Methods and intermediates for preparing macrocyclic MCL1 inhibitors

Abstract

In particular, the present invention relates to methods and intermediates for the synthesis of Compound 1, which inhibits MCL1 and is useful in the treatment of cancer.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit under 35 U.S.C. §119(e) of U.S. Provisional Application No. 63 / 115,723, filed November 19, 2020, which is incorporated by reference in its entirety for all purposes.

[0002] The present disclosure relates to methods and intermediates for the synthesis of certain compounds that inhibit MCL1 for use in the treatment of cancer. [Background technology]

[0003] Apoptosis (programmed cell death) is a process for the elimination of unwanted or potentially dangerous cells from an organism. Avoidance of apoptosis is important for the development and sustained growth of tumors. Myeloid cell leukemia 1 protein (MCL1) is an anti-apoptotic member of the Bcl-2 family of proteins. MCL1 is overexpressed in many cancers. Overexpression of MCL1 prevents cancer cells from undergoing apoptosis. Several studies have shown that MCL1 inhibitors may be used to treat cancer. Although compounds that inhibit MCL1 have been disclosed, there remains a need for synthetic methods for preparing such compounds on a manufacturing scale.

[0004] PCT Application No. PCT / US2019 / 032053 (International Publication No. WO 2019 / 222112) discloses novel compounds useful as MCL1 inhibitors. This patent publication describes compounds of formula (I):

[0005] [ka] and pharma- ceutical acceptable salts thereof are effective as MCL1 inhibitors and are useful in the treatment of cancer. 2 , R 3 , R 4 , R 5 , R 6 , and R 12Each of these is defined in PCT / US2019 / 032053. Currently, 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. [Prior art documents] [Patent documents]

[0006] [Patent Document 1] International Publication No. 2019 / 222112 Summary of the Invention [Means for solving the problem]

[0007] In one embodiment, the present disclosure provides Compound 1:

[0008] [ka] or a salt thereof, comprising the steps of:

[0009] [ka] with the corresponding compound of formula 1-K:

[0010] [ka] and the corresponding compound of formula 6-L:

[0011] [ka] to provide a compound of formula 9-A or a salt thereof, and a compound of formula 1-K is prepared by reacting a corresponding compound of formula 1-Q:

[0012] [ka] to a compound of formula 1-K or a salt thereof, In the formula, R x and R y are each independently H or C 1~6 is alkyl, R 2 is H and R 3 and R 5 are CH3 and R z is halogen or CN, R p is -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, each aryl being selected from C 1~3 Alkyl and -OC 1~3 Optionally substituted with 1 to 4 groups independently selected from alkyl.

[0013] In one embodiment, the present disclosure provides a compound of formula 1-Q:

[0014] [ka] or a salt thereof, with the corresponding compound of formula 1-P:

[0015] [ka] and the corresponding compound of formula 1-I:

[0016] [ka] to provide a compound of formula 1-P.

[0017] In one embodiment, the present disclosure provides a compound of formula 1-P:

[0018] [ka] with the corresponding compound of formula 1-N:

[0019] [ka] and a compound of formula 1-N is prepared by converting The corresponding compound of formula 1-M:

[0020] [ka] is prepared by converting a compound of formula 1-N into n is independently C 1~6 alkyl or two R n The parts are joined together to form C 2~4 Form an alkyl bridge, the bridge being C 1~3 It is optionally substituted with 1 to 4 groups independently selected from alkyl and phenyl.

[0021] In one embodiment, the present disclosure provides Compound 1:

[0022] [ka] or a salt thereof, comprising:

[0023] [ka] with the corresponding compound of formula 2-L:

[0024] [ka] or a salt thereof, In the formula, R X is H or C 1~6 is alkyl, R 5is -CH3, R 6 is Cl, and R a is C 1~6 It is an alkyl.

[0025] In one embodiment, the present disclosure provides Compound 1:

[0026] [ka] or a salt thereof, comprising:

[0027] [ka] with the corresponding compound of formula 3-H:

[0028] [ka] or a salt thereof, In the formula, R X is H or C 1~6 is alkyl, R 5 is CH3, R 6 is Cl.

[0029] In one embodiment, the present disclosure provides a compound of formula 3-H:

[0030] [ka] with the corresponding compound of formula 2-L:

[0031] [ka] to provide a compound of formula 3-H.

[0032] In one embodiment, the present disclosure provides a compound of formula 2-L:

[0033] [ka] with the corresponding compound of formula 2-K:

[0034] [ka] and a compound of formula 5-I:

[0035] [ka] to provide a compound of formula 2-L.

[0036] In one embodiment, the present disclosure provides a compound of formula 2-K:

[0037] [ka] with the corresponding compound of formula 2-H:

[0038] [ka] to a compound of formula 2-K, wherein the compound of formula 2-H is converted to a corresponding compound of formula 2-G:

[0039] [ka] to a compound of formula 2-H, and a compound of formula 2-G is prepared by converting the compound of formula 2-H to a corresponding compound of formula 2-F:

[0040] [ka] is prepared by converting Wherein PG is tri-C 1~6 Alkylsilyl group, di-C 1~6 Alkyl-phenylsilyl group, C 1~6wherein the phenylsilyl group is selected from an alkyl-di-phenylsilyl group, and a tri-phenylsilyl group.

[0041] In one embodiment, the present disclosure provides a compound of formula 2-L:

[0042] [ka] with the corresponding compound of formula 3-G:

[0043] [ka] to prepare a compound of formula 3-L by converting the compound of formula 3-G to the corresponding compound of formula 3-E:

[0044] [ka] and compounds:

[0045] [ka] to provide a compound of formula 3-E, In the formula, R a is C 1~6 The method further comprises the steps of:

[0046] In one embodiment, the present disclosure provides Compound 1:

[0047] [ka] or a salt thereof, comprising the steps of:

[0048] [ka] or its salts and compounds:

[0049] [ka] to provide compound 1 or a salt thereof, wherein the compound of formula 4-N is reacted with a corresponding compound of formula 4-M:

[0050] [ka] or a salt thereof, In the formula, R c is C1-6 alkyl.

[0051] In one embodiment, the present disclosure provides a compound of formula 4-M:

[0052] [ka] or a salt thereof, with the corresponding compound of formula 4-L:

[0053] [ka] or a salt thereof, by converting the corresponding compound of formula 4-L to a corresponding compound of formula 4-K:

[0054] [ka] and the corresponding compound of formula 4-J:

[0055] [ka] or a salt thereof to provide a compound of formula 4-L, and a compound of formula 4-J is prepared by reacting a corresponding compound of formula 4-I:

[0056] [ka] or a salt thereof, by converting a compound of formula 4-J or a salt thereof into In the formula, R4 is a halogen or a boronate; R b is C 1~6 is alkyl, R c is C 1~6 alkyl, and R p is -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, each aryl being selected from C 1~3 Alkyl and -OC 1~3 and X is optionally substituted with 1 to 4 groups independently selected from

[0057] [ka] C(O)2R 1 , -OS(O)2R 2 , or -OP(O)(R 2 )2, and R 1 is H or C 1~6 alkyl, and each R 2 is C 1~6 Alkyl or C 6~10 aryl, and each R 7 are independently H or C 1~3 and each alkyl or aryl is selected from the group consisting of 1 to 4 halogens or C 1~3 wherein m is 1, 2, or 3 and n is 0 or 1.

[0058] In one embodiment, the present disclosure provides a compound of formula 4-I:

[0059] [ka] or a salt thereof, with the corresponding compound of formula 4-H:

[0060] [ka] to a compound of formula 4-I, wherein the compound of formula 4-H is converted to a corresponding compound of formula 4-G:

[0061] [ka] or a salt thereof, by converting a compound of formula 4-H or a salt thereof into

[0062] In one embodiment, the present disclosure provides a compound of formula 4-G:

[0063] [ka] or a salt thereof, with the corresponding compound of formula 4-F:

[0064] [ka] or a salt thereof, by converting a compound of formula 4-G or a salt thereof into

[0065] In one embodiment, the present disclosure provides Compound 1:

[0066] [ka] or a salt thereof, with the corresponding compound of formula 9-J:

[0067] [ka] or a salt thereof, by converting the corresponding compound of formula 9-J or a salt thereof into compound 1 or a salt thereof,

[0068] [ka] or a salt thereof and the corresponding compound of formula 9-I:

[0069] [ka] or a salt thereof to provide a compound of formula 9-J, wherein R u and R w are independently H, C 1~6 Alkyl or C 6~10 aryl, R 2 is H and R 3 and R 5 are each independently CH3, R 12 teeth,

[0070] [ka] The present invention provides a method for

[0071] In one embodiment, the present disclosure provides a compound of formula 9-I:

[0072] [ka] or a salt thereof, with the corresponding compound of formula 9-H:

[0073] [ka] or a salt thereof to prepare a corresponding compound of formula 9-I, wherein the corresponding compound of formula 9-H or a salt thereof is converted to a corresponding compound of formula 9-G:

[0074] [ka] or a salt thereof and the corresponding compound of formula 9-K:

[0075] [ka] or a salt thereof to provide a compound of formula 9-H or a salt thereof.

[0076] In one embodiment, the present disclosure provides a compound of formula 9-J:

[0077] [ka] or a salt thereof, with the corresponding compound of formula 9-L:

[0078] [ka] or a salt thereof and the corresponding compound of formula 9-I:

[0079] [ka] or a salt thereof to provide a compound of formula 9-J or a salt thereof.

[0080] In one embodiment, the present disclosure provides a compound of formula 9-I:

[0081] [ka] or a salt thereof, with the corresponding compound of formula 9-H:

[0082] [ka] or a salt thereof by converting the compound of formula 9-I to the corresponding compound of formula 9-I.

[0083] In one embodiment, the present disclosure provides a compound of formula 9-H:

[0084] [ka] or a salt thereof, with the corresponding compound of formula 9-G:

[0085] [ka] or a salt thereof and the corresponding compound of formula 9-K:

[0086] [ka] or a salt thereof to provide a compound of formula 9-H or a salt thereof. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0087] I. Overview The present disclosure provides a method for preparing compound 1 or a salt thereof. The present disclosure also provides a method for preparing a compound 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, 9-A. The disclosure also provides methods for preparing compounds of formulas 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.

[0088] II. Definition The abbreviations used herein have their conventional meaning within the chemical and biological arts.

[0089] The description set forth herein should be considered as an illustration of the subject matter described in the claims, with the understanding that it is not intended to limit the scope of the appended claims to the specific embodiments illustrated. The headings used throughout this disclosure are for convenience only and should not be construed as limiting the scope of the claims in any way. An embodiment illustrated under any heading can be combined with an embodiment illustrated under any other heading. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art.

[0090] When trade names are used herein, they are intended to independently include the trade name product and the active pharmaceutical ingredient(s) of the trade name product.

[0091] As used in this specification and 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, reference to "an assay" includes reference to one or more assays, and so forth.

[0092] A squiggly line between two chemical groups:

[0093] [ka] " is used at this point to indicate a mixture of isomers.

[0094] "Isomers" are different compounds that have the same molecular formula. Isomers include stereoisomers, enantiomers, and diastereomers.

[0095] "Stereoisomers" are isomers that differ only in the arrangement of the atoms in space.

[0096] "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 "scalemic" mixture.

[0097] "Diastereomers" or "diastereomers" are stereoisomers that have at least two asymmetric atoms, but which are not mirror-images of each other.

[0098] Absolute stereochemistry is designated according to the Cahn-Ingold-Prelog RS system. When a compound is a pure enantiomer, the stereochemistry at each chiral carbon may be designated by either R or S. Resolved compounds of unknown absolute configuration may be designated (+) or (-) depending on the direction (dextrorotatory or levorotatory) that they rotate plane polarized light at the wavelength of the sodium D line. Certain compounds described herein may contain one or more asymmetric centers and / or constrained rotation about a bond axis and thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that may be defined with respect to absolute stereochemistry as (R)- or (S)-. The present disclosure is intended to include all such possible isomers, including racemic mixtures, scalemic mixtures, diastereomeric mixtures, optically pure forms, and intermediate mixtures. Optically active (R)- and (S)-isomers may be prepared using chiral synthons or chiral reagents or resolved using conventional techniques.

[0099] Unless expressly defined otherwise, the present disclosure includes all tautomers of the compounds detailed herein, even if only one tautomer is explicitly represented (e.g., where two tautomer pairs may exist, both tautomeric forms are intended and described by the presentation of one tautomeric form). For example, when referring to a compound containing an amide (e.g., by structural or chemical name), it is understood that the corresponding imidic acid tautomer is included in the disclosure and described in the same manner as if the amide was explicitly described alone or together with the imidic acid. Where more than two tautomers may exist, the present disclosure includes all such tautomers, even if only a single tautomeric form is represented by chemical name and / or structure.

[0100] The compounds described herein contain chiral centers and The compounds may have chiral or / and / or geometric isomeric centers (E and Z isomers), and it is to be understood that all such optical isomers, enantiomers, diastereoisomers and geometric isomers are encompassed. Where compounds are represented in their chiral form, it is understood that the embodiments include, but are not limited to, the specific diastereomerically or enantiomerically enriched forms. Where no chirality is specified, it is understood that the embodiments are directed to either the specific diastereomerically or enantiomerically enriched forms, or racemic or scalemic mixtures of such compounds.

[0101] In some embodiments disclosed herein, the catalyst used in the reaction may be an "asymmetric" or catalytic. The term "asymmetric catalyst" as used herein 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 may generate an enantiomeric excess of the product. Exemplary asymmetric catalysts include transition metals and chiral ligands. Non-limiting examples of chiral ligands include BINAP / SEGPHOS®, salens, bisoxazolines, tartrate ligands, cinchona alkaloids, DuPhos phosphoranes, BPE phosphoranes, DSM phosphoramidites, Solvias® Josiphos family, phosphine-oxazolines, Reetz and Trost ligands, and ChiralQuest phosphines.

[0102] Also provided herein are pharma- ceutically acceptable hydrates, solvates, cocrystals, tautomers, polymorphs, and prodrugs of the compounds described herein.

[0103] The term "hydrate" refers to the complex formed by combining a compound of Formula I, or any formula disclosed herein, with water.

[0104] 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 that contains an amount of solvent incorporated into the crystal structure. As used herein, the term "solvate" includes hydrates.

[0105] Any formula or structure given herein or any formula described herein is also intended to represent unlabeled and isotopically labeled forms of the compound. Isotopically labeled compounds have the structure shown by the 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: 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, and other isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, and chlorine. Various isotopically labeled compounds of the present disclosure include, for example, 3 H, 13 C and 14 C. Such isotopically labeled compounds may be useful in detection or imaging techniques such as metabolism studies, reaction kinetic studies, positron emission tomography (PET) or single-photon emission computed tomography (SPECT) including drug or substrate tissue distribution assays, or in radiation treatment of patients.

[0106] The present disclosure also includes compounds of Formula A or Formula I or Formula I(a), or any formula disclosed herein, in which 1 to n hydrogens attached to carbon atoms are replaced by deuterium, where n is the number of hydrogens in the molecule. Such compounds may exhibit increased resistance to metabolism and thus may be useful for increasing 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.5(12): 524-527 (1984). Such compounds are synthesized by means well known in the art, for example, by using starting materials in which one or more hydrogen atoms have been replaced with deuterium.

[0107] Deuterium-labeled or deuterium-substituted therapeutic compounds of the present disclosure may have improved DMPK (drug metabolism and pharmacokinetics) properties with respect to distribution, metabolism and excretion (ADME). Substitution with heavier isotopes such as deuterium may confer certain therapeutic advantages due to greater metabolic stability, e.g., increased in vivo half-life, reduced dosage requirements, and / or improved therapeutic index. 18 F-labeled compounds may be useful in PET or SPECT studies. The isotopically labeled compounds of the present disclosure and their prodrugs can generally be prepared by carrying out the procedures disclosed in the schemes or in the examples and preparations described below by substituting readily available isotopically labeled reagents with non-isotopically labeled reagents. In addition, heavier isotopes, particularly deuterium (i.e., 2 Substitution with H or D) may confer certain therapeutic advantages due to greater metabolic stability, such as increased half-life in vivo, or reduced dosage requirements, or improved therapeutic index. It is understood that deuterium in this context is considered a substituent in the compounds of Formula I or any formula disclosed herein.

[0108] The concentration of such heavier isotopes, specifically deuterium, can be defined by the isotopic enrichment factor. In the compounds of the present disclosure, any atom not specifically designated as a particular isotope is meant to represent any stable isotope of that atom. Unless otherwise stated, when a position is specifically designated as "H" or "hydrogen", the position is understood to have that hydrogen in the natural abundance isotopic composition of hydrogen. Thus, in the compounds of the present disclosure, any atom specifically designated as deuterium (D) is meant to represent deuterium.

[0109] The modifier "about" used 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 can be interpreted as ±10%, ±5%, or ±3%, or ±2%, or ±1%.

[0110] The term "chiral" refers to molecules that possess the property of non-superimposability of their mirror image partners, and the term "achiral" refers to molecules that are superimposable on their mirror image partners.

[0111] "C u~v ", i.e. (C u ~C v A prefix such as "C" indicates that the group that follows has u to v carbon atoms, where u and v are integers. For example, 1~6 "Alkyl" indicates that the alkyl group has from 1 to 6 carbon atoms.

[0112] A dash ("-" or "-") that is not between two letters or symbols is used to indicate a point of attachment for a substituent. For example, -C(O)NH2 is attached through a carbon atom. Dashes at the front or end of a chemical group are for convenience, and chemical groups may be depicted with or without one or more dashes without losing their ordinary meaning. Unless chemically or structurally required, no directionality is indicated or implied by the order in which chemical groups are written or named.

[0113] Wavy lines over chemical groups, such as:

[0114] [ka] indicates a point of attachment, i.e., it indicates a broken bond where a group is attached to another depicted group.

[0115] The term "substituted" or "optionally substituted" means that one or more hydrogen atoms on a hydrocarbon (either aliphatic or aromatic) have been replaced with 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 "substituted." Unless otherwise specified, if a group is described as optionally substituted, any substituents on the group are themselves unsubstituted. The term "optionally substituted," unless otherwise modified, includes at least the following optional substituents: halogen, hydroxy, amino, thiol, C 1~6 Alkyl, C 1~6 Haloalkyl, 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 1~6Alkyl)(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又は2) (C 1~6 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.

[0116] As used herein, "alkyl" refers to 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, i-propyl, -CH(CH3)2), 1-butyl (n-Bu, n-butyl, -CH2CH2CH2CH3), 2-methyl-1-propyl (i-Bu, i-butyl, -CH2CH(CH3)2), 2-butyl (s-B u, s-Butyl, -CH(CH3)CH2CH3), 2-Methyl-2-propyl (t-Bu, t-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 (-CH2CH2CH2CH2CH2CH2CH3), 2-hexyl (-CH(CH3)CH2CH2CH2CH3), 3-hexyl (-CH(CH2CH3)(CH2CH2CH3)), 2-methyl-2-pentyl (-C(CH3)2CH2CH2CH3), 3-methyl-2-pentyl ( Examples of isomeric groups include -CH(CH3)CH(CH3)CH2CH3), 4-methyl-2-pentyl (-CH(CH3)CH2CH(CH3)2), 3-methyl-3-pentyl (-C(CH3)(CH2CH3)2), 2-methyl-3-pentyl (-CH(CH2CH3)CH(CH3)2), 2,3-dimethyl-2-butyl (-C(CH3)2CH(CH3)2), and 3,3-dimethyl-2-butyl (-CH(CH3)C(CH3)3). Whenever any alkyl group can exist in two or more isomeric forms (e.g., n-butyl, sec-butyl, and tert-butyl), any reference herein lacking a prefix (e.g., "butyl") should be interpreted as the normal isomer (e.g., "n-butyl"). Thus, "propyl" means "n-propyl" and "butyl" means "n-butyl".

[0117] "Alkenyl" refers to an aliphatic group containing at least one carbon-carbon double bond. Examples of alkenyl groups include ethenyl, propenyl, butadienyl (such as 1,2-butadienyl and 1,3-butadienyl).

[0118] As used herein, "alkoxy" refers to a group of the formula -OR A where R A is an alkyl radical, as defined above. Non-limiting examples of alkoxy include methoxy, ethoxy, propoxy, and butoxy.

[0119] "Alkynyl" refers to an aliphatic group containing at least one carbon-carbon triple bond.

[0120] "Aryl" refers to a monoradical or diradical aromatic carbocyclic group having a single ring (e.g., monocyclic) or multiple rings (e.g., polycyclic), including fused ring systems in which one or more fused rings are fully or partially unsaturated. Non-limiting examples of aryl groups as used herein include phenyl, naphthyl, fluorenyl, indanyl, tetrahydroindanyl, and anthryl. However, aryl does not in any way encompass and does not overlap with heteroaryl, as defined below. When one or more aryl groups are fused with a heteroaryl ring, the resulting ring system is heteroaryl. The mono- or diradical classification 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, and the aryl group in "AB-aryl" is a monoradical, but additional substituents may be present on each aryl group.

[0121] The term "aryloxy" refers to the group O-aryl.

[0122] "Cycloalkyl" refers to saturated or partially saturated cyclic alkyl groups having single 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 that contains a heteroatom within the ring.

[0123] As used herein, "halo" or "halogen" refers to fluoro (-F), chloro (-Cl), bromo (-Br), and iodo (-I).

[0124] When the prefix "halo" is added to another term, it refers to one or more of the hydrogens associated with that term being independently replaced by a halogen atom. Thus, as used herein, the term "haloalkyl" refers to an alkyl, as defined herein, in which one or more hydrogen atoms of the alkyl are independently replaced with halogen substituents, which may be the same or different. For example, C 1~6 Haloalkyl (or haloC 1~6 Alkyl) is C 1~6 Alkyl, C 1~6 One or more of the hydrogen atoms of the alkyl are replaced with 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 relevant term may be replaced with halogen, thereby resulting in a perfluorinated substituent (e.g., perfluoroalkyl).

[0125] "Heteroaryl" refers to a radical or diradical aromatic group having a monocyclic, polycyclic, or fused polycyclic ring with one or more ring heteroatoms independently selected from nitrogen, oxygen, and sulfur. The heteroatoms in "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 mono- or diradical classification indicates whether the heteroaryl group terminates a chain (monoradical) or is within a 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, and the heteroaryl group in "AB-heteroaryl" is a monoradical, but additional substituents can be present on each heteroaryl group. Heteroaryl does not encompass and does not overlap with aryl as defined above.Non-limiting examples of heteroaryl groups include azepinyl, acridinyl, benzimidazolyl, benzothiazolyl, benzoyldolyl, benzodioxolyl, benzofuranyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxepinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzooxypyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophenyl), benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridinyl, carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, furanonyl, isothiazolyl, imidazolyl, indazolyl, indolyl, inda ... Examples of aryl groups include, but are not limited to, zolyl, isoindolyl, indolinyl, isoindolinyl, isoquinolyl, indolizinyl, isoxazolyl, naphthyridinyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl, 1-oxidopyridinyl, 1-oxidopyrimidinyl, 1-oxidopyranidyl, 1-oxidopyridazinyl, 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.

[0126] The term "heteroaryloxy" refers to the group O-heteroaryl.

[0127] The terms "heterocyclyl", "heterocycle", or "heterocyclic" or "heterocycloalkyl" refer to a monoradical or diradical saturated or unsaturated group having a single ring or multiple fused rings with one or more heteroatoms selected from nitrogen, sulfur, phosphorus, and / or oxygen in the ring. The heteroatoms in a "heterocyclyl" may be oxidized, e.g., -N(O)-, -S(O)-, -S(O)2-. A heterocyclyl may be monocyclic or polycyclic, and polycyclic rings may be fused, bridged, or spiro. Any non-aromatic ring containing at least one heteroatom is considered a heterocyclyl, regardless of bond (i.e., it may be bonded through a carbon atom or a heteroatom). Exemplary heterocyclic groups include, but are not limited to, azetidinyl, dioxolanyl, thienyl[1,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, thietanyl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, and 1,1-dioxo-thiomorpholinyl.

[0128] The term "cyano" refers to the group -CN.

[0129] The term "oxo" refers to the group ═O.

[0130] The term "carboxy" refers to the group -C(O)-OH.

[0131] The term "dioxane" refers to "1,4-dioxane."

[0132] 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 a compound that has the desired pharmacological activity of the free base. These salts can be derived from inorganic or organic acids or inorganic or organic bases. For example, compounds that contain a basic nitrogen can be prepared as pharmaceutically acceptable salts by contacting the compound with an inorganic or organic acid. Non-limiting examples of pharma- ceutically acceptable salts include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caproate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyrate-1,4-diol, hexaphosphate ... Examples of suitable pharma- ceutically acceptable salts include phenyl-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, sulfonate, methylsulfonate, propylsulfonate, besylate, xylenesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, gamma-hydroxybutyrate, glycolate, tartrate, and mandelate. A list of other suitable pharma- ceutically acceptable salts can be found in Remington: The Science and Practice of Pharmacy, 21 st Edition, Lippincott Williams and Wilkins, Philadelphia, Pa., 2006.

[0133] Non-limiting examples of "pharmaceutically acceptable salts" of the compounds disclosed herein also include alkali metal (e.g., sodium, potassium), alkaline earth metal (e.g., magnesium), ammonium, and NY4 salts. + (wherein Y is C1-C4 alkyl). Base addition salts such as sodium or potassium salts are also included.

[0134] The terms "non-polar", "polar aprotic", and "polar protic", as used herein to refer to solvents, are intended as a means of classifying solvents for use in the various methods and processes described herein. For purposes of classification herein, the term "non-polar solvent" refers to any ethereal solvent, 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 t-butyl ether, cyclopentyl methyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, diethylene glycol diethyl ether, triethylene glycol dimethyl ether, anisole, and the like. 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, hexafluorobenzene, and benzonitrile. Halogenated solvents include dichloromethane, tetrachloromethane, chloroform, 1,1-dichloroethane, 1,1,1-trichloroethane, vinyl chloride, vinylidene dichloride, trichloroethylene, perchloroethylene, chlorobenzene, 1,2-dichlorobenzene, fluorobenzene, trifluorotoluene, hexachlorobenzene, and hexafluorobenzene.For purposes of classification herein, the term "polar aprotic solvent" refers to any ester, nitrile, or ketone solvent, as well as N,N-dimethylformamide, N,N-dimethylacetamide, dimethylsulfoxide, sulfolane, N-methyl-2-pyrrolidinone, N,N-dimethylethyleneurea, N,N-dimethylpropyleneurea, hexamethylphosphoric acid 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, t-butyl acetate, vinyl acetate, 2,2,2-trichloroethyl acetate, 2-ethoxyethyl acetate, and the like. Nitrile solvents include acetonitrile, propionitrile, and benzonitrile. Ketone solvents include acetone, methyl ethyl ketone, methyl n-butyl ketone, methyl t-butyl ketone, 3-pentanone, cyclopentanone, cyclohexanone, 2,5-hexanedione, and the like. For purposes of classification herein, the term "polar protic solvent" refers to any alcohol or acid solvent, or water, or ammonia, as well as 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. Acidic solvents include formic acid, acetic acid, trichloroacetic acid, and trifluoroacetic acid.

[0135] "Salt" refers to an acid or base salt of a compound used in the method of the present disclosure. Salts useful in the present disclosure include, but are not limited to, hemisulfate, sulfate, chloride, bromide, carbonate, nitrate, and acetate. Hemisulfate refers to a compound in which only one of the two basic groups forms a salt with sulfuric acid. Carbonate includes hydrogen carbonate (or bicarbonate). Illustrative examples of pharmaceutically acceptable salts are mineral acid (such as hydrochloric acid, hydrobromic acid, phosphoric acid), organic acid (such as acetic acid, propionic acid, glutamic acid, citric acid), and quaternary ammonium (such as methyl iodide, ethyl iodide). It is understood that pharmaceutically acceptable salts are non-toxic. Additional information regarding 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.

[0136] III. Methods of Preparing the Compounds The present disclosure includes several methods for preparing compound 1.

[0137] A. Method for Preparing Compound 1 from Formula 1-L and Formula 5-E In one embodiment, the present disclosure provides a compound selected from 1-M, 1-N, 1-O, 1-P, 1-Q, 1-R, 1-S, 1-K, 9-A, and a method for making compound 1, as shown in Scheme 1, wherein R x and R y are independently H, C 1~6 Alkyl or C 6~10 Aryl and alkyl is C 6~10 Optionally substituted with aryl, R 2 is H and R 3 is methyl, R 5 is methyl, R z is halo or CN, and each R n is independent, C 1~6 alkyl or two R n The parts are joined together to form C 2~4 Form an alkyl bridge, the bridge being C1~3 optionally substituted with 1 to 4 groups independently selected from alkyl and phenyl; R p is -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 each aryl or heteroaryl is selected from 1~3 Alkyl and -OC 1~3 Each heteroaryl has 1 to 4 heteroatoms, each heteroatom is independently selected from N, O, and S, and each heteroaryl has 5 to 10 ring members. z is Br. In one embodiment, R z is CN. In one embodiment, R n is methyl. In one embodiment, R z is Br and R n is methyl. In one embodiment, R x is CN and R n is methyl. In one embodiment, R 5 is methyl. In one embodiment, R x is H. In one embodiment, two R n The moieties are linked together to form a cyclic acetal. In one embodiment, two R n The moieties are linked together to form a bridge selected from CH2CH2-, -CH(CH3)CH(CH3)-, -CH2CH(CH3)-, -CH2CH(CH3)-, -CH2CH(CH6H5)-, -C(CH3)2C(CH3)2-, -CH2CH2CH2-, -CH2CBr2CH2-, -CH2(C=CH)CH2-, -CH2CH(C6H5)CH2-, -CH(CH3)CH2CH(CH3)-, -CH2CH(CH3)CH2-, -CH2CH(CH3)CH2-, -CH2C(CH3)2CH2-, -CH2C(CH2CH3)2CH2-, -CH2CH2CH2CH2-, -CH2CH2CH2CH2CH2-, -CH(C6H5)CH(C6H5), -CH2CH(C6H5)CH2-, and -(o-C6H4)-. nThe moieties are joined together to form -C(CH3)2C(CH3)2-.

[0138] [ka]

[0139] In one embodiment, the disclosure provides a method for preparing compound 1-M from compound 1-L and compound 5-E.

[0140] In one embodiment, the method comprises reacting compound 1-L with compound 5-E and a base in a suitable solvent for a time and under conditions effective to form compound 1-M. In one embodiment, a promoter is present.

[0141] 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 and potassium, alkoxides such as sodium methoxide, sodium tert-butoxide, or lithium tert-butoxide, or tert-pentoxide analogs, alkali amide bases such as lithium, sodium, and potassium hexamethyldisilazane, and lithium diisopropylamide. In one embodiment, the base is potassium tert-butoxide.

[0142] In one embodiment, the accelerator is selected from NaI and tetrabutylammonium iodide.

[0143] In one embodiment, the solvent is selected from ethers (e.g., 2-methyltetrahydrofuran, tert-butyl methyl ether (MTBE), cyclopentyl methyl ether (CPME), tetrahydrofuran (THF)), polar aprotic solvents (e.g., dimethylsulfoxide (DMSO), N,N-dimethylformamide (DMF), N,N-dimethylacetamide, N-methyl-2-pyrrolidone (NMP)), nitriles (e.g., acetonitrile), hydrocarbon solvents (e.g., toluene, heptane (n-heptane, heptanes), halogenated solvents (e.g., dichloromethane, 1,2-dichloroethane, chloroform, chlorobenzene), alcohols (e.g., 2-propanol). In one embodiment, the solvent is tetrahydrofuran (THF).

[0144] In one embodiment, the reaction temperature is about -50 to 100°C. In one embodiment, the reaction temperature is about 0 to 100°C. In one embodiment, the reaction temperature is about -50 to -35°C. In one embodiment, the reaction temperature is about 0 to 20°C.

[0145] In one embodiment, the disclosure provides a method for preparing compound 1-N from compound 1-M.

[0146] In one embodiment, the method comprises treating compound 1-M with an acid in a suitable solvent for a time and under conditions effective to form compound 1-N.

[0147] In one embodiment, the acid is selected from Lewis acids such as 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, erbium(III) triflate, etc. In one embodiment, the acid is methanesulfonic acid.

[0148] In one embodiment, the solvent is selected from ethers (e.g., 2-methyltetrahydrofuran, tert-butyl methyl ether, cyclopentyl methyl ether, tetrahydrofuran), polar aprotic solvents (e.g., dimethylsulfoxide, 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.

[0149] In one embodiment, the temperature of the reaction is about 0-100° C. In one embodiment, the temperature of the reaction is about 40-60° C.

[0150] In one embodiment, the disclosure provides a method for preparing compound 1-O from compound 1-N.

[0151] In one embodiment, the method comprises treating compound 1-N with a reducing agent in a suitable solvent for a time and under conditions effective to form compound 1-O.

[0152] In one embodiment, the reducing agent is selected from tin or zinc in combination with an acid such as hydrochloric acid, acetic acid, ammonium chloride, transition metals such as Pd, Pd(OH)2, Pt, PtO2 or Rh in combination with H2 or formate, poisoned heterogeneous catalysts such as Pt / S / C, and iron powder. In one embodiment, the reducing agent is iron powder.

[0153] In one embodiment, the solvent is selected from a mixture of acids (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-methylpyrrolidinone, dimethylsulfoxide), 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.

[0154] In one embodiment, the temperature of the reaction is about 0-100° C. In one embodiment, the temperature of the reaction is about 40-60° C.

[0155] In one embodiment, the disclosure provides a method for preparing compound 1-P from compound 1-O.

[0156] In one embodiment, the method includes treating compound 1-O with a reducing agent in a suitable solvent for a time and 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.

[0157] In one embodiment, the reducing agent is selected from sodium cyanoborohydride, sodium borohydride and lithium borohydride, trialkylsilanes (e.g., triethylsilane) in combination with additives, poisoned heterogeneous catalysts (e.g., Pt / S / C), transition metals (e.g., Pd or Rh) in combination with H or formates with additives, Pd and Pt catalysts (e.g., Pd(OH)2, PtO2), and sodium triacetoxyborohydride. In one embodiment, the reducing agent is sodium triacetoxyborohydride.

[0158] In one embodiment, the additive is selected from trifluoroacetic acid, pivalic acid, B(OR), Ti(OEt), and Ti(Oi-Pr), where R is C 1~6 It is an alkyl.

[0159] 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., dimethylsulfoxide, 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.

[0160] In one embodiment, the reaction temperature is about 0-80° C. In one embodiment, the reaction temperature is about 10-30° C.

[0161] In one embodiment, the disclosure provides a method for preparing compound 1-Q from compound 1-P.

[0162] In one embodiment, the method comprises treating compound 1-P with compound 1-I, a reducing agent, and an acid in a suitable solvent for a time and under conditions effective to form compound 1-Q.

[0163] 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.

[0164] In one embodiment, the acid is selected from acetic acid, citric acid, pivalic acid, p-toluenesulfonic acid, methanesulfonic acid, hydrochloric acid, and trifluoroacetic acid, hi one embodiment, the acid is trifluoroacetic acid.

[0165] 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-pyrrolidinone, dimethylsulfoxide). In one embodiment, the solvent is dichloromethane.

[0166] In one embodiment, the reaction temperature is about -30 to 50°C. In one embodiment, the reaction temperature is about 10 to 30°C.

[0167] In one embodiment, the disclosure provides a method for preparing compound 1-K from compound 1-Q.

[0168] In one embodiment, the method comprises treating compound 1-Q with a ligand, an additive, and a base in the presence of a catalyst in a suitable solvent for a time and under conditions effective to form compound 1-K. In one embodiment, an acid is present. In one embodiment, R zis Br.

[0169] In one embodiment, the method comprises treating compound 1-Q with an acid and a base in a suitable solvent for a time and under conditions effective to form compound 1-K. In one embodiment, an additive is present. In one embodiment, R z is CN.

[0170] In one embodiment, the catalyst is selected from bis(triphenylphosphine)palladium dichloride, diiodobis(3-methyl-2(3H)-benzothiazolylidene)palladium, bis(benzonitrile)dichloropalladium, dichloro(1,5-cyclooctadiene)palladium, dicobalt hexacarbonyl, and palladium acetate. In one embodiment, the catalyst is palladium acetate (Pd(OAc)2).

[0171] 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).

[0172] 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).

[0173] In one embodiment, the acid is formic acid.

[0174] In one embodiment, the acid is selected from acetic acid, citric acid, pivalic acid, p-toluenesulfonic acid, methanesulfonic acid, hydrochloric acid, and trifluoroacetic acid, hi one embodiment, the acid is trifluoroacetic acid.

[0175] In one embodiment, the acid is selected from methanesulfonic acid, sulfuric acid, phosphoric acid, and hydrochloric acid, hi one embodiment, the acid is hydrochloric acid.

[0176] 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 triethanolamine, hi one embodiment, the base is triethylamine.

[0177] 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.

[0178] In one embodiment, the solvent is selected from benzene, toluene, dimethylacetamide, dimethylformamide, alcohol (e.g., ethanol, methanol, isopropanol, butanol), dimethylsulfoxide, 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.

[0179] In one embodiment, the temperature of the reaction is about -30 to 155°C. In one embodiment, the temperature is about 80 to 110°C. In one embodiment, the temperature is about 80 to 100°C.

[0180] In one embodiment, the present disclosure provides a method for preparing compound 9-A from compound 1-K and compound 6-L.

[0181] In one embodiment, the present disclosure provides a method for preparing compound 1 from compound 9-A.

[0182] In one embodiment, the disclosure provides a method of making 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.

[0183] In one embodiment, the disclosure provides a method of making 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.

[0184] In one embodiment, the disclosure provides a method of making compound 1-K from a compound selected from 1-L, 5-E, 1-M, 1-N, 1-O, 1-P, or 1-Q.

[0185] B. Method for Preparing Compound 1 from Formula 2-F In one embodiment, the present disclosure provides a method of making 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 is H and R 3 is methyl, R x and R y are independently H, C 1~6 Alkyl or C 6~10 Aryl and alkyl is C 6~10 Optionally substituted with aryl, R a is C 1~6 alkyl, and PG is tri-C 1~6 Alkylsilyl group, di-C 1~6 Alkyl-phenylsilyl group, C 1~6 R is selected from alkyl-di-phenylsilyl groups and tri-phenylsilyl groups; p is -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 each aryl or heteroaryl is selected from 1~3 Alkyl and -OC 1~3In one embodiment, PG is optionally substituted with 1 to 4 groups independently selected from alkyl, each heteroaryl having 1 to 4 heteroatoms, each heteroatom being independently selected from N, O, and S, and each heteroaryl having 5 to 10 ring members. In one embodiment, PG is tert-butyldiphenylsilyl. In one embodiment, R a is methyl. In one embodiment, R x is methyl.

[0186] [ka]

[0187] In one embodiment, the disclosure provides a method for preparing compound 2-G from compound 2-F.

[0188] In one embodiment, the method includes reacting compound 2-F with a catalyst, an oxidant, and an additive in a suitable solvent for a time and under conditions effective to form compound 2-G.

[0189] In one embodiment, the catalyst is selected from ruthenium chloride, potassium osmate, tungstophosphoric acid, and osmium tetroxide (OsO4). In one embodiment, the catalyst is osmium tetroxide (OsO4).

[0190] In one embodiment, the oxidizing agent is selected from oxone, potassium permanganate, potassium periodate, lead tetraacetate, sodium hypochlorite, hydrogen peroxide, N-methylmorpholine N-oxide (NMO), sodium periodate (NaIO4), and combinations thereof.

[0191] In one embodiment, the oxidizing agent is a combination of N-methylmorpholine N-oxide (NMO) and sodium periodate (NaIO4).

[0192] In one embodiment, the additive is selected from aluminum oxide, cerium trichloride, trimethylamine, triphenylphosphine, bis(diphenylphosphine)ethane, pyridine, 2,6-lutidine, dimethylsulfide, zinc, potassium acetate carbonate, trimethoxyphosphine, and potassium iodide. In one embodiment, the additive is 2,6-lutidine.

[0193] In one embodiment, the solvent is selected from methanol, ethanol, dichloromethane, dichloroethane, dioxane, dimethylsulfoxide, acetonitrile, acetone, tert-butanol, tetrahydrofuran (THF), water, and combinations thereof, hi one embodiment, the solvent is a combination of tetrahydrofuran (THF) and water.

[0194] In one embodiment, the temperature of the reaction is about -80 to 35° C. In one embodiment, the temperature is about 20 to 35° C.

[0195] In one embodiment, the disclosure provides a method for preparing compound 2-H from compound 2-G.

[0196] In one embodiment, the method comprises reacting compound 2-G with a promoter and a base in a suitable solvent for a time and under conditions effective to form compound 2-H. In one embodiment, an additive is present.

[0197] In one embodiment, the accelerator is selected from (dichloromethyl)diethoxyphosphine oxide, lithium (trimethylsilyl)diazomethane, (trimethylsilyl)diazomethane, imidazolesulfonyl azide hydrochloride, (2-oxopropyl)phosphonic acid dimethyl ester, p-toluenesulfonyl azide, azidotris(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.

[0198] In one embodiment, the base is selected from n-butyllithium, sec-butyllithium, tert-butyllithium, methyllithium, lithium diisopropylamine, 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.

[0199] In one embodiment, the additive is tetrabutylammonium fluoride.

[0200] In one embodiment, the solvent is selected from diethyl ether, tetrahydrofuran, acetonitrile, dichloromethane, ethanol, and methanol, hi one embodiment, the solvent is methanol.

[0201] In one embodiment, the temperature of the reaction is about -80 to 40° C. In one embodiment, the temperature is about 20 to 30° C.

[0202] In one embodiment, the disclosure provides a method for preparing compound 2-I from compound 2-H.

[0203] In one embodiment, the method comprises treating compound 2-H with a base and an alkylating agent in a suitable solvent for a time and under conditions effective to form compound 2-I. In one embodiment, a promoter is present.

[0204] In one embodiment, the promoter is selected from dichlorobis(triphenylphosphine)palladium, tris(4-methoxyphenyl)phosphine, and copper iodide.

[0205] In one embodiment, the base is selected from lithium diisopropylamine, 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).

[0206] In one embodiment, the alkylating reagent is selected from dimethyl sulfate, methyl triflate, methyl tosylate, bromomethane, trimethyl trifluoromethanesulfonate benzaminium, and methyl iodide. In one embodiment, the alkylating agent is methyl iodide.

[0207] In one embodiment, the solvent is selected from dimethylsulfoxide, dioxane, diethyl ether, DMPU hexamethylphosphoramide, hexane, heptane, pyridine, and tetrahydrofuran, hi one embodiment, the solvent is tetrahydrofuran.

[0208] In one embodiment, the temperature of the reaction is about -80 to 100° C. In one embodiment, the temperature is about -80 to 20° C.

[0209] In one embodiment, the disclosure provides a method for preparing compound 2-J from compound 2-I.

[0210] In one embodiment, the method comprises treating compound 2-I with a reagent, in a suitable solvent, for a time and under conditions effective to form compound 2-J.

[0211] 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 hydrofluoride, triethylamine hydrofluoride, potassium fluoride, sodium fluoride, lithium fluoride, tetramethylammonium fluoride, and tetrabutylammonium fluoride (TBAF). In one embodiment, the reagent is tetrabutylammonium fluoride (TBAF).

[0212] 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-pyrrolidinone, dimethylsulfoxide), and water. In one embodiment, the solvent is tetrahydrofuran.

[0213] In one embodiment, the reaction temperature is about -20 to 50°C. In one embodiment, the reaction temperature is about 20 to 30°C.

[0214] In one embodiment, the disclosure provides a method for preparing compound 2-K from compound 2-J.

[0215] In one embodiment, the method comprises treating compound 2-J with an oxidizing agent in the presence of a catalyst in a suitable solvent for a time and under conditions effective to form compound 2-K. In one embodiment, an additive is present.

[0216] In one embodiment, the oxidizing agent is selected from sodium hypochlorite / TEMPO, sulfur trioxide pyridine, dimethylsulfoxide (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).

[0217] In one embodiment, the catalyst is selected from 2-azaadamantane N-oxyl, 9-azabicyclo[3.3.1]nonane N-oxyl, 9-azanoradamantane 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).

[0218] In one embodiment, the additive is selected from sodium bromide, lithium bromide, and potassium bromide.

[0219] 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-pyrrolidinone, dimethylsulfoxide), and water. In one embodiment, the solvent is tetrahydrofuran.

[0220] In one embodiment, the temperature of the reaction is about -80 to 50° C. In one embodiment, the temperature is about 20 to 30° C.

[0221] In one embodiment, the present disclosure provides a method for preparing compound 2-L from compound 2-K and compound 5-I.

[0222] In one embodiment, the method comprises treating compound 2-K with compound 5-I, a reducing agent, and an acid in the presence of a catalyst in a suitable solvent for a time and under conditions effective to form compound 2-L. ​​In one embodiment, an additive is present.

[0223] In one embodiment, the reducing agent is selected from 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.

[0224] In one embodiment, the acid is selected from acetic acid, citric acid, pivalic acid, p-toluenesulfonic acid, methanesulfonic acid, hydrochloric acid, and trifluoroacetic acid, hi one embodiment, the acid is trifluoroacetic acid.

[0225] 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-pyrrolidinone, dimethylsulfoxide), and acetonitrile. In one embodiment, the solvent is acetonitrile.

[0226] In one embodiment, the temperature of the reaction is about -30 to 50°C. In one embodiment, the temperature is about 10 to 30°C.

[0227] In one embodiment, the disclosure provides a method for preparing compound 1-J from compound 2-L.

[0228] In one embodiment, the disclosure provides a method for preparing compound 1-K from compound 1-J.

[0229] In one embodiment, the present disclosure provides a method for preparing compound 9-A from compound 1-K and compound 6-L.

[0230] In one embodiment, the present disclosure provides a method for preparing compound 1 from compound 9-A.

[0231] In one embodiment, the present disclosure provides a method of making 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.

[0232] In one embodiment, the disclosure provides a method of making 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.

[0233] In one embodiment, the disclosure provides a method of making compound 1-K from a compound selected from 2-G, 2-H, 2-I, 2-J, 2-K, 2-L, and 1-J.

[0234] In one embodiment, the disclosure provides a method of making compound 1-J from a compound selected from 2-G, 2-H, 2-I, 2-J, 2-K, and 2-L.

[0235] C. Method for Preparing Compound 1 from Formula 3-E In one embodiment, the present disclosure provides a method of making 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 , H, R 3 Methyl, R x and R y are independently H, C 1~6 Alkyl or C 6~10 Aryl, C 1~6Alkyl is C 6~10 Optionally substituted with aryl, R a is C 1~6 is alkyl, R p is -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, each C 6~10 Aryl or heteroaryl is C 1~3 Alkyl and -OC 1~3 In one embodiment, PG is optionally substituted with 1 to 4 groups independently selected from alkyl, each heteroaryl having 1 to 4 heteroatoms, each heteroatom being independently selected from N, O, and S, and each heteroaryl having 5 to 10 ring members. In one embodiment, PG is tert-butyldiphenylsilyl. In one embodiment, R a is methyl. In one embodiment, R x is methyl.

[0236] [ka]

[0237] In one embodiment, the disclosure provides a method for preparing compounds 3-F and 3-G from compound 3-E.

[0238] In one embodiment, the method comprises treating compound 3-E with a nucleophile in a suitable solvent for a time and under conditions effective to form compounds 3-F and 3-G. In one embodiment, a promoter is present.

[0239] In one embodiment, the nucleophile is selected from propyne, propynyl lithium, propynyl magnesium chloride, dipropynyl zinc, propyl zinc chloride, propynyl magnesium bromide, and 3-bromopropyne. In one embodiment, the nucleophile is propynyl magnesium bromide.

[0240] In one embodiment, the accelerator is selected from alkyllithium (e.g., n-butyllithium, s-butyllithium, t-butyllithium, methyllithium), Grignard (e.g., ethylmagnesium bromide, isopropylmagnesium chloride, butylmagnesium bromide) lithium diisopropylamine, copper iodide, lithium perchlorate, lithium bromide, lanthanum chloride lithium chloride complex, cerium trichloride, boron trifluoride, titanium (IV) isopropoxide, zinc triflate, diethylzinc, N-methylephedrine, L-tartaric acid, R-2,2-binaphthol, trimethylamine, tetramethylethylenediamine, diisopropylamine, and zinc.

[0241] In one embodiment, the solvent is selected from ethereal 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.

[0242] In one embodiment, the temperature of the reaction is about -80 to 30° C. In one embodiment, the temperature is about -80 to 20° C.

[0243] In one embodiment, the present disclosure provides a method for preparing compound 2-L from compound 3-G.

[0244] In one embodiment, the method comprises treating compound 3-G with an alkylating agent and a base in a suitable solvent for a time and under conditions effective to form compound 2-L.

[0245] In one embodiment, the alkylating reagent is iodomethane.

[0246] In one embodiment, the base is sodium tert-butoxide.

[0247] In one embodiment, the solvent is tetrahydrofuran.

[0248] In one embodiment, the temperature of the reaction is about 0-30°C.

[0249] In one embodiment, the present disclosure provides a method for preparing compound 3-H from compound 2-L.

[0250] In one embodiment, the method comprises treating compound 2-L with an additive in a suitable solvent for a time and under conditions effective to form compound 3-H.

[0251] In one embodiment, the additive is a base selected from hydroxides (e.g., lithium hydroxide, sodium hydroxide, potassium hydroxide, cesium hydroxide, calcium hydroxide, magnesium hydroxide, ammonium hydroxide, tetramethylammonium hydroxide), alkoxides (e.g., lithium, sodium, potassium, magnesium, calcium methoxide, ethoxide, isopropoxide, t-butoxide, or t-pentoxide), trimethyltin hydroxide, sodium trimethylsilanolate, and potassium trimethylsilanolate. In one embodiment, the additive is lithium hydroxide.

[0252] In one embodiment, the additive is an acid selected from inorganic acids (e.g., hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid) and organic acids (e.g., acetic acid, trifluoroacetic acid, methanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid).

[0253] 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, t-butanol, t-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.

[0254] In one embodiment, the temperature of the reaction is about 20-100° C. In one embodiment, the temperature is about 40-60° C.

[0255] In one embodiment, the disclosure provides a method for preparing compound 1-K from compound 3-H.

[0256] In one embodiment, the present disclosure provides a method for making 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.

[0257] D. Method for preparing compound 1 from formula 4-F In one embodiment, the present disclosure provides a method of making 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 halo or boronic ester; R b is C 1~6 is alkyl, R c is C 1~6 is an alkyl group, and X is a halogen, a boronate, or -OS(O)R 2 , or -OP(O)(R 2 )2, and R 2 is C 1~6 Alkyl or C 6~10 and each alkyl or aryl is selected from the group consisting of 1 to 4 halogens or C 1~3 Optionally substituted with alkyl, R p is -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 each aryl or heteroaryl is selected from 1~3 Alkyl and -OC 1~3 Each heteroaryl has 1 to 4 heteroatoms, each heteroatom is independently selected from N, O, and S, and each heteroaryl has 5 to 10 ring members. bis methyl. In one embodiment, R c is methyl. In one embodiment, R p In one embodiment, X is

[0258] [ka] In the formula, 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

[0259] [ka] It is.

[0260] [ka]

[0261] In one embodiment, the disclosure provides a method for preparing compound 4-G from compound 4-F.

[0262] In one embodiment, the method comprises treating compound 4-F with a promoter and an oxidizing agent in a suitable solvent for a time and under conditions effective to form compound 4-G.

[0263] In one embodiment, the promoter is selected from ruthenium chloride, potassium osmate, tungstophosphate, hi one embodiment, the promoter is ruthenium chloride.

[0264] In one embodiment, the oxidizing agent is selected from oxone, potassium permanganate, potassium periodate, lead tetraacetate, sodium hypochlorite, hydrogen peroxide, and sodium periodate, hi one embodiment, the oxidizing agent is sodium periodate.

[0265] 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-pyrrolidinone, dimethylsulfoxide), acetonitrile, and combinations thereof. In one embodiment, the solvent is a combination of acetonitrile and water.

[0266] In one embodiment, the temperature of the reaction is about -80 to 80° C. In one embodiment, the temperature is 10 to 30° C.

[0267] In one embodiment, the disclosure provides a method for preparing compound 4-H from compound 4-G.

[0268] In one embodiment, the method comprises treating compound 4-G with N-hydroxyphthalimide and an acid activating agent in a suitable solvent for a time and under conditions effective to form compound 4-H.

[0269] In one embodiment, the acid activator is 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-methylmorpholinium chloride (DMTMM), thionyl chloride, oxalyl chloride, (chloromethylene)-dimethyliminium chloride, isobutyric acid, ... The acid activator is selected from N-(3-dimethylaminopropyl)-N-ethylcarbodiimide hydrochloride (EDC·HCl), N,N,N,N'-tetramethylchloroformamidinium 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), and N-(3-dimethylaminopropyl)-N-ethylcarbodiimide hydrochloride (EDC·HCl). In one embodiment, the acid activator is N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (EDC·HCl).

[0270] 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-pyrrolidinone, dimethylsulfoxide), 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.

[0271] In one embodiment, the temperature of the reaction is about -50 to 50° C. In one embodiment, the temperature is 10 to 30° C.

[0272] In one embodiment, the present disclosure provides a method for preparing compound 4-I from compound 4-H.

[0273] In one embodiment, the method comprises treating compound 4-H with a diboron reagent, a promoter, and an additive in a suitable solvent for a time and under conditions effective to form compound 4-I.

[0274] In one embodiment, the accelerator is selected from visible light (380-700 nm), UV light (10-400 nm), and blue LED (420 nm). In one embodiment, the accelerator is a blue LED (420 nm).

[0275] In one embodiment, the diboron reactant is selected from bis(pinacolato)diboron, bis(neopentylglycolato)diboron, bis(hexyleneglycolato)diboron, 2,2'-bi-1,3,2-dioxaborinane, and bis(catecholato)diboron. In one embodiment, the diboron reagent is bis(catecholato)diboron.

[0276] In one embodiment, the additive is selected from pinacol, diethanolamine, methyliminodiacetic acid, and alcohol (e.g., methanol, isopropanol, n-propanol). In one embodiment, the additive is methyliminodiacetic acid.

[0277] 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-pyrrolidinone, dimethylsulfoxide, 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.

[0278] In one embodiment, the temperature of the reaction is about -80 to 120° C. In one embodiment, the temperature is 10 to 30° C.

[0279] In one embodiment, the disclosure provides a method for preparing compound 4-J from compound 4-I.

[0280] In one embodiment, the present disclosure provides a method for preparing compound 4-L from compound 4-J and compound 4-K.

[0281] In one embodiment, the disclosure provides a method for preparing compound 4-M from compound 4-L.

[0282] In one embodiment, the disclosure provides a method for preparing compound 4-N from compound 4-M.

[0283] In one embodiment, the present disclosure provides a method of making 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.

[0284] E. Method for preparing compound 1 from formula 5-J In one embodiment, the present disclosure provides a method of making 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 halo or boronic ester, and X is halogen, boronate, -OS(O)R 2 , or -OP(O)(R 2 )2, and R 2 is C 1~6 Alkyl or C 6~10 aryl, each alkyl or aryl being selected from 1 to 4 halogens or C 1~3 and each R n is independently C 1~6 alkyl, or two R n The parts are joined together to form C 2~4 Form an alkyl bridge, the bridge being C 1~3 optionally substituted with 1 to 4 groups independently selected from alkyl and phenyl; R p is -C(=O)-C 1~6Alkyl, -C(=O)-heteroaryl, -C(=O)-OC 1~6 Alkyl, and -C(=O)-OC 1~6 Alkyl-C 6~10 each aryl or heteroaryl is selected from 1~3 Alkyl and -OC 1~3 Each heteroaryl has 1 to 4 heteroatoms, each heteroatom is independently selected from N, O, and S, and each heteroaryl has 5 to 10 ring members. p is 1-phenylethoxycarbonyl. In one embodiment, R n is methyl. In one embodiment, X is

[0285] [ka] 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

[0286] [ka] It is.

[0287] In one embodiment, Y is

[0288] [ka] It is.

[0289] [ka]

[0290] In one embodiment, the disclosure provides a method for preparing compound 5-K from compound 5-J.

[0291] In one embodiment, the method comprises treating compound 5-J with a promoter and an oxidizing agent in a suitable solvent for a time and under conditions effective to form compound 5-K.

[0292] In one embodiment, the promoter is selected from ruthenium chloride, potassium osmate, tungstophosphate, hi one embodiment, the promoter is ruthenium chloride.

[0293] In one embodiment, the oxidizing agent is selected from oxone, potassium permanganate, potassium periodate, lead tetraacetate, sodium hypochlorite, hydrogen peroxide, and sodium periodate, hi one embodiment, the oxidizing agent is sodium periodate.

[0294] 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-pyrrolidinone, dimethylsulfoxide), acetonitrile, and combinations thereof. In one embodiment, the solvent is a combination of acetonitrile and water.

[0295] In one embodiment, the temperature of the reaction is about -80 to 80° C. In one embodiment, the temperature is about -10 to 10° C.

[0296] In one embodiment, the present disclosure provides a method for preparing compound 5-L from compound 5-K.

[0297] In one embodiment, the method comprises treating compound 5-K with an acid in a suitable solvent for a time and under conditions effective to form compound 5-L.

[0298] 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) triflate, hi one embodiment, the acid is methanesulfonic acid.

[0299] In one embodiment, the solvent is selected from ethers (e.g., 2-methyltetrahydrofuran, tert-butyl methyl ether, cyclopentyl methyl ether, polar aprotic solvents (e.g., dimethylsulfoxide, 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.

[0300] In one embodiment, the temperature of the reaction is about 0-100° C. In one embodiment, the temperature is about 60-70° C.

[0301] In one embodiment, the present disclosure provides a method for preparing compound 5-M from compound 5-L.

[0302] In one embodiment, the method comprises treating compound 5-L with a reducing agent in a suitable solvent for a time and under conditions effective to form compound 5-M.

[0303] In one embodiment, the reducing agent is selected from reducing agents such as tin or zinc in combination with an acid such as hydrochloric acid, acetic acid, ammonium chloride, transition metals such as Pd or Rh in combination with H or formate, poisoned heterogeneous catalysts such as Pt / S / C, and iron powder. In one embodiment, the reducing agent is iron powder.

[0304] 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., N,N-dimethylacetamide, N,N-dimethylformamide, N-methylpyrrolidinone, dimethylsulfoxide), 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, hydrogen chloride) in combination with other solvents, including combinations thereof. In one embodiment, the solvent is acetic acid.

[0305] In one embodiment, the temperature of the reaction is about 0-100° C. In one embodiment, the temperature is about 65-85° C.

[0306] In one embodiment, the disclosure provides a method for preparing compound 5-N from compound 5-M.

[0307] In one embodiment, the present disclosure provides a method for preparing compound 5-P from compound 5-N and compound 5-O.

[0308] In one embodiment, the disclosure provides a method for preparing compound 5-Q from compound 5-P.

[0309] In one embodiment, the present disclosure provides a method of making 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.

[0310] F. Method for preparing compound 1 from formula 10-E In one embodiment, the present disclosure provides a method of making a compound selected from 6-M, 6-N, 4-N, and Compound 1, as shown in Scheme 6, wherein R x and R y are independently H, C 1~6Alkyl or C 6~10 Aryl and alkyl is C 6~10 Optionally substituted with aryl, R p is -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, each aryl or heteroaryl being selected from C 1~3 Alkyl and -OC 1~3 Each heteroaryl is optionally substituted with 1 to 4 groups independently selected from alkyl, and each heteroaryl has 1 to 4 heteroatoms, where each heteroatom is independently selected from N, O, and S, and each heteroaryl has 5 to 10 ring members.

[0311] [ka]

[0312] In one embodiment, the method includes carrying out a cross-metathesis reaction between compound 10-E and compound 1-I using a suitable catalyst in a suitable solvent for a time and under conditions effective to form compound 6-M.

[0313] In one embodiment, R x and R y are both hydrogen.

[0314] In one embodiment, R p is selected from 1-phenylethoxycarbonyl, ethoxycarbonyl, methoxycarbonyl, t-butoxycarbonyl, isopropoxycarbonyl, phenoxycarbonyl, 4-methoxyphenoxycarbonyl, and benzyloxycarbonyl.

[0315] In one embodiment, R p is 1-phenylethoxycarbonyl, optionally in the (R) or (S) form.

[0316] In one embodiment, the catalyst is a ruthenium catalyst or a molybdenum catalyst.

[0317] In one embodiment, the catalyst is [1,3-bis(2,4,6-trimethylphenyl)-2-imidazolidinylidene](2-isopropoxyphenylmethylene)ruthenium(II), (benzylidene)bis(tricyclohexylphosphine)ruthenium(II), [1,3-bis(2,4,6-trimethylphenyl)-2-imidazolidinylidene](benzylidene)(tricyclohexylphosphine)ruthenium(II), (o-isopropoxyphenylmethylene)(tricyclohexylphosphine)ruthenium(II), [1,3- Bis(2,4,6-trimethylphenyl)-2-imidazolidinylidene](2-isopropoxyphenylmethylene)ruthenium(II), [1,3-bis(2-methylphenyl)-2-imidazolidinylidene](benzylidene)(tricyclohexylphosphine)ruthenium(II), [1,3-bis(2,4,6-trimethylphenyl)-2-imidazolidinylidene][3-(2-pyridinyl)propylidene]ruthenium(II), [1,3-dimesityl-2-imidazolidinylidene](phenylmethylene)bis(3-bromopyridinyl)propylidene (1,3-dimesityl-2-imidazolidinylidene)(3-isopropoxyphenylmethylene)ruthenium(II), (1,3-dimesityl-2-imidazolidinylidene)(3-isopropoxyphenylmethylene)ruthenium(II), (1,3-dimesityl-2-imidazolidinylidene)(3-isopropoxyphenylmethylene)ruthenium(II), (1,3-dimesityl-2-imidazolidinylidene)(3-isopropoxyphenylmethylene)ruthenium(II), (1,3-dimesityl-2-imidazolidinylidene)(3-isopropoxyphenylmethylene)ruthenium(II), propoxy-5-nitrobenzylidene)ruthenium(II), tricyclohexylphosphine[4,5-dimethyl-1,3-bis(2,4,6-trimethylphenyl)imidazol-2-ylidene][2-thienylmethylene]ruthenium(II) dichloride, tricyclohexylphosphine[1,3-bis(2,4,6-trimethylphenyl)imidazol-2-ylidene][2-thienylmethylene]ruthenium(II) dichloride, tricyclohexylphosphine[2,4-dihydro-2,4,5-triphenyl-3H-1,2,4-triazol-3-ylidene][2-thienylmethylene]ruthenium(II) dichloride, tricyclohexylphosphine[1,3-bis(2,4,6-trimethylphenyl)imidazol-2-ylidene][3-phenyl-1H-inden-1-ylidene]ruthenium(II) dichloride, and bis(tricyclohexylphosphine)-3-phenyl-1H-inden-1-ylideneruthenium(II) dichloride.

[0318] In one embodiment, the catalyst is selected from 2,6-diisopropyl-phenylimido-neophyllidene[(S)-(-)-BIPHEN]molybdenum(VI), dichlorobis[(2,6-diisopropylphenyl)imido](1,2-dimethoxyethane)molybdenum(VI), and (T-4)-chloro(2,2-dimethylpropylidene)[2,2',4,4',6,6'-hexakis(1-methylethyl)[1,1':3',1-terphenyl]-2'-olato][2-methyl-2-propaneaminoato(2-)]molybdenum(VI).

[0319] In one embodiment, a suitable catalyst is Hoveyda-Grubbs II catalyst (dichloro[1,3-bis(2,4,6-trimethylphenyl)-2-imidazolidinylidene](2-isopropoxyphenylmethylene)ruthenium(II)).

[0320] In one embodiment, the solvent is a non-polar solvent or a polar aprotic solvent.

[0321] 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).

[0322] 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).

[0323] In one embodiment, the temperature of the reaction is about 0 to 150°C.

[0324] In one embodiment, the temperature of the reaction is about 20-90°C.

[0325] In one embodiment, the temperature of the reaction is about 40-90°C.

[0326] In one embodiment, the temperature of the reaction is about 20-60°C.

[0327] In one embodiment, the temperature of the reaction is about 40-80°C.

[0328] In one embodiment, the temperature of the reaction is about 80°C.

[0329] In one embodiment, the method comprises treating compound 6-M in a suitable solvent with a reducing agent for a time and under conditions effective to form a tertiary amine compound 6-N.

[0330] In one embodiment, the reducing agent is selected from a hydride reducing agent, a silane reducing agent, or hydrogenation.

[0331] In one embodiment, the reducing agent is a hydride reducing agent.

[0332] In one embodiment, the hydride reducing agent is selected from sodium borohydride, lithium borohydride, sodium cyanoborohydride, zinc borohydride, sodium triacetoxyborohydride, and tetramethylammonium triacetoxyborohydride.

[0333] In one embodiment, the hydride reducing agent is sodium triacetoxyborohydride or sodium cyanoborohydride.

[0334] In one embodiment, the hydride reducing agent is combined with an agent to adjust the hydride reduction activity (eg, titanium isopropoxide, titanium ethoxide, borate, magnesium perchlorate, or zinc chloride).

[0335] In one embodiment, the silane reducing agent is triethylsilane.

[0336] 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).

[0337] In one embodiment, the suitable solvent is a non-polar solvent, a polar protic solvent, or a polar aprotic solvent.

[0338] 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).

[0339] 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).

[0340] In one embodiment, the polar aprotic solvent is selected from N,N-dimethylacetamide, N,N-dimethylformamide, N-methyl-2-pyrrolidinone, dimethylsulfoxide, esters (e.g., methyl acetate, ethyl acetate, isopropyl acetate), and nitriles (e.g., acetonitrile).

[0341] In one embodiment, the suitable solvent is dichloromethane.

[0342] In one embodiment, the reaction temperature is -30 to 80°C, for example, 0 to 80°C, or 10 to 30°C.

[0343] In one embodiment, the present disclosure provides a method for preparing compound 4-N from compound 6-N.

[0344] In one embodiment, the present disclosure provides a method for making compound 1 from a compound selected from 10-E, 6-M, 6-N, and 4-N, as shown in Scheme 6.

[0345] G. Method for Preparing Compound 1 from Formula 7-A In one embodiment, the present disclosure provides a method of making 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 are independently H, C 1~6 Alkyl or C 6~10 Aryl and alkyl is C 6~10 Optionally substituted with aryl, R v is C 1~6 Alkyl, C 1~6 alkoxy, halo; 1~6 Alkyl and C 1~6 Alkoxy is aryl, C 1~6 Alkyl, C 1~6 is optionally substituted with 1 to 3 substituents selected from alkoxy and halo; R q is a silyl group, an alkylcarbonyl group (e.g., -C(=O)-C such as acetyl, isobutyryl, and pivaloyl). 1~6 Alkyl, or -C(=O)-C such as 2-phenylethylcarbonyl or 1-phenylethylcarbonyl 1~6alkyl(aryl)), arylcarbonyl group (e.g., benzoyl), alkoxycarbonyl group (e.g., -C(=O)-OC such as methoxycarbonyl, ethoxycarbonyl, t-butoxycarbonyl or benzyloxycarbonyl); 1~6 Alkyl, or -C(=O)-OC such as 2-phenylethoxycarbonyl or 1-phenylethoxycarbonyl 1~6 Alkyl (aryl), aryloxycarbonyl group (e.g., phenoxycarbonyl), tertiary alkyl group (e.g., t-butyl or trityl), C 1~6 Alkoxy C 1~6 Alkyl groups (e.g., C such as methoxymethyl or ethoxymethyl) 1~6 Alkoxymethyl), C 1~6 C alkylaryl groups (e.g., benzyl, 3,5-dimethoxybenzyl, 1-methylbenzyl), diarylalkyl groups (e.g., diphenylmethyl, etc. 1~6 Alkyl (aryl) (aryl), alkylsulfonyl groups (e.g., SO2C such as methanesulfonyl or isopropylsulfonyl) 1~6 alkyl), and arylsulfonyl groups (e.g., SO-aryl, such as benzenesulfonyl, toluenesulfonyl), each phenyl or heteroaryl being selected from C 1~3 Alkyl and -OC 1~3 Each heteroaryl has 1 to 4 heteroatoms independently selected from N, O, and S, and each heteroaryl has 5 to 10 ring members.

[0346] [ka]

[0347] In one embodiment, the method comprises treating a secondary amine compound 7-A with an aldehyde compound 7-B using a reducing agent in a suitable solvent for a time and under conditions effective to form a tertiary amine compound 7-C.

[0348] In one embodiment, R x and R y are H, respectively.

[0349] In one embodiment, R q is -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, t-butoxycarbonyl, or benzyloxycarbonyl), -C(=O)-OC 1~6 It is selected from alkyl(aryl) (e.g., 2-phenylethoxycarbonyl or 1-phenylethoxycarbonyl), and -C(=O)-O-aryl (e.g., phenoxycarbonyl).

[0350] In one embodiment, R q is selected from 1-phenylethoxycarbonyl, ethoxycarbonyl, methoxycarbonyl, t-butoxycarbonyl, isopropoxycarbonyl, phenoxycarbonyl, 4-methoxyphenoxycarbonyl, and benzyloxycarbonyl.

[0351] In one embodiment, R q is 1-phenylethoxycarbonyl, optionally in the (R) or (S) form.

[0352] In one embodiment, R q is selected from trialkylsilyl groups (e.g., trimethylsilyl, triethylsilyl, tripropylsilyl, triisopropylsilyl, t-butyldimethylsilyl), dialkylarylsilyl groups (e.g., dimethylphenylsilyl), alkyldiarylsilyl groups (e.g., t-butyldiphenylsilyl), and triarylsilyl groups (e.g., triphenylsilyl).

[0353] In one embodiment, R q is selected from a tert-butyldiphenylsilyl group and a tert-butyldimethylsilyl group.

[0354] In one embodiment, the reducing agent is selected from a hydride reducing agent, a silane reducing agent, or a hydrogenating agent.

[0355] In one embodiment, the reducing agent is a hydride reducing agent.

[0356] In one embodiment, the hydride reducing agent is selected from sodium borohydride, lithium borohydride, sodium cyanoborohydride, zinc borohydride, sodium triacetoxyborohydride, and tetramethylammonium triacetoxyborohydride.

[0357] In one embodiment, the hydride reducing agent is sodium triacetoxyborohydride or sodium cyanoborohydride.

[0358] In one embodiment, the hydride reducing agent is combined with an agent to adjust the hydride reduction activity (eg, titanium isopropoxide, titanium ethoxide, borate, magnesium perchlorate, or zinc chloride).

[0359] In one embodiment, the silane reducing agent is triethylsilane.

[0360] In one embodiment, the reaction further comprises an acid selected from acetic acid, trifluoroacetic acid, citric acid, pivalic acid, p-toluenesulfonic acid, methanesulfonic acid, and hydrochloric acid.

[0361] In one embodiment, the suitable solvent is a non-polar solvent, a polar protic solvent, or a polar aprotic solvent.

[0362] 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).

[0363] 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).

[0364] In one embodiment, the polar aprotic solvent is selected from N,N-dimethylacetamide, N,N-dimethylformamide, N-methyl-2-pyrrolidinone, dimethylsulfoxide, esters (e.g., methyl acetate, ethyl acetate, isopropyl acetate), and nitriles (e.g., acetonitrile).

[0365] In one embodiment, the suitable solvent is tetrahydrofuran, dichloromethane, or acetonitrile.

[0366] In one embodiment, the reaction temperature is -30 to 80°C, for example, 0 to 80°C, or 10 to 30°C.

[0367] In one embodiment, the method comprises performing a ring-closing alkyne metathesis on compound 7-C using a suitable catalyst in a suitable solvent for a time and under conditions effective to form compound 7-D.

[0368] In one embodiment, the catalyst is a ruthenium catalyst or a molybdenum catalyst.

[0369] In one embodiment, the catalyst is (SP-5-32)-nitrido(pyridine)tris(1,1,1-triphenylsilanolate)molybdenum(VI), [amidotris(2,3,4,5,6pentafluorophenyl)borato(3-)κN]bis(1,1,1 trimethylsilanolate)[1,1,1-trimethylsilyl)silaneaminato]molybdenum(VI), (T-4)-tris(2-methyl-2-propanolate) Nitridomolybdenum(VI), (T-4)-nitridobis(1,1,1-trimethylsilanolate)[1,1,1-trimethyl-N-(trimethylsilyl)silaneaminato]molybdenum(VI), [amidotris(2,3,4,5,6-pentafluorophenyl)borato(3-)-κN]tris(1,1,1-triphenylsilanolate)molybdenum(IV), and molybdenum hexacarbonyl.

[0370] In one embodiment, the reaction further comprises an additive, for example, 5 Å molecular sieves or 4-(trifluoromethyl)phenol.

[0371] In one embodiment, the solvent is a non-polar solvent or a polar aprotic solvent, or any combination thereof.

[0372] 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).

[0373] 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).

[0374] In one embodiment, the temperature of the reaction is about 0 to 150°C.

[0375] In one embodiment, the temperature of the reaction is about 20-90°C.

[0376] In one embodiment, the temperature of the reaction is between 40°C and 90°C.

[0377] In one embodiment, the temperature of the reaction is between 20°C and 60°C.

[0378] In one embodiment, the temperature of the reaction is between 40°C and 80°C.

[0379] In one embodiment, the temperature of the reaction is about 80°C.

[0380] In one embodiment, the method comprises hydrosilylating compound 7-D with a silane reagent and a catalyst in a suitable solvent for a time and under conditions effective to form vinylsilane compound 7-E.

[0381] In one embodiment, each R v are independently H, C 1~6 Alkyl (e.g., methyl, ethyl, isopropyl, propyl), C 1~6 alkoxy (e.g., methoxy, ethoxy), halo (e.g., chloro, bromo); 1~6 Alkyl and C 1~6 Alkoxy includes aryl (e.g., phenyl), C 1~6 Alkyl, C 1~6 It is optionally substituted with 1 to 3 substituents selected from alkoxy, and halo.

[0382] In one embodiment, R v is independently selected from methyl, ethyl, methoxy, ethoxy, benzyl, and chloro.

[0383] In one embodiment, the group Si(R v )3 is selected from trimethylsilyl, triethylsilyl, trimethoxysilyl, triethoxysilyl, benzyldimethylsilyl, chlorodimethylsilyl, and ethoxydimethylsilyl.

[0384] In one embodiment, the silane reagent has the formula H—Si(R v ) 3.

[0385] In one embodiment, the silane reactant is selected from 1,1,3,3-tetramethyldisiloxane, trimethoxyhydrosilane, triethoxysilane, trimethylhydrosilane, benzyldimethylsilane, dimethylchlorosilane, ethoxy(dimethyl)silane, and triethylsilane.

[0386] In one embodiment, the catalyst is a ruthenium, rhodium, or platinum catalyst.

[0387] In one embodiment, the catalyst is (tris(acetonitrile)(η 5 -pentamethylcyclopentadienyl)ruthenium(II) hexafluorophosphate, benzenedichlororuthenium(II) dimer, dichlorodiparacymene)ruthenium(II) dimer, (bis(1,5-cyclooctadiene)rhodium(II) tetrafluoroborate hydrate, (biscyclo[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.

[0388] In one embodiment, the solvent is a non-polar solvent, a polar protic solvent, or a polar aprotic solvent, or any combination thereof, or the solvent is the pure silane reagent.

[0389] In one embodiment, the solvent is selected from ethers (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, cyclopentyl methyl ether, or dioxane), hydrocarbon solvents (e.g., toluene, n-hexane, n-heptane, anisole, trifluorotoluene, hexafluorobenzene, fluorobenzene, or xylene), and halogenated solvents (e.g., dichloromethane, 1,2-dichloroethane, chloroform, or chlorobenzene).

[0390] In one embodiment, the polar aprotic solvent is selected from N,N-dimethylformamide, N,N-dimethylacetamide, dimethylsulfoxide, 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).

[0391] In one embodiment, the polar protic solvent is an alcohol (eg, methanol, ethanol, propanol, or isopropanol).

[0392] In one embodiment, the reaction temperature is 0 to 100°C, for example, 20 to 80°C, or 40 to 80°C, or 20 to 60°C, or 50 to 90°C.

[0393] In one embodiment, the method includes deprotecting compound 7-E with a suitable deprotecting agent in a suitable solvent to obtain either compound 7-F or compound 4-N.

[0394] In one embodiment, the deprotecting agent is a fluoride agent.

[0395] In one embodiment, the fluoride agent is selected from sodium fluoride, potassium fluoride, potassium bifluoride, tetra-n-butylammonium fluoride, triethylamine trihydrofluoride, and hydrofluoric acid.

[0396] In one embodiment, the protecting group R q is a silyl protecting group, and the product of deprotection is compound 4-N.

[0397] In one embodiment, the deprotecting agent is an organic acid.

[0398] In one embodiment, the organic acid is selected from formic acid, trifluoroacetic acid, methanesulfonic acid, acetic acid, 4-toluenesulfonic acid, and trifluoromethanesulfonic acid.

[0399] In one embodiment, the protecting group R q is a silyl or carbamate protecting group, and the product of deprotection is compound 4-N.

[0400] In one embodiment, the solvent is a non-polar solvent, a polar protic solvent, or a polar aprotic solvent, or any combination thereof, or the solvent is the neat deprotection reagent (eg, an organic acid).

[0401] 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).

[0402] In one embodiment, the polar aprotic solvent is selected from N,N-dimethylformamide, N,N-dimethylacetamide, dimethylsulfoxide, 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).

[0403] In one embodiment, the polar protic solvent is an alcohol (eg, methanol, ethanol, propanol, isopropanol), water, or a combination thereof.

[0404] In one embodiment, the reaction temperature is 0 to 100°C, for example, 20 to 80°C, or 40 to 80°C, or 20 to 60°C, or 50 to 90°C.

[0405] In one embodiment, the method includes converting compound 7-F to compound 4-N.

[0406] In one embodiment, the method includes converting compound 4-N to compound 1.

[0407] In one embodiment, the present disclosure provides a method for making 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.

[0408] H. Method for preparing compound 1 from formula 8-A In one embodiment, the present disclosure provides a method for making 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 are independently H, C 1~6 Alkyl or C 6~10 Aryl and alkyl is C 6~10PG is optionally substituted with aryl, and PG is a silyl group, an alkylcarbonyl group, an arylcarbonyl group, an alkoxycarbonyl group, a silylalkoxycarbonyl group, an aryloxycarbonyl group, or C 1~6 alkylaryl groups; R p is -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, each aryl or heteroaryl being selected from C 1~3 Alkyl and -OC 1~3 Each heteroaryl has 1 to 4 heteroatoms, each heteroatom being independently selected from N, O, and S, and each heteroaryl has 5 to 10 ring members.

[0409] [ka]

[0410] In one embodiment, the method includes reacting compound 6-L with compound 8-A in a cross-metathesis reaction using a suitable catalyst, in a suitable solvent, for a time and under conditions effective to form compound 8-B.

[0411] In one embodiment, PG is a silyl group, an alkylcarbonyl group (e.g., —C(═O)—C such as acetyl, isobutyryl, pivaloyl, etc. 1~6 alkyl), arylcarbonyl groups (e.g., benzoyl), alkoxycarbonyl groups (e.g., methoxycarbonyl, ethoxycarbonyl, t-butoxycarbonyl, or benzyloxycarbonyl, such as -C(=O)-OC 1~6 alkyl), silylalkoxycarbonyl groups (e.g., -C(=O)-OC such as 2-(trimethylsilyl)ethoxycarbonyl) 1~6 Alkyl-Si(C 1~6alkyl) 3), aryloxycarbonyl group (e.g., phenoxycarbonyl), or C 1~6 It is selected from alkylaryl groups (eg, benzyl, 4-methoxybenzyl, 3,5-dimethoxybenzyl).

[0412] In one embodiment, PG is a silyl group, an alkoxycarbonyl group (e.g., -C(=O)-OC, such as methoxycarbonyl, ethoxycarbonyl, t-butoxycarbonyl, or benzyloxycarbonyl). 1~6 alkyl), silylalkoxycarbonyl groups (e.g., -C(=O)-OC such as 2-(trimethylsilyl)ethoxycarbonyl) 1~6 Alkyl-Si(C 1~6 Alkyl)3) or C 1~6 It is selected from alkylaryl groups (eg, benzyl, 4-methoxybenzyl, 3,5-dimethoxybenzyl).

[0413] In one embodiment, the substituent PG is selected from trialkylsilyl groups (e.g., trimethylsilyl, triethylsilyl, tripropylsilyl, triisopropylsilyl, t-butyldimethylsilyl), dialkylarylsilyl groups (e.g., dimethylphenylsilyl), alkyldiarylsilyl groups (e.g., t-butyldiphenylsilyl), and triarylsilyl groups (e.g., triphenylsilyl).

[0414] In one embodiment, R x and R y are both hydrogen.

[0415] In one embodiment, R p is selected from 1-phenylethoxycarbonyl, ethoxycarbonyl, methoxycarbonyl, t-butoxycarbonyl, isopropoxycarbonyl, phenoxycarbonyl, 4-methoxyphenoxycarbonyl, and benzyloxycarbonyl.

[0416] In one embodiment, R pis 1-phenylethoxycarbonyl, optionally in the (R) or (S) form.

[0417] In one embodiment, the suitable catalyst is a ruthenium catalyst or a molybdenum catalyst.

[0418] In one embodiment, suitable catalysts include [1,3-bis(2,4,6-trimethylphenyl)-2-imidazolidinylidene](2-isopropoxyphenylmethylene)ruthenium(II), (benzylidene)bis(tricyclohexylphosphine)ruthenium(II), [1,3-bis(2,4,6-trimethylphenyl)-2-imidazolidinylidene](benzylidene)(tricyclohexylphosphine)ruthenium(II), (o-isopropoxyphenylmethylene)(tricyclohexylphosphine)ruthenium(II), [1,3 -Bis(2,4,6-trimethylphenyl)-2-imidazolidinylidene](2-isopropoxyphenylmethylene)ruthenium(II), [1,3-bis(2-methylphenyl)-2-imidazolidinylidene](benzylidene)(tricyclohexylphosphine)ruthenium(II), [1,3-bis(2,4,6-trimethylphenyl)-2-imidazolidinylidene][3-(2-pyridinyl)propylidene]ruthenium(II), [1,3-dimesityl-2-imidazolidinylidene](phenylmethylene)bis(3-bromopyridinyl)propylidene]ruthenium(II), lysine)ruthenium(II), [1,3-bis(2,4,6-trimethylphenyl)-2-imidazolidinylidene](3-methyl-2-butenylidine)(tricyclohexylphosphine)ruthenium(II), [1,3-bis(2-methylphenyl)-2-imidazolidinylidene](2-isopropoxyphenylmethylene)ruthenium(II), [1,3-dimesityl-2-imidazolidinylidene], [3-(2-pyridinyl)propylidene]-ruthenium(II), (1,3-dimesityl-2-imidazolidinylidene)(2-isopropoxyphenylmethylene)ruthenium(II). isopropoxy-5-nitrobenzylidene)ruthenium(II), tricyclohexylphosphine[4,5-dimethyl-1,3-bis(2,4,6-trimethylphenyl)imidazol-2-ylidene][2-thienylmethylene]ruthenium(II) dichloride, tricyclohexylphosphine[1,3-bis(2,4,6-trimethylphenyl)imidazol-2-ylidene][2-thienylmethylene]ruthenium(II) dichloride, tricyclohexylphosphine[2,4-dihydro-2,4,5-triphenyl-3H-1,2,4-triazol-3-ylidene][2-thienylmethylene]ruthenium(II) dichloride, tricyclohexylphosphine[1,3-bis(2,4,6-trimethylphenyl)imidazol-2-ylidene][3-phenyl-1H-inden-1-ylidene]ruthenium(II) dichloride, and bis(tricyclohexylphosphine)-3-phenyl-1H-inden-1-ylideneruthenium(II) dichloride.

[0419] In one embodiment, the catalyst is selected from 2,6-diisopropyl-phenylimido-neophyllidene[(S)-(-)-BIPHEN]molybdenum(VI), dichlorobis[(2,6-diisopropylphenyl)imido](1,2-dimethoxyethane)molybdenum(VI), and (T-4)-chloro(2,2-dimethylpropylidene)[2,2',4,4',6,6'-hexakis(1-methylethyl)[1,1':3',1-terphenyl]-2'-olato][2-methyl-2-propaneaminoato(2-)]molybdenum(VI).

[0420] In one embodiment, a suitable catalyst is Hoveyda-Grubbs II catalyst (dichloro[1,3-bis(2,4,6-trimethylphenyl)-2-imidazolidinylidene](2-isopropoxyphenylmethylene)ruthenium(II)).

[0421] In one embodiment, the suitable solvent is a non-polar solvent or a polar aprotic solvent.

[0422] 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).

[0423] 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).

[0424] In one embodiment, the reaction temperature is 0 to 150°C, for example, 0 to 120°C, for example, 20 to 90°C, or 40 to 90°C, or 20 to 60°C, or 40 to 80°C, or about 80°C.

[0425] In one embodiment, the method includes treating compound 8-G with 4-fluoro-5-X-benzoic acid under conditions and for a time effective to form an ether adduct compound 8-C, where X is selected from bromo, chloro, iodo, sulfonate (e.g., trifluoromethanesulfonate, methylsulfonate, p-toluenesulfonate, imidazolyl sulfonate), and phosphinate (e.g., diphenylphosphinate), and each R n is independently 1~6 alkyl (e.g., methyl, ethyl, or isopropyl) or two R n The parts are joined together to form C 2~10 Alkyl or C 2~10 Forms an alkenyl bridge (i.e., a cyclic acetal), the bridge being 1-4 C 1~6 Optionally substituted with alkyl, halo, or aryl, or two R n The moieties are linked together to form an optionally substituted 1,2-hydroxyaryl bridge (eg, a catechol bridge).

[0426] In one embodiment, R n The two Rs of compound 8-G nThe moieties of compound 8-G are joined together to form a bridge selected from CH2CH2-, -CH(CH3)CH(CH3)-, -CH2CH(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-CH2CH2CH2CH2-CH2CH2CH2CH2-, -CH(C6H5)CH(C6H5), -CH2CH(C6H5)CH2-, and -(o-C6H4)-.

[0427] In one embodiment, compound 8-G is dissolved or suspended in a suitable solvent and treated with a strong base and optionally a promoter (eg, sodium iodide, tetrabutylammonium iodide).

[0428] In one embodiment, the base is an inorganic hydride (e.g., sodium hydride, potassium hydride), an alkoxide (e.g., sodium methoxide, sodium ethoxide, sodium t-butoxide, potassium methoxide, potassium ethoxide, potassium t-butoxide, lithium t-butoxide, potassium t-pentoxide, sodium t-pentoxide, lithium t-pentoxide), an inorganic hydroxide (e.g., sodium hydroxide, potassium hydroxide, lithium hydroxide), an amide base (sodium hexamethyldisilazide, lithium hexamethyldisilazide, potassium hexamethyldisilazide, The base is selected from lithium diisopropylamide, lithium diisopropylamide, sodium diisopropylamide, potassium diisopropylamide), organolithium bases (e.g., methyllithium, ethyllithium, butyllithium, s-butyllithium, t-butyllithium), 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 (monobasic, dibasic or tribasic), sodium phosphate (monobasic, dibasic or tribasic)).

[0429] In one embodiment, the suitable solvent is a non-polar solvent or a polar aprotic solvent.

[0430] 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).

[0431] In one embodiment, the polar aprotic solvent is selected from formamide, N,N-dimethylformamide, N,N-dimethylacetamide, dimethylsulfoxide, 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).

[0432] In one embodiment, the reaction temperature is -80 to 120°C, for example, -45 to 10°C, or -30 to 10°C, or -10 to 5°C, or about 0°C, or -10 to 50°C, or -10 to 30°C, or 10 to 30°C, or 25 to 120°C, or 50 to 80°C.

[0433] In one embodiment, the method includes the step of acylating compound 8-B with a benzoic acid compound 8-C using an acid activating agent and a base in a suitable solvent for a time and under conditions effective to form compound 8-D.

[0434] In one embodiment, the acid activator is 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-dimethoxyphenyl) ... N,N'-diisopropylcarbodiimide, and N,N'-dicyclohexylcarbodiimide are preferably selected from N,N'-diisopropylcarbodiimide, N,N'-dicyclohexyl ...

[0435] In one embodiment, the acid activating agent is N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (EDC-HCl).

[0436] In one embodiment, the base is selected from tertiary amines (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-methylpyrrolidine), aromatic amines (e.g., pyridine, 2,6-lutidine, picoline, collidine, imidazole, 1-methylimidazole, indole, isoindole, quinoline, isoquinoline, 4-dimethylaminopyridine), hydroxides (e.g., sodium hydroxide, potassium hydroxide, tetrabutylammonium hydroxide), and inorganic bases (e.g., lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, potassium phosphate (monobasic, dibasic or tribasic), and sodium phosphate (monobasic, dibasic or tribasic)).

[0437] In one embodiment, the reaction further comprises a promoter selected from dichloromethylene-dimethyliminium chloride, 4-dimethylaminopyridine (DMAP), N-methylimidazole, 1-hydroxy-7-azabenzotriazole (HOAt), and 1-hydroxybenzotriazole (HOBt).

[0438] In one embodiment, the acid activator is EDC-HCl, the base is 1-methylimidazole, and the promoter is DMAP.

[0439] In one embodiment, the suitable solvent is a non-polar solvent or a polar aprotic solvent, or a combination thereof, optionally including water or a two-phase reaction.

[0440] 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).

[0441] In one embodiment, the polar aprotic solvent is selected from N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidinone, dimethylsulfoxide, 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).

[0442] In one embodiment, the reaction temperature is -50 to 60°C, for example, 0 to 60°C, or 10 to 40°C, or 20 to 40°C.

[0443] In one embodiment, the method comprises treating compound 8-D with a deprotecting agent in a suitable solvent for a time and under conditions effective to form compound 8-E.

[0444] In one embodiment, PG is a silyl group, an alkoxycarbonyl group (e.g., -C(=O)-OC, such as methoxycarbonyl, ethoxycarbonyl, t-butoxycarbonyl, or benzyloxycarbonyl). 1~6 alkyl), silylalkoxycarbonyl groups (e.g., -C(=O)-OC such as 2-(trimethylsilyl)ethoxycarbonyl) 1~6 Alkyl-Si(C 1~6 Alkyl)3) or C 1~6 It is selected from alkylaryl groups (eg, benzyl, 4-methoxybenzyl, 3,5-dimethoxybenzyl).

[0445] In one embodiment, the substituent PG is selected from trialkylsilyl groups (e.g., trimethylsilyl, triethylsilyl, tripropylsilyl, triisopropylsilyl, t-butyldimethylsilyl), dialkylarylsilyl groups (e.g., dimethylphenylsilyl), alkyldiarylsilyl groups (e.g., t-butyldiphenylsilyl), and triarylsilyl groups (e.g., triphenylsilyl).

[0446] In one embodiment, R p is selected from 1-phenylethoxycarbonyl, ethoxycarbonyl, methoxycarbonyl, t-butoxycarbonyl, isopropoxycarbonyl, phenoxycarbonyl, 4-methoxyphenoxycarbonyl, and benzyloxycarbonyl.

[0447] In one embodiment, R p is 1-phenylethoxycarbonyl, optionally in the (R) or (S) form.

[0448] In one embodiment, the deprotection reagent 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 hydrogenation agent (e.g., hydrogen in combination with 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), which may optionally further comprise a phase transfer agent.

[0449] In one embodiment, the deprotecting agent is a fluoride agent or an acid.

[0450] In one embodiment, the deprotection reagent 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, triethylamine hydrogen fluoride, potassium fluoride, sodium fluoride, lithium fluoride, cesium fluoride, potassium bifluoride, tetramethylammonium fluoride, tetraethylammonium fluoride, and tetrabutylammonium fluoride.

[0451] 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 including water for a two-phase reaction.

[0452] 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).

[0453] In one embodiment, the polar protic solvent is an alcohol solvent (eg, methanol, ethanol, propanol, isopropanol, tert-butanol, tert-amyl alcohol) optionally in combination with water, or the polar protic solvent is water.

[0454] In one embodiment, the polar aprotic solvent is selected from N,N-dimethylacetamide, N,N-dimethylformamide, N-methyl-2-pyrrolidinone, and dimethylsulfoxide, sulfolane, nitriles (e.g., acetonitrile, propionitrile), and esters (methyl acetate, ethyl acetate, isopropyl acetate, butyl acetate, isobutyl acetate, dimethyl carbonate).

[0455] In one embodiment, the reaction temperature is -15 to 60°C, for example, 0°C to 60°C, or -5 to 40°C, or 0°C to 30°C, or 10°C to 30°C.

[0456] In one embodiment, the method comprises treating compound 8-E with a reducing agent in a suitable solvent for a time and under conditions effective to form compound 8-F.

[0457] In one embodiment, the reducing agent is selected from a hydride reducing agent, a silane reducing agent, or hydrogenation.

[0458] In one embodiment, the reducing agent is a hydride reducing agent.

[0459] In one embodiment, the hydride reducing agent is selected from sodium borohydride, lithium borohydride, sodium cyanoborohydride, zinc borohydride, sodium triacetoxyborohydride, and tetramethylammonium triacetoxyborohydride.

[0460] In one embodiment, the hydride reducing agent is sodium triacetoxyborohydride or sodium cyanoborohydride.

[0461] In one embodiment, the hydride reducing agent is combined with an agent to adjust the hydride reduction activity (eg, titanium isopropoxide, titanium ethoxide, borate, magnesium perchlorate, or zinc chloride).

[0462] In one embodiment, the silane reducing agent is triethylsilane.

[0463] 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).

[0464] In one embodiment, the suitable solvent is a non-polar solvent, a polar protic solvent, or a polar aprotic solvent.

[0465] 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).

[0466] 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).

[0467] In one embodiment, the polar aprotic solvent is selected from N,N-dimethylacetamide, N,N-dimethylformamide, N-methyl-2-pyrrolidinone, dimethylsulfoxide, esters (e.g., methyl acetate, ethyl acetate, isopropyl acetate), and nitriles (e.g., acetonitrile).

[0468] In one embodiment, the suitable solvent is tetrahydrofuran, dichloromethane, or acetonitrile.

[0469] In one embodiment, the reaction temperature is -30 to 80°C, for example, -30 to 50°C, or 0 to 50°C, or 10 to 30°C.

[0470] In one embodiment, the method comprises 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.

[0471] In one embodiment, the base is selected from inorganic bases (e.g., lithium, sodium, potassium and cesium carbonates, sodium or potassium phosphates (each in monobasic, dibasic or tribasic form)), organic bases (e.g., alkali metal carboxylates such as sodium or potassium acetate, pivalates, or propionates), hydroxides (e.g., lithium hydroxide, sodium hydroxide, tartrate butylammonium hydroxide) and alkoxides (e.g., sodium tert-butoxide, potassium tert-butoxide, sodium t-pentoxide).

[0472] In one embodiment, the reaction may be carried out using, for example, 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'-trichlorophenylphosphino-κP)ferrocene]dichloropalladium(II), triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate, [(2-di-tert-butylphosphino-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)-2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate, (2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate, [di(1-adamantine (2-di-tert-butylphosphine)-2-(2'-amino-1,1'-biphenyl))]palladium(II) methanesulfonate, [(2-di-cyclohexylphosphino-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)-2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate, [(2-di-tert-butylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)-2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate, 1,3,5,7-tetramethyl-6-phenyl-2,4,6-trioxa-6-phosphaadamantane)-2-(2'-amino-1,1'-biphenyl)]palladium(II) 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)]palladium(II) methanesulfonate, (2-dicyclohexylphosphino-2',6'-bis(N,N-dimethylamine)-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate, (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate, [(2-di-tert-butylphosphino-3-methoxy-6-methyl-2',4',6'-triisopropyl-1,1'-biphenyl)-2-(2-aminobiphenyl)]palladium(II) methanesulfonate, [2-(di-1-adamantylphosphino)-2',4',6'-triisopropyl-3,6-dimethoxybiphenyl][2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate The catalyst further comprises a catalyst selected from the group consisting of [(di-tert-butylneopentylphosphine)-2-(2-aminobiphenyl)]palladium(II) methanesulfonate, [(di-tert-butylneopentylphosphine)-2-(2-aminobiphenyl)]palladium(II) methanesulfonate, mesyl(2-(di-tert-butylphosphino)-1,1'-binaphthyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II), methanesulfonato(di-tert-butyl)methylphosphino(2'-amino-1,1'-biphenyl-2-yl)palladium(II), and methanesulfonato2-dicyclohexylphosphino-2-(N,N-dimethylamino)biphenyl(2'-amino-1,1'-biphenyl-2-yl)palladium(II).

[0473] In one embodiment, the reaction may be carried out using, for example, triphenylphosphine, tri-ortho-tolylphosphine, tri-tert-butylphosphine, di-tert-butyl-(methyl)phosphine, di-tert-butyl(phenyl)phosphine, tricyclohexylphosphine, tri-isopropylphosphine, 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, di(1-adamantyl)-2-morpholinophenylphosphine, N,N'-(2,6-diisopropylphenyl)dihydroimidazolium chloride, ( 2-biphenyl)di-tert-butylphosphine, (2-biphenylyl)di-tert-butylphosphine, 2-(di-tert-butylphosphino)biphenyl, (2-biphenyl)dicyclohexylphosphine, 2-dicyclohexylphosphino-2'-(N,N-dimethylamino)biphenyl, 2-dicyclohexylphosphino-2',6'-diisopropoxybiphenyl, 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl, 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl phenyl, 2-(dicyclohexylphosphino)3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl, 2-di-tert-butylphosphino-2',4',6'-triisopropyl-3,6-dimethoxy-1,1'-biphenyl, 2-(di-tert-butylphosphino)-2',4',6'-triisopropyl-3,6-dimethoxy-1,1'-biphenyl, 2-di-tert-butylphosphino-3,4,5,6-tetramethyl-2',4',6'-triisopropyl-1,1'-biphenyl.

[0474] In one embodiment, the suitable solvent is a non-polar solvent, a polar protic solvent, or a polar aprotic solvent.

[0475] 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).

[0476] In one embodiment, the polar protic solvent is an alcohol (eg, methanol, ethanol, propanol, isopropanol, butanol, tert-butanol, 2-methyl-2-butanol).

[0477] In one embodiment, the polar aprotic solvent is selected from N,N-dimethylacetamide, N,N-dimethylformamide, N-methyl-2-pyrrolidinone, dimethylsulfoxide, sulfolane, and nitriles (e.g., acetonitrile, propionitrile, benzonitrile).

[0478] In one embodiment, the suitable solvent is tetrahydrofuran, dichloromethane, or acetonitrile.

[0479] In one embodiment, the reaction temperature is from 25 to 120°C, for example, from 40 to 100°C, or from 60 to 80°C.

[0480] 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.

[0481] In one embodiment, the product compound 6-N is further elaborated to compound 4-N or compound 1.

[0482] In one embodiment, the present disclosure provides a method for making 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.

[0483] I. Method for Preparing Compound 1 from Formula 9-G In one embodiment, the present disclosure provides a method of making a compound selected from 9-H, 9-I, 9-J, and Compound 1, as shown in Scheme 9, wherein R 2 is H and R 3 and R 5 are each independently CH3, and R 12 teeth

[0484] [ka] and R u and R w are independently H, C 1~6 Alkyl or C 6~10 Aryl and alkyl is C 6~10 Optionally substituted with aryl, R p is -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, each aryl or heteroaryl being selected from C 1~3 Alkyl and -OC 1~3 In one embodiment, R is optionally substituted with 1 to 4 groups independently selected from alkyl, each heteroaryl having 1 to 4 heteroatoms, each heteroatom being independently selected from N, O, and S, and each heteroaryl having 5 to 10 ring members. u is H. In one embodiment, R w is H. In one embodiment, R p is 1-phenylethoxycarbonyl. In one embodiment, R p teeth,

[0485] [ka] It is.

[0486] [ka]

[0487] In one embodiment, the present disclosure provides a method for preparing compound 9-H from compound 9-G and compound 9-K.

[0488] In one embodiment, the method includes reacting compound 9-G with compound 9-K, an acid activator, a promoter, and a base in a suitable solvent for a time and under conditions effective to form compound 9-H.

[0489] In one embodiment, the acid activator is 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-methylmorpholinium chloride (DMTMM), salts. The acid activator is selected from thionyl chloride, oxalyl chloride, (chloromethylene)-dimethyliminium chloride, isobutyl chloroformate, N,N,N,N',N'-tetramethylchloroformamidinium 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.

[0490] 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.

[0491] 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, monobasic, dibasic and tribasic potassium phosphates and sodium phosphates). In one embodiment, the base is 1-methylimidazole.

[0492] 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-pyrrolidinone, dimethylsulfoxide), 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.

[0493] In one embodiment, the temperature of the reaction is about -50 to 50° C. In one embodiment, the temperature is about 10 to 30° C.

[0494] In one embodiment, the present disclosure provides a method for preparing compound 9-I from compound 9-H.

[0495] In one embodiment, the method comprises reacting compound 9-H with an acid in a suitable solvent for a time and under conditions effective to form compound 9-I.

[0496] 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, hi one embodiment, the acid is citric acid.

[0497] 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-pyrrolidinone, dimethylsulfoxide), 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.

[0498] In one embodiment, the temperature of the reaction is about -50 to 70°C. In one embodiment, the temperature is about 50 to 70°C.

[0499] In one embodiment, the present disclosure provides a method for preparing compound 9-J from compound 9-I and compound 9-L.

[0500] In one embodiment, the method includes reacting compound 9-I with compound 9-L, an acid activator, a promoter, and a base in a suitable solvent for a time and under conditions effective to form compound 9-J.

[0501] In one embodiment, the acid activator is 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-methylmorpholinium chloride (DMTMM), The acid activator is selected from thionyl chloride, oxalyl chloride, (chloromethylene)-dimethyliminium chloride, isobutyl chloroformate, N,N,N,N',N'-tetramethylchloroformamidinium 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.

[0502] 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.

[0503] 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, monobasic, dibasic and tribasic potassium phosphates and sodium phosphates). In one embodiment, the base is 1-methylimidazole.

[0504] 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-pyrrolidinone, dimethylsulfoxide), 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.

[0505] In one embodiment, the temperature of the reaction is about -50 to 50° C. In one embodiment, the temperature is about 10 to 30° C.

[0506] In one embodiment, the method includes converting compound 9-G to compound 9-H.

[0507] In one embodiment, the method includes converting compound 9-H to 9-I.

[0508] In one embodiment, the method includes converting compound 9-I to 9-J.

[0509] In one embodiment, the disclosure provides a method of making a compound selected from 9-H, 9-I, and 9-J.

[0510] In one embodiment, the present disclosure provides a method of making compound 1 from a compound selected from 9-G, 9-H, 9-I, 9-L, and 9-J, as shown in Scheme 9.

[0511] Method for preparing formula 1-I from J.10-A In one embodiment, the present disclosure provides a method of making 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 is C 1~6 Alkyl, where alkyl is C 6~10 Optionally substituted with aryl, R x is H or C 1~6 In one embodiment, R 8 is isopropyl, n-butyl, or benzyl. 8 is methyl. In one embodiment, R 8 is ethyl. In one embodiment, R x is H.

[0512] 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 It is selected from alkyl-di-phenylsilyl groups, and tri-phenylsilyl groups. In one embodiment, PG is tert-butyldimethylsilyl (TBS).

[0513] [ka]

[0514] In one embodiment, the disclosure provides a method for preparing compound 10-B from compound 10-A.

[0515] In one embodiment, the method comprises treating compound 10-A with a protecting reagent and a base in a suitable solvent for a time and under conditions effective to form compound 10-B.

[0516] In one embodiment, the protecting reagent is selected from silyl chlorides (e.g., chlorotrimethylsilane, chlorotriethylsilane, chlorotripropylsilane, triisopropylsilyl chloride, e.g., chlorotriethylsilane), tert-butyldiphenylsilyl chloride, chlorodimethylphenylsilane, chlorotriphenylsilane tert-butyl(chloro)dimethylsilane), silyl trifluoromethanesulfonates (e.g., trimethylsilyl trifluoromethanesulfonate, triethylsilyl trifluoromethanesulfonate, triisopropylsilyl trifluoromethanesulfonate, tertbutyldimethylsilyl trifluoromethanesulfonate, dimethylphenylsilyl trifluoromethanesulfonate, triphenylsilyl trifluoromethanesulfonate), silyl bromides (e.g., bromotrimethylsilane, bromotriethylsilane, bromotripropylsilane, triisopropylsilyl bromide tert-butyldimethylsilyl bromide, bromodiphenyl ...ethylsilane, bromotripropylsilane, triisopropylsilyl b The protecting agent is selected from the group consisting of methylphenylsilane, bromotriphenylsilane), N,O-bis(trimethylsilyl)acetamide, N,O-bis(trimethylsilyl)trifluoroacetamide, N-methyl-N(trimethylsilyl)trifluoroacetamide, benzyl halides (e.g., 3,5-dimethoxybenzyl chloride, 3,5-dimethoxybenzyl bromide), dibenzyl carbonate, acid chlorides (e.g., pivaloyl chloride, 1-adamantanecarbonyl chloride), anhydrides (e.g., di-tert-butyl carbonate), chloroformates (e.g., methyl chloroformate, ethyl chloroformate, benzyl chloroformate, phenyl chloroformate), alkyl chlorides (e.g., trityl chloride), and alkoxymethyl chlorides (e.g., methoxymethyl chloride). In one embodiment, the protecting agent is tert-butyl(chloro)dimethylsilane.

[0517] 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.

[0518] 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-pyrrolidinone, dimethylsulfoxide), nitriles (e.g., acetonitrile), and combinations thereof. In one embodiment, the solvent is dichloromethane.

[0519] In one embodiment, the reaction temperature is about -30 to 60°C. In one embodiment, the reaction temperature is about 10 to 30°C.

[0520] In one embodiment, the disclosure provides a method for preparing compound 10-C from compound 10-B.

[0521] In one embodiment, the method comprises treating compound 10-B with a Grignard reagent and a promoter in a suitable solvent for a time and under conditions effective to form compound 10-C.

[0522] In one embodiment, the Grignard reagent is selected from ethylmagnesium bromide in other ethereal solvents (e.g., methyl tert-butyl ether, diethyl ether, dibutyl ether, dioxane), ethylmagnesium chloride in ethereal solvents (e.g., tetrahydrofuran, methyl tert-butyl ether, diethyl ether, dibutyl ether, dioxane), n-propylmagnesium bromide, 2-phenylethylmagnesium bromide. In one embodiment, the Grignard reagent is ethylmagnesium bromide.

[0523] 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.

[0524] 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-pyrrolidinone, dimethylsulfoxide), nitriles (e.g., acetonitrile), and combinations thereof. In one embodiment, the solvent is tetrahydrofuran.

[0525] In one embodiment, the reaction temperature is about -20 to 30°C. In one embodiment, the reaction temperature is about -5 to 15°C.

[0526] In one embodiment, the disclosure provides a method for preparing compound 10-D from compound 10-C.

[0527] In one embodiment, the method comprises treating compound 10-C with a halogenating reagent and a base in a suitable solvent for a time and under conditions effective to form compound 10-D.

[0528] In one embodiment, the halogenating reagent 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-iodosuccinide, N-iodophthalimide, N-bromosuccinimide, iodine. In one embodiment, the halogenating reagent is N-bromosuccinimide.

[0529] 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.

[0530] In one embodiment, the 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.

[0531] In one embodiment, the reaction temperature is about -20 to 30°C. In one embodiment, the reaction temperature is about -5 to 20°C.

[0532] In one embodiment, the disclosure provides a method for preparing compound 10-E from compound 10-D.

[0533] In one embodiment, the method includes treating compound 10-D with an enzyme, cofactor, recycle system, and buffer, in a suitable solvent, at a suitable pH, for a time and under conditions effective to form compound 10-E.

[0534] In one embodiment, the enzyme is a selected ketoreductase, hi one embodiment, the halogenating reagent is CRED-A151.

[0535] In one embodiment, the cofactor is NADP. In one embodiment, the cofactor is NAD.

[0536] In one embodiment, the recycle system is selected from isopropanol, phosphite dehydrogenase (PDH) and phosphorous acid, formate dehydrogenase (FDH) and ammonium formate, glucose dehydrogenase (GDH) and glucose monohydrate, hi one embodiment, the recycle system is glucose dehydrogenase (GDH) and glucose monohydrate.

[0537] In one embodiment, the buffer is an aqueous buffer (e.g., sodium phosphate). In one embodiment, the buffer is an aqueous 0.1 M citrate buffer.

[0538] In one embodiment, the pH value is from 4 to 9. In one embodiment, the pH value is 6.2.

[0539] 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., N,N-dimethylacetamide, N-methyl-2-pyrrolidinone, DMSO), and combinations thereof. In one embodiment, the solvent is DMSO.

[0540] In one embodiment, the temperature of the reaction is about 20-40° C. In one embodiment, the temperature of the reaction is about 25-35° C.

[0541] In one embodiment, the disclosure provides a method for preparing compound 10-F from compound 10-E.

[0542] In one embodiment, the method comprises treating compound 10-E with a base and a methylating reagent in a suitable solvent for a time and under conditions effective to form compound 10-F.

[0543] In one embodiment, the methylating reagent is selected from dimethyl sulfate, iodomethane, methyl triflate, methyl tosylate, hi one embodiment, the methylating reagent is iodomethane.

[0544] In one embodiment, the base is selected from sodium hydride, potassium tert-butoxide, lithium tert-butoxide, sodium hydroxide, potassium hydroxide, lithium hydroxide, potassium tert-pentoxide, sodium tert-pentoxide, lithium tert-pentoxide, sodium hexamethyldisilazide, lithium hexamethyldisilazide, potassium hexamethyldisilazide, lithium diisopropylamide, sodium diisopropylamide, potassium diisopropylamide, sodium tert-butoxide. In one embodiment, the base is sodium tert-butoxide.

[0545] 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-butanol, tert-amyl alcohol), polar aprotic solvents (e.g., N,N-dimethylacetamide, N,N-dimethylformamide, N-methyl-2-pyrrolidinone, dimethylsulfoxide), water, and combinations thereof. In one embodiment, the solvent is tetrahydrofuran.

[0546] In one embodiment, the reaction temperature is about -78 to 50°C. In one embodiment, the reaction temperature is about -10 to 10°C.

[0547] In one embodiment, the disclosure provides a method for preparing compound 10-G from compound 10-F.

[0548] In one embodiment, the method comprises treating compound 10-F with a deprotecting reagent in a suitable solvent for a time and under conditions effective to form compound 10-G.

[0549] In one embodiment, the deprotection reagent is selected from sodium hydroxide, potassium hydroxide, lithium hydroxide, sulfuric acid, trifluoroacetic acid, phosphoric acid, hydrofluoric acid, hydrochloric acid (concentrated), pyridine hydrofluoride, triethylamine hydrofluoride, potassium fluoride, sodium fluoride, lithium fluoride, cesium fluoride, tetramethylammonium fluoride, tetrabutylammonium fluoride. In one embodiment, the deprotection reagent is hydrochloric acid (concentrated).

[0550] 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-pyrrolidinone, dimethylsulfoxide), water, and combinations thereof. In one embodiment, the solvent is methanol.

[0551] In one embodiment, the reaction temperature is about -15 to 50°C. In one embodiment, the reaction temperature is about 10 to 30°C.

[0552] In one embodiment, the present disclosure provides a method for making 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.

[0553] In one embodiment, the present disclosure provides a method for making 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.

[0554] K. Method for preparing formula 5-E from 5-C In one embodiment, the present disclosure provides a method for making compound 5-E from 5-C as shown in Scheme 11, wherein R m is C 1~6 alkyl, and two R n The parts are joined together to form C 2~4 Forms an alkyl bridge, the bridge is C 1~3 In one embodiment, R is optionally substituted with 1 to 4 groups independently selected from alkyl and phenyl. m is methyl. In one embodiment, two R n The moieties are joined together to form a bridge selected from -CH2CH2-, -CH(CH3)CH(CH3)-, -CH2CH(CH3)-, -CH2CH(CH3)-, -CH2CH(CH6H5)-, -C(CH3)2C(CH3)2-, -CH2CH2CH2-, -CH2CBr2CH2-, -CH2(C=CH)CH2-, -CH2CH(C6H5)CH2-, -CH(CH3)CH2CH(CH3)-, -CH2CH(CH3)CH2-, -CH2CH(CH3)CH2-, -CH2C(CH3)2CH2-, -CH2C(CH2CH3)2CH2-, -CH2CH2CH2CH2-, -CH2CH2CH2CH2CH2-, -CH(C6H5)CH(C6H5), -CH2CH(C6H5)CH2-, and -(o-C6H4)-. n The moieties are joined together to form -C(CH3)2C(CH3)2-.

[0555] [ka]

[0556] In one embodiment, the disclosure provides a method for preparing compound 5-D from compound 5-C.

[0557] In one embodiment, the method comprises treating compound 5-C with an acid in a suitable solvent for a time and under conditions effective to form compound 5-D.

[0558] 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, hi one embodiment, the acid is p-toluenesulfonic acid.

[0559] 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-pyrrolidinone, dimethylsulfoxide), hydrocarbon solvents (e.g., cyclohexane, methylcyclohexane, hexane, heptane), and combinations thereof. In one embodiment, the solvent is toluene.

[0560] In one embodiment, the temperature of the reaction is about 0-60° C. In one embodiment, the temperature of the reaction is about 45° C.

[0561] In one embodiment, the disclosure provides a method for preparing compound 5-E from compound 5-D.

[0562] In one embodiment, the method comprises treating compound 5-D with a base in a suitable solvent for a time and under conditions effective to form compound 5-E.

[0563] In one embodiment, the base is selected from a hydroxide base (e.g., lithium hydroxide, sodium hydroxide, potassium hydroxide, ammonium hydroxide), a carbonate base (e.g., sodium carbonate, potassium carbonate, cesium carbonate), a phosphate base, potassium tert-butoxide, potassium methoxide, and sodium methoxide. In one embodiment, the base is sodium hydroxide.

[0564] 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-pyrrolidinone, dimethylsulfoxide), hydrocarbon solvents (e.g., cyclohexane, methylcyclohexane, hexane, heptane), and combinations thereof. In one embodiment, the solvent is a combination of 2-methyltetrahydrofuran and ethanol.

[0565] In one embodiment, the temperature of the reaction is about 0-60° C. In one embodiment, the temperature of the reaction is about 20° C.

[0566] In one embodiment, the present disclosure provides a method for making compound 1 from a compound selected from 5-C, 5-D, and 5-E, as shown in Scheme 1 and Scheme 11.

[0567] IV.Compound In one embodiment, the present disclosure provides:

[0568] [ka] providing a compound selected from During the ceremony, Each R n is independent, C 1~6 alkyl or two R n The parts are joined together to form C 2~4 forming an alkyl bridge, the bridge being C 1~3 optionally substituted with 1 to 4 groups independently selected from alkyl and phenyl; R z is halogen or CN.

[0569] In one embodiment, R n is methyl.

[0570] In one embodiment, two R n The moieties are joined together to form a bridge selected from -CH2CH2-, -CH(CH3)CH(CH3)-, -CH2CH(CH3)-, -CH2CH(CH3)-, -CH2CH(CH6H5)-, -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)-.

[0571] In one embodiment, two R n The moieties are joined together to form -C(CH 3)2 Forms C(CH3)2-.

[0572] In one embodiment, the present disclosure provides:

[0573] [ka] The present invention provides a compound selected from the group consisting of:

[0574] In one embodiment, the present disclosure provides:

[0575] [ka] The present invention provides a compound selected from the group consisting of:

[0576] In one embodiment, the present disclosure provides:

[0577] [ka] The present invention provides a compound selected from the group consisting of:

[0578] In one embodiment, the present disclosure provides:

[0579] [ka] providing a compound selected from During the ceremony, X is a halogen.

[0580] [ka] C(O)2R 1 , -OS(O)2R 2 , or -OP(O)(R 2 )2, and R 1 is H or C 1~6 alkyl, and each R 2 is C 1~6 Alkyl or C 6~10 aryl, and each R 7 are independently H or C 1~3 and each alkyl or aryl is selected from the group consisting of 1 to 4 halogens or C 1~3 optionally substituted with alkyl, m is 1, 2, or 3, and n is 0 or 1; R 4 is a halogen, and R c is C 1~6 It is an alkyl.

[0581] In one embodiment, X is halogen, COOH,

[0582] [ka] is selected from.

[0583] In one embodiment, the present disclosure provides:

[0584] [ka]

[0585] The present invention provides a compound selected from the group consisting of:

[0586] In one embodiment, the present disclosure provides:

[0587] [ka] The present invention provides a compound selected from the group consisting of: EXAMPLES

[0588] V. Working Examples Oxidative cleavage of EX-52 to EX-109:

[0589] [ka]

[0590] EX-52 (1.0 equiv., conversion factor), ruthenium(III) chloride hydrate (0.1 equiv.), sodium periodate (6.0 equiv.), and 1:1 v / v acetonitrile:water (20 vol.) were charged to a reactor. The reaction mixture was stirred at about 20° C. for about 16 hours. The reaction mixture was diluted with ethyl acetate (50 vol.) and 5 wt. % aqueous acetic acid (50 vol.). The aqueous layer was extracted twice with ethyl acetate (50 vol.) and the combined organic layers were washed with 10 wt. % aqueous sodium thiosulfate (15 vol.) and water (15 vol.). The combined organic layers were dried over sodium sulfate, filtered, and concentrated to provide EX-109.1 H NMR(400MHz,CDCl3)δ7.40-7.26(m,5H),5.78(q,J=6.6Hz,1H),3.83(dd,J=14.6,6.3Hz,1H),3.68(dd,J=14.5,6.0 Hz,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).

[0591] Esterification of EX-109 to EX-110:

[0592] [ka]

[0593] A reactor was charged with EX-109 (1.0 equiv., conversion factor), N-hydroxyphthalimide (2.0 equiv.), EDC·HCl (2.0 equiv.), and dichloromethane (10 vol.). The reaction mixture was stirred at about 20° C. for about 2 h. The reaction mixture was diluted with ethyl acetate (50 vol.) and the organic layer was washed with 5 wt. % aqueous acetic acid (20 vol.), 3 M aqueous potassium carbonate (20 vol.), and water (20 vol.). The organic layer was dried over sodium sulfate, filtered, and concentrated. The crude product was purified by chromatography using ethyl acetate, heptane, and acetic acid to give EX-110. 1 H 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=6.6Hz,3H).

[0594] Boronation of EX-110 to EX-111:

[0595] [ka]

[0596] A reaction vessel was charged with EX-110 (1.0 equiv., conversion factor), bis(catecholato)diboron (1.3 equiv.), and dimethylacetamide (20 vol.). The reaction mixture was irradiated with a 34 W blue LED lamp at about 20° C. for about 3 h. Methyliminodiacetic acid (5.0 equiv.) was added and the reaction mixture was heated to about 50-60° C. for about 1 h. The reaction mixture was diluted with ethyl acetate (100 vol.) and water (50 vol.). The aqueous layer was extracted twice with ethyl acetate (75 vol.) and the combined organic layers were washed with saturated aqueous sodium chloride solution (50 vol.). The organic layers were dried over sodium sulfate, filtered, and concentrated. The crude product was purified by chromatography using dichloromethane and methanol to give EX-111. 1 H NMR(400MHz,CDCl3)δ7.34(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).

[0597] Oxidative cleavage of EX-84 and deprotection to EX-112:

[0598] [ka]

[0599] A reactor was charged with EX-84 (1.0 equiv., conversion factor), ruthenium(III) chloride hydrate (0.3 equiv.), sodium periodate (6.0 equiv.), and 1:1 v / v acetonitrile:methanol (20 vol.). The reaction mixture was stirred at about 0° C. for about 2 hours. The reaction mixture was diluted with ethyl acetate (80 vol.) and 5 wt. % aqueous acetic acid (40 vol.). The mixture was filtered through Celite and the filtrate was extracted twice with ethyl acetate (40 vol.). The combined organic layers were dried over sodium sulfate, filtered, and concentrated. The crude product was charged with 15 v / v % water in tetrahydrofuran (10 vol.). The solution was charged with methanesulfonic acid (2 vol.) and stirred at about 65° C. for about 18 hours. The reaction mixture was cooled to about 20° C., and then the mixture was diluted with ethyl acetate (20 vol.) and water (20 vol.). The aqueous layer was extracted with ethyl acetate (20 mL) and the combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by chromatography using ethyl acetate and heptane to give EX-112. 1 H NMR(400MHz,DMSO)δ12.12(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,2 H),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).

[0600] Reductive cyclization of EX-112 to EX-113:

[0601] [ka]

[0602] A reactor was charged with EX-112 (1.0 equiv., conversion factor), iron (10.0 equiv.), and acetic acid (10 vol.). The mixture was stirred at about 70° C. for about 2 hours. The reaction mixture was cooled to about 20° C. and charged with sodium triacetoxyborohydride (2.0 vol.). The mixture was stirred at about 20° C. for about 30 hours. The reaction mixture was diluted with ethyl acetate (150 vol.) and filtered through Celite. The organic layer was washed with two portions of water (40 vol.). The organic layer was dried over sodium sulfate, filtered, and concentrated to dryness. The crude product was purified by chromatography using ethyl acetate, heptane, and acetic acid to give EX-113. 1 H NMR(400MHz,DMSO)δ12.09(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).

[0603] Oxidative cleavage of EX-9 to EX-114:

[0604] [ka]

[0605] A reactor was charged with EX-9 (1.0 equiv., conversion factor), methylmorpholine N-oxide (1.5 equiv.), tetrahydrofuran (10 vol.), and water (1 vol.) and stirred. Once homogeneous, 2,6-lutidine (2.0 equiv.) and osmium tetroxide (0.05 equiv., 4 wt. % in water) were added and the reaction was stirred at about 20° C. for about 3 days. At that point, sodium periodate (2.5 equiv.) was added and stirred for about 6 hours. The reaction was then diluted with ethyl acetate (60 vol.) and water (30 vol.) before being charged to a separatory funnel and the resulting layers separated. The aqueous layer was extracted with ethyl acetate (2 times, 100 vol. total) and the organic layer was washed with a 30 wt. % aqueous solution of citric acid (1 time, 30 vol.), water (1 time, 30 vol.), and saturated aqueous sodium chloride solution (1 time, 30 vol.) before being dried over sodium sulfate. The dried organic layer was then filtered and concentrated to give EX-114. The crude material was used directly for the preparation of EX-115. 1 H NMR(400MHz,CDCl3)δ9.51(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).

[0606] Seyferth-Gilbert homologation of EX-114 to EX-115:

[0607] [ka]

[0608] Prior to stirring, the reactor was charged with EX-114 (1.0 equiv., conversion factor), potassium carbonate (3.5 equiv.), and methanol (100 vol.). Once homogeneous, dimethyl (1-azoacetonyl)phosphonate (1.5 equiv., 10 wt. % solution in acetonitrile) was charged and then stirred at about 20° C. for about 14 hours. At that point, the reaction was diluted with methyl tert-butyl ether (200 vol.) before transferring the mixture to a separatory funnel. The organic layer was washed with 2.5 wt. % aqueous sodium bicarbonate (2×, 200 vol. total) and saturated aqueous sodium chloride (1×, 100 vol.) before drying over sodium sulfate. The dried organic layer was then filtered, concentrated, and purified by column chromatography using ethyl acetate and heptane to provide EX-115. 1 H NMR(400MHz,CDCl3)δ7.71(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).

[0609] Methylation of EX-115 to EX-116:

[0610] [ka]

[0611] The reactor was charged with EX-115 (1.0 equiv, conversion factor) and tetrahydrofuran (3.0 vol), after which the flask was cooled to about -80°C. The resulting solution was charged with n-butyllithium (2.0 equiv, 2.5M in hexanes) and aged at about -80°C for about 1 hour, after which methyl iodide (2.0 equiv) was charged and warmed to about 20°C overnight. At this point, triethylamine (1.5 equiv), methyl tert-butyl ether (50 vol), and water (50 vol) were added before the crude reaction was transferred to a separatory funnel and the resulting phases were separated. The aqueous layer was extracted with methyl tert-butyl ether (2 times, 150 vol total) and the organic layer was washed with 0.1 M aqueous hydrochloric acid (50 vol), water (50 vol), and saturated aqueous sodium chloride (50 vol) before being dried over sodium sulfate. The dried organic layer was then filtered and concentrated to provide EX-116. The crude material was used directly in the preparation of EX-117. 1 H NMR(400MHz,CDCl3)δ7.69(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).

[0612] Desilylation of EX-116 to EX-117:

[0613] [ka]

[0614] A reactor was charged with EX-116 (1.0 equiv., conversion factor) and tetrahydrofuran (10 vol.) at about 25° C. Tetrabutylammonium fluoride (3.0 equiv., 1M in tetrahydrofuran) was then added and stirred for about 20 hours. At this point, water (50 vol.) was added before transferring to a separatory funnel and separating the resulting phases. The aqueous layer was extracted with ethyl acetate (2×200 vol. total) and the combined organic layers were washed with saturated aqueous sodium chloride (1×100 vol.) before drying over sodium sulfate. The dried organic layer was then filtered, concentrated, and purified by column chromatography using ethyl acetate and heptane to provide EX-117. 1 H NMR(400MHz,CDCl3)δ3.72(dd,J=9.0,2.1Hz,1H),3.56(dd,J=10.5,4.3Hz,1H),3.47-3.35(m,4 H),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).

[0615] Oxidation of EX-117 to EX-118:

[0616] [ka]

[0617] A reactor was charged with EX-117 (1.0 equivalent, conversion factor), acetonitrile (18 volumes), iodobenzene diacetate (1.1 equivalents), and tetramethylpiperidinyloxyl (0.075 equivalents) at about 20° C. and then stirred for about 20 hours. The resulting solution then contained EX-118 and was used directly in the preparation of EX-119. 1 H NMR (400MHz, CDCl3) δ9.75(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).

[0618] Reductive amination of EX-118 to EX-119:

[0619] [ka]

[0620] A reactor was charged with EX-12 (1.1 equiv.), EX-118 (1 equiv., conversion factor) dissolved in acetonitrile, acetonitrile (40 vol.), magnesium sulfate (200 wt.%), triethylsilane (2.0 equiv.), and TFA (2 equiv.) and stirred at about 20° C. for about 3 hours. The reaction mixture was diluted with dichloromethane (250 vol.) and filtered through Celite. The organic layer was washed with 2M aqueous potassium carbonate (400 vol.) and water (400 vol.). 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 give EX-119. 1 H NMR (400MHz, chloroform-d) δ7.75(d,J=8.5Hz,1H),7.50-7.41(m,2H),7.21(dd,J=8.5,2.2Hz,1H),7.13(d,J= 2.2Hz,1H),6.96(d,J=8.1Hz,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=14.3Hz,1H),3.28(dd,J=14.9,8.7Hz,1H),2.86-2.77(m,2H),2.64(pd,J=8.8,3.3Hz,1H),2.34(p,J=8.4 Hz,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).

[0621] Propynylmagnesium bromide addition of EX-120 to EX-121 and EX-122:

[0622] [ka]

[0623] The reactor was charged with EX-120 (1.0 equiv., conversion factor) and tetrahydrofuran (18V), after which the solution was stirred and cooled to about -80°C. The contents were charged with propynyl magnesium bromide (1.5 equiv., 0.5 M solution in tetrahydrofuran) and stirred at about -80°C for about 1 hour before warming to about 20°C. The reaction was then treated with a 25 wt% aqueous solution of ammonium chloride (30 vols.) and then transferred to a separatory funnel. The resulting layers were separated. The aqueous layer was extracted with ethyl acetate (2x, 30 vols. total), after which the combined organic layers were washed with saturated aqueous sodium chloride (1x, 10 vols.) and then dried over sodium sulfate. The dried organic layers were then filtered, concentrated, and purified by column chromatography using ethyl acetate and heptane to provide EX-121 and EX-122. EX-121: 1 H NMR(400MHz,CDCl3)δ7.74(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),3.33(d,J=14.3Hz,1H),3.23(dd,J=14.9,9.0Hz,1H),3.05(d,J=4.4Hz,1H),2.85-2.67(m,3H),2.33(qd,J= 8.6,6.1Hz,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). EX-122: 1H NMR (400 MHz, chloroform-d) δ 7.73 (d, J = 8.5 Hz, 1H), 7.62 (d, J = 2.0 Hz, 1H), 7.39 (dd, J = 8.2, 2.0 Hz, 1H), 7.18 (dd, J = 8.5, 2.4 Hz, 1H), 7.10 (d, J = 2.3 Hz, 1H), 6.92 (d, J = 8.2 Hz, 1H), 4.33 (dq, J = 6.9, 2.2 Hz, 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(d d,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).

[0624] Methylation of EX122 to EX119:

[0625] [ka]

[0626] The reactor was charged with EX122 (1 equiv., conversion factor), followed by tetrahydrofuran (10 vol.), iodomethane (5.0 equiv.) and cooled to about 0° C. Sodium tert-butoxide (1.5 equiv., 2M in tetrahydrofuran) was charged and the mixture was stirred at about 0° C. for about 4 hours. At this point, an additional portion of sodium tert-butoxide (0.25 equiv., 2M in tetrahydrofuran) was charged at about 0° C. and stirred for about 4 hours. Triethylamine (4.1 equiv.) was charged and the mixture was diluted with methyl tert-butyl ether (30 vol.) and water (20 vol.). The layers were separated and the aqueous layer was back extracted with methyl tert-butyl ether (2 times, 35 vol. total). The combined organic layers were washed with a solution of sodium metabisulfite (5 equiv.) in water (10 vol.), followed by saturated aqueous sodium chloride solution (20 vol.), then dried over magnesium sulfate, filtered, and concentrated. The crude product was purified by chromatography using ethyl acetate and hexanes to give EX-119. 1H NMR(400MHz,CDCl3)δ7.71(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).

[0627] Saponification of EX-119 to EX-123:

[0628] [ka]

[0629] A reactor was charged with EX-119 (1.0 equiv., conversion factor), tetrahydrofuran (20 vol.), water (20 vol.), and lithium hydroxide (10 equiv.), and the reaction was then heated (50° C.) for approximately 5 days. At that time, the reaction was cooled to 20° C. before being charged with 1 M aqueous hydrochloric acid (60 vol.), the reaction was transferred to a separatory funnel, and the resulting layers were separated. The aqueous layer was extracted with ethyl acetate (three times, 60 vol. total), and the combined organic layers were 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 EX-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).

[0630] SNAr of EX-11 with 4-bromo-1-fluoro-2-nitrobenzene to give EX-124:

[0631] [ka]

[0632] A reactor was charged with EX-11 (1.0 equiv., conversion factor), 4-bromo-1-fluoro-2-nitrobenzene (1.05 equiv.), and tetrahydrofuran (10 vol.). To the reaction mixture was added a solution of potassium tert-butoxide in tetrahydrofuran (2.4 equiv.) over about 10 minutes. The reaction mixture was stirred at about 20° C. for about 1 hour. The reaction mixture was quenched with water (10 vol.) and extracted with ethyl acetate (40 vol.). The combined organic layers were washed with brine (20 vol.), dried over magnesium sulfate, filtered, and concentrated. The crude product was purified by chromatography using ethyl acetate and heptane to give EX-124. 1H NMR (400MHz, chloroform-d) δ8.04(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,1 H),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).

[0633] Acetal hydrolysis and reductive cyclization of EX-124 to EX-126:

[0634] [ka]

[0635] A vial was charged with EX-124 (1.0 equiv., conversion factor), water (2 vol.), and tetrahydrofuran (10 vol.). The solution was charged with methanesulfonic acid (4 equiv.) and stirred at about 50° C. for about 48 hours. The reaction mixture was cooled to about 20° C. and saturated aqueous sodium bicarbonate (10 vol.) was charged, followed by extraction of the crude reaction mixture with ethyl acetate (30 vol.). The organic layer was washed with water (15 vol.). The organic layer was dried over magnesium sulfate, filtered, and concentrated to dryness. The crude product (EX-125) was used directly in the next step. A vial was charged with EX-125 (1.0 equiv., conversion factor), iron (10 equiv.), and acetic acid (10 vol.). The mixture was stirred at about 50° C. for about 18 hours. The reaction mixture was cooled to about 20° C. and diluted with dichloromethane (20 vol.), followed by filtration of the reaction mixture through a pad of Celite. The solution was then added with sodium triacetoxyborohydride (1.2 eq.) and stirred at about 20° C. for about 3 hours. After the reaction mixture was quenched with saturated aqueous sodium bicarbonate (10 vol.), the resulting solution was extracted with dichloromethane (100 vol.). 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 give EX-126. 1 H NMR (400MHz, chloroform-d) δ7.85(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),4.1 4(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).

[0636] Reductive amination of EX-126 with EX-11 to give EX-127:

[0637] [ka]

[0638] A vial was charged with EX-126 (1 equivalent, conversion factor), EX-11 (1.2 equivalents, 6.5 wt % solution in acetonitrile), trifluoroacetic acid (0.5 equivalents), triethylsilane (2.0 equivalents), and acetonitrile (10 volumes) and then stirred for about 24 hours at about 20° C. The mixture was then concentrated to dryness and directly purified by chromatography using ethyl acetate and heptane to provide EX-127. 1 H NMR (400MHz, chloroform-d) δ 7.72 (d, J = 8.5 Hz, 1H), 7.19 (dd, J = 8.5, 2.4 Hz, 1H), 7.09 (d, J = 2.3 Hz, 1H), 6.92 (d, J = 1.3 Hz, 1H), 6.77 (d, J = 1.5 Hz, 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).

[0639] Carboxylation of EX-127 to EX-60:

[0640] [ka]

[0641] EX-127 (1.0 equiv., conversion factor), palladium acetate (0.1 equiv.), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0.1 equiv.), dicyclohexylcarbodiimide (0.2 equiv. of a 1.0 M solution in dichloromethane), dimethylformamide (20 volumes), formic acid (3.5 equiv.), and trimethylamine (2.0 equiv.) were charged to the vial, which was then sealed and heated at about 90° C. for about 18 hours. The reaction was cooled to about 20° C., then concentrated to dryness and directly purified by chromatography using ethyl acetate and heptane to provide EX-60. 1H NMR (400MHz, chloroform-d) δ7.71(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).

[0642] SNAr of EX-11 with 4-fluoro-3-nitrobenzonitrile to give EX-128:

[0643] [ka]

[0644] To the vial was added EX-11 (1.0 equiv., conversion factor), 4-fluoro-3-nitrobenzonitrile (1.2 equiv.), and tetrahydrofuran (10 vol.), and the vial was then cooled to about -40°C. To the reaction mixture was charged a solution of potassium tert-butoxide in tetrahydrofuran (1.2 equiv.) over about 10 minutes. The reaction mixture was stirred at about -40°C for about 1 hour. The reaction mixture was warmed to about 20°C, then quenched with water (10 vol.) and extracted with ethyl acetate (40 vol.). The combined organic layers were washed with brine (20 vol.), dried over magnesium sulfate, filtered, and concentrated. The crude product was purified by chromatography using ethyl acetate and heptane to give EX-128. 1H NMR(400MHz,chloroform-d)δ8.12(d,J=2.1Hz,1H),7.72(dd,J=8.7,2.2Hz,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=15.8,14.2,7.5Hz,2H),2.04(t,J=10.5Hz,1H),1.86(t,J=9.0Hz,2H),1.47(s,1H).

[0645] Acetal hydrolysis and reductive cyclization of EX-128 to EX-130:

[0646] [ka]

[0647] A vial was charged with EX-128 (1.0 equiv., conversion factor), water (2 vol.) and tetrahydrofuran (10 vol.). The solution was charged with methanesulfonic acid (4 equiv.) and stirred at about 50° C. for about 48 hours. The reaction mixture was cooled to about 20° C. and saturated aqueous sodium bicarbonate (10 vol.) was charged, after which the crude reaction mixture was extracted with ethyl acetate (30 vol.). The organic layer was washed with water (15 vol.). The organic layer was dried over magnesium sulfate, filtered and concentrated to dryness. The crude product (EX-129) was used directly in the next step.

[0648] A vial was charged with EX-129 (1.0 equiv., conversion factor), iron (10 equiv.), and acetic acid (10 vol.). The mixture was stirred at about 50° C. for about 18 hours. The reaction mixture was cooled to about 20° C. and diluted with dichloromethane (20 vol.), after which the reaction mixture was filtered through a pad of celite. The solution was then charged with sodium triacetoxyborohydride (1.2 equiv.) and stirred at about 20° C. for about 3 hours. The reaction mixture was quenched with saturated aqueous sodium bicarbonate (10 vol.), after which the resulting solution was extracted with dichloromethane (100 vol.). 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 give EX-130. 1 H NMR(400MHz,chloroform-d)δ7.83(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,2 H),1.97-1.72(m,3H),1.66(ddd,J=12.2,9.6,2.7Hz,1H),1.34-1.21(m,2H).

[0649] Reductive amination of EX-130 with EX-11 to EX-131:

[0650] [ka]

[0651] A vial was charged with EX-130 (1 equivalent, conversion factor), EX-11 (1.2 equivalents, 6.5 wt % solution in acetonitrile), trifluoroacetic acid (0.5 equivalents), triethylsilane (2.0 equivalents), and acetonitrile (10 volumes) and then stirred for about 24 hours at about 20° C. The mixture was then concentrated to dryness and directly purified by chromatography using ethyl acetate and heptane to provide EX-131. 1H NMR(400MHz,chloroform-d)δ7.62(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).

[0652] Nitrile hydrolysis of EX-60 in EX-131:

[0653] [ka]

[0654] To a vial was added EX-131 (1 equivalent, conversion factor), methanol (40 volumes), water (4 volumes), and potassium hydroxide (10 equivalents), then stirred at about 110° C. for about 48 hours. The reaction mixture was then charged with aqueous HCl (1.0 M, 20 volumes) and heated to about 100° C. for about 2 hours, then cooled to about 20° C. The reaction was then concentrated and directly purified by chromatography using ethyl acetate and heptane to provide EX-60.

[0655] Acetal formation of EX-132 to EX-133 and acetate hydrolysis:

[0656] [ka]

[0657] A reactor equipped with a Dean-Stark apparatus was charged with EX-132 (1.0 equiv., conversion factor), pinacol (2.0 equiv.), p-toluenesulfonic acid (0.05 equiv.), and toluene (15 vol.). The reaction mixture was heated to about 45° C. and a partial vacuum was applied. The mixture was stirred for about 24 h. The mixture was concentrated to dryness and the crude material was diluted with MeTHF (10 vol.). 1N aqueous NaOH (3 equiv.) and EtOH (4 vol.) were charged and the resulting biphasic mixture was stirred for about 5 h. The layers were separated and the organic layer was washed with aqueous NaCl (15 vol.). The organic layer was then concentrated to dryness and the resulting residue was dissolved in EtOH (21 vol.). Water (37 vol.) was added in a dropwise fashion. The resulting slurry was filtered, rinsed with water (10 vol.), and dried to provide EX-133. 1 H NMR (400MHz, CDCl3): δ7.37(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=1 1.4Hz,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).

[0658] SNAr of EX-133 with 4-bromo-1-fluoro-2-nitrobenzene to give EX-134:

[0659] [ka]

[0660] A reactor was charged with EX-133 and tetrahydrofuran (10 vol) and cooled to about 0° C. Potassium tert-butoxide (2.5 eq) in tetrahydrofuran was added over about 20 min, followed by 4-bromo-1-fluoro-2-nitrobenzene over about 20 min. The reaction mixture was stirred at 0° C. for about 2 h and then quenched with water (5 vol). The mixture was concentrated and then dissolved in ethyl acetate (10 vol). The organic layer was washed with saturated sodium chloride solution (5 vol). The phases were separated and then the aqueous layer was extracted twice with ethyl acetate (10 vol). 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 give EX-134. 1 H NMR (400MHz, chloroform-d) δ7.97(d,J=2.4Hz,1H),7.68-7.53(m,2H),7.12(d,J=7.2Hz,2H),6.96(d,J=9. 0Hz, 1H), 5.39 (s, 1H), 4.38-4.17 (m, 2H), 2.78 (t, J=6.3Hz, 2H), 2.26-1.71 (m, 4H), 1.40-0.85 (m, 12H).

[0661] Pinacol hydrolysis of EX-134 to EX-125:

[0662] [ka]

[0663] The reactor was charged with EX-134 and tetrahydrofuran (10 vol), followed by water (2 vol) and MSA (4 eq). The reaction mixture was stirred under reflux for about 17 hours and then quenched with saturated NaHCO3 in water (7 vol) at 20°C. The mixture was extracted with ethyl acetate (10 vol). The phases were separated and the aqueous layer was extracted with ethyl acetate (10 vol). The combined organic layers were washed with water (10 vol), dried over magnesium sulfate, filtered and concentrated. The crude product was purified by silica gel chromatography using ethyl acetate and heptane to give EX-125. 1H NMR(400MHz,chloroform-d)δ9.56(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).

[0664] SNAr of EX-133 with 4-fluoro-3-nitrobenzonitrile to give EX-135:

[0665] [ka]

[0666] A reactor was charged with EX-133 and tetrahydrofuran (10 vol) and cooled to about -20°C. Potassium tert-butoxide in tetrahydrofuran (2.5 eq) was added over about 40 min, followed by 4-fluoro-3-nitrobenzonitrile over about 10 min. The reaction mixture was stirred at 0°C for about 2 h and then quenched with water (5 vol). The mixture was concentrated and then dissolved in ethyl acetate (10 vol). The organic layer was washed with saturated sodium chloride solution (5 vol). The phases were separated and then the aqueous layer was extracted twice with ethyl acetate (10 vol). 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 give EX-135. 1 H 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).

[0667] Pinacol hydrolysis of EX-135 to EX-129:

[0668] [ka]

[0669] The reactor was charged with EX-135 and tetrahydrofuran (10 vol), followed by water (2 vol) and MSA (4 eq). The reaction mixture was stirred under reflux for about 17 hours and then quenched with saturated NaHCO3 in water (7 vol) at 20°C. The mixture was extracted with ethyl acetate (10 vol). The phases were separated and the aqueous layer was extracted with ethyl acetate (10 vol). The combined organic layers were washed with water (10 vol), dried over magnesium sulfate, filtered and concentrated. The crude product was purified by silica gel chromatography using ethyl acetate and heptane to give EX-129. 1 H NMR (400MHz, chloroform-d) δ9.53(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).

[0670] Amide coupling of EX-51 and EX-72 and deprotection to EX-136:

[0671] [ka]

[0672] An inert reaction vessel was charged with EX-51 (1.0 equiv., conversion factor), EX-72 (1.06 equiv.), 4-dimethylaminopyridine (1.0 equiv.), and acetonitrile (15 vol.). To this mixture was charged 1-methylimidazole (3.0 equiv.) and N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (1.3 equiv.) and the contents were stirred at about 20°C for about 20 hours. Dichloromethane (15 vol.) and 10% (w / w) aqueous citric acid (12 vol.) were charged to the vessel and the layers were separated. The aqueous layer was washed with dichloromethane (15 vol.) and the layers were separated. The combined organic layers were concentrated under reduced pressure and then charged with 2-methyltetrahydrofuran (20 vol.). The contents were stirred at about 60°C and then charged with 10% (w / w) aqueous citric acid (12 vol.). The contents were stirred at about 60° C. for about 48 hours, then the layers were separated. 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 provide EX-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).

[0673] Amide coupling of EX-60 and EX-136 to EX-73:

[0674] [ka]

[0675] An inert reaction vessel was charged with EX-60 (1.0 equiv., conversion factor), EX-136 (1.06 equiv.), 4-dimethylaminopyridine (1.0 equiv.), and acetonitrile (10 vol.). To this mixture was charged 1-methylimidazole (3.0 equiv.) and N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (1.3 equiv.) and the contents were stirred at about 20°C for about 24 hours. Ethyl acetate (10 vol.) and 10% (w / w) aqueous citric acid (10 vol.) were charged to the vessel and the layers were separated. The crude product was carried forward to compound 1 utilizing ring-closing metathesis of EX-73 to compound 1 and matched the authentic material.

[0676] Esterification of EX-137 to EX-138:

[0677] [ka]

[0678] An inert reaction vessel was charged with EX-137 (1.0 equiv., conversion factor), ethanol (5 vol.), and sulfuric acid (0.02 vol.). The reaction mixture was then heated to about 80° C. and stirred overnight. The reaction mixture was concentrated to dryness under vacuum. The residue was then diluted with methyl tert-butyl ether (2 vol.), followed by the addition of saturated aqueous sodium bicarbonate (2 vol.). The layers were separated, the aqueous layer was back-extracted with methyl tert-butyl ether (2 vol.), and the combined organic layers were washed with 15 wt. % aqueous sodium chloride (2 vol.). The layers were separated and the organic layer was placed over sodium sulfate. The drying agent was removed by filtration and the filtrate was concentrated to provide EX-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)

[0679] Enzymatic hydrolysis of EX-138 to EX-139:

[0680] [ka]

[0681] The reactor was charged with EX-138 (1.0 equiv., conversion factor), acetone (4 vol.), 0.1 M pH 7 phosphate buffer (20 vol.), and Lipozyme CALB L (0.05 vol.). The reaction mixture was warmed to approximately 30° C. and the pH was maintained between 7.0-7.5 by addition of 1 N NaOH. After approximately 4 h, the reaction mixture was diluted with dichloromethane (10 vol.) and acidified with 1 M aqueous HCl (5 vol.). The layers were separated and the aqueous layer was back extracted with dichloromethane (10 vol.). The organic layers were combined and dried over sodium sulfate. The drying agent was removed by filtration and the filtrate was then concentrated to dryness under vacuum to provide EX-139. 1 H NMR (400MHz, DMSO-d6) δ12.31 (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).

[0682] Reduction of EX-139 to EX-140:

[0683] [ka]

[0684] To 2-methyltetrahydrofuran (10 volumes) was added borane dimethylsulfide complex (1.5 equivalents) and the resulting solution was cooled to about 0° C., followed by the addition of a solution of EX-139 (1.0 equivalents, conversion factor) in 2-methyltetrahydrofuran (5 volumes) at a rate to maintain the internal temperature below about 10° C. Upon completion of the addition, the reaction mixture was warmed to about room temperature and stirred for about 2 hours. The reaction mixture was quenched by the slow addition of methanol (10 volumes). The resulting solution was concentrated to dryness and the resulting material was 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 EX-140. 1H 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).

[0685] Silyl protection of EX-140 to EX-141:

[0686] [ka]

[0687] An inert reaction vessel was charged with EX-140 (1.0 equiv., conversion factor) and dichloromethane (10 vol.) and the mixture was cooled to about 0° C. To this mixture was charged imidazole (2.5 equiv.) and tert-butyldimethylsilyl chloride (1.2 equiv.) and the contents were stirred for about 17 hours while warming to about 20° C. Dichloromethane (10 vol.) and water (10 vol.) were charged to the vessel and the layers were separated. Water (10 vol.) was added to the organic layer and the layers were separated. The organic layer was dried over sodium sulfate and concentrated to provide EX-141. 1 H 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).

[0688] Klinkovich cyclopropanation of EX-141 to EX-142:

[0689] [ka]

[0690] An inert reaction vessel was charged with EX-141 (1.0 equiv., conversion factor) and THF (10 vol.) and the mixture was cooled to about 0° C. To this mixture was charged titanium(IV) isopropoxide (1.0 equiv.) followed by a 40 wt % solution of ethylmagnesium bromide in 2-MeTHF (3.0 equiv.) and the contents were stirred for about 17 hours while warming to about 20° C. A 20 wt % aqueous solution of citric acid (6.5 vol.) and a 25 wt % aqueous solution of ammonium chloride (6.5 vol.) were combined and charged to the vessel and the layers were separated. MTBE (22 vol.) was charged to the aqueous layer and the layers were separated. A 15 wt % aqueous solution of sodium chloride (6.5 vol.) was charged to the combined organic layers and the layers were separated. The organic layer was dried over sodium sulfate, filtered, and concentrated to provide EX-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, 5.1 Hz, 1H), 0.09 (d, J = 1.1 Hz, 6H).

[0691] Protection of EX-143 to EX-144:

[0692] [ka]

[0693] A reactor was charged with EX-143 (1.0 equiv., conversion factor) and dichloromethane (8 vol.). The resulting mixture was cooled to about 0° C. and charged with imidazole (2.5 equiv.) and tert-butyldimethylchlorosilane (1.2 equiv.). The reaction mixture was stirred for about 12 hours and then charged with water (10 vol.) and dichloromethane (8 vol.). The layers were separated and the organic layer was washed with water (10 vol.). The layers were separated and the organic layer was dried over sodium sulfate, filtered, and concentrated to provide EX-144. 1 H NMR (400MHz, CDCl3): δ3.16(s,3H),3.59-3.49(m,2H),2.96-2.92(m,1H),2.7 0-2.59(m,1H),2.13-1.94(m,2H),1.86-1.71(m,2H),0.85(s,9H),0.01(s,6H) Klinkovich cyclopropanation of EX-144 to EX-142:

[0694] [ka]

[0695] A reactor was charged with EX-144 (1.0 equiv., conversion factor) and tetrahydrofuran (11 vol.) and cooled to about 0° C. Titanium(IV) isopropoxide (1.0 equiv.) was charged to the mixture followed by the addition of 40 wt. % ethylmagnesium bromide (3.0 equiv.) in 2-methyltetrahydrofuran at about 0° C. over about 1 h. The mixture was warmed to about 22° C. and quenched with 25 wt. % aqueous ammonium chloride solution (6 vol.), followed by 20 wt. % citric acid solution (6 vol.). The aqueous layer was removed and back extracted with methyl tert-butyl ether (22 vol.). The organic layers were combined, washed with 15 wt. % aqueous sodium chloride solution (7 vol.), dried over sodium sulfate, filtered, and concentrated to provide EX-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 = 1.1 Hz, 6H).

[0696] Synthesis of EX-145 from EX-142:

[0697] [ka]

[0698] The reactor was charged with EX-142 (1.0 equiv., conversion factor) in dichloromethane (8 vol.) and cooled to about 0° C. N-bromosuccinimide (1.05 equiv.) was charged in one portion and stirred at about 0° C. for about 1.5 hours. Triethylamine (2.0 equiv.) was charged at 0° C. and stirred at about 0° C. for about 2.5 hours. The reaction mixture was quenched with 20 wt % ammonium chloride solution (6 vol.) and then adjusted to about 20° C. The layers were separated and the organic layer was washed with 5 wt % sodium bicarbonate solution (8 vol.), followed by 15 wt % aqueous sodium chloride solution (15 vol.), dried over magnesium sulfate, filtered, and then concentrated to provide EX-145. 1 H NMR(400MHz,CDCl3)δ6.27-6.36(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).

[0699] Ketoreductase reduction of EX-145 to EX-146:

[0700] [ka]

[0701] A reaction vessel was charged with NAD (1.0 wt%), GDH (2.0 wt%), glucose monohydrate (1.2 eq), 0.1 M aqueous citrate buffer at pH 6.2 (17 vol), and a solution of EX-145 (1.0 eq) in DMSO (2 vol). CRED-A151 (50 wt%) was charged to this mixture and the contents were stirred at about 30° C. for about 14 hours. Additional NAD (0.2 wt%), GDH (0.4 wt%), and CRED-A151 (10 wt%) were charged to the vessel and the contents were stirred for about 9 hours. 1 M citrate buffer (pH 3.6) was charged to the vessel to adjust the pH of the contents to about 4.5, and then the contents were cooled to about 4° C. Saturated aqueous sodium chloride solution (20 vol) and MTBE (120 vol) were charged to the vessel and the layers were separated. The organic layer was filtered through Celite. Saturated aqueous sodium chloride (20 vol) was added to the organic layer and the layers were separated. This was repeated once more. The organic layer was dried over sodium sulfate and concentrated to give EX-146. 1 H NMR (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).

[0702] Methylation of EX-146 to EX-147:

[0703] [ka]

[0704] An inert reaction vessel was charged with EX-146 (1.0 equiv., conversion factor) and THF (10 vol.) and the mixture was cooled to about 0° C. To this mixture was charged sodium tert-butoxide (3.0 equiv.) and iodomethane (6.0 equiv.) and the contents were stirred at about 0° C. for about 2 hours. Triethylamine (7.6 equiv.) was charged to the vessel and the contents were stirred at about 0° C. for about 1 hour. MTBE (20 vol.) and water (20 vol.) were charged to the vessel and the layers were separated. MTBE (20 vol.) was charged to the aqueous layer and the layers were separated. 15 wt. % aqueous sodium chloride solution (20 vol.) was charged to the combined organic layer and the layers were separated. The combined organic layers were dried over sodium sulfate and concentrated to provide EX-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).

[0705] Deprotection of EX-147 to EX-148:

[0706] [ka]

[0707] An inert reaction vessel was charged with EX-147 (1.0 equiv., conversion factor) and methanol (10 vol.). To this mixture was charged concentrated HCl (3.0 equiv.) and the contents were stirred at about 22° C. for about 3 hours. Saturated aqueous sodium bicarbonate (12 vol.) and dichloromethane (12 vol.) were charged to the vessel and the layers were separated. Dichloromethane (12 vol.) was charged to the aqueous layer and the layers were separated. This was repeated once more. The combined organic layers were dried over magnesium sulfate and concentrated to provide EX-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).

[0708] Although the above disclosure has been described in some detail by way of illustration and example for clarity of understanding, it will be understood by those skilled in the art 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 any inconsistency between this application and the references provided herein, this application shall control. According to a preferred embodiment of the present invention, for example, the following is provided: (Section 1) A compound selected from [ka] During the ceremony, Each R n is independent, C 1~6 alkyl or two R n The parts are joined together to form C 2~4 forming an alkyl bridge, the bridge being C 1~3 optionally substituted with 1 to 4 groups independently selected from alkyl and phenyl; R z is a halogen or CN. (Section 2) [ka] The compound according to item 1, selected from: (Section 3)

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Claims

1. A compound selected from 【Chemistry 133】 During the ceremony, Each R ｎ is independent, C １～６ alkyl or two R ｎ The parts are joined together to form C ２～４ forming an alkyl bridge, said bridge being １～３ optionally substituted with 1 to 4 groups independently selected from alkyl and phenyl; R ｚ is a halogen or CN. 【Request 2】 【Chemical 134】 2. The compound of claim 1 , selected from: 【Request 3】 【Chemical 135】 A compound selected from: 【Request 4】 【Chemical 136】 A compound selected from: 【Request 5】 【Chemical 137】 A compound selected from During the ceremony, X is a halogen; 【Chemistry 138】 C (O) ２ R １ , -OS(O) ２ R ２ or -OP(O)(R ２ ) ２ and R １ is H or C １～６ alkyl, and each R ２ is C １～６ Alkyl or C ６～１０ aryl, and each R ７ are independently H or C １～３ and each alkyl or aryl is selected from the group consisting of 1 to 4 halogens or C １～３ optionally substituted with alkyl, m is 1, 2, or 3, and n is 0 or 1; R ４ is a halogen, R ｃ is hydrogen or C １～６ A compound which is an alkyl.

6. X is COOH, 【Chemistry 139】 6. The compound of claim 5,

7. 【Chemical 140】 6. The compound of claim 5, selected from:

8. 【Chemical 141】 A compound selected from:

9. Compound 1: 【Chemistry 142】 or a salt thereof, comprising the steps of: 【Chemistry 143】 with the corresponding compound of formula 1-K: 【Chemistry 144】 and the corresponding compound of formula 6-L: 【Chemistry 145】 to provide said compound of formula 9-A or a salt thereof, and said compound of formula 1-K is prepared by reacting with a corresponding compound of formula 1-Q: 【Chemistry 146】 or a salt thereof, In the formula, R ｘ and R ｙ are each independently H or C １～６ alkyl, R ２ is H, R ３ and R ５ are CH ３ R 6 is Cl; R ｚ is halogen or CN, R ｐ is -C(=O)-C １～６ Alkyl, -C(=O)-C ６～１０ Aryl, -C(=O)-O-C １～６ Alkyl, -C(=O)-O-C １～６ Alkyl-C ６～１０ Aryl, and -C(=O)-O-C ６～１０ aryl, each aryl being selected from C １～３ Alkyl and -OC １～３ optionally substituted with 1 to 4 groups independently selected from alkyl.

10. The compound of formula 1-Q: 【Chemistry 147】 or a salt thereof, with the corresponding compound of formula 1-P: 【Chemistry 148】 and the corresponding compound of formula 1-I: 【Chemistry 149】 to provide the compound of formula 1-Q.

11. The compound of formula 1-P: 【Chemistry 150】 with the corresponding compound of formula 1-N: 【Chemistry 151】 wherein the compound of formula 1-N is converted to a corresponding compound of formula 1-M: 【Chemistry 152】 is prepared by converting the compound of formula 1-N into ｎ is independently C １～６ alkyl or two R ｎ The parts are joined together to form C ２～４ forming an alkyl bridge, said bridge being １～３ The method of claim 10, optionally substituted with 1 to 4 groups independently selected from alkyl and phenyl.

12. The compound of formula 1-M: 【Chemistry 153】 with the corresponding compound of formula 5-E: 【Chemistry 154】 and the corresponding compound of formula 1-L: 【Chemistry 155】 to provide the compound of formula 1-M, During the ceremony, Each R ｎ is independent, C １～６ alkyl or two R ｎ The parts are joined together to form C ２～４ forming an alkyl bridge, said bridge being １～３ optionally substituted with 1 to 4 groups independently selected from alkyl and phenyl; R ｚ The method of claim 11 , wherein is halogen or CN.

13. The compound of formula 1-L is 【Chemistry 156】 The method of claim 12, wherein the

14. The compound of formula 5-E is 【Chemistry 157】 The method of claim 12, wherein

15. The compound of formula 5-E is 【Chemistry 158】 The method of claim 12, wherein

16. The compound of formula 1-I is 【Chemistry 159】 The method according to claim 10, wherein

17. Compound 1: 【Chemistry 160】 or a salt thereof, with the corresponding compound of formula 9-J: 【Chemistry 161】 or a salt thereof, wherein the compound of formula 9-J or a salt thereof is converted to the corresponding compound of formula 9-L: 【Chemistry 162】 or a salt thereof and the corresponding compound of formula 9-I: 【Chemistry 163】 or a salt thereof to provide a compound of formula 9-J or a salt thereof; In the formula, R ｕ and R ｗ are each independently H, C １～６ Alkyl or C ６～１０ aryl, R ２ is H, R ３ and R ５ Each independently represents CH ３ and R １２ teeth, 【Chemistry 164】 That is, the method.

18. The compound of formula 9-I: 【Chemistry 165】 or a salt thereof, with the corresponding compound of formula 9-H: 【Chemistry 166】 or a salt thereof, to prepare a corresponding compound of formula 9-I, wherein the corresponding compound of formula 9-H or a salt thereof is converted to a corresponding compound of formula 9-G: 【Chemistry 167】 or a salt thereof and the corresponding compound of formula 9-K: 【Chemistry 168】 or a salt thereof to provide a compound of formula 9-H or a salt thereof.

20. The method of claim 17, Here, R ｐ is -C(=O)-C １～６ Alkyl, -C(=O)-heteroaryl, -C(=O)-O-C １～６ Alkyl, and -C(=O)-O-C １～６ Alkyl-C ６～１０ aryl, where each aryl or heteroaryl is selected from C １～３ Alkyl and -OC １～３ and optionally substituted with 1 to 4 groups independently selected from alkyl, heteroaryl, and aryl groups, wherein each heteroaryl has 1 to 4 heteroatoms, wherein each heteroatom is independently selected from N, O, and S, and wherein each heteroaryl has 5 to 10 ring members. method.

19. Compound of formula 9-J: 【Chemistry 169】 or a salt thereof, with the corresponding compound of formula 9-L: 【Chemistry 170】 or a salt thereof and the corresponding compound of formula 9-I: 【Chemistry 171】 or a salt thereof to provide said compound of formula 9-J or a salt thereof, Here, R ２ is H, and R ３ and R ５ are each independently CH ３ and R １２ teeth, 【Chemistry 19-1】 and R ｕ and R ｗ are each independently H, C １～６ Alkyl, or C ６～１０ aryl, wherein said alkyl is C ６～１０ optionally substituted with aryl; method.

20. Compound of formula 9-I: 【Chemistry 172】 or a salt thereof, with the corresponding compound of formula 9-H: 【Chemistry 173】 or a salt thereof, by converting said compound of formula 9-I to the corresponding compound of formula 9-I, Here, R ３ is CH ３ and R １２ teeth 【Chemical 79】 and R ｗ is H, C １～６ Alkyl, or C ６～１０ aryl, wherein said alkyl is C ６～１０ aryl optionally substituted, and R ｐ is -C(=O)-C １～６ Alkyl, -C(=O)-heteroaryl, -C(=O)-O-C １～６ Alkyl, and -C(=O)-O-C １～６ Alkyl-C ６～１０ aryl, where each aryl or heteroaryl is selected from C １～３ Alkyl and -OC １～３ and optionally substituted with 1 to 4 groups independently selected from alkyl, heteroaryl, and aryl groups, wherein each heteroaryl has 1 to 4 heteroatoms, wherein each heteroatom is independently selected from N, O, and S, and wherein each heteroaryl has 5 to 10 ring members. method.

21. Compound of formula 9-H: 【Chemistry 174】 or a salt thereof, with the corresponding compound of formula 9-G: 【Chemistry 175】 or a salt thereof and the corresponding compound of formula 9-K: 【Chemistry 176】 or a salt thereof to provide said compound of formula 9-H or a salt thereof, Here, R ３ is CH ３ and R １２ teeth 【Chemical 79】 and R ｗ is H, C １～６ Alkyl, or C ６～１０ aryl, wherein said alkyl is C ６～１０ aryl optionally substituted, and R ｐ is -C(=O)-C １～６ Alkyl, -C(=O)-heteroaryl, -C(=O)-O-C １～６ Alkyl, and -C(=O)-O-C １～６ Alkyl-C ６～１０ aryl, where each aryl or heteroaryl is selected from C １～３ Alkyl and -OC １～３ and optionally substituted with 1 to 4 groups independently selected from alkyl, heteroaryl, and aryl groups, wherein each heteroaryl has 1 to 4 heteroatoms, wherein each heteroatom is independently selected from N, O, and S, and wherein each heteroaryl has 5 to 10 ring members. method.

22. The compound of formula 9-I is 【Chemistry 177】 The method according to any one of claims 17 to 20, wherein

23. The compound of formula 9-G is 【Chemistry 178】 The method of claim 18 or claim 21, wherein

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