Method for synthesizing 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

[Background technology]

[0001] The complement system is part of the innate immune system, which does not adapt to changes throughout the host's life, but is recruited and used by the adaptive immune system. For example, the complement system assists or complements the ability of antibodies and phagocytes to eliminate pathogens. This elaborate regulatory pathway allows for a rapid response to pathogens while protecting host cells from destruction. More than 30 proteins and protein fragments make up the complement system. These proteins act through opsonization (enhancing phagocytosis of antigens), chemotaxis (attraction of macrophages and neutrophils), cytolysis (rupture of the membrane of foreign cells), and agglutination (clustering and binding of pathogens to each other).

[0002] The complement system has three pathways, the classical pathway, the alternative pathway and the lectin pathway. Complement factor D plays an early and central role in the activation of the alternative pathway of the complement cascade. Activation of the alternative pathway is initiated by spontaneous hydrolysis of the thioester bond in the C3 protein, resulting in the synthesis of C3(H 2 O), which combines with factor B to produce C3 (H 2 Complement factor D forms the C3(H 2 O) acts to cleave factor B in the B complex to form Ba and Bb. The Bb fragment is C3(H 2 O), and the alternative pathway C3 convertase C3 (H 2 O)Bb. Additionally, C3b generated by any of the C3 convertases also binds to factor B to form C3bB, which is cleaved by factor D to generate the late alternative pathway C3 convertase C3bBb. This latter form of the alternative pathway C3 convertase may provide important downstream amplification within all three defined complement pathways, ultimately leading to the recruitment and assembly of additional factors into 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 cells.

[0003] Complement dysfunction or excessive activation is associated with 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 generation of C3a and C5a, both of which are potent anaphylatoxins and are also involved in many inflammatory diseases. Therefore, in some instances, it is desirable to reduce the response of the complement pathway, including the alternative 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.

[0004] Additional complement-mediated disorders include those classified as C3 nephropathy (C3G), a recently defined subtype of dense deposit disease (DDD) and C3 glomerulonephritis (C3GN) that encompasses a group of chronic kidney diseases in which increased activity of the alternative and terminal complement pathways leads to glomerular deposits of only complement C3, without immunoglobulin (Ig).

[0005] Immune complex membranoproliferative glomerulonephritis (IC-MPGN) is a renal disease that shares many clinical, pathological, genetic, and laboratory features with C3G and can therefore be considered a sister disease of C3G. In the majority of patients with IC-MPGN, an underlying disease or disorder (most commonly an infection, autoimmune disease, or monoclonal gammopathy) has been identified that causes renal disease. Patients with idiopathic IC-MPGN may have similar low C3 and normal C4 levels as observed in C3G, as well as many of the same genetic or acquired factors associated with abnormal alternative pathway activity. Although the current hypothesis suggests that the majority of IC-MPGN results from excessive classical pathway activity, patients with low C3 and normal C4 are likely to have significantly excessive alternative pathway activity. Patients with IC-MPGN who have low C3 and normal C4 may benefit from inhibiting the alternative pathway.

[0006] Other disorders that are associated with 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), hepatitis, cirrhosis, liver failure, dermatomyositis, and amyotrophic lateral sclerosis.

[0007] Factor D is an attractive target for inhibition or modulation of the complement cascade because of its early essential role in the alternative pathway and its potential role in signal amplification within the classical and lectin complement pathways. Inhibition of factor D effectively blocks the pathway and attenuates formation of the membrane attack complex.

[0008] To this end, a number of small molecule Factor D inhibitors have been developed and investigated for potential therapeutic applications. Examples of methods for preparing these Factor D inhibitor compounds are described in PCT Patent Publications WO2015 / 130838, WO2017 / 035353, WO2017 / 035409, WO2018 / 160891, and WO2018 / 160892. New methods for the synthesis of small molecule Factor D inhibitors and intermediates therefor are desirable. [Prior art documents] [Patent documents]

[0009] [Patent Document 1] International Publication No. 2015 / 130838 [Patent Document 2] International Publication No. 2017 / 035353 [Patent Document 3] International Publication No. 2017 / 035409 [Patent Document 4] International Publication No. 2018 / 160891 [Patent Document 5] International Publication No. 2018 / 160892 Summary of the Invention

[0010] The present disclosure relates generally to improved methods for preparing compounds useful in the treatment of disorders mediated by complement factor D and its intermediates.

[0011] In particular, the present disclosure relates to a compound of formula (VIII): [ka] wherein P 1 is H or an N-protecting group, P 2 is H or a hydroxyl protecting group. The method comprises preparing a compound of formula (VII): [ka] (wherein P 1 is H or an N-protecting group, P 2 is H or a hydroxyl protecting group (e.g., an ester hydroxyl protecting group such as benzoyl)), forming a compound of formula (VIII) from a compound of formula (VII), wherein forming said compound of formula (VII) comprises reacting said compound of formula (II) under Simmons-Smith reaction conditions.

[0012] In some embodiments, reacting the compound of formula (VII) under Simmons-Smith reaction conditions comprises reacting the compound of formula (VII) with diethylzinc and chloroiodomethane. The reaction is typically carried out in an organic solvent, such as toluene or methylene chloride.

[0013] In some embodiments, providing the compound of formula (VII) comprises providing a compound of formula (VI): [ka] (wherein P 1 is an N-protecting group, P 2is a hydroxyl protecting group (e.g., an ester hydroxyl protecting group such as benzoyl), subjecting the compound of formula (VI) to a dehydration reaction. The dehydration reaction may comprise reacting the compound of formula (VI) with trifluoroacetic anhydride in the presence of 2,6-lutidine.

[0014] In some embodiments, providing the compound of formula (VI) comprises providing a compound of formula (V): [ka] (wherein P 1 is an N-protecting group, P 2 is a hydroxyl protecting group (e.g., an ester hydroxyl protecting group such as benzoyl), by reacting a compound of formula (V) with a reducing agent, e.g., a superhydride.

[0015] In some embodiments, providing the compound of formula (V) comprises providing a compound of formula (IV): [ka] (wherein P 1 is H or an N-protecting group, P 2 is H or a hydroxyl protecting group (e.g., an ester hydroxyl protecting group such as benzoyl), by subjecting a compound of formula (IV) to a hydrogenolysis reaction in the presence of a hydrogenation catalyst, for example palladium on carbon (Pd / C).

[0016] In some embodiments, providing the compound of formula (IV) comprises providing a compound of formula (III): [ka] (wherein P 1 is an N-protecting group, P 2 is a hydroxyl protecting group (e.g. an ester hydroxyl protecting group such as benzoyl), by reacting a compound of formula (III) with Bredereck's reagent.

[0017] In some embodiments, providing the compound of formula (III) comprises providing a compound of formula (IIA): [ka] (wherein P 2 is a hydroxyl protecting group), reacting the compound of formula (IIA) with an N-protecting reagent. In some embodiments, providing the compound of formula (IIA) comprises reacting (S)-5-(hydroxymethyl)pyrrolidin-2-one with a hydroxyl protecting reagent.

[0018] In some embodiments, providing the compound of formula (III) comprises providing a compound of formula (IIB): [ka] (wherein P 1 is an N-protecting group), reacting the compound of formula (IIB) with a hydroxyl-protecting reagent. In some embodiments, providing the compound of formula (IIB) comprises reacting (S)-5-(hydroxymethyl)pyrrolidin-2-one with an N-protecting reagent.

[0019] In some embodiments, P in formula (VIII) 2 is a hydroxyl protecting group, for example an ester hydroxyl protecting group such as benzoyl, and the method further comprises reacting the compound of formula (VIII) with a hydroxyl protecting group removal agent to produce a compound of formula (IX): [ka] wherein P 1 is H or an N-protecting group.

[0020] In some embodiments, P in formula (IX) 1 is an N-protecting group, and the method may further include forming a compound of formula (I) from the compound of formula (IX), the compound of formula (I) having the following structure: [ka] (In the formula, P 1 is H or an N-protecting group), forming the compound of formula (I) includes oxidizing the compound of formula (IX) in the presence of, for example, (2,2,6,6-tetramethylpiperidin-1-yl)oxyl, sodium hypochlorite, and sodium chlorite.

[0021] In some embodiments, the method further comprises reacting the compound of formula (I) with an organic amine to form an organic ammonium salt of the compound of formula (I) and reacting the organic ammonium salt of the compound of formula (I) with an acid to form the compound of formula (I). In some embodiments, the organic amine is a benzylamine and the organic ammonium salt is a benzylammonium salt.

[0022] In some embodiments, P in formula (I) 1 is an N-protecting group, and the method further comprises converting a compound of formula (I) to a compound of formula (X): [ka] or a salt thereof, 1 is H or optionally substituted C 1 -C 6 is alkyl, R 2 and R 3 is independently H or methyl; m is 0, 1, or 2; and B is an optionally substituted C 1 -C 6 Alkyl, optionally substituted C 2 -C 6 Alkenyl, optionally substituted C 3 -C 10 Carbocyclyl, optionally substituted C 6 -C 14 aryl, or optionally substituted 5-10 membered heterocyclyl), a compound of formula (XI): [ka] (wherein P 1 is an N-protecting group, and all other variables are as defined for formula (X), reacting a compound of formula (XI) with an N-protecting group removing agent to provide a compound of formula (XII): [ka] or a salt thereof, wherein all variables are as defined for formula (XI).

[0023] In some embodiments, the method further comprises reacting a compound of formula (XII) or a salt thereof with a compound of formula (XIII): [ka] or a salt thereof, 4 H, halo, OH, NH 2 , cyano, optionally substituted C 1 -C 6 Alkyl, optionally substituted C 2 -C 6 Alkenyl, optionally substituted 3-8 membered heterocyclyl, -C(O)NR a R a ' and R a and R a ’ each independently represents H, optionally substituted C 1 -C 6 Alkyl, optionally substituted C 2 -C 6 Alkenyl, optionally substituted C 2 -C 6 Alkynyl, or optionally substituted C 3 -C 8 Cycloalkyl, -C(O)R b , -OC(O)R b , or -C(O)OR b where R b are H, optionally substituted C 1 -C 6 Alkyl, optionally substituted C 1 -C 6Alkoxy and optionally substituted C 3 -C 8 carbocyclyl, R 5 and R 6 Each of 1 -C 6 is alkyl, and X 1 is N or CR c and R c is H, halo, optionally substituted C 1 -C 6 Alkyl, or optionally substituted C 1 -C 6 Alkoxy, X 2 and X 5 each independently represents N or CR d And each R d are independently H, halo, cyano, optionally substituted C 1 -C 6 Alkyl, optionally substituted C 1 -C 6 Alkoxy, optionally substituted C 3 -C 8 carbocyclyl, and optionally substituted 5- to 8-membered heteroaryl; X 3 and X 4 Each of the groups is independently N, CR e , and C.R. f Selected from R e is H, halo, cyano, optionally substituted C 1 -C 6 Alkyl, optionally substituted C 1 -C 6 Alkoxy and -C(O)OR g wherein R g is H or optionally substituted C 1 -C 6 is alkyl, R f is an arbitrarily substituted C 4 -C 10aryl, optionally substituted 5-10 membered heteroaryl containing 1, 2 or 3 heteroatoms selected from N, O and S, and optionally substituted 4-10 membered saturated or unsaturated non-aromatic heterocyclic groups containing 1-4 heteroatoms selected from N, O and S; X 3 and X 4 At least one of the following is CR f ), a compound of formula (XIV): [ka] or a pharma- ceutically acceptable salt thereof, wherein R 1 , R 2 , R 3 , m, and B are as defined for formula (XII), and all other variables are as defined for formula (XIII).

[0024] In some embodiments, P in each of formula (I) and formula (XI) 1 is tert-butoxycarbonyl.

[0025] In some embodiments, P in each of formula (I) and formula (XI) 1 is tert-butoxycarbonyl, and the N-protecting group removing agent may be hydrogen chloride, to form the hydrochloride salt of the compound of formula (XII). In some embodiments, the hydrochloride salt of the compound of formula (II) is then coupled with a compound of formula (XIII) in the presence of 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate and N,N-diisopropylethylamine in dimethylformamide.

[0026] In some embodiments, P in each of formula (I) and formula (XI) 1is tert-butoxycarbonyl and the N-protecting group removing agent is hydrogen bromide, the compound of formula (XI) is reacted with the N-protecting group removing agent to form the hydrobromide salt of the compound of formula (XII). In some embodiments, the hydrobromide salt of the compound of formula (XII) is then coupled with a compound of formula (XIII) in acetonitrile in the presence of propanephosphonic anhydride and N,N-diisopropylethylamine.

[0027] In some embodiments, P in each of formula (I) and formula (XI) 1 is tert-butoxycarbonyl, and the N-protecting group removal agent is trifluoroacetic acid, and the compound of formula (XI) is reacted with the N-protecting group removal agent to form the trifluoroacetate salt of the compound of formula (XII). In some embodiments, the trifluoroacetate salt of the compound of formula (I) is then coupled with the compound of formula (XIII) in dimethylformamide in the presence of N,N-diisopropylethylamine and 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate or 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethylaminium tetrafluoroborate.

[0028] In some embodiments, R 1 is H.

[0029] In some embodiments, R 1 CH 3 It is.

[0030] In some embodiments, m is 1.

[0031] In some embodiments, m is 2.

[0032] In some embodiments, m is 0.

[0033] In some embodiments, R 2 and R 3Each of is H.

[0034] In some embodiments, R 2 is H and R 3 CH 3 It is.

[0035] In some embodiments, R 2 and R 3 Each of the CH 3 It is.

[0036] In some embodiments, B is an optionally substituted 5-10 membered heteroaryl.

[0037] In some embodiments, B is an optionally substituted 6-membered heteroaryl, such as an optionally substituted pyridyl, an optionally substituted pyridazinyl, an optionally substituted pyrimidinyl, or an optionally substituted pyrazinyl.

[0038] In some embodiments, B is an optionally substituted pyridyl, e.g., [ka] [ka] [ka] Preferably [ka] It is.

[0039] In some embodiments, B is an optionally substituted pyrazinyl, e.g., [ka] It is.

[0040] In some embodiments, B is an optionally substituted pyrimidinyl, e.g., [ka] It is.

[0041] In some embodiments, B is an optionally substituted pyridazinyl, such as, [ka] It is.

[0042] In some embodiments, B is an optionally substituted 5-membered heteroaryl, such as [ka] It is.

[0043] In some embodiments, B is a bicyclic 9- or 10-membered bicyclic heteroaryl, such as [ka] It is.

[0044] In some embodiments, B is optionally substituted C 6 -C 14 Aryl, for example [ka] and the like.

[0045] In some embodiments, B is an optionally substituted 5-9 membered unsaturated heterocyclyl, such as [ka] It is.

[0046] In some embodiments, B is optionally substituted C 3 -C 10 Cycloalkyl, for example [ka] It is.

[0047] In some embodiments, B is optionally substituted C 2 -C 6 Alkenyl, for example [ka] It is.

[0048] In some embodiments, B is optionally substituted C 1 -C 6 Alkyl, e.g. [ka] It is.

[0049] In some embodiments, X 1 is N.

[0050] In some embodiments, X 1 CR c , e.g., C(CH 3 ) or CH.

[0051] In some embodiments, X 2 CR d , for example, CH or C(C 1 -C 6 alkyl) (e.g., methyl).

[0052] In some embodiments, X 5 CR d , for example CH.

[0053] In some embodiments, X 3 CR f and X 4 may be, for example, N or CH.

[0054] In some embodiments, X 4 CR f and X 3may be, for example, N or CH.

[0055] In some embodiments, R f is an optionally substituted 5-10 membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S.

[0056] In some embodiments, R f is a 6-membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S.

[0057] In some embodiments, R f is optionally substituted pyrimidinyl, e.g. [ka] [ka] and preferably [ka] It is.

[0058] In some embodiments, R f teeth: [ka] It is.

[0059] In some embodiments, R f is an optionally substituted 8-10 membered bicyclic heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S. In some embodiments, R fare optionally substituted pyrazolo[1,5-a]pyrimidinyl, optionally substituted [1,2,4]triazolo[1,5-a]pyridinyl, optionally substituted thiazolo[5,4-b]pyridinyl, optionally substituted imidazo[1,2-a]pyrimidinyl, optionally substituted 3H-imidazo[4,5-b]pyridinyl, 1H-thieno[3,2-c]pyrazolyl, imidazo[1,2-b]pyridazinyl, optionally substituted quinazolinyl, optionally substituted quinolinyl, and 1H-benzo[d]imidazolyl, such as [ka] and Preferably [ka] It is.

[0060] In some embodiments, R f is an arbitrarily substituted C 6 -C 14 Aryl, for example [ka] and the like.

[0061] In some embodiments, R f is an optionally substituted 6-9 membered unsaturated heterocyclyl having 1-4 heteroatoms selected from N, O, or S. For example, R f is a heterocyclyl bonded to a carbon atom bonded via a carbon ring atom contained therein, e.g. [ka] In another example, R f is a heterocyclyl bonded to a carbon atom bonded via a nitrogen atom contained therein, e.g. [ka] It could be.

[0062] In some embodiments, R f is an optionally substituted 5-membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S, e.g., [ka] It is.

[0063] In some embodiments, R 4 is -C(O)R b ,for example, [ka] and preferably [ka] It is.

[0064] In some embodiments, R 4 is -C(O)NR a R a ’ ,for example, [ka] and preferably [ka] It is.

[0065] In some embodiments, R 4 is -C(O)OR b , e.g., -C(O)OCH 3 Or -C(O)OH.

[0066] In some embodiments, R 4 is an arbitrarily substituted C 1 -C 6 Alkyl, e.g. [ka] It is.

[0067] In some embodiments, R 4 teeth [ka] It is.

[0068] In some embodiments, R 4 is cyano.

[0069] In some embodiments, R 4 is a halo.

[0070] In some embodiments, R 5 is H.

[0071] In some embodiments, R 6 is H.

[0072] In some embodiments, the compound of formula (XIV) is: [ka] or a pharma- ceutically acceptable salt thereof.

[0073] In some embodiments, the compound of formula (XIV) is: [ka] or a pharma- ceutically acceptable salt thereof.

[0074] In some embodiments, the compound of formula (XIV) is: [ka] or a pharma- ceutically acceptable salt thereof.

[0075] In some embodiments, the compound of formula (XIV) is: [ka] or a pharma- ceutically acceptable salt thereof.

[0076] In some embodiments, the compound of formula (XIV) is: [ka] or a pharma- ceutically acceptable salt thereof.

[0077] In some embodiments, the compound of formula (XIV) is: [ka] or a pharma- ceutically acceptable salt thereof.

[0078] In some embodiments, the compound of formula (XIV) is: [ka] or a pharma- ceutically acceptable salt thereof.

[0079] definition In order to facilitate understanding of the present invention, certain terms are defined below. Terms defined herein have meanings commonly understood by those skilled in the art in the field related to the present invention. Terms such as "a", "an", and "the" are not intended to refer only to a singular entity, but include a general class for which a specific example may be used for illustration. Terms in this specification are used to describe specific embodiments of the present invention, but their usage does not limit the present invention, except as outlined in the claims.

[0080] As used herein, the term "about" refers to a value within 10% above or below the stated value.

[0081] As used herein, any value provided in a range of values ​​includes both the upper and lower limits, as well as any value subsumed within the upper and lower limits.

[0082] As used herein, the term "pharmaceutically acceptable salt" refers to a salt of a compound that is described within the normal scope of sound medical judgment as being suitable for use in contact with human and animal tissues without excessive toxicity, irritation, allergic response, etc., and that is 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 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, including inorganic or organic acids. Salts may be prepared in situ during the final isolation and purification of the compounds described herein, or may be prepared separately by reacting the free base group with a suitable acid. Methods for preparing suitable salts are well established in the art. Representative acid addition salts include acetate, adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, bromide, butyrate, camphorate, camphorsulfonate, chloride, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, fumarate, glucoheptonate, glycerophosphate, hemisulfate, heptonate, hexanoate, hydrobromide, hydrochloride, hydroiodide, 2-hydroxy-ethanesulfate, and 2-hydroxy-ethanesulfate. Examples of the salts include sulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, toluenesulfonate, undecanoate, and valerate.

[0083] As used herein, the term "acyl" refers to a monovalent radical having the structure -COR, where R is alkyl, alkenyl, aryl, arylalkyl, heteroaryl, or heteroarylalkyl. Acyl can be optionally substituted as defined for each R group.

[0084] As used herein, the term "alkyl" refers to a branched or straight chain monovalent saturated aliphatic radical that, when unsubstituted, contains only C and H. The monovalency of an alkyl group does not include optional substituents on the alkyl group. For example, if an alkyl group is attached to a compound, the 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, an alkyl group can contain, for example, 1 to 12, 1 to 10, 1 to 8, 1 to 6, 1 to 4, or 1 to 2 carbon atoms (e.g., C 1 -C 12 , C 1 -C 10 , C 1 -C 8 , C 1 -C 6 , C 1 -C 4 , or C 1 -C 2 ). Examples include, but are not limited to, methyl, ethyl, isobutyl, sec-butyl, and tert-butyl.

[0085] 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 the alkylene group does not include optional substituents on the alkylene group.

[0086] As used herein, the term "alkenyl" refers to a branched or straight-chain monovalent unsaturated aliphatic radical that contains at least one carbon-carbon double bond, no carbon-carbon triple bonds, and, if unsubstituted, contains only C and H. The monovalency of an alkenyl group does not include optional substituents on the alkenyl group. For example, if an alkenyl group is attached to a compound, the 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, an alkenyl group can contain, for example, 2 to 12, 2 to 10, 2 to 8, 2 to 6, or 2 to 4 carbon atoms (e.g., C 2 -C 12 , C 2 -C 10 , C 2 -C 8 , C 2 -C 6 , or C 2 -C 4 Examples include, but are not limited to, ethenyl, 1-propenyl, 2-propenyl, 1-methylethenyl, 1-butenyl, 2-butenyl, 3-butenyl, and the like.

[0087] As used herein, the term "alkenyloxy" refers to a monovalent radical having the structure -O-alkenyl, where "alkenyl" is as defined herein. Examples include, but are not limited to, ethenyloxy, propenyloxy, and the like.

[0088] As used herein, the term "alkoxy" refers to a monovalent radical having the structure -O-alkyl, where "alkyl" is as defined herein. Examples include, but are not limited to, methoxy, ethoxy, and n-butoxy, i-butoxy, t-butoxy, and the like.

[0089] As used herein, the term "alkoxyalkyl" refers to a monovalent radical having the structure -R'OR" where R' is alkylene and R" is alkyl. Alkoxyalkyl can be optionally substituted in the same manner as defined for each R' and R" group.

[0090] As used herein, the term "alkynyl" refers to a branched or straight-chain monovalent unsaturated aliphatic radical that contains at least one carbon-carbon triple bond and, if unsubstituted, contains only C and H. The monovalency of an alkynyl group does not include optional substituents on the alkynyl group. For example, if an alkynyl group is attached to a compound, the 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, an alkynyl group can contain, for example, 2 to 12, 2 to 10, 2 to 8, 2 to 6, or 2 to 4 carbon atoms (e.g., C 2 -C 12 , C 2 -C 10 , C 2 -C 8 , C 2 -C 6 , or C 2 -C 4 ). Examples include, but are not limited to, ethynyl, 1-propynyl, and 3-butynyl.

[0091] As used herein, the term "alkylthioalkyl" refers to a monovalent radical having the structure -R'SR" where R' is alkylene and R" is alkyl. Alkylthioalkyl can be optionally substituted in the same manner as defined for each R' and R" group.

[0092] As used herein, the term "aryl" refers to a monovalent, monocyclic or fused ring bicyclic or polycyclic ring system having aromatic character with respect to the distribution of electrons throughout the ring system, e.g., phenyl, naphthyl, or phenanthryl. Aryl groups can have, for example, 6 to 16 carbons (e.g., C 6 -C 16 Aryl, C6 -C 14 Aryl, C 6 -C 13 Aryl, or C 6 -C 10 aryl).

[0093] As used herein, the term "arylalkoxy" refers to a monovalent radical having the structure -OR'R", where R' is alkylene and R" is aryl. Arylalkoxy can be optionally substituted in the same manner as defined for each R' and R" group.

[0094] As used herein, the term "arylalkoxyalkyl" refers to a monovalent radical having the structure -R'OR'R", where each R' is an alkylene and R" is an aryl. Arylalkoxyalkyl can be optionally substituted in the same manner as defined for each R' and R" group.

[0095] As used herein, the term "arylalkyl" refers to a monovalent radical having the structure -R'R", where R' is alkylene and R" is aryl. Arylalkyl can be optionally substituted in the same manner as defined for each R' and R" group.

[0096] The term "arylene," as used herein, refers to a divalent radical obtained by removing a hydrogen atom from a carbon atom of an aryl group. The divalency of the arylene group does not include optional substituents on the arylene group.

[0097] As used herein, the term "carbamate" refers to a compound having the structural formula -OC(O)NR 2 where each R is independently H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted aryl, or optionally substituted arylalkyl.

[0098] As used herein, the term "carbocyclyl" refers to a monovalent, saturated or unsaturated, non-aromatic cyclic group that, when unsubstituted, contains only C and H. A carbocyclyl (e.g., cycloalkyl or cycloalkenyl) can have, for example, 3 to 14 carbons (e.g., C 3 -C 7 , C 3 -C 8 , C 3 -C 9 , C 3 -C 10 , C 3 -C 11 , C 3 -C 12 , C 3 -C 14 The term "carbocyclyl" also includes bicyclic and polycyclic (eg, tricyclic and tetracyclic) fused ring structures.

[0099] The term "carbocyclylene," as used herein, refers to a divalent radical obtained by removing a hydrogen atom from a carbon atom of a carbocyclyl group. The divalency of the carbocyclylene group does not include optional substituents on the carbocyclylene group.

[0100] As used herein, the term "carbocyclyloxy" refers to a monovalent radical having the structure -O-carbocyclyl, e.g., an -O-cycloalkyl or an -O-cycloalkenyl radical. Included in -O-carbocyclyl, -O-cycloalkyl, and -O-cycloalkenyl are the terms "carbocyclyl," "cycloalkyl," and "cycloalkenyl," as defined herein.

[0101] As used herein, the term "carbonate" refers to a monovalent radical having the structure -OC(O)OR, where R is an optionally substituted alkyl, optionally substituted alkenyl, optionally substituted aryl, or optionally substituted arylalkyl.

[0102] As used herein, the term "cycloalkyl" refers to saturated carbocyclyl. Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. The term "cycloalkyl" also includes cyclic groups having bridged polycyclic structures in which one or more carbons bridge two non-adjacent members of a monocyclic ring, such as bicyclo[2.2.1]heptyl and adamantyl. The term "cycloalkyl" also includes bicyclic, tricyclic, and tetracyclic fused ring structures, such as decalin and spirocyclic compounds.

[0103] As used herein, the term "cyano" refers to a monovalent radical having the structure --CN.

[0104] As used herein, the term "cycloalkenyl" refers to a monovalent unsaturated carbocyclyl group that contains at least one carbon-carbon double bond, no carbon-carbon triple bonds, and, if unsubstituted, contains only C and H and is not fully aromatic. Cycloalkenyls can have, for example, 4 to 14 carbons (e.g., C 4 -C 7 , C 4 -C 8 , C 4 -C 9 , C 4 -C 10 , C 4 -C 11 , C 4 -C 12 , C 4 -C 13 , or C 4 -C 14 Cycloalkenyl). Exemplary cycloalkenyl groups include, but are not limited to, cyclopentenyl, cyclohexenyl, and cycloheptenyl. The term "cycloalkenyl" also includes cyclic groups having bridged polycyclic structures in which one or more carbons bridge two non-adjacent members of a monocyclic ring, such as bicyclo[2.2.2]oct-2-ene. The term "cycloalkenyl" also includes fused ring bicyclic and polycyclic systems containing one or more double bonds, such as fluorene.

[0105] As used herein, the term "ester" refers to a monovalent radical having the structure -OCOR, where R is alkyl, alkenyl, aryl, arylalkyl, heteroaryl, or heteroarylalkyl. Esters can be optionally substituted as defined for each R group.

[0106] As used herein, the term "ether" refers to a monovalent radical having the structure -OR, where R is alkyl, alkenyl, arylalkyl, silyl, or 2-tetrahydropyranyl. Ethers can be optionally substituted as defined for each R group.

[0107] As used herein, the term "halo" refers to a fluorine (fluoro), chlorine (chloro), bromine (bromo), or iodine (iodo) radical.

[0108] As used herein, the term "heteroarylalkyl" refers to a monovalent radical of the structure -R'R", where R' is alkylene and R" is heteroaryl. Heteroarylalkyl can be optionally substituted in the same manner as defined for each R' and R" group.

[0109] As used herein, the term "heterocyclyl" refers to one or more carbon atoms and at least one heteroatom, e.g., 1 to 4 heteroatoms (e.g., 1 to 4, 1 to 3, 1 or 2, 1, 2, 3, or 4 heteroatoms) selected from N, O, and S. Heterocyclyl groups include both non-aromatic and aromatic systems. Aromatic heterocyclyl groups are referred to as "heteroaryl" groups. In some embodiments, heterocyclyl groups are 3-8 membered ring systems, 3-6 membered ring systems, 4-6 membered ring systems, 4-10 membered ring systems, 6-10 membered ring systems, 6-12 membered ring systems, 5 membered rings, or 6 membered rings, or rings or ring systems having numbers of ring atoms included within the aforementioned ranges. Exemplary 5 membered heterocyclyl groups can have 0 to 2 double bonds, and exemplary 6 membered heterocyclyl groups can have 0 to 3 double bonds. Exemplary five-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 2H-pyran, optionally substituted 4H-pyran, and optionally substituted tetrahydropyran. Exemplary 7-membered heterocyclyl groups include, but are not limited to, optionally substituted azepine, optionally substituted 1,4-diazepine, optionally substituted thiepine, and optionally substituted 1,4-thiazepine.Exemplary 8-10 membered bicyclic groups include, but are not limited to, optionally substituted pyrazolo[1,5-a]pyrimidinyl, optionally substituted [1,2,4]triazolo[1,5-a]pyridinyl, optionally substituted thiazolo[5,4-b]pyridinyl, optionally substituted imidazo[1,2-a]pyrimidinyl, optionally substituted 3H-imidazo[4,5-b]pyridinyl, optionally substituted 1H-thieno[3,2-c]pyrazolyl, optionally substituted imidazo[1,2-b]pyridazinyl, optionally substituted quinazolinyl, optionally substituted quinolinyl, and optionally substituted 1H-benzo[d]imidazolyl.

[0110] As used herein, the term "hydroxyl protecting group" refers to any group capable of protecting the oxygen atom attached thereto from reaction or binding. Hydroxyl protecting groups are introduced by reacting a molecule containing an unprotected hydroxyl group with a hydroxyl protecting reagent. Hydroxyl protecting groups are known in the art and described, for example, in Wuts, Greene's Protective Groups in Organic Synthesis, Wiley-Interscience, 4th Edition, 2006. Exemplary protecting groups (together with the oxygen atom to which they are attached) are independently selected from the group consisting of esters, carbonates, carbamates, sulfonates, and ethers. In an exemplary ester hydroxyl protecting group, R of the acyl group is C 1 -C 12 Alkyl (e.g., C 1 -C 8 , C 1 -C 6 , C 1 -C 4 , C 2 -C 7 , C 3 -C 12 , and C 3 -C 6 Alkyl), C 2 -C 12 Alkenyl (e.g., C 2 -C 8 , C 2 -C6 , C 2 -C 4 , C 3 -C 12 , and C 3 -C 6 alkenyl), carbocyclic C 6 -C 20 Aryl (e.g., C 6 -C 15 , C 6 -C 10 , C 8 -C 20 , and C 8 -C 15 aryl), monocyclic C 1 -C 6 Heteroaryl (e.g., C 1 -C 4 and C 2 -C 6 Heteroaryl), C 4 -C 19 Heteroaryl (e.g., C 4 -C 10 Heteroaryl), (C 6 -C 15 )Aryl(C 1 -C 6 ) alkyl, (C 4 -C 19 ) Heteroaryl (C 1 -C 6 ) alkyl, or (C 1 -C 6 ) Heteroaryl (C 1 -C 6) alkyl. Specific examples of acyl groups for use in the esters include formyl, benzoylformyl, acetyl (e.g., unsubstituted or chloroacetyl, trifluoroacetyl, methoxyacetyl, triphenylmethoxyacetyl, and p-chlorophenoxyacetyl), 3-phenylpropionyl, 4-oxopentanoyl, 4,4-(ethylenedithio)pentanoyl, pivaloyl (Piv), vinylpivaloyl, crotonoyl, 4-methoxy-crotonoyl, naphthoyl (e.g., 1- or 2-naphthoyl), and benzoyl (e.g., unsubstituted or substituted, e.g., p-methoxybenzoyl, phthaloyl (including salts such as triethylamine and potassium), p-bromobenzoyl, and 2,4,6-trimethylbenzoyl). As defined herein, any heteroaryl group present in the ester group has 1 to 4 heteroatoms independently selected from O, N, and S. In an exemplary carbonate hydroxyl protecting group, R is C 1 -C 12 Alkyl (e.g., C 1 -C 8 , C 1 -C 6 , C 1 -C 4 , C 2 -C 7 , C 3 -C 12 , and C 3 -C 6 Alkyl), C 2 -C 12 Alkenyl (e.g., C 2 -C 8 , C 2 -C 6 , C 2 -C 4 , C 3 -C 12 , and C 3 -C 6 alkenyl), carbocyclic C 6 -C 20 Aryl (e.g., C 6 -C 15 , C 6 -C 10 , C 8 -C 20 , and C8 -C 15 aryl), monocyclic C 1 -C 6 Heteroaryl (e.g., C 1 -C 4 and C 2 -C 6 Heteroaryl), C 4 -C 19 Heteroaryl (e.g., C 4 -C 10 Heteroaryl), (C 6 -C 15 )Aryl(C 1 -C 6 ) alkyl, (C 4 -C 19 ) Heteroaryl (C 1 -C 6 ) alkyl, or (C 1 -C 6 ) Heteroaryl (C 1 -C 6 ) alkyl. Specific examples include methyl, 9-fluorenylmethyl, ethyl, 2,2,2-trichloroethyl, 2-(trimethylsilyl)ethyl, 2-(phenylsulfonyl)ethyl, vinyl, allyl, t-butyl, p-nitrobenzyl, and benzyl carbonate. As defined herein, any heteroaryl group present in the carbonate group has 1 to 4 heteroatoms independently selected from O, N, and S. In exemplary carbamate hydroxyl protecting groups, each R is independently selected from H, C, 1 -C 12 Alkyl (e.g., C 1 -C 8 , C 1 -C 6 , C 1 -C 4 , C 2 -C 7 , C 3 -C 12 , and C 3 -C 6 Alkyl), C 2 -C 12 Alkenyl (e.g., C 2 -C 8 , C 2 -C 6 , C2 -C 4 , C 3 -C 12 , and C 3 -C 6 alkenyl), carbocyclic C 6 -C 20 Aryl (e.g., C 6 -C 15 , C 6 -C 10 , C 8 -C 20 , and C 8 -C 15 aryl), monocyclic C 1 -C 6 Heteroaryl (e.g., C 1 -C 4 and C 2 -C 6 Heteroaryl), C 4 -C 19 Heteroaryl (e.g., C 4 -C 10 Heteroaryl), (C 6 -C 15 )Aryl(C 1 -C 6 ) alkyl, (C 4 -C 19 ) Heteroaryl (C 1 -C 6 ) alkyl, or (C 1 -C 6 ) Heteroaryl (C 1 -C 6 ) alkyl. Specific examples include N-phenyl and N-methyl-N-(o-nitrophenyl) carbamates. As defined herein, any heteroaryl group present in the carbamate group has 1 to 4 heteroatoms independently selected from O, N, and S. Exemplary ether hydroxyl protecting groups include C 1 -C 12 Alkyl (e.g., C 1 -C 8 , C 1 -C 6 , C 1 -C 4 , C 2 -C 7 , C 3 -C12 , and C 3 -C 6 Alkyl), C 2-12 Alkenyl (e.g., C 2 -C 8 , C 2 -C 6 , C 2 -C 4 , C 3 -C 12 , and C 3 -C 6 alkenyl), (C 6 -C 15 )Aryl(C 1 -C 6 ) alkyl, (C 4 -C 19 ) Heteroaryl (C 1 -C 6 ) alkyl, (C 1 -C 6 ) Heteroaryl (C 1 -C 6 ) alkyl, (C 1 -C 6 )Alkoxy(C 1 -C 6 ) alkyl, (C 1 -C 6 )Alkylthio(C 1 -C 6 ) alkyl, (C 6 -C 10 )Aryl(C 1 -C 6 )Alkoxy(C 1 -C 6 ) alkyl, and silyl (e.g., tri(C 1 -C 6 Alkyl)silyl, tri(C 6 -C 10 Aryl or C 1 -C 6 Heteroaryl)silyl, di(C 6 -C 10 Aryl or C 1 -C 6 Heteroaryl)(C 1 -C 6 alkyl)silyl, and (C 6 -C 10 Aryl or C 1-C 6 Heteroaryl)di(C 1 -C 6 Specific examples of alkyl ethers include methyl and t-butyl, and examples of alkenyl ethers include allyl. An ether hydroxyl protecting group can be used to protect a carboxyl group (e.g., C 1-12 Alkyl (e.g., C 1-8 , C 1-6 , C 1-4 , C 2-7 , C 3-12 , and C 3-6 Alkyl), (C 6-15 )Aryl(C 1-6 ) alkyl, (C 1-6 )Alkoxy(C 1-6 ) alkyl, (C 1-6 )Alkylthio(C 1-6 ) alkyl, or (C 6-10 )Aryl(C 1-6 )Alkoxy(C 1-6) alkyl). Examples of alkoxyalkyl and alkylthioalkyl groups that can be used as ether hydroxyl protecting groups include methoxymethyl, methylthiomethyl, (2-methoxyethoxy)methyl, and β-(trimethylsilyl)ethoxymethyl. Examples of arylalkyl groups that can be used as ether hydroxyl protecting groups include benzyl, p-methoxybenzyl (MPM), 3,4-dimethoxybenzyl, triphenylmethyl (trityl), o-nitrobenzyl, p-nitrobenzyl, p-halobenzyl, 2,6-dichlorobenzyl, p-cyanobenzyl, naphthylmethyl, and 2- and 4-picolyl ethers. Specific examples of silyl ethers include trimethylsilyl (TMS), triethylsilyl (TES), t-butyldimethylsilyl (TBS), t-butyldiphenylsilyl (TBDPS), triisopropylsilyl (TIPS), and triphenylsilyl (TPS) ethers. An example of an arylalkyloxyalkyl ether is benzyloxymethyl ether. As defined herein, any heteroaryl group present in the ether group has 1 to 4 heteroatoms independently selected from O, N, and S. Alkyl groups, such as methyl, ethyl, isopropyl, n-propyl, t-butyl, n-butyl, and sec-butyl, and alkenyl groups, such as vinyl and allyl, can also be substituted with oxo, arylsulfonyl, halogen, and trialkylsilyl groups. Protecting groups can be introduced and removed using methods known in the art.

[0111] As used herein, the term "N-protecting group" refers to a group that protects a nitrogen atom in a molecule from participating in one or more undesired reactions during chemical synthesis (e.g., oxidation reactions, or certain nucleophilic and electrophilic substitutions). N-protecting groups are introduced by reacting a molecule containing a nitrogen atom with an N-protecting reagent. Commonly used N-protecting groups and corresponding N-protecting reagents are disclosed in Wuts, Greene's Protective Groups in Organic Synthesis, Wiley-Interscience, 4th Edition, 2006.Exemplary N-protecting groups include acyl (e.g., formyl, acetyl, trifluoroacetyl, propionyl, pivaloyl, t-butylacetyl, 2-chloroacetyl, 2-bromoacetyl, trifluoroacetyl, trichloroacetyl, phthalyl, o-nitrophenoxyacetyl, α-chlorobutyryl, benzoyl, 4-chlorobenzoyl, 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-dimethoxybenzyloxycarbonyl, 2,4-dimethoxybenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, benzyloxycarbonyl, 2-nitro-4,5-dimethoxybenzyloxycarbonyl, 3,4,5-trimethoxybenzyloxycarbonyl, 1-(p-biphenylyl)-1-methylethoxycarbonyl, α,α-dimethyl-3,5-dimethoxybenzyloxycarbonyl, benzhydryloxycarbonyl, t-butyloxycarbonyl, diisopropylmethoxycarbonyl, isopropyloxycarbonyl, ethoxycarbonyl, methoxycarbonyl, allyloxycarbonyl, 2,2,2,-trichloroethoxycarbonyl, phenoxycarbonyl, 4-nitrophenoxycarbonyl, fluorenyl-9-methoxycarbonyl, cyclopentyloxycarbonyl, adamantyloxycarbonyl, cyclohexyloxycarbonyl, and phenylthiocarbonyl), arylalkyl (e.g., triphenylmethyl), silyl groups (e.g., trimethylsilyl), and imine-forming groups (e.g., diphenylmethylene). Preferred N-protecting groups are cetyl, benzoyl, phenylsulfonyl, p-toluenesulfonyl, p-nitrobenzenesulfonyl, o-nitrobenzenesulfonyl, t-butyloxycarbonyl (Boc), and benzyloxycarbonyl (Cbz).

[0112] As used herein, the term "oxo" refers to a divalent oxygen atom represented by the structure =O.

[0113] As used herein, the term "silyl" refers to -SiR 3 where each R is independently alkyl, alkenyl, aryl, or arylalkyl. Examples of silyl groups include tri(C 1 -C 6 Alkyl)silyl, tri(C 6 -C 10 Aryl or C 1 -C 6 Heteroaryl)silyl, di(C 6 - 10 Aryl or C 1 -C 6 Heteroaryl)(C 1 -C 6 alkyl)silyl, and (C 6 -C 10 Aryl or C 1 -C 6 Heteroaryl)di(C 1 -C 6 Examples of suitable silyl groups include alkyl)silyl. When the silyl group contains two or more alkyl, alkenyl, aryl, heteroaryl, or arylalkyl groups, it is understood that these groups are independently selected. As defined herein, any heteroaryl group present in the silyl group has 1 to 4 heteroatoms independently selected from O, N, and S. Silyl can be optionally substituted in the same manner as defined for each R group.

[0114] As defined herein, the term "sulfonyl" refers to -S(O) 2 R refers to a group of optionally substituted alkyl, optionally substituted alkenyl, optionally substituted aryl, optionally substituted arylalkyl, or silyl. In an exemplary sulfonyl group, R is C 1 -C 12 Alkyl (e.g., C 1 -C 8 , C 1 -C 6 , C1 -C 4 , C 2 -C 7 , C 3 -C 12 , or C 3 -C 6 Alkyl), C 2 -C 12 Alkenyl (e.g., C 2 -C 8 , C 2 -C 6 , C 2 -C 4 , C 3 -C 12 , or C 3 -C 6 alkenyl), carbocyclic C 6 -C 20 Aryl (e.g., C 6 -C 15 , C 6 -C 10 , C 8 -C 20 , or C 8 -C 15 aryl), monocyclic C 1 -C 6 Heteroaryl (e.g., C 1 -C 4 and C 2 -C 6 Heteroaryl), C 4 -C 19 Heteroaryl (e.g., C 4 -C 10 Heteroaryl), (C 6 -C 15 )Aryl(C 1 -C 6 ) alkyl, (C 4 -C 19 ) Heteroaryl (C 1 -C 6 ) alkyl, or (C 1 -C 6 ) Heteroaryl (C 1 -C 6 ) alkyl. As defined herein, any heteroaryl group present in the sulfonate group has 1 to 4 heteroatoms independently selected from O, N, and S.

[0115] As used herein, the term "thioalkyl" refers to a monovalent radical having the structure -S-alkyl, where "alkyl" is as defined herein.

[0116] As used herein, the phrase "optionally substituted X" is intended to be equivalent to "X, where X is optionally substituted" (e.g., "alkyl, where the alkyl is optionally substituted"). It is not intended to imply that the feature "X" (e.g., alkyl) itself is optional. As used herein, the term "optionally substituted" 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).

[0117] Alkyl, alkylene, alkenyl, alkynyl, carbocyclyl, cycloalkyl, cycloalkenyl, aryl, and heterocyclyl groups include carbocyclyl, cycloalkyl, cycloalkenyl, aryl, heterocyclyl, heteroaryl, halo, OH, cyano, alkoxy, alkenyloxy, thioalkyl, NO 2 , N 3 , N.R.R. ’ (Wherein, R and R ’ each is independently H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, or heterocyclyl), SO 2 R (wherein R is H, alkyl, or aryl), SO 2 NRR ’ (Wherein, R and R ’ each is independently H, alkyl, or aryl, or NRSO 2 R (wherein R and R ’Each of may be substituted with one or more of, independently, H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, or heterocyclyl. The aryl, carbocyclyl, cycloalkyl, cycloalkenyl, heteroaryl, and heterocyclyl groups may also be substituted with alkyl, alkenyl, or alkynyl. The alkyl, alkoxy, carbocyclyl, cycloalkyl, cycloalkenyl, and unsaturated heterocyclyl groups may also be substituted with oxo. In some embodiments, the substituents are further substituted as described herein. For example, C 6 The aryl group, ie, phenyl, may be substituted with an alkyl group, which may be further substituted with a heterocyclyl group. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0118] The present invention provides methods for the synthesis of small molecule complement factor D inhibitors and intermediates thereof. Complement factor D inhibitors are compounds of formula (XIV): [ka] or a pharma- ceutically acceptable salt thereof, and the variable R 1 ~R 6 , X 1 ~X 5 , m, and B are as defined herein. Exemplary compounds of formula (XIV) are described, for example, in U.S. Pat. Nos. 10,011,612, 10,287,301, and 10,822,352, and U.S. Patent Publication No. 2020 / 0071301A1, the contents of which are incorporated herein by reference in their entirety.

[0119] The method comprises reacting a compound of formula (VIII): [ka] wherein P 1 is H or an N-protecting group, P 2is H or a hydroxyl protecting group (e.g., an ester hydroxyl protecting group such as benzoyl). This process produces a compound of formula (VII): [ka] (wherein P 1 is H or an N-protecting group, P 2 is H or a hydroxyl protecting group (e.g., an ester hydroxyl protecting group such as benzoyl), to form a compound of formula (VIII) from a compound of formula (VII) via a cyclopropanation reaction carried out under Simmons-Smith reaction conditions. The Simmons-Smith reaction involves the formation of an organozinc carbenoid (e.g., iodomethylzinc iodide formed from the reaction of Zn / Cu with diiodomethane) which reacts with an alkene to form a cyclopropane. Well-known variations of the Simmons-Smith reaction include the Furukawa modification, in which Zn / Cu is replaced with diethylzinc, the Charette modification, in which diethylzinc is replaced with an aryl diazo compound such as phenyldiazomethane, and the use of non-zinc agents, e.g., Sm / Hg and i-Bu. 3 Other modifications include those involving Al. In some embodiments, the compound of formula (VII) is reacted with diethylzinc and chloroiodomethane to form a compound of formula (VIII).

[0120] In accordance with embodiments of the methods disclosed herein (e.g., 2 is benzoyl), unexpectedly provides high stereoselectivity (about 95:5) to compounds of formula (VIII), which is carried over to subsequent reactions, for example in the multi-step synthesis of compounds of formula (XIV).

[0121] Previously reported procedures for preparing compounds of formula (XIV) require the use of compounds of formula (I), which were generally prepared prior to this disclosure using procedures reported in US Publication No. 2011 / 0274648A1, which yield approximately a 1:3 diastereomeric mixture of compounds of formula (I) and their diastereomers. Other published procedures use silyl protecting groups (Bioorg. Med. Chem., 21 (2013) 5725-5737), which makes purification of the resulting mixture difficult compared to the reactions disclosed herein. Another published procedure relies on lithium diisopropyl-amide and methyl iodide to insert the methyl group (see formulas III-V), which results in a mixture of methylated compounds (both mono- and dimethylated) and unreacted starting material, necessitating additional chromatographic separation.

[0122] The ability to prepare intermediates in the synthesis of compounds of formula (VIII) with high stereoselectivity significantly improves the overall yield of the overall process for preparing compounds of formula (XIV).

[0123] Compound of formula (VII) In some embodiments, the compound of formula (VII): [ka] (In the formula, P 1 and P 2 is as defined above) with a compound of formula (VI): [ka] (In the formula, P 1 is an N-protecting group, P 2is a hydroxyl protecting group (e.g., an ester hydroxyl protecting group such as benzoyl)) to a dehydration reaction (elimination reaction). The dehydration reaction is usually carried out at elevated temperature (in the presence of a strong acid such as sulfuric acid, phosphoric acid, or trifluoroacetic acid (e.g., formed from the hydrolysis of trifluoroacetic anhydride). The dehydration may also be carried out in refluxing methylene chloride in the presence of p-toluenesulfonyl chloride (TsCl) as a catalyst. Such reactions are well known in the art. In some embodiments, the compound of formula (VII) is prepared by reacting the compound of formula (VI) with trifluoroacetic anhydride (e.g., in the presence of 2,6-lutidine).

[0124] Compound of formula (VI) In some embodiments, the compound of formula (VI): [ka] (In the formula, P 1 and P 2 is as defined above) with a compound of formula (V): [ka] (In the formula, P 1 is an N-protecting group, P 2 is prepared by reducing a hydroxyl protecting group (e.g., an ester hydroxyl protecting group such as benzoyl). The compound of formula (V) may be reduced using reducing agents including, but not limited to, lithium triethylborohydride (a "super hydride") and sodium borohydride. In some embodiments, the compound of formula (V) is reduced with lithium triethylborohydride.

[0125] Compound of formula (V) In some embodiments, the compound of formula (V): [ka] (In the formula, P 1 and P 2is as defined above) with a compound of formula (IV): [ka] (In the formula, P 1 is H or an N-protecting group, P 2 is prepared by subjecting a protecting group such as H or a hydroxyl protecting group (e.g., an ester hydroxyl protecting group such as benzoyl) to a hydrogenolysis reaction in the presence of a hydrogenation catalyst. Suitable hydrogenation catalysts include, but are not limited to, palladium on carbon, platinum(IV) oxide, palladium(II) hydroxide, Raney nickel, and platinum metal. In some embodiments, the hydrogenolysis reaction is carried out in the presence of palladium on carbon.

[0126] Compounds of formula (IIA), (IIB), (III), and (IV) In some embodiments, the compound of formula (IV): [ka] (In the formula, P 1 and P 2 is as defined above) with a compound of formula (III): [ka] (In the formula, P 1 is an N-protecting group, P 2 is a hydroxyl protecting group (e.g., an ester hydroxyl protecting group such as benzoyl) with Bredereck's reagent (tert-butoxybis(dimethylamino)methane; see, e.g., Rosso, Synlett. 2006;5:0809-0810). Compounds of formula (III) may then be prepared from (S)-5-(hydroxymethyl)pyrrolidin-2-one (commercially available) by protecting its hydroxyl group and pyrrolidine nitrogen with a hydroxyl protecting reagent and an N-protecting reagent, respectively. The hydroxyl group and pyrrolidine may be protected in either order; i.e., the hydroxyl group is protected first to give a compound of formula (IIA): [ka] (In the formula, P 2 is a hydroxyl protecting group (e.g., an ester hydroxyl protecting group such as benzoyl) or the pyrrolidine nitrogen can be first protected to give compound (IIB): [ka] (In the formula, P 1 is H or an N-protecting group). The unprotected pyrrolidine nitrogen or hydroxyl group may then be protected to provide a compound of formula (III). In some embodiments, the N-protecting reagent is (Boc) 2 O and P 1 is Boc. In some embodiments, the hydroxyl protecting reagent is benzoyl chloride, and P 2 is benzoyl.

[0127] Compounds of formula (IX) and (I) In some embodiments, the compound of formula (VIII): [ka] (In the formula, P 1 and P 2 is as defined above) with a hydroxyl protecting group removing agent to give a compound of formula (IX): [ka] wherein P 1 is H or an N-protecting group. The compound of formula (IX) can further be prepared by reacting a compound of formula (I): [ka] (In the formula, P 1is H or an N-protecting group) by oxidizing a primary alcohol to a carboxylic acid. Methods for oxidizing a primary alcohol to a carboxylic acid are well known in the art. In some embodiments, the compound of formula (IX) is oxidized in the presence of (2,2,6,6-tetramethylpiperidin-1-yl)oxyl, sodium hypochlorite, and sodium chlorite. Alternatively, the compound of formula (IX) is oxidized under Jones oxidation conditions (i.e., in the presence of chromium trioxide dissolved in aqueous sulfuric acid) or potassium permanganate (KMnO 4 ), pyridinium chlorochromate (PCC), tetrapropylammonium perruthenate (TPAP), or chromium trioxide / periodic acid (CrO 3 -H 5 IO 6 ) may be used to oxidize the compound of formula (IX).

[0128] In some embodiments, the compound of formula (I) is first reacted with an organic amine to form an organic ammonium salt of the compound of formula (I) (e.g., in an organic solvent such as THF or toluene), and then the organic ammonium salt of the compound of formula (I) is reacted with an acid to reform the compound of formula (I). Suitable organic amines include, but are not limited to, benzylamines and chiral amines, such as α-methylbenzylamine. In some embodiments, the organic amine is benzylamine, which forms the benzylammonium salt of the compound of formula (I).

[0129] Compounds of formula (XI) and (XII) In some embodiments, the compound of formula (I): [ka] (In the formula, P 1 is an N-protecting group) to a compound of formula (X): [ka] or a salt thereof, 1 is H or optionally substituted C 1 -C6 is alkyl, R 2 and R 3 is independently H or methyl; m is 0, 1, or 2; and B is an optionally substituted C 1 -C 6 Alkyl, optionally substituted C 2 -C 6 Alkenyl, optionally substituted C 3 -C 10 Carbocyclyl, optionally substituted C 6 -C 14 aryl, or optionally substituted 5-10 membered heterocyclyl), in an amidation reaction to produce a compound of formula (XI): [ka] (In the formula, P 1 is an N-protecting group, and all other variables are as defined for formula (X). 1 A compound of formula (I) in which is H may be first reacted with an N-protecting agent before coupling with a compound of formula (X) or a salt thereof. Then, P in a compound of formula (XI) is removed using an N-protecting group removing agent. 1 to obtain a compound of formula (XII): [ka] or a salt thereof, wherein all variables are as defined for formula (XI).

[0130] In some embodiments, the N-protected reagent is di-tert-butyl dicarbonate (Boc 20), the reaction is carried out in an organic solvent (e.g., acetonitrile) in the presence of a base (e.g., 4-dimethylaminopyridine), and the N-protecting group is tert-butyl carbonate (Boc). In some embodiments where the N-protecting group is Boc, the deprotection reaction comprises treating the compound of formula (XI) with an acid in an organic solvent. In some embodiments, the acid is hydrogen chloride (4N HCl in dioxane), e.g., the reaction is carried out in dioxane. In some embodiments, the acid is hydrogen bromide (e.g., a 33% HBr solution in acetic acid), e.g., the reaction is carried out in ethyl acetate. In some embodiments, the acid is trifluoroacetic acid, e.g., the reaction is carried out in dichloromethane. Other suitable N-protecting reagents and reaction conditions required for the introduction and removal of N-protecting groups are well known in the art (see, e.g., Wuts, Greene's Protective Groups in Organic Synthesis, Wiley-Interscience, 4th Edition, 2006).

[0131] In some embodiments, the compound of formula (I) and the compound of formula (X), or salts thereof, are coupled in an organic solvent in the presence of a base and a coupling reagent. In some embodiments, the organic solvent is dimethylformamide. In some embodiments, the base is diisopropylethylamine. In some embodiments, the coupling reagent is (1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU).

[0132] Compounds of formula (XI) and (XII) can be prepared, for example, according to the methods described in U.S. Pat. Nos. 10,011,612, 10,287,301, and 10,822,352, and U.S. Patent Publication No. 2020 / 0071301A1, the contents of which are incorporated herein by reference in their entireties.

[0133] Compound of formula (XIV) In some embodiments, the compound of formula (XII): [ka] or a salt thereof, with a compound of formula (XIII): [ka] where variable R 4 , R 5 , R 6 , X 1 , X 2 , X 3 , X 4 , and X 5 is as defined herein) to obtain a compound of formula (XIV): [ka] (XIV), or a pharma- ceutically acceptable salt thereof, wherein all variables are as defined in formulas (XII) and (XIII). In some embodiments, the reaction is carried out using the hydrochloride salt of a compound of formula (XII) and a compound of formula (XIII) in dimethylformamide in the presence of 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate and N,N-diisopropylethylamine. In some embodiments, the reaction is carried out using the hydrobromide salt of a compound of formula (XII) and a compound of formula (XIII) in acetonitrile in the presence of propanephosphonic anhydride and N,N-diisopropylethylamine. In some embodiments, the reaction is carried out using a trifluoroacetate salt of a compound of formula (XII) with a compound of formula (XIII) in dimethylformamide in the presence of N,N-diisopropylethylamine and 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate or 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethylaminium tetrafluoroborate. In some embodiments, the reaction is carried out using a compound of (XIII) and a salt of a compound of formula (XII) (e.g., hydrochloride, hydrobromide, or trifluoroacetate).

[0134] Exemplary compounds of formula (XII), (XIII), and (XIV) and procedures for their synthesis are described, for example, in U.S. Pat. Nos. 10,011,612, 10,287,301, and 10,822,352, and U.S. Patent Publication No. 2020 / 0071301A1, the contents of which are incorporated by reference in their entireties. EXAMPLES

[0135] The examples described herein serve to illustrate the present disclosure, and the present disclosure is not limited to the examples given.

[0136] Example 1: Synthesis of (1R,3S,5R)-2-(tert-butoxycarbonyl)-5-methyl-2-azabicyclo[3.1.0]hexane-3-carboxylic acid [ka] Step 1: Synthesis of (S)-(5-oxopyrrolidin-2-yl)methyl benzoate [ka] CH under nitrogen atmosphere at 25±5℃ 2 Cl 2 (1232 kg) was added to the reactor followed by (S)-5-(hydroxymethyl)-2-pyrrolidinone (154 kg). The temperature of the reaction mixture was then cooled to 0±5°C and 4-(dimethylamino)pyridine (16.94 kg) was added. Triethylamine (158.62 kg) was slowly added to the reaction mixture while maintaining the reaction mixture at 0±5°C. Benzoyl chloride (190.96 kg) was then slowly added to the reaction mixture, under nitrogen atmosphere at 0±5°C and stirred at the same temperature for 3 hours. Then, 5% NaHCO 3 Aqueous solution (approximately 46 Kg) was added and the reaction mixture was warmed to 25±5° C. and stirred. The organic layer was separated, washed with 10% aqueous NaCl solution (770 kg) and concentrated under vacuum to below 40° C., after which n-heptane (209 kg) was added to the reactor. The organic layer was then concentrated and cooled to 25±5° C. A 10% ethyl acetate in heptane solution (546.7 kg) was then added to the reaction mixture from which (S)-(5-oxopyrrolidin-2-yl)methyl benzoate precipitated from solution and was used directly in the next step.

[0137] Step 2: Synthesis of (S)-tert-butyl 2-((benzoyloxy)methyl)-5-oxopyrrolidine-1-carboxylate [ka] The (S)-(5-oxopyrrolidin-2-yl)methyl benzoate was collected by filtration and added to CH 2 Cl2 (1001 kg) and to the resulting solution was added 4-(dimethylamino)pyridine (72.38 kg) at 25±5° C. Di-tert-butyl dicarbonate (495.88 kg) was charged to an addition vessel and added to the reaction mixture at 25±5° C. under nitrogen atmosphere. The reaction mixture was stirred at 25±5° C. for 1 hour, after which water (1540 kg) was added and the reaction mixture was stirred for an additional 10 minutes. The organic layer was separated, washed with 5% HCl (1725 kg) and aqueous NaCl (770 kg) and concentrated under vacuum below 40° C. Subsequently, N-heptane (209 kg) was added to the reactor and the mixture was then concentrated under reduced pressure and cooled to 25±5° C. 10% ethyl acetate in heptane (546.7 kg) was then added to the mixture. The precipitate so formed was collected by filtration and dried to give the title compound (390 kg, 91.3% from step 1), which was characterized by LC-MS and compared with a reference sample.

[0138] Step 3: Synthesis of (S,E)-tert-butyl 5-((benzoyloxy)methyl)-3-((dimethylamino)methylene)-2-oxopyrrolidine-1-carboxylate [ka] 1,2-Dimethoxyethane (234 kg) was charged to the reactor under nitrogen atmosphere followed by the addition of (S)-tert-butyl 2-((benzoyloxy)methyl)-5-oxopyrrolidine-1-carboxylate (180 kg). The reaction mixture was stirred at 25±5° C. for not less than 10 minutes and tert-butyl-bis(dimethylamino)methane (147.6 kg) was added. The reaction temperature was increased to 75±5° C. and maintained until the (S)-tert-butyl 2-((benzoyloxy)methyl)-5-oxopyrrolidine-1-carboxylate was completely consumed as determined by reverse phase HPLC using gradient elution. The reaction temperature was then cooled to 25±5° C. and ethyl acetate (810 kg) and water (900 kg) were added. The reaction mixture was stirred for 10 minutes after which the organic layer was separated and the solvent removed. Heptane (1476 Kg) was added slowly and the mixture was stirred for 60 minutes during which time (S,E)-tert-butyl 5-((benzoyloxy)methyl)-3-((dimethylamino)methylene)-2-oxopyrrolidine-1-carboxylate was obtained as a precipitate. The precipitate was collected by filtration, dried under vacuum and used in the next step without purification.

[0139] Step 4: Synthesis of tert-butyl (5S)-5-((benzoyloxy)methyl)-3-methyl-2-oxopyrrolidine-1-carboxylate [ka] Dry (S,E)-tert-butyl 5-((benzoyloxy)methyl)-3-((dimethylamino)methylene)-2-oxopyrrolidine-1-carboxylate, isopropyl alcohol (IPA; 150 L), and palladium on carbon (10%-50% wet basis, 18 kg) were added to a hydrogenator. 2(4-5 atm) was introduced into the hydrogenator and the reaction mixture was heated to 60±5°C and stirred for 20 hours. The reaction mixture was filtered using Celite and the solvent was removed under reduced pressure with heating at about 30-40°C. To the resulting residue, 20% ethyl acetate in heptane (1750 kg), Celite (36 kg), and silica gel (54 kg) were added and the mixture was stirred at 25±5°C for 60 minutes. The reaction mixture was filtered and the solvent was removed under reduced pressure. The residue was redissolved in toluene (313 kg) and stirred for 10 minutes to obtain a toluene solution of tert-butyl (5S)-5-((benzoyloxy)methyl)-3-methyl-2-oxopyrrolidine-1-carboxylate, which was used directly in the next step.

[0140] Step 5: Synthesis of tert-butyl (5S)-5-((benzoyloxy)methyl)-2-hydroxy-3-methylpyrrolidine-1-carboxylate [ka] Toluene (1131 kg) was charged into the reactor, followed by a toluene solution of tert-butyl (5S)-5-((benzoyloxy)methyl)-3-methyl-2-oxopyrrolidine-1-carboxylate (130 Kg) obtained in the previous step. The solution was then cooled to -65±5°C and lithium triethylborohydride (20% in THF, superhydride) (225.5 Kg) was slowly added to the reactor, after which the reaction mixture was stirred at the same temperature for 1.5 hours. Acetic acid (28.6 kg) in toluene (452.4 kg) was then slowly added to the reaction mixture at -65±5°C and the mixture was warmed to -10±5°C. Sodium hypochlorite solution (1079 kg) at about 4% was then added and the reaction mixture was stirred at -5±5°C for 15 minutes. The organic layer was then separated. About 4% sodium hypochlorite solution (1079 kg) was added to the organic layer and the reaction mixture was then stirred for 15 minutes at -5±5°C. The separation, addition of about 4% sodium hypochlorite solution and stirring was repeated once more after which the organic layer was separated again. The organic layer was washed with water (1300 kg) followed by 10% aqueous sodium chloride solution (715 kg) and then concentrated to approximately 10% w / v of the title compound in solution below 40°C and the reaction mass was cooled to 0±5°C.

[0141] Step 6: Synthesis of (S)-tert-butyl 2-((benzoyloxy)methyl)-4-methyl-2,3-dihydro-1H-pyrrole-1-carboxylate [ka] 2,6-lutidine (91 kg) was charged into the reactor containing the reaction mass obtained from the previous step at 0±5° C. Then, trifluoroacetic anhydride (89.7 kg) was slowly charged into the reactor at 0±5° C. The reaction temperature was increased to 50±5° C. and maintained at the same temperature until (5S)-tert-butyl 5-((benzoyloxy)methyl)-2-hydroxy-3-methylpyrrolidine-1-carboxylate was completely consumed as confirmed by LC-MS. The reaction mixture was diluted with 10% NaHCO 3Water solution (650 kg), 0% aqueous citric acid solution (1430 kg), and 5% aqueous sodium chloride solution (617.5 kg), and then the concentrated organic layer was concentrated to obtain the compound in crude form, which was used directly in the next step.

[0142] Step 7: Synthesis of tert-butyl (1R,3S,5R)-3-((benzoyloxy)methyl)-5-methyl-2-azabicyclo[3.1.0]hexane-2-carboxylate [ka] Toluene (2232 kg) was charged into the reactor at 25±5° C., to which was added (S)-tert-butyl 2-((benzoyloxy)methyl)-4-methyl-2,3-dihydro-1H-pyrrole-1-carboxylate (124 kg). The reaction mixture was cooled to −25±5° C., after which 1.5 M diethylzinc in toluene (595.5 kg) was added slowly under nitrogen atmosphere, followed by gradual addition of chloroiodomethane (405.48 kg). The reaction was warmed to −2±5° C. and stirred for 12 hours, after which 10% NaHCO was added while maintaining the same temperature. 3 Aqueous solution (1116 kg) was added. The reaction mixture was then warmed to 25±5° C. and Celite (37.2 kg) was charged to the reactor. After stirring at 25±5° C. for 10 minutes, the mixture was filtered through a bed of Celite and the layers were separated. The organic layer was washed with 5% aqueous sodium chloride solution (1240 kg) and then the solvent was removed under reduced pressure with heating to give crude (1R,3S,5R)-3-((benzoyloxy)methyl)-5-methyl-2-azabicyclo[3.1.0]hexane-2-carboxylate (95:5 as determined by reverse phase HPLC with gradient elution), which was used directly in the next step.

[0143] Step 8: Synthesis of tert-butyl (1R,3S,5R)-3-(hydroxymethyl)-5-methyl-2-azabicyclo[3.1.0]hexane-2-carboxylate [ka] Crude (1R,3S,5R)-3-((benzoyloxy)methyl)-5-methyl-2-azabicyclo[3.1.0]hexane-2-carboxylate tert-butyl was dissolved in MeOH (979.6 kg) and the solution was cooled to 0±5° C. Then, 25% sodium methoxide solution (73.1 kg) was slowly added to the reaction mixture at 0±5° C. and the mixture was stirred for 2 hours. Then, water (1240 kg) was slowly added and the reaction mixture was stirred at 25±5° C. for 8 hours. Then, ethyl acetate (8.89 w / w) was charged into the reaction mixture and the layers were separated. The organic layer was washed with 5% aqueous sodium chloride solution (620 kg) and concentrated under vacuum below 45° C. to obtain crude (1R,3S,5R)-3-(hydroxymethyl)-5-methyl-2-azabicyclo[3.1.0]hexane-2-carboxylate tert-butyl, which was used directly in the next step.

[0144] Step 9: Synthesis of (1R,3S,5R)-2-(tert-butoxycarbonyl)-5-methyl-2-azabicyclo[3.1.0]hexane-3-carboxylic acid [ka] Acetonitrile (169.3 kg) and crude (1R,3S,5R)-3-(hydroxymethyl)-5-methyl-2-azabicyclo[3.1.0]hexane-2-carboxylate (42.96 kg) were charged to a reactor and stirred at 25±5° C. for 5-10 minutes, after which monobasic sodium phosphate solution (107.4 kg in 232.0 kg water), TEMPO (3.01 kg), sodium chlorite solution (12.89 kg in 30.1 kg water) were added. The reaction mixture was stirred below 35° C. for 8 hours. Sodium sulfite solution (171.84 kg in 859.2 kg water) was then added slowly at 20±5° C. After stirring the reaction mixture for 10 minutes, aqueous NaOH was added until the mixture reached a pH of 9-10, and the mixture was extracted with methyl tert-butyl ether (MTBE; 159.0 kg) and the organic layer was discarded. The aqueous layer was adjusted to pH 2-3 with 2M aqueous HCl and extracted with ethyl acetate (382.3 kg), the organic layer thus obtained was washed with 5% aqueous sodium chloride solution (451.1 kg), isolated and concentrated under vacuum at less than 55°C. THF (176.1 kg) and 2M benzylamine in THF (21.48 kg benzylamine in 77.3 kg THF) were then added at 15±5°C, the reaction mixture was then stirred at less than 30°C for 12 hours and then cooled to 0°C±5°C, during which time the benzylammonium salt of (1R,3S,5R)-2-(tert-butoxycarbonyl)-5-methyl-2-azabicyclo[3.1.0]hexane-3-carboxylic acid precipitated out of solution and was collected by filtration. The filtered solid was washed with aqueous HCl (98.8 kg in 859 kg water) and CH 2 Cl 2 (257.8 Kg) was added, then the organic layer was washed with 5% aqueous sodium chloride (451.1 kg) and concentrated under vacuum at less than 45° C. Heptane was added to the resulting residue, then a solid formed. The solid was collected by filtration and dried under vacuum at less than 35° C. to give 18.32 kg (40.2%) of the title compound. 1 H NMR (400 MHz, DMSO-d 6) d 12.42 (s, 1H), 3.85 (t, 1H), 3.06 (m, 1H), 2.40 (m, 1H), 1.85 (m, 1H), 1.36 (m, 9H), 1.17 (s, 3H), 0.63 (m, 2H). HPLC: Retention time 19.039; purity 95%. Chiral HPLC: Retention time 8.964 minutes; purity 99.7%.

[0145] Reversed-phase HPLC with gradient program and DAD / VWD detection technique was performed using an Agilent 1200 / 1260 HPLC series system equipped with an Atlantis T3 (150×4.6 mm, 3 μm) and DAD / VWD (or equivalent) at a column temperature of 40° C. under the following conditions: [Table 1] UV detection was performed at 210 nm.

[0146] Chiral HPLC was performed using a CHIRALPAK® IG-3, 250×4.6 mm, 3 μm column at a column temperature of 40° C. The isocratic mobile phase was formed by mixing 70% aqueous trifluoroacetic acid (0.1%) and 30% acetonitrile and applied at a flow rate of 0.8 mL / min for 30 min. UV detection was performed at 210 nm. Samples were dissolved in methanol at 1 mg / ml. The injection volume was 5 μL.

[0147] Other embodiments Various modifications and variations of the disclosed compositions and methods are 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 described in the claims, should not be unduly limited to such specific embodiments.In fact, various modifications of the described methods for carrying out the disclosed methods that are apparent to those skilled in the art are intended to be within the scope of the disclosure.

[0148] Other embodiments are within the claims.

Claims

1. A process for preparing a compound of formula (VIII): 【Chemical 86】 In the formula, P １ is H or an N-protecting group, P ２ is H or a hydroxyl protecting group, and said process comprises providing a compound of formula (VII): 【Transformation 87】 wherein P １ is H or an N-protecting group, and P ２ is H or a hydroxyl protecting group, and said process also comprises: forming a compound of formula (VIII) from a compound of formula (VII), wherein forming the compound of formula (VIII) comprises reacting the compound of formula (VII) under Simmons-Smith reaction conditions.

2. Providing a compound of formula (VII) Compound of formula (VI): 【Chemical 88】 wherein P １ is an N-protecting group, and P ２ is a hydroxyl protecting group, and said method also comprises:

2. The method of claim 1, comprising subjecting the compound of formula (VI) to a dehydration reaction.

3. Providing a compound of formula (VI) Compound of formula (V): 【Chemical 89】 wherein P １ is an N-protecting group, and P ２ is a hydroxyl protecting group, and said method also comprises:

3. The method of claim 2, comprising reacting the compound of formula (V) with a reducing agent.

4. Providing a compound of formula (V) Compound of formula (IV): [Chemical 90] wherein P １ is H or an N-protecting group, and P ２ is H or a hydroxyl protecting group, and said process also comprises:

4. The method of claim 3, comprising subjecting the compound of formula (IV) to a hydrogenolysis reaction in the presence of a hydrogenation catalyst.

5. Providing a compound of formula (IV) Compounds of formula (III): 【Chemistry 91】 wherein P １ is an N-protecting group, and P ２ is a hydroxyl protecting group, and said method also comprises:

5. The method of claim 4, comprising reacting the compound of formula (III) with Bredereck's reagent.

6. Providing a compound of formula (III) Compound of formula (IIA): 【Chemistry 92】 wherein P ２ is a hydroxyl protecting group, and said method also comprises: reacting said compound of formula (IIA) with an N-protecting reagent; or Compound of formula (IIB): 【Chemistry 93】 wherein P １ is an N-protecting group, and said process also comprises 6. The method of claim 5, comprising reacting the compound of formula (IIB) with a hydroxyl protecting reagent.

7. P of formula (VIII) ２ is a hydroxyl protecting group, and the method further comprises reacting the compound of formula (VIII) with a hydroxyl protecting group removing agent to produce a compound of formula (IX): 【Chemical 94】 2. The method of claim 1, comprising forming: wherein P 1 is H or an N-protecting group.

8. P of formula (IX) １ is an N-protecting group, and the method further comprises forming a compound of formula (I) from the compound of formula (IX), wherein the compound of formula (I) has the structure: 【Chemical 95】 wherein P 1 is H or an N-protecting group; 8. The method of claim 7, wherein forming the compound of formula (I) comprises oxidizing the compound of formula (IX).

9. reacting the compound of formula (I) with an organic amine to form an organic ammonium salt of the compound of formula (I); 9. The method of claim 8, further comprising reacting the organic ammonium salt of the compound of formula (I) with an acid to form the compound of formula (I).

10. P in formula (I) １ is an N-protecting group, and the method further comprises converting the compound of formula (I) to a compound of formula (X): 【Chemistry 96】 or a salt thereof, wherein R １ is H or optionally substituted C １ -C ６ is alkyl, R ２ and R ３ each is independently H or methyl; m is 0, 1, or 2; B is optionally substituted C １ -C ６ Alkyl, optionally substituted C ２ -C ６ Alkenyl, optionally substituted C ３ -C １０ Carbocyclyl, optionally substituted C ６ -C １４ aryl, or optionally substituted 5- to 10-membered heterocyclyl, Compound of formula (XI): 【Chemistry 97】 wherein: P １ is an N-protecting group and all other variables are as defined for formula (X), and said process also comprises: The compound of formula (XI) is reacted with an N-protecting group removing agent to give a compound of formula (XII): 【Chem.98】 9. The method of claim 8, comprising forming: (XI), or a salt thereof, wherein all variables are as defined for formula (XI).

11. The compound of formula (XII) or a salt thereof is reacted with a compound of formula (XIII): 【Chem.99】 or a salt thereof, wherein R ４ But, H, halo, OH, NH ２ , cyano, optionally substituted C １ -C ６ Alkyl, optionally substituted C ２ -C ６ alkenyl, optionally substituted 3- to 8-membered heterocyclyl, —C(O)NR ａ R ａ ' and R ａ and R ａ ’ each independently represents H, optionally substituted C １ -C ６ Alkyl, optionally substituted C ２ -C ６ Alkenyl, optionally substituted C ２ -C ６ Alkynyl or optionally substituted C ３ -C ８ cycloalkyl, —C(O)R ｂ , -OC(O)R ｂ , or —C(O)OR ｂ and R ｂ are each H, optionally substituted C １ -C ６ Alkyl, optionally substituted C １ -C ６ Alkoxy, and optionally substituted C ３ -C ８ carbocyclyl, R ５ and R ６ each independently represents H or an optionally substituted C １ -C ６ is alkyl, X １ But N or CR ｃ and R ｃ is H, halo, optionally substituted C １ -C ６ alkyl, or optionally substituted C １ -C ６ is an alkoxy, X ２ and X ５ each independently represents N or CR ｄ and each R ｄ are independently H, halo, cyano, optionally substituted C １ -C ６ Alkyl, optionally substituted C １ -C ６ Alkoxy, optionally substituted C ３ -C ８ carbocyclyl, and optionally substituted 5- to 8-membered heteroaryl; and X ３ and X ４ each independently represents N, CR ｅ , and C.R. ｆ and R ｅ is H, halo, cyano, optionally substituted C １ -C ６ Alkyl, optionally substituted C １ -C ６ Alkoxy, and —C(O)OR ｇ is selected from In the formula, R ｇ is H or optionally substituted C １ -C ６ alkyl, and R ｆ is optionally substituted C ４ -C １０ aryl, optionally substituted 5- to 10-membered heteroaryl having 1, 2, or 3 heteroatoms selected from N, O, and S, optionally substituted 4- to 10-membered saturated or unsaturated non-aromatic heterocyclyl having 1 to 4 heteroatoms selected from N, O, and S; ３ and X ４ At least one of the following is CR ｆ and performing the coupling to Compound of formula (XIV): 【Chemistry 100】 or a pharmaceutically acceptable salt thereof, wherein R １ , R ２ , R ３ 11. The method of claim 10, wherein m, B, and B are as defined for formula (XII), and all other variables are as defined for formula (XIII).

12. R １ 12. The method of claim 10 or 11, wherein is H and / or m is 0.

13. 12. The method of claim 10 or 11, wherein B is an optionally substituted 6-membered heteroaryl.

14. B, 【Chemistry 101】 【Chemical Engineering 102】 【Chemistry 103】 The method of claim 13, wherein

15. B is 【Chemical 104】 The method of claim 14, wherein

16. 12. The method of claim 10 or 11, wherein B is an optionally substituted 5-membered heteroaryl.

17. B, 【Chemistry 109】 17. The method of claim 16, wherein:

18. 12. The method of claim 10 or 11, wherein B is optionally substituted phenyl.

19. B, 【Chemistry 111】 19. The method of claim 18, wherein:

20. X １ is N or CH; and / or X 2 is CH or C(CH 3 ); and / or X 5 is CH; and / or X 3 is N or CH and X 4 is CR f ; and / or R 4 is —C(O)R b or —C(O)NR a R a ′; and / or R 5 is H; and / or 12. The method of claim 10 or 11, wherein R6 is H.

21. R ｆ 21. The method of claim 20, wherein is an optionally substituted 5-10 membered heteroaryl having 1, 2, or 3 heteroatoms selected from N, O, and S.

22. R ｆ 22. The method of claim 21, wherein is a 6-membered heteroaryl having 1, 2, or 3 heteroatoms selected from N, O, and S.

23. R ｆ but, 【Chemistry 116】 【Chemistry 117】 23. The method of claim 22, wherein:

24. R ｆ but 【Chemistry 118】 24. The method of claim 23, wherein:

25. R ｆ 22. The method of claim 21, wherein is an optionally substituted 8-10 membered bicyclic heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S.

26. R ｆ but, 【Chemical 120】 26. The method of claim 25, wherein:

27. R ４ but, 【Chemistry 126】 21. The method of claim 20, wherein:

28. R ４ but 【Chemistry 127】 28. The method of claim 27, wherein:

29. The compound of formula (XIV) 【Chemistry 132】 or a pharmaceutically acceptable salt thereof.

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