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 THEREOFRELATED APPLICATIONS

[0001] This application claims the benefit of priority to U.S. Provisional Application No. 63 / 726.701, filed December 2, 2024 and U.S. Provisional Application No. 63 / 658,487, filed June 11 , 2024, the entire contents of each 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 DI, cyclin El). CDKs are activated by binding of their respective cyclins during specific phases of the cell cycle, triggering phosphory lation 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 tumori genesis.

[0003] Activation of CDK2 by cyclin El (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, R2, R3, R4, and p 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 DESCRIPTION1. General Description of Compounds

[0008] In a first embodiment, provided herein is a compound of Formula I:or a pharmaceutically acceptable salt thereof, whereinY is CH2, CH(CH?), or C(O);X is N or CRX;Rxis (Ci-C- alkyl or halo; p is 0, 1, or 2R1is (C1-C4)alkyl, halo(C1-C4)alkyl. halo, cyano, (C1-C4)alkoxy, or halo(Ci- C4)alkoxy;R2and R3are each independently selected from (C1-C4)alkyl, halo(C1-C4)alkyl, halo, (C1-C4)alkoxy, (C3-C6)cycloalkyl, halo(C1-C4)alkoxy. and -(C1-C4)alkylene(C3- C6)cycloalkyl, wherein said (C3-C6)cycloalkyl alone, or as part of -(C1-C4)alkylene(C3-Cejcycloalkyl is optionally substituted with 1 to 3 groups selected from RA; or R2and R?are taken together to form a (C3-C6)cycloalkyl is optionally substituted with 1 to 3 groups selected from RB;R4is benzothiazolyl or tetrahydrobenzothiazolyl, each of which are optionally substituted with 1 to 4 groups selected from Rc;Rcis selected from (Ci-C4)alkyl, halo(C1-C4)alkyl, halo, -ORV, cyano, (Ci- C4)alkyleneNRxRY, (Ci-C4)alkyleneORv. NRXRY, C(O)NRXRY, C(O)ORV, C(O)RV. (Ci- C4)alkyleneC(O)NRxRY, (Ci-C4)alkyleneC(O)ORv, (Ci-C4)alkyleneC(O)Rv, - C(O)NRXSO3H, -NRXC(O)RV, -NRXC(O)ORV, -NRXC(S)ORV, -NRXC(O)NRXRY, - NRXC(S)NRXRY, -NRXS(O)2NRXRY, -C(S)RX, -S(O)2RX, -S(O)RX. -C(S)ORV, -C(S)NRXRY, -NRXC(S)RY, -SRX, (C3-C6)cycloalkyl, (Ci-C4)alkylene(C3-C6)cycloalkyl, phenyl, (Ci- C4)alkylene[phenyl], 4- to 7- membered heterocyclyl, (Ci-C4)alkylene[4- to 7- membered heterocyclyl], 5- to 7- membered heteroaryl, and (Ci-C4)alkylene[5- to 7- membered heteroaryl]; and / or two Rcare taken together on adjacent carbon atoms to form a 5- to 7- membered heterocyclyl optionally substituted with 1 to 3 groups selected from RD;Rx, RY, and Rvare each independently selected from hydrogen, (Ci-C4)alkyl, halo(Ci-C4)alkyl, (C3-C6)cycloalkyL 4- to 7- membered heterocyclyl, 5- to 7- membered heteroaryl, phenyl and benzy l, wherein each of said (Cs-C’elcycloalkyl. 4- to 7- membered heterocyclyl, 5- to 7- membered heteroaryl, phenyl and benzyl are optionally substituted with 1 to 3 groups selected from RE; and each RA, RB, RE, and REis selected from (Ci-C4)alkyl, halo(Ci-C4)alkyl, halo, cyano, (Ci-C4)alkoxy, and halo(Ci-C4)alkoxy; provided the compound is not l-(2-(benzo[d]thiazol- 2-yl)propan-2-yl)-3-(2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-5-yl)urea or a salt thereof.Alternatively, as part of a first embodiment, Rcin the compound of Formula I, or a pharmaceutically acceptable salt thereof, is selected from (Ci-C4)alkyl, halo(Ci-C4)alkyl, halo, -ORV, cyano, -(Ci-C4)alkyleneNRxRY, -(Ci-C4)alkyleneORv, -NRXRY, -C(O)NRXRY, - C(O)ORV, -C(O)RV, -(Ci-C4)alkyleneC(O)NRxRY, -(Ci-C4)alkyleneC(O)ORv, -(Ci- C4)alkyleneC(O)Rv, -C(O)NRXSO3H, -NRXC(O)RV, -NRXC(O)ORV. -NRXC(S)ORV, - NRXC(O)NRXRY, -NRXC(S)NRXRY, -NRXS(O)2NRXRY, -C(S)RX, -S(O)2RX, -S(O)RX, - C(S)ORV, -C(S)NRXRY, -NRXC(S)RY, -SRX, (C3-C6)cycloalkyl, -(Ci-C4)alkylene(C3- Cejcycloalkyl, phenyl, -(Ci-C4)alkylene[phenyl], 4- to 7- membered heterocyclyl, -(Ci- C4)alkylene[4- to 7- membered heterocyclyl], 5- to 7- membered heteroaryl, and -(Ci- C4)alkylene[5- to 7- membered heteroaryl]; and / or two Rcare taken together on adjacent carbon atoms to form a 5- to 7- membered heterocyclyl optionally substituted with 1 to 3groups selected from RD; and Rx, RY, and Rvare each independently selected from hydrogen, (C1-C4)alkyl. halo(C1-C4)alkyl, (C3-Ce)cycloalkyl, 4- to 7- membered heterocyclyl, 5- to 7- membered heteroaryl, phenyl and benzyl, wherein each of said (C3-C6)cycloalkyl, 4- to 7- membered heterocyclyl, 5- to 7- membered heteroaryl, phenyl and benzyl are optionally substituted with 1 to 3 groups selected from RE, wherein the remaining variables are as described above for Formula I.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. -[(Ci-C6)alkyl]heteroaryl means that the point of attachment for this group occurs on the (Ci-Ce)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.. -OCHF2 or -OCF3.

[0015] As used herein, the term “alkylene” refers to divalent aliphatic hydrocarbyl groups, for example, having from 1 to 4 carbon atoms that are either straight-chained or branched. This term includes, by way of example, methylene (-CH2-), ethylene (-CH2CH2-), n-propylene (-CH2CH2CH2-), iso-propylene (-CH2CH(CH3)-), and the like.

[0016] As used herein, the term “alkenyl” denotes a monovalent group derived from a hydrocarbon moiety containing at least two carbon atoms and at least one carbon-carbon double bond. The double bond may or may not be the point of attachment to another group. Alkenyl groups (e.g., C2-Cs-alkenyl) include, but are not limited to, for example, ethenyl, propenyl, prop-l-en-2-yl, butenyl, l-methyl-2-buten-l-yl, heptenyl, octenyl and the like.

[0017] As used herein, the term "alkyny l" denotes a monovalent group derived from a hydrocarbon moiety containing at least two carbon atoms and at least one carbon-carbon triple bond. The triple bond may or may not be the point of attachment to another group. Alkynyl groups (e.g., C2-Cs-alkynyl) include, but are not limited to, for example, ethynyl, propynyl, prop-l-yn-2-yl, butynyl, 1 -methyl -2-butyn-l-yl, hepty nyl, octynyl and the like.

[0018] The term oxo means the group =0.

[0019] The term “aryl’7refers 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.

[0020] The term “heteroar ’ 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, benzooxazoly 1, 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.

[0021] 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, oxazohdinyl, piperazinyl, dioxanyl, dioxolanyl, morpholinyl, dihydrofuranyl, dihydropyranyl, dihydropyridinyl, tetrahydropy ridinyl, 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.

[0022] The term '‘spiro” refers to two rings that shares one ring atom (e.g., carbon).

[0023] The term “fused” refers to two rings that share two adjacent ring atoms with one another.

[0024] The term “bridged” refers to two rings that share three ring atoms with one another.

[0025] 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-lH-indenyl, bicyclo[2.2.1]heptanyl, bicyclo[2.2.2]octanyl, and the like.

[0026] 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 cycloalkyd 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.

[0027] It is to be understood that if an aryl, heteroaryl, cycloalkyl, or heterocyclyl moiety may be bonded or otherwise attached to a designated moiety’ through differing ring atoms (z.e., shown or described without denotation of a specific point of attachment), then all possible points are intended, whether through a carbon atom or. for example, a trivalent nitrogen atom. For example, the term “pyridinyl” means 2-, 3- or 4-pyridinyl, the term “thiophenyl” means 2- or 3-thiophenyl, and so forth.

[0028] As used herein, the term “substituted” means that an atom or group of atoms has replaced hydrogen as the substituent attached to another group.

[0029] As used herein, the articles “a” and “an” refer to one or to more than one (i.e., to at least one) of the grammatical object of the article. By way of example, “an element” means one element or more than one element. Furthermore, use of the term “including” as well as other forms, such as “include,” “includes,” and “included.” is not limiting.

[0030] As used herein, the term “about” w ill be understood by persons of ordinary skill in the art and will vary to some extent on the context in which it is used. As used herein whenreferring to a measurable value such as an amount, a temporal duration, and the like, the term “about’7is meant to encompass variations of ±20% or ±10%, including ±5%, ±1%, and ±0.1% from the specified value, as such variations are appropriate to perform the disclosed methods.

[0031] 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 to substituents oriented on the same side of the ring, whereas “trans” refers to substituents oriented on opposite sides of the ring.

[0032] 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.

[0033] 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.

[0034] 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.

[0035] 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.

[0036] The term “inhibit,” “inhibition” or “inhibiting” includes a decrease in the baseline activity of a biological activity or process.

[0037] 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 other susceptibility factors), i.e., prophylactic treatment. Treatment may also be continued after symptoms have resolved, for example to delay their recurrence.

[0038] 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 maybe 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.

[0039] For use in medicines, the salts of the compounds described herein refer to nontoxic “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 acceptablebase(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.

[0040] 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

[0041] As part of a second embodiment. Y in the compound of Formula I is is CH2 or C(O), wherein the remaining variables are as described above for Formula I.

[0042] As part of a third embodiment, p in the compound of Formula I is 0, wherein the remaining variables are as described above for Formula I or the second embodiment.

[0043] As part of a fourth embodiment, Rxin the compound of Formula I is halo, wherein the remaining variables are as described above for Formula I or any one of the second to third embodiments. Alternatively, as part of a fourth embodiment, Rxin the compound of Formula I is fluoro, wherein the remaining variables are as described above for Formula I or any one of the second to third embodiments.

[0044] As part of a fifth embodiment, R2and R3in the compound of Formula I are each independently selected from (C1-C4)alkyl, halo(C1-C4)alkyl, (C3-C6kycloalkyl, halo(Ci- C4)alkoxy, and -(C1-C4)alkylene(C3-Ce)cycloalkyl, wherein said (C3-Cg)cycloalkyl alone, or as part of -(C1-C4)alkylene(C3-C6)cycloalkyl is optionally substituted with 1 to 3 groups selected from RA; or R2and R3are taken together to form a (C3-C6)cycloalkyl is optionally- substituted with 1 to 3 groups selected from RB, wherein the remaining variables are as described above for Formula I or any one of the second to fourth embodiments. Alternatively, as part of a fifth embodiment, R2and R3in the compound of Formula I are each independently selected from (C1-C4)alkyl, halo(C1-C4)alkyl, (C3-C6)cycloalkyl, halo(Ci- C4)alkoxy, and -(C1-C4)alkylene(C3-C6)cycloalkyl; or R2and R3are taken together to form a (Cs-C6)cycloalkyl, wherein the remaining variables are as described above for Formula I or any one of the second to fourth embodiments. In another alternative, as part of a fifth embodiment, R2and R3in the compound of Formula I are each independently selected from CH3. CH2CH(CH3)2. CH(CH3)2. CH2CH3. CH2CH2F. CFhcyclopropyL and cyclopropyk orR2and R3are taken together to form cyclopropyl, wherein the remaining variables are as described above for Formula I or any one of the second to fourth embodiments.

[0045] As part of a sixth embodiment, R4in the compound of Formula I is benzothiazolyl optionally substituted with 1 to 4 groups selected from Rc, wherein the remaining variables are as described above for Formula I or any one of the second to fifth embodiments.

[0046] As part of a seventh embodiment, Rcin the compound of Formula I is selected from (C1-C4)alkyl. halo(C1-C4)alkyl, halo. -ORV, (Cs-Csjcycloalkyl, cyano, (Ci- Ci)alkylene(C -G,)cycloalkyl. phenyl, 4- to 7- membered heterocyclyl, 5- to 7- membered heteroaryl, -NRXRY, -(C2-C4)alkynyl(C3-C6)cycloalkyl), and (C1-C4)alkyleneNRxRY; and / or two Rcare taken together on adjacent carbon atoms to form a 5- to 7- membered heterocyclyl. wherein the remaining variables are as described above for Formula I or any one of the second to sixth embodiments. Alternatively, as part of a seventh embodiment, Rcin the compound of Formula I is selected from (C1-C4)alkyl, halo(C1-C4)alkyl, halo, -ORV, (C3-C6)cycloalkyl, cyano, phenyl, and (C1-C4)alkyleneNRxRY; and / or two Rcare taken together on adjacent carbon atoms to form a 5- to 7- membered heterocyclyl, wherein the remaining variables are as described above for Formula I or any one of the second to sixth embodiments. Alternatively, as part of a seventh embodiment, Rcin the compound of Formula I is selected from (C1-C4)alkyl, halo(C1-C4)alkyl, halo, -ORV, cyclopropyl, cyclopentyl, cyclobutyl, cyano, phenyl, tetrahydrofuranyl, oxazolyl, (Ci- C4)alkylene(cyclopropyl), -(C2-C4)alkynyl(cyclopropyl)-NRXRY. and (Ci-C i)alkyleneNRxR and / or two Rcare taken together on adjacent carbon atoms to form a 1,3- dioxolanyl, wherein the remaining variables are as described above for Formula I or any one of the second to sixth embodiments. Alternatively, as part of a seventh embodiment, Rcin the compound of Formula I is selected from (C1-C4)alkyl, halo(C1-C4)alkyl, halo, -ORV. cyclopropyl, cyano, phenyl, and (C1-C4)alkyleneNRxRx; and / or two Rcare taken together on adjacent carbon atoms to form a 1,3-dioxolanyl, wherein the remaining variables are as described above for Formula I or any one of the second to sixth embodiments.

[0047] As part of an eighth embodiment, Rvin the compound of Formula I is selected from hydrogen, (C1-C4)alkyl, halo(C1-C4)alkyl, (C3-C6)cycloalkyl, and 4- to 7- membered heterocyclyl, wherein the remaining variables are as described above for Formula I or any one of the second to seventh embodiments. Alternatively, as part of an eighth embodiment, Rvin the compound of Formula I is selected from hydrogen, (C1-C4)alkyl, halo(C1-C4)alkyl, cyclopropyl, cyclopentyl, cyclobutyl, cyclobutyl, -(C1-C4)alkylene(cyclopropyl). and pyrrolidinyl, wherein the remaining variables are as described above for Formula I or any oneof the second to seventh embodiments. Alternatively, as part of an eighth embodiment, Rvin the compound of Formula I is selected from hydrogen, (Ci-C- alkyl, halo(Ci -Chalky 1. cyclopropyl, and pyrrolidinyl, wherein the remaining variables are as described above for Formula I or any one of the second to seventh embodiments.

[0048] In a ninth embodiment, Rxand RYin the compound of Formula I are each independently hydrogen or (C1-C4)alkyl, wherein the remaining variables are as described above for Formula 1 or any one of the second to eighth embodiments.

[0049] In a tenth embodiment, Rcin the compound of Formula I is selected fromabove for Formula I or any one of the second to ninth embodiments.

[0050] Additional compounds are described and exemplified herein, and are included in the present disclosure. Pharmaceutically acceptable salts thereof as well as the neutral forms of such compounds are included.4. Uses, Formulation and Administration

[0051] 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.

[0052] 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.

[0053] 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.

[0054] 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.

[0055] 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, intrastemal, 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.

[0056] In some aspects, the pharmaceutical compositions are administered orally.

[0057] 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.EXEMPLIFICATIONPreparation of Compounds

[0058] 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.

[0059] Intermediates

[0060] Intermediate A; Carbamates coupling partners

[0061] Carbamate coupling partners were made according to several general procedures as follows:

[0062] Intermediate A-l; Phenyl (2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-5- yllcarbamate

[0063] Step - 1: methyl 2-(bromomethyl)-4-nitrobenzoate and methyl 2- (dibromomethyl)-4-nitrobenzoate

[0064] To a stirred solution of methyl 2-methyl-4-nitrobenzoate (5 g, 26 mmol) in carbon tetrachloride (150 mL). / V-bromosuccinimide (6.8 g, 38 mmol) and dibenzoyl peroxide, (0.93 g, 3.8 mmol) was added. The reaction mixture was heated at 85 °C 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 %.

[0065] Step - 2: methyl 2-(bromomethyl)-4-nitrobenzoate

[0066] 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 0 °C. 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 (2 x 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 %. 'H NMR (400 MHz. DMSO-de): 5 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).

[0067] Step - 3: 3-(5-nitro-l-oxoisoindolin-2-yl)piperidine-2, 6-dione

[0068] 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 0 °C, ALV-diisopropylethylamine (3.8 g, 30 mmol) were added. The reaction mass was heated to 85 °C 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-l-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 - punty: 82 %. 1H NMR (400 MHz, DMSO-d6): 5 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).

[0069] Step - 4: 3-(5-amino-l-oxoisoindolin-2-yl)piperidine-2, 6-dione

[0070] To a stirred solution of 3-(5-nitro-l-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 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 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-l -oxoisoindolin-2-yl)piperidine-2, 6-dione as a pale purple solid (3.0 g, 67 %). MS (ESI) z 260.24 [M+H]+. LC-MS - purity: 93%.

[0071] Step - 5 : phenyl (2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-5-yl)carbamate

[0072] A suspension of 3-(5-amino-l-oxoisoindolin-2-yl)piperidine-2, 6-dione (5 g, 19 mmol) and phenyl chloroformate (150 mL) was heated under stirring at 70 °C 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 fdtered, 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)- l-oxoisoindolin-5-yl)carbamate (2.5 g, 34 %) as an off white solid. MS (ESI) m / z 380.49. LC- MS purity: 96 %. 'H NMR (400 MHz, DMSO-rfc): 8 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).

[0073] Intermediate A-2: Phenyl (2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-5- vDcarbamate

[0074] To a stirred solution of 5-amino-2-(2,6-dioxopiperidin-3-yl)isoindoline-l ,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 70 °C 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 compound which was triturated with diethyl ether (20 mL) and dried under reduced pressure to afford phenyl (2-(2,6-dioxopiperidin-3-yl)-l-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]+;

[0075] Intermediate A-3: Phenyl (6-(2,6-dioxopiperidin-3-yl)-5-oxo-6.,7-dihvdro-5H- py rrolo [3,4-b ] py ridin-2-yl)carbamate

[0076] Step-1: Synthesis of Methyl 6-chloro-4-methylnicotinate

[0077] To a stirred solution of 6-chloro-2-methylnicotinic acid (10 g, 58 mmol) inPOCI3 (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 POCL was evaporated and the residue was quenched with MeOH. The solvent was evaporated and the residue was taken in sat. NaHCCh solution and stirred for 15 min. The residue was extracted by DCM (3 x 30 mL) and the combined organic layers were dried over anhydrous MgSCh and 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]+:

[0078] Step-2: Synthesis of methyl 2-(bromomethyl)-6-chloronicotinate:

[0079] 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 gel column 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 o / / - white solid. MS (ESI) m / z 264.02 [M+H]+.

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

[0081] 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-67 / -pyrrolo[3,4-b]pyridin-6-yl)piperidine-2, 6-dione (1.5 g, 57%). MS (ESI) m / z 280.17 [M+H]+.

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

[0083] In a sealed tube, to a stirred solution of 3-(2-chloro-5-oxo-5,7-dihydro-677- pyrrolo[3,4-b]pyridin-6-yl)piperidine-2.6-dione (1 g, 3.6 mmol) in 1.4-di oxane (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 ofXantphos (0.21 g, 0.36 mmol) and Pd2dbas (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-dioxopiperi din-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]+.

[0084] Step-5: Synthesis of 3-(2-amino-5-oxo-5,7-dihydro-61Z-pyrrolo[3,4-b]pyridin- 6-yl)piperidine-2, 6-dione:

[0085] To a stirred solution of tert-butyl (6-(2,6-dioxopiperidin-3-yl)-5-oxo-6,7-dihydro- 5 / 7-pyrrolo[3,4-b]pyridin-2-yl)carbamate (0.7 g, 1.9 mmol) in DCM (1.4 mL), was added 4M HCI 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]+.

[0086] Step-6: Phenyl (6-(2,6-dioxopiperidin-3-yl)-5-oxo-6,7-dihydro-5H- pyrrolo [3,4-b] pyridin-2-yl)carbamate

[0087] To a stirred solution of 3-(2-amino-5-oxo-5,7-dihydro-6H-pyrrolo[3,4-b]pyridin- 6-yl)pipendine-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-577-pyrrolo[3,4-b]pyridin-2-yl)carbamate (0.25 g, 68%) as an oj^white solid. MS (ESI) m / z 381.43 [M+H]+

[0088] Intermediate A-4; tert- butyl (6-(2,6-dioxopiperidin-3-yl)-5,7-dioxo-6,7- dihvdr()-5 / / -pyn ()lo|3.4-b|pyridin-2-yl)carbamate

[0089] Step-1: 6-bromopyridine-2,3-dicarboxylic acid

[0090] To a solution of CC14 (300 mL) and NaOCl (600mL) was added Rut (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% HC1 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-cL) 3 13.90 (br s, 2H), 8.28 (d, J= 8.4 Hz, 1H), 7.75 (d, J= 8.4 Hz, 1H)

[0091] Step-2 ; 2-bromo-6-(2,6-dioxopiperidin-3-yl)-5J / -p yrrolo [3,4-b] pyridine- 5,7(6H)-dione

[0092] 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)-5 / 7-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%. 'H-NMR (400 MHz, DMSO-rfe ) 5 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).

[0093] Step-3; tert-butyl (6-(2,6-dioxopiperidin-3-yl)-5,7-dioxo-6,7-dihydro-5 / 7- pyrrolo [3,4-b ] p yridin-2-yl)carbamate

[0094] To a stirred solution of 2-bromo-6-(2,6-dioxopiperidin-3-yl)-527-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 Zert-butyl (6-(2,6-dioxopiperidin-3-yl)-5,7- dioxo-6,7-dihydro-5 / / -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-tL) 5 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).

[0095] Intermediate A-5; Phenyl (2-(2,6-dioxopiperidin-3-yl)-4-fluoro-l- oxoisoindolin-5-yl)carbamate

[0096] Step-1: 4-Bromo-2-fluoro-3-methylaniline

[0097] 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)-lH-indole-l -carboxylate (2) (17 g, 52% ) as a colorless solid . MS (ESI) m / z 203.00 [M+H]+, LC-MS purity : 97.34 %. 'H-NMR (400 MHz. CDC13) 6 7.09 (dd, J= 8.4, 1.6 Hz, 1H), 6.49 (t, J= 8.8 Hz, 1H). 3.68 (s, 2H).

[0098] Step-2; Methyl 4-amino-3-fluoro-2-methylbenzoateeCO, NaOAc, PdCI2(dppf)

[0099] 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 PdCh(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 120 °C 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 . 'H-NMR (400 MHz, CDCls ) 5 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).

[0100] Step-3; Methyl 4-( butoxycarbonyl)amino)-3-fluoro-2-methylbenzoate

[0101] 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 800C 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-((terAbutoxycarbonyl)amino)-3-fluoro-2-methylbenzoate (4) (5.5 g, 25%) as a product. MS (ESI) m / z 283.1 [M+H]+;

[0102] Step-4: Methyl 2-(bromomethyl)-4-(ftgr / -butoxycarbonyl)amino)-3- fluorobenzoate

[0103] To a solution of methyl 4-((fert-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]+.

[0104] Step- Butyl (2-(2,6-dioxopiperidin-3-yl)-4-fluoro-l-oxoisoindolin-5-vDcarbamate

[0105] To a stirred solution of methyl 2-(bromomethyl)-4-((terZ- 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-l-oxoisomdolin-5-yl)carbamate (2.4 g, 58%) as violet solid. MS (ESI) m / z 377.1 [M+H]+.

[0106] Step-6 : 3-(5-Amino-4-fhioro- l-oxoisoindolin-2-yl)piperidine-2, 6-dione

[0107] To a stirred solution of tert-butyl (2-(2,6-dioxopiperidin-3-yl)-4-fluoro-l- 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 Ih. 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-l-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 puritv: 92.15%.

[0108] Step-7 ; phenyl (2-(2,6-dioxopiperidin-3-yl)-4-fluoro-l-oxoisoindolin-5-

[0109] To a stiired solution of 3-(5-amino-4-fluoro-l-oxoisoindolin-2-yl)piperidine- 2, 6-dione (1 g, 3.6 mmol) in acetonitrile (23 mL) and water (3 mL) at room temperature, phenyl carbonochloridate (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-l-oxoisoindolin-5-yl)carbamate (0.9 g, 63%) as a product. MS (ESI) m / z 397.1 [M+H]+, LC-MS purity: 80.84%.

[0110] Intermediate A-6; Phenyl (2-(2,6-dioxopiperidin-3-yl)-4-fliioro-l,3- dioxoisoindolin-5-yl)carbamate

[0111] Step-1: 4-bromo-3-fluorophthalic acid

[0112] 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 HC1 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 fdtered 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 NaHCCL solution (30 mL). The aqueous layer was washed with ethyl acetate (3 x 200 mL). The aqueous layer was acidified with IM HC1 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 sodiumsulphate and concentrated under reduced pressure to afford 4-bromo-3-fluorophthalic acid (2) (7.5 g, 62%) as an « / / -white solid. MS (ESI) m / z 261.9 [M-H]’.

[0113] Step-2: Synthesis of5-bromo-2-(2,6-dioxopiperidin-3-yl)-4-fhioroisoindoline-1, 3-dione

[0114] 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 o / / - white solid. MS (ESI) m / z 355.25[M+H]+.

[0115] Step-3: Synthesis of tert-butyl (2-(2,6-dioxopiperidin-3-yl)-4-fluoro-l,3- dioxoisoindolin-5-yl)carbamate

[0116] 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 at40 °C to afford / c77-butyl (2-(2,6-dioxopiperidin-3-yl)-4-fluoro-L3-dioxoisoindolin-5- yl)carbamate (0.8 g, 72 %) as grey solid (5). MS (ESI) m / z 390.5 [M-H]’.

[0117] Step-4: Synthesis of5-amino-2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindoline- 1, 3-dione

[0118] To a stirred solution of tert-butyl (2-(2,6-dioxopiperidin-3-yl)-4-fluoro-L3- 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-l, 3-dione (6) (0.3 g, 73%) as grey solid. MS (ESI) m / z 292.42 [M+H]+.

[0119] Step-5: Phenyl (2-(2,6-dioxopiperidin-3-yl)-4-fluoro-l,3-dioxoisoindolin-5- yl)carbamate

[0120] 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 o / - white solid. MS (ESI) m / z 412.50 [M+H]+.

[0121] Intermediates B: Amine coupling partners

[0122] Amine coupling partners were made according to several general procedures as follows:

[0123] Amine coupling partners general procedure B:

[0124] General procedure B-l: Intermediate B-l: 2-(6-bromobenzo|r / |thiazol-2- yl)propan-2-amine hydrochloride

[0125] Step-1: 2-(6-bromobenzo[<Z|thiazol-2-yl)propan-2-ol

[0126] To a solution of 6-bromobenzo[< ]thiazole (3.0 g, 14 mmol, 1.0 equiv.) in DMF (30 mL), Sodium tert-butoxide, 98%, pure (4.8 g, 50 mmol, 3.6 equiv.) was added at -20 °C. The reaction mixture w as stirred under argon gas for 10 minutes, Acetone, 99+%, for spectroscopy (1.2 mL, 15 mmol. 1.1 equiv.) was added at -20 °C. The reaction mixture was stirred at room temperature for Ih under argon gas. The progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, the reaction mixture was quenched with ice cold w ater (40 mL), extracted with ethyl acetate (2 x 50 mL). The combined organic layer was washed with brine solution (35 mL), dried over anhydrous sodium sulphate and concentrated under reduced pressure to afford crude as yellow liquid. The crude was purified by silica gel flash chromatography using 0 to 30% EtOAc in petroleum ether as eluent to afford 2-(6-bromobenzo[d]thiazol-2-yl)propan-2-ol (1 g, 26 %) as yellow solid. MS (ESI) m / z 270.97 [M+H]+, LC-MS purity : 80%.

[0127] Step-2: 2-(2-azidopropan-2-yl)-6-bromobenzo[rf]thiazole(i) Thinyl chloride,DMSO, 60 °C, 16 h

[0128] Step-I: 2-(6-bromobenzo[<7]thiazol-2-yl)propan-2-ol (0.7 g, 2.6 mmol, 1.0 equiv.) was added in Thionyl chloride, 99.7% (1.8 mL) at 0 °C under argon gas. The reaction mixture was stirred at 0 °C for 1 h under argon atmosphere, the reaction monitored by TLC and LCMS. The reaction was concentrated to get the crude (0.7 g) Step-II: To a solution of Crude (0.7 g, 2.572 mmol, 1.0 equiv.) in DMSO (7.00 mL) was added Sodium azide, 99%, extra pure (0.334 g, 5. 144 mmol, 2.0 equiv.). The reaction mixture was stirred at 50 °C for 16 h under N2 atmosphere. The progress of the reaction was monitored by TLC and LCMS. After completion of reaction, the reaction mixture was quenched with aq NaHCCL (20 mL) andextracted with EtOAc (3 x 20 mL). The combined organic layer was washed with brine solution (20 mL), dried over anhydrous sodium sulphate and concentrated under reduced pressure to afford crude as red liquid. The crude was purified by silica gel flash chromatography using 0 to 30% EtOAc in petroleum ether as eluent to afford 2-(2- azidopropan-2-yl)-6-bromobenzo[d]thiazole (0.5 g, 65 %) as yellow oil. MS (ESI) m / z 295.97 [M+H] , LC-MS punty : 74%.

[0129] Step-3; 2-(6- 2-yl)propan-2-amine hydrochlorideZinc, Ammonium

[0130] To a solution of 2-(2-azidopropan-2-yl)-6-bromobenzo[d]thiazole (0.5 g, 1.7 mmol, 1.0 equiv.) in Methanol (5.0 mL), Ammonium formate, 97% (0.53 mL, 8.4 mmol, 5.0 equiv.) was added followed by the addition of Zinc powder (0.17 g, 2.5 mmol, 1.5 equiv.) . The reaction mixture was stirred at room temperature for 16 h under N2 atmosphere. The progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, the reaction mixture was concentrated to get the crude. Reaction was quenched by sat. Aq. NH4CI solution and extracted by 10 % MeOH:DCM (2 X 30 mL. The combined organic layer was washed with brine solution (20 mL), dried over anhydrous sodium sulphate and concentrated under reduced pressure to afford crude as colorless liquid. Crude was added with dioxane HC1 and resultant salt product was triturated with diethyl ether (3 times) to get the pure

[0131] General procedure B-2; Intermediate B-2; 2-(benzok / |thiazol-2-yl)propan-2- amine

[0133] 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 reactionmixture 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 rnL), 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 %.

[0134] Step-2: 2-(benzo[rf]thiazol-2-yl)-2-methylpropanenitrile

[0135] To a solution of 2-(benzo[< / ]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 N2 atmosphere 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 %.

[0136] Step-3: 2-(benzo[rf|thiazol-2-yl)-2-methylpropanamide

[0137] To a solution of 2-(benzo[d]thiazol-2-yl)-2-methylpropanenitrile (0.4 g, 2.0 mmol) in formic acid, (4 mL), HC1 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 silicagel 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 %. 'H NMR (400 MHz, DMSO-r6) : 5 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).

[0138] Step-4: 2-(benzo[rf]thiazol-2-yl)propan-2-amine

[0139] To a solution of 2-(benzo[<7]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 l,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 HC1 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%.

[0140] General procedure B-3: Intermediate B-3: 2-(6-Methoxybenzo[<Z|thiazol-2- yl)propan-2-amine

[0141] Step- propanenitrile

[0142] To a stirred solution of isobutyronitrile (0.67 mL, 7.5 mmol) in toluene (15 mL) at 0 °C under nitrogen atmosphere was added sodium bis(trimethylsilyl)amide (1.4 g, 7.5 mmol) and stirred for 15 mins. Then, 2-chloro-6-methoxybenzo|<7|thiazolc (1 g, 5.009 mmol) was added to the reaction mixture and the resulting reaction mixture was stirred at 0 °C for 2 h. The reaction was monitored by TLC and LCMS. After the completion of the reaction, the reaction mixture was quenched with aq. ammonium chloride solution (100 mL) and extractedwith ethyl acetate (3 x 250 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 100-200 mesh and the compound was eluted in 4-5 % EtOAc : w-hexane to afford 2-(6- methoxybenzo[<7]thiazol-2-yl)-2-methylpropanenitrile (0.865 g, 74%) as colorless liquid. MS (ESI) m / z 233.1 [M+H]+.

[0143] Step-2: 2-(6-VIethoxybenzo|r / |thiazol-2-yl)-2-methylpropanamide

[0144] To a solution of 2-(6-methoxybenzo[<7]thiazol-2-yl)-2-methylpropanenitrile (0.3 g, 1.3 mmol, 1.0 equiv.) in formic acid, 98+%, pure (3 mL), HC1 gas was purged while stirring condition at 60 °C for 2 h under N2 atmosphere. The reaction was monitored by TLC and LCMS. After the completion of the reaction, the reaction mixture was quenched with ice water (15 mL) and extracted with EtOAc (2 x 150 mL). The combined organic layers were washed with brine solution (5 mL), dried over anhydrous sodium sulphate and concentrated under reduced pressure to afford crude as yellow liquid. The crude was purified by silica gel flash chromatography using 0 to 30% EtOAc in petroleum ether as eluent to afford 2-(6- methoxybenzo[<7]thiazol-2-yl)-2-methylpropanamide (4) (0.25 g, 77 %) as a white solid. MS (ESI) m / z 251.1 [M+H]+.

[0145] Step-3: 2-(6-Methoxybenzo[rf]thiazol-2-yI)propan-2-amine

[0146] To a solution of benzo [<7]thiazol-2-yl)-2-methylpropanamide (0.2 g. 0.8 mmol, 1.0 equiv.) in acetonitrile (1.0 mL) and water (1.0 mL). was added potassium hydroxide (0.18 g.3.2 mmol, 4.0 equiv.) at 0 °C. The reaction mixture was stirred at 0 °C with argon gas for 10 minutes, then l,3-dibromo-5,5-dimethylhydantoin, 98% (0.11 g, 0.4 mmol, 0.5 equiv.) was added. The reaction mixture was stirred at room temperature for 1 h under N2 atmosphere, the reaction was monitored by TLC and LCMS. After the completion of the reaction, the reaction mixture was quenched with ice water (15 mL) and extracted with EtOAc (2 x 250 mL). The combined organic layers were washed with brine solution (5 mL),dried over anhydrous sodium sulphate and concentrated under reduced pressure to afford crude as an yellow liquid. The crude was purified by silica gel flash chromatography using 0 to 30% EtOAc in petroleum ether as eluent to afford 2-(6-methoxybenzo|c / |thiazol-2- yl)propan-2-amine (0.13 g, 74 %) as an colorless oil. MS (ESI) m / z 224.1 [M+H]+

[0147] General procedure B-4: Intermediate B-4-1; l-(6-bromobenzo[rf]thiazol-2- vDcydopropan-l-amine

[0148] Step-1: Synthesis of l-(6-chlorobenzo[r / ]thiazol-2-yl)cyclopropane-l- carbonitrileD^CNNaHMDS,

[0149] To a stirred solution of cyclopropanecarbonitrile (0.405 g. 6.04 mmol) in Toluene (15 mL) at 0 °C under nitrogen atmosphere was added sodium bis(trimethylsilyl)amide (1.1 g, 6.04 mmol) and stirred for 15 mins. Then, 6-bromo-2-chlorobenzo[<7]thiazole (1.0 g, 4.024 mmol) was added to the reaction mixture and the resulting reaction mixture was stirred at 0 °C for 3 h. the reaction was monitored by TLC and LCMS. After the completion of the reaction, the reaction mixture was quenched with aq. ammonium chloride solution (100 mL) and extracted with ethyl acetate (3 x 250 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 100- 200 mesh and the compound was eluted in 4-5 % EtOAc : Pet ether to afford of l-(6- chlorobenzo[<7]thiazol-2-yl)cyclopropane-l-carbonitrile (0.5 g, 40-50 %) as an yellow solid. MS (ESI) m / z 281.04 [M+H]".

[0150] Step-2: 2-(6-bromobenzo[r / |thiazol-2-yl)-4-chlorobutanamideFormic acid,

[0151] To a solution l-(6-bromobenzo[J]thiazol-2-yl)cyclopropane-l -carbonitrile (0.5 g, 1.8 mmol) in Formic acid, 98+%, pure (10.0 mL). HC1 gas were purged in stirring condition at 60 °C for 2 h under N2 atmosphere. The reaction monitored by TLC and LCMS. After completion of the reaction, the mixture was quenched with ice water (15 mL) and extracted with EtOAc (2 x 150 mL). The combined organic layers were washed with brine (5 mL), dried over anhydrous sodium sulphate and concentrated under reduced pressure to afford crude as yellow solid. The crude was purified by silica gel flash chromatography using 0 to 30% EtOAc in petroleum ether as eluent to afford 2-(6-bromobenzo[<7]thiazol-2-yl)-4- chlorobutanamide (0.450 g, 75 %) as a yellow solid. MS (ESI) m / z 335 [M+H]+.

[0152] Step-3: l-(6-bromobenzo[rf]thiazol-2-yl)cyclopropane-l-carboxamide

[0153] To a solution 2-(6-bromobenzo[J]thiazol-2-yl)-4-chlorobutanenitrile (0.45 g, 1.35 mmol) in DMF (3.0 mL), potassium carbonate (0.5 g, 3.6 mmol) was added in stirring condition at room temperature. The resulting reaction mixture was heated at 100 °C for 2 h. and the reaction monitored by TLC and LCMS. After completion of the reaction, the mixture was diluted with ice water (5 mL) and extracted with EtOAc (2 x 5 mL). The combined organic layers were washed with brine solution (5 mL), dried over anhydrous sodium sulphate and concentrated under reduced pressure to afford crude as yellow liquid. The crude was purified by silica gel flash chromatography using 0 to 30% EtOAc in petroleum ether as eluent to affordl-(6-bromobenzo[J]thiazol-2-yl)cyclopropane-l -carboxamide (5) (0.390 , 80%) as a yellow solid. MS (ESI) m / z 297 [M+H]+.

[0154] Step-4: Synthesis of l-(6-bromobenzo[rf]thiazol-2-yl)cyclopropan-l-aniineKOH, 1 ,3-Dibromo-5,5- dimethylhydantoin, ACN / HpO 0 °C to r.t. 2h

[0155] To a solution of l-(6-bromobenzo[< ]thiazol-2-yl)cyclopropane-l-carboxamide (0. 1 g, 0.337 mmol) in acetonitrile (0.25 mL) and water (0.250 mL), potassium hydroxide (0.038 g, 0.67 mmol,) was added at 0 °C. The reaction mixture was purged with argon gas for 10 minutes, then l,3-Dibromo-5,5-dimethylhydantoin (0.048 g, 0.17 mmol) was added. The reaction mixture was stirred at room temperature for 16 h under N2 atmosphere. The reactionwas monitored by TLC and LCMS. After completion of the reaction, the reaction was quenched with ice water (15 mL) and extracted with EtOAc (2 x 150 mL). The combined organic layers were washed with brine solution (5 mL), dried over anhydrous sodium sulphate and concentrated under reduced pressure to afford l-(6-bromobenzo[d]thiazol-2- yl)cy cl opropan-1 -amine (0.1 g) as yellow liquid. MS (ESI) m / z 271.08 [M+H]+.

[0156] Alternatively, intermediate B-4-1 may be prepared as follows:

[0157] Intermediate B-4-2: l-(6- 2-yl)cvclopropan-l-amine

[0158] Step 1: 2-amino-5-methoxybenzenethiol

[0159] To a solution of 6-methoxybenzo[d][l,3]thiazol-2-amine (5 g, 28 mmol) in H2O(20 mL) was added KOH (9.3 g, 166 mmol). Then the mixture was stirred at 100 °C overnight under nitrogen. The mixture was cooled to room temperature. The pH of the mixture was adjusted to 5 by 6 M HCl.aq. Then the mixture was extracted with ethyl acetate. The organic layer was dried and concentrated to give 2-amino-5-methoxybenzene-l -thiol (4.8 g) as a crude. [M]+calcd: 155, found: 156.

[0160] Step 2: 2-(6-methoxybenzo[d]thiazol-2-yl)acetonitrile

[0161] To a solution of 2-amino-5-methoxybenzene-l-thiol (4.8 g, 31 mmol) in MeOH (24 mL) was added AcOH (4 mL) and propanedinitrile (2.06 g, 31 mmol). Then the mixture was stirred at 60 °C for 1 hour. The starting material was consumed, and the mixture was concentrated. The residue was diluted with water and extracted with ethyl acetate. The organic layer was dried an concentrated and purified by chromatography (silica gel, PE:EA=3: 1) to give (6-methoxybenzo[d][l,3]thiazol-2-yl)acetonitrile (3.2 g) as a crude. [M]+calcd:204,found:205. 'H NMR (400 MHz, CDCh) 5 7.91 (d. 9.0 Hz. 1H), 7.33 (d, J= 2.6 Hz. 1H), 7.12 (dd, J= 9.0, 2.6 Hz, 1H), 4.19 (s, 2H), 3.89 (s, 3H).

[0162] Step 3: l-(6-methoxybenzo[d]thiazol-2-yl)cyclopropane-l-carbonitrile

[0163] To a solution of (6-methoxybenzo[d][l,3]thiazol-2-yl)acetonitrile (2 g, 9.8 mmol) in KOH aq.(50 %,15 mL) was added TBAB (16 mg, 0.049 mmol). Then the mixture was warmed up to 50 °C and 1,2-dibromoethane (1.7 mL, 20 mmol) was added. The mixture was stirred at 50 °C for 2 hours. LCMS analysis showed the starting material was consumed. The mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with brine and dried and concentrated. The residue was purified by chromatography (silica gel PE:EA=3: 1) to give l-(6-methoxybenzo[d][l,3]thiazol-2-yl)cyclopropane-l- carbonitrile (1.3 g, 5.6 mmol, 57%). [M]+calcd:230,found:231.

[0164] Step 4: l-(6-methoxybenzo[d]thiazol-2-yl)cyclopropane-l-carboxamide

[0165] l-(6-methoxybenzo[d][1.3]thiazol-2-yl)cyclopropane-l-carbonitrile (1.3 g, 5.6 mmol) was dissolved in H2SO4 (12 mL) and the mixture was stirred at room temperature overnight. LCMS analysis showed the starting material was consumed. The mixture was basified by 4 N NaOH aq., diluted with water, and extracted with ethyl acetate. The organic layer was dried and concentrated and purified by chromatography silica gel, (DCM: MeOH=10: l) to give l-(6-methoxybenzo[d][l,3]thiazol-2-yl)cyclopropane-l-carboxamide (800 mg, 3.2 mmol, 58%). [M]+calcd:248, found:249.

[0166] Step 5: l-(6-methoxybenzo[d]thiazol-2-yl)cyclopropan-l-amine

[0167] Bromine (64 mg. 0.40 mmol) was added dropwise to the NaOH aq (50 %, 4 mL) at 0 °C. The the mixture was stirred at 0 °C for 5 minutes followed by the addition of 1 -(6- methoxybenzo[d][l,3]thiazol-2-yl)cyclopropane-l -carboxamide (100 mg, 0.40 mmol). The mixture was stirred at room temperature for 20 minutes and then warmed up to 75 °C and stirred for 2 hours. The starting material was consumed. The mixture was purified by prep- HPLC to give l-(6-methoxybenzo[d][l,3]thiazol-2-yl)cyclopropan-l-amine (55 mg, 0.25 mmol, 62%). [M]+calcd:220,found:221. ’H NMR (400 MHz, DMSO) 5 7.66 (dd, J= 13.8,8.8 Hz, 1H), 7.54 (dd, J= 25.8, 2.6 Hz, 1H), 7.00 (dd, J= 8.8, 2.6 Hz, 1H). 3.81 (d, J = 3.6 Hz. 3H), 2.86 (s, 2H), 1.38 (dd, J= 7.0, 3.8 Hz, 2H), 1.22 (dd, J= 12, 4.0 Hz, 3H).

[0168] General procedure B-5: Interme iate B-5: 2-(4-(trifluoromethoxy)benzo[< / |thiazol-2-yl)propan-2-amine

[0169] Step - 1: 4-(trifliioromethoxy)benzo[r / |thiazol-2-amineAmmonium thiocyanate pottasium thiosulfide,

[0170] To a mixture of 2-(trifluoromethoxy (aniline (15 g, 85 mmol) in HC120% (50 mL), ammonium thiocyanate (16 g, 210 mmol) was added and the resulting mixture stirred in at room temperature for 15 - 30 minutes. Then added potassium hydrogen sulfide (0.6 g) to the reaction mixture and stirred at 90°C for 16 h . Precipitation was observed and was filtered dried under high vaccum to afford 5 g of intermediate which was dissolved in carbon tetrachloride (50 mL) followed by the addition of bromine solution (2 mL in 10 mL of carbon tetrachloride at room temperature. The resulting reaction mixture was stirred for 16 h at 80°C. The progress of the reaction was monitored by TLC and LCMS. After completion of the reaction most of the solvent was evaporated, aq. ammonia (50 mL) was added and the solution stirred vigorously for 30 minutes. The reaction was extracted by DCM ( 2X200 mL) to afford crude product. The crude product was purified over silica gel column chromatography using 100-200 mesh silica gel, desired compound was eluted in 4 - 5 % EtOAc : Pet ether to afford 4-(trifluoromethoxy)benzo[d]thiazol-2-amine (5 g, 25.21%) as an off white solid. MS (ESI) m / z 233.3[M+H]+.

[0171] Step - 2: 2-chloro-4-(trifluoromethoxy)benzo[r / | thiazole tert-Butyl nitrite,

[0172] t-Butyl nitrite (1.166 mL,9.607 mmol) was added to a suspension of copper (II) chloride (1 g, 8.3 mmol) in acetonitrile (15 mL). 4-(trifluoromethoxy)benzo[t ]thiazol-2- amine (1.5 g, 6.4 mmol) was added portion wise over ~30 min and the reaction mixture was stirred at room temperature for 3 h. The reaction progress was monitored by LCMS and TLC. After the completion of the reaction, the reaction mixture was quenched with 20% aqueous HC1 (20 mL) and extracted with ethyl acetate (3 x 100 mL). The combined organic layers were dried over sodium sulphate, filtered and the filtrate was concentrated under reduced pressure to afford crude product. The crude was purified over silica gel column chromatography using 100-200 mesh silica gel and the compound was eluted in 1 - 2 % EtOAc:Pet ether to afford 2-chloro-4-(trifluoromethoxy)benzo[[d]thiazole (1 g. 62%) as an off white solid. MS (ESI) m / z 253.94 [M+H]+.

[0173] Step - 3: 2-methyl-2-(4-(trifliioromethoxy)benzo[r / ]thiazol-2-yl)propanenitrile

[0174] To a stirred solution of isobutyronitrile (0.48 mL,5.9 mmol) in Toluene (15 mL) at 0 °C under nitrogen atmosphere was added sodium bis(trimethylsilyl)amide (1.09 g, 5.9 mmol) and stirred for 15 mins. Then, 2-chloro-4-(trifluoromethoxy)benzo[i / ]thiazole (1 g .3.9 mmol) was added to the reaction mixture and the resulting reaction mixture was stirred at 0 °C for 3 h. After the completion of the reaction, the reaction mixture was quenched with aq. ammonium chloride solution (100 mL) and extracted with ethyl acetate (3 x 100 mL). The combined organic layers were dried over sodium sulphate, filtered and the filtrate was concentrated under reduced pressure to afford (0.8 g. 70%) crude 2-methyl-2-(4- (trifluoromethoxy)benzo[[dt]hiazol-2-yl)propanenitrile which was used for next reaction without further purification. MS (ESI) m / z 287.4 [M+H]+.

[0175] Step - 4: 2-methyl-2-(4-(trifluoromethoxy)benzo[d]thiazol-2-yl)propanamide

[0176] To a solution 2-methyl-2-(4-(tri fluoromethoxy )benzo|c / |thiazol-2- yl)propanenitrile (0.8 g, 2.8 mmol) in Formic acid, (6 mL), HC1 gas was purged in stirringcondition at 60 °C for 2 h under N2 atmosphere, the reaction monitored by TLC and LCMS. After completion of the reaction, the reaction mixture was quenched with ice water (15 mL) and extracted with EtOAc (2 x 150 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 as yellow solid. The crude was purified by silica gel flash chromatography using 0 to 30% EtOAc in petroleum ether as eluent to afford (0.5 g, 59 %) as a white solid which was used for next reaction without further purification.. MS (ESI) m / z 305.4 [M+H]+.

[0177] Step 5: 2-(4-(trifluoromethoxy)benzo[rf]thiazol-2-yl)propan-2-aniine1 ,3-Dibromo-5,5- dimethylhydantoin

[0178] To a stirred solution of 2-methyl-2-(4-(tnfluoromethoxy)benzo|c / |thiazol-2- yl)propanamide (0.5 g, 1.6 mmol) in acetonitrile (2.5 mL) and water (2.5 mL), Potassium hydroxide (0.37 g, 6.6 mmol) was added at 0 °C. The reaction mixture was stirred at 0 °C for 10 minutes, followed by the addition of l,3-Dibromo-5,5-dimethylhydantoin, 98% (0.24 g, 0.82 mmol). The reaction mixture was stirred at room temperature for 1 h, the reaction monitored by TLC and LCMS. After completion of reaction, the reaction mixture was quenched with ice water (15 mL) and extracted with EtOAc (2 x 150 mL). The combined organic layers were washed with brine solution (5 mL), dried over anhydrous sodium sulphate and concentrated under reduced pressure to afford crude as orange solid. The crude was purified by silica gel flash chromatography using 90 to 100% EtOAc in petroleum ether as eluent to afford2-(4-(trifluoromethoxy)benzo[<7]thiazol-2-yl)propan-2-amine as a brownish sticky solid (0.2 g. 38.85 %) which was used for next reaction without further purification.MS (ESI) m / z 277.3 [M+H]+

[0179] General procedure B-6; Intermediate B-6; l-(2-(4-bromo-6- methoxy benzo [d] thiazol-2-yl)propan-2-yl)-3-(2-(2,6-dioxopiperidin-3-yl)- 1- oxoisoindolin-5-yl)urea

[0180] Step-1: Synthesis of 4-bromo-6-methoxybenzo[rf]thiazol-2-amine

[0181] To a mixture of 2-bromo-4-methoxyaniline (5 g. 25 mmol) in acetonitrile (100 mL), ammonium thiocyanate (2.8 g, 37 mmol) was added and the resulting mixture was stirred in at room temperature for 30 minutes. Then Benzyltrimethylammonium tribromide (9.7 g, 25 mmol) was added to the mixture and stirred for 16 h at room temperature. The reaction was quenched with 100 mL sat. NaHCCf and stirred vigorously for 30 minutes. The solid was filtered and washed with water. The collected solid was azeotroped twice with toluene to remove residual water. The solid was dried on HVAC (high vacuum) to give 4- bromo-6-methoxybenzo[<7]thiazol-2-amine (4.0 g,62 %,66 % purity) as yellow solid.MS (ESI) m / z 259.1 [M+H]+.

[0182] Step-2: Synthesis of 4-bromo-2-chloro-6-methoxybenzo[rf]thiazole

[0183] t-Butyl nitrite (2.8 mL, 27 mmol) was added to a suspension of copper (II) chloride (3.6 g. 27 mmol) in acetonitrile (35 mL). 4-bromo-6-methoxybenzo[<7|thiazol-2- amine (3.5 g. 13.5 mmol) was added portion wise over ~30 min at 0 °C to room temperature, and the reaction mixture was stirred for 3 h. The reaction was monitored by LCMS and TLC. After the completion of the reaction, the reaction mixture was quenched with water (30 mL) and extracted with ethyl acetate (3 x 100 mL). The combined organic layers were dried over sodium sulphate, filtered and the filtrate was concentrated under reduced pressure to afford crude 4-bromo-2-chloro-6-methoxybenzo[< / ]thiazole. The crude was purified by silica gel flash chromatography using 40% EtOAc in petroleum ether as eluent to afford 4-bromo- 2-chloro-6-methoxybenzo[d]thiazole (3.0 g, 80 %, 87 % purity) as an yellow Solid.MS (ESI) m / z 280.0 [M+H]+.

[0184] Step-3: Synthesis of 2-(4-bromo-6-methoxybenzo[r / |thiazol-2-yl)-2- methylpropanenitrile

[0185] To a stirred solution of isobutyronitrile (0.97 mL,l 1 mmol) in Toluene (38 mL) at 0°C under nitrogen atmosphere was added Sodium bis(trimethylsilyl)amide (5.4 mL, 11 mmol) and stirred for 15 mins. Then, 4-bromo-2-chloro-6-methoxybenzo|c / | thiazole (2.5 g, 8.9 mmol) was added to the reaction mixture and the resulting reaction mixture was stirred at 0 °C for 2 h. After the completion of the reaction, the reaction mixture was quenched with aq. ammonium chloride solution (50 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were dried over sodium sulphate, filtered and the filtrate was concentrated under reduced pressure to afford 2-(4-bromo-6-melhoxybenzo|t / |thiazol-2-yl)-2- methylpropanenitrile (2.3 g, 82 %,75 % purity.) as yellow solid which was was used for next step without further purification. MS (ESI) m / z 311.2 [M+H]+.

[0186] Step-4: Synthesis of 2-(4-bromobenzo[rf]thiazol-2-yl)-2-methylpropanamide

[0187] To a solution 2-(4-bromobenzo[< / ]thiazol-2-yl)-2-methylpropanenitrile (2.5 g, 8.9 mmol) in formic acid (50 mL), HC1 gas were purged in stirring condition at 80 °C for 2 h under N2 atmosphere, the reaction monitored by TLC and LCMS. After completion of the reaction, the reaction mixture was quenched with aqueous solution of sodium bicarbonate (100 mL) and extracted with ethyl acetate (2 x 150 mL). The combined organic layers were washed with brine solution (20 mL), dried over anhydrous sodium sulphate and concentrated under reduced pressure to afford crude as yellow' liquid. The crude was purified by silica gel flash chromatography using 10 to 50% EtOAc in petroleum ether as eluent to afford 2-(4-bromobenzo[c / ]thiazol-2-yl)-2-methylpropanamide (5) (1.7 g, 64 %, 85 % purity) as a white solid. MS (ESI) m / z 329.3 [M+H]+.

[0188] Step-5: Synthesis of 2-(4-bromo-6-methoxybenzo|r / |thiazol-2-yl)propan-2- amineKOH, 1,3-Dibromo-5,5-MeO dimethylhydantoin, ACN / H2O 0 °C to r.t. 2he

[0189] To a solution of 2-(4-bromo-6-methoxybenzo[<L]thiazol-2-yl)-2- methylpropanamide (1 .2 g, 3.6 mmol, 1 .0 equiv.) in acetonitrile (6 mL) and water (6 mL), potassium hydroxide (0.82 g, 15 mmol, 4.0 equiv.) was added at 0 °C. The reaction mixture was stirred at 0 °C with argon gas for 10 minutes, then l,3-Dibromo-5,5-dimethylhydantoin (0.52 g, 1.8 mmol, 0.5 equiv.) was added. The reaction mixture was stirred at room temperature for 2 h under N2 atmosphere, the reaction monitored by TLC and LCMS. After completion of the reaction, the reaction mixture was quenched with ice water (20 mL) and extracted with ethyl acetate (2 x 150 mL). The combined organic layers were washed with brine solution (20 mL), dried over anhydrous sodium sulphate and concentrated under reduced pressure to afford 2-(4-bromo-6-methoxybenzo[< / ]thiazol-2-yl)propan-2-amine (1.01 g, 92 %, 95 % purity) as brown oil . MS (ESI) m / z 301.2 [M+H]+.

[0190] General procedure B-7: Intermediate B-7: 2-(6-methoxy-4- methyl benzo [rf|thiazol-2-yl)propan-2-amine

[0191] Step-1: Synthesis of 2-(6-methoxy-4-methylbenzo[rf]thiazol-2-yl)-2-methyl propan amideTrimetyl boroxine, K2CO3,

[0192] To a stirred solution of 2-(4-bromo-6-methoxybenzo[< / ]thiazol-2-yl)-2- methylpropanamide (0.10 g, 0.304 mmol) in DMF (1.5 mL) were added trimethylboroxine (ca. 50% in tetrahydrofuran) (0.23 g, 1.8 mmol) and potassium carbonate (0.11 g, 0.76 mmol). The resulting solution was degassed with argon gas for 15 minutes followed by added Pd(PPh3)4 (0.035 g, 0.030 mmol). The reaction mixture was again degassed with argon gas for another 5 minutes and heated to 90 °C, stirred for 16 h. After completion of reaction, the reaction mixture was quenched with ice water (20 mL) and extracted with EtOAc (2 x150 mL). The combined organic layers were washed with brine solution 20 mL), dried over anhydrous sodium sulphate and concentrated under reduced pressure to afford crude. The crude was purified by silica gel flash chromatography using 0 to 30% EtOAc in petroleum ether as eluent to afford 2-(6-methoxy-4-methylbenzo[< / ]thiazol-2-yl)-2-methylpropanamide (0.040g, 50%, 91% purity ) as brown solid .MS (ESI) m / z 265.2 [M+H]+.

[0193] Step-2: Synthesis of 2-(6-methoxy-4-methylbenzo[rZ]thiazol-2-yl)propan-2- amineKOH, 1,3-Dibromo-5,5-

[0194] To a solution of 2-(6-methoxy-4-methylbenzo| / |lhiazol-2-yl)-2- methylpropanamide (0.040 g, 0.15 mmol, 1.0 equiv.) in acetonitrile (0.2 mL) and water (0.200 mL), potassium hydroxide (0.034 g, 0.61 mmol, 4.0 equiv.) was added at 0 °C. The reaction mixture was stirred at 0 °C with argon gas for 10 minutes, then l,3-Dibromo-5,5- dimethylhydantoin (0.022 g, 0.076 mmol, 0.5 equiv.) was added. The reaction mixture was stirred at room temperature for 1 h under N2 atmosphere, the reaction monitored by TLC and LCMS. After completion of reaction, the reaction mixture was quenched with ice water (20 mL) and extracted with EtOAc (2 x 50 mL). The combined organic layers were washed with brine solution 20 mL), dried over anhydrous sodium sulphate and concentrated under reduced pressure to afford 2-(6-methoxy-4-methylbenzo[<L]thiazol-2-yl)propan-2-amine (0.035 g, 98 %, 63 % purity) as a brown oil, MS (ESI) m / z 236.60 [M+H]+. Intermediate was used as is.

[0195] General procedure B-8: Intermediate B-8: 2-(6-methoxy-4- methylbenzo[rf|thiazol-2-yl)propan-2-amine

[0196] Step 1: 2-(6-Cvclopropyl-4-methoxybenzo[<Z|thiazol-2-yl)-2- methylpropanamide (1):CyclopropylBF3K,

[0197] A solution of 2-(6-chloro-4-methoxybenzo[ri]thiazol-2-yl)-2-methylpropanamide (0.4 g, 1.4 mmol) and potassium cyclopropyltrifluoroborate (0.23 g, 1.5 mmol) in toluene (7.2 mL) and water (0.8 mL) was degassed with argon gas for 15 min, followed by the addition of potassium phosphate (0.9 g, 4.2 mmol) and SPhos Pd G3 (0.11 g, 0.14 mmol). Later the resulting mixture was degassed with Ar gas for 10 minutes, heated to 80 °C and stirred for 24 h. After completion of the reaction, reaction mixture was concentrated under reduced pressure to afford crude compound. Thus obtained crude compound was purified by column chromatography (230-400 silica gel) using 35 to 40% ethyl acetate in petroleum ether as an eluent to afford 2-(6-cyclopropyl-4-methoxybenzo|<7|thiazol-2-yl)-2- methylpropanamide (0.250 g, 58%) as a pale yellow solid. MS (ESI) m'z 291.20 [M+H]+.

[0198] Step 2; 2-(6-Cvclopropyl-4-methoxybenzo[rf]thiazol-2-yl) propan-2-amine (2); 1 ,3-Dibromo-5,5- dimethylhydantoin, KOH, ACN:Water, 0 °C to RT, 1 h 2 *

[0199] To a stirred solution of 2-(6-cyclopropyl-4-methoxybenzo[ri]thiazol-2-yl)-2- methylpropanamide (0.24 g, 0.83 mmol) in a mixture of ACN (1.2 mL) and water (1.2 mL) was added potassium hydroxide (0. 19 g. 3.3 mmol) at 0 °C. The reaction mixture was stirred at 0 C for 10 min, then l,3-dibromo-5,5-dimethylhydantoin (0.12 g, 0.41 mmol) was added. Later, the reaction mixture was warmed to room temperature and stirred for 1 h under N2atmosphere. After completion of reaction, the reaction mixture was diluted with EtOAc (15 mL), washed with water (2 x 5 mL) followed by brine (10 mL). dried over Na2SO4, filtered and filtrate was concentrated under reduced pressure to afford 2-(6-cyclopropyl-4- methoxybenzo[ri]thiazol-2-yl) propan-2-amine (0.18 g, 83%) as a pale yellow solid. MS (ESI) m'z 263.32 [M+H]+.

[0200] General procedure B-8: Intermediate B-8: 2-(4-propoxybenzok / |thiazol-2- yl)propan-2-amine

[0201] Step-1: 4-propoxybenzo[rf]thiazol-2-ainineK2CO3, n-Propyl iodide ,

[0202] To a stirred solution of 2-aminobenzo[d]thiazol-4-ol (1 g, 6. mmol) in DMF (10 rnL), was added potassium carbonate (2.08 g, 15 mmol), n-Propyl iodide (0.88 mL, 9.03 mmol) at 0 °C. The resulting reaction mixture was stirred at room temperature for 16 h. The reaction was monitored as per the TLC and LCMS. After the completion of the reaction, the reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (3 x 100 mL). The combined organic layers were combined, dried over sodium sulphate, filtered and concentrated under vacuum to afford crude (1.2 g). The crude was purified over silica gel column chromatography using 100-200 mesh and the compound was eluted in 50 % EtOAc : Pet ether to afford 4-propo\ybenzo|t / |thiazol-2-amine (0.8 g, 58%) as an off white solid. MS (ESI) m / z 209.2 [M+H]+.

[0203] Step-2: 2-chloro-4-propoxybenzo[rf]thiazole

[0204] To a stirred solution of Copper(II) chloride (0.93 g , 6.9 mmol) in ACN (8 mL) at 0 °C under nitrogen atmosphere was added tert-Butyl Nitrite (0.91 g, 6.9 mmol) and stirred it for 15 mins. Then 4-propoxybenzo[d]thiazol-2-amine (0.8 g, 3.8 mmol) was added to the reaction mixture at 0 °C and the reaction was stirred at room temperature for Ih. The reaction was monitored by TLC and LCMS. After the completion of the reaction, the reaction mixture was quenched with aq. (50 mL) and extracted with ethyl acetate (3 x 250 mL). The combined organic layers were dried over sodium sulphate, filtered and the filtrate was concentrated under reduced pressure to afford crude (1.2g) solid. The crude was purified over silica gel column chromatography using 100-200 mesh and the compound was eluted in 4-5 % EtOAc : Pet ether to afford 2-chloro-4-propo.x benzo|c / | thiazole (0.560 g, 64%) as an off white solid. MS (ESI) m / z 228.2 [M+H]+.

[0205] Step-3: 2-methyl-2-(4-propoxybenzo|J|thiazol-2-yl)propanenitrile

[0206] To a stirred solution of isobutyronitrile (0.33 mL, 3.6 mmol) in Toluene (8.3 mL) at 0 °C under nitrogen atmosphere was added Sodium bis(trimethylsilyl)amide (1.6 mL, 3.1 mmol) and stirred it for 15 mins. Then, 2-chloro-4-propoxybenzo[d]thiazole (0.550 g, 2.4 mmol) was added to the reaction mixture and the resulting reaction mixture was stirred at 0 °C for 3 h. The reaction was monitored by TLC and LCMS. After the completion of the reaction, the reaction mixture was quenched with aq. ammonium chloride solution (200 mL) and extracted with ethyl acetate (3 x 250 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 100- 200 mesh and the compound was eluted in 10 % EtOAc : Pet ether to afford 2-methyl-2-(4- propoxybenzo[<7]thiazol-2-yl)propanenitrile (0.38 g, 60 %) as an off white solid. MS (ESI) m / z 260.1 [M+H]+.

[0207] Step-4: Synthesis of 2-methyl-2-(4-propoxybenzo[rf|thiazol-2-yl)propanamideFormic acid, HCI gas 60 °C

[0208] To a solution of 2-methyl-2-(4-propoxybenzo[d]thiazol-2-yl)propanenitrile (0.38 g, 1.5 mmol, 1.0 equiv.) in Formic acid, 98+%, pure (3.8 mL), HCI gas were purged under stirring condition at 60 °C for 2 h under N2 atmosphere. The reaction was monitored by TLC and LCMS. After completion of reaction, the reaction mixture was quenched with sodium bicarbonate (15 mL) and extracted with EtOAc (2 x 250 mL). The combined organic layers were washed with brine solution (5 mL), dried over anhydrous sodium sulphate and concentrated under reduced pressure to afford crude solid. The crude was purified by silica gel flash chromatography using 0 to 30% EtOAc in petroleum ether as eluent to afford 2-methyl-2-(4-propoxybenzo[<L]thiazol-2-yl)propanamide (0.26 g, 63%) as an off white solid.MS (ESI) m / z 279.3 [M+H]1.

[0209] Step-5: 2-(4-propoxybenzo[rf]thiazol-2-yl)propan-2-amineKOH, 1,3-Dibromo-5,5-

[0210] To a solution of 2-methyl-2-(4-propoxybenzo[J|thiazol-2-yl)propanamide (0.25 g, 0.9 mmol, 1.0 equiv.) in acetonitrile (1.25 rnL) and water (1.3 mL), Potassium hydroxide, ca. 85%, for analysis, pellets (0.2 g, 3.6 mmol, 4.0 equiv.) was added at 0 °C. The reaction mixture was stirred at 0 °C with argon gas for 10 minutes, then l,3-Dibromo-5,5- dimethylhydantoin, 98% (0.13 g, 0.45 mmol, 0.5 equiv.) was added. The reaction mixture was stirred at room temperature for 1 h under N2 atmosphere, the reaction monitored by TLC and LCMS. After completion of reaction, the reaction mixture was quenched with ice water (15 mL) and extracted with EtOAc (2 x 150 mL). The combined organic layers were washed with brine solution (5 mL), dried over anhydrous sodium sulphate and concentrated under reduced pressure to afford crude as a yellow liquid. The crude was purified by washed with petroleum ether as eluent to afford 2-(4-propoxybenzo|<7|thiazol-2-yl)propan-2-amine (0. 110 g, 48 %) as an off white solid .MS (ESI) m / z 251.2 [M+H]+.

[0211] General procedure B-9: Intermediate B-9: 2-(5-bromobenzo[d]thiazol-2- yl)propan-2-amine

[0212] Step-1: Synthesis of 2-(5-bromobenzo[r / ]thiazol-2-yI)propan-2-oI

[0213] To a solution of 5-bromobenzo[d]thiazole (3 g, 14 mmol) in DMF (30 mL), Sodium tert-butoxide, (4.8 g. 50 mmol) was added at - 10 °C. The reaction mixture was stirred under argon gas for 10 minutes at -10 °C, Acetone, 99+%, for spectroscopy (1.2 mL, 15 mmol) was added and the resulting reaction mixture was stirred at room temperature for 2 h. The progress of the reaction was monitored by TLC and LCMS. After completion of reaction, the reaction mixture was quenched with water (20 mL) and extracted with EtOAc (3 x 250 mL). The combined organic layers were washed with brine solution (20 mL). dried over anhydrous sodium sulphate and concentrated under reduced pressure to afford crude as yellow7liquid. The crude w as purified by silica gel flash chromatography using 40% EtOAcin petroleum ether as eluent to afford 2-(5 -bromobenzo |t / |lhiazol-2-yl)propan-2-ol (1.3 g, 34%) as light yellow liquid. MS (ESI) m / z 272.05 [M+H]+.

[0214] Step-2: Synthesis of 2-(2-azidopropan-2-yl)-5-bromobenzo[d]thiazole

[0215] Step-I : To a stirred solution of 2-(5-bromobenzo[d]thiazol-2-yl)propan-2-ol (1.2 g, 4.409 mmol), cooled at 0 °C, then added thionyl chloride, (3.0 mL). The reaction mixture was stirred at room temperature for 1 h under nitrogen atmosphere then evaporated under reduced pressure to get crude product (0.950g ).

[0216] Step-II: To a stirred solution of crude 5-bromo-2-(2-chloropropan-2- yl)benzo[d]thiazole (0.9 g, 3.1 mmol) in DMSO (9 mL), Sodium azide, (0.604 g, 9.3 mmol) was added. The reaction mixture was stirred at 60 °C for 16 h under N2 atmosphere. The progress of the reaction was monitored by TLC and LCMS. After completion of reaction, the reaction mixture was quenched with Aq NaHCOs (20 mL) and extracted with EtOAc (3 x 250 mL). The combined organic layers were combined and washed with brine solution (20 mL), dried over anhy drous sodium sulphate and concentrated under reduced pressure to afford crude as red liquid. The crude product, which was purified by column chromatography using devisil silica and 10 % ethyl acetate as eluent to 2-(2-azidopropan-2-yl)-5- bromobenzo[d]thiazole (0.850 g, 92%) as an yellow light oil. MS (ESI) m / z 297.4 [M+H]+.

[0217] Step-3: Synthesis of 2-(5-bromobenzo[d]thiazol-2-yl)propan-2-amine

[0218] To a stirred solution of 2-(2-azidopropan-2-yl)-5-bromobenzo[< ]thiazole (0.8 g, 2.7 mmol,) in methanol (8.0 mL), was added ammonium formate (0.85 g, 13 mmol) and Zinc (0.26 g, 4.04 mmol). The reaction mixture was stirred at room temperature for 2 h under N2 atmosphere. The progress of the reaction was monitored by TLC and LCMS. After completion of reaction, the reaction mixture was quenched with water (20mL) and extracted with DCM (3 x 150 mL). The combined organic layer was washed with brine solution (20 mL), dried over anhydrous sodium sulphate and concentrated under reduced pressure to afford crude as red liquid. The crude product, which was purified by column chromatography using devisil sihca and 70% ethyl acetate as eluent to 2-(5-bromobenzo[< ]thiazol-2- yl)propan-2-amine (0.65 g, 89 %) as an off white solid. MS (ESI) m / z 271.06 [M+H]+.

[0219] General procedure B-10; Intermediate B-10; 2-(4-Methoxy-4,5,6,7- tetrahydrobenzo [ dl thiazol-2-yl)propan-2-amine

[0220] Step-1: 3-Bromocyclohexane-l, 2-dione

[0221] To a solution of cyclohexane- 1,2-dione (5 g. 45 mmol) in diethyl ether(50 mL) was added bromine (7. 1 g, 45 mmol) in diethyl ether (50 mL) at 0 °C and the reaction mixture was stirred at room temperature for 15 minutes. The progress of the reaction was monitored by LCMS and TLC. The reaction mixture was evaporated completely under vacuum to afford crude material which was triturated with diethyl ether (50 mL) to afford 3- bromocyclohexane-1, 2-dione (3.8 g, 45%) as white solid. MS (ESI) m / z 191.07 [M+H]+.

[0222] Step-2: 2-Amino-6,7-dihydrobenzo[rf]thiazol-4(5H)-one

[0223] To a stirred solution of 3-bromocyclohexane-l, 2-dione (3.8 g. 20 mmol) in ethanol (38 mL), thiourea (1.06 g, 14 mmol) was added and stirred at 80 °C for 16 h. The progress of the reaction was monitored by LCMS and TLC. After completion of reaction, the action mixture was evaporated completely to get crude, which was purified by column chromatography using 2-5% MeOH in DCM as eluent to afford 2-amino-6,7- dihydrobenzo[< / ]thiazol-4(5H)-one (1.5 g. 45%) as pale yellow solid. MS (ESI) m / z 169.08 [M+H]+.

[0224] Step-3: 2-Chloro-6,7-dihydrobenzo[rf]thiazol-4(5H)-one

[0225] To a stirred solution of copper(II) chloride, anhydrous, 99%, extra pure (4.3 g, 32 mmol) in acetonitrile (30 mL) at 0 °C under nitrogen atmosphere was added tert-butyl nitrite(4.2 mL, 32 mmol) and stirred for 15 mins. Then, 2-amino-6,7-dihydrobenzo[c7]thiazol- 4(5H)-one (3 g, 18 mmol) was added to the reaction mixture at 0 °C and the reaction was stirred at room temperature for 1 h. The reaction monitored by TLC and LCMS. After the completion of the reaction, the reaction mixture was quenched with ice cold water (50 mL) and extracted with ethyl acetate (3 x 50 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 davisil silica gel column chromatography by using 20-30% EtOAc in w-hexane as eluent to afford 2-chloro-6.7-dihydrobenzo|c / |thiazol-4(5H)- one (1.01 g, 30%) as an pale yellow solid. 'H-NMR (400 MHz, DMSO- e): 5 11.42 (t, J= 2284.0 Hz, 2H), 8.82 (t, J= 1764.8 Hz, 2H), 2.29 - 2.25 (m, 2H).

[0226] Step-4: 2-Methyl-2-(4-oxo-4,5,6,7-tetrahydrobenzo[rf|thiazol-2- yl)propanenitrileIsobutyronitrile NaHMDS

[0227] To a stirred solution of isobutyronitrile (0.57 mL, 6.4 mmol) in toluene (15 mL) at 0 °C under nitrogen atmosphere was added sodium bis(trimethylsilyl)amide (3.2 mL, 6.4 mmol) and stirred at 0 °C for 15 mins. Then, 2-chloro-6,7-dihydrobenzo[c / ]thiazol-4(5H)-one (1 g, 5.3 mmol) was added to the reaction mixture and the resulting reaction mixture was stirred at 0 °C for 2 h. Progress of the reaction was monitored by LCMS and TLC. After the completion of the reaction, the reaction mixture was quenched with aq. ammonium chloride solution (30 mL) and extracted with ethyl acetate (2 x 40 mL). The combined organic layers were dried over anhydrous sodium sulphate, filtered and the filtrate was concentrated under reduced pressure to afford crude. Crude compound was purified by combi flash using 20- 30% EtOAc in «-hexane as eluent to afford 2-methyl-2-(4-oxo-4, 5,6,7- tetrahydrobenzo[<7]thiazol-2-yl)propanenitrile (0.220 g, 19%) as pale brown solid. MS (ESI) m / z 221.23 [M+H]+.

[0228] Step-5: 2-(4-Hydroxy-4,5,6,7-tetrahydrobenzo|r / |thiazol-2-yl)-2- methylpropanenitrile

[0229] To a stirred solution of 2-methyl-2-(4-oxo-4,5,6,7-tetrahydrobenzo[<7]thiazol-2- yl)propanenitrile (0.2 g, 0.91 mmol) in ethanol (2 mL) at 0 °C under nitrogen atmosphere was added sodium borohydride, 98% (0.052 g, 1.4 mmol) and stirred at room temperature for 2 h. Progress of the reaction was monitored by LCMS and TLC. After the completion of the reaction, the reaction was quenched with water (20 mL) and extracted with ethyl acetate (2 x 30 mL). The combined organic layers were dried over anhydrous sodium sulphate, filtered and the filtrate was concentrated under reduced pressure to afford crude 2-(4- hydroxy-4,5,6,7-tetrahydrobenzo[<L]thiazol-2-yl)-2-methylpropanenitrile (0.19 g, 94%) as brown solid. MS (ESI) m / z 223.20 [M+H]+.

[0230] Step-6: 2-(4-Methoxy-4,5,6,7-tetrahydrobenzo[rf]thiazol-2-yl)-2- methyl prop aneni trile

[0231] To a stirred solution of 2-(4-hydroxy-4,5,6,7-tetrahydrobenzo[J]thiazol-2-yl)-2- methylpropanenitrile (0.19 g, 0.86 mmol) in dimethylformamide (1.9 mL) at 0 °C under nitrogen atmosphere was added sodium hydride (0.068 g, 1.7 mmol) and stirred at room temperature for 15 mins. Then, iodomethane, 99%, stabilized (0.064 mL, 1.03 mmol) was added at 0 °C to the reaction mixture and the resulting reaction mixture was stirred at room temperature for 2 h. Progress of the reaction was monitored by LCMS and TLC. After the completion of the reaction, the reaction mixture was quenched with water (20 mL) and extracted with ethyl acetate (2 x 20 mL). The combined organic layers were dried over anhydrous sodium sulphate, filtered and the filtrate was concentrated under reduced pressure to afford crude. Crude compound was purified by combi flash using 20-30% EtOAc in pet ether as eluent to afford 2-(4-methoxy-4,5,6,7-tetrahydrobenzo[<7]thiazol-2-yl)-2- methylpropanenitrile (0.06 g, 28%) as pale yelow liquid. MS (ESI) m / z 237.20 [M+H]+.

[0232] Step-7 : 2-(4-Methoxy-4,5,6,7-tetrahydrobenzo[rf]thiazol-2-yl)-2- methylpropan amide lnCI3A t ld i

[0233] To a solution of 2-(4-methoxy -4.5.6.7-tetrahydrobenzo|c / |thiazol-2-yl)-2- methylpropanenitrile (0.06 g, 0.25 mmol) in toluene (0.6 mL), was added acetaldoxime (0.062 mL, 1.02 mmol) and indium(III)chloride (0.028 g, 0.127 mmol) at room temperature and the reaction mixture was stirred at 110 °C for 5 h. Progress of the reaction was monitored by LCMS and TLC. Reaction mixture was evaporated completely to get crude. Crude compound was purified by combi flash using 60-100% EtOAc in n-hexane as eluent to afford 2-(4-methoxy-4.5.6.7-tetrahydrobenzo|<7|thiazol-2-yl)-2-methylpropanamide (0.04 g, 62%) as pale yellow semi solid. MS (ESI) m / z 255.23 [M+H]+.

[0234] Step-8: 2-(4-Methoxy-4,5,6,7-tetrahydrobenzo[rf]thiazol-2-yl)propan-2-amineKOH

[0235] To a solution of 2-(4-methoxy -4.5.6.7-tetrahydrobenzo|c / |thiazol-2-yl)-2- methylpropanamide (0.04 g, 0.16 mmol) in acetonitrile (0.4 mL) and water (0.2 mL), were added potassium hydroxide (0.035 g, 0.63 mmol), l,3-dibromo-5,5-dimethylhydantoin, 98% (0.022 g, 0.079 mmol) at 0 °C. The resulting reaction mixture was stirred at room temperature for 1 h. Progress of the reaction was monitored by LCMS and TLC. After completion of reaction, the reaction mixture was quenched with ice water (10 mL) and extracted with EtOAc (2 x 10 mL). The combined organic layers were washed with brine solution (5 mL), dried over anhydrous sodium sulphate and concentrated under reduced pressure to afford crude 2-(4-mcthoxy-4.5.6.7-tetrahydrobenzo|c / |thiazol-2-yl)propan-2- amine (0.03 g, 84%) as pale yellow semi solid. MS (ESI) m / z 227.27 [M+H]+.

[0236] General procedure B-ll: Intermediate B-ll: 2-(6-methoxybenzo[rf]thiazol-2- yl)butan-2- amine (Peak-1)Peak-1

[0237] 2-(6-methoxy benzo |r / ]thiazol-2-yl)-2-methylbutanamide (Peak-1) and 2-(6- methoxybenzo|J|thiazol-2-yl)-2-methylbutanamide (Peak- 2)Peak-2

[0238] To a solution 2-(6-methoxybenzo[( / |thiazol-2-yl)-2-methylbutanenitrile (5 g, 20.298 mmol) in formic acid, 98+%, pure (100 mL), HCI gas was purged while stirring condition at 80 °C for 2 h under N2 atmosphere. The progress of the reaction was monitored by TLC and LCMS. After completion of reaction, the reaction was quenched with sodium bicarbonate solution (200 mL) and extracted with EtOAc (2 x 350 mL). The combined organic layers were washed with brine solution (100 mL), dried over anhydrous sodium sulphate and concentrated under reduced pressure to afford crude as yellow solid (2.5 g). The crude (2.00 g) was purified by analytical SFC conditions column / dimensions : Lux i- Amylose-3 (4.6x250)mm,5p % CO2 : 65% % Co solvent : 35 % ( MeOH) flow' : 3mL / min back pressure : 100 bar temperature : 300C UV : 275 nm preparative SFC conditions column / dimensions : Lux i-Amylose-3 (30x250)mm,5p % CO2 : 65% % Co solvent : 35 % (0. 1%DEA in MeOH) flow : 100ml I min back pressure : 100 bar temperature : 300C UV : 275 nm solubility: ACN+MeOH No. of injections: 60, total purification time: 11 :30 hrs run time per injection: 11:00 Mins Instrument details: Make / Model: ANL-BLR-SFC-00 to afford rel-(R)-2-(6-methoxybenzo[<7]thiazol-2-yl)-2-methylbutanamide (9.14 RT) (0.600 g, 31 %, 99 % purity) as brown solid. MS (ESI) m / z 265.20 [M+H]+, ‘H-NMR (400 MHz, DMSO- e) S 7.84 (d, J= 8.8 Hz, 1H), 7.84 (d, J= 8.8 Hz, 1H), 7.32 (s, 1H), 7.24 (s, 1H), 7.07 (dd, J= 9.0, 2.6 Hz, 1H), 3.82 (s, 3H), 2.21 - 2.12 (m, 1H), 2.08 - 1.96 (m, 1H), 1.59 (s, 3H), 0.84 (t, J= 7.2 Hz, 3H) and rel-(S)-2-(6-methoxybenzo[<7]thiazol-2-yl)-2- methylbutanamide (4.82 RT) (0.660 g, 31 % ,99 % purity) as brown solid MS (ESI) m / z 265.23 [M+H]+. ‘H-NMR (400 MHz, DMSO- 6) 6 7.84 (d, J= 8.8 Hz, 1H), 7.61 (d, J= 2.4 Hz, 1H), 7.32 (s, 1H), 7.24 (s, 1H), 7.07 (dd, J= 8.8, 2.4 Hz, 1H), 3.82 (s, 3H), 2.19 - 2.12 (m, 1H), 2.04 - 1.97 (m, 1H), 1.59 (s, 3H) 0.84 (t. J= 7.2 Hz. 3H). (Note: Relative stereochemistry has been assigned arbitrarily)

[0239] 2-(6-inethoxybenzo[r / |thiazol-2-yl)bu tan-2- amine (Peak-1)DBDMH, KOHPeak-1 Peak-1

[0240] To a solution of 2-(6-methoxybenzo[< ]thiazol-2-yl)-2-methylbutanamide (Peak- 1) (0.4 g, 1.5 mmol) in acetonitrile (2 mL) and water (2 mL), potassium hydroxide (0.34 g, 6.05 mmol) was added at 0 °C. The reaction mixture was stirred at 0 °C with argon gas for 10 minutes. Then, l,3-dibromo-5,5-dimethylhydantoin (0.22 g, 0.76 mmol) was added and reaction mixture was stirred at room temperature for 1 h under N2 atmosphere. Progress of the reaction monitored by TLC and LCMS. After completion of reaction, the reaction was quenched with ice water (20 mL) and extracted with EtOAc (2 x 150 mL). The combined organic layer was washed with brine solution 20 mL), dried over anhydrous sodium sulphate and concentrated under reduced pressure to afford crude rel-(S)-2-(6- methoxybenzo[<7|thiazol-2-yl)butan-2-amine (Peak-1) (0.35 g, 98%, 94% purity) as an brown solid. MS (ESI) m / z 237.20 [M+H]+.

[0241] General procedure B-12: Intermediate B-12: 2-(5-Methoxy-lH-indol-2- yl)propan-2-amine hydrochloride

[0242] Step 1; Af,5-Dimethoxy- / V-methyl-l / / -indole-2-carboxaniide

[0243] To a solution of 5-methoxy-177-indole-2-carboxylic acid (5 g, 26 mmol) in DCM (50 mL) and triethylamine (22 mL, 156 mmol), were added l-(3-dimethylaminopropyl)-3- ethylcarbodiimide hydrochloride (7.5 g, 39 mmol) followed by 4-dimethyl aminopyridine (0.32 g, 2.6 mmol) at 0 °C. The resulting reaction mixture was stirred at room temperature for 15 min, then O-methylhydroxylamine hydrochloride (2.4 g, 29 mmol) was added at room temperature, then the resulting reaction mixture was stirred at room temperature for 3 h. After completion of the reaction, the reaction mixture was quenched with ice cold water (70 mL)and extracted with DCM (3 x 60 mL). The combined organic layers were dried over anhydrous sodium sulphate, filtered and the filtrate was concentrated under reduced pressure to afford crude (6 g). The obtained crude was purified by column chromatography (230-400 silica gel) by using 10% EtOAc in petroleum ether as an eluent to afford V,5-dimethoxy- / V- methyl-H7-indole-2-carboxamide (4 g, 69%) as a yellow solid. MS (ESI) m / z 235.15 [M+H]+. 'H NMR (400 MHz, CDCh) 5 9.16 (br, 1H), 7.32 (d, J= 8.8 Hz, 1H), 7.15 (d, J = 0.8 Hz. 1H), 7.10 (d. J = 1.6 Hz. 1H), 6.97 (dd, J = 13.2 Hz, 2.4 Hz, 1H). 3.84 (d, J = 11.4 Hz, 6H), 3.42 (s, 3H).

[0244] St

[0245] To a stirred solution of A,5-dimethoxy-JV-methyl-177-indole-2-carboxamide (4 g, 17 mmol) in THF (80 mL), was added methyllithium (1.6M in diethyl ether, 32 mL, 51.226 mmol) dropwise at -78 °C under nitrogen atmosphere. The resulting reaction mixture was stirred at -78 °C for 3 h. After completion, the reaction mixture was quenched with saturated aq. NH4CI solution (70 mL) at 0 °C, diluted with water (50 mL) and extracted using EtOAc (3 x 100 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered and the filtrate was concentrated under reduced pressure to afford crude (6.2 g). The obtained crude was purified by davisil silica gel column chromatography by using 20-30% EtOAc in petroleum ether as an eluent to afford l-(5-methoxy-177-indol-2-yl)ethan-l-one (3 g, 93%) as ayellow solid. MS (ESI) m / z 190.22 [M+H]+. *H NMR (400 MHz. CDCh) 5 8.93 (br s, 1H), 7.31 (d, .7= 8.8 Hz, 1H), 7.1 1 (d, .7= 1.2 Hz, 1H), 7.O9 (d, .7= 2.4 Hz, 1H), 7.03 (dd, .7= 8.8, 2.4 Hz, 1H), 3.85 (s, 3H), 2.58 (s, 3H).

[0246] Step 3; (£')- -(l-(5-methoxy-LZ / -indol-2-yl)ethylidene)-2-methylpropane-2- sulfinamide

[0247] To a stirred solution of l-(5-methoxy-177-indol-2-yl)ethan-l-one (3 g, 16 mmol) and 2-methylpropane-2-sulfmamide (2 g, 17 mmol) in THF (30 mL) w as added titanium (IV)ethoxide (5.4 g, 24 mmol) at room temperature. The resulting reaction mixture was stirred at 75 °C for 16 h. After completion of the reaction, the mixture was concentrated under reduced pressure to afford crude (3 g). The crude was purified by column chromatography (230-400 silica gel) by using 20-30% EtOAc in petroleum ether as an eluent to get (E)-A-(l-(5- methoxy-177-indol-2-yl)ethylidene)-2-methylpropane-2-sulfinamide ( 2 g, 43%) as yellowsolid. MS (ESI) m / z 291.12 [M-H]'. ’H NMR (400 MHz. CDCh) 5 8.94 (br s, 1H), 7.29 (d, J = 8.8 Hz. 1H). 7.06 (s. 1H), 7.01 (s, 1H), 7.00 (d, J = 2.4 Hz, 1H), 3.85 (s, 3H), 2.72 (s, 3H). 1.32 (s, 9H),

[0248] Step 4; / V-(2-(5-Methoxy-lE7-indol-2-yl)propan-2-yl)-2-methylpropane-2- snlfinamide

[0249] To a stirred solution of (E)- / V-(l-(5-methoxy-lE7-indol-2-yl)ethylidene)-2- methylpropane-2-sulfinamide (2 g, 6.8 mmol) in THF (20 mL) was added methylmagnesium chloride, 3M in THF (10 mL, 30 mmol) at -78 °C under nitrogen atmosphere. Then the resulting mixture was stirred at room temperature for 16 h. After completion, the reaction mixture was quenched with sat. NH4CI solution (50 mL) dropwise at 0 °C, then extracted with ethyl acetate (3 x 40 mL). The combined organic layers were dried over anhydrous sodium sulphate, filtered and filtrate was concentrated under reduced pressure to afford N-(2- (5-methoxy-12 / -indol-2-yl)propan-2-yl)-2-methylpropane-2-sulfinamide as a crude (2.5 g). The obtained crude was purified by column chromatography (230-400 silica gel ) by using 15-20% EtOAc in petrolium ether as an eluent to afford A-(2-(5-methoxy-177-indol-2- yl)propan-2-yl)-2-methylpropane-2-sulfinamide (1 g, 47% ) as a yellow solid. MS (ESI) m / z 309.39 [M+H]+. 'H-NMR (400 MHz, CDCh) 5 9.76 (br s, 1H). 7.00 (d, J= 2.4 Hz, 1H). 6.81 (dd, J= 8.8 Hz, 2.4 Hz, 1H), 6.25 (d, J= 2.4 Hz, 1H), 3.83 (s, 3H), 3.73 (s, 6H), 1.27 (s, 9H).

[0250] Step 5; 2-(5-Methoxy-17I-indol-2-yl)propan-2-amine hydrochloride

[0251] To a stirred solution of A-(2-(5-methoxy-17 / -indol-2-yl)propan-2-yl)-2- methylpropane-2-sulfinamide (0.3 g, 0.97 mmol) in DCM (3 mL) was added 2Mhydrochloric acid in diethyl ether (0.9 mL) at 0 °C. The resulting reaction was stirred at 0 °C for 1 h. After completion, the reaction mixture was concentrated under reduced pressure at 40 °C to afford crude 2-(5-methoxy-17 / -indol-2-yl)propan-2-amine hydrochloride (0.240 g, quantitative yield) as brown solid. MS (ESI) m / z 167.07 [M+H]+.

[0252] General Procedure B-13:

[0253] 2-(6-Chloro-4-(oxazol-2-yl)benzo[rf|thiazol-2-yl)propan-2-amine

[0254] Step 1; 4-Bromo-6-chlorobenzo[rf]thiazol-2-amineAmmonium thiocyanate, Benzyltrimethylammonium tribromide, ACN, RT, 16 h T |TNH2*Br

[0255] To a stirred solution of 2-bromo-4-chloroaniline (10 g, 48.4 mmol) in acetonitrile (100 mL) at 0 °C, ammonium thiocyanate (5.53 g, 72.7 mmol) was added and the resulting reaction mixture was allowed to stired at room temperature for 30 min. To this mixture, benzyltrimethylammonium tribromide (17.26 g. 48.4 mmol) was added at room temperature and the resulting reaction mixture was stirred at room temperature for 16 h. After completion of reaction, the reaction mixture was diluted with water (300 mL) and the precipitated solid was filtered, washed with water (2 x 50 mL) and Et20 (2 x 50 mL) to afford 4-bromo-6- chlorobenzo[<7]thiazol-2-amine (7 g, 55%) as a yellow solid. The compound was used as such for next step without further purification MS (ESI) m / z 265.37 [M+H]1. 'H NMR (400 MHz, DMSO- e) 5 7.95 (s, 2H), 7.82 (s, 1H), 7.50 (s, 1H).

[0256] Step 2; 4-Bromo-2,6-dichlorobenzo[rf]thiazole tert-Butyl nitrite,

[0257] To a stirred solution of copper (II) chloride (6.43 g, 47.8 mmol) in ACN (70 mL) at 0 °C, / c / 7-butyl nitrite (6.32 mL, 47.8 mmol) was added and the resulting reaction mixture was allowed to room temperature and stirred for 15 min. To this mixture at 0 °C, 4-bromo-6- chlorobenzo[<7]thiazol-2-amine (7 g. 26.6 mmol) was added and the reaction mixture was allowed to warm to room temperature and stirred for 1 h. After completion of the reaction,the reaction mixture was quenched with ice-cold water (100 mL) and extracted with EtOAc (3 x 300 mL). The combined organic layer was dried over anhydrous sodium sulphate, filtered and the filtrate was concentrated under reduced pressure to afford crude compound. The crude compound was purified by silica gel (230 - 400 mesh) column chromatography using 10 - 20% EtOAc in petroleum ether as eluent to afford 4-bromo-2,6- dichlorobenzo[<7]thiazole (6.01 g, 80%) as a off white solid. MS (ESI) m / z 284.40 [M+H]+. 'H NMR (400 MHz. CDCL) 5 7.72 (d, J = 2.0 Hz, 1H), 7.70 (d, J = 1.6 Hz, 1H).

[0258] Step 3; 2-(4-Bromo-6-chlorobenzo[r / |thiazol-2-yl)-2-methylpropanenitrile

[0259] To a stirred solution of isobutyronitrile (4.57 mL,50.9 mmol) in toluene (180 mL) at -10 °C, sodium bis(trimethylsilyl)amide (25 mL, 50.9 mmol, 2M in THF) was added drop wise over a period of 5 min. The resulting solution was stirred for 30 min at same temperature. To this mixture at -10 °C, 4-bromo-2,6-dichlorobenzo[r / |thiazole (12 g, 42.408 mmol) was added and the resulting reaction mixture was stirred at -10 °C for 2 h. After completion of the reaction, the reaction mixture was quenched with saturated aq. ammonium chloride solution (50 mL) and extracted with EtOAc (3 x 250 mL). The combined organic layer was dried over anhydrous sodium sulphate, filtered and the filtrate was concentrated under reduced pressure to afford 2-(4-bromo-6-chlorobenzo|<7|thiazol-2-yl)-2- methylpropanenitrile (10.01 g, 75%) as a brown solid. The compound was used as such for next step without further purification MS (ESI) m / z 317.47 [M+H]+.

[0260] Step 4: 2-(4-Bromo-6-chlorobenzo[rf|thiazol-2-yl)-2-methylpropanamide lnCI3, acetaldioxime, toluene, 110 °C, 2 hBr Br

[0261] To a stirred solution of 2-(4-bromo-6-chlorobenzo[ar]thiazol-2-yl)-2- methylpropanenitrile (10 g, 31.7 mmol) in toluene (100 mL), acetaldoxime (7.72 mL, 127 mmol) and indium (III) chloride (3.50 g, 15.8 mmol) were added at room temperature. To this mixture, the resulting reaction mixture was stirred at 110 °C for 2 h. After completion of the reaction, the reaction mixture was diluted with water (50 mL) and extracted with EtOAc (2 x 100 mL). The combined organic layer was dried over anhydrous Na2SO4, filtered and thefiltrate was concentrated under reduced pressure to afford crude compound. The crude compound was purified by silica gel (230 - 400 mesh) column chromatography and eluted by using 45-50% EtOAc in petroleum ether to afford 2-(4-bromo-6-chlorobenzo[[dt]hiazol-2-yl)- 2-methylpropanamide (8.02 g, 76%) as a brown solid. MS (ESI) m, z 334.92 [M+H]+ JH NMR (400 MHz, DMSO-i / 6) 8.28 (d, J = 2.0 Hz, 1H), 7.86 (d, J= 1.6 Hz, 1H), 7.40 (s, 1H), 7.33 (s, 1H), 1.66 (s, 6H).

[0262] Step 5; 2-(4-Bromo-6-chlorobenzo|rf|thiazol-2-yl)propan-2-amine

[0263] To a stirred solution of 2-(4-bromo-6-chlorobenzo[<7]thiazol-2-yl)-2- methylpropanamide (5) (4 g, 11.989 mmol) in a mixture of acetonitrile (20 rnL) and water (20 mL) at 0 °C, potassium hydroxide pellets (2.691 g, 47.958 mmol) followed by 1,3- dibromo-5.5-dimethylhydantoin (1.714 g, 5.995 mmol) were added and the resulting reaction mixture was stirred at 0 C for 5 min and then warmed to room temparature and stirred for 1 h. After completion of the reaction, the reaction mixture was diluted with EtOAc (30 mL) and washed with water (5 mL), dried over anhydrous Na2SO4, filtered and filtrate was concentrated under reduced pressure to afford 2-(4-bromo-6-chlorobenzo|r / |thiazol-2- yl)propan-2-amine (6) (1.4 g, 95%) as a brown liquid. The compound was used as such for next step without further purification. MS (ESI) m / z 307.47 [M+H]+. 'H NMR (400 MHz, CDCh) 5 7.78 (d, J= 2.0 Hz, 1H), 7.64 (d, J= 2.0 Hz, 1H), 41.66 (s, 6H). Note: -NHz protons were not visible in 'H NMR spectrum

[0264] Step 6; tert- Butyl (2-(4-bromo-6-chlorobenzo[<Zlthiazol-2-yl)propan-2-vDcarbamate

[0265] To a stirred solution of 2-(4-bromo-6-chlorobeiizo|<7|lhiazol-2-yl)propaii-2-amine (3.0 g, 9.82 mmol) in DCM (30 mL) at 0 °C, triethylamine (4. 1 mL, 29.4 mmol) was added and the resulting reaction mixture was stirred for 15 min at same temperature. To this mixture, di -tert -butyl dicarbonate (5.6 mL, 24.5 mmol) was added and the reaction mixture was allowed to stir at room temperature for 16 h. After completion of the reaction, the reaction mixture was quenched with ice-cold water (30 mL) and extracted with EtOAc (3 x50 mL). The combined organic layer was dried over anhydrous sodium sulphate, filtered and the filtrate was concentrated under reduced pressure to afford crude compound. The crude compound was purified by silica gel (230 - 400 mesh) column chromatography and eluted by using 10-20% EtOAc in petroleum ether to afford tert-butyl (2-(4-bromo-6- chlorobenzo|c / |thiazol-2-yl)propaii-2-yl)carbaniatc (1.6 g, 40%) as a off white solid. MS (ESI) m / z 406.96 [M+H]+.

[0266] Step 7; (2-(2-((tert-Butoxycarbonyl)amino)propan-2-yl)-6-

[0267] To a stirred solution of tert-butyl (2-(4-bromo-6-chlorobenzo[rf]thiazol-2- yl)propan-2-yl)carbamate (1.0 g, 2.47 mmol) in 1.4 dioxane (15 mL) at room temperature, bis(pinacolato)diboron (0.939 g. 3.697 mmol) and potassium acetate (0.726 g, 7.39 mmol) were added and the resulting reaction mixture was purged with argon gas for 15 min. To this mixture, Pd(dppf)C12 (0. 180 g, 0.246 mmol) was added and the reaction mixture was again purged with argon gas for another 3 min and stirred at 90 °C for 16 h. After completion of the reaction, the reaction mixture was quenched with ice-cold water (50 mL) and extracted with EtOAc (3 x 50 mL). The combined organic layer was dried over anhydrous sodium sulphate, filtered and the filtrate was concentrated under reduced pressure to afford crude compound. The crude compound w as purified by silica gel (230 - 400 mesh) column chromatography and eluted by using 10-20% EtOAc in petroleum ether to afford (2-(2-((tert- butoxycarbonyl)amino)propan-2-yl)-6-chlorobenzo[<7]thiazol-4-yl)boronic acid (0.61 g, 67%) as a off white solid. MS (ESI) z 371.63 [M+H]+.

[0268] Step 8: tert-Butyl (2-(6-chloro-4-(oxazol-2-yl)benzo[rf|thiazol-2-yl)propan-2- vDcarbamate

[0269] To a stirred solution of (2-(2-(( / c / 7-buto\y carbonyl )amino)propan-2-y 1 )-6- chlorobenzo[< / ]thiazol-4-yl)boronic acid (0.400 g. 1.079 mmol) in a mixture of toluene (7.2 mL) and water (0.8 mL) at room temperature, 2-bromooxazole (0.240 g, 1.619 mmol) and cesium carbonate (1.052 g, 3.24 mmol) were added and the resulting reaction mixture was purged with argon gas for 15 min. To this mixture, Pd(dppf)C12. DCM (0.088 g, 0.108 mmol) was added and the reaction mixture was again purged with argon gas for another 3 min and stirred at 100 °C for 16 h. After completion of the reaction, the reaction mixture was quenched with ice-cold water (30 mL) and extracted with EtOAc (3 x 60 mL). The combined organic layer w as dried over anhydrous sodium sulphate, filtered and the filtrate was concentrated under reduced pressure to afford crude compound. Thus, obtained crude compound was purified by silica gel (230 - 400 mesh) column chromatography and eluted by using 10-20% EtOAc in petroleum ether to afford / c / 7-butyl (2-(6-chloro-4-(oxazol-2- yl)benzo[<7]thiazol-2-yl)propan-2-yl)carbamate (0.32 g, 75%) as a off white solid. MS (ESI) m / z 394.11 [M+H]+.

[0270] Step 9: 2-(6-Chloro-4-(oxazol-2-yl)benzo[rf]thiazol-2-yl)propan-2-amine

[0271] To a stirred solution of tert-butyl (2-(6-chloro-4-(oxazol-2-yl)benzo[< / ]thiazol-2- yl)propan-2-yl)carbamate (0.300 g, 0.762 mmol) in DCM (2 mL) at 0 °C, HCI (1.5 mL, 0.960 mmol, 4M in dioxane) was added and the resulting reaction mixture was stirred at 0 °C for 5 min and then allowed to warm to room temperature and stirred for 1 h. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to afford (2-(6- chloro-4-(oxazol-2-yl)benzo[<7|thiazol-2-yl)propan-2-amine (0.18 g, 80%) as a off white solid. The compound was used as such for next step without further purification. MS (ESI) m / z 294.57 [M+H]+.Examples

[0272] General method A

[0273] l-(2-(2,6-Dioxopiperidin-3-yl)-l-oxoisoindolin-5-yl)-3-(2-(6- methoxybenzo[rf|thiazol-2-yl)propan-2-yl)urea (Example 1)

[0274] To a solution of phenyl (2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-5- yl)carbamate (0.120 g, 0.32 mmol) and 2-(6-methoxybenzo[<7|thiazol-2-yl)propan-2-amine (0.077 g, 0.35 mmol) in tetrahydrofuran (2.4 mL), triethylamine, 99%, pure (0.22 mL, 1.58 mmol) were added to the reaction mixture. Then the reaction mixture was refluxed at 70 °C under N2 atmosphere for 16 h, the reaction was monitored by TLC and LCMS. After completion of the reaction. The reaction mixture was concentrated to get the crude material. The crude was purified RP HPLC using {column / dimensions : XSELECT C18 (19*250, 5um) mobile phase A : 0. 1% formic acid in water mobile phase B : 100% gradient (Time / %B) : 0 / 15, 1 / 15, 10 / 55, 13 / 58, 13.1 / 100. 15 / 100, 15.1 / 15, 17 / 15 Flow rate : 17ml / min solubility : acetonitrile + water THF} after the lyophilization to affourd l-(2-(2,6- dioxopiperidin-3-yl)-l-oxoisoindolin-5-yl)-3-(2-(6-methoxybenzo[< / ]thiazol-2-yl)propan-2- yl)urea (0.060 g, 37%) as an off white solid. MS (ESI) m / z 508.3 [M+H]+; 'H-NMR (400 MHz, DMSO-64): 5 10.94 (br s, 1H), 8.99 (s, 1H), 7.81 (d, 8.8 Hz, 1H), 7.74 (br s, 1H),7.58 - 7.55 (m. 2H), 7.29 (dd, J= 8.2. 1.8 Hz. 1H), 7. 19 (br s, 1H). 7.06 (dd. J= 9.0. 2.6 Hz, 1H), 5.04 (dd, J= 13.4, 5.0 Hz, 1H), 4.33 (d, J = 17.2 Hz, 1H), 4.21 (d, J= 17.2 Hz, 1H), 3.80 (s, 3H), 2.93 - 2.84 (m, 1H), 2.59 - 2.51 (m, 1H), 2.40 - 2.29 (m, 1H), 1.98 - 1.96 (m, 1H), 1.73 (s, 6H).

[0275] Compounds below may be synthesized utilizing the General method A. Note that in the tables that follow, when the stereochemistry is drawn, the stereochemistry has been arbitrary assigned, but the HPLC peak has been indentifed to correlated the biological data to said isomer.

[0276] General method B

[0277] Example 343: l-(2-(6-((dimethylamino)methyl)benzo[rf]thiazol-2-yl)propan-2- yl)-3-(2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-5-yl)urea

[0278] Step-1: Synthesis of l-(2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-5-yl)-3-(2-(6-formylbenzo|^ / ]thiazol-2-yl)propan-2-yl)urea

[0279] To a stirred solution of 1 -(2-(6-bromobenzo[<7]thiazol-2-yl)propan-2-yl)-3-(2-(2,6- dioxopiperidin-3-yl)-l-oxoisoindolin-5-yl)urea (0.3 g, 0.5 mmol) in DMF (9.0 rnL), triethyl silane (0.5 g, 4.3 mmol) and N,N-diisopropylethylamine (0.47 mL, 2.7 mmol) were added. The resulting solution was degassed with argon gas for 15 minutes followed by the addition of [l,l'-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.059 g, 0.081 mmol). The reaction mixture was heated at 80 °C, under CO pressure (120 psi) for 6 h in steel autoclave. The reaction was monitored by TLC and LCMS. After the completion of the reaction, thereaction mixture was diluted with ice cold water (30 mL) and extracted with ethyl acetate (3 x 150 mL). The combined organic layers were washed with brine, dried over sodium sulphate, filtered and the filtrate was concentrated under vacuum to afford crude (0.680 g) as an brown solid. The crude compound was purified by silica gel (100-200 mesh) column chromatography and eluted by using 50% EtOAc in pet ether to afford l-(2-(2,6- dioxopiperidin-3-yl)-l-oxoisoindolin-5-yl)-3-(2-(6-formylbenzo[< / ]thiazol-2-yl)propan-2- yl)urea (2) (0.125 g, 45%) as an brown gummy liquid. MS (ESI) m / z 506.3 [M+H]+.

[0280] Step-2: Synthesis of l-(2-(6-((dimethylamino)methyl)benzo|r / |thiazol-2- yl)propan-2-yl)-3-(2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-5-yl)urea

[0281] To a solution of l-(2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-5-yl)-3-(2-(6- formylbenzo[< / ]thiazol-2-yl)propan-2-yl)urea (0.13 g, 0.26 mmol.) and dimethylamine hydrochloride (0.031 g, 0.39 mmol.) in EtOH (2.6 mL), Zinc chloride (0.07 g, 0.51 mmol) was added and the reaction was stirred at room temperature for 16 h. Then, sodium cyanoborohydride (0.048 g, 0.77 mmol.) was added in reaction mixture and stirred under N2 atmosphere for 1 h. The reaction was monitored by TLC and LCMS. After completion of reaction, the reaction mixture was diluted with EtOAc (100 mL) and washed with water (2 x 10 mL). The separated organic layer was dried over anhydrous MgSO4, filtered and filtrate was evaporated under reduced pressure to afford crude (0.25 g). The crude compound was purified RP HPLC {column / dimensions : X-bridge C18 (19*250*5p) mobile phase A : 10 mM AA in in water (aq) mobile phase B : acetonitrile gradient (Time / %B) : 0 / 5, 3 / 5, 10 / 35, 13 / 35, 13.10 / 100, 15 / 100, 15.10 / 5, 19 / 5 flow rate : 16ml / min solubility : water+THF+ acetonitrile} to afford l-(2-(6-((dimethylamino)methyl)benzo[<7]thiazol-2-yl)propan-2-yl)-3- (2-(2.6-dioxopiperidin-3-yl)-l-oxoisoindolin-5-yl)urea (TRN-0670) (0.020 g, 14%) as an off white solid. MS (ESI) m / z 535.3 [M+H]+; 'H-NMR (400 MHz, DMSO-d6): 5 10.94 (s, 1H), 9.09 (s, 1H), 8.00 (br s, 1H), 7.93 (d, J= 8.0 Hz, 1H), 7.73 (s, 1H), 7.56 (d, J= 8.4 Hz, 1H), 7.47 (d, J= 8.0 Hz, 1H), 7.31 (d, J= 5.6 Hz, 2H), 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), 3.83 (br s, 2H), 2.95 - 2.84 (m, 1H), 2.50 - 2.59 (m, 1H), 2.36 - 2.30 (m, 7H), 1.97 - 1.94 (m, 1H), 1.75 (s, 6H).

[0282] Compounds below may be synthesized utilizing the General method B.

[0283] General method C

[0284] Example 347 : l-(2-(2,6-dioxopiperidin-3-yl)-4-fluoro-l-oxoisoindolin-5-yl)-3-(2-(4-phenylbenzo[d]thiazol-2-yl)propan-2-yl)urea

[0285] Step-1: l-(2-(4-bromobenzo[< / ]thiazol-2-yl)propan-2-yl)-3-(2-(2,6- dioxopiperidiii-3-yl)-4-fluoro-l-oxoisoindolin-5-yl)urea

[0286] To a stirred solution of phenyl (2-(2, -dioxopiperi din-3 -yl)-4-fluoro-l- oxoisoindolin-5-yl)carbamate (0.15 g, 0.38 mmol) and 2-(4-bromobenzo|c / |lhiazol-2- yl)propan-2-amine (0.102 g, 0.38 mmol) in THF (3 mL) was added triethylamine (0.26 rnL, 1.9 mmol) at room temperature. The resulting reaction mixture was stirred at 80 °C for 3 h. After the completion of the reaction, the reaction mixture was concentrated under reduced pressure and triturated with ether (2 x 10 mL) to afford l-(2-(4- bromobenzo[d]thiazol-2-yl)propan-2-yl)-3-(2-(2, 6-dioxopiperi din-3 -yl)-4-fluoro-l- oxoisoindolin-5-yl)urea as an off white solid (2) (0.200 g, 92.23%). MS (ESI) m / z 576.60 [M+H]+, LC-MS purity : 79%.

[0287] Step 2; l-(2-(2,6-dioxopiperidin-3-yl)-4-fluoro-l-oxoisoindolin-5-yl)-3-(2-(4- phenylbenzo[rf]thiazol-2-yl)propan-2-yl)urea

[0288] To a stirred solution of l-(2-(4-bromobenzo[d]thiazol-2-yl)propan-2-yl)-3-(2-(2,6- dioxopiperidin-3-yl)-4-fluoro-l-oxoisoindolin-5-yl)urea (0.2 g, 0.35 mmol) in dimethylformamide (2 mL) at room temperature under nitrogen atmosphere was added Tripotassium phosphate (0.074 g, 0.348 mmol) and phenylboronic acid (0.064 g, 0.52 mmol) and was purged for 15 mins. Then, Bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.028 g, 0.035 mmol) was added to the reaction mixture. The resulting reaction mixture was stirred at 100 °C for 16 h. After the completion of the reaction, the reaction mixture was filter 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 by PREP-HPLC (Column / dimensions : X BRIDGE PENYL (19*250*5um). Mobile phase A : 0. 1% FA IN WATER, Mobile phase B : ACETONITRILE, Gradient (Time / %B) : 0 / 35,1 / 35,10 / 65,14 / 65,14.1 / 100,17.5 / 100,17.6 / 35,9.5 / 35, FL0W: 17ml / min / , solubility : Acetonitrile + THF+WATER) to afford l-(2-(2,6-dioxopiperidin-3-yl)-4-fluoro-l- oxoisoindolin-5-yl)-3-(2-(4-phenylbenzo[i / ]thiazol-2-yl)propan-2-yl)urea (0.029 g. 15%) as an off white solid. MS (ESI) m / z 586.28 [M+H]+ , LC-MS punty: 96.93 %. 'H-NMR (400 MHz, DMSO-6 / 6) 8 ‘H-NMR (400 MHz, DMSO-t / ty 8 10.98 (s, 1H), 8.80 (d, J= 2.0 Hz, 1H), 8.23 (t, J= 7.8 Hz, 1H), 8.04 - 8.10 (m, 1H), 7.89 (d, J= 7.2 Hz, 2H), 7.67 (s, 1H), 7.61 - 7.59 (m, 1H), 7.51 - 7.37 (m, 5H). 5.08 (dd, J= 13.2, 5.2 Hz, 1H), 4.55 (d, J= 16.8 Hz, 1H), 4.37 (d. J= 16.8 Hz, 1H), 2.96 - 2.87 (m, 1H). 2.62 - 2.57 (m, 1H). 2.44 - 2.39 (m, 1H), 2.01 - 1.98 (m, 1H), 1.76 (s, 1H).

[0289] Compounds below may be synthesized utilizing the General method C.

[0290] Example 359; l-(2-(4-amino-6-methoxybenzo[rf]thiazol-2-yl)propan-2-yl)-3-(2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-5-yl)urea

[0291] Step-1: Synthesis of l-(2-(4-amino-6-methoxy benzo [rf] thiazol-2-yl)propan-2- yl)-3-(2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-5-yl)urea

[0292] To a stirred solution of 1 -(2-(4-bromo-6-methoxybenzo[[dt]hiazol-2-yl)propan- 2-yl)-3-(2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-5-yl)urea (0.100 g, 0.17 mmol) in dimethylformamide (1 mL) and MiliQ- water (0.5 mL) were added L-Proline (0.002 g, 0.017 mmol). Sodium carbonate (0.023 g, 0.22 mmol), Sodium azide. (0.014 g, 0.22 mmol). Sodium ascorbate (0.044 g, 0.22 mmol), Copper(II) sulfate, anhydrous (0.027 g,0.17 mmol). The reaction mixture was degassed with argon gas for another 15 minutes and heated to 90°C, and stirred for 16 hr. After completion of reaction, the reaction mixture was extracted with water (20 mL) and EtOAc (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 compound 1 -(2-(4-amino-6- methoxybenzo[<7|thiazol-2-yl)propan-2-yl)-3-(2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindohn-5- yl)urea. The crude was purified by HPLC (Column / dimensions: X-Select C18(19*250mm) 5p; Mobile phase A: 0. 1% formic acid in water (aq), Mobile phase B: acetonitrile; gradient (time / %B): 0.01 / 15, 1 / 15, 10 / 45, 12 / 45, 12.1 1 100, 16.5 / 100, 16.51 / 15, 18 / 15; flow rate: 18 mL / min.; solubility: THF+ACN) to afford l-(2-(4-amino-6-methoxybenzo[< / |thiazol- 2-yl)propan-2-yl)-3-(2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-5-yl)urea (0.0021 g, 2 %, 97 % purity) as off white solid.MS (ESI) m / z 523.26 [M+H]+. 'H-NMR (400 MHz, DMSO- <76) d 10.90 (s. 1H), 8.98 (s, 1H). 7.75 (s, 1H). 7.56 (d, J= 8.4 Hz, 1H). 7.28 (d, J= 1.6 Hz, 1H), 7.15 (s, 1H), 6.67 (d, J= 2.0 Hz, 1H), 6.25 (d, J= 2.4 Hz, 1H), 5.51 (s, 2H), 5.05 (dd, J = 13.2, 5.2 Hz, 1H), 4.34 (d, J= 17.6 Hz, 1H), 4.21 (d, J= 17.2 Hz, 1H), 3.70 (s, 3H), 2.81 - 2.92 (m, 1H), 2.59 - 2.51 (m, 1H). 2.36 - 2.40 (m. 1H), 1.95 - 1.88 (m, 1H), 1.73 (s, 6H).

[0293] General Method D

[0294] Example 360: l-(2-(6-bromobenzo[d]thiazol-2-yl)propan-2-yl)-3-(6-(2.6- dioxopiperidin-3-yl)-5,7-dioxo-6,7-dihvdro-57 / -pyrrolo[3,4-blpyridin-2-yl)urea

[0295] 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 (0.1 g, 0.27 mmol) and 2-(5-fluoro-6- methoxybenzo[<7|thiazol-2-yl)propan-2-amine (0.071 g, 0.29 mmol) in acetonitrile (5 mL) was added 1.5,7-Triazabicyclo[4.4.0]dec-5-ene (0.006 g, 0.040 mmol). The resulting reaction mixture was heated at 100 °C for 16 h. The reaction mixed was fdtered and the residue was collected to afford l-(6-(2,6-dioxopiperidin-3-yl)-5,7-dioxo-6,7-dihydro-577-pyrrolo[3,4- b]pyri din-2 -yl)-3-(2-(5-fluoro-6-methoxybenzo[< ]thiazol-2-yl)propan-2-yl) urea as crude. The crude was purified by PREP-HPLC (Column / dimensions : X-SELECT Cl 8(30* 150), Mobile phase A : 0.1% FA IN WATER, Mobile phase B : Acetonitrile, Gradient (Time / %B) : 0 / 20,1 / 20,15 / 75,15.1 / 100,18 / 100,18.1 / 20,20 / 20, Flow rate : 17ml / min„ Solubility : THF+ACN+WATER ). The organic layer was collected and concentrated at 35 °C followed by lypholiziation to afford l-(6-(2,6-dioxopiperidin-3-yl)-5,7-dioxo-6,7-dihydro- 5 / / -pyrrolo[3,4-b]pyridin-2-yl)-3-(2-(5-fluoro-6-methoxybenzo[J]thiazol-2-yl)propan-2- yl)urea (0.010 g, 7%) as an off white solid. MS (ESI) m'z 541.32 [M+H]+ , LC-MS purity: 99.37 %. 'H-NMR (400 MHz, DMSO-c / e) 5 11.14 (s, 1H), 10.17 (s, 1H), 8.37 (s, 1H), 8.19 (d, J= 8.8 Hz, 1H), 7.88 - 7.81 (m, 3H), 5.16 (dd. J= 12.8, 5.6 Hz, 1H), 3.89 (s, 3H), 2.92 - 2.85 (m, 1H), 2.63 - 2.57 (m, 2H). 2.07 - 2.05 (m, 1H). 1.78 (s. 9H).

[0296] Compounds below may be synthesized utilizing the General method D.

[0297] Examples 669, 670, 671, and 672 - l-(2-(4-Chloro-5-fluoro-6- methoxybenzo [ rf| thiazol-2-yl)propan-2-yl)-3-(-2-(-2,6-dioxopiperidin-3-yl)-3-methyl- 1- oxoisoindolin-5-yl)ureaStereochemistry assigned arbitrarily

[0298] Step 1: Methyl 4-bromo-2-ethylbenzoate

[0299] To a stirred solution of 4-bromo-2-ethylbenzoic acid (5 g, 21.827 mmol) in methanol (50 mL) at 0 °C under nitrogen atmosphere, thionyl chloride (6.3 rnL, 87.309 mmol) was added and the resulting reaction mixture was stirred at 80 °C for 2 h. Aftercompletion of reaction, the reaction mixture was concentrated under reduced pressure to afford crude compound. The crude compound was basified by using sat. NaHCOs solution (50 mL) and then extracted with ethyl acetate (3 x 150 mL). The combined organic layer was dried over anhydrous Na2SO4, filtered and the filtrate was concentrated under reduced pressure to afford crude compound. The crude compound was purified by silica gel (230 - 400 mesh) column chromatography using 4% EtOAc in petroleum ether to afford methyl 4- bromo-2-ethylbenzoate (4.8 g. 90%) as colourless liquid. The compound was used as such for next step without further purification. MS (ESI) m / z 243.46 [M+H]+.XH NMR (400 MHz, CDCh) 5 7.73 (d, J= 8.4 Hz, 1H), 7.43 (d, J= 2.0 Hz, 1H), 7.37 (dd, J= 8.4, 2.0 Hz, 1H) 3.88 (s, 3H), 2.96 (q, J= 7.6 Hz, 2H), 1.23 (t, .7= 7.6 Hz, 1H).

[0300] Step 2: Methyl 4-bromo-2-(l-bromoethyl)benzoate

[0301] To a stirred solution of methyl 4-bromo-2 -ethylbenzoate (4.8 g. 19.7 mmol) in aCCh (96 mL) were added N-bromosuccinimide (3.87 g, 21.7 mmol) and benzoyl peroxide (0.478 g, 1.97 mmol) at room temperature. The resulting reaction mixture was stirred at 85 °C for 16 h. After completion of the reaction, the reaction mixture was concentrated under reduced pressure. The residue was diluted with DCM (150 mL) and washed with water (100 mL), brine solution (100 mL), dried over anhydrous sodium sulphate, filtered and the filtrate was concentrated under reduced pressure to afford crude compound. The crude compound was purified by silica gel (230 - 400 mesh) column chromatography using 5% EtOAc in petroleum ether to afford methyl 4-bromo-2-(l-bromoethyl)benzoate (6.1 g, 96%) as an off- white solid. 'H NMR (400 MHz, CDCI3) 5 7.93 (d. J = 1.6 Hz. 1H), 7.71 (d. J = 8.4 Hz. 1H), 7.46 (dd, J= 8.4, 2.0 Hz, 1H), 6.26 (d, J = 7.2 Hz, 1H), 3.92 (s, 3H), 2.02 (t, J= 6.8 Hz, 3H).

[0302] Step 3; tert-Butyl (4A)-5-amino-4-(5-bromo-3-methyl-l-oxoisoindolin-2-yl)-5- oxopentanoate

[0303] To a stirred solution of methyl 4-bromo-2-(l-bromoethyl)benzoate (5 g, 15.5 mmol) in acetonitrile (100 mL) were added tert-butyl ( j-TS-diamino-S-oxopentanoate hydrochloride (4.077 g, 17.08 mmol), potassium iodide (1.29 g, 7.76 mmol) and potassium carbonate (6.44 g, 46.6 mmol) at room temparature. The resulting reaction mixture was stirred at 80 °C for 16 h. After completion of the reaction, the reaction mixture was quenched with ice-cold water (100 mL) and extracted with ethyl acetate (2 x 100 mL). The combined organic layer was washed with brine solution (75 mL), dried over anhydrous sodium sulphate, filtered and the filtrate was concentrated under reduced pressure to afford crude compound. The crude compound was purified by silica gel (100 - 200 mesh) column chromatography using 40 - 50% EtOAc in petroleum ether as eluent to afford tert-butyl (4S)- 5-amino-4-(5-bromo-3-methyl-l-oxoisoindolin-2-yl)-5-oxopentanoate (5.5 g, 86%) as a yellow solid. MS (ESI) m / z 41 1.63 [M+H]+. ‘H NMR (400 MHz, DMSO-cL) 5 7.91 (d, J = 7.2 Hz, 1H), 7.68 (d, J= 8.0 Hz, 1H), 7.60 (d, J= 8.0 Hz, 1H), 7.45 - 7.14 (m, 2H), 4.72 - 4.63 (m, 1H), 4.47 - 4.40 (m, 1H), 2.32 - 2.09 (m, 4H), 1.51 - 1.43 (m, 3H), 1.42 (s, 9H).

[0304] Step 4; tert-Butyl (A)-5-amino-4-((R)-5-bromo-3-methyl-l-oxoisoindolin-2-yl)- 5-oxopentanoate & tert-Butyl (5)-5-amino-4-((5)-5-bromo-3-methyl-l-oxoisoindolin-2- yl)-5-oxopentanoate

[0305] The rcemic mixture of tert-butyl (4<S)-5-amino-4-(5-bromo-3-methyl-l- oxoisoindohn-2-yl)-5-oxopentanoate (1.2 g) was separated by chiral SFC [column / dimensions: Chiralpak AD-H (30 x 250mm),5p, % of CO2: 60%, % co solvent: 40% (methanol), back pressure: 100 bar, temp: 30 °C, UV: 220 nm, flow rate: 100 mL / min, solubility: MeOH + ACN + few drops formic acid] and the obtained fractions were concentrated under reduced pressure to afford tert-butyl (.S)-5-amino-4-(( / ?)-5-bromo-3- methyl-l-oxoisoindolin-2-yl)-5-oxopentanoate (Peak-1, RT: tret(min) = 6.70 min ) (0.3 g, chiral purity: 99%) as an colourless liquid along with tert-butyl tert-butyl (S)-5-amino-4-((S)- 5-bromo-3-methyl-l-oxoisoindolin-2-yl)-5-oxopentanoate (Peak-2, RT: tret(min) = 4.449 min) (0.28 g. chiral purity: 99%) as an off white solid.Peak-1: MS (ESI) m'z 411.47 [7.90 (s, 1H), 7.68 (dd, J= 8.0, 1.2 Hz, 1H), 7.60 (d, J= 8.0 Hz, 1H), 7. 19 (br s, 1H), 7. 14 (br s. 1H), 4.65 (q, J = 6.4 Hz, 1H), 4.42 - 4.38 (m, 1H), 2.36 - 2.24 (m, 1H), 2.19 - 2.08 (m, 3H), 1.41 (d, J = 6.8 Hz, 3H), 1.35 (s, 9H).Peak-2: MS (ESI) m'z 413.65 [M+H]+.JH NMR (400 MHz, DMSO- J6) 5 7.91 (s, 1H), 7.68 (dd, J= 8.0, 1.2 Hz, 1H), 7.60 (d, J= 8.4 Hz, 1H), 7.45 (br s, 1H), 7.21 (br s, 1H), 4.70 (q, J= 6.4 Hz. 1H), 4.47 - 4.44 (m. 1H), 2.26 - 2.09 (m, 4H), 1.49 (d, J = 6.8 Hz, 3H), 1.37 (s, 9H).

[0306] Step 5; (A)-3-((R)-5-Bromo-3-methyl-l-oxoisoindolin-2-yl)piperidine-2,6- dione

[0307] To a stirred solution of Ze / 7-butyl (<S)-5-amino-4-((A)-5-bromo-3-methyl-l- oxoisoindolin-2-yl)-5-oxopentanoate (Peak-1) (0.300 g, 0.729 mmol) in acetic acid (12 mL), benzenesulfonic acid (0.231 g, 1.46 mmol)) was added at room temparature. The resulting reaction mixture was irradiated under microwaves at 150 °C for 1 h. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to afford crude compound. The crude compound was diluted with NaHCO? solution (30 mL) and extracted with ethyl acetate (2 x 75 mL). The combined organic layer was dried over anhydrous sodium sulphate, filtered and the filtrate was concentrated under reduced pressure to afford (S)-3- ((R)-5-bromo-3-methyl-l-oxoisoindolin-2-yl)piperidine-2, 6-dione (0.2 g, 81%) as a off white solid. MS (ESI) m / z 337.02 [M+H]+. *H NMR (400 MHz. DMSO-Je) 5 10.93 (s, 1H), 7.95 (d, J= 6.0 Hz. 1H), 7.71 - 7.68 (m. 1H), 7.62 - 7.58 (m, 1H), 4.78 - 4.65 (m, 2H), 2.86 - 2.70 (m, 1H), 2.68 - 2.54 (m, 2H), 2.02 - 1.96 (m, 1H), 1.46 - 1.42 (m, 3H).Step 6; tert-Butyl ((R)-2-((5)-2,6-dioxopiperidin-3-yl)-3-methyl-l-oxoisoindolin-5- vDcarbamate

[0308] To a stirred solution of (<S)-3-((A)-5-bromo-3-methyl-l-oxoisoindolin-2- yl)piperidine-2, 6-dione (0.200 g, 0.593 mmol) in a 1,4-dioxane (4 mL) at room temperature, / c / 7-butyl carbamate (0.104 g, 0.890 mmol) and potassium phosphate tribasic (0.189 g, 0.890 mmol) were added and the resulting reaction mixture was purged with argon gas for 15 min. To this mixture, XPhos Pd G3 (0.025 g, 0.030 mmol) was added and the reaction mixture was again purged with argon gas for another 3 min and then stirred at 110 °C for 1 h. After completion of the reaction, the reaction mixture was quenched with ice-cold water (30 mL) and extracted with ethyl acetate (3 x 30 mL). The combined organic layer was dried over anhydrous sodium sulphate, filtered and the filtrate was concentrated under reduced pressure to afford crude compound. The crude compound was triturated with / ?- Pentane (50 mL) and collected the solid by filtration. The solid was washed with n-Pentane (30 mL) and dried under vaccum to afford / c / 7-butyl ((R)-2-((S)-2,6-dioxopiperidin-3-yl)-3-methyl-l- oxoisoindolin-5-yl)carbamate (0.2 g, 90%) as an off white solid. MS (ESI) mdz 374.11 [M+H]+. 'H NMR (400 MHz, DMSO-tZe) 5 10.84 (d, J= 12.4 Hz, 1H), 9.76 (s, 1H), 7.80 (s, 1H), 7.55 - 7.52 (m, 1H), 7.48 - 7.35 (m, 1H), 4.71 - 4.61 (m, 2H), 2.87 - 2.70 (m, 1H). 2.68- 2.50 (m, 2H), 2.02 - 1.96 (m, 1H), 1.49 (s, 9H), 1.43 (s, 3H).

[0309] Step 7; (A)-3 R Amino-3-methyl-l-oxoisoindolin-2-yl)piperidine-2,6-dionesa

[0310] To a stirred solution of / c / 7-butyl ((R)-2-((S)-2,6-dioxopiperidin-3-yl)-3-methyl-l- oxoisoindolin-5-yl)carbamate (0.200 g, 0.536 mmol) in DCM (1 mL) at 0 °C, trifluoro acetic acid (1 mL) was added and the resulting reaction mixture was stirred at 0 °C for 5 min and then allowed to stir at room temperature for 1 h. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to afford crude compound. The crude compound was triturated with / 7-Pentane (20 mL) and collected the solid by filtration. The solid was further washed with diethyl ether (20 mL) and dried under vacuum to afford TFA salt of (,S)-3-((R)-5-amino-3-methyl-l-oxoisoindolin-2-yl)piperidine-2, 6-dione (0.2 g, quantitaive) as an off-white solid. MS (ESI) m / z 274.16 [M+H]+. 'l l NMR (400 MHz, DMSO- d6) 5 10.84 (d. J= 10.8 Hz, 1H), 7.28 (dd, J= 8.6, 2.6 Hz, 1H), 7.21 (s, 1H), 7.08 (s, 1H), 6.61 - 6.59 (m, 2H), 5.80 - 5.72 (m, 1H), 4.63 - 4.45 (m, 1H), 2.86 - 2.70 (m, 1H), 2.68- 2.54 (m, 2H), 2.07 - 1.90 (m, 1H), 1.36 - 1.31 (m, 3H).

[0311] Step 8: Phenyl (( / ?)-2- -2,6-dioxoniperidin-3-yl)-3-methyl-l-oxoisoindolin-5-vDcarbamateQ A

[0312] To a stirred solution of TFA salt of (S)-3-((J?)-5-amino-3-methyl-l-oxoisoindolin- 2-yl)piperidine-2, 6-dione (0.200 g, 0.539 mmol) in acetonitrile (4 mL) at room temperature, pyridine (0.05 mL, 0.646 mmol) and phenyl chloroformate (0.101 mL, 0.808 mmol) were added sequentially and the resulting reaction mixture was stirred at room temperature for 1 h. After completion of the reaction, the reaction mixture was diluted with DCM (30 mL) and washed with water (25 mL), dried over anhydrous Na2SO4, filtered and the filtrate was concentrated under reduced pressure to afford ((A)-2-((5)-2,6-dioxopiperidin-3-yl)-3-methyl-1-oxoisoindolin-5-yl)carbamate (0.2 g, 94%) as a brown gummy liquid. The resulting compound was used as such for next step without further purification. MS (ESI) m / z 394.59 [M+H]+.

[0313] Example 669: l-(2-(4-Chloro-5-fluoro-6-methoxybenzo[<Z]thiazol-2- yl)propan-2-yl)-3-((R)-2-((A)-2,6-dioxopiperidin-3-yl)-3-methyl-l-oxoisoindolin-5- vDurea (Peak-1)

[0314] Example 670: l-(2-(4-chloro-5-fluoro-6- 2-yl)propan-2-yl)-3-((A)-2-((5')-2,6-dioxopiperidin-3-yl)-3-methyl-l-oxoisoindolin-5-yl)urea (Peak-2)

[0315] Example 671 : l-(2-(4-chloro-5-fluoro-6-methoxybenzo[< / |thiazol-2-yl)propan- 2-yl)-3-((A)-2-( -2.,6-dioxopiperidin-3-yl)-3-methyl-l-oxoisoindolin-5-yl)urea (Peak-3)

[0316] Example 672: l-(2-(4-chloro-5-fhioro-6-methoxybenzo[rf|thiazol-2-yl)propan- 2-yl)-3-((R)-2-((R)-2.,6-dioxopiperidin-3-yl)-3-methyl-l-oxoisoindolin-5-yl)urea Peak-4)

[0317] To a stirred solution of phenyl ((R)-2-((1S’)-2,6-dioxopiperidin-3-yl)-3-methyl-l- oxoisoindolin-5-yl)carbamate (0.18 g, 0.458 mmol) in THF (2 mL) at room temperature, 2- (4-chloro-5-fluoro-6-methoxybenzo[[dt]hiazol-2-yl)propan-2-amine (0.126 g, 0.458 mmol) and triethylamine (0.3 mL. 2.288 mmol) were added and the resulting reaction mixture was stirred at 90 °C for 1 h. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to afford crude compound. The crude compound was purified by RP prep-HPLC [column / dimensions: Gemini NX-C18 (10 x 250, 5 pm), mobile phase (A): 0.1% FA in water, mobile phase (B): 100% acetonitrile, gradient (Time / %B): 0 / 35, 1 / 35, 10 / 65, 13 / 65, 13.1 / 100, 15 / 100, 15.1 / 35, 17 / 35. Flow rate: 7 mL / min, solubility: THF+ACN+ water] and the fractions were concentrated under reduced pressure followed by lyophilized to afford l-(2-(4-chloro-5-fluoro-6-methoxybenzo[d]thiazol-2-yl)propan-2-yl)-3- ((A)-2-((<S’)-2,6-dioxopiperidin-3-yl)-3-methyl-l-oxoisoindolin-5-yl)urea (0.032 g, 12%)as an off-white solid.

[0318] The racemic mixture of l-(2-(4-chloro-5-fluoro-6-methoxybenzo[d]thiazol-2- yl)propan-2-yl)-3-((R)-2-((1S)-2,6-dioxopiperidin-3-yl)-3-methyl-l-oxoisoindolin-5-yl)urea (0.032 g) was separated by chiral SFC [column / dimensions: Chiralpak IK (4.6 x 250)mm,5p, % of CO2: 55%, % co solvent: 45% (ACN:IPA)(1.1), back pressure: 1500 bar, temp: 30 °C, UV: 260 nm, flow rate: 3 mL / min, solubility: MeOH] and the obtained fractions were concentrated under reduced pressure to afford l-(2-(4-chloro-5-fluoro-6- methoxybenzo[[dt]hiazol-2-yl)propan-2-yl)-3-((J?)-2-((<S)-2,6-dioxopiperidin-3-yl)-3-methyl- l-oxoisoindolin-5-yl)urea (Peak-1), RT: tret(min) = 4.43 min (0.03 g, chiral purity: 99%), 1- (2-(4-chloro-5-fluoro-6-methoxybenzo[[dt]hiazol-2-yl)propan-2-yl)-3-((5)-2-((<S’)-2.6-dioxopiperidin-3-yl)-3-methyl-l-oxoisoindolin-5-yl)urea (Peak-2), RT: tret(min) = 6.60 min (0.03 g, chiral purity: 99%), l-(2-(4-chloro-5-fluoro-6-methoxybenzo[< / ]thiazol-2-yl)propan- 2-yl)-3-((S)-2-((R)-2,6-dioxopiperidin-3-yl)-3-methyl-l-oxoisoindolin-5-yl)urea (Peak-3), RT: tret(min) = 9.83 min (0.08 g, chiral purity: 97%), l-(2-(4-chloro-5-fluoro-6- methoxybenzo[<7|thiazol-2-yl)propan-2-yl)-3-((J?)-2-((R)-2,6-dioxopiperidin-3-yl)-3-methyl- l-oxoisoindolin-5-yl)urea (Peak-4), RT: tret(min) = 11.68 min) (0.08 g, 8, chiral purity: 95%) as off white solids.Peak-1: MS (ESI) m / z 574.30 [M+H]+. 'H NMR (400 MHz, DMS0-J6) 8 10.87 (s, 1H), 9.08 (s, 1H), 7.85 (d, J= 7.6 Hz, 1H), 7.76 (br s, 1H), 7.49 (d, J= 8.4 Hz, 1H), 7.33 (br s, 1H), 7.23 (dd, J = 8.4, 1.6 Hz, 1H), 4.65 (q, J = 6.4 Hz, 2H), 3.91 (s, 3H), 2.77 - 2.68 (m, 1H), 2.57 - 2.50 (m, 2H), 2.00 - 1.95 (m, 1H). 1.74 (s, 6H). 1.36 (d, J = 6.4 Hz, 3H).Peak-2: MS (ESI) m / z 574.32 [M+H]+. ‘H NMR (400 MHz, DMSO-c / e) 8 10.89 (s, 1H), 9.06 (s, 1H), 7.85 (d, J= 7.6 Hz, 1H), 7.74 (br s, 1H), 7.50 (d, J= 8.0 Hz, 1H), 7.31 (br s, 1H), 7.26 (dd, J= 8.4, 1.6 Hz, 1H), 4.67 (q, J= 5.2 Hz, 1H), 4.55 (q, J= 6.4 Hz, 1H), 3.91 (s, 3H), 2.85 - 2.76 (m, 1H), 2.62 - 2.58 (m. 2H), 1.96 - 1.91 (m, 1H), 1.74 (s, 6H). 1.33 (d, J = 6.8 Hz, 3H).Peak-3: MS (ESI) m / z 574.30 [M+H]+. 'H NMR (400 MHz, DMSO-J6) 8 10.89 (s, 1H), 9.04 (s, 1H), 7.85 (d, J= 8.0 Hz, 1H), 7.74 (br s, 1H), 7.50 (d, J= 8.4 Hz, 1H), 7.29 (br s, 1H), 7.26 (dd, J= 8.4, 1.6 Hz, 1H). 4.67 (dd, J= 12.4, 4.8 Hz, 1H), 4.55 (q, J= 6.4 Hz, 1H). 3.91 (s, 3H), 2.85 - 2.76 (m, 1H). 2.64 - 2.54 (m, 2H), 1.96 - 1.91 (m, 1H), 1.74 (s, 6H), 1.33 (d, J = 6.4 Hz, 3H)Peak-4: MS (ESI) m'z 574.26 [M+H]+. 'H NMR (400 MHz, DMSO-c / e) 8 10.86 (s, 1H), 9.07 (s, 1H). 7.85 (d, J= 7.6 Hz, 1H), 7.76 (br s, 1H), 7.49 (d, J= 8.4 Hz, 1H). 7.33 (br s, 1H), 7.23 (dd, J = 8.0, 1.6 Hz, 1H), 4.65 (q. J = 6.4 Hz, 2H). 3.91 (s, 3H). 2.76 - 2.69 (m, 1H), 2.57 - 2.50 (m, 2H), 1.98 - 1.95 (m, 1H), 1.74 (s, 6H), 1.36 (d, J= 6.4 Hz, 3H)Biochemical and Cellular Assays

[0319] In vitro proximity assay for CDK2 / CCNE1 and CR / BN

[0320] 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 pM) 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-[l-(6- bromo-1 ,3-benzothiazol-2-yl)-l -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 1

[0321] 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

1. Listing of Claims:

1. A compound having the structural Formula I:or a pharmaceutically acceptable salt thereof, whereinY is CH2, CH(CH3), or C(O);X is N or CRX;Rxis (C1-C4)alkyl or halo; p is 0, 1, or 2R1is (C1-C4)alkyl, halo(C1-C4)alkyl, halo, cyano, (C1-C4)alkoxy, or halo(Ci- C4)alkoxy;R2and R3are each independently selected from (C1-C4)alkyl, halo(C1-C4)alkyl, halo. (C1-C4)alkoxy, (C3-C6)cycloalkyl, halo(C1-C4)alkoxy, and -(C1-C4)alkylene(C3- Ce)cycloalkyl, wherein said (C3-Ce)cycloalkyl alone, or as part of -(C1-C4)alkylene(C3- C6)cycloalkyl is optionally substituted with 1 to 3 groups selected from RA; or R2and R?are taken together to form a (C3-C6)cycloalkyl is optionally substituted with 1 to 3 groups selected from RB;R4is benzothiazolyl or tetrahydrobenzothiazolyl, each of which are optionally substituted with 1 to 4 groups selected from Rc;Rcis selected from (C1-C4)alkyl, halo(C1-C4)alkyl, halo, -ORV, cyano, -(Ci- C4)alkyleneNRxRY, -(Ci-C4)alkyleneORv, -NRXRY, -C(O)NRXRY. -C(O)ORV. -C(O)RV, - (Ci-C4)alkyleneC(O)NRxRY, -(Ci-C4)alkyleneC(O)ORv, -(Ci-C4)alkyleneC(O)Rv, -(C2- C4)alkynyl(C3-C6)cycloalkyl), -C(O)NRXSO3H, -NRXC(O)RV, -NRXC(O)ORV, - NRXC(S)ORV, -NRXC(O)NRXRY, -NRXC(S)NRXRY, -NRXS(O)2NRXRY, -C(S)RX, -S(O)2RX, -S(O)RX-C(S)ORV, -C(S)NRXRY, -NRXC(S)RY, -SRX(C3-C6)cycloalkyl, -(Ci- C4)alkylene(C3-C6)cycloalkyl, phenyl, -(C1-C4)alkylene[phenyl], 4- to 7- membered heterocyclyl, -(C1-C4)alkylene[4- to 7- membered heterocyclyl], 5- to 7- membered heteroaryl, and -(C1-C4)alkylene[5- to 7- membered heteroaryl]; and / or two Rcare taken together on adjacent carbon atoms to form a 5- to 7- membered heterocyclyl optionally- substituted with 1 to 3 groups selected from RD;Rx, RY, and Rvare each independently selected from hydrogen. (C1-C4)alkyl, halo(C1-C4)alkyl, (C3-C6)cycloalkyl. -(C1-C4)alkylene(C3-C6)cycloalkyl, 4- to 7- membered heterocyclyl, -(C1-C4)alkylene(4- to 7- membered heterocyclyl), 5- to 7- membered heteroaryl, -(C1-C4)alkylene(5- to 7- membered heteroaryl), phenyl and benzyl, wherein each of said (C3-C6)cycloalkyl, 4- to 7- membered heterocyclyl, 5- to 7- membered heteroaryl, phenyl and benzyl are optionally substituted with 1 to 3 groups selected from RE; and each RA, RB, RE, and RFis selected from (C1-C4)alkyl, halo(C1-C4)alkyl, halo, cyano. (C1-C4)alkoxy, and halo(C1-C4)alkoxy; provided the compound is not l-(2-(benzo[d]thiazol- 2-yl)propan-2-yl)-3-(2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-5-yl)urea or a salt thereof.

2. The compound of Claim 1. or a pharmaceutically acceptable salt thereof, whereinRcis selected from (C1-C4)alkyl, halo(C1-C4)alkyl, halo, -OR cyano, -(Ci- C4)alkyleneNRxRY, -(Ci-C4)alkyleneORv, -NRXRY, -C(O)NRXRY, -C(O)ORV, -C(O)RV, - (Ci-C4)alkyleneC(O)NRxRY, -(Ci-C4)alkyleneC(O)ORv, -(Ci-C4)alkyleneC(O)Rv, - C(O)NRXSO3H, -NRXC(O)RV, -NRXC(O)ORV, -NRXC(S)ORV, -NRXC(O)NRXRY, - NRXC(S)NRXRY, -NRXS(O)2NRXRY, -C(S)RX, -S(O)2RX, -S(O)RX, -C(S)ORV, -C(S)NRXRY, -NRXC(S)RY, -SRX, (C3-C6)cycloalkyl, -(Ci-C4)alkylene(C3-C6)cycloalkyl, phenyl, -(Ci- C4)alkylene[phenyl], 4- to 7- membered heterocyclyl, -(C1-C4)alkylene[4- to 7- membered heterocyclyl], 5- to 7- membered heteroaryl, and -(C1-C4)alkylene[5- to 7- membered heteroaryl]; and / or two Rcare taken together on adjacent carbon atoms to form a 5- to 7- membered heterocyclyl optionally substituted with 1 to 3 groups selected from Ru; andRx, RY, and Rvare each independently selected from hydrogen, (Ci -Chalk I. halo(C1-C4)alkyl, (C3-C6)cycloalkyl. 4- to 7- membered heterocyclyl, 5- to 7- membered heteroaryl, phenyl and benzyl, wherein each of said (C3-C6)cycloalkyl, 4- to 7- membered heterocyclyl, 5- to 7- membered heteroaryl, phenyl and benzyl are optionally substituted with 1 to 3 groups selected from RE.

3. The compound of Claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein Y is CH2or C(O).

4. The compound of any one of Claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein p is 0.

5. The compound of any one of Claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein Rxis halo.

6. The compound of any one of Claims 1 to 5, or a pharmaceutically acceptable salt thereof, wherein Rxis fluoro.

7. The compound of any one of Claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein R2and R3are each independently selected from (Ci-C^alky l, halo(Ci- C4)alkyl, (C3-C6)cycloalkyl, halo(C1-C4)alkoxy, and -(C1-C4)alkylene(C3-Ce)cycloalkyl, wherein said (C3-C6)cycloalkyl alone, or as part of -(C1-C4)alkylene(C3-C6)cycloalkyl is optionally substituted with 1 to 3 groups selected from RA; or R2and R3are taken together to form a (C3-C6)cycloalkyl is optionally substituted with 1 to 3 groups selected from RB.

8. The compound of any one of Claims 1 to 7, or a pharmaceutically acceptable salt thereof, wherein R2and R3are each independently selected from (C1-C4)alkyl, halo(Ci- C4)alkyl, (C3-C6)cycloalkyl, halo(C1-C4)alkoxy, and -(C1-C4)alkylene(C3-C6)cycloalkyl; or R2and R3are taken together to form a (C3-C6)cycloalkyl.

9. The compound of any one of Claims 1 to 8, or a pharmaceutically acceptable salt thereof, wherein R2and R3are each independently selected from CH3, CFTCHtCTkh. CH(CHS)2, CH2CH3, CH2CH2F, CH2Cyclopropyl, and cyclopropyl; or R2and R3are taken together to form cyclopropyl.

10. The compound of any one of Claims 1 to 9, or a pharmaceutically acceptable salt thereof, wherein R4is benzothiazolyl optionally substituted with 1 to 4 groups selected from Rc.

11. The compound of any one of Claims 1 to 10, or a pharmaceutically acceptable salt thereof, wherein Rcis selected from (C1-C4)alkyl, halo(C1-C4)alkyl, halo, -ORV, (C3- Cejcycloalkyl, cyano, (C1-C4)alkylene(C3-C6)cycloalkyl, phenyl, 4- to 7- membered heterocyclyl, 5- to 7- membered heteroaryl, -NRXRY, -(C2-C4)alkynyl(C3-Ce)cycloalkyl), and (C1-C4)alkyleneNRxRY; and / or two Rcare taken together on adjacent carbon atoms to form a 5- to 7- membered heterocyclyl.

12. The compound of any one of Claims 1 to 11, or a pharmaceutically acceptable salt thereof, wherein Rcis selected from (C1-C4)alkyl. halo(C1-C4)alkyl, halo, -ORV, (C3- C6)cycloalkyl, cyano, phenyl, and (Ci-C'4)alkyleneNR R and / or two Rcare taken together on adjacent carbon atoms to form a 5- to 7- membered heterocyclyl.

13. The compound of any one of Claims 1 to 11, or a pharmaceutically acceptable salt thereof, wherein Rcis selected from (C1-C4)alkyl. halo(C1-C4)alkyl, halo, -ORV. cyclopropyl, cyclopentyl, cyclobutyl, cyano, phenyl, tetrahydrofuranyl, oxazolyl, (C 1- C4)alkylene(cyclopropyl), -(C2-C4)alkynyl(cyclopropyl)-NRXRY, and (Ci-C'4)alkyleneNR R ; and / or two Rcare taken together on adjacent carbon atoms to form a 1,3- dioxolanyl.

14. The compound of any one of Claims 1 to 11, or a pharmaceutically acceptable salt thereof, wherein Rcis selected from (C1-C4)alkyl, halo(C1-C4)alkyl, halo, -ORV, cyclopropyl, cyano, phenyl, and (C1-C4)alkyleneNRxRY; and / or two Rcare taken together on adjacent carbon atoms to form a 1,3-dioxolanyl.

15. The compound of any one of Claims 1 to 14, or a pharmaceutically acceptable salt thereof, wherein Rvis selected from hydrogen, (C1-C4)alkyl, halo(C1-C4)alkyl, (C3- Cejcycloalkyl, (C1-C4)alkylene(C3-C6)cycloalkyl, and 4- to 7- membered heterocyclyl.

16. The compound of any one of Claims 1 to 14, or a pharmaceutically acceptable salt thereof, wherein Rvis selected from hydrogen, (C1-C4)alkyl, halo(C1-C4)alkyl, (C3- Cejcycloalkyl, and 4- to 7- membered heterocyclyl.

17. The compound of any one of Claims 1 to 14, or a pharmaceutically acceptable salt thereof, wherein Rvis selected from hydrogen, (C1-C4)alkyl, halo(C1-C4)alkyl, cyclopropyl, cyclopentyl, cyclobutyl, cyclobutyl, -(C1-C4)alkylene(cyclopropyl). and pyrrolidinyl.

18. The compound of any one of Claims 1 to 14, or a pharmaceutically acceptable salt thereof, wherein Rvis selected from hydrogen, (C1-C4)alkyl, halo(C1-C4)alkyl, cyclopropyl, and pyrrolidinyl.

19. The compound of any one of Claims 1 to 14, or a pharmaceutically acceptable salt thereof, wherein Rxand RYare each independently hydrogen or (C1-C4)alkyl.

20. The compound of any one of Claims 1 to 10, or a pharmaceutically acceptable salt21. The compound of any one of Claims 1 to 10, or a pharmaceutically acceptable salt thereof, wherein Rcis selected from22. The compound of Claim 1, wherein the compound is selected from any one of Compounds 1 to 672; or a pharmaceutically acceptable salt thereof.

23. A pharmaceutical composition comprising a compound of any one of Claims 1 to 21, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

24. 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 21, or a pharmaceutically acceptable salt thereof, or the composition of Claim 23.

25. The method of Claim 24. wherein the proliferative disorder is cancer.

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