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

ANAPLASTIC LYMPHOMA KINASE (ALK) DEGRADERS AND USES THEREOF RELATED APPLICATIONS

[0001] This application claims the benefit of priority to U.S. Provisional Application No. 63 / 747,667, filed January 21, 2025, U.S. Provisional Application No.63 / 681,228, filed August 9, 2024, and U.S. Provisional Application No. 63 / 668,355, filed July 8, 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 ligand- independent 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:and pharmaceutically acceptable salts and compositions thereof, wherein R1, R2, X, Y, and z 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 DESCRIPTION 1. General Description of Compounds

[0006] In a first embodiment, provided herein is a compound of Formula I:or a pharmaceutically acceptable salt thereof, wherein the dotted line represents and single or double bond;a monocyclic heteroaryl or monocyclic heterocyclyl; R1is selected from cyano, halo, (C1-C4)alkyl, halo(C1-C4)alkyl, (C1-C4)alkoxy, halo(C1-C4)alkoxy, hydroxy, (C1-C4)alkyleneOH, -NRX1RY1, and (C1-C4)alkyleneNRX1RY1, - C(O)NRX1RY1, -C(O)RX1, and -C(O)ORX1; z is 0, 1, 2, 3, or 4 XR3and R3aare each independently hydrogen or (C1-C4)alkyl; or R3and R3aare taken together to form a cycloalkyl or heterocyclyl, each optionally substituted with 1 to 3 groups selected from halo, (C1-C4)alkyl, halo(C1-C4)alkyl, (C1-C4)alkoxy, halo(C1-C4)alkoxy, and cyano; v is 1, 2, or 3; Y is aryl, heteroaryl, or heterocyclyl, each optionally substituted with 1 to 3 groups selected from RA; R2is absent or is aryl, cycloalkyl, or heteroaryl, each of which are optionally substituted with 1 to 4 groups selected from RB; RAis selected from cyano, halo, (C1-C4)alkyl, halo(C1-C4)alkyl, (C1-C4)alkoxy, and halo(C1-C4)alkoxy; RBis selected from halo, (C1-C4)alkyl, halo(C1-C4)alkyl, (C1-C4)alkoxy, halo(C1- C4)alkoxy, hydroxy, (C1-C4)alkyleneOH, (C1-C4)alkylene(C1-C4)alkoxy, -(C1- C4)alkyleneNRXRY, cyano, oxo, -(C1-C4)alkoxyNRXRY, -(C1-C4)alkyleneC(O)ORX, -(C1- C4)alkoxyC(O)ORX, -(C1-C4)alkyleneC(O)RX, -(C1-C4)alkoxyC(O)RX, -(C1- C4)alkyleneheterocyclyl, -(C1-C4)alkyleneheteroaryl, -(C1-C4)alkoxyheterocyclyl, -(C1- C4)alkoxyheteroaryl, -(C1-C4)alkylenecycloalkyl, -(C1-C4)alkoxycycloalkyl, -(C1- C4)alkylenephenyl, -(C1-C4)alkoxyphenyl -NRX(C1-C4)alkyleneheteroaryl, -NRX(C1- C4)alkyleneheterocyclyl, -NRX(C1-C4)alkylenecycloalkyl, cycloalkyl, heteroaryl, heterocyclyl, -NRXRY, -NRXC(O)RY, -NRXC(O)ORY, -NRX(C1-C4)alkyleneC(O)NRXRZ, - NRXC(O)NRXRZ, -(C1-C4)alkyleneNRXC(O)RY, -(C1-C4)alkyleneNRXC(O)ORY, -(C1- C4)alkyleneNRX(C1-C4)alkyleneC(O)NRXRZ, -(C1-C4)alkyleneNRXC(O)NRXRZ, -(C1- C4)alkoxyNRXC(O)RY, -(C1-C4)alkoxyNRXC(O)ORY, -(C1-C4)alkoxyNRX(C1- C4)alkyleneC(O)NRXRZ, -(C1-C4)alkoxyNRXC(O)NRXRZ, -S(C1-C4)alkyl, -O(heteroaryl), - O(heterocyclyl), -O(cycloalkyl), -C(O)NRXRY, -(C1-C4)alkyleneC(O)NRXRY, -(C1- 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 (C1-C4)alkyl, halo(C1-C4)alkyl, (C1-C4)alkoxy, halo(C1-C4)alkoxy cyano, oxo, -C(O)NRX2RY2, -(C1-C4)alkyleneNRX2RY2, -C(O)NRX2RY2, -C(O)ORX2, - C(O)RX2, NRX2RY2, and hydroxy; and RX, RX1, RX2, RY, RY1, RY2, and RZare each independently selected from hydrogen, (C1-C4)alkyl, halo(C1-C4)alkyl, phenyl, benzyl, (C3-C6)cycloalkyl, 4- to 6-membered heterocyclyl, and 5- to 7-membered heteroaryl.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 “ ” indicates thepoint of attachment of the particular depicted structure or substituent group to the appropriate atom(s) in the remainder of the molecule. For example, -[(C1-C6)alkyl]heteroaryl means that the point of attachment for this group occurs on the (C1-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).

[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, “(C1-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., –OCHF2or –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 =O.

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

[0017] The term “heteroaryl” used alone or as part of a larger moiety refers to, unless otherwise specified, a 5- to 12-membered aromatic radical containing 1-4 heteroatoms selected from N, O, and S. A heteroaryl group may be mono- or bi-cyclic. Monocyclic heteroaryl includes, for example, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl,tetrazolyl, oxazolyl, isoxazolyl, triazinyl, tetrazinyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, etc. Bi-cyclic heteroaryls include groups in which a monocyclic heteroaryl ring is fused to one or more aryl or heteroaryl rings. Nonlimiting examples include indolyl, imidazopyridinyl, benzooxazolyl, benzooxodiazolyl, indazolyl, benzimidazolyl, benzthiazolyl, 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, fused, or spiro bicyclic ring), or tricyclic. A heterocyclyl ring can be attached to its pendant group at any heteroatom or carbon atom that results in a stable structure. Examples of such saturated or partially unsaturated heterocyclic radicals include, without limitation, tetrahydrofuranyl, tetrahydrothienyl, terahydropyranyl, pyrrolidinyl, pyridinonyl, pyrrolidonyl, piperidinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, morpholinyl, dihydrofuranyl, dihydropyranyl, dihydropyridinyl, tetrahydropyridinyl, dihydropyrimidinyl, oxetanyl, azetidinyl and tetrahydropyrimidinyl. A heterocyclyl group may be mono- or bicyclic. The term “heterocyclyl” also includes, e.g., unsaturated heterocyclic radicals fused to another unsaturated heterocyclic radical or aryl or heteroaryl ring, such as for example, tetrahydronaphthyridine, indolinone, dihydropyrrolotriazole, imidazopyrimidine, quinolinone, dioxaspirodecane. It will also be understood that when specified, optional substituents on a heterocyclyl group may be present on any substitutable position.

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

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

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

[0022] The 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.

[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 (i.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.

[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.

[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 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.

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

[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 maybe used in the compositions described herein include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol and wool fat.

[0036] For use in medicines, the salts of the compounds described herein refer to non- toxic “pharmaceutically acceptable salts.” Pharmaceutically acceptable salt forms include pharmaceutically acceptable acidic / anionic or basic / cationic salts. Suitable pharmaceutically acceptable acid addition salts of the compounds described herein include e.g., salts of inorganic acids (such as hydrochloric acid, hydrobromic, phosphoric, nitric, and sulfuric acids) and of organic acids (such as, acetic acid, benzenesulfonic, benzoic, methanesulfonic, and p-toluenesulfonic acids). Compounds of the present teachings with acidic groups such as carboxylic acids can form pharmaceutically acceptable salts with pharmaceutically acceptable base(s). Suitable pharmaceutically acceptable basic salts include e.g., ammonium salts, alkali metal salts (such as sodium and potassium salts) and alkaline earth metal salts (such as magnesium and calcium salts). Compounds with a quaternary ammonium group also contain a counteranion such as chloride, bromide, siodide, acetate, perchlorate and the like. Other examples of such salts include hydrochlorides, hydrobromides, sulfates, methanesulfonates, nitrates, benzoates and salts with amino acids such as glutamic acid.

[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, R3and R3ain the compound having the Formula I, or a pharmaceutically acceptable salt thereof, are each hydrogen, wherein the remaining variables are as described above for Formula I.

[0039] As part of a third embodiment, v in the compound having the Formula I, or a pharmaceutically acceptable salt thereof, is 1, wherein the remaining variables are as described above for Formula I or the second embodiment.

[0040] As part of a fourth embodiment,in the compound having the Formula I, or a pharmaceutically acceptable salt thereof, is a 5-membered heteroaryl or a 6-membered heterocyclyl, wherein the remaining variables are as described above for Formula I or any one of the second or third embodiments.

[0041] As part of a fifth embodiment, the compound having the Formula I is of the structural Formula Ia:or 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.

[0042] As part of a sixth embodiment, z in the compound having the Formula I or Ia, or a pharmaceutically acceptable salt thereof, is 0, wherein the remaining variables are as described above for Formula I or any one of the second to fourth embodiments.

[0043] As part of a seventh embodiment, Y in the compound having the Formula I or Ia, or a pharmaceutically acceptable salt thereof, is aryl or heteroaryl each of which is optionally substituted with 1 to 3 groups selected from RA, wherein the remaining variables are as described above for Formula I or any one of the second to fourth and sixth embodiments. Alternatively, as part of a seventh embodiment, Y in the compound having the Formula I or Ia, or a pharmaceutically acceptable salt thereof, is phenyl, naphthyl, or heteroaryl each of which optionally substituted with 1 to 3 groups selected from RA, wherein the remaining variables are as described above for Formula I or any one of the second to fourth and sixth embodiments. In another alternative, as part of a seventh embodiment, Y in the compound having the Formula I or Ia, or a pharmaceutically acceptable salt thereof, is a heteroaryl optionally substituted with 1 to 3 groups selected from RA, wherein the remaining variables are as described above for Formula I or any one of the second to fourth and sixth embodiments. In another alternative, as part of a seventh embodiment, Y in the compound having the Formula I or Ia, or a pharmaceutically acceptable salt thereof, is a 5- to 9- membered heteroaryl optionally substituted with 1 to 3 groups selected from RA, wherein theremaining variables are as described above for Formula I or any one of the second to fourth and sixth embodiments. In another alternative, as part of a seventh embodiment, Y in the compound having the Formula I or Ia, or a pharmaceutically acceptable salt thereof, is a 5- to 7-membered heteroaryl optionally substituted with 1 to 3 groups selected from RA, wherein the remaining variables are as described above for Formula I or any one of the second to fourth and sixth embodiments. In another alternative, as part of a seventh embodiment, Y in the compound having the Formula I or Ia, or a pharmaceutically acceptable salt thereof, is a 5-membered heteroaryl optionally substituted with 1 to 3 groups selected from RA, wherein the remaining variables are as described above for Formula I or any one of the second to fourth and sixth embodiments. In another alternative, as part of a seventh embodiment, Y in the compound having the Formula I or Ia, or a pharmaceutically acceptable salt thereof, is benzooxazolyl, pyrimidinyl, quinolinyl, pyrazinyl, oxazolyl, benzothiazolyl, pyridinyl, oxadiazolyl, or thiadiazolyl, each of which is optionally substituted with 1 to 3 groups selected from RA, wherein the remaining variables are as described above for Formula I or any one of the second to fourth and sixth embodiments. In another alternative, as part of a seventh embodiment, Y in the compound having the Formula I or Ia, or a pharmaceutically acceptable salt thereof, is oxadiazolyl or thiadiazolyl optionally substituted with 1 to 3 groups selected from RA, wherein the remaining variables are as described above for Formula I or any one of the second to fourth and sixth embodiments. In another alternative, as part of a seventh embodiment, Y in the compound having the Formula I or Ia, or a pharmaceutically acceptable salt thereof,,wherein * indicates the attachment position to R2, wherein the remaining variables are as described above for Formula I or any one of the second to fourth and sixth embodiments. In another alternative, as part of a seventh embodiment, Y in the compound having the FormulaI or Ia, or a pharmaceutically acceptable salt thereof,indicates the attachment position to R2, wherein the remaining variables are as described above for Formula I or any one of the second to fourth and sixth embodiments.

[0044] As part of an eighth embodiment, R2in the compound having the Formula I or Ia, or a pharmaceutically acceptable salt thereof, is aryl, cycloalkyl, 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 to fourth, sixth, and seventh embodiments. Alternatively, as part of an eighth embodiment, R2in the compound having the Formula I or Ia, or a pharmaceutically acceptable salt thereof, is aryl, 5- to 9- membered heteroaryl, or (C3-C6)cycloakyl, 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 to fourth, sixth, and seventh embodiments. In another alternative, as part of an eighth embodiment, R2in the compound having the Formula I or Ia, or a pharmaceutically acceptable salt thereof, is phenyl, cyclohexyl, benzothiopheneyl, naphthalenyl, quinolinyl, isoquinolinyl, pyridinyl, oxazolyl, or isoxazolyl 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 to fourth, sixth, and seventh embodiments. In another alternative, as part of an eighth embodiment, R2in the compound having the Formula I or Ia, or a pharmaceutically acceptable salt thereof, is R2is phenyl, cyclohexyl, benzothiopheneyl, benzothiazolyl, thiazolyl, naphthalenyl, quinolinyl, pyridinyl, pyrimidinyl, oxazolyl, pyrazolyl, pyrrolopyrdinyl, dihydrobenzofuranyl, pyrrolopyridazinyl, dihydrobenzodioxinyl, pyrazolopyridinyl, imidazopyridinyl, benzofuranyl, indazolyl, or isoxazolyl, 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 to fourth, sixth, and seventh embodiments.

[0045] As part of a ninth embodiment, RBin the compound having the Formula I or Ia, or a pharmaceutically acceptable salt thereof, is selected from halo, (C1-C4)alkyl, halo(C1- C4)alkyl, (C1-C4)alkoxy, -(C1-C4)alkyleneNRXRY, -C(O)NRXRY, -C(O)ORX, -C(O)RX, NRXRY, OH, -phenyl, heteroaryl, heterocyclyl, wherein said 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 to fourth and sixth to eighth embodiments. Alternatively, as part of a ninth embodiment, RBin the compound having the Formula I or Ia, or a pharmaceutically acceptable salt thereof, is selected from halo, (C1-C4)alkyl, halo(C1-C4)alkyl, (C1-C4)alkoxy, -(C1-C4)alkyleneNRXRY, - C(O)NRXRY, -C(O)ORX, -C(O)RX, NRXRY, hydroxy, -phenyl, heteroaryl, heterocyclyl,wherein said 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 to fourth and sixth to eighth embodiments. In another alternative, as part of a ninth embodiment, RBin the compound having the Formula I or Ia, or a pharmaceutically acceptable salt thereof, is selected from halo, (C1-C4)alkyl, (C1-C4)alkoxy, phenyl, heteroaryl, heterocyclyl, wherein said 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 to fourth and sixth to eighth embodiments. In another alternative, as part of a ninth embodiment, RBin the compound having the Formula I or Ia, or a pharmaceutically acceptable salt thereof, is selected from halo, (C1-C4)alkyl, (C1-C4)alkoxy, phenyl, 5- to 7-membered heteroaryl, 4- to 6-membered heterocyclyl, wherein said phenyl, 4- to 6-membered heterocyclyl, and 5- to 7-membered 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 to fourth and sixth to eighth embodiments. In another alternative, as part of a ninth embodiment, RBin the compound having the Formula I or Ia, or a pharmaceutically acceptable salt thereof, is selected from halo, (C1-C4)alkyl, (C1-C4)alkoxy, phenyl, oxazolyl, pyridinyl, pyrazinyl, pyrrolidinyl, tetrahydrofuranyl, pyrimidinyl, azetidinyl, piperidinyl, thiopheneyl, thiazolyl, and 1,2-dihydropyridinyl, wherein said phenyl, oxazolyl, pyridinyl, pyrazinyl, pyrrolidinyl, tetrahydrofuranyl, pyrimidinyl, azetidinyl, piperidinyl, thiopheneyl, thiazolyl, and 1,2- dihydropyridinyl 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 to fourth and sixth to eighth embodiments. In another alternative, as part of a ninth embodiment, RBin the compound having the Formula I or Ia, or a pharmaceutically acceptable salt thereof, is selected from halo, (C1-C4)alkyl, (C1-C4)alkoxy, phenyl, oxazolyl, pyridinyl, pyrazinyl, pyridazinyl, tetrahydropyranyl, pyrazolyl, cyclohexyl, imidazolyl, and 1,2-dihydropyridinyl, wherein said phenyl, oxazolyl, pyridinyl, pyrazinyl, pyridazinyl, tetrahydropyranyl, pyrazolyl, cyclohexyl, imidazolyl, and 1,2-dihydropyridinyl 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 to fourth and sixth to eighth embodiments.

[0046] As part of a tenth embodiment, RCin the compound having the Formula I or Ia, or a pharmaceutically acceptable salt thereof, is selected from (C1-C4)alkyl, halo(C1-C4)alkyl, (C1-C4)alkoxy, halo(C1-C4)alkoxy cyano, oxo, and hydroxy, wherein the remaining variables are as described above for Formula I or any one of the second to fourth and sixth to ninthembodiments. Alternatively, as part of a tenth embodiment, RCin the compound having the Formula I or Ia, or a pharmaceutically acceptable salt thereof, is selected from (C1-C4)alkyl, halo(C1-C4)alkyl, -C(O)NRX2RY2, and oxo, wherein the remaining variables are as described above for Formula I or any one of the second to fourth and sixth to ninth embodiments. In another alternative, as part of a tenth embodiment, RCin the compound having the Formula I or Ia, or a pharmaceutically acceptable salt thereof, is selected from (C1-C4)alkyl and oxo, wherein the remaining variables are as described above for Formula I or any one of the second to fourth and sixth to ninth embodiments.

[0047] As part of an eleventh embodiment, RXand RYin the compound having the Formula I or Ia, or a pharmaceutically acceptable salt thereof, are each independently selected from hydrogen, (C1-C4)alkyl, and 4- to 6-membered heterocyclyl (e.g., pyrrolidinyl), wherein the remaining variables are as described above for Formula I or any one of the second to fourth and sixth to tenth embodiments.

[0048] As part of a twelfth embodiment, RX2and RY2in the compound having the Formula I or Ia, or a pharmaceutically acceptable salt thereof, are each independently selected from hydrogen and (C1-C4)alkyl, wherein the remaining variables are as described above for Formula I or any one of the second to fourth and sixth to eleventh embodiments.

[0049] As part of a thirteenth embodiment, R2in the compound having the Formula I or Ia, or a pharmaceutically acceptable salt thereof, is selected from, ,above for Formula I or any one of the second to fourth and sixth to twelfth embodiments. Alternatively, as part of a thirteenth embodiment, R2in the compound having the Formula Iremaining variables are as described above for Formula I or any one of the second to fourth and sixth to twelfth embodiments. In another alternative, as part of a thirteenth embodiment, R2in the compound having the Formula I or Ia, or a pharmaceutically acceptable salt thereof,, wherein the remaining variables are as described above for Formula I or any one of the second to fourth and sixth to twelfth embodiments.

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

[0051] The compounds and compositions described herein are generally useful for modulating the activity of anaplastic lymphoma kinase (ALK). In some aspects, the compounds, pharmaceutical acceptable salts, and pharmaceutical compositions described herein degrade ALK.

[0052] 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.

[0053] Also provided is the use of a compound described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a disclosed compound or pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treating a disorder associated with 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.

[0054] 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, oropharyngealcancer, 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.

[0055] 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)

[0056] In some aspects, the cancer treated by the compounds, pharmaceutically acceptable salt thereof, and pharmaceutical compositions described herein is an ALK positive cancer.

[0057] 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.

[0058] 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.

[0059] 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" asused 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.

[0060] In some aspects, the pharmaceutical compositions are administered orally.

[0061] 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

[0062] 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. To the extent there is a discrepancy between the compound name and the structure, the structure controls. Intermediates

[0063] Intermediate A: 6-(2,6-dioxo-1-((2-(trimethylsilyl)ethoxy)methyl)piperidin-3- yl)-1,2,3,4-tetrahydro-5H-pyrrolo[3,4-b]pyridine-5,7(6H)-dione

[0064] Preparation of 6-(2,6-dioxopiperidin-3-yl)-5H-pyrrolo[3,4-b]pyridine- 5,7(6H)-dione

[0065] To a solution of furo[4,3-b]pyridine-5,7-dione (20 g, 134.13 mmol) in AcOH (200 mL) were added AcONa (22.00 g, 268.27 mmol) and 3-aminohexahydropyridine-2,6-dione (17.19 g, 134.13 mmol) at 20 !. The mixture was stirred at 110 ! for 2h, then poured into ice-water and stirred at 0 ! for 30 min. The mixture was filtered, and the filter cake was washed with water and dried to give 6-(2,6-dioxopiperidin-3-yl)-5H-pyrrolo[3,4-b]pyridine- 5,7(6H)-dione (22 g, 84.87 mmol, 63.27%) as a white solid. LCMS (m / z): [M+H]+calcd: 259; found: 260.1H NMR (400 MHz, DMSO-d6) " 11.17 (s, 1H), 9.04 (dd, J = 5.0, 1.4 Hz, 1H), 8.38 (dd, J = 7.6, 1.4 Hz, 1H), 8.03 – 7.69 (m, 1H), 5.24 (dd, J = 12.8, 5.4 Hz, 1H), 3.07 – 2.77 (m, 1H), 2.70 – 2.52 (m, 2H), 2.23 – 2.00 (m, 1H).

[0066] Preparation of 6-(2,6-dioxo-1-((2-(trimethylsilyl)ethoxy)methyl)piperidin-3- yl)-5H-pyrrolo[3,4-b]pyridine-5,7(6H)-dione

[0067] To a solution of 6-(2,6-dioxopiperidin-3-yl)-5H-pyrrolo[3,4-b]pyridine-5,7(6H)- dione (5 g, 19.28 mmol) in DMF (50 mL) was added NaH (0.93 g, 38.57 mmol, 60% in oil) at 0 !. The mixture was stirred at 0 ! for 30 min. To the mixture was added SEMCl (4.82 g, 28.93 mmol). The mixture was stirred at 0 ! for 30 min. LCMS indicated the reaction was complete. The mixture was cooled and quenched with saturated aqueous NH4Cl dropwise. The mixture was extracted with EA. The combined organic layers were dried over anhydrous Na2SO4 and concentrated in vacuo to give a residue, which was purified by FCC onsilica gel (0-15% EA in PE) to give 6-(2,6-dioxo-1-((2-(trimethylsilyl)ethoxy)methyl)piperidin-3-yl)-5H-pyrrolo[3,4-b]pyridine-5,7(6H)-dione (3500 mg, 8.98 mmol, 46.59%) as a yellow oil. LCMS (m / z): [M-H]- calcd: 389; found: 388.

[0068] Preparation of 6-(2,6-dioxo-1-((2-(trimethylsilyl)ethoxy)methyl)piperidin-3- yl)-1,2,3,4-tetrahydro-5H-pyrrolo[3,4-b]pyridine-5,7(6H)-dione

[0069] To a solution of 6-(2,6-dioxo-1-((2-(trimethylsilyl)ethoxy)methyl)piperidin-3-yl)- 5H-pyrrolo[3,4-b]pyridine-5,7(6H)-dione (500 mg, 1.28 mmol) in EA (10 mL) and AcOH (5 mL) was added 10% Pd / C (100 mg, 0.94 mmol), and the reaction was stirred under H2 atmosphere at 40 ! for 3h. The suspension was filtered, and the filter cake was washed with EA. The combined filtrates were concentrated in vacuo and purified by FCC on silica gel (PE:EA=1:1) to give 6-(2,6-dioxo-1-((2-(trimethylsilyl)ethoxy)methyl)piperidin-3-yl)- 1,2,3,4-tetrahydro-5H-pyrrolo[3,4-b]pyridine-5,7(6H)-dione (150 mg, 0.38 mmol, 29.63%) as a yellow oil. LCMS (m / z): [M-H]- calcd: 393; found: 392.1H NMR (400 MHz, DMSO-d6) " 7.85 (s, 1H), 5.06 (s, 2H), 4.96 (dd, J = 13.0, 5.4 Hz, 1H), 3.56 – 3.47 (m, 2H), 3.31 – 3.26 (m, 2H), 3.06 – 2.90 (m, 1H), 2.86 – 2.65 (m, 1H), 2.51 – 2.41 (m, 1H), 2.23 (t, J = 5.8 Hz, 2H), 2.00 – 1.94 (m, 1H), 1.83 – 1.71 (m, 2H), 0.97 – 0.72 (m, 2H), 0.00 (s, 9H).

[0070] Intermediate B: Alkylation partners

[0071] Amine coupling partners general procedures:

[0072] Intermediate B-1: 3-(3-bromophenyl)-5-(chloromethyl)-1,2,4-oxadiazole

[0073] Preparation of 3-bromo-N-hydroxybenzimidamide

[0074] To a solution of NH2OH (1.81 g, 54.93 mmol) in MeOH (110 mL) were added KOH (3.08 g, 54.93 mmol) in MeOH (110 mL) at 0 !, and the reaction was stirred at 0 ! - RT for 30 min. KCl 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 ! for 2 hours, then cooled, poured into saturated NH4Cl, and extracted with EtOAc. The 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: 215.1H NMR (400 MHz, DMSO-d6) " 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).

[0075] Preparation of 3-(3-bromophenyl)-5-(chloromethyl)-1,2,4-oxadiazole

[0076] 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 !. The resulting mixture was stirred at 110 ! 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)-1,2,4-oxadiazole (1.60 g, 5.85 mmol, 62.90%) as a white solid. LCMS (m / z): [M+H]+calcd: 272; found: 273.1H NMR (400 MHz, DMSO-d6) " 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).

[0077] Intermediates below were synthesized similarly to Intermediate B-1:

[0078] Intermediate B-39: 5-(chloromethyl)-3-(4-methyloxazol-2-yl)-1,2,4-oxadiazole

[0079] 4-methyloxazole-2-carboxamide

[0080] A mixture of ethyl 4-methyloxazole-2-carboxylate (900 mg, 5.80 mmol) in MeOH (1 mL) and NH3·H2O (10 mL) was refluxed for 1 h. The mixture was cooled and the MeOH was removed in vacuo. The mixture was stirred for 30 min at RT and filtered. The precipitate was dried in vacuo to afford 4-methyl-1,3-oxazole-2-carboxamide (683 mg, 5.42 mmol, 93.36%) as a white solid. LCMS (m / z): [M+H]+calcd: 126.0; found: 127.2. 2. (Z)-N'-hydroxy-4-methyloxazole-2-carboximidamide

[0081] To a mixture of 4-methyloxazole-2-carboxamide (800 mg, 6.34 mmol) in DCM (12 mL) were added PPh3 (2495.7 mg, 9.52 mmol), I2 (4220.8 mg, 9.52 mmol), TEA (3209.5 mg, 31.72 mmol) and NH2OH·HCl (661.3 mg, 9.52 mmol) under nitrogen atmosphere. The resulting mixture was stirred at RT overnight. LCMS indicated that the reaction was complete. The mixture was concentrated in vacuo. The residue was purified by FCC on silica gel (10-20% MeOH in DCM) to give (Z)-N'-hydroxy-4-methyloxazole-2-carboximidamide (694 mg, 45.92 mmol, 77.52%) as a brown solid. LCMS (m / z): [M+H]+calcd: 141.0; found: 142.3.

[0082] 5-(chloromethyl)-3-(4-methyloxazol-2-yl)-1,2,4-oxadiazole

[0083] To a solution of (Z)-N'-hydroxy-4-methyloxazole-2-carboximidamide (1.2 g, 8.50 mmol) and TEA (0.9 g, 8.50 mmol) in toluene (15 mL) at 0 ! was added chloroacetyl chloride (1.0 g, 8.50 mmol) dropwise in toluene (1 mL). The solution was stirred at RT for 15 min, and then at 110 ! for 4 h. The mixture was then cooled to room temperature, extractedwith toluene, washed with water and brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by FCC on silica gel (20-30% EA in PE) to give 5-(chloromethyl)- 3-(4-methyloxazol-2-yl)-1,2,4-oxadiazole (451 mg, 2.26 mmol, 26.57%) as a brown solid. LCMS (m / z): [M+H]+calcd: 199.0; found: 200.1.

[0084] Intermediate B-40: 6-(2,6-dioxohexahydropyridin-3-yl)-1-[(3-phenyl-1,2,4- thiadiazol-5-yl)methyl]-1,2,3,4-tetra -b]pyridine-5,7-dione

[0085] Preparation of 5-phenyl-1,3,4-oxathiazol-2-one

[0086] To a solution of benzamide (5.00 g, 41.28 mmol) in toluene (40 mL) was added chlorosulfanecarbonyl chloride (6.98 mL, 82.55 mmol), and the reaction was stirred at 90 ! for 18 h. TLC indicated the reaction was complete. The mixture was concentrated under reduced pressure and washed with H2O twice, 5% of NaHCO3 twice, and H2O. The organic layer was concentrated under reduced pressure to give 5-phenyl-1,3,4-oxathiazol-2-one (4.00 g, 22.32 mmol, 54.08%) as a white solid.

[0087] Preparation of 3-phenyl-1,2,4-thiadiazole-5-carboxylate

[0088] To a solution of 5-phenyl-1,3,4-oxathiazol-2-one (4.00 g, 22.32 mmol) in dichlorobenzene (20 mL) was added ethyl cyanomethanoate (8.85 g, 89.29 mmol), and the reaction was stirred at 150 ! for 18 h. LCMS indicated the reaction was complete. The reaction was washed with H2O twice, then concentrated under reduced pressure to give ethyl 3-phenyl-1,2,4-thiadiazole-5-carboxylate (3.00 g, 12.81 mmol, 57.37%) as a white solid. LCMS (m / z): [M+H]+calcd: 234.0; found: 235.2.

[0089] Preparation of (3-phenyl-1,2,4-thiadiazol-5-yl)methanol

[0090] To a solution of ethyl 3-phenyl-1,2,4-thiadiazole-5-carboxylate (3.50 g, 14.94 mmol) in EtOH (20 mL) was added NaBH4 (1.13 g, 29.88 mmol), the reaction was stirred at RT for 2h. LCMS indicated the reaction was complete. The reaction was cooled to 0 !, quenched with H2O and extracted with EA, the organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure, the residue was purified by FCC on silica gel (10-20% EA in PE) to give (3-phenyl-1,2,4-thiadiazol-5-yl)methanol (2.00 g, 10.40 mmol, 69.64%) as a white solid. [M+H]+calcd: 192.0; found: 193.2.

[0091] Preparation of 5-(chloromethyl)-3-phenyl-1,2,4-thiadiazole

[0092] To a solution of (3-phenyl-1,2,4-thiadiazol-5-yl)methanol (2.00 g, 10.40 mmol) and TEA (4.34 mL, 31.21 mmol) in DCM (15 mL) was added thionyl chloride(1.51 mL, 20.81 mmol). The reaction was stirred RT for 2h. LCMS indicated the reaction wascomplete. Water was added and the mixture was extracted with DCM. The organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was used directly in the next step. [M+H]+calcd: 210.0 found: 211.7.

[0093] Intermediate B-41: 4-(chloromethyl)-2-phenylpyrimidine

[0094] Preparation of 6-methyl-2-phenylpyrimidine 1-oxide

[0095] To a mixture of (E)-N'-hydroxybenzimidamide (3.0 g, 22 mmol) and 4,4- dimethoxybutan-2-one (3.2 g, 24 mmol) in iso-propanol (60 mL) was added TFA (2.8 g, 24mmol) at the atmosphere of nitrogen. The resulting mixture was stirred at 100oC for 16 hrs. LCMS indicated the reaction was complete. Then the mixture was concentrated and purified by FCC (silica gel, 0~70% EA in PE) to afford 6-methyl-2-phenylpyrimidine 1-oxide (2.9 g, yield: 71%) as a yellow solid. LCMS (m / z): [M]+calcd, 186.08; found, 187.2

[0096] Preparation of 4-(chloromethyl)-2-phenylpyrimidine

[0097] To a mixture of 6-methyl-2-phenylpyrimidine 1-oxide (2.9 g, 15.6 mmol) in dioxane (58 mL) was added POCl3(23.9 g, 156 mmol) at the atmosphere of nitrogen. The resulting mixture was stirred at 100oC for 2 hrs. LCMS indicated the reaction was complete. Then the mixture was cooled and concentrated under reduced pressure. The residue was quenched by ice-water and extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous Na2SO4and concentrated to give a residue. The residue was purified by FCC (silica gel, 0~8% EA in PE) to afford 4-(chloromethyl)-2-phenylpyrimidine (1.6 g, yield: 51.61%) as a white solid. LCMS (m / z): [M]+calcd, 204.05; found, 205.2

[0098] Intermediate B-42: 2-(chloromethyl)-6-phenylpyrazine

[0099] Preparation of (6-phenylpyrazin-2-yl)methanol

[0100] To a mixture of 4-chloro-2-methylpyrimidine (1.0 g, 6.9 mmol), phenylboronic acid (1.7 g, 14 mmol) and K2CO3 (2.9 g, 21 mmol) in dioxane / H2O (20 mL, 10:1) was added Pd(dppf)Cl2 (510 mg, 0.7 mmol) under an atmosphere of nitrogen. The resulting mixture was stirred at 90oC for 18 hrs. LCMS indicated the reaction was completed. The mixture was thencooled, poured into water and extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous Na2SO4 and concentrated to give a residue. The residue was purified by flash column chromatography (silica gel, 0~70% EA in PE) to afford (6- phenylpyrazin-2-yl)methanol (1.0 g, yield: 83%) as a light yellow solid. LCMS (m / z): [M]+calcd, 186.08; found, 187.2.

[0101] Preparation of 2-(chloromethyl)-6-phenylpyrazine

[0102] To a solution of (6-phenylpyrazin-2-yl)methanol (300 mg, 1.6 mmol) in DCM (3.0 mL) was added thionyl chloride (290 mg, 2.4 mmol) dropwise with stirring at 0oC. The resulting mixture was allowed to warm to room temperature over 1 hr. The mixture was concentrated under vacuum to afford 2-(chloromethyl)-6-phenylpyrazine (300 mg, crude) as a yellow solid. LCMS (m / z): [M]+calcd, 204.05; found, 205.2.

[0103] Intermediate B-43: 6(3-(2'-methyl-[2,4'-bipyridin]-6-yl)-1,2,4-thiadiazol-5-

[0104] Preparation of ethyl 3-(2'-methyl-[2,4'-bipyridin]-6-yl)-1,2,4-thiadiazole-5-carboxylate

[0105] A mixture of 3-(6-(((trifluoromethyl)sulfonyl)oxy)pyridin-2-yl)-1,2,4-thiadiazole- 5-carboxylate (1 g, 2.61 mmol), (2-methylpyridin-4-yl)boronic acid (429 mg, 3.1 mmol), K2CO3 (1 g, 7.8 mmol) and Pd(dppf)Cl2 (212 mg, 0.26 mmol) in dioxane (20 mL) was stirred at 80 °C for 3h. LCMS showed the reaction was completed. The reaction mixture was cooled to room temperature and water was added. The mixture was extracted with ethyl acetate (30 mL *3). The combined organic layers was concentrated under reduced pressure and the residue was purified by flash column chromatography (silica gel, 60~90% EA in PE) to giveethyl 3-(2'-methyl-[2,4'-bipyridin]-6-yl)-1,2,4-thiadiazole-5-carboxylate (650 mg, 2.24 mmol, 76%) as a yellow solid. LCMS (m / z): [M]+calcd: 326.37, found: 327.1.

[0106] Preparation of (3-(2'-methyl-[2,4'-bipyridin]-6-yl)-1,2,4-thiadiazol-5- yl)methanol

[0107] To a solution of ethyl 3-(2'-methyl-[2,4'-bipyridin]-6-yl)-1,2,4-thiadiazole-5- carboxylate (650 mg, 2.24 mmol) in EtOH (15 mL) was added NaBH4 (255 mg, 6.72 mmol) at 0 °C. The reaction was stirred at room temperature for 1h. LCMS showed the reaction was completed. The reaction was quenched with iced aq. NH4Cl and extracted with DCM. The organic layer was dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 80~100% EA in PE) to give (3-(2'- methyl-[2,4'-bipyridin]-6-yl)-1,2,4-thiadiazol-5-yl)methanol (450 mg, 1.58 mmol, 79.47%) as a yellow solid. LCMS (m / z): [M]+calcd: 284.34, found: 285.2.

[0108] Preparation of (3-(2'-methyl-[2,4'-bipyridin]-6-yl)-1,2,4-thiadiazol-5- yl)methyl methanesulfonate

[0109] To a solution of (3-(2'-methyl-[2,4'-bipyridin]-6-yl)-1,2,4-thiadiazol-5- yl)methanol (200 mg, 0.70 mmol) and triethylamine (212 mg, 2.10 mmol) in DCM (5 mL) was added MsCl (381 mg, 1.4 mmol) at 0 °C. The reaction was stirred at rt for 1h. LCMS showed the reaction was completed. The reaction was quenched with ice water and extracted with DCM. The organic layer was dried over Na2SO4and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 60~90% EA in PE) to give (3-(2'-methyl-[2,4'-bipyridin]-6-yl)-1,2,4-thiadiazol-5-yl)methyl methanesulfonate (220 mg, 0.61 mmol, 86%) as a yellow solid. LCMS (m / z): [M]+ calcd: 362.42, found: 363.1.

[0110] Intermediates below were synthesized similarly to Intermediate B-43:

[0111] Intermediate B-45: 2-(chloromethyl)-5-(2-fluoro-3-(pyrimidin-2-yl)phenyl)- 1,3,4-oxadiazole

[0112] methyl 2-fluoro-3-(pyrimidin-2-yl)benzoate

[0113] To a solution of (2-fluoro-3-(methoxycarbonyl)phenyl)boronic acid (4.0 g, 0.02 mol) and 2-bromopyrimidine (3.22 g, 0.02 mol) in dioxane (40 mL) and H2O (10 mL) was added Pd(dppf)Cl2(1.5 g, 2.02 mmol) and K2CO3(8.37 g, 0.06 mmol) under nitrogen atmosphere. The mixture reaction was stirred 2 h at 90! under nitrogen atmosphere. LCMS showed the reaction was completed. The reaction mixture was quenched with water and extracted with EA (5 mL x 3). The combined organic layer was washed with water (4 mL) and brine (4 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a crude product which was purified by flash chromatography (0-20% EA in PE) to afford methyl 2-fluoro-3-(pyrimidin-2-yl)benzoate (4.3 g, 0.02 mol, 91.72 %) as a colorless oil. [M]+ calcd:232.06, found:233.06.

[0114] Preparation of 2-fluoro-3-(pyrimidin-2-yl)benzoic acid

[0115] To a solution of methyl 2-fluoro-3-(pyrimidin-2-yl)benzoate (4.0 g, 17.24 mmol) in MeOH (40 mL) and H2O (10 mL) was added lithium hydroxide (825.86 mg, 0.03 mol).The mixture reaction was stirred 4 hours at room temperature. LCMS showed the reaction was completed. The reaction mixture was adjusted the PH to 4 by 4 M hydrochloric acid aqueous solution and extracted with EA (5 mL x 3). The combined organic layer was washed with brine (4 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a crude product which was purified by flash chromatography (0-10% MeOH in DCM) to afford 2-fluoro-3-(pyrimidin-2-yl)benzoic acid (3.5 g, 16.05 mmol, 93.12 %) as a colorless oil. [M]+ calcd:218.05, found:219.05.

[0116] Preparation of 2-fluoro-3-(pyrimidin-2-yl)benzohydrazide

[0117] To a solution of 2-fluoro-3-(pyrimidin-2-yl)benzoic acid (1.5 g, 6.88 mmol) in THF (20 mL) was added di(1H-imidazol-1-yl)methanone (2.23 g, 13.76 mmol), the reaction was stirred at room temperature for 1 hours. LCMS showed the start ingredient was consumed. The reaction was added to the solution of hydrazinium hydroxide solution (0.7 mL, 13.76 mmol) in THF (10 mL), and the reaction was stirred at room temperature for 1 h. LCMS showed the reaction was completed. The mixture was concentrated under reduced pressure and the residue was purified by flash chromatography (0-10% MeOH in DCM) to give 2-fluoro-3-(pyrimidin-2-yl)benzohydrazide (1.4 g, 6.03 mmol, 87.7%) as a white solid. [M]+ calcd:232.08, found:233.08.

[0118] Preparation of N'-(2-chloroacetyl)-2-fluoro-3-(pyrimidin-2- yl)benzohydrazide

[0119] To a solution of 2-fluoro-3-(pyrimidin-2-yl)benzohydrazide (1.0 g, 4.30 mmol) in ethyl acetate (10 mL) was added 2-chloroacetyl chloride (729.96 mg, 6.46 mmol). The mixture reaction was stirred for 1 hours at room temperature. LCMS showed the reaction was completed. The reaction mixture was quenched with water (10 mL) and extracted with EA (10 mL x 3). The combined organic layer was washed with brine (4 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a crude product which was purified by flash chromatography (50-100% EA in PE) to afford N'-(2-chloroacetyl)-2-fluoro-3-(pyrimidin-2-yl)benzohydrazide (680 mg, 2.21 mmol, 51.23 %) as a white solid. [M]+ calcd:308.05, found:309.05.

[0120] Preparation of 2-(chloromethyl)-5-(2-fluoro-3-(pyrimidin-2-yl)phenyl)- 1,3,4-oxadiazole

[0121] To a solution of N'-(2-chloroacetyl)-2-fluoro-3-(pyrimidin-2-yl)benzohydrazide (680 mg, 2.21 mmol) in phosphorus oxychloride (10 mL). The mixture reaction was stirred for 1 hours at 120°C. LCMS showed the reaction was completed. The reaction mixture was concentrated under reduced pressure and the residue was quenched with water (10 mL) and extracted with EA (10 mL x 3). The combined organic layer was washed with brine (4 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a crude product which was purified by flash chromatography (0-30% EA in PE) to afford 2- (chloromethyl)-5-(2-fluoro-3-(pyrimidin-2-yl)phenyl)-1,3,4-oxadiazole (260 mg, 0.89 mmol, 40.47 %) as a colorless oil. [M]+ calcd:290.04, found:291.04.

[0122] Intermediate C: 5-(chloromethyl)-3-(2-(2-fluorophenyl)pyrimidin-4-yl)- 1,2,4-oxadiazole

[0123] Step 1: 2-(2-fluorophenyl)pyrimidine-4-carbonitrile

[0124] To a solution of 2-chloropyrimidine-4-carbonitrile (200 mg, 1.44 mmol) indioxane / H2O (5 mL / 0.5 mL) were added (2-fluorophenyl)boronic acid (240 mg, 1.73 mmol), K2CO3 (596 mg, 4.32 mmol) and Pd(dppf)Cl2 (105 mg, 0.14 mmol). The mixture was stirred at 90oC for 3 hours. LCMS showed the reaction was completed. The mixture was concentrated and purified by FCC (silica gel, 0~10 % MeOH in DCM) to give 2-(2- fluorophenyl)pyrimidine-4-carbonitrile (240 mg, 1.20 mmol, yield:84%) as a white solid. [M]+calcd: 199.05, found: 200.8.1H NMR (400 MHz, DMSO-d6) " 9.29 (d, J = 4.8 Hz, 1H), 8.14 (d, J = 4.8 Hz, 1H), 8.07 (td, J = 7.8, 1.8 Hz, 1H), 7.71 – 7.58 (m, 1H), 7.46 – 7.35 (m, 2H).

[0125] Step 2: 2-(2-fluorophenyl)-N-hydroxypyrimidine-4-carboximidamide

[0126] To a solution of 2-(2-fluorophenyl)pyrimidine-4-carbonitrile (240 mg, 1.21 mmol) in EtOH(10 mL) were added Hydroxylamine hydrochloride (166 mg, 2.41 mmol) and EtONa (163 mg, 2.41 mmol). The mixture was stirred at 50oC overnight under nitrogen. LCMS showed the reaction was completed. The mixture was concentrated and purified by FCC (silica gel, 0~10 % MeOH in DCM) to give 2-(2-fluorophenyl)-N-hydroxypyrimidine-4- carboximidamide (250 mg, 1.08 mmol, yield:90%) as a white solid. [M]+calcd: 232.08, found: 233.2.

[0127] Step 3: 5-(chloromethyl)-3-(2-(2-fluorophenyl)pyrimidin-4-yl)-1,2,4- oxadiazole

[0128] At 0oC, to a solution of 2-(2-fluorophenyl)-N-hydroxypyrimidine-4- carboximidamide (250 mg, 1.08 mmol) in toluene (5 mL) were added TEA (0.13 mL, 1.65 mmol) and 2-chloroacetyl chloride (0.17 mL, 1.21 mmol) dropwise. The reaction was stirred at 0oC for 30 min under N2, then stirred at 110oC for 4 h. The reaction was complete confirmed by LCMS. Then the mixture was concentrated under reduced pressure. The residue was purified by FCC (silica gel, 0~50% EA in PE) to obtain 5-(chloromethyl)-3-(2-(2- fluorophenyl)pyrimidin-4-yl)-1,2,4-oxadiazole (240 mg, 0.83 mmol, yield: 77%) as a yellow solid. [M]+calcd, 290.04; found, 291.1.1H NMR (400 MHz, DMSO-d6) " 9.23 (d, J = 5.2Hz, 1H), 8.31 – 7.95 (m, 2H), 7.63 (ddd, J = 7.2, 5.0, 1.8 Hz, 1H), 7.51 – 7.13 (m, 2H), 5.27 (s, 2H).

[0129] Intermediates below were synthesized similarly to Intermediate C:

[0130] Intermediate D: Synthesis of 5-(chloromethyl)-3-(4-fluoro-6-phenylpyridin- 2-yl)-1,2,4-oxadiazole

[0131] Step 1: 4-fluoro-2-phenylpyridine

[0132] Dissolve 2-bromo-4-fluoropyridine (2 g, 11.36 mmol) in dioxane - water (20 mL) with phenylboronic acid (1.5 g, 12.50 mmol), K2CO3 (4.7 g, 34.09 mmol) and Pd(dppf)Cl2 (0.8 g, 1.14 mmol). The reaction mixture is replaced with gas three times under nitrogen protection, and then the reaction system is heated to 90oC and stirred for 3 hr. The reaction was monitored by LCMS. The suspension was filtered and the filter cake was washed with MeOH. The combined filtrates concentrated to give a residue. The residue was purified by FCC (silica gel, 0~10% EA in PE) to give 4-fluoro-2-phenylpyridine (1.7 g, 9.82 mmol, yield: 86.37%) as an orange oil. LCMS (m / z): [M]+calcd, 173.06; found, 174.3.

[0133] Step 2: 4-fluoro-2-phenylpyridine 1-oxide

[0134] A mixture of 4-fluoro-2-phenylpyridine (800 mg, 4.62 mmol) and mCPBA (1992.8 mg, 11.55 mmol) in chloroform (15 mL) was stirred at rt overnight. LCMS indicated the reaction was complete. Then the mixture was poured into water and extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous Na2SO4and concentrated to give a residue. The residue was purified by FCC (silica gel, 0~5% MeOH in DCM) to give 4-fluoro-2-phenylpyridine 1-oxide (640 mg, 3.38 mmol, yield: 73.23%) as brown solid. LCMS (m / z): [M]+calcd: 189.06, found: 190.1.

[0135] Step 3: 4-fluoro-6-phenylpicolinonitrile

[0136] A mixture of 4-fluoro-2-phenylpyridine 1-oxide (640 mg, 3.38 mmol), dimethylcarbamic chloride (473 mg, 4.40 mmol) and TMSCN (1.4 g, 13.53 mmol) in DCM (10 mL) was stirred at rt overnight. LCMS indicated the reaction was complete. The mixture was washed with H2O. The water phase was extracted with EA for 3 times. The combined organic layers were dried over anhydrous Na2SO4and concentrated to give a residue. The residue was purified by FCC (silica gel, 0~30% EA in PE) to give 4-fluoro-6- phenylpicolinonitrile (531 mg, 2.68 mmol, yield: 79.20%) as white solid. LCMS (m / z): [M]+calcd: 198.06, found: 199.2.1H NMR (400 MHz, DMSO-d6) " 8.36 (d, J = 2.2 Hz, 1H), 8.33 (d, J = 2.2 Hz, 1H), 8.16 (s, 1H), 8.13 (d, J = 2.2 Hz, 1H), 7.58 (d, J = 3.3 Hz, 3H).

[0137] Step 4: (Z)-4-fluoro-N'-hydroxy-6-phenylpicolinimidamide

[0138] A mixture of 4-fluoro-6-phenylpicolinonitrile (510 mg, 2.57 mmol), NH2OH·HCl (357.7 mg, 5.15 mmol) and NaHCO3 (432.3 mg, 5.15 mmol) in EtOH (10 mL) and Water (4 mL) were stirred at 85oC for 4 hrs. LCMS indicated the reaction was complete.The mixture was concentrated to give a residue. The residue was purified by FCC (silica gel, 30~40% EA in PE) to give (Z)-4-fluoro-N'-hydroxy-6-phenylpicolinimidamide (544 mg, 2.35 mmol, yield: 91.43%) as a white solid. LCMS (m / z): [M]+calcd: 231.08, found: 232.2. Step 5: 5-(chloromethyl)-3-(4-fluoro-6-phenylpyridin-2-yl)-1,2,4-oxadiazole

[0139] To a solution of (Z)-4-fluoro-N'-hydroxy-6-phenylpicolinimidamide (544 mg, 2.35 mmol) and TEA (238.1 mg, 2.35 mmol) in toluene (8 mL) at 0oC was added dropwise 2-chloroacetyl chloride (265.7 mg, 2.35 mmol) in toluene (1 mL). The solution was stirred at rt for 15 min, and then at 110oC for 4 h. The mixture was then cooled to room temperature, extracted with toluene, washed with water and brine, dried over anhydrous Na2SO4, and concentrated under vacuum. The residue was purified by FCC (silica gel, 20~30% EA in PE) to give 5-(chloromethyl)-3-(4-fluoro-6-phenylpyridin-2-yl)-1,2,4-oxadiazole (433 mg, 1.49 mmol, yield: 63.53%) as a white solid. LCMS (m / z): [M]+calcd, 289.04; found, 290.2.

[0140] Intermediates below were synthesized similarly to Intermediate C:

[0141] Intermediate D: Synthesis of 5-bromo-2-(chloromethyl)-4- fluorobenzo[d]oxazole

[0142] To a solution of 2-amino-4-bromo-3-fluorophenol (500 mg, 2.43 mmol) in DCM (10 mL) was added ethyl 2-chloroacetimidate hydrochloride (575 mg, 3.64 mmol) at 0oC. Then the mixture was stirred at rt overnight under nitrogen. LCMS showed the reaction was completed. The mixture was concentrated and purified by FCC (silica gel, 0~20 % EA in PE) to give 5-bromo-2-(chloromethyl)-4-fluorobenzo[d]oxazole (560 mg, 2.12 mmol, yield: 87%) as a white solid. [M]+calcd: 262.91, found: 263.9Examples

[0143] General Method A

[0144] 6-(2,6-dioxopiperidin-3-yl)-1-((3-phenyl-1,2,4-oxadiazol-5-yl)methyl)-1,2,3,4- tetrahydro-5H-pyrrolo[3,4-b]pyridine-5,7(6H)-dione; Compound 1

[0145] Preparation of of 6-(2,6-dioxo-1-((2-(trimethylsilyl)ethoxy)methyl)piperidin- 3-yl)-1-((3-phenyl-1,2,4-oxadiazol-5-yl)methyl)-1,2,3,4-tetrahydro-5H-pyrrolo[3,4- b]pyridine-5,7(6H)-dione

[0146] To a mixture of 6-(2,6-dioxo-1-((2-(trimethylsilyl)ethoxy)methyl)piperidin-3-yl)- 1,2,3,4-tetrahydro-5H-pyrrolo[3,4-b]pyridine-5,7(6H)-dione (60 mg, 0.15 mmol) and 5- (chloromethyl)-3-phenyl-1,2,4-oxadiazole (35.61 mg, 0.18 mmol) in ACN (5 mL) were added K2CO3 (46.21 mg, 0.33 mmol) and KI (55.84 mg, 0.33 mmol). The mixture was stirred at 90 ! for 20 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 FCC on silica gel (0-50% EA in PE) to afford 6-[1-(5,5-dimethyl-2-oxa-5- silahex-1-yl)-2,6-dioxohexahydropyridin-3-yl]-1-[(3-phenyl-1,2,4-oxadiazol-5-yl)methyl]- 1,2,3,4-tetrahydropyrrolo[4,3-b]pyridine-5,7-dione (15 mg, 0.027 mmol, 17.83%) as a yellow solid. LCMS (m / z): [M-H]- calcd: 551; found: 550.1H NMR (400 MHz, DMSO-d6) " 8.08 (dd, J = 7.9, 1.5 Hz, 2H), 7.80 – 7.56 (m, 3H), 5.54 – 5.30 (m, 2H), 5.16 – 4.97 (m, 3H), 3.75 – 3.49 (m, 6H), 3.05 – 2.93 (m, 1H), 2.83 – 2.71 (m, 1H), 2.52 – 2.43 (m, 1H), 2.40 – 2.27 (m, 2H), 2.11 – 1.90 (m, 3H), 0.00 (s, 9H).

[0147] Preparation of 6-(2,6-dioxopiperidin-3-yl)-1-((3-phenyl-1,2,4-oxadiazol-5- yl)methyl)-1,2,3,4-tetrahydro-5H-pyrrolo[3,4-b]pyridine-5,7(6H)-dione

[0148] To a solution of 6-(2,6-dioxo-1-((2-(trimethylsilyl)ethoxy)methyl)piperidin-3-yl)- 1-((3-phenyl-1,2,4-oxadiazol-5-yl)methyl)-1,2,3,4-tetrahydro-5H-pyrrolo[3,4-b]pyridine- 5,7(6H)-dione (10 mg, 0.02 mmol) in DCM (1 mL) was added TFA (0.5 mL) at RT under N2. The mixture was stirred at 30 ! for 0.5 hours, then concentrated and purified by prep-HPLC (NH3.H2O) to give 6-(2,6-dioxopiperidin-3-yl)-1-((3-phenyl-1,2,4-oxadiazol-5-yl)methyl)- 1,2,3,4-tetrahydro-5H-pyrrolo[3,4-b]pyridine-5,7(6H)-dione (3 mg, 0.01 mmol, 28.01%) as a yellow solid. LCMS (m / z): [M+H]+calcd: 421; found: 422.1H NMR (400 MHz, DMSO-d6) " 10.98 (s, 1H), 8.13 – 7.86 (m, 2H), 7.68 – 7.39 (m, 3H), 5.31 (s, 2H), 4.84 (dd, J = 13.0, 5.4 Hz, 1H), 3.65 – 3.38 (m, 2H), 2.97 – 2.70 (m, 1H), 2.56 – 2.51 (m, 1H), 2.46 – 2.32 (m, 1H), 2.27 (t, J = 6.0 Hz, 2H), 1.96 – 1.79 (m, 3H).

[0149] Compounds below may be synthesized utilizing General Method A.4850515253545556575860616263646566676869707172747576

[0150] General Method B

[0151] Preparation of 1-((3-([1,1'-biphenyl]-3-yl)-1,2,4-oxadiazol-5-yl)methyl)-6-(2,6- dioxopiperidin-3-yl)-1,2,3,4-tetrahydro-5H-pyrrolo[3,4-b]pyridine-5,7(6H)-dione, Compound 19

[0152] To a solution of 1-{[3-(3-bromophenyl)-1,2,4-oxadiazol-5-yl]methyl}-6-(2,6- dioxohexahydropyridin-3-yl)-1,2,3,4-tetrahydropyrrolo[4,3-b]pyridine-5,7-dione (60 mg, 0.12 mmol) in dioxane / H2O (3 mL) were added phenylboranediol (29.25 mg, 0.24 mmol), potassium carbonate (33.15 mg, 0.24 mmol), and Pd-118 (7.72 mg, 0.01 mmol) at RT under N2. Then the mixture was stirred at 60 ! for 2 hours. LCMS indicated the reaction was complete. The mixture was concentrated in vacuo and purified by FCC on silica gel (25%- 40% EA in PE) and prep-HPLC (C18, wavelength: 220nm / 254nm phase A: H2O;phase B: MeCN 25%-95%, 10.8min / 18 min) to give 6-(2,6-dioxohexahydropyridin-3-yl)-1-{[3-(3-phenylphenyl)-1,2,4-oxadiazol-5-yl]methyl}-1,2,3,4-tetrahydropyrrolo[4,3-b]pyridine- 5,7-dione (23.5 mg, 0.05 mmol, 39.39%) as a yellow solid. LCMS (m / z): [M+H]+calcd: 497; found: 498.1H NMR (400 MHz, DMSO-d6) " 10.98 (s, 1H), 8.21 (s, 1H), 8.00 (d, J = 7.8 Hz, 1H), 7.90 (d, J = 7.9 Hz, 1H), 7.74 – 7.66 (m, 3H), 7.52 (t, J = 7.6 Hz, 2H), 7.43 (t, J = 7.3 Hz, 1H), 5.33 (s, 2H), 4.85 (dd, J = 12.9, 5.4 Hz, 1H), 3.55 – 3.47 (m, 2H), 2.85 – 2.75 (m, 1H), 2.53 (s, 1H), 2.43 – 2.33 (m, 1H), 2.27 (t, J = 5.9 Hz, 2H), 1.91 (d, J = 5.1 Hz, 3H).

[0153] Compounds below may be synthesized utilizing General Method B.798081828384858687

[0154] General Method C

[0155] 6-(2,6-dioxopiperidin-3-yl)-1-((3-(3-(pyrazin-2-yl)phenyl)-1,2,4-oxadiazol-5- yl)methyl)-1,2,3,4-tetrahydro-5H-pyrrolo[3,4-b]pyridine-5,7(6H)-dione, Compound 29

[0156] Preparation of 6-(2,6-dioxopiperidin-3-yl)-1-((3-(3-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)phenyl)-1,2,4-oxadiazol-5-yl)methyl)-1,2,3,4-tetrahydro-5H- pyrrolo[3,4-b]pyridine-5,7(6H)-dione

[0157] To a solution of 1-((3-(3-bromophenyl)-1,2,4-oxadiazol-5-yl)methyl)-6-(2,6- dioxopiperidin-3-yl)-1,2,3,4-tetrahydro-5H-pyrrolo[3,4-b]pyridine-5,7(6H)-dione (520.00 mg, 1.04 mmol) in dioxane (20 mL) were added 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (396.69 mg, 1.56 mmol), Pd(dppf)Cl2 (38.06 mg, 0.05 mmol) and potassium acetate (306.61 mg, 3.12 mmol), and the reaction was stirred at 100 ! under N2 for 18 h. LCMS indicated the reaction was complete. The reaction mixture was concentrated in vacuo and purified by FCC on silica gel (0-6% MeOH in DCM) to give 6-(2,6-dioxopiperidin-3-yl)-1-((3-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1,2,4-oxadiazol-5-yl)methyl)-1,2,3,4-tetrahydro-5H-pyrrolo[3,4- b]pyridine-5,7(6H)-dione (630.00 mg, 0.87 mmol, 83.19%) as a yellow solid. LCMS (m / z): [M+H]+calcd: 547.2; found: 548.3.1H NMR (400 MHz, DMSO-d6) " 10.99 (s, 1H), 8.29 (s, 1H), 8.16 – 8.09 (m, 1H), 7.88 (d, J = 7.4 Hz, 1H), 7.60 (t, J = 7.7 Hz, 1H), 5.32 (s, 2H), 4.86 (dd, J = 12.9, 5.4 Hz, 1H), 3.49 (s, 2H), 2.87 – 2.76 (m, 1H), 2.39 (dd, J = 13.4, 3.8 Hz, 2H), 2.28 (t, J = 6.1 Hz, 2H), 1.90 (d, J = 8.9 Hz, 3H), 1.33 (s, 12H).

[0158] Preparation of 6-(2,6-dioxopiperidin-3-yl)-1-((3-(3-(pyrazin-2-yl)phenyl)- 1,2,4-oxadiazol-5-yl)methyl)-1,2,3,4-tetrahydro-5H-pyrrolo[3,4-b]pyridine-5,7(6H)- dione

[0159] To a solution of 6-(2,6-dioxopiperidin-3-yl)-1-((3-(3-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)phenyl)-1,2,4-oxadiazol-5-yl)methyl)-1,2,3,4-tetrahydro-5H-pyrrolo[3,4- b]pyridine-5,7(6H)-dione (100.00 mg, 0.18 mmol) in 10:1 dioxane / H2O (10 mL) were added 2-bromopyrazine (29.05 mg, 0.18 mmol), potassium carbonate (75.74 mg, 0.55 mmol) and Pd(dppf)Cl2(13.35 mg, 0.02 mmol), and the reaction was stirred at 80 ! under N2for 2 h. LCMS indicated the reaction was complete. The reaction mixture was concentrated in vacuo and purified by prep TLC (100% EA, Rf= 0.3) and prep-HPLC(C18, wavelength: 220nm / 254nm phase A: H2O ; phase B: MeCN 25%-95%) to give 6-(2,6-dioxopiperidin-3-yl)-1-((3-(3-(pyrazin-2-yl)phenyl)-1,2,4-oxadiazol-5-yl)methyl)-1,2,3,4- tetrahydro-5H-pyrrolo[3,4-b]pyridine-5,7(6H)-dione (21.20 mg, 0.04mmol, 23.19%) as a yellow solid. LCMS (m / z): [M+H]+calcd: 499.2; found: 500.2.1H NMR (400 MHz, DMSO-d6) " 10.97 (s, 1H), 9.36 (d, J = 1.3 Hz, 1H), 8.81 – 8.77 (m, 1H), 8.76 (s, 1H), 8.69 (d, J = 2.5 Hz, 1H), 8.38 (d, J = 8.0 Hz, 1H), 8.13 (d, J = 7.8 Hz, 1H), 7.76 (t, J = 7.8 Hz, 1H), 5.34 (s, 2H), 4.85 (dd, J = 12.9, 5.4 Hz, 1H), 3.56 – 3.45 (m, 2H), 2.80 (ddd, J = 17.2, 14.0, 5.4 Hz, 1H), 2.53 (d, J = 2.7 Hz, 1H), 2.45 – 2.35 (m, 1H), 2.28 (t, J = 6.0 Hz, 2H), 1.96 – 1.86 (m, 3H).

[0160] Compounds below may be synthesized utilizing General Method C.500.2 500.2 4999293949596979899

[0161] General Method D

[0162] 1-((3-([1,1'-biphenyl]-3-yl)-1,2,4-thiadiazol-5-yl)methyl)-6-(2,6- dioxopiperidin-3-yl)-1,2,3,4-tetrahydro-5H-pyrrolo[3,4-b]pyridine-5,7(6H)-dione, Comound 35

[0163] Preparation of 1-((3-([1,1'-biphenyl]-3-yl)-1,2,4-thiadiazol-5-yl)methyl)-6- (2,6-dioxo-1-((2-(trimethylsilyl)ethoxy)methyl)piperidin-3-yl)-1,2,3,4-tetrahydro-5H- pyrrolo[3,4-b]pyridine-5,7(6H)-dione#

[0164] The starting material 1-((3-(3-bromophenyl)-1,2,4-thiadiazol-5-yl)methyl)-6-(2,6- dioxo-1-((2-(trimethylsilyl)ethoxy)methyl)piperidin-3-yl)-1,2,3,4-tetrahydro-5H-pyrrolo[3,4- b]pyridine-5,7(6H)-dione was prepared analogously to previous examples except without the SEM deprotection step.

[0165] To a mixture of 1-((3-(3-bromophenyl)-1,2,4-thiadiazol-5-yl)methyl)-6-(2,6- dioxo-1-((2-(trimethylsilyl)ethoxy)methyl)piperidin-3-yl)-1,2,3,4-tetrahydro-5H-pyrrolo[3,4- b]pyridine-5,7(6H)-dione (80.00 mg, 0.12 mmol) and phenylboronic acid (29.24 mg, 0.24 mmol) in dioxane (3.0 mL) and H2O (0.3 ml) were added Pd-118 (6.44 mg, 0.01 mmol) and K2CO3(33.17 mg, 0.24 mmol) under nitrogen atmosphere. The mixture was stirred at 60 ! for 2 hrs. LCMS indicated the reaction was complete. The mixture was cooled, poured into sat. NH4Cl and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated to give a residue, which was purified by FCC on silica gel (0-10% MeOH in DCM) to afford 1-((3-([1,1'-biphenyl]-3-yl)-1,2,4-thiadiazol-5- yl)methyl)-6-(2,6-dioxo-1-((2-(trimethylsilyl)ethoxy)methyl)piperidin-3-yl)-1,2,3,4- tetrahydro-5H-pyrrolo[3,4-b]pyridine-5,7(6H)-dione (70.00 mg, 0.11 mmol, 87.88%) as a yellow solid. LCMS (m / z): [M+H]+calcd: 643.2; found: 644.2.

[0166] Preparation of 1-((3-([1,1'-biphenyl]-3-yl)-1,2,4-thiadiazol-5-yl)methyl)-6- (2,6-dioxopiperidin-3-yl)-1,2,3,4-tetrahydro-5H-pyrrolo[3,4-b]pyridine-5,7(6H)-dione

[0167] A solution of 1-((3-([1,1'-biphenyl]-3-yl)-1,2,4-thiadiazol-5-yl)methyl)-6-(2,6- dioxo-1-((2-(trimethylsilyl)ethoxy)methyl)piperidin-3-yl)-1,2,3,4-tetrahydro-5H-pyrrolo[3,4- b]pyridine-5,7(6H)-dione (70.00 mg, 0.11 mmol) in TFA:DCM (1:2, 3 mL) was stirred at RT for 10 min. LCMS indicated the reaction was complete. The reaction was concentrated under reduced pressure and purified by prep-HPLC (C18, wavelength: 220nm / 254nm phase A: H2O (0.1% NH3.H2O); phase B: MeCN 30%-95%, 9 min / 20 min) to give 1-((3-([1,1'-biphenyl]-3- yl)-1,2,4-thiadiazol-5-yl)methyl)-6-(2,6-dioxopiperidin-3-yl)-1,2,3,4-tetrahydro-5H- pyrrolo[3,4-b]pyridine-5,7(6H)-dione (23.50 mg, 0.05 mmol, 42.08%) as a yellow solid. LCMS (m / z): [M+H]+calcd: 513.2; found: 514.2.1H NMR (400 MHz, DMSO-d6) " 10.98 (s, 1H), 8.45 (d, J = 1.6 Hz, 1H), 8.20 (d, J = 7.8 Hz, 1H), 7.84 (d, J = 7.9 Hz, 1H), 7.74 – 7.70 (m, 2H), 7.65 (t, J = 7.8 Hz, 1H), 7.52 (t, J = 7.6 Hz, 2H), 7.42 (t, J = 7.3 Hz, 1H), 5.45 – 5.34 (m, 2H), 4.86 (dd, J = 12.9, 5.4 Hz, 1H), 3.55 – 3.45 (m, 2H), 2.79 (ddd, J = 17.2, 14.1, 5.5 Hz, 1H), 2.48 – 2.31 (m, 2H), 2.27 (t, J = 6.0 Hz, 2H), 1.94 – 1.83 (m, 3H).

[0168] Compounds below may be synthesized utilizing General Method D.

[0169] General Method E

[0170] 6-(2,6-dioxopiperidin-3-yl)-1-((3-(3-(pyrazin-2-yl)phenyl)-1,2,4-thiadiazol-5- yl)methyl)-1,2,3,4-tetrahydro-5H-pyrrolo[3,4-b]pyridine-5,7(6H)-dione, Compound 37

[0171] Preparation of 6-(2,6-dioxo-1-((2-(trimethylsilyl)ethoxy)methyl)piperidin-3- yl)-1-((3-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1,2,4-thiadiazol-5- yl)methyl)-1,2,3,4-tetrahydro-5H-pyrrolo[3,4-b]pyridine-5,7(6H)-dione#

[0172] To a mixture of 1-((3-(3-bromophenyl)-1,2,4-thiadiazol-5-yl)methyl)-6-(2,6- dioxo-1-((2-(trimethylsilyl)ethoxy)methyl)piperidin-3-yl)-1,2,3,4-tetrahydro-5H-pyrrolo[3,4- b]pyridine-5,7(6H)-dione (130.0 mg, 0.2 mmol) and 4,4,4',4',5,5,5',5'-octamethyl-2,2'- bi(1,3,2-dioxaborolane) (76.8 mg, 0.3 mmol) in dioxane (2.0 mL) were added Pd(dppf)Cl2(7.3 mg, 0.01 mmol) and KOAc (58.8 mg, 0.6 mmol) under nitrogen atmosphere. The resulting mixture was stirred at 100 ! for 18 hrs. LCMS indicated the reaction wascomplete. Then the mixture was cooled, poured into sat. NH4Cl and extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous Na2SO4 and concentrated to give a residue, which was purified by FCC on silica gel (0-3% MeOH in DCM) to give 6- (2,6-dioxo-1-((2-(trimethylsilyl)ethoxy)methyl)piperidin-3-yl)-1-((3-(3-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)phenyl)-1,2,4-thiadiazol-5-yl)methyl)-1,2,3,4-tetrahydro-5H- pyrrolo[3,4-b]pyridine-5,7(6H)-dione (70.0 mg, 0.1 mmol, 50.0%) as a yellow solid.

[0173] Preparation of 6-(2,6-dioxo-1-((2-(trimethylsilyl)ethoxy)methyl)piperidin-3- yl)-1-((3-(3-(pyrazin-2-yl)phenyl)-1,2,4-thiadiazol-5-yl)methyl)-1,2,3,4-tetrahydro-5H- pyrrolo[3,4-b]pyridine-5,7(6H)-dione#

[0174] To a mixture of 6-(2,6-dioxo-1-((2-(trimethylsilyl)ethoxy)methyl)piperidin-3-yl)- 1-((3-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1,2,4-thiadiazol-5-yl)methyl)- 1,2,3,4-tetrahydro-5H-pyrrolo[3,4-b]pyridine-5,7(6H)-dione (70.0 mg, 0.1 mmol) and 2- bromopyrazine (15.7 mg, 0.1 mmol) in dioxane (1.0 mL) and H2O (0.1 ml) were added Pd(dppf)Cl2(7.3 mg, 0.01 mmol) and K2CO3(41.7 mg, 0.3 mmol) under nitrogen atmosphere. The resulting mixture was stirred at 90 ! for 2 hrs. LCMS indicated the reaction was complete. The mixture was cooled, poured into sat. NH4Cl and extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous Na2SO4and concentrated to give a residue, which was purified by FCC on silica gel (0-35% PE in EA) to give 6-(2,6- dioxo-1-((2-(trimethylsilyl)ethoxy)methyl)piperidin-3-yl)-1-((3-(3-(pyrazin-2-yl)phenyl)- 1,2,4-thiadiazol-5-yl)methyl)-1,2,3,4-tetrahydro-5H-pyrrolo[3,4-b]pyridine-5,7(6H)-dione (60.0 mg, 0.093 mmol, 92.3%) as a yellow solid. LCMS (m / z): [M+H]+calcd: 645.2; found: 646.3.

[0175] Preparation of 6-(2,6-dioxopiperidin-3-yl)-1-((3-(3-(pyrazin-2-yl)phenyl)- 1,2,4-thiadiazol-5-yl)methyl)-1,2,3,4-tetrahydro-5H-pyrrolo[3,4-b]pyridine-5,7(6H)- dione

[0176] To a solution of 6-(2,6-dioxo-1-((2-(trimethylsilyl)ethoxy)methyl)piperidin-3-yl)- 1-((3-(3-(pyrazin-2-yl)phenyl)-1,2,4-thiadiazol-5-yl)methyl)-1,2,3,4-tetrahydro-5H- pyrrolo[3,4-b]pyridine-5,7(6H)-dione (60.0 mg, 0.093 mmol) in DCM (2.0 mL) was added TFA (1.0 mL) dropwise with stirring at 0 !. The resulting mixture was allowed to warm to RT over 0.5 hr. LCMS indicated the reaction was complete. The mixture was concentrated to give a residue, which was purified by prep-HPLC (C18, wavelength: 220nm / 254nm phase A: H2O (0.1%NH3.H2O); phase B: MeCN 10%-95%, 10 min / 18 min) to afford 6-(2,6- dioxopiperidin-3-yl)-1-((3-(3-(pyrazin-2-yl)phenyl)-1,2,4-thiadiazol-5-yl)methyl)-1,2,3,4- tetrahydro-5H-pyrrolo[3,4-b]pyridine-5,7(6H)-dione (20.0 mg, 0.038 mmol, 41.6%) as a white solid. LCMS (m / z): [M+H]+calcd: 515.14; found: 516.3.1H NMR (400 MHz, DMSO- d6) " 10.99 (s, 1H), 9.34 (d, J = 1.5 Hz, 1H), 8.99 (t, J = 1.6 Hz, 1H), 8.80 – 8.76 (m, 1H), 8.68 (d, J = 2.5 Hz, 1H), 8.32 (dd, J = 9.3, 8.1 Hz, 2H), 7.72 (t, J = 7.8 Hz, 1H), 5.48 – 5.33 (m, 2H), 4.87 (dd, J = 12.9, 5.4 Hz, 1H), 3.52 (d, J = 4.8 Hz, 2H), 2.80 (ddd, J = 17.2, 14.0, 5.4 Hz, 1H), 2.53 (d, J = 2.8 Hz, 1H), 2.46 – 2.32 (m, 1H), 2.28 (t, J = 6.1 Hz, 2H), 1.92 (d, J = 2.9 Hz, 3H).

[0177] Compounds below may be synthesized utilizing General Method E.

[0178] General Method F

[0179] 3-(5-((6-(2,6-dioxopiperidin-3-yl)-5,7-dioxo-2,3,4,5,6,7-hexahydro-1H- pyrrolo[3,4-b]pyridin-1-yl)methyl)-1,2,4-oxadiazol-3-yl)-N-methylbenzamide, Compound 129

[0180] Preparation of tert-butyl 3-(5-((6-(2,6-dioxo-1-((2- (trimethylsilyl)ethoxy)methyl)piperidin-3-yl)-5,7-dioxo-2,3,4,5,6,7-hexahydro-1H- pyrrolo[3,4-b]pyridin-1-yl)methyl)-1,2,4-oxadiazol-3-yl)benzoate

[0181] To a mixture of tert-butyl 3-(5-(chloromethyl)-1,2,4-oxadiazol-3-yl)benzoate (560 mg, 1.9 mmol) and 6-(2,6-dioxo-1-((2-(trimethylsilyl)ethoxy)methyl)piperidin-3-yl)- 1,2,3,4-tetrahydro-5H-pyrrolo[3,4-b]pyridine-5,7(6H)-dione (500 mg, 1.3 mmol) in DMF (10.0 mL) were added K2CO3 (390 mg, 2.8 mmol) and potassium iodide (460 mg, 2.8 mmol) at the atmosphere of nitrogen. The resulting mixture was stirred at 80oC for 4 hrs. LCMS indicated the reaction was completed. The solvent was removed and the residue was purified by FCC (silica gel, 0~50% ethyl acetate in petroleum ether) to afford tert-butyl 3-(5-((6-(2,6- dioxo-1-((2-(trimethylsilyl)ethoxy)methyl)piperidin-3-yl)-5,7-dioxo-2,3,4,5,6,7-hexahydro- 1H-pyrrolo[3,4-b]pyridin-1-yl)methyl)-1,2,4-oxadiazol-3-yl)benzoate (580mg, yield: 70%) as a yellow solid. LCMS (m / z): [M]+calcd, 651.27; found, 652.0.1H NMR (400 MHz, DMSO- d6) " 8.48 (s, 1H), 8.23 (d, J = 7.8 Hz, 1H), 8.11 (d, J = 7.9 Hz, 1H), 7.71 (t, J = 7.8 Hz, 1H), 5.31 (t, J = 12.7 Hz, 2H), 5.03 – 4.93 (m, 3H), 3.54 – 3.40 (m, 6H), 2.97 – 2.88 (m, 1H), 2.75 – 2.65 (m, 1H), 2.45 – 2.37 (m, 1H), 2.27 (d, J = 5.4 Hz, 2H), 1.94 (d, J = 5.1 Hz, 1H), 1.57 (s, 9H), 0.76 (ddd, J = 13.9, 8.3, 4.8 Hz, 2H), -0.09 (s, 9H).

[0182] Preparation of 3-(5-((6-(2,6-dioxopiperidin-3-yl)-5,7-dioxo-2,3,4,5,6,7- hexahydro-1H-pyrrolo[3,4-b]pyridin-1-yl)methyl)-1,2,4-oxadiazol-3-yl)benzoic acid, Compound 146

[0183] To a solution of tert-butyl 3-(5-((6-(2,6-dioxo-1-((2- (trimethylsilyl)ethoxy)methyl)piperidin-3-yl)-5,7-dioxo-2,3,4,5,6,7-hexahydro-1H- pyrrolo[3,4-b]pyridin-1-yl)methyl)-1,2,4-oxadiazol-3-yl)benzoate (580 mg, 0.89 mmol) in DCM (4.0 mL) was added TFA (2.0 mL) dropwise with stirring at 0oC. The resulting mixture was allowed to warm to room temperature over 2 hrs. The reaction was completed as judged by LCMS. The mixture was concentrated to give 3-(5-((6-(2,6-dioxopiperidin-3-yl)-5,7- dioxo-2,3,4,5,6,7-hexahydro-1H-pyrrolo[3,4-b]pyridin-1-yl)methyl)-1,2,4-oxadiazol-3- yl)benzoic acid (480 mg, crude) as a yellow solid. LCMS (m / z): [M]+calcd, 465.13; found, 466.1

[0184] Preparation of 3-(5-((6-(2,6-dioxopiperidin-3-yl)-5,7-dioxo-2,3,4,5,6,7- hexahydro-1H-pyrrolo[3,4-b]pyridin-1-yl)methyl)-1,2,4-oxadiazol-3-yl)-N- methylbenzamide

[0185] A suspension of 3-(5-((6-(2,6-dioxopiperidin-3-yl)-5,7-dioxo-2,3,4,5,6,7-hexahydro-1H-pyrrolo[3,4-b]pyridin-1-yl)methyl)-1,2,4-oxadiazol-3-yl)benzoic acid (100 mg, 0.22 mmol), DIEA (85.0 mg, 0.66 mmol) and HATU (167 mg, 0.44 mmol) in DCM (2.0 mL) was stirred at rt for 30 min. To the mixture was added Methylamine hydrochloride (22 mg, 0.33 mmol). The resulting mixture was stirred at room temperature for 2 hrs. The reaction was complete confirmed by LCMS. The mixture was washed with H2O and the water phase was extracted with DCM for 3 times. The combined organic layers were dried over anhydrous Na2SO4 and concentrated to give a residue. The residue was purified by prep- HPLC (C18, Wave length: 220nm / 254nm phase A: H2O (0.1% FA); phase B: MeCN 5%- 95%, 10.5 min / 20 min) to afford 3-(5-((6-(2,6-dioxopiperidin-3-yl)-5,7-dioxo-2,3,4,5,6,7- hexahydro-1H-pyrrolo[3,4-b]pyridin-1-yl)methyl)-1,2,4-oxadiazol-3-yl)-N-methylbenzamide (10 mg, yield: 10%) as a yellow solid. LCMS (m / z): [M]+calcd, 478.16; found, 478.2;1H NMR (400 MHz, DMSO-d6) " 10.98 (s, 1H), 8.67 (d, J = 4.5 Hz, 1H), 8.45 (t, J = 1.5 Hz, 1H), 8.13 (d, J = 7.8 Hz, 1H), 8.04 (d, J = 8.0 Hz, 1H), 7.67 (t, J = 7.8 Hz, 1H), 5.33 (s, 2H), 4.85 (dd, J = 12.9, 5.4 Hz, 1H), 3.54 – 3.45 (m, 2H), 2.85 – 2.75 (m, 4H), 2.53 (d, J = 2.7 Hz, 1H), 2.43 – 2.33 (m, 1H), 2.28 (t, J = 6.0 Hz, 2H), 1.96 – 1.87 (m, 3H).

[0186] Compounds below may be synthesized utilizing General Method F.

[0187] General Method G 6-(2,6-dioxopiperidin-3-yl)-1-((3-(3-(methylamino)phenyl)-1,2,4-oxadiazol-5-yl)methyl)- 1,2,3,4-tetrahydro-5H-pyrrolo[3,4-b]pyridine-5,7(6H)-dione (Compound 133)

[0188] 6-(2,6-dioxo-1-((2-(trimethylsilyl)ethoxy)methyl)piperidin-3-yl)-1-((3-(3- (methylamino)phenyl)-1,2,4-oxadiazol-5-yl)methyl)-1,2,3,4-tetrahydro-5H-pyrrolo[3,4- b]pyridine-5,7(6H)-dione

[0189] To a solution of 1-((3-(3-aminophenyl)-1,2,4-oxadiazol-5-yl)methyl)-6-(2,6- dioxo-1-((2-(trimethylsilyl)ethoxy)methyl)piperidin-3-yl)-1,2,3,4-tetrahydro-5H-pyrrolo[3,4- b]pyridine-5,7(6H)-dione (49 mg, 0.09 mmol) in DCM (3.0 mL) were added formaldehyde (3.0 mg, 0.09 mmol), one drop of HOAc (5.0 mg, 0.03 mmol) and NaBH(OAc)3 (46.0 mg, 0.22 mmol). The reaction was stirred at 25oC for 3 hrs. LCMS indicated the reaction was completed. Then the mixture was concentrated under reduced pressure to afford 6-(2,6-dioxo- 1-((2-(trimethylsilyl)ethoxy)methyl)piperidin-3-yl)-1-((3-(3-(methylamino)phenyl)-1,2,4- oxadiazol-5-yl)methyl)-1,2,3,4-tetrahydro-5H-pyrrolo[3,4-b]pyridine-5,7(6H)-dione (20 mg, yield: 40%) as a yellow solid. The crude product was used directly in the next step without further purification. LCMS (m / z): [M]+calcd, 580.25; found, 581.6.

[0190] 6-(2,6-dioxopiperidin-3-yl)-1-((3-(3-(methylamino)phenyl)-1,2,4-oxadiazol- 5-yl)methyl)-1,2,3,4-tetrahydro-5H-pyrrolo[3,4-b]pyridine-5,7(6H)-dione

[0191] To a solution of 6-(2,6-dioxo-1-((2-(trimethylsilyl)ethoxy)methyl)piperidin-3- yl)-1-((3-(3-(methylamino)phenyl)-1,2,4-oxadiazol-5-yl)methyl)-1,2,3,4-tetrahydro-5H- pyrrolo[3,4-b]pyridine-5,7(6H)-dione (50 mg, 0.09 mmol) in DCM (2.0 mL) was added TFA (2.0 mL). The reaction was stirred at rt for 1 hr. LCMS indicated the reaction was complete. Then the mixture was filtered. The filtrate was concentrated to give a residue. The residue was purified by prep-HPLC (C18, Wave length: 220nm / 254nm phase A: H2O (0.1% NH3.H2O); phase B: MECN 25%-95%, 10 min / 18 min) and prep-HPLC (C18, Wave length: 220nm / 254nm phase A: H2O (0.1% FA); phase B: MECN 20%-95%, 12 min / 25 min) to give6-(2,6-dioxopiperidin-3-yl)-1-((3-(3-(methylamino)phenyl)-1,2,4-oxadiazol-5-yl)methyl)- 1,2,3,4-tetrahydro-5H-pyrrolo[3,4-b]pyridine-5,7(6H)-dione (2.0 mg, yield: 5.16%) as a yellow solid. LCMS (m / z): [M]+calcd, 450.17; found, 451.1;1H NMR (400 MHz, DMSO- d6) " 10.98 (s, 1H), 7.25 (t, J = 8.0 Hz, 1H), 7.20 – 7.08 (m, 2H), 6.78 – 6.66 (m, 1H), 6.01 (q, J = 5.1 Hz, 1H), 5.29 (s, 2H), 4.84 (dd, J = 12.9, 5.4 Hz, 1H), 3.50 – 3.45 (m, 2H), 2.85 – 2.76 (m, 1H), 2.71 (d, J = 5.0 Hz, 3H), 2.56 – 2.52 (m, 1H), 2.44 – 2.35 (m, 1H), 2.27 (t, J = 5.8 Hz, 2H), 1.94 – 1.85 (m, 3H).

[0192] Compounds below may be synthesized utilizing General Method G.

[0193] 6-(2,6-dioxopiperidin-3-yl)-1-((3-(3-hydroxyphenyl)-1,2,4-oxadiazol-5- yl)methyl)-1,2,3,4-tetrahydro-5H-pyrrolo[3,4-b]pyridine-5,7(6H)-dione (Compound 140)

[0194] Preparation of 6-(2,6-dioxopiperidin-3-yl)-1-((3-(3-hydroxyphenyl)-1,2,4- oxadiazol-5-yl)methyl)-1,2,3,4-tetrahydro-5H-pyrrolo[3,4-b]pyridine-5,7(6H)-dione

[0195] A solution of 6-(2,6-dioxopiperidin-3-yl)-1-((3-(3-methoxyphenyl)-1,2,4-oxadiazol-5-yl)methyl)-1,2,3,4-tetrahydro-5H-pyrrolo[3,4-b]pyridine-5,7(6H)-dione (15 mg,0.03 mmol) in BBr3 / DCM (1:4, 2 mL) was stirred at room temperature for 30 min. 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; phase B: MECN 25%-95%, 9 min / 18 min) to give 6-(2,6-dioxopiperidin-3-yl)-1-((3-(3- hydroxyphenyl)-1,2,4-oxadiazol-5-yl)methyl)-1,2,3,4-tetrahydro-5H-pyrrolo[3,4-b]pyridine- 5,7(6H)-dione (4.7 mg, 0.01 mmol, yield: 36%) as a yellow solid. LCMS (m / z): [M]+ calcd: 437.13, found: 438.10;1H NMR (400 MHz, DMSO-d6) " 10.98 (s, 1H), 9.85 (s, 1H), 7.44 – 7.39 (m, 2H), 7.35 (t, J = 7.8 Hz, 1H), 6.97 (m, J = 8.1, 2.5, 1.1 Hz, 1H), 5.30 (s, 2H), 4.84 (dd, J = 12.9, 5.4 Hz, 1H), 3.48 (d, J = 4.9 Hz, 2H), 2.80 (m, J = 17.1, 14.0, 5.4 Hz, 1H), 2.53 (d, J = 3.4 Hz, 1H), 2.44 – 2.35 (m, 1H), 2.27 (t, J = 5.8 Hz, 2H), 1.95 – 1.86 (m, 3H).

[0196] 1-((3-(3-aminophenyl)-1,2,4-oxadiazol-5-yl)methyl)-6-(2,6-dioxopiperidin-3- yl)-1,2,3,4-tetrahydro-5H-pyrrolo[3,4-b]pyridine-5,7(6H)-dione (Compound 141)

[0197] 1-((3-(3-aminophenyl)-1,2,4-oxadiazol-5-yl)methyl)-6-(2,6-dioxo-1-((2- (trimethylsilyl)ethoxy)methyl)piperidin-3-yl)-1,2,3,4-tetrahydro-5H-pyrrolo[3,4- b]pyridine-5,7(6H)-dione

[0198] To a solution of 6-(2,6-dioxo-1-((2-(trimethylsilyl)ethoxy)methyl)piperidin-3- yl)-1-((3-(3-nitrophenyl)-1,2,4-oxadiazol-5-yl)methyl)-1,2,3,4-tetrahydro-5H-pyrrolo[3,4- b]pyridine-5,7(6H)-dione (60 mg, 0.10 mmol) in EtOH (2.0 mL) and H2O (2.0 mL) were added NH4Cl (11.0 mg, 0.20 mmol) and Zinc powder (13.0 mg, 0.20 mmol). The mixture was stirred at rt for 2hrs. LCMS indicated the reaction was complete. Then the mixture was quenched with NH4Cl solution and extracted with EA. The organic layer was dried over anhydrous Na2SO4and concentrated to give a residue. The residue was purified by prep-TLC (silica gel, PE:EA=3:1, Rf=0.5) to afford 1-((3-(3-aminophenyl)-1,2,4-oxadiazol-5- yl)methyl)-6-(2,6-dioxo-1-((2-(trimethylsilyl)ethoxy)methyl)piperidin-3-yl)-1,2,3,4- tetrahydro-5H-pyrrolo[3,4-b]pyridine-5,7(6H)-dione (40 mg, yield: 70.19%) as a yellow solid. LCMS (m / z): [M]+calcd, 566.23; found, 567.5 (M+H)+.

[0199] 1-((3-(3-aminophenyl)-1,2,4-oxadiazol-5-yl)methyl)-6-(2,6-dioxopiperidin-3- yl)-1,2,3,4-tetrahydro-5H-pyrrolo[3,4-b]pyridine-5,7(6H)-dione

[0200] To a solution of 1-((3-(3-aminophenyl)-1,2,4-oxadiazol-5-yl)methyl)-6-(2,6- dioxo-1-((2-(trimethylsilyl)ethoxy)methyl)piperidin-3-yl)-1,2,3,4-tetrahydro-5H-pyrrolo[3,4- b]pyridine-5,7(6H)-dione (40 mg, 0.07 mmol) in DCM (2.0 mL) was added TFA (2.0 mL,0.07 mmol). The mixture was stirred at rt for 1h. LCMS indicated the reaction was complete. Then the mixture was concentrated to give a residue and it was purified by prep-HPLC (C18, Wave length: 220nm / 254nm phase A: H2O (0.1% NH3.H2O); phase B: MECN 15%-95%, 10 min / 20 min) to give 1-((3-(3-aminophenyl)-1,2,4-oxadiazol-5-yl)methyl)-6-(2,6- dioxopiperidin-3-yl)-1,2,3,4-tetrahydro-5H-pyrrolo[3,4-b]pyridine-5,7(6H)-dione (6.0 mg, yield: 19%) as a yellow solid. LCMS (m / z): [M]+calcd, 436.15; found, 437.1 (M+H)+;1H NMR (400 MHz, DMSO-d6) " 10.98 (s, 1H), 7.25 – 7.21 (m, 1H), 7.17 (t, J = 7.7 Hz, 1H), 7.11 (d, J = 7.7 Hz, 1H), 6.76 – 6.70 (m, 1H), 5.41 (s, 2H), 5.28 (s, 2H), 4.84 (dd, J = 13.0, 5.4 Hz, 1H), 3.55 – 3.42 (m, 2H), 2.87 – 2.73 (m, 1H), 2.55 – 2.52 (m, 1H), 2.38 (dd, J = 13.4, 4.3 Hz, 1H), 2.27 (t, J = 6.0 Hz, 2H), 1.90 (dt, J = 11.2, 4.0 Hz, 3H).

[0201] Compound 145: 6-(2,6-dioxopiperidin-3-yl)-1-((3-(3-ethylphenyl)-1,2,4- oxadiazol-5-yl)methyl)-1,2,3,4-tetrahydro-5H-pyrrolo[3,4-b]pyridine-5,7(6H)-dione

[0202] Preparation of 6-(2,6-dioxopiperidin-3-yl)-1-((3-(3-vinylphenyl)-1,2,4- oxadiazol-5-yl)methyl)-1,2,3,4-tetrahydro-5H-pyrrolo[3,4-b]pyridine-5,7(6H)-dione

[0203] To a solution of 6-(2,6-dioxo-1-((2-(trimethylsilyl)ethoxy)methyl)piperidin-3- yl)-1-((3-(3-vinylphenyl)-1,2,4-oxadiazol-5-yl)methyl)-1,2,3,4-tetrahydro-5H-pyrrolo[3,4- b]pyridine-5,7(6H)-dione (140 mg, 0.24 mmol) in DCM (4 mL) was added TFA (2 mL) at rt under N2. The mixture was stirred at 25oC for 1 hour. The mixture was concentrated and purified by prep-HPLC (C18, Wave length: 220nm / 254nm phase A: H2O (0.1% NH); phase B: MECN 25%-95%, 12 min) to give 6-(2,6-dioxopiperidin-3-yl)-1-((3-(3-vinylphenyl)- 1,2,4-oxadiazol-5-yl)methyl)-1,2,3,4-tetrahydro-5H-pyrrolo[3,4-b]pyridine-5,7(6H)-dione(68 mg, 0.15 mmol, yield: 62.71%) as a yellow solid LCMS (m / z): [M]- calcd:447.15, found:448.13.

[0204] Preparation of 6-(2,6-dioxopiperidin-3-yl)-1-((3-(3-ethylphenyl)-1,2,4- oxadiazol-5-yl)methyl)-1,2,3,4-tetrahydro-5H-pyrrolo[3,4-b]pyridine-5,7(6H)-dione

[0205] To a solution of 6-(2,6-dioxopiperidin-3-yl)-1-((3-(3-vinylphenyl)-1,2,4- oxadiazol-5-yl)methyl)-1,2,3,4-tetrahydro-5H-pyrrolo[3,4-b]pyridine-5,7(6H)-dione (68 mg, 0.15 mmol) in THF (5 mL ) was added Pd / C (10%, 15 mg ) under H2. The suspension was degassed under vacuum and purged with H2for 3 times. The mixture was stirred under H2balloon at rt for 1 hr. The reaction was complete determined by LCMS. The suspension was filtered and the filter cake was washed with THF. The mixture was concentrated and purified by prep-HPLC (C18, Wave length: 220nm / 254nm phase A: H2O (0.1% FA); phase B: MECN 25%-95%, 12 min) to give 6-(2,6-dioxopiperidin-3-yl)-1-((3-(3-ethylphenyl)-1,2,4-oxadiazol- 5-yl)methyl)-1,2,3,4-tetrahydro-5H-pyrrolo[3,4-b]pyridine-5,7(6H)-dione (17.2 mg, yield: 25.3%) as a yellow solid LCMS (m / z): [M]- calcd:449.17, found:450.13.1H NMR (400 MHz, DMSO-d6) " 10.98 (s, 1H), 7.90 – 7.78 (m, 2H), 7.54 – 7.41 (m, 2H), 5.31 (s, 2H), 4.84 (dd, J = 12.9, 5.4 Hz, 1H), 3.49 (t, J = 5.5 Hz, 2H), 2.80 (ddd, J = 17.1, 13.9, 5.4 Hz, 1H), 2.70 (q, J = 7.6 Hz, 2H), 2.53 (d, J = 4.1 Hz, 1H), 2.45 – 2.32 (m, 1H), 2.27 (t, J = 6.1 Hz, 2H), 1.95 – 1.86 (m, 3H), 1.21 (t, J = 7.6 Hz, 3H).

[0206] (2,6-dioxopiperidin-3-yl)-1-((3-phenyl-1,2,4-oxadiazol-5-yl) methyl)-1,2,3,4- tetrahydro-5H-pyrrolo[3,4-b]pyrazine-5,7(6H)-dione (Compound 142)

[0207] Preparation of 6-(2,6-dioxopiperidin-3-yl)-5H-pyrrolo[3,4-b]pyrazine- 5,7(6H)-dione

[0208] To a solution of furo[3,4-b]pyrazine-5,7-dione (5.0g, 33.3 mmol) in HOAc (50 mL) were added 3-aminopiperidine-2,6-dione (4.3 g, 33.3 mmol) and NaOAc (4.13 g, 66.6 mmol), and the reaction was stirred at 80oC for 12 hours. LCMS indicated the reaction was completed. Then the mixture was quenched with ice water and filtered. The filter cake was washed with water and dried under high vacuum to give 6-(2,6-dioxopiperidin-3-yl)-5H- pyrrolo[3,4-b]pyrazine-5,7(6H)-dione (4.33 g, 16.6 mmol, yield: 50%) as a grey solid. LCMS (m / z): [M]+calcd: 260.05, found: 261.3;1H NMR (400 MHz, DMSO-d6) " 11.19 (s, 1H), 9.08 (s, 2H), 5.31 (dd, J = 12.8, 5.4 Hz, 1H), 2.91 (ddd, J = 17.3, 13.9, 5.4 Hz, 1H), 2.64 (ddd, J = 17.1, 4.1, 2.4 Hz, 1H), 2.58 – 2.50 (m, 1H), 2.10 (dtd, J = 13.0, 5.3, 2.3 Hz, 1H).

[0209] Preparation of 6-(2,6-dioxo-1-((2-(trimethylsilyl)ethoxy)methyl)piperidin-3- yl)-5H-pyrrolo[3,4-b]pyrazine-5,7(6H)-dione

[0210] To a solution of 6-(2,6-dioxopiperidin-3-yl)-5H-pyrrolo[3,4-b]pyrazine-5,7(6H)- dione (0.5 g, 1.92 mmol) in DMF (5.0 mL) was added portionwise NaH (0.09 g, 3.84 mmol, 60% in mineral oil) at 0oC. The mixture was stirred at 0oC for 30 min, followed by addition of SEMCl (0.51 g, 3.07 mmol). The resulting mixture was warmed to room temperature and stirred for 60 min. LCMS indicated the reaction was completed. The mixture was cooled to 0oC and quenched with HOAc and ice water. The mixture was extracted with EA (5.0 mL*3). The combined organic layers were dried over anh. Na2SO4 and concentrated by high vacuum to give a residue. The residue was purified by FCC (silica gel, 10~50% EA in PE) to give 6- (2,6-dioxo-1-((2-(trimethylsilyl)ethoxy)methyl)piperidin-3-yl)-5H-pyrrolo[3,4-b]pyrazine- 5,7(6H)-dione (393 mg, 1.01 mmol, yield: 54.63%) as a pale yellow oil. LCMS (m / z): [M]- calcd: 390.14, found: 389.4.

[0211] Preparation of 6-(2,6-dioxo-1-((2-(trimethylsilyl)ethoxy)methyl)piperidin-3- yl)-1,2,3,4-tetrahydro-5H-pyrrolo[3,4-b] pyrazine-5,7(6H)-dione

[0212] To a solution of 6-(2,6-dioxo-1-((2-(trimethylsilyl)ethoxy)methyl)piperidin-3- yl)-5H-pyrrolo[3,4-b]pyrazine-5,7(6H)-dione (540 mg, 1.38 mmol) in THF (25 mL) was added Pd / C (324 mg) and AcOH (0.8 mL) under N2. The suspension was degassed under vacuum and purged with H2for 3 times. The mixture was stirred under Hydrogen bag at room temperature overnight. The reaction was completed determined by LCMS. The suspension was filtered and the filter cake was washed with DCM. The combined filtrates were concentrated to dryness to give 6-(2,6-dioxo-1-((2- (trimethylsilyl)ethoxy)methyl)piperidin-3-yl)-1,2,3,4-tetrahydro-5H-pyrrolo[3,4-b]pyrazine- 5,7(6H)-dione (272 mg, 0.689 mmol, yield: 50%) as a yellowish-brown oil. LCMS (m / z): [M]- calcd: 394.17, found: 393.0.

[0213] Preparation of 6-(2,6-dioxo-1-((2-(trimethylsilyl)ethoxy)methyl)piperidin-3- yl)-1-((3-phenyl-1,2,4-oxadiazol-5-yl)methyl)-1,2,3,4-tetrahydro-5H-pyrrolo[3,4- b]pyrazine-5,7(6H)-dione

[0214] To a mixture of 6-(2,6-dioxo-1-((2-(trimethylsilyl)ethoxy)methyl)piperidin-3- yl)-1,2,3,4-tetrahydro-5H-pyrrolo[3,4-b]pyrazine-5,7(6H)-dione (320 mg, 0.81 mmol) in DMF (4.0 mL) were added 5-(chloromethyl)-3-phenyl-1,2,4-oxadiazole (316 mg, 1.62 mmol) and DBU (247 mg, 1.62 mmol) under the atmosphere of nitrogen. The reaction mixture was stirred at r.t. overnight. The reaction was monitored by LCMS. The mixture was quenched with water and extracted with EA for 3 times. The combined organic layers were dried over anhydrous Na2SO4and concentrated to give a residue. The residue was purified by FCC (silica gel, 40~50% EA in PE) to give 6-(2,6-dioxo-1-((2- (trimethylsilyl)ethoxy)methyl)piperidin-3-yl)-1-((3-phenyl-1,2,4-oxadiazol-5-yl)methyl)- 1,2,3,4-tetrahydro-5H-pyrrolo[3,4-b]pyrazine-5,7(6H)-dione (97 mg, 0.176 mmol, yield: 22%) as a red oil. LCMS (m / z): [M]- calcd: 552.22, found: 551.3.

[0215] Preparation of 6-(2,6-dioxopiperidin-3-yl)-1-((3-phenyl-1,2,4-oxadiazol-5- yl)methyl)-1,2,3,4-tetrahydro-5H-pyrrolo[3,4-b]pyrazine-5,7(6H)-dione

[0216] To a solution of 6-(2,6-dioxo-1-((2-(trimethylsilyl)ethoxy)methyl)piperidin-3- yl)-1-((3-phenyl-1,2,4-oxadiazol-5-yl)methyl)-1,2,3,4-tetrahydro-5H-pyrrolo[3,4-b]pyrazine- 5,7(6H)-dione (25 mg, 0.045 mmol) in DCM (3.0 mL) was added TFA (1.0 mL). The solution was stirred at r.t. for 15 min. The reaction was monitored by LCMS. The resulting mixture was concentrated under vacuum. The residue was purified by prep-HPLC (C18, Wave length: 220nm / 254nm; phase A: H2O (0.1% NH3·H2O); phase B: MeCN 25%-95%, 10.5 min / 20 min) to afford 6-(2,6-dioxopiperidin-3-yl)-1-((3-phenyl-1,2,4-oxadiazol-5- yl)methyl)-1,2,3,4-tetrahydro-5H-pyrrolo[3,4-b]pyrazine-5,7(6H)-dione (11.1 mg, 0.026 mmol, yield: 57.78%) as a red solid. LCMS (m / z): [M]+calcd: 422.13, found: 423.3;1H NMR (400 MHz, DMSO-d6) " 10.97 (s, 1H), 8.02 (d, J = 1.4 Hz, 1H), 8.00 – 7.99 (m, 1H), 7.61 – 7.55 (m, 3H), 6.82 (s, 1H), 4.85 (s, 2H), 4.78 (dd, J = 13.0, 5.4 Hz, 1H), 3.24 (s, 4H), 2.85 – 2.76 (m, 1H), 2.56 – 2.52 (m, 1H), 2.43 – 2.33 (m, 1H), 1.96 – 1.88 (m, 1H).

[0217] Preparation of 6-(2,6-dioxopiperidin-3-yl)-1-methyl-4-((3-phenyl-1,2,4- oxadiazol-5-yl)methyl)-1,2,3,4-tetrahydro-5H-pyrrolo[3,4-b]pyrazine-5,7(6H)-dione (Compound 143)

[0218] Preparation of 6-(2,6-dioxo-1-((2-(trimethylsilyl)ethoxy)methyl)piperidin-3- yl)-1-methyl-4-((3-phenyl-1,2,4-oxadiazol-5-yl)methyl)-1,2,3,4-tetrahydro-5H- pyrrolo[3,4-b]pyrazine-5,7(6H)-dione

[0219] To a solution of 6-(2,6-dioxo-1-((2-(trimethylsilyl)ethoxy)methyl)piperidin-3- yl)-1-((3-phenyl-1,2,4-oxadiazol-5-yl)methyl)-1,2,3,4-tetrahydro-5H-pyrrolo[3,4-b]pyrazine- 5,7(6H)-dione (65 mg, 0.12 mmol) in DMF (2.0 mL) was added DBU (36.0 mg, 0.24 mmol). Then to the mixture was added dropwise methyl iodide (25.0 mg, 0.18 mmol) at 0oC. The reaction mixture was stirred for 2 hours at rt. The reaction was monitored by LCMS. The resulting mixture was concentrated in vacuo and the residue was purified by prep-TLC (silica gel, PE:EA=1:1, Rf=0.5) to afford 6-(2,6-dioxo-1-((2- (trimethylsilyl)ethoxy)methyl)piperidin-3-yl)-1-methyl-4-((3-phenyl-1,2,4-oxadiazol-5- yl)methyl)-1,2,3,4-tetrahydro-5H-pyrrolo[3,4-b]pyrazine-5,7(6H)-dione (15 mg, 0.026 mmol, yield: 22.22%) as a brown solid. LCMS (m / z): [M]- calcd: 566.23, found: 565.3.

[0220] Preparation of 6-(2,6-dioxopiperidin-3-yl)-1-methyl-4-((3-phenyl-1,2,4- oxadiazol-5-yl)methyl)-1,2,3,4-tetrahydro-5H-pyrrolo[3,4-b]pyrazine-5,7(6H)-dione

[0221] To a solution of 6-(2,6-dioxo-1-((2-(trimethylsilyl)ethoxy)methyl)piperidin-3- yl)-1-methyl-4-((3-phenyl-1,2,4-oxadiazol-5-yl)methyl)-1,2,3,4-tetrahydro-5H-pyrrolo[3,4- b]pyrazine-5,7(6H)-dione (15 mg, 0.026 mmol) in DCM (1.0 mL) was added TFA (3.0 mL). The solution was stirred at r.t. for 15 min. The reaction was monitored by LCMS. The resulting mixture was concentrated under vacuum. The residue was purified by prep-HPLC (C18, Wave length: 220nm / 254nm; phase A: H2O (0.1% NH3·H2O); phase B: MeCN 25%- 95%, 10.5 min / 20 min) to afford 6-(2,6-dioxopiperidin-3-yl)-1-methyl-4-((3-phenyl-1,2,4- oxadiazol-5-yl)methyl)-1,2,3,4-tetrahydro-5H-pyrrolo[3,4-b]pyrazine-5,7(6H)-dione (3.9 mg, 0.0089 mmol, yield: 34.23%) as a red solid. LCMS (m / z): [M]+calcd: 436.15, found: 437.2;1H NMR (400 MHz, DMSO-d6) " 10.96 (s, 1H), 8.01 (d, J = 1.5 Hz, 1H), 7.99 (d, J = 1.9 Hz, 1H), 7.60 – 7.55 (m, 3H), 4.95 (s, 2H), 4.79 (dd, J = 13.0, 5.4 Hz, 1H), 3.34 (d, J = 3.9 Hz,2H), 3.18 (dd, J = 5.0, 3.2 Hz, 2H), 3.02 (s, 3H), 2.83 – 2.75 (m, 1H), 2.55 – 2.51 (m, 1H), 2.41 – 2.33 (m, 1H), 1.94 – 1.88 (m, 1H).

[0222] Compound 144: 6-(2,6-dioxopiperidin-3-yl)-4-methyl-1-((3-phenyl-1,2,4- oxadiazol-5-yl)methyl)-1,2,3,4-tetrahydro-5H-pyrrolo[3,4-b]pyridine-5,7(6H)-dione

[0223] Preparation of 4-chloropyridine-2,3-dicarboxylic acid

[0224] To a solution of 4-chloroquinoline (5.0 g, 30.67 mmol) in water (300 mL) was added KMnO4 (305 mg, 306.7 mmol) under N2 atmosphere. The reaction was stirred at 100oC for 16h. LCMS showed the reaction was completed. The mixture was adjusted pH to 1 with 6N HCl and then concentrated under reduced pressure. The residue was dissolved with DCM / MeOH (10:1, 200 mL×3), filtered and concentrated under reduced pressure to give a crude product of 4-chloropyridine-2,3-dicarboxylic acid (1.9 g, 9.45 mmol, 30.82%) as a white solid. LCMS (m / z): [M]- calcd: 200.98, found: 200.0.

[0225] Preparation of 4-chlorofuro[3,4-b]pyridine-5,7-dione

[0226] A solution of 4-chloropyridine-2,3-dicarboxylic acid (1.9 g, 9.45 mmol) and DIPEA (252 mg, 1.95 mmol) in Ac2O (30 mL) was stirred at 130oC for 3 hours. The resulting mixture was concentrated under reduced pressure to give 4-chlorofuro[3,4-b]pyridine-5,7-dione (1.4 g, 7.65 mmol, 80.94%) as a white solid. LCMS (m / z): [M]+calcd: 182.97, found: 184.1.

[0227] Preparation of 4-chloro-6-(2,6-dioxopiperidin-3-yl)-5H-pyrrolo[3,4- b]pyridine-5,7(6H)-dione

[0228] To a solution of 4-chlorofuro[3,4-b]pyridine-5,7-dione (1.4 g, 7.65 mmol) and NaOAc (1.3 g, 15.30 mmol) in AcOH (40 mL) was added 3-aminopiperidine-2,6-dione hydrochloride (100 mg, 0.53 mmol) and the reaction was stirred at 80oC for 16 hour. LCMS showed the reaction was completed. The reaction was concentrated under reduced pressure. The residue was purified using silica gel column chromatography (PE:EA=3:1) to give 4- chloro-6-(2,6-dioxopiperidin-3-yl)-5H-pyrrolo[3,4-b]pyridine-5,7(6H)-dione (830 mg, 2.83 mmol, 37.02%) as a white solid. LCMS (m / z): [M]+calcd: 293.02, found: 294.0.

[0229] Preparation of 4-chloro-6-(2,6-dioxo-1-((2- (trimethylsilyl)ethoxy)methyl)piperidin-3-yl)-5H-pyrrolo[3,4-b]pyridine-5,7(6H)-dione

[0230] At 0oC, to a solution of 4-chloro-6-(2,6-dioxopiperidin-3-yl)-5H-pyrrolo[3,4- b]pyridine-5,7(6H)-dione (830 mg, 2.83 mmol) in DMF (10 mL) was added NaH (60% in mineral oil, 226 mg, 5.66 mmol) and the reaction was stirred at room temperature for 1 hour. Then SEMCl (707 mg, 4.24 mmol) was added and the reaction mixture was stirred at room temperature for 1 hour. LCMS showed the reaction was completed. The reaction was quenched with ice aqueous NH4Cl and extracted with EA (15 mL × 3). The organic layer was dried over Na2SO4and concentrated under reduced pressure. The residue was purified using silica gel column chromatography (PE:EA=3:1) to give 4-chloro-6-(2,6-dioxo-1-((2-(trimethylsilyl)ethoxy)methyl)piperidin-3-yl)-5H-pyrrolo[3,4-b]pyridine-5,7(6H)-dione (870 mg, 2.06 mmol, 72.59%) as a white solid. LCMS (m / z): [M]- calcd: 423.10, found: 422.0.

[0231] Preparation of 6-(2,6-dioxo-1-((2-(trimethylsilyl)ethoxy)methyl)piperidin-3-yl)-4-methyl-5H-pyrrolo[3,4-b]pyridine-5,7(6H)-dione

[0232] A mixture of 4-chloro-6-(2,6-dioxo-1-((2- (trimethylsilyl)ethoxy)methyl)piperidin-3-yl)-5H-pyrrolo[3,4-b]pyridine-5,7(6H)-dione (870 mg, 2.06 mmol), methylboronic acid (370 mg, 6.18 mmol), K3PO4 (1.3 g, 6.18 mmol) and Pd(dppf)Cl2 (154 mg, 0.21 mmol) in dioxane (15 mL) was stirred at 110 °C for 1 hour. LCMS showed the reaction was complete. The reaction was diluted with H2O and extracted with EA. The organic layer was concentrated under reduced pressure and concentrated under reduced pressure. The residue was purified using silica gel column chromatography (PE:EA=3:1) to give 6-(2,6-dioxo-1-((2-(trimethylsilyl)ethoxy)methyl)piperidin-3-yl)-4- methyl-5H-pyrrolo[3,4-b]pyridine-5,7(6H)-dione (570 mg, 1.41 mmol, 68.76%) as a yellow solid. LCMS (m / z): [M]- calcd: 403.16, found: 402.1.

[0233] Preparation of 6-(2,6-dioxo-1-((2-(trimethylsilyl)ethoxy)methyl)piperidin-3-yl)-4-methyl-1,2,3,4-tetrahydro-5H-pyrrolo[3,4-b]pyridine-5,7(6H)-dione

[0234] To a solution of 6-(2,6-dioxo-1-((2-(trimethylsilyl)ethoxy)methyl)piperidin-3- yl)-4-methyl-5H-pyrrolo[3,4-b]pyridine-5,7(6H)-dione (570 mg, 1.41 mmol) in THF (15 mL) was added Pd / C (10%, 570 mg). The mixture was stirred at 50 °C for 16 hours. LCMS showed the reaction was complete. The reaction was filtered and concentrated under reduced pressure. The residue was purified using silica gel column chromatography (PE:EA=1:1) to give 6-(2,6-dioxo-1-((2-(trimethylsilyl)ethoxy)methyl)piperidin-3-yl)-4-methyl-1,2,3,4-tetrahydro-5H-pyrrolo[3,4-b]pyridine-5,7(6H)-dione (230 mg, 0.56 mmol, 39.95%) as a yellow solid. LCMS (m / z): [M]- calcd: 407.19, found: 406.1.

[0235] Preparation of 6-(2,6-dioxo-1-((2-(trimethylsilyl)ethoxy)methyl)piperidin-3-yl)-4-methyl-1-((3-phenyl-1,2,4-oxadiazol-5-yl)methyl)-1,2,3,4-tetrahydro-5H- pyrrolo[3,4-b]pyridine-5,7(6H)-dione

[0236] To a solution of 5-(chloromethyl)-3-phenyl-1,2,4-oxadiazole (108 mg, 0.56 mmol) in MeCN (3 mL) were added potassium iodide (171.70 mg, 1.03 mmol), potassium carbonate (142.96 mg, 1.03 mmol) and 6-(2,6-dioxo-1-((2- (trimethylsilyl)ethoxy)methyl)piperidin-3-yl)-4-methyl-1,2,3,4-tetrahydro-5H-pyrrolo[3,4- b]pyridine-5,7(6H)-dione (150 mg, 0.56 mmol). The reaction was stirred at 90°C for 3 hours. LCMS showed the reaction was completed. The reaction mixture was concentrated under reduced pressure. Water (15 mL) was added and the mixture was extracted with EA (15 mL x 3). The combined organic layer was washed with brine (5 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a crude product which was purified by flash chromatography (PE:EA=1:1) to afford 6-(2,6-dioxo-1-((2- (trimethylsilyl)ethoxy)methyl)piperidin-3-yl)-4-methyl-1-((3-phenyl-1,2,4-oxadiazol-5- yl)methyl)-1,2,3,4-tetrahydro-5H-pyrrolo[3,4-b]pyridine-5,7(6H)-dione (30 mg, 0.05 mmol, 14.41%) as a yellow solid. LCMS (m / z): [M]- calcd: 565.24, found: 564.2.

[0237] Preparation of 6-(2,6-dioxopiperidin-3-yl)-4-methyl-1-((3-phenyl-1,2,4- oxadiazol-5-yl)methyl)-1,2,3,4-tetrahydro-5H-pyrrolo[3,4-b]pyridine-5,7(6H)-dione

[0238] To a solution of 6-(2,6-dioxo-1-((2-(trimethylsilyl)ethoxy)methyl)piperidin-3- yl)-4-methyl-1-((3-phenyl-1,2,4-oxadiazol-5-yl)methyl)-1,2,3,4-tetrahydro-5H-pyrrolo[3,4- b]pyridine-5,7(6H)-dione (30 mg, 0.05 mmol) in DCM (2 mL) was added trifluoroacetic acid (1 mL). The reaction was stirred at room temperature for 3 hours. LCMS showed the reaction was completed. Then the reaction was purified by prep-HPLC (C18, Wave length: 220nm / 254nm phase A: H2O (0.5% HCL); phase B: MeCN 10%-95%, 10 min / 20 min) to give 6-(2,6-dioxopiperidin-3-yl)-4-methyl-1-((3-phenyl-1,2,4-oxadiazol-5-yl)methyl)-1,2,3,4- tetrahydro-5H-pyrrolo[3,4-b]pyridine-5,7(6H)-dione (22 mg, 0.04 mmol, 55.07%) as a white solid. LCMS (m / z): [M]+calcd: 435.15, found: 436.4.1H NMR (400 MHz, DMSO) " 10.97 (s, 1H), 8.04 – 7.97 (m, 2H), 7.63 – 7.55 (m, 3H), 5.40 – 5.28 (m, 2H), 4.84 (ddd, J = 12.9, 5.3, 3.2 Hz, 1H), 3.50 (d, J = 5.1 Hz, 2H), 2.85 – 2.75 (m, 1H), 2.71 – 2.66 (m, 1H), 2.53 (s, 1H), 2.37 (dd, J = 17.6, 7.7 Hz, 1H), 1.94 (dd, J = 13.7, 5.8 Hz, 2H), 1.71 – 1.60 (m, 1H), 1.16 (dd, J = 6.8, 3.4 Hz, 3H). Biochemical Assays

[0239] In Vitro TR-FRET ternary – ALK Mutant (Mut) CRBN:

[0240] 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-1,2,4-oxadiazol-5-yl)methyl]amino}-2,5-dioxo-3-pyrrolin-1-yl)-2,6- piperidinedione (“Control 1”; final concentration 10 µM) 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 50mM 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-1,2,4-oxadiazol-5-yl)methyl]amino}-2,5-dioxo-3-pyrrolin-1-yl)-2,6- piperidinedione (100% activity). Normalized data for each compound were then subjected to a 4-parameter logistic fit.

[0241] In Vitro TR-FRET ternary – ALK Mutant (Mut) CRBN (v3):

[0242] 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 2-(2,6- dioxo-3-piperidyl)-4-[(3-phenyl-1,2,4-oxadiazol-5-yl)methyl]-2,4-diaza-4,5,6,7-tetrahydro- 1H-indene-1,3(2H)-dione (“Control 2”; final concentration 20 µM) 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-1,2,4-oxadiazol-5-yl)methyl]-2,4- diaza-4,5,6,7-tetrahydro-1H-indene-1,3(2H)-dione (100% activity). Normalized data for each compound were then subjected to a 4-parameter logistic fit.

[0243] 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 1143 +

[0244] The contents of all references (including literature references, issued patents, published patent applications, and co-pending patent applications) cited throughout this application are hereby expressly incorporated herein in their entireties by reference. Unless otherwise defined, all technical and scientific terms used herein are accorded the meaning commonly known to one with ordinary skill in the art.

Claims

Listing of Claims:

1. A compound having the structural formula I:or a pharmaceutically acceptable salt thereof, wherein the dotted line represents and single or double bond;a monocyclic heteroaryl or monocyclic heterocyclyl; R1is selected from cyano, halo, (C1-C4)alkyl, halo(C1-C4)alkyl, (C1-C4)alkoxy, halo(C1-C4)alkoxy, hydroxy, (C1-C4)alkyleneOH, -NRX1RY1, and (C1-C4)alkyleneNRX1RY1, - C(O)NRX1RY1, -C(O)RX1, and -C(O)ORX1; z is 0, 1, 2, 3, or 4R3and R3aare each independently hydrogen or (C1-C4)alkyl; or R3and R3aare taken together to from a cycloalkyl or heterocyclyl, each optionally substituted with 1 to 3 groups selected from halo, (C1-C4)alkyl, halo(C1-C4)alkyl, (C1-C4)alkoxy, halo(C1-C4)alkoxy, and cyano; v is 1, 2, or 3; Y is aryl, heteroaryl or heterocyclyl, each optionally substituted with 1 to 3 groups selected from RA; R2is absent or is aryl, cycloalkyl, or heteroaryl, each of which are optionally substituted with 1 to 4 groups selected from RB; RAis selected from cyano, halo, (C1-C4)alkyl, halo(C1-C4)alkyl, (C1-C4)alkoxy, and halo(C1-C4)alkoxy; RBis selected from halo, (C1-C4)alkyl, halo(C1-C4)alkyl, (C1-C4)alkoxy, halo(C1- C4)alkoxy, hydroxy, (C1-C4)alkyleneOH, (C1-C4)alkylene(C1-C4)alkoxy, -(C1-C4)alkyleneNRXRY, cyano, oxo, -(C1-C4)alkoxyNRXRY, -(C1-C4)alkyleneC(O)ORX, -(C1- C4)alkoxyC(O)ORX, -(C1-C4)alkyleneC(O)RX, -(C1-C4)alkoxyC(O)RX, -(C1- C4)alkyleneheterocyclyl, -(C1-C4)alkyleneheteroaryl, -(C1-C4)alkoxyheterocyclyl, -(C1- C4)alkoxyheteroaryl, -(C1-C4)alkylenecycloalkyl, -(C1-C4)alkoxycycloalkyl, -(C1- C4)alkylenephenyl, -(C1-C4)alkoxyphenyl -NRX(C1-C4)alkyleneheteroaryl, -NRX(C1- C4)alkyleneheterocyclyl, -NRX(C1-C4)alkylenecycloalkyl, cycloalkyl, heteroaryl, heterocyclyl, -NRXRY, -NRXC(O)RY, -NRXC(O)ORY, -NRX(C1-C4)alkyleneC(O)NRXRZ, - NRXC(O)NRXRZ, -(C1-C4)alkyleneNRXC(O)RY, -(C1-C4)alkyleneNRXC(O)ORY, -(C1- C4)alkyleneNRX(C1-C4)alkyleneC(O)NRXRZ, -(C1-C4)alkyleneNRXC(O)NRXRZ, -(C1- C4)alkoxyNRXC(O)RY, -(C1-C4)alkoxyNRXC(O)ORY, -(C1-C4)alkoxyNRX(C1- C4)alkyleneC(O)NRXRZ, -(C1-C4)alkoxyNRXC(O)NRXRZ, -S(C1-C4)alkyl, -O(heteroaryl), - O(heterocyclyl), -O(cycloalkyl), -C(O)NRXRY, -(C1-C4)alkyleneC(O)NRXRY, -(C1- 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 (C1-C4)alkyl, halo(C1-C4)alkyl, (C1-C4)alkoxy, halo(C1-C4)alkoxy cyano, oxo, -C(O)NRX2RY2, -(C1-C4)alkyleneNRX2RY2, -C(O)NRX2RY2, -C(O)ORX2, - C(O)RX2, NRX2RY2, and hydroxy; and RX, RX1, RX2, RY, RY1, RY2, and RZare each independently selected from hydrogen, (C1-C4)alkyl, halo(C1-C4)alkyl, phenyl, benzyl, (C3-C6)cycloalkyl, 4- to 6-membered heterocyclyl, and 5- to 7-membered heteroaryl.

2. The compound of Claim 1, or a pharmaceutically acceptable salt thereof, wherein R3and R3aare each hydrogen.

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

4. The compound of any one of Claims 1 to 3, or a pharmaceutically acceptable saltthereof, whereinis a 5-membered heteroaryl or a 6-membered heterocyclyl.

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

6. The compound of any one of Claims 1 to 5, or a pharmaceutically acceptable salt thereof, wherein z is 0.

7. The compound of any one of Claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein Y is aryl or heteroaryl each of which is optionally substituted with 1 to 3 groups selected from RA.

8. The compound of any one of Claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein Y is phenyl, naphthyl, or heteroaryl each of which optionally substituted with 1 to 3 groups selected from RA.

9. The compound of any one of Claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein Y is a heteroaryl optionally substituted with 1 to 3 groups selected from RA.

10. The compound of any one of Claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein Y is a 5- to 9-membered heteroaryl optionally substituted with 1 to 3 groups selected from RA.

11. The compound of any one of Claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein Y is a 5- to 7-membered heteroaryl optionally substituted with 1 to 3 groups selected from RA.

12. The compound of any one of Claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein Y is a 5-membered heteroaryl optionally substituted with 1 to 3 groups selected from RA.

13. The compound of any one of Claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein Y is benzooxazolyl, pyrimidinyl, quinolinyl, pyrazinyl, oxazolyl, benzothiazolyl, pyridinyl, oxadiazolyl, or thiadiazolyl, each of which is optionally substituted with 1 to 3 groups selected from RA.

14. The compound of any one of Claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein Y is oxadiazolyl or thiadiazolyl, each of which is optionally substituted with 1 to 3 groups selected from RA.

15. The compound of any one of Claims 1 to 6, or a pharmaceutically acceptable saltthe attachment position to R2.

16. The compound of any one of Claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein wherein * indicates the attachment position 2to R .

17. The compound of any one of Claims 1 to 16, or a pharmaceutically acceptable salt thereof, wherein R2is aryl, cycloalkyl, 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 R2is aryl, 5- to 9-membered heteroaryl, or (C3-C6)cycloakyl, each of which are optionally substituted with 1 to 4 groups selected from RB.

19. The compound of any one of Claims 1 to 17, or a pharmaceutically acceptable salt thereof, wherein R2is phenyl, cyclohexyl, benzothiopheneyl, naphthalenyl, quinolinyl, isoquinolinyl, pyridinyl, oxazolyl, or isoxazolyl each of which are optionally substituted with 1 to 4 groups selected from RB.

20. The compound of any one of Claims 1 to 17, or a pharmaceutically acceptable salt thereof, wherein R2is phenyl, cyclohexyl, benzothiopheneyl, benzothiazolyl, thiazolyl, naphthalenyl, quinolinyl, pyridinyl, pyrimidinyl, oxazolyl, pyrazolyl, pyrrolopyrdinyl, dihydrobenzofuranyl, pyrrolopyridazinyl, dihydrobenzodioxinyl, pyrazolopyridinyl, imidazopyridinyl, benzofuranyl, indazolyl, or isoxazolyl each of which are optionally substituted with 1 to 4 groups selected from RB.

21. The compound of any one of Claims 1 to 20, or a pharmaceutically acceptable salt thereof, wherein RBis selected from halo, (C1-C4)alkyl, halo(C1-C4)alkyl, (C1-C4)alkoxy, - (C1-C4)alkyleneNRXRY, -C(O)NRXRY, -C(O)ORX, -C(O)RX, NRXRY, OH, -phenyl, heteroaryl, heterocyclyl, wherein said phenyl, heterocyclyl, and heteroaryl are optionally substituted with 1 to 3 groups selected from RC.

22. The compound of any one of Claims 1 to 20, or a pharmaceutically acceptable salt thereof, wherein RBis selected from halo, (C1-C4)alkyl, halo(C1-C4)alkyl, (C1-C4)alkoxy, - (C1-C4)alkyleneNRXRY, -C(O)NRXRY, -C(O)ORX, -C(O)RX, NRXRY, hydroxy, -phenyl, heteroaryl, heterocyclyl, wherein said phenyl, heterocyclyl, and heteroaryl 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 RBis selected from halo, (C1-C4)alkyl, (C1-C4)alkoxy, phenyl, 5- to 7- membered heteroaryl, 4- to 6-membered heterocyclyl, wherein said phenyl, 4- to 6-membered heterocyclyl, and 5- to 7-membered heteroaryl are optionally substituted with 1 to 3 groups selected from RC.

24. The compound of any one of Claims 1 to 23, or a pharmaceutically acceptable salt thereof, wherein RBis selected from halo, (C1-C4)alkyl, (C1-C4)alkoxy, phenyl, oxazolyl, pyridinyl, pyrazinyl, pyrrolidinyl, tetrahydrofuranyl, pyrimidinyl, azetidinyl, piperidinyl, thiopheneyl, thiazolyl, and 1,2-dihydropyridinyl, wherein said phenyl, oxazolyl, pyridinyl, pyrazinyl, pyrrolidinyl, tetrahydrofuranyl, pyrimidinyl, azetidinyl, piperidinyl, thiopheneyl, thiazolyl, and 1,2-dihydropyridinyl are optionally substituted with 1 to 3 groups selected from RC.

25. The compound of any one of Claims 1 to 23, or a pharmaceutically acceptable salt thereof, wherein RBis selected from halo, (C1-C4)alkyl, (C1-C4)alkoxy, phenyl, oxazolyl, pyridinyl, pyrazinyl, pyridazinyl, tetrahydropyranyl, pyrazolyl, cyclohexyl, imidazolyl, and 1,2-dihydropyridinyl, wherein said phenyl, oxazolyl, pyridinyl, pyrazinyl, pyridazinyl, tetrahydropyranyl, pyrazolyl, cyclohexyl, imidazolyl, and 1,2-dihydropyridinyl are optionally substituted with 1 to 3 groups selected from RC.

26. The compound of any one of Claims 1 to 25, or a pharmaceutically acceptable salt thereof, wherein RCis selected from (C1-C4)alkyl, halo(C1-C4)alkyl, (C1-C4)alkoxy, halo(C1- C4)alkoxy cyano, oxo, and hydroxy.

27. The compound of any one of Claims 1 to 25, or a pharmaceutically acceptable salt thereof, wherein RCis selected from halo, (C1-C4)alkyl, halo(C1-C4)alkyl, -C(O)NRX2RY2, and oxo.

28. The compound of any one of Claims 1 to 25, or a pharmaceutically acceptable salt thereof, wherein RCis selected from (C1-C4)alkyl and oxo.

29. The compound of any one of Claims 1 to 28, wherein RXand RYare each independently selected from hydrogen, (C1-C4)alkyl, and 4- to 6-membered heterocyclyl.

30. The compound of any one of Claims 1 to 29, wherein RXand RYare each independently selected from hydrogen, (C1-C4)alkyl, and pyrrolidinyl.

31. The compound of any one of Claims 1 to 29, wherein RX2and RY2are each independently selected from hydrogen and (C1-C4)alkyl.

32. The compound of any one of Claims 1 to 16, or a pharmaceutically acceptable salt thereof, wherein R2is selected from33. The compound of any one of Claims 1 to 16, or a pharmaceutically acceptable salt thereof, wherein R2is selected from, , , , ,, and .

34. The compound of any one of Claims 1 to 16, or a pharmaceutically acceptable salt thereof, wherein R2is selected from35. The compound of Claim 1, wherein the compound is selected from any one of Compounds 1 to 212; or a pharmaceutically acceptable salt thereof.

36. A pharmaceutical composition comprising a compound of any one of Claims 1 to 35, or a pharmaceutically acceptable salt.

37. A method of treating a condition responsive to the modulation of ALK comprising administering to a subject a therapeutically effective amount of a compound of any one of Claims 1 to 35, or a pharmaceutically acceptable salt; or the composition of Claim 36.

38. The method of Claim 37, wherein the condition is cancer.

Images