HPK1 targeting compounds and uses thereof

Abstract

Described herein are compounds that modulate hematopoietic progenitor kinase (HPK1), and are useful in the treatment cancer and other conditions responsive to the modulation of HPK1. Such compounds include those having the Formula I and pharmaceutically acceptable salts thereof.

Description

[0001] HPK1 TARGETING COMPOUNDS AND USES THEREOF

[0002] RELATED APPLICATIONS

[0003] This application claims priority to U.S. Provisional Application No. 63 / 530,173, filed on August 1, 2023. The entire contents of the foregoing application are expressly incorporated herein by reference.

[0004] BACKGROUND

[0005] Hematopoietic Progenitor Kinase 1 (HPK1) also known as MAP4K1, is a serine-threonine kinase from the germinal center family of kinases, which regulates the function of a number of immune cells, including T cells, B cells, and dendritic cells. HPK1 functions as a negative immune regulator of activation signals generated by the T cell antigen receptor (TCR) and B- cell signaling. In T-cells, following T-cell receptor activation, HPK1 is recruited to the plasma membrane where it phosphorylates the adapter protein SH2 domain-containing leukocyte protein, down-regulating signaling events required for T cell activation and proliferation, and suppressing the innate immune response. HPK1 inhibitors block inhibitory signals that would reduce the ability of T cells to clear the tumor and has been recognized as a novel antitumor immunotherapy target. HPK1 inhibition and knockdown shows enhanced T-cell signaling, cytokine production, and in vivo tumor growth inhibition. The need for new HPK1 compounds which target HPK1 are therefore needed to treat cancer and other conditions responsive to the inhibition or degradation of HPK1.

[0006] SUMMARY

[0007] Described herein are compounds that modulate hematopoietic progenitor kinase (HPK1). In certain embodiments, the compounds described herein are inhibitors of HPK1. In certain embodiments, the compounds described herein are degraders of HPK1.

[0008] In certain embodiments, compounds described herein have desirable efficacy, stability, bioavailability, therapeutic index, and toxicity values that are important to their use as pharmaceuticals.

[0009] In embodiments, provided herein are compounds of having the structure of Formula (I): or a pharmaceutically acceptable salt thereof, wherein

[0010] R1, R3, and R4are each independently selected from hydrogen, halo, optionally substituted (Ci-C4)alkyl, optionally substituted (Ci-C4)alkoxy, cyano, hydroxyl, and optionally substituted (C3-Ce)cycloalkyl;

[0011] R2is selected from an optionally substituted 5- to 7-membered heteroaryl and an optionally substituted 9- to 11 -membered heterocyclyl;

[0012] RNis selected from hydrogen and (Ci-C4)alkyl;

[0013] L is a chemical linker; R5is represented by the chemical structure: wherein:

[0014] W is CH2, CHRV, or C(O);

[0015] Y and Y1are each independently N, CH, or CRy;

[0016] Q1, Q2, Q3, Q4, Q5, T1, T2, T3, T4, and T5are each independently CH, CRW, or N;

[0017] Z1and Z2are each independently CH, CRXor N;

[0018] V is absent or is NRnor C(O)NRZ;

[0019] V1is absent or (Ci-C4)alkylene;

[0020] R6and R7are each independently hydrogen or optionally substituted (Ci-C4)alkyl;

[0021] Rv, Rw, Ry, and Rxare each independently selected from halo, optionally substituted (Ci-C4)alkyl, optionally substituted (Ci-C4)alkoxy, cyano, OH, -NH(optionally substituted (Ci-C4)alkyl), and -NH(optionally substituted (Ci-C4)alkyl)2; and

[0022] Rnand Rzare each independently hydrogen or optionally substituted (Ci-Ce)alkyl, optionally substituted cycloalkyl, or optionally substituted heterocyclyl, wherein ''' indicates the part of the structure to which the chemical linking moiety (L) is attached.

[0023] Also described herein are pharmaceutical compositions comprising one or more compounds described herein and a pharmaceutically acceptable excipient.

[0024] In certain embodiments, described herein are methods treating cancer, comprising administering a therapeutically effective amount of one or more compounds described herein, or a pharmaceutical composition thereof, to a subject in need thereof.

[0025] In certain embodiments, described herein are methods of inhibiting the activity of hematopoietic progenitor kinase (HPK1), comprising administering a therapeutically effective amount one or more compounds described herein, or a pharmaceutical composition thereof, to a subject.

[0026] DETAILED DESCRIPTION Described herein are compounds that have activity as inhibitors of HPK1. In certain embodiments, the described compounds selectively inhibit HPK1. In certain embodiments, the compounds described herein cause the degradation of HPK1.

[0027] In certain mbodiments, the compounds described herein have desirable efficacy, stability, bioavailability, therapeutic index, and toxicity values that are important to their use as pharmaceuticals.

[0028] The described compounds can be used to treat diseases or disorders responsive to the modulation of HPK1 (e.g., the inhibition of HPK1) such as cancer.

[0029] Definitions

[0030] Unless otherwise defined herein, scientific, and technical terms used in this application shall have the meanings that are commonly understood by those of ordinary skill in the art. Generally, nomenclature used in connection with, and techniques of, chemistry, cell and tissue culture, molecular biology, cell and cancer biology, neurobiology, neurochemistry, virology, immunology, microbiology, pharmacology, genetics and protein and nucleic acid chemistry, described herein, are those well-known and commonly used in the art.

[0031] The methods and techniques of the present disclosure are generally performed, unless otherwise indicated, according to conventional methods well-known in the art and as described in various general and more specific references that are cited and discussed throughout this specification. See, e.g., “Principles of Neural Science,” McGraw-Hill Medical, New York, N.Y. (2000); Motulsky, “Intuitive Biostatistics”, Oxford University Press, Inc. (1995); Lodish et al. “Molecular Cell Biology, 4th ed.,” W. H. Freeman & Co., New York (2000); Griffiths et al. “Introduction to Genetic Analysis, 7th ed. ,” W. H. Freeman & Co., N.Y. (1999); and Gilbert et al. “Developmental Biology, 6th ed.,” Sinauer Associates, Inc., Sunderland, M A (2000).

[0032] Chemistry terms used herein are used according to conventional usage in the art, as exemplified by “The McGraw-Hill Dictionary of Chemical Terms,” Parker S., Ed., McGraw- Hill, San Francisco, Calif. (1985).

[0033] All the above, and all other publications, patents, and published patent applications referred to in this application are specifically incorporated by reference herein. In case of conflict, the present specification, including its specific definitions, will control.

[0034] The term “HPK1 inhibitor” or “inhibitor of HPK1” refers to an agent capable of inhibiting the activity of HPK1.

[0035] The terms “patient,” “subject,” and “individual” are used interchangeably herein and refer to either a human or a non-human animal. These terms include mammals, such as humans, primates, livestock animals (including bovines, porcines, etc.), companion animals (e.g., canines, felines, etc.) and rodents (e.g., mice and rats). In embodiments, the subject is a human.

[0036] “Treating” a condition or patient, and “treatment” refer to taking steps to obtain beneficial or desired results, including clinical results, via administration of a compound or composition of the present invention. Beneficial or desired results include, but are not limited to, alleviation or amelioration of one or more symptoms or conditions, diminishment of extent of disease, stabilized (z.e., not worsening) state of disease, preventing spread of disease, delay or slowing of disease progression, amelioration or palliation of the disease state, and remission (whether partial or total. “Treatment” also can mean prolonging survival as compared to expected survival if not receiving treatment.

[0037] “Administering” or “administration of’ a described compound or a composition to a subject can be carried out using any of a variety of routes and methods known to those skilled in the art based on the directions of an attending healthcare provider. For example, a described compound or pharmaceutical composition can be administered to a subject such treatment by any of the following routes: intravenously, arterially, intradermally, intramuscularly, intraperitoneally, subcutaneously, ocularly, sublingually, buccally, orally (by ingestion), intranasally (by inhalation), intravaginally, intraspinally, intrathecally, intracerebrally, and transdermally (by absorption through the skin). A described compound or composition can also appropriately be introduced by rechargeable or biodegradable polymeric devices or other devices, e.g., patches and pumps, or formulations, which provide for the extended, slow, delayed, or controlled release of the compound or composition. Administering also can be performed, for example, once, a plurality of times, and / or over one or more extended periods.

[0038] Appropriate methods of administering a described compound or pharmaceutical composition to the subject will also depend on a variety of factors such as, for example, age, weight, gender, and physical condition of the subject, as well as the chemical and biological properties of the compound or pharmaceutical composition (e.g., solubility, absorption, bioavailability, metabolism, stability, and toxicity).

[0039] In certain embodiments, a described compound or pharmaceutical composition is administered orally, e.g., to a subject by ingestion. In certain embodiments, the orally administered compound or pharmaceutical composition is in a controlled release (e.g., a delayed release, extended release, or slow release) formulation.

[0040] As used herein, the phrase “conjoint administration” refers to any form of administration of two or more different therapeutic agents such that the second agent is administered while the previously administered therapeutic agent is still effective in the body (e.g., the two agents are simultaneously effective in the patient, which may include synergistic effects of the two agents). For example, the different therapeutic compounds can be administered either in the same formulation or in separate formulations, either simultaneously or sequentially. Thus, an individual who receives such treatment can benefit from a combined effect of different therapeutic agents.

[0041] A “therapeutically effective amount” or a “therapeutically effective dose” of a described compound or pharmaceutical composition is an amount of the drug or composition that, when administered to a subject, will have the intended therapeutic effect. The full therapeutic effect does not necessarily occur by administration of one dose and may occur only after administration of a series of doses. Thus, a therapeutically effective amount may be administered in one or more administrations. The effective amount needed for a subject will depend, for example, upon the subject’s age, weight, health, gender, and the nature and extent of the condition (e.g., cancer) being treated. The attending healthcare provider will generally determine the effective amount for a given situation according to these and other factors.

[0042] When used in connection to describe a chemical group that may have multiple points of attachment, a hyphen (-) designates the point of attachment of that group to the variable to which it is defined. For example, -NH(optionally substituted (Ci-C4)alkyl) means the attachment point is on the nitrogen atom.

[0043] The term “alkyl” refers to saturated aliphatic groups, including straight-chain and branched- chain alkyl groups. In preferred embodiments, a straight chain or branched chain alkyl has six or fewer carbon atoms in its backbone e.g, Ci-Ce for straight chains, C3-C6 for branched chains), and more preferably four or less carbons in its backbone.

[0044] The term “alkoxy” refers to an alkyl group having an oxygen attached thereto, represented by -O-alkyl. For example, “C1-C4 alkoxy” includes methoxy, ethoxy, propoxy, isopropoxy, and butoxy.

[0045] The term “Cx-Cy,” when used in conjunction with a chemical moiety (e.g, alkyl, alkoxy) is meant to include groups that contain from x to y carbons in the chain. A Ci-Ce alkyl group, for example, contains from one to six carbon atoms in the chain; a Ci-C4-alkyl contains from one to four carbon atoms in the chain. The terms “halo,” “halogen,” and “halogen groups,” as used herein, refer to a substituent group from Group 17 of the periodic table of the elements and includes fluoro (-F), chloro (-C1), bromo(-Br), and iodo (-1) substituent groups.

[0046] The terms “haloalkyl” and “haloalkoxy” mean alkyl or alkoxy, respectively, substituted with one or more halogen atoms.

[0047] The term “cycloalkyl” 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 or cycloaliphatic group may be present on any substitutable position and, include, e.g., the position at which the cycloalkyl group is attached.

[0048] Unless otherwise specified, the term “heteroaryl” refers to a 5- to 12-membered aromatic radical containing 1-4 heteroatoms selected from N, O, and S. In some instances, nitrogen atoms in a heteroaryl may be quaternized. The term “heteroaryl” may be used interchangeably with the terms “heteroaryl ring,” “heteroaryl group,” or “heteroaromatic”. A heteroaryl group may be mono- or bi-cyclic. Monocyclic heteroaryl includes, for example, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, 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, benzooxazolyl, benzooxodiazolyl, indazolyl, benzimidazolyl, benzthiazolyl, benzothiopheneyl, quinolinyl, quinazolinyl, quinoxalinyl, pyrrolopyridinyl, pyrrolopyrimidinyl, pyrrolopyridinyl, thienopyridinyl, thienopyrimidinyl, indolizinyl, purinyl, cinnolinyl, naphthyridinyl, and pteridinyl. It will be understood that when specified, optional substituents on a heteroaryl group may be present on any substitutable position and, include, e.g., the position at which the heteroaryl is attached (where valency permits).

[0049] Unless otherwise specified, the term “heterocyclyl” means a 4- to 12-membered saturated or partially unsaturated heterocyclic ring containing 1 to 4 heteroatoms independently selected from N, O, and S. The terms “heterocycle,” “heterocyclyl,” “heterocyclyl ring,” “heterocyclic group,” “heterocyclic moiety,” and “heterocyclic radical,” are used interchangeably herein. A heterocyclyl ring can be attached to its pendant group at any heteroatom or carbon atom that results in a stable structure. A heterocyclyl group may be mono- or bicyclic (e.g., a bridged, fused, or spiro bicyclic ring). Examples of monocyclic saturated or partially unsaturated heterocyclic radicals include, without limitation, azetidinyl, tetrahydrofuranyl, tetrahydrothienyl, terahydropyranyl, pyrrolidinyl, pyrrolidonyl, piperidinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, morpholinyl, dihydrofuranyl, dihydropyranyl, dihydropyridinyl, tetrahydropyridinyl, dihydropyrimidinyl, tetrahydropyrimidinyl, dihydrooxadizolyl, and dihydroisoxazolyl. Bi-cyclic heterocyclyl groups include, e.g., unsaturated heterocyclic radicals fused to another unsaturated heterocyclic radical, cycloalkyl, aryl, or heteroaryl ring, such as for example, benzodioxolyl, dihydrobenzodioxinyl, dihydrobenzofuranyl, dihydrobenzothiophenyl, 5-oxa-2,6- diazaspiro[3.4]oct-6-enyl, 6-thia-2,7-diazaspiro[3.4]octanyl, 2,6-diazaspiro[3.3]heptanyl, spiro[indoline-3,3'-pyrrolidine]-yl, indolinyl, isoindolinyl 6,7-dihydro-5H-pyrrolo[3,4- b]pyridinyl, thiochromanyl, dihydropyrido[2,3-b][l,4]oxazinyl, tetrahydropyrido[2,3- b][l,4]oxazepinyl, dihydro-2H-pyrano[2,3-b]pyridinyl, 5,6-dihydro-4H-pyrazolo[l,5- d][l,4]diazepin-7(8H)-only, 7-azaspiro[3.5]nonanyl, 2-azaspiro[3.3]heptanyl, 2- azaspiro[3.5]nonanyl, 3-azaspiro[5.5]undecanyl, 3-azabicyclo[3.1.0]hexanyl, and the like. It will be understood that when specified, optional substituents on a heterocyclyl group may be present on any substitutable position and, include, e.g., the position at which the heterocyclyl is attached (where valency permits).

[0050] The term “spiro” refers to two rings that shares one ring atom e.g., carbon).

[0051] The term “fused” refers to two rings that share two adjacent ring atoms with one another.

[0052] The term “bridged” refers to two rings that share three adjacent ring atoms with one another.

[0053] The term “substituted” refers to moieties having substituents replacing a hydrogen on one or more carbons of the backbone. It will be understood that “substitution” or “substituted with” includes the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and the substituent, and that the substitution results in a stable compound, e.g., which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc. As used herein, the term “substituted” is contemplated to include all permissible substituents of organic compounds. Broadly, the permissible substituents include acyclic and cyclic, branched, and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic substituents of organic compounds. The permissible substituents can be one or more and the same or different for appropriate organic compounds. For purposes of this invention, the heteroatoms such as nitrogen may have hydrogen substituents and / or any permissible substituents of organic compounds described herein which satisfy the valences of the heteroatoms. Substituents can include any substituents described herein, for example, a halogen, a hydroxyl, a carbonyl (such as a carboxyl, an alkoxycarbonyl, a formyl, or an acyl), a thiocarbonyl (such as a thioester, a thioacetate, or a thioformate), an alkoxyl, a phosphoryl, a phosphate, a phosphonate, a phosphinate, an amino, an amido, an amidine, an imine, a cyano, a nitro, an azido, a sulfhydryl, an alkylthio, a sulfate, a sulfonate, a sulfamoyl, a sulfonamido, a sulfonyl, a heterocyclyl, an aralkyl, or an aromatic or heteroaromatic moiety. It will be understood by those skilled in the art that the moieties substituted on the hydrocarbon chain can themselves be substituted, if appropriate.

[0054] 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, iodide, 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.

[0055] Certain compounds described herein may exist in various stereoisomeric forms. Stereoisomers are compounds that differ only in their spatial arrangement. When a disclosed compound is named or depicted by structure with or without indicating stereochemistry, it is understood that the name or structure encompasses all possible stereoisomers, geometric isomers, including essentially pure stereo or geometric isomers, as well as combination thereof. When the stereochemical configuration at a chiral center in a compound having one or more chiral centers is depicted by its chemical name e.g., where the configuration is indicated in the chemical name by “R” or “S”) or structure (e.g., the configuration is indicated by “wedge” bonds), the enrichment of the indicated configuration relative to the opposite configuration is greater than 50%, 60%, 70%, 80%, 90%, 99%, or 99.9%. “Enrichment of the indicated configuration relative to the opposite configuration” is a mole percent and is determined by dividing the number of compounds with the indicated stereochemical configuration at the chiral center(s) by the total number of all the compounds with the same or opposite stereochemical configuration in a mixture.

[0056] Compounds of the Invention

[0057] In embodiments, described herein are compounds of having a structure according to Formula (I): or a pharmaceutically acceptable salt thereof, wherein

[0058] R1, R3, and R4are each independently selected from hydrogen, halo, optionally substituted (Ci-C4)alkyl, optionally substituted (Ci-C4)alkoxy, cyano, hydroxyl, and optionally substituted (C3-Ce)cycloalkyl;

[0059] R2is selected from an optionally substituted 5- to 7-membered heteroaryl and an optionally substituted 9- to 11 -membered heterocyclyl;

[0060] RNis hydrogen or (Ci-C4)alkyl;

[0061] L is a chemical linker;

[0062] R5is represented by the chemical structure:

[0063] wherein: W is CH2, CHRV, or C(O);

[0064] Y and Y1are each independently N, CH, or CRy;

[0065] Q1, Q2, Q3, Q4, Q5, T1, T2, T3, T4, and T5are each independently CH, CRW, or N;

[0066] Z1and Z2are each independently CH, CRX, or N;

[0067] V is absent or is NRnor C(O)NRZ; V1is absent or (Ci-C4)alkylene;

[0068] R6and R7are each independently hydrogen or optionally substituted (Ci-C4)alkyl;

[0069] Rv, Rw, Ry, and Rxare each independently selected from halo, optionally substituted (Ci-C4)alkyl, optionally substituted (Ci-C4)alkoxy, cyano, OH, -NH(optionally substituted (Ci-C4)alkyl), and -NH(optionally substituted (Ci-C4)alkyl)2; and Rnand Rzare each independently hydrogen or optionally substituted (Ci-Ce)alkyl, optionally substituted cycloalkyl, or optionally substituted heterocyclyl, wherein ''' indicates the part of the structure to which the chemical linking moiety (L) is attached.

[0070] In embodiments, the compounds have the structural Formula (IA) or (IB): or a pharmaceutically acceptable salt thereof.

[0071] In embodiments, for the compounds of Formula (I), (IA), or (IB), RNis hydrogen or CH3.

[0072] In embodiments, for the compounds of Formula (I), (IA), or (IB), RNis hydrogen.

[0073] In embodiments, for the compounds of Formula (I), (IA), or (IB), R1, R3, and R4are each independently selected from hydrogen, halo, (Ci-C4)alkyl, halo(Ci-C4)alkyl, (Ci-C4)alkoxy, halo(Ci-C4)alkoxy, hydroxyl, cyano, and C3-C6)cycloalkyl.

[0074] In embodiments, for the compounds of Formula (I), (IA), or (IB), R1, R3, and R4are each independently selected from hydrogen, halo, and (Ci-C4)alkyl.

[0075] In embodiments, for the compounds of Formula (I), (IA), or (IB), R1, R3, and R4are each hydrogen.

[0076] In embodiments, for the compounds of Formula (I), (IA), or (IB), R1is halo and R3and R4are each hydrogen.

[0077] In embodiments, for the compounds of Formula (I), (IA), or (IB), R1is fluoro or chloro and R3and R4are each hydrogen.

[0078] In embodiments, for the compounds of Formula (I), (IA), or (IB), R3is halo and R1and R4are each hydrogen.

[0079] In embodiments, for the compounds of Formula (I), (IA), or (IB), R3is chloro and R1and R4are each hydrogen.

[0080] In embodiments, for the compounds of Formula (I), (IA), or (IB), R1and R3are each halo and R4is hydrogen.

[0081] In embodiments, for the compounds of Formula (I), (IA), or (IB), R3is chloro, R1is fluoro, and R4is hydrogen.

[0082] In embodiments, for the compounds of Formula (I), (IA), or (IB), R1is halo, R4is (Ci- C4)alkyl, and R3is hydrogen. In embodiments, for the compounds of Formula (I), (IA), or (IB), R1is fluoro, R4is methyl, and R3is hydrogen.

[0083] In embodiments, for the compounds of Formula (I), (IA), or (IB), R1is halo, R3is (Ci- C4)alkyl, and R4is hydrogen.

[0084] In embodiments, for the compounds of Formula (I), (IA), or (IB), R1is fluoro or chloro, R3is methyl, and R4is hydrogen.

[0085] In embodiments, for the compounds of Formula (I), (IA), or (IB), R2is a 5- to 7-membered heteroaryl or a 9- to 11 -membered heterocyclyl, each of which are optionally substituted with 1 to 3 groups selected from RA, wherein RAis selected from halo, (Ci-C4)alkyl, halo(Ci- C4)alkyl, (Ci-C4)alkoxy, halo(Ci-C4)alkoxy, cyano, hydroxyl, oxo, and (C3-C6)cycloalkyl.

[0086] In embodiments, for the compounds of Formula (I), (IA), or (IB), R2is a 5- to 6-membered nitrogen containing heteroaryl or a 10- to 11 -membered nitrogen containing heterocyclyl, each of which are optionally substituted with 1 to 3 groups selected from RA, wherein RAis selected from halo, (Ci-C4)alkyl, halo(Ci-C4)alkyl, (Ci-C4)alkoxy, halo(Ci-C4)alkoxy, cyano, hydroxyl, oxo, and (C3-C6)cycloalkyl.

[0087] In embodiments, for the compounds of Formula (I), (IA), or (IB), R2is selected from pyridinyl, triazolyl, pyrimidinyl, pyridazinyl, dihydropyrido[2,3-b][l,4]oxazinyl, tetrahydropyrido[2,3-b][l,4]oxazepinyl, and dihydro-2H-pyrano[2,3-b]pyridinyl, each of which are optionally substituted with 1 to 3 groups selected from RA, wherein RAis selected from halo, (Ci-C4)alkyl, halo(Ci-C4)alkyl, (Ci-C4)alkoxy, halo(Ci-C4)alkoxy, cyano, hydroxyl, oxo, and (C3-C6)cycloalkyl.

[0088] In embodiments, for the compounds of Formula (I), (IA), or (IB), R2is selected from each of which are optionally substituted with 1 to 3 groups selected from RA, wherein RAis selected from halo, (Ci-C4)alkyl, halo(Ci-C4)alkyl, (Ci-C4)alkoxy, halo(Ci-C4)alkoxy, cyano, hydroxyl, oxo, and (C3-C6)cycloalkyl.

[0089] In embodiments, for the compounds of Formula (I), (IA), or (IB), RAis selected from (Ci- C4)alkyl, (Ci-C4)alkoxy, hydroxyl, and oxo. In embodiments, for the compounds of Formula (I), (IA), or (IB), R2is selected from In embodiments, for the compounds of Formula (I), (IA), or (IB), R5is represented by the chemical structure:

[0090] In embodiments, for the compounds of Formula (I), (IA), or (IB), Q1, Q2, Q3, and Q4are each CH for the chemical structure Em

[0091] In embodiments, for the compounds of Formula (I), (IA), or (IB), Q1, Q2, Q3, and Q4are each CH for the chemical structure Em.

[0092] In embodiments, for the compounds of Formula (I), (IA), or (IB), Q5is CH for the chemical structure Em. In embodiments, for the compounds of Formula (I), (IA), or (IB), R6is hydrogen or (Ci- C4)alkyl.

[0093] In embodiments, for the compounds of Formula (I), (IA), or (IB), V is C(O)NH.

[0094] In embodiments, for the compounds of Formula (I), (IA), or (IB), R7is (Ci-C4)alkyl.

[0095] In embodiments, for the compounds of Formula (I), (IA), or (IB), Y is CH. In embodiments, for the compounds of Formula (I), (IA), or (IB), Rvis (Ci-C4)alkyl.

[0096] In embodiments, for the compounds of Formula (I), (IA), or (IB), Rwis halo, (Ci-C4)alkyl, or (Ci-C4)alkoxy.

[0097] In embodiments, for the compounds of Formula (I), (IA), or (IB), R5is selected from In embodiments, for the compounds of Formula (I), (IA), or (IB), the chemical linking moiety (L) is represented by the chemical structure: wherein:

[0098] YL1, YL2, YL3, YM, and YL5are each independently absent or selected from O, NH, - N(Ci-C4)alkyl, and an optionally substituted (Ci-Ce)alkylene, wherein said (Ci-Ce)alkylene may also be optionally interrupted by one or more -C=C-, O, NH, and -N(Ci-C4)alkyl, and wherein two hydrogens on the same carbon of said (Ci-Ce)alkylene may be taken together to form oxo; and

[0099] WL1, WL2, WL3, and WMare each independently selected from phenyl, heterocyclyl, heteroaryl, and cycloalkyl, each of which are optionally substituted.

[0100] In embodiments, for the compounds of Formula (I), (IA), or (IB), YL1is absent or is (Ci- C4)alkylene optionally interrupted by one or two O, and wherein two hydrogens on the same carbon of said (Ci-Ce)alkylene may be taken together to form oxo .

[0101] In embodiments, for the compounds of Formula (I), (IA), or (IB), WL1is an optionally substituted 5- to 6-membered monocyclic heterocyclyl or 6- to 12- membered bicyclic heterocyclyl.

[0102] In embodiments, for the compounds of Formula (I), (IA), or (IB), WL1is 5,6-dihydro-4H- pyrazolo[l,5-d][l,4]diazepin-7(8H)-onyl, 7-azaspiro[3.5]nonanyl, 2-azaspiro[3.3]heptanyl, 3- azabicyclo[3.1.0]hexanyl, 2-azaspiro[3.5]nonanyl, piperdinyl, or 3-azaspiro[5.5]undecanyl, each of which is optionally substituted with halo or -CH3.

[0103] In embodiments, for the compounds of Formula (I), (IA), or (IB), YL2is absent or is (Ci- C4)alkylene.

[0104] In embodiments, for the compounds of Formula (I), (IA), or (IB), WL2is an optionally substituted Cs-ecyloalkyl, 4- to 6-membered monocyclic heterocyclyl or 6- to 10- membered bicyclic heterocyclyl.

[0105] In embodiments, for the compounds of Formula (I), (IA), or (IB), WL2is piperdinyl, azetidinyl, 2-azaspiro[3.3]heptanyl, 2-azaspiro[3.5]nonanyl, or cyclohexyl.

[0106] In embodiments, for the compounds of Formula (I), (IA), or (IB), YL3is absent, O, or (Ci- C4)alkylene optionally interrupted by one or two O or -C=C-, and wherein two hydrogens on the same carbon of said (Ci-Ce)alkylene may be taken together to form oxo.

[0107] In embodiments, for the compounds of Formula (I), (IA), or (IB), WL3is an optionally substituted Cs-ecyloalkyl, 4- to 6-membered monocyclic heterocyclyl or 6- to 12- membered bicyclic heterocyclyl.

[0108] In embodiments, for the compounds of Formula (I), (IA), or (IB), WL3is piperidinyl, azetidinyl, piperazinyl, 3-azaspiro[5.5]undecanyl, or cyclobutyl, each of which is optionally substituted with halo or -OH.

[0109] In embodiments, for the compounds of Formula (I), (IA), or (IB), Y14is absent, O, or (Ci- C4)alkylene.

[0110] In embodiments, for the compounds of Formula (I), (IA), or (IB), WMis an optionally substituted 4- to 6-membered monocyclic heterocyclyl.

[0111] In embodiments, for the compounds of Formula (I), (IA), or (IB), WMis piperidinyl.

[0112] In embodiments, for the compounds of Formula (I), (IA), or (IB), YL5is absent.

[0113] In embodiments, for the compounds of Formula (I), (IA), or (IB), L is selected from:

[0114] wherein the dashed bond indicates the attachment point to R5.

[0115] In embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is any one of Examples 1 to 158.

[0116] In embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is any one of the compounds in the Table 1 below:

[0117]

[0118] Compounds having the chemical structure of Formula (I) are further described in the Exemplification and are included in the present disclosure. Pharmaceutically acceptable salts thereof as well as the neutral forms of the compounds described herein are also included. Pharmaceutical Compositions

[0119] Described herein are pharmaceutical composition comprising a compound described herein, or a pharmaceutically acceptable salt thereof, in association with a pharmaceutically acceptable carrier.

[0120] The compositions may be in a form suitable for oral use (for example, as tablets, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups, or elixirs), for topical use (for example, as creams, ointments, gels, or aqueous or oily solutions, suspensions, or transdermal patches), for administration by inhalation (for example, as a finely divided powder or a liquid aerosol), for administration by insufflation (for example, as a finely divided powder), or for parenteral administration (for example, as a sterile aqueous or oily solution for intravenous, subcutaneous, intramuscular, intraperitoneal, or as a suppository for rectal or intravaginal dosing).

[0121] Pharmaceutical compositions can be obtained by conventional procedures in view of this disclosure using conventional pharmaceutical excipients well-known in the art. Thus, compositions intended for oral use may contain, for example, one or more coloring agents, sweetening agents, flavoring agents, and / or preservative agents.

[0122] The term “pharmaceutically acceptable carrier” refers to a non-toxic carrier, adjuvant, or vehicle that does not destroy the pharmacological activity of the compound with which it is formulated. Pharmaceutically acceptable carriers, adjuvants, or vehicles that may be used in the compositions described herein include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene- polyoxypropylene-block polymers, polyethylene glycol and wool fat.

[0123] The amount of the compound(s) that can be administered and the dosage regimen for treating a disease condition with the compounds and / or compositions of this invention depends on a variety of factors, including the age, weight, sex, the medical condition of the subject, the type of disease, the severity of the disease, the route and frequency of administration, and the particular compound employed. Thus, the dosage regimen can vary widely, but may be routinely determined using standard methods. The daily dose can be administered in one to four doses divided per day. Other dosing schedules include one dose per week and one dose per two-day cycle.

[0124] Methods of Treatment

[0125] In embodiments, the described compounds and pharmaceutically acceptable salts thereof are useful for the treatment of cancer. Such cancers include, but are not limited to, microsatelliteinstability high (MSI-H) cancers, brain cancers, skin cancers, bladder cancers, ovarian cancers, breast cancers, gastric cancers, pancreatic cancers, prostate cancers, colon cancers, blood cancers, lung cancers and bone cancers. Examples of such cancer types include neuroblastoma, intestine carcinoma such as rectum carcinoma, colon carcinoma, familiar adenomatous polyposis carcinoma and hereditary non-polyposis colorectal cancer, esophageal carcinoma, labial carcinoma, larynx carcinoma, hypopharynx carcinoma, tongue carcinoma, salivary gland carcinoma, gastric carcinoma, adenocarcinoma, medullary thyroid carcinoma, papillary thyroid carcinoma, renal carcinoma, clear cell or non-clear cell renal cell carcinoma, kidney parenchymal carcinoma, ovarian carcinoma, cervix carcinoma, uterine corpus carcinoma, endometrium carcinoma, chorion carcinoma, pancreatic carcinoma, prostate carcinoma, testis carcinoma, breast carcinoma, triple negative breast cancer, urinary carcinoma, melanoma, choroid melanoma, cutaneous melanoma seminoma, Merkel cell carcinoma, gastroesophageal cancer, cervical cancer, endometrial cancer, squamous cell carcinoma of head and neck, anal canal, or skin, urothelial cancer, brain tumors such as glioblastoma, astrocytoma, meningioma, medulloblastoma and peripheral neuroectodermal tumors, Hodgkin’s lymphoma, non-Hodgkin’s lymphoma, Burkitt lymphoma, acute lymphatic leukemia (ALL), chronic lymphatic leukemia (CLL), acute myeloid leukemia (AML), chronic myeloid leukemia (CML), adult T-cell leukemia lymphoma, diffuse large B- cell lymphoma (DLBCL), hepatocellular carcinoma, gall bladder carcinoma, bronchial carcinoma, small cell lung carcinoma, non-small cell lung carcinoma, multiple myeloma, basalioma, teratoma, retinoblastoma, rhabdomyosarcoma, craniopharyngioma, osteosarcoma, chondrosarcoma, myosarcoma, liposarcoma, fibrosarcoma, Ewing sarcoma, and plasmocytoma. In preferred embodiments, the cancer is colon cancer, mall cell lung carcinoma, non-small cell lung carcinoma, cutaneous melanoma, Merkel cell carcinoma, squamous cell carcinoma of head and neck, anal canal, or skin, urothelial cancer, clear cell or non-clear cell renal cell carcinoma, triple negative breast cancer, endometrial cancer, cervical cancer, gastroesophageal cancer, hepatocellular cancer, microsatellite-instability high (MSI- H) cancer, and solid tumors.

[0126] In embodiments, the compounds described herein can cause the degradation of HPK1. For example, the compounds of the invention can be used to degrade HPK1 in a cell or in a subject in need of said treatment by administering a therapeutically effective amount of a described compound or a pharmaceutically acceptable salt thereof. Also described herein are methods of treating diseases or conditions associated with activity or expression, including abnormal activity and / or overexpression, of HPK1 in a subject by administering to the subject in need of such treatment a therapeutically effective amount or dose of any one or more compounds described herein or a pharmaceutical composition thereof.

[0127] Methods of Preparation

[0128] The described compounds may be synthesized by many methods available to those skilled in the art in view of the present disclosure. General synthetic schemes for preparing compounds of the present invention are described below. These schemes are illustrative and are not meant to limit the possible techniques one skilled in the art may use to prepare the compounds described herein. Different methods to prepare the compounds of the present invention will be evident to those skilled in the art.

[0129] EXEMPLIFICATION

[0130] General Intermediates

[0131] Intermediate 1

[0132] Step 1: Preparation of 2-(5-(2-aminoethyl)-3-bromo-lH-pyrazol-l-yl)acetic acid

[0133] To a solution of 2-bromo-4,5,6,8-tetrahydropyrazolo[l,5-d][l,4]diazepin-7-one (500 mg, 2.17 mmol, 1 eq) in tetrahydrofuran (2 mL), methanol (2 mL) and water (2 mL) was added lithium hydroxide (912 mg, 21.73 mmol, 10 eq). The reaction mixture was stirred at 25 °C for 12 hr. The reaction mixture was concentrated under reduced pressure to give a residue. The product was taken to the next step without purification. The desired compound 2-(5-(2-aminoethyl)-3- bromo-lH-pyrazol-l-yl)acetic acid (530 mg, crude) was obtained as white solid.

[0134] Intermediate 2

[0135] Intermediate 2, 6-cyclohexyl-2-((7-fluoro-6-(8-methyl-2,3-dihydro-lH-pyrido[2,3- b][l,4]oxazin-7-yl)isoquinolin-3-yl)amino)-5,6-dihydro-4H-pyrazolo[l,5-d][l,4]diazepin- 7(8H)-one, was prepared according to Example 1 below.

[0136] Intermediate 3

[0137] To a solution of 2,2-diethoxyacetonitrile (5 g, 38.71 mmol, 5.38 mL, 1 eq) in methanol (38.7 mL) was added sodium;methanolate (697 mg, 3.87 mmol, 30% purity, 0.1 eq). The mixture was stirred at 30 °C for 3 hr. The reaction mixture was adjusted to pH 7~8 with acetic acid (0.22 mL). The reaction mixture was used into the next step without further purification. Methyl 2,2-diethoxyethanimidate (6.2 g, crude) was obtained as a light yellow oil.

[0138] Step 2: Preparation of 6-bromo-7-fluoro-isoquinolin-3-anune

[0139] To a solution of (4-bromo-3-fluoro-phenyl)methanamine (3 g, 12.47 mmol, 1 eq, hydrochloride) in methanol (40 mL) was added methyl 2,2-diethoxyethanimidate (2.01 g, 12.47 mmol, 1 eq). The mixture was stirred at 40°C for 3.5 hr. The reaction mixture was concentrated. Sulfuric acid (36.80 g, 375.21 mmol, 20.00 mL, 30.08 eq) was added and the stirred at 40°C for another 12 hr. The reaction mixture was diluted with water (200 mL) at 0°C and stirred for 0.5 hr. The reaction mixture was filtered, and the filter cake was concentrated. The residue was purified by prep-HPLC (column: Phenomenex luna C18 250*50mm*10 pm;mobile phase: [water(0.225%FA)-ACN];B%: 5%-35%,22min) to give 6- bromo-7-fluoro-isoquinolin-3 -amine (1.7 g, 7.05 mmol, 56% yield) as a yellow soild.

[0140] LCMS: MS (ESI) m / z: 241.0[M]+.XH NMR: (400 MHz, DMSO-d6) 8.80 (s, 1H), 8.01 (d, J= 6.8 Hz, 1H), 7.76 (d, J= 9.2 Hz, 1H), 6.61 (s, 1H), 6.08 (s, 2H).

[0141] Step 3: Preparation of tert-butyl 7-(3-anuno-7-fluoro-6-isoquinolyl)-8- methyl-2,3- dihydropyrido[2,3-b][l,4]oxazine-l-carboxylate

[0142] A mixture of tert-butyl 8-methyl-7-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-2,3 - dihydropyrido[2,3-b][l,4]oxazine-l-carboxylate (312 mg, 0.82 mmol, 1 eq) , 6-bromo-7- fhioro-isoquinolin-3 -amine (200 mg, 0.82 mmol, 1 eq) , [l,T-bis(diphenylphosphino)ferrocene]dichloropalladium(ii) (78 mg, 0.10 mmol, 0.13 eq) , sodium carbonate (175 mg, 1.66 mmol, 2 eq) and water (1 mL) in dioxane (5 mL) and then the mixture was stirred at 95 °C for 12 hr under nitrogen atmosphere. The reaction mixture was diluted with water (20 mL) and extracted with tetrahydrofuran (10 mL x 2). The combined organic phase was washed with saturated brine (5 mL x 2), dried with anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by flash silica gel chromatography (ISCO®; 4 g SepaFlash® Silica Flash Column, Eluent of 0~3% dichloromethane: methanol gradient @ 40 mL / min) to give tert-butyl 7-(3-amino-7-fluoro-6- isoquinolyl)-8-methyl- 2,3-dihydropyrido[2,3-b][l,4]oxazine-l-carboxylate (180 mg, 0.43 mmol, 52% yield) as a yellow solid. LCMS: MS (ESI) m z. 411.3 [M+l]+. Step 4: Preparation of tert-butyl 7-[3-[(7-tert-butoxycarbonyl-7- azaspiro [3.5]nonan-2- yl)oxycarbonylanuno]-7-fluoro-6-isoquinolyl]-8-methyl-2,3-dihydropyrido[2,3- b][l,4]oxazine-l -carboxylate

[0143] To a solution of tert-butyl 7-(3-amino-7-fluoro-6-isoquinolyl)-8-methyl-2,3- dihydropyrido[2,3-b][l,4]oxazine-l-carboxylate (100 mg, 0.24 mmol, 1 eq) , tert-butyl 2- hydroxy-7-azaspiro[3.5]nonane-7-carboxylate (117 mg, 0.48 mmol, 2 eq) in di chloromethane (3 mL) was added diisopropylethylamine (157 mg, 1.22 mmol, 5 eq) and triphosgene (72 mg, 0.24 mmol, 1 eq) at 0°C. The mixture was stirred at 0°C for 1 hr. The reaction mixture was diluted with water (10 mL) and extracted di chloromethane (5 mL x 2). The combined organic phase was washed with saturated brine (5 mL x 2), dried with anhydrous sodium sulfate, filtered and concentrated to give tert-butyl 7-[3-[(7-tert-butoxycarbonyl-7- azaspiro[3.5]nonan-2-yl)oxycarbonylamino]-7-fluoro-6-isoquinolyl]-8-methyl-2,3- dihydropyrido[2,3-b][l,4]oxazine-l-carboxylate (120 mg, crude) as a yellow solid was used into the next step without further purification. LCMS: MS (ESI) m / r. 678.1 [M+l]+.

[0144] Step 5: Preparation of 7-azaspiro[3.5]nonan-2-yl N-[7-fluoro-6-(8- methyl-2,3-dihydro-lH- pyrido[2,3-b][l,4]oxazin-7-yl)-3-isoquinolyl]carbamate

[0145] To a solution of tert-butyl 7-[3-[(7-tert-butoxycarbonyl-7-azaspiro[3.5]nonan-2- yl)oxycarbonylamino]-7-fluoro-6-isoquinolyl]-8-methyl-2,3-dihydropyrido[2,3- b][l,4]oxazine-l-carboxylate (120 mg, 0.17 mmol, 1 eq) in dichloromethane (4 mL) was added trifluoroacetic acid (3.24 g, 28.38 mmol, 2.10 mL, 160.32 eq). The mixture was stirred at 30 °C for 0.5 hr. The reaction mixture was concentrated. The residue was purified by prep- HPLC (column: Unisil 3-100 C18 Ultra 150*50mm*3 pm;mobile phase: [water(0.225%FA)- ACN];B%: 15%-35%,10min). 7-azaspiro[3.5]nonan-2-yl N-[7-fhioro-6-(8-methyl-2,3- dihydro-lH-pyrido[2,3-b][l,4]oxazin-7-yl)-3-isoquinolyl]carbamate (40.5 mg, 0.07 mmol, 43 % yield, 99% purity, formate) as a off-white solid. LCMS: MS (ESI) m / z 479.1 [M+l]+.JH NMR: (400 MHz, DMSO-d6) 3 10.25 (s, 1H), 9.11 (s, 1H), 8.35 (s, 1H), 8.19 (s, 1H), 7.92 (d, J= 10.0 Hz, 1H), 7.84 (d, J= 7.2 Hz, 1H), 7.36 (s, 1H), 5.73 (s, 1H), 5.00 (t, J= 7.2 Hz, 1H), 4.29 (t, J= 4.0 Hz, 2H), 3.38 - 3.36(m, 2H), 2.93 - 2.84 (m, 4H), 2.42 - 2.31 (m, 2H), 1.92 - 1.86 (m, 5H), 1.72 - 1.62 (m, 4H), 1.13 - 1.02 (m, 1H).

[0146] Intermediate 4

[0147] Preparation of 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline- 1,3-dione

[0148] To a solution of 5-fluoroisobenzofuran-l, 3-dione (15 g, 90.30 mmol, 1.00 eq) in acetic acid (200 mL) was added sodium acetate (14.8 g, 180.60 mmol, 2.00 eq) and 3-aminopiperidine- 2, 6-dione (14.9 g, 90.30 mmol, 1.00 eq, hydrochloric acid). The mixture was stirred at 120 °C for 12 hr. The reaction mixture was concentrated under reduced pressure to remove most acetic acid. The residue was poured into water (200 mL) and the mixture was stirred for lOmin. The mixture was filtered. The filtrate cake was washed with water (30 mL x 2) and concentrated to give 2-(2,6-dioxo-3-piperidyl)-5-fluoro-isoindoline-l, 3-dione (24 g, 86.89 mmol, 96% yield) as an off-white solid. LCMS: MS (ESI) m / z: 277.1 [M+l]+. ’H NMR: (400MHz, DMSO-t / 6) 3: 11.13 (s, 1H), 8.00 (dd, J=4.4, 8.4 Hz, 1H), 7.84 (dd, J=2.4, 7.2 Hz, 1H), 7.75 - 7.68 (m, 1H), 5.16 (dd, J=5.2, 12.8 Hz, 1H), 2.95 - 2.84 (m, 1H), 2.66 - 2.52 (m, 2H), 2.14 - 2.02 (m, 1H).

[0149] Intermediate 5

[0150] Step 1: Preparation of benzyl 4-(hydroxy methyl) piperidine-l- carboxylate

[0151] To a solution of 4-piperidylmethanol (Reactant 1) (5 g, 43.41 mmol, 1 eq in dichloromethane (100 mL) was added sodium carbonate (20.71 g, 195.36 mmol, 4.5 eq) in water (100 mL) at 0°C,and carbobenzoxy chloride (8.15 g, 47.75 mmol, 6.8 mL, 1.1 eq was added dropwise. The mixture was stirred at 20 °C for 16 hr. The mixture was diluted with water (100 mL), extracted with dichloromethane (100 mL x 2). The combined organic layers were washed with brine (100 mL x 2), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (petroleum etherethyl acetate=10: l to 2: 1). Benzyl 4-(hydroxymethyl) piperidine-l -carboxylate (14.2 g, 56.96 mmol, 66% yield) was obtained as a colorless oil.1H NMR: (400MHz, CHLOROFORM-d) 5 7.44 - 7.30 (m, 5H), 5.15 (s, 2H), 4.35 - 4.16 (m, 2H), 3.53 (t, 7=5.7 Hz, 2H), 2.81 (s, 2H), 1.82 - 1.64 (m, 3H), 1.42 (t, 7=5.4 Hz, 1H), 1.19 (d, 2H).

[0152] Step 2: Preparation of benzyl 4-formylpiperidine-l -carboxylate

[0153] To a solution of benzyl 4-(hydroxymethyl) piperidine-l -carboxylate (Reactant 1) (13.2 g, 52.95 mmol, 1 eq) in dichloromethane (200 mL) was added Dess-Martin (24.70 g, 58.24 mmol, 18 mL, 1.1 eq at 0 °C. The mixture was stirred at 20 °C for 2 hr. The mixture was diluted with saturated sodium bicarbonate solution (300 mL), and extracted with dichloromethane (200 mL x 2). The combined organic layers were washed with brine (200 mL x 2), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (petroleum ether : ethyl acetate=10: l to 3: 1). Benzyl 4-formylpiperidine-l -carboxylate (11.6 g, 46.91 mmol, 88% yield) was obtained as a colorless oil.1H NMR: (400MHz, CHLOROFORM-d) 5 9.69 (s, 1H), 7.44 - 7.30 (m, 5H), 5.15 (s, 2H), 4.13 - 3.99 (m, 2H), 3.05 (t, 7=11.0 Hz, 2H), 2.51 - 2.42 (m, 1H), 1.94 (s, 2H), 1.68 - 1.58 (t, 7=7.2 Hz, 2H).

[0154] Step 3: Preparation of benzyl 4-(dimethoxymethyl) piperidine-l- carboxylate

[0155] To a solution of benzyl 4-formylpiperidine-l -carboxylate (Reactant 1) (11 g, 44.48 mmol, 1 eq in methanol (100 mL) was added trimethoxymethane (23.6 g, 222.41 mmol, 24 mL, 5 eq) and 4-methylbenzenesulfonic acid; hydrate (423 mg, 2.22 mmol, 0.05 eq . The mixture was stirred at 20 °C for 12 hr. The mixture was quenched by addition water (200 mL), diluted with dichloromethane (200 mL), extracted with dichloromethane (200mL x 2). The combined organic layers were washed with brine (200 mL x 2), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was used into next step without further purification. Benzyl 4-(dimethoxymethyl) piperidine- 1 -carboxylate (11.2 g, 38.18 mmol, 86% yield) was obtained as a colorless oil.1H NMR: (400MHz, CHLOROFORM-d) 5 7.42 - 7.30 (m, 5H), 5.14 (s, 2H), 4.33 - 4.13 (m, 2H), 4.04 (d, J=6.9 Hz, 1H), 3.37 (s, 6H), 2.76 (s, 2H), 1.86 - 1.70 (m, 3H), 1.34 - 1.16 (m, 2H).

[0156] Intermediate 6

[0157] Step 1: Preparation of 2-(3-bromo-5-(2-((l-(tert-butoxycarbonyl)piperidin-4- yl)amino)ethyl)-LH-pyrazol-l-yl)acetic acid

[0158] To a stirred of 2-(5-(2-aminoethyl)-3-bromo-lH-pyrazol-l-yl)acetic acid (640 mg, 2.58 mmol, 1 eq) and tert-butyl 4-oxopiperidine-l -carboxylate (1 g, 5.02 mmol, 1.95 eq) in dimethylsulfoxide (2 mL) and di chloroethane (4 mL) was added acetic acid (619.70 mg, 10.32 mmol, 590.19 uL, 4 eq), The mixture was stirred at 25 °C for 0.5 h. then to the mixture was added sodium borohydride acetate (1.64 g, 7.74 mmol, 3 eq), The mixture was stirred at 25 °C for 11.5 hr. The reaction mixture was quenched by addition diisopropyl ethylamine 10 mL at 0 °C, and then concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex luna C18 250x50mmx l0 pm;mobile phase: [water(10mM ammonium bicarbonate)- acetonitrile];B%: 5%-35%,20min). 2-(3-bromo-5-(2- ((l-(tert-butoxycarbonyl)piperidin-4-yl)amino)ethyl)-lH-pyrazol-l-yl)acetic acid (970 mg,

[0159] 2.25 mmol, 87% yield) was obtained as a white solid. LCMS: MS (ESI) m / z: 432.9 [M+l]+.

[0160] Step 2: Preparation of tert-butyl 4-(2-bromo-7-oxo-7,8-dihydro-4H-pyrazolo[l,5- d][l,4]diazepin-6(5H)-yl)piperidine-l-carboxylate

[0161] Boc

[0162] To a solution of 2-(3-bromo-5-(2-((l-(tert-butoxycarbonyl)piperidin-4-yl)amino)ethyl)-lH- pyrazol-l-yl)acetic acid (960 mg, 2.23 mmol, 1 eq in N,N-dimethylformamide (20 mL) was added diisopropyl ethyl amine (1.44 g, 11.14 mmol, 1.94 mL, 5.01 eq) and 2-(3H- [l,2,3]triazolo[4,5-b]pyridin-3-yl)-l,l,3,3-tetramethylisouronium hexafluorophosphate(V) (1.73 g, 4.56 mmol, 2.05 eq . The mixture was stirred at 25 °C for 2 hr. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. Then quenched by addition water 10 mL at 0 °C, and then diluted with ethyl acetate 30 mL and extracted with ethyl acetate (10 mL x 3). The combined organic layers were washed with brine (10 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Waters Xbridge 150x25mmx 5 pm;mobile phase: [water (0.05% ammonia hydroxide v / v)- acetonitrile] ;B%: 30%-60%,7min). Tert-butyl 4-(2-bromo-7-oxo-7,8-dihydro-4H-pyrazolo[l,5-d][l,4]diazepin- 6(5H)-yl)piperidine-l -carboxylate (470 mg, 1.14 mmol, 51% yield) was obtained as a white solid. LCMS: MS (ESI) m / z: 358.9 [M-55]+.

[0163] Step 3: Preparation of tert-butyl 7-(3-((6-(l-(tert-butoxycarbonyl)piperidin-4-yl)-7-oxo-

[0164] 5, 6, 7, 8-tetrahydro-4H-pyrazolo[l, 5-d][l,4]diazepin-2-yl)amino)- 7-fluoroisoquinolin-6-yl)-

[0165] 8-methyl-2,3-dihydro-lH-pyrido[2,3-b][l,4]oxazine-l-carboxylate , ,

[0166] To a stirred of tert-butyl 4-(2-bromo-7-oxo-7,8-dihydro-4H-pyrazolo[l,5-d][l,4]diazepin- 6(5H)-yl)piperidine-l -carboxylate (70 mg, 169.37 umol, 1 eq and tert-butyl 7-(3-amino-7- fluoroisoquinolin-6-yl)-8-methyl-2,3-dihydro-lH-pyrido[2,3-b][l,4]oxazine-l-carboxylate (70.00 mg, 170.55 pmol, 1.01 eq) in dioxane (3 mL) was added cesium carbonate (168.00 mg, 515.62 pmol, 3.04 eq), ditert-butyl-[3,6-dimethoxy-2-(2,4,6- triisopropylphenyl)phenyl]phosphane (42.00 mg, 86.65 pmol, 5.12e-l eq) and [2-(2- aminophenyl)phenyl]-methylsulfonyloxy-palladium; ditert-butyl-[3,6-dimethoxy-2-(2,4,6- triisopropylphenyl)phenyl]phosphane (60 mg, 70.22 pmol, 4.15e-l eq), the mixture was stirred under nitrogen atmosphere at 130 °C for 1 hr. The reaction mixture was quenched by addition water 10 mL at 0 °C, and then diluted with di chloromethane 30 mL and extracted with dichloromethane (10 mL x 3). The combined organic layers were washed with brine (10 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by prep-thin layer chromatography (silicon dioxide, dichloromethane : methanol = 13: 1). Tert-butyl 7-(3-((6-(l-(tert- butoxycarbonyl)piperidin-4-yl)-7-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[l,5-d][l,4]diazepin-2- yl)amino)-7-fluoroisoquinolin-6-yl)-8-methyl-2,3-dihydro-lH-pyrido[2,3-b][l,4]oxazine-l- carboxylate (56 mg, 75.39 umol, 44% yield) was obtained as a yellow oil. LCMS: MS (ESI) m / z: 743.6 [M+l]+.

[0167] Step 4: Preparation of 2-((7-fluoro-6-(8-methyl-2,3-dihydro-lH-pyrido[2,3-b][l,4]oxazin-7- yl)isoquinolin-3-yl)amino)-6-(piperidin-4-yl)-5,6-dihydro-4H-pyrazolo[l,5-d][l,4]diazepin- 7(8H)-one

[0168] To a solution of tert-butyl 7-(3-((6-(l-(tert-butoxycarbonyl)piperidin-4-yl)-7-oxo-5,6,7,8- tetrahydro-4H-pyrazolo[l,5-d][l,4]diazepin-2-yl)amino)-7-fluoroisoquinolin-6-yl)-8-methyl- 2,3-dihydro-lH-pyrido[2,3-b][l,4]oxazine-l-carboxylate (56 mg, 75.39 pmol, 1 eq in dichloromethane (3 mL) was added trifluoroacetic acid (3 mL). The mixture was stirred at 25 °C for 0.5 hr. The reaction mixture was concentrated under reduced pressure to give a residue. Then the mixture was dilutied by dichloromethane: methanol =10: 1 (50 mL), to the mixture was added triethylamine until the pH is 7-8, then the reaction mixture was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. 22-((7-fhioro-6-(8-methyl-2,3-dihydro-lH-pyrido[2,3-b][l,4]oxazin-7-yl)isoquinolin-3- yl)amino)-6-(piperidin-4-yl)-5,6-dihydro-4H-pyrazolo[l,5-d][l,4]diazepin-7(8H)-one (40 mg, 73.72 umol, 97% yield) was obtained as a yellow solid. LCMS: MS (ESI) m / z: 543.5 [M+l]+.

[0169] Intermediate 7

[0170] Step 1: Preparation of 5-[4-(2,2-dimethoxyethyl)-l-piperidyl]-2-(2,6- dioxo-3- piperidyl)isoindoline-l, 3-dione

[0171] To a solution of 2-(2,6-dioxo-3-piperidyl)-5-fluoro-isoindoline-l, 3-dione (200 mg, 0.72 mmol, 1 eq) and 4-(2,2-dimethoxyethyl)piperidine (138 mg, 0.80 mmol, 1.1 eq in dimethyl sulfoxide (3 mL) was added N,N-diisopropyl ethylamine (187 mg, 1.45 mmol, 2 eq . The mixture was stirred at 120 °C for 2 hr. The mixture was diluted with water (20 mL) and extracted with ethyl acetate (10 mL x 3). The combined organic layers was washed with brine (20 mL x 3), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The crude product was purified with prep-HPLC (column: Unisil 3-100 C18 Ultra 150*50mm*3 pm;mobile phase: [water(0.225%FA)-ACN]; B%: 30%-60%,10min) to give 5- [4-(2,2-dimethoxyethyl)-l-piperidyl]-2-(2,6-dioxo-3- piperidyl)isoindoline-l, 3-dione (120 mg, 0.28 mmol, 38.59% yield) as a yellow oil. LCMS: MS (ESI) m / z 430.2[M+l]+.

[0172] Step 2: Preparation of 2-[l-[2-(2,6-dioxo-3-piperidyl)-l,3-(lioxo- isoindolin-5-yl]-4- piperidyljacetaldehyde

[0173] To a solution of 5-[4-(2,2-dimethoxyethyl)-l-piperidyl]-2-(2,6-dioxo-3-piperidyl)isoindoline- 1,3-dione (120 mg, 0.28 mmol, 1 eq) in tetrahydrofuran (1 mL) was added sulfuric acid (2 M,

[0174] 1 mL, 7.16 eq). The mixture was stirred at 70 °C for 0.5 hour The mixture was adjusted to pH 8 with saturated sodium bicarbonate at 0 °C. Then the mixture was extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with brine (40 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The crude product was used in next step without further purification. 2-[l-[2-(2,6-dioxo-3-piperidyl)-l,3-dioxo- isoindolin-5-yl]-4- piperidyl]acetaldehyde (80 mg, 0.21 mmol, 74.68% yield) was obtained as a yellow solid. LCMS: MS (ESI) m / z 384.2[M+1]+.

[0175] Intermediate 8

[0176] Step 1: Preparation of 5-[4-(3,3-dimethoxypropyl)piperazin-l-yl]-2- (2,6-dioxo-3- piperidyl)isoindoline-l, 3-dione , ,

[0177] To a solution of 2-(2,6-dioxo-3-piperidyl)-5-piperazin-l-yl-isoindoline-l, 3-dione (300 mg, 0.79 mmol, 1 eq, hydrochloride) and 3 -bromo- 1,1 -dimethoxy-propane (289 mg, 1.58 mmol, 2 eq in acetonitrile (6 mL) and N,N-dimethylformamide (3 mL) was added N,N- diisopropylethylamine (307 mg, 2.38 mmol, 3 eq . The mixture was stirred at 80 °C for 12 hr. The mixture was diluted with water (20 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic layers was washed with brine (40 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by flash silica gel chromatography (ISCO®; 4 g SepaFlash® Silica Flash Column, eluent of 0~2% methanol / dichloromethane gradient @ 30 mL / min) to give 5-[4-(3,3- dimethoxypropyl)piperazin-l-yl]-2-(2,6-dioxo-3-piperidyl)isoindoline-l, 3-dione (180 mg, 0.40 mmol, 51.14% yield) as a yellow oil.

[0178] Step 2: Preparation of 3-[4-[2-(2,6-dioxo-3-piperidyl)-l,3-(lioxo- isoindolin-5-yl]piperazin- l-yl]propanal

[0179] To a solution of 5-[4-(3,3-dimethoxypropyl)piperazin-l-yl]-2-(2,6-dioxo-3-piperidyl) isoindoline-1, 3-dione (100 mg, 0.22 mmol, 1 eq in dichloromethane (3 mL) was added trifluoroacetic acid (1.54 g, 13.51 mmol, 60.03 eq). The mixture was stirred at 20 °C for 1 hr. LCMS showed the reaction was completed. The mixture was adjusted to pH 8 by saturated sodium bicarbonate and extracted with ethyl acetate (20 mL x 2). The combined organic layers were washed with brine (30 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The crude product was used into next step without further purification. 3-[4-[2-(2,6-dioxo-3-piperidyl)-l,3-dioxo-isoindolin-5-yl] piperazin-1- yl]propanal (50 mg, 0.12 mmol, 55.78% yield) was obtained as a yellow oil. LCMS: MS (ESI) m / z 417.2[M+18+1]+.

[0180] Intermediate 9

[0181] Step 1: Preparation of 5-[4-(2,2-dimethoxyethyl)piperazin-l-yl]-2-(2,6- dioxo-3- piperidyl)isoindoline-l, 3-dione , ,

[0182] To a solution of 2-(2,6-dioxo-3-piperidyl)-5-piperazin-l-yl-isoindoline-l, 3-dione (400 mg, 1.06 mmol, 1 eq, hydrochloride) in dichloromethane (6 mL) and methanol (2 mL) was added sodium caetate (129 mg, 1.58 mmol, 1.5 eq). The mixture was stirred at 20 °C for 0.5 hr. Then 2,2-dimethoxyacetaldehyde (549 mg, 5.28 mmol, 5 eq) and acetic acid (63 mg, 1.06 mmol, 1 eq) was added to the mixture. The mixture was stirred at 20 °C for 0.5 hr. Then sodium cyanob orohydri de (132 mg, 2.11 mmol, 2 eq) was added to the mixture. The mixture was stirred at 20 °C for 1 hour. The mixture was diluted with water (30 mL) and extracted with dichloromethane (20 mL x 3). The combined organic layers were washed with brine (30 mL x 3), dried over anhydrous sodium suflate, filtered, and concentrated under vacuum. The residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 0-1.5% methanol / dichloromethane gradient @ 40 mL / min) to give 5-[4-(2,2-dimethoxyethyl) piperazin-l-yl]-2-(2,6-dioxo-3-piperidyl)isoindoline-l, 3-dione (320 mg, 743.40 umol, 70.40% yield) as a yellow solid. LCMS: MS (ESI) m / z 431.2[M+1]+. ’H NMR: (400 MHz, CHLOROFORM-tZ) 5: 8.20 - 8.04 (m, 1H), 7.70 (d, J= 8.8 Hz, 1H), 7.29 (d, J= 2.4 Hz, 1H), 7.06 (dd, J= 2.4, 8.8 Hz, 1H), 5.00 - 4.90 (m, 1H), 4.57 (t, J= 5.2 Hz, 1H), 3.47 - 3.42 (m, 4H), 3.40 (s, 6H), 2.95 - 2.74 (m, 3H), 2.73 - 2.68 (m, 4H), 2.61 (d, J = 5.2 Hz, 2H), 2.17 - 2.10 (m, 1H). Step 2: Preparation of 2-[4-[2-(2,6-dioxo-3-piperidyl)-l,3-(lioxo- isoindolin-5-yl]piperazin- 1 -yl] acetaldehyde

[0183] To a solution of 5-[4-(2,2-dimethoxyethyl)piperazin-l-yl]-2-(2,6-dioxo-3-piperidyl) isoindoline-1, 3-dione (270 mg, 0.63 mmol, 1 eq in tetrahydrofuran (3 mL) was added sulfuric acid (4 M, 3 mL, 19.13 eq). The mixture was stirred at 80 °C for 2 hr. LCMS showed the reaction was completed. The mixture was adjusted to pH 8 with saturated sodium bicarbonate and extracted with ethyl acetate (50 mL x 2). The combined organic layers were washed with brine (80 mL x 2), dried over anhydrous sodium suflate, filtered, and concentrated under vacuum. The residue was purified by flash silica gel chromatography (ISCO®; 4 g SepaFlash® Silica Flash Column, eluent of 0~2% methanol / di chloromethane gradient @ 30 mL / min) to give 2-[4-[2-(2,6-dioxo-3-piperidyl)-l,3-dioxo-isoindolin-5-yl] piperazin-l-yl]acetaldehyde (60 mg, 0.16 mmol, 24.89% yield) as a yellow oil. LCMS: MS (ESI) m / z:403.3[M+18+l]+.

[0184] Intermediate 10

[0185] Preparation of 3-benzyloxycyclobutanol

[0186] To a solution of 3-benzyloxycyclobutanone (10 g, 56.75 mmol, 1 eq) in ethanol (100 mL) was added sodium borohydride (2.8 g, 74.01 mmol, 1.3 eq at 0 °C. The mixture was stirred at 0 °C for 2 hours. Thin layer chromatography (petroleum ether: ethyl acetate=2:l) showed the reaction was completed. The reaction mixture was quenched by added water (100 mL) and then extracted with ethyl acetate (100 mL x 3). The combined organic phases were washed with brine (200 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® Silica Flash Column, Eluent of 0~20 % Ethyl acetate / Petroleum ether gradient @ 50 mL / min) to give 3-benzyloxycyclobutanol (9.5 g, 53.30 mmol, 93.93% yield) as a colorless oil. ’ H NMR: (400 MHz, CHLOROFORM-d) 5: 7.40 - 7.27 (m, 5H), 4.43 (s, 2H), 3.92 (quin, J= 7.2 Hz, 1H), 3.64 (quin, J= 6.8 Hz, 1H), 2.73 (dtd, J= 3.2, 6.4, 9.2 Hz, 2H), 2.01 - 1.89 (m, 2H).

[0187] Step 2: Preparation of dimethyl 4-(3-benzyloxycyclobutoxy)benzene- 1,2-dicarboxylate

[0188] To a solution of 3 -benzyl oxy cyclobutanol (1 g, 5.61 mmol, 1 eq) in tetrahydrofuran (20 mL) was added sodium hydride (269 mg, 6.73 mmol, 60% purity, 1.2 eq). The mixture was stirred at 0 °C for 0.5 hr. Then dimethyl 4-fluorobenzene- 1,2-dicarboxylate (1.31 g, 6.17 mmol, 1.1 eq) was added to the mixture. The mixture was stirred at 10 °C for 11.5 hr. The mixture was diluted with water (30 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with brine (50 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The crude product was purified by prep- HPLC (column: Phenomenex Synergi Max-RP 250*50mm*10 pm;mobile phase: [water(0.225%FA)-ACN];B%: 40%-70%,21min) to give dimethyl 4-(3- benzyl oxy cy cl obutoxy)benzene- 1,2-dicarboxylate (500 mg, 1.35 mmol, 24.06% yield) as a colorless oil. LCMS: MS (ESI) m / z: 393.0[M+23]+.

[0189] Intermediate 11

[0190] Step 1: Preparation of methyl 2-bromo-4-[4-(dimethoxy methyl)-!- piperidyl / benzoate

[0191] To a solution of 4-(dimethoxymethyl)piperidine (44.41 g, 278.93 mmol, 1.3 eq) and methyl 2-bromo-4-fluoro-benzoate (50 g, 214.56 mmol, 1 eq) in dimethyl sulfoxide (500 mL) was added N,N-diisopropylethylamine (55.46 g, 429.12 mmol, 2 eq). The mixture was stirred at 120 °C for 2 hr. The mixture was diluted with water (1500 mL) and extracted with ethyl acetate (500 mL x 3). The combined organic layers were washed with brine (1000 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The crude product was triturated with petroleum ether and ethyl acetate (V: V=20: 1, 200 mL) to give methyl 2-bromo-4-[4-(dimethoxymethyl)-l-piperidyl]benzoate (64 g, 170.03 mmol, 79.25% yield, 98.9% purity) as a light yellow solid.

[0192] Step 2: Preparation of methyl 4-[4-(dimethoxymethyl)-l-piperidyl]-2- formyl-benzoate

[0193] To a solution of methyl 2-bromo-4-[4-(dimethoxymethyl)-l-piperidyl]benzoate (52 g, 139.69 mmol, 1 eq in N,N-dimethylformamide (500 mL) was added 2-isocyano-2-methyl-propane (23.23 g, 279.38 mmol, 2 eq , palladium acetate (3.14 g, 13.97 mmol, 0.1 eq), tricyclohexylphosphane (3.92 g, 13.97 mmol, 0.1 eq , sodium carbonate (14.81 g, 139.69 mmol, 1 eq and triethylsilane (48.73 g, 419.07 mmol, 3 eq . The mixture was stirred at 65 °C for 12 hours at autoclave. Thin layer chromatography (petroleum ether: ethyl acetate=3: l) showed the reaction was completed. The mixture was diluted with water (500 mL) and extracted with ethyl acetate (300 mL x 3). The combined organic layers were washed with brine (500 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by flash silica gel chromatography (ISCO®; 120 g SepaFlash® silica flash column, eluent of 0—15 % ethyl acetate / petroleum ether gradient @ 100 mL / min). Then the crude product was triturated with petroleum ether and ethyl acetate (v: v=10:l. 300 mL) to give methyl 4-[4-(dimethoxymethyl)-l-piperidyl]-2-formyl -benzoate (22 g, 68.46 mmol, 49.01% yield) as a light yellow solid.1H NMR: (400 MHz, CHLOROFORM-tZ) 5: 10.74 (s, 1H), 7.90 (d, J= 8.8 Hz, 1H), 7.33 (d, J= 2.8 Hz, 1H), 7.00 (dd, J= 2.8, 8.8 Hz, 1H), 4.06 (d, J= 6.4 Hz, 1H), 3.96 (d, J= 12.8 Hz, 2H), 3.91 (s, 3H), 3.38 (s, 6H), 2.93 - 2.82 (m, 2H), 1.86 (d, J= 10.0 Hz, 3H), 1.46 - 1.35 (m, 2H).

[0194] Step 3: Preparation of 3-[5-[4-(dimethoxymethyl)-l-piperidyl]-l-oxo- isoindolin-2- yl]piperidine-2, 6-dione

[0195] To a solution of 3 -aminopiperidine-2, 6-dione (12.11 g, 73.59 mmol, 1.1 eq, hydrochloride) in methanol (400 mL) was added sodium acetate (10.98 g, 133.80 mmol, 2 eq). The mixture was stirred at 15 °C for 10 min. Then acetic acid (40.18 g, 669.00 mmol, 10 eq) and methyl 4-[4- (dimethoxymethyl)-l-piperidyl]-2-formyl -benzoate (21.5 g, 66.90 mmol, 1 eq) was added to the mixture. The mixture was stirred at 15 °C for 20 min. Then NaBHsCN (8.41 g, 133.80 mmol, 2 eq) was added to the mixture. The mixture was stirred at 35 °C for 11.5 hr. The crude product was poured into ice water (1000 mL) and adjusted to pH 8 by saturated sodium bicarbonate. The mixture was stirred at 15 °C for 10 min. The mixture was filtered, and the filter cake was washed with water (200 mL) and acetonitrile (200 mL x 2). The filter cake was concentrated under vacuum. The crude product was triturated with ethyl acetate (100 mL) to give 3-[5-[4-(dimethoxymethyl)-l-piperidyl]-l-oxo-isoindolin-2-yl]piperidine-2,6- dione (20 g, 48.97 mmol, 73.20% yield, 98.3% purity) as a light yellow solid. LCMS: MS (ESI) m / z 402.2 [M+l]+. ’H NMR: (400 MHz, DMSO-tL) 8: 10.93 (s, 1H), 7.49 (d, J= 8.4 Hz, 1H), 7.07 - 7.00 (m, 2H), 5.04 (dd, J= 5.2, 13.2 Hz, 1H), 4.35 - 4.25 (m, 1H), 4.24 - 4.14 (m, 1H), 4.07 (d, J= 6.8 Hz, 1H), 3.89 (d, J= 12.8 Hz, 2H), 3.27 (s, 6H), 2.94 - 2.85 (m, 1H), 2.83 - 2.72 (m, 2H), 2.63 - 2.54 (m, 1H), 2.36 (dq, J= 4.4, 13.2 Hz, 1H), 2.00 - 1.91 (m, 1H), 1.80 (dtd, J= 3.6, 7.6, 15.2 Hz, 1H), 1.70 (d, J= 12.8 Hz, 2H), 1.30 (dq, J= 3.6, 12.4 Hz, 2H).

[0196] Intermediate 12

[0197] Step 1: Preparation of 4-[4-(dimethoxymethyl)-l-piperidyl]-2-(2,6-dioxo- 3- piperidyl)isoindoline-l, 3-dione

[0198] To a solution of 2-(2,6-dioxo-3-piperidyl)-4-fluoro-isoindoline-l, 3-dione (300 mg, 1.09 mmol, 1 eq and 4-(dimethoxymethyl)piperidine (190 mg, 1.19 mmol, 1.1 eq) in dimethyl sulfoxide (5 mL) was added N,N-diisopropylethylamine (421 mg, 3.26 mmol, 3 eq . The mixture was stirred at 120 °C for 2 hr. The mixture was diluted with water (20 mL) and extracted with ethyl acetate (10 mL x 2). The combined organic layers were washed with brine (20 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by flash silica gel chromatography (ISCO®; 4 g SepaFlash® Silica flash column, eluent of 0~40 % ethyl acetate / petroleum ether gradient @ 30 mL / min) to give 4-[4-(dimethoxymethyl)-l-piperidyl]- 2-(2,6-dioxo-3- piperidyl)isoindoline-l, 3-dione (300 mg, 0.72 mmol, 66.49% yield) as a yellow oil. LCMS: MS (ESI) m / z: 416.1[M+1]+.

[0199] Step 2: Preparation of l-[2-(2,6-dioxo-3-piperidyl)-l,3-(lioxo- isoindolin-4-yl]piperidine-4- carbaldehyde

[0200] To a solution of 4-[4-(dimethoxymethyl)-l-piperidyl]-2-(2,6-dioxo-3-piperidyl)isoindoline- 1, 3-dione (100 mg, 0.24 mmol, 1 eq in tetrahydrofuran (1 mL) was added sulfuric acid (2 M, 1 mL, 8.31 eq). The mixture was stirred at 70 °C for 0.5 hr. The mixture was adjusted to pH 8 by saturated sodium bicarbonate and extracted with ethyl acetate (10 mL x 3). The combined organic layers were washed with brine (20 mL x 2), dried over anhydrous sodium suflate, filtered, and concentrated under vacuum. The crude product was used into next step without further purification. l-[2-(2,6-dioxo-3-piperidyl)-l,3-dioxo- isoindolin-4-yl]piperidine-4- carbaldehyde (70 mg, 189.51 umol, 78.73% yield) was obtained as a yellow oil.

[0201] Intermediate 13

[0202] Step 1: Preparation of 2-(2,6-dioxo-3-piperidyl)-4-fluoro -isoindoline-1, 3-dione

[0203] To a solution of 3 -aminopiperidine-2, 6-dione (8.05 g, 48.88 mmol, 3 eq, hydrochloric acid) in acetic acid (30 mL) was added sodium acetate (2.67 g, 32.59 mmol, 2 eq) and 3- fluorophthalic acid (3 g, 16.29 mmol, 1 eq). The mixture was stirred at 120 °C for 2 hr. The reaction mixture was concentrated under reduced pressure then diluted with water (10 mL) and extracted with ethyl acetate (10 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 2-(2,6- di oxo-3 -piperidyl)-4-fluoro -isoindoline-1, 3-dione (4.7 g, crude) was as a gray solid was used into next step without further purification. LCMS: MS (ESI) m / z 277.1 [M+l]+.

[0204] Intermediate 14

[0205] Step 1: Preparation of 5-(4-(dimethoxymethyl)piperidin-l-yl)-2-(2,6- dioxopiperidin-3-yl)- 6-fluoroisoindoline-l, 3-dione

[0206] To a solution of 2-(2,6-dioxo-3-piperidyl)-5,6-difluoro-isoindoline-l, 3-dione (5 g, 16.99 mmol, 1.00 eq in dimethylsulfoxide(30 mL) was added diisopropylethyllamine (4.39 g, 33.99 mmol, 2.00 eq) and 4-(dimethoxymethyl)piperidine (2.71 g, 16.99 mmol, 1.00 eq . The mixture was stirred at 120°C for 2 hr. The reaction mixture was diluted with water (80 mL) and extracted with ethyl acetate (100 mL x 3). The combined organic layers were washed with brine (100 mL * 3), dried over sodium acetate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (petroleum ether / ethyl acetate=10 / l to 1 : 1) to give 5-[4-(dimethoxymethyl)-l-piperidyl]-2-(2,6-dioxo-3-piperidyl)- 6-fluoro-isoindoline-l, 3-dione (5.5 g, 12.69 mmol, 74% yield) as a yellow solid. LCMS: MS (ESI) m / z: 434.3 [M+l]+.

[0207] Step 2: Preparation of l-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-l,3- dioxoisoindolin-5- yl)piperidine-4-carbaldehyde

[0208] To a solution of 5-[4-(dimethoxymethyl)-l-piperidyl]-2-(2,6-dioxo-3-piperidyl)-6-fluoro - isoindoline-1, 3-dione (2.8 g, 6.46 mmol, 1.00 eq in tetrahydrofuran (40 mL) was added sulfuric acid (2 M, 64.60 mL, 20.00 eq . The mixture was stirred at 50 °C for 0.25 hr. The mixture was poured into sodium bicarbonate solution (30 mL) and extracted with dichloromethane 90 mL (30 mL x 3). The organic layer was washed with brine 30 mL (10 mL * 3) dried over sodium sulfate anhydrous and concentrated under reduced pressure. l-[2- (2,6-dioxo-3-piperidyl)-6-fluoro- l,3-dioxo-isoindolin-5-yl]piperidine-4-carbaldehyde (2.3 g, crude) as a yellow solid was used into the next step without further purification. LCMS: MS (ESI) m / z: 388.1[M+1]+.

[0209] Intermediate 15

[0210] Step 1: Preparation of methyl 4-[4-(dimethoxymethyl)-l-piperidyl]-2-fluoro-benzoate

[0211] To a solution of methyl 2,4-difluorobenzoate (500 mg, 2.90 mmol, 1 eq) in dimethylsulfoxide (15 mL) was added N,N-diisopropylethylamine (5.81 mmol, 1.0 mL, 2 eq) and 4- (dimethoxymethyl)piperidine (462 mg, 2.90 mmol, 1 eq) .The mixture was stirred at 120 °C for 2 hr. The reaction mixture was diluted with water 30 mL and extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with brine (50 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® silica flash column, eluent of 0~8% ethyl acetate / petroleum ether gradient @ 40 mL / min). Methyl 4-[4- (dimethoxymethyl)-l-piperidyl]-2-fluoro-benzoate (260 mg, 0.81 mmol, 27% yield, 97% purity) was obtained as a white solid. LCMS: MS (ESI) m / r. 312.5 [M+l]+.

[0212] Step 2: Preparation of 4-[4-(dimethoxymethyl)-l-piperidyl]-2-fluoro-benzoic acid.

[0213] To a solution of methyl 4-[4-(dimethoxymethyl)-l-piperidyl]-2-fluoro-benzoate (350 mg, 1.12 mmol, 1 eq) in tetrahydrofuran (4 mL), methanol (2 mL) and water (1 mL) was added lithium hydroxide (235 mg, 5.62 mmol, 5 eq). The mixture was stirred at 40 °C for 2 hr. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was diluted with water 10 mL and hydrochloric acid (1 M) was added to adjust pH to 3-4. The mixture was extracted with dichloromethane 40 mL (20 mL x 2). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was used into next step without further purification. 4-[4- (dimethoxymethyl)-l-piperidyl]-2-fluoro-benzoic acid (320 mg, 1.08 mmol, 95% yield) was obtained as a white solid. LCMS: MS (ESI) m / z 298.5 [M+l]+. Step 3: Preparation of 4-[4-(dimethoxymethyl)-l-piperidyl]-N-(2,6-dioxo-3-piperidyl)-2- fluoro-benz amide

[0214] To a solution of 4-[4-(dimethoxymethyl)-l-piperidyl]-2-fluoro-benzoic acid (320 mg, 1.08 mmol, 1 eq) 3-aminopiperidine-2, 6-dione (212 mg, 1.29 mmol, 1.2 eq, Hydrochloride) in N,N-dimethylformamide (5 mL) was added O-(7-azabenzotriazol-l-yl)-N,N,N’,N’- tetramethyluronium hexafluorophosphate (613 mg, 1.61 mmol, 1.5 eq) and triethylamine (217 mg, 2.15 mmol, 2 eq). The mixture was stirred at 15 °C for 12 h. The reaction mixture was diluted with water 30 mL and extracted with di chloromethane (50 mL x 3). The combined organic layers were washed with brine (50 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by prep- thin layer chromatography (silica, dichloromethane: methanol = 20: 1). 4-[4- (dimethoxymethyl)-l-piperidyl]-N-(2,6-dioxo-3-piperidyl)-2-fluoro-benzamide (290 mg, 0.67 mmol, 62% yield, 94% purity) was obtained as a white solid. LCMS: MS (ESI) m / z 408.4 [M+l]+.

[0215] Step 4: Preparation ofN-(2,6-dioxo-3-piperidyl)-2-fluoro-4-(4-formyl-l- piperidyl)benzanude

[0216] To a solution of 4-[4-(dimethoxymethyl)-l-piperidyl]-N-(2,6-dioxo-3-piperidyl)-2 -fluorobenzamide (290 mg, 0.67 mmol, 1 eq) in tetrahydrofuran (5 mL) was added sulfuric acid (2 M, 4.70 mL, 14.05 eq) .The mixture was stirred at 70 °C for 2 hr. The reaction mixture was diluted with water (30 mL), and extracted with dichloromethane (50 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was used into next step without further purification. N-(2,6- dioxo-3-piperidyl)-2-fluoro-4-(4-formyl-l -piperidyl )benzamide (240 mg, 0.66 mmol, 99% yield) was obtained as a white solid. LCMS: MS (ESI) m / z 362.1 [M+l]+.

[0217] Intermediate 16

[0218] Step 1: Preparation of methyl 5-bromo-2-(bromomethyl)benzoate

[0219] To a solution of methyl 5 -bromo-2-methyl -benzoate (30 g, 131 mmol, 1 eq) in carbon tetrachloride (300 mL) was added N-bromosuccinimide (34.96 g, 196 mmol, 1.5 eq) and azobisisobutyronitrile (10.7 g, 65 mmol, 0.5 eq). Then the mixture was stirred at 90 °C for 12 hr. The mixture was concentrated to give the yellow oil. Water (300 mL) was added, and extracted with ethyl acetate (400 mL x 3). The organics were dried with anhydrous sodium sulfate, filtered, and concentrated to give the residue. The residue was purified by Pre-HPLC (column: Phenomenex luna cl8 250mm* 100mm* 10 pm; mobile phase: [water(0.225%FA)- ACN];B%: 50%-80%,20min). The solution was concentrated and extracted with ethyl acetate (300 mL x 3). The organics were dried with anhydrous sodium sulfate, filtered and concentrated to give the compound. Methyl 5-bromo-2-(bromomethyl)benzoate (28 g, 91 mmol, 69% yield) was yellow oil. ’H NMR: (CDCI3) 5: 8.11 (d, J = 2.0 Hz, 1H), 7.62 (dd, J = 2.0, 8.0 Hz, 1H), 7.35 (d, J = 8.4 Hz, 1H), 4.91 (s, 2H), 3.96 (s, 3H).

[0220] Step 2: Preparation of 3-(6-bromo-l-oxo-isoindolin-2-yl)piperidine-2, 6-dione

[0221] To a solution of 3 -aminopiperidine-2, 6-dione (27.8 g, 168.85 mmol, 2 eq, HC1) in N,N- dimethylformamide (260 mL) was added 7V,7V-diisopropylethylamine (43.65 g, 337.70 mmol, 4 eq) and methyl 5-bromo-2-(bromomethyl)benzoate (26 g, 84.42 mmol, 1 eq). The mixture was stirred at 50 °C for 3 hr. The mixture was warmed to 80 °C and stirred for 12 hr. Water (1000 mL) was added, and the mixture was stirred at 15 °C for 30 min. Then the mixture was filtered, and the filter cake was washed with water (100 mL x 3) and petroleum ether (100 mL x 2), then the filter cake was collected and concentrated under reduced pressure to give a residue. The crude product was triturated with ethyl acetate (500 mL) at 15 °C for 30 min. The mixture was filtered, and the filter cake was collected and concentrated to give the compound. 3-(6-bromo-l-oxo-isoindolin-2-yl)piperidine-2, 6-dione (22 g, 68.08 mmol, 81% yield) was purple solid. LCMS: MS (ESI) m / z 325.0[M+l]+. ’ H NMR: (DMSO-t / 6) 8: 11.00 (s, 1H), 7.98 - 7.71 (m, 2H), 7.60 (d, J = 8.0 Hz, 1H), 5.12-5.08 (m, 1H), 4.55 - 4.19 (m, 2H), 3.01 - 2.83 (m, 1H), 2.65 - 2.55 (m, 1H), 2.42 - 2.32 (m, 1H), 2.02-2.00 (m, 1H).

[0222] Intermediate 17

[0223] Step 1: Preparation of l-(2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-5-yl)azetidine-3- carbaldehyde

[0224] To a solution of 3-[5-[3-(dimethoxymethyl)azetidin-l-yl]-l-oxo-isoindolin-2-yl]piperidine- 2, 6-dione (Reactant 1) (3.3 g, 8.84 mmol, 1 eq) in dichloromethane (40 mL) was added trifluoroacetic acid (20 mL, 30 eq). The reaction mixture was stirred at 40°C for 2 hr. The pH was adjusted to pH 7 with triethylamine. l-[2-(2,6-dioxo-3-piperidyl)-l-oxo-isoindolin-5- yl]azetidine-3-carbaldehyde (2.8 g, 8.55 mmol, 96% yield) was obtained as a yellow oil and used into next step directly without further purification.

[0225] Intermediate 17

[0226] Step 1: Preparation of ethyl 2-[(5-bromo-4-methyl-3-nitro-2- pyridyl)oxy] acetate

[0227] To a solution of 5-bromo-2-chloro-4-methyl-3-nitro-pyridine (24 g, 95.44 mmol, 1 eq) in ethyl 2-hydroxyacetate (59.61 g, 572.64 mmol, 55.20 mL, 6 eq) was added 1,8- diazabicyclo[5.4.0]undec-7-ene (43.58 g, 286.29 mmol, 43.15 mL, 3.00 eq). The mixture was stirred at 30 °C for 12 hr. The reaction mixture was diluted with water (300 mL) and extracted with ethyl acetate (150 mL x 3). The combined organic phases were washed with saturated brine (200 mL x 2), dried with anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® silica flash column, eluent of 0-10% ethyl acetate / petroleum ether gradient @ 80 mL / min) to give ethyl 2-[(5-bromo-4-methyl-3 -nitro- 2-pyridyl)oxy]acetate (13 g, 40.74 mmol, 42% yield) as a light yellow solid.XH NMR: (400 MHz, CDC13) 8.27 (s, 1H), 4.94 (s, 2H), 4.22 (q, J= 7.2 Hz, 2H), 2.39 (s, 3H), 1.27 (t, J= 7.2 Hz, 3H).

[0228] Step 2: Preparation of 7-bronw-8-methyl-lH-pyrido[2,3- b][l,4]oxazin-2-one

[0229] A mixture of ethyl 2-[(5-bromo-4-methyl-3-nitro-2-pyridyl)oxy]acetate (12 g, 37.60 mmol, 1 eq , iron powder (8.40 g, 150.42 mmol, 4 eq) and acetic acid (677 mg, 11.28 mmol, 0.64 mL, 0.3 eq in toluene (120 mL) and water (12 mL) and then the mixture was stirred at 100°C for 12 hr under nitrogen. Hydrochloric acid (6 M, 31.34 mL, 5 eq was added and then the mixture was stirred at 120°C for 12 hr. The mixture was filtered at 60°C and the filter was concentrated. The residue was diluted with water (100 mL) and adjusted to pH 8~9 with saturated sodium bicarbonate. The mixture was extracted with ethyl acetate (50 mL x 3). The combined organic phase was washed with saturated brine (50 mL x 2), dried with anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was triturated with dichloromethane: methanol (V / V=l :20, 200 mL) to give 7-bromo-8-methyl-lH-pyrido[2,3- b][l,4]oxazin-2-one (7 g, 28.80 mmol, 76.59% yield) as a white solid.JH NMR: (400 MHz, CDC13) 3 10.66 (s, 1H), 7.92 (s, 1H), 4.73 (s, 2H), 2.31 (s, 3H).

[0230] Step 3: Preparation of 7-bronio-8-inethyl-2,3-dihydro-lH- pyrido[2,3-b][l,4]oxazine

[0231] To a solution of 7-bromo-8-methyl-lH-pyrido[2,3-b][l,4]oxazin-2-one (7 g, 28.80 mmol, 1 eq in tetrahydrofuran (200 mL) was added borane dimethyl sulfide complex (10 M, 8.64 mL, 3 eq) at 0°C.The mixture was stirred at 25°C for 0.5 hours and the mixture was warmed to 50°C. The mixture was stirred at 50°C for another 24 hr. The mixture was quenched by slowly addition water (200 mL) and methanol (200 mL) at 0°C. The residue was diluted with water (300 mL) and extracted with ethyl acetate (200 mL x 2). The combined organic phase was washed with saturated brine (200 mL x 2), dried with anhydrous sodium sulfate, filtered, and concentrated to give 7-bromo-8-methyl-2,3-dihydro-lH-pyrido[2,3-b][l,4]oxazine (6 g, 26.19 mmol, 90.95% yield) as a yellow solid. LCMS: MS (ESI) m / z 229.0[M]+.

[0232] Step 4: Preparation of tert-butyl 7-bromo-8-methyI-2,3- dihydropyrido[2,3-b][l,4]oxazine- 1-carboxylate

[0233] To a solution of 7-bromo-8-methyl-2,3-dihydro-lH-pyrido[2,3-b][l,4]oxazine (6 g, 26.19 mmol, 1 eq) in tetrahydrofuran (20 mL) was dropwise added hexamethyldisilimine lithium (1 M, 52.38 mL, 2 eq) at 0°C.The mixture was stirred at 0°C for 0.5 hr. Tert-butoxycarbonyl tert-butyl carbonate (17.15 g, 78.58 mmol, 18.05 mL, 3 eq was added and the mixture was stirred at 30°C for 12 hr. The mixture was quenched with water (100 mL) at 0°C and extracted with ethyl acetate (50 mL x 2). The combined organic phases were washed with saturated brine (50 mL x 2), dried with anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® Silica Flash Column, eluent of 5-20% ethyl acetate / petroleum ether gradient @ 80 mL / min) to give tert-butyl 7-bromo-8-methyl-2,3-dihydropyrido[2,3-b][l,4]oxazine-l- carboxylate (3.5 g, 10.63 mmol, 40.59% yield) as a light yellow solid. LCMS: MS (ESI) m / z 329.2[M]+. ’ H NMR: (400 MHz, CDC13) 8.14 (s, 1H), 4.61 - 4.30 (m, 4H), 2.29 (s, 3H), 1.48 (s, 9H).

[0234] Step 5: Preparation of tert-butyl 8-methyl-7-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)- 2,3-dihydropyrido[2,3-b][l,4]oxazine-l-carboxylate

[0235] A mixture of tert-butyl 7-bromo-8-methyl-2,3-dihydropyrido[2,3-b][l,4]oxazine-l- carboxylate (1 g, 3.04 mmol, 1 eq) , 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl- 1,3,2- dioxaborolan-2-yl)-l,3,2-dioxaborolane (3.86 g, 15.20 mmol, 5.00 eq) , [1,1 - bis(diphenylphosphino)ferrocene]dichloropalladium(ii) (445.16 mg, 608.39 umol, 0.2 eq , potassium acetate (895 mg, 9.12 mmol, 3.00 eq) in dioxane (30 mL) and then the mixture was stirred at 90 °C for 2.5 hr under nitrogen atmosphere. The reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (60 mL x 2). The combined organic phase was washed with saturated brine (60 mL x 2), dried with anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® silica flash column, eluent of 0-5% ethyl acetate / petroleum ether gradient @ 50 mL / min) to give tert-butyl-8-methyl-7-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)-2,3- dihydropyrido[2,3-b][l,4]oxazine-l-carboxylate (1 g, 2.66 mmol, 87.49% yield) as a white solid. LCMS: MS (ESI) m / z IAI 3A [M+l]+ / [M-82+l],

[0236] Intermediate 18

[0237] Step 1: Preparation of azetidin-3-ylmethanol To a solution of tert-butyl 3 -(hydroxymethyl)azetidine-l -carboxylate (20 g, 106.82 mmol, 1 eq in dichloromethane (200 mL) was added trifluoroacetic acid (61.60 g, 540.24 mmol, 40 mL, 5.06 eq), the reaction solution was stirred at 25 °C for 2 hr. The reaction solution was concentrated under vacuum to get the crude product. The crude product was used in the next step directly without any further purification. Azeti din-3 -ylmethanol (21.5 g, crude, trifluoroacetate) was obtained as a light yellow oil.

[0238] Step 2: Preparation of benzyl 3-(hydroxymethyl)azetidine-l-carboxylate . Cbz

[0239] To a solution of azeti din-3 -ylmethanol (16 g, 79.55 mmol, 1 eq, trifluoroacetic acid) and sodium carbonate (45 g, 424.57 mmol, 5.34 eq in tetrahydrofuran (100 mL) and water (100 mL) was added benzyl carbonochloridate (15 g, 87.93 mmol, 12.50 mL, 1.11 eq at 0 °C. The mixture was stirred at 25 °C for 12 hr. The reaction mixture was poured into water 500 mL at 0 °C and extracted with ethyl acetate (200 mL x 3). The combined organic layers were washed with saturated brine (200 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate=10 / l to 1 / 1). Benzyl 3- (hydroxymethyl)azetidine-l -carboxylate (15 g, 67.80 mmol, 85% yield) was obtained as a yellow oil. LCMS: MS (ESI) m / z 222.2 [M+l]+. ’H NMR : (400MHz, DMSO-d6, ppm) 5 = 7.40 - 7.30 (m, 5H), 5.02 (s, 2H), 4.80 (t, J = 5.2 Hz, 1H), 4.10 - 3.80 (m, 2H), 3.75 - 3.65 (m, 2H), 3.50 (t, J = 5.6 Hz, 2H), 2.70 - 2.60 (m, 1H)

[0240] Step 3: Preparation of benzyl 3-formylazetidine-l -carboxylate , , ,

[0241] To a mixture of dimethylsulfoxide (34.78 g, 445.19 mmol, 34. 8 mL, 5 eq in dichloromethane (300 mL) was added oxalyl dichloride (22.60 g, 178.08 mmol, 15.6 mL, 2 eq at -65 °C and stirred for 0.5 h under nitrogen. Then the mixture was added a solution of benzyl 3 -(hydroxymethyl)azetidine-l -carboxylate (19.7 g, 89.04 mmol, 1 eq in dichloromethane (60 mL) at -65 °C and stirred for 1 hr. The resulting mixture was added triethylamine (36.04 g, 356.16 mmol, 49.6 mL, 4 eq at -65 °C and stirred for 1 hr. The mixture was warmed to 25 °C and added ice-water (50 mL) and stirred for 15 min. The aqueous phase was extracted with ethyl acetate (200 mL x 2). The combined organic phase was washed with brine (200 mL x 2), dried with anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was used in the next step directly without further purification. Benzyl 3 -formylazetidine- 1- carboxylate (18 g, crude) as a yellow oil.

[0242] Step 4: Preparation of benzyl 3fdinietlioxynietliyl)a~etidine-l- carboxylate

[0243] To a mixture of benzyl 3-formylazetidine-l-carboxylate (18 g, 82.10 mmol, 1 eq) in trimethoxymethane (200 mL) and methanol (100 mL) was added pyridinium p- toluenesulfonate (1.03 g, 4.11 mmol, 0.05 eq) in one portion at 25 °C under nitrogen. The mixture was stirred at 25 °C for 6 hr. The mixture was diluted with ethyl acetate (300 mL), washed with brine (100 mL x 3), dried with anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography (petroleum ether / ethyl acetate=20 / l, 1 / 1) to afford benzyl 3 -(dimeth oxymethyl)azeti dine- 1- carboxylate (18.2 g, 68.60 mmol, 84% yield) as a yellow oil.1H NMR: (400 MHz, CDCh) d: 7.37 - 7.28 (m, 5H), 5.11 (s, 2H), 4.53 (d, J= 10.4 Hz, 1H), 4.07 - 4.03 (m, 2H), 3.88 - 3.86 (m, 2H), 3.39 (d, J= 2.4 Hz, 6H), 2.88 - 2.85 (m, 1H).

[0244] Step 5: Preparation of 3-(dimethoxymethyl)azetidine

[0245] To a solution of benzyl 3 -(dimethoxymethyl)azetidine-l -carboxylate (18.2 g, 68.60 mmol, 1 eq) in trifluoroethanol (300 mL) was added palladium on activated carbon catalyst (10 g, 5% purity) under nitrogen. The suspension was degassed under vacuum and purged with hydrogen several times. The mixture was stirred under hydrogen (50 psi) at 45°C for 24 hr. The reaction mixture was filtered and the filtrate was concentrated. The crude product was used in the next step directly without further purification. 3 -(dimethoxymethyl) azetidine (9.0 g, crude) was obtained as a yellow oil.

[0246] Step 6: Preparation of 5-[3-(dimethoxymethyl)azetidin-l-yl]-2-(2,6 -dioxo-3- piperidyl)isoindoline-l, 3-dione

[0247] To a mixture of 3-(dimethoxymethyl)azetidine (2.85 g, 21.72 mmol, 1.5 eq) and 2-(2,6- dioxo- 3-piperidyl)-5-fluoro-isoindoline-l, 3-dione (4.0 g, 14.48 mmol, 1 eq) in dimethylsulfoxide (60 mL) was added N, / f-diisopropylethylamine (5.61 g, 43.44 mmol, 7.6 mL, 3 eq) in one portion at 25°C under nitrogen. The mixture was stirred at 115 °C for 6 hr. The mixture was cooled to 25 °C, diluted with ethyl acetate (200 mL), washed with brine (60 mL x 3), dried with anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was triturated with ethyl acetate (20 mL). 5-[3-(dimethoxymethyl)azetidin-l-yl]-2- (2, 6-dioxo-3-piperidyl)isoindoline-l, 3-dione (4.6 g, 11.87 mmol, 82% yield) as a yellow solid. LCMS: MS (ESI) m / z: 387.9 [M+l]+. ’H NMR: (400 MHz, DMSO-t / 6) d: 11.07 (br s, 1H), 7.63 (d, J= 8.4 Hz, 1H), 6.79 (d, J= 2.0 Hz, 1H), 6.65 (dd, J= 2.0, 8.4 Hz, 1H), 5.05 (dd, J= 5.6, 12.8 Hz, 1H), 4.63 (d, J= 6.4 Hz, 1H), 4.11 - 4.03 (m, 2H), 3.83 (dd, J= 5.6, 8.4 Hz, 2H), 3.33 - 3.19 (m, 7H), 3.09 - 3.04 (m, 1H), 2.94 - 2.82 (m, 1H), 2.63 - 2.53 (m, 2H), 2.02 (td, = 2.4, 5.2 Hz, 1H).

[0248] Step 7: Preparation of l-[2-(2,6-dioxo-3-piperidyl)-l,3-(lioxo- isoindolin-5-yl]azetidine-3- carbaldehyde

[0249] To a mixture of 5-[3-(dimethoxymethyl)azetidin-l-yl]-2-(2,6-dioxo-3-piperidyl)isoindoline - 1,3-dione (1.48 g, 3.82 mmol, 1 eq) in dichloromethane (20 mL) was added trifluoroacetic acid (10.78 g, 94.54 mmol, 7 mL, 24.75 eq) and stirred at 25 °C for 1 hr under nitrogen. The mixture was cooled to 25 °C and concentrated in reduced pressure at 45 °C. The residue was diluted with ethyl acetate (100 mL), washed with brine (50 mL x 3), dried with anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was triturated t-butyl methyl ether (20 mL). l-[2-(2,6 -dioxo-3-piperidyl)-l,3-dioxo-isoindolin-5-yl]azetidine-3- carbaldehyde (1.0 g, 2.93 mmol, 77% yield) as a yellow solid. LCMS: MS (ESI) m / z'. 360.3 [M+19]+.

[0250] Intermediate 19

[0251] Step 1: Preparation of 4-[4-(dimethoxymethyl)-l-piperidyl]-2-(2,6-(lioxo- 3- piperidyl)isoindoline-l, 3-dione

[0252] A mixture of 2-(2,6-dioxo-3-piperidyl)-4-fluoro-isoindoline-l, 3-dione (3 g, 10.86 mmol, 1 eq), 4-(dimethoxymethyl)piperidine (3.46 g, 21.72 mmol, 2 eq), 7V,7V-diisopropylethylamine (4.45 g, 34.45 mmol, 6 mL, 3.17 eq) in dimethyl sulfoxide (50 mL) and then the mixture was stirred at 120 °C for 12 hr under nitrogen atmosphere. The reaction mixture was filtered and concentrated under vacuum. The residue was purified by prep-HPLC (column: Phenomenex luna C18 (250*70 mm, 15 um); mobile phase: [water (0.225% FA) - ACN]; B%: 30ACN% - 60ACN%, 19 min). 4-[4-(dimethoxy methyl)- l-piperidyl]-2-(2,6-dioxo-3- piperidyl)isoindoline-l, 3-dione (4.4 g, 10.59 mmol, 97% yield) was obtained as a yellow solid. LCMS: MS (ESI) m / z 416.25 [M+l]+.

[0253] Step 2: Preparation of l-[2-(2,6-dioxo-3-piperidyl)-l,3-dioxo-isoindolin-4- yl]piperidine-4- carbaldehyde

[0254] To a solution of 4-[4-(dimethoxymethyl)-l-piperidyl]-2-(2,6-dioxo-3-piperidyl)isoindoline- 1, 3-dione (4.4 g, 10.59 mmol, 1 eq) in tetrahydrofuran (50 mL) and water (50 mL) was added sulfuric acid (16.90 g, 172.33 mmol, 9.2 mL, 16.27 eq). The mixture was stirred at 70 °C for 1 h. LCMS showed 4-[4-(dimethoxymethyl)-l-piperidyl]-2-(2,6-dioxo-3-piperidyl) isoindoline-1, 3-dione (4.4 g, 10.59 mmol, 1 eq) was consumed completely and one main peak with desired mass was detected. The reaction mixture was diluted with saturated sodium bicarbonate (200 mL) and extracted with ethyl acetate (200 mL x 2). The combined organic phase was washed with saturated brine (200 mL), dried with anhydrous sodium sulfate, filtered, and concentrated under vacuum. The crude product was used into the next step without further purification. l-[2-(2,6-dioxo-3-piperidyl)-l,3-dioxo-isoindolin-4-yl] piperidine-4-carbaldehyde (3.9 g, 10.56 mmol, 99% yield) was obtained as a yellow solid, the product was confirmed by ’H NMR. LCMS: MS (ESI) m / z: 370.3 [M+l]+. ’H NMR: (400 MHz, DMSO-tL) 3: 11.09 (s, 1H), 9.67 (s, 1H), 7.69 (dd, J= 7.2, 8.4 Hz, 1H), 7.40 - 7.27 (m, 2H), 5.10 (dd, J= 5.6, 12.8 Hz, 1H), 3.67 - 3.53 (m, 2H), 3.02 (br t, J= 10.4 Hz, 2H), 2.94 - 2.82 (m, 1H), 2.65 - 2.52 (m, 3H), 2.51 - 2.48 (m, 1H), 2.08 - 2.01 (m, 1H), 1.99 - 1.94 (m, 1H), 1.79 - 1.64 (m, 2H).

[0255] Intermediate 20

[0256] Step 1: Preparation of 4-[3-(dimethoxymethyl)azetidin-l-yl]-2-(2,6-dioxo-3- piperidyl)isoindoline-l, 3-dione

[0257] To a solution of 2-(2,6-dioxo-3-piperidyl)-4-fluoro-isoindoline-l, 3-dione (300 mg, 1.09 mmol, 1 eq) in dimethylsulfoxide (2 mL) was added diisopropyl ethylamine (421 mg, 3.26 mmol, 0.6 mL, 3 eq) and 3-(dimethoxymethyl)azetidine (171 mg, 1.30 mmol, 1.2 eq). The mixture was stirred at 120 °C for 1 h. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (10 mL x 3). The combined organic phase was washed with saturated brine (30 mL), dried with anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by column chromatography ( dichloromethane / methanol =400 / 1 to 50 / 1). 4-[3-(dimethoxymethyl)azetidin-l-yl]-2-(2,6- dioxo-3-piperidyl)isoindoline-l, 3-dione (249 mg, 0.64 mmol, 59% yield). LCMS: MS (ESI) m / z =387.4 [M +1]+. ’H NMR (400 MHz, CHLOROFORM-d) 5: 8.16 (s, 1H), 7.45 (dd, J= 7.2, 8.5 Hz, 1H), 7.17 (d, J= 6.8 Hz, 1H), 6.58 (d, J = 8.4 Hz, 1H), 4.93 (dd, J= 5.6, 12.4 Hz, 1H), 4.61 (d, J= 6.8 Hz, 1H), 4.31 (t, J= 8.8 Hz, 2H), 4.11 (dd, J= 5.6, 8.8 Hz, 2H), 3.49 (s, 1H), 3.38 (s, 5H), 3.05 - 2.62 (m, 4H), 2.18 - 2.01 (m, 1H).

[0258] Step 2: Preparation of l-[2-(2,6-dioxo-3-piperidyl)-l,3-dioxo-isoindolin-4-yl]azetidine-3- carbaldehyde

[0259] To a solution 4-[3-(dimethoxymethyl)azetidin-l-yl]-2-(2,6-dioxo-3-piperidyl)isoindoline-l,3- dione (85 mg, 0.22 mmol, 1 eq in acetone (4.5 mL) and water (1.5 mL) was added p-toluene sulphonic acid (7.56 mg, 43.88 umol, 0.2 eq). The mixture was stirred at 80 °C for 1 hr. The reaction mixture was partitioned sodium bicarbonate solution (20 mL) and extracted with ethyl acetate (8 mL x 3). The combined organic phase was washed with saturated brine (15mL), dried with anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by column chromatography (SiCL, dichloromethane:methanol to 100: 1 to 30: 1) l-[2-(2,6-dioxo-3-piperidyl)-l,3-dioxo-isoindolin-4-yl]azetidine-3- carbaldehyde (63 mg, 0.18 mmol, 84% yield) was obtained as a yellow oil. LCMS: MS (ESI) m / z: 341.3 [M +1]+.

[0260] Intermediate 21

[0261] Step 1: Preparation of methyl 2-(3-bromo-5-methyl-pyrazol-l-yl)acetate. 20°C, 12 h

[0262] To a solution of 3-bromo-5-methyl-lH-pyrazole (5 g, 31.06 mmol, 1 eq) and methyl 2- chloroacetate (5.06 g, 46.58 mmol, 4.11 mL, 1.5 eq in dimethyl formamide (150 mL) was added potassium carbonate (8.58 g, 62.11 mmol, 2 eq) and tetrabutyl ammonium iodide (573 mg, 1.55 mmol, 0.05 eq). The mixture was stirred at 20 °C for 12 hr. Water (100 mL) was poured into the mixture and stirred for 1 min. The aqueous phase was extracted with ethyl acetate (100 mL x 3). The combined organic phase was washed with brine (100 mL x 2), dried with anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by column chromatography (petroleum ether / ethyl acetate=50 / l to 3 / 1). Methyl 2-(3-bromo -5-methyl-pyrazol-l-yl)acetate (5.5 g, 23.60 mmol, 75% yield) was obtained as a white solid. LCMS: MS (ESI) m / z: 232.7 [M+l]+. ’H NMR: (400MHz, DMSO-t / 6) d : 6.21 (s, 1H), 5.03 (s, 2H), 3.69 (s, 3H), 2.20 (s, 3H).

[0263] Step 2: Preparation of methyl 2-[3-bromo-5-(bromomethyl)pyrazol-l-yl]acetate

[0264] To a solution of methyl 2-(3-bromo-5-methyl-pyrazol-l-yl)acetate (5.5 g, 23.60 mmol, 1 eq) in tetrachloromethane (150 mL) was added azobisisobutyronitrile (387 mg, 2.36 mmol, 0.1 eq), the mixture was stirred at 25 °C for 10 min, and N-bromosuccinimide (4.41 g, 24.78 mmol, 1.05 eq) was added to the mixture, the mixture was stirred at 80 °C for 50 min. The reaction mixture concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether / ethyl acetate=50 / l to 5 / 1). Methyl 2-[3-bromo-5- (bromomethyl) pyrazol-l-yl]acetate (6 g, 19.23 mmol, 81% yield) was obtained as a yellow oil. LCMS: MS (ESI) m / z 312.9 [M+l]+.

[0265] Step 3: Preparation of methyl 2-[3-bromo-5-(cyanomethyl)pyrazol-l-yl]acetate

[0266] To a solution of methyl 2-[3-bromo-5-(bromomethyl)pyrazol-l-yl]acetate (6 g, 19.23 mmol, 1 eq) in dimethylsulfoxide (120 mL) was added sodium cyanide (1.51 g, 30.77 mmol, 1.6 eq). The mixture was stirred at 25 °C for 1 h. Water (100 mL) was poured into the mixture and stirred for 1 min. The aqueous phase was extracted with ethyl acetate (100 mL x 3). The combined organic phase was washed with brine (100 mL x 2), dried with anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by column chromatography (petroleum ether / ethyl acetate=50 / l to 3 / 1). Methyl 2-[3-bromo-5- (cyanomethyl) pyrazol-l-yl]acetate (2.5 g, 9.69 mmol, 50% yield) was obtained as a yellow oil. LCMS: MS (ESI) m / r. 260.0 [M+l]+. ’H NMR: (400MHz, DMSO-t / 6) 3 : 6.50 (s, 1H), 5.13 (s, 2H), 4.21 (s, 2H), 3.69 (s, 3H).

[0267] Step 4: Preparation of methyl 2-[5-(2-aminoethyl)-3-bromo-pyrazol-l-yl]acetate

[0268] To a solution of methyl 2-[3-bromo-5-(cyanomethyl)pyrazol-l-yl]acetate (500 mg, 1.94 mmol, 1 eq) in methanol (15 mL) was added platinum dioxide (150 mg, 0.66 mmol, 3.41e-l eq) under nitrogen. The suspension was degassed under vacuum and purged with hydrogen several times. The mixture was stirred under hydrogen (1 MPa) at 25 °C for 12 hr. The reaction mixture was filtered and the filtrate was concentrated. The crude product was used into the next step without further purification. Methyl 2-[5-(2-aminoethyl)-3-bromo-pyrazol- 1-yl] acetate (500 mg, crude) was obtained as a yellow oil.

[0269] Step 5: Preparation of 2-bromo-4,5,6,8-tetrahydropyrazolo[l,5-d][l,4]diazepin-7-one

[0270] To a solution of methyl 2-[5-(2-aminoethyl)-3-bromo-pyrazol-l-yl]acetate (500 mg, 1.91 mmol, 1 eq) in methanol (30 mL) was added triethylamine (7.27 g, 71.85 mmol, 10 mL, 37.66 eq). The mixture was stirred at 25 °C for 12 h. The reaction mixture concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® Silica Flash Column, eluent of 0-10% methanol / dichloromethane @ 40 mL / min). 2-bromo-4,5,6,8-tetrahydropyrazolo [l,5-d][l,4]diazepin-7-one (150 mg, 0.65 mmol, 34.18% yield) was obtained as a white solid. LCMS: MS (ESI) m / z\rL31' 2> [M+l]+.

[0271] Intermediate 22

[0272] Step 1: Preparation of methyl 4-bromo-3-hydroxy-2-methyl-benzoate

[0273] To a solution of 2-methylpropan-2-amine (2.20 g, 30.09 mmol, 3.16 mL, 1 eq) in dichloromethane (200 mL) at -70 °C was added a solution of Br2 (4.81 g, 30.09 mmol, 1.55 mL, 1 eq) in di chloromethane (10 mL) drop wise and the mixture was stirred at - 70°C for Ihr, A solution of methyl 3-hydroxy-2-methyl-benzoate (5 g, 30.09 mmol, 1 eq) in dichloromethane (10 mL) was stirred at 25 °C for 11 hr. The reaction mixture was quenched with water (100 mL) at 20 °C, and extracted with dichloromethane (200 mL * 3), The combined organic layers were washed with brine (150 mL * 3), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® silica flash column, eluent of 0~5% ethyl acetate / petroleum ether gradient @ 80 mL / min). Methyl 4-bromo-3 -hydroxy-2 - methyl-benzoate (3.95 g, 16.12 mmol, 53% yield) was confirmed byJH NMR as a white solid. ’ H NMR: (400MHz, DMSO-d6) d: 9.39 (s, 1H), 7.45 (d, J= 8.4 Hz, 1H), 7.17 (d, J= 8.5 Hz, 1H), 3.80 (s, 3H), 2.37 (s, 3H).

[0274] Step 2: Preparation of methyl 4-hromo-3-methoxy-2-inethyl-hen~,oate

[0275] To a solution of methyl 4-bromo-3-hydroxy-2-methyl-benzoate (12 g, 48.97 mmol, 1 eq) in acetonitrile (200 mL) was added potassium carbonate (8.12 g, 58.76 mmol, 1.2 eq) and iodomethane (17.38 g, 122 mmol, 7.62 mL, 2.5 eq), the mixture was stirred at 50 °C for 5 hr. The reaction mixture was quenched by aqueous ammonium chloride solution (300 mL) at 20 °C, and extracted with ethyl acetate (500 mL x 3), the combined organic layers were washed with brine (500 mL x 3), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. Methyl 4-bromo-3-methoxy-2-methyl -benzoate (25 g, 96.49 mmol, 98% yield) was confirmed by1H NMR as a yellow oil. 'H NMR: (400MHz, CHLOROFORM-d) d: 7.53 - 7.48 (m, 1H), 7.46 - 7.41 (m, 1H), 3.88 (s, 3H), 3.82 - 3.78 (m, 3H), 2.56 (s, 3H). Step 3: Preparation of 4-bronw-2-(broinoinethyI)-3-methoxy-ben~,oate

[0276] To a solution of methyl 4-bromo-3-methoxy-2-methyl-benzoate (9.5 g, 36.67 mmol, 1 eq) in carbontetrachloride (100 mL) was added N-bromosuccinimide (8.48 g, 47.67 mmol, 1.3 eq) and (E)-2,2'-(diazene-l,2-diyl)bis(2 -methylpropanenitrile) (602 mg, 3.67 mmol, 0.1 eq), the mixture was stirred at 70 °C for 12 hr. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. Methyl 4-bromo-2-(bromomethyl)-3 -methoxy- benzoate (24 g, 71 mmol, 96% yield) was confirmed byJH NMR as yellow oil.1H NMR: (400MHz, CHLOROFORM-d) d: 7.66 - 7.55 (m, 2H), 5.08 (s, 2H), 4.02 (s, 3H), 3.96 - 3.90 (m, 3H).

[0277] Step 4: Preparation of 3-(5-bromo-4-niethoxy-l-oxo-isoindolin-2-yl)piperidine-2, 6-dione

[0278] To a solution of 3 -aminopiperidine-2, 6-dione (7.30 g, 44.38 mmol, 1.5 eq, hydrochloride) and diisopropylethylamine (19.12 g, 148 mmol, 25.77 mL, 5 eq) in 7V,7V-dimethylformamide (300 mL) was added methyl 4-bromo-2-(bromomethyl)-3 -methoxy-benzoate (10 g, 29.59 mmol, 1 eq), the mixture was stirred at 100 °C for 12 hr. The reaction mixture was diluted with water (500 mL), filtered, and the filter cake concentrated under reduced pressure to give a residue. 3-(5-bromo-4-methoxy-l-oxo-isoindolin-2-yl)piperidine-2, 6-dione (20 g, 56.63 mmol, 64 % yield) was confirmed by1H NMR as a brown solid. LCMS: MS (ESI) m / z 355.1[M+1]+. ’H NMR: (400MHz, DMSO-d6) 11.01 (s, 1H), 7.76 (d, J= 8.0 Hz, 1H), 7.36 (d, J= 8.0 Hz, 1H), 5.10 (dd, J= 5.1, 13.3 Hz, 1H), 4.80 - 4.65 (m, 1H), 4.62 - 4.47 (m, 1H), 4.02 - 3.94 (m, 3H), 2.91 (ddd, J= 5.4, 13.6, 17.4 Hz, 1H), 2.64 - 2.57 (m, 1H), 2.46 - 2.38 (m, 1H), 2.08 - 1.96 (m, 1H).

[0279] Intermediate 23

[0280] Step 1: Preparations of 2-(2,6-dioxo-3-piperidyl)-4-fluoro-isoindoline-l, 3-dione

[0281] To a mixture of 3-aminopiperidine-2, 6-dione (10.90 g, 66.22 mmol, 1.1 eq, hydrochloride) and 4-fluoroisobenzofuran-l, 3-dione (10 g, 60.20 mmol, 1 eq} in acetic acid (150 mL) was added potassium acetate (18.32 g, 186.63 mmol, 3.1 eq in one portion at 100°C under nitrogen. The mixture was stirred at 100 °C for 16 hr. The mixture was cooled to 20 °C and concentrated under reduced pressure at 55 °C. The residue was triturated with ethyl acetate (100 mL) and water (30mL), the cake was collected under reduced pressure, and dried under high vacuum. 2-(2,6-dioxo-3-piperidyl)-4-fluoro-isoindoline-l, 3-dione (8.9 g, 32.22 mmol, 53% yield) was obtained as a black solid.1H NMR: (400 MHz, DMSO-d6) 5 11.15 (br s, 1H), 7.95 (dt, J= 4.6, 7.9 Hz, 1H), 7.82 - 7.70 (m, 2H), 5.17 (dd, J= 5.3, 12.9 Hz, 1H), 2.99 - 2.81 (m, 1H), 2.66 - 2.52 (m, 2H), 2.13 - 2.02 (m, 1H).

[0282] Intermediate 24

[0283] Step 1: Preparation of 7-bromo-l,8-dimethyl-pyri(lo[2,3-b][l,4]oxazin-2-one

[0284] To a solution of 7-bromo-8-methyl-lH-pyrido[2,3-b][l,4]oxazin-2-one (Reactant 1) (4 g, 16.46 mmol, 1 eq} in tetrahydrofuran (20 mL) under nitrogen atmosphere was added sodium hydride (800 mg, 20.00 mmol, 60% purity, 1.22 eq} at 0 °C and stirred at 0 °C for 1 hr. Then iodomethane (11.68 g, 82.29 mmol, 5.12 mL, 5 eq} in tetrahydrofuran (10 mL) was added to the mixture at 0 °C and stirred at 25 °C for another 1 h. The reaction mixture was quenched by water (50 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic phase was washed with saturated brine (5 mL), dried with anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by column chromatography (silicon dioxide, petroleum ether / ethyl acetate = 10 / 1 to 1 / 1). 7-bromo-l,8-dimethyl-pyrido[2,3- b][l,4]oxazin-2-one (2.8 g, 10.89 mmol, 66% yield) was obtained as a white solid. LCMS: MS (ESI) m / z: 259.0 [M +1]+. ’H NMR: (400 MHz, CHLOROFORM-d) 5 = 8.09 (s, 1H), 4.66 (s, 2H), 3.37 (s, 3H), 2.48 (s, 3H).

[0285] Intermediate 25

[0286] Step 1: Preparation of 4-fluorophthalic acid

[0287] A mixture of KMnCE (8kg, 50.71mol, 6.3eq.), H2O(14L, 14V) and t-BuOH(5L , 5V) was added to 100L reactor. The solution of 4-fluoro-l,2-dimethylbenzene (1kg, 8.05mol, l.Oeq.) in t-BuOH(lL ,1V) was drop wise to the reactor slowly at 76-85 °C. The resulting solution was stirred for 5 hr at 82-85 °C. After cooling to 70 °C, EtOH (10L , 10V) was added and stirred for 0.5 hr, then filtered through kieselguhr, and washed the filter cake with water (2.5L,2.5V)*2. Then EtOH and t-BuOH was removed by concentration under vacuum. The residue was washed with ethyl acetate (10L,10V)*2. The pH of aqueous phase was adjusted to pH 1.0 with cone HC1 (about 3 V), then extracted with ethyl acetate (5L,5V) once, and ethyl acetate (3L,3 V) once. The ethyl acetate layers were combined and dried with anhydrous MgSO4 and concentrated to afford 0.99kg 4-fluorophthalic acid as a white solid with 68% yield.

[0288] Step 2: Preparation of 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-l, 3-dione

[0289] A mixture of 4-fluorophthalic acid (4kg, 21.72mol, l.Oeq), 4-fluorophthalic acid HC1 (3.933kg, 23.90mol, l.leq ), CH3COONa (4.713kg, 26.07mol, 1.2eq), CH3COOH(20L , 5V). The resulting solution was stirred for 4 hrs at 118 °C. Then H2O (60 kg, 15 V) was added to the mixture slowly at 90°C -118°C. After cooling to 30 °C, the reaction mixture was filtered and washed the filter cake with water (8L,2V)*2. The filter cake was collected and dried at 60 °C to get 5.2 kg product as off-white solid with 86.7% yield.

[0290] Intermediate 26 Step 1: Preparation of 5-(4-(dimethoxymethyl)piperi(lin-l-yl)-2-(2,6-(lioxopiperi(lin-3-yl)iso indoline-1, 3 -dione

[0291] To a solution of 2-(2,6-dioxo-3-piperidyl)-5-fluoro-isoindoline-l, 3-dione (1 g, 3.62 mmol, 1 eq in dimethylsulfoxide (10 mL) was added N, / f-diisopropylethylamine (1.40 g, 10.86 mmol, 1.89 mL, 3 eq) and 4-(dimethoxymethyl)piperidine (692 mg, 4.34 mmol, 1.2 eq). The mixture was stirred at 120 °C for 4 hr. The residue was poured into water (40 mL) and stirred for 0.5 min. The aqueous phase was extracted with ethyl acetate (20mL x 2). The combined organic phase was washed with brine (15 mL), dried with anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® Silica Flash Column, Eluent of 0-100% ethyl acetate / petroleum ether gradient @ 60 mL / min). 5-[4-(dimethoxymethyl)-l-piperidyl]-2-(2,6-dioxo-3- piperidyl)isoindoline-l, 3-dione (970 mg, 2.33 mmol, 64% yield) was obtained as a yellow solid. LCMS: MS (ESI) m / z: 426.3 [M+H]+. ’H NMR: (400 MHz, CHLOROFORM-d) 5 = 7.96 (br s, 1H), 7.68 (d, J= 8.4 Hz, 1H), 7.29 (d, J= 2.0 Hz, 1H), 7.07 (dd, J= 2.4, 8.4 Hz, 1H), 4.95 (dd, J= 5.2, 12.4 Hz, 1H), 4.07 (d, J= 6.4 Hz, 1H), 3.98 (br d, J= 13.2 Hz, 2H), 3.39 (s, 6H), 2.99 - 2.92 (m, 2H), 2.90 - 2.69 (m, 3H), 2.17 - 2.10 (m, 1H), 1.92 - 1.84 (m, 3H), 1.50 - 1.36 (m, 2H).

[0292] Intermediate 27

[0293] Step 1: Preparation of l-[2-(2,6-dioxo-3-piperidyl)-l,3-dioxo-isoindolin-5-yl]piperidine-4- carbaldehyde To a solution of 5-[4-(dimethoxymethyl)-l-piperidyl]-2-(2,6-dioxo-3-piperidyl)isoindoline- 1, 3-dione (200 mg, 0.48 mmol, eq) in tetrahydrofuran (4 mL) was added vitriol (2 M, 4 mL, 16.62 eq . The mixture was stirred at 40 °C for 1 hr. The reaction was adjusted to pH 8 by saturated sodium bicarbonate, and the aqueous phase was extracted with ethyl acetate (30 mL x 3). The combined organic phase was washed with brine (30 mL), dried with anhydrous sodium sulfate, filtered, and concentrated under vacuum. l-[2-(2,6-dioxo-3-piperidyl)-l,3- dioxo-isoindolin-5-yl]piperidine-4-carbaldehyde (170 mg, 0.46 mmol, 96% yield) was obtained as a yellow solid. LCMS: MS (ESI) m / z: 370.3 [M+H]+. ’H NMR: (400 MHz, CHLOROFORM-d) 5 = 9.73 (s, 1H), 7.97 (br s, 1H), 7.71 (d, J= 8.4 Hz, 1H), 7.31 (d, J= 2.0 Hz, 1H), 7.10 (dd, J= 2.4, 8.8 Hz, 1H), 5.01 - 4.88 (m, 1H), 3.86 (td, J= 4.0, 13.2 Hz, 2H), 3.28 - 3.12 (m, 2H), 2.95 - 2.73 (m, 3H), 2.64 - 2.52 (m, 1H), 2.19 - 2.06 (m, 3H), 1.81 (dtd, J= 4.0, 10.0, 14.0 Hz, 2H).

[0294] Intermediate 28

[0295] Step 1: Preparation of 2-[5-(2-aminoethyl)-3-bromo-pyrazol-l-yl] acetic acid

[0296] To a solution of 2-bromo-4,5,6,8-tetrahydropyrazolo[l,5-d][l,4]diazepin-7-one (500 mg, 2.17 mmol, 1 eq) in tetrahydrofuran (2 mL), methanol (2 mL) and water (2 mL) was added lithium hydroxide (912 mg, 21.73 mmol, 10 eq). The reaction mixture was stirred at 25 °C for 12 hr. The reaction mixture was concentrated under reduced pressure to give a residue. The product was taken to the next step without purification. The desired 2-[5-(2-aminoethyl)-3-bromo- pyrazol-l-yl]acetic acid (530 mg, crude) was obtained as white solid.

[0297] Intermediate 29

[0298] To a solution of tert-butyl 3 -(hydroxymethyl)azetidine-l -carboxylate (28 g, 149.54 mmol, 1 eq) in dichloromethane (300 mL) was added hydrochloric acid in dioxane (4 M, 250 mL, 6.69 eq . The mixture was stirred at 15 °C for 1 hr. The mixture was concentrated under vacuum. The crude product was used into the next step without further purification. Azeti din-3 - ylmethanol (54 g, 436.96 mmol, 97% yield, hydrochloride) was obtained as a white oil.

[0299] Intermediate 30

[0300] Step 1: Preparation of 2,6-diben~yloxy-3-hronw-pyridine

[0301] To a solution of 3-bromo-2,6-difluoro-pyridine (Reactant 1) (5 g, 25.78 mmol, 1 eq) and phenyl methanol (7.00 g, 64.73 mmol, 6.73 mL, 2.51 eq) in acetonitrile (100 mL) was added cesium carbonate (25.20 g, 77.33 mmol, 3 eq). The reaction mixture was stirred at 80 °C for 12 hr. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give a residue and purified by column chromatography (silicon dioxide, petroleum ether / ethyl acetate = 100 / 1 to 10 / 1). 2,6-dibenzyloxy-3-bromo-pyridine (8.6 g, 23.23 mmol, 90% yield) was obtained as a white solid. LCMS: MS (ESI) m / z: 372.1 [M+l]+. ’H NMR: (400 MHz, dimethylsulfoxide-d6) 8 = 7.89 (d, J= 8.4 Hz, 1H), 7.45 - 7.29 (m, 10H), 6.44 (d, J= 8.4 Hz, 1H), 5.42 (s, 2H), 5.33 (s, 2H).

[0302] Step 2: Preparation of 2,6-dibenzyloxy-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)pyridine

[0303] A mixture of 2, 6-dibenzyl oxy-3 -bromo-pyridine (4 g, 10.80 mmol, 1 eq), bis(pinacolato)diboron (4.12 g, 16.21 mmol, 1.5 eq), potassium acetate (2.12 g, 21.61 mmol, 2 eq), [l,T-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (790 mg, 1.08 mmol, 0.1 eq) in dioxane (50 mL) and then the mixture was stirred at 100 °C for 12 hr under nitrogen atmosphere. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (silicon dioxide, petroleum ether / ethyl acetate = 1 / 0 to 50 / 1). 2,6-dibenzyloxy-3-(4,4,5,5-tetramethyl- l,3,2-dioxaborolan-2-yl)pyridine (3.2 g, crude) was obtained as a colorless oil. LCMS: MS (ESI) m / z 418.3 [M+l]+. Intermediate 31

[0304] Step 1: Preparation of tert-butyl 7-(3-anuno-7-fluoro-6-isoquinolyl)-8- methyl-2,3- dihydropyrido[2,3-b][l,4]oxazine-l-carboxylate

[0305] A mixture of tert-butyl 8-methyl-7-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-2,3 - dihydropyrido[2,3-b][l,4]oxazine-l-carboxylate (312 mg, 0.82 mmol, 1 eq), 6-bromo-7- fluoro-isoquinolin-3 -amine (200 mg, 0.82 mmol, 1 eq), [1,1'- bis(diphenylphosphino)ferrocene]dichloropalladium(ii) (78 mg, 0.10 mmol, 0.13 eq), sodium carbonate (175 mg, 1.66 mmol, 2 eq) and water (1 mL) in dioxane (5 mL) and then the mixture was stirred at 95 °C for 12 hr under nitrogen atmosphere. The reaction mixture was diluted with water (20 mL) and extracted with tetrahydrofuran (10 mL x 2). The combined organic phase was washed with saturated brine (5 mL x 2), dried with anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by flash silica gel chromatography (ISCO®; 4 g SepaFlash® Silica Flash Column, Eluent of 0~3% dichloromethane: methanol gradient @ 40 mL / min) to give tert-butyl 7-(3-amino-7-fluoro-6- isoquinolyl)-8-methyl- 2,3-dihydropyrido[2,3-b][l,4]oxazine-l-carboxylate (180 mg, 0.43 mmol, 52% yield) as a yellow solid. LCMS: MS (ESI) m / z 411.3 [M+l]+.

[0306] Step 2: Preparation of tert-butyl 7-[3-[(7-tert-butoxycarbonyl-7-azaspiro[3.5]nonan-2- yl)oxycarbonylanuno]-7-fluoro-6-isoquinolyl]-8-methyl-2,3-diliydropyrido[2,3- b][l,4]oxazine-l-carboxylate

[0307] A mixture of tert-butyl 7-(3-amino-7-fluoro-6-isoquinolyl)-8-methyl-2,3-dihydropyrido[2,3- b][l,4]oxazine-l-carboxylate (Reactant 1) (1.7 g, 4.14 mmol, 1 eq), tert-butyl 2-hydroxy-7- azaspiro[3.5]nonane-7-carboxylate (2.00 g, 8.28 mmol, 2 eq) and diisopropylethylamine (2.68 g, 20.71 mmol, 3.61 mL, 5 eq) in di chloromethane (25 mL) was added bis(trichloromethyl) carbonate (1.47 g, 4.95 mmol, 1.20 eq) at 0 °C. The mixture was stirred at 0 °C for 1 hr. The reaction mixture was quenched by saturated sodium hydrogen carbonate solution 50 mL and extracted with dichloromethane (20 mL x 3), washed with saturated brine (20 mL x 1), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® Silica Flash Column, Eluent of 0-30% ethyl acetate / petroleum ether gradient @ 100 mL / min). Tert-butyl 7-[3-[(7-tert-butoxycarbonyl-7- azaspiro[3.5]nonan-2-yl)oxycarbonylamino]-7-fluoro-6-isoquinolyl]-8-methyl-2,3- dihydropyrido[2,3-b][l,4]oxazine-l-carboxylate (1.5 g, 2.21 mmol, 53% yield) was obtained as a white solid. LCMS: MS (ESI) m / z: 678.4 [M+l]+. ’H NMR: (400 MHz, CHLOROFORM-d) 5 = 8.99 (s, 1H), 8.29 (s, 1H), 7.98 (s, 1H), 7.96 (s, 1H), 7.69 (d, J= 6.8 Hz, 1H), 7.59 (d, J= 9.6 Hz, 1H), 5.14 (quin, J= 7.2 Hz, 1H), 4.67 - 4.34 (m, 3H), 3.41 - 3.36 (m, 2H), 3.36 - 3.31 (m, 2H), 3.25 - 3.06 (m, 1H), 2.48 - 2.39 (m, 2H), 2.13 (s, 3H), 2.01 - 1.93 (m, 2H), 1.63 - 1.57 (m, 4H), 1.52 (s, 9H), 1.46 (s, 9H).

[0308] Step 3: Preparation of 7-azaspiro[3.5]nonan-2-yl N-[7-fluoro-6-(8-methyl-2,3-dihydro-lH- pyrido[2,3-b][l,4]oxazin-7-yl)-3-isoquinolyl]carbamate

[0309] To a solution of tert-butyl 7-[3-[(7-tert-butoxycarbonyl-7-azaspiro[3.5]nonan-2- yl)oxycarbonylamino]-7-fluoro-6-isoquinolyl]-8-methyl-2,3-dihydropyrido[2,3- b][l,4]oxazine-l-carboxylate (800 mg, 1.18 mmol, 1 eq) in methanol (8 mL) was added hydrogen chloride / dioxane (4 M, 8.00 mL, 27.11 eq). The mixture was stirred at 25 °C for 1 hr. The solution was evaporated on a water bath under reduced pressure. 7- azaspiro[3.5]nonan-2-yl N-[7-fhroro-6-(8-methyl-2,3-dihydro-lH-pyrido[2,3-b][l,4]oxazin- 7-yl)-3-isoquinolyl]carbamate (500 mg, 1.05 mmol, 89% yield) was obtained as a yellow solid.

[0310] Intermediate 32

[0311] Step 1: Preparation of 3-(6-bromo-l-oxoisoindolin-2-yl)piperidine-2, 6-dione

[0312] To a solution of methyl 5-bromo-2-(bromomethyl)benzoate (5 g, 16.24 mmol, 1 eq) in N,N- dimethylformamide (50 mL) was added N,N-diisopropylethylamine (8.39 g, 64.94 mmol, 11.31 mL, 4 eq) and 3 -aminopiperidine-2, 6-dione (2.94 g, 17.86 mmol, 1.1 eq, hydrochloride). The mixture was stirred at 80 °C for 20 hr. The mixture was concentrated under reduced pressure. The crude product was triturated with water for 15 min. Then the residue was filtered to give a black solid. 3-(6-bromo-l-oxo-isoindolin-2-yl)piperidine-2,6- dione (4.6 g, 14.24 mmol, 88% yield) was obtained as a black solid. LCMS: MS (ESI) m / z 323.0 [M+l]+.

[0313] Intermediate 33

[0314] Step 1: Preparation of tert-butyl 7-[3-[(7-tert-butoxycarbonyl-7-azaspiro[3.5]nonan-2- yl)oxycarbonylanuno]-7-fluoro-6-isoquinolyl]-8-methoxy-2,3-dihydropyrido[2,3- b][l,4]oxazine-l -carboxylate

[0315] A mixture of tert-butyl 7-(3-amino-7-fluoro-6-isoquinolyl)-8-methoxy-2,3- dihydropyrido[2,3-b][l,4]oxazine-l-carboxylate (Reactant 1) (500 mg, 1.17 mmol, 1 eq), tert-butyl 2-hydroxy-7-azaspiro[3.5]nonane-7-carboxylate (570 mg, 2.36 mmol, 2.01 eq) and diisopropylethylamine (758 mg, 5.86 mmol, 1.02 mL, 5 eq) in dichloromethane (15 mL) was added bis(trichloromethyl) carbonate (344 mg, 1.16 mmol, 9.89e-l eq) at 0 °C. The mixture was stirred at 0 °C for 1 hr. The reaction mixture was quenched by saturated sodium hydrogen carbonate solution 20 mL and extracted with di chloromethane (10 mL x 3), washed with saturated brine (10 mL x 1), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®;12 g SepaFlash® Silica Flash Column, Eluent of 0-50% ethyl acetate / petroleum ether gradient @ 100 mL / min). Tert-butyl 7-[3-[(7-tert- butoxycarbonyl-7-azaspiro[3.5]nonan-2-yl)oxycarbonylamino]-7-fluoro-6-isoquinolyl]-8- methoxy-2,3-dihydropyrido[2,3-b][l,4]oxazine-l-carboxylate (600 mg, 0.86 mmol, 74% yield) was obtained as a yellow solid. LCMS: MS (ESI) m / z: 694.4 [M +1]+.1H NMR: (400 MHz, CHLOROFORM-d) 5 = 8.96 (s, 1H), 8.31 (s, 1H), 8.06 - 7.86 (m, 2H), 7.74 (d, J= 6.8 Hz, 1H), 7.59 (d, J= 8.0 Hz, 1H), 5.14 (t, J= 7.2 Hz, 1H), 4.52 (s, 2H), 3.71 (s, 3H), 3.41 - 3.31 (m, 4H), 2.47 - 2.39 (m, 2H), 2.00 - 1.74 (m, 5H), 1.60 (s, 3H), 1.50 (s, 9H), 1.46 (s, 9H).

[0316] Intermediate 34

[0317] Step 1: Preparation of 2-[[7-fluoro-6-(8-methyl-2,3-dihydro-lH-pyrido[2,3-b][l,4]oxazin-7- yl)-3-isoquinolyl]anuno]-6-(4-piperidyl)-5,8-dihydro-4H-pyrazolo[l,5-d][l,4]diazepin-7- one

[0318] To a solution of tert-butyl 7-[3-[[6-(l-tert-butoxycarbonyl-4-piperidyl)-7-oxo-5,8-dihydro- 4H-pyrazolo[l,5-d][l,4]diazepin-2-yl]amino]-7-fluoro-6-isoquinolyl]-8-methyl-2,3- dihydropyrido[2,3-b][l,4]oxazine-l-carboxylate (100 mg, 134.62 pmol, 1 eq in dichloromethane (2 mL) was added trifluoroacetic acid (3.08 g, 27.01 mmol, 2 mL, 200.66 eq). The mixture was stirred at 25 °C for 0.5 hr. The reaction mixture was concentrated under reduced pressure to give a residue. 2-[[7-fhroro-6-(8-methyl-2,3-dihydro-lH-pyrido[2,3- b][l,4]oxazin-7-yl)-3-isoquinolyl]amino]-6-(4-piperidyl)-5,8-dihydro-4H-pyrazolo[l,5- d][l,4]diazepin-7-one (70 mg, crude) was obtained as a yellow oil. Step 2: Preparation of 2-(2,6-dioxo-3-piperidyl)-5-[3-[[4-[2-[[7-fluoro-6-(8-methyl-2,3- dihydro-LH-pyrido[2,3-b][l,4]oxazin- 7-yl)-3-isoquinolyl]amino]~ 7-oxo-5, 8-dihydro-4H- pyrazolo[l,5-d][l,4]diazepin-6-yl]-l-piperidyl]methyl]azetidin-l-yl]isoindoline-l, 3-dione

[0319] To a solution of l-[2-(2,6-dioxo-3-piperidyl)-l,3-dioxo-isoindolin-5-yl]azetidine-3- carbaldehyde (48.44 mg, 141.91 umol, 1.1 eq and 2-[[7-fluoro-6-(8-methyl-2,3-dihydro-lH- pyrido[2,3-b][l,4]oxazin-7-yl)-3-isoquinolyl]amino]-6-(4-piperidyl)-5,8-dihydro-4H- pyrazolo[l,5-d][l,4]diazepin-7-one (70 mg, 129.01 pmol, 1 eq in dimethylsulfoxide (5 mL) was added acetic acid (7.75 mg, 129.01 pmol, 7.38 uL, 1 eq and stirred at 25 °C for 0.5 hr, then sodium tri acetoxyb orohydri de (82.03 mg, 387.02 umol, 3 eq was added to the mixture and stirred at 25 °C for 11.5 hr. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex Luna C18 150*25mm*10 pm; mobile phase: [water(FA)-ACN];B%: 8%-38%,10min). 2- (2,6-dioxo-3-piperidyl)-5-[3-[[4-[2-[[7-fluoro-6-(8-methyl-2,3-dihydro-lH-pyrido[2,3- b][l,4]oxazin-7-yl)-3-isoquinolyl]amino]-7-oxo-5,8-dihydro-4H-pyrazolo[l,5- d][l,4]diazepin-6-yl]-l-piperidyl]methyl]azetidin-l-yl]isoindoline-l, 3-dione (32 mg, 34.40 umol, 26.67% yield, 93.31% purity) was obtained as a yellow solid. LCMS: MS (ESI) m / z 868.1 [M+H]+. ’H NMR: (400MHz, DMSO) 3 .- 11.07 (s, 1H), 9.24 (s, 1H), 8.98 (s, 1H), 8.31 (s, 1H), 7.90 (s, 1H), 7.78 (d, J= 10.0 Hz, 1H), 7.65 (dd, Ji = 7.6, J2= 14.4 Hz, 2H), 7.37 (s, 1H), 6.77 (d, J= 2.0 Hz, 1H), 6.64 (dd, Ji = 2.0, J2= 8.4 Hz, 1H), 5.97 (s, 1H), 5.70 (s, 1H), 5.05 (dd, Ji = 5.2, J2= 12.8 Hz, 1H), 5.00 (s, 2H), 4.29 (t, J= 4.0 Hz, 2H), 4.23 - 4.17 (m, 1H), 4.13 (t, J= 8.0 Hz, 2H), 3.81 (s, 2H), 3.68 (dd, Ji = 5.6, J2= 8.0 Hz, 2H), 3.43 (s, 2H), 3.00 - 2.90 (m, 6H), 2.61 (d, J= 7.2 Hz, 2H), 2.08 - 1.97 (m, 4H), 1.92 (d, J= 1.6 Hz, 3H), 1.79 - 1.70 (m, 2H), 1.57 - 1.51 (m, 2H).

[0320] Intermediate 35

[0321] Step 1: Preparation of benzyl 4-(hydroxy methyl) piperidine-1- carboxylate

[0322] To a solution of 4-piperidylmethanol (Reactant 1) (5 g, 43.41 mmol, 1 eq) in dichloromethane (100 mL) was added sodium carbonate (20.71 g, 195.36 mmol, 4.5 eq) in water (100 mL) at 0°C, and carbobenzoxy chloride (8.15 g, 47.75 mmol, 6.8 mL, 1.1 eq) was added dropwise. The mixture was stirred at 20 °C for 16 hr. The mixture was diluted with water (100 mL), extracted with dichloromethane (100 mL x 2). The combined organic layers were washed with brine (100 mL x 2), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (petroleum etherethyl acetate=10: l to 2: 1). Benzyl 4-(hydroxymethyl) piperidine- 1 -carboxylate (14.2 g, 56.96 mmol, 66% yield) was obtained as a colorless oil.1H NMR: (400MHz, CHLOROFORM-d) 5 7.44 - 7.30 (m, 5H), 5.15 (s, 2H), 4.35 - 4.16 (m, 2H), 3.53 (t, 7=5.7 Hz, 2H), 2.81 (s, 2H), 1.82 - 1.64 (m, 3H), 1.42 (t, 7=5.4 Hz, 1H), 1.19 (d, 2H).

[0323] Step 2: Preparation of benzyl 4-formylpiperidine-l -carboxylate

[0324] To a solution of benzyl 4-(hydroxymethyl) piperidine- 1 -carboxylate (Reactant 1) (13.2 g, 52.95 mmol, 1 eq) in dichloromethane (200 mL) was added Dess-Martin (24.70 g, 58.24 mmol, 18 mL, 1.1 eq) at 0 °C. The mixture was stirred at 20 °C for 2 hr. The mixture was diluted with saturated sodium bicarbonate solution (300 mL) and extracted with dichloromethane (200 mL x 2). The combined organic layers were washed with brine (200 mL x 2), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (petroleum ether : ethyl acetate=10: l to 3: 1). Benzyl 4-formylpiperidine-l -carboxylate (11.6 g, 46.91 mmol, 88% yield) was obtained as a colorless oil.1H NMR: (400MHz, CHLOROFORM-d) 5 9.69 (s, 1H), 7.44 - 7.30 (m, 5H), 5.15 (s, 2H), 4.13 - 3.99 (m, 2H), 3.05 (t, 7=11.0 Hz, 2H), 2.51 - 2.42 (m, 1H), 1.94 (s, 2H), 1.68 - 1.58 (t, 7=7.2 Hz, 2H).

[0325] Step 3: Preparation of benzyl 4-(dimethoxymethyl) piperidine-1- carboxylate

[0326] To a solution of benzyl 4-formylpiperidine-l -carboxylate (Reactant 1) (11 g, 44.48 mmol, 1 eq in methanol (100 mL) was added trimethoxymethane (23.6 g, 222.41 mmol, 24 mL, 5 eq) and 4-methylbenzenesulfonic acid; hydrate (423 mg, 2.22 mmol, 0.05 eq . The mixture was stirred at 20 °C for 12 hr. The mixture was quenched by addition water (200 mL), diluted with dichloromethane (200 mL), extracted with dichloromethane (200mL x 2). The combined organic layers were washed with brine (200 mL x 2), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was used into next step without further purification. Benzyl 4-(dimethoxymethyl) piperidine- 1 -carboxylate (11.2 g, 38.18 mmol, 86% yield) was obtained as a colorless oil.1H NMR: (400MHz, CHLOROFORM-d) 5 7.42 - 7.30 (m, 5H), 5.14 (s, 2H), 4.33 - 4.13 (m, 2H), 4.04 (d, J=6.9 Hz, 1H), 3.37 (s, 6H), 2.76 (s, 2H), 1.86 - 1.70 (m, 3H), 1.34 - 1.16 (m, 2H).

[0327] Step 4: Preparation of 4-(dimethoxymethyl) piperidine

[0328] To a solution of benzyl 4-(dimethoxymethyl) piperidine- 1 -carboxylate (Reactant 1) (11.2 g, 38.18 mmol, 1 eq in methanol (150 mL) was added palladium on activated carbon catalyst (1.25 g, 3.82 mmol, 10% purity, 0.1 eq) under nitrogen. The suspension was degassed under vacuum and purged with hydrogen several times. The mixture was stirred under hydrogen (15 psi) at 20 °C for 12 hr. The mixture was filtered, and the filtrate was concentrated under vacuum. The residue was used into next step without further purification. 4- (dimethoxymethyl)piperidine (5.92 g, 37.18 mmol, 97 % yield) was obtained as a colorless oil. ’H NMR: (400MHz, CHLOROFORM-d) 5 3.95 (d, =6.8 Hz, 1H), 3.28 (s, 6H), 3.03 (d, J=12.0 Hz, 2H), 2.50 (d, 2H), 1.75 - 1.64 (m, 4H), 1.24 - 1.04 (m, 2H).

[0329] Intermediate 36

[0330] Step 1: Preparation of 3-(4-bromo-l-oxo-isoindolin-2-yl)piperidine-2, 6-dione

[0331] To a solution of 3 -aminopiperidine-2, 6-dione (2.14 g, 12.99 mmol, 2 eq, hydrochloride) and diisopropylethylamine (3.36 g, 25.98 mmol, 4.52 mL, 4 eq) in N,N-dimethylformamide (30 mL) was added methyl 3-bromo-2-(bromomethyl)benzoate (2 g, 6.49 mmol, 1 eq). The reaction mixture was stirred at 50 °C for 3 hr and then stirred at 80 °C for 10 hr. The reaction mixture was poured into water (150 mL) and was filtered, the filter cake was washed with water (20 mL x 3). The crude product was triturated with ethyl acetate (10 mL) at 25 °C for 15 min. The mixture was filtered, and the filter cake was washed with 5 mL of ethyl acetate, dried under vacuum to give product. 3-(4-bromo-l-oxo-isoindolin-2-yl)piperidine-2, 6-dione (1.5 g, 4.64 mmol, 71% yield) was obtained as a black brown solid. LCMS: MS (ESI) m / z: 322.7 [M +l]+.

[0332] Step 2: Preparation of 3-[4-[3-(dimethoxymethyl)azetidin-l-yl]-l-oxo-isoindolin-2- yl]piperidine-2, 6-dione

[0333] To a solution of 3-(4-bromo-l-oxo-isoindolin-2-yl)piperidine-2, 6-dione (Reactant 1) (500 mg, 1.55 mmol, 1 eq and 3-(dimethoxymethyl)azetidine (220 mg, 1.68 mmol, 1.08 eq) in dimethylsulfoxide (10 mL) was added cesium carbonate (1.01 g, 3.09 mmol, 2 eq and 1,3- bis[2,6-bis(l-propylbutyl)phenyl]-4,5-dichloro-2H-imidazol-l-ium-2-ide;3- chloropyridine;dichloropalladium (151 mg, 0.15 mmol, 0.1 eq . The mixture was stirred at 80 °C for 2 hr. The reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate (10 mL x 3). The combined organic phases were washed with saturated brine (10 mL x 1), dried with anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® silica flash column, eluent of 0-30% ethyl acetate / petroleum ether gradient @ 100 mL / min). 3-[4- [3-(dimethoxymethyl)azetidin-l-yl]-l-oxo-isoindolin-2-yl]piperidine-2, 6-dione (150 mg, 0.40 mmol, 26% yield) was obtained as a yellow solid. LCMS: MS (ESI) m / z: 374.2 [M +1]+. ’H NMR: (400 MHz, CHLOROFORM-d) 5 = 7.94 (s, 1H), 7.38 - 7.30 (m, 2H), 6.55 (dd, J= 1.2, 7.6 Hz, 1H), 5.24 (dd, J= 5.2, 13.2 Hz, 1H), 4.65 (d, J= 7.2 Hz, 1H), 4.49 (d, J = 15.6 Hz, 1H), 4.30 (d, J= 15.6 Hz, 1H), 4.06 (dt, J= 3.2, 7.6 Hz, 2H), 3.90 - 3.83 (m, 2H), 3.39 (d, J= 2.0 Hz, 6H), 3.03 (d, J= 7.6 Hz, 1H), 2.93 - 2.78 (m, 2H), 2.35 (dd, J= 5.2, 12.8 Hz, 1H), 2.25 - 2.17 (m, 1H).

[0334] Step 3: Preparation of l-[2-(2,6-dioxo-3-piperidyl)-l-oxo-isoindolin-4-yl]azetidine-3- carbaldehyde

[0335] To a solution of 3-[4-[3-(dimethoxymethyl)azetidin-l-yl]-l-oxo-isoindolin-2-yl]piperidine- 2, 6-dione (Reactant 1) (60 mg, 0.16 mmol, 1 eq in dichloromethane (1 mL) was added trifluoroacetic acid (660 mg, 5.79 mmol, 36.02 eq). The mixture was stirred at 25 °C for 1 hr. The reaction mixture was concentrated under reduced pressure to remove solvent. The crude product l-[2-(2,6-dioxo-3-piperidyl)-l-oxo-isoindolin-4-yl]azetidine-3-carbaldehyde (70 mg, 0.16 mmol, 99% yield, trifluoroacetate) was used into the next step without further purification as a yellow solid. LCMS: MS (ESI) m / z: 328.2 [M +1]+.

[0336] Intermediate 37

[0337] Step 1: Preparation of methyl 3,4-difluoro-2-methyl-benzoate

[0338] To a solution of 3, 4-difluoro-2-m ethyl -benzoic acid (50.00 g, 290.48 mmol, 1 eq) in methanol (500 mL) was added thionyl chloride (103.68 g, 871.44 mmol, 63.2 mL, 3 eq) drop- wise. The mixture was stirred at 80 °C for 12 hr. The mixture was poured into ice water (1 L) drop-wise at 0 °C, and the solid was filtered. The solid was dissolved in ethyl acetate (10 mL) and filtered to give methyl 3, 4-difluoro-2-methyl -benzoate (51.00 g, 273.97 mmol, 94% yield) as a white solid.1H NMR: (400MHz, CDCh-tZ) d: 7.74 - 7.68 (m, 1H), 7.08 - 6.99 (m, 1H), 3.90 (s, 3H), 2.60 - 2.53 (m, 3H).

[0339] Step 2: Preparation of methyl 2-(bromomethyl)-3,4-difluoro-benzoate

[0340] To a mixture of methyl 3, 4-difluoro-2-m ethyl -benzoate (40.00 g, 214.87 mmol, 1 eq) in 1,2- di chloroethane (400 mL) was added n-bromosuccinimide (57.37 g, 322.31 mmol, 1.5 eq) and benzoyl peroxide (520 mg, 2.15 mmol, 0.01 eq). The mixture and then the mixture was stirred at 80 °C for 2 hr. The mixture was cooled to 20 °C, filtered, and concentrated under reduce pressure to give a residue. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1 :0 to 20: 1) to give methyl 2- (bromomethyl)-3,4-difluoro-benzoate (51.00 g, 192.42 mmol, 89% yield) as a colorless oil. ’H NMR: (400MHz, CDCh-d)3: 7.85-7.80 (m, 1H), 7.16-7.23 (m, 1H), 5.02 (d, J= 2.2 Hz, 2H), 3.96 (s, 3H).

[0341] Step 3: Preparation of 3-(4,5-difluoro-l-oxo-isoindolin-2-yl)piperi(line -2,6-dione

[0342] To a mixture of methyl 2-(bromomethyl)-3,4-difluoro-benzoate (51.00 g, 192.42 mmol, 1 eq) and 3-aminopiperidine-2, 6-dione (33.25 g, 202.04 mmol, 1.05 eq, hydrochloride) in N,N- dimethylformamide (600 mL) was added diisopropylethylamine (74.61 g, 577.25 mmol, 100.5 mL, 3 eq). The mixture was stirred at 40 °C for 1 hr, and then heated to 110 °C for 12 hr. The mixture was poured into water (800 mL), filtered, and the solid was obtained. The solid was dissolved in ethyl acetate (500 mL), filtered, and the solid was obtained. 3-(4,5- difluoro-l-oxo-isoindolin-2-yl)piperidine-2, 6-dione (29.70 g, 105.99 mmol, 55% yield) was obtained as a gray solid. ’H NMR: (400MHz, DMSO-t / 6) d: 11.02 (s, 1H), 7.66 - 7.58 (m, 2H), 5.11 (dd, J= 5.2, 13.2 Hz, 1H), 4.66 - 4.59 (m, 1H), 4.49 - 4.42 (m, 1H), 2.97 - 2.86 (m, 1H), 2.65 - 2.57 (m, 1H), 2.46 - 2.37 (m, 1H), 2.05 - 1.98 (m, 1H).

[0343] Intermediate 38

[0344] Step 1: Preparation of methyl 2-cyano-4-[3-(hydroxymethyl) azetidin-l-yl]benzoate

[0345] To a solution of azeti din-3 -ylmethanol (18 g, 145.65 mmol, 1 eq, Hydrochloride) in dimethylsulfoxide (300 mL) was added diisopropyl ethylamine (94.12 g, 728.27 mmol, 126.85 mL, 5 eq). The mixture was stirred at 15 °C for 0.5 hr. Then methyl 2-cyano-4-fluoro- benzoate (20.87 g, 116.52 mmol, 0.8 eq) was added to the mixture. The mixture was stirred at 120 °C for 11.5 hr. The mixture was diluted with water (2000 mL) and extracted with ethyl acerate (1000 mL x 5). The combined organic layers were washed with brine (2000 mL x3), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The crude product was triturated with petroleum ether and ethyl acetate (V:V=2:1, 300 mL). Methyl 2- cyano-4-[3-(hydroxymethyl)azetidin-l-yl]benzoate (60 g, 243.64 mmol, 55 % yield) was obtained as a light yellow solid. LCMS: MS (ESI) m / z 247.2 [M+l]+.

[0346] Step 2: Preparation of methyl 2-cyano-4-(3-formylazetidin-l-yl) benzoate

[0347] To a solution of oxalyl chloride (77.31 g, 609.11 mmol, 53.32 mL, 3 eq) in dichloromethane (400 mL) was added drop wised dimethylsulfoxide (63.46 g, 812.15 mmol, 63.46 mL, 4 eq) in dichloromethane (100 mL) at -70 °C. The mixture was stirred at -70 °C for 1 hr. Then methyl 2-cyano-4-[3-(hydroxymethyl)azetidin-l-yl]benzoate (50 g, 203.04 mmol, 1 eq) in dichloromethane (500 mL) was added drop wised to the mixture. The mixture was stirred at - 70 °C for 2 hr. Then triethylamine (164.36 g, 1.62 mol, 226.08 mL, 8 eq) was added dropwised to the mixture. The mixture was warmed to 20 °C and stirred at 20 °C for 1 hr. The mixture was diluted with water (1500 mL) and extracted with dichloromethane (500 mL x 2). The combined organic layers were washed with brine (1000 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The crude product was used into the next step without further purification. Methyl 2-cyano-4-(3-formylazetidin-l- yl)benzoate (45 g, 184.24 mmol, 90.74% yield) was obtained as a yellow oil. LCMS: MS (ESI) m / z: 245.5 [M+l]+.

[0348] Step 3: Preparation of methyl 2-cyano-4-[3-(dimethoxymethyl) azetidin-l-yl]benzoate

[0349] To a solution of methyl 2-cyano-4-(3-formylazetidin-l-yl)benzoate (45 g, 184.24 mmol, 1 eq) in methanol (200 mL) was added p-toluenesulfonic acid (3.17 g, 18.42 mmol, 0.1 eq) and trimethoxymethane (97.76 g, 921.20 mmol, 100.99 mL, 5 eq) . The mixture was stirred at 15 °C for 12 hr. The mixture was diluted with water (500 mL) and extracted with ethyl acetate (300 mL x 4). The combined organic layers were washed with brine (1000 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The crude product was triturated with petroleum ether and ethyl acetate (V:V= 5: 1, 200 mL). The filterate was purified by prep-HPLC (column: Phenomenex luna C18 250*50mm*10 pm; mobile phase: [water(0.225%FA)-ACN];B%: 30%-60%,35min). Methyl 2-cyano-4-[3- (dimethoxymethyl)azetidin-l-yl]benzoate (40 g, 137.78 mmol, 74% yield) was obtained as a light yellow solid. LCMS: MS (ESI) m / z: 291.2[M+1]+. ’H NMR: (400 MHz, DMSO-d6) 8: 7.87 (d, J= 8.8 Hz, 1H), 6.86 (d, J= 2.4 Hz, 1H), 6.65 (dd, J= 2.4, 8.8 Hz, 1H), 4.64 - 4.60 (m, 1H), 4.04 - 3.98 (m, 2H), 3.82 - 3.77 (m, 5H), 3.30 (s, 6H), 3.08 - 2.98 (m, 1H).

[0350] Step 4: Preparation of methyl 4-[3-(dimethoxymethyl)azetidin-l-yl] -2-formyl-benzoate To a solution of methyl 2-cyano-4-[3-(dimethoxymethyl)azetidin-l-yl]benzoate (3 g, 10.33 mmol, 1 eq in pyridine (60 mL) was added Raney -Ni (2 g, 23.34 mmol, 2.26 eq) . Then acetic acid (30 mL) was added to the mixutre. Sodium dihydrogen phosphate;hydrate (14.26 g, 103.34 mmol, 10 eq in water (15 mL) was added to the mixture. The mixture was stirred at 50 °C for 2 hr. The mixture was washed with ethyl acetate (100 mL x 2). The mixture was diluted with water (200 mL) and extracted with ethyl acetate (100 mL x 2). The combined organic layers were washed with brine (100 mL x 2), 2 M sulfuric acid (100 mL x 2), brine (100 mL), saturated sodium bicarbonate (100 mL) and brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 0~10 % ethyl acetate / petroleum ether gradient @ 50 mL / min). Methyl 4-[3 - (dimethoxymethyl)azeti din- l-yl]-2-formyl -benzoate (5.2 g, 17.73 mmol, 57% yield) was obtained as a yellow oil. LCMS: MS (ESI) m / z 294.2 [M+l]+.

[0351] Step 5: Preparation of 3-[5-[3-(dimethoxymethyl)azetidin-l-yl] -l-oxo-isoindolin-2- yl]piperidine-2, 6-dione

[0352] To a solution of 3 -aminopiperidine-2, 6-dione (3.21 g, 19.50 mmol, 1.1 eq, Hydrochloride) in methanol (100 mL) was added sodium acetate (2.91 g, 35.46 mmol, 2 eq . The mixture was stirred at 15 °C for 10 min. Then acetic acid (10.65 g, 177.28 mmol, 10.14 mL, 10 eq and methyl 4-[3-(dimethoxymethyl)azetidin-l-yl]-2-formyl-benzoate (5.2 g, 17.73 mmol, 1 eq was added to the mixture. The mixture was stirred at 15 °C for 20 min. Then sodium cyanoborohydride (2.23 g, 35.46 mmol, 2 eq was added to the mixture. The mixture was stirred at 35 °C for 11 hr. The crude product was poured into ice water (100 mL) and adjusted to pH 8 by saturated sodium bicarbonate. The mixture was stirred at 15 °C for 10 min. The mixture was filtered, and the filter cake was washed with water (20 mL) and acetonitrile (20 mL x 2). The filter cake was concentrated under vacuum. The crude product was triturated with ethyl acetate (20 mL). 3-[5-[3-(dimethoxymethyl)azetidin-l-yl]-l-oxo-isoindolin-2- yl]piperidine-2, 6-dione (5.4 g, 14.11 mmol, 79% yield, 97.6% purity) was obtained as a white solid. LCMS: MS (ESI) m / z 374.1 [M+l]+. ’H NMR: (400 MHz, DMSO-d6) 8: 10.93 (s, 1H), 7.48 (d, J= 8.4 Hz, 1H), 6.51 (s, 1H), 6.47 (dd, J= 1.6, 8.4 Hz, 1H), 5.02 (dd, J= 5.2, 13.2 Hz, 1H), 4.61 (d, .7= 6.8 Hz, 1H), 4.34 - 4.26 (m, 1H), 4.21 - 4.13 (m, 1H), 3.98 - 3.90 (m, 2H), 3.75 - 3.66 (m, 2H), 3.29 (s, 6H), 3.07 - 2.98 (m, 1H), 2.95 - 2.83 (m, 1H), 2.61 - 2.55 (m, 1H), 2.35 (dq, J= 4.4, 13.2 Hz, 1H), 2.02 - 1.89 (m, 1H).

[0353] Intermediate 39

[0354] Step 1: Preparation of 5-hydroxy-3-methoxyphthalic acid

[0355] To a solution of dimethyl 5-hydroxy-3-methoxy-benzene-l,2-dicarboxylate (10 g, 41.63 mmol, 1 eq) in tetrahydrofuran (30 mL) and methyl alcohol (30 mL) was added lithium hydroxide (3.99 g, 166.52 mmol, 4 eq) in water (30 mL). The mixture was stirred at 25 °C for 10 h. The reaction mixture was added hydrochloric acid 30 mL (pH=5) at 0°C, and extracted with di chloromethane 50 mL (50 mL><3). The combined organic layers were washed with brine 100 mL (100 mL><3), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (silicon dioxide, dichloromethane / methyl alcohol=50 / l to 24 / 1). 5-hydroxy-3-methoxy- phthalic acid (8.8 g, 41.48 mmol, 99% yield) was obtained as a yellow solid.

[0356] Step 2: Preparation of 2-(2,6-dioxopiperidin-3-yl)-6-hydroxy-4-methoxyisoindoline-l,3- dione

[0357] To a solution of 3 -aminopiperidine-2, 6-dione (7.97 g, 62.22 mmol, 1.5 eq) in Acetic acid (80 mL) was added Sodium acetate (13.61 g, 165.92 mmol, 4 eq) and 5 -hydroxy-3 -methoxyphthalic acid (8.8 g, 41.48 mmol, 1 eq). The mixture was stirred at 120 °C for 12 h. The reaction mixture was adjusted to pH<7 with hydrochloric acid ( < 1 mol), and then filtered to give a solid mixture. The residue was purified by column chromatography (silicon dioxide, dichloromethane / methyl alcohol = 50 / 1 to 20 / 1). 2-(2,6-dioxo-3-piperidyl)-6-hydroxy-4- methoxy-isoindoline-1, 3-dione (12 g, 39.44 mmol, 95% yield) was obtained as a yellow solid. LCMS: MS (ESI) m / z 305.3 [M-100]+. ’H NMR: (400 MHz, DMSO-d6, 298 K) 5 = 11.05 (s, 1H), 6.76 (d, J = 1.6 Hz, 1H), 6.71 (d, J = 1.6 Hz, 1H), 5.01 (dd, J = 5.2, 12.8 Hz, 1H), 3.33 (br s, 3H), 2.87 (ddd, J = 5.2, 14.0, 17.2 Hz, 1H), 2.54 (br s, 2H), 2.49 - 2.42 (m, 1H), 2.05 - 1.92 (m, 1H).

[0358] Step 3: Preparation of 2-(2,6-dioxopiperidin-3-yl)-7-niethoxy-l,3-(lioxoisoin(lolin-5-yl

[0359] 1,1,2,2,3,3,4,4,4-nonafluorobutane-l-sulfonate

[0360] To a solution of 2-(2,6-dioxo-3-piperidyl)-6-hydroxy-4-methoxy-isoindoline-l, 3-dione (2 g, 6.57 mmol, 1 eq) in N,N-dimethylformamide (1 mL) was added potassium carbonate (1.82 g, 13.15 mmol, 2 eq) and 1,1,2,2,3,3,4,4,4-nonafhiorobutane-l-sulfonyl fluoride (23.83 g, 78.88 mmol, 13.85 mL, 12 eq). The mixture was stirred at 50 °C for 1 hr. The mixture was concentrated to give a residue. The residue was purified by silica gel column chromatography (silicon dioxide, dichloromethane / methyl alcohol=l / 0 to 20 / 1). [2-(2,6-dioxo-3 -piperidylsmethoxy- 1,3 -di oxo-isoindolin-5-yl] 1,1,2,2,3,3,4,4,4-nonafhiorobutane-l-sulfonate (3 g, 5.12 mmol, 77% yield) was obtained as a yellow solid.

[0361] Example 40

[0362] Step 1: Preparation of 3-methoxycyclohex-2-enone

[0363] To a solution of cyclohexane- 1, 3-dione (15 g, 133.78 mmol, 1 eq) in MeOH (260 mL) was added titanium tetrachloride (1 M, 4 mL, 0.03 eq) in dichloromethane (4 mL), at 15 °C, the mixture was stirred at 15 °C for 0.5hr. The mixture was poured into water (200 mL) and the aqueous phase was extracted with ether (50 mL x 5). The combined organic phase was washed with brine (50 mL x 2), dried with anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by prep-high performance liquid chromatography column: Phenomenex luna C18 250*50mm*10 pm; mobile phase: [water(0.225% formic acid)- acetonitrile] ;B%: l%-30%, 30min, 50%min 3- methoxycyclohex-2-en-l-one (8.9 g, 70 mmol, 52% yield) was obtained as a yellow oil. LCMS: MS (ESI) m / z 127.2 [M+l]+.

[0364] Step 2: Preparation of ((5-methoxycyclohexa-l,5-dien-l-yl)oxy)trimethylsilane

[0365] To a solution of 3-methoxycyclohex-2-en-l-one (8.65 g, 68 mmol, 1 eq) in tetrahydrofuran (80 mL) was added lithium diisopropylamide, lithium (2 M, 41 mL, 1.2 eq) under nitrogen. The mixture was stirred at -70 °C for 10 min, then trimethyl chlorosilane (7.45 g, 68 mmol, 8.70 mL, 1 eq) was added into the mixture. The mixture was stirred at -70 °C for 1 hr used to next step without monitor. The mixture was poured into ammonium chloride (sat, 20 mL) and the aqueous phase was extracted with ethyl acetate (50 mL x 3). The combined organic phases was washed with brine (50 mL x 2), dried with anhydrous sodium sulfate, filtered, and concentrated under vacuum. (5-methoxycyclohexa-l,5-dien-l-yl)oxy-trimethyl-silane (13.5 g, crude) was obtained as a yellow oil.

[0366] Step 3: Preparation of dimethyl l-methoxy-5-((trimethylsilyl)oxy) bicyclo[2.2.2]octa-2,5- diene-2, 3-dicarboxylate

[0367] To a solution of (5-methoxycyclohexa-l,5-dien-l-yl)oxy-trimethyl-silane (13.5 g, 68 mmol, 1 eq in tetrahydrofuran (100 mL) was added dimethyl but-2-ynedioate (9.77 g, 68 mmol, 1.01 eq) dropwise at -70 °C. The reaction temperature was then raised to 50 °C over a period of 1 hr. the mixture was stirred at 50 °C for 1 hr. The mixture was concentrated under vacuum and then taken on to the next step without purification. Dimethyl 4-methoxy-6-trimethylsilyloxy- bicyclo[2.2.2]octa-2,5-diene-2,3 -di carboxyl ate (20 g, crude) was obtained as a yellow oil. Step 4: Preparation of dimethyl 5-hydroxy-3-methoxyphthalate

[0368] A solution of dimethyl 4-methoxy-6-trimethylsilyloxy-bicyclo[2.2.2]octa-2,5-diene-2, 3- dicarboxylate (20 g, 58.75 mmol, 1 eq) in xylene (5 mL) was stirred at 120°C for 12 hr. The mixture was concentrated under vacuum. The residue was purified by prep-high performance liquid chromatography (column: Phenomenex luna C18 250*50mm*10 pm;mobile phase: [water(0.225% formic acid)- acetonitrile] ;B%: 15%-45%,30min,50%min. dimethyl 5- hydroxy-3-methoxy-benzene-l,2-dicarboxylate (11 g, 45.79 mmol, 77% yield) was obtained as a white solid. LCMS: MS (ESI) m / z 503.1 [2M+Na]+.

[0369] Intermediate 41

[0370] Step 1: Preparation of 7-bromo-l-methylindoline-2, 3-dione

[0371] To a mixture of 7-bromoindoline-2, 3-dione (12 g, 53.09 mmol, 1 eq), potassium carbonate (11.01 g, 79.64 mmol, 1.5 eq) and water (1.2 mL) in N,N-dimethylformamide (60 mL) was dropwise added methyl iodide (8.44 g, 59.43 mmol, 3.7 mL, 1.12 eq) in N,N- dimethylformamide (24 mL) The mixture was stirred at 25 °C for 2 hr. Upon completion of the reaction, water (120 mL) was added, and the mixture was stirred at 0 °C for 1 hr. The resultant precipitate was collected by filtration, washed with water (50 mL x 2), and dried under vacuum to give a residue. The residue was used for the next step without further purification. 7-bromo-l -methylindoline-2, 3-dione (8 g, 33.33 mmol, 62% yield) was obtained as a red solid. LCMS: MS (ESI) m / z: 242.3 [M+l]+. ’H NMR: (400 MHz, dimethylsulfoxide-tL) <5: 7.81 (br d, .7=7.6 Hz, 1 H) 7.55 (br d, .7=7.2 Hz, 1 H) 7.05 (t, .7=8.0 Hz, 1 H) 3.47 (s, 3 H).

[0372] Step 2: Preparation of 3-bromo-2-(methylamino)benzoic acid

[0373] Aqueous hydrogen peroxide (38 g, 335.15 mmol, 32.20 mL, 30% purity, 10.06 eq) was added dropwise to a mixture of 7-bromo-l -methylindoline-2, 3-dione (8 g, 33.33 mmol, 1 eq) and sodium hydroxide (2 M, 199.96 mL, 12 eq) below 15 °C. The mixture was stirred at 25 °C for 5 h. LC-MS showed the reaction was completed. After the pH was adjusted to 4.0 with hydrochloric acid (1 M), the mixture was stirred at 10 °C for 1 hr. The mixture was then extracted with ethyl acetate (80 mL x 3). The combined organic phase was washed with water (60 mL), dried with anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was used for the next step without further purification. 3-bromo-2- (methylamino)benzoic acid (6.0 g, crude) was obtained as a brown oil. LCMS: MS (ESI) m / r. 252.2 [M+23]+.

[0374] Step 3: Preparation of 7-bromo-l-methyl-lH-benzo[d]imidazol-2(3H)-one

[0375] To a solution of 3-bromo-2-(methylamino)benzoic acid (6 g, 26.08 mmol, 1 eq, crude) and N,N-diisopropylethylamine (5.04 g, 39.01 mmol, 6.80 mL, 1.50 eq) in N,N- dimethylformamide (40 mL) was dropwise added diphenylphosphoryl azide (10.76 g, 39.10 mmol, 8.47 mL, 1.50 eq) at 75 °C. The reaction mixture was stirred at 75 °C for 3 hr. Water (30 mL) was added at 25 °C, and the mixture was stirred at 0 °C for 0.5 hr. The resultant precipitate was collected by filtration, washed with water (30 mL) and diisopropylether (15 mL), and dried under vacuum at 50 °C to give a residue. The residue was used for the next step without further purification. 7-bromo- l -methyl- l H-benzo[t / ]imidazol-2(3H)-one (4 g, 17.62 mmol, 67% yield) was obtained as a off-white solid. LCMS: MS (ESI) m / z 226.9 [M+l]+.1H NMR: (400 MHz, dimethylsulfoxide- e) 11.17 (br s, 1 H) 7.14 (dd, J=8.0, 1.2 Hz, 1 H) 6.96 - 6.99 (m, 1 H) 6.88 - 6.93 (m, 1 H) 3.55 (s, 3 H).

[0376] Step 4: Preparation of 5-oxotetrahydrofuran-2-carboxylic acid

[0377] To a solution of 2-aminopentanedioic acid (50 g, 339.84 mmol, 1 eq) in water (300 mL) hydrochloric acid (37%, 50 mL) was added sodium nitrite (35.17 g, 509.76 mmol, 1.5 eq) at - 5 °C. The mixture was stirred at 25 °C for 12 hr. The reaction was filtered, and the filtrate was concentrated under vacuum to give the crude product. The residue was used for the next step without further purification. 5-oxotetrahydrofuran-2-carboxylic acid (34 g, crude) was obtained as a colorless oil.1H NMR: (400 MHz, chloroform-t / ) d 7.27 (s, 1 H) 4.98 - 5.03 (m, 1 H) 2.51 - 2.72 (m, 4 H).

[0378] Step 5: Preparation of N-(4-methoxybenzyl)-5-oxotetrahydrofuran-2-carboxamide

[0379] To a solution of 5-oxotetrahydrofuran-2-carboxylic acid (67 g, 514.99 mmol, 1 eq, crude) in dichloromethane (400 mL) was added sulfoxide chloride (135 g, 1.13 mol, 82.32 mL, 2.20 eq) at 0 °C. The mixture was stirred at 85°C for 3 h and 25°C for 6 h. The reaction mixture was concentrated under vacuum to give the crude product. Additional dichloromethane (400 mL) was added, and / ?-methoxyaniline (56.52 g, 411.99 mmol, 53.32 mL, 0.8 eq), triethylamine (104.22 g, 1.03 mol, 143.36 mL, 2 eq) were added at 0 °C. The mixture was stirred at 25°C for 12 hr. To the reaction mixture was added water (500 mL) and the mixture was extracted with ethyl acetate (500 mL x 3). The combined organic phases were washed with brine (200 mL), dried over anhydrous indicated the reaction was completed, filtered, and concentrated under vacuum and was purified by column chromatography (petroleum ether / ethyl acetate=3 / l to 1 / 1), desired product (Rf=0.20). N-(4-methoxybenzyl)-5- oxotetrahydrofuran-2-carboxamide (59 g, 236.70 mmol, 45 % yield) was obtained as a yellow solid. ’H NMR: (400 MHz, dimethylsulfoxide-tL) d. 8.68 (br t, J=5.6 Hz, 1 H) 7.19 (d, .7=8,4 Hz, 2 H) 6.87 - 6.91 (m, 2 H) 4.89 (dd, J=8.0, 5.6 Hz, 1 H) 4.23 (d, J=6.Q Hz, 2 H) 3.73 (s, 3 H) 2.51 - 2.55 (m, 1 H) 2.36 - 2.47 (m, 1 H) 2.01 - 2.16 (m, 1 H).

[0380] Step 6: Preparation of 3-hydroxy-l-(4-methoxyben~ l)piperidine-2, 6-dione

[0381] To a solution of N-(4-methoxybenzyl)-5-oxotetrahydrofuran-2-carboxamide (10 g, 40.12 mmol, 1 eq) in tetrahydrofuran (120 mL) was added dropwise potassium 2-methylpropan-2- olate (1 M, 40.52 mL, 1.01 eq) at -78 °C under nitrogen. The resulting reaction mixture was stirred at -40 °C for 1 hr. The reaction mixture was quenched by addition ammonium chloride (50 mL) at -40 °C, and then diluted with water (150 mL) and extracted with ethyl acetate (100 mL x 3). The combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate=5 / l to 2 / 1). 3 -hydroxy- l-[(4-methoxyphenyl)methyl]piperidine-2, 6-dione (7.5 g, 30.09 mmol, 75% yield) was obtained as a light yellow solid.1H NMR: (400 MHz, chloroforms / ) 3 7.31 (m, 2 H) 6.79 - 6.84 (m, 2 H) 4.87 (s, 2 H) 4.19 (ddd, J=12.4, 5.6, 1.2 Hz, 1 H) 3.77 (s, 3 H) 3.69 (d, J=1.6 Hz, 1 H) 2.84 - 2.93 (m, 1 H) 2.63 (m, 1 H) 2.30 (m, 1 H) 1.80 - 1.95 (m, 1 H).

[0382] Step 7: Preparation of l-(4-methoxybenzyl)-2,6-(Hoxopiperidin-3-yl trifluoromethanesulfonate

[0383] To a solution of 3 -hydroxy- l-(4-methoxybenzyl)piperidine-2, 6-dione (3 g, 12.04 mmol, 1 eq) and Py (1.90 g, 24.02 mmol, 1.94 mL, 2.00 eq) in dichloromethane (100 mL) was added 1,3- bis((trifluoromethyl)sulfonyl)trioxidane (5.67 g, 18.05 mmol, 1.5 eq) at -20 °C. The mixture was stirred at -20 °C for 2 hr. The reaction mixture was purified by silica gel column chromatography (petroleum ether / ethyl acetate=10 / l to 2 / 1). l-(4-methoxybenzyl)-2,6- di ox opiperi din-3 -yl trifluoromethanesulfonate (4.2 g, 11.01 mmol, 92% yield) was obtained as a colorless oil. ’ H NMR: 400 MHz, chloroform-d) 5 = 7.39 - 7.33 (m, 2H), 6.86 - 6.81 (m, 2H), 5.33 - 5.27 (m, 1H), 4.91 (s, 2H), 3.79 (s, 3H), 3.04 - 2.95 (m, 1H), 2.80 - 2.68 (m, 1H), 2.46 - 2.26 (m, 2H). Step 8: Preparation of 3-(4-bromo-3-methyl-2-oxo-2,3-dihydro-lH-benzo[d]imidazol-l-yl)- l-(4-methoxybenzyl)piperidine-2, 6-dione

[0384] To a solution of 7-bromo-l -methyl- lH-benzo[d]imidazol-2(3H)-one (2.00 g, 8.81 mmol, 1 eq in tetrahydrofuran (40 mL) was added potassium 2-methylpropan-2-olate (1 M, 10.67 mL, 1.21 eq) and stirred at 0 °C for 0.5 hr. Then l-(4-methoxybenzyl)-2,6-di ox opiperi din-3 - yl trifluoromethanesulfonate (4.2 g, 11.01 mmol, 1.25 eq in tetrahydrofuran (20 mL) was added dropwise. The mixture was stirred at 0-25 °C for 0.5 hr. The reaction mixture was quenched by addition 10 % ammonium chloride solution 10 mL at 0 °C and stirred at 0 °C for 1 h, extracted with Ethyl acetate (50 mL x 3). The combined organic layers were washed with brine 50 mL, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a solid. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate=6 / l to 1 / 1). 3-(4-bromo-3-methyl-2-oxo-2,3-dihydro-lH- benzo[d]imidazol-l-yl)-l-(4-m ethoxybenzyl )piperidine-2, 6-dione (3.5 g, 7.64 mmol, 87% yield) was obtained as a white solid. LCMS: MS (ESI) m / z 460.1 [M+H]+.1H NMR : (400 MHz, DMSO-d6) 5 = 7.24 (dd, J = 0.8, 8.0 Hz, 1H), 7.22 - 7.18 (m, 2H), 7.11 - 7.04 (br m, 1H), 6.97 - 6.92 (m, 1H), 6.88 - 6.82 (m, 2H), 5.57 (dd, J = 5.6, 12.8 Hz, 1H), 4.79 (q, J = 14.4 Hz, 2H), 3.72 (s, 3H), 3.64 (s, 3H), 3.12 - 2.97 (m, 1H), 2.89 - 2.64 (m, 2H), 2.13 - 2.01 (m, 1H).

[0385] Step 9: Preparation of 3-(4-bromo-3-methyl-2-oxo-2,3-dihydro-lH-benzo[d]imidazol-l- yl)piperidine-2, 6-dione Methanesulfonic acid toluene, 120 °C, 2h

[0386] To a solution of 3-(4-bromo-3-methyl-2-oxo-2,3-dihydro-lH-benzo[d]imidazol-l-yl)-l-(4- methoxybenzyl)piperidine-2, 6-dione (3.50 g, 7.64 mmol, 1 eq) in toluene (20 mL) was added methanesulfonic acid (15.75 g, 163.89 mmol, 11.67 mL, 21.46 eq) and the mixture was stirred at 120 °C for 2 h under nitrogen atmosphere. The reaction mixture was concentrated under reduced pressure to remove toluene. The residue was poured into water / ice (1 / 1, 50 mL) and extracted with ethyl acetate (150 mL x 3). The combined organic layers were washed with brine 50 mL, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate=6 / l to 0 / 1). 3-(4-bromo-3-methyl-2-oxo-2,3- dihydro-lH-benzo[d]imidazol-l-yl)piperidine-2, 6-dione (1.8 g, 5.32 mmol, 70% yield) was obtained as a yellow solid. LCMS: MS (ESI) m / z 340.0[M+H]+. ’H NMR: (400 MHz, DMSO-d6) 5 = 11.13 (s, 1H), 7.28 - 7.22 (m, 1H), 7.17 (d, J= 8.0 Hz, 1H), 7.01 - 6.95 (m, 1H), 5.41 (dd, J= 5.2, 12.8 Hz, 1H), 3.63 (s, 3H), 2.95 - 2.82 (m, 1H), 2.77 - 2.59 (m, 2H), 2.08 - 1.98 (m, 1H).

[0387] Step 10: Preparation of 3-(4-(3-(dimethoxymethyl)azetidin-l-yl)-3-methyl-2-oxo-2,3- dihydro-lH-benzo[d]imidazol-l -yl)piperidine-2, 6-dione

[0388] 3-(dimethoxymethyl)azetidine (150.00 mg, 1.14 mmol, 1.29 eq), 3-(4-bromo-3-methyl-2- oxo-2, 3-dihydro-lH-benzo[d]imidazol-l-yl)piperidine-2, 6-dione (300 mg, 887.16 umol, 1 eq), [2-(2-aminophenyl)phenyl]-methylsulfonyloxy-palladium;dicyclohexyl-[2-(2,6- diisopropoxyphenyl)phenyl]phosphane (75.00 mg, 89.67 umol, 1.01e-l eq), [2-(2- aminoethyl)phenyl]-chloro-palladium;dicyclohexyl-[2-(2,6- diisopropoxyphenyl)phenyl]phosphane;2-methoxy-2-methyl-propane (75.00 mg, 91.82 umol, 1.03e-l eq) and sodium 2-methylpropan-2-olate (1 M, 1.80 mL, 2.03 eq) in tetrahydrofuran (15 mL) was heated to 45 °C for 2 h under N2 atmosphere. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep- HPLC (formic acid condition; column: Shim-pack Cl 8 150*25*10 pm; mobile phase: [water (0.225% formic acid) - acetonitrile]; B%: 25%-45%,10 min). 3-(4-(3- (dimethoxymethyl)azetidin-l-yl)-3-methyl-2-oxo-2,3-dihydro-lH-benzo[d]imidazol-l- yl)piperidine-2, 6-dione (20 mg, 51.49 umol, 9% yield) was obtained as a white solid. LCMS: MS (ESI) m / z: 389.2 [M+H]+. ’H NMR: (400 MHz, CHLOROFORM-d) 5 = 8.04 - 7.97 (m, 1H), 7.03 - 6.94 (m, 1H), 6.70 (d, J= 7.6 Hz, 1H), 6.46 (d, J= 8.0 Hz, 1H), 5.24 - 5.14 (m, 1H), 4.68 (d, J= 7.2 Hz, 1H), 4.08 - 4.02 (m, 1H), 3.93 (t, J= 8.4 Hz, 2H), 3.76 - 3.71 (m, 5H), 3.39 (s, 6H), 3.00 - 2.91 (m, 2H), 2.87 - 2.66 (m, 2H), 2.30 - 2.16 (m, 1H).

[0389] Step 11: Preparation of l-(l-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-lH- benzo[d]inudazol-4-yl)azetidine-3-carbaldehyde

[0390] To a mixture of 3-(4-(3-(dimethoxymethyl)azetidin-l-yl)-3-methyl-2-oxo-2,3-dihydro-lH- benzo[d]imidazol-l-yl)piperidine-2, 6-dione (8 mg, 20.60 pmol, 1 eq in tetrahydrofuran (0.4 mL) was added sulphuric acid (2 M, 400.00 uL, 38.84 eq) and stirred at 50 °C for 2 h under N2 atmosphere. The reaction mixture was quenched by addition 10 % sodium bicarbonate solution 2 mL at 0 °C, and then extracted with dichloromethane (4 mL x 10). The combined organic layers were washed with brine 10 mL, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The crude product 1 -(1 -(2,6- dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-lH-benzo[d]imidazol-4-yl)azetidine-3- carbaldehyde (7 mg, 20.45 pmol, 99% yield) as a yellow solid was used into the next step without further purification. LCMS: MS (ESI) m / z 361.2 [M+H2O]+.

[0391] Intermediate 42 .

[0392] Step 1: Preparation of methyl 2-bromo-3,5-difluoro-benzoate

[0393] To a 2-bromo-3,5-difluoro-benzoic acid (15 g, 63.29 mmol, 1 eq) in methanol (150 mL) was added thionyl chloride (22.59 g, 189.87 mmol, 13.77 mL, 3 eq . The reaction mixture was stirred at 60°C for 2 hours. TLC (petroleum ether: ethyl acetate = 1 : 1) showed reactant was consumed completely. The reaction mixture was concentrated under reduced pressure. Methyl 2-bromo-3,5-difluoro-benzoate (15 g, 59.76 mmol, 94% yield) was obtained as a white solid and used in the next step directly without further purification. Step 2: Preparation of methyl 2-cyano-3,5-difluoro-benzoate

[0394] A solution of methyl 2-bromo-3,5-difluoro-benzoate (1.5 g, 5.98 mmol, 1 eq) and cuprous cyanide (802 mg, 8.96 mmol, 1.96 mL, 1.5 eq) in dimethyl formamide (5 mL) was divided into two vessels and microwaved at 180 °C for 10 min. The reaction mixture was diluted with ethyl acetate (200 mL), filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate=100 / l to 10 / 1). Methyl 2-cyano-3,5-difluoro-benzoate (3.5 g, 17.75 mmol, 49% yield) was obtained as a white solid.

[0395] Step 3: Preparation of 3,5-difluorophthalic acid

[0396] A solution of methyl 2-cyano-3,5-difluoro-benzoate (1 g, 5.07 mmol, 1 eq) in concentrated hydrochloric acid (10 mL) was stirred at 100°C for 12 hours. The reaction mixture was concentrated under reduced pressure. The pH was adjusted to 5 with sodium hydroxide. The mixture was filtered. The filtered cake was collected and concentrated under reduced pressure. 3,5-difhiorophthalic acid (1.8 g, 8.91 mmol, 87% yield) was obtained as a white solid.1H NMR: (400 MHz, DMSO-d6) 8 :7.52 - 7.45 (m, 1H), 7.44 - 7.33 (m, 1H).

[0397] Step 4: Preparation of 2-(2,6-dioxo-3-piperidyl)-4,6-(lifluoro- isoindoline-1, 3-dione

[0398] A solution of 3,5-difluorophthalic acid (800 mg, 3.96 mmol, 1 eq), 3 -aminopiperidine -2,6- dione (1.95 g, 11.87 mmol, 3 eq, hydrochloride) and sodium acetate (974 mg, 11.87 mmol, 3 eq) in acetic acid (8 mL) was stirred at 120°C for 2 hr. The crude product was triturated with water (30 mL). 2-(2,6-dioxo-3-piperidyl)-4,6-difluoro- isoindoline-1, 3-dione (800 mg, 2.72 mmol, 68% yield) was obtained as gray solid.1H NMR: (400 MHz, DMSO-de) 8: 11.15 (s, 1H), 7.88 - 7.80 (m, 1H), 7.80 - 7.76 (m, 1H), 5.22 - 5.11 (m, 1H), 2.95 - 2.82 (m, 1H), 2.60 (d, J= 17.6 Hz, 1H), 2.55 (d, J= 4.4 Hz, 1H), 2.11 - 2.00 (m, 1H).

[0399] Intermediate 43

[0400] Step 1: Preparation of 5-[4-(dimethoxymethyl)-l-piperidyl]-2-(2,6-dioxo-3- piperidyl)isoindoline-l, 3-dione.

[0401] To a solution of 2-(2,6-dioxo-3-piperidyl)-5-fluoro-isoindoline-l, 3-dione (300 mg, 1.09 mmol, 1 eq and 4-(dimethoxymethyl)piperidine (208 mg, 1.30 mmol, 1.2 eq) in dimethylsulfoxide (5 mL) was added N, / f-diisopropylethylamine (421 mg, 3.26 mmol, 0.6 mL, 3 eq . The mixture was stirred at 100 °C for 3 hr. The mixture was poured into water (20 mL) and extracted with dichloromethane (20 mL x 2), the organic phase was dried by anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give crude product. This crude product was purified by silica gel column chromatography (dichloromethane: methanol = 100: 1 to 50: 1) to give the product. 5-[4-(dimethoxymethyl)-l-piperidyl]-2-(2,6- dioxo-3-piperidyl)isoindoline-l, 3-dione (600 mg, crude) was obtained as a yellow solid. LCMS: MS (ESI) m / z: 416.1 [M+H]+.

[0402] Step 2: Preparation of l-[2-(2,6-dioxo-3-piperidyl)-l,3-dioxo-isoindolin-5-yl]piperidine-4- carbaldehyde

[0403] To a solution of 5-[4-(dimethoxymethyl)-l-piperidyl]-2-(2,6-dioxo-3-piperidyl)isoindoline- 1, 3-dione (450 mg, 1.08 mmol, 1 eq in tetrahydrofuran (4 mL) was added sulfuric acid (2 M, 4 mL, 7 eq). The mixture was stirred at 40 °C for 1 hr. The pH of the mixture was adjusted to pH 7 with saturated aqueous sodium bicarbonate, and extracted with ethyl acetate (30 mL, twice). The organic phase was dried by anhydrous sodium sulfate and filtered. Then the filtrate was concentrated to give the product. l-[2-(2,6-dioxo-3-piperidyl)-l,3-dioxo- isoindolin-5-yl]piperidine-4-carbaldehyde (500 mg, crude) was obtained as a yellow solid. LCMS: MS (ESI) m / z: 370.3 [M+H]+. ’H NMR: (400MHz, CHLOROFORM -d) 3: 9.72 (s, 1H), 8.12 (s, 1H), 7.70 (d, J= 8.4 Hz, 1H), 7.30 (d, J= 2.4 Hz, 1H), 7.07 (dd, J= 2.4, 8.8 Hz, 1H), 4.95 (dd, J= 5.2, 12.4 Hz, 1H), 3.86 (td, J= 4.0, 13.2 Hz, 2H), 3.19 (ddd, J= 3.2, 10.4, 13.2 Hz, 2H), 2.94 - 2.70 (m, 3H), 2.60 - 2.52 (m, 1H), 2.18 - 2.11 (m, 1H), 1.86 - 1.84 (m, 1H), 1.85 - 1.76 (m, 1H).

[0404] Intermediate 44

[0405] Step 1: Preparation of tert-butyl 7-[3-[(2-tert-butoxycarbonyl-2-azaspiro[3.5]nonan-7- yl)oxycarbonylanuno]-7-fluoro-6-isoquinolyl]-8-methyl-2,3-dihydropyrido[2,3- b][l,4]oxazine-l -carboxylate

[0406] A mixture of tert-butyl 7-(3-amino-7-fluoro-6-isoquinolyl)-8-methyl-2,3-dihydropyrido[2,3- b][l,4]oxazine-l-carboxylate (Reactant 1) (300 mg, 0.73 mmol, 1 eq), tert-butyl 7-hydroxy- 2-azaspiro[3.5]nonane-2-carboxylate (353 mg, 1.46 mmol, 2 eq) and diisopropyl ethylamine (472 mg, 3.65 mmol, 5 eq) in dichloromethane (5 mL) was added bis(trichloromethyl) carbonate (225 mg, 0.76 mmol, 1.04 eq) at 0 °C. The mixture was stirred at 0 °C for 1 hr. The reaction mixture was quenched by saturated sodium hydrogen carbonate solution 50 mL and extracted with dichloromethane (20 mL x 3), washed with saturated brine (20 mL x 1), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® silica flash column with an eluent of 0-30% ethyl acetate / petroleum ether radient @ 100 mL / min). Tert-butyl 7-[3-[(2-tert-butoxycarbonyl-2-azaspiro[3.5]nonan-7- yl)oxycarbonylamino]-7-fluoro-6-isoquinolyl]-8-methyl-2,3-dihydropyrido[2,3- b][l,4]oxazine-l-carboxylate (290 mg, 0.43 mmol, 59% yield) was obtained as a yellow solid. LCMS: MS (ESI) m / z: 678.4 [M +1]+. ’H NMR: (400 MHz, CHLOROFORM-d) 5 = 8.96 (s, 1H), 8.27 (s, 1H), 7.98 (s, 1H), 7.69 (d, J= 6.8 Hz, 1H), 7.60 - 7.57 (m, 2H), 4.87 - 4.79 (m, 1H), 4.66 - 4.32 (m, 3H), 3.24 - 3.05 (m, 1H), 2.13 (d, J= 0.8 Hz, 3H), 1.98 - 1.87 (m, 7H), 1.82 (dd, J= 3.6, 13.2 Hz, 3H), 1.46 - 1.44 (m, 18H), 1.34 (d, J= 10.8 Hz, 2H).

[0407] Intermediate 45

[0408] Step 1: Preparation of benzyl 4-(4-ethoxycarbonylcyclohexoxy)piperidine-l-carboxylate .3, , , .

[0409] To a solution of ethyl 4-hydroxycyclohexanecarboxylate (70 g, 406.45 mmol, 1.0 eq) in tetrahydrofuran (1400 mL) was added chlorotrimethylsilane (48.57 g, 447.10 mmol, 56.74 mL, 1.1 eq) and triethylamine (61.69 g, 609.68 mmol, 84.86 mL, 1.5 eq) at 0 °C. The mixture was stirred at 25 °C for 0.5 hr. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give a residue. Then to a stirred solution of the residue in dichloramethane (1600 mL) was added benzyl 4-oxopiperidine-l -carboxylate (123.25 g, 528.39 mmol, 105.35 mL, 1.3 eq), the temperature was cooled to -60 °C, tri ethyl si lane (94.53 g, 812.91 mmol, 129.84 mL, 2.0 eq), trimethyl silyl trifluoromethanesulfonate (81.30 g, 365.81 mmol, 66.10 mL, 0.9 eq) was added dropwise, the temperature was allowed to warm to 25 °C, and stirred for 7.5 hr. The reaction mixture was diluted with water (1500 mL) and extracted with ethyl acetate (1000 mL x 2). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiCL, petroleum ether / ethyl acetate=l / O to 5 / 1). Benzyl 4-(4- ethoxycarbonylcyclohexoxy)piperidine-l -carboxylate (120 g, 308.10 mmol, 75.80% yield) was obtained as a colorless oil. LCMS: MS (ESI) m / z: 350.8 [M+H]+. ’H NMR: (400MHz, CDC13) 3 7.30 - 7.41 (m, 5 H) 5.14 (s, 2 H) 4.10 - 4.16 (m, 2 H) 3.80 - 3.90 (m, 2 H) 3.58- 3.65 (m, 1 H) 3.35 (tt, J=10.48, 3.70 Hz, 1 H) 3.20 (ddd, J=13.20, 9.29, 3.42 Hz, 2 H) 2.26 (tt, J=11.69, 3.29 Hz, 1 H) 1.99 -2.06 (m, 4 H) 1.80 (br s, 2 H) 1.43 - 1.58 (m, 4 H) 1.24 - 1.34 (m, 5 H).

[0410] Step 2: Preparation of benzyl 4-(4-formylcyclohexoxy)piperidine-l -carboxylate

[0411] To a solution of benzyl 4-(4-ethoxycarbonylcyclohexoxy)piperidine-l-carboxylate (115 g, 295.26 mmol, 1 eq in dichloromethane (1500 mL) was added diisobutylaluminum hydride (1 M, 442.89 mL, 1.5 eq) at -70 °C. The mixture was stirred at -70 °C for 2 hr. Into the mixture was added 2 M hydrochloric acid (100 mL) at -70 °C slowly, then sodium sulfate. The reaction solution was filtered and concentrated under vacuum. The residue was purified by flash silica gel chromatography (ISCO®; 330 g SepaFlash® silica flash column with an eluent of 0-50% ethyl acetate / petroleum ether gradient @ 80 mL / min). Benzyl 4-(4- formylcyclohexoxy)piperidine-l-carboxylate (168 g, 82% yield) was obtained as a yellow oil. ’H NMR: (400 MHz, CHLOROFORM-d) 5 = 9.63 - 9.53 (m, 1H), 7.33 - 7.21 (m, 5H), 5.05 (s, 2H), 3.76 (br d, J= 7.6 Hz, 2H), 3.52 (dt, .7 = 4,0, 7.6 Hz, 1H), 3.31 - 3.18 (m, 1H), 3.18 - 3.04 (m, 2H), 2.20 - 2.07 (m, 1H), 1.97 - 1.86 (m, 3H), 1.83 - 1.65 (m, 3H), 1.49 - 1.39 (m, 2H), 1.31 - 1.15 (m, 4H).

[0412] Step 3: Preparation of benzyl 4-[4-(dimethoxymethyl)cyclohexoxy]piperi(line-l-carboxylate

[0413] To a solution of benzyl 4-(4-formylcyclohexoxy)piperidine-l -carboxylate (120 g, 347.39 mmol, 1 eq in methanol (1000 mL) was added trimethoxymethane (73.73 g, 694.78 mmol, 76.17 mL, 2 eq and -toluenesulfonicacidmonohydrate (2 g, 10.51 mmol, 0.03 eq.). The mixture was stirred at 25 °C for 1 hr. Saturated sodium bicarbonate solution (200 mL) was added, and the mixture was concentrated under vacuum to remove most of the methanol, and the mixture was extracted with ethyl acetate (100 mL x 3). The combined organic phases were washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by flash silica gel chromatography (ISCO®; 120 g SepaFlash® silica flash column, eluent of 0-20% ethyl acetate / petroleum ether gradient @ 45 mL / min). Benzyl 4-[4-(dimethoxymethyl)cyclohexoxy]piperidine-l- carboxylate (240 g, 88% yield) was obtained as a yellow oil. ’H NMR: (400 MHz, CHLOROFORM-d) 5 = 7.39 - 7.29 (m, 5H), 5.13 (s, 2H), 3.99 (d, J= 7.2 Hz, 1H), 3.85 (br d, J= 11.2 Hz, 2H), 3.60 (tt, J= 3.6, 8.0 Hz, 1H), 3.43 - 3.23 (m, 7H), 3.17 (ddd, J= 3.6, 9.2, 13.2 Hz, 2H), 1.99 (br d, J= 9.6 Hz, 2H), 1.89 - 1.74 (m, 4H), 1.63 - 1.47 (m, 3H), 1.27 - 1.15 (m, 2H), 1.14 - 0.95 (m, 2H).

[0414] Step 4: Preparation of 4-[4-(dimethoxymethyl)cyclohexoxy]piperidine

[0415] To a solution of benzyl 4-[4-(dimethoxymethyl)cyclohexoxy]piperidine-l -carboxylate (120 g, 306.51 mmol, 1 eq) in methanol (900 mL) was added palladium on carbon (10 g, 10% purity) under nitrogen. The suspension was degassed under vacuum and purged with hydrogen several times. The mixture was stirred under hydrogen (50 psi) at 50 °C for 12 hr. The reaction mixture was filtered and concentrated under vacuum. 4-[4- (dimethoxymethyl)cyclohexoxy]piperidine (78.5 g, 99% yield) was obtained as a yellow oil without further purification. ’H NMR: (400 MHz, CHLOROFORM-d) 5 = 3.99 (d, J = 6.8 Hz, 1H), 3.51 - 3.45 (m, 1H), 3.34 (s, 6H), 3.32 - 3.22 (m, 1H), 3.09 (td, J = 4.0, 12.8 Hz, 2H), 2.68 - 2.58 (m, 2H), 1.99 (br d, J = 9.6 Hz, 2H), 1.92 - 1.79 (m, 4H), 1.62 - 1.51 (m, 1H), 1.47 - 1.38 (m, 2H), 1.33 - 1.16 (m, 2H), 1.12 - 0.96 (m, 2H).

[0416] Step 5: Preparation of methyl 2-bromo-3,4-difluoro-benzoate

[0417] To a solution of 2-bromo-3,4-difluoro-benzoic acid (123 g, 518.99 mmol, 1 eq) in methanol (1300 mL) was added thionyl chloride (123.49 g, 1.04 mol, 75.30 mL, 2 eq) at 0 °C. The mixture was stirred at 70 °C for 12 hr. The mixture was concentrated under vacuum to give methyl 2-bromo-3,4-difluoro-benzoate (251.2 g, 1.00 mol, 96% yield) as a yellow oil without further purification.1H NMR: (400 MHz, CHLOROFORM-d) 5 = 7.77 - 7.61 (m, 1H), 7.25 - 7.10 (m, 1H), 3.95 (s, 3H).

[0418] Step 6: Preparation of methyl 2-bromo-4-[4-[4-(dimethoxymethyl)cyclohexoxy]-l- piperidyl]-3-flu oro-benz.oate

[0419] To a solution of 4-[4-(dimethoxymethyl)cyclohexoxy]piperidine (78 g, 303.07 mmol, 1.05 eq) in dimethylsulfoxide (1000 mL) was added TV, 7V-diisopropylethylamine (111.91 g, 865.91 mmol, 150.83 mL, 3 eq) and methyl 2-bromo-3,4-difhioro-benzoate (72.45 g, 288.64 mmol, 1 eq). The mixture was stirred at 100 °C for 12 hr. The residue was poured into ice water (1000 mL) and stirred for 0.5 min. The aqueous phase was extracted with ethyl acetate (200 mL*3). The combined organic phases were washed with brine (200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography (petroleum ether: ethyl acetate=7: l to 1 : 1) to get 100 g pure product and 30 g crude product. Methyl 2-bromo-4-[4-[4-(dimethoxymethyl)cyclohexoxy]-l-piperidyl]-3- fhioro-benzoate (130 g, 92% yield) was obtained as a white solid.1H NMR: (400 MHz, CHLOROFORM-d) 5 = 7.64 (dd, J = 1.6, 8.8 Hz, 1H), 6.87 (t, J = 8.4 Hz, 1H), 4.02 (d, J = 6.8 Hz, 1H), 3.91 (s, 3H), 3.64 (tt, J = 4.0, 8.0 Hz, 1H), 3.52 - 3.42 (m, 2H), 3.42 - 3.25 (m, 7H), 3.05 - 2.91 (m, 2H), 2.06 - 1.93 (m, 4H), 1.92 - 1.83 (m, 2H), 1.80 - 1.70 (m, 2H), 1.61 - 1.41 (m, 1H), 1.32 - 1.28 (m, 1H), 1.27 - 1.21 (m, 1H), 1.18 - 0.97 (m, 2H).

[0420] Step 7: Preparation of methyl 4-(4-(((lr,4r)-4-(dimethoxymethyl)cyclohexyl)oxy)piperidin- 1 -yl)-3-fluoro-2-vinylbenzoate

[0421] To a stirred solution of methyl 2-bromo-4-[4-[4-(dimethoxymethyl)cyclohexoxy]-l- piperidyl]-3-fluoro-benzoate (125 g, 255.94 mmol, 1 eq) in 1,4-dioxane (1050 mL) and water (210 mL) was added potassium;trifluoro(vinyl)boranuide (102.85 g, 767.83 mmol, 3 eq), [l,r-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (14.63 g, 17.92 mmol, 0.07 eq) and sodium carbonate (67.82 g, 639.86 mmol, 2.5 eq). The reaction mixture was stirred at 110°C for 12 hr. The mixture was filtered, and the filtrate was diluted with water (800 mL). The aqueous was extracted with ethyl acetate (400 mL * 2). The combined organic layer was washed with brine (500 mL * 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under vacuum. The residue was purified by MPLC (ISCO®; X g SepaFlash® silica flash column, eluent of 0-30% ethyl acetate / petroleum ether gradient @200 mL / min) to obtain methyl 4-[4-[4-(dimethoxymethyl)cyclohexoxy]-l-piperidyl]-3- fluoro-2-vinyl-benzoate (80 g, 71% yield) as a yellow oil.1H NMR: (400 MHz, CHLOROFORM-d) 3 : 7.63 (dd, J= 1.2, 8.4 Hz, 1H), 7.03 (dd, J= 11.6, 18.0 Hz, 1H), 6.83 (t, J= 8.4 Hz, 1H), 5.70 - 5.50 (m, 2H), 4.00 (d, J= 6.8 Hz, 1H), 3.85 (s, 3H), 3.61 (td, J= 4.2, 8.2 Hz, 1H), 3.48 - 3.40 (m, 2H), 3.38 - 3.26 (m, 7H), 2.93 (ddd, J= 2.8, 9.4, 12.2 Hz, 2H), 2.09 - 1.92 (m, 4H), 1.90 - 1.81 (m, 2H), 1.80 - 1.71 (m, 2H), 1.65 - 1.55 (m, 1H), 1.33 - 1.20 (m, 2H), 1.14 - 1.00 (m, 2H).

[0422] Step 8: Preparation of methyl 4-(4-(((lr,4r)-4-(dimethoxymethyl)cyclohexyl)oxy)piperidin- 1 -yl)-3-fluoro-2-formylbenzoate

[0423] To a stirred solution of methyl 4-[4-[4-(dimethoxymethyl)cyclohexoxy]-l-piperidyl]-3- fluoro-2-vinyl-benzoate (85 g, 195.17 mmol, 1 eq in 1,4-dioxane (1100 mL) and water (380 mL) was added 2,6-lutidine (41.82 g, 390.33 mmol, 45.46 mL, 2 eq , potassium osmate (VI) (1.44 g, 3.90 mmol, 0.02 eq and sodium periodate (166.98 g, 780.66 mmol, 43.26 mL, 4 eq in portions. The reaction mixture was stirred at 20°C for 1 hr. Water (800 mL) was added to the mixture and the mixture was filtered. The filtrate was extracted with ethyl acetate (600 mL x 3). The combined organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under vacuum. The residue was purified by MPLC (ISCO®; X g SepaFlash® silica flash column, eluent of 0-30% ethyl acetate / petroleum ether gradient @200 mL / min) to obtain methyl 4-[4-[4-(dimethoxymethyl)cyclohexoxy]-l-piperidyl]-3- fluoro-2-formyl-benzoate (65 g, 76% yield) as a yellow oil.1H NMR: (400 MHz, CHLOROFORM-d) 3: 10.42 (s, 1H), 7.65 (d, J= 8.4 Hz, 1H), 7.01 (t, J= 8.4 Hz, 1H), 4.00 (d, J= 6.8 Hz, 1H), 3.90 (s, 3H), 3.68 - 3.59 (m, 1H), 3.53 - 3.43 (m, 2H), 3.41 - 3.25 (m, 7H), 3.01 (ddd, J= 3.0, 9.0, 12.0 Hz, 2H), 2.09 - 1.91 (m, 4H), 1.90 - 1.82 (m, 2H), 1.79 - 1.68 (m, 2H), 1.62 - 1.54 (m, 1H), 1.33 - 1.20 (m, 2H), 1.14 - 0.99 (m, 2H).

[0424] Step 9: Preparation of 3-(5-(4-(((lr,4r)-4-(dimethoxymethyl)cyclohexyl)oxy)piperidin-l-yl)~ 4-fluoro-l -oxoisoindolin-2-yl)piperidine-2, 6-dione

[0425] To a stirred solution of 3 -aminopiperidine-2, 6-dione (36.12 g, 219.43 mmol, 1.2 eq, hydrochloride) in methanol (600 mL) was added sodium acetate (45.00 g, 548.57 mmol, 3 eq). The mixture was stirred at 25°C for 30 min. Then methyl 4-[4-[4- (dimethoxymethyl)cyclohexoxy]-l-piperidyl]-3-fluoro-2-formyl-benzoate (80 g, 182.86 mmol, 1 eq) was added to the mixture. The mixture was stirred at 25°C for another 0.5 hr. At last, Sodium cyanoborohydride (22.98 g, 365.71 mmol, 2 eq) was added. The resulting mixture was stirred at 40°C for 15 h. The mixture was filtered, and the cake was washed with methanol (50 mL x 3). Then the solid was suspended into water (3 L) and the mixture was stirred at 20°C for 10 min. The mixture was filtered, washed with acetonitrile (200 mL x 3), then the cake was dried to afford 3-[5-[4-[4-(dimethoxymethyl)cyclohexoxy]-l-piperidyl]-4- fluoro-l-oxo-isoindolin-2-yl]piperidine-2, 6-dione (76 g, 146.83 mmol, 80% yield) as a light purple solid which was confirmed byJH NMR. LCMS: MS (ESI) m / z: 518.0 [M+H]+.1H NMR: (400 MHz, DMSO-d6) d : 10.97 (s, 1H), 7.45 (d, J= 8.2 Hz, 1H), 7.16 (br t, J= 7.8 Hz, 1H), 5.07 (dd, J= 5.2, 13.2 Hz, 1H), 4.56 - 4.41 (m, 1H), 4.38 - 4.22 (m, 1H), 3.98 (d, J = 6.8 Hz, 1H), 3.70 - 3.55 (m, 1H), 3.40 - 3.33 (m, 2H), 3.30 - 3.16 (m, 6H), 2.99 - 2.84 (m, 3H), 2.58 (br d, J= 17.0 Hz, 1H), 2.49 - 2.36 (m, 2H), 2.03 - 1.85 (m, 5H), 1.71 (br d, J= 12.4 Hz, 2H), 1.62 - 1.43 (m, 3H), 1.21 - 0.93 (m, 4H).

[0426] Step 10: Preparation of (lr,4r)-4-((l-(2-(2,6-dioxopiperidin-3-yl)-4-fluoro-l-oxoisoindolin- 5-yl)piperidin-4-yl)oxy)cyclohexanecarbaldehyde

[0427] To a stirred solution of 3-[5-[4-[4-(dimethoxymethyl)cyclohexoxy]-l-piperidyl]-4-fluoro-l- oxo-isoindolin-2-yl]piperidine-2, 6-dione (71 g, 137.17 mmol, 1 eq) in acetone (800 mL) and water (80 mL) was added / ?-toluenesulfonic acid (4.72 g, 27.43 mmol, 0.2 eq). The reaction mixture was stirred at 70°C for 12 hr. The mixture was filtered, and the cake was washed with acetone (30 mL x 3), then dried. The solid was collected without further purification to afford 4- [ [ 1 -[2-(2, 6-dioxo-3 -piperidyl)-4-fluoro- 1 -oxo-i soindolin-5 -yl] -4- piperidyl]oxy]cyclohexanecarbaldehyde (58 g, 123.01 mmol, 89% yield) as a white solid. LCMS: MS (ESI) m / z: 471.9 [M+H]+. ’H NMR: (400 MHz, DMSO-t / 6) (5: 10.97 (s, 1H), 9.57 (s, 1H), 7.46 (d, J= 8.2 Hz, 1H), 7.16 (t, J= 7.9 Hz, 1H), 5.07 (dd, J= 5.2, 13.2 Hz, 1H), 4.47 (d, J= 16.8 Hz, 1H), 4.31 (d, J= 16.8 Hz, 1H), 3.66 - 3.54 (m, 1H), 3.42 - 3.35 (m, 2H), 3.00 - 2.84 (m, 3H), 2.63 - 2.52 (m, 1H), 2.49 - 2.35 (m, 2H), 2.32 - 2.18 (m, 1H), 2.01 - 1.86 (m, 7H), 1.63 - 1.50 (m, 2H), 1.41 - 1.15 (m, 4H).

[0428] Intermediate 46

[0429] Step 1: Preparation of tert-butyl 7-[3-[[(lS,5R)-3-tert-butoxycarbonyl-3- azabicyclo[3.1.0]hexan-6-yl]oxycarbonylanuno]~ 7-fluoro-6-isoquinolyl]-8-methyl-2,3- dihydropyrido[2,3-b][l,4]oxazine-l-carboxylate

[0430] To a solution of tert-butyl 7-(3-amino-7-fluoro-6-isoquinolyl)-8-methyl-2,3- dihydropyrido[2,3-b][l,4]oxazine-l-carboxylate (1 g, 2.44 mmol, 1 eq), tert-butyl 6-hydroxy- 3 -azabicyclo[3.1.0]hexane-3 -carboxylate (583 mg, 2.93 mmol, 1.2 eq in dichloromethane (10 mL) was added N,N-Diisopropylethylamine (1.58 g, 12.20 mmol, 2.1 mL, 5 eq) and triphosgene (290 mg, 0.98 mmol, 0.4 eq at 0 °C. The reaction mixture was stirred at 0 °C for 1 hr. Water (20 mL) was added to the mixture, the aqueous phase was extracted with ethyl acetate (20 mL x 3). The combined organic phases were washed with brine (20 mL), dried over sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography (petroleum ether: ethyl acetate = 100: 1 to 1 : 1). tert-butyl 7-[3- [[(lS,5R)-3-tert-butoxycarbonyl-3-azabicyclo[3.1.0]hexan-6-yl]oxycarbonylamino]-7-fluoro- 6-isoquinolyl]-8-methyl-2,3-dihydropyrido[2,3-b][l,4]oxazine-l-carboxylate (250 mg, 0.39 mmol, 16% yield, 98% purity) was obtained as a light yellow solid. LCMS: MS (ESI) m / z: 636.4 [M +1]+. ’H NMR: (400 MHz, CDC13) 8: 8.97 (s, 1H), 8.33 (s, 1H), 8.17 (s, 1H), 7.99 (s, 1H), 7.71 (d, J= 6.8 Hz, 1H), 7.61 (d, J= 9.2 Hz, 1H), 4.73 - 4.31 (m, 3H), 3.88 (s, 1H), 3.79 (s, 1H), 3.78 - 3.71 (m, 2H), 3.52 - 3.39 (m, 2H), 3.32 - 2.92 (m, 1H), 2.14 (s, 3H), 1.90 - 1.82 (m, 2H), 1.52 (s, 9H), 1.45 (s, 9H). Step 2: Preparation of [(IS, 5R)-3-azabicyclo[3.1.0]hexan-6-yl] N-[7-fluoro-6-(8-methyl- 2,3-dihydro-lH-pyrido[2,3-b][l,4]oxazin-7-yl)-3-isoquinolyl]carbamate

[0431] To a solution of tert-butyl 7-[3-[[(lS,5R)-3-tert-butoxycarbonyl-3-azabicyclo[3.1.0]hexan-6- yl]oxycarbonylamino]-7-fluoro-6-isoquinolyl]-8-methyl-2,3-dihydropyrido[2,3-b][l,4] oxazine- 1 -carboxylate (90 mg, 0.14 mmol, 1 eq) in dichloromethane (3 mL) was added trifluoroacetic acid (1.54 g, 13.51 mmol, 1 mL, 95.39 eq). The mixture was stirred at 25 °C for 1 h. The solution was concentrated under vacuum for the next step. The crude product was used into the next step without further purification. [(lS,5R)-3-azabicyclo[3.1.0]hexan-6- yl] N-[7-fhioro-6-(8-methyl-2,3-dihydro-lH-pyrido[2,3-b][l,4]oxazin-7-yl)-3- isoquinolyl]carbamate (94 mg, crude, 2 trifluoroacetic) was obtained as a light green oil. LCMS: MS (ESI) m / z: 436.2 [M +1]+.

[0432] Intermediate 47

[0433] Step 1: Preparation of Methyl 2,2-diethoxyethanimidate

[0434] To a solution of 2,2-diethoxyacetonitrile (1.7 g, 13.16 mmol, 1.83 mL, 1 eq) in methanol (20 mL) was added sodium methylate (71.11 mg, 1.32 mmol, 0.1 eq). The solution was stirred at 40°C for 12hr. The crude product, methyl 2,2-diethoxyethanimidate (2.12 g, 13.15 mmol, 100.00% yield), was used in next step directly without further purification as a solution (MeOH). Step 2: Preparation of N-[(4-bromo-3-chloro-phenyl)methyl] -2,2-diethoxy-acetanudine

[0435] To a solution of methyl 2,2-diethoxyethanimidate (2.12 g, 13.15 mmol, 1 eq) in methanol (20 mL) was added (4-bromo-3-chloro-phenyl)methanamine (2.90 g, 13.15 mmol, 1 eq). The solution was stirred at 40°C for 12 hr. The reaction was not monitored and work up directly. Solvent was removed under vacuum and the crude product was used in next step directly without further purification. N-[(4-bromo-3-chloro-phenyl)methyl]-2,2-diethoxy-acetamidine (4.5 g, 12.87 mmol, 97.86% yield) was obtained as a pale yellow oil.

[0436] Step 3: Preparation of 6-bronto-7-chloro-isoquinolin-3-aniine / 6-bromo-5-chIoro- isoquinolin-3-anune

[0437] A flask was charged with N-[(4-bromo-3-chloro-phenyl)methyl]-2,2-diethoxy-acetamidine (4.5 g, 12.87 mmol, 1 eq) and sulfuric acid (20 mL). The solution was stirred at 40°C for 2hr.The reaction solution was added dropwise to ammonium hydroxide / ice (V / V=200 mL / 300 mL) at 0°C and stirred for 0.5hr. The mixture was extracted with ethyl acetate (100 mL*3). Organic layer was washed with brine (100 mL), dried over sodium sulfate, filtered, and the filtrate was concentrated under vacuum. Crude was triturated in dichloromethane / methanol=50 mL(V / V=10: l), solid was collected, and the filtrate was concentrated under vacuum. 6-bromo-7-chloro-isoquinolin-3-amine (1.4 g, 5.44 mmol, 84.48% yield) was obtained as brown solid. 6-bromo-5-chloro-isoquinolin-3-amine (1.4 g, 2.72 mmol, 42.24% yield, 50% purity) (filtrate, will be purified next) was obtained as brown solid. LCMS: MS (ESI) m / z: 257.2 / 259.2 [M+H]+.

[0438] Intermediate 48 Step 1: Preparation of methyl 6-chloro-2-methylnicotinate

[0439] To a solution of 6-chloro-2-methylnicotinic acid (30 g, 174.84 mmol, 1 eq) in N,N- dimethylformamide (300 mL) was added potassium carbonate (60.41 g, 437.11 mmol, 2.5 eq) and iodomethane (99.27 g, 699.38 mmol, 44 mL, 4 eq), then the mixture was stirred at 25 °C for 12 h. The reaction mixture was diluted with water 50 mL and extracted with ethyl acetate (100 mL x 2). The combined organic layers were washed with brine (100 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The crude product methyl 6-chloro-2-methyl-pyridine-3-carboxylate (34.93 g, crude) was used into the next step without further purification. Methyl 6-chloro-2-methylnicotinate (34.93 g, crude) was obtained as a brown oil, confirmed byJH NMR. LCMS: MS (ESI) m / z: 186.1 [M+l]+. ’H NMR: (400 MHz, DMSO-t / 6) 8.17 (br d, J= 8.0 Hz, 1H), 7.46 (br d, J = 8.0 Hz, 1H), 3.85 (s, 3H), 2.66 (s, 3H).

[0440] Step 2: Preparation of methyl 2-(bromomethyl)-6-chloronicotinate

[0441] To a solution of methyl 6-chloro-2-methylnicotinate (34.93 g, 188.19 mmol, 1 eq) in carbon tetrachloride (350 mL) was added 2,2'-azobis(2-methylpropionitrile) (927 mg, 5.65 mmol, 0.03 eq) and N-bromosuccinimide (40.19 g, 225.83 mmol, 1.2 eq), then the mixture was stirred at 80 °C for 16 hr. The reaction mixture was diluted with water 150 mL and extracted with ethyl acetate (150 mL x 2). The combined organic layers were washed with sodium sulfite (50 mL x 2) and brine (50 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by prep- HPLC (column: Phenomenex luna Cl 8 (250*70mm,10 um); mobile phase: [water(FA)- ACN];B%: 45%-70%,21min). Methyl 2-(bromomethyl)-6-chloron-icotinate (10.05 g, 38.00 mmol, 20% yield) was obtained as a white solid, confirmed by 'H NMR. LCMS: MS (ESI) m / z 266.0 [M+2]+. ’H NMR: (400 MHz, DMSO-t / 6) : 8.29 (d, J= 8.4 Hz, 1H), 7.64 (d, J = 8.4 Hz, 1H), 4.92 (s, 2H), 3.93 - 3.85 (m, 3H). Step 3: Preparation of 3-(2-chloro-5-oxo-5H-pyrrolo[3,4-b]pyridin-6(7H)-yl)piperidine-2,6- dione

[0442] To a solution of methyl 2-(bromomethyl)-6-chloronicotinate (9 g, 34.03 mmol, 1 eq) and 3- aminopiperidine-2, 6-dione (5.60 g, 34.03 mmol, 1 eq, hydrochloride) in / f-di methyl formamide (90 mL) was added N, / f-diisopropylethylamine (13.19 g, 102.08 mmol, 17.8 mL, 3 eq), then the mixture was stirred at 110 °C for 6 hr. The mixture was cooled to 25 °C and poured into ice-water (w / w = 1 / 1) (50 mL) and stirred for 5 min. The suspension was filtered, and the fiter cake was washed with methyl tert-butyl ether (30 mL). The filtrate was diluted with water 30 mL and extracted with ethyl acetate (30 mL x 2). The combined organic layers were washed with brine (30 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was triturated with methyl tert-butyl ether (30mL). 3-(2-chloro-5-oxo-5H-pyrrolo[3,4-b]pyridin-6(7H)-yl)piperidine- 2, 6-dione (5.68 g, 20.31 mmol, 59% yield) was obtained as a purple solid. LCMS: MS (ESI) m / z: 280.1 [M+l]+. ’H NMR: (400 MHz, DMSO-t / 6) 3 : 11.03 (s, 1H), 8.20 (d, J= 8.0 Hz, 1H), 7.68 (d, J= 8.0 Hz, 1H), 5.17 (dd, J= 5.2, 13.2 Hz, 1H), 4.61 - 4.35 (m, 2H), 2.97 - 2.90 (m, 1H), 2.65 - 2.56 (m, 1H), 2.45 - 2.35 (m, 1H), 2.02 (dtd, J= 2.0, 5.2, 12.4 Hz, 1H).

[0443] Intermediate 49

[0444] Step 1: Preparation of methyl 2-ethylpyridine-3-carboxylate

[0445] To a mixture of methyl 2-chloropyridine-3 -carboxylate (7 g, 40.80 mmol, 5.3 mL, 1 eq) and diethylzinc (1 M, 49.0 mL, 1.2 eq) in dioxane (70 mL) was added [1,1'- bis(diphenylphosphino)ferrocene]dichloropalladium(II) (2.39 g, 3.26 mmol, 0.08 eq) in one portion at 20°C under nitrogen. The mixture was stirred at 60 °C for 2 hr. The reaction mixture was diluted with water (200 ml) and extracted with ethyl acetate (3 x 300 mL). The combined organic extracts were dried over sodium sulfate, and concentrated under vacuum. The residue was purified by silica gel chromatography (petroleum ether / ethyl acetate=20 / l, 5 / 1). Methyl 2-ethylpyridine-3- carboxylate (6.4 g, 38.74 mmol, 95% yield) as a yellow oil. LCMS: MS (ESI) m / z 166.2 [M+l]+.

[0446] Step 2: Preparation of methyl 2-ethyl-6-fluoro-pyridine-3-carboxylate

[0447] A mixture of methyl 2-ethylpyridine-3 -carboxylate (500 mg, 3.03 mmol, 1 eq) and silver(ii) fluoride (1.32 g, 9.08 mmol, 3 eq) in acetonitrile (8 mL) was stirred at 25°C for 16 hr under nitrogen. The mixture was filtered and concentrated under reduced pressure at 45 °C. The residue was purified by silica gel chromatography petroleum ether / ethyl acetate=30 / l, 7 / 1). Methyl 2-ethyl-6-fluoro-pyridine -3 -carboxylate (280 mg, 1.53 mmol, 50% yield) was obtained as a colorless oil.

[0448] Step 3: Preparation of methyl 2-(l-bromoethyl)-6-fluoro-pyridine-3- carboxylate

[0449] To a mixture of methyl 2-ethyl-6-fluoro-pyridine-3-carboxylate (3.93 g, 21.45 mmol, 1 eq) in carbontetrachloride (60 mL) was added 2,2-azobis(2-methypronitrile) (3.52 g, 21.45 mmol, 1 eq) and N-bromosuccinimide (5.73 g, 32.18 mmol, 1.5 eq) in one portion at 25 °C under nitrogen. The mixture was stirred at 25 °C for 5 min, then heated to 80 °C and stirred for 16 hr. The mixture was filtrated at 25 °C and the filtrate was concentrated in 45 °C. The residue was purified by flash silica gel chromatography (80g SepaFlash® Silica flash column, eluent of 0-20% ethyl acetate / petroleum ether gradient @ 120mL / min). Methyl 2-(l-bromoethyl)-6- fluoro-pyridine-3 -carboxylate (4.87 g, 18.58 mmol, 86% yield) was obtained as a yellow oil.

[0450] Step 4: Preparation of 3-(2-fluoro-7-methyl-5-oxo-7H-pyrrolo[3,4-b] pyridin-6- yl)piperidine-2, 6-dione

[0451] To a mixture of 3-aminopiperidine-2, 6-dione (3.06 g, 18.58 mmol, 1 eq, hydrochloride) and methyl 2-(l-bromoethyl)-6-fluoro-pyridine-3 -carboxylate (4.87 g, 18.58 mmol, 1 eq) in N,N- dimethylformamide (40 mL) was added M / f-diisopropylethylamine (12.01 g, 92.91 mmol, 16.18 mL, 5 eq) in one portion at 20 °C under nitrogen. The mixture was stirred at 90 °C for 16 hr. The mixture was cooled to 25 °C. The residue was poured into water (200 mL) and stirred for 5 min. The aqueous phase was extracted with ethyl acetate (100 mL x 2). The combined organic phase was washed with brine (200 mL x 2), dried with anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography (column height: 250 mm, diameter: 100 mm, 100-200 mesh silica gel, petroleum ether / ethyl acetate=l / O to 0 / 1). 3-(2-fluoro-7-methyl-5-oxo-7H-pyrrolo[3,4- b]pyridin-6-yl) piperidine-2, 6-dione (2.14 g, 7.72 mmol, 42% yield) was obtained as a yellow solid. LCMS: MS (ESI) m / z: 276.1 [M-l]+.

[0452] Intermediate 50

[0453] Step 1: Preparation of 3,4-difluorophthalic acid

[0454] A mixture of 3, 4-difluoro-2-m ethyl -benzoic acid (5 g, 29.05 mmol, 1 eq) in water (100 mL) was added potassium hydroxide (9.78 g, 174.29 mmol, 6 eq) and potassium permanganate (18.36 g, 116.19 mmol, 4 eq) at 25 °C, then the mixture was stirred for 12 hr at 85 °C. The mixture was quenched with saturated sodium sulfite solution (100 mL), the mixture was extracted with ethyl acetate (100 mL), after separated, the water phase was followed by addition concentrated hydrochloric acid (30 mL). The solution was further acidified to pH 2~3, the mixture extracted with ethyl acetate (100 mL x 2), the combined organic phase washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. 3,4-difluorophthalic acid (3.8 g, 18.80 mmol, 65% yield) was obtained as a white solid. ’ H NMR: (400 MHz, DMSO-t / 6) d: 14.2 - 13.0 (m, 2H), 7.82 - 7.75 (m, 1H), 7.67 - 7.57 (m, 1H).

[0455] Step 2: Preparation of 2-(2,6-dioxo-3-piperidyl)-4,5-difluoro-isoindoline- 1,3-dione

[0456] A solution of 3,4-difluorophthalic acid (3.8 g, 18.80 mmol, 1 eq) and 3 -aminopiperidine- 2,6- dione;hydrochloride (4.64 g, 28.20 mmol, 1.5 eq) in acetic acid (40 mL) was added sodium acetate (4.63 g, 56.40 mmol, 3 eq) at 25 °C, then the mixture was stirred for 12 hr at 120 °C. Water (300 mL) was added to the mixture, the resultant precipitate solid was collected by filtration, washed with water (50 mL x 3), and dried under vacuum. 2-(2,6-dioxo-3- piperidyl)-4,5-difluoro- isoindoline-1, 3-dione (3.8 g, 12.92 mmol, 69% yield) was obtained as a gray solid. ’H NMR: (400 MHz, DMSO-t / 6) d: 11.16 (s, 1H), 8.00 - 7.90 (m, 1H), 7.85 - 7.80 (m, 1H), 5.17 (dd, J=12.8, 5.2 Hz, 1 H), 2.97 - 2.82 (m, 1H), 2.65 - 2.57 (m, 1H), 2.55 - 2.50 (m, 1H), 2.12 - 2.00 (m, 1H).

[0457] Intermediate 51

[0458] Step 1: Preparation of (3-amino-7-fluoro -6-isoquinolyl)boronic acid

[0459] To a solution of 6-bromo-7-fluoro-isoquinolin-3 -amine (200 mg, 0.83 mmol, 1 eq), 4, 4, 5, 5- tetramethyl-2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l,3,2-dioxaborolane (1.05 g, 4.15 mmol, 5 eq), potassium acetate (244 mg, 2.49 mmol, 3 eq) in dioxane (10 mL) was added [l,l'-Bis(diphenylphosphino)ferrocene]palladium(II) chloride (121 mg, 0.17 mmol, 0.2 eq). The mixture was heated to 90 °C for 2 hr under nitrogen protection. The reaction was quenched with water (30 mL) extracted with ethyl acetate (15 mL x 3). The combined organic layers were dried over sodium sulfate, filtered, and filtrate was concentrated under vacuum. The crude produce was used in next step without purification. (3-amino-7-fluoro -6- isoquinolyl)boronic acid (170 mg, 0.83 mmol, 99% yield) was obtained as a yellow solid.

[0460] Step 2: Preparation of 6-(4,6-dimethyl-3-pyridyl)-7-fluoro- isoquinolin-3 -amine A flask was charged with 5-bromo-2,4-dimethyl-pyridine (154 mg, 0.83 mmol, 1 eq (3- amino-7-fluoro-6-isoquinolyl)boronic acid (170 mg, 0.83 mmol, 1 eq). [l,l'-Bis(diphenyl phosphino)ferrocene]palladium(II) chloride (60 mg, 0.083 mmol, 0.1 eq sodium carbonate (175 mg, 1.65 mmol, 2 eq dioxane (10 mL) and water (1 mL). The mixture was heated to 100 °C for 12 hr. The reaction solution was filtered, and the filtrate was diluted with water (20 mL) and extracted with ethyl acetate (15 mL x 3). Organic layer was dried over sodium sulfate, filtered, and filtrate was concentrated under vacuum. Crude was purified by prep- TLC (dichloromethane: methanol = 10: 1). 6-(4,6-dimethyl-3-pyridyl)-7 -fluoro-isoquinolin- 3-amine (300 mg, crude) was obtained as a yellow solid. LCMS: MS (ESI) m / z 268.3 [M+H]+. Step 3: Preparation of tert-butyl 4-[2-[[6-(4,6-dimethyl-3-pyridyl) -7-fluoro-3- isoquinolyl]amino]-7-oxo-5,8-dihydro-4H-pyrazolo[l,5-d][l,4]diazepin -6-yl]piperidine-l- carboxylate A flask was charged with 6-(4,6-dimethyl-3-pyridyl)-7-fluoro-isoquinolin-3-amine (200 mg, 0.75 mmol, 1 eq), tert-butyl 4-(2-bromo-7-oxo-5,8-dihydro-4H-pyrazolo[l,5-d][l,4] diazepin-6-yl)piperidine-l -carboxylate (340 mg, 0.82 mmol, 1.1 eq), [2-(2-aminophenyl) phenyl]-methylsulfonyloxy-palladium;ditert-butyl-[3,6-dimethoxy-2-(2,4,6- triisopropylphenyl)phenyl]phosphane (256 mg, 0.30 mmol, 0.4 eq), ditert-butyl-[3,6- dimethoxy-2-(2,4,6- triisopropylphenyl)phenyl]phosphane (181 mg, 0.37 mmol, 0.5 eq), dicesium;carbonate (731 mg, 2.24 mmol, 3 eq) and dioxane (15 mL). The mixture was heated to 130 °C for 1 hr. Reaction solution was filtered, and the filtrate was concentrated under vacuum. The crude product was purified by prep-TLC (dichloromethane: methanol = 20: 1). Tert-butyl 4-[2-[[6-(4,6-dimethyl-3-pyridyl)-7-fluoro-3-isoquinolyl]amino]-7-oxo-5,8- dihydro -4H-pyrazolo[l,5-d][l,4]diazepin-6-yl]piperidine-l-carboxylate (100 mg, 0.17 mmol, 22% yield) was obtained as a yellow solid. LCMS: MS (ESI) m / z 600.3 [M+H]+.

[0461] Step 4: Preparation of 2-[[6-(4,6- dimethyl-3-pyridyl)-7-fluoro-3- isoquinolyl]amino]-6-(4- piperidyl)-5, 8-dihydro-4H-pyrazolo[l, 5-d] [1,4] diazepin- 7-one

[0462] To a solution of tert-butyl 4-[2-[[6-(4,6-dimethyl-3-pyridyl)-7-fluoro-3-isoquinolyl]amino] - 7-oxo-5,8-dihydro-4H-pyrazolo[l,5-d][l,4]diazepin-6-yl]piperidine-l -carboxylate (70 mg, 0.12 mmol, 1 eq) in dichloromethane (3 mL) was added trifluoroacetic acid (67 mg, 0.58 mmol, 5 eq). The solution was stirred at 20 °C for 1 hr. LCMS showed reaction was complete. Solvent was removed under vacuum. The crude product was used in next step directly without further purification. 2-[[6-(4,6-dimethyl-3-pyridyl)-7-fluoro-3- isoquinolyl]amino]-6-(4-piperidyl)-5,8-dihydro-4H-pyrazolo[l,5-d][l,4]diazepin-7-one (58 mg, 0.12 mmol, 99% yield) was obtained as a yellow solid. LCMS: MS (ESI) m / z 500.3 [M+H]+.

[0463] Intermediate 52

[0464] Step 1: Preparation of 3-[5-[4-(dimethoxymethyl)-l-piperidyl]-4-fluoro-l-oxo-isoindolin-2- yl]piperidine-2, 6-dione

[0465] To a solution of 3-(4,5-difluoro-l-oxo-isoindolin-2-yl)piperidine-2, 6-dione (2 g, 7.14 mmol, 1 eq) in dimethylsulfoxide (20 mL) was added diisopropyl ethylamine (4.61 g, 35.69 mmol, 6.22 mL, 5 eq) and 4-(dimethoxymethyl)piperidine (2.27 g, 14.27 mmol, 2 eq). The mixture was stirred at 130 °C for 2 hr. The reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (50 mL x 3). The organic layer was washed with brine (50 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by prep-HPLC (column: Phenomenex luna C18 (250*70mm,10um);mobile phase: [water(FA)-ACN];B%: 25%-55%,20min). 3-[5-[4- (dimethoxymethyl)-l-piperidyl]-4-fluoro-l-oxo-isoindolin-2-yl]piperidine-2, 6-dione (200 mg, 0.48 mmol, 7% yield) was obtained as a brown solid. LCMS: MS (ESI) m / z: 420.3 [M +1]+.

[0466] Step 2: Preparation of l-[2-(2,6-dioxo-3-piperidyl)-4-fluoro-l-oxo-isoindolin-5- yl]piperidine-4-carbaldehyde

[0467] To a solution of 3-[5-[4-(dimethoxymethyl)-l-piperidyl]-4-fluoro-l-oxo-isoindolin-2- yl]piperidine-2, 6-dione (110 mg, 0.26 mmol, 1 eq) in dichloromethane (3 mL) was added trifluoroacetic acid (2.31 g, 20.26 mmol, 1.5 mL, 77.25 eq). The mixture was stirred at 20°C for 1 hr. The mixture was adjusted to pH 7 ~ 8 with triethylamine. The crude product was used into the next step without further purification. l-[2-(2,6-dioxo-3-piperidyl)-4-fluoro-l- oxo-isoindolin-5-yl]piperidine-4-carbaldehyde (97 mg, crude) was as a yellow solid. LCMS: MS (ESI) m / z: 374.3 [M +l]+.

[0468] Intermediate 53 Step 1: Preparation of 3-[2-[4-(dimethoxymethyl)-l-piperidyl]-5-oxo-7H-pyrrolo[3,4- b]pyridin-6-yl]piperidine-2, 6-dione

[0469] To a solution of 3-(2-chloro-5-oxo-7H-pyrrolo[3,4-b]pyridin-6-yl)piperidine-2, 6-dione (Reactant 1) (150 mg, 0.54 mmol, 1 eq in N,N-dimethylformamide (3 mL) was added diisopropylethylamine (208 mg, 1.61 mmol, 0.28 mL, 3 eq) and 4- (dimethoxymethyl)piperidine (102 mg, 0.64 mmol, 1.2 eq . The mixture was stirred a 120 °C for 4 hr. The reaction mixture was diluted with water (1000 mL) and extracted with ethyl acetate (500 mL x 3). The combined organic phase was washed with brine (500 mL x 3), dried with anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by prep-TLC (silicon dioxide, dichloromethane: methanol = 10: 1). 3-[2-[4- (dimethoxymethyl)-l-piperidyl]-5-oxo-7H-pyrrolo[3,4-b]pyridin-6-yl]piperidine-2, 6-dione (105 mg, 0.26 mmol, 49% yield) was obtained as yellow oil.1H NMR: (400 MHz, DMSO- d6) 5 = 10.95 - 10.93 (m, 1H), 7.73 (d, J= 9.2 Hz, 1H), 6.89 (d, J= 9.2 Hz, 1H), 5.06 (dd, J = 4.8, 13.2 Hz, 1H), 4.45 (d, J= 13.2 Hz, 2H), 4.23 (s, 1H), 4.10 (s, 1H), 4.07 - 4.04 (m, 1H), 3.26 (s, 6H), 2.95 - 2.85 (m, 3H), 2.62 - 2.54 (m, 1H), 2.00 - 1.85 (m, 3H), 1.74 - 1.66 (m, 2H), 1.25 - 1.12 (m, 2H).

[0470] Step 2: Preparation of l-[6-(2,6-dioxo-3-piperidyl)-5-oxo-7H-pyrrolo[3,4-b]pyridin-2- yl]piperidine-4-carbaldehyde

[0471] To a solution of 3-[2-[4-(dimethoxymethyl)-l-piperidyl]-5-oxo-7H-pyrrolo[3,4-b]pyridin-6- yl]piperidine-2, 6-dione (Reactant 1) (35 mg, 0.09 mmol, 1 eq in dichloromethane (1.5 mL) was added trifluoroacetic acid (770 mg, 6.75 mmol, 0.5 mL, 77.65 eq . The mixture was stirred at 25 °C for 4 hr. The crude product was used into the next step without further purification. l-[6-(2,6-dioxo-3-piperidyl)-5-oxo-7H-pyrrolo[3,4-b]pyridin-2-yl]piperidine-4- carbaldehyde (29 mg, 0.08 mmol, 93% yield) was obtained as a yellow oil. LCMS: MS (ESI) m / z: 357.1[M +1]+.

[0472] Intermediate 54

[0473] Step 1: Preparation of tert-butyl 2-[[6-(4,6-dimethyl-3-pyridyl)-7-fluoro-3- isoquinolyljcarbamoyloxy]- 7-azaspiro[3.5] nonane- 7-carboxylate

[0474] A mixture of 6-(4,6-dimethyl-3-pyridyl)-7-fluoro-isoquinolin-3-amine (Reactant 1) (1.5 g, 5.61 mmol, 1 eq), tert-butyl 2-hydroxy-7-azaspiro[3.5]nonane-7-carboxylate (1.35 g, 5.61 mmol, 1 eq and diisopropylethylamine (3.63 g, 28.06 mmol, 4.89 mL, 5 eq) in di chloromethane (20 mL) was added bis(tri chloromethyl) carbonate (840 mg, 2.83 mmol, 5.04e-l eq at 0 °C. The mixture was stirred at 0 °C for 1 hr. The reaction mixture was quenched by saturated sodium hydrogen carbonate solution 30 mL and extracted with dichloromethane (20 mL x 3), washed with saturated brine (20 mL x 1), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® Silica flash column, eluent of 0-50% ethyl acetate / petroleum ether gradient @ 150 mL / min). Tertbutyl 2-[[6-(4,6-dimethyl-3-pyridyl)-7-fluoro-3-isoquinolyl]carbamoyloxy]-7- azaspiro[3.5]nonane-7-carboxylate (800 mg, 1.50 mmol, 27% yield) was obtained as a yellow solid. LCMS: MS (ESI) m / z: 535.3 [M +1]+. ’H NMR: (400 MHz, CHLOROFORM-d) 5: 9.00 (s, 1H), 8.37 (s, 1H), 8.29 (s, 1H), 8.04 (s, 1H), 7.68 (d, J= 6.8 Hz, 1H), 7.60 (d, J= 9.6 Hz, 1H), 7.14 (s, 1H), 5.14 (t, J= 7.2 Hz, 1H), 3.40 - 3.36 (m, 2H), 3.35 - 3.32 (m, 2H), 2.61 (s, 3H), 2.48 - 2.40 (m, 2H), 2.22 (s, 3H), 2.00 - 1.93 (m, 2H), 1.62 - 1.58 (m, 4H), 1.46 (s, 9H). Step 2: Preparation of 7-azaspiro[3.5]nonan-2-yl N-[6-(4,6-dimethyl-3-pyridyl)-7-fluoro-3- isoquinolyljcarbamate

[0475] To a solution of tert-butyl 2-[[6-(4,6-dimethyl-3-pyridyl)-7-fluoro-3- isoquinolyl]carbamoyloxy]-7-azaspiro[3.5]nonane-7-carboxylate (Reactant 1) (80 mg, 0.15 mmol, 1 eq} in di chloromethane (2 mL) was added trifluoroacetic acid (1.54 g, 13.51 mmol, 1 mL, 90.26 eq . The mixture was stirred at 25 °C for 0.5 hr. The reaction mixture was concentrated under reduced pressure to give a residue. The crude product 7- azaspiro[3.5]nonan-2-yl N-[6-(4,6-dimethyl-3-pyridyl)-7-fluoro-3-isoquinolyl]carbamate (80 mg, 0.15 mmol, 97% yield, trifluoroacetate) was used into the next step without further purification as a yellow oil. LCMS: MS (ESI) m / z: 435.2 [M +1]+.

[0476] Intermediate 55

[0477] Step 1: Preparation of tert-butyl 7-[3-[[(lR,5S)-3-tert-butoxycarbonyl-3- azabicyclo[3.1.0]hexane-6-carbonyl]amino]- 7-fluoro-6-isoquinolyl]-8-methyl-2,3- dihydropyrido[2,3-b][l,4]oxazine-l-carboxylate

[0478] To a solution of tert-butyl 7-(3-amino-7-fluoro-6-isoquinolyl)-8-methyl-2,3- dihydropyrido[2,3-b][l,4]oxazine-l-carboxylate (Reactant 1) (300 mg, 0.73 mmol, 1 eq), (lR,5S)-3-tert-butoxycarbonyl-3-azabicyclo[3.1.0]hexane-6-carboxylic acid (831 mg, 3.65 mmol, 5 eq) in dimethylformamide (10 mL), diisopropylethylamine (472 mg, 3.65 mmol, 0.6 mL, 5 eq). Tetramethylurea hexafluorophosphate (556 mg, 1.46 mmol, 2 eq) at 0 °C was then added slowly. The mixture was stirred at 20 °C for 1 hr. The reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (lOOmL x 3). The combined organic phase was washed with saturated brine (lOOmL x 3), dried with anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by prep-TLC (silicon dioxide, petroleum ether: ethyl acetate = 0: 1). Tert-butyl 7-[3-[[(lR,5S)-3-tert- butoxycarbonyl-3-azabicyclo[3.1.0]hexane-6-carbonyl]amino]-7-fluoro-6-isoquinolyl]-8- methyl-2,3-dihydropyrido[2,3-b][l,4]oxazine-l-carboxylate (153 mg, 0.25 mmol, 34% yield) was obtained as a yellow solid. LCMS: MS (ESI) m / z: 620.1[M +1]+.

[0479] Step 2: Preparation of (lR,5S)-N-[7-fluoro-6-(8-methyl-2,3-dihydro-lH-pyrido[2,3- b] [1,4] oxazin- 7-yl)-3-isoquinolyl]-3-azabicyclo[3.1.0]hexane-6-carboxamide

[0480] To a solution of tert-butyl 7-[3-[[(lR,5S)-3-tert-butoxycarbonyl-3-azabicyclo[3.1.0]hexane- 6-carbonyl]amino]-7-fluoro-6-isoquinolyl]-8-methyl-2,3-dihydropyrido[2,3-b][l,4]oxazine- 1-carboxylate (Reactant 1) (75 mg, 0.12 mmol, 1 eq) in dichloromethane (3 mL) was added trifluoroacetic acid (1.54 g, 13.51 mmol, 1 mL, 104.62 eq). The mixture was stirred at 25 °C for 1 h. The solvent was concentrated under vacuum. The crude product was used into the next step without further purification. (lR,5S)-N-[7-fluoro-6-(8-methyl-2,3-dihydro-lH- pyrido[2,3-b][l,4]oxazin-7-yl)-3-isoquinolyl]-3-azabicyclo[3.1.0]hexane-6-carboxamide (60 mg, 0.11 mmol, 93% yield, trifluoroacetate) was obtained as a yellow solid. LCMS: MS (ESI) m / z: 420.0 [M +l]+.

[0481] Intermediate 56

[0482] Step 1: Preparation of (4-fluoro-4-piperidy I) methanol To a solution of tert-butyl 4-fluoro-4-(hydroxymethyl)piperidine-l -carboxylate (50 g, 214.34 mmol, 1 eq) in dichloromethane (500 mL) was added hydrochloric acid / dioxane (4 M, 250 mL). The mixture was stirred at 25 °C for 3 hr. The reaction mixture was concentrated under reduced pressure to give residue. The residue was triturated with petroleum ether: ethyl acetate = 10: 1 (150 mL) at 25 °C for 10 min to obtain (4-fluoro-4-piperidyl)methanol (72 g, 424.47 mmol, 99% yield, Hydrochloride) as white solid.1H NMR: (400MHz, DMSO- e) d: 9.46 - 8.75 (m, 2H), 5.70 - 4.59 (m, 1 H), 3.46 - 3.41 (m, 2 H), 3.24 - 3.15 (m, 2 H), 3.03 - 2.85 (m, 2 H), 2.00 - 1.73 (m, 4 H).

[0483] Step 2: Preparation of methyl 3-fluoro-4-[4-fluoro-4-(hydroxy methyl)-! -piperidyl / benzoate

[0484] To a solution of (4-fluoro-4-piperidyl)methanol (24 g, 141.49 mmol, 1 eq, Hydrochloride) in dimethyl sulfoxide (320 mL) was added N,N-Diisopropyl ethylamine (54.86 g, 424.47 mmol, 74 mL, 3 eq) and methyl 3,4-difluorobenzoate (29.23 g, 169.79 mmol, 1.2 eq). The mixture was stirred at 80 °C for 12 hr. The reaction mixture was diluted with water (2000 mL) and extracted with ethyl acetate (1200 mL x 3). The combined organic layers were washed with brine (1000 mL x 5) dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give residue. The residue was purified by column chromatography (silicon dioxide, petroleum ether / ethyl acetate=8 / l to 1 / 1) to obtain methyl 3-fluoro-4-[4- fhioro-4-(hydroxymethyl)-l-piperidyl]benzoate (54 g, 189.28 mmol, 45% yield) as a yellow solid. LCMS: MS (ESI) m / z: 286.0 [M+l]+. ’H NMR: (400MHz, CDCh-d) d: 7.76 (dd, J= 1.6, 8.4 Hz, 1 H), 7.67 (dd, J= 1.6, 13.6 Hz, 1 H), 6.96 (t, J= 8.4 Hz, 1 H), 3.89 (s, 3 H), 3.74 - 3.61 (m, 2 H), 3.52 - 3.41 (m, 2 H), 3.12 (dt, J= 2.4, 12.4 Hz, 2 H), 2.11 - 2.00 (m, 2 H), 1.99 - 1.75 (m, 3 H).

[0485] Step 3: Preparation of methyl 3-fluoro-4-(4-fluoro-4-formyl-l-piperidyl)benzoate To a solution of oxalyl chloride (29.36 g, 231.35 mmol, 20 mL, 3 eq) in dichloromethane (180 mL) was added a solution of dimethyl sulfoxide (24.10 g, 308.46 mmol, 24 mL, 4 eq) in di chloromethane (110 mL) at -70°C under the protection of nitrogen, the reaction was stirred at -70 °C for 30 min and a solution of methyl 3-fluoro-4-[4-fhioro-4-(hydroxymethyl)-l- piperidyl]benzoate (22 g, 77.12 mmol, 1 eq) in dichloromethane (110 mL) was added. The reaction was stirred at -70 °C for 30 min and triethylamine (62.43 g, 616.93 mmol, 86 mL, 8 eq) was added. After addition, the reaction was stirred at -70 °C for 30 min. The reaction mixture was diluted with water (400 mL) and extracted with dichloromethane (800 mL x 2). The combined organic layers were brine (300 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give methyl 3-fluoro-4-(4-fluoro-4- formyl-1 -piperidyl )benzoate (44 g, crude) as a yellow oil. The residue was used for next step without further purification.1H NMR: (400MHz, CDCh-d) d: 9.79 (d, J= 4.8 Hz, 1 H), 7.77 (d, J= 8.4 Hz, 1 H), 7.69 (d, J= 13.6 Hz, 1 H), 6.98 - 6.94 (m, 1 H), 3.89 (s, 3 H), 3.59 - 3.40 (m, 2 H), 3.20 - 3.10 (m, 2 H), 2.15 - 1.91 (m, 4 H).

[0486] Step 4: Preparation of methyl 4-[4-(dimethoxymethyl)-4-fluoro-l-piperidyl]-3-fluoro- benzoate

[0487] A mixture of methyl 3 -fluoro-4-(4-fluoro-4-formyl-l -piperidyl )benzoate (22 g, 77.66 mmol, 1 eq), trimethoxymethane (300.08 g, 2.83 mol, 310 mL, 36.41 eq) and 4- methylbenzenesulfonic acid;pyridine (1.95 g, 7.77 mmol, 0.1 eq) was stirred at 25 °C for 16 hr. Trimethoxymethane (96.80 g, 912.17 mmol, 100 mL, 11.75 eq) and pyridinium p- toluenesulfonate (976 mg, 3.88 mmol, 0.05 eq) in methanol (50 mL) was added and the resulting solution was stirred at 40 °C for 5 hr. The reaction mixture was diluted with saturated sodium hydrogencarbonate (400 mL) and extracted with ethyl acetate (800 mL x 2). The combined organic layers were washed with brine (300 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give residue. The residue was purified by flash silica gel chromatography (ISCO®; 120 g SepaFlash® silica flash column, eluent of 0-10% ethyl acetate / petroleum ether gradient @ 60 mL / min) to obtain methyl 4-[4-(dimethoxymethyl)-4-fluoro-l-piperidyl]-3-fluoro-benzoate (42 g, 127.53 mmol, 82% yield) as a white solid. LCMS: MS (ESI) m / z: 330.2 [M+l]+. ’H NMR: (400MHz, CDCh-d) d: 7.74 (dd, J= 2.0, 8.4 Hz, 1 H), 7.66 (dd, J= 2.0, 13.6 Hz, 1 H), 6.95 (t, J= 8.4 Hz, 1 H), 4.17 (d, J= 8.0 Hz, 1 H), 3.88 (s, 3 H), 3.58 - 3.46 (m, 8 H), 3.13 - 3.02 (m, 2 H), 2.11 - 2.01 (m, 1 H), 1.99 - 1.90 (m, 3 H).

[0488] Step 5: Preparation of 4-[4-(dimethoxymethyl)-4-fluoro-l-piperidyl]-3-fluoro-benzoic acid

[0489] To a solution of methyl 4-[4-(dimethoxymethyl)-4-fluoro-l-piperidyl]-3-fluoro-benzoate (22 g, 66.80 mmol, 1 eq) in tetrahydrofuran (100 mL), water (100 mL) and methanol (100 mL) was added lithium; hydroxide;hydrate (14.02 g, 334.00 mmol, 5 eq), the mixture was stirred at 25 °C for 2 hr. The reaction was adjusted to pH 4 with IN hydrochloric acid, then the reaction was diluted with ethyl acetate (2000 mL) and washed with brine (400 mL x 2). The organic layer was dried over anhydrous sodium sulfate and concentrated to give 4-[4- (dimethoxymethyl)-4-fluoro-l-piperidyl]-3-fluoro-benzoic acid (42 g, 133.20 mmol, 100% yield) as a white solid, the obtained product was used for next step directly without further purification. LCMS: MS (ESI) m / z: 315.8 [M+l]+. ’ H NMR: (400MHz, CDCh-d) d: 7.82 (dd, J= 2.0, 8.4 Hz, 1 H), 7.72 (dd, J= 2.0, 13.6 Hz, 1 H), 6.97 (t, J= 8.4 Hz, 1 H), 4.18 (d, J = 8.0 Hz, 1 H), 3.62 - 3.47 (m, 8 H), 3.19 - 3.03 (m, 2 H), 2.16 - 1.88 (m, 4 H).

[0490] Step 6: Preparation of 4-[4-(dimethoxymethyl)-4-fluoro-l-piperidyl]-3-fluoro-2-formyl- benzoic acid

[0491] To a solution of 4-[4-(dimethoxymethyl)-4-fluoro-l-piperidyl]-3-fluoro-benzoic acid (16 g, 50.74 mmol, 1 eq) in tetrahydrofuran (360 mL) was added butyllithium (2.5 M, 60.89 mL, 3 eq) at -70 °C under the protection of nitrogen, the reaction was stirred at -70 °C for 30 min and dimethyl formamide (37.09 g, 507.43 mmol, 39 mL, 10 eq) was added and the reaction was stirred at -70 °C for 1 hr. The reaction was quenched by IN hydrochloric acid to adjust the pH to 6 and extracted with ethyl acetate (800 mL x 2). Then the organic layer was washed with brine (300 mL x 2), dried over anhydrous sodium sulfate, and concentrated to give 4-[4- (dimethoxymethyl)-4-fluoro-l-piperidyl]-3-fluoro-2-formyl-benzoic acid (35 g, crude) was obtained as a yellow oil. The crude product was used for next step directly without further purification. LCMS: MS (ESI) m / z: 343.8 [M+l]+.

[0492] Step 7: Preparation of methyl 4-[4-(dimethoxymethyl)-4-fluoro-l-piperidyl]-3-fluoro-2- formyl-benzoate

[0493] To a solution of 4-[4-(dimethoxymethyl)-4-fluoro-l-piperidyl]-3-fluoro-2-formyl-benzoic acid (35 g, 101.95 mmol, 1 eq) in dimethyl formamide (350 mL) was added methyl iodide (43.41 g, 305.84 mmol, 19 mL, 3 eq) and potassium carbonate (42.27 g, 305.84 mmol, 3 eq), then the reaction was stirred at 25 °C for 12 hr. The reaction was filtered, and the filtrate was diluted with water (400 mL) and extracted with ethyl acetate (600 mL x 2). The combined organic layers were washed with brine (200 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the residue. The residue was purified by flash silica gel chromatography (ISCO®; 10 g SepaFlash® Silica Flash Column, Eluent of 0-20% ethyl acetate / petroleum ether gradient @ 40 mL / min) to give methyl 4-[4- (dimethoxymethyl)-4-fluoro-l-piperidyl]-3-fluoro-2-formyl-benzoate (17.7 g, 49.53 mmol, 49% yield, 100% purity) as a white solid. LCMS: MS (ESI) m / z: 358.2 [M+l]+. ’H NMR: (400MHz, CDCh-d) d: 10.42 (s, 1 H), 7.67 (d, J= 8.0 Hz, 1 H), 7.04 (t, J= 8.4 Hz, 1 H), 4.17 (d, J= 8.0 Hz, 1H), 3.90 (s, 3 H), 3.59 - 3.46 (m, 8 H), 3.18 - 3.03 (m, 2 H), 2.10 - 1.88 (m, 4 H). Step 8: Preparation of 3-[5-[4-(dimethoxyntethyl)-4-fluoro-l-piperidyl]-4-fluoro-l-oxo- isoindolin-2-yl]piperidine-2, 6-dione

[0494] To a mixture of 3-aminopiperidine-2, 6-dione (7.70 g, 46.79 mmol, 1.1 eq, Hydrochloride) in methanol (300 mL) was added sodium acetate (10.47 g, 127.61 mmol, 3 eq), and then methyl 4-[4-(dimethoxymethyl)-4-fluoro-l-piperidyl]-3-fluoro-2-formyl-benzoate (15.2 g, 42.54 mmol, 1 eq) was added. The mixture was stirred at 25 °C for 30 min. Then acetic acid (12.77 g, 212.68 mmol, 12 mL, 5 eq) and sodium cyanob orohydri de (5.35 g, 85.07 mmol, 2 eq) were added. The mixture was stirred at 40 °C for 12 hr. The reaction mixture was concentrated under reduced pressure to give residue. The residue was triturated with water: acetonitrile = (6: 1, 200 mL) at 25 °C for 30 min to obtain 3-[5-[4-(dimethoxymethyl)-4-fluoro-l- piperidyl]-4-fluoro-l-oxo-isoindolin-2-yl]piperidine-2, 6-dione (17.2 g, 39.32 mmol, 92% yield) as an off-white solid. LCMS: MS (ESI) m / z: 437.9 [M+l]+. ’ H NMR: (400MHz, DMSO-tfc) d: 10.97 (s, 1 H), 7.47 (d, J= 8.0 Hz, 1 H), 7.21 (t, J= 8.0 Hz, 1 H), 5.07 (dd, J= 4.8, 13.2 Hz, 1 H), 4.54 - 4.43 (m, 1 H), 4.38 - 4.24 (m, 2 H), 3.47 - 3.37 (m, 8 H), 3.04 - 2.82

[0495] (m, 3 H), 2.70 - 2.54 (m, 1 H), 2.47 - 2.31 (m, 1 H), 2.02 - 1.76 (m, 5 H).

[0496] Step 9: Preparation of 3-[5-[4-(dihydroxymethyl)-4-fluoro-l-piperidyl]-4-fluoro-l-oxo- isoindolin-2-yl]piperidine-2, 6-dione To a solution of 3-[5-[4-(dimethoxymethyl)-4-fhioro-l-piperidyl]-4-fluoro-l-oxo-isoindolin- 2-yl]piperidine-2, 6-dione (20.8 g, 47.55 mmol, 1 eq) in water (104 mL) was added trifluoroacetic acid (640.64 g, 5.62 mol, 416 mL, 118.16 eq), the reaction was stirred at 60 °C for 36 hr. The reaction mixture was concentrated under reduced pressure to give residue. The residue was triturated with petroleum ether: ethyl acetate = 5: 1 (150 mL) at 25 °C for 20 min to obtain 3-[5-[4-(dihydroxymethyl)-4-fluoro-l-piperidyl]-4-fluoro-l-oxo-isoindolin-2- yl]piperidine-2, 6-dione (22 g, 42.03mmol, 88% yield, Trifluoroacetate) as a yellow solid. LCMS: MS (ESI) m / z: 409.9 [M+l]+. ’H NMR: (400MHz, DMSO-t / 6) d: 10.98 (s, 1 H), 7.52 - 7.40 (m, 1 H), 7.30 - 7.15 (m, 1 H), 5.14 - 5.02 (m, 1 H), 4.86 - 4.67 (m, 1 H), 4.53 - 4.45 (m, 1 H), 4.38 - 4.27 (m, 1 H), 3.53 - 3.37 (m, 3 H), 3.03 - 2.84 (m, 3 H), 2.65 - 2.52 (m, 2 H), 2.48 - 2.33 (m, 1 H), 2.29 - 2.05 (m, 1 H), 1.98 - 1.80 (m, 4 H).

[0497] Intermediate 57

[0498] Step 1: Preparation of 5-fluoro-2-(3-methyl-2,6-dioxo-3-piperidyl)isoindoline-l, 3-dione

[0499] A mixture of tert-butyl 7-(3-amino-7-fluoro-6-isoquinolyl)-8-methyl-2,3-dihydropyrido[2,3- b][l,4]oxazine-l-carboxylate (200 mg, 0.48 mmol, 1 eq), l-tert-butoxycarbonyl-4-fluoro- piperidine-4-carboxylic acid (180 mg, 0.73 mmol, 1.5 eq), diisopropyl ethyl amine (188 mg, 1.46 mmol, 0.3 mL, 3 eq) in methyl form am ide (5 mL) then 2-(7-azobentriazole)-

[0500] N,N,N’,N’-tetramethyluronium hexafluorophosphate (277 mg, 0.73 mmol, 1.5 eq) was added into the mixture at 0 °C. Next the mixture was stirred at 20 °C for 1 h under nitrogen atmosphere. The residue was poured into ice-water (10 mL) and stirred for 3 min. The aqueous phase was extracted with ethyl acetate (10 mL x 3). The combined organic phase was washed with brine (10 mL x 3), dried with anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by prep-HPLC (column: Phenomenex luna C18 150*25mm* lOum; mobile phase: [water(FA)-ACN];B%: 71%-100%,10min), was confirmed by 'H NMR. Tert-butyl 7-[3-[(l-tert-butoxycarbonyl-4-fluoro-piperidine-4- carbonyl)amino]-7-fluoro-6-isoquinolyl]-8-methyl-2,3-dihydropyrido[2,3-b][l,4]oxazine-l- carboxylate (146 mg, 0.22 mmol, 47% yield) was obtained as black gray solid. LCMS: MS (ESI) m / z: 640.4 [M+l]+. ’H NMR: (400 MHz, Dimethylsulfoxide-d6) 8 = 10.22 (d, J= 3.2 Hz, 1H), 9.22 (s, 1H), 8.51 (s, 1H), 8.07 - 7.95 (m, 3H), 3.95 (d, J= 11.6 Hz, 2H), 3.84 (d, J = 13.2 Hz, 4H), 2.99 (d, J= 1.6 Hz, 2H), 2.03 (s, 3H), 1.87 - 1.83 (m, 4H), 1.40 (s, 18H).

[0501] Step 3: Preparation of 4-fluoro-N-[7-fluoro-6-(8-methyl-2,3-dihydro-lH-pyrido[2,3- b][l,4]oxazin-7-yl)-3-isoquinolyl]piperidine-4-carboxamide

[0502] To a solution of tert-butyl 7-[3-[(l-tert-butoxycarbonyl-4-fluoro-piperidine-4- carbonyl)amino]-7-fluoro-6-isoquinolyl]-8-methyl-2,3-dihydropyrido[2,3-b][l,4]oxazine-l- carboxylate (80 mg, 0.12 mmol, 1 eq) in di chloromethane (3 mL) was added trifluoroacetic acid (1.54 g, 13.51 mmol, 1 mL, 108.00 eq). The mixture was stirred at 20 °C for 1 h. The residue was concentrated under vacuum for the next step. The crude product was used in the next step without further purification. 4-fluoro-N-[7-fluoro-6-(8-methyl-2,3-dihydro-lH- pyrido[2,3-b][l,4]oxazin-7-yl)-3-isoquinolyl]piperidine-4-carboxamide (83 mg, crude, 2 trifluoroacetate) was obtained as yellow oil. LCMS: MS (ESI) m / z: 440.2 [M+l]+.

[0503] Intermediate 58

[0504] Step 1: Preparation of tert-butyl 3-(bronioniethyl)-3-fluoroa~,etidine-l-carboxylate

[0505] To a solution of tert-butyl 3 -methyleneazetidine- 1 -carboxylate (20 g, 118.19 mmol, 1 eq) in dichloromethane (200 mL) was added dropwise N,N-diethylethanamine;trihydrofluoride (47.63 g, 295.47 mmol, 48.16 mL, 2.5 eq) at 0 °C. After addition, then 1-bromopyrrolidine- 2, 5-dione (37.86 g, 212.74 mmol, 1.8 eq) was added at 0 °C. The resulting mixture was stirred at 0 °C for 3 h. The reaction mixture was quenched by addition water (100 mL) at 25°C, and then diluted with di chloromethane 100 mL and extracted with di chloromethane (100 mL x 2). The combined organic layers were washed with 0.5 M sodium hydroxide (200 mL x 2), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (petroleum ether / ethyl acetate = 10 / 1 to 3 / 1). Tert-butyl 3-(bromomethyl)-3-fluoroazetidine-l-carboxylate (25 g, 93.24 mmol, 79% yield) was obtained as a white solid.

[0506] Intermediate 59

[0507] Step 1: Preparation of 3-(4-chloro-5-(4-(dimethoxymethyl)piperidin-l-yl)-l-oxoisoindolin- 2-yl)piperidine-2, 6-dione

[0508] To a solution of 3-(5-(4-(dimethoxymethyl)piperidin-l-yl)-l-oxoisoindolin-2-yl)piperidine- 2, 6-dione (500 mg, 1.25 mmol, 1 eq in dichloromethane (15 mL) and methanol (1.5 mL) was added 2-chloro-lH-indene-l,3(2H)-dione (332 mg, 2.49 mmol, 2 eq) and trifluoroacetic acid (284 mg, 2.49 mmol, 0.18 mL, 2 eq). The mixture was stirred at 25 °C for 12 h. Then, the mixture was stirred at 35 °C for 12 h. The residue was diluted with water 30 mL and extracted with ethyl acetate (30 mL x 2). The combined organic layers were washed with brine (30 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Welch Ultimate XB-CN 250*50*10 pm; mobile phase: [Hexane-EtOH];B%: 10%-50%,15min). 3- (4-chloro-5-(4-(dimethoxymethyl)piperi din-1 -yl)-l -ox oisoindolin-2-yl)piperidine-2, 6-dione (188 mg, 0.43 mmol, 35% yield) was obtained as a white solid, characterized by 'H NMR. LCMS: MS (ESI) m / z 436.2 [M+l]+. 'll NMR: (400 MHz, DMSO-d6) d : 10.98 (s, 1H), 7.64 (d, J= 8.0 Hz, 1H), 7.25 (d, J= 8.4 Hz, 1H), 5.09 (dd, J= 4.8, 13.2 Hz, 1H), 4.41 (d, J= 17.4 Hz, 1H), 4.30 - 4.21 (m, 1H), 4.14 (d, J= 6.2 Hz, 1H), 3.45 - 3.38 (m, 3H), 3.29 (s, 6H), 2.96 - 2.85 (m, 2H), 2.74 - 2.65 (m, 3H), 2.05 - 1.94 (m, 2H), 1.76 (d, J= 9.8 Hz, 3H). Step 2: Preparation of l-(4-chloro-2-(2,6-dioxopiperidin-3-yl)-l-oxoiso-indolin-5- yl)piperidine-4-carbaldehyde

[0509] To a solution of 3-(4-chloro-5-(4-(dimethoxymethyl)piperidin-l-yl)-l-oxoisoindolin-2- yl)piperidine-2, 6-dione (32 mg, 0.07 mmol, 1 eq) in dichloromethane (4 mL) was added trifluoroacetic acid (2 mL) at 25 °C for 1 h. LCMS showed desired mass was detected. The mixture was basied with triethylamine to pH=8.00. The mixture was used into next step without purification. l-(4-chloro-2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-5-yl)piperidine- 4-carbaldehyde (28 mg, 0.07 mmol, 97% yield) was obtained as a yellow oil. LCMS: MS (ESI) m / z: 390.1 [M+l]+.

[0510] Intermediate 60

[0511] Step 1: Preparation of 5-[4-(dimethoxymethyl)-4-fluoro-l-piperidyl]-2-(2, 6-dioxo-3- piperidyl) isoindoline-1, 3-dione

[0512] To a solution of 2-(2,6-dioxo-3-piperidyl)-5-fluoro-isoindoline-l, 3-dione (779 mg, 2.82 mmol, 1 eq), 4-(dimethoxymethyl)-4-fluoro-piperidine (500 mg, 2.82 mmol, 1 eq) in dimethylsulfoxide (2 mL) was added diisopropylethylamine (1.82 g, 14.11 mmol, 5 eq). The mixture was stirred at 120 °C for 12 hr. The reaction mixture was diluted with water 10 mL and extracted with Ethyl acetate (20 mL x 2). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® silica flash column, eluent of 0-50% ethyl acetate / petroleum ether gradient @ 80 mL / min) to give the crude product, then the crude product was purified by prep-HPLC (column: Phenomenex Luna C18 200*40mm*10pm;mobile phase: [water(FA)-ACN];B%: 27%-57%,9min). 5-[4- (dimethoxymethyl)-4-fluoro-l-piperidyl]-2-(2, 6-dioxo-3 -piperidyl) isoindoline- 1, 3-dione (640 mg, 1.48 mmol, 52.34% yield) was obtained as a yellow solid. LCMS: MS (ESI) m / r. 434.2[M+1]+. ’H NMR: (400MHz, CDC13) 8.07 (s, 1 H), 7.69 (d, J= 8.4 Hz, 1 H), 7.29 (d, J= 2.4 Hz, 1 H), 7.07 (dd, J= 2.2, 8.6 Hz, 1 H), 4.95 (dd, J= 5.2, 12.4 Hz, 1 H), 4.16 (d, J= 7.6 Hz, 1 H), 3.85 ( d, J= 13.0 Hz, 2 H), 3.53 (s, 6 H), 3.56 - 3.37 (m, 1 H), 3.36 - 3.27 (m, 2 H), 2.99 - 2.67 (m, 3 H), 2.17 - 2.08 (m, 1 H), 1.99 - 1.79 (m, 4 H).

[0513] Intermediate 61

[0514] Step 1: Preparation of benzyl l-oxa-6-azaspiro[2.5]octane-6-carboxylate Cbz

[0515] To a solution of sodium hydride (8.57 g, 214.35 mmol, 60% purity, 2 eq) in dimethylacetamide (180 mL) was added trimethylsulfonium; iodide (43.74 g, 214.35 mmol, 2 eq) at 0°C under the protection of nitrogen. The reaction was stirred at 25°C for 0.5 hr and then benzyl 4-oxopiperidine-l -carboxylate (25 g, 107.18 mmol, 1 eq) in dimethylacetamide (60 mL) was added at 0°C. After addition, the reaction was stirred at 55°C for 2 hr. The reaction was quenched by water (200 mL) and the resulting mixture was extracted with ethyl acetate (150 mL x 3). Then the residue was purified by flash silica gel chromatography (ISCO®; 120 g SepaFlash® silica flash column, eluent of 0-30% ethyl acetate / petroleum ethergradient @ 150 mL / min). Benzyl l-oxa-6-azaspiro[2.5]octane-6-carboxylate (40 g, crude) was obtained as a yellow oil. ’H NMR: (400MHz, CDCI3) 3: 7.41 - 7.29 (m, 5 H), 5.16 (s, 2 H), 3.86 - 3.82 (m, 2 H), 3.53 - 3.46 (m, 2 H), 2.71 (s, 2 H), 1.84 (s, 2 H), 1.48 - 1.44 (m, 2 H).

[0516] Step 2: Preparation of benzyl 4-fluoro-4-(hydroxymethyl)piperidine-l -carboxylate. pyridine; hydrofluoride

[0517] DCM, 0~25°C, 10h

[0518] Cbz

[0519] Pyridine;hydrofluoride (13.74 g, 97.05 mmol, 12 mL, 70% purity, 1.2 eq) was added to the solution of benzyl l-oxa-6-azaspiro[2.5]octane-6-carboxylate (20 g, 80.88 mmol, 1 eq) in di chloromethane (190 mL) at 0°C under the protection of nitrogen. After addition, the reaction was stirred at 25 °C for 10 hr. Then reaction was quenched by water (300 mL) and the resulting mixture was extracted with dichloromethane (200 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate and concentrated. The residue was purified by flash silica gel chromatography (ISCO®; 80 g SepaFlash® silica flash column, eluent of 0-50% ethyl acetate / petroleum ether gradient @ 100 mL / min). Benzyl 4-fluoro-4- (hydroxymethyl)piperidine-l -carboxylate (36 g, crude) was obtained as a yellow oil. LCMS: MS (ESI) m / z: 268.0 [M+l]+. ’H NMR: (400MHz, CDC13) d : 7.40 - 7.29 (m, 5 H), 5.14 (s, 2 H), 4.17-3.88 (m, 2 H), 3.74-3.33 (m, 2 H), 3.27-3.04 (m, 2 H), 1.97-1.84 (m, 2 H), 1.72-1.50 (m, 2 H).

[0520] Step 3: Preparation of benzyl 3-ethyl-4-fluoro-4-(hydroxyniethyl)piperidine-l -carboxylate Cbz Cbz

[0521] To a stirred solution of oxalyl dichloride (25.64 g, 202.02 mmol, 18 mL, 3 eq) in anhydrous dichloromethane (80 mL) at -60°C was added a solution of dimethylsulfoxide (21.05 g, 269.37 mmol, 21 mL, 4 eq) in dichloromethane (80 mL) slowly. The mixture was stirred at - 60°C for 30 min. Benzyl 4-fluoro-4-(hydroxymethyl)piperidine-l -carboxylate (18 g, 67.34 mmol, 1 eq) in dichloromethane (70 mL) was added slowly and the mixture was stirred at - 60°C for 60 min. N,N-diethylethanamine (34.07 g, 336.71 mmol, 47 mL, 5 eq) was added and the mixture was stirred at -60°C for another 0.5 h. TLC (Petroleum ether : Ethyl acetate=l : 1) showed the reaction was completed. Then the reaction was quenched by water (600 mL) and the resulting mixture was extracted with dichloromethane (300 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate and concentrated to give the crude product. The crude product was used for the next step without further purification. Benzyl 4-fluoro-4-formyl-piperidine-l -carboxylate (37 g, crude) was obtained as a yellow oil. ’H NMR: (400MHz, CDCh) d : 9.76 - 9.64 (m, 1 H), 7.39 - 7.31 (m, 5 H), 5.17 - 5.13 (m, 2 H), 4.28 - 3.92 (m, 2 H), 3.25 - 3.00 (m, 2 H), 1.99 - 1.52 (m, 4 H).

[0522] Step 4: Preparation of benzyl 4-(dimethoxymethyl)-4-fluoro-piperidine-l -carboxylate Cbz

[0523] To a mixture of benzyl 4-fluoro-4-formyl-piperidine-l -carboxylate (37 g, 139.48 mmol, 1 eq) in trimethoxymethane (290.40 g, 2.74 mol, 300 mL, 19.62 eq) was added pyridinium p- toluensulfonate (3.51 g, 13.95 mmol, 0.1 eq) and methanol (63.34 g, 1.98 mol, 80 mL, 14.17 eq), the reaction was stirred at 40°C for 10 hr. The reaction was concentrated under reduced pressure to remove methanol and diluted with water 90 mL and extracted with ethyl acetate 100 mL (100 mL x 2). The combined organic layers were dried over anhydrous sodium sulfate and concentrated. The residue was purified by flash silica gel chromatography (ISCO®; 80 g SepaFlash® silica flash column, eluent of 0-25% ethyl acetate / petroleum ether gradient @ 100 mL / min). Benzyl 4-(dimethoxymethyl)-4-fluoro-piperidine-l -carboxylate (25 g, 80.30 mmol, 57% yield) was obtained as a yellow oil. LCMS: MS (ESI) m / z: 312.0 [M+l]+. ’H NMR: (400MHz, CDCh) d : 7.37-7.31 (m, 5 H), 5.04 (s, 2 H), 4.14 - 3.89 (m, 3 H), 3.51 - 3.23 (m, 6 H), 3.13 - 2.90 (m, 2 H), 1.83 - 1.44 (m, 4 H).

[0524] Step 5: Preparation of 4-(diniethoxymethyl)-4-fluoro-piperidine

[0525] Cbz

[0526] To a solution of benzyl 4-(dimethoxymethyl)-4-fluoro-piperidine-l -carboxylate (4.5 g, 14.45 mmol, 1 eq) in methanol (50 mL) was added palladium on activated carbon catalyst (1 g, 14.45 mmol, 10% purity, 1.00 eq) and palladium hydroxide catalyst (900.00 mg, 6.41 mmol, 4.43e-l eq), then the reaction was stirred at 30°C for 12hr under hydrogen (50 Psi). The reaction mixture was concentrated to give the crude product. The crude product was used for the next step without further purification. 4-(dimethoxymethyl)-4-fluoro-piperidine (2.3 g, 12.98 mmol, 90% yield) was obtained as a colorless oil.JH NMR: (400MHz, CDCh) <5 : 4.10 - 4.07 (m, 2 H), 3.52 - 3.46 (m, 6 H), 3.10 - 2.89 (m, 4 H), 1.90 - 1.69 (m, 4 H).

[0527] Intermediate 62

[0528] Step 1: Preparation of 7-chloro-8-methyl-6-(4,4,5,5-tetramethyl-l,3,2-dioxahorolan-2- yl)isoquinolin-3-amine

[0529] To a solution of 6-bromo-7-chloro-8-methyl-isoquinolin-3-amine (Reactant 1) (1 g, 3.68 mmol, 1 eq), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l,3,2- dioxaborolane (1.12 g, 4.42 mmol, 1.2 eq), potassium acetate (904 mg, 9.21 mmol, 2.5 eq), [l,T-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (135 mg, 0.18 mmol, 0.05 eq) in dioxane (15 mL) and then the mixture was stirred at 90 °C for 4 h under nitrogen atmosphere. The reaction mixture was filtered to remove the insoluble, the solvent was concentrated under vacuum. The residue was purified by column chromatography (silicon dioxide, petroleum ether / ethyl acetate = 50 / 1 to 5 / 1). 7-chloro-8-methyl-6-(4, 4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)isoquinolin-3-amine (879 mg, 2.76 mmol, 75% yield) was obtained as a red solid.

[0530] Step 2: Preparation of 7-chloro-6-(4,6-dimethyl-3-pyridyl)-8-methyl-isoquinolin-3-aniine

[0531] To a solution of 5-bromo-2,4-dimethyl-pyridine (616 mg, 3.31 mmol, 1.2 eq), 7-chloro-8- methyl-6-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)isoquinolin-3-amine (Reactant 1) (879 mg, 2.76 mmol, 1 eq), potassium carbonate (953 mg, 6.90 mmol, 2.5 eq) and [1,T- bis(diphenylphosphino)ferrocene]dichloropalladium(II) (101 mg, 0.14 mmol, 0.05 eq) in dioxane (15 mL)and water (3 mL) and then the mixture was stirred at 90 °C for 12 h under nitrogen atmosphere. The reaction mixture was filtered to remove the insoluble. The solvent was concentrated under vacuum. The residue was purified by column chromatography (Petroleum ether / Ethyl acetate = 50 / 1 to 5 / 1). 7-chloro-6-(4,6-dimethyl-3-pyridyl)-8-methyl- isoquinolin-3 -amine (400 mg, 1.34 mmol, 49% yield) was obtained as a yellow solid.

[0532] LCMS: MS (ESI) m / z: 298.0 [M +1]+.

[0533] Intermediate 63

[0534] Step 1: Preparation of 4-broino-2-chloro-3-inethyl-aniline

[0535] To a solution of 2-chl oro-3 -methyl -aniline (2 g, 14.12 mmol, 1 eq) in dichloromethane (10 mL) at 0 °C was added slowly a solution of N-bromosuccinimide (2.51 g, 14.12 mmol, 1 eq) in dichloromethane (10 mL) The reaction mixture was warmed to 30 °C and was stirred at that temperature for 5 h. The reaction mixture was added a saturated aqueous sodium carbonate solution (100 mL), followed by ethyl acetate (100 mL). The layers were separated, and the aqueous phase was extracted with ethyl acetate (100 mL x 4). The combined organic extracts were dried (sodium sulfate), filtered, and concentrated under vacuum. The crude material was purified by silica-gel column chromatography (petroleum ether / ethyl acetate, 100: 1). 4-bromo-2-chloro-3-methyl-aniline (2.63 g, 11.93 mmol, 84% yield) was obtained as yellow oil. ’H NMR: (400 MHz, dimethylsulfoxide-d6) 8: 7.20 (d, J = 8.8 Hz, 1H), 6.62 (d, J = 8.8 Hz, 1H), 5.47 (s, 2H), 2.37 (s, 3H).

[0536] Step 2: Preparation of 4-amino-3-chloro-2-methyl-benzonitrile

[0537] Cl

[0538] To a solution of 4-bromo-2-chloro-3-methyl-aniline (Reactant 1) (2.63 g, 11.93 mmol, 1 eq) in dimethylformamide (30 mL) was added cuprous cyanide (3.20 g, 35.78 mmol, 7.82 mL, 3 eq) under nitrogen. The reaction mixture was heated to 140 °C and was stirred at that temperature for 16 h. The reaction mixture was cooled to ambient temperature and a solution of ammonium hydroxide (10 mL) was added. The reaction mixture was filtered, and water (20 mL) was added to the filtrate. The aqueous phase was extracted with ethyl acetate (20 mL x 3). The combined organic extracts were dried with anhydrous sodium sulfate, filtered, and concentrated under vacuum. The crude material was purified by silica-gel column chromatography (petroleum ether / ethyl acetate, 7: 3). 4-amino-3-chloro-2-methyl- benzonitrile (1.33 g, 7.98 mmol, 67% yield) was obtained as a white solid.1H NMR: (400 MHz, Dimethylsulfoxide-de) 8: 7.36 (d, J = 8.4 Hz, 1H), 6.70 (d, J = 8.8 Hz, 1H), 6.33 (s, 2H), 2.40 (s, 3H).

[0539] Step 3: Preparation of 4-bromo-3-chloro-2-methyl-ben~,onitrile

[0540] To a suspension of cuprous bromide (1.72 g, 11.97 mmol, 1.5 eq) in acetonitrile (20 mL) was added tert-butyl nitrite (1.23 g, 11.97 mmol, 1.42 mL, 1.5 eq). The mixture was stirred at 65 °C for 10 min, the 4-amino-3-chloro-2-methyl-benzonitrile (Reactant 1) (1.33 g, 7.98 mmol, 1 eq) was added to the mixture. The reaction was stirred at 65 °C for 12 h. Water (30 mL) and ethyl acetate (20 mL) was added to the mixture, the mixture was filtered, and the aqueous phase was extracted with ethyl acetate (20 mL x 3). The combined organic phase was washed with brine (30 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography (petroleum ether: ethyl acetate = 1 : 0 to 10: 1). 4-bromo-3-chloro-2-methyl-benzonitrile (800 mg, 3.47 mmol, 43% yield) was obtained as white solid. ’ H NMR: (400 MHz, Dimethylsulfoxide-de) 6: 7.84 (d, J = 8.4 Hz, 1H), 7.72 (d, J = 8.4 Hz, 1H), 2.59 (s, 3H).

[0541] Step 4: Preparation of (4-bromo-3-chloro-2-methyl-phenyl)methanainine

[0542] To a solution of 4-bromo-3-chloro-2-methyl-benzonitrile (800 mg, 3.47 mmol, 1 eq) in tetrahydrofuran (5 mL) was added borane tetrahydrofuran (1 M, 8.68 mL, 2.5 eq) at 0 °C. The mixture was stirred at 20 °C for 12 h. TLC showed 4-bromo-3 -chi oro-2-m ethyl - benzonitrile was consumed, and one new point was detected. The reaction was quenched with aqueous hydrochloric acid (3 M, 20 mL) solution at 0°C dropwise. The mixture was washed with methyl tertiary butyl ether (30mL x 3), aqueous layer was adjusted to pH 13 with aqueous sodium hydroxide solution (2 M) and extracted with di chloromethane (20 mL x 3). Organic layer was concentrated under vacuum. The product was used in next step directly without further purification. (4-bromo-3-chloro-2-methyl-phenyl)methanamine (450 mg, 1.92 mmol, 55% yield) was obtained as white solid.1H NMR: (400 MHz, Dimethylsulfoxide-de) 5: 7.57 (d, J = 8.4 Hz, 1H), 7.34 - 7.27 (m, 1H), 3.70 (s, 2H), 2.37 (s, 3H), 2.02 - 1.56 (m, 2H).

[0543] Step 5: Preparation of N-[(4-bromo-3-chloro-2-methyl-phenyl)methyl]-2,2-diethoxy- acetamidine

[0544] To a solution of (4-bromo-3-chloro-2-methyl-phenyl)methanamine (450 mg, 1.92 mmol, 1 eq) in methanol (10 mL) was added acetic acid (23 mg, 0.38 mmol, 0.02 mL, 0.2 eq) and methyl 2,2-diethoxyethanimidate (402 mg, 2.49 mmol, 1.3 eq). The mixture was stirred at 25 °C for 2 h. TLC (Petroleum ether: Ethyl acetate = 5: 1) showed starting material (4-bromo-3- chloro-2-methyl-phenyl)methanamine was consumed. LCMS showed the desired mass was detected. The solution was concentrated under vacuum for the next step. The crude product was used into the next step without further purification. N-[(4-bromo-3-chloro-2-methyl- phenyl)methyl]-2,2-diethoxy-acetamidine (690 mg, crude) was obtained as a brown oil. LCMS: MS (ESI) m / z: 365.0 [M +1]+.

[0545] Step 6: Preparation of 6-bromo-7-chloro-8-methyl-isoquinolin-3-anune To a solution of sulfuric acid (15 mL) was added N-[(4-bromo-3-chloro-2-methyl- phenyl)methyl]-2,2-diethoxy-acetamidine (Reactant 1) (690 mg, 1.90 mmol, 1 eq) at 0 °C. The mixture was stirred at 60 °C for 12 h. TLC showed Reactant 1 was consumed and one major new spot was detected. The mixture was added to ammonium hydroxide (100 mL) at 0 °C to adjust pH about 8. The aqueous phase was extracted with ethyl acetate (50 mL x 3). The combined organic phases were washed with brine (50 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The crude product was stirred stirred with dimethyl formamide (30 ml) and methanol (5 mL) at 25 °C for 10 min, filtered, concentrated under vacuum to give a residue. Compound 6-bromo-7-chloro-8-methyl- isoquinolin-3 -amine (380 mg, 1.40 mmol, 74% yield) was obtained as an orange solid.

[0546] LCMS: MS (ESI) m / z: 272.9 [M +1]+. ’H NMR: (400 MHz, Dimethylsulfoxide-d6) 8: 9.01 (s, 1H), 7.93 (s, 1H), 6.56 (s, 1H), 6.20 (s, 2H), 2.73 (s, 3H).

[0547] Intermediate 64

[0548] Step 1: Preparation of 5-fluoro-N-methyl-2-nitro-aniline

[0549] To a solution of 2, 4-difluoro-l -nitro-benzene (9 g, 56.57 mmol, 1 eq) in tetrahydrofuran (100 mL) was added diisopropylethylamine (7.31 g, 56.57 mmol, 1 eq) and methylamine (4.58 g, 67 mmol, 1.2 eq, hydrogen chloride) at 0°C, then the reaction was stirred at 0°C for 5 hr. LCMS showed one main peak with desired mass was detected. The reaction mixture was diluted with water 100 mL and extracted with ethyl acetate (200 mL x 2). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® silica flash column, eluent of 0~4% ethyl acetate / petroleum ether gradient @ 50 mL / min). 5-fluoro- N-methyl-2-nitro-aniline (470 mg, 2.76 mmol, 5% yield) was obtained as a yellow solid. LCMS: MS (ESI) m / z 170.9[M+l]+. ’H NMR: (400MHz, DMSO) 5: 8.32 (s, 1 H), 8.16 - 8.14 (m, 1 H), 6.79 - 6.76 (m, 1 H), 6.59 - 6.47 (m, 1 H), 2.93 (d, J = 4.8 Hz, 3 H). Step 2: Preparation of 5-[4-(dimethoxymethyl)-l-piperidyl]-N-methyl-2-nitro-aniline

[0550] To a solution of 5-fluoro-N-methyl-2-nitro-aniline (470 mg, 2.76 mmol, 1 eq), 4- (dimethoxymethyl)piperidine (879 mg, 5.52 mmol, 2 eq) in dimethylsulfoxide (5 mL) was added diisopropyl ethyl amine (1.79 g, 13.81 mmol, 2.41 mL, 5 eq). The mixture was stirred at 120 °C for 12 hr. TLC (petroleum ether: ethyl acetate= 3: 1) indicated one new spot formed. The reaction mixture was diluted with water 10 mL and extracted with ethyl acetate (20 mL x 2). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® silica flash column, eluent of 0-50% ethyl acetate / petroleum ether gradient @ 80 mL / min). 5-[4-(dimethoxymethyl)-l-piperidyl]-N-methyl-2-nitro-aniline (840 mg, 2.72 mmol, 98% yield) was obtained as a yellow solid.

[0551] Step 3: Preparation of 4-[4-(dimethoxymethyl)-l-piperidyl]-N2-methyl-benzene-l, 2- dianune

[0552] To a solution of 5-[4-(dimethoxymethyl)-l-piperidyl]-N-methyl-2-nitro-aniline (840 mg, 2.72 mmol, 1 eq) in methanol (10 mL) and water (10 mL) was added iron (758 mg, 13.58 mmol, 5 eq) and ammonium chloride (726 mg, 13.58 mmol, 5 eq). The mixture was stirred at 80 °C for 1 hr . LC-MS showed one main peak with desired mass was detected. The reaction mixture was filtered, and the filtrate was poured into water (50 mL), the resulting mixture was extracted with ethyl acetate (100 mL x 2), dried over sodium sulfate, and concentrated to give the crude product. The product was used for next step directly without further purification. Compound 4-[4-(dimethoxymethyl)-l-piperidyl]-N2-methyl -benzene- 1, 2- diamine (758 mg, crude) was obtained as a brown oil. LCMS: MS (ESI) m / z'. 279.7[M+1]+.

[0553] Step 4: Preparation of 5-[4-(dimethoxymethyl)-l-piperidyl]-3-methyl-lH-benzinudazol-2- one

[0554] To a solution of 4-[4-(dimethoxymethyl)-l-piperidyl]-N2-methyl-benzene-l,2-diamine (750 mg, 2.68 mmol, 1 eq) in dichloromethane (5 mL) was added di(lH-imidazol-l-yl)methanone (565 mg, 3.49 mmol, 1.3 eq). The mixture was stirred at 25 °C for 12 hr. LC-MS showed one main peak with desired mass was detected. The reaction was diluted with water (20 mL) and the resulting mixture was extracted with ethyl acetate (50 mL x 2). The combined organic layers were dried over sodium sulfate and concentrated. The residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® silica flash column, eluent of 0~5% dichloromethane: methanol gradient @ 40 mL / min). 5-[4-(dimethoxymethyl)-l-piperidyl]-3- methyl-lH-benzimidazol-2-one (590 mg, 1.93 mmol, 72% yield) was obtained as a yellow solid. LCMS: MS (ESI) m / z 305.9[M+l]+. ’H NMR: (400MHz, DMSO) 3 10.49 (s, 1 H), 6.79 (d, J= 8.4 Hz, 1 H), 6.71 (d, J= 2.0 Hz, 1 H), 6.57 (dd, J= 2.0, 8.4 Hz, 1 H), 4.09 (d, J = 6.8 Hz, 1 H), 3.55 (d, J= 12.0 Hz, 2 H), 3.34 (s, 3 H), 3.33 (s, 3 H), 3.23 (s, 3 H), 2.58 - 2.51 (m, 2 H), 1.74 - 1.69 (m, 2 H), 1.40 - 1.30 (m, 2 H).

[0555] Step 5: Preparation of 3-[5-[4-(dimethoxymethyl)-l-piperidyl]-3-methyl-2-oxo- benzinudazol-l-yl] piperidine-2, 6-dione

[0556] To a stirred solution of 5-[4-(dimethoxymethyl)-l-piperidyl]-3-methyl-lH-benzimidazol-2- one (200 mg, 0.6 mmol, 1 eq) in tetrahydrofuran (6 mL) was added Lithium bi s(trimethyl silyl) amide (1 M, 1.96 mL, 3 eq) at 0 °C under nitrogen atmosphere. The reaction mixture was stirred for 20 min at 0 °C. To the above mixture was added dropwise 3- bromopiperidine-2, 6-dione (213 mg, 1.11 mmol, 1.7 eq) in at 0 °C. The mixture was stirred at 75 °C for 3 h. LC-MS showed one main peak with desired mass was detected. The reaction was adjusted to pH=5~6 with IN hydrogen chloride, the reaction mixture was diluted with water (10 mL) and the resulting mixture was extracted with di chloromethane (20 mL x 2). The combined organic layers were dried over sodium sulfate and concentrated. The residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® silica flash column, eluent of 0~5% dichloromethane: methanol gradient @ 40 mL / min) to give the crude product, then the crude product was purified by prep-HPLC (column: Phenom enex luna Cl 8 150*25mm* lOum; mobile phase: [water (FA)-ACN]; B%: 0%-26%, 9min). Compound 3-[5- [4-(dimethoxymethyl)-l-piperidyl]-3-methyl-2-oxo-benzimidazol-l-yl] piperidine-2, 6-dione (95 mg, 0.23 mmol, 35% yield) was obtained as a white solid. LCMS: MS (ESI) m / z 417.0[M+l]+. ’H NMR: (400MHz, DMSO) 3 11.06 (s, 1 H), 6.92 (d, J= 8.4 Hz, 1 H), 6.82 (d, J= 2.0 Hz, 1 H), 6.62 (dd, J = 2.0, 8.4 Hz, 1 H), 5.28 (dd, J= 5.4, 12.8 Hz, 1 H), 4.10 (d, J= 6.4 Hz, 1 H), 3.60 (d, J= 12.0 Hz, 2 H), 3.30 (s, 3 H), 3.27 (s, 6 H), 2.96 - 2.83 (m, 1 H), 2.73 - 2.55 (m, 4 H), 2.05 - 1.93 (m, 1 H), 1.81 - 1.61 (m, 3 H), 1.47 - 1.28 (m, 2 H). Step 6: Preparation of l-[l-(2, 6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzinudazol-5-yl] piperidine-4-carbaldehyde

[0557] To a solution of 3-[5-[4-(dimethoxymethyl)-l-piperidyl]-3-methyl-2-oxo-benzimidazol-l- yl]piperidine-2, 6-dione (95 mg, 0.2 mmol, 1 eq) in trifluoroacetic acid (2 mL) was added water (82 mg, 4 mmol, 20 eq). The mixture was stirred at 60 °C for 1.5 hr. The reaction mixture was concentrated under reduced pressure to give the crude product. The crude product was used into the next step without further purification. 1 -[ 1 -(2, 6-dioxo-3- piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl] piperidine-4-carbaldehyde (110 mg, crude, trifluoroacetic acid) was obtained as a purple oil. LCMS: MS (ESI) m / z 388.9[M+18+1]+.

[0558] Intermediate 65

[0559] Step 1: Preparation of 2,6-dibenzyloxy-3-bromo-pyridine 80 °C, 12 h

[0560] To a solution of 3-bromo-2,6-difluoro-pyridine (6 g, 30.93 mmol, 1 eq), benzyl alcohol (7.36 g, 68.05 mmol, 7.08 mL, 2.2 eq) in acetonitrile (80 mL) was added cesium carbonate (44.34 g, 136.10 mmol, 4.4 eq). The reaction was stirred at 80 °C for 12 h. The reaction mixture was added water (50 mL) and extracted with ethyl acetate (30mL x 3). The combined organic layers were washed with brine (30 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (silicon dioxide, Petroleum ether / Ethyl acetate=100 / 0 to 100 / 1.5). 2,6-dibenzyloxy-3-bromo-pyridine (10.72 g, 25.01 mmol, 80% yield, 86% purity) was obtained as a light yellow oil. LCMS: MS (ESI) m / z 370.0 [M+l]+. ’H NMR: (400MHz, CDC13) 3 = 7.68 (d, J = 8.0 Hz, 1H), 7.49 - 7.44 (m, 2H), 7.43 - 7.28 (m, 8H), 6.32 (d, J = 8.4 Hz, 1H), 5.43 (s, 2H), 5.31 (s, 2H).

[0561] Step 2: Preparation of 2,6-dibenzyloxy-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)pyridine

[0562] To a solution of 2,6-dibenzyloxy-3-bromo-pyridine (Reactant 1) 20.7 g, 55.91 mmol, 1 eq), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l,3,2-dioxaborolane (14.91 g, 58.71 mmol, 1.05 eq in dioxane (200 mL) was added [2-(2-aminophenyl)phenyl]- methylsulfonyloxy-palladium;dichloromethane;tricyclohexylphosphane (410.99 mg, 0.55 mmol, 0.01 eq , cesium fluoride (16.99 g, 111.82 mmol, 4.12 mL, 2 eq . The suspension and then the mixture was stirred at 90 °C for 12 hr under nitrogen atmosphere. Water (100 mL) was added, then the aqueous phase was extracted with ethyl acetate (50 mL x 3). The combined organic phase was washed with brine (50 mL x 3), dried with anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was mixed with scale-up experiment to be puried by prep-HPLC (column: Welch Ultimate XB-CN 250*50* lOum; mobile phase: [Hexane-EtOH];B%: 0%-0%,15min). The solution was concentrated under reduced pressure to give a residue. 2,6-dibenzyloxy-3-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)pyridine (12.37 g, 29.64 mmol, 53 % yield) was obtained as a light yellow oil. LCMS: MS (ESI) m / z 418.2 [M+l]+. Hl NMR: (400MHz, CDC13) 3 = 7.97 - 7.88 (m, 1H), 7.61 - 7.50 (m, 2H), 7.46 - 7.41 (m, 2H), 7.40 - 7.32 (m, 6H), 6.41 - 6.34 (m, 1H), 5.46 - 5.41 (m, 2H), 5.38 (s, 2H), 1.36 (s, 12H).

[0563] Step 3: Preparation of 2,6-dibenzyloxy-3-(6-fluoro-3-pyridyl)pyridine H2O, 90 C, 12 h

[0564] To a solution of 2,6-dibenzyloxy-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridine (Reactant 1) (5.78 g, 13.85 mmol, 1 eq), 5-bromo-2-fluoro-pyridine (2.56 g, 14.54 mmol, 1.50 mL, 1.05 eq in dioxane (60 mL), water (12 mL) was added [1,1’- bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (1.13 g, 1.39 mmol, 0.1 eq), sodium carbonate (2.94 g, 27.70 mmol, 2 eq . The suspension and then the mixture was stirred at 90 °C for 12 h under nitrogen atmosphere. Water (30 mL) was added, then the aqueous phase was extracted with ethyl acetate (20 mL * 3). The combined organic phase was washed with brine (20 mL * 3), dried with anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by flash silica gel chromatography (ISCO®; 120 g SepaFlash® silica flash column, eluent of 0~0.5~1.5~5% ethyl acetate / petroleum ether gradient @ 80 mL / min). 2,6-dibenzyloxy-3-(6-fluoro-3- pyridyl)pyridine (3.12 g, 8.07 mmol, 58% yield) was obtained as a light yellow oil. LCMS: MS (ESI) m / z: 387.1 [M+l]+.

[0565] Step 4: Preparation of 3-(6-fluoropyridin-3-yl)piperidine-2, 6-dione

[0566] To a solution of 2,6-dibenzyloxy-3-(6-fluoro-3-pyridyl)pyridine (Reactant 1) (3.12 g, 8.07 mmol, 1 eq) in iprocrolol (30 mL) was added palladium on carbon (300 mg, 0.81 mmol, 10% purity, 0.1 eq). The suspension was degassed under vacuum and purged with hydrogen several times. The mixture was stirred at 40 °C for 12 hours under hydrogen (15 psi). The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by semi-preparative reverse phase (column: Phenomenex Luna C18 (250*80mm*15um); mobile phase: [water(TFA)-ACN];B%: l%-20%,20min). Compound 3- (6-fluoro-3-pyridyl)piperidine-2, 6-dione (1.60 g, 4.97 mmol, 62% yield, trifluoroacetic acid) was obtained as colorless oil. LCMS: MS (ESI) m / z 209.1 [M+l]+. ’H NMR: (400MHz, CDC13) <5 = 8.13 (br d, J= 2.0 Hz, 2H), 7.67 (dt, J= 5.4, 8.4 Hz, 1H), 6.98 (dd, J= 2.8, 8.4 Hz, 1H), 3.79 (dd, = 5.6, 11.2 Hz, 1H), 2.91 - 2.79 (m, 1H), 2.79 - 2.66 (m, 1H), 2.39 - 2.17 (m, 2H).

[0567] Intermediate 66

[0568] Step 1: Preparation of methyl 2-bromo-4-[3-(dimethoxymethyl)azetidin-l-yl]-3-fluoro- benzoate

[0569] A mixture of methyl 2-bromo-3,4-difluoro-benzoate (Reactant 1) (10 g, 39.84 mmol, 1 eq), 3- (dimethoxymethyl)azetidine (5.2 g, 39.84 mmol, 1 eq , N-ethyl-N-isopropyl-propan-2-amine (15.5 g, 119.51 mmol, 3 eq , in dimethylsulfoxide (20 mL) and then the mixture was stirred at 100 °C for 2 h under nitrogen atmosphere. The residue was poured into ice-water (w / w = 1 / 1) (10 mL) and stirred for 5 min. The aqueous phase was extracted with ethyl acetate (20 mL x 3). The combined organic phase was washed with brine (10 mL x 3), dried with anhydrous sodium sulfate, filtered, and concentrated under vacuum. The crude product was purified by column chromatography on silica gel eluted with petroleum ether / ethyl acetate = 1 : 0 to 10: 1. Compound methyl 2-bromo-4-[3-(dimethoxymethyl)azetidin-l-yl]-3-fluoro- benzoate (8.3 g, 22.64 mmol, 56% yield, 98% purity) was obtained as a colorless oil, LCMS (product: RT = 0.786 min, MS: 361.9) confirmed the obtained compound is the desired compound. LCMS: MS (ESI) m / z: 361.9 [M +1]+.

[0570] Step 2: Preparation of methyl 4-[3-(dimethoxymethyl)azetidin-l-yl]-3-fluoro-2-vinyl- benzoate

[0571] A mixture of methyl 2-bromo-4-[3-(dimethoxymethyl)azetidin-l-yl]-3-fluoro-benzoate (Reactant 1) (8.3 g, 22.64 mmol, 98% purity, 1 eq , potassium;trifluoro(vinyl)boranuide (6 g, 45.28 mmol, 2 eq , cyclopentyl(diphenyl)phosphane;dichloropalladium;iron (828 mg, 1.13 mmol, 0.05 eq , disodium;carbonate (7.2 g, 67.92 mmol, 3 eq in dioxane (100 mL) and water (20 mL) and then the mixture was stirred at 90 °C for 3 h under nitrogen atmosphere. The residue was poured into ice-water (w / w = 1 / 1) (20 mL) and stirred for 5 min. The aqueous phase was extracted with ethyl acetate (20 mL x 3). The combined organic phase was washed with brine (20 mL x 3), dried with anhydrous sodium sulfate, filtered, and concentrated under vacuum. The crude product was purified by column chromatography on silica gel eluted with petroleum ether / ethyl acetate = 1 : 0 to 10: 1. Compound methyl 4-[3- (dimethoxymethyl)azetidin-l-yl]-3-fluoro-2-vinyl-benzoate (6 g, 19.40 mmol, 85% yield) was obtained as a yellow oil, LCMS (product: RT = 0.799min,MS: 309.9) confirmed the obtained compound is the desired compound. LCMS: MS (ESI) m / z: 309.9 [M +1]+.

[0572] Step 3: Preparation of methyl 4-[3-(dimethoxymethyl)azetidin-l-yl]-3-fluoro-2-formyl- benzoate

[0573] A mixture of methyl 4-[3-(dimethoxymethyl)azetidin-l-yl]-3-fluoro-2-vinyl-benzoate (Reactant 1) (6 g, 19.40 mmol, 1 eq), 2,6-dimethylpyridine (4.2 g, 38.79 mmol, 4.56 mL, 2 eq), sodium;periodate (16.6 g, 77.59 mmol, 4 eq) and dipotassium;dioxido(dioxo)osmium;dihydrate (142 mg, 0.39 mmol, 0.02 eq) in dioxane (80 mL) and water (20 mL) and then the mixture was stirred at 20 °C for 12 h under nitrogen atmosphere. The residue was poured into ice-water (20 mL) and stirred for 2 min. The aqueous phase was extracted with ethyl acetate (20 mL x 3). The combined organic phase was washed with brine (20 mL x 3), dried with anhydrous sodium sulfate, filtered and concentrated under vacuum. The crude product was purified by column chromatography on silica gel eluted with petroleum ether / ethyl acetate = 10: 1 to 1 : 1. Compound methyl 4-[3- (dimethoxymethyl)azetidin-l-yl]-3-fluoro-2-formyl-benzoate (2.5 g, 7.65 mmol, 39% yield, 95% purity) was obtained as a yellow solid, LCMS (product: RT =0.715 min, MS: 311.9) confirmed the obtained compound is the desired compound. LCMS: MS (ESI) m / z: 311.9 [M +1]+.

[0574] Step 4: Preparation of 3-[5-[3-(dimethoxymethyl)azetidin-l-yl]-4-fluoro-l-oxo-isoindolin- 2-yl]piperidine-2, 6-dione

[0575] To a solution of methyl 3 -aminopiperidine-2, 6-dione hydrochloride (1.5 g, 9.18 mmol, 1.2 eq) in methanol (20 mL) was added sodium; acetate (1.9 g, 22.96 mmol, 3 eq), the mixture was stirred at 20 °C for 0.5 h. Then methyl methyl 4-[3-(dimethoxymethyl)azetidin-l-yl]-3- fluoro-2-formyl-benzoate (Reactant 1) (2.5 g, 7.65 mmol, 95% purity, 1 eq) was added to the mixture, the reaction mixture was stirred at 20 °C for 0.5 h. Sodium;cyanoborohydride (961 mg, 15.31 mmol, 2 eq) was added to the mixture, the reaction mixture was stirred at 35 °C for 11 h. LCMS (product: RT = 0.597 min, MS: 392.0) showed the starting material (Reactant 1) was consumed completely and desired compound was detected. The mixture was filtered and the filtrate was concentrated under reduced pressure to get a residue. 3-[5-[3- (dimethoxymethyl)azetidin-l-yl]-4-fluoro-l-oxo-isoindolin-2-yl]piperidine-2, 6-dione (1.7 g, 4.34 mmol, 56% yield) was obtained as a white solid. LCMS: MS (ESI) m / z: 392.0 [M +1]+. ’H NMR: (400 MHz, Dimethylsulfoxide-d6) 8: 10.96 (s, 1H), 7.36 (d, J= 8.4 Hz, 1H), 6.62 (t, J= 8.0 Hz, 1H), 5.04 J= 5.2, 13.2 Hz, 1H), 4.64 (d, J= 6.8 Hz, 1H), 4.48 - 4.40 (m, 1H), 4.30 - 4.22 (m, 1H), 4.12 - 4.04 (m, 2H), 3.84( = 3.2, 5.6 Hz, 2H), 3.28 (s, 6H), 3.06 - 2.96 (m, 1H), 2.96 - 2.84 (m, 1H), 2.56 (td, J= 2.0, 15.6 Hz, 1H), 2.44 - 2.32 (m, 1H), 1.96 J = 2.8, 5.2, 10.0 Hz, 1H).

[0576] Step 5: Preparation of l-[2-(2,6-dioxo-3-piperidyl)-4-fluoro-l-oxo-isoindolin-5- yl]azetidine-3-carbaldehyde

[0577] A mixture of 3-[5-[3-(dimethoxymethyl)azetidin-l-yl]-4-fluoro-l-oxo-isoindolin-2- yl]piperidine-2, 6-dione (Reactant 1) (60 mg, 0.15 mmol, 1 eq), 2,2,2-trifluoroacetic acid (770 mg, 6.75 mmol, 44.05 eq), in dichloromethane (2 mL) and the mixture was stirred at 20 °C for 2 h under nitrogen atmosphere. The pH was adjusted to about pH 9 by progressively adding triethylamine. l-[2-(2,6-dioxo-3-piperidyl)-4-fluoro-l-oxo-isoindolin-5-yl]azetidine- 3-carbaldehyde (52 mg, 0.15 mmol, 98% yield) was obtained as a colorless oil.

[0578] Intermediate 67

[0579] Step 1: Preparation of benzyl 4-(2-tert-butoxy-2-oxo-ethyl)-4-hydroxy-piperidine-l- carboxylate

[0580] Cbz

[0581] WX-ARV-KH-161 C-4

[0582] To a solution of N-isopropylpropan-2-amine (7.05 g, 69.70 mmol, 2.50 eq) in tetrahydrofuran (60 mL) was added n-BuLi (2.5 M in tetrahydrofuran, 27.87 mL, 2.5 eq) at 0°C and and then the was stirred at 0°C for 0.5 h under nitrogen atmosphere. Then the mixture cooled to -70°C and tert-butyl acetate (8.09 g, 69.65 mmol, 2.50 eq) was added. The mixture was stirred at - 70°C for 1 h. Then benzyl 4-oxopiperidine-l-carboxylate (6.5 g, 27.87 mmol, 1 eq) in tetrahydrofuran (35 mL) was added and stirred at -70°C for 1 h. The mixture was poured into ice and saturated aqueous ammonium chloride solution (w / w = 1 / 10) (200 mL) and stirred for 30min. The aqueous phase was extracted with ethyl acetate (300 mL x 3). The combined organic phase was washed with brine (200mL x 3), dried with anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by column chromatography (silicon dioxide, petroleum ether / ethyl acetate=100 / l to 3 / 1) to give benzyl 4-(2-tert-butoxy-2-oxo-ethyl)-4-hydroxy-piperidine-l-carboxylate (9.5 g, 27.19 mmol, 97% yield) as a yellow oil. LCMS: MS (ESI) m / z: 372.4 [M+23]+.

[0583] Step 2: Preparation of tert-butyl 2-(4-hydroxy-4-piperidyl)acetate

[0584] To a solution of benzyl 4-(2-tert-butoxy-2-oxo-ethyl)-4-hydroxy-piperidine-l -carboxylate (Reactant 1) (9 g, 25.76mmol, eq) in ethyl acetate (200 mL) was added palladium on carbon (1 g, 25.76 mmol, 10% purity, eq) under nitrogen atmosphere. The suspension was degassed and purged with hydrogen for 3 times. The mixture was stirred under hydrogen (15 Psi.) at 25 °C for 16 hr. The mixture was filtered. The filtrate was concentrated under vacuum to give tert-butyl 2-(4-hydroxy-4-piperidyl)acetate (5.08g, crude) was obtained as a white solid.

[0585] Intermediate 68

[0586] Step 1: Preparation of tert-butyl 4-(l-oxo-3H-isobenzofuran-5-yl)pipera zine -1- carboxylate

[0587] To a solution of 5-bromo-3H-isobenzofuran-l-one (45 g, 211.24 mmol, 1.00 eq) and tertbutyl piperazine- 1 -carboxylate (39.34 g, 211.24 mmol, 1.00 eq) in dioxane (500 mL) was added tris(dibenzylideneacetone)dipalladium(0) (19.34 g, 21.12 mmol, 0.10 eq), 4,5-bis (diphenylphosphino)-9,9-dimethylxanthene (12.22 g, 21.12 mmol, 0.10 eq) and potassium phosphate (89.68 g, 422.48 mmol, 2.00 eq). The mixture was heated to 100 °C for 16 hr under nitrogen protection. The mixture was filtered through a pad of celite, and filtrate was concentrated under vacuum. The residue was triturated in ethyl acetate: petroleum ether (500 mL, v / v=l:2). tert-butyl 4-(l-oxo-3H-isobenzofuran-5-yl)piperazine-l -carboxylate (50 g, 122.5 mmol, 58% yield, 78% purity) was obtained as yellow solid.1H NMR: (400MHz, DMSO) 3: 7.62 (d, J=8.8 Hz, 1H), 7.10 (dd, =8.8 Hz, 2 Hz, 1H), 7.04 (s, 1H), 5.25 (s, 2H), 3.47-3.45 (m, 4H), 3.45-3.38 (m, 4H), 1.42 (s, 9H).

[0588] Step 2: Preparation of 4-(4-tert-butoxycarbonylpiperazin-l-yl)-2- (hydroxyhnethyl)benzoic acid

[0589] To a mixture of tert-butyl 4-(l-oxo-3H-isobenzofuran-5-yl)piperazine-l-carboxylate (47.8 g, 150.14 mmol, 1.00 eq) in tetrahydrofuran (150 mL), methanol (150 mL) and water (150 mL) was added sodium hydroxide (24 g, 600 mmol, 4.00 eq). The mixture was stirred at 25 °C for 1 hr. The solution was adjusted pH = 4 - 5 with aqueous hydrochloride solution (IM) and extracted with ethyl acetate (100 mL x 5). The organic layers were concentrated under vacuum. The crude was triturated in ethyl acetate: petroleum ether (450 mL, v: v=l:2). 4-(4- tert-butoxy carbonyl piperazin- l-yl)-2-(hydroxym ethyl )benzoic acid (40 g, 118.91 mmol, 79% yield) was obtained as yellow solid. ’H NMR: (400MHz, DMSO) d: 12.36 (s, 1H), 7.78 (d, .7=8,8 Hz, 1H), 7.22 (d, J=2 Hz, 1H), 6.81 (dd, J=8.8, 1 Hz), 5.10 (s, 1H), 4.80 (s, 2H), 3.47-3.44 (m, 4H), 3.29-3.27 (m, 4H), 1.42 (s, 9H).

[0590] Step 3: Preparation of tert-butyl 4-[3-(hydroxymethyl)-4-methoxy carbony l-phenyl] piperazine-1 -carboxylate

[0591] To a solution of 4-(4-tert-butoxycarbonylpiperazin-l-yl)-2-(hydroxymethyl)benzoic acid (20 g, 59.46 mmol, 1.00 eq in methanol (100 mL) and ethyl acetate (100 mL) was added imino(trimethylsilylmethylene)ammonium (2 M, 89 mL, 3.00 eq) at -10 °C. The solution was stirred at -10 °C for 0.25 hr.. The solution was quenched with water (300 mL) and extracted with ethyl acetate (150 mL x 3). The organic layer was dried over sodium sulfate and filtered. The filtrate was concentrated. Tert-butyl 4-[3-(hydroxymethyl)-4-methoxycarbonyl- phenyl] piperazine- 1- carboxylate (20.84 g, crude) was obtained as brown oil.

[0592] Step 4: Preparation of tert-butyl 4-[3-(bromomethyl)-4-methoxycarbony l-phenyl] piperazine-1 -carboxylate

[0593] To a solution of tert-butyl 4-[3-(hydroxymethyl)-4-methoxycarbonyl-phenyl]piperazine -1- carboxylate (20.84 g, 59.47 mmol, 1.00 eq in tetrahydrofuran (200 mL) was added triphenylphosphine (23.4 g, 89.21 mmol, 1.50 eq and perbromomethane (29.58 g, 89.21 mmol, 1.50 eq . The solution was stirred at 25 °C for 1 hr. The solution was quenched with water (200 mL) and extracted with ethyl acetate (100 mL x 2). The organic layer was dried over sodium sulfate and filtered. The filtrate was concentrated under vacuum. The residue was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 1 :50 - 1 :8). Tert-butyl 4-[3-(bromomethyl)-4-methoxycarbonyl -phenyl]piperazine-l -carboxylate (12 g, 29.03 mmol, 49% yield) was obtained as a pale-yellow oil.1H NMR: (300MHz, CDC13) d: 7.93 (s, .7=9,0 Hz, 1H), 6.88 (d, .7=2,4 Hz, 1H), 6.78 (dd, J=9.0, 2.4 Hz, 1H), 4.97 (s, 2H), 3.89 (s, 3H), 3.64-3.57 (m, 4H), 3.34-3.30 (m, 4H), 1.42 (s, 9H).

[0594] Step 5: Preparation of tert-butyl 4-[2-(2,6-dioxo-3-piperidyl)-l-oxo- isoindolin-5- yl]piperazine-l -carboxylate

[0595] To a solution of tert-butyl 4-[3-(bromomethyl)-4-methoxycarbonyl-phenyl]piperazine -1- carboxylate (12 g, 29.03 mmol, 1.00 eq in acetonitrile (300 mL) was added 3- aminopiperidine-2,6-dione;hydrochloride (7.17 g, 43.55 mmol, 1.50 eq) and N-ethyl-N- isopropylpropan-2-amine (11.26 g, 87.09 mmol, 15 mL, 3.00 eq . The solution was stirred at 80 °C for 16 hrThe reaction mixture was cooled to 20 °C and filtered. The solid was washed with acetonitrile (30 mL). tert-butyl 4-[2-(2,6-dioxo-3-piperidyl)-l-oxo-isoindolin-5- yl]piperazine-l -carboxylate (6 g, 14 mmol, 48% yield) was obtained as a white solid.1H NMR: (400MHz, DMSO) d: 10.91 (s, 1H), 7.53 (d, J=8.4 Hz, 1H), 7.06-7.04 (m, 2H), 5.03 (dd, .7=13.2, 5.2 Hz, 1H), 4.35-4.19 (m, 2H), 3.48-3.45 (m, 4H), 3.27-3.26 (m, 4H), 2.89-2.87 (m, 1H), 2.60-2.56 (m, 1H), 2.38-2.34 (m, 1H), 1.98-1.96 (m, 1H), 1.42 (s, 9H).

[0596] Intermediate 69

[0597] Step 1: Preparation of O2-benzyl 05-tert-butyl 3, 3a, 4, 6, 7, 7a-hexahydro-lH-pyrrolo[3 ,4- c]pyridine-2, 5-dicarboxylate

[0598] To a solution of phenylmethanol (16.59 g, 153.37 mmol, 16.0 mL, 2.5 eq) in tetrahydrofuran (200 mL) was added potassium / c / 7-butoxide (17.21 g, 153.37 mmol, 2.5 eq portion-wise. The mixture was stirred at 25 °C for 2 h. To the mixture was added 2,6-dichloropyridin-3- amine (10 g, 61.35 mmol, 1 eq, the reaction mixture was stirred at 75 °C for 24 h. The mixture was cooled to 25 °C, diluted with ethyl acetate (600 mL). The organic layer was washed with water (100 mL x 3). The water layer wash extracted with ethyl acetate (100 mL x 2). The combined organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to get the residue. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate=50 / l to 10: 1) to get the crude product. The crude product was purified by prep-HPLC (column: Welch Ultimate XB-Diol 250*50* 10pm; mobile phase: [heptane-EtOH (0.1%NH3H2O)];B%: l%-10%,15min) to get the product. 2,6- dibenzyloxy pyri din-3 -amine (3.1 g, 10.12 mmol, 16% yield) was obtained as a black-orange oil. The product was confirmed by 'H NMR. LCMS: MS (ESI) m / z 307.4 [M+l]+.1H NMR: (400 MHz, CDC13) 7.51 - 7.30 (m, 10H), 6.99 (d, J= 8.0 Hz, 1H), 6.28 (d, J= 8.0 Hz, 1H), 5.39 (s, 2H), 5.28 (s, 2H), 3.27 - 2.56 (m, 2H).

[0599] Intermediate 70

[0600] Step 1: Preparation ofN-[(4-bromo-2-chloro-phenyl)methyl]-2,2-diethoxy-acetanu(line

[0601] To a solution of (4-bromo-2-chloro-phenyl)methanamine (2.01 g, 7.82 mmol, 0.9 eq, hydrochloric salt) in methanol (10 mL) was added acetic acid (104 mg, 1.74 mmol, 0.1 mL, 0.2 eq) and methyl 2,2-diethoxyethanimidate (1.4 g, 8.68 mmol, 1 eq). The mixture was stirred at 20 °C for 2 h. The solution was concentrated under vacuum for the next step. The crude product was used into the next step without further purification. N-[(4-bromo-2-chloro- phenyl)methyl]-2,2-diethoxy-acetamidine (3 g, crude) was obtained as a gray oil. LCMS: MS (ESI) m / z: 351.0 [M +l]+.

[0602] Step 2: Preparation of 6-bromo-8-chloro-isoquinolin-3-anune To a solution of sulfuric acid (20 mL) was added N-[(4-bromo-2-chloro-phenyl)methyl]-2,2- diethoxy-acetamidine (Reactant 1) (3 g, 8.58 mmol, 1 eq) was stirred at 40 °C for 12 h. The mixture was added to ammonium hydroxide (100 mL) at 0 °C to adjust pH about 8. The aqueous phase was extracted with ethyl acetate (50 mL x 3). The combined organic phase was washed with brine (50 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The crude product was stirred with dimethyl formamide (30 mL) and methanol (5 mL) at 25 °C for 10 min, filtered, and concentrated in vacuum to give a residue. 6-bromo-8-chloro-isoquinolin-3-amine (1 g, 3.88 mmol, 45% yield) was obtained as a green-black solid. LCMS: MS (ESI) m / z: 258.9 [M +1]+.

[0603] Intermediate 71

[0604] Step 1: Preparation of 3-[4-chloro-5-[4-(dimethoxymethyl)-l- piperidyl]-l-oxo-isoindolin- 2-yl]piperidine-2, 6-dione

[0605] To a solution of 3-[5-[4-(dimethoxymethyl)-l-piperidyl]-l-oxo-isoindolin-2-yl]piperidine - 2,6-dione (Reactant 1) (500 mg, 1.25 mmol, 1 eq in dichloromethane (20 mL) and methanol (2 mL) was added N-chlorosuccinimide (166 mg, 1.25 mmol, 1 eq) and trifluoroacetic acid (284 mg, 2.49 mmol, 0.2 mL, 2 eq). The mixture was stirred at 40 °C for 12 h. The reaction mixture was filtered to get the cake. The crude product 3-[4-chloro-5-[4-(dimethoxymethyl)- 1 -piperidyl]- l-oxo-isoindolin-2-yl]piperidine-2, 6-dione (350 mg, 0.80 mmol, 64% yield) was used into the next step without further purification as a white solid. LCMS: MS (ESI) m / z: 436.2 [M +1]+. ’H NMR: (400 MHz, DMSO-d6) 8: 10.98 (s, 1H), 7.64 (d, J= 8.4 Hz, 1H), 7.26 (d, J= 8.0 Hz, 1H), 5.09 (dd, J= 5.2, 13.2 Hz, 1H), 4.45 - 4.37 (m, 1H), 4.29 - 4.21 (m, 1H), 4.14 (d, J= 6.0 Hz, 1H), 3.44 - 3.37 (m, 2H), 3.32 (s, 6H), 2.90 (s, 1H), 2.73 - 2.69 (m, 1H), 2.62 - 2.54 (m, 3H), 2.01 - 1.96 (m, 1H), 1.79 - 1.72 (m, 3H), 1.44 (d, J= 11.2 Hz, 2H).

[0606] Intermediate 72

[0607] Step 1: Preparation of 6,8-dimethyl-[l,2,4]triazolo[4,3-b]pyridazine 125 C, 16 h

[0608] To a solution of l,2,4-triazol-4-amine (Reactant 1) (10 g, 118.93 mmol, 1 eq) in anhydrous toluene (100 mL) was added pentane-2, 4-dione (11.91 g, 118.93 mmol, 12.2 mL, 1 eq) and p- toluenesulfonic acid (123 mg, 0.7 mmol, 0.006 eq). The mixture was stirred at 125 °C for 16 h. The mixture was evaporated to dryness after cool to 20 °C. The mixture was diluted with dichloromethane 300 mL and washed with saturated sodium hydrogen carbonate solution 150 mL. The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. 6,8-dimethyl-[l,2,4]triazolo[4,3- b]pyridazine (17.26 g, 116.49 mmol, 98% yield) was obtained as a light yellow solid. LCMS: MS (ESI) m / z 149.0 [M+l]+. ’H NMR: (400MHz, CHLOROFORM-d) 5 = 8.95 (s, 1H), 6.77 (d, J= 1.2 Hz, 1H), 2.66 (d, J= 1.2 Hz, 3H), 2.56 - 2.48 (m, 3H).

[0609] Step 2: Preparation of 4,6-dimethylpyridazin-3-anune

[0610] To a solution of 6,8-dimethyl-[l,2,4]triazolo[4,3-b]pyridazine (Reactant 1) (7.5 g, 50.62 mmol, 1 eq) in acetonitrile (50 mL) was added 2-bromo-l-phenyl-ethanone (10.08 g, 50.62 mmol, 1 eq). The mixture was stirred at 85 °C for 2 h. After most of solvent was removed, sodium hydroxide (10.12 g, 253.10 mmol, 5 eq) in water (125mL) was added to the mixture in one portion at 20 °C. The mixture was stirred at 100 °C for 16 h. After cooling to 25°C, the residue was filtered off and washed with water 50 mL. The mixture was used into the next step without further purification. 4,6-dimethylpyridazin-3-amine (2.49 g, 20.22 mmol, 40% yield) was obtained as a yellow solid. LCMS: MS (ESI) m / z 124.2 [M+l]+. ’ H NMR: (400MHz, DMSO-6) 8 = 6.99 (s, 1H), 5.89 (s, 2H), 2.33 (s, 3H), 2.03 (s, 3H).

[0611] Step 3: Preparation of 4,6-dimethylpyridazin-3-anune To a solution of 4,6-dimethylpyridazin-3-amine (14.26 g, 115.79 mmol, 1 eq) in hydrobromic acid (260 mL, 33% purity) was added sodium nitrite (8.07 g, 116.95 mmol, 1.01 eq) in water (20 mL) in one portion at 0 °C. Then cuprous bromide (23.25 g, 162.10 mmol, 4.9 mL, 1.4 eq) in hydrobromic acid (260 mL, 33% purity) was added to the mixture at 0 °C. The mixture was stirred at 100 °C for 5 h. The reaction mixture was quenched by addition sodium hydroxide solution (10%) till pH = 10. Then diluted with ethyl acetate 50 mL and extracted with ethyl acetate 300 mL. The combined organic layers were washed with ethyl acetate 30 mL, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 120 g SepaFlash® Silica flash column, eluent of 0-30% ethyl acetate / petroleum ether gradient). The residue was purified by prep-HPLC (column: 3_Phenomenex Luna C18 75*30mm*3pm;mobile phase: [water(formic acid)- acetonitrile];B%: 12%-32%,8min). 3- bromo-4,6-dimethyl-pyridazine (349 mg, 1.87 mmol, 1.61% yield) was obtained as a purple solid. ’ H NMR: (400MHz, DMSO-t / 6) 8 = 7.57 (s, 1H), 2.53 (s, 3H), 2.32 (d, J= 0.4 Hz, 3H).

[0612] Intermediate 73

[0613] Step 1: Preparation of 6-(4-(dimethoxymethyl)piperidin-l-yl)-2-(2,6-dioxopiperidin-3-yl)-4- methoxyisoindoline-1, 3-dione

[0614] To a solution of 2-(2,6-dioxopiperidin-3-yl)-7-methoxy-l,3-dioxoisoindolin-5-yl 1,1,2,2,3,3,4,4,4-nonafhiorobutane-l-sulfonate (100 mg, 0.17 mmol, 1 eq) and 4- (dimethoxymethyl)piperidine (40 mg, 0.26 mmol, 1.5 eq) in N,N-dimethylformamide (3 mL) was added sodium carbonate (36 mg, 0.34 mmol, 2 eq) and 1 ,3-bis[2,6-bis( 1 - propylbutyl)phenyl]-4,5-dichloro-2H-imidazol-l-ium-2-ide;3- chloropyridine;dichloropalladium (16 mg, 0.017 mmol, 0.1 eq), then the mixture was stirred at 80 °C for 12 h. The reaction mixture was filtered, and the filtrate was added with 0.5 M hydrochloric acid to pH 6, and the solution was diluted with water 30 mL and extracted with ethyl acetate (30 mL x 2). The combined organic layers were washed with brine (30 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (petroleum ether / ethyl acetate = 0: 1). 6-(4-(dimethoxymethyl)piperidin-l-yl)-2-(2,6-dioxopiperidin-3-yl)-4-methoxyisoindoline- 1,3-dione (50 mg, 0.11 mmol, 66% yield) was obtained as a yellow solid, characterized byJH NMR. LCMS: MS (ESI) m z 446.3 [M+l]+. 'II NMR: (400 MHz, DMSO-d6) <5 : 11.03 (s, 1H), 6.92 (d, .7= 1.6 Hz, 1H), 6.63 (d, J= 1.6 Hz, 1H), 4.99 (dd, J= 5.2, 12.8 Hz, 1H), 4.14 - 4.06 (m, 3H), 3.91 (s, 3H), 3.27 (s, 6H), 2.99 - 2.89 (m, 2H), 2.88 - 2.80 (m, 1H), 2.58 (d, J= 2.5 Hz, 1H), 1.97 - 1.82 (m, 2H), 1.71 (d, J= 12.3 Hz, 2H), 1.36 - 1.20 (m, 3H).

[0615] Step 2: Preparation of l-(2-(2,6-dioxopiperidin-3-yl)-7-methoxy-l,3-dioxoisoindolin-5- yl)piperidine-4-carbaldehyde

[0616] To a solution of 6-(4-(dimethoxymethyl)piperidin-l-yl)-2-(2,6-dioxopiperidin-3-yl)-4-metho- xyisoindoline-1, 3-dione (50 mg, 0.11 mmol, 1 eq) in dichloromethane (3 mL) was added trifluoroacetic acid (1 mL) ,then the mixture was stirred at 25 °C for 1 h. The mixture was basified with triethylamine to pH 8.00 to give a residue. The residue was used into next step without purification. l-(2-(2,6-dioxopiperidin-3-yl)-7-methoxy-l,3-dioxoisoindolin-5- yl)piperidine-4-carbaldehyde (44 mg, 0.11 mmol, 98% yield) was obtained as a yellow oil. LCMS: MS (ESI) m / z 400.2 [M+l]+.

[0617] Examples

[0618] Example 1

[0619] TFA

[0620] Cs2CO3, t-BuBrettphos Pd G3 [2-(2-aminophenyl)phenyl]- DCM, 25 °C, 0.5 h methylsulfonyloxy-palladium;ditert-butyl- [3,6-dimethoxy-2-(2,4,6- triisopropylphenyl)phenyl]phosphane dioxnae, 130 °C, 1 h Step 1: Preparation of 2-(3-bromo-5-(2-((l-(tert-butoxycarbonyl)piperidin-4- yl)anuno)ethyl)-LH-pyrazol-l-yl)acetic acid

[0621] To a stirred of 2-(5-(2-aminoethyl)-3-bromo-lH-pyrazol-l-yl)acetic acid (640 mg, 2.58 mmol, 1 eq) and tert-butyl 4-oxopiperidine-l -carboxylate (1 g, 5.02 mmol, 1.95 eq) in dimethylsulfoxide (2 mL) and di chloroethane (4 mL) was added acetic acid (619.70 mg, 10.32 mmol, 590.19 uL, 4 eq), The mixture was stirred at 25 °C for 0.5 h. then to the mixture was added Sodium borohydride acetate (1.64 g, 7.74 mmol, 3 eq), The mixture was stirred at 25 °C for 11.5 h. The reaction mixture was quenched by addition diisopropylethylamine 10 mL at 0 °C, and then concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex luna C18 250x50mm>< 10 pm;mobile phase: [water(10mM ammonium bicarbonate)- acetonitrile];B%: 5%-35%,20min). 2-(3-bromo-5-(2- ((l-(tert-butoxycarbonyl)piperidin-4-yl)amino)ethyl)-lH-pyrazol-l-yl)acetic acid (970 mg, 2.25 mmol, 87% yield) was obtained as a white solid. LCMS: MS (ESI) m / z: 432.9 [M+l]+.

[0622] Step 2: Preparation of tert-butyl 4-(2-bromo-7-oxo-7,8-dihydro-4H-pyrazolo[l,5- d][l,4]diazepin-6(5H)-yl)piperidine-l-carboxylate i

[0623] Boc

[0624] To a solution of 2-(3-bromo-5-(2-((l-(tert-butoxycarbonyl)piperidin-4-yl)amino)ethyl)-lH- pyrazol-l-yl)acetic acid (960 mg, 2.23 mmol, 1 eq in N,N-dimethylformamide (20 mL) was added diisopropyl ethyl amine (1.44 g, 11.14 mmol, 1.94 mL, 5.01 eq) and 2-(3H- [l,2,3]triazolo[4,5-b]pyridin-3-yl)-l,l,3,3-tetramethylisouronium hexafluorophosphate(V) (1.73 g, 4.56 mmol, 2.05 eq . The mixture was stirred at 25 °C for 2 h. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. Then quenched by addition water 10 mL at 0 °C, and then diluted with ethyl acetate 30 mL and extracted with ethyl acetate (10 mL x 3). The combined organic layers were washed with brine (10 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Waters Xbridge 150x25mmx 5pm; mobile phase: [water (0.05% ammonia hydroxide v / v)- acetonitrile] ;B%: 30%-60%,7min). Tert-butyl 4-(2-bromo-7-oxo-7,8-dihydro-4H-pyrazolo[l,5-d][l,4]diazepin- 6(5H)-yl)piperidine-l -carboxylate (470 mg, 1.14 mmol, 51% yield) was obtained as a white solid. LCMS: MS (ESI) m / z: 358.9 [M-55]+.

[0625] Step 3: Preparation of tert-butyl 7-(3-((6-(l-(tert-butoxycarbonyl)piperidin-4-yl)-7-oxo- 5, 6, 7, 8-tetrahydro-4H-pyrazolo[l, 5-d][l,4]diazepin-2-yl)amino)- 7-fluoroisoquinolin-6-yl)~ 8-methyl-2,3-dihydro-lH-pyrido[2,3-b][l,4]oxazine-l-carboxylate , ,

[0626] To a stirred of tert-butyl 4-(2-bromo-7-oxo-7,8-dihydro-4H-pyrazolo[l,5-d][l,4]diazepin- 6(5H)-yl)piperidine-l -carboxylate (70 mg, 169.37 umol, 1 eq and tert-butyl 7-(3-amino-7- fluoroisoquinolin-6-yl)-8-methyl-2,3-dihydro-lH-pyrido[2,3-b][l,4]oxazine-l-carboxylate (70.00 mg, 170.55 pmol, 1.01 eq) in dioxane (3 mL) was added cesium carbonate (168.00 mg, 515.62 pmol, 3.04 eq), ditert-butyl-[3,6-dimethoxy-2-(2,4,6- triisopropylphenyl)phenyl]phosphane (42.00 mg, 86.65 pmol, 5.12e-l eq) and [2-(2- aminophenyl)phenyl]-methylsulfonyloxy-palladium; ditert-butyl-[3,6-dimethoxy-2-(2,4,6- triisopropylphenyl)phenyl]phosphane (60 mg, 70.22 umol, 4.15e-l eq), the mixture was stirred under nitrogen atmosphere at 130 °C for 1 h. The reaction mixture was quenched by addition water 10 mL at 0 °C, and then diluted with di chloromethane 30 mL and extracted with dichloromethane (10 mL x 3). The combined organic layers were washed with brine (10 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by prep-thin layer chromatography (silicon dioxide, dichloromethane : methanol = 13: 1). Tert-butyl 7-(3-((6-(l-(tert- butoxycarbonyl)piperidin-4-yl)-7-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[l,5-d][l,4]diazepin-2- yl)amino)-7-fluoroisoquinolin-6-yl)-8-methyl-2,3-dihydro-lH-pyrido[2,3-b][l,4]oxazine-l- carboxylate (56 mg, 75.39 umol, 44% yield) was obtained as a yellow oil. LCMS: MS (ESI) m / z: 743.6 [M+l]+.

[0627] Step 4: Preparation of 2-((7-fluoro-6-(8-methyl-2,3-dihydro-lH-pyrido[2,3-b][l,4]oxazin-7- yl)isoquinolin-3-yl)amino)-6-(piperidin-4-yl)-5,6-dibydro-4H-pyrazolo[l,5-d][l,4]diazepin- 7(8H)-one

[0628] To a solution of tert-butyl 7-(3-((6-(l-(tert-butoxycarbonyl)piperidin-4-yl)-7-oxo-5,6,7,8- tetrahydro-4H-pyrazolo[l,5-d][l,4]diazepin-2-yl)amino)-7-fluoroisoquinolin-6-yl)-8-methyl- 2,3-dihydro-lH-pyrido[2,3-b][l,4]oxazine-l-carboxylate (56 mg, 75.39 umol, 1 eq) in dichloromethane (3 mL) was added trifluoroacetic acid (3 mL). The mixture was stirred at 25 °C for 0.5 h. The reaction mixture was concentrated under reduced pressure to give a residue. Then the mixture was diluted by dichloromethane: methanol =10: 1 (50 mL), to the mixture was added tri ethylamine until the pH 7-8, then the reaction mixture was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. 22-((7-fluoro-6-(8-methyl-2,3-dihydro-lH-pyrido[2,3-b][l,4]oxazin-7-yl)isoquinolin-3- yl)amino)-6-(piperidin-4-yl)-5,6-dihydro-4H-pyrazolo[l,5-d][l,4]diazepin-7(8H)-one (40 mg, 73.72 umol, 97% yield) was obtained as a yellow solid. LCMS: MS (ESI) m / z: 543.5 [M+l]+.

[0629] Step 5: Preparation of 2-(2,6-dioxopiperidin-3-yl)-5-(4-((4-(2-((7-fluoro-6-(8-methyl-2,3- dihydro-LH-pyrido[2,3-b][l,4]oxazin- 7-yl)isoquinolin-3-yl)amino)~ 7 -oxo- 7, 8-dihydro-4H- pyrazolo[l,5-d][l,4]diazepin-6(5H)-yl)piperidin-l-yl)methyl)piperidin-l-yl)isoindoline-l,3- dione

[0630] To a stirred of 2-((7-fluoro-6-(8-methyl-2,3-dihydro-lH-pyrido[2,3-b][l,4]oxazin-7- yl)isoquinolin-3-yl)amino)-6-(piperidin-4-yl)-5,6-dihydro-4H-pyrazolo[l,5-d][l,4]diazepin- 7(8H)-one (30 mg, 55.29 umol, 1 eq and l-(2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin- 5-yl)piperidine-4-carbaldehyde (40 mg, 108.29 pmol, 1.96 eq) in dimethyl sulfoxide (2 mL) and dichloroethane (2 mL) was added acetic acid (13.28 mg, 221.15 pmol, 12.65 uL, 4 eq), The mixture was stirred at 25 °C for 0.5 h. then to the mixture was added sodium borohydride acetate (35.15 mg, 165.87 umol, 3 eq), The mixture was stirred at 25 °C for 11.5 h. The reaction mixture was quenched by addition water 10 mL at 0 °C and added sodium bicarbonate until pH 7-8. Then extracted with ethyl acetate (10 mL x 3). The combined organic layers were washed with brine (100 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Shim-pack C18 150x25x 10pm; mobile phase: [water(0.225% formic acid)- acetonitrile] ;B%: 9%-39%,10min). 2-(2,6-dioxopiperidin-3-yl)-5-(4-((4-(2-((7- fhioro-6-(8-methyl-2,3-dihydro-lH-pyrido[2,3-b][l,4]oxazin-7-yl)isoquinolin-3-yl)amino)-7- oxo-7, 8-dihydro-4H-pyrazolo[ 1 , 5-d] [ 1 ,4]diazepin-6(5H)-yl)piperidin- 1 -yl)methyl)piperidin- l-yl)isoindoline-l, 3-dione (17.7 mg, 17.85 umol, 32% yield, 95% purity, formic acid) was obtained as a yellow solid. LCMS: MS (ESI) m / z: 896.4[M+H]+. ’H NMR: (400MHz, dimethylsulfoxide -d6) 8 = 11.08 (s, 1 H), 9.24 (s, 1 H), 9.06 - 8.91 (m, 1 H), 8.26 (s, 1 H), 7.97 - 7.86 (m, 1 H), 7.78 (d, J = 10.0 Hz, 1 H), 7.71 - 7.61 (m, 2 H), 7.37 (s, 1 H), 7.33 - 7.28 (m, 1 H), 7.23 (d, J = 8.8 Hz, 1 H), 5.97 (s, 1 H), 5.70 (s, 1 H), 5.13 - 4.94 (m, 3 H), 4.29 (m, 2 H), 4.24 - 4.14 (m, 1 H), 4.04 (m, 2 H), 3.81 (m, 2 H), 3.55 - 3.48 (m, 3 H), 3.03 - 2.86 (m, 7 H), 2.65 - 2.54 (m, 3 H), 2.14 (m, 2 H), 2.06 - 1.94 (m, 2 H), 1.92 (s, 3 H), 1.84 - 1.69 (m, 5 H), 1.53 (m, 2 H), 1.21 - 1.09 (m, 2 H).

[0631] Example 2

[0632] Step 1: Preparation of 2-[3-bromo-5-[2-[(l-tert-butoxycarbonylazetidin-3- yl)amino]ethyl]pyrazol-l -yl] acetic acid

[0633] To a solution of 2-[5-(2-aminoethyl)-3-bromo-pyrazol-l-yl]acetic acid (430 mg, 1.73 mmol, 1 eq) and acetic acid (520 mg, 8.67 mmol, 5 eq) in 1,2-di chloroethane (10 mL) was added tert-butyl 3-oxoazetidine-l-carboxylate (1.48 g, 8.67 mmol, 5 eq) and sodium triacetoxyborohydride (1.84 g, 8.67 mmol, 5 eq). The reaction mixture was stirred at 25 °C for 12 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-high performance liquid chromatography (neutral condition: column: Phenomenex luna C18 250*50mm*10 pm; mobile phase: [water(10mM ammonium bicarbonate)-acetonitrile];B%: 0%-30%, 20min). The desired compound 2-[3 - bromo-5-[2-[(l-tert-butoxycarbonylazetidin-3-yl)amino]ethyl]pyrazol-l-yl]acetic acid (200 mg, 0.49 mmol, 28% yield) was obtained as white solid. LCMS: MS (ESI) m / r. 403.3 [M+l],

[0634] Step 2: Preparation of tert-butyl 3-(2-bromo-7-oxo-5,8-dihydro-4H-pyrazolo[l,5- d][l,4]diazepin-6-yl)azetidine-l-carboxylate

[0635] To a solution of 2-[3-bromo-5-[2-[(l-tert-butoxycarbonylazetidin-3-yl)amino]ethyl]pyrazol- l-yl]acetic acid (180 mg, 0.45 mmol, 1 eq) in A( A -di methyl form am ide (6 mL) was added Af, A -di isopropyl ethyl amine (288 mg, 2.23 mmol, 5 eq) and o-(7-azabenzotriazol-l-yl)- n,n,n',n'-tetramethyluronium hexafluorophosphate (255 mg, 0.67 mmol, 1.5 eq). The reaction mixture was stirred at 25 °C for 0.15 h. The reaction mixture was quenched by addition water (10 mL), and then diluted with water (30 mL) and extracted with di chloromethane (30 mL x 3). The combined organic layers were washed with brine (60 mL x 3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-high performance liquid chromatography (neutral condition: column: Waters Xbridge 150*25mm* 5pm; mobile phase: [water(10mM ammonium bicarbonate)-acetonitrile];B%: 20%-53%,8min). The desired compound tert-butyl 3-(2- bromo-7-oxo-5, 8-dihydro-4H-pyrazolo[ 1 , 5-d] [ 1 ,4]diazepin-6-yl)azetidine- 1 -carboxylate (84 mg, 0.22 mmol, 48% yield) was obtained as white solid. LCMS: MS (ESI) m / r. 385.0 [M+l],

[0636] Step 3: Preparation of tert-butyl tert-butyl 7-[3-[[6-(l-tert-butoxycarbonylazetidin-3-yl)-7- oxo-5, 8-dihydro-4H-pyrazolo[l, 5-d][l,4]diazepin-2-yl]anuno]- 7-fluoro-6-isoquinolyl]-8- methyl-2,3-dihydropyrido[2,3-b][l,4]oxazine-l-carboxylate

[0637] To a solution of tert-butyl 7-(3-amino-7-fluoro-6-isoquinolyl)-8-methyl-2,3- dihydropyrido[2,3-b][l,4]oxazine-l-carboxylate (22 mg, 0.054 mmol, 1 eq) and tert-butyl 3- (2-bromo-7-oxo-5,8-dihydro-4H-pyrazolo[l,5-d][l,4]diazepin-6-yl)azetidine-l-carboxylate (21 mg, 0.054 mmol, 1 eq) in dioxane (3 mL) was added cesium carbonate (53 mg, 0.16 mmol, 3 eq), ditert-butyl-[3,6-dimethoxy-2-(2,4,6-triisopropylphenyl)phenyl]phosphane (13 mg, 0.027 mmol, 0.5 eq) and [2-(2-aminophenyl)phenyl]-methylsulfonyloxy- palladium;ditert-butyl-[3,6-dimethoxy-2-(2,4,6-triisopropylphenyl)phenyl]phosphane (19 mg, 0.022 mmol, 0.4 eq) under nitrogen. The reaction mixture was stirred at 130 °C for 1 h. The reaction mixture was quenched by addition water (10 mL), and then diluted with water (20 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with brine (40 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by prep-thin layer chromatography (dichloromethane: methanol = 10: 1). The desired compound tert-butyl 7-[3- [[6-(l-tert-butoxycarbonylazetidin-3-yl)-7-oxo-5,8-dihydro-4H-pyrazolo[l,5-d][l,4]diazepin- 2-yl]amino]-7-fluoro-6-isoquinolyl]-8-methyl-2,3-dihydropyrido[2,3-b][l,4]oxazine-l- carboxylate (35 mg, 0.049 mmol, 89% yield) was obtained as yellow solid. LCMS: MS (ESI) m / r. 515.3 [M-100+1],

[0638] Step 4 Preparation of 6-(azetidin-3-yl)-2-[[7-fluoro-6-(8-methyl-2,3-dihydro-lH-pyrido[2,3- b][l,4]oxazin-7-yl)-3-isoquinolyl]anuno]-5,8-dihydro-4H-pyrazolo[l,5-d][l,4]diazepin-7- one

[0639] To a solution of tert-butyl 7-[3-[[6-(l-tert-butoxycarbonylazetidin-3-yl)-7-oxo-5,8-dihydro- 4H-pyrazolo[l,5-d][l,4]diazepin-2-yl]amino]-7-fluoro-6-isoquinolyl]-8-methyl-2,3- dihydropyrido[2,3-b][l,4]oxazine-l-carboxylate (35 mg, 0.049 mmol, 1 eq) in dichloromethane (1 mL) was added trifluoroacetic acid (1.54 g, 13.51 mmol, 1 mL). The reaction mixture was stirred at 25 °C for 0.5 h. The reaction mixture was concentrated under reduced pressure to give a residue. To the mixture was added (2 mL) dichloromethane, then added triethylamine to adjust pH 8~9, the reaction mixture was concentrated under reduced pressure to give a residue. The product was taken to the next step without purification. The desired compound, 6-(azetidin-3-yl)-2-[[7-fhioro-6-(8-methyl-2,3-dihydro-lH-pyrido[2,3- b][l,4]oxazin-7-yl)-3-isoquinolyl]amino]-5,8-dihydro-4H-pyrazolo[l,5-d][l,4]diazepin-7-one (20 mg, 0.039 mmol, 79% yield), was obtained as yellow solid. LCMS: MS (ESI) m / z 515.2 [M+l],

[0640] Step 5 Preparation of 2-(2,6-dioxo-3-piperidyl)-5-[4-[[3-[2-[[7-fluoro-6-(8-methyl-2,3- dihydro-LH-pyrido[2,3-b][l,4]oxazin- 7-yl)-3-isoquinolyl]amino]~ 7-oxo-5, 8-dihydro-4H- pyrazolo[l,5-d][l,4]diazepin-6-yl]azetidin-l-yl]methyl]-l-piperidyl]isoindoline-l, 3-dione

[0641]

[0642] To a solution of 6-(azetidin-3-yl)-2-[[7-fluoro-6-(8-methyl-2,3-dihydro-lH-pyrido[2,3- b][l,4]oxazin-7-yl)-3-isoquinolyl]amino]-5,8-dihydro-4H-pyrazolo[l,5-d][l,4]diazepin-7-one (20 mg, 0.039 mmol, 1 eq) in dimethyl sulfoxide (1 mL) and 1,2-di chloroethane (1 mL) was added acetic acid (7 mg, 0.012 mmol, 3 eq) and l-[2-(2,6-dioxo-3-piperidyl)-l,3-dioxo- isoindolin-5-yl]piperidine-4-carbaldehyde (14 mg, 0.039 mmol, 1 eq). 30 min later, sodium triacetoxyborohydride (16 mg, 0.078 mmol, 2 eq) was added to the mixture. The reaction mixture was stirred at 25 °C for 12 h. The reaction mixture was quenched by addition water (20 mL), and then diluted with water (30 mL) and extracted with di chloromethane (40 mL x 3). The combined organic layers were washed with brine (60 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by prep-high performance liquid chromatography (formic acid condition: column: Shim-pack C18 150*25*10 pm; mobile phase: [water(0.225%formic acid)-acetonitrile];B%: l l%-41%,10min). The desired compound, 2-(2,6-dioxo-3-piperidyl)- 5-[4-[[3-[2-[[7-fhioro-6-(8-methyl-2,3-dihydro-lH-pyrido[2,3-b][l,4]oxazin-7-yl)-3- isoquinolyl]amino]-7-oxo-5,8-dihydro-4H-pyrazolo[l,5-d][l,4]diazepin-6-yl]azetidin-l- yl]methyl]-l-piperidyl]isoindoline-l, 3-dione (16.8 mg, 0.017 mmol, 45% yield, 95% purity, formic acid), was obtained as yellow solid. LCMS: MS (ESI) m / r. 868.3 [M+l],1H NMR: (400 MHz, DMSO-tfc) 5 = 11.07 (s, 1H), 9.26 (s, 1H), 8.98 (s, 1H), 8.21 (s, 1H), 7.89 (s, 1H), 7.78 (d, J= 10.0 Hz, 1H), 7.65 (t, J= 8.8 Hz, 2H), 7.36 (s, 1H), 7.29 (s, 1H), 7.25 - 7.19 (m, 1H), 5.99 (s, 1H), 5.70 (s, 1H), 5.06 (dd, J= 5.2, 13.2 Hz, 1H), 5.00 (s, 2H), 4.81 - 4.67 (m, 1H), 4.29 (t, J= 3.6 Hz, 2H), 4.08 - 3.97 (m, 4H), 3.52 - 3.45 (m, 5H), 3.08 - 3.02 (m, 4H), 2.99 - 2.78 (m, 4H), 2.36 - 2.30 (m, 2H), 2.06 - 1.96 (m, 1H), 1.95 - 1.89 (m, 3H), 1.81 - 1.71 (m, 2H), 1.64 - 1.52 (m, 1H), 1.25 - 1.06 (m, 2H). Example 3

[0643] Step 1: Preparation of 5-[4-(dimethoxymethyl)-l-piperidyl]-2- (2,6-dioxo-3- piperidyl)isoindoline-l, 3-dione

[0644] To a solution of 2-(2,6-dioxo-3-piperidyl)-5-fluoro-isoindoline-l, 3-dione (200 mg, 0.72 mmol, 1 eq in dimethylsulfoxide (3 mL) was added diisopropylethylamine (280 mg, 2.17 mmol, 3 eq) and 4-(dimethoxymethyl)piperidine (115 mg, 0.72 mmol, 1 eq .The mixture was stirred at 120 °C for 2 hours. Water (30 mL) was poured into the mixture and stirred for 1 minute. The aqueous phase was extracted with ethyl acetate (10 mL x 3). The combined organic phase was washed with brine (10 mL x 2), dried with anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by column chromatography (dichloromethane: methanol = 1 :0 to 50: 1) to give 5-[4-(dimethoxymethyl)- l-piperidyl]-2-(2,6-dioxo-3- piperidyl)isoindoline-l, 3-dione (250 mg, 0.60 mmol, 83.11% yield) as a yellow solid. LCMS: MS (ESI) m / z 416.1 [M+l]+. Step 2: Preparation of l-[2-(2,6-dioxo-3-piperidyl)-l,3-(lioxo-isoin(lolin- 5-yl]piperidine-4- carbaldehyde

[0645] To a solution of 5-[4-(dimethoxymethyl)-l-piperidyl]-2-(2,6-dioxo-3-piperidyl)isoindoline- 1,3-dione (250 mg, 0.60 mmol, 1 eq in tetrahydrofuran (6 mL) was added sulfuric acid (2 M, 6.02 mL, 20 eq). The mixture was stirred at 70 °C for 0.5 hour. The reaction mixture was diluted with water (15 mL) and adjusted to pH 7~8 with saturated sodium bicarbonate. The mixture was extracted with ethyl acetate (15 mL x 2). The combined organic phase was washed with saturated brine (15 mL x 2), dried with anhydrous sodium sulfate, filtered, and concentrated to give l-[2-(2,6-dioxo-3-piperidyl)-l,3-dioxo-isoindolin-5-yl]piperidine-4- carbaldehyde (200 mg, crude) as a yellow solid was used into the next step without further purification. LCMS: MS (ESI) m / z 370.3[M+l]+.

[0646] Step 3: Preparation of [7-[[l-[2-(2,6-dioxo-3-piperidyl)-l,3-dioxo- isoindolin-5-yl]-4- piperidyl]methyl]-7-azaspiro[3.5]nonan-2-yl]N-[7-fluoro-6-(8-niethyl-2,3-dihydro-lH- pyrido[2,3-b][l,4]oxazin- 7-yl)-3-isoquinolyl]carbamate To a solution of 7-azaspiro[3.5]nonan-2-yl N-[7-fluoro-6-(8-methyl-2,3-dihydro- 1H- pyrido[2,3-b][l,4]oxazin-7-yl)-3-isoquinolyl]carbamate (60 mg, 0.11 mmol, 1 eq, hydrochloride) in dichloromethane (2 mL) and isopropanol (2 mL) was added sodium acetate (47 mg, 0.58 mmol, 5 eq}. The mixture was stirred at 35°C for 10 min. l-[2-(2,6-dioxo-3- piperidyl)-l,3-dioxo-isoindolin-5-yl]piperidine-4-carbaldehyde (51 mg, 0.14 mmol, 1.2 eq} was added, and the mixture was stirred at 35°C for 20min. Sodium tri acetoxyb or ohy dr ogen (49 mg, 0.23 mmol, 2 eq was added and the mixture was stirred at 35°C for another 12 hours. The reaction mixture was diluted with water (5 mL) and extracted with dichloromethane (5 mL x 2). The combined organic phase was washed with saturated brine (5 mL x 2), dried with anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by prep-HPLC (column: Phenomenex Synergi C18 150*25mm* 10 pm;mobile phase: [water(0.225%FA)-ACN];B%: l l%-41%,10min) to give [7-[[l-[2-(2,6-dioxo-3- piperidyl)- l,3-dioxo-isoindolin-5-yl]-4-piperidyl]methyl]-7-azaspiro[3.5]nonan-2-yl] N-[7- fhioro-6-(8- methyl -2, 3-dihydro-lH-pyrido[2,3-b][l,4]oxazin-7-yl)-3-isoquinolyl]carbamate (21.9 mg, 0.02 mmol, 22% yield, 99.9% purity) as a yellow solid. LCMS: MS (ESI) m / z 831.3 [M+l]+. H NMR: (400 MHz, DMSO-d6) <5: 11.07 (s, 1H), 10.21 (s, 1H), 9.10 (s, 1H), 8.19 (s, 1H), 7.92 (d, J= 10.4 Hz, 1H), 7.84 (d, J= 7.2 Hz, 1H), 7.68 - 7.61 (m, 1H), 7.36 (s, 1H), 7.29 (s, 1H), 7.25 - 7.17 (m, 1H), 5.72 (s, 1H), 5.09 - 5.03 (m, 1H), 5.02 - 4.95 (m, 1H), 4.33 - 4.25 (m, 2H), 4.09 - 3.97 (m, 2H), 2.99 - 2.90 (m, 2H), 2.89 - 2.80 (m, 1H), 2.62 - 2.58 (m, 2H), 2.44 - 2.38 (m, 4H), 2.30 - 2.23 (m, 4H), 2.09 (br d, J= 6.4 Hz, 2H), 2.03 - 1.99 (m, 1H), 1.91 (s, 3H), 1.85 - 1.73 (m, 5H), 1.61 - 1.52 (m, 4H), 1.19 - 1.03 (m, 2H).

[0647] Example 4

[0648]

[0649] Step 1: Preparation of 5-[3-(dimethoxymethyl)azetidin-l-yl]-2-(2,6-dioxo-3- piperidyl)isoindoline-l, 3-dione To a solution of 2-(2,6-dioxo-3-piperidyl)-5-fluoro-isoindoline-l, 3-dione (200 mg, 0.72 mmol, 1 eq and 3-(dimethoxymethyl)azetidine (94 mg, 0.72 mmol, 1 eq) in dimethylsulfoxide (2 mL) was added diisopropylethylamine (280 mg, 2.17 mmol, 3 eq . The mixture was stirred at 120 °C for 2 h. Water (30 mL) was poured into the mixture and stirred for 1 minute. The aqueous phase was extracted with ethyl acetate (10 mL x 3). The combined organic phase were washed with brine (10 mL x 2), dried with anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by column chromatography (dichloromethane: methanol = 1 :0 to 50: 1). 5-[3-(dimethoxymethyl)azetidin- l-yl]-2-(2,6-dioxo-3-piperidyl) isoindoline- 1,3 -di one (200 mg, 0.51 mmol, 71% yield) was obtained as a yellow solid. LCMS: MS (ESI) m / z 388.1 [M+l]+. Step 2: Preparation of l-[2-(2, 6-dioxo-3-piperidyl)-l,3-dioxo-isoindolin-5-yl]azetidine-3- carbaldehyde

[0650] To a solution of 5-[3-(dimethoxymethyl)azetidin-l-yl]-2-(2,6-dioxo-3-piperidyl)isoindoline - 1,3-dione (200 mg, 0.51 mmol, 1 eq in dichloromethane (6 mL) was added trifluoroacetic acid (3.08 g, 27.01 mmol, 2 mL, 52.32 eq . The mixture was stirred at 20 °C for 1 h. The reaction mixture was adjusted to pH 8 with saturated aqueous sodium bicarbonate. The aqueous phase was extracted with ethyl acetate (10 mL x 3). The combined organic phase was washed with brine (10 mL x 2), dried with anhydrous sodium sulfate, filtered, and concentrated under vacuum. The crude product was used into the next step without further purification. l-[2-(2,6-dioxo-3-piperidyl)-l,3-dioxo-isoindolin-5-yl]azetidine-3-carbaldehyde (160 mg, crude) was obtained as a yellow solid. LCMS: MS (ESI) m / z 360.3 [M+19]+.

[0651] Step 3: Preparation of 2-(2,6-dioxo-3-piperidyl)-5-[3-[[4-[2-[[7-fluoro-6-(8-methyl-2,3- dihydro-LH-pyrido[2,3-b][l,4]oxazin- 7-yl)-3-isoquinolyl]amino]~ 7-oxo-5, 8-dihydro-4H- pyrazolo[l,5-d][l,4]diazepin-6-yl]-l-piperidyl]methyl]azetidin-l-yl]isoindoline-l, 3-dione

[0652] To a solution of l-[2-(2,6-dioxo-3-piperidyl)-l,3-dioxo-isoindolin-5-yl]azetidine-3- carbaldehyde (15 mg, 0.043 mmol, 1 eq and 2-[[7-fluoro-6-(8-methyl-2,3-dihydro-lH- pyrido [2,3-b][l,4]oxazin-7-yl)-3-isoquinolyl]amino]-6-(4-piperidyl)-5,8-dihydro-4H- pyrazolo[l,5-d][l,4]diazepin-7-one (25 mg, 0.043 mmol, 1 eq, hydrochloride) in dichloromethane (1 mL) was added triethylamine (8 mg, 0.087 mmol, 12.23 uL, 2 eq , the mixture was stirred at 25 °C for 0.5 h. Sodium tri acetoxyb orohydri de (27 mg, 0.13 mmol, 3 eq was added to the mixture, the mixture was stirred at 25 °C for 0.5 h. The reaction mixture concentrated under reduced pressure. The residue was purified by prep-HPLC (column: Phenomenex Synergi C18 150*25mm* 10 pm; mobile phase: [water(0.1%TFA)-ACN];B%: 13%-43%,10min). The reaction mixture was adjusted to pH 8 with saturated aqueous sodium bicarbonate. The aqueous phase was extracted with ethyl acetate (10 mL x 3). The combined organic phases were washed with brine (10 mL x 2), dried with anhydrous sodium sulfate, filtered, and concentrated under vacuum. 2-(2,6-dioxo-3-piperidyl)-5-[3-[[4-[2-[[7-fluoro-6- (8-methyl-2,3-dihydro-lH-pyrido[2,3-b][l,4]oxazin-7-yl)-3-isoquinolyl]amino]-7-oxo-5,8- dihydro-4H-pyrazolo[l,5-d][l,4]diazepin-6-yl]-l-piperidyl]methyl]azetidin-l-yl]isoindoline- 1,3-dione (7.1 mg, 0.008 mmol, 18% yield, 97% purity) was obtained as a yellow solid.

[0653] LCMS: MS (ESI) m / z 868.2 [M+l]+. ’H NMR: (400MHz, DMSO-t / 6) 3 : 11.14 - 11.03 (m, 1H), 9.32 - 9.23 (m, 1H), 9.02 - 8.95 (m, 1H), 7.91 (s, 1H), 7.83 - 7.76 (m, 1H), 7.72 - 7.61 (m, 2H), 7.37 (s, 1H), 6.85 - 6.74 (m, 1H), 6.71 - 6.60 (m, 1H), 6.04 - 5.92 (m, 1H), 5.75 - 5.66 (m, 1H), 5.09 - 5.00 (m, 3H), 4.35 - 4.10 (m, 6H), 3.89 - 3.76 (m, 4H), 3.31 (s, 4H), 3.04 - 2.84 (m, 4H), 2.60 (dd, J= 1.2, 3.6 Hz, 3H), 2.08 - 1.96 (m, 3H), 1.92 (s, 3H), 1.29 - 1.19 (m, 4H).

[0654] Example 5

[0655] Step 1: Preparation of 2-(2,6-dioxo-3-piperidyl)-5-[4-[2-[4-[2-[[7-fluoro-6-(8-methyl-2,3- dihydro-LH-pyrido[2,3-b][l,4]oxazin- 7-yl)-3-isoquinolyl]amino]~ 7-oxo-5, 8-dihydro-4H- pyrazolo[l,5-d][l,4]diazepin-6-yl]-l-piperidyl]ethyl]-l-piperidyl]isoindoline-l, 3-dione

[0656] To a solution of 2-[l-[2-(2,6-dioxo-3-piperidyl)-l,3-dioxo-isoindolin-5-yl]-4-piperidyl] acetaldehyde (16 mg, 0.041 mmol, 1 eq) and 2-[[7-fluoro-6-(8-methyl-2,3-dihydro-lH- pyrido[2,3-b][l,4]oxazin-7-yl)-3-isoquinolyl]amino]-6-(4-piperidyl)-5,8-dihydro-4H- pyrazolo[l,5-d][l,4]diazepin-7-one (24 mg, 0.041 mmol, 1 eq, hydrochloride) in dichloromethane (2 mL) was added triethylamine (8 mg, 0.083 mmol, 11.62 uL, 2 eq}, the mixture as stirred at 25 °C for 0.5 h. Sodium tri acetoxyb or ohydri de (26 mg, 0.12 mmol, 3 eq} was added to the mixture, the mixture was stirred at 25 °C for 0.5 h. The reaction mixture concentrated under reduced pressure. The residue was purified by prep-HPLC (column: Phenomenex Synergi C18 150*25mm* 10 pm; mobile phase: [water(0.225%FA)-ACN];B%: 9%-39%,10min). 2-(2,6- dioxo-3-piperidyl)-5-[4-[2-[4-[2-[[7-fluoro-6-(8-methyl-2,3- dihydro-lH-pyrido[2,3-b][l,4]oxazin-7-yl)-3-isoquinolyl]amino]-7-oxo-5,8-dihydro-4H- pyrazolo[l,5-d][l,4]diazepin-6-yl]-l-piperidyl]ethyl]-l-piperidyl]isoindoline-l, 3-dione (16.2 mg, 0.016 mmol, 39% yield, 97% purity, formate) was obtained as a yellow solid. LCMS: MS (ESI) m / z: 910.3 [M+l]+. ’H NMR: (400MHz, DMSO-t / 6) d : 11.12 - 11.04 (m, 1H), 9.24 (s, 1H), 8.98 (s, 1H), 8.18 - 8.13 (m, 1H), 7.92 - 7.88 (m, 1H), 7.78 (d, J= 10.4 Hz, 1H), 7.70 - 7.61 (m, 2H), 7.37 (s, 1H), 7.30 (s, 1H), 7.27 - 7.20 (m, 1H), 6.00 - 5.94 (m, 1H), 5.74 - 5.66 (m, 1H), 5.09 - 5.03 (m, 1H), 5.03 - 4.97 (m, 2H), 4.29 (s, 4H), 4.07 - 4.01 (m, 2H), 3.83 - 3.76 (m, 2H), 3.03 - 2.93 (m, 6H), 2.92 (dd, J= 2.0, 3.6 Hz, 2H), 2.60 (d, J= 2.0 Hz, 2H), 2.40 - 2.34 (m, 2H), 2.05 - 1.96 (m, 3H), 1.84 - 1.68 (m, 5H), 1.68 - 1.49 (m, 4H), 1.39 (d, J= 7.6 Hz, 2H), 1.28 - 1.08 (m, 3H).

[0657] Example 6

[0658] To a solution of 2-[[7-fhroro-6-(8-methyl-2,3-dihydro-lH-pyrido[2,3- b][l,4]oxazin-7-yl)-3- isoquinolyl]amino]-6-(4-piperidyl)-5,8-dihydro-4H-pyrazolo[l,5-d][l,4]diazepin-7-one (25 mg, 0.04 mmol, 1 eq, hydrochloride) in dimethylsulfoxide (1 mL) was added diisopropyl ethyl amine (27 mg, 0.21 mmol, 5 eq and 2-(2,6-dioxo-3-piperidyl)-5- fluoro-isoindoline-1, 3-dione (14.31 mg, 51.81 pmol, 1.2 eq) .The mixture was stirred at 120 °C for 12 hours. The reaction mixture was diluted with water (5 mL) and extracted with ethyl acetate (5 mL x 2). The combined organic phase was washed with saturated brine (5 mL x 2), dried with anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by prep-HPLC (column: Phenomenex Synergi Cl 8 150*25mm* 10 pm;mobile phase: [water(0.225%FA)-ACN];B%: 22%-52%,10min) and further purified by prep-HPLC (column: 3_Phenomenex Luna C18 75*30mm*3 pm;mobile phase: [water(0.1%TFA)- ACN];B%: 28%-48%,7min) to give 2-(2,6-dioxo-3-piperidyl)-5-[4-[2-[[7-fluoro-6-(8- methyl-2,3- dihydro-lH-pyrido[2,3-b][l,4]oxazin-7-yl)-3-isoquinolyl]amino]-7-oxo-5,8- dihydro-4H-pyrazolo[l,5-d][l,4]diazepin-6-yl]-l-piperidyl]isoindoline-l, 3-dione (6.3 mg, 0.006 mmol, 14 % yield, 90% purity, trifluoroacetate) as a yellow solid. LCMS: MS (ESI) m / z: 799.3 [M+l]+. H NMR: (400 MHz, DMSO-d6) 11.08 (s, 1H), 9.30 (s, 1H), 9.00 (s, 1H), 7.92 (s, 1H), 7.80 (d, J= 10.0 Hz, 1H), 7.72 - 7.65 (m, 2H), 7.42 (s, 1H), 7.37 (d, J= 1.6 Hz, 1H), 7.32 - 7.27 (m, 1H), 5.97 (s, 1H), 5.08 (dd, J= 5.2, 13.2 Hz, 1H), 5.03 (s, 2H), 4.60 - 4.46 (m, 2H), 4.36 - 4.31 (m, 2H), 4.22 - 4.16 (m, 2H), 3.78 - 3.76 (m, 2H), 3.41 - 3.37 (m,

[0659] 2H), 3.09 - 3.03 (m, 2H), 2.97 - 2.93 (m, 2H), 2.92 - 2.87 (m, 1H), 2.64 - 2.60 (m, 2H), 2.06 - 2.00 (m, 1H), 1.94 (d, J= 1.2 Hz, 3H), 1.87 - 1.74 (m, 2H), 1.71 - 1.63 (m, 2H), 1.26 - 1.22 (m, 1H).

[0660] Example 7

[0661] Step 1: Preparation of tert-buty I2-(3-hromo-5-inethyI-pyraz,oI-l- yl)acetate

[0662] To a solution of 3-bromo-5-methyl-lH-pyrazole (10 g, 62.11 mmol, 1 eq) and tert-butyl 2- chloroacetate (14.03 g, 93.16 mmol, 13.36 mL, 1.5 eq) in dimethyl formamide (300 mL) was added potassium carbonate (17.17 g, 124.22 mmol, 2 eq) and tetrabutyl ammonium iodide (1.15 g, 3.11 mmol, 0.05 eq). The mixture was stirred at 15 °C for 12 hours. The reaction mixture was diluted with water (1.5 L) and extracted with ethyl acetate (500 mL x 2). The combined organic phase was washed with saturated brine (1 L x 3), dried with anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by flash silica gel chromatography (ISCO®; 80 g SepaFlash® silica flash column, eluent of 0-20% ethyl acetate / petroleum ether gradient @ 100 mL / min) to give tert-butyl 2-(3-bromo-5-methyl- pyrazol-l-yl)acetate (15 g, 54.52 mmol, 87% yield) as a light yellow solid. LCMS: MS (ESI) m / z: 219.3 [M+2-56]+. ’H NMR: (400MHz, DMSO-t / 6) d: 6.08 (s, 1H), 4.69 (s, 2H), 2.23 (s, 3H), 1.46 (s, 9H).

[0663] Step 2: Preparation of tert-butyl 2-[3-bromo-5-(bromomethyl)pyrazol-l- yl / acetate

[0664] To a solution of tert-butyl 2-(3-bromo-5-methyl-pyrazol-l-yl)acetate (15 g, 54.52 mmol, 1 eq) in tetrachloromethane (300 mL) was added azobisisobutyronitrile (895 mg, 5.45 mmol, 0.1 eq). The mixture was stirred at 15°C for 30min. N-bromosuccinimide (9.70 g, 54.52 mmol, 1 eq) was added and then the mixture was stirred at 80°C for 1 hour. The reaction mixture was diluted with water (1 L) and extracted with dichloromethane (500 mL x 3). The combined organic phase was washed with saturated brine (500 mL x 2), dried with anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by flash silica gel chromatography (ISCO®; 100 g SepaFlash® silica flash column, eluent of 0-10% ethyl acetate / petroleum ether gradient @ 100 mL / min) to give tert-butyl 2-[3-bromo-5- (bromomethyl)pyrazol-l-yl]acetate (18.6 g, 52.54 mmol, 96% yield) as a light yellow solid.

[0665] Step 3: Preparation of tert-butyl 2-[3-bromo-5-(cyanomethyl)pyrazol-l- yl / acetate

[0666] To a solution of tert-butyl 2-[3-bromo-5-(bromomethyl)pyrazol-l-yl]acetate (18.6 g, 52.54 mmol, 1 eq) in dimethylsulfoxide (300 mL) was added sodium cyanide (4.72 g, 96.31 mmol, 1.83 eq . The mixture was stirred at 15 °C for 1 hour. The reaction mixture was diluted with water (600 mL) and extracted with ethyl acetate (300 mL x 2). The combined organic phase was washed with saturated brine (300 mL x 2), dried with anhydrous sodium sulfate, filtered, and concentrated under vacuum. The aqueous phase was quenched by addition saturated sodium hypochlorite (5 L) and adjusted to pH >13 with sodium hydroxide. The aqueous phase was placed in fume hood overnight. The residue was purified by flash silica gel chromatography (ISCO®; 80 g SepaFlash® silica flash column, eluent of 0-20% ethyl acetate / petroleum ether gradient @ 100 mL / min) to give tert-butyl 2-[3-bromo-5- (cyanomethyl)pyrazol-l-yl]acetate (5 g, 16.66 mmol, 31% yield) as a white solid. LCMS: MS (ESI) m / z 244.1 [M-56]+. ’H NMR: (400MHz, DMSO-t / 6) d: 6.39 (s, 1H), 4.82 (s, 2H), 3.77 (s, 2H), 1.48 (s, 9H).

[0667] Step 4: Preparation of tert-butyl2-[5-(2-aminoethyl)-3-bromo-pyrazol- 1-yl] acetate

[0668] To a solution of tert-butyl 2-[3-bromo-5-(cyanomethyl)pyrazol-l-yl]acetate (5 g, 16.66 mmol, 1 eq in methanol (500 mL) was added platinum dioxide (1 g) under nitrogen atmosphere. The suspension was degassed and purged with hydrogen for 3 times. The mixture was stirred under hydrogen (1 MPa.) at 25 °C for 12 hours. The reaction mixture was filtered, and the filter was concentrated. The residue was triturated with petroleum ether: ethyl acetate (V / V=5: l) to give tert-butyl 2-[5-(2-aminoethyl)-3-bromo-pyrazol-l-yl]acetate (2.3 g, 7.56 mmol, 45% yield) as a white solid.1H NMR: (400MHz, DMSO-t / 6) d: 6.24 (s, 1H), 4.81 (s, 2H), 4.41 (d, J= 1.2 Hz, 4H), 3.20 - 3.12 (m, 2H), 2.97 - 2.86 (m, 2H), 1.47 (s, 9H)

[0669] Step 5: Preparation of 2-[5-(2-aminoethyl)-3-bromo-pyrazol-l-yl]acetic acid

[0670] To a solution of tert-butyl 2-[5-(2-aminoethyl)-3-bromo-pyrazol-l-yl]acetate (1.8 g, 5.92 mmol, 1 eq} in dichloromethane (20 mL) was added 4 M hydrochloric acid in dioxane (18.00 mL). The mixture was stirred at 15 °C for 0.5 hour. The reaction mixture was concentrated to give 2-[5-(2-aminoethyl)-3-bromo-pyrazol-l-yl]acetic acid (1.8 g, crude, hydrochloride) as a white solid was used into the next step without further purification.

[0671] Step 6: Preparation of 2-[3-bromo-5-[2-[(l-tert-butoxycarbonyl-4- piperidyl)amino]ethyl]pyrazol-l -yljacetic acid

[0672] To a solution of 2-[5-(2-aminoethyl)-3-bromo-pyrazol-l-yl]acetic acid (1 g, 3.51 mmol, 1 eq, hydrochloride) in dichloromethane (20 mL) and isopropanol (20 mL) was added triethylamine (1.78 g, 17.57 mmol, 2.45 mL, 5 eq}. The mixture was stirred at 30°C for 10 min. tert-butyl 4-oxopiperidine-l -carboxylate (1.40 g, 7.03 mmol, 2 eq was added, and then the mixture was stirred at 30°C for 20 min. Sodium tri acetoxyb orohydri de (1.49 g, 7.03 mmol, 2 eq} was added and the mixture was stirred at 30°C for another 12 hours. The reaction mixture was concentrated. The residue was purified by prep-HPLC (column: Kromasil Eternity XT 250*80mm*10 pm; mobile phase: [water(10mM NH4HCO3)- ACN];B%: 15%-35%,18min) to give 2-[3-bromo-5-[2-[(l-tert-butoxycarbonyl-4- piperidyl)amino]ethyl]pyrazol-l-yl]acetic acid (800 mg, 1.85 mmol, 52.77% yield) as a white solid. LCMS: MS (ESI) m / z 433.1 [M+2]+.

[0673] Step 7: Preparation of tert-butyl 4-(2-bromo-7-oxo-5,8-dihydro-4H- pyrazolo[l,5- d][l,4]diazepin-6-yl)piperidine-l-carboxylate

[0674] To a solution of 2-[3-bromo-5-[2-[(l-tert-butoxycarbonyl-4-piperidyl)amino]ethyl]pyrazol-l- yl]acetic acid (1.2 g, 2.78 mmol, 1 eq in N,N-dimethylformamide (30 mL) was added 2-(3H- [l,2,3]triazolo[4,5-b]pyridin-3-yl)-l,l,3,3-tetramethylisouronium hexafluorophosphate(V) (2.12 g, 5.56 mmol, 2 eq) and diisopropylethylamine (1.80 g, 13.91 mmol, 2.42 mL, 5 eq .The mixture was stirred at 15 °C for 0.5 hour. The reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (40 mL x 3). The combined organic phase was washed with saturated brine (50 mL x 2), dried with anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® silica flash column, eluent of 0~3% dichloromethane : methanol gradient @ 50 mL / min) to give tert-butyl 4-(2-bromo-7-oxo-5,8-dihydro-4H-pyrazolo[l,5- d][l,4]diazepin-6-yl)piperidine-l-carboxylate (850 mg, 2.06 mmol, 73% yield) as a light yellow solid. LCMS: MS (ESI) m / z 357.2 [M-56]+. ’H NMR: (400MHz, DMSO-t / 6) d: 6.25 (s, 1H), 5.03 (s, 2H), 4.37 - 4.27 (m, 1H), 4.10 - 3.95 (m, 2H), 3.85 - 3.75 (m, 2H), 3.69 - 3.55 (m, 1H), 3.19 - 3.08 (m, 1H), 2.99 - 2.91 (m, 2H), 1.68 - 1.49 (m, 4H), 1.43 - 1.39 (m, 9H).

[0675] Step 8: Preparation of tert-butyl 7-[3-[[6-(l -tert-butoxycarbonyl- 4-piperidyl)-7-oxo-5,8- dihydro-4H-pyrazolo[l,5-d][l,4]diazepin-2-yl]amino]-7-fluoro-6-isoquinolyl]-8-methyl-2,3- dihydropyrido[2,3-b][l,4]oxazine-l-carboxylate A mixture of tert-butyl 4-(2-bromo-7-oxo-5,8-dihydro-4H-pyrazolo[l,5-d][l,4]diazepin- 6- yl)piperidine-l -carboxylate (800 mg, 1.94 mmol, 1 eq , tert-butyl 7-(3-amino-7-fluoro-6- isoquinolyl)-8-methyl-2,3-dihydropyrido[2,3-b][l,4]oxazine-l-carboxylate (794 mg, 1.94 mmol, 1 eq) , [2-(2-aminophenyl)phenyl]-methylsulfonyloxy-palladium;ditert-butyl-[3,6- dimethoxy-2-(2,4,6-triisopropylphenyl)phenyl]phosphane (826 mg, 0.96 mmol, 0.5 eq) , ditert-butyl-[3,6-dimethoxy-2-(2,4,6-triisopropylphenyl)phenyl]phosphane (375 mg, 0.77 mmol, 0.4 eq and cesium carbonate (1.89 g, 5.81 mmol, 3 eq in dioxane (50 mL) and then the mixture was stirred at 130 °C for 2 hours under nitrogen atmosphere. The reaction mixture was diluted with water (80 mL) and extracted with ethyl acetate (40 mL x 2). The combined organic phase was washed with saturated brine (40 mL x 2), dried with anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® silica flash column, eluent of 0~5% dichloromethane: methanol gradient @ 60 mL / min) to give tert-butyl 7-[3-[[6-(l -tert- butoxycarbonyl-4-piperidyl)-7-oxo-5,8-dihydro-4H- pyrazolo[l,5-d][l,4]diazepin-2- yl]amino]-7-fluoro-6-isoquinolyl]-8-methyl-2,3-dihydropyrido[2,3-b][l,4]oxazine-l- carboxylate (500 mg, 0.67 mmol, 34% yield) as a yellow solid. LCMS: MS (ESI) m / z 743.2 [M+l]+.

[0676] Step 9: Preparation of 2-[[7-fluoro-6-(8-methyl-2,3-dihydro-lH- pyrido[2,3-b][l,4]oxazin- 7-yl)-3-isoquinolyl]amino]-6-(4-piperidyl)-5,8-dihydro-4H-pyrazolo[l,5-d][l,4]diazepin-7- one

[0677] To a solution of tert-butyl 7-[3-[[6-(l-tert-butoxycarbonyl-4-piperidyl)-7-oxo-5,8-dihydro- 4H-pyrazolo[l,5-d][l,4]diazepin-2-yl]amino]-7-fluoro-6-isoquinolyl]-8-methyl-2,3- dihydropyrido[2,3-b][l,4]oxazine-l-carboxylate (0.5 g, 0.67 mmol, 1 eq in dichloromethane (5 mL) was added 4 M hydrochloric acid in dioxane (5.00 mL). The mixture was stirred at 15 °C for 0.5 hour. The reaction mixture was concentrated to give 2-[[7-fluoro-6-(8-methyl-2,3- dihydro-lH- pyrido[2,3-b][l,4]oxazin-7-yl)-3-isoquinolyl]amino]-6-(4-piperidyl)-5,8- dihydro-4H-pyrazolo[l,5-d][l,4]diazepin-7-one (400 mg, crude, hydrochloride) as a yellow solid was used in the next step without further purification. LCMS: MS (ESI) m / r. 543.1 [M+l]+.

[0678] Step 10: Preparation of tert-butyl 4-[4-[2-[[7-fluoro-6-(8-methyl-2,3- dihydro-lH- pyrido[2,3-b][l,4]oxazin-7-yl)-3-isoquinolyl]anuno]-7-oxo-5,8-dihydro-4H-pyrazolo[l,5- d][l,4]diazepin-6-yl]-l -piperidyl]piperidine-l -carboxylate

[0679] To a solution of 2-[[7-fluoro-6-(8-methyl-2,3-dihydro-lH-pyrido[2,3-b][l,4]oxazin-7- yl)-3- isoquinolyl]amino]-6-(4-...

Claims

CLAIMSListing of Claims '.

1. A compound having the Formula I:or a pharmaceutically acceptable salt thereof, whereinR1, R3, and R4are each independently selected from hydrogen, halo, optionally substituted (Ci-C4)alkyl, optionally substituted (Ci-C4)alkoxy, cyano, hydroxyl, and optionally substituted (C3-Ce)cycloalkyl;R2is selected from an optionally substituted 5- to 7-membered heteroaryl and an optionally substituted 9- to 11 -membered heterocyclyl;RNis selected from hydrogen and (Ci-C4)alkyl;L is a chemical linker;R5is represented by the chemical structure:wherein:W is CH2, CHRV, or C(O);Y and Y1are each independently N, CH, or CRy;Q1, Q2, Q3, Q4, Q5, T1, T2, T3, T4, and T5are each independently CH, CRW, or N;Z1and Z2are each independently CH, CRXor N;V is absent or is NRnor C(O)NRZ;V1is absent or (Ci-C4)alkylene;R6and R7are each independently hydrogen or optionally substituted (Ci-C4)alkyl;Rv, Rw, Ry, and Rxare each independently selected from halo, optionally substituted (Ci-C4)alkyl, optionally substituted (Ci-C4)alkoxy, cyano, OH, -NH(optionally substituted (Ci-C4)alkyl), and -NH(optionally substituted (Ci-C4)alkyl)2; andRnand Rzare each independently hydrogen or optionally substituted (Ci-Ce)alkyl, optionally substituted cycloalkyl, or optionally substituted heterocyclyl, whereinindicates the part of the structure to which the chemical linking moiety (L) is attached.

2. The compound of claim 1, wherein the compound has the structural Formula (IA) or (IB):or a pharmaceutically acceptable salt thereof.

3. The compound of claim 1 or 2, wherein RNis hydrogen or CH3.

4. The compound of claim 3, wherein RNis hydrogen.

5. The compound of any one of claims 1 to 4, wherein R1, R3, and R4are each independently selected from hydrogen, halo, (Ci-C4)alkyl, halo(Ci-C4)alkyl, (Ci-C4)alkoxy, halo(Ci-C4)alkoxy, hydroxyl, cyano, and Cs-Cejcycloalkyl.

6. The compound of any one of claims 1 to 4, wherein R1, R3, and R4are each independently selected from hydrogen, halo, and (Ci-C4)alkyl.

7. The compound of any one of claims 1 to 4, wherein R1, R3, and R4are each hydrogen.

8. The compound of any one of claims 1 to 4, wherein R1is halo and R3and R4are each hydrogen.

9. The compound of claim 8, wherein R1is fluoro or chloro and R3and R4are each hydrogen.

10. The compound of any one of claims 1 to 4, wherein R3is halo and R1and R4are each hydrogen.

11. The compound of claim 10, wherein R3is chloro and R1and R4are each hydrogen.

12. The compound of any one of claims 1 to 4, wherein R1and R3are each halo and R4is hydrogen.

13. The compound of claim 12, wherein R3is chloro, R1is fluoro, and R4is hydrogen.

14. The compound of any one of claims 1 to 4, wherein R1is halo, R4is (Ci-C4)alkyl, and R3is hydrogen.

15. The compound of claim 14, wherein R1is fluoro, R4is methyl, and R3is hydrogen.

16. The compound of any one of claims 1 to 4, wherein R1is halo, R3is (Ci-C4)alkyl, and R4is hydrogen.

17. The compound of claim 16, wherein R1is fluoro or chloro, R3is methyl, and R4is hydrogen.

18. The compound of any one of claims 1 to 17, wherein R2is selected from a 5- to 7- membered heteroaryl and a 9- to 11 -membered heterocyclyl, each of which are optionally substituted with 1 to 3 groups selected from RA, wherein RAis selected from halo, (Ci- C4)alkyl, halo(Ci-C4)alkyl, (Ci-C4)alkoxy, halo(Ci-C4)alkoxy, cyano, hydroxyl, oxo, and (C3-C6)cycloalkyl.

19. The compound of any one of claims 1 to 18, wherein R2is selected from a 5- to 6- membered nitrogen containing heteroaryl and a 10- to 11 -membered nitrogen containing heterocyclyl, each of which are optionally substituted with 1 to 3 groups selected from RA, wherein RAis selected from halo, (Ci-C4)alkyl, halo(Ci-C4)alkyl, (Ci-C4)alkoxy, halo(Ci- C4)alkoxy, cyano, hydroxyl, oxo, and (C3-C6)cycloalkyl.

20. The compound of any one of claims 1 to 19, wherein R2is selected from pyridinyl, triazolyl, pyrimidinyl, pyridazinyl, dihydropyrido[2,3-b][l,4]oxazinyl, tetrahydropyrido[2,3- b][l,4]oxazepinyl, and dihydro-2H-pyrano[2,3-b]pyridinyl, each of which are optionally substituted with 1 to 3 groups selected from RA, wherein RAis selected from halo, (Ci- C4)alkyl, halo(Ci-C4)alkyl, (Ci-C4)alkoxy, halo(Ci-C4)alkoxy, cyano, hydroxyl, oxo, and (C3-C6)cycloalkyl.

21. The compound of any one of claims 1 to 20, wherein R2is selected fromeach of which are optionally substituted with 1 to 3 groups selected from RA, wherein RAis selected from halo, (Ci-C4)alkyl, halo(Ci-C4)alkyl, (Ci-C4)alkoxy, halo(Ci-C4)alkoxy, cyano, hydroxyl, oxo, and (Cs-Cejcycloalkyl.

22. The compound of any one of claims 18 to 21, wherein RAis selected from (Ci- C4)alkyl, (Ci-C4)alkoxy, hydroxyl, and oxo.

23. The compound of any one of claims 1 to 22, wherein R2is selected from24. The compound of any one of claims 1 to 23, wherein R5is represented by the chemical structure:(Em).

25. The compound of any one of claims 1 to 24, wherein Q1, Q2, Q3, and Q4are each CH for the chemical structure En.

26. The compound of any one of claims 1 to 24, wherein Q1, Q2, Q3, and Q4are each CH for the chemical structure Em.

27. The compound of any one of claims 1 to 24 or 26, wherein Q5is CH for the chemical structure Em.

28. The compound of any one of claims 1 to 27, wherein R6is hydrogen or (Ci-C4)alkyl.

29. The compound of any one of claims 1 to 28, wherein V is C(O)NH.

30. The compound of any one of claims 1 to 29, wherein R7is (Ci-C4)alkyl.

31. The compound of any one of claims 1 to 30, wherein Y is CH.

32. The compound of any one of claims 1 to 31, wherein Rvis (Ci-C4)alkyl.

33. The compound of any one of claims 1 to 32, wherein Rwis halo, (Ci-C4)alkyl, or (Ci-C4)alkoxy.

34. The compound of any one of claims 1 to 33, wherein R5is selected from35. The compound of any one of claims 1 to 34, wherein the chemical linking moiety (L) is represented by the chemical structure:wherein:YL1, YL2, YL3, YM, and YL5are each independently absent or selected from O, NH, - N(Ci-C4)alkyl, and an optionally substituted (Ci-Ce)alkylene, wherein said (Ci-Ce)alkylene may also be optionally interrupted by one or more -C=C-, O, NH, and -N(Ci-C4)alkyl, and wherein two hydrogens on the same carbon of said (Ci-Ce)alkylene may be taken together to form oxo; andWL1, WL2, WL3, and WMare each independently selected from phenyl, heterocyclyl, heteroaryl, and cycloalkyl, each of which are optionally substituted.

36. The compound of claim 35, wherein YL1is absent or is (Ci-C4)alkylene optionally interrupted by one or two O, and wherein two hydrogens on the same carbon of said (Ci- Ce)alkylene may be taken together to form oxo.

37. The compound of claim 35 or 36, wherein WL1is an optionally substituted 5- to 6- membered monocyclic heterocyclyl or 6- to 12- membered bicyclic heterocyclyl.

38. The compound of claim 37, wherein WL1is 5,6-dihydro-4H-pyrazolo[l,5- d][l,4]diazepin-7(8H)-onyl, 7-azaspiro[3.5]nonanyl, 2-azaspiro[3.3]heptanyl, 3- azabicyclo[3.1.0]hexanyl, 2-azaspiro[3.5]nonanyl, piperdinyl, or 3-azaspiro[5.5]undecanyl, each of which is optionally substituted with halo or -CH3.

39. The compound of any one of claims 35 to 38, wherein YL2is absent or is (Ci- C4)alkylene.

40. The compound of any one of claims 35 to 39, wherein WL2is an optionally substituted Cs-ecyloalkyl, 4- to 6-membered monocyclic heterocyclyl or 6- to 10- membered bicyclic heterocyclyl.

41. The compound of claim 40, wherein WL2is piperdinyl, azetidinyl, 2- azaspiro[3.3]heptanyl, 2-azaspiro[3.5]nonanyl, or cyclohexyl.

42. The compound of any one of claims 35 to 41, wherein YL3is absent, O, or (Ci- C4)alkylene optionally interrupted by one or two O or -C=C-, and wherein two hydrogens on the same carbon of said (Ci-Ce)alkylene may be taken together to form oxo.

43. The compound of any one of claims 35 to 42, wherein WL3is an optionally substituted Cs-ecyloalkyl, 4- to 6-membered monocyclic heterocyclyl or 6- to 12- membered bicyclic heterocyclyl.

44. The compound of claim 43, wherein WL3is piperidinyl, azetidinyl, piperazinyl, 3- azaspiro[5.5]undecanyl, or cyclobutyl, each of which is optionally substituted with halo or - OH.

45. The compound of any one of claims 35 to 44, wherein YL4is absent, O, or (Ci-C4)alkylene.

46. The compound of any one of claims 35 to 45, wherein WL4is an optionally substituted 4- to 6-membered monocyclic heterocyclyl.

47. The compound of claim 46, wherein WMis piperidinyl.

48. The compound of any one of claims 35 to 47, wherein YL5is absent.

50. The compound of claim 1, wherein the compound is selected from the compounds in Table 1, or a pharmaceutically acceptable salt thereof.

51. A pharmaceutical composition comprising a compound of any one of claims 1 to 50, and a pharmaceutically acceptable carrier.

52. A method of treating a disease or disorder responsive to the modulation of HPK1, comprising administering to a subject an effective amount of a compound of any one of claims 1 to 50.

53. The method of claim 52, wherein the disease or disorder is a cancer.

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