Macrocyclic HCV NS3 inhibits the synthesis of tripeptides.

Abstract

This disclosure relates to the synthesis of a macrocyclic HCV NS3 inhibitory tripeptide. This disclosure provides a method for preparing a compound of formula I that can be used as an antiviral agent. This disclosure also provides a compound as a synthetic intermediate for a compound of formula I and a method for preparing that compound.

Description

[0001] This application is a divisional application of patent application No. 201480070017.2, filed on December 18, 2014, entitled "Synthesis of macrocyclic HCV NS3 inhibitory tripeptide", and application No. 202010152008.5, filed on December 18, 2014, entitled "Synthesis of macrocyclic HCV NS3 inhibitory tripeptide". Background Technology

[0002] This application claims priority to U.S. Provisional Application No. 61 / 920,446, filed December 23, 2013, based on 35 USC §119(e), the entire contents of which are incorporated herein by reference.

[0003] This disclosure generally relates to the field of organic synthetic methods for preparing compounds of inhibitors of Flaviviridae viruses and synthetic intermediates thereof.

[0004] Hepatitis C virus (HCV), a member of the genus *Hepatitisvirus* in the family Flaviviridae, is a leading cause of chronic liver disease worldwide (Boyer, N. et al., *J Hepatol.* 2000, 32, 98-112). Therefore, current antiviral research focuses primarily on developing improved methods for treating chronic HCV infection in humans (Ciesek, S., von Hahn T. and Manns, MP., *Clin. Liver Dis.* 2011, 15, 597-609; Soriano, V. et al., *J. Antimicrob. Chemother.* 2011, 66, 1573-1686; Brody, H., *Nature Outlook* 2011, 474, S1-S7; Gordon, CP et al., *J. Med. Chem.* 2005, 48, 1-20; Maradpour, D. et al., *Nat. Rev. Micro.* 2007, 5, 453-463).

[0005] Virological cure for chronic HCV infection is difficult to achieve due to the large daily viral load in patients with chronic infection and the high spontaneous mutation rate of HCV (Neumann et al., Science 1998, 282, 103-7; Fukimoto et al., Hepatology, 1996, 24, 1351-4; Domingo et al., Gene 1985, 40, 1-8; Martell et al., J. Virol. 1992, 66, 3225-9). HCV treatment is further complicated by the fact that HCV is genetically diverse and expressed as several different genotypes and multiple subtypes. For example, HCV is currently classified into six major genotypes (named 1-6), many subtypes (named a, b, c, etc.), and approximately 100 different strains (numbered 1, 2, 3, etc.).

[0006] Globally, HCV is mainly distributed in the United States, Europe, Australia, Thailand, and East Asia (Japan and China) with genotypes 1, 2, and 3. Genotype 4 is mainly found in the Middle East, Egypt, and Central Africa, while genotypes 5 and 6 are mainly found in South Africa and Southeast Asia, respectively (Simmonds, P. et al., J Virol. 84:4597-4610, 2010).

[0007] Effective treatments for HCV infection still need to be developed. Suitable compounds for treating HCV infection are disclosed in U.S. Publication No. 2014-0017198, filed July 2, 2013, entitled “Inhibitors of hepatitis C virus,” which includes compounds of formula I:

[0008] Summary of the Invention

[0009] This paper presents an improved method for preparing compounds of formula I, offering several advantages over known syntheses. Specifically, route I disclosed herein uses a ring-closure metathesis step at a different position than previously disclosed routes. This results in several advantages over disclosed syntheses, such as higher efficiency and higher overall yield. Furthermore, routes II and III provide novel synthetic pathways for compounds of formula I.

[0010] This disclosure provides, in one embodiment, a method for preparing a compound of formula I or a eutectic or salt thereof, wherein the compound of formula I is named (1aR,5S,8S,9S,10R,22aR)-5-tert-butyl-N-[(1R,2R)-2-(difluoromethyl)-1-{[(1-methylcyclopropyl)sulfonyl]carbamoyl}cyclopropyl]-9-ethyl-18,18-difluoro-14-methoxy-3,6-dioxo-1,1a,3,4,5,6,9,10,18,19,20,21,22,22a-tetradecanohydro-8H-7,10-methylbridged cyclopropano[18,19][1,10,3,6]dioxadiazaaranenonadecanocyclo[11,12-b]quinoxaline-8-carboxamide.

[0011]

[0012] In another embodiment, this disclosure provides a method for preparing compounds of formula V or their eutectic or salt:

[0013]

[0014] This includes contacting a compound of formula III or its eutectic or salt with a compound of formula IV under O-arylation conditions to provide a compound of formula V or its eutectic or salt:

[0015]

[0016] Where R is C 1-6 Alkyl groups, PG is a protecting group and R 1 It is a leaving group.

[0017] In another embodiment, this disclosure provides a method for preparing a compound of formula VI or its eutectic or salt:

[0018]

[0019] This includes subjecting a compound of formula V or its eutectic or salt to N-deprotection conditions to provide a compound of formula VI or its eutectic or salt:

[0020]

[0021] Where R is C 1-6 Alkyl groups and PG are protecting groups.

[0022] In another embodiment, this disclosure provides a method for preparing a compound of formula VIII or its eutectic or salt:

[0023]

[0024] This includes contacting a compound of formula VI or its eutectic or salt with a compound of formula VII or its eutectic or salt under amide coupling conditions to provide a compound of formula VIII or its eutectic or salt:

[0025]

[0026]

[0027] Where R is C 1-6 alkyl.

[0028] In another embodiment, this disclosure provides a method for preparing a compound of formula IX or its eutectic or salt:

[0029]

[0030] This includes the cyclic metathesis of a compound of formula VIII or its eutectic or salt to provide a compound of formula IX or its eutectic or salt:

[0031]

[0032] Where R is C 1-6 alkyl.

[0033] In another embodiment, this disclosure provides a method for preparing a compound of formula I (named (1aR,5S,8S,9S,10R,22aR)-5-tert-butyl-N-[(1R,2R)-2-(difluoromethyl)-1-{[(1-methylcyclopropyl)sulfonyl]carbamoyl}cyclopropyl]-9-ethyl-18,18-difluoro-14-methoxy-3,6-dioxo-1,1a,3,4,5,6,9,10,18,19,20,21,22,22a-tetradecanohydro-8H-7,10-methylbridged cyclopropano[18,19][1,10,3,6]dioxadiazaaranenonadecanocyclo[11,12-b]quinoxaline-8-carboxamide) or its cocrystal or salt thereof:

[0034]

[0035] include:

[0036] a) Contacting a compound of formula III or its eutectic or salt with a compound of formula IV under O-arylation conditions to provide a compound of formula V or its eutectic or salt:

[0037]

[0038] b) Subjecting a compound of formula V, or its eutectic or salt thereof, to N-deprotection conditions to provide a compound of formula VI, or its eutectic or salt thereof:

[0039]

[0040] c) Contacting a compound of formula VI or its eutectic or salt with a compound of formula VII or its eutectic or salt under amide coupling conditions to provide a compound of formula VIII or its eutectic or salt:

[0041]

[0042] d) Perform ring-closure metathesis of a compound of formula VIII or its eutectic or salt to provide a compound of formula IX or its eutectic or salt:

[0043]

[0044] e) Hydrogenating a compound of formula IX or its eutectic or salt in the presence of a catalyst to provide a compound of formula X or its eutectic or salt:

[0045]

[0046] f) Hydrolyze a compound of formula X or its eutectic or salt to provide a compound of formula XI or its eutectic or salt:

[0047]

[0048] g) Contacting a compound of formula XI or its eutectic or salt with a compound of formula XII or its eutectic or salt under amide coupling conditions to provide a compound of formula I or its eutectic or pharmaceutically acceptable salt:

[0049]

[0050] Where R is C 1-6 Alkyl groups, PG is a protecting group and R 1 It is a leaving group.

[0051] In another embodiment, this disclosure provides a method for preparing a compound of formula XVIII or its eutectic or salt:

[0052]

[0053] Including hydrolyzable compounds of formula VIII or their eutectic or salt to provide compounds of formula XVIII or their eutectic or salt:

[0054]

[0055] Where R is C 1-6 alkyl.

[0056] In another embodiment, this disclosure provides a method for preparing a compound of formula XIX or its eutectic or salt:

[0057]

[0058] This includes the cyclic metathesis of compounds of formula XVIII or their eutectic or salt in the presence of a catalyst to provide compounds of formula XIX.

[0059] In another embodiment, this disclosure provides a method for preparing a compound of formula XI or its eutectic or salt:

[0060]

[0061] This includes hydrogenating a compound of formula XIX or its eutectic or salt in the presence of a catalyst to provide a compound of formula XI or its eutectic or salt:

[0062]

[0063] In another embodiment, this disclosure provides a method for preparing a compound of formula I (named (1aR,5S,8S,9S,10R,22aR)-5-tert-butyl-N-[(1R,2R)-2-(difluoromethyl)-1-{[(1-methylcyclopropyl)sulfonyl]carbamoyl}cyclopropyl]-9-ethyl-18,18-difluoro-14-methoxy-3,6-dioxo-1,1a,3,4,5,6,9,10,18,19,20,21,22,22a-tetradecano-8H-7,10-methylbridged cyclopropano[18,19][1,10,3,6]dioxadiazaarnedodecano[11,12-b]quinoxaline-8-carboxamide) or a cocrystal or pharmaceutically acceptable salt thereof:

[0064]

[0065] include:

[0066] a) Contacting a compound of formula III or its eutectic or salt with a compound of formula IV under O-arylation conditions to provide a compound of formula V or its eutectic or salt:

[0067]

[0068] b) Subjecting a compound of formula V, or its eutectic or salt thereof, to N-deprotection conditions to provide a compound of formula VI, or its eutectic or salt thereof:

[0069]

[0070] c) Contacting a compound of formula VI or its eutectic or salt with a compound of formula VII or its eutectic or salt under amide coupling conditions to provide a compound of formula VIII or its eutectic or salt:

[0071]

[0072] d) Hydrolyzing a compound of formula VIII or its eutectic or salt to provide a compound of formula XVIII or its eutectic or salt:

[0073]

[0074] e) To perform ring-closure metathesis of a compound of formula XVIII or its eutectic or salt in the presence of a catalyst to provide a compound of formula XIX or its eutectic or salt:

[0075]

[0076] f) Hydrogenating a compound of formula XIX in the presence of a catalyst to provide a compound of formula XI or its eutectic or salt:

[0077]

[0078] g) Contacting a compound of formula XI or its eutectic or salt with a compound of formula XII or its eutectic or salt under amide coupling conditions to provide a compound of formula I or its eutectic or salt:

[0079]

[0080] Where R is C 1-6 Alkyl groups, PG is a protecting group and R 1 It is a leaving group.

[0081] In another embodiment, this disclosure provides a method for preparing a compound of formula XV or its eutectic or salt:

[0082]

[0083] This includes contacting a compound of formula XIII or its eutectic or salt with a compound of formula XIV or its eutectic or salt under cross-metathesis conditions to provide a compound of formula XV or its eutectic or salt:

[0084]

[0085] Where R is C 1-6 Alkyl groups and PG are protecting groups.

[0086] In another embodiment, this disclosure provides a method for preparing a compound of formula XVI or its eutectic or salt:

[0087]

[0088] This includes hydrogenating a compound of formula XV or its eutectic or salt in the presence of a catalyst to provide a compound of formula XVI or its eutectic or salt:

[0089]

[0090] Where R is C 1-6 Alkyl groups and PG are protecting groups.

[0091] In another embodiment, this disclosure provides a method for preparing compounds of formula XVII or their eutectic or salt:

[0092]

[0093] This includes subjecting compounds of formula XVI or their eutectic or salt to N-deprotection conditions to provide compounds of formula XVII or their eutectic or salt:

[0094]

[0095] Where R is C 1-6 Alkyl groups and PG are protecting groups.

[0096] In another embodiment, this disclosure provides a method for preparing a compound of formula X or its eutectic or salt:

[0097]

[0098] This includes contacting a compound of formula XVII with an amide coupling agent under lactamation conditions to provide a compound of formula X or its eutectic or salt, wherein R is C 1-6 alkyl.

[0099] In another embodiment, this disclosure provides a method for preparing a compound of formula I (named (1aR,5S,8S,9S,10R,22aR)-5-tert-butyl-N-[(1R,2R)-2-(difluoromethyl)-1-{[(1-methylcyclopropyl)sulfonyl]carbamoyl}cyclopropyl]-9-ethyl-18,18-difluoro-14-methoxy-3,6-dioxo-1,1a,3,4,5,6,9,10,18,19,20,21,22,22a-tetradecanohydro-8H-7,10-methylbridged cyclopropano[18,19][1,10,3,6]dioxadiazaaranenonadecanocyclo[11,12-b]quinoxaline-8-carboxamide) or its cocrystal or salt thereof:

[0100]

[0101] include:

[0102] a) Contacting a compound of formula XIII or its eutectic or salt with a compound of formula XIV or its eutectic or salt under cross-metathesis conditions to provide a compound of formula XV or its eutectic or salt:

[0103]

[0104] b) Hydrogenating a compound of formula XV or its eutectic or salt in the presence of a catalyst to provide a compound of formula XVI or its eutectic or salt:

[0105]

[0106] c) Subjecting a compound of formula XVI or its eutectic or salt to N-deprotection conditions to provide a compound of formula XVII or its eutectic or salt:

[0107]

[0108] d) Contacting a compound of formula XVII with an amide coupling agent under lactamation conditions to provide a compound of formula X or its eutectic or salt:

[0109]

[0110] e) Hydrolyzing a compound of formula X or its eutectic or salt to provide a compound of formula XI or its eutectic or salt:

[0111]

[0112] f) Contacting a compound of formula XI or its eutectic or salt with a compound of formula XII or its eutectic or salt under amide coupling conditions to provide a compound of formula I or its eutectic or salt:

[0113]

[0114] R is C 1-6 Alkyl groups and PG are protecting groups.

[0115] In another embodiment, this disclosure provides a method for preparing a Vv compound or its eutectic or salt:

[0116]

[0117] include:

[0118] a) Hydrolyzed Ab compounds or their eutectic or salt to provide Ac compounds or their eutectic or salt:

[0119]

[0120] b) Contacting a compound of formula Ac or its eutectic or salt with dicyclohexylamine to provide a compound of formula Ag or its eutectic or salt:

[0121]

[0122] c) Contacting Ag or its eutectic or salt with cinconidine to provide a compound of formula Ah or its eutectic or salt:

[0123]

[0124] d) Subjecting Ah or its eutectic or salt to a Coultis rearrangement in the presence of tert-butanol to provide a compound of formula Ai or its eutectic or salt:

[0125]

[0126] e) Hydrolysis of Ai or its eutectic or salt to provide Vv or its eutectic or salt.

[0127] In another embodiment, this disclosure provides a compound of formula IV or its eutectic or salt:

[0128] Where R 1 It is a leaving group.

[0129] In another embodiment, this disclosure provides a compound of formula V or its eutectic or salt:

[0130] Where R is C 1-6 Alkyl groups and PG are protecting groups.

[0131] In another embodiment, this disclosure provides a compound of formula VI or its eutectic or salt:

[0132] Where R is C 1-6 alkyl.

[0133] In another embodiment, this disclosure provides a compound of formula VII or its eutectic or salt:

[0134] In another embodiment, this disclosure provides a compound of formula VIII or its eutectic or salt:

[0135] Where R is C 1-6 alkyl.

[0136] In another embodiment, this disclosure provides compounds of formula XIII or their eutectic or salt:

[0137]

[0138] In another embodiment, this disclosure provides compounds of formula XIV or their eutectic or salt:

[0139]

[0140] Where R is C 1-6 Alkyl groups and PG are protecting groups.

[0141] In another embodiment, this disclosure provides compounds of formula XV or their eutectic or salt:

[0142]

[0143] Where R is C 1-6 Alkyl groups and PG are protecting groups.

[0144] In another embodiment, this disclosure provides compounds of formula XVI or their eutectic or salt:

[0145]

[0146] Where R is C 1-6 Alkyl groups and PG are protecting groups.

[0147] In another embodiment, this disclosure provides compounds of formula XVII or their eutectic or salt:

[0148]

[0149] Where R is C 1-6 alkyl.

[0150] In another embodiment, this disclosure provides compounds of formula XVIII or their eutectic or salt:

[0151]

[0152] In another embodiment, this disclosure provides compounds of formula XIX or their eutectic or salt:

[0153] In another embodiment, this disclosure provides a compound of formula IV-d or its eutectic or salt:

[0154] In another embodiment, this disclosure provides compounds of formula M3 or their eutectic or salt:

[0155] In another embodiment, this disclosure provides a compound of formula IV-a or its eutectic or salt:

[0156] In another embodiment, this disclosure provides a compound of formula IV-b or its eutectic or salt:

[0157] In another embodiment, this disclosure provides a compound of formula IV-c or its eutectic or salt:

[0158] More detailed implementation methods are described below. Detailed Implementation

[0159] definition

[0160] As used in this specification, the following words and phrases are generally intended to have the meanings given below, unless the context in which they are used indicates otherwise.

[0161] As used herein, the term "alkyl" refers to a straight-chain or branched saturated hydrocarbon having the indicated number of carbon atoms. For example, (C1-C8)alkyl means including, but not limited to, methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, isohexyl, and neohexyl. In certain embodiments, the alkyl group has 1-20 carbon atoms. The alkyl group may be unsubstituted or optionally substituted with one or more substituents described throughout this document.

[0162] The term "substituted alkyl" refers to:

[0163] 1) An alkyl group as defined above having 1, 2, 3, 4 or 5 substituents selected from the following (1, 2 or 3 substituents in some embodiments): alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkenyl, cycloalkoxy, cycloalkenyloxy, acyl, amide, acyloxy, amino, substituted amino, aminocarbonyl, alkoxycarbonylamino, azide, cyano, halogen, hydroxyl, ketone, thiocarbonyl, carboxyl, carboxylalkyl, arylthio, heteroarylthio, heterocyclic thio, mercapto, alkylthio, aryl, aryloxy, heteroaryl, aminosulfonyl, aminocarbonylamino, heteroaryloxy, heterocyclic, heterocyclic, hydroxylamino, alkoxyamino, nitro, -SO-alkyl, -SO-cycloalkyl, -SO-heterocyclic, -SO-aryl, -SO-heteroaryl, -SO2-alkyl, -SO2-cycloalkyl, -SO2-heterocyclic, -SO2-aryl and -SO2-heteroaryl. Unless otherwise defined, all substituents may optionally be further substituted with one, two, or three substituents selected from the following: alkyl, alkenyl, alkynyl, carboxyl, carboxyalkyl, aminocarbonyl, hydroxyl, alkoxy, halogen, CF3, amino, substituted amino, cyano, cycloalkyl, heterocyclic, aryl, heteroaryl, and -S(O). n R a , where R a It is an alkyl, aryl, or heteroaryl group and n is 0, 1, or 2; or

[0164] 2) An alkyl group as defined above, independently interrupted by 1-10 atoms (e.g., 1, 2, 3, 4, or 5 atoms) selected independently of oxygen, sulfur, and NRa, wherein Ra is selected from hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heteroaryl, and heterocyclic groups. All substituents may optionally be further distinguished by alkyl, alkenyl, alkynyl, carboxyl, carboxyalkyl, aminocarbonyl, hydroxyl, alkoxy, halogen, CF3, amino, substituted amino, cyano, cycloalkyl, heterocyclic, aryl, heteroaryl, and -S(O). n R a Replace, where Ra It is an alkyl, aryl, or heteroaryl group and n is 0, 1, or 2, or

[0165] 3) Alkyl groups as defined above that have 1, 2, 3, 4 or 5 substituents as defined above and are also interrupted by 1 to 10 atoms (e.g., 1, 2, 3, 4 or 5 atoms) as defined below.

[0166] As used herein, the term “interrupted” means that a carbon atom of a group (e.g., an alkyl group) is replaced by a heteroatom.

[0167] The term "alkylene" refers to a dimethyl group of a branched or unbranched saturated hydrocarbon chain having 1 to 20 carbon atoms (e.g., 1 to 10 carbon atoms or 1, 2, 3, 4, 5, or 6 carbon atoms). Examples of this term include groups such as methylene (-CH2-), ethylene (-CH2CH2-), and propylene isomers (e.g., -CH2CH2CH2- and -CH(CH3)CH2-).

[0168] The term "aralkyl" refers to an aryl group covalently linked to an alkylene group, wherein the aryl group and the alkylene group are as defined herein. "Optionally substituted aralkyl" refers to an aryl group covalently linked to an optionally substituted alkylene group. Examples of such aralkyl groups include benzyl, phenylethyl, and 3-(4-methoxyphenyl)propyl.

[0169] The term "aralkyloxy" refers to an -O-aralkyl group. "Optionally substituted aralkyloxy" refers to an optionally substituted aralkyl group covalently linked to an optionally substituted alkylene group. Examples of such aralkyl groups include benzyloxy and phenylethoxy.

[0170] The term "alkenyl" refers to a monomolecular unsaturated hydrocarbon group having 2-20 carbon atoms (in some embodiments, 2-10 carbon atoms, e.g., 2-6 carbon atoms) and 1-6 carbon-carbon double bonds (e.g., 1, 2, or 3 carbon-carbon double bonds). In some embodiments, alkenyl includes vinyl (or vinyl, i.e., -CH=CH2), 1-propenyl (or allyl, i.e., -CH2CH=CH2), isopropenyl (-C(CH3)=CH2), etc.

[0171] The term "lower alkenyl" refers to alkenyl groups as defined above that have 2 to 6 carbon atoms.

[0172] The term "substituted alkenyl" refers to an alkenyl group as defined above, having 1 to 5 substituents (in some embodiments, 1, 2, or 3 substituents) as defined above for substituted alkyl groups.

[0173] In some embodiments, the term "alkynyl" refers to a monomer of an unsaturated hydrocarbon having 2-20 carbon atoms (in some embodiments, 2-10 carbon atoms, for example, 2-6 carbon atoms) and 1-6 carbon-carbon triple bonds (e.g., 1, 2, or 3 carbon-carbon triple bonds). In some embodiments, alkynyl includes ethynyl (-C≡CH), propynyl (or propynyl, i.e., -C≡CCH3), etc.

[0174] The term "substituted alkynyl" refers to an alkynyl group as defined above, having 1 to 5 substituents (in some embodiments, 1, 2, or 3 substituents) as defined above for substituted alkyl groups.

[0175] The term "hydroxyl" or "hydroxyl group" refers to the -OH group.

[0176] The term "alkoxy" refers to an -OR group, where R is an alkyl group or -YZ, where Y is an alkylene group and Z is an alkenyl or alkynyl group, wherein the alkyl, alkenyl, and alkynyl groups are as defined herein. In some embodiments, the alkoxy group is alkyl-O- and includes, for example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, 1,2-dimethylbutoxy, etc.

[0177] The term "cycloalkyl" refers to a cyclic alkyl group having 3 to 20 carbon atoms, either a single cyclic ring or multiple fused rings. Such cycloalkyl groups include, for example, monocyclic structures such as cyclopropyl, cyclobutyl, cyclopentyl, cyclooctyl, etc., or polycyclic structures such as adamantyl and bicyclic [2.2.1]heptyl, or cyclic alkyl groups fused with aryl groups (e.g., indanyl, etc.), provided that the connecting point is through the cyclic alkyl group.

[0178] The term "cycloalkenyl" refers to a cycloalkyl group having a single cyclic ring or multiple fused rings and having at least one double bond and, in some embodiments, 3-20 carbon atoms with 1-2 double bonds.

[0179] The terms "substituted cycloalkyl" and "substituted cycloalkenyl" refer to cycloalkyl or cycloalkenyl groups having 1, 2, 3, 4, or 5 substituents selected from the following (in some embodiments, 1, 2, or 3 substituents): alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkoxy, cycloalkenyloxy, acyl, amide, acyloxy, amino, substituted amino, aminocarbonyl, alkoxycarbonylamino, azide, cyano, halogen, hydroxyl, ketone, thiocarbonyl, carboxyl, carboxyl The terms "substituted cycloalkyl" also include alkyl groups, such as arylthio, heteroarylthio, heterocyclic thio, mercapto, alkylthio, aryl, aryloxy, heteroaryl, aminosulfonyl, aminocarbonylamino, heteroaryloxy, heterocyclic, heterocyclic, hydroxyamino, alkoxyamino, nitro, -SO-alkyl, -SO-cycloalkyl, -SO-heterocyclic, -SO-aryl, -SO-heteroaryl, -SO2-alkyl, -SO2-cycloalkyl, -SO2-heterocyclic, -SO2-aryl, and -SO2-heteroaryl. The term "substituted cycloalkyl" further includes cycloalkyl groups in which one or more ring carbon atoms of the cycloalkyl group have an oxo group bonded thereto. Unless otherwise defined, all substituents may optionally be further substituted by one, two, or three substituents selected from the following: alkyl, alkenyl, alkynyl, carboxyl, carboxyalkyl, aminocarbonyl, hydroxyl, alkoxy, halogen, CF3, amino, substituted amino, cyano, cycloalkyl, heterocyclic, aryl, heteroaryl, and -S(O). n R a , where R a It is an alkyl, aryl, or heteroaryl group and n is 0, 1, or 2.

[0180] The term "cycloalkoxy" refers to an -O-cycloalkyl group.

[0181] The term "cycloalkenyloxy group" refers to the -O-cycloalkenyl group.

[0182] The term "aryl" refers to an aromatic carbocyclic group having 6 to 20 carbon atoms, consisting of a single ring (e.g., phenyl), multiple rings (e.g., biphenyl), or multiple fused (fused) rings (e.g., naphthyl, fluorenyl, and anthracene). In some embodiments, aryl groups include phenyl, fluorenyl, naphthyl, anthracene, etc.

[0183] Unless otherwise defined by the definition, such an aryl group may optionally be substituted with 1, 2, 3, 4, or 5 substituents selected from the following (in some embodiments, 1, 2, or 3 substituents): alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkoxy, cycloalkenyloxy, acyl, amide, acyloxy, amino, substituted amino, aminocarbonyl, alkoxycarbonylamino, azide, cyano, halogen, hydroxyl, ketone, thiocarbonyl, carboxyl, carboxyl The substituents include alkyl, arylthio, heteroarylthio, heterocyclic thio, mercapto, alkylthio, aryl, aryloxy, heteroaryl, aminosulfonyl, aminocarbonylamino, heteroaryloxy, heterocyclic, heterocyclic, hydroxylamino, alkoxyamino, nitro, -SO-alkyl, -SO-cycloalkyl, -SO-heterocyclic, -SO-aryl, -SO-heteroaryl, -SO2-alkyl, -SO2-cycloalkyl, -SO2-heterocyclic, -SO2-aryl, and -SO2-heteroaryl. Unless otherwise defined, all substituents may optionally be further substituted by one, two, or three substituents selected from: alkyl, alkenyl, alkynyl, carboxyl, carboxyalkyl, aminocarbonyl, hydroxyl, alkoxy, halogen, CF3, amino, substituted amino, cyano, cycloalkyl, heterocyclic, aryl, heteroaryl, and -S(O). n R a , where R a It is an alkyl, aryl, or heteroaryl group and n is 0, 1, or 2.

[0184] The term "aryloxy group" refers to an -O-aryl group, wherein the aryl group is as defined above and includes optionally substituted aryl groups as defined above. The term "arylthio group" refers to an RS- group, wherein R is as defined for the aryl group.

[0185] The term “triaryl” in this document refers to a diaryl group that becomes bivalent as defined above by formally removing a hydrogen atom from the aryl group.

[0186] The terms "heterocyclic group," "heterocyclic," or "heterocyclic" refer to a monomolecular saturated group having a single ring or multiple fused rings, having 1-40 carbon atoms and 1-10 heteroatoms selected from nitrogen, sulfur, phosphorus, and / or oxygen (1-4 heteroatoms in some embodiments). In some embodiments, the "heterocyclic group," "heterocyclic," or "heterocyclic" group is attached to the remainder of the molecule by one of the heteroatoms within the ring.

[0187] Unless otherwise defined by the definition, such heterocyclic substituents may optionally be substituted with 1 to 5 substituents selected from the following (in some embodiments, 1, 2, or 3 substituents): alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkoxy, cycloalkenyloxy, acyl, amide, acyloxy, amino, substituted amino, aminocarbonyl, alkoxycarbonylamino, azide, cyano, halogen, hydroxyl, ketone, thiocarbonyl, carboxyl, carboxylalkyl. The substituents include: arylthio, heteroarylthio, heterocyclic thio, mercapto, alkylthio, aryl, aryloxy, heteroaryl, aminosulfonyl, aminocarbonylamino, heteroaryloxy, heterocyclic, heterocyclic, hydroxylamino, alkoxyamino, nitro, SO-alkyl, -SO-cycloalkyl, -SO-heterocyclic, -SO-aryl, -SO-heteroaryl, -SO2-alkyl, -SO2-cycloalkyl, -SO2-heterocyclic, -SO2-aryl, and -SO2-heteroaryl. Unless otherwise defined, all substituents may optionally be further substituted by one, two, or three substituents selected from: alkyl, alkenyl, alkynyl, carboxyl, carboxyalkyl, aminocarbonyl, hydroxyl, alkoxy, halogen, CF3, amino, substituted amino, cyano, cycloalkyl, heterocyclic, aryl, heteroaryl, -S(O). n R a , where R a It is an alkyl, aryl, or heteroaryl group and n is 0, 1, or 2. Examples of heterocyclic groups include tetrahydrofuranyl, morpholinyl, piperidinyl, etc.

[0188] The term "heterocyclic group" refers to the -O-heterocyclic group.

[0189] The term "heteroaryl" refers to a group comprising a single ring or multiple rings containing 1-15 carbon atoms and 1-4 heteroatoms selected from oxygen, nitrogen, and sulfur within at least one ring. The term "heteroaryl" is a superordinate concept of the terms "aromatic heteroaryl" and "partially saturated heteroaryl." The term "aromatic heteroaryl" refers to a heteroaryl in which at least one ring is aromatic, regardless of the bonding point. Examples of aromatic heteroaryls include pyrrole, thiophene, pyridine, quinoline, and pteridine. The term "partially saturated heteroaryl" refers to a heteroaryl with a structure equivalent to the basic aromatic heteroaryl, having one or more double bonds in the aromatic ring. Examples of partially saturated heteroaryls include dihydropyrrole, dihydropyridine, chromium, 2-oxo-1,2-dihydropyridin-4-yl, etc.

[0190] Unless otherwise defined by definition, such heteroaryl substituents may optionally be substituted with 1 to 5 substituents selected from the following (in some embodiments, 1, 2, or 3 substituents): alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkoxy, cycloalkenyloxy, acyl, amide, acyloxy, amino, substituted amino, aminocarbonyl, alkoxycarbonylamino, azide, cyano, halogen, hydroxyl, ketone, thiocarbonyl, carboxyl, carboxylalkyl. The substituents include: arylthio, heteroarylthio, heterocyclic thio, mercapto, alkylthio, aryl, aryloxy, heteroaryl, aminosulfonyl, aminocarbonylamino, heteroaryloxy, heterocyclic, heterocyclic, hydroxylamino, alkoxyamino, nitro, -SO-alkyl, -SO-cycloalkyl, -SO-heterocyclic, -SO-aryl, -SO-heteroaryl, -SO2-alkyl, -SO2-cycloalkyl, -SO2-heterocyclic, -SO2-aryl, and -SO2-heteroaryl. Unless otherwise defined, all substituents may optionally be further substituted by one, two, or three substituents selected from: alkyl, alkenyl, alkynyl, carboxyl, carboxyalkyl, aminocarbonyl, hydroxyl, alkoxy, halogen, CF3, amino, substituted amino, cyano, cycloalkyl, heterocyclic, aryl, heteroaryl, -S(O). n R a , where R a It is an alkyl, aryl, or heteroaryl group and n is 0, 1, or 2. Such heteroaryl groups can have a single ring (e.g., pyridyl or furanyl) or multiple fused rings (e.g., indazinyl, benzothiazole, or benzothiophene). Examples of nitrogen-containing heterocyclic groups and heteroaryl groups include, but are not limited to, pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, indazine, isoindole, indole, indazole, purine, quinazine, isoquinoline, quinoline, phthalazine, naphthylpyridine, quinoxaline, quinazoline, cyclophosphine, pteridine, carbazole, caroline, phenanthridine, acridine, phenanthroxaline, isothiazine, phenazine, isoxazine, isoxazine, phenoxazine, phenthiazine, imidazoline, imidazoline, etc., as well as N-alkoxy-nitrogen-containing heteroaryl compounds.

[0191] The term "heteroaryloxy group" refers to the -O-heteroaryl group.

[0192] The term "amino" refers to the -NH2 group.

[0193] The term "substituted amino" refers to a -NRR group, where each R is independently selected from hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclic groups, provided that the two Rs are not simultaneously hydrogen or -YZ groups, where Y is an optionally substituted alkylene and Z is alkenyl, cycloalkenyl, or ynyl. Unless otherwise defined, all substituents may optionally be further substituted by one, two, or three substituents selected from: alkyl, alkenyl, ynyl, carboxyl, carboxyalkyl, aminocarbonyl, hydroxyl, alkoxy, halogen, CF3, amino, substituted amino, cyano, cycloalkyl, heterocyclic, aryl, heteroaryl, and -S(O).n R a , where R a It is an alkyl, aryl, or heteroaryl group and n is 0, 1, or 2.

[0194] The term "alkylamine" refers to R-NH2, where R is an optionally substituted alkyl group.

[0195] The term "dialkylamine" refers to R-NHR, where each R is an optional substituted alkyl group.

[0196] The term "trialkylamine" refers to NR3, where each R is an optional substituted alkyl group.

[0197] The term "cyano" refers to the -CN group.

[0198] The term "azido group" refers to Group.

[0199] The terms "ketone" or "oxo" refer to the =O group.

[0200] The term "carboxyl group" refers to the -C(O)-OH group.

[0201] The term "ester" or "carboxylic acid ester" refers to a -C(O)OR group, where R is an alkyl, cycloalkyl, aryl, heteroaryl, or heterocyclic group, which may optionally be further modified by an alkyl, alkoxy, halogen, CF3, amino, substituted amino, cyano, or -S(O) group. n R a Replace, where R a It is an alkyl, aryl, or heteroaryl group and n is 0, 1, or 2.

[0202] The term "acyl" means -C(O)R group, where R is hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted heterocyclic, optionally substituted aryl or optionally substituted heteroaryl.

[0203] The term "carboxyalkyl" refers to a -C(O)O-alkyl or -C(O)O-cycloalkyl group (wherein alkyl and cycloalkyl are as defined herein), and may optionally be further modified by alkyl, alkenyl, alkynyl, carboxyl, carboxyalkyl, aminocarbonyl, hydroxyl, alkoxy, halogen, CF3, amino, substituted amino, cyano, cycloalkyl, heterocyclic, aryl, heteroaryl, -S(O) n R a Replace, where R a It is an alkyl, aryl, or heteroaryl group and n is 0, 1, or 2.

[0204] The term "aminocarbonyl" refers to a -C(O)NRR group, where each R is independently hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, heterocyclic, or two of the Rs are bonded to form a heterocyclic group (e.g., morpholino). Unless otherwise defined, all substituents may optionally be further substituted by one, two, or three substituents selected from: alkyl, alkenyl, alkynyl, carboxyl, carboxyalkyl, aminocarbonyl, hydroxyl, alkoxy, halogen, CF3, amino, substituted amino, cyano, cycloalkyl, heterocyclic, aryl, heteroaryl, -S(O). n R a , where R a It is an alkyl, aryl, or heteroaryl group and n is 0, 1, or 2.

[0205] The term "acyloxy" refers to -OC(O)-alkyl, -OC(O)-cycloalkyl, -OC(O)-aryl, -OC(O)-heteroaryl, and -OC(O)-heterocyclic groups. Unless otherwise defined, all substituents may optionally be further substituted by one, two, or three substituents selected from the following: alkyl, alkenyl, alkynyl, carboxyl, carboxyalkyl, aminocarbonyl, hydroxyl, alkoxy, halogen, CF3, amino, substituted amino, cyano, cycloalkyl, heterocyclic, aryl, heteroaryl, -S(O). n R a , where R a It is an alkyl, aryl, or heteroaryl group and n is 0, 1, or 2.

[0206] The term "amide" refers to the -NRC(O)R group, where each R is independently hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, or heterocyclic. All substituents may optionally be further replaced by alkyl, alkenyl, alkynyl, carboxyl, carboxyalkyl, aminocarbonyl, hydroxyl, alkoxy, halogen, CF3, amino, substituted amino, cyano, cycloalkyl, heterocyclic, aryl, heteroaryl, or -S(O). n R a Replace, where R a It is an alkyl, aryl, or heteroaryl group and n is 0, 1, or 2.

[0207] The term "alkoxycarbonylamino" refers to -N(R c )C(O)OR group, wherein R is an optionally substituted alkyl group and R c It is hydrogen or an alkyl group that is optionally substituted.

[0208] The term "aminocarbonylamino" refers to -NR d C(O)NRR group, where R dR is hydrogen or optionally substituted alkyl and each R is independently selected from hydrogen, alkyl, cycloalkyl, aryl, heteroaryl and heterocyclic. Unless otherwise defined, all substituents may optionally be further substituted by one, two or three substituents selected from the following: alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkenyl, cycloalkoxy, cycloalkenyloxy, acyl, amide, acyloxy, amino, substituted amino, aminocarbonyl, alkoxycarbonylamino, azide, cyano, halogen, hydroxyl, ketone, thiocarbonyl, carboxyl, carboxylalkyl, arylthio, heteroarylthio, heterocyclic thio, mercapto, alkylthio, aryl, aryloxy, heteroaryl, aminosulfonyl, aminocarbonylamino, heteroaryloxy, heterocyclic, heterocyclic, hydroxylamino, alkoxyamino, nitro, SO-alkyl, -SO-cycloalkyl, -SO-heterocyclic, -SO-aryl, -SO-heteroaryl, -SO2-alkyl, -SO2-cycloalkyl, -SO2-heterocyclic, -SO2-aryl and -SO2-heteroaryl.

[0209] The term "thiol" refers to the -SH group.

[0210] The term "thiocarbonyl" refers to the =S group.

[0211] The term "alkylthio" refers to an -S-alkyl group.

[0212] The term "substituted alkylthio" refers to an -S-substituted alkyl group.

[0213] The term "heterocyclic thio group" refers to the -S-heterocyclic group.

[0214] The term "arylthio" refers to the -S-aryl group.

[0215] The term "heteroarylthio" refers to a -S-heteroaryl group, wherein the heteroaryl is as defined above, including optionally substituted heteroaryl groups as defined above.

[0216] The term "sulfoxide" refers to a -S(O)R group, where R is an alkyl, cycloalkyl, heterocyclic, aryl, or heteroaryl group. "Substituted sulfoxide" refers to a -S(O)R group, where R is a substituted alkyl, substituted cycloalkyl, substituted heterocyclic, substituted aryl, or substituted heteroaryl group as defined herein.

[0217] The term "sulfone" refers to a -S(O)2R group, where R is an alkyl, cycloalkyl, heterocyclic, aryl, or heteroaryl group. "Substituted sulfone" refers to a -S(O)2R group, where R is a substituted alkyl, substituted cycloalkyl, substituted heterocyclic, substituted aryl, or substituted heteroaryl group as defined herein.

[0218] The term "aminosulfonyl" refers to the -S(O)2NRR group, where each R is independently selected from hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclic groups. Unless otherwise defined, all substituents may optionally be further substituted by one, two or three substituents selected from the following: alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkenyl, cycloalkoxy, cycloalkenyloxy, acyl, amide, acyloxy, amino, substituted amino, aminocarbonyl, alkoxycarbonylamino, azide, cyano, halogen, hydroxyl, ketone, thiocarbonyl, carboxyl, carboxylalkyl, arylthio, heteroarylthio, heterocyclic thio, mercapto, alkylthio, aryl, aryloxy, heteroaryl, aminosulfonyl, aminocarbonylamino, heteroaryloxy, heterocyclic, heterocyclic, hydroxylamino, alkoxyamino, nitro, SO-alkyl, -SO-cycloalkyl, -SO-heterocyclic, -SO-aryl, -SO-heteroaryl, -SO2-alkyl, -SO2-cycloalkyl, -SO2-heterocyclic, -SO2-aryl and -SO2-heteroaryl.

[0219] The term "hydroxyamino" refers to the -NHOH group.

[0220] The term "alkoxyamino" refers to the -NHOR group, where R is an optionally substituted alkyl group.

[0221] The term "halogen" or "halogenated" refers to fluorinated, brominated, chlorinated, and iodinated compounds.

[0222] The term "trifluoromethanesulfonate" refers to the trifluoromethanesulfonate group (-OSO2-CF3).

[0223] "Optional" or "optionally" means that the event or situation described below may or may not occur, and the description includes both the scenario in which the event or situation occurs and the scenario in which it does not occur.

[0224] The “substituted” group includes embodiments in which a mono-substituent is bonded to a single atom of the substituted group (e.g., forming a branch), and also includes embodiments in which the substituent can be a bridging di-base bonded to two adjacent atoms of the substituted group, thereby forming a fused ring on the substituted group.

[0225] In cases where a given group (partially) is described herein as being attached to a second group and the attachment site is not specified, the given group may be attached to any available site of the second group at any available site of the given group. For example, an "alkyl-substituted phenyl" (where the attachment site is not specified) may be attached to any available site of the alkyl group at any available site of the phenyl group. In this regard, an "available site" is a group site where the hydrogen of the group can be replaced by a substituent.

[0226] It should be understood that polymers obtained by limiting the substituents to those having further substituents relative to themselves (e.g., substituted aryl groups having a substituted aryl group as a substituent of the aryl group itself being substituted, etc.) are not intended to be included among all the substituted groups defined above. Nor are an unlimited number of substituents included, whether the substituents are the same or different. In these cases, the maximum number of such substituents is 3. Therefore, the above definitions are limited, for example, by the limitation of substituted aryl groups to -substituted aryl-(substituted aryl)-substituted aryl.

[0227] Compounds having a given formula (e.g., compounds of Formula I) are intended to encompass the compounds of this disclosure and their salts (e.g., pharmaceutically acceptable salts), esters, isomers, tautomers, solvates, isotopes, hydrates, cocrystals, co-formers, and / or prodrugs. Additionally, the compounds of this disclosure may have one or more asymmetric centers and may be produced as racemic mixtures or as single enantiomers or diastereomers. The number of stereoisomers present in any given compound of a given formula depends on the number of asymmetric centers present (2^n possible stereoisomers exist in the case of n asymmetric centers). A single stereoisomer can be obtained by resolving a racemic or diastereomer mixture of intermediates at some suitable stage of synthesis or by resolving the compound by conventional means. Single stereoisomers (including single enantiomers and diastereomers) and racemic and diastereomer mixtures of stereoisomers are included within the scope of this disclosure, and are entirely intended to be described structurally in this specification unless otherwise expressly indicated.

[0228] "Isomers" are different compounds that have the same molecular formula. Isomers include stereoisomers, enantiomers, and diastereomers.

[0229] "Stereoisomers" are isomers that contain chiral atoms with the same connectivity but differ only in the spatial arrangement of the atoms. As used herein, the term "stereoisomer" includes both "enantiomers" and "diastereomers".

[0230] "Enantiomers" are stereoisomers that are non-overlapping mirror images of each other and do not contain a plane of symmetry. A 1:1 mixture of a pair of stereoisomers is a "racemic" mixture. The term "(±)" is used where appropriate to specify racemic mixtures.

[0231] A “diastereomer” is a stereoisomer that has at least two chiral atoms and may contain a plane of symmetry, but is not a mirror image of each other in the absence of a plane of symmetry.

[0232] Absolute stereochemistry is specified according to the Cahn Ingold Prelog RS system. When a compound is a pure enantiomer, the stereochemistry at each chiral carbon can be indicated by R or S. Resolved compounds whose absolute configuration is unknown are named (+) or (-) according to the direction (dextrorotatory or levorotatory) of the polarization plane of the wavelength of the sodium D line.

[0233] If there is a contradiction between the described structure and the name given to that structure, the described structure shall prevail. Furthermore, if the stereochemistry of a structure or part thereof is not indicated by, for example, a thick line, a wedge line, or a dashed line, then that structure or part thereof shall be interpreted as encompassing all its stereoisomers.

[0234] The term "solvent" refers to a complex formed by combining a compound of formula I or any other formula disclosed herein with a solvent. As used herein, the term "solvent" includes hydrates (i.e., solvates in which water is the solvent).

[0235] The term "hydrate" refers to a complex formed by combining a compound of formula I or any other formula disclosed herein with water.

[0236] The term "eutectic" refers to a crystalline material formed by combining a compound of Formula I or any of the formulas disclosed herein with one or more eutectic forming agents (i.e., molecules, ions, or atoms). In some cases, the eutectic may have improved properties compared to the parent form (i.e., free molecules, zwitterions, etc.) or a salt of the parent compound. Improved properties may include increased solubility, enhanced bioavailability, improved dose-response, reduced hygroscopicity, crystalline form of a normally amorphous compound, crystalline form of a compound that is difficult or impossible to salt, reduced form diversity, more desirable morphology, etc. Methods for preparing and characterizing eutectics are known to those skilled in the art.

[0237] The terms "co-forming agent" or "eutectic forming agent" refer to the nonionic association of a compound of formula I or any of the formulas disclosed herein with one or more molecules, ions, or atoms. Exemplary co-forming agents are inorganic or organic bases and / or acids.

[0238] Any formula or structure given herein, including Formula I or any other formula disclosed herein, is also intended to represent the unlabeled form of the compound as well as its isotopically labeled form. Isotopically labeled compounds have the structures depicted by the formulas given herein, except that one or more atoms are replaced by atoms having a chosen atomic weight or mass number. Examples of isotopes that may be incorporated into the compounds of this disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, and chlorine, for example, but not limited to, those of other elements. 2 H(deuterium,D) 3 H (tritium) 11 C13 C 14 C 15 N、 18 F, 31 P, 32 P, 35 S, 36 Cl and 125 I. Various isotope-labeled compounds disclosed herein, for example, those doped with radioactive isotopes such as 3 H, 13 C and 14 Compounds containing C. Such isotopically labeled compounds can be used in metabolic studies, reaction kinetic studies, detection or imaging techniques such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT), including drug or substrate tissue distribution analysis, or for use in patients undergoing radiotherapy.

[0239] This disclosure also includes compounds of Formula I or any of the formulas disclosed herein, wherein one to "n" hydrogen atoms attached to a carbon atom are replaced by deuterium, where n is the number of hydrogen atoms in the molecule. Such compounds exhibit enhanced metabolic resistance and can therefore be used to increase the half-life of any compound of Formula I when administered to mammals. See, for example, Foster, "Deuterium Isotope Effects in Studies of Drug Metabolism", Trends Pharmacol. Sci. 5(12):524-527 (1984). Such compounds are synthesized by means known in the art, for example, by using starting materials in which one or more hydrogen atoms have been replaced by deuterium.

[0240] The deuterium-labeled or substituted therapeutic compounds disclosed herein can have improved DMPK (drug metabolism and pharmacokinetics) properties, involving distribution, metabolism, and excretion (ADME). Substitution with heavier isotopes such as deuterium can provide certain therapeutic advantages due to higher metabolic stability, such as prolonged in vivo half-life or reduced dose requirements. 18 F-labeled compounds can be used in PET or SPECT studies. The isotope-labeled compounds and their prodrugs disclosed herein can generally be prepared by replacing the non-isotope-labeled reagents with readily available isotope-labeled reagents using the processes disclosed in the embodiments and preparations described below. Furthermore, heavier isotopes, particularly deuterium (i.e.,...), can also be used. 2 Substitution with H or D can provide certain therapeutic advantages due to increased metabolic stability, such as prolonged in vivo half-life, reduced dose requirement, or improved therapeutic index. It should be understood that in this context, deuterium is considered a substituent in compounds of formula I or any of the formulas disclosed herein.

[0241] The concentration of such heavier isotopes (particularly deuterium) can be defined by the isotope enrichment factor. In the compounds disclosed herein, any atom not specifically designated as a particular isotope means any stable isotope of that atom. Unless otherwise stated, when a position is specifically designated as "H" or "hydrogen," that position is understood to have hydrogen with its naturally occurring isotopic composition. Therefore, in the compounds disclosed herein, any atom specifically designated as deuterium (D) means deuterium.

[0242] In many cases, the compounds of this disclosure are capable of forming acidic and / or basic salts in the presence of amino and / or carboxyl groups or similar groups.

[0243] The salts of the compounds disclosed herein can be either base addition salts or acid addition salts, depending on the reactivity of the functional groups present on the specific compound. Base addition salts can be derived from inorganic or organic bases. Salts derived from inorganic bases include, by way of example only, sodium, potassium, lithium, ammonium, calcium, and magnesium salts. Salts derived from organic bases include, but are not limited to, primary, secondary, and tertiary amines (such as alkylamines, dialkylamines, trialkylamines, substituted alkylamines, di(substituted alkyl)amines, tri(substituted alkyl)amines, alkenylamines, dienylamines, trienylamines, substituted alkenylamines, di(substituted alkenyl)amines, tri(substituted alkenyl)amines, cycloalkylamines, di(cycloalkyl)amines, tri(cycloalkyl)amines, substituted cycloalkylamines, disubstituted cycloalkylamines, trisubstituted cycloalkylamines, cycloalkenylamines, di(cycloalkenyl)amines). Salts of tri(cycloalkenyl)amines, substituted cycloalkenylamines, disubstituted cycloalkenylamines, trisubstituted cycloalkenylamines, arylamines, diarylamines, triarylamines, heteroarylamines, diheteroarylamines, triheteroarylamines, heterocyclic amines, diheterocyclic amines, triheterocyclic amines, and mixed di- and tri-amines, wherein at least two substituents on the amine are different and selected from alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, heteroaryl, heterocyclic, etc. Also included are amines in which two or three substituents together with the amino nitrogen form a heterocyclic or heteroaryl group. Amines have the general structure N(R) 30 (R) 31 (R) 32 ), in which the three substituents (R) on the nitrogen of the monosubstituted amine 30 R 31 and R 32 In this amine, two atoms are hydrogen, and the three substituents (R) on the nitrogen atom are disubstituted amines. 30 R 31 and R 32 One of them is hydrogen, while the three substituents (R) on the nitrogen of the trisubstituted amine are hydrogen. 30 R 31 and R 32 None of them are hydrogen. R 30 R 31 and R 32Selected from various substituents such as hydrogen, optionally substituted alkyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocyclic, etc. The aforementioned amines refer to compounds in which any one, two, or three substituents on the nitrogen atom are listed in the name. For example, the term "cycloalkenylamine" refers to cycloalkenyl-NH2, where "cycloalkenyl" is as defined herein. The term "diheteroarylamine" refers to NH(heteroaryl)2, where "heteroaryl" is as defined herein, and so on.

[0244] Specific examples of suitable amines include, for example, isopropylamine, trimethylamine, diethylamine, tri(isopropyl)amine, tri(n-propyl)amine, ethanolamine, 2-dimethylaminoethanol, aminobutanetriol, lysine, arginine, histidine, caffeine, procaine, physalin, choline, betaine, ethylenediamine, glucosamine, N-alkylglucosamine, theobromine, purine, piperazine, morpholine, N-ethylpiperidine, etc.

[0245] Acid addition salts can be derived from inorganic or organic acids. Salts derived from inorganic acids include hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid. Salts derived from organic acids include acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, and salicylic acid.

[0246] Any salt disclosed herein may optionally be pharmaceutically acceptable. The term “pharmaceutically acceptable salt” for a given compound means a salt that retains the biological potency and properties of the given compound and is not biologically or otherwise undesirable. See P. Heinrich Stahl and Camille G. Wermuth (Eds.) Pharmaceutical Salts: Properties, Selection, and Use (International Union of Pure and Applied Chemistry), Wiley-VCH; 2nd Revised Edition (May 16, 2011). Pharmaceutically acceptable base addition salts may be prepared from inorganic and organic bases.

[0247] Pharmaceutically acceptable base addition salts can be salts prepared from inorganic and organic bases, and pharmaceutically acceptable acid addition salts can be salts prepared from inorganic and organic acids.

[0248] The term "leaving group" refers to an atom or group of atoms that is removed as a stabilizing agent along with its bond electrons during a chemical reaction. Non-limiting examples of leaving groups include halogens, methanesulfonyloxy, p-toluenesulfonyloxy, trifluoromethanesulfonyloxy, nonafluorobutanesulfonyloxy, (4-bromobenzene)sulfonyloxy, (4-nitrobenzene)sulfonyloxy, (2-nitrobenzene)sulfonyloxy, (4-isopropylbenzene)sulfonyloxy, (2,4,6-triisopropylbenzene)sulfonyloxy, (2,4,6-trimethylbenzene)sulfonyloxy, (4-tert-butylbenzene)sulfonyloxy, benzenesulfonyloxy, (4-methoxybenzene)sulfonyloxy, etc.

[0249] The term “O-arylation reaction conditions” refers to the reaction conditions under which the -O-R' moiety is attached to a suitable aromatic matrix. “O-arylation reaction conditions” as disclosed herein typically include a base. Non-limiting examples of bases include sodium carbonate (Na₂CO₃) and potassium carbonate (K₂CO₃), potassium tert-butoxide (KOtBu), lithium tert-butoxide (LiOtBu), magnesium tert-butoxide (Mg(OtBu)₂), sodium tert-butoxide (NaOtBu), sodium hydride (NaH), potassium hexamethyldisilizide (KHMDS), potassium phosphate (K₃PO₄), potassium hydroxide (KOH), lithium hydroxide (LiOH), and organic bases such as 1,4-diazabicyclo[2.2.2]octane (DABCO), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), etc.

[0250] The term "protecting group" refers to a portion of a compound that shields or alters the properties of a functional group or the compound as a whole. The chemical substructure of protecting groups varies widely. One function of protecting groups is as intermediates in the synthesis of parent drug substances. Chemical protecting groups and strategies for protection / deprotection are well known in the art. See "Protective Groups in Organic Chemistry," Theodora W. Greene (John Wiley & Sons, Inc., New York, 1991). Protecting groups are frequently used to shield the reactivity of specific functional groups to favor the efficiency of desired chemical reactions, for example, by forming and breaking chemical bonds in an ordered and planned manner. Protection of a compound's functional group alters physical properties other than the reactivity of the protected functional group, such as polarity, lipophilicity (hydrophobicity), and other properties measurable by common analytical tools. Chemically protected intermediates can themselves be biologically active or inactive. Non-limiting examples of protecting groups for amines include tert-butyloxycarbonyl (Boc), benzyloxycarbonyl (Cbz), 9-fluorenylmethoxycarbonyl (Fmoc), etc.

[0251] The term "N-deprotection conditions" refers to the reaction conditions under which a protecting group is removed from an amine. Non-limiting examples of protecting groups for amines include tert-butoxycarbonyl (Boc), benzyloxycarbonyl (Cbz), and 9-fluorenylmethoxycarbonyl (Fmoc). N-deprotection conditions for Boc include the use of acids such as HCl, methanesulfonic acid, and p-toluenesulfonic acid. N-deprotection conditions for Cbz include the use of hydrogen and catalysts such as the hydrogenation of Pd. N-deprotection conditions for Fmoc include the use of bases such as 1,8-diazabicyclo[5.4.0]undecyl-7-ene (DBU) and piperidine.

[0252] The term "amide coupling conditions" refers to the reaction conditions under which an amine and a carboxylic acid are coupled using a coupling agent in the presence of a base to form an amide. Non-limiting examples of coupling agents include 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC) with hydroxybenzotriazole monohydrate (HOBt), O-(7-azabenzotriazol-1-yl)-N,N,N,N'-tetramethylurea hexafluorophosphate (HATU), and 1-hydroxy-7-azabenzotriazole. Non-limiting examples of bases include N-methylmorpholine, pyridine, morpholine, and imidazole.

[0253] The term "closed-ring metathesis" refers to the reaction conditions under which two olefins in the same molecule react in the presence of a catalyst to produce cycloalkanes and volatile olefins.

[0254] The term "Curtis rearrangement" refers to a reaction in which a carboxylic acid (R-COOH) is converted into an amine (RNH2) through the following steps: the carboxylic acid first reacts with a diphenylphosphino azide to provide an acyl azide (RCON3), which then rearranges to form an isocyanate (RNCO), which is hydrolyzed in the presence of an alcohol (e.g., tert-butanol) to provide a boc-protected amine (R-NHBoc).

[0255] The term "cross metathesis conditions" refers to the reaction conditions under which two olefins in a single molecule react in the presence of a catalyst to produce cycloalkanes and volatile olefins.

[0256] Non-limiting examples of catalysts for "closed-ring metathesis" and "cross-metathesis conditions" include Zhan 1B, ruthenium-based Grubbs, Grubbs-Hoveyda, saturated and unsaturated imidazole and phosphine-based catalysts, and molybdenum-based catalysts and their variants. A representative, non-exhaustive list is provided below, where Cy is cyclohexyl, Me is methyl, Ph is phenyl, and iPr is isopropyl.

[0257]

[0258] Additionally, the abbreviations used in this article have the following corresponding meanings:

[0259]

[0260]

[0261]

[0262]

[0263] method

[0264] As generally described above, this disclosure provides methods for preparing compounds of formula I in some embodiments. In another embodiment, this disclosure provides a method for preparing intermediates of compounds of formula I. This method can also be applied to synthesizing stereoisomers or mixtures of stereoisomers of compounds of formula I.

[0265] Approach I

[0266] This disclosure provides, in one embodiment, a method for preparing a compound of formula I or a stereoisomer thereof, a mixture of stereoisomers, a eutectic, or a pharmaceutically acceptable salt thereof, wherein the compound of formula I is named (1aR,5S,8S,9S,10R,22aR)-5-tert-butyl-N-[(1R,2R)-2-(difluoromethyl)-1-{[(1-methylcyclopropyl)sulfonyl]carbamoyl}cyclopropyl]-9-ethyl-18,18-difluoro-14-methoxy-3,6-dioxo-1,1a,3,4,5,6,9,10,18,19,20,21,22,22a-tetradecano-8H-7,10-methylbridged cyclopropano[18,19][1,10,3,6]dioxadiazaarnedodecano[11,12-b]quinoxaline-8-carboxamide:

[0267]

[0268] In another embodiment, this disclosure provides a method for preparing a compound of formula I or a eutectic or salt thereof, wherein the compound of formula I is named (1aR,5S,8S,9S,10R,22aR)-5-tert-butyl-N-[(1R,2R)-2-(difluoromethyl)-1-{[(1-methylcyclopropyl)sulfonyl]carbamoyl}cyclopropyl]-9-ethyl-18,18-difluoro-14-methoxy-3,6-dioxo-1,1a,3,4,5,6,9,10,18,19,20,21,22,22a-tetradecano-8H-7,10-methylbridged cyclopropano[18,19][1,10,3,6]dioxadiazarocyclopropano[11,12-b]quinoxaline-8-carboxamide:

[0269]

[0270] include:

[0271] a) Contacting a compound of formula III or its eutectic or salt with a compound of formula IV under O-arylation conditions to provide a compound of formula V or its eutectic or salt:

[0272]

[0273]

[0274] b) Subjecting a compound of formula V, or its eutectic or salt thereof, to N-deprotection conditions to provide a compound of formula VI, or its eutectic or salt thereof:

[0275]

[0276] c) Contacting a compound of formula VI or its eutectic or salt with a compound of formula VII or its eutectic or salt under amide coupling conditions to provide a compound of formula VIII or its eutectic or salt:

[0277]

[0278] d) Perform ring-closure metathesis of a compound of formula VIII or its eutectic or salt to provide a compound of formula IX or its eutectic or salt:

[0279]

[0280] e) Hydrogenating a compound of formula IX or its eutectic or salt in the presence of a catalyst to provide a compound of formula X or its eutectic or salt:

[0281]

[0282] f) Hydrolyze a compound of formula X or its eutectic or salt to provide a compound of formula XI or its eutectic or salt:

[0283]

[0284] g) Contacting a compound of formula XI or its eutectic or salt with a compound of formula XII or its eutectic or salt under amide coupling conditions to provide a compound of formula I or its eutectic or pharmaceutically acceptable salt:

[0285]

[0286] Where R is C 1-6 Alkyl groups, PG is a protecting group and R 1 It is a leaving group.

[0287] The O-arylation conditions in step a) include a base. Non-limiting examples of bases include sodium carbonate (Na₂CO₃) and potassium carbonate (K₂CO₃), potassium tert-butoxide (KOtBu), cesium carbonate (Cs₂CO₃), lithium tert-butoxide (LiOtBu), magnesium tert-butoxide (Mg(OtBu)₂), sodium tert-butoxide (NaOtBu), sodium hydride (NaH), potassium hexamethyldisilamide (KHMDS), potassium phosphate (K₃PO₄), potassium hydroxide (KOH), lithium hydroxide (LiOH), and organic bases such as DABCO, DBU, etc. In one embodiment, the base is cesium carbonate (Cs₂CO₃).

[0288] Non-limiting examples of leaving groups include halogenated, methanesulfonyloxy, p-toluenesulfonyloxy, trifluoromethanesulfonyloxy, nonafluorobutanesulfonyloxy, (4-bromo-benzene)sulfonyloxy, (4-nitro-benzene)sulfonyloxy, (2-nitro-benzene)sulfonyloxy, (4-isopropyl-benzene)sulfonyloxy, (2,4,6-triisopropyl-benzene)sulfonyloxy, (2,4,6-trimethyl-benzene)sulfonyloxy, (4-tert-butyl-benzene)sulfonyloxy, benzenesulfonyloxy, and (4-methoxy-benzene)sulfonyloxy.

[0289] The O-arylation conditions in step a) further include a solvent. Non-limiting examples of solvents include N,N-dimethylformamide (DMF), N-methyl-2-pyrrolidone (NMP), dimethyl sulfoxide (DMSO), acetonitrile (MeCN), acetone; aprotic solvents with small amounts of added water (H2O), ethers such as tetrahydrofuran (THF) and 1,4-dioxane, toluene (in the presence of a phase transfer catalyst), etc. In one embodiment, the solvent is N,N-dimethylacetamide (DMAc). In another embodiment, the O-arylation conditions in step a) include a temperature of about 100-110°C.

[0290] Various protecting groups, PG, can be used in compounds of formula III. Non-limiting examples of protecting groups for amines include tert-butoxycarbonyl (Boc), benzyloxycarbonyl (Cbz), 9-fluorenylmethoxycarbonyl (Fmoc), etc. In one embodiment, PG is Boc. The N-deprotection condition in step b) refers to the condition under which the protecting group PG is removed. In one embodiment, PG is Boc and the N-deprotection condition includes acids such as HCl, methanesulfonic acid, toluenesulfonic acid, etc. In one embodiment, the acid is p-toluenesulfonic acid.

[0291] The N-deprotection conditions in step b) further include a solvent. Non-limiting examples of solvents include methyltetrahydrofuran, MTBE, dioxane, isopropyl acetate, and combinations thereof. In one embodiment, the solvent is a mixture of methyltetrahydrofuran and MTBE. In another embodiment, the N-deprotection conditions in step b) include a temperature of about 50-55°C.

[0292] The amide coupling conditions in step c) include a coupling agent in the presence of a base. Non-limiting examples of coupling agents include 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC) with hydroxybenzotriazole (HOBt), 1-hydroxy-7-azabenzotriazole, O-(7-azabenzotriazole-1-yl)-N,N,N,N'-tetramethylurea hexafluorophosphate (HATU), etc. Non-limiting examples of bases include N-methylmorpholine, pyridine, morpholine, triethylamine, N,N-diisopropylethylamine, imidazole, etc. In one embodiment, the coupling conditions in step c) include the use of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide and hydroxybenzotriazole with N-methylmorpholine. The amide coupling conditions in step c) include a solvent. Non-limiting examples of solvents include dimethylacetamide, acetonitrile, N,N-dimethylformamide, etc. In one embodiment, the solvent is N,N-dimethylformamide. In another embodiment, the amide coupling conditions in step c) include a temperature of about 0-20°C.

[0293] The ring-closure metathesis in step d) involves a catalyst. Non-limiting examples of catalysts for "ring-closure metathesis" include Zhan 1B, ruthenium-based Grubbs, Grubbs-Hoveyda, saturated and unsaturated imidazole and phosphine-based catalysts, and molybdenum-based catalysts and their variants. A representative non-exhaustive list is provided below, where Cy is cyclohexyl, Me is methyl, Ph is phenyl, and iPr is isopropyl.

[0294]

[0295] In one embodiment, the closed-loop metathesis in step d) includes the catalyst Zhan 1B.

[0296] The ring-closure metathesis in step d) further includes a solvent. Non-limiting examples of solvents include dichloromethane, 1,2-dichloroethane, chlorobenzene, hexafluorobenzene, benzene, toluene, THF, methyl tert-butyl ether, cyclopentyl methyl ether, ethyl acetate, methanol, isopropanol, n-heptane, dimethyl carbonate, dimethylformamide, acetonitrile, etc. In one embodiment, the solvent is toluene. In another embodiment, the ring-closure metathesis in step d) includes a temperature of about 40-110°C. In another embodiment, the temperature is about 105-110°C.

[0297] The ring-closure metathesis in step d) optionally includes a promoter. Non-limiting examples of promoters include acetic acid, benzoquinones, CuI, CsCl, Ti(Oi-Pr)4, microwave irradiation, ethylene, etc.

[0298] The hydrogenation conditions in step e) include hydrogen in the presence of a catalyst. Non-limiting examples of catalysts include platinum, palladium, ruthenium, nickel, and other metals on carbon, alumina, silica, and other heterogeneous supports; metal nanoparticles; frustrated Lewis pairs such as hydroxy[4-[bis(2,4,6-trimethylphenyl)phosphino]-2,3,5,6-tetrafluorophenyl]hydrobis(2,3,4,5,6-pentafluorophenyl)boronic acid esters; and homogeneous metal catalysts such as trichlorotriphenylphosphine (I) rhodium(I) or (1,5-cyclooctadiene)(pyridine)(tricyclohexylphosphine)-iridium(I) hexafluorophosphate. In one embodiment, the catalyst is platinum on carbon.

[0299] The hydrogenation conditions in step e) further include a solvent. Non-limiting examples of solvents include water, protic solvents such as methanol, ethanol, or acetic acid; aprotic solvents such as dimethyl sulfoxide, tetrahydrofuran, ethyl acetate, isopropyl acetate, acetonitrile, toluene, dichloromethane, or acetone; and combinations thereof. In one embodiment, the solvent is isopropyl acetate. In another embodiment, the hydrogenation conditions in step e) include a temperature of about 20-150°C. In another embodiment, the temperature is about 20-25°C.

[0300] The hydrogenation conditions in step e) include hydrogen gas or formate such as ammonium formate or formic acid as the hydrogen source.

[0301] The hydrolysis conditions in step f) include acid hydrolysis or alkaline hydrolysis. Non-limiting examples of acids used for acid hydrolysis include protic acids such as sulfuric acid, hydrochloric acid, p-toluenesulfonic acid, or solid-supported acids; Lewis acids such as boron trifluoride, metal salts, metal complexes, or hydrogen bond donors. Non-limiting examples of bases used for alkaline hydrolysis include carbonates such as lithium, sodium, and cesium carbonates; metal hydrides such as sodium hydride and potassium hydride; alkoxides such as sodium methoxide, sodium tert-butoxide, lithium tert-butoxide, potassium tert-butoxide, or tetraalkylammonium alkoxides; hydroxides such as sodium hydroxide, potassium hydroxide, tin hydroxide, or tetraalkylammonium hydroxide; and amine bases such as 1,8-diazabicycloundecyl-7-ene. In one embodiment, the hydrolysis in step f) includes a base. In another embodiment, the base is lithium hydroxide.

[0302] The hydrolysis conditions in step f) further include a solvent. Non-limiting examples of solvents include polar protic solvents (including water, alcohols such as methanol, ethanol, IPA, tert-butanol, neopentyl alcohol, glycols, and combinations thereof with water), polar aprotic solvents (including dimethyl sulfoxide, dimethylformamide, tetrahydrofuran, 1,4-dioxane, and combinations thereof with water), and ionic liquids such as 3-methylimidazolium hexafluorophosphate. In one embodiment, the solvent is a mixture of isopropanol and water.

[0303] The amide coupling conditions in step g) include coupling agents in the presence of a base and are similar to those described in step c). In one embodiment, the coupling agent is O-(7-azabenzotriazol-1-yl)-N,N,N,N'-tetramethylurea hexafluorophosphate (HATU). In another embodiment, the base is N,N-diisopropylethylamine. In yet another embodiment, the solvent is DMF.

[0304] In one implementation, R is C 1-6 Alkyl group. In another embodiment, R is methyl. In another embodiment, R is tert-butyl.

[0305] In one implementation, R 1 Selected from halogenated, methanesulfonyloxy, p-toluenesulfonyloxy, trifluoromethanesulfonyloxy, nonafluorobutyryloxy, (4-bromo-benzene)sulfonyloxy, (4-nitro-benzene)sulfonyloxy, (2-nitro-benzene)sulfonyloxy, (4-isopropyl-benzene)sulfonyloxy, (2,4,6-triisopropyl-benzene)sulfonyloxy, (2,4,6-trimethyl-benzene)sulfonyloxy, (4-tert-butyl-benzene)sulfonyloxy, benzenesulfonyloxy, and (4-methoxy-benzene)sulfonyloxy. In another embodiment, R 1 It is halogenated. In another embodiment, R 1 It is chlorinated.

[0306] In another embodiment, this disclosure provides a method for preparing a compound of formula V or its stereoisomers, mixtures of stereoisomers, or eutectics or salts:

[0307]

[0308] This includes contacting a compound of formula III or its eutectic or salt with a compound of formula IV under O-arylation conditions to provide a compound of formula V or its eutectic or salt:

[0309]

[0310] Where R is C 1-6 Alkyl groups, PG is a protecting group and R 1 It is a leaving group.

[0311] In another embodiment, this disclosure provides a method for preparing a VI compound or its eutectic or salt:

[0312]

[0313] This includes subjecting a compound of formula V or its eutectic or salt to N-deprotection conditions to provide a compound of formula VI or its eutectic or salt:

[0314]

[0315] Where R is C 1-6 Alkyl groups and PG are protecting groups.

[0316] In another embodiment, this disclosure provides a method for preparing a compound of formula VIII or its eutectic or salt:

[0317]

[0318] This includes contacting a compound of formula VI or its eutectic or salt with a compound of formula VII or its eutectic or salt under amide coupling conditions to provide a compound of formula VIII or its eutectic or salt:

[0319]

[0320] Where R is C 1-6 alkyl.

[0321] In another embodiment, this disclosure provides a method for preparing a compound of formula IX or its eutectic or salt:

[0322]

[0323] This includes the cyclic metathesis of a compound of formula VIII or its eutectic or salt to provide a compound of formula IX or its eutectic or salt:

[0324]

[0325] Where R is C 1-6 alkyl.

[0326] Approach II

[0327] In another embodiment, this disclosure provides a method for preparing a compound of formula I or a eutectic or pharmaceutically acceptable salt thereof, the compound of formula I being named (1aR,5S,8S,9S,10R,22aR)-5-tert-butyl-N-[(1R,2R)-2-(difluoromethyl)-1-{[(1-methylcyclopropyl)sulfonyl]carbamoyl}cyclopropyl]-9-ethyl-18,18-difluoro-14-methoxy-3,6-dioxo-1,1a,3,4,5,6,9,10,18,19,20,21,22,22a-tetradecano-8H-7,10-methylbridged cyclopropano[18,19][1,10,3,6]dioxadiazaaranenonadecanocyclo[11,12-b]quinoxaline-8-carboxamide:

[0328]

[0329] include:

[0330] a) Contacting a compound of formula III or its eutectic or salt with a compound of formula IV under O-arylation conditions to provide a compound of formula V or its eutectic or salt:

[0331]

[0332] b) Subjecting a compound of formula V, or its eutectic or salt thereof, to N-deprotection conditions to provide a compound of formula VI, or its eutectic or salt thereof:

[0333]

[0334] c) Contacting a compound of formula VI or its eutectic or salt with a compound of formula VII or its eutectic or salt under amide coupling conditions to provide a compound of formula VIII or its eutectic or salt:

[0335]

[0336] d) Hydrolyzing a compound of formula VIII or its eutectic or salt to provide a compound of formula XVIII or its eutectic or salt:

[0337]

[0338] e) To perform ring-closure metathesis of a compound of formula XVIII or its eutectic or salt in the presence of a catalyst to provide a compound of formula XIX or its eutectic or salt:

[0339]

[0340] f) Hydrogenating a compound of formula XIX in the presence of a catalyst to provide a compound of formula XI or its eutectic or salt:

[0341]

[0342] g) Contacting a compound of formula XI or its eutectic or salt with a compound of formula XII or its eutectic or salt under amide coupling conditions to provide a compound of formula I or its eutectic or pharmaceutically acceptable salt:

[0343]

[0344] Where R is C 1-6 Alkyl groups, PG is a protecting group and R 1 It is a leaving group.

[0345] In pathway II, there is a change in the assembly sequence, in which the compound of formula VIII is first hydrolyzed to provide the compound of formula XVIII, which then undergoes ring-closed metathesis to provide the compound of formula XIX, which is hydrogenated to provide the compound of formula XI.

[0346] In one implementation, R is C 1-6 Alkyl group. In another embodiment, R is methyl. In another embodiment, R is tert-butyl.

[0347] In one implementation, R 1 Selected from halogenated, methanesulfonyloxy, p-toluenesulfonyloxy, trifluoromethanesulfonyloxy, nonafluorobutyryloxy, (4-bromo-benzene)sulfonyloxy, (4-nitro-benzene)sulfonyloxy, (2-nitro-benzene)sulfonyloxy, (4-isopropyl-benzene)sulfonyloxy, (2,4,6-triisopropyl-benzene)sulfonyloxy, (2,4,6-trimethyl-benzene)sulfonyloxy, (4-tert-butyl-benzene)sulfonyloxy, benzenesulfonyloxy, and (4-methoxy-benzene)sulfonyloxy. In another embodiment, R 1 It is halogenated. In another embodiment, R 1 It is chlorinated.

[0348] In another embodiment, this disclosure provides a method for preparing a compound of formula XVIII or its eutectic or salt:

[0349]

[0350] Including hydrolyzable compounds of formula VIII or their eutectic or salt to provide compounds of formula XVIII or their eutectic or salt:

[0351]

[0352] Where R is C 1-6 alkyl.

[0353] In another embodiment, this disclosure provides a method for preparing a compound of formula XIX or its eutectic or salt:

[0354]

[0355] This includes the cyclic metathesis of compounds of formula XVIII or their eutectic or salt in the presence of a catalyst to provide compounds of formula XIX.

[0356] In another embodiment, this disclosure provides a method for preparing a compound of formula XI or its eutectic or salt:

[0357]

[0358] This includes hydrogenating a compound of formula XIX or its eutectic or salt in the presence of a catalyst to provide a compound of formula XI or its eutectic or salt:

[0359]

[0360] Pathway III

[0361] In another embodiment, this disclosure provides a method for preparing a compound of formula I or a eutectic or pharmaceutically acceptable salt thereof, the compound of formula I being named (1aR,5S,8S,9S,10R,22aR)-5-tert-butyl-N-[(1R,2R)-2-(difluoromethyl)-1-{[(1-methylcyclopropyl)sulfonyl]carbamoyl}cyclopropyl]-9-ethyl-18,18-difluoro-14-methoxy-3,6-dioxo-1,1a,3,4,5,6,9,10,18,19,20,21,22,22a-tetradecano-8H-7,10-methylbridged cyclopropano[18,19][1,10,3,6]dioxadiazaaranenonadecanocyclo[11,12-b]quinoxaline-8-carboxamide:

[0362]

[0363] include:

[0364] a) Contacting a compound of formula XIII or its eutectic or salt with a compound of formula XIV or its eutectic or salt under cross-metathesis conditions to provide a compound of formula XV or its eutectic or salt:

[0365]

[0366]

[0367] b) Hydrogenating a compound of formula XV or its eutectic or salt in the presence of a catalyst to provide a compound of formula XVI or its eutectic or salt:

[0368]

[0369] c) Subjecting a compound of formula XVI or its eutectic or salt to N-deprotection conditions to provide a compound of formula XVII or its eutectic or salt:

[0370]

[0371] d) Contacting a compound of formula XVII with an amide coupling agent under lactamation conditions to provide a compound of formula X or its eutectic or salt:

[0372]

[0373] e) Hydrolyzing a compound of formula X or its eutectic or salt to provide a compound of formula XI or its eutectic or salt:

[0374]

[0375] f) Contacting a compound of formula XI or its eutectic or salt with a compound of formula XII or its eutectic or salt under amide coupling conditions to provide a compound of formula I or its eutectic or pharmaceutically acceptable salt:

[0376]

[0377]

[0378] Where R is C 1-6 Alkyl groups and PG are protecting groups.

[0379] Cross-metathesis conditions include a catalyst and a solvent. In one embodiment, the catalyst is Zhan B. In another embodiment, the solvent is toluene. In yet another embodiment, the cross-metathesis conditions include a temperature of approximately 90-100°C.

[0380] The hydrogenation conditions in step b) include a catalyst and a solvent. In one embodiment, the catalyst is platinum on carbon. In another embodiment, the solvent is isopropyl acetate.

[0381] The N-deprotection conditions in step c) include an acid and a solvent. In one embodiment, PG is Boc. In another embodiment, the acid is HCl. In yet another embodiment, the solvent is dioxane.

[0382] The lactamation conditions in step d) include the coupling agent in the presence of a base and a solvent. In one embodiment, the coupling agent is 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC) with hydroxybenzotriazole monohydrate (HOBt). In another embodiment, the base is triethylamine. In yet another embodiment, the solvent is N,N-dimethylformamide (DMF).

[0383] In one implementation, R is C 1-6Alkyl group. In another embodiment, R is methyl. In another embodiment, R is tert-butyl.

[0384] In another embodiment, this disclosure provides a method for preparing a compound of formula XV or its eutectic or salt:

[0385]

[0386] This includes contacting a compound of formula XIII or its eutectic or salt with a compound of formula XIV or its eutectic or salt under cross-metathesis conditions to provide a compound of formula XV or its eutectic or salt:

[0387]

[0388] Where R is C 1-6 Alkyl groups and PG are protecting groups.

[0389] In another embodiment, this disclosure provides a method for preparing a compound of formula XVI or its eutectic or salt:

[0390]

[0391] This includes hydrogenating a compound of formula XV or its eutectic or salt in the presence of a catalyst to provide a compound of formula XVI or its eutectic or salt:

[0392]

[0393] Where R is C 1-6 Alkyl groups and PG are protecting groups.

[0394] In another embodiment, this disclosure provides a method for preparing compounds of formula XVII or their eutectic or salt:

[0395]

[0396] This includes subjecting compounds of formula XVI or their eutectic or salt to N-deprotection conditions to provide compounds of formula XVII or their eutectic or salt:

[0397]

[0398] Where R is C 1-6 Alkyl groups and PG are protecting groups.

[0399] In another embodiment, this disclosure provides a method for preparing a compound of formula X or its eutectic or salt:

[0400]

[0401] This includes contacting a compound of formula XVII with an amide coupling agent under lactamation conditions to provide a compound of formula X or its eutectic or salt, wherein R is C 1-6 alkyl.

[0402] compound

[0403] In another embodiment, this disclosure provides a compound of formula IV or its eutectic or salt:

[0404]

[0405] Where R 1 It is a leaving group. In one embodiment, R 1 Selected from halogenated, -O-(toluenesulfonyl), -O-(trifluoromethanesulfonyl), -O-(4-nitrophenyl), and -B(OY)2, wherein Y is independently H or C. 1-4 Alkyl groups, or two Y groups together with the atoms they are attached to, form a 5- or 6-membered ring. In another embodiment, R 1 It is halogenated. In another embodiment, R 1 It is chlorinated.

[0406] In another embodiment, R 1 It is NH2.

[0407] In another embodiment, this disclosure provides a compound of formula V or its eutectic or salt:

[0408]

[0409] Where R is C 1-6 Alkyl groups and PG are protecting groups. In one embodiment, PG is selected from Boc, Cbz, and Fmoc. In another embodiment, PG is Boc. In another embodiment, R is methyl. In another embodiment, R is tert-butyl.

[0410] In another embodiment, this disclosure provides a compound of formula VI or its eutectic or salt:

[0411]

[0412] Where R is C 1-6 Alkyl group. In another embodiment, R is methyl. In another embodiment, R is tert-butyl.

[0413] In another embodiment, this disclosure provides a compound of formula VII or its eutectic or salt:

[0414]

[0415] In another embodiment, this disclosure provides a compound of formula VIII or its eutectic or salt:

[0416]

[0417] Where R is C 1-6 Alkyl group. In another embodiment, R is methyl. In another embodiment, R is tert-butyl.

[0418] In another embodiment, this disclosure provides compounds of formula XIII or their eutectic or salt:

[0419]

[0420] In another embodiment, this disclosure provides compounds of formula XIV or their eutectic or salt:

[0421]

[0422] Where R is C 1-6 Alkyl groups and PG are protecting groups. In one embodiment, PG is selected from Boc, Cbz, and Fmoc. In another embodiment, PG is Boc. In another embodiment, R is methyl. In another embodiment, R is tert-butyl.

[0423] In another embodiment, this disclosure provides compounds of formula XV or their eutectic or salt:

[0424]

[0425] Where R is C 1-6 Alkyl groups and PG are protecting groups. In one embodiment, PG is selected from Boc, Cbz, and Fmoc. In another embodiment, PG is Boc. In another embodiment, R is methyl. In another embodiment, R is tert-butyl.

[0426] In another embodiment, this disclosure provides compounds of formula XVI or their eutectic or salt:

[0427]

[0428] Where R is C 1-6 Alkyl groups and PG are protecting groups. In one embodiment, PG is selected from Boc, Cbz, and Fmoc. In another embodiment, PG is Boc. In another embodiment, R is methyl. In another embodiment, R is tert-butyl.

[0429] In another embodiment, this disclosure provides compounds of formula XVII or their eutectic or salt:

[0430]

[0431] Where R is C 1-6Alkyl group. In one embodiment, R is methyl. In another embodiment, R is tert-butyl.

[0432] In another embodiment, this disclosure provides compounds of formula XVIII or their eutectic or salt:

[0433]

[0434] In another embodiment, this disclosure provides compounds of formula XIX or their eutectic or salt:

[0435]

[0436] Intermediates in the synthesis of Formula I can be used in the next step with or without purification. Conventional purification methods include recrystallization, chromatography (e.g., adsorption, ion exchange, and HPLC).

[0437] In some embodiments, purification methods may include one or more intermediates from the synthesis of Formula I and / or chiral resolution of Formula I. Non-limiting examples of such methods include crystallization, chiral resolution reagents, and / or chiral chromatography. For example, in some embodiments, the Formula I compound may be further purified by crystallization with cincorine alkaloids.

[0438] Example

[0439] The compounds disclosed herein can be prepared using the methods disclosed herein, with conventional modifications that are obvious based on the disclosure herein, and methods known in the art. Conventional and well-known synthetic methods can be used outside of the teachings herein. The synthesis of the compounds described herein can be carried out as illustrated in the following examples. Reagents, if available, can be purchased from, for example, Sigma Aldrich or other suppliers. Unless otherwise stated, starting materials used in the following reactions are available from commercial sources.

[0440] Example 1. Synthesis of (1aR,5S,8S,9S,10R,22aR)-5-tert-butyl-N-[(1R,2R)-2-(difluoromethyl)-1-{[(1-methylcyclopropyl)sulfonyl]carbamoyl}cyclopropyl]-9-ethyl-18,18-difluoro-14-methoxy-3,6-dioxo-1,1a,3,4,5,6,9,10,18,19,20,21,22,22a-tetradecanohydro-8H-7,10-methylbridged-cyclopropano[18,19][1,10,3,6]dioxadiazarocyclo[11,12-b]quinoxaline-8-carboxamide (I) via route I

[0441] Compound I is synthesized via pathway I as shown below:

[0442]

[0443] Synthesis of intermediates for compounds of formula I

[0444] A. Synthesis of (2S,3S,4R)-3-ethyl-4-hydroxypyrrolidine-2-carboxylic acid methyl ester toluenesulfonate (II)

[0445]

[0446] The reduction sequence of the double bond and ketone is reversed, resulting in new intermediates, B (R = tert-butyl) and C (R = tert-butyl). Tert-butyl ester is used in the preparation of D in US Publication No. 2014-0017198; however, it is directly converted to methyl ester toluenesulfonate without chromatography and crystallized to remove diastereomer impurities. Single-crystal X-ray data of toluenesulfonate II were obtained.

[0447] Step 1: Synthesis of A

[0448]

[0449] I. Enamine forms A

[0450]

[0451] DMF-DMA (125.3 g, 2.0 eq.) and DCM (300 mL) were combined in a reaction vessel and heated to 45 °C. In a separate vessel, commercially available (S)-4-oxopyrrolidone-1,2-dicarboxylic acid di-tert-butyl ester (150 g) was dissolved in DCM (300 mL) under N2. This solution was loaded into the reaction vessel containing the DMF-DMA solution over approximately 3 hours. Upon completion of the reaction, the solution was cooled to approximately room temperature. 5% LiCl (750 mL) was added to the reactor and the mixture was stirred. The layers were separated, and the aqueous layer was removed. The organic layer was washed with water (750 mL) and dried with Na2SO4, and the mixture was filtered.

[0452] The filtrate was concentrated to ~200 mL and loaded with heptane (600 mL) to obtain a turbid solution. The mixture was further concentrated to remove residual DCM. Another 600 mL of heptane was added, and the mixture was heated to about 50-60 °C and aged for about 1 h to obtain a slurry. The slurry was cooled to about 15 °C for about 4 hours before aging overnight (~18 h) at about 15 °C. Intermediate A (R = tert-butyl) was separated by vacuum filtration and washed with 2X heptane. The resulting solid was dried at about 45 °C to obtain A (R = tert-butyl). 1¹H NMR (400MHz, CDCl₃) (mixture of E / Z isomers): δ 7.4 (s, 1H), 5.2–5.3 (s, 1H), 3.8 (d, 2H), 3.2 (wide s, 6H), 1.5 (s, 9H), 1.4 (s, 9H). UPLC / MS M+1 = 341 amu.

[0453] Alternative reagents and reaction conditions to those disclosed above may also be used. For example, alternative solvents may be used, such as other polar aprotic solvents (e.g., dimethylformamide, methyl tert-butyl ether, and isopropyl acetate) or nonpolar solvents (e.g., toluene, cyclohexane, and heptane). The reaction may also be carried out without a solvent or in a mixture of the above solvents. Furthermore, temperatures in the range of about 25–about 50 °C may be used. Optional crystallization solvent systems (e.g., DCM:heptane, toluene:heptane, cyclohexane:heptane, and cyclohexane) may also be used.

[0454] Step 2: Synthesis of B (R = tert-butyl)

[0455]

[0456] IA (R = tert-butyl) methylated to B (R = tert-butyl):

[0457]

[0458] Add A (151 g, 0.44 mol, 1.0 equiv) to the reaction vessel. Evacuate the vessel, purge with nitrogen, and dissolve the matrix in MeTHF (450 mL, 3 vol). Cool the reaction mixture to an internal temperature of approximately -12 °C and treat it dropwise over approximately 1 h with methyl magnesium bromide (3.0 M solution in 155 mL diethyl ether, 0.55 mol, 1.25 equiv). At the completion of the reaction (approximately 2 h), reverse quench the reaction by adding the reaction mixture to a cold, saturated aqueous solution of ammonium chloride (400 mL). If emulsification is observed, add more aqueous solution of ammonium chloride or 2 M HCl. Extract the aqueous layer with toluene (1 x 200 mL). Combine the organic layers, wash with 1 M HCl (150 mL), then wash with brine (150 mL), and concentrate under vacuum to provide B. 1 H NMR (400MHz, CDCl3): δ6.90-6.92(1H,m),5.08-5.16(1H,m),3.94-4.00(2H,m),2.02-2.04(3H,m),1.44-1.49(18H,m).

[0459] Alternative reagents and reaction conditions to those disclosed above may also be used. For example, other nucleophiles such as methylmagnesium reagent, methyllithium, methyllithium-lithium chloride, methylcopper oxide, and other methyl metal reagents may be used. Additionally, alternative solvents such as other polar or nonpolar aprotic solvents may be used.

[0460] Step 3: Synthesis of C (R = tert-butyl)

[0461]

[0462] IB (R = tert-butyl) hydrogenated to C (R = tert-butyl):

[0463]

[0464] Enone B (R = tert-butyl) (32.0 g, 0.10 mol) was dissolved in toluene (3 vol) under a nitrogen atmosphere. Pd / C (1.1 g, 0.5 mol%) was then added, and the reactants were washed with nitrogen, followed by washing with H2, and vigorously stirred at 1 atm H2 at room temperature. After the reaction was complete, diatomaceous earth (0.1 s, 13.2 g) was added, and the mixture was stirred for 5 minutes. The heterogeneous mixture was filtered through diatomaceous earth and washed with additional toluene (0.5–1 vol) and concentrated to dryness to provide C. 1 HNMR (400MHz, CD3OD): δ4.68(dd,J=36.9,9.3Hz,1H),3.99–3.75(m,2H),2.63(tdd,J=13.7,9.2,4.6Hz ,1H),1.89(dt,J=13.8,6.7Hz,1H),1.46(s,9H),1.43(s,9H),1.30–1.16(m,1H),1.07(t,J=7.4Hz,3H).

[0465] Alternative reagents and reaction conditions to those disclosed above may also be used. For example, other heterogeneous metal catalysts may be used, such as platinum, palladium, ruthenium, nickel, and other metals, or metal nanoparticles, on carbon, alumina, silica, and other heterogeneous supports. Lewis pairs such as hydroxy[4-[bis(2,4,6-trimethylphenyl)phosphino]-2,3,5,6-tetrafluorophenyl]hydrobis(2,3,4,5,6-pentafluorophenyl)borate or homogeneous metal catalysts such as trichlorotriphenylphosphine (I) rhodium(I) or (1,5-cyclooctadiene)(pyridine)(tricyclohexylphosphine)-iridium(I) hexafluorophosphate may also be used. Other solvents (e.g., water, protic solvents such as methanol, ethanol, or acetic acid), aprotic solvents (e.g., dimethyl sulfoxide, tetrahydrofuran, ethyl acetate, acetonitrile, toluene, dichloromethane, or acetone), or combinations thereof may be used. Furthermore, the temperature may be in the range of about -20°C to about 150°C. Alternatively, hydrogen gas within a certain pressure range can be used, or formates such as ammonium formate or formic acid can be used. Alternatively, diimide reduction conditions can be used.

[0466] Step 4: Synthesis of D (R = tert-butyl)

[0467]

[0468] The reduction of IC (R = tert-butyl) to provide D (R = tert-butyl)

[0469]

[0470] ZnCl2 (27.3 g, 200 mmol, 2 equiv) and CPME (7 vol, 220 mL relative to C) were mixed and the heterogeneous mixture was heated to an internal temperature of approximately 95 °C and stirred at that temperature for approximately 1.5 hours. The resulting slurry was cooled to approximately 25 °C, NaBH4 (7.56 g, 200 mmol, 2 equiv) was added, and the mixture was stirred overnight (~18 hours).

[0471] The slurry was cooled to approximately 0°C, and a C(R = tert-butyl) solution (~100 mmol) in toluene (total 3 vol) was slowly added while maintaining the temperature to approximately below +3°C. After the addition, the mixture was stirred at approximately 0°C until the starting material was completely consumed. The reaction was quenched by adding it in reverse to a solution of citric acid (2.5 equiv, 48 g) in ice water (200 mL). The layers were separated, and the organic layer was washed with brine (60 mL, 2 vol), dried with MgSO4 (0.05 s, 1.5 g), and filtered. The crude organic solution was concentrated, diluted with 2 volumes of hexane, filtered through silica gel, and eluted with 1:1 acetone:hexane. Vacuum concentration yielded a compound of formula D(R = tert-butyl).

[0472] 1 H NMR (400MHz, CDCl3): δ4.30 (dd, J=26.4, 8.4Hz, 1H), 4.24–4.14 (m, 1H), 3.89 (ddd, J=14.6, 10.6, 7.5Hz, 1H), 3.15 (ddd, J=17. 7,10.6,7.1Hz,1H),2.20–2.05(m,2H),1.70–1.59(m,1H),1.48(s,9H),1.44(s,9H),1.35-1.23(m,1H),1.07(t,J=7.4Hz,3H).

[0473] Alternative reagents and reaction conditions to those disclosed above may also be used. For example, other reducing agents may be used, such as borohydrides (e.g., sodium borohydride, lithium borohydride, or calcium borohydride), acyloxyborohydrides (e.g., sodium acetoxyborohydride or lithium trifluoroacetoxyborohydride), boranes or borane complexes, hydrogen, aluminum hydride reagents (e.g., lithium aluminum hydride or diisobutylaluminum hydride), diborane, diazonium, sodium cyanoborohydride, 9-BBN, tributyltin hydrogenation, silanes (e.g., triethylsilane), and aluminum isopropoxides in combination with isopropanol. In addition, alternative catalysts or promoters can be used, such as Lewis or Bronsted acids or combinations thereof; bases; heterogeneous metal catalysts (e.g., platinum, palladium, ruthenium, nickel, and other metals on carbon, alumina, silica, and other heterogeneous supports); metal nanoparticles; hindered Lewis acid-base pairs (e.g., hydrogen[4-[bis(2,4,6-trimethylphenyl)phosphino]-2,3,5,6-tetrafluorophenyl]hydrobis(2,3,4,5,6-pentafluorophenyl)boronic acid esters); homogeneous metal catalysts (e.g., trichlorotriphenylphosphine)rhodium(I) or (1,5-cyclooctadiene)(pyridine)(tricyclohexylphosphine)-iridium(I)hexafluorophosphate). Furthermore, other solvents such as water, protic solvents (e.g., methanol, ethanol, or acetic acid), aprotic solvents (e.g., dimethyl sulfoxide, tetrahydrofuran, ethyl acetate, acetonitrile, toluene, dichloromethane, or acetone), and combinations thereof can be used.

[0474] Synthesis of compounds of formula II (R=CH3)

[0475]

[0476] Deprotection and transesterification of D (R = tert-butyl) to give II (R = CH3):

[0477]

[0478] D(R=tBu) (5.55 g, 17.6 mmol) and methanol (55.5 mL) were mixed in a reaction vessel. p-Toluenesulfonic acid (10.7 g, 3.2 eq.) was added to the solution and the mixture was stirred at room temperature for about 1 hour. The mixture was then heated to about 60 °C. The reaction was stirred until the reaction was complete. The reaction mixture was concentrated to about 4 times its volume and cooled to about 45 °C. MTBE (4 times its volume) was slowly added, followed by seed crystal II (0.05%). The mixture was then aged for about 30 minutes. An additional MTBE (5 times its volume) was added over about 90 minutes and the resulting mixture was stirred overnight.

[0479] The mixture was filtered and washed with 2 volumes of MTBE. The resulting wet filter cake was vacuum dried at about 40°C to obtain compound II (R=CH3) as a toluenesulfonate. 1 H NMR(400MHz,MeOD)δ7.7(d,2H),7.2(d,2H),4.7(d,1H),4.3(m,1H),3.8(s, 3H),3.6(m,1H),3.2(m,1H),2.4(m,1H),2.3(s,3H),1.3(m,2H),1.0(t,3H). LC / MS M+1=174.1.

[0480] Alternative reagents and reaction conditions to those disclosed above may also be used. For example, methanol and MTBE co-solution, toluene, or other non-alcoholic solvents may be used, and temperatures in the range of approximately 0-60°C may be employed. Additionally, alternative crystallization solvent systems may include methanol:MTBE, ethanol:MTBE, or acetone:MTBE. Furthermore, alternative salts (e.g., HCl, HBr, methanesulfonates, p-bromobenzenesulfonates, trifluoromethanesulfonates, benzenesulfonates) may be used.

[0481] Synthesis of B. 3-chloro-2-(1,1-difluorobut-3-en-1-yl)-6-methoxyquinoxaline (IV)

[0482] Compound IV was synthesized via two different routes as described below.

[0483] Approach I

[0484]

[0485] Compound IV contains one more methylene group than the analog used in U.S. Publication No. 2014-0017198 and therefore requires a different starting material. Ethyl trifluoropyruvate is converted to intermediate G in three steps. Intermediate G is ttelescoped through to form a 4:1 regioisomer mixture of J and K. In U.S. Publication No. 2014-0017198, nitro, amino-anisole is used to form a ring in a two-step process of first reacting the amine and then reducing the nitro to achieve cyclization. Two regioisomers are formed. In this pathway, the starting material is changed to a diamino analog and a similar mixture is obtained. The mixture is chlorinated and the desired isomer IV is purified by conventional methods.

[0486] Step 1: Synthesis of G

[0487]

[0488] I. Intermediate for the synthesis of formula G from ethyl trifluoropyruvate:

[0489]

[0490] a. Allylation of ethyl trifluoropyruvate to provide E:

[0491]

[0492] Ethyl trifluoropyruvate (86 g, 0.5056 mol, 1.0 equivalent) and dichloromethane (260 mL) were added to the reaction vessel. Allyl alcohol (31 g, 0.5337 mol, 1.1 equivalent) was added dropwise over approximately 30 minutes while maintaining the reaction temperature below approximately 27 °C. The reaction was cooled to approximately 5 °C, and pyridine (123 mL, 1.52 mol, 3.0 equivalent) was added over approximately 50 minutes while maintaining the reaction temperature below approximately 8 °C. Then, thionyl chloride (90 g, 0.76 mol, 1.5 equivalent) was added over approximately 90 minutes while maintaining the reaction temperature below approximately 12 °C. The reaction was stirred at 5–10 °C for approximately 30 minutes, then heated to approximately 22 °C over approximately 30 minutes and maintained at approximately 22 °C until the reaction was considered complete. The reaction mixture was poured into 860 mL of chilled (approximately 8 °C) water and the phases were separated. The aqueous phase was back-extracted with 200 mL of dichloromethane. The combined dichloromethane phases were sequentially washed with water (860 mL), 5 wt% NaHCO3 solution (2 x 250 mL), and a final water wash (250 mL) and dried over Na2SO4. After solvent removal, the crude product E was separated and used directly in the next step. 1H NMR (300MHz, CDCl3): δ5.92 (m, l H), 5.38 (dq, J=14.1, 1.4Hz, l H), 5.27 (dq, J=10.3, 1.2Hz, l H), 4.40 (d, J = 7.1Hz, 2H), 4.34 (m, 2H), 1.30 (t, J = 7.1Hz, 3H).

[0493] II. Zn-mediated elimination of ClF from E to provide F, followed by Claisen to provide G:

[0494]

[0495] Zinc powder (324 g, 4.95 mol, 2.0 equivalent), CuI (6 g, 0.032 mmol, 0.013 equivalent), and N,N-dimethylformamide (DMF) (3.0 L) were loaded into the reaction vessel. The mixture was vigorously stirred while being added dropwise over approximately 10 minutes via a funnel with Me3SiCl (309 mL, 2.43 mmol, 1.0 equivalent), maintaining the reaction temperature at approximately <25 °C. The reaction was stirred at approximately 25 °C for approximately 30 minutes. The reaction was then cooled to 0–5 °C over 20 minutes, and a solution of compound E (600 g, 2.43 mol, 1.0 equivalent) in DMF (3.0 L) was slowly added over approximately 60 minutes, maintaining the reaction temperature at approximately <10 °C. The reaction was stirred at 5–10 °C for approximately 30 minutes, then heated to approximately 22 °C over approximately 30 minutes and maintained at approximately 22 °C until the reaction proceeded. 19 F NMR is considered complete (usually 1-2 hours).

[0496] III.F's Claisen rearrangement to provide G

[0497] The above reaction mixture was filtered and washed with ethyl acetate (2 x 3 L). Water (1.5 L) was added to the organic phase and the layers were separated. The organic layer was then washed with two portions of water (2 x 1.5 L). The organic solution was concentrated to obtain crude F. It was dissolved in 3.0 L (5 times its volume) of toluene and heated to about 80 °C until the reaction was considered complete (usually 1–3 h). The reaction was cooled to about 22 °C and the solvent was removed by rotary evaporation to obtain crude product G (~70 wt%). 1 H NMR (300MHz, CDCl3): δ5.90 (m, l H), 5.28 (m, 2H), 4.40 (q, J = 7.1Hz, 2H), 2.83 (dt, J = 18.5, 7.0Hz, 2H), 1.32 (t, J = 7.0Hz, 3H); 19 F NMR (CDC13)δ-112.8(t).

[0498] Alternative reagents and reaction conditions to those disclosed above may also be used. For example, other amine bases (e.g., 4-dimethylaminopyridine, imidazole, or triethylamine) may be used. Additionally, optional allylating agents (e.g., allyl chloride, allyl bromide), halogenating agents (e.g., thionyl bromide), olefinizing agents (e.g., magnesium), or zinc activators (e.g., methanesulfonic acid, hydrochloric acid, diisobutylaluminum hydride, diethylaluminum chloride) may be used. Furthermore, other solvents (e.g., dichloromethane, benzene, toluene, methyl tert-butyl ether, tetrahydrofuran, or 2-methyltetrahydrofuran) may be used.

[0499] Step 2: Synthesis of H

[0500]

[0501] IH from the synthesis of G

[0502]

[0503] G (26.2 g, 136.6 mmol, 1.0 equiv.) and THF (236 mL, 9 vol.) were loaded into the reaction flask. Water (52 mL, 2 vol.) was added, followed by LiOH·H₂O (14.9 g, 354.5 mmol, 2.6 equiv.), maintaining the reaction temperature below approximately 33 °C. The reaction was maintained at approximately 22 °C for approximately 3 hours, followed by quenching with 250 mL of 1 M HCl. The pH was then adjusted to 3 by adding concentrated HCl (20 mL). The phases were separated, and the aqueous phase was back-extracted with methyl tert-butyl ether (260 mL). Layer separation was performed, and NaCl (52 g) was added to the aqueous phase extracted with MTBE (2 x 130 mL) and then with EtOAc (50 mL). All organic phases were combined and dried over Na₂SO₄, filtered, concentrated, and dried under vacuum to obtain H₂. 1 H-NMR (400MHz, DMSO-d6) δ13.2(br s,1H),6.92(br s,2H),5.83-5.70(m,1H),5.20-5.13(m,2H),2.83-2.65(m,2H). 19 F-NMR(DMSO-d6)δ-88.20(t,J=20.8Hz).

[0504] Alternative reagents and reaction conditions to those disclosed above may also be used. For example, other bases such as potassium hydroxide / sodium hydroxide, potassium tert-butoxide, or sodium / potassium trimethylsilanolate may be used. Additionally, optional catalysts (e.g., tetrabutylammonium chloride) may be used. Furthermore, other solvents such as methyl-tert-butyl ether / water, 2-methyltetrahydrofuran / water, tetrahydrofuran / water, and methyl-tert-butyl ether / water / heptane may be used.

[0505] Step 3: Synthesis of J

[0506]

[0507] I. Condensation followed by cyclization to provide J from H:

[0508]

[0509] Diamine (6.06 g, 28.7 mmol, 1.0 equivalent) and ethanol (130 mL) were loaded into the reaction vessel. Triethylamine (8.8 mL, 63.1 mol, 2.2 equivalent) was added over approximately 5 minutes, maintaining the reaction temperature at approximately <25 °C. The reaction was stirred for approximately 10 minutes to provide solution. Acetic acid (16.4 mL, 287 mmol, 10 equiv.) was added, followed by a solution of H in ethanol (40 mL) (5.75 g, 31.6 mmol, 1.1 equiv.), and the reaction was maintained at approximately 22 °C until completion. The reaction mixture was solvent-exchanged into approximately 80 mL of dichloromethane and washed sequentially with 0.1 N HCl (60 mL), saturated NaHCO3 solution (60 mL), and a final brine wash (60 mL). The organic layer was dried over Na2SO4 and filtered. After solvent removal, a crude mixture of J / K was obtained. The crude mixture was dissolved in dichloromethane, washed twice with 0.1N HCl, once with water, and once with brine. It was then dried with sodium sulfate, filtered, and concentrated to obtain J / K. 1 H NMR (300MHz, CDCl3): δ7.82 (d, J=9.0Hz, lH), 7.38 (m, 1H), 6.97 (dd, J=9.0, 3.0Hz, lH), 6. 82(d,J=3.0Hz,lH),5.88(m,1H),5.22(m,2H),3.91(s,3H),3.28(td,J=12.0,3.0Hz,2H). 19 F NMR (282.2MHz, CDCl3): δ-100.3ppm (J) and –100.8ppm (K). LCMS: m / z=266.93.

[0510] Alternative reagents and reaction conditions to those disclosed above may also be used. For example, when R = NH₂, other bases (e.g., potassium hydroxide / sodium hydroxide, potassium tert-butoxide, sodium trimethylsilanolate / potassium hydroxide) may be used. Other additives and optional solvents (e.g., ethanol, ethanol / isopropyl acetate, or toluene) may also be used.

[0511] Alternatively, when R = NO2, alternative reagents and reaction conditions to those disclosed above can be used. For example, iron, BHT, and AcOH can be used in combination with ethanol as a solvent and a temperature range of approximately 60°C to approximately 70°C.

[0512] Step 4: Synthesis of IV

[0513]

[0514] Chlorination of IJ to provide compounds of formula IV:

[0515]

[0516] J (7.4 g, 27.79 mmol, 1.0 equivalent) and DMF (148 mL) were loaded into the reaction vessel. Phosphorus oxychloride (POCl3) (4.2 mL, 44.47 mmol, 1.6 equivalent) was loaded over approximately 3 minutes, maintaining the reaction temperature below approximately 30 °C. The reaction was heated to approximately 75 °C until the reaction was complete. The reaction mixture was slowly poured into 150 mL of water while maintaining the temperature below approximately 25 °C. Methyl tert-butyl ether (MTBE) (75 mL) was loaded and the phases were separated. The aqueous phase was back-extracted with 4 x 75 mL of MTBE. The combined MTBE phases were washed sequentially with saturated NaHCO3 solution (200 mL) and saturated NaCl solution (150 mL) and dried over Na2SO4. After solvent removal, the crude product IV was separated. The crude material was suspended in hexane (4.3 times its volume), heated to dissolve, and slowly cooled to approximately 20 °C, resulting in a slurry forming the desired regioisomer IV, which was subsequently separated by filtration and dried. 1 H NMR (300MHz, CDCl3): δ8.02 (d, J=9.0Hz, lH), 7.48 (dd, J=9.0, 3.0Hz, lH), 7.34 (d, J=3.0Hz,lH),5.97(m,1H),5.31(m,2H),4.0(s,3H),3.35(td,J=12.0,3.0Hz,2H). 19 F NMR (282.2 MHz, CDCl3): δ -96.3 ppm (IV) and –97.1 ppm (regioisomer). LCMS: m / z = 285.27.

[0517] Alternative reagents and reaction conditions to those disclosed above may also be used. For example, other chlorinating agents (e.g., trichloroisocyanuric acid, chlorine, 1,3-dichloro-5,5-dimethylhydantoin, N-chlorosuccinimide, thionyl chloride / DMF, oxalyl chloride / DMF) may be used. Additionally, other solvents such as acetonitrile or acetic acid, as well as hydrocarbon solvents (e.g., toluene or heptane), ethers (e.g., methyl tert-butyl ether or THF), or chlorinating solvents (e.g., dichloromethane or chloroform) may be used. Other amine additives (e.g., DABCO, triethylamine, or N-methylmorpholine) or phase-transfer catalysts (e.g., benzyltrimethylammonium chloride) may be used. Furthermore, temperatures in the range of about 20°C to about 80°C may be used.

[0518] Approach II

[0519]

[0520] Compounds G and H were synthesized as described in route I above.

[0521] Step 1: Synthesis of IV-b

[0522] Synthesis of I.IV-b from H

[0523]

[0524] In a reaction vessel, triphenylphosphine (235.2 g, 896.3 mmol) was dissolved in tetrachloride (300 mL) at ambient temperature. The solution was cooled to below about 5 °C, and then triethylamine (73 mL, 523.7 mmol) and H (41.8 g of active material, 295.4 mmol) were added. Aniline (32 mL, 351.2 mmol) was then slowly added over about 30 minutes. The mixture was stirred at below about 5 °C for about 1 hour, allowing the temperature to rise to ambient temperature. The solution was then heated to 50–55 °C, at which point the reaction became exothermic. The reaction temperature was rapidly increased to about 92 °C without heating, accompanied by vigorous reflux and gas release. The temperature was cooled to about 75 °C, and the mixture was stirred for about ten hours. Heptane (700 mL) was added to the reaction mixture, followed by concentration to remove about 700 mL of the filtrate. Add the second portion of heptane (700 mL), and heat the mixture to reflux at approximately 100°C for about 30 minutes, then cool to approximately 20°C. Stir the mixture at approximately 20°C for about 30 minutes, then filter. Mix the filter cake with another 700 mL of heptane, heat to reflux for about 30 minutes, cool to approximately 20°C, and stir for about 30 minutes. Filter the mixture, and combine the two filtrates and concentrate to provide purified IV-b. Crude IV-b is used directly in the next step without further processing. 1H NMR (300Hz, CDCl3): δ7.37–7.45 (m, 2H), δ7.25 (tt, J=7.8, 0.9Hz, 1H), δ6.98 (dd, J=8.7, 1.2Hz, 2H ), δ5.82–5.96(m,1H), δ5.35(d,J=8.4Hz,1H), δ5.30(s,1H), δ3.07(tdt,J=15.9,7.2,1.2Hz,2H); 13 C NMR (75Hz, CDCl3): δ 144.8, 139.7 (t, J = 36.7Hz), 129.0, 127.7 (t, J = 5.8Hz), 126.4, 124.2 (t, J = 282.8Hz), 121.7, 120.2, 39.5 (t, J = 24.0Hz).

[0525] Alternative reagents and reaction conditions to those disclosed above may also be used. For example, other bases may be used (e.g., diisopropylethylamine (DIPEA), pyridine, tributylamine, DBU, N-methylmorpholine (NMM)). Additionally, optional halogenating agents may be used (e.g., N-chlorosuccinimide, chloride(g), chloramine-T). Furthermore, other solvents may be used (e.g., dichloromethane, chloroform, chlorobenzene).

[0526] II. IV-b from the synthesis of G

[0527]

[0528] a.IV-a synthesis from G

[0529]

[0530] In a reaction vessel, G (10.0 g, 60.9 mmol) was dissolved in aniline (50 mL, 548.7 mmol) at ambient temperature. The solution was heated to reflux at approximately 150 °C under nitrogen for approximately 24 hours. The mixture was cooled to below approximately 5 °C and then diluted with MTBE (100 mL). The pH was then adjusted to acidic by adding approximately 100 mL of 6N HCl aqueous solution at below approximately 5 °C. The mixture was heated to the maximum ambient temperature, allowed to settle, and separated. The aqueous phase was extracted with MTBE (2 × 100 mL). The combined organic phases were washed sequentially with 1N HCl aqueous solution and 5% NaHCO3 aqueous solution. The organic phase was filtered through a Na2SO4 pad and concentrated to provide crude IV-a. 1HNMR (300Hz, CDCl3): δ7.95 (bs, 1H), δ7.57 (d, J = 7.5Hz, 1H), δ7.37 (tt, J = 8.7, 2.4Hz, 1H), δ7.19 (t t,J=7.8,1.2Hz,1H), δ5.72–5.86(m,1H), δ5.27–5.35(m,2H), δ2.96(tdt,J=17.1,7.5,1.2Hz,2H); 13 C NMR (75 Hz, CDCl3): δ 161.6 (t, J = 28.7 Hz), 135.9, 129.2, 127.0 (t, J = 5.7 Hz), 125.6, 122.2, 120.2, 117.1 (t, J = 254.3 Hz), 38.4 (t, J = 24.0 Hz); MP: 48.0 ℃; GCMS m / z (relative intensity): 211 (100, M + ).

[0531] Alternatively, alternative reagents and reaction conditions to those disclosed above may be used. For example, other solvents (toluene, xylene, chlorobenzene, acetonitrile) may be used.

[0532] b. Synthesis of IV-b from IV-a

[0533]

[0534] IV-a (6.1 g, 28.0 mmol) was dissolved in DCM (60 mL) in a reaction vessel at ambient temperature. Phosphorus pentachloride (10.8 g, 51.9 mmol) was added in a single addition. The mixture was stirred at ambient temperature for approximately 16 hours. The reaction mixture was quenched by slowly transferring the mixture to a 40% aqueous solution of K3PO4 while maintaining the temperature below approximately 20 °C. The pH of the aqueous phase was adjusted to approximately 7.5 by adding another 40% aqueous solution of K3PO4. The phases were separated, and the aqueous phase was extracted with DCM (60 mL). The combined organic phases were filtered through a Na2SO4 pad and concentrated to provide crude IV-b. 1 H NMR (300Hz, CDCl3): δ7.37–7.45 (m, 2H), δ7.25 (tt, J=7.8, 0.9Hz, 1H), δ6.98 (dd, J=8.7, 1.2Hz, 2H ), δ5.82–5.96(m,1H), δ5.35(d,J=8.4Hz,1H), δ5.30(s,1H), δ3.07(tdt,J=15.9,7.2,1.2Hz,2H); 13C NMR (75Hz, CDCl3): δ 144.8, 139.7 (t, J = 36.7Hz), 129.0, 127.7 (t, J = 5.8Hz), 126.4, 124.2 (t, J = 282.8Hz), 121.7, 120.2, 39.5 (t, J = 24.0Hz).

[0535] Alternative reagents and reaction conditions to those disclosed above may also be used. For example, other bases may be used (e.g., sodium hydroxide, potassium hydroxide, dipotassium hydrogen phosphate, potassium carbonate, sodium carbonate). Additionally, optional halogenating agents may be used (e.g., N-chlorosuccinimide, chloride(g), chloramine-T, phosphorus trichloride, thionyl chloride). Furthermore, other solvents may be used (e.g., dichloromethane, chloroform, chlorobenzene, toluene, acetonitrile).

[0536] Step 2: Synthesis of IV-c from IV-b

[0537]

[0538] In a reaction vessel, IV-b (29.5 g of active material or 32 g of crude material, 128.2 mmol) was dissolved in acetonitrile (500 mL), followed by the addition of potassium cyanide (8.5 g, 130.5 mmol). The mixture was degassed under nitrogen vacuum and stirred at ambient temperature for approximately 16 hours. The mixture was concentrated under vacuum to completely remove acetonitrile and then suspended in toluene (500 mL). A 5% aqueous solution of NaHCO3 (250 mL) was added to dissolve the inorganic salt. The mixture settled and separated. The aqueous phase was extracted with toluene (250 mL). The combined organic phases were filtered through a Na2SO4 pad and concentrated to provide crude IV-c. 1 H NMR (300Hz, CDCl3): δ7.49 (tt, J=7.2, 1.8Hz, 2H), δ7.41 (tt, J=7.2, 1.2Hz, 1H), δ7.26 (dt, J=7.2, 1.8Hz, 2H), δ5.79–5.92(m,1H), δ5.37(dd,J=5.1,1.2Hz,1H), δ5.32(s,1H), δ3.07(tdt,J=16.5,7.2,1.2Hz,2H); 13 C NMR (75Hz, CDCl3): δ 146.0, 135.7 (t, J = 35.5Hz), 129.5, 127.0 (t, J = 4.7), 122.4, 120.9, 120.2, 117.3 (t, J = 245.0Hz), 108.9, 38.8 (t, J = 24.1Hz); GCMS m / z (relative intensity): 220 (70, M + ).

[0539] Alternative reagents and reaction conditions to those disclosed above may also be used. For example, other bases may be used (e.g., sodium hydroxide, potassium hydroxide, dipotassium hydrogen phosphate, potassium carbonate, sodium carbonate). Additionally, optional cyaniding agents may be used (e.g., trimethylsilyl cyanide, sodium cyanide, potassium ferrocyanide, lithium cyanide). Furthermore, other solvents may be used (e.g., dichloromethane, chloroform, chlorobenzene, toluene).

[0540] Step 3: Synthesis of IV-d from IV-c

[0541]

[0542] In a reaction vessel, methoxy-o-phenylenediamine was mixed with toluene (41 mL) at ambient temperature, followed by the addition of acetic acid (14.2 mL, 248 mmol). The black solution was degassed under nitrogen vacuum. At approximately 20 °C, a solution of IV-c in 11 mL of the prepared toluene (4.89 g of active material or 6.4 g of crude material, 22.2 mmol) was slowly added to the above solution over approximately three hours while maintaining the temperature at approximately 20 °C. The resulting mixture was then heated to approximately 30 °C for approximately 64 hours. The reaction mixture was cooled to below approximately 20 °C, and EtOAc (40 mL) was added, followed by adjustment of the pH to approximately 9–9.5 with approximately 76.5 mL of 3N NaOH aqueous solution. The mixture was filtered through diatomaceous earth (5 g), followed by sedimentation and phase separation. The separated aqueous phase was extracted with EtOAc (80 mL). The two organic phases were combined, and activated carbon (5 g) was added. The mixture was stirred at ambient temperature for approximately 16 hours and then filtered through diatomaceous earth (5 g). The filtrate was concentrated under vacuum to completely remove the solvent, and IPA (20 mL) was added. The mixture was heated to dissolve the crude solids at about 40 °C. The solution was heated to reflux for about 30 minutes and then cooled to about 20 °C. IV-d seed crystals (5 mg) were added to induce crystallization. The suspension was stirred at about 20 °C for about 1 hour. Water (30 mL) was added in a buffer over about five hours while maintaining the temperature at about 20 °C. The resulting suspension was stirred at about 20 °C for more than about 10 hours, then filtered and washed with 33% IPA / H2O (15 mL). The filter cake was dried to provide IV-d. 1 H NMR (300Hz, CDCl3): δ7.77(d,J=8.7Hz,1H), δ7.09(dd,J=9.6,3.0Hz,1H), δ6.98(d,J=3.0Hz,1 H), δ5.93–6.07(m,1H), δ5.25–5.37(m,4H), δ3.92(s,3H), δ3.32(tdt,J=17.4,6.9,1.2Hz,2H); 13C NMR (75 Hz, CDCl3): δ 162.3, 149.9, 144.1, 134.5 (t, J = 30.9 Hz), 131.6, 130.4, 128.9 (t, J = 4.6 Hz), 122.6 (t, J = 238.2 Hz), 120.9, 118.2, 104.0, 55.7, 39.4 (t, J = 24.1 Hz); MP: 102.4℃; LCMS m / z (relative intensity) 265.70 (100, M + ).

[0543] Alternatively, alternative reagents and reaction conditions to those disclosed above may be used. For example, other solvents (e.g., dichloromethane, chloroform, chlorobenzene, toluene, acetonitrile) and temperatures in the range of 10-80°C may be used.

[0544] Step 4: Synthesis of IV from IV-d

[0545]

[0546] In a reaction vessel, IV-d (5.0 g, 18.8 mmol) was dissolved in 100 mL of DCM at ambient temperature. The solution was cooled to below about 5 °C, and then 1 M BCl3 (19 mL, 19 mmol) was added to DCM in a buffer over about 15 minutes. Then t-BuNO2 (9 mL) was slowly added over about two hours while maintaining the temperature below about 5 °C. The mixture was allowed to warm to ambient temperature and stirred for about 12 hours. When the reaction reached completion, the mixture was concentrated under vacuum to remove the solvent and then dissolved in EtOAc (100 mL). The solution was cooled to below about 5 °C, and then 5% NaHCO3 aqueous solution was slowly added. The resulting mixture was allowed to warm to ambient temperature, settle, and separate. The aqueous phase was extracted with EtOAc (2 × 100 mL). Activated carbon (2.0 g) was added to the combined organic phases, and the mixture was stirred for about 16 hours, then filtered through diatomaceous earth (5 g). The filtrate was concentrated under vacuum to completely remove the solvent and IPA (25 mL) was added. The mixture was heated to reflux for about 30 minutes and then slowly cooled. IV seed crystals (5 mg) were added at 35–40 °C to induce crystallization. The mixture was cooled to about 20 °C and stirred for about two hours. Water (10 mL) was slowly added over about two hours. The mixture was stirred for about 1 hour and then cooled to below about 5 °C. The mixture was stirred at below about 5 °C for about 1 hour, then filtered and washed with 50% IPA / H2O (15 mL). The filter cake was dried to provide IV. 1H NMR (400Hz, CDCl3): δ8.00(d,J=9.2Hz,1H), δ7.45(dd,J=9.6,2.8Hz,1H), δ7.32(d,J=2.8Hz,1 H), δ5.91–6.01(m,1H), δ5.23–5.34(m,2H), δ3.98(s,3H), δ3.32(tdt,J=16.8,7.2,1.2Hz,2H); 13 C NMR (400 Hz, CDCl3): δ 162.8, 144.7, 143.9, 142.9 (t, J = 29.7 Hz), 134.9, 130.4, 128.6 (t, J = 4.6 Hz), 124.3, 122.4, 120.0 (t, J = 241.8 Hz), 105.5, 56.0, 40.2 (t, J = 24.5 Hz); MPa: 82.8℃; LCMS m / z (relative intensity): 284.69 (100, M + ).

[0547] Alternative reagents and reaction conditions to those disclosed above may also be used. For example, other bases (e.g., sodium hydroxide, potassium hydroxide, dipotassium hydrogen phosphate, potassium carbonate, sodium carbonate) may be used. Furthermore, other solvents (e.g., dichloromethane, chloroform, chlorobenzene, toluene, acetonitrile) may be used.

[0548] Synthesis of C.(S)-2-((((1R,2R)-2-allylcyclopropoxy)carbonyl)amino)-3,3-dimethylbutyric acid (S)-1-phenylethyl-1-amine salt (VII)

[0549] Compound VII was synthesized via two different routes as described below.

[0550] Approach I

[0551]

[0552] Compound VII was obtained from 5-bromo-pent-1-ene via Kulinkovich cyclopropanation, acylation, and enzymatic resolution. Cyclopropanol and then cyclopropyl acetate were distilled, but this was not mandatory. Acid extraction was used to remove any remaining acetylated material. The final product was separated as an S-1-phenylethylamine salt, which improved the diastereomeric purity and overall purity of the product. Recrystallization could be used to further improve the purity of the product. Other salts were also possible.

[0553] Step 1: Synthesis of (1R,2R)-2-allylcyclopropane-1-ol (M1)

[0554]

[0555] Kulinkovich reaction, acetylation, and enzymatic resolution:

[0556]

[0557] I. Reaction with ethyl formate and 5-bromo-1-pentene (Kulinkovich reaction)

[0558]

[0559] Magnesium shavings (2.45 equivalents) and MeTHF (8 volumes) were added to the reaction vessel. The flask was then purged with nitrogen, and 5-bromo-1-pentene (2.4 equivalents) was added to the addition funnel. The mixture was heated to approximately 60°C, and 0.05 volumes of 5-bromo-1-pentene were added dropwise to the mixture to initiate the reaction. Once the reaction had started, the remaining 5-bromo-1-pentene was slowly added to the flask over approximately 3 hours. After the addition, the reaction was allowed to stir at approximately 60°C for approximately 1 hour, after which Grignard L was cooled to room temperature. In a separate flask, ethyl formate (1.0 equivalent) and titanium isopropoxide (0.5 equivalent) in MeTHF (2 volumes) were added under nitrogen. The mixture was cooled to approximately 0°C, and Grignard L was slowly added to the flask over 3 hours. Upon completion of the addition, the reaction mixture was allowed to heat to room temperature and the reaction was stirred for approximately 12 hours. The mixture was then cooled to approximately 0°C, and 4M sulfuric acid (10 volumes) was slowly added. The slurry was stirred for 30 minutes, after which the salt dissolved. The mixture was then finely filtered. The two-phase mixture was separated, and the organic layer was washed twice with 10 wt.% sodium bicarbonate (10 times the volume) and once with water (10 times the volume). The organic layer was concentrated under reduced pressure at about 0°C to obtain crude 2-allylcyclopentanol M. 1 H NMR (400MHz, CDCl3): δ5.53-5.43(m,1H),4.76-4.70(m,1H),4.65-4.59(m,1H),2.90-2.86(m,1H),1.75(br s,1H),1.65-1.51(m,2H),0.69-0.59(m,1H),0.40-0.35(m,1H),0.05-0.01(m,1H).

[0560] Alternative reagents and reaction conditions to those disclosed above may also be used. For example, other aprotic solvents (e.g., tetrahydrofuran or diethyl ether) may be used. Additionally, other titanium catalysts, such as titanium(IV) alkoxides (e.g., MeTi(OiPr)3, MeTi(OtBu)3, ClTi(OiPr)3, ClTi(OtBu)3, or Ti(OtBu)4), may be used. Furthermore, temperatures in the range of approximately -20°C to approximately 100°C may be used.

[0561] II. Acetylation of 2-allylcyclopentanol (+ / -)-M:

[0562]

[0563] 2-Allylcyclopentanol M (1 equivalent) in 10 volumes of MeTHF was added to the reaction vessel. The vessel was purged with nitrogen, and the solution was subsequently cooled to 0°C. Triethylamine (3.0 equivalents) was then slowly added to the solution over approximately 30 minutes. The mixture was allowed to be stirred for approximately 30 minutes, after which acetyl chloride (2.5 equivalents) was added, maintaining the internal temperature below approximately 20°C. The reaction was then allowed to be stirred at approximately 21°C for at least 12 hours. After the specified time, water (6 volumes) was slowly added to the reactor, and the phases separated. The organic layer was then washed with 2M hydrochloric acid (6 volumes), 10 wt.% sodium bicarbonate (6 volumes), and subsequently brine (6 volumes). The organic layer was concentrated under reduced pressure at approximately 0°C to obtain crude racemic 2-allylcyclopropyl acetate N. 1 H NMR (400MHz, CDCl3): δ5.85-5.73(m,1H),5.10-5.04(m,1H),5.00-4.97(m,1H),3.85-3.82(m,1H),2.13 -2.07(m,1H),1.99(s,3H),2.01-1.89(m,1H),1.14-1.03(m,1H),0.87-0.76(m,1H),0.64-0.57(m,1H).

[0564] Alternative reagents and reaction conditions to those disclosed above may also be used. For example, other acetylation agents, such as acetic anhydride, may be used. Additionally, other acyl groups may be used for enzymatic resolution, such as alkyl homologues (e.g., C1-C10) or aromatic groups (e.g., benzoic acid, substituted benzoic acids, or naphtholic acids). Furthermore, other amine bases (e.g., N,N'-diisopropylethylamine, pyridine, or piperidine), metal hydrides (e.g., sodium hydride and potassium hydride), and alkoxides (e.g., sodium tert-butoxide, lithium tert-butoxide, or potassium tert-butoxide) may be used. Other halogenated solvents (e.g., dichloromethane or dichloroethane), and combinations thereof with 2-methyltetrahydrofuran or tetrahydrofuran, may also be used. Additionally, other temperature ranges between approximately -20°C and approximately 80°C may be used.

[0565] III. Enzymatic resolution of 2-allylcyclopentanol

[0566]

[0567] 2-Allylcyclopropyl acetate N was loaded into a reaction vessel in MeTHF (2 volumes) and MTBE phosphate buffer (10 volumes). The MTBE phosphate buffer was prepared by first dissolving dipotassium hydrogen phosphate (283 g) and potassium dihydrogen phosphate (104.8 g) in water (1.6 L). MTBE (800 mL) was added to the solution, and the two-phase mixture was stirred at about 21 °C for about 1 h. The organic layer was then separated and used as the MTBE phosphate buffer. The reaction mixture was then cooled to about 0 °C and loaded with a solid-loaded Novozyme 435 (1.7 wt.%). The reaction was allowed to proceed with stirring at about 0 °C for about 6 h, after which the mixture was filtered. The filtrate was then concentrated under reduced pressure at approximately 0°C to obtain a mixture of racemic (1S,2S)-2-allylcyclopropane-1-ol in a ratio of 10:1 to 15:1, consisting mainly of (1R,2R)-2-allylcyclopropane-1-ol M1 and a mixture of the corresponding residual acylation initiating materials. The crude mixture was then further processed as is.

[0568] Alternative reagents and reaction conditions to those disclosed above may also be used. For example, ether solvents (e.g., tetrahydrofuran (THF), methyltetrahydrofuran (MeTHF), diethyl ether (Et₂O), or 1,4-dioxane), water-miscible solvents (e.g., methanol, ethanol, and isopropanol), or other organic solvents (e.g., acetone or acetonitrile) may be used. Additionally, other deacylation ligases may be used. Furthermore, temperatures in the range of approximately -20°C to approximately 20°C may be used.

[0569] Step 2: Synthesis of VII

[0570]

[0571] I. Coupling to obtain VII

[0572]

[0573] A solution of alcohol M1 in MTBE and MeTHF (containing 14 g of the desired alcohol) was loaded into the reactor. DMF (140 mL) and N,N'-disuccinimidyl carbonate (DSC) (47.5 g, 1.3 eq) were loaded into the reactor to obtain a thin slurry. Pyridine (11.3 g, 1 eq) was loaded and the reaction mixture was heated to about 45 °C. Upon completion of the reaction, the reaction mixture was cooled to about 0 °C and quenched with water (196 mL). The reaction mixture was stirred for at least 30 minutes. Succinimidyl O could optionally be separated by extraction with ethyl acetate, washing the organic layer and removing the solvent by distillation, or used directly in subsequent steps without purification. 1HNMR (400MHz, CDCl3): δ5.83-5.74(m,1H),5.12-4.99(m,2H),4.13-3.99(m,1H),2.8 1(s,4H),2.13-1.92(m,2H),1.39-1.30(m,1H),1.11-1.04(m,1H),0.73-0.68(m,1H).

[0574]

[0575] The reaction continued with crude succinate intermediate O, followed by the addition of tert-leucine (23.4 g, 1.25 eq.) and K3PO4 (84.8 g, 2.8 eq.) to the reactor. The resulting mixture was heated to room temperature and stirred for approximately 18 h. At the end of the reaction, the mixture was diluted with MTBE (210 mL) and the pH was adjusted to pH 3 with 6 M HCl (~180 mL). The layers were separated, and the organic layer was adjusted to pH >10 with 2.5 M NaOH (~70 mL). The aqueous layer was removed, and the organic layer was washed with 0.5 M NaOH (100 mL). The combined alkaline aqueous layers were readjusted to pH <3 with 6 M HCl (~50 mL) and washed twice with MTBE (100 mL x 2).

[0576]

[0577] The combined organic layer solvent was exchanged with MTBE (107 mL). In a separate container, S(-)1-phenylethylamine (10.9 g, 1 eq.) was dissolved in MTBE (32.7 mL). The amine solution was slowly loaded into the solution containing the succinimide intermediate. A small amount of VII(S)-1-phenylethyl-1-amine salt (0.055 g, 0.5%) was loaded, followed by the remaining amine solution. The slurry was aged overnight to obtain a thick slurry. The resulting slurry was filtered and washed with MTBE (50 mL). The solids were dried in a vacuum furnace until a constant weight was reached, thus obtaining VII as (S)-1-phenylethyl-1-amine salt. NMR of the free acid: 1 H NMR (400MHz, CDCl3) δ7.4(m,5H),6.3(width s,3H),5.8(m,1H),5.3(d,1H),5.1(d,1H),4.2(q,1H),3.8(d ,1H),3.7(m,1H),2.1(m,1H),1.9(m,1H),1.5(d,3H),1.1(m,1H),0.9(d,9H),0.8(m,1H),0.5(q,1H). 13C-NMR(CDCl3)δ173.1,157.0,115.7,63.3,53.9,36.2,34.9,33.7,27.1,17.3,11.7.

[0578] Alternative reagents and reaction conditions to those disclosed above may also be used. For example, polar aprotic solvents (e.g., dimethylacetamide) and temperatures in the range of about 25°C to about 65°C may be used. Alternatively, optional crystallization solvent systems (e.g., acetonitrile) may be used.

[0579] Approach II

[0580]

[0581] The difference between pathway II and pathway I is that of the formation of intermediate M3 and its transformation into M1. The synthesis of M3 and its transformation into VII are discussed below.

[0582] M3 is synthesized from M2

[0583]

[0584] Alcohol M2 (100.0 g, 1019.0 mmol, provided as a solution in MTBE along with acetate impurity N1 from the previous enzymatic resolution step) was loaded into the reaction vessel. The actual amount of the loaded solution was calculated by determining the wt% of the enzymatic resolution solution and subsequently adjusting the loading amount to ensure 100.0 g of alcohol was present in the loading. Dichloromethane (300 mL) and triethylamine (134.0 g, 1324.6 mmol) were then loaded into the vessel. The reaction was cooled to an internal temperature of approximately 0 °C. In a separate flask, 3,5-dinitrobenzoyl chloride (305.4 g, 1324.6 mmol) was dissolved in dichloromethane (300 mL). The dinitrobenzoyl chloride stream was then loaded into the alcohol stream over approximately 15 minutes, maintaining an internal temperature below approximately 5 °C. The combined mixture was aged for approximately 4 hours. The reaction mixture was allowed to warm to room temperature and then water (600 mL) was added while the phase was vigorously stirred to ensure good mixing. The phase was allowed to settle, and the bottom phase separated and washed twice with additional water (600 mL). Silica gel (200 g) was loaded onto the final organic phase, and the slurry was allowed to age at room temperature for approximately 30 minutes. The slurry was filtered, and the silica gel cake was washed with 20 vol% isopropanol in heptane (the volume of washing solution was determined by eluting with 4 times the volume of the silica gel pad). The combined filtrate and washings were concentrated to approximately 200 mL by rotary evaporation. Isopropanol (600 mL) was loaded onto the concentrated stream and distilled to approximately 200 mL by rotary evaporation. This process was repeated until the desired concentration was reached. 1¹H NMR revealed less than 5% dichloromethane compared to isopropanol. Heptane was then loaded into the reaction mixture to reach a final volume of approximately 500 mL. The mixture was then heated to an internal temperature of approximately 45 °C. Crystallization was then carried out by seeding with 0.5 wt% (500 mg) of ester M3. The reaction was then cooled to approximately 0 °C over approximately 5 h and aged at that temperature for at least approximately 12 h. The resulting slurry was filtered and the filter cake was washed with heptane (100 mL). The separated solids were then vacuum dried at approximately 21 °C to provide M3. 1 H NMR (400MHz, CDCl3): δ9.22-9.21(m,1H),9.11-9.10(m,2H),5.95-5.85(m,1H),5.17-5.05(m,2H), 4.27-4.24(m,1H),2.22-2.07(m,2H),1.41-1.33(m,1H),1.14-1.09(m,1H),0.85-0.80(m,1H); HRMS calc`d C 13 H 13 N₂O₆[M+H] + Measured value: 293.0774.

[0585] Alternative reagents and reaction conditions to those disclosed above may also be used. For example, other bases (e.g., diisopropylethylamine, N-methylmorpholine) and other solvents (e.g., chloroform, tetrahydrofuran, MTBE, 2-methyltetrahydrofuran, cyclopentylmethyl ether) may be used.

[0586] M3 hydrolyzes into M1

[0587]

[0588] M3 (100.0 g, 342.2 mmol) was added to the reaction vessel and dissolved in tetrahydrofuran (300 mL). Sodium hydroxide (300 mL of 1.0 M aqueous solution) was added, and the resulting mixture was stirred at room temperature for about 1 h. Toluene (200 mL) was added to the reaction vessel, followed by HCl (120 mL of 1.0 M aqueous solution). The resulting two-phase mixture was separated, and the organic phase was washed with sodium bicarbonate (120 mL of 5 wt% aqueous solution). The phases were separated again, and the organic layer was washed twice with water (200 mL). The final organic phase was washed with brine (200 mL of 10 wt% aqueous solution), dried over MgSO4, and then filtered. The final alcohol M1 solution was used in subsequent steps without further purification.

[0589] Alternatively, alternative reagents and reaction conditions to those disclosed above may be used. For example, other bases (e.g., potassium hydroxide, tetrabutylammonium hydroxide) and other solvents (e.g., 2-methyltetrahydrofuran, MTBE, toluene) may be used.

[0590] O from the synthesis of M1

[0591]

[0592] A toluene solution of alcohol M1 is loaded into the reaction vessel (the amount of solution loaded is determined by using...). 1 HNMR was used to determine the wt% of alcohol in solution and the amount required to obtain 28.0 g, 285.3 mmol of alcohol M1 by loading it into the reaction. Pyridine (29.3 g, 370.9 mmol) was loaded into it, followed by N,N′-disuccinimidyl carbonate (116.9 g, 456.5 mmol). The resulting heterogeneous reaction mixture was heated to 45 °C and stirred at that temperature for 4 h. The reaction was then cooled to room temperature and water (170 mL) was added. The mixture was stirred at room temperature for 30 min and then the phases were separated. The final toluene solution was used for subsequent steps without further purification. In this way, O (52.9 g, by...) was synthesized. 1 ¹H NMR analysis (wt%), 221.3 mmol, 77.6%.

[0593] Alternative reagents and reaction conditions to those disclosed above may also be used. For example, other bases (e.g., diisopropylamine, triethylamine, diisopropylethylamine) and other solvents (e.g., xylenes, chlorobenzene, MTBE) may be used. Moreover, temperatures in the range of about 0°C to about 110°C may be used.

[0594] VII Synthesis from O

[0595]

[0596] A toluene solution of carbonate O is loaded into the reaction vessel (the amount of solution loaded is determined by using...). 1¹H NMR was used to determine the wt% of carbonate in the solution and then the amount of carbonate O required to be loaded into the reaction (9.9 g, 41.4 mmol). Additional toluene was loaded into the reaction to bring the final reaction volume to 60 mL. Diisopropylethylamine (10.7 g, 82.8 mmol) and L-tert-leucine (6.0 g, 45.52 mmol) were loaded into the solution. The reaction mixture was heated to about 45 °C and stirred at that temperature for about 6 h. The reaction was then cooled to room temperature and hydrochloric acid (60 mL of 3N aqueous solution) was loaded. The two-phase mixture was stirred at room temperature for about 30 min and then the phases separated. The organic-rich stream was then concentrated to about 20 mL by rotary evaporation and subsequently 80 mL of acetonitrile was added. Concentration to 20 mL and then continued with the addition of acetonitrile until the amount of toluene was about <5% v / v. The final stream was adjusted to a volume of 80 mL using acetonitrile and heated to about 50 °C. The mixture was then heated to about 50°C and loaded with (S)-phenylethylamine (6.0 g, 49.7 mmol as a solution in 30 mL of acetonitrile at 50°C). The reaction mixture was inoculated with 0.5 wt% seed crystals of VII (0.05 g) and the dilute slurry was aged at 50°C for 1 h. The mixture was then cooled to room temperature for about 3 h and the resulting slurry was aged for at least about 12 h. The solids were collected by filtration and the filter cake was washed with about 20 mL of acetonitrile. The final wet filter cake was vacuum dried in an oven at about 40°C to provide VII.

[0597] Alternative reagents and reaction conditions to those disclosed above may also be used. For example, other bases (e.g., potassium carbonate, sodium carbonate, potassium phosphate) and other solvents (e.g., dimethylformamide, dimethylacetamide) may be used. Moreover, other salting amines (e.g., (R)-phenylethylamine, D-phenylpropanol, (1S,2S)-(+)-2-amino-1-(4-nitrophenyl)-1,3-propanediol, (S)-(+)-2-phenylglycine) may be used.

[0598] Synthesis of (1R,2R)-1-amino-2-(difluoromethyl)-N-((1-methylcyclopropyl)sulfonyl)cyclopropane-1-carboxamide hydrochloride (XII)

[0599]

[0600] The existing process described above is disclosed in U.S. Publication No. 2014-0017198. The following pathway proceeds via a common, known intermediate, Vv. This intermediate Vv is synthesized using two alternative schemes. In the first scheme, racemic Ab is selectively hydrolyzed to racemic (±)-Ac, having cis / trans diastereomers in an approximately 10:1 ratio. This monoacid is classically resolved by a chiral amine to form chiral Ac as a salt. Recrystallization can be performed to enhance the enantiomer excess. The carboxylic acid is then converted to and separated from the amide Ad. In the condensation step, the amide undergoes a Hoffman rearrangement, hydrolyzes to an amine, which is protected with Boc and hydrolyzed with a methyl ester to form the desired amino acid, Vv. Vv is then converted to XII as shown in the above scheme.

[0601] Intermediate Vv is the first alternative for the synthesis of XII.

[0602]

[0603] Synthesis of (1S,2R)-2-(difluoromethyl)-1-(isopropoxycarbonyl)cyclopropane-1-carboxylic acid (Ac)

[0604]

[0605] Synthesis of (1S,2R)-2-(difluoromethyl)-1-(isopropoxycarbonyl)cyclopropane-1-carboxylic acid (B)

[0606] Step 1: Synthesis of intermediate Z

[0607]

[0608] Difluoroacetaldehyde ethyl hemiacetal Y (100 g, 0.79 mol), cyclopentyl methyl ether (CPME, 500 mL, 5 mL / g), and diisopropyl malonate (150 mL, 1 eq.) were loaded into the reactor. Triethylamine (Et3N, 100 mL, 1 mL / g) was added to the resulting solution, which was maintained at approximately 20 °C. The mixture was heated to approximately 35 °C and stirred for approximately 20 hours. At the completion of the reaction, a small sample of this CPME solution of alcohol Z was obtained and washed with 1 M aq. KH2PO4 until the pH decreased to ~7, followed by washing with brine. The organic layer was dried over MgSO4 and concentrated to dryness under vacuum. The residue was purified by column chromatography on silica gel using a gradient of 0%–25% MTBE in hexane to provide a clean sample of alcohol Z. 1HNMR (300MHz, CDCl3): δ1.275-1.30(m,12H),3.63(d,J=4.5Hz,1H),3.95(d,J=7.8Hz,1H),4.32-4.45(m,1H),5.06-5.20(m,2H)and5.93(dt,J=55.4Hz and 4.2Hz). 19 F NMR (282MHz, CDCl3): δ-129.0 (m). LCMS: (m / z) 291.1(M+Na), 269.1(M+H).

[0609] Alternative reagents and reaction conditions to those disclosed above may also be used. For example, other ether solvents (e.g., THF, MeTHF, or MTBE) may be used. Additionally, temperatures in the range of about 0°C to about 60°C may be used. Furthermore, other organic amines (e.g., DIPEA) and malonate analogs (e.g., methyl esters, ethyl esters, benzyl esters, and many other esters) may be used.

[0610] Step 2: Synthesis of intermediate Aa from Z:

[0611]

[0612] The CPME solution of alcohol Z was cooled to approximately 20°C, followed by the addition of acetic anhydride (Ac₂O, 200 mL, 2 mL / g) and 4-(dimethylamino)pyridine (DMAP, 4.83 g, 0.05 eq.), which resulted in an exothermic reaction up to approximately 50°C. The resulting solution was stirred at approximately 20°C for approximately 20 hours. Upon completion of the reaction, 1 Maq. K₂HPO₄ (1.0 L, 10 mL / g) was added, which resulted in an exothermic reaction. After 15 minutes, the layers separated. The CPME layer was washed with 1 Maq. K₂HPO₄ (500 mL, 5 mL / g), a 1:1 mixture of 1 Maq. K₂HPO₄ and 1 Maq. KH₂PO₄ (100 mL), and brine (500 mL, 5 mL / g). CPME (500 mL, 5 mL / g) was added to the CPME solution, and the volume was reduced to approximately 400 mL (4 mL / g) by vacuum distillation. A small sample of olefin Aa was obtained from this CPME solution and the solution was concentrated to dryness under vacuum. The residue was purified by column chromatography on silica gel using a gradient of 0%–15% MTBE in hexane to provide a clean sample of olefin Aa. 1 HNMR (300MHz, CDCl3): δ 1.25-1.29 (m, 12H), 5.06-5.21 (m, 2H), 6.50 (dt, J = 54.6 Hz and 5.72 Hz) and 6.67-6.75 (m, 1H). 19F NMR (282MHz, CDCl3): δ-114.4 (m). GCMS: (m / z)251(M+H).

[0613] Alternative reagents and reaction conditions to those disclosed above may also be used. For example, other ether solvents (e.g., THF, MeTHF, or MTBE) or non-ether solvents (e.g., toluene) may be used. Additionally, strong organic bases (e.g., DBU) may be used. Furthermore, other activating groups (e.g., trifluoromethanesulfonic anhydride, methanesulfonyl chloride, or toluenesulfonyl chloride) and temperatures ranging from about 0°C to about 60°C may be used.

[0614] Step 3: Synthesis of Ab from Aa:

[0615]

[0616] Trimethyl sulfoxide (Me3SOI, 200 g, 1.15 eq.), potassium tert-butoxide (KOtBu, 97.5 g, 1.0 eq.), and dimethyl sulfoxide (DMSO, 500 mL, 5 mL / g) were loaded into the reactor. The resulting suspension was stirred at approximately 25 °C for about 4 hours, after which a clear solution was formed. A CPME solution of olefin C was slowly added to this DMSO solution at a rate not exceeding approximately 55 °C. The resulting suspension was stirred overnight at approximately 25 °C. The temperature was lowered to approximately 20 °C, followed by the addition of 1 M aq. H2SO4 (1.0 L, 10 mL / g), which resulted in exothermic reaction. After 15 minutes, the layers separated. CPME (400 mL, 4 mL / g) and 10% aq. K2CO3 (500 mL, 5 mL / g) were added to the organic layer. The layers separated again. The organic layer was washed with water (250 mL, 2.5 mL / g), followed by the addition of CPME (200 mL, 2 mL / g) and reduction of the volume to approximately 500 mL (approximately 5 mL / g) by vacuum distillation. Charcoal (5.0 g, 0.05 g / g) was added to the resulting suspension. The resulting suspension was filtered through diatomaceous earth and then washed with CPME (200 mL, 2 mL / g). A small sample was obtained from the CPME solution of cyclopropane Ab and concentrated to dryness under vacuum for analysis. The residues were purified by column chromatography on silica gel using a gradient of 0%–15% MTBE in hexane to provide a clean sample of cyclopropane Ab. 1 ¹H NMR (300MHz, CDCl₃): δ 1.24–1.30 (m, 12H), 1.46–1.51 (m, 1H), 1.69–1.74 (m, 1H), 2.26–2.40 (m, 1H), 5.01–5.14 (m, 2H) and 5.68 (dt, J = 56.0 Hz and 5.1 Hz). 19F NMR (282MHz, CDCl3): δ-114.1 (m). GCMS: (m / z)223(M+H). LCMS: (m / z) 287.1(M+Na), 265.1(M+H).

[0617] Alternative reagents and reaction conditions to those disclosed above may also be used. For example, a mixture of DMSO with other aprotic solvents (e.g., THF, MeTHF, or MTBE) and a temperature range of approximately 0°C to approximately 60°C may be used. Additionally, strong bases such as NaH may be used.

[0618] Step 4: Synthesis of intermediate Ac from Ab:

[0619] Synthesis of (1S,2R)-2-(difluoromethyl)-1-(isopropoxycarbonyl)cyclopropane-1-carboxylic acid (Ac)

[0620]

[0621] The CPME solution of cyclopropane Ab was diluted with isopropanol (IPA, 800 mL) and the volume was reduced to approximately 400 mL by vacuum distillation. The resulting solution was cooled to approximately -3 °C, and then 35% tetraethylammonium hydroxide aqueous solution (Et4NOH, 266 mL, 0.80 eq.) was added at a rate not exceeding approximately 0 °C. The reaction mixture was stirred overnight. 1 M aq. HCl (200 mL) was slowly added at a rate not exceeding approximately 5 °C, followed by water (400 mL). The temperature was raised to approximately 15 °C, and CPME (200 mL) was added. The layers were separated. The pH of the aqueous layer was checked and confirmed to be approximately 6.5. The CPME layer was extracted with 0.5 M aq. K2CO3 (100 mL). The two aqueous layers were combined, and then concentrated H2SO4 (20 mL) was added to lower the pH to approximately 2. CPME (400 mL) was then added, and the layers were separated. The CPME was extracted twice with 0.5 Maq. K2CO3. The two aqueous layers were combined and acidified to pH ~2 with H₂SO₄ (20 mL). Then, CPME (500 mL) was added. The layers were separated. The CPME layer was washed with water (250 mL), followed by the addition of CPME (400 mL). The volume was reduced to ~500 mL by vacuum distillation. Activated carbon (5.0 g) was then added, and the resulting suspension was filtered through diatomaceous earth and washed with CPME (100 mL). The volume was again reduced to ~500 mL by vacuum distillation. A small sample was obtained from this CPME solution of half-ester / acid(±)-Ac, forming a CPA salt. The solids were obtained by filtration. The solids were suspended in CPME and 1 M aq. NaOH. After all the solids dissolved, the layers were separated. The aqueous layer was acidified to pH ~2 with concentrated H₂SO₄, and the half-ester / acid(±)-Ac was extracted into the CPME. This solution was concentrated to dryness under vacuum to provide a clean sample of half-ester / acid(±)-Ac. 1 H NMR (300MHz, CDCl3): δ 1.31 (d, J = 6.3Hz, 5H), 1.91–1.98 (m, 2H), 2.52–2.59 (m, 1H), 5.15–5.24 (m, 2H) and 5.80 (dt, J = 55.7Hz and 6.3Hz). 19 F NMR (282MHz, CDCl3): δ-111.9 (m). LCMS: (m / z)443.0(2M-H),220.9(MH).

[0622] (R)-(+)-1-(4-methylphenyl)ethylamine (62.5 mL, 0.55 eq.) was added to a solution of half-ester / acid (±)-Ac in CPME, which resulted in exothermic reaction. Next, seed crystals of Ac (100 mg) in heptane (20 mL) were added, followed by the addition of heptane (500 mL, 5 mL / g). After the suspension thickened, the temperature was raised to approximately 50 °C. After stirring overnight, the temperature was lowered to approximately 25 °C over approximately 5 hours. The temperature was then lowered to 0 °C–5 °C and maintained at this temperature for approximately 1 hour. The solids were collected by filtration and washed with 33% CPME in heptane (250 mL, 2.5 mL / g). The solids were dried to constant weight in a vacuum furnace at approximately 40 °C to provide the salt of half-ester / acid Ac. This material was suspended in CPME (500 mL, 10 mL / g) and heated to approximately 70 °C, at which point a clear solution was obtained. This solution was cooled to approximately 65 °C, and then seed crystals were added. The resulting suspension was cooled to approximately 50°C over approximately 3 hours. The resulting viscous suspension was then left at approximately 50°C overnight. The temperature was lowered to approximately 30°C over approximately 4 hours, then lowered to 0°C–5°C and held at this temperature for approximately 1 hour. The solids were obtained by filtration and then washed with 50% CPME in heptane (100 mL). The solids were dried to constant weight in a vacuum oven at approximately 40°C to provide the salt of the half-ester / acid Ac. 1 ¹H NMR (300MHz, DMSO-d6): δ 1.08–1.17 (m, 7H), 1.44 (d, J = 6.3 Hz, 3H), 1.86–1.90 (m, 1H), 2.30 (s, 3H), 4.23–4.30 (m, 1H), 4.81–4.89 (m, 1H), 5.70 (dt, J = 56.3 Hz and 6.0 Hz, 1H), 7.20 (d, J = 7.5 Hz, 2H) and 7.35 (d, J = 7.5 Hz, 2H). 19 F NMR (282MHz, DMSO-d6): δ-111.4 (m).

[0623] The two mother liquors were combined and extracted twice with 0.5 M aq. K2CO3 (500 mL). The two aqueous layers were combined and acidified to pH ~2 with H2SO4 (30 mL, 0.3 mL / g) at a rate not exceeding approximately 30 °C. CPME (500 mL) was then added and the layers were separated. The CPME layer was washed with water (250 mL). CPME (600 mL) was then added and the volume was reduced to ~500 mL by vacuum distillation. Charcoal (5.0 g) was then added and the resulting suspension was filtered through diatomaceous earth and then washed with CPME (100 mL). The volume of the filtrate was reduced to ~500 mL by vacuum distillation. (S)-(-)-1-(4-methylphenyl)ethylamine (51 mL, 0.45 eq.) was then added, which resulted in an exothermic reaction. Seed crystals (100 mg) were added to the resulting solution, followed by heptane (500 mL). After approximately 1 hour, the resulting suspension was heated to approximately 60 °C. After approximately 1.5 hours, the temperature was reduced to approximately 50°C over approximately 1 hour. The resulting suspension was then maintained at approximately 50°C overnight.

[0624] The temperature was lowered to approximately 25°C over approximately 5 hours. The temperature was further lowered to approximately 0°C–5°C and maintained at this temperature for approximately 1 hour. The solids were collected by filtration and washed with 33% CPME in heptane (200 mL). The solids were dried to constant weight in a vacuum furnace at approximately 40°C to provide the salt of the half-ester / acid Ac. This substance was suspended in CPME (500 mL) and heated to approximately 75°C, at which point a clear solution was obtained. This solution was cooled to approximately 65°C, and then seed crystals were added. The resulting suspension was cooled to approximately 50°C over approximately 5 hours. The resulting thick suspension was maintained at approximately 50°C overnight. The temperature was then lowered to approximately 30°C over approximately 4 hours, followed by a decrease to 0°C–5°C and maintenance at this temperature for approximately 1 hour. The solids were obtained by filtration and then washed with 50% CPME in heptane (110 mL). The solids were dried to constant weight in a vacuum furnace at approximately 40°C to provide the salt of the half-ester / acid Ac. 1 H NMR (300MHz, DMSO-d6): δ 1.08–1.17 (m, 7H), 1.44 (d, J = 6.3 Hz, 3H), 1.86–1.90 (m, 1H), 2.30 (s, 3H), 4.23–4.30 (m, 1H), 4.81–4.89 (m, 1H), 5.70 (dt, J = 56.3 Hz and 6.0 Hz, 1H), 7.20 (d, J = 7.5 Hz, 2H) and 7.35 (d, J = 7.5 Hz, 2H). 19 F NMR (282MHz, DMSO-d6): δ-111.4 (m).

[0625] Alternative reagents and reaction conditions to those disclosed above may also be used. For example, other alcohol solvents that match the remaining ester may be used. Additionally, other soluble hydroxides of IPA (e.g., KOH) and additional phase-transfer catalysts (e.g., tetrabutylammonium hydroxide) may be used. Furthermore, other chiral amines (crystalline salts that produce suitable stereoisomers of the product) and temperatures ranging from about -20°C to about 60°C may be used.

[0626] Vv from the synthesis of Ac

[0627]

[0628] Ad is derived from the synthesis of Ac.

[0629]

[0630] The salt of the half-ester / acid Ac (35 g, 97.9 mmol) was suspended in CPME (105 mL) and 1 Maq. HCl (105 mL). The resulting suspension was stirred until all solids dissolved. The layers were separated, and the CPME layer was washed with 1 Maq. HCl (35 mL) and brine (70 mL), then dried over Na2SO4 and concentrated under vacuum. 1,1'-carbonyl-diimidazole (CDI, 19.9 g, 1.25 eq.) was slowly added to the resulting solution at a rate that allowed for controlled off-gassing. The reaction mixture was stirred for 1 hour, during which time a precipitate formed. Then, 28% ammonium hydroxide aqueous solution (NH4OH, 35 mL, 2.86 eq.) was added. The reaction mixture was stirred overnight. The next morning, the layers were separated, and the CPME layer was washed with 0.5 Maq. H2SO4 (105 mL), 0.5 Maq. K2CO3 (105 mL), and brine (70 mL), respectively. The CPME solution was dried over MgSO4 and concentrated to dryness under vacuum to provide crude amide Ad. GCMS: 221 (M+).

[0631] Alternative reagents and reaction conditions to those disclosed above may also be used. For example, ether solvents (e.g., THF, MeTHF, or MTBE) and temperatures ranging from about 0°C to about 60°C may be used. Additionally, other ammonia sources (e.g., liquid ammonia) may be used. Furthermore, other activators may be used, such as any peptide coupling agent (e.g., T3P) or chlorinating agents (e.g., thionyl chloride).

[0632] Ae from the synthesis of Ad

[0633]

[0634] Crude amide Ad was dissolved in methanol (MeOH, 262 mL, 7.5 mL / g) and trichloroisocyanuric acid (TCCA, 8.65 g, 0.38 eq.) was added, followed by the slow addition of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU, 35 mL, 2.4 eq.) at a rate not exceeding 40 °C. After about 1 hour, the temperature was raised to about 65 °C and the reaction mixture was maintained at this temperature for 20 hours. MeOH was then removed by vacuum distillation. The residue was diluted with isopropyl acetate (IPAC, 175 mL) and 1 M aq. KH₂PO₄ (175 mL). After vigorous stirring for 15 minutes, the solids were removed by diatomaceous earth filtration, followed by washing with IPAC (35 mL). The filtrate was separated into layers. The IPAC layer was washed with brine (70 mL, 2 mL / g), dried over MgSO₄, and concentrated to dryness under vacuum to provide carbamate Ae. GCMS: 223 (M+).

[0635] Alternative reagents and reaction conditions to those disclosed above may also be used. For example, mixtures of methanol with aprotic solvents (e.g., THF, MeTHF, or MTBE) and temperatures ranging from about 0°C to about 60°C may be used. Additionally, other halogenated solvents (e.g., chlorine, bromine, NBS, or NCS) and sterically hindered organic bases (e.g., DIPEA) may be used.

[0636] Synthesis of Af from Ae:

[0637]

[0638] The residue containing crude carbamate Ae was dissolved in isopropyl acetate (70 mL), followed by the addition of di-tert-butyl dicarbonate (Boc₂O, 21.4 g, 1.0 eq.) and DMAP (598 mg, 0.05 eq.). The reaction mixture was stirred for approximately 20 hours. The reaction mixture was concentrated to dryness under vacuum to provide dicarbamate Af. GCMS: 257 (M-tBu), 223 (M-Boc).

[0639] Alternative reagents and reaction conditions to those disclosed above may also be used. For example, aprotic solvents (e.g., THF, MeTHF, MTBE, or toluene) and temperatures in the range of about 0°C to about 60°C may be used. Alternatively, sterically hindered organic bases (e.g., DIPEA) may be used.

[0640] Vv from the synthesis of Af

[0641]

[0642] The residue containing dicarboxylate Af was dissolved in IPA (100 mL, 2.5 mL / g), followed by the addition of 2 M aq. KOH (100 mL). After stirring overnight, 2 M aq. HCl (100 mL) and then CPME (100 mL) were added. The layers were separated. The CPME layer was extracted twice with 1 M aq. NaOH (35 mL). The two aqueous layers were combined, followed by the addition of IPA (70 mL) and 1 M aq. HCl (70 mL). After stirring overnight, the resulting suspension was filtered and the solids (racemic Vv) were washed with 50% aq. IPA (35 mL). The filtrate was extracted with IPAC (100 mL). The IPAC layer was dried over Na2SO4 and concentrated to dryness under vacuum. The residue was dissolved in heptane and concentrated to dryness under vacuum. The residue was dissolved in THF (25 mL) and 1 M aq. NaOH (25 mL), followed by the addition of Boc2O (21.4 g, 1.0 eq.). The reaction mixture was stirred overnight. The next morning, IPAC (25 mL) and water (25 mL) were added. Layer separation was performed. The IPAC layer was extracted with 0.5 Maq. K2CO3 (12.5 mL). The two aqueous layers were combined and IPAC (25 mL) was added, followed by acidification with 1 M aq. HCl to pH ~2. Layer separation was performed. The IPAC layer was washed with water (25 mL). The IPAC layer was then dried with Na2SO4 and concentrated to dryness under vacuum. The residue was dissolved in IPAC (10 mL) and hexane (200 mL) was slowly added. The resulting suspension was stirred for several hours. The solids were collected by filtration, washed with hexane, and dried in a vacuum oven at approximately 40 °C to provide Vv (6.8 g).

[0643] Alternative reagents and reaction conditions to those disclosed above may also be used. For example, other alcohol solvents (e.g., methanol or ethanol) and temperatures in the range of about 0°C to about 60°C may be used. Additionally, other hydroxide sources (e.g., LiOH or tetrabutylammonium hydroxide) may be used.

[0644] In a second alternative, racemic Ab is selectively hydrolyzed to racemic (±)-Ac. This monoacid (±)-Ac reacts with dicyclohexylamine to form the salt Ag. This salt is then free-based and classically resolved by conversion to the cinconidine salt Ah. The coultides rearrangement of Ah is then hydrolyzed to provide the intermediate Vv, which is then converted to XII as shown in the above alternative.

[0645] A second alternative for the synthesis of intermediate Vv of XII

[0646]

[0647] Ab hydrolyzes to (±)-Ac

[0648]

[0649] Add isopropanol (250 mL) to the solution of Ab and cool the solution to between approximately -15 and -10 °C. Add tetraethylammonium hydroxide (35 wt% in H₂O, 365.2 g, 0.88 mol, 2.2 equiv) to the solution after at least two hours, maintaining the temperature below approximately -10 °C. Stir between approximately -15 and -10 °C for approximately 12 hours until the reaction is complete, then add toluene (250 mL) and water (200 mL), maintaining the temperature below approximately 0 °C. Stir this mixture at approximately -5 to 0 °C for approximately 15 minutes, then raise the temperature to approximately 20 °C–25 °C. Stir this mixture at approximately 20 °C–25 °C for approximately 15 minutes, allowing phase separation for 30 minutes.

[0650] The aqueous layer was transferred to a second reactor and toluene (150 mL) was added. This mixture was stirred at approximately 20°C–25°C for approximately 15 minutes, allowing phase separation for approximately 30 minutes. Phase separation occurred, and toluene (400 mL) was added to the aqueous layer. The mixture was cooled to approximately 10°C, and 50% aq. H₂SO₄ (ca. 20 mL) was added, maintaining the temperature below approximately 15°C until approximately pH 2–3 was reached. This mixture was stirred at approximately 10°C for approximately 15 minutes, allowing phase separation for approximately 30 minutes. The organic layer was analyzed, and the volume was reduced from 550 mL to 80 mL by vacuum distillation at approximately 40°C–45°C to provide Ac.

[0651] Alternative reagents and reaction conditions to those disclosed above may also be used. For example, other bases may be used (e.g., sodium hydroxide, potassium hydroxide, lithium hydroxide, tetrabutylammonium hydroxide, tetramethylammonium hydroxide, tetrapropylammonium hydroxide, dipotassium hydrogen phosphate, potassium carbonate, sodium carbonate). Additionally, other solvents may be used (e.g., cyclopentylmethyl ether, methyl tert-butyl ether, dichloromethane, chloroform, chlorobenzene, tetrahydrofuran, 2-methyltetrahydrofuran, acetonitrile, methanol, ethanol, tert-butanol). Furthermore, temperatures in the range of approximately -15°C to approximately -10°C may be used.

[0652] Synthesis of Ag from (±)-Ac

[0653]

[0654] Add toluene (54 mL) to the above toluene solution. Then, while maintaining the temperature below about 40 °C, add dicyclohexylamine (26.2 g, 140 mmol, 0.36 equiv). Heat the mixture to 75 °C until dissolution is achieved. Cool the mixture to about 65 °C to allow crystallization, then stir at about 65 °C for about 30 minutes, and then cool to about 0 °C over three hours. Stir the slurry at about 0 °C for about two hours, then filter. Wash the filter cake three times with 10:1 heptane:toluene (20 mL), and dry the solids under vacuum at about 40 °C to provide Ag. 1 ¹H NMR (400MHz, CDCl₃): δ 1.18–1.26 (m, 12H), 1.28–1.33 (m, 1H), 1.39–1.48 (m, 5H), 1.65 (d, J = 8Hz, 2H), 1.79 (d, J = 12Hz, 4H), 1.99 (d, J = 11.6Hz, 4H), 2.1–2.2 (m, 1H), 2.95 (tt, J = 8Hz and 3.6, 2H), 5.03 (Shinetsu, J = 6Hz, 1H), 5.63 (td, J = 56.4 and 5.6, 1H). 19 F NMR (376MHz, CDCl3): δ-113 (ddd, J = 2326Hz, 285Hz and 8.3Hz).

[0655] Alternatively, alternative reagents and reaction conditions to those disclosed above may be used. For example, other solvents may be used (e.g., dichloromethane, chloroform, chlorobenzene, methyl tert-butyl ether, cyclopentyl methyl ether, 2-methyltetrahydrofuran, hexane, cyclohexane).

[0656] Alternatively, alternative reagents and reaction conditions to those disclosed above may be used. For example, other solvents may be used (e.g., dichloromethane, chloroform, chlorobenzene, MTBE, cyclopentylmethyl ether, 2-methyltetrahydrofuran, hexane, cyclohexane).

[0657] Synthesis of Ah from Ag

[0658]

[0659] Solid Ag (444.8 g, 1.10 mol) was loaded into a 5 L reactor under N2 atmosphere. Methyl isobutyl ketone (MIBK, 2200 mL) was added, followed by 1 M H3PO4 (2200 mL), and the mixture was stirred for approximately 15 minutes and then separated. The organic layer was washed with water (1 L). The reaction mixture was concentrated by distillation of approximately 500 mL of solvent (including H2O). The solution was filtered through diatomaceous earth.

[0660] Cinconidine (304.5 g, 1.03 mol, 1.0 equiv.) was added to the reactor along with MIBK (2500 ml). A solution of (±)-Ac in MIBK (in 2000 ml MIBK) was added to this suspension. The reaction mixture was heated to approximately 50 °C. Ah (534 mg, 0.1 wt%) was added as a seed crystal, and the mixture was then treated with the following temperature program: approximately 50 °C for approximately 1 hr, approximately 30 min by heating to approximately 60 °C, aging at approximately 60 °C for approximately 3 h, cooling to approximately 58 °C for approximately 4 h, cooling to approximately 50 °C for approximately 4 h, cooling to approximately 40 °C for approximately 2 h, cooling to approximately 20 °C for approximately 2 h, and holding at approximately 20 °C for approximately 2 h. The slurry was filtered. The filter cake was washed with MIBK (400 ml). The material was dried in a vacuum oven.

[0661] The resulting solids were added to a 5-L reactor under N2, followed by the addition of MIBK (1438 mL, 7 V) and methanol (144 mL, 0.7 V). The resulting slurry was heated to approximately 60 °C to obtain a solution, which was then inoculated with 0.1 wt% Ah. The light suspension was maintained at approximately 60 °C for approximately three hours, followed by parabolic cooling to approximately 20 °C and held at approximately 20 °C for approximately five hours. Next, MIBK (200 mL, 1 V) was added, and the slurry was vacuum distilled to approximately 6.5-7 V to remove MeOH. Once the MeOH content was below 0.5%, the slurry was cooled to approximately 5 °C over approximately 2.5 hours and held at approximately 5 °C for approximately 1 hour. The slurry was filtered, and the filter cake was washed three times with MIBK (150 mL, 0.7 V). The material was dried in a vacuum oven to provide Ah. 1H NMR (400MHz, CDCl3): δ1.24(t,J=6Hz,7H),1.41-1.45(m,1H),1.52(t,J=5.6Hz,1H),1.70-1.8 0(m,1H),2.02(m,1H),2.10(m,1H),2.20-2.30(m,1H),2.60(bs,1H),3.03(td,J=13.6Hz and 4.4Hz 1H), 3.10-3.16(m,1H), 3.33(dt,J=10.4Hz and 3.2Hz,2H), 4.30(m,1H), 4.98-5.00(m,1H), 5.08(Seven,J=6.4Hz,1H), 5.48-5.55(m,1H), 5.69(td,J=56.8Hz and 5.2Hz,1H), 6.26(s,1H), 7.46(t,J=8Hz,1H), 7.63(t,J=8Hz,1H), 7.69(d,4.4Hz,1H), 7.92(d,8.4Hz,1H), 8.03(d,J=8Hz,1H), 8.86(d,J=4.4Hz,1H). 19 F NMR (376MHz, CDCl3): δ-113 (ddd, J = 2435Hz, 286Hz and 7.1Hz).

[0662] Alternatively, alternative reagents and reaction conditions to those disclosed above may be used. For example, other acids (e.g., sulfuric acid) and other solvents (e.g., isopropyl acetate, MTBE) may be used.

[0663] Ah's Kurtis rearrangement to obtain Ai

[0664]

[0665] Load Ah (200 g, 387 mmol) and 15% aq. H3PO4 (800 mL, 4 mL / g) into a reaction vessel. Add MTBE (400 mL, 2 mL / g) to the resulting suspension and observe the exothermic reaction from about 22 °C to about 25 °C. All solids dissolve within about 5 minutes. After about 15 minutes, stop stirring and allow layer separation for about 10 minutes. Remove the bottom layer (~880 mL; pH ~2.5; aq. layer 1). Resume stirring and then add water (400 mL, 2 mL / g). After about 15 minutes, stop stirring and allow layer separation for about 10 minutes. Remove the bottom layer (~400 mL; pH ~2.5; aq. layer 2). Resume stirring and then add toluene (400 mL, 2 mL / g). Reduce the volume to 300 mL under vacuum (1.5 mL / g; 40 Torr, jacket temperature about 50 °C ~575 mL distillate; distillate 1). Check KF and consider it acceptable (32ppm; <100ppm).

[0666] DMAP (94.5 g, 774 mmol, 2 equiv.) and toluene (300 mL, 1.5 mL / g) were loaded into the reaction vessel, followed by DPPA (125 mL, 581 mmol, 1.5 eq.). The resulting suspension was heated to approximately 85 °C. The ambiguous product in the toluene solution was finely filtered into the hot DMAP / DPPA suspension at a rate that maintained the temperature between approximately 80 °C and approximately 100 °C. The mixture was then washed with toluene (100 mL, 0.5 mL / g). Upon completion of the addition, the reaction contents were cooled to approximately 80 °C–83 °C. tBuOH (65.5 mL, 774 mmol, 2 equiv.) was added. The reaction mixture was aged at approximately 75 °C–80 °C for approximately 6 hours. The reaction mixture was cooled to approximately 20 °C, followed by the addition of water (400 mL, 2 mL / g), which resulted in an exothermic reaction up to approximately 23 °C. Stirring was stopped after approximately 15 minutes, and layer separation was allowed for approximately 15 minutes. Remove the bottom layer (~600 mL, pH ~9; aq. layer 3). Resume stirring and add water (200 mL, 1 mL / g). After about 10 minutes, stop stirring and allow the layers to settle for about 10 minutes. Remove the bottom layer (~200 mL, pH ~9; aq. layer 4). Resume stirring and reduce the volume to 300 mL (1.5 mL / g) by distillation. Cool the resulting solution to about 20°C.

[0667] Alternatively, alternative reagents and reaction conditions to those disclosed above may be used. For example, other acids (e.g., sulfuric acid) and other bases (e.g., diisopropylethylamine, triethylamine) may be used. Moreover, temperatures in the range of approximately 70°C to 100°C may be used.

[0668] Ai hydrolyzes into Vv

[0669]

[0670] MeOH (300 mL, 1.5 mL / g) and powdered KOH (43.4 g, 774 mmol, 2 equiv) were added to the reaction vessel. After the exothermic reaction subsided, the resulting turbid solution was added to a two-liter reactor, which resulted in an exothermic reaction to approximately 40°C. The reaction was considered complete after about 3 hours.

[0671] At this point, 15% aq. H3PO4 (600 mL, 3 mL / g) was added, which resulted in an exothermic reaction to a maximum of approximately 32 °C and a pH of approximately 2.5. After approximately 10 minutes, the resulting suspension was filtered and then washed with MTBE (200 mL, 1 mL / g). The filtrate was stirred for approximately five minutes, then stirring was stopped. Layer separation was allowed for approximately five minutes. The bottom layer (~900 mL, pH ~2.5; aq. layer 5) was removed. Stirring was resumed and water (200 mL, 1 mL / g) was added. After approximately five minutes, stirring was stopped and layer separation was allowed for approximately 5 minutes. The bottom layer (~250 mL, pH ~2.5; aq. layer 6) was removed. Stirring was resumed and toluene (400 mL, 2 mL / g) was added. The volume was reduced to 300 mL (1.5 mL / g) by distillation. The resulting solution was stirred at approximately 20 °C and a suspension formed within approximately 1 hour. Approximately 3 hours later, heptane (300 mL, 1.5 mL / g) was slowly added over approximately 30 minutes. The resulting suspension was stirred overnight and then cooled to approximately 5°C. The solid was obtained by filtration. The mother liquor was used for washing and to wash the filter cake. After the filter cake was dried, it was washed with 40% toluene (100 mL, 0.5 mL / g) in heptane, followed by washing the filter cake with this solution. The solid was dried in a vacuum oven at approximately 40°C to provide Vv. 1 H NMR (400MHz, CD3OD): δ1.43 (s, 10H), 1.64-1.80 (m, 1H), 1.89-2.00 (m, 1H), 5.87 (td, J = 53.6Hz and 7.2Hz, 1H). 19 F NMR (376MHz, CDCl3): δ-113 (m).

[0672] Assembly steps to obtain compound I via route I

[0673] A. Synthesis of compound of formula III (R = CH3)

[0674] I. II (R=CH3) free basification and Boc-protection to provide III (R=CH3):

[0675]

[0676] II (10.1 g, 29.3 mmol, 1.00 equivalent) was mixed with dichloromethane (40 mL) and stirred at about 20–25 °C. Triethylamine (8.36 g, 82.6 mmol, 3.00 equivalent) was added dropwise using a syringe, maintaining the reaction temperature at about 20–25 °C. 4-Dimethylaminopyridine (360 mg, 2.95 mmol, 0.1 equivalent) was added to the resulting solution, followed by a solution of di-tert-butyl dicarbonate (6.52 g, 29.9 mmol, 1.02 equivalent) in dichloromethane (40 mL), while maintaining the reaction temperature at about 20–25 °C. The mixture was stirred for about 2–4 hours and monitored for completion. At completion, 100 mL of 1.0 N HCl was added dropwise, while maintaining the reaction temperature below about 30 °C. The two-phase mixture was stirred vigorously for about 15 minutes, followed by layer separation. The bottom organic layer was separated and washed sequentially with 5% wt / wt sodium bicarbonate aqueous solution (100 mL) and water (100 mL). The organic phase was concentrated under reduced pressure and dried under vacuum to provide III (R = CH3). 1 H NMR (300MHz, CD3OD): δ4.41 (d, J = 6.0Hz, 1H), 4.01-4.07 (m, 1H), 3.65-3.79 (m ,4H),3.05-3.15(m,1H),2.10-2.20(m,1H),1.50-1.60(m,1H),1.39-1.45(app d,9H),1.10-1.20(m,2H),0.99-1.08(m,3H). 13 C NMR (75MHz, CDCl3): δ12.3, 21.3, 28.2, 50.5, 50.6, 51.4, 52.2, 61.8, 71.9, 80.2, 154.2, 171.9.

[0677] Alternative reagents and reaction conditions to those disclosed above may also be used. For example, amine bases (e.g., diisopropylethylamine or sodium hexamethyldisilamide), carbonates (e.g., potassium carbonate or cesium carbonate), bicarbonates (e.g., sodium bicarbonate), or inorganic / organic hydroxides (e.g., sodium hydroxide or tetramethylammonium hydroxide) may be used. Additionally, other Boc-delivering agents (e.g., BOC-ON=C(CN)Ph, BOC-ONH2, 1,2,2,2-tetrachloroethyl tert-butyl carbonate, or 1-(tert-butoxycarbonyl)benzotriazole) and promoters (e.g., imidazole or sonication) may be used. In addition, other organic solvents (toluene, acetonitrile, or acetone), water, polar aprotic solvents (e.g., N,N-dimethylformamide (DMF) or dimethyl sulfoxide (DMSO) or combinations thereof with water), alcohols (e.g., methanol or ethanol), ethers (e.g., tetrahydrofuran, dioxane, or methyl tert-butyl ether), or esters (e.g., ethyl acetate) may be used.

[0678] Synthesis of compound B (R = CH3)

[0679]

[0680] II.IV and III (R=CH3) S N Ar reacts to form V (R = CH3).

[0681]

[0682] IV (1.00 equivalent) and cesium carbonate (1.20 equivalent) were added to a reactor containing N,N-dimethylacetamide (6 volumes) of III (R=CH3) (1.00 equivalent). The heterogeneous reaction was carried out with stirring and heating to about 100-110 °C. Upon completion of the reaction, the reaction mixture was then cooled to about 20 °C and MTBE (10 volumes) was added. The resulting mixture was washed twice with water (6 volumes), and the MTBE solvent was exchanged with isopropanol (6 volumes) by vacuum distillation. The solution was then heated to about 60 °C and water (3 volumes) was added after a buffer of about 1.5 hours. Once the addition was complete, the mixture was held at about 60 °C for about 30 minutes. A small amount of V (R=CH3) (1-2 wt / wt%) was then added, followed by slow cooling to room temperature over about 3 hours. The contents were then aged for at least about 12 hours, after which the slurry was filtered through a suitable filter. The wet filter cake was washed with 2:1 isopropanol / water (3.5 times the volume), then washed twice with water (3.5 times the volume) and dried in a vacuum oven at about 40-45°C. 1H NMR (400MHz, CDCl3): δ7.93-7.90(m,1H),7.25-7.22(m,1H),7.20-7.16(m,1H),5.95-5. 85(m,1H),5.44-5.38(m,1H),5.25-5.21(m,2H),4.54-4.52(m,1H),4.47-4.40(m,1H),3. 97(s,3H),3.77(s,3H),3.43-3.39(m,1H),3.27-3.17(m,2H),2.79-2.68(m,1H),1.64-1 .55(m,1H),1.44-1.43(m,9H),1.44-1.32(m,1H),1.10-1.06(m,3H).LCMS(M+1):521.97.

[0683] Alternative reagents and reaction conditions to those disclosed above may also be used. For example, other inorganic bases (e.g., sodium carbonate (Na₂CO₃), potassium carbonate (K₂CO₃), potassium tert-butoxide (KOtBu), lithium tert-butoxide (LiOtBu), magnesium tert-butoxide (Mg(OtBu)₂), sodium tert-butoxide (NaOtBu), sodium hydride (NaH), potassium hexamethyldisilamide (KHMDS), potassium phosphate (K₃PO₄), potassium hydroxide (KOH), or lithium hydroxide (LiOH)) or organic bases (e.g., DABCO or DBU) may be used in the presence of a phase-transfer catalyst. Additionally, aprotic solvents (e.g., N,N-dimethylformamide (DMF), N-methyl-2-pyrrolidone (NMP), dimethyl sulfoxide (DMSO), acetonitrile (MeCN), or acetone), aprotic solvents, and small amounts of added water, ethers (e.g., tetrahydrofuran (THF) or 1,4-dioxane), or toluene may be used. In addition, other additives (e.g., tetra-n-butylammonium bromide (TBAB), tetra-n-butylammonium iodide (TBAI), tetra-n-butylammonium chloride (TBACl), sodium iodide (NaI) or tetra-n-butylphosphonium bromide (TBPB)) and temperatures ranging from about 20°C to about 120°C can be used.

[0684] Synthesis of toluenesulfonate of compound C.VI (R=CH3)

[0685]

[0686] Boc deprotection of IV (R=CH3) to provide VI (R=CH3)

[0687]

[0688] V(R=CH3) (50.0 g, 95.9 mmol, 1.00 equivalent) was mixed with methyltetrahydrofuran (150 mL, 3.0 times the volume) and the mixture was stirred at about 15–25 °C, preferably about 20 °C. p-Toluenesulfonic acid (45.6 g, 240 mmol, 2.50 equivalent) in methyltetrahydrofuran (100 mL, 2.0 times the volume) was added to the reaction mixture. Once the acid addition was complete, the contents were heated to about 50–60 °C and the reaction mixture was stirred for about 3–5 hours. At the completion of the reaction, MTBE (100 mL, 2 times the volume) was slowly added to the slurry. The contents were then cooled to about 15–25 °C, and the slurry was filtered and washed with a mixture of methyltetrahydrofuran (105 mL, 2.1 times the volume) and MTBE (45 mL, 0.9 times the volume). The solids were dried in a vacuum oven at about 35–45 °C. 1 H NMR (400MHz, CDCl3) δ10.33(s,1H),9.58(s,1H),7.92(d,J=9.2Hz,1H),7.72(d,J=8.1Hz,2H),7.31–7.21(m,1H),7.1 1(t,J=5.7Hz,3H),5.97–5.77(m,1H),5.49(t,J=7.1Hz,1H),5.19(dd,J=27.6,13.7Hz,2H),4.73(dd,J=12.1,5.7Hz, 1H),4.49(dd,J=11.8,6.4Hz,1H),3.93(d,J=9.1Hz,3H),3.77(s,3H),3.60(dd,J=13.2,3.5Hz,1H),3.17(td,J=16.8 ,7.0Hz,2H),2.84(dd,J=14.1,6.9Hz,1H),2.30(s,3H),1.67–1.34(m,2H),1.05(t,J=7.4Hz,3H).LC / MS:M / Z=422.2.

[0689] Alternative reagents and reaction conditions to those disclosed above may also be used. For example, other acids (e.g., hydrochloric acid or methanesulfonic acid) may be used. Additionally, other organic solvents (e.g., isopropyl acetate) may be used.

[0690] Synthesis of compound D. VIII (R = CH3)

[0691]

[0692] Salt breakage of I and VII to provide free acid of VII

[0693]

[0694] VII (33.0 g, 87.6 mmol, 1.0 equivalent) was mixed with MTBE (198 mL, 6.0 times the volume) and stirred to obtain a suspension. A solution of concentrated hydrochloric acid (33 mL, 1.0 volume) and water (165 mL, 5.0 times the volume) was added to the suspension at a rate maintaining a reaction temperature of about 15–25 °C. As the acid was added, the suspension became a biphasic solution. The resulting reaction mixture was stirred at about 15–25 °C for about 1 hour. Stirring was stopped and the layers were allowed to separate for about 15 minutes, after which the aqueous layer was removed. Water (330 mL, 10 times the volume) was added to the organic layer and stirred at about 15–25 °C for about 15 minutes. Stirring was stopped and the layers were allowed to separate for about 15 minutes, after which the aqueous layer was removed. Water (330 mL, 10 times the volume) was added to the organic layer and stirred at about 15–25 °C for about 15 minutes. Stirring was stopped and the layers were allowed to separate for about 15 minutes, after which the aqueous layer was removed. A 10 wt.% sodium chloride solution in water (300 mL, 9 times the volume) was added to the organic layer, and the mixture was stirred at approximately 15–25 °C for about 15 min. Stirring was stopped, and the layers were allowed to separate for about 15 minutes, after which the aqueous layer was removed. The resulting organic layer was then concentrated to a minimum volume and diluted with dimethylformamide (297 mL, 9.0 times the volume). The final solution was removed and finely filtered.

[0695] Alternative reagents and reaction conditions to those disclosed above may also be used. For example, other acids (e.g., sulfuric acid or phosphoric acid) may be used. Furthermore, other organic solvents (e.g., methyl-THF or ethyl acetate) may be used.

[0696] Amide coupling of II.VI (R=CH3) and VII (free acid) to provide VIII (R=CH3)

[0697]

[0698] VII (free acid) (40.0 g; 67.4 mmol; 0.77 eq.), EDC·HCl (16.8 g, 87.6 mmol, 1.0 eq.), and HOBt monohydrate (13.4 g, 87.6 mmol, 1.0 eq.) were mixed in a reaction vessel. The previously prepared VII (free acid) was loaded onto the solid in DMF solution, washed with DMF (39.6 mL, 1.2 vol), and stirred to form a solution. The reaction mixture was cooled to about 0–10 °C, and then NMM (19.3 mL, 175 mmol, 2.0 eq.) was added. The contents were stirred at about 0–10 °C for at least about 1 hour. The reaction mixture was then subjected to about 15–25 °C and stirred until the reaction was confirmed to be complete by LC analysis. Upon completion of the reaction, toluene (429 mL, 13 times the volume) was added to the reactor, and the temperature was adjusted to about -5 to 5 °C. Water (198 mL, 6 times the volume) was slowly added to maintain the reaction temperature between approximately 0 and 25 °C. After the water addition was complete, the contents were adjusted to approximately 15–25 °C. Stirring was stopped and the contents were allowed to settle for at least 15 minutes, after which the aqueous layer was removed. A solution of potassium carbonate (20.6 g, 149 mmol, 1.7 equivalents) in water (181 mL, 5.5 times the volume) was added to the organic phase, and the resulting solution was allowed to be stirred for approximately 15 minutes, after which stirring was stopped and the contents were allowed to settle for approximately 15 minutes. The alkaline aqueous layer was removed. Water (181 mL, 5.5 times the volume) was added to the organic phase and stirred for approximately 15 minutes, after which stirring was stopped and the contents were allowed to settle for approximately 15 minutes. The alkaline aqueous layer was removed. The organic phase was again divided in water (181 mL, 5.5 times the volume) and stirred for approximately 15 minutes, after which stirring was stopped and the contents were allowed to settle for approximately 15 minutes. The alkaline aqueous layer was removed. A solution of sodium chloride (20.5 g; 350 mmol 4.00 equivalent) in water (181 mL; 5.5 times the volume) was loaded onto the organic layer and stirred for approximately 15 minutes, after which stirring was stopped and the contents were allowed to settle for approximately 15 minutes. The alkaline aqueous layer was removed. The organic layer was concentrated to the minimum stirring volume and removed and finely filtered.

[0699] 1H NMR(400MHz, CDCl3)δ8.01(d,J=9.1Hz,1H),7.19-7.34(m,3H),6.09–5.78(m,2H),5.55–5.21(m,3H),5.06(dd,J=32.9,13.4Hz,2 H),4.92(d,J=8.5Hz,1H),4.59(dd,J=10.7,6.3Hz,1H),4.35(d,J=9.7Hz,1H),4.11–3.92(s,3H),3.95–3.87(m,1H),3.85(d,J=2 8.1Hz,3H),3.78–3.70(m,1H),3.37–3.17(m,2H),2.81–2.69(m,1H),2.18–2.06(m,1H),1.95(d,J=7.4Hz,1H),1.63(dd,J=14.4, 7.3Hz, 1H), 1.48 (dd, J = 14.4, 7.2Hz, 1H), 1.17 (t, J = 7.4Hz, 3H), 1.12 (s, 9H), 0.84 (s, 1H), 0.54 (d, J = 6.4Hz, 1H). LC / MS: m / z = 659.

[0700] Alternative reagents and reaction conditions to those disclosed above may also be used. For example, other coupling agents (e.g., 1-hydroxy-7-azabenzotriazole) and bases (e.g., pyridine, morpholine, or imidazole) may be used. Additionally, other organic solvents (e.g., dimethylacetamide or acetonitrile) may be used.

[0701] Synthesis of compound E. IX (R = CH3)

[0702]

[0703] The closed-loop metathesis of VIII (R=CH3) provides IX (R=CH3):

[0704]

[0705] VIII (R=CH3) (33 g, 14.3 wt.% solution in toluene, 7.1 mmol, 1.00 equivalent) and toluene (27 mL) were mixed and heated to reflux (110 °C) and maintained at reflux temperature for about 3–5 hours. Separately, toluene (20 mL) was loaded into the reaction vessel and vigorously degassed. Zhan 1B catalyst (173 mg, 0.24 mmol, 0.033 equivalent) was loaded and the mixture was stirred at about 20–25 °C for about 60 minutes to obtain a homogeneous solution. The toluene solution of Zhan catalyst was added to the reflux toluene solution of VIII (R=CH3) for about 2 hours, maintaining the reaction temperature at about 111 °C. At the end of the reaction, the reaction was cooled to about 20 °C and 9.4 g (2 S) of silica gel was loaded. The slurry was vigorously stirred for about 4 hours and then filtered. The reactor and filter were washed with isopropyl acetate (2 x 32 mL) and the filtrate was concentrated to 50% volume (approximately 11 times the volume). 2.4 g of activated carbon (0.5 s) was added to the solution. The slurry was stirred vigorously for about 4 hours and then filtered. The reactor and filter were washed with isopropyl acetate (2 x 16 mL) and the filtrate was solvent-exchanged to 5 times its volume of isopropyl acetate and used directly in the next step. 1 H NMR (300MHz, CDCl3): δ7.95(d,J=6.0Hz,1H),7.26(m,1H),7.12(m,1H),5.89(m,1H),5.69(m,2H),5 .22(d,J=9.0Hz,1H),4.77(d,J=6.0Hz,1H),4.40(d,J=9.0Hz,1H),4.29(d,J=6.0Hz,1H),4.02-3.95 (m,1H),3.96(s,3H),3.85(m,1H),3.73(s,3H),3.21(s,2H),2.90-2.70(m,1H),2.49(d,J=12.0Hz,1 H), 1.41 (m, 2H), 1.25-1.18 (m, 4H), 1.06 (s, 9H), 1.00-0.93 (m, 2H), 0.50 (m, 1H). LCMS: m / z=631.02.

[0706] Alternative reagents and reaction conditions to those disclosed above may also be used. For example, other ruthenium-based Grubbs, Grubbs-Hoveyda, saturated and unsaturated imidazole and phosphine-based catalysts, as well as molybdenum-based catalysts and their variants may be used (see below for a representative non-exhaustive list, where Cy is cyclohexyl, Me is methyl, Ph is phenyl and iPr is isopropyl).

[0707]

[0708] Alternatively, other accelerators (e.g., acetic acid, benzoquinones, CuI, CsCl, or Ti(Oi-Pr)4), ethylene, or accelerating conditions (e.g., microwave radiation) can be used. Furthermore, temperatures in the range of approximately 40°C to 110°C can be used. Other solvents can be used, such as halogenated solvents (e.g., dichloromethane, 1,2-dichloroethane, chlorobenzene, or hexafluorobenzene), organic solvents (e.g., benzene, THF, methyl tert-butyl ether, cyclopentyl methyl ether, ethyl acetate, n-heptane, dimethyl carbonate, dimethylformamide, acetonitrile), or alcohols (e.g., methanol, isopropanol).

[0709] Synthesis of compound F. X (R = CH3)

[0710]

[0711] Hydrogenation of IX (R=CH3) to provide X (R=CH3):

[0712]

[0713] Five volumes of isopropyl acetate (IPAc) containing IX (R=CH3) and Pt / C (5 wt%, relative to IX (R=CH3)) were loaded into the reaction vessel. The reactor was inert with N2, then evacuated and filled with H2 to 5 psig. The mixture was vigorously stirred at room temperature with 5 psig H2 for approximately 12–24 hours. After the reaction was complete, diatomaceous earth (5 wt%) was added, and the mixture was filtered to remove solids and washed with additional IPAc. The IPAc solution was treated overnight at approximately 50°C with six volumes of 5% N-acetylcysteine ​​aqueous solution under N2 with vigorous stirring. After cooling to room temperature, the aqueous layer was removed, and the organic layer was washed with six volumes of 5–10% NaHCO3 aqueous solution and six volumes of 10% NaCl aqueous solution. Diatomaceous earth was added (0.5 s), the mixture was stirred for approximately 5 minutes, and the solids were subsequently removed by filtration. The solution of X (R=CH3) was proceeded without further purification.

[0714] 1H NMR (400MHz, CDCl3) δ7.97(d,J=9.2Hz,1H),7.26(dd,J=9.2,2.7Hz,1H),7.09(d,J=2.7Hz,1H),5.88(d,J=3.9Hz,1 H),5.29(d,J=9.9Hz,1H),4.74(d,J=7.2Hz,1H),4.38–4.25(m,2H),4.13–4.07(m,1H),3.94(s,3H),3.78–3.76(m, 1H),3.71(s,3H)2.63(appdd,J=15.0,7.5Hz,1H),2.54–2.32(m,1H),2.02–1.98(m,1H),1.84–1.63(m,4H),1.53–1 .33(m,3H),1.30–1.10(m,4H),1.07(s,9H),0.95–0.80(m,2H),0.77–0.64(m,1H),0.46(dd,J=12.9,6.3Hz,1H).19F NMR (376MHz, CDCl3) δ-102.43 (ddd, J=250.4, 25.4, 8.6Hz), -103.47 (ddd, J=250.4, 28.7, 11.3Hz).

[0715] Alternative reagents and reaction conditions to those disclosed above may also be used. For example, other catalysts may be used, such as heterogeneous metal catalysts (e.g., platinum, palladium, ruthenium, or nickel), metals on carbon, alumina, silica, and other heterogeneous supports, metal nanoparticles, hindered Lewis acid-base pairs (e.g., hydroxy[4-[bis(2,4,6-trimethylphenyl)phosphino]-2,3,5,6-tetrafluorophenyl]hydrobis(2,3,4,5,6-pentafluorophenyl)boronic acid esters), and homogeneous metal catalysts (e.g., trichlorotriphenylphosphine)rhodium(I) or (1,5-cyclooctadiene)(pyridine)(tricyclohexylphosphine)-iridium(I)hexafluorophosphate). Additionally, water, protic solvents (e.g., methanol, ethanol, or acetic acid), aprotic solvents (e.g., dimethyl sulfoxide, tetrahydrofuran, ethyl acetate, acetonitrile, toluene, dichloromethane, or acetone), or combinations thereof may be used. In addition, hydrogen or formate (e.g., ammonium formate or formic acid) within a certain pressure range can be used. Alternatively, diimide and a temperature range of approximately -20°C to approximately 150°C can be used.

[0716] Synthesis of compound G. XI (R = H) from X (R = CH3)

[0717]

[0718] Hydrolysis of II.X to provide XI:

[0719]

[0720] An aqueous solution of LiOH (1 M, 2.3 eq) was added to a solution of X (R = CH3) in IPA (7 volumes) over approximately 5–10 minutes at approximately 30 °C and N2. The reaction mixture was heated to an internal temperature of approximately 40 °C and stirred. After cooling to room temperature, MTBE (8 volumes) was added. The resulting mixture was acidified to pH 3 with 1 M HCl. The aqueous layer was removed and the organic layer was washed twice with a 10% NaCl aqueous solution. Diatomaceous earth (0.1 s) was added, and the resulting slurry was filtered and washed with additional MTBE. The MTBE was removed by vacuum distillation, and the resulting solids were dissolved in 5 volumes of ethanol and 5 volumes of heptane at approximately 60–65 °C. The solution was then cooled to approximately 45–50 °C and inoculated with a slurry of XI in ethanol / heptane (0.005 s). After stirring at approximately 45 °C for approximately 6 hours, the slurry was cooled to approximately 15 °C over approximately 10 hours. An additional 5 volumes of heptane were added over approximately 1 hour. XI was separated by vacuum filtration and washed with 5 times its volume of 1:9 EtOH:heptane. The resulting solid was dried to constant weight in a vacuum furnace at approximately 40°C. 1 H NMR (400MHz, CDCl3) δ7.95 (d, J=9.2Hz, 1H), 7.24 (dd, J=9.2, 2.6Hz, 1H), 7.07 (d, J=2.6 Hz,1H),5.87(d,J=3.5Hz,1H),5.47(d,J=9.9Hz,1H),4.72(d,J=7.2Hz,1H),4.33(d,J=1 2.2Hz,1H),4.32(d,J=9.9Hz,1H),4.04(dd,J=11.9,4.0Hz,1H),3.93(s,3H),3.7(m,1H) ,2.64(m,1H),2.43(m,1H),1.99(m,1H),1.8-1.3(m,6H),1.25-1.15(m,3H),1.0(m,1H). 13 C NMR (75MHz, CDCl3): δ172.63,171.64,162.06,157.49,153.37,142.42,139.12(dd,J CF =30.6,25.8Hz),133.06,130.44,120.1(t,J CF =245Hz),119.93,105.31,77.45,61.66,59.49,55.74,54.98,51.92,46.52,36.42(t,J CF=25.0),34.91,30.35,27.74,26.19,21.53,19.99,18.34,12.06,11.33.

[0721] Alternative reagents and reaction conditions to those disclosed above may also be used. For example, carbonates (e.g., lithium, sodium, or cesium carbonates), metal hydrides (e.g., sodium hydride or potassium hydride), alkoxides (e.g., sodium methoxide, sodium tert-butoxide, lithium tert-butoxide, potassium tert-butoxide, or tetraalkylammonium alkoxides), hydroxides (e.g., sodium hydroxide, potassium hydroxide, tin hydroxide, or tetraalkylammonium hydroxide), or amine bases (e.g., DBU) may be used. Additionally, protic acids (e.g., sulfuric acid, hydrochloric acid, p-toluenesulfonic acid, or solid-supported acids), Lewis acids (e.g., boron trifluoride), metal salts, metal complexes, or hydrogen bond donors may be used. In addition, polar protic solvents, including water, alcohols (e.g., methanol, ethanol, isopropanol, tert-butanol, neopentyl alcohol, glycols and combinations thereof with water), polar aprotic solvents (e.g., dimethyl sulfoxide, dimethylformamide, tetrahydrofuran, 1,4-dioxane or combinations thereof with water), or ionic liquids (e.g., 3-methylimidazolium hexafluorophosphate), can be used.

[0722] Synthesis of Compound H. from X (R = CH3)

[0723] The synthesis of compound I from X is similar to that described in U.S. Publication No. 2014-0017198. X (R=CH3) is hydrolyzed to form XI (R=H), which is coupled with XII to form I.

[0724] Alternative approach using tert-butyl esters on proline

[0725] Alternatives using the tert-butyl ester of the proline moiety, such as those described in U.S. Publication No. 2014-0017198, include novel RCM pathway homologues with both proline and cyclopropyl-leucine moieties. The tert-butyl group can be removed by acid treatment following the hydrogenation stage.

[0726] Synthesis of compound VI (R = tert-Bu), (2S,3S,4R)-4-((3-(1,1-difluorobut-3-en-1-yl)-7-methoxyquinoxalin-2-yl)oxy)-3-ethylpyrrolidine-2-carboxylic acid tert-butyl ester

[0727]

[0728] Boc deprotection of IV (R = tert-Bu) to provide VI (R = tert-Bu)

[0729]

[0730] V(R = tert-Bu) (0.88 g, 1.56 mmol, 1.0 eq.), t-BuOAc (9.5 mL, 11 vols.), and CH2Cl2 (2.4 mL, 2.7 vols.) were loaded into a round-bottom flask equipped with a magnetic stir bar. Methanesulfonic acid (0.51 mL, 7.8 mmol, 5.0 eq.) was added, and the reaction mixture was stirred overnight at approximately 20 °C for about two hours. The reaction solution was then poured into 60 mL of a 1:1 saturated NaHCO3 / EtOAc mixture, and the organic layers were separated. The aqueous layer was subsequently back-extracted with EtOAc, and the combined organic layers were washed sequentially with saturated NaHCO3 and brine, then dried over magnesium sulfate, filtered, and concentrated to obtain VI(R = tert-Bu). LCMS: m / z = 464.4.

[0731] Alternative reagents and reaction conditions to those disclosed above may also be used. For example, other acids, such as inorganic acids (e.g., hydrochloric acid) or organic acids (e.g., p-toluenesulfonic acid), may be used. Additionally, other organic solvents (e.g., isopropyl acetate, methyl tert-butyl ether, or 2-methyltetrahydrofuran) and temperatures in the range of about 50°C to about 60°C may be used.

[0732] Synthesis of compound VIII (R = tert-Bu), (2S,3S,4R)-1-((S)-2-((((1R,2R)-2-allylcyclopropoxy)carbonyl)amino)-3,3-dimethylbutyryl)-4-((3-(1,1-difluorobut-3-en-1-yl)-7-methoxyquinoxalin-2-yl)oxy)-3-ethylpyrrolidine-2-carboxylic acid tert-butyl ester

[0733] Amide coupling of I.VI (R = tert-Bu) and VII to provide VIII (R = tert-Bu)

[0734]

[0735] VI (R = tert-Bu) (4.12 g, 8.9 mmol, 1.0 eq.), VII (2.72 g, 10.7 mmol, 1.2 eq.), and acetonitrile (120 mL, 29 vols.) were loaded into a flask. HATU (4.4 g, 11.6 mmol, 1.3 eq.) was then loaded, followed by DIPEA (6.2 mL, 35.6 mmol, 4 eq.). The reaction mixture was stirred overnight at approximately 20 °C. The reaction mixture was then concentrated and purified by silica gel rapid column chromatography (elution gradient of 0% to 18% to 25% ethyl acetate in hexane) to obtain VIII. LCMS: m / z = 701.1.

[0736] Alternative reagents and reaction conditions to those disclosed above may also be used. For example, other coupling reagents (e.g., ethyl-3-(3-dimethylaminopropyl)carbodiimide or hydroxybenzotriazole monohydrate) may be used. Additionally, other bases (e.g., pyridine, morpholine, imidazole, or N-methylmorpholine) and organic solutions (e.g., dimethylacetamide or N,N-dimethylformamide) may be used.

[0737] Synthesis of compound IX (R = tert-Bu)(33R,34S,35S,91R,92R,5S)-5-(tert-butyl)-34-ethyl-14,14-difluoro-17-methoxy-4,7-dioxo-2,8-dioxa-6-aza-1(2,3)-quinoxalino-3(3,1)-pyrrolidine-9(1,2)-cyclopropanecyclotetradecanoic acid-11-en-35-carboxylic acid tert-butyl ester

[0738]

[0739] The closed-loop multiple decomposition of I.VIII (R = tert-Bu) is used to provide IX (R = tert-Bu).

[0740]

[0741] Zhan 1B catalyst (26 mg, 0.036 mmol, 0.025 equiv.) was loaded into the flask. The flask was evacuated and backfilled three times with nitrogen. Nitrogen-injected toluene (25 mL) was loaded and the mixture was stirred and heated to reflux (approximately 110 °C). After 30 minutes, a solution of compound VIII (R = tert-Bu) in 5 mL of toluene (1.0 g, 1.4 mmol, 1.00 equiv.) was added, maintaining the reaction temperature at approximately 110 °C. Upon completion of the reaction, the reaction mixture was cooled to approximately 20 °C and purified by rapid column chromatography (54 g silica gel, 20% ethyl acetate in hexane as eluent) to produce IX (R = tert-Bu). 1H NMR (300MHz, CDCl3): δ7.95(d,J=6.0Hz,1H),7.26(m,1H),7.12(m,1H),5.89(m,1H),5.69(m,2 H),5.27(d,J=9.0Hz,1H),4.62(d,J=6.0Hz,1H),4.35(d,J=9.0Hz,1H),4.29(d,J=6.0Hz,1H),4 .02-3.95(m,1H),3.96(s,3H),3.88(m,1H),3.21(s,2H),2.90-2.70(m,1H),2.49(d,J=12.0Hz, 1H),1.48(m,9H),1.41(m,2H),1.25-1.18(m,4H),1.06(s,9H),1.00-0.93(m,2H),0.50(m,1H). 19 F NMR (282.2MHz, CDCl3): δ-101.0ppm (m).

[0742] Alternative reagents and reaction conditions to those disclosed above may also be used. For example, other ruthenium-based Grubbs, Grubbs-Hoveyda, saturated and unsaturated imidazole and phosphine-based catalysts, as well as molybdenum-based catalysts and their variants may be used (see below for a representative non-exhaustive list, where Cy is cyclohexyl, Me is methyl, Ph is phenyl and iPr is isopropyl).

[0743]

[0744] Alternatively, other accelerators (e.g., acetic acid, benzoquinones, CuI, CsCl, or Ti(Oi-Pr)) or accelerating conditions (e.g., microwave irradiation or ethylene) can be used. Furthermore, temperatures in the range of approximately 40°C to 110°C can be used. Other solvents can be used, such as halogenated solvents (e.g., dichloromethane, 1,2-dichloroethane, chlorobenzene, or hexafluorobenzene), organic solvents (e.g., benzene, THF, methyl tert-butyl ether, cyclopentyl methyl ether, ethyl acetate, n-heptane, dimethyl carbonate, dimethylformamide, or acetonitrile), or alcohols (e.g., methanol, isopropanol).

[0745] Example 2. Synthesis of (1aR,5S,8S,9S,10R,22aR)-5-tert-butyl-N-[(1R,2R)-2-(difluoromethyl)-1-{[(1-methylcyclopropyl)sulfonyl]carbamoyl}cyclopropyl]-9-ethyl-18,18-difluoro-14-methoxy-3,6-dioxo-1,1a,3,4,5,6,9,10,18,19,20,21,22,22a-tetradecanoyl-8H-7,10-methylbridged cyclopropano[18,19][1,10,3,6]dioxadiazarocyclo[11,12-b]quinoxaline-8-carboxamide (I) via pathway II

[0746]

[0747] a. Hydrolysis, closed-ring metathesis, and hydrogenation:

[0748]

[0749] The difference between Pathway II and Pathway I of Example 1 lies in the order of assembly. Compound VIII is first hydrolyzed to provide compound XVIII and subsequently undergoes ring-closure metathesis to provide compound XIX, which, upon hydrogenation, yields compound XI. The reaction conditions used for hydrolysis, ring-closure metathesis, and hydrogenation are similar to those disclosed in Pathway I. Compound XI is converted to compound I as described in Example 1 above.

[0750] Example 3. Synthesis of (1aR,5S,8S,9S,10R,22aR)-5-tert-butyl-N-[(1R,2R)-2-(difluoromethyl)-1-{[(1-methylcyclopropyl)sulfonyl]carbamoyl}cyclopropyl]-9-ethyl-18,18-difluoro-14-methoxy-3,6-dioxo-1,1a,3,4,5,6,9,10,18,19,20,21,22,22a-tetradecanoyl-8H-7,10-methylbridged cyclopropano[18,19][1,10,3,6]dioxadiazarocyclo[11,12-b]quinoxaline-8-carboxamide (I) via pathway III

[0751] The compound of formula I is synthesized via pathway III as shown below:

[0752]

[0753] Synthesis of A.XV

[0754]

[0755] Compounds XIV (R=CH3) (180 mg, 0.35 mmol, 1 equivalent v) and XIII (180 mg, 0.67 mmol, 1.9 equivalent v) were dissolved in 15 volumes of degassed toluene (2.7 mL). The system was inert under nitrogen and loaded with Zhan 1B catalyst (53 mg, 0.073 mmol, 0.20 equivalent v). The mixture was heated to approximately 95 °C and stirred for approximately 45 min. The reaction was cooled to approximately 20 °C and purified by silica gel chromatography to provide intermediate XV (R=CH3). LCMS (M+1): 749 m / z. 1 H NMR (400MHz, CDCl3): δ7.98-7.90(m,1H),7.28-7.14(m,2H),6.30-5.95(m,1H ),5.58-5.19(m,3H),4.56(dd,1H,J=36.8,8.5Hz),4.46-4.24(m,1H),4.22-4. 01(m,3H),3.95(s,3H),3.85-3.67(m,5H),3.40-3.27(m,1H),2.50-1.98(m,4 H),1.65-1.55(m,1H),1.43-1.41(m,9H),1.1-0.7(m,11H),0.57-0.40(m,2H).

[0756] B. Hydrogenation of intermediate XV (R=CH3) and hydrolysis of XVI (R=CH3):

[0757]

[0758] Intermediate XV (R=CH3) (117 mg, 0.156 mmol) and Pt / C (13 mg, 5 wt%) were mixed in 14 volumes of IPAc (1.6 mL) and stirred at 5 psig H2 at room temperature for 20 hours. The mixture was filtered through diatomaceous earth, concentrated under vacuum, and purified by silica gel chromatography to yield ~75 mg of intermediate XVI (64% yield). Intermediate XVI was dissolved in 1 mL of CH2Cl2 and mixed with 0.5 mL of 4 M HCl in dioxane at rt. After approximately 40 minutes, the mixture was concentrated to yield intermediate XVII, which was continued without further purification.

[0759] The lactamation of C.(S)-2-((((1S,2S)-2-(5-(3-(((3R,4S,5S)-4-ethyl-5-(methoxycarbonyl)pyrrolidine-3-yl)oxy)-6-methoxyquinoxalin-2-yl)-5,5-difluoropentyl)cyclopropoxy)carbonyl)amino)-3,3-dimethylbutyrate salt (XVII(R=CH3)) to form X(R=CH3):

[0760]

[0761] HOBt (39.3 mg, 0.29 mmol, 10 equiv) was added to a solution of XVII (20 mg, 0.029 mmol, 1 equiv) in 100 V DMF (2 mL), followed by EDC (56 mg, 0.29 mmol, 10 equiv). The mixture was stirred for 5 minutes, at which point triethylamine (0.1 mL, 0.72 mmol, 25 equiv) was added. After 4.5 hours, the mixture was diluted with MTBE, washed twice with saturated NH4Cl aqueous solution, washed twice with saturated NaHCO3 aqueous solution, dried over MgSO4, filtered, and concentrated under vacuum. The crude product thus obtained was diluted to 25 mL in a volumetric flask. UPLC analysis showed the presence of X (R = CH3) (10.6 mg, 59% yield).

[0762] However, alternative reagents and reaction conditions to those disclosed above may also be used. For example, other coupling reagents may be used (e.g., carbodiimidazole, N,N'-dicyclohexylcarbodiimide, N,N'-diisopropylcarbodiimide, benzotriazol-1-yl-oxytripyrrolylphosphonium hexafluorophosphate, 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridine 3-oxide hexafluorophosphate, or 2,4,6-trichlorobenzoyl chloride). Additionally, other bases such as amines (e.g., diisopropylethylamine, pyridine, or sodium hexamethyldisilamide), carbonates (e.g., potassium carbonate or cesium carbonate), bicarbonates (e.g., sodium bicarbonate), or inorganic / organic hydroxides (e.g., sodium hydroxide or tetramethylammonium hydroxide) may be used. Other promoters (e.g., 4-dimethylaminopyridine or 1-hydroxy-7-azabenzotriazole) may be used. In addition, other solvents such as water, polar aprotic solvents (e.g., N,N-dimethylformamide (DMF) and dimethyl sulfoxide (DMSO) (or combinations of these with water), organic solvents (e.g., toluene, acetonitrile, or acetone), alcohols (e.g., methanol or ethanol), ethers (e.g., tetrahydrofuran, dioxane, or methyl tert-butyl ether), esters (e.g., ethyl acetate) or chlorinated solvents (e.g., dichloromethane) can be used.

[0763] As described in Example 1 above, compound X is converted into compound I.

[0764] This application also involves the following items.

[0765] 1. A method for preparing a compound of formula V or its eutectic or salt:

[0766]

[0767] This includes contacting a compound of formula III or its eutectic or salt with a compound of formula IV under O-arylation conditions to provide a compound of formula V or its eutectic or salt:

[0768]

[0769] Where R is C 1-6 Alkyl group, PG is a protecting group, and R 1 It is a leaving group.

[0770] 2. A method for preparing a compound of formula VI or its eutectic or salt:

[0771]

[0772] This includes subjecting a compound of formula V or its eutectic or salt to N-deprotection conditions to provide a compound of formula VI or its eutectic or salt:

[0773]

[0774] Where R is C 1-6 Alkyl groups and PG are protecting groups.

[0775] 3. A method for preparing a compound of formula VIII or its eutectic or salt:

[0776]

[0777] This includes contacting a compound of formula VI or its eutectic or salt with a compound of formula VII or its eutectic or salt under amide coupling conditions to provide a compound of formula VIII or its eutectic or salt:

[0778]

[0779] Where R is C 1-6 alkyl.

[0780] 4. A method for preparing a compound of formula IX or its eutectic or salt:

[0781]

[0782] This includes the cyclic metathesis of compounds of formula VIII or their eutectic or salt to provide compounds of formula IX or their eutectic or salt:

[0783]

[0784] Where R is C 1-6 alkyl.

[0785] 5. A method for preparing a compound of formula I or a eutectic or pharmaceutically acceptable salt thereof:

[0786]

[0787] include:

[0788] a) Contacting a compound of formula III, or its eutectic or salt, with a compound of formula IV under O-arylation conditions to provide a compound of formula V, or its eutectic or salt.

[0789]

[0790] b) Subjecting a compound of formula V, or its eutectic or salt, to N-deprotection conditions to provide a compound of formula VI, or its eutectic or salt:

[0791]

[0792] c) Contacting a compound of formula VI or its eutectic or salt with a compound of formula VII or its eutectic or salt under amide coupling conditions to provide a compound of formula VIII or its eutectic or salt:

[0793]

[0794] d) Perform cyclic metathesis of a compound of formula VIII or its eutectic or salt to provide a compound of formula IX or its eutectic or salt;

[0795]

[0796] e) Hydrogenating a compound of formula IX or its eutectic or salt in the presence of a catalyst to provide a compound of formula X or its eutectic or salt:

[0797]

[0798] f) Hydrolyze a compound of formula X or its eutectic or salt to provide a compound of formula XI or its eutectic or salt:

[0799]

[0800] g) Contacting a compound of formula XI or its eutectic or salt with a compound of formula XII or its eutectic or salt under amide coupling conditions to provide a compound of formula I or its eutectic or pharmaceutically acceptable salt:

[0801]

[0802] Where R is C 1-6 Alkyl groups, PG is a protecting group and R 1 It is a leaving group.

[0803] 6. A method for preparing a compound of formula XVIII or its eutectic or salt:

[0804]

[0805] Including compounds of formula VIII hydrolyzed or their eutectic or salt to provide compounds of formula XVIII or their eutectic or salt:

[0806]

[0807] Where R is C 1-6 alkyl.

[0808] 7. A method for preparing a compound of formula XIX or its eutectic or salt:

[0809]

[0810] This includes the cyclic metathesis of compounds of formula XVIII or their eutectic or salt in the presence of a catalyst to provide compounds of formula XIX.

[0811] 8. A method for preparing a compound of formula XI or its eutectic or salt:

[0812]

[0813] This includes hydrogenating a compound of formula XIX or its eutectic or salt in the presence of a catalyst to provide a compound of formula XI or its eutectic or salt:

[0814]

[0815]

[0816] 9. A method for preparing a compound of formula I or a eutectic or pharmaceutically acceptable salt thereof:

[0817]

[0818] include:

[0819] a) Contacting a compound of formula III or its eutectic or salt with a compound of formula IV under O-arylation conditions to provide a compound of formula V or its eutectic or salt:

[0820]

[0821] b) Contacting a compound of formula V, or its eutectic or salt, with an acid under N-deprotection conditions to provide a compound of formula VI, or its eutectic or salt:

[0822]

[0823] c) Contacting a compound of formula VI or its eutectic or salt with a compound of formula VII or its eutectic or salt under amide coupling conditions to provide a compound of formula VIII or its eutectic or salt:

[0824]

[0825] d) Hydrolyzing a compound of formula VIII or its eutectic or salt to provide a compound of formula XVIII or its eutectic or salt:

[0826]

[0827] e) To perform ring-closure metathesis of a compound of formula XVIII or its eutectic or salt in the presence of a catalyst to provide a compound of formula XIX or its eutectic or salt:

[0828]

[0829] f) Hydrogenating a compound of formula XIX in the presence of a catalyst to provide a compound of formula XI or its eutectic or salt:

[0830]

[0831] g) Contacting a compound of formula XI or its eutectic or salt with a compound of formula XII or its eutectic or salt under amide coupling conditions to provide a compound of formula I or its eutectic or pharmaceutically acceptable salt:

[0832]

[0833]

[0834] Where R is C 1-6 Alkyl groups, PG is a protecting group, and R 1 It is a leaving group.

[0835] 10. A method for preparing a compound of formula XV or its eutectic or salt:

[0836]

[0837] This includes contacting a compound of formula XIII or its eutectic or salt with a compound of formula XIV or its eutectic or salt under cross-metathesis conditions to provide a compound of formula XV or its eutectic or salt:

[0838]

[0839] Where R is C 1-6 Alkyl groups and PG are protecting groups.

[0840] 11. A method for preparing a compound of formula XVI or its eutectic or salt:

[0841]

[0842] This includes hydrogenating a compound of formula XV or its eutectic or salt in the presence of a catalyst to provide a compound of formula XVI or its eutectic or salt:

[0843]

[0844] Where R is C 1-6 Alkyl groups and PG are protecting groups.

[0845] 12. A method for preparing compounds of formula XVII or their eutectic or salt:

[0846]

[0847] This includes subjecting compounds of formula XVI or their eutectic or salt to N-deprotection conditions to provide compounds of formula XVII or their eutectic or salt:

[0848]

[0849] Where R is C 1-6 Alkyl groups and PG are protecting groups.

[0850] 13. A method for preparing a compound of formula X or its eutectic or salt:

[0851]

[0852] This includes contacting a compound of formula XVII with an amide coupling agent under lactamation conditions to provide a compound of formula X or its eutectic or salt, wherein R is C 1-6 alkyl.

[0853] 14. A method for preparing a compound of formula I or a eutectic or pharmaceutically acceptable salt thereof:

[0854]

[0855] include:

[0856] a) Contacting a compound of formula XIII or its eutectic or salt with a compound of formula XIV or its eutectic or salt under cross-metathesis conditions to provide a compound of formula XV or its eutectic or salt:

[0857]

[0858] b) Hydrogenating a compound of formula XV or its eutectic or salt in the presence of a catalyst to provide a compound of formula XVI or its eutectic or salt:

[0859]

[0860] c) subjecting a compound of formula XVI or its eutectic or salt to N-deprotection conditions to provide a compound of formula XVII or its eutectic or salt;

[0861]

[0862] d) Contacting a compound of formula XVII with an amide coupling agent under lactamation conditions to provide a compound of formula X or its eutectic or salt:

[0863]

[0864] e) Hydrolyzing a compound of formula X or its eutectic or salt to provide a compound of formula XI or its eutectic or salt:

[0865]

[0866] f) Contacting a compound of formula XI or its eutectic or salt with a compound of formula XII or its eutectic or salt under amide coupling conditions to provide a compound of formula I or its eutectic or salt:

[0867]

[0868] Where R is C 1-6 Alkyl groups and PG are protecting groups.

[0869] 15. A method for preparing a compound of formula Vv or its eutectic or salt:

[0870]

[0871] include:

[0872] a) Hydrolyze compounds of formula Ab or their eutectic or salt to provide compounds of formula Ac or their eutectic or salt:

[0873]

[0874] b) Contacting a compound of formula Ac or its eutectic or salt with dicyclohexylamine to provide a compound of formula Ag or its eutectic or salt:

[0875]

[0876] c) Contacting Ag or its eutectic or salt with cinconidine to provide a compound of formula Ah or its eutectic or salt:

[0877]

[0878] d) Subjecting Ah or its eutectic or salt to a Coultis rearrangement in the presence of tert-butanol to provide a compound of formula Ai or its eutectic or salt:

[0879]

[0880] e) Hydrolysis of Ai or its eutectic or salt to provide Vv or its eutectic or salt.

[0881] 16. Compounds of formula IV or their eutectic or salt:

[0882]

[0883] Where R 1 It is a leaving group.

[0884] 17. Compounds of formula V or their eutectic or salt:

[0885]

[0886] Where R is C 1-6 Alkyl groups and PG are protecting groups.

[0887] 18. Compounds of formula VI or their eutectic or salt:

[0888]

[0889] Where R is C 1-6 alkyl.

[0890] 19. Compounds of formula VII or their eutectic or salt:

[0891]

[0892] 20. Compounds of formula VIII, or their eutectic or salt:

[0893]

[0894] Where R is C 1-6 alkyl.

[0895] 21. Compounds of formula XIII, or their eutectic or salt:

[0896]

[0897] 22. Compounds of formula XIV or their eutectic or salt:

[0898]

[0899] Where R is C 1-6 alkyl.

[0900] 23. Compounds of formula XV or their eutectic or salt:

[0901]

[0902] Where R is C 1-6 Alkyl groups and PG are protecting groups.

[0903] 24. Compounds of formula XVI or their eutectic or salt:

[0904]

[0905] Where R is C 1-6 Alkyl groups and PG are protecting groups.

[0906] 25. Compounds of formula XVII or their eutectic or salt;

[0907]

[0908] Where R is C 1-6 alkyl.

[0909] 26. Compounds of formula XVIII, or their eutectic or salt:

[0910]

[0911] 27. Compounds of formula XIX or their eutectic or salt:

[0912] 28. Compounds of formula IV-d or their eutectic or salt:

[0913] 29. Compounds of formula M3 or their eutectic or salt:

[0914] 30. Compounds of formula IV-a, or their eutectic or salt:

[0915] 31. Compounds of formula IV-b, or their eutectic or salt:

[0916] 32. Compounds of formula IV-c or their eutectic or salt:

Claims

1. A compound of formula XVIII or a pharmaceutically acceptable salt thereof:

Images