Processes and intermediates for preparation of macrocyclic MCL1 inhibitors

Abstract

The present invention specifically relates to methods and intermediates for the synthesis of Compound 1 that inhibits MCL1 and can be used in the treatment of cancer. # imgabs0 #

Description

[0001] This application is a divisional application of the Chinese invention patent application (application date: November 17, 2021; application number: 202180077387.9 (international application number: PCT / US2021 / 059648); invention name: Methods and intermediates for preparing macrocyclic MCL1 inhibitors).

[0002] CROSS-REFERENCE TO RELATED APPLICATIONS

[0003] This application claims the benefit under 35 USC § 119(e) of U.S. Provisional Application No. 63 / 115,723, filed on November 19, 2020, which is hereby incorporated by reference in its entirety for all purposes. Technical Field

[0004] The present disclosure relates to methods and intermediates for the synthesis of certain compounds that inhibit MCL1 for use in treating cancer. Background Art

[0005] Apoptosis (programmed cell death) is the process of eliminating unwanted or potentially dangerous cells from an organism. Preventing apoptosis is crucial for the development and continued growth of tumors. Myeloid cell leukemia 1 (MCL1) is an anti-apoptotic member of the Bcl-2 protein family. MCL1 is overexpressed in many cancers. Overexpression of MCL1 prevents cancer cells from undergoing apoptosis. Research suggests that MCL1 inhibitors may be useful in treating cancer. Compounds that inhibit MCL1 have been described, but there remains a need for synthetic methods for preparing such compounds on a production scale.

[0006] PCT Application No. PCT / US2019 / 032053 (Publication No. WO 2019 / 222112) discloses novel compounds that can be used as MCL1 inhibitors. This patent publication discloses compounds according to formula (I):

[0007] (I);

[0008] and pharmaceutically acceptable salts thereof are effective as inhibitors of MCL1 and can be used to treat cancer. 2 、R 3 、R 4 、R 5 、R 6 and R 12 Each is as defined in PCT / US2019 / 032053.

[0009] There is a need for synthetic methods and intermediates that can be used to prepare compounds of formula (I) and their salts. There is also a need for methods for preparing intermediate compounds that can be used to prepare compounds of formula I and their salts. Summary of the Invention

[0010] In one embodiment, the present disclosure provides a method for preparing Compound 1:

[0011] 1,

[0012] or a salt thereof, comprising preparing a compound of formula 9-A by the following manner:

[0013] ,

[0014] Make the corresponding compound of formula 1-K:

[0015]

[0016] Reaction with the corresponding compound of formula 6-L:

[0017] ,

[0018] A compound of formula 9-A or a salt thereof is obtained, wherein the compound of formula 1-K is prepared by the following manner: the corresponding compound of formula 1-Q:

[0019]

[0020] Converting into a compound of formula 1-K or a salt thereof;

[0021] where R x and R y are each independently H or C 1-6 Alkyl; R 2 It is H; R 3 and R 5 are independently CH3; R z is halogen or CN; and R p Selected from -C(=O)-C 1-6 Alkyl, -C(=O)-C 6-10 Aryl, -C(=O)-OC 1-6 Alkyl, -C(=O)-OC 1-6 Alkyl-C 6-10 Aryl and -C(=O)-OC 6-10 Aryl, wherein each aryl group is optionally substituted by one to four independently selected C 1-3 Alkyl and -OC 1-3 Alkyl groups are substituted.

[0022] In one embodiment, the present disclosure provides a method for preparing a compound of formula 1-Q:

[0023] ,

[0024] or its salt, which is carried out in the following manner: making the corresponding compound of formula 1-P:

[0025]

[0026] React with the corresponding compound of formula 1-I:

[0027]

[0028] A compound of formula 1-P is obtained.

[0029] In one embodiment, the present disclosure provides a method for preparing a compound of Formula 1-P:

[0030] ,

[0031] The method is carried out in the following manner: the corresponding compound of formula 1-N:

[0032]

[0033] Converted to a compound of formula 1-P, wherein the compound of formula 1-N is prepared by the following manner:

[0034] The corresponding compound of formula 1-M:

[0035] ,

[0036] Converted to a compound of formula 1-N, wherein each R n Independently C 1-6 Alkyl, or two R n Parts are linked together to form C 2-4 Alkyl bridge, wherein the bridge is optionally substituted by one to four independently selected C 1-3 Alkyl and phenyl groups are substituted.

[0037] In one embodiment, the present disclosure provides a method for preparing Compound 1:

[0038] 1,

[0039] or a salt thereof, comprising preparing a compound of formula 1-K by the following manner:

[0040] ,

[0041] The corresponding compound of formula 2-L:

[0042]

[0043] Converted into a compound of formula 1-K or a salt thereof,

[0044] where R x Is H or C 1-6 Alkyl; R 5 is CH3; R 6 is Cl; and R a It is C 1-6 alkyl.

[0045] In one embodiment, the present disclosure provides a method for preparing Compound 1:

[0046] 1,

[0047] or a salt thereof, comprising preparing a compound of formula 1-K by the following manner:

[0048] ,

[0049] The corresponding compound of formula 3-H:

[0050]

[0051] Converted into a compound of formula 1-K or a salt thereof,

[0052] where R x Is H or C 1-6 Alkyl; R 5 is CH3; and R 6 It's Cl.

[0053] In one embodiment, the present disclosure provides a method for preparing a compound of formula 3-H:

[0054] ,

[0055] The method is carried out by converting the corresponding compound of formula 2-L:

[0056]

[0057] A compound of formula 3-H is obtained.

[0058] In one embodiment, the present disclosure provides a method for preparing a compound of formula 2-L:

[0059] ,

[0060] The method is carried out by: making the corresponding compound of formula 2-K:

[0061]

[0062] React with a compound of formula 5-I:

[0063]

[0064] A compound of formula 2-L is obtained.

[0065] In one embodiment, the present disclosure provides a method for preparing a compound of Formula 2-K:

[0066] ,

[0067] The method is carried out in the following manner: the corresponding compound of formula 2-H:

[0068]

[0069] is converted to a compound of formula 2-K, wherein the compound of formula 2-H is prepared by: reacting the corresponding compound of formula 2-G:

[0070]

[0071] is converted to a compound of formula 2-H, wherein the compound of formula 2-G is prepared by: reacting the corresponding compound of formula 2-F:

[0072]

[0073] Converted into a compound of formula 2-G;

[0074] Wherein PG is selected from tri-C 1-6 Alkylsilyl group, di-C 1-6 Alkyl-phenylsilyl group, C 1-6 Alkyl-diphenylsilyl groups and triphenylsilyl groups.

[0075] In one embodiment, the present disclosure provides a method for preparing a compound of formula 2-L:

[0076] ,

[0077] The method is carried out in the following manner: the corresponding compound of formula 3-G:

[0078]

[0079] is converted to a compound of formula 2-L, wherein a compound of formula 3-G is prepared by reacting the corresponding compound of formula 3-E:

[0080]

[0081] Reacts with the following compounds:

[0082]

[0083] Obtaining a compound of formula 3-E;

[0084] where R a It is C 1-6 alkyl.

[0085] In one embodiment, the present disclosure provides a method for preparing Compound 1:

[0086] 1,

[0087] or a salt thereof, comprising making the corresponding compound of formula 4-N:

[0088] ,

[0089] or its salts react with the following compounds:

[0090]

[0091] Compound 1 or a salt thereof is obtained, wherein the compound of formula 4-N is prepared by the following manner: the corresponding compound of formula 4-M:

[0092]

[0093] Converted into a compound of formula 4-N or a salt thereof,

[0094] where R c It is a C1-6 alkyl group.

[0095] In one embodiment, the present disclosure provides a method for preparing a compound of formula 4-M

[0096] ,

[0097] or its salt, which is carried out in the following manner: the corresponding compound of formula 4-L:

[0098] ,

[0099] or a salt thereof is converted into a compound of formula 4-M or a salt thereof, wherein the compound of formula 4-L is prepared by the following manner: the corresponding compound of formula 4-K:

[0100]

[0101] and the corresponding compound of formula 4-J:

[0102] ,

[0103] or a salt thereof to obtain a compound of formula 4-L, wherein the compound of formula 4-J is prepared by the following manner: the corresponding compound of formula 4-I:

[0104] ,

[0105] or a salt thereof is converted into a compound of formula 4-J or a salt thereof,

[0106] where R 4 is a halogen or borate, R b It is C 1-6 Alkyl, R c It is C 1-6 Alkyl, and R p Selected from -C(=O)-C 1-6 Alkyl, -C(=O)-C 6-10 Aryl, -C(=O)-OC 1-6 Alkyl, -C(=O)-OC 1-6 Alkyl-C 6-10 Aryl and -C(=O)-OC 6-10 Aryl, wherein each aryl group is optionally substituted by one to four independently selected C 1-3 Alkyl and -OC 1-3 Alkyl group substituted, X is halogen, 、 、C(O)2R 1 、-OS(O)2R 2 or -OP(O)(R 2 )2, where R 1 Is H or C 1-6 Alkyl, each R 2 It is C 1-6 Alkyl or C 6-10 Aryl, each R 7 are independently H or C 1-3 Alkyl, wherein each alkyl or aryl group is optionally substituted by one to four halogen or C 1-3 Alkyl substituted, m is 1, 2 or 3, and n is 0 or 1.

[0107] In one embodiment, the present disclosure provides a method for preparing a compound of formula 4-1:

[0108] ,

[0109] or its salt, which is carried out in the following manner: the corresponding compound of formula 4-H:

[0110]

[0111] is converted to a compound of formula 4-I, wherein the compound of formula 4-H is prepared by the following manner: the corresponding compound of formula 4-G:

[0112] ,

[0113] or a salt thereof is converted into a compound of formula 4-H or a salt thereof.

[0114] In one embodiment, the present disclosure provides a method for preparing a compound of formula 4-G:

[0115] ,

[0116] or its salt, which is carried out in the following manner: the corresponding compound of formula 4-F:

[0117] ,

[0118] or a salt thereof is converted into a compound of formula 4-G or a salt thereof.

[0119] In one embodiment, the present disclosure provides a method for preparing Compound 1:

[0120] 1,

[0121] or its salt, which is carried out in the following manner: the corresponding compound of formula 9-J:

[0122] ,

[0123] or a salt thereof is converted into compound 1 or a salt thereof, wherein the compound of formula 9-J or a salt thereof is prepared by the following manner: making the corresponding compound of formula 9-L:

[0124] ,

[0125] or a salt thereof and a corresponding compound of formula 9-I:

[0126] ,

[0127] or its salt to obtain a compound of formula 9-J or its salt, wherein R u and R w Each independently is H, C 1-6 Alkyl or C 6-10 Aryl; R 2 It is H; R 3 and R 5 are each independently CH3; and R 12 yes .

[0128] In one embodiment, the present disclosure provides a method for preparing a compound of formula 9-I:

[0129] ,

[0130] or its salt, which is carried out in the following manner: the corresponding compound of formula 9-H:

[0131] ,

[0132] or a salt thereof is converted into the corresponding compound of formula 9-I, wherein the compound of formula 9-H or a salt thereof is prepared by the following manner: the corresponding compound of formula 9-G:

[0133] ,

[0134] or its salt and the corresponding compound of formula 9-K:

[0135]

[0136] or a salt thereof to obtain a compound of formula 9-H or a salt thereof.

[0137] In one embodiment, the present disclosure provides a method for preparing a compound of formula 9-J:

[0138] ,

[0139] or its salt, which is carried out in the following manner: making the corresponding compound of formula 9-L:

[0140] ,

[0141] or a salt thereof and a corresponding compound of formula 9-I:

[0142] ,

[0143] or a salt thereof to obtain a compound of formula 9-J or a salt thereof.

[0144] In one embodiment, the present disclosure provides a method for preparing a compound of formula 9-I:

[0145] ,

[0146] or its salt, which is carried out in the following manner: the corresponding compound of formula 9-H:

[0147] ,

[0148] or a salt thereof is converted into the corresponding compound of formula 9-I.

[0149] In one embodiment, the present disclosure provides a method for preparing a compound of formula 9-H:

[0150] ,

[0151] or its salt, which is carried out in the following manner: making the corresponding compound of formula 9-G:

[0152] ,

[0153] or its salt and the corresponding compound of formula 9-K:

[0154]

[0155] or a salt thereof to obtain a compound of formula 9-H or a salt thereof. DETAILED DESCRIPTION

[0156] I. Overview

[0157] The present disclosure provides a method for preparing Compound 1 or a salt thereof. The present disclosure also provides a method for preparing compounds of Formula 1-M, 1-N, 1-O, 1-P, 1-Q, 1-R, 1-S, 2-G, 2-H, 2-I, 2-J, 2-K, 2-L, 1-J, 1-K, 3-F, 3-G, 2-L, 3-H, 4-G, 4-H, 4-I, 4-J, 4-L, 4-M, 4-N, 5-K, 5-L, 5-M, 5-N, 5-P, 5-Q, 6-M, 6-N, 7-C, 7-D, 7-E, 7-F, 8-B, 8-C, 8-D, 8-E, 8-F, and 9-A. The present disclosure also provides methods for preparing compounds of Formula 1-I, 5-D, 5-E, 9-H, 9-I, 9-J, 10-B, 10-C, 10-D, 10-E, 10-F, and 10-G.

[0158] II. Definitions

[0159] Abbreviations used herein have their conventional meanings in the fields of chemistry and biology.

[0160] It should be understood that the present disclosure is considered to be an illustration of the claimed subject matter and is not intended to limit the appended claims to the specific embodiments described. The headings used throughout this disclosure are provided for convenience and should not be construed as limiting the claims in any way. The embodiments illustrated under any heading may be combined with the embodiments illustrated under any other heading. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those generally understood by those of ordinary skill in the art.

[0161] When a trade name is used herein, it is intended to independently include both the trade name product and the active pharmaceutical ingredient of the trade name product.

[0162] As used herein and in the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "a compound" includes a plurality of such compounds and reference to "an assay" includes reference to one or more assays, etc.

[0163] The wavy line between two chemical groups" ” is used to denote a mixture of isomers at this point.

[0164] "Isomers" are different compounds that have the same molecular formula. Isomers include stereoisomers, enantiomers, and diastereomers.

[0165] "Stereoisomers" are isomers that differ only in the way their atoms are arranged in space.

[0166] "Enantiomers" are a pair of stereoisomers that are non-superimposable mirror images of each other. A 1:1 mixture of a pair of enantiomers is a "racemic" mixture. A mixture of enantiomers in a ratio other than 1:1 is a "non-racemic" mixture.

[0167] "Diastereomers" are stereoisomers that have at least two asymmetric atoms, but which are not mirror images of one another.

[0168] Absolute stereochemistry is assigned according to the Cahn-Ingold-Prelog RS system. When a compound is enantiomerically pure, the stereochemistry of each chiral carbon can be assigned as R or S. Resolved compounds whose absolute configuration is unknown can be assigned as (+) or (-) based on the direction (right- or left-handed) that they rotate plane-polarized light at the wavelength of the sodium D line. Certain compounds described herein contain one or more asymmetric centers and / or hindered rotation about a bond axis and can therefore give rise to enantiomers, diastereomers, and other stereoisomeric forms that can be defined, based on absolute stereochemistry, as (R)- or (S)-. This disclosure is intended to include all such possible isomers, including racemic mixtures, non-racemic mixtures, diastereomeric mixtures, optically pure forms, and intermediate mixtures. Optically active (R)- and (S)-isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques.

[0169] Unless otherwise expressly defined, the present disclosure includes all tautomers of the compounds described herein, even if only one tautomer is explicitly indicated (e.g., both tautomeric forms are contemplated and described by presenting a tautomeric form where a pair of two tautomers is possible). For example, if a compound containing an amide is referred to (e.g., by structure or chemical name), it is understood that the corresponding imidic acid tautomer is included in the present disclosure and described as if the amide were explicitly recited alone or with the imidic acid. Where more than two tautomers are possible, the present disclosure includes all such tautomers, even if the chemical name and / or structure only describes a single tautomeric form.

[0170] The compounds described herein may have chiral centers and / or geometric isomeric centers (E- and Z-isomers), and it is understood that all such optical, enantiomeric, diastereomeric, and geometric isomers are contemplated. Where a compound is represented in its chiral form, it is understood that the embodiment encompasses, but is not limited to, the specific diastereomeric or enantiomerically enriched form. Where chirality is not specified but is present, it is understood that the embodiment relates to the specific diastereomeric or enantiomerically enriched form; or a racemic or non-racemic mixture of such a compound.

[0171] In some embodiments disclosed herein, the catalyst used in the reaction can be an "asymmetric" or catalyst. As used herein, the term "asymmetric catalyst" refers to a catalyst that promotes the enantioselective and / or diastereoselective conversion of an achiral center or molecule to a chiral center or molecule, respectively. For example, an asymmetric catalyst can produce an enantiomeric excess of the product. Exemplary asymmetric catalysts include a transition metal and a chiral ligand. Non-limiting examples of chiral ligands include BINAP / SEGPHOS ® , salen, bisoxazoline, tartrate ligand, cinchona alkaloid, DuPhos phospholane, BPE phospholane, DSM phosphoramidite, Solvias ® Josiphos family, phosphine-oxazolines, Reetz and Trost ligands, and ChiralQuest phosphines.

[0172] Also provided are pharmaceutically acceptable hydrates, solvates, co-crystals, tautomeric forms, polymorphs, and prodrugs of the compounds described herein.

[0173] The term "hydrate" refers to a complex formed by the combination of a compound of Formula I or any formula disclosed herein and water.

[0174] The term "solvate" refers to a complex formed by combining a compound of Formula I, or any other formula disclosed herein, with a solvent or a crystalline solid containing an amount of solvent incorporated into the crystal structure. As used herein, the term "solvate" includes hydrates.

[0175] Any formula or structure given herein or any formula disclosed herein is also intended to represent unlabeled forms as well as isotopically labeled forms of the compounds. An isotopically labeled compound has a structure depicted by a formula given herein except that one or more atoms are replaced by an atom having a selected atomic mass or mass number. Examples of isotopes that can be incorporated into the compounds of the present disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, and chlorine, such as, but not limited to, 2 H (deuterium, D), 3 H (tritium), 11 C. 13 C. 14 C. 15 N. 18 F. 31 P. 32 P. 35 S. 36 Cl and 125 I. Various isotopically labeled compounds of the present disclosure, for example, wherein a radioactive isotope such as 3 H. 13 C and 14 Such isotopically labeled compounds are useful in metabolism 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 assays, or in radiotherapy of patients.

[0176] The present disclosure also includes compounds of Formula A or Formula I or Formula I(a) or any formula disclosed herein, wherein 1 to "n" hydrogen atoms attached to carbon atoms are replaced by deuterium, where n is the number of hydrogen atoms in the molecule. Such compounds may exhibit increased resistance to metabolism and, therefore, may be used to increase the half-life of any compound of Formula I when administered to a mammal. See, for example, Foster, "Deuterium Isotope Effects in Studies of Drug Metabolism," Trends Pharmacol. Sci. Vol. 5 (No. 12): pp. 524-527 (1984). Such compounds are synthesized by methods well known in the art, for example, by using starting materials in which one or more hydrogen atoms have been replaced by deuterium.

[0177] Deuterium-labeled or substituted therapeutic compounds of the present disclosure may have improved DMPK (drug metabolism and pharmacokinetic) properties, which relate to distribution, metabolism, and excretion (ADME). Substitution with heavier isotopes such as deuterium may provide certain therapeutic advantages resulting from greater metabolic stability, such as increased in vivo half-life and reduced dosage requirements. 18 F-labeled compounds can be used for PET or SPECT studies. Isotopically labeled compounds of the present disclosure and their prodrugs can generally be prepared by substituting readily available isotopically labeled reagents for non-isotopically labeled reagents and following the procedures disclosed in the Schemes or Examples and formulations described below. In addition, the use of heavier isotopes, particularly deuterium (i.e. 2 H or D) can provide certain therapeutic advantages resulting from greater metabolic stability, such as increased in vivo half-life or reduced dosage requirements or improved therapeutic index. It should be understood that deuterium in this context is considered a substituent in the compound of Formula I or any formula disclosed herein.

[0178] The concentration of such heavier isotopes, particularly deuterium, can be defined by an isotopic enrichment factor. In the compounds of the present disclosure, any atom not specifically designated as a particular isotope is intended to represent any stable isotope of that atom. Unless otherwise indicated, when a position is specifically designated as "H" or "hydrogen," that position is understood to be hydrogen at its natural abundance isotopic composition. Thus, in the compounds of the present disclosure, any atom specifically designated as deuterium (D) is intended to represent deuterium.

[0179] The modifier "about" in connection with a quantity is inclusive of the stated value and has the meaning dictated by the context (e.g., includes the degree of error associated with measurement of the particular quantity). In the absence of any other definition or any context to the contrary, the term "about" may be interpreted as meaning ±10%, ±5% or ±3%, or ±2% or ±1%.

[0180] The term "chiral" refers to molecules that have the property that their mirror image partner is non-superimposable, whereas the term "achiral" refers to molecules that are superimposable on their mirror image partner.

[0181] Prefixes such as "C u-v " or (C u -C v ) indicates that the following group has u to v carbon atoms, where u and v are integers. For example, "C 1-6 "Alkyl" indicates that the alkyl group has 1 to 6 carbon atoms.

[0182] A dash ("-" or "–") that is not between two letters or symbols is used to indicate the point of attachment of a substituent. For example, -C(O)NH2 is attached through the carbon atom. Dashes at the beginning or end of a chemical group are for convenience; a chemical group can be depicted without one or more dashes without losing its ordinary meaning. Unless chemically or structurally required, directionality is not indicated or implied by the order in which chemical groups are written or named.

[0183] For example, the wavy lines on the chemical groups shown below, The point of attachment is indicated, ie, it shows the broken bond through which the group is connected to the other described group.

[0184] The term "substituted" or "optionally substituted" means that one or more hydrogen atoms on a carbon atom (aliphatic or aromatic) are replaced by one or more atoms or groups other than hydrogen, provided that the normal valence of the designated carbon atom is not exceeded. A "substituent" is an atom or group that replaces a hydrogen atom on a carbon when it is "substituted". Unless otherwise specified, where a group is described as optionally substituted, any substituents of these groups are themselves unsubstituted. If not otherwise modified, the term "optionally substituted" includes at least the following optional substituents: halogen, hydroxy, amino, thiol, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-10 Aryl, 3-12 membered heterocycloalkyl and 5-10 membered heteroaryl, -OC 1-6 Alkyl, -C(O)-C 1-6 Alkyl, -C(O)OC 1-6 Alkyl, -C(O)-OH, -C(O)-NH2, -C(O)N(C 1-6 Alkyl)(C 1-6 alkyl), -C(O)NH(C 1-6 alkyl)-、OC(O)N(C 1-6 Alkyl)(C 1-6 alkyl), OC(O)NH(C 1-6 Alkyl), -N(C 1-6 Alkyl)(C 1-6 Alkyl), -NH(C 1-6 Alkyl), -N(C 1-6 alkyl)-C(O)-(C 1-6 alkyl), NH-C(O)-(C 1-6 Alkyl), -N(C 1-6 alkyl)-C(O)O-(C 1-6 alkyl), -S(O)2NH2, -S(O) (1或2) (C1-6 alkyl), -S(O)2N(C 1-6 Alkyl)(C 1-6 Alkyl), -N(C 1-6 alkyl)S(O)2R b , -N3, -CN and -NO2.

[0185] As used herein, "alkyl" is a straight or branched chain saturated monovalent hydrocarbon. Examples of alkyl groups include, but are not limited to, methyl (Me, -CH3), ethyl (Et, -CH2CH3), 1-propyl (n-Pr, n-propyl, -CH2CH2CH3), 2-propyl (i-Pr, isopropyl, -CH(CH3)2), 1-butyl (n-Bu, n-butyl, -CH2CH2CH2CH3), 2-methyl-1-propyl (i-Bu, isobutyl, -CH2CH(CH3)2), 2-butyl (s-Bu, sec-butyl, -CH( CH3)CH2CH3), 2-methyl-2-propyl (t-Bu, tert-butyl, -C(CH3)3), 1-pentyl (n-pentyl, -CH2CH2CH2CH2CH3), 2-pentyl (-CH(CH3)CH2CH2CH3), 3-pentyl (-CH(CH2CH3)2), 2-methyl-2-butyl (-C(CH3)2CH2CH3), 3-methyl-2-butyl (-CH(CH3)CH(CH3)2), 3-methyl-1- Butyl (-CH2CH2CH(CH3)2), 2-methyl-1-butyl (-CH2CH(CH3)CH2CH3), 1-hexyl (-CH2CH2CH2CH2CH2CH3), 2-hexyl (-CH(CH3)CH2CH2CH2CH3), 3-hexyl (-CH(CH2CH3)(CH2CH2CH3)), 2-methyl-2-pentyl (-C(CH3)2CH2CH2CH3), 3-methyl-2-pentyl (-C )2), 3,3-dimethyl-2-butyl (-CH(CH3)C(CH3)3). Whenever any alkyl group can exist in more than one isomeric form, such as n-butyl, sec-butyl, and tert-butyl, any reference herein lacking a prefix, such as "butyl," should be interpreted as referring to the normal isomer (e.g., "n-butyl"). Thus, "propyl" means "n-propyl," and "butyl" means "n-butyl."

[0186] "Alkenyl" refers to an aliphatic group containing at least one carbon-carbon double bond. Examples of alkenyl groups include ethenyl, propenyl, butadienyl (including 1,2-butadienyl and 1,3-butadienyl).

[0187] As used herein, "alkoxy" refers to a radical of the formula -OR A A group in which R A is an alkyl group as defined above. Non-limiting examples of alkoxy groups include methoxy, ethoxy, propoxy, and butoxy.

[0188] "Alkynyl" refers to an aliphatic group containing at least one carbon-carbon triple bond.

[0189] "Aryl" refers to a monovalent or divalent aromatic carbocyclic group having a single ring (e.g., monocyclic) or multiple rings (e.g., bicyclic or tricyclic), including fused ring systems, in which one or more of the fused rings is fully or partially unsaturated. Non-limiting examples of aryl groups, as used herein, include phenyl, naphthyl, fluorenyl, indanyl, tetrahydroindanyl, and anthracenyl. However, aryl does not encompass or overlap in any way with heteroaryl, as defined below. If one or more aryl groups are fused to a heteroaryl ring, the resulting ring system is a heteroaryl. The classification as monoradical or diradical indicates whether the aryl group terminates the chain (monoradical) or is within the chain (diradical). The above definition does not exclude additional substituents on the aryl group. For example, as used herein, the aryl group in "A-aryl-B" is a diradical, while the aryl group in "AB-aryl" is a monoradical, but additional substituents may be present on each aryl group.

[0190] The term "aryloxy" refers to the group -O-aryl.

[0191] "Cycloalkyl" refers to a saturated or partially saturated cyclic alkyl group having a single ring or multiple rings including fused, bridged, and spiro ring systems. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. "Cycloalkyl" does not include any ring containing a heteroatom in the ring.

[0192] "Halo" and "halogen" are used herein to refer to fluoro (-F), chloro (-Cl), bromo (-Br), and iodo (-I).

[0193] When the prefix "halo" is attached to another term, it means that any one or more hydrogen atoms associated with that term are independently replaced by a halogen atom. Thus, as used herein, the term "haloalkyl" refers to an alkyl group as defined herein wherein one or more of the hydrogen atoms of the alkyl group are independently replaced by a halogen substituent, which halogen substituents may be the same or different. For example, C 1-6 Haloalkyl (or halo C 1-6 Alkyl) is C 1-6 Alkyl, where C 1-6One or more hydrogen atoms of the alkyl group have been replaced by a halo substituent. Examples of haloalkyl groups include, but are not limited to, fluoromethyl, fluorochloromethyl, difluoromethyl, difluorochloromethyl, trifluoromethyl, 1,1,1-trifluoroethyl, and pentafluoroethyl. Up to all hydrogen atoms of the related terms may be replaced by a halo, resulting in a perfluorinated substituent (e.g., perfluoroalkyl).

[0194] "Heteroaryl" refers to a monoradical or diradical aromatic group having a single ring, multiple rings, or multiple fused rings, wherein one or more ring heteroatoms are independently selected from nitrogen, oxygen, and sulfur. The heteroatoms within "heteroaryl" can be oxidized, for example, -N(O)-, -S(O)-, -S(O)2-. The term includes fused ring systems in which one or more fused rings are fully or partially unsaturated. The classification as monoradical or diradical indicates whether the heteroaryl group terminates the chain (monoradical) or is within the chain (diradical). The above definition does not exclude additional substituents on the heteroaryl group. For example, the heteroaryl group in "A-heteroaryl-B" is a diradical, while the heteroaryl group in "AB-heteroaryl" is a monoradical, but additional substituents may be present on each heteroaryl group. Heteroaryl does not encompass or overlap with aryl as defined above. Non-limiting examples of heteroaryl groups include, but are not limited to, azaquinone, acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzodioxolyl, benzofuranyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, benzo[b][l,4]dioxepenyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyrone, benzofuranyl, benzofuranone, benzothiophenyl (benzothiophenyl), benzotriazolyl, benzo[4,6]imidazo[l,2-a]pyridinyl, carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiophenyl, furanyl ... 1-oxoazepinyl, oxazolyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl, 1-pyridinyl oxide, 1-pyrimidinyl oxide, 1-pyrazinyl oxide, 1-pyridazinyl oxide, 1-phenyl-1H-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl, quinoxalinyl, quinolinyl, quinuclidinyl, isoquinolinyl, tetrahydroquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, and thiophenyl.

[0195] The term "heteroaryloxy" refers to the group -O-heteroaryl.

[0196] The term "heterocyclyl," "heterocycle," or "heterocyclic," or "heterocycloalkyl" refers to a monovalent or divalent saturated or unsaturated radical having a single ring or multiple fused rings containing one or more heteroatoms selected from nitrogen, sulfur, phosphorus, and / or oxygen. The heteroatoms within a "heterocyclyl" group may be oxidized, e.g., -N(O)-, -S(O)-, -S(O)2-. A heterocyclyl group may be a single ring or multiple rings, wherein the multiple rings may be fused, bridged, or spiro. Any non-aromatic ring containing at least one heteroatom is considered a heterocyclyl group, regardless of how it is attached (i.e., whether it is attached through carbon atoms or heteroatoms). Exemplary heterocyclic groups include, but are not limited to, azetidinyl, dioxolanyl, thienyl[1,3]dithianyl, decahydroisoquinolinyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidinyl, pyrrolidinyl, pyrazolidinyl, quinuclidine, thiazolidinyl, tetrahydrofuranyl, thienyl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, and 1,1-dioxo-thiomorpholinyl.

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

[0198] The term "oxo" refers to the group =0.

[0199] The term "carboxy" refers to the group -C(O)-OH.

[0200] The term "dioxane" refers to "1,4-dioxane".

[0201] The compounds described herein can be prepared and / or formulated as pharmaceutically acceptable salts. Pharmaceutically acceptable salts are non-toxic salts of the free base form of the compound that have the desired pharmacological activity of the free base. These salts can be derived from inorganic acids, organic acids, or bases. For example, a compound containing a basic nitrogen can be prepared as a pharmaceutically acceptable salt by contacting the compound with an inorganic acid or an organic acid. Non-limiting examples of pharmaceutically acceptable salts include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, phosphates, monohydrogen phosphates, dihydrogen phosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, propionates, decanoates, octanoates, acrylates, formates, isobutyrates, hexanoates, heptanoates, propiolates, oxalates, malonates, succinates, suberates, sebacates, fumarates, maleates, butyrates, succinates, octanedioates ... The pharmaceutically acceptable salts of the present invention include benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, sulfonate, methylsulfonate, propylsulfonate, benzenesulfonate, xylenesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, gamma-hydroxybutyrate, glycolate, tartrate and mandelate. A list of other suitable pharmaceutically acceptable salts can be found in "Remington: The Science and Practice of Pharmacy", 21st edition, Lippincott Wiliams and Wilkins, Philadelphia, Pa., 2006.

[0202] Non-limiting examples of "pharmaceutically acceptable salts" of the compounds disclosed herein also include those derived from suitable bases such as alkali metals (e.g., sodium, potassium), alkaline earth metals (e.g., magnesium), ammonium, and NY4 + (wherein Y is C1-C4 alkyl). Also included are base addition salts such as sodium or potassium salts.

[0203] As used herein, the terms "non-polar," "polar aprotic," and "polar protic" refer to solvents and are intended as a means of classifying the solvents used in the various methods and steps described herein. For the purposes of this classification, the term "non-polar solvent" refers to any ether, hydrocarbon, or halogenated solvent, carbon dioxide, and carbon disulfide, as well as other solvents traditionally classified as non-polar solvents. Ether solvents include dimethyl ether, diethyl ether, dipropyl ether, diisopropyl ether, dibutyl ether, methyl isopropyl ether, methyl tert-butyl ether, cyclopentyl methyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, diethylene glycol diethyl ether, triethylene glycol dimethyl ether, and anisole. Hydrocarbon solvents include petroleum ether, pentane (or mixed pentanes), heptane (or mixed heptanes), hexane (or mixed hexanes), octane, isooctane, decane, dodecane, cyclopentane, cyclohexane, methylcyclohexane, benzene, toluene, o-xylene, m-xylene, p-xylene, pyridine, chlorobenzene, 1,2-dichlorobenzene, fluorobenzene, phenol, anisole, trifluorotoluene, hexachlorobenzene, hexafluorobenzene, and benzonitrile. Halogenated solvents include dichloromethane, tetrachloromethane, chloroform, 1,1-dichloroethane, 1,1,1-trichloroethane, vinyl chloride, vinylidene chloride, trichloroethylene, perchloroethylene, chlorobenzene, 1,2-dichlorobenzene, fluorobenzene, trifluorotoluene, hexachlorobenzene, and hexafluorobenzene. For the purposes of this classification, the term "polar aprotic solvent" refers to any ester, nitrile, or ketone solvent, as well as N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, sulfolane, N-methyl-2-pyrrolidone, N,N-dimethylethyleneurea, N,N-dimethylpropyleneurea, hexamethylphosphoric triamide, dimethyl carbonate, diethyl carbonate, ethylene carbonate, propylene carbonate, and nitromethane, as well as other solvents traditionally classified as polar protic solvents. Ester solvents include methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate, isobutyl acetate, tert-butyl acetate, vinyl acetate, 2,2,2-trichloroethyl acetate, and 2-ethoxyethyl acetate. Nitrile solvents include acetonitrile, propionitrile, and benzonitrile. Ketone solvents include acetone, methyl ethyl ketone, methyl n-butyl ketone, methyl isobutyl ketone, methyl tert-butyl ketone, 3-pentanone, cyclopentanone, cyclohexanone and 2,5-hexanedione. For the purpose of classification herein, the term "polar protic solvent" refers to any alcohol or acid solvent, or water, or ammonia, and other solvents traditionally classified as polar protic solvents. Alcohol solvents include methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, sec-butanol, tert-butanol, pentanol, 3-methyl-1-butanol, cyclopentanol, cyclohexanol, phenol, 2-methoxyethanol, 2-ethoxyethanol, ethylene glycol, 1,2-propylene glycol, 1,3-propylene glycol, glycerol, 1,4-butanediol and 1,4-cyclohexanediol. Acid solvents include formic acid, acetic acid, trichloroacetic acid and trifluoroacetic acid.

[0204] "Salt" refers to an acid or base salt of a compound used in the methods of the present disclosure. Salts useful in the present disclosure include, but are not limited to, hemisulfates, sulfates, chlorides, bromides, carbonates, nitrates, and acetates. Hemisulfates refer to compounds in which only one of the two basic groups forms a salt with sulfuric acid. Carbonates include salts of bicarbonates (or bicarbonates). Illustrative examples of pharmaceutically acceptable salts are salts of mineral acids (hydrochloric acid, hydrobromic acid, phosphoric acid, etc.), organic acids (acetic acid, propionic acid, glutamic acid, citric acid, etc.), and quaternary ammonium salts (methyl iodide, ethyl iodide, etc.). It should be understood that pharmaceutically acceptable salts are non-toxic. Additional information on suitable pharmaceutically acceptable salts can be found in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, which is incorporated herein by reference.

[0205] III. Methods for preparing compounds

[0206] The present disclosure includes several methods for preparing Compound 1.

[0207] A. Method for preparing compound 1 from formula 1-L and formula 5-E

[0208] In one embodiment, the present disclosure provides a method for preparing a compound selected from 1-M, 1-N, 1-O, 1-P, 1-Q, 1-R, 1-S, 1-K, 9-A and Compound 1, as shown in Scheme 1, wherein R x and R y Independently H, C 1-6 Alkyl or C 6-10 Aryl, wherein the alkyl group is optionally replaced by C 6-10 Aryl substitution, R 2 It's H, R 3 is methyl, R 5 is methyl, R z is halogenated or CN, each R n Independently C 1-6 Alkyl, or two R n Parts are linked together to form C 2-4 Alkyl bridge, wherein the bridge is optionally substituted by one to four independently selected C 1-3 Alkyl and phenyl groups are substituted, and R p Selected from -C(=O)-C 1-6 Alkyl, -C(=O)-heteroaryl, -C(=O)-OC 1-6 Alkyl and -C(=O)-OC 1-6 Alkyl-C 6-10 Aryl, wherein each aryl or heteroaryl is optionally substituted by one to four independently selected C 1-3Alkyl and -OC 1-3 wherein each heteroaryl group has one to four heteroatoms; wherein each heteroatom is independently selected from N, O, and S, and wherein each heteroaryl group has 5 to 10 ring members. In one embodiment, R z is Br. In one embodiment, R z In one embodiment, R n In one embodiment, R z is Br, and R n In one embodiment, R z is CN, and R n In one embodiment, R x In one embodiment, R x is H. In one embodiment, both R n In one embodiment, the two R n The moieties are linked together to form a bridge selected from the group consisting of CH2CH2-, -CH(CH3)CH(CH3)-, -CH2CH(CH3)-, -CH2CH(C6H5)-, -C(CH3)2C(CH3)2-, -CH2CH2CH2-, -CH2CBr2CH2-, -CH2(C=CH)CH2-, -CH2CH(C6H5)CH2-, -CH(CH3)CH2CH(CH3)-, -CH2CH(CH3)CH2-, -CH2C(CH3)2CH2-, -CH2C(CH2CH3)2CH2-, -CH2CH2CH2CH2-, -CH2CH2CH2CH2CH2-, -CH(C6H5)CH(C6H5), -CH2CH(C6H5)CH2-, and -(o-C6H4)-. In one embodiment, the two R n The parts are linked together to form -C(CH3)2C(CH3)2-.

[0209]

[0210] Solution 1

[0211] In one embodiment, the present disclosure provides a method for preparing compound 1-M from compound 1-L and compound 5-E.

[0212] In one embodiment, the method includes the step of reacting compound 1-L with compound 5-E using a base in a suitable solvent and under conditions and for a time effective to form compound 1-M. In one embodiment, a promoter is present.

[0213] In one embodiment, the base is selected from inorganic bases (lithium carbonate, sodium carbonate, potassium carbonate, potassium tert-butoxide, calcium carbonate, potassium phosphate, sodium phosphate), metal hydrides such as sodium hydride and potassium hydride; alkoxides such as sodium methoxide, sodium tert-butoxide or lithium tert-butoxide, or tert-amyl alcohol analogs, alkali metal amide bases such as lithium hexamethyldisilazane, sodium and potassium and lithium diisopropylamide. In one embodiment, the base is potassium tert-butoxide.

[0214] In one embodiment, the promoter is selected from NaI and tetrabutylammonium iodide.

[0215] In one embodiment, the solvent is selected from ethers (e.g., 2-methyltetrahydrofuran, methyl tert-butyl ether (MTBE), cyclopentyl methyl ether (CPME), tetrahydrofuran (THF)), polar aprotic solvents (e.g., dimethyl sulfoxide (DMSO), N,N-dimethylformamide (DMF), N,N-dimethylacetamide, N-methyl-2-pyrrolidone (NMP)), nitriles (e.g., acetonitrile), hydrocarbon solvents (e.g., toluene, heptanes (n-heptane, heptane), halogenated solvents (e.g., dichloromethane, 1,2-dichloroethane, chloroform, chlorobenzene), alcohols (e.g., 2-propanol). In one embodiment, the solvent is tetrahydrofuran (THF).

[0216] In one embodiment, the temperature of the reaction is from -50°C to 100°C. In one embodiment, the temperature of the reaction is from 0°C to 100°C. In one embodiment, the temperature of the reaction is from -50°C to -35°C. In one embodiment, the temperature of the reaction is from 0°C to 20°C.

[0217] In one embodiment, the present disclosure provides a method for preparing compound 1-N from compound 1-M.

[0218] In one embodiment, the method includes the step of treating Compound 1-M with an acid in a suitable solvent and under conditions and for a time effective to form Compound 1-N.

[0219] In one embodiment, the acid is selected from methanesulfonic acid, trifluoromethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, camphorsulfonic acid, pyridinium p-toluenesulfonate, sulfuric acid, hydrochloric acid, hydrobromic acid, acetic acid, formic acid, phosphoric acid, oxalic acid, citric acid, Lewis acids such as erbium(III) trifluoromethanesulfonate. In one embodiment, the acid is methanesulfonic acid.

[0220] In one embodiment, the solvent is selected from ethers (e.g., 2-methyltetrahydrofuran, methyl tert-butyl ether, cyclopentyl methyl ether, tetrahydrofuran), polar aprotic solvents (e.g., dimethyl sulfoxide, N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone), nitriles (e.g., acetonitrile), hydrocarbons (e.g., toluene, n-heptane), halogenated solvents (e.g., dichloromethane, 1,2-dichloroethane, chloroform, chlorobenzene), alcohols (e.g., 2-propanol), esters (e.g., ethyl acetate, isopropyl acetate), ketones (e.g., acetone, 2-butanone, 4-methyl-2-pentanone), water, or combinations thereof. In one embodiment, the solvent is a combination of tetrahydrofuran (THF) and water.

[0221] In one embodiment, the temperature of the reaction is from 0°C to 100°C. In one embodiment, the temperature of the reaction is from 40°C to 60°C.

[0222] In one embodiment, the present disclosure provides a method for preparing compound 1-O from compound 1-N.

[0223] In one embodiment, the method includes the step of treating compound 1-N with a reducing agent in a suitable solvent and under conditions and for a time effective to form compound 1-O.

[0224] In one embodiment, the reducing agent is selected from the group consisting of tin or zinc in combination with an acid such as hydrochloric acid, acetic acid, ammonium chloride, a transition metal such as Pd, Pd(OH)2, Pt, PtO2 or Rh in combination with H2 or formate, a poisoned heterogeneous catalyst such as Pt / S / C, and iron powder. In one embodiment, the reducing agent is iron powder.

[0225] In one embodiment, the solvent is selected from a mixture of an acid (e.g., acetic acid, hydrogen chloride) in combination with other solvents, including ethers (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, cyclopentyl methyl ether), polar aprotic solvents (e.g., N,N-dimethylacetamide, N,N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide), nitriles (e.g., acetonitrile), hydrocarbons (e.g., toluene, n-heptane), halogenated solvents (e.g., dichloromethane, 1,2-dichloroethane, chloroform, chlorobenzene), alcohols (e.g., 2-propanol), esters (e.g., ethyl acetate, isopropyl acetate). In one embodiment, the solvent is acetic acid.

[0226] In one embodiment, the temperature of the reaction is from 0°C to 100°C. In one embodiment, the temperature of the reaction is from 40°C to 60°C.

[0227] In one embodiment, the present disclosure provides a method for preparing compound 1-P from compound 1-O.

[0228] In one embodiment, the step of treating compound 1-0 with a reducing agent in a suitable solvent and for a period of time under conditions effective to form compound 1-P. In one embodiment, an additive is present. In one embodiment, intermediate 1-R is formed. In one embodiment, intermediate 1-S is formed.

[0229] In one embodiment, the reducing agent is selected from sodium cyanoborohydride, sodium borohydride and lithium borohydride, a combination of trialkylsilanes (e.g., triethylsilane) and additives, a poisoned heterogeneous catalyst (e.g., Pt / S / C), a transition metal (e.g., Pd or Rh) and H2 or a combination of formate and additives, Pd and Pt catalysts (e.g., Pd(OH)2, PtO2), and sodium triacetoxyborohydride. In one embodiment, the reducing agent is sodium triacetoxyborohydride.

[0230] In one embodiment, the additive is selected from trifluoroacetic acid, pivalic acid, B(OR)3, Ti(OEt)4 and Ti(Oi-Pr)4, wherein R is C 1-6 alkyl.

[0231] In one embodiment, the solvent is selected from ethers (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, cyclopentyl methyl ether), polar aprotic solvents (e.g., dimethyl sulfoxide, N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone), nitriles (e.g., acetonitrile), hydrocarbons (e.g., toluene, n-heptane), halogenated solvents (e.g., dichloromethane, 1,2-dichloroethane, chloroform, chlorobenzene), alcohols (e.g., 2-propanol), esters (e.g., ethyl acetate, isopropyl acetate), and acids (e.g., acetic acid). In one embodiment, the solvent is acetic acid.

[0232] In one embodiment, the temperature of the reaction is from 0°C to 80°C. In one embodiment, the temperature of the reaction is from 10°C to 30°C.

[0233] In one embodiment, the present disclosure provides a method for preparing compound 1-Q from compound 1-P.

[0234] In one embodiment, the method includes the step of treating Compound 1-P with Compound 1-I, a reducing agent, and an acid in a suitable solvent and for a time and under conditions effective to form Compound 1-Q.

[0235] In one embodiment, the reducing agent is selected from silanes (e.g., triisopropylsilane, triphenylsilane, triethylsilane, diethylsilane), sodium borohydride, sodium borohydride / acetic acid, sodium triacetoxyborohydride, sodium cyanoborohydride, titanium isopropoxide / sodium cyanoborohydride, zinc / acetic acid, sodium borohydride / magnesium perchlorate, zinc borohydride / zinc chloride, tetramethylammonium triacetoxyborohydride. In one embodiment, the reducing agent is triethylsilane.

[0236] In one embodiment, the acid is selected from acetic acid, citric acid, pivalic acid, p-toluenesulfonic acid, methanesulfonic acid, hydrochloric acid and trifluoroacetic acid. In one embodiment, the acid is trifluoroacetic acid.

[0237] In one embodiment, the solvent is selected from ethers (e.g., 2-methyltetrahydrofuran, tetrahydrofuran, methyl tert-butyl ether, cyclopentyl methyl ether), hydrocarbon solvents (e.g., toluene, n-heptane), halogenated solvents (e.g., 1,2-dichloroethane, dichloromethane, chloroform, chlorobenzene), polar aprotic solvents (e.g., N,N-dimethylacetamide, N,N-dimethylformamide, N-methyl-2-pyrrolidone, dimethyl sulfoxide). In one embodiment, the solvent is dichloromethane.

[0238] In one embodiment, the temperature of the reaction is from -30°C to 50°C. In one embodiment, the temperature of the reaction is from 10°C to 30°C.

[0239] In one embodiment, the present disclosure provides a method for preparing compound 1-K from compound 1-Q.

[0240] In one embodiment, the method comprises the step of treating compound 1-Q with a ligand, an additive, and a base in the presence of a catalyst in a suitable solvent and under conditions effective to form compound 1-K for a period of time. In one embodiment, an acid is present. In one embodiment, R z It's Br.

[0241] In one embodiment, the method comprises the step of treating compound 1-Q with an acid and a base in a suitable solvent for a period of time under conditions effective to form compound 1-K. In one embodiment, an additive is present. In one embodiment, R z It is CN.

[0242] In one embodiment, the catalyst is selected from bis(triphenylphosphine)palladium dichloride, bis(3-methyl-2(3H)-benzothiazolylidene)palladium diiodide, bis(benzonitrile)palladium dichloride, (1,5-cyclooctadiene)palladium dichloride, dicobalt hexacarbonyl, and palladium acetate. In one embodiment, the catalyst is palladium acetate (Pd(OAc)2).

[0243] In one embodiment, the ligand is selected from triphenylphosphine, 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (XPhos), and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (XantPhos). In one embodiment, the ligand is 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (XPhos).

[0244] In one embodiment, the additive is selected from ethyl oxalate, potassium fluoride, carbon monoxide, tetrabutylammonium bromide, propylene oxide, acetic anhydride and dicyclohexylcarbodiimide (DCC). In one embodiment, the additive is dicyclohexylcarbodiimide (DCC).

[0245] In one embodiment, the acid is formic acid.

[0246] In one embodiment, the acid is selected from acetic acid, citric acid, pivalic acid, p-toluenesulfonic acid, methanesulfonic acid, hydrochloric acid and trifluoroacetic acid. In one embodiment, the acid is trifluoroacetic acid.

[0247] In one embodiment, the acid is selected from methanesulfonic acid, sulfuric acid, phosphoric acid and hydrochloric acid. In one embodiment, the acid is hydrochloric acid.

[0248] In one embodiment, the base is selected from N,N-dimethylaminopyridine, N,N,N',N'-tetramethylethylenediamine, sodium hydroxide, sodium acetate, sodium hydroxide, potassium carbonate and triethylamine. In one embodiment, the base is triethylamine.

[0249] In one embodiment, the base is selected from an alkoxide base (e.g., sodium hydroxide, sodium methoxide, potassium tert-butoxide, lithium hydroxide, cesium hydroxide, barium hydroxide, potassium hydroxide), a carbonate base (e.g., potassium carbonate, cesium carbonate, sodium carbonate, sodium bicarbonate), pyridine, triethylamine, potassium benzoate. In one embodiment, the base is potassium hydroxide.

[0250] In one embodiment, the solvent is selected from benzene, toluene, dimethylacetamide, dimethylformamide, alcohols (e.g., ethanol, methanol, isopropanol, butanol), dimethyl sulfoxide, dichloromethane, tetrahydrofuran, water, and combinations thereof. In one embodiment, the solvent is dimethylformamide. In one embodiment, the solvent is a combination of methanol and water.

[0251] In one embodiment, the temperature of the reaction is from -30°C to 155°C. In one embodiment, the temperature is from 80°C to 110°C. In one embodiment, the temperature is from 80°C to 100°C.

[0252] In one embodiment, the present disclosure provides a method for preparing compound 9-A from compound 1-K and compound 6-L.

[0253] In one embodiment, the present disclosure provides a method for preparing Compound 1 from Compound 9-A.

[0254] In one embodiment, the present disclosure provides a method for preparing compound 1 from a compound selected from 1-L, 5-E, 1-M, 1-N, 1-O, 1-P, 1-Q, 1-K or 9-A, as shown in Scheme 1.

[0255] In one embodiment, the present disclosure provides a method for preparing compound 9-A from a compound selected from 1-L, 5-E, 1-M, 1-N, 1-O, 1-P, 1-Q, or 1-K.

[0256] In one embodiment, the present disclosure provides a method for preparing compound 1-K from a compound selected from 1-L, 5-E, 1-M, 1-N, 1-O, 1-P, or 1-Q.

[0257] B. Method for preparing compound 1 from formula 2-F

[0258] In one embodiment, the present disclosure provides a method for preparing a compound selected from 2-G, 2-H, 2-I, 2-J, 2-K, 2-L, 1-J, 1-K, 9-A and Compound 1, as shown in Scheme 2, wherein R 2 It's H, R 3 is methyl, R x and R y Independently H, C 1-6 Alkyl or C 6-10 Aryl, wherein the alkyl group is optionally replaced by C 6-10 Aryl substitution, R a It is C 1-6 Alkyl, PG is selected from tri-C 1-6 Alkylsilyl group, di-C 1-6 Alkyl-phenylsilyl group, C 1-6 alkyl-diphenylsilyl group and triphenylsilyl group, and R p Selected from -C(=O)-C 1-6 Alkyl, -C(=O)-heteroaryl, -C(=O)-OC 1-6 Alkyl and -C(=O)-OC 1-6 Alkyl-C 6-10 Aryl, wherein each aryl or heteroaryl is optionally substituted by one to four independently selected C 1-3 Alkyl and -OC 1-3 In one embodiment, PG is tert-butyldiphenylsilyl. In one embodiment, Ra In one embodiment, R x It's methyl.

[0259]

[0260] Option 2

[0261] In one embodiment, the present disclosure provides a method for preparing compound 2-G from compound 2-F.

[0262] In one embodiment, the method includes the step of reacting compound 2-F with a catalyst, an oxidant, and an additive in a suitable solvent and under conditions and for a time effective to form compound 2-G.

[0263] In one embodiment, the catalyst is selected from ruthenium chloride, potassium osmate, phosphotungstic acid, and osmium tetroxide (OsO4). In one embodiment, the catalyst is osmium tetroxide (OsO4).

[0264] In one embodiment, the oxidizing agent is selected from potassium persulfate, potassium permanganate, potassium periodate, lead tetraacetate, sodium hypochlorite, hydrogen peroxide, N-methylmorpholine N-oxide (NMO), sodium periodate (NaIO4), and combinations thereof.

[0265] In one embodiment, the oxidizing agent is a combination of N-methylmorpholine N-oxide (NMO) and sodium periodate (NaIO4).

[0266] In one embodiment, the additive is selected from the group consisting of aluminum oxide, cerium trichloride, triethylamine, triphenylphosphine, bis(diphenylphosphino)ethane, pyridine, 2,6-lutidine, dimethyl sulfide, zinc, acetic acid, potassium carbonate, trimethoxyphosphine, and potassium iodide. In one embodiment, the additive is 2,6-lutidine.

[0267] In one embodiment, the solvent is selected from methanol, ethanol, dichloromethane, dichloroethane, dioxane, dimethyl sulfoxide, acetonitrile, acetone, tert-butanol, tetrahydrofuran (THF), water, and combinations thereof. In one embodiment, the solvent is a combination of tetrahydrofuran (THF) and water.

[0268] In one embodiment, the temperature of the reaction is from -80°C to 35°C. In one embodiment, the temperature is from 20°C to 35°C.

[0269] In one embodiment, the present disclosure provides a method for preparing compound 2-H from compound 2-G.

[0270] In one embodiment, the method comprises the step of reacting compound 2-G with a promoter and a base in a suitable solvent and under conditions and for a time effective to form compound 2-H. In one embodiment, an additive is present.

[0271] In one embodiment, the accelerator is selected from (dichloromethyl)diethoxyphosphine oxide, (trimethylsilyl)diazomethane lithium, (trimethylsilyl)diazomethane, imidazolesulfonyl azide hydrochloride, dimethyl (2-oxopropyl)phosphonate, p-toluenesulfonyl azide, tris(diethylamino)phosphonium bromide, acetamidobenzenesulfonyl azide, diethyl (1-diazo-2-oxopropyl)phosphonate, carbon tetrabromide, carbon tetrachloride, triiodomethane, triphenylphosphine, dibromomethyl (triphenyl)phosphonium bromide, (iodomethyl)triphenylphosphonium iodide, isopropyl phosphite, chromium chloride, and dimethyl (acetyldiazomethyl)phosphonate. In one embodiment, the accelerator is dimethyl (acetyldiazomethyl)phosphonate.

[0272] In one embodiment, the base is selected from n-butyllithium, sec-butyllithium, tert-butyllithium, methyllithium, lithium diisopropylamide, sodium hexamethyldisilazane, diazabicycloundecene, potassium tert-butoxide, potassium methoxide, sodium methoxide, sodium hydroxide, cesium carbonate and potassium carbonate. In one embodiment, the base is potassium carbonate.

[0273] In one embodiment, the additive is tetrabutylammonium fluoride.

[0274] In one embodiment, the solvent is selected from diethyl ether, tetrahydrofuran, acetonitrile, dichloromethane, ethanol and methanol. In one embodiment, the solvent is methanol.

[0275] In one embodiment, the temperature of the reaction is from -80°C to 40°C. In one embodiment, the temperature is from 20°C to 30°C.

[0276] In one embodiment, the present disclosure provides a method for preparing compound 2-I from compound 2-H.

[0277] In one embodiment, the method comprises the step of treating compound 2-H with a base and an alkylating agent in a suitable solvent and for a time and under conditions effective to form compound 2-1. In one embodiment, a promoter is present.

[0278] In one embodiment, the promoter is selected from bis(triphenylphosphine)palladium dichloride, tris(4-methoxyphenyl)phosphine, and cuprous iodide.

[0279] In one embodiment, the base is selected from lithium diisopropylamide, hexamethyldisilazane, sodium hexamethyldisilazane, sodium amide, lithium amide, diisopropylamine, triethylamine, tert-butyllithium, sodium hydride, sodium tert-butoxide, potassium tert-butoxide and n-butyllithium (n-BuLi). In one embodiment, the base is n-butyllithium (n-BuLi).

[0280] In one embodiment, the alkylating agent is selected from dimethyl sulfate, methyl trifluoromethanesulfonate, methyl toluenesulfonate, methyl bromide, trimethylanilinium trifluoromethanesulfonate, and methyl iodide. In one embodiment, the alkylating agent is methyl iodide.

[0281] In one embodiment, the solvent is selected from the group consisting of dimethyl sulfoxide, dioxane, diethyl ether, DMPU hexamethylphosphoramide, hexane, heptane, pyridine and tetrahydrofuran. In one embodiment, the solvent is tetrahydrofuran.

[0282] In one embodiment, the temperature of the reaction is from -80°C to 100°C. In one embodiment, the temperature is from -80°C to 20°C.

[0283] In one embodiment, the present disclosure provides a method for preparing compound 2-J from compound 2-I.

[0284] In one embodiment, the method includes the step of treating compound 2-I with a reagent in a suitable solvent and for a time and under conditions effective to form compound 2-J.

[0285] In one embodiment, the reagent is selected from sodium hydroxide, potassium hydroxide, lithium hydroxide, sulfuric acid, trifluoroacetic acid, phosphoric acid, hydrochloric acid, hydrofluoric acid, pyridine hydrogen fluoride, triethylamine hydrogen fluoride, potassium fluoride, sodium fluoride, lithium fluoride, tetramethylammonium fluoride and tetrabutylammonium fluoride (TBAF). In one embodiment, the reagent is tetrabutylammonium fluoride (TBAF).

[0286] In one embodiment, the solvent is selected from ethers (e.g., 2-methyltetrahydrofuran, tetrahydrofuran, methyl tert-butyl ether, cyclopentyl methyl ether), hydrocarbon solvents (e.g., toluene, n-heptane), halogenated solvents (e.g., dichloromethane, 1,2-dichloroethane, chloroform, chlorobenzene), alcohols (e.g., methanol, ethanol, n-propanol, isopropanol), polar aprotic solvents (e.g., N,N-dimethylacetamide, N,N-dimethylformamide, N-methyl-2-pyrrolidone, dimethyl sulfoxide) and water. In one embodiment, the solvent is tetrahydrofuran.

[0287] In one embodiment, the temperature of the reaction is from -20°C to 50°C. In one embodiment, the temperature is from 20°C to 30°C.

[0288] In one embodiment, the present disclosure provides a method for preparing compound 2-K from compound 2-J.

[0289] In one embodiment, the method includes the step of treating compound 2-J with an oxidizing agent in the presence of a catalyst in a suitable solvent and for a time and under conditions effective to form compound 2-K. In one embodiment, an additive is present.

[0290] In one embodiment, the oxidizing agent is selected from sodium hypochlorite / TEMPO, sulfur trioxide pyridine, dimethyl sulfoxide (DMSO) / oxalyl chloride, DMSO / acetic anhydride, diacetoxyiodobenzene / TEMPO, tetrapropylammonium perruthenate / N-methylmorpholine N-oxide, and diacetoxyiodobenzene (DAIB). In one embodiment, the oxidizing agent is diacetoxyiodobenzene (DAIB).

[0291] In one embodiment, the catalyst is selected from 2-azaadamantane N-oxyl, 9-azabicyclo[3.3.1]nonane N-oxyl, 9-azasopentane N-oxyl, and (2,2,6,6-tetramethylpiperidin-1-yl)oxyl (TEMPO). In one embodiment, the catalyst is (2,2,6,6-tetramethylpiperidin-1-yl)oxyl (TEMPO).

[0292] In one embodiment, the additive is selected from sodium bromide, lithium bromide, and potassium bromide.

[0293] In one embodiment, the solvent is selected from ethers (e.g., 2-methyltetrahydrofuran, tetrahydrofuran, methyl tert-butyl ether, cyclopentyl methyl ether), hydrocarbon solvents (e.g., toluene, n-heptane), halogenated solvents (e.g., 1,2-dichloroethane, chloroform, dichloromethane, chlorobenzene), polar aprotic solvents (e.g., N,N-dimethylacetamide, N,N-dimethylformamide, N-methyl-2-pyrrolidone, dimethyl sulfoxide) and water. In one embodiment, the solvent is tetrahydrofuran.

[0294] In one embodiment, the temperature of the reaction is from -80°C to 50°C. In one embodiment, the temperature is from 20°C to 30°C.

[0295] In one embodiment, the present disclosure provides a method for preparing compound 2-L from compound 2-K and compound 5-I.

[0296] In one embodiment, the method comprises the step of treating compound 2-K with compound 5-1, a reducing agent, and an acid in the presence of a catalyst in a suitable solvent and under conditions effective to form compound 2-L for a time and in an embodiment, an additive is present.

[0297] In one embodiment, the reducing agent is selected from the group consisting of silanes (e.g., triisopropylsilane, triphenylsilane, diethylsilane, triethylsilane), sodium borohydride, sodium borohydride / acetic acid, sodium triacetoxyborohydride, sodium cyanoborohydride, titanium isopropoxide / sodium cyanoborohydride, zinc / acetic acid, sodium borohydride / magnesium perchlorate, zinc borohydride / zinc chloride, and tetramethylammonium triacetoxyborohydride. In one embodiment, the reducing agent is triethylsilane.

[0298] In one embodiment, the acid is selected from acetic acid, citric acid, pivalic acid, p-toluenesulfonic acid, methanesulfonic acid, hydrochloric acid and trifluoroacetic acid. In one embodiment, the acid is trifluoroacetic acid.

[0299] In one embodiment, the solvent is selected from ethers (e.g., 2-methyltetrahydrofuran, tetrahydrofuran, methyl tert-butyl ether, cyclopentyl methyl ether), hydrocarbon solvents (e.g., toluene, n-heptane), halogenated solvents (e.g., 1,2-dichloroethane, chloroform, chlorobenzene), polar aprotic solvents (e.g., N,N-dimethylacetamide, N,N-dimethylformamide, N-methyl-2-pyrrolidone, dimethyl sulfoxide) and acetonitrile. In one embodiment, the solvent is acetonitrile.

[0300] In one embodiment, the temperature of the reaction is from -30°C to 50°C. In one embodiment, the temperature is from 10°C to 30°C.

[0301] In one embodiment, the present disclosure provides a method for preparing compound 1-J from compound 2-L.

[0302] In one embodiment, the present disclosure provides a method for preparing compound 1-K from compound 1-J.

[0303] In one embodiment, the present disclosure provides a method for preparing compound 9-A from compound 1-K and compound 6-L.

[0304] In one embodiment, the present disclosure provides a method for preparing Compound 1 from Compound 9-A.

[0305] In one embodiment, the present disclosure provides a method for preparing compound 1 from a compound selected from 2-F, 2-G, 2-H, 2-I, 2-J, 2-K, 2-L, 1-J, 1-K and 9-A, as shown in Scheme 2.

[0306] In one embodiment, the present disclosure provides a method for preparing compound 9-A from a compound selected from 2-G, 2-H, 2-I, 2-J, 2-K, 2-L, 1-J and 1-K.

[0307] In one embodiment, the present disclosure provides a method for preparing compound 1-K from a compound selected from 2-G, 2-H, 2-I, 2-J, 2-K, 2-L, and 1-J.

[0308] In one embodiment, the present disclosure provides a method for preparing compound 1-J from a compound selected from 2-G, 2-H, 2-I, 2-J, 2-K, and 2-L.

[0309] C. Method for preparing compound 1 from formula 3-E

[0310] In one embodiment, the present disclosure provides a method for preparing a compound selected from 3-F, 3-G, 2-L, 3-H, 1-K, 9-A and Compound 1, as shown in Scheme 3, wherein R 2 It's H, R 3 is methyl, R x and R y Independently H, C 1-6 Alkyl or C 6-10 Aryl, where C 1-6 The alkyl group is optionally replaced by a C 6-10 Aryl substitution, R a It is C 1-6 Alkyl, and R p Selected from -C(=O)-C 1-6 Alkyl, -C(=O)-heteroaryl, -C(=O)-OC 1-6 Alkyl and -C(=O)-OC 1-6 Alkyl-C 6-10 Aryl, wherein each C 6-10 Aryl or heteroaryl is optionally substituted by one to four independently selected 1-3 Alkyl and -OC 1-3 In one embodiment, PG is tert-butyldiphenylsilyl. In one embodiment, R a In one embodiment, R x It's methyl.

[0311]

[0312] Option 3

[0313] In one embodiment, the present disclosure provides a method for preparing compounds 3-F and 3-G from compound 3-E.

[0314] In one embodiment, the method comprises the step of treating compound 3-E with a nucleophile in a suitable solvent and for a time and under conditions effective to form compounds 3-F and 3-G. In one embodiment, a promoter is present.

[0315] In one embodiment, the nucleophile is selected from propyne, lithium propyne, propyne magnesium chloride, dipropyne zinc, propyne zinc chloride, propyne magnesium bromide and 3-bromopropyne. In one embodiment, the nucleophile is propyne magnesium bromide.

[0316] In one embodiment, the promoter is selected from alkyl lithium (e.g., n-butyl lithium, sec-butyl lithium, tert-butyl lithium, methyl lithium), Grignard reagents (e.g., ethyl magnesium bromide, isopropyl magnesium chloride, butyl magnesium bromide), lithium diisopropylamide, cuprous iodide, lithium perchlorate, lithium bromide, lanthanum chloride lithium chloride complex, cerium trichloride, boron trifluoride, titanium (IV) isopropoxide, zinc trifluoromethanesulfonate, diethylzinc, N-methylephedrine, L-tartaric acid, R-2,2-binaphthol, triethylamine, tetramethylethylenediamine, diisopropylamine and zinc.

[0317] In one embodiment, the solvent is selected from ether solvents (e.g., diethyl ether, 2-methyltetrahydrofuran, tetrahydrofuran), hydrocarbon solvents (e.g., hexane, heptane, cyclohexane), dimethyl sulfide, halogenated solvents (e.g., dichloromethane) and aromatic solvents (e.g., benzene, toluene). In one embodiment, the solvent is tetrahydrofuran.

[0318] In one embodiment, the temperature of the reaction is from -80°C to 30°C. In one embodiment, the temperature is from -80°C to 20°C.

[0319] In one embodiment, the present disclosure provides a method for preparing compound 2-L from compound 3-G.

[0320] In one embodiment, the method includes the step of treating compound 3-G with an alkylating agent and a base in a suitable solvent and under conditions and for a time effective to form compound 2-L.

[0321] In one embodiment, the alkylating agent is iodomethane.

[0322] In one embodiment, the base is sodium tert-butoxide.

[0323] In one embodiment, the solvent is tetrahydrofuran.

[0324] In one embodiment, the temperature of the reaction is from 0°C to 30°C.

[0325] In one embodiment, the present disclosure provides a method for preparing compound 3-H from compound 2-L.

[0326] In one embodiment, the method includes the step of treating compound 2-L with an additive in a suitable solvent and for a time and under conditions effective to form compound 3-H.

[0327] In one embodiment, the additive is a base selected from the group consisting of hydroxides (e.g., lithium hydroxide, sodium hydroxide, potassium hydroxide, cesium hydroxide, calcium hydroxide, magnesium hydroxide, ammonium hydroxide, tetramethylammonium hydroxide), alkoxides (e.g., methoxide, ethoxide, isopropoxide, tert-butoxide, or tert-amyloxide of lithium, sodium, potassium, magnesium, or calcium), trimethyltin hydroxide, sodium trimethylsilanolate, and potassium trimethylsilanolate. In one embodiment, the additive is lithium hydroxide.

[0328] In one embodiment, the additive is an acid selected from inorganic acids (eg, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid) and organic acids (eg, acetic acid, trifluoroacetic acid, methanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid).

[0329] In one embodiment, the solvent is selected from ethers (e.g., 2-methyltetrahydrofuran, tetrahydrofuran, methyl tert-butyl ether, cyclopentyl methyl ether), alcohols (methanol, ethanol, isopropanol, tert-butyl alcohol, tert-amyl alcohol, etc.), water, halogenated solvents (e.g., 1,2-dichloroethane, chloroform, chlorobenzene), and combinations thereof. In one embodiment, the solvent is a combination of tetrahydrofuran and water.

[0330] In one embodiment, the temperature of the reaction is from 20°C to 100°C. In one embodiment, the temperature is from 40°C to 60°C.

[0331] In one embodiment, the present disclosure provides a method for preparing compound 1-K from compound 3-H.

[0332] In one embodiment, the present disclosure provides a method for preparing compound 1 from a compound selected from 3-E, 3-G, 2-L, 3-H, 1-K and 9-A, as shown in Scheme 3.

[0333] D. Method for preparing compound 1 from formula 4-F

[0334] In one embodiment, the present disclosure provides a method for preparing a compound selected from 4-G, 4-H, 4-I, 4-J, 4-L, 4-M, 4-N and Compound 1, as shown in Scheme 4, wherein R 4 is a halogenated or boronate ester, R b It is C 1-6 Alkyl, R c It is C 1-6 Alkyl, X is halogen, borate, -OS(O)2R 2 or -OP(O)(R 2 )2, where R 2It is C 1-6 Alkyl or C 6-10 Aryl, wherein each alkyl or aryl group is optionally substituted by one to four halogen or C 1-3 Alkyl substituted, and R p Selected from -C(=O)-C 1-6 Alkyl, -C(=O)-heteroaryl, -C(=O)-OC 1-6 Alkyl and -C(=O)-OC 1-6 Alkyl-C 6-10 Aryl, wherein each aryl or heteroaryl is optionally substituted by one to four independently selected C 1-3 Alkyl and -OC 1-3 wherein each heteroaryl group has one to four heteroatoms; wherein each heteroatom is independently selected from N, O, and S, and wherein each heteroaryl group has 5 to 10 ring members. In one embodiment, R b In one embodiment, R c In one embodiment, R p In one embodiment, X is or , where each R 7 are independently H or C 1-3 alkyl, m is 1, 2 or 3, and n is 0 or 1. In one embodiment, X is or .

[0335]

[0336] Option 4

[0337] In one embodiment, the present disclosure provides a method for preparing compound 4-G from compound 4-F.

[0338] In one embodiment, the method includes the step of treating compound 4-F with a promoter and an oxidizing agent in a suitable solvent and under conditions and for a time effective to form compound 4-G.

[0339] In one embodiment, the promoter is selected from ruthenium chloride, potassium osmate, phosphotungstic acid. In one embodiment, the promoter is ruthenium chloride.

[0340] In one embodiment, the oxidizing agent is selected from the group consisting of potassium persulfate, potassium permanganate, potassium periodate, lead tetraacetate, sodium hypochlorite, hydrogen peroxide, and sodium periodate. In one embodiment, the oxidizing agent is sodium periodate.

[0341] In one embodiment, the solvent is selected from ethers (e.g., 2-methyltetrahydrofuran, tetrahydrofuran, methyl tert-butyl ether, cyclopentyl methyl ether), hydrocarbon solvents (e.g., toluene, n-heptane), halogenated solvents (e.g., dichloromethane, 1,2-dichloroethane, chloroform, chlorobenzene), alcohols (e.g., methanol, isopropanol, n-propanol), polar aprotic solvents (e.g., N,N-dimethylacetamide, N,N-dimethylformamide, N-methyl-2-pyrrolidone, dimethyl sulfoxide), acetonitrile, and combinations thereof. In one embodiment, the solvent is a combination of acetonitrile and water.

[0342] In one embodiment, the temperature of the reaction is from -80°C to 80°C. In one embodiment, the temperature is from 10°C to 30°C.

[0343] In one embodiment, the present disclosure provides a method for preparing compound 4-H from compound 4-G.

[0344] In one embodiment, the method includes the step of treating compound 4-G with N-hydroxyphthalimide and an acid activator in a suitable solvent and for a time and under conditions effective to form compound 4-H.

[0345] In one embodiment, the acid activator is selected from carbonyldiimidazole (CDI), propylphosphonic anhydride (T3P), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU), 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methyl-morpholinium chloride (DMTMM), thionyl chloride, oxalyl chloride, (chloromethylene)-dimethyl The activator may be any of the following: 1,2-dimethylaminopropyl ...

[0346] In one embodiment, the solvent is selected from ethers (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, cyclopentyl methyl ether), esters (e.g., ethyl acetate, isopropyl acetate), polar aprotic solvents (e.g., N,N-dimethylacetamide, N-methyl-2-pyrrolidone, dimethyl sulfoxide), nitriles (e.g., acetonitrile), hydrocarbon solvents (e.g., toluene), halogenated solvents (e.g., dichloromethane, 1,2-dichloroethane, chloroform, chlorobenzene). In one embodiment, the solvent is dichloromethane.

[0347] In one embodiment, the temperature of the reaction is from -50°C to 50°C. In one embodiment, the temperature is from 10°C to 30°C.

[0348] In one embodiment, the present disclosure provides a method for preparing compound 4-I from compound 4-H.

[0349] In one embodiment, the method includes the step of treating compound 4-H with a diboron reagent, a promoter, and an additive in a suitable solvent and for a time and under conditions effective to form compound 4-I.

[0350] In one embodiment, the accelerator is selected from visible light (380 nm-700 nm), ultraviolet light (10 nm-400 nm), and blue LED (420 nm). In one embodiment, the accelerator is a blue LED (420 nm).

[0351] In one embodiment, the diboron reagent is selected from bis(pinacolato)diboron, bis(neopentyl glycolate)diboron, bis(hexenyl glycolate)diboron, 2,2′-bis-1,3,2-dioxaborolane, and bis(catechol)diborate. In one embodiment, the diboron reagent is bis(catechol)diborate.

[0352] In one embodiment, the additive is selected from pinacol, diethanolamine, methyliminodiacetic acid, and alcohols (e.g., methanol, isopropanol, n-propanol). In one embodiment, the additive is methyliminodiacetic acid.

[0353] In one embodiment, the solvent is selected from ethers (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, cyclopentyl methyl ether), esters (e.g., ethyl acetate, isopropyl acetate), polar aprotic solvents (e.g., N,N-dimethylacetamide, N-methyl-2-pyrrolidone, dimethyl sulfoxide, dimethylacetamide), nitriles (e.g., acetonitrile), hydrocarbon solvents (e.g., toluene), and halogenated solvents (e.g., dichloromethane, 1,2-dichloroethane, chloroform, chlorobenzene). In one embodiment, the solvent is dimethylacetamide.

[0354] In one embodiment, the temperature of the reaction is from -80°C to 120°C. In one embodiment, the temperature is from 10°C to 30°C.

[0355] In one embodiment, the present disclosure provides a method for preparing compound 4-J from compound 4-I.

[0356] In one embodiment, the present disclosure provides a method for preparing compound 4-L from compound 4-J and compound 4-K.

[0357] In one embodiment, the present disclosure provides a method for preparing compound 4-M from compound 4-L.

[0358] In one embodiment, the present disclosure provides a method for preparing compound 4-N from compound 4-M.

[0359] In one embodiment, the present disclosure provides a method for preparing compound 1 from a compound selected from 4-F, 4-G, 4-H, 4-I, 4-J, 4-L, 4-M and 4-N, as shown in Scheme 4.

[0360] E. Method for preparing compound 1 from formula 5-J

[0361] In one embodiment, the present disclosure provides a method for preparing a compound selected from 5-K, 5-L, 5-M, 5-N, 5-P, 5-Q and Compound 1, as shown in Scheme 5, wherein R 4 is halogen or borate, X is halogen, borate, -OS(O)2R 2 or -OP(O)(R 2 )2, where R 2 It is C 1-6 Alkyl or C 6-10 Aryl, wherein each alkyl or aryl group is optionally substituted by one to four halogen or C 1-3 Alkyl substitution, each R n Independently C 1-6 Alkyl, or two R n Parts are linked together to form C 2-4 Alkyl bridge, wherein the bridge is optionally substituted by one to four independently selected C 1-3 Alkyl and phenyl groups are substituted, and R p Selected from -C(=O)-C 1-6 Alkyl, -C(=O)-heteroaryl, -C(=O)-OC 1-6 Alkyl and -C(=O)-OC 1-6 Alkyl-C 6-10 Aryl, wherein each aryl or heteroaryl is optionally substituted by one to four independently selected C 1-3 Alkyl and -OC 1-3 wherein each heteroaryl group has one to four heteroatoms; wherein each heteroatom is independently selected from N, O, and S, and wherein each heteroaryl group has 5 to 10 ring members. In one embodiment, R p In one embodiment, R n In one embodiment, X is or , where each R 7 are independently H or C 1-3alkyl, m is 1, 2 or 3, and n is 0 or 1. In one embodiment, X is or .

[0362] In one embodiment, X is or .

[0363]

[0364] Option 5

[0365] In one embodiment, the present disclosure provides a method for preparing compound 5-K from compound 5-J.

[0366] In one embodiment, the method includes the step of treating compound 5-J with a promoter and an oxidizing agent in a suitable solvent and under conditions and for a time effective to form compound 5-K.

[0367] In one embodiment, the promoter is selected from ruthenium chloride, potassium osmate, phosphotungstic acid. In one embodiment, the promoter is ruthenium chloride.

[0368] In one embodiment, the oxidizing agent is selected from the group consisting of potassium persulfate, potassium permanganate, potassium periodate, lead tetraacetate, sodium hypochlorite, hydrogen peroxide, and sodium periodate. In one embodiment, the oxidizing agent is sodium periodate.

[0369] In one embodiment, the solvent is selected from ethers (e.g., 2-methyltetrahydrofuran, tetrahydrofuran, methyl tert-butyl ether, cyclopentyl methyl ether), hydrocarbon solvents (e.g., toluene, n-heptane), halogenated solvents (e.g., dichloromethane, 1,2-dichloroethane, chloroform, chlorobenzene), alcohols (e.g., methanol, isopropanol, n-propanol), polar aprotic solvents (e.g., N,N-dimethylacetamide, N,N-dimethylformamide, N-methyl-2-pyrrolidone, dimethyl sulfoxide), acetonitrile, and combinations thereof. In one embodiment, the solvent is a combination of acetonitrile and water.

[0370] In one embodiment, the temperature of the reaction is from -80°C to 80°C. In one embodiment, the temperature is from -10°C to 10°C.

[0371] In one embodiment, the present disclosure provides a method for preparing compound 5-L from compound 5-K.

[0372] In one embodiment, the method includes the step of treating compound 5-K with an acid in a suitable solvent and under conditions and for a time effective to form compound 5-L.

[0373] In one embodiment, the acid is selected from acids such as p-toluenesulfonic acid, methanesulfonic acid, HCl, HBr, or Lewis acids such as erbium(III) trifluoromethanesulfonate. In one embodiment, the acid is methanesulfonic acid.

[0374] In one embodiment, the solvent is selected from ethers (e.g., 2-methyltetrahydrofuran, methyl tert-butyl ether, cyclopentyl methyl ether), polar aprotic solvents (e.g., dimethyl sulfoxide, N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone), nitriles (e.g., acetonitrile), hydrocarbons (e.g., toluene, n-heptane), halogenated solvents (e.g., dichloromethane, 1,2-dichloroethane, chloroform, chlorobenzene), alcohols (e.g., 2-propanol), esters (e.g., ethyl acetate, isopropyl acetate), ketones (e.g., acetone, 2-butanone, 4-methyl-2-pentanone), water, and combinations thereof. In one embodiment, the solvent is a combination of tetrahydrofuran and water.

[0375] In one embodiment, the temperature of the reaction is from 0°C to 100°C. In one embodiment, the temperature is from 60°C to 70°C.

[0376] In one embodiment, the present disclosure provides a method for preparing compound 5-M from compound 5-L.

[0377] In one embodiment, the method includes the step of treating compound 5-L with a reducing agent in a suitable solvent and under conditions and for a time effective to form compound 5-M.

[0378] In one embodiment, the reducing agent is selected from a reducing agent such as tin or zinc in combination with an acid such as hydrochloric acid, acetic acid, ammonium chloride, a transition metal such as Pd or Rh in combination with H2 or formate, a poisoned heterogeneous catalyst such as Pt / S / C, and iron powder. In one embodiment, the reducing agent is iron powder.

[0379] In one embodiment, the solvent is selected from a combination of an acid (e.g., acetic acid, hydrogen chloride) and other solvents, including ethers (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, cyclopentyl methyl ether), polar aprotic solvents (e.g., N,N-dimethylacetamide, N,N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide), nitriles (e.g., acetonitrile), hydrocarbons (e.g., toluene, n-heptane), halogenated solvents (e.g., dichloromethane, 1,2-dichloroethane, chloroform, chlorobenzene), alcohols (e.g., 2-propanol), esters (e.g., ethyl acetate, isopropyl acetate), and combinations thereof. In one embodiment, the solvent is acetic acid.

[0380] In one embodiment, the temperature of the reaction is from 0°C to 100°C. In one embodiment, the temperature is from 65°C to 85°C.

[0381] In one embodiment, the present disclosure provides a method for preparing compound 5-N from compound 5-M.

[0382] In one embodiment, the present disclosure provides a method for preparing compound 5-P from compound 5-N and compound 5-O.

[0383] In one embodiment, the present disclosure provides a method for preparing compound 5-Q from compound 5-P.

[0384] In one embodiment, the present disclosure provides a method for preparing Compound 1 from a compound selected from 5-K, 5-L, 5-M, 5-N, 5-P, and 5-Q, as shown in Scheme 5.

[0385] F. Method for preparing compound 1 from formula 10-E

[0386] In one embodiment, the present disclosure provides a method for preparing a compound selected from 6-M, 6-N, 4-N and Compound 1, as shown in Scheme 6, wherein R x and R y Independently H, C 1-6 Alkyl or C 6-10 Aryl, wherein the alkyl group is optionally replaced by C 6-10 Aryl substitution, R p Selected from -C(=O)-C 1-6 Alkyl, -C(=O)-heteroaryl, -C(=O)-OC 1-6 Alkyl and -C(=O)-OC 1-6 Alkyl-C 6-10 Aryl, wherein each aryl or heteroaryl is optionally substituted by one to four independently selected C 1-3 Alkyl and -OC 1-3 The alkyl radical is substituted with a radical wherein each heteroaryl group has one to four heteroatoms; wherein each heteroatom is independently selected from N, O, and S, and wherein each heteroaryl group has 5 to 10 ring members.

[0387]

[0388] Option 6

[0389] In one embodiment, the method includes the step of conducting a cross-metathesis reaction between compound 10-E and compound 1-I using a suitable catalyst in a suitable solvent and under conditions effective to form compound 6-M for a period of time.

[0390] In one embodiment, R x and R y All are hydrogen.

[0391] In one embodiment, R p Selected from 1-phenylethoxycarbonyl, ethoxycarbonyl, methoxycarbonyl, tert-butoxycarbonyl, isopropoxycarbonyl, phenoxycarbonyl, 4-methoxyphenoxycarbonyl and benzyloxycarbonyl.

[0392] In one embodiment, R p is 1-phenethoxycarbonyl, optionally in the (R) or (S) form.

[0393] In one embodiment, the catalyst is a ruthenium catalyst or a molybdenum catalyst.

[0394] In one embodiment, the catalyst is selected from dichloro[1,3-bis(2,4,6-trimethylphenyl)-2-imidazolidinylidene](2-isopropoxyphenylmethylene)ruthenium(II), dichloro(benzylidene)bis(tricyclohexylphosphine)ruthenium(II), dichloro[1,3-bis(2,4,6-trimethylphenyl)-2-imidazolidinylidene](benzylidene)(tricyclohexylphosphine)ruthenium(II), dichloro(o-isopropoxyphenylmethylene)(tricyclohexylphosphine)ruthenium(II), dichloro[1,3-bis(2,4,6-trimethylphenyl)-2-imidazolidinylidene](2-isopropoxyphenylmethylene)ruthenium(II), Ruthenium(II), dichloro[1,3-bis(2-methylphenyl)-2-imidazolidinyl](benzylidene)(tricyclohexylphosphine)ruthenium(II), dichloro[1,3-bis(2,4,6-trimethylphenyl)-2-imidazolidinyl][3-(2-pyridyl)propylene]ruthenium(II), [1,3-dimesityl-2-imidazolidinyl]dichloro(phenylmethylene)bis(3-bromopyridinyl)ruthenium(II), dichloro[1,3-bis(2,4,6-trimethylphenyl)-2-imidazolidinyl](3-methyl-2-butenyl)(tricyclohexylphosphine)ruthenium(II) ), dichloro[1,3-bis(2-methylphenyl)-2-imidazolidinyl](2-isopropoxyphenylmethylene)ruthenium(II), [1,3-dimesityl-2-imidazolidinyl]dichloro[3-(2-pyridyl)propylene]-ruthenium(II), (1,3-dimesityl-imidazolidinyl-2-yl)dichloro(2-isopropoxy-5-nitrobenzylidene)ruthenium(II), tricyclohexylphosphine[4,5-dimethyl-1,3-bis(2,4,6-trimethylphenyl)imidazolidinyl-2-yl][2-thienylmethylene]ruthenium(II) dichloride, tricyclohexylphosphine [1,3-bis(2,4,6-trimethylphenyl)imidazolidin-2-ylidene][2-thienylmethylene]ruthenium(II) dichloride, tricyclohexylphosphino[2,4-dihydro-2,4,5-triphenyl-3H-1,2,4-triazol-3-ylidene][2-thienylmethylene]ruthenium(II) dichloride, tricyclohexylphosphino[1,3-bis(2,4,6-trimethylphenyl)imidazolidin-2-ylidene][3-phenyl-1H-inden-1-ylidene]ruthenium(II) dichloride and bis(tricyclohexylphosphino)-3-phenyl-1H-inden-1-ylideneruthenium(II) dichloride.

[0395] In one embodiment, the catalyst is selected from 2,6-diisopropyl-phenylimino-neophenylene [(S)-(−)-BIPHEN] platinum (VI), dichlorobis[(2,6-diisopropylphenyl)imino](1,2-dimethoxyethane) platinum (VI), and (T-4)-chloro(2,2-dimethylpropylidene)[2,2",4,4',6,6'-hexa(1-methylethyl)[1,1':3',1-terphenyl]-2'-olato][2-methyl-2-propylaminoester(2-)] platinum (VI).

[0396] In one embodiment, a suitable catalyst is the Hoveyda-Grubbs II catalyst (dichloro[1,3-bis(2,4,6-trimethylphenyl)-2-imidazolidinylidene](2-isopropoxyphenylmethylene)ruthenium(II)).

[0397] In one embodiment, the solvent is a non-polar solvent or a polar aprotic solvent.

[0398] In one embodiment, the solvent is selected from ethers (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, cyclopentyl methyl ether, dioxane), hydrocarbon solvents (e.g., toluene, n-hexane, n-heptane, anisole, trifluorotoluene, hexafluorobenzene, fluorobenzene, xylene) and halogenated solvents (e.g., dichloromethane, 1,2-dichloroethane, chloroform, chlorobenzene).

[0399] In one embodiment, the polar aprotic solvent is selected from esters (e.g., ethyl acetate, methyl acetate, isopropyl acetate, butyl acetate, isobutyl acetate), ketones (e.g., acetone, methyl ethyl ketone, methyl isobutyl ketone, 2-pentanone), and carbonates (e.g., dimethyl carbonate, diethyl carbonate, diisopropyl carbonate).

[0400] In one embodiment, the temperature of the reaction is from 0°C to 150°C.

[0401] In one embodiment, the temperature of the reaction is from 20°C to 90°C.

[0402] In one embodiment, the temperature of the reaction is from 40°C to 90°C.

[0403] In one embodiment, the temperature of the reaction is from 20°C to 60°C.

[0404] In one embodiment, the temperature of the reaction is from 40°C to 80°C.

[0405] In one embodiment, the temperature of the reaction is about 80°C.

[0406] In one embodiment, the method includes the step of treating compound 6-M with a reducing agent in a suitable solvent and under conditions and for a time effective to form tertiary amine compound 6-N.

[0407] In one embodiment, the reducing agent is selected from a hydride reducing agent, a silane reducing agent, or a hydrogenating agent.

[0408] In one embodiment, the reducing agent is a hydride reducing agent.

[0409] In one embodiment, the hydride reducing agent is selected from the group consisting of sodium borohydride, lithium borohydride, sodium cyanoborohydride, zinc borohydride, sodium triacetoxyborohydride, and tetramethylammonium triacetoxyborohydride.

[0410] In one embodiment, the hydride reducing agent is sodium triacetoxyborohydride or sodium cyanoborohydride.

[0411] In one embodiment, the hydride reducing agent is combined with an agent that modulates hydride reducing activity (eg, titanium isopropoxide, titanium ethoxide, borates, magnesium perchlorate, or zinc chloride).

[0412] In one embodiment, the silane reducing agent is triethylsilane.

[0413] In one embodiment, the reaction further comprises an acid (eg, selected from acetic acid, trifluoroacetic acid, citric acid, pivalic acid, p-toluenesulfonic acid, methanesulfonic acid, and hydrochloric acid).

[0414] In one embodiment, the suitable solvent is a non-polar solvent, a polar protic solvent, or a polar aprotic solvent.

[0415] In one embodiment, the non-polar solvent is selected from ethers (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, cyclopentyl methyl ether, dioxane), hydrocarbon solvents (e.g., toluene, n-hexane, n-heptane) and halogenated solvents (e.g., dichloromethane, 1,2-dichloroethane, chloroform, chlorobenzene).

[0416] In one embodiment, the polar protic solvent is selected from alcohols (eg, methanol, ethanol, propanol, isopropanol) and acids (eg, acetic acid, formic acid, trifluoroacetic acid).

[0417] In one embodiment, the polar aprotic solvent is selected from N,N-dimethylacetamide, N,N-dimethylformamide, N-methyl-2-pyrrolidone, dimethyl sulfoxide, esters (eg, methyl acetate, ethyl acetate, isopropyl acetate), and nitriles (eg, acetonitrile).

[0418] In one embodiment, the suitable solvent is dichloromethane.

[0419] In one embodiment, the temperature of the reaction is from -30°C to 80°C, such as from 0°C to 80°C or from 10°C to 30°C.

[0420] In one embodiment, the present disclosure provides a method for preparing compound 4-N from compound 6-N.

[0421] In one embodiment, the present disclosure provides a method for preparing compound 1 from a compound selected from 10-E, 6-M, 6-N and 4-N, as shown in Scheme 6.

[0422] G. Method for preparing compound 1 from formula 7-A

[0423] In one embodiment, the present disclosure provides a method for preparing a compound selected from 7-C, 7-D, 7-E, 7-F, 4-N and Compound 1, as shown in Scheme 7, wherein R x and R y Independently H, C 1-6 Alkyl or C 6-10 Aryl, wherein the alkyl group is optionally replaced by C 6-10 Aryl substitution, R v Independently selected from H, C 1-6 Alkyl, C 1-6 Alkoxy, halo, wherein the C 1-6 Alkyl and C 1-6 Alkoxy is optionally substituted by 1 to 3 groups selected from aryl, C 1-6 Alkyl, C 1-6 Alkoxy and halogenated substituents, R q Selected from silyl groups, alkylcarbonyl groups (e.g., -C(=O)-C 1-6 Alkyl such as acetyl, isobutyryl, pivaloyl, or -C(=O)-C 1-6 Alkyl (aryl) groups such as 2-phenylethylcarbonyl or 1-phenylethylcarbonyl), arylcarbonyl groups (e.g., benzoyl), alkoxycarbonyl groups (e.g., -C(=O)-OC 1-6 Alkyl such as methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl or benzyloxycarbonyl, or -C(=O)-OC 1-6 alkyl (aryl) such as 2-phenylethoxycarbonyl or 1-phenylethoxycarbonyl), aryloxycarbonyl groups (e.g., phenoxycarbonyl), tertiary alkyl groups (e.g., tert-butyl or trityl), C 1-6 Alkoxy C 1-6 Alkyl groups (e.g., C 1-6 alkoxymethyl such as methoxymethyl or ethoxymethyl), C 1-6 Alkylaryl groups (e.g., benzyl, 3,5-dimethoxybenzyl, 1-methylbenzyl), diarylalkyl groups (e.g., C 1-6 Alkyl (aryl) (aryl) such as benzhydryl), alkylsulfonyl group (e.g., SO2C 1-6alkyl such as methylsulfonyl or isopropylsulfonyl) and arylsulfonyl groups (e.g., SO2-aryl such as phenylsulfonyl, toluenesulfonyl), wherein each phenyl or heteroaryl group is optionally substituted by one to four independently selected C 1-3 Alkyl and -OC 1-3 The alkyl radical is substituted with a radical wherein each heteroaryl group has one to four heteroatoms, wherein each heteroatom is independently selected from N, O, and S, and wherein each heteroaryl group has 5 to 10 ring members.

[0424]

[0425] Option 7

[0426] In one embodiment, the method includes the step of treating the secondary amine compound 7-A with the aldehyde compound 7-B and a reducing agent in a suitable solvent and for a time and under conditions effective to form the tertiary amine compound 7-C.

[0427] In one embodiment, R x and R y All are H.

[0428] In one embodiment, R q Selected from -C(=O)-C 1-6 Alkyl (e.g., acetyl, isobutyryl, pivaloyl), -C(=O)-aryl (e.g., benzoyl), -C(=O)-OC 1--6 Alkyl (e.g., methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl, or benzyloxycarbonyl), -C(=O)-OC 1-6 alkyl(aryl) (e.g., 2-phenethoxycarbonyl or 1-phenethoxycarbonyl) and -C(=O)-O-aryl (e.g., phenoxycarbonyl).

[0429] In one embodiment, R q Selected from 1-phenylethoxycarbonyl, ethoxycarbonyl, methoxycarbonyl, tert-butoxycarbonyl, isopropoxycarbonyl, phenoxycarbonyl, 4-methoxyphenoxycarbonyl and benzyloxycarbonyl.

[0430] In one embodiment, R q is 1-phenethoxycarbonyl, optionally in the (R) or (S) form.

[0431] In one embodiment, R qis selected from trialkylsilyl groups (e.g., trimethylsilyl, triethylsilyl, tripropylsilyl, triisopropylsilyl, tert-butyldimethylsilyl), dialkylarylsilyl groups (e.g., dimethylphenylsilyl), alkyldiarylsilyl groups (e.g., tert-butyldiphenylsilyl) and triarylsilyl groups (e.g., triphenylsilyl).

[0432] In one embodiment, R q is selected from the group consisting of a tert-butyldiphenylsilyl group and a tert-butyldimethylsilyl group.

[0433] In one embodiment, the reducing agent is selected from a hydride reducing agent, a silane reducing agent, or a hydrogenating agent.

[0434] In one embodiment, the reducing agent is a hydride reducing agent.

[0435] In one embodiment, the hydride reducing agent is selected from the group consisting of sodium borohydride, lithium borohydride, sodium cyanoborohydride, zinc borohydride, sodium triacetoxyborohydride, and tetramethylammonium triacetoxyborohydride.

[0436] In one embodiment, the hydride reducing agent is sodium triacetoxyborohydride or sodium cyanoborohydride.

[0437] In one embodiment, the hydride reducing agent is combined with an agent that modulates hydride reducing activity (eg, titanium isopropoxide, titanium ethoxide, borates, magnesium perchlorate, or zinc chloride).

[0438] In one embodiment, the silane reducing agent is triethylsilane.

[0439] In one embodiment, the reaction further comprises an acid selected from the group consisting of acetic acid, trifluoroacetic acid, citric acid, pivalic acid, p-toluenesulfonic acid, methanesulfonic acid, and hydrochloric acid.

[0440] In one embodiment, the suitable solvent is a non-polar solvent, a polar protic solvent, or a polar aprotic solvent.

[0441] In one embodiment, the non-polar solvent is selected from ethers (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, cyclopentyl methyl ether, dioxane), hydrocarbon solvents (e.g., toluene, n-hexane, n-heptane) and halogenated solvents (e.g., dichloromethane, 1,2-dichloroethane, chloroform, chlorobenzene).

[0442] In one embodiment, the polar protic solvent is selected from alcohols (eg, methanol, ethanol, propanol, isopropanol) and acids (eg, acetic acid, formic acid, trifluoroacetic acid).

[0443] In one embodiment, the polar aprotic solvent is selected from N,N-dimethylacetamide, N,N-dimethylformamide, N-methyl-2-pyrrolidone, dimethyl sulfoxide, esters (eg, methyl acetate, ethyl acetate, isopropyl acetate), and nitriles (eg, acetonitrile).

[0444] In one embodiment, the suitable solvent is tetrahydrofuran, dichloromethane or acetonitrile.

[0445] In one embodiment, the temperature of the reaction is from -30°C to 80°C, such as from 0°C to 80°C or from 10°C to 30°C.

[0446] In one embodiment, the method comprises the step of subjecting compound 7-C to ring-closing alkyne metathesis using a suitable catalyst in a suitable solvent and under conditions and for a time effective to form compound 7-D.

[0447] In one embodiment, the catalyst is a ruthenium catalyst or a molybdenum catalyst.

[0448] In one embodiment, the catalyst is selected from (SP-5-32)-nitrilo(pyridine)tris(1,1,1-triphenylsilanol)molybdenum(VI), [amidotris(2,3,4,5,6-pentafluorophenyl)boronato(3-)κN]bis(1,1,1-trimethylsilanol)[1,1,1-trimethylsilyl)silanylamino]molybdenum(VI), (T-4)-tris(2-methyl-2-propanoate)nitrilomolybdenum(VI), (T-4)-nitrilobis(1,1,1-trimethylsilanol)[1,1,1-trimethyl-N-(trimethylsilyl)silanylamino]molybdenum(VI), [amidotris(2,3,4,5,6-pentafluorophenyl)boronato(3-)-κN]tris(1,1,1-triphenylsilanol)molybdenum(IV) and molybdenum hexacarbonyl.

[0449] In one embodiment, the reaction further comprises an additive, such as 5Å molecular sieves or 4-(trifluoromethyl)phenol.

[0450] In one embodiment, the solvent is a non-polar solvent or a polar aprotic solvent or any combination thereof.

[0451] In one embodiment, the solvent is selected from ethers (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, cyclopentyl methyl ether, dioxane), hydrocarbon solvents (e.g., benzene, toluene, n-hexane, n-heptane, anisole, trifluorotoluene, hexafluorobenzene, fluorobenzene, xylene) and halogenated solvents (e.g., dichloromethane, 1,2-dichloroethane, chloroform, chlorobenzene, bromobenzene).

[0452] In one embodiment, the polar aprotic solvent is selected from esters (e.g., ethyl acetate, methyl acetate, isopropyl acetate, butyl acetate, isobutyl acetate), ketones (e.g., acetone, methyl ethyl ketone, methyl isobutyl ketone, 2-pentanone), and carbonates (e.g., dimethyl carbonate, diethyl carbonate, diisopropyl carbonate).

[0453] In one embodiment, the temperature of the reaction is from 0°C to 150°C.

[0454] In one embodiment, the temperature of the reaction is from 20°C to 90°C.

[0455] In one embodiment, the temperature of the reaction is from 40°C to 90°C.

[0456] In one embodiment, the temperature of the reaction is from 20°C to 60°C.

[0457] In one embodiment, the temperature of the reaction is from 40°C to 80°C.

[0458] In one embodiment, the temperature of the reaction is about 80°C.

[0459] In one embodiment, the method includes the step of hydrosilylating compound 7-D with a silane reagent and a catalyst in a suitable solvent and for a period of time under conditions effective to form vinylsilane compound 7-E.

[0460] In one embodiment, each R v Independently selected from H, C 1-6 Alkyl (e.g., methyl, ethyl, isopropyl, propyl), C 1-6 Alkoxy (e.g., methoxy, ethoxy), halo (e.g., chloro, bromo); wherein the C 1-6 Alkyl and C 1-6 Alkoxy is optionally substituted by 1 to 3 groups selected from aryl (e.g., phenyl), C 1-6 Alkyl, C 1-6 Alkoxy and halo substituents are substituted.

[0461] In one embodiment, R v Independently selected from methyl, ethyl, methoxy, ethoxy, benzyl and chloro.

[0462] In one embodiment, the group Si(R v )3 is selected from trimethylsilyl, triethylsilyl, trimethoxysilyl, triethoxysilyl, benzyldimethylsilyl, chlorodimethylsilyl and ethoxydimethylsilyl.

[0463] In one embodiment, the silane reagent is a silane having the formula H—Si(R v )3 reagent.

[0464] In one embodiment, the silane agent is selected from 1,1,3,3-tetramethyldisiloxane, trimethoxyhydrogensilane, triethoxysilane, trimethylhydrogensilane, benzyldimethylsilane, dimethylchlorosilane, ethoxy(dimethyl)silane, and triethylsilane.

[0465] In one embodiment, the catalyst is a ruthenium, rhodium or platinum catalyst.

[0466] In one embodiment, the catalyst is selected from (tris(acetonitrile)(η 5 -pentamethylcyclopentadienyl)ruthenium(II) hexafluorophosphate, dichlorophenylruthenium(II) dimer, dichloro(p-cymene)ruthenium(II) dimer, (bis(1,5-cyclooctadiene)rhodium(II) tetrafluoroborate) hydrate, (bicyclo[2.2.21]hepta-2,5-diene)rhodium(I) chloride dimer, tris(triphenylphosphine)rhodium(I) chloride, chloroplatinic acid hydrate and platinum(0)-1,3-divinyl-1,1,3,3-tetramethyldisiloxane complex.

[0467] In one embodiment, the solvent is a non-polar solvent, a polar protic solvent or a polar aprotic solvent or any combination thereof, or wherein the solvent is a neat silane reagent.

[0468] In one embodiment, the solvent is selected from an ether (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, cyclopentyl methyl ether or dioxane), a hydrocarbon solvent (e.g., toluene, n-hexane, n-heptane, anisole, trifluorotoluene, hexafluorobenzene, fluorobenzene or xylene) and a halogenated solvent (e.g., dichloromethane, 1,2-dichloroethane, chloroform or chlorobenzene).

[0469] In one embodiment, the polar aprotic solvent is selected from N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, N-methyl-2-pyrrolidone, sulfolane, esters (e.g., ethyl acetate, methyl acetate, isopropyl acetate, butyl acetate, or isobutyl acetate), ketones (e.g., acetone, methyl ethyl ketone, methyl isobutyl ketone, or 2-pentanone), and carbonates (e.g., dimethyl carbonate, diethyl carbonate, or diisopropyl carbonate).

[0470] In one embodiment, the polar protic solvent is an alcohol (eg, methanol, ethanol, propanol, or isopropanol).

[0471] In one embodiment, the temperature of the reaction is from 0°C to 100°C, such as from 20°C to 80°C, or from 40°C to 80°C, or from 20°C to 60°C, or from 50°C to 90°C.

[0472] In one embodiment, the method includes the step of deprotecting compound 7-E with a suitable deprotecting agent in a suitable solvent to provide compound 7-F or compound 4-N.

[0473] In one embodiment, the deprotecting agent is a fluoride reagent.

[0474] In one embodiment, the fluoride reagent is selected from the group consisting of sodium fluoride, potassium fluoride, potassium bifluoride, tetra-n-butylammonium fluoride, triethylamine trihydrofluoride, and hydrofluoric acid.

[0475] In one embodiment, the protecting group R q is a silyl protecting group and the deprotected product is compound 4-N.

[0476] In one embodiment, the deprotecting agent is an organic acid.

[0477] In one embodiment, the organic acid is selected from the group consisting of formic acid, trifluoroacetic acid, methanesulfonic acid, acetic acid, 4-toluenesulfonic acid, and trifluoromethanesulfonic acid.

[0478] In one embodiment, the protecting group R q is a silyl protecting group or a carbamate protecting group and the deprotected product is compound 4-N.

[0479] In one embodiment, the solvent is a nonpolar solvent, a polar protic solvent, or a polar aprotic solvent, or any combination thereof, or wherein the solvent is a pure deprotecting reagent (eg, an organic acid).

[0480] In one embodiment, the solvent is selected from ethers (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, cyclopentyl methyl ether, dioxane), hydrocarbon solvents (e.g., toluene, n-hexane, n-heptane, anisole, trifluorotoluene, hexafluorobenzene, fluorobenzene, xylene) and halogenated solvents (e.g., dichloromethane, 1,2-dichloroethane, chloroform, chlorobenzene).

[0481] In one embodiment, the polar aprotic solvent is selected from N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, N-methyl-2-pyrrolidone, sulfolane, esters (e.g., ethyl acetate, methyl acetate, isopropyl acetate, butyl acetate, isobutyl acetate), ketones (e.g., acetone, methyl ethyl ketone, methyl isobutyl ketone, 2-pentanone) and nitriles (e.g., acetonitrile).

[0482] In one embodiment, the polar protic solvent is an alcohol (eg, methanol, ethanol, propanol, isopropanol), water, or a combination thereof.

[0483] In one embodiment, the temperature of the reaction is from 0°C to 100°C, such as from 20°C to 80°C, or from 40°C to 80°C, or from 20°C to 60°C, or from 50°C to 90°C.

[0484] In one embodiment, the method includes the step of converting compound 7-F to compound 4-N.

[0485] In one embodiment, the method includes the step of converting compound 4-N to compound 1.

[0486] In one embodiment, the present disclosure provides a method for preparing compound 1 from a compound selected from 7-A, 7-B, 7-C, 7-D, 7-E, 7-F and 4-N, as shown in Scheme 7.

[0487] H. Method for preparing compound 1 from formula 8-A

[0488] In one embodiment, the present disclosure provides a method for preparing a compound selected from 8-B, 8-C, 8-D, 8-E, 8-F, 6-N and Compound 1, as shown in Scheme 8, wherein R x and R y Independently H, C 1-6 Alkyl or C 6-10 Aryl, wherein the alkyl group is optionally replaced by C 6-10 Aryl substituted, PG is selected from a silyl group, an alkylcarbonyl group, an arylcarbonyl group, an alkoxycarbonyl group, a silylalkoxycarbonyl group, an aryloxycarbonyl group or a C 1-6 Alkylaryl group, R p Selected from -C(=O)-C 1-6 Alkyl, -C(=O)-heteroaryl, -C(=O)-OC 1-6 Alkyl and -C(=O)-OC 1-6 Alkyl-C 6-10 Aryl, wherein each aryl or heteroaryl is optionally substituted by one to four independently selected C 1-3 Alkyl and -OC 1-3 The alkyl radical is substituted with a radical wherein each heteroaryl group has one to four heteroatoms; wherein each heteroatom is independently selected from N, O, and S, and wherein each heteroaryl group has 5 to 10 ring members.

[0489]

[0490] Option 8

[0491] In one embodiment, the method includes the step of reacting compound 6-L with compound 8-A in a cross metathesis reaction using a suitable catalyst in a suitable solvent and under conditions effective to form compound 8-B for a period of time.

[0492] In one embodiment, PG is selected from a silyl group, an alkylcarbonyl group (e.g., -C(=O)-C 1-6 alkyl groups such as acetyl, isobutyryl, pivaloyl), arylcarbonyl groups (e.g., benzoyl), alkoxycarbonyl groups (e.g., -C(=O)-OC 1-6 alkyl, such as methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl or benzyloxycarbonyl), silylalkoxycarbonyl groups (e.g., -C(=O)-OC 1-6 Alkyl-Si(C 1-6 alkyl) 3, such as 2-(trimethylsilyl)ethoxycarbonyl), an aryloxycarbonyl group (e.g., phenoxycarbonyl) or C 1-6 Alkylaryl groups (eg, benzyl, 4-methoxybenzyl, 3,5-dimethoxybenzyl).

[0493] In one embodiment, PG is selected from a silyl group, an alkoxycarbonyl group (e.g., -C(=O)-OC 1-6 alkyl, such as methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl or benzyloxycarbonyl), silylalkoxycarbonyl groups (e.g., -C(=O)-OC 1-6 Alkyl-Si(C 1-6 alkyl) 3, such as 2-(trimethylsilyl)ethoxycarbonyl) or C 1-6 Alkylaryl groups (eg, benzyl, 4-methoxybenzyl, 3,5-dimethoxybenzyl).

[0494] In one embodiment, the substituent PG is selected from a trialkylsilyl group (e.g., trimethylsilyl, triethylsilyl, tripropylsilyl, triisopropylsilyl, tert-butyldimethylsilyl), a dialkylarylsilyl group (e.g., dimethylphenylsilyl), an alkyldiarylsilyl group (e.g., tert-butyldiphenylsilyl), and a triarylsilyl group (e.g., triphenylsilyl).

[0495] In one embodiment, R x and R y All are hydrogen.

[0496] In one embodiment, R p Selected from 1-phenylethoxycarbonyl, ethoxycarbonyl, methoxycarbonyl, tert-butoxycarbonyl, isopropoxycarbonyl, phenoxycarbonyl, 4-methoxyphenoxycarbonyl and benzyloxycarbonyl.

[0497] In one embodiment, R p is 1-phenethoxycarbonyl, optionally in the (R) or (S) form.

[0498] In one embodiment, the suitable catalyst is a ruthenium catalyst or a molybdenum catalyst.

[0499] In one embodiment, the suitable catalyst is selected from dichloro[1,3-bis(2,4,6-trimethylphenyl)-2-imidazolidinylidene](2-isopropoxyphenylmethylene)ruthenium(II), dichloro(benzylidene)bis(tricyclohexylphosphine)ruthenium(II), dichloro[1,3-bis(2,4,6-trimethylphenyl)-2-imidazolidinylidene](benzylidene)(tricyclohexylphosphine)ruthenium(II), dichloro(o-isopropoxyphenylmethylene)(tricyclohexylphosphine)ruthenium(II), dichloro[1,3-bis(2,4,6-trimethylphenyl)-2-imidazolidinylidene](benzylidene)(tricyclohexylphosphine)ruthenium(II), phenylmethylene)ruthenium(II), dichloro[1,3-bis(2-methylphenyl)-2-imidazolidinyl](benzylidene)(tricyclohexylphosphine)ruthenium(II), dichloro[1,3-bis(2,4,6-trimethylphenyl)-2-imidazolidinyl][3-(2-pyridyl)propylene]ruthenium(II), [1,3-dimesityl-2-imidazolidinyl]dichloro(phenylmethylene)bis(3-bromopyridinyl)ruthenium(II), dichloro[1,3-bis(2,4,6-trimethylphenyl)-2-imidazolidinyl](3-methyl-2-butenyl)(tricyclohexylphosphine)ruthenium(II) II), dichloro[1,3-bis(2-methylphenyl)-2-imidazolidinyl](2-isopropoxyphenylmethylene)ruthenium(II), [1,3-dimesityl-2-imidazolidinyl]dichloro[3-(2-pyridyl)propylene]-ruthenium(II), (1,3-dimesityl-2-imidazolidinyl)dichloro(2-isopropoxy-5-nitrobenzylidene)ruthenium(II), tricyclohexylphosphine[4,5-dimethyl-1,3-bis(2,4,6-trimethylphenyl)imidazolidinyl][2-thienylmethylene]ruthenium(II) dichloride, tricyclohexylphosphine Phosphino[1,3-bis(2,4,6-trimethylphenyl)imidazolidin-2-ylidene][2-thienylmethylene]ruthenium(II) dichloride, tricyclohexylphosphino[2,4-dihydro-2,4,5-triphenyl-3H-1,2,4-triazol-3-ylidene][2-thienylmethylene]ruthenium(II) dichloride, tricyclohexylphosphino[1,3-bis(2,4,6-trimethylphenyl)imidazolidin-2-ylidene][3-phenyl-1H-inden-1-ylidene]ruthenium(II) dichloride, and bis(tricyclohexylphosphino)-3-phenyl-1H-inden-1-ylideneruthenium(II) dichloride.

[0500] In one embodiment, the catalyst is selected from 2,6-diisopropyl-phenylimino-neophenylene [(S)-(−)-BIPHEN] platinum (VI), dichlorobis[(2,6-diisopropylphenyl)imino](1,2-dimethoxyethane) platinum (VI), and (T-4)-chloro(2,2-dimethylpropylidene)[2,2",4,4',6,6'-hexa(1-methylethyl)[1,1':3',1-terphenyl]-2'-olato][2-methyl-2-propylaminoester(2-)] platinum (VI).

[0501] In one embodiment, a suitable catalyst is the Hoveyda-Grubbs II catalyst (dichloro[1,3-bis(2,4,6-trimethylphenyl)-2-imidazolidinylidene](2-isopropoxyphenylmethylene)ruthenium(II)).

[0502] In one embodiment, the suitable solvent is a non-polar solvent or a polar aprotic solvent.

[0503] In one embodiment, the solvent is selected from ethers (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, cyclopentyl methyl ether, dioxane), hydrocarbon solvents (e.g., toluene, n-hexane, n-heptane, anisole, trifluorotoluene, hexafluorobenzene, fluorobenzene, xylene) and halogenated solvents (e.g., dichloromethane, 1,2-dichloroethane, chloroform, chlorobenzene).

[0504] In one embodiment, the polar aprotic solvent is selected from esters (e.g., ethyl acetate, methyl acetate, isopropyl acetate, butyl acetate, isobutyl acetate), ketones (e.g., acetone, methyl ethyl ketone, methyl isobutyl ketone, 2-pentanone), and carbonates (e.g., dimethyl carbonate, diethyl carbonate, diisopropyl carbonate).

[0505] In one embodiment, the temperature of the reaction is 0°C to 150°C, such as 0°C to 120°C, such as 20°C to 90°C, or 40°C to 90°C, or 20°C to 60°C, or 40°C to 80°C, or about 80°C.

[0506] In one embodiment, the method comprises the step of treating compound 8-G with 4-fluoro-5-X-benzoic acid for a period of time and under conditions effective to form the ether adduct compound 8-C, wherein X is selected from bromine, chlorine, iodine, a sulfonate (e.g., trifluoromethanesulfonate, methanesulfonate, p-toluenesulfonate, imidazolylsulfonate) and a phosphinate (e.g., diphenyl phosphinate), wherein each R n Independently C 1-6 Alkyl (e.g., methyl, ethyl, or isopropyl), or two R n Parts are linked together to form C 2-10 Alkyl or C 2-10an alkenyl bridge (ie, a cyclic acetal), wherein the bridge is optionally substituted by one to four C 1-6 Alkyl, halogen or aryl substituted; or two R n The moieties are linked together to form an optionally substituted 1,2-hydroxyaryl bridge (e.g., a catechol bridge).

[0507] In one embodiment, R of compound 8-G n The part is methyl or ethyl, or the two R n The moieties are linked together to form a bridge selected from the group consisting of CH2CH2-, -CH(CH3)CH(CH3)-, -CH2CH(CH3)-, -CH2CH(C6H5)-, -C(CH3)2C(CH3)2-, -CH2CH2CH2-, -CH2CBr2CH2-, -CH2(C=CH)CH2-, -CH2CH(C6H5)CH2-, -CH(CH3)CH2CH(CH3)-, -CH2CH(CH3)CH2-, -CH2C(CH3)2CH2-, -CH2C(CH2CH3)2CH2-, -CH2CH2CH2CH2-, -CH2CH2CH2CH2CH2-, -CH(C6H5)CH(C6H5), -CH2CH(C6H5)CH2-, and -(o-C6H4)-.

[0508] In one embodiment, compound 8-G is dissolved or suspended in a suitable solvent and treated with a strong base, and optionally with a promoter (eg, sodium iodide, tetrabutylammonium iodide).

[0509] In one embodiment, the base is selected from an inorganic hydride (e.g., sodium hydride, potassium hydride), an alkoxide (e.g., sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium methoxide, potassium ethoxide, potassium tert-butoxide, lithium tert-butoxide, potassium tert-amylate, sodium tert-amylate, lithium tert-amylate), an inorganic hydroxide (e.g., sodium hydroxide, potassium hydroxide, lithium hydroxide), an amide base (sodium hexamethyldisilazide, lithium hexamethyldisilazide, potassium hexamethyldisilazide, ammonium hexamethyldisilazide, diisopropylamine (e.g., lithium propylamide, sodium diisopropylamide, potassium diisopropylamide), organic lithium bases (e.g., methyl lithium, ethyl lithium, butyl lithium, sec-butyl lithium, tert-butyl lithium), Grignard reagents (e.g., methyl, ethyl, propyl, isopropyl, or butyl magnesium chloride or bromide), and inorganic bases (e.g., lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, potassium phosphate (monopotassium dihydrogen phosphate, dipotassium hydrogen phosphate, or tripotassium phosphate), sodium phosphate (monosodium dihydrogen phosphate, disodium hydrogen phosphate, or trisodium phosphate)).

[0510] In one embodiment, the suitable solvent is a non-polar solvent or a polar aprotic solvent.

[0511] In one embodiment, the non-polar solvent is selected from ethers (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, cyclopentyl methyl ether, dioxane), hydrocarbon solvents (e.g., toluene, n-hexane, n-heptane, benzene, trifluorotoluene, benzonitrile, xylene) and halogenated solvents (e.g., dichloromethane, 1,2-dichloroethane, chloroform, chlorobenzene).

[0512] In one embodiment, the polar aprotic solvent is selected from formamide, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, N-methyl-2-pyrrolidone, sulfolane, esters (e.g., methyl acetate, ethyl acetate, n-butyl acetate, isopropyl acetate, isobutyl acetate), ketones (e.g., acetone, methyl ethyl ketone, methyl butyl ketone, 2-propanone, 3-pentanone) and nitriles (e.g., acetonitrile, propionitrile, benzonitrile).

[0513] In one embodiment, the temperature of the reaction is from -80°C to 120°C, e.g., from -45°C to 10°C, or from -30°C to 10°C, or from -10°C to 5°C, or about 0°C, or from -10°C to 50°C, or from -10°C to 30°C, or from 10°C to 30°C, or from 25°C to 120°C, or from 50°C to 80°C.

[0514] In one embodiment, the method includes the step of subjecting compound 8-B to an acylation reaction using benzoic acid compound 8-C, an acid activator, and a base in a suitable solvent for a period of time under conditions effective to form compound 8-D.

[0515] In one embodiment, the acid activator is selected from N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (EDC-HCl), (PhO)2POCl, carbonyldiimidazole (CDI), propylphosphonic anhydride (T3P), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU), 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methyl-morpholinium chloride (DMTMM), thionyl chloride, oxalyl chloride, sulfuryl chloride, isobutyl chloroformate, N,N,N'N'-tetramethylchloroformamidine hexafluorophosphate, 2,4,6-trichlorobenzoyl chloride, N,N'-diisopropylcarbodiimide and N,N'-dicyclohexylcarbodiimide.

[0516] In one embodiment, the acid activator is N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (EDC-HCl).

[0517] In one embodiment, the base is selected from a tertiary amine (e.g., trimethylamine, triethylamine, N-methylmorpholine, N-ethylmorpholine, tripropylamine, N,N-diisopropylethylamine, tributylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene, 1,4-diazabicyclo[2.2.2]octane, N-methylpyrrolidone), an aromatic amine (e.g., pyridine, 2,6-lutidine, picoline, collidine, imidazole, 1-methylimidazole, indole, isoindole, quinoline, isoquinoline, 4-dimethylaminopyridine), a hydroxide (e.g., sodium hydroxide, potassium hydroxide, tetrabutylammonium hydroxide), and an inorganic base (e.g., lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, potassium phosphate (monopotassium dihydrogen phosphate, dipotassium hydrogen phosphate, or tripotassium phosphate), and sodium phosphate (monosodium dihydrogen phosphate, disodium hydrogen phosphate, or trisodium phosphate)).

[0518] In one embodiment, the reaction further comprises an accelerator selected from the group consisting of dichloromethylene-dimethyliminium chloride, 4-dimethylaminopyridine (DMAP), N-methylimidazole, 1-hydroxy-7-azabenzotriazole (HOAt), and 1-hydroxybenzotriazole (HOBt).

[0519] In one embodiment, the acid activator is EDC-HCl, the base is 1-methylimidazole, and the accelerator is DMAP.

[0520] In one embodiment, the suitable solvent is a non-polar solvent or a polar aprotic solvent or a combination thereof, optionally comprising water or a biphasic reaction.

[0521] In one embodiment, the non-polar solvent is selected from ethers (e.g., diethyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, cyclopentyl methyl ether, dioxane), hydrocarbon solvents (e.g., toluene, n-hexane, n-heptane, benzene, xylene) and halogenated solvents (e.g., dichloromethane, 1,2-dichloroethane, chloroform, chlorobenzene).

[0522] In one embodiment, the polar aprotic solvent is selected from N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone, dimethyl sulfoxide, sulfolane, esters (e.g., ethyl acetate, methyl acetate, isopropyl acetate, butyl acetate, isobutyl acetate), carbonates (e.g., dimethyl carbonate, diethyl carbonate) and nitriles (e.g., acetonitrile).

[0523] In one embodiment, the temperature of the reaction is from -50°C to 60°C, such as from 0°C to 60°C, or from 10°C to 40°C, or from 20°C to 40°C.

[0524] In one embodiment, the method includes the step of treating compound 8-D with a deprotecting agent in a suitable solvent and for a time and under conditions effective to form compound 8-E.

[0525] In one embodiment, PG is selected from a silyl group, an alkoxycarbonyl group (e.g., -C(=O)-OC 1-6 alkyl, such as methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl or benzyloxycarbonyl), silylalkoxycarbonyl groups (e.g., -C(=O)-OC 1-6 Alkyl-Si(C 1-6 alkyl) 3, such as 2-(trimethylsilyl)ethoxycarbonyl) or C 1-6 Alkylaryl groups (eg, benzyl, 4-methoxybenzyl, 3,5-dimethoxybenzyl).

[0526] In one embodiment, the substituent PG is selected from a trialkylsilyl group (e.g., trimethylsilyl, triethylsilyl, tripropylsilyl, triisopropylsilyl, tert-butyldimethylsilyl), a dialkylarylsilyl group (e.g., dimethylphenylsilyl), an alkyldiarylsilyl group (e.g., tert-butyldiphenylsilyl), and a triarylsilyl group (e.g., triphenylsilyl).

[0527] In one embodiment, R p Selected from 1-phenylethoxycarbonyl, ethoxycarbonyl, methoxycarbonyl, tert-butoxycarbonyl, isopropoxycarbonyl, phenoxycarbonyl, 4-methoxyphenoxycarbonyl and benzyloxycarbonyl.

[0528] In one embodiment, R p is 1-phenethoxycarbonyl, optionally in the (R) or (S) form.

[0529] In one embodiment, the deprotecting agent is selected from an inorganic base (e.g., an aqueous solution thereof), an acid (e.g., an aqueous solution thereof or a solution in an organic solvent), a fluoride agent (e.g., in an organic solvent), a hydrogenating agent (e.g., a combination of hydrogen gas and a heterogeneous catalyst (e.g., a transition metal catalyst) or a homogeneous catalyst (e.g., a soluble transition metal complex) or a phase transfer hydrogenation system), optionally further comprising a phase transfer agent.

[0530] In one embodiment, the deprotecting agent is a fluoride reagent or an acid.

[0531] In one embodiment, the deprotecting agent is selected from hydrochloric acid (e.g., aqueous HCl, HCl in ether, HCl in methanol, HCl in isopropanol), hydrobromic acid (e.g., aqueous HBr), sulfuric acid, formic acid, acetic acid, trifluoroacetic acid, phosphoric acid, methanesulfonic acid, 4-toluenesulfonic acid, hydrofluoric acid, pyridine hydrogen fluoride, triethylammonium hydrogen fluoride, potassium fluoride, sodium fluoride, lithium fluoride, cesium fluoride, potassium bifluoride, tetramethylammonium fluoride, tetraethylammonium fluoride, and tetrabutylammonium fluoride.

[0532] In one embodiment, the suitable solvent is a non-polar solvent, a polar protic solvent or a polar aprotic solvent or a mixture thereof, optionally comprising water as a biphasic reaction.

[0533] In one embodiment, the non-polar solvent is selected from ethers (e.g., diethyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, cyclopentyl methyl ether, dioxane), hydrocarbon solvents (e.g., toluene, n-hexane, n-heptane, benzene, xylene) and halogenated solvents (e.g., dichloromethane, 1,2-dichloroethane, chloroform, chlorobenzene).

[0534] In one embodiment, the polar protic solvent is an alcoholic solvent (eg, methanol, ethanol, propanol, isopropanol, tert-butanol, tert-amyl alcohol), optionally in combination with water, or wherein the polar protic solvent is water.

[0535] In one embodiment, the polar aprotic solvent is selected from N,N-dimethylacetamide, N,N-dimethylformamide, N-methyl-2-pyrrolidone and dimethyl sulfoxide, sulfolane, nitriles (e.g., acetonitrile, propionitrile) and esters (methyl acetate, ethyl acetate, isopropyl acetate, butyl acetate, isobutyl acetate, dimethyl carbonate).

[0536] In one embodiment, the temperature of the reaction is from -15°C to 60°C, such as from 0°C to 60°C, or from -5°C to 40°C, or from 0°C to 30°C, or from 10°C to 30°C.

[0537] In one embodiment, the method includes the step of treating compound 8-E with a reducing agent in a suitable solvent and under conditions and for a time effective to form compound 8-F.

[0538] In one embodiment, the reducing agent is selected from a hydride reducing agent, a silane reducing agent, or a hydrogenating agent.

[0539] In one embodiment, the reducing agent is a hydride reducing agent.

[0540] In one embodiment, the hydride reducing agent is selected from the group consisting of sodium borohydride, lithium borohydride, sodium cyanoborohydride, zinc borohydride, sodium triacetoxyborohydride, and tetramethylammonium triacetoxyborohydride.

[0541] In one embodiment, the hydride reducing agent is sodium triacetoxyborohydride or sodium cyanoborohydride.

[0542] In one embodiment, the hydride reducing agent is combined with an agent that modulates hydride reducing activity (eg, titanium isopropoxide, titanium ethoxide, borates, magnesium perchlorate, or zinc chloride).

[0543] In one embodiment, the silane reducing agent is triethylsilane.

[0544] In one embodiment, the reaction further comprises an acid (eg, selected from acetic acid, trifluoroacetic acid, citric acid, pivalic acid, p-toluenesulfonic acid, methanesulfonic acid, and hydrochloric acid).

[0545] In one embodiment, the suitable solvent is a non-polar solvent, a polar protic solvent, or a polar aprotic solvent.

[0546] In one embodiment, the non-polar solvent is selected from ethers (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, cyclopentyl methyl ether, dioxane), hydrocarbon solvents (e.g., toluene, n-hexane, n-heptane) and halogenated solvents (e.g., dichloromethane, 1,2-dichloroethane, chloroform, chlorobenzene).

[0547] In one embodiment, the polar protic solvent is selected from alcohols (eg, methanol, ethanol, propanol, isopropanol) and acids (eg, acetic acid, formic acid, trifluoroacetic acid).

[0548] In one embodiment, the polar aprotic solvent is selected from N,N-dimethylacetamide, N,N-dimethylformamide, N-methyl-2-pyrrolidone, dimethyl sulfoxide, esters (eg, methyl acetate, ethyl acetate, isopropyl acetate), and nitriles (eg, acetonitrile).

[0549] In one embodiment, the suitable solvent is tetrahydrofuran, dichloromethane or acetonitrile.

[0550] In one embodiment, the temperature of the reaction is from -30°C to 80°C, such as from -30°C to 50°C, or from 0°C to 50°C, or from 10°C to 30°C.

[0551] In one embodiment, the method comprises the step of treating compound 8-F with a base and optionally a catalyst and optionally a ligand in a suitable solvent for a time and under conditions effective to form compound 6-N.

[0552] In one embodiment, the base is selected from an inorganic base (e.g., lithium carbonate, sodium carbonate, potassium carbonate, and cesium carbonate, sodium phosphate or potassium phosphate (each in monobasic, dibasic, or ternary form)), an organic base (e.g., an alkali metal carboxylate such as sodium or potassium acetate, pivalate, or propionate), a hydroxide (e.g., lithium hydroxide, sodium hydroxide, tetrabutylammonium hydroxide), and an alkoxide (e.g., sodium tert-butoxide, potassium tert-butoxide, sodium tert-amylate).

[0553] In one embodiment, the reaction further comprises a catalyst, for example, the catalyst is selected from palladium (II) acetate, palladium (II) pivalate, palladium (II) propionate, palladium (II) trifluoroacetate, palladium (II) bromide, palladium (II) chloride, tris (dibenzylideneacetone) dipalladium (0), (SP-4-3)-[(2R)-1-[(1R)-1-[bis (1,1-dimethylethyl) phosphino-κP] ethyl] -2- (dicyclohexylphosphino-κP) ferrocene] dichloropalladium (II), (2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl) [2-(2′-amino-1,1′-biphenyl)] methanesulfonate palladium (II), [(2-di-tert-butylphosphino-3,6-dimethoxy-2′, palladium(II) methanesulfonate, (2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl)[2-(2'-amino-1,1'-biphenyl)]methanesulfonate, palladium(II) methanesulfonate, [(bis(1-adamantyl)-butylphosphine)-2-(2'-amino-1,1'-biphenyl)]methanesulfonate, [(2-dicyclohexylphosphino-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)-2-(2'-amino-1,1'-biphenyl)]methanesulfonate, palladium(II) methanesulfonate, [(2-di-tert-butylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)-2-( palladium(II) methanesulfonate, [(1,3,5,7-tetramethyl-6-phenyl-2,4,6-trioxa-6-phosphinoadamantane)-2-(2′-amino-1,1′-biphenyl)] methanesulfonate, [(2-{bis[3,5-bis(trifluoromethyl)phenyl]phosphine}-3,6-dimethoxy-2′,4′,6′-triisopropyl-1,1′-biphenyl)-2-(2′-amino-1,1′-biphenyl)] methanesulfonate, [(2-dicyclohexylphosphino-2′,6′-bis(N,N-dimethylamino)-1,1′-biphenyl)-2-(2′-amino-1,1′-biphenyl)] methanesulfonate, palladium(II) methanesulfonate, [(2-dicyclohexylphosphino-2′,6′-bis(N,N-dimethylamino)-1,1′-biphenyl)-2-(2′-amino-1,1′-biphenyl)] methanesulfonate, palladium(II) methanesulfonate, [(2-di-tert-butylphosphino-3-methoxy-6-methyl-2′,4′,6′-triisopropyl-1,1′-biphenyl)-2-(2-aminobiphenyl)] methanesulfonate, [2-(di-1-adamantylphosphino)-2′,4′,6′-triisopropyl-3,6-dimethoxybiphenyl][2-(2′-amino-1,1′-biphenyl)] methanesulfonate, [(di-tert-butylneopentylphosphino)-2-(2-aminobiphenyl)] methanesulfonate, palladium(II) methanesulfonate, [2-(di-tert-butylphosphino)-1,1′-binaphthyl][2-(2′-amino-1,1′-biphenyl)] palladium(II), methanesulfonyl(di-tert-butyl)methylphosphino(2′-amino-1,1′-biphenyl-2-yl)palladium(II) and methanesulfonyl-2-dicyclohexylphosphino-2-(N,N-dimethylamino)biphenyl(2′-amino-1,1′-biphenyl-2-yl)palladium(II).

[0554] In one embodiment, the reaction further comprises a ligand, for example, the ligand is selected from triphenylphosphine, tri-o-tolylphosphine, tri-tert-butylphosphine, di-tert-butyl-(methyl)phosphine, di-tert-butyl(phenyl)phosphine, tricyclohexylphosphine, triisopropylphosphine, n-butyldiadamantylphosphine, 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl, 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene, bis[(2-diphenylphosphino)phenyl]ether, 1,1′-bis(diphenylphosphino)ferrocene, (2R)-1-[(1R)-1-[bis(1,1-dimethylethyl)phosphino]ethyl]-2-(dicyclohexylphosphino)ferrocene, 1,3-bis(diphenylphosphino)propane, 5-(di-tert-butylphosphino)-1′, 3′, 5′-Triphenyl-1′H-[1,4′]bipyrazole, bis(1-adamantyl)-2-morpholinophenylphosphine, N,N′-(2,6-diisopropylphenyl)dihydroimidazolium chloride, (2-biphenyl)di-tert-butylphosphine, (2-biphenyl)di-tert-butylphosphine, 2-(di-tert-butylphosphino)biphenyl, (2-biphenyl)dicyclohexylphosphine, 2-dicyclohexylphosphino-2′-(N,N-dimethylamino)biphenyl, 2-dicyclohexylphosphino-2′,6′-diisopropylbiphenyl, 2-dicyclohexylphosphino-2′,6′-diisopropylbiphenyl Methoxybiphenyl, 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl, 2-(dicyclohexylphosphino)3,6-dimethoxy-2′,4′,6′-triisopropyl-1,1′-biphenyl, 2-di-tert-butylphosphino-2′,4′,6′-triisopropylbiphenyl, 2-(di-tert-butylphosphino)-2′,4′,6′-triisopropyl-3,6-dimethoxy-1,1′-biphenyl, and 2-di-tert-butylphosphino-3,4,5,6-tetramethyl-2′,4′,6′-triisopropyl-1,1′-biphenyl.

[0555] In one embodiment, the suitable solvent is a non-polar solvent, a polar protic solvent, or a polar aprotic solvent.

[0556] In one embodiment, the non-polar solvent is selected from ethers (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, cyclopentyl methyl ether, dioxane, dimethoxyethane), hydrocarbon solvents (e.g., toluene, n-hexane, n-heptane, benzene, trifluorotoluene, xylene) and halogenated solvents (e.g., dichloromethane, 1,2-dichloroethane, chloroform, chlorobenzene).

[0557] In one embodiment, the polar protic solvent is an alcohol (eg, methanol, ethanol, propanol, isopropanol, butanol, tert-butanol, 2-methyl-2-butanol).

[0558] In one embodiment, the polar aprotic solvent is selected from N,N-dimethylacetamide, N,N-dimethylformamide, N-methyl-2-pyrrolidone, dimethyl sulfoxide, sulfolane, and nitriles (eg, acetonitrile, propionitrile, benzonitrile).

[0559] In one embodiment, the suitable solvent is tetrahydrofuran, dichloromethane or acetonitrile.

[0560] In one embodiment, the temperature of the reaction is from 25°C to 120°C, such as from 40°C to 100°C or from 60°C to 80°C.

[0561] In one embodiment, the method produces a compound according to one or more of compounds 8-B, 8-C, 8-D, 8-E, 8-F, or 6-N.

[0562] In one embodiment, the product Compound 6-N is further processed to Compound 4-N or Compound 1.

[0563] In one embodiment, the present disclosure provides a method for preparing compound 1 from a compound selected from 8-A, 6-L, 8-B, 8-C, 8-D, 8-E, 8-F, 8-G and 6-N, as shown in Scheme 8.

[0564] I. Method for preparing compound 1 from formula 9-G

[0565] In one embodiment, the present disclosure provides a method for preparing a compound selected from 9-H, 9-I, 9-J and Compound 1, as shown in Scheme 9, wherein R 2 It's H, R 3 and R 5 are independently CH3, R 12 yes , R u and R w Each independently is H, C 1-6 Alkyl or C 6-10 Aryl, wherein the alkyl group is optionally replaced by C 6-10 Aryl substitution, R p Selected from -C(=O)-C 1-6 Alkyl, -C(=O)-heteroaryl, -C(=O)-OC 1-6 Alkyl and -C(=O)-OC 1-6 Alkyl-C 6-10 Aryl, wherein each aryl or heteroaryl is optionally substituted by one to four independently selected C 1-3 Alkyl and -OC1-3 In one embodiment, R u is H. In one embodiment, R w is H. In one embodiment, R p In one embodiment, R p yes .

[0566]

[0567] Option 9

[0568] In one embodiment, the present disclosure provides a method for preparing compound 9-H from compound 9-G and compound 9-K.

[0569] In one embodiment, the method includes the step of reacting compound 9-G with compound 9-K, an acid activator, a promoter, and a base in a suitable solvent and under conditions and for a time effective to form compound 9-H.

[0570] In one embodiment, the acid activator is selected from N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride, carbonyldiimidazole (CDI), propylphosphonic anhydride (T3P), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU), 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methyl- Morpholinium chloride (DMTMM), thionyl chloride, oxalyl chloride, (chloromethylene)-dimethyliminium chloride, isobutyl chloroformate, N,N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (TCFH), N,N'-diisopropylcarbodiimide, N,N'-dicyclohexylcarbodiimide, diphenyl chlorophosphate, 2,4,6-trichlorobenzoyl chloride and 2-chloro-4,6-dimethoxy-1,3,5-triazine (CDMT). In one embodiment, the acid activator is N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride.

[0571] In one embodiment, the accelerator is selected from 4-dimethylaminopyridine, N-methylimidazole, 1-hydroxy-7-azabenzotriazole (HOAt), 1-hydroxybenzotriazole (HOBt), N,N-dimethylacetamide and N-methylimidazole. In one embodiment, the accelerator is 4-dimethylaminopyridine.

[0572] In one embodiment, the base is selected from tertiary amines (e.g., N-methylmorpholine, triethylamine, tripropylamine, N,N-diisopropylethylamine, tributylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene, 1,4-diazabicyclo[2.2.2]octane, DABCO), aromatic amines (e.g., pyridine, 2,6-lutidine, collidine, 1-methylimidazole), inorganic bases (e.g., lithium carbonate, sodium carbonate, potassium carbonate, calcium carbonate and bicarbonate derivatives, potassium dihydrogen phosphate, dipotassium hydrogen phosphate and tripotassium phosphate, and sodium dihydrogen phosphate, disodium hydrogen phosphate and trisodium phosphate). In one embodiment, the base is 1-methylimidazole.

[0573] In one embodiment, the solvent is selected from ethers (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, cyclopentyl methyl ether), esters (e.g., ethyl acetate, isopropyl acetate), polar aprotic solvents (e.g., N,N-dimethylacetamide, N-methyl-2-pyrrolidone, dimethyl sulfoxide), nitriles (e.g., acetonitrile), hydrocarbon solvents (e.g., toluene), halogenated solvents (e.g., dichloromethane, 1,2-dichloroethane, chloroform, chlorobenzene), and combinations thereof. In one embodiment, the solvent is acetonitrile.

[0574] In one embodiment, the temperature of the reaction is from -50°C to 50°C. In one embodiment, the temperature is from 10°C to 30°C.

[0575] In one embodiment, the present disclosure provides a method for preparing compound 9-I from compound 9-H.

[0576] In one embodiment, the method includes the step of reacting compound 9-H with an acid in a suitable solvent and under conditions and for a time effective to form compound 9-I.

[0577] In one embodiment, the acid is selected from citric acid, trifluoroacetic acid, methanesulfonic acid, trifluoromethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, camphorsulfonic acid, pyridinium p-toluenesulfonate, sulfuric acid, hydrochloric acid, hydrobromic acid, acetic acid, formic acid, phosphoric acid, oxalic acid. In one embodiment, the acid is citric acid.

[0578] In one embodiment, the solvent is selected from ethers (e.g., tetrahydrofuran, methyl tert-butyl ether, cyclopentyl methyl ether), esters (e.g., ethyl acetate, isopropyl acetate), polar aprotic solvents (e.g., N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone, dimethyl sulfoxide), nitriles (e.g., acetonitrile), hydrocarbon solvents (e.g., toluene), halogenated solvents (e.g., dichloromethane, 1,2-dichloroethane, chloroform, chlorobenzene), 2-methyltetrahydrofuran, water, and combinations thereof. In one embodiment, the solvent is a combination of 2-methyltetrahydrofuran and water.

[0579] In one embodiment, the temperature of the reaction is from -50°C to 70°C. In one embodiment, the temperature is from 50°C to 70°C.

[0580] In one embodiment, the present disclosure provides a method for preparing compound 9-J from compound 9-I and compound 9-L.

[0581] In one embodiment, the method includes the step of reacting compound 9-I with compound 9-L, an acid activator, a promoter, and a base in a suitable solvent and under conditions and for a time effective to form compound 9-J.

[0582] In one embodiment, the acid activator is selected from N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride, carbonyldiimidazole (CDI), propylphosphonic anhydride (T3P), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU), 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methyl- Morpholinium chloride (DMTMM), thionyl chloride, oxalyl chloride, (chloromethylene)-dimethyliminium chloride, isobutyl chloroformate, N,N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (TCFH), N,N'-diisopropylcarbodiimide, N,N'-dicyclohexylcarbodiimide, diphenyl chlorophosphate, 2,4,6-trichlorobenzoyl chloride, 2-chloro-4,6-dimethoxy-1,3,5-triazine (CDMT). In one embodiment, the acid activator is N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride.

[0583] In one embodiment, the accelerator is selected from 4-dimethylaminopyridine, N-methylimidazole, 1-hydroxy-7-azabenzotriazole (HOAt), 1-hydroxybenzotriazole (HOBt), N,N-dimethylacetamide, N-methylimidazole. In one embodiment, the accelerator is 4-dimethylaminopyridine.

[0584] In one embodiment, the base is selected from tertiary amines (e.g., N-methylmorpholine, triethylamine, tripropylamine, N,N-diisopropylethylamine, tributylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene, 1,4-diazabicyclo[2.2.2]octane, DABCO), aromatic amines (e.g., pyridine, 2,6-lutidine, collidine, 1-methylimidazole), inorganic bases (e.g., lithium carbonate, sodium carbonate, potassium carbonate, calcium carbonate and bicarbonate derivatives, potassium dihydrogen phosphate, dipotassium hydrogen phosphate and tripotassium phosphate, and sodium dihydrogen phosphate, disodium hydrogen phosphate and trisodium phosphate). In one embodiment, the base is 1-methylimidazole.

[0585] In one embodiment, the solvent is selected from ethers (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, cyclopentyl methyl ether), esters (e.g., ethyl acetate, isopropyl acetate), polar aprotic solvents (e.g., N,N-dimethylacetamide, N-methyl-2-pyrrolidone, dimethyl sulfoxide), other nitriles (e.g., acetonitrile), hydrocarbon solvents (e.g., toluene), halogenated solvents (e.g., dichloromethane, 1,2-dichloroethane, chloroform, chlorobenzene), and combinations thereof. In one embodiment, the solvent is acetonitrile.

[0586] In one embodiment, the temperature of the reaction is from -50°C to 50°C. In one embodiment, the temperature is from 10°C to 30°C.

[0587] In one embodiment, the method includes the step of converting compound 9-G to compound 9-H.

[0588] In one embodiment, the method includes the step of converting compound 9-H to 9-I.

[0589] In one embodiment, the method includes the step of converting compound 9-I to 9-J.

[0590] In one embodiment, the present disclosure provides a method for preparing Compound 1 from a compound selected from 9-H, 9-I, and 9-J.

[0591] In one embodiment, the present disclosure provides a method for preparing compound 1 from a compound selected from 9-G, 9-H, 9-I, 9-L and 9-J, as shown in Scheme 9.

[0592] J. Method for preparing formula 1-I from 10-A

[0593] In one embodiment, the present disclosure provides a method for preparing a compound selected from 10-B, 10-C, 10-D, 10-E, 10-F, 10-G and 1-I, as shown in Scheme 10, wherein R 5 is methyl, R 8 It is C 1-6 Alkyl, wherein the alkyl group is optionally replaced by C 6-10 aryl substituted, and R x Is H or C 1-6 Alkyl, in one embodiment, R 8 is isopropyl, n-butyl or benzyl. In one embodiment, R 8 In one embodiment, R 8 In one embodiment, R x It’s H.

[0594] In one embodiment, PG is selected from silyl (e.g., tert-butyldiphenylsilyl, tert-butyldimethylsilyl (TBS)), alkylcarbonyl (e.g., COMe), arylcarbonyl (e.g., COPh), alkoxycarbonyl (e.g., CO2tBu), aryloxycarbonyl (CO2Ph), alkyl (e.g., trityl), alkoxymethyl (e.g., MOM). In one embodiment, PG is selected from tri-C 1-6 Alkylsilyl group, di-C 1-6 Alkyl-phenylsilyl group, C 1-6 Alkyl-diphenylsilyl groups and triphenylsilyl groups. In one embodiment, PG is tert-butyldimethylsilyl (TBS).

[0595]

[0596] Plan 10

[0597] In one embodiment, the present disclosure provides a method for preparing compound 10-B from compound 10-A.

[0598] In one embodiment, the method includes the step of treating compound 10-A with a protecting agent and a base in a suitable solvent and under conditions and for a time effective to form compound 10-B.

[0599] In one embodiment, the protecting agent is selected from silyl chlorides (e.g., trimethylsilyl chloride, triethylsilyl chloride, tripropylsilyl chloride, triisopropylsilyl chloride, tert-butyldiphenylsilyl chloride, dimethylphenylsilyl chloride, triphenylsilyl chloride, tert-butyl(chloro)dimethylsilane), silyl trifluoromethanesulfonates (e.g., trimethylsilyl trifluoromethanesulfonate, triethylsilyl trifluoromethanesulfonate, triisopropylsilyl trifluoromethanesulfonate, tert-butyldimethylsilyl trifluoromethanesulfonate, dimethylphenylsilyl trifluoromethanesulfonate, triphenylsilyl trifluoromethanesulfonate), silyl bromides (e.g., trimethylsilyl bromide, triethylsilyl bromide, tripropylsilyl bromide, triisopropylsilyl bromide, In one embodiment, the protecting agent is tert-butyl(chloro)dimethylsilane.

[0600] In one embodiment, the base is selected from tertiary amines (e.g., N-methylmorpholine, tripropylamine, N,N-diisopropylethylamine, tributylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene, 1,4-diazabicyclo[2.2.2]octane), aromatic amines (e.g., pyridine, 2,6-lutidine, collidine, 1-methylimidazole, imidazole), inorganic bases (e.g., lithium carbonate, sodium carbonate, potassium carbonate, calcium carbonate, potassium phosphate, sodium phosphate). In one embodiment, the base is imidazole.

[0601] In one embodiment, the suitable solvent is selected from ethers (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, cyclopentyl methyl ether), hydrocarbon solvents (e.g., toluene, n-heptane), halogenated solvents (e.g., 1,2-dichloroethane, chloroform, dichloromethane, chlorobenzene), polar aprotic solvents (e.g., N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone, dimethyl sulfoxide), nitriles (e.g., acetonitrile), and combinations thereof. In one embodiment, the solvent is dichloromethane.

[0602] In one embodiment, the temperature of the reaction is from -30°C to 60°C. In one embodiment, the temperature of the reaction is from 10°C to 30°C.

[0603] In one embodiment, the present disclosure provides a method for preparing compound 10-C from compound 10-B.

[0604] In one embodiment, the method includes the step of treating compound 10-B with a Grignard reagent and a promoter in a suitable solvent and under conditions and for a time effective to form compound 10-C.

[0605] In one embodiment, the Grignard reagent is selected from ethylmagnesium bromide in other ether solvents (e.g., methyl tert-butyl ether, diethyl ether, dibutyl ether, dioxane), ethylmagnesium chloride, n-propylmagnesium bromide, 2-phenylethylmagnesium bromide in ether solvents (e.g., tetrahydrofuran, methyl tert-butyl ether, diethyl ether, dibutyl ether, dioxane). In one embodiment, the Grignard reagent is ethylmagnesium bromide.

[0606] In one embodiment, the promoter is selected from titanium (IV) alkoxides (e.g., titanium (IV) methoxide, titanium (IV) ethoxide, titanium (IV) propoxide, titanium (IV) isopropoxide, titanium (IV) butoxide). In one embodiment, the promoter is titanium (IV) isopropoxide.

[0607] In one embodiment, the suitable solvent is selected from ethers (e.g., 2-methyltetrahydrofuran, methyl tert-butyl ether, cyclopentyl methyl ether), hydrocarbons (e.g., toluene, n-heptane), polar aprotic solvents (e.g., N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone, dimethyl sulfoxide), nitriles (e.g., acetonitrile), and combinations thereof. In one embodiment, the solvent is tetrahydrofuran.

[0608] In one embodiment, the temperature of the reaction is from -20°C to 30°C. In one embodiment, the temperature of the reaction is from -5°C to 15°C.

[0609] In one embodiment, the present disclosure provides a method for preparing compound 10-D from compound 10-C.

[0610] In one embodiment, the method includes the step of treating compound 10-C with a halogenating agent and a base in a suitable solvent and for a time and under conditions effective to form compound 10-D.

[0611] In one embodiment, the halogenating agent is selected from N-bromophthalimide, bromine, 1,3-dibromo-5,5-dimethylhydantoin, N-bromosaccharin, hypobromous acid, N-chlorophthalimide, N-chlorosuccinimide, N-chlorosaccharin, 1,3-dichloro-5,5-dimethylhydantoin, N-iodosuccinimide, N-iodophthalimide, N-bromosuccinimide, iodine. In one embodiment, the halogenating agent is N-bromosuccinimide.

[0612] In one embodiment, the base is selected from tertiary amines (e.g., N-methylmorpholine, tripropylamine, N,N-diisopropylethylamine, tributylamine, triethylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene, 1,4-diazabicyclo[2.2.2]octane, DABCO), aromatic amines (e.g., pyridine, 2,6-lutidine, collidine, 1-methylimidazole). In one embodiment, the base is triethylamine.

[0613] In one embodiment, the suitable solvent is selected from ethers (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, cyclopentyl methyl ether), hydrocarbon solvents (e.g., toluene, n-heptane), esters (e.g., ethyl acetate, isopropyl acetate), halogenated solvents (e.g., 1,2-dichloroethane, dichloromethane, chloroform, chlorobenzene), and combinations thereof. In one embodiment, the solvent is dichloromethane.

[0614] In one embodiment, the temperature of the reaction is from -20°C to 30°C. In one embodiment, the temperature of the reaction is from -5°C to 20°C.

[0615] In one embodiment, the present disclosure provides a method for preparing compound 10-E from compound 10-D.

[0616] In one embodiment, the method includes the step of treating compound 10-D with an enzyme, a cofactor, a recycling system, and a buffer at a suitable pH, in a suitable solvent, and for a period of time under conditions effective to form compound 10-E.

[0617] In one embodiment, the enzyme is selected from ketoreductase. In one embodiment, the halogenating agent is CRED-A151.

[0618] In one embodiment, the cofactor is NADP. In one embodiment, the cofactor is NAD.

[0619] In one embodiment, the recycling system is selected from isopropanol, phosphite dehydrogenase (PDH) and phosphite, formate dehydrogenase (FDH) and ammonium formate, glucose dehydrogenase (GDH) and glucose monohydrate. In one embodiment, the recycling system is glucose dehydrogenase (GDH) and glucose monohydrate.

[0620] In one embodiment, the buffer is an aqueous buffer (e.g., sodium phosphate). In one embodiment, the buffer is a 0.1 M aqueous citrate buffer.

[0621] In one embodiment, the pH is between 4 and 9. In one embodiment, the pH is 6.2.

[0622] In one embodiment, the suitable solvent is selected from ethers (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, cyclopentyl methyl ether), polar aprotic solvents (e.g., N,N-dimethylacetamide, N-methyl-2-pyrrolidone, DMSO), and combinations thereof. In one embodiment, the solvent is DMSO.

[0623] In one embodiment, the temperature of the reaction is from 20°C to 40°C. In one embodiment, the temperature of the reaction is from 25°C to 35°C.

[0624] In one embodiment, the present disclosure provides a method for preparing compound 10-F from compound 10-E.

[0625] In one embodiment, the method includes the step of treating compound 10-E with a base and a methylating agent in a suitable solvent and under conditions and for a time effective to form compound 10-F.

[0626] In one embodiment, the methylating agent is selected from dimethyl sulfate, methyl iodide, methyl trifluoromethanesulfonate, methyl tosylate. In one embodiment, the methylating agent is methyl iodide.

[0627] In one embodiment, the base is selected from sodium hydride, potassium tert-butoxide, lithium tert-butoxide, sodium hydroxide, potassium hydroxide, lithium hydroxide, potassium tert-butoxide, sodium tert-amylate, lithium tert-amylate, sodium hexamethyldisilazide, lithium hexamethyldisilazide, potassium hexamethyldisilazide, lithium diisopropylamide, sodium diisopropylamide, potassium diisopropylamide, sodium tert-butoxide. In one embodiment, the base is sodium tert-butoxide.

[0628] In one embodiment, the suitable solvent is selected from ethers (e.g., 2-methyltetrahydrofuran, methyl tert-butyl ether, cyclopentyl methyl ether, tetrahydrofuran), hydrocarbon solvents (e.g., toluene, n-heptane), halogenated solvents (e.g., dichloromethane, 1,2-dichloroethane, chloroform, chlorobenzene), alcohols (e.g., tert-butyl alcohol, tert-amyl alcohol), polar aprotic solvents (e.g., N,N-dimethylacetamide, N,N-dimethylformamide, N-methyl-2-pyrrolidone, dimethyl sulfoxide), water, and combinations thereof. In one embodiment, the solvent is tetrahydrofuran.

[0629] In one embodiment, the temperature of the reaction is from -78°C to 50°C. In one embodiment, the temperature of the reaction is from -10°C to 10°C.

[0630] In one embodiment, the present disclosure provides a method for preparing compound 10-G from compound 10-F.

[0631] In one embodiment, the method includes the step of treating compound 10-F with a deprotecting agent in a suitable solvent and under conditions and for a time effective to form compound 10-G.

[0632] In one embodiment, the deprotecting agent is selected from sodium hydroxide, potassium hydroxide, lithium hydroxide, sulfuric acid, trifluoroacetic acid, phosphoric acid, hydrofluoric acid, hydrochloric acid (concentrated), pyridine hydrogen fluoride, triethylamine hydrogen fluoride, potassium fluoride, sodium fluoride, lithium fluoride, cesium fluoride, tetramethylammonium fluoride, tetrabutylammonium fluoride. In one embodiment, the deprotecting agent is hydrochloric acid (concentrated).

[0633] In one embodiment, the suitable solvent is selected from ethers (e.g., 2-methyltetrahydrofuran, methyl tert-butyl ether, cyclopentyl methyl ether), hydrocarbon solvents (e.g., toluene, n-heptane), halogenated solvents (e.g., dichloromethane, 1,2-dichloroethane, chloroform, chlorobenzene), alcohols (e.g., ethanol, n-propanol, isopropanol, methanol), polar aprotic solvents (e.g., N,N-dimethylacetamide, N,N-dimethylformamide, N-methyl-2-pyrrolidone, dimethyl sulfoxide), water, and combinations thereof. In one embodiment, the solvent is methanol.

[0634] In one embodiment, the temperature of the reaction is from -15°C to 50°C. In one embodiment, the temperature of the reaction is from 10°C to 30°C.

[0635] In one embodiment, the present disclosure provides a method for preparing compound 1-I from a compound selected from 10-A, 10-B, 10-C, 10-C, 10-D, 10-E, 10-F and 10-G, as shown in Scheme 10.

[0636] In one embodiment, the present disclosure provides a method for preparing compound 1 from a compound selected from 1-I, 10-A, 10-B, 10-C, 10-C, 10-D, 10-E, 10-F and 10-G, as shown in Scheme 1 and Scheme 10.

[0637] K. Method for preparing formula 5-E from 5-C

[0638] In one embodiment, the present disclosure provides a method for preparing compound 5-E from 5-C, as shown in Scheme 11. m It is C 1-6 Alkyl, and two R n Parts are linked together to form C 2-4 Alkyl bridge, wherein the bridge is optionally substituted by one to four independently selected C 1-3 In one embodiment, R m In one embodiment, two R nThe moieties are linked together to form a bridge selected from the group consisting of -CH2CH2-, -CH(CH3)CH(CH3)-, -CH2CH(CH3)-, -CH2CH(C6H5)-, -C(CH3)2C(CH3)2-, -CH2CH2CH2-, -CH2CBr2CH2-, -CH2(C=CH)CH2-, -CH2CH(C6H5)CH2-, -CH(CH3)CH2CH(CH3)-, -CH2CH(CH3)CH2-, -CH2C(CH3)2CH2-, -CH2C(CH2CH3)2CH2-, -CH2CH2CH2CH2-, -CH2CH2CH2CH2CH2-, -CH(C6H5)CH(C6H5), -CH2CH(C6H5)CH2-, and -(o-C6H4)-. In one embodiment, the two R n The parts are linked together to form -C(CH3)2C(CH3)2-.

[0639]

[0640] Plan 11

[0641] In one embodiment, the present disclosure provides a method for preparing compound 5-D from compound 5-C.

[0642] In one embodiment, the method includes the step of treating compound 5-C with an acid in a suitable solvent and under conditions and for a time effective to form compound 5-D.

[0643] In one embodiment, the acid is selected from methanesulfonic acid, trifluoroacetic acid, trifluoromethanesulfonic acid, benzenesulfonic acid, camphorsulfonic acid, pyridinium p-toluenesulfonate, sulfuric acid, hydrochloric acid, hydrobromic acid, acetic acid, formic acid, phosphoric acid and oxalic acid. In one embodiment, the acid is p-toluenesulfonic acid.

[0644] In one embodiment, the suitable solvent is selected from halogenated solvents (e.g., dichloromethane, 1,2-dichloroethane, chloroform, chlorobenzene), ethers (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, cyclopentyl methyl ether), aromatic solvents (e.g., benzene, trifluorotoluene, xylene, toluene), polar aprotic solvents (e.g., N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone, dimethyl sulfoxide), hydrocarbon solvents (e.g., cyclohexane, methylcyclohexane, hexane, heptane), and combinations thereof. In one embodiment, the solvent is toluene.

[0645] In one embodiment, the temperature of the reaction is from 0°C to 60°C. In one embodiment, the temperature of the reaction is about 45°C.

[0646] In one embodiment, the present disclosure provides a method for preparing compound 5-E from compound 5-D.

[0647] In one embodiment, the method includes the step of treating compound 5-D with a base in a suitable solvent and under conditions and for a time effective to form compound 5-E.

[0648] In one embodiment, the base is selected from hydroxide bases (e.g., lithium hydroxide, sodium hydroxide, potassium hydroxide, ammonium hydroxide), carbonate bases (e.g., sodium carbonate, potassium carbonate, cesium carbonate), phosphate bases, potassium tert-butoxide, potassium methoxide, and sodium methoxide. In one embodiment, the base is sodium hydroxide.

[0649] In one embodiment, the suitable solvent is selected from 2-methyltetrahydrofuran, halogenated solvents (e.g., dichloromethane, 1,2-dichloroethane, chloroform, chlorobenzene), ethers (e.g., tetrahydrofuran, methyl tert-butyl ether, cyclopentyl methyl ether), alcohols (e.g., ethanol, methanol, n-propanol, isopropanol), aromatic solvents (e.g., benzene, trifluorotoluene, xylene), polar aprotic solvents (e.g., N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone, dimethyl sulfoxide), hydrocarbon solvents (e.g., cyclohexane, methylcyclohexane, hexane, heptane), and combinations thereof. In one embodiment, the solvent is a combination of 2-methyltetrahydrofuran and ethanol.

[0650] In one embodiment, the temperature of the reaction is from 0°C to 60°C. In one embodiment, the temperature of the reaction is about 20°C.

[0651] In one embodiment, the present disclosure provides a method for preparing Compound 1 from a compound selected from 5-C, 5-D, and 5-E, as shown in Scheme 1 and Scheme 11.

[0652] IV. Compounds

[0653] In one embodiment, the present disclosure provides a compound selected from the group consisting of:

[0654] 、 、 、

[0655] and

[0656] in

[0657] Each R n Independently C 1-6 Alkyl, or two R n Parts are linked together to form C 2-4Alkyl bridge, wherein the bridge is optionally substituted by one to four independently selected C 1-3 alkyl and phenyl groups; and R z is halogen or CN.

[0658] In one embodiment, R n It's methyl.

[0659] In one embodiment, both R n The moieties are linked together to form a bridge selected from the group consisting of -CH2CH2-, -CH(CH3)CH(CH3)-, -CH2CH(CH3)-, -CH2CH(C6H5)-, -C(CH3)2C(CH3)2-, -CH2CH2CH2-, -CH2CBr2CH2-, -CH2(C=CH)CH2-, -CH2CH(C6H5)CH2-, -CH(CH3)CH2CH(CH3)-, -CH2CH(CH3)CH2-, -CH2C(CH3)2CH2-, -CH2C(CH2CH3)2CH2-, -CH2CH2CH2CH2-, -CH2CH2CH2CH2CH2-, -CH(C6H5)CH(C6H5), -CH2CH(C6H5)CH2-, and -(o-C6H4)-.

[0660] In one embodiment, both R n The parts are linked together to form -C(CH3)2C(CH3)2-.

[0661] In one embodiment, the present disclosure provides a compound selected from the group consisting of:

[0662] 、 、 、 、 、 、 、 、 and .

[0663] In one embodiment, the present disclosure provides a compound selected from the group consisting of:

[0664] 、 、 and .

[0665] In one embodiment, the present disclosure provides a compound selected from the group consisting of:

[0666] 、 、 and .

[0667] In one embodiment, the present disclosure provides a compound selected from the group consisting of:

[0668] 、 、 、 、 、 and

[0669] in

[0670] X is a halogen, 、 、C(O)2R 1 、-OS(O)2R 2 or -OP(O)(R 2 )2, where R 1 Is H or C 1-6 Alkyl, each R 2 It is C 1-6 Alkyl or C 6-10 Aryl, each R 7 are independently H or C 1-3 Alkyl, wherein each alkyl or aryl group is optionally substituted by one to four halogen or C 1-3 alkyl substituted, m is 1, 2 or 3, and n is 0 or 1; and

[0671] R 4 is a halogen, and R c It is C 1-6 alkyl.

[0672] In one embodiment, X is selected from halogen, COOH, and .

[0673] In one embodiment, the present disclosure provides a compound selected from the group consisting of:

[0674] 、 and .

[0675] In one embodiment, the present disclosure provides a compound selected from the group consisting of:

[0676] 、 、 、 、 、 and .

[0677] V. Examples

[0678] Example 52 was oxidatively cleaved to produce Example 109:

[0679]

[0680] Example 52 (1.0 equivalent, scale factor), ruthenium(III) chloride hydrate (0.1 equivalent), sodium periodate (6.0 equivalents), and 1:1 v / v acetonitrile:water (20 volumes) were added to a reactor. The reaction mixture was stirred at approximately 20°C for approximately 16 hours. The reaction mixture was diluted with ethyl acetate (50 volumes) and 5 wt% aqueous acetic acid (50 volumes). The aqueous layer was extracted with two portions of ethyl acetate (50 volumes), and the combined organic layers were washed with 10 wt% aqueous sodium thiosulfate (15 volumes) and water (15 volumes). The combined organic layers were dried over sodium sulfate, filtered, and concentrated to provide Example 109. 1 H NMR(400MHz, CDCl3) δ 7.40 – 7.26 (m, 5H), 5.78 (q, J = 6.6Hz, 1H), 3.83 (dd, J =14.6, 6.3Hz, 1H), 3.68 (dd, J = 14.5, 6.0Hz, 1H), 2.72 – 2.54 (m, 2H), 2.42 (dd, J = 16.2, 6.7Hz, 1H), 2.12 (s, 3H), 1.59 (d, J = 6.6Hz, 3H), 1.20 (d, J= 6.7Hz, 3H).

[0681] Example 109 was esterified to Example 110:

[0682]

[0683] Example 109 (1.0 equivalent, scale factor), N-hydroxyphthalimide (2.0 equivalents), EDC•HCl (2.0 equivalents), and dichloromethane (10 volumes) were added to a reactor. The reaction mixture was stirred at approximately 20°C for approximately 2 hours. The reaction mixture was diluted with ethyl acetate (50 volumes), and the organic layer was washed with 5 wt% aqueous acetic acid (20 volumes), 3 M aqueous potassium carbonate (20 volumes), and water (20 volumes). The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by chromatography using ethyl acetate, heptane, and acetic acid to provide Example 110. 1H NMR (400MHz, CDCl3) δ7.88 (dt, J = 7.3, 3.6Hz, 2H), 7.80 (dq, J = 6.7, 4.0, 3.6Hz, 2H), 7.39 –7.25 (m, 4H), 5.76 (q, J = 6.6Hz, 1H), 3.74 (qd, J = 14.6, 6.2Hz, 2H), 2.94 (dd, J = 15.2, 4.6Hz, 1H), 2.76 (ddt, J = 22.5, 15.3, 6.9Hz, 2H), 2.10 (d, J= 5.8Hz, 3H), 1.57 (d, J = 6.6Hz, 3H), 1.28 (d, J = 6.6 Hz, 3H).

[0684] Example 110 was boronized to Example 111:

[0685]

[0686] Example 110 (1.0 equivalent, scale factor), bis(catechol) diborate (1.3 equivalents), and dimethylacetamide (20 volumes) were added to a reactor. The reaction mixture was irradiated with a 34W blue LED lamp at approximately 20°C for approximately 3 hours. Methyliminodiacetic acid (5.0 equivalents) was added and the reaction mixture was heated to approximately 50°C to 60°C for approximately 1 hour. The reaction mixture was diluted with ethyl acetate (100 volumes) and water (50 volumes). The aqueous layer was extracted with ethyl acetate (75 volumes), and the combined organic layers were washed with saturated aqueous sodium chloride solution (50 volumes). The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by chromatography using dichloromethane and methanol to provide Example 111. 1 H NMR (400MHz, CDCl3) δ 7.34 (dd, J = 8.3, 5.3Hz, 4H), 7.28 (s, 1H), 5.72 (q, J = 6.6Hz, 1H), 3.84 (dd, J = 16.8, 3.1Hz, 2H), 3.73 – 3.54 (m, 4H), 2.65 (s, 3H), 2.46– 2.36 (m, 1H), 2.08 (s, 3H), 1.55 (d, J = 6.6Hz, 3H), 1.16 (d, J = 6.9Hz, 3H), 0.91 (dd, J = 14.3, 4.9Hz, 1H), 0.62 (dd, J = 14.4, 8.0Hz, 1H).

[0687] Example 84 was oxidatively cleaved and deprotected to Example 112:

[0688]

[0689] To a reactor, Example 84 (1.0 equivalent, scale factor), ruthenium(III) chloride hydrate (0.3 equivalent), sodium periodate (6.0 equivalent), and 1:1 v / v acetonitrile:water (20 volumes) were added. The reaction mixture was stirred at approximately 0°C for approximately 2 hours. The reaction mixture was diluted with ethyl acetate (80 volumes) and 5 wt% aqueous acetic acid (40 volumes). The mixture was filtered through celite and the filtrate was extracted with two portions of ethyl acetate (40 volumes). The combined organic layers were dried over sodium sulfate, filtered, and concentrated. To the crude product was added a 15 v / v% water solution in tetrahydrofuran (10 volumes). Methanesulfonic acid (2 volumes) was added to the solution and stirred at approximately 65°C for approximately 18 hours. The reaction mixture was cooled to approximately 20°C and diluted with ethyl acetate (20 volumes) and water (20 volumes). The aqueous layer was extracted with ethyl acetate (20 mL), and the combined organic layers were dried over sodium sulfate, filtered, and concentrated to dryness. The crude product was purified by chromatography using ethyl acetate and heptane to afford Example 112. 1 H NMR(400MHz, DMSO) δ 12.12 (s, 1H), 9.68 (s, 1H), 8.40 (d, J = 2.1Hz, 1H), 8.19(dd, J = 8.9, 2.1Hz, 1H), 7.51 (s, 2H), 7.48 (d, J = 5.9Hz, 1H), 7.36 (d, J =8.4Hz, 1H), 7.31 (d, J = 2.3Hz, 1H), 7.27 (dd, J = 8.4, 2.3Hz, 1H), 4.75 (d,J = 9.6Hz, 1H), 4.46 (d, J = 9.5Hz, 1H), 3.61 – 3.45 (m, 2H), 2.79 (t, J =6.3Hz, 2H), 2.49 – 2.42 (m, 2H), 2.28 – 2.15 (m, 2H), 2.02 (dd, J = 8.5,3.2Hz, 1H), 1.85 (t, J = 4.6Hz, 1H), 1.77 (dt, J = 9.0, 4.4Hz, 1H), 1.07 (t,J = 7.5Hz, 3H).

[0690] Example 112 was reductively cyclized to Example 113:

[0691]

[0692] Example 112 (1.0 equivalent, scale factor), iron (10.0 equivalents), and acetic acid (10 volumes) were added to a reactor. The mixture was stirred at approximately 70°C for approximately 2 hours. The reaction mixture was cooled to approximately 20°C and sodium triacetoxyborohydride (2.0 equivalents) was added. The mixture was stirred at approximately 20°C for approximately 30 minutes. The reaction mixture was diluted with ethyl acetate (150 volumes) and filtered through celite. The organic layer was washed with two portions of water (40 volumes). The organic layer was dried over sodium sulfate, filtered, and concentrated to dryness under reduced pressure. The crude product was purified by chromatography using ethyl acetate, heptane, and acetic acid to provide Example 113. 1 HNMR (400MHz, DMSO) δ 12.09 (s, 1H), 7.83 (d, J = 8.5Hz, 1H), 7.41 (d, J =2.1Hz, 1H), 7.32 (s, 2H), 7.25 (dd, J = 8.3, 2.1Hz, 2H), 7.15 (d, J = 2.4Hz,1H), 6.79 (d, J = 8.2Hz, 1H), 5.96 – 5.85 (m, 1H), 4.12 – 4.02 (m, 2H), 3.50– 3.40 (m, 2H), 3.31 (d, J = 4.4Hz, 2H), 3.26 (d, J = 3.3Hz, 1H), 3.19 (dd, J= 13.6, 4.6Hz, 1H), 2.71 (q, J = 6.7, 5.9Hz, 2H), 2.22 (dd, J = 15.1, 7.6Hz,1H), 1.83 (d, J = 11.8Hz, 1H), 1.74 (d, J = 24.7Hz, 2H), 1.55 (t, J = 10.3Hz, 1H), 1.07 (d, J = 6.3Hz, 3H).

[0693] Example 9 was oxidatively cleaved to produce Example 114:

[0694]

[0695] Example 9 (1.0 equivalent, scale factor), methylmorpholine N-oxide (1.5 equivalents), tetrahydrofuran (10 volumes), and water (1 volume) were initially added to a reactor and stirred. Once homogeneous, 2,6-lutidine (2.0 equivalents) and osmium tetroxide (0.05 equivalents, 4 wt% in water) were added, and the reaction was stirred at approximately 20°C for approximately 3 days. At this point, sodium periodate (2.5 equivalents) was added and stirred for approximately 6 hours. The reaction was then diluted with ethyl acetate (60 volumes) and water (30 volumes), then charged to a separatory funnel and the resulting layers separated. The aqueous layer was extracted with ethyl acetate (twice, 100 volumes total), and the organic layer was washed with 30 wt% aqueous citric acid (once, 30 volumes), water (once, 30 volumes), and saturated aqueous sodium chloride (once, 30 volumes), then dried over sodium sulfate. The dried organic layer was then filtered and concentrated to yield Example 114. The crude material was used directly to prepare Example 115. 1 H NMR (400MHz, CDCl3) δ 9.51 (d, J =2.5Hz, 1H), 7.70 – 7.58 (m, 5H), 7.39 – 7.27 (m, 8H), 3.61 – 3.47 (m, 2H), 3.45 – 3.36 (m, 1H), 3.34 (s, 3H), 2.55 – 2.43 (m, 2H), 1.89 – 1.68 (m, 4H), 1.01 (s, 12H).

[0696] Example 114 Seyferth-Gilbert homologation to Example 115:

[0697]

[0698] Example 114 (1.0 equivalent, scale factor), potassium carbonate (3.5 equivalents), and methanol (100 volumes) were initially added to the reactor and stirred. Once homogeneous, dimethyl (1-diazooxypropyl)phosphonate (1.5 equivalents, 10 wt% in acetonitrile) was added, followed by stirring at approximately 20°C for approximately 14 hours. At this point, the reaction was diluted with methyl tert-butyl ether (200 volumes) before the mixture was transferred to a separatory funnel. The organic layer was washed with 2.5 wt% aqueous sodium bicarbonate (twice, 200 volumes total) and saturated aqueous sodium chloride (once, 100 volumes) before being dried over sodium sulfate. The dried organic layer was then filtered, concentrated, and purified by column chromatography using ethyl acetate and heptane to provide Example 115. 1H NMR(400MHz, CDCl3) δ 7.71 (dt, J = 8.0, 2.1Hz, 4H), 7.50 – 7.36 (m, 6H), 3.97(dd, J = 6.0, 2.1Hz, 1H), 3.69 (d, J = 5.4Hz, 2H), 3.42 (s, 3H), 2.66 – 2.42(m, 2H), 2.02 – 1.74 (m, 4H), 1.11 (s, 9H).

[0699] Example 115 was methylated to Example 116:

[0700]

[0701] Example 115 (1.0 equivalent, scale factor) and tetrahydrofuran (3.0 volumes) were added to a reactor, and the flask was cooled to approximately -80°C. The resulting solution was then added with n-butyllithium (2.0 equivalents, 2.5 M in hexane) and aged at approximately -80°C for approximately one hour before adding iodomethane (2.0 equivalents) and allowed to warm to approximately 20°C overnight. At this point, triethylamine (1.5 equivalents), methyl tert-butyl ether (50 volumes), and water (50 volumes) were added, and the crude reaction was transferred to a separatory funnel and the phases separated. The aqueous layer was extracted with methyl tert-butyl ether (twice, 150 volumes total), and the organic layer was washed with 0.1 M aqueous hydrochloric acid (50 volumes), water (50 volumes), and saturated aqueous sodium chloride (50 volumes), then dried over sodium sulfate. The dried organic layer was then filtered and concentrated to provide Example 116. The crude material was used directly to prepare Example 117. 1 H NMR(400MHz, CDCl3) δ 7.69 (ddt, J = 6.6, 2.6, 1.6Hz, 5H), 7.48 – 7.34 (m, 5H), 3.90 (dq, J = 6.1, 2.1Hz, 1H), 3.72 – 3.63 (m, 2H), 3.37 (s, 3H), 3.23 (s,3H), 2.57 – 2.39 (m, 2H), 1.88 (dd, J = 7.5, 2.5Hz, 4H) 1.08 (s, 9H).

[0702] Desilylation of Example 116 to Example 117:

[0703]

[0704] Example 116 (1.0 equivalent, scale factor) and tetrahydrofuran (10 volumes) were added to a reactor at approximately 25°C. Tetrabutylammonium fluoride (3.0 equivalents, 1 M in tetrahydrofuran) was then added and stirred for approximately 20 hours. At this point, water (50 volumes) was added before transferring to a separatory funnel and separating the resulting phases. The aqueous layer was extracted with ethyl acetate (twice, 200 volumes total), and the combined organic layers were washed with saturated aqueous sodium chloride (once, 100 volumes) and then dried over sodium sulfate. The dried organic layer was then filtered, concentrated, and purified by column chromatography using ethyl acetate and heptane to provide Example 117. 1 H NMR (400MHz, CDCl3) δ 3.72 (dd, J = 9.0, 2.1Hz, 1H), 3.56 (dd, J = 10.5,4.3Hz, 1H), 3.47 – 3.35 (m, 4H), 2.37 – 2.17 (m, 2H), 2.05 – 1.79 (m, 6H), 1.71 (dq, J = 10.5, 9.2, 8.6Hz, 1H), 1.64 – 1.47 (m, 1H).

[0705] Example 117 was oxidized to Example 118:

[0706]

[0707] Example 117 (1.0 equivalent, scale factor), acetonitrile (18 volumes), iodobenzene diacetate (1.1 equivalents), and tetramethylpiperidinoxide (0.075 equivalents) were initially added to a reactor at approximately 20°C and stirred for approximately 20 hours. The resulting solution then contained Example 118 and was used directly to prepare Example 119. 1 H NMR (400MHz, CDCl3) δ 9.75 (d, J =1.7Hz, 1H), 3.98 – 3.86 (m, 1H), 3.42 (s, 3H), 3.18 (q, J = 8.7Hz, 1H), 2.91– 2.74 (m, 2H), 2.12-1.88 (m, 6H).

[0708] Example 118 was reductively aminated to Example 119:

[0709]

[0710] Example 12 (1.1 equivalents), Example 118 dissolved in acetonitrile (1 equivalent, scale factor), acetonitrile (40 volumes), magnesium sulfate (200 wt%), triethylsilane (2.0 equivalents), and TFA (2 equivalents) were added to a reactor and stirred at approximately 20°C for approximately 3 hours. The reaction mixture was diluted with dichloromethane (250 volumes) and filtered through celite. The organic layer was washed with 2M aqueous potassium carbonate (400 volumes) and water (400 volumes). The organic layer was dried over magnesium sulfate, filtered, and concentrated to dryness. The crude product was purified by chromatography using ethyl acetate and heptane to provide Example 119. 1 H NMR (400 MHz, CHLOROFORM-d) δ 7.75 (d, J = 8.5 Hz, 1H), 7.50 – 7.41 (m, 2H), 7.21 (dd, J = 8.5,2.2 Hz, 1H), 7.13 (d, J = 2.2 Hz, 1H), 6.96 (d, J = 8.1 Hz, 1H), 4.21 – 4.08 (m,2H), 3.93 (s, 3H), 3.75 – 3.62 (m, 2H), 3.48 (s, 3H), 3.36 (d, J = 14.3 Hz,1H), 3.28 (dd, J = 14.9, 8.7 Hz, 1H), 2.86 – 2.77 (m, 2H), 2.64 (pd, J = 8.8,3.3Hz, 1H), 2.34 (p, J = 8.4Hz, 1H), 2.10 – 1.99 (m, 2H), 1.98 – 1.80 (m,7H), 1.83 – 1.64 (m, 1H), 1.62 – 1.51 (m, 1H), 1.36 (t, J = 6.8Hz, 1H).

[0711] Example 120 propynylmagnesium bromide was added to form Example 121 and Example 122:

[0712]

[0713] Example 120 (1.0 equivalent, scale factor) and tetrahydrofuran (18 volumes) were first added to the reactor, and the solution was stirred and cooled to about -80°C. Propylene magnesium bromide (1.5 equivalents, 0.5M in tetrahydrofuran) was added to the contents, stirred at about -80°C for about one hour, and then warmed to about 20°C. The reaction was then treated with 25 wt% aqueous ammonium chloride (30 volumes) and then transferred to a separatory funnel. The resulting layers were separated. The aqueous layer was first extracted with ethyl acetate (twice, 30 volumes in total), and the combined organic layers were washed with saturated aqueous sodium chloride (once, 10 volumes) and then dried over sodium sulfate. The dried organic layer was then filtered, concentrated, and purified by column chromatography using ethyl acetate and heptane to provide Examples 121 and 122. Example 121: 1 H NMR (400MHz, CDCl3) δ 7.74 (d, J = 8.5Hz, 1H), 7.57 (d, J = 1.9Hz, 1H), 7.41 (dd, J = 8.2, 1.9Hz, 1H), 7.17 (dd, J = 8.5,2.3Hz, 1H), 7.09 (d, J = 2.3Hz, 1H), 6.93 (d, J = 8.2Hz, 1H), 4.41 (tt, J =4.6, 2.4Hz, 1H), 4.15 – 4.08 (m, 2H), 3.91 (s, 3H), 3.80 (dd, J = 15.0,2.7Hz, 1H), 3.65 (d, J = 14.2Hz, 1H), δ δ 1.57 – 2.44 (m, 1H), 3.33 (d, J = 14.3 Hz, 1H), 3.23 (dd, J = 14.9, 9.0 Hz, 1H), 3.05 (d, J = 4.4 Hz, 1H), 2.85 – 2.67 (m, 3H), 2.33 (qd, J = 8.6, 6.1 Hz, 1H), 2.13 – 1.97 (m, 2H), 2.01 – 1.86 (m, 2H), 1.91 – 1.72 (m, 1H), 1.74 – 1.62 (m, 1H), 1.59 – 1.47 (m, 1H), 1.35 – 1.26 (m, 4H). 1HNMR (400MHz, chloroform-d) δ 7.73 (d, J = 8.5Hz, 1H), 7.62 (d, J = 2.0Hz, 1H), 7.39 (dd, J = 8.2, 2.0Hz, 1H), 7.18 (dd, J = 8.5, 2.4Hz, 1H), 7.10 (d, J = 2.3Hz,1H), 6.92 (d, J = 8.2Hz, 1H), 4.33 (dq, J = 6.9, 2.2Hz, 1H), 4.19 – 4.06 (m,2H), 3.91 (s, 3H), 3.83 (dd, J = 15.0, 2.6Hz, 1H), 3.63 (d, J = 14.2Hz, 1H), 3.28 (d, J = 14.2Hz, 1H), 3.18 (dd, J = 15.0, 8.7Hz, 1H), 2.78 (q, J = 5.4Hz, 2H), 2.65 – 2.51 (m, 1H), 2.30 (p, J = 8.4Hz, 1H), 2.06 – 1.46 (m, 12H).

[0714] Example 122 was methylated to Example 119:

[0715]

[0716] Example 122 (1 equivalent, scale factor) along with tetrahydrofuran (10 volumes) and iodomethane (5.0 equivalents) were added to a reactor and cooled to approximately 0°C. Sodium tert-butoxide (1.5 equivalents, 2M solution in tetrahydrofuran) was added, and the mixture was stirred at approximately 0°C for approximately 4 hours. At this point, an additional portion of sodium tert-butoxide (0.25 equivalents, 2M solution in tetrahydrofuran) was added at approximately 0°C and stirred for approximately 4 hours. Triethylamine (4.1 equivalents) was added, and the mixture was diluted with methyl tert-butyl ether (30 volumes) and water (20 volumes). The layers were separated, and the aqueous layer was back-extracted with methyl tert-butyl ether (twice, 35 volumes total). The combined organic layers were washed with sodium metabisulfite (5 equivalents) in water (10 volumes) and then with saturated aqueous sodium chloride (20 volumes), then dried over magnesium sulfate, filtered, and concentrated. The crude product was purified by chromatography using ethyl acetate and hexanes to yield Example 119. 1H NMR (400MHz, CDCl3) δ 7.71 (d, J = 8.5Hz, 1H), 7.47 – 7.38 (m, 2H), 7.18 (dd, J = 8.5, 2.3Hz, 1H), 7.10 (d, J = 2.3Hz, 1H), 6.93 (d, J = 8.2Hz,1H), 4.19 – 4.05 (m, 2H), 3.90 (s, 3H), 3.77 – 3.73 (m, 1H), 3.67 – 3.63 (m,1H), , 3.40 – 3.24 (m, 5H), 2.80 – 2.76 (m, 3H), 2.31 (tq, J = 8.7, 5.3Hz,1H), 2.06 – 1.71 (m, 10H), 1.53-1.42 (t, J = 12.7Hz, 1H), 1.28 (t, J = 7.1Hz, 1H).

[0717] Example 119 was saponified to Example 123:

[0718]

[0719] Example 119 (1.0 equivalent, scale factor), tetrahydrofuran (20 volumes), water (20 volumes), and lithium hydroxide (10 equivalents) were initially added to a reactor, and the reaction was heated (50°C) for approximately 5 days. At this point, the reaction was cooled to 20°C before adding 1M aqueous hydrochloric acid (60 volumes). The reaction was transferred to a separatory funnel and the layers separated. The aqueous layer was extracted with ethyl acetate (three times, 60 volumes total), and the combined organic layers were dried over sodium sulfate. The dried organic layer was then filtered, concentrated, and purified by column chromatography using ethyl acetate and heptane to provide Example 123. 1H NMR (400MHz, CDCl3) δ12.18 (s, 1H), 7.73 (d, J = 8.4Hz, 1H), 7.56 – 7.47 (m, 2H), 7.19 (d, J =8.3Hz, 1H), 7.13 – 7.08 (m, 1H), 6.96 (d, J = 8.1Hz, 1H), 4.20 – 4.08 (m,2H), 3.90 (d, J = 7.1Hz, 1H), 3.79-3.68 (m, 2H), 3.47 (s, 3H), 3.36 (d, J =14.2Hz, 1H), 3.32 – 3.21 (m, 1H), 2.79 (q, J = 6.3, 5.5Hz, 2H), 2.61 (q, J =8.4, 7.8Hz, 1H), 2.30 (q, J = 8.5Hz, 1H), 2.06 (d, J = 11.9Hz, 3H), 1.93 (t,J = 8.6Hz, 3H), 1.88 – 1.66 (m, 4H), 1.60 – 1.48 (m, 1H).

[0720] 4-Bromo-1-fluoro-2-nitrobenzene was reacted with Example 11 to give Example 124:

[0721]

[0722] Example 11 (1.0 equivalent, scale factor), 4-bromo-1-fluoro-2-nitrobenzene (1.05 equivalents), and tetrahydrofuran (10 volumes) were added to the reactor. A solution of potassium tert-butoxide in tetrahydrofuran (2.4 equivalents) was added to the reaction mixture over approximately 10 minutes. The reaction mixture was stirred at approximately 20°C for approximately 1 hour. The reaction mixture was quenched with water (10 volumes) and extracted with ethyl acetate (40 volumes). The organic layer was washed with brine (20 volumes), dried over magnesium sulfate, filtered, and concentrated. The crude product was purified by chromatography using ethyl acetate and heptane to provide Example 124. 1H NMR (400MHz, chloroform-d) δ 8.04 (d, J = 2.5Hz, 1H), 7.71 (d, J = 8.4Hz, 1H), 7.62 (dd, J = 8.9,2.5Hz, 1H), 7.20 – 7.09 (m, 2H), 6.96 (d, J = 8.9Hz, 1H), 4.75 (s, 1H), 4.20 (d, J = 8.6Hz, 1H), 4.10 (d, J = 8.5Hz, 1H), 3.50 (s, 3H), 3.43 (s, 3H), 2.87– 2.68 (m, 2H), 2.19 – 2.04 (m, 1H), 2.01 – 1.87 (m, 2H), 1.79 – 1.64 (m,1H).

[0723] The acetal of Example 124 was hydrolyzed and reductively cyclized to Example 126:

[0724]

[0725] To a vial, Example 124 (1.0 equivalent, scale factor), water (2 volumes), and tetrahydrofuran (10 volumes) were added. Methanesulfonic acid (4 equivalents) was added to the solution and stirred at approximately 50°C for approximately 48 hours. The reaction mixture was cooled to approximately 20°C and saturated aqueous sodium bicarbonate (10 volumes) was added. The crude reaction mixture was then extracted with ethyl acetate (30 volumes). The organic layer was washed with water (15 volumes). The organic layer was dried over magnesium sulfate, filtered, and concentrated to dryness. The crude product (Example 125) was used directly in the next step. To a vial, Example 125 (1.0 equivalent, scale factor), iron (10 equivalents), and acetic acid (10 volumes) were added. The mixture was stirred at approximately 50°C for approximately 18 hours. The reaction mixture was cooled to approximately 20°C and diluted with dichloromethane (20 volumes). The reaction mixture was then filtered through a pad of Celite. Sodium triacetoxyborohydride (1.2 equivalents) was then added to the solution and stirred at approximately 20°C for approximately 3 hours. The reaction mixture was quenched with saturated aqueous sodium bicarbonate (10 volumes) and the resulting solution was extracted with dichloromethane (100 volumes). The organic layer was dried over magnesium sulfate, filtered, and concentrated to dryness. The crude product was purified by chromatography using ethyl acetate and heptane to provide Example 126. 1H NMR (400MHz, chloroform-d) δ 7.85 (d, J = 8.4Hz, 1H), 7.19 (dd, J = 8.5, 2.4Hz, 1H), 7.10 (d, J = 2.3Hz, 1H), 6.86 – 6.74 (m, 3H), 4.14 (q, J = 12.2Hz, 2H), 3.86(s, 1H), 3.50 (d, J = 13.7Hz, 1H), 3.33 (d, J = 13.6Hz, 1H), 2.75 (t, J =6.3Hz, 2H), 1.93-1.53 ​​(m, 4H).

[0726] Example 126 and Example 11 were reductively aminated to Example 127:

[0727]

[0728] To a vial was added Example 126 (1 equivalent, scale factor), Example 11 (1.2 equivalents, 6.5 wt% solution in acetonitrile), trifluoroacetic acid (0.5 equivalents), triethylsilane (2.0 equivalents), and acetonitrile (10 volumes) and stirred at approximately 20°C for approximately 24 hours. The mixture was then concentrated to dryness and purified directly by chromatography using ethyl acetate and heptane to provide Example 127. 1 H NMR (400MHz, chloroform-d) δ 7.72 (d, J = 8.5Hz, 1H), 7.19 (dd, J =8.5, 2.4Hz, 1H), 7.09 (d, J = 2.3Hz, 1H), 6.92 (d, J = 1.3Hz, 1H), 6.77 (d, J= 1.5Hz, 2H), 5.64 – 5.50 (m, 1H), 5.29 – 5.19 (m, 2H), 4.10 – 3.97 (m, 2H), 3.79 – 3.68 (m, 2H), 3.50 (t, J = 8.4Hz, 1H), 3.42 (s, 3H), 3.25 (d, J =14.3Hz, 1H), 3.06 (dd, J = 15.0, 9.8Hz, 1H), 2.82 – 2.73 (m, 2H), 2.49 (q, J= 8.7Hz, 1H), 2.05-1.57 (m, 8H), 1.45 (t, J = 12.5Hz, 1H).

[0729] Example 127 was carboxylated to Example 60:

[0730]

[0731] To a vial was added Example 127 (1.0 equiv, scale factor), palladium acetate (0.1 equiv), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0.1 equiv), dicyclohexylcarbodiimide (0.2 equiv, 1.0 M in dichloromethane), dimethylformamide (20 volumes), formic acid (3.5 equiv), and triethylamine (2.0 equiv), which was then sealed and heated to approximately 90° C. for approximately 18 hours. The reaction was cooled to approximately 20° C., then concentrated to dryness and purified directly by chromatography using ethyl acetate and heptane to provide Example 60. 1 H NMR (400MHz, chloroform-d) δ 7.71 (d, J = 8.5Hz,1H), 7.54 – 7.42 (m, 2H), 7.17 (dd, J = 8.5, 2.3Hz, 1H), 7.08 (d, J = 2.4Hz,1H), 6.93 (d, J = 8.2Hz, 1H), 5.64 – 5.51 (m, 1H), 5.26 – 5.15 (m, 2H), 4.18– 4.05 (m, 2H), 3.76 (dd, J = 14.8, 3.3Hz, 1H), 3.67 (d, J = 14.4Hz, 1H), 3.49 (t, J = 8.1Hz, 1H), 3.39 – 3.27 (m, 4H), 3.19 (dd, J = 14.9, 9.4Hz, 1H), 2.87 – 2.68 (m, 2H), 2.54 (tq, J = 11.8, 4.7, 3.0Hz, 1H), 2.17 – 1.96 (m,3H), 1.97 – 1.73 (m, 3H), 1.73 – 1.41 (m, 3H).

[0732] 4-Fluoro-3-nitrobenzonitrile was reacted with Example 11 to give Example 128:

[0733]

[0734] To a vial, Example 11 (1.0 equivalent, scale factor), 4-fluoro-3-nitrobenzonitrile (1.2 equivalents), and tetrahydrofuran (10 volumes) were added, and the vial was cooled to approximately -40°C. A solution of potassium tert-butoxide in tetrahydrofuran (1.2 equivalents) was added to the reaction mixture over approximately 10 minutes. The reaction mixture was stirred at approximately -40°C for approximately 1 hour. The reaction mixture was warmed to approximately 20°C, quenched with water (10 volumes), and extracted with ethyl acetate (40 volumes). The organic layer was washed with brine (20 volumes), dried over magnesium sulfate, filtered, and concentrated. The crude product was purified by chromatography using ethyl acetate and heptane to provide Example 128. 1 H NMR (400 MHz, CHLOROFORM-d) δ 8.12 (d, J = 2.1 Hz, 1H), 7.72 (dd, J = 8.7, 2.2 Hz, 1H), 7.61 – 7.54 (m, 1H), 7.12 – 7.01 (m, 3H), 4.62 (s,1H), 4.24 – 4.09 (m, 2H), 3.40 (s, 3H), 3.34 (s, 3H), 2.68 (td, J = 15.8,14.2, 7.5 Hz, 2H), 2.04 (t, J = 10.5 Hz, 1H), 1.86 (t, J = 9.0 Hz, 2H), 1.47 (s,1H).

[0735] The acetal of Example 128 was hydrolyzed and reductively cyclized to Example 130:

[0736]

[0737] To a vial, Example 128 (1.0 equivalent, scale factor), water (2 volumes), and tetrahydrofuran (10 volumes) were added. Methanesulfonic acid (4 equivalents) was added to the solution and stirred at approximately 50°C for approximately 48 hours. The reaction mixture was cooled to approximately 20°C and saturated aqueous sodium bicarbonate (10 volumes) was added. The crude reaction mixture was then extracted with ethyl acetate (30 volumes). The organic layer was washed with water (15 volumes). The organic layer was dried over magnesium sulfate, filtered, and concentrated to dryness. The crude product (Example 129) was used directly in the next step.

[0738] To a vial was added Example 129 (1.0 equivalent, scale factor), iron (10 equivalents), and acetic acid (10 volumes). The mixture was stirred at approximately 50°C for approximately 18 hours. The reaction mixture was cooled to approximately 20°C and diluted with dichloromethane (20 volumes), then filtered through a pad of Celite. Sodium triacetoxyborohydride (1.2 equivalents) was then added to the solution and stirred at approximately 20°C for approximately 3 hours. The reaction mixture was quenched with saturated aqueous sodium bicarbonate (10 volumes), and the resulting solution was extracted with dichloromethane (100 volumes). The organic layer was dried over magnesium sulfate, filtered, and concentrated to dryness. The crude product was purified by chromatography using ethyl acetate and heptane to provide Example 130. 1 H NMR (400MHz, chloroform-d) δ 7.83(d, J = 8.5Hz, 1H), 7.19 (dd, J = 8.5, 2.4Hz, 1H), 7.10 (d, J = 2.3Hz, 1H), 7.03 (dd, J = 8.2, 1.9Hz, 1H), 6.97 – 6.88 (m, 2H), 4.02 (s, 1H), 3.51 (d, J= 13.7Hz, 1H), 3.36 (d, J = 13.8Hz, 1H), 2.76 (dd, J = 7.3, 5.3Hz, 2H), 1.97– 1.72 (m, 3H), 1.66 (ddd, J = 12.2, 9.6, 2.7Hz, 1H), 1.34 – 1.21 (m, 2H).

[0739] Example 130 and Example 11 were reductively aminated to Example 131:

[0740]

[0741] To a vial was added Example 130 (1 equivalent, scale factor), Example 11 (1.2 equivalents, 6.5 wt% solution in acetonitrile), trifluoroacetic acid (0.5 equivalents), triethylsilane (2.0 equivalents), and acetonitrile (10 volumes) and stirred at approximately 20°C for approximately 24 hours. The mixture was then concentrated to dryness and purified directly by chromatography using ethyl acetate and heptane to provide Example 131. 1H NMR (400MHz, chloroform-d) δ 7.62 (d, J = 8.5Hz, 1H), 7.10 (dd, J =8.5, 2.3Hz, 1H), 7.00 (dd, J = 6.0, 2.1Hz, 2H), 6.93 – 6.80 (m, 2H), 5.57 –5.40 (m, 1H), 5.25 – 5.07 (m, 2H), 4.01 (s, 2H), 3.79 – 3.53 (m, 2H), 3.49 –3.07 (m, 5H), 3.06 – 2.83 (m, 1H), 2.78 – 2.60 (m, 2H), 2.45 – 2.26 (m, 1H),2.05 – 1.28 (m, 8H), 0.86 – 0.74 (m, 1H).

[0742] Example 131 nitrile was hydrolyzed to Example 60:

[0743]

[0744] Example 131 (1 equivalent, scale factor), methanol (40 volumes), water (4 volumes), and potassium hydroxide (10 equivalents) were initially added to a vial and stirred at approximately 110°C for approximately 48 hours. Aqueous HCl (1.0 M, 20 volumes) was then added to the reaction mixture and heated to approximately 100°C for approximately 2 hours before being cooled to approximately 20°C. The reaction was then concentrated and purified directly by chromatography using ethyl acetate and heptane to provide Example 60.

[0745] The acetaldehyde of Example 132 was formed and the acetate was hydrolyzed to Example 133:

[0746]

[0747] To a reactor equipped with a Dean-Stark apparatus was added Example 132 (1.0 equivalent, scale factor), pinacol (2.0 equivalents), p-toluenesulfonic acid (0.05 equivalents), and toluene (15 volumes). The reaction mixture was heated to approximately 45°C and a partial vacuum was applied. The mixture was stirred for approximately 24 hours. The mixture was concentrated to dryness, and the crude material was diluted with MeTHF (10 volumes). A 1N aqueous solution of NaOH (3 equivalents) and EtOH (4 volumes) was added, and the resulting biphasic mixture was stirred for approximately 5 hours. The layers were separated, and the organic layer was washed with an aqueous NaCl solution (15 volumes). The organic layer was concentrated to dryness, and the resulting residue was dissolved in EtOH (21 volumes). Water (37 volumes) was added dropwise. The resulting slurry was filtered, rinsed with water (10 volumes), and dried to yield Example 133.1 H NMR (400MHz, CDCl3): δ 7.37 (d, J = 8.4Hz, 1H), 7.10 (d, J= 8.9Hz, 2H), 5.27 (s, 1H), 3.89 (d, J = 11.3Hz, 1H), 3.56 (d, J = 11.4Hz, 1H), 2.74 (q, J = 7.1, 6.1Hz, 2H), 2.02 – 1.87 (m, 3H), 1.82 – 1.71 (m, 1H), 1.65 – 1.50 (m, 1H), 1.28 – 1.10 (m, 12H).

[0748] 4-Bromo-1-fluoro-2-nitrobenzene was reacted with Example 133 to give Example 134:

[0749]

[0750] Example 133 and tetrahydrofuran (10 volumes) were added to a reactor and cooled to approximately 0°C. Potassium tert-butoxide (2.5 equivalents) in tetrahydrofuran was added over approximately 20 minutes, followed by 4-bromo-1-fluoro-2-nitrobenzene over approximately 20 minutes. The reaction mixture was stirred at 0°C for approximately 2 hours and then quenched with water (5 volumes). The mixture was concentrated and then dissolved in ethyl acetate (10 volumes). The organic layer was washed with saturated sodium chloride solution (5 volumes). The phases were separated, and the aqueous layer was extracted twice with ethyl acetate (10 volumes). The combined organic layers were dried over magnesium sulfate, filtered, and concentrated. The crude product was purified by silica gel chromatography using ethyl acetate and heptane to provide Example 134. 1 H NMR (400 MHz, CHLOROFORM-d) δ 7.97 (d, J =2.4 Hz, 1H), 7.68 – 7.53 (m, 2H), 7.12 (d, J = 7.2 Hz, 2H), 6.96 (d, J = 9.0 Hz,1H), 5.39 (s, 1H), 4.38 – 4.17 (m, 2H), 2.78 (t, J = 6.3 Hz, 2H), 2.26 – 1.71 (m, 4H), 1.40 – 0.85 (m, 12H).

[0751] Example 134 pinacol was hydrolyzed to Example 125:

[0752]

[0753] Example 134 and tetrahydrofuran (10 volumes) were added to a reactor, followed by water (2 volumes) and MSA (4 equivalents). The reaction mixture was stirred at reflux for approximately 17 hours and then quenched with saturated aqueous NaHCO₃ (7 volumes) at 20°C. The mixture was extracted with ethyl acetate (10 volumes). The phases were separated, and the aqueous layer was extracted with ethyl acetate (10 volumes). The combined organic layers were washed with water (10 volumes), dried over magnesium sulfate, filtered, and concentrated. The crude product was purified by silica gel chromatography using ethyl acetate and heptane to provide Example 125. 1 H NMR (400MHz, chloroform-d) δ 9.56 (d, J= 0.8Hz, 1H), 8.01 (d, J = 2.5Hz, 1H), 7.64 (dd, J = 8.9, 2.5Hz, 1H), 7.26 –6.98 (m, 4H), 4.52 (d, J = 9.0Hz, 1H), 4.21 (dd, J = 8.9, 0.9Hz, 1H), 2.89 (td, J = 7.1, 6.5, 3.4Hz, 2H), 2.38 – 2.14 (m, 2H), 2.06 – 1.88 (m, 2H).

[0754] 4-Fluoro-3-nitrobenzonitrile was reacted with Example 133 to give Example 135:

[0755]

[0756] Example 133 and tetrahydrofuran (10 volumes) were added to a reactor and cooled to approximately -20°C. Potassium tert-butoxide (2.5 equivalents) in tetrahydrofuran was added over approximately 40 minutes, followed by 4-fluoro-3-nitrobenzonitrile over approximately 10 minutes. The reaction mixture was stirred at 0°C for approximately 2 hours and then quenched with water (5 volumes). The mixture was concentrated and then dissolved in ethyl acetate (10 volumes). The organic layer was washed with saturated sodium chloride solution (5 volumes). The phases were separated, and the aqueous layer was extracted twice with ethyl acetate (10 volumes). The combined organic layers were dried over magnesium sulfate, filtered, and concentrated. The crude product was purified by silica gel chromatography using ethyl acetate and heptane to provide Example 135. 1H NMR (400 MHz, CHLOROFORM-d) δ 7.97 (d, J = 2.1 Hz, 1H), 7.61 (dd, J = 8.8, 2.1 Hz, 1H), 7.36 (d, J = 8.3 Hz, 1H), 7.04 – 6.89 (m, 3H), 5.19 (s, 1H), 4.24 – 4.11 (m, 2H), 2.61 (t, J = 6.3 Hz, 2H),2.10 – 1.52 (m, 4H), 1.20 – 0.68 (m, 12H).

[0757] Example 135 pinacol was hydrolyzed to Example 129:

[0758]

[0759] Example 135 and tetrahydrofuran (10 volumes) were added to a reactor, followed by water (2 volumes) and MSA (4 equivalents). The reaction mixture was stirred at reflux for approximately 17 hours and then quenched with saturated aqueous NaHCO₃ (7 volumes) at 20°C. The mixture was extracted with ethyl acetate (10 volumes). The phases were separated, and the aqueous layer was extracted with ethyl acetate (10 volumes). The combined organic layers were washed with water (10 volumes), dried over magnesium sulfate, filtered, and concentrated. The crude product was purified by silica gel chromatography using ethyl acetate and heptane to provide Example 129. 1 H NMR (400MHz, chloroform-d) δ 9.53 (d, J= 0.8Hz, 1H), 8.19 (d, J = 2.1Hz, 1H), 7.83 (dd, J = 8.8, 2.1Hz, 1H), 7.27 –7.04 (m, 4H), 4.62 (d, J = 9.1Hz, 1H), 4.29 (dd, J = 9.1, 1.0Hz, 1H), 2.97 –2.83 (m, 2H), 2.40 – 1.88 (m, 4H).

[0760] Example 51 and Example 72 amide were coupled and deprotected to give Example 136:

[0761] Step 1:

[0762]

[0763] Step 2:

[0764]

[0765] To an inert reaction vessel, add Example 51 (1.0 equivalent, scale factor), Example 72 (1.06 equivalents), 4-dimethylaminopyridine (1.0 equivalent), and acetonitrile (15 volumes). To this mixture, add 1-methylimidazole (3.0 equivalents) and N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (1.3 equivalents), and stir the contents at approximately 20°C for approximately 20 hours. Add dichloromethane (15 volumes) and 10% (w / w) aqueous citric acid (12 volumes) to the vessel, and separate the layers. Wash the aqueous layer with dichloromethane (15 volumes), and separate the layers. Concentrate the combined organic layers under reduced pressure, then add 2-methyltetrahydrofuran (20 volumes). Stir the contents at approximately 60°C, then add 10% (w / w) aqueous citric acid (12 volumes). Stir the contents at approximately 60°C for approximately 48 hours, then separate the layers. The aqueous layer was washed with 2-methyltetrahydrofuran (10 volumes) and the layers were separated. The combined organic layers were dried over sodium sulfate and concentrated. The crude product was purified by chromatography using ethyl acetate and hexanes to afford Example 136. 1 H NMR (400 MHz, CHLOROFORM-d) δ 7.72 (s, 1H), 5.80– 5.60 (m, 1H), 5.15 – 4.99 (m, 2H), 3.98 (s, 3H), 3.73 (s, 3H), 3.50 (dd, J = 14.3, 5.0 Hz, 1H), 3.22 (dd, J = 14.3, 7.2 Hz, 1H), 2.38 – 2.07 (m, 3H), 1.13 (d, J = 6.7 Hz, 3H).

[0766] Example 60 and Example 136 amide were coupled to give Example 73:

[0767]

[0768] To an inert reaction vessel, Example 60 (1.0 equivalent, scale factor), Example 136 (1.06 equivalents), 4-dimethylaminopyridine (1.0 equivalent), and acetonitrile (10 volumes) were added. To this mixture, 1-methylimidazole (3.0 equivalents) and N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (1.3 equivalents) were added, and the contents were stirred at approximately 20°C for approximately 24 hours. Ethyl acetate (10 volumes) and 10% (w / w) aqueous citric acid (10 volumes) were added to the vessel, and the layers were separated. The crude product was further processed to Compound 1 using ring-closing metathesis from Example 73 to Compound 1, matching the authentic material.

[0769] Example 137 was esterified to Example 138:

[0770]

[0771] To an inert reaction vessel was added Example 137 (1.0 equivalents, scale factor), ethanol (5 volumes), and sulfuric acid (0.02 volumes). The resulting mixture was then warmed to approximately 80°C and stirred overnight. The reaction mixture was concentrated to dryness in vacuo. The residue was then diluted with methyl tert-butyl ether (2 volumes), followed by the addition of saturated aqueous sodium bicarbonate (2 volumes). The layers were separated, the aqueous layer back-extracted with methyl tert-butyl ether (2 volumes), and the combined organic layers were washed with 15 wt% aqueous sodium chloride (2 volumes). The layers were separated, and the organic layer was dried over sodium sulfate. The desiccant was removed by filtration, and the filtrate was concentrated to provide Example 138. 1 H NMR (400 MHz, CHLOROFORM-d) δ 4.20 – 4.09 (m, 4H), 3.41–3.36 (m, 2H), 2.19–2.16 (m, 4H), 1.59 – 1.18 (m, 6H)

[0772] Example 138 was enzymatically hydrolyzed to Example 139:

[0773]

[0774] Example 138 (1.0 equivalent, scale factor), acetone (4 volumes), 0.1 M pH 7 phosphate buffer (20 volumes), and Lipozyme CALB L (0.05 volumes) were added to a reactor. The reaction mixture was warmed to approximately 30°C, and the pH was maintained between 7.0 and 7.5 by adding 1N NaOH. After approximately 4 hours, the reaction mixture was diluted with dichloromethane (10 volumes) and acidified with 1M aqueous HCl (5 volumes). The layers were separated, and the aqueous layer was back-extracted with dichloromethane (10 volumes). The organic layers were combined and dried over sodium sulfate. The desiccant was removed by filtration, and the filtrate was then concentrated to dryness in vacuo to provide Example 139. 1 H NMR (400MHz, DMSO-d6) δ 12.31 (s, 1H), 4.07 (q, J = 7.1Hz, 2H), 3.30 – 3.16 (m, 2H), 2.15 – 1.94 (m, 4H), 1.17 (t, J = 7.1Hz, 3H).

[0775] Example 139 was reduced to Example 140:

[0776]

[0777] Borane dimethyl sulfide complex (1.5 equiv) was added to 2-methyltetrahydrofuran (10 volumes) and the resulting solution was cooled to approximately 0°C. A solution of Example 139 (1.0 equiv, scale factor) in 2-methyltetrahydrofuran (5 volumes) was then added at a rate to maintain the internal temperature below approximately 10°C. Once the addition was complete, the reaction mixture was warmed to approximately room temperature and stirred for approximately 2 hours. The reaction mixture was quenched by the slow addition of methanol (10 volumes). The resulting solution was concentrated to dryness and diluted with methanol (10 volumes). The solution was concentrated to dryness and diluted with methanol (10 volumes). The solution was concentrated to dryness to provide Example 140. 1 H NMR (400 MHz, CHLOROFORM-d) δ 4.14 (qd, J = 7.1, 0.7 Hz, 2H), 3.63 (qd, J = 10.9, 6.2 Hz, 2H), 2.95 – 2.87 (m, 1H), 2.77 – 2.66 (m, 1H), 2.28 – 2.12 (m, 1H), 2.12 – 2.02 (m, 1H), 2.00 – 1.84 (m, 2H), 1.72 (ddt, J =11.1, 10.1, 9.0 Hz, 1H), 1.25 (t, J = 7.2 Hz, 3H).

[0778] Silyl protection of Example 140 gave Example 141:

[0779]

[0780] To an inert reaction vessel, Example 140 (1.0 equivalent, scale factor) and dichloromethane (10 volumes) were added, and the mixture was cooled to approximately 0°C. Imidazole (2.5 equivalents) and tert-butyldimethylsilyl chloride (1.2 equivalents) were added to this mixture, and the contents were stirred for approximately 17 hours while warming to approximately 20°C. Dichloromethane (10 volumes) and water (10 volumes) were added to the vessel, and the layers were separated. Water (10 volumes) was added to the organic layer, and the layers were separated. The organic layer was dried over sodium sulfate and concentrated to provide Example 141. 1H NMR (400 MHz, CHLOROFORM-d) δ 4.11 (q, J =7.1 Hz, 2H), 3.65 – 3.52 (m, 2H), 2.95 (qd, J = 8.8, 0.9 Hz, 1H), 2.78 – 2.61(m, 1H), 2.21 – 1.98 (m, 2H), 1.89 – 1.77 (m, 2H), 1.24 (t, J = 7.1 Hz, 3H), 0.90 (s, 9H), 0.05 (s, 6H).

[0781] Example 141 Kulinkovich cyclopropanation to Example 142:

[0782]

[0783] To an inert reaction vessel, Example 141 (1.0 equivalent, scale factor) and THF (10 volumes) were added, and the mixture was cooled to approximately 0°C. Titanium (IV) isopropoxide (1.0 equivalent) was added to this mixture, followed by a 40 wt% solution of ethylmagnesium bromide in 2-MeTHF (3.0 equivalents), and the contents were stirred for approximately 17 hours while warming to approximately 20°C. A 20 wt% aqueous solution of citric acid (6.5 volumes) and a 25 wt% aqueous solution of ammonium chloride (6.5 volumes) were combined and added to the vessel, and the layers were separated. MTBE (22 volumes) was added to the aqueous layer, and the layers were separated. A 15 wt% aqueous solution of sodium chloride (6.5 volumes) was added to the combined organic layers, and the layers were separated. The organic layer was dried over sodium sulfate and concentrated to provide Example 142. 1 H NMR (400 MHz, CHLOROFORM-d) δ 3.70 (dd, J = 9.7, 4.5 Hz, 1H), 3.45 (t, J =9.9 Hz, 1H), 2.61 – 2.51 (m, 1H), 2.38 – 2.24 (m, 1H), 1.81 – 1.66 (m, 2H),1.57 – 1.41 (m, 1H), 1.23 (qd, J = 10.0, 8.4 Hz, 1H), 0.90 (s, 9H), 0.74 (ddd,J = 10.8, 6.3, 5.1 Hz, 1H), 0.66 – 0.52 (m, 2H), 0.37 (ddd, J = 10.4, 6.7,5.1Hz, 1H), 0.09 (d, J = 1.1Hz, 6H).

[0784] Example 143 was protected as Example 144:

[0785]

[0786] Example 143 (1.0 equivalents, scale factor) and dichloromethane (8 volumes) were added to the reactor. The resulting mixture was cooled to approximately 0°C and imidazole (2.5 equivalents) and tert-butyldimethylsilyl chloride (1.2 equivalents) were added. The reaction mixture was stirred for approximately 12 hours, after which water (10 volumes) and dichloromethane (8 volumes) were added. The layers were separated, and the organic layer was washed with water (10 volumes). The layers were separated, dried over sodium sulfate, filtered, and concentrated to provide Example 144. 1 HNMR (400MHz, CDCl3): δ 3.16 (s, 3H), 3.59 – 3.49 (m, 2H), 2.96 – 2.92 (m,1H), 2.70 – 2.59 (m, 1H), 2.13 – 1.94 (m, 2H), 1.86 – 1.71 (m, 2H), 0.85 (s,9H), 0.01 (s, 6H)

[0787] Example 144 Kulinkovich cyclopropanation to Example 142:

[0788]

[0789] Example 144 (1.0 equivalent, scale factor) and tetrahydrofuran (11 volumes) were added to a reactor and cooled to approximately 0°C. Titanium (IV) isopropoxide (1.0 equivalent) was added to the mixture, followed by the addition of a 40 wt% solution of ethylmagnesium bromide in 2-methyltetrahydrofuran (3.0 equivalents) at approximately 0°C over approximately 1 hour. The mixture was warmed to approximately 22°C and quenched with a 25 wt% aqueous ammonium chloride solution (6 volumes) followed by a 20 wt% citric acid solution (6 volumes). The aqueous layer was removed and back-extracted with methyl tert-butyl ether (22 volumes). The organic layers were combined, washed with a 15 wt% aqueous sodium chloride solution (7 volumes), dried over sodium sulfate, filtered, and concentrated to provide Example 142. 1H NMR (400 MHz, CHLOROFORM-d) δ 3.70 (dd, J = 9.7,4.5 Hz, 1H), 3.45 (t, J = 9.9 Hz, 1H), 2.61 – 2.51 (m, 1H), 2.38 – 2.24 (m,1H), 1.81 – 1.66 (m, 2H), 1.57 – 1.41 (m, 1H), 1.23 (qd, J = 10.0, 8.4 Hz,1H), 0.90 (s, 9H), 0.74 (ddd, J = 10.8, 6.3, 5.1 Hz, 1H), 0.66 – 0.52 (m, 2H),0.37 (ddd, J = 10.4, 6.7, 5.1 Hz, 1H), 0.09 (d, J = 1.1Hz, 6H).

[0790] Example 145 was synthesized from Example 142:

[0791]

[0792] A solution of Example 142 (1.0 equivalent, scale factor) in dichloromethane (8 volumes) was added to the reactor and cooled to approximately 0°C. N-Bromosuccinimide (1.05 equivalents) was added in one portion and stirred at approximately 0°C for approximately 1.5 hours. Triethylamine (2.0 equivalents) was added at 0°C and stirred at approximately 0°C for approximately 2.5 hours. The reaction mixture was quenched with 20 wt% citric acid solution (6 volumes) and warmed to approximately 20°C. The layers were separated, and the organic layer was washed with 5 wt% sodium bicarbonate solution (8 volumes) followed by 15 wt% aqueous sodium chloride solution (15 volumes), dried over magnesium sulfate, filtered, and concentrated to provide Example 145. 1 H NMR (400MHz, CDCl3) δ 6.27 – 6.36 (m, 1H), 6.22 – 6.13 (m, 1H), 5.75 –5.70 (m, 1H), 3.61 – 3.51 (m, 2H), 3.43 – 3.33 (m, 1H), 2.66 – 2.55 (m, 1H), 2.18 – 2.07 (m, 1H), 2.00 – 1.91 (m, 1H), 1.85 – 1.76 (m, 2H), 0.85 (s, 9H), 0.01 (s, 6H).

[0793] Example 145 ketoreductase was reduced to Example 146:

[0794]

[0795] To a reaction vessel were added NAD (1.0 wt%), GDH (2.0 wt%), glucose monohydrate (1.2 equivalents), 0.1 M aqueous citrate buffer at pH 6.2 (17 volumes), and Example 145 (1.0 equivalent) in DMSO (2 volumes). CRED-A151 (50 wt%) was added to this mixture, and the contents were stirred at approximately 30°C for approximately 14 hours. Additional NAD (0.2 wt%), GDH (0.4 wt%), and CRED-A151 (10 wt%) were added to the vessel, and the contents were stirred for approximately 9 hours. 1 M aqueous citrate buffer at pH 3.6 was added to the vessel to adjust the pH to approximately 4.5, and the contents were then cooled to approximately 4°C. Saturated aqueous sodium chloride (20 volumes) and MTBE (120 volumes) were added to the vessel, and the layers were separated. The organic layer was filtered through celite. Saturated aqueous sodium chloride (20 volumes) was added to the organic layer and the layers were separated; this process was repeated once more. The organic layer was dried over magnesium sulfate and concentrated to afford Example 146. 1 HNMR (400 MHz, CHLOROFORM-d) δ 5.72 (ddd, J = 17.0, 10.4, 6.5 Hz, 1H), 5.24 (ddd, J =17.1, 2.0, 1.2 Hz, 1H), 5.07 (ddd, J = 10.4, 1.9, 1.0 Hz, 1H), 3.94 – 3.81 (m,2H), 3.70 (dd, J = 9.6, 4.4 Hz, 1H), 3.38 (dd, J = 10.7, 9.6 Hz, 1H), 2.39 –2.22 (m, 1H), 2.09 – 1.95 (m, 1H), 1.91 – 1.75 (m, 2H), 1.70 – 1.41 (m, 2H), 0.91 (s, 9H), 0.09 (s, 6H).

[0796] Example 146 was methylated to Example 147:

[0797]

[0798] To an inert reaction vessel, Example 146 (1.0 equivalent, scale factor) and THF (10 volumes) were added, and the mixture was cooled to approximately 0°C. Sodium tert-butoxide (3.0 equivalents) and iodomethane (6.0 equivalents) were added to the mixture, and the contents were stirred at approximately 0°C for approximately 2 hours. Triethylamine (7.6 equivalents) was added to the vessel, and the contents were stirred at approximately 0°C for approximately 1 hour. MTBE (20 volumes) and water (20 volumes) were added to the vessel, and the layers were separated. MTBE (20 volumes) was added to the aqueous layer, and the layers were separated. 15 wt% aqueous sodium chloride solution (20 volumes) was added to the combined organic layers, and the layers were separated. The organic layer was dried over magnesium sulfate and concentrated to provide Example 147. 1 H NMR (400MHz, chloroform-d) δ5.61 (ddd, J = 16.6, 10.8, 7.8Hz, 1H), 5.23 – 5.13 (m, 2H), 3.64 (dd, J =10.2, 4.9Hz, 1H), 3.52 (dd, J = 10.2, 6.8Hz, 1H), 3.44 (t, J = 7.5Hz, 1H), 3.26 (s, 3H), 2.38 – 2.24 (m, 1H), 2.22 – 2.10 (m, 1H), 1.94 – 1.81 (m, 1H), 1.84 – 1.72 (m, 1H), 1.72 – 1.58 (m, 2H), 0.90 (s, 9H), 0.04 (s, 6H).

[0799] Example 147 was deprotected to Example 148:

[0800]

[0801] To an inert reaction vessel, Example 147 (1.0 equivalent, scale factor) and methanol (10 volumes) were added. Concentrated HCl (3.0 equivalents) was added to the mixture, and the contents were stirred at approximately 22°C for approximately 3 hours. Saturated aqueous sodium bicarbonate (12 volumes) and dichloromethane (12 volumes) were added to the vessel, and the layers were separated. Dichloromethane (12 volumes) was added to the aqueous layer, and the layers were separated; this process was repeated once more. The combined organic layers were dried over magnesium sulfate and concentrated to provide Example 148. 1H NMR (400 MHz, CHLOROFORM-d) δ 5.53 (ddd, J = 16.4, 11.2, 8.2 Hz, 1H), 5.35 – 5.21 (m, 2H), 3.61 (dd, J = 10.4, 4.3 Hz, 1H), 3.44 – 3.34 (m, 2H), 3.32 (s, 3H), 2.34 (qd, J = 12.6, 12.2, 9.2 Hz, 1H), 2.14 – 1.96 (m, 1H), 1.94– 1.75 (m, 2H), 1.67 – 1.48 (m, 2H).

[0802] The present invention also relates to the following aspects:

[0803] 1. A compound selected from:

[0804] 、 、 、

[0805] and ;

[0806] in

[0807] Each R n Independently C 1-6 Alkyl, or two R n Parts are linked together to form C 2-4 Alkyl bridge, wherein the bridge is optionally substituted by one to four independently selected C 1-3 Alkyl and phenyl groups are substituted; and

[0808] R z is halogen or CN.

[0809] 2. The compound according to item 1, selected from:

[0810] 、 、 、 、 、 、 、 、 and .

[0811] Although the foregoing disclosure has been described in considerable detail by way of illustration and example for purposes of clarity of understanding, those skilled in the art will appreciate that certain changes and modifications may be implemented within the scope of the appended claims. In addition, each reference provided herein is incorporated by reference in its entirety to the same extent as if each reference were individually incorporated by reference. In the event of a conflict between the present application and a reference provided herein, the present application shall control.

Claims

1. A compound selected from: 、 、 and .

2. A compound selected from: 、 、 、 and .

3. A compound selected from: 、 、 、 、 and ; in X is a halogen, 、 、C(O)2R 1 、-OS(O)2R 2 or -OP(O)(R 2 )2, where R 1 Is H or C 1-6 Alkyl, each R 2 It is C 1-6 Alkyl or C 6-10 Aryl, each R 7 are independently H or C 1-3 Alkyl, wherein each alkyl or aryl group is optionally substituted by one to four halogen or C 1-3 alkyl substituted, m is 1, 2 or 3, and n is 0 or 1; and R 4 is a halogen, and R c It is C 1-6 alkyl.

4. The compound according to claim 3, wherein X is COOH, or .

5. The compound according to claim 3, selected from: 、 and .

6. A compound selected from: 、 、 、 、 、 and .

7. A method for preparing compound 1: 1， or a salt thereof, comprising preparing a compound of formula 9-A by the following manner: ， Make the corresponding compound of formula 1-K: Reaction with the corresponding compound of formula 6-L: The compound of formula 9-A or its salt is obtained, wherein the compound of formula 1-K is prepared by the following method: the corresponding compound of formula 1-Q: Converting into the compound of formula 1-K or a salt thereof; where R x and R y are each independently H or C 1-6 Alkyl; R 2 It is H; R 3 and R 5 are independently CH3; R z is halogen or CN; and R p Selected from -C(=O)-C 1-6 Alkyl, -C(=O)-C 6-10 Aryl, -C(=O)-OC 1-6 Alkyl, -C(=O)-OC 1-6 Alkyl-C 6-10 Aryl and -C(=O)-OC 6-10 Aryl, wherein each aryl group is optionally substituted by one to four independently selected C 1-3 Alkyl and -OC 1-3 Alkyl groups are substituted.

8. The method according to claim 7, further comprising preparing the compound of formula I-Q by the following manner: ， or its salt: the corresponding compound of formula 1-P: React with the corresponding compound of formula 1-I: The compound of formula 1-Q is obtained.

9. The method according to claim 8, further comprising preparing the compound of formula 1-P by the following manner: , the corresponding compound of formula 1-N: Converted into the compound of formula 1-P, wherein the compound of formula 1-N is prepared by the following manner: the corresponding compound of formula 1-M: Converted into the compound of formula 1-N, wherein each R n Independently C 1-6 Alkyl, or two R n Parts are linked together to form C 2-4 Alkyl bridge, wherein the bridge is optionally substituted by one to four independently selected C 1-3 Alkyl and phenyl groups are substituted.

10. The method according to claim 9, further comprising preparing the compound of formula 1-M by the following manner: ， Make the corresponding compound of formula 5-E: React with the corresponding compound of formula 1-L: Obtaining the compound of formula 1-M; in Each R n Independently C 1-6 Alkyl, or two R n Parts are linked together to form C 2-4 Alkyl bridge, wherein the bridge is optionally substituted by one to four independently selected C 1-3 Alkyl and phenyl groups are substituted; and R z is halogen or CN.

11. The method according to claim 10, wherein the compound of formula I-L is selected from: and .

12. The method according to claim 10, wherein the compound of formula 5-E is: 。 13. The method according to claim 10, wherein the compound of formula 5-E is: 。 14. The method according to claim 8, wherein the compound of formula 1-1 is: 。 15. A method for preparing compound 1: 1， or a salt thereof, the method being carried out in the following manner: the corresponding compound of formula 9-J: ， or its salt is converted into the compound 1 or its salt, wherein the compound of formula 9-J or its salt is prepared by the following manner: making the corresponding compound of formula 9-L: ， or a salt thereof and a corresponding compound of formula 9-I: ， or a salt thereof to obtain the compound of formula 9-J or a salt thereof; where R u and R w Each independently is H, C 1-6 Alkyl or C 6-10 Aryl; R 2 It is H; R 3 and R 5 are each independently CH3; and R 12 yes .

16. The method according to claim 15, further comprising preparing the compound of formula 9-1 by the following manner: ， or its salt: the corresponding compound of formula 9-H: ， or a salt thereof is converted into the corresponding compound of formula 9-I, wherein the compound of formula 9-H or a salt thereof is prepared by the following manner: the corresponding compound of formula 9-G: ， or its salt and the corresponding compound of formula 9-K: or a salt thereof to obtain the compound of formula 9-H or a salt thereof.

17. A method for preparing a compound of formula 9-J: ， or a salt thereof, the method being carried out in the following manner: making the corresponding compound of formula 9-L: ， or a salt thereof and a corresponding compound of formula 9-I: ， or a salt thereof to obtain the compound of formula 9-J or a salt thereof.

18. A method for preparing a compound of formula 9-I: ， or a salt thereof, the method being carried out in the following manner: the corresponding compound of formula 9-H: ， or a salt thereof is converted into the corresponding compound of formula 9-I.

19. A method for preparing a compound of formula 9-H: ， or a salt thereof, the method being carried out in the following manner: making the corresponding compound of formula 9-G: ， or its salt and the corresponding compound of formula 9-K: or a salt thereof to obtain the compound of formula 9-H or a salt thereof.

20. The method according to any one of claims 15 to 18, wherein the compound of formula 9-I is: 。 21. The method according to claim 16 or 19, wherein the compound of formula 9-G is: 。

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