Synthesis of leucine-rich repeat kinase 2 modulators

Abstract

Provided are methods for synthesizing compounds having activity against Leucine- rich repeat kinase 2 (LRRK2), as well as intermediates generated during said methods.

Description

[0001] 137508-02320 SYNTHESIS OF LEUCINE-RICH REPEAT KINASE 2 MODULATORS RELATED APPLICATIONS

[0001] This application claims priority to U.S. Provisional Application No.63 / 607,284, filed on December 7, 2023. The entire contents of the foregoing application are expressly incorporated herein by reference. BACKGROUND

[0002] Leucine-rich repeat kinase 2 (LRRK2) is a member of the leucine-rich repeat kinase family and is a large multi-domain protein with an N-terminal armadillo domain, ankryin repeat region, a leucine-rich repeat (LRR) domain, a tandem Roco type GTPase domain, a kinase domain containing a DFG-like motif, and a C-terminal WD40 domain. Increased activity of LRKK2 has been shown to be linked to various diseases, such as Parkinson’s Disease (PD), LRRK2 mutation associated PD (e.g., PD associated with one or more LRRK2 activating mutations), primary tauopathies (e.g., supranuclear palsy (PSP) or corticobasal degeneration (CBD)), lewy body dementia, Crohn’s Disease, Leprosy (e.g., Leprosy with type 1 inflammatory reactions), and / or neuroinflammation.

[0003] Compounds having LRRK2 degradation activity have been previously described (see e.g., WO 2021 / 194879 and WO 2022 / 198112) and are believed to be useful for treating, preventing, or ameliorating the diseases associated with LRRK2. To facilitate further studies, alternative methods for preparing such compounds are needed. SUMMARY

[0004] Provided are methods for synthesizing compounds, including those having activity against LRRK2, as well as intermediates generated during said methods.

[0005] Accordingly, provided herein are methods of preparing a compound of Formula I: 1 ME151383177v.1 137508-02320

[0006] Also provided herein are methods of preparing a compound of Formula (I’): or a salt thereof.

[0007] Also provided herein are methods of preparing a compound of Formula (V):

[0008] Also provided herein are methods of preparing compounds of Formula (Ia): wherein: X1, X2, X3, and X4are each N or CRX; each RXis, independently, H, halo, C1-3alkyl, C1-3haloalkyl, -ORXa, -NRXaRXb, - C(O)H, -C(O)OH, -C(O)ORXa, or -C(O)NRXaRXb; RXaand RXbare each, independently, H, halo, C1-3alkyl, C1-3haloalkyl, or C3-6cycloalkyl; R1is a protecting group; Z is a bond or -CH2-; Ring A and Ring B are each, independently, 4- to 12-membered heterocyclyl; each RAand RBis, independently, halo, C1-3alkyl, C1-3haloalkyl, -ORA1, -NRA1RA1, - C(O)H, -C(O)OH, -C(O)ORA1, or –C(O)NRA1RA1; each RA1is, independently, H, halo, C1-4alkyl, C1-3haloalkyl, or C3-6cycloalkyl; 2 ME151383177v.1 137508-02320 each R4is, independently, halo, C1-3alkyl, C1-3haloalkyl, -OR4a, -NR4aR4b, -C(O)H, - C(O)OH, -C(O)OR4a, or –C(O)NR4aR4b; R4aand R4bare each, independently, H, halo, C1-3alkyl, C1-3haloalkyl, or C3-6cycloalkyl, wherein the C3-6cycloalkyl is optionally substituted by C1-3alkyl; and n, o, and p are each, independently, 0, 1, 2, 3, or 4.

[0009] Also provided herein are methods of preparing compounds of Formula (Ia’): wherein: X1, X2, X3, and X4are each N or CRX; each RXis, independently, H, halo, C1-3alkyl, C1-3haloalkyl, -ORXa, -NRXaRXb, - C(O)H, -C(O)OH, -C(O)ORXa, or -C(O)NRXaRXb; RXaand RXbare each, independently, H, halo, C1-3alkyl, C1-3haloalkyl, or C3-6cycloalkyl; Z is a bond or -CH2-; Ring A and Ring B are each, independently, 4- to 12-membered heterocyclyl; each RAand RBis, independently, halo, C1-3alkyl, C1-3haloalkyl, -ORA1, -NRA1RA1, - C(O)H, -C(O)OH, -C(O)ORA1, or –C(O)NRA1RA1; each RA1is, independently, H, halo, C1-4alkyl, C1-3haloalkyl, or C3-6cycloalkyl; each R4is, independently, halo, C1-3alkyl, C1-3haloalkyl, -OR4a, -NR4aR4b, -C(O)H, - C(O)OH, -C(O)OR4a, or -C(O)NR4aR4b; R4aand R4bare each, independently, H, halo, C1-3alkyl, C1-3haloalkyl, or C3-6cycloalkyl, wherein the C3-6cycloalkyl is optionally substituted by C1-3alkyl; and n, o, and p are each, independently, 0, 1, 2, 3, or 4.

[0010] Also provided herein are methods of preparing compounds of Formula (Va’): wherein: 3 ME151383177v.1 137508-02320 X1, X2, X3, and X4are each N or CRX; each RXis, independently, H, halo, C1-3alkyl, C1-3haloalkyl, -ORXa, -NRXaRXb, - C(O)H, -C(O)OH, -C(O)ORXa, or -C(O)NRXaRXb; RXaand RXbare each, independently, H, halo, C1-3alkyl, C1-3haloalkyl, or C3-6cycloalkyl; Z is a bond or –CH2-; Ring A and Ring B are each, independently, 4- to 12-membered heterocyclyl; each RAand RBis, independently, halo, C1-3alkyl, C1-3haloalkyl, -ORA, -NRARA, - C(O)H, -C(O)OH, -C(O)ORA, or –C(O)NRARA; each RAis, independently, H, halo, C1-4alkyl, C1-3haloalkyl, or C3-6cycloalkyl; each R4is, independently, halo, C1-3alkyl, C1-3haloalkyl, -OR4a, -NR4aR4b, -C(O)H, -C(O)OH, -C(O)OR4a, or -C(O)NR4aR4b; R4aand R4bare each, independently, H, halo, C1-3alkyl, C1-3haloalkyl, or C3-6cycloalkyl, wherein the C3-6cycloalkyl is optionally substituted by C1-3alkyl; n, o, and p are each, independently, 0, 1, 2, 3, or 4; Ring C, Ring D, and Ring E are each, independently, 4- to 12-membered heterocyclyl; each RC, RD, and REis, independently, halo, C1-3alkyl, C1-3haloalkyl, -ORC, -NRCRC, -C(O)H, -C(O)OH, -C(O)ORC, oxo, or –C(O)NRCRC; each RCis, independently, H, halo, C1-4alkyl, or C1-3haloalkyl; q, r, and s are each, independently, 0, 1, 2, 3, or 4.

[0011] Also provided herein are alternative synthetic procedures for the materials needed for the synthesis of the compounds of Formula (I) or (I’). DETAILED DESCRIPTION

[0012] Compounds having LRRK2 degradation activity have been previously described (see e.g., WO 2021 / 194879 and WO 2022 / 198112) and are believed to be useful for treating, preventing, or ameliorating the diseases associated with LRRK2 (e.g., idiopathic Parkinson’s Disease (PD), LRRK2 mutation-associated Parkinson’s Disease (PD), supranuclear palsy (PSP), corticobasal degeneration (CBD), lewy body dementia, Crohn’s Disease, Leprosy with type 1 inflammatory reactions, neuroinflammation, Kennedy’s disease, TDP-43 ALS, c9orf ALS, Huntington’s disease, Alzheimer’s disease, Picks disease, multiple systems atrophy, systemic lupus erythematosus (SLE), acute kidney injury, rhabdomyolysis, lipofusinosis, fabry’s disease, batten’s disease, ulcerative colitis, irritable bowel disease, Kufor–Rakeb syndrome, gaucher Disease, Frontal Temporal Dementia, spinocerebellar ataxias (SCAs) 1, 2, 4 ME151383177v.1 137508-02320 3, 6, 7 and 17, and / or dentatorubral pallidoluysian atrophy (DRPLA)). Provided are methods for synthesizing compounds having activity against LRRK2 as well as intermediates generated during said methods.

[0013] Definitions

[0014] 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.

[0015] 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).

[0016] 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).

[0017] The term “palladium source” refers to a chemical compound which comprises palladium, either alone or in combination with one or more elements.

[0018] The term “base” refers to a (1) chemical compound with an electron pair which is not involved in bonding and can be used to form a dative bond; (2) a chemical compound which dissociates in an aqueous solution to provide hydroxide (-OH) ions; and / or (3) a chemical compound which can accept hydrogen cations (H+). The term “base” comprises both organic and inorganic bases. Examples of bases include, but are not limited to n-butyl lithium, t-butyl lithium, LDA, K2CO3, Sodium tert-butoxide, Cs2CO3, KOH, NaOH, CsF, NaOAc, trimethylamine, N,N-diisopropylethylamine, 1,8-diazabicyclo(5.4.0)undec-7-ene (DBU), 1,5- diazabicyclo[4.3.0]non-5-ene (DBN), guanidine, 1,1,3,3-tetramethylguanidine, optionally substituted pyridine, N-methylmorpholine, and 1,4-diazabicyclo[2.2.2]-octane (DABCO).

[0019] The term “inorganic base” refers to a base comprising at least one inorganic element. Examples of inorganic bases include, but are not limited to K2CO3, Sodium tert-butoxide, Cs2CO3, KOH, NaOH, CsF, and NaOAc. 5 ME151383177v.1 137508-02320

[0020] The term “organic base” refers to a base comprising all organic elements. Examples of organic bases include, but are not limited to trimethylamine, N,N-diisopropylethylamine, 1,8-diazabicyclo(5.4.0)undec-7-ene (DBU), 1,5-diazabicyclo[4.3.0]non-5-ene (DBN), guanidine, 1,1,3,3-tetramethylguanidine, optionally substituted pyridine, N- methylmorpholine, and 1,4-diazabicyclo[2.2.2]-octane (DABCO).

[0021] The term “acid” refers to a (1) chemical compound with an empty orbital that can be used to form a dative bond; (2) a chemical compound which dissociates in an aqueous solution to provide hydrogen cations (H+); and / or (3) a chemical compound which can donate hydrogen cations (H+). Examples of acids include, but are not limited to HF, HCl, HBr, HI, HCN, H3BO3, H3PO4, H2SO3, H2SO4, HClO4, HNO3, H2C2O4, HIO4, CH3C(O)OH, C5H5NH+, HN+(CH2CH3)3, and HN+(CH2CH3)(CH(CH3)2)2.

[0022] The term “reducing agent” refers to a chemical compound which donates one or more electrons to a second chemical compound. Examples of reducing agents include, but are not limited to NaBH(OAc)3, NaCNBH3, NaBH4, BH3 · NCH3, and 2-methylpyridine borane.

[0023] The term “solvent” refers to a substance which a chemical compound is either dissolved in to form a solution or suspended in to form a suspension.

[0024] The term “organic solvent” refers to a solvent comprising all organic elements.

[0025] 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., C1–C6for straight chains, C3–C6for branched chains), and more preferably four or less carbons in its backbone.

[0026] The term “alkoxy” refers to an alkyl group having an oxygen attached thereto, represented by -O-alkyl. For example, “C1–C4alkoxy” includes methoxy, ethoxy, propoxy, isopropoxy, and butoxy.

[0027] 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 C1–C6alkyl group, for example, contains from one to six carbon atoms in the chain; a C1–C4-alkyl contains from one to four carbon atoms in the chain.

[0028] 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 (-Cl), bromo(-Br), and iodo (-I) substituent groups.

[0029] The terms “haloalkyl” and “haloalkoxy” refer to alkyl or alkoxy, respectively, substituted with one or more halogen atoms. 6 ME151383177v.1 137508-02320

[0030] The term “oxo” refers to an oxygen atom which is connected to a carbon atom via a double bond (=O).

[0031] 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.

[0032] 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][1,4]oxazinyl, tetrahydropyrido[2,3- b][1,4]oxazepinyl, dihydro-2H-pyrano[2,3-b]pyridinyl, 5,6-dihydro-4H-pyrazolo[1,5- d][1,4]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). 7 ME151383177v.1 137508-02320

[0033] The term “spiro” refers to two rings that shares one ring atom (e.g., carbon).

[0034] The term “fused” refers to two rings that share two adjacent ring atoms with one another.

[0035] The term “bridged” refers to two rings that share three adjacent ring atoms with one another.

[0036] The term “group I element” refers to elements in the group I column of the periodic table. Group I elements are also called alkali metals and include the elements Li, Na, K, Rb, Cs, and Fr.

[0037] The term “protecting group” refers to a substituent that is commonly employed to block or protect a particular functionality while reacting other functional groups on the compound, a derivative thereof, or a conjugate thereof. Protecting groups are also well known in the art (see for example P. Wuts and T. Greene, 2007, Protective Groups in Organic Synthesis, Chapter 7, J. Wiley & Sons, NJ). Examples of protecting groups include, but are not limited to tetrohydropyranyl (THP), benzyl, acetyl, benzoyl, methoxyethoxymethyl ether (MEM), methoxymethyl ether (MOMO, trimethylsilyl ether (TMS) tert-butyldimethylsilyl ether (TBDMS), tert-butoxycarbonyl (Boc), 2,2,2-trichloroethyloxycarbonyl (Troc), benzyloxycarbonyl (Cbz), 9- fluorenylmethoxycarbonyl (Fmoc), methylsulfonyl, p- toluenesulfonyl (Tos), 4- nitrobenzenesulfonyl (NOSyl), 2-nitrobenzenesulfonyl, p- bromobenzenesulfonyl (Brosyl), trifluoroacetyl, acetyl, benzoyl, 2-trimethylsilylethyl, (2- phenyl-2-trimethylsilyl)ethyl, triisopropylsiloxy, 2-(trimethylsilyl)ethoxymethyl, allyloxycarbonyl, and 2- (trimethylsilyl)ethoxycarbonyl.

[0038] The term “ligand” refers to an element or chemical compound which coordinates to a metal ion to form a complex.

[0039] The term “complex” refers to a chemical compound comprising one or more coordinated ligands and one or more metals.

[0040] 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 8 ME151383177v.1 137508-02320 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.

[0041] Salts of the compounds described herein refer to “salts thereof.” Salt forms include pharmaceutically acceptable acidic / anionic or basic / cationic salts. Suitable 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 salts with base(s). Suitable 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.

[0042] In embodiments, provided herein is a method of preparing a compound of Formula (I): the method comprising: 9 ME151383177v.1 137508-02320 reacting a compound of Formula (II): with a compound of Formula (III): and a palladium source in the presence of a base.

[0043] In embodiments, for the method of preparing a compound of Formula (I), the palladium source is a complex comprising palladium optionally substituted with one or more ligands. In embodiments, for the method of preparing a compound of Formula (I), the ligands are independently selected from PPh3, P(o-tolyl)3, Pt-Bu3, Pt-Bu3· HBF4, PCy3, n-BuP(Ad)2, BINAP, Xantphos, DPEPhos, CyPFt-Bu, dppp, dppf, dtbpf, JohnPhos, CyJohnPhos, DavePhos, RuPhos, SPhos, XPhox, BrettPhos, t-BuXPhos, t-BuBrettPhos, Me4t-BuXPhos, BippyPhos, MorDalPhos, and IPr · HCl. In embodiments, for the method of preparing a compound of Formula (I), the palladium source is Pd(dppf)Cl2.

[0044] In embodiments, for the method of preparing a compound of Formula (I), the base is an inorganic base. In embodiments, for the method of preparing a compound of Formula (I), the base is K2CO3.

[0045] In embodiments, for the method of preparing a compound of Formula (I), the base is an organic base. In embodiments, for the method of preparing a compound of Formula (I), the base is selected from NH2(C1-6alkyl), NH(C1-6alkyl)2,N(C1-6alkyl)3, a phosphazene, 1,8- diazabicyclo(5.4.0)undec-7-ene (DBU), 1,5-diazabicyclo[4.3.0]non-5-ene (DBN), guanidine, 1,1,3,3-tetramethylguanidine, optionally substituted pyridine, N-methylmorpholine, and 1,4- diazabicyclo[2.2.2]-octane (DABCO), wherein each C1-6 alkyl of the NH(C1-6 alkyl)2 and N(C1-6alkyl)3is independently selected.

[0046] In embodiments, for the method of preparing a compound of Formula (I), the reaction is performed in the presence of a solvent. In embodiments, for the method of preparing a 10 ME151383177v.1 137508-02320 compound of Formula (I), the solvent is a mixture of an organic solvent and water. In embodiments, for the method of preparing a compound of Formula (I), the solvent is a mixture of dioxane and water.

[0047] In embodiments, for the method of preparing a compound of Formula (I), the method further comprises reacting the compound of Formula I with acid to form a compound of Formula (I’): or a salt thereof.

[0048] In embodiments, for the method of preparing a compound of Formula (I’), the acid is selected from HF, HCl, HBr, HI, HCN, H3BO3, H3PO4, H2SO3, H2SO4, HClO4, HNO3, H2C2O4, HIO4, CH3C(O)OH, C5H5NH+, and HN+(C1-6alkyl)4, wherein each C1-6alkyl of the HN+(C1-6alkyl)4is independently selected. In embodiments, for the method of preparing a compound of Formula (I’), the acid is HCl.

[0049] In embodiments, for the method of preparing a compound of Formula (I’), the salt is a mono-salt, a di-salt, tri-salt, tetra-salt, penta-salt, or hexa-salt. In embodiments, for the method of preparing a compound of Formula (I’), the salt is a tri-salt. In embodiments, for the method of preparing a compound of Formula (I’), the salt is an HCl salt. In embodiments, the salt is a tri-HCl salt.

[0050] In embodiments, for the method of preparing a compound of Formula (I’), the reaction is performed in the presence of a solvent. In embodiments, for the method of preparing a compound of Formula (I’), the solvent is a mixture of two organic solvents. In embodiments, for the method of preparing a compound of Formula (I’), the solvent is a mixture of Methanol (MeOH) and Ethyl Acetate (EtOAc).

[0051] In embodiments, for the method of preparing a compound of Formula (I), the method further comprises reacting the compound of Formula (I’) in the presence of a base and reducing agent with a compound of Formula (IV): 11 ME151383177v.1 137508-02320 to form a compound of Formula (V):

[0052] In embodiments, for the method of preparing a compound of Formula (V), the reducing agent comprised boron. In embodiments, for the method of preparing a compound of Formula (V), the reducing agent is selected from NaBH(OAc)3, NaCNBH3, NaBH4, BH3· NCH3, and 2-methylpyridine borane. In embodiments, for the method of preparing a compound of Formula (V), the reducing agent is NaBH(OAc)3.

[0053] In embodiments, for the method of preparing a compound of Formula (V), the base is an organic base. In embodiments, for the method of preparing a compound of Formula (V), the base is selected from NH2(C1-6 alkyl), NH(C1-6 alkyl)2, N(C1-6 alkyl)3, a phosphazene, 1,8- diazabicyclo(5.4.0)undec-7-ene (DBU), 1,5-diazabicyclo[4.3.0]non-5-ene (DBN), guanidine, 1,1,3,3-tetramethylguanidine, optionally substituted pyridine, N-methylmorpholine, and 1,4- diazabicyclo[2.2.2]-octane (DABCO), wherein each C1-6 alkyl of the NH(C1-6 alkyl)2 and N(C1-6 alkyl)3 is independently selected. In embodiments, for the method of preparing a compound of Formula (V), the base is N-methylmorpholine.

[0054] In embodiments, for the method of preparing a compound of Formula (V), the reaction is performed in the presence of a solvent. In embodiments, for the method of preparing a compound of Formula (V), the solvent is an organic solvent. In embodiments, for the method of preparing a compound of Formula (V), the solvent is dimethylformamide (DMF) or dimethylacetamide (DMA). In embodiments, for the method of preparing a compound of Formula (V), the solvent is dimethylacetamide (DMA). 12 ME151383177v.1 137508-02320

[0055] In embodiments, provided herein is a method of preparing a compound of Formula wherein: X1, X2, X3, and X4are each N or CRX; each RXis, independently, H, halo, C1-3alkyl, C1-3haloalkyl, -ORXa, -NRXaRXb, - C(O)H, -C(O)OH, -C(O)ORXa, or -C(O)NRXaRXb; RXaand RXbare each, independently, H, halo, C1-3alkyl, C1-3haloalkyl, or C3-6cycloalkyl; R1is a protecting group; Z is a bond or –CH2-; Ring A and Ring B are each, independently, 4- to 12-membered heterocyclyl; each RAand RBis, independently, halo, C1-3alkyl, C1-3haloalkyl, -ORA, -NRARA, - C(O)H, -C(O)OH, -C(O)ORA, or –C(O)NRARA; each RAis, independently, H, halo, C1-4alkyl, C1-3haloalkyl, or C3-6cycloalkyl; each R4is, independently, halo, C1-3alkyl, C1-3haloalkyl, -OR4a, -NR4aR4b, -C(O)H, -C(O)OH, -C(O)OR4a, or -C(O)NR4aR4b; R4aand R4bare each, independently, H, halo, C1-3alkyl, C1-3haloalkyl, or C3-6cycloalkyl, wherein the C3-6cycloalkyl is optionally substituted by C1-3alkyl; and n, o, and p are each, independently, 0, 1, 2, 3, or 4; the method comprising: reacting a compound of Formula (IIa) or (IIb): wherein: R1, R4, and n are as described for Formula (Ia) above; R2and R3are each, independently, H, OH, C1-4alkoxy; 13 ME151383177v.1 137508-02320 or R2and R3, together with the atom to which they are attached, form 5- to 12- membered heterocyclyl optionally substituted with 1 to 6 C1-3alkyl or oxo; R5, R6, and R7are each, independently halo or C1-4alkoxy; or R5, R6, and R7, together with the atom to which they are attached, form 8- to 12- membered heterocyclyl optionally substituted with 1 to 6 C1-3alkyl; and Y is a group I element; with a compound of Formula (IIIa): (IIIa), wherein X1, X2, X3, X4, Ring A, Ring B, Z, RA, RB, o, and p are as described for Formula (Ia) above; and T is halo; and a palladium source in the presence of a base.

[0056] In embodiments, for the method of preparing a compound of Formula (Ia), R1is selected from Fmoc, Boc, Cbz, THP, MOM, -C(CH3)3, -CH2CH=CH2, -Si(CH3)2C(CH3)3, - Si(phenyl)2C(CH3)3, -C(O)CH3, -C(O)CF3, -C(O)phenyl, -CH2-phenyl, -C(phenyl)3, and - SO2(4-methylphenyl).

[0057] In embodiments, for the method of preparing a compound of Formula (Ia), R1is THP.

[0058] In embodiments, for the method of preparing a compound of Formula (Ia), R2and R3are each OH; or R2and R3, together with the atom to which they are attached, form 5- to 12-membered heterocyclyl optionally with 1 to 4 C1-3alkyl or oxo.

[0059] In embodiments, for the method of preparing a compound of Formula (Ia), the compound of Formula (IIa) or Formula (IIb) is Formula (IIa-1), (IIa-2), (IIa-3), (IIa-4), (IIa- 5), (IIa-6), (IIa-7), (IIa-8), (IIa-9), (IIa-10), or (IIa-11): 14 ME151383177v.1 137508-02320

[0060] In embodiments, for the method of preparing a compound of Formula (Ia), the compound of Formula (IIa) is Formula (IIa-2).

[0061] In embodiments, for the method of preparing a compound of Formula (Ia), n is 1. 15 ME151383177v.1 137508-02320

[0062] In embodiments, for the method of preparing a compound of Formula (Ia), R4is – OR4aand R4ais C3-4cycloalkyl is optionally substituted by C1-3alkyl. In embodiments, for the method of preparing a compound of Formula (Ia), R4is .

[0063] In embodiments, for the method of preparing a compound of Formula (Ia), X1, X2, X3, and X4are each independently N or CH. In embodiments, for the method of preparing a compound of Formula (Ia), X1and X3are N and X2and X4are CH.

[0064] In embodiments, for the method of preparing a compound of Formula (Ia), Z is -CH2-.

[0065] In embodiments, for the method of preparing a compound of Formula (Ia), Ring A and Ring B are each 6-membered heterocyclyl.In embodiments, for the method of preparing a compound of Formula (Ia), Ring A and Ring B are each, independently, piperdinyl or piperazinyl.

[0066] In embodiments, for the method of preparing a compound of Formula (Ia), o is 0 and p is 0, 1, 2, or 3.

[0067] In embodiments, for the method of preparing a compound of Formula (Ia), each RBis, independently, C1-3alkyl or –C(O)OC1-4alkyl. In embodiments, for the method of preparing a compound of Formula (Ia), each RBis, independently, –CH3or –C(O)OC(CH3)3.

[0068] In embodiments, for the method of preparing a compound of Formula (Ia), T is -Cl.

[0069] In embodiments, for the method of preparing a compound of Formula (Ia),

[0070] In embodiments, for the method of preparing a compound of Formula (I), the palladium source is a complex comprising palladium optionally substituted with one or more ligands. In embodiments, for the method of preparing a compound of Formula (I), the ligands are independently selected from PPh3, P(o-tolyl)3, Pt-Bu3, Pt-Bu3· HBF4, PCy3, n-BuP(Ad)2, BINAP, Xantphos, DPEPhos, CyPFt-Bu, dppp, dppf, dtbpf, JohnPhos, CyJohnPhos, DavePhos, RuPhos, SPhos, XPhox, BrettPhos, t-BuXPhos, t-BuBrettPhos, Me4t-BuXPhos, BippyPhos, MorDalPhos, and IPr · HCl. In embodiments, for the method of preparing a compound of Formula (Ia), the palladium source is Pd(dppf)Cl2.

[0071] In embodiments, for the method of preparing a compound of Formula (Ia), the base is an inorganic base. In embodiments, for the method of preparing a compound of Formula (Ia), the base is K2CO3.

[0072] In embodiments, for the method of preparing a compound of Formula (Ia), the base is an organic base. In embodiments, for the method of preparing a compound of Formula (Ia), the base is selected from NH2(C1-6alkyl), NH(C1-6alkyl)2,N(C1-6alkyl)3, a phosphazene, 1,8- 16 ME151383177v.1 137508-02320 diazabicyclo(5.4.0)undec-7-ene (DBU), 1,5-diazabicyclo[4.3.0]non-5-ene (DBN), guanidine, 1,1,3,3-tetramethylguanidine, optionally substituted pyridine, N-methylmorpholine, and 1,4- diazabicyclo[2.2.2]-octane (DABCO), wherein each C1-6alkyl of the NH(C1-6alkyl)2and N(C1-6 alkyl)3 is independently selected.

[0073] In embodiments, for the method of preparing a compound of Formula (Ia), the reaction is performed in the presence of a solvent. In embodiments, for the method of preparing a compound of Formula (Ia), the solvent is a mixture of an organic solvent and water.In embodiments, for the method of preparing a compound of Formula (Ia), the solvent is a mixture of dioxane and water.

[0074] In embodiments, for the method of preparing a compound of Formula (Ia), the method further comprises reacting the compound of Formula I with acid to form a compound of Formula (Ia’): wherein the variables are as defined for Formula (Ia) above.

[0075] In embodiments, for the method of preparing a compound of Formula (Ia’), the acid is selected from HF, HCl, HBr, HI, HCN, H3BO3, H3PO4, H2SO3, H2SO4, HClO4, HNO3, H2C2O4, HIO4, CH3C(O)OH, C5H5NH+, and HN+(C1-6alkyl)4, wherein each C1-6alkyl of the HN+(C1-6alkyl)4 is independently selected. In embodiments, for the method of preparing a compound of Formula (Ia’), the acid is HCl.

[0076] In embodiments, for the method of preparing a compound of Formula (Ia’), the reaction is performed in the presence of a solvent. In embodiments, for the method of preparing a compound of Formula (Ia’), the solvent is a mixture of two organic solvents.

[0077] In embodiments, for the method of preparing a compound of Formula (Ia’), the solvent is a mixture of Methanol (MeOH) and Ethyl Acetate (EtOAc).

[0078] In embodiments, for the method of preparing a compound of Formula (Ia), the method further comprises reacting the compound of Formula (Ia’) in the presence of a base and reducing agent with a compound of Formula (IVa): 17 ME151383177v.1 137508-02320 wherein: Ring C, Ring D, and Ring E are each, independently, 4- to 12-membered heterocyclyl; each RC, RD, and REis, independently, halo, C1-3alkyl, C1-3haloalkyl, -ORC, -NRCRC, - C(O)H, -C(O)OH, -C(O)ORC, oxo, or –C(O)NRCRC; each RCis, independently, H, halo, C1-4alkyl, or C1-3haloalkyl; q, r, and s are each, independently, 0, 1, 2, 3, or 4; to form a compound of Formula (Va): wherein the variables Ring C, Ring D, Ring E, RC, RD, RE, q, r, and s are as defined in Formula (IVa) above.

[0079] In embodiments, for the method of preparing a compound of Formula (Va), Ring C, Ring D, and Ring E are each, independently, a 5-or 6-membered monocyclic heterocyclyl or a 9- or 10-membered bicyclic heterocyclyl. In embodiments, for the method of preparing a compound of Formula (Va), Ring C, Ring D, and Ring E are each, independently, piperdinyl or isoindolinyl.

[0080] In embodiments, for the method of preparing a compound of Formula (Va), q is 0 or 1 and r and s are each, independently, 0, 1, or 2.

[0081] In embodiments, for the method of preparing a compound of Formula (Va), each RC, RD, and REare, independently, halo and oxo.

[0082] In embodiments, for the method of preparing a compound of Formula (Va), the reducing agent comprised boron. In embodiments, for the method of preparing a compound of Formula (Va), the reducing agent is selected from NaBH(OAc)3, NaCNBH3, NaBH4, BH3· NCH3, and 2-methylpyridine borane. In embodiments, for the method of preparing a compound of Formula (Va), the reducing agent is NaBH(OAc)3. 18 ME151383177v.1 137508-02320

[0083] In embodiments, for the method of preparing a compound of Formula (Va), the base is an organic base. In embodiments, for the method of preparing a compound of Formula (Va), the base is selected from NH2(C1-6alkyl), NH(C1-6alkyl)2,N(C1-6alkyl)3, a phosphazene, 1,8-diazabicyclo(5.4.0)undec-7-ene (DBU), 1,5-diazabicyclo[4.3.0]non-5-ene (DBN), guanidine, 1,1,3,3-tetramethylguanidine, optionally substituted pyridine, N- methylmorpholine, and 1,4-diazabicyclo[2.2.2]-octane (DABCO), wherein each C1-6alkyl of the NH(C1-6alkyl)2and N(C1-6alkyl)3is independently selected. In embodiments, for the method of preparing a compound of Formula (Va), the base is N-methylmorpholine.

[0084] In embodiments, for the method of preparing a compound of Formula (Va), the reaction is performed in the presence of a solvent. In embodiments, for the method of preparing a compound of Formula (Va), the solvent is an organic solvent.

[0085] In embodiments, for the method of preparing a compound of Formula (Va), the solvent is dimethylformamide (DMF) or dimethylacetamide (DMA). In embodiments, for the method of preparing a compound of Formula (Va), the solvent is dimethylacetamide (DMA).

[0086] In embodiments, provided herein is a method of preparing a compound of Formula (XIII): or a salt thereof, the method comprising: reacting a compound of Formula (XVI): or a salt thereof, with CH2X2 and a catalyst, wherein each X is independently halo.

[0087] In embodiments, for the method of preparing a compound of Formula (XIII), both X are the same halo. In embodiments, for the method of preparing a compound of Formula (XIII), CH2X2 is CH2I2.

[0088] In embodiments, for the method of preparing a compound of Formula (XIII), the catalyst is a metal catalyst. In embodiments, for the method of preparing a compound of Formula (XIII), the catalyst is an aluminum or zinc catalyst. In embodiments, for the method 19 ME151383177v.1 137508-02320 of preparing a compound of Formula (XIII), the catalyst is ZnEt2, i-Bu3Al, or n-Oct3Al. In embodiments, for the method of preparing a compound of Formula (XIII), the catalyst is ZnEt2.

[0089] In embodiments, for the method of preparing a compound of Formula (XIII), the reacting step is performed in the presence of a solvent. In embodiments, for the method of preparing a compound of Formula (XIII), the solvent is an organic solvent. In embodiments, for the method of preparing a compound of Formula (XIII), the solvent is trifluorotoluene.

[0090] In embodiments, for the method of preparing a compound of Formula (XIII), the method further comprises the addition of an acid. In embodiments, for the method of preparing a compound of Formula (XIII), the acid is an organic acid. In embodiments, for the method of preparing a compound of Formula (XIII), the acid is trichloroacetic acid, trifluoroacetic acid, acetic acid, or formic acid. In embodiments, for the method of preparing a compound of Formula (XIII), the acid is trichloroacetic acid.

[0091] In embodiments, provided herein is a method of preparing a compound of Formula (XVI): or a salt thereof, the method comprising reacting a compound of Formula (XIV): or a salt thereof, with pentane-2,4-dione, a base, a catalyst, and a compound of Formula (XV): or a salt thereof, wherein X1is halo.

[0092] In embodiments, for the method of preparing a compound of Formula (XVI), X1is Br, Cl, or I. In embodiments, for the method of preparing a compound of Formula (XVI), X1is Br. 20 ME151383177v.1 137508-02320

[0093] In embodiments, for the method of preparing a compound of Formula (XVI), the catalyst is a metal catalyst. In embodiments, for the method of preparing a compound of Formula (XVI), the catalyst is a copper catalyst. In embodiments, for the method of preparing a compound of Formula (XVI), the catalyst is CuCl.

[0094] In embodiments, for the method of preparing a compound of Formula (XVI), the base is an inorganic base. In embodiments, for the method of preparing a compound of Formula (XVI), the base is K2CO3, sodium tert-butoxide, Cs2CO3, KOH, NaOH, CsF, and NaOAc. In embodiments, for the method of preparing a compound of Formula (XVI), the base is Cs2CO3.

[0095] In embodiments, for the method of preparing a compound of Formula (XVI), pentane- 2,4-dione is provided in a catalytic amount.

[0096] In embodiments, for the method of preparing a compound of Formula (XVI), the reacting step is performed in the presence of a solvent. In embodiments, for the method of preparing a compound of Formula (XVI), the solvent is an organic solvent. In embodiments, for the method of preparing a compound of Formula (XVI), the solvent is tetrahydrofuran.

[0097] In embodiment, provided herein is a method of preparing a compound of Formula (II): or a salt thereof, the method comprising reacting a compound of Formula (XIII): or a salt thereof, with bis(pinacolato)diboron and an iridium source.

[0098] In embodiments, for the method of preparing a compound of Formula (II), the iridium source is a complex comprising iridium optionally substituted with one or more ligands. In embodiments, for the method of preparing a compound of Formula (II), the iridium source is Ir(acac)3, (1,5-cyclooctadiene)(pyridine)(tricyclohexylphosphine)-Ir ● PF6, Ir(ppy)3, (1,5- 21 ME151383177v.1 137508-02320 cyclooctadiene)(hexafluoroacetylacetonato)iridium, diiodo(pentamethylcyclopentadienyl)iridium dimer, tris[2-(4,6-difluorophenyl)pyridinato- C2,N]iridium, (acetylacetonato)(1,5-cyclooctadiene)iridium, (1,5- Cyclooctadiene)(methoxy)iridium dimer, (1,5- cyclooctadiene)bis(methyldiphenylphosphine)iridium(I) hexafluorophosphate, or tris[2-(p- tolyl)pyridine]iridium, or bis[2-(4,6-difluorophenyl)pyridinato-C2,N](picolinato)iridium. In embodiments, for the method of preparing a compound of Formula (II), the iridium source is (1,5-cyclooctadiene)(methoxy)iridium(I) dimer.

[0099] In embodiments, for the method of preparing a compound of Formula (II), the method further comprises the addition of a ligand. In embodiments, for the method of preparing a compound of Formula (II), the ligand is 4-tert-butyl-2-(4-tert-butyl-2-pyridyl)pyridine, PPh3, P(o-tolyl)3, Pt-Bu3, Pt-Bu3 · HBF4, PCy3, n-BuP(Ad)2, BINAP, Xantphos, DPEPhos, CyPFt- Bu, dppp, dppf, dtbpf, JohnPhos, CyJohnPhos, DavePhos, RuPhos, SPhos, XPhox, BrettPhos, t-BuXPhos, t-BuBrettPhos, Me4t-BuXPhos, BippyPhos, MorDalPhos, or IPr · HCl. In embodiments, for the method of preparing a compound of Formula (II), the ligand is 4-tert- butyl-2-(4-tert-butyl-2-pyridyl)pyridine.

[0100] In embodiments, for the method of preparing a compound of Formula (II), the reacting step is performed in the presence of a solvent. In embodiments, for the method of preparing a compound of Formula (II), the solvent is an organic solvent. In embodiments, for the method of preparing a compound of Formula (II), the solvent is methyl tert-butyl ether.

[0101] In embodiments, provided herein is a method of preparing a compound of Formula (VIa): or a salt thereof, wherein: Ring F is cycloalkyl, heterocyclyl, phenyl, or heteroaryl, each of which are optionally substituted by one or more RF; RNis H, C1-4alkyl, C1-4haloalkyl, cycloalkyl, heterocyclyl, phenyl, or heteroaryl, wherein the cycloalkyl, heterocyclyl, phenyl, and heteroaryl are each optionally substituted by one or more R10; each R10is independently halo, C1-4alkyl, or C1-4haloalkyl; or two R10, together with the carbon to which they are attached, form oxo; 22 ME151383177v.1 137508-02320 each RFis independently halo, C1-4alkyl, C1-4haloalkyl, -ORFa, -N(RFa)2, -SO2RFb, - C(O)RFb, -N(RFa)SO2RFb, cycloalkyl, heterocyclyl, phenyl, or heteroaryl, wherein the cycloalkyl, heterocyclyl, phenyl, and heteroaryl are each optionally substituted by one or more R9; each RFbis independently C1-4alkyl, C1-4haloalkyl, -ORFa, or -N(RFa)2; each R9is independently halo, C1-4alkyl, C1-4haloalkyl, -OR9a, -N(R9a)2, cycloalkyl, heterocyclyl, phenyl, or heteroaryl, wherein the C1-4alkyl is optionally substituted by one or more C1-4alkoxy; each R9aand RFais independently H, C1-4alkyl, or C1-4haloalkyl; the method comprising: reacting a compound of Formula (VIIa): (VIIa), or a salt thereof, wherein R8is H, C1-4alkyl or C1-4haloalkyl; with a compound of Formula (VIIIa): (VIIIa), or a salt thereof.

[0102] In embodiments, for the method of preparing a compound of Formula (VIa), the reaction is performed in the presence of a reducing agent. In embodiments, for the method of preparing a compound of Formula (VIa), the reducing agent comprises boron. In embodiments, for the method of preparing a compound of Formula (VIa), the reducing agent is selected from NaBH(OAc)3, NaCNBH3, NaBH4, BH3· NCH3, and 2-methylpyridine borane. In embodiments, for the method of preparing a compound of Formula (VIa), the reducing agent is 2-methyl pyridine borane.

[0103] In embodiments, for the method of preparing a compound of Formula (VIa), the method further comprises the steps of preparing the compound of Formula (VIIa) by reacting a compound of Formula (IXa): 23 ME151383177v.1 137508-02320 or a salt thereof, with HC(O)ORO1in the presence of a base, wherein ROand RO1are each independently H, C1-4alkyl, or C1-4haloalkyl.

[0104] In embodiments, for the method of preparing a compound of Formula (VIIa), the base is a lithium base. In embodiments, for the method of preparing a compound of Formula (VIIa), the base is n-butyl lithium.

[0105] In embodiments, for the method of preparing a compound of Formula (VIa) or (VIIa), the reaction is performed in the presence of a solvent. In embodiments, for the method of preparing a compound of Formula (VIa) or (VIIa), the solvent is an organic solvent. In embodiments, for the method of preparing a compound of Formula (VIa) or (VIIa), the solvent is methanol or 2-methyl tetrahydrofuran.

[0106] In embodiments, for the method of preparing a compound of Formula (VIa) or (VIIa), Ring F is phenyl or heteroaryl, each of which is optionally substituted by 1, 2, or 3 RF. In embodiments, for the method of preparing a compound of Formula (VIa) or (VIIa), Ring F is phenyl or 5- to 7-membered heteroaryl, each of which is optionally substituted by 1, 2, or 3 RF. In embodiments, for the method of preparing a compound of Formula (VIa) or (VIIa), Ring F is phenyl or 6-membered heteroaryl, each of which is optionally substituted by 1, 2, or 3 RF. In embodiments, for the method of preparing a compound of Formula (VIa) or (VIIa), Ring F is phenyl, pyridinyl, or pyrimidinyl, each of which is optionally substituted by 1, 2, or 3 RF. In embodiments, for the method of preparing a compound of Formula (VIa) or (VIIa), Ring F is phenyl substituted by 2 RF.

[0107] In embodiments, for the method of preparing a compound of Formula (VIa) or (VIIa), each RFis independently halo, C1-3alkyl, C1-3haloalkyl, C4-6cycloalkyl, or 4- to 6-membered heterocyclyl, wherein the C4-6cycloalkyl and 4- to 6-membered heterocyclyl are each optionally substituted by 1, 2, or 3 R9. In embodiments, for the method of preparing a compound of Formula (VIa) or (VIIa), each RFis independently halo or 4- to 6-membered heterocyclyl, wherein the 4- to 6-membered heterocyclyl is optionally substituted by 1 or 2 R9. In embodiments, for the method of preparing a compound of Formula (VIa) or (VIIa), each RFis independently halo or 6-membered heterocyclyl, wherein the 6-membered heterocyclyl is optionally substituted by 1 or 2 R9. In embodiments, for the method of preparing a compound of Formula (VIa) or (VIIa), each RFis independently -F or piperdinyl, wherein the piperdinyl is substituted by 1 R9.

[0108] In embodiments, for the method of preparing a compound of Formula (VIa) or (VIIa), each R9is independently halo, C1-3alkyl, C1-3haloalkyl, wherein the C1-3alkyl is optionally substituted by 1 or 2 C1-3alkoxy. In embodiments, for the method of preparing a compound of 24 ME151383177v.1 137508-02320 Formula (VIa) or (VIIa), each R9is independently C1-3alkyl optionally substituted by 1 or 2 C1-3alkoxy. In embodiments, for the method of preparing a compound of Formula (VIa) or (VIIa), each R9is -CH(OCH3)2.

[0109] In embodiments, for the method of preparing a compound of Formula (VIa), RNis a heterocyclyl optionally substituted by 1, 2, 3, 4, 5, or 6 R10. In embodiments, for the method of preparing a compound of Formula (VIa), RNis a 5- to 7-membered heterocyclyl optionally substituted by 1, 2, 3, 4, 5, or 6 R10. In embodiments, for the method of preparing a compound of Formula (VIa), RNis a 6-membered heterocyclyl optionally substituted by 1, 2, 3, 4, 5, or 6 R10. In embodiments, for the method of preparing a compound of Formula (VIa) , RNis piperdinyl optionally substituted by 1, 2, 3, 4, or 5 R10.

[0110] In embodiments, for the method of preparing a compound of Formula (VIa), R10, together with the carbon to which they are attached, form oxo.

[0111] In embodiments, for the method of preparing a compound of Formula (VIIa), ROis H.

[0112] In embodiments, for the method of preparing a compound of Formula (VIIa), RO1is C1-3alkyl. In embodiments, for the method of preparing a compound of Formula (VIIa), RO1is -CH3.

[0113] In embodiments, for the method of preparing a compound of Formula (VIa), the compound of Formula (VIa) is a compound of Formula (VI): or a salt thereof.

[0114] In embodiments, for the method of preparing a compound of Formula (VIa) or (VIIa), the compound of Formula (VIIa) is a compound of Formula (VII): or a salt thereof.

[0115] In embodiments, for the method of preparing a compound of Formula (VIa), the compound of Formula (VIIIa) is a compound of Formula (VIII): 25 ME151383177v.1 137508-02320 or a salt thereof.

[0116] In embodiments, for the method of preparing a compound of Formula (VIa), the compound of Formula (VIIIa) or (VIII) is a salt. In embodiments, for the method of preparing a compound of Formula (VIa), the compound of Formula (VIIIa) or (VIII) is a hydrochloride salt.

[0117] In embodiments, for the method of preparing a compound of Formula (VIIa), the compound of Formula (IXa) is a compound of Formula (IX): or a salt thereof.

[0118] In embodiments, provided herein is a method of preparing a compound of Formula (IIIa): or a salt thereof, wherein: X1, X2, X3, and X4are each N or CRX; each RXis, independently, H, halo, C1-3alkyl, C1-3haloalkyl, -ORXa, -NRXaRXb, - C(O)H, -C(O)OH, -C(O)ORXa, or -C(O)NRXaRXb; RXaand RXbare each, independently, H, halo, C1-3alkyl, C1-3haloalkyl, or C3-6cycloalkyl; Ring A and Ring B are each, independently, 4- to 12-membered heterocyclyl; each RAand RBis, independently, halo, C1-3alkyl, C1-3haloalkyl, -ORA1, -NRA1RA1, - C(O)H, -C(O)OH, -C(O)ORA1, or –C(O)NRA1RA1; each RA1is, independently, H, halo, C1-4alkyl, C1-3haloalkyl, or C3-6cycloalkyl; T is halo; and o and p are each, independently, 0, 1, 2, 3, or 4; 26 ME151383177v.1 137508-02320 the method comprising: reacting a compound of Formula (Xa): or a salt thereof, with a compound of Formula (XIa): or a salt thereof, in the presence of a reducing agent.

[0119] In embodiments, for the method of preparing a compound of Formula (IIIa), the reducing agent comprises boron. In embodiments, for the method of preparing a compound of Formula (IIIa), the reducing agent is selected from NaBH(OAc)3, NaCNBH3, NaBH4, BH3 · NCH3, and 2-methylpyridine borane. In embodiments, for the method of preparing a compound of Formula (IIIa), the reducing agent is NaBH(OAc)3.

[0120] In embodiments, for the method of preparing a compound of Formula (IIIa), the method further comprises the steps of preparing the compound of Formula (Xa) by reacting a compound of Formula (XIIa): (XIIa), or a salt thereof, with an acid, and wherein each R11is independently H, C1-3alkyl, or C1- 3haloalkyl.

[0121] In embodiments, for the method of preparing a compound of Formula (Xa), the acid is an aqueous acid. In embodiments, for the method of preparing a compound of Formula (Xa), the acid is HF, HCl, HBr, HI, HCN, H3PO4, H2SO3, H2SO4, or HNO3. In embodiments, for the method of preparing a compound of Formula (Xa), the acid is H2SO4.

[0122] In embodiments, for the method of preparing a compound of Formula (IIIa) or (Xa), the reaction is performed in the presence of a solvent. In embodiments, for the method of 27 ME151383177v.1 137508-02320 preparing a compound of Formula (IIIa) or (Xa), the solvent is an organic solvent. In embodiments, for the method of preparing a compound of Formula (IIIa) or (Xa), the solvent is dichloromethane or 2-methyl tetrahydrofuran.

[0123] In embodiments, for the method of preparing a compound of Formula (IIIa) or (Xa), X1and X3are N and X2and X4are CH.

[0124] In embodiments, for the method of preparing a compound of Formula (IIIa) or (Xa), T is -Cl.

[0125] In embodiments, for the method of preparing a compound of Formula (IIIa) or (Xa), Ring A is a 5- to 7-membered heterocyclyl. In embodiments, for the method of preparing a compound of Formula (IIIa) or (Xa), Ring A is a 6-membered heterocyclyl. In embodiments, for the method of preparing a compound of Formula (IIIa) or (Xa), Ring A is piperdinyl.

[0126] In embodiments, for the method of preparing a compound of Formula (IIIa) or (Xa), o is 0.

[0127] In embodiments, for the method of preparing a compound of Formula (IIIa), Ring B is a 5- to 7-membered heterocyclyl. In embodiments, for the method of preparing a compound of Formula (IIIa), Ring B is a 6-membered heterocyclyl. In embodiments, for the method of preparing a compound of Formula (IIIa), Ring B is piperazinyl.

[0128] In embodiments, for the method of preparing a compound of Formula (IIIa), p is 0, 1, 2, or 3. In embodiments, for the method of preparing a compound of Formula (IIIa), p is 3.

[0129] In embodiments, for the method of preparing a compound of Formula (IIIa), each RBis independently halo, C1-3alkyl, C1-3haloalkyl, or -C(O)OR4a. In embodiments, for the method of preparing a compound of Formula (IIIa), each RBis independently C1-3alkyl or - C(O)OR4a. In embodiments, for the method of preparing a compound of Formula (IIIa), RBis independently -CH3 or -C(O)OC(CH3)3.

[0130] In embodiments, for the method of preparing a compound of Formula (IIIa), R4ais C1-4alkyl.

[0131] In embodiments, for the method of preparing a compound of Formula (Xa), each R11is independently C1-3alkyl. In embodiments, for the method of preparing a compound of Formula (Xa), each R11is -CH3.

[0132] In embodiments, for the method of preparing a compound of Formula (IIIa), the compound of Formula (IIIa) is a compound of Formula (III): 28 ME151383177v.1 137508-02320 or a salt thereof.

[0133] In embodiments, for the method of preparing a compound of Formula (IIIa) or (Xa), the compound of Formula (Xa) is a compound of Formula (X): or a salt thereof.

[0134] In embodiments, for the method of preparing a compound of Formula (IIIa), the compound of Formula (XIa) is a compound of Formula (XI): or a salt thereof.

[0135] In embodiments, for the method of preparing a compound of Formula (Xa), the compound of Formula (XIIa) is a compound of Formula (XII): or a salt thereof. EXEMPLIFICATION Compounds having the Formula (I), Formula (Ia), Formula (I’), Formula (Ia’), Formula (II), Formula (IIa), Formula (III), Formula (IIIa), Formula (IV), Formula (IVa), Formula (V), Formula (Va), Formula (VI), Formula (VIa), Formula (VII), Formula (VIIa), Formula (VIII), Formula (VIIIa), Formula (IX), Formula (IXa), Formula (X), Formula (Xa), Formula (XI), Formula (XIa), Formula (XII), Formula (XIIa), Formula (XIII), Formula (XIV), and Formula (XI) can be prepared following the procedures described below. Additional procedures are as described in WO 2022 / 198112, the entire contents of which is incorporated herein by reference.

[0136] Abbreviations 2-MeTHF = 2-methyl tetrahydrofuran 2-MePy ● BH3 = 2-methylpyridine borane 29 ME151383177v.1 137508-02320 BINAP = 2,2′-Bis(diphenylphosphino)-1,1′-binaphthalene BippyPhos = 5-[Bis(1-adamantyl)phosphino]-1′,3′,5′-triphenyl-1,4′-bi-1H-pyrazole BrettPhos = 2-(Dicyclohexylphosphino)3,6-dimethoxy-2′,4′,6′-triisopropyl-1,1′- biphenyl Cs2CO3 = cesium carbonate CyJohnPhos = 2-(Dicyclohexylphosphino)biphenyl CyPFt-Bu = (2R)-1-[(1R)-1-[Bis(1,1-dimethylethyl)phosphino]ethyl]-2- (dicyclohexylphosphino)ferrocene DavePhos = 2-Dicyclohexylphosphino-2′-(N,N-dimethylamino)biphenyl DCE = 1,2-Dichloroethane DCM = CH2Cl2 = dichloromethane DHP = 3,4-dihydropyran DMA = dimethylacetamide DMF = dimethylformamide DMSO = dimethylsulfoxide DPEPhos = [Oxydi(2,1-phenylene)]bis(diphenylphosphane) dppf = 1,1′-Ferrocenediyl-bis(diphenylphosphine) dppp = 1,3-Bis(diphenylphosphino)propane dtbpf = 1,1′-Bis(di-tert-butylphosphino)ferrocene eq = equivalent EtOAc = ethyl acetate EtOH = ethanol g = grams IPr · HCl = 1,3-Bis-(2,6-diisopropylphenyl)imidazolium chloride IPAc = isopropyl acetate JohnPhos = (2-Biphenyl)di-tert-butylphosphine K2CO3= potassium carbonate kg = kilogram LiAlH4 = lithium aluminium hydride Me4t-BuXPhos = 2-Di-tert-butylphosphino-3,4,5,6-tetramethyl-2′,4′,6′-triisopropyl- 1,1′-biphenyl MeCN = ACN = acetonitrile MeOH= methanol MorDalPhos = Di(1-adamantyl)-2-morpholinophenylphosphine 30 ME151383177v.1 137508-02320 MsOH = methanesulfonic acid MTBE = methyl tert-butyl ether Na2SO3= sodium sulfite NaBH(OAc)3 = sodium triacetoxyborohydride NaBH4 = sodium borohydride n-BuLi = n-butyl lithium n-BuP(Ad)2= bis(1-adamantyl)-butylphosphane NH4Cl= ammonium chloride P(o-tolyl)3 = tris(o-tolyl)phosphine PCy3= tricyclohexylphosphine Pd(dppf)Cl2 = [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) PPh3 = triphenylphosphine Pt-Bu3= tri-tert-butylphosphine Pt-Bu3 · HBF4 = tri-tert-butylphosphonium tetrafluoroborate RuPhos = 2-Dicyclohexylphosphino-2′,6′-diisopropoxybiphenyl SPhos = 2-Dicyclohexylphosphino-2′,6′-dimethoxybiphenyl t-BuBrettPhos = 2-(Di-tert-butylphosphino)-2′,4′,6′- triisopropyl-3,6-dimethoxy-1,1′- biphenyl, t-BuOK = potassium tert-butoxide t-BuXPhos = 2-Di-tert-butylphosphino-2′,4′,6′-triisopropylbiphenyl THF = tetrahydrofuran THP = tetrahydropyran TMP = trimethylolpropane TsOH = p-toluenesulfonic acid Xantphos = (9,9-Dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphane) XPhox = 2-Dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl General Methods

[0137] HPLC Method 1:（10~80AB,20min） MS instrument type: SHIMADZU LC-20AB; column: Kinetex EVO C183.5um 4.6x150mm; mobile Phase A: 0.0375% TFA in water (v / v), B: 0.01875% TFA in Acetonitrile (v / v); gradient: 0.00 min 0% B→ 10.0 min 60% B→ 15.0 min 60% B→15.01 min 0% B→ 31 ME151383177v.1 137508-02320 15.02 min 0% B→ 20.0 min 0% B; flow rate: 1.00 mL / min; oven temperature: 40 °C; Detector: PDA(220nm&215nm&254nm).

[0138] HPLC Method 2:（10~80AB,6min） MS instrument type: SHIMADZU LC-20AD, Column: Kinetex C18 LC Column 4.6 X 50 mm, 5um, mobile phase A: 0.0375% TFA in water (v / v), B: 0.01875% TFA in Acetonitrile (v / v), gradient: 0.0 min 10% B→4.2 min 80% B→5.3 min 80% B→5.31 min 10%B→6.00 min 10%B, flow rate: 1.5 mL / min, oven temperature: 50 °C; UV detection: 220 nm & 215 nm & 254 nm.

[0139] LCMS Method 1:（5~95AB,4min） MS instrument type: SHIMADZU LCMS-20AB, Kinetex EVO C1830*2.1mm,5um, mobile phase A: 0.0375% TFA in water (v / v), B: 0.01875% TFA in Acetonitrile (v / v), gradient: 0.0 min 10% B→2.4 min 80% B→3.70 min 80% B→3.71 min 10% B→4.00 min 10% B, flow rate: 1.5 mL / min, oven temperature: 50°C; UV detection: 220 nm & 254 nm.

[0140] Scheme 1: Synthesis of a Compound of Formula (II) 32 ME151383177v.1 137508-02320

[0141] Step 1: Synthesis of 1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-ol DHP (19.75 kg, 235 mol, 21.5 L, 1.05 eq.) was dropwise added to a mixture of 1H- indazol-5-ol (30.0 kg, 224 mol, 1.00 eq.) and MsOH (2.14 g, 22.4 mol, 1.6 L, 0.100 eq.) in DMF (150 L) at 25 °C. The mixture was stirred at 80 °C for 12 h, then poured into sodium bicarbonate solution (900 L) to adjust the pH to 7, and extracted with ethyl acetate (240 L x 1 and 180 L x 3). The combined organic layers were washed with 10% NaCl solution (150 L x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was triturated by MTBE (30.0 L) at 20 °C the filter cake was washed with cooled MTBE (15.0 L) and dried to give methyl 4-bromo-2-(1-tetrahydropyran-2-ylindazol-5- yl)oxy-butanoate (31.5 kg, 64.5% yield) as a yellow solid.1H NMR: (400 MHz, CDCl3) δ ppm 7.88 (s, 1 H), 7.47 - 7.45 (m, 1H), 7.02 - 7.00 (m, 2H), 5.59 - 5.66 (m, 1H), 4.07 - 4.03 (m, 1H), 3.77 - 3.72 (m,1H), 2.57 - 2.54 (m,1H),2.14 - 2.06 (m, 2H), 1.77 -1.65 (m, 3H) 33 ME151383177v.1 137508-02320

[0142] Step 2: Synthesis of methyl 4-bromo-2-((1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5- yl)oxy)butanoate To a solution of 1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-ol (21.5 kg, 98.5 mol, 1.00 eq.) in acetonitrile (215 L,168 kg) was added cesium carbonate (41.7 kg, 128 mol, 1.30 eq.) at 0 °C in portions under nitrogen. To the mixture was dropwise added methyl 2,4- dibromobutanoate (28.2 kg, 108 mol, 1.10 eq.) at 0 °C under nitrogen.The mixture was stirred at 25 °C for 12 h. This batch was combined with another 10.0 kg scale for work up. The reaction mixture was poured into ice water (630 L) and stirred at 0~10 °C for 1 hr, extracted with ethyl acetate (158 L x 1 and 95.0 L x 2). The combined organic layers were washed with 10% NaCl solution (158 L), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel column chromatography (petroleum ether : ethyl acetate = 10 : 1 to 1: 1) and dried to give methyl 4- bromo-2-((1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)oxy)butanoate (33.0 kg, 52.2% yield) as a yellow oil.1H NMR: (400 MHz, CDCl3) δ ppm 7.94 (s, 1 H), 7.53 (d, J = 9.2 Hz, 1H), 7.17 - 7.11 (m, 2H), 5.69 - 5.66 (m, 1H), 4.90 - 4.87 (m, 1H), 4.02 - 4.00 (m,1H), 3.76 (s, 3H), 3.74 - 3.63 (m, 3H), 2.58 -2.50 (m, 2H), 2.18 - 2.08 (m, 1H), 2.09 - 2.06 (m, 1H), 1.74 - 1.66 (m, 4H).

[0143] Step 3: Synthesis of methyl 1-((1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5- yl)oxy)cyclopropane-1-carboxylate To a solution of methyl 4-bromo-2-(1-tetrahydropyran-2-ylindazol-5-yl)oxy- butanoate (20.0 kg, 50.3 mol, 1.00 eq.) in THF (200 L) was added potassium tert-butoxide (6.21 kg, 55.4 mol, 1.10 eq.) in portions at 0~5 °C under N2. The mixture was stirred at 0~5 °C for 6 h. This batch was combined with another 13.0 kg scale for work up. The reaction mixture was poured into ice NH4Cl solution (132 L) and stirred at 0~10 °C for 1 h, then the mixture was extracted with ethyl acetate (100 L x 3). The combined organic layers were washed with 10% NaCl solution (100 L x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel column chromatography (petroleum ether : ethyl acetate = 10 : 1 to 2: 1) to give methyl 1-(1- tetrahydropyran-2-ylindazol-5-yl) oxycyclopropanecarboxylate (15.7 kg, 51.2% yield) as a yellow oil.1H NMR: (400 MHz, CDCl3) δ ppm 7.91 (s, 1H), 7.48 (d, J = 8.80 Hz, 1H), 7.11 (d, J = 2.40 Hz, 1H), 7.06 - 7.03 (m, 1H), 5.67 - 5.64 (m, 1H), 4.00 – 3.97 (m, 1H), 3.74 - 3.70 (m, 4H), 2.54 - 2.51 (m, 1H), 2.06 - 2.12 (m, 2H), 1.74 – 1.71(m,2H), 1.63-1.61 (m, 3H), 1.34 - 1.31 (m, 2H). 34 ME151383177v.1 137508-02320

[0144] Step 4: Synthesis of (1-((1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5- yl)oxy)cyclopropyl)methanol To a stirred solution of LAlH4(1.32 kg, 34.8 mol, 1.10 eq.) in THF (70.0 L) was added dropwise a solution of methyl 1-(1-tetrahydropyran-2-ylindazol-5-yl) oxycyclop- ropanecarboxylate (10.0 kg, 31.6 mol, 1.00 eq.) in THF (30.0 L) at 0-5 °C under N2. The mixture was stirred at 0-5 °C for 1 h. The reaction was quenched at 0 °C by water (1.32 L), sodium hydroxide (aq.15%, 1.32 L), then water (3.96 L). This batch was combined with another 7.0 kg scale for work up. The mixture was filtered, the resulting solid was washed with DCM (85.0 L x 2), the filtrate was dried over anhydrous sodium sulfate and concentrated to give [1-(1-tetrahydropyran-2-ylindazol-5-yl)oxycyclopropyl]methanol (13.0 kg, 78.0% yield) as a white solid.1H NMR: (400 MHz, CDCl3) δ ppm 7.93 (s, 1H), 7.49 (d, J = 9.20 Hz, 1H), 7.30 (s, 1H), 7.11- 7.08 (m, 1H), 5.68 - 5.66 (m, 1H), 4.03 - 4.00 (m, 1H), 3.87 (s, 2H), 3.76 - 3.71 (m, 1H), 2.56 - 2.53 (m, 1H), 2.14 - 2.06 (m, 2H), 1.89 - 1.66 (m, 4H), 1.12-1.09 (m, 2H), 0.95 - 0.91 (m, 2H)

[0145] Step 5: Synthesis of 5-(1-(iodomethyl)cyclopropoxy)-1-(tetrahydro-2H-pyran-2-yl)- 1H-indazole To a solution of triphenylphosphine (7.59 kg, 28.9 mol, 1.20 eq.) in DCM (49.0 L) was added iodine (7.34 kg, 28.9 mol, 1.20 eq.) and imidazole (4.15 kg, 72.3 mol, 3.00 eq.) at 0 °C. The mixture was stirred at 0 °C for 0.5 h under nitrogen. Then a solution of [1-(1- tetrahydropyran-2-ylindazol-5-yl)-oxy-cyclopropyl] methanol (6.97 kg, 44.7 mol, 1.00 eq.) in DCM (21.0 L) was added under nitrogen. The reaction was stirred at 25 °C for 12 hrs under nitrogen. Another 6.00 kg scale was combined and worked up together. The reaction was quenched at 0 °C by sodium thiosulfate (65.0 L) and extracted with DCM (39.0 L x 2). The combined organic layers were washed with 10% NaCl solution (100 L) dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was triturated with heptane : EtOAc = 1:1 (6 V) at 20 ℃, the filter cake was washed with heptane : EtOAc = 1:1 (1.00 V x 2) and the filtrate was concentrated. The crude product was triturated with i-PrOH (3 V) at 20 °C, the filter cake was washed with i-PrOH (0.50 V x 2) and dried to give 5-[1- (iodomethyl)cyclopropoxy]-1-tetrahydropyran-2-yl-indazole (9.30 kg , 52.2% yield) as a white solid . The i-PrOH filtrate was concentrated, then purified by flash silica gel column chromatography (petroleum ether : ethyl acetate = 20 : 1 to 5: 1) to give 5-[1- (iodomethyl)cyclopropoxy]-1-tetrahydropyran-2-yl-indazole (2.80 kg , 15.7% yield) as a white solid.1H NMR: (400 MHz, CDCl3) δ ppm 7.95 (s, 1H), 7.53 (d, J = 8.8 Hz, 1H), 7.32 (d, J = 2.0 Hz, 1H), 7.19 - 7.16 (m,1H), 5.70 - 5.67 (m, 1H), 4.05 - 4.02 (m, 1H), 3.78 - 3.72 35 ME151383177v.1 137508-02320 (m, 1H), 3.57 (s, 2H), 2.58 - 2.55 (m, 1 H), 2.18 - 2.10 (m, 2H), 1.78 - 1.67 (m, 3H), 1.50- 1.47 (m, 2H), 1.04 - 1.01 (m, 2H)

[0146] Step 6: Synthesis of 5-(1-methylcyclopropoxy)-1-(tetrahydro-2H-pyran-2-yl)-1H- indazole To a solution of 5-[1-(iodomethyl)cyclopropoxy]-1-tetrahydropyran-2-yl-indazole (8.00 kg, 20.1 mol, 1.00 eq.) in DMSO (40.0 L) was portion wise added sodium borohydride (1.14 kg, 30.1 mol, 1.50 eq.) at 20 ~25 °C for 4 h. Then the mixture was cooled to 25 °C, MeOH (4.06 L) was added to the mixture at 25 °C, and the mixture was stirred at 20 ~25 °C for 12 h. Another 4.00 kg scale was combined to work up together. The reaction was quenched by NH4Cl solution (180 L) at 0 ~ 10 °C, the mixture was extracted with EtOAc (120 L x 3). The combined organic layers were washed with 10% NaCl solution (60.0 L), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column flash silica gel column chromatography (petroleum ether : ethyl acetate = 50 : 1 to 10: 1) to give 5-(1-methylcyclopropoxy)-1-tetrahydropyran-2-yl- indazole (6.80 kg, 83.3% yield) as a white solid.1H NMR: (400 MHz, CDCl3) δ ppm 7.95 (s, 1H), 7.49 (d, J = 8.8 Hz, 1H), 7.31 (d, J = 2.4 Hz, 1H), 7.07 - 7.05 (m, 1H), 5.69 - 5.66 (m, 1H), 4.04 - 4.01(m, 1H), 3.77 - 3.71 (m, 1H), 2.58 - 2.55 (m, 1H), 2.16 - 2.10 (m, 2H), 1.78- 1.66 (m, 3H), 1.58 (s, 3H), 1.06 - 1.02 (m, 2H), 0.75 - 0.72 (m, 2H).

[0147] Step 7: Synthesis of 5-(1-methylcyclopropoxy)-1-(tetrahydro-2H-pyran-2-yl)-3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole (Formula (II)) A mixture of 5-(1-methylcyclopropoxy)-1-tetrahydropyran-2-yl-indazole (3.30 kg, 12.1 mol, 1.00 eq.), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)- 1,3,2-dioxaborolane (3.70 kg, 14.6 mol, 1.20 eq.) and 4-tert-butyl-2-(4-tert-butyl-2- pyridyl)pyridine (0.0976 kg, 364 mmol, 0.03 eq.) in MTBE (33.0 L) was degassed and purged with argon for 3 times at 25 °C. Then (1Z, 5Z)-cycloocta-1,5-diene ; (1,5- cyclooctadiene)(methoxy)iridium(I) dimer (0.0803 kg, 121 mmol, 0.01 eq.) was added and the mixture was stirred at 40 °C for 12 h under argon. The reactions were performed as 2 batches in parallel. Two batches were combined to work up together. The reaction mixture was filtered through Celite pad (200% wt x 3) and then triturated with MTBE: hexane = 1: 7 (33.0 L) at 25 °C for 5 h, the mixture was cooled and filtered, the filtered cake was washed with MTBE: hexane = 1: 2 (6.60 L x 2) to get 5-(1-methylcyclopropoxy)-1-tetrahydropyran- 2-yl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indazole (7.50 kg, 76.8% yield) as a white solid. (Formula (II)).1H NMR: (400 MHz, CDCl3) δ ppm 7.68 (d, J = 2.0 Hz, 1H), 7.58 (d, J = 9.2 Hz, 1H), 7.12 - 7.09 (m, 1H), 5.82 - 5.79 (m, 1H), 4.11 - 4.08 (m, 1H), 3.75 - 36 ME151383177v.1 137508-02320 3.69 (m, 1H), 2.57 - 2.51 (m, 1H), 2.10 - 2.01 (m, 2H), 1.72 -1.61 (m, 3H), 1.59 (s, 3H), 1.40 (s, 12H), 1.08 - 1.05 (m, 2H), 0.74 - 0.71 (m, 2H).

[0148] Alternative Synthesis for the Preparation of 5-(1-methylcyclopropoxy)-1-(tetrahydro- 2H-pyran-2-yl)-1H-indazole To a 100 mL seal tube, a mixture of Cs2CO3(11.3 g, 17.0 mmol, 1.50 equiv), CuCl (575 mg, 5.75 mmol, 0.25 equiv), and acetylacetone (1.2 mL, 11.5 mmol, 0.50 equiv) in toluene (2V) was stirred at room temperature. After 5 min, 1-(tetrahydro-2H-pyran-2-yl)-1H- indazol-5-ol (5.0 g, 22.5 mmol, 1.00 equiv) and vinyl bromide (12.25 mL, 135mmol, 6.00 equiv) were added, the reaction was heated at 105°C for 16 hours and the progress was monitored by LCMS. After completion, the reaction mixture was diluted with IPAc and filtered through celite. The organic layer was washed with water and the organic were concentrated and impurities were filtered off by filter column to yield 5-(prop-1-en-2-yloxy)- 1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (4.6 g, 85.23%).

[0149] Screening of additives for the Simmons-Smith cyclopropanation Initial screening started with Simmons-Smith cyclopropanation with diethyl zinc and diiodomethane, complete conversion was observed at 20–25 °C in presence of ZnBr2as additive as shown in Table 1. The screening was performed on 50 mg scale. However, the reaction kinetics was slower on 500 mg scale compared to 50 mg scale with 60.7% Isolated yield using 10V of DCE. 37 ME151383177v.1 137508-02320 Table 1. Screening of additives for Simmons-Smith cyclopropanation The reaction kinetics were monitored with ZnBr2as additive and it was observed that cyclopropanation on 500 mg showed 100% conversion at 50 °C in 20 h. The loading of ZnBr2 was tested as shown in table 2 with 0.5 eq of ZnBr2 resulted in complete conversion in 60 h at 50 °C (vs 20 h with 1.0 eq). Table 2. Screening of ZnBr2 reaction conditions

[0150] Alternative Simmons-Smith Conditions Alternatively, process friendly triisobutyl aluminium was tested and the reaction condition showed complete conversion with respect to the starting material, with a major impurity of 1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-ol. Optimization of loadings for equiv. of triisobutyl aluminium, solvent and temperature were carried out. It was found that 1.5 equiv. of triisobutyl aluminium works better with DCM as reaction solvent at 0 °C. MeTHF as reaction solvent showed majorly starting material. In addition to the above discussed conditions cyclopropanation with trioctyl aluminium (varied equiv.1.0 / 1.5 / 2.1) and Zn-Cu couple were also tested and the reaction profiles showed mostly starting material.

[0151] Alternative Synthesis of 5-(prop-1-en-2-yloxy)-1-(tetrahydro-2H-pyran-2-yl)-1H- indazole 38 ME151383177v.1 137508-02320 To a 1 L reactor purged with N2 and equipped with an overhead stirrer, water condenser, baffle, and temperature probe was added THF (6.0 vols, 150 mL). Cs2CO3(93.3 g, 2.5 eq), CuCl (2.83 g, 0.25 eq), and acetylacetone (5.88 mL, 0.5 eq) were then added to the reactor and allowed to stir at ambient temperature for approximately 5 minutes.1- (tetrahydro-2H-pyran-2-yl)-1H-indazol-5-ol (24.3 g, 1 eq) was then charged to the reactor followed by 2-bromopropene (61.0 mL, 6 eq), then the N2was turned off to ensure the reaction was taking place under a static, inert atmosphere. The mixture was warmed to 35 °C and stirred overnight (240 rpm). The next day, the heterogeneous mixture was sampled (250 µL to 100 mL w / MeCN and ~5 mL MeOH) for HPLC, revealing that the reaction had gone to near-completion, leaving <4 A% of unreacted starting material. The mixture was then brought to ambient temperature before being filtered through a pad of Solka-Floc topped with filter paper. Filtration was complete within ~5-10 min (Initial Filtrate). The brown solids remaining on the filter were then slurry washed with THF (125 mL, 5 vols, Cake wash #1). This filtration took ~10 min and the solids on the funnel changed color from brown to green. The solids were then slurry washed an additional 3 times with 100 mL (4 vols) of THF and the filtrates were collected separately and sampled, showing that three cake washes were needed. The filtrate and cake washes 1-3 were combined and concentrated under reduced pressure on the rotary evaporator to a brown, oily residue before being taken back up in trifluorotoluene (250 mL, 10 vols). The crude solution was charged to the reactor along with a 9:1 NH4Cl / NH4OH solution (500 mL, 20 vols). The biphasic mixture was stirred for 15 mins, the layers were separated, and an additional 500 mL of the 9:1 NH4Cl / NH4OH solution was added to the reactor with the organic layer. The mixture was stirred for 15 mins and the layers were then separated. The first wash resulted in a dark blue aqueous layer, and the second wash produced a clear aqueous layer maintaining a faint green color. The organic layer was then stirred with water (500 mL, 20 vols) for 5 min. The aqueous layer was pH 9, so the organic was washed with additional water (500 mL, 20 vols) and the pH = 7. The organic layer (KF= 0.1% water) was assayed then concentrated under reduced pressure on the rotary evaporator to ~3 vols (75 mL) before being diluted up with trifluorotoluene (100 mL, 4 vols) and concentrated to 3 vols again. This process was carried out one more time, then the 39 ME151383177v.1 137508-02320 water content was assessed again (KF= < 0.01% water). The resulting stock solution was assayed and found to be 405 mg / mL and the flask was purged thoroughly with N2.

[0152] Alternative Synthesis of 5-(1-methylcyclopropoxy)-1-(tetrahydro-2H-pyran-2-yl)-1H- indazole To a 1 L reactor equipped with a baffle, temperature probe, overhead stirrer, N2inlet, and addition funnel was added trifluorotoluene (150 mL, 7.75 vols). The solvent was cooled to -10 °C then ZnEt2 (1 M in hexanes, 150 mL, 150 mmol, 2.0 mol eq) was added dropwise, ensuring the exotherm did not exceed 0 °C. Then trichloroacetic acid (24.5 g, 150 mmol, 2.0 eq) as a solution in trifluorotoluene (32.0 mL, 1.65 vols) was added dropwise, again ensuring the resulting exotherm did not exceed 0 °C. The mixture was then stirred for 15 min at - 10 °C. Diiodomethane (12.1 mL, 150 mmol, 2.0 mol eq) was added to the mixture dropwise and the batch was stirred an additional 10 min at -10 °C. The stock solution of 5-(prop-1-en- 2-yloxy)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (485 mg / mL, 40.0 mL, 19.4 g, 75.1 mmol, 1.0 eq) was added dropwise, again maintaining a temperature below 0 °C then the batch was warmed to 0 °C and allowed to stir overnight. The next day, IPC analysis revealed the reaction had gone to completion, then the reaction mixture was quenched with dropwise addition of 1 M KH2PO4 (155 mL, 8 vols), maintaining T < 7 °C. The mixture was warmed to ambient temperature then was stirred for 15 min. The layers were separated then the aqueous layer was extracted once with trifluorotoluene (97 mL, 5 vols). The organic layers were combined then charged back to the reactor with 1 M NaOH (155 mL, 8 vols) and stirred for 10 min. The layers were separated and the organic layer was washed with water (155 mL, 8 vols) before separating the layers one more time. After the workup, the organic layer was assayed (17.7 g, 87% yield) then concentrated down to approximately 100 mL (5 vols). The solution was diluted with IPA (100 mL, 5 vols) and concentrated down to 5 vols total volume. This dilution / concentration process was then carried out two more times. The hazy solution was sampled for trifluorotoluene content (0.9% v / v trifluorotoluene by HPLC). The mixture was then warmed to 35-40 °C before water (120 mL, 6 vols) was added dropwise over 15-20 min. After complete addition of the water, the suspension was held at 38 °C for 30 min before the suspension was cooled to ambient temperature slowly and was stirred overnight. The next day, the mixture was cooled in an ice bath for 1 h and the solids were filtered off (<5 min filtration time) and the cake was washed with cold 4:1 water / IPA (2 x 20 40 ME151383177v.1 137508-02320 mL, 2 x 1 vol). The solid was allowed to dry on the fritted funnel under vacuum / N2.5-(1- methylcyclopropoxy)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole was isolated as a white to off-white solid (17.5 g, 99.1 A%, 96.0 wt% by HPLC vs. working standard = 16.8 assay g, 61.7 mmol, 82% isolated yield).

[0153] Alternative Synthesis of 5-(1-methylcyclopropoxy)-1-(tetrahydro-2H-pyran-2-yl)-1H- indazole 5-(prop-1-en-2-yloxy)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (5g, 19.35 mmol, 1.0 equiv) was dissolved in 4V of DCM. The reaction was stirred under nitrogen. The solution was stirred and isobutyl aluminum (1M in hexanes) (38.7 mL, 38.7 mmol, 2.1 equiv) was added over a 20-min period at 25 °C and stirred for 20 min. Diiodomethane (2mL, 25.155 mmol, 1.3 equiv) was added dropwise with a syringe over a 10-min period. The mixture was stirred at room temperature for 20 hours progress monitored by HPLC. The reaction mixture was poured into 4 mL of ice-cold 8% aqueous sodium hydroxide. The organic layer was separated, and the aqueous layer extracted twice with 10-mL portions of DCM. The combined extracts were dried over anhydrous sodium sulfate. The organic layer was separated and concentrated to dryness to yield 5-(1-methylcyclopropoxy)-1-(tetrahydro- 2H-pyran-2-yl)-1H-indazole (3.04 g, 60% yield).

[0154] Alternative Synthesis of 5-(1-methylcyclopropoxy)-1-(tetrahydro-2H-pyran-2-yl)-3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole (Formula (II))

[0155] Scheme 2: Synthesis of a Compound of Formula (III) 41 ME151383177v.1 137508-02320

[0156] Step 1a: Synthesis of tert-butyl 3,3-dimethylpiperazine-1-carboxylate To EtOH (5V) at 20oC was added 2,2-dimethylpiperazine (1 eq.). To this mixture was added a solution of Boc2O (1.05 eq) in EtOH (1V) at 10-20oC, and the reaction was allowed to stir at 20oC for 12 hours. Afterwards, the mixture was concentrated under reduced pressure and DCM was added. This DCM solution was used in the next step without further purification.

[0157] Step 1b: Synthesis of 4-chloro-6-(4-(dimethoxymethyl)piperidin-1-yl)pyrimidine 4-(dimethoxymethyl)piperidine (0.95 eq.) was dissolved in isopropanol (15 V) followed by TEA (3 eq.) at 20-30oC. To this mixture was added 4,6-dichloropyrimidine (1 eq.), and allowed to stir for 18 hr at 20-30oC. Afterwards, the mixture was concentrated to ~1-2V under reduced pressure at 45oC. After cooling to 20-30oC, 5V of water was added to cause a precipitation to form. An additional 10-15 V of water was added and the mixture cooled to 0-10oC, and stirred at this temperature for 18 hr. The solids were collected and filter cake washed with water (3V) and dried at 30-40oC for 18h.

[0158] Step 2: Synthesis of 1-(6-chloropyrimidin-4-yl)piperidine-4-carbaldehyde 4-chloro-6-(4-(dimethoxymethyl)piperidin-1-yl)pyrimidine was dissolved in 2- MeTHF (10V), followed by 2M H2SO4 (4.6 eq.). The mixture was heated to 50oC and stirred at this temperature for 1 hr. Afterwards, the mixture was cooled to 15oC and neutralized to a pH of 7-8 by the addition of 20% aqueous NaHCO3 solution (7 V) over 1 hr. The organic and aqueous layers were separated and organic layer collected. The aqueous layer was extracted with 2-MeTHF (14V). The combined organic layers were dried over Na2SO4and concentrated to yield the product (90% yield) 42 ME151383177v.1 137508-02320

[0159] Step 3: Synthesis of tert-butyl 4-((1-(6-chloropyrimidin-4-yl)piperidin-4-yl)methyl)- 3,3-dimethylpiperazine-1-carboxylate tert-butyl 3,3-dimethylpiperazine-1-carboxylate (1.2 eq.) and 1-(6-chloropyrimidin-4- yl)piperidine-4-carbaldehyde (1.0 eq.) were dissolved in 2-MeTHF (10V) and stirred for 1 hr at 20oC. The mixture was then cooled to 0oC and NaBH(OAc)3 (1.3 eq.) added. The mixture was stirred at 16 hr at -10-0oC. Afterwards, the reaction was quenched with 10V of a saturated aqueous sodium bicarbonate solution. The organic and aqueous layers were separated, organic layer collected, and concentrated to ~1-2V at 40oC under reduced pressure.5V of EtOH was added to the mixture which was then stirred for 1 hr at 50oC. After cooling to 20-30oC a solid precipitated.7V of water was added and the solid collected, washed with water (3V), and dried at 40oC for 20 hr to yield tert-butyl 4-((1-(6- chloropyrimidin-4-yl)piperidin-4-yl)methyl)-3,3-dimethylpiperazine-1-carboxylate (Formula (III), 75% yield).

[0160] Scheme 3: Synthesis of a compound of Formula (I)

[0161] Step 1: Synthesis of tert-butyl 3,3-dimethyl-4-((1-(6-(5-(1-methylcyclopropoxy)-1- (tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)pyrimidin-4-yl)piperidin-4-yl)methyl)piperazine- 1-carboxylate (Formula (I)) Tert-butyl 4-((1-(6-chloropyrimidin-4-yl)piperidin-4-yl)methyl)-3,3- dimethylpiperazine-1-carboxylate (443.0 g) and 5-(1-methylcyclopropoxy)-1-(tetrahydro-2H- pyran-2-yl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole (457.5 g, 1.1 eq) were added to 1,4-dioxane (5.50 kg). Then a solution of K2CO3 (289.1 g, 2.0 eq) in water (975 kg) was added and the two-phase reaction mixture was evacuated to approximately 100 mbar and the vacuum was released with nitrogen. This vacuum / refill process was completed two more times. Pd(dppf)Cl2(38.5 g, 0.05 eq) was added to the reaction mixture. The 43 ME151383177v.1 137508-02320 reaction mixture was evacuated to approximately 100 mbar and the vacuum was released with nitrogen. The reaction mixture was then heated to 88oC over 69 minutes and stirred at 88oC for 60 minutes then cooled to room temperature. EtOAc (2.73 kg) and water (2.66 kg) were added, and the product was extracted into the organic phase and the organic phase concentrated at reduced pressure. Toluene (6.1 kg) was added to the concentrate, which was then concentrated again. This process was completed a second time with 3.05 kg of toluene. The concentrated solution was stored at room temperature overnight. 150 mL of toluene was added to the concentrated solution which was then purified by silica gel column (heptanes:EtOAc, 9:1 to 7:3) to yield tert-butyl 3,3-dimethyl-4-((1-(6-(5-(1- methylcyclopropoxy)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)pyrimidin-4- yl)piperidin-4-yl)methyl)piperazine-1-carboxylate (Formula (I)).

[0162] Scheme 4: Synthesis of a compound of Formula (I’)

[0163] Step 1: Synthesis of 3-(6-(4-((2,2-dimethylpiperazin-1-yl)methyl)piperidin-1- yl)pyrimidin-4-yl)-5-(1-methylcyclopropoxy)-1H-indazole (Formula (I’)) To tert-butyl 3,3-dimethyl-4-((1-(6-(5-(1-methylcyclopropoxy)-1-(tetrahydro-2H- pyran-2-yl)-1H-indazol-3-yl)pyrimidin-4-yl)piperidin-4-yl)methyl)piperazine-1-carboxylate suspended in MeOH was added 4M HCl in EtOAc (2.61 kg) over 4 minutes, with a final temperature of 22oC. The reaction was heated to a general reflux (about 57oC) for 5.5 hours then cooled to room temperature. The solids were filtered and the filter cake was washed with EtOAc (1.89 kg) and dried under vacuum at 30oC for 4 hours to yield 3-(6-(4-((2,2- dimethylpiperazin-1-yl)methyl)piperidin-1-yl)pyrimidin-4-yl)-5-(1-methylcyclopropoxy)-1H- indazole [3 HCl] (Formula (I’), 599.6 g, 98.6% yield).

[0164] Scheme 5: Synthesis of a compound of Formula (VI) 44 ME151383177v.1 137508-02320

[0165] Step 1: Synthesis of methyl 4-(4-(dimethoxymethyl)piperidin-1-yl)-3-fluorobenzoate Methyl 3,4-difluorobenzoate (1.0 eq.), 4-(dimethoxymethyl)piperidine (1.0 eq.), and TEA (2.5 eq.) were dissolved in DMSO (10V). The mixture was heated to 70-80oC and stirred at this temperature for 16-24 hr. After cooling to 35-45oC, water (20V) was added dropwise, then stirred at 15-25oC for 8-16 hr, during which a solid precipitate formed. The solid was collected and dried to obtain the product (80% yield).

[0166] Step 2: Synthesis of 5-(4-(dimethoxymethyl)piperidin-1-yl)-4-fluoro-3- hydroxyisobenzofuran-1(3H)-one TMP (2.5 eq.) was dissolved in 2-MeTHF (10V) and cooled to -10 to -5oC. n-BuLi (2 eq.) was added dropwise and stirred for 0.5-1 hr at this temperature. Afterwards, the mixture was cooled to -75 to -45oC and a clear solution of methyl 4-(4-(dimethoxymethyl)piperidin- 1-yl)-3-fluorobenzoate (1 eq.) in 2-MeTHF (10V) was added dropwise followed by HC(O)OMe (2 eq), after which the mixture was stirred for 0.5-1.5 hr at -75 to -45oC. The mixture was quenched at -75 to -30oC with a 0.5 M aqueous LiOH solution (1V) and warmed to -15 to -5oC, where 9V more of the 0.5 M LiOH solution was added. The mixture was further warmed to 15-25oC and stirred at this temperature for 1-3 hr. The mixture was 45 ME151383177v.1 137508-02320 separated and organic and aqueous phases both collected. The aqueous phase was extracted with 2-MeTHF (5V). The combined organic phases were washed with the 0.5 M LiOH solution (5V). The combined aqueous phases were adjusted to pH 3.5-4.5 with a 1 M aqueous HCl solution, upon which a suspension formed and was stirred for 2-10 hr. The solid was collected and tried to obtain the product (73% yield).

[0167] Step 3: Synthesis of 3-(5-(4-(dimethoxymethyl)piperidin-1-yl)-4-fluoro-1- oxoisoindolin-2-yl)piperidine-2,6-dione (Formula (V)) 2,6-dioxopiperidin-3-aminium chloride (2 eq.) and NaOAc (2 eq.) were dissolved in MeOH (20V) and stirred for 0.5 hr at 20-30oC.5-(4-(dimethoxymethyl)piperidin-1-yl)-4- fluoro-3-hydroxyisobenzofuran-1(3H)-one (1 eq.) and AcOH (5 eq.) were added and the mixture stirred for an additional 0.5 hr.2-MePy ● BH3 (2 eq) was added, the mixture warmed to 48-58oC, and stirred for 0.5-1 hr at this temperature. AcOH (35 eq.) was added and mixture continued to stir at 48-58oC for 15-24 hr. Afterwards, the mixture was cooled to 15- 25oC, water was added (30V), and the mixture stirred for an additional 18 hr at this temperature, during which a suspension was formed. The solid was collected, washed with a 2:3 MeOH:water solution (5V), and dried to obtain 3-(5-(4-(dimethoxymethyl)piperidin-1- yl)-4-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione (Formula (V), 66.4% yield).

[0168] Scheme 6: Synthesis of a compound of Formula (IV)

[0169] Step 1: Synthesis of 1-(2-(2,6-dioxopiperidin-3-yl)-4-fluoro-1-oxoisoindolin-5- yl)piperidine-4-carbaldehyde (Formula (IV)) 3-(5-(4-(dimethoxymethyl)piperidin-1-yl)-4-fluoro-1-oxoisoindolin-2-yl)piperidine- 2,6-dione (403 g) was added to acetone (4.0 kg), followed by water (530 g) and TsOH monohydrate (31 g, 0.2 eq.). The reaction mixture was heated to a gentle reflux (approximately 56oC), and stirred at this temperature for 16 hours. Then the reaction was cooled to room temperature and stirred at room temperature for 1 hour. The solid was collected by filtration, and filter cake was washed with acetone (1.9 kg) and dried under vacuum to 30oC for 17 hours to yield 1-(2-(2,6-dioxopiperidin-3-yl)-4-fluoro-1- oxoisoindolin-5-yl)piperidine-4-carbaldehyde (Formula (IV), 354.8 g, 98.8% yield). 46 ME151383177v.1 137508-02320

[0170] Scheme 7: Synthesis of a compound of Formula (V)

[0171] Step 1: Synthesis of 3-(5-(4-((3,3-dimethyl-4-((1-(6-(5-(1-methylcyclopropoxy)-1H- indazol-3-yl)pyrimidin-4-yl)piperidin-4-yl)methyl)piperazin-1-yl)methyl)piperidin-1-yl)-4- fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione (Formula (V)) 3-(6-(4-((2,2-dimethylpiperazin-1-yl)methyl)piperidin-1-yl)pyrimidin-4-yl)-5-(1- methylcyclopropoxy)-1H-indazole [3 HCl] (Formula (I’), 582.8g, 1.05 eq) was added to N,N- dimethylacetamide (2.9 kg), and to this mixture was added N-methylmorpholine (288g, 3 eq.) at room temperature. After stirring for 20 minutes, 1-(2-(2,6-dioxopiperidin-3-yl)-4-fluoro-1- oxoisoindolin-5-yl)piperidine-4-carbaldehyde (Formula (IV), 353.7g) was added, followed by NaBH(OAc)3(442, 2.2 eq) in portions such that the reaction temperature was kept at 20oC to 37oC during addition. The resulting yellow suspension was reaction was stirred at 27oC – 30oC for 4.5 hours. The reaction quenched with the addition of water (84 g), which warmed the mixture to 32oC. The mixture was cooled to 26oC and stirred at this temperature for 15 minutes, after which acetone (2.4 kg) and additional water (1.5 kg) were added, which warmed the mixture to 32oC. The mixture was warmed to 33oC and a seed crystal added. Additional water (4.0 kg) was added at 33oC – 39oC over 1 hour and the mixture stirred at this temperature for another hour. The reaction was cooled to 22oC – 30oC and stirred at this temperature for 15 hours. The solid was collected by filtration and washed with water (6.4kg). The collected wet filter cake (1.8 kg) was added to a mixture of CH2Cl2(7.0 kg) and MeOH (489 g), and acetic acid (417 g). The mixture was stirred at room temperature until a 2-phase solution was obtained. The phases were separated, and the organic phase collected. 47 ME151383177v.1 137508-02320 The organic phase was set up for distillation at atmospheric pressure under elevated temperature. At the same time acetonitrile (2.0 kg) was added to the mixture. After 2.5 L of solution was removed, crystallization begun to occur. Additional acetonitrile (7.1 kg) was added to the mixture to maintain a constant volume. Distillation stopped when about 9L of distillate was collected. The resulting suspension was cooled to room temperature and stirred at this temperature for 12 hours. Then the solids were collected by filtration and washed with acetonitrile (3.2 kg) and dried under vacuum at 60oC – 65oC. To the resultant solid was added acetic acid (400 mL) and water (175 mL), and the mixture heated to 50oC, and stirred for 30 minutes. The mixture was concentrated under reduced pressure, and EtOH (3.9 L) was added. The mixture was warmed to 50oC and additional EtOH (2.1 L) was allowed to cool while stirring. After stirring 18 hours at room temperature, the solids were collected by filtration and washed with EtOH (2.1 kg). The collected filter cake was dried at 60oC – 65oC under vacuum for 3 days to yield 3-(5-(4-((3,3- dimethyl-4-((1-(6-(5-(1-methylcyclopropoxy)-1H-indazol-3-yl)pyrimidin-4-yl)piperidin-4- yl)methyl)piperazin-1-yl)methyl)piperidin-1-yl)-4-fluoro-1-oxoisoindolin-2-yl)piperidine- 2,6-dione (Formula (V), 657.7 g, 83.4%).

[0172] The contents of all references (including literature references, issued patents, published patent applications, and co-pending patent applications) cited throughout this application are hereby expressly incorporated herein in their entireties by reference. Unless otherwise defined, all technical and scientific terms used herein are accorded the meaning commonly known to one with ordinary skill in the art. 48 ME151383177v.1

Claims

137508-02320 CLAIMS What is claimed is:

1. A method of preparing a compound of Formula (I):the method comprising: reacting a compound of Formula (II):with a compound of Formula (III):and a palladium source in the presence of a base.

2. The method of claim 1 or 2, wherein the palladium source is a complex comprising palladium optionally substituted with one or more ligands.

3. The method of claim 2, wherein the ligands are independently selected from PPh3, P(o-tolyl)3, Pt-Bu3, Pt-Bu3 · HBF4, PCy3, n-BuP(Ad)2, BINAP, Xantphos, DPEPhos, CyPFt- Bu, dppp, dppf, dtbpf, JohnPhos, CyJohnPhos, DavePhos, RuPhos, SPhos, XPhox, BrettPhos, t-BuXPhos, t-BuBrettPhos, Me4t-BuXPhos, BippyPhos, MorDalPhos, and IPr · HCl. 49 ME151383177v.1137508-02320 4. The method of any one of claims 1 to 3, wherein the palladium source is Pd(dppf)Cl2.

5. The method of any one of claims 1 to 4, wherein the base is an inorganic base.

6. The method of any one of claims 1 to 5, wherein the base is K2CO3.

7. The method of any one of claims 1 to 4, wherein the base is an organic base.

8. The method of any one of claims 1 to 4 and 7, wherein the base is selected from NH2(C1-6 alkyl), NH(C1-6 alkyl)2, N(C1-6 alkyl)3, a phosphazene, 1,8- diazabicyclo(5.4.0)undec-7-ene (DBU), 1,5-diazabicyclo[4.3.0]non-5-ene (DBN), guanidine, 1,1,3,3-tetramethylguanidine, optionally substituted pyridine, N-methylmorpholine, and 1,4- diazabicyclo[2.2.2]-octane (DABCO), wherein each C1-6 alkyl of the NH(C1-6 alkyl)2 and N(C1-6 alkyl)3 is independently selected.

9. The method of any one of claims 1 to 8, wherein the reaction is performed in the presence of a solvent.

10. The method of claim 9, wherein the solvent is a mixture of an organic solvent and water.

11. The method of claim 9 or 10, wherein the solvent is a mixture of dioxane and water.

12. The method of any one of claims 1 to 11, further comprising reacting the compound of Formula I with acid to form a compound of Formula (I’):or a salt thereof. 50 ME151383177v.1137508-02320 13. The method of claim 12, wherein the acid is selected from HF, HCl, HBr, HI, HCN, H3BO3, H3PO4, H2SO3, H2SO4, HClO4, HNO3, H2C2O4, HIO4, CH3C(O)OH, C5H5NH+, and HN+(C1-6alkyl)4, wherein each C1-6alkyl of the HN+(C1-6alkyl)4is independently selected.

14. The method of claim 12 or 13, wherein the acid is HCl.

15. The method of any one of claims 12 to 14, wherein the salt is an HCl salt.

16. The method of any one of claims 12 to 15, wherein the reaction is performed in the presence a solvent.

17. The method of claim 16, wherein the solvent is solvent mixture of two organic solvents.

18. The method of claim 16 or 17, wherein the solvent is a mixture of MeOH and EtOAc.

19. The method of any one of claims 12 to 18, further comprising reacting the compound of Formula (I’) in the presence of a base and reducing agent with a compound of Formula (IV):to form a compound of Formula (V):

20. The method of claim 19, wherein the reducing agent comprises boron. 51 ME151383177v.1137508-02320 21. The method of claim 19 or 20, wherein the reducing agent is selected from NaBH(OAc)3, NaCNBH3, NaBH4, BH3· NCH3, and 2-methylpyridine borane.

22. The method of any one of claims 19 to 21, wherein the reducing agent is NaBH(OAc)3.

23. The method of any one of claims 19 to 22, wherein the base is an organic base.

24. The method of any one of claims 19 to 23, wherein the base is selected from NH2(C1-6alkyl), NH(C1-6 alkyl)2, N(C1-6 alkyl)3, a phosphazene, 1,8-diazabicyclo(5.4.0)undec-7-ene (DBU), 1,5-diazabicyclo[4.3.0]non-5-ene (DBN), guanidine, 1,1,3,3-tetramethylguanidine, optionally substituted pyridine, N-methylmorpholine, and 1,4-diazabicyclo[2.2.2]-octane (DABCO), wherein each C1-6 alkyl of the NH(C1-6 alkyl)2 and N(C1-6 alkyl)3 is independently selected.

25. The method of any one of claims 19 to 24, wherein the base is N-methylmorpholine.

26. The method of any one of claims 19 to 25, wherein the reaction is performed in the presence a solvent.

27. The method of claim 26, wherein the solvent is an organic solvent.

28. The method of claim 26 or 27, wherein the solvent is dimethylformamide or dimethylacetamide.

29. The method of claim 26 or 27, wherein the solvent is dimethylacetamide.

30. A method of preparing a compound of Formula (XIII):52 ME151383177v.1137508-02320 or a salt thereof, the method comprising: reacting a compound of Formula (XVI):or a salt thereof, with CH2X2 and a catalyst, wherein each X is independently halo.

31. The method of claim 30, wherein both X are the same halo.

32. The method claim 30 or 31, wherein CH2X2 is CH2I2.

33. The method of any one of claims 30 to 32, wherein the catalyst is a metal catalyst.

34. The method of any one of claims 30 to 33, wherein the catalyst is an aluminum or zinc catalyst.

35. The method of any one of claims 30 to 34, wherein the catalyst is ZnEt2, i-Bu3Al, or n-Oct3Al.

36. The method of any one of claims 30 to 35, wherein the catalyst is ZnEt2.

37. The method of any one of claims 30 to 36, wherein the reacting step is performed in the presence of a solvent.

38. The method of claim 37, wherein the solvent is an organic solvent.

39. The method of claim 37 or 38, wherein the solvent is trifluorotoluene.

40. The method of any one of claims 30 to 39, further comprising the addition of an acid.

41. The method of claim 40, wherein the acid is an organic acid. 53 ME151383177v.1137508-02320 42. The method of claim 40 or 41, wherein the acid is trichloroacetic acid, trifluoroacetic acid, acetic acid, or formic acid.

43. The method of any one of claims 40 to 42, wherein the acid is trichloroacetic acid.

44. A method of preparing a compound of Formula (XVI):or a salt thereof, the method comprising reacting a compound of Formula (XIV):or a salt thereof, with pentane-2,4-dione, a base, a catalyst, and a compound of Formula (XV):or a salt thereof, wherein X1is halo.

45. The method of claim 44, wherein X1is Br, Cl, or I.

46. The method of claim 44 or 45, wherein X1is Br.

47. The method of any one of claims 44 to 46, wherein the catalyst is a metal catalyst.

48. The method of any one of claims 44 to 47, wherein the catalyst is a copper catalyst.

49. The method of any one of claims 44 to 48, wherein the catalyst is CuCl. 54 ME151383177v.1137508-02320 50. The method of any one of claims 44 to 49, wherein the base is an inorganic base.

51. The method of any one of claims 44 to 50, wherein the base is K2CO3, sodium tert- butoxide, Cs2CO3, KOH, NaOH, CsF, and NaOAc.

52. The method of any one of claims 44 to 51, wherein the base is Cs2CO3.

53. The method of any one of claims 44 to 52, wherein pentane-2,4-dione is provided in a catalytic amount.

54. The method of any one of claims 44 to 53, wherein the reacting step is performed in the presence of a solvent.

55. The method of claim 54, wherein the solvent is an organic solvent.

56. The method of claim 54 or 55, wherein the solvent is tetrahydrofuran.

57. A method preparing a compound of Formula (II):or a salt thereof, the method comprising reacting a compound of Formula (XIII): (XIII), or a salt thereof, with bis(pinacolato)diboron and an iridium source.

58. The method of claim 57, wherein the iridium source is a complex comprising iridium optionally substituted with one or more ligands. 55 ME151383177v.1137508-02320 59. The method of claim 57 or 58, wherein the iridium source is Ir(acac)3, (1,5- cyclooctadiene)(pyridine)(tricyclohexylphosphine)-Ir ● PF6, Ir(ppy)3, (1,5- cyclooctadiene)(hexafluoroacetylacetonato)iridium, diiodo(pentamethylcyclopentadienyl)iridium dimer, tris[2-(4,6-difluorophenyl)pyridinato- C2,N]iridium, (acetylacetonato)(1,5-cyclooctadiene)iridium, (1,5- Cyclooctadiene)(methoxy)iridium dimer, (1,5- cyclooctadiene)bis(methyldiphenylphosphine)iridium(I) hexafluorophosphate, or tris[2-(p- tolyl)pyridine]iridium, or bis[2-(4,6-difluorophenyl)pyridinato-C2,N](picolinato)iridium.

60. The method of any one of claims 57 to 59, wherein the iridium source is (1,5- cyclooctadiene)(methoxy)iridium(I) dimer.

61. The method of any one of claims 57 to 60, further comprising the addition of a ligand.

62. The method of claim 61, wherein the ligand is 4-tert-butyl-2-(4-tert-butyl-2- pyridyl)pyridine, PPh3, P(o-tolyl)3, Pt-Bu3, Pt-Bu3· HBF4, PCy3, n-BuP(Ad)2, BINAP, Xantphos, DPEPhos, CyPFt-Bu, dppp, dppf, dtbpf, JohnPhos, CyJohnPhos, DavePhos, RuPhos, SPhos, XPhox, BrettPhos, t-BuXPhos, t-BuBrettPhos, Me4t-BuXPhos, BippyPhos, MorDalPhos, or IPr · HCl.

63. The method of claim 61 or 62, wherein the ligand is 4-tert-butyl-2-(4-tert-butyl-2- pyridyl)pyridine.

64. The method of any one of claims 57 to 63, wherein the reacting step is performed in the presence of a solvent.

65. The method of claim 64, wherein the solvent is an organic solvent.

66. The method of claim 64 or 65, wherein the solvent is methyl tert-butyl ether. 56 ME151383177v.1

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