Modulators of CDK2 and uses thereof

Abstract

Provided are compounds of Formula (I): and pharmaceutically acceptable salts and compositions thereof, which are useful for treating a variety of conditions associated with CDK2.

Description

MODULATORS OF CDK2 AND USES THEREOF RELATED APPLICATIONS

[0001] This application claims the benefit of priority to US provisional application No. 63 / 472,407, filed June 12, 2023, the entire contents of which are incorporated herein by reference. BACKGROUND

[0002] Cell proliferation depends on the progression through four phases of the cell cycle, G0 / G1, S, G2 and M. Cell cycle progression is regulated by a set of cyclin-dependent kinases (CDKs, e.g. CDK1, CDK2, CDK4, CDK6) and their cyclin binding partners (e.g. cyclin A2, cyclin D1, cyclin E1). CDKs are activated by binding of their respective cyclins during specific phases of the cell cycle, triggering phosphorylation events that promote cell cycle progression. Cyclin expression is tightly regulated during the cell cycle. In some cancer cells, cyclin expression is dysregulated, driving uncontrolled cancer cell proliferation and tumorigenesis.

[0003] Activation of CDK2 by cyclin E1 (CCNE1) is critical for the progression from G1 to S phase of the cell cycle. Upon mitogenic stimuli such as growth factors and hormones, D type cyclins (CCND1, CCND2 and CCND3) interact with CDK4 and CDK6 to initiate phosphorylation of the retinoblastoma (Rb) protein which is then further phosphorylated by CDK2 upon interaction with CCNE1. Phosphorylation inactivates Rb, which in turn triggers release of E2F transcription factors. E2F release subsequently activates the transcription of E2F-target genes to initiate G1 to S phase transition.

[0004] Pharmacological inhibitors of CDK4 and CDK6 have been demonstrated to have clinical efficacy in patients with hormone receptor (HR) positive, human epidermal growth factor receptor 2 (HER2) negative breast cancer. However, patients eventually progress due to acquired resistance mechanisms such as loss of Rb and increased CCNE1 protein levels (Guarducci et al, 2018; Herrera-Abreu et al, 2016; Turner et al, 2019). CCNE1 is frequently amplified in human cancers, such as ovarian, lung, breast, and endometrial cancers (Gao et al, 2013). CCNE1 amplification or overexpression is associated with poor prognosis in both high-grade serous ovarian cancer and breast cancer (Chan et al, 2020; Zhao et al, 2019). CCNE1 amplification is also associated with primary resistance to standard of care chemotherapy in ovarian cancer (Etemadmoghadam et al, 2009; Gorski et al, 2020). Genetic depletion of CDK2 or CCNE1 by siRNA-mediated knockdown or CRISPR-mediatedknockout inhibits the proliferation of CCNE1 amplified cancer cells and CDK4 / CDK6 inhibitor resistant breast cancer cells (Herrera-Abreu et al., 2016).

[0005] Targeting CDK2 has the potential to benefit patients with CCNE1 amplified tumors or developed resistance to CDK4 / CDK6 inhibitors. SUMMARY

[0006] Provided herein are compounds having the Formula (I):and pharmaceutically acceptable salts and compositions thereof, wherein R1, R1a, R2, Z1, Z2, Z3, X, Y, q, and the dashed lines are as described herein. In one aspect, the disclosed compounds of Formula I and pharmaceutically acceptable salts thereof modulate CDK2 (e.g., as degraders of CDK2), and are useful in a variety of therapeutic applications such as, for example, in treating cancer.

[0007] Pharmaceutical compositions comprising the described compounds and pharmaceutically acceptable salts of the described compounds, as well as methods for their preparation are also included. DETAILED DESCRIPTION 1. General Description of Compounds

[0008] In a first embodiment, provided herein is a compound of Formula (I):or a pharmaceutically acceptable salt thereof, wherein one of X or Y is C(O) and the other is selected from C(O) and CH2; Z1, Z2, and Z3 are each independently selected from CH2, CR3, and N, provided that only one of Z1, Z2, and Z3 can be N; R1is selected from (C1-C6)alkyl, halo(C1-C6)alkyl, hydroxy(C1-C6)alkyl, aryl, heterocyclyl, heteroaryl, and carbocyclyl, wherein said aryl, heterocyclyl, heteroaryl, and carbocyclyl for R1are each optionally substituted with one to three groups selected fromselected from R4, and wherein said (C1-C6)alkyl, halo(C1-C6)alkyl, and hydroxy(C1-C6)alkyl for R1are each substituted with one or two groups selected from aryl, heterocyclyl, heteroaryl, and carbocyclyl, wherein said aryl, heterocyclyl, heteroaryl, and carbocyclyl are each optionally substituted with one to three groups selected from R5; R1aand R2are each independently hydrogen or (C1-C4)alkyl; the dashed lines represent additional bonds which may be present; R3is selected from halo, cyano, (C1-C4)alkyl, halo(C1-C4)alkyl, (C1-C4)alkoxy, and halo(C1-C4)alkoxy; R4and R5are each independently selected from (C1-C6)alkyl, halo(C1-C6)alkyl, -[(C1- C6)alkyl]NRbRc, [(C1-C6)alkyl]O[(C1-C6)alkyl], -[OCH2CH2]m-OCH2C(O)ORb, halo, cyano, - ORa, -NRbRc, -C(O)NRbRc, -C(O)ORb, -C(O)Rd, -[(C1-C6)alkyl]C(O)NRbRc, -[(C1- C6)alkyl]C(O)ORb, -[(C1-C6)alkyl]-C(O)Rd, -[(C1-C6)alkyl]phenyl, -[(C1-C6)alkyl]heteroaryl, NO2, -[(C1-C6)alkyl]cycloalkyl, -[(C1-C6)alkyl]heterocyclyl, -C(O)NRbSO3H, -NRbC(O)Rc, - NRbC(O)ORc, -NRbC(S)ORc, -NRbC(O)NRbRc, -NRbC(S)NRbRc, -NRbS(O)2NRbRc, -C(S)Rb, -S(O)2Rb, -S(O)Rb, -C(S)ORb, -C(S)NRbRc, -NRbC(S)Rc, -SRb, phenyl, heteroaryl, cycloalkyl, and heterocyclyl, wherein for each occurrence of phenyl, heteroaryl, cycloalkyl, and heterocyclyl, said groups are optionally substituted with one to three groups selected from halo, cyano, phenyl, benzyl, (C3-C6)cycloalkyl, (C1-C4)alkyl, halo(C1-C4)alkyl, (C1- C4)alkoxy, halo(C1-C4)alkoxy, -C(O)NRbRc, -C(O)ORb; Ra, Rb, Rc, and Rdare each independently selected from hydrogen, (C1-C6)alkyl, halo(C1-C6)alkyl, phenyl, benzyl, heterocyclyl, heteroaryl, and cycloalkyl, wherein said phenyl, benzyl, heterocyclyl, heteroaryl, and cycloalkyl are each optionally substituted with 1 to three groups selected from halo, (C1-C4)alkyl, halo(C1-C4)alkyl, (C1-C4)alkoxy, and halo(C1-C4)alkoxy; m 1, 2, 3, 4, or 5; and q is 0, 1, 2 or 3. 2. Definitions

[0009] When used in connection to describe a chemical group that may have multiple points of attachment, a hyphen (-) designates the point of attachment of that group to the variable to which it is defined. For example, -[(C1-C6)alkyl]heteroaryl means that the point of attachment for this group occurs on the (C1-C6)alkyl.

[0010] The terms “halo” and “halogen” refer to an atom selected from fluorine (fluoro, -F), chlorine (chloro, -Cl), bromine (bromo, -Br), and iodine (iodo, -I).

[0011] The term “alkyl” when used alone or as part of a larger moiety, such as “haloalkyl”, and the like, means a saturated straight-chain or branched monovalent hydrocarbon radical.

[0012] “Alkoxy” means an alkyl radical attached through an oxygen linking atom, represented by –O-alkyl. For example, “(C1-C4)alkoxy” includes methoxy, ethoxy, proproxy, and butoxy.

[0013] The term “haloalkyl” includes mono, poly, and perhaloalkyl groups where the halogens are independently selected from fluorine, chlorine, bromine, and iodine.

[0014] “Haloalkoxy” is a haloalkyl group which is attached to another moiety via an oxygen atom such as, e.g., –OCHF2or –OCF3.

[0015] The term oxo means the group =O.

[0016] The term “aryl” refers to an aromatic carbocyclic single ring or two fused ring system containing 6 to 10 carbon atoms. Examples include phenyl, indanyl, tetrahydronaphthalene, and naphthyl. In one aspect, the aryl is phenyl or naphthyl.

[0017] The term “heteroaryl” used alone or as part of a larger moiety refers to, unless otherwise specified, a 5- to 12-membered aromatic radical containing 1-4 heteroatoms selected from N, O, and S. A heteroaryl group may be mono- or bi-cyclic. Monocyclic heteroaryl includes, for example, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, triazinyl, tetrazinyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, etc. Bi-cyclic heteroaryls include groups in which a monocyclic heteroaryl ring is fused to one or more aryl or heteroaryl rings. Nonlimiting examples include indolyl, imidazopyridinyl, benzooxazolyl, benzooxodiazolyl, indazolyl, benzimidazolyl, benzthiazolyl, quinolyl, quinazolinyl, quinoxalinyl, pyrrolopyridinyl, pyrrolopyrimidinyl, pyrazolopyridinyl, thienopyridinyl, thienopyrimidinyl, indolizinyl, purinyl, naphthyridinyl, and pteridinyl. It will be understood that when specified, optional substituents on a heteroaryl group may be present on any substitutable position.

[0018] The term “heterocyclyl” means, unless otherwise specified, a 5- to 12-membered saturated or partially unsaturated heterocyclic ring containing 1 to 4 heteroatoms independently selected from N, O, and S. It can be monocyclic, bicyclic (e.g., a bridged, fused, or spiro bicyclic ring), or tricyclic. A heterocyclyl ring can be attached to its pendant group at any heteroatom or carbon atom that results in a stable structure. Examples of such saturated or partially unsaturated heterocyclic radicals include, without limitation, tetrahydrofuranyl, tetrahydrothienyl, terahydropyranyl, pyrrolidinyl, pyridinonyl, pyrrolidonyl, piperidinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, morpholinyl,dihydrofuranyl, dihydropyranyl, dihydropyridinyl, tetrahydropyridinyl, dihydropyrimidinyl, oxetanyl, azetidinyl and tetrahydropyrimidinyl. A heterocyclyl group may be mono- or bicyclic. The term “heterocyclyl” also includes, e.g., unsaturated heterocyclic radicals fused to another unsaturated heterocyclic radical or aryl or heteroaryl ring, such as for example, tetrahydronaphthyridine, indolinone, dihydropyrrolotriazole, imidazopyrimidine, quinolinone, dioxaspirodecane. It will also be understood that when specified, optional substituents on a heterocyclyl group may be present on any substitutable position.

[0019] The term “spiro” refers to two rings that shares one ring atom (e.g., carbon).

[0020] The term “fused” refers to two rings that share two adjacent ring atoms with one another.

[0021] The term “bridged” refers to two rings that share three ring atoms with one another.

[0022] The term “carbocyclyl” means a saturated or partially saturated cyclic hydrocarbon group having from, unless specified otherwise, from 3 to 10 ring carbon atoms. A carbocyclyl can be monocyclic or bicyclic (e.g., a bridged, fused, or spiro bicyclic ring). Examples of monocyclic carbocyclyls include, without limitation, cycloalkyl rings, cyclopropenyl, cyclobuteny, cyclohexyl, cyclohexenyl, and the like. Examples of monocyclic carbocyclyls include, without limitation, 2,3-dihydro-1H-indenyl, bicyclo[2.2.1]heptanyl, bicyclo[2.2.2]octanyl, and the like.

[0023] The terms “cycloalkyl”, used alone or as part of a larger moiety, refers to a saturated cyclic aliphatic monocyclic or bicyclic ring system, as described herein, having from, unless otherwise specified, 3 to 10 carbon ring atoms. Monocyclic cycloalkyl groups include, without limitation, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cycloheptenyl, and cyclooctyl. It will be understood that when specified, optional substituents on a cycloalkyl may be present on any substitutable position.

[0024] Compounds having one or more chiral centers can exist in various stereoisomeric forms. Stereoisomers are compounds that differ only in their spatial arrangement. Stereoisomers include all diastereomeric, enantiomeric, and epimeric forms as well as racemates and mixtures thereof. A “geometric isomer” refers to isomers that differ in the orientation of substituent group in relationship to a carbon-carbon double bond, a cycloalkyl ring, or a bridged bicyclic system. Atoms (other than H) on each side of a carbon-carbon double bond may be in an E (substituents are on opposite sides of the carbon-carbon double bond) or Z (substituents are oriented on the same side) configuration. “Cis” refers tosubstituents oriented on the same side of the ring, whereas “trans” refers to substituents oriented on opposite sides of the ring.

[0025] When the stereochemical configuration at a chiral center in a compound having one or more chiral centers is depicted by its chemical name (e.g., where the configuration is indicated in the chemical name by “R” or “S”) or structure (e.g., the configuration is indicated by “wedge” bonds), the enrichment of the indicated configuration relative to the opposite configuration is greater than 50%, 60%, 70%, 80%, 90%, 99% or 99.9%. “Enrichment of the indicated configuration relative to the opposite configuration” is a mole percent and is determined by dividing the number of compounds with the indicated stereochemical configuration at the chiral center(s) by the total number of all of the compounds with the same or opposite stereochemical configuration in a mixture.

[0026] When a geometric isomer is depicted by name or structure, the enrichment of the indicated isomer relative to the opposite isomer is greater than 50%, 60%, 70%, 80%, 90%, 99% or 99.9%. “Enrichment of the indicated isomer relative to the opposite isomer” is a mole percent and is determined by dividing the number of compounds with the indicated geometrical configuration by the total number of all of the compounds with the same or opposite geometrical configuration in a mixture.

[0027] When a disclosed compound is named or depicted by structure without indicating stereochemistry, it is understood that the name or the structure encompasses one of the possible stereoisomers or geometric isomers free of the others, or a mixture of the encompassed stereoisomers or geometric isomers.

[0028] The terms “subject” and “patient” may be used interchangeably, and means a mammal in need of treatment, e.g., companion animals (e.g., dogs, cats, and the like), farm animals (e.g., cows, pigs, horses, sheep, goats and the like) and laboratory animals (e.g., rats, mice, guinea pigs and the like). Typically, the subject is a human in need of treatment.

[0029] The term “inhibit,” “inhibition” or “inhibiting” includes a decrease in the baseline activity of a biological activity or process.

[0030] As used herein, the terms “treatment,” “treat,” and “treating” refer to reversing, alleviating, delaying the onset of, or inhibiting the progress of a disease or disorder, or one or more symptoms thereof, as described herein. In some aspects, treatment may be administered after one or more symptoms have developed, i.e., therapeutic treatment. In other aspects, treatment may be administered in the absence of symptoms. For example, treatment may be administered to a susceptible individual prior to the onset of symptoms (e.g., in light of a history of symptoms and / or in light of exposure to a particular organism, or othersusceptibility factors), i.e., prophylactic treatment. Treatment may also be continued after symptoms have resolved, for example to delay their recurrence.

[0031] The term “pharmaceutically acceptable carrier” refers to a non-toxic carrier, adjuvant, or vehicle that does not destroy the pharmacological activity of the compound with which it is formulated. Pharmaceutically acceptable carriers, adjuvants or vehicles that may be used in the compositions described herein include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol and wool fat.

[0032] For use in medicines, the salts of the compounds described herein refer to non- toxic “pharmaceutically acceptable salts.” Pharmaceutically acceptable salt forms include pharmaceutically acceptable acidic / anionic or basic / cationic salts. Suitable pharmaceutically acceptable acid addition salts of the compounds described herein include e.g., salts of inorganic acids (such as hydrochloric acid, hydrobromic, phosphoric, nitric, and sulfuric acids) and of organic acids (such as, acetic acid, benzenesulfonic, benzoic, methanesulfonic, and p-toluenesulfonic acids). Compounds of the present teachings with acidic groups such as carboxylic acids can form pharmaceutically acceptable salts with pharmaceutically acceptable base(s). Suitable pharmaceutically acceptable basic salts include e.g., ammonium salts, alkali metal salts (such as sodium and potassium salts) and alkaline earth metal salts (such as magnesium and calcium salts). Compounds with a quaternary ammonium group also contain a counteranion such as chloride, bromide, siodide, acetate, perchlorate and the like. Other examples of such salts include hydrochlorides, hydrobromides, sulfates, methanesulfonates, nitrates, benzoates and salts with amino acids such as glutamic acid.

[0033] The term “effective amount” or “therapeutically effective amount” refers to an amount of a compound described herein that is sufficient to achieve the desired therapeutic effect (such as treatment of a condition recited herein) under the conditions of administration. 3. Compounds

[0034] As part of a second embodiment, the compound of Formula I is of the Formula II:or a pharmaceutically acceptable salt thereof, wherein Y is CH2or C(O); R1is selected from (C1-C6)alkyl, halo(C1-C6)alkyl, hydroxy(C1-C6)alkyl, aryl, heterocyclyl, heteroaryl, and carbocyclyl, wherein said aryl, heterocyclyl, heteroaryl, and carbocyclyl for R1are each optionally substituted with one to three groups selected from selected from R4, and wherein said (C1-C6)alkyl, halo(C1-C6)alkyl, and hydroxy(C1-C6)alkyl for R1are each substituted with one or two groups selected from aryl, heterocyclyl, heteroaryl, and carbocyclyl, wherein said aryl, heterocyclyl, heteroaryl, and carbocyclyl are each optionally substituted with one to three groups selected from R5; provided that R1is not cyclopentyl, 1-cyclopropylpiperidine-4-yl, para-2- phenoxyacetonitrilyl, 4-fluorophenyl, 1-neopentylcyclopropan-1-yl, 4- trifluoromethoxyphenyl, 1-propyl-1H-pyrazole-3-yl, 1-benzyl-3-methyl-1H-pyrazol-3-yl, unsubstituted spiro[3.3]heptanyl, an unsubstituted pyrimidinyl, unsubstituted pyridinyl, unsubstituted indolyl, unsubstituted benzooxazolyl, unsubstituted cubanyl, -CH2(unsubsituted thiazolyl), or -(CH2)2[unsubsituted indolyl]; R1aand R2are each independently hydrogen or (C1-C4)alkyl; the dashed lines represent additional bonds which may be present; R4and R5are each independently selected from (C1-C6)alkyl, halo(C1-C6)alkyl, -[(C1- C6)alkyl]NRbRc, [(C1-C6)alkyl]O[(C1-C6)alkyl], halo, cyano, -ORa, -NRbRc, -C(O)NRbRc, - C(O)ORb, -C(O)Rd, -[(C1-C6)alkyl]C(O)NRbRc, -[(C1-C6)alkyl]C(O)ORb, -[(C1-C6)alkyl]- C(O)Rd, -[(C1-C6)alkyl]phenyl, -[(C1-C6)alkyl]heteroaryl, NO2, -[(C1-C6)alkyl]cycloalkyl, - [(C1-C6)alkyl]heterocyclyl, -C(O)NRbSO3H, -NRbC(O)Rc, -NRbC(O)ORc, -NRbC(S)ORc, - NRbC(O)NRbRc, -NRbC(S)NRbRc, -NRbS(O)2NRbRc, -C(S)Rb, -S(O)2Rb, -S(O)Rb, -C(S)ORb, -C(S)NRbRc, -NRbC(S)Rc, -SRb, phenyl, heteroaryl, cycloalkyl, and heterocyclyl, wherein for each occurrence of phenyl, heteroaryl, cycloalkyl, and heterocyclyl, said groups are optionally substituted with one to three groups selected from halo, cyano, (C1-C4)alkyl, halo(C1-C4)alkyl, (C1-C4)alkoxy, halo(C1-C4)alkoxy, -C(O)NRbRc, -C(O)ORb; and Ra, Rb, Rc, and Rdare each independently selected from hydrogen, (C1-C6)alkyl, halo(C1-C6)alkyl, phenyl, benzyl, heterocyclyl, heteroaryl, and cycloalkyl, wherein saidphenyl, benzyl, heterocyclyl, heteroaryl, and cycloalkyl are each optionally substituted with 1 to three groups selected from halo, (C1-C4)alkyl, halo(C1-C4)alkyl, (C1-C4)alkoxy, and halo(C1-C4)alkoxy. Alternatively, as part of the second embodiment, the compound is of Formula IIa:or a pharmaceutically acceptable salt thereof, wherein Y is CH2or C(O); Z is CRZor N; RZis H or halo; R1is selected from (C1-C6)alkyl, halo(C1-C6)alkyl, hydroxy(C1-C6)alkyl, aryl, heterocyclyl, heteroaryl, and carbocyclyl, wherein said aryl, heterocyclyl, heteroaryl, and carbocyclyl for R1are each optionally substituted with one to three groups selected from selected from R4, and wherein said (C1-C6)alkyl, halo(C1-C6)alkyl, and hydroxy(C1-C6)alkyl for R1are each substituted with one or two groups selected from aryl, heterocyclyl, heteroaryl, and carbocyclyl, wherein said aryl, heterocyclyl, heteroaryl, and carbocyclyl are each optionally substituted with one to three groups selected from R5; provided that R1is not cyclopentyl, 1-cyclopropylpiperidine-4-yl, para-2- phenoxyacetonitrilyl, 4-fluorophenyl, 1-neopentylcyclopropan-1-yl, 4- trifluoromethoxyphenyl, 1-propyl-1H-pyrazole-3-yl, 1-benzyl-3-methyl-1H-pyrazol-3-yl, unsubstituted spiro[3.3]heptanyl, an unsubstituted pyrimidinyl, unsubstituted pyridinyl, unsubstituted indolyl, unsubstituted benzooxazolyl, unsubstituted cubanyl, -CH2(unsubsituted thiazolyl), or -(CH2)2[unsubsituted indolyl]; R1aand R2are each independently hydrogen or (C1-C4)alkyl; the dashed lines represent additional bonds which may be present; R4and R5are each independently selected from (C1-C6)alkyl, halo(C1-C6)alkyl, -[(C1- C6)alkyl]NRbRc, [(C1-C6)alkyl]O[(C1-C6)alkyl], -[OCH2CH2]m-OCH2C(O)ORb, halo, cyano, - ORa, -NRbRc, -C(O)NRbRc, -C(O)ORb, -C(O)Rd, -[(C1-C6)alkyl]C(O)NRbRc, -[(C1- C6)alkyl]C(O)ORb, -[(C1-C6)alkyl]-C(O)Rd, -[(C1-C6)alkyl]phenyl, -[(C1-C6)alkyl]heteroaryl, NO2, -[(C1-C6)alkyl]cycloalkyl, -[(C1-C6)alkyl]heterocyclyl, -C(O)NRbSO3H, -NRbC(O)Rc, - NRbC(O)ORc, -NRbC(S)ORc, -NRbC(O)NRbRc, -NRbC(S)NRbRc, -NRbS(O)2NRbRc, -C(S)Rb,-S(O)2Rb, -S(O)Rb, -C(S)ORb, -C(S)NRbRc, -NRbC(S)Rc, -SRb, phenyl, heteroaryl, cycloalkyl, and heterocyclyl, wherein for each occurrence of phenyl, heteroaryl, cycloalkyl, and heterocyclyl, said groups are optionally substituted with one to three groups selected from halo, cyano, phenyl, benzyl, (C3-C6)cycloalkyl, (C1-C4)alkyl, halo(C1-C4)alkyl, (C1- C4)alkoxy, halo(C1-C4)alkoxy, -C(O)NRbRc, and -C(O)ORb; Ra, Rb, Rc, and Rdare each independently selected from hydrogen, (C1-C6)alkyl, halo(C1-C6)alkyl, phenyl, benzyl, heterocyclyl, heteroaryl, and cycloalkyl, wherein said phenyl, benzyl, heterocyclyl, heteroaryl, and cycloalkyl are each optionally substituted with 1 to three groups selected from halo, (C1-C4)alkyl, halo(C1-C4)alkyl, (C1-C4)alkoxy, and halo(C1-C4)alkoxy; and m is 1-5.

[0035] In embodiments, Z in the compound of Formula IIa is CR3. In embodiments, R3in the compound of Formula IIa is H or -F. In embodiments, R3in the compound of Formula IIa is H. In embodiments, Z in the compound of Formula IIa is N.

[0036] As part of a third embodiment, the compound of Formula I or II is of the Formula II:or a pharmaceutically acceptable salt thereof, wherein the remaining variables as defined above for Formula II. Alternatively, as part of a third embodiment, the compound of Formula I or II is of the Formula IV:or a pharmaceutically acceptable salt thereof, wherein the remaining variables as defined above for Formula II.

[0037] As part of a fourth embodiment, Y in the compound of any one of Formula I to IV is C(O), wherein the remaining variables as defined above for any one of Formula I to IV. Alternatively, as part of a fourth embodiment, Y in the compound of any one of Formula I to IV is CH2, wherein the remaining variables as defined above for any one of Formula I to IV.

[0038] As part of a fifth embodiment, R2in the compound of any one of Formula I to IV is hydrogen, wherein the remaining variables are as described above for any one of Formula I to IV and / or the fourth embodiment.

[0039] As part of a sixth embodiment, R1ain the compound of any one of Formula I to IV is hydrogen, wherein the remaining variables are as described above for any one of Formula I to IV and / or any one of the fourth or fifth embodiments. Alternatively, as part of a sixth embodiment, R1ain the compound of any one of Formula I to IV is CH3, wherein the remaining variables are as described above for any one of Formula I to IV and / or any one of the fourth or fifth embodiments.

[0040] As part of a seventh embodiment, R1in the compound of any one of Formula I to IV is selected from (C1-C6)alkyl, halo(C1-C4)alkyl, hydroxy(C1-C4)alkyl, aryl, heterocyclyl, heteroaryl, and carbocyclyl, wherein said aryl, heterocyclyl, heteroaryl, and carbocyclyl for R1are each substituted with one to three groups selected from selected from R4, and wherein said (C1-C6)alkyl, halo(C1-C4)alkyl, and hydroxy(C1-C4)alkyl for R1are each substituted with one or two groups selected from aryl, heterocyclyl, heteroaryl, and carbocyclyl, wherein said aryl, heterocyclyl, heteroaryl, and carbocyclyl are each optionally substituted with one to three groups selected from R5, wherein the remaining variables are as described above for any one of Formula I to IV and / or any one of the fourth to sixth embodiments. Alternatively, as part of a seventh embodiment, R1in the compound of any one of Formula I to IV is selected from (C1-C6)alkyl, halo(C1-C4)alkyl, hydroxy(C1-C4)alkyl, (C6-C10)aryl, 4- to 10- membered heterocyclyl, 5- to 10-membered heteroaryl, and 3- to 10-membered carbocyclyl, wherein said (C6-C10)aryl, 4- to 10-membered heterocyclyl, 5- to 10-membered heteroaryl, and 3- to 10-membered carbocyclyl for R1are each substituted with one to three groups selected from selected from R4, and wherein said (C1-C6)alkyl, halo(C1-C4)alkyl, and hydroxy(C1-C4)alkyl for R1are each substituted with one or two groups selected from (C6- C10)aryl, 4- to 10-membered heterocyclyl, and 5- to 10-membered heteroaryl, wherein said (C6-C10)aryl, 4- to 10-membered heterocyclyl, and 5- to 10-membered heteroaryl are each optionally substituted with one to three groups selected from R5, wherein the remaining variables are as described above for any one of Formula I to IV and / or any one of the fourth to sixth embodiments. In another alternative, as part of a seventh embodiment, R1in the compound of any one of Formula I to IV is selected from (C1-C4)alkyl, halo(C1-C4)alkyl, hydroxy(C1-C4)alkyl, (C6-C10)aryl, 4- to 10-membered heterocyclyl, and 3- to 10-membered carbocyclyl, wherein said (C6-C10)aryl, 4- to 10-membered heterocyclyl, and 3- to 10- membered carbocyclyl for R1are each substituted with one to three groups selected fromselected from R4, and wherein said (C1-C4)alkyl, halo(C1-C4)alkyl, and hydroxy(C1-C4)alkyl for R1are each substituted with one or two groups selected from (C6-C10)aryl, 4- to 10- membered heterocyclyl, and 5- to 10-membered heteroaryl, wherein said (C6-C10)aryl, 4- to 10-membered heterocyclyl, and 5- to 10-membered heteroaryl are each optionally substituted with one to three groups selected from R5, wherein the remaining variables are as described above for any one of Formula I to IV and / or any one of the fourth to sixth embodiments. In yet another alternative, as part of a seventh embodiment, R1in the compound of any one of Formula I to IV is selected from (C1-C4)alkyl, halo(C1-C4)alkyl, hydroxy(C1-C4)alkyl, phenyl, 9- to 10-membered bicyclic heterocyclyl, and 9- to 10-membered bicyclic carbocyclyl, and 3- to 5-membered monocyclic carbocyclyl, wherein said phenyl, 9- to 10- membered bicyclic heterocyclyl, 9- to 10-membered bicyclic carbocyclyl, and 3- to 5- membered monocyclic carbocyclyl for R1are each substituted with one to three groups selected from selected from R4, and wherein said (C1-C4)alkyl, halo(C1-C4)alkyl, and hydroxy(C1-C4)alkyl for R1are each substituted with one or two groups selected from phenyl, naphthalenyl, 9- to 10-membered heterocyclyl, and 6- to 10-membered heteroaryl, wherein said phenyl, naphthalenyl, 9- to 10-membered heterocyclyl, and 6- to 10-membered heteroaryl are each optionally substituted with one to three groups selected from R5, wherein the remaining variables are as described above for any one of Formula I to IV and / or any one of the fourth to sixth embodiments. In yet another alternative, as part of a seventh embodiment, R1in the compound of any one of Formula I to IV is selected from (C1- C4)alkyl, hydroxy(C1-C4)alkyl, phenyl, cyclopropyl, cyclobutyl, cyclopentyl, chromanyl, benzodioxolyl, and 2,3-dihydro-1H-indenyl, wherein said phenyl, cyclopropyl, cyclobutyl, cyclopentyl, chromanyl, benzodioxolyl, and 2,3-dihydro-1H-indenyl for R1are each substituted with one to three groups selected from selected from R4, and wherein said (C1- C4)alkyl and hydroxy(C1-C4)alkyl for R1are each substituted with phenyl, naphthalenyl, benzothiazolyl, benzodioxolyl, oxazolyl, thiazolyl, pyrazolyl, benzooxazolyl, quinolinyl, isoquinolinyl, pyrimidinyl, and pyridinyl, wherein said phenyl, naphthalenyl, benzothiazolyl, benzodioxolyl, oxazolyl, thiazolyl, pyrazolyl, benzooxazolyl, quinolinyl, isoquinolinyl, pyrimidinyl, and pyridinyl are each optionally substituted with one to three groups selected from R5, wherein the remaining variables are as described above for any one of Formula I to IV and / or any one of the fourth to sixth embodiments. In yet another alternative, as part of a seventh embodiment, R1in the compound of any one of Formula I to IV is selected from (C1- C4)alkyl, hydroxy(C1-C4)alkyl, phenyl, cyclopropyl, chromanyl, benzodioxolyl, and 2,3- dihydro-1H-indenyl, wherein said phenyl, cyclopropyl, chromanyl, benzodioxolyl, and 2,3-dihydro-1H-indenyl for R1are each substituted with one to three groups selected from selected from R4, and wherein said (C1-C4)alkyl and hydroxy(C1-C4)alkyl for R1are each substituted with phenyl, naphthalenyl, benzothiazolyl, benzodioxolyl, pyrazolyl, benzooxazolyl, quinolinyl, isoquinolinyl, and pyridinyl, wherein said phenyl, naphthalenyl, benzothiazolyl, benzodioxolyl, pyrazolyl, benzooxazolyl, quinolinyl, isoquinolinyl, and pyridinyl are each optionally substituted with one to three groups selected from R5, wherein the remaining variables are as described above for any one of Formula I to IV and / or any one of the fourth to sixth embodiments.

[0041] As part of an eighth embodiment, R4and R5in the compound of any one of Formula I to IV are each independently selected from R4and R5are each independently selected from (C1-C6)alkyl, halo(C1-C6)alkyl, cyano, halo, NO2, -ORa, -NRbRc, -C(O)NRbRc, -C(O)ORb, -[OCH2CH2]m-OCH2C(O)OH, -C(O)Rd, phenyl, heteroaryl, cycloalkyl, and heterocyclyl, wherein, said phenyl, heteroaryl, cycloalkyl, and heterocyclyl are each optionally substituted with one to three groups selected from halo, cyano, phenyl, benzyl, (C3-C6)cycloalkyl, -C(O)O(C1-C4)alkyl, (C1-C4)alkyl, halo(C1-C4)alkyl, (C1-C4)alkoxy, and halo(C1-C4)alkoxy, wherein the remaining variables are as described above for any one of Formula I to IV and / or any one of the fourth to seventh embodiments. In another alternative, as part of an eighth embodiment, R4and R5in the compound of any one of Formula I to IV are each independently selected from (C1-C6)alkyl, halo(C1-C6)alkyl, halo, NO2, -ORa, - NRbRc, -C(O)NRbRc, -C(O)ORb, -C(O)Rd, phenyl, heteroaryl, cycloalkyl, and heterocyclyl, wherein, said phenyl, heteroaryl, cycloalkyl, and heterocyclyl are each optionally substituted with one to three groups selected from halo, (C1-C4)alkyl, halo(C1-C4)alkyl, (C1-C4)alkoxy, and halo(C1-C4)alkoxy, wherein the remaining variables are as described above for any one of Formula I to IV and / or any one of the fourth to seventh embodiments. In another alternative, as part of an eighth embodiment, R4and R5in the compound of any one of Formula I to IV are each independently selected from (C1-C6)alkyl, halo(C1-C6)alkyl, cyano, halo, NO2, -ORa, -NRbRc, -C(O)NRbRc, -C(O)ORb, -[OCH2CH2]5-OCH2C(O)ORb,-C(O)Rd, phenyl, pyridinyl, oxazolyl, pyridazinyl, pyrazinyl, cyclopentyl, pyrimidinyl, benzoxazolyl, cyclobutyl, cyclopropyl, cyclopentyl, dihydropyranyl, piperdinyl, and morpholinyl, wherein said phenyl, pyridinyl, oxazolyl, pyridazinyl, pyrazinyl, cyclopentyl, pyrimidinyl, benzoxazolyl, cyclobutyl, cyclopropyl, cyclopentyl, dihydropyranyl, piperdinyl, and morpholinyl are each optionally substituted with one to three groups selected from halo, cyano, phenyl, benzyl, (C3-C6)cycloalkyl, -C(O)O(C1-C4)alkyl, (C1-C4)alkyl, halo(C1- C4)alkyl, (C1-C4)alkoxy, and halo(C1-C4)alkoxy, and wherein the remaining variables are asdescribed above for any one of Formula I to IV and / or any one of the fourth to seventh embodiments. In another alternative, as part of an eighth embodiment, R4and R5in the compound of any one of Formula I to IV are each independently selected from (C1-C6)alkyl, halo(C1-C6)alkyl, halo, NO2, -ORa, -NRbRc, -C(O)NRbRc, -C(O)ORb, -C(O)Rd, phenyl, pyridinyl, oxazolyl, pyridazinyl, pyrazinyl, cyclopentyl, pyrimidinyl, cyclobutyl, cyclopropyl, dihydropyranyl, and morpholinyl, l, wherein said phenyl, pyridinyl, oxazolyl, pyridazinyl, pyrazinyl, cyclopentyl, pyrimidinyl, cyclobutyl, cyclopropyl, dihydropyranyl, and morpholinyl are each optionally substituted with one to three groups selected from halo, (C1- C4)alkyl, halo(C1-C4)alkyl, (C1-C4)alkoxy, and halo(C1-C4)alkoxy, and wherein the remaining variables are as described above for any one of Formula I to IV and / or any one of the fourth to seventh embodiments.

[0042] As part of a ninth embodiment, Rain the compound of any one of Formula I to IV is selected from hydrogen, (C1-C6)alkyl, halo(C1-C6)alkyl, phenyl, benzyl, and pyridinyl, wherein said benzyl is optionally substitued with (C1-C6)alkoxy, wherein the remaining variables are as described above for any one of Formula I to IV and / or any one of the fourth to eighth embodiments.

[0043] As part of a tenth embodiment, Rband Rcin the compound of any one of Formula I to IV are each independently selected from hydrogen and (C1-C6)alkyl, wherein the remaining variables are as described above for any one of Formula I to IV and / or any one of the fourth to ninth embodiments.

[0044] As part of an eleventh embodiment, Rdin the compound of any one of Formula I to IV is 5- to 7-membered heterocyclyl, wherein the remaining variables are as described above for any one of Formula I to IV and / or any one of the fourth to tenth embodiments. Alternatively, as part of an eleventh embodiment, Rdin the compound of any one of Formula I to IV is morpholinyl or piperdinyl, wherein the remaining variables are as described above for any one of Formula I to IV and / or any one of the fourth to tenth embodiments. Alternatively, as part of an eleventh embodiment, Rdin the compound of any one of Formula I to IV is morpholinyl, wherein the remaining variables are as described above for any one of Formula I to IV and / or any one of the fourth to tenth embodiments.

[0045] As part of a twelfth embodiment, R1in the compound of any one of Formula I to IV is selected from:,above for any one of Formula I to IV and / or any one of the fourth or fifth embodiments.Alternatively, as part of a twelfth embodiment, R1in the compound of any one of Formula I to IV is selected from:,variables are as described above for any one of Formula I to IV and / or any one of the fourth or fifth embodiments.

[0046] Additional compounds are included in the present disclosure. Pharmaceutically acceptable salts thereof as well as the neutral forms are included. 4. Uses, Formulation and Administration

[0047] The compounds and compositions described herein are generally useful for modulating the activity of CDK2. In some aspects, the compounds, pharmaceutical acceptable salts, and pharmaceutical compositions described herein degrade CDK2.

[0048] In some aspects, the compounds and pharmaceutical compositions described herein are useful in treating a disorder associated with CDK2 function. Thus, provided herein are methods of treating a disorder associated with CDK2 function, comprising administering to a subject in need thereof, a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a disclosed compound or pharmaceutically acceptable salt thereof.

[0049] Also provided is the use of a compound described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a disclosed compound or pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treating a disorder associated with CDK2 function. Also provided is a compound described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a disclosed compound or pharmaceutically acceptable salt thereof, for use in treating a disorder associated with CDK2.

[0050] In one aspect, the disorder associated with CDK2 is a proliferative disease such as cancer. In some aspects, the cancer treated by the compounds, pharmaceutically acceptable salt thereof, and pharmaceutical compositions described herein is selected from breast cancer, ovarian cancer, bladder cancer, uterine cancer (e.g., uterine endometrial cancer), prostate cancer, lung cancer (such as e.g., non-small cell lung cancer, small cell lung cancer,squamous cell carcinoma or adenocarcinoma), esophageal cancer, head and neck cancer, colorectal cancer, kidney cancer (such as e.g., renal cell cancer), liver cancer (such as e.g., hepatocellular carcinoma), pancreatic cancer, stomach (i.e., gastric) cancer, gallbladder cancer, esophagogastric cancer, sarcoma (e.g., bone sarcoma), cervical cancer, and thyroid cancer.

[0051] In certain aspects, a pharmaceutical composition described herein is formulated for administration to a patient in need of such composition. Pharmaceutical compositions described herein may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir. The term "parenteral" as used herein includes subcutaneous, intravenous, intramuscular, intra-articular, intra-synovial, intrasternal, intrathecal, intrahepatic, intralesional and intracranial injection or infusion techniques. In some embodiments, the compositions are administered orally, intraperitoneally or intravenously. Sterile injectable forms of the pharmaceutical compositions described herein may be aqueous or oleaginous suspension. These suspensions may be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents.

[0052] In some aspects, the pharmaceutical compositions are administered orally.

[0053] A specific dosage and treatment regimen for any particular patient will depend upon a variety of factors, including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination, and the judgment of the treating physician and the severity of the particular disease being treated. The amount of a compound described herein in the composition will also depend upon the particular compound in the pharmaceutical composition. EXEMPLIFICATION Preparation of Compounds

[0054] Compounds of the disclosure can be prepared by methods described in the General Schemes, procedures, and Examples set forth within, and by related methods known in the art.

[0055] Intermediates

[0056] Intermediate A: Carbamates coupling partners

[0057] Carbamate coupling partners were made according to several general procedures as follows:

[0058] Intermediate A-1: Phenyl (2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5- yl)carbamate

[0059] Step – 1: methyl 2-(bromomethyl)-4-nitrobenzoate and methyl 2- (dibromomethyl)-4-nitrobenzoate

[0060] To a stirred solution of methyl 2-methyl-4-nitrobenzoate (5 g, 26 mmol) in carbon tetrachloride (150 mL). N-bromosuccinimide (6.8 g, 38 mmol) and dibenzoyl peroxide, (0.93 g, 3.8 mmol) was added. The reaction mixture was heated at 85oC for 16 h. The Progress of the reaction was monitored by LCMS and thin layer chromatography. After completion of the reaction (thin layer chromatography eluent: 10 % Ethyl acetate in Petroleum ether, UV active), reaction mass was quenched with water (50 mL), and extracted with ethyl acetate (3 x 50 mL). Organic layer was washed with brine solution (50 mL), dried over sodium sulphate, filtered, and concentrated under reduce pressure to get a 1:1 mixture of methyl 2- (bromomethyl)-4-nitrobenzoate and methyl 2-(dibromomethyl)-4-nitrobenzoate as crude compound (6.3 g, 100%). Crude taken directly for next step without further purification. MS (ESI) m / z 272.9637 [M+H]+. LC-MS – RT - 3.33, purity: 54 %. LC-MS – RT - 3.16, purity: 39 %.

[0061] Step – 2: methyl 2-(bromomethyl)-4-nitrobenzoate

[0062] To a stirred solution of methyl 2-(bromomethyl)-4-nitrobenzoate and methyl 2- (dibromomethyl) – 4 – nitrobenzoate (5.0 g, crude) in tetrahydrofuran (100 mL) at 0oC. N,N – diisopropylethylamine (2.5 mL, 14 mmol) and diethyl phosphite (1.9 mL, 14 mmol) were added. The reaction mixture was stirred at ambient temperature for 16 h. The progress of the reaction was monitored by LCMS and thin layer chromatography. After completion of the reaction (thin layer chromatography eluent: 10 % Ethyl acetate in Petroleum ether, UV active), reaction mass was quenched with water (50 mL), and extracted with ethyl acetate (2x 50 mL). Organic layers were combined, washed with brine solution (50 mL), dried over sodium sulphate, filtered, and concentrated under reduce pressure to get crude compound (6.6 g). Crude compound was purified by combi flash, silica of 100- 200 mesh column with ethyl acetate - pet ether (0 - 30%) as an eluent to get pure methyl 2-(bromomethyl)-4- nitrobenzoate as an off white solid (3.5 g, 90 %). MS (ESI) m / z 272.96 [M+H]+. LC-MS – purity: 85 %.1H NMR (400 MHz, DMSO-d6): δ 8.34 (s, 1H), 8.28 (d, J = Hz, 1H), 8.20 (d, J = 6.40 Hz, 1H), 4.97 (s, 2H), 4.00 (s, 3H).

[0063] Step – 3: 3-(5-nitro-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[0064] To a stirred solution of methyl 2-(bromomethyl)-4-nitrobenzoate (5.4 g, 20 mmol) and 3-aminopiperidine-2,6-dione hydrochloride (3.8 g, 30 mmol) in acetonitrile (55 mL) at 0oC, N,N-diisopropylethylamine (3.8 g, 30 mmol) were added. The reaction mass was heated to 85oC for 16 h. The progress of the reaction was monitored by LCMS and thin layer chromatography. After completion of the reaction (thin layer chromatography eluent: 70 % Ethyl acetate in petroleum ether, UV active, Ninhydrin), reaction was concentrated to dryness.100 mL of 10 % acetonitrile and ethyl acetate solvent mixture was added, and solids precipitated out. The solids were filtered and dried under vacuum for 30 min to get crude compound (6.6 g). Crude compound was recrystallized from ethyl acetate to get pure 3-(5- nitro-1-oxoisoindolin-2-yl)piperidine-2,6-dione as a dark brown solid (2.4 g, 42 %). MS (ESI) m / z 290.28 [M+H]+. LC-MS – purity: 82 %.1H NMR (400 MHz, DMSO-d6): δ 11.04 (s, 1H), 8.56 (s, 1H), 8.34 (d, J = 3.60 Hz, 1H), 7.92 (d, J = 1.60 Hz, 1H), 5.19 – 5.14 (m, 1H), 4.63 – 4.47 (m, 2H), 2.67 – 2.62 (m, 2H), 2.51 – 2.50 (m, 2H).

[0065] Step – 4: 3-(5-amino-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[0066] To a stirred solution of 3-(5-nitro-1-oxoisoindolin-2-yl)piperidine-2,6-dione (5.0 g, 17 mmol) in DCM (250 mL) and methanol (250 mL).10% Pd / C (wet) (2.8 g, 26 mmol) was added, and Hydrogen gas (50 PSI, Parr Shaker) was purged through the reaction. The reaction mixture was stirred at ambient temperature for 16 h. The Progress of the reactionwas monitored by LCMS and thin layer chromatography. After completion of the reaction (thin layer chromatography eluent: 70 % ethyl acetate in petroleum ether, UV active, Ninhydrin), reaction mass was filtered through Celite® using methanol in excess. Filtrate was concentrated under reduced pressure to get the crude material, which was triturated with diethyl ether to get pure 3-(5-amino-1-oxoisoindolin-2-yl)piperidine-2,6-dione as a pale purple solid (3.0 g, 67 %). MS (ESI) m / z 260.24 [M+H]+. LC-MS – purity: 93%.

[0067] Step – 5 : phenyl (2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)carbamate

[0068] A suspension of 3-(5-amino-1-oxoisoindolin-2-yl)piperidine-2,6-dione (5 g, 19 mmol) and phenyl chloroformate (150 mL) was heated under stirring at 70oC for 16 h. After completion of the reaction (Monitored by thin layer chromatography, eluent: 70 % ethyl acetate in petroleum ether), the reaction was quenched with cold water (50 mL), which led to precipitation. The precipitate was filtered, washed with excess of cold water, and dried to get crude compound (3.1 g). The crude product was washed with a 5% acetonitrile in diethyl ether solution (50 mL) and pentane (30 mL) to get pure phenyl (2-(2,6-dioxopiperidin-3-yl)- 1-oxoisoindolin-5-yl)carbamate (2.5 g, 34 %) as an off white solid. MS (ESI) m / z 380.49. LC- MS purity: 96 %.1H NMR (400 MHz, DMSO-d6): δ 10.97 (s, 1H), 10.63 (s, 1H), 7.82 (s, 1H), 7.69 (d, J = 8.40 Hz, 1H), 7.58 (d, J = 8.00 Hz, 1H), 7.45 – 7.43 (m, 3H), 7.27 – 7.25 (m, 2H), 5.09 (q, J = 4.80 Hz, 1H), 4.30 (d, J = 17.60 Hz, 1H), 4.44 (d, J = 17.20 Hz, 1H), 2.88 – 2.87 (m, 1H), 2.57 – 2.50 (m, 1H), 2.35 – 2.33 (m, 1H), 1.99 – 1.98 (m, 1H).

[0069] Intermediate A-2: Phenyl (2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5- yl)carbamate

[0070] To a stirred solution of 5-amino-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3- dione (0.5 g, 1.8 mmol) and phenyl chloroformate (3.5 mL) was added at room temperature, Then the reaction mixture was stirred at 70oC for 16 h under N2 atm. The progress of the reaction mixture was monitered by LCMS. The reaction mixture was quenched with water (50 mL) and extracted with ethyl acetate (2 x 20 mL), organic layer was separated and dried over anhydrous sodium sulphate. Organic layer concentrated at 40 °C to get crude compoundwhich was triturated with diethyl ether (20 mL) and dried under reduced pressure to afford phenyl (2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)carbamate (0.4 g, 55 %) as an off- white solid. Note: The crude compound was used for next step without any purification. MS (ESI) m / z 394.10 [M+H]+.

[0071] Intermediate A-3: Phenyl (6-(2,6-dioxopiperidin-3-yl)-5-oxo-6,7-dihydro-5H- pyrrolo[3,4-b]pyridin-2-yl)carbamate

[0072] Step-1: Synthesis of Methyl 6-chloro-4-methylnicotinate

[0073] To a stirred solution of 6-chloro-2-methylnicotinic acid (10 g, 58 mmol) in POCl3(100 mL) was heated at 100° C for 16 h. The progress of reaction was monitored by TLC and LCMS. After completion of the reaction, the excess of POCl3was evaporated and the residue was quenched with MeOH. The solvent was evaporated and the residue was taken in sat. NaHCO3solution and stirred for 15 min. The residue was extracted by DCM (3 x 30 mL) and the combined organic layers were dried over anhydrous MgSO4and evaporated under reduced pressure to afford methyl 6-chloro-2-methylnicotinate (5 g, 92%) as transparent liquid. MS (ESI) m / z 186.11 [M+H]+.

[0074] Step-2: Synthesis of methyl 2-(bromomethyl)-6-chloronicotinate:

[0075] To a stirred solution of methyl 6-chloro-2-methylnicotinate (5 g, 27 mmol) in carbon tetrachloride (150 mL) at room temperature, N-Bromosuccinimide, (12 g, 67 mmol) was added and stirred for 30 min at same temperature. Then benzoyl peroxide (0.98 g, 4 mmol) was added and the mixture was stirred at 80 °C for 16 h. The reaction was monitored with TLC. After completion of reaction, the reaction mixture was quenched with water (50 mL) and extracted with DCM (2 x 80 mL). The combined organic layers were washed with brine solution (50 mL), dried over anhydrous sodium sulphate and concentrated under reduced pressure to afford crude. The crude compound was purified by silica gelcolumn chromatography by using 0-2% EtOAc in pet ether as an eluent to afford (2.5g, 35%) as an off white solid. (3) as an off-white solid. MS (ESI) m / z 264.02 [M+H]+.

[0076] Step-3: Synthesis of 3-(2-chloro-5-oxo-5,7-dihydro-6H-pyrrolo[3,4-b]pyridin- 6-yl)piperidine-2,6-dione:

[0077] To a stirred solution of methyl 2-(bromomethyl)-6-chloronicotinate (2.5 g, 9.5 mmol) in acetonitrile (50 mL) at room temperature, N,N-diisopropylethylamine (8.2 mL, 47 mmol) and 3-aminopiperidine-2,6-dionehydrogen chloride (1.5 g, 11 mmol) were added sequentially. The reaction was stirred at 80 °C for 16 h, the progress of the reaction was monitored by TLC and LCMS. After completion of reaction, the reaction mixture was concentrated under reduced pressure. The residue was washed with diethyl ether (50 mL) to afford 3-(2-chloro-5-oxo-5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl)piperidine-2,6-dione (1.5 g, 57%). MS (ESI) m / z 280.17 [M+H]+.

[0078] Step-4: tert- butyl (6-(2,6-dioxopiperidin-3-yl)-5-oxo-6,7-dihydro-5H- pyrrolo[3,4-b]pyridin-2-yl)carbamate:

[0079] In a sealed tube, to a stirred solution of 3-(2-chloro-5-oxo-5,7-dihydro-6H- pyrrolo[3,4-b]pyridin-6-yl)piperidine-2,6-dione (1 g, 3.6 mmol) in 1,4-dioxane (20 mL) were added tert-butyl carbamate (0.5 g, 4.3 mmol) and cesium carbonate (3.5 g, 10.7 mmol). The resulting reaction mixture was degassed with argon gas for 10 minutes, followed by the addition of Xantphos (0.21 g, 0.36 mmol) and Pd2dba3 (0.16 g, 0.18 mmol) then degassed with argon for 5 more minutes. Then the sealed tube was sealed with cap, heated to 100 °C, and stirred for 1 h. The progress of the reaction was monitored by TLC and LCMS. The reaction mixture was diluted with ethyl acetate (20 mL), washed with water (2 x 25 mL)followed by brine solution (2 x 25 mL). The organic layer was dried over anhydrous magnesium sulphate, filtered and the filtrate was concentrated under reduced pressure to afford crude. The obtained crude was purified over silica gel column chromatography by using 70-75% EtOAc / pet ether as an eluent to afford tert- butyl (6-(2,6-dioxopiperidin-3- yl)-5-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-2-yl)carbamate (0.7 g, 54%) as an off white solid. MS (ESI) m / z 216.18 [M+H]+.

[0080] Step-5: Synthesis of 3-(2-amino-5-oxo-5,7-dihydro-6H-pyrrolo[3,4-b]pyridin- 6-yl)piperidine-2,6-dione:

[0081] To a stirred solution of tert-butyl (6-(2,6-dioxopiperidin-3-yl)-5-oxo-6,7-dihydro- 5H-pyrrolo[3,4-b]pyridin-2-yl)carbamate (0.7 g, 1.9 mmol) in DCM (1.4 mL), was added 4M HCl in 1,4 dioxane (3.5 mL) at 0°C. The resulting reaction mixture was stirred at room temperature for 3h. The progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, the mixture was evaporated under reduced pressure to afford crude. The obtained crude was triturated with diethyl ether (2 x 20 mL) and dried under reduced pressure. (8) (0.5 g, 98 %) as brown solid. MS (ESI) m / z 261.11 [M+H]+.

[0082] Step-6: Phenyl (6-(2,6-dioxopiperidin-3-yl)-5-oxo-6,7-dihydro-5H- pyrrolo[3,4-b]pyridin-2-yl)carbamate

[0083] To a stirred solution of 3-(2-amino-5-oxo-5,7-dihydro-6H-pyrrolo[3,4-b]pyridin- 6-yl)piperidine-2,6-dione (0.25 g, 0.96 mmol) in acetonitrile (5 mL) at 0°C were added pyridine (0.074 mL, 1.2 mmol) and phenyl carbonochloridate (0.23 mL, 1.4 mmol). The resulting reaction mixture was stirred at room temperature for 6 h. The progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, the mixture was filtered and solid was dried under vacuum to afford phenyl (6-(2,6-dioxopiperidin-3-yl)- 5-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-2-yl)carbamate (0.25 g, 68%) as an off-white solid. MS (ESI) m / z 381.43 [M+H]+

[0084] Intermediate A-4: tert-butyl (6-(2,6-dioxopiperidin-3-yl)-5,7-dioxo-6,7- dihydro-5H-pyrrolo[3,4-b]pyridin-2-yl)carbamate

[0085] Step-1: 6-bromopyridine-2,3-dicarboxylic acid

[0086] To a solution of CCl4 (300 mL) and NaOCl (600mL) was added RuO2 (1.6 g, 12 mmol) under vigorous stirring at room temperature, when the reaction mixture was yellow, 2- chloroquinoline (20 g, 120 mmol) was added in the reaction mixture and stirred at room temperature for 12 h. The reaction mixture was treated with diethyl ether (2 x 50 mL) and the aqueous layer was separated and acidified to pH 1–2 with 37% HCl which was extracted with ethyl acetate (5 x 50 mL). The organic layers were combined dried over sodium sulfate and evaporated to dryness gave the crude product as a Cream solid (10.2 g, 41%).1H-NMR (400 MHz, DMSO-d6) δ 13.90 (br s, 2H), 8.28 (d, J = 8.4 Hz, 1H), 7.75 (d, J = 8.4 Hz, 1H)

[0087] Step-2: 2-bromo-6-(2,6-dioxopiperidin-3-yl)-5H-pyrrolo[3,4-b]pyridine- 5,7(6H)-dione

[0088] To a stirred solution of 6-chloropyridine-2,3-dicarboxylic acid (10 g, 50 mmol) in acetic acid (100 mL) at room temperature were added 3-aminopiperidine-2,6-dione (13 g, 99 mmol) and Sodium acetate (12 g, 149 mmol) was added and the resulting reaction mixture was stirred at 150 °C for 16 h. After completion of reaction, the reaction mixture was treated with sodium bicarbonate solution (50 mL) and extracted with ethyl acetate (2 x 30 mL). The combined organic layers were dried over sodium sulphate, filtered and the filtrate was concentrated under reduced pressure to afford crude. The crude was purified over silica gel column chromatography using 230-400 mesh and the compound was eluted in 50%EtOAc : Pet ether to afford 2-chloro-6-(2,6-dioxopiperidin-3-yl)-5H-pyrrolo[3,4-b]pyridine- 5,7(6H)-dione (3 g, 41%) as a product. MS (ESI) m / z 294.2 [M+H]+, LC-MS purity : 98.44%.1H-NMR (400 MHz, DMSO-d6) δ 11.17 (s, 1H), 8.43 (d, J = 8.0 Hz, 1H), 7.99 (d, J = 8.0 Hz, 1H), 5.24 (dd, J = 13.0, 5.4 Hz, 1H), 2.89 – 2.86 (m, 1H), 2.64 – 2.63 (m, 1H), 2.60 – 2.59 (m, 1H), 2.09 - 2.06 (m, 1H).

[0089] Step-3: tert-butyl (6-(2,6-dioxopiperidin-3-yl)-5,7-dioxo-6,7-dihydro-5H- pyrrolo[3,4-b]pyridin-2-yl)carbamate

[0090] To a stirred solution of 2-bromo-6-(2,6-dioxopiperidin-3-yl)-5H-pyrrolo[3,4- b]pyridine-5,7(6H)-dione (3 g, 10 mmol) in dioxane (30 mL) at room temperature under nitrogen atmosphere was added Potassium phosphate (4.3 g, 20 mmol) and tert-Butyl carbamate (2.8 g, 15 mmol) and purged it for 15 mins. Later was added XPhos Pd G3 (1.3 g, 1.5 mmol) to the reaction mixture. The resulting reaction mixture was stirred at 100 °C for 1 h. After the completion of the reaction, the reaction mixture was filtered through celite. The filtrate was collected, dried over sodium sulphate, concentrated under reduced pressure and the crude was triturated with ether (2 x 30 mL) to afford crude. The crude was purified and product was eluted in 60% EA:petether to afford tert-butyl (6-(2,6-dioxopiperidin-3-yl)-5,7- dioxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-2-yl)carbamate (1.9 g, 50%). MS (ESI) m / z 373.5 [M-H]-, LC-MS purity : 90%.1H-NMR (400 MHz, DMSO-d6) δ 11.13 (s, 1H), 10.86 (s, 1H), 8.27 (d, J = 8.8 Hz, 1H), 8.20 (d, J = 8.4 Hz, 1H), 5.17 (dd, J = 12.8, 5.2 Hz, 1H), 2.89 – 2.84 (m, 1H), 2.63 – 2.56 (m, 1H), 2.51 – 2.46 (m, 1H), 2.08 – 2.04 (m, 1H), 1.49 (s, 9H).

[0091] Intermediate A-5: Phenyl (2-(2,6-dioxopiperidin-3-yl)-4-fluoro-1- oxoisoindolin-5-yl)carbamate

[0092] Step-1: 4-Bromo-2-fluoro-3-methylaniline

[0093] To a stirred solution of 2-fluoro-3-methylaniline (20 g, 160 mmol) in DMF (200 mL) at room temperature was added NBS (28 g, 160 mmol) dissolved in dimethylformamide dropwise over the period of 1 hour. The resulting reaction mixture was stirred at room temperature for 30 min. After the completion of the reaction, the reaction mixture was diluted with ice cooled water (50 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic layers were dried over sodium sulphate, filtered and the filtrate was concentrated under vacuum to afford crude. The crude was purified over silica gel column chromatography using 230-400 mesh and the compound was eluted in 2% EtOAc : Pet ether to afford tert-butyl 4-bromo-2-(2-(tert-butoxy)-2-oxoethyl)-1H-indole-1-carboxylate (2) (17 g, 52% ) as a colorless solid . MS (ESI) m / z 203.00 [M+H]+, LC-MS purity : 97.34 %.1H-NMR (400 MHz, CDCl3 ) δ 7.09 (dd, J = 8.4, 1.6 Hz, 1H), 6.49 (t, J = 8.8 Hz, 1H), 3.68 (s, 2H).

[0094] Step-2: Methyl 4-amino-3-fluoro-2-methylbenzoatee

[0095] To a stirred solution in steel tube, 4-bromo-2-fluoro-3-methylaniline (17 g, 83 mmol) in methanol (340 mL) at room temperature was added sodium acetate (14 g, 170 mmol) and the reaction mixture was purged for 15 mins under nitrogen atmosphere. Then PdCl2(dppf) (6.1 g, 8.3 mmol) was added and further purged for 5 mins. The sealed tube was filled with 130 psi CO pressure and stirred at 1200C for 16 hr. After the completion of the reaction, the reaction mixture was concentrated under reduced pressure to remove excess of methanol. Then, the reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (3 x 200 mL). The combined organic layers were dried over sodium sulphate, filtered and the filtrate was concentrated under vacuum to afford crude. The crude was purified over silica gel column chromatography using 230-400 mesh and the compound was eluted in 8% EtOAc : Pet ether to afford methyl 4-amino-3-fluoro-2-methylbenzoate (14 g, 82% ) as light yellow solid .1H-NMR (400 MHz, CDCl3 ) δ 7.62 (dd, J = 8.4, 1.2 Hz, 1H), 6.56 (t, J = 8.6 Hz, 1H), 4.05 (s, 2H), 3.82 (s, 3H), 2.51 (s, 3H).

[0096] Step-3: Methyl 4-((tert-butoxycarbonyl)amino)-3-fluoro-2-methylbenzoate

[0097] To a solution of methyl 4-amino-3-fluoro-2-methylbenzoate (14 g, 76 mmol) in THF (140 mL) at 0 °C were added triethylamine (23 g, 230 mmol), dimethylaminopyridine (4.7 g, 38 mmol) and Boc anhydride (25 g, 115 mmol) and stirred at reaction mixture at 80 ° C for 2 h. After the completion of the reaction, the reaction mixture was diluted with water (20 mL) and extracted with DCM (3 x 20 mL). The combined organic layers were dried over sodium sulphate, filtered and the filtrate was concentrated under vacuum to afford crude. The crude was purified over silica gel column chromatography using 230-400 mesh and the compound was eluted in 1% EtOAc : Pet ether to afford methyl 4-((tert-butoxycarbonyl)amino)-3-fluoro-2-methylbenzoate (4) (5.5 g, 25%) as a product. MS (ESI) m / z 283.1 [M+H]+;

[0098] Step-4: Methyl 2-(bromomethyl)-4-((tert-butoxycarbonyl)amino)-3- fluorobenzoate

[0099] To a solution of methyl 4-((tert-butoxycarbonyl)amino)-3-fluoro-2- methylbenzoate (5.5 g, 30 mmol) in carbon tetrachloride (220 mL) at room temperature was added N-Bromosuccinimide (8.02 g, 45 mmol) and stirred for 30 min at room temperature. Then benzoyl peroxide (3.6 g, 15 mmol) was added and stirred at 80 °C for 16 h. The reaction was monitored with TLC. After the completion of the reaction, the reaction mixture was quenched with water (90 mL) and extracted with DCM (3 x 90 mL). The combined organic layers were dried over sodium sulphate, filtered and the filtrate was concentrated under vacuum to afford crude. The crude was purified over silica gel column chromatography using 230-400 mesh and the compound was eluted in 2% EtOAc : Pet ether to afford methyl 2-(bromomethyl)-4-((tert-butoxycarbonyl)amino)-3-fluorobenzoate (4 g, 37%) as an yellow solid. MS (ESI) m / z 226.2 [M+H]+.

[0100] Step-5: tert-Butyl (2-(2,6-dioxopiperidin-3-yl)-4-fluoro-1-oxoisoindolin-5- yl)carbamate

[0101] To a stirred solution of methyl 2-(bromomethyl)-4-((tert-butoxycarbonyl)amino)- 3-fluorobenzoate (4 g, 11 mmol) in acetonitrile (80 mL) at room temperature, N,N- diisopropylethylamine (9.6 mL, 55 mmol) and 3-aminopiperidine-2,6-dione hydrochloride (3.6 g, 22 mmol) were added sequentially. The reaction was stirred at 100 °C for 16 h. The progress of the reaction was monitored by TLC and LCMS. After completion of reaction, the reaction mixture was concentrated under reduced pressure to afford crude. The crude was purified over silica gel column chromatography using 230-400 mesh and the compound was eluted in 70% EtOAc : Pet ether to afford tert-butyl (2-(2,6-dioxopiperidin-3-yl)-4-fluoro-1- oxoisoindolin-5-yl)carbamate (2.4 g, 58%) as violet solid. MS (ESI) m / z 377.1 [M+H]+.

[0102] Step-6: 3-(5-Amino-4-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[0103] To a stirred solution of tert-butyl (2-(2,6-dioxopiperidin-3-yl)-4-fluoro-1- oxoisoindolin-5-yl)carbamate (1.3 g, 3.4 mmol) in DCM (6.5 mL) was added TFA (6.5 mL) at 0°C. The resulting reaction mixture was stirred at room temperature for 1h. The reaction mixture was evaporated and triturated with diethyl ether (2 x 10 mL) and dried under reduced vaccum to afford 3-(5-amino-4-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione (1 g, Quantitative) as a product. Crude was used as such for next step without any purification. MS (ESI) m / z 278.35 [M+H]+, LC-MS purity: 92.15%.

[0104] Step-7: phenyl (2-(2,6-dioxopiperidin-3-yl)-4-fluoro-1-oxoisoindolin-5- yl)carbamate

[0105] To a stiired solution of 3-(5-amino-4-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6- dione (1 g, 3.6 mmol) in acetonitrile (23 mL) and water (3 mL) at room temperature, phenylcarbonochloridate (5 mL) was added at same temperature. The reaction was stirred at room temperature for 16 h. The progress of the reaction was monitored by TLC and LCMS. After completion of reaction, the reaction mixture was concentrated under reduced pressure to afford crude. The crude was purified over silica gel column chromatography using 230-400 mesh and the compound was eluted in 90% EtOAc : Pet ether to afford phenyl (2-(2,6- dioxopiperidin-3-yl)-4-fluoro-1-oxoisoindolin-5-yl)carbamate (0.9 g, 63%) as a product. MS (ESI) m / z 397.1 [M+H]+, LC-MS purity: 80.84%.

[0106] Intermediate A-6: Phenyl (2-(2,6-dioxopiperidin-3-yl)-4-fluoro-1,3- dioxoisoindolin-5-yl)carbamate

[0107] Step-1: 4-bromo-3-fluorophthalic acid

[0108] To a stirred solution of 4-bromo-3-fluorobenzoic acid (10 g, 46 mmol) in THF (100 mL) was added lithium diisopropylamide (2 M in THF) (69 mL, 140 mmol) dropwise at -78°C under an atmosphere of argon. The resulting mixture was stirred at -78 °C for 1.5 h before the reaction mixture was purged with CO2 gas at -78 °C for 30 min. The reaction mixture was quenched with 4 M HCl in dioxane (30 mL) and then concentrated under reduced pressure to give a crude residue which was washed with ethyl acetate (2 x 100 mL). The solids were filtered off and the ethyl acetate layer was concentrated under reduced pressure to afford crude (20 g) as brown gummy solid. Cold water (100 mL) was added to the crude compound and the mixture was basified with NaHCO3solution (30 mL). The aqueous layer was washed with ethyl acetate (3 x 200 mL). The aqueous layer was acidified with 1M HCl solution (30 mL) and was extracted with 10% IPA in DCM (5 x 200 mL). The combined organic were washed with brine solution (100 mL), dried over anhydrous sodium sulphate and concentrated under reduced pressure to afford 4-bromo-3-fluorophthalic acid (2) (7.5 g, 62%) as an off-white solid. MS (ESI) m / z 261.9 [M-H]-.

[0109] Step-2: Synthesis of 5-bromo-2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindoline- 1,3-dione

[0110] To a stirred solution of 4-bromo-3-fluorophthalic acid (5.0 g, 19 mmol) in acetic acid (50 mL) was added 3-aminopiperidine-2,6-dione hydrochloride (2.4 g, 19 mmol) at room temperature. The resulting reaction mixture was stirred at 120 °C under atmosphere of N2 for 48 h. The reaction mixture was cooled to room temperature, diluted with water (5 mL), and stirred for 10 minutes. The solids were filtered, washed with chilled water, and dried to afford 5-bromo-2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindoline-l,3-dione (2.5 g, 37%) as an off-white solid. MS (ESI) m / z 355.25[M+H]+.

[0111] Step-3: Synthesis of tert-butyl (2-(2,6-dioxopiperidin-3-yl)-4-fluoro-1,3- dioxoisoindolin-5-yl)carbamate

[0112] In a sealed tube, to a stirred solution of 5-bromo-2-(2,6-dioxopiperidin-3-yl)-4- fluoroisoindoline-1,3-dione (1 g, 2.8 mmol) in 1,4-dioxane (20 mL) were added tert-butyl carbamate (0.4g, 3.4 mmol) and K3PO4 (0.9 g, 4.2 mmol).The resulting reaction mixture was degassed with argon gas for 20 minutes, Xanphos-PdG3 (0.36 g, 0.42 mmol) was added and then degassed with argon for 1 more minutes. The tube was then sealed, heated to 100 °C, and stirred for 1 h. The progress of the reaction was monitored by TLC and LCMS. The reaction mixture was diluted with ethyl acetate (50 mL) and filtered through celite filtrate was concentrated under reduced pressure to afford crude. The obtained crude triturated with diethyl ether (50 mL) solid was filtered, washed with diethyl ether and dried under vacuum at 40 °C to afford tert-butyl (2-(2,6-dioxopiperidin-3-yl)-4-fluoro-1,3-dioxoisoindolin-5- yl)carbamate (0.8 g, 72 %) as grey solid (5). MS (ESI) m / z 390.5 [M-H]-.

[0113] Step-4: Synthesis of 5-amino-2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindoline- 1,3-dione

[0114] To a stirred solution of tert-butyl (2-(2,6-dioxopiperidin-3-yl)-4-fluoro-1,3- dioxoisoindolin-5-yl)carbamate (0.55 g, 1.4 mmol) in dichloromethane (5.5 mL), was added trifluoroacetic acid (5.5 mL) at 0°C. The resulting reaction mixture was stirred at room temperature for 2h. The progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, the mixture was evaporated under reduced pressure to afford crude. The obtained crude was triturated with diethyl ether (2 x 20 mL) and dried under reduced pressure 5-amino-2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindoline-1,3-dione (6) (0.3 g, 73%) as grey solid. MS (ESI) m / z 292.42 [M+H]+.

[0115] Step-5: Phenyl (2-(2,6-dioxopiperidin-3-yl)-4-fluoro-1,3-dioxoisoindolin-5- yl)carbamate

[0116] To a stirred solution of 5-amino-2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindoline- 1,3-dione (0.3 g, 1.03 mmol) in acetonitrile (2.7 mL) and water (0.3 mL) was added phenyl carbonochloridate (1.5 mL). The resulting reaction mixture was stirred at room temperature for 6 h. The progress of the reaction was monitored by TLC and LCMS. After completion of reaction, the mixture was filtered and the solid was dried under vacuum to afford phenyl (2-(2,6-dioxopiperidin-3-yl)-4-fluoro-1,3-dioxoisoindolin-5-yl)carbamate (7) (0.12 g, 28%) as an off-white solid. MS (ESI) m / z 412.50 [M+H]+.

[0117] Intermediates B: Amine coupling partners

[0118] Amine coupling partners were made according to several general procedures as follows:

[0119] Amine coupling partners general procedures:

[0120] General procedure B-1: Intermediate B-1: 2-(3-nitrophenyl)propan-2-amine hydrochloride

[0121] Step – 1 : 2-methyl-2-(3-nitrophenyl)propanenitrile.

[0122] To a stirred solution 2-(3-nitrophenyl)acetonitrile (10 g, 62 mmol) in Toluene (100 mL) was added a 10% aqueous solution NaOH (100 mL) at 0oC. Tetra-n- butylammonium bromide (4.0 g, 12 mmol) was added and stirred for 15 min. Iodomethane (39 mL, 308 mmol) was then added dropwise. The reaction mixture was stirred at room temperature for 16 h. The progress of the reaction was monitored by LCMS and thin layer chromatography. After completion of the reaction (thin layer chromatography; 10 % ethyl acetate in petroleum ether), the reaction was quenched with water (50 mL), and extracted with ethyl acetate (4 x 50 mL). The organic layers were washed with brine (50 mL), dried over sodium sulphate, filtered, and concentrated under reduced pressure to get crude material (12.8 g). The crude material was purified by combi flash using silica of 100 - 200 mesh column with ethyl acetate - petroleum ether (0 - 10%) as eluent to get pure phenyl (2-(3- bromophenyl)propan-2-yl)carbamate (10 g, 85 %) as an off white solid. LC-MS purity: 96 %.1H NMR (400 MHz, DMSO-d6) : δ 8.32 (t, J = 2.00 Hz, 1H), 8.23 (d, J = 8.00 Hz, 1H), 8.03 (d, J = 0.80 Hz, 1H), 7.76 (t, J = 8.00 Hz, 1H), 1.76 (s, 6H).

[0123] Step – 2: 2-methyl-2-(3-nitrophenyl)propanamide

[0124] To a stirred solution of 2-methyl-2-(3-nitrophenyl)propanenitrile (1.0 g, 5.3 mmol) in toluene (10 mL), acetyl oxyme (2.1 g, 16 mmol) and indium(II) chloride (98 mg, 0.53 mmol) were added. The reaction mixture was heated at 100oC and stirred for 16 h. The progress of the reaction was monitored by LCMS and thin layer chromatography. After completion of the reaction (thin layer chromatography eluent: 30 % ethyl acetate in petroleum ether, UV active, Ninhydrin), the reaction was quenched with water (20 mL), and extracted with ethyl acetate (3 x 20 mL). The organic layers were combined, washed with brine (30 mL), dried over sodium sulphate, and concentrated under reduced pressure to getcrude material (1.9 g). The crude material was purified by combi flash, silica of 100 - 200 mesh column with ethyl acetate - petroleum ether (0 – 30 %) as eluent to get pure 2-methyl- 2-(3-nitrophenyl)propanamide (0.68 g, 62 %) as an off white solid. MS (ESI) m / z 209.52 [M+H]+. LC-MS purity: 95%.1H NMR (400 MHz, DMSO-d6): δ 8.10 – 8.12 (m, 2H), 7.81 (d, J = 7.60 Hz, 1H), 7.64 (t, J = 8.00 Hz, 1H), 7.07 (d, J = 22.40 Hz, 2H), 1.50 (s, 6H).

[0125] Step – 3: 2-(3-nitrophenyl)propan-2-amine hydrochloride.

[0126] To a stirred solution of 2-methyl-2-(3-nitrophenyl)propanamide (1.0 g, 4.8 mmol) in an aqueous solution of 50% NaOH (5 mL) at 0oC was added an aqueous solution of bromine (1 mL). The reaction mixture was stirred at 0oC for 30 min. The progress of the reaction was monitored by LCMS and thin layer chromatography. After completion of the reaction (thin layer chromatography eluent: 70 % ethyl acetate in petroleum ether, UV active, Ninhydrin), the reaction was quenched with water (20 mL), and extracted with ethyl acetate (3 x 20 mL). The organic layers were washed with an aqueous solution of 5% (20 mL), brine (30 mL), and dried over sodium sulphate. The resulting mixture was filtered and concentrated under reduce pressure to get crude material (1 g). The crude was purified by making HCl salt using 4M HCl in dioxane, non polar impurity was removed to get pure 2-(3- nitrophenyl)propan-2-amine hydrochloride (0.71 g, 82%) as an off white solid. MS (ESI) m / z 181.59 [M+H]+. LC-MS purity: 99 %.1H NMR (400 MHz, DMSO-d6) : δ 8.82 (bs, 2H), 8.43 (s, 1H), 8.24 (d, J = 1.20 Hz, 1H), 8.06 (d, J = 8.80 Hz, 1H), 7.77 (t, J = 8.00 Hz, 1H), 1.69 (s, 6H),

[0127] General procedure B-2: Intermediate B-3: 2-(isoquinolin-7-yl)propan-2- amine hydrochloride

[0128] To a stirred solution of isoquinoline-7-carbonitrile (1.0 g, 6.5 mmol) in tetrahydrofuran (10 mL) was added a 3M solution of methylmagnesium bromide (11 mL, 33 mmol). The mixture was transferred to a microwave reactor and heated to 100oC for 10 min. The reaction was cooled to 0oC and titanium(IV) isopropoxide (1.8 mL, 6.5 mmol) was added slowly. The mixture was transferred to a microwave reactor and heated to 50oC for 1 h. The progress of the reaction was monitored by LCMS and thin layer chromatography. After completion of the reaction (eluent: 10 % methanol in Dichloromethane, UV &Ninhydrin active, Rf – 0.2), the reaction mixture was diluted using a saturated aqueous solution of ammonium chloride (20 mL), and extracted with ethyl acetate (3 X 20 mL). The organic layers were combined and extracted with an aqueous solution of 10% HCl (30 mL). The aqueous solution was washed with diethyl ether (30 mL) to remove nonpolar impurities. The aqueous layer was basified with an aqueous solution of 10 % NaOH (30 mL) and extracted with DCM (20 mL X 3). The organic layers were washed with brine (20 mL), dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure to get crude material. The crude was dissolved with an solution of 4M HCl in Dioxane to get 2- (isoquinolin-7-yl)propan-2-amine hydrochloride (0.63 g, Quantitative yield). The obtained product was directly taken for next step with out further purification. MS (ESI) m / z 187.17 [M+H]+. LC-MS purity: 38 %.

[0129] General procedure B-3: Intermediate B-3: 2-(4-(pyridin-3-yl)phenyl)propan- 2-amine hydrochloride

[0130] Step-1: Synthesis of tert-butyl (2-(4-(pyridin-3-yl)phenyl)propan-2- yl)carbamate

[0131] To a stirred solution of tert-butyl (2-(4-bromophenyl)propan-2-yl)carbamate (0.4 g, 1.3 mmol) in 1,4 dioxane (3.6 mL) were added 3-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)pyridine (0.29 g, 1.4 mmol) and Cs2CO3 (1.2 g, 3.8 mmol). The reaction mixture was degassed with argon gas for 15 minutes. Then, Pd(dppf)Cl2.DCM (0.1 g, 0.13 mmol) was added. The reaction mixture was again degassed with argon for another 5 minutes and the reaction mixture was stirred at 1000C for 16 h. The reaction mixture was diluted with ethyl acetate (20 mL) and washed with water (10mL). The organic layer was dried over anhydrous MgSO4, filtered and concentrated under reduced pressure to afford crude product. The crude compound was purified by silica gel (230-400 mesh) column chromatography and eluted by using 20% ethyl acetate in petroleum ether to afford tert-butyl (2-(4-(pyridin-3-yl)phenyl)propan-2-yl)carbamate (0.38 g, 96%) as pale yellow solid. MS (ESI) m / z 313.25 [M+H]+]+;1H NMR (400 MHz, DMSO-d6) δ 8.88 (d, J = 1.6 Hz, 1H), 8.55 (dd, J = 4.6, 1.4 Hz, 1H), 8.08 - 8.05 (m, 1H), 7.65 (d, J = 8.4 Hz, 2H), 7.49 - 7.43 (m, 3H), 7.25 (s, 1H), 1.52 (s, 6H), 1.35 (s, 9H).

[0132] Step-2: Synthesis of 2-(4-(pyridin-3-yl)phenyl)propan-2-amine hydrochloride

[0133] To a solution of tert-butyl (2-(4-(pyridin-3-yl)phenyl)propan-2-yl)carbamate (0.38 g,1.2 mmol) in DCM (0.76 mL) was added 2M HCl in diethyl ether (1.90 mL) at 0 °C and the reaction mixture was stirred at room temperature for 5 h. The reaction mixture was concentrated under reduced pressure to get the crude product, which was triturated with diethyl ether (10 mL) to afford 2-(4-(pyridin-3-yl)phenyl)propan-2-amine (0.23 g, 89 %) as an off-white solid. Note: The isolated hydrochloride salt was used for next step without any purification. MS (ESI) m / z 213.22 [M+H]+.

[0134] General procedure B-4: Intermediate B-4: 2-(benzo[d]thiazol-2-yl)propan-2- amine

[0135] Step-1: 2-(benzo[d]thiazol-2-yl)acetonitrile

[0136] To a solution of 2-aminobenzenethiol (15 g, 120 mmol) in EtOH (30 mL), was added acetic acid, 99.5%, pure (22 mL, 120 mmol). The reaction mixture was stirred at 5 °C under nitrogen for 5 minutes, then malononitrile (7.9 g, 120 mmol) was added. The reaction mixture was stirred at room temperature for 16 h. The progress of the reaction was monitored by thin layer chromatography and LCMS. After completion of the reaction, the reaction mixture was quenched with ice cold water (80 mL), the contents was filtered, washed with water and pentane to afford 2-(benzo[d]thiazol-2-yl)acetonitrile (9.8 g, 47 % ) as a white solid. MS (ESI) m / z 175.03 [M+H]+, LC-MS purity : 98 %.

[0137] Step-2: 2-(benzo[d]thiazol-2-yl)-2-methylpropanenitrile

[0138] To a solution of 2-(benzo[d]thiazol-2-yl)acetonitrile (7 g, 40.2 mmol) in tetrahydrofuran (70 mL), was added sodium hydride, 60% dispersion in mineral oil, (2.03 g, 84 mmol) at 0 °C. The reaction mixture was stirred at 80°C under N2atmosphere for 60 minutes, then cool to 0 °C and iodomethane (13 mL, 84 mmol) was added. The reaction mixture was stirred at room temperature for 16 h under N2 atmosphere. The progress of the reaction was monitored by thin layer chromatography and LCMS. After completion of reaction, the reaction mixture was quenched with ice water (70 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulphate and concentrated under reduced pressure to afford crude product as a red liquid. The crude was purified by silica gel flash chromatography using 0 to 30% ethyl acetate in petroleum ether as eluent to afford 2-(benzo[d]thiazol-2-yl)-2- methylpropanenitrile (4.1 g, 50 %) as red oil. MS (ESI) m / z 203.06 [M+H]+, LC-MS purity : 52 %.

[0139] Step-3: 2-(benzo[d]thiazol-2-yl)-2-methylpropanamide

[0140] To a solution of 2-(benzo[d]thiazol-2-yl)-2-methylpropanenitrile (0.4 g, 2.0 mmol) in formic acid, (4 mL), HCl gas were purged in stirring condition at 60 °C for 2 h under N2 atmosphere. The progress of the reaction was monitored by thin layer chromatography and LCMS. After completion of the reaction, it was quenched with ice water (20 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulphate and concentrated under reduced pressure to afford crude product as a brown liquid. The crude was purified by silica gel flash chromatography using 0 to 70% ethyl acetate in petroleum ether as eluent to afford 2-(benzo[d]thiazol-2-yl)-2-methylpropanamide (0.2 g, 46%) as a white solid. MS (ESI) m / z 221.07 [M+H]+, LC-MS purity : 89 %.1H NMR (400 MHz, DMSO-d6) : δ 8.06 (d, J = 8.0 Hz, 1H), 7.98 (d, J = 8.0 Hz, 1H), 7.52-7.48 (m, 1H), 7.44-7.40 (m, 1H), 7.30 (s, 1H), 7.23 (s, 1H), 1.66 (s, 6H).

[0141] Step-4: 2-(benzo[d]thiazol-2-yl)propan-2-amine

[0142] To a solution of 2-(benzo[d]thiazol-2-yl)-2-methylpropanamide (0.2 g, 0.91 mmol) in acetonitrile (1 mL) and water (1 mL), was added potassium hydroxide (0.204 g, 3.6 mmol) at 0 °C. The reaction mixture was stirred at 0°C with argon gas for 10 minutes, then 1,3-Dibromo-5,5-dimethylhydantoin (0.13 g, 0.45 mmol) was added. The reaction mixture was stirred at room temperature for 1 h under argon atmosphere, the reaction was monitored by thin layer chromatography and LCMS. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to afford crude as yellow liquid. The crude was purified by acid base work up with 2N HCl and sodium carbonate followed by the extraction in 10% MeOH / DCM to afford 2-(benzo[d]thiazol-2-yl)propan-2-amine (0.1 g, 76%) as a yellow solid. MS (ESI) m / z 193.07 [M+H]+,LC-MS purity : 90%.

[0143] General procedure B-5: Intermediate B-5: 5-(4-(2-amino-1-fluoropropan-2- yl)phenyl)nicotinonitrile

[0144] Step 1: f(Z)-N-(1-(4-bromophenyl)ethylidene)-2-methylpropane-sulfinamide

[0145] To a solution of 1-(4-bromophenyl)ethan-1-one (5 g, 25 mmol) in tetrehydrofuran (50 mL) were added Ti(IOEt)4(13 mL, 42 mmol) and 2-methylpropane-2-sulfinamide (3 g, 25 mmol). The mixture was stirred at 60oC for overnight. The mixture was concentrated. The residue was diluted with water and extracted with ethylacetate. The organic layer was dried and concentrated. The residue was purified by chromatography (silica gel, PE: EA= 5:1) to give (Z)-N-(1-(4-bromophenyl)ethylidene)-2-methylpropane-sulfinamide (5.10 g, 16.90 mmol, 67%) as light yellow. [M]+ calcd:301. found: 302.1H NMR (400 MHz, CDCl3) δ 7.75 (d, J = 8.5 Hz, 2H), 7.56 (dd, J = 6.4, 4.5 Hz, 2H), 2.74 (s, 3H), 1.32 (s, 9H).

[0146] Step 2: N-(2-(4-bromophenyl)-1-fluoro-1-(phenylsulfonyl)propan-2-yl)-2- methylpropane-2-sulfinamide

[0147] To a stirred solution of (fluoromethyl)sulfonyl)benzene (2.9 g, 16 mmol) in THF (50 mL) was added N-BuLi (10 mL, 16 mmol, 1.6M in hexane) dropwise at -40oC and the mixture was stirred at -40oC for 1 hour. Then to the solution was added a solution of (Z)-N- (1-(4-bromophenyl)ethylidene)-2-methylpropane-sulfinamide (3.8 g, 13 mmol) in THF (50 mL) at -40oC. The resulting mixture was stirred at -40oC for 2 hours. The mixture was poured into water and extracted with ethyl acetate. The organic layer was dried and concentrated. The residue was purified by chromatography (silica gel, EtOAc: PE= 5:1) to give N-(2-(4- bromophenyl)-1-fluoro-1-(phenylsulfonyl)propan-2-yl)-2-methylpropane-2-sulfinamide (1.60 g, 3.36 mmol, 27%) as light yellow. [M]+ calcd:475. found: 476.1H NMR (400 MHz, CDCl3) δ 7.93 (d, J = 8.0 Hz, 2H), 7.72 (t, J = 7.5 Hz, 1H), 7.59 (t, J = 7.8 Hz, 2H), 7.50 (d, J = 8.7 Hz, 2H), 7.34 (d, J = 8.7 Hz, 2H), 5.30 – 5.05 (m, 1H), 1.55 (s, 3H), 1.29 (s, 9H).

[0148] Step 3: N-(2-(4-(5-cyanopyridin-3-yl)phenyl)-1-fluoro-1- (phenylsulfonyl)propan-2-yl)-2-methylpropane-2-sulfinamide

[0149] To a solution of N-(2-(4-bromophenyl)-1-fluoro-1-(phenylsulfonyl)propan-2-yl)- 2-methylpropane-2-sulfinamide (1.6 g, 3.4 mmol) in dioxane (30 mL) and H2O (3 mL) were added (5-cyanopyridin-3-yl)boronic acid (600 mg, 4 mmol), Na2CO3 (710 mg, 6.7 mmol) and Pd(dppf)Cl2 (370 mg, 0.50 mmol). The mixture was degassed and purged with N2 three times and the mixture was stirred at 100oC for 5hours. The mixture was concentrated and purified by chromatography (silica gel, EtOAc: PE=2:1) to give N-(2-(4-(5-cyanopyridin-3- yl)phenyl)-1-fluoro-1-(phenylsulfonyl)propan-2-yl)-2-methylpropane-2-sulfinamide (540 mg, 1.08 mmol, 32%) as light yellow. [M]+ calcd:499. found: 500.1H NMR (400 MHz, CDCl3) δ 9.03 (d, J = 2.3 Hz, 1H), 8.87 (d, J = 1.9 Hz, 1H), 8.13 (t, J = 2.1 Hz, 1H), 7.96 (d, J = 8.1 Hz, 2H), 7.72 (t, J = 7.5 Hz, 1H), 7.61 (dd, J = 16.8, 8.9 Hz, 6H), 5.20 (d, J = 44.7 Hz, 1H), 2.20 (s, 3H), 1.32 (s, 9H).

[0150] Step 4: N-(2-(4-(5-cyanopyridin-3-yl)phenyl)-1-fluoropropan-2-yl)-2- methylpropane-2-sulfinamide

[0151] To a solution of N-(2-(4-(5-cyanopyridin-3-yl)phenyl)-1-fluoro-1- (phenylsulfonyl)propan-2-yl)-2-methylpropane-2-sulfinamide (540 mg, 1.1 mmol) in DMF (22 mL) and AcOH (6.8 mL) was added NaOAc (4.00 g, 50 mmol) at 0oC. The mixture was stirred at 0oC for 0.5 hour. Mg (790 mg, 16 mmol) was added to the mixture at 0oC. The resulting mixture was stirred at room temperature overnight. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was dried and concentrated to give N-(2-(4-(5-cyanopyridin-3-yl)phenyl)-1-fluoropropan-2-yl)-2- methylpropane-2-sulfinamide (500 mg, 1.39 mmol, 128.00%) as a crude. [M]+ calcd:359. found: 360.

[0152] Step 5: 5-(4-(2-amino-1-fluoropropan-2-yl)phenyl)nicotinonitrile

[0153] To a solution of N-(2-(4-(5-cyanopyridin-3-yl)phenyl)-1-fluoropropan-2-yl)-2- methylpropane-2-sulfinamide (500 mg, crude) in MeOH (20 mL) was added HCl / dioxane (2 mL, 4M in dioxane). The mixture was stirred at room temperature for 1 hour. The mixture was concentrated. The residue was adjusted to pH = 8 with Sat. aqueous NaHCO3solution and extracted with ethyl acetate. The organic layer was dried and concentrated. The residue was purified by chromatography (silica gel, MeOH(0.5% NH3H2O): DCM=1:5) to give 5-(4- (2-amino-1-fluoropropan-2-yl)phenyl)nicotinonitrile (90 mg, 0.35 mmol, 33% over two step) as light yellow. [M]+ calcd:255. found: 239.1H NMR (400 MHz, CDCl3) δ 9.07 – 8.97 (m, 1H), 8.86 (d, J = 1.8 Hz, 1H), 8.12 (s, 1H), 7.68 (s, 2H), 7.58 (d, J = 8.5 Hz, 2H), 4.44 (dq, J = 47.6, 8.9 Hz, 2H), 1.55 (d, J = 1.9 Hz, 3H).

[0154] General procedure B-6: Intermediate B-6-1: S)-5-methyl-2,3-dihydro-1H-inden-1-amine hydrochloride

[0155] Intermediate B-6-2: rel-(R)-5-methyl-2,3-dihydro-1H-inden-1-amine hydrochloride

[0156] Step-1: Synthesis of (Z)-5-methyl-2,3-dihydro-1H-inden-1-one oxime

[0157] To a stirred solution of 5-methyl-2,3-dihydro-1H-inden-1-one (2 g, 14 mmol) in ethanol (30 mL), under argon atmosphere, were added hydroxylamine hydrochloride (1.4 g, 21 mmol) and sodium acetate anhydrous (1.7 g, 21 mmol) and the resulting reaction mixture was stirred at 60oC for 16 h. The progress of the reaction was monitored by thin layer chromatography and LCMS. After completion of the reaction, the reaction mixture was quenched with ice cold water (50 mL), the contents was filtered, washed with water and pentane to afford (Z)-5-methyl-2,3-dihydro-1H-inden-1-one oxime (1.5 g, 68 % ) as an off - white solid. MS (ESI) m / z 162.03 [M+H]+;1H NMR (400 MHz, DMSO-d6) δ 10.69 (s, 1H), 7.42 (d, J = 8 Hz, 1H), 7.16 (s, 1H), 7.06 (d, J = 8 Hz, 1H), 2.94 (t, J = 6.4 Hz, 2H), 2.77 – 2.73 (m, 2H), 2.31 (s, 3H).

[0158] Step-2: Synthesis of 5-methyl-2,3-dihydro-1H-inden-1-amine

[0159] To a stirred solution of (Z)-5-methyl-2,3-dihydro-1H-inden-1-one oxime (1.5 g , 9.3 mmol) in acetic acid (45 mL) at room temperature was added palladium 10% on carbon (1.5 g, 19 mmol) under Parr shaker H2 pressure of 60 PSI. The resulting reaction mixture was stirred at rt for 16 h. The progress of the reaction was monitored by thin layer chromatography and LCMS. Upon completion of the reaction, the content was passed through Celite® and washed with ethyl acetate (100 mL), and concentrated under reduced pressure. The residue was suspended between an aqueous solution of saturated NaHCO3(100mL) and ethyl acetate (100 mL). The organic layer was isolated and washed with brine (100 mL). The organic layer was dried over sodium sulfate, and concentrated under reduced pressure to get crude material. The crude material 5-methyl-2,3-dihydro-1H-inden-1-amine (0.85 g, 62%) was isolated as brown gummy used for next step without further purification.1H NMR (400 MHz, DMSO-d6) δ 7.20 (d, J = 8 Hz, 1H), 6.97 (d, J = 9.6 Hz, 2H), 4.13 (t, J = 7.2 Hz, 1H), 2.83 – 2.76 (m, 1H), 2.68 – 2.60 (m, 1H), 2.34 – 2.25 (m, 6H), 1.57 – 1.52 (m, 1H).

[0160] Step-3: Synthesis of tert-butyl (5-methyl-2,3-dihydro-1H-inden-1- yl)carbamate

[0161] To a stirred solution of 5-methyl-2,3-dihydro-1H-inden-1-amine (0.85g, 5.8 mmol) in tetrahydrofuran (13 mL), at 0oC, were added triethylamine (1 mL, 0.77 mmol), di-tert-butyl dicarbonate, (1.2 mL, 5.2 mmol) and 4-dimethylaminopyridine (0.035 g, 0.29 mmol). The resulting reaction mixture was stirred at room temperature for 2 h. The progress of the reaction was monitored by thin layer chromatography and LCMS. After completion of reaction, the reaction mixture was diluted with water (100 mL) and extracted with Ethyl acetate (2 x 50 mL). The combined organic layer were washed with brine solution (100 mL), dried over anhydrous sodium sulphate and concentrated under reduced pressure to afford the crude compound. The crude compound was purified by column chromatography, (eluting solvent 30% Ethyl acetate in hexane) to afford tert-butyl (5-methyl-2,3-dihydro-1H- inden-1-yl)carbamate (0.85 g, 60 % ) as an off - white solid.1H NMR (400 MHz, DMSO-d6) δ 7.14 (d, J = 9.2 Hz, 1H), 7.05 (d, J = 7.2 Hz, 1H), 6.97 (t, J = 10.4 Hz, 2H), 4.92 (dd, J = 16, 8 Hz, 1H), 2.86 – 2.79 (m, 1H), 2.72 – 2.64 (m, 1H), 2.34 – 2.62 (m, 4H), 1.81 – 1.76 (m, 1H), 1.45 (s, 9H).

[0162] Step-4: Synthesis rel-tert-butyl (R)-(5-methyl-2,3-dihydro-1H-inden-1- yl)carbamate and rel-tert-butyl (S)-(5-methyl-2,3-dihydro-1H-inden-1-yl)carbamate

[0163] Racemic tert-butyl (5-methyl-2,3-dihydro-1H-inden-1-yl)carbamate was purified by chiral SFC to get rel-tert-butyl (R)-(5-methyl-2,3-dihydro-1H-inden-1- yl)carbamate (0.31 g, 49 % Peak 1) and rel-tert-butyl (S)-(5-methyl-2,3-dihydro-1H- inden-1-yl)carbamate (0.31 g, 49 % Peak 2) as an off - white solid.

[0164] Purification Method Conditions: Instrument ID ANL-BLR-SFC-008 (AP SFC150), column name Chiralpeak IG (30*250)mm,5μ, column no# 26, mobile phase-A CO2, mobile phase-B ( ACETONITRILE:IPA )(1:1), gradient program (T / %B) 15, flow rate (mL / minute) 100, sample Loading(mg / Injection) 0.042, No. of Injection's 20.

[0165] Peak-1 rel-(R)-5-methyl-2,3-dihydro-1H-inden-1-amine hydrochloride:NMR (400 MHz, DMSO-d6) δ 7.14 (d, J = 9.2 Hz, 1H), 7.05 (d, J = 7.2 Hz, 1H), 6.98 (t, J = 10.4 Hz, 2H), 4.92 (dd, J = 16, 8 Hz, 1H), 2.86 – 2.79 (m, 1H), 2.72 – 2.68 (m, 1H), 2.33 – 2.26 (m, 4H), 1.81 – 1.71 (m, 1H), 1.42 (s, 9H).

[0166] Peak-2 rel-(S)-5-methyl-2,3-dihydro-1H-inden-1-amine hydrochloride:1H NMR (400 MHz, DMSO-d6) δ 7.14 (d, J = 9.2 Hz, 1H), 7.05 (d, J = 7.2 Hz, 1H), 6.98 (t, J = 10.4 Hz, 2H), 4.92 (dd, J = 16, 8 Hz, 1H), 2.86 – 2.79 (m, 1H), 2.72 – 2.64 (m, 1H), 2.33 – 2.26 (m, 4H), 1.81 – 1.78 (m, 1H), 1.42 (s, 9H).

[0167] Step-5: Synthesis of rel-(R)-5-methyl-2,3-dihydro-1H-inden-1-amine hydrochloride

[0168] To a stirred solution of rel-tert-butyl (R)-(5-methyl-2,3-dihydro-1H-inden-1- yl)carbamate (0.3 g, 1.2 mmol) in DCM (1.5 mL) at 0oC, was added 4M HCl in dioxane (1.5 mL) and the resulting reaction mixture was stirred at room temperature for 1 h. The progress of the reaction was monitored by thin layer chromatography and LCMS.The reaction mixture was concentrated under reduced pressure to get the crude material, which was triturated with diethyl ether (5 mL) to afford rel-(R)-5-methyl-2,3-dihydro-1H- inden-1-amine hydrochloride (0.13 g, 72 % ) as an off - white solid.1H NMR (400 MHz, DMSO-d6) δ 7.14 (s, 1H), 7.42 (d, J = 7.6 Hz, 1H), 7.10 (t, J = 12 Hz, 2H), 4.64 (t, J = 6 Hz, 1H), 3.01 – 2.99 (m, 1H), 2.84 – 2.82 (m, 1H), 2.31 (d, J = 8 Hz, 4H), 1.98 – 1.95 (m, 1H), 1.28 – 1.23 (m, 1H) 0.86 (d, J = 5.2 Hz, 1H).

[0169] Step-5A: Synthesis of rel-(S)-5-methyl-2,3-dihydro-1H-inden-1-amine hydrochloride

[0170] To a stirred solution of rel-tert-butyl (S)-(5-methyl-2,3-dihydro-1H-inden-1- yl)carbamate (0.3 g, 1.2 mmol) in DCM (1.5 mL) at 0oC, was added 4M HCl in dioxane (1.5 mL) and the resulting reaction mixture was stirred at room temperature for 1 h. The progress of the reaction was monitored by thin layer chromatography and LCMS. The reaction mixture was concentrated under reduced pressure to get the crude product, which was triturated with diethyl ether (5 mL) to afford rel-(S)-5-methyl-2,3-dihydro-1H- inden-1-amine hydrochloride) (0.12 g, 53 %) as an off - white solid. Confirmed by NMR;1H NMR (400 MHz, DMSO-d6) δ 8.16 (s, 1H), 7.42 (d, J = 7.6 Hz, 1H), 7.10 (t, J = 12 Hz, 2H), 4.64 (t, J = 6 Hz, 1H), 3.01 – 2.99 (m, 1H), 2.84 – 2.82 (m, 1H), 2.31 (d, J = 8 Hz, 4H), 1.98 – 1.95 (m, 1H), 1.28 – 1.23 (m, 1H) 0.86 (d, J = 5.2 Hz, 1H).

[0171] Intermediates below may be synthesized utilizing the General method for the synthesis of intermediate F.

[0172] General procedure B-7: Intermediate B-7: 2-amino-2-(4- chlorophenyl)propan-1-ol hydrochloride.

[0173] To a stirred solution of 2-amino-2-(4-chlorophenyl)propanoic acid (0.2 g, 1. mmol) in tetrahydrofuran (2 mL), was added a 2 M solution in tetrahydrofuran of lithium aluminium hydride (4 mL) at 0oC. The reaction mixture was gradually warmed to room temperature and stirred at room temperature for 16 h. After completion of the reaction (monitored thin layer chromatography, eluent: 10 % methanol in dichloromethane, UV & Ninhydrin active, Rf – 0.2), the reaction mixture was diluted using water (20 mL), and extracted with ethyl acetate (3 X 20 mL). The organic layers were combined, washed with brine (2 x 20 mL), dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure to get crude material (0.13 g, Quantative yield). The crude product was directly taken into the next step without further purification. MS (ESI) m / z 186.57 [M+H]+.

[0174] General procedure B-8: Intermediate B-8: 7-methylchroman-4-amine

[0175] Step-1: Synthesis of 3-(m-tolyloxy)propanoic acid

[0176] To a stirred solution of m-cresol (2.0 g, 18 mmol) in water (15 mL) under argon atmosphere, was added 3-bromopropanoic acid (2.8 g, 18 mmol) and the resulting reaction was stirred at 0 °C for 10 minutes. Then, a 30 % aqueous sodium hydroxide solution (15 mL) was added and the reaction mixture was stirred 70°C for 16 h. The progress of the reaction was monitored by thin layer chromatography (90 % ethyl acetate in petroleum ether) and LCMS. After completion of the reaction, the reaction mixture was diluted with water and extracted with DCM. The organic layer was acidified with 5% HCl and the water layers were extracted with DCM. The organic layers were combined, dried over sodium sulphate, filtered and concentrated under reduced pressure to afford the crude 3-(m-tolyloxy)propanoic acid (3.0 g). The crude product was purified by flash column chromatography with 70 to 80% ethyl acetate in petroleum ether to afford 3-(m-tolyloxy)propanoic acid (0.6 g, 18 %) as an off white solid. MS (ESI) m / z 179.01 [M-H]-

[0177] Step-2: Synthesis of 7-methylchroman-4-one

[0178] To a stirred solution of 3-(m-tolyloxy)propanoic acid (0.6 g, 3.3 mmol) in toluene (9 mL), was added DMF (0.052 mL, 0.67 mmol) and oxalyl chloride (0.57 mL, 6.6 mmol) at 0°C . The reaction was stirred to room temperature for 3h. The reaction was concentrate under reduced pressure and dissolved in DCM (6 mL). To the solution was added AlCl3 (0.89 g, 6.6 mmol) at 0°C. The reaction was stirred room temperature for 2h. The progress of the reaction was monitored by thin layer chromatography (90 % ethyl acetate in petroleum ether) and LCMS. After completion of reaction, the reaction was quenched with an aqueous solution of 1N HCl (20 mL) and extracted with DCM (2x20 mL). The organic layers were combined, dried with sodium sulphate and concentrated under reduced pressure to get crude 7-methylchroman-4-one (0.5 g). The crude compound was purified by flash column chromatography using 20 to 30 % ethyl acetate in petroleum ether to afford 7- methylchroman-4-one (0.15 g, 33%) as an yellowish liquid. MS (ESI) m / z 163.06 [M+H]+.

[0179] Step-3: Synthesis of (Z)-7-methylchroman-4-one oxime

[0180] To a stirred solution of 7-methylchroman-4-one (0.15 g, 0.93 mmol) in ethanol (3 mL), were added hydroxylamine hydrochloride (0.096 g, 1.4 mmol), sodium acetate (0.11 g, 1.4 mmol). The reaction mixture was heated at 60 °C for 2h, 16 h at room temperature. The progress of the reaction was monitored by thin layer chromatography (90 % ethyl acetate in petroleum ether) and LCMS. After completion of reaction, the reaction mixture was quenched with cold water (2 x 10 mL). The precipitate was filtered and dried under reduced pressure to afford crude product. The crude product was purified by trituration (50% diethyl ether\pentane) to get (Z)-7-methylchroman-4-one oxime (0.11 g, 67%) as an off white solid. (MS (ESI) m / z 178.09 [M+H]+

[0181] Step-4: Synthesis of 7-methylchroman-4-amine

[0182] To a stirred solution of (Z)-7-methylchroman-4-one oxime (0.11g, 0.62 mmol) in acetic acid (1.1 mL), was added palladium on carbon (0.11 g). The resulting solution was stirred at room temperature under H2 atmosphere for 16 h. The progress of the reaction was monitored by thin layer chromatography (90 % ethyl acetate in petroleum ether) and LCMS. The reaction mixture was filtered and concentrated under reduced pressure to afford crude 7- methylchroman-4-amine as an yellow solid. The crude material was purified over silica gel column chromatography using 2 to 5 % methanol in DCM to afford (7-methylchroman-4- amine (0.07 g, 69%) as a yellow solid. (MS (ESI) m / z 162.08 [M-H]-

[0183] General procedure B-9: Intermediate B-9: 5-(4-(2-aminopropan-2-yl)phenyl)- 2-benzylnicotinonitrile hydrochloride

[0184] Step 1 :- Synthesis of ethyl 2-(5-bromo-3-cyanopyridin-2-yl)-2-phenylacetate

[0185] To a stirred solution of ethyl 2-phenylacetate (3.0 g, 18 mmol) in a dry THF (120 mL) was added LDA (18 mL) at -58°C. The resulting reaction mixture was stirred at -58°C for 15 min. Then, 5-bromo-2-chloronicotinonitrile (7.7 mL) was added dropwise. The resulting reaction mixture was stirred at room temperature for 5h. After the completion of the reaction, the reaction mixture was diluted with water (500 mL) and extracted with DCM (3 x 200 mL). The combined organic layers were dried over sodium sulphate, filtered and the filtrate was concentrated under vacuum to afford crude. The crude compound was purified by combi- flash using 1-5% EtOAc in pet-ether to afford a ethyl 2-(5-bromo-3- cyanopyridin-2-yl)-2-phenylacetate (2.1 g, 33%) as pale yellow solid. MS (ESI) m / z 345.2 [M+H]+.

[0186] Step 2 :- Synthesis of 2-benzyl-5-bromonicotinonitrile

[0187] To a stirred solution of ethyl 2-(5-bromo-3-cyanopyridin-2-yl)-2-phenylacetate (1.3 g, 3.8 mmol) in a THF : EtOH : water (3.9 : 3.9 : 3.9 mL) was added LiOH (0.32 g, 7.5 mmol) at rt. The resulting reaction mixture was stirred at room temperature for 16 h. After the completion of the reaction, the reaction mixture was poured in ice water and set a pH 3.0, then extracted with Ethyl acetate (3 x 80 mL). The combined organic layers were dried over sodium sulphate, filtered and the filtrate was concentrated under vacuum to afford crude. The crude compound was purified by combi- flash using 1-5% EtOAc in pet-ether to afford 2-benzyl-5-bromonicotinonitrile (0.9 g, 88%) as an pale yellow gummy solid. MS (ESI) m / z 275.1 [M+H]+2.

[0188] Step 3 :- Synthesis of tert-butyl (2-(4-(6-benzyl-5-cyanopyridin-3- yl)phenyl)propan-2-yl)carbamate

[0189] To a stirred solution of 2-benzyl-5-bromonicotinonitrile (0.15 g, 0.55 mmol) in dimethylformamide (2.5 mL) were added tert-butyl (2-(4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)phenyl)propan-2-yl)carbamate (0.3 g, 0.82 mmol) and potassium phosphate (0.12 g, 0.55 mmol). The resulting solution was degassed with argon gas for 15 minutes followed by added Pd(dppf)Cl2.DCM (0.045 g, 0.055 mmol). The reaction mixture was again degassed with argon gas for another 5 minutes and stirred at 100°C for 2 h. After the completion of the reaction, the reaction mixture was quenched with water (500 mL) and extracted with EtOAc (3 x 80 mL). The combined organic layers were dried over sodium sulphate, filtered and the filtrate was concentrated under vacuum to afford crude. The crude compound was purified by combi- flash using 80-85% EtOAc in pet-ether to afford tert-butyl (2-(4-(6-benzyl-5-cyanopyridin-3-yl)phenyl)propan-2-yl)carbamate (0.2 g, 85.18%) as an off white solid. MS (ESI) m / z 427.2 [M+H]+.

[0190] Step 4 : Synthesis of 5-(4-(2-aminopropan-2-yl)phenyl)-2- benzylnicotinonitrile hydrochloride

[0191] To a stirred solution of tert-butyl (2-(4-(6-benzyl-5-cyanopyridin-3- yl)phenyl)propan-2-yl)carbamate (0.2 g, 0.47 mmol) in DCM (1.0 mL) was added 4M HCl in 1,4 dioxane (2.0 mL) at 0°C. The resulting reaction mixture was stirred at 0°C for 1h. Reaction mixture was evaporated completely and afford a 5-(4-(2-aminopropan-2-yl)phenyl)- 2-benzylnicotinonitrile hydrochloride (0.2g, quantitative). Intermediate used as is. Examples

[0192] General method A

[0193] Example 1: Synthesis of 1-(2-(4-bromophenyl)propan-2-yl)-3-(2-(2,6- dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)urea

[0194] To a stirred solution phenyl (2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5- yl)carbamate (0.5 g, 1.3 mmol) in tetrahydrofuran (10.0 mL) at room temperature were added 2-(4-bromophenyl)propan-2-amine hydrochloride (0.36 g, 1.5 mmol) and triethylamine (0.28 mL, 2.0 mmol) and reaction mixture was stirred at 70 °C for 16 h. The progress of the reaction was monitored by thin layer chromatography. The reaction mixture was quenched with water (25 mL) and extracted with ethyl acetate (2 x 50 mL). The organic layers were combined, dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure to afford crude product. The crude material was triturated with diethyl ether (20 mL) and concentrated under reduced pressure to afford 1-(2-(4-bromophenyl)propan-2-yl)-3-(2- (2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)urea (0.51 g, 77%) as gray solid. MS (ESI) m / z 499.24 [M+H]+;1H NMR (400 MHz, DMSO-d6) δ 1H-NMR (400 MHz, DMSO-d6) δ 11.00 (s, 1H), 8.83 (s, 1H), 7.72 (s, 1H), 7.55 - 7.48 (m, 3H), 7.35 (d, J = 8.4 Hz, 2H), 7.24 (d, J = 8.4 Hz, 1H), 6.80 (s, 1H), 5.04 (dd, J = 13.2, 5.2 Hz, 1H), 4.33 (d, J = 17.2 Hz, 1H), 4.20 (d, J = 17.2 Hz, 1H), 2.92 - 2.85 (m, 1H), 2.67 - 2.55 (m, 1H), 2.37 - 2.33 (m, 1H), 1.97 - 1.95 (m, 1H), 1.58 (s, 6H)

[0195] Compounds below may be synthesized utilizing the General method A.

[0196] General Method B

[0197] Example 81: Synthesis of 1-(2-(2'-cyano-[1,1'-biphenyl]-4-yl)propan-2-yl)-3- (2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)urea

[0198] To a stirred solution of 1-(2-(4-bromophenyl)propan-2-yl)-3-(2-(2,6- dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)urea (0.1 g, 0.2 mmol) and 2-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)benzonitrile (0.18 g, 0.8 mmol) in DMF (1.5 mL) at roomtemperature, was added potassium phosphate tribasic (0.04 g, 0.2 mmol). The resulting reaction mixture was degassed using nitrogen for 5 minutes. To this mixture, Pd(dppf)Cl2DCM (0.033 g, 0.04 mmol) was added and the reaction mixture degassed again with nitrogen for 5 minutes. The resulting reaction mixture was stirred at 100 °C for 16 h. The progress of the reaction was monitored by thin layer chromatography and LCMS. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to afford crude product. The crude material was purified by reverse phase HPLC Column / dimensions : sunfire C18 (19*300, 7um) mobile phase A : 0.1% formic acid in water, mobile phase B : acetonitrile gradient (time% B) : 0 / 10, 1 / 10, 10 / 50, 15 / 55, 15.1 / 100, 17 / 100, 17.1 / 10, 19 / 10 Flow rate : 16ml / min Solubility : tetrahydrofuran+water+acetonitrile to afford 1-(2-(2'-cyano- [1,1'-biphenyl]-4-yl)propan-2-yl)-3-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)urea (0.031 g, 29.68%) as an off white solid. MS (ESI) m / z 522.30 [M+H]+1H NMR (400 MHz, DMSO-d6) δ 10.94 (s, 1H), 8.91 (s, 1H), 7.94 (d, J = 7.6 Hz, 1H), 7.77s (t, J = 7.8 Hz, 2H), 7.63 (d, J = 7.6 Hz, 1H), 7.54 (t, J = 10.2 Hz, 6H), 7.27 (d, J = 9.6 Hz, 1H), 6.87 (s, 1H), 5.05 (dd, J = 13.4, 5.0 Hz, 1H), 4.40 (d, J = 17.2 Hz, 1H), 4.26 (d, J = 17.6 Hz, 1H), 2.86-2.72 (m, 1H), 2.67-2.55 (m, 1H), 2.41-2.38 (m, 1H), 2.05-2.02 (m, 1H), 1.67 (s, 6H).

[0199] Alternatively, some examples were made according to this procedure:

[0200] Example 1: 1-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-3-(2-(3- (pyridin-2-yl)phenyl)propan-2-yl)urea

[0201] Step-1: Synthesis of 2-(tributylstannyl)pyridine

[0202] To a stirred solution of 2-bromopyridine (1.0 g, 6.3 mmol) in tetrahydrofuran (10 mL) cooled at -78oC, was added n-butyllithium 1.6 M hexanes (4.4 mL, 7 mmol) and resulting reaction mixture was stirred at -78oC for 1 h. Then, tributylchlorostannane (2 mL, 7.6 mmol) was added and the reaction was warmed to room temperature and stirred for 16h. The progress of the reaction was monitored by thin layer chromatography and LCMS.After completion of reaction, the reaction mixture was extracted with water (10 mL) and washed with ethyl acetate (2 x 30 mL). The combined organic layers were washed with brine solution (10 mL), dried over anhydrous sodium sulphate and concentrated under reduced pressure to afford the crude product. The crude was purified by column chromatography (eluting solvent 30% EtOAc in hexane) to afford 2-(tributylstannyl)pyridine (1.2 g, 51.64 % ) as a liquid compound. MS (ESI) m / z 370.29 [M+H]+.

[0203] Step-2: Synthesis of 1-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-3-(2- (3-(pyridin-2-yl)phenyl)propan- 2-yl)urea

[0204] To a stirred solution of 1-(2-(3-bromophenyl)propan-2-yl)-3-(2-(2,6- dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)urea (0.07 g, 0.14 mmol) in 1,4-Dioxane (1 mL) was added 2-(tributylstannyl)pyridine (0.1 g, 0.28 mmol). The resulting solution was degassed with argon gas for 15 minutes followed by the addition of Pd(PPh3)4(0.016 g, 0.014 mmol). The reaction mixture was again degassed with argon gas for another 5 minutes and heated to 100°C for 4 h. After completion of reaction, the reaction mixture was quenched with water (15 mL) and washed with EtOAc (2 x 15 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous sodium sulphate and concentrated under reduced pressure to afford the crude compound (0.080 g). The crude compound was purified by reverse phase HPLC to get 1-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-3-(2-(3- (pyridin-2-yl)phenyl)propan-2-yl)urea (0.014 g, 98 % purity, 20.07 %) as an off white solid. Prep-HPLC method: using column: acquity UPLC BEH C18, 1.7μm (50 mm X 2.1 mm) mobile phase A: 0.1% formic acid in water, B: 100% CAN gradient (T % B): 0 / 3, 1.0 / 3, 7.0 / 95, 7.5 / 95, 9.0 / 3, 10 / 3 flow rate: 0.5 ml / min. sample diluent : CAN + H2O . MS (ESI) m / z 498.26 [M+H]+;1H NMR (400 MHz, DMSO-d6) δ 10.91 (s, 1H), 8.94 (s, 1H), 8.66 (d, J = 4.0 Hz, 1H), 8.46 (s, 1H), 8.15 - 7.86 (m, 3H), 7.74 (s, 1H), 7.54 - 7.42 (m, 3H), 7.36 - 7.27 (m, 1H), 7.26 (d, J = 6.8 Hz, 1H), 6.91 (s, 1H), 5.04 (dd, J = 13.4, 5.0 Hz, 1H), 4.32 (d, J = 17.2 Hz, 1H), 4.19 (d, J = 16.8 Hz, 1H), 2.92 - 2.84 (m, 1H), 2.59 - 2.58 (m, 1H), 2.36 - 2.32 (m, 1H), 1.97 - 1.94 (m, 1H), 1.68 - 1.68 (m, 6H).

[0205] Alternatively, some examples were made according to this procedure:

[0206] Example 130: 1-(2-(2, 6-dioxopiperidin-3-yl)-1, 3-dioxoisoindolin-5-yl)-3-(2- (4-(pyridazin-4-yl) phenyl) propan-2-yl) urea

[0207] Step-1: 1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)-3-(2-(4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propan-2-yl)urea

[0208] To a stirred solution of 1-(2-(4-bromophenyl)propan-2-yl)-3-(2-(2,6- dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)urea (0.300g,0.58 mmol) and Bis(pinacolato)boron, 98% (0.3 g, 1.2 mmol) in 1,4-Dioxane stabilized (6.00 mL) at room temperature, potassium acetate (0.12 g, 1.12 mmol) was added and the resulting reaction mixture was degassed using nitrogen for 5 minutes. To this mixture,[1,1′- Bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.043 g, 0.058 mmol) was added and the mixture was degassed again with nitrogen for 5 minutes. The resulting reaction mixture was stirred at 100 °C for 16 h. The progress of the reaction was monitored by TLC and LCMS. After completion of reaction, the reaction mixture was evaporated completely to get crude. The crude was purified by flash chromatography using 0 to 70 % EtOAc in petroleum ether as eluent to afford 1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)- 3-(2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl)propan-2-yl)urea ( 0.153 g, 46.72 %) as a brown solid. MS (ESI) m / z 560.85 [M+H]+ 1 H NMR (400 MHz, DMSO-d6) δ 11.08 (s, 1H), 9.22 (s, 1H), 8.00 (s, 1H), 7.74 (d, J = 8.4 Hz, 1H), 7.63 (d, J = 8.0 Hz, 2H), 7.54 (dd, J = 8.2, 1.8 Hz, 1H), 7.42 (d, J = 8.0 Hz, 2H), 6.96 (s, 1H), 5.08 (q, J = 6.0 Hz, 1H), 2.92 – 2.83 (m, 1H), 2.60 – 2.51 (m, 2H), 2.04 – 1.99 (m, 1H), 1.61 (s, 6H), 1.28 (s, 12H).

[0209] Step-2:- 1-(2-(2, 6-dioxopiperidin-3-yl)-1, 3-dioxoisoindolin-5-yl)-3-(2-(4- (pyridazin-4-yl) phenyl) propan-2-yl) urea

[0210] To a stirred solution of 1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)-3- (2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propan-2-yl)urea (1) (0.15 g, 0.27 mmol) and 4-bromopyridazine (0.064 g, 0.4 mmol) (2) in 1,4-dioxane (1.4 mL) and water (0.15 mL) at room temperature, potassium phosphate tribasic (0.085 g, 0.40 mmol) was added and the resulting reaction mixture was degassed using nitrogen for 5 minutes. To this mixture, X-Phos Pd G3 (0.023 g, 0.027 mmol) was added and degassed again with nitrogen for 5 minutes. The resulting reaction mixture was stirred at 110 °C for 16 h. The progress of the reaction was monitored by thin layer chromatography and LCMS. After completion of reaction, the reaction mixture was quenched with water (10 mL) and extracted with 10% methanol in dichloromethane (2 x 20 mL). The combined organic layer was washed with brine solution (10 mL), dried over anhydrous sodium sulphate and concentrated under reduced pressure to afford crude as brown solid. Crude compound was purified by reverse phase HPLC using Column / dimensions : SUNFIRE(C18(19*150)5MICRON Mobile phase A : 0.1% FA IN WATER Mobile phase B : Acetonitrile Gradient (Time / %B) : 0 / 10.1 / 10.10 / 40, 13.5 / 47, 13.6 / 100, 17 / 100, 17.120, 20 / 20 Flow rate : 16ml / min Solubility : Acetonitrile+ THF+WATER to afford 1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)-3-(2-(4- (pyridazin-4-yl)phenyl)propan-2-yl)urea (0.025 g, 18%) as an off white solid. MS (ESI) m / z 513.49 [M+H]+;1H NMR (400 MHz, DMSO-d6) δ 11.08 (s, 1H), 9.63 (d, J = 1.2 Hz, 1H), 9.36 (s, 1H), 9.25 (d, J = 0.8 Hz, 1H), 8.02-8.00 (m, 2H), 8.00 – 7.98 (m, 2H), , 7.75 (d, J = 8.0 Hz, 1H), 7.61-7.55 (m, 3H), 7.12 (s, 1H), 5.08 (q, J = 6.1 Hz, 1H), 2.91 – 2.82 (m, 1H), 2.60 – 2.51 (m, 1H), 2.50 – 2.46 (m, 1H), 2.04 – 2.01 (m, 1H), 1.66 (s, 6H).

[0211] Compounds below may be synthesized utilizing the General method B.

[0212] General method C

[0213] Example 132: 1-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-3-(2-(3- nitrophenyl)propan-2-yl)urea.

[0214] To a stirred solution of 2-(3-nitrophenyl)propan-2-amine (0.2 g, 1.1 mmol) in acetonitrile (10 mL). at 0oC, was added triethylamine (0.46 mL, 3.3 mmol) and stirred for 15 min. In another round bottom flask, 3-(5-amino-1-oxoisoindolin-2-yl)piperidine-2,6-dione (0.35g, 1.3 mmol) was dissolved in acetonitrile (10 mL), and Triethylamine (0.46 mL, 3.3 mmol) was added. The resulting solution was added drop wise to the reaction mixture at 0oC and stirred for 15 min. CDI (0.49 g, 1.7 mmol) was added portion-wise. The reaction was heated to 80oC and stirred for 16h. The progress of the reaction was monitored by LCMS and thin layer chromatography. After completion of the reaction (10 % MeOH in DCM. UV active, Ninhydrin), the reaction was quenched with water (10 mL), and extracted with ethyl acetate (3 x 10 mL). The organic layers were washed with brine (20 mL), dried over sodium sulphate, and concentrated under reduced pressure to get crude product (0.37 g). The crude was purified by preparative HPLC method: Column / dimensions: X SELECT C18 (19 * 250 * 5 um) Mobile phase A : 0.1 % FA in water Mobile phase B : Acetonitrile Gradient: 0.01 / 10, 1 / 10, 17 / 70, 17.1 / 100, 20 / 100, 20.1 / 10, 22 / 10 solubility : acetonitrile + tetrahydrofuran + water. Flow rate: 17 mL / min. The fractions containing the product were concentrated, lyophilized to get pure 1-(2 - (2,6 – dioxopiperidin – 3 - yl) - 1- oxoisoindolin - 5 - yl) – 3 - (2 - (3 -nitrophenyl) propan – 2 - yl) urea as an off white solid (0.14 g, 26 %). MS (ESI) m / z 466.34 [M+H]+. LC-MS purity: 96 %.1H NMR (400 MHz, DMSO-d6) : δ 11.03 (s, 1H), 8.97 (s, 1H), 8.21 (t, J = 2.0 Hz, 1H), 8.09 - 8.06 (m, 1H), 7.89 – 7.87 (m, 1H), 7.71 (s, 1H), 7.63 (t, J = 8.00 Hz, 1H), 7.54 (d, J = 8.40 Hz, 1H), 7.26 (dd, J = 8.40 Hz, 1.60 Hz, 1H), 7.03 (s, 1H), 5.04 (q, J = 4.80 Hz, 1H), 4.32 (d, J = 17.20 Hz, 1H), 4.20 (d, J = 17.20 Hz, 1H), 2.86 – 2.84- (m, 1H), 2.51 – 2.50- (m, 1H), 2.33 – 2.32 (m, 1H), 1.95 – 1.94 (m, 1H), 1.65 (s, 6H).

[0215] Compounds below may be synthesized utilizing the General method C.

[0216] General method D

[0217] Example 138: 1-(2-(4-cyclopropylphenyl)propan-2-yl)-3-(2-(2,6- dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)urea

[0218] To a stirred solution of 2-(4-cyclopropylphenyl)propan-2-amine (0.1 g, 0.57 mmol) in acetonitrile (5 mL). At 0oC, was added triethylamine (0.082 mL, 0.57 mmol) and stirred for 15 min. A solution of 3-(5-amino-1-oxoisoindolin-2-yl)piperidine-2,6-dione (0.22 g, 0.86 mmol) and triethylamine ( 0.082 ml, 0.57 mmol) in acetonitrile (5 mL) was added drop wise to the amine solution. Triphosgene (0.25 g, 0.86 mmol) was added portion-wise. The reaction was heated to 80oC and stirred for 16 h. After completion of the reaction (Monitored by thin layer chromatography: eluent: 70 % ethyl acetate in petroleum ether UV, Ninhydrin active), it was quenched with water (20 mL), and extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with water (30 mL), brine (20 mL), dried over sodium sulphate, filtered, and concentrated under reduce pressure to afford crude product (0.13 g). The crude was purified by reverse phase HPLC method: Column / dimensions: X SELECT C18 (19 x 250 x 5um). Mobile phase A: 0.1 % FA in water (aq) Mobile phase B : Acetonitrile Gradient (Time / %B) : 0.01 / 10, 1 / 10, 17 / 70, 17.1 / 100, 20 / 100, 20.1 / 10, 22 / 10. Solubility : Acetonitrile + tetrahydrofuran + Water. Flow rate : 17 ml / min. to afford 1-(2-(3-aminophenyl)propan-2-yl)-3-(2-(2,6-dioxopiperidin-3-yl)-1- oxoisoindolin-5-yl) urea (0.035 g, 12 %) as an off white solid. MS (ESI) m / z 461.44 [M+H]+. LC-MS purity: 94 %.1H NMR (400 MHz, DMSO – d6): δ 10.94 (s, 1H), 8.86 (s, 1H), 7.73 (s, 1H), 7.53 (d, J = 8.40 Hz, 1H), 7.24 – 7.23 (m, 3H), 7.01 (d, J = 8.00 Hz, 2H), 6.74 (s, 1H), 5.04 (q, J = 5.20 Hz, 1H), 4.33 (d, J = 17.20 Hz, 1H), 4.20 (d, J = 17.20 Hz, 1H), 2.51-2.50 (m, 1H), 2.33 – 1.97 (m, 1H), 1.89 – 1.88 (m, 1H), 1.85 – 1.58 (m, 1H), 0.92 – 0.91 (m, 1H), 1.58 (s, 6H), 0.89 – 0.88 (m, 2H), 0.62 – 0.61 (m, 2H).

[0219] Compounds below may be synthesized utilizing the General method D.

[0220] General method E

[0221] Example 141: Synthesis of 4-(2-(3-(2-(2,6-dioxopiperidin-3-yl)-1- oxoisoindolin-5-yl)ureido)propan-2-yl)benzoic acid

[0222] To a stirred solution of 1-(2-(4-bromophenyl)propan-2-yl)-3-(2-(2,6- dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)urea (0.15 g, 0.3 mmol)) in DMF (1.5 mL), were added formic acid (0.079 mL, 2.1 mmol) , N,N'-dicyclohexylcarbodiimide (0.012 g, 0.060 mmol), Xantphos (0.005 g, 0.009 mmol), Triethylamine (0.084 mL, 0.601 mmol). The resulting solution was degassed with argon gas for 15 minutes followed by the addition ofpalladium(II) acetate (0.002 g, 0.009 mmol). The reaction mixture was again degassed with argon gas for another 5 minutes and heated at 100°C for 20h. The progress of the reaction was monitored by thin layer chromatography and LCMS. The reaction mixture was diluted with ethyl acetate (30 mL) and washed with water (2 x 20 mL). The organic layer was dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure to afford the crude product. The crude material was purified by combi flash to afford 4-(2-(3-(2-(2,6- dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)ureido)propan-2-yl)benzoic acid (0.015 g 11 % ) as an off white solid MS (ESI) m / z 465.23 [M+H]+;1H NMR (400 MHz, DMSO-d6) δ 10.93 (bs, 1H), 9.13 (s, 1H), 7.85 (d, J = 8.4 Hz, 2H), 7.75 (s, 1H), 7.53 (d, J = 8.4 Hz, 1H), 7.45 (d, J = 8.4 Hz, 2H), 7.27 (dd, J = , 8.4 Hz, 16. Hz, 1H), 7.05 (s, 1H), 5.04 (dd, J = 13.2, 5.2Hz, 1H), 4.32 (d, J = 17.2 Hz, 1H), 4.19 (d, J = 17.2 Hz, 1 H), 2.93 – 2.84 (m, 1H), 2.51 - 2.50 (m, 1H), 2.39 – 2.37 (m, 1H), 1.97 -1.94 (m, 1H), 1.61 (s, 6H).

[0223] Example 142: 4-(2-(3-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5- yl)ureido)propan-2-yl)-N,N-dimethylbenzamide

[0224] To a stirred solution of 4-(2-(3-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5- yl)ureido)propan-2-yl)benzoic acid (0.08 g, 0.17 mmol) in dimethylformamide (1 mL) under argon atmosphere were added HATU (0.098 g, 0.26 mmol) and diisopropylethylamine (0.090 mL, 0.52 mmol). The resulting reaction mixture was stirred at room temperature for 10 minutes. To the reaction mixture was added dimethylamine hydrochloride (0.017 mg, 0.21 mmol) and the reaction was stirred at room temperature for 16 h. The reaction was monitored by LCMS. After completion of the reaction, the reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate (2 x 20 mL). The organic layers were combined, washed with water (2 x 10 mL), brine (20 mL), dried over sodium sulphate, filtered and concentrated under reduced pressure to afford crude product. The crude was purified by reverse phase- HPLC. Column / dimensions: C18;150x20mm;5u Mobile Phase-A 0.10 % Formic acid in Water Mobile Phase-B Acetonitrile Gradient program (T / %B) 0 / 10, 1 / 10, 12 / 60, 12.10 / 100, 14 / 100, 14.10 / 10, 17 / 10 Flow rate 15mL / minute), After lyophilized to afford 4-(2-(3-(2-(2,6- dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)ureido)propan-2-yl)-N,N-dimethylbenzamide (0.013 g, 15%) as an off white solid. MS (ESI) m / z 491.54 [M+H]+;1H NMR (400 MHz, DMSO-d6) δ 10.94 (s, 1H), 9.22 (s, 1H), 7.76 (s, 1H), 7.53 (d, J = 8.4 Hz, 1H), 7.44 (d, J =8.4 Hz, 2H), 7.34 (d, J = 8.0 Hz, 2H), 7.28 (dd, J = 8.2, 1.4 Hz, 1H), 7.15 (s, 1H), 5.04 (dd, J = 13.2, 5.2 Hz, 1H), 4.20 (d, J = 17.2 Hz, 1H), 4.33 (d, J = 17.2 Hz, 1H), 2.94 - 2.84 (m, 7H), 2.60 - 2.55 (m, 1H), 2.37 - 2.30 (m, 1H), 1.97 - 1.94 (m, 1H), 1.61 (s, 6H).

[0225] Compounds below may be synthesized utilizing the General method E.

[0226] General method F

[0227] Example 146: 1-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-3-(2-(3- hydroxy-4-(pyridin-3-yl)phenyl)propan-2-yl)urea

[0228] To a stirred solution of 1-(2-(3-(benzyloxy)-4-(pyridin-3-yl)phenyl)propan-2- yl)-3-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)urea (0.25 g, 0.41 mmol) in THF (0.7 mL) and ethanol (0.5 mL) was added palladium on activated carbon (0.1 g). The reaction mixture was stirred under H2 gas 90 psi pressure at 60 °C for 16 h. After completion of the reaction, the mixture was filtered through Celite® and concentrated under reduced pressure to get crude product. The crude compound was purified by silica gel (100-200 mesh) chromatography using MeOH in DCM ( 0-10%) to get 1-(2-(2,6-dioxopiperidin-3-yl)-1- oxoisoindolin-5-yl)-3-(2-(3-hydroxy-4-(pyridin-3-yl)phenyl)propan-2-yl)urea which was further purified by reverse phase HPLC purification by using column / dimensions : X SELECT C18 (19*250)mm 5um mobile phase A : 0.1 % formic acid in water (aq) mobilephase B : Acetonitrile gradient (Time / %B) : 0 / 10, 1 / 10, 12 / 50, 12.1 / 100, 14 / 100, 14.1 / 10,17 / 10 flow rate : 16ml / min. Solubility : ACN + THF + water to afford 1-(2-(2,6- dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-3-(2-(3-hydroxy-4-(pyridin-3-yl)phenyl)propan-2- yl)urea (0.0141 g, 7%) as white solid. MS (ESI) m / z 514.39 [M+H]+;1H NMR (400 MHz, DMSO-d6) δ 10.94 (s, 1H), 8.90 (s, 1H), 8.74 (s, 1H), 8.48 (s, 1H), 8.19 (s, 1H), 7.94 (d, J = 8.0 Hz, 1H), 7.77 (s, 1H), 7.55 (d, J = 8.0 Hz, 1H), 7.42 (s, 1H), 7.27 (d, J = 8.4 Hz, 2H), 7.04 (s, 1H), 6.96 (q, J = 3.2 Hz, 1H), 6.82 (s, 1H), 5.05 (dd, J = 13.4, 5.0 Hz, 1H), 4.34 (d, J = 17.2 Hz, 1H), 4.21 (d, J = 17.2 Hz, 1H), 2.92-2.85 (m, 1H), 2.60 – 2.52 (m, 1H), 2.42 – 2.35 (m, 1H), 2.01 - 1.95 (m, 1H), 1.61 (s, 6H) .

[0229] Compounds below may be synthesized utilizing the General method F.

[0230] General Method G

[0231] Example 258: 1-(2-(4-(5-cyanopyridin-3-yl)phenyl)propan-2-yl)-3-(6-(2,6- dioxopiperidin-3-yl)-5,7-dioxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-2-yl)urea

[0232] To a stirred solution of tert-butyl (6-(2,6-dioxopiperidin-3-yl)-5,7-dioxo-6,7- dihydro-5H-pyrrolo[3,4-b]pyridin-2-yl)carbamate (0.100 g, 0.267 mmol) and 5-(4-(2- aminopropan-2-yl)phenyl)nicotinonitrile (0.063 g, 0.27 mmol) in ACN (5 mL) was added 1,5,7-Triazabicyclo[4.4.0]dec-5-ene (0.007 g, 0.053 mmol). The resulting reaction mixture was stirred in microwave at 120 °C for 5 h. The reaction mixture was filtered and the residue was collected to afford 1-(2-(4-(5-cyanopyridin-3-yl)phenyl)propan-2-yl)-3-(6- (2,6-dioxopiperidin-3-yl)-5,7-dioxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-2-yl)urea as crude. The crude was purified by PREP-HPLC (Column / dimensions : XSELECT C18(19*\250), 5um Mobile phase A : 0.1% formic acid in water (aq), Mobile phase B : Acetonitrile, Gradient (Time / %B) : 0 / 25,1 / 25,10 / 50,14.5 / 50,14.6 / 100,17.5100,17.6 / 25,19.5 / 25, Flow rate : 17ml / min, Solubility : THF+WATER+ACN ). The pure fraction was collected and concentrated at 35 °C followed by lypholiziation to afford 1-(2-(4-(5-cyanopyridin-3-yl)phenyl)propan-2-yl)-3-(6-(2,6- dioxopiperidin-3-yl)-5,7-dioxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-2-yl)urea (8 mg, 6%) as an off white solid. MS (ESI) m / z 538.35 [M+H]+ , LC-MS purity: 99.88 %.1H-NMR (400 MHz, DMSO-d6) δ 11.09 (s, 1H), 10.07 (s, 1H), 9.19 (d, J = 2.0 Hz, 1H), 9.00 (d, J = 1.2 Hz, 1H), 8.64 (s, 1H), 8.17 (d, J = 8.8 Hz, 2H), 7.86 – 7.77 (m, 3H), 7.56 (d, J = 8.4 Hz, 2H), 5.15 (dd, J = 12.8, 4.8, 1H), 2.93 – 2.84 (m, 1H), 2.62 – 2.58 (m, 2H), 2.10 – 2.05 (m, 1H), 1.69 (s, 6H).

[0233] Example 259: 1-(2-(3-aminophenyl)propan-2-yl)-3-(2-(2,6-dioxopiperidin-3- yl)-1-oxoisoindolin-5-yl)urea.

[0234] To a stirred solution of 1-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-3-(2- (3-nitrophenyl)propan-2-yl)urea (0.1 g, 0.22 mmol) in dichloromethane (5 mL) and ethanol (5 mL) at room temperature, was added 10% Pd / C (0.034 g, 0.32 mmol). Hydrogen gas of ~ 5 psi was used for this reaction. The reaction mixture was stirred at room temperature for 16 h. The progress of the reaction was monitored by LCMS and thin layer chromatography. After completion of the reaction (thin layer chromatography eluent: 10 % MeOH in DCM. UV active, Ninhydrin), the reaction was filtered through Celite®. The filtrate was concentrated under reduced pressure to get crude material. The crude was triturated with diethyl ether and purified by reverse phase HPLC method: Column / dimensions : X SELECTC18 (19 * 250 * 5 um) Mobile phase A : 0.1 % FA in water (aq) Mobile phase B : Acetonitrile Gradient (Time / %B) : 0.01 / 10, 1 / 10, 17 / 70, 17.1 / 100, 20 / 100, 20.1 / 10, 22 / 10. solubility : Acetonitrile + TETRAHYDROFURAN + WATER Flow rate : 17 ml / min. to get pure 1-(2-(3-aminophenyl)propan-2-yl)-3-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl) urea as an off white solid (6.7 mg, 6 %). MS (ESI) m / z 436.38 [M+H]+. LC-MS purity: 98.79 %.1H NMR (400 MHz, DMSO-d6) : δ 11.03 (s, 1H), 8.83 (s, 1H), 7.76 (s, 1H), 7.54 (d, J = 8.40 Hz, 1H), 7.24 (d, J = 2.00 Hz, 1H), 6.94 (t, J = 7.60 Hz, 1H), 6.64 (d, J = 2.00 Hz, 2H), 6.59 (d, J = 7.60 Hz, 1H), 6.40 (d, J = 1.20 Hz, 1H), 5.02 – 4.97 (m, 3H), 4.34 (d, J = 17.20 Hz, 1H), 4.21 (d, J = 17.20 Hz, 1H), 2.86 – 2.85 (m, 1H), 2.57 – 2.56 (m, 1H), 2.49 – 2.38 (m, 1H), 2.32 – 1.98 (m, 1H), 1.57 (s, 6H).

[0235] Example 260: 1-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-3-(2-(4- (tetrahydro-2H-pyran-4-yl)phenyl)propan-2-yl)urea

[0236] Step 1:- 1-(2-(4-(3,6-dihydro-2H-pyran-4-yl)phenyl)propan-2-yl)-3-(2-(2,6- dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)urea

[0237] To a stirred solution of 1-(2-(4-bromophenyl)propan-2-yl)-3-(2-(2,6- dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)urea (0.3 g, 0.6 mmol) and 2-(3,6-dihydro-2H- pyran-4-yl)-4,4,5-trimethyl-1,3,2-dioxaborolane (0.47 g, 2.4 mmol) in DMF (4.5 mL) at room temperature, was added potassium phosphate tribasic (0.13 g, 0.6 mmol) and the resulting reaction mixture was degassed using nitrogen for 5 minutes. To this mixture, Pd(dppf)cl2 dcm (0.098 g, 0.12 mmol) was added and the reaction was degassed again with nitrogen for 5 minutes. The resulting reaction mixture was stirred at 100 °C for 16 h. The progress of the reaction was monitored by thin layer chromatography and LCMS. After completion of reaction, the reaction mixture was concentrated under reduced pressure to afford crude as brown solid. The crude compound was purified by flash column chromatography using 1-2% MeOH in DCM to afford 1-(2-(4-(3,6-dihydro-2H-pyran-4-yl)phenyl)propan-2-yl)-3-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)urea (0.22 g, 73 mmol) as brown solid .MS (ESI) m / z 503 [M+H]+.

[0238] Step 2:- 1-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-3-(2-(4- (tetrahydro-2H-pyran-4-yl)phenyl)propan-2-yl)urea

[0239] To a stirred solution of 1-(2-(4-(3,6-dihydro-2H-pyran-4-yl)phenyl)propan-2-yl)- 3-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)urea (0.2 g, 0.4 mmol) in a solution of tetrahydrofuran and ethanol (6 : 4) mL at room temperature was added palladium on carbon (0.2 g, 2 mmol) was added at same temperature. The reaction was stirred in a Parr shaker instrument with hydrogen (60 PSI) at room temperature for 16h. The progress of the reaction was monitored by thin layer chromatography and LCMS. After completion of reaction, the reaction mixture was filtered through a Celite® pad and the filtrate was concentrated under reduced pressure to afford the crude product. The crude was purified by reverse phase HPLC using Column / dimensions : sunfire C18 (19*150)5uM Mobile phase A : 0.1% FA IN water Mobile phase B : Acetonitrile Gradient (Time / %B): 0 / 20,1 / 20,10 / 45,14 / 45,14.1 / 100,17 / 100,17.1 / 20,19 / 20 Flow rate : 16ml / MIN Solubility : acetonitrile+ tetrahydrofuran + water to afford 1-(2-(2,6-dioxopiperidin-3-yl)-1- oxoisoindolin-5-yl)-3-(2-(4-(tetrahydro-2H-pyran-4-yl)phenyl)propan-2-yl)urea (13 mg , 6 %) as an off white solid. MS (ESI) m / z 505.42 [M+H]+;1H NMR (400 MHz, DMSO-d6) δ 10.94 (s, 1H), 8.84 (s, 1H), 7.74 (s, 1H), 7.54 (d, J = 8.0 Hz, 1H), 7.33 (d, J = 8.0 Hz, 2H), 7.25 (d, J = 9.6 Hz, 1H), 7.19 (d, J = 8.0 Hz, 2H), 6.73 (s, 1H), 5.05 (q, J = 6.1 Hz, 1H), 4.35 (d , J = 17.2 Hz, 1H), 4.20 (d , J = 17.2 Hz, 1H), 3.94 – 3.92 (m, 2H), 3.45 - 3.42 (m, 2H), 2.93 - 2.86 (m, 1H), 2.74 - 2.71 (m, 1H), 2.60 - 2.59 (m, 1H), 2.50 -2.37 (m, 1H), 1.97 - 1.95 (m, 1H), 1.69 -1.63 (m, 10 H).

[0240] Compounds below may be synthesized utilizing the General method G.

[0241] General Method H

[0242] Example 263: Synthesis of 1-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5- yl)-3-(2-(3-(piperidin-3-yl)phenyl)propan-2-yl)urea

[0243] To a solution of tert-butyl 3-(3-(2-(3-(2-(2,6-dioxopiperidin-3-yl)-1- oxoisoindolin-5-yl)ureido)propan-2-yl)phenyl)piperidine-1-carboxylate (0.070 g, 0.12 mmol) in dichloromethane (1.0 mL) was added Aluminium chloride, anhydrous, powder, 99% (0.031 g, 0.232 mmol) at 0 °C was added. The reaction mixture was stirred at room temperature for 3h while being monitored by TLC and LCMS. Reaction was then concentrated under reduced pressure to get the residue product. Crude compound was purified by RP-HPLC using Column / dimensions : X BRIDGE PHENYL (19*250) 5µm Mobile phase A :10mM AA in water Mobile phase B : Acetonitrile Gradient (Time / %B) : 0 / 10, 1 / 10, 12 / 55, 13 / 56, 13.1 / 100, 16 / 100, 16.110, 19 / 10 Flow rate : 15ml / min Solubility : ACN+THF+WATER method, pure fraction was collected and dried under lyophilization to afford 1-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-3-(2-(3-(piperidin-3- yl)phenyl)propan-2-yl)urea (27 mg, 50 %) as an off white solid. MS (ESI) m / z 504.47[M+H]+;1H NMR (400 MHz, DMSO-d6) δ 10.99 (br s, 1H), 8.93 (s, 1H), 7.74 (s, 1H), 7.53 (d, J = 8.4 Hz, 1H), 7.28 (d, J = 5.2 Hz, 2H), 7.26 (d, J = 6.4 Hz, 2H), 7.09 (t, J = 2.8 Hz, 1H), 6.81 (s, 1H), 5.06 (dd, J = 13.2, 5.2 Hz, 1H), 4.33 (d, J = 17.2 Hz, 1H), 4.20 (d, J = 17.2 Hz, 1H), 3.98 – 3.95 (m, 2H), 2.99 – 2.89 (m, 3H), 2.73 – 2.60 (m, 2H), 2.40 – 2.37 (m, 1H), 2.01 – 1.96 (m, 2H), 1.86 – 1.75 (m, 1H), 1.71 – 1.66 (m, 3H), 1.60 (s, 6H).

[0244] Compounds below may be synthesized utilizing the General method H.

[0245] General Method I

[0246] Example 265: Synthesis of 17-(5-(2-(3-(2-(2,6-dioxopiperidin-3-yl)-1- oxoisoindolin-5-yl)ureido)propan-2-yl)-2-(pyridin-3-yl)phenoxy)-3,6,9,12,15- pentaoxaheptadecanoic acid

[0247] Step-1: Synthesis of 2-bromo-5-(2-hydroxypropan-2-yl)phenol

[0248] To a solution of methyl 4-bromo-3-hydroxybenzoate (20 g, 86 mmol) in THF (200 mL) at 0 °C, was added methylmagnesium chloride 3 M in THF (115 mL, 346 mmol) dropwise to the reaction mixture. The resulting reaction mixture was stirred at room temperature for 16 h. The reaction mixture was cooled to 0 °C and quenched with aq. NH4Cl solution (200 mL) by dropwise addition. Reaction mixture was extracted with ethyl acetate (2 X 300 mL), organic layer separated and dried over anhydrous sodium sulphate. Organic layer concentrated at 40 °C to afford 2-bromo-5-(2-hydroxypropan-2-yl)phenol (2) (21 g, Quantitative) as an brown liquid. MS (ESI) m / z 229.07 [M+H]+ 1H-NMR (400 MHz, DMSO-d6): δ 10.01 (br s, 1H), 7.35 (d, J = 8.4 Hz, 1H), 7.11 (d, J = 2.4 Hz, 1H), 6.78 (t, J = 4.2 Hz, 1H), 5.01 (s, 1H), 1.37 (s, 6H).

[0249] Step-2: Synthesis 5-(2-azidopropan-2-yl)-2-bromophenol

[0250] To a soultion of 2-bromo-5-(2-hydroxypropan-2-yl)phenol (11 g, 48 mmol) in Toluene (110 mL), were added trimethylsilyl azide (62 mL, 476 mmol) and boron trifluoride diethyl etherate (59 mL, 476 mmol) at 0 °C. The resulting reaction mixture was stirred for 16 h at room temperature. The reaction mixture was cooled to 0 °C and quenched with 10 % NaHCO3solution (500 mL) by dropwise addition and then extracted with ethyl aceate (2 X 300 mL), organic layer separated and dried over anhydrous sodium sulphate. The organic layers were combined and concentrated at 40 °C to afford 5-(2-azidopropan-2-yl)-2-bromophenol (12 g, Quantitative) as brown liquid. Crude compound was used as such taken for next step without any further purification. MS (ESI) m / z 254.1[M+H]-

[0251] Step-3: Synthesis of 5-(2-aminopropan-2-yl)-2-bromophenol

[0252] To a soultion of 4-(2-azidopropan-2-yl)-2-(benzyloxy)-1-bromobenzene (8 g, 23 mmol ) in diethylether (80 mL), was added lithium aluminium hydride, 1M solution in THF (35 mL, 35 mmol) at 0 °C. The resulting reaction mixture was stirred for 1 h at room temperature. The reaction mixture was quenched with careful addition of saturated NH4Cl (200 mL), 10% aqueous NaOH (100 mL), and water (100 mL) and stirred at rt for 1 h, then filtered through celite and the filtrate concentrated under reduced pressure to get 5-(2- aminopropan-2-yl)-2-bromophenol (9.1g, Quantitative) as off white solid. Crude compound as such taken for next step without any further purification. MS (ESI) m / z 228.17[M+H];1H- NMR (400 MHz, DMSO-d6): δ 7.35 (d, J = 8.4 Hz, 1H), 7.11 (d, J = 2.4 Hz, 1H), 6.78 (t, J = 4.2 Hz, 1H), 5.01 (s, 1H), 1.33 (s, 6H).

[0253] Step-4: Synthesis of tert-butyl (2-(4-bromo-3-hydroxyphenyl)propan-2- yl)carbamate

[0254] To a stirred solution of 5-(2-aminopropan-2-yl)-2-bromophenol (4.0 g, 17 mmol) in dichloromethane (80 mL), was added triethylamine (4.9 mL, 35 mmol). The reaction mixture was cooled to 0 °C and Boc anhydride (3.8 g, 17 mmol) was added dropwise. The resulting reaction mixture was stirred at room temperature for 5 h and monitored by TLC. The reaction mixture was poured into aq. NH4Cl solution (50 mL) and extracted by ethyl acetate (2 x 70 mL). The organic layers were combined and dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to get crude tert-butyl (2-(4-bromo- 3-hydroxyphenyl)propan-2-yl)carbamate (5.6 g) as a brown liquid. Crude material which was purified by column chromatography using 100-150 silica mesh with EtOAc:Pet ether (2:10) as eluent, pure fraction was collected and concentrated at 40 °C to afford tert-butyl (2-(4- bromo-3-hydroxyphenyl)propan-2-yl)carbamate (3.0 g, 50%) as an off white solid. Crude material was purified by column chromatography using 100-150 silica mesh with EtOAc:Pet ether (2:10) as eluent, afforded tert-butyl (2-(4-bromo-3-hydroxyphenyl)propan-2-yl)carbamate (3.0 g, 50%) as white solid. MS (ESI) m / z 328.0[M+H]- 1H-NMR (400 MHz, DMSO-d6): δ 9.99 (br s, 1H), 7.34 (d, J = 8.4 Hz, 1H), 7.19 (br s, 1H), 6.93 (d, J = 2.0 Hz, 1H), 6.68 (t, J = 4.2 Hz, 1H), 1.43 (s, 6H), 1.33 (s, 9H).

[0255] Step-5: Synthesis of tert-butyl (2-(3-hydroxy-4-(pyridin-3-yl)phenyl)propan- 2-yl)carbamate:

[0256] To a stirred solution of tert-butyl (2-(4-bromo-3-hydroxyphenyl)propan-2- yl)carbamate (3.0 g, 9.1 mmol) and 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (3.7 g, 18 mmol) in dioxane (45 mL) and water (5 mL) at room temperature. K2CO3 (2.5 g, 18 mmol) was added and the resulting reaction mixture was degassed using nitrogen gas for 5 minutes. To this mixture, Pd(dppf)Cl2.DCM (0.74 g, 0.91 mmol) was added and degassed again with nitrogen for 5 minutes. The resulting reaction mixture was stirred at 100 °C for 16 h. The progress of the reaction was monitored by TLC and LCMS. The reaction was quenched with water (100 mL) and extracted with ethyl acetate (2 X 250 mL). The organic layers were combined, separated and dried over anhydrous sodium sulphate. The organic fraction was concentrated at 40 °C to afford crude (3.5 g). Crude material which was purified by column chromatography using 230-400 silica mesh with EtOAc:Pet ether (2:10) as eluent, pure fraction was collected and concentrated at 40 °C to afford tert-butyl (2-(3-hydroxy-4- (pyridin-3-yl)phenyl)propan-2-yl)carbamate (2.9 g, 97%) as an brown solid. MS (ESI) m / z 329.38[M+H]+ 1H-NMR (400 MHz, DMSO-d6): δ 9.60 (br s, 1H), 8.73 (d, J = 1.6 Hz, 1H), 8.47 (d, J = 3.2 Hz, 1H), 7.94 (d, J = 4.4 Hz, 1H), 7.40 (t, J = 3.8 Hz, 1H), 7.24 (d, J = 8.0 Hz, 1H), 7.19 (br s, 1H), 6.88 (s, 1H), 6.87 (d, J = 1.6 Hz, 1H), 1.49 (s, 6H), 1.07 (s, 9H).

[0257] Step-6: Synthesis of tert-butyl 17-(5-(2-((tert-butoxycarbonyl)amino)propan- 2-yl)-2-(pyridin-3-yl)phenoxy)-3,6,9,12,15-pentaoxaheptadecanoate:

[0258] To a solution of tert-butyl (2-(3-hydroxy-4-(pyridin-3-yl)phenyl)propan-2- yl)carbamate (2.4 g, 7.3 mmol) in DMF (48 mL), were added tert-butyl 18-(tosyloxy)-3,6,9,12,15-pentaoxaoctadecanoate (4.2 g, 8.0 mmol) and potassium carbonate (3.0 g, 22 mmol) at room temperature. The resulting reaction mixture was heated at 80 °C for 16 h. The reaction mixture was quenched with water (250 mL) and extracted with ethyl acetate (2 X 300 mL). The organic layers were combined, dried over anhydrous sodium sulphate, and concentrated at 40 °C to afford (5.0 g, Crude). Crude material which was purified by column chromatography using 230-400 silica mesh with EA:Pet ether(6:10) as eluent, pure fraction was collected and concentrated at 40 °C to afford tert-butyl 17-(5-(2-((tert- butoxycarbonyl)amino)propan-2-yl)-2-methylphenoxy)-3,6,9,12,15-pentaoxaheptadecanoate (3.6 g, 74 %) as pale brown liquid. MS (ESI) m / z 663.79[M+H]+ 1H-NMR (400 MHz, DMSO-d6): δ 8.73 (d, J = 1.2 Hz, 1H), 8.49 (d, J = 3.6 Hz, 1H), 7.98 (br s, 1H), 7.95 (s, 1H), 7.41 (dd, J = 7.6, 4.8 Hz, 1H), 7.31 (d, J = 8.0 Hz, 1H), 7.20 (s, 1H), 7.01 (t, J = 10.6 Hz, 1H), 4.11 – 3.32 (m, 22H), 1.41 (s, 6H), 1.07 (s, 18H).

[0259] Step-7: Synthesis of 17-(5-(2-((tert-butoxycarbonyl)amino)propan-2-yl)-2- (pyridin-3-yl)phenoxy)-3,6,9,12,15-pentaoxaheptadecanoic acid

[0260] To a solution of tert-butyl 17-(5-(2-((tert-butoxycarbonyl)amino)propan-2-yl)-2- (pyridin-3-yl)phenoxy)-3,6,9,12,15-pentaoxaheptadecanoate (3.0 g, 4.5 mmol) in THF:MeOH (30 mL) and water (15 mL), was added lithium hydroxide monohydrate (0.95 g, 23 mmol) at room temperature. The resulting reaction mixture was heated at 50 °C for 16 h and evaporated completely at 40 °C. The crude mixture was diluted with water (20 mL) and extracted diethyl ether (2 X 20 mL). The aqueous layer was separated and acidified with cold 10% citric acid solution and extracted with ethyl acetate (2 X50 mL). The organic layers were combined and dried over anhydrous sodium sulphate. The organic solution was concentrated at 40 °C to afford 17-(5-(2-((tert-butoxycarbonyl)amino)propan-2-yl)-2-(pyridin-3- yl)phenoxy)-3,6,9,12,15-pentaoxaheptadecanoic acid (2.9 g, quantitative) as pale yellow liquid. Crude as such taken for next without any purification. MS (ESI) m / z 607.67[M+H]+1H-NMR (400 MHz, DMSO-d6): δ 12.51 (br s, 1H), 8.74 (d, J = 1.2 Hz, 1H), 8.49 (d, J = 3.6 Hz, 1H), 7.98 (br s, 1H), 7.95 (s, 1H), 7.41 (dd, J = 7.6, 4.8 Hz, 1H), 7.31 (d, J = 8.0 Hz, 1H), 7.20 (s, 1H), 7.01 (t, J = 10.6 Hz, 1H), 4.10 – 3.31 (m, 22H), 1.360 (s, 6H), 1.07 (s, 8H).

[0261] Step-8: Synthesis of benzyl 17-(5-(2-((tert-butoxycarbonyl)amino)propan-2- yl)-2-(pyridin-3-yl)phenoxy)-3,6,9,12,15-pentaoxaheptadecanoate

[0262] To a solution of 17-(5-(2-((tert-butoxycarbonyl)amino)propan-2-yl)-2- methylphenoxy)-3,6,9,12,15-pentaoxaheptadecanoic acid (2.9 g, 4.8 mmol) in acetonitrile (29 mL), were added potassium carbonate (0.99 g, 7.2 mmol) and benzyl chloride (0.8 mL, 7.2 mmol) at room temperature. The resulting reaction mixture was heated at 50 °C for 16 h, filtered and concentrated at 40 °C to afford (1.5 g, crude) as pale yellow liquid. The crude material which was purified by column chromatography using 230-400 silica mesh with MeOH:DCM (4:10) as eluent afforded benzyl 17-(5-(2-((tert-butoxycarbonyl)amino)propan- 2-yl)-2-methylphenoxy)-3,6,9,12,15-pentaoxaheptadecanoate (1.1g, 33%) as brown liquid. MS (ESI) m / z 697.75[M+H]+

[0263] Step-9: Benzyl of 17-(5-(2-aminopropan-2-yl)-2-(pyridin-3-yl)phenoxy)- 3,6,9,12,15-pentaoxaheptadecanoate

[0264] To a solution of benzyl 17-(5-(2-((tert-butoxycarbonyl)amino)propan-2-yl)-2- (pyridin-3-yl)phenoxy)-3,6,9,12,15-pentaoxaheptadecanoate (1.1 g, 1.5 mmol) in dichloromethane (2.1 mL), was added 4M HCl in 1,4 dioxane (5.3 mL) at 0 °C. The resulting reaction mixture was stirred at room temperature for 2 h, then filtered and concentrated at 40 °C to afford benzyl 17-(5-(2-aminopropan-2-yl)-2-(pyridin-3-yl)phenoxy)-3,6,9,12,15- pentaoxaheptadecanoate (1.01 g, crude) as brown liquid. The crude material was purified by column chromatography using 230-400 silica mesh with ammonia in MeOH:DCM (3:10) as eluent to afford benzyl 17-(5-(2-aminopropan-2-yl)-2-(pyridin-3-yl)phenoxy)-3,6,9,12,15- pentaoxaheptadecanoate (0.85 g, 95%) as brown liquid. MS (ESI) m / z 597.31[M+H]+

[0265] Step-10: Synthesis benzyl 17-(5-(2-(3-(2-(2,6-dioxopiperidin-3-yl)-1- oxoisoindolin-5-yl)ureido)propan-2-yl)-2-(pyridin-3-yl)phenoxy)-3,6,9,12,15- pentaoxaheptadecanoate

[0266] To a stirred solution of phenyl (2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5- yl)carbamate (0.54 g, 1.4 mmol) in THF (11 mL), were added benzyl 17-(5-(2-aminopropan- 2-yl)-2-methylphenoxy)-3,6,9,12,15-pentaoxaheptadecanoate (0.85 g, 1.4 mmol) and triethylamine (0.99 mL, 7.2 mmol) at room temperature. The resulting reaction mixture was heated at 70 °C for 16 h and then evaporated completely at 40 °C to afford crude (1.15 g) as brown gummy. Crude material was purified by column chromatography using 230- 400 silica mesh with MeOH:DCM (1:10) as eluent to afford benzyl 17-(5-(2-(3-(2-(2,6- dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)ureido)propan-2-yl)-2-(pyridin-3-yl)phenoxy)- 3,6,9,12,15-pentaoxaheptadecanoate (1.02 g, 76 %) as an brown gummy. MS (ESI) m / z 882.86[M+H]+

[0267] Step-11: Synthesis of 17-(5-(2-(3-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin- 5-yl)ureido)propan-2-yl)-2-(pyridin-3-yl)phenoxy)-3,6,9,12,15-pentaoxaheptadecanoic acid

[0268] To a stirred solution of benzyl 17-(5-(2-(3-(2-(2,6-dioxopiperidin-3-yl)-1- oxoisoindolin-5-yl)ureido)propan-2-yl)-2-(pyridin-3-yl)phenoxy)-3,6,9,12,15- pentaoxaheptadecanoate (1.0 g, 1.1 mmol) in tetrahydrofuran:ethanol (30: 20) mL at room temperature, palladium on carbon (1.2 g, 11 mmol) was added and the reaction was stirred under hydrogen pressure (ballon) at room temperature for 16 h. The progress of the reaction was monitored by TLC and LCMS. After the completion of the reaction, the reaction mixture was filter through the celite pad and filtrated was concentrated under reduced pressure to afford 17-(5-(2-(3-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)ureido)propan-2-yl)-2- (pyridin-3-yl)phenoxy)-3,6,9,12,15-pentaoxaheptadecanoic acid (0.750 g, crude) as brown gummy. The crude compound was purified by RP-HPLC using (Column / dimensions : X-bridge c8 (19*250*5) Mobile phase A : 0.1% FA IN water Mobile phase B : Acetonitrile Gradient (Time / %B) : 0 / 10.3 / 10.7 / 28.12 / 28.12.01 / 100.18 / 100.18.01 / 10.20 / 10 Flow rate : 16ml / min. Solubility : THF+ACN+WATER) method to afford 17-(5-(2-(3-(2-(2,6- dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)ureido)propan-2-yl)-2-(pyridin-3-yl)phenoxy)- 3,6,9,12,15-pentaoxaheptadecanoic acid (0.25 g, 25%) as white solid. MS (ESI) m / z 792.64[M+H]+,1H-NMR (400 MHz, DMSO-d6): δ 12.68 (br s, 1H), 10.94 (s, 1H), 8.98 (br s, 1H), 8.73 (d, J = 1.6 Hz, 1H), 8.49 (dd, J = 4.8, 1.6 Hz, 1H), 7.97 (d, J = 8.0 Hz, 1H), 7.76 (s, 1H), 7.54 (d, J = 8.4 Hz, 1H), 7.41 (dd, J = 8.0, 4.8 Hz, 1H), 7.33 (d, J = 8.0 Hz, 1H), 7.28 (d, J = 8.8 Hz, 1H), 7.15 (s, 1H), 7.11 (d, J = 8.0 Hz, 1H), 6.91 (br s, 1H), 5.05 (dd, J = 13.2, 5.2 Hz, 1H), 4.34 (d, J = 17.2 Hz, 1H), 4.21 (d, J = 17.2 Hz, 1H), 4.13 (t, J = 4.4 Hz, 2H), 3.99 (s, 2H), 3.67 (t, J = 4.4 Hz, 2H), 3.58 – 3.46 (m, 16H), 2.92 – 2.85 (m, 1H), 2.61 – 2.50 (m, 1H), 2.40 – 2.31 (m, 1H), 1.98 – 1.92 (m, 1H), 1.66 (s, 6H).

[0269] Compounds below may be synthesized utilizing the General method I.

[0270] Example 148: 1-(2-(2,4-dioxo-3-azabicyclo[3.1.1]heptan-1-yl)-1,3- dioxoisoindolin-5-yl)-3-(2-(p-tolyl)propan-2-yl)urea

[0271]

[0272]

[0273] Step-1: Synthesis of methyl 3-cyano-3-((4-methoxybenzyl)amino)cyclobutane- 1-carboxylate (3):-

[0274] To a stirred solution of methyl 3-oxocyelobutane-1 –carboxylate (Int-1) (5,0 g, 39.02 mmol) in methanol (50.0 ml.) was added (4-methoxyphenyi)methanamine (Int-2) (5.89 g, 42.96 mmol, 5.61 mL), and the reaction was stirred at room temperature for one hour. Trimethylsilyl cyanide (9.80 mL,80.39 mmol) was then added drop-wise to the reaction mixture at 0°C. The reaction mixture was then stirred at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure. The crude material was purified by silica gel column chromatography (0-10% ethyl acetate / hexanes) to afford methyl 3- cyano-3-((4-methoxybenzyl)amino)cyclobutane-l-carboxylate (3) (7.2 g, 67% ) as a light yellow oil. MS (ESI) m / z 275.2 [M+H]+.

[0275] Step-2: Synthesis of 1-((4-methoxybenzyl)amino)-3-azabicyclo[3.1.1]heptane- 2,4-dione (4):-

[0276] To a stirred solution of afford methyl 3-cyano-3-((4- methoxybenzyl)amino)cyclobutane-1-carboxylate (7.2 g, 26.24 mmol) in acetic acid (40.32 mL) was added sulfuric acid (5.76 mL), and the reaction mixture was refluxed for 16 hours. The reaction mixture was concentrated under reduced pressure and diluted with ethyl acetate. The organic layer was washed with saturated aqueous NaHCO3 solution, water, and brine, dried over sodium sulfate, and concentrated under reduced pressure. The crude material was purified by silica gel column chromatography (0-2% methanol / DCM) to afford l-((4- methoxybenzyl)amino)-3- azabicyclo[3.1.1]heptane-2,4-dione (4) (0.9 g, 13%) as an off-white solid. MS (ESI) m / z 259.3 [M-H]-.

[0277] Step-3: Synthesis of 1-((4-methoxybenzyl)amino)-3-azabicyclo[3.1.1]heptane- 2,4-dione (5):-

[0278] A stirred solution of l-((4-methoxybenzyl)amino)-3-azabicyclo[3.1.1]heptane- 2,4~dione (0.9 g, 3.458 mmol) in ethanol (18 mL) was degassed for 15 minutes under argon. 10% palladium on carbon (0.25 g) was added, and the reaction mixture was placed under a balloon of hydrogen gas for six hours. The reaction mixture was filtered through a pad of celite, and the filter pad was washed with ethanol. The combined filtrated was concentrated to afford 1-amino-3-azabicyclo[3.1.1]heptane-2,4-dione (0.4 g, 83%) as a pale brown liquid. MS (ESI) m / z 139.05 [M-H]-

[0279] Step-4: Synthesis of 1-(5-nitro-1,3-dioxoisoindolin-2-yl)-3- azabicyclo[3.1.1]heptane-2,4-dione (7):-

[0280] To a stirred solution of 1-amino-3-azabicyclo[3.1.1]heptane-2,4-dione (5) (0.2 g, 1.427 umol) in methanol (4 mL) was added 5-nitroisobenzofuran-1,3-dione (6) (0.331 g, 1.713 mmol) and the reaction mixture was heated at 80 °C for three hours. The reaction mixture was evaporated under reduced pressure. The crude material was purified by combiflash d with 2% methanol / DCM.) to afford methyl 1-(5-nitro-1,3-dioxoisoindolin-2-yl)- 3-azabicyclo[3.1.1]heptane-2,4-dione (7) (0.07 g, 16%) as a pale yellow liquid. MS (ESI) m / z 316.21 [M+H]+.

[0281] Step-5: Synthesis of 1-(5-amino-1,3-dioxoisoindolin-2-yl)-3- azabicyclo[3.1.1]heptane-2,4-dione (8):-

[0282] To a stirred solution of 1-(5-nitro-1,3-dioxoisoindolin-2-yl)-3- azabicyclo[3.1.1]heptane-2,4-dione (7) (0.07 g, 0.222 mmol) in DMF (1.4 mL), was added 4,4'-Dipyridyl (0.002 g, 0.011 mmol) reaction mixture was stirred for 5 min at room temperature. Tetrahydroxydiboron (0.080 g, 0.888 mmol) lotwise to above reaction mixture. Resulting reaction mixture was stirred at room temperature for 1h. The reaction mixture was quenched with water (10 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic layer was washed with brine solution (10 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford 1-(5-amino-1,3- dioxoisoindolin-2-yl)-3-azabicyclo[3.1.1]heptane-2,4-dione (8)(0.07 g, Quantitative) as a pale yellow solid. MS (ESI) m / z 284.15 [M-H]- Step-6: Synthesis of phenyl (2-(2,4-dioxo-3-azabicyclo[3.1.1]heptan-1-yl)-1,3- dioxoisoindolin-5-yl)carbamate (10)

[0283] To a stirred solution of 1-(5-amino-1,3-dioxoisoindolin-2-yl)-3- azabicyclo[3.1.1]heptane-2,4-dione (0.07 g, 0.245 mmol) in ACN (1.89 mL) and water (0.21 mL), then were added phenyl carbonochloridate (9) (0.21 mL, 3 V ) and resulting reaction mixture was stirred at room temprature for 2 h. The progress of the reaction was monitored by TLC and LCMS. The reaction mixture was filtured to get the crude product, which was triturated with diethyl ether (10 mL) to afford phenyl (2-(2,4-dioxo-3- azabicyclo[3.1.1]heptan-1-yl)-1,3-dioxoisoindolin-5-yl)carbamate (10)(0.05 g, 50%) as an yellow solid. (MS (ESI) m / z 406.22 [M+H]+.

[0284] Step-7: Synthesis of 1-(2-(2,4-dioxo-3-azabicyclo[3.1.1]heptan-1-yl)-1,3- dioxoisoindolin-5-yl)-3-(2-(p-tolyl)propan-2-yl)urea (TRN-0386):-

[0285] To a solution of phenyl (2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5- yl)carbamate (10) (0.05 g, 0.123 mmol ) and 2-(p-tolyl)propan-2-amine (11) (0.022 g, 0.148 mmol) in THF (0.5 mL) was added TEA (0.026 mL, 0.185 mmol) at RT. The reaction mixture was stirred at 70 °C for 16 h. The progress of the reaction mixture was monitered by LCMS. The reaction mixture was quenched with water (10 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic layer was washed with brine solution (10 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to get crude product, which was purified by reverse phase preparative HPLC to afford 1-(2-(2,4-dioxo-3- azabicyclo[3.1.1]heptan-1-yl)-1,3-dioxoisoindolin-5-yl)-3-(2-(p-tolyl)propan-2-yl)urea (0.02 mg, 35%) as white solid. HPLC Method Conditions: Column / dimensions : SUNFIRE C18 (19*150*5um) Mobile phase A : 0.1%FA in water Mobile phase B : ACN Gradient :0 / 135, 2 / 35, 10 / 50, 14 / 50, 14.2 / 100, 15.5 / 100, 15.6 / 35, 18 / 35. Flow rate : 18ml / min Solubility :THF + ACN + WATER. MS (ESI) m / z 461.24 [M+H]+;1H NMR (400 MHz, DMSO-d6) δ 11.05 (s, 1H), 9.37 (s, 1H), 7.98 (s, 1H), 7.70 (d, J = 8.4 Hz, 1H), 7.54 (d, J =8.4 Hz, 1H), 7.29 (d, J = 8.0 Hz, 2H), 7.11 (d, J = 7.6 Hz, 2H), 6.99 (s, 1H), 3.09 (t, J = 5.8 Hz, 1H), 2.99 - 2.91 (m, 4H), 2.27 (s, 3H), 1.60 (s, 6H).

[0286] Compounds below may be synthesized utilizing the General method G.Biochemical and Cellular Assays

[0287] In vitro proximity assay 1 for CDK2 and CRBN

[0288] A TR-FRET proximity assay was used to measure ternary complex formation induced by test compounds. Compounds dissolved in 100% DMSO were dispensed to a 384- well plate by an SPT Labtech Mosquito LV as duplicate 10-point dilution series to a total volume of 100 nanoliters of DMSO. Two columns of DMSO only and two columns of control compound (final concentration 10 µM) served as neutral and stimulator controls, respectively. To this plate was added 10 microliters of a reaction mixture containing 150 nM avi-tagged CDK2, 75 nM ULight-Streptavidin (PerkinElmer), 50 nM 6xHis-tagged CRBN / DDB1, and 0.3 nM Eu-W1024 Anti-6xHis (PerkinElmer) in a buffer consisting of 50 mM Tris, 150 mM NaCl, 1 mM TCEP, 0.02% Tween-20, and 0.5 mg / mL BSA at pH 7.4. The plate was incubated at room temperature for 2 hours, then read on a BMG PHERAstar plate reader with a 337 nm excitation laser and 620 nm and 665 nm emission filters. The TR- FRET signal was calculated as the ratio of emission signals at 665 nm over 620 nm, and the compound-containing wells were normalized to DMSO (0% activity) and example 26 (3-(5- {3-[1-methyl-1-(p-tolyl)ethyl]ureido}-1-oxo-2-isoindolinyl)-2,6-piperidinedione) (100% activity). Normalized data for each compound were then subjected to a 4-parameter logistic fit. Results are shown in Table 1. The letter codes for EC50 include; A (<100 nM), B (100- 1000 nM), C (>1000 nM). The sign codes for Emaxinclude; + (<10 %), ++ (10-100), +++ (>100).

[0289] In vitro proximity assay 2 for CDK2 / CCNE1 and CRBN

[0290] A TR-FRET proximity assay was used to measure ternary complex formation induced by test compounds. Compounds dissolved in 100% DMSO were dispensed to a 384- well plate by an SPT Labtech Mosquito LV as duplicate 10-point dilution series to a total volume of 100 nanoliters of DMSO. Two columns of DMSO only and two columns of control compound (final concentration 5 µM) served as neutral and stimulator controls, respectively. To this plate was added 10 microliters of a reaction mixture containing 20 nM avi-tagged CDK2 / CCNE1, 0.3 nM Eu-W1024-Streptavidin (PerkinElmer), 20 nM 6xHis- tagged CRBN / DDB1, and 100 nM ULight-Anti-6xHis (PerkinElmer) in a buffer consisting of 50 mM Tris, 150 mM NaCl, 1 mM TCEP, 0.02% Tween-20, and 0.5 mg / mL BSA at pH 7.4. The plate was incubated at room temperature for 2 hours, then read on a BMG PHERAstar plate reader with a 337 nm excitation laser and 620 nm and 665 nm emission filters. The TR- FRET signal was calculated as the ratio of emission signals at 665 nm over 620 nm, and the compound-containing wells were normalized to DMSO (0% activity) and 3-(5-{3-[1-(6- bromo-1,3-benzothiazol-2-yl)-1-methylethyl]ureido}-1-oxo-2-isoindolinyl)-2,6- piperidinedione (100% activity). Normalized data for each compound were then subjected to a 4-parameter logistic fit. Results are shown in Table 1. The letter codes for EC50 include; A (<100 nM), B (100-1000 nM), C (>1000 nM). The sign codes for Emax include; + (<10 %), ++ (10-100), +++ (>100). Table 1NT = Not Tested

[0291] The contents of all references (including literature references, issued patents, published patent applications, and co-pending patent applications) cited throughout this application are hereby expressly incorporated herein in their entireties by reference. Unless otherwise defined, all technical and scientific terms used herein are accorded the meaning commonly known to one with ordinary skill in the art.

Claims

CLAIMS Listing of Claims:

1. A compound having the structural Formula IIa:or a pharmaceutically acceptable salt thereof, wherein Y is CH2 or C(O); Z is CR3or N; R3is H or halo; R1is selected from (C1-C6)alkyl, halo(C1-C6)alkyl, hydroxy(C1-C6)alkyl, aryl, heterocyclyl, heteroaryl, and carbocyclyl, wherein said aryl, heterocyclyl, heteroaryl, and carbocyclyl for R1are each optionally substituted with one to three groups selected from selected from R4, and wherein said (C1-C6)alkyl, halo(C1-C6)alkyl, and hydroxy(C1-C6)alkyl for R1are each substituted with one or two groups selected from aryl, heterocyclyl, heteroaryl, and carbocyclyl, wherein said aryl, heterocyclyl, heteroaryl, and carbocyclyl are each optionally substituted with one to three groups selected from R5; provided that R1is not cyclopentyl, 1-cyclopropylpiperidine-4-yl, para-2- phenoxyacetonitrilyl, 4-fluorophenyl, 1-neopentylcyclopropan-1-yl, 4- trifluoromethoxyphenyl, 1-propyl-1H-pyrazole-3-yl, 1-benzyl-3-methyl-1H-pyrazol-3-yl, unsubstituted spiro[3.3]heptanyl, an unsubstituted pyrimidinyl, unsubstituted pyridinyl, unsubstituted indolyl, unsubstituted benzooxazolyl, unsubstituted cubanyl, -CH2(unsubsituted thiazolyl), or -(CH2)2[unsubsituted indolyl]; R1aand R2are each independently hydrogen or (C1-C4)alkyl; the dashed lines represent additional bonds which may be present; R4and R5are each independently selected from (C1-C6)alkyl, halo(C1-C6)alkyl, -[(C1- C6)alkyl]NRbRc, [(C1-C6)alkyl]O[(C1-C6)alkyl], -[OCH2CH2]m-OCH2C(O)ORb, halo, cyano, - ORa, -NRbRc, -C(O)NRbRc, -C(O)ORb, -C(O)Rd, -[(C1-C6)alkyl]C(O)NRbRc, -[(C1- C6)alkyl]C(O)ORb, -[(C1-C6)alkyl]-C(O)Rd, -[(C1-C6)alkyl]phenyl, -[(C1-C6)alkyl]heteroaryl, NO2, -[(C1-C6)alkyl]cycloalkyl, -[(C1-C6)alkyl]heterocyclyl, -C(O)NRbSO3H, -NRbC(O)Rc, - NRbC(O)ORc, -NRbC(S)ORc, -NRbC(O)NRbRc, -NRbC(S)NRbRc, -NRbS(O)2NRbRc, -C(S)Rb, -S(O)2Rb, -S(O)Rb, -C(S)ORb, -C(S)NRbRc, -NRbC(S)Rc, -SRb, phenyl, heteroaryl,cycloalkyl, and heterocyclyl, wherein for each occurrence of phenyl, heteroaryl, cycloalkyl, and heterocyclyl, said groups are optionally substituted with one to three groups selected from halo, cyano, phenyl, benzyl, (C3-C6)cycloalkyl, (C1-C4)alkyl, halo(C1-C4)alkyl, (C1- C4)alkoxy, halo(C1-C4)alkoxy, -C(O)NRbRc, and -C(O)ORb; Ra, Rb, Rc, and Rdare each independently selected from hydrogen, (C1-C6)alkyl, halo(C1-C6)alkyl, phenyl, benzyl, heterocyclyl, heteroaryl, and cycloalkyl, wherein said phenyl, benzyl, heterocyclyl, heteroaryl, and cycloalkyl are each optionally substituted with 1 to three groups selected from halo, (C1-C4)alkyl, halo(C1-C4)alkyl, (C1-C4)alkoxy, and halo(C1-C4)alkoxy; and m is 1, 2, 3, 4, or 5.

2. The compound of Claim 1, wherein the compound is of the Formula :or a pharmaceutically acceptable salt thereof, wherein Y is CH2 or C(O); R1is selected from (C1-C6)alkyl, halo(C1-C6)alkyl, hydroxy(C1-C6)alkyl, aryl, heterocyclyl, heteroaryl, and carbocyclyl, wherein said aryl, heterocyclyl, heteroaryl, and carbocyclyl for R1are each optionally substituted with one to three groups selected from selected from R4, and wherein said (C1-C6)alkyl, halo(C1-C6)alkyl, and hydroxy(C1-C6)alkyl for R1are each substituted with one or two groups selected from aryl, heterocyclyl, heteroaryl, and carbocyclyl, wherein said aryl, heterocyclyl, heteroaryl, and carbocyclyl are each optionally substituted with one to three groups selected from R5; provided that R1is not cyclopentyl, 1-cyclopropylpiperidine-4-yl, para-2- phenoxyacetonitrilyl, 4-fluorophenyl, 1-neopentylcyclopropan-1-yl, 4- trifluoromethoxyphenyl, 1-propyl-1H-pyrazole-3-yl, 1-benzyl-3-methyl-1H-pyrazol-3-yl, unsubstituted spiro[3.3]heptanyl, an unsubstituted pyrimidinyl, unsubstituted pyridinyl, unsubstituted indolyl, unsubstituted benzooxazolyl, unsubstituted cubanyl, -CH2(unsubsituted thiazolyl), or -(CH2)2[unsubsituted indolyl]; R1aand R2are each independently hydrogen or (C1-C4)alkyl; the dashed lines represent additional bonds which may be present;R4and R5are each independently selected from (C1-C6)alkyl, halo(C1-C6)alkyl, -[(C1- C6)alkyl]NRbRc, [(C1-C6)alkyl]O[(C1-C6)alkyl], halo, cyano, -ORa, -NRbRc, -C(O)NRbRc, - C(O)ORb, -C(O)Rd, -[(C1-C6)alkyl]C(O)NRbRc, -[(C1-C6)alkyl]C(O)ORb, -[(C1-C6)alkyl]- C(O)Rd, -[(C1-C6)alkyl]phenyl, -[(C1-C6)alkyl]heteroaryl, NO2, -[(C1-C6)alkyl]cycloalkyl, - [(C1-C6)alkyl]heterocyclyl, -C(O)NRbSO3H, -NRbC(O)Rc, -NRbC(O)ORc, -NRbC(S)ORc, - NRbC(O)NRbRc, -NRbC(S)NRbRc, -NRbS(O)2NRbRc, -C(S)Rb, -S(O)2Rb, -S(O)Rb, -C(S)ORb, -C(S)NRbRc, -NRbC(S)Rc, -SRb, phenyl, heteroaryl, cycloalkyl, and heterocyclyl, wherein for each occurrence of phenyl, heteroaryl, cycloalkyl, and heterocyclyl, said groups are optionally substituted with one to three groups selected from halo, cyano, (C1-C4)alkyl, halo(C1-C4)alkyl, (C1-C4)alkoxy, halo(C1-C4)alkoxy, -C(O)NRbRc, -C(O)ORb; and Ra, Rb, Rc, and Rdare each independently selected from hydrogen, (C1-C6)alkyl, halo(C1- C6)alkyl, phenyl, benzyl, heterocyclyl, heteroaryl, and cycloalkyl, wherein said phenyl, benzyl, heterocyclyl, heteroaryl, and cycloalkyl are each optionally substituted with 1 to three groups selected from halo, (C1-C4)alkyl, halo(C1-C4)alkyl, (C1-C4)alkoxy, and halo(C1- C4)alkoxy.

3. The compound of Claim 1, or a pharmaceutically acceptable salt thereof, wherein Z is CR3.

4. The compound of Claim 3, or a pharmaceutically acceptable salt thereof, wherein R3is H or -F.

5. The compound of Claim 3 or 4, or a pharmaceutically acceptable salt thereof, wherein R3is H.

6. The compound of Claim 1, or a pharmaceutically acceptable salt thereof, wherein Z is N.

7. The compound of any one of Claims 1 to 4, wherein the compound is of the Formula III:or a pharmaceutically acceptable salt thereof.

8. The compound of any one of Claims 1 to 4, wherein the compound is of the Formula IV:or a pharmaceutically acceptable salt thereof.

9. The compound of any one of Claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein Y is C(O).

10. The compound of any one of Claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein Y is CH2.

11. The compound of any one of Claims 1 to 5, or a pharmaceutically acceptable salt thereof, wherein R2is hydrogen.

12. The compound of any one of Claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein R1ais hydrogen.

13. The compound of any one of Claims 1 to 7, or a pharmaceutically acceptable salt thereof, wherein R1ais CH3.

14. The compound of any one of Claims 1 to 8, or a pharmaceutically acceptable salt thereof, wherein R1is selected from (C1-C6)alkyl, halo(C1-C4)alkyl, hydroxy(C1-C4)alkyl, aryl, heterocyclyl, heteroaryl, and carbocyclyl, wherein said aryl, heterocyclyl, heteroaryl, and carbocyclyl for R1are each substituted with one to three groups selected from selectedfrom R4, and wherein said (C1-C6)alkyl, halo(C1-C4)alkyl, and hydroxy(C1-C4)alkyl for R1are each substituted with one or two groups selected from aryl, heterocyclyl, heteroaryl, and carbocyclyl, wherein said aryl, heterocyclyl, heteroaryl, and carbocyclyl are each optionally substituted with one to three groups selected from R5.

15. The compound of any one of Claims 1 to 9, or a pharmaceutically acceptable salt thereof, wherein R1is selected from (C1-C6)alkyl, halo(C1-C4)alkyl, hydroxy(C1-C4)alkyl, (C6-C10)aryl, 4- to 10-membered heterocyclyl, 5- to 10-membered heteroaryl, and 3- to 10- membered carbocyclyl, wherein said (C6-C10)aryl, 4- to 10-membered heterocyclyl, 5- to 10- membered heteroaryl, and 3- to 10-membered carbocyclyl for R1are each substituted with one to three groups selected from selected from R4, and wherein said (C1-C6)alkyl, halo(C1- C4)alkyl, and hydroxy(C1-C4)alkyl for R1are each substituted with one or two groups selected from (C6-C10)aryl, 4- to 10-membered heterocyclyl, and 5- to 10-membered heteroaryl, wherein said (C6-C10)aryl, 4- to 10-membered heterocyclyl, and 5- to 10- membered heteroaryl are each optionally substituted with one to three groups selected from R5.

16. The compound of any one of Claims 1 to 10, or a pharmaceutically acceptable salt thereof, wherein R1is selected from (C1-C4)alkyl, halo(C1-C4)alkyl, hydroxy(C1-C4)alkyl, (C6-C10)aryl, 4- to 10-membered heterocyclyl, and 3- to 10-membered carbocyclyl, wherein said (C6-C10)aryl, 4- to 10-membered heterocyclyl, and 3- to 10-membered carbocyclyl for R1are each substituted with one to three groups selected from selected from R4, and wherein said (C1-C4)alkyl, halo(C1-C4)alkyl, and hydroxy(C1-C4)alkyl for R1are each substituted with one or two groups selected from (C6-C10)aryl, 4- to 10-membered heterocyclyl, and 5- to 10- membered heteroaryl, wherein said (C6-C10)aryl, 4- to 10-membered heterocyclyl, and 5- to 10-membered heteroaryl are each optionally substituted with one to three groups selected from R5.

17. The compound of any one of Claims 1 to 11, or a pharmaceutically acceptable salt thereof, wherein R1is selected from (C1-C4)alkyl, halo(C1-C4)alkyl, hydroxy(C1-C4)alkyl, phenyl, 9- to 10-membered bicyclic heterocyclyl, and 9- to 10-membered bicyclic carbocyclyl, and 3- to 5-membered monocyclic carbocyclyl, wherein said phenyl, 9- to 10- membered bicyclic heterocyclyl, 9- to 10-membered bicyclic carbocyclyl, and 3- to 5- membered monocyclic carbocyclyl for R1are each substituted with one to three groupsselected from selected from R4, and wherein said (C1-C4)alkyl, halo(C1-C4)alkyl, and hydroxy(C1-C4)alkyl for R1are each substituted with one or two groups selected from phenyl, naphthalenyl, 9- to 10-membered heterocyclyl, and 6- to 10-membered heteroaryl, wherein said phenyl, naphthalenyl, 9- to 10-membered heterocyclyl, and 6- to 10-membered heteroaryl are each optionally substituted with one to three groups selected from R5.

18. The compound of any one of Claims 1 to 12, or a pharmaceutically acceptable salt thereof, wherein R1is selected from (C1-C4)alkyl, hydroxy(C1-C4)alkyl, phenyl, cyclopropyl, cyclobutyl, cyclopentyl, chromanyl, benzodioxolyl, and 2,3-dihydro-1H-indenyl, wherein said phenyl, cyclopropyl, cyclobutyl, cyclopentyl, chromanyl, benzodioxolyl, and 2,3- dihydro-1H-indenyl for R1are each substituted with one to three groups selected from selected from R4, and wherein said (C1-C4)alkyl and hydroxy(C1-C4)alkyl for R1are each substituted with phenyl, naphthalenyl, benzothiazolyl, benzodioxolyl, oxazolyl, thiazolyl, pyrazolyl, benzooxazolyl, quinolinyl, isoquinolinyl, pyrimidinyl, and pyridinyl, wherein said phenyl, naphthalenyl, benzothiazolyl, benzodioxolyl, oxazolyl, thiazolyl, pyrazolyl, benzooxazolyl, quinolinyl, isoquinolinyl, pyrimidinyl, and pyridinyl are each optionally substituted with one to three groups selected from R5.

19. The compound of any one of Claims 1 to 12, or a pharmaceutically acceptable salt thereof, wherein R1is selected from (C1-C4)alkyl, hydroxy(C1-C4)alkyl, phenyl, cyclopropyl, chromanyl, benzodioxolyl, and 2,3-dihydro-1H-indenyl, wherein said phenyl, cyclopropyl, chromanyl, benzodioxolyl, and 2,3-dihydro-1H-indenyl for R1are each substituted with one to three groups selected from selected from R4, and wherein said (C1-C4)alkyl and hydroxy(C1-C4)alkyl for R1are each substituted with phenyl, naphthalenyl, benzothiazolyl, benzodioxolyl, pyrazolyl, benzooxazolyl, quinolinyl, isoquinolinyl, and pyridinyl, wherein said phenyl, naphthalenyl, benzothiazolyl, benzodioxolyl, pyrazolyl, benzooxazolyl, quinolinyl, isoquinolinyl, and pyridinyl are each optionally substituted with one to three groups selected from R5.

20. The compound of any one of Claims 1 to 13, or a pharmaceutically acceptable salt thereof, wherein R4and R5are each independently selected from (C1-C6)alkyl, halo(C1- C6)alkyl, cyano, halo, NO2, -ORa, -NRbRc, -C(O)NRbRc, -C(O)ORb, -[OCH2CH2]m- OCH2C(O)OH, -C(O)Rd, phenyl, heteroaryl, cycloalkyl, and heterocyclyl, wherein, said phenyl, heteroaryl, cycloalkyl, and heterocyclyl are each optionally substituted with one tothree groups selected from halo, cyano, phenyl, benzyl, (C3-C6)cycloalkyl, -C(O)O(C1- C4)alkyl, (C1-C4)alkyl, halo(C1-C4)alkyl, (C1-C4)alkoxy, and halo(C1-C4)alkoxy.

21. The compound of any one of Claims 1 to 13, or a pharmaceutically acceptable salt thereof, wherein R4and R5are each independently selected from (C1-C6)alkyl, halo(C1- C6)alkyl, halo, NO2, -ORa, -NRbRc, -C(O)NRbRc, -C(O)ORb, -C(O)Rd, phenyl, heteroaryl, cycloalkyl, and heterocyclyl, wherein, said phenyl, heteroaryl, cycloalkyl, and heterocyclyl are each optionally substituted with one to three groups selected from halo, (C1-C4)alkyl, halo(C1-C4)alkyl, (C1-C4)alkoxy, and halo(C1-C4)alkoxy.

22. The compound of any one of Claims 1 to 14, or a pharmaceutically acceptable salt thereof, wherein R4and R5are each independently selected from (C1-C6)alkyl, halo(C1- C6)alkyl, cyano, halo, NO2, -ORa, -NRbRc, -C(O)NRbRc, -C(O)ORb, -[OCH2CH2]5- OCH2C(O)ORb,-C(O)Rd, phenyl, pyridinyl, oxazolyl, pyridazinyl, pyrazinyl, cyclopentyl, pyrimidinyl, benzoxazolyl, cyclobutyl, cyclopropyl, cyclopentyl, dihydropyranyl, piperdinyl, and morpholinyl, wherein said phenyl, pyridinyl, oxazolyl, pyridazinyl, pyrazinyl, cyclopentyl, pyrimidinyl, benzoxazolyl, cyclobutyl, cyclopropyl, cyclopentyl, dihydropyranyl, piperdinyl, and morpholinyl are each optionally substituted with one to three groups selected from halo, cyano, phenyl, benzyl, (C3-C6)cycloalkyl, -C(O)O(C1-C4)alkyl, (C1-C4)alkyl, halo(C1-C4)alkyl, (C1-C4)alkoxy, and halo(C1-C4)alkoxy.

23. The compound of any one of Claims 1 to 14, or a pharmaceutically acceptable salt thereof, wherein R4and R5are each independently selected from (C1-C6)alkyl, halo(C1- C6)alkyl, halo, NO2, -ORa, -NRbRc, -C(O)NRbRc, -C(O)ORb, -C(O)Rd, phenyl, pyridinyl, oxazolyl, pyridazinyl, pyrazinyl, cyclopentyl, pyrimidinyl, cyclobutyl, cyclopropyl, dihydropyranyl, and morpholinyl, wherein said phenyl, pyridinyl, oxazolyl, pyridazinyl, pyrazinyl, cyclopentyl, pyrimidinyl, cyclobutyl, cyclopropyl, dihydropyranyl, and morpholinyl are each optionally substituted with one to three groups selected from halo, (C1- C4)alkyl, halo(C1-C4)alkyl, (C1-C4)alkoxy, and halo(C1-C4)alkoxy.

24. The compound of any one of Claims 1 to 15, or a pharmaceutically acceptable salt thereof, wherein Rais selected from hydrogen, (C1-C6)alkyl, halo(C1-C6)alkyl, phenyl, benzyl, and pyridinyl, wherein said benzyl is optionally substitued with (C1-C6)alkoxy.

25. The compound of any one of Claims 1 to 16, or a pharmaceutically acceptable salt thereof, wherein Rband Rcare each independently selected from hydrogen and (C1-C6)alkyl.

26. The compound of any one of Claims 1 to 17, or a pharmaceutically acceptable salt thereof, wherein Rdis 5- to 7-membered heterocyclyl.

27. The compound of any one of Claims 1 to 18, or a pharmaceutically acceptable salt thereof, wherein Rdis morpholinyl or piperdinyl.

28. The compound of any one of Claims 1 to 18, or a pharmaceutically acceptable salt thereof, wherein Rdis morpholinyl.

29. The compound of any one of Claims 1 to 8, or a pharmaceutically acceptable salt thereof, wherein R1is selected from:

30. The compound of any one of Claims 1 to 8, or a pharmaceutically acceptable salt thereof, wherein R1is selected from:

31. The compound of Claim 1, wherein the compound is selected from Compounds 1 to 266; or a pharmaceutically acceptable salt thereof.

32. A pharmaceutical composition comprising an compound of any one of Claims 1 to 31, or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier.

33. A method of treating a proliferative disorder in a subject in need therefore, comprising administering to the subject an effective amount of a compound of any one of Claims 1 to 31, or a pharmaceutically acceptable salt thereof, or the composition of Claim 32.

34. The method of Claim 33, wherein the proliferative disorder is cancer.

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