Anaplastic lymphoma kinase (ALK) degraders 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 ALK.

Description

136883-01520ANAPLASTIC LYMPHOMA KINASE (ALK) DEGRADERS AND USES THEREOFRELATED APPLICATIONS

[0001] This application claims the benefit of priority to U.S. Provisional Application No. 63 / 681,226 filed August 9, 2024 and U.S. Provisional Application No. 63 / 710,416, filed October 22, 2024, the entire contents of each of which are incorporated herein by reference.BACKGROUND

[0002] Anaplastic Lymphoma Kinase (ALK) is a receptor tyrosine kinase whose expression and function in normal organisms is limited to the developing nervous system, and whose activity is regulated by extracellular ligand binding. In certain cancers including subsets of lung cancer, T-cell lymphoma, and neuroblastoma, ALK is rendered ligandindependent by activating mutations or fusion events that cause uncontrolled proliferation, survival, and metastatic spread. In approximately 5% of non-small cell lung cancer (NSCLC), ALK is involved in fusions, the most common of which involve coding sequences from the Echinoderm Microtubule Associated Like 4 (EML4) gene, creating EML4-ALK oncogenic fusions. Given the prevalence of ALK fusion events in NSCLC, multiple generations of ALK tyrosine kinase inhibitors (TKI) are approved by the FDA for treatment of ALK positive NSCLC. While highly efficacious, durable response to these drugs is limited by selection of ALK resistance mutations that prevent drug binding. Removing oncogenic ALK protein via targeted protein degradation presents an alternative therapeutic option for treating ALK positive cancers.

[0003] Currently disclosed degraders of ALK use a bivalent approach that requires binding to the enzymatic active site and would be subject to known TKI resistance mutations. However, a monovalent ALK molecular glue degrader that recruits an E3 ligase via sites distal to the sites involved in inhibitor binding has the potential to expand the treatment options for ALK positive cancers by addressing both wild-type and all clinically relevant resistance alleles. Further, an ALK molecular glue degrader that acts independently of kinase inhibition can be combined with approved TKI drugs to improve efficacy and tolerability.SUMMARY

[0004] Provided herein are compounds having the Formula I:1MEl\56453932.vl136883-01520and pharmaceutically acceptable salts and compositions thereof, wherein R1, R2, R3, R3a, R4, Y, and v are as described herein. In one aspect, the disclosed compounds of Formula I and pharmaceutically acceptable salts thereof modulate ALK (e.g., as degraders of ALK), and are useful in a variety of therapeutic applications such as, for example, in treating cancer.

[0005] 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

[0006] In a first embodiment, provided herein is a compound of Formula I:or a pharmaceutically acceptable salt thereof, whereinR1, R2, R3, and R3aare each independently hydrogen or (Ci-C4)alkyl; or the nitrogen atom attached to R2is taken together with the carbon atom attached to R1to form a 5- to 7- membered heterocyclyl, wherein the substituents R1and R2are no longer present as a result of the ring formation and wherein said 5- to 7-membered heterocyclyl is optionally substituted with 1 to 4 groups selected from RA;Y is heteroaryl or heterocyclyl, each optionally substituted with 1 to 3 groups selected from RE;R4is absent or is phenyl or heteroaryl, each of which are optionally substituted with 1 to 4 group selected from RB;RAand REare each independently selected from cyano, halo, (Ci-C4)alkyl, halo(Ci- C4)alkyl, (Ci-C4)alkoxy, and halo(Ci-C4)alkoxy;2MEl\56453932.vl136883-01520RBis selected from halo, (Ci-C4)alkyl, halo(Ci-C4)alkyl, (Ci-C4)alkoxy, halo(Ci- C4)alkoxy, hydroxy, (Ci-C4)alkyleneOH, (Ci-C4)alkylene(Ci-C4)alkoxy, -(Ci- C4)alkyleneNRxRY, cyano, oxo, -(Ci-C4)alkoxyNRxRY, -(Ci-C4)alkyleneC(O)ORx, -(Ci- C4)alkoxyC(O)ORx, -(Ci-C4)alkyleneC(O)Rx, -(Ci-C4)alkoxyC(O)Rx, -(Ci- C4)alkyleneheterocyclyl, -(Ci-C4)alkyleneheteroaryl, -(Ci-C4)alkoxyheterocyclyl, -(Ci- C4)alkoxyheteroaryl, -(Ci-C4)alkylenecycloalkyl, -(Ci-C4)alkoxy cycloalkyl, -(Ci- C4)alkylenephenyl, -(Ci-C4)alkoxyphenyl -NRx(Ci-C4)alkyleneheteroaryl, -NRx(Ci- C4)alkyleneheterocyclyl, -NRx(Ci-C4)alkylenecycloalkyl, cycloalkyl, heteroaryl, heterocyclyl, -NRXRY, -NRXC(O)RY, -NRXC(O)ORY, -NRx(Ci-C4)alkyleneC(O)NRxRz, - NRXC(O)NRXRZ, -(Ci-C4)alkyleneNRxC(O)RY, -(Ci-C4)alkyleneNRxC(O)ORY, -(Ci- C4)alkyleneNRx(Ci-C4)alkyleneC(O)NRxRz, -(Ci-C4)alkyleneNRxC(O)NRxRz, -(Ci- C4)alkoxyNRxC(O)RY, -(Ci-C4)alkoxyNRxC(O)ORY, -(Ci-C4)alkoxyNRx(Ci- C4)alkyleneC(O)NRxRz, -(Ci-C4)alkoxyNRxC(O)NRxRz, -S(Ci-C4)alkyl, -O(heteroaryl), - O(heterocyclyl), -O(cycloalkyl), -C(O)NRXRY-(Ci-C4)alkyleneC(O)NRxRY, -(Ci- C4)alkoxyC(O)NRxRY, -C(O)RX, and -C(O)ORX, wherein each of said cycloalkyl, phenyl, heteroaryl, and heterocyclyl recited alone, or recited as being part of a larger group, are optionally substituted with 1 to 3 groups selected from Rc;Rcis selected from (Ci-C4)alkyl, halo(Ci-C4)alkyl, (Ci-C4)alkoxy, halo(Ci-C4)alkoxy cyano, oxo, and hydroxy;Rx, RY, and Rzare each independently selected from hydrogen, (Ci-C4)alkyl, halo(Ci- C4)alkyl, phenyl, benzyl, (C3-Ce)cycloalkyl, 4- to 6-membered heterocyclyl, and 5- to 7- membered heteroaryl; and v is 1, 2, or 3; provided the compound is not 3-[2,5-Dihydro-3-[methyl[(3-phenyl-l,2,4-oxadiazol-5- yl)methyl]amino]-2,5-dioxo-lH-pyrrol-l-yl]-2,6-piperidinedione, 3-[2,5-Dihydro-3-[[(l- methyl-lH-indol-6-yl)methyl]amino]-2,5-dioxo-lH-pyrrol-l-yl]-2,6-piperidinedione, 3-[2,5- Dihydro-2,5-dioxo-3-[(3-pyridinylmethyl)amino]-lH-pyrrol-l-yl]-2,6-piperidinedione, 3-(3- (((4-chloropyri din-2 -yl)methyl)(methyl)amino)-2,5-di oxo-2, 5-dihydro- IH-pyrrol-l- yl)piperidine-2, 6-dione, or a pharmaceutically acceptable salt of any of the foregoing.2. Definitions

[0007] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure pertains. The terminology used in the description is for describing particular embodiments only and is not intended to be limiting of the disclosure.3MEl\56453932.vl136883-01520

[0008] As used in the structure herein a hyphen (-) or squiggly line “ ” indicates the point of attachment of the particular depicted structure or substituent group to the appropriate atom(s) in the remainder of the molecule. For example, -[(Ci-C6)alkyl]heteroaryl means that the point of attachment for this group occurs on the (Ci-Ce)alkyl.

[0009] The terms “halo” and “halogen” refer to an atom selected from fluorine (fluoro, -F), chlorine (chloro, -Cl), bromine (bromo, -Br), and iodine (iodo, -I).

[0010] 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.

[0011] “Alkoxy” means an alkyl radical attached through an oxygen linking atom, represented by -O-alkyl. For example, “(Ci-C4)alkoxy” includes methoxy, ethoxy, proproxy, and butoxy.

[0012] The term “haloalkyl” includes mono, poly, and perhaloalkyl groups where the halogens are independently selected from fluorine, chlorine, bromine, and iodine.

[0013] “Haloalkoxy” is a haloalkyl group which is attached to another moiety via an oxygen atom such as, e.g., -OCHF2 or -OCF3.

[0014] 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.

[0015] The term oxo means the group =0.

[0016] The term “heteroaryl” used alone or as part of a larger moiety refers to, unless otherwise specified, a 5- to 12-membered aromatic radical containing 1-4 heteroatoms selected from N, O, and S. A heteroaryl group may be mono- or bi-cyclic. Monocyclic heteroaryl includes, for example, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, triazinyl, tetrazinyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, etc. Bi-cyclic heteroaryls include groups in which a monocyclic heteroaryl ring is fused to one or more aryl or heteroaryl rings. Nonlimiting examples include indolyl, imidazopyridinyl, benzooxazolyl, benzooxodiazolyl, indazolyl, benzimidazolyl, benzthiazolyl, quinolinyl, 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.4MEl\56453932.vl136883-01520

[0017] The term “heterocyclyl” means, unless otherwise specified, a 5- to 12-membered saturated or partially unsaturated heterocyclic ring containing 1 to 4 heteroatoms independently selected from N, O, and S. It can be monocyclic, bicyclic (e.g., a bridged, fused, or spiro bicyclic ring), or tricyclic. A heterocyclyl ring can be attached to its pendant group at any heteroatom or carbon atom that results in a stable structure. Examples of such saturated or partially unsaturated heterocyclic radicals include, without limitation, tetrahydrofuranyl, tetrahydrothienyl, terahydropyranyl, pyrrolidinyl, pyridinonyl, pyrrolidonyl, piperidinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, morpholinyl, dihydrofuranyl, dihydropyranyl, dihydropyridinyl, tetrahydropyridinyl, dihydropyrimidinyl, oxetanyl, azetidinyl and tetrahydropyrimidinyl. A heterocyclyl group may be mono- or bicyclic. The term “heterocyclyl” also includes, e.g., unsaturated heterocyclic radicals fused to another unsaturated heterocyclic radical or aryl or heteroaryl ring, such as for example, tetrahydronaphthyridine, indolinone, dihydropyrrolotriazole, imidazopyrimidine, quinolinone, dioxaspirodecane. It will also be understood that when specified, optional substituents on a heterocyclyl group may be present on any substitutable position.

[0018] The term “spiro” refers to two rings that shares one ring atom (e.g., carbon).

[0019] The term “fused” refers to two rings that share two adjacent ring atoms with one another.

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

[0021] The terms “cycloalkyl”, used alone or as part of a larger moiety, refers to a saturated cyclic aliphatic monocyclic or bicyclic ring system, as described herein, having from, unless otherwise specified, 3 to 10 carbon ring atoms. Monocyclic cycloalkyl groups include, without limitation, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cycloheptenyl, and cyclooctyl. It will be understood that when specified, optional substituents on a cycloalkyl may be present on any substitutable position.

[0022] 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.5MEl\56453932.vl136883-01520

[0023] The term “optionally substituted,” as used herein to describe a chemical moiety defined herein, means that the moiety may, but is not required to be, substituted with one or more suitable functional groups or other substituents as provided herein.

[0024] As used herein, the term “substituted” means that an atom or group of atoms has replaced hydrogen as the substituent attached to another group.

[0025] 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.

[0026] As used herein, the term “about” will 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 when referring to a measurable value such as an amount, a temporal duration, and the like, the term “about” is 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.

[0027] 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.

[0028] 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.6MEl\56453932.vl136883-01520

[0029] 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.

[0030] 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.

[0031] 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.

[0032] The term “inhibit,” “inhibition” or “inhibiting” includes a decrease in the baseline activity of a biological activity or process.

[0033] 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, z.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), z.e., prophylactic treatment. Treatment may also be continued after symptoms have resolved, for example to delay their recurrence.

[0034] The term “pharmaceutically acceptable carrier” refers to a non-toxic carrier, adjuvant, or vehicle that does not destroy the pharmacological activity of the compound with which it is formulated. Pharmaceutically acceptable carriers, adjuvants or vehicles that may be used in the compositions described herein include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based7MEl\56453932.vl136883-01520 substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol and wool fat.

[0035] 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 acceptable base(s). Suitable pharmaceutically acceptable basic salts include e.g., ammonium salts, alkali metal salts (such as sodium and potassium salts) and alkaline earth metal salts (such as magnesium and calcium salts). Compounds with a quaternary ammonium group also contain a counteranion such as chloride, bromide, siodide, acetate, perchlorate and the like. Other examples of such salts include hydrochlorides, hydrobromides, sulfates, methanesulfonates, nitrates, benzoates and salts with amino acids such as glutamic acid.

[0036] 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

[0037] As part of a second embodiment, R2in the compound having the Formula I, or a pharmaceutically acceptable salt thereof, is (Ci-C4)alkyl, wherein the remaining variables are as described above for Formula I. Alternatively, as part of a second embodiment, R2in the compound having the Formula I, or a pharmaceutically acceptable salt thereof, is CH3, wherein the remaining variables are as described above for Formula I.

[0038] As part of a third embodiment, R1in the compound having the Formula I, or a pharmaceutically acceptable salt thereof, is CH3, CH2CH3, or hydrogen, wherein the remaining variables are as described above for Formula I or the second embodiment. Alternatively, as part of a third embodiment, R1in the compound having the Formula I, or a pharmaceutically acceptable salt thereof, is hydrogen, wherein the remaining variables are as described above for Formula I or the second embodiment.

[0039] As part of a fourth embodiment, the compound having the Formula I is of the structural Formula II:8MEl\56453932.vl136883-01520or a pharmaceutically acceptable salt thereof, wherein the remaining variables are as described above for Formula I or any one of the second to fourth embodiments.

[0040] As part of a fifth embodiment, v in the compound of Formula I or II is 1, wherein the remaining variables are as described above for Formula I or any one of the second or third embodiment.

[0041] As part of a sixth embodiment, R3ain the compound having the Formula I or II, or a pharmaceutically acceptable salt thereof, is hydrogen, wherein the remaining variables are as described above for Formula I or any one of the second, third, and fifth embodiments.

[0042] As part of a seventh embodiment, R3in the compound having the Formula I or II, or a pharmaceutically acceptable salt thereof, is CH3 or hydrogen, wherein the remaining variables are as described above for Formula I or any one of the second, third, fifth, and sixth embodiments. Alternatively, as part of a seventh embodiment, R3in the compound having the Formula I or II, or a pharmaceutically acceptable salt thereof, is hydrogen, wherein the remaining variables are as described above for Formula I or any one of the second, third, fifth, and sixth embodiments.

[0043] As part of an eighth embodiment, Y in the compound having the Formula I or II, or a pharmaceutically acceptable salt thereof, is heteroaryl optionally substituted with 1 to 3 groups selected from RE, wherein the remaining variables are as described above for Formula I or any one of the second, third, and fifth to seventh embodiments. Alternatively, as part of an eighth embodiment, Y in the compound having the Formula I or II, or a pharmaceutically acceptable salt thereof, is 5- to 9-membered heteroaryl optionally substituted with 1 to 3 groups selected from RE, wherein the remaining variables are as described above for Formula I or any one of the second, third, and fifth to seventh embodiments. In another alternative, as part of an eighth embodiment, Y in the compound having the Formula I or II, or a pharmaceutically acceptable salt thereof, is 5-membered heteroaryl optionally substituted with 1 to 3 groups selected from RE, wherein the remaining variables are as described above for Formula I or any one of the second, third, and fifth to seventh embodiments. In another alternative, as part of an eighth embodiment, Y in the compound having the Formula I or II, or a pharmaceutically acceptable salt thereof, is oxadiazolyl, triazolyl, oxazolyl, isoxazolyl,9MEl\56453932.vl136883-01520 or thiadiazolyl, each optionally substituted with 1 to 3 groups selected from RE, wherein the remaining variables are as described above for Formula I or any one of the second, third, and fifth to seventh embodiments. In another alternative, as part of an eighth embodiment, Y in the compound having the Formula I or II, or a pharmaceutically acceptable salt thereof, is benzooxazolyl or benzothiazolyl, each optionally substituted with 1 to 3 groups selected from RE, wherein the remaining variables are as described above for Formula I or any one of the second, third, and fifth to seventh embodiments.

[0044] As part of a ninth embodiment, REin the compound having the Formula I or II, or a pharmaceutically acceptable salt thereof, is (Ci-C4)alkyl, wherein the remaining variables are as described above for Formula I or any one of the second, third, and fifth to eighth embodiments.

[0045] As part of a tenth embodiment, Y in the compound having the Formula I or II, orwherein * indicates the attachment position to R4, wherein the remaining variables are as described above for Formula I or any one of the second, third, and fifth to ninth embodiments.

[0046] As part of an eleventh embodiment, R4in the compound having the Formula I or II, or a pharmaceutically acceptable salt thereof, is phenyl or heteroaryl, each of which are optionally substituted with 1 to 4 groups selected from RB, wherein the remaining variables are as described above for Formula I or any one of the second, third, and fifth to tenth embodiments. Alternatively, as part of an eleventh embodiment, R4in the compound having the Formula I or II, or a pharmaceutically acceptable salt thereof, is phenyl, pyridinyl, imidazolyl, pyrazolyl, pyrrolyl, thiazolyl, oxazolyl, isoxazolyl, benzooxazolyl, indolyl, or benzoimidazolyl, each of which are optionally substituted with 1 to 4 groups selected from RB, each of which are optionally substituted with 1 to 4 groups selected from RB, wherein the10MEl\56453932.vl136883-01520 remaining variables are as described above for Formula I or any one of the second, third, and fifth to tenth embodiments.

[0047] As part of a twelfth embodiment, RBin the compound having the Formula I or II, or a pharmaceutically acceptable salt thereof, is selected from halo, (Ci-C4)alkyl, halo(Ci- C4)alkyl, (Ci-C4)alkoxy, -C(O)ORX, (Ci-C4)alkyleneOH, OH, cycloalkyl, -O(cycloalkyl), phenyl, -O(phenyl), heteroaryl, -O(heteroaryl), heterocyclyl, -NRXRY, -C(O)NRXRY, (Ci- C4)alkyleneNRxC(O)ORY, and (Ci-C4)alkyleneNRxRY, wherein said cycloalkyl, phenyl, heterocyclyl, and heteroaryl are optionally substituted with 1 to 3 groups selected from Rc, wherein the remaining variables are as described above for Formula I or any one of the second, third, and fifth to eleventh embodiments. Alternatively, as part of a twelfth embodiment, RBin the compound having the Formula I or II, or a pharmaceutically acceptable salt thereof, is selected from halo, (Ci-C4)alkyl, halo(Ci-C4)alkyl, (Ci-C4)alkoxy, - C(O)ORX, (Ci-C4)alkyleneOH, OH, 3- to 6-membered cycloalkyl, -0(3- to 6-membered cycloalkyl), phenyl, -O(phenyl), -0(5- to 10-membered heteroaryl), 5- to 10-membered heteroaryl, 4- to 6-membered heterocyclyl, -NRXRY, -C(O)NRXRY, (Ci- C4)alkyleneNRxC(O)ORY, and (Ci-C4)alkyleneNRxRY, wherein said 3- to 6-membered cycloalkyl, phenyl, 5- to 9-membered heteroaryl, and 4- to 6-membered heterocyclyl are each optionally substituted with 1 to 3 groups selected from Rc, wherein the remaining variables are as described above for Formula I or any one of the second, third, and fifth to eleventh embodiments. In another alternative, as part of a twelfth embodiment, RBin the compound having the Formula I or II, or a pharmaceutically acceptable salt thereof, is selected from halo, (Ci-C4)alkyl, halo(Ci-C4)alkyl, (Ci-C4)alkoxy, -C(0)0Rx, (Ci-C4)alkyleneOH, OH, cyclopropyl, cyclopentyl, cyclohexyl, -O(phenyl), -O(cyclopropyl), phenyl, -O(pyridinyl), pyridinyl, quinolinyl, imidazolyl, pyrimidinyl, pyridazinyl, pyrazinyl, pyrrolidinyl, pyrrolopyridinyl, benzoxazolyl, oxazolyl, isooxazolyl dihydropyranyl, isothiazolyl, tetrahydropyranyl, morpholinyl, piperazinyl, -NRXRY, (Ci-C4)alkyleneNRxC(O)ORY, - C(0)NRXRY, and (Ci-C4)alkyleneNRxRY, wherein said cyclopropyl, cyclopentyl, cyclohexyl, phenyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, pyrrolopyridinyl, benzoxazolyl, oxazolyl, morpholinyl, dihydropyranyl, isothiazolyl, tetrahydropyranyl, and piperazinyl are optionally substituted with 1 to 3 groups selected from Rc, wherein the remaining variables are as described above for Formula I or any one of the second, third, and fifth to eleventh embodiments.

[0048] As part of a thirteenth embodiment, Rxand RYin the compound having the Formula I or II, or a pharmaceutically acceptable salt thereof, are independently selected11MEl\56453932.vl136883-01520 from hydrogen and (Ci-C4)alkyl, wherein the remaining variables are as described above for Formula I or any one of the second, third, and fifth to twelfth embodiments.

[0049] As part of a fourteenth embodiment, Rcin the compound having the Formula I or II, or a pharmaceutically acceptable salt thereof, is selected from (Ci-C4)alkyl, halo(Ci- C4)alkyl, oxo, and (Ci-C4)alkoxy, wherein the remaining variables are as described above for Formula I or any one of the second, third, and fifth to thirteenth embodiments.

[0050] As part of a fifteenth embodiment, R4in the compound having the Formula I or cAII, or a pharmaceutically acceptable salt thereof, is selected from i12MEl\56453932.vl136883-0152013MEl\56453932.vl136883-01520variables are as described above for Formula I or any one of the second, third, and fifth to fourteenth embodiments.

[0051] 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

[0052] The compounds and compositions described herein are generally useful for modulating the activity of anaplastic lymphoma kinase (ALK). In some aspects, the compounds, pharmaceutical acceptable salts, and pharmaceutical compositions described herein degrade ALK.

[0053] In some aspects, the compounds and pharmaceutical compositions described herein are useful in treating a disorder associated with ALK function. Thus, provided herein14MEl\56453932.vl136883-01520 are methods of treating a disorder associated with ALK 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.

[0054] 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 ALK 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 ALK.

[0055] In one aspect, the disorder associated with ALK is a proliferative disease such as cancer. Representative examples of cancers include adrenocortical carcinoma, AIDS-related cancers (e.g., Kaposi’s and AIDS-related lymphoma), appendix cancer, childhood cancers (e.g., childhood cerebellar astrocytoma, childhood cerebral astrocytoma), basal cell carcinoma, skin cancer (non-melanoma), biliary cancer, extrahepatic bile duct cancer, intrahepatic bile duct cancer, bladder cancer, urinary bladder cancer, brain cancer (e.g., gliomas and glioblastomas such as brain stem glioma, gestational trophoblastic tumor glioma, cerebellar astrocytoma, cerebral astrocytoma / malignant glioma, ependymoma, medulloblastoma, supratentorial primitive neuroectodeimal tumors, visual pathway and hypothalamic glioma), breast cancer, bronchial adenomas / carcinoids, carcinoid tumor, nervous system cancer (e.g, central nervous system cancer, central nervous system lymphoma), cervical cancer, chronic myeloproliferative disorders, colorectal cancer (e.g, colon cancer, rectal cancer), polycythemia vera, lymphoid neoplasm, mycosis fungoids, Sezary Syndrome, endometrial cancer, esophageal cancer, extracranial germ cell tumor, extragonadal germ cell tumor, extrahepatic bile duct cancer, eye cancer, intraocular melanoma, retinoblastoma, gallbladder cancer, gastrointestinal cancer (e.g, stomach cancer, small intestine cancer, gastrointestinal carcinoid tumor, gastrointestinal stromal tumor (GIST)), germ cell tumor, ovarian germ cell tumor, head and neck cancer, Hodgkin’s lymphoma, leukemia, lymphoma, multiple myeloma, hepatocellular carcinoma, hypopharyngeal cancer, intraocular melanoma, ocular cancer, islet cell tumors (endocrine pancreas), renal cancer (e.g, Wilm’s Tumor, clear cell renal cell carcinoma), liver cancer, lung cancer (e.g, non-small cell lung cancer and small cell lung cancer), Waldenstrom’s macroglobulinema, melanoma, intraocular (eye) melanoma, merkel cell carcinoma,15MEl\56453932.vl136883-01520 mesothelioma, metastatic squamous neck cancer with occult primary, multiple endocrine neoplasia (MEN), myelodysplastic syndromes, essential thrombocythemia, myelodysplastic / myeloproliferative diseases, nasopharyngeal cancer, neuroblastoma, oral cancer (e.g, mouth cancer, lip cancer, oral cavity cancer, tongue cancer, oropharyngeal cancer, throat cancer, laryngeal cancer), ovarian cancer (e.g, ovarian epithelial cancer, ovarian germ cell tumor, ovarian low malignant potential tumor), pancreatic cancer, islet cell pancreatic cancer, paranasal sinus and nasal cavity cancer, parathyroid cancer, penile cancer, pharyngeal cancer, pheochromocytoma, pineoblastoma, pituitary tumor, plasma cell neoplasm, pleuropulmonary blastoma, prostate cancer, retinoblastoma rhabdomyosarcoma, salivary gland cancer, uterine cancer (e.g., endometrial uterine cancer, uterine sarcoma, uterine corpus cancer), squamous cell carcinoma, testicular cancer, thymoma, thymic carcinoma, thyroid cancer, transitional cell cancer of the renal pelvis and ureter and other urinary organs, urethral cancer, gestational trophoblastic tumor, vaginal cancer and vulvar cancer.

[0056] Sarcomas that may be treatable with compounds, pharmaceutically acceptable salts of the compounds and compostions comprising such as described herein include both soft tissue and bone cancers alike, representative examples of which include osteosarcoma or osteogenic sarcoma (bone) (e.g., Ewing’s sarcoma), chondrosarcoma (cartilage), leiomyosarcoma (smooth muscle), rhabdomyosarcoma (skeletal muscle), mesothelial sarcoma or mesothelioma (membranous lining of body cavities), fibrosarcoma (fibrous tissue), angiosarcoma or hemangioendothelioma (blood vessels), liposarcoma (adipose tissue), glioma or astrocytoma (neurogenic connective tissue found in the brain), myxosarcoma (primitive embryonic connective tissue) and mesenchymous or mixed mesodermal tumor (mixed connective tissue types)

[0057] In some aspects, the cancer treated by the compounds, pharmaceutically acceptable salt thereof, and pharmaceutical compositions described herein is an ALK positive cancer.

[0058] In some aspects, the cancer treated by the compounds, pharmaceutically acceptable salt thereof, and pharmaceutical compositions described herein is selected from non-small cell lung cancer (NSCLC), large cell lymphoma (ALCL), or neuroblastomas.

[0059] In one aspect, the disorder associated with ALK is selected from a non-cancerous disorder such as inflammatory diseases and conditions, autoimmune diseases, neurodegenerative diseases, heart diseases, viral diseases, chronic and acute kidney diseases or injuries, metabolic diseases, and allergic and genetic diseases.16MEl\56453932.vl136883-01520

[0060] In certain aspects, a pharmaceuticalcomposition described herein is formulated for administration to a patient in need of such composition. Pharmaceutical compositions described herein may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir. The term "parenteral" as used herein includes subcutaneous, intravenous, intramuscular, intra-articular, intra-synovial, intrasternal, intrathecal, intrahepatic, intralesional and intracranial injection or infusion techniques. In some embodiments, the compositions are administered orally, intraperitoneally or intravenously. Sterile injectable forms of the pharmaceutical compositions described herein may be aqueous or oleaginous suspension. These suspensions may be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents.

[0061] In some aspects, the pharmaceutical compositions are administered orally.

[0062] A specific dosage and treatment regimen for any particular patient will depend upon a variety of factors, including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination, and the judgment of the treating physician and the severity of the particular disease being treated. The amount of a compound described herein in the composition will also depend upon the particular compound in the pharmaceutical composition.EXEMPLIFICATION

[0063] 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.Intermediates

[0064] Intermediate A: Maleimide electrophile partner

[0065] Intermediate A-l; 3-(3-bromo-2.,5-dioxo-2.,5-dihydro-lH-pyrrol-l- yl)piperidine-2.,6-dione

[0066] To a solution of commercially available 3-aminopiperidine-2, 6-dione hydrochloride (1.0 g, 6.1 mmol) in dioxane (14 mL) was added 3-bromofuran-2, 5-dione (1.2 g, 6.7 mmol, 0.62 mL). The mixture was stirred at 80 °C for 1 hour. AcONa (550 mg, 6.717MEl\56453932.vl136883-01520 mmol) was added, and the resulting mixture was stirred for 5 hours at 80 °C. Then, AC2O (680 mg, 6.7 mmol) was added. The resulting mixture was stirred at 100 °C overnight. The reaction mixture was concentrated under reduced pressure and diluted with DCM. The suspension was filtered, and the filtrate was washed with a solution of sat. aqueous NaHCCh. The organic layer was dried over anh. sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluent MeOH: DCM=20: l) to afford 3-(3-bromo-2,5-dioxo-2,5-dihydro-lH-pyrrol-l-yl)piperidine-2, 6-dione (440 mg, 1.5 mmol, 25%) as light yellow. [M+H]+calcd: 286; found: 287. 'H NMR (400 MHz, DMSO) 5 11.11 (s, 1H), 7.59 (d, J= 4.5 Hz, 1H), 5.04 (dd, J= 13.1, 5.4 Hz, 1H), 2.84 (ddd, J= 17.5, 13.9, 5.4 Hz, 1H), 2.57 (d, J= 17.3 Hz, 1H), 2.40 (qd, J= 13.3, 4.5 Hz, 1H), 2.02 (ddd, J= 10.2, 6.7, 2.6 Hz, 1H).

[0067] Intermediate A-2: 3-(3-bromo-4-methyl-2.,5-dioxo-2.,5-dihvdro-lH-pyrrol-l- yl)hexahydroDyridine-2.,6-dione

[0068] Preparation of 3-bromo-4-methylfuran-2, 5-dione

[0069] To a solution of 3-methylfuran-2, 5-dione (5 g, 45 mmol) in bromine (7.8 g, 49 mmol) was added aluminium tribromide (1.2 g, 4.5 mmol) at 20°C. The solution was stirred at 100 °C for 18 hr. The mixture was diluted with EtOAc (50 mL) and filtered. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated to give 3-bromo-4-methylfuran-2, 5-dione (7 g, 37 mmol, 82%) as a white solid.1H NMR (400 MHz, DMSO-tfc) 52.09 (s, 3H).

[0070] Preparation of 3-(3-bromo-4-methyl-2,5-dioxo-2,5-dihydro-lH-pyrrol-l- yl)hexahydropyridine-2, 6-dione18MEl\56453932.vl136883-01520

[0071] To a solution of 3-bromo-4-methylfuran-2, 5-dione (500 mg, 2.6 mmol) in AcOH (5 mL) were added sodium acetate (430 mg, 5.2 mmol) and 3 -aminopiperidine-2, 6-dione hydrochloride (430 mg, 2.6 mmol) at 20 °C. The mixture was stirred at 100 °C for 2h. A saturated aqueous solution of NH4Q (40 mL) and water (40 mL) were added. The resulting mixture was extracted with EtOAc (2 x 50 mL) and the combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated. The crude residue was purified by flash column chromatography eluting with a gradient of 20-40% EtOAc in heptanes to give 3-(3-bromo-4-methyl-2,5-dioxo-2,5-dihydro-lH-pyrrol-l- yl)hexahydropyridine-2, 6-dione (600 mg, 2.0 mmol, 76%) as a yellow solid. LCMS (m / z): [M+H]+calcd: 300; found: 301. 'H NMR (400 MHz, DMSO-tA) 5 11.11 (s, 1H), 5.04 (dd, J = 13.0, 5.4 Hz, 1H), 2.85 (ddd, J= 17.4, 14.0, 5.4 Hz, 1H), 2.58 (d, J= 17.6 Hz, 1H), 2.42 (qd, J= 13.3, 4.4 Hz, 1H), 2.07 - 1.96 (m, 4H).

[0072] Intermediate B: Amine nucleophile partners

[0073] Amine coupling partners general procedures:

[0074] Intermediate B-l: 3-(3-bromophenyl)-5-(chloromethyl)-l.,2.,4-oxadiazole

[0075] Preparation of 3-bromo-N-hydroxybenzimidamide

[0076] To a solution of NH2OH (1.81 g, 54.93 mmol) in MeOH (110 mL) was added KOH (3.08 g, 54.93 mmol) in MeOH (110 mL) at 0 °C, and the reaction was stirred at 0 °C - RT for 30 min. KC1 salt was removed by filtration, and the filtrate was added to 3- bromobenzene-1 -carbonitrile (10 g, 54.93 mmol). The reaction mixture was stirred at 60 °C for 2 hours, then cooled, poured into saturated NH4Q, and extracted with EtOAc. The19MEl\56453932.vl136883-01520 organic layer was washed with brine, dried over anhydrous Na2SO4 and concentrated to give N-[azanylidene(3-bromophenyl)methyl]hydroxylamine (11 g, 51.15 mmol, 93.10%) as a white solid. LCMS (m / z): [M+H]+calcd: 214; found: 215. 'HNMR (400 MHz, DMSO-tL) 5 9.79 (s, 1H), 7.85 (t, J= 1.6 Hz, 1H), 7.63 (dd, J= 45.8, 8.4 Hz, 2H), 7.34 (t, J= 7.8 Hz, 1H), 5.90 (s, 2H).

[0077] Preparation of 3-(3-bromophenyl)-5-(chloromethyl)-l,2,4-oxadiazole

[0078] To a solution of N-[azanylidene(3-bromophenyl)methyl]hydroxylamine (2 g, 9.30 mmol) in toluene (20 mL) were added TEA (3.23 mL, 23.25 mmol) and chloroacetyl chloride (0.81 mL, 10.23 mmol) dropwise at 0 °C. The resulting mixture was stirred at 110 °C under N2 for 2 hours, after which the reaction mixture was quenched with ice water and extracted with EtOAc twice. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated, and the residue was purified by FCC on silica gel (0-50%, EA in PE) to obtain 3-(3-bromophenyl)-5-(chloromethyl)-l,2,4-oxadiazole (1.60 g, 5.85 mmol, 62.90%) as a white solid. LCMS (m / z): [M+H]+calcd: 272; found: 273. 'HNMR (400 MHz, DMSO-tL) 5 8.07 (t, J= 1.7 Hz, 1H), 7.97 (d, J= 7.8 Hz, 1H), 7.79 - 7.75 (m, 1H), 7.50 (t, J = 7.8 Hz, 1H), 5.18 (s, 2H).

[0079] Preparation of 3-(3-bromophenyl)-5-[(methylamino)methyl]-l,2,4-oxadiazole

[0080] A solution of 3-(3-bromophenyl)-5-(chloromethyl)-l,2,4-oxadiazole (1.6 g, 5.9 mmol) and methylamine in THF (20 mL, 2 M in THF) was stirred at 60 °C for 18 hours. The mixture was concentrated under reduced pressure. The crude was purified by flash column chromatography eluting with a gradient of 20-40% EtOAc in heptanes to afford 3-(3- bromophenyl)-5-[(methylamino)methyl]-l,2,4-oxadiazole (980 mg, 3.65 mmol, 62.48%) as a white solid. LCMS (m / z): [M+H]+calcd: 267; found: 268. 'H NMR (400 MHz, DMSO-tL) 5 8.11 (t, J= 1.6 Hz, 1H), 8.00 (d, = 7.8 Hz, 1H), 7.79 (dd, J= 8.0, 0.8 Hz, 1H), 7.54 (d, J = 7.8 Hz, 1H), 4.02 (s, 2H), 2.36 (s, 3H).20MEl\56453932.vl136883-01520

[0081] Intermediates below may be synthesized similarly to Intermediate B-l :21MEl\56453932.vl136883-0152022MEl\56453932.vl136883-0152023MEl\56453932.vl136883-0152024MEl\56453932.vl136883-0152025MEl\56453932.vl136883-0152026MEl\56453932.vl136883-0152027MEl\56453932.vl136883-0152028MEl\56453932.vl136883-01520

[0082] Intermediate C-l: 5-(chloromethyl)-3-(o-tolyl)-l.,2.,4-oxadiazole

[0083] Preparation of 2-chloro- V-hydroxyacetimidamide

[0084] To a solution of NaOEt (4.6 g, 67 mmol) in ethanol (30 mL) was added NH2OH HC1 (0.93 g, 13 mmol) at 0 °C. The reaction was stirred at 0 °C for 10 min under N2. Then, 3- chloroprop-l-yne (5 g, 67 mmol) was added at 0 °C to stirred at room temperature for 2 h under N2 at which point TLC indicated the reaction was complete. The solvent was removed in vacuo. Then the residue was purified by column chromatography on silica gel (0-10% MeOH in DCM) to afford 2-chloro-7V-hydroxyacetimidamide (2.8 g, 26 mmol, 38%) as a yellow solid. 'HNMR (400 MHz, DMSO) 5 9.43 (s, 1H), 5.63 (s, 2H), 4.00 (s, 2H).

[0085] Preparation of 3-(chloromethyl)-5-(p-tolyl)-l,2,4-oxadiazole29MEl\56453932.vl136883-01520

[0086] To a solution of 2-chloro-7V-hydroxyacetimidamide (2.7 g, 25 mmol) in DMF (20 mL) were added 4-methylbenzoyl chloride (3.9 g, 25 mmol) and triethylamine (3.6 mL, 27 mmol). The reaction was stirred at 130 °C for 5 h under N2. LCMS showed about 40 % of product was detected. The residue was extracted with ethyl acetate three times. The combined organic layers were dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (10-30% EA in PE) to afford 3- (chloromethyl)-5-(4-m ethylphenyl)- 1,2, 4-oxadiazole (960 mg, 4.6 mmol, 18%) as a white solid. [M+H]+calcd: 208.65; found: 209.00. 'HNMR (400 MHz, DMSO) 5 8.02 (d, J= 8.2 Hz, 2H), 7.47 (d, J= 8.1 Hz, 2H), 4.95 (s, 2H), 2.43 (s, 3H).

[0087] Preparation of 5-(chloromethyl)-3-(o-tolyl)- 1,2, 4-oxadiazole

[0088] To a solution of 3-(chloromethyl)-5-(4-methylphenyl)-l, 2, 4-oxadiazole (200 mg,0.96 mmol) in tetrahydrofuran (10 mL) was added methylamine (2 M in THF, 3.8 mL, 7.7 mmol). The reaction was stirred at 55 °C for 18 h under N2. LCMS indicated the reaction was complete. The solvent was removed under reduced pressure. Then the residue was purified by column chromatography on silica (0-5% MeOH in DCM) gel to afford 7V-methyl-l-(5-( / 2- tolyl)-l,2,4-oxadiazol-3-yl)methanamine (60 mg, 0.29 mmol, 31%) as a white solid. [M+H]+calcd: 203.25; found: 204.10.

[0089] Intermediates below may be synthesized similarly to Intermediate C-l:

[0090] Intermediate D-l: A-methyl-l-(4-(p-tolyl)oxazol-2-yl)methanamine

[0091] Preparation of 2-oxo-2-(p-tolyl)ethyl 2-hydroxyacetate30MEl\56453932.vl136883-01520

[0092] To a solution of 2-hydroxyacetic acid (1.8 g, 23 mmol) in ethanol (50 mL) was added CS2CO3 (7.7 g, 23 mmol), and the reaction was stirred at room temperature for 10 min. Then the solvent was removed under reduced pressure. The residue was dissolved in DMF (5 mL) and 2-bromo-l-(p-tolyl)ethan-l-one (10 g, 47 mmol) was added. The solution was stirred at room temperature for 18 h under N2. TLC indicated the reaction was complete. Then the reaction was extracted with ethyl acetate three times. The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (0-10% MeOH in DCM) to afford 2-oxo-2-( >- tolyl)ethyl 2-hydroxyacetate (7.1 g, 34 mmol, 73%) as a yellow solid. ’H NMR (400 MHz, DMSO) 5 7.87 (d, J= 8.2 Hz, 2H), 7.37 (d, J= 8.0 Hz, 2H), 5.50 (s, 2H), 4.17 (d, J= 6.3 Hz, 2H), 2.40 (s, 3H).

[0093] Preparation of (4-(p-tolyl)oxazol-2-yl)methyl acetate

[0094] To a solution of 2-oxo-2-( / 2-tolyl)ethyl 2-hydroxyacetate (4.0 g, 19 mmol) in acetic acid (60 mL) was added ammonium acetate (15 g, 190 mmol), and the reaction was stirred at 120 °C for 18 h under N2. LCMS indicated the reaction was complete. The solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (silica gel, 10-30% EA in PE) to afford (4-(p-tolyl)oxazol-2-yl)methyl acetate (210 mg, 0.91 mmol, 5%) as a yellow solid. [M+H]+calcd: 231.25; found: 232.10. 'H NMR (400 MHz, DMSO) 5 7.95 (s, 1H), 7.87 (d, J= 8.2 Hz, 2H), 7.37 (d, J= 8.1 Hz, 2H), 5.50 (s, 2H), 2.89 (s, 3H), 2.73 (s, 3H).

[0095] Preparation of (4-(p-tolyl)oxazol-2-yl)methanol

[0096] To a solution of (4-(p-tolyl)oxazol-2-yl)methyl acetate (210. mg, 0.91 mmol) in ethanol (10 mL) was added NaOMe (330 mg, 1.8 mmol), and the reaction was stirred at room temperature for 1 h. LCMS indicated the reaction was complete. The solvent was removed under reduced pressure to afford (4-(p-tolyl)oxazol-2-yl)methanol (250 mg, 0.79 mmol). The crude was used directly in next step. [M+H]+calcd: 189.08; found: 190.00.31MEl\56453932.vl136883-01520

[0097] Preparation of 2-(chloromethyl)-4-(p-tolyl)oxazole

[0098] To a solution of (4-( / 2-tolyl)oxazol-2-yl)methanol (270 mg, 1.43 mmol) in DCM(10 mL) was added chloranesulfinyl chloride (170 mg, 1.4 mmol) at 0 °C. The reaction was stirred at room temperature for 18 h under N2. LCMS indicated about 50 % of product remained. The solvent was removed under reduced pressure and purified by prep-HPLC to give 2-(chloromethyl)-4-( / 2-tolyl)oxazole (60 mg, 0.29 mmol, 20%) as a white solid. [M+H] calcd: 207.05; found: 208.00. 'HNMR (400 MHz, DMSO) 5 8.62 (s, 1H), 7.67 (d, J= 8.1 Hz, 2H), 7.26 (d, J= 7.9 Hz, 2H), 4.94 (s, 2H), 2.33 (s, 3H).

[0099] Preparation of A methyl-l-(4-(p-tolyl)oxazol-2-yl)methanamine

[0100] To a solution of 2-(chloromethyl)-4-( / 2-tolyl)oxazole (60 mg, 0.29 mmol) in tetrahydrofuran (10 mL) was added methylamine (2 M in THF, 1.16 mL, 2.31 mmol). The reaction was stirred at 55 °C for 18 h under N2. LCMS showed about 50% of product was detected. The reaction was removed under reduced pressure and purified by prep-HPLC to give 7V-methyl-l-(4-( / 2-tolyl)oxazol-2-yl)methanamine (30. mg, 0.15 mmol, 51%) as a white solid. [M+H]+calcd: 202.11; found: 203.10.

[0101] Intermediates below may be synthesized similarly to Intermediate D-l :

[0102] Intermediate E-l: N-methyl-l-(3-phenylisoxazol-5-yl)methanamine32MEl\56453932.vl136883-01520

[0103] Preparation of (E)-benzaldehyde oxime

[0104] To a solution of benzaldehyde (1.9 mL, 19 mmol) in EtOH-H2O (10: 1, 22 mL) was added NH2OH-HCI (2.0 g, 28 mmol) and Na2COs (2.0 g, 19 mmol). The resulting mixture was stirred at room temperature under N2 for 2 h. The reaction mixture was concentrated under reduced pressure. The residue was extracted with EA twice, the combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure to afford (E)-phenylmethanal oxime (1.9 g, 16 mmol, 83%) as a pink solid. [M+H]+calcd: 121; found: 122.

[0105] Preparation of (3-phenylisoxazol-5-yl)methanolCHCI3

[0106] Prop-2-yn-l-ol (0.73 mL, 12 mmol) was added dropwise to a cooled solution (- 5 °C) of triethylamine (0.11 mL, 0.82 mmol) in chloroform (7 mL), maintaining the temperature in the range -5 °C - 0 °C. At this temperature a solution of (E)-phenylmethanal oxime (1.0 g, 8.3 mmol) in CHCI3 (8 mL) was added dropwise followed by NaCIO (26 mL, 0.04 mmol) added dropwise. The biphasic mixture was energetically stirred at room temperature for 2 h. Then the organic phase was separated, and the aqueous phase was extracted with chloroform. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 0-50%, EA in PE) to afford (3-phenylisoxazol-5- yl)methanol (420 mg, 2.1 mmol, 25%) as a white solid. [M+H]+calcd: 175; found: 176.JH NMR (400 MHz, DMSO) 5 7.91 - 7.84 (m, 2H), 7.55 - 7.49 (m, 3H), 6.93 (s, 1H), 5.72 (t, J = 6.0 Hz, 1H), 4.62 (dd, J= 6.0, 0.6 Hz, 2H).

[0107] Preparation of 5-(chloromethyl)-3-phenylisoxazole33MEl\56453932.vl136883-01520

[0108] To a solution of (3-phenylisoxazol-5-yl)methanol (200 mg, 1.1 mmol) in DCM (5 mL) at 0 °C was added SOCI2 (204 mg, 1.7 mmol). The reaction mixture was stirred at room temperature under N2 for 18 h. The reaction mixture was then concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 0-10%, EA in PE) to afford 5-(chloromethyl)-3-phenylisoxazole (190 mg, 0.98 mmol, 86%) as a white solid. [M+H]+calcd: 193; found: 194. 'HNMR (400 MHz, DMSO) 5 7.96 - 7.92 (m, 2H), 7.61 - 7.56 (m, 3H), 7.22 (s, 1H), 5.07 (s, 2H).

[0109] Preparation of N-methyl-l-(3-phenylisoxazol-5-yl)methanamine

[0110] To a solution of 5-(chloromethyl)-3-phenylisoxazole (190 mg, 0.98 mmol) in tetrahydrofuran (5 mL) was added methylamine (2 M in THF, 3.9 mL, 7.9 mmol). The reaction mixture was stirred at 55 °C under N2 for 18 h. The reaction mixture then concentrated under reduced pressure, and the residue was purified by flash column chromatography (silica gel, 0-20%, MeOH in DCM) to afford N-methyl-l-(3-phenylisoxazol- 5 -yl)m ethanamine (140 mg, 0.74 mmol, 76%) as a colorless oil. [M+H]+calcd: 188; found: 189. 'HNMR (400 MHz, DMSO) 5 7.91 - 7.84 (m, 2H), 7.55 - 7.47 (m, 3H), 6.89 (s, 1H), 3.82 (s, 2H), 2.33 (s, 3H).

[0111] Intermediate F-l: N-methyl-l-(l-Dhenyl-lH-l.,2.,3-triazol-4-yl)methanamine

[0112] Preparation of 4-(chloromethyl)-l-phenyl-lH-l,2,3-triazole

[0113] At 0 °C, to a solution of commercially available (l-phenyl-lH-l,2,3-triazol-4- yl)methanol (100 mg, 0.57 mmol) in DCM (5 mL) was added SOCI2 (0.06 mL, 0.85 mmol). The reaction mixture was stirred at room temperature under N2 for 18 h. The solvent was removed under reduced pressure, and the residue was purified by flash column chromatography (silica gel, 0-10%, EA in PE) to afford 4-(chloromethyl)-l-phenyl-lH-l,2,3-34MEl\56453932.vl136883-01520 triazole (90 mg, 0.46 mmol, 81%) as a white solid. [M+H]+calcd: 193; found: 194. 'H NMR (400 MHz, DMSO) 5 8.91 (s, 1H), 7.93 - 7.88 (m, 2H), 7.65 - 7.59 (m, 2H), 7.55 - 7.49 (m, 1H), 4.93 (s, 2H).

[0114] Preparation of N-methyl-l-(l-phenyl-lH-l,2,3-triazol-4-yl)methanamine

[0115] To the solution of 4-(chloromethyl)-l-phenyl-lH-l,2,3-triazole (90 mg, 0.46 mmol) in tetrahydrofuran (5 mL) was added methylamine (2 M in THF, 1.86 mL, 3.72 mmol). The reaction mixture was stirred at 55 °C under N2 for 18 h. The solvent was removed under reduced pressure, and the residue was purified by flash column chromatography (silica gel, 0-20%, MeOH in DCM) to afford N-methyl-l-(l-phenyl-lH- 1,2, 3 -triazol-4-yl)m ethanamine (20 mg, 0.11 mmol, 23%) as a white solid. [M+H]+calcd: 188; found: 189.

[0116] Intermediate G-l: N-methyl-l-(3-phenyl-lH-l.,2.,4-triazol-5-yl)methanamine

[0117] Preparation of 5-(chloromethyl)-3-phenyl-lH-l,2,4-triazole

[0118] To a solution of commercially available (3-phenyl-lH-l,2,4-triazol-5-yl)methanol (50 mg, 0.29 mmol) in THF (1 mL) was added SOCh (68 mg, 0.57 mmol) and the reaction was stirred at 50 °C for 30 min. The reaction was concentrated under reduced pressure to afford crude 5-(chloromethyl)-3-phenyl-lH-l,2,4-triazole (35 mg) as a white solid. [M+H]+calcd: 193.04; found: 194.1. ‘HNMR (400 MHz, DMSO-tL) 5 14.32 (d, J= 72.8 Hz, 1H), 7.89 (d, J= 7.4 Hz, 2H), 7.42 (s, 3H), 4.68 (s, 2H).

[0119] Preparation of N-methyl-l-(3-phenyl-lH-l,2,4-triazol-5-yl)methanamine35MEl\56453932.vl136883-01520

[0120] To a solution of 5-(chloromethyl)-3-phenyl-lH-l,2,4-triazole (35 mg, 0.18 mmol) in THF (1 mL) was added methylamine (0.016 mL, 0.36 mmol) and the reaction was stirred at 50 °C for 30 min. LCMS indicated the reaction was complete. The reaction was concentrated under reduced pressure to afford crude product 5-[(methylamino)methyl]-3- phenyl-lH-l,2,4-triazole (20 mg, 59%) as a white solid. [M+H]+calcd: 188.11; found: 189.30. ‘H NMR (400 MHz, DMSO-tL) 5 9.30 (s, 1H), 8.04 (d, J= 6.5 Hz, 2H), 7.65 - 7.48 (m, 3H), 4.30 (t, J= 5.7 Hz, 2H), 2.68 (t, J= 5.3 Hz, 3H).

[0121] Intermediates below may be synthesized similarly to Intermediate H-l :

[0122] Intermediate H-l: l-(benzo[J]thiazol-2-yl)-7V-methylmethanamine

[0123] To a solution of 2-(chloromethyl)benzo[ ]thiazole (100 mg, 0.55 mmol) in THF (10 mL) was added methylamine (2M in THF, 4.4 mL). The reaction was stirred at 55 °C for 18 h under N2. LCMS indicated the reaction was complete. The reaction was concentrated under reduced pressure and the resulting residue was purified by column chromatography on silica gel (0~5% MeOH in DCM) to give l-(benzo[ ]thiazol-2-yl)-7V-methylmethanamine (10 mg, 0.06 mmol, 10%) as a colorless transparent oil. LCMS (m / z): [M+H]+calcd: 178.06; found: 179.10.

[0124] Intermediates below may be synthesized similarly to Intermediate 1-1:

[0125] Intermediate 1-1: N-methyl-l-(5-Dhenyloxazol-2-yl)methanamine36MEl\56453932.vl136883-01520

[0126] Preparation of 2-chloro-N-(2-oxo-2-phenylethyl)acetamide

[0127] To a stirred mixture of 2-amino-l-phenylethan-l-one hydrochloride (1.0 g, 5.8 mmol) in DCM (10 mL) was added 2-chloroacetyl chloride (0.70 mL, 8.8 mmol) dropwise at 0 °C through a constant pressure drip funnel. After the addition was complete, the reaction was stirred for 2 h at 0 °C. After the reaction was complete, the mixture was concentrated under reduced pressure and purified by flash column chromatography (silica gel, 0-50% EA in PE) to afford 2-chloro-N-(2-oxo-2-phenylethyl)acetamide (650 mg, 3.07 mmol, 53%) as a white solid. LCMS (m / z): [M+H]+calcd: 193.03; found: 194.5.1H NMR (400 MHz, DMSO- de) 5 8.55 (t, J= 5.0 Hz, 1H), 8.04 - 7.97 (m, 2H), 7.72 - 7.65 (m, 1H), 7.56 (t, J= 7.7 Hz, 2H), 4.69 (d, J= 5.5 Hz, 2H), 4.21 (s, 2H).

[0128] Preparation of 2-(chloromethyl)-5-phenyloxazole

[0129] To a solution of 2-chloro-N-(2-oxo-2-phenylethyl)acetamide (300 mg, 1.4 mmol) in acetonitrile (5 mL) was added POCh (0.26 mL, 2.8 mmol) slowly. The reaction mixture was refluxed for 5 h. After the completion of the reaction, the excess phosphorus oxychloride and acetonitrile were evaporated under reduced pressure. Then ethyl acetate (40 mL) was added to the residue and washed twice with water (10 mL), twice with saturated sodium bicarbonate aqueous solution (10 mL), and once with brine (10 mL). Ethyl acetate was evaporated to afford 2-(chloromethyl)-5-phenyloxazole (220 mg, 1.1 mmol, 80%) as a white solid. LCMS (m / z): [M+H]+calcd: 193.03; found: 194.3. 'HNMR (400 MHz, DMSO-tL) 5 7.77 - 7.70 (m, 3H), 7.54 - 7.48 (m, 2H), 7.45 - 7.38 (m, 1H), 4.96 (s, 2H).

[0130] Preparation of N-methyl-l-(5-phenyloxazol-2-yl)methanamineMEl\56453932.vl136883-01520

[0131] To 2-(chloromethyl)-5-phenyloxazole (100 mg, 0.51 mmol) was added MeNTh (2 M in THF, 5 mL). The reaction mixture was stirred at 35 °C under N2 for 20 h. The reaction was followed by LCMS. After completion, the mixture was concentrated under reduced pressure to give a residue that was purified by flash column chromatography (silica gel, 0- 10% MeOH in DCM) to afford N-methyl-l-(5-phenyloxazol-2-yl)methanamine (20 mg, 0.11 mmol, 21%) as a white solid. LCMS (m / z): [M+H]+calcd: 188.09; found: 189.4.

[0132] Intermediate K-l: 6-(Dvridin-4-yl)-2.,3.,4.,5-tetrahydro-lH-pvrido[4.,3-b]indole

[0133] To a mixture of 6-bromo-l,2,3,4-tetrahydropyrido[4,3-b]indol-4a-ide (800 mg, 3.19 mmol), pyridin-4-ylboranediol (590 mg, 4.8 mmol) and sodium carbonate (1020 mg, 9.6 mmol) in IPA:H2O=3: 1 (12 mL) was added Pd(PPh3)2Ch (158 mg, 0.22 mmol) under nitrogen atmosphere. The resulting mixture was stirred at 80 °C for 16 hrs. LCMS indicated the reaction was complete. Then the mixture was extracted with EtOAc twice. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography (silica gel, 0-15%, MeOH in DCM) to afford 6-(pyridin-4-yl)-l,2,3,4-tetrahydropyrido[4,3-b]indol-4a-ide (200 mg, 0.80 mmol, 25%) as a yellow solid. LCMS (m / z): [M+H]+calcd: 249.13; found: 250.1. *H NMR (400 MHz, DMSO-t / e) 5 11.18 (s, 1H), 9.57 (s, 1H), 8.70 (dd, J= 4.5, 1.5 Hz, 2H), 7.66 (dd, J= 4.5, 1.5 Hz, 2H), 7.57 (d, J= 7.7 Hz, 1H), 7.25 (d, J= 6.6 Hz, 1H), 7.17 (t, J= 7.6 Hz, 1H), 4.31 (s, 2H), 3.44 (t, J= 6.0 Hz, 2H), 3.05 (t, J= 5.8 Hz, 2H).

[0134] Intermediate J-l: 3-[3-({[5-(3-bromophenyl)-l.,2.,4-thiadiazol-3- yl]methyl}(methyl)amino)-2,5-dioxo-2,5-dihydro-lH-pyrrol-l-yl]hexahydropyridine- 2, 6-dione

[0135] Preparation of ethyl 5-oxo-l,4,3-oxathiazole-2-carboxylate38MEl\56453932.vl136883-01520

[0136] To a solution of ethyl carbarn oylmethanoate (5.0 g, 43 mmol) in toluene (20 mL) was added chlorosulfanecarbonyl chloride (3.6 mL, 43 mmol). The reaction was stirred at 90 °C for 18 h. TLC showed the reaction was complete. The reaction was concentrated under reduced pressure and purified by FCC (silica gel, 10-20% EA in PE) to give ethyl 5-oxo- l,4,3-oxathiazole-2-carboxylate (2.80 g, 15.99 mmol, yield: 37.44%) as a white solid. [M]+ calcd: 175.1, found: 176.4.

[0137] Preparation of ethyl 5-(3-bromophenyl)-l,2,4-thiadiazole-3-carboxylate

[0138] To a solution of ethyl 5-oxo-l,4,3-oxathiazole-2-carboxylate (2.0 g, 11 mmol) in di chlorobenzene (10 mL) was added 3 -bromobenzene- 1 -carbonitrile (10 g, 57 mmol). The reaction was stirred at 160 °C for 48 h. LCMS showed the reaction was completed. The reaction mixtrue was washed with H2O, 5% of NaHCCh, again with H2O, dried over anhydrous Na2SO4 and concentrated under high vacuum to give ethyl 5-(3-bromophenyl)- 1, 2, 4-thiadiazole-3 -carboxylate (0.20 g, 0.64 mmol, yield: 5.6%) as a white solid. [M]+ calcd:313.1, found: 314.1.

[0139] Preparation of [5-(3-bromophenyl)-l,2,4-thiadiazol-3-yl]methanol

[0140] To a solution of ethyl 5-(3-bromophenyl)-l,2,4-thiadiazole-3-carboxylate (300 mg, 0.96 mmol) in EtOH (10 mL) was added NaBEL (72 mg, 1.9 mmol). The reaction was stirred at room temperature for 2 h. LCMS showed the reaction was completed. The reaction was cooled to 0 °C, quenched with H2O and extracted with EA. The organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified39MEl\56453932.vl136883-01520 by FCC (silica gel, 10-20% EA in PE) to give [5-(3-bromophenyl)-l,2,4-thiadiazol-3- yl]methanol (200 mg, 0.74 mmol, yield: 77.00%) as a white solid. [M]+ calcd:271.1, found: 272.2. ‘H NMR (400 MHz, DMSO-tL) 5 8.21 (t, J= 1.8 Hz, 1H), 8.07 - 8.00 (m, 1H), 7.90 - 7.78 (m, 1H), 7.56 (t, J= 7.9 Hz, 1H), 5.71 (s, 1H), 4.74 (s, 2H).

[0141] Preparation of 5-(3-bromophenyl)-3-(chloromethyl)-l,2,4-thiadiazole

[0142] To a solution of [5-(3-bromophenyl)-l,2,4-thiadiazol-3-yl]methanol (250 mg, 0.92 mmol) and TEA (0.38 mL, 2.8 mmol) in DCM (10 mL) was added SOCh (0.13 mL, 1.8 mmol) dropwise under 0 °C. The reaction was stirred at room temperature for 2h. TLC showed the reaction was complete. The reaction was quenched with water and extracted with ethyl acetate. The organic layer was concentrated under pressure. The residue was purified by FCC (silica gel, 10-50% ethyl acetate in petroleum ether) to give 5-(3-bromophenyl)-3- (chloromethyl)-l,2,4-thiadiazole (200 mg, 0.69 mmol, yield: 75%) as a white solid. [M]+ calcd:289.5, found: 290.1.

[0143] Preparation of 5-(3-bromophenyl)-3-[(methylamino)methyl]-l,2,4-thiadiazol

[0144] To a solution of 5-(3-bromophenyl)-3-(chloromethyl)-l,2,4-thiadiazole (100 mg, 0.35 mmol) in THF (3 mL) was added MeNH2 / THF (1.4 mL, 2.8 mmol). The reaction was stirred at 55 °C for 24 h. LCMS showed the reaction was complete. The reaction was added into water and extracted DCM, the organic layer was dried over anhydous Na2SO4 and concentrated under reduced pressure. The residue was purified by FCC (silica gel, 10-50% ethyl acetate in petroleum ether) to give 5-(3-bromophenyl)-3-[(methylamino)methyl]-l,2,4- thiadiazole (30 mg, 0.11 mmol, yield: 31%) as a yellow solid. [M]+ calcd:284.1, found: 285.2.

[0145] Intermediates below may be synthesized similarly to Intermediate J-l :40MEl\56453932.vl136883-01520Examples

[0146] General Method A

[0147] Compound 1: Preparation of 3-[3-({[3-(3-bromophenyl)-l,2,4-oxadiazol-5- yl]methyl}(methyl)amino)-2,5-dioxo-2,5-dihydro-lH-pyrrol-l-yl]hexahydropyridine-2, 6-dione

[0148] To a solution of 3-(3-bromophenyl)-5-[(methylamino)methyl]-l,2,4-oxadiazole (450 mg, 1.7 mmol) in dioxane (5 mL) were added triethylamine (0.46 mL, 3.4 mmol) and 3- (3-bromo-2,5-dioxo-2,5-dihydro-lH-pyrrol-l-yl)hexahydropyridine-2, 6-dione (480 mg, 1.7 mmol) at 20 °C. The mixture was stirred at 45 °C for 2 hours. The reaction mixture was concentrated under reduced pressure and purified by flash column chromatography eluting with a gradient of 20-40% EtOAc in heptanes to afford 3-[3-({[3-(3-bromophenyl)-l,2,4- oxadiazol-5-yl]methyl}(methyl)amino)-2,5-di oxo-2, 5-dihy dro-lH-pyrrol-1- yl]hexahydropyridine-2, 6-dione (290 mg, 0.61 mmol, 36%) as a yellow solid. 100 mg was purified by prep-HPLC to give 3-[3-({[3-(3-bromophenyl)-l,2,4-oxadiazol-5- yl]methyl}(methyl)amino)-2, 5 -di oxo-2, 5-dihy dro-lH-pyrrol-1 -yl]hexahydropyridine-2, 6- dione (60 mg, ) as a yellow solid. LCMS (m / z): [M+H]+calcd: 473; found: 474. 'H NMR (400 MHz, DMSO-tC) 5 10.99 (s, 1H), 8.10 (s, 1H), 8.01 (d, J= 7.8 Hz, 1H), 7.83 (d, J= 8.0 Hz, 1H), 7.55 (t, J= 7.9 Hz, 1H), 5.37 (s, 3H), 4.87 (dd, J= 12.9, 5.3 Hz, 1H), 3.21 (s, 3H), 2.92 - 2.74 (m, 1H), 2.54 (s, 1H), 2.39 (qd, J= 13.2, 4.1 Hz, 1H), 1.98 - 1.82 (m, 1H).

[0149] Compounds below may be synthesized utilizing General Method A.41MEl\56453932.vl136883-0152042MEl\56453932.vl136883-0152043MEl\56453932.vl136883-0152044MEl\56453932.vl136883-0152045MEl\56453932.vl136883-0152046MEl\56453932.vl136883-0152047MEl\56453932.vl136883-0152048MEl\56453932.vl136883-0152049MEl\56453932.vl136883-0152050MEl\56453932.vl136883-0152051MEl\56453932.vl136883-0152052MEl\56453932.vl136883-0152053MEl\56453932.vl136883-0152054MEl\56453932.vl136883-0152055MEl\56453932.vl136883-0152056MEl\56453932.vl136883-0152057MEl\56453932.vl136883-0152058MEl\56453932.vl136883-0152059MEl\56453932.vl136883-0152060MEl\56453932.vl136883-0152061MEl\56453932.vl136883-0152062MEl\56453932.vl136883-0152063MEl\56453932.vl136883-0152064MEl\56453932.vl136883-0152065MEl\56453932.vl136883-0152066MEl\56453932.vl136883-0152067MEl\56453932.vl136883-01520

[0150] General Method B

[0151] Compound 90: Preparation of 3-{3-[methyl({3-[3-(pyridin-3-yl)phenyl]-l,2,4- oxadiazol-5-yl}methyl)amino]-2,5-dioxo-2,5-dihydro-lH-pyrrol-l- yl}hexahydropyridine-2, 6-dione

[0152] To a solution of 3-[3-({[3-(3-bromophenyl)-l,2,4-oxadiazol-5- yl]methyl}(methyl)amino)-2,5-dioxo-2,5-dihydro-lH-pyrrol-l-yl]hexahydropyridine-2,6- dione (30 mg, 0.06 mmol) in dioxane - water (10: 1, 3 mL) were added pyridin-3- ylboranediol (16 mg, 0.12 mmol), K2CO3 (17 mg, 0.12 mmol) and Pd-118 (4.1 mg, 0.01 mmol) at room temperature under N2. The mixture was stirred at 60 °C for Ih. The reaction mixture cooled and filtered. The filtrate was purified by prep-HPLC (C18, Wave length: 220nm / 254nm phase A: H2O (HCOOH 0.1%); phase B: MECN 25%-95%, 13min / 18 min) to afford 3-{3-[methyl({3-[3-(pyridin-3-yl)phenyl]-l,2,4-oxadiazol-5-yl}methyl)amino]-2,5- dioxo-2,5-dihydro-lH-pyrrol-l-yl}hexahydropyridine-2, 6-dione (6.2 mg, 0.013 mmol, 21%) as a yellow solid. LCMS (m / z): [M+H]+calcd: 472; found: 473. 'HNMR (400 MHz, DMSO-t / e) 5 11.01 (s, IH), 8.01 (dd, J= 7.9, 1.6 Hz, 2H), 7.75 (t, J= 6.7 Hz, IH), 7.63 - 7.42 (m, 3H), 4.99 (d, J= 6.7 Hz, 2H), 4.87 (dd, J= 13.0, 5.4 Hz, IH), 2.91 - 2.74 (m, IH), 2.56 (s, IH), 2.47 - 2.28 (m, IH), 2.00 - 1.87 (m, IH), 1.81 (s, 3H).

[0153] Compounds below may be synthesized utilizing General Method B.68MEl\56453932.vl136883-0152069MEl\56453932.vl136883-01520MEl\56453932.vl136883-0152071MEl\56453932.vl136883-0152072MEl\56453932.vl136883-0152073MEl\56453932.vl136883-0152074MEl\56453932.vl136883-0152075MEl\56453932.vl136883-0152076MEl\56453932.vl136883-0152077MEl\56453932.vl136883-01520

[0154] General Method C

[0155] Compound 119: Preparation of 3-(3-(((3-(3-hydroxyphenyl)-l,2,4-oxadiazol-5-yl)methyl)(methyl)amino)-2,5-dioxo-2,5-dihydro-lH-pyrrol-l-yl)piperidine-2, 6-dione

[0156] To a solution of 3-(3-(((3-(3-methoxyphenyl)-l,2,4-oxadiazol-5- yl)methyl)(methyl)amino)-2,5-dioxo-2,5-dihydro-lH-pyrrol-l-yl)piperidine-2, 6-dione (7078MEl\56453932.vl136883-01520 mg, 0.16 mmol) in DCM (4 mL) was added BBn (0.4 mL) at 0 °C. The resulting mixture was stirred at room temperature under N2 for 18 h, then quenched with water and concentrated under reduced pressure at low temperature. The residue was purified by prep-HPLC (Cl 8, wavelength: 220 nm / 254 nm phase A: H2O; phase B: MeCN 20%-95%, 11.5 min / 20 min) to afford 3-(3-(((3-(3-hydroxyphenyl)-l,2,4-oxadiazol-5-yl)methyl)(methyl)amino)-2,5-dioxo- 2, 5-dihydro-lH-pyrrol-l-yl)piperidine-2, 6-dione (5.0 mg, 0.01 mmol, 7%) as a yellow solid. LCMS (m / z): [M+H]+calcd: 411.12; found: 412.0. 'H NMR (400 MHz, DMSO-tfc) 5 10.99 (s, 1H), 9.85 (s, 1H), 7.45 - 7.39 (m, 2H), 7.38 - 7.33 (m, 1H), 7.00 - 6.94 (m, 1H), 5.59 - 5.11 (m, 3H), 4.90 - 4.83 (m, 1H), 3.32 - 3.07 (m, 3H), 2.85 - 2.75 (m, 1H), 2.57 - 2.52 (m,1H), 2.45 - 2.33 (m, 1H), 1.96 - 1.85 (m, 1H).

[0157] Compounds below may be synthesized utilizing General Method C.

[0158] General Method D

[0159] Compound 121: 3-(3-(methyl((3-(3-(pyrimidin-4-yl) phenyl)- 1,2, 4-oxadiazol-5-yl) methyl) amino)-2,5-dioxo-2,5-dihydro-lH-pyrrol-l-yl) piperidine-2, 6-dione

[0160] 3-(3-(methyl ((3-(3-(4, 4,5, 5-tetramethyl- 1,3, 2-dioxaborolan-2-yl)phenyl)- 1,2,4- oxadiazol-5-yl)methyl)amino)-2,5-dioxo-2,5-dihydro-lH-pyrrol-l-yl)piperidine-2,6- dione79MEl\56453932.vl136883-01520

[0161] To a solution of 3-(3-(((3-(3-bromophenyl)-l,2,4-oxadiazol-5- yl)methyl)(methyl)amino)-2,5-dioxo-2,5-dihydro-lH-pyrrol-l-yl)piperidine-2, 6-dione (1.0 g, 2.1 mmol) in Dioxane (20 mL) were added 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(l,3,2- dioxaborolane) (0.80 g, 3.2 mmol), Pd(dppf)C12 (0.08 g, 0.11 mmol) and potassium acetate (0.62 g, 6.3 mmol). The reaction was stirred at 100 °C for 18 h. LCMS showed the reaction was completed. The reaction was concentrated in vacuo and purified by flash chromatography (silica gel, 20-80% EA in PE) to give 3-(3-(methyl((3-(3-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)-l,2,4-oxadiazol-5-yl)methyl)amino)-2,5-dioxo- 2, 5-dihydro-lH-pyrrol-l-yl)piperidine-2, 6-dione (1.2 g, 1.9 mmol, 87%) as a yellow solid. LCMS (m / z): [M]+ calcd: 521.21, found:522.20.

[0162] 3-(3-(methyl((3-(3-(pyrimidin-4-yl) phenyl)-!, 2, 4-oxadiazol-5-yl) methyl) amino)-2,5-dioxo-2,5-dihydro-lH-pyrrol-l-yl) piperidine-2, 6-dione

[0163] To a mixture of 3-(3-(methyl((3-(3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl) phenyl)-l,2,4-oxadiazol-5-yl) methyl) amino)-2,5-dioxo-2,5-dihydro-lH-pyrrol-l-yl) piperidine-2, 6-dione (60 mg, 0.12 mmol) in dioxane - water (2.0 mL) were added 4- chloropyrimidine hydrochloride (13 mg, 0.12 mmol), NaHCCh (29 mg, 0.35 mmol) and Pd(PPhs)4 (13 mg, 0.01 mmol) under an atmosphere of nitrogen. The resulting mixture was stirred at 80 °C for 2 hrs. LCMS indicated the reaction was complete. The mixture was washed with water and extracted with ethyl acetate, and the organic layer was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC to afford 3- (3-(methyl((3-(3-(pyrimidin-4-yl) phenyl)- 1, 2, 4-oxadiazol-5-yl) methyl) amino)-2,5-dioxo- 2,5-dihydro-lH-pyrrol-l-yl) piperidine-2, 6-dione (6.0 mg, yield: 11%) as a green solid.JH NMR (400 MHz, DMSO-t / 6) 5 10.99 (s, 1H), 9.32 (s, 1H), 8.93 (d / = 5.4 Hz, 1H), 8.84 (s, 1H), 8.42 (d,J= 8.0 Hz, 1H), 8.22 - 8.17 (m, 2H), 7.78 (t,J= 7.8 Hz, 1H), 5.62 - 5.10 (m,80MEl\56453932.vl136883-015203H), 4.87 (dd,J= 12.8, 5.4 Hz, 1H), 3.23 (s, 3H), 2.86 - 2.73 (m, 1H), 2.54 (d,J= 3.1 Hz, 1H), 2.42 - 2.29 (m, 1H), 1.95 - 1.87 (m, 1H). LCMS (m / z): [M+H]+calcd: 473.13; found: 474.5.

[0164] Compounds below may be synthesized utilizing General Method D.81MEl\56453932.vl136883-0152082MEl\56453932.vl136883-0152083MEl\56453932.vl136883-01520

[0165] General Method E

[0166] Compound 131: Preparation of 3-(4-ethyl-3-{methyl[(3-phenyl-l,2,4- oxadiazol-5-yl)methyl]amino}-2,5-dioxo-2,5-dihydro-lH-pyrrol-l- yl)hexahydropyridine-2, 6-dione84MEl\56453932.vl136883-01520

[0167] Preparation of 3-(4-bromo-3-{methyl[(3-phenyl-l,2,4-oxadiazol-5- yl)methyl]amino}-2,5-dioxo-2,5-dihydro-lH-pyrrol-l-yl)hexahydropyridine-2, 6-dione

[0168] To a solution of 3-(3-{methyl[(3-phenyl-l,2,4-oxadiazol-5-yl)methyl]amino}-2,5- dioxo-2,5-dihydro-lH-pyrrol-l-yl)hexahydropyridine-2, 6-dione (200 mg, 0.50 mmol) in AcOH (5 mL) were added NBS (108.04 mg, 0.60 mmol) at 0°C under N2, and it was stirred at 0°C for Ih. LCMS indicated the reaction was complete. Then the mixture was cooled, poured into H2O and extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4 and concentrated to give a residue. The residue was purified by flash chromatography (silica gel, 0-50%, EA in PE) to afford 3-(4-bromo-3-{methyl[(3-phenyl- l,2,4-oxadiazol-5-yl)methyl]amino}-2,5-dioxo-2,5-dihydro-lH-pyrrol-l- yl)hexahydropyridine-2, 6-dione (100 mg, 0.21 mmol, 41.68%) as a yellow soild. LCMS (m / z): [M+H]+calcd: 473; found: 474. *H NMR (400 MHz, DMSO-tfc) 5 11.03 (s, IH), 8.01 (dd, J= 8.0, 1.6 Hz, 2H), 7.70 - 7.43 (m, 3H), 5.48 - 5.21 (m, 2H), 4.96 (dd, J= 13.0, 5.4 Hz, IH), 3.55 (s, 3H), 2.90 - 2.70 (m, IH), 2.55 (d, J= 3.4 Hz, IH), 2.44 - 2.29 (m, IH),2.03 - 1.89 (m, 1H).

[0169] Preparation of 3-(3-{methyl[(3-phenyl-l,2,4-oxadiazol-5-yl)methyl]amino}-2, 5-dioxo-4-vinyl-2,5-dihydro-lH-pyrrol-l-yl)hexahydropyridine-2, 6-dione85MEl\56453932.vl136883-01520

[0170] To a solution of 3-(4-bromo-3-{methyl[(3-phenyl-l,2,4-oxadiazol-5- yl)methyl]amino}-2, 5-di oxo-2, 5-dihydro-lH-pyrrol-l-yl)hexahydropyridine-2, 6-dione (200 mg, 0.42 mmol) in dioxane / water (2 mL) were added 4,4,5,5-tetramethyl-2-vinyl-l,3,2- dioxaborolane (129.90 mg, 0.84 mmol), K2CO3 (174.84 mg, 1.26 mmol) and Pd-118 (31.25 mg, 0.04 mmol) at RT under N2, and the reaction was stirred at 80 °C for 2h. The suspension was filtered and the filter cake was washed with MeCN. The combined filtrates were concentrated and purified by prep-HPLC (Cl 8, wavelength: 220nm / 254nm phase A: H2O; phase B: MECN 30%-95%, 1 lmin / 18 min) to give 3-(3-{methyl[(3-phenyl-l,2,4-oxadiazol- 5-yl)methyl]amino}-2,5-dioxo-4-vinyl-2,5-dihydro-lH-pyrrol-l-yl)hexahydropyridine-2,6- dione (100 mg, 0.23 mmol, 56.27%) as a yellow solid. LCMS (m / z): [M+H]+calcd: 421; found: 422. 'HNMR (400 MHz, DMSO-tL) 5 11.01 (s, 1H), 8.01 (dd, J= 7.8, 1.6 Hz, 2H), 7.82 - 7.47 (m, 3H), 6.78 (dd, J= 17.4, 11.6 Hz, 1H), 5.88 (dd, J= 17.2, 2.4 Hz, 1H), 5.44 - 5.17 (m, 3H), 4.90 (dd, J= 12.9, 5.4 Hz, 1H), 3.93 (s, 1.5H), 3.40 (s, 1.5H), 2.86 - 2.72 (m,1H), 2.54 (s, 1H), 2.39 (dt, J= 13.0, 8.7 Hz, 1H), 1.96 - 1.84 (m, 1H).

[0171] Preparation of 3-(4-ethyl-3- {methyl [(3-phenyl-l, 2, 4-oxadiazol-5- yl)methyl]amino}-2,5-dioxo-2,5-dihydro-lH-pyrrol-l-yl)hexahydropyridine-2, 6-dione

[0172] To a solution of 3-(3-{methyl[(3-phenyl-l,2,4-oxadiazol-5-yl)methyl]amino}-2,5- dioxo-4-vinyl-2,5-dihydro-lH-pyrrol-l-yl)hexahydropyridine-2, 6-dione (120 mg, 0.28 mmol) in THF (10 mL) was added Pd / C 10% (30 mg, 0.28 mmol), and the reaction was stirred at RT under H2 for 2 hours. The suspension was filtered, and the filter cake was washed with THF. The combined filtrates were concentrated in vacuo. The reaction mixture was purified by prep-HPLC (Cl 8, wavelength: 220nm / 254nm phase A: H2O; phase B: MECN 30%-95%, 1 lmin / 18 min) to give 3-(4-ethyl-3-{methyl[(3-phenyl-l,2,4-oxadiazol-5-yl)methyl]amino}- 2, 5-di oxo-2, 5-dihydro-lH-pyrrol-l-yl)hexahydropyridine-2, 6-dione (27 mg, 0.06 mmol, 22.39%) as a yellow solid. LCMS (m / z): [M+H]+calcd: 423; found: 424. 'HNMR (400 MHz, DMSO-t / e) 5 10.97 (s, 1H), 8.00 (dd, J= 7.8, 1.6 Hz, 2H), 7.64 - 7.52 (m, 3H), 5.25 (s, 2H), 4.86 (dd, J= 12.8, 5.4 Hz, 1H), 3.34 (s, 3H), 2.86 - 2.71 (m, 1H), 2.57 - 2.51 (m, 1H), 2.48 - 2.41 (m, 2H), 2.40 - 2.27 (m, 1H), 1.95 - 1.82 (m, 1H), 1.06 (t, J = 7.4 Hz, 3H).86MEl\56453932.vl136883-01520

[0173] Compound 132: 3-(4-iodo-3-{methyl[(3-phenyl-l,2,4-oxadiazol-5- yl)methyl]amino}-2,5-dioxo-2,5-dihydro-lH-pyrrol-l-yl)hexahydropyridine-2, 6-dione

[0174] To a solution of 3-(3-{methyl[(3-phenyl-l,2,4-oxadiazol-5-yl)methyl]amino}-2,5- dioxo-2,5-dihydro-lH-pyrrol-l-yl)hexahydropyridine-2, 6-dione (900 mg, 2.27 mmol) in acetonitrile (10 mL) was added NIS (610 mg, 2.7 mmol) at 0 °C under N2. The mixture was stirred at 0 °C for Ih. LCMS indicated the reaction was complete. The mixture was then cooled, poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried over Na2SO4 and concentrated to give a residue which was purified by flash chromatography (silica gel, 0-80%, EA in PE) to afford 3-(4-iodo-3-{methyl[(3-phenyl-l,2,4- oxadiazol-5-yl)methyl]amino}-2,5-dioxo-2,5-dihydro-lH-pyrrol-l-yl)hexahydropyridine-2,6- dione (600 mg, 1.15 mmol, 51%) as a yellow solid. LCMS (m / z): [M+H]+calcd: 521; found: 522.1H NMR (400 MHz, DMSO-de) 5 11.66 (d, J= 515.0 Hz, IH), 8.01 (dd, = 7.9, 1.5 Hz, 2H), 7.71 - 7.39 (m, 3H), 5.44 - 5.17 (m, 2H), 4.94 (dd, J= 12.9, 5.4 Hz, IH), 3.59 (s, 3H), 2.99 - 2.70 (m, IH), 2.58 - 2.52 (m, IH), 2.44 - 2.24 (m, IH), 2.03 - 1.81 (m, IH).

[0175] Comound 133: 3-(3-{methyl[(3-phenyl-l,2,4-oxadiazol-5-yl)methyl]amino}- 2, 5-dioxo-4-(prop-2-yl)-2,5-dihydro-lH-pyrrol-l-yl)hexahydropyridine-2, 6-dione and 3- (2,5-dihydroxy-3-{methyl[(3-phenyl-l,2,4-oxadiazol-5-yl)methyl]amino}-4-(prop-2- yl)pyrrol-l-yl)hexahydropyridine-2, 6-dione

[0176] Preparation of 3-(3-{methyl[(3-phenyl-l,2,4-oxadiazol-5-yl)methyl]amino}-2, 5-dioxo-4-(prop-l-en-2-yl)-2,5-dihydro-lH-pyrrol-l-yl)hexahydropyridine-2, 6-dione87MEl\56453932.vl136883-01520

[0177] To a solution of 3-(4-iodo-3-{methyl[(3-phenyl-l,2,4-oxadiazol-5- yl)methyl]amino}-2, 5-di oxo-2, 5-dihydro-lH-pyrrol-l-yl)hexahydropyridine-2, 6-dione (200 mg, 0.38 mmol) in dioxane - water (2 mL) were added 4,4,5,5-tetramethyl-2-vinyl-l,3,2- dioxaborolane (130 mg, 0.84 mmol), K2CO3 (160 mg, 1.2 mmol) and Pd-18 (28 mg, 0.04 mmol) at room temperature under N2. The mixture was stirred at 80 °C for 2h. The suspension was filtered, and the filter cake was washed with acetonitrile. The combined filtrates were concentrated under reduced pressure. The residue was purified by prep-HPLC (C18, wavelength: 220nm / 254nm phase A: H2O; phase B: MECN 30%-95%, 10min / 18 min) to give 3-(3-{methyl[(3-phenyl-l,2,4-oxadiazol-5-yl)methyl]amino}-2,5-dioxo-4-(prop-l-en- 2-yl)-2,5-dihydro-lH-pyrrol-l-yl)hexahydropyridine-2, 6-dione (120 mg, 0.27 mmol, 72%) as a yellow solid. LCMS (m / z): [M+H]+calcd: 435; found: 436. 'H NMR (400 MHz, DMSO- d6) 5 11.00 (s, 1H), 8.01 (dd, J= 7.8, 1.6 Hz, 2H), 7.75 - 7.37 (m, 3H), 5.45 - 5.13 (m, 3H), 5.01 - 4.70 (m, 1.5H), 3.94 (s, 1.5H), 3.17 (s, 2H), 2.92 - 2.69 (m, 1H), 2.55 (s, 1H), 2.43 - 2.30 (m, 1H), 1.99 (s, 3H), 1.92 (dd, J= 8.9, 3.6 Hz, 1H).

[0178] Preparation of 3-(3-{methyl[(3-phenyl-l,2,4-oxadiazol-5-yl)methyl]amino}- 2, 5-dioxo-4-(prop-2-yl)-2,5-dihydro-lH-pyrrol-l-yl)hexahydropyridine-2, 6-dione and 3- (2,5-dihydroxy-3-{methyl[(3-phenyl-l,2,4-oxadiazol-5-yl)methyl]amino}-4-(prop-2- yl)pyrrol-l-yl)hexahydropyridine-2, 6-dione

[0179] To a solution of 3-(3-{methyl[(3-phenyl-l,2,4-oxadiazol-5-yl)methyl]amino}-2,5- dioxo-4-(prop-l-en-2-yl)-2,5-dihydro-lH-pyrrol-l-yl)hexahydropyridine-2, 6-dione (100 mg, 0.23 mmol) in THF (5 mL) was added Pd / C 10% (24 mg, 0.23 mmol) at room temperature under H2. The mixture was stirred at 20 °C for 4h. The suspension was filtered, and the filter cake was washed with THF. The combined filtrates were concentrated under reduced pressure. The residue was purified by prep-HPLC (Cl 8, wavelength: 220nm / 254nm phase A: H2O; phase B: MECN 30%-95%, 10min / 18 min) to afford 3-(3-{methyl[(3-phenyl-l,2,4-88MEl\56453932.vl136883-01520 oxadi azol-5 -yl)m ethyl] amino } -2, 5 -dioxo-4-(prop-2-yl)-2, 5 -dihy dro- 1 H-pyrrol- 1 - yl)hexahydropyridine-2, 6-dione (20 mg, 0.04 mmol, 20%) as a yellow solid and 3-(2,5- dihydroxy-3-{methyl[(3-phenyl-l,2,4-oxadiazol-5-yl)methyl]amino}-4-(prop-2-yl)pyrrol-l- yl)hexahydropyridine-2, 6-dione (8 mg, 0.02 mmol, 7.91%) as a yellow solid. LCMS (m / z): [M+H]+calcd: 437, found: 438. 'HNMR (400 MHz, DMSO-d6) 5 10.97 (s, 1H), 8.01 (dd, J= 7.8, 1.6 Hz, 2H), 7.58 (q, J= 6.4 Hz, 3H), 5.17 (s, 2H), 4.83 (dd, J= 12.9, 5.4 Hz, 1H), 3.29 (s, 3H), 3.25 - 3.13 (m, 1H), 2.87 - 2.69 (m, 1H), 2.57 - 2.51 (m, 1H), 2.42 - 2.30 (m, 1H), 1.94 - 1.84 (m, 1H), 1.25 (dd, J= 6.7, 5.0 Hz, 6H).

[0180] Compound 134: 3-(5-(((l-(2,6-dioxopiperidin-3-yl)-2,5-dioxo-2,5-dihydro-lH- pyrrol-3-yl)(methyl)amino)methyl)- 1 ,2,4-oxadiazol-3-yl)benzoic acid

[0181] To a sealed tube containing methyl 3-(5-(((l-(2,6-dioxopiperidin-3-yl)-2,5-dioxo-2.5-dihydro-lH-pyrrol-3-yl)(methyl)amino)methyl)-l,2,4-oxadiazol-3-yl)benzoate (45 mg, 0.1 mmol) in DCE (1 mL) was added (CHfhSnOH (54 mg, 0.30 mmol). The resulting mixture was heated to 80 °C for 40 h. LCMS indicated the reaction was complete. The reaction mixture was filtered, and the solvent was evaporated under reduced pressure. The residue was purified by prep-HPLC to afford 3-(5-(((l-(2,6-dioxopiperidin-3-yl)-2,5-dioxo-2.5-dihydro-lH-pyrrol-3-yl)(methyl)amino)methyl)-l,2,4-oxadiazol-3-yl)benzoic acid (8.7 mg, 0.02 mmol, 20%) as a yellow solid. LCMS (m / z): [M+H]+calcd: 439.11; found: 440.3. 'HNMR (400 MHz, DMSO-tL) 5 13.10 (s, 1H), 10.99 (s, 1H), 8.52 (s, 1H), 8.24 (d, J= 7.8 Hz, 1H), 8.15 (d, J= 7.9 Hz, 1H), 7.72 (t, J= 7.8 Hz, 1H), 5.33 (d, J= 36.3 Hz, 3H), 4.90 - 4.83 (m, 1H), 3.30 - 3.06 (m, 3H), 2.85 - 2.75 (m, 1H), 2.57 - 2.52 (m, 1H), 2.45 - 2.32 (m, 1H), 1.96 - 1.85 (m, 1H).

[0182] Compound 135: Preparation of 3-(3-(((3-(4-((dimethylamino) methyl) phenyl)-!, 2, 4-oxadiazol-5-yl) methyl) (methyl)amino)-2,5-dioxo-2,5-dihydro-lH-pyrrol- 1-yl) piperidine-2, 6-dione89MEl\56453932.vl136883-01520

[0183] 4-(5-(((l-(2,6-dioxopiperidin-3-yl)-2,5-dioxo-2,5-dihydro-lH-pyrrol-3-yl)(methyl)amino) methyl)-!, 2, 4-oxadiazol-3-yl) benzaldehyde

[0184] To a solution of 3-(3-(((3-(4-(hydroxymethyl) phenyl)- 1, 2, 4-oxadiazol-5-yl) methyl) (methyl)amino)-2,5-dioxo-2,5-dihydro-lH-pyrrol-l-yl) piperidine-2, 6-dione (30 mg, 0.07 mmol) in DCM (1.0 mL) was added Dess-Martin’s reagent (90 mg, 0.21 mmol) dropwise at 0 °C, and the resulting mixture was stirred at 0 °C for 2 hr. LCMS indicated the reaction was complete. The mixture was concentrated under reduced pressure to give a residue that was purified by prep-TLC to afford 4-(5-(((l-(2,6-dioxopiperidin-3-yl)-2,5- di oxo-2, 5-dihydro-lH-pyrrol-3-yl) (methyl)amino) methyl)-!, 2, 4-oxadiazol-3-yl) benzaldehyde (20 mg, yield: 67%) as a white solid. LCMS (m / z): [M+H]+calcd: 423.12; found: 424.3.

[0185] 3-(3-(((3-(4-((dimethylamino) methyl) phenyl)-!, 2, 4-oxadiazol-5-yl) methyl)(methyl)amino)-2,5-di oxo-2, 5 -dihydro- IH-pyrrol-l-yl) piperidine-2, 6-dione

[0186] To a mixture of 4-(5-(((l-(2,6-dioxopiperidin-3-yl)-2,5-dioxo-2,5-dihydro-lH- pyrrol-3-yl) (methyl)amino) methyl)-!, 2, 4-oxadiazol-3-yl) benzaldehyde (30 mg, 0.07 mmol) in DCM (1.0 mL) was added dimethylamine hydrochloride (3.0 mg, 0.07 mmol) and NaBH(OAc)3 (30.0 mg, 0.14 mmol) under nitrogen atmosphere. The resulting mixture was stirred at room temperature for 2 h. LCMS indicated the reaction was complete. The mixture was concentrated under reduced pressure to give a residue that was purified by prep-HPLC to afford 3-(3-(((3-(4-((dimethylamino) methyl) phenyl)-!, 2, 4-oxadiazol-5-yl) methyl) (methyl)amino)-2,5-dioxo-2,5-dihydro-lH-pyrrol-l-yl) piperidine-2, 6-dione (1.4 mg, yield: 4%) as a yellow solid. 'H NMR (400 MHz, DMSO-t / 6) 5 10.99 (s, 1H), 7.96 (d,J= 8.1 Hz, 2H), 7.50 (d,J= 8.1 Hz, 2H), 5.35 (d,J= 15.9 Hz, 3H), 4.87 (dd,J= 12.9, 5.4 Hz, 1H), 3.5190MEl\56453932.vl136883-01520(s, 3H), 2.84 - 2.76 (m, 1H), 2.54 (dd,J= 2.6, 0.7 Hz, 2H), 2.41 - 2.36 (m, 1H), 2.20 (s, 6H), 2.03 - 1.98 (m, 1H), 1.94 - 1.88 (m, 1H). LCMS (m / z): [M+H]+calcd: 452.18; found: 453.4.

[0187] Compound 136: Preparation of 3-{3-[methyl({3-[3-(pyridin-4-yl)phenyl]- l,2,4-thiadiazol-5-yl}methyl)amino]-2,5-dioxo-2,5-dihydro-lH-pyrrol-l- yl}hexahydropyridine-2, 6-dione

[0188] Preparation of 3-bromobenzene-l-carboxamide

[0189] To a solution of 3 -bromobenzene- 1 -carbonitrile (1.0 g, 5.5 mmol) in tert-Butanol (10 mL) was added KOH (2.2 g, 38 mmol). The reaction was stirred at 80 °C for 4 h. LCMS showed the reaction was complete. To the reaction was added brine and ethyl acetate. The organic layer was concentrated under reduced pressure to afford 3-bromobenzene-l- carboxamide (0.90 g, 4.5 mmol, 82%) as a white solid. [M]+ calcd:200.2, found: 201.2. 'H NMR (400 MHz, DMSO-tL) 5 8.09 (s, 1H), 8.05 (d, J= 1.7 Hz, 1H), 7.88 (d, J= 7.8 Hz, 1H), 7.77 - 7.66 (m, 1H), 7.52 (s, 1H), 7.43 (t, J= 7.9 Hz, 1H).

[0190] Preparation of 5-(3-bromophenyl)-l,3,4-oxathiazol-2-one

[0191] To a solution of 3-bromobenzene-l-carboxamide (0.95 g, 4.8 mmol) in toluene (5 mL) was added chlorosulfanecarbonyl chloride (0.80 mL, 9.5 mmol). The reaction was stirred at 90 °C for 18 h. LCMS showed the reaction was complete. The reaction was concentrated under reduced pressure and washed with H2O, 5% of NaHCCh, again with H2O, concentrated under reduced pressure to afford 5-(3-bromophenyl)-l,3,4-oxathiazol-2-one (0.90 g, 3.5 mmol, 73%) as a white solid. 'H NMR (400 MHz, DMSO-tL) 5 8.03 (t, J= 1.7 Hz, 1H), 7.96 - 7.90 (m, 1H), 7.88 (m, J= 8.0, 1.9, 0.9 Hz, 1H), 7.56 (t, J= 8.0 Hz, 1H).

[0192] Preparation of ethyl 3-(3-bromophenyl)-l,2,4-thiadiazole-5-carboxylate91MEl\56453932.vl136883-01520

[0193] To a solution of 5-(3-bromophenyl)-l,3,4-oxathiazol-2-one (0.50 g, 1.9 mmol) in di chlorobenzene (5 mL) was added ethyl cyanomethanoate (0.77 mL, 7.8 mmol). The reaction was stirred at 150 °C for 18 h. LCMS showed the reaction was completed. The reaction was poured into water and extracted with ethyl acetate. The organic layers were dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 10-50% EA in PE) to give ethyl 3-(3- bromophenyl)-l,2,4-thiadiazole-5-carboxylate (0.35 g, 1.2 mmol, 58%) as a brown solid. [M]+ calcd:313.2, found: 314.2.

[0194] Preparation of [3-(3-bromophenyl)-l,2,4-thiadiazol-5-yl]methanol

[0195] To a solution of ethyl 3-(3-bromophenyl)-l,2,4-thiadiazole-5-carboxylate (0.35 g, 1.1 mmol) in EtOH (5 mL) was added NaBEL (0.08 g, 2.2 mmol). The reaction was stirred at room temperature for 2h. LCMS showed the reaction was complete. The reaction was cooled to 0 °C, quenched with H2O and extracted with ethyl acetate. The organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 10-50% EA in PE) to afford [3-(3- bromophenyl)-l,2,4-thiadiazol-5-yl]methanol (0.25 g, 0.92 mmol, 83%) as a yellow solid.JH NMR (400 MHz, DMSO-tL) 5 8.32 (t, J= 1.7 Hz, 1H), 8.20 (d, J = 7.8 Hz, 1H), 7.84 - 7.68 (m, 1H), 7.52 (t, J= 7.9 Hz, 1H), 6.55 (t, J= 5.6 Hz, 1H), 5.00 (d, J= 5.6 Hz, 2H).

[0196] Preparation of 3-(3-bromophenyl)-5-(chloromethyl)-l,2,4-thiadiazole

[0197] To a solution of [3-(3-bromophenyl)-l,2,4-thiadiazol-5-yl]methanol (240 mg, 0.89 mmol) and TEA (0.37 mL, 2.7 mmol) in DCM (5 mL) was added Thionyl chloride (0.13 mL, 1.8 mmol). The reaction was stirred at room temperature for 2h. LCMS showed the reaction92MEl\56453932.vl136883-01520 was completed. To the reaction was added water and extracted DCM. The organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was used to next step directly. [M]+ calcd:256.2, found: 257.2.

[0198] Preparation of 3-(3-bromophenyl)-5-[(methylamino)methyl]-l,2,4-thiadiazole

[0199] To a solution of 3-(3-bromophenyl)-5-(chloromethyl)-l,2,4-thiadiazole (100 mg, 0.35 mmol) in THF (4 mL) was added Methylamine (1.4 mL, 2.8 mmol). The reaction was stirred at 50 °C for 18 h. LCMS showed the reaction was complete. The reaction was concentrated under reduced pressure and purified by flash column chromatography (silica gel, 0-10% MeOH in DCM) to give 3-(3-bromophenyl)-5-[(methylamino)methyl]-l,2,4- thiadiazole (50 mg, 0.18 mmol, 51%) as a yellow solid. [M]+ calcd:453.4, found:454.4.JH NMR (400 MHz, DMSO-tL) 5 11.00 (s, 1H), 7.84 - 7.78 (m, 2H), 7.75 - 7.69 (m, 2H), 5.35 (s, 3H), 4.93 - 4.82 (m, 1H), 3.68 (s, 3H), 3.18 (s, 2H), 2.87 - 2.73 (m, 1H), 2.54 (s, 1H), 2.39 (m, J= 13.1, 4.2 Hz, 1H), 1.95 - 1.86 (m, 1H).

[0200] Preparation of 3-[3-({[3-(3-bromophenyl)-l,2,4-thiadiazol-5- yl]methyl}(methyl)amino)-2,5-dioxo-2,5-dihydro-lH-pyrrol-l-yl]hexahydropyridine- 2, 6-dione

[0201] To a solution of 3-(3-bromo-2,5-dioxo-2,5-dihydro-lH-pyrrol-l- yl)hexahydropyridine-2, 6-dione (60 mg, 0.21 mmol) and 3-(3-bromophenyl)-5- [(methylamino)methyl]-l,2,4-thiadiazole (59 mg, 0.21 mmol) in Dioxane (5 mL) was added triethylamine (0.03 mL, 0.21 mmol). The reaction was stirred at 40 °C for 18 h. LCMS showed the reaction was completed. The reaction was concentrated under reduced pressure and purified by prep-HPLC (C18, Wave length: 220nm / 254nm phase A: H2O (0.1% FA); phase B: MECN 5%-95%, 10min / 20 min) to give 3-[3-({[3-(3-bromophenyl)-l,2,4-93MEl\56453932.vl136883-01520 thiadiazol-5-yl]methyl}(methyl)amino)-2, 5-di oxo-2, 5-dihydro-lH-pyrrol-l- yl]hexahydropyridine-2, 6-dione (42 mg, 0.09 mmol, 41%) as a yellow solid. [M]+ calcd:490.2, found: 492.2.

[0202] Preparation of 3-{3-[methyl({3-[3-(pyridin-4-yl)phenyl]-l,2,4-thiadiazol-5- yl}methyl)amino]-2,5-dioxo-2,5-dihydro-lH-pyrrol-l-yl}hexahydropyridine-2, 6-dione

[0203] To a solution of 3-[3-({[3-(3-bromophenyl)-l,2,4-thiadiazol-5- yl]methyl}(methyl)amino)-2, 5-di oxo-2, 5-dihy dro-lH-pyrrol-1 -yl]hexahydropyridine-2, 6- dione (30 mg, 0.06 mmol), pyridin-4-ylboranediol (30 mg, 0.25 mmol) and Pd-118 (7 mg, 0.01 mmol) in dioxane (3 mL) and H2O (0.3 mL) was added K2CO3 (25.37 mg, 0.18 mmol). The reaction was stirred at 80 °C for Ih. LCMS showed the reaction was completed. The reaction was filtered through Celite® and the filtrate was concentrated under reduced pressure. The residue was purified by prep-HPLC (Cl 8, Wave length: 220nm / 254nm phase A: H2O (0.1% FA); phase B: MECN 5%-95%, 10min / 20 min) to give 3-{3-[methyl({3-[3- (pyridin-4-yl)phenyl]-l, 2, 4-thiadiazol-5-yl}methyl)amino]-2, 5-di oxo-2, 5-dihy dro-lH-pyrrol- l-yl}hexahydropyridine-2, 6-dione (20 mg, 0.04 mmol, 67%) as a yellow solid. [M]+ calcd:488.2, found:489.2. 'H NMR (400 MHz, DMSO-tL) 5 11.00 (s, IH), 8.72 - 8.67 (m, 2H), 8.55 (s, IH), 8.30 (d, J= 7.9 Hz, IH), 7.98 (d, J= 8.4 Hz, IH), 7.79 - 7.74 (m, 2H), 7.72 (t, J= 7.8 Hz, IH), 5.42 (d, J= 28.9 Hz, 3H), 4.95 - 4.84 (m, IH), 3.21 (s, 3H), 2.88 - 2.74 (m, IH), 2.55 - 2.52 (m, IH), 2.43 - 2.36 (m, IH), 1.93 - 1.83 (m, IH).

[0204] Compound 137: 3-(3-(methyl((3-phenyl-l,2,4-oxadiazol-5-yl)methyl)amino)-2,5- di oxo-4-(trifluoromethyl)-2, 5-dihy dro-lH-pyrrol-l-yl)piperidine-2, 6-dione

[0205] To a solution of 3-(3-iodo-4-(methyl((3-phenyl-l,2,4-oxadiazol-5- yl)methyl)amino)-2,5-dioxo-2,5-dihydro-lH-pyrrol-l-yl)piperidine-2, 6-dione (106 mg, 0.20 mmol) in DMF (3.0 mL) were added Cu powder (39 mg, 0.61 mmol) and Umem oto's reagent94MEl\56453932.vl136883-01520(180 mg, 0.41 mmol) at 0°C. The reaction was stirred at 0°C for 18hr. LCMS indicated the reaction was complete. Then the mixture was filtered through Celite® and concentrated under recued pressure to afford a residue, which was purified by prep-HPLC(C18, Wave length: 220nm / 254nm phase A: H2O (0.1% FA); phase B: MECN 30%-88 %, 11 min / 20 min) to afford 3-(3-(methyl((3-phenyl-l,2,4-oxadiazol-5-yl)methyl)amino)-2,5- dioxo-4-(trifluoromethyl)-2,5-dihydro-lH-pyrrol-l-yl)piperidine-2, 6-dione (6.9 mg, yield: 9%) as a white solid. LCMS (m / z): [M]+calcd, 463.11; found, 464.1 (M+H)+.1H NMR (400 MHz, DMSO-tL) 5 11.03 (s, 1H), 8.01 (dd, J= 7.9, 1.6 Hz, 2H), 7.66 - 7.53 (m, 3H), 5.49 (q, J= 17.8 Hz, 2H), 4.97 (dd, J= 12.9, 5.4 Hz, 1H), 3.46 - 3.41 (m, 3H), 2.83 - 2.74 (m, 1H), 2.55 (s, 1H), 2.36 (dd, J= 13.5, 4.4 Hz, 1H), 1.98 - 1.89 (m, 1H).19F NMR (377 MHz, DMSO-tfc) 5 -47.80 (s).Biochemical Assays

[0206] In Vitro TR-FRET ternary - ALK Mutant (Mut) CRBN:

[0207] 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. One column of DMSO only and one column of 3-(3-{N- methyl[(3-phenyl-l,2,4-oxadiazol-5-yl)methyl]amino}-2,5-dioxo-3-pyrrolin-l-yl)-2,6- piperidinedione (final concentration 10 pM) served as negative and positive controls, respectively. To this plate was added 10 microliters of a reaction mixture containing 150 nM avi-tagged ALK, 75 nM ULight- Streptavidin (PerkinElmer), 50 nM 6xHis-tagged CRBN / DDB 1, and 0.5 nM Eu-W1024 Anti-6xHis (PerkinElmer) in a buffer consisting of 50 mM Tris, 150 mM NaCl, 1 mM TCEP, 0.02% Tween-20, and 0.5 mg / mL BSA at pH 7.4. The plate was incubated at room temperature for 2 hours, then read on a BMG PHERAstar plate reader with a 337 nm excitation laser and 620 nm and 665 nm emission filters. The TR- FRET signal was calculated as the ratio of emission signals at 665 nm over 620 nm, and the compound-containing wells were normalized to negative controls (0% activity) and 3-(3-{N- methyl[(3-phenyl-l,2,4-oxadiazol-5-yl)methyl]amino}-2,5-dioxo-3-pyrrolin-l-yl)-2,6- piperidinedione (100% activity). Normalized data for each compound were then subjected to a 4-parameter logistic fit.

[0208] In Vitro TR-FRET ternary - ALK Mutant (Mut) CRBN (v3):

[0209] 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 384-95MEl\56453932.vl136883-01520 well plate by an SPT Labtech Mosquito LV as duplicate 10-point dilution series to a total volume of 100 nanoliters of DMSO. One column of DMSO only and one column of 2-(2,6- dioxo-3-piperidyl)-4-[(3-phenyl-l,2,4-oxadiazol-5-yl)methyl]-2,4-diaza-4,5,6,7-tetrahydro- lH-indene-l,3(2H)-dione (final concentration 20 pM) served as negative and positive controls, respectively. To this plate was added 10 microliters of a reaction mixture containing 5 nM avi -tagged ALK, 0.5 nM Eu-W1024-Streptavidin (PerkinElmer), 5 nM 6xHis-tagged CRBN / DDB1, and 30 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 negative controls (0% activity) and 2-(2,6- dioxo-3-piperidyl)-4-[(3-phenyl-l,2,4-oxadiazol-5-yl)methyl]-2,4-diaza-4,5,6,7-tetrahydro- lH-indene-l,3(2H)-dione (100% activity). Normalized data for each compound were then subjected to a 4-parameter logistic fit.

[0210] Results are shown in Table 1. The letter codes for EC50 include; A (<10 nM), B (10-100 nM), C (100-1000 nM), D (>1000nM), The sign codes for Emax include; + (<50 %), ++ (50-120), +++ (>120).Table 196MEl\56453932.vl136883-0152097MEl\56453932.vl136883-0152098MEl\56453932.vl136883-01520

[0211] 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.99MEl\56453932.vl

Claims

1. 136883-01520Listing of Claims:

1. A compound having the structural formula I:or a pharmaceutically acceptable salt thereof, whereinR1, R2, R3, and R3aare each independently hydrogen or (Ci-C4)alkyl; or the nitrogen atom attached to R2is taken together with the carbon atom attached to R1to form a 5- to 7- membered heterocyclyl, wherein the substituents R1and R2are no longer present as a result of the ring formation and wherein said 5- to 7-membered heterocyclyl is optionally substituted with 1 to 4 groups selected from RA;Y is heteroaryl or heterocyclyl, each optionally substituted with 1 to 3 groups selected from RE;R4is absent or is phenyl or heteroaryl, each of which are optionally substituted with 1 to 4 group selected from RB;RAand REare each independently selected from cyano, halo, (Ci-C4)alkyl, halo(Ci- C4)alkyl, (Ci-C4)alkoxy, and halo(Ci-C4)alkoxy;RBis selected from halo, (Ci-C4)alkyl, halo(Ci-C4)alkyl, (Ci-C4)alkoxy, halo(Ci- C4)alkoxy, hydroxy, (Ci-C4)alkyleneOH, (Ci-C4)alkylene(Ci-C4)alkoxy, -(Ci- C4)alkyleneNRxRY, cyano, oxo, -(Ci-C4)alkoxyNRxRY, -(Ci-C4)alkyleneC(O)ORx, -(Ci- C4)alkoxyC(O)ORx, -(Ci-C4)alkyleneC(O)Rx, -(Ci-C4)alkoxyC(O)Rx, -(Ci- C4)alkyleneheterocyclyl, -(Ci-C4)alkyleneheteroaryl, -(Ci-C4)alkoxyheterocyclyl, -(Ci- C4)alkoxyheteroaryl, -(Ci-C4)alkylenecycloalkyl, -(Ci-C4)alkoxy cycloalkyl, -(Ci- C4)alkylenephenyl, -(Ci-C4)alkoxyphenyl -NRx(Ci-C4)alkyleneheteroaryl, -NRx(Ci- C4)alkyleneheterocyclyl, -NRx(Ci-C4)alkylenecycloalkyl, cycloalkyl, heteroaryl, heterocyclyl, -NRXRY, -NRXC(O)RY, -NRXC(O)ORY, -NRx(Ci-C4)alkyleneC(O)NRxRz, - NRXC(O)NRXRZ, -(Ci-C4)alkyleneNRxC(O)RY, -(Ci-C4)alkyleneNRxC(O)ORY, -(Ci- C4)alkyleneNRx(Ci-C4)alkyleneC(O)NRxRz, -(Ci-C4)alkyleneNRxC(O)NRxRz, -(Ci- C4)alkoxyNRxC(O)RY, -(Ci-C4)alkoxyNRxC(O)ORY, -(Ci-C4)alkoxyNRx(Ci- C4)alkyleneC(O)NRxRz, -(Ci-C4)alkoxyNRxC(O)NRxRz, -S(Ci-C4)alkyl, -O(heteroaryl), -100MEl\56453932.vl136883-01520O(heterocyclyl), -O(cycloalkyl), -C(O)NRXRY-(Ci-C4)alkyleneC(O)NRxRY, -(Ci- C4)alkoxyC(O)NRxRY, -C(O)RX, and -C(O)ORX, wherein each of said cycloalkyl, phenyl, heteroaryl, and heterocyclyl recited alone, or recited as being part of a larger group, are optionally substituted with 1 to 3 groups selected from Rc;Rcis selected from (Ci-C4)alkyl, halo(Ci-C4)alkyl, (Ci-C4)alkoxy, halo(Ci-C4)alkoxy cyano, oxo, and hydroxy;Rx, RY, and Rzare each independently selected from hydrogen, (Ci-C4)alkyl, halo(Ci- C4)alkyl, phenyl, benzyl, (C3-Ce)cycloalkyl, 4- to 6-membered heterocyclyl, and 5- to 7- membered heteroaryl; and v is 1, 2, or 3; provided the compound is not 3-[2,5-Dihydro-3-[methyl[(3-phenyl-l,2,4-oxadiazol-5- yl)methyl]amino]-2,5-dioxo-lH-pyrrol-l-yl]-2,6-piperidinedione, 3-[2,5-Dihydro-3-[[(l- methyl-lH-indol-6-yl)methyl]amino]-2,5-dioxo-lH-pyrrol-l-yl]-2,6-piperidinedione, 3-[2,5- Dihydro-2,5-dioxo-3-[(3-pyridinylmethyl)amino]-lH-pyrrol-l-yl]-2,6-piperidinedione, 3-(3- (((4-chloropyri din-2 -yl)methyl)(methyl)amino)-2,5-di oxo-2, 5-dihydro- IH-pyrrol-l- yl)piperidine-2, 6-dione, or a pharmaceutically acceptable salt of any of the foregoing.

2. The compound of Claim 1, or a pharmaceutically acceptable salt thereof, wherein R2is (Ci-C4)alkyl.

3. The compound of Claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R2is CH3.

4. The compound of any one of Claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein R1is CH3, CH2CH , or hydrogen.

5. The compound of any one of Claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein R1is hydrogen.

6. The compound of Claim 1 or 2, wherein the compound of Formula I is of the structural Formula II:101MEl\56453932.vl136883-01520or a pharmaceutically acceptable salt thereof.

7. The compound of any one of Claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein v is 1.

8. The compound of any one of Claims 1 to 7, or a pharmaceutically acceptable salt thereof, wherein R3ais hydrogen.

9. The compound of any one of Claims 1 to 8, or a pharmaceutically acceptable salt thereof, wherein R3is CH3 or hydrogen.

10. The compound of any one of Claims 1 to 9, or a pharmaceutically acceptable salt thereof, wherein R3is hydrogen.

11. The compound of any one of Claims 1 to 10, or a pharmaceutically acceptable salt thereof, wherein Y is a heteroaryl optionally substituted with 1 to 3 groups selected from RE.

12. The compound of any one of Claims 1 to 11, or a pharmaceutically acceptable salt thereof, wherein Y is a 5- to 9-membered heteroaryl optionally substituted with 1 to 3 groups selected from RE.

13. The compound of any one of Claims 1 to 12, or a pharmaceutically acceptable salt thereof, wherein Y is a 5-membered heteroaryl optionally substituted with 1 to 3 groups selected from RE.

14. The compound of any one of Claims 1 to 13, or a pharmaceutically acceptable salt thereof, wherein Y is oxadiazolyl, triazolyl, oxazolyl, isoxazolyl, or thiadiazolyl, each optionally substituted with 1 to 3 groups selected from RE.102MEl\56453932.vl136883-0152015. The compound of any one of Claims 1 to 14, or a pharmaceutically acceptable salt thereof, wherein REis (Ci-C4)alkyl.

16. The compound of any one of Claims 1 to 12, or a pharmaceutically acceptable saltwherein * indicates the attachment position to R4.

17. The compound of any one of Claims 1 to 16, or a pharmaceutically acceptable salt thereof, wherein R4is phenyl or heteroaryl, each of which are optionally substituted with 1 to 4 groups selected from RB.

18. The compound of any one of Claims 1 to 17, or a pharmaceutically acceptable salt thereof, wherein R4is phenyl or 5- to 9-membered heteroaryl, each of which are optionally substituted with 1 to 4 groups selected from RB.

19. The compound of any one of Claims 1 to 18, or a pharmaceutically acceptable salt thereof, wherein R4is phenyl, pyridinyl, imidazolyl, pyrazolyl, pyrrolyl, thiazolyl, oxazolyl, isoxazolyl, benzooxazolyl, indolyl, or benzoimidazolyl, each of which are optionally substituted with 1 to 4 groups selected from RB.

20. The compound of any one of Claims 1 to 19, or a pharmaceutically acceptable salt thereof, wherein RBis selected from halo, (Ci-C4)alkyl, halo(Ci-C4)alkyl, (Ci-C4)alkoxy, - C(O)ORX, (Ci-C4)alkyleneOH, OH, cycloalkyl, -O(cycloalkyl), phenyl, -O(phenyl), heteroaryl, -O(heteroaryl), heterocyclyl, -NRXRY, -C(O)NRXRY, (Ci-103MEl\56453932.vl136883-01520C4)alkyleneNRxC(0)0RY, and (Ci-C4)alkyleneNRxRY, wherein said cycloalkyl, phenyl, heterocyclyl, and heteroaryl are optionally substituted with 1 to 3 groups selected from Rc.

21. The compound of any one of Claims 1 to 20, or a pharmaceutically acceptable salt thereof, wherein RBis selected from halo, (Ci-C4)alkyl, halo(Ci-C4)alkyl, (Ci-C4)alkoxy, - C(O)ORX, (Ci-C4)alkyleneOH, OH, 3- to 6-membered cycloalkyl, -0(3- to 6-membered cycloalkyl), phenyl, -O(phenyl), -0(5- to 10-membered heteroaryl), 5- to 10-membered heteroaryl, 4- to 6-membered heterocyclyl, -NRXRY, -C(O)NRXRY, (Ci- C4)alkyleneNRxC(0)0RY, and (Ci-C4)alkyleneNRxRY, wherein said 3- to 6-membered cycloalkyl, phenyl, 5- to 9-membered heteroaryl, and 4- to 6-membered heterocyclyl are each optionally substituted with 1 to 3 groups selected from Rc.

22. The compound of any one of Claims 1 to 21, or a pharmaceutically acceptable salt thereof, wherein RBis selected from halo, (Ci-C4)alkyl, halo(Ci-C4)alkyl, (Ci-C4)alkoxy, - C(0)0Rx, (Ci-C4)alkyleneOH, OH, cyclopropyl, cyclopentyl, cyclohexyl, -O(phenyl), - O(cyclopropyl), phenyl, -O(pyridinyl), pyridinyl, quinolinyl, imidazolyl, pyrimidinyl, pyridazinyl, pyrazinyl, pyrrolidinyl, pyrrolopyridinyl, benzoxazolyl, oxazolyl, isooxazolyl dihydropyranyl, isothiazolyl, tetrahydropyranyl, morpholinyl, piperazinyl, -NRXRY, (Ci- C4)alkyleneNRxC(0)0RY, -C(O)NRXRY, and (Ci-C4)alkyleneNRxRY, wherein said cyclopropyl, cyclopentyl, cyclohexyl, phenyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, pyrrolopyridinyl, benzoxazolyl, oxazolyl, morpholinyl, dihydropyranyl, isothiazolyl, tetrahydropyranyl, and piperazinyl are optionally substituted with 1 to 3 groups selected from Rc.

23. The compound of any one of Claims 1 to 22, or a pharmaceutically acceptable salt thereof, wherein Rxand RYare independently selected from hydrogen and (Ci-C4)alkyl.

24. The compound of any one of Claims 1 to 23, or a pharmaceutically acceptable salt thereof, wherein Rcis selected from (Ci-C4)alkyl, halo(Ci-C4)alkyl, oxo, and (Ci-C4)alkoxy.104MEl\56453932.vl136883-01520105MEl\56453932.vl136883-01520106MEl\56453932.vl136883-0152026. The compound of Claim 1, wherein the compound is selected from Compounds 1 to 145; or a pharmaceutically acceptable salt thereof.

27. A pharmaceutical composition comprising a compound of any one of Claims 1 to 26, or a pharmaceutically acceptable salt.

28. A method of treating a condition responsive to the degradation of Anaplastic Lymphoma Kinase (ALK) comprising administering to a subject a therapeutically effective amount of a compound of any one of Claims 1 to 26, or a pharmaceutically acceptable salt; or the composition of Claim 27.

29. The method of Claim 28, wherein the condition is cancer.107MEl\56453932.vl

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