2-(2, 6-dioxopiperidine-3-yl)-1, 3-dioxoisoindoline derivatives bearing an heteroaryl group as anaplastic lymphoma kinase (ALK) degraders and uses thereof

Abstract

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

Description

136883-01820ANAPLASTIC LYMPHOMA KINASE (ALK) DEGRADERS AND USES THEREOF Related Applications

[0001] This application claims the benefit of priority to U.S. Provisional Application No.63 / 743,459, filed January 9, 2025, the entire contents 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.Summary

[0004] Provided herein are compounds having the Formula I:MEl\59506850.vl136883-01820and pharmaceutically acceptable salts and compositions thereof, wherein R1, R2, q, and R3are as described herein. In one aspect, the described 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 having the structural Formula I:or a pharmaceutically acceptable salt thereof, wherein:X is O, NH, N(Ci-C4)alkyl, S, or (CR^q;A is an optionally substituted heteroaryl;R1and R2are each independently hydrogen or (Ci-C4)alkyl; or R1and R2taken together form a (C3-C6)cycloalkyl optionally substituted with 1 to 3 groups selected from RA;RAis selected from cyano, halo, (Ci-C4)alkyl, halo(Ci-C4)alkyl, (Ci-C4)alkoxy, and halo(Ci-C4)alkoxy; andq is 1, 2, or 3.2. 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.

[0008] As used in the structure herein a hyphen (-) or squiggly line “ -~w ” 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-C6)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).2MEl\59506850.vl136883-01820

[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] The term “alkene” when used alone or as part of a larger moiety, means a saturated straight-chain or branched hydrocarbon radical containing at least one carbon to carbon double bond.

[0012] “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.

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

[0014] “Haloalkoxy” is a haloalkyl group which is attached to another moiety via an oxygen atom such as, e.g., -OCHF2 or -OCF3.

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

[0016] The term oxo means the group =0.

[0017] The term “heteroaryl” used alone or as part of a larger moiety refers to, unless otherwise specified, a 5- to 12-membered aromatic radical containing 1-4 heteroatoms selected from N, O, and S. A heteroaryl group may be mono- or bi-cyclic. Monocyclic heteroaryl includes, for example, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, triazinyl, tetrazinyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, etc. Bi-cyclic heteroaryls include groups in which a monocyclic heteroaryl ring is fused to one or more aryl or heteroaryl rings. Nonlimiting examples include indolyl, imidazopyridinyl, benzooxazolyl, benzooxodi azolyl, 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.

[0018] The term “heterocyclyl” means, unless otherwise specified, a 5- to 12-membered saturated or partially unsaturated heterocyclic ring containing 1 to 4 heteroatoms independently selected from N, O, and S. It can be monocyclic, bicyclic (e.g., a bridged,3MEl\59506850.vl136883-01820fused, or spiro bicyclic ring), or tricyclic. A heterocyclyl ring can be attached to its pendant group at any heteroatom or carbon atom that results in a stable structure. Examples of such saturated or partially unsaturated heterocyclic radicals include, without limitation, tetrahydrofuranyl, tetrahydrothienyl, terahydropyranyl, pyrrolidinyl, pyridinonyl, pyrrolidonyl, piperidinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, morpholinyl, dihydrofuranyl, dihydropyranyl, dihydropyridinyl, tetrahydropyridinyl, dihydropyrimidinyl, oxetanyl, azetidinyl and tetrahydropyrimidinyl. A heterocyclyl group may be mono- or bicyclic. The term “heterocyclyl” also includes, e.g., unsaturated heterocyclic radicals fused to another unsaturated heterocyclic radical or aryl or heteroaryl ring, such as for example, tetrahydronaphthyridine, indolinone, dihydropyrrolotriazole, imidazopyrimidine, quinolinone, dioxaspirodecane. It will also be understood that when specified, optional substituents on a heterocyclyl group may be present on any substitutable position.

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

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

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

[0022] The 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, cyclohexyl, cycloheptyl, and cyclooctyl. It will be understood that when specified, optional substituents on a cycloalkyl may be present on any substitutable position.

[0023] 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 ( / .< ., 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.

[0024] 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. In some aspect, an optional substituents is defined by RB, where RBis selected from halo, (Ci-C4)alkyl, halo(Ci-C4)alkyl, (Ci-C4)alkoxy, halo(Ci-C4)alkoxy, hydroxy, (Ci-C4)alkyleneOH, (Ci- 4MEl\59506850.vl136883-01820C4)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)alkoxycycloalkyl, -(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; and Rx, RY, and Rzare each independently selected from hydrogen, (Ci-C4)alkyl, halo(Ci-C4)alkyl, phenyl, benzyl, (C3-C6)cycloalkyl, 4- to 6-membered heterocyclyl, and 5- to 7-membered heteroaryl

[0025] As used herein, the term “substituted” means that an atom or group of atoms has replaced hydrogen as the substituent attached to another group.

[0026] 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.

[0027] 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.

[0028] 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 as5MEl\59506850.vl136883-01820racemates 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.

[0029] 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.

[0030] 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.

[0031] 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.

[0032] 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.

[0033] The term “inhibit,” “inhibition” or “inhibiting” includes a decrease in the baseline activity of a biological activity or process.

[0034] 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 6MEl\59506850.vl136883-01820more symptoms thereof, as described herein. In some aspects, treatment may be administered after one or more symptoms have developed, / .< ., therapeutic treatment. In other aspects, treatment may be administered in the absence of symptoms. For example, treatment may be administered to a susceptible individual prior to the onset of symptoms (e.g., in light of a history of symptoms and / or in light of exposure to a particular organism, or other susceptibility factors), i.e., prophylactic treatment. Treatment may also be continued after symptoms have resolved, for example to delay their recurrence.

[0035] The term “pharmaceutically acceptable carrier” refers to a non-toxic carrier, adjuvant, or vehicle that does not destroy the pharmacological activity of the compound with which it is formulated. Pharmaceutically acceptable carriers, adjuvants or vehicles that may be used in the compositions described herein include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, poly acrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol and wool fat.

[0036] 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.7MEl\59506850.vl136883-01820

[0037] 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

[0038] As part of a second embodiment, the compound of structural Formula I is of the structural Formula II:or a pharmaceutically acceptable salt thereof, wherein the variables are as described above for Formula I.

[0039] As part of a third embodiment, A in the compound of structural Formula I or structural Formula II, or a pharmaceutically acceptable salt thereof, is an optionally substituted monocyclic heteroaryl, wherein the remaining variables are as described above for Formula I. Alternatively, as part of a third embodiment, A in the compound of structural Formula I or structural Formula II, or a pharmaceutically acceptable salt thereof, is an optionally substituted 5-membered monocyclic heteroaryl, wherein the remaining variables are as described above for Formula I. In another alternative, as part of a third embodiment, A in the compound of structural Formula I or structural Formula II, or a pharmaceutically acceptable salt thereof, is an optionally substituted oxadiazolyl, wherein the remaining variables are as described above for Formula I.

[0040] As part of a fourth embodiment, X in the compound of structural Formula I or structural Formula II, or a pharmaceutically acceptable salt thereof, is O, NH, or (CRjR^q, wherein the remaining variables are as described above for Formula I or the third embodiment. Alternatively, as part of a fourth embodiment, X in the compound of structural Formula I or structural Formula II, or a pharmaceutically acceptable salt thereof, is (Cl R^q, wherein the remaining variables are as described above for Formula I or the third embodiment.

[0041] As part of a fifth embodiment, R1in the compound of structural Formula I or structural Formula 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 third or fourth embodiments.8MEl\59506850.vl136883-01820

[0042] As part of a sixth embodiment, R2in the compound of structural Formula I or structural Formula 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 third to fifth embodiments.

[0043] As part of a seventh embodiment, q in the compound of structural Formula I or structural Formula II, or a pharmaceutically acceptable salt thereof, is 1, wherein the remaining variables are as described above for Formula I or any one of the third to sixth embodiments.

[0044] As part of an eighth embodiment, A in the compound of structural Formula I orstructural Formula II, or a pharmaceutically acceptable salt thereof, is; R3is (Ci-C4)alkyl, phenyl, heterocyclyl, or heteroaryl, wherein each of said phenyl, heterocyclyl, and heteroaryl are optionally substituted with 1 to 4 groups selected from RB; 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)alkoxycycloalkyl, -(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; and Rx, RY, and Rzare each independently selected from hydrogen, (Ci-C4)alkyl, halo(Ci-C4)alkyl, phenyl, benzyl, (C3-C6)cycloalkyl, 4- to 6-9MEl\59506850.vl136883-01820membered heterocyclyl, and 5- to 7-membered heteroaryl, wherein the remaining variables are as described above for Formula I or any one of the third to seventh embodiments.

[0045] As part of a ninth embodiment, R3is phenyl 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 third to eighth embodiments.

[0046] As part of a tenth embodiment, RBis selected from halo and heteroaryl, wherein said heteroaryl is 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 third to ninth embodiments. Alternatively, as part of a tenth embodiment, RBis selected from halo and 5- to 7-membered heteroaryl, wherein said 5- to 7-membered heteroaryl is 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 third to ninth embodiments. In another alternative, as part of a tenth embodiment, RBis selected from halo, pyridinyl, pyrazinyl, and pyrimidinyl, wherein said pyridinyl, pyrazinyl, and pyrimidinyl 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 third to ninth embodiments.

[0047] As part of an eleventh embodiment, Rcis (Ci-C4)alkyl, wherein the remaining variables are as described above for Formula I or any one of the third to tenth embodiments.

[0048] 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

[0049] 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.

[0050] In some aspects, the compounds and pharmaceutical compositions described herein are useful in treating a disorder associated with ALK function. Thus, provided herein 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.

[0051] 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 10MEl\59506850.vl136883-01820pharmaceutically 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.

[0052] 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, 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 11MEl\59506850.vl136883-01820pancreatic 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.

[0053] 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).

[0054] In some aspects, the cancer treated by the compounds, pharmaceutically acceptable salt thereof, and pharmaceutical compositions described herein is an ALK positive cancer.

[0055] 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.

[0056] 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.

[0057] In certain aspects, a pharmaceutical composition described herein is formulated for administration to a patient in need of such composition. Pharmaceutical compositions described herein may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir. The term "parenteral" as used herein includes subcutaneous, intravenous, intramuscular, intra-articular, intra-synovial, intrastemal, intrathecal, intrahepatic, intralesional and intracranial injection or infusion 12MEl\59506850.vl136883-01820techniques. 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.

[0058] In some aspects, the pharmaceutical compositions are administered orally.

[0059] 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

[0060] 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

[0061] Intermediate A: 2-(2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4-yl)acetic acid

[0062] 4-allyl-2-(2,6-dioxopiperidin-3-yl)isoindoline-l, 3-dione

[0063] To a mixture of 4-bromo-2-(2,6-dioxopiperidin-3-yl)isoindoline-l, 3-dione (6.5 g, 19.3 mmol), allyltributylstannane (9.58 g, 28.92 mmol) in DMF (65 mL) was added Pd(PPhs)4 (2.23 g, 1.93 mmol) at the atmosphere of nitrogen. The resulting mixture was stirred at 100°C for 12 hrs. LCMS indicated the reaction was complete. Then the mixture was cooled to room temperature, poured into sat. NH4CI and extracted with EtOAc. The organic13MEl\59506850.vl136883-01820layer was washed with brine, dried over anh. Na2SC>4 and concentrated to afford a residue. The residue was purified by flash column chromatography (silica gel, 0-40% EA in PE) to afford 4-allyl-2-(2,6-dioxopiperidin-3-yl)isoindoline-l, 3-dione (5.76 g, 19.3 mmol, yield: 100%) as a yellow solid. LCMS (m / z): [M]+calcd, 298.10; found, 299.4 (M+H)+.

[0064] 2-(2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4-yl)acetic acid

[0065] To a solution of 4-allyl-2-(2,6-dioxopiperidin-3-yl)isoindoline-l, 3-dione (500 mg, 1.68 mmol) in CCh (5.0 mL) and acetonitrile (5.0 mL) was added RuCh (6.0 mg, 0.03 mmol). The mixture was stirred at room temperature for 30min. To the mixture was added NaICU (1.35M, 1440 mg, 6.71 mmol) solution dropwise, and the reaction was stirred at room temperature for 18 hrs. LCMS indicated the reaction was complete. Then the mixture was quenched with NaHCCh solution and extracted with ethyl acetate. The aqueous layer was acidified with potassium bisulfate and extracted with ethyl acetate. The organic layer was washed with brine, dried by Na2SO4 and concentrated to give 2-(2-(2, 6-dioxopiperi din-3 -yl)-l,3-dioxoisoindolin-4-yl)acetic acid (480 mg, 1.52 mmol, yield: 91%) as a yellow solid. LCMS (m / z): [M]+calcd, 316.07; found, 317.4. 'HNMR (400 MHz, DMSO-tL) 6 12.52 (s, 1H), 11.13 (s, 1H), 7.87 - 7.65 (m, 3H), 5.14 (dd, J= 12.7, 5.4 Hz, 1H), 4.08 (s, 2H), 2.94 -2.82 (m, 1H), 2.67 -2.54 (m, 2H), 2.12 -2.01 (m, 1H).

[0066] Alternatively, Intermediate A can be synthesized as follows:

[0067] tert-butyl 2-(2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4-yl)acetate

[0068] To a solution of 4-bromo-2-(2,6-dioxopiperidin-3-yl)isoindoline-l, 3-dione (500 mg, 1.49 mmol) and ((l-(tert-butoxy)vinyl)oxy)(tert-butyl)dimethylsilane (1.03 g, 4.46 mmol) in DMF (4 mL) were added Pd(t-BusP)2 (76.4 mg, 0.15 mmol) and LiF (232 mg, 8.93 mmol). The reaction was stirred at 100°C for 3 h. LCMS showed the reaction was completed. The reaction was concentrated under reduced pressure, then the residue was added to water (100 mL) and extracted by EA (50 mLx 3). The organic layer was separated and dried with 14MEl\59506850.vl136883-01820anhydrous sodium sulfate, filtered and the organic layer was concentrated under reduced pressure and purified using silica gel column chromatography (PE:EA=3:2) to give tert-butyl 2-(2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4-yl)acetate (430 mg, 1.16 mmol, 78%) as a white solid. LCMS (m / z): [M]+ calcd:372.13, found: 373.2.

[0069] 2-(2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4-yl)acetic acid

[0070] To a solution of tert-butyl 2-(2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4-yl)acetate (430 mg, 1.16 mmol) in DCM (3 mL) was added trifluoroacetic acid (1 mL). The reaction was stirred at room temperature for 1 hour. LCMS showed the reaction was completed. Then the reaction was concentrated under reduced pressure to give 2-(2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4-yl)acetic acid (280.0 mg, 0.89 mmol, 77 %) as a brown solid. LCMS (m / z): [M]+ calcd: 316.27, found: 317.2.Examples

[0071] General Method A: 2-(2.6-dioxoDiDeridin-3-vl)-4-((3-Dhenyl-l.,2.,4-oxadiazol- 5-yl)methyl)isoindoline-l,3 dione (Compound 1)

[0072] 2-(2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4-yl)acetyl chloride

[0073] To a solution of 2-(2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4-yl)acetic acid (306 mg, 0.97 mmol) in DCM (6.0 mL) were added oxalyl chloride (0.97 mL) and one drop of DMF at 0°C. The reaction was stirred at RT for 30 min. LCMS indicated the reaction was complete. Then the mixture was concentrated to give 2-(2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4-yl)acetyl chloride (300 mg, crude) as a yellow solid.15MEl\59506850.vl136883-01820

[0074] (E)-2-(2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4-yl)-N- ((hydroxyimino)(phenyl)methyl)acetamide

[0075] To a solution of 2-(2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4-yl)acetyl chloride (100 mg, 0.30 mmol) in DCM (5.0 mL) were added (Z)-N'-hydroxybenzimidamide (82.0 mg, 0.60 mmol) and TEA (39.0 mg, 0.39 mmol), and the reaction was stirred at RT for 30min. LCMS indicated the reaction was complete. Then the mixture was concentrated to give (E)-2-(2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4-yl)-N-((hydroxyimino)(phenyl)methyl)acetamide (126 mg, crude) as a yellow solid. LCMS (m / z):[M]+calcd, 434.12; found, 435.4.

[0076] 2-(2,6-dioxopiperidin-3-yl)-4-((3-phenyl-l,2,4-oxadiazol-5-yl)methyl)isoindoline-l,3 dione

[0077] A solution of E)-2-(2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4-yl)-N-((hydroxyimino)(phenyl)methyl)acetamide (126 mg, 0.30 mmol) in dioxane (5.0 mL) was stirred at 80°C overnight. LCMS indicated the reaction was complete. Then the mixture was concentrated and purified by prep- HPLC (Cl 8, Wave length: 220nm / 254nm phase A: H2O (0.1% FA); phase B: MeCN 30%-95%, 10 min / 20 min) to give 2-(2,6-dioxopiperidin-3-yl)-4-((3-phenyl-l, 2, 4-oxadiazol-5-yl)methyl)isoindoline-l, 3-dione (24.7 mg, yield: 20%) as a yellow solid. LCMS (m / z): [M]+calcd, 416.11; found, 417.1. 'HNMR (400 MHz, DMSO-d6) 8 11.12 (s, 1H), 8.01 - 7.88 (m, 5H), 7.56 (dt, J= 14.1, 5.9 Hz, 3H), 5.14 (dd, J= 12.8, 5.4 Hz, 1H), 4.91 (s, 2H), 2.87 (ddd, J= 16.8, 13.7, 5.3 Hz, 1H), 2.58 (dd, J= 22.5, 7.1 Hz, 2H), 2.10 - 2.01 (m, 1H).

[0078] The compounds below may be synthesized utilizing General Method A.16MEl\59506850.vl136883-01820

[0079] General method B: 2-(2,6-dioxopiperidin-3-yl)-4-((3-(3-(pyridin-4-yl)phenyl)-1, 2, 4-oxadiazol-5-yl)methyl)isoindoline-l, 3-dione (Compound 3)

[0080] To a mixture of 4-((3-(3-bromophenyl)-l,2,4-oxadiazol-5-yl)methyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-l, 3-dione (60.0 mg, 0.12 mmol), K2CO3 (34.0 mg, 0.24 mmol) and pyridin-4-ylboronic acid (23.0 mg, 0.18 mmol) in dioxane / water (3.0 mL, 10:1) was added Pd(dppf)C12 (10.0 mg, 0.01 mmol) under atmosphere of nitrogen. The resulting mixture was stirred at 90°C for 4 hrs. LCMS indicated the reaction was complete. Then the mixture was cooled, poured into saturated NH4CI and extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous Na2SC>4 and concentrated to give a residue. The residue was purified by prep-HPLC (Cl 8, Wave length: 220nm / 254nm phase A: H2O (0.1% NH3.H2O); phase B: MeCN 25%-95%, 10 min / 18 min) to afford 2-(2,6-dioxopiperidin-3-yl)-4-((3-(3-(pyridin-4-yl)phenyl)-l,2,4-oxadiazol-5-yl)methyl)isoindoline-1,3-dione (9.1 mg, 0.02 mmol, yield: 15%) as a yellow solid. LCMS (m / z): [M]+calcd, 493.14; found, 494.2.[HNMR (400 MHz, DMSO-tL) 6 11.12 (s, 1H), 8.71 - 8.65 (m, 2H), 8.27 (s, 1H), 8.03 (dd, J= 15.5, 8.1 Hz, 2H), 7.96 - 7.91 (m, 3H), 7.76 (dd, J= 4.6, 1.5 Hz, 2H), 7.72 (t, J= 7.8 Hz, 1H), 5.15 (dd, J= 12.8, 5.4 Hz, 1H), 4.94 (s, 2H), 2.91 - 2.81 (m, 1H), 2.59 (dd, J= 14.1, 3.4 Hz, 2H), 2.07 - 1.99 (m, 1H).17MEl\59506850.vl136883-01820

[0081] Compounds below may be synthesized utilizing General Method B.

[0082] 2-(2,6-dioxopiperidin-3-yl)-4-((3-(3-(pyrimidin-4-yl) phenyl)- 1,2, 4-oxadiazol- 5-yl) methyl) isoindoline-1, 3-dione (Compound 5)

[0083] 1.2-(2,6-dioxopiperidin-3-yl)-4-((3-(3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl) phenyl)-!, 2, 4-oxadiazol-5-yl) methyl) isoindoline-1, 3-dione

[0084] To a mixture of 4-((3-(3-bromophenyl)-l,2,4-oxadiazol-5-yl)methyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-l, 3-dione (250 mg, 0.50 mmol) in dioxane (3.0 mL) were added 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(l,3,2-dioxaborolane) (385 mg, 1.51 mmol), KOAc (149 mg, 1.51 mmol) and Pd(dppf)C12 (37.0 mg, 0.05 mmol) under atmosphere of nitrogen. The resulting mixture was stirred at 100 °C for 18 hrs. The reaction was completed detected by LCMS. After cooling to room temperature, the reaction mixture was filtered and concentrated under vacuum. The residue was purified by prep-TLC (silica gel, PE:EA=1 :3,18MEl\59506850.vl136883-01820Rf=0.5) to afford 2-(2,6-dioxopiperidin-3-yl)-4-((3-(3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)-l, 2, 4-oxadiazol-5-yl)methyl)isoindoline-l, 3-dione (142 mg, 0.26 mmol, yield: 52%) as a yellow solid. LCMS (m / z): [M]+calcd, 542.20; found, 543.3.

[0085] 2-(2,6-dioxopiperidin-3-yl)-4-((3-(3-(pyrimidin-4-yl) phenyl)- 1,2, 4-oxadiazol- 5-yl) methyl) isoindoline-1, 3-dione

[0086] To a mixture of 2-(2,6-dioxopiperidin-3-yl)-4-((3-(3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl) phenyl)-l,2,4-oxadiazol-5-yl) methyl) isoindoline-1, 3-dione (56 mg, 0.10 mmol) in dioxane / water (4 mL, 10:1) were added 4-chloropyrimidine hydrochloride (13.0 mg, 0.11 mmol), NaHCCh (26.0 mg, 0.31 mmol) andPd(PPhs)4 (12.0 mg, 0.01 mmol) at the atmosphere of nitrogen. The mixture was stirred at 100 °C overnight. The reaction was completed by LCMS. After cooling to room temperature, the reaction mixture was concentrated under vacuum. The residue was purified by prep-HPLC (Cl 8, Wave length: 220nm / 254nm phase A: H2O; phase B: MeCN 25%-95%, 10 min / 20 min) to afford 2-(2,6-dioxopiperidin-3-yl)-4-((3-(3-(pyrimidin-4-yl) phenyl)- 1, 2, 4-oxadiazol-5-yl) methyl) isoindoline-1, 3-dione (1.4 mg, 2.74 umol, yield: 3%) as a white solid. LCMS (m / z): [M]+calcd, 494.13; found, 495.2. 'HNMR (400 MHz, DMSO-tfc) 5 11.11 (s, 1H), 9.30 (d / = 1.2 Hz, 1H), 8.92 (d,J= 5.4 Hz, 1H), 8.79 (t,J = 1.6 Hz, 1H), 8.40 (d,J= 8.3 Hz, 1H), 8.19 (dd,J = 5.4, 1.4 Hz, 1H), 8.14 (d / = 8.1 Hz, 1H), 7.95 - 7.93 (m, 3H), 7.75 (t / = 7.8 Hz, 1H), 5.14 (dd,J= 12.9, 5.3 Hz, 1H), 4.94 (s, 2H), 2.91 - 2.82 (m, 1H), 2.69 - 2.54 (m, 2H), 2.04 (dd / = 14.1, 6.5 Hz, 1H).

[0087] 2-(2,6-dioxopiperidin-3-yl)-4-((3-phenyl-l,2,4-oxadiazol-5-yl)amino)isoindoline-l, 3-dione (Compound 6)

[0088] 2-(2,6-dioxo-l-((2-(trimethylsilyl)ethoxy)methyl)piperidin-3-yl)-4-nitroisoindoline-1, 3-dione19MEl\59506850.vl136883-01820

[0089] To a solution of 2-(2,6-dioxopiperidin-3-yl)-4-nitroisoindoline-l, 3-dione (1 g, 3.3 mmol) in DMF (10 ml) was added NaH (60% in mineral oil, 438 mg, 10.96 mmol) under N2 at 0 °C. The mixture was stirred at 0 °C for 30 min. To the mixture was added SEMC1 (0.82 g, 4.95 mmol). The resulting mixture was stirred for 1 hr at 0 °C. LCMS indicated the reaction was complete. The mixture was poured into an acetic acid aqueous solution and extracted with MTBE (50 mL*2). The combined organic layers were dried over anhydrous Na2SC>4, concentrated in vacuo and purified by flash chromatography (silica gel, 20-70% EA in PE) to afford 2-(2,6-dioxo-l-((2-(trimethylsilyl)ethoxy)methyl)piperidin-3-yl)-4-nitroisoindoline-1, 3-dione (330 mg, 0.76 mmol, yield: 23%) as a yellow solid. LCMS (m / z):[M]+calcd: 433.13, found: 434.01.

[0090] 4-amino-2-(2,6-dioxo-l-((2-(trimethylsilyl)ethoxy)methyl)piperidin-3-yl)isoindoline-l, 3-dione

[0091] To a solution of 2-(2,6-dioxo-l-((2-(trimethylsilyl)ethoxy)methyl)piperidin-3-yl)-4-nitroisoindoline-l, 3-dione (330 mg, 0.76 mmol) in THF (30 mL ) was added Pd / C (10%, 40 mg) under N2. The suspension was degassed under vacuum and purged with H2 for 3 times. The mixture was stirred under H2 balloon at room temperature for 1 hr. The reaction was completed as judged by LCMS. The suspension was filtered, and the filter cake was washed with THF. The combined filtrates were concentrated in vacuo and purified by flash chromatography (silica gel, 20-80% EA in PE) to give 4-amino-2-(2,6-dioxo-l-((2-(trimethylsilyl)ethoxy)methyl)piperidin-3-yl)isoindoline-l, 3-dione (220 mg, 0.55 mmol, yield: 72%). LCMS (m / z): [M]+calcd: 403.16, found: 404.02.

[0092] 2-(2,6-dioxo-l-((2-(trimethylsilyl)ethoxy)methyl)piperidin-3-yl)-4-((3-phenyl-1, 2, 4-oxadiazol-5-yl)amino)isoindoline-l, 3-dione20MEl\59506850.vl136883-01820

[0093] To a mixture of 4-amino-2-(2,6-dioxo-l-((2-(trimethylsilyl)ethoxy)methyl)piperidin-3-yl)isoindoline-l, 3-dione (120 mg, 0.30 mmol) in toluene (10 mL) were added 5-chloro-3-phenyl-l,2,4-oxadiazole (60 mg, 0.33 mmol), CS2CO3 (242 mg, 0.74 mmol), Pd2(dba)s (27 mg, 0.03 mmol) and Xantphos (18 mg, 0.03 mmol). The mixture was stirred at 110°C for 3 hrs. LCMS indicated the reaction was complete. The suspension was filtered, and the filter cake was washed with ACN. The combined filtrates were concentrated in vacuo and purified by flash chromatography (silica gel, 20 to 70% EA in PE) to give 2-(2,6-dioxo-l-((2-(trimethylsilyl)ethoxy)methyl)piperidin-3 -yl)-4-((3 -phenyl- 1, 2, 4-oxadiazol-5-yl)amino)isoindoline-l, 3-dione (100 mg, 0.18 mmol, yield: 61%). LCMS (m / z): [M]+calcd: 547.19, found: 548.03.

[0094] Preparation of 2-(2,6-dioxopiperidin-3-yl)-4-((3-phenyl-l,2,4-oxadiazol-5-yl)amino)isoindoline-l, 3-dione

[0095] To a solution of 2-(2,6-dioxo-l-((2-(trimethylsilyl)ethoxy)methyl)piperidin-3-yl)-4-((3 -phenyl- 1, 2, 4-oxadiazol-5-yl)amino)isoindoline-l, 3-dione (100 mg, 0.18 mmol) in DCM (4 mL) was added TFA (2 mL) at rt under N2, and stirred at 25 °C for 1 hours. The mixture was concentrated and purified by prep-HPLC (Cl 8, Wave length: 220nm / 254nm phase A: H2O (0.1% NH3); phase B: MeCN 25%-95%, 12 min) to give 2-(2,6-dioxopiperidin-3-yl)-4-((3 -phenyl- 1, 2, 4-oxadiazol-5-yl)amino)isoindoline-l, 3-dione (27.52 mg, 0.07 mmol, yield: 36%) as ayellow solid. LCMS (m / z): [M]+calcd: 417.11.19, found: 418.13.XH NMR (400 MHz, DMSO-tL) 6 11.15 (s, 1H), 8.42 (d, J= 8.3 Hz, 1H), 8.04 - 7.94 (m, 3H), 7.71 (d, J= 7.3 Hz, 1H), 7.62 - 7.53 (m, 3H), 5.17 (dd, J= 12.8, 5.4 Hz, 1H), 2.90 (ddd, J= 17.4, 13.9, 5.4 Hz, 1H), 2.65 - 2.52 (m, 3H), 2.08 (ddd, J= 9.6, 5.4, 2.7 Hz, 1H).Biochemical Assays

[0096] In Vitro TR-FRET ternary - ALK Mutant (Mut) CRBN:21MEl\59506850.vl136883-01820

[0097] 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 / DDB1, 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.

[0098] In Vitro TR-FRET ternary - ALK Mutant (Mut) CRBN (v3):

[0099] 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 of2-(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-22MEl\59506850.vl136883-01820lH-indene-l,3(2H)-dione (100% activity). Normalized data for each compound were then subjected to a 4-parameter logistic fit.

[0100] 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 123MEl\59506850.vl

Claims

136883-01820Listing of Claims:

1. A compound having the structural Formula I:or a pharmaceutically acceptable salt thereof, wherein:X is O, NH, N(Ci-C4)alkyl, S, or (CR1!^;A is an optionally substituted heteroaryl;R1and R2are each independently hydrogen or (Ci-C4)alkyl; or R1and R2taken together form a (C3-C6)cycloalkyl optionally substituted with 1 to 3 groups selected from RA;RAis selected from cyano, halo, (Ci-C4)alkyl, halo(Ci-C4)alkyl, (Ci-C4)alkoxy, and halo(Ci-C4)alkoxy; andq is 1, 2, or 3.

2. The compound of Claim 1, wherein the compound is of the structural Formula II:or a pharmaceutically acceptable salt thereof.

3. The compound of Claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein A is an optionally substituted monocyclic heteroaryl.

4. The compound of any one of Claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein A is an optionally substituted 5-membered monocyclic heteroaryl.

5. The compound of any one of Claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein A is an optionally substituted oxadiazolyl.

6. The compound of any one of Claims 1 to 5, or a pharmaceutically acceptable salt thereof, wherein24MEl\59506850.vl136883-018207. The compound of any one of Claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein X is (CRjR^q.

8. The compound of any one of Claims 1 to 7, or a pharmaceutically acceptable salt thereof, wherein R1is hydrogen.

9. The compound of any one of Claims 1 to 8, or a pharmaceutically acceptable salt thereof, wherein R2is hydrogen.

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

11. The compound of any one of Claims 1 to 10, or a pharmaceutically acceptable salt thereof, wherein:R3is (Ci-C4)alkyl, phenyl, heterocyclyl, or heteroaryl, wherein each of said phenyl, heterocyclyl, and heteroaryl are optionally substituted with 1 to 4 groups selected from RB;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)alkoxycycloalkyl, -(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,25MEl\59506850.vl136883-01820heteroaryl, 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; andRx, RY, and Rzare each independently selected from hydrogen, (Ci-C4)alkyl, halo(Ci-C4)alkyl, phenyl, benzyl, (C3-C6)cycloalkyl, 4- to 6-membered heterocyclyl, and 5- to 7-membered heteroaryl.

12. The compound of Claim 11, or a pharmaceutically acceptable salt thereof, wherein R3is phenyl optionally substituted with 1 to 4 groups selected from RB.

13. The compound of Claim 11 or 12, or a pharmaceutically acceptable salt thereof, wherein RBis selected from halo and heteroaryl, wherein said heteroaryl is optionally substituted with 1 to 3 groups selected from Rc.

14. The compound of any one of Claims 11 to 13, or a pharmaceutically acceptable salt thereof, wherein RBis selected from halo and 5- to 7-membered heteroaryl, wherein said 5- to 7-membered heteroaryl is optionally substituted with 1 to 3 groups selected from Rc.

15. The compound of any one of Claims 11 to 14, or a pharmaceutically acceptable salt thereof, wherein RBis selected from halo, pyridinyl, pyrazinyl, and pyrimidinyl, wherein said pyridinyl, pyrazinyl, and pyrimidinyl are each optionally substituted with 1 to 3 groups selected from Rc.

16. The compound of any one of Claims 11 to 15, or a pharmaceutically acceptable salt thereof, wherein Rcis (Ci-C4)alkyl.

17. The compound of Claim 1, wherein the compound is selected from Compounds 1-6, or a pharmaceutically acceptable salt thereof.

18. A pharmaceutical composition comprising a compound of any one of Claims 1 to 17, or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier.26MEl\59506850.vl136883-0182019. 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 17, or a pharmaceutically acceptable salt; or the composition of Claim 18.

20. The method of Claim 16, wherein the condition is cancer.27MEl\59506850.vl

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