,6,7,8,9,10- octahydropyrimido[l,2-a]azepine (55.5 mg, 365 umol, 55.0 uL, 1.00 eq) and triethylamine (37.0 mg, 3645 umol, 51.0 uL, 1.00 eq) in dimethylformamide (1.50 mL). The reaction mixture was stirred at 20 °C for 16 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was dissolved in dimethylformamide (1.5 mL) and then filtered. The filtrate was purified by / Vc / i-HPLC (column: Phenomenex luna C18 150*25mm* 10um; mobile phase: [water (formic acid) - acetonitrile]; B%: 51%-81%,10 min) and lyophilized to afford spiro[3.3]heptan-2-ylmethyl ((3S)-l-(4-(2,6-dioxopiperidin-3-yl)-3,5- difhiorophenyl)pyrrolidin-3-yl) carbamate (10.00 mg, 21.67 umol, 28% yield, 99% purity) as a white solid.Synthesis of Compound 62Compound 62Step 1. Procedure for preparation of Compound 2 - methyl 4-(4-bromophenyl)-4-cyanobutanoate.

[0315] To the solution of 2-(4-bromophenyl)acetonitrile (5.00 g, 25.5 mmol, 1.00 eq) in tetrahydrofuran (50.0 mL) was added lithium diisopropylamide (2.00 M, 19.2 mL, 1.50 eq) at -70 °C under nitrogen atmosphere and the mixture was stirred at -70 °C for 30 min. After 30 min, methyl 3-bromopropanoate (4.69 g, 28. 1 mmol, 3.06 mL, 1.10 eq) was added dropwise into the mixture at -70 °C. Then the reaction was stirred at 25 °C for 3.5 h. The mixture was quenched by addition of 10 mL of saturated aqueous ammonium chloride, then extracted by ethyl acetate (2 x 50 mL). The combined organic layers were washed with brine (2 x 10 mL), and dried over anhydrous sodium sulfate, filtered and concentrate to give a residue The residue was purified by column chromatography (SiCfe, petroleum ether / ethyl acetate = 10 / 1) to afford methyl 4-(4- bromophenyl)-4-cyanobutanoate (2.50 g, 8.86 mmol, 35% yield) as colorless oil.Step 2. Procedure for preparation of Compound 3 - 3-(4-bromophenyl)piperidine-2, 6-dione.

[0316] To the solution of methyl 4-(4-bromophenyl)-4-cyanobutanoate (2.70 g, 9.57 mmol, 1.00 eq) in acetic acid (20.0 mL) was added sulfuric acid (2.00 mL). Then the reaction was stirred at 90 °C for 2 h. The reaction mixture was added dropwised into cold water and stirred for 0.5 h. The mixture was filtered. The filter cake was concentrated under reduced pressure to afford 3 -(4-bromophenyl)piperidine-2, 6-dione (1.60 g, 5.97 mmol, 62% yield) as a white solid.Step 3. Procedure for preparation of Compound 4 - tert-butyl (l-(4-(2,6-dioxopiperidin-3-yl)phenyl)azetidin- 3-yl)carbamate.

[0317] To the solution of 3-(4-bromophenyl)piperidine-2, 6-dione (400 mg, 1.49 mmol, 1.00 eq), tert- butyl azetidin-3-ylcarbamate (308 mg, 1.79 mmol, 1.20 eq) in dioxane (20.0 mL) were added cesium carbonate (1.46 g, 4.48 mmol, 3.00 eq), l,3-bis[2,6-bis(l-propylbutyl)phenyl]-4,5-dichloro-2H-imidazol-l-ium-2-ide;3- chloropyridine;dichloropalladium (40.0 mg, 41.1 umol, 2.76e-2 eq) under nitrogen atmosphere. Then the reaction was stirred at 110 °C for 12 h. The mixture was diluted with water (10 mL), extracted with a solution of dichloromethane / isopropanol = 3 / 1 (2 x 20mL). The combined organic layers were washed with brine (2 x 10 mL), dried over anhydrous sodium sulfate, filtered and concentrate to give a residue. The residue was purified by column chromatography (SiCL, petroleum ether / ethyl acetate = 1 / 1 to 1 / 2) to afford tert-butyl (1- (4-(2,6-dioxopiperidin-3-yl)phenyl)azetidin-3-yl)carbamate (140 mg, 389 umol, 26% yield) as a white solid.Step 4. Procedure for preparation of Compound 5 - 3-(4-(3-aminoazetidin-l-yl)phenyl)piperidine-2, 6-dione.

[0318] To the solution of tert-butyl (l-(4-(2,6-dioxopiperidin-3-yl)phenyl)azetidin-3-yl)carbamate (220 mg, 612 umol, 1.00 eq) in dichloromethane (3.00 mL) was added trifluoroacetic acid (813 mg, 7. 13 mmol, 528 uL, 11.7 eq). Then the reaction was stirred at 25 °C for 4 h. The reaction mixture was concentrated under reduced pressure to to afford 3 -(4-(3-aminoazetidin-l-yl)phenyl)piperidine-2, 6-dione (158 mg, crude, trifluoroacetate) as brown oil. MS (ESI) m / z 260. 1 [M+H]+Step 5. Procedure for preparation of spiro[3.3]heptan-2-ylmethyl (l-(4-(2,6-dioxopiperidin-3- yl)phenyl)azetidin-3-yl)carbamate.

[0319] To the solution of spiro[3.3]heptan-2-ylmethanol (50.0 mg, 396 umol, 1.00 eq) in tetrahydrofuran (0.500 mL) was added di( IH-imidazol- 1 -yl)methanone (64.2 mg, 396.2 umol, 1.00 eq) at 0 °C. Then the reaction was stirred at 25 °C for 0.5 h. Then to the mixture were added tetrahydrofuran (0.500 mL), 3-(4-(3-aminoazetidin-l-yl)phenyl)piperidine-2, 6-dione (108 mg, 289 umol, 1.00 eq, trifluoroacetate), triethylamine (29.3 mg, 289 umol, 40.3 uL, 1.00 eq), 2,3,4,6,7,8,9,10-octahydropyrimido[l,2-a]azepine (44.0 mg, 289 umol, 43.6 uL, 1.00 eq). Then the reaction was stirred at 25 °C for 12 h. The reaction mixture wasconcentrated under reduced pressure to give a residue. The residue was purified by prep-WLC (column: Phenomenex luna C18 150*25 mm* lOum; mobile phase: [water (formic acid) - acetonitrile]; B%: 45%-75%, 10 min) and lyophilized to afford spiro[3.3]heptan-2-ylmethyl (l-(4-(2,6-dioxopiperidin-3-yl)phenyl)azetidin- 3-yl)carbamate (35.16 mg, 82.03 umol, 28% yield, 96% purity) as an off-white solid.

[0320] 1H NMR (400 MHz, DMSO-c / ) 3 = 10.7 (s, 1H), 7.76 (br d, J= 7.3 Hz, 1H), 7.00 (d, J= 7.9 Hz, 2H), 6.39 (br d, J= 8.0 Hz, 2H), 4.44 - 4.38 (m, 1H), 4.05 (t, J= 7.3 Hz, 2H), 3.89 (br d, J= 6.8 Hz, 2H), 3.70 (br dd, J= 4.9, 10.6 Hz, 1H), 3.54 (br t, J= 6.6 Hz, 2H), 2.65 - 2.57 (m, 1H), 2.47 - 2.42 (m, 1H), 2.37 - 2.32 (m, 1H), 2.13 - 2.08 (m, 1H), 2.04 - 1.95 (m, 5H), 1.89-1.86 (m, 2H), 1.76-1.70 (m, 4H). MS (ESI) m / z 412.1 [M+H]+Synthesis of Compound 63Compound 63Step 1. Procedure for preparation of Compound 2 - l-bromo-4-(bromomethyl)-3-chloro-2-methoxybenzene.

[0321] To a solution of l-bromo-3-chloro-2-methoxy-4-methyl-benzene (4.00 g, 17.0 mmol, 1.00 eq) in carbon tetrachloride (40.0 mL) were added A'-bromosiiccinimidc (3.02 g, 17.0 mmol, 1.00 eq) and azodiisobutyronitrile (139 mg, 849 nmol, 0.0500 eq). The reaction mixture was stirred at 80 °C for 2 h. The mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate=l / to 10 / 1) to afford l-bromo-4-(bromomethyl)-3-chloro- 2-methoxybenzene (2.70 g, 8.59 mmol, 51% yield) as colorless oil.Step 2. Procedure for preparation of Compound 3 - 2-(4-bromo-2-chloro-3-methoxyphenyl)acetonitrile.

[0322] To a solution of l-bromo-4-(bromomethyl)-3-chloro-2-methoxybenzene (2.70 g, 8.59 mmol, 1.00 eq) in acetonitrile (5.00 mL) were added trimethylsilyl cyanide (2.56 g, 25.8 mmol, 3.22 mL, 3.00 eq) and tetrabutylammonium fluoride (1.00 M, 25.8 mL, 3.00 eq). The reaction mixture was stirred at 20 °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 =1 / 0 to 10 / 1) and concentrated under reduced pressure to afford 2-(4-bromo-2-chloro-3-methoxyphenyl)acetonitrile (2.25 g, crude) as colorless oil.Step 3. Procedure for preparation of Compound 4 - methyl 4-(4-bromo-2-chloro-3-methoxyphenyl)-4- cyanobutanoate.

[0323] To a solution of 2-(4-bromo-2-chloro-3-methoxyphenyl)acetonitrile (2.25 g, 8.64 mmol, 1.00 eq) and methyl acrylate (818 mg, 9.50 mmol, 856 uL, 1.10 eq) in tetrahydrofuran (20.0 mL) was added sodium methoxide (46.7 mg, 864 umol, 0.100 eq) at 0 °C. The reaction mixture was stirred at 20 °C for 1 h. The mixture was quenched with saturated ammonium chloride aqueous solution (30 mL) and extracted with ethyl acetate (3 x 30 mL). The combined organic layers were washed with brine (2 x 30 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford methyl 4-(4-bromo-2-chloro-3- methoxyphenyl)-4-cyanobutanoate (2.90 g, 8.37 mmol, 97% yield) as colorless oil.Step 4. Procedure for preparation of Compound 5 - 3-(4-bromo-2-chloro-3-methoxyphenyl)piperidine-2,6- dione.

[0324] To a solution of methyl 4-(4-bromo-2-chloro-3-methoxyphenyl)-4-cyanobutanoate (2.90 g, 8.37 mmol, 1.00 eq) in acetic acid (30.0 mL) was added sulfuric acid (5.48 g, 55.9 mmol, 2.98 mL, 6.68 eq). The mixture was stirred at 90 °C for 2 h. The mixture was poured into ice water (20.0 mL) and filtered. The filter cake was dried under reduced pressure to afford 3-(4-bromo-2-chloro-3-methoxyphenyl)piperidine-2,6- dione (1.49 g, 4.48 mmol, 54% yield) as a white solid.Step 5. Procedure for preparation of Compound 6 - tert-butyl (l-(3-chloro-4-(2,6-dioxopiperidin-3-yl)-2- methoxyphenyl)azetidin-3-yl)carbamate.

[0325] To a solution of 3-(4-bromo-2-chloro-3-methoxy-phenyl)piperidine-2, 6-dione (400 mg, 1.20 mmol, 1.00 eq), tert-butyl azetidin-3-ylcarbamate (269 mg, 1.56 mmol, 1.30 eq) and cesium carbonate (1.18 g, 3.61 mmol, 3.00 eq) in dioxane (4.00 mL) were added [l,3-bis[2,6-bis(l-propylbutyl)phenyl]-4,5-dichloro- imidazol-2-ylidene]-dichloro-(3-chloropyridin-l-ium-l-yl)palladium (40.0 mg, 41.12 umol, 3.42e-2eq). Thereaction mixture was stirred at 100 °C for 12 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 (SiCL, petroleum ether / ethyl acetate= 100 / 1 to 1 / 1) and concentrated under reduced pressure to afford tert-butyl (l-(3-chloro-4-(2,6-dioxopiperidin-3-yl)-2-methoxyphenyl)azetidin-3-yl)carbamate (70.0 mg, 165 umol, 14% yield) as a yellow solid.Step 6. Procedure for preparation of Compound 7 - 3-(4-(3-aminoazetidin-l-yl)-2-chloro-3- methoxyphenyl)piperidine-2, 6-dione.

[0326] To a solution of tert-butyl (l-(3-chloro-4-(2,6-dioxopiperidin-3-yl)-2- methoxyphenyl)azetidin-3-yl)carbamate (60.0 mg, 142 umol, 1.00 eq) in dichloromethane (1.00 mL) were added trifluoroacetic acid (154 mg, 1.35 mmol, 0. 100 mL, 9.54 eq). The reaction mixture was stirred at 20 °C for 1 h. The reaction mixture was concentrated under reduce pressure to afford 3-[4-(3-aminoazetidin-l-yl)-2- chloro-3-methoxy-phenyl]piperidine-2, 6-dione (45.0 mg, crude) as a yellow solid.Step 7. Procedure for preparation of spiro[3.3]heptan-2-ylmethyl (l-(3-chloro-4-(2,6-dioxopiperidin-3-yl)-2- methoxyphenyl)azetidin-3-yl)carbamate.

[0327] To a solution of spiro[3.3]heptan-2-ylmethanol (20.0 mg, 158 umol, 1.00 eq) in tetrahydrofuran (1.00 mL) were added di( 1 / 7-imidazol- l-yl)methanone (51.4 mg, 317 umol, 2.00 eq) at 0 °C. The reaction mixture was stirred at 25 °C for 1 h. The resulting solution was added to a mixture of 3-(4-(3- aminoazetidin-l-yl)-2-chloro-3-methoxyphenyl)piperidine-2, 6-dione (45.0 mg, 139 umol, 1.00 eq) in tetrahydrofuran (0.500 mL) and dimethylformamide (0.500 mL) were added triethylamine (14.1 mg, 139 umol, 19.4 uL, 1.00 eq), 2,3,4,6,7,8,9,10-octahydropyrimido[l,2-a]azepine (21.2 mg, 139 umol, 21.0 uL, 1.00 eq). The reaction mixture was stirred at 25 °C for 16 h. Then, a solution of spiro[3.3]heptan-2-ylmethanol (20.0 mg, 158 umol, 1.00 eq) in tetrahydrofuran (1.00 mL) were added di(l / / -imidazol-l-yl)methanone (51.4 mg, 317 umol, 2.00 eq), and the solution was added into the mixture. Finally, the reaction mixture was stirred at 25 °C for 48 h. The reaction mixture was filtered. The filtrate was purified by / Vc / i-HPLC (column: Phenomenex luna C18 150*25 mm* 10 um; mobile phase: [water (formic acid)-acetonitrile]; B%: 50%-80%, 10 min) and lyophilized to afford spiro[3.3]heptan-2-ylmethyl (l-(3-chloro-4-(2,6-dioxopiperidin-3-yl)-2- methoxyphenyl)azetidin-3-yl)carbamate (9.01 mg, 18.74 umol, 13% yield, 99% purity) as a white solid..

[0328] 1H NMR (400 MHz, DMSO-d6 ) δ = 10.82 (s, 1H), 7.77 (br d, J= 7.5 Hz, 1H), 6.89 (d, J= 8.4 Hz, 1H), 6.42 (d, J = 8.5 Hz, 1H), 4.47 - 4.31 (m, 1H), 4.14 (br t, J= 7.5 Hz, 2H), 4.05 (dd, J= 5.0, 12.1 Hz, 1H), 3.89 (d, J = 7.0 Hz, 2H), 3.70 - 3.59 (m, 5H), 2.78 - 2.69 (m, 1H), 2.49 - 2.43 (m, 1H), 2.40 - 2.31 (m,1H), 2.27 - 2.15 (m, 1H), 2.06 - 1.92 (m, 5H), 1.91 - 1.84 (m, 2H), 1.80 - 1.66 (m, 4H). MS (ESI) m / z.476.1 [M+H]+Synthesis of Compound 64Step 1. Procedure for preparation of Compound 2 - tert-butyl ((3R)-l-(4-(2,6-dioxopiperidin-3-yl)-3,5- difluorophenyl)pyrrolidin-3-yl)carbamate.

[0329] To a solution of 3-(4-bromo-2,6-difluorophenyl)piperidine-2, 6-dione (100 mg, 329 umol, 1.00 eq) in dioxane (2.00 mL) were added cesium carbonate (321 mg, 987 umol, 3.00 eq), (7?)-fert-butyl pyrrolidin- 3-ylcarbamate (91.9 mg, 493 umol, 1.50 eq) and [l,3-bis[2,6-bis(l-propylbutyl)phenyl]-4,5-dichloro-imidazol- 2-ylidene]-dichloro-(3-chloropyridin-l-ium-l-yl)palladium (32.0 mg, 32.9 umol, 0.100 eq). The reaction mixture was stirred at 110 °C for 12 h. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by reverse phase chromatography (Cl 8, 40 g; condition: water / acetonitrile = 100:0 to 0: 100, 0.1% formic acid) and lyophilized to afford / c / 7-butyl ((37?)-l-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)pyrrolidin-3-yl)carbamate (70.0 mg, 171 umol, 52% yield) as yellow oil.Step 2. Procedure for preparation of Compound 3 - 3-(4-((R)-3-aminopyrrolidin-l-yl)-2,6- difluorophenyl)piperidine-2, 6-dione.

[0330] To a solution of tert-butyl ((37?)-l-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)pyrrolidin- 3-yl)carbamate (70.0 mg, 171 umol, 1.00 eq) in dioxane (1.00 mL) was added hydrochloric acid / dioxane (4.00 M, 1.75 mL, 40.9 eq). The reaction mixture was stirred at 20 °C for 2 h. The reaction mixture was concentrated under reduced pressure to afford 3-(4-((R)-3-aminopyrrolidin-l-yl)-2,6-difluorophenyl)piperidine-2, 6-dione (59.0 mg, 171 umol, 99% yield, hydrochloride) as a yellow solid.Step 3. Procedure for preparation of spiro[3.3]heptan-2-ylmethyl ((3R)-l-(4-(2,6-dioxopiperidin-3-yl)-3,5- difluorophenyl)pyrrolidin-3-yl)carbamate.

[0331] To a solution of spiro[3.4]octan-2-ylmethanol (25.0 mg, 198 umol, 1.00 eq) in tetrahydrofuran (0.300 mL) was added di(lH-imidazol-l-yl)methanone (48.2 mg, 297 umol, 1.50 eq). The reaction mixture was stirred at 20 °C for 1 h. The resulting solution was added to a mixture of 3-(4-((R)-3-aminopyrrolidin-l- yl)-2,6-difluorophenyl)piperidine-2, 6-dione (59.0 mg, 171 umol, 99% yield, hydrochloride), 2,3,4,6,7,8,9,10- octahydropyrimido[l,2-a]azepine (26.0 mg, 171 umol, 25.7 uL, 1.00 eq) and A / A'-diisopropylcthylaminc (22.1 mg, 171 umol, 29.7 uL, 1.00 eq) in dimethylformamide (0.500 mL). The reaction mixture was stirred at 20 °C for 16 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was dissolved in dimethylformamide (1.5 mL) and then filtered. The filtrate was purified by / Vc / i-HPLC (column: Phenomenex luna C18 150*25mm* lOum; mobile phase: [water (formic acid)- acetonitrile]; B%: 52%-82%,9 min) and lyophilized to afford spiro[3.3]heptan-2-ylmethyl ((3R)-l-(4-(2,6-dioxopiperidin-3-yl)-3,5- difhiorophenyl)pyrrolidin-3-yl) carbamate (22. 10 mg, 47.41 umol, 28% yield, 99% purity) as a white solid.

[0332] 1H NMR (400 MHz, DMSO-O 8 = 10.83 (s, 1H), 7.48 (br d, J = 6.5 Hz, 1H), 6.20 (s, 1H),6.17 (s, 1H), 4.21 - 4.10 (m, 1H), 4.01 (br dd, J= 5.1, 12.5 Hz, 1H), 3.89 (br d, J= 6.9 Hz, 2H), 3.48 - 3.41 (m, 1H), 3.34 (br s, 1H), 3.26 - 3. 18 (m, 1H), 3.04 (br dd, J= 4.3, 9.4 Hz, 1H), 2.83 - 2.72 (m, 1H), 2.52 (br d, J = 1.9 Hz, 1H), 2.43 - 2.34 (m, 1H), 2.18 - 2.11 (m, 1H), 2.10 - 1.99 (m, 3H), 1.99 - 1.89 (m, 4H), 1.86 (br d, J= 7.5 Hz, 2H), 1.78 - 1.67 (m, 4H).

[0333] 1H NMR (400 MHz, DMSO-rZ6, T=80 °C) 3 = 10.55 (br s, 1H), 7.16 (br d, J = 3.6 Hz, 1H),6.18 (s, 1H), 6.15 (s, 1H), 4.22 - 4.13 (m, 1H), 3.99 (dd, J= 5.4, 12.4 Hz, 1H), 3.92 (d, J= 6.8 Hz, 2H), 3.47 (dd, J= 6.7, 9.8 Hz, 1H), 3.41 - 3.32 (m, 1H), 3.29 - 3.19 (m, 1H), 3.05 (br s, 1H), 2.84 - 2.71 (m, 1H), 2.54(br d, J= 3.8 Hz, 1H), 2.42 - 2.34 (m, 1H), 2.22 - 2.14 (m, 1H), 2.13 - 2.02 (m, 3H), 2.01 - 1.92 (m, 4H), 1.92- 1.87 (m, 2H), 1.82 - 1.69 (m, 4H). MS (ESI) m / z 462.2 [M+H]+.Synthesis of Compound 65Compound 65Step 1. Procedure for preparation of Compound 2- diethyl 2-(2-cyclopropylpropan-2-yl)malonate.

[0334] To a solution of copper iodide (19.0 g, 100 mmol, 2.00 eq) in tetrahydrofuran (125 mL) at -40 °C was added bromo(cyclopropyl)magnesium (0.500, 400 mL, 4.00 eq) under nitrogen atmosphere. After stirring for 15 min, the suspension was allowed to warm up and stirred at 20 °C for 20 min before cooling back to -40°C. A solution of diethyl 2-(propan-2-ylidene) malonate (10.0 g, 50.0 mmol, 1.00 eq) in tetrahydrofuran (125 mL) was added, and the reaction was allowed to warm to 20 °C 12 h. The reaction mixture was then quenched with saturated sodium bicarbonate (50 mL) and filtered. The filtrate was extracted with ethyl acetate (3 x 125 mL). The combined extracts were dried over sodium sulfate and concentrated to get a residue. The residue was purified by column chromatography (SiCL, petroleum ether / ethyl acetate = 100 / 1 to 50 / 1) and concentrated under reduced pressure to afford diethyl 2-(l -cyclopropyl- 1 -methyl -ethyl)propanedioate (4.30 g, crude) as colorless oil.Step 2. Procedure for preparation of Compound 3- ethyl 3-cyclopropyl-3-methylbutanoate.

[0335] To a solution of diethyl 2-(2-cyclopropylpropan-2-yl)malonate (1.00 g, 4.13 mmol, 1.00 eq) and lithium chloride (1.05 g, 24.8 mmol, 507 uL, 6.00 eq) in dimethylsulfoxide (25.0 mL) and water (0.300 mL). The mixture was stirred at 170 °C for 12 h. Then, the mixture was stirred at 150 °C for 12 h. The reaction mixture was quenched with water (20 mL) and extracted with methyl fert-butylether (3 x 30 mL). The combined organic layers were washed with brine (40 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= 100 / 1 to 50 / 1) and concentrated under reduced pressure to afford ethyl 3- cyclopropyl-3-methylbutanoate (190 mg, crude) as colorless oil.Step 3. Procedure for preparation of Compound 4- 3-cyclopropyl-3-methylbutan-l-ol.

[0336] To a solution of ethyl 3-cyclopropyl-3-methylbutanoate (100 mg, 587 umol, 1.00 eq) in tetrahydrofuran (5.00 mL) was added lithium aluminium hydride (33.4 mg, 881 umol, 1.50 eq) at 0 °C. The reaction mixture was stirred at 25 °C for 2 h. The reaction was quenched by addition of water (5 mL), 15% sodium hydroxide (5 mL) and water (15.00 mL). Then the mixture was filtered. The filtrate was extracted with ethyl acetate (3 x 15 mL). The combined organic layers were washed with brine (3x 15 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to afford 3-cyclopropyl-3-methylbutan-l-ol (60.0 mg, 468 mol, 80% yield) as colorless oil.Step 4. Procedure for preparation of 3-cyclopropyl-3-methylbutyl (l-(4-(2,6-dioxopiperidin-3-yl)-3,5- difluorophenyl)azetidin-3-yl)carbamate.

[0337] To a solution of 3-cyclopropyl-3-methylbutan-l-ol (10.0 mg, 78.0 umol, 1.00 eq) in tetrahydrofuran (1.00 mL) was added di( 1 / 7-imidazol- l-yl)methanone (19.0 mg, 117 umol, 1.50 eq). The mixture was stirred at 25 °C for 1 h. The resulting solution was added to a mixture of 3-(4-(3-aminoazetidin- l-yl)-2,6-difluorophenyl)piperidine-2, 6-dione (31.9 mg, 77.8 umol, 1.00 eq, trifluoroacetate), 2,3,4,6,7,8,9,10- octahydropyrimido[l,2-a]azepine (11.9 mg, 77.8 umol, 11.7 uL, 1.00 eq) and triethylamine (7.88 mg, 77.8 umol, 10.8 uL, 1.00 eq) in dimethylformamide (0.500 mL) and tetrahydrofuran (0.500 mL). The reaction mixture was stirred at 25 °C for 24 h. The reaction mixture was filtered. The filtrate was purified by Prep- HPLC(column: Phenomenex luna C18 150*25mm* lOum; mobile phase: [water (formic acid)-acetonitrile]; B%: 50%-80%,8 min) and lyophilized to afford 3 -cyclopropyl-3 -methylbutyl (l-(4-(2,6-dioxopiperidin-3-yl)- 3,5-difluorophenyl)azetidin-3-yl)carbamate (5.49 mg, 11.85 umol, 15% yield, 97% purity) as a white solid.

[0338] 1H NMR (400 MHz, DMSO-<7„) 3 = 10.85 (s, 1H), 7.76 (br d, J= 7.0 Hz, 1H), 6. 14 (d, J= 11. 1 Hz, 2H), 4.51 - 4.32 (m, 1H), 4.07 (br s, 5H), 3.63 (br t, J= 6.7 Hz, 2H), 2.83 - 2.69 (m, 1H), 2.47 (br s, 1H), 2.14 - 2.02 (m, 1H), 1.99 - 1.88 (m, 1H), 1.54 (br t, J= 7.6 Hz, 2H), 0.74 (s, 6H), 0.71 - 0.61 (m, 1H), 0.27 - 0.21 (m, 2H), 0.18 - 0.12 (m, 2H). MS (ESI) m / z.472.0 [M+Na]+Synthesis of Compound 66Compound 66Step 1. Procedure for preparation of Compound 2 - 4-methylpent-4-en-l-ol.

[0339] To a solution of ethyl 4-methylpent-4-enoate (2.00 g, 14.1 mmol, 1.00 eq) in tetrahydrofuran (20.0 mL) was added lithium aluminum hydride (1.07 g, 28.1 mmol, 2.00 eq) at 0 °C. The reaction mixture was stirred at 20 °C for 12 h. The reaction mixture was quenched with water (1.07 mL), 15% sodium hydroxide (1.07 mL), water (3.21 mL), then filtered and the filtrate was concentrated under reduced pressure to afford 4- methylpent-4-en-l-ol (600 mg, 5.99 mmol, 43% yield) as yellow oil.Step 2. Procedure for preparation of Compound 3 - benzyl (4-methylpent-4-en-l-yl) carbonate.

[0340] To a solution of 4-methylpent-4-en-l-ol (500 mg, 4.99 mmol, 1.00 eq) in dichloromethane (5.00 mL) were added pyridine (790 mg, 9.98 mmol, 806 uL, 2.00 eq), 4-dimethylaminopyridine (30.5 mg, 250 nmol, 0.0500 eq) and benzyl carbonochloridate (937 mg, 5.49 mmol, 781 uL, 1.10 eq). The reaction mixture was stirred at 20 °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 (SiCL, petroleum ether / ethyl acetate=l / O = to 50 / 1) to afford benzyl (4-methylpent-4-en-l-yl) carbonate (600 mg, 2.56 mmol, 51 % yield) as yellow oil.Step 3. Procedure for preparation of Compound 4 - benzyl (3-(l-methylcyclopropyl)propyl) carbonate.

[0341] To a solution of diethylzinc (1.00 M, 1.28 mL, 3.00 eq) in dichloromethane (1.00 mL) was dropwise added trifluoroacetic acid (146 mg, 1.28 mmol, 94.8 uL, 3.00 eq) in dichloromethane (1.00 mL) at 0 °C for 25 min under nitrogen atmosphere. To this suspension was dropwise added diiodomethane (343 mg, 1.28 mmol, 103 uL, 3.00 eq) in dichloromethane (1.00 mL) at 0 °C for 10 min under nitrogen atmosphere. The resulting solution was stirred at 0 °C for 25 min, at which time benzyl 4-methylpent-4-enyl carbonate (100 mg, 427 umol, 1.00 eq) was added. The reaction mixture was stirred at 0 °C for 30 min and then warmed to 20 °C for 11 h. The reaction mixture was added saturated aqueous ammonium chloride solution (2.00 mL) to quench diethylzinc, and then the mixture was extracted with ethyl acetate (3 x 3 mL). The combined organic phases were dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford benzyl (3-(l-methylcyclopropyl)propyl) carbonate (100 mg, 403 umol, 94% yield) as yellow oil.Step 4. Procedure for preparation of Compound 5 - 3-(l-methylcyclopropyl)propan-l-ol.

[0342] To a solution of benzyl 3-(l-methylcyclopropyl)propyl carbonate (100 mg, 403 umol, 1.00 eq) in dioxane (1.00 mL) was added palladium on activated carbon (100 mg, 10 % purity). The reaction mixture was stirred at 20 °C for 12 h under 15 psi of hydrogen atmosphere. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to afford 3-(l-methylcyclopropyl)propan-l-ol (30.0 mg, 263 umol, 65 % yield) as yellow oil.Step 5. Procedure for preparation of 3-(l-methylcyclopropyl)propyl (l-(4-(2,6-dioxopiperidin-3-yl)-3,5- difluorophenyl)azetidin-3-yl)carbamate.

[0343] To a solution of 3-(l-methylcyclopropyl)propan-l-ol (30.0 mg, 263 umol, 1.00 eq) in tetrahydrofuran (0.300 mL) was added di( 1 / 7-imidazol- l-yl)methanone (63.9 mg, 394 umol, 1.50 eq) at 0 °C.The mixture was stirred at 20 °C for 2 h. The resulting solution was added to a mixture of 3-(4-(3- aminoazetidin-l-yl)-2,6-difluorophenyl)piperidine-2, 6-dione (85.0 mg, 208 umol, 1.00 eq, trifluoroacetate), 2,3,4,6,7,8,9,10-octahydropyrimido[l,2-a]azepine (31.6 mg, 208 umol, 31.3 uL, 1.00 eq) and N,N- diisopropylethylamine (40.3 mg, 312 umol, 54.3 uL, 1.50 eq) in tetrahydrofuran (0.300 mL) and dimethylformamide (0.300 mL). The reaction mixture was stirred at 20 °C for 12 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was diluted with dimethylformamide (1.00 mL) and then filtered. The filtrate was purified by / Vc / i-HPLCTcolumn: Phenomenex luna C18 150*25mm* 10um;mobile phase: [water (formic acid)- acetonitrile] ;B%: 47%-77%, 9 min) and lyophilized to afford 3-(l- methylcyclopropyl)propyl ( 1 -(4-(2,6-dioxopiperidin-3-yl)-3 ,5 -difluorophenyl)azetidin-3 -yl)carbamate (21.16 mg, 48. 11 umol, 23 % yield, 99 % purity) as a white solid.

[0344] 1H NMR (400 MHz, DMSO-d6 =) δ 10.85 (s, 1H), 7.79 (br d, J = 6.6 Hz, 1H), 6.15 (s, 1H), 6.13 (s, 1H), 4.48 - 4.33 (m, 1H), 4.08 (br t, J= 7.6 Hz, 2H), 4.05 - 4.00 (m, 1H), 3.95 (br t, J= 6.4 Hz, 2H), 3.62 (br t, J= 6.4 Hz, 2H), 2.82 - 2.73 (m, 1H), 2.56 (br d, J= 5. 1 Hz, 1H), 2. 12 - 2.05 (m, 1H), 2.03 - 1.92 (m, 1H), 1.66 - 1.58 (m, 2H), 1.27 - 1.20 (m, 2H), 0.99 (s, 3H), 0.22 (br d, J= 2.4 Hz, 4H). MS (ESI) m / z 436.0 [M+H]+Synthesis of Compound 67Step 1. Procedure for preparation of Compound 2 - 3-(4-(3-aminoazetidin-l-yl)-2,6- difluorophenyl)piperidine-2, 6-dione.

[0345] A solution of tert-butyl (l-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)azetidin-3- yl)carbamate (200 mg, 505 umol, 1.00 eq) in methyl tert-butyl ether (1.00 mL) was added into a mixture of sulfuric acid (151 mg, 1.52 mmol, 82.5 uL, 98% purity, 3.00 eq) and methyl tert-butyl ether (2.00 mL). The mixture was stirred at 25 °C for 1 h. The mixture was diluted with acetonitrile (15 mL) and stirred for 15 min. Then the mixture was filtered and the filter cake was concentrated under reduced pressure to affcrd 3-(4-(3- aminoazetidin-l-yl)-2,6-difluorophenyl)piperidine-2, 6-dione (145 mg, 258 umol, 51% yield, 70% purity, sulfate salt) as a yellow solid.Step 2. Procedure for preparation of Compound 2A - spiro[3.5]nonan-2-yl IH-imidazole-l -carboxylate.

[0346] To a solution of spiro[3.5]nonan-2-ol (40.0 mg, 285 umol, 1.00 eq) in tetrahydrofuran (1.00 mL) was added di( 1 / 7-imidazol- l-yl)methanone (37.0 mg, 228 umol, 0.800 eq) at 0 °C. The mixture was stirred at 20 °C for 1 h. The mixture was used directly to the next step.Step 3. Procedure for preparation of spiro [3.5]nonan-2-yl (l-(4-(2,6-dioxopiperidin-3-yl)-3,5- difluorophenyl)azetidin-3-yl)carbamate.

[0347] To a solution of 3-(4-(3-aminoazetidin-l-yl)-2,6-difluorophenyl)piperidine-2, 6-dione (143 mg, 256 umol, 70% purity, 1.00 eq, sulfate salt) in tetrahydrofuran (1.00 mL) and dimethylformamide (1.00 mL) was added 2,3,4,6,7,8,9,10-octahydropyrimido[l,2-a]azepine (38.9 mg, 256 umol, 38.6 uL, 1.00 eq) and A'. A'-di isopropyl ethyl amine (33.1 mg, 256 umol, 44.6 uL, 1.00 eq) . The mixture was stirred at 20 °C for 0.5 h. Then spiro[3.5]nonan-2-yl I / / -imidazole- 1 -carboxylate (60.0 mg, 256 umol, 1.00 eq) was added into the mixture. The mixture was stirred at 20 °C for 11.5 h. / V, / V-diisopropylethylamine (66.2 mg, 512 umol, 89.2 uL, 2.00 eq) was added into the mixture. The mixture was stirred at 20 °C for 12 h. The mixture was concentrated under reduced pressure to give a residue. The residue was purified by / Vc / i-HPLC (column: Phenomenex luna C18 150*25mm* 10um;mobile phase: [water (formic acid)-acetonitrile];B%: 53%-83%,10 min) and lyophilized to afford spiro[3.5]nonan-2-yl (l-(4-(2,6-dioxopiperidin-3-yl)-3,5- difluorophenyl)azetidin-3-yl)carbamate (6.67 mg, 14.31 umol, 5% yield, 99% purity) as an off-white solid.

[0348] 1H NMR (400 MHz, DMSO-<7„) S = 10.85 (s, 1H), 7.82 (br d, J= 7.3 Hz, 1H), 6. 14 (d, J= 11. 1 Hz, 2H), 4.82 (quin, J= 7.2 Hz, 1H), 4.43 - 4.34 (m, 1H), 4.08 (br t, J= 7.8 Hz, 2H), 4.05 - 4.00 (m, 1H), 3.61 (br t, J= 6.8 Hz, 2H), 2.83 - 2.72 (m, 1H), 2.47 (br s, 1H), 2.20 - 2.13 (m, 2H), 2.10 - 2.00 (m, 1H), 1.99 - 1.88 (m, 1H), 1.67 - 1.60 (m, 2H), 1.43 - 1.29 (m, 10H). MS (ESI) m / z 462.1 [M+H]+Synthesis of Compound 68Step 1. Procedure for preparation of Compound 2 - (3-isopropylcyclobutyl)methanol.

[0349] To a solution of 3 -isopropylcyclobutanecarboxylic acid (200 mg, 1.41 mmol, 1.00 eq) in tetrahydrofuran (2.00 mL)was added borane dimethyl sulfide complex (10.0 M, 281 uL, 2.00 eq) at 0 °C. The reaction mixture was stirred at 20 °C for 2 h. The reaction mixture was quenched by methanol (20 mL) and concentrated under reduced pressure to afford (3-isopropylcyclobutyl)methanol (160 mg, crude) as a white solid.Step 2. Procedure for preparation of Compound 3 - (3-isopropylcyclobutyl)methyl IH-imidazole-l- carboxylate.

[0350] To a solution of (3-isopropylcyclobutyl)methanol (50.0 mg, 390 umol, 1.00 eq) in tetrahydrofuran (0.500 mL) was added di(l / / -imidazol-l-yl)methanone (95.0 mg, 585 umol, 1.50 eq). The reaction mixture was stirred at 20 °C for 1 h. The reaction mixture was concentrated under reduced pressure to (3-isopropylcyclobutyl)methyl I / / -imidazole- 1 -carboxylate (86.0 mg, crude) which was used into next step directly.Step 3. Procedure for preparation of (3-isopropylcyclobutyl)methyl (l-(4-(2,6-dioxopiperidin-3-yl)-3,5- difluorophenyl)azetidin-3-yl)carbamate.

[0351] To a solution of 3-(4-(3-aminoazetidin-l-yl)-2,6-difluorophenyl)piperidine-2, 6-dione (70.3 mg, 227 umol, 1.00 eq, hydrochloride) in tetrahydrofuran (1.00 mL) and dimethylformamide (1.00 mL), thenadded 2,3,4,6,7,8,9,10-octahydropyrimido[l,2-a]azepine (58.9 mg, 387 umol, 58.3 uL, 1.00 eq), triethylamine (39.2 mg, 387 umol, 53.9 uL, 1.00 eq) and (3-isopropylcyclobutyl)methyl I / / -imidazole- 1 -carboxylate (55.0 mg, 227 umol, 1.00 eq). The reaction mixture was stirred at 20 °C for 12 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was diluted with dimethylformamide (1 mL) and then filtered. The filtrate was purified by / ’re / i-HPLCTcolumn: Phenomenex luna C18 150*25mm* 10um;mobile phase: [water (formic acid)- acetonitrile] ;B%: 52%-82%, 9 min) and lyophilized to afford (3- isopropylcyclobutyl)methyl (l-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)azetidin-3-yl)carbamate (22.00 mg, 48.45 umol, 13% yield, 99% purity) as a white solid.

[0352] 1H NMR (400 MHz, DMSO-O 5 = 10.86 (s, 1H), 7.83 (br t, J= 6.6 Hz, 1H), 6.15 (s, 1H), 6. 13 (s, 1H), 4.41 (br dd, J= 2.2, 4.8 Hz, 1H), 4.08 (t, J= 7.7 Hz, 2H), 4.05 - 4.00 (m, 2H), 3.86 (d, J= 6.3 Hz, 1H), 3.62 (t, J= 6.8 Hz, 2H), 2.82 - 2.73 (m, 1H), 2.54 (br d, J= 1.4 Hz, 1H), 2.40 - 2.33 (m, 1H), 2.05 (br d, J= 4.0 Hz, 1H), 2.03 - 1.99 (m, 1H), 1.99 - 1.89 (m, 2H), 1.76 - 1.72 (m, 2H), 1.53 - 1.38 (m, 1H), 1.37 - 1.32 (m, 1H), 0.76 (t, J= 7.3 Hz, 6H). MS (ESI) m / z 450.3 [M+H]+Synthesis of Compound 69Compound 69Step 1. Procedure for preparation of Compound 2 - l-(benzo[d]oxazol-2-yl)azetidin-3-ol.

[0353] To a solution of 2-chloro-l,3-benzoxazole (500 mg, 3.26 mmol, 370 uL, 1.00 eq) and azetidin- 3-ol (428 mg, 3.91 mmol, 1.20 eq, mesylate) in dimethylformamide (5.00 mL) was added potassium carbonate (450 mg, 3.26 mmol, 1.00 eq). The mixture was stirred at 80 °C for 12 h. The reaction mixture was diluted with water (30 mL) and exacted with ethyl acetate (3 x 30 mL). The organic phase was washed with brine (2 x 10 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to give a residue. Theresidue was purified by column chromatography (SiCL, petroleum ether / ethyl acetate = 1 / 1 to 0 / 1) to afford 1- (benzo[d]oxazol-2-yl)azetidin-3-ol (600 mg, 3. 15 mmol, 97% yield) as a yellow solid.Step 2. Procedure for preparation of l-(benzo[d]oxazol-2-yl)azetidin-3-yl (l-(4-(2,6-dioxopiperidin-3-yl)-3.5-difluorophenyl)azetidin-3-yl)carbamate.

[0354] To a solution of l-(benzo[d]oxazol-2-yl)azetidin-3-ol (80.0 mg, 421 umol, 1.00 eq) in tetrahydrofuran (1.00 mL) was added I. I'-carbonyldiimidazolc (68.2 mg, 421 umol, 1.00 eq) at 0 °C. The mixture was stirred at 25 °C for 0.5 h to give a resulting solution. A solution of 3-(4-(3-aminoazetidin-l-yl)-2.6-difluorophenyl)piperidine-2, 6-dione (165 mg, 422 umol, 1.00 eq, mesylate), 2,3,4,6,7,8,9,10- octahydropyrimido[l,2-a]azepine (64.3 mg, 422 umol, 63.6 uL, 1.00 eq) and A / A'-diisopropylcthylaminc (54.6 mg, 422 umol, 73.5 uL, 1.00 eq) in dimethylformamide (1.00 mL) was added into the resulting solution. The mixture was stirred at 25 °C for 12 h. The mixture was filtered to give filtrate. The filtrate was purified by / Vc / i-HPLC (column: Phenomenex luna C18 150*25mm* 10um;mobile phase: [water(formic acid)- acetonitrile];B%: 33%-63%,9min) and lyophilized in vacuo to afford l-(benzo[d]oxazol-2-yl)azetidin-3-yl (1- (4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)azetidin-3-yl)carbamate (26.07 mg, 49.4 umol, 12% yield, 97% purity) as a white solid.

[0355] 1H NMR (400 MHz, DMSO-d6 ) δ = 10.86 (s, 1H), 8.20 (br d, J= 7.0 Hz, 1H), 7.43 (d, J= 7.8 Hz, 1H), 7.33 (d, J= 7.8 Hz, 1H), 7.18 (t, J= 7.6 Hz, 1H), 7.10 - 7.03 (m, 1H), 6.16 (d, J= 11.0 Hz, 2H), 5.32 - 5.23 (m, 1H), 4.52 (dd, J= IP, 9.2 Hz, 2H), 4.49 - 4.42 (m, 1H), 4.16 - 4.09 (m, 4H), 4.04 (br dd, J= 5.1, 12.6 Hz, 1H), 3.67 (br t, J= 6.8 Hz, 2H), 2.84 - 2.74 (m, 1H), 2.49 - 2.40 (m, 1H), 2.12 - 2.05 (m, 1H), 2.00 - 1.90 (m, 1H). MS (ESI) m / z 512.1 [M+H]+Synthesis of Compound 74Step 1. Procedure for preparation of Compound 2 - azetidin-3-yl (l-(4-(2,6-dioxopiperidin-3-yl)-3,5- difluorophenyl)azetidin-3-yl)carbamate.

[0356] To a solution of tert-butyl 3-(((l-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)azetidin-3- yl)carbamoyl)oxy)azetidine-l -carboxylate (100 mg, 202 umol, 1.00 eq) in dichloromethane (2.00 mL) were added trifluoroacetic acid (616 mg, 5.40 mmol, 0.400 mL, 26.7 eq). The reaction mixture was stirred at 20 °C for 1 h. The reaction mixture was concentrated under reduced pressure to afford azetidin-3-yl (l-(4-(2,6- dioxopiperidin-3-yl)-3,5-difluorophenyl)azetidin-3-yl)carbamate (102 mg, 201 umol, 99% yield, trifluoroformate) as yellow oil, and directly used to next step. MS (ESI) m / z 394.9 [M+H]+Step 2. Procedure for preparation of l-(2-phenylacetyl)azetidin-3-yl (l-(4-(2,6-dioxopiperidin-3-yl)-3,5- difluorophenyl)azetidin-3-yl)carbamate.

[0357] To a solution of 2-phenylacetic acid (17.3 mg, 127 umol, 16.0 uL, 1.00 eq) in dimethylformamide (2 mL) were added MA'-diisopropylcthylaminc (49.2 mg, 380 umol, 66.3 uL, 3.00 eq). azetidin-3-yl (l-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)azetidin-3-yl)carbamate (100 mg, 254 umol, 2.00 eq) and 2-(3H-[ l,2,3]triazolo[4,5-A]pyridin-3-yl)-l,l,3,3-tetramethyluronium hexafluorophosphate(V) (72.3 mg, 190 umol, 1.50 eq). The reaction mixture was stirred at 25 °C for 4 h. The reaction mixture was diluted with water (2 mL) and extracted with ethyl acetate (2 x 3 mL). The combined layers was concentrated under reduced pressure to give a residue. The residue was purified by / Vc / i-HPLC (column: Phenomenex C18150*25mm* lOum; mobile phase: [water (ammonium bicarbonate) - acetonitrile]; B%: 20%-50%,8min) and lyophilized to give a white solid. The white solid was purified by Prep-TLC (UV 254 run, petroleum ether: ethyl acetate=0: 1, Rf =0.59) to afford a crude product. The crude product was triturated with petroleum ether (10 ml) at 25 °C for 1 h to afford [l-(2-phenylacetyl)azetidin-3-yl] N-[l-[4-(2,6-dioxo-3-piperidyl)-3,5- difluoro-phenyl]azetidin-3-yl]carbamate (17.24 mg, 33.3 umol, 26.27% yield, 99% purity) as a white solid.

[0358] 1H NMR (400 MHz, DMSO-O b = 10.85 (s, 1H), 8. 13 (br d, J= 7.3 Hz, 1H), 7.33 - 7.26 (m, 2H), 7.25 - 7.17 (m, 3H), 6.14 (d, J = 10.9 Hz, 2H), 5.10 - 5.01 (m, 1H), 4.49 - 4.38 (m, 2H), 4.16 - 4.00 (m, 5H), 3.71 (br dd, J = 3.9, 10.8 Hz, 1H), 3.63 (br t, J = 6.8 Hz, 2H), 3.43 (s, 2H), 2.83 - 2.71 (m, 1H), 2.60 - 2.54 (m, 1H), 2.11 - 2.02 (m, 1H), 1.97 - 1.88 (m, 1H). MS (ESI) m / z.512.9 [M+H]+Synthesis of Compound 75Compound 75Step 1. Procedure for preparation of Compound 2 - l-(l-methyl-lH-benzo[d]imidazol-2-yl)azetidin-3-ol.

[0359] To a solution of azetidin-3-ol (236 mg, 2.16 mmol, 1.20 eq, hydrochloric acid) and 2-chloro- 1 -methyl- lH-benzo[d] imidazole (300 mg, 1.80 mmol, 1.00 eq) in dimethylsulfoxide (2.00 mL) was added potassium carbonate (746 mg, 5.40 mmol, 3.00 eq). The reaction was stirred at 100 °C for 3 h. The reaction was filtered to give a filtrate. The filtrate was purified by reversed-phase HPLC (0. 1% formic acid condition) to afford I -(4 -methyl- l / / -bcnzo|d|imidazol-2-yl)azctidin-3-ol (150 mg, 738 umol, 41% yield) as a white solid.Step 2. Procedure for preparation of l-(l-methyl-lH-benzo[d]imidazol-2-yl)azetidin-3-yl (l-(4-(2,6- dioxopiperidin-3-yl)-3,5-difluorophenyl)azetidin-3-yl)carbamate.

[0360] To a solution of l-(l-methyl-l / / -benzo[d]imidazol-2-yl)azetidin-3-ol (40.0 mg, 196 umol, 1.00 eq) in tetrahydroforan (1.00 mL) was added di( 1 / 7-imidazol- 1 -yl)methanone (31.9 mg, 196 umol, 1.00 eq) at 0 °C. The reaction was stirred at 25 °C for 0.5 h to give a resulting solution. A solution of 3-(4-(3- aminoazetidin-l-yl)-2,6-difluorophenyl)piperidine-2, 6-dione (54.6 mg, 184 umol, 1.00 eq), 2,3,4,6,7,8,9,10- octahydropyrimido[l,2-a]azepine (28. 1 mg, 184 umol, 27.8 uL, 1.00 eq), A'A'-diisopropylcthylaminc (23.9 mg, 184 umol, 32.2 uL, 1.00 eq) in dimethylformamide (1.00 mL) was added to the resulting solution at 25 °C. The reaction was stirred at 25 °C for 12 h. The reaction was concentrated under reduced pressure and filtered to give residue. The residue was purified by / Vc / i-HPLC (column: Phenomenex luna C18 150*25mm* 10um;mobile phase: [water(formic acid)- acetonitrile] ;B%: 9%-39%,9min) to afford 1 -(1 -methyl- 1H- benzo[d]imidazol-2-yl)azetidin-3-yl (l-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)azetidin-3- yl)carbamate (33.51 mg, 62.61 umol, 34% yield, 98% purity) as a white solid.

[0361] 1H NMR (400 MHz, DMSO-cA) 3 = 10.86 (s, 1H), 8. 18 - 8. 14 (m, 1H), 7.37 - 7.23 (m, 2H), 7.08 - 6.95 (m, 2H), 6. 16 (br d, J= 11.2 Hz, 2H), 5.22 (br t, J= 4.4 Hz, 1H), 4.49 (br dd, J= 7.2, 8.3 Hz, 2H), 4.47 . 4.37 (m, 1H), 4. 17 - 4.08 (m, 4H), 4.04 (br dd, J= 4.8, 12.7 Hz, 1H), 3.67 (br t, J= 6.8 Hz, 2H), 3.53 (s, 3H), 2.84 - 2.73 (m, 1H), 2.50 - 2.43 (m, 1H), 2.13 - 2.01 (m, 1H), 2.00 - 1.91 (m, 1H). MS (ESI) m / z 525.4 [M+H]+Synthesis of Compound 76, 78Compound 76Step 1. Procedure for preparation of Compound 2 - 3-hydroxy-N,N-dimethylbicyclo[l.l.l]pentane-l- carboxamide.

[0362] To a solution of 3-hydroxybicyclo[l. 1. l]pentane-l-carboxylic acid (50.0 mg, 390 umol, 1.00 eq) in dimethyl formamide (1.00 mL) was added 1 -hydroxybenzotriazole (36.9 mg, 273 umol, 0.70 eq), l-(3- dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (82.3 mg, 429 umol, 1.10 eq) and N,N- diisopropylethylamine (101 mg, 780 umol, 136 uL, 2.00 eq) followed by dimethylamine (318 mg, 3.90 mmol, 10.0 eq, hydrochloride). The mixture was stirred at 25 °C for 12 h. The reaction was filtered. The filtrate was purified by / Vc / i-HPLC (column: Phenomenex luna C 18 150*25mm* 10um;mobile phase: [water (formic acid) - acetonitrile]; B%: 0%-20%,10 min) and lyophilized to afford 3-hydroxy-A''.A''-dimcthylbicyclo| 1. 1. 1 Ipcntanc- 1-carboxamide (50.0 mg, 258 umol, 66% yield, 80% purity) as a white solid.Step 2. Procedure for preparation of Compound 3 - 3-(dimethylcarbamoyl)bicyclo[l. l.l]pentan-l-yl carbonochloridate.

[0363] To a solution of 3-hydroxy-A''.A''-dimcthylbicyclo| I . I . I Ipcntanc- l-carboxamidc (70.0 mg, 451 umol, 1.00 eq) in dichloromethane (3.00 mL) was added bis(trichloromethyl) carbonate (201 mg, 677 nmol, 1.50 eq) and A'.A'-diisopropylcthylaminc (87.4 mg, 677 umol, 118 uL, 1.50 eq) at 0 °C. The mixture was stirred at 20 °C for 1 h. The reaction mixture was concentrated under reduced pressure to afford 3- (dimethylcarbamoyl) bicyclo[l. 1. l]pentan-l-yl carbonochloridate (90.0 mg, 414 umol, 92% yield) as white oil.Step 3. Procedure for preparation of 3-(dimethylcarbamoyl)bicyclo[l.1. l]pentan-l-yl (l-(4-(2,6- dioxopiperidin-3-yl)-3,5-difluorophenyl)azetidin-3-yl)carbamate.

[0364] To a solution of 3-(4-(3-aminoazetidin-l-yl)-2,6-difluorophenyl)piperidine-2, 6-dione (122 mg, 414 umol, 1.00 eq, mesylate) in dimethyl formamide (2.00 mL) was added A'.A'-diisopropylcthylaminc (160 mg, 1.24 mmol, 216 uL, 3.00 eq) followed by 3-(dimethylcarbamoyl)bicyclo[l. l. l]pentan-l-yl carbonochloridate (90.0 mg, 414 umol, 1.00 eq) at 0 °C. The mixture was stirred at 25 °C for 12 h. The reaction was filtered. The filtrate was purified by / Vc / i-HPLC (column: Phenomenex luna C18 150*25mm* 10um;mobile phase: [water(formic acid) - acetonitrile]; B%: 23%-53%, 10 min) and lyophilized to afford 3- (dimethylcarbamoyl)bicyclo[l. 1.1] pentan-l-yl (l-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)azetidin-3- yl)carbamate (12.63 mg, 12.47 umol, 4% yield, 95% purity, formate) as a white solid.

[0365] 1H NMR (400 MHz, DMSO-cA) b = 10.86 (s, 1H), 8.50 - 8.44 (m, 1H), 7.97 (br d, J= 7.5 Hz, 1H), 6.15 (d, J = 11.1 Hz, 2H), 4.48 - 4.34 (m, 1H), 4.08 (br t, J = 7.5 Hz, 2H), 4.03 (br dd, .7 = 5.4. 12.8 Hz, 1H), 3.62 (br t, J= 6.6 Hz, 2H), 3.01 (s, 3H), 2.81 (s, 3H), 2.79 - 2.72 (m, 1H), 2.48 - 2.46 (m, 1H), 2.36 (s, 6H), 2.13 - 2.01 (m, 1H), 1.99 - 1.89 (m, 1H). MS (ESI) m / z 477.1 [M+H]+

[0366] Compound 78 was synthesized in analogy to compound 76:Synthesis of Compound 772Step 1. Procedure for preparation of Compound 2 - 2-(3-(benzyloxy)azetidin-l-yl)-l-methyl-lH-imidazole.

[0367] A mixture of 2-bromo- 1 -methyl- 1 / / -imidazole (200 mg, 1.24 mmol, 1.00 eq), 3- (benzyloxy)azetidine (496 mg, 2.48 mmol, 2.00 eq, hydrochloride), l,3-bis[2,6-bis(l-propylbutyl)phenyl]-4,5- dichloro-2 / / -imidazol-l-ium-2-ide;3-chloropyridine;dichloropalladium (121 mg, 124 umol, 0.100 eq), cesium carbonate (1.21 g, 3.73 mmol, 3.00 eq) in dioxane (2.00 mL) was degassed and purged with nitrogen atmosphere for 3 times. The mixture was stirred at 100 °C for 12 h under nitrogen atmosphere. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by reverse phase chromatography (C18, 40 g; condition: water / acetonitrile = 100:0 to 0: 100, 0.1% formic) and lyophilized to afford 2-(3-(benzyloxy)azetidin-l-yl)-l -methyl- l / / -imidazole (300 mg, 1.23 mmol, 99% yield) as yellow oil.Step 2. Procedure for preparation of Compound 3 - l-(l-methyl-lH-imidazol-2-yl)azetidin-3-ol.

[0368] To a solution of 2-(3-(benzyloxy)azetidin-l-yl)-l -methyl- l / / -imidazole (200 mg, 822 umol, 1.00 eq) in methanol (2.00 mL) was added palladium / carbon (100 mg, 822 umol, 10% purity, 1.00 eq) at 25 C. The mixture was degassed and purged with hydrogen atmosphere for 3 times. The mixture was stirred at 25 °C for 4 h under hydrogen atmosphere. The reaction mixture was filtered and concentrated under reduced pressure to afford l-(l-methyl-l / / -imidazol-2-yl)azetidin-3-ol (72.0 mg, 470 umol, 57% yield) as colorless oil.Step 3. Procedure for preparation of l-(l-methyl-lH-imidazol-2-yl)azetidin-3-yl (l-(4-(2,6-dioxopiperidin-3- yl)-3,5-difluorophenyl)azetidin-3-yl)carbamate.

[0369] To a solution of l-( 1-methyl- l / / -imidazol-2-yl)azetidin-3-ol (72.0 mg, 470.03 umol, 1.00 eq) in tetrahydrofuran (5.00 mL) was added l,l'-carbonyldiimidazole (83.8 mg, 517 umol, 1.10 eq). The mixture was stirred at 25 °C for 0.5 h. The reaction mixture was concentrated under reduced pressure to afford 2-(3- ((l / 7-imidazol-l-yl)oxy)azetidin-l-yl)-l -methyl- 1 / / -imidazole (116 mg, 469 umol, 99% yield) as colorless oil. To a solution of 3-[4-(3-aminoazetidin-l-yl)-2,6-difluoro-phenyl]piperidine-2, 6-dione (180 mg, 460 umol, 1.00 eq, methanesulfonic acid) in / V, / V-dimethyl formamide (5.00 mL) was added triethylamine (46.5 mg, 460 umol, 64.0 uL, 1.00 eq) and l,8-diazabicyclo[5.4.0]undec-7-ene (70.0 mg, 460 umol, 69.3 uL, 1.00 eq) and 2- (3-((l / / -imidazol-l-yl)oxy)azetidin-l-yl)-l-methyl-l / / -imidazole (114 mg, 460 umol, 1.00 eq) at 25°C. 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 / W / J-HPLC (column: Phenomenex Luna C18 150*25mm* 10um;mobile phase: [water(formic)- acetonitrile] ;B%: 3%-33%,10min) and lyophilized to afford 1-(1 -methyl- l / / -imidazol- 2-yl)azetidin-3-yl (l-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)azetidin-3-yl)carbamate (23.39 mg, 48.81 umol, 10.61% yield, 99% purity) as a white solid.

[0370] 1H NMR (400 MHz, DMSO-cL) 3 = 10.86 (s, 1H), 8. 12 (br d, J = 6.6 Hz, 1H), 6.75 (s, 1H), 6.50 (s, 1H), 6.16 (br d, J= 11.1 Hz, 2H), 5.19 - 4.99 (m, 1H), 4.51 - 4.36 (m, 1H), 4.25 - 4.14 (m, 2H), 4.11 (br t, J= 7.8 Hz, 2H), 4.05 - 3.98 (m, 1H), 3.89 - 3.78 (m, 2H), 3.70 - 3.60 (m, 2H), 3.35 - 3.34 (m, 3H), 2.82- 2.72 (m, 1H), 2.57 - 2.54 (m, 1H), 2.13 - 2.05 (m, 1H), 2.00 - 1.92 (m, 1H)

[0371] 1H NMR (400 MHz, DMSO-d6 ) δ = 6.74 (s, 1H), 6.48 (s, 1H), 6.14 (d, J= 11.3 Hz, 2H), 5.18- 5.05 (m, 1H), 4.42 (br dd, J= 6.0, 6.8 Hz, 1H), 4.20 (t, J= 7.7 Hz, 2H), 4.10 (br t, J= 7.4 Hz, 2H), 4.02 (br dd, J= 4.8, 12.3 Hz, 1H), 3.83 (br dd, J= 4.5, 8.6 Hz, 2H), 3.66 (br s, 2H), 3.33 (s, 3H), 2.81 - 2.72 (m, 1H), 2.59 - 2.55 (m, 1H), 2.14 - 1.99 (m, 1H), 1.99 - 1.87 (m, 1H). MS (ESI) m / z 475.2 [M+H]+Synthesis of Compound 79, 80, 83Compound 79Step 1. Procedure for compound 2 - l-(5-methylpyridin-2-yl)azetidin-3-ol.

[0372] To a solution of 2-fluoro-5 -methyl -pyridine (500 mg, 4.50 mmol, 467 uL, 1.00 eq) in dimethylsulfoxide (8.00 mL) was added cesium carbonate (2.93 g, 9.00 mmol, 2.00 eq) and azetidin-3-ol (788 mg, 7.20 mmol, 1.60 eq, hydrochloride). The mixture was stirred at 100 °C for 12 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by reverse phase chromatography (C18, 40 g; condition: water / acetonitrile = 100:0 to 0: 100, 0. 1% formic acid) and lyophilized to afford l-(5-methyl-2-pyridyl)azetidin-3-ol (590 mg, 3.56 mmol, 79% yield, 99% purity) as yellow oil.Step 2. Procedure for l-(5-methylpyridin-2-yl)azetidin-3-yl (l-(4-(2,6-dioxopiperidin-3-yl)-3,5- difluorophenyl)azetidin-3-yl)carbamate.

[0373] To a solution of l-(5-methylpyridin-2-yl)azetidin-3-ol (200 mg, 1.22 mmol, 1.00 eq) in tetrahydrofuran (2.00 mL) were added l,l'-carbonyldiimidazole (217 mg, 1.34 mmol, 1.10 eq) at 0 °C. The mixture was stirred at 25 °C for 0.5 h. The reaction mixture was concentrated under reduced pressure to afford l-(5-methylpyridin-2-yl)azetidin-3-yl I / / -imidazole- 1 -carboxylate (314 mg, crude) as colorless oil. To a solution of 3-(4-(3-aminoazetidin-l-yl)-2,6-difluorophenyl)piperidine-2, 6-dione (470 mg, 1.20 mmol, 1.00 eq, methanesulfonic acid) in tetrahydrofuran (2.00 mL) and / V, / V-dimethyl formamide (4.00 mL) were added triethylamine (121 mg, 1.20 mmol, 167 uL, 1.00 eq), l,8-diazabicyclo[5.4.0]undec-7-ene (183 mg, 1.20 mmol, 181 uL, 1.00 eq), and l-(5-methylpyridin-2-yl)azetidin-3-yl I / / -imidazole- 1 -carboxylate (310 mg, 1.20 mmol, 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 prep-W\J2 (column: Waters xbridge 150*25mm10um;mobile phase: [water( ammonium bicarbonate)- acetonitrile]; B%: 25%-55%,8min) and lyophilized to afford l-(5-methylpyridin-2-yl)azetidin-3-yl (l-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)azetidin-3- yl)carbamate (43.07 mg, 79.9 nmol, 6.66% yield, 97% purity) as a white soild.

[0374] 1H NMR (400 MHz, DMSO-fo) 3 = 10.85 (s, 1H), 8.17 - 8.06 (m, 1H), 7.91 (s, 1H), 7.39 - 7.34 (m, 1H), 6.37 (d, J= 8.4 Hz, 1H), 6.15 (br d, J= 11.1 Hz, 2H), 5.21 - 5.13 (m, 1H), 4.48 - 4.38 (m, 1H), 4.23 - 4. 15 (m, 2H), 4. 10 (br t, J= 7.6 Hz, 2H), 4.03 (br dd, J= 4.9, 12.2 Hz, 1H), 3.76 (br dd, J= 3.9, 9.2 Hz, 2H), 3.65 (br t, J = 6.6 Hz, 2H), 2.83 - 2.71 (m, 1H), 2.58 - 2.52 (m, 1H), 2.14 (s, 3H), 2.10 - 2.03 (m, 1H), 1.99 - 1.91 (m, 1H). MS (ESI) m / z 486.5 [M+H]+

[0375] Compounds 80 and 83 were synthesized in analogy to Compound 79:Synthesis of Compound 81, 82Compound 81Step 1. Procedure for Compound 2 - 3-hydroxy-N-methyl-N-phenylbicyclo[l.l.l]pentane-l-carboxamide.

[0376] To a solution of 3-hydroxybicyclo[l. l. l]pentane-l-carboxylic acid (100 mg, 780 umol, 1.00 eq) in A'.A'-dimcthyl formamide (1.00 mL) were added A'. A-di isopropyl ethyl amine (201 mg, 1.56 mmol, 271 uL, 2.00 eq), l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (164 mg, 858 umol, 1. 10 eq), 1- hydroxybenzotriazole (73.8 mg, 546 umol, 0.700 eq) and A-mcthylanilinc (836 mg, 7.80 mmol, 847 uL, 10.0 eq). The reaction mixture was stirred at 20 °C for 3 h. The reaction was filtered. The filtrate was purifiedby reverse phase chromatography (C18, 40 g; condition: water / acetonitrile = 100:0 to 80:20, 0. 1% formic acid) and lyophilized to afford 3-hydroxy-A''-mcthyl-A''-phcnylbicyclo| 1. 1. 1 |pcntanc- l-carboxamidc (61.0 mg, 280 umol, 35% yield) as a white solid.Step 2. Procedure for 3-(methyl(phenyl)carbamoyl)bicyclo[l.l.l]pentan-l-yl (l-(4-(2,6-dioxopiperidin-3-yl)- 3,5-difluorophenyl)azetidin-3-yl)carbamate.

[0377] To a solution of 3-hydroxy-A''-mcthyl-A''-phcnylbicyclo| 1. 1. 1 ]pentane-l -carboxamide (61.0 mg, 280 umol, 1.00 eq) in tetrahydrofuran (1.00 mL) was added di(l / / -imidazol-l-yl)methanone (45.5 mg, 280 umol, 1.00 eq) at 0 °C. The reaction mixture was stirred at 20 °C for 2 h. The resulting solution was added to a mixture of 3-(4-(3-aminoazetidin-l-yl)-2,6-difluorophenyl)piperidine-2, 6-dione (106 mg, 273 umol, 1.00 eq, mesylate) and A'.A'-diisopropylcthylaminc (52.9 mg, 409 umol, 71.3 uL, 1.50 eq) in A'.A'-dimcthyl formamide (1.00 mL). The reaction mixture was stirred at 20 °C for 12 h. The reaction mixture was concentrated under reduced pressure to give a residue and then filtered. The filtrate was purified by / Vc / i-HPLCicoliimn:Phenomenex luna C18 150*25 mm* 10 urn; mobile phase: [water (formic acid) - acetonitrile]; B%: 39%-69%, 58 min) and lyophilized to afford 3-(methyl(phenyl)carbamoyl)bicyclo[l. l. l]pentan-l-yl (l-(4-(2,6- dioxopiperidin-3-yl)-3,5-difluorophenyl)azetidin-3-yl)carbamate (24.9 mg, 44.39 nmol, 16% yield, 96% purity) as a white solid.

[0378] 1H NMR (400 MHz, DMSO-^) 5 = 10.85 (s, 1H), 7.83 (br d, J= 7.5 Hz, 1H), 7.50 - 7.37 (m, 3H), 7.31 (d, J= 7.1 Hz, 2H), 6.11 (d, J= 11.0 Hz, 2H), 4.36 - 4.25 (m, 1H), 4.05 - 3.99 (m, 3H), 3.54 (br t, J = 6.8 Hz, 2H), 3.13 (s, 3H), 2.81 - 2.72 (m, 1H), 2.47 (br d, J= 2.6 Hz, 1H), 2.09 - 2.03 (m, 1H), 1.95 - 1.89 (m, 1H), 1.89 - 1.76 (m, 6H). MS (ESI) m / z.539.4 [M+H]+

[0379] Compound 82 was synthesized in analogy to Compound 81 :Synthesis of Compound 84Compound 84Step 1. Procedure for compound 2 - 3-cyclopropylprop-2-yn-l-yl carbonochloridate.

[0380] To a solution of 3-cyclopropylprop-2-yn-l-ol (80.0 mg, 832 umol, 1.00 eq) in dichloromethane (5.00 mL) were added A'.A'-diisopropylcthylaminc (215 mg, 1.66 mmol, 290 uL, 2.00 eq) and bis(trichloromethyl) carbonate (395 mg, 1.33 mmol, 1.60 eq) at 0 °C. The mixture was stirred at 25 °C for 1 h. The reaction mixture was concentrated under reduced pressure to afford 3-cyclopropylprop-2-yn-l-yl carbonochloridate (130 mg, crude) as yellow solid.Step 2. Procedure for 3-cyclopropylprop-2-yn-l-yl (l-(4-(2,6-dioxopiperidin-3-yl)-3,5- difluorophenyl)azetidin-3-yl)carbamate.

[0381] To a solution of 3-(4-(3-aminoazetidin-l-yl)-2,6-difluorophenyl)piperidine-2, 6-dione (150 mg, 383 nmol, 1.00 eq, mesylate) in dichloromethane (4.00 mL) were added A'A'-diisopropylcthylaminc (149 mg, 1.15 mmol, 200 uL, 3.00 cc / ) and 3-cyclopropylprop-2-yn-l-yl carbonochloridate (91.2 mg, 575 nmol, 1.50 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 purified by Prep-HPLC (column: Phenomenex luna C18 150*25mm* 10um; mobile phase: [water (formic acid) - acetonitrile]; B%: 42%-72%, 10 min) and lyophilizedto afford 3-cyclopropylprop-2-yn-l-yl (l-(4-(2, 6-dioxopiperidin-3-yl)-3,5-difluorophenyl)azetidin-3- yl)carbamate (30.52 mg, 72.39 umol, 19% yield, 99% purity) as an white solid.

[0382] 1H NMR (400 MHz, DMSO-rfc) 3 = 10.86 (s, 1H), 8.01 (br d, J= 7.6 Hz, 1H), 6. 16 (d, J= 11. 1 Hz, 2H), 4.59 (d, J= 1.8 Hz, 2H), 4.49 - 4.35 (m, 1H), 4. 10 (t, J= 7.7 Hz, 2H), 4.04 (dd, J= 5.2, 12.4 Hz, 1H), 3.63 (br t, J= 6.8 Hz, 2H), 2.85 - 2.70 (m, 1H), 2.59 - 2.53 (m, 1H), 2.14 - 2.02 (m, 1H), 1.99 - 1.89 (m, 1H), 1.44 - 1.27 (m, 1H), 0.84 - 0.72 (m, 2H), 0.66 - 0.53 (m, 2H). MS (ESI) m / z 418.3 [M+H]+Synthesis of Compound 85Step 1. Procedure for preparation of Compound 2 - 6-amino-3-bromo-2-chlorobenzonitrile.

[0383] To a solution of 2-amino-6-chloro-benzonitrile (10.0 g, 65.5 mmol, 1.00 eq) in acetonitrile (150 mL) was added A'-bromosiiccinimidc (11.7 g, 65.5 mmol, 1.00 eq). The reaction mixture was stirred at 25 °C for 3 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=10 / l to 3 / 1) and concentrated under reduced pressure to afford 6-amino-3-bromo-2-chlorobenzonitrile (14.2 g, 61.4 mmol, 94% yield) as a yellow solid.Step 2. Procedure for preparation of Compound 3 - 6-amino-2-chloro-3-methylbenzonitrile.

[0384] To a solution of 6-amino-3-bromo-2-chloro-benzonitrile (14.2 g, 61.4 mmol, 1.00 eq) in dioxane (200 mL) and water (40.0 mL) were added methylboronic acid (3.67 g, 61.4 mmol, 1.00 eq), cesium carbonate (40.0 g, 123 mmol, 2.00 eq) and [l,l-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (4.49 g, 6. 13 mmol, 0. 100 eq) under nitrogen atmosphere. The reaction was stirred at 100 °C for 12 h. The reaction mixture was filtered and the filtrate was concentrated under reduce pressure to give a residue. The residue was extracted with ethyl acetate (3 x 100 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a crude product. The crude product was purified by column chromatography (SiCL, petroleum ether / ethyl acetate=l / O to 3 / 1) and concentrated under reduced pressure to afford 6-amino-2-chloro-3-methylbenzonitrile (7.30 g, 43.8 mmol, 71% yield) as a white solid.Step 3. Procedure for preparation of Compound 4 - 6-bromo-2-chloro-3 -methylbenzonitrile.

[0385] To a solution of 6-amino-2-chloro-3-methyl-benzonitrile (12.0 g, 72.0 mmol, 1.00 eq) in acetonitrile (150 mL) were added cuprous bromide (15.5 g, 108 mmol, 3.29 mL, 1.50 eq) and tert-butyl nitrite (11.1 g, 108 mmol, 12.9 mL, 1.50 eq). The reaction mixture was stirred at 60 °C for 6 h under nitrogen atmosphere. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiCL, petroleum ether / ethyl acetate=l / O to 5 / 1) and concentrated under reduced pressure to afford 6-bromo-2-chloro-3-methyl-benzonitrile (5.50 g, 23.9 mmol, 33% yield) as a white solid.Step 4. Procedure for preparation of Compound 5 - 6-bromo-3-(bromomethyl)-2-chlorobenzonitrile.

[0386] To a solution of 6-bromo-2-chloro-3-methyl-benzonitrile (5.50 g, 23.9 mmol, 1.00 eq) in carbon tetrachloride (90.0 mL) were added / V-bromosuccinimide (4.29 g, 24.1 mmol, 1.01 eq) and (£)-2,2'- (diazene-l,2-diyl)bis(2-methylpropanenitrile) (392 mg, 2.39 mmol, 0.100 eq). The reaction was stirred at 80 °C for 12 h. The reaction mixture was concentrated under reduce pressure to give a residue. The residue waspurified by column chromatography (SiCL, petroleum ether / ethyl acetate=l / O to 10 / 1) and concentrated under reduced pressure to afford 6-bromo-3-(bromomethyl)-2-chloro-benzonitrile (4.40 g, 14.2 mmol, 60% yield) as a white solid.Step 5. Procedure for preparation of Compound 6 - 6-bromo-2-chloro-3-(cyanomethyl)benzonitrile.

[0387] To a solution of 6-bromo-3-(bromomethyl)-2-chloro-benzonitrile (4.40 g, 14.2 mmol, 1.00 eq) in acetonitrile (10.0 mL) were added trimethylsilyl cyanide (4.23 g, 42.7 mmol, 5.34 mL, 3.00 eq) and tetrabutylammonium fluoride (1.00 M, 42.7 mL, 3.00 eq) at 0 °C. The reaction was stirred at 25 °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) and concentrated under reduced pressure to afford 6-bromo-2-chloro-3-(cyanomethyl)benzonitrile (2.50 g, 9.78 mmol, 69% yield) as a pink solid.Step 6. Procedure for preparation of Compound 7 - methyl 4-(4-bromo-2-chloro-3-cyanophenyl)-4- cyanobutanoate.

[0388] To a solution of 6-bromo-2-chloro-3-(cyanomethyl)benzonitrile (1.20 g, 4.70 mmol, 1.00 eq) and sodium methoxide (254 mg, 4.70 mmol, 1.00 eq) in tetrahydrofuran (240 mL) was added methyl acrylate (364 mg, 4.23 mmol, 381 uL, 0.900 eq) in tetrahydrofuran (12.0 mL) at 0 °C. The reaction mixture was stirred at 20 °C for 16 h. The mixture was quenched with saturated ammonium chloride aqueous solution (50 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine (2 x 50 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 2 / 1) and concentrated under reduced pressure to afford methyl 4-(4-bromo-2-chloro-3-cyano-phenyl)-4-cyano- butanoate (900 mg, 2.63 mmol, 56% yield) as a yellow solid.Step 7. Procedure for preparation of Compound 8 - 6-bromo-2-chloro-3-(2,6-dioxopiperidin-3- yl)benzonitrile.

[0389] To a solution of methyl 4-(4-bromo-2-chloro-3-cyanophenyl)-4-cyanobutanoate (620 mg, 1.82 mmol, 1.00 eq) in acetic acid (6.00 mL) was added sulfuric acid (1.10 g, 11.3 mmol, 0.600 mL, 6.20 eq). The reaction mixture was stirred at 90 °C for 12 h. The reaction mixture was poured into ice water, and the mixture was filtered to give a brown filter cake. The filter cake was concentrated under reduced pressure to afford 6- bromo-2-chloro-3-(2,6-dioxopiperidin-3-yl)benzonitrile (298 mg, 910 umol, 50% yield) as a brown solid.

[0390] 1H NMR (400 MHz, DMSO-O b = 11.02 (s, 1H), 7.90 (d, J = 8.5 Hz, 1H), 7.76 - 7.62 (m, 1H), 4.36 (dd, J= 4.9, 12.8 Hz, 1H), 2.88 - 2.77 (m, 1H), 2.59 (br d, J= 2.8 Hz, 1H), 2.35 (dd, J= 4.1, 12.9 Hz, 1H), 2.05 - 1.99 (m, 1H).Step 8. Procedure for preparation ofCompound9 - tert-butyl (l-(3-chloro-2-cyano-4-(2,6-dioxopiperidin-3- yl)phenyl)azetidin-3-yl)carbamate.

[0391] To a solution of 6-bromo-2-chloro-3-(2,6-dioxo-3-piperidyl)benzonitrile (100 mg, 305 umol, 1.00 eq), tert-butyl azetidin-3-ylcarbamate (68.4 mg, 397 umol, 1.30 eq) and [l,3-bis[2,6-bis(l- propylbutyl)phenyl]-4,5-dichloro-imidazol-2-ylidene]-dichloro-(3-chloropyridin-l-ium-l-yl)palladium (29.7 mg, 30.5 umol, 0. 100 eq) in dioxane (3.00 mL) was added cesium carbonate (298 mg, 916 umol, 3.00 eq). The reaction mixture was stirred at 105 °C for 16 h under nitrogen atmosphere. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by reverse phase chromatography (C18, 40 g, condition: water / acetonitrile = 100:0 to 0: 100, 0.1% formic acid) and lyophilized to afford tert-butyl (l-(3-chloro-2-cyano-4-(2,6-dioxopiperidin-3-yl)phenyl)azetidin-3- yl)carbamate (40.0 mg, 95.5 umol, 31% yield) as a yellow solid.Step 9. Procedure for preparation of Compound 10 - 6-(3-aminoazetidin-l-yl)-2-chloro-3-(2,6- dioxopiperidin-3-yl)benzonitrile.

[0392] To a solution of tert-butyl (l-(3-chloro-2-cyano-4-(2,6-dioxopiperidin-3-yl)phenyl)azetidin-3- yl)carbamate (40.0 mg, 95.5 umol, 1.00 eq) in dichloromethane (1.00 mL) was added trifluoroacetic acid (821 mg, 7.20 mmol, 533 uL, 75.4 eq). The reaction mixture was stirred at 25 °C for 1 h. The reaction mixture was concentrated under reduced pressure to afford 6-(3-aminoazetidin-l-yl)-2-chloro-3-(2,6-dioxopiperidin-3- yl)benzonitrile (30.0 mg, crude) as yellow oil. MS (ESI) m / z.319.2 [M+H]+Step 10. Procedure for preparation of Compound 10A - spiro [3.3]heptan-2-ylmethyl carbonochloridate.

[0393] To a solution of spiro[3.3]heptan-2-ylmethanol (45.0 mg, 357 umol, 1.00 eq) in dichloromethane (1.50 mL) were added bis(trichloromethyl) carbonate (106 mg, 357 umol, 1.00 eq) an N.N- diisopropylethylamine (69. 1 mg, 535 umol, 93.2 uL, 1.50 eq) at 0 °C. The reaction mixture was stirred at 20 °C for 1 hr. The reaction mixture was concentrated under reduced pressure to afford spiro[3.3]heptan-2- ylmethyl carbonochloridate (67.0 mg, crude) as a white solid.Step 11. Procedure for preparation of spiro[3.3]heptan-2-ylmethyl (l-(3-chloro-2-cyano-4-(2,6- dioxopiperidin-3-yl)phenyl)azetidin-3-yl)carbamate.

[0394] To a solution of 6-(3-aminoazetidin-l-yl)-2-chloro-3-(2,6-dioxo-3-piperidyl)benzonitrile (30.0 mg, 94.1 umol, 1.00 eq) in dimethylformamide (1.00 mL) were added A'.A'-diisopropylcthylaminc (24.3 mg, 188 umol, 32.8 uL, 2.00 eq) and spiro[3.3]heptan-2-ylmethyl carbonochloridate (35.5 mg, 188 umol, 2.00 eq). The reaction was stirred at 25 °C for 30 min. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by / Vc / i-HPLC (column: Phenomenex luna C18 150*25mm* 10um; mobile phase: [water (formic acid) - acetonitrile]; B%: 47%-77%, 10 min) and lyophilized to afford spiro[3.3]heptan-2-ylmethyl (l-(3-chloro-2-cyano-4-(2,6-dioxopiperidin-3-yl)phenyl)azetidin-3- yl)carbamate (6.66 mg, 14.00 umol, 15% yield, 99% purity) as a white solid.’H NMR (400 MHz, DMSO-d6 ) δ = 10.88 (s, 1H), 7.86 (br d, J= 2.9 Hz, 1H), 7.36 (d, J= 8.9 Hz, 1H), 6.57 (d, J= 9.0 Hz, 1H), 4.40 (br s, 3H), 4. 14 (dd, J= 5.0, 12.6 Hz, 1H), 3.96 (br d, J= 3.6 Hz, 2H), 3.90 (d, J= 6.9 Hz, 2H), 2.82 - 2.71 (m, 1H), 2.53 (br d, J= 4.0 Hz, 1H), 2.40 - 2.32 (m, 1H), 2.24 (dq, J= 4.1, 13.1 Hz, 1H), 2.06 - 1.94 (m, 4H), 1.93 - 1.85 (m, 3H), 1.79 - 1.68 (m, 4H). MS (ESI) m / z.471.3 [M+H]+Synthesis of Compound 86Step 1. Procedure for preparation of Compound 2 - (4-bromo-2,6-dimethylphenyl)methanol.

[0395] To a solution of 4-bromo-2,6-dimethylbenzoic acid (5.00 g, 21.8 mmol, 1.00 eq) in tetrahydrofuran (50.0 mL) was slowly added borane tetrahydrofuran (1.00 M, 109 mL, 5.00 eq) at 0 °C under nitrogen, the mixture was stirred at 0 °C for 0.5 h, then heated to 70 °C and stirred for 1.5 h under nitrogen atmosphere. The reaction mixture was quenched with methanol (50 mL) and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiCL, petroleum ether / ethyl acetate=l / 0 to 1 / 1) to afford (4-bromo-2,6-dimethylphenyl)methanol (4.30 g, 20.0 mmol, 92% yield) as a white solid.Step 2. Procedure for preparation of Compound 3 - 5-bromo-2-(chloromethyl)-l,3- dimethylbenzene.

[0396] To a solution of (4-bromo-2,6-dimethylphenyl)methanol (4.30 g, 20.0 mmol, 1.00 eq) in dichloromethane (40.0 mL) was added thionyl chloride (12.0 g, 100 mmol, 7.25 mL, 5.00 eq). The mixture was stirred at 20 °C for 1 h. The reaction mixture was concentrated under reduced pressure to give a residue and extracted with ethyl acetate (3 x 50 mL). The combined organic phases were washed with brine (2 x 20 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to afford 5-bromo-2- (chloromethyl)-l,3- dimethylbenzene (4.60 g, crude) as yellow oil.Step 3. Procedure for preparation of Compound 2 - (4-bromo-2,6-dimethylphenyl)methanol.

[0397] To a solution of 5-bromo-2-(chloromethyl)-l,3-dimethylbenzene (4.60 g, 19.7 mmol, 1.00 eq) in tetrahydrofuran (5.00 mL) were added trimethylsilylcyanide (3.91 g, 39.4 mmol, 4.93 mL, 2.00 eq) follow by tetrabutylammoniumfluoride (1.00 M, 39.4 mL, 2.00 eq) at 0 °C, the mixture was stirred at 25 °C for 12 h. The reaction mixture was extracted with ethyl acetate (3 x 50 mL). The combined organic phases were washed with brine (2 x 30 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=l / O to 50 / 1) to afford 2-(4-bromo-2,6-dimethyl-phenyl)acetonitrile (3.50 g, 15.6 mmol, 79% yield) as yellow oil.Step 4. Procedure for preparation of Compound 5 - 5-bromo-2-(chloromethyl)-l ,3- dimethylbenzene.

[0398] To a solution of 2-(4-bromo-2,6-dimethylphenyl)acetonitrile (500 mg, 2.23 mmol, 1.00 eq) in tetrahydrofuran (5.00 mL) were added sodium hydride (134 mg, 3.35 mmol, 60% purity, 1.50 eq) and methyl acrylate (300 mg, 3.48 mmol, 314 uL, 1.56 eq) at 0 °C, the mixture was stirred at 20 °C for 1 h. The mixture was quenched with saturated ammonium chloride aqueous solution (10 mL) and extracted with ethyl acetate (3 x 30 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=l / O to 10 / 1) to afford methyl 4-(4-bromo-2,6-dimethylphenyl)-4-cyanobutanoate (500 mg, 1.61 mmol, 72% yield) as yellow oil.Step 5. Procedure for preparation of Compound 6 - 5-bromo-2-(chloromethyl)-l ,3- dimethylbenzene.

[0399] To a solution of methyl 4-(4-bromo-2,6-dimethylphenyl)-4-cyanobutanoate (200 mg, 645 umol, 1.00 eq) in acetic acid (5.00 mL) was added sulfuric acid (920 mg, 9.38 mmol, 0.500 mL, 14.6 eq). The mixture was stirred at 90 °C for 2 h. The reaction mixture was poured into cold water and then filtered. The filter cake was concentrated under reduced pressure to afford 3-(4-bromo-2,6-dimethylphenyl) piperidine-2,6- dione (130 mg, 439 umol, 68% yield) as a white solid.

[0400] 1H NMR (400 MHz, DMSO-O b = 10.89 (s, 1H), 7.27 (s, 1H), 7.22 (s, 1H), 4. 17 (dd, J= 5.4, 12.8 Hz, 1H), 2.81 (ddd, J= 5.8, 13.8, 16.8 Hz, 1H), 2.42 (br d, J= 11.5 Hz, 1H), 2.32 (s, 3H), 2.19 - 2.10 (m, 1H), 2.09 (s, 3H), 1.93 - 1.84 (m, 1H)Step 6. Procedure for preparation of Compound 7 - tert-butyl (l-(4-(2,6-dioxopiperidin-3- yl)-3,5- dimethylphenyl)azetidin-3-yl)carbamate.

[0401] To a solution of 3-(4-bromo-2,6-dimethylphenyl)piperidine-2, 6-dione (130 mg, 439 nmol, 1.00 eq) and tert-butyl azetidin-3-ylcarbamate (90.7 mg, 527 umol, 1.20 eq) in dioxane (5.00 mL) were added [ 1 ,3 -bis [2,6-bis( 1 -propylbutyl)phenyl]-4,5-dichloro-imidazol-2-ylidene]-dichloro-(3-chloropyridin- 1 -ium- 1 - yl)palladium (8.54 mg, 8.78 umol, 0.0200 eq) and cesium carbonate (429 mg, 1.32 mmol, 3.00 eq). The mixture was stirred at 100 °C for 12 h under nitrogen atmosphere. The reaction mixture was diluted with water (20 mL) and exacted with ethyl acetate (3 x 20 mL). The combined organic phases were washed with brine (2 x 10 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=l / O to 5 / 1) to afford tertbutyl (l-(4-(2,6-dioxopiperidin-3-yl)-3,5-dimethylphenyl)azetidin-3-yl)carbamate (70.0 mg, 181 umol, 41% yield) as a yellow solid.Step 7. Procedure for preparation of Compound 8 - 3-(4-(3-aminoazetidin-l-yl)-2,6- dimethylphenyl)piperidine-2, 6-dione.

[0402] To a solution of tert-butyl (l-(4-(2,6-dioxopiperidin-3-yl)-3,5-dimethylphenyl)azetidin-3- yl)carbamate (70.0 mg, 181 umol, 1.00 eq) in dichloromethane (2.50 mL) was added trifluoroacetic acid (7.06 mg, 61.9 umol, 4.59 uL, 3.43e-1eq) at 20 °C. The mixture was stirred at 20 °C for 2 h. The reaction mixture was concentrated under reduced pressure to afford 3-(4-(3-aminoazetidin-l-yl)-2,6-dimethylphenyl)piperidine- 2, 6-dione (50.0 mg, 174 umol, 96% yield) as yellow oil. MS (ESI) m / z 287.9 [M+H]+Step 8. Procedure for preparation of l-(cyclopropyl(methyl)carbamoyl)azetidin- 3-yl (l-(4-(2,6- dioxopiperidin-3-yl)-3,5-dimethylphenyl)azetidin-3-yl)carbamate.

[0403] To a solution of A'-cyclopropy I -3 -hydro xy-A'-mcthyl-azctidinc- 1 -carboxamide (40.0 mg, 235 umol, 1.00 eq) in tetrahydrofuran (1.00 mL) was added di( IH-imidazol- l-yl)methanone (38. 1 mg, 235 umol, 1.00 eq), the mixture was stirred at 25 °C for 1 h. The resulting solution was added to a mixture of 3-(4-(3- aminoazetidin-l-yl)-2,6-dimethylphenyl)piperidine-2, 6-dione (50.0 mg, 174 umol, 1.00 eq), 2,3,4,6,7,8,9,10- octahydropyrimido[l,2-a]azepine (26.5 mg, 174 umol, 26.2 uL, 1.00 eq) and A'.A'-diisopropylcthylaminc (22.5 mg, 174umol, 30.3 uL, 1.00 eq) in dimethylformamide (1.00 mL). The mixture was stirred at 25 °C for 11 h.The mixture was filtered. The filtrate was purified by Prep-HPLC (column: Phenomenex luna C18 150*25mm* lOum; mobile phase: [water (formic acid) - acetonitrile]; B%: 23%-53%, 58 min) and lyophilized to afford l-(cyclopropyl(methyl)carbamoyl) azetidin-3-yl(l-(4-(2,6-dioxopiperidin-3-yl)-3,5- dimethylphenyl)azetidin -3-yl)carbamate (12.57 mg, 25.5 umol, 15% yield, 97% purity) as a white solid.

[0404] 1H NMR (400 MHz, DMSO-d6 ) δ = 10.75 (s, 1H), 8.06 (br d, J= 7.6 Hz, 1H), 6.11 (br d, J = 16.0 Hz, 2H), 5.06 - 4.98 (m, 1H), 4.44 - 4.38 (m, 1H), 4.23 (dd, J= 6.8, 9.6 Hz, 2H), 4.06 - 3.99 (m, 3H), 3.82 (br dd, J= 3.8, 9.6 Hz, 2H), 3.56 - 3.52 (m, 2H), 2.83 - 2.78 (m, 1H), 2.73 (s, 3H), 2.57 (br d, J= 3.4 Hz, 1H), 2.47 (br s, 1H), 2.24 (s, 3H), 2.09 - 2.04 (m, 1H), 2.01 (s, 3H), 1.87 - 1.80 (m, 1H), 0.75 - 0.70 (m, 2H), 0.64 - 0.60 (m, 2H). MS (ESI) m / z 484.3 | M+H [Synthesis of compound 87Step 1. Procedure for Compound 2 - (4-bromo-2-chloro-6-methylphenyl)methanol.

[0405] To a solution of 4-bromo-2-chloro-6-methylbenzoic acid (3.00 g, 12.0 mmol, 1.00 eq) in tetrahydrofuran (30.0 mL) was added borane dimethyl sulfide complex (10.0 M, 3.61 mL, 3.00 eq) at 0 °C. The mixture was stirred at 25 °C for 12 h under nitrogen atmosphere. The reaction mixture was quenched with methanol (10 mL) at 0 °C. The mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiCL, petroleum ether / ethyl acetate=10 / l to 2 / 1) to afford (4-bromo- 2-chloro-6-methylphenyl)methanol (2.00 g, 8.49 mmol, 70% yield) as a yellow solid.Step 2. Procedure for preparation of Compound 3 - 5-bromo-l-chloro-2-(chloromethyl)-3-methylbenzene.

[0406] To a solution of (4-bromo-2-chloro-6-methylphenyl)methanol (2.00 g, 8.49 mmol, 1.00 eq) in dichloromethane (20.0 mL) was added thionyl chloride (2.02 g, 17.0 mmol, 1.23 mL, 2.00 eq). The mixture was stirred at 25 °C for 12 h under nitrogen atmosphere. The mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiCL, petroleum ether / ethyl acetate=10 / 0 to 1 / 1) to afford 5 -bromo- l-chloro-2-(chloromethyl)-3 -methylbenzene (1.00 g, 2.36 mmol, 27% yield, 60% purity) as colorless oil.Step 3. Procedure for Compound 4 - 2-(4-bromo-2-chloro-6-methylphenyl)acetonitrile.

[0407] To a solution of 5-bromo-l-chloro-2-(chloromethyl)-3-methylbenzene (800 mg, 3.15 mmol, 1.00 eq) in acetonitrile (5.00 mL) were added trimethylsilyl cyanide (938 mg, 9.45 mmol, 1.18 mL, 3.00 eq) and tetrabutylammonium fluoride (1 M, 9.45 mL, 3.00 eq) at 0 °C. The mixture was stirred at 25 °C for 2 h. The mixture was diluted with water (100 mL), extracted with ethyl acetate (3 x 40 mL). The combined organic layer was 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=10 / 0 to 10 / 1) to afford 2-(4-bromo-2-chloro-6-methylphenyl)acetonitrile (600 mg, 2.45 mmol, 77% yield) as a white solid.Step 4. Procedure for Compound 5 - methyl 4-(4-bromo-2-chloro-6-methylphenyl)-4-cyanobutanoate.

[0408] To a solution of 2-(4-bromo-2-chloro-6-methylphenyl)acetonitrile (600 mg, 2.45 mmol, 1.00 eq) in tetrahydrofuran (6.00 mL) were added sodium methoxide (26.5 mg, 491 umol, 0.200 eq) and methyl acrylate (232 mg, 2.70 mmol, 243 uL, 1.10 eq) at 0 °C. The mixture was stirred at 25 °C for 2 h. The mixture was quenched with saturated ammonium chloride aqueous solution (10 mL). The mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiCL,petroleum ether / ethyl acetate=20 / l to 3 / 1) to afford methyl 4-(4-bromo-2-chloro-6-methylphenyl)-4- cyanobutanoate (800 mg, 2. 18 mmol, 88% yield, 90% purity) as colorless oil.Step 5. Procedure for Compound 6 - 3-(4-bromo-2-chloro-6-methylphenyl)piperidine-2, 6-dione.

[0409] To a solution of methyl 4-(4-bromo-2-chloro-6-methylphenyl)-4-cyanobutanoate (800 mg, 2.42 mmol, 1.00 eq) in acetic acid (8.00 mL) was added sulfuric acid (1.47 g, 15.0 mmol, 0.800 mL, 6.20 eq). The mixture was stirred at 90 °C for 2 h. The reaction mixture was poured into ice water (50 mL) and filtered. The filter cake was concentrated under reduced pressure to afford 3-(4-bromo-2-chloro-6- methylphenyl)piperidine-2, 6-dione (660 mg, 2.08 mmol, 86% yield) as a white solid.

[0410] 1H NMR (400 MHz, CDCL-rZ) <5 = 8.10 (br s, 1H), 7.44 (s, 1H), 7.32 (s, 1H), 3.99 - 3.92 (m, 1H), 2.85 (d, J= 2.3 Hz, 1H), 2.80 - 2.70 (m, 1H), 2.69 (br d, J = 4.3 Hz, 1H), 2.66 - 2.59 (m, 1H), 2.41 (s, 3H).Step 6. Procedure for Compound 7 - tert-butyl (l-(3-chloro-4-(2,6-dioxopiperidin-3-yl)-5- methylphenyl)azetidin-3-yl)carbamate.

[0411] To a solution of 3-(4-bromo-2-chloro-6-methylphenyl)piperidine-2, 6-dione (250 mg, 790 umol, 1.00 eq) in dioxane (4.00 mL) were added sodium tert-butoxide (152 mg, 1.58 mmol, 2.00 eq). tert-butyl azetidin-3-ylcarbamate (272 mg, 1.58 mmol, 2.00 eq) and methanesulfonato[2-(di-tert-butylphosphino)-3,6- dimethoxy-2’,4’,6’-tri-i-propyl-l,l’-biphenyl](2’-amino-l,l’-biphenyl-2-yl)palladium(II) (67.5 mg, 790 umol, 0. 100 eq). The mixture was stirred at 90 °C for 6 h under nitrogen atmosphere. The mixture was filtered and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by reverse phase chromatography (C18, 80 g; condition: water / acetonitrile = 100:0 to 0: 100, 0.1% formic acid) and lyophilized to afford tert-butyl (l-(3-chloro-4-(2,6-dioxopiperidin-3-yl)-5-methylphenyl)azetidin-3- yl)carbamate (65.0 mg, 159 umol, 10% yield) as a white solid.Step 7. Procedure for Compounds - 3-(4-(3-aminoazetidin-l-yl)-2-chloro-6-methylphenyl)piperidine-2,6- dione.

[0412] To a solution of tert-butyl (l-(3-chloro-4-(2,6-dioxopiperidin-3-yl)-5-methylphenyl)azetidin- 3-yl)carbamate (65.0 mg, 159 umol, 1.00 eq) in dichloromethane (2.00 mL) was added trifluoroacetic acid (616 mg, 5.40 mmol, 0.400 mL, 33.9 eq). The mixture was stirred at 25 °C for 2 h. The mixture was filtered and the filtrate was concentrated under reduced pressure to afford 3-(4-(3-aminoazetidin-l-yl)-2-chloro-6- methylphenyl)piperidine-2, 6-dione (48.0 mg, crude) as a white solid. MS (ESI) m / z 308.0 [M+H]+Step 8. Procedure for l-(cyclopropyl(methyl)carbamoyl)azetidin-3-yl (l-(3-chloro-4-(2,6-dioxopiperidin-3- yl)-5-methylphenyl)azetidin-3-yl)carbamate.

[0413] To a solution of A''-cyclopropyl-3-hydroxy-A''-mcthylazctidinc- l -carboxamide (50.0 mg, 294 umol, 1.00 eq) in tetrahydrofuran (1.00 mL) was added di( IH-imidazol- l-yl)methanone (57.2 mg, 353 umol, 1.20 eq) at 0 °C. The mixture was stirred at 25 °C for 1 h. The resulting solution was added to a mixture of 3- (4-(3-aminoazetidin-l-yl)-2-chloro-6-methylphenyl)piperidine-2, 6-dione (48.0 mg, 156 umol, 1.00 eq). triethylamine (15.8 mg, 156 umol, 21.7 uL, 1.00 eq) and 2,3,4,6,7,8,9,10-octahydropyrimido[l,2-a]azepine (23.7 mg, 156 umol, 23.5 uL, 1.00 eq) in tetrahydrofuran (0.500 mL) and dimethylformamide (0.500 mL). The mixture was stirred at 25 °C for 12 h. The mixture was concentrated under reduced pressure to give a residue. The residue was purified by reverse phase chromatography (C18, 80 g; condition: water / acetonitrile = 100:0 to 0: 100, 0.1% formic acid) and lyophilized to afford l-(cyclopropyl(methyl)carbamoyl)azetidin-3-yl (l-(3- chloro-4-(2,6-dioxopiperidin-3-yl)-5-methylphenyl)azetidin-3-yl)carbamate (11.22 mg, 22.04 umol, 14% yield, 99% purity) as a white solid.

[0414] 1H NMR (400 MHz, DMSO-cA) 3 = 10.94 - 10.67 (m, 1H), 8.08 (d, J = 7.5 Hz, 1H), 6.37 - 6.22 (m, 2H), 5.04 - 4.97 (m, 1H), 4.45 - 4.38 (m, 1H), 4.26 - 4. 18 (m, 2H), 4.08 (br t, J = 7. 1 Hz, 2H), 3.86 - 3.78 (m, 2H), 3.59 (br t, J= 6.6 Hz, 2H), 2.84 - 2.74 (m, 1H), 2.74 - 2.69 (m, 3H), 2.61 - 2.52 (m, 2H), 2.47 (br d, J = 1.5 Hz, 1H), 2.34 - 2.25 (m, 3H), 2.13 - 2.05 (m, 1H), 1.90 - 1.78 (m, 1H), 0.75 - 0.68 (m, 2H), 0.65 - 0.58 (m, 2H).

[0415] 1H NMR (400 MHz, DMSO -d6, T=80 °C) 3 = 10.56 - 10.39 (m, 1H), 7.84 - 7.70 (m, 1H), 6.31 (br s, 1H), 6.25 (s, 1H), 5.08 - 5.00 (m, 1H), 4.46 - 4.37 (m, 1H), 4.26 - 4.20 (m, 2H), 4.09 (t, J= 7.5 Hz, 2H), 3.88 - 3.80 (m, 2H), 3.66 (t, J= 6.6 Hz, 2H), 2.85 - 2.75 (m, 1H), 2.74 (s, 3H), 2.61 - 2.51 (m, 3H), 2.40 - 2.30 (m, 1H), 2.29 - 2.08 (m, 3H), 1.92 - 1.84 (m, 1H), 0.76 - 0.68 (m, 2H), 0.68 - 0.59 (m, 2H). MS (ESI) m / z 504.4 [M+H]+Synthesis of Compound 88Compound M87-3 87-1AStep 1. Procedure for Compound 1A - cyclopropyl(methyl)carbamic chloride.

[0416] A solution of A'-mcthylcyclopropanaminc (500 mg, 7.03 mmol, 1.00 eq) and bis(trichloromethyl) carbonate (3.13 g, 10.6 mmol, 1.50 eq) in dichloromethane (10.0 mL) was added A'.A'- diisopropylethylamine (1.82 g, 14. 1 mmol, 2.45 mL, 2.00 eq) at 0 °C. The mixture was stirred at 25 °C for 1 h. The mixture was concentrated under reduced pressure to afford cyclopropyl(methyl)carbamic chloride (800 mg, crude) as yellow oil.Step 2. Procedure for Compound 2 - N-cyclopropyl-4-hydroxy-N-methylpiperidine-l-carboxamide.

[0417] To mixture of piperidin-4-ol (500 mg, 4.94 mmol, 1.00 eq) in dimethylformamide (2.00 mL) was added A,A-diisopropylethylamine (1.28 g, 9.89 mmol, 1.72 mL, 2.00 eq) at 0 °C for 15 min. Then cyclopropyl(methyl)carbamic chloride (726 mg, 5.44 mmol, 1. 10e<?) was added and the mixture was stirred at 25 °C for 1 h. The mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 0 / 1) to afford A''-cyclopropyl-4-hydroxy-A''- methylpiperidine-1 -carboxamide (560 mg, 2.77 mmol, 56% yield, 98% purity) as a white solid.Step 3. Procedure for l-(cyclopropyl(methyl)carbamoyl)piperidin-4-yl (l-(4-(2,6-dioxopiperidin-3-yl)-3,5- difluorophenyl)azetidin-3-yl)carbamate.

[0418] To a solution of A''-cyclopropyl-4-hydroxy-A''-mcthy I piperidine- 1 -carboxamide (200 mg, 1.01 mmol, 1.00 eq) in tetrahydrofuran (5.00 mL) was added di( 1 / 7-imidazol- l-yl)methanone (196 mg, 1.21 mmol, 1.20 eq) at 0 °C. The mixture was stirred at 25 °C for 12 h. The resulting solution was added to a mixture of 3 -(4-(3-aminoazetidin-l-yl)-2,6-difluorophenyl)piperidine-2, 6-dione (101 mg, 258 umol, 1.00 eq, mesylate), 2,3,4,6,7,8,9,10-octahydropyrimido[l,2-a]azepine (39.3 mg, 258 umol, 38.9 uL, 1.00 eq) and triethylamine (26.1 mg, 258 umol, 35.9 uL, 1.00 eq) in dimethylformamide (2.00 mL) and tetrahydrofuran (2.00 mL). The mixture was stirred at 25 °C for 12 h. The mixture was concentrated under reduced pressure to give a residue. The residue was purified by reverse phase chromatography (Cl 8, 80 g; condition: water / acetonitrile = 100:0 to 0: 100, 0. 1% formic acid) and lyophilized to give a crude product. The crude product was purified by column chromatography (SiCE, petroleum ether / ethyl acetate = 0 / 1) to afford 1-(cyclopropyl(methyl)carbamoyl)piperidin-4-yl (l-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)azetidin -3- yl)carbamate (24.41 mg, 46.5 umol, 18% yield, 99% purity) as a white solid.

[0419] 1H NMR (400 MHz, DMSO-<7„) S = 10.85 (s, 1H), 7.85 (br d, J= 7.4 Hz, 1H), 6. 14 (d, J= 11.0 Hz, 2H), 4.67 (td, J= 4.2, 8. 1 Hz, 1H), 4.48 - 4.33 (m, 1H), 4.09 (t, J= 7.6 Hz, 2H), 4.03 (br dd, J= 5.0, 12.6 Hz, 1H), 3.63 (t, J= 6.8 Hz, 2H), 3.55 - 3.39 (m, 2H), 2.97 (br t, J= 10.0 Hz, 2H), 2.82 - 2.74 (m, 1H), 2.71 (s, 3H), 2.60 - 2.55 (m, 1H), 2.54 - 2.51 (m, 1H), 2.07 (dq, J= 4.0, 13.0 Hz, 1H), 1.98 - 1.90 (m, 1H), 1.82 (br d, J= 9.6 Hz, 2H), 1.45 (q, J= 9.0 Hz, 2H), 0.68 - 0.59 (m, 2H), 0.51 - 0.39 (m, 2H). MS (ESI) m / z.520.2 [M+H]+Synthesis of Compound 89Step 1. Procedure for preparation of Compound 7 - tert-butyl 3-((5-(spiro[3.3]heptan-2-yl)-l,3,4-oxadiazol- 2-yl)amino)azetidine-l-carboxylate.

[0420] To a solution of 2-bromo-5-(spiro[3.3]heptan-2-yl)-l,3,4-oxadiazole (470 mg, 1.93 mmol, 1.00 eq) and tert-butyl 3-aminoazetidine-l-carboxylate (499 mg, 2.90 mmol, 1.50 eq) in dimethylsulfoxide (7.00 mL) was added MA'-diisopropylcthylaminc (249 mg, 1.93 mmol, 336 uL, 1.00 eq). The reaction wasstirred at 80 °C for 6 h. The reaction was filtered to give a filtrate. The residue was purified by reverse phase chromatography (C18, 80 g; condition: water / acetonitrile = 95:5 to 40:60, 0.1% formic) and lyophilized to afford tert-butyl 3-((5-(spiro[3.3]heptan-2-yl)-l,3,4-oxadiazol-2-yl)amino)azetidine-l-carboxylate (330 mg, 986 umol, 51% yield) as a yellow solid.Step 2. Procedure for preparation of Compound 5 A -N-(azetidin-3-yl)-5-(spiro[3.3]heptan-2-yl)-l,3,4- oxadiazol-2-amine.

[0421] To a solution of tert-butyl 3-((5-(spiro[3.3]heptan-2-yl)-l,3,4-oxadiazol-2-yl)amino)azetidine- 1-carboxylate (300 mg, 89.7 umol, 1.00 eq) in dichloromethane (1.00 mL) was added methanesulfonic acid (25.8 mg, 269 umol, 19. 1 uL, 3.00 eq). The reaction was stirred at 20 °C for 2 h. The reaction was concentrated under reduced pressure to give / V-(azetidin-3-yl)-5-(spiro[3.3]heptan-2-yl)-l,3,4-oxadiazol-2-amine (40.0 mg, 170 umol, 95% yield) as yellow oil. MS (ESI) m / z 234.9 [M+H]+Step 3. Procedure for preparation of Compound 2 - 2-bromo-5-(bromomethyl)benzonitrile.

[0422] To a solution of 2-bromo-5-methylbenzonitrile (6.00 g, 30.6 mmol, 1.00 eq) in chloroform (60.0 mL) was added A'-bromosiiccinimidc (5.99 g, 33.6 mmol, 1.10 eq) and (E)-2,2'-(diazene-l,2-diyl)bis(2- methylpropanenitrile) (5.03 g, 30.6 mmol, 1.00 eq). The reaction was stirred at 80 °C for 2 h. The reaction was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiCL, petroleum ether / ethyl acetate = 10 / 1 to 5 / 1) to afford 2-bromo-5-(bromomethyl) benzonitrile (8.20 g, 29.8 mmol, 97 % yield) as a white solid.Step 4. Procedure for preparation of Compound 3- 2-bromo-5-(cyanomethyl)benzonitrile.

[0423] To a solution of 2-bromo-5-(bromomethyl)benzonitrile (8.20 g, 29.8 mmol, 1.00 eq) in tetrahydrofuran (60.0 mL) was added trimethylsilanecarbonitrile (5.92 g, 59.6 mmol, 7.46 mL, 2.00 eq) and tetrabutylammonium fluoride (1.00 M, 59.6 mL, 2.00 eq) at 0 °C. The reaction was stirred at 20 °C for 2 h. The reaction was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiCL, petroleum ether / ethyl acetate=3 / l to 2 / 1) to afford 2-bromo-5- (cyanomethyl)benzonitrile (4.00 g, 18.1 mmol, 61% yield) as a white solid.Step 5. Procedure for preparation of Compound 4- methyl 4-(4-bromo-3-cyanophenyl)-4-cyanobutanoate.

[0424] To a solution of 2-bromo-5-(cyanomethyl)benzonitrile (1.00 g, 4.52 mmol, 1.00 eq) in tetrahydrofuran (100 mL) was added sodium methoxide (244 mg, 4.52 mmol, 1.00 eq) and methyl acrylate(350 mg, 4.07 mmol, 366 uL, 0.900 eq) at 0 °C. The reaction was stirred at 20 °C for 1 h. The reaction was diluted with water (100 mL) and extracted with ethyl acetate (3 x 100 mL), then the organic layers were washed with brine (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=10 / l to 8 / 1) and re-purified by reverse phase chromatography (Cl 8, 80 g; condition: water / acetonitrile = 95:5 to 40:60, 0.1% formic) and lyophilized to afford methyl 4-(4-bromo-3-cyanophenyl)-4-cyanobutanoate (300 mg, 976 umol, 22% yield) as colorless oil.Step 6. Procedure for preparation of Compound 5 - 2-bromo-5-(2,6-dioxopiperidin-3-yl)benzonitrile.

[0425] To a solution of methyl 4-(4-bromo-3-cyanophenyl)-4-cyanobutanoate (300 mg, 976 umol, 1.00 eq) in sulfuric acid (300 uL) was added acetic acid (3.00 mL). The mixture was stirred at 90 °C for 2 h. The reaction was added ice water (50.0 mL) and filtered to give 2-bromo-5-(2,6-dioxopiperidin-3- yl)benzonitrile (130 mg, 443 umol, 45% yield) as a white solid

[0426] 1H NMR (400 MHz, DMSO-^) 8 = 10.92 (s, 1H), 8.02 - 7.75 (m, 2H), 7.55 (dd, J= 2.0, 8.4 Hz, 1H), 4.00 (dd, J= 4.8, 12.4 Hz, 1H), 2.71 - 2.65 (m, 1H), 2.60 - 2.57 (m, 1H), 2.35 - 2.26 (m, 1H), 2.07 - 1.99 (m, 1H).Step 7. Procedure for preparation of 5-(2,6-dioxopiperidin-3-yl)-2-(3-((5-(spiro[3.3]heptan-2-yl)-l,3,4- oxadiazol-2-yl)amino)azetidin-l-yl)benzonitrile.

[0427] To a solution of 2-bromo-5-(2,6-dioxopiperidin-3-yl)benzonitrile (30.0 mg, 102 umol, 1.20 eq) and / V-(azetidin-3-yl)-5-(spiro[3.3]heptan-2-yl)-l,3,4-oxadiazol-2-amine (20.0 mg, 85.3 umol, 1.00 eq) in dioxane (2.00 mL) was added cesium carbonate (139 mg, 426 umol, 5.00 eq) and l,3-bis[2,6-bis(l- propylbutyl)phenyl]-4,5-dichloro-2 / / -imidazol-l-ium-2-ide;3-chloropyridine;dichloropalladium (1.66 mg, 1.71 umol, 0.0200 eq). The reaction mixture was stirred at 100 °C for 2 h. The reaction mixture was filtered to give a filtrate. The filtrate was concentrated under reduced pressure to give a residue. The residue was purified by / Vc / i-HPLC (column: Phenomenex luna C18 150*25mm* 10um;mobile phase: [water(formic acid)- acetonitrile] ;B%: 34%-64%,10min) and lyophilized to afford 5-(2,6-dioxopiperidin-3-yl)-2-(3-((5- (spiro[3.3]heptan-2-yl)-l,3,4-oxadiazol-2-yl)amino)azetidin-l-yl)benzonitrile (12.26 mg, 26.6 umol, 16% yield, 97% purity) as a white solid.

[0428] 1H NMR (400 MHz, DMSO-d6 ) δ = 10.82 (br s, 1H), 8.17 (br d, J= 5.2 Hz, 1H), 7.38 (d, J = 2.0 Hz, 1H), 7.32 (dd, J = 2.0, 8.8 Hz, 1H), 6.61 (d, J = 8.8 Hz, 1H), 4.43 (br d, J = 4.0 Hz, 3H), 4.00 (br d, J = 4.0 Hz, 2H), 3.78 (dd, J = 4.8, 12.4 Hz, 1H), 3.46 - 3.42 (m, 1H), 2.71 - 2.62 (m, 1H), 2.55 - 2.52 (m, 1H),2.38 - 2.33 (m, 2H), 2.24 - 2. 16 (m, 3H), 2.08 - 2.04 (m, 2H), 1.98 (br dd, J= 4.8, 8.0 Hz, 1H), 1.94 - 1.89 (m, 2H), 1.81 - 1.75 (m, 2H). MS (ESI) m / z 447.2 [M+H]+Synthesis of Compound 90Step 1. Procedure for Compound 1 - methyl 4-(trifluoromethoxy)benzoate.

[0429] 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 added stirred at 60 °C for 3 ...

Claims

CLAIMSWhat is claimed is:

1. A combination comprising:(i) a compound of F ormula (I) :or a pharmaceutically acceptable salt thereof, wherein:X is selected from H and deuterium;L1is selected from the group consisting of:membered heteroaryl;L2is selected from a bondeach of R1, R2, R3, and R4is independently selected from the group consisting of hydrogen, halogen, C1-6alkoxy, cyano, hydroxy, C3-6 monocyclic cycloalkyl, and C1-6alkyl; ring A is selected from C3-6 monocyclic cycloalkyl and 3 to 6 membered heterocyclyl, wherein each of CWmonocyclic cycloalkyl and 3 to 6 membered heterocyclyl is optionally substituted with one or more occurrences of R5; each occurrence of R5is independently selected from the group consisting of hydrogen, C1-6 alkyl, hydroxy, and oxo, wherein C1-6 alkyl is optionally substituted with one or more occurrences of halogen; ring B is selected from the group consisting of C3-12 monocyclic or C3-12 bicyclic cycloalkyl, 3 to 10 membered heterocyclyl, aryl, and heteroaryl, wherein each of C3-12 monocyclic or C3-12 bicyclic cycloalkyl, 3 to 10 membered heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more occurrences of R6; each occurrence of R6is independently selected from the group consisting of halogen, cyano, Ci- ealkoxy, C1-6alkyl, -C(O)R7, -C(O)NR7R8, -S(O)2R7, pyridine,, wherein each C1-6alkyl, C1-6alkoxy, and pyridine is optionally substituted with one or more occurrences of a substitutent selected from C1-6alkyl and halogen; each occurrence of R7is independently selected from the group consisting of C1-6alkyl, phenyl, cyclopropane, an N-linked C3-9 heterocycloalkyl, an N-linked heteroaryl,,XX JO , wherein R7is optionally substituted with one or more occurrences of a substituent selected from the group consisting of C1-6alkyl, halogen, cyano, trifluoro(methoxy)methane, and C1-6alkoxy (e.g., methoxy); each occurrence of R8, R9, and R10is independently selected from hydrogen, deuterium, Ci- ealkyl, and deuterated C1-6alkyl (e.g., -CD3); and n is an integer selected from the group consisting of 0, 1, 2, and 3; and(ii) a CDK4 / 6 inhibitor.

2. A kit comprising (i) a unit dosage form comprising a compound of Formula (I) as defined in claim 1 or a pharmaceutically acceptable salt thereof, and, separately, (ii) a unit dosage form comprising a CDK4 / 6 inhibitor.

3. The kit of claim 2, wherein each unit dosage form is a pharmaceutical composition additionally comprising one or more pharmaceutically acceptable excipients.

4. A method of treating a subject suffering from a disorder, wherein the method comprises administering to the subject a compound of Formula (I) or a pharmaceutically acceptable salt thereof, and a CDK4 / 6 inhibitor.

5. The method of claim 4, wherein the compound of Formula (I) or pharmaceutically acceptable salt thereof and the CDK4 / 6 inhibitor are administered to the subject simultaneously, separately, or sequentially.

6. The method of claim 4 or claim 5, wherein the disorder is cancer.

7. The method of claim 6, wherein the cancer is breast cancer.

8. The method of claim 7, wherein the breast cancer is HR+ (hormone receptor positive) HER2- (human epidermal growth factor receptor 2 negative) breast cancer.

9. The method of claim 8, wherein the breast cancer is HR+ (hormone receptor positive) HER2- (human epidermal growth factor receptor 2 negative) advanced or metastatic breast cancer.

10. The method of any one of claims 6-9, wherein the cancer is resistant to treatment with a CDK4 / 6 inhibitor.

11. The method of any one of claims 4-10, wherein the compound of Formula (I) or pharmaceutically acceptable salt thereof and the CDK4 / 6 inhibitor are administered within 24 hours of each other.

12. The method of any one of claims 4-11, wherein the CDK4 / 6 inhibitor is administered in combination with endocrine therapy.

13. The method of claim 12, wherein the endocrine therapy is an estrogen receptor antagonist such as fulvestrant, or an aromatase inhibitor such as letrozole.

14. The method of claim 13, wherein the CDK4 / 6 inhibitor is administered in combination with fulvestrant.

15. The combination, kit, or method of any one of claims 1-14, wherein the CDK4 / 6 inhibitor is palbociclib, ribociclib, abemaciclib, lerociclib, trilaciclib, dalpiciclib, birociclib, BPI-16350, or in each case a pharmaceutically acceptable salt thereof.

16. The combination, kit, or method of claim 15, wherein the CDK4 / 6 inhibitor is ribociclib or a pharmaceutically acceptable salt thereof.

17. The combination, kit, or method of any one of claims 1-16, wherein the CDK4 / 6 inhibitor is in the form of a pharmaceutically acceptable salt.

18. The combination, kit, or method of any one of claims 1-17, wherein the compound of Formula (I) is a compound of Formula (1-1-0):

9. The combination, kit, or method of any one of claims 1-18, wherein the compound of Formula (I) or pharmaceutically acceptable salt thereof is a compound selected from:, or in each case a pharmaceutically acceptable salt thereof.

20. The combination, kit, or method of claim 19, wherein the compound of Formula (I) or pharmaceutically acceptable salt thereof is:pharmaceutically acceptable salt thereof.

21. The combination, kit, or method of claim 19, wherein the compound of Formula (I) or pharmaceutically acceptable salt thereof is:

Images