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-0759-PCT01-NP

[0002] METHODS FOR THE SYNTHESIS OF COMPLEMENT FACTOR D INHIBITORS AND INTERMEDIATES THEREOF

[0003] Background

[0004] 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).

[0005] 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.

[0006] 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.

[0007] 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).

[0008] 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-0759-PCT01-NP

[0009] 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.

[0010] 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.

[0011] 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.

[0012] 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, WG2020 / 041301 , and WO2021 / 168320.

[0013] New methods for the synthesis of small molecule Factor D inhibitors and intermediates thereof are desirable.

[0014] Summary

[0015] The present disclosure generally relates to an improved method of preparing compounds useful for treating disorders mediated by complement factor D and intermediates thereof.

[0016] In particular, the present disclosure relates to compounds of Formula (IV): in which P1and P2are as defined herein, which are intermediates for the synthesis of complement factor

[0017] D inhibitors of Formula (X) in which variables R1, R2, are as defined herein.

[0018] Accordingly, in one aspect, the present disclosure provides a method of preparing a compound of Formula (IV). The method includes:

[0019] (a) providing a compound of Formula (I): ALXN-0759-PCT01-NP

[0020] (b) reacting the compound of Formula (I) in a Wittig reaction to form a compound of Formula (II):

[0021] (c) reacting the compound of Formula (II) in an olefin isomerization reaction with a transition metal catalyst to form a compound of Formula (

[0022] (d) forming the compound of Formula (IV) from the compound of Formula (III), said forming the compound of Formula (IV) includes contacting the compound of Formula (III) with a Co(ll) catalyst in the presence of Zn and CH2Br2.

[0023] Also provided herein are methods of preparing compounds of Formula (X): from the compound of Formula (IV) as prepared by any one of the methods disclosed herein.

[0024] Definitions

[0025] To facilitate the understanding of this disclosure, a number 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.

[0026] 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.

[0027] 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 ALXN-0759-PCT01-NP 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.

[0028] The term “alkanoyl,” as used herein, refers to a monovalent radical having the structure -C(O)R, in which R is alkyl, as defined herein.

[0029] 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.

[0030] 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, / -butoxy, f-butoxy, and the like.

[0031] The term “alkoxyalkyl,” as used herein, refers to a monovalent radical having the structure -RR’, in which R is “alkylene” as defined herein, and R’ is “alkoxy” as defined herein.

[0032] 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, Ci-Cs, C1-C6, C1-C4, or C1-C2). Examples include, but are not limited to, methyl, ethyl, isobutyl, sec-butyl, and tert-butyl.

[0033] The term “mono-alkylamino,” as used herein, refers to a monovalent radical having the structure -NHR, wherein R is “alkyl” as defined herein. The term “di-alkylamino,” as used herein, refers to a monovalent radical having the structure -NR2, wherein each R is “alkyl” as defined herein.

[0034] 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.

[0035] The term “alkylester,” as used herein, refers to a monovalent radical having the structure -C(O)R, in which R is “alkyl” as defined herein.

[0036] The term “alkylsulfinyl,” as used herein, refers to a monovalent radical having the structure -S(O)R, in which R is “alkyl” as defined herein.

[0037] The term “alkylsulfonyl,” as used herein, refers to a monovalent radical having the structure -S(O)2R, in which R is “alkyl” as defined herein.

[0038] The term “alkylsulfonamide,” as used herein, refers to a monovalent radical having the structure -NHS(O)2R, in which R is “alkyl” as defined herein.

[0039] 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 ALXN-0759-PCT01-NP 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.

[0040] The term “aminoalkyl,” as used herein, refers to a monovalent radical having the structure -RNH2, in which R is “alkylene” as defined herein. The term “mono-alkylaminoalkyl,” as used herein, refers to a monovalent radical having the structure -RN(H)(R’), in which R is “alkylene” as defined herein, and R’ is “alkyl” as defined herein. The term “di-alkylaminoalkyl,” as used herein, refers to a monovalent radical having the structure -RN(R’)2, in which R is “alkylene” as defined herein, and each R’ is “alkyl” as defined herein.

[0041] 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., Ce-Cie aryl, Ce-Cu aryl, C6-C13 aryl, or C6-C10 aryl).

[0042] The term “arylalkyl,” as used herein, refers to a monovalent radical having the structure -R’R”, where R’ is alkylene and R” is aryl, as defined herein. Arylalkyl can be optionally substituted in the same manner as defined for each R’ and R” group.

[0043] The term “carbocyclyl,” as used herein, represents a monovalent, saturated or unsaturated nonaromatic 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.

[0044] 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-lnterscience, 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, p-(trimethylsilyl)ethyl, p- (di(n-butyl)methylsilyl)ethyl, p-toluenesulfonylethyl, 4-nitrobenzylsulfonylethyl, allyl, cinnamyl, and 1- (trimethylsilylmethyl)-propenyl.

[0045] 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 ALXN-0759-PCT01-NP adamantyl. The term “cycloalkyl” also includes bicyclic, tricyclic, and tetracyclic fused ring structures, e.g., decalin and spirocyclic compounds.

[0046] The term “cyano,” as used herein, refers to a monovalent radical having the structure -CN.

[0047] 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-C14 cycloalkenyl). 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.

[0048] The term “halo,” as used herein, refers to a fluorine (fluoro), chlorine (chloro), bromine (bromo), or iodine (iodo) radical.

[0049] The term “haloalkoxy,” as used herein, refers to a monovalent radical having the structure -O- haloalkyl, in which haloalkyl is as defined herein.

[0050] The term “haloalkoxyalkyl,” as used herein, refers to a monovalent radical having the structure -RR’, in which R is “alkylene” as defined herein, and R’ is “haloalkoxy” as defined herein.

[0051] The term “haloalkyl,” as used herein, refers to an alkyl group, as defined herein, in which one or more hydrogen atoms is replaced with halo.

[0052] 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 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 2 / 7-pyran, optionally substituted 4 / 7-pyran, and optionally substituted tetrahydropyran. Exemplary 7-membered heterocyclyl groups include, but are not limited to, optionally substituted azepine, ALXN-0759-PCT01-NP 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 3 / 7-imidazo[4,5-b]pyridinyl, 1 / 7-thieno[3,2-c]pyrazolyl, imidazo[1 ,2-b]pyridazinyl, optionally substituted quinazolinyl, optionally substituted quinolinyl, and 1 / 7-benzo[cf]imidazolyl.

[0053] The term “hydroxyalkyl,” as used herein, refers to a monovalent radical having the structure -ROH, in which R is alkylene, as defined herein.

[0054] 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-lnterscience, 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, a- 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, 4-methoxybenzyloxycarbonyl, 2-nitro-4,5-dimethoxybenzyloxycarbonyl,

[0055] 3.4.5-trimethoxybenzyloxycarbonyl, 1 -(p- bi ph e ny ly I)- 1 -methylethoxycarbonyl, a,a-dimethyl-

[0056] 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).

[0057] The term “oxo,” as used herein, refers to a divalent oxygen atom represented by the structure =O.

[0058] The term “thioalkyl,” as used herein, refers to a monovalent radical having the structure -S-alkyl, in which “alkyl” is as defined herein.

[0059] 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) perse 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).

[0060] 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; thioalkyl; NO2; N3; NRR'; wherein each of R and R' is, independently, H, alkyl, ALXN-0759-PCT01-NP alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, or heterocyclyl; SO2R, wherein R is H, alkyl or aryl;

[0061] 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 Ce aryl group, i.e., phenyl, may be substituted with an alkyl group, which may be further substituted with a heterocyclyl group.

[0062] Detailed Description

[0063] 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 (X): or pharmaceutically acceptable salts thereof, in which variables R1-R6, X1-X5, m, and B are as defined herein. Exemplary compounds of Formula (X) are described in, e.g., PCT Publications Nos.

[0064] WO2015 / 130838, WO2017 / 035353, WO2017 / 035409, WO2018 / 160889, W02020 / 041301 , and

[0065] WO2021 / 168320, the entire contents of which are incorporated herein by reference.

[0066] In particular, the present disclosure provides a method of preparing a compound of Formula (IV): in which P1is H or an N-protecting group (e.g., tert-butoxycarbonyl) and P2is H or a carboxyl-protecting group (e.g., an alkyl group such as methyl). The method includes:

[0067] (a) providing a compound of Formula (I):

[0068] (b) reacting the compound of Formula (I) in a Wittig reaction to form a compound of Formula (II):

[0069] (c) reacting the compound of Formula (II) in an olefin isomerization reaction with a transition metal catalyst to form a compound of Formula ALXN-0759-PCT01-NP

[0070] (d) forming the compound of Formula (IV) from the compound of Formula (III), said forming the compound of Formula (IV) includes contacting the compound of Formula (III) with a Co(ll) catalyst in the presence of Zn and CH2Br2.

[0071] In some embodiments, said reacting the compound of Formula (I) in a Wittig reaction comprises reacting the compound of Formula (I) with a triphenyl phosphonium ylide. In some embodiments, the triphenyl phosphonium ylide is methyl phosphonium bromide. In some embodiments, the methyl phosphonium bromide is present at 1-2 equivalents (e.g., 1.1 equivalents) relative to the compound of Formula (I). In some embodiments, said reacting the compound of Formula (I) with the triphenyl phosphonium ylide is performed in the presence of a base. In some embodiments, the base is an organosodium reagent, an organolithium reagent, an organopotassium reagent, a sodium amide reagent, a lithium amide reagent, or a potassium amide reagent. In some embodiments, the base is selected from n-BuLi, LiHMDS, NaHMDS, and KO‘Bu. In some embodiments, the base is KO‘Bu. In some embodiments, the base is an alkali metal base, e.g., NaOH, KOH, or LiOH. In some embodiments, the base is present at 1-2 equivalents (e.g., 1 .05 equivalents) relative to the compound of Formula (I). In some embodiments, the compound of Formula (II) is stirred with CaBr2 to remove residual triphenylphosphine oxide (PPH3O or TPPO) generated in step (b).

[0072] In some embodiments, the transition metal catalyst is an Ir catalyst, a Pd catalyst, a Ni catalyst, or a Co catalyst. In some embodiments, the transition metal catalyst is a Ti catalyst, a Cr catalyst, a Mn catalyst, a Fe catalyst, a Cu catalyst, a Zn catalyst, a Mo catalyst, a Ru catalyst, an Os catalyst, a Rh catalyst, a W catalyst, a Pt catalyst, or an Au catalyst. Examples of transition metal catalysts suitable for alkene isomerization reactions are described in, e.g., Crossly, W. M., et al., J. Am. Chem. Soc. 2014, 136, 16788-16791 and Florito, D., et al., Chem. Soc. Rev. 2021 , 50, 1391 , the contents of which are incorporated by reference in their entirety.

[0073] In some embodiments, transition metal catalyst is an Ir catalyst. In some embodiments, the transition metal catalyst is Crabtree’s catalyst ([C8Hi2lrP(C6Hn)3C5H5N]PF6 or [lr(COD)PCy3Py]PFe).

[0074] In some embodiments, the transition metal catalyst is a Pd catalyst. In some embodiments, the transition metal catalyst is a Pd catalyst generated in situ with a Pd complex and a phosphine ligand. In some embodiments, the Pd complex is a Pd(0) complex, e.g., bis(dibenzylideneacetone)palladium(0) (Pd(dba)2). In some embodiments, the phosphine is tri-tert-butylphosphonium tetrafluoroborate (tBusP- HBF4). In some embodiments, the phosphine ligand is tricyclohexylphosphine tetrafluoro bo rate (CysP- HBF4). In some embodiments, the Pd catalyst is a Pd(0) catalyst or Pd(ll) catalyst. In some embodiments, the Pd catalyst is [1 ,1 ’-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(ll) (Pd(dtbpf)Cl2). In some embodiments, the Pd catalyst is [P(t-Bu)3PdBr]2.

[0075] In some embodiments, the transition metal catalyst is a Ni catalyst. In some embodiments, the transition metal catalyst is generated in situ with a Ni complex and a phosphine ligand. In some embodiments, the Ni complex is a N i(0) complex. In some embodiments, N i(0) complex is bis(cyclooctadiene)nickel(0) (Ni(COD)2). In some embodiments, the Ni complex is a Ni(ll) complex, and step (c) is performed in the presence of a reducing agent. In some embodiments, the Ni(ll) complex is nickel(ll) acetate tetrahydrate (Ni(OAc)2.4H2O). In some embodiments, the Ni(ll) complex is nickel(ll) acetylacetonate (Ni(acac)2). In some embodiments, the Ni(ll) complex is nickel(ll) chloride ethylene glycol dimethyl ether complex (Ni(DME)Cl2). In some embodiments, the phosphine ligand is triisopropylphosphonium tetraflouoroborate (iPr3PHBF4). In some embodiments, the phosphine ligand is ALXN-0759-PCT01-NP tricyclohexylphosphine tetrafluoro bo rate (Cy3PHBF4). In some embodiments, the phosphine ligand is tricyclopentylphosphine tetrafluoro bo rate (Cyp3PHBF4). In some embodiments, the reducing agent is lithium triethylborohydride (LiHBEts). In some embodiments, the reducing agent is H2. In some embodiments, the reducing agent is an alkali metal trisubstituted borohydride compound. In some embodiments, the reducing agent is lithium aluminum hydride. In some embodiments, the reducing agent is Sn. In some embodiments the reducing agent is tin(ll) halide. In some embodiments, the reducing agent is Fe. In some embodiments, the reducing agent is a trialkyl silane, e.g., triethylsilane.

[0076] In some embodiments, the transition metal catalyst is a Co catalyst In some embodiments, the transition metal catalyst is generated in situ with a Co salt and a phosphine ligand, and step (c) is performed in the presence of a reducing agent. In some embodiments, the Co salt is C0CI2. In some embodiments, the Co salt is CoBr2. In some embodiments, the Co salt is C0I2. In some embodiments, the phosphine ligand is 1 ,4-bis(diphenylphosphino)butane (DPPB). In some embodiments, the phosphine ligand is 1 ,4-bis(diphenylphosphino)propane (DPPP). In some embodiments, the phosphine ligand is 1 '- bis(diphenylphosphino)ferrocene (DPPF). In some embodiments, the reducing agent is LiHBEts. In some embodiments, the reducing agent is Zn. In some embodiments, the reducing agent is an alkali metal trisubstituted borohydride compound. In some embodiments, the reducing agent is lithium aluminum hydride. In some embodiments, the reducing agent is Sn. In some embodiments the reducing agent is tin(ll) halide. In some embodiments, the reducing agent is Fe. In some embodiments, the reducing agent is a trialkyl silane, e.g., triethylsilane. In some embodiments, step (c) is performed in the presence of water.

[0077] In some embodiments, step (c) is performed in MeTHF. In some embodiments, step (c) is performed in toluene. In some embodiments, step (c) is performed in THF. In some embodiments, step (c) is performed in CH3CN. In some embodiments, step (c) is performed in a mixture of MeTHF and CH3CN. In some embodiments, step (c) is performed in a mixture of THF and CH3CN.

[0078] In some embodiments, said forming the compound of Formula (IV) comprises contacting the compound of Formula (III) with a Co(ll) catalyst in the presence of Zn, CH2Br2, and ZnCh. In some embodiment, the Zn in step (d) is zinc dust. In some embodiments, the Zn in step (d) is activated. In some embodiments, the Zn is present in an amount of 2-10 equivalents (e.g., 3-8 equivalents, 4-6 equivalents, or 5 equivalents) relative to the compound of Formula (III). In some embodiments, the ZnCh is present in an amount of 2-10 equivalents (e.g., 3-8 equivalents, 4-6 equivalents, or 5 equivalents) relative to the compound of Formula (III). In some embodiments, the CH2Br2 is present in an amount of 1- 10 equivalents (e.g., 2-8 equivalents, 4-6 equivalents, or 5 equivalents) relative to the compound of Formula (III). In some embodiments, the Zn, ZnCh, and / or CH2Br2 are added in one or more portions.

[0079] In some embodiments, the Co(ll) catalyst in step (d) is a compound of structure: in which each X is independently Cl, Br, or I; each R is independently C1-C6 alkyl; each R is independently H or Ci-Ce alkyl; and R” is H, halo, Ci-Ce haloalkyl, Ci-Ce alkoxy, or C6-C10 aryl. In some embodiments, the Co(ll) catalyst in step (d) is a compound of structure: ALXN-0759-PCT01-NP in which each X is independently Br or I; and each R is independently Ci-Ce alkyl. In some embodiments, each R is tert-butyl. In some embodiments, each X is Br.

[0080] Compounds of Formulas (V), (VI), (VII), and (VIII)

[0081] In some embodiments, the compound of Formula (IV): 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 (V): 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-lnterscience, 4th Edition, 2006). In some embodiments, the carboxyl-protecting-group- removing agent is NaOH. In some embodiments, the NaOH is added in an amount sufficient to achieve a pH of > 11 .

[0082] In some embodiments, the compound of formula (V) is purified by first reacting it with an organic amine to form an organoammonium salt of the compound of Formula (V) (e.g., in an organic solvent such as THF or toluene), then reacting the organoammonium salt of the compound of Formula (V) with an acid to reform the compound of Formula (V). Suitable organic amines include, but are not limited to, benzylamine and chiral amines such as (R)-a-methylbenzylamine. In some embodiments, the organic amine is benzylamine, which forms a benzylammonium salt of the compound of Formula (V). In some embodiments, the organic amine is (R)-a-methylbenzylamine, which forms a (R)-a- methylbenzylammonium salt of the compound of Formula (V).

[0083] The compound of Formula (V) can then be coupled to a compound of Formula (VI): or a salt thereof, in which R1is H or Ci-Ce alkyl; each of R2and R3is independently H or methyl; m is 0, 1 , or 2; B is Ci-Ce alkyl optionally substituted with one or more substituents independently selected from halo, hydroxyl, -COOH, Ci-Cealkoxy, Ci-Cehaloalkoxy, and cyclopropyl; C2-C6 alkenyl optionally substituted with one or more substituents selected from halo, C1-C6 alkyl, and cyclopropyl, and optionally further substituted with phenyl optionally substituted with halo; C3-C10 cycloalkyl optionally substituted with ALXN-0759-PCT01-NP one or more substituents independently selected form halo, cyano, and Ci-Ce alkyl, and optionally further substituted with phenyl optionally substituted with halo; -(Co-C4alkyl)(phenyl), in which the phenyl is optionally substituted with one or more substituents independently selected from halo, -COOH, cyano, Ci- Ce alkyl, Ci-Ce alkoxy, SO2R, and Ci-Ce haloalkyl, and further optionally substituted with 5- to 10- membered heteroaryl containing 1 or 2 heteroatom independently selected from N and S, in which the heteroaryl is substituted with halo; 5- to 10-membered heteroaryl containing 1 , 2, or 3 heteroatoms independently selected from N, O, and S, in which the heteroaryl is optionally substituted with one or more substituents independently selected from halo, cyano, hydroxy, -COOH, -COONH2, Ci-Ce alkyl, C2-C6 alkanoyl, Ci-Ce alkoxy, Ci-Ce haloalkyl, Ci-Ce haloalkoxy, Ci-Ce alkylester, Ci-Ce thioalkyl, Ci-Ce hydroxyalkyl, (Ci-Ce alkoxy)(Ci-Ce alkyl), and (Ci-Ce haloalkoxy)(Ci-Ce alkyl), and further optionally substituted with C3-C6 cycloalkyl, phenyl optionally substituted with halo, or 5- or 6-membered heteroaryl containing 1 or 2 heteroatoms independently selected from N, O, and S and optionally substituted with halo; or biphenyl optionally substituted with one or more substituents independently selected from halo, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, and further optionally substituted with CONH2, C2-Cealkanoyl, or SO2R; and R is selected from Ci-Ce alkyl, Ci-Ce haloalkyl, NH2, NH(Ci-Ce alkyl), NH(cyclopropyl), and N(Ci-Ce alkyl)2; in an amidation reaction to form a compound of Formula (VII): in which P1is an N-protecting group (e.g., tert-butoxycarbonyl), and all other variables are as defined for Formula (VI). Alternatively, a compound of Formula (V) in which P1is H may first be reacted with an N- protecting reagent (e.g., d-tert-butyl dicarbonate) before it is coupled to the compound of Formula (VI) or salt thereof to form a compound of Formula (VII). Subsequent removal of P1that is an N-protecting group in the compound of Formula (VII) with an N-protecting-group-removing agent provides a compound of Formula (VIII): or a salt thereof, in which all variables are as defined for Formula (VII). 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-lnterscience, 4th Edition, 2006).

[0084] In some embodiments, the N-protecting reagent is di-tert-butyl dicarbonate (B0C2O), and the reaction is performed in an organic solvent (e.g., acetonitrile) in the presence of a base (e.g., 4- dimethylaminipyridine), and the N-protecting group is tert-butoxycarbonyl (Boc). In some embodiments in which the N-protecting group is Boc, the deprotection reaction includes treating the compound of Formula (VII) 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 HCI in dioxane), the reaction is performed in, e.g., dioxane, and the deprotection reaction forms a hydrochloride salt of the compound of Formula (VIII). In some embodiments, the N-protecting-group-removing agent 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 hydrobromide salt of the compound of Formula (VIII). In some embodiments, the N- ALXN-0759-PCT01-NP protecting-group-removing agent 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 (VIII).

[0085] In some embodiments, the compound of Formula (V) and the compound of Formula (VI) 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]- 1 H-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-(1 H-benzotriazol-1-yl)- 1 ,1 ,3,3-tetramethyluronium hexafluorophosphate (HBTU).

[0086] Exemplary compounds of Formulas (VI), (VI), (VII), and (VIII) 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, W02020 / 041301 , and WO2021 / 168320, the entire contents of which are incorporated herein by reference.

[0087] Compounds of Formula (X)

[0088] In some embodiments, the compound of Formula (VIII): or the salt thereof is coupled to a compound of Formula (IX): in which:

[0089] R4is H; halo; OH; NH2; cyano; C1-C6 alkyl; C1-C6 haloalkyl; C1-C6 hydroxyalkyl; C2-C6 alkenyl; 3- to 8-membered heterocyclyl; -C(O)NRaRa’, wherein each of Raand Rais, independently, H, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, or Cs-Cs cycloalkyl; -C(O)Rb; -OC(O)Rb; or -C(Q)ORb; wherein Rb, in each instance, is selected from H, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, and C3-C8 carbocyclyl; each of R5and R6is, independently, H, halo, or C1-C6 alkyl;

[0090] X1is N or CRc, wherein Rcis H, halo, or Ci-Ce alkyl; each of X2and X5is independently N or CRd, wherein each Rd is independently selected from H, halo, cyano, C1-C6 alkyl, Ci-Ce alkoxy, C3-C8 carbocyclyl, and 5- to 8-membered heteroaryl; and one of X3and X4is selected from N and CReand the other of X3and X4is CRf, in which Reis selected from H; halo; cyano; Ci-Ce alkyl; Ci-Ce alkoxy; -C(O)NRgRh, in which Rgand Rh are independently H or Ci-Ce alkyl; and -C(O)ORi, in which Ri is H or Ci-Ce alkyl; and Rf is 5- or 6-membered heteroaryl containing 1 or 2 nitrogen atoms or 8- to 10-membered bicyclic heteroaryl containing 1 , 2, or, 3 heteroatoms independently selected from N and S, in which Rf is optionally substituted with 1 or 2 groups independently selected from halo, hydroxyl, amino, cyano, -COOH, -CONH2, Ci-Ce alkyl, Ci-Ce alkoxy, ALXN-0759-PCT01-NP

[0091] C1-C6 haloalkyl, C2-Ce alkanoyl, Ci-Ce haloalkoxy, Ci-Ce alkylester, (mono- or di-Ci-Ce alkyl)amino, Ci-Ce hydroxyalkyl, cyclopropyl, Ci-Ce alkylsulfinyl, Ci-Ce alkylsulfonyl, Ci-Ce alkylsulfonamide, Ci-Ce thioalkyl, amino(Ci-C6 alkyl), (mono- or di-Ci-Ce alkyl)amino(Ci-C6 alkyl), and (Ci-Ce alkoxy)(Ci-Ce alkyl); to form a compound of Formula or a pharmaceutically acceptable salt thereof, in which all variables are as defined for Formulas (VIII) and (IX). In some embodiments, the reaction is performed with a hydrochloride salt of the compound of Formula (VIII) and a compound of Formula (IX) in dimethylformamide in the presence of 1- [bis(dimethylamino)methylene]-1 H-1 ,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate and N,N- diisopropylethylamine. In some embodiments, the reaction is performed with a hydrobromide salt of the compound of Formula (VIII) and a compound of Formula (IX) in acetonitrile in the presence of propanephosphonic acid anhydride and N,N-diisopropylethylamine. In some embodiments, the reaction is performed with a trifluoroacetic acid salt of the compound of Formula (VIII) with a compound of Formula (IX) in dimethylformamide in the presence of N,N-diisopropylethylamine and 1- [bis(dimethylamino)methylene]-1 H-1 ,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate or 2-(1 H- benzotriazole-1-yl)-1 ,1 ,3,3-tetramethylaminium tetrafluoroborate.

[0092] Exemplary compounds of Formulas (VIII), (IX), and (X) and their synthetic procedures are described in, e.g., PCT Publications Nos. WO2015 / 130838, WO2017 / 035353, WO2017 / 035409, WO2018 / 160889, W02020 / 041301 , and WO2021 / 168320, the entire contents of which are incorporated herein by reference.

[0093] Further Embodiments of the Present Disclosure

[0094] In some embodiments of any of the aspects described herein (e.g., Formulas (VI), (VII), (VIII), and (X)), R1is H. In some embodiments of any of the aspects described herein (e.g., Formulas (VI), (VII), (VIII), and (X)), R1is CH3.

[0095] In some embodiments of any of the aspects described herein (e.g., Formulas (VI), (VII), (VIII), and (X)), m is 0. In some embodiments of any of the aspects described herein (e.g., Formulas (VI), (VII), (VIII), and (X)), m is 1 . In some embodiments of any of the aspects described herein (e.g., Formulas (VI), (VII), (VIII), and (X)), m is 2.

[0096] In some embodiments of any of the aspects described herein (e.g., Formulas (VI), (VII), (VIII), and (X)), each of R2and R3is H. In some embodiments of any of the aspects described herein (e.g., Formulas (VI), (VII), (VIII), and (X)), R2is H and R3is CH3. In some embodiments of any of the aspects described herein (e.g., Formulas (VI), (VII), (VIII), and (X)), each of R2and R3is CH3.

[0097] In some embodiments of any of the aspects described herein (e.g., Formulas (VI), (VII), (VIII), and (X)), B is 5- to 10-membered heteroaryl containing 1 , 2, or 3 heteroatoms independently selected from N, ALXN-0759-PCT01-NP

[0098] O, and S and optionally substituted with one or more substituents independently selected from halo, cyano, hydroxy, -COOH, -COONH2, C1-C6 alkyl, C2-Ce alkanoyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, Ci-Ce alkylester, C1-C6 thioalkyl, C1-C6 hydroxyalkyl, (C1-C6 alkoxy)(Ci-Ce alkyl), and (C1-C6 haloalkoxy)(Ci-Ce alkyl), and further optionally substituted with C3-C6 cycloalkyl, phenyl optionally substituted with halo, or 5- or 6-membered heteroaryl containing 1 or 2 heteroatoms independently selected from N, O, and S and optionally substituted with halo.

[0099] In some embodiments of any of the aspects described herein (e.g., Formulas (VI), (VII), (VIII), and (X)), B is 6-membered heteroaryl containing 1 or 2 nitrogen atoms, e.g., pyridyl, pyridazinyl, pyrimidinyl, or pyrazinyl, and optionally substituted with one or more substituents independently selected from halo, cyano, hydroxy, -COOH, -COONH2, Ci-Ce alkyl, C2-C6 alkanoyl, Ci-Ce alkoxy, Ci-Ce haloalkyl, Ci-Ce haloalkoxy, Ci-Ce alkylester, Ci-Ce thioalkyl, Ci-Ce hydroxyalkyl, (Ci-Ce alkoxy)(Ci-Ce alkyl), and (Ci-Ce haloalkoxy)(Ci-C6 alkyl), and further optionally substituted with C3-C6 cycloalkyl, phenyl optionally substituted with halo, or 5- or 6-membered heteroaryl containing 1 or 2 heteroatoms independently selected from N, O, and S and optionally substituted with halo.

[0100] In some embodiments of any of the aspects described herein (e.g., Formulas (VI), (VII), (VIII), and (X)), B is pyridyl optionally substituted with one or more substituents independently selected from halo, cyano, hydroxy, -COOH, -COONH2, Ci-Ce alkyl, C2-Ce alkanoyl, Ci-Ce alkoxy, Ci-Ce haloalkyl, Ci-Ce haloalkoxy, Ci-Ce alkylester, Ci-Ce thioalkyl, Ci-Ce hydroxyalkyl, (Ci-Ce alkoxy)(Ci-Ce alkyl), and (Ci-Ce haloalkoxy)(Ci-Ce alkyl), and further optionally substituted with C3-C6 cycloalkyl, phenyl optionally substituted with halo, or 5- or 6-membered heteroaryl containing 1 or 2 heteroatoms independently selected from N, O, and S and optionally substituted with halo. In some embodiments, B is selected from ALXN-0759-PCT01-NP ALXN-0759-PCT01-NP

[0101] In some embodiments of any of the aspects described herein (e.g., Formulas (VI), (VII), (VIII), and (X)), B is pyrazinyl optionally substituted with one or more substituents independently selected from halo, Ci-Ce alkyl, and C1-C6 haloalkyl. In some embodiments, B is

[0102] In some embodiments of any of the aspects described herein (e.g., Formulas (VI), (VII), (VIII), and (X)), B is pyrimidinyl optionally substituted with one or more substituents independently selected from C1- Ce alkyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, and thiophenyl optionally substituted with halo. In some

[0103] In some embodiments of any of the aspects described herein (e.g., Formulas (VI), (VII), (VIII), and ■p

[0104] (X)), B is pyridazinyl. In some embodiments, B is 7^-

[0105] In some embodiments of any of the aspects described herein (e.g., Formulas (VI), (VII), (VIII), and (X)), B is five-membered heteroaryl optionally substituted with one or more substituents independently selected from halo, C1-C6 alkyl, and C1-C6 haloalkyl, and further optionally substituted with phenyl optionally substituted with halo, or pyridyl optionally substituted with halo. In some embodiments, B is ALXN-0759-PCT01-NP

[0106] In some embodiments of any of the aspects described herein (e.g., Formulas (VI), (VII), (VIII), and (X)), B is phenyl optionally substituted with one or more substituents independently selected from halo, cyano, Ci-Ce alkyl, Ci-Ce alkoxy, SO2R, and C1-C6 haloalkyl, and further optionally substituted with 5- to 10-membered heteroaryl containing 1 or 2 heteroatom independently selected from N and S, wherein the F3CO CI CI FF0 heteroaryl is substituted with halo. In some embodiments, B is

[0107] In some embodiments of any of the aspects described herein (e.g., Formulas (VI), (VII), (VIII), and

[0108] (X)), B is biphenyl optionally substituted with one or more halo, and optionally further substituted with

[0109] CONH2, C2-Cealkanoyl, or optionally substituted with SO2R,. In some embodiments, B is ALXN-0759-PCT01-NP

[0110] In some embodiments of any of the aspects described herein (e.g., Formulas (VI), (VII), (VIII), and

[0111] (X)), B is C3-C10 cycloalkyl optionally substituted with one or more substituents independently selected form halo, cyano, and C1-C6 alkyl, and optionally further substituted with phenyl optionally substituted with

[0112] In some embodiments of any of the aspects described herein (e.g., Formulas (VI), (VII), (VIII), and (X)), B is C2-C6 alkenyl optionally substituted with one or more substituents selected from halo, C1-C6 alkyl, and cyclopropyl, and optionally further substituted with one substituent selected from phenyl

[0113] In some embodiments of any of the aspects described herein (e.g., Formulas (VI), (VII), (VIII), and (IX)), B is Ci-Ce alkyl optionally substituted with one or more substituents independently selected from halo, hydroxyl, -COOH, Ci-Cealkoxy, Ci-Cehaloalkoxy, and cyclopropyl. In some embodiments, B is , ALXN-0759-PCT01-NP

[0114] In some embodiments of any of the aspects described herein (e.g., Formulas (VI), (VII), (VIII), and

[0115] (X)), B is -(Co-C4alkyl)(phenyl). In some embodiments,

[0116] In some embodiments of any of the aspects described herein (e.g., Formulas (IX) and (X)), X1is

[0117] N. In some embodiments of any of the aspects described herein (e.g., Formulas (IX) and (X)), X1is CRd. In some embodiments of any of the aspects described herein (e.g., Formulas (IX) and (X)), X1is C(CH3). In some embodiments of any of the aspects described herein (e.g., Formulas (IX) and (X)), X1is CH.

[0118] In some embodiments of any of the aspects described herein (e.g., Formulas (IX) and (X)), X2is CRd. In some embodiments of any of the aspects described herein (e.g., Formulas (IX) and (X)), X2is

[0119] C(Ci-Ce alkyl). In some embodiments of any of the aspects described herein (e.g., Formulas (IX) and (X)), X2is C(CH3). In some embodiments of any of the aspects described herein (e.g., Formulas (IX) and (X)), X2is CH.

[0120] In some embodiments of any of the aspects described herein (e.g., Formulas (IX) and (X)), X5is CRd. In some embodiments of any of the aspects described herein (e.g., Formulas (IX) and (X)), X5is

[0121] CH.

[0122] In some embodiments of any of the aspects described herein (e.g., Formulas (IX) and (X)), X3is CRf and X4is N. In some embodiments of any of the aspects described herein (e.g., Formulas (IX) and (X)), X3is CRf and X4is CH.

[0123] In some embodiments of any of the aspects described herein (e.g., Formulas (IX) and (X)), X4is CRf and Xcis N. In some embodiments of any of the aspects described herein (e.g., Formulas (IX) and (X)), X4is CRf and X3is CH.

[0124] In some embodiments of any of the aspects described herein (e.g., Formulas (IX) and (X)), Rf is 5- to 10-membered heteroaryl containing 1 , 2, or 3 heteroatoms selected from N and S and optionally substituted with 1 or 2 groups independently selected from halo, hydroxyl, amino, cyano, -COOH, - CONH2, Ci-Ce alkyl, Ci-Ce alkoxy, Ci-Ce haloalkyl, C2-Ce alkanoyl, Ci-Ce haloalkoxy, Ci-Ce alkylester, (mono- or di-Ci-Ce alkyl)amino, Ci-Ce hydroxyalkyl, cyclopropyl, Ci-Ce alkylsulfinyl, Ci-Ce alkylsulfonyl, Ci- Ce alkylsulfonamide, Ci-Ce thioalkyl, amino(Ci-Ce alkyl), (mono- or di-Ci-Ce alkyl)amino(Ci-Ce alkyl), and (Ci-Ce alkoxy)(Ci-Ce alkyl).

[0125] In some embodiments of any of the aspects described herein (e.g., Formulas (IX) and (X)), Rf is pyrimidinyl optionally substituted with 1 or 2 groups independently selected from halo, hydroxyl, amino, cyano, -COOH, -CONH2, Ci-Ce alkyl, Ci-Ce alkoxy, Ci-Ce haloalkyl, 02-Ce alkanoyl, Ci-Ce haloalkoxy, Ci- Ce alkylester, (mono- or di-Ci-Ce alkyl)amino, Ci-Ce hydroxyalkyl, cyclopropyl, Ci-Ce alkylsulfinyl, Ci-Ce alkylsulfonyl, Ci-Ce alkylsulfonamide, Ci-Ce thioalkyl, amino(Ci-Ce alkyl), (mono- or di-Ci-Ce ALXN-0759-PCT01-NP ALXN-0759-PCT01-NP

[0126] In some embodiments of any of the aspects described herein (e.g., Formulas (IX) and (X)), RHs pyridinyl, pyrazinyl, or pyridazinyl, each of which is optionally substituted with 1 or 2 groups independently selected from halo, hydroxyl, amino, cyano, -COOH, -CONH2, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C2-Ce alkanoyl, C1-C6 haloalkoxy, C1-C6 alkylester, (mono- or di-Ci-Ce alkyl)amino, C1-C6 hydroxyalkyl, cyclopropyl, Ci-Cs alkylsulfinyl, C1-C6 alkylsulfonyl, C1-C6 alkylsulfonamide, C1-C6 thioalkyl, amino(Ci-Ce alkyl), (mono- or di-Ci-Ce alkyl)amino(Ci-C6 alkyl), and (C1-C6 alkoxy)(Ci-Ce alkyl). In some

[0127] In some embodiments of any of the aspects described herein (e.g., Formulas (IX) and (X)), Rf is 8- to 10-membered bicyclic heteroaryl containing 1 , 2, or 3 heteroatoms selected from N and S optionally substituted with 1 or 2 groups independently selected from halo, hydroxyl, amino, cyano, -COOH, - CONH2, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C2-C6 alkanoyl, C1-C6 haloalkoxy, C1-C6 alkylester, (mono- or di-Ci-Ce alkyl)amino, C1-C6 hydroxyalkyl, cyclopropyl, Ci-Cs alkylsulfinyl, C1-C6 alkylsulfonyl, C1- Ce alkylsulfonamide, C1-C6 thioalkyl, amino(Ci-Ce alkyl), (mono- or di-Ci-Ce alkyl)amino(Ci-C6 alkyl), and (C1-C6 alkoxy)(Ci-Ce alkyl). In some embodiments, Rf is pyrazolo[1 ,5-a]pyrimidinyl, [1 ,2,4]triazolo[1 ,5- a]pyridinyl, thiazolo[5,4-b]pyridinyl, imidazo[1 ,2-a]pyrimidinyl, 3 / 7-imidazo[4,5-b]pyridinyl, 1 / 7-thieno[3,2- c]pyrazolyl, imidazo[1 ,2-b]pyridazinyl, quinazolinyl, quinolinyl, and 1 / 7-benzo[cf]imidazolyl, each of which is optionally substituted with 1 or 2 groups independently selected from halo, hydroxyl, amino, cyano, - COOH, -CONH2, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C2-Ce alkanoyl, C1-C6 haloalkoxy, C1-C6 alkylester, (mono- or di-Ci-Ce alkyl)amino, C1-C6 hydroxyalkyl, cyclopropyl, Ci-Cs alkylsulfinyl, C1-C6 alkylsulfonyl, C1-C6 alkylsulfonamide, C1-C6 thioalkyl, amino(Ci-Ce alkyl), (mono- or di-Ci-Ce alkyl)amino(Ci-C6 alkyl), and (C1-C6 alkoxy)(Ci-Ce alkyl). In some embodiments, Rf is ALXN-0759-PCT01-NP

[0128] In some embodiments of any of the aspects described herein (e.g., Formulas (IX) and (X)), Rf is C6-C14 aryl (such as phenyl) optionally substituted with 1 or 2 groups independently selected from halo, hydroxyl, amino, -COOH, -CONH2, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C2-Ce alkanoyl, C1-C6 alkylester, mono-Ci-Ce alkylamin

[0129] Ci-Cethioalkyl, and morpholino,

[0130] In some embodiments of any of the aspects described herein (e.g., Formulas (IX) and (X)), Rf is 6- to 9-membered unsaturated heterocyclyl containing 1-4 heteroatoms selected from N, O, or S and optionally substituted with one or more with 1 or 2 groups independently selected from halo, hydroxyl, amino, cyano, oxo, -COOH, -CONH2, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C2-Ce alkanoyl, C1-C6 alkylester, mono-Ci-Ce alkylamino, C1-C6 hydroxyalkyl, cyclopropyl, Ci-Cs alkylsulfinyl, C1-C6 alkylsulfonyl, and C1-C6 thioalkyl. For example, Rf may be heterocyclyl bonded to the carbon atom to which it is attached through a carbon ring atom contained therein, e.g., ALXN-0759-PCT01-NP heterocyclyl bonded to the carbon atom to which it is attached through a nitrogen atom contained therein

[0131] In some embodiments of any of the aspects described herein (e.g., Formulas (IX) and (X)), Rf is optionally substituted 5-membered heteroaryl containing 1 , 2, or 3 heteroatoms selected from N, O, and

[0132] S o, e c .oy . ,

[0133] In some embodiments of any of the aspects described herein (e.g., Formulas (IX) and (X)), R4is -

[0134] C(O)Rb. In some embodiments of any of the aspects described herein (e.g., Formulas (IX) and (X)), R4is

[0135] In some embodiments of any of the aspects described herein (e.g., Formulas (IX) and (X)), R4is -

[0136] C(O)NRaRa . In some embodiments of any of the aspects described herein (e.g., Formulas (IX) and (X)),

[0137] In some embodiments of any of the aspects described herein (e.g., Formulas (IX) and (X)), R4is - C(O)ORb. In some embodiments of any of the aspects described herein (e.g., Formulas (IX) and (X)), R4is -C(O)OCH3. In some embodiments of any of the aspects described herein (e.g., Formulas (IX) and (X)), R4is -C(O)OH.

[0138] In some embodiments of any of the aspects described herein (e.g., Formulas (IX) and (X)), R4is optionally substituted Ci-Ce alkyl. In some embodiments of any of the aspects described herein (e.g., ALXN-0759-PCT01-NP

[0139] Formulas (IX) and (X)), R4is In some embodiments of any of the aspects described herein

[0140] (e.g., Formulas

[0141] In some embodiments of any of the aspects described herein (e.g., Formulas (IX) and (X)), R4is

[0142] In some embodiments of any of the aspects described herein (e.g., Formulas (IX) and (X)), R4is cyano. In some embodiments of any of the aspects described herein (e.g., Formulas (IX) and (X)), R4is halo, e.g., Br.

[0143] In some embodiments of any of the aspects described herein (e.g., Formulas (IX) and (X)), R5is H.

[0144] In some embodiments of any of the aspects described herein (e.g., Formulas (IX) and (X)), R6is H.

[0145] In some embodiments, the compound of Formula (X) is: or a pharmaceutically acceptable salt thereof.

[0146] In some embodiments, the compound of Formula (X) is: or a pharmaceutically acceptable salt thereof.

[0147] In some embodiments, the compound of Formula (X) is: ALXN-0759-PCT01-NP or a pharmaceutically acceptable salt thereof.

[0148] In some embodiments, the compound of Formula (X) is: or a pharmaceutically acceptable salt thereof.

[0149] In some embodiments, the compound of Formula (X) is: or a pharmaceutically acceptable salt thereof.

[0150] In some embodiments, the compound of Formula (X) is: or a pharmaceutically acceptable salt thereof.

[0151] In some embodiments, the compound of Formula (X) is: or a pharmaceutically acceptable salt thereof.

[0152] Examples

[0153] The examples described herein serve to illustrate the present disclosure, and the disclosure is not limited to the examples given. ALXN-0759-PCT01-NP

[0154] Example 1. Synthesis of (1 R,3S,5R)-2-(tert-butoxycarbonyl)-5-methyl-2-azabicyclo[3.1.0]hexane-3- carboxylic acid

[0155] Procedure 1 : To a clean 2 L EasyMax RV1 reactor equipped with nitrogen flow was charged methyltriphenylphosphonium bromide (1.1 equiv, 904.39 mmol, 323.07 g) and 800 mL of anhydrous THF. Solid KO‘Bu (1 .05 equiv, 863.2 mmol, 96.8 g) was added slowly into the reactor at room temperature. A yellow heterogenous mixture forms in 10 min. Stir the reaction mixture for 1 h at the same temperature at 400 RPM. The reaction mass was cooled to -5 °C. 1 -(tert-Butyl) 2-methyl 4-oxopyrrolidine-1 ,2- dicarboxylate (3a) (200 g, 822.17 mmol, 1.0 equiv) was dissolved in 200 mL anhydrous THF and slowly added to the reactor over 45 min while maintaining the internal reaction temperature over a range of 0 to - 5 °C. After the addition of 3a, the reaction mass was allowed to warm to room temperature over 30 min and was allowed to stir for 2.0 h at the same temperature. After 3 h, reaction completion was confirmed by HPLC and1H NMR, and the reaction mixture was quenched by slowly adding 10% aq. NH4CI (3 v, 600 mL) over 15-25 min. The reaction mixture was extracted with methyl t-butyl ether (3 v, 600 mL) and organic layer was concentrated. The crude oil thus obtained was purified by passing it through a silica pad (1 .0 kg, 5 w / W) using a mixture of hexanes / ethyl acetate (0-15%), and the fractions containing the product were concentrated to obtain 3b as a transparent oil (62% corrected yield; er >99.5:0.5; 92 wt%; > 98 A%).

[0156] Procedure 2: A Witting reaction was performed on Compound 3a (1 .0 equiv, 27.95 mmol, 6.8 g) following the procedure above. After concentrating the organic layer after workup, the crude reaction mass was dissolved in THF (34 mL, 5 v) and MTBE (136 mL, 20 v). CaBr2 (3 equiv, 83.7 mmol, 16.7 g) was added to the reaction mixture, which was stirred at room temperature for over 12 h. The reaction mass was filtered through Celite 545 (2 w / W, 13.6 g), and the filtrate was concentrated to obtained 3b as an oil with 0.88 wt% residual PPhsO (reduced from 30.6 wt%). The use of CaBr2 operation removed more than 95 wt% of PPhsO from the crude reaction mixture. Methods of removing PPhsO are previously reported in, e.g., Batesly, D.C., et al., J. Org. Chem. 2017, 82, 9931-9936 and Hergueta, A. R.,Org. Process Res. Dev. 2022, 26, 1845-1853, the contents of which are incorporated by reference in their entirety.

[0157] Procedure 3: To a clean 2 L EasyMax RV1 reactor equipped with nitrogen flow was charged methyltriphenylphosphonium bromide (1.1 equiv, 904.39 mmol, 323.07 g) and anhydrous THF (800 mL). ALXN-0759-PCT01-NP

[0158] Solid KO‘Bu (1 .05 equiv, 863.2 mmol, 96.8 g) was added slowly into the reactor at room temperature. A yellow heterogenous mixture formed in 10 min. The reaction mixture was stirred for 1 h at the same temperature at 400 RPM. The reaction mass was cooled to -5 to -10 °C. Compound 3a (200 g, 822.17 mmol, 1 .0 equiv) was dissolved in 200 mL anhydrous THF and added slowly to the reactor over 45 min while the internal reaction temperature was maintained over a range of 0 to -5 °C. After completion of the addition of 3a, the reaction mass was allowed to warm to room temperature over 30 min and was allowed to stir for 2.0 h at room temperature. After 3 h, reaction completion was confirmed by HPLC and1H NMR, and the reaction mixture was quenched by slowly adding 10% aq. NH4CI (3 v, 600 mL) over 15-25 min. The reaction mixture was extracted with MTBE (3 v, 600 mL) and organic layer was concentrated. The organic layer was evaporated to 2 v and MTBE (7.5 v, 1500 mL) was added. The resulting mixture was heated to 50 °C for 30 min then cooled to room temperature. The solution was then filtered to remove precipitated PPhsO. To the filtrate 5 v (n-heptane, 1000 mL) was added and MTBE was removed at 50 °C under reduced pressure. The solution was then cooled to 0 °C, and the resulting precipitate was removed by filtration. To the precipitate n-heptane / cyclohexane (1 :1 , 5 v, 1000 mL) was added, and the mixture was heated to 50 °C and cooled to room temperature, after which the precipitate was filtered. The combined filtrates were concentrated to 2 v and cooled to 0 °C for 12 h. The precipitate thus formed was filtered, and the filtrate was concentrated to obtain Compound 3b (60% isolated correct yield; 85 wt%; > 87 A%; er 99:1 ; 3.8 wt% residual PPhsO.

[0159] Compound 3b:1H NMR (400 MHz, CDCb) 64.93 (dt, J = 11 .2, 2.3 Hz, 2H), 4.38 (ddd, J = 43.5, 9.5, 3.1 Hz, 1 H), 4.00 (d, J = 14.3 Hz, 2H), 3.65 (s, 3H), 2.88 (td, J = 15.8, 6.0 Hz, 1 H), 2.55 (d, J = 16.1 Hz, 1 H), 1.38 (d, J = 19.8 Hz, 9H);13C NMR (101 MHz, CDCb) 6 173.15, 172.89, 154.38, 153.74, 143.48, 142.40, 107.98, 107.78, 80.17, 77.35, 77.23, 77.03, 76.71 , 59.08, 58.54, 52.15, 52.03, 50.76, 50.56, 36.76, 36.05, 28.39, 28.28.

[0160] Optimizing the Reaction Conditions

[0161] It was discovered that the enantiomeric ratio (er) was 80:20 when Step 1 was performed 1 .5 equiv of Wittig salt and 1 .4 equiv of KOtBu. Additionally, the er reached 60:40 on prolonged reaction times. It was hypothesized that the chiral erosion was due to the unreacted ylide generated during the reaction. To confirm this, Compound 3b was treated with 0.8 equiv of ylide and the er reached 67:33. On the other hand, treating Compound 3b with 1 .0 equiv of KOtBu changed the er to 50:50. Therefore, an excess base or ylide in the Wittig reaction were thought to be responsible for the chiral erosion observed during the Wittig reaction. As such, the amount of ylide generated was reduced to achieve the required chiral specifications (er >99.5:0.5) and various bases and temperatures were screened to optimize the reaction conditions to improve yield and er.

[0162] The reactions using 1 .1 equiv of Wittig salt and 1 .05 equiv of KO‘Bu was found to be effective in reducing the chiral erosion to the specification required (er >99.5:0.5) (Table 1 , entries 6-10). Under this reaction condition, 1.05 equiv of ylide generation was anticipated and the absence of excess base and ylide minimized the chiral erosion in the Wittig reaction. The effect of reaction temperature was also investigated, and it was found that the optimal temperature for addition of Compound 3a to the generated ylide is 0 °C to -5 °C. Further reducing the temperature to -10 °C slowed down the Wittig reaction (Table 1 , entry 11). ALXN-0759-PCT01-NP

[0163] Table 1 : Optimization of Stoichiometry of Reaction

[0164] ¥Corrected mass based of wt% purity of SM; * Reaction solution yield;§purified by developed slurry method described herein (Procedure 3); entries 1-10 were purified by silica pad. The Wittig reaction was further tested with other organic solubilized bases, i.e.,nBuLi, LiHMDS,

[0165] NaHMDS (See Table 2). The outcome suggested that KO‘Bu remained the best choice for Step 1 .

[0166] Alternative Approach for Preparing Compound 3b

[0167] An alternative approach is shown below: This approach is expected to provide a higher yield and prevent potential chiral erosion with a crystalline solid of the carboxylic acid of Compound 3b. This approach will allow easy removal of TPPO impurities during the reaction workup. As the enantiomeric purity of Compound 3b determines the chiral purity of Compound 2e formed in Step 2, and erosion in enantiomeric purity was observed in Step 1 , this alternative approach may be used to obtain highly enantiomerically pure Compound 2e by preventing chiral erosion of Compound 3b (via a carboxylate anion intermediate) and further preservice enantiomeric purity in subsequent steps. ALXN-0759-PCT01-NP

[0168] Step 2 Synthesis of 1 -(tert-butyl) 2-methyl (S)-4-methyl-2,3-dihydro-1 H-pyrrole-1 ,2-dicarboxylate (2e)

[0169] To a clean and dry 5 L HEL reactor equipped with an overhead stirrer was charged Me-THF (4 v).

[0170] 2.2 mol% Crabtree catalyst (8.8 g; 10.94 mmol, 0.022 equiv) was then charged to the reactor with a wide funnel under nitrogen flow, and another 5 v of Me-THF was charged at room temperature. The HEL reactor was closed, and the catalyst was activated at 23 °C using H2 (200 PSI) for 4-6 h with 800 RPM stirring. The HEL reactor was then then purged with N2 with stirring. Crude starting material (143.0 g, containing 84 wt% Compound 3b; 497.3 mmol, 1 .0 equiv) was dissolved in Me-THF (1 v) and degassed for 15 min. The solution was then added to the activated catalyst under nitrogen, and the mixture was stirred at 60±5 °C for 16-20 h in the PolyBLOCK chamber of the HEL reactor, during which the reaction progress was monitored by HPLC and1H NMR. After completion of the reaction, the reaction mass was cooled slowly to 22 ± 5 °C. The reaction mixture was then filtered using a sintered funnel, and the reactor and funnel were further rinsed with MTBE (1 v). The reaction mixture was concentrated and dried under vacuum for the next 8-10 h. Compound 2e was obtained as a brown liquid (138.1 g; 73wt % purity based on qNMR; 84% crude yield, corrected based on starting material purity; > 98:2 regioselectivity; er 99.2:0.8).1H NMR (400 MHz, CDCI3) 6 6.28 (dd, J = 45.6, 1 .9 Hz, 1 H), 4.61 (ddd, J = 31 .2, 11 .8, 5.3 Hz, 1 H), 3.76 (s, 3H), 2.96 (q, J = 14.5 Hz, 1 H), 2.52 (ddd, J = 22.3, 16.4, 5.3 Hz, 1 H), 1.68 (d, J = 1.7 Hz, 3H), 1.45 (s, 9H);13C NMR (100 MHz, CDCh) 6 (compound showed rotamer peaks) 172.6 (172.4), 151.4 (151.2), 124.4 (124.2), 115.7 (115.6), 80.6 (80.4), 58.8 (58.3), 52.3 (52.1), 39.5 (38.4), 28.3 (28.2), 13.2.

[0171] Optimizing the Reaction Conditions

[0172] Efforts to optimize Ir-catalyzed (Crabtree catalyst) exocyclic to endocyclic alkene isomerization with highly controlled stereochemistry on Compound 3b are described below.

[0173] The Ir-catalyzed transformation is a two-step process. The first step involves activation of Ir- catalyst under H2 atmosphere then the activated complex undergoes alkene isomerization in the second step. Screening for proper activation of Ir-catalyst in the first step was first performed. During this process, it was observed that the purity of Ir-catalyst plays a significant role in hydrogen uptake and the time required for the complete catalyst activation. The Crabtree catalyst ([lr(COD)PCy3Py]PFe) purchased from different vendors behaved differently in the activation process. These preliminary data demanded proper investigation on the Crabtree catalyst activation step. The purity of the Crabtree catalysts purchased from Sigma, Strem, and Ambeed was determined by1H NMR spectroscopy, and it was found that The measured purity levels were below the vendor’s claimed purity (Sigma: >99%; Strem: 98%; and Ambeed: 97% pure) and it clearly reflected on the Ir-catalyst activation process. Crabtree catalyst from Sigma has been activated at 30 PSI H2 within 30 min at r.t., whereas catalyst from Strem and Ambeed required 3-6 h at 200 PSI H2 for proper activation (Table 2). The results clearly showed that the experiments without proper activation of Ir-catalyst in the first step did not go for the complete alkene isomerization in the second step (Table 2, entries 2-5, 7). The data suggest that 3-6 h under 200 PSI H2 atmosphere at room temperature is the optimal condition for Ir-catalyst activation to perform exo to endocyclic alkene isomerization. ALXN-0759-PCT01-NP

[0174] Table 2. Screening of Ir-Catalyst Activation with H2

[0175] Next, the conditions for alkene isomerization with 2.2 mol% Crabtree catalyst were screened. The reaction was performed at temperatures ranging from 35 °C to 75 °C (Table 3, entries 1-5). To draw better conclusions, additional reactions were performed under some of the best reaction conditions identified in the screening process, and the data clearly showed that an increase in temperature significantly increased the rate of the isomerization reaction, which required 6-10 hours to complete. The isomerization completed within 6 hours at above 65 °C, 10 hours at 55 °C, and 14 hours at 45 °C. The regioselectivity was high (>98:2) and was consistent within the temperature range of 45 to 75 °C. At 35 °C, the isomerization was slow, with 54A% starting material conversion in 14 h along with a slight decrease in regioselectivity (>96:4). To understand and control regioselectivity, the isomerization reaction kinetics were studied at 55 °C. The kinetic data show that the initial reaction rate determines selectivity, and the desired isomer formed over the course of the reaction. Based on the kinetic profile, it was postulated that the kinetically favored, undesired regioisomer generated more rapidly under low temperatures at the beginning of the reaction. However, addition of the starting material at a higher temperature (55 °C) did not improve regioselectivity (Table 3, entries 6-7). Switching the solvent from Me-THF to THF showed slow reactivity and the same regioselectivity (Table 3, entry 8). The Ir-catalyst loading screen revealed that isomerization works with 3.3 mol% to as low as 0.5 mol% catalyst providing consistent regioselectivity >98:2 (Table 3, entries 9-12).

[0176] Since the starting material (3b) generated from the Wittig reaction in Step 1 could include trace PhsPO as an impurity, the reaction was further examined with 1 to 6% Ph3PO content in the starting material (3b) in order to determine the effect of Ph3PO, if any . The results clearly indicate that the presence of Ph3PO (up to 6%) neither accelerates nor inhibits Ir-catalyzed alkene isomerization (Table 3, entries 13-15). ALXN-0759-PCT01-NP

[0177] Various in situ generated Crabtree catalyst derivatives with different phosphine ligand varying steric bulk were also tested. It was found that tris-cyclohexyl phosphine ligand is the best ligand for this reaction out of the phosphine ligands tested (Table 6, entries 16-18). In all these cases, Me-THF (10 v) was used as the solvent, 200 PSI H2 was used for catalyst activation, and the reaction temperature was kept at 60 °C for the alkene isomerization step.

[0178] Table 3. Screening of Ir-Catalyzed Exocyclic Alkene Isomerization of Compound 3b

[0179] * SM in Me-THF was added at 55 °C for 1 min. ** SM in Me-THF was added at 55 °C for 10 min. *** Ir-Crabtree catalyst derivatives generated in situ by stirring lr(COD)2BARF (1.0 eq), Pyridine (1.5 eq) and X3P (1.0 eq) in Me-THF at 40 °C for 30 min followed by activated under H2 atmosphere. ALXN-0759-PCT01-NP

[0180] Step 3: Synthesis of 2-(tert-butyl) 3-methyl (1 R,3S,5R)-5-methyl-2-azabicyclo[3. 1 ,0]hexane-2,3- dicarboxylate (2f)

[0181] A clean and dry 5 L reactor was assembled with an overhead stirrer, and tBu-PDI (80.96 g,

[0182] 189.45 mmol, 35 mol%) ligand was charged followed by THF (10 v). The mixture was allowed to stir for 10-20 minutes. Then, CoBr2 (41.61 g, 190.23 mmol, 30 mol%) was charged into the reactor, followed by 5-8 v of THF, after which the mixture was allowed to stir for 1 -1 .5 hours. Activated Zn (1 .66 equiv) was subsequently charged into the reactor, followed by ZnCb (1 .6 equiv), and the reaction mixture was stirred for 10-15 minutes. The reaction mass in the reactor was purged with nitrogen using long tubing for 10-15 minutes and a deep purple color appeared. Compound 2e (150 g, 622.40 mmol, 1.0 equiv) was dissolved in THF (1-2 v), and solution was degassed with nitrogen over 10-15 minutes. The degassed solution of Compound 2e in in THF was then charged into the reactor. CH2Br2 (1 .5 equiv) was added dropwise into the reactor using an addition funnel over 10-15 minutes. Additional Zn (1 .66 equiv) and ZnCb (1 .6 equiv) were added to the reaction mixture after it was allowed to run for 1-1 .2 hours, and an additional portion of CH2Br2 (1 .5-2.0 equiv) was added over 10 minutes. After 5-5.5 h, an additional portion of CH2Br2 (1.0 equiv) was added, and the reaction mixture was allowed to stir 0.5-1 .0 hours. Completion of the reaction was confirmed by HPLC and1H NMR after 4.5-6 hours, which showed more than >99A% product formation. The reaction mixture was quenched by slowly adding 50% citric acid solution (6-8 v), and it was allowed to stir 30-45 minutes. A phase cut was performed to remove the aqueous layer. The organic layer was then washed with 1 N HCI (2-3 v) to remove any remaining metal impurities. After washing, the reaction mass was concentrated to 6-7 v by distilling under 45-50 mbar pressure at 35 °C, then ethanol (5 v) was charged into reactor, and mixture was further distilled to 3-4 vto obtain crude Compound 2f, which was directly used for the next step without further purification.1H NMR (400 MHz, CDCb) 6 3.89- 3.91 (m, 1 H), 3.71-3.76 (s, 3H), 3.17 (m, 1 H), 2.46 - 2.30 (m, 1 H), 1.93 (dt, J = 13.7, 6.2 Hz, 1 H), 1.37 (s, 9H), 1 .18 (s, 3H), 0.63-0.58 (m, 1 H), 0.57 (d, J = 6.4 Hz, 1 H);13C NMR (101 MHz, CDCb) 6 172.63, 80.27, 59.98, 52.10, 42.99, 38.65, 37.96, 28.26, 23.16, 22.03, 20.68.

[0183] Activation of Zinc

[0184] Protocol 1 : Zn powder was suspended in aq HCI and stirred for 30 min. It was then filtered and washed with 2 v water, 2v EtOH, and 2v MTBE and dried in oven at 85 °C for 16 h.

[0185] Protocol 2: Zn powder was placed in a sintered funnel and 1 N HCI (3.5v) was added and let it settle for 30 min. After 30 min vacuum was applied and it was washed with water (2x2 v), EtOH (2x2 v), and MTBE (2x2 v) and dried in an oven at 85 °C for 16 h.

[0186] Evaluation of the Effects of Water Content

[0187] The effects of the overall water content on reaction outcome in Step 3 was evaluated. The results are shown in Table 4. All reactions were performed on 4.0 g (corrected mass based on wt.% of 3a). Water ALXN-0759-PCT01-NP content of all Zn, ZnCh, tBu-PDI, and Co(tBu-PDI)Br2 were measures measured by TGA; Co(tBuPDI)Br2 water content was measured by both TGA and KF volumetric titration.

[0188] Table 4. Reaction Screening with Varying Combined Water Content

[0189] #CH2Br2 was added into four portions (1 .5, 1.0, 1.5.1.0 equiv); *Zn was added into two portions (3.0, 2.0 equiv);¥ZnCh was added into two portions (3.0, 2.0 equiv);KF1150 ppm;KF2100 ppm;KF34000 ppm;KF44000 ppm;KF54000 ppm;KF65300 ppm;KF721000 ppm; Compound 2e: 200 ppm; THF: 80 ppm.

[0190] It was observed that variation in water content has a significant effect on reaction progress. Excess amount of water will be responsible for catalyst decomposition via hydrolysis reaction. As a result, higher amount of catalyst was required to offset the high-water content in the reaction mixture.

[0191] Step 4: Exemplary synthesis of (1 R,3S,5R)-2-(tert-butoxycarbonyl)-5-methyl-2-azabicyclo[3. 1 ,0]hexane-3- carboxylic acid (2g)

[0192] A crude mixture of Compound 2f (84.6 g, 331 .1 mmol, 1 .0 equiv) was diluted with EtOH (5 v) and charged in a 5 L reactor, followed by an additional 10 v of EtOH added into the reactor. The reaction mass was cooled to 5±10 °C with stirring at 500 RPM. NaOH (124.2g, 3105 mmol, 9.4 eq.) while maintaining the internal temperature below 15 °C until the pH reached >12. The reaction was allowed to reach RT and stirred over 4 h.

[0193] Upon completion of the reaction as confirmed by HPLC, reaction mass of distilled to 3-4 v to remove ethanol azeotropically with water and aqueous reaction mass was washed with EtOAc. Organic layer was washed with 1 N NaOH (2 v). The aqueous layer was charged in reactor and cooled to 0 ± 5 °C. Ice cold solution of 3 M HCI solution was added to reactor until the pH reached 1 to 2. The aqueous layer was extracted with IPAc (10-15 v) twice. The IPAc solution was then used in the next step. ALXN-0759-PCT01-NP

[0194] 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 25 °C 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.

[0195] The reaction mixture (containing approx. 45 g Compound 2g, as solution in approx. 225 mL (5 v) isopropyl acetate, washed with 3 v water twice) was charged into a 1 L reactor. Activated charcoal (Acticarbone HPX7) 1 .35 g (3% by mass of the compound) was charged into the solution. The mixture was stirred for 2 hours at 20-25 °C. The slurry was then filtered over celite. The filtrate was collected, and approx. 90 mL (2 v) isopropyl acetate was used to wash the equipment. The filtrate from charcoal treatment was distilled under vacuum at 50 °C at 200 torr to reduce the volume to 225 mL (5.0 v). 225 mL (5.0 v) isopropyl acetate was charged into the reactor. The solution was distilled under vacuum at 50 °C at 200 torr to reduce the volume to 225 mL (5.0 v). Water content in the solution should be < 350 ppm (if not, charge 5.0 v isopropyl acetate and reduce to 5.0 v by distillation under vacuum). The solution was kept 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)-a-methylbenzylamine (0.5 eq.) was dosed in 2 hours. The system was aged for 1 h, and additional (R)-a-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.

[0196] Upon drying, the (R)-a-methylbenzylamine salt was dispersed in 10 V isopropyl acetate while stirring at 20-25 °C. 4.5 v 2 M HCI (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. Isopropyl acetate (3 v) was charged into the solution, and the solution was distilled to 1 .5-2 v under vacuum.

[0197] 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 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.

[0198] 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.

[0199] This procedure consistently produced purified Compound 2g with > 95% yield and chiral purity of > 99.5% as determined by HPLC. ALXN-0759-PCT01-NP

[0200] Example 2. Synthesis of the Co-PDI Complex

[0201] The Co-PDI can be prepared based on the following procedure.

[0202] To a clean and dry 1 L round bottom flask equipped with magnetic stirrer was charged 2,6- diacetylpyridine (50 g, 1 eq) in toluene (350 mL) at rt under N2. 2-t-butylan iline (50 mL, 2.2 eq) to reaction 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, 1 M 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.

[0203] THF (4 v) was charged in a 1 L reactor, followed by the addition of PDI ligand (10 g, 23.49 mmol, 1 .0 equiv) under the nitrogen flow. Additional THF (1 1 v) was subsequently charged in the reactor, and the reaction mixture was allowed to stir for 10-30 min to provide a homogeneous solution. CoBr2 (5.14 g, 23.49 mmol, 1 .0 equiv) was charged in the reaction under nitrogen flow, followed by the addition of THF (5 v). The reaction mass allowed to stir for 10-12 h at room temperature under nitrogen flow and subsequently filtered. The cake thus obtained was dried at 50-55 °C under vacuum over 24 h and was used without further purification.

[0204] Example 3. Catalyst Screening for Olefin Isomerization Reaction

[0205] Additional catalysts were screened for the olefin isomerization reaction (see Step 2 in Example 1) in order to identify suitable replacements for the Crabtree catalyst. The results are shown in Table 5 and Table 6 below.

[0206] First Round Screening

[0207] Reaction conditions:

[0208] Substrate: 20 pmol Compound 3b and 4 pmol di-tert-butyl-biphenyl in each vial Catalyst and ligand: 5 mol% Pd and 10 mol% free ligand (where applicable) Additive: 10 mol% Additive (where applicable) Solvent: 96 pL solvent (20 vol.) in each vial Reaction Conditions: 80 °C for 18 h under N2 ALXN-0759-PCT01-NP

[0209] Table 5. Summary of First Round Screening Results

[0210] Different Pd catalysts, additives and solvents were screened, and Pd(dba)2 with tBu3P-HBF4 or Cy3P-HBF4 in toluene or 2-MeTHF was found to give full conversion and 95.1 % to 91 .9% purity as determined by HPLC after 7 minutes of reaction.

[0211] Second Round Screening

[0212] Reaction condition:

[0213] Substrate: 20 pmol Compound 3b and 4 pmol ditert-butyl-biphenyl in each vial

[0214] Catalyst and ligand: 10 mol% catalyst and 20 mol% P source or not in each vial

[0215] Additive: 30 mol% Additive or 10 mol% PhSiHs or not in each vial

[0216] Solvent: 96 pL solvent (20 vol.) in each vial

[0217] Reaction Conditions: 80 °C for 18 h under N2

[0218] Table 6. Summary of Second Round Screening Results

[0219] Different non-precious catalysts, ligands, additives and solvents were screened, Ni(COD)2 with Cy3P-HBF4 in four different solvents gave 88.6% to 95.5% conversion and 83.5% to 92.7% IPC purity in 7 minutes HPLC. The conversion was less than 10% when using Mn(OAc)2, Cu(OAc)2, Cu(OTf)2, Co(OAc)2, Co(OTf)2 or Co-PDI (not shown). The IPC purity was 26.4% to 49.1 % when using N,N'-bis(salicylidene) ethylenediiminocobalt(ll) or (S,S)-(+)-N,N'-bis(3,5-di-tert-butylsalicylidene)-1 ,2- cyclohexanediaminocobalt(ll) in 2-MeTHF or toluene (not shown). ALXN-0759-PCT01-NP

[0220] Screening of Additional Catalysts

[0221] Additional screenings of Ni and Co catalysts were performed. The reaction conditions and results are summarized in Table 7. All reactions were performed in Me-THF unless noted otherwise.

[0222] Table 7. Summary of Screening Results for Additional Catalysts ALXN-0759-PCT01-NP ALXN-0759-PCT01-NP ALXN-0759-PCT01-NP ALXN-0759-PCT01-NP aCompound 3b was added before the additive.bCompound 3b was added 2 minute after the additive.cCompound 3b was added 2 minute after the additive.dCompound 3b was added 2 minute after the additive.eThe reaction was performed in THF.fThe reaction was performed in toluene.eThe reaction was performed in MeOH.eThe reaction was performed in dioxane.

[0223] Based on the results summarized in Table 7, it was found that:

[0224] 2.5 mol% Ni(COD)2 with Cy3PHBF4, iPr3PHBF4, and Cyp3PHBF4 led to complete conversion of the starting material within 1-2 h and up to 98.8:1 .2 regioselectivity iPrsP and CypsP ligands led to slightly better reactivity than CysP - 1.5 mol% Ni(COD)2 with Cyp3PHBF4 led to 96A% starting material conversion with >98:2 regioselectivity ALXN-0759-PCT01-NP

[0225] 5.0 mol% Ni(DME)Ch with Cy3PHBF4 led to 96A% starting material conversion with >95:5 regioselectivity

[0226] 5.0 mol% Ni(OAc)2 with CysP led to complete conversion of the starting material with 92:8 regioselectivity - 5.0 mol% C0CI2 with DPPP led to complete conversion of the starting material with >92:8 regioselectivity

[0227] 10.0 mol% C0I2 with DPPF and Zn as the reductant led to the complete conversion of the starting material with >98:2 regioselectivity

[0228] 5.0 mol% Ni(acac)2 with Cy3PHBF4 led to the complete conversion of the starting material with >95:5 regioselectivity

[0229] Other Embodiments

[0230] 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.

[0231] Other embodiments are in the claims.

Claims

ALXN-0759-PCT01-NPClaims1 . A method, comprising preparing a compound of Formula (IV):wherein P1is H or an N-protecting group and P2is H or a carboxyl-protecting group, comprising(a) providing a compound of Formula (I):(b) reacting the compound of Formula (I) in a Wittig reaction to form a compound of Formula (II):(c) reacting the compound of Formula (II) in an olefin isomerization reaction with a transition metal catalyst to form a compound of Formula(d) forming the compound of Formula (IV) from the compound of Formula (III), said forming the compound of Formula (IV) comprising contacting the compound of Formula (III) with a Co(ll) catalyst in the presence of Zn and CH2Br2.

2. The method of claim 1 , wherein said reacting the compound of Formula (I) in a Wittig reaction comprises reacting the compound of Formula (I) with a triphenyl phosphonium ylide.

3. The method of claim 2, wherein the methyl phosphonium bromide is present at 1-2 equivalents relative to the compound of Formula (I).

4. The method of claim 3, wherein the methyl phosphonium bromide is present at 1.1 equivalents relative to the compound of Formula (I).

5. The method of any one of claims 2-4, wherein said reacting the compound of Formula (I) with methyl phosphonium bromide is performed in the presence of a base selected from n-BuLi, LiHMDS, NaHMDS, and KO‘Bu.

6. The method of claim 5, wherein the base is KO‘Bu.

7. The method of claim 5 or 6, wherein the base is present at 1-2 equivalents relative to the compound of Formula (I).ALXN-0759-PCT01-NP8. The method of claim 7, wherein the base is present at 1 .05 equivalents relative to the amount of the Compound of Formula (I).

9. The method of any one of claims 1-7, wherein the transition metal catalyst is an Ir catalyst, a Pd catalyst, a Ni catalyst, or a Co catalyst.

10. The method of claim 9, wherein the transition metal catalyst is an Ir catalyst.11 . The method of claim 10, wherein the transition metal catalyst is Crabtree’s catalyst.

12. The method of claim 9, wherein the transition metal catalyst is a Pd catalyst.

13. The method of claim 10, wherein the transition metal catalyst is a Pd catalyst generated in situ with a Pd complex and a phosphine ligand.

14. The method of claim 13, wherein the Pd complex is a Pd(0) complex.

15. The method of claim 14, wherein the Pd(0) complex is bis(dibenzylideneacetone)palladium(0).

16. The method of any one of claims 11-15, wherein the phosphine ligand is tri-tert- butylphosphonium tetrafluoroborate or tricyclohexylphosphine tetrafluoro borate.

17. The method of claim 12, wherein the Pd catalyst is a Pd(0) catalyst or Pd(ll) catalyst.

18. The method of claim 17, wherein the Pd catalyst is [1 ,1 ’-bis(di-tert- butylphosphino)ferrocene]dichloropalladium(ll) or [P(t-Bu)3PdBr]2.

19. The method of claim 9, wherein the transition metal catalyst is a Ni catalyst.

20. The method of claim 19, wherein the transition metal catalyst is generated in situ with a Ni complex and a phosphine ligand.21 . The method of claim 20, wherein the Ni complex is a Ni(0) complex.

22. The method of claim 21 , wherein the Ni(0) complex is bis(cyclooctadiene)nickel(0),23. The method of claim 21 or 22, wherein the phosphine ligand is triisopropylphosphonium tetraflouoroborate, tricyclohexylphosphine tetrafluoroborate, or tricyclopentylphosphine tetrafluoro borate.

24. The method of claim 20, wherein the Ni complex is a Ni(ll) complex, and step (c) is performed in the presence of a reducing agent.ALXN-0759-PCT01-NP25. The method of claim 24, wherein the Ni(ll) complex is nickel(ll) acetate tetrahydrate, nickel(ll) acetylacetonate, or nickel(ll) chloride ethylene glycol dimethyl ether complex.

26. The method of claim 24 or 25, wherein the phosphine ligand is tricyclohexylphosphine, tricyclohexylphosphine tetrafluoro bo rate, or tricyclopentylphosphine tetrafluoroborate.

27. The method of any one of claims 24-26, wherein the reducing agent is lithium triethylborohydride.

28. The method of claim 9, wherein the transition metal catalyst is a Co catalyst.

29. The method of claim 28, wherein the transition metal catalyst is generated in situ with a Co salt and a phosphine ligand, and step (c) is performed in the presence of a reducing agent.

30. The method of claim 29, wherein the Co salt is C0CI2, CoBr2, or C0I2.31 . The method of claim 29 or 30, wherein the phosphine ligand is 1 ,4- bis(diphenylphosphino)butane (DPPB) or 1 ,4-bis(diphenylphosphino)propane (DPPP).

32. The method of claim 31 , wherein the reducing agent is lithium triethylborohydride.

33. The method of claim 29 or 30, wherein the phosphine ligand is 1 ,1'- bis(diphenylphosphino)ferrocene (DPPF).

34. The method of claim 33, wherein the reducing agent in Zn.

35. The method of claim 33 or 34, wherein step (c) is performed in the presence of water.

36. The method of any one of claims 1 -35, wherein said forming the compound of Formula (IV) comprises contacting the compound of Formula (III) with a Co(ll) catalyst in the presence of Zn, CH2Br2, and ZnCh.

37. The method of any one of claims 1 -36, wherein the Zn in step (d) is zinc dust.

38. The method of any one of claims 1-37, wherein the Zn in step (d) is activated.

39. The method of claim 1-38, wherein the Zn is present in an amount of 2-10 equivalents relative to the compound of Formula (III).

40. The method of claim 39, wherein the Zn is present in an amount of 5 equivalents relative to the compound of Formula (III).ALXN-0759-PCT01-NP41 . The method of any one of claims 36-40, wherein the ZnCh is present in an amount of 2- 10 equivalents relative to the compound of Formula (III).

42. The method of claim 41 , wherein the ZnCh is present in an amount of 5 equivalents relative to the compound of Formula (III).

43. The method of any one of claims 1 -42, wherein the CH2Br2 is present in an amount of 1 - 10 equivalents relative to the compound of Formula (III).

44. The method of claim 43, wherein the CH2Br2 is present in an amount of 5 equivalents relative to the compound of Formula (III).

45. The method of any one of claims 1-44, wherein the Co(ll) catalyst in step (d) is a compound of structure:wherein each X is independently Cl, Br, or I; each R is independently Ci-Ce alkyl; each R is independently H or Ci-C6alkyl; and R” is H, halo, Ci-Ce haloalkyl, Ci-Ce alkoxy, or Ce-Cio aryl.

46. The method of claim 45, wherein the Co(ll) catalyst is a compound of structure:wherein each X is independently Br or I; and each R is independently Ci-Ce alkyl.

47. The method of claim 46, wherein each R is tert-butyl.

48. The method of claim 46 or 47, wherein each X is Br.

49. The method of any one of claims 1-48, wherein P2in Formula (IV) is a carboxyl-protecting group.

50. The method of claim 49, wherein the method further comprises reacting the compound of Formula (VI) with a carboxyl-protecting-group-removing agent to form a compound of Formula (V):wherein P1is H or an N-protecting group.ALXN-0759-PCT01-NP51 . The method of claim 50, wherein P1in Formula (V) is an N-protecting group.

52. The method of claim 50 or 51 , further comprising: reacting the compound of Formula (V) with an organic amine to form an organoammonium salt of the compound of Formula (V); and reacting the organoammonium salt of the compound of Formula (V) with an acid to form the compound of Formula (V).

53. The method of claim 52, wherein the organic amine is (R)-a-methylbenzylamine, and the organoammonium salt is a (R)-a-methylbenzylammonium salt.

54. The method of claim 53, wherein the method further comprises coupling the compound of Formula (V) to a compound of Formula (VI):R1BH R31(VI), or a salt thereof, whereinR1is H or Ci-C6alkyl; each of R2and R3is independently H or methyl; m is 0, 1 , or 2;B is Ci-C6alkyl optionally substituted with one or more substituents independently selected from halo, hydroxyl, -COOH, Ci-Cealkoxy, Ci-Cehaloalkoxy, and cyclopropyl; C2-C6 alkenyl optionally substituted with one or more substituents selected from halo, C1-C6 alkyl, and cyclopropyl, and optionally further substituted with phenyl optionally substituted with halo; C3-C10 cycloalkyl optionally substituted with one or more substituents independently selected form halo, cyano, and C1-C6 alkyl, and optionally further substituted with phenyl optionally substituted with halo; -(Co-C4alkyl)(phenyl), wherein the phenyl is optionally substituted with one or more substituents independently selected from halo, -COOH, cyano, Ci- Ce alkyl, Ci-Ce alkoxy, SO2R, and Ci-Ce haloalkyl, and further optionally substituted with 5- to 10- membered heteroaryl containing 1 or 2 heteroatom independently selected from N and S, wherein the heteroaryl is substituted with halo; 5- to 10-membered heteroaryl containing 1 , 2, or 3 heteroatoms independently selected from N, O, and S, wherein the heteroaryl is optionally substituted with one or more substituents independently selected from halo, cyano, hydroxy, -COOH, -COONH2, Ci-Ce alkyl, C2-C6 alkanoyl, Ci-Ce alkoxy, Ci-Ce haloalkyl, Ci-Ce haloalkoxy, Ci-Ce alkylester, Ci-Ce thioalkyl, Ci-Ce hydroxyalkyl, (Ci-Ce alkoxy)(Ci-Ce alkyl), and (Ci-Ce haloalkoxy)(Ci-Ce alkyl), and further optionally substituted with C3-C6 cycloalkyl, phenyl optionally substituted with halo, or 5- or 6-membered heteroaryl containing 1 or 2 heteroatoms independently selected from N, O, and S and optionally substituted with halo; or biphenyl optionally substituted with one or more substituents independently selected from halo, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, and further optionally substituted with CONH2, C2-Cealkanoyl, or SO2R; andR is selected from Ci-Ce alkyl, Ci-Ce haloalkyl, NH2, NH(Ci-Ce alkyl), NH(cyclopropyl), and N(Ci- Ce alky 1)2;ALXN-0759-PCT01-NP to form a compound of Formula (VII):(VII), whereinP1is an N-protecting group, and all other variables are as defined for Formula (VI); and reacting the compound of Formula (VII) with a N-protecting-group-removing agent to form a compound of formula (VIII):(VIII), or a salt thereof, wherein all variables are as defined for Formula (VII).

55. The method of claim 54, further comprising coupling the compound of Formula (VIII) or the salt thereof to a compound of Formula (IX):(IX), or a salt thereof, whereinR4is H; halo; OH; NH2; cyano; C1-C6 alkyl; C1-C6 haloalkyl; C1-C6 hydroxyalkyl; C2-C6 alkenyl; 3- to 8-membered heterocyclyl; -C(O)NRaRa’, wherein each of Raand Rais, independently, H, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, or Cs-Cs cycloalkyl; -C(O)Rb; -OC(O)Rb; or -C(Q)ORb; wherein Rb, in each instance, is selected from H, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, and C3-C8 carbocyclyl; each of R5and R6is, independently, H, halo, or C1-C6 alkyl;X1is N or CRc, wherein Rcis H, halo, or Ci-Ce alkyl; each of X2and X5is independently N or CRd, wherein each Rd is independently selected from H, halo, cyano, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, Ci-Ce hydroxyalkyl, C3-C8 carbocyclyl, and 5- to 8- membered heteroaryl; and one of X3and X4is selected from N and CRe, and the other of X3and X4is CRf, wherein Reis selected from H, halo, cyano, hydroxyl, Ci-Ce alkyl, Ci-Ce alkoxy, -C(O)NRgRh, wherein Rgand Rh are independently H or Ci-Ce alkyl; and -C(O)ORi, wherein Ri is H or Ci-Ce alkyl; and Rf is 5- or 6-membered heteroaryl containing 1 or 2 nitrogen atoms or 8- to 10-membered bicyclic heteroaryl containing 1 , 2, or, 3 heteroatoms independently selected from N and S, wherein Rf is optionally substituted with 1 or 2 groups independently selected from halo, hydroxyl, amino, cyano, -COOH, -CONH2, Ci-Ce alkyl, Ci-Ce alkoxy, Ci-Ce haloalkyl, C2-Ce alkanoyl, Ci-Ce haloalkoxy, Ci-Ce alkylester, (mono- or di-Ci-Ce alkyl)amino, Ci-CeALXN-0759-PCT01-NP hydroxyalkyl, cyclopropyl, Ci-Cs alkylsulfinyl, Ci-Ce alkylsulfonyl, Ci-Ce alkylsulfonamide, Ci-Ce thioalkyl, amino(Ci-C6 alkyl), (mono- or di-Ci-Ce alkyl)amino(Ci-C6 alkyl), and (Ci-Ce alkoxy)(Ci-Ce alkyl); to form a compound of Formula (X):or a pharmaceutically acceptable salt thereof, wherein R1, R2, R3, m, and B are as defined for Formula (VIII), and all other variables are as defined for Formula (IX).

56. The method of claim 54 or 55, wherein P1is tert-butoxycarbonyl.

57. The method of claim 56, wherein the N-protecting-group-removing agent is hydrogen chloride, and said reacting the compound of Formula (VII) with the N-protecting-group-removing agent forms a hydrochloride salt of the compound of Formula (VIII).

58. The method of claim 57, wherein the hydrochloride salt of the compound of Formula (VIII) is coupled to the compound of Formula (IX) in dimethylformamide in the presence of 1- [bis(dimethylamino)methylene]-1 H-1 ,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate and N,N- diisopropylethylamine.

59. The method of claim 56, wherein the N-protecting-group-removing agent is hydrogen bromide, and said reacting the compound of Formula (VII) with the N-protecting-group-removing agent forms a hydrobromide salt of the compound of Formula (VIII).

60. The method of claim 59, wherein the hydrobromide salt of the compound of Formula (VIII) is coupled to the compound of Formula (IX) in acetonitrile in the presence of propanephosphonic acid anhydride and N,N-diisopropylethylamine.61 . The method of claim 56, wherein the N-protecting-group-removing agent is trifluoroacetic acid, and said reacting the compound of Formula (VII) with the N-protecting-group-removing agent forms a trifluoroacetic acid salt of the compound of Formula (VIII).

62. The method of claim 61 , wherein the trifluoroacetic acid salt of the compound of Formula (VIII) is coupled to the compound of Formula (IX) in dimethylformamide in the presence of N, N- diisopropylethylamine and 1-[bis(dimethylamino)methylene]-1 H-1 ,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate or 2-(1 H-benzotriazole-1-yl)-1 ,1 ,3,3-tetramethylaminium tetrafluoroborate.

63. The method of any one of claims 54-62, wherein R1is H.ALXN-0759-PCT01-NP64. The method of any one of claims 54-63, wherein m is 1 .

65. The method of any one of claims 54-63, wherein m is 0.

66. The method of any one of claims 54-65, wherein each of R2and R3is H.

67. The method of any one of claims 54-66, wherein B is 5- or 6-membered heteroaryl containing 1 , 2, or 3 heteroatoms independently selected from N and S, wherein the heteroaryl is optionally substituted with one or more substituents independently selected from halo, cyano, hydroxy, - COOH, -COONH2, C1-C6 alkyl, C2-Ce alkanoyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 alkylester, Ci-Ce thioalkyl, C1-C6 hydroxyalkyl, (C1-C6 alkoxy)(Ci-Ce alkyl), and (C1-C6 haloalkoxy)(Ci-Ce alkyl), and further optionally substituted with C3-C6 cycloalkyl, phenyl optionally substituted with halo, or 5- or 6-membered heteroaryl containing 1 or 2 heteroatoms independently selected from N, O, and S and optionally substituted with halo.

68. The method of claim 67, wherein B is 6-membered heteroaryl containing 1 , 2, or 3 heteroatoms independently selected from N and S, wherein the heteroaryl is optionally substituted with one or more substituents independently selected from halo, cyano, hydroxy, -COOH, -COONH2, C1-C6 alkyl, C2-C6 alkanoyl, Ci-Ce alkoxy, Ci-Ce haloalkyl, Ci-Ce haloalkoxy, Ci-Ce alkylester, Ci-Ce thioalkyl, Ci- Ce hydroxyalkyl, (Ci-Ce alkoxy)(Ci-Ce alkyl), and (Ci-Ce haloalkoxy)(Ci-Ce alkyl), and further optionally substituted with C3-C6 cycloalkyl, phenyl optionally substituted with halo, or 5- or 6-membered heteroaryl containing 1 or 2 heteroatoms independently selected from N, O, and S and optionally substituted with halo.

69. The method of claim 68, wherein B is pyridyl, pyridazinyl, pyrimidinyl, or pyrazinyl, each of which is optionally substituted with one or more substituents independently selected from halo, cyano, hydroxy, -COOH, -COONH2, Ci-Ce alkyl, C2-Ce alkanoyl, Ci-Ce alkoxy, Ci-Ce haloalkyl, Ci-Ce haloalkoxy, Ci-Ce alkylester, Ci-Ce thioalkyl, Ci-Ce hydroxyalkyl, (Ci-Ce alkoxy)(Ci-Ce alkyl), and (Ci-Ce haloalkoxy)(Ci-Ce alkyl), and further optionally substituted with C3-C6 cycloalkyl, phenyl optionally substituted with halo, or 5- or 6-membered heteroaryl containing 1 or 2 heteroatoms independently selected from N, O, and S and optionally substituted with halo.

70. The method of claim 69, wherein B is pyridyl optionally substituted with one or more substituents independently selected from halo, cyano, hydroxy, -COOH, -COONH2, Ci-Ce alkyl, C2-C6 alkanoyl, Ci-Ce alkoxy, Ci-Ce haloalkyl, Ci-Ce haloalkoxy, Ci-Ce alkylester, Ci-Ce thioalkyl, Ci-Ce hydroxyalkyl, (Ci-Ce alkoxy)(Ci-Ce alkyl), and (Ci-Ce haloalkoxy)(Ci-Ce alkyl), and further optionally substituted with C3-C6 cycloalkyl, phenyl optionally substituted with halo, or 5- or 6-membered heteroaryl containing 1 or 2 heteroatoms independently selected from N, O, and S and optionally substituted with halo.ALXN-0759-PCT01-NP71. The method of claim 70, wherein72. The method of any one of claims 55-71 , wherein X1is N.

73. The method of any one of claims 55-71 , wherein X1is CH.

74. The method of any one of claims 55-73, wherein X2is CRd.

75. The method of claim 74, wherein X2is CH or C(CH3).

76. The method of any one of claims 55-75, wherein X5is CRd.

77. The method of claim 76, wherein X5is CH.

78. The method of any one of claims 55-77, wherein X4is CRf.

79. The method of claim 78, wherein X3is N or CH.

80. The method of claim any one of claims 55-79, wherein Rf is 6-membered heteroaryl containing 1 or 2 nitrogen atoms and optionally substituted with 1 or 2 groups independently selected from halo, hydroxyl, amino, cyano, -COOH, -CONH2, Ci-Ce alkyl, Ci-Ce alkoxy, Ci-Ce haloalkyl, C2-Ce alkanoyl, Ci-Ce haloalkoxy, Ci-Ce alkylester, (mono- or di-Ci-Ce alkyl)amino, Ci-Ce hydroxyalkyl, cyclopropyl, Ci-Ce alkylsulfinyl, Ci-Ce alkylsulfonyl, Ci-Ce alkylsulfonamide, Ci-Cethioalkyl, amino(Ci-Ce alkyl), (mono- or di- Ci-Ce alkyl)amino(Ci-C6 alkyl), and (Ci-Ce alkoxy)(Ci-Ce alkyl).81 . The method of claim 80, wherein Rf is pyrimidinyl optionally substituted with 1 or 2 groups independently selected from halo, hydroxyl, amino, cyano, -COOH, -CONH2, Ci-Ce alkyl, Ci-Ce alkoxy, Ci-Ce haloalkyl, C2-Ce alkanoyl, Ci-Ce haloalkoxy, Ci-Ce alkylester, (mono- or di-Ci-Ce alkyl)amino, Ci-Ce hydroxyalkyl, cyclopropyl, Ci-Ce alkylsulfinyl, Ci-Ce alkylsulfonyl, Ci-Ce alkylsulfonamide, Ci-Ce thioalkyl, amino(Ci-C6 alkyl), (mono- or di-Ci-Ce alkyl)amino(Ci-C6 alkyl), and (Ci-Ce alkoxy)(Ci-Ce alkyl).

82. The method of any one of claims 55-79, wherein Rf is 8- to 10-membered bicyclic heteroaryl containing 1 , 2, or 3 heteroatoms selected from N and S optionally substituted with 1 or 2 groups independently selected from halo, hydroxyl, amino, cyano, -COOH, -CONH2, Ci-Ce alkyl, Ci-Ce alkoxy, Ci-Ce haloalkyl, 02-Ce alkanoyl, Ci-Ce haloalkoxy, Ci-Ce alkylester, (mono- or di-Ci-Ce alkyl)amino, Ci-Ce hydroxyalkyl, cyclopropyl, Ci-Ce alkylsulfinyl, Ci-Ce alkylsulfonyl, Ci-Ce alkylsulfonamide, Ci-Ce thioalkyl, amino(Ci-Ce alkyl), (mono- or di-Ci-Ce alkyl)amino(Ci-Ce alkyl), and (Ci-Ce alkoxy)(Ci-Ce alkyl).ALXN-0759-PCT01-NP83. The method of claim 82, wherein Rf is pyrazolo[1 ,5-a]pyrimidinyl, optionally substituted [1 ,2,4]triazolo[1 ,5-a]pyridinyl, optionally substituted thiazolo[5,4-b]pyrid inyl, optionally substituted imidazo[1 ,2-a]pyrimidinyl, optionally substituted 3 / 7-imidazo[4,5-b]pyridinyl, 1 / 7-thieno[3,2-c]pyrazolyl, imidazo[1 ,2-b]pyridazinyl, optionally substituted quinazolinyl, optionally substituted quinolinyl, and 1 / 7- benzo[cf]imidazolyl, each of which is optionally substituted with 1 or 2 groups independently selected from halo, hydroxyl, amino, cyano, -COOH, -CONH2, Ci-Ce alkyl, Ci-Ce alkoxy, Ci-Ce haloalkyl, C2-Ce alkanoyl, C1-C6 haloalkoxy, Ci-Ce alkylester, (mono- or di-Ci-Ce alkyl)amino, Ci-Ce hydroxyalkyl, cyclopropyl, Ci-Ce alkylsulfinyl, Ci-Ce alkylsulfonyl, Ci-Ce alkylsulfonamide, Ci-Cethioalkyl, amino(Ci-Ce alkyl), (mono- or di- C1-C6 alkyl)amino(Ci-C6 alkyl), and (Ci-Ce alkoxy)(Ci-Ce alkyl).

84. The method of any one of claims 55-83, wherein R4is85. The method of any one of claims 55-84, wherein each of R5and R6is H.

86. The method of any one of claims 55-62, wherein the compound of Formula (X) is:or a pharmaceutically acceptable salt thereof.

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