Methods for preparing intermediates and compounds useful in protein degradation

Abstract

Provided are methods for synthesizing compounds that are useful in the production of protein targeting chimeras (PROTACs).

Description

[0001] 137508-03520

[0002] METHODS FOR PREPARING INTERMEDIATES AND COMPOUNDS USEFUL IN PROTEIN DEGRADATION

[0003] RELATED APPLICATIONS

[0004]

[0001] This application claims priority to U.S. Provisional Application No. 63 / 729,855, filed on December 9, 2024. The entire contents of the foregoing application are expressly incorporated herein by reference.

[0005] BACKGROUND

[0006]

[0002] Targeted protein degradation is an emerging area of research which provides a means for attacking disease-causing proteins that are otherwise challenging to combat with traditional small molecules. One particular and successful approach has been to employ the use of proteolysis-targeting chimera (PROTAC) molecules. These molecules engage in targeted protein degradation by inducing selective intracellular proteolysis. Clinical trials have shown that PROTACs can effectively treat a variety of cancers and new-generation PROTACs are emerging at a rapid rate.

[0007]

[0003] PROTACs are heterobifunctional molecules that comprise three main components, (1) a domain which is responsible for binding a target protein, (2) a domain which is capable of engaging an E2 ubiquitin ligase and (3) a linker connecting these two active domains. Each of these three components play a role in the stability, efficacy, and overall pharmacokinetic properties of the PROTAC. Giving the emerging interest and therapeutic potential of PROTACs, more efficient means for preparing not only PROTACs as a whole, but also each component of a PROTAC, are needed.

[0008] SUMMARY

[0009]

[0004] Provided are methods for synthesizing compounds useful in the production of PROTACs. In one aspect, these methods can be used to synthesize compounds which form part of, or the entire linker component for PROTAC molecules. In another aspect, these methods can be used to synthesize certain ubiquitin ligase E3 ubiquitin ligase (or similar) binding components.

[0010]

[0005] Such methods include, in one aspect, methods of preparing a ubiquitin ligase binding component represented by a compound of Formula (Via):

[0011] N

[0012]

[0013] MEI 51411438v.l 137508-03520

[0014] or a salt thereof, wherein:

[0015] Ring F is cycloalkyl, heterocyclyl, phenyl, or heteroaryl, each of which are optionally substituted by one or more RF;

[0016] RNis H, Ci-4alkyl, Ci-4haloalkyl, cycloalkyl, heterocyclyl, phenyl, or heteroaryl, wherein the cycloalkyl, heterocyclyl, phenyl, and heteroaryl are each optionally substituted by one or more R10;

[0017] each R10is independently halo, Ci-4alkyl, or Ci-4haloalkyl;

[0018] or two R10, together with the carbon to which they are attached, form oxo;

[0019] each RFis independently halo, Ci-4alkyl, Ci-4haloalkyl, -ORFa, -N(RFa)2, -SC>2RFb, -C(O)RFb, -N(RFa)SC>2RFb, cycloalkyl, heterocyclyl, phenyl, or heteroaryl, wherein the cycloalkyl, heterocyclyl, phenyl, and heteroaryl are each optionally substituted by one or more R9;

[0020] each RFbis independently Ci-4alkyl, Ci-4haloalkyl, -ORFa, or -N(RFa)2;

[0021] each R9is independently halo, Ci-4alkyl, Ci-4haloalkyl, -OR9a, -N(R9a)2, cycloalkyl, heterocyclyl, phenyl, or heteroaryl, wherein the Ci-4alkyl is optionally substituted by one or more Ci-4alkoxy;

[0022] each R9aand RFais independently H, Ci-4alkyl, or Ci-4haloalkyl;

[0023] the method comprising:

[0024] reacting a compound of Formula (Vila):

[0025] O

[0026]

[0027] OR8(Vila),

[0028] or a salt thereof, wherein R8is H, Ci-4alkyl or Ci-4haloalkyl;

[0029] with a compound of Formula (Villa):

[0030] H

[0031] N-RN

[0032] H (Villa),

[0033] or a salt thereof.

[0034]

[0006] In another aspect, provided herein are methods of preparing a PROTAC linker component represented by a compound of Formula (Illa):

[0035]

[0036] MEI 51411438v.l 137508-03520

[0037] or a salt thereof, wherein:

[0038] X1, X2, X3, and X4are each N or CRX;

[0039] each Rxis, independently, H, halo, Ci-3alkyl, Ci-3haloalkyl, -ORXa, -NRXaRxb, -C(O)H, -C(O)OH, -C(O)ORXa, or -C(O)NRXaRxb;

[0040] RXaand Rxbare each, independently, H, halo, Ci-3alkyl, Ci-3haloalkyl, or C3-ecycloalkyl;

[0041] Ring A and Ring B are each, independently, 4- to 12-membered heterocyclyl; each RAand RBis, independently, halo, Ci-3alkyl, Ci-3haloalkyl, -ORA1, -NRA1RA1, -C(O)H, -C(O)OH, -C(O)ORA1, or -C(O)NRA1RA1;

[0042] each RA1is, independently, H, halo, Ci-4alkyl, Ci-3haloalkyl, or C3-6cycloalkyl;

[0043] T is halo; and

[0044] o and p are each, independently, 0, 1, 2, 3, or 4;

[0045] the method comprising:

[0046] reacting a compound of Formula (Xa):

[0047] T

[0048] Vx4

[0049] ,0

[0050] X2-X3

[0051]

[0052] H

[0053] or a salt thereof,

[0054] with a compound of Formula (Xia):

[0055] 'P

[0056] B

[0057]

[0058] (Xia),

[0059] or a salt thereof,

[0060] in the presence of a reducing agent.

[0061]

[0007] In certain aspect, the methods described herein are higher yielding, have less reaction steps, have reduced purification needs (such as avoidance of column chromatography), and / or are less expensive (due to the absence of higher priced materials, less purification, and reaction less steps) then previous methods.

[0062] DETAILED DESCRIPTION

[0063]

[0008] Definitions

[0064] MEI 51411438v.l 137508-03520

[0065]

[0009] 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.

[0066]

[0010] 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.

[0067] Freeman & Co., N. Y. (1999); and Gilbert et al. “Developmental Biology, 6th ed.,” Sinauer Associates, Inc., Sunderland, M A (2000).

[0068] [Oil] 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).

[0069]

[0012] 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 / / -butyl lithium, / -butyl lithium, LDA, K2CO3, Sodium Zc / 'Z-butoxide, CS2CO3, KOH, NaOH, CsF, NaOAc, trimethylamine, N, N-diisopropylethylamine, l,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 l,4-diazabicyclo[2.2.2]-octane (DABCO).

[0070]

[0013] 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, HC1, HBr, HI, HCN, H3BO3, H3PO4, H2SO3, H2SO4, HCIO4, HNO3, H2C2O4, HIO4, CH3C(O)OH, C5H5NH+ HN+(CH2CH3)3, and HN+(CH2CH3)(CH(CH3)2)2.

[0071]

[0014] 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, NaCNBH?, NaBH4, BH3 • NCH3, and 2-methylpyridine borane.

[0072] 4

[0073] MEI 51411438v.l 137508-03520

[0074]

[0015] 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.

[0075]

[0016] The term “organic solvent” refers to a solvent comprising all organic elements.

[0076]

[0017] The term “alkyl” refers to saturated aliphatic groups, including straight-chain and branched-chain alkyl groups. In preferred embodiments, a straight chain or branched chain alkyl has six or fewer carbon atoms in its backbone (e.g., Ci-Ce for straight chains, C3-C6 for branched chains), and more preferably four or less carbons in its backbone.

[0077]

[0018] The term “alkoxy” refers to an alkyl group having an oxygen attached thereto, represented by -O-alkyl. For example, “C1-C4 alkoxy” includes methoxy, ethoxy, propoxy, isopropoxy, and butoxy.

[0078]

[0019] The term “C -G-,” when used in conjunction with a chemical moiety (e.g, alkyl, alkoxy) is meant to include groups that contain from x to y carbons in the chain. A Ci-Ce alkyl group, for example, contains from one to six carbon atoms in the chain; a Ci-C4-alkyl contains from one to four carbon atoms in the chain.

[0079]

[0020] The terms “halo,” “halogen,” and “halogen groups,” as used herein, refer to a substituent group from Group 17 of the periodic table of the elements and includes fluoro (-F), chloro (-C1), bromo(-Br), and iodo (-1) substituent groups.

[0080]

[0021] The terms “haloalkyl” and “haloalkoxy” refer to alkyl or alkoxy, respectively, substituted with one or more halogen atoms.

[0081]

[0022] The term “oxo” refers to an oxygen atom which is connected to a carbon atom via a double bond (=0).

[0082]

[0023] 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.

[0083]

[0024] 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 5

[0084] MEI 51411438v.l 137508-03520

[0085] 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, benzodi oxolyl, dihydrobenzodioxinyl, dihydrobenzofuranyl, dihydrobenzothiophenyl, 5-oxa-2,6-diazaspiro[3.4]oct-6-enyl, 6-thia-2,7-diazaspiro[3.4]octanyl, 2,6-diazaspiro[3.3]heptanyl, spiro[indoline-3,3'-pyrrolidine]-yl, indolinyl, isoindolinyl 6,7-dihydro-5H-pyrrolo[3,4-b]pyridinyl, thiochromanyl, dihydropyrido[2,3-b][l,4]oxazinyl, tetrahydropyrido[2,3-b][l,4]oxazepinyl, dihydro-2H-pyrano[2,3-b]pyridinyl, 5,6-dihydro-4H-pyrazolo[l,5-d][l,4]diazepin-7(8H)-only, 7-azaspiro[3.5]nonanyl, 2-azaspiro[3.3]heptanyl, 2-azaspiro[3.5]nonanyl, 3-azaspiro[5.5]undecanyl, 3-azabicyclo[3.1.0]hexanyl, and the like. It will be understood that when specified, optional substituents on a heterocyclyl group may be present on any substitutable position and, include, e.g., the position at which the heterocyclyl is attached (where valency permits).

[0086]

[0025] The term “spiro” refers to two rings that shares one ring atom e.g., carbon).

[0087]

[0026] The term “fused” refers to two rings that share two adjacent ring atoms with one another.

[0088]

[0027] The term “bridged” refers to two rings that share three adjacent ring atoms with one another.

[0089]

[0028] The term “substituted” refers to moieties having substituents replacing a hydrogen on one or more carbons of the backbone. It will be understood that “substitution” or “substituted with” includes the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and the substituent, and that the substitution results in a stable compound, e.g., which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc. As used herein, the term “substituted” is contemplated to include all permissible substituents of organic compounds. Broadly, the permissible substituents include acyclic and cyclic, branched, and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic substituents of organic compounds. The permissible substituents can be one or more and the same or different for appropriate organic compounds. For purposes of this invention, the heteroatoms such as nitrogen may have 6

[0090] MEI 51411438v.l 137508-03520

[0091] 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.

[0092]

[0029] 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.

[0093] A. Ubiquitin Ligase Binding Component

[0094]

[0030] In embodiments, provided herein is a method of preparing a ubiquitin ligase binding component represented by a compound of Formula (Via):

[0095] O

[0096]

[0097] or a salt thereof, wherein:

[0098] Ring F is cycloalkyl, heterocyclyl, phenyl, or heteroaryl, each of which are optionally substituted by one or more RF;

[0099] RNis H, Ci-4alkyl, Ci-4haloalkyl, cycloalkyl, heterocyclyl, phenyl, or heteroaryl, wherein the cycloalkyl, heterocyclyl, phenyl, and heteroaryl are each optionally substituted by one or more R10;

[0100] 7

[0101] MEI 51411438v.l 137508-03520

[0102] each R10is independently halo, Ci-4alkyl, or Ci-4haloalkyl;

[0103] or two R10, together with the carbon to which they are attached, form oxo;

[0104] each RFis independently halo, Ci-4alkyl, Ci-4haloalkyl, -ORFa, -N(RFa)2, -SC>2RFb, -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;

[0105] each RFbis independently Ci-4alkyl, Ci-4haloalkyl, -ORFa, or -N(RFa)2;

[0106] each R9is independently halo, Ci-4alkyl, Ci-4haloalkyl, -OR9a, -N(R9a)2, cycloalkyl, heterocyclyl, phenyl, or heteroaryl, wherein the Ci-4alkyl is optionally substituted by one or more Ci-4alkoxy;

[0107] each R9aand RFais independently H, Ci-4alkyl, or Ci-4haloalkyl;

[0108] the method comprising:

[0109] reacting a compound of Formula (Vila):

[0110] O

[0111]

[0112] OR8(Vila),

[0113] or a salt thereof, wherein R8is H, Ci-4alkyl or Ci-4haloalkyl;

[0114] with a compound of Formula (Villa):

[0115] H

[0116] N-RN

[0117] H (Villa),

[0118] or a salt thereof.

[0119]

[0031] 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.

[0120]

[0032] In embodiments, for the method of preparing a compound of Formula (Via), the method further comprises the steps of preparing the compound of Formula (Vila) by reacting a compound of Formula (IXa):

[0121] 8

[0122] MEI 51411438v.l 137508-03520

[0123] o

[0124] ( F 0-R°z x

[0125]

[0126] (IXa),

[0127] or a salt thereof, with HC(O)OR01in the presence of a base, wherein R° and RO1are each independently H, Ci-4alkyl, or Ci-4haloalkyl.

[0128]

[0033] In embodiments, for the method of preparing a compound of Formula (Vila), the base is a lithium base. In embodiments, for the method of preparing a compound of Formula (Vila), the base is / / -butyl lithium.

[0129]

[0034] In embodiments, for the method of preparing a compound of Formula (Via) or (Vila), the reaction is performed in the presence of a solvent. In embodiments, for the method of preparing a compound of Formula (Via) or (Vila), the solvent is an organic solvent. In embodiments, for the method of preparing a compound of Formula (Via) or (Vila), the solvent is methanol or 2-methyl tetrahydrofuran.

[0130]

[0035] In embodiments, for the method of preparing a compound of Formula (Via) or (Vila), 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 (Vila), 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 (Vila), 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 (Vila), 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 (Vila), Ring F is phenyl substituted by 2 RF.

[0131]

[0036] In embodiments, for the method of preparing a compound of Formula (Via) or (Vila), each RFis independently halo, Ci-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 (Vila), 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 (Vila), 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 (Vila), each RFis independently -F or piperdinyl, wherein the piperdinyl is substituted by 1 R9.

[0132] 9

[0133] MEI 51411438v.l 137508-03520

[0134]

[0037] In embodiments, for the method of preparing a compound of Formula (Via) or (Vila), each R9is independently halo, Ci-3alkyl, C1-3haloalkyl, wherein the Ci-3alkyl is optionally substituted by 1 or 2 Ci-3alkoxy. In embodiments, for the method of preparing a compound of Formula (Via) or (Vila), each R9is independently Ci-3alkyl optionally substituted by 1 or 2 Ci-3alkoxy. In embodiments, for the method of preparing a compound of Formula (Via) or (Vila), each R9is -CH(OCH3)2.

[0135]

[0038] 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.

[0136]

[0039] In embodiments, for the method of preparing a compound of Formula (Via), R10, together with the carbon to which they are attached, form oxo.

[0137]

[0040] In embodiments, for the method of preparing a compound of Formula (Vila), R° is H.

[0138]

[0041] In embodiments, for the method of preparing a compound of Formula (Vila), RO1is Ci-3alkyl. In embodiments, for the method of preparing a compound of Formula (Vila), RO1is -CH3.

[0139]

[0042] In embodiments, for the method of preparing a compound of Formula (Via), the compound of Formula (Via) is a compound of Formula (VI):

[0140]

[0141] or a salt thereof.

[0142]

[0043] In embodiments, for the method of preparing a compound of Formula (Via) or (Vila), the compound of Formula (Vila) is a compound of Formula (VII):

[0143] O

[0144]

[0145] (VII),

[0146] 10

[0147] MEI 51411438v.l 137508-03520

[0148] or a salt thereof.

[0149]

[0044] In embodiments, for the method of preparing a compound of Formula (Via), the compound of Formula (Villa) is a compound of Formula (VIII):

[0150] O

[0151]

[0152] (VIII),

[0153] or a salt thereof.

[0154]

[0045] In embodiments, for the method of preparing a compound of Formula (Via), the compound of Formula (Villa) or (VIII) is a salt. In embodiments, for the method of preparing a compound of Formula (Via), the compound of Formula (Villa) or (VIII) is a hydrochloride salt.

[0155]

[0046] In embodiments, for the method of preparing a compound of Formula (Vila), the compound of Formula (IXa) is a compound of Formula (IX):

[0156] O

[0157]

[0158] (IX),

[0159] or a salt thereof.

[0160] B. PROTAC Linker Component

[0161]

[0047] In embodiments, provided herein is a method of preparing a PROTAC linker component represented by a compound of Formula (Illa):

[0162]

[0163] (Illa),

[0164] or a salt thereof, wherein:

[0165] X1, X2, X3, and X4are each N or CRX;

[0166] each Rxis, independently, H, halo, Ci-3alkyl, C1-3haloalkyl, -ORXa, -NRXaRxb, -C(O)H, -C(O)OH, -C(O)ORXa, or -C(O)NRXaRxb;

[0167] RXaand Rxbare each, independently, H, halo, Ci-3alkyl, Ci-3haloalkyl, or C3-ecycloalkyl;

[0168] Ring A and Ring B are each, independently, 4- to 12-membered heterocyclyl;

[0169] 11

[0170] MEI 51411438v.l 137508-03520

[0171] each RAand RBis, independently, halo, Ci-3alkyl, Ci-3haloalkyl, -ORA1, -NRA1RA1, -C(O)H, -C(O)OH, -C(O)ORA1, or -C(O)NRA1RA1;

[0172] each RA1is, independently, H, halo, Ci-4alkyl, Ci-3haloalkyl, or C3-6cycloalkyl;

[0173] T is halo; and

[0174] o and p are each, independently, 0, 1, 2, 3, or 4;

[0175] the method comprising:

[0176] reacting a compound of Formula (Xa):

[0177]

[0178] or a salt thereof,

[0179] with a compound of Formula (Xia):

[0180] (RB)P

[0181] I B

[0182] N

[0183]

[0184] H (Xia),

[0185] or a salt thereof,

[0186] in the presence of a reducing agent.

[0187]

[0048] In embodiments, for the method of preparing a compound of Formula (Illa), the reducing agent comprises boron. In embodiments, for the method of preparing a compound of Formula (Illa), the reducing agent is selected from NaBH(OAc)3, NaCNBH3, NaBH4U, BH3 • NCH3, and 2-methylpyridine borane. In embodiments, for the method of preparing a compound of Formula (Illa), the reducing agent is NaBH(OAc)3.

[0188]

[0049] In embodiments, for the method of preparing a compound of Formula (Illa), the method further comprises the steps of preparing the compound of Formula (Xa) by reacting a compound of Formula (Xlla):

[0189]

[0190] or a salt thereof, with an acid, and wherein each R11is independently H, Ci-3alkyl, or C1-3haloalkyl.

[0191] MEI 51411438v.l 137508-03520

[0192]

[0050] 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, HC1, HBr, HI, HCN, H3PO4, H2SO3, H2SO4, or HNO3. In embodiments, for the method of preparing a compound of Formula (Xa), the acid is H2SO4.

[0193]

[0051] In embodiments, for the method of preparing a compound of Formula (Illa) or (Xa), the reaction is performed in the presence of a solvent. In embodiments, for the method of preparing a compound of Formula (Illa) or (Xa), the solvent is an organic solvent. In embodiments, for the method of preparing a compound of Formula (Illa) or (Xa), the solvent is di chloromethane or 2-methyl tetrahydrofuran.

[0194]

[0052] In embodiments, for the method of preparing a compound of Formula (Illa) or (Xa), X1and X3are N and X2and X4are CH.

[0195]

[0053] In embodiments, for the method of preparing a compound of Formula (Illa) or (Xa), T is -Cl.

[0196]

[0054] In embodiments, for the method of preparing a compound of Formula (Illa) or (Xa), Ring A is a 5- to 7-membered heterocyclyl. In embodiments, for the method of preparing a compound of Formula (Illa) or (Xa), Ring A is a 6-membered heterocyclyl. In embodiments, for the method of preparing a compound of Formula (Illa) or (Xa), Ring A is piperdinyl.

[0197]

[0055] In embodiments, for the method of preparing a compound of Formula (Illa) or (Xa), o is 0.

[0198]

[0056] In embodiments, for the method of preparing a compound of Formula (Illa), Ring B is a 5- to 7-membered heterocyclyl. In embodiments, for the method of preparing a compound of Formula (Illa), Ring B is a 6-membered heterocyclyl. In embodiments, for the method of preparing a compound of Formula (Illa), Ring B is piperazinyl.

[0199]

[0057] In embodiments, for the method of preparing a compound of Formula (Illa), p is 0, 1, 2, or 3. In embodiments, for the method of preparing a compound of Formula (Illa), p is 3.

[0200]

[0058] In embodiments, for the method of preparing a compound of Formula (Illa), each RBis independently halo, Ci-3alkyl, Ci-3haloalkyl, or -C(O)OR4a. In embodiments, for the method of preparing a compound of Formula (Illa), each RBis independently Ci-3alkyl or -C(O)OR4a. In embodiments, for the method of preparing a compound of Formula (Illa), RBis independently -CH3 or -C(O)OC(CH3)3.

[0201]

[0059] In embodiments, for the method of preparing a compound of Formula (Illa), R4ais Ci-4alkyl.

[0202] 13

[0203] MEI 51411438v.l 137508-03520

[0204]

[0060] In embodiments, for the method of preparing a compound of Formula (Xa), each R11is independently Ci-3alkyl. In embodiments, for the method of preparing a compound of Formula (Xa), each R11is -CH3.

[0205]

[0061] In embodiments, for the method of preparing a compound of Formula (Illa), the compound of Formula (Illa) is a compound of Formula (III):

[0206]

[0207] or a salt thereof.

[0208]

[0062] In embodiments, for the method of preparing a compound of Formula (Illa) or (Xa), the compound of Formula (Xa) is a compound of Formula (X):

[0209] Cl

[0210]

[0211] or a salt thereof.

[0212]

[0063] In embodiments, for the method of preparing a compound of Formula (Illa), the compound of Formula (Xia) is a compound of Formula (XI):

[0213] HN NBoc

[0214] (XI),

[0215] or a salt thereof.

[0216]

[0064] In embodiments, for the method of preparing a compound of Formula (Xa), the compound of Formula (Xlla) is a compound of Formula (XII):

[0217] Cl\ \

[0218] N W y— N / \ ) — / (°

[0219] \ ' O

[0220]

[0221] / (xii),

[0222] or a salt thereof.

[0223] EXEMPLIFICATION

[0224]

[0065] The procedures described herein were used to prepare the ubiquitin ligase binding component and linker component for the following PROTAC disclosed in WO 2022 / 198112, which has been shown to have activity against LRRK2:

[0225] 14

[0226] MEI 51411438v.l 137508-03520

[0227]

[0228]

[0066] Compounds having the Formula (Illa), (III), (Via), (VI), (Vila), (VII), (Villa), (VIII), (IXa), (IX), (Xa), (X), (Xia), (XI), (Xlla), or (XII) 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.

[0229]

[0067] Abbreviations

[0230] 2-MeTHF = 2-methyl tetrahydrofuran

[0231] 2-MePy • BH3 = 2-methylpyridine borane

[0232] CS2CO3 = cesium carbonate

[0233] DCE = 1,2-Dichloroethane

[0234] DCM = CH2Q2 = dichloromethane

[0235] DHP = 3,4-dihydropyran

[0236] DMA = dim ethyl acetamide

[0237] DMF = dimethylformamide

[0238] DMSO = dimethylsulfoxide

[0239] eq = equivalent

[0240] EtOAc = ethyl acetate

[0241] EtOH = ethanol

[0242] g = grams

[0243] IPr • HC1 = l,3-Bis-(2,6-diisopropylphenyl)imidazolium chloride

[0244] IP Ac = isopropyl acetate

[0245] K2CO3 = potassium carbonate

[0246] kg = kilogram

[0247] LiAlH4= lithium aluminium hydride

[0248] MeCN = ACN = acetonitrile

[0249] MeOH= methanol

[0250] MsOH = methanesulfonic acid

[0251] MTBE = methyl tert-butyl ether

[0252] 15

[0253] MEI 51411438v.l 137508-03520

[0254] Na2SO3= sodium sulfite

[0255] NaBH(OAc)3= sodium triacetoxyborohydride

[0256] NaBH4 = sodium borohydride

[0257] / r-BuLi = / / -butyl lithium

[0258] / / -BuP(Ad)2 = bis(l-adamantyl)-butylphosphane

[0259] NH4CU ammonium chloride

[0260] P(o-tolyl)3 = tris(o-tolyl)phosphine

[0261] PCy3 = tricyclohexylphosphine

[0262] Z-BuOK = potassium Zc / V-butoxide

[0263] THF = tetrahydrofuran

[0264] THP = tetrahydropyran

[0265] TMP = trimethylolpropane

[0266] TsOH = / / -toluenesulfonic acid

[0267] General Methods

[0268]

[0068] HPLC Method 1: (10~80AB,20min)

[0269] MS instrument type: SHIMADZU LC-20AB; column: Kinetex EVO C18 3.5um 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^ 15.02 min 0% B— 20.0 min 0% B; flow rate: 1.00 mL / min; oven temperature: 40 °C;

[0270] Detector: PD A(220nm& 215 nm&254nm).

[0271]

[0069] HPLC Method 2: (10~80AB,6min)

[0272] 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.

[0273]

[0070] LCMS Method i: (5~95AB,4min)

[0274] MS instrument type: SHIMADZU LCMS-20AB, Kinetex EVO C18 30*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.

[0275] 16

[0276] MEI 51411438v.l 137508-03520

[0277]

[0071] Scheme 1: Synthesis of a Compound of Formula (III)

[0278] TEA H2SO4IPA, 25 °C 2-MeTHF, 20 °C

[0279] NaBH(OAc)3DCM, 25 °C Formula (X) Formula (XI)

[0280] BOC2O HN NH → HN NBoc

[0281]

[0282] Formula (XI)

[0283]

[0072] Step la: Synthesis of tert-butyl 3,3-dimethylpiperazine-l-carboxylate

[0284] To EtOH (5V) at 20 °C was added 2,2-dimethylpiperazine (1 eq.). To this mixture was added a solution of BOC2O (1.05 eq) in EtOH (IV) at 10-20 °C, and the reaction was allowed to stir at 20 °C 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.

[0285]

[0073] Step lb'. Synthesis of 4-chloro-6-(4-(dimethoxymethyl)piperidin-l-yl)pyrimidine 4-(dimethoxymethyl)piperidine (0.95 eq.) was dissolved in isopropanol (15 V) followed by TEA (3 eq.) at 20-30 °C. To this mixture was added 4,6-dichloropyrimidine (1 eq.), and allowed to stir for 18 hr at 20-30 °C. Afterwards, the mixture was concentrated to -1-2V under reduced pressure at 45 °C. After cooling to 20-30 °C, 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 0-10 °C, and stirred at this temperature for 18 hr. The solids were collected and filter cake washed with water (3 V) and dried at 30-40 °C for 18h.

[0286]

[0074] Step 2: Synthesis of l-(6-chloropyrimidin-4-yl)piperidine-4-carbaldehyde

[0287] 4-chloro-6-(4-(dimethoxymethyl)piperidin-l-yl)pyrimidine was dissolved in 2- MeTHF (10V), followed by 2M H2SO4 (4.6 eq.). The mixture was heated to 50 °C and stirred at this temperature for 1 hr. Afterwards, the mixture was cooled to 15 °C and neutralized to a pH of 7-8 by the addition of 20% aqueous NaHCCh solution (7 V) over 1 hr. The organic and aqueous layers were separated and organic layer collected. The aqueous layer was extracted

[0288] 17

[0289] MEI 51411438v.l 137508-03520

[0290] with 2-MeTHF (14V). The combined organic layers were dried over Na2SO4and concentrated to yield the product (90% yield)

[0291]

[0075] Step 3: Synthesis of tert-butyl 4-((l-(6-chloropyrimidin-4-yl)piperidin-4-yl)methyl)-3, 3-dimethylpiperazine-l -carboxylate

[0292] tert-butyl 3,3-dimethylpiperazine-l-carboxylate (1.2 eq.) and l-(6-chloropyrimidin-4-yl)piperidine-4-carbaldehyde (1.0 eq.) were dissolved in 2-MeTHF (10V) and stirred for 1 hr at 20 °C. The mixture was then cooled to 0 °C and NaBH(OAc)3(1.3 eq.) added. The mixture was stirred at 16 hr at -10-0 °C. 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 40 °C under reduced pressure. 5V of EtOH was added to the mixture which was then stirred for 1 hr at 50 °C.

[0293] After cooling to 20-30 °C a solid precipitated. 7 V of water was added and the solid collected, washed with water (3V), and dried at 40 °C for 20 hr to yield tert-butyl 4-((l-(6-chloropyrimidin-4-yl)piperidin-4-yl)methyl)-3,3 -dimethylpiperazine- 1 -carboxylate (Formula (III), 75% yield).

[0294]

[0076] Scheme 2: Synthesis of a compound of Formula (VI)

[0295] O O

[0296]

[0297] 18

[0298] MEI 51411438v.l 137508-03520

[0299]

[0077] Step 1: Synthesis of methyl 4-(4-(dimethoxymethyl)piperidin-l-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 70-80 °C and stirred at this temperature for 16-24 hr. After cooling to 35-45 °C, water (20V) was added dropwise, then stirred at 15-25 °C for 8-16 hr, during which a solid precipitate formed. The solid was collected and dried to obtain the product (80% yield).

[0300]

[0078] Step 2: Synthesis of 5-(4-(dimethoxymethyl)piperidin-l-yl)-4-fluoro-3-hydroxyisobenzofuran-l( 3H)-one

[0301] TMP (2.5 eq.) was dissolved in 2-MeTHF (10V) and cooled to -10 to -5 °C. / / -BuLi (2 eq.) was added dropwise and stirred for 0.5-1 hr at this temperature. Afterwards, the mixture was cooled to -75 to -45 °C and a clear solution of methyl 4-(4-(dimethoxymethyl)piperidin-l-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 -45 °C. The mixture was quenched at -75 to -30 °C with a 0.5 M aqueous LiOH solution (IV) and warmed to -15 to -5 °C, where 9V more of the 0.5 M LiOH solution was added. The mixture was further warmed to 15-25 °C and stirred at this temperature for 1-3 hr. The mixture was separated and organic and aqueous phases both collected. The aqueous phase was extracted with 2-MeTHF (5 V). 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 HC1 solution, upon which a suspension formed and was stirred for 2-10 hr. The solid was collected and dried to obtain the product (73% yield).

[0302]

[0079] Step 3: Synthesis of 3-(5-(4-(dimethoxymethyl)piperidin-l-yl)-4-fluoro-l-oxoisoindolin-2-yl)piperidine-2, 6-dione (Formula (V))

[0303] 2,6-dioxopiperidin-3-aminium chloride (2 eq.) and NaOAc (2 eq.) were dissolved in MeOH (20V) and stirred for 0.5 hr at 20-30 °C. 5-(4-(dimethoxymethyl)piperidin-l-yl)-4-fluoro-3 -hydroxyisobenzofuran- l(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 48-58 °C, and stirred for 0.5-1 hr at this temperature. AcOH (35 eq.) was added and mixture continued to stir at 48-58 °C for 15-24 hr. Afterwards, the mixture was cooled to 15-25 °C, 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-l-yl)-4-fluoro-l-oxoisoindolin-2-yl)piperidine-2, 6-dione (Formula (V), 66.4% yield).

[0304] 19

[0305] MEI 51411438v.l 137508-03520

[0306]

[0080] 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.

[0307] 20

[0308] MEI 51411438v.l

Claims

137508-03520CLAIMSWhat is claimed is:

1. A method of preparing a compound of Formula (Via):ON-RN(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, Ci-4alkyl, Ci-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, Ci-4alkyl, or Ci-4haloalkyl;or two R10, together with the carbon to which they are attached, form oxo;each RFis independently halo, Ci-4alkyl, Ci-4haloalkyl, -ORFa, -N(RFa)2, -SC>2RFb, -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 Ci-4alkyl, Ci-4haloalkyl, -ORFa, or -N(RFa)2;each R9is independently halo, Ci-4alkyl, Ci-4haloalkyl, -OR9a, -N(R9a)2, cycloalkyl, heterocyclyl, phenyl, or heteroaryl, wherein the Ci-4alkyl is optionally substituted by one or more Ci-4alkoxy;each R9aand RFais independently H, Ci-4alkyl, or Ci-4haloalkyl;the method comprising:reacting a compound of Formula (Vila):O F OOR8(Vila),or a salt thereof, wherein R8is H, Ci-4alkyl or Ci-4haloalkyl;with a compound of Formula (Villa):HN-RNH (Villa),21MEI 51411438v.l137508-03520or a salt thereof.

2. The method of claim 1, wherein the reaction is performed in the presence of a reducing agent.

3. The method of claim 2, wherein the reducing agent comprises boron.

4. The method of claim 2 or 3, wherein the reducing agent is selected from NaBH(OAc)3, NaCNBH3, NaBH4, BH3 • NCH3, and 2-methylpyridine borane.

5. The method of any one of claims 2 to 4, wherein the reducing agent is 2-m ethyl pyridine borane.

6. The method of any one of claims 1 to 5, further comprising the steps of preparing the compound of Formula (Vila) by reacting a compound of Formula (IXa):OO-R° Z x(IXa),or a salt thereof, with HC(O)OR01in the presence of a base, wherein R° and RO1are each independently H, Ci-4alkyl, or Ci-4haloalkyl.

7. The method of claim 6, wherein the base is a lithium base.

8. The method of claim 6 or 7, wherein the base is / / -butyl lithium.

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 an organic solvent.

11. The method of claim 9 or 10, wherein the solvent is methanol or 2-m ethyl tetrahydrofuran.22MEI 51411438v.l137508-0352012. The method of any one of claims 1 to 11, wherein Ring F is phenyl or heteroaryl, each of which is optionally substituted by 1, 2, or 3 RF.

13. The method of claim any one of claims 1 to 12, wherein Ring F is phenyl or 5- to 7-membered heteroaryl, each of which is optionally substituted by 1, 2, or 3 RF.

14. The method of claim any one of claims 1 to 13, wherein Ring F is phenyl or 6-membered heteroaryl, each of which is optionally substituted by 1, 2, or 3 RF.

15. The method of any one of claims 1 to 14, wherein Ring F is phenyl, pyridinyl, or pyrimidinyl, each of which is optionally substituted by 1, 2, or 3 RF.

16. The method of any one of claims 1 to 15, wherein Ring F is phenyl substituted by 2 RF.

17. The method of any of claims 1 to 16, wherein each RFis independently halo, Cisalkyl, C1-3haloalkyl, C4-6cycloalkyl, or 4- to 6-membered heterocyclyl, wherein the C4-ecycloalkyl and 4- to 6-membered heterocyclyl are each optionally substituted by 1, 2, or 3 R918. The method of any one of claims 1 to 7, wherein 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.

19. The method of any one of claims 1 to 18, wherein each RFis independently halo or 6-membered heterocyclyl, wherein the 6-membered heterocyclyl is optionally substituted by 1 or 2 R9.

20. The method of any one of claims 1 to 19, wherein each RFis independently -F or piperdinyl, wherein the piperdinyl is substituted by 1 R9.

21. The method of any one of claims 1 to 20, wherein each R9is independently halo, Cisalkyl, C1-3haloalkyl, wherein the Ci-salkyl is optionally substituted by 1 or 2 Ci-salkoxy.23MEI 51411438v.l137508-0352022. The method of any one of claims 1 to 21, wherein each R9is independently Ci-3alkyl optionally substituted by 1 or 2 Ci-3alkoxy.

23. The method of any one of claims 1 to 22, wherein each R9is -CH(OCH3)2.

24. The method of any one of claims 1 to 23, wherein RNis a heterocyclyl optionally substituted by 1, 2, 3, 4, 5, or 6 R10.

25. The method of any one of claims 1 to 24, wherein RNis a 5- to 7-membered heterocyclyl optionally substituted by 1, 2, 3, 4, 5, or 6 R10.

26. The method of any one of claims 1 to 25, wherein RNis a 6-membered heterocyclyl optionally substituted by 1, 2, 3, 4, 5, or 6 R10.

27. The method of any one of claims 1 to 26, wherein RNis piperdinyl optionally substituted by 1, 2, 3, 4, or 5 R10.

28. The method of any one of claims 1 to 27, wherein two R10, together with the carbon to which they are attached, form oxo.

29. The method of any one of claims 6 to 28, wherein R° is H.

30. The method of any one of claims 6 to 29, wherein RO1is Ci-3alkyl.

31. The method of any one of claims 6 to 30, wherein RO1is -CH3.

32. The method of any one of claims 1 to 31, wherein the compound of Formula (Via) is a compound of Formula (VI):(VI), or a salt thereof.24MEI 51411438v.l137508-0352033. The method of any one of claims 1 to 32, wherein the compound of Formula (Vila) is a compound of Formula (VII):O(VII),or a salt thereof.

34. The method of any one of claims 1 to 33, wherein the compound of Formula (Villa) is a compound of Formula (VIII):o(VIII),or a salt thereof.

35. The method of any of claims 1 to 34, wherein the compound of Formula (Villa) or (VIII) is a salt.

36. The method of claim 35, wherein the compound of Formula (Villa) or (VIII) is a hydrochloride salt.

37. The method of any one of claims 6 to 36, wherein the compound of Formula (IXa) is a compound of Formula (IX):Oor a salt thereof.

38. A method of preparing a compound of Formula (Illa):25MEI 51411438v.l137508-03520(Illa),or a salt thereof, wherein:X1, X2, X3, and X4are each N or CRX;each Rxis, independently, H, halo, Ci-3alkyl, Ci-3haloalkyl, -ORXa, -NRXaRxb, -C(O)H, -C(O)OH, -C(O)ORXa, or -C(O)NRXaRxb;RXaand Rxbare each, independently, H, halo, Ci-3alkyl, Ci-3haloalkyl, or C3-ecycloalkyl;Ring A and Ring B are each, independently, 4- to 12-membered heterocyclyl; each RAand RBis, independently, halo, Ci-3alkyl, Ci-3haloalkyl, -ORA1, -NRA1RA1, -C(O)H, -C(O)OH, -C(O)ORA1, or -C(O)NRA1RA1;each RA1is, independently, H, halo, Ci-4alkyl, Ci-3haloalkyl, or C3-6cycloalkyl; T is halo; ando and p are each, independently, 0, 1, 2, 3, or 4;the method comprising:reacting a compound of Formula (Xa):or a salt thereof,with a compound of Formula (Xia):(RB)PI BNH (Xia),or a salt thereof,in the presence of a reducing agent.

39. The method of claim 38, wherein the reducing agent comprises boron.26MEI 51411438v.l137508-0352040. The method of claim 38 or 39, wherein the reducing agent is selected from NaBH(OAc)3, NaCNBH3, NaBH4, BH3 • NCH3, and 2-methylpyridine borane.

41. The method of any one of claims 38 to 40, wherein the reducing agent is NaBH(OAc)3.

42. The method of any one of claims 38 to 41, further comprising the steps of preparing the compound of Formula (Xa) by reacting a compound of Formula (Xlla):or a salt thereof, with an acid, and wherein each R11is independently H, Ci-3alkyl, or C1-3haloalkyl.

43. The method of claim 42, wherein the acid is an aqueous acid.

44. The method of claim 43, wherein the acid is HF, HC1, HBr, HI, HCN, H3PO4, H2SO3, H2SO4, or HNO3.

45. The method of claim 43 or 44, wherein the acid is H2SO4.

46. The method of any one of claims 38 to 45, wherein the reaction is performed in the presence of a solvent.

47. The method of claim 46, wherein the solvent is an organic solvent.

48. The method of claim 46 or 47, wherein the solvent is dichloromethane or 2-methyl tetrahydrofuran.

49. The method of any one of claim 38 to 48, wherein X1and X3are N and X2and X4are CH.27MEI 51411438v.l137508-0352050. The method of any one of claims 38 to 49, wherein T is -Cl.

51. The method of any one of claims 38 to 50, wherein Ring A is a 5- to 7-membered heterocyclyl.

52. The method of any one of claims 38 to 51, wherein Ring A is a 6-membered heterocyclyl.

53. The method of any one of claims 38 to 52, wherein Ring A is piperdinyl.

54. The method of any one of claims 38 to 53, wherein o is 0.

55. The method of any one of claims 38 to 54, wherein Ring B is a 5- to 7-membered heterocyclyl.

56. The method of any one of claims 38 to 55, wherein Ring B is a 6-membered heterocyclyl.

57. The method of any one of claims 38 to 56, wherein Ring B is piperazinyl.

58. The method of any one of claims 38 to 57, wherein p is 0, 1, 2, or 3.

59. The method of any one of claims 38 to 58, wherein p is 3.

60. The method of any one of claims 38 to 59, wherein each RBis independently halo, Cisalkyl, C1-3haloalkyl, or -C(O)OR4a.

61. The method of any one of claims 38 to 60, wherein each RBis independently Ci-3alkyl or -C(O)OR4a.

62. The method of any one of claims 38 to 61, wherein R4ais Ci-4alkyl.

63. The method of any one of claims 38 to 62, wherein each RBis independently -CH3 or -C(O)OC(CH3)3.28MEI 51411438v.l137508-0352064. The method of any one of claims 42 to 63, wherein each R11is independently Cisalkyl.

65. The method of any one of claims 42 to 64, wherein each R11is -CH3.

66. The method of any one of claims 38 to 65, wherein the compound of Formula (Illa) is a compound of Formula (III):Nor a salt thereof.

67. The method of any one of claims 38 to 66, wherein the compound of Formula (Xa) is a compound of Formula (X):,0Nor a salt thereof.

68. The method of any one of claims 38 to 67, wherein the compound of Formula (Xia) is a compound of Formula (XI):or a salt thereof.

69. The method of any one of claims 42 to 68, wherein the compound of Formula (Xlla) is a compound of Formula (XII):N / (XII),or a salt thereof.MEI 51411438v.l

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