CDK2 inhibitors for the treatment of cancer

Abstract

The present disclosure provides compounds of Formula (I) and pharmaceutically acceptable salts thereof, that are degraders of cyclin-dependent kinase 2 (CDK2), as well as pharmaceutical compositions thereof, and methods of treating cancer using the same.

Description

CDK2 INHIBITORS FOR THE TREATMENT OF CANCERCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to U.S. Patent Application No. 63 / 658,410 filed June 10, 2024, and U.S. Patent Application No. 63 / 804,487 filed May 12, 2025, the entire contents of which are hereby incorporated herein by reference. BACKGROUND OF THE DISCLOSURE

[0002] The field of the disclosure relates generally to cyclin dependent kinase 2 degrader compounds.

[0003] The ubiquitin-proteasome pathway (UPP) is a critical pathway that controls protein metabolism in cells by degrading / eliminating misfolded and abnormal proteins. UPP is central to multiple cellular processes, and if defective or imbalanced, it leads to pathogenesis of a variety of diseases, such as cancer.

[0004] Cyclin dependent kinases (CDKs) are a family of serine / threonine kinases that, when heterodimerized with cyclin regulatory subunits, become activated and regulate key cellular processes including cell cycle progression and cell division. Deregulation of CDK activity is implicated with abnormal regulation of cell-cycle, and is detected in virtually all forms of human cancers which are characterized by uncontrolled cell proliferation. As such, therapeutic agents that leverage UPP mediated protein degradation to target cancer-associated proteins such as cyclin-dependent kinase 2 (“CDK2”) are believed to be chemo-therapeutic agents. Accordingly, there remains a need to find compounds that are CDK2 degraders useful as therapeutic agents. BRIEF DESCRIPTION OF THE DISCLOSURE

[0005] In one aspect, provided herein are compounds of Formula (I):or a pharmaceutically acceptable salt thereof; wherein: X1and X4are each independently C, CH, or N; X2and X3are each independently C, CH or N; or one of X2and X3is C=O, the other one is NR4; wherein at least one of X1, X2, X3, and X4comprises N; represents a single or double bond; each R1is independently selected from halogen, cyano, C1-6alkyl, hydroxy, C1-6haloalkyl, C1-6hydroxyalkyl, C1-6alkoxy, O-C1-6haloalkyl, O-C3-6cycloalkyl, and -N(Ra)(Rb); p is selected from 0, 1, 2, and 3; each R2is independently selected from halogen, cyano, hydroxy, optionally substituted C1-6alkyl, optionally substituted C2-6alkenyl, optionally substituted C2-6alkynyl, optionally substituted C1-6alkoxy, optionally substituted C1-6haloalkyl, optionally substituted O-C1-6haloalkyl, optionally substituted C3-10cycloalkyl, optionally substituted 3-10 membered heterocycloalkyl, optionally substituted C6-11aryl, optionally substituted 5-15 membered heteroaryl, N(R5)(R6), O(R7), S(R7), NC(O)(R8)(R9), and C(O)N(R8)(R9); q is selected from 0, 1, 2, 3, and 4; R3is hydrogen or C1-4alkyl; R4, when present, is hydrogen or C1-4alkyl; each Raand Rb, when present, is independently selected from hydrogen and C1-6alkyl, or Raand Rbtogether with the nitrogen atom they are attached to form a heterocycloalkyl; R5, R6, R7, R8, and R9are each independently selected from the group consisting of hydrogen, optionally substituted C1-6alkyl, optionally substituted C2-6alkenyl, optionally substituted C2-6alkynyl, optionally substituted acyl, optionally substituted C3-10cycloalkyl,optionally substituted 3-10 membered heterocycloalkyl, optionally substituted aryl, and optionally substituted 5-12 membered heteroaryl; or R8and R9together with the nitrogen atom to which they are attached form a 3 to 10 membered heterocycloalkyl optionally substituted with one or more groups each independently selected from the group consisting of halogen, cyano, nitro, oxo, C1-6alkyl, C1-6haloalkyl, and C1-6haloalkoxy; with the proviso that when q is 1, p is not 0.

[0006] In one embodiment,is selected from the group consisting , ,

[0007] In one embodiment, the compound of Formula (I) is a compound of Formula (II):, or a pharmaceutically acceptable salt thereof.

[0008] In one embodiment, the compound of Formula (I) is a compound of Formula (II-a):Ĥor a pharmaceutically acceptable saltthereof.

[0009] In one embodiment, the compound of Formula (I) is a compound of Formula (II-b):, or a pharmaceutically acceptable salt thereof.

[0010] In one embodiment, the compound of Formula (I) is a compound of Formula (II-c):, or a pharmaceutically acceptable salt thereof.

[0011] In one embodiment, the compound of Formula (I) is a compound of Formula (II-d):, or a pharmaceutically acceptable salt thereof, wherein w is selected from 0, 1, 2, 3, 4, and 5;each R2His independently selected from the group consisting of C1-6haloalkyl, -O-C1-6haloalkyl, C1-6alkyl, halogen, cyano, -S(O)(Rc), -S(O)2(Rc), -P(O)(ORc)2, -P(O)(Rc)2, -S(Rd)5, and optionally substituted C3-6cycloalkyl; wherein when w is 2, 3, 4, or 5, two R2Hon adjacent carbon atoms, taken together with the carbon atoms to which they are attached, may optionally form a 5- or 6-membered heterocycloalkyl; each Rcis independently C1-6alkyl; and each Rdis independently halogen.

[0012] In one embodiment, the compound of Formula (I) is a compound of Formula (II-e):, or a pharmaceutically acceptable salt thereof, wherein w is selected from 0, 1, 2, 3, 4, and 5; each R2His independently selected from the group consisting of C1-6haloalkyl, -O-C1-6haloalkyl, C1-6alkyl, halogen, cyano, -S(O)(Rc), -S(O)2(Rc), -P(O)(ORc)2, -P(O)(Rc)2, and - S(Rd)5; each Rcis independently C1-6alkyl; and each Rdis independently halogen.

[0013] In one embodiment, the compound of Formula (I) is a compound of Formula (II-f):or a pharmaceutically acceptable salt thereof, wherein, each of R2B, R2C, R2D, R2E, and R2Fis independently selected from hydrogen, halogen, cyano, C1-6alkyl optionally substituted with one R2B3, C1-6cyanoalkyl, C1-6alkenyl optionally substituted with one R2B4, hydroxy, C1-6hydroxyalkyl, -NR2B2R2B3, C3-8cycloalkyl, phenyl, 5- to 6-membered heterocycloalkyl, 5- to 6-membered heteroaryl, and C1-6haloalkyl optionally substituted with one R2B3, wherein the C3-8cycloalkyl, phenyl, 5- to 6-membered heterocycloalkyl, and 5- to 6-membered heteroaryl are optionally substituted with one, two, or three R2B1; and wherein R2B1, R2B2, and R2B3are as defined herein.

[0014] In one embodiment, the compound of Formula (I) is a compound of Formula (II-j):or a pharmaceutically acceptable salt thereof; wherein X5is a bond, -CH2-, -CH2CH2- O, or NR2MX6is -CH2- or -CH2CH2-; R2Kis phenyl or 5- to 9-membered heteroaryl, wherein the phenyl or 5- to 9- membered heteroaryl is optionally substituted with one, two, three, or four R2L; each R2Lis independently selected from the group consisting of halo, cyano, C1-6alkyl, C1-6haloalkyl, C1-6hydroxyalkyl, C1-6alkoxy, C1-6haloalkoxy, C(O)(C1-6alkoxy), -CH2(C1-6alkoxy), -OCD3, -O-cyclopropyl, -C(O)NR2L1R2L2, and 5-membered heteroaryl optionally substituted with C1-6alkyl; R2L1and R2L2are independently selected from H and C1-6alkyl; or R2L1and R2L2, taken together with the N to which they are attached, for an optionally substituted 4- to 6- membered heterocycloalkyl; R2Mis C1-6alkyl; and s is 0 or 1.

[0015] In another aspect, also provided herein are methods of degrading CDK2 in a subject, the method comprising administering to the subject: (i) the compound disclosed herein (e.g., a compound of Formula (I)), or a pharmaceutically acceptable salt thereof; or (ii) the pharmaceutical composition of the present disclosure.

[0016] In yet another aspect, also provided herein are methods of treating a cancer in a subject in need thereof, the method comprising administering to the subject: (i) an effective amount of the compound disclosed herein (e.g., a compound of Formula (I)), or a pharmaceutically acceptable salt thereof; or (ii) the pharmaceutical composition disclosed herein.

[0017] In yet another aspect, also provided herein are methods of treating a solid tumor in a subject in need thereof, comprising administering to the subject: (i) an effective amount of the compound disclosed herein (e.g., a compound of Formula (I)), or a pharmaceutically acceptable salt thereof; or (ii) the pharmaceutical composition disclosed herein.

[0018] In yet another aspect, also provided herein are methods of treating a liquid tumor in a subject in need thereof, comprising administering to the subject: (i) an effective amount of the compound disclosed herein (e.g., a compound of Formula (I)), or a pharmaceutically acceptable salt thereof; or (ii) the pharmaceutical composition disclosed herein.DETAILED DESCRIPTION OF THE DISCLOSURE

[0019] Provided herein are degraders of CDK2, e.g., degraders of Formula (I), or a pharmaceutically acceptable salt thereof. Further provided are pharmaceutical compositions thereof, and methods for their use, e.g., for treating CDK2-mediated diseases such as cancer. Also provided are methods of making the CDK2 degraders described herein such as degraders of Formula (I) or a pharmaceutically acceptable salt thereof.

[0020] The cell cycle plays a critical and central role in control of cell growth and proliferation. Every cell cycle step is a well-regulated process controlled by CDKs defined by serine / threonine-protein kinases, and their associated cyclin partners. It is known that CDK2 controls cell division and is central to oncogenic signaling. (See, e.g., Chi, et. al., “A novel landscape of nuclear human CDK2 substrates revealed by in situ phosphorylation”, Sci. Adv. 2020, vol 6, issue 16.) Cyclin is activated by cyclin E and cyclin A, where E-CDK2 complexes regulate cell cycle reentry, G1 progression, and S phase entry, and where cyclin A–CDK2 complexes coordinate S phase progression and function in G2 and M phase cells. (Id.) Thus, CDK2 inhibition could be an effective therapy to arrest or inhibit proliferation of cancer cells.

[0021] Without being bound to any particular theory, it is believed that the compounds of the present disclosure function as CDK2 degrader compounds that induce protein-protein interactions (aggregation) and that, in the context of an ubiquitin ligase, promote ubiquitination and degradation of CDK2. The compounds provided herein can achieve degradation selectivity against other related targets, such as GSPT1 (G1 to S phase transition 1; a reported protein being degraded by similar class of compounds) or cyclin-dependent kinase 1 (“CDK1”). GSPT1 is a translation termination factor that is commonly essential. Depletion of GSPT1 could lead to downstream effects on a large number of proteins and on cellular functions, as such, achieving degradation selectivity against GSPT1 is critical to avoid broad toxicity. The compounds provided herein can effectively degrade CDK2 with desirable selectivity over related targets such as GSPT1 and CDK1. Definitions

[0022] Unless specifically indicated otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by those of ordinary skill in the art. In addition, any method or material similar or equivalent to a method or material described herein can be used. For purposes as described herein, the following terms are defined.

[0023] “A,” “an,” or “the” as used herein not only include aspects with one member, but also include aspects with more than one member. For instance, the singular forms “a,” “an,” and “the” include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to “a cell” includes a plurality of such cells and reference to “the agent” includes reference to one or more agents known to those skilled in the art, and so forth.

[0024] The term “alkyl,” by itself or as part of another substituent, is used in its conventional sense, and refers to a straight or branched chain hydrocarbon radical. The number of carbons may suitably be from 1 to 20, from 1 to 12, from 1 to 8, from 1 to 6, or from 1 to 4. Non-limiting examples of alkyl groups include methyl, ethyl, n-propyl, iso-propyl, n-butyl, t- butyl, iso-butyl, sec-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl. The term “alkenyl” refers to an unsaturated alkyl radical having one or more double bonds. Similarly, the term “alkynyl” refers to an unsaturated alkyl radical having one or more triple bonds. Non-limiting examples of such unsaturated alkyl groups include linear and branched groups including vinyl, 2- propenyl, crotyl, 2-isopentenyl, 2-(butadienyl), 2,4-pentadienyl, 3-(1,4-pentadienyl), ethynyl, 1- and 3-propynyl, 3-butynyl, and the higher homologs and isomers.

[0025] The term “alkoxy” is used in its conventional sense, and refers to those alkyl groups attached to the remainder of the molecule via an oxygen atom (“oxy”), and further include mono- and poly-halogenated variants thereof (i.e., “haloalkoxy”).

[0026] The terms “halo” or “halogen,” by themselves or as part of another substituent, are used in their conventional sense, and refer to a fluorine, chlorine, bromine, or iodine atom. Additionally, terms such as “haloalkyl,” for instance C1-6haloalkyl and C1-4haloalkyl, are meant to include monohaloalkyl and polyhaloalkyl. For example, the term “C1-4haloalkyl” is meant to include trifluoromethyl (-CF3), difluoromethyl (-CHF2), fluoromethyl (-CH2F), 2,2,2- trifluoroethyl (-CH2CH3), 4-chlorobutyl (-CH2CH2CH2CH2Cl), 3-bromopropyl (- CH2CH2CH2Br), and the like. Additionally, terms such as “haloalkoxy,” for instance C1-6haloalkoxy and C1-4haloalkoxy, are meant to include monohaloalkoxy and polyhaloalkoxy.

[0027] The terms “cycloalkyl” and “cycloalkylene” are used in their conventional sense and refer to a saturated or partially saturated carbocyclic moiety having mono- or bicyclic rings and 3 to 10 carbon atoms in the ring. The cycloalkyl moiety can optionally be substituted with one or more substituents. In particular embodiments, cycloalkyl contains from 3 to 8 carbon atoms (i.e., (C3-C8)cycloalkyl). In other particular embodiments, cycloalkyl containsfrom 3 to 6 carbon atoms (i.e., (C3-C6)cycloalkyl). Non-limiting examples of cycloalkyl moieties include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and partially saturated (cycloalkenyl) derivatives thereof (e.g., cyclopentenyl, cyclohexenyl, and cycloheptenyl). In some aspects, bicyclic cycloalkyl rings are fused rings sharing two carbon atoms. In some aspects, bicyclic cycloalkyl rings include bridged bicyclic and spiro bicyclic ring structures. In some embodiments, cycloalkyl isIn some embodiments, cycloalkyl is. In some embodiments, cycloalkyl is. In some embodiments, cycloalkyl is. In some embodiments, cycloalkyl is. In some embodiments, cycloalkyl is.

[0028] The terms “heterocycle”, “heterocycloalkyl”, and “heterocycloalkylene” are used in their conventional sense and refer to a 3- to 10-membered heterocyclic moiety, including 3, 4, 5, 6 or 7-membered monocyclic or a 6, 7, 8, 9 or 10-membered bicyclic heterocyclic moiety, that is saturated or partially saturated, and has one or more (e.g., 1, 2, 3 or 4) heteroatoms selected from oxygen, nitrogen and sulfur in the ring with the remaining ring atoms being carbon. In some embodiments, bicyclic heterocyclic rings are fused rings sharing two carbon atoms. In some embodiments, bicyclic heterocyclic rings are fused rings sharing one or more heteroatoms selected from oxygen, nitrogen and sulfur. In some embodiments, bicyclic heterocyclic rings include bridged ring structures and spiro ring structures. In some embodiments, one ring of a bicyclic heterocyclic ring structure comprises one or more heteroatoms. In some embodiments, both rings of a bicyclic ring structure comprise one or more heteroatoms. Heterocycloalkyls can optionally be substituted as defined herein. Examples of heterocycloalkyl include piperidinyl, piperazinyl, azetidinyl, pyrrolidinyl, and oxetanyl. In some embodiments, heterocycloalkyl is. In some embodiments, heterocycloalkyl is. In some embodiments, heterocycloalkyl is. In someembodiments, heterocycloalkyl is. In some embodiments, heterocycloalkyl is. In some embodiments, heterocycloalkyl is. In some embodiments, heterocycloalkyl is. In some embodiments, heterocycloalkyl isIn some embodiments, heterocycloalkyl is. In some embodiments, heterocycloalkyl is . Insome embodiments, heterocycloalkyl is . In some embodiments, heterocycloalkyl is. In some embodiments, heterocycloalkyl isIn some embodiments, heterocycloalkyl is. In some embodiments, the heterocycloalkyl is. In some embodiments, heterocycloalkyl is. In some embodiments, heterocycloalkyl is. In some embodiments, heterocycloalkyl is. In some embodiments, heterocycloalkyl is. In some embodiments, heterocycloalkyl is. In some embodiments, heterocycloalkyl is. In some embodiments,heterocycloalkyl is. In some embodiments, heterocycloalkyl is. In some embodiments, heterocycloalkyl is.

[0029] The term “aryl” refers to a cyclic aromatic hydrocarbon moiety having a mono- or bi-cyclic aromatic ring of 5 to 10 carbon ring atoms (e.g., a C5-10aryl), including, for example, 6 to 9 carbon ring atoms (C6-9aryl), and 6 to 8 carbon ring atoms (C6-8aryl). Bicyclic aryl ring systems include fused bicyclics having two fused five-membered aryl rings, having a five-membered aryl ring and a fused six-membered aryl ring, and having two fused six- membered aryl rings. Bicyclic aryl ring systems further include fused bicyclics having one aryl ring (e.g., a five- or six-membered aryl ring) fused to a cycloalkyl (e.g., a 3-6 membered cycloalkyl). The aryl group can be optionally substituted as defined herein. In one embodiment, the aryl is phenyl.

[0030] The term "heteroaryl" is used in its conventional sense and refers to an aromatic radical of a 5-15-membered monocyclic, bicyclic, tricyclic, or tetracyclic ring system, including monocyclic 5-, 6-, or 7-membered rings, fused ring systems (at least one of which is aromatic), and / or bridged ring systems (at least one of which is aromatic) containing one or more heteroatoms each independently selected from nitrogen, oxygen, and sulfur. Examples of heteroaryl groups include, but are not limited to, pyridinyl, imidazolyl, imidazopyridinyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, triazolyl, thiadiazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothiophenyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, and furopyridinyl. Heteroaryl groups may be optionally substituted independently with one or more substituents described herein. 5 or 6 membered heteroaryl can be selected from the group consisting of optionally substituted pyridinyl, pyrimidinyl, thiazolyl, imidazolyl, oxazolyl, isoxazolyl, pyrazolyl, pyridinone and triazolyl. In one embodiment, the heteroaryl is benzimidazolyl. In one embodiment, the heteroaryl. In one embodiment, theheteroaryl is. In one embodiment, the heteroaryl is. In one embodiment, the heteroaryl is. In one embodiment, the heteroaryl is

[0031] The term “heteroatom,” refers to an atom other than hydrogen or carbon. Non- limiting examples of heteroatoms include N, O, and S.

[0032] Certain compounds of the present disclosure possess asymmetric carbon atoms (optical centers). Racemates, diastereomers, geometric isomers, regioisomers, and individual isomers (e.g., separate enantiomers) are all intended to be encompassed within the scope of the present disclosure.

[0033] The term “chiral” refers to molecules which have the property of non- superimposability of the mirror image partner, while the term “achiral” refers to molecules which are superimposable on their mirror image partner.

[0034] The term “chiral purity” refers to the mole% of one chiral compound based on the total moles of chiral compounds.

[0035] The term “stereoisomers” refers to compounds which have identical chemical constitution, but differ with regard to the arrangement of the atoms or groups in space.

[0036] The term E / Z refers to the IUPAC isomerism convention where the substituents at each end of a double bond are assigned priority based on their atomic number. If the high-priority substituents are on the same side of the bond it is assigned Z, and if they are on opposite sides of the bond it is assigned E.

[0037] In the structures shown herein, where the stereochemistry of any particular chiral atom is not specified, then all stereoisomers are contemplated and included as the compounds of the disclosure. Where stereochemistry is specified by a solid wedge or dashed line representing a particular configuration, then that stereoisomer is so specified and defined. Unless otherwise specified, if solid wedges or dashed lines are used, relative stereochemistry is intended.

[0038] The term “spiro” refers to bicyclic molecules for which the two constitutive cyclic moieties have one carbon atom in common.

[0039] The term “bridged” refers to bicyclic molecules for which the two constitutive cyclic moieties have two non-adjacent carbon atoms in common.

[0040] The term “fused” refers to bicyclic molecules for which the two constitutive cyclic moieties have two adjacent carbon atoms in common.

[0041] The term "substituent" denotes an atom or a group of atoms replacing a hydrogen atom on the parent molecule. The term "substituted" denotes that a specified group bears one or more substituents. Where any group may carry multiple substituents and a variety of possible substituents is provided, the substituents are independently selected and need not to be the same. The term "unsubstituted" means that the specified group bears no substituents. The term "optionally substituted" means that the specified group is unsubstituted or substituted by one or more substituents, independently chosen from the group of possible substituents. When indicating the number of substituents, the term "one or more" means from one substituent to the highest possible number of substitution, i.e., replacement of one hydrogen up to replacement of all hydrogens by substituents. Examples of substituents include, but are not limited to, hydroxy, alkyl, alkenyl, alkynyl, acyl, alkoxy, halo, haloalkyl, haloalkoxy, oxo, cyano, nitro, amino, monoalkylamino, dialkylamino, 3-10-membered cycloalkyl, 3-10- membered heterocycloalkyl, 5-10-membered aryl, and 5-12 membered heteroaryl.

[0042] In the description herein, if there is a discrepancy between a depicted structure and a name given to that structure, then the depicted structure controls.

[0043] The term “salts” is meant to include salts of the active compounds which are prepared with relatively nontoxic acids or bases (e.g., those salts that are pharmaceutically acceptable), depending on the particular substituents found on the compounds described herein. When compounds of the present disclosure contain relatively acidic functionalities, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired base, either neat or in a suitable inert solvent. Examples of salts derived from pharmaceutically-acceptable inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic, manganous, potassium, sodium, zinc and the like. Salts derived from pharmaceutically-acceptable organic bases include salts of primary, secondary and tertiary amines, including substituted amines,cyclic amines, naturally-occurring amines and the like, such as arginine, betaine, caffeine, choline, N,N'-dibcnzylcthylcncdiaminc, diethylamine, 2-diethylaminoethanol, 2- dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N- ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine and the like. When compounds of the present disclosure contain relatively basic functionalities, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include those derived from inorganic acids like hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydriodic, or phosphorous acids and the like, as well as the salts derived from relatively nontoxic organic acids like acetic, propionic, isobutyric, malonic, benzoic, succinic, suberic, fumaric, mandelic, phthalic, benzenesulfonic, p-tolylsulfonic, citric, tartaric, methanesulfonic, and the like. Also included are salts of amino acids such as arginate and the like, and salts of organic acids like glucuronic or galactunoric acids and the like (see, for example, Berge, S. M., et al., Pharmaceutical Salts, Journal of Pharmaceutical Science, 1977, 66, 1-19).

[0044] Neutral forms of the compounds of the present disclosure can be regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner. The parent form of the compound differs from the various salt forms in certain physical properties, such as solubility in polar solvents, but otherwise the salts are equivalent to the parent form of the compound for the purposes of the present disclosure.

[0045] The term “subject” refers to refers to animals such as mammals, including but not limited to, humans.

[0046] The terms “treat”, “treating” and “treatment” refer to any indicia of success in the treatment or amelioration of an injury, pathology, condition, or symptom (e.g., pain), including any objective or subjective parameter such as abatement; remission; diminishing of symptoms or making the symptom, injury, pathology or condition more tolerable to the patient; decreasing the frequency or duration of the symptom or condition; or, in some situations, preventing the onset of the symptom. The treatment or amelioration of symptoms can be based on any objective or subjective parameter; including, e.g., the result of a physical examination.

[0047] The term “solid tumor” refers to a solid mass of cancer cells that grow in organ systems and can occur anywhere in the body, for example breast cancer.

[0048] The term “liquid tumor” refers to tumors that occur in the blood, bone marrow, or lymph nodes and includes types of leukemia, lymphoma, and myeloma.

[0049] The term "pharmaceutically acceptable" refers to an anion, cation, carrier, diluent or excipient that is compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.

[0050] The terms “effective dosage,” “effective amount” and “therapeutically effective amount” of a compound or pharmaceutical composition of the present disclosure is an amount sufficient to affect any one or more beneficial or desired, including biochemical, histological and / or behavioral symptoms, of the disease, its complications and intermediate pathological phenotypes presenting during development of the disease. For therapeutic use, a “therapeutically effective amount” refers to that amount of a compound being administered which will relieve to some extent one or more of the symptoms of the disorder being treated. In reference to the treatment of cancer, a therapeutically effective amount refers to that amount which has the effect of (1) reducing the size of the tumor, (2) inhibiting (that is, slowing to some extent, preferably stopping) tumor metastasis, (3) inhibiting to some extent (that is, slowing to some extent, preferably stopping) tumor growth or tumor invasiveness, (4) relieving to some extent (or, preferably, eliminating) one or more signs or symptoms associated with the cancer, (5) decreasing the dose of other medications required to treat the disease, (6) enhancing the effect of another medication, and / or (7) delaying the progression of the disease in a patient.

[0051] An effective dosage can be administered in one or more administrations. For the purposes of the present disclosure, an effective dosage of a compound or a pharmaceutical composition is an amount sufficient to accomplish prophylactic or therapeutic treatment either directly or indirectly. As is understood in the clinical context, an effective dosage of drug, compound or pharmaceutical composition may or may not be achieved in conjunction with another drug, compound or pharmaceutical composition.

[0052] The term "co-administering" refers to either simultaneous administration, or any manner of separate sequential administration, of a compound as described herein or a salt thereof, and a further active pharmaceutical ingredient or ingredients, including a chemotherapeutic agent. If the administration is not simultaneous, the compounds areadministered in a close time proximity to each other. Furthermore, it does not matter if the compounds are administered in the same dosage form, e.g., one compound may be administered topically and another compound may be administered orally.

[0053] As used herein, the terms “combination,” “combined,” and related terms refer to the simultaneous or sequential administration of therapeutic agents in accordance with this disclosure. For example, a compound as described herein may be administered with another therapeutic agent simultaneously or sequentially in separate unit dosage forms or together in a single unit dosage form. Accordingly, provided is a single unit dosage form comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof, an additional therapeutic agent, and a pharmaceutically acceptable carrier, adjuvant, or vehicle.

[0054] The term “IC50” refers to the half maximal inhibitory concentration of a substance required to inhibit a specific biological or biochemical function as measured by an appropriate assay method.

[0055] The term “DC50” refers to the concentration of a substance required to achieve half maximal protein degradation as measured by an appropriate assay method.

[0056] The term “Dmax” refers to the maximum level of protein degradation observed across a titration of substance, as measured by an appropriate assay method and a defined time point. Compounds of Formula (I)

[0057] In some aspects, the present disclosure is directed to compounds of Formula (I):, or a pharmaceutically acceptable salt thereof;wherein: X1and X4are each independently C, CH, or N; X2and X3are each independently C, CH or N; or one of X2and X3is C=O, the other one is NR4; wherein at least one of X1, X2, X3, and X4comprises N; represents a single or double bond; each R1is independently selected from halogen, cyano, C1-6alkyl, hydroxy, C1-6haloalkyl, C1-6hydroxyalkyl, C1-6alkoxy, O-C1-6haloalkyl, O-C3-6cycloalkyl, and - N(Ra)(Rb); p is selected from 0, 1, 2, and 3; each R2is independently selected from halogen, cyano, hydroxy, optionally substituted C1-6alkyl, optionally substituted C2-6alkenyl, optionally substituted C2-6alkynyl, optionally substituted C1-6alkoxy, optionally substituted C1-6haloalkyl, optionally substituted O-C1-6haloalkyl, optionally substituted C3-10cycloalkyl, optionally substituted 3-10 membered heterocycloalkyl, optionally substituted C6-11aryl, optionally substituted 5-15 membered heteroaryl, N(R5)(R6), O(R7), S(R7), NC(O)(R8)(R9), and C(O)N(R8)(R9); q is selected from 0, 1, 2, 3, and 4; R3is hydrogen or C1-4alkyl; R4, when present, is hydrogen or C1-4alkyl; each Raand Rb, when present, is independently selected from hydrogen and C1-6alkyl, or Raand Rbtogether with the nitrogen atom they are attached to form a heterocycloalkyl; R5, R6, R7, R8, and R9are each independently selected from the group consisting of hydrogen, optionally substituted C1-6alkyl, optionally substituted C2-6alkenyl, optionally substituted C2-6alkynyl, optionally substituted acyl, optionally substituted C3-10cycloalkyl, optionally substituted 3-10 membered heterocycloalkyl, optionally substituted aryl, and optionally substituted 5-12 membered heteroaryl. or R8and R9together with the nitrogen atom to which they are attached form a 3 to 10 membered heterocycloalkyl optionally substituted with one or more groups each independently selected from the group consisting of halogen, cyano, nitro, oxo, C1-6alkyl, C1-6haloalkyl, and C1-6haloalkoxy;with the proviso that when q is 1, p is not 0.

[0058] In one embodiment when R2is optionally substituted C1-6alkyl, optionally substituted C2-6alkenyl, optionally substituted C2-6alkynyl, optionally substituted C1-6alkoxy, optionally substituted C1-6haloalkyl, optionally substituted O-C1-6haloalkyl, optionally substituted C3-10cycloalkyl, optionally substituted 3-10 membered heterocycloalkyl, optionally substituted aryl, or optionally substituted 5-15 membered heteroaryl, said alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl are optionally substituted with one or more groups independently selected from the group consisting of halogen, hydroxy, cyano, oxo, optionally substituted C1-6alkyl, -O-C1-6alkyl, C1-6haloalkyl, - O-C1-6haloalkyl, optionally substituted C2-6alkenyl, optionally substituted aryl (e.g., C5-6aryl such as phenyl), optionally substituted C3-6cycloalkyl, optionally substituted 3- to 6-membered heterocycloalkyl, optionally substituted 5-12 membered heteroaryl, -S(O)2-C1-6alkyl, - P(O)(OC1-6alkyl)2, -P(O)(C1-6alkyl)2, -S-C1-6haloalkyl, -SF5, and -C(O)O-C1-6alkyl, wherein the optionally substituted C2-6alkenyl, optionally substituted C1-6alkyl, optionally substituted C3-6cycloalkyl, optionally substituted aryl, optionally substituted 5-12 membered heteroaryl, and the optionally substituted 3- to 6-membered heterocycloalkyl are independently optionally further substituted with one or more group selected from halogen, oxo, C1-6alkyl, C1-6alkoxy, C1-6haloalkyl, -O-C1-6haloalkyl, C1-6hydroxyalkyl, -OCD3, -CD3, -O-cyclopropyl, cyano, C(O)NR2L1R2L2, optionally substituted C3-6cycloalkyl, and optionally substituted 5-12- membered heteroaryl, wherein R2L1and R2L2are as defined herein. In one embodiment, the optionally substituted 5-12 membered heteroaryl is a 5- or 6-membered heteroaryl and is further optionally substituted with C1-6haloalkyl.

[0059] In one embodiment when R2is optionally substituted C1-6alkyl, optionally substituted C2-6alkenyl, optionally substituted C2-6alkynyl, optionally substituted C1-6alkoxy, optionally substituted C1-6haloalkyl, optionally substituted O-C1-6haloalkyl, optionally substituted C3-10cycloalkyl, optionally substituted 3-10 membered heterocycloalkyl, optionally substituted aryl, or optionally substituted 5-15 membered heteroaryl, said alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl are optionally substituted with one or more C1-3haloalkyl. In one embodiment, the C1-3haloalkyl is CF3.

[0060] In one embodiment, when R5, R6, R7, R8, and R9are optionally substituted C1-6alkyl, optionally substituted C2-6alkenyl, optionally substituted C2-6alkynyl, optionally substituted acyl, optionally substituted C3-10cycloalkyl, optionally substituted 3-10 memberedheterocycloalkyl, optionally substituted aryl, or optionally substituted 5-12 membered heteroaryl, wherein said alkyl, alkenyl, alkynyl, acyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally substituted with one or more groups independently selected from the group consisting of halogen, cyano, nitro, C1-6alkyl, C1-6haloalkyl, and C1-6haloalkoxy.

[0061] In one embodiment, R5and R6are each independently selected from the group of hydrogen and optionally substituted aryl. In one embodiment, R5and R6are each independently selected from the group consisting of hydrogen and optionally substituted C5-6aryl. In one embodiment, the aryl is optionally substituted with C1-6haloalkyl. In one embodiment, the optionally substituted aryl is optionally substituted phenyl. In one embodiment, one of R5and R6is hydrogen and the other is phenyl substituted with C1-6haloalkyl. In one embodiment, the haloalkyl is -CF3.

[0062] In one embodiment, each R7is independently selected from the group consisting of optionally substituted aryl, and optionally substituted 5-12 membered heteroaryl. In one embodiment, each R7is independently selected from the group consisting of optionally substituted C5-6aryl, and optionally substituted 5-12 membered heteroaryl, wherein the aryl and heteroaryl are optionally substituted with C1-6haloalkyl. In one embodiment, the haloalkyl is CF3. In one embodiment, R7is phenyl. In one embodiment, R7is phenyl substituted with one or more C1-6haloalkyl. In one embodiment, the haloalkyl is CF3. In one embodiment, R7is optionally substituted pyridyl, wherein the pyridyl is optionally substituted with one or more C1-6haloalkyl. In one embodiment, the haloalkyl is CF3.

[0063] In one embodiment, R8and R9are each independently selected from the group consisting of hydrogen, optionally substituted C3-10cycloalkyl, and optionally substituted 3-10 membered heterocycloalkyl. In one embodiment, R8and R9are each independently selected from the group consisting of hydrogen and optionally substituted C3-10cycloalkyl. In one embodiment, the cycloalkyl is substituted with C1-3haloalkyl. In one embodiment, R8and R9are each independently selected from the group consisting of hydrogen and optionally substituted C3-6cycloalkyl. In one embodiment, R8is hydrogen and R9is optionally substituted C3-6cycloalkyl. In one embodiment, R8is hydrogen and R9is optionally substituted cyclopropyl, cyclopropyl, cyclopentyl, or cyclohexyl. In one embodiment, R8is hydrogen and R9is optionally substituted cyclopropyl. In one embodiment, the cyclopropyl is substituted with -CF3. In one embodiment, R8is hydrogen and R9is optionally substituted 3-10 membered heterocycloalkyl.

[0064] In some embodiments of Formula (I), p is 1, 2, or 3. In some embodiments, p is 1 or 2. In some embodiments, p is 1. In some embodiments, p is 2.

[0065] In some embodiments, the compound of Formula (I) is a compound of Formula (I-a):, or a pharmaceutically acceptable salt thereof, wherein X1, X2, X3, X4, R1, R2, R3, and q are as defined herein for Formula (I).

[0066] In some embodiments, the compound of Formula (I) is a compound of Formula (I-b):, or a pharmaceutically acceptable salt thereof, wherein X1, X2, X3, X4, R1, R2, R3, and q are as defined herein for Formula (I).

[0067] In some embodiments, the compound of Formula (I) is a compound of Formula (I-c):, or a pharmaceutically acceptable salt thereof, wherein X1, X2, X3, X4, R1, R2, R3, and q are as defined herein for Formula (I).

[0068] In some embodiments of Formulas (I), (I-a), (I-b), or (I-c), q is 1, 2, or 3. In some embodiments, q is 1 or 2. In some embodiments, q is 1.

[0069] In some embodiments of Formulas (I), (I-a), (I-b), or (I-c), each R1is independently selected from the group consisting of halogen, C1-6alkyl, hydroxy, C1-6haloalkyl, C1-6hydroxyalkyl, C1-6alkoxy, O-C1-6haloalkyl, and O-C3-6cycloalkyl. In some embodiments, each R1is independently selected from the group consisting of CH3, -F, -Cl, CF3, CF2CH3, CH2CHF2, CH2CF3, CF2CH3, CH2OH, OCH3, OCHF2, OCF3, and O- cyclopropyl. In some embodiments, each R1is independently selected from CH3, -F, -Cl, and hydroxy. In some embodiments, each R1is halogen. In some embodiments, each R1is independently selected from -F and -Cl. In some embodiments, p is 2, wherein one R1is -F and the other R1is -Cl. In some embodiments, p is 2 and each R1is –F. In some embodiments, p is 2 and each R1is –Cl. In some embodiments, p is 1, and R1is -F. In some embodiments, p is 1, and R1is -Cl. In some embodiments, each R1is C1-6alkyl. In some embodiments, p is 2, wherein one R1is halogen, and the other R1is selected from the group consisting of C1-6haloalkyl, C1-6hydroxyalkyl, C1-6alkoxy, O-C1-6haloalkyl, and O-C3-6cycloalkyl. In some embodiments, p is 2, wherein one R1is Cl or F, and the other R1is selected from the group consisting of -CF3, -CH2CF3, -CH2CHF2, -CF2CH3, -CH2OH, -OCH3, -OCHF2, -OCF3, and - O-cyclopropyl. In some embodiments, p is 2, wherein one R1is -F and the other R1is selected from the group consisting of C1-6haloalkyl, C1-6alkoxy, O-C1-6haloalkyl, and O-C3-6cycloalkyl. In some embodiments, p is 2, wherein one R1is -F and the other R1is selected from the group consisting of -CF3, -CH2CF3, -CH2CHF2, -CF2CH3, -OCH3, -OCHF2, -OCF3, and O-cyclopropyl. In some embodiments, p is 2, wherein one R1is -F and the other R1is - OCHF2. In some embodiments, p is 2, wherein one R1is -Cl and the other R1is C1-6hydroxyalkyl.

[0070] In some embodiments of Formulas (I), (I-a), (I-b), or (I-c), R3is hydrogen or methyl. In some embodiments, R3is hydrogen. In some embodiments, R3is methyl.

[0071] In some embodiments of Formulas (I), (I-a), (I-b), or (I-c), least two of X1, X2, X3, and X4comprise N. In some embodiments, three of X1, X2, X3, and X4comprise N.

[0072] In some embodiments of Formulas (I), (I-a), (I-b), or (I-c),is selected from the group consisting of:,and

[0073] In some embodiments of Formulas (I), (I-a), (I-b), or (I-c),is selected from the group consisting of:and

[0074] In some embodiments of Formulas (I), (I-a), (I-b), or (I-c),In some embodiments,isor, wherein each R2is independently selected from halogen, cyano, hydroxy, optionally substituted C1-6alkyl, optionally substituted C2-6alkenyl, optionally substituted C2-6alkynyl, optionally substituted C1-6alkoxy, optionally substituted C1-6haloalkyl, optionally substituted O-C1-6haloalkyl, optionally substituted C3-8cycloalkyl, optionally substituted 3-10 membered heterocycloalkyl, optionally substituted C6-11aryl, optionally substituted 5-15 membered heteroaryl, N(R5)(R6), O(R7), NC(O)(R8)(R9), and C(O)N(R8)(R9). In one embodiment, the heterocycloalkyl is selected from bridged heterocycloalkyl and spiro heterocycloalkyl. In one embodiment, the heterocycloalkyl is bridged heterocycloalkyl. In one embodiment, the heterocycloalkyl is spiro heterocycloalkyl. In one embodiment, the cycloalkyl is selected from bridged cycloalkyl and spiro cycloalkyl. In one embodiment, the cycloalkyl is bridged cycloalkyl. In one embodiment, the cycloalkyl is spiro cycloalkyl.

[0075] In some embodiments,iswherein R2is selected from halogen, cyano, hydroxy, optionally substituted C1-6alkyl, optionally substituted C2-6alkenyl, optionally substituted C2-6alkynyl, optionally substituted C1-6alkoxy, optionally substituted C1-6haloalkyl, optionally substituted O-C1-6haloalkyl, optionally substituted C3-8cycloalkyl, optionally substituted 3-10 membered heterocycloalkyl, optionally substituted C6-11 aryl, optionally substituted 5-15 membered heteroaryl, N(R5)(R6), O(R7), NC(O)(R8)(R9), and C(O)N(R8)(R9). In one such embodiment, R2is selected from cyano and optionally substituted aryl. In one embodiment, the heterocycloalkyl is selected from bridged heterocycloalkyl and spiro heterocycloalkyl. In one embodiment, the heterocycloalkyl is bridged heterocycloalkyl. In one embodiment, the heterocycloalkyl is spiro heterocycloalkyl. In one embodiment, the cycloalkyl is selected from bridged cycloalkyl and spiro cycloalkyl.In one embodiment, the cycloalkyl is bridged cycloalkyl. In one embodiment, the cycloalkyl is spiro cycloalkyl.

[0076] In some embodiments,2, wherein each R is independently selected from halogen, cyano, hydroxy, optionally substituted C1-6alkyl, optionally substituted C2-6alkenyl, optionally substituted C2-6alkynyl, optionally substituted C1-6alkoxy, optionally substituted C1-6haloalkyl, optionally substituted O-C1-6haloalkyl, optionally substituted C3-8cycloalkyl, optionally substituted 3-10 membered heterocycloalkyl, optionally substituted C6-11aryl, optionally substituted 5-15 membered heteroaryl, N(R5)(R6), O(R7), NC(O)(R8)(R9), and C(O)N(R8)(R9). In one embodiment, the heterocycloalkyl is selected from bridged heterocycloalkyl and spiro heterocycloalkyl. In one embodiment, the heterocycloalkyl is bridged heterocycloalkyl. In one embodiment, the heterocycloalkyl is spiro heterocycloalkyl. In one embodiment, the cycloalkyl is selected from bridged cycloalkyl and spiro cycloalkyl. In one embodiment, the cycloalkyl is bridged cycloalkyl. In one embodiment, the cycloalkyl is spiro cycloalkyl.

[0077] In some embodiments of Formulas (I), (I-a), (I-b), or (I-c),. In some embodiments,isorwherein each R2is independently selected from halogen, cyano, hydroxy, optionally substituted C1-6alkyl, optionally substituted C2-6alkenyl, optionally substituted C2-6alkynyl, optionally substituted C1-6alkoxy, optionally substituted C1-6haloalkyl, optionally substituted O-C1-6haloalkyl, optionally substituted C3-8cycloalkyl, optionally substituted 3-10 membered heterocycloalkyl, optionally substituted C6-11aryl, optionally substituted 5-15 membered heteroaryl, N(R5)(R6), O(R7), NC(O)(R8)(R9), and C(O)N(R8)(R9). In one such embodiment, each R2is independently selected from cyano and optionally substituted phenyl. In one embodiment, the heterocycloalkyl is selected from bridged heterocycloalkyl and spiro heterocycloalkyl. In one embodiment, the heterocycloalkylis bridged heterocycloalkyl. In one embodiment, the heterocycloalkyl is spiro heterocycloalkyl. In one embodiment, the cycloalkyl is selected from bridged cycloalkyl and spiro cycloalkyl. In one embodiment, the cycloalkyl is bridged cycloalkyl. In one embodiment, the cycloalkyl is spiro cycloalkyl.

[0078] In some embodiments,is, wherein each R2is independently selected from halogen, cyano, hydroxy, optionally substituted C1-6alkyl, optionally substituted C2-6alkenyl, optionally substituted C2-6alkynyl, optionally substituted C1-6alkoxy, optionally substituted C1-6haloalkyl, optionally substituted O-C1-6haloalkyl, optionally substituted C3-8cycloalkyl, optionally substituted 3-10 membered heterocycloalkyl, optionally substituted C6-11aryl, optionally substituted 5-15 membered heteroaryl, N(R5)(R6), O(R7), NC(O)(R8)(R9), and C(O)N(R8)(R9). In one such embodiment, each R2is independently selected from cyano and optionally substituted phenyl. In one embodiment, the heterocycloalkyl is selected from bridged heterocycloalkyl and spiro heterocycloalkyl. In one embodiment, the heterocycloalkyl is bridged heterocycloalkyl. In one embodiment, the heterocycloalkyl is spiro heterocycloalkyl. In one embodiment, the cycloalkyl is selected from bridged cycloalkyl and spiro cycloalkyl. In one embodiment, the cycloalkyl is bridged cycloalkyl. In one embodiment, the cycloalkyl is spiro cycloalkyl.

[0079] In some embodiments,is, wherein R2is selected from halogen, cyano, hydroxy, optionally substituted C1-6alkyl, optionally substituted C2-6alkenyl, optionally substituted C2-6alkynyl, optionally substituted C1-6alkoxy, optionally substituted C1-6haloalkyl, optionally substituted O-C1-6haloalkyl, optionally substituted C3-8cycloalkyl, optionally substituted 3-10 membered heterocycloalkyl, optionally substituted C6-11aryl, optionally substituted 5-15 membered heteroaryl, N(R5)(R6), O(R7), NC(O)(R8)(R9), and C(O)N(R8)(R9). In one such embodiment, R2is optionally substituted phenyl. In one embodiment, the heterocycloalkyl is selected from bridged heterocycloalkyl and spiro heterocycloalkyl. In one embodiment, the heterocycloalkyl is bridged heterocycloalkyl. In one embodiment, the heterocycloalkyl is spiro heterocycloalkyl. In one embodiment, thecycloalkyl is selected from bridged cycloalkyl and spiro cycloalkyl. In one embodiment, the cycloalkyl is bridged cycloalkyl. In one embodiment, the cycloalkyl is spiro cycloalkyl.

[0080] In some embodiments of Formulas (I), (I-a), (I-b), or (I-c),is. In some embodiments, ,is, wherein R2is selected from halogen, cyano, hydroxy, optionally substituted C1-6alkyl, optionally substituted C2-6alkenyl, optionally substituted C2-6alkynyl, optionally substituted C1-6alkoxy, optionally substituted C1-6haloalkyl, optionally substituted O-C1-6haloalkyl, optionally substituted C3-8cycloalkyl, optionally substituted 3-10 membered heterocycloalkyl, optionally substituted C6-11aryl, optionally substituted 5-15 membered heteroaryl, N(R5)(R6), O(R7), NC(O)(R8)(R9), and C(O)N(R8)(R9). In one embodiment, R2is O(R7) or C(O)N(R8)(R9). In some such embodiments, R7is optionally substituted C6-11aryl. In some embodiments, R8and R9together with the nitrogen atom to which they are attached form a 3 to 10 membered heterocycloalkyl optionally substituted with one or more groups each independently selected from the group consisting of halogen, cyano, nitro, C1-6alkyl, haloalkyl, and haloalkoxy. In some embodiments, the 3 to 10 membered heterocycloalkyl is substituted with haloalkyl. In one embodiment, the heterocycloalkyl is selected from bridged heterocycloalkyl and spiro heterocycloalkyl. In one embodiment, the heterocycloalkyl is bridged heterocycloalkyl. In one embodiment, the heterocycloalkyl is spiro heterocycloalkyl. In one embodiment, the cycloalkyl is selected from bridged cycloalkyl and spiro cycloalkyl. In one embodiment, the cycloalkyl is bridged cycloalkyl. In one embodiment, the cycloalkyl is spiro cycloalkyl.

[0081] In some embodiments of Formulas (I), (I-a), (I-b), or (I-c),is. In some embodiments,is. In some embodiments,is. In some embodiments,is. In some embodiments,is, , or, wherein each R2is independently selected from halogen, cyano, hydroxy, optionally substituted C1-6alkyl, optionally substituted C2-6alkenyl, optionally substituted C2-6alkynyl, optionally substituted C1-6alkoxy, optionally substituted C1-6haloalkyl, optionally substituted O-C1-6haloalkyl, optionally substituted C3-8cycloalkyl, optionally substituted 3-10 membered heterocycloalkyl, optionally substituted C6- 11aryl, optionally substituted 5-15 membered heteroaryl, N(R5)(R6), O(R7), NC(O)(R8)(R9), and C(O)N(R8)(R9). In one embodiment, the heterocycloalkyl is selected from bridged heterocycloalkyl and spiro heterocycloalkyl. In one embodiment, the heterocycloalkyl is bridged heterocycloalkyl. In one embodiment, the heterocycloalkyl is spiro heterocycloalkyl. In one embodiment, the cycloalkyl is selected from bridged cycloalkyl and spiro cycloalkyl. In one embodiment, the cycloalkyl is bridged cycloalkyl. In one embodiment, the cycloalkyl is spiro cycloalkyl. In one embodiment, each R2is independently selected from halo, cyano, optionally substituted C3-8cycloalkyl, optionally substituted phenyl, optionally substituted 5-6 membered heteroaryl, and optionally substituted C2-6alkynyl, or O(R7), wherein R7is optionally substituted aryl. In one embodiment, each R2is independently selected from halogen and optionally substituted 3-10 membered heterocycloalkyl, wherein the heterocycloalkyl is a bridged heterocycloalkyl optionally substituted with C1-4haloalkyl.

[0082] In some embodiments of Formulas (I), (I-a), (I-b), or (I-c),is. In some embodiments,is. In one such embodiment, R2is selected from halogen, cyano, hydroxy,optionally substituted C1-6alkyl, optionally substituted C2-6alkenyl, optionally substituted C2-6 alkynyl, optionally substituted C1-6alkoxy, optionally substituted C1-6haloalkyl, optionally substituted O-C1-6haloalkyl, optionally substituted C3-8cycloalkyl, optionally substituted 3-10 membered heterocycloalkyl, optionally substituted C6-11aryl, optionally substituted 5-15 membered heteroaryl, N(R5)(R6), O(R7), NC(O)(R8)(R9), and C(O)N(R8)(R9). In one embodiment, R2is optionally substituted C6-11aryl. In one embodiment, the heterocycloalkyl is selected from bridged heterocycloalkyl and spiro heterocycloalkyl. In one embodiment, the heterocycloalkyl is bridged heterocycloalkyl. In one embodiment, the heterocycloalkyl is spiro heterocycloalkyl. In one embodiment, the cycloalkyl is selected from bridged cycloalkyl and spiro cycloalkyl. In one embodiment, the cycloalkyl is bridged cycloalkyl. In one embodiment, the cycloalkyl is spiro cycloalkyl.

[0083] In some embodiments of Formulas (I), (I-a), (I-b), or (I-c),

[0084] In some embodiments,is2, wherein R is selected from halogen, cyano, hydroxy, optionally substituted C1-6alkyl, optionally substituted C2-6alkenyl, optionally substituted C2-6alkynyl, optionally substituted C1-6alkoxy, optionally substituted C1-6haloalkyl, optionally substituted O-C1-6haloalkyl, optionally substituted C3-8cycloalkyl, optionally substituted 3-10 membered heterocycloalkyl, optionally substituted C6- 11 aryl, optionally substituted 5-15 membered heteroaryl, N(R5)(R6), O(R7), NC(O)(R8)(R9), and C(O)N(R8)(R9). In one embodiment, R2is optionally substituted C3-8cycloalkyl or optionally substituted C6-11aryl. In one embodiment, the heterocycloalkyl is selected from bridged heterocycloalkyl and spiro heterocycloalkyl. In one embodiment, the heterocycloalkyl is bridged heterocycloalkyl. In one embodiment, the heterocycloalkyl is spiro heterocycloalkyl. In one embodiment, the cycloalkyl is selected from bridged cycloalkyl and spiro cycloalkyl. In one embodiment, the cycloalkyl is bridged cycloalkyl. In one embodiment, the cycloalkyl is spiro cycloalkyl.

[0085] In some embodiments of Formulas (I), (I-a), (I-b), or (I-c),is. In some embodiments,iswherein R2is selected from halogen, cyano, hydroxy, optionally substituted C1-6alkyl, optionally substituted C2-6alkenyl, optionally substituted C2-6alkynyl, optionally substituted C1-6alkoxy, optionally substituted C1-6haloalkyl, optionally substituted O-C1-6haloalkyl, optionally substituted C3-8cycloalkyl, optionally substituted 3-10 membered heterocycloalkyl, optionally substituted C6-11aryl, optionally substituted 5-15 membered heteroaryl, N(R5)(R6), O(R7), NC(O)(R8)(R9), and C(O)N(R8)(R9). In one embodiment, the heterocycloalkyl is selected from bridged heterocycloalkyl and spiro heterocycloalkyl. In one embodiment, the heterocycloalkyl is bridged heterocycloalkyl. In one embodiment, the heterocycloalkyl is spiro heterocycloalkyl. In one embodiment, the cycloalkyl is selected from bridged cycloalkyl and spiro cycloalkyl. In one embodiment, the cycloalkyl is bridged cycloalkyl. In one embodiment, the cycloalkyl is spiro cycloalkyl. In one embodiment, R2is optionally substituted C6-11aryl. In some embodiments, R4is hydrogen or optionally substituted C1-6alkyl. In some embodiments, R4is hydrogen. In other embodiments, R4is optionally substituted C1-6alkyl. In more specific embodiments, R4is selected from hydrogen, methyl or ethyl. In one embodiment, R4is hydrogen or methyl. In another embodiment, R4is methyl.

[0086] In some embodiments of Formulas (I), (I-a), (I-b), or (I-c),isIn some embodiments,is In some embodiments,isIn someembodiments,is. In some embodiments,is or , and e2ach R is independently selected from halogen, cyano, hydroxy, optionally substituted C1-6alkyl, optionally substituted C2-6alkenyl, optionally substituted C2-6alkynyl, optionally substituted C1-6alkoxy, optionally substituted C1-6haloalkyl, optionally substituted O-C1-6haloalkyl, optionally substituted C3-8cycloalkyl, optionally substituted 3-10 membered heterocycloalkyl, optionally substituted C6-11aryl, optionally substituted 5-15 membered heteroaryl, N(R5)(R6), O(R7), NC(O)(R8)(R9), and C(O)N(R8)(R9). In one embodiment, each R2is independently selected from optionally substituted aryl, cyano, or C1-6haloalkyl. In one embodiment, the heterocycloalkyl is selected from bridged heterocycloalkyl and spiro heterocycloalkyl. In one embodiment, the heterocycloalkyl is bridged heterocycloalkyl. In one embodiment, the heterocycloalkyl is spiro heterocycloalkyl. In one embodiment, the cycloalkyl is selected from bridged cycloalkyl and spiro cycloalkyl. In one embodiment, the cycloalkyl is bridged cycloalkyl. In one embodiment, the cycloalkyl is spiro cycloalkyl.

[0087] In some embodiments of Formulas (I), (I-a), (I-b), or (I-c),isor. In some embodiments,is. In some embodiments,is. In some such embodiments, R2is independently selected from halogen, cyano, hydroxy, optionally substituted C1-6alkyl, optionally substituted C2-6alkenyl, optionally substituted C2-6alkynyl, optionally substituted C1-6alkoxy, optionally substituted C1-6haloalkyl, optionally substituted O-C1-6haloalkyl, optionally substituted C3-8cycloalkyl, optionally substituted 3-10 membered heterocycloalkyl, optionally substituted C6-11aryl,optionally substituted 5-15 membered heteroaryl, N(R5)(R6), O(R7), NC(O)(R8)(R9), and C(O)N(R8)(R9). In one embodiment, each R2is independently selected from optionally substituted aryl, cyano, or C1-6haloalkyl. In one embodiment, the heterocycloalkyl is selected from bridged heterocycloalkyl and spiro heterocycloalkyl. In one embodiment, the heterocycloalkyl is bridged heterocycloalkyl. In one embodiment, the heterocycloalkyl is spiro heterocycloalkyl. In one embodiment, the cycloalkyl is selected from bridged cycloalkyl and spiro cycloalkyl. In one embodiment, the cycloalkyl is bridged cycloalkyl. In one embodiment, the cycloalkyl is spiro cycloalkyl.

[0088] In some embodiments of Formulas (I), (I-a), (I-b), or (I-c),is. In some embodiments,is. In some embodiments,is. In some embodiments,isor, wherein R2is independently selected from halogen, cyano, hydroxy, optionally substituted C1-6alkyl, optionally substituted C2-6alkenyl, optionally substituted C2-6alkynyl, optionally substituted C1-6alkoxy, optionally substituted C1-6haloalkyl, optionally substituted O-C1-6haloalkyl, optionally substituted C3-8cycloalkyl, optionally substituted 3-10 membered heterocycloalkyl, optionally substituted C6-11aryl, optionally substituted 5-15 membered heteroaryl, N(R5)(R6), O(R7), NC(O)(R8)(R9), and C(O)N(R8)(R9). In one embodiment, each R2is independently selected from optionally substituted aryl, cyano, or C1-6haloalkyl. In one embodiment, the heterocycloalkyl is selected from bridged heterocycloalkyl and spiro heterocycloalkyl. In one embodiment, the heterocycloalkyl is bridged heterocycloalkyl. In one embodiment, the heterocycloalkyl is spiro heterocycloalkyl. In one embodiment, the cycloalkyl is selected from bridged cycloalkyl and spiro cycloalkyl. In one embodiment, the cycloalkyl is bridged cycloalkyl. In one embodiment, the cycloalkyl is spiro cycloalkyl.

[0089] In some embodiments of Formulas (I), (I-a), (I-b), or (I-c), each R2is independently selected from the group consisting of optionally substituted C3-8cycloalkyl,optionally substituted C2-6alkynyl, optionally substituted 3-10 membered heterocycloalkyl, optionally substituted C6-11aryl, optionally substituted 5-15 membered heteroaryl, N(R5)(R6), O(R7), halogen, C1-6haloalkyl, C1-6alkynyl, and C(O)N(R8)(R9).

[0090] In some embodiments of Formulas (I), (I-a), (I-b), or (I-c), each R2is independently selected from the group consisting of optionally substituted C3-8cycloalkyl, optionally substituted C2-6alkynyl, optionally substituted 3-10 membered heterocycloalkyl, optionally substituted C6-11aryl, optionally substituted 5-15 membered heteroaryl, N(R5)(R6), and O(R7).

[0091] In some embodiments of Formulas (I), (I-a), (I-b), or (I-c), each R2is independently selected from optionally substituted phenyl, optionally substituted acetylenyl, optionally substituted pyridyl, optionally substituted C3-8cycloalkyl, and optionally substituted 4-8 membered heterocycloalkyl. In some such embodiments, the optionally substituted phenyl, optionally substituted pyridyl, optionally substituted C3-8cycloalkyl, and optionally substituted 4-8 membered heterocycloalkyl are substituted with 1-4 substituents each independently selected from the group consisting of C1-6haloalkyl, optionally substituted C1-6alkyl, C1-6cyanoalkyl, C1-6hydroxyalkyl, -NR2B2R2B3, C1-6alkoxy, optionally substituted C2-6alkenyl, - S-C1-6haloalkyl, C2-6alkenyl, optionally substituted C3-8cycloalkyl (e.g. optionally substituted C3-6cycloalkyl), optionally substituted aryl (e.g. optionally substituted phenyl), optionally substituted 5- to 9-membered heteroaryl, optionally substituted 5- to 6-membered heterocycloalkyl, CD3, halogen, hydroxy, and cyano; wherein R2B2is C1-6alkyl, and R2B3is 5- to 6-membered heteroaryl optionally substituted with one or two substituents independently selected from halo and C1-6haloalkyl.

[0092] In some embodiments of Formulas (I), (I-a), (I-b), or (I-c), each R2is independently selected from halogen, optionally substituted C1-6alkyl, optionally substituted C3-10cycloalkyl, optionally substituted 3-10 membered heterocycloalkyl, optionally substituted C6-11aryl, and optionally substituted 5-15 membered heteroaryl.

[0093] In some embodiments of Formulas (I), (I-a), (I-b), or (I-c), each R2is independently halogen or cyano. In some such embodiments, the halogen is selected from Cl and F. In one embodiment, the halogen is Cl. In one embodiment, the halogen is F.

[0094] In some embodiments of Formulas (I), (I-a), (I-b), or (I-c), R2is optionally substituted C1-6alkyl. In some embodiments, R2is optionally substituted C1-3alkyl. In someembodiments, R2is optionally substituted methyl. In one such embodiment, the alkyl is optionally substituted with alkoxy. In one embodiment, the alkyl is optionally substituted with methoxy. In one embodiment, R2is methoxymethyl.

[0095] In some embodiments of Formulas (I), (I-a), (I-b), or (I-c), R2is selected from optionally substituted C3-10cycloalkyl, optionally substituted 3-10 membered heterocycloalkyl, optionally substituted C5-10 aryl, and optionally substituted 5-15 membered heteroaryl. In one embodiment, R2is optionally substituted phenyl.

[0096] In one embodiment of Formulas (I), (I-a), (I-b), or (I-c), R2is selected from optionally substituted C3-10cycloalkyl and optionally substituted 3-10 membered heterocycloalkyl. In one embodiment, the heterocycloalkyl is selected from bridged heterocycloalkyl and spiro heterocycloalkyl. In one embodiment, the heterocycloalkyl is bridged heterocycloalkyl. In one embodiment, the heterocycloalkyl is spiro heterocycloalkyl. In one embodiment, the cycloalkyl is selected from bridged cycloalkyl and spiro cycloalkyl. In one embodiment, the cycloalkyl is bridged cycloalkyl. In one embodiment, the cycloalkyl is spiro cycloalkyl.

[0097] In one embodiment of Formulas (I), (I-a), (I-b), or (I-c), R2is optionally substituted C3-10cycloalkyl. In one embodiment, R2is optionally substituted C3-7cycloalkyl. In one embodiment, R2is an optionally substituted bridged or spiro cycloalkyl. In one embodiment, R2is an optionally substituted bridged cycloalkyl. In one embodiment, R2is an optionally substituted spiro cycloalkyl. In one embodiment, R2is an optionally substituted cyclohexyl. In one embodiment, R2is an optionally substituted cyclopentyl. In one embodiment, R2is an optionally substituted cyclobutyl. In one embodiment, R2is an optionally substituted cyclopropyl.

[0098] In one embodiment of Formulas (I), (I-a), (I-b), or (I-c), R2is selected from the group consisting of,, andwherein w is 0, 1, 2, 3, 4, or 5; Y2 is absent or -C(O)NH-; and each R2Ais independently selected from the group consisting of halogen, cyano, hydroxy, optionally substituted C1-6alkyl, C1-6cyanoalkyl, optionally substituted C1-6haloalkyl, C1-6hydroxyalkyl, -NR2B2NR2B3, optionally substituted C1-6alkenyl, optionally substituted C3-8cycloalkyl, optionally substituted 3- to 6-membered heterocycloalkyl, optionally substituted C5-10 aryl, and optionally substituted 5- to 12-membered heteroaryl, wherein the alkyl, haloalkyl, alkenyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally substituted with one or more substituents selected from halogen, cyano, oxo, CD3, C1-6haloalkoxy, optionally substituted 5- to 12-membered heteroaryl, C1-6alkyl, C1-6alkoxy, C1-6cyanoalkyl, and C1-6haloalkyl.

[0099] In one embodiment, w is 0, 1, 2, or 3. In one embodiment, w is 0. In one embodiment, w is 1. In one embodiment, w is 2. In one embodiment, w is 3.

[0100] In one embodiment, Y2 is absent. In one embodiment, Y2 is -C(O)NH-.

[0101] In one embodiment, each R2Ais independently selected from the group consisting of halogen, cyano, optionally substituted C1-6alkyl, optionally substituted C1-6haloalkyl, optionally substituted C3-6cycloalkyl, phenyl, and optionally substituted 5- to 6- membered heteroaryl, wherein the alkyl, haloalkyl, or 5- to 6-membered heteroaryl is optionally substituted with halogen, cyano, C1-6alkoxy, C1-6haloalkoxy, or optionally substituted 6-membered heteroaryl, and the 6-membered heteroaryl is optionally substituted with 1 or 2 substituents selected from halogen and C1-6alkoxy. In one embodiment, each R2Ais independently selected from halogen, optionally substituted C1-3alkyl, optionally substituted C1-3haloalkyl, cyclopropyl, and phenyl, wherein the alkyl or haloalkyl is optionally substituted with cyano, C1-3haloalkoxy, or optionally substituted 6-membered heteroaryl. In one embodiment, R2Ais selected from halogen, cyano, methyl, -CF3, and cyclopropyl. In one embodiment, each R2Ais independently F or CF3.

[0102] In one embodiment of Formulas (I), (I-a), (I-b), or (I-c), R2is selected from the group consisting of, and, wherein each R2A is independently selected from hydrogen,halogen, cyano, hydroxy, optionally substituted C1-6alkyl, C1-6cyanoalkyl, optionally substituted C1-6haloalkyl, C1-6hydroxyalkyl, -NR2B2NR2B3, optionally substituted C3-8cycloalkyl, optionally substituted phenyl, optionally substituted 5- to 6-membered heterocycloalkyl, optionally substituted C1-6alkenyl, and optionally substituted 5- to 6- membered heteroaryl; R2B2is C1-6alkyl; and R2B3is 5- to 6-membered heteroaryl optionally substituted with one or two substituents independently selected from halo and C1-6haloalkyl. In one embodiment, R2Ais C1-6alkyl or C1-6haloalkyl substituted with cyano, C1-6haloalkoxy, and / or 5- to 6-membered heteroaryl optionally substituted with one or two substituents independently selected from halo, C1-6haloalkyl, and C1-6alkoxy. In one embodiment, R2Ais C3-8cycloalkyl, phenyl, 5- to 6-membered heterocycloalkyl, 5- to 6-membered heteroaryl, or C1-6alkenyl, wherein the cycloalkyl, phenyl, heterocycloalkyl, heteroaryl, or alkenyl aresubstituted with one, two, or three substituents independently selected from halo, cyano, C1-6alkyl, C1-6alkoxy, C1-6haloalkyl, C1-6cyanoalkyl, and CD3. In one embodiment, each R2Ais independently halogen, cyano, C1-3alkyl, C1-3haloalkyl, or cyclopropyl. In one embodiment, each R2Ais independently halogen. In one embodiment, the halogen is Cl or F. In one embodiment, the halogen is F. In one embodiment, R2Ais optionally substituted C1-3alkyl. In one embodiment, R2Ais methyl. In one embodiment, R2Ais CH2CN or CH2OCF3. In one embodiment, R2Ais C1-3haloalkyl. In one embodiment, R2Ais CF3. In one embodiment, R2Ais CHCF2or -CCH3F2. In one embodiment, R2Ais cyclopropyl. In one embodiment, R2Ais cyano.

[0103] In one embodiment of Formulas (I), (I-a), (I-b), or (I-c), R2is, wherein each of R2B, R2C, R2D, R2E, and R2Fis independently selected from hydrogen, halogen, cyano, hydroxy, optionally substituted C1-6alkyl, C1-6cyanoalkyl, C1-6alkenyl optionally substituted with one R2B4, C1-6hydroxyalkyl, -NR2B2R2B3, optionally substituted C1-6haloalkyl, optionally substituted C3-8cycloalkyl, optionally substituted C5-10 aryl, optionally substituted 3- to 10-membered heterocycloalkyl, and optionally substituted 5- to 12-membered heteroaryl; wherein R2B2is C1-6alkyl; R2B3is 5- to 6-membered heteroaryl optionally substituted with one or two substituents independently selected from halo, C1-6haloalkyl, and -O(C1-6alkyl); and R2B4is halogen. In one embodiment, the alkyl, haloalkyl, cycloalkyl, aryl, heterocycloalkyl, and heteroaryl are optionally substituted with 1-4 substituents independently selected from halogen, cyano, oxo, C1-6alkyl, C1-6haloalkyl, C1-6haloalkoxy, C1-6cyanoalkyl, CD3, and optionally substituted 5- to 12-membered heteroaryl. In one embodiment, halogen is F.

[0104] In one embodiment, each of R2B, R2C, R2D, R2E, and R2Fis independently selected from hydrogen, halogen, cyano, optionally substituted C1-3alkyl, optionally substituted C1-3haloalkyl, optionally substituted C3-6cycloalkyl, phenyl, optionally substituted 4- to 6-membered heterocycloalkyl, and 9- to 10-membered heteroaryl. In one embodiment, the halogen is F. In one embodiment, the optionally substituted alkyl is methyl optionally substituted with a substituent selected from cyano, C1-3haloalkoxy, and optionally substituted 5- to 10-membered heteroaryl. In one embodiment, the optionally substituted cycloalkyl is cyclopropyl optionally substituted with one, two, or three substituents independently selectedfrom C1-6alkyl, halogen, and CD3. In one embodiment, the optionally substituted 4- 6- membered heterocycloalkyl is pyrrolidinyl optionally substituted with one or more substituent independently selected from oxo and C1-3haloalkyl.

[0105] In one embodiment, each of R2C, R2D, R2E, and R2Fis independently selected from hydrogen, halogen, C5-10aryl, and C3-8cycloalkyl. In one embodiment, each of R2C, R2D, R2E, and R2Fis independently selected from hydrogen, halogen, phenyl, and cyclopropyl. In one embodiment, each of R2Cand R2Dis independently selected from hydrogen and halogen, and each of R2Eand R2Fis independently selected from hydrogen, halogen, C5-10aryl, and C3-8cycloalkyl. In one embodiment, R2C, R2D, and R2Fare hydrogen, and R2Eis selected from hydrogen, C5-10aryl, and C3-8cycloalkyl. In one embodiment, R2C, R2D, and R2Fare hydrogen, and R2Eis selected from hydrogen, phenyl, and cyclopropyl. In one embodiment, each of R2Cand R2Dis halogen, and each of R2Eand R2Fis hydrogen. In one embodiment the halogen is F. In one such embodiment, R2Bis selected from C1-6alkyl and C1-6haloalkyl. In one such embodiment, R2Bis -CF3.In one such embodiment, R2Bis methyl.

[0106] In one embodiment of Formulas (I), (I-a), (I-b), or (I-c), R2is selected from, , ,, , and,wherein m is 0, 1, 2, or 3, n is 0, 1, 2, or 3, and each R2Gis independently selected from halogen, cyano, hydroxy, CD3, oxo, C1-6alkyl, C1-6haloalkyl, and -O(C1-6alkyl). In one embodiment, halogenis F. In another embodiment, halogen is Cl. In yet another embodiment, one of the R2Gis CF3. In some embodiments, R2is. In some embodiments, R2is . In some embodimen2ts, R is. In some embodiments, R2is2. In some embodiments, R is . In s2ome embodiments, R is. In some embodiments, R2is2. In some embodiments, R is . In some embod2iments, R is. In some embodiments, R2 is . In s 2ome embodiments, R is. In some embodiments, R2isIn someembodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 3. In some embodiments, m is 0 or 1. In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, m is 1 and n is 0. In some embodiments, m is 1 and n is 1. In someembodiments, m is 0 and n is 0. In some embodiments, m is 0 and n is 1. In some embodiments, m is 0 and n is 2. In some embodiments, m is 0 and n is 3.

[0107] In some embodiments, R2is, m is 0 and n is 0. In some embodiments, R2is2G, m is 0, n is 1, and R is CD3, halogen or C1-6haloalkyl. In some embodiments, R2is, m is 0, n is 1, and R2Gis halogen or CF3. In some embodiments, R2is, m is 0, n is 1, and R2Gis halogen. In some embodiments, R2is, m is 0, n is 2, and each R2Gis independently CD3, halogen or C1-6haloalkyl. In some embodiments, R2is, m is 0, n is 2, and each R2Gis independently halogen or CF3. In some embodiments, R2is, m is 0, n is 2, and each R2Gis independently halogen or CD3. In some embodiments, R2is, m is 0, n is 2, and each R2Gis independently halogen. In some embodiments, R2is , m is 0, n2Gis 3, and each R is independently CD3, halogen or C1-6 haloalkyl. In some embodiments, R2is, m is 0, n is 3, and each R2Gis independently halogen or CF3. In some embodiments, R2is, m is 0, n is 3, and each R2Gis independently halogen or CD3. In some embodiments, R2is, m is 0, n is 3, and each R2Gis independently halogen.

[0108] In one embodiment, m is 0. In one embodiment, m is 1. In one embodiment, m is 2. In one embodiment, m is 3. In one embodiment, n is 0. In one embodiment, n is 1. In one embodiment, n is 2. In one embodiment, n is 3. In one embodiment, m is 0 and n is 0. In one embodiment, m is 1 and n is 1. In one embodiment, m is 0 and n is 1. In one embodiment, m is 1 and n is 0. In one embodiment, m is 0 and n is 2. In one embodiment, m is 0 and n is 3.

[0109] In one embodiment, R2Gis selected from halogen, oxo, cyano, CD3, C1-6alkyl, C1-6haloalkyl, and -O(C1-6alkyl). In one embodiment, R2Gis selected from halogen, oxo, CD3, C1-3alkyl, C1-3haloalkyl, and -O(C1-3alkyl). In one embodiment, R2Gis selected from halogen, oxo, CD3, methyl, CF3, and -OCH3.

[0110] In one embodiment, m is 1, n is 1, and R2Gis C1-6haloalkyl. In one embodiment, m is 0, n is 1, and R2Gis selected from C1-6alkyl and C1-6haloalkyl. In one embodiment, m is 0, n is 2, and each R2Gis independently selected from halogen, oxo, C1-6alkyl, and C1-6haloalkyl. In one embodiment, m is 0, n is 3, and each R2Gis independently selected from halogen and oxo. In one embodiment, the alkyl is methyl. In one embodiment, the haloalkyl is CF3. In one embodiment, the halogen is F. In one embodiment of Formulas (I), (I-a), (I-b), or (I-c), R2is selected from the group consisting of, , , , ,, and, .

[0111] In one embodiment of Formulas (I), (I-a), (I-b), or (I-c), R2is, wherein: Y is absent, –O-, C1-6alkylene, -NH-, C2-6alkenylene or C2-6alkynylene; w is 0, 1, 2, 3, 4, or 5;each R2His independently selected from halogen, cyano, C1-6alkyl, C1-6haloalkyl, -O- C1-6haloalkyl, -P(O)(Rc)2, -P(O)(ORc)2, -S(O)(Rc), -S(O)2Rc, -SRd, and optionally substituted C3-6cycloalkyl; wherein when w is 2, 3, 4, or 5, two R2Hon adjacent carbon atoms, taken together with the carbon atoms to which they are attached, may optionally form a 5- or 6-membered heterocycloalkyl; each Rcis independently C1-6alkyl; and each Rdis independently halogen.

[0112] In one embodiment, Rdis F or Cl. In one embodiment, Rdis F. In one embodiment, each Rcis independently methyl.

[0113] In one embodiment, w is 0. In one embodiment, w is 1, In one embodiment, w is 2. In one embodiment, w is 3.

[0114] In one embodiment, each R2His independently selected from halogen, cyano, C1-3alkyl, C1-3haloalkyl, C1-3haloalkoxy, -P(O)(C1-3alkyl)2, -P(O)(OC1-3alkyl)2, S(O)2C1-3alkyl, -SF5, and optionally substituted cyclopropyl. In one embodiment, each R2His independently selected from halogen, cyano, methyl, -CH2CH3, CF3, -CHFCH2F, - CF2CF3, - OCF3, -P(O)(CH3)2, -P(O)(OCH3)2, S(O)2CH3, -SF5, and cyclopropyl substituted with CF3. In one embodiment, R2His CF3.

[0115] In one embodiment, Y is absent, and w is 0. In one embodiment, Y is absent, and w is 1. In one embodiment, Y is absent, and w is 2. In one embodiment, Y is absent, and w is 3. In one embodiment, Y is absent, w is 1, and R2His selected from halogen, cyano, C1-6alkyl, C1-6haloalkyl, C1-6haloalkoxy, -S(O)2C1-6alkyl, -P(O)(C1-6alkyl)2, -P(O)(OC1-6alkyl)2, -SF5, and cyclopropyl substituted with CF3. In one embodiment, Y is absent, w is 2, and each R2His independently selected from halogen, cyano, C1-6alkyl, and C1-6haloalkyl. In one embodiment, Y is absent, w is 3, and each R2His independently selected from C1-3alkyl, C1-3haloalkyl, and cyano. In one embodiment, R2His selected from halogen, cyano, C1-3alkyl, C1-3haloalkyl, C1-3haloalkoxy, -S(O)2C1-3alkyl, -P(O)(C1-3alkyl)2, -P(O)(OC1-3alkyl)2, -SF5, and cyclopropyl substituted with C1-3haloalkyl. In one embodiment, R2His selected from halogen, cyano, methyl, CF3, -OCF3, -S(O)2CH3, -P(O)(CH3)2, -P(O)(OCH3)2, -SF5, and cyclopropyl substituted with CF3. In one embodiment, the halogen is F or Cl. In one embodiment, Y isabsent, w is 2, and each R2His independently selected from C1-6alkyl and C1-6haloalkyl. In one embodiment, Y is absent, w is 2, and each R2His independently selected from methyl and CF3.

[0116] In one embodiment, Y is O and w is 0. In one embodiment, Y is O and w is 1. In one embodiment, Y is O and w is 2. In one embodiment, Y is O, w is 1 and R2His C1-6alkyl or C1-6haloalkyl. In one embodiment, Y is O, w is 1 and R2His C1-6haloalkyl. In one embodiment, R2His C1-3haloalkyl. In one embodiment, R2His CF3.

[0117] In one embodiment, Y is C1-6alkylene and w is 0. In one embodiment, Y is C1-6alkyl and w is 1. In one embodiment, Y is C1-6alkyl and w is 2. In one embodiment, Y is C1-3alkylene, and w is 0, 1, or 2. In one embodiment, Y is CH2, and w is 0, 1, or 2. In one embodiment, Y is C1-6alkylene, w is 1 or 2, and each R2His independently C1-6alkyl or C1-6haloalkyl. In one embodiment, R2His C1-3haloalkyl. In one embodiment, R2His CF3.

[0118] In one embodiment, Y is NH and w is 0. In one embodiment, Y is NH and w is 1. In one embodiment, Y is NH and w is 2. In one embodiment, Y is NH, w is 1, and R2His selected from C1-6alkyl or C1-6haloalkyl. In one embodiment, R2His C1-3haloalkyl. In one embodiment, R2His CF3.

[0119] In one embodiment, Y is C2-6alkynylene, and w is 0. In one embodiment, Y is C2-6alkynylene, and w is 1. In one embodiment, Y is C2-6alkynylene, and w is 2. In one embodiment, Y is C2alkynylene.

[0120] In one embodiment of Formulas (I), (I-a), (I-b), or (I-c), R2is selected fromthe group consisting of, , ,and

[0121] In one embodiment of Formulas (I), (I-a), (I-b), or (I-c), R2is selected from the group consisting of, , ,, , , , , , ,, , , and, wherein w is 0, 1, 2, 3, 4, or 5; Y1is absent, -C(O)-, or C1-6alkylene; and each R2Iis independently selected from the group consisting of halogen, oxo, cyano, C1-6alkyl, C1-6haloalkyl, optionally substituted C2-6alkenyl, optionally substituted C3-8cycloalkyl, 3- to 6-membered heterocycloalkyl, optionally substituted C5-10 aryl (e.g., optionally substituted phenyl), optionally substituted 6-membered heteroaryl, -S-C1-6haloalkyl, and -C(O)OC1-6alkyl, wherein the alkenyl, cycloalkyl, heteroaryl, and aryl are optionally substituted with one or more substituent independently selected from halogen, cyano, and C1-6haloalkyl. In one embodiment, the halogen is F.

[0122] In one embodiment, w is 0, 1, 2, or 3. In one embodiment, w is 0. In one embodiment, w is 1. In one embodiment, w is 2. In one embodiment, w is 3.

[0123] In one embodiment, Y1is -C(O)-. In one embodiment, Y1is C1-3alkylene. In one embodiment, Y1is CH2.In one embodiment, Y1is absent.

[0124] In one embodiment, each R2Iis independently selected from the group consisting of halogen, oxo, cyano, C1-3alkyl, C1-3haloalkyl, optionally substituted C2-3 alkenyl, optionally substituted C3-6cycloalkyl, 3- to 6-membered heterocycloalkyl, optionally substituted C5-6aryl (e.g., optionally substituted phenyl), optionally substituted 6-membered heteroaryl, -S-C1-3haloalkyl, and -C(O)OC1-3alkyl, wherein the alkenyl, cycloalkyl, aryl, and heteroaryl are optionally substituted with one or more substituent independently selected from halogen, cyano, and C1-3haloalkyl. In one embodiment, each R2Iis independently selected from the group consisting of halogen, oxo, methyl, CF3, optionally substituted C2alkenyl, optionally substituted cyclopropyl, oxetanyl, optionally substituted phenyl, optionally substituted 6-membered heteroaryl, -SCF3, and -C(O)OC(CH3)3, wherein the alkenyl, cyclopropyl, phenyl, and heteroaryl are optionally substituted with one or more substituent independently selected from halogen, cyano, and C1-3haloalkyl. In one embodiment, the halogen is F.

[0125] In one embodiment of Formulas (I), (I-a), (I-b), or (I-c), R2is selected from the group consisting of, , ,, wherein w is 0, 1, 2, 3, 4, or 5; Y1is absent, -C(O)-, or C1-6alkylene; and each R2Iis independently selected from the group consisting of halogen, oxo, cyano, C1-6alkyl, C1-6haloalkyl, optionally substituted C2-6alkenyl, optionally substituted C3-8cycloalkyl, 3- to 6-membered heterocycloalkyl, optionally substituted C5-10 aryl (e.g., optionally substituted phenyl), optionally substituted 6-membered heteroaryl, -S-C1-6haloalkyl, and -C(O)OC1-6alkyl, wherein the alkenyl, cycloalkyl, aryl, and heteroaryl are optionally substituted with one or more substituent independently selected from halogen, cyano, C1-6alkyl, C1-6alkoxy, C1-6haloalkoxy, and C1-6haloalkyl. In one embodiment, the halogen is F. In one embodiment, Y1is absent. In one embodiment, Y1is CH2.In one embodiment, Y1is -C(O)-.

[0126] In one embodiment, each R2Iis independently selected from the group consisting of halogen, oxo, cyano, C1-3alkyl, C1-3haloalkyl, optionally substituted C2-3 alkenyl, optionally substituted C3-6cycloalkyl, 3- to 6-membered heterocycloalkyl, optionally substituted C5-6aryl (e.g., optionally substituted phenyl), optionally substituted 6-membered heteroaryl, -S-C1-3haloalkyl, and -C(O)OC1-3alkyl, wherein the alkenyl, cycloalkyl, aryl, and heteroaryl are optionally substituted with one or more substituent independently selected from halogen, cyano, C1-3alkyl, C1-3alkoxy, C1-3haloalkoxy, and C1-3haloalkyl. In one embodiment, each R2Iis independently selected from the group consisting of halogen, oxo, methyl, CF3, optionally substituted C2alkenyl, optionally substituted cyclobutyl, oxetanyl, optionally substituted phenyl, -SCF3, and -C(O)OC(CH3)3, wherein the alkenyl, cyclobutyl, and phenyl are optionally substituted with one or more substituent independently selected from halogen, cyano, C1-3alkyl, C1-3alkoxy, C1-3haloalkoxy, and C1-3haloalkyl. In one embodiment, the halogen is F. In one embodiment, R2Iis CF3. In one embodiment, R2Iis optionally substituted phenyl.

[0127] In one embodiment of Formulas (I), (I-a), (I-b), or (I-c), or a pharmaceutically acceptable salt thereof,, wherein X5, X6, R2K, R2L, and s are as defined for Formula (II-j).

[0128] In some embodiments of Formulas (I), (I-a), (I-b), or (I-c), or a pharmaceutically acceptable salt thereof, wherei7 8 9 2N 2On X , X , X , R , R , and s are as defined for Formula (II-k).

[0129] In one embodiment of Formulas (I), (I-a), (I-b), or (I-c), R2is selected from the group consisting,,,,,, and

[0130] In one embodiment of Formulas (I), (I-a), (I-b), or (I-c), R2is selected from the group consisting of, ,, and, wherein w is 0, 1, 2, 3, 4, or 5; Y3 is absent or O; and each R2Jis independently selected from the group consisting of cyano, halogen, C1-6alkyl, C1-6haloalkyl, -O-C1-6haloalkyl, -S(O)(Rc), -S(O)2(Rc), -P(O)(ORc)2, -P(O)(Rc)2, and - S(Rd)5; each Rcis independently C1-6alkyl; and each Rdis independently halogen.

[0131] In one embodiment, w is 0, 1, 2, or 3. In one embodiment, w is 0, 1, or 2. In one embodiment, w is 0. In one embodiment, w is 1. In one embodiment, w is 2. In one embodiment, w is 3.

[0132] In one embodiment, Y3is O. In one embodiment, Y3is absent.

[0133] In one embodiment, each R2Jis independently selected from the group consisting of halogen, C1-3alkyl, and C1-3haloalkyl. In one embodiment, the halogen is F. In one embodiment, the halogen is Cl. In one embodiment, R2Jis methyl. In one embodiment, R2Jis CF3. In one embodiment, R2Jis -CH2CF3.

[0134] In one embodiment of Formulas (I), (I-a), (I-b), or (I-c), R2is selected from the group consisting of, ,, , ,, and, wherein Y3 is absent or O; and each R2Jis independently selected from the group consisting of halogen, cyano, C1-6alkyl, and C1-6haloalkyl. In one embodiment, each R2Jis independently selected from the group consisting of halogen, cyano, C1-3alkyl, and C1-3haloalkyl. In one embodiment, each R2Jis independently selected from the group consisting of halogen, cyano, methyl, CF3, and CH2CF3. In one embodiment, R2Jis CF3. In one embodiment, halogen is Cl. In one embodiment, halogen is F.

[0135] In one embodiment of Formulas (I), (I-a), (I-b), or (I-c), R2is selected from the group consisting of,,,,, ,,, , ,

[0136] In some embodiments, the compound of Formula (I) is a compound of Formula (II):, or a pharmaceutically acceptable salt thereof, wherein R1, R2, R3, and p are as defined for Formula (I).

[0137] In some embodiments, the compound of Formula (I) is a compound of Formula (II-a):, or a pharmaceutically acceptable salt thereof, wherein R1, R2, and R3are as defined for Formula (I).

[0138] In some embodiments, the compound of Formula (I) is a compound of Formula (II-b):, or a pharmaceutically acceptable salt thereof, wherein R1, R2, and R3are as defined for Formula (I).

[0139] In some embodiments, the compound of Formula (I) is a compound of Formula (II-c):, or a pharmaceutically acceptable salt thereof, wherein R1, R2, and R3are as defined for Formula (I).

[0140] In some embodiments of Formulas (II), (II-a), (II-b), or (II-c), each R1is independently selected from the group consisting of halogen, C1-6alkyl, hydroxy, C1-6haloalkyl, C1-6hydroxyalkyl, C1-6alkoxy, O-C1-6haloalkyl, and O-C3-6cycloalkyl. In some embodiments, each R1is independently selected from the group consisting of CH3, -F, -Cl, CF3, CF2CH3, CH2CHF2, CH2CF3, CF2CH3, CH2OH, OCH3, OCHF2, OCF3, and O- cyclopropyl. In some embodiments, each R1is independently selected from CH3, -F, -Cl, -Br, -I, and hydroxy. In some embodiments, each R1is independently halogen. In some embodiments, each R1is independently selected from -F, -Cl, -Br, and -I. In someembodiments, at least one R1is -F. In some embodiments, at least one R1is -Cl. In some embodiments, one R1is -F and the other R1is -Cl. In some embodiments, each R1is –F. In some embodiments, each R1is –Cl. In some embodiments, each R1is C1-6alkyl. In some embodiments, p is 2, wherein one R1is halogen, and the other R1is selected from the group consisting of C1-6haloalkyl, C1-6hydroxyalkyl, C1-6alkoxy, O-C1-6haloalkyl, and O-C3-6cycloalkyl. In some embodiments, p is 2, wherein one R1is Cl or F, and the other R1is selected from the group consisting of -CF3, -CH2CF3, -CH2CHF2, -CF2CH3, -CH2OH, -OCH3, -OCHF2, -OCF3, and -O-cyclopropyl. In some embodiments, p is 2, wherein one R1is -F and the other R1is selected from the group consisting of C1-6haloalkyl, C1-6alkoxy, O-C1-6haloalkyl, and O-C3-6cycloalkyl. In some embodiments, p is 2, wherein one R1is -F and the other R1is selected from the group consisting of -CF3, -CH2CF3, -CH2CHF2, -CF2CH3, -OCH3, -OCHF2, -OCF3, and O-cyclopropyl. In some embodiments, p is 2, wherein one R1is -F and the other R1is -OCHF2. In some embodiments, p is 2, wherein one R1is -Cl and the other R1is C1-6hydroxyalkyl.

[0141] In some embodiments of Formulas (II), (II-a), (II-b), or (II-c), p is 2, wherein one R1is Cl or F, and the other R1is Cl or -OCF3. In some embodiments, p is 2, wherein one R1is F, and the other R1is Cl or -OCF3. In some embodiments, p is 2, wherein one R1is F, and the other R1is Cl. In some embodiments, p is 2, wherein one R1is F, and the other R1is - OCF3. In some embodiments, p is 2, wherein one R1is Cl, and the other R1is Cl or -OCF3. In some embodiments, p is 2, wherein one R1is Cl, and the other R1is Cl. In some embodiments, p is 2, wherein one R1is Cl, and the other R1is -OCF3.

[0142] In some embodiments of Formulas (II), (II-a), (II-b), or (II-c), R3is hydrogen.

[0143] In some embodiments of Formulas (II), (II-a), (II-b), or (II-c), R2is selected from the group consisting of optionally substituted C3-8cycloalkyl, optionally substituted 3-10 membered heterocycloalkyl, optionally substituted aryl, optionally substituted 5-10 membered heteroaryl, N(R5)(R6), and O(R7), wherein R5, R6, and R7are as defined for Formula (I). In one embodiment, R2is optionally substituted aryl.

[0144] In some embodiments of Formulas (II), (II-a), (II-b), or (II-c), R2is selected from the group consisting of optionally substituted, optionally substituted,optionally substituted, and optionally substituted. In some embodiments of Formulas (II), (II-a), (II-b), or (II-c), R2is selected from the group consisting of optionally substituted, optionally substituted, and optionally substituted. In some embodiments of Formulas (II), (II-a), (II-b), or (II-c), R2is selected from the group consisting of optionally substituted, optionally substituted, and optionally substituted. f In some embodiments of Formulas (II), (II-a), (II-b), or (II-c), R2is selected from the group consisting of optionally substituted, optionally substituted, and optionally substituted. In some embodiments of Formulas (II), (II-a), (II-b), or (II-c), R2is selected from the group consisting of optionally substituted, optionally substituted, and optionally substituted . In some embodiments of Formu2las (II), (II-a), (II-b), or (II-c), R is selected from the group consisting of optionally substitutedand optionally substituted. In some embodiments of Formulas (II), (II-a), (II-b), or (II-c), R2is optionally substituted. In some embodiments of Formulas (II), (II-a), (II-b), or (II-c), R2is optionally substituted. In some embodiments of Formulas (II), (II-a), (II-b), or (II-c), R2is optionally substituted. In some embodiments of Formulas (II), (II-a), (II- b), or (II-c), R2is optionally substituted.

[0145] In some embodiments of Formulas (II), (II-a), (II-b), or (II-c), p is 2, wherein one R1is F, and the other R1is Cl or -OCF3; R2is, m is 0, n is 1, 2, or 3, and each R2Gis independently selected from halogen, CD3, and C1-6haloalkyl. In some embodiments of Formulas (II), (II-a), (II-b), or (II-c), p is 2, wherein one R1is F, and the other R1is Cl or -OCF3; R2is, m is 0, n is 1, and R2Gis independently selected from halogen, CD3, and C1-6haloalkyl. In some embodiments of Formulas (II), (II-a), (II-b), or (II-c), p is 2, wherein one R1is F, and the other R1is Cl or -OCF3; R2is, m is 0, n is 2, and each R2Gis independently selected from halogen, CD3, and C1-6haloalkyl.

[0146] In some embodiments of Formulas (II), (II-a), (II-b), or (II-c), p is 2, wherein one R1is F, and the other R1is -OCF3; R2is, m is 0, n is 1, 2, or 3, and each R2Gis independently selected from halogen, CD3, and C1-6haloalkyl. In some embodiments of Formulas (II), (II-a), (II-b), or (II-c), p is 2, wherein one R1is F, and the other R1is -OCF3; R2is, m is 0, n is 1, and R2Gis independently selected from halogen, CD3, and C1-6haloalkyl. In some embodiments of Formulas (II), (II-a), (II-b), or (II-c), p is 2, wherein one R1is F, and the other R1is -OCF3; R2is, m is 0, n is 1, and R2Gis halogen. In some embodiments of Formulas (II), (II-a), (II-b), or (II-c), p is 2, wherein one R1is F, and the other R1is -OCF3; R2is, m is 0, n is 1, and R2Gis F or Cl. In some embodiments of Formulas (II), (II-a), (II-b), or (II-c), p is 2, wherein one R1is F, and the other R1is -OCF3; R2is, m is 0, n is 2, and each R2Gis independently selected from halogen, CD3, and C1-6haloalkyl. In some embodiments of Formulas (II), (II-a), (II-b), or (II- c), p is 2, wherein one R1is F, and the other R1is -OCF3; R2is, m is 0, n is 3, and each R2Gis independently selected from halogen, CD3, and C1-6haloalkyl. In some embodiments of Formulas (II), (II-a), (II-b), or (II-c), p is 2, wherein one R1is F, and the other R1is Cl; R2is, m is 0, n is 1, 2, or 3, and each R2Gis independently selected from halogen, CD3, and C1-6haloalkyl. In some embodiments of Formulas (II), (II-a), (II-b), or (II-c), p is 2, wherein one R1is F, and the other R1is Cl; R2is, m is 0, n is 1, and R2Gis independently selected from halogen, CD3, and C1-6haloalkyl. In some embodiments of Formulas (II), (II-a), (II-b), or (II-c), p is 2, wherein one R1is F, and the other R1is Cl; R2is, m is 0, n is 1, and R2Gis halogen. In some embodiments of Formulas (II), (II-a), (II-b), or (II-c), p is 2, wherein one R1is F, and the other R1is Cl; R2is, m is 0, n is 1, and R2Gis F or Cl. In some embodiments of Formulas (II), (II-a), (II-b), or (II-c), p is 2, whereinone R1is F, and the other R1is Cl; R2is, m is 0, n is 2, and each R2Gis independently selected from halogen, CD3, and C1-6haloalkyl. In some embodiments of Formulas (II), (II-a), (II-b), or (II-c), p is 2, wherein one R1is F, and the other R1is Cl; R2is, m is 0, n is 3, and each R2Gis independently selected from halogen, CD3, and C1-6haloalkyl.

[0147] In some embodiments of Formulas (II), (II-a), (II-b), or (II-c), p is 2, wherein one R1is F, and the other R1is Cl or -OCF3; R2is, R2Iis optionally substituted C6-10aryl (e.g., optionally substituted phenyl) or optionally substituted 6-membered heteroaryl (e.g., optionally substituted pyridyl), wherein the C6-10 aryl or the 6-membered heteroaryl are optionally substituted with one, two, or three substituents independently selected from halogen, cyano, C1-6alkyl, C1-6alkoxy, C1-6haloalkoxy, and C1-6haloalkyl. In some embodiments of Formulas (II), (II-a), (II-b), or (II-c), p is 2, wherein one R1is F, and the other R1is Cl or - OCF3; R2is, R2Iis optionally substituted phenyl or optionally substituted 6- membered pyridyl or pyrimidinyl, wherein the C6-10 aryl or the 6-membered heteroaryl are optionally substituted with one, two, or three substituents each independently selected from F, Cl, cyano, methyl, ethyl, i-propyl, n-propyl, methoxy, ethoxy, i-propoxy, n-propoxy, -OCF3, - OCHF2, -OCH2F, -CF3, -CHF2, and -CH2F. In some embodiments of Formulas (II), (II-a), (II- b), or (II-c), p is 2, wherein one R1is F, and the other R1is Cl; R2is, R2Iis optionally substituted phenyl or optionally substituted 6-membered pyridyl or pyrimidinyl, wherein the C6-10 aryl or the 6-membered heteroaryl are optionally substituted with one, two, or three substituents each independently selected from F, Cl, cyano, methyl, ethyl, i-propyl, n- propyl, methoxy, ethoxy, i-propoxy, n-propoxy, -OCF3, -OCHF2, -OCH2F, -CF3, -CHF2, and - CH2F. In some embodiments of Formulas (II), (II-a), (II-b), or (II-c), p is 2, wherein one R1isF, and the other R1is -OCF3; R2is, R2Iis optionally substituted phenyl or optionally substituted 6-membered pyridyl or pyrimidinyl, wherein the C6-10aryl or the 6- membered heteroaryl are optionally substituted with one, two, or three substituents each independently selected from F, Cl, cyano, methyl, ethyl, i-propyl, n-propyl, methoxy, ethoxy, i-propoxy, n-propoxy, -OCF3, -OCHF2, -OCH2F, -CF3, -CHF2, and -CH2F.

[0148] In some embodiments of Formulas (II), (II-a), (II-b), or (II-c), p is 2, wherein one R1is F, and the other R1is Cl or -OCF3; R2is, R2Iis optionally substituted C6-10 aryl (e.g., optionally substituted phenyl) or optionally substituted 6-membered heteroaryl (e.g., optionally substituted pyridyl), wherein the C6-10aryl or the 6-membered heteroaryl are optionally substituted with one, two, or three substituents independently selected from halogen, cyano, C1-6alkyl, C1-6alkoxy, C1-6haloalkoxy, and C1-6haloalkyl. In some embodiments of Formulas (II), (II-a), (II-b), or (II-c), p is 2, wherein one R1is F, and the other R1is Cl or - OCF3; R2is, R2Iis optionally substituted phenyl or optionally substituted 6- membered pyridyl or pyrimidinyl, wherein the C6-10aryl or the 6-membered heteroaryl are optionally substituted with one, two, or three substituents each independently selected from F, Cl, cyano, methyl, ethyl, i-propyl, n-propyl, methoxy, ethoxy, i-propoxy, n-propoxy, -OCF3, - OCHF2, -OCH2F, -CF3, -CHF2, and -CH2F. In some embodiments of Formulas (II), (II-a), (II- b), or (II-c), p is 2, wherein one R1is F, and the other R1is Cl; R2is2I, R is optionally substituted phenyl or optionally substituted 6-membered pyridyl or pyrimidinyl, wherein the C6-10 aryl or the 6-membered heteroaryl are optionally substituted with one, two, or three substituents each independently selected from F, Cl, cyano, methyl, ethyl, i-propyl, n- propyl, methoxy, ethoxy, i-propoxy, n-propoxy, -OCF3, -OCHF2, -OCH2F, -CF3, -CHF2, and - CH2F. In some embodiments of Formulas (II), (II-a), (II-b), or (II-c), p is 2, wherein one R1is F, and the other R1is -OCF3; R2is, R2Iis optionally substituted phenyl or optionally substituted 6-membered pyridyl or pyrimidinyl, wherein the C6-10aryl or the 6- membered heteroaryl are optionally substituted with one, two, or three substituents eachindependently selected from F, Cl, cyano, methyl, ethyl, i-propyl, n-propyl, methoxy, ethoxy, i-propoxy, n-propoxy, -OCF3, -OCHF2, -OCH2F, -CF3, -CHF2, and -CH2F.

[0149] In some embodiments of Formulas (II), (II-a), (II-b), or (II-c), p is 2, wherein one R1is F, and the other R1is Cl or -OCF3; R2is, R2Iis optionally substituted C6-10 aryl (e.g., optionally substituted phenyl) or optionally substituted 6-membered heteroaryl (e.g., optionally substituted pyridyl), wherein the C6-10aryl or the 6-membered heteroaryl are optionally substituted with one, two, or three substituents independently selected from halogen, cyano, C1-6alkyl, C1-6alkoxy, C1-6haloalkoxy, and C1-6haloalkyl. In some embodiments of Formulas (II), (II-a), (II-b), or (II-c), p is 2, wherein one R1is F, and the other R1is Cl or - OCF3; R2is, R2Iis optionally substituted phenyl or optionally substituted 6- membered pyridyl or pyrimidinyl, wherein the C6-10 aryl or the 6-membered heteroaryl are optionally substituted with one, two, or three substituents each independently selected from F, Cl, cyano, methyl, ethyl, i-propyl, n-propyl, methoxy, ethoxy, i-propoxy, n-propoxy, -OCF3, - OCHF2, -OCH2F, -CF3, -CHF2, and -CH2F. In some embodiments of Formulas (II), (II-a), (II- b), or (II-c), p is 2, wherein one R1is F, and the other R1is Cl; R2is2I, R is optionally substituted phenyl or optionally substituted 6-membered pyridyl or pyrimidinyl, wherein the C6-10 aryl or the 6-membered heteroaryl are optionally substituted with one, two, or three substituents each independently selected from F, Cl, cyano, methyl, ethyl, i-propyl, n- propyl, methoxy, ethoxy, i-propoxy, n-propoxy, -OCF3, -OCHF2, -OCH2F, -CF3, -CHF2, and - CH2F. In some embodiments of Formulas (II), (II-a), (II-b), or (II-c), p is 2, wherein one R1is F, and the other R1is -OCF3; R2is2, RIis optionally substituted phenyl or optionally substituted 6-membered pyridyl or pyrimidinyl, wherein the C6-10 aryl or the 6- membered heteroaryl are optionally substituted with one, two, or three substituents each independently selected from F, Cl, cyano, methyl, ethyl, i-propyl, n-propyl, methoxy, ethoxy, i-propoxy, n-propoxy, -OCF3, -OCHF2, -OCH2F, -CF3, -CHF2, and -CH2F.

[0150] In some embodiments of Formulas (II), (II-a), (II-b), or (II-c), p is 2, wherein one R1is F, and the other R1is Cl or -OCF3; R2is, R2Iis optionally substituted C6-10 aryl (e.g., optionally substituted phenyl) or optionally substituted 6-membered heteroaryl (e.g., optionally substituted pyridyl), wherein the C6-10aryl or the 6-membered heteroaryl are optionally substituted with one, two, or three substituents independently selected from halogen, cyano, C1-6alkyl, C1-6alkoxy, C1-6haloalkoxy, and C1-6haloalkyl. In some embodiments of Formulas (II), (II-a), (II-b), or (II-c), p is 2, wherein one R1is F, and the other R1is Cl or - OCF3; R2is, R2Iis optionally substituted phenyl or optionally substituted 6- membered pyridyl or pyrimidinyl, wherein the C6-10aryl or the 6-membered heteroaryl are optionally substituted with one, two, or three substituents each independently selected from F, Cl, cyano, methyl, ethyl, i-propyl, n-propyl, methoxy, ethoxy, i-propoxy, n-propoxy, -OCF3, - OCHF2, -OCH2F, -CF3, -CHF2, and -CH2F. In some embodiments of Formulas (II), (II-a), (II- b), or (II-c), p is 2, wherein one R1is F, and the other R1is Cl; R2is, R2Iis optionally substituted phenyl or optionally substituted 6-membered pyridyl or pyrimidinyl, wherein the C6-10aryl or the 6-membered heteroaryl are optionally substituted with one, two, or three substituents each independently selected from F, Cl, cyano, methyl, ethyl, i-propyl, n- propyl, methoxy, ethoxy, i-propoxy, n-propoxy, -OCF3, -OCHF2, -OCH2F, -CF3, -CHF2, and - CH2F. In some embodiments of Formulas (II), (II-a), (II-b), or (II-c), p is 2, wherein one R1is F, and the other R1is -OCF3; R2is, R2Iis optionally substituted phenyl or optionally substituted 6-membered pyridyl or pyrimidinyl, wherein the C6-10 aryl or the 6- membered heteroaryl are optionally substituted with one, two, or three substituents each independently selected from F, Cl, cyano, methyl, ethyl, i-propyl, n-propyl, methoxy, ethoxy, i-propoxy, n-propoxy, -OCF3, -OCHF2, -OCH2F, -CF3, -CHF2, and -CH2F.

[0151] In some embodiments, the compound of Formula (I) is a compound of Formula (II-d):or a pharmaceutically acceptable salt thereof, wherein: R1, R3, and p are as defined for Formula (I),each R2His independently selected from the group consisting of C1-6haloalkyl, -O-C1-6haloalkyl, C1-6alkyl, halogen, cyano, -S(O)(Rc), -S(O)2(Rc), -P(O)(ORc)2, -P(O)(Rc)2, -S(Rd)5, and optionally substituted C3-6cycloalkyl; wherein when w is 2, 3, 4, or 5, two R2Hon adjacent carbon atoms, taken together with the carbon atoms to which they are attached, may optionally form a 5- or 6-membered heterocycloalkyl; each Rcis independently C1-6alkyl; each Rdis independently halogen; and w is selected from 0, 1, 2, 3, 4, and 5.

[0152] In one embodiment of Formula (II-d), each Rcis independently C1-3alkyl. In one embodiment, Rcis methyl.

[0153] In one embodiment of Formula (II-d), w is 0, 1, 2, or 3. In one embodiment, w is 0 or 1. In one embodiment, w is 0. In one embodiment, w is 1. In one embodiment, w is 2. In one embodiment, w is 3.

[0154] In one embodiment of Formula (II-d), R2His optionally substituted C3-6cycloalkyl. In one embodiment, R2His C3-6cycloalkyl substituted with one C1-6haloalkyl. In one embodiment, R2His C3-6cycloalkyl substituted with one C1-3haloalkyl. In one embodiment, w is 1, and R2His cyclopropyl substituted with CF3.

[0155] In one embodiment of Formula (II-d), R2His C1-6haloalkyl. In one embodiment, R2His C1-3haloalkyl. In one embodiment, R2His –CF3. In one embodiment, R2His halo. In one embodiment, w is 1 and R2His -CF3.

[0156] In one embodiment, w is 3, and each R2His independently selected from C1-6haloalkyl, C1-6alkyl, and cyano. In one embodiment, w is 3, and each R2His independently selected from C1-3haloalkyl, C1-3alkyl, and cyano. In one embodiment, w is 3, and each R2His independently selected from CH3, CF3, and cyano.

[0157] In one embodiment, w is 3, two R2Hon adjacent carbon atoms, taken together with the carbon atoms to which they are attached, form a 5- or 6-membered heterocycloalkyl, and the other R2His C1-6alkyl.

[0158] In some embodiments, the compound of Formula (I) is a compound of Formula (II-e):or a pharmaceutically acceptable salt thereof, wherein: R1, R3, and p is as defined for Formula (II-d); each R2His independently selected from the group consisting of C1-6haloalkyl, -O-C1-6haloalkyl, C1-6alkyl, halogen, cyano, -S(O)(Rc), -S(O)2(Rc), -P(O)(ORc)2, -P(O)(Rc)2, and - S(Rd)5, each Rcis independently C1-6alkyl; each Rdis independently halogen; and w is selected from 0, 1, 2, 3, 4, and 5.

[0159] In one embodiment of Formula (II-e), w is 0, 1 or 2. In one embodiment, w is 0 or 1. In one embodiment, w is 0. In one embodiment, w is 1.

[0160] In one embodiment of Formula (II-e), R2His C1-6haloalkyl. In one embodiment, R2His C1-3haloalkyl. In one embodiment, R2His –CF3. In one embodiment, R2His halo. In one embodiment, w is 1 and R2His -CF3.

[0161] In some embodiments, the compound of Formula (I) is a compound of Formula (II-f):or a pharmaceutically acceptable salt thereof, wherein: R1, R3, and p are as defined for Formula (I); and each of R2B, R2C, R2D, R2E, and R2Fis independently selected from hydrogen, halogen, cyano, hydroxy, optionally substituted C1-6alkyl, C1-6cyanoalkyl, optionally substituted C1-6alkenyl, C1-6hydroxyalkyl, -NR2B2R2B3, optionally substituted C1-6haloalkyl, optionally substituted C3-8cycloalkyl, optionally substituted C5-10 aryl, optionally substituted 3- to 10- membered heterocycloalkyl, and optionally substituted 5- to 12-membered heteroaryl. In one embodiment, R2B2is C1-6alkyl. In one embodiment, R2B3is 5- to 6-membered heteroaryl optionally substituted with one or two substituents independently selected from halo, C1-6haloalkyl, and -O(C1-6alkyl).

[0162] In one embodiment of Formula (II-f), each of R2B, R2C, R2D, R2E, and R2Fis independently selected from hydrogen, halogen, cyano, C1-6alkyl optionally substituted with one R2B3, C1-6cyanoalkyl, C1-6alkenyl optionally substituted with one R2B4; hydroxy, C1-6hydroxyalkyl, -NR2B2R2B3, C3-8cycloalkyl, phenyl, 5- to 6-membered heterocycloalkyl, 5- to 6-membered heteroaryl, and C1-6haloalkyl optionally substituted with one R2B3, wherein the C3-8cycloalkyl, phenyl, 5- to 6-membered heterocycloalkyl, and 5- to 6-membered heteroaryl are optionally substituted with one, two, or three R2B1; each R2B1is independently selected from the group consisting of halo, cyano, C1-6alkyl, C1-6haloalkyl, C1-6cyanoalkyl, and CD3; R2B2is C1-6alkyl; R2B3is 5- to 6-membered heteroaryl optionally substituted with one or twosubstituents independently selected from halo, C1-6haloalkyl, and -O(C1-6alkyl); and R2B4is halogen.

[0163] In one embodiment of Formula (II-f), R2C, R2D, R2E, and R2Fare all hydrogen, and R2Bis selected from hydrogen, halogen, cyano, C1-6alkyl optionally substituted with one R2B3, C1-6cyanoalkyl, C1-6alkenyl optionally substituted with one R2B4; hydroxy, C1-6hydroxyalkyl, -NR2B2R2B3, C3-8cycloalkyl, phenyl, 5- to 6-membered heterocycloalkyl, 5- to 6-membered heteroaryl, and C1-6haloalkyl optionally substituted with one R2B3, wherein the C3-8cycloalkyl, phenyl, 5- to 6-membered heterocycloalkyl, and 5- to 6-membered heteroaryl are optionally substituted with one, two, or three R2B1; each R2B1is independently selected from the group consisting of halo, cyano, C1-6alkyl, C1-6haloalkyl, C1-6cyanoalkyl, and CD3; R2B2is C1-6alkyl; R2B3is 5- to 6-membered heteroaryl optionally substituted with one or two substituents independently selected from halo, C1-6haloalkyl, and -O(C1-6alkyl); and R2B4is halogen.

[0164] In one embodiment of Formula (II-f), each of R2B, R2C, R2D, R2E, and R2Fis independently selected from hydrogen, halogen, C1-6alkyl, C1-6cyanoalkyl, C3-8cycloalkyl, and C1-6haloalkyl.

[0165] In one embodiment of Formula (II-f), each of R2C, R2D, R2E, and R2Fis hydrogen, and R2Bis C1-6haloalkyl, C1-6alkyl, C1-6cyanoalkyl, C1-6hydroxyalkyl, C3-8cycloalkyl, halogen, or C1-6alkenyl optionally substituted with halogen.

[0166] In one embodiment of Formula (II-f), each of R2C, R2D, R2E, and R2Fis hydrogen, and R2Bis C1-6haloalkyl. In one embodiment, each of R2C, R2D, R2E, and R2Fis hydrogen, and R2Bis C1-3haloalkyl. In one embodiment, each of R2C, R2D, R2E, and R2Fis hydrogen, and R2Bis CF3.

[0167] In one embodiment of Formula (II-f), each of R2C, R2D, R2E, and R2Fis hydrogen, and R2Bis C1-6cyanoalkyl. In one embodiment, each of R2C, R2D, R2E, and R2Fis hydrogen, and R2Bis C1-3cyanoalkyl.

[0168] In one embodiment of Formula (II-f), each of R2C, R2D, R2E, and R2Fis hydrogen, and R2Bis C3-8cycloalkyl optionally substituted with one, two, or three R2B1. In one embodiment, each of R2C, R2D, R2E, and R2Fis hydrogen, and R2Bis C3-6cycloalkyl. In one embodiment, each of R2C, R2D, R2E, and R2Fis hydrogen, and R2Bis C3-6cycloalkyl substitutedwith one, two, or three R2B1, wherein each R2B1is independently selected from halogen, cyano, C1-3alkyl, C1-3haloalkyl, and CD3.

[0169] In one embodiment of Formula (II-f), each of R2C, R2D, R2E, and R2Fis hydrogen, and R2Bis halogen.

[0170] In one embodiment of Formula (II-f), each of R2C, R2D, R2E, and R2Fis hydrogen, and R2Bis C1-6alkyl. In one embodiment, each of R2C, R2D, R2E, and R2Fis hydrogen, and R2Bis C1-3alkyl. In one embodiment, each of R2C, R2D, R2E, and R2Fis hydrogen, and R2Bis methyl.

[0171] In one embodiment of Formula (II-f), each of R2C, R2D, R2E, and R2Fis hydrogen, and R2Bis C1-6alkyl substituted with one R2B3. In one embodiment, R2Bis methyl substituted with one R2B3. In one embodiment, R2B3is a 5-membered heteroaryl substituted with C1-3haloalkyl. In one embodiment, R2B3is a 6-membered heteroaryl substituted with two substituents selected from halogen, and -O(C1-3alkyl).

[0172] In one embodiment of Formula (II-f), each of R2C, R2D, R2E, and R2Fis hydrogen, and R2Bis C1-6haloalkyl substituted with one R2B3. In one embodiment, R2Bis C1-3haloalkyl substituted with one R2B3. In one embodiment, R2B3is a 6-membered heteroaryl substituted with two substituents independently selected from halogen, and -O(C1-3alkyl).

[0173] In one embodiment of Formula (II-f), each of R2C, R2D, R2E, and R2Fis hydrogen, and R2Bis phenyl substituted with one, two, or three R2B1. In one embodiment, R2Bis phenyl substituted with halogen.

[0174] In one embodiment of Formula (II-f), each of R2C, R2D, R2E, and R2Fis hydrogen, and R2Bis 5- to 6-membered heteroaryl substituted with one, two, or three R2B1. In one embodiment, R2Bis 5-membered heteroaryl substituted with C1-3haloalkyl.

[0175] In one embodiment of Formula (II-f), each of R2C, R2D, R2E, and R2Fis hydrogen, and R2Bis 5- to 6-membered heterocycloalkyl substituted with one, two, or three R2B1. In one embodiment, R2Bis 5-membered heterocycloalkyl substituted with C1-3haloalkyl.

[0176] In one embodiment of Formula (II-f), each of R2C, R2D, R2E, and R2Fis hydrogen, and R2Bis -NR2B2R2B3. In one such embodiment, R2B2is C1-3alkyl and R2B3is 5- to 6-membered heteroaryl substituted with two halogen.

[0177] In one embodiment of Formula (II-f), each of R2Eand R2Fis hydrogen, each of R2Cand R2Dis halogen, and R2Bis C1-6haloalkyl.

[0178] In some embodiments, the compound of Formula (I) is a compound of Formula (II-g):or a pharmaceutically acceptable salt thereof, wherein: R1, R3, and p are as defined for Formula (I).

[0179] In some embodiments, the compound of Formula (I) is a compound of Formula (II-h):or a pharmaceutically acceptable salt thereof, wherein: R1, R3, and p are as defined for Formula (I).

[0180] In some embodiments, the compound of Formula (I) is a compound of Formula (II-i):or a pharmaceutically acceptable salt thereof, wherein: R1, R3, w, and p are as defined for Formula (II-d),each R2Jis independently selected from the group consisting of C1-6haloalkyl, -O-C1-6haloalkyl, C1-6alkyl, halogen, cyano, -S(O)(Rc), -S(O)2(Rc), -P(O)(ORc)2, -P(O)(Rc)2, and - S(Rd)5, each Rcis independently C1-6alkyl; each Rdis independently halogen; and w is selected from 0, 1, 2, 3, 4, and 5.

[0181] In some embodiments of Formula (II-i), w is 0, 1 or 2. In one embodiment, w is 0 or 1. In one embodiment, w is 0. In one embodiment, w is 1.

[0182] In one embodiment of Formula (II-i), R2Jis C1-6haloalkyl. In one embodiment, R2Jis C1-3haloalkyl. In one embodiment, R2Jis –CF3. In one embodiment, R2Jis halogen. In one embodiment, w is 1 and R2Jis -CF3.

[0183] In some embodiments, the compound of Formula (I) is a compound of Formula (II-j):, or a pharmaceutically acceptable salt thereof, wherein: R1, R3, and p are as defined for Formula (I), X5is a bond, -CH2-, -CH2CH2-, O, or NR2MX6is -CH2- or -CH2CH2-; R2Kis phenyl or 5- to 9-membered heteroaryl, wherein the phenyl or 5- to 9- membered heteroaryl is optionally substituted with one, two, three, or four R2L; each R2Lis independently selected from the group consisting of halo, cyano, C1-6alkyl, C1-6haloalkyl, C1-6hydroxyalkyl, C1-6alkoxy, C1-6haloalkoxy, C(O)(C1-6alkoxy), -CH2(C1-6alkoxy), -OCD3, -O-cyclopropyl, -C(O)NR2L1R2L2, and 5-membered heteroaryl optionally substituted with C1-6alkyl; R2L1and R2L2are independently selected from H and C1-6alkyl; or R2L1and R2L2, taken together with the N to which they are attached, for an optionally substituted 4- to 6- membered heterocycloalkyl; R2Mis C1-6alkyl; and s is 0 or 1.

[0184] In some embodiments of Formula (II-j), or a pharmaceutically acceptable salt thereof, X5and X6are both -CH2-. In some embodiments, X5is -CH2and X6is -CH2CH2-. In some embodiments, X5is O and X6is -CH2-. In some embodiments, X5is O and X6is - CH2CH2-. In some embodiments, X5is NR2Mand X6is -CH2-. In some embodiments, X5is a bond, and X6is -CH2-. In some embodiments, X5is -CH2CH2- and X6is -CH2-.

[0185] In some embodiments of Formula (II-j), or a pharmaceutically acceptable salt thereof,is selected from the group consisting of:,, , , , ,, and.

[0186] In some embodiments of Formula (II-j), or a pharmaceutically acceptable salt thereof, R2Kis selected from the group consisting of,, ,and

[0187] In some embodiments of Formula (II-j), or a pharmaceutically acceptable salt thereof, each R2Lis independently selected from the group consisting of halo, cyano, C1-3alkyl,C1-3 haloalkyl, C1-3 hydroxyalkyl, C1-3 alkoxy, C1-3 haloalkoxy, C(O)(C1-3 alkoxy), -CH2(C1-3alkoxy), -OCD3, -O-cyclopropyl, -C(O)NR2L1R2L2, and 5-membered heteroaryl optionally substituted with C1-3alkyl. In some embodiments, R2Lis -C(O)NR2L1R2L2, wherein R2L1and R2L2are independently selected from H and C1-3alkyl. In some embodiments, R2Lis - C(O)NR2L1R2L2, wherein R2L1and R2L2, taken together with the N to which they are attached, for an optionally substituted 4- to 6-membered heterocycloalkyl. In some embodiments, the 4- to 6-membered heterocycloalkyl is substituted with one substituent selected from halogen and cyano.

[0188] In some embodiments of Formula (II-j), or a pharmaceutically acceptable salt thereof,is selected from the group consisting of:,,,, , , ,, and.

[0189] In some embodiments, the compound of Formula (I) is a compound of Formula (II-k):, or a pharmaceutically acceptable salt thereof, wherein: R1, R3, and p are as defined for Formula (I), X7is -CH2- or -CH2CH2-; X8is a bond, O, or -CH2-; X9is -CH2- or -CH2CH2-; R2Ois phenyl or 6-membered heteroaryl, wherein the phenyl or 6-membered heteroaryl is optionally substituted with one, two, or three R2N; each R2Nis independently selected from the group consisting of halo, cyano, C1-6alkyl,C1-6haloalkyl, C1-6hydroxyalkyl, C1-6alkoxy, C1-6haloalkoxy, C(O)(C1-6alkoxy), and -CH2(C1-6alkoxy); and s is 0 or 1.

[0190] In some embodiments of Formula (II-k), or a pharmaceutically acceptable salt thereof, X7and X9are both -CH2- and X8is a bond. In some embodiments, X7is -CH2-, X8is O, and X9is -CH2CH2-. In some embodiments, X7is -CH2CH2-, X8is a bond, and X9is -CH2- . In some embodiments, X7, X8, and X9are all -CH2-.

[0191] In some embodiments of Formula (II-k), or a pharmaceutically acceptable salt thereof, s is 0. In some embodiments, s is one and R2Nis halogen.

[0192] In some embodiments of Formula (II-k), or a pharmaceutically acceptable salt thereof, each R2Nis independently selected from the group consisting of halo, cyano, and C1-6haloalkyl.

[0193] In some embodiments of Formula (II-k), or a pharmaceutically acceptable salt thereof,is selected from the group consisting of,, and

[0194] In some embodiments of Formula (II-k), or a pharmaceutically acceptable salt thereof, R2Ois selected from the group consisting ofand

[0195] In some embodiments of Formula (II-k), or a pharmaceutically acceptable salt thereof,is selected from the group consisting of,.

[0196] In some embodiments of Formula (II-a), (II-b), (II-c), (II-d), (II-e), (II-f), (II- g), (II-h), (II-i), (II-j) and (II-k), R3is hydrogen.

[0197] In some embodiments, the compound of Formula (I) is a compound of Formula (IV):or a pharmaceutically acceptable salt thereof, wherein R1, R2, R3, and p are as defined forFormula (I).

[0198] In some embodiments, the compound of Formula (I) is a compound of Formula (IV-a), Formula (IV-b), or Formula (IV-c):or a pharmaceutically acceptable salt thereof, wherein R1, R2, and R3are as defined for Formula (I).

[0199] In some embodiments of Formulas (IV), (IV-a), (IV-b), or (IV-c), each R1is independently selected from the group consisting of halogen, C1-6alkyl, and hydroxy. In some embodiments, each R1is independently selected from CH3, -F, -Cl, -Br, -I, and hydroxy. In some embodiments, each R1is independently halogen. In some embodiments, each R1is independently selected from -F, -Cl, -Br, and -I. In some embodiments, at least one R1is -F. In some embodiments, at least one R1is -Cl. In some embodiments, one R1is -F and the other R1is -Cl. In some embodiments, each R1is –F. In some embodiments, each R1is –Cl. In some embodiments, each R1is C1-6alkyl.

[0200] In some embodiments of Formulas (IV), (IV-a), (IV-b), or (IV-c), R3is hydrogen or methyl. In some embodiments, R3is hydrogen. In some embodiments, R3is methyl.

[0201] In some embodiments of Formulas (IV), (IV-a), (IV-b), or (IV-c), each R2is independently optionally substituted aryl, optionally substituted C1-6alkyl, or halogen.

[0202] In some embodiments, the compound of Formula (I) is a compound of Formula (V):or a pharmaceutically acceptable salt thereof, wherein R1, R2, R3, and p are as defined forFormula (I).

[0203] In some embodiments, the compound of Formula (I) is a compound of Formula (V-a), Formula (V-b), or Formula (V-c):or a pharmaceutically acceptable salt thereof, wherein R1, R2, and R3are as defined for Formula (I).

[0204] In some embodiments of Formulas (V), (V-a), (V-b), or (V-c), each R1is independently selected from the group consisting of halogen, C1-6alkyl, and hydroxy. In some embodiments, each R1is independently selected from CH3, -F, -Cl, -Br, -I, and hydroxy. In some embodiments, each R1is independently halogen. In some embodiments, each R1is independently selected from -F, -Cl,-Br, and -I. In some embodiments, at least one R1is -F. In some embodiments, at least one R1is -Cl. In some embodiments, one R1is -F and the other R1is -Cl. In some embodiments, each R1is –F. In some embodiments, each R1is –Cl. In some embodiments, each R1is C1-6alkyl.

[0205] In some embodiments of Formulas (V), (V-a), (V-b), or (V-c), R3is hydrogen or methyl. In some embodiments, R3is hydrogen. In some embodiments, R3is methyl.

[0206] In some embodiments of Formulas (V), (V-a), (V-b), or (V-c), each R2is independently optionally substituted aryl or cyano.

[0207] In some embodiments, the compound of Formula (I) is a compound of Formula (VI):or a pharmaceutically acceptable salt thereof, wherein R1, R2, R3, and p are as defined forFormula (I).

[0208] In some embodiments, the compound of Formula (I) is a compound of Formula (VI-a), Formula (VI-b), or Formula (VI-c):or a pharmaceutically acceptable salt thereof, wherein R1, R2, and R3are as defined for Formula (I).

[0209] In some embodiments of Formulas (VI), (VI-a), (VI-b), or (VI-c), each R1is independently selected from the group consisting of halogen, C1-6alkyl, and hydroxy. In some embodiments, each R1is independently selected from CH3, -F, -Cl, -Br, -I, and hydroxy. In some embodiments, each R1is independently halogen. In some embodiments, each R1is independently selected from -F, -Cl, -Br, and -I. In some embodiments, at least one R1is -F. In some embodiments, at least one R1is -Cl. In some embodiments, one R1is -F and the other R1is -Cl. In some embodiments, each R1is –F. In some embodiments, each R1is –Cl. In some embodiments, each R1is C1-6alkyl.

[0210] In some embodiments of Formulas (VI), (VI-a), (VI-b), or (VI-c), R3is hydrogen or methyl. In some embodiments, R3is hydrogen. In some embodiments, R3is methyl.

[0211] In some embodiments of Formulas (VI), (VI-a), (VI-b), or (VI-c), R2is optionally substituted aryl or cyano.

[0212] In some embodiments, the compound of Formula (I) is a compound of Formula (VII):or a pharmaceutically acceptable salt thereof, wherein R1, R2, R3, and p are as defined forFormula (I).

[0213] In some embodiments, the compound of Formula (I) is a compound of Formula (VII-a), Formula (VII-b), or Formula (VII-c):,or a pharmaceutically acceptable salt thereof, wherein R1, R2, and R3are as defined for Formula (I).

[0214] In some embodiments of Formulas (VII), (VII-a), (VII-b), or (VII-c), each R1is independently selected from the group consisting of halogen, C1-6alkyl, and hydroxy. In some embodiments, each R1is independently selected from CH3, -F, -Cl, -Br, -I, and hydroxy. In some embodiments, each R1is independently halogen. In some embodiments, each R1is independently selected from -F, -Cl, -Br, and -I. In some embodiments, at least one R1is -F. In some embodiments, at least one R1is -Cl. In some embodiments, one R1is -F and the other R1is -Cl. In some embodiments, each R1is –F. In some embodiments, each R1is –Cl. In some embodiments, each R1is C1-6alkyl.

[0215] In some embodiments of Formulas (VII), (VII-a), (VII-b), or (VII-c), R3is hydrogen or methyl. In some embodiments, R3is hydrogen. In some embodiments, R3is methyl.

[0216] In some embodiments of Formulas (VII), (VII-a), (VII-b), or (VII-c), R2is O(R7) or C(O)N(R8)(R9), wherein R7is optionally substituted aryl, and R8and R9together with the nitrogen atom to which they are attached form a 3 to 10 membered heterocycloalkyl optionally substituted with one or more groups each independently selected from the group consisting of halogen, cyano, nitro, oxo, C1-6alkyl, C1-6haloalkyl, and C1-6haloalkoxy. In one particular embodiment, the 3 to 10 membered heterocycloalkyl is substituted with C1-6haloalkyl.

[0217] In some embodiments, the compound of Formula (I) is a compound of Formula (VIII):or a pharmaceutically acceptable salt thereof, wherein R1, R2, R3, and p are as defined forFormula (I).

[0218] In some embodiments, the compound of Formula (I) is a compound of Formula (VIII-a), Formula (VIII-b), or Formula (VIII-c):or a pharmaceutically acceptable salt thereof, wherein R1, R2, and R3are as defined for Formula (I).

[0219] In some embodiments of Formulas (VIII), (VIII-a), (VIII-b), or (VIII-c), each R1is independently selected from the group consisting of halogen, C1-6alkyl, and hydroxy. In some embodiments, each R1is independently selected from CH3, -F, -Cl, -Br, -I, and hydroxy.In some embodiments, each R1is independently halogen. In some embodiments, each R1is independently selected from -F, -Cl, -Br, and -I. In some embodiments, at least one R1is -F. In some embodiments, at least one R1is -Cl. In some embodiments, one R1is -F and the other R1is -Cl. In some embodiments, each R1is –F. In some embodiments, each R1is –Cl. In some embodiments, each R1is C1-6alkyl.

[0220] In some embodiments of Formulas (VIII), (VIII-a), (VIII-b), or (VIII-c), R3is hydrogen or methyl. In some embodiments, R3is hydrogen. In some embodiments, R3is methyl.

[0221] In some embodiments of Formulas (VIII), (VIII-a), (VIII-b), or (VIII-c), R2is optionally substituted aryl, optionally substituted 5-12 membered heteroaryl, optionally substituted C2-6alkynyl or O(R7), where R7is optionally substituted aryl.

[0222] In some embodiments, the compound of Formula (I) is a compound of Formula (IX):,or a pharmaceutically acceptable salt thereof, wherein R1, R2, R3, and p are as defined forFormula (I).

[0223] In some embodiments, the compound of Formula (I) is a compound of Formula (IX-a), Formula (IX-b), or Formula (IX-c):,or a pharmaceutically acceptable salt thereof, wherein R1, R2, and R3are as defined for Formula (I).

[0224] In some embodiments of Formulas (IX), (IX-a), (IX-b), or (IX-c), each R1is independently selected from the group consisting of halogen, C1-6alkyl, and hydroxy. In some embodiments, each R1is independently selected from CH3, -F, -Cl, -Br, -I, and hydroxy. In some embodiments, each R1is independently halogen. In some embodiments, at least one R1is -F. In some embodiments, at least one R1is -Cl. In some embodiments, each R1is independently selected from –F, -Cl, -Br and -I. In some embodiments, one R1is -F and the other R1is -Cl. In some embodiments, each R1is –F. In some embodiments, each R1is –Cl. In some embodiments, each R1is C1-6alkyl.

[0225] In some embodiments of Formulas (IX), (IX-a), (IX-b), or (IX-c), R3is hydrogen or methyl. In some embodiments, R3is hydrogen. In some embodiments, R3is methyl.

[0226] In some embodiments of Formulas (IX), (IX-a), (IX-b), or (IX-c), R2is optionally substituted aryl.

[0227] In some embodiments, the compound of Formula (I) is a compound of Formula (X):or a pharmaceutically acceptable salt thereof, wherein R1, R2, R3, and p are as defined forFormula (I).

[0228] In some embodiments, the compound of Formula (I) is a compound of Formula (X-a), Formula (X-b), or Formula (X-c):or a pharmaceutically acceptable salt thereof, wherein R1, R2, and R3are as defined for Formula (I).

[0229] In some embodiments of Formulas (X), (X-a), (X-b), or (X-c), each R1is independently selected from the group consisting of halogen, C1-6alkyl, and hydroxy. In some embodiments, each R1is independently selected from CH3, -F, -Cl, -Br, -I, and hydroxy. In some embodiments, each R1is independently halogen. In some embodiments, each R1is independently selected from -F, -Cl, -Br, and -I. In some embodiments, at least one R1is -F. In some embodiments, at least one R1is -Cl. In some embodiments, one R1is -F and the otherR1is -Cl. In some embodiments, each R1is –F. In some embodiments, each R1is –Cl. In some embodiments, each R1is C1-6alkyl.

[0230] In some embodiments of Formulas (X), (X-a), (X-b), or (X-c), R3is hydrogen or methyl. In some embodiments, R3is hydrogen. In some embodiments, R3is methyl.

[0231] In some embodiments of Formulas (X), (X-a), (X-b), or (X-c), each R2is independently halogen, cyano, optionally substituted C3-8cycloalkyl, optionally substituted aryl.

[0232] In some embodiments, the compound of Formula (I) is a compound of Formula (XI):or a pharmaceutically acceptable salt thereof, wherein R1, R2, R3, and p are as defined forFormula (I).

[0233] In some embodiments, the compound of Formula (I) is a compound of Formula (XI-a), Formula (XI-b), or Formula (XI-c):or a pharmaceutically acceptable salt thereof, wherein R1, R2, and R3are as defined for Formula (I).

[0234] In some embodiments of Formulas (XI), (XI-a), (XI-b), or (XI-c), each R1is independently selected from the group consisting of halogen, C1-6alkyl, and hydroxy. In some embodiments, each R1is independently selected from CH3, -F, -Cl, -Br, -I, and hydroxy. In some embodiments, each R1is independently halogen. In some embodiments, each R1is independently selected from -F, -Cl, -Br, and -I. In some embodiments, at least one R1is -F. In some embodiments, at least one R1is -Cl. In some embodiments, one R1is -F and the other R1is -Cl. In some embodiments, each R1is –F. In some embodiments, each R1is –Cl. In some embodiments, each R1is C1-6alkyl.

[0235] In some embodiments of Formulas (XI), (XI-a), (XI-b), or (XI-c), R3is hydrogen or methyl. In some embodiments, R3is hydrogen. In some embodiments, R3is methyl.

[0236] In some embodiments of Formulas (XI), (XI-a), (XI-b), or (XI-c), R2is optionally substituted aryl.

[0237] In some embodiments, the compound of Formula (I) is a compound of Formula (XII):or a pharmaceutically acceptable salt thereof, wherein R1, R2, R3, and p are as defined for Formula (I).

[0238] In some embodiments, the compound of Formula (I) is a compound of Formula (XII-a), Formula (XII-b), or Formula (XII-c):or a pharmaceutically acceptable salt thereof, wherein R1, R2, and R3are as defined for Formula (I).

[0239] In some embodiments of Formulas (XII), (XII-a), (XII-b), or (XII-c), each R1is independently selected from the group consisting of halogen, C1-6alkyl, and hydroxy. In some embodiments, each R1is independently selected from CH3, -F, -Cl, -Br, -I, and hydroxy. In some embodiments, each R1is independently halogen. In some embodiments, each R1is independently selected from -F, -Cl, -Br, and -I. In some embodiments, at least one R1is -F. In some embodiments, at least one R1is -Cl. In some embodiments, one R1is -F and the other R1is -Cl. In some embodiments, each R1is –F. In some embodiments, each R1is –Cl. In some embodiments, each R1is C1-6alkyl.

[0240] In some embodiments of Formulas (XII), (XII-a), (XII-b), or (XII-c), R3is hydrogen or methyl. In some embodiments, R3is hydrogen. In some embodiments, R3is methyl.

[0241] In some embodiments of Formulas (XII), (XII-a), (XII-b), or (XII-c), R2is optionally substituted C3-8cycloalkyl or optionally substituted aryl.

[0242] In some embodiments, the compound of Formula (I) is a compound of Formula (XIII):or a pharmaceutically acceptable salt thereof, wherein R1, R2, R3, R4, and p are as defined for Formula (I).

[0243] In some embodiments, the compound of Formula (I) is a compound of Formula (XIII-a), Formula (XIII-b), or Formula (XIII-c):or a pharmaceutically acceptable salt thereof, wherein R1, R2, R3, and R4are as defined for Formula (I).

[0244] In some embodiments of Formulas (XIII), (XIII-a), (XIII-b), or (XIII-c), each R1is independently selected from the group consisting of halogen, C1-6alkyl, and hydroxy. In some embodiments, each R1is independently selected from CH3, -F, -Cl, -Br, -I, and hydroxy. In some embodiments, each R1is independently halogen. In some embodiments, each R1is independently selected from -F, -Cl, -Br, and -I. In some embodiments, at least one R1is -F. In some embodiments, at least one R1is -Cl. In some embodiments, one R1is -F and the other R1is -Cl. In some embodiments, each R1is –F. In some embodiments, each R1is –Cl. In some embodiments, each R1is C1-6alkyl.

[0245] In some embodiments of Formulas (XIII), (XIII-a), (XIII-b), or (XIII-c), R3is hydrogen or methyl. In some embodiments, R3is hydrogen. In some embodiments, R3is methyl.

[0246] In some embodiments of Formulas (XIII), (XIII-a), (XIII-b), or (XIII-c), R4is methyl. In some embodiments, R4is hydrogen.

[0247] In some embodiments of Formulas (XIII), (XIII-a), (XIII-b), or (XIII-c), R2is optionally substituted aryl.

[0248] In some embodiments, the compound of Formula (I) is a compound of Formula (XIV):or a pharmaceutically acceptable salt thereof, wherein R1, R2, R3, and p are as defined for Formula (I).

[0249] In some embodiments, the compound of Formula (I) is a compound of Formula (XIV-a), Formula (XIV-b), or Formula (XIV-c):or a pharmaceutically acceptable salt thereof, wherein R1, R2, and R3are as defined for Formula (I).

[0250] In some embodiments of Formulas (XIV), (XIV-a), (XIV-b), or (XIV-c), each R1is independently selected from the group consisting of halogen, C1-6alkyl, and hydroxy. In some embodiments, each R1is independently selected from CH3, -F, -Cl, -Br, -I, and hydroxy. In some embodiments, each R1is independently halogen. In some embodiments, each R1is independently selected from -F, -Cl, -Br, and -I. In some embodiments, at least one R1is -F. In some embodiments, at least one R1is -Cl. In some embodiments, one R1is -F and the other R1is -Cl. In some embodiments, each R1is –F. In some embodiments, each R1is –Cl. In some embodiments, each R1is C1-6alkyl.

[0251] In some embodiments of Formulas (XIV), (XIV-a), (XIV-b), or (XIV-c), R3is hydrogen or methyl. In some embodiments, R3is hydrogen. In some embodiments, R3is methyl.

[0252] In some embodiments of Formulas (XIV), (XIV-a), (XIV-b), or (XIV-c), R2is optionally substituted aryl.

[0253] In some embodiments, the compound of Formula (I) is a compound of Formula (XV):or a pharmaceutically acceptable salt thereof, wherein R1, R2, R3, and p are as defined forFormula (I).

[0254] In some embodiments, the compound of Formula (I) is a compound of Formula (XV-a), Formula (XV-b), or Formula (XV-c):or a pharmaceutically acceptable salt thereof, wherein R1, R2, and R3are as defined for Formula (I).

[0255] In some embodiments of Formulas (XV), (XV-a), (XV-b), or (XV-c), each R1is independently selected from the group consisting of halogen, C1-6alkyl, and hydroxy. In some embodiments, each R1is independently selected from CH3, -F, -Cl, -Br, -I, and hydroxy. In some embodiments, each R1is independently halogen. In some embodiments, each R1is independently selected from -F, -Cl, -Br, and -I. In some embodiments, at least one R1is -F. In some embodiments, at least one R1is -Cl. In some embodiments, one R1is -F and the otherR1is -Cl. In some embodiments, each R1is –F. In some embodiments, each R1is –Cl. In some embodiments, each R1is C1-6alkyl.

[0256] In some embodiments of Formulas (XV), (XV-a), (XV-b), or (XV-c), R3is hydrogen or methyl. In some embodiments, R3is hydrogen. In some embodiments, R3is methyl.

[0257] In some embodiments of Formulas (XV), (XV-a), (XV-b), or (XV-c), each R2is independently optionally substituted aryl, cyano, or C1-6haloalkyl.

[0258] In some embodiments, the compound of Formula (I) is a compound of Formula (XVI):or a pharmaceutically acceptable salt thereof, wherein R1, R2, R3, and p are as defined for Formula (I).

[0259] In some embodiments, the compound of Formula (I) is a compound of Formula (XVI-a), Formula (XVI-b), or Formula (XVI-c):or a pharmaceutically acceptable salt thereof, wherein R1, R2, and R3are as defined for Formula (I).

[0260] In some embodiments of Formulas (XVI), (XVI-a), (XVI-b), or (XVI-c), each R1is independently selected from the group consisting of halogen, C1-6alkyl, and hydroxy. In some embodiments, each R1is independently selected from CH3, -F, -Cl, -Br, -I, and hydroxy. In some embodiments, each R1is independently halogen. In some embodiments, each R1is independently selected from -F, -Cl, -Br, and -I. In some embodiments, at least one R1is -F. In some embodiments, at least one R1is -Cl. In some embodiments, one R1is -F and the other R1is -Cl. In some embodiments, each R1is –F. In some embodiments, each R1is –Cl. In some embodiments, each R1is C1-6alkyl.

[0261] In some embodiments of Formulas (XVI), (XVI-a), (XVI-b), or (XVI-c), R3is hydrogen or methyl. In some embodiments, R3is hydrogen. In some embodiments, R3is methyl.

[0262] In some embodiments of Formulas (XVI), (XVI-a), (XVI-b), or (XVI-c), R2is optionally substituted aryl.

[0263] In some embodiments of Formulas (XVII), (XVII-a), (XVII-b), or (XVII-c), R3is hydrogen or methyl. In some embodiments, R3is hydrogen. In some embodiments, R3is methyl.

[0264] The compounds described herein (e.g., compounds of Formula (I)) encompass both stereoisomers at the carbon in the glutarimide moiety as indicated by the asterisk in, i.e., including both (R) and (S) stereoisomers at the chiral carbon indicated by the asterisk.

[0265] In some embodiments, the compounds provided herein can effectively degrade CDK2 with desirable selectivity over related targets such as GSPT1 and CDK1. In some embodiments, the compounds provided herein show degradation selectivity over GSPT1. In some embodiments, the compounds provided herein show degradation selectivity over CDK1. In some embodiments, the compounds provided herein show degradation selectivity over both GSPT1 and CDK1. In some embodiments, the compounds provided herein also have desirable pharmacokinetic properties, such as desirable bioavailability, Cmax, tmax, AUC (area under the curve), elimination half-life (t1 / 2), total plasma clearance (CL), and volume of distribution (VD).

[0266] In some embodiments, the compounds disclosed herein (or a pharmaceutically acceptable salt thereof) are characterized by IC50values measured at 6 hours by CDK2 HiBiT assay of less than 10 µM, less than 5 µM, less than 1 µM, less than 0.5 µM, less than 0.25 µM, less than 0.1 µM, less than 0.075 µM, less than 0.05 µM, or less than 0.025 µM, and any range constructed therefrom, such as from about 10 µM to about 0.025 µM, from about 1 µM to about 0.025 µM, or from about 0.5 µM to about 0.025 µM,. In some such embodiments, 6 hours IC50values may be less than 0.5 µM, less than 0.25 µM, less than 0.1 µM, less than 0.075 µM, less than 0.05 µM, or less than 0.025 µM. Dmaxvalues measured at 6 hours by CDK2 HiBiT assay can be at least 25%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, or at least 70%, and any range constructed therefrom, such as from about 25% to about 70%, or from about 45% to about 70%. In some such embodiments, 6 hour Dmaxvalues can be at least 50%, at least 55%, at least 60%, at least 65%, or at least 70%.

[0267] In some embodiments, compounds of formula (I) (or a pharmaceutically acceptable salt thereof) are characterized by IC50 values measured at 18 hours by CDK2 HiBiT assay of less than 10 µM, less than 5 µM, less than 1 µM, less than 0.5 µM, less than 0.25 µM, less than 0.1 µM, less than 0.075 µM, or less than 0.05 µM, and any range constructed therefrom, such as from about 10 µM to about 0.025 µM, from about 1 µM to about 0.025 µM, or from about 0.5 µM to about 0.025 µM. In some such embodiments, 18 hour IC50values may be less than 0.5 µM, less than 0.25 µM, less than 0.1 µM, less than 0.075 µM, or less than 0.05 µM. Dmax values measured at 18 hours by CDK2 HiBiT assay can be at least 25%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, or at least 60%, and any range constructed therefrom, such as from about 25% to about 60%, or from about 40% to about 60%. In some such embodiments, 18 hour Dmax values can be at least 50%, at least 55%, or at least 60%.

[0268] In some embodiments, compounds of Formula (I) (or a pharmaceutically acceptable salt thereof) are characterized by a CDK2 DC50 of less than 500 nM, less than 400 nM, less than 300 nM, less than 200 nM, less than 100 nM, or less than 50 nM when measured by HiBiT assay.

[0269] In some embodiments, the HiBiT assay is conducted in HEK293 cells.

[0270] In some embodiments, the compound of Formula (I) is a compound selected from the group consisting of the compounds in Table 1, or a pharmaceutically acceptable salt thereof. Table 1

[0271] In some embodiments, the compound of Formula (I) is selected from the group consisting of Compounds 155, 173, 189, 214, 229, 231, 252, 259, 265, 270, 271, 274, 323, 326, 327, 301, 306, 307, 309, 310, 311, 316, 318, 344, 349, 368, 369, 372, 388, 391, and 397. In some embodiments, the compound of Formula (I) is selected from the group consisting of Compounds 189, 214, 229, 231, 252, 259, 270, 271, 274, 323, 326, 327, 301, 306, 307, 309, 310, 311, 316, 318, 372, and 388. Pharmaceutical Compositions

[0272] In some embodiments, pharmaceutical compositions of compound Formula (I) are provided. In such embodiments, the pharmaceutical compositions comprise a compound described herein (e.g., a compound Formula (I)) or a pharmaceutically acceptable salt thereof in combination with at least one pharmaceutically acceptable excipient.

[0273] The pharmaceutical compositions of the present disclosure can take the form of tablets, pills, capsules, suppositories, powders, enterically coated or other protected formulations (e.g., binding on ion-exchange resins or packaging in lipid-protein vesicles), sustained release formulations, solutions, suspensions, elixirs, aerosols, and the like. In the practice of methods of the present disclosure, a therapeutically effective amount of any one of the compounds of this disclosure or a combination of any of the compounds of this disclosure or a pharmaceutically acceptable salt thereof, is administered via any of the usual and acceptable methods known in the art. For instance, compounds or compositions of the present disclosure can be administered orally (e.g., buccal cavity), sublingually, parenterally (e.g., intramuscularly, intravenously, or subcutaneously), rectally (e.g., by suppositories or washings), transdermally (e.g., skin electroporation) or by inhalation (e.g., by aerosol), and in the form of solid, liquid or gaseous dosages, including tablets and suspensions. The administration can be conducted in a single unit dosage form with continuous therapy or in a single dose therapy ad libitum.

[0274] Suitable excipients are known to those skilled in the art and are described in detail in, e.g.: (i) Ansel, Howard C., et al., Ansel’s Pharmaceutical Dosage Forms and Drug Delivery Systems. Philadelphia: Lippincott, Williams & Wilkins, 2004; (ii) Gennaro, Alfonso R., et al. Remington: The Science and Practice of Pharmacy. Philadelphia: Lippincott, Williams & Wilkins, 2000; and (iii) Rowe, Raymond C. Handbook of Pharmaceutical Excipients. Chicago, Pharmaceutical Press, 2005. Examples of pharmaceutically acceptable excipients include, without limitation, carriers, diluents, adjuvants, and vehicles. Non-limiting examples include, buffers, stabilizing agents, surfactants, wetting agents, lubricating agents, emulsifiers, suspending agents, preservatives, antioxidants, opaquing agents, glidants, processing aids, colorants, sweeteners, perfuming agents, and flavoring agents.

[0275] The compositions comprising compound Formula (I) may be formulated as a pharmaceutical composition in accordance with standard pharmaceutical practice. A typical formulation is prepared by mixing a compound of the present disclosure and one or more excipients.

[0276] When a pharmaceutical composition according to the present disclosure is prepared as a formulation for oral administration, the carrier and / or diluent to be used may include, for instance and without limitation: cellulose and cellulose derivatives (e.g., microcrystalline cellulose); calcium silicate; corn starch; saccharides (e.g., lactose, sucrose, dextrose, mannitol, and combinations thereof); calcium phosphate, stearic acid, magnesium stearate, calcium stearate, gelatin, talc, surfactant, suspending agents, emulsifying agents, diluents, and combinations thereof. Formulations for oral administration may also include, for instance and without limitation: polymers (for instance hydrophilic polymers such as polyvinylpyrrolidone); antioxidants; preservatives; wetting agents; lubricating agents; glidants; processing aids; granulating agents; dispersing agents; colorants; and flavoring agents.

[0277] Compressed tablets can be prepared in a suitable tableting device by compressing the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with or more of a carrier, binder, lubricant, inert diluent, preservative, surface active, dispersing agent, and an inert liquid diluent. The tablets can optionally be coated or scored. Tablets may be coated by known techniques including microencapsulation to delay disintegration and adsorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay coating material such as glyceryl monostearate or glyceryl distearate alone or with a wax can be employed and optionally are formulated so as to provide slow or controlled release of the active ingredient therefrom.

[0278] When the pharmaceutical composition according to the present disclosure is prepared as a formulation for injections, the carrier to be used may include, for instance and without limitation, water, saline, an aqueous glucose solution, an aqueous sugar-like solution, alcohols, glycols (e.g., polyethylene glycol 400), ethers, oils, fatty acids, fatty acid esters, glycerides, surfactants, suspending agents, emulsifying agents, and combinations thereof.

[0279] The pharmaceutical compositions may further comprise pharmaceutical additives such as preservatives, stabilizing agents, wetting or emulsifying agents, salts for adjusting osmotic pressure, buffers and the like.

[0280] In some embodiments, pharmaceutical compositions comprising a compound described herein (e.g., a compound of Formula (I)), or a pharmaceutically acceptable salt thereof, further comprise an additional therapeutic agent. Combination Therapy

[0281] The compounds of the present disclosure may be administered in combination with other additional therapeutic agents, such as for instance and without limitation, standard of care agents appropriate for a particular cancer.

[0282] The compounds as described herein or pharmaceutically acceptable salts thereof may be employed alone or in combination with other agents for treatment. For example, the second agent of the pharmaceutical combination formulation or dosing regimen may have complementary activities to the compound as described herein such that they do not adversely affect each other. The compounds may be administered together in a unitary pharmaceutical composition or separately. In one embodiment a compound or a pharmaceutically acceptable salt can be co-administered with a chemotherapeutic agent to treat proliferative diseases and cancer.

[0283] Those additional agents may be administered separately from the compound or pharmaceutically acceptable salt thereof described herein, as part of a multiple dosage regimen. Alternatively, those agents may be part of a single dosage form, mixed together with a compound as described herein in a single composition. If administered as part of a multiple dosage regime, the two active agents may be submitted simultaneously, sequentially or within a period of time from one another normally within five hours from one another.

[0284] The amount of both an inventive compound and additional therapeutic agent (in those compositions which comprise an additional therapeutic agent as described above) thatmay be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. In some embodiments, compositions as described herein are formulated such that a dosage of between 0.01 - 100 mg / kg body weight / day of an inventive can be administered.

[0285] Typically, any agent that has activity against a disease or condition being treated may be co-administered. Examples of such agents can be found in Cancer Principles and Practice of Oncology by V.T. Devita and S. Hellman (editors), 6thedition (February 15, 2001), Lippincott Williams & Wilkins Publishers. A person of ordinary skill in the art would be able to discern which combinations of agents would be useful based on the particular characteristics of the drugs and the disease involved.

[0286] In some embodiments, the treatment method includes the co-administration of a compound as described herein or a pharmaceutically acceptable salt thereof and at least one chemotherapeutic agent. The term “chemotherapeutic agent” is an agent useful in the treatment of cancer, and includes, but is not limited to, cytotoxic agents such as radioactive isotopes (e.g., At211, I131, I125, Y90, Re186, Re188, Sm153, Bi212, P32, Pb212and radioactive isotopes of Lu); growth inhibitory agents; anti- microtubule agents; platinum analogs; topoisomerase II inhibitors; anti- metabolites; topoisomerase I inhibitors; hormones and hormonal analogues; signal transduction pathway inhibitors; non-receptor tyrosine kinase angiogenesis inhibitors; immunotherapeutic agents; proapoptotic agents; cell cycle signaling inhibitors; nitrogen mustards; alkylating agents; toxoids or taxanes; aromatase inhibitors; chromoprotein enediyne antibiotic chromophores; mitomycins; anti-hormonal agents; anti-androgens; protein kinase inhibitors; lipid kinase inhibitors; antisense oligonucleotides; tyrosine kinase inhibitors; Raf-1 inhibitors; EGFR inhibitors; camptothecins; anthracycline antibiotics; nucleoside metabolic inhibitors, and other CDK inhibitors. Methods of Treatment

[0287] In some embodiments, the compounds of the present disclosure may be administered as single agents. In some embodiments, the compounds of the present disclosure may be administered in combination with at least one additional therapeutic agent.

[0288] In one aspect, provided herein are methods of treating a disease, disorder or condition in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound described herein (e.g., a compound of Formula(I)), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described herein.

[0289] In another aspect, provided herein are methods of treating a CDK2-mediated disorder in a subject in need thereof, the method comprising administering to the human a therapeutically effective amount of a compound described herein (e.g., a compound of Formula (I)), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described herein.

[0290] In yet another aspect, provided herein are methods of degrading CDK2 in a subject, the method comprising administering to the subject a therapeutically effective amount of a compound described herein (e.g., a compound of Formula (I)) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described herein.

[0291] In yet another aspect, provided herein are methods of selectively reducing the level of CDK2 in a subject, the method comprising administering to the subject a therapeutically effective amount of a compound described herein (e.g., a compound of Formula (I)) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described herein, wherein the level of GSPT1 in the subject is not reduced.

[0292] In yet another aspect, provided herein are uses of a compound of Formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described herein, in the manufacture of a medicament for the treatment of a disease, disorder or condition in a subject in need thereof.

[0293] In yet another aspect, provided herein are uses of a compound of Formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described herein, in the manufacture of a medicament for the treatment of a CDK2-mediated disorder in a subject in need thereof.

[0294] In yet another aspect, provided herein are uses of a compound of Formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described herein, for the manufacture of a medicament for degrading CDK2 in a subject.

[0295] In yet another aspect, provided herein are uses of a compound of Formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described herein, for the manufacture of a medicament for selectively reducing the level of CDK2 in a subject, wherein the level of GSPT1 in the subject is not reduced.

[0296] In yet another aspect, provided herein are uses of a compound of Formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described herein, for the manufacture of a medicament for selectively reducing the level of CDK2 in a subject, wherein the level of CDK1 in the subject is not reduced.

[0297] In yet another aspect, provided herein are compounds of Formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described herein, for use in the treatment of a disease, disorder or condition in a subject in need thereof.

[0298] In yet another aspect, provided herein are compounds of Formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described herein, for use in the treatment of a CDK2-mediated disorder in a subject in need thereof.

[0299] In yet another aspect, provided herein are compounds of Formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described herein, for use in degrading CDK2 in a subject.

[0300] In yet another aspect, provided herein are compounds of Formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described herein, for use in selectively reducing the level of CDK2 in a subject, wherein the level of GSPT1 in the subject is not reduced.

[0301] In some embodiments, the disease, disorder or condition is cancer. In some embodiments, the cancer is selected from bladder cancer; bone cancer; brain cancer; breast cancer; cervical cancer; colorectal cancer; endometrial cancer; prostate cancer; esophagus cancer; eye cancer; head cancer; kidney cancer; liver cancer; lymph node cancer; lung cancer; upper aerodigestive tract cancer; oral cancer; oropharynx cancer; larynx cancer; hypopharynx cancer; salivary gland cancer; neck cancer; thyroid cancer; ovarian cancer; pancreatic cancer; prostate cancer; rectal cancer; skin cancer; stomach cancer; testicular cancer; throat cancer; uterine cancer; neuroblastoma; meningioma; hemangiopericytoma; leiomyoma; leukemia; lymphoma; and myeloma.

[0302] In some embodiments, the cancer is selected from: hormone-receptor positive breast cancer; estrogen receptor positive breast cancer; triple negative breast cancer; multiple brain metastase; glioblastoma multiforms; glioblastoma; brain stem glioma; malignant glioma; anaplastic astrocytoma; anaplastic oligodendroglioma; neuroendocrine cancer; metastatic hepatocellular carcinoma; Kaposi's sarcoma; malignant melanoma; malignant mesothelioma; malignant pleural effusion mesothelioma syndrome; peritoneal carcinoma; papillary serouscarcinoma; gynecologic sarcoma; soft tissue sarcoma; scleroderma; cutaneous vasculitis; Langerhans cell histiocytosis; leiomyosarcoma; hormone refractory prostate cancer; resected high-risk soft tissue sarcoma; unresectable hepatocellular carcinoma; fallopian tube cancer; androgen independent prostate cancer; androgen dependent stage IV non-metastatic prostate cancer; hormone-insensitive prostate cancer; papillary thyroid carcinoma; follicular thyroid carcinoma; medullary thyroid carcinoma; diffuse large B-cell lymphoma; B-cell immunoblastic lymphoma; small non-cleaved cell lymphoma; human lymphotropic virus-type 1 leukemia / lymphoma; adult T-cell lymphoma; peripheral T-cell lymphoma; cutaneous T-cell lymphoma; mantle cell lymphoma; Hodgkin’s lymphoma; non-Hodgkin’s lymphoma; AIDS- related lymphoma; follicular lymphoma; small lymphocytic lymphoma; T-cell / histiocyte rich large B-cell lymphoma; transformed lymphoma, primary mediastinal (thymic) large B-cell lymphoma; splenic marginal zone lymphoma; Richter's transformation; nodal marginal zone lymphoma; ALK-positive large B-cell lymphoma; indolent lymphoma; acute myelogenous leukemia; acute lymphocytic leukemia; adult T-cell leukemia; chronic lymphocytic leukemia; small lymphocytic lymphoma; hairy cell leukemia; myelodysplasia; myeloproliferative disorders; chronic myelogenous leukemia; acute monocytic leukemia; myelodysplastic syndrome; human lymphotropic virus- type 1 leukemia; mastocytosis, B-cell acute lymphoblastic leukemia; and multiple myeloma.

[0303] Exemplary cancers include, but are not limited to, leukemia (e.g., acute myelocytic leukemia), bladder cancer, brain cancer, breast cancer (e.g., hormone receptor positive breast cancer, triple negative breast cancer, HER2+ breast cancer), cervical cancer, colorectal cancer (e.g., including colon cancer and / or rectal cancer), endometrial cancer, esophageal cancer, gastric cancer (e.g. stomach adenocarcinoma), kidney cancer (e.g., renal cell carcinoma), liver cancer (e.g., hepatocellular cancer), lung cancer (e.g., non-small cell lung cancer, small cell lung cancer), neuroblastoma, ovarian cancer (e.g., serous ovarian cancer), prostate cancer, skin cancer (e.g., melanoma), thyroid cancer, and uterine cancer (e.g., uterine carcinosarcoma).

[0304] In certain embodiments, the cancer is ovarian cancer, gastric cancer, uterine cancer, esophageal cancer, lung cancer, or breast cancer. In certain embodiments, the cancer is ovarian cancer. In certain embodiments, the cancer is gastric cancer. In certain embodiments, the cancer is uterine cancer. In certain embodiments, the cancer is esophageal cancer. In certain embodiments, the cancer is lung cancer.

[0305] In certain embodiments, the cancer is breast cancer. In certain embodiments, the breast cancer is HR+, and the subject in need thereof has progressed on CDK4 / 6 inhibitors. In certain embodiments, the breast cancer is HER2+ and the subject has progressed on trastuzumab.

[0306] In certain embodiments, the cancer is lung cancer. In certain embodiments, the cancer is non-small cell lung cancer (NSCLC). In certain embodiments, the cancer is NSCLC and the subject has progressed on an epidermal growth factor receptor (EGFR) inhibitor.

[0307] In certain embodiments, treatment may be administered after one or more symptoms have developed. Treatment may also be continued after symptoms have resolved, for example to prevent or delay their recurrence.

[0308] Administration of the compounds of the disclosure may be affected by any method that enables delivery of the compounds to the site of action. These methods include oral routes, intraduodenal routes, parenteral injection (including intravenous, subcutaneous, intramuscular, intravascular or infusion), topical, and rectal administration.

[0309] The dosage regimen may be adjusted to provide the optimum desired response. For instance, a single dose may be administered, several doses may be administered over time, or the dose may be proportionally reduced or increased as indicated by the exigencies of the therapeutic situation. Each unit dose may contain a predetermined quantity of a compound of Formula (I) or a pharmaceutically acceptable salt thereof calculated to produce the desired therapeutic effect in association with the pharmaceutical carrier. The specification for the dosage unit forms of the present disclosure are influenced by (i) the unique characteristics of the particular active compound formula, (ii) and the particular therapeutic or prophylactic effect to be achieved, and (iii) pharmacokinetic factors associated with the drug and associated excipients, and the disease to be treated.

[0310] Thus, the skilled artisan would appreciate, based upon the disclosure provided herein, that the dose and dosing regimen may be adjusted in accordance with methods well- known in the therapeutic arts. That is, the maximum tolerable dose can be readily established, and the effective amount providing a detectable therapeutic benefit to a patient may also be determined. Dosage values may vary with the type and severity of the condition to be alleviated and may include single or multiple doses. It is to be further understood that for any particular subject, specific dosage regimens should be adjusted over time according to the individual needand the professional judgment of the person administering or supervising the administration of the compositions, and that dosage ranges set forth herein are exemplary only and are not intended to limit the scope or practice of the claimed composition. For example, doses may be adjusted based on pharmacokinetic or pharmacodynamic parameters, which may include clinical effects such as toxic effects and / or laboratory values. Thus, the present disclosure encompasses intra-patient dose-escalation as determined by the skilled artisan. Determining appropriate dosages and regimens for administration of the chemotherapeutic agent are well- known in the relevant art and would be understood to be encompassed by the skilled artisan once provided the teachings disclosed herein.

[0311] The amount of the compound of the disclosure administered will be dependent on the subject being treated, the severity of the disorder or condition, the rate of administration, the disposition of the compound and the discretion of the prescribing physician. However, an effective dosage is in the range of about 0.001 to about 100 mg per kg body weight per day, preferably about 1 to about 35 mg / kg / day, in single or divided doses. For a 70 kg human, this would amount to about 0.05 to about 7 g / day, preferably about 0.1 to about 2.5 g / day. In some instances, dosage levels below the lower limit of the aforesaid range may be more than adequate, while in other cases still larger doses may be employed without causing any harmful side effect, for instance by dividing such larger doses into several small doses for administration throughout the day.

[0312] While certain dose and administration regimens are disclosed herein, said disclosure does not limit the dose and administration regimen that may be provided to a patient in practicing the present disclosure.

[0313] In some embodiments, a method of degrading CDK2 in a subject suffering from cancer is provided. Such a method comprises administering to the subject an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of Formula (I) as described elsewhere herein.

[0314] In some embodiments, a method of cancer treatment in a subject suffering from cancer is provided. Such a method comprises administering to the subject an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of Formula (I) as described elsewhere herein.

[0315] In some embodiments, a method of treating a solid tumor is provided. Such a method comprises administering to the subject an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of Formula (I) as described elsewhere herein.

[0316] In some embodiments, a method of treating a liquid tumor is provided. Such a method comprises administering to the subject an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of Formula (I) as described elsewhere herein. Examples Intermediate 1 (Approach 1) 3-(6-(Aminomethyl)-7-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione hydrochlorideStep 1: 3-Bromo-2-fluoro-6-methyl-benzaldehyde

[0317] A mixture of 3-bromo-2-fluoro-benzaldehyde (5 g, 24.63 mmol), 2- aminobenzenesulfonic acid (1.92 g, 11.08 mmol), potassium trifluoro(methyl)borate (12.01 g, 98.52 mmol), 1-fluoro-2,4,6-trimethylpyridiniumtetrafluoroborate (11.18 g, 49.26 mmol) and palladium(ii)acetate (553 mg, 2.46 mmol) in mixture of TFA (6.7 mL) and 1,1,1,3,3,3- hexafluoropropan-2-ol (60 mL) was degassed for 3 times with argon atmosphere and the mixture was stirred at 20oC for 20 min, then heated to 90oC for 24h. The mixture was filteredthrough diatomite, the filtrate was concentrated to residue, which was purified by flash column separation, eluting with 2-5% ethyl acetate in petroleum ether to afford the title compound (1.70 g, -50% purity) as colorless oil. The crude product was used for next step directly.Step 2: 3-Bromo-2-fluoro-6-methyl-benzoic acid

[0318] 3-Bromo-2-fluoro-6-methyl-benzaldehyde (4.1 g, 18.89 mmol) in THF (100 mL), Water (50 mL), t-BuOH (25 mL) was cooled to -5 °C. Sodium dihydrogenphosphate (9.07 g, 75.56 mmol) was added in one portion. Then sodium chlorite (6.8 g, 75.56 mmol) was added in batches. After addition, the mixture was stirred at -5 °C for Ih. 2-Methyl-2 -butene (9.3 g, 132.23 mmol) was added drop-wise, maintaining the temperature below 0 °C. After addition, the mixture was stirred for Ih below 0 °C. To the mixture was added ethyl acetate (100 mL) and 2M HC1 solution (20 mL). Organic phase was concentrated to residue to afford 5 g crude product (overlapped with the none Me product). The crude product was dissolved in Methyl alcohol (10 mL), then thionyl chloride (3.11 mL) was added slowly. The mixture was heated to 75 °C for 6 h. The mixture was concentrated to residue, which was purified by flash column separation, eluting with 0-5% methanol in di chloromethane to afford the title compound (2.0 g, 45%) as a white solid.1H NMR (400MHz, methanol-d4) δ 7.56 (t, J = 8.0 Hz, 1H), 7.02 (d, J= 8.4 Hz, IH), 2.36 (s, 3H).Step 3: Methyl 3-bromo-2-fluoro-6-methyl-benzoate

[0319] To a solution of 3-bromo-2-fluoro-6-methyl-benzoic acid (1.2 g, 5.15mmol) in DMF (10 mL) was added Cs2CO3(2.5 g, 7.72 mmol). The mixture was stirred at 25 °C for 30 min. Then iodomethane (0.38 mL, 6.18 mmol) was injected. The mixture was stirred at 25 °C for 16 h under nitrogen atmosphere. The mixture was poured to water (10 mL), extracted with ethyl acetate (10 mL x 2), organic phase was washed with brine (10 mL x 2). Organic phase was purified by flash column separation, eluting with 5% ethyl acetate in petroleum etherto afford the title compound (750 mg, 59 %) as a white solid.1H NMR (400MHz, methanol-d4) δ 7.58 (t, J = 8.0 Hz, 1H), 7.02 (d, J = 8.4 Hz, 1H), 3.92(s, 3H), 2.32 (s, 3H).Step 4: Methyl 3-bromo-6-(bromomethyl)-2-fluorobenzoate

[0320] To a solution of methyl 3-bromo-2-fluoro-6-methyl-benzoate (750 mg, 3.04 mmol) in 1,2-Dichloroethane (10 mL) was added NBS (594 mg, 3.34 mmol) and AIBN (50 mg, 0.30 mmol) at 25 °C. Then the solution was stirred at 90oC for 16 h under nitrogen atmosphere. The solution was concentrated and purified by flash chromatography on silica gel eluting with 2% ethyl acetate in petroleum ether to afford the title compound (950 mg, 96%) as a white solid.1H NMR (400MHz, CDCl3) δ 7.62 (dd, J= 6.8, 8.4 Hz, 1H), 7.12 (d, J = 8.4 Hz, 1H), 4.60 (s, 2H), 4.01 (s, 3H). Step 5: 3-(6-Bromo-7-fluoro-1-oxoisoindolin-2-yl) piperidine-2,6-dione

[0321] To the solution of methyl 3-bromo-6-(bromomethyl)-2-fluoro-benzoate (950 mg, 2.91 mmol) in Acetonitrile (10 mL) was added 3-aminopiperidine-2,6-dion hydrochloride (575 mg, 3.50 mmol) and DIPEA (2.89 mL, 17.49 mmol). The mixture was heated to 80oC for 20 hours. The mixture was concentrated to residue, which was precipitated in 1M HCl solution(10 mL) filtered and washed with ethyl acetate (10 mL × 2) and water (10 mL × 2). The solid was filtered and dried to afford the title compound (690 mg, 69%) as a gray solid. LCMS (ESI): m / z 341.1,343.1[M + H]+. 1H NMR (400MHz, DMSO-d6) δ 1 1.01 (s, 1H), 8.01 - 7.88 (m, 1H), 7.42 (d, J = 8.4 Hz, 1H), 5.08 (dd, J = 4.8, 13.2 Hz, 1H), 4.51 - 4.43 (m, 1H), 4.38 - 4.30 (m, 1H), 2.95-2.84 (m, 1H), 2.65 - 2.55 (m, 1H), 2.45 - 2.30 (m, 1H), 2.09 - 1.97 (m, 1H).Step 6: 2-(2,6-Dioxopiperidin-3-yl)-4-fluoro-3-oxoisoindoline-5-carbonitrile

[0322] To a solution of 3-(6-bromo-7-fluoro-l-oxoisoindolin-2-yl)piperidine-2,6- dione (400 mg, 1.17 mmol) in DMF (5 mL) was added Pd(PPh3)4(135 mg, 0.12 mmol) and zinc cyanide (300 mg, 2.56 mmol), the mixture was stirred at 100 °C for 3 h under nitrogen atmosphere. The resulting solution was filtered through diatomite, washed with ethyl acetate (10 mL x 2) and MeOH (10 mL x 2), the filtrate was concentrated to residue, which was precipitated in ethyl acetate (10 mL), solid was filtered and washed with water (5 mL x 2), and dried to afford the title compound (260 mg, 77%) as a grey solid. LCMS (ESI): m / z 288.1 [M + H]+.1H NMR (400MHz, DMSO-d6)δ 11.03 (s, 1H), 8.16 (dd, J = 6.0, 8.0 Hz, 1H), 7.66 (d, .J= 8.0 Hz, 1H), 5.11 (dd, J= 5.2, 13.2 Hz, 1H), 4.65 - 4.57 (m, 1H), 4.53 - 4.43 (m, 1H), 2.95 - 2.85 (m, 1H), 2.65 - 2.55 (m, 1H), 2.45 - 2.30 (m, 1H), 2.09 - 1.97 (m, 1H).Step 7: 3-(6-(Aminomethyl)-7-fluoro-l-oxoisoindolin-2-yl)piperidine-2, 6-dione hydrochloride

[0323] A mmiixxttuurree ooff 2-(2,6-dioxo-3-piperidyl)-4-fluoro-3-oxo-isoindoline-5- carbonitrile (260 mg, 0.91 mmol) and PdCl2(200 mg, 1.13 mmol) in Methyl alcohol (20 mL) was stirred under H2atmosphere(15 psi) at 20 °C for 5 h. The mixture was filtered through diatomite and the filtrate was concentrated under reduced pressure to afford the title compound (100 mg, 32%) as a white solid. LCMS (ESI): m / z 583.3 (2M+H)+ 1H NMR (400MHz, DMSO- d6) δ 11.00 (s, 1H), 8.53 - 8.33 (m, 2H), 7.80 (t, J= 7.2 Hz, 1H), 7.50 (d, J = 7.6 Hz, 1H), 5.08 (dd, J=5.2, 13.2 Hz, 1H), 4.55 - 4.47 (m, 1H), 4.41 - 4.33 (m, 1H), 4.15 (br s, 2H), 2.97 - 2.85 (m, 1H), 2.68 - 2.58 (m, 1H), 2.42 - 2.31 (m, 1H), 2.06 - 1.97 (m, 1H).Intermediate 1 (Approach 2)3-(6-(Aminomethyl)-7-fluoro-l-oxoisoindolin-2-yl)piperidine-2, 6-dione hydrochlorideStep 1: 3-Bromo-2-fluoro-6-methylbenzoic acid

[0324] To the mixture of diisopropylamine (11.8 g, 116.4 mmol) in THF (400 mL) was added n-butyllithium (46.6 mL, 116.39 mmol) at -70 °C. After stirred for 20 minutes, 1- bromo-2-fluoro-4-methylbenzene (20.0 g, 105.81 mmol) dissolved in THF (50 mL) was added, after stirred for 20 minutes, dry ice carbon dioxide (34.9 g, 793.57 mmol) was added quickly. The reaction mixture was stirred for 1 hour and quenched with water (200 mL). The reaction mixture was raised to 20 °C, extracted with ethyl acetate (200 mL). The aqueous layer was adjusted with 6 M HCI to pH = 1. The white precipitate was filtered to afford title compound (12.0 g, 48%) as a white solid.1H NMR (400MHz, DMSO-d6)δ 13.82 (s, 1H), 7.67 (t, J= 7.6 Hz, 1H), 7.10 (d, J= 8.0 Hz, 1H), 2.30 (s, 3H).Step 2: Methyl 3-bromo-2-fluoro-6-methylbenzoate

[0325] To a solution of 3 -bromo-2-fluoro-6-m ethylbenzoic acid (13.5 g, 57.93 mmol) in DMF (100 mL) was added CS2CO3(28.3 g, 86.9 mmol). The mixture was stirred at 25 °C for 30 minutes under N2. Then iodomethane (4.3 mL, 69.52 mmol) was injected. The mixture was stirred at 25 °C for 3 hours. The reaction mixture was poured into water (100 mL), extractedwith ethyl acetate (100 mL × 2), organic phase was washed with brine (10 mL × 2), concentrated under vacuo, the residue was purified by silica gel chromatography 0 - 5% ethyl acetate in petroleum ether to give the title compound (9.0 g, 63%) as a white solid.1H NMR (400 MHz, CDCl3) δ 2) / 4 #RR' J = 8.4 Hz, 7.2 Hz, 1H), 6.91 (d, J = 8.4 Hz, 1H), 3.96 (s, 3H), 2.36 (s, 3H). Step 3: Methyl 3-bromo-6-(bromomethyl)-2-fluorobenzoate

[0326] To a solution of methyl 3-bromo-2-fluoro-6-methylbenzoate (9.0 g, 36.43 mmol) in 1,2-Dichloroethane (100 mL) was added methyl 1-bromopyrrolidine-2,5-dione (7.1 g, 40.07 mmol) and AIBN (1.2 g, 7.29 mmol) at 25 °C. Then the solution was stirred at 90oC for 16 hours under nitrogen atmosphere. The solution was concentrated under vacuo, the residue was purified by silica gel chromatography (0 - 2% ethyl acetate in petroleum ether) to afford the title compound (7.5 g, 63%) as a white solid. 1H NMR (400 MHz, CDCl3$ n 2)1, (dd, J = 6.8 Hz, 8.4 Hz, 1H), 7.12 (dd, J = 1.2 Hz, 8.4 Hz, 1H), 4.60 (s, 2H), 4.01 (s, 3H). Step 4: 3-(6-Bromo-7-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[0327] To a solution of methyl 3-bromo-6-(bromomethyl)-2-fluorobenzoate (7.0 g, 21.48 mmol), DIPEA (11.2 mL, 64.43 mmol) in Acetonitrile (70 mL) was added 3- aminopiperidine-2,6-dione hydrochloride (4.6 g, 27.92 mmol). The reaction mixture was stirred at 80oC for 16 hours. The mixture was concentrated, precipitated in 1M HCl solution (10 mL), filtered and washed with ethyl acetate (20 mL x 2) and water (20 mL x 2) to afford the title compound (6.0 g, 82% yield) as purple solid. LCMS (ESI): m / z 341.1, 343.1 [M + H]+.Step 5: tert-Butyl ((2-(2,6-dioxopiperidin-3-yl)-4-fluoro-3-oxoisoindolin-5-yl)methyl) carbamate

[0328] To a solution of 3-(6-bromo-7-fluoro-l-oxoisoindolin-2-yl)piperidine-2,6- dione (0.5 g, 1.46 mmol) in 1,4-Dioxane (10 mL) and Water (1 mL), was added potassium ((( / ert-butoxycarbonyl)amino)methyl)trifluoroborate (0.5 g, 2.2 mmol), Cs2CO3(1.4 g, 4.39 mmol) and CATACXIUM A Pd G3 (98 mg, 0.15 mmol), the solution was purged with N2for 1 min and stirred at 100 °C for 1.5 hours. The solution was concentrated under vacuo, diluted with water (20 mL) and ethyl acetate (20 mL), the solid was filtered to give the title compound (300 mg, 52 % yield) as a brown solid. LCMS (ESI): m / z 336.3 (M-56)+.1H NMR (400 MHz, DMSO-d6)δ 11.0 (s, 1H), 7.55 (t, J= 7.2 Hz, 1H), 7.47 (t, J= 6.4 Hz, 1H), 7.38 (d, J= 7.6 Hz, 1H), 5.07 (dd, J= 5.2 Hz, 13.2 Hz, 1H), 4.47-4.45 (m, 1H), 4.33-4.30 (m, 1H), 4.21 (d, J= 6.0 Hz, 2H), 2.95 - 2.86 (m, 1H), 2.67 - 2.27 (m, 1H), 2.43 - 2.32 (m, 1H), 2.02 - 1.99 (m, 1H), 1.38 (s, 9H).Step 6: 3-(6-(Aminomethyl)-7-fluoro-l-oxoisoindolin-2-yl)piperidine-2, 6-dione hydrochloride

[0329] To aa ssoolluuttiioonn of tert-butyl ((2-(2,6-dioxopiperidin-3-yl)-4-fluoro-3- oxoisoindolin-5-yl)methyl)carbamate (7.0 g, 17.88 mmol) in 1,2-Dichloroethane (20 mL), was added 2M HCl / dioxane (50 mL). The mixture was stirred at 25 °C for 12 hours. The solution was concentrated under vacuo to afford the title compound (5.2 g, 88.7%). LCMS (ESI): m / z 292.1[M + H]+.1H NMR (400 MHz, DMSO-d6)δ 11.02 (s, 1H), 8.46 (s, 3H), 7.83 (t, J= 7.2 Hz, 1H), 7.50 (d, .J = 8.0 Hz, 1H), 5.09 (dd, J = 5.2 Hz, 13.6 Hz, 1H), 4.54 - 4.36 (m, 2H), 4.14 (s, 2H), 2.97 - 2.87 (m, 1H), 2.68 - 2.59 (m, 1H), 2.45 - 2.34 (m, 1H), 2.04 - 2.00 (m, 1H).Intermediate 23-(6-(Aminomethyl)-4-chloro-7-fluoro-l-oxoisoindolin-2-yl)piperidine-2, 6-dioneStep 1: 3-Bromo-5-chloro-2-fluoro-6-methylbenzoic acid

[0330] To a solution of 3 -bromo-2-fluoro-6-m ethylbenzoic acid (5.02 g, 25.49 mmol) in H2SO4(40 mL) was added l,3-dichloro-5,5-dimethylimidazolidine-2, 4-dione (5.4 g, 23.17 mmol), the mixture was stirred at 90 °C for 3 hours. The reaction mixture was poured into ice- water (100 mL) and stirred. The precipitate was filtered to afford the title compound (4.4 g, 71%) as a yellow solid.1H NMR (400 MHz, DMSO-d6)δ 7.97 (d, J = 6.8 Hz, 1H), 2.29 (s, 3H).Step 2: Methyl 3-bromo-5-chloro-2-fluoro-6-methylbenzoate

[0331] To a solution of 3-bromo-5-chloro-2-fluoro-6-methylbenzoic acid (0.5 g, 1.87 mmol) in DMF (10 mL), was added Cs2CO3(0.91 g, 2.8 mmol). The mixture was stirred at 25°C for 30 minutes under N2. Then iodomethane (0.14 mL, 2.24 mmol) was injected. The mixture was stirred at 25 °C for 3 hours under N2. The mixture was poured into water (20 mL), extracted with ethyl acetate (20 mL x 2), organic phase was washed with brine (20 mL x 2). Organic phase was dried, concentrated under vacuo, the residue was purified by flash column chromatography (0 - 5% ethyl acetate in petroleum ether) to afford the title compound (360 mg, 68 %) as a white solid.1H NMR (400 MHz, DMSO-d6)δ 8.05 (d, J = 6.8 Hz, 1H), 3.92 (s, 3H), 2.28 (s, 3H).Step 3: Methyl 3-bromo-6-(bromomethyl)-5-chloro-2-fluorobenzoate

[0332] To a solution of methyl 3-bromo-5-chloro-2-fluoro-6-methylbenzoate (0.33 g, 1.34 mmol) in 1,2-Dichloroethane (10 mL), was added NBS (0.26 g, 1.47 mmol) and AIBN (0.04 g, 0.27 mmol) at 25 °C. Then the solution was stirred at 90 °C for 16 hours under N2. The solution was concentrated under vacuo, and the residue was purified by column chromatography (0 - 2% ethyl acetate in petroleum ether) to afford the title compound (0.20 g, 46%) as a white solid.1H NMR (400 MHz, DMSO-d6)δ 8.21 (d, J= 6.4 Hz, 1H), 4.66 (s, 2H), 3.96 (s, 3H).Step 4: 3-(6-Bromo-4-chloro-7-fluoro-l-oxoisoindolin-2-yl)piperidine-2, 6-dione

[0333] To a solution of methyl 3-bromo-6-(bromomethyl)-5-chloro-2-fluorobenzoate (0.33 g, 0.92 mmol), 3 -aminopiperidine-2, 6-dione hydrochloride (196.93 mg, 1.2 mmol) in Acetonitrile (40 mL) was added DIPEA (4.81 mL, 27.61 mmol). The reaction mixture was stirred at 90 °C for 16 hours. The mixture was concentrated to residue, diluted with 1M HC1 solution (5 mL) and ethyl acetate (10 mL x 2). The solid was filtered and washed with water(10 mL x 2), the solid was dried to afford the title compound (130 mg, 38%) as purple solid.LCMS (ESI): m / z 376.9.Step 5: tert-Butyl ((7-chloro-2-(2,6-dioxopiperidin-3-yl)-4-fluoro-3-oxoisoindolin-5- yl)methyl)carbamateMethod 1

[0334] To a solution ooff 3-(6-bromo-4-chloro-7-fluoro-l-oxoisoindolin-2- yl)piperidine-2, 6-dione (130.0 mg, 0.35 mmol) in 1,4-Dioxane (3 mL), wwaass added CATACXIUM A Pd G3(23.14 mg, 0.03 mmol), (((lerl- butoxycarbonyl)amino)methyl)trifluoroborate (82.06 mg, 0.35 mmol) and Cs2CO3(338.33 mg, 1.04 mmol) and Water (0.3 mL). The mixture was stirred at 90 °C at MW for 2 hours. The solution was diluted with IM HC1 and extracted with ethyl acetate (10 mL x 2), the organic layer was concentrated under vacuo and purified by pre-TLC (ethanol: ethyl acetate:petroleum ether = 1 :3:8, Rf = 0.3) to give the title compound (30 mg, 20%) as a brown solid. LCMS (ESI): m / z 370.0(M-56+H)+.1H NMR (400 MHz, DMSO-d6)δ 11.01 (s, 1H), 7.59 (d, J = 7.2 Hz, 1H), 7.51 (t, J = 6.4 Hz, 1H), 5.11 - 5.07 (m, 1H), 4.49-4.46 (m, 1H), 4.34-4.30 (m, 1H), 4.23- 4.20 (m, 2H), 2.95 - 2.86 (m, 1H), 2.67 - 2.61 (m, 1H), 2.46 - 2.43 (m, 1H), 2.04 - 2.01 (m, 1H), 1.39 (s, 9H).Method 2

[0335] To a solution 3-(6-bromo-4-chloro-7-fluoro-l-oxoisoindolin-2-yl)piperidine- 2, 6-dione (1.0 g, 2.66 mmol) in 1,4-Dioxane (10 mL) and Water (1 mL), was added (((terL butoxycarbonyl)amino)methyl)trifluoroborate (0.79 g, 3.99 mmol), Cs2CO3(1.75 g, 5.33 mmol), Amphos Pd G3 (0.34 g, 0.53 mmol). The mixture was purged under N2for 3 times and then stirred at 110 °C for 30 minutes under MW. The solution was acidified with IM HC1 to pH = 6 and then extracted with ethyl acetate (10 mL x 2), the organic layers were concentrated under vacuo and purified by column chromatography (0- 15% EE (ethanol: ethyl acetate = 1 :3) in dichloromethane) to give the title compound (350 mg, 31%) as a yellow solid.Method 3 (procedure for photo flow chemistry)

[0336] Combine the following reagents in a 3 L round-bottom flask equipped with a magnetic stir bar: 3-(6-bromo-4-chloro-7-fluoro-l-oxoisoindolin-2-yl)piperidine-2, 6-dione (50 g, 133.13 mmol), potassium (((tert-butoxycarbonyl)amino)methyl)trifluoroborate (52.7 g, 266.26 mmol), [Ir(dFCF3ppy)2(dtbbpy)]PF6(2.99 g, 2.66 mmol), Ni(dtbbpy)Cl2(5.30 g, 13.31 mmol), and Na2CO3(7.05 g, 66.56 mmol). Then, fill the flask with 2.5 L of DMA and purge the flow system with N2gas to create an inert atmosphere. Activate the 450 nm LEDs (2400 W) and the cooling system. Begin the peristaltic pump, adjusting the flow rate to 40 mL / min for the DMA solution. Direct the solution into the photo reactor, collecting the effluent in the original container. After circulating and irradiated for three hours, collect all the reaction mixture into the flask. The reaction mixture was acidified with HC1 (IM) solution until pH = 6. Extracted with ethyl acetate (IL x 3), and washed with water (200 mL x 3). The organic layer was concentrated to dryness. The residue was purified by column chromatography (0- 10% dichloromethane in EE (EtOH / EtOAc=l / 3)) to give the title compound (28 g, 49%) as a faint yellow solid.Step 6: 3-(6-(Aminomethyl)-4-chloro-7-fluoro-l-oxoisoindolin-2-yl)piperidine-2, 6-dione hydrochloride

[0337] The solution of tert-butyl ((7-chloro-2-(2,6-dioxopiperidin-3-yl)-4-fluoro-3- oxoisoindolin-5-yl)methyl)carbamate (220 g, 17.88 mmol) in 2M HCl / di oxane (2 L) was stirred at 25 °C for 16 hours. The precipitate was filtered, washed with ethyl acetate (800 mL), the solid was dried to afford the title compound (180 g, 96%).1H NMR (400 MHz, DMSO-d6)δ 11.03 (s, 1H), 8.51 (br s, 3H), 7.99 (d, J= 5.2 Hz, 1H), 5.10 (dd, J= 13.6, 5.2 Hz, 1H), 4.58 - 4.49 (m, 1H), 4.44 - 4.27 (m, 1H), 4.14 (d, J= 5.2 Hz, 2H), 2.96 - 2.85 (m, 1H), 2.61 - 2.57 (m, 1H), 2.47 - 2.42 (m, 1H), 2.06 - 1.97 (m, 1H).Intermediate 3 (Approach 1)3-(6-(aminomethyl)-l-oxoisoindolin-2-yl)piperidine-2, 6-dione hydrochlorideStep 1: 3-aminopiperidine-2, 6-dione

[0338] To a stirred solution of methyl 5-bromo-2-methylbenzoate (40 g, 174.6 mmol) in 1,2-di chloroethane (1 L) was added AIBN (2.88 g, 17.48 mmol), NBS (34.4 g, 183.36 mmol). The reaction mixture was degassed with argon for 3 times. The resulting mixture was stirred at 80 °C for 16 hours. The reaction mixture was poured into ice-water (100 mL) and extracted with EtOAc (200 mL x 3). The combined organic layers were washed with brine (300 mL), dried with Na2SO4, concentrated to give crude product, which was purified by column chromatography on silica gel (0-20% EtOAc in petroleum ether) to afford the title compound (20 g, 37%) as a white solid.1H NMR (400 MHz, CDCI3) δ 8.12 (d, J= 2.0 Hz, 1 H), 7.63 (dd, J= 8.0, 2.0 Hz, 1 H), 7.35 (d, J= 8.0 Hz, 1 H), 4.91 (s, 2 H), 3.96 (s, 3 H).Step 2: 3-(6-Bromo-l-oxoisoindolin-2-yl)piperidine-2, 6-dione

[0339] To a solution of methyl 5-bromo-2-(bromomethyl)benzoate(13.0 g, 42.21 mmol) in acetonitrile (250 mL) was added DIPEA (29.41 mL, 168.85 mmol) and 3- aminopiperidine-2, 6-dione (8.11 g, 63.32 mmol). The mixture was stirred at 80 °C for 4 h. The precipitate was filtrated, the filtrate was dried to give the title compound (10.6 g, 77.8%) as apurple solid.1H NMR (400 MHz, DMSO-d6)δ 11.02 (s, 1 H), 7.88 (d, J= 1.6 Hz, 1 H), 7.61 (d, .J= 8.4 Hz, 1 H), 5.13 (J= 13.2, 5.2 Hz, 1 H), 4.45 - 4.33 (m, 1 H), 3.34 (s, 2 H), 2.98 - 2.85 (m, 1 H), 2.70 -2.56 (m, 1 H), 2.46 - 2.32(m, 1 H), 1.98 - 2.07 (m, 1 H).Step 3: 2-(2,6-Dioxopiperidin-3-yl)-3-oxoisoindoline-5-carbonitrile

[0340] To a solution of 3-(6-bromo-l-oxoisoindolin-2-yl)piperidine-2, 6-dione (10 g, 30.95 mmol) in DMF (100 mL) was added RuPhos Pd G2 (2.4 g, 3.09 mmol) and zinc cyanide (4.72 g, 40.23 mmol), the mixture was stirred at 100 °C for 16h. The resulting solution was extracted with EtOAc (2 30 m× L) and the organic layers were combined. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product was washed by DCM to afford 2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindoline-5-carbonitrile (3.30 g, 39.6%) as white solid.1H NMR (400MHz, DMSO-d6)δ 11.03 (s, 1H), 8.21 (s, 1H), 8.10 (dd, J= 8.0, 1.6 Hz, 1H), 7.85 (d, J= 7.6 Hz, 1H), 5.15 (dd, J = 13.6, 5.2 Hz, 1H), 4.68 - 4.34 (m, 2H), 2.97 - 2.87 (m, 1H), 2.60 (d, J = 17.6 Hz, 1H), 2.47 - 2.32 (m, 1H), 2.08 - 1.98 (m, 1H).Step 4: 2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindoline-5-carbonitrile

[0341] To a stirred solution of 2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindoline-5- carbonitrile (1.3 g, 4.83 mmol) in methanol (20 mL) was added PdCl2(424 mg, 2.42 mmol). The mixture was stirred at 25 °C for 12h under H2(15 psi). The mixture was filtered and concentrated to afford Intermediate 3 (900 mg, 68%) as a white solid.1H NMR (400MHz, DMSO-d6)δ 11.0(s, 1H),8.44 (s, 2H), 7.88 (s, 1H), 7.73 - 7.64 (m, 2H), 5.18 - 5.06 (m, 1H), 4.55 - 4.32 (m, 2H), 4.16 - 4.10 (m, 2H), 2.96 - 2.89 (m, 1H), 2.63-2.58 (m, 1H), 2.43-2.39 (m, 1H), 2.06-2.00 (m, 1H).Intermediate 3 (Approach 2)3-(6-(aminomethyl)-l-oxoisoindolin-2-yl)piperidine-2, 6-dione hydrochlorideStep 1: tert-butyl ((2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)methyl)carbamate

[0342] To the mixture of 3-(6-bromo-l-oxoisoindolin-2-yl)piperidine-2, 6-dione (500 mg, 1.55 mmol), potassium ((( / ert-butoxycarbonyl)amino)methyl)trifluoroborate (733.64 mg, 3.09 mmol) and [2-(2-aminophenyl)phenyl]-chloro-palladium;bis(l-adamantyl)-butyl- phosphane (103 mg, 0.15 mmol) in 1,4-dioxane (10mL) and water (2mL) was added cesium carbonate (1008.29 mg, 3.09 mmol) . Then the resulting mixture was stirred at 100 °C for 16 h under nitrogen atmosphere. The mixture was concentrated under vacuo and the residue was purified by column chromatography (0 - 5% (25% ethanol in ethyl acetate) in petroleum ether) to give the title compound (200 mg, 34.6%) as a white solid. LCMS (ESI): m / z 318.1 [M -56 + H]+.1H NMR (400 MHz,CD3OD) δ 7.73 (s, 1H), 7.59-7.52 (m, 2H), 5.15 (dd, J = 13.2, 5.2 Hz, 1H), 4.54-4.42 (m, 2H), 4.34 (s, 2H), 2.97-2.85 (m, 1H), 2.83-2.73 (m, 1H), 2.57-2.42 (m, 1H), 2.22-2.12 (m, 1H), 1.46 (s, 9H).Step 2: 3-(6-(aminomethyl)-l-oxoisoindolin-2-yl)piperidine-2, 6-dione hydrochloride

[0343] A solution of tert-butyl ((2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5- yl)methyl)carbamate (150 mg, 0.4 mmol) in hydrogen chloride in dioxane (0.1 mL, 0.4 mmol) in was stirred at 25 °C for 1 h. The mixture was diluted with ethyl acetate (20 mL) and concentrated to afford Intermediate 3 (120 mg, 96.4%) as a white solid. LCMS (ESI): m / z 274.1 [M + H]+Intermediate 43-(6-(bromomethyl)-4-chloro-7-fluoro-l-oxoisoindolin-2-yl)piperidine-2, 6-dioneStep 1 : 3-(4-chloro-7-fluoro-6-(hydroxymethyl)-l-oxoisoindolin-2-yl)piperidine-2,6- dione

[0344] To a solution ooff 3-(6-bromo-4-chloro-7-fluoro-l-oxo-isoindolin-2- yl)piperidine-2, 6-dione (15.0g, 39.94mmol) in 1,4-Dioxane (250mL) wwaass added tributyl stannylmethanol (16.33 mL, 59.91 mmol) and Pd(PPh3)4(2.31g, 2. mmol). The mixture was stirred at 100 °C for 16 hours. The reaction was concentrated and purified by flash column (30% ethyl alcohol in ethyl acetate / di chloromethane, 0-30%) to give the title compound (1500 mg, 11.5%) as white solid.1H NMR (400 MHz, DMSO-d6)δ 11.02 (s, 1H), 7.74 (d, J = 5.2 Hz, 1H), 5.54 (t, J = 5.8 Hz, 1H), 5.09 (dd, J = 13.2, 5.2 Hz, 1H), 4.61 (d, J = 5.6 Hz, 2H), 4.51 - 4.43 (m, 1H), 4.35 - 4.25 (m, 1H), 2.97 - 2.84 (m, 1H), 2.62-2.57 (m, 1H), 2.48- 2.40 (m, 1H), 2.06 - 1.97 (m, 1H)Step 2: 3-(6-(Bromomethyl)-4-chloro-7-fluoro-l-oxoisoindolin-2-yl)piperidine-2, 6-dione

[0345] To the solution of 3-(4-chloro-7-fluoro-6-(hydroxymethyl)-l-oxoisoindolin- 2-yl)piperidine-2, 6-dione (1500 mg, 4.59mmol) in DCM (30mL) was added phosphorous tribromide (1.29 mL, 13.77mmol) at 0 °C. The mixture was stirred at 25 °C for 0.5 hour. The reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by flash column (30% ethyl alcohol in ethyl acetate / petroleum ether, 0-30%) to give Intermediate 4 (1.0 g 55.9%) as a white solid.1H NMR (400 MHz, DMSO-d6)δ 11.03 (s, 1H), 7.98 (d, J= 4.8 Hz, 1H), 5.10 (dd, J= 13.2, 4.8 Hz, 1H), 4.77 (s, 2H), 4.54-4.46 (m, 1H),4.37 - 4.31 (m, 1H), 2.92 - 2.85 (m, 1H), 2.62 (d, J = 1.0 Hz, 1H), 2.48-2.43 (m, 1H), 2.04 - 1.98 (m, 1H).Intermediate 53-(6-(((6-bromopyrimidin-4-yl)amino)methyl)-4-chloro-7-fluoro-l-oxoisoindolin-2- yl)piperidine-2, 6-dione

[0346] To a solution of 4-bromo-6-fluoropyrimidine (146 mg, 0.83 mmol) in DMA (4 mL), was added DIPEA (0.72 mL, 4.14 mmol) at 0 °C. Then 3-(6-(aminomethyl)-4-chloro- 7-fluoro-l-oxoisoindolin-2-yl)piperidine-2, 6-dione hydrochloride (300.0 mg, 0.83 mmol) was added quickly. The reaction was stirred at 0 °C under N2(15 psi) for 3 h. The reaction was diluted with water and solid was precipitate and filtered. The solid was washed with water and the solid was diluted with ethyl acetate (40 mL), dried over Na2SO4and concentrated to afford Intermediate 5 (140 mg, 35%) as a white solid. LCMS (ESI): m / z 484.1 [M + H]+.1H NMR (400 MHz,DMSO-d6)δ 11.02 (s, 1H), 8.29-8.20 (m, 2H), 7.68 (d, J = 5.6 Hz, 1H), 6.80 (s, 1H), 5.09 (dd, J= 13.6, 5.2 Hz, 1H), 4.52-4.43 (m, 1H), 4.35-4.25 (m, 1H), 2.92-2.85 (m, 1H), 2.63-2.57 (m, 1H), 2.48-2.38 (m, 1H), 2.05-1.99 (m, 1H), 1.28-1.21 (m, 1H), 0.89- 0.80 (m, 1H).Intermediate 66-(2-azabicyclo[2.1.1]hexan-4-yl)pyrimidin-4-ol hydrochlorideStep 1: tert-butyl 4-((2,2-dimethyl-4,6-dioxo-l,3-dioxan-5-ylidene)(hydroxy)methyl)-2- azabicyclo [2.1.1] hexane-2-carboxylate

[0347] To the solution of 2-(tert-butoxycarbonyl)-2-azabicyclo[2.1.1]hexane-4- carboxylic acid (300 mg, 1.32 mmol) in DCM (8 mL) was added DMAP (242 mg, 1.98 mmol) and 2, 2-dimethyl-l,3-dioxane-4, 6-dione (209 mg, 1.45 mmol). Then dicyclohexylmethanediimine (300 mg, 1.45 mmol) was added at 0 °C. The mixture was stirred at 20 °C for 2 hours. The reaction was filtrated. The filtrate was diluted with water (20 mL), extracted with DCM (30 mL) and washed with HC1 aqueous solution (IM, 20 mL x 2). The organic layers were combined. The organic layer was concentrated and dried over anhydrous sodium sulfate to get the title compound (460 mg, crude) as a yellow solid.Step 2: tert-butyl 4-(3-methoxy-3-oxopropanoyl)-2-azabicyclo[2.1.1]hexane-2- carboxylate

[0348] To a solution of tert-butyl 4-(2,2-dimethyl-4,6-dioxo-l,3-dioxane-5- carbonyl)-2-azabicyclo[2.1.1]hexane-2-carboxylate (460 mg, 1.3 mmol) in Methyl alcohol (8 mL) at 70 °C. The mixture was stirred at 70 °C for 16 hours. The reaction was concentrated and purified by flash column (0 - 20% ethyl acetate in petroleum ether) to afford the title compound (300 mg, 82% yield) as yellow oil.Step 3: tert-butyl 4-(6-hydroxypyrimidin-4-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate

[0349] To aa ssoolluuttiioonn tert-butyl 4-((2,2-dimethyl-4,6-dioxo-l,3-dioxan-5- ylidene)(hydroxy)methyl)-2-azabicyclo[2.1.1]hexane-2-carboxylate (300 mg, 1.06 mmol) and K2CO3(220 mg, 1.59 mmol) in Methyl alcohol (4 mL) was added formimidamidehydrochloride (102 mg, 1.27 mmol). The mixture was stirred at 50 °C for 16 hours. The reaction was filtrated. The filtrate was concentrated under reduced pressure and purified by flash column (0 - 10% methyl alcohol in DCM) to afford the title compound (200 mg, 68% yield) as a white solid. LCMS (ESI): m / z 278.1 [M + H]+.Step 4: 6-(2-azabicyclo[2.1.1]hexan-4-yl)pyrimidin-4-ol hydrochloride

[0350] The mixture of tert-butyl 4-(6-hydroxypyrimidin-4-yl)-2- azabicyclo[2.1.1]hexane-2-carboxylatee (200 mg, 0.72 mmol) in HC1 (6 mL)(2 M in dioxane) was stirred concentrated to afford the title compound (150 mg, crude) as a white solid. LCMS (ESI): m / z 178.1 [M + H]+.Intermediate 76-(2-azabicyclo[2.2.1]heptan-4-yl)pyrimidin-4-ol hydrochlorideStep 1: tert-butyl 4-((2,2-dimethyl-4,6-dioxo-l,3-dioxan-5-ylidene)(hydroxy)methyl)-2- azabicyclo[2.2.1]heptane-2-carboxylate

[0351] A solution ooff 2-(tert-butoxycarbonyl)-2-azabicyclo[2.2.1]heptane-4- carboxylic acid (9 g, 37.3 mmol) in DCM (200 mL) was added DMAP (6.9 g, 56 mmol) and 2, 2-dimethyl-l,3-dioxane-4, 6-dione (5.9 g, 41.0 mmol). Then was added dicyclohexylmethanediimine (8.5 g, 41.0 mmol) at 0 °C. The mixture was stirred at 20 °C for 2 hours. The reaction was filtrated. The filtrate was extracted with DCM (100 mL x 2) andwashed with HC1 aqueous solution (IM, 100 mL). The organic layers were combined. The organic layer was concentrated and dried over anhydrous sodium sulfate to get the title compound (13 g, crude) as a yellow solid.Step 2: tert-butyl 4-(3-methoxy-3-oxopropanoyl)-2-azabicyclo[2.2.1]heptane-2- carboxylate

[0352] To a ssoolluuttiioonn of tert-butyl 4-((2,2-dimethyl-4,6-dioxo-l,3-dioxan-5- ylidene)(hydroxy)methyl)-2-azabicyclo[2.2.1]heptane-2-carboxylate (13 g, 35.4 mmol) in Methyl alcohol (160 mL) at 70 °C. The mixture was stirred at 70 °C for 16 hours. The reaction was concentrated and was purified by silica gel chromatography (mobile phase: ethyl acetate / petroleum ether, gradient 0% to 20%) to afford the title compound (8.7 g, 82% yield) as yellow oil.Step 3: tert-butyl 4-(6-hydroxypyrimidin-4-yl)-2-azabicyclo[2.2.1]heptane-2-carboxylate

[0353] To aa ssoolluuttiioonn tert-butyl 4-(3-methoxy-3-oxopropanoyl)-2- azabicyclo[2.2.1]heptane-2-carboxylate (8.7 g, 29.3 mmol) and K2CO3(6.1 g, 43.9 mmol) in Methyl alcohol (100 mL) was added formimidamide hydrochloride (2.8 g, 35.1 mmol). The mixture was stirred at 50 °C for 16 hours. The reaction was filtrated. The filtrate was concentrated under reduced pressure and was purified by silica gel chromatography (mobile phase: methanol / DCM, gradient 0% to 10%) to afford the title compound (6.4 g, 75% yield) as a yellow solid.1H NMR (400 MHz, DMSO-d6)δ 12.64 - 12.31 (m, 1H), 8.14 (s, 1H), 6.22 (d, J= 2.8 Hz, 1H), 4.21 - 4.07 (m, 1H), 3.28 - 3.22 (m, 2H), 1.86 - 1.68 (m, 6H), 1.39 (d, J= 5.6 Hz, 9 H).Step 4: 6-(2-azabicyclo[2.2.1]heptan-4-yl)pyrimidin-4-ol hydrochloride

[0354] The ssoolluuttiioonn of tert-butyl 4-(6-hydroxypyrimidin-4-yl)-2- azabicyclo[2.2.1]heptane-2-carboxylate (6.4 g, 22.0 mmol) in HCI (2 M in dioxane) was stirred at 20 °C for 16h. The mixture was concentrated to afford the title compound (5 g, crude) as a yellow solid. LCMS (ESI): m / z 192.1. [M + H]+ 1H NMR (400 MHz, DMSO-d6)δ 9.60 - 8.89 (m, 2H), 8.21 (s, 1H), 6.34 (d, J = 0.8 Hz, 1H), 4.09 (s, 1H), 3.21 (t, J = 4.8 Hz, 2H), 2.00 - 1.80 (m, 6H).Intermediate 83-(6-(((6-(2-azabicyclo[2.2.1]heptan-4-yl)pyrimidin-4-yl)amino)methyl)-4-chloro-7- fluoro-l-oxoisoindolin-2-yl)piperidine-2, 6-dione hydrochlorideStep 1: tert-butyl 4-(6-chloropyrimidin-4-yl)-2-azabicyclo[2.2.1]heptane-2-carboxylate

[0355] To aa ssoolluuttiioonn ooff tert-butyl 4-(6-hydroxypyrimidin-4-yl)-2- azabicyclo[2.2.1]heptane-2-carboxylate (3.5 g, 12 mmol) in acetonitrile (53 mL) was added DIEA (4.19 mL, 24 mmol), 4-methylmorpholine (105 uL, 0.96 mmol) and phosphoryl trichloride (5.6 mL, 60 mmol), the solution was stirred at 20 °C for 2 h. The reaction mixture was quenched with saturated sodium bicarbonate aqueous solution (20 mL), then extracted with ethyl acetate (100 mL x 2), washed with brine (50 mL), the organic layer was dried over anhydrous sodium sulfate, after filtration, the filtrate was concentrated under reduced pressure, the crude was purified by column chromatography (0-25% ethyl acetate in petroleum ether) toobtain the title compound (2.7 g, 72% yield) as a yellow oil. LCMS (ESI): m / z 254.1 [M + H- 56]+.Step 2: tert-butyl 4-(6-(((7-chloro-2-(2,6-dioxopiperidin-3-yl)-4-fluoro-3-oxoisoindolin-5- yl)methyl)amino)pyrimidin-4-yl)-2-azabicyclo[2.2.1]heptane-2-carboxylate

[0356] To a solution of 3-(6-(aminomethyl)-4-chloro-7-fluoro-l-oxoisoindolin-2- yl)piperidine-2, 6-dione hydrochloride (3.1 g, 8.56 mmol) and DIEA (3.6 mL, 20.61 mmol) in dimethyl sulfoxide (40 mL) wwaass added tert-butyl 4-(6-chloropyrimidin-4-yl)-2- azabicyclo[2.2.1]heptane-2-carboxylate (2.1 g, 6.78 mmol). The resulting mixture was stirred at 100 °C for 12 hours. The reaction mixture was diluted with water (100 mL), extracted with ethyl acetate (100 mL x 2) and the combined organic layers were washed with brine (50 mL x 3). The organic layer was dried over with Na2SO4, filtered and concentrated under reduced pressure, the residue was purified by flash chromatography on silica gel (0-50% [(3: 1) ethyl acetate / ethyl alcohol] in n-hexane) to afford the title compound (3.7 g, 91% yield) as a yellow solid. LCMS (ESI): m / z 599.1 [M + H]+.Step 3: 3-(6-(((6-(2-azabicyclo[2.2.1]heptan-4-yl)pyrimidin-4-yl)amino)methyl)-4-chloro-7-fluoro-l-oxoisoindolin-2-yl)piperidine-2, 6-dione hydrochloride

[0357] To a solution of tert-butyl 4-(6-(((7-chloro-2-(2,6-dioxopiperidin-3-yl)-4- fluoro-3-oxoisoindolin-5-yl)methyl)amino)pyrimidin-4-yl)-2-azabicyclo[2.2.1]heptane-2- carboxylate (3.7 g, 6.18 mmol) in 1,4-dioxane (5 mL) was added (2 M) hydrogen chloride / 1,4-dioxane (30 mL, 61 mmol), then the resulting mixture was stirred at 20 °C for 2 hours. The reaction mixture was concentrated to afford the title compound (3.3 g, 99% yield) as a yellow solid. LCMS (ESI): m / z 499.1 [M + H]+.Intermediate 93-(6-(((6-((1S,4S)-2-azabicyclo[2.2.1]heptan-4-yl)pyrimidin-4-yl)amino)methyl)-4- chloro-7-fluoro-l-oxoisoindolin-2-yl)piperidine-2, 6-dione hydrochlorideStep 1:: tert-butyl (1S,4S)-4-(2,2-dimethyl-4,6-dioxo-l,3-dioxane-5-carbonyl)-2- azabicyclo[2.2.1]heptane-2-carboxylate

[0358] A solution of (1S,4S)-2-(tert-butoxycarbonyl)-2-azabicyclo[2.2.1]heptane-4- carboxylic acid (15 g, 62.2 mmol) in Dichloromethane (200 mL) was added DMAP (11.4 g, 93 mmol) and 2, 2-dimethyl-l,3-dioxane-4, 6-dione (11.6 g, 80.8 mmol). Then was added DCC (19.2 g, 93.2 mmol) at 0 °C. The mixture was stirred at 20 °C for 16 hours. The reaction was filtrated. The filtrate was extracted with di chloromethane (300 mL x 2) and washed with HC1 aqueous solution (IM, 300 mL x 3). The organic layers were combined. The organic layer was concentrated and dried over anhydrous sodium sulfate to get the title compound (22 g, crude) as a yellow solid.Step 2: tert-butyl 4-(3-methoxy-3-oxopropanoyl)-2-azabicyclo[2.2.1]heptane-2- carboxylate

[0359] To aa ssoolluuttiioonn of tert-butyl 4-(2,2-dimethyl-4,6-dioxo-l,3-dioxane-5- carbonyl)-2-azabicyclo[2.2.1]heptane-2-carboxylate (22 g, 59.9 mmol) in Methyl alcohol (250 mL) at 70 °C. The mixture was stirred at 70 °C for 16 hours. The reaction was concentratedand was purified by silica gel chromatography (mobile phase: ethyl acetate / petroleum ether, gradient 0% to 20%) to afford the title compound (17.4 g, 97% yield) as yellow oil.Step 3: tert-butyl (1S,4S )-4-(6-hydroxypyrimidin-4-yl)-2-azabicyclo[2.2.1]heptane-2- carboxylate

[0360] To aa solution tert-butyl 4-(3-methoxy-3-oxopropanoyl)-2- azabicyclo[2.2.1]heptane-2-carboxylate (17.4 g, 58.5 mmol) and K2CO3(12.1 g, 87.8 mmol) in Methyl alcohol (200 mL) was added formimidamide hydrochloride (5.7 g, 70.2 mmol). The mixture was stirred at 50 °C for 16 hours. The reaction was filtrated. The filtrate was concentrated under reduced pressure and was purified by silica gel chromatography (mobile phase: methanol / dichloromethane, gradient 0% to 10%) to afford the title compound (12 g, 70% yield) as a yellow solid.1H NMR (400 MHz, DMSO-d6)δ 12.59 - 12.30 (m, 1H), 8.14 (s, 1H), 6.22 (d, J= 2.8 Hz, 1H), 4.14 (d, J = 13.6 Hz, 1H), 3.32 - 3.22 (m, 2H), 1.83 - 1.59 (m, 6H), 1.39 (d, . J=5.6 Hz, 9H).Step 4: tert-butyl (1S,4S )-4-(6-chloropyrimidin-4-yl)-2-azabicyclo[2.2.1]heptane-2- carboxylate

[0361] To aa ssoolluuttiioonn of tert-butyl (1S,4S)-4-(6-hydroxypyrimidin-4-yl)-2- azabicyclo[2.2.1]heptane-2-carboxylate (6.6 g, 22.7 mmol) in acetonitrile (95 mL) was added DIEA (7.89 mL, 45.3 mmol), 4-methylmorpholine (0.2 uL,1.8 mmol) and phosphoryl trichloride (10.6 mL, 113 mmol), the solution was stirred at 20 °C for 2 h. The reaction mixture was quenched with saturated sodium bicarbonate aqueous solution (100 mL) then extracted with ethyl acetate (200 mL x 2), washed with brine (50 mL), the organic layer was dried over anhydrous sodium sulfate, after filtration, the filtrate was concentrated under reduced pressure, the crude was purified by column chromatography (0-25% ethyl acetate in petroleum ether) to obtain the title compound (7 g, 90% yield) as a yellow oil. LCMS (ESI): m / z 254.1 / 256.1 [M - 56 + H]+.Step 5: tert-butyl (1S,4S)-4-(6-(((7-chloro-2-(2,6-dioxopiperidin-3-yl)-4-fluoro-3- oxoisoindolin-5-yl)methyl)amino)pyrimidin-4-yl)-2-azabicyclo [2.2.1] heptane-2- carboxylate

[0362] To aa ssoolluuttiioonn of tert-butyl (1S,4S)-4-(6-chloropyrimidin-4-yl)-2- azabicyclo[2.2.1]heptane-2-carboxylate e (8.9 g, 28.7 mmol) and DIEA (15.0 mL, 86.2 mmol) in dimethyl sulfoxide (110 mL) was added tert-butyl 4-(6-chloropyrimidin-4-yl)-2- azabicyclo[2.2.1]heptane-2-carboxylate (18.7 g, 51.7 mmol), then the resulting mixture was stirred at 100 °C for 12 hours. The reaction mixture was diluted with water (300 mL), extracted with ethyl acetate (300 mL x 2) and the combined organic layers were washed with brine (60 mL x 3). The organic layer was dried over with Na2SO4, filtered and concentrated under reduced pressure, the residue was purified by flash chromatography on silica gel (0-50% [(3: 1) ethyl acetate / ethyl alcohol] in n-hexane) to afford the title compound (17 g, 97% yield) as a yellow solid. LCMS (ESI): m / z 599.1 [M + H]+.Step 6: 3-(6-(((6-((1S',4S)-2-azabicyclo[2.2.1]heptan-4-yl)pyrimidin-4-yl)amino)methyl)-4-chloro-7-fluoro-l-oxoisoindolin-2-yl)piperidine-2, 6-dione hydrochloride

[0363] To a solution of tert-butyl 4-(6-(((7-chloro-2-(2,6-dioxopiperidin-3-yl)-4- fluoro-3-oxoisoindolin-5-yl)methyl)amino)pyrimidin-4-yl)-2-azabicyclo[2.2.1]heptane-2- carboxylate (17 g, 28.4 mmol) in 1,4-dioxane (10 mL) was added (2 M) hydrogen chloride in 1,4-dioxane (250 mL, 500 mmol), then the resulting mixture was stirred at 20 °C for 2 hours. The reaction mixture was concentrated to afford the title compound (15 g, 99% yield) as a yellow solid. LCMS (ESI): m / z 499.1 [M + H]+.Intermediate 103-(6-(((6-((1S,4S)-2-azabicyclo[2.2.1]heptan-4-yl)pyrimidin-4-yl)amino)methyl)-4-(difluoromethoxy)-7-fluoro-l-oxoisoindolin-2-yl)piperidine-2, 6-dione hydrochlorideStep 1: tert-butyl (1S,4S ')-4-(6-(((7-(difluoromethoxy)-2-(2,6-dioxopiperidin-3-yl)-4- fluoro-3-oxoisoindolin-5-yl)methyl)amino)pyrimidin-4-yl)-2-azabicyclo[2.2.1]heptane-2- carboxylate

[0364] To aa ssoolluuttiioonn of tert-butyl (1S,4S)-4-(6-chloropyrimidin-4-yl)-2- azabicyclo[2.2.1]heptane-2-carboxylate e (400 mg, 1.3 mmol) and DIEA (0.7 mL, 3.9 mmol) in dimethyl sulfoxide (4 mL) was added 3-(6-(aminomethyl)-4-(difluoromethoxy)-7-fluoro-l- oxoisoindolin-2-yl)piperidine-2, 6-dione hydrochloride (632 mg, 1.5 mmol), then the resulting mixture was stirred at 100 °C for 12 hours. The reaction mixture was diluted with water (30 mL), extracted with ethyl acetate (80 mL x 2) and the combined organic layers were washed with brine(30 mL x 3). The organic layer was dried over with Na2SO4, filtered and concentrated under reduced pressure, the residue was purified by flash chromatography on silica gel (0-50% [(3: 1) ethyl acetate / ethyl alcohol] in n-hexane) to afford the title compound (17 g, 97% yield) as a yellow solid. LCMS (ESI): m / z 631.3 [M + H]+.Step 2: tert-butyl (1S,4S) -4-(6-(((7-(difluoromethoxy)-2-(2,6-dioxopiperidin-3-yl)-4- fluoro-3-oxoisoindolin-5-yl)methyl)amino)pyrimidin-4-yl)-2-azabicyclo[2.2.1]heptane-2- carboxylate

[0365] To a solution of tert-butyl 4-(6-(((7-chloro-2-(2,6-dioxopiperidin-3-yl)-4- fluoro-3-oxoisoindolin-5-yl)methyl)amino)pyrimidin-4-yl)-2-azabicyclo[2.2.1]heptane-2- carboxylate (770 mg, 1.2 mmol) in (2 M) hydrogen chloride / 1,4-dioxane (10 mL, 1.2 mmol), then the resulting mixture was stirred at 20 °C for 2 hours. The reaction mixture was concentrated to afford the title compound (690 mg, 99% yield) as a yellow solid. LCMS (ESI): m / z 531.1 [M + H]+.Intermediate 11Step 1: tert-butyl l-(3-ethoxy-3-oxopropanoyl)-2-oxa-5-azabicyclo[2.2.1]heptane-5- carboxylate

[0366] To a solution of 5-(tert-butoxycarbonyl)-2-oxa-5-azabicyclo[2.2.1 ]heptane-l - carboxylic acid (1.2 g, 4.93 mmol) in Acetonitrile (20 mL) was added di(1H -imidazol-l- yl)methanone (960 mg, 5.92 mmol) at 25 °C and stirred for 1 hour. Then was added potassium 3 -ethoxy-3 -oxopropanoate (840 mg, 4.93 mmol) and magnesium chloride (470 mg, 4.93 mmol). The mixture was stirred at 25 °C for 12 hours. The reaction mixture was quenched by addition of water (10 mL), extracted with ethyl acetate (10 mL x 3) and the combined organic layers were washed with brine (12 mL). The organic layer was dried over with Na2SO4, filtered and concentrated under reduced pressure to afford the title compound (550 mg, 35% yield) as a yellow oil. LCMS (ESI): m / z 214.1 [M - Boc + H]+Step 2: tert-butyl l-(6-hydroxypyrimidin-4-yl)-2-oxa-5-azabicyclo[2.2.1]heptane-5- carboxylate

[0367] A solution of K2CO3(364 mg, 2.63 mmol), tert-butyl l-(3-ethoxy-3- oxopropanoyl)-2-oxa-5-azabicyclo[2.2.1]heptane-5-carboxylate (550 mg, 1.76 mmol) and formimidamide hydrochloride (170 mg, 2.11 mmol) in Methyl alcohol (5 mL) was stirred at 50 °C for 12 hours. The reaction was concentrated and purified by flash column (5-10% menthol in DCM) to afford the title compound (500 mg, 97% yield) as a yellow solid.1H NMR (400 MHz, CDCl3-d)δ 8.12 (s, 1H), 6.81 - 6.72 (m, 1H), 4.71 - 4.55 (m, 1H), 4.14 - 4.02 (m, 2H), 3.86 - 3.78 (m, 1H), 3.53 - 3.41 (m, 1H), 2.37 - 2.26 (m, 1H), 1.91 (d, J = 10.0 Hz, 1H), 1.49 - 1.44 (m, 9H).Step 3: 6-(2-oxa-5-azabicyclo[2.2.1]heptan-l-yl)pyrimidin-4-ol hydrochloride

[0368] A solution ooff tert-butyl l-(6-hydroxypyrimidin-4-yl)-2-oxa-5- azabicyclo[2.2.1]heptane-5-carboxylate (500 mg, 1.7 mmol) in (2 M) HCl / dioxane (5 mL, 10 mmol) was added and stirred at 25 °C for 1 hour. The solvent was removed under reduced pressure to afford the title compound (390 mg, 99 % yield) as a white solid. LCMS (ESI): m / z 194.1 [M + H]+.Intermediate 126-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-l-yl)pyrimidin-4-ol hydrochlorideStep 11:: tert-butyl (1 S. 4S)-l-(3-ethoxy-3-oxopropanoyl)-2-oxa-5- azabicyclo [2.2.1] heptane-5-carboxylate

[0369] To a solution of (IS, 4S)-5-te / 7-butoxycarbonyl-2-oxa-5-azabicyclo [2.2.1] heptane- 1 -carboxylic acid (200 mg, 0.82 mmol) in Acetonitrile (6 mL) was added CDI (186.6 mg, 1.15 mmol). The mixture was stirred at 25 °C for 1 hour. Then ethylpotassiummal onate (153.9 mg, 0.9 mmol) and magnesium chloride (86.1 mg, 0.9 mmol) was added, and the resulting mixture was stirred at 25 °C for 16 hours. The reaction mixture was quenched by addition of water (2 mL), extracted with ethyl acetate (10 mL x 3) and the combined organic layers were washed with brine (6 mL), dried over with Na2SO4, filtered and concentrated under reduced pressure to afford the title compound (130 mg, 51% yield) as a yellow oil. LCMS (ESI): m / z 214.1.Step 2: tert-butyl (IS, 4S)-l-(6-hydroxypyrimidin-4-yl)-2-oxa-5-azabicyclo [2.2.1] heptane-5-carboxylate

[0370] The mixture of K2CO3(86.0mg, 0.62mmol) and tert-butyl (1S, 4S)-l-(3- ethoxy-3-oxo-propanoyl)-2-oxa-5-azabicyclo[2.2.1]heptane-5-carboxylate (130 mg, 0.41 mmol) and imidoformamide hydrochloride (40 mg, 0.5 mmol) in MeOH (8 mL) was stirred at 60 °C for 12 hours. The reaction was concentrated and was purified by flash column (2% MeOH in DCM) to afford title compound (60 mg, 49% yield) as a white solid. LCMS (ESI): m / z 294.2.1H NMR (400 MHz, CDCl3) δ 12.76 - 11.58 (m, 1H), 8.11 (s, 1H), 6.93 - 6.43 (m, 1H), 4.85 - 4.43 (m, 1H), 4.15 - 3.94 (m, 2H), 3.88 - 3.73 (m, 1H), 3.63 - 3.34 (m, 1H), 2.46 - 2.21 (m, 1H), 1.97 - 1.87 (m, 1H), 1.47 (s, 9H).Step 3: 6-((1S, 4S)-2-oxa-5-azabicyclo [2.2.1] heptan-l-yl)pyrimidin-4-ol

[0371] The solution of tert-butyl (IS, 4S)-l-(6-hydroxypyrimidin-4-yl)-2-oxa-5- azabicyclo [2.2.1] heptane-5-carboxylate (60 mg, 0.2 mmol) in (2M) HCl / dioxane (8 mL) was stirred at 25 °C for 2 hours. The solvent was removed under reduced pressure to afford title compound (45 mg, 96% yield) as a white solid (HC1 salt). LCMS (ESI): m / z 194.1.Intermediate 13Step 1: tricyclo[1.1.1.01,3]pentane

[0372] To a mixture of l,l-dibromo-2,2-bis(chloromethyl)cyclopropane (120.0 g, 404.29 mmol) in Pentane (50 mL) was added MeLi (505.36 mL, 808.57 mmol) (1.6 M in ethoxyethane) dropwise under N2, the mixture was stirred at -78 °C for 1 h. Then the mixture was stirred at 0 °C for Ih. The product was purified by distillation under 20 °C to afford tricyclo[1.1.1.01’3]pentane (26 g, 97.3% yield) in heptane and ethoxyethane (lg / 23mL). The rest mixture was quenched by aq.NH4Cl (200 mL) under N2atmosphere.1H NMR (400 MHz, CDC13) δ 1.98 (s, 6H).Intermediate 143-(4-chloro-7-fluoro-6-(((6-(3-isopropylbicyclo[1.1.1]pentan-l-yl)pyrimidin-4- yl)amino)methyl)-l-oxoisoindolin-2-yl)piperidine-2, 6-dioneStep 1: 3-bromo-2-fluoro-6-methylbenzoic acid

[0373] The reaction was carried out in flow.1. Install the equipment as illustrated above. Prepare the below solution.Solution 1 : 2,2,6,6-tetramethylpiperidine (1.2 eq, 450 g in THF total 3750 mL) under N2.Solution 2: n-BuLi (2.5 M, 1.2 eq, 1.25 L) under N2.Solution 3: l-bromo-2-fluoro-4-methyl-benzene (500 g in THF total 5000 mL) under N2.2. Calibrate the flow rate of Pump 1 to 30 mL / min, Pump 2 to 10 mL / min. Set the bath 1 at -20 °C. Start Pump 1 and Pump 2 at the same time. Collect the flowing out LiTMP solution and keep it at 0 °C under N2.3. Calibrate the flow rate of Pump 3 to 10 mL / min, Pump 4 to 10 mL / min. Set the bath 2 at -70 °C. Start Pump 3 and Pump 4 at the same time. The reaction was flowed intothe PF A coil and flowed out dropping into excessive dry ice in THF with a weak stream of nitrogen to keep it from moisture in the air under stirring at -70 °C.4. After collecting all the solution, the reaction mixture was raised to 20 °C slowly and quenched with water (2 L) and 6M NaOH solution (500 mL) was added. The reaction mixture was extracted with EtOAc (1 L x 2). The aq. layer was acidified with 6 M HC1 to pH 1. The white precipitate was filtered to afford 3-bromo-2-fluoro-6-methyl-benzoic acid (440 g, 71% yield) as a white solid.1H NMR (400 MHz, DMSO-d6)δ 7.67 (t, J= 7.6 Hz, 1H), 7.10 (d, 8.0 Hz, 1H), 2.30 (s, 3H).Step 2: 3-bromo-2-fluoro-5-iodo-6-methylbenzoic acid

[0374] To a solution of 3-bromo-2-fluoro-6-methyl-benzoic acid (10.0 g, 42.91 mmol) in H2SO4(100 mL) was added NIS (11.59 g, 51.5 mmol), the mixture was stirred at 60 °C for 3 hours. The reaction mixture was poured into ice-water (500 mL) and stirred. The precipitate was filtered to afford the title compound (14 g, 91% yield) as a brown solid.1H NMR (400 MHz, DMSO-d6)δ 8.29 - 8.22 (m, 1H), 2.35 (s, 3H).Step 3: methyl 3-bromo-2-fluoro-5-iodo-6-methylbenzoate

[0375] To a solution of 3-bromo-2-fluoro-5-iodo-6-methyl-benzoic acid (10.0 g, 27.86 mmol) in DMF (100 mL) was added K2CO3(5.78 g, 41.79 mmol). The mixture was stirred at 25 °C for 30 min under N2 atmosphere. Then Mel (2.08 mL, 33.43 mmol) was injected. The mixture was stirred at 25 °C for 3 hours under nitrogen atmosphere. Once the reaction was complete, the reaction was diluted with water (300 mL) and extracted with ethyl acetate (150 mL x 3). The organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated. The residue was purified by flash column chromatography (10% ethyl acetate in petroleum ether) to afford the title compound (8 g, 77% yield) as a white solid.1H NMR (400 MHz, DMSO-d6)δ 8.32 (d, J= 7.2 Hz, 1H), 3.91 (s, 3H), 2.32 (s, 3H).Step 4: methyl 3-bromo-2-fluoro-5-hydroxy-6-methylbenzoate

[0376] A mixture of methyl 3-bromo-2-fluoro-5-iodo-6-methyl-benzoate (5.0 g, 13.41 mmol) in DMSO (80 mL) and Water (20 mL) was added KOH (3.01 g, 53.63 mmol), Cu(acac)2(7.02 g, 26.81 mmol) and BHMPO (9.18 g, 26.81 mmol) was stirred for 4 h at 80 °C under N2. Once the reaction was complete, the reaction was diluted with water (100 mL) and extracted with ethyl acetate (80 mL x 3). The organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated. The residue was purified by flash column chromatography (25% ethyl acetate in petroleum ether) to afford the title compound (3 g, 85% yield) as a yellow solid.1H NMR (400 MHz, CDCl3) δ 7.04 (d, J= 5.6 Hz, 1H), 3.96 (s, 3H), 2.19 (s, 3H).Step 5: methyl 3-bromo-5-(difluoromethoxy)-2-fluoro-6-methylbenzoate

[0377] To a solution of methyl 3-bromo-2-fluoro-5-hydroxy-6-methyl-benzoate (400 mg, 1.52 mmol) and sodium 2-chloro-2,2-difluoroacetate (348 mg, 2.28 mmol) in DMF (4 mL) and was added Cs2CO3(1.24 g, 3.8 mmol). The resulting mixture was heated to 80 °C for 16 h under N2. Once the reaction was complete, the reaction was diluted with water (50 mL) and extracted with ethyl acetate (30 mL x 3). The organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated. The residue was purified by flash column chromatography (10% ethyl acetate in petroleum ether) to afford the title compound (380 mg, 80% yield) as a white oil.1H NMR (400 MHz, CDCl3) δ 7.42 (d, J = 6.0 Hz, 1H), 6.67 - 6.27 (m, 1H), 3.97 (s, 3H), 2.25 (s, 3H)Step 6: methyl 3-bromo-6-(bromomethyl)-5-(difluoromethoxy)-2-fluorobenzoate

[0378] The reaction was carried out in flow.1. Solution 1 : methyl 3-bromo-5-(difluoromethoxy)-2-fluoro-6-methyl-benzoate,1.0 eq, 0.38 g, NBS,1.28 eq, 0.26g in MeCN,5 mL2. The solution 1 was pumped by Pump 1 [SI, Pl, 0.348 mL / min} to flow reactor 1 {FER1, PF A, Coils reactor, 1.588(1 / 16”) mm, 8 mL, 40 °C} with 450 nm LED light (24 W).3. The reaction mixture was continuous for {FLR1, 23 min}.4. Wash the tubing with solvent5. Turn on the 450 nm LED light (24 W)6. Collected all the reaction mixture and take a sample for analysis, take a sample for LC-MS analysis7. Turn off the 450 nm LED light (24 W) and cooler and peristaltic pump, wash the tubing with solvent.

[0379] The reaction solution was concentrated under vacuo, petroleum ether (50 mL) was added. The precipitate was filtered off and washed with petroleum ether (50 mL). The filtrate was concentrated under reduced pressure to afford the title compound (400 mg, 84% yield) as a white solid.1H NMR (400 MHz, CDCI3) δ 7.52 (d, J= 5.6 Hz, 1H), 6.77 - 6.36 (m, 1H), 4.61 (s, 2H), 4.02 (s, 3H).Step 7: 3-(6-bromo-4-(difluoromethoxy)-7-fluoro-l-oxoisoindolin-2-yl)piperidine-2,6- dione

[0380] To a solution of methyl 5-bromo-2-(bromomethyl)-3-(difluoromethoxy)-6- fluoro-benzoate (400.0 mg, 1.02 mmol), 3 -aminopiperidine-2, 6-dione hydrochloride (184.76 mg, 1.12 mmol) in MeCN (5 mL) was added DIEP A (0.53 mL, 3.06 mmol). The reaction mixture was stirred at 90 °C for 16 hours. After cooled to room temperature, the precipitate in the reaction mixture was collected by filtration, the filter cake was, washed with EtOAc (5 mL) and water (2 mL x 2). The solid was dried to afford the title compound (180 mg, 43% yield) as black solid.1H NMR (400 MHz, DMSO-d6)δ 11.02 (s, 1H), 7.88 (d, J = 4.8 Hz, 1H), 7.59 - 7.15 (m, 1H), 5.09 (dd, J= 5.2, 13.2 Hz, 1H), 4.56 - 4.44 (m, 1H), 4.39 - 4.25 (m, 1H), 2.98 - 2.85 (m, 1H), 2.58 (d, J= 16.8 Hz, 1H), 2.44 (dd, J= 4.4, 12.8 Hz, 1H), 2.04 - 1.95 (m, 1H).Step 8:: tert-butyl ((7-(difluoromethoxy)-2-(2,6-dioxopiperidin-3-yl)-4-fluoro-3- oxoisoindolin-5-yl)methyl)carbamate

[0381] A mixture of potassium (((tert-butoxycarbonyl)amino)methyl)trifluoroborate (126 mg, 0.53 mmol), 3-[6-bromo-4-(difluoromethoxy)-7-fluoro-l-oxo-isoindolin-2- yl]piperidine-2, 6-dione (180 mg, 0.44 mmol) and Cs2CO3(432 mg, 1.33 mmol) ,CATACXIUM A Pd G3 (32.2 mg, 0.04 mmol) in 1,4-Dioxane (5 mL) and Water (0.50 mL). The mixture was stirred at 90 °C under MW for 1 hour. The residue was purified by flash column chromatography (70% ethyl acetate in petroleum ether) to afford the title compound (100 mg, 59% yield) as a white solid. LCMS (ESI): m / z 402.0(M-56+H)+.Step 9: 3-(6-(aminomethyl)-4-(difluoromethoxy)-7-fluoro-l-oxoisoindolin-2- yl)piperidine-2, 6-dione 2,2,2-trifluoroacetate

[0382] The solution of tert-butylN-[[7-(difluoromethoxy)-2-(2,6-dioxo-3-piperidyl)- 4-fluoro-3-oxo-isoindolin-5-yl]methyl]carbamate (80 mg, 0.17 mmol) in 2,2,2-trifluoroacetic acid (0.25 mL, 3.33 mmol) was stirred at 25 °C for 3 hours. The mixture was concentrated in vacuo to give title compound (60 mg, 96% yield) as a white solid. LCMS (ESI): m / z 358.1 [M + H]+.1H NMR (400 MHz, DMSO-d6)δ 11.02 (s, 1H), 8.25 (br s, 3H), 7.69 (d, J = 4.4 Hz, 1H), 7.23 (t, J= 72.8 1H), 5.08 (dd, J= 5.2, 13.2 Hz, 1H), 4.59 - 4.49 (m, 1H), 4.44 - 4.33 (m, 1H), 4.17 (d, J= 5.2 Hz, 2H), 2.95 - 2.87 (m, 1H), 2.64 - 2.58 (d, J= 18.0 Hz, 1H), 2.44 (d, J = 4.0 Hz, 1H), 1.94 - 1.87 (m, 1H).Intermediate 153-(6-(aminomethyl)-7-fluoro-l-oxo-4-(trifluoromethoxy)isoindolin-2-yl)piperidine-2,6-dione hydrochlorideStep 1 : 2-(5-bromo-4-fluoro-3-(methoxycarbonyl)-2-methylphenoxy)-2,2-difluoroacetic acid

[0383] To a solution of methyl 3-bromo-2-fluoro-5-hydroxy-6-methylbenzoate (5.0 g, 19.01 mmol) in 1,4-Dioxane (100 mL) was added NaH (0.91 g, 22.81 mmol, 60%) at 25°C under N2. After 0.5 hours, sodium 2-bromo-2,2-difluoroacetate (5.61 g, 28.51 mmol) was added to the mixture. The reaction mixture was stirred at 80 °C for 16 hours. The mixture was poured to water (50 mL), extracted with ethyl acetate (50 mL x 3), organic phase was washed with brine (50 mL). The organic layer was dried over sodium sulfate, filtered and concentrated in vacuum to get crude 2-(5-bromo-4-fluoro-3 -(methoxy carbonyl)-2-methylphenoxy)-2, 2- difluoroacetic acid (4 g, 59% yield) as brown oil. LCMS (ESI): m / z 357.0 & 359.0 [M + H]+.1H NMR (400 MHz, DMSO-d6)δ 7.55 (d, J= 6.4 Hz, 1H), 3.91 (s, 3H), 2.16 (s, 3H).Step 2: methyl 3-bromo-2-fluoro-6-methyl-5-(trifluoromethoxy)benzoate

[0384] Method 1: A solution of 2-(5-bromo-4-fluoro-3-(methoxycarbonyl)-2- methylphenoxy)-2,2-difluoroacetic acid (4.0 g, 11.2 mmol) and Selectfluor (cas: 140681-55-6) (13.89 g, 39.21 mmol) and Ag2NO3(380.58 mg, 2.24 mmol) in (trifluoromethyl)benzene (60 mL, 492.37 mmol) and Water (6 mL) at 25 °C under N2, then TfOH (2.97 mL, 33.61 mmol) was added. Then stirred at 80 °C for 16 hours. The mixture was filtered and filtrate was extracted with ethyl acetate (30 mL x 3), organic phase was washed with brine (30 mL). The organic layer was dried over sodium sulfate, filtered and concentrated in vacuum The residue was purified by flash column chromatography (10% ethyl acetate in petroleum ether) to afford methyl 3-bromo-2-fluoro-6-methyl-5-(trifluoromethoxy)benzoate (350 mg, 9.4% yield) as colorless oil.1H NMR (400 MHz, CDCl3) δ 7.51 (d, J = 6.0 Hz, 1H), 3.98 (s, 3H), 2.28 (s, 3H).

[0385] Method 2 : A solution of 2-(5-bromo-4-fluoro-3-(methoxycarbonyl)-2- methylphenoxy)-2,2-difluoroacetic acid (100.0 mg, 0.28 mmol) in CDCI3(2 mL), then F2Xe (0.01 mL, 0.28 mmol) was added. Then stirred at 25 °C for 1 hour. The solvent was concentrated under vacuum. The residue was purified by pre-TLC (10% ethyl acetate in petroleum ether) to afford methyl 3-bromo-2-fluoro-6-methyl-5-(trifluoromethoxy)benzoate (40 mg, 43% yield) as colorless oil.

[0386] Method 3 :

[0387] Under N2, a solution of methyl 3-bromo-2-fluoro-5-hydroxy-6-methyl- benzoate (200.0 mg, 0.76 mmol) and Selectfluor (cas: 140681-55-6) (538 mg, 1.52 mmol) AgOTf (781 mg, 3.04 mmol) and KF (185 mg, 3.19 mmol) in Ethyl acetate (10 mL), then 2- fluoropyridine (0.26 mL, 3.04 mmol) was added at 20°C. Then warm to 40°C and TMSCF3 (0.45 mL, 3.04 mmol) was added dropwise. Then the mixture was stirred 20 h at 40 °C. The solvent was concentrated under vacuum. The residue was purified by pre-TLC (10% ethyl acetate in petroleum ether) to afford methyl 3-bromo-2-fluoro-6-methyl-5-(trifluorom ethoxy )benzoate (20 mg, 8% yield) as colorless oil.Step 3: methyl 3-bromo-6-(bromomethyl)-2-fluoro-5-(trifluoromethoxy)benzoate

[0388] The reaction was carried out in flow.1. Solution 1 : methyl 3-bromo-2-fluoro-6-methyl-5-(trifluoromethoxy)benzoate (350.0 mg, 1.06 mmol) and NBS (244 mg, 1.37 mmol) in Acetonitrile (8 mL)2. The solution 1 was pumped by Pump 1 [SI, Pl, 0.348 mL / min] to flow reactor 1 {FLRI, PF A, Coils reactor, 1.588(1 / 16”) mm, 8 mL, 45 °C] with 450 nm LED light (24 W).3. The reaction mixture was continuous for {FLR1, 20 min}.4. Wash the tubing with solvent.5. Turn on the 450 nm LED light (24 W).6. Collected all the reaction mixture and take a sample for analysis, take a sample for LC-MS analysis.7. Turn off the 450 nm LED light (24 W) and cooler and peristaltic pump, wash the tubing with solvent.

[0389] The reaction solution was concentrated under vacuo, petroleum ether (5 mL) was added. The precipitate was filtered off, and washed with petroleum ether (5 mL). The filtrate was concentrated under reduced pressure to afford the title compound (400 mg, 92% yield) as a white solid.1H NMR (400 MHz, CDCI3) δ 7.61 - 7.57 (m, 1H), 4.61 (s, 2H), 4.03 (s, 3H)Step 4: 3-(6-bromo-7-fluoro-l-oxo-4-(trifluoromethoxy)isoindolin-2-yl)piperidine-2,6- dione

[0390] To a solution of methyl 3-bromo-6-(bromomethyl)-2-fluoro-5- (trifluoromethoxy)benzoate (400.0 mg, 00..9988 mmol), 3-aminopiperidine-2, 6-dione; hydrochloride (176.65 mg, 1.07 mmol) in Acetonitrile (6 mL) was added DIEA (0.51 mL, 2.93 mmol). The reaction mixture was stirred at 90 °C for 16 hours. The mixture was concentrated and purified by flash column chromatography (0-30% (30% ethanol in ethyl acetate) in dichloromethane) to afford 3-(6-bromo-7-fluoro-l-oxo-4-(trifluoromethoxy)isoindolin-2- yl)piperidine-2, 6-dione (260 mg, 63% yield) as a yellow solid. LCMS (ESI): m / z 425.0 & 427.0 [M + H]+.Step 5:: tert-butyl ((2-(2,6-dioxopiperidin-3-yl)-4-fluoro-3-oxo-7-(trifluoromethoxy)isoindolin-5-yl)methyl)carbamate

[0391] A solution of 3-(6-bromo-7-fluoro-l-oxo-4-(trifluoromethoxy)isoindolin-2- yl)piperidine-2, 6-dione (260.0 mg, 0.61 mmol), Ni(dtbbpy)Cl2(24.34 mg, 0.06 mmol), potassium (((tert-butoxycarbonyl)amino)methyl)trifluoroborate (242.15 mg, 1.22 mmol), 2,6- Lutidine (32.22 uL, 0.31 mmol), [Ir(dFCF3ppy)2(dtbbpy)]PF6, (13.72 mg, 0.01 mmol) in DMA (4 mL) was stirred 2 h at 450nm LED under N2. The mixture was poured into water (4 mL), extracted with ethyl acetate (5 mL x 3), organic phase was washed with brine (5 mL x 3). The organic layer was purified by flash column chromatography (70% ethyl acetate in petroleum ether) to afford tert-butyl ((2-(2,6-dioxopiperidin-3-yl)-4-fluoro-3-oxo-7- (trifluoromethoxy)isoindolin-5-yl)methyl)carbamate (70 mg, 24% yield) as a yellow solid. LCMS (ESI): m / z 420.1 [M-56+H]+.Step 6: 3-(6-(aminomethyl)-7-fluoro-l-oxo-4-(trifluoromethoxy)isoindolin-2- yl)piperidine-2, 6-dione hydrochloride

[0392] To a solution of tert-butyl N-[[2-(2,6-dioxo-3-piperidyl)-4-fluoro-3-oxo-7- (trifluoromethoxy)isoindolin-5-yl]methyl]carbamate (55 mg, 0.12 mmol) in hydrogen chloride (80 mg, 2.2 mmol). The resulting solution was stirred at 25 °C for 3 hours. The mixture was concentrated in vacuo to give title compound (46 mg, 99% yield) as a white solid. LCMS (ESI): m / z 376.1 [M + H]+.1H NMR (400 MHz, DMSO-d6)δ 11.06 - 11.02 (m, 1H), 8.36 - 8.21 (m, 3H), 7.90 (d, J = 4.0 Hz, 1H), 5.10 (dd, J= 4.8, 13. Hz, 1H), 4.65 - 4.57 (m, 1H), 4.48 - 4.40 (m, 1H), 4.20 (s, 2H), 2.96 - 2.85 (m, 1H), 2.62 (d, J = 2.8 Hz, 1H), 2.44 (d, J = 5.2 Hz, 1H), 2.05 - 1.98 (m, 1H).Intermediate 163-(6-(aminomethyl)-7-fluoro-4-methoxy-l-oxoisoindolin-2-yl)piperidine-2, 6-dione hydrochlorideStep 1: methyl 3-bromo-2-fluoro-5-methoxy-6-methylbenzoate

[0393] To a solution of 3-bromo-2-fluoro-5-hydroxy-6-methyl-benzoic acid (1.0 g, 4.02 mmol) in DMF (10 mL) was added K2CO3(0.83 g, 6.02 mmol). The mixture was stirred at 0 °C for 30 min under N2atmosphere. Then Mel (0.5 mL, 8.03 mmol) was injected. The mixture was stirred at 25 °C for 3 hours under nitrogen atmosphere. The mixture was poured into water (20 mL), extracted with ethyl acetate (50 mL x 3), organic phase was washed with brine (20 mL x 3). The organic layer was purified by flash column chromatography (20% ethyl acetate in petroleum ether) to afford the title compound (900 mg, 81% yield) as colorless oil. LCMS (ESI): m / z 277.1 [M + H]+.1H NMR (400 MHz, CDCl3) δ 7.02 (d, J = 5.6 Hz, 1H), 3.95 (s, 3H), 3.82 (s, 3H), 2.16 (s, 3H).Step 2: methyl 3-bromo-6-(bromomethyl)-2-fluoro-5-methoxybenzoate

[0394] The reaction was carried out in flow.1. Solution 1 : methyl 3-bromo-2-fluoro-5-methoxy-6-methyl-benzoate (800 mg, 2.89 mmol), NBS (0.59 g, 3.32 mmol) in Acetonitrile (16 mL).2. The solution 1 was pumped by Pump 1 [SI, Pl, 0.348 mL / min] to flow reactor 1 {FERI, PF A, Coils reactor, 1.588(1 / 16”) mm, 8 mL, 40 °C} with 450 nm LED light (24 W).3. The reaction mixture was continuous for {FERI, 23 min}.4. Wash the tubing with solvent5. Turn on the 450 nm LED light (24 W)6. Collected all the reaction mixture and take a sample for analysis, take a sample for LC-MS analysis7. Turn off the 450 nm LED light (24 W) and cooler and peristaltic pump, wash the tubing with solvent.

[0395] The reaction solution was concentrated under vacuo, petroleum ether (5 mL) was added. The precipitate was filtered off, and washed with petroleum ether (5 mL). The filtrate was concentrated under reduced pressure to afford the title compound (800 mg, 78% yield) as a white solid.1H NMR (400 MHz, CDCI3) δ = 7.14 (d, J= 5.6 Hz, 1H), 4.62 (s, 2H), 4.00 (s, 3H), 3.91 (s, 3H).Step 3: 3-(6-bromo-7-fluoro-4-methoxy-l-oxoisoindolin-2-yl)piperidine-2, 6-dione

[0396] To a solution of methyl 5 -bromo-2-(bromomethyl)-6-fluoro-3 -methoxy- benzoate (800 mg, 2.25 mmol), 3-aminopiperidine-2,6-dione;hydrochloride (0.41 g, 2.47 mmol) in Acetonitrile (10 mL) was added DIPEA (1.17 mL, 6.74 mmol). The reaction mixture was stirred at 90 °C for 16 hours. The mixture was concentrated and purified by flash column chromatography (0-30% (30% ethanol in ethyl acetate) in DCM) to afford the title compound (700 mg, 84% yield) as black solid. LCMS (ESI): m / z 371.0 & 373.1 [M + H]+.1H NMR (400 MHz, DMSO-d6)δ 11.00 (s, 1H), 7.54 (d, J = 4.6 Hz, 1H), 5.06 (dd, J = 5.2, 13.2 Hz, 1H), 4.40 - 4.32 (m, 1H), 4.23 - 4.16 (m, 1H), 3.89 (s, 3H), 2.90 (ddd, J = 5.4, 13.6, 17.6 Hz, 1H), 2.62 - 2.56 (m, 1H), 2.41 (dd, J= 4.4, 13.2 Hz, 1H), 2.03 - 1.95 (m, 1H).Step 4: test -butyl ((2-(2,6-dioxopiperidin-3-yl)-4-fluoro-7-methoxy-3-oxoisoindolin-5- yl)methyl)carbamate

[0397] A mixture of potassium (((tert-butoxycarbonyl)arnino)methyl )trifluoroborate (537 mg, 2.26 mmol), 3-(6-bromo-7-fluoro-4-methoxy-l-oxo-isoindolin-2-yl)piperidine-2,6- dione (700 mg, 1.89 mmol) and Cs2CO3(1843 mg, 5.66 mmol) in 1,4-Dioxane (7 mL) and Water (0.2 mL) was added CATACXIUM A Pd G3 (137 mg, 0.19 mmol) at 100 °C. Then the resulting mixture was stirred at 100 °C in a microwave reactor for 1 h under nitrogen atmosphere. The mixture was concentrated and purified by flash column chromatography (70% ethyl acetate in petroleum ether) to afford the title compound (330 mg, 42% yield) as a brown solid. LCMS (ESI): m / z 366.1 [M + H]+. 1HNMR (400 MHz, DMSO-d6)δ 10.99 (s, 1H), 7.46 (t, J= 6.0 Hz, 1H), 7.16 (d, J = 4.8 Hz, 1H), 5.05 (dd, J= 5.2, 13.2 Hz, 1H), 4.39 - 4.30 (m, 1H), 4.24 - 4.13 (m, 3H), 3.84 (s, 3H), 2.96 - 2.85 (m, 1H), 2.62 - 2.54 (m, 1H), 2.41 (dd, J = 4.0, 12.8 Hz, 1H), 1.96 (d, J= 3.2 Hz, 1H), 1.39 (s, 9H).Step 5: 3-(6-(aminomethyl)-7-fluoro-4-methoxy-l-oxoisoindolin-2-yl)piperidine-2,6- dione hydrochloride

[0398] The solution of tert-butyl N-[[2-(2,6-dioxo-3-piperidyl)-4-fluoro-7-methoxy- 3-oxo-isoindolin-5-yl]methyl]carbamate (330 mg, 0.78 mmol) in hydrogen chloride (543 mg, 14.89 mmol) was stirred at 25 °C for 3 hours. The mixture was concentrated in vacuo to give title compound (46 mg, 99% yield) as a white solid.1H NMR (400 MHz, DMSO-d6)δ 11.00 (s, 1H), 8.41 - 8.19 (m, 3H), 7.47 (d, J= 4.8 Hz, 1H), 5.06 (dd, J = 4.8, 13.2 Hz, 1H), 4.45 - 4.34 (m, 1H), 4.24 (d, J = 18.0 Hz, 1H), 4.14 (d, J = 5.6 Hz, 2H), 3.89 (s, 3H), 2.89 (dd, J = 4.4, 17.6 Hz, 1H), 2.61 (d, J= 2.8 Hz, 1H), 2.44 (d, J= 4.0 Hz, 1H), 2.00 - 1.95 (m, 1H).Intermediate 173-(4-chloro-7-fluoro-l-oxo-6-(((6-(piperidin-3-yl)pyrimidin-4- yl)amino)methyl)isoindolin-2-yl)piperidine-2, 6-dione trifluoro acetateStep 1:

[0399] To a 250 mL round bottomed flask was added 1-tert- butoxycarbonylpiperidine-3-carboxylic acid (5000 mg, 21.8 mmol, 5 g), and acetonitrile (72.7 mL, 0.3 M). l,l'-carbonyldimiidazole (4330 mg, 26.21 mmol, 1.2 equiv.) was added portion wise over 10 minutes. The reaction was allowed to stir at room temperature for 20 minutes, and to this was then added (3 -ethoxy-3 -oxo propanoyl) oxypotassium (4083 mg, 24.0 mmol, 1.1 equiv.) and magnesium chloride (2340 mg, 1.01 mL, 24.0 mmol, 1.1 equiv.). The reaction was allowed to let stir at room temperature overnight. Gas evolves so a septum was used and equipped with an outlet needle. After 16 hours of stirring at room temperature, it looks like there is conversion to the desired product, although there's some starting material remaining. Concentrated in vacuo, then diluted with water and aq. citric acid until pH = 3. The mixture was transferred to a separatory funnel with DCM. The layers were separated, and the aqueous layer was extracted lx more with DCM. Dried over Na2SO4, filtered, concentrated in vacuo. The material was flashed using an 80 g column eluting 0 to 80% heptane in iPrOAc. Isolated tert-butyl (3 -(3 -ethoxy-3 -oxo-propanoyl)piperidine-l -carboxylate (4800 mg, 16 mmol, 4.8 g, 74% Yield) which contained some impurities but was taken forward without further purification.Step 2:

[0400] To a 250 mL round bottomed flask containing tert-butyl-3 -(3 -ethoxy-3 -oxo- propanoyl)piperidine-l -carboxylate (4800 mg, 16 mmol, 4.8 g) was added methanol (16 mL,1.0 M) and then cooled to 0 °C followed by sodium methoxide in methanol (5.25 mol / L, 12000 mg, 12 mL, 64 mmol, 4 equiv.) and then formamidine acetate (3300 mg, 32 mmol, 2 equiv.). The reaction was allowed to stir at room temperature and then heated to 75 °C, which was a very nice reflux rate for this setup. Monitored by LCMS - the starting material starts to convert to product when gets to refluxing temperature. After 4 hours refluxing at this temperature, the reaction was done. At this time, the resulting mixture was concentrated and 1 N aqueous solution of HC1 was used to acidify the mixture to pH 5 ~ 6. The mixture was extracted withDCM. The combined organic layers were washed with brine and dried over anhydrous Na2SO4, followed by concentration in vacuo. The organic residue was taken up in DCM, and quenched with aqueous saturated NH4CI. The aqueous layer was extracted 3x with 9: 1 CH Cl3 / IPA solution and concentrated in vacuo. The material was flashed with 80 g silica cartridge eluting 0 to 30% MeOH in DCM. Isolated tert-butyl -3-(6-hydroxypyrimidin-4-yl)piperidine-l- carboxylate (1060 mg, 3.79 mmol, 1.06 g, 24% Yield)Step 3:

[0401] To an oven dried 2-dram vial was added tert-butyl 3-(6-hydroxypyrimidin-4- yl)piperidine-l -carboxylate (350 mg, 1.25 mmol), 1 gram of PS-PPh3resin (Biotage, 2.0-2.2 mmol / g, 2.2 mmol) and purged with N2. 1,2-dichloroethane (2.5 mL, 0.5 M) added followed by carbon tetrachloride (578 mg, 0.364 mL, 3.76 mmol, 3 equiv.). Then an additional 5 mL of 1,2-dichloroethane was added and transferred to a 40 mL vial as the Biotage PS resin makes stirring difficult and required more solvent. The vial was sealed, and heated to 70 °C in a heating block. After 2 hours of stirring at this temperature, trace starting material remained, and another 400 mg of PS-PPh3resin (Biotage) and 1 mL CCl4were added. The vial was re- sealed and heated again. After an additional 30 min, the vial was cooled to room temperature, filtered, and flushed with DCM. Concentrated in vacuo. Flashed using a 40g silica gel cartridge, 0 to 90 % iPrOAc in heptane. Isolated tert-butyl 3-(6-chloropyrimidin-4-yl)piperidine-l- carboxylate (240 mg, 0.81 mmol, , 64% Yield)Step 4:

[0402] To 40 mL vial was added 3-[6-(aminomethyl)-4-chloro-7-fluoro-l-oxo- isoindolin-2-yl]piperidine-2, 6-dione (327 mg, 1.0 mmol, 1.3 equiv.) and tert-butyl 3-(6- chloropyrimidin-4-yl)piperidine-l -carboxylate (230 mg, 0.77 mmol) followed by DMSO (3.1 mL, 0.25 M) and N,N- diisopropylethylamine (299 mg, 0.40 mL, 2.32 mmol, 3 equiv.). The vial purged with N2, sealed, heated to 100 °C overnight. After 3 hours of stirring at this temperature,the reaction was checked by LCMS and looks pretty good by this time, but there was some starting material aryl chloride remaining so the reaction was allowed to continue stirring overnight. After 16 hours at this temperature, the reaction had gone to completion. The reaction mixture was diluted with water and DCM and transferred to a separatory funnel. The layers were separated; the aqueous layer extracted with DCM a further 3x. Dried over Na2SO4, filtered and concentrated in vacuo. Flashed on a 40 g silica gel cartridge, eluting with 0 to 60% MeOH in DCM. The material looks good but contains DMSO; DMSO was removed by using the Genevac set to 45 °C for 2 hours. Isolated tert-butyl 3-[6-[[7-chloro-2-(2,6-dioxo-3-piperidyl)- 4-fluoro-3-oxo-isoindolin-5-yl]methylamino]pyrimidin-4-yl]piperidine-l -carboxylate (500 mg, 0.85 mmol, 110 % Yield)Step 5:

[0403] To a 2 dram vial was added tert-butyl 3-[6-[[7-chloro-2-(2,6-dioxo-3- piperidyl)-4-fluoro-3-oxo-isoindolin-5-yl]methylamino]pyrimidin-4-yl]piperidine-l- carboxylate (400 mg, 0.68mmol, 400 mg), followed by DCM (2.7 mL, 0.25 M) and then HC1 in dioxane (4M HC1 in dioxane solution, 1.70 mL, 6.81 mmol, 10 equiv.). After 2 hours, no material was left and the reaction was concentrated in vacuo and concentrated again from toluene. Isolated 3-[4-chloro-7-fluoro-l-oxo-6-[[[6-(3-piperidyl)pyrimidin-4- yl]amino]methyl]isoindolin-2-yl]piperidine-2, 6-dione (330 mg, 0.68 mmol, 330 mg, 99% Yield).Intermediate 183-(6-(((6-((1S,4S )-2-oxa-5-azabicyclo[2.2.1]heptan-l-yl)pyrimidin-4-yl)amino)methyl)-4- chloro-7-fluoro-l-oxoisoindolin-2-yl)piperidine-2, 6-dione hydrochlorideStep 1:: tert-butyl (1S,4S)-l-(2,2-dimethyl-4,6-dioxo-l,3-dioxane-5-carbonyl)-2-oxa-5- azabi cy cl o [2.2.1 ] h eptan e- 5 -carb oxy 1 ate

[0404] To a solution of 2, 2-dimethyl-l,3-dioxane-4, 6-dione (13.7 g, 95.1 mmol) and (1S,4S)-5-(tert-butoxycarbonyl)-2-oxa-5-azabicyclo[2.2.1]heptane-l-carboxylic acid (21.04 g, 86.5 mmol) and N,N -dimethylpyridin-4-amine (11.6 g, 95.1 mmol) in dichloromethane (300 mL) was added dicyclohexylmethanediimine (26.8 g, 129.7 mmol) at 0 °C. The mixture was stirred at 20 °C for 16 hours. Then the mixture was filtered and the filtrate was washed withIM HC1 aqueous solution (150 mL x 4) and brine (100 mL x 2). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to give the title compound (31.9 g, crude) as yellow oil.1H NMR (400 MHz, CDCl3) δ 4.74 - 4.50 (m, 1H), 4.10 - 3.94 (m, 2H), 3.94 - 3.83 (m, 1H), 3.72 (d, J = 10.0 Hz, 1H), 2.90 - 2.73 (m, 1H), 2.33 (dd, J = 2.0, 9.6 Hz, 1H), 2.18 (s, 1H), 1.83 - 1.73 (m, 6H), 1.50 - 1.45 (m, 9H) LCMS (ESI): m / z 314.1 [M + H-56]+Step 2: tert-butyl (1S,4S)-l-(6-hydroxypyrimidin-4-yl)-2-oxa-5-azabicyclo[2.2.1]heptane-5- carb oxy late

[0405] The mixture of tert-butyl (1S,4S)-l-(2,2-dimethyl-4,6-dioxo-l,3-dioxane-5- carbonyl)-2-oxa-5-azabicyclo[2.2.1]heptane-5-carboxylate (31.9 g, 86.4 mmol) in methanol (500 mL) was stirred at 70 °C for 16 hours. The reaction solution was concentrated and the residue was purified by silica gel chromatography (0 - 9% ethyl acetate in petroleum ether) to give the title compound (18.9 g, 73% yield) as yellow oil.1H NMR (400 MHz, CDCl3) δ 4.66 - 4.48 (m, 1H), 4.09 - 3.93 (m, 2H), 3.79 - 3.62 (m, 6H), 3.54 - 3.37 (m, 1H), 2.25 - 2.09 (m, 1H), 2.03 - 1.85 (m, 1H), 1.46 (s, 9H)Step 3: tert-butyl (1S,4S)-l-(6-hydroxypyrimidin-4-yl)-2-oxa-5-azabicyclo[2.2.1]heptane-5- carb oxy late

[0406] To a solution of tert-butyl (1S,4S)-l-(3-methoxy-3-oxopropanoyl)-2-oxa-5- azabicyclo[2.2.1]heptane-5-carboxylate (18.5 g, 68.1 mmol) in methanol (300 mL) was added potassium carbonate (13.1 g, 94.7 mmol) and formimidamide hydrochloride (6.1 g, 75.8 mmol) at 25 °C. The mixture was stirred at 50 °C for 16 hours. The reaction mixture was filtered, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (0 - 5% methanol in di chloromethane) to afford the title compound (13.5 g, 73% yield) as a yellow solid.1H NMR (400 MHz, CDCl3) δ 8.13 (s, 1H), 6.80 (s, 1H), 4.74 - 4.53 (m, 1H), 4.15 - 3.98 (m, 2H), 3.82 (d, J = 10.0 Hz, 1H), 3.54 - 3.42 (m, 1H), 2.38 - 2.28 (m, 1H), 1.90 (d, J =10.0 Hz, 1H), 1.51 (s, 9H)Step 4: tert-butyl (1S,4S)-l-(6-chloropyrimidin-4-yl)-2-oxa-5-azabicyclo[2.2.1]heptane-5- carb oxy late

[0407] To a solution of tert-butyl (1S,4S)-l-(6-hydroxypyrimidin-4-yl)-2-oxa-5- azabicyclo[2.2.1]heptane-5-carboxylate (12.0 g, 40.91 mmol) and PPh3(21.5 g, 81.82 mmol) in DCE (200 mL) was added CCl4(11.9 mL, 123.53 mmol) at 25 °C, then the reaction mixture was stirred at 70 °C for 2.5 hours under N2. The reaction was concentrated and the residue waspurified by silica gel chromatography (0 - 11% ethyl acetate in hexane) to afford the title compound (11g, 86% yield) as colorless oil.1H NMR (400 MHz, CDCl3) δ 8.94 (d, J = 0.8 Hz, 1H), 7.73 (s, 1H), 4.77 - 4.57 (m, 1H), 4.20 - 4.02 (m, 2H), 3.91 (d, J = 10.4 Hz, 1H), 3.61 - 3.43 (m, 1H), 2.46 - 2.31 (m, 1H), 1.94 (d, J = 10.5 Hz, 1H), 1.51 (s, 9H)Step 5:: tert-butyl (1S,4S)-l-(6-(((7-chloro-2-(2,6-dioxopiperidin-3-yl)-4-fluoro-3- oxoisoindolin-5-yl)methyl)amino)pyrimidin-4-yl)-2-oxa-5-azabicyclo[2.2.1]heptane-5- carb oxy late

[0408] To a solution of 3-(6-(aminomethyl)-4-chloro-7-fluoro-l-oxoisoindolin-2- yl)piperidine-2, 6-dione hydrochloride (15.33 g, 42.34 mmol) in DMSO (100 mL) was added tert-butyl (1S,4S)-l-(6-chloropyrimidin-4-yl)-2-oxa-5-azabicyclo[2.2.1]heptane-5- carboxylate (11.0 g, 35.28 mmol) and DIEA (18.4 mL, 105.85 mmol). The mixture was stirred at 100 °C for 16 hours then diluted with water (300 mL), The precipitate was filtered and collected the cake, the filtrate was extracted with DCM (with 10% ethanol) (100 mL X 3), the combined organic layers were washed with brine (100 mL x 3). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue and the filter cake were combined and was purified by silica gel chromatography (0 - 10% EE (ethyl acetate / ethanol=3 / l) in dichloromethane) to afford the title compound (17.5 g, 83% yield) as a yellow solid. LCMS (ESI): m / z 601.2 [M + H]+.1H NMR (400 MHz, DMSO-d6)δ 11.03 (s, 1H), 8.41 (s, 1H), 8.09 (s, 1H), 7.67 (d, J = 4.8 Hz, 1H), 6.79 (s, 1H), 5.10 (dd, J = 5.2, 13.2 Hz, 1H), 4.65 (s, 2H), 4.55 - 4.43 (m, 2H), 4.30 (d, J = 18.0 Hz, 1H), 3.98 - 3.84 (m, 2H), 3.76 - 3.61 (m, 1H), 3.32 - 3.22 (m, 1H), 2.98 - 2.85 (m, 1H), 2.64 - 2.57 (m, 1H), 2.48 - 2.38 (m, 1H), 2.22 - 2.12 (m, 1H), 2.05 - 1.97 (m, 1H), 1.88 (d, J = 9.6 Hz, 1H), 1.41 (d, J = 8.6 Hz, 9H)Step 6:: 3-(6-(((6-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-l-yl)pyrimidin-4- yl)amino)methyl)-4-chloro-7-fluoro-l-oxoisoindolin-2-yl)piperidine-2, 6-dione hydrochloride

[0409] To a solution of tert-butyl (1S,4S)-l-(6-(((7-chloro-2-(2,6-dioxopiperidin-3- yl)-4-fluoro-3-oxoisoindolin-5-yl)methyl)amino)pyrimidin-4-yl)-2-oxa-5- azabicyclo[2.2.1]heptane-5-carboxylate (17.5 g, 29.12 mmol) in DCM (10 mL) was added 2M HCl / di oxane (80 mL, 160 mmol) at 0 °C, then the mixture was stirred at 25 °C for 2 hours. The reaction mixture was concentrated to give title compound (19.5 g, 99.7% yield) as a yellow solid.1HNMR (400 MHz, DMSO-d6)δ 11.03 (s, 1H), 10.17 (s, 1H), 9.94 (s, 1H), 9.66 (s, 1H), 8.69 (s, 1H), 7.77 (d, J = 4.8 Hz, 1H), 6.97 (s, 1H), 5.09 (dd, J = 5.2, 13.2 Hz, 1H), 4.77 (d, J = 4.0 Hz, 2H), 4.58 (s, 1H), 4.48 (d, J = 18.0 Hz, 1H), 4.37 - 4.26 (m, 2H), 4.01 - 3.95 (m, 1H), 3.67 - 3.60 (m, 1H), 3.47 - 3.37 (m, 1H), 2.97 - 2.86 (m, 1H), 2.64 - 2.55 (m, 1H), 2.47 - 2.37 (m, 2H), 2.30 - 2.19 (m, 1H), 2.05 - 1.99 (m, 1H)Intermediate 193-(6-(((6-((1S,4S )-2-oxa-5-azabicyclo[2.2.1]heptan-l-yl)pyrimidin-4-yl)amino)methyl)-4-(difluoromethoxy)-7-fluoro-l-oxoisoindolin-2-yl)piperidine-2, 6-dione hydrochlorideStep 1: tert-butyl (1S,4S)-l-(6-(((7-(difluoromethoxy)-2-(2,6-dioxopiperidin-3-yl)-4-fluoro-3- oxoisoindolin-5-yl)methyl)amino)pyrimidin-4-yl)-2-oxa-5-azabicyclo[2.2.1]heptane-5- carboxylate

[0410] To aa ssoolluuttiioonn of 3-(6-(aminomethyl)-4-(difluoromethoxy)-7-fluoro-l- oxoisoindolin-2-yl)piperidine-2, 6-dione hydrochloride (709 mg, 1.8 mmol) in DMSO (5 mL) was added tert-butyl (1S,4S)-l-(6-chloropyrimidin-4-yl)-2-oxa-5-azabicyclo[2.2.1]heptane-5- carboxylate (510 mg, 1.64 mmol) and DIEA (0.9 mL, 4.97 mmol). The mixture was stirred at 100 °C for 16 hours then was diluted with water (30 mL), extracted with DCM (with 10% ethanol) (20 mL x 3), the combined organic layers were washed with brine (20 mL x 3) then dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (0 - 10% EE (ethyl acetate / ethanol=3 / l) in dichloromethane) to afford the title compound (1 g, 97% yield) as a yellow solid. LCMS (ESI): m / z 633.4 [M + H]+.1H NMR (400 MHz, CDCI3) δ 8.55 (s, 1H), 8.53 - 8.43 (m, 1H), 7.45 (d, J = 4.0 Hz, 1H), 6.81 - 6.29 (m, 2H), 5.88 - 5.61 (m, 1H), 5.12 (dd, J = 5.6, 13.2 Hz, 1H), 4.88 - 4.51 (m, 3H), 4.44 (d, J = 17.2 Hz, 1H), 4.33 (d, J = 17.2 Hz, 1H), 4.17 - 3.99 (m, 2H), 3.95 - 3.80 (m, 1H), 3.53 - 3.39 (m, 1H), 2.99 - 2.89 (m, 1H), 2.89 - 2.75 (m, 1H), 2.43 - 2.28 (m, 2H), 2.28 - 2.18 (m, 1H), 1.98 - 1.86 (m, 1H), 1.50 (s, 9H)Step 2:: 3-(6-(((6-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-l-yl)pyrimidin-4- yl)amino)methyl)-4-(difluoromethoxy)-7-fluoro-l-oxoisoindolin-2-yl)piperidine-2, 6-dione hydrochloride

[0411] To a solution of tert-butyl (1S,4S)-l-(6-(((7-(difluoromethoxy)-2-(2,6- dioxopiperidin-3-yl)-4-fluoro-3-oxoisoindolin-5-yl)methyl)amino)pyrimidin-4-yl)-2-oxa-5- azabicyclo[2.2.1]heptane-5-carboxylate (1 g, 1.58 mmol) in DCM (5 mL) was added 2M HCl / di oxane (10 mL, 20 mmol) at 0 °C, then the mixture was stirred at 25 °C for 2 hours. The reaction mixture was concentrated to afford the title compound (890 mg, 99% yield) as a yellow solid.Intermediate 203-(6-(((6-((1S,4S )-2-oxa-5-azabicyclo[2.2.1]heptan-l-yl)pyrimidin-4-yl)amino)methyl)-7- fluoro-l-oxo-4-(trifluoromethoxy)isoindolin-2-yl)piperidine-2, 6-dione hydrochlorideStep 1:: tert-butyl (1S,4S)-l-(6-(((2-(2,6-dioxopiperidin-3-yl)-4-fluoro-3-oxo-7-(tri fluoromethoxy )isoindolin-5-yl)methyl)amino)pyrimidin-4-yl)-2-oxa-5- azabi cy cl o [2.2.1 ] h eptan e- 5 -carb oxy 1 ate

[0412] To a mixture of tert-butyl (1S,4S)-l-(6-chloropyrimidin-4-yl)-2-oxa-5- azabicyclo[2.2.1]heptane-5-carboxylate (200.0 mg, 0.64 mmol), 3-(6-(aminomethyl)-7-fluoro- l-oxo-4-(trifluoromethoxy)isoindolin-2-yl)piperidine-2, 6-dione (277.0 mg, 0.67 mmol) in DMSO (3 mL) was added DIPEA (0.34 mL, 1.92 mmol), the mixture was stirred at 80 °C for 16h. The mixture was diluted with water (100 mL), extracted with EtOAc (60 mL x 3), combined the organic phase and washed with brine (60 mL x 2). The organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The crude product was purified by silica gel chromatography (0 - 10% MeOH in di chloromethane) to afford the title compound (350 mg, 84%) as a white solid.1H NMR (400 MHz, CDCb) δ 8.56 (s, 1H), 8.28 (s, 1H), 7.57 (s, 1H), 6.82 - 6.64 (m, 1H), 5.74 - 5.46 (m, 1H), 5.16 (dd, J= 5.2, 13.2 Hz, 1H), 4.75 (d, J = 4.4 Hz, 2H), 4.70 - 4.68 (m, 1H), 4.54 - 4.45 (m, 1H), 4.41 - 4.30 (m, 1H), 4.13 - 3.96 (m, 2H), 3.91 - 3.76 (m, 1H), 3.52 - 3.37 (m, 1H), 3.01 - 2.92 (m, 1H), 2.90 - 2.77 (m, 1H), 2.44 - 2.31 (m, 2H), 2.30 - 2.19 (m, 1H), 1.95 - 1.81 (m, 1H), 1.53 - 1.42 (m, 9H)Step 22:: 3-(6-(((6-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-l-yl)pyrimidin-4- yl)amino)methyl)-7-fluoro-l -oxo-4-(tri fluoromethoxy )isoindolin-2-yl)piperidine-2, 6-dione hydrochloride

[0413] To a solution of tert-butyl (1S,4S)-1-(6-(((2-(2,6-dioxopiperidin-3-yl)-4- fluoro-3-oxo-7-(trifluoromethoxy)isoindolin-5-yl)methyl)amino)pyrimidin-4-yl)-2-oxa-5- azabicyclo[2.2.1]heptane-5-carboxylate (350.0 mg, 0.54 mmol) in DCM (2 mL) was added 2M HCl / dioxane (6 mL, 12 mmol), the mixture was stirred at 20oC for 2h. The mixture was concentrated under vacuum to afford the title compound (315 mg, 99.8%) as a white solid. LCMS (ESI): m / z 551.1 [M + H]+Intermediate 21 3-[6-[[[6-[(1S,5S)-3-azabicyclo[3.1.0]hexan-1-yl]pyrimidin-4-yl]amino]methyl]-4-chloro- 7-fluoro-1-oxo-isoindolin-2-yl]piperidine-2,6-dione;hydrochlorideStep 1: tert-butyl (1S,5S)-1-(3-ethoxy-3-oxopropanoyl)-3-azabicyclo[3.1.0]hexane-3- carboxylate

[0414] To a solution of (1S,5S)-3-tert-butoxycarbonyl-3-azabicyclo[3.1.0]hexane-1- carboxylic acid (2.0 g, 8.8 mmol) in Acetonitrile (10 mL) was added di(imidazol-1- yl)methanone (2.85 g, 17.6 mmol). The mixture was stirred at 50 °C for 1h. Then a solution of potassium 2-carboxybutanoate (3.0 g, 17.6 mmol) and magnesium chloride (1.68 g, 17.6 mmol) in Acetonitrile (10 mL) was added. The resulting mixture was stirred at 50 °C for 16 hours and concentrated directly. The residue was purified by silica gel chromatography (0 - 28% ethylacetate in petroleum ether) to afford the title compound (1.96 g, 61% yield) as a colorless solid. LCMS (ESI): m / z 242.1 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 4.12 - 7.40.707 (m, 2H), 3.74- 3.28 (m, 7H), 2.28 (s, 1H), 1.69 (s, 1H), 1.38 (s, 9H), 1.176 (s, 3H)Step 22:: tert-butyl (1S,5S)-l-(6-hydroxypyrimidin-4-yl)-3-azabicyclo[3.1.0]hexane-3- carboxylate

[0415] To a solution of imidoformamide hydrochloride (796.13 mg, 9.89 mmol) and NaOMe (3.05 mL, 16.48 mmol) (5.4 M in MeOH) in methanol (20 mL) was added tert-butyl (1S,5S)-l-(3-ethoxy-3-oxo-propanoyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (1.96 g, 6.59 mmol). The mixture was stirred at 80 °C for 16 hours then concentrated. The residue was purified by silica gel chromatography (0 - 10% MeOH in di chloromethane) to afford the title compound (1.3 g, 71% yield) as a white solid. LCMS (ESI): m / z 242.1 [M+H]+.1HNMR (400 MHz, DMSO-d6)δ 12.35 (d, .J= 2.0 Hz, 1H), 8.07 (s, 1H), 6.13 (d, .J= 7.6 Hz, 1H), 3.71 - 3.60 (m, 2H), 3.58 - 3.44 (m, 2H), 2.10 - 2.03 (m, 1H), 1.99 (s, 1H), 1.39 (s, 9H), 0.79 (t, J = 4.0 Hz, 1H)Step 3: tert-butyl (1S,5S)-l-(6-chloropyrimidin-4-yl)-3-azabicyclo[3.1.0]hexane-3- carboxylate

[0416] To a ssoolluuttiioonn of tert-butyl (1S,5S)-l-(6-hydroxypyrimidin-4-yl)-3- azabicyclo[3.1.0]hexane-3-carboxylate (1.3 g, 4.69 mmol) in 1,2-Dichloroethane (20 mL) was added PPh3(2.46 g, 9.38 mmol) and CCl4(20 mL). The mixture was stirred at 70 °C for 16 hours then concentrated. The residue was purified by silica gel chromatography (0 - 20% ethyl acetate in petroleum ether) to afford the title compound (534 mg, 39% yield) as a colorless oil. LCMS (ESI): m / z 240.1 [M+H]+.1HNMR (400 MHz, CDCI3) δ 8.80 (d, . J= 4.0 Hz, 1H), 7.20 - 7.03 (m, 1H), 3.97 - 3.66 (m, 3H), 3.52 - 3.42 (m, 1H), 2.30 - 2.21 (m, 1H), 1.67 - 1.58 (m, 1H), 1.48 (d, J = 6.0 Hz, 9H), 1.14 (d, J = 4.4 Hz, 1H)Step 4: tert-butyl (1S,5S)-1-(6-(((7-chloro-2-(2,6-dioxopiperidin-3-yl)-4-fluoro-3-oxoisoindolin-5-yl)methyl)amino)pyrimidin-4-yl)-3-azabicyclo[3.1.0]hexane-3-carboxylate

[0417] To a solution of tert-butyl (1S,5S)-1-(6-chloropyrimidin-4-yl)-3- azabicyclo[3.1.0]hexane-3-carboxylate (300.0 mg, 1.01 mmol) and 3-[6-(aminomethyl)-4- chloro-7-fluoro-1-oxo-isoindolin-2-yl]piperidine-2,6-dione (396.45 mg, 1.22 mmol) in DMSO (3 mL) was added DIPEA (394 mg, 3.04 mmol). The mixture was stirred at 80 °C for 16 h. The reaction mixture was diluted with ethyl acetate (10 mL), washed with brine (10 mL × 3), dried over anhydrous sodium sulfate, filtered and concentrated to dryness. The residue was purified by silica gel chromatography (0-55% ethyl acetate in petroleum ether) to afford the title compound (266 mg, 45% yield) as a white solid. LCMS (ESI): m / z 585.2 [M+H]+.1HNMR (400 MHz, DMSO-d6$ n 11.02 (s, 1H), 8.30 (s, 1H), 7.83 (s, 1H), 7.64 (d, J = 4.4 Hz,1H), 6.41 (s, 1H), 5.09 (dd, J = 5.2, 13.2 Hz, 1H), 4.62 (d, J = 4.4 Hz, 2H), 4.49 - 4.24 (m, 2H), 3.75 - 3.61 (m, 2H), 3.50 (d, J = 11.2 Hz, 1H), 3.25 – 3.15 (m, 2H), 2.95 - 2.85 (m, 1H), 2.61 – 2.56 (m, 1H), 2.47 - 2.34 (m, 1H), 2.10 - 2.00 (m, 2H), 1.40 (s, 9H), 0.79 (d, J = 3.6 Hz, 1H). Step 5: 3-(6-(((6-((1S,5S)-3-azabicyclo[3.1.0]hexan-1-yl)pyrimidin-4-yl)amino)methyl)-4- chloro-7-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione hydrochloride

[0418] The solution of tert-butyl (1S,5S)-1-(6-(((7-chloro-2-(2,6-dioxopiperidin-3- yl)-4-fluoro-3-oxoisoindolin-5-yl)methyl)amino)pyrimidin-4-yl)-3-azabicyclo[3.1.0]hexane- 3-carboxylate (266 mg, 0.45 mmol) in HCl (2 M in dioxane) was stirred at 20 °C for 1 h. The mixture was concentrated to afford the title compound (216 mg, crude) as a white solid. LCMS (ESI): m / z 485.2. [M + H]+Intermediate 223-(6-(((6-((1S,5S)-3-azabicyclo[3.1.0]hexan-1-yl)pyrimidin-4-yl)amino)methyl)-4- (difluoromethoxy)-7-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione hydrochlorideStep 1: tert-butyl (1S,5S)-1-(6-(((7-(difluoromethoxy)-2-(2,6-dioxopiperidin-3-yl)-4-fluoro-3- oxoisoindolin-5-yl)methyl)amino)pyrimidin-4-yl)-3-azabicyclo[3.1.0]hexane-3-carboxylate

[0419] To a solution of tert-butyl (1S,5S)-1-(6-chloropyrimidin-4-yl)-3- azabicyclo[3.1.0]hexane-3-carboxylate (300 mg, 1.01 mmol) and 3-(6-(aminomethyl)-4- (difluoromethoxy)-7-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione (435 mg, 1.22 mmol) in DMSO (3 mL) was added DIPEA (394 mg, 3.04 mmol). The mixture was stirred at 80 °C for 16 h. The reaction mixture was diluted with ethyl acetate (10 mL), washed with brine (10 mL × 3), dried over anhydrous sodium sulfate, filtered and concentrated to dryness. The residue was purified by silica gel chromatography (0-70% ethyl acetate in petroleum ether) to afford the title compound to afford the title compound (120 mg, 19% yield) as a white solid. LCMS (ESI): m / z 617.3 [M+H]+. Step 2: 3-(6-(((6-((1S,5S)-3-azabicyclo[3.1.0]hexan-1-yl)pyrimidin-4-yl)amino)methyl)-4- (difluoromethoxy)-7-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione hydrochloride

[0420] The solution of tert-butyl (1S,5S)-1-(6-(((7-(difluoromethoxy)-2-(2,6- dioxopiperidin-3-yl)-4-fluoro-3-oxoisoindolin-5-yl)methyl)amino)pyrimidin-4-yl)-3- azabicyclo[3.1.0]hexane-3-carboxylate (100 mg, 0.16 mmol) in HCl (2 M in dioxane) was stirred at 20 °C for 1 h. The mixture was concentrated to afford the title compound (83 mg, 93% yield) as a white solid. LCMS (ESI): m / z 517.2 [M + H]+Intermediate 23 3-(6-(((6-((1R,5R)-3-azabicyclo[3.1.0]hexan-1-yl)pyrimidin-4-yl)amino)methyl)-4-chloro- 7-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione hydrochlorideStep 1:tert-butyl (1R,5R)-1-(3-ethoxy-3-oxopropanoyl)-3-azabicyclo[3.1.0]hexane-3- carboxylate

[0421] To a solution of (1R,5R)-3-(tert-butoxycarbonyl)-3-azabicyclo[3.1.0]hexane- 1-carboxylic acid (2.0 g, 8.8 mmol) in Acetonitrile (10 mL) was added di(1H-imidazol-1- yl)methanone (2.9 g, 17.88 mmol) at 25 °C, the mixture was stirred at 50 °C for 16 hours. Then a solution of potassium 2-carboxybutanoate (3.0 g, 17.63 mmol) and magnesium chloride (1.7 g, 17.86 mmol) in Acetonitrile (10 mL) was added under N2. The mixture was stirred at 50 °Cfor 3 hours. The mixture was filtered and the filtrate was concentrated to residue, which was purified by silica gel chromatography (30 - 50% ethyl acetate in n-hexane) to afford the title compound (1.50 g, 57% yield) as colorless oil. LCMS (ESI): m / z 242.1. [M -56+ H]+.1H NMR (400 MHz, DMSO-d6) δ4.11 -4.06 (m, 2H), 3.75 - 3.17 (m, 7H), 2.28 (d, J= 3.6 Hz, 1H), 1.69 (s, 1H), 1.39 (s, 9H), 1.17 (t, J= 6.8 Hz, 3H)Step 22:: tert-butyl (1R,5R) -l-(6-hydroxypyrimidin-4-yl)-3-azabicyclo[3.1.0]hexane-3- carboxylate

[0422] To a solution of formimidamide hydrochloride (0.6 g, 7.45 mmol) and sodium methanolate (2.4 mL, 12.96 mmol) in methanol (20 mL) was added tert-butyl (1R,5R) -l-(3- ethoxy-3-oxopropanoyl)-3-azabicyclo[3.1.0]hexane-3 -carboxylate (1.5 g, 5.04 mmol). The mixture was stirred at 50 °C for 16 hours then was concentrated. The residue was purified by silica gel chromatography (0 - 10% methanol in dichloromethane) to afford the title compound (506 mg, 36% yield) as a brown solid. LCMS (ESI): m / z 222.1 [M -56+ H]+.JH NMR (400 MHz, DMSO- d6)δ 12.35 (br s, 1H), 8.07 (s, 1H), 6.13 (d, J= 7.2 Hz, 1H), 3.72 - 3.36 (m, 4H), 2.12 - 2.03 (m, 1H), 1.46 - 1.41 (m, 1H), 1.39 (s, 9H), 0.83 - 0.75 (m, 1H)Step 3: tert-butyl (1R,5R) -l-(6-chloropyrimidin-4-yl)-3-azabicyclo[3.1.0]hexane-3- carboxylate

[0423] To a solution of CCl4(0.1 mL, 1.08 mmol), tert-butyl (1R,5R)-1-(6- hydroxypyrimidin-4-yl)-3-azabicyclo[3.1.0]hexane-3 -carboxylate (100 mg, 0.36 mmol) in 1,2- Di chloroethane (5 mL) was added PPh3(189 mg, 0.72 mmol) at 25 °C. The reaction was stirred at 70 °C for 2 hours. The mixture was poured to water (10 mL), extracted with ethyl acetate (10 mL x 2), organic phase was washed with brine (10 mL x 2). The organic phase was dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated, the residue was purified by silica gel chromatography (30% ethyl acetate in n-hexane) to afford the titlecompound (96 mg, 87 % yield) as a yellow solid. LCMS (ESI): m / z 240.0 [M -56+ H]+.1H NMR (400 MHz, CDCI3) δ 8.80 (d, J= 3.6 Hz, 1H), 7.23 - 7.06 (m, 1H), 3.98 - 3.65 (m, 3H), 3.53 - 3.45 (m, 1H), 2.26 (s, 1H), 1.70 - 1.61 (m, 1H), 1.58 (s, 1H), 1.48 (d, J = 5.6 Hz, 9H), 1.14 (d, 4.4 Hz, 1H)Step 4: tert-butyl (1R,5R) -l-(6-(((7-chloro-2-(2,6-dioxopiperidin-3-yl)-4-fluoro-3- oxoisoindolin-5-yl)methyl)amino)pyrimidin-4-yl)-3-azabicyclo[3.1.0]hexane-3-carboxylate

[0424] To aa mmiixxttuurree of tert-butyl (1R,5R) -l-(6-chloropyrimidin-4-yl)-3- azabicyclo[3.1.0]hexane-3-carboxylate (96 mg, 0.31 mmol) and 3-(6-(aminomethyl)-4-chloro- 7-fluoro-l-oxoisoindolin-2-yl)piperidine-2, 6-dione hydrochloride (172 mg, 0.47 mmol) in Dimethyl sulfoxide (3.5 mL) was added N-ethyl-N-isopropylpropan-2-amine (0.18 mL, 1.03 mmol) at 25 °C. The mixture was stirred at 80 °C for 16 hours. The reaction mixture was diluted with ethyl acetate (10 mL), washed with brine (10 mL x 3), dried over anhydrous sodium sulfate, filtered and concentrated to dryness. The residue was purified by silica gel chromatography (0 - 70% ethyl acetate in petroleum ether) to afford the title compound (62 mg, 29% yield) as a yellow oil. LCMS (ESI): m / z 585.2 [M + H]+.1H NMR (400 MHz, DMSO-d6) 8 11.02 (s, 1H), 8.30 (s, 1H), 7.91 - 7.77 (m, 1H), 7.64 (d, J= 4.8 Hz, 1H), 6.41 (s, 1H), 5.09 (dd, J = 4.8, 13.2 Hz, 1H), 4.62 (d, J= 5.2 Hz, 2H), 4.52 - 4.41 (m, 1H), 4.35 - 4.23 (m, 1H), 3.83 - 3.57 (m, 2H), 3.55 - 3.47 (m, 1H), 3.44 - 3.33 (m, 1H), 3.02 - 2.82 (m, 1H), 2.64 - 2.53 (m, 1H), 2.46 - 2.37 (m, 1H), 2.10 - 1.99 (m, 2H), 1.40 (d, .J= 4.0 Hz, 9H), 0.98 - 0.67 (m, 2H).Step 5: 3-(6-(((6-((1R,5R) -3-azabicyclo[3.1.0]hexan-l-yl)pyrimidin-4-yl)amino)methyl)-4- chloro-7-fluoro-l-oxoisoindolin-2-yl)piperidine-2, 6-dione hydrochloride

[0425] To a solution of tert-butyl (1R,5R) - l-(6-(((7-chloro-2-(2,6-dioxopiperi din-3 - yl)-4-fluoro-3-oxoisoindolin-5-yl)methyl)amino)pyrimidin-4-yl)-3-azabicyclo[3.1.0]hexane- 3-carboxylate (62 mg, 0.11 mmol) in 1,4-Dioxane (2 mL) was added hydrogen chloride (1 mL, 4 mmol, 4M in Dioxane) at 25 °C. The reaction was stirred at 25 °C for 16 hours. The precipitate was filtered and dried to afford the title compound (50 mg, 85% yield) as a white solid. The crude product was used directly in the next step without further purification. LCMS (ESI): m / z 485.2 [M + H]+.Intermediate 243-(6-(((6-((1R, 5R) -3-azabicyclo[3.L0]hexan-l-yl)pyrimidin-4-yl)amino)methyl)-4- (difluoromethoxy)-7-fluoro-l-oxoisoindolin-2-yl)piperidine-2, 6-dione hydrochlorideStep 1: tert-butyl (1R,5R) -l-(6-(((7-(difluoromethoxy)-2-(2,6-dioxopiperidin-3-yl)-4-fluoro-3-oxoisoindolin-5-yl)methyl)amino)pyrimidin-4-yl)-3-azabicyclo[3.1.0]hexane-3-carboxylate

[0426] To aa mixture of tert-butyl (1R,5R) -l-(6-chloropyrimidin-4-yl)-3- azabicyclo[3.1.0]hexane-3-carboxylate (131 mg, 0.44 mmol) and 3-[6-(aminomethyl)-4- (difluoromethoxy)-7-fluoro-l-oxo-isoindolin-2-yl]piperidine-2, 6-dione (317 mg, 0.89 mmol) in Dimethyl sulfoxide (2 mL) was added N-ethyl-N-isopropylpropan-2-amine (0.23 mL, 1.33 mmol). The mixture was stirred at 80 °C for 16 hours. The reaction mixture was diluted with ethyl acetate (10 mL), washed with brine (10 mL x 3), dried over anhydrous sodium sulfate, filtered and concentrated to dryness. The residue was purified by silica gel chromatography (0- 80% ethyl acetate in petroleum ether) to afford the title compound (207 mg, 60%) as a yellow solid. LCMS (ESI): m / z 617.2 [M + H]+.1H NMR (400 MHz, DMSO-d6)δ 10.97 (s, 1H), 8.30(s, 1H), 7.78 (t, J = 5.6 Hz, 1H), 7.47 (d, J= 5.2 Hz, 1H), 7.21 (t, J= 73.6 Hz, 1H), 6.40 (s, 1H), 5.07 (dd, J= 5.2, 13.2 Hz, 1H), 4.61 (d, J= 5.6 Hz, 2H), 4.53 - 4.42 (m, 1H), 4.40 - 4.25 (m, 1H), 3.82 - 3.59 (m, 2H), 3.55 - 3.47 (m, 1H), 3.44 - 3.33 (m, 1H), 2.98 - 2.84 (m, 1H), 2.68 - 2.60 (m, 1H), 2.46 - 2.39 (m, 1H), 2.09 - 1.99 (m, 2H), 1.40 (s, 9H), 1.38 - 1.21 (m, 1H), 0.79 (s, 1H).Step 2: 3-(6-(((6-((1R,5R) -3-azabicyclo[3.1.0]hexan-l-yl)pyrimidin-4-yl)amino)methyl)-4-(difluoromethoxy)-7-fluoro-l-oxoisoindolin-2-yl)piperidine-2, 6-dione hydrochloride

[0427] To a solution of tert-butyl (1R,5R) -l-(6-((7-(difluoromethoxy)-2-(2,6- dioxopiperidin-3-yl)-4-fluoro-3-oxoisoindolin-5-yl)(methyl)amino)pyrimidin-4-yl)-3- azabicyclo[3.1.0]hexane-3-carboxylate (62 mg, 0.11 mmol) in 1,4-Dioxane (2 mL) was added hydrogen chloride (4M in dioxane, 1 mL, 4 mmol) at 25 °C . The reaction was stirred at 25 °C for 2 hours. The solid was filtered and dried to afford the title compound (200 mg, crude) as a white solid. The crude product was used directly in the next step without further purification. LCMS (ESI): m / z 517.2 [M + H]+.Intermediate 253-(6-(((6-((1R,4R) -2-oxa-5-azabicyclo[2.2.1]heptan-l-yl)pyrimidin-4-yl)amino)methyl)-4- chloro-7-fluoro-l-oxoisoindolin-2-yl)piperidine-2, 6-dione hydrochlorideStep 1: tert-butyl (1R,4R) -l-(3-methoxy-3-oxopropanoyl)-2-oxa-5-azabicyclo[2.2.1]heptane- 5-carboxylate

[0428] To a solution of (1R,4R) -5-(tert-butoxycarbonyl)-2-oxa-5- azabicyclo[2.2.1]heptane-l -carboxylic acid (5.5 g, 22.61 mmol) in DCM (100 mL) was added 2, 2-dimethyl-l,3-dioxane-4, 6-dione (3.58 g, 24.87 mmol) and DMAP (3.04 g, 24.87 mmol). Then DCC (5.61 mL, 33.91 mmol) was added at 0 °C. The reaction mixture was stirred at 25 °C for 16 hours. The reaction was filtrated and the cake was washed with DCM (50 mL), then the filtrate was washed with 0.5 M HC1 aqueous (50 mL x 3) and brine (50 mL) and the organic layer was dried over anhydrous sodium sulfate. Filtered and concentrated under reduced pressure. The crude product was stirred in methanol (80 mL) at 70 °C for 16 hours. The mixture was concentrated under reduced pressure. The residue was purified by silica gel chromatography (0 - 10% methanol in di chloromethane) to afford the title compound (4.2 g, 65%) as a yellow oil.1H NMR (400 MHz, DMSO-d6)δ 4.48 (d, J= 16.4 Hz, 1H), 3.97 - 3.90 (m, 1H), 3.83 (s, 2H), 3.64 (s, 2H), 3.56 - 3.47 (m, 1H), 3.30 (s, 1H), 2.15 - 2.02 (m, 2H), 1.40 (s, 9H).Step 2: tert-butyl (1R,4R) -l-(6-hydroxypyrimidin-4-yl)-2-oxa-5-azabicyclo[2.2.1]heptane-5- carb oxy late

[0429] To a solution of tert-butyl (1R,4R) -l-(3-methoxy-3-oxo-propanoyl)-2-oxa-5- azabicyclo[2.2.1]heptane-5-carboxylate (4.0 g, 13.36 mmol) in methanol (100 mL) was added K2CO3(2.77 g, 20.05 mmol) and formimidamide hydrochloride (1.29 g, 16.04 mmol). The mixture was stirred at 50 °C for 3 hours. The reaction was cooled to room temperature, the precipitate was filtered and the cake was washed with DCM (10 mL), the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (0 - 10% methanol in di chloromethane) to afford the title compound (3.9 g, 75%) as a white solid. LCMS (ESI): m / z 294.2 [M+H]+.Step 3: tert-butyl (1R,4R) -l-(6-chloropyrimidin-4-yl)-2-oxa-5-azabicyclo[2.2.1]heptane-5- carb oxy late

[0430] To a solution of tert-butyl (1R,4R)-l-(6-hydroxypyrimidin-4-yl)-2-oxa-5- azabicyclo[2.2.1]heptane-5-carboxylate (300 mg, 1.02 mmol) in DME (10 mL) was added CCl4(0.3 mL, 3.07 mmol) and PPh3(536 mg, 2.05 mmol). The mixture was stirred at 80 °C for 16 h. The mixture was diluted with water (30 mL), extracted with ethyl acetate (30 mL x 3) and the combined organic layers was washed with brine (30 mL). The organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (0 - 30% ethyl acetate in petroleum ether) to afford the title compound (280 mg, 88%) as a yellow oil. LCMS (ESI): m / z 312.2 [M+H]+.Step 4: tert-butyl (1R,4R)-l-(6-(((7-chloro-2-(2,6-dioxopiperidin-3-yl)-4-fluoro-3- oxoisoindolin-5-yl)methyl)amino)pyrimidin-4-yl)-2-oxa-5-azabicyclo[2.2.1]heptane-5- carb oxy late

[0431] To a solution of tert-butyl (1R,4R)-l-(6-chloropyrimidin-4-yl)-2-oxa-5- azabicyclo[2.2.1]heptane-5-carboxylate (100 mg, 0.32 mmol) in DMSO (5 mL) was added 3- (6-(aminomethyl)-4-chloro-7-fluoro-l-oxoisoindolin-2-yl)piperidine-2, 6-dione (125 mg, 0.38 mmol) and DIEA (0.17 mL, 0.96 mmol). The mixture was stirred at 100 °C for 16 hours. The mixture was diluted with water (30 mL), extracted with ethyl acetate (30 mL x 3) and the combined organic layers was washed with brine (30 mL). The organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (0 - 30% ethyl acetate in petroleum ether) to afford the title compound (130 mg, 67%) as a yellow oil. LCMS (ESI): m / z 602.3 [M+H]+.Step 5: 3-(6-(((6-((1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-l-yl)pyrimidin-4- yl)amino)methyl)-4-chloro-7-fluoro-l-oxoisoindolin-2-yl)piperidine-2, 6-dione hydrochloride

[0432] To a solution of tert-butyl ( 1R, 4R)- l-(6-(((7-chloro-2-(2,6-dioxopiperi din-3 - yl)-4-fluoro-3-oxoisoindolin-5-yl)methyl)amino)pyrimidin-4-yl)-2-oxa-5- azabicyclo[2.2.1]heptane-5-carboxylate (130 mg, 0.22 mmol) in DCM (5 mL) was added HC1 (1.3 mL, 2.6 mmol) (2M in dioxane). The mixture was stirred at 25 °C for 2 hours. The reaction solvent was removed under vacuo to afford the title compound (110 mg, 95%) as a white solid. LCMS (ESI): m / z 501.2 [M+H]+.Intermediate 263-(6-(((6-( (1R,4R) -2-oxa-5-azabicyclo[2.2.1]heptan-l-yl)pyrimidin-4-yl)amino)methyl)-4-(difluoromethoxy)-7-fluoro-l-oxoisoindolin-2-yl)piperidine-2, 6-dioneStep 1: tert-butyl (1R,4R) -l-(6-(((7-(difluoromethoxy)-2-(2,6-dioxopiperidin-3-yl)-4-fluoro-3-oxoisoindolin-5-yl)methyl)amino)pyrimidin-4-yl)-2-oxa-5-azabicyclo[2.2.1]heptane-5- carboxylate

[0433] To a solution of tert-butyl (1R,4R)-l-(6-chloropyrimidin-4-yl)-2-oxa-5- azabicyclo[2.2.1]heptane-5-carboxylate (180 mg, 0.58 mmol) in DMSO (5 mL) was added 3- (6-(aminomethyl)-4-(difluoromethoxy)-7-fluoro-l-oxoisoindolin-2-yl)piperidine-2, 6-dione hydrochloride (273 mg, 0.69 mmol) and DIEA (0.3 mL, 1.73 mmol). The mixture was stirred at 100 °C for 16 hours. The mixture was diluted with water (30 mL), extracted with ethyl acetate (30 mL x 3) and the combined organic layers was washed with brine (30 mL). The organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (0 - 30% ethyl acetate in petroleum ether) to afford the title compound (360 mg, 98%) as a yellow oil. LCMS (ESI): m / z 633.2 [M+H]+.Step 22:: 3-(6-(((6-((1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-l-yl)pyrimidin-4- yl)amino)methyl)-4-(difluoromethoxy)-7-fluoro-l-oxoisoindolin-2-yl)piperidine-2, 6-dione hydrochloride

[0434] To a solution of tert-butyl (1R,4R)-l-[6-[[7-(difluoromethoxy)-2-(2,6-dioxo- 3-piperidyl)-4-fluoro-3-oxo-isoindolin-5-yl]methylamino]pyrimidin-4-yl]-2-oxa-5- azabicyclo[2.2.1]heptane-5-carboxylate (360 mg, 0.57 mmol) in DCM (5 mL) was added HCI (3.6 mL, 7.2 mmol) (2M in dioxane). The mixture was stirred at 25 °C for 2 hours. The reaction solvent was removed under vacuo to afford the title compound (300 mg, 93%) as a white solid. LCMS (ESI): m / z 533.3[M+H]+.Intermediate 273-(6-(((6-(2-azabicyclo[2.2.2]octan-4-yl)pyrimidin-4-yl)amino)methyl)-4- (difluoromethoxy)-7-fluoro-l-oxoisoindolin-2-yl)piperidine-2, 6-dione hydrochlorideStep 1: tert-butyl 4-(3-ethoxy-3-oxopropanoyl)-2-azabicyclo[2.2.2]octane-2-carboxylate

[0435] To a ssoolluuttiioonn of 2-(tert-butoxycarbonyl)-2-azabicyclo[2.2.2]octane-4- carboxylic acid (1.8 g, 7.05 mmol) in acetonitrile (30 mL) was added CDI (2.3 g, 14.1 mmol) at 50 °C and stirred for 1 hour. Then TEA (2.0 mL, 14.1 mmol), potassium 3-ethoxy-3- oxopropanoate (2.4 g, 14.1 mmol) and MgCl2(1.3 g, 14.1 mmol) was added to the mixture and stirred at 50 °C for another16 hours. The reaction mixture was filtered, the filtrate was concentrated under vacuum. The residue was purified by silica gel chromatography (0 - 20% ethyl acetate in petroleum ether) to afford the title compound (1.1 g, 48% yield) as colorless oil. LCMS (ESI): m / z 270.1 [M + H-56]+Step 2: tert-butyl 4-(6-hydroxypyrimidin-4-yl)-2-azabicyclo[2.2.2]octane-2-carboxylate

[0436] To aa ssoolluuttiioonn ooff tert-butyl 4-(3 -ethoxy-3 -oxopropanoyl)-2- azabicyclo[2.2.2]octane-2-carboxylate (1.1 g, 3.38 mmol) in methanol (10 mL) was added K2CO3(700.1 mg, 5.07 mmol) and formimidamide hydrochloride (326.6 mg, 4.06 mmol), the mixture was stirred at 60 °C for 16 hours. The reaction mixture was filtered, the filtrate was concentrated under vacuum, the residue was purified by silica gel chromatography ( 0-5% methanol in di chloromethane) to afford the title compound (630 mg, 61 % yield) as colorless oil. LCMS (ESI): m / z 250.1 [M + H-56]+Step 3: tert-butyl 4-(6-chloropyrimidin-4-yl)-2-azabicyclo[2.2.2]octane-2-carboxylate

[0437] To aa ssoolluuttiioonn ooff tert-butyl 4-(6-hydroxypyrimidin-4-yl)-2- azabicyclo[2.2.2]octane-2-carboxylate (630.0 mg, 2.06 mmol), NMM (18.1 uL, 0.17 mmol) and DIEA (718.7 uL, 4.13 mmol) in acetonitrile (9 mL) was added POCl3(960 uL, 10.3 mmol) at 0 °C. The solution was stirred at 25 °C for 2 hours. The reaction mixture was quenched with NaHCO3saturated aqueous solution (10 mL), the mixture was extracted with ethyl acetate (50 mL x 2) and the combined organic layers were washed with brine (20 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (0 - 20 % ethyl acetate in n- hexane) to afford the title compound (600 mg, 89% yield) as a white solid. LCMS (ESI): m / z 268.0 [M + H-56]+Step 44:: tert-butyl 4-(6-(((7-(difluoromethoxy)-2-(2,6-dioxopiperidin-3-yl)-4-fluoro-3- oxoisoindolin-5-yl)methyl)amino)pyrimidin-4-yl)-2-azabicyclo[2.2.2]octane-2-carboxylate

[0438] To a solution of tert-butyl 4-(6-chloropyrimidin-4-yl)-2- azabicyclo[2.2.2]octane-2-carboxylate (200.0 mg, 0.62 mmol) in dimethyl sulfoxide (5 mL) was added DIEA (0.32 mL, 1.85 mmol) and 3-(6-(aminomethyl)-4-(difluoromethoxy)-7- fluoro-l-oxoisoindolin-2-yl)piperidine-2, 6-dione hydrochloride (291.8 mg, 0.74 mmol), the mixture was stirred at 80 °C for 16 hours. The reaction mixture was diluted with water (20 mL), extracted with ethyl acetate (50 mL x 2) and the combined organic layers were washed with brine (30 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (0 - 20% EE (ethyl acetate / ethanol = 3 / 1) in dichloromethane) to afford the title compound (350 mg, 87% yield) as a yellow solid. LCMS (ESI): m / z 645.3 [M + H]+Step 5: 3-(6-(((6-(2-azabicyclo[2.2.2]octan-4-yl)pyrimidin-4-yl)amino)methyl)-4-(difluoromethoxy)-7-fluoro-l-oxoisoindolin-2-yl)piperidine-2, 6-dione hydrochloride

[0439] To a solution of tert-butyl 4-(6-(((7-(difluoromethoxy)-2-(2,6-dioxopiperidin- 3 -yl)-4-fluoro-3 -oxoi soindolin-5 -yl)methyl)amino)pyrimidin-4-yl)-2- azabicyclo[2.2.2]octane-2-carboxylate (350.0 mg, 0.54 mmol) in 1,4-dioxane (1 mL) was added HC1 (2 mL, 8 mmol) (4M in dioxane). Then the resulting mixture was stirred at 20 °C for 2 hours. The reaction mixture was concentrated to afford the title compound (315 mg, 99% yield) as a yellow solid. LCMS (ESI): m / z 545.1 [M + H]+Intermediate 283-(6-(((6-(2-azabicyclo[2.2.2]octan-4-yl)pyrimidin-4-yl)amino)methyl)-4-chloro-7-fluoro- l-oxoisoindolin-2-yl)piperidine-2, 6-dione hydrochlorideStep 1: tert-butyl 4-(6-(((7-chloro-2-(2,6-dioxopiperidin-3-yl)-4-fluoro-3-oxoisoindolin-5- yl)methyl)amino)pyrimidin-4-yl)-2-azabicyclo[2.2.2]octane-2-carboxylate

[0440] To a solution ooff tert-butyl 4-(6-chloropyrimidin-4-yl)-2- azabicyclo[2.2.2]octane-2-carboxylate (150.0 mg, 0.46 mmol) and 3-(6-(aminomethyl)-4- chloro-7-fluoro-l-oxoisoindolin-2-yl)piperidine-2, 6-dione hydrochloride (251.6 mg, 0.69 mmol) in dimethyl sulfoxide (5 mL) was added DIEA (242.0 uL, 1.39 mmol). Then the resulting mixture was stirred at 80 °C for 16 hours. The reaction mixture was diluted with water (20 mL), extracted with ethyl acetate (50 mL x 2) and the combined organic layers were washed with brine (30 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (0-20% EE (ethyl acetate / ethanol = 3 / 1) in dichloromethane) to afford the title compound (230 mg, 81% yield) as a yellow solid. LCMS (ESI): m / z 613.1 [M + H]+Step 2: 3-(6-(((6-(2-azabicyclo[2.2.2]octan-4-yl)pyrimidin-4-yl)amino)methyl)-4-chloro-7- fluoro-l-oxoisoindolin-2-yl)piperidine-2, 6-dione hydrochloride

[0441] To a solution of tert-butyl 4-(6-(((7-chloro-2-(2,6-dioxopiperidin-3-yl)-4- fluoro-3-oxoisoindolin-5-yl)methyl)amino)pyrimidin-4-yl)-2-azabicyclo[2.2.2]octane-2- carboxylate (230. Omg, 0.38mmol) in 1,4-Dioxane (1 mL) was added HC1 (2 mL, 4 mmol)(2M in dioxane). Then the resulting mixture was stirred at 20 °C for 2 hours. The reaction mixture was concentrated to afford the title compound (206 mg, 99 % yield) as a yellow solid. LCMS (ESI): m / z 513.1 [M + H]+Intermediate 293-(6-(((6-(2-azabicyclo[2.2.2]octan-4-yl)pyrimidin-4-yl)amino)methyl)-7-fluoro-l-oxo-4-(trifluoromethoxy)isoindolin-2-yl)piperidine-2, 6-dione hydrochlorideStep 1: tert-butyl 4-(6-(((2-(2,6-dioxopiperidin-3-yl)-4-fluoro-3-oxo-7-(tri fluoromethoxy )isoindolin-5-yl)methyl)amino)pyrimidin-4-yl)-2-azabicyclo[2.2.2]octane- 2-carboxylate

[0442] To a solution of tert-butyl 4-(6-chloropyrimidin-4-yl)-2- azabicyclo[2.2.2]octane-2-carboxylate (100 mg, 0.31 mmol) and 3-(6-(aminomethyl)-7-fluoro- l-oxo-4-(trifluoromethoxy)isoindolin-2-yl)piperidine-2, 6-dione hydrochloride (140 mg, 0.34 mmol) in DMSO (1 mL) was added DIEA (0.16 mL, 0.93 mmol). Then the resulting mixture was stirred at 80 °C for 16 hours. The reaction mixture was diluted with water (10 mL), extracted with ethyl acetate (20 mL x 3) and the combined organic layers were washed with brine (10 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (0-30% EE (ethyl acetate: ethanol = 3: 1) in DCM) to afford the title compound (180 mg, 88% yield) as a yellow solid. LCMS (ESI): m / z 663.3&664.3 [M + H]+.Step 2: 3-(6-(((6-(2-azabicyclo[2.2.2]octan-4-yl)pyrimidin-4-yl)amino)methyl)-7-fluoro-l- oxo-4-(trifluoromethoxy)isoindolin-2-yl)piperidine-2, 6-dione hydrochloride

[0443] To a solution of tert-butyl 4-(6-(((2-(2,6-dioxopiperidin-3-yl)-4-fluoro-3-oxo- 7-(trifluoromethoxy)isoindolin-5-yl)methyl)amino)pyrimidin-4-yl)-2- azabicyclo[2.2.2]octane-2-carboxylate (180 mg, 0.27 mmol) in dioxane was added HCI (2 mL, 4 mmol)(2M in dioxane) was stirred at 20 °C for 2 hours. The reaction mixture was concentrated to afford the title compound (160 mg, 98% yield) as a yellow solid.Intermediate 30 (1S,4S)-l-(6-((4-methoxybenzyl)oxy)pyrimidin-4-yl)-2-oxa-5-azabicyclo[2.2.1]heptaneStep 1: / ert-butyl (1S,4S)-1-(6-((4-methoxybenzyl)oxy)pyrimidin-4-yl)-2-oxa-5- azabi cy cl o [2.2.1]heptane- 5 -carb oxy 1 ate

[0444] To a solution of (4-methoxyphenyl)m ethanol (222 mg, 1.6 mmol) in tetrahydrofuran (10mL) was added sodium hydride (192.45 mg, 4.81 mmol, 60%) at 0 °C under N2. The mixture was stirred at 0 °C for 60 minutes. Then tert-butyl (1S,4S)-l-(6- chloropyrimidin-4-yl)-2-oxa-5-azabicyclo[2.2.1]heptane-5-carboxylate (500 mg, 1.6 mmol) in tetrahydro furan (5 mL) was added. The mixture was stirred at 25 °C for 2 hours. The reaction was quenched with water (5 mL) and then extracted with ethyl acetate (10 mL x 2). The organic layer was combined and washed with brine (10 mL), dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting (0 - 33% ethyl acetate in petroleum ether) to give title compound (550 mg, 83% yield) as a white solid.1H NMR (400 MHz, DMSO-d6)δ 8.79 (s, 1H), 7.40 (d, J= 8.8 Hz, 2H), 7.05 (s,1H), 6.94 (d, J= 8.8 Hz, 2H), 5.37 (s, 2H), 4.59 - 4.48 (m, 1H), 4.40 (d, J= 5.6 Hz, 1H), 3.97 (s, 1H), 3.91 - 3.86 (m, 1H), 3.75 (s, 3H), 3.73 (s, 1H), 2.26 - 2.17 (m, 1H), 2.00 - 1.97 (m, 1H), 1.41 (d, J = 7.2 Hz, 9H)Step 2: (1S,4S)-l-(6-((4-methoxybenzyl)oxy)pyrimidin-4-yl)-2-oxa-5- azabicyclo[2.2.1]heptane

[0445] To a solution of / ert-butyl (1S,4S)-l-(6-((4-methoxybenzyl)oxy)pyrimidin-4- yl)-2-oxa-5-azabicyclo[2.2.1]heptane-5-carboxylate (400 mg, 1 mmol) in dichloromethane (5 mL) was added 2,6-dimethylpyridine (0.34 mL, 2.9 mmol) and TMSOTf (0.35 mL, 1.93 mmol) at 0 °C. The mixture was stirred at 25 °C for 1 hours. The solvent was concentrated under vacuum. The residue was purified by flash chromatography on silica gel eluting (0-100% ethyl acetate in petroleum ether) to afford (1S,4S)-l-(6-((4-methoxybenzyl)oxy)pyrimidin-4-yl)-2- oxa-5-azabicyclo[2.2.1]heptane (250 mg, 83% yield) as a yellow solid.1H NMR (400 MHz, DMSO-d6)δ 9.26 - 9.00 (m, 2H), 8.84 (s, 1H), 7.45 - 7.35 (m, 2H), 7.09 (s, 1H), 6.95 (d, J = 8.4 Hz, 2H), 5.39 (s, 2H), 4.59 (s, 1H), 4.15 (d, J = 9.2 Hz, 1H), 4.03 (d, J= 8.8 Hz, 1H), 3.76 (s, 3H), 3.64 - 3.57 (m, 1H), 3.52 - 3.43 (m, 1H), 2.36 - 2.25 (m, 2H).Example 1Step 1: N-cyano-4-(trifluoromethyl)benzimidamide

[0446] The solution of 4-(trifluoromethyl)benzonitrile (200 mg, 1 mmol) and sodium methanolate (5.4 mg, 0.10 mmol) in Methyl alcohol (4 mL) was stirred for 4h. Then cyanamide (62.9 mg, 1.50 mmol) was added. The resulting mixture was stirred at 25 °C for 16 h. The mixture was diluted with water (5 mL) and extracted with dichloromethane (5 mL x 3). The combined organic extracts were concentrated to dryness under reduced pressure to afford the title compound (110 mg, 45%).1H NMR (400 MHz, DMSO-d6)δ 8.92 (br s, 2H), 8.11 (d, J = 8.0 Hz, 2H), 7.88 (d, J= 8.0 Hz, 2H).Step 2: 2-Chloro-4-(4-(trifluoromethyl)phenyl)-l,3,5-triazine

[0447] To a solution of and N-cyano-4-(trifluoromethyl)benzamidine (110 mg, 0.52 mmol) in Acetonitrile (2 mL) was added N-(chloromethylene)-N-methylmethanaminium chloride (99 mg, 0.77 mmol), the mixture was stirred at 25 °C for 16 h. The mixture was diluted with water (1 mL) and extracted with ethyl acetate (5 mL x 3). The combined organic extracts were concentrated to dryness under reduced pressure. The resulting residue was purified by pre-TLC (25 % ethyl acetate in petroleum ether) to afford the title compound (30 mg, 22%) as a yellow solid.1H NMR (400 MHz, DMSO-d6)δ 9.39 (s, 1H), 8.61 (d, J= 8.4 Hz, 2H), 8.00 (d, J = 8.4 Hz, 2H).Step 3: 3-(4-Chloro-7-fluoro-l-oxo-6-(((4-(4-(trifluoromethyl)phenyl)-l,3,5-triazin-2- yl)amino)methyl)isoindolin-2-yl)piperidine-2, 6-dione

[0448] To a solution of 3-(6-(aminomethyl)-4-chloro-7-fluoro-l-oxoisoindolin-2- yl)piperidine-2, 6-dione (50 mg, 0.14 mmol) in DMA (2 mL) was added DIPEA (0.06 mL, 0.35 mmol) and 2-chloro-4-[4-(trifluoromethyl)phenyl]-l,3,5-triazine (30.0 mg, 0.12 mmol). The mixture was stirred at 80 °C for 5 hours. The crude product was purified by Prep-HPLC (Xtimate C18 150*30mm*5um, water (HCl)-ACN, 50-80%) to afford Compound 1 (22.6 mg, 35%) as a white solid. LCMS (ESI): m / z 548.9 [M + H]+.1H NMR (400 MHz, DMSO-d6)δ 11.09 (s, 1H), 9.01 - 8.85 (m, 1H), 8.82 - 8.66 (m, 1H), 8.62 - 8.39 (m, 2H), 7.93 - 7.87 (m, 2H), 7.85 - 7.65 (m, 1H), 5.16 - 4.97 (m, 1H), 4.80 - 4.61 (m, 2H), 4.52 - 4.36 (m, 1H), 4.36 - 4.17 (m, 1H), 3.00 - 2.83 (m, 1H), 2.63-2.60 (m, 1H), 2.39-2.36 (m, 1H), 2.10 - 1.90 (m, 1H).Example 23-(7-Fluoro-l-oxo-6-(((6-(4-(trifluoromethyl)phenyl)pyridazin-4- yl)amino)methyl)isoindolin-2-yl)piperidine-2, 6-dioneStep 1 : 3-(6-(((6-Chloropyridazin-4-yl)amino)methyl)-7-fluoro-l-oxoisoindolin-2- yl)piperidine-2, 6-dione

[0449] To a solution of 3,5-dichloropyridazine (400.0 mg, 2.68 mmol) in DMA (6 mL) was added DIPEA (1.4 mL, 8.05 mmol) and 3-(6-(aminomethyl)-7-fluoro-l- oxoisoindolin-2-yl)piperidine-2, 6-dione (1.58 g, 4.83 mmol). The mixture was stirred at 80 °C for 16 hours. The residue was purified by Prep-HPLC (Xtimate C18 150*40mm*5um, water (HCl)-ACN, 10-40%) to afford 3-(6-(((6-chloropyridazin-4-yl)amino)methyl)-7-fluoro-l- oxoisoindolin-2-yl)piperidine-2, 6-dione (150 mg, 14% yield). LCMS (ESI): m / z 404.1 [M +H]+.1H NMR (400 MHz, DMSO-d6)δ 11.00 (s, 1H), 8.63 (s, 1H), 8.47 - 8.28 (m, 1H), 7.67 (t, J= 7.6 Hz, 1H), 7.42 (d, J= 7.6 Hz, 1H), 6.98 (s, 1H), 5.07 (dd, J= 13.2, 4.2 Hz, 1H), 4.57 (d, J = 5.2 Hz, 2H), 4.51 - 4.42 (m, 1H), 4.40 - 4.27 (m, 1H), 3.01 - 2.82 (m, 1H), 2.66 - 2.57 (m, 1H), 2.40 - 2.38 (m, 1H), 2.02 - 2.01 (m, 1H). The regioselectivity was confirmed by NOE.Step 2: 3-(7-Fluoro-l-oxo-6-(((6-(4-(trifluoromethyl)phenyl)pyridazin-4- yl)amino)methyl)isoindolin-2-yl)piperidine-2, 6-dione

[0450] Under nitrogen atmosphere, a mixture of 3-(6-(((6-chloropyridazin-4- yl)amino)methyl)-7-fluoro-l-oxoisoindolin-2-yl)piperidine-2, 6-dione (150 mg, 0.37 mmol) in 1,4-Dioxane (1 mL) and Water (0.10 mL) was added (4-(trifluoromethyl)phenyl)boronic acid (106 mg, 0.56 mmol), Pd(dppf)Cl2(27 mg, 0.04 mmol) and Na2CO3(118 mg, 1.11 mmol) at 20 °C. Then the resulting mixture was stirred heated at 100 °C for 0.5 h by microwave. The reaction mixture was filtered, the filtrate was concentrated in vacuo. The residue was purified by pre-TLC to afford a crude product which was further purified by Prep-HPLC to afford Compound 2 (3.4 mg, 2%) as a white solid. LCMS (ESI): m / z 513.9 [M + H]+.1H NMR (400 MHz, DMSO-d6)δ 11.00 (s, 1H), 9.63 - 9.09 (m, 1H), 8.70 (s, 1H), 8.16 (d, J= 8.0 Hz, 2H), 8.02 (d, J= 8.0 Hz, 2H), 7.81 - 7.68 (m, 1H), 7.57 (t, J= 6.0 Hz, 1H), 7.45 (d, J= 7.6 Hz, 1H), 5.07 (dd, J= 13.6, 5.6 Hz, 1H), 4.90 - 4.76 (m, 2H), 4.56 - 4.44 (m, 1H), 4.40 - 4.29 (m, 1H), 2.93 - 2.84 (m, 1H), 2.62 ( s, 1H), 2.40 - 2.35 (m, 1H), 2.04 - 1.97 (m, 1H).Example 33-(7-Fluoro-l-oxo-6-(((5-(4-(trifluoromethyl)phenyl)pyridazin-3- yl)amino)methyl)isoindolin-2-yl)piperidine-2, 6-dioneStep 1: 3-chloro-5-(4-(trifluoromethyl)phenyl)pyridazine

[0451] To a mixture of 5-bromo-3-chloropyridazine (1.0 g, 5.17mmol) was added 4- (trifluoromethyl)phenylboronic acid (0.88g, 4.65mmol), sodium carbonate (2.19g, 20.68mmol) and Pd(dppf )Cl2(75.66mg, O.lmmol) in 1,4-Dioxane (16mL) and Water (4mL). The mixture was stirred at 80 °C for Ih under nitrogen atmosphere. The reaction mixture was diluted with ethyl acetate (150 × 3 mL), washed with brine (20 mL), dried over Na2SO4and concentrated to dryness. The crude was purified by column chromatography (silica gel, 100-200 mesh, 4% ethyl acetate in petroleum ether) to give the title compound (1 g, 75%) as a white solid. LCMS (ESI): m / z 258.8 [M + H]+.Step 2: 3-(7-Fluoro-l-oxo-6-(((5-(4-(trifluoromethyl)phenyl)pyridazin-3- yl)amino)methyl)isoindolin-2-yl)piperidine-2, 6-dione

[0452] To a solution of 3-chloro-5-(4-(trifluoromethyl)phenyl)pyridazine (50 mg, 0.19 mmol) in 2-methyl-2-butanol (2 mL) was added sodium 2-methylpropan-2-olate (56 mg, 0.58 mmol) and 3-(6-(aminomethyl)-7-fluoro-l-oxoisoindolin-2-yl)piperidine-2, 6-dione (67 mg, 0.23 mmol) and BrettPhos-Pd-G3(CAS#: 1470372-59-8) at 0 °C. Then the resulting mixture was stirred at 110 °C for 16 h. The resulting residue was purified by reverse phase chromatography (acetonitrile 23 - 53% / 0.2% formic acid in water) to afford Compound 3 (4.2 mg, 4%) as a white solid. LCMS (ESI): m / z 514.2 [M + H]+ 1H NMR (400 MHz, DMSO- d6)δ 11.00 (s, 1H), 8.87 (d, J= 1.6 Hz, 1H), 8.01 - 7.94 (m, 2H), 7.93 - 7.86 (m, 2H), 7.69 (t, J = 7.2 Hz, 1H), 7.58 (t, J = 6.0 Hz, 1H), 7.37 (d, J = 7.6 Hz, 1H), 7.15 (d, J = 1.6 Hz, 1H), 5.11 - 5.03 (m, 1H), 4.75 (d, J = 5.6 Hz, 2H), 4.50 - 4.40 (m, 1H), 4.36 - 4.27 (m, 1H), 2.96 - 2.85 (m, 1H), 2.62 - 2.57 (m, 1H), 2.39-2.36 (m, 1H), 2.04 - 1.95 (m, 1H).Example 43-(7-Fluoro-l-oxo-6-(((4-(4-(trifluoromethyl)phenyl)pyridin-2- yl)amino)methyl)isoindolin-2-yl)piperidine-2, 6-dioneStep 1: 2-Bromo-4-(4-(trifluoromethyl)phenyl)pyridine

[0453] To a solution of 2-bromo-4-iodopyridine (400 mg, 1.41 mmol), 4- (trifluoromethyl)phenylboronic acid (267.61 mg, 1.41 mmol) and Na2CO3(597 mg, 5.64 mmol) in Toluene (8 mL) and Ethanol (1.6 mL) was added Pd(PPh3)4(81 mg, 0.07 mmol). The mixture was stirred at 100 °C for 16 hoursunder N2atmosphere. The reaction mixture was extracted with EtOAc (20 mL x 3). The organic layer was washed with water (20 mL) and brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give a residue. The crude was purified by column chromatography 0 - 20% ethyl acetate in petroleum ether to give the title compound (320 mg, 75%) as yellow solid.Step 2: 3-(7-Fluoro-l-oxo-6-(((4-(4-(trifluoromethyl)phenyl)pyridin-2- yl)amino)methyl)isoindolin-2-yl)piperidine-2, 6-dione

[0454] To a solution of 2-bromo-4-[4-(trifluoromethyl)phenyl]pyridine (100 mg, 0.33 mmol) and sodium tert-butoxide (95 mg, 0.99 mmol) in 1,4-Dioxane (3 mL) was added Gphos-Pd-G6 (31 mg, 0.03 mmol) (CAS#: 2489525-81-5) and 3-[6-(aminomethyl)-7-fluoro- l-oxo-isoindolin-2-yl]piperidine-2, 6-dione hydrochloride (217 mg, 0.66 mmol). The mixture was stirred at 110 °C for 16 hours under N2. The solution was purified by prep-HPLC(acetonitrile 20-50 % / 0.225% formic acid in water) to give Compound 4 (7.1 mg, 4%) as white solid. LCMS (ESI): m / z 513.1 [M + H]+.1H NMR (400 MHz, DMSO-d6)δ 11.00 (s, 1H), 8.07 (d, J= 6.0 Hz, 1H), 7.88 - 7.81 (m, 4H), 7.64 (t, J= 7.2 Hz, 1H), 7.34 (d, J= 7.6 Hz, 1H), 7.30 (t, J= 6.0 Hz, 1H), 6.87 - 6.84 (m, 2H), 5.05 (dd, J= 5.2, J = 13.2 Hz, 1H), 4.63 (d, J = 5.6 Hz, 2H), 4.47 - 4.25 (m, 2H), 2.94 - 2.85 (m, 1H), 2.62 - 2.56 (m, 1H), 2.41 - 2.31 (m, 1H), 2.05 - 1.94 (m, 1H).Example 56-(((2-(2,6-Dioxopiperidin-3-yl)-4-fluoro-3-oxoisoindolin-5-yl)methyl)amino)-4-(4-(trifluoromethyl)phenyl)nicotinonitrileStep 1: 6-Methoxy-4-(4-(trifluoromethyl)phenyl)nicotinonitrile

[0455] To the mixture of 4-chloro-6-methoxynicotinonitrile (100 mg, 0.59 mmol) in Water (0.5 mL) and 1,4-Dioxane (2 mL) was added potassium phosphate (315 mg, 1.48 mmol), (4-(trifluoromethyl)phenyl)boronic acid (124 mg, 0.65 mmol) and XPhos-Pd-G2(23 mg, 0.03 mmol) at 20 °C. Then the resulting mixture was stirred at 80 °C for 12 h under nitrogen atmosphere. The reaction mixture was filtered, the filtrate was concentrated in vacuo. The residue was purified by column chromatography 0 - 2% ethyl acetate in petroleum ether to afford the title compound (160 mg, 97%) as white solid.1H NMR (400 MHz, DMSO-d6)δ 8.85 (s, 1H), 7.95 (d, J= 8.4 Hz, 2H), 7.88 (d, J= 8.0 Hz, 2H), 7.18 (s, 1H), 4.00 (s, 3H).Step 2: 6-Hydroxy-4-(4-(trifluoromethyl)phenyl)nicotinonitrile

[0456] To a solution of 6-methoxy-4-(4-(trifluoromethyl)phenyl)nicotinonitrile (130 mg, 0.47 mmol) in Acetonitrile (2 mL) was added Nal (210 mg, 1.4 mmol), then was added TMSC1 (178.3 uL, 1.4 mmol). The mixture was stirred at 80 °C for 2 hours. The mixture was concentrated and purified by column chromatography 0 - 10% methyl alcohol in dichloromethane to afford the title compound (100 mg, 81%) as a white solid. LCMS (ESI): m / z 264.9 [M + H]+.Step 3: 6-Chloro-4-(4-(trifluoromethyl)phenyl)nicotinonitrile

[0457] To a solution of 6-hydroxy-4-(4-(trifluoromethyl)phenyl)nicotinonitrile (100 mg, 0.38 mmol) was added phosphoryl trichloride (0.5 mL, 5.36 mmol) and the solution was heated to 100 °C. and stirred for 2 hours. The reaction mixture was diluted with NH4CI saturated aqueous solution (5 mL), extracted with ethyl acetate (3 x 10 mL) and the combined organic layers was washed with brine (5 mL). The organic layers were dried over with Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by prep-TLC (20% ethyl acetate in petroleum ether) to afford the title compound (100 mg, 94%) as a white solid. LCMS (ESI): m / z 283.0 [M + H]+.Step 4: 6-(((2-(2,6-Dioxopiperidin-3-yl)-4-fluoro-3-oxoisoindolin-5-yl)methyl)amino)-4-(4-(trifluoromethyl)phenyl)nicotinonitrile

[0458] To a solution of 6-chloro-4-(4-(trifluoromethyl)phenyl)nicotinonitrile (100 mg, 0.35 mmol) and 3-(6-(aminomethyl)-7-fluoro-l-oxoisoindolin-2-yl)piperidine-2, 6-dionehydrochloride (174 mg, 0.53 mmol) in DMA (3 mL) was added 2,3,4,6,7,8,9,10- octahydropyrimido[l,2-α]azepine (79.4 uL, 0.53 mmol) and DIPEA (92.4 uL, 0.53 mmol). The mixture was stirred at 80 °C for 12 hours. The crude product was purified by Prep-HPLC (Welch Xtimate C18 150*30mm*5um, water (0.225%FA)-ACN, 47-77%) to afford Compound 5 (88 mg, 46%) as a white solid. LCMS (ESI): m / z 538.2 [M + H]+.1H NMR (400 MHz, DMSO-d6)δ 11.01 (s, 1H), 8.54 (s, 1H), 8.33 (t, J = 5.2 Hz, 1H), 7.92 (d, J= 8.4 Hz, 2H), 7.78 (d, J = 8.0 Hz, 2H), 7.64 (t, J= 7.2 Hz, 1H), 7.38 (d, J = 7.6 Hz, 1H), 6.71 (s, 1H), 5.07 (dd, J= 5.2, 13.2 Hz, 1H), 4.71 (d, J= 6.0 Hz, 2H), 4.51 - 4.39 (m, 1H), 4.37 - 4.26 (m, 1H), 2.96 - 2.85 (m, 1H), 2.63 - 2.56 (m, 1H), 2.44 - 2.34 (m, 1H), 2.05 - 1.96 (m, 1H).Example 63-(7-Fluoro-l-oxo-6-(((5-(3-(trifluoromethyl)piperidine-l-carbonyl)pyrazin-2- yl)amino)methyl)isoindolin-2-yl)piperidine-2, 6-dioneStep 1: 5-Chloropyrazine-2-carbonyl chloride

[0459] To a mixture of 5-chloropyrazine-2-carboxylic acid (300 mg, 1.89 mmol) in Dichloromethane (3 mL) was added 1 drop of DMF and oxalyl di chloride (0.18 mL, 2.18 mmol) at 0 °C. Then the resulting mixture was stirred at 20 °C for 30 min. The reaction mixture was concentrated to afford the title compound (335 mg, crude) as a brown oil which was used directly in the next step without purification.Step 2: (5-Chloropyrazin-2-yl)(3-(trifluoromethyl)piperidin-l-yl)methanone

[0460] To a mixture of 3-(trifluoromethyl)piperidine hydrochloride (395 mg, 2.08 mmol) and triethylamine (0.87 mL, 6.24 mmol) in Dichloromethane (6 mL) was added 5- chloropyrazine-2-carbonyl chloride (335 mg, 1.89 mmol) at 0 °C. Then the resulting mixture was stirred at 20 °C for 12 h. The reaction mixture was concentrated to dryness. The residue was purified by column chromatography 0 - 10% ethyl acetate in petroleum ether to afford the title compound (500 mg, 90%) as colorless oil.1H NMR (400 MHz, DMSO-d6)δ 8.84 (d, J= 1.2 Hz, 1H), 8.77 - 8.68 (m, 1H), 4.57 - 4.31 (m, 1H), 3.98 - 3.62 (m, 1H), 3.19 - 2.95 (m, 2H), 2.70 - 2.55 (m, 1H), 1.89 - 1.44 (m, 4H).Step 3: 3-(7-Fluoro-l-oxo-6-(((5-(3-(trifluoromethyl)piperidine-l-carbonyl)pyrazin-2- yl)amino)methyl)isoindolin-2-yl)piperidine-2, 6-dione

[0461] To a solution of (5-chloropyrazin-2-yl)(3-(trifluoromethyl)piperidin-l- yl)methanone (200 mg, 0.68 mmol) in 2-methyl-2-butanol (8 mL) was added 3-(6- (aminomethyl)-7-fluoro-l-oxoisoindolin-2-yl)piperidine-2, 6-dione (238 mg, 0.82 mmol) and sodium 2-methylpropan-2-olate (196 mg, 2.04 mmol), 4A molecular sieve and BrettPhos-Pd- G3(CAS#: 1470372-59-8) (62 mg, 0.07 mmol). The reaction mixture was stirred at 110 °C for 2 hours. The reaction mixture was filtered, the filtrate was concentrated in vacuo. The residue was purified by Prep-HPLC (Cl 8 150*30mm, water (0.225% FA)-ACN, 30-60%) to afford Compound 6 (10.1 mg, 3%) as a yellow solid. LCMS (ESI): m / z 549.3 [M + H]+.1H NMR (400 MHz, DMSO-d6)δ 11.00 (s, 1H), 8.27 (s, 1H), 8.18 (t, J= 5.6 Hz, 1H), 7.94 (s, 1H), 7.64 (t, J= 7.2 Hz, 1H), 7.37 (d, J= 7.6 Hz, 1H), 5.07 (dd, J= 5.2, 13.2 Hz, 1H), 4.63 (d, J= 5.6 Hz, 2H), 4.38 - 4.25 (m, 1H), 4.58 - 4.08 (m, 3H), 3.09 - 2.83 (m, 3H), 2.65 - 2.63 (m, 1H),2.65 - 2.52 (m, 1H), 2.44 - 2.34 (m, 1H), 2.05 - 1.92 (m, 2H), 1.80 - 1.64 (m, 1H), 1.63 - 1.44 (m, 2H).Example 73-(7-Fluoro-l-oxo-6-(((5-(3-(trifluoromethyl)phenoxy)pyrazin-2- yl)amino)methyl)isoindolin-2-yl)piperidine-2, 6-dioneStep 1: 2-Chloro-5-(3-(trifluoromethyl)phenoxy)pyrazine

[0462] To a mixture of 3-(trifluoromethyl)phenol (300 mg, 1.85 mmol) in DMF (10 mL) was added NaH (96 mg, 2.41 mmol, 60% purity) at 0 °C under N2. The mixture was stirred at 25 °C for 30 minutes. Then 2, 5 -dichloropyrazine (276 mg, 1.85 mmol) was added to the solution and stirred at 25 °C for 16 hours. The reaction was quenched with water (10 mL) and extracted with ethyl acetate (10 mL x 3). the organic layer was dried with anhydrous Na2SO4, filtered and concentrated under vacuo, the residue was purified by column chromatography 0 - 10% ethyl acetate in petroleum ether to afford the title compound (150 mg, 30%) as a yellow solid, LCMS (ESI): m / z 274.8 [M + H]+.Step 2: 3-(7-Fluoro-l-oxo-6-(((5-(3-(trifluoromethyl)phenoxy)pyrazin-2- yl)amino)methyl)isoindolin-2-yl)piperidine-2, 6-dione

[0463] To a solution of 2-chloro-5-(3-(trifluoromethyl)phenoxy)pyrazine (150 mg, 0.55 mmol) in 2-methylbutan-2-ol (4 mL), was added BrettPhos-Pd-G3(CAS#: 1470372-59-8)(49.5 mg, 0.05 mmol), 3-(6-(aminomethyl)-7-fluoro-l-oxoisoindolin-2-yl)piperidine-2,6- dione hydrochloride (190 mg, 0.66 mmol) and NaOtBu (157 mg, 1.64 mmol). The reaction mixture was stirred at 110 °C for 2 hours. The solution was filtered and purified by Prep-HPLC (Welch Xtimate C18 150*30mm*5um water (0.225%FA)-ACN, 52% - 72%) to afford Compound 7 (15.1 mg, 5%) as white solid. LCMS (ESI): m / z 530.0 [M + H]+.1H NMR (400 MHz, DMSO-d6)δ 11.00 (s, 1H), 7.98 (d, J= 1.2 Hz, 1H), 7.73 (d, J= 1.2 Hz, 1H), 7.68 - 7.65 (m, 1H), 7.63 - 7.57 (m, 2H), 7.47 (d, J= 7.6 Hz, 1H), 7.39 - 7.35 (m, 2H), 7.32 - 7.30 (m, 1H), 5.07 (dd, J= 5.2 Hz, 13.6 Hz, 1H), 4.59 (d, J= 5.6 Hz, 2H), 4.47-4.32 (m, 2H), 2.96 - 2.87 (m, 1H), 2.63 - 2.58 (m, 1H), 2.43 - 2.33 (m, 1H), 2.04 - 1.99 (m, 1H).Example 83-(7-Fluoro-l-oxo-6-(((6-(4-(trifluoromethyl)phenoxy)pyrimidin-4- yl)amino)methyl)isoindolin-2-yl)piperidine-2, 6-dioneStep 1: 4-Chloro-6-(4-(trifluoromethyl)phenoxy)pyrimidine

[0464] To a solution of 4-(trifluoromethyl)phenol(2.0g, 12.34mmol) in DMF (40mL) was added sodium hydride (0.59 g, 14.8 mmol). The mixture was stirred at 0 °C for 30 min under N2. Then 4,6-dichloropyrimidine (3.68 g, 24.67mmol) was added. The mixture was stirred at 0 °C for 3 hours under nitrogen atmosphere. The mixture was poured to water (200mL), extracted with ethyl acetate (100 mL x2), organic phase was washed with brine (20 mL x 2). Organic phase was dried, concentrated under vacuum, the residue was purified by flash column chromatography (0 - 5% ) to give the title compound (3 g, 88%) as a white solid.1H NMR (400 MHz, CDCl3) δ 8.60 (s, 1H), 7.74 (d, J= 8.4 Hz, 2H), 7.30 (d, J= 8.4 Hz, 2H), 7.04 (s, 1H)Step 2: 3-(7-Fluoro-l-oxo-6-(((6-(4-(trifluoromethyl)phenoxy)pyrimidin-4- yl)amino)methyl)isoindolin-2-yl)piperidine-2, 6-dione

[0465] To a solution of 4-chloro-6-(4-(trifluoromethyl)phenoxy)pyrimidine (200 mg, 0.73 mmol) in 2-methylbutan-2-ol (2 mL) was added BrettPhos-Pd-G3(CAS#: 1470372-59-8) (66 mg, 0.07 mmol) and 3-[6-(aminomethyl)-7-fluoro-l-oxo-isoindolin-2-yl]piperidine-2,6- dione (255 mg, 0.87 mmol). The reaction mixture was stirred at 110 °C for 16 hours. The reaction mixture was purified by prep-HPLC (Welch Xtimate C18 150*30mm*5um; mobile phase:water (FA)-ACN; B%: 40%-70%, 25 mL / min) to give a product and then the reaction mixture was further purified by prep-HPLC ( Welch Xtimate C18 150*30mm*5um; mobile phase:water (HCl)-ACN; B%: 40%-70%, 25 mL / min) to give Compound 8 (11.6 mg, 3% yield, HC1 salt) as a white solid. LCMS (ESI): m / z 530.0 [M + H]+.1H NMR (400MHz, DMSO-d6) 8 11.00 (s, 1H), 8.20 (s, 1H), 8.12 (s, 1H), 7.79 (d, J= 8.4 Hz, 2H), 7.62 (t, J = 7.2 Hz, 1H), 7.39 - 7.36 (m, 3H), 6.04 (s, 1H), 5.07 (dd, J =5.2, 13.2 Hz, 1H), 4.63 (s, 2H), 4.49 - 4.28 (m, 2H), 2.96 - 2.84 (m, 1H), 2.68 - 2.57 (m, 1H), 2.43 - 2.32 (m, 1H), 2.06 - 1.94 (m, 1H).Example 93-(7-Fluoro-l-oxo-6-(((6-(4-(trifluoromethyl)phenoxy)pyrimidin-4- yl)amino)methyl)isoindolin-2-yl)piperidine-2, 6-dioneStep 1: 2-Chloro-5-(4-(trifluoromethyl)phenoxy)pyrazine

[0466] A solution of 2,5-dichloropyrazine (200 mg, 1.34 mmol) and 4- (trifluoromethyl)phenol (218 mg, 1.34 mmol) in DMF (5 mL) was added K2CO3(557 mg, 4.03 mmol) and stirred at 80 °C for 4 hours. The reaction mixture was diluted with water (50 mL), extracted with ethyl acetate (30 mL x 3) and the combined organic layers was washed withbrine (40 mL x 2). The organic layers were dried over with Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography 5 - 15% ethyl acetate in petroleum ether to afford the title compound (360 mg, 97% yield) as a white oil.1H NMR (400 MHz, DMSO-d6)δ 8.52 (d, J= 1.2 Hz, 1H), 8.40 (d, J = 1.2 Hz, 1H), 7.83 (d, J = 8.8 Hz, 2H), 7.47 (d, J= 8.8 Hz, 2H).Step 2: 3-(7-Fluoro-l-oxo-6-(((5-(4-(trifluoromethyl)phenoxy)pyrazin-2- yl)amino)methyl)isoindolin-2-yl)piperidine-2, 6-dione

[0467] To a solution of 2-chloro-5-(4-(trifluoromethyl)phenoxy)pyrazine (160 mg, 0.58 mmol) in 2-methyl-2-butanol (5 mL) was added 3-(6-(aminomethyl)-7-fluoro-l- oxoisoindolin-2-yl)piperidine-2, 6-dione (229 mg, 0.70 mmol) and sodium tert-butoxide (168 mg, 1.75 mmol), 4A molecular sieve and BrettPhos-Pd-G3(CAS#: 1470372-59-8) (53 mg, 0.06 mmol). The reaction mixture was stirred at 110 °C for 2 hours. The reaction mixture was concentrated to dryness. The residue was purified by Prep-HPLC (Cl 8 150x30mm, water( FA)-ACN, 50-80%) to afford Compound 9 (4.7 mg, 2%) as a white solid. LCMS (ESI): m / z 530.0 [M + H]+.1H NMR (400 MHz, DMSO-d6) δ 11.00 (s, 1H), 7.99 (d, J= 1.2 Hz, 1H), 7.76 (d, J= 1.2 Hz, 1H), 7.71 (s, 1H), 7.70 - 7.64 (m, 3H), 7.37 (d, J= 8.0 Hz, 1H), 7.15 (d, J = 8.8 Hz, 2H), 5.07 (dd, J= 4.8, 13.2 Hz, 1H), 4.59 (d, J= 5.2 Hz, 2H), 4.50 - 4.41 (m, 1H), 4.36 - 4.27 (m, 1H), 2.98 - 2.84 (m, 1H), 2.63 - 2.56 (m, 1H), 2.41 - 2.34 (m, 1H), 2.03 - 1.98 (m, 1H).Example 103-(7-Fluoro-l-oxo-6-(((5-(4-(trifluoromethyl)piperidine-l-carbonyl)pyrazin-2- yl)amino)methyl)isoindolin-2-yl)piperidine-2, 6-dioneStep 1: 5-Chloropyrazine-2-carbonyl chloride

[0468] To a mixture of 5-chloropyrazine-2-carboxylic acid (200 mg, 1.26 mmol) in Dichloromethane (2 mL) was added 1 drop of DMF and oxalyl dichloride (0.12 mL, 1.45 mmol) at 0 °C. Then the resulting mixture was stirred at 20 °C for 30 min. The reaction mixture was concentrated to afford the title compound 5-chloropyrazine-2-carbonyl chloride (223 mg, 1.26 mmol, crude) as a brown oil and was used directly in the next step without purification.Step 2: (5-Chloropyrazin-2-yl)(4-(trifluoromethyl)piperidin-l-yl)methanone

[0469] To aa mmiixxttuurree of triethylamine (0.39 mL, 2.77 mmol) and 4- (trifluoromethyl)piperidine (212 mg, 1.39 mmol) in Dichloromethane (2 mL) was added 5- chloropyrazine-2-carbonyl chloride (223 mg, 1.26 mmol) at 0 °C. Then the resulting mixture was stirred at 20 °C for 12 h. The reaction mixture was concentrated to dryness. The residue was purified by column chromatography 0 - 50% ethyl acetate in petroleum ether to afford the title compound (5-chloropyrazin-2-yl)(4-(trifluoromethyl)piperidin-l-yl)methanone (209 mg, 57%) as colorless oil.1H NMR (400 MHz, DMSO-d6)δ 8.83 (d, J= 1.6 Hz, 1H), 8.73 (d, J = 1.2 Hz, 1H), 4.59 - 4.57 (m, 1H), 3.82-3.79 (m, 1H), 3.19 - 3.09 (m, 1H), 2.92 - 2.81 (m, 1H), 2.74 - 2.61 (m, 1H), 1.97-1.95 m, 1H), 1.79-1.76 (m, 1H), 1.52 - 1.37 (m, 2H).Step 3: 3-(7-Fluoro-l-oxo-6-(((5-(4-(trifluoromethyl)piperidine-l-carbonyl)pyrazin-2- yl)amino)methyl)isoindolin-2-yl)piperidine-2, 6-dione

[0470] To a solution of (5-chloropyrazin-2-yl)(4-(trifluoromethyl)piperidin-l- yl)methanone (209 mg, 0.71 mmol) in 2-methyl-2 -butanol (6 mL) was added sodium 2- methylpropan-2-olate (205 mg, 2.14 mmol) and 3-(6-(aminomethyl)-7-fluoro-l-oxoisoindolin- 2-yl)piperidine-2, 6-dione (249 mg, 0.85 mmol), 4A molecular sieve and BrettPhos-Pd- G3(CAS#: 1470372-59-8) (64 mg, 0.07 mmol). The reaction mixture was stirred at 110 °C for 2 hours. The reaction mixture was filtered, the filtrate was concentrated in vacuo. The residue was purified by Prep-HPLC (Cl 8 150*30mm, water (0.225% FA)-ACN, 30-60%) to afford Compound 10 (9.7 mg, 2%) as a yellow solid. LCMS (ESI): m / z 549.3 [M + H]+.1H NMR (400 MHz, DMSO-d6)δ 11.00 (s, 1H), 8.25 (s, 1H), 8.16 (t, J= 5.6 Hz, 1H), 7.94 (s, 1H), 7.64 (t, J= 7.6 Hz, 1H), 7.37 (d, J= 7.6 Hz, 1H), 5.07 (dd, J= 5.2, 13.2 Hz, 1H), 4.63 (d, J= 5.6 Hz, 2H), 4.47 - 4.41 (m, 1H), 4.58 - 4.38 (m, 1H), 4.35 - 4.10 (m, 2H), 2.97 - 2.83 (m, 2H), 3.15 - 2.81 (m, 1H), 2.68 - 2.56 (m, 2H), 2.44 - 2.30 (m, 1H), 2.05 - 1.96 (m, 1H), 1.95 - 1.70 (m, 2H), 1.50 - 1.30 (m, 2H).Example 113-(6-(((6-(Benzo[d]thiazol-5-yl)pyrimidin-4-yl)amino)methyl)-7-fluoro-l-oxoisoindolin-2-yl)piperidine-2, 6-dione hydrochlorideStep 1: 5-(6-Chloropyrimidin-4-yl)benzo[-dt]hiazole

[0471] A mixture of 4,6-dichloropyrimidine (86 mg, 0.57 mmol), 5-(4, 4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)benzo[d]thiazole (100 mg, 0.38 mmol) and Pd(dppf)Cl2(28 mg, 0.04 mmol), Na2CO3(122 mg, 1.15 mmol) in 1,4-Dioxane (4 mL) and Water (0.5 mL) was stirred at 100°C for 3 hours under nitrogen atmosphere (IKA). The reaction mixture was concentrated and filtered, washed with EtOAc (10 mL). the filtrate was concentrated in vacuo. The residue was purified by flash column 3-8% ethyl acetate in petroleum ether to afford the title compound (65 mg, 69%) as a white solid. LCMS (ESI): m / z 248.0 [M + H]+.1H NMR (400 MHz, CDCl3) δ 9.11 (S, 1H), 9.09 (s, 1H), 8.84 (d, J= 1.6 Hz, 1H), 8.23 (dd, J= 8.4, 1.6 Hz, 1H), 8.14-8.11 (m, 1H), 7.88 (d, J= 1.2 Hz, 1H).Step 2: 3-(6-(((6-(Benzo[d]thiazol-5-yl)pyrimidin-4-yl)amino)methyl)-7-fluoro-l- oxoisoindolin-2-yl)piperidine-2, 6-dione hydrochloride

[0472] To aa ssoolluuttiioonn ooff 3-(6-(aminomethyl)-7-fluoro-l-oxoisoindolin-2- yl)piperidine-2, 6-dione hydrochloride (106 mg, 0.32 mmol) and DIEA (0.28 mL, 1.61 mmol) in DMSO (3 mL) was added 5-(6-chloropyrimidin-4-yl)benzo[d]thiazole (80 mg, 0.32 mmol) and the mixture was stirred at 80 °C for 16h (IKA). The reaction mixture was purified by prep- HPLC (water (HCl)-ACN, 5-35%) to afford Compound 11 (66 mg, 37%, HCI salt) as a light yellow solid. LCMS (ESI): m / z503.0 [M + H]+.1H NMR (400 MHz,DMSO-d6)δ 10.77 (s, 1H), 10.10-10.00 (m, 1H), 9.53 (d, J =2.0 Hz, 1H), 8.82 (s, 1H), 8.70 (s, 1H), 8.41 (d, J =8.4 Hz, 1H), 8.01 (d, J = 6.0 Hz, 1H), 7.75 (t, J = 7.6 Hz, 1H), 7.43-7.41 (m, 2H), 5.03 (dd, J = 12.8, 5.2 Hz, 1H), 4.90 (s, 2H), 4.51-4.46 (m, 1H), 4.40-4.35 (m, 1H), 2.93-2.84 (m, 1H), 2.65- 2.60 (m, 1H), 2.45-2.33 (m, 1H), 2.06-2.03 (m, 1H).Example 12Step 1: 4-(6-Chloropyrimidin-4-yl)benzo[J|thiazole

[0473] A mixture of 4-(6-chloropyrimidin-4-yl)benzo[d]thiazole (170 mg, 1.95 mmol), 4,6-dichloropyrimidine (146 mg, 0.97 mmol), Pd(dppf)Cl2(48 mg, 0.07 mmol) and Na2CO3(207 mg, 1.95 mmol). Then the resulting mixture was stirred at 100 °C for 3 hours under nitrogen atmosphere. The residue was concentrated and purified by Prep-TLC (25% ethyl acetate in petroleum ether, Rf= 0.5) to give the title compound (100 mg, 62%) as a yellow solid. LCMS (ESI): m / z 248.0 [M + H]+.1H NMR (400 MHz, CDCI3) δ 9.19 (s, 1H), 9.12 (d, J= 1.2 Hz, 1H), 8.96 (d, J= 0.8 Hz, 1H), 8.51 (dd, J= 1.2, 7.6 Hz, 1H), 8.16 (dd, J= 1.2, 8.0 Hz, 1H), 7.64 (t, J= 8.0 Hz, 1H).Step 2: 3-(6-(((6-(Benzo[d]thiazol-4-yl)pyrimidin-4-yl)amino)methyl)-7-fluoro-l- oxoisoindolin-2-yl)piperidine-2, 6-dione

[0474] To a solution of 4-(6-chloropyrimidin-4-yl)benzo[d]thiazole (80 mg, 0.32 mmol) in DMA (3 mL) was added DIPEA (0.07 mL, 0.42 mmol) and 3-(6-(aminomethyl)-7- fluoro-l-oxoisoindolin-2-yl)piperidine-2, 6-dione (94 mg, 0.32 mmol). Then the mixture was stirred at 80 °C for 16 hours. The crude was further purified by prep-HPLC (Welch Xtimate C18 150*30mm*5um, water(HCl)-CAN, 5% -35%) to afford Compound 12 (16.5 mg, 10%) as white solid. LCMS (ESI): m / z 503.1 [M + H]+.1HNMR (400 MHz, DMSO-d6)δ 11.01 (s, 1H), 10.06 - 9.86 (m, 1H), 9.65 (s, 1H), 8.92 (s, 1H), 8.49 (d, J= 8.0 Hz, 1H), 8.04 (d, J= 7.2 Hz, 1H), 7.73 (t, J = 8.0 Hz, 2H), 7.64 (s, 1H), 7.44 (d, J= 8.0 Hz, 1H), 5.10 - 5.04 (m, 1H), 4.86 (s, 2H), 4.53 - 4.42 (m, 1H), 4.39 - 4.29 (m, 1H), 2.95 - 2.87 (m, 1H), 2.65 - 2.58 (m, 1H), 2.42 - 2.33 (m, 1H), 2.05 - 1.98 (m, 1H).Example 133-(7-Fluoro-l-oxo-6-(((6-(4-(trifluoromethyl)phenyl)pyrimidin-4- yl)amino)methyl)isoindolin-2-yl)piperidine-2, 6-dione

[0475] To a solution of 4-chloro-6-(4-(trifluoromethyl)phenyl)pyrimidine (30.0 mg, 0.12 mmol) in DMF (0.5 mL) was added 3-(6-(aminomethyl)-7-fluoro-l-oxoisoindolin-2- yl)piperidine-2, 6-dione hydrochloride (76 mg, 0.23 mmol) and DIPEA (0.06 mL, 0.35 mmol). The reaction mixture was stirred at 80 °C for 16h. The reaction mixture was purified by prep- HPLC (Cl 8 150x30mm, water (HCl)-ACN, 20%-50%) to afford Compound 13 (14 mg, 24%, HC1 salt) as a white solid. LCMS (ESI): m / z 514.1 [M + H]+.1H NMR (400 MHz, DMSO-d6) 8 11.00 (s, 1H), 9.29 - 8.99 (m, 1H), 8.75 (s, 1H), 8.19 - 8.06 (m, 2H), 7.95 (d, J= 8.4 Hz, 2H), 7.68 (t, J = 7.2 Hz, 1H), 7.41 (d, J= 8.0 Hz, 1H), 7.25 - 7.09 (m, 1H), 5.07 (dd, J= 5.2, 13.2 Hz, 1H), 4.80 (d, J= 5.6 Hz, 2H), 4.50 - 4.43 (m, 1H), 4.35 - 4.29 (m, 1H), 2.95 - 2.86 (m, 1H), 2.63 - 2.57 (m, 1H), 2.42 - 2.33 (m, 1H), 2.05 - 1.95 (m, 1H).Example 143-(7-Fluoro-l-oxo-6-(((6-(3-(trifluoromethoxy)phenyl)pyrimidin-4- yl)amino)methyl)isoindolin-2-yl)piperidine-2, 6-dioneStep 1: 4-Chloro-6-(3-(trifluoromethoxy)phenyl)pyrimidine

[0476] To a solution of 4-(trifluoromethoxy)phenylboronic acid (100 mg, 0.49 mmol) in 1,2-Dimethoxy ethane (10 mL) and water (1 mL) was added 4,6-dichloropyrimidine (108 mg, 0.73 mmol) and Pd(PPh3)4(56 mg, 0.05 mmol) and Na2CO3(154 mg, 1.46 mmol). The result mixture was stirred at 90 °C for 2 hour. The reaction was diluted with water (10 mL) and extracted with ethyl acetate (20 mL x 3). The organic layers were washed with brine (20 mL x 2), dried over sodium sulfate, filtered and concentrated. The residue was purified by preparative TLC (30% ethyl acetate in petroleum ether) to afford the title compound (76.0 mg, 57%) as a yellow oil. LCMS (ESI): m / z 275.1 [M + H]+.1H NMR (400 MHz, DMSO-d6)δ 9.12 (d, J = 1.2 Hz, 1H), 8.44 (d, J = 0.8 Hz, 1H), 8.29 (d, .J= 8.0 Hz, 1H), 8.22 (s, 1H), 7.70 (t, J= 8.0 Hz, 1H), 7.62 - 7.58 (m, 1H).Step 2: 3-(7-Fluoro-l-oxo-6-(((6-(3-(trifluoromethoxy)phenyl)pyrimidin-4- yl)amino)methyl)isoindolin-2-yl)piperidine-2, 6-dione

[0477] To aa ssoolluuttiioonn ooff 3-[6-(aminomethyl)-7-fluoro-l-oxo-isoindolin-2- yl]piperidine-2, 6-dione (121 mg, 0.42 mmol) in DMF (2 mL) was added 4-chloro-6-(3- (trifluoromethoxy)phenyl)pyrimidine (76.0 mg, 0.28 mmol) and DIPEA (0.14 mL, 0.83 mmol). The reaction mixture was stirred at 80 °C for 16 hours. The reaction mixture was concentrated and purified by prep-HPLC (C18 150x30mm, water (HCl)-ACN, 24%-54%) to afford Compound 14 (39.4 mg, 26%) as a white solid. LCMS (ESI): m / z 530.1 [M + H]+. 1H NMR (400 MHz, DMSO-d6)δ 11.00 (s, 1H), 9.37 - 9.07 (m, 1H), 8.75 (s, 1H), 7.98 - 7.88 (m, 2H), 7.75 - 7.71 (m, 1H), 7.68 (t, J= 6.8 Hz, 1H), 7.61 (d, J= 7.2 Hz, 1H), 7.41 (d, J= 7.8 Hz, 1H), 7.23 - 7.06 (m, 1H), 5.07 (dd, J= 5.2, 13.2 Hz, 1H), 4.80 (d, J= 5.8 Hz, 2H), 4.49 - 4.44 (m, 1H), 4.35 - 4.30 (m, 1H), 2.92 - 2.86 (m, 1H), 2.63-2.59 (m, 1H), 2.39-2.35 (m, 1H), 2.03 - 1.98 (m, 1H).Example 153-(7-Fluoro-l-oxo-6-(((6-(4-(trifluoromethoxy)phenyl)pyrimidin-4- yl)amino)methyl)isoindolin-2-yl)piperidine-2, 6-dione hydrochlorideStep 1: 4-Chloro-6-(4-(trifluoromethoxy)phenyl)pyrimidine

[0478] To the mixture of (4-(trifluoromethoxy)phenyl)boronic acid (1.0 g, 4.86 mmol) in 1,4-Dioxane (20 mL) and Water (2 mL) was added 4,6-dichloropyrimidine (1.09 g, 7.28 mmol), Na2CO3...

Claims

1. WHAT IS CLAIMED IS:

1. A compound of Formula (I):or a pharmaceutically acceptable salt thereof; wherein:X1and X4are each independently C, CH, or N;X2and X3are each independently C, CH or N; or one of X2and X3is C=O, the other one is NR4; wherein at least one of X1, X2, X3, and X4comprises N; represents a single or double bond; each R1is independently selected from halogen, cyano, C1-6alkyl, hydroxy, C1-6haloalkyl, C1-6hydroxyalkyl, C1-6alkoxy, O-C1-6haloalkyl, O-C3-6cycloalkyl, and - N(Ra)(Rb); p is selected from 0, 1, 2, and 3; each R2is independently selected from halogen, cyano, hydroxy, optionally substituted C1-6alkyl, optionally substituted C2-6alkenyl, optionally substituted C2-6alkynyl, optionally substituted C1-6alkoxy, optionally substituted C1-6haloalkyl, optionally substituted O-C1-6haloalkyl, optionally substituted C3-10cycloalkyl, optionally substituted 3-10 membered heterocycloalkyl, optionally substituted C6-11aryl, optionally substituted 5-15 membered heteroaryl, N(R5)(R6), O(R7), S(R7), NC(O)(R8)(R9), and C(O)N(R8)(R9); q is selected from 0, 1, 2, 3, and 4;R3is hydrogen or C1-4 alkyl;R4, when present, is hydrogen or Ci-4 alkyl; each Raand Rb, when present, is independently selected from hydrogen and C1-6alkyl, or Raand Rbtogether with the nitrogen atom they are attached to form a heterocycloalkyl;R5, R6, R7, R8, and R9are each independently selected from the group consisting of hydrogen, optionally substituted C1-6alkyl, optionally substituted C2-6alkenyl, optionally substituted C2-6alkynyl, optionally substituted acyl, optionally substituted C3-10cycloalkyl, optionally substituted 3-10 membered heterocycloalkyl, optionally substituted aryl, and optionally substituted 5-12 membered heteroaryl; or R8and R9together with the nitrogen atom to which they are attached form a 3 to 10 membered heterocycloalkyl optionally substituted with one or more groups each independently selected from the group consisting of halogen, cyano, nitro, oxo, C1-6alkyl, C1-6haloalkyl, and C1-6haloalkoxy; with the proviso that when q is 1, p is not 0.

2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein at least two of X1, X2, X3, and X4comprises N.

3. The compound of claim 1, or a pharmaceutically acceptable salt thereof,5. The compound of any one of claims 1-4, or a pharmaceutically acceptable salt thereof, wherein6. The compound of claim 5, or a pharmaceutically acceptable salt thereof, wherein7. The compound of claim 5, or a pharmaceutically acceptable salt thereof, wherein, wherein each R2is independently selected from halogen, cyano, optionally substituted C1-6alkyl, optionally substituted C2-6alkenyl, optionally substituted C2-6alkynyl, optionally substituted C1-6alkoxy, hydroxy, optionally substituted C1-6haloalkyl, optionally substituted O-C1-6haloalkyl, optionally substituted C3-8cycloalkyl, optionally substituted 3-10 membered heterocycloalkyl, optionally substituted C6-11aryl, optionally substituted 5-6 membered heteroaryl, N(R5)(R6), O(R7), C(O)N(R8)(R9).

8. The compound of any one of claims 1-4, or a pharmaceutically acceptable salt thereof, wherein9. The compound of claim 8, or a pharmaceutically acceptable salt thereof, wherein10. The compound of any one of claims 1-4, or a pharmaceutically acceptable salt thereof, wherein11. The compound of claim 10, or a pharmaceutically acceptable salt thereof, wherein12. The compound of any one of claims 1-4, or a pharmaceutically acceptable salt thereof, wherein13. The compound of claim 12, or a pharmaceutically acceptable salt thereof, wherein14. The compound of any one of claims 1-4, or a pharmaceutically acceptable salt thereof, wherein15. The compound of claim 14, or a pharmaceutically acceptable salt thereof, wherein16. The compound of any one of claims 1-4, or a pharmaceutically acceptable salt thereof, wherein17. The compound of claim 16, or a pharmaceutically acceptable salt thereof, wherein18. The compound of any one of claims 1-4, or a pharmaceutically acceptable salt thereof, wherein19. The compound of claim 18, or a pharmaceutically acceptable salt thereof, wherein20. The compound of any one of claims 1-4, or a pharmaceutically acceptable salt thereof, wherein21. The compound of claim 20, or a pharmaceutically acceptable salt thereof, wherein22. The compound of claim any one of claims 1-4, or a pharmaceutically acceptable salt thereof, wherein23. The compound of claim 22, or a pharmaceutically acceptable salt thereof, wherein, wherein each R2is independently selected from halogen, cyano, optionally substituted C1-6alkyl, optionally substituted C2-6alkenyl, optionally substituted C2-6alkynyl, optionally substituted C1-6alkoxy, hydroxy, optionally substituted C1-6haloalkyl, optionally substituted O-C1-6haloalkyl, optionally substituted C3-8cycloalkyl, optionally substituted 3-10 membered heterocycloalkyl, optionally substituted C6-11aryl, optionally substituted 5-6 membered heteroaryl, N(R5)(R6), O(R7), and C(O)N(R8)(R9).

24. The compound of claim any one of claims 1-4, or a pharmaceutically acceptable salt thereof, wherein25. The compound of claim 24, or a pharmaceutically acceptable salt thereof, wherein26. The compound of claim 24, or a pharmaceutically acceptable salt thereof, wherein27. The compound of any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein q is 1, 2, or 3.

28. The compound of any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein q is 1 or 2.

29. The compound of any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein q is 1.

30. The compound of any one of claims 1 to 29, or a pharmaceutically acceptable salt thereof, wherein p is 1 or 2.

31. The compound of any one of claims 1 to 30, or a pharmaceutically acceptable salt thereof, wherein p is 2.

32. The compound of any one of claims 1 to 31, or a pharmaceutically acceptable salt thereof, wherein each R1is independently selected from the group consisting of halogen, C1-6alkyl, C1-6haloalkyl, C1-6hydroxyalkyl, C1-6alkoxy, O-C1-6haloalkyl, O-C3-6cycloalkyl, and hydroxy.

33. The compound of claim 32, or a pharmaceutically acceptable salt thereof, wherein each R1is independently selected from -CH3, -F, -Cl, -CF3,-CF2CH3, -CH2CHF2, - CH2CF3, -CH2OH, -OCH3, -OCHF2, -OCF3, O-cyclopropyl, and hydroxy.

34. The compound of claim 32, or a pharmaceutically acceptable salt thereof, wherein each R1is halogen.

35. The compound of claim 34, or a pharmaceutically acceptable salt thereof, wherein each R1is independently selected from -F and -Cl.

36. The compound of claim 34, or a pharmaceutically acceptable salt thereof, wherein p is 2, one R1is -F and the other one is -Cl.

37. The compound of claim 34, or a pharmaceutically acceptable salt thereof, wherein p is 1, and R1is -F.

38. The compound of claim 32, or a pharmaceutically acceptable salt thereof, wherein each R1is C1-6alkyl.

39. The compound of claim 32, or a pharmaceutically acceptable salt thereof, wherein p is 2, one R1is halogen, and the other R1is selected from the group consisting of C1-6haloalkyl, C1-6hydroxyalkyl, C1-6alkoxy, O-C1-6haloalkyl, and O-C3-6cycloalkyl.

40. The compound of claim 39, or a pharmaceutically acceptable salt thereof, wherein p is 2, one R1is Cl or F, and the other R1is selected from the group consisting of - CF3, -CH2CF3, -CH2CHF2, -CF2CH3, -CH2OH, -OCH3, -OCHF2, -OCF3, and -O-cyclopropyl.

41. The compound of any one of claims 1 to 40, or a pharmaceutically acceptable salt thereof, wherein R3is hydrogen.

42. The compound of any one of claims 1 to 40, or a pharmaceutically acceptable salt thereof, wherein R3is methyl.

43. The compound of any one of claims 1 to 42, or a pharmaceutically acceptable salt thereof, wherein each R2is independently selected from the group consisting of optionally substituted C3-8cycloalkyl, optionally substituted 3-10 membered heterocycloalkyl, optionally substituted C6-11aryl, optionally substituted 5-15 membered heteroaryl, N(R5)(R6), O(R7), halogen, C1-6haloalkyl, C1-6alkynyl, and C(O)N(R8)(R9).

44. The compound of claim 42, or a pharmaceutically acceptable salt thereof, wherein each R2is independently selected from the group consisting of optionally substituted C3-8cycloalkyl, optionally substituted 3-10 membered heterocycloalkyl, optionally substituted C6-11aryl, optionally substituted 5-15 membered heteroaryl, N(R5)(R6), and O(R7).

45. The compound of claim 44, or a pharmaceutically acceptable salt thereof, wherein each R2is independently selected from optionally substituted phenyl, optionally substituted pyridyl, optionally substituted C3-7cycloalkyl, optionally substituted 4-8 membered heterocycloalkyl, and optionally substituted 15-membered heteroaryl.

46. The compound of claim 45, or a pharmaceutically acceptable salt thereof, wherein the optionally substituted phenyl, optionally substituted pyridyl, optionally substituted C3-7cycloalkyl, optionally substituted 4-8 membered heterocycloalkyl, and optionally substituted 15-membered heteroaryl are substituted with 1-4 substituents each independently selected from the group consisting of C1-6haloalkyl, optionally substituted C1-6alkyl, C2-6alkenyl, halogen, hydroxy, cyano, optionally substituted phenyl, optionally substituted 5- to 9-membered heteroaryl, and optionally substituted C3-6cycloalkyl.

47. The compound of claim 1, wherein the compound of Formula (I) is a compound of Formula (II):, or a pharmaceutically acceptable salt thereof.

48. The compound of claim 47, wherein the compound of Formula (I) is a compound of Formula (Il-a): . . 1 1 1, or a pharmaceutically acceptable salt thereof.

49. The compound of claim 47, wherein the compound of Formula (I) is a compound of Formula (Il-b):R or a pharmaceutically acceptable saltthereof.

50. The compound of claim 47, wherein the compound of Formula (I) is a compound of Formula (II-c): or a pharmaceutically acceptable saltthereof.

51. The compound of any one of claims 47-51, or a pharmaceutically acceptable salt thereof, wherein each R1is independently selected from the group consisting of halogen, C1-6alkyl, C1-6haloalkyl, C1-6hydroxyalkyl, C1-6alkoxy, O-C1-6haloalkyl, and hydroxy.

52. The compound of any one of claims 47-51, or a pharmaceutically acceptable salt thereof, wherein each R1is independently selected from -F, -Cl, -Br, and -I.

53. The compound of any one of claims 47-52, or a pharmaceutically acceptable salt thereof, wherein R3is hydrogen.

54. The compound of any one of claims 47-53, or a pharmaceutically acceptable salt thereof, wherein R2is selected from the group consisting of optionally substituted C3-8cycloalkyl, optionally substituted 3-10 membered heterocycloalkyl, optionally substituted C6-il aryl, optionally substituted 5-15 membered heteroaryl, N(R5)(R6), and O(R7).

55. The compound of claim 54, or a pharmaceutically acceptable salt thereof, wherein R2is optionally substituted phenyl.

56. The compound of claim 47, or a pharmaceutically acceptable salt thereof, wherein the compound of Formula (I) is a compound of Formula (Il-d):wherein w is selected from 0, 1, 2, 3, 4, and 5;each R2His independently selected from the group consisting of C1-6haloalkyl, -O-C1-6haloalkyl, C1-6alkyl, halogen, cyano, -S(O)(Rc), -S(O)2(Rc), -P(O)(ORc)2, -P(O)(Rc)2, - S(Rd)5, and optionally substituted C3-6cycloalkyl; wherein when w is 2, 3, 4, or 5, two R2Hon adjacent carbon atoms, taken together with the carbon atoms to which they are attached, may optionally form a 5- or 6-membered heterocycloalkyl; each Rcis independently C1-6alkyl; and each Rdis independently halogen.

57. The compound of claim 47, or a pharmaceutically acceptable salt thereof, wherein the compound of Formula (I) is a compound of Formula (Il-e):wherein w is selected from 0, 1, 2, 3, 4, and 5; each R2His independently selected from the group consisting of C1-6haloalkyl, -O-C1-6haloalkyl, C1-6alkyl, halogen, cyano, -S(O)(Rc), -S(O)2(Rc), -P(O)(ORc)2, -P(O)(Rc)2, and - S(Rd)5; each Rcis independently C1-6alkyl; and each Rdis independently halogen.

58. The compound of claim 47, or a pharmaceutically acceptable salt thereof, wherein the compound of Formula (I) is a compound of Formula (Il-f):wherein, each of R2B, R2C, R2D, R2E, and R2Fis independently selected from hydrogen, halogen, cyano, C1-6alkyl optionally substituted with one R2B3, C1-6cyanoalkyl, C1-6alkenyl optionally substituted with one R2B4, hydroxy, C1-6hydroxyalkyl, -NR2B2R2B3, C3-8cycloalkyl, phenyl, 5- to 6-membered heterocycloalkyl, 5- to 6-membered heteroaryl, and C1-6 haloalkyl optionally substituted with one R2B3, wherein the C3-8cycloalkyl, phenyl, 5- to 6- membered heterocycloalkyl, and 5- to 6-membered heteroaryl are optionally substituted with one, two, or three R2B1; each R2B1is independently selected from the group consisting of halo, cyano, C1-6alkyl, C1-6haloalkyl, C1-6cyanoalkyl, and CD3;R2B2is C1-6alkyl;R2B3is 5- to 6-membered heteroaryl optionally substituted with one or two substituents independently selected from halo, C1-6haloalkyl, and -O(C1-6alkyl); andR2B4is halogen.

59. The compound of claim 47, or a pharmaceutically acceptable salt thereof, wherein the compound of Formula (I) is a compound of Formula (Il-j):whereinX5is a bond, -CH2-, -CH2CH2-, O, or NR2MX6is -CH2- or -CH2CH2-;R2Kis phenyl or 5- to 9-membered heteroaryl, wherein the phenyl or 5- to 6- membered heteroaryl is optionally substituted with one, two, three, or four R2L; each R2Lis independently selected from the group consisting of halo, cyano, oxo, C1-6alkyl, C1-6haloalkyl, C1-6hydroxyalkyl, C1-6alkoxy, C1-6haloalkoxy, C(O)(C1-6alkoxy), -CH2(C1-6alkoxy), -OCD3, -O-cyclopropyl, -C(O)NR2L1R2L2, and 5-membered heteroaryl optionally substituted with C1-6 alkyl R2L1and R2L2are independently selected from H and C1-6 alkyl; or R2L1and R2L2, taken together with the N to which they are attached, for an optionally substituted 4- to 6- membered heterocycloalkyl; R2Mis C1-6alkyl; and s is 0 or 1.

60. The compound of claim 59, or a pharmaceutically acceptable salt thereof,61. The compound of claim 59 or 60, or a pharmaceutically acceptable salt thereof, wherein R2K is selected from the group consisting of62. The compound of claim 1, selected from the group consisting of the compounds in Table 1, or a pharmaceutically acceptable salt thereof.

63. A pharmaceutical composition comprising the compound of any one of claims 1 to 62, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.

64. The pharmaceutical composition of claim 63, further comprising an additional therapeutic agent.

65. A method of degrading CDK2 in a subject, the method comprising administering to the subject: (i) the compound of any one of claims 1 to 62, or apharmaceutically acceptable salt thereof; or (ii) the pharmaceutical composition of claim 63 or claim 64.

66. A method of treating a cancer in a subject in need thereof, the method comprising administering to the subject: (i) an effective amount of the compound of any one of claims 1 to 62, or a pharmaceutically acceptable salt thereof; or (ii) the pharmaceutical composition of claim 63 or claim 64.

67. The method of claim 66, wherein the cancer is selected from bladder cancer; bone cancer; brain cancer; breast cancer; cervical cancer; colorectal cancer; endometrial cancer; prostate cancer; esophagus cancer; eye cancer; head cancer; kidney cancer; liver cancer; lymph node cancer; lung cancer; upper aerodigestive tract cancer; oral cancer; oropharynx cancer; larynx cancer; hypopharynx cancer; salivary gland cancer; neck cancer; thyroid cancer; ovarian cancer; pancreatic cancer; prostate cancer; rectal cancer; skin cancer; stomach cancer; testicular cancer; throat cancer; uterine cancer; neuroblastoma; meningioma; hemangiopericytoma; leiomyoma; leukemia; lymphoma; and myeloma.

68. The method of claim 66, wherein the cancer is selected from: leukemia; bladder cancer; brain cancer; breast cancer; cervical cancer; colorectal cancer; endometrial cancer; esophageal cancer; gastric cancer; kidney cancer; liver cancer; lung cancer; neuroblastoma; ovarian cancer; prostate cancer; skin cancer; thyroid cancer; and uterine cancer.

69. A method of treating a solid tumor in a subject in need thereof, comprising administering to the subject: (i) an effective amount of the compound of any one of claims 1 to 63, or a pharmaceutically acceptable salt thereof; or (ii) the pharmaceutical composition of claim 63 or claim 64.

70. A method of treating a liquid tumor in a subject in need thereof, comprising administering to the subject: (i) an effective amount of the compound of any one of claims 1 to 63, or a pharmaceutically acceptable salt thereof; or (ii) the pharmaceutical composition of claim 63 or claim 64.