Methods for the synthesis of complement factor d inhibitors and intermediates thereof

Abstract

The present disclosure provides methods for the synthesis of complement factor D inhibitors and intermediates thereof.

Description

[0001] ALXN. DOCKET ALXN-0761-WO-PCT METHODS FOR THE SYNTHESIS OF COMPLEMENT FACTOR D INHIBITORS AND INTERMEDIATES THEREOF Background The complement system is a part of the innate immune system which does not adapt to changes over the course of the host’s life, but is recruited and used by the adaptive immune system. For example, it assists, or complements, the ability of antibodies and phagocytic cells to clear pathogens. This sophisticated regulatory pathway allows rapid reaction to pathogenic organisms while protecting host cells from destruction. Over thirty proteins and protein fragments make up the complement system. These proteins act through opsonization (enhancing phagocytosis of antigens), chemotaxis (attracting macrophages and neutrophils), cell lysis (rupturing membranes of foreign cells), and agglutination (clustering and binding of pathogens together). The complement system has three pathways: classical, alternative, and lectin. Complement Factor D plays an early and central role in activation of the alternative pathway of the complement cascade. Activation of the alternative complement pathway is initiated by spontaneous hydrolysis of a thioester bond within the C3 protein to produce C3(H2O), which associates with Factor B to form the C3(H2O)B complex. Complement Factor D acts to cleave Factor B within the C3(H2O)B complex to form Ba and Bb. The Bb fragment remains associated with C3(H2O) to form the alternative pathway C3 convertase C3(H2O)Bb. Additionally, C3b generated by any of the C3 convertases also associates with Factor B to form C3bB, which Factor D cleaves to generate the later stage alternative pathway C3 convertase C3bBb. This latter form of the alternative pathway C3 convertase may provide important downstream amplification within all three of the defined complement pathways, leading ultimately to the recruitment and assembly of additional factors in the complement cascade pathway, including the cleavage of C5 to C5a and C5b. C5b acts in the assembly of factors C6, C7, C8, and C9 into the membrane attack complex, which can destroy pathogenic cells by lysing the cell. The dysfunction of or excessive activation of complement has been linked to certain autoimmune, inflammatory, and neurodegenerative diseases, as well as ischemia-reperfusion injury and cancer. For example, activation of the alternative pathway of the complement cascade contributes to the production of C3a and C5a, both potent anaphylatoxins, which also have roles in a number of inflammatory disorders. Therefore, in some instances, it is desirable to decrease the response of the complement pathway, including the alternative complement pathway. Some examples of disorders mediated by the complement pathway include age-related macular degeneration (AMD), paroxysmal nocturnal hemoglobinuria (PNH), multiple sclerosis, and rheumatoid arthritis. Additional complement-mediated disorders include those classified under component 3 glomerulopathy (C3G). C3G is a recently defined entity comprised of dense deposit disease (DDD) and C3 glomerulonephritis (C3GN) which encompasses a population of chronic kidney diseases wherein elevated activity of the alternative complement pathway and terminal complement pathway results in glomerular deposits made solely of complement C3 and no immunoglobulin (Ig). Immune-complex membranoproliferative glomerulonephritis (IC-MPGN) is a renal disease which shares many clinical, pathologic, genetic and laboratory features with C3G, and therefore can be considered a sister disease of C3G. In the majority of patients with IC-MPGN, an underlying disease or disorder—most commonly infections, autoimmune diseases, or monoclonal gammopathies—are identified to which the renal disease is secondary. Patients with idiopathic IC-MPGN can have low C3 and normal ALXN. DOCKET ALXN-0761-WO-PCT C4 levels, similar to those observed in C3G, as well as many of the same genetic or acquired factors that are associated with abnormal alternative pathway activity. Although there are current hypotheses suggesting that the majority of IC-MPGN is attributable to over activity of the classical pathway, those patients with a low C3 and a normal C4 are likely to have significant overactivity of the alternative pathway. IC-MPGN patients with a low C3 and a normal C4 may benefit from alternative pathway inhibition. Other disorders that have been linked to the complement cascade include atypical hemolytic uremic syndrome (aHUS), hemolytic uremic syndrome (HUS), abdominal aortic aneurysm, hemodialysis complications, hemolytic anemia, or hemodialysis, neuromyelitis optica (NMO), myasthenia gravis (MG), fatty liver, nonalcoholic steatohepatitis (NASH), liver inflammation, cirrhosis, liver failure, dermatomyositis, and amyotrophic lateral sclerosis. Factor D is an attractive target for inhibition or regulation of the complement cascade due to its early and essential role in the alternative complement pathway, and for its potential role in signal amplification within the classical and lectin complement pathways. Inhibition of Factor D effectively interrupts the pathway and attenuates the formation of the membrane attack complex. To this end, a number of small molecule Factor D inhibitors have been developed and investigated for potential therapeutic uses. Examples of these Factor D inhibiting compounds methods of preparing them are described in, e.g., PCT Publications Nos. WO2015 / 130838, WO2017 / 035353, WO2017 / 035409, WO2018 / 160889, WO2020 / 041301, and WO2021 / 168320. New methods for the synthesis of small molecule Factor D inhibitors and intermediates thereof are desirable. Summary The present disclosure generally relates to an improved method of preparing compounds useful for treating disorders mediated by complement factor D and intermediates thereof. In particular, the present disclosure relates to compounds of Formula (VI): , in which P1and P2are as defined herein, for the synthesis of complement factor D inhibitors of Formula (XI): , in which variables R1, B are as defined herein. The present discovery that the compounds of Formula (VI) can be the use of hazardous reagents, e.g., diethyl zinc required by In addition to the elimination of ALXN. DOCKET ALXN-0761-WO-PCT the use of hazardous reagents, the methods also provides improved selectivity for cyclopropanation, the ability to use easily available starting materials, a reduction in total reaction steps to prepare the compounds of Formula (VI), and improved yield. Accordingly, in one aspect, the present disclosure provides a method of preparing a compound of Formula (VI). The method includes providing a compound of Formula (V): , in which P1and P2are as defined herein, of Formula (VI) from the compound of Formula (V). Forming the compound contacting the compound of Formula (V) with a Co(II) catalyst in the presence of Zn and CH2Br2. Also provided herein are methods of preparing compounds of Formula (XI): , from the compound of Formula (VI) methods disclosed herein. To facilitate the of terms are defined below. Terms defined herein have meanings as commonly understood by a person of ordinary skill in the areas relevant to the disclosure. Terms such as "a", "an," and "the" are not intended to refer to only a singular entity, but include the general class of which a specific example may be used for illustration. The terminology herein is used to describe specific embodiments of the invention, but their usage does not limit the invention, except as outlined in the claims. As used herein, any values provided in a range of values include both the upper and lower bounds, and any values contained within the upper and lower bounds. As used herein, the term “pharmaceutically acceptable salt” represents those salts of the compounds described that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and animals without undue toxicity, irritation, allergic response and the like and are commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, pharmaceutically acceptable salts are described in: Berge et al., J. Pharmaceutical Sciences 66:1-19, 1977 and in Handbook of Pharmaceutical Salts: Properties, Selection, and Use, (Eds. P.H. Stahl and C.G. Wermuth), Wiley-VCH, 2008. These salts may be acid addition salts involving inorganic or organic acids. The salts can be prepared in situ during the final isolation and purification of the compounds described herein or separately by reacting the free base group with a suitable acid. Methods for preparation of the appropriate salts are well-established in the art. ALXN. DOCKET ALXN-0761-WO-PCT The term “acyl,” as used herein, refers to a monovalent radical having the structure –COR, where R is alkyl, alkenyl, aryl, arylalkyl, heteroaryl, or heteroarylalkyl. Acyl can be optionally substituted as defined for each R group. The term “alkyl,” as used herein, refers to a branched or straight-chain monovalent saturated aliphatic radical containing only C and H when unsubstituted. The monovalency of an alkyl group does not include the optional substituents on the alkyl group. For example, if an alkyl group is attached to a compound, monovalency of the alkyl group refers to its attachment to the compound and does not include any additional substituents that may be present on the alkyl group. In some embodiments, the alkyl group may contain, e.g., 1-12, 1-10, 1-8, 1-6, 1-4, or 1-2 carbon atoms (e.g., C1-C12, C1-C10, C1-C8, C1-C6, C1-C4, or C1-C2). Examples include, but are not limited to, methyl, ethyl, isobutyl, sec-butyl, and tert-butyl. The term “alkylene,” as used herein, refers to a divalent radical obtained by removing a hydrogen atom from a carbon atom of an alkyl group. The divalency of an alkylene group does not include the optional substituents on the alkylene group. The term “alkenyl,” as used herein, refers to a branched or straight-chain monovalent unsaturated aliphatic radical containing at least one carbon-carbon double bond and no carbon-carbon triple bonds, and only C and H when unsubstituted. Monovalency of an alkenyl group does not include the optional substituents on the alkenyl group. For example, if an alkenyl group is attached to a compound, monovalency of the alkenyl group refers to its attachment to the compound and does not include any additional substituents that may be present on the alkenyl group. In some embodiments, the alkenyl group may contain, e.g., 2-12, 2-10, 2-8, 2-6, or 2-4 carbon atoms (e.g., C2-C12, C2-C10, C2-C8, C2-C6, or C2-C4). Examples include, but are not limited to, ethenyl, 1-propenyl, 2-propenyl, 1-methylethenyl, 1- butenyl, 2-butenyl, 3-butenyl, and the like. The term “alkenyloxy,” as used herein, refers to a monovalent radical having the structure -O- alkenyl, in which “alkenyl” is as defined herein. Examples include, but are not limited to ethenyloxy, propenyloxy, and the like. The term “alkoxy,” as used herein, refers to a monovalent radical having the structure -O-alkyl, in which “alkyl” is as defined herein. Examples include, but are not limited to methoxy, ethoxy, and n-butoxy, i-butoxy, t-butoxy, and the like. The term “alkynyl,” as used herein, refers to a branched or straight-chain monovalent unsaturated aliphatic radical containing at least one carbon-carbon triple bond and only C and H when unsubstituted. Monovalency of an alkynyl group does not include the optional substituents on the alkynyl group. For example, if an alkynyl group is attached to a compound, monovalency of the alkynyl group refers to its attachment to the compound and does not include any additional substituents that may be present on the alkynyl group. In some embodiments, the alkynyl group may contain, e.g., 2-12, 2-10, 2-8, 2-6, or 2-4 carbon atoms (e.g., C2-C12, C2-C10, C2-C8, C2-C6, or C2-C4). Examples include, but are not limited to, ethynyl, 1-propynyl, and 3-butynyl. The term “aryl,” as used herein, refers to a monovalent, monocyclic or fused ring bicyclic or polycyclic system which has the characteristics of aromaticity in terms of electron distribution throughout the ring system, e.g., phenyl, naphthyl, or phenanthryl. An aryl group may have, e.g., six to sixteen carbons (e.g., C6-C16aryl, C6-C14aryl, C6-C13aryl, or C6-C10aryl). ALXN. DOCKET ALXN-0761-WO-PCT The term “arylalkyl,” as used herein, refers to a monovalent radical having the structure –R’R”, where R’ is alkylene, and R” is aryl. Arylalkyl can be optionally substituted in the same manner as defined for each R’ and R” group. The term “carbocyclyl,” as used herein, represents a monovalent, saturated or unsaturated non- aromatic cyclic group containing only C and H when unsubstituted. A carbocyclyl (e.g., a cycloalkyl or a cycloalkenyl) may have, e.g., three to fourteen carbons (e.g., a C3-C7, C3-C8, C3-C9, C3-C10, C3-C11, C3- C12, C3-C14 carbocyclyl). The term “carbocyclyl” also includes bicyclic and polycyclic (e.g., tricyclic and tetracyclic) fused ring structures. The term “cycloalkyl”, as used herein refers to a saturated carbocyclyl. Examples of cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. The term “cycloalkyl” also includes cyclic groups having a bridged multicyclic structure in which one or more carbons bridges two non-adjacent members of a monocyclic ring, e.g., bicyclo[2.2.1]heptyl and adamantyl. The term “cycloalkyl” also includes bicyclic, tricyclic, and tetracyclic fused ring structures, e.g., decalin and spirocyclic compounds. The term “cyano,” as used herein, refers to a monovalent radical having the structure -CN. The term “cycloalkenyl,” as used herein, represents a monovalent, unsaturated carbocyclyl group that includes at least one carbon-carbon double bond, no carbon-carbon triple bond, only C and H when unsubstituted, and is not fully aromatic. A cycloalkenyl may have, e.g., four to fourteen carbons (e.g., a C4-C7, C4-C8, C4-C9, C4-C10, C4-C11, C4-C12, C4-C13, or C4-C14cycloalkenyl). Exemplary cycloalkenyl groups include, but are not limited to, cyclopentenyl, cyclohexenyl, and cycloheptenyl. The term “cycloalkenyl” also includes cyclic groups having a bridged multicyclic structure in which one or more carbons bridges two non-adjacent members of a monocyclic ring, e.g., bicyclo[2.2.2]oct-2-ene. The term “cycloalkenyl” also includes fused ring bicyclic and multicyclic systems containing one or more double bonds, e.g., fluorene. The term “halo,” as used herein, refers to a fluorine (fluoro), chlorine (chloro), bromine (bromo), or iodine (iodo) radical. The term “heteroarylalkyl,” as used herein, represents a monovalent radical of structure –R’R”, where R’ is alkylene, and R” is heteroaryl. Heteroarylalkyl can be optionally substituted in the same manner as defined for each R’ and R” group. The term “heterocyclyl,” as used herein, represents a saturated or unsaturated monocyclic or fused ring bicyclic or polycyclic system having one or more carbon atoms and at least one heteroatom, e.g., one to four heteroatoms (e.g., one to four, one to three, one or two, one, two, three, or four heteroatoms), selected from N, O, and S. Heterocyclyl groups include both non-aromatic and aromatic systems. An aromatic heterocyclyl group is referred to as a “heteroaryl” group. In some embodiments, a heterocyclyl group is a 3- to 8-membered ring system, a 3- to 6-membered ring system, a 4- to 6- membered ring system, a 4- to 10-membered ring system, a 6- to 10-membered ring system, a 6- to 12- membered ring system, a 5-membered ring, or a 6-membered ring, or a ring or ring system having a number of ring atoms that fall within any of the above-mentioned ranges. Exemplary 5-membered heterocyclyl groups may have zero to two double bonds, and exemplary 6-membered heterocyclyl groups may have zero to three double bonds. Exemplary 5-membered groups include, for example, optionally substituted pyrrole, optionally substituted pyrazole, optionally substituted isoxazole, optionally substituted pyrrolidine, optionally substituted imidazole, optionally substituted thiazole, optionally substituted ALXN. DOCKET ALXN-0761-WO-PCT thiophene, optionally substituted thiolane, optionally substituted furan, optionally substituted tetrahydrofuran, optionally substituted diazole, optionally substituted triazole, optionally substituted tetrazole, optionally substituted oxazole, optionally substituted 1,3,4-oxadiazole, optionally substituted 1,3,4-thiadiazole, optionally substituted 1,2,3,4-oxatriazole, and optionally substituted 1,2,3,4-thiatriazole. Exemplary 6-membered heterocyclyl groups include, but are not limited to, optionally substituted pyridine, optionally substituted piperidine, optionally substituted piperazine, optionally substituted pyrimidine, optionally substituted pyrazine, optionally substituted pyridazine, optionally substituted triazine, optionally substituted 2H-pyran, optionally substituted 4H-pyran, and optionally substituted tetrahydropyran. Exemplary 7-membered heterocyclyl groups include, but are not limited to, optionally substituted azepine, optionally substituted 1,4-diazepine, optionally substituted thiepine, and optionally substituted 1,4- thiazepine. Exemplary 8- to 10-membered bicyclic groups include, but are not limited to, optionally substituted pyrazolo[1,5-a]pyrimidinyl, optionally substituted [1,2,4]triazolo[1,5-a]pyridinyl, optionally substituted thiazolo[5,4-b]pyridinyl, optionally substituted imidazo[1,2-a]pyrimidinyl, optionally substituted 3H-imidazo[4,5-b]pyridinyl, 1H-thieno[3,2-c]pyrazolyl, imidazo[1,2-b]pyridazinyl, optionally substituted quinazolinyl, optionally substituted quinolinyl, and 1H-benzo[d]imidazolyl. The term “carboxyl-protecting group,” as used herein, refers to any group capable of protecting the oxygen atom of the -OH functionality of a carboxyl group from participating in one or more undesirable reactions during chemical synthesis. A carboxyl-protecting group is installed by reacting a molecule including an unprotected carboxyl group with a carboxyl-protecting reagent, which can be removed by a carboxyl-protecting-group-removing agent. Carboxyl-protecting groups, their corresponding carboxyl- protecting reagents, and carboxyl-protecting-group-removing agents suitable for removing carboxyl- protecting groups are known in the art, e.g., as described in Wuts, Greene's Protective Groups in Organic Synthesis, Wiley-Interscience, 4th Edition, 2006. Exemplary carboxyl-protecting groups include, but are not limited to alkyl (e.g., methyl, ethyl, or tert-butyl), benzyl, 4-nitrobenzyl, 4-methoxybenzyl, 3,4- dimethoxybenzyl, 2,4-dimethoxybenzyl, 2,4,6-trimethoxybenzyl, 2,4,6-trimethoxybenzyl, pentamethylbenzyl, benzydryl, 3,4-methylenedioxybenzyl, 4,4-dimethoxytrityl, 4,4′,4″-trimethoxytrityl, 2- phenylpropyl, trimethylsilyl, t-butyldimethylsilyl, phenacyl, 2,2,2-trichloroethyl, β-(trimethylsilyl)ethyl, β-(di(n- butyl)methylsilyl)ethyl, p-toluenesulfonylethyl, 4-nitrobenzylsulfonylethyl, allyl, cinnamyl, and 1- (trimethylsilylmethyl)-propenyl. The term “N-protecting group,” as used herein, refers to a group protecting a nitrogen atom in a molecule from participating in one or more undesirable reactions during chemical synthesis. An N- protecting group is installed by reacting the molecule including a nitrogen atom with an N-protecting reagent and can be removed using an N-protecting-group-removing agent. Commonly used N-protecting groups, their corresponding N-protecting reagents, and N-protecting-group-removing agents are disclosed in Wuts, Greene's Protective Groups in Organic Synthesis, Wiley-Interscience, 4th Edition, 2006. Exemplary N-protecting groups include acyl (e.g., formyl, acetyl, trifluoroacetyl, propionyl, pivaloyl, t- butylacetyl, 2-chloroacetyl, 2-bromoacetyl, trifluoroacetyl, trichloroacetyl, phthalyl, o-nitrophenoxyacetyl, α- chlorobutyryl, benzoyl, 4-chlorobenzoyl, and 4-bromobenzoyl); sulfonyl-containing groups (e.g., benzenesulfonyl, p-toluenesulfonyl, o-nitrobenzenesulfonyl, and p-nitrobenzenesulfonyl); carbamate forming groups (e.g., benzyloxycarbonyl, p-chlorobenzyloxycarbonyl, p-methoxybenzyloxycarbonyl, p- nitrobenzyloxycarbonyl, 2-nitrobenzyloxycarbonyl, p-bromobenzyloxycarbonyl, 3,4- dimethoxybenzyloxycarbonyl, 3,5-dimethoxybenzyl oxycarbonyl, 2,4-dimethoxybenzyloxycarbonyl, ALXN. DOCKET ALXN-0761-WO-PCT 4-methoxybenzyloxycarbonyl, 2-nitro-4,5-dimethoxybenzyloxycarbonyl, 3,4,5-trimethoxybenzyloxycarbonyl, 1-(p-biphenylyl)-1-methylethoxycarbonyl, α,α-dimethyl- 3,5-dimethoxybenzyloxycarbonyl, benzhydryloxy carbonyl, t-butyloxycarbonyl, diisopropylmethoxycarbonyl, isopropyloxycarbonyl, ethoxycarbonyl, methoxycarbonyl, allyloxycarbonyl, 2,2,2,-trichloroethoxycarbonyl, phenoxycarbonyl, 4-nitrophenoxy carbonyl, fluorenyl-9-methoxycarbonyl, cyclopentyloxycarbonyl, adamantyloxycarbonyl, cyclohexyloxycarbonyl, and phenylthiocarbonyl), arylalkyl (e.g., triphenylmethyl); silyl groups (e.g., trimethylsilyl); and imine-forming groups (e.g., diphenylmethylene). Further examples of N-protecting groups include acetyl, benzoyl, phenylsulfonyl, p- toluenesulfonyl, p-nitrobenzenesulfonyl, o-nitrobenzenesulfonyl, t-butyloxycarbonyl (Boc), and benzyloxycarbonyl (Cbz). The term “oxo,” as used herein, refers to a divalent oxygen atom represented by the structure =O. The term “thioalkyl,” as used herein, refers to a monovalent radical having the structure -S-alkyl, in which “alkyl” is as defined herein. The phrase “optionally substituted X,” as used herein, is intended to be equivalent to “X, wherein X is optionally substituted” (e.g., “alkyl, wherein said alkyl is optionally substituted”). It is not intended to mean that the feature “X” (e.g., alkyl) per se is optional. The term “optionally substituted,” as used herein, refers to having 0, 1, or more substituents (e.g., 0-10, 0-9, 0-8, 0-7, 0-6, 0-5, 0-4, 0-3, 0-2, 0 or 1, 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 substituents). Alkyl, alkylene, alkenyl, alkynyl, carbocyclyl, cycloalkyl, cycloalkenyl, aryl, and heterocyclyl groups may be substituted with one or more of carbocyclyl, cycloalkyl; cycloalkenyl; aryl; heterocyclyl; heteroaryl; halo; OH; cyano; alkoxy; alkenyloxy; thioalkyl; NO2; N3; NRR′; wherein each of R and R′is, independently, H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, or heterocyclyl; SO2R, wherein R is H, alkyl or aryl; SO2NRR′, wherein each of R and R′is, independently, H, alkyl, or aryl; or NRSO2R, wherein each of R and R′is, independently, H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, or heterocyclyl. Aryl, carbocyclyl, cycloalkyl, cycloalkenyl, heteroaryl, and heterocyclyl groups may also be substituted with alkyl, alkenyl, or alkynyl. Alkyl, alkoxy, carbocyclyl, cycloalkyl, cycloalkenyl, and unsaturated heterocyclyl groups may also be substituted with oxo. In some embodiments, a substituent is further substituted as described herein. For example, a C6aryl group, i.e., phenyl, may be substituted with an alkyl group, which may be further substituted with a heterocyclyl group. Brief Description of the Drawing FIG.1 is a schematic of a continuous flow setup used for the synthesis of Compound 2d described in Example 3. Detailed Description The present disclosure provides methods for the synthesis of small molecule complement factor D inhibitors and intermediates thereof. The complement factor D inhibitors are compounds of Formula (XIII): ALXN. DOCKET ALXN-0761-WO-PCT , or pharmaceutically acceptable salts R6, X1-X5, m, and B are as defined herein. Exemplary compounds of Formula (XIII) are described in, e.g., PCT Publications Nos. WO2015 / 130838, WO2017 / 035353, WO2017 / 035409, WO2018 / 160889, WO2020 / 041301, and WO2021 / 168320, the entire contents of which are incorporated herein by reference. In particular, the methods herein relate to the preparation of a compound of Formula (VI): , in which P1is H or an N-protecting group and P2is H or a carboxyl-protecting group (e.g., an alkyl group such as providing a compound of Formula (V): , in which P1is H or an N-protecting group protecting group (e.g., an alkyl group such as methyl); and forming the the compound of Formula (V) via a cyclopropanation reaction performed with a Co(II) catalyst in the presence of Zn and CH2Br2. In some embodiments, the reaction is performed with a Co(II) catalyst in the presence of Zn, CH2Br2, and ZnCl2. In some embodiments, the Zn is in the form of Zinc dust (e.g., having a particle size of less than 10 microns). In some embodiments, the Zn, e.g., in the form of Zinc dust, is activated (e.g., with HCl). Methods of preparing activated Zn is generally known in the art. In some embodiments, the Zn is present in amount of 2-10 equivalents (e.g., 3-8 equiv, 4-6 equiv, 3 equiv, 4 equiv, 5 equiv, 6 equiv, 7 equiv, 8 equiv, 9 equiv, or 10 equiv) relative to the compound of Formula (V). In some embodiments, the Zn is present in amount of 5 equiv relative to the compound of Formula (V). In some embodiments, the Zn is sequentially added in more than one portion. In some embodiments, the Zn is sequentially added in two portions (e.g., a first portion of 3 equiv relative to the compound of Formula (V), then a second portion of 2 equiv relative to the compound of Formula (V)). In some embodiments, the ZnCl2 is present in an amount of 2-10 equivalents (e.g., 3-8 equiv, 4-6 equiv, 3 equiv, 4 equiv, 5 equiv, 6 equiv, 7 equiv, 8 equiv, 9 equiv, or 10 equiv) relative to the compound of Formula (V). In some embodiments, the ZnCl2is present in amount of 5 equiv relative to the compound of Formula (V). In some embodiments, the ZnCl2is sequentially added in more than one portion. In some embodiments, the ZnCl2 is sequentially added in two portions (e.g., a first portion of 3 equiv relative to the compound of Formula (V), then a second portion of 2 equiv relative to the compound of Formula (V)). In some embodiments, the CH2Br2 is present in an amount of 1-10 (e.g., 2-9 equiv, 3-7 equiv, 4-6 equiv, 2 equiv, 3 equiv, 4 equiv, 5 equiv, 6 equiv, 7 equiv, 8 equiv, 9 equiv, or 10 equiv) relative to the compound of Formula (V). In some embodiments, the CH2Br2is present in an amount of 4 equiv relative ALXN. DOCKET ALXN-0761-WO-PCT to the compound of Formula (V). In some embodiments, the CH2Br2is sequentially added in more than one portion. In some embodiments, the CH2Br2is sequentially added in three portions (e.g., a first portion of 1.5 equiv relative to the compound of Formula (V), a second portion of 1 equiv relative to the compound of Formula (V), then a third portion of 1.5 equiv relative to the compound of Formula (V)). Embodiments of the method disclosed herein unexpectedly provides the compound of Formula (VI) with high stereoselectivity (~97:3), which is carried over in, e.g., subsequent reactions in the multi- step synthesis of the compounds of Formula (XI). The compound of Formula (VI), prior to the present disclosure, was typically prepared using a procedure reported in US Publication No.2011 / 0274648 A1, which provides a ~1:3 diastereomeric mixture of the compound of Formula (VI) and its diastereomer. Other published procedures used silyl protective groups (Bioorg. Med. Chem., 21 (2013) 5725-5737), which render the product difficult to purify, compared to the reaction disclosed herein. Another published procedure relies on LiHMDS and methyl iodide for methyl insertion into the compound of Formula (I), which results in a mixture of mono- and di- methylated compounds in addition to unreacted starting material, thus requiring additional chromatographic separation. The ability to prepare intermediates in the synthesis of the compound of Formula (VI) with high stereoselectivity substantially improves overall yield of the overall process for preparing the compounds of Formula (XI). In some embodiments, the Co(II) catalyst is Co(II) complex containing a pyridine(diimine) (PDI) ligand. In some embodiments, the Co(II) complex is of structure: , wherein each X is independently Cl, C1-C6 alkyl; each R is independently H or C1-C6alkyl; and R” is H, halo, C1- or C6-C10aryl. For example, the Co(II) complex may be of structure: , in which each X is independently Br, C1-C6alkyl. In some embodiments, the Co(II) catalyst is (i.e., as opposed to being assembled in situ). In some embodiments, each X is independently Cl and Br. In some embodiments, each X is independently Cl or I. In some embodiments, each X is independently Br or I. In some embodiments, each X is Cl. In some embodiments, each X is Br. In some embodiments, each X is I. In some embodiments, each R is independently ethyl, n-propyl, isopropyl, or tert-butyl. In some embodiments, each R is ethyl. In some embodiments, each R is n-propyl. In some embodiments, each R is isopropyl. In some embodiments, each R is tert-butyl. ALXN. DOCKET ALXN-0761-WO-PCT Compounds of Formula (V) In some embodiments, the compound of Formula (V): (V), in which P1and P2are as defined above, a compound of Formula (IV): (IV), in which P1is an N-protecting group t- and P2is a carboxyl-protecting group (e.g., an alkyl group such as methyl), to a reaction). The dehydration reaction is typically performed under the presence of a strong acid, such as sulfuric acid, phosphoric acid, or from the hydrolysis of trifluoroacetic anhydride). The dehydration may also be performed in refluxing methylene chloride in the presence of catalytic p-toluenesulfonic acid (TsOH). Such reactions are well-known in the art. In some embodiments, the compound of Formula (V) is prepared by reacting the compound of Formula (IV) with trifluoroacetic anhydride, e.g., in the presence of 2,6-lutidine. Compounds of Formula (IV) In some embodiments, the compound of Formula (IV): (IV), in which P1and P2are as defined above, is prepared by reducing a compound of Formula (III): , in which P1is an N-protecting group P2is a carboxyl-protecting group (e.g., an alkyl group such as methyl). The compound of Formula (IV) may be reduced using a reducing agent such as lithium triethylborohydride borohydride. In some embodiments, the compound of Formula (IV) is reduced Compounds of Formula (III) In some embodiments, the compound of Formula (III): (III), in which P1and P2are as defined above, is prepared by subjecting a compound of Formula (II): ALXN. DOCKET ALXN-0761-WO-PCT (II), in which P1is H or an N-protecting group tert- and P2is H or a carboxyl-protecting group (e.g., an alkyl group such as reaction in the presence of a hydrogenation catalyst. Suitable but are not limited to, palladium on carbon, platinum(IV) oxide, palladium(II) and platinum metal. In some embodiments, the hydrogenolysis presence of palladium on carbon (Pd / C). Compounds of Formula (II) In some embodiments, the compound of Formula (II): (II), in which P1and P2are as defined above, is prepared by reacting a compound of Formula (I): , in which P1is an N-protecting group (e.g., and P2is a carboxyl-protecting group (e.g., an alkyl group such as methyl), with butoxy bis(dimethylamino)methane; see, e.g., Rosso, Synlett.2006; 5: 0809-0810). Compounds of Formulas (VI’), (VII), In some embodiments, the : (VI), in which P1is H or an N-protecting group (e.g., t-butoxycarbonyl) and P2is a carboxyl-protecting group (e.g., an alkyl group such as methyl), is reacted with a carboxyl-protecting-group-removing agent to obtain a compound of Formula (VI’): (VI’), in which P1is H or an N-protecting group. In some embodiments, the carboxyl-protecting group is alkyl (e.g., methyl), and the carboxyl-protecting-group-removing agent is a base (e.g., NaOH, LiOH, or KOH). Suitable carboxyl-protecting reagents and reaction conditions required to install and remove carboxyl- protecting groups are well known in the art (see, e.g., Wuts, Greene's Protective Groups in Organic Synthesis, Wiley-Interscience, 4th Edition, the carboxyl-protecting-group- removing agent is NaOH. In some is added in an amount sufficient to achieve a pH of > 11. ALXN. DOCKET ALXN-0761-WO-PCT In some embodiments, the compound of formula (VI’) is purified by first reacting it with an organic amine to form an organoammonium salt of the compound of formula (I) (e.g., in an organic solvent such as THF or toluene), then reacting the organoammonium salt of the compound of formula (I) with an acid to reform the compound of formula (I). Suitable organic amines include, but are not limited to, benzylamine and chiral amines such as (R)-α-methylbenzylamine. In some embodiments, the organic amine is benzylamine, which forms a benzylammonium salt of the compound of formula (I). In some embodiments, the organic amine is (R)-α-methylbenzylamine, which forms a (R)-α-methylbenzylammonium salt of the compound of Formula (I). The compound of Formula (VI’) can then be coupled to a compound of Formula (VII): (VII), or a salt thereof, in which R1is H or optionally substituted C1-C6alkyl; each of R2and R3is independently H or methyl; m is 0, 1, or 2; and B is optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C3-C10 carbocyclyl, C6-C14 aryl, optionally substituted 5- to 10- membered heterocyclyl, or optionally heteroaryl; in an amidation reaction to form a compound of Formula (VIII): (VIII), in which P1is an N-protecting group (e.g., tert-butoxycarbonyl), and all other variables are as defined for Formula (VII). Alternatively, a compound of Formula (VI’) in which P1is H may first be reacted with an N- protecting reagent (e.g., d-tert-butyl to the compound of Formula (VII) or salt thereof to form a compound of removal of P1that is an N-protecting group in the compound of Formula removing agent provides a compound of Formula (IX): (IX), or a salt thereof, in which all variables are as defined for Formula (VIII). Suitable N-protecting reagents and reaction conditions required to install and remove N-protecting groups are well known in the art (see, e.g., Wuts, Greene's Protective Groups in Organic Synthesis, Wiley-Interscience, 4th Edition, 2006). In some embodiments, the N- butyl dicarbonate (Boc2O), and the reaction is performed in an organic the presence of a base (e.g., 4- dimethylaminipyridine), and the N- (Boc). In some embodiments in which the N-protecting group is Boc, includes treating the compound of Formula (VIII) in an organic solvent with an acid as the N-protecting-group-removing agent. In some embodiments, the N-protecting-group-removing agent is hydrogen chloride (4 N HCl in dioxane), the reaction is performed in, e.g., dioxane, and the deprotection reaction forms a hydrochloride salt of the compound of Formula (IX). In some embodiments, the acid is hydrogen bromide (e.g., 33% HBr solution in acetic acid), the reaction is performed in, e.g., ethyl acetate, and the deprotection reaction forms a ALXN. DOCKET ALXN-0761-WO-PCT hydrobromide salt of the compound of Formula (IX). In some embodiments, the acid is trifluoroacetic acid, the reaction is performed in, e.g., dichloromethane, and the deprotection reaction forms a trifluoroacetic acid salt of the compound of Formula (IX). In some embodiments, the compound of Formula (VI’) and the compound of Formula (VII) or salt thereof are coupled in an organic solvent in the presence of a base and a coupling reagent. In some embodiments, the organic solvent is dimethylformamide. In some embodiments, the base is diisopropylethylamine. In some embodiments, the coupling reagent is (1-[bis(dimethylamino)methylene]- 1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU). Other suitable coupling reagents include, but are not limited to n-propanephosphonic acid anhydride (T3P) and (2-(1H-benzotriazol-1-yl)- 1,1,3,3-tetramethyluronium hexafluorophosphate (HBTU). Exemplary compounds of Formulas (VIII) and (IX) and methods of preparing such compounds are described in, e.g., U.S. Patents Nos. PCT Publications Nos. WO2015 / 130838, WO2017 / 035353, WO2017 / 035409, WO2018 / 160889, WO2020 / 041301, and WO2021 / 168320, the entire contents of which are incorporated herein by reference. Compounds of Formula (XI) In some embodiments, the compound of Formula (IX): (IX), or the salt thereof is coupled to a compound of Formula (X): , in which: R4is H; halo; OH; NH2; cyano; C1-C6 alkyl; optionally substituted C2-C6 alkenyl; optionally substituted 3- to 8- -C(O)NRaRa’, in which each of Ra and Ra’is, independently, H, optionally substituted substituted C2-C6alkenyl, optionally substituted C2-C6 alkynyl, or optionally -C(O)Rb; -OC(O)Rb; or -C(O)ORb; in which Rb, in each instance, substituted C1-C6 alkyl, optionally substituted C1-C6 alkoxy, and optionally each of R5and R6is, independently, H, halo, or optionally substituted C1-C6alkyl; X1is N or CRc, in which Rcis H, halo, optionally substituted C1-C6alkyl, or optionally substituted C1-C6 alkoxy; each of X2and X5is independently N or CRd, wherein each Rd is independently selected from H, halo, cyano, optionally substituted C1-C6alkyl, optionally substituted C1-C6alkoxy, optionally substituted C3-C8carbocyclyl, and optionally substituted 5- to 8-membered heteroaryl; and one of X3and X4is selected from N and CRe and the other of X3and X4is CRf, in which Re is selected from H, halo, cyano, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkoxy, and - C(O)ORg, in which Rgis H or optionally substituted C1-C6alkyl; and Rfis selected from optionally ALXN. DOCKET ALXN-0761-WO-PCT substituted C4-C10aryl, optionally substituted 5- to 10-membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S, and optionally substituted 4- to 10-membered saturated or unsaturated non-aromatic heterocyclyl containing 1-4 heteroatoms selected from N, O, and S; to form a compound of Formula (XI): or a pharmaceutically acceptable salt are as defined for Formulas (IX) and (X). In some embodiments, the salt of the compound of Formula (IX) and a compound of in the presence of 1- [bis(dimethylamino)methylene]-1H- 3-oxide hexafluorophosphate and N,N- diisopropylethylamine. In some with a hydrobromide salt of the compound of Formula (IX) and a in the presence of propanephosphonic acid anhydride In some embodiments, the reaction is performed with a trifluoroacetic acid salt of the compound of Formula (IX) with a compound of Formula (X) in dimethylformamide in the presence of N,N-diisopropylethylamine and 1-[bis(dimethylamino)methylene]- 1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate or 2-(1H-benzotriazole-1-yl)-1,1,3,3- tetramethylaminium tetrafluoroborate. Exemplary compounds of Formulas (IX), (X), and (XI) and their synthetic procedures are described in, e.g., PCT Publications Nos. WO2015 / 130838, WO2017 / 035353, WO2017 / 035409, WO2018 / 160889, WO2020 / 041301, and WO2021 / 168320, the entire contents of which are incorporated herein by reference. Further Embodiments of the Present Disclosure In some embodiments of any of the aspects described herein (e.g., Formulas (VII), (VIII), (IX), and (XI)), R1is H. In some embodiments of any of the aspects described herein (e.g., Formulas (VII), (VIII), (IX), and (XI)), R1is CH3. In some embodiments of any of the aspects described herein (e.g., Formulas (VII), (VIII), (IX), and (XI)), m is 0. In some embodiments of any of the aspects described herein (e.g., Formulas (VII), (VIII), (IX), and (XI)), m is 1. In some embodiments of any of the aspects described herein (e.g., Formulas (VII), (VIII), (IX), and (XI)), m is 2. In some embodiments of any of the aspects described herein (e.g., Formulas (VII), (VIII), (IX), and (XI)), each of R2and R3is H. In some embodiments of any of the aspects described herein (e.g., Formulas (VII), (VIII), (IX), and (XI)), R2is H and R3is CH3. In some embodiments of any of the aspects described herein (e.g., Formulas (VII), (VIII), (IX), and (XI)), each of R2and R3is CH3. In some embodiments of any of the aspects described herein (e.g., Formulas (VII), (VIII), (IX), and (XI)), B is optionally substituted 5- to 10-membered heteroaryl. ALXN. DOCKET ALXN-0761-WO-PCT In some embodiments of any of the aspects described herein (e.g., Formulas (VII), (VIII), (IX), and (XI)), B is optionally substituted 6-membered heteroaryl, e.g., optionally substituted pyridyl, optionally substituted pyridazinyl, optionally substituted pyrimidinyl, or optionally substituted pyrazinyl. In some embodiments of any of the aspects described herein (e.g., Formulas (VII), (VIII), (IX), and (XI)), B is optionally substituted pyridyl, e.g., , , , , , , F3C N , ,

[0002] ALXN. DOCKET ALXN-0761-WO-PCT , In

[0003] ALXN. DOCKET ALXN-0761-WO-PCT In some embodiments of any of the aspects described herein (e.g., Formulas (VII), (VIII), (IX), and , or some any , , , and , or and (XI)), B is optionally substituted pyridazinyl, . In some embodiments of any of the aspects herein (e.g., Formulas (VII), (VIII), (IX), and (XI)), B , or ALXN. DOCKET ALXN-0761-WO-PCT In some embodiments of any of the aspects described herein (e.g., Formulas (VII), (VIII), (IX), and (XI)), B is bicyclic 9- or 10-membered . In some embodiments of any of the and (XI)), B is optionally substituted C6-C14aryl, e.g., optionally substituted phenyl, , , ALXN. DOCKET ALXN-0761-WO-PCT In some embodiments of any of the aspects described herein (e.g., Formulas (VII), (VIII), (IX), and (XI)), B is optionally substituted 5- to 9-membered unsaturated , . described herein (e.g., Formulas (VII), (VIII), (IX), and , , (IX), and , , and , is ALXN. DOCKET ALXN-0761-WO-PCT In some embodiments of any of the aspects described herein (e.g., Formulas (X) and (XI)), X1is C(CH3). In some embodiments of any of the aspects described herein (e.g., Formulas (X) and (XI)), X1is CH. In some embodiments of any of the aspects described herein (e.g., Formulas (X) and (XI)), X2is CRd. In some embodiments of any of the aspects described herein (e.g., Formulas (X) and (XI)), X2is C(C1-C6alkyl). In some embodiments of any of the aspects described herein (e.g., Formulas (X) and (XI)), X2is C(CH3). In some embodiments of any of the aspects described herein (e.g., Formulas (X) and (XI)), X2is CH. In some embodiments of any of the aspects described herein (e.g., Formulas (X) and (XI)), X5is CRd. In some embodiments of any of the aspects described herein (e.g., Formulas (X) and (XI)), X5is CH. In some embodiments of any of the aspects described herein (e.g., Formulas (X) and (XI)), X3is CRf and X4is N. In some embodiments of any of the aspects described herein (e.g., Formulas (X) and (XI)), X3is CRf and X4is CH. In some embodiments of any of the aspects described herein (e.g., Formulas (X) and (XI)), X4is CRfand Xcis N. In some embodiments of any of the aspects described herein (e.g., Formulas (X) and (XI)), X4is CRf and X3is CH. In some embodiments of any of the aspects described herein (e.g., Formulas (X) and (XI)), Rf is optionally substituted 5- to 10-membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S. In some embodiments of any of the aspects described herein (e.g., Formulas (X) and (XI)), Rf is , ALXN. DOCKET ALXN-0761-WO-PCT , ), Rf is e.g., , or , Rf is from N, O, and S. In some embodiments, Rf is optionally substituted pyrazolo[1,5-a]pyrimidinyl, optionally substituted [1,2,4]triazolo[1,5-a]pyridinyl, optionally substituted thiazolo[5,4-b]pyridinyl, optionally substituted imidazo[1,2-a]pyrimidinyl, optionally substituted 3H-imidazo[4,5-b]pyridinyl, 1H-thieno[3,2- c]pyrazolyl, imidazo[1,2-b]pyridazinyl, optionally substituted quinazolinyl, optionally substituted quinolinyl, and 1H-benzo[d]imidazolyl, e.g., , , , ALXN. DOCKET ALXN-0761-WO-PCT is is or may to atom to through a carbon ring atom contained , ALXN. DOCKET ALXN-0761-WO-PCT . In other examples, Rf may be a nitrogen atom contained therein . is optionally substituted 5-membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and . an4 d (XI)), R is - C(O)Rb. In some embodiments of any of the aspects described herein (e.g., Formulas (X) and (XI)), R4is , R4is - (XI)), , . ), R4is - (XI)), R4is -C(O)OCH3. In some embodiments of any of the aspects described herein (e.g., Formulas (X) and (XI)), R4is -C(O)OH. In some embodiments of any of the aspects described herein (e.g., Formulas (X) and (XI)), R4is optionally substituted C1-C6 alkyl. In some embodiments of any of the aspects described herein (e.g., ALXN. DOCKET ALXN-0761-WO-PCT Formulas . In some embodiments of any of the aspects described herein (e.g., Formulas . of the aspects described herein (e.g., Formulas (X) and (XI)), R4is . In some embodiments of any of the aspects described herein (e.g., Formulas (X) and (XI)), R4is cyano. In some embodiments of any of the aspects described herein (e.g., Formulas (X) and (XI)), R4is halo, e.g., Br. In some embodiments of any of the aspects described herein (e.g., Formulas (X) and (XI)), R5is H. In some embodiments of any of the aspects described herein (e.g., Formulas (X) and (XI)), R6is H. In some embodiments, the compound of Formula (XI) is: , or a pharmaceutically acceptable salt In some embodiments, the is: , or a pharmaceutically acceptable salt In some embodiments, the is: , ALXN. DOCKET ALXN-0761-WO-PCT or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (XI) is: , or a pharmaceutically acceptable salt In some embodiments, the compound of Formula (XI) is: , or a pharmaceutically acceptable salt In some embodiments, the compound of Formula (XI) is: , or a pharmaceutically acceptable salt In some embodiments, the , or a pharmaceutically acceptable salt The examples described herein serve to illustrate the present disclosure, and the disclosure is not limited to the examples given. ALXN. DOCKET ALXN-0761-WO-PCT Example 1. Synthesis of (1R,3S,5R)-2-(tert-butoxycarbonyl)-5-methyl-2-azabicyclo[3.1.0]hexane-3- carboxylic acid Step 1,2- To a stirred (100 g, 0.411 mol) in toluene (250 ml), temperature, and the reaction was stirred at was cooled to −5 °C and stirred for 0.5-1.5 h. The with cold cyclohexane (200 ml). The product was dried under reduced pressure and yielded 1-(tert-butyl) 2-methyl (E)-4- ((dimethylamino)methylene)-5-oxopyrrolidine-1,2-dicarboxylate (2b) as a white solid (100 g, 82% yield).1H NMR (400 MHz, CDCl3): δ 7.06 (s, 1H), 4.56 (dd, 1H), 3.75 (s, 3H), 3.28− 3.23 (m, 1H), 3.02 (s, 6H), 2.91−2.87 (m, 1H), 1.49 (s, 9H). Step 2: Synthesis of 1-(tert-butyl) 2-methyl (2S)-4-methyl-5-oxopyrrolidine-1,2-dicarboxylate (2c) (E)-4- Pd / C then After was concentrated under reduced pressure at 45 ºC to afford a light-brown thick oil. Cyclohexane (40 mL) was added to the oil, and it was allowed to stir at -5 ºC for 30-50 min. The obtained solids were filtrated at -5 ALXN. DOCKET ALXN-0761-WO-PCT ºC. The product was dried under reduced pressure to obtain 1-(tert-butyl) 2-methyl (4S)-4-methyl-5- oxopyrrolidine-1,2-dicarboxylate (2c) as a white solid (14.48 g, 84% yield) with high diastereoselectivity (dr = 88:12).1H NMR (400 MHz, CDCl3): δ 4.59 – 4.45 (m, 1H), 3.77 (s, 3H), 2.71 – 2.49 (m, 2H), 1.68 – 1.57 (m, 1H), 1.48 (s, 9H), 1.30 – 1.17 (m, 3H). Step 3: Synthesis of 1-(tert-butyl) 2-methyl (2S)-5-hydroxy-4-methylpyrrolidine-1,2-dicarboxylate (2d) 1,2- under in °C. mixture at -75 °C, and reaction mixture was gradually warmed to room temperature. The organic layer was separated, and aqueous layer was further extracted with toluene (180 mL). The combined organic phase was used directly in the next step. Step 4: Synthesis of 1-(tert-butyl) 2-methyl (S)-4-methyl-2,3-dihydro-1H-pyrrole-1,2-dicarboxylate (2e) mmol, 14 h. and layer was washed by 1M HCl (360 mL). The reaction mixture was further washed with 10% NaHCO3(360 mL) solution. The organic layer was collected and dried over Na2SO4, filtered, and concentrated under vacuum, and 1-(tert-butyl) 2-methyl 4-methyl-2,3-dihydro-1H-pyrrole-1,2-dicarboxylate (2e) was obtained (116.9 g, 70% yield over 2 steps) as a yellow oil.1H NMR (400 MHz, CDCl3): δ 6.28 (dd, J = 45.6, 1.9 Hz, 1H), 4.61 (ddd, J = 31.2, 11.8, 5.3 Hz, 1H), 3.76 (s, 3H), 2.96 (q, J = 14.5 Hz, 1H), 2.52 (ddd, J = 22.3, 16.4, 5.3 Hz, 1H), 1.68 (d, J = 1.7 Hz, 3H), 1.45 (s, 9H). ALXN. DOCKET ALXN-0761-WO-PCT Step 5: Synthesis of 2-(tert-butyl) 3-methyl (1R,3S,5R)-5-methyl-2-azabicyclo[3.1.0]hexane-2,3- dicarboxylate (2f) Procedure A: premade Co(PDI)I2 complex (2.3 g, 3.11 was addition of Zn dust (2.44 g.37.3 mmol) (activated with dilute HCl). The reaction mixture was allowed to stir for the 20-40 minutes until a dark purple color appeared. 1-(Tert-butyl) 2-methyl 4-methyl-2,3-dihydro-1H-pyrrole-1,2- dicarboxylate (2e) (3.0 g, 12.43 mmol,) was dissolved in THF (7.5 mL) and degassed with N2 for 10 minutes. CH2Br2 (8.65 g, 49.73 mmol) was weighted out in a vial containing THF (22.5 mL) and degassed for 10 minutes with N2. The degassed solution of 1-(tert-butyl) 2-methyl 4-methyl-2,3-dihydro-1H-pyrrole- 1,2-dicarboxylate (2e) in THF was added dropwise to the reaction mixture and allowed to stir for next 10 minutes. The degassed solution of CH2Br2 (1 / 3 portion of total volume) in THF was added dropwise over 30 min to the reaction mixture, and it was allowed to stir at RT for 1h. The internal temperature was gradually increased to 41 ºC and decreased to 22 ºC within an hour. A second portion of Zn (1.63 g. 24.87 mmol, 2.0 eq) was added to the reaction mixture and the reaction mixture was allowed to stir for 10- 20 min, then a second portion of CH2Br2(1 / 3 portion of total solution) was added dropwise for 10 min, after which the reaction mixture was allowed to stir for 1h. The remaining third portion of Zn (1.63 g. 24.87 mmol) was added to the reaction mixture, and it was allowed to stir for 10 min. The third portion of CH2Br2(remaining 1 / 3 portion) was added dropwise for 10 min, and the reaction mixture was allowed to stir for 2h. After full conversion as monitored by HPLC, it was diluted with EtOAc (30 mL) and washed with 0.1 M HCl (40 mL). The aqueous layer was extracted with EtOAc, and the organic layer was filtered through short celite bed to remove the solid impurity. The combined organic layer was dried with Na2SO4 and concentrated under reduced pressure. The crude reaction mixture was purified by flash column chromatography with 5 to 20% EtOAc / Hexanes to obtain 2-(tert-butyl) 3-methyl (1R,3S,5R)-5-methyl-2- azabicyclo[3.1.0]hexane-2,3-dicarboxylate (2f) as a liquid (2.7 g, 85% yield) with high diastereoselectivity (dr = 97:3).1H NMR (400 MHz, CDCl3) δ 3.89-3.91 (m, 1H), 3.71-3.76 (s, 3H), 3.17 (m, 1H), 2.46 – 2.30 (m, 1H), 1.93 (dt, J = 13.7, 6.2 Hz, 1H), 1.37 (s, 9H), 1.18 (s, 3H), 0.63-0.58 (m, 1H), 0.57 (d, J = 6.4 Hz, 1H);13C NMR (101 MHz, CDCl3) δ 172.63, 80.27, 59.98, 52.10, 42.99, 38.65, 37.96, 28.26, 23.16, 22.03, 20.68. Procedure B: To a clean and dry 1L three-neck round-bottom with a magnetic stirrer was charged with a first portion of Co(PDI)Br2 complex (0.43 g, 0.66 mmol, 8 mol%), THF (20 mL), ZnCl2 (0.56 g, 4.14 mmol) and the first portion of Zn dust ((1.08 g, 16.58 mmol; directly used from commercially available bottle). The reaction mixture was allowed to stir until a dark purple color appeared. 1-(Tert- butyl) 2-methyl 4-methyl-2,3-dihydro-1H-pyrrole-1,2-dicarboxylate (2e) (2.0 g, 8.29 mmol) was dissolved in THF (5 mL) and degassed with N2 for 10 minutes. CH2Br2 (5.76 g, 33.16 mmol) was weighted out in vial containing THF (15 mL) and degassed for 10 minutes with N2. The degassed solution of 2e in THF was added dropwise to the reaction mixture and allowed to stir for 10 minutes. The first portion of degassed solution of CH2Br2(1 / 3 of the total solution) in THF was added dropwise over 10 min. to the reaction mixture, which was allowed to stir at RT for 1h. The internal reaction temperature gradually increased to 28.3 ºC. The second portion of Co(PDI)Br2 complex (0.43 g, 0.66 mmol, 8 mol%) and Zn ALXN. DOCKET ALXN-0761-WO-PCT (1.08 g, 16.58 mmol) were added to the reaction mixture and allowed to stir for 10 min. The second portion of CH2Br2(1 / 3 of the total solution) was added dropwise over 10 min, and the reaction mixture was allowed to stir 1 h. Finally, the third portion of Co(PDI)Br2 complex (0.43 g, 0.66 mmol, 8 mol%) and 2.0 equiv. of Zn (1.08 g, 16.58 mmol) were added to the mixture and allowed to stir for 10 min. The third portion of CH2Br2(remaining 1 / 3 portion) was added dropwise over 10 min. The mixture was allowed to stir for 16 h. After reaction completion, reaction workup was performed as mentioned above and crude product 2-(tert-butyl) 3-methyl (1R,3S,5R)-5-methyl-2-azabicyclo[3.1.0]hexane-2,3-dicarboxylate (2f) was obtained with high diastereoselectivity (dr = 97:3). Step 6: Synthesis of (1R,3S,5R)-2-(tert-butoxycarbonyl)-5-methyl-2-azabicyclo[3.1.0]hexane-3-carboxylic acid (2g) Procedure A: To mmol) in 3:1 mixture of EtOH / H2O (37 mL) LiOH 6-8 h. After completion of reaction, the reaction layer was further washed with 7.4 mL of EtOAc. The aqueous layer was collected, and its pH was adjusted to between 1-2 by adding aqueous 2M HCl solution. The solution was extracted with EtOAc (18.5 mL), and the combined organic layer was washed with 10% NaCl solution (7.4 mL). The organic layer was collected and concentrated under reduced pressure at 45 ºC to afford the product as a light-yellow thick oil (3.0g, 85% yield).1H NMR (400 MHz, CDCl3): δ 11.28 (s, 1H), 4.09 (dd, J = 31.9, 18.4 Hz, 1H), 3.20 (d, J = 49.3 Hz, 1H), 2.57 – 2.39 (m, 1H), 2.25 – 2.08 (m, 1H), 1.63 – 1.30 (m, 11H), 1.25 (s, 3H), 0.79 – 0.53 (m, 2H). Procedure B: To the stirring solution of Compound 2f (5 g, 14.49 mmol) in 3:1 mixture of EtOH / H2O (50 mL) NaOH (0.85 g, 36.23 mmol) was added and stir for 6-8 h. After completion of the reaction, the reaction mixture was diluted with EtOAc (20 mL), and the aqueous layer was further washed with 10 mL of EtOAc. The aqueous layer was collected, and its pH was adjusted to between 1-2 by adding a aqueous 2M HCl solution. The solution was extracted with EtOAc (25 mL), and the combined organic layer was washed with 10% NaCl solution (10 mL). The organic layer was collected and concentrated under reduced pressure at 45 ºC to afford the product (Compound 2g) as a light-yellow thick oil (3.0 g, 85% yield).1H NMR (400 MHz, CDCl3): δ 11.28 (s, 1H), 4.09 (dd, J = 31.9, 18.4 Hz, 1H), 3.20 (d, J = 49.3 Hz, 1H), 2.57 – 2.39 (m, 1H), 2.25 – 2.08 (m, 1H), 1.63 – 1.30 (m, 11H), 1.25 (s, 3H), 0.79 – 0.53 (m, 2H). Example 2. Preparation of Co(PDI)X2Complexes Co(PDI)X2 complexes can be prepared based on the following procedure. Step 1. Synthesis of PDI Ligand charged 2,6- 2.2 eq) to reaction ALXN. DOCKET ALXN-0761-WO-PCT mixture at rt. After the addition of p-TsOH (500 mg), the solution was refluxed and distilled for 6 h. Upon cooling to room temperature, 1M NaOH (2V) was added, and the reaction mixture was filtered through funnel and the product was diluted with ethanol and refluxed for 0.5 h. Upon cooling, the slurry was filtered through filtration flask and washed with cold ethanol and dried in a vacuum oven (50 °C) for overnight (isolated yield: 93 g, 62%). The identity of the product was confirmed by1H NMR and13C NMR. Other sterically and electronically diverse PDI ligands were prepared following the procedure above using the appropriate pyridine and aniline synthons. Pyridine Synthon Aniline Synthon PDI Ligand a To to ALXN. DOCKET ALXN-0761-WO-PCT obtain the Co(PDI)X2complex, which is dried under vacuum overnight. The prepared complex can be used without any further purification. Co(tBu-PDI)Br2 Complex THF (4 v) was charged in a 5 L reactor followed by the addition of PDI ligand (200 g, 469.9 mmol,1.0 equiv) under the nitrogen flow, subsequently, additional THF (11 v) was charged in the reactor and allowed to stir for 10-30 min and gives the homogeneous solution. CoBr2 (102.8 g, 469.9 mmol, 1.0 equiv) was charged in the reaction under nitrogen flow followed by the addition of THF (5 v). The reaction mass was allowed to stir for 60-72 h at room temperature under nitrogen flow. After 60-72 h, the reaction mixture was filtered and dried 8-12 h under vacuum at room temperature and was used without further purification. The isolated yield of was quantitative. Other PDI complexes were prepared using the procedure above with the PDI ligands disclosed above. Example 3. Improved Synthesis of (1R,3S,5R)-2-(tert-butoxycarbonyl)-5-methyl-2- azabicyclo[3.1.0]hexane-3-carboxylic acid Step 1,2- 2a (2.5 v, 625 . the reaction mass was heated at 75 ± 3 °C over 6-8 h. Upon completion of the reaction, the reaction mass was cooled to -5 ± 3 °C. was washed with cold cyclohexane (2.5 v). yielded Compound 2b as a light-yellow solid with : δ 7.06 (s, 1H), 4.56 (dd, 1H), 3.75 (s, 3H), (s, 9H);13C NMR (100 ALXN. DOCKET ALXN-0761-WO-PCT MHz, CDCl3): δ 172.60, 168.40, 150.40, 146.41,128.18.90.83.82.36, 82.17, 55.91, 52.29, 41.97, 28.20, 28.02, 27.81, 26.22. Step 2: Synthesis of 1-(tert-butyl) 2-methyl (2S)-4-methyl-5-oxopyrrolidine-1,2-dicarboxylate (2c) Compound 2b (40 g, 298.34 mmol, 1.0 equiv) was charged into a reactor, followed by IPA (4-7 v, 160-280 mL) and 10%w / w of 10% Pd / C (50% wet) (0.5 w / w Pd content). The reactor was equipped with overhead, sealed and placed in polyblock at 1500 rpm for 12-18 h. After completion of the reaction, mass was passed through celite (2-4 w / w) bed. IPA was removed by azeotroping with toluene, and the solution of Compound MHz, CDCl3) (dr = 8.8:1.2) δ 4.59 – 4.45 (m, 1H), 3.77 , 1.48 (s, 9H), 1.30 – 1.17 (m, 3H);1H NMR (100 MHz, 83.65, 83.53, 57.35, 56.87, 52.56, 52.48, 37.51, 36.60, Multiple batches of procedure with an isolated corrected yield of 81-89% purity of 75-89% as determined by HPLC. Step 3: Synthesis of 1-(tert-butyl) 2-methyl (2S)-5-hydroxy-4-methylpyrrolidine-1,2-dicarboxylate (2d) Continuous Flow Protocol The synthesis of Compound 2d using continuous flow chemistry was also considered. For synthesis, a continuous flow setup providing a throughput of 148 g / h based on 1 / 4” OD PFA tubular reactor (170 mL) (FIG.1) was used. Feed 1: Carboy charged with Compound 2c (411.5 g, 1612.80 mmol, 1.0 equiv) and toluene (3320 mL, 8 v) under N2 atmosphere. Feed 2: Super Hydride (1 M in THF, 2096.9 mL, 1.3 way valve was used to switch empty. Methanol for quenching was mL pre-cooling loops. The reaction and -78 to -70°C. Streams with Compound 2c loop at flow rate of 21.81 and 12.19 tR= 5 the first loop, the stream with methanol supply at a flow rate 7.72 mL / min (by HPLC pump) for additional tR= 2 min. ALXN. DOCKET ALXN-0761-WO-PCT Batch Protocol In a four neck 5 L RB connected to an overhead stirrer, Compound 2c (238.52 g, 1.0 equiv) was charged and dissolved in toluene (10 v) under nitrogen. The reaction solution was cooled to -78 °C and a 1.0 M solution of super-hydride (834.34 mL, 0.9 equiv) in THF was added slowly using a a peristaltic pump (4 mL / min). The mixture was stirred for 2 h at around -75 °C to -70 °C. The progress was monitored by1H NMR analysis. Based on the conversion of Compound 2c, another 0.16 equiv of super- hydride was charged slowly using a peristaltic pump (4 mL / min), and reaction was stirred for 30 min at around -75 °C to -70 °C. The progress was monitored by1H NMR. Based on the conversion Compound 2c, another 0.09 equiv of Super-hydride was charged slowly using peristaltic pump (4 mL / min), and the reaction mixture was stirred for 30 min at around -75 °C to -70 °C. The progress was monitored by1H NMR. Upon completion of the reaction, aqueous NH4Cl (1 v) solution was slowly added using a peristaltic pump (4 mL / min) to the reaction mixture at -75 °C to -65 °C, which was then allowed to warm to room temperature slowly. The reaction mixture was charged into a 5 L reactor and the aqueous layer was removed. The organic layer was washed with water (1 v) and brine (1 v), then distilled under a vacuum to distilled to 4-5 v while keeping jacket temperature 50 °C to 55 °C to remove the water content azeotropically and to bring water content to not more than 0.3%. Step 4: Synthesis of 1-(tert-butyl) 2-methyl (S)-4-methyl-2,3-dihydro-1H-pyrrole-1,2-dicarboxylate (2e) Compound 2d (240.4 g, 927.1 mmol, 1.0 equiv) in 10 v toluene (2.4 L) was charged to 5 L reactor with the help of a wide funnel under nitrogen flow. The reaction temperature was cooled to 0 °C.2,6- Lutidine (280.7 mL, 2410.4 mmol, 2.6 equiv) was added under nitrogen flow. Trifluoroacetic anhydride (TFAA) (167.5 funnel (connected with a long tube while maintaining the the reaction mass was was monitored by1H NMR to 22 ± 5 °C. The reaction combined wash with 10% NaHCO3 (1 v) and 10% brine (1 v). Toluene was distilled to till 1-2 v reaction mass and then the reaction mass was diluted with cyclohexane (2-4 v) and distilled to remove the toluene content as much as possible. The pale-yellow liquid was dried under vacuum for the next 8-10 h. Compound 2e was obtained as a pale-yellow liquid (176.1 g) was obtained with 94 wt.% purity based on quantitative NMR and 74% isolated yield over 2 steps (corrected based on starting material purity).1H NMR (400 MHz, ALXN. DOCKET ALXN-0761-WO-PCT CDCl3) δ 6.28 (dd, J = 45.6, 1.9 Hz, 1H), 4.61 (ddd, J = 31.2, 11.8, 5.3 Hz, 1H), 3.76 (s, 3H), 2.96 (q, J = 14.5 Hz, 1H), 2.52 (ddd, J = 22.3, 16.4, 5.3 Hz, 1H), 1.68 (d, J = 1.7 Hz, 3H), 1.45 (s, 9H). Step 5: Synthesis of 2-(tert-butyl) 3-methyl (1R,3S,5R)-5-methyl-2-azabicyclo[3.1.0]hexane-2,3- dicarboxylate (2f) Co(tBu-PDI) Br2 (40.06 of THF also and subsequently, activated Zn (48.78, 745.99 mmol, 3.0 equiv) dust was charged into the reactor and rinsed the reactor with 3 v of THF. Then, the reaction mass in the reactor was deep subsurface purged with N2using long tubing for 10-15 minutes and it was allowed to stir for next 20-50 min. A deep purple color appeared. Compound 2e (60.0 g, 248.66 mmol, 1.0 equiv) was dissolved in THF (1.5 v) and degassed with N2over 15-20 minutes in a separate round bottom flask and then it was charged into the reactor. The round bottom flask was rinsed with 0.5 v of THF and charged into the reactor. The color of the reaction mixture was unchanged. The reaction mass was allowed to stir for 20-50 mins. CH2Br2 (64.84 g, 373.0 mmol, 1.5 equiv) was added dropwise into reactor using addition funnel over 10-25 min. The reaction mixture was stirred for 1h, followed by dropwise addition of CH2Br2(43.23 g, 248.66 mmol, 1.0 equiv) into reactor using addition funnel over 10-25 min. After another 1 h stirring, the remaining ZnCl2(67.79 g, 497.33 mmol, 2.0 equiv) and Zn (32.52 g, 497.33 mmol, 2.0 equiv) were charged into the reactor and then the reaction mass in the reactor was again deep subsurface purged with N2 using long tubing for 10-15 minutes. CH2Br2 (64.84 g, 373.0 mmol, 1.5 equiv) was added dropwise into the reactor using addition funnel over 10-25 min. The progress of the reaction was monitored again by1H NMR at the 6thhour of the reaction, and the conversion was at 97A%. The reaction mass was passed through MTBE wetted sloka floc (4 w / w) bed, and the bed was washed with 6-8 v of MTBE. Filtrate was charged in a 5 L reactor followed by a mixture of 1:1 ratio of 10% NH4Cl (2 v) and 10% NaCl solution (2 v) was also charged into the reactor and stirred the RM for 20-40 min. Phase cut was done to remove the aqueous layer. The reaction mixture was distilled to 2-3 v and the crude RM was used for the next step.1H NMR (400 MHz, CDCl3) δ 3.89-3.91 (m, 1H), 3.71-3.76 (s, 3H), 3.17 (m, 1H), 2.46 – 2.30 (m, 1H), 1.93 (dt, J = 13.7, 6.2 Hz, 1H), 1.37 (s, 9H), 1.18 (s, 3H), 0.63-0.58 (m, 1H), 0.57 (d, J = 6.4 Hz, 1H);13C NMR (101 MHz, CDCl3) δ 172.63, 80.27, 59.98, 52.10, 42.99, 38.65, 37.96, 28.26, 23.16, 22.03, 20.68. Step 5 was tested with Zn activated with 1 N HCl and unactivated Zn, as well as various amounts of ZnCl2. The results are shown in Tables 1-3 below. ALXN. DOCKET ALXN-0761-WO-PCT Table 1. Reaction with 1 N HCl Activated Zn with Higher Loading of ZnCl2B h i PDIB Z¥Z l HB R i i .0 .5 .5 size is three portions into the reaction mixture. Table 2. Reaction with 1 N HCl Activated Zn with 1-1.5 equiv of ZnCl2 Batch Batch Co(PDI)Br2 Zn¥ / ZnCl2 CH2Br2 Reaction Conversion er No size (mol%) (equiv.) (equiv.) time Yield* (% area by HPLC) / .5 .5 size is All q . q . (hours) area by HPLC) / 6 25 g40 mol%a 6.0 equivc 5.0 equivc 18 h 84%*95:5 (61(100 A%)(95:5) wt.%) THF (20 v) ALXN. DOCKET ALXN-0761-WO-PCT 4 4) 4 4) 4 rtions.bse duced oxylic (5 v) ction mass was cooled to 5±10 °C with stirring at 500 RPM. NaOH (124.2g, 3105 mmol, 9.4 eq.) while ALXN. DOCKET ALXN-0761-WO-PCT maintaining the internal temperature below 15 °C until the pH reached >12. The reaction was allowed to reach RT and stirred over 4 h. °C. The formation of salt with an amine, such as benzylamine, can be used to remove process impurities from crude Compound 2g. In cases where the chiral purity of crude Compound 2g was lower than expected, a chiral amine was used for chiral resolution. (R)-a-methylbenzylamine was selected as the chiral amine as it was (1) easy to handle as a liquid at 25oC and could be added directly to the crude for salt formation; (2) its salt with Compound 2g has lower solubility compared to other chiral amines studied for salt formation; (3) it could also achieve chiral upgrading at the same time. The reaction mixture (containing approx.45 g Compound 2g, as solution in approx.225 mL (5 v) and mL °C at (if not, . at 50-55 °C. The reaction mixture after charcoal treatment and azeotropic distillation was kept at 50-55 °C while stirring in a nitrogen atmosphere, into which (R)-α-methylbenzylamine (0.5 eq.) was dosed in 2 hours. The system was aged for 1 h, and additional (R)-α-methylbenzylamine (0.5 eq.) was dosed in 2 h. The final mixture was kept stirring at 50-55 °C for 1 hour. The reaction mixture was then cooled to 20 °C with a linear temperature profile over 4 hours, and stirred at 20 °C for NLT 16 h. Upon drying, the (R)-α-methylbenzylamine salt was dispersed in 10 V isopropyl acetate while stirring at 20-25 °C.4.5 v 2 M HCl (aq.) was dosed to the mixture at 20-25 °C over 15 min. The mixture was then stirred for 10-15 min. The aqueous layer was discharged.3 v of water was charged into the remaining organic layer, and was stirred for 30 min. The aqueous layer was discharged. The organic layer was heated to 55-60 °C while stirring and was distilled to 1.5-2 v under vacuum.3 v isopropyl acetate was charged into the solution, and the solution was distilled to 1.5-2 v under vacuum. While maintaining the temperature at 55-60 °C, 10 v n-heptane was dosed over 1 h while stirring. The solution was distilled under vacuum to 10-11 v. Seed (1% by mass) was charged. The mixture was ALXN. DOCKET ALXN-0761-WO-PCT then stirred for 1 h at 55-60 °C. The mixture was then distilled under vacuum to 1.5-2 v.8 v. n-heptane was dosed over 1 h at 55-60 °C while stirring. The solution was distilled under vacuum to 1.5-2 v.3 v n- heptane was dosed over 0.5 h at 55-60 °C while stirring. The mixture was stirred at 55-60 °C for 1 h and cooled to 20-25 °C in no less than 2 h. The mixture was stirred at 20-25 °C for no less than 16 h. The mixture was filtered under vacuum. The cake was washed with n-heptane (2x1 v; slurry wash and displacement wash). The cake was then dried under vacuum at 50-55 °C for no less than 16 h. This procedure consistently produced purified Compound 2g with > 95% yield and chiral purity of > 99.5% as determined by HPLC. Other Embodiments Various modifications and variations of the described compositions and methods of the disclosure will be apparent to those skilled in the art without departing from the scope and spirit of the disclosure. Although the disclosure has been described in connection with specific embodiments, it should be understood that the disclosure as claimed should not be unduly limited to such specific embodiments. Indeed, various modifications of the described modes for carrying out the disclosed methods that are obvious to those skilled in the art are intended to be within the scope of the disclosure. Other embodiments are in the claims.

Claims

ALXN. DOCKET ALXN-0761-WO-PCT Claims 1. A method of preparing a compound of Formula (VI): , wherein P1is H or an N-or a carboxyl-protecting group, comprising providing a compound of Formula (V): , wherein P1is H or an N-protectingor a carboxyl-protecting group; and forming the compound of Formula (VI) from the compound of Formula (V), said forming the compound of Formula (VI) comprising contacting the compound of Formula (V) with a Co(II) catalyst in the presence of Zn and CH2Br2.

2. The method of claim 1, wherein said forming the compound of Formula (VI) comprises contacting the compound of Formula (V) with a Co(II) catalyst in the presence of Zn, CH2Br2, and ZnCl2.

3. The method of claim 1 or 2, wherein the Zn is zinc dust.

4. The method of claim 3, wherein the Zn is activated Zn dust.

5. The method of claim 1-4, wherein the Zn is present in amount of 2-10 equivalents relative to the compound of Formula (V).

6. The method of any one of claims 2-5, wherein the ZnCl2is present in an amount of 2-10 equivalents relative to the compound of Formula (V).

7. The method of any one of claims 1-6, wherein the CH2Br2is present in an amount of 1-10 equivalents relative to the compound of Formula (V).

8. The method of any one of claims 1-7, wherein the Co(II) catalyst is a compound of structure: , wherein each X is independently Cl, C1-C6alkyl; each R is independently H or C1-C6 alkyl; and R” is H, halo, C1- or C6-C10 aryl.

9. The method of claim 8, wherein the Co(II) catalyst is a compound of structure:ALXN. DOCKET ALXN-0761-WO-PCT , wherein each X is independently Br or C1-C6 alkyl.

10. The method of claim 9, wherein each R is tert-butyl.

11. The method of claim 9 or 10, wherein each X is Br.

12. The method of claim any one of claims 1-11, wherein said providing the compound of Formula (V) comprises: providing a compound of Formula (IV): , wherein P1is an N-protecting protecting group; and subjecting the compound of reaction.

13. The method of claim 12, wherein the dehydration reaction comprises reacting the compound of Formula (IV) with trifluoroacetic anhydride in the presence of 2,6-lutidine.

14. The method of claim 12 or 13, wherein said providing the compound of Formula (IV) comprises: providing a compound of Formula (III): (III), wherein P1is an N-protecting protecting group; and reacting the compound of agent.

15. The method of claim 14, agent is super hydride.

16. The method of claim 13 or 14, wherein said providing the compound of Formula (III) comprises: providing a compound of Formula (II): , wherein P1is H or an N- or a carboxyl-protecting group; andALXN. DOCKET ALXN-0761-WO-PCT subjecting the compound of Formula (II) to a hydrogenolysis reaction in the presence of a hydrogenation catalyst.

17. The method of claim 16, wherein the hydrogenation catalyst is palladium on carbon.

18. The method of claim 16 or 17, wherein said providing the compound of Formula (II) comprises: providing a compound of Formula (I): , wherein P1is an N-protectingprotecting group; and reacting the compound of Formula (I) with Bredereck’s reagent.

19. The method of any one of claims 1-18, wherein P2in Formula (VI) is a carboxyl-protecting group.

20. The method of claim 19, wherein the method further comprises reacting the compound of Formula (VI) with a carboxyl-protecting-group-removing agent to form a compound of Formula (VI’): , wherein P1is H or an N-21. The method of claim 20, wherein P1in Formula (VI’) is an N-protecting group.

22. The method of claim 20 or 21, further comprising: reacting the compound of formula (VI) with an organic amine to form an organoammonium salt of the compound of formula (VI); and reacting the organoammonium salt of the compound of formula (I) with an acid to form the compound of formula (VI).

23. The method of claim 19, wherein the organic amine is (R)-α-methylbenzylamine, and the organoammonium salt is a (R)-α-methylbenzylammonium salt.

24. The method of claim 23, wherein the method further comprises coupling the compound of Formula (VI’) to a compound of Formula (VII): (VII), or a salt thereof, whereinALXN. DOCKET ALXN-0761-WO-PCT R1is H or optionally substituted C1-C6alkyl; each of R2and R3is independently H or methyl; m is 0, 1, or 2; and B is optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C3-C10carbocyclyl, optionally substituted C6-C14aryl, optionally substituted 5- to 10-membered heterocyclyl, or optionally substituted 5- to 10-membered heteroaryl; to form a compound of Formula (VIII):wherein P1is an N-protecting group, and all other variables are as defined for Formula (VII); and reacting the compound of Formula (VIII) with a N-protecting-group-removing agent to form a compound of formula (IX):or a salt thereof, wherein all variables are as defined for Formula (VIII).

25. The method of claim 24, further comprising coupling the compound of Formula (IX) or the salt thereof to a compound of Formula (X): or a salt thereof, wherein R4is H; halo; OH; NH2; cyano; C1-C6 alkyl; optionally substituted C2-C6alkenyl; optionally substituted 3- to 8- -C(O)NRaRa’, wherein each of Ra and Ra’is, independently, H, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6alkynyl, or optionally substituted C3-C8cycloalkyl; -C(O)Rb; -OC(O)Rb; or -C(O)ORb; wherein Rb, in each instance, is selected from H, optionally substituted C1-C6alkyl, optionally substituted C1-C6 alkoxy, and optionally substituted C3-C8 carbocyclyl; each of R5and R6is, independently, H, halo, or optionally substituted C1-C6 alkyl; X1is N or CRc, wherein Rcis H, halo, optionally substituted C1-C6alkyl, or optionally substituted C1-C6alkoxy;ALXN. DOCKET ALXN-0761-WO-PCT each of X2and X5is independently N or CRd, wherein each Rdis independently selected from H, halo, cyano, optionally substituted C1-C6alkyl, optionally substituted C1-C6alkoxy, optionally substituted C3-C8 carbocyclyl, and optionally substituted 5- to 8-membered heteroaryl; and one of X3and X4is selected from N and CRe, and the other of X3and X4is CRf, wherein Re is selected from H, halo, cyano, optionally substituted C1-C6alkyl, optionally substituted C1-C6alkoxy, and - C(O)ORg, wherein Rgis H or optionally substituted C1-C6alkyl; and Rfis selected from optionally substituted C4-C10 aryl, optionally substituted 5- to 10-membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S, and optionally substituted 4- to 10-membered saturated or unsaturated non-aromatic heterocyclyl containing 1-4 heteroatoms selected from N, O, and S; to form a compound of formula (XI): , or a pharmaceutically acceptable salt and B are as defined for formula (IX), and all other variables are as26. The method of claim 24 or 25, wherein P1is tert-butoxycarbonyl.

27. The method of claim 26, wherein the N-protecting-group-removing agent is hydrogen chloride, and said reacting the compound of Formula (VIII) with the N-protecting-group-removing agent forms a hydrochloride salt of the compound of Formula (IX).

28. The method of claim 27, wherein the hydrochloride salt of the compound of Formula (IX) is coupled to the compound of Formula (X) in dimethylformamide in the presence of 1- [bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate and N,N- diisopropylethylamine.

29. The method of claim 26, wherein the N-protecting-group-removing agent is hydrogen bromide, and said reacting the compound of Formula (VIII) with the N-protecting-group-removing agent forms a hydrobromide salt of the compound of Formula (IX).

30. The method of claim 29, wherein the hydrobromide salt of the compound of Formula (IX) is coupled to the compound of Formula (X) in acetonitrile in the presence of propanephosphonic acid anhydride and N,N-diisopropylethylamine.

31. The method of claim 26, wherein the N-protecting-group-removing agent is trifluoroacetic acid, and said reacting the compound of Formula (VIII) with the N-protecting-group-removing agent forms a trifluoroacetic acid salt of the compound of Formula (IX).ALXN. DOCKET ALXN-0761-WO-PCT 32. The method of claim 31, wherein the trifluoroacetic acid salt of the compound of Formula (IX) is coupled to the compound of Formula (X) in dimethylformamide in the presence of N, N- diisopropylethylamine and 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate or 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethylaminium tetrafluoroborate.

33. The method of any one of claims 24-32, wherein R1is H.

34. The method of any one of claims 24-33, wherein m is 1.

35. The method of any one of claims 24-33, wherein m is 0.

36. The method of any one of claims 24-34, wherein each of R2and R3is H.

37. The method of any one of claims 24-36, wherein B is optionally substituted 5- to 10- membered heteroaryl.

38. The method of claim 37, wherein B is optionally substituted 6-membered heteroaryl.

39. The method of claim 38, wherein B is optionally substituted pyridyl, optionally substituted pyridazinyl, optionally substituted pyrimidinyl, or optionally substituted pyrazinyl.

40. The method of claim 39, wherein B is optionally substituted pyridyl.

41. The method of claim 40, wherein B is or .

42. The method of any one of substituted C6-C14 aryl.

43. The method of claim 42, phenyl.

44. The method of any one of claims 24-36, wherein B is optionally substituted 5- to 9- membered unsaturated heterocyclyl.

45. The method of any one of claims 24-36, wherein B is optionally substituted C3-C10cycloalkyl.

46. The method of any one of claims 24-36, wherein B is optionally substituted C2-C6 alkenyl.ALXN. DOCKET ALXN-0761-WO-PCT 47. The method of any one of claims 24-36, wherein B is optionally substituted C1-C6alkyl.

48. The method of any one of claims 25-47, wherein X1is N.

49. The method of any one of claims 25-47, wherein X1is CH.

50. The method of any one of claims 25-49, wherein X2is CRd.

51. The method of claim 50, wherein X2is CH or C(CH3).

52. The method of any one of claims 25-51, wherein X5is CRd.

53. The method of claim 52, wherein X5is CH.

54. The method of any one of claims 25-53, wherein X4is CRf.

55. The method of claim 54, wherein X3is N or CH.

56. The method of any one of claims 25-55, wherein Rfis optionally substituted 5- to 10- membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S.

57. The method of claim 56, wherein Rf is 6-membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S.

58. The method of claim 57, wherein Rf is optionally substituted pyrimidinyl.

59. The method of claim 56, wherein Rfis optionally substituted 8- to 10-membered bicyclic heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S.

60. The method of claim 59, wherein Rf is optionally substituted pyrazolo[1,5-a]pyrimidinyl, optionally substituted [1,2,4]triazolo[1,5-a]pyridinyl, optionally substituted thiazolo[5,4-b]pyridinyl, optionally substituted imidazo[1,2-a]pyrimidinyl, optionally substituted 3H-imidazo[4,5-b]pyridinyl, 1H- thieno[3,2-c]pyrazolyl, imidazo[1,2-b]pyridazinyl, optionally substituted quinazolinyl, optionally substituted quinolinyl, and 1H-benzo[d]imidazolyl.

61. The method of any one of claims 25-55, wherein Rfis optionally substituted 6- to 9- membered unsaturated heterocyclyl containing 1-4 heteroatoms selected from N, O, or S.

62. The method of claim 61, wherein the Rf is bonded to the carbon atom to which it is attached through a carbon ring atom contained therein.ALXN. DOCKET ALXN-0761-WO-PCT 63. The method of claims 56, wherein Rfis optionally substituted 5-membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S.

64. The method of any one of claims 25-63, wherein R4.

65. The method of any one of claims 25-64, wherein each of R5and R6is H.

66. The method of any one of claims 25-32, wherein the compound of Formula (XI) is: ,

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